U.S. patent application number 12/507907 was filed with the patent office on 2009-11-12 for macrocyclic factor viia inhibitors useful as anticoagulants.
This patent application is currently assigned to Bristol-Myers Squibb Company. Invention is credited to Daniel L. Cheney, Peter W. Glunz, Eldon Scott Priestley, Nicolas Ronald Wurtz.
Application Number | 20090281139 12/507907 |
Document ID | / |
Family ID | 37897422 |
Filed Date | 2009-11-12 |
United States Patent
Application |
20090281139 |
Kind Code |
A1 |
Priestley; Eldon Scott ; et
al. |
November 12, 2009 |
MACROCYCLIC FACTOR VIIA INHIBITORS USEFUL AS ANTICOAGULANTS
Abstract
The present invention relates generally to novel macrocycles of
Formula (I): ##STR00001## or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
wherein the variables A, B, L, M, W, Z, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, and R.sup.10
are as defined herein. These compounds are selective inhibitors of
the serine protease coagulation factor VIIa which can be used as
medicaments.
Inventors: |
Priestley; Eldon Scott;
(Yardley, PA) ; Cheney; Daniel L.; (Ringoes,
NJ) ; Wurtz; Nicolas Ronald; (Pennington, NJ)
; Glunz; Peter W.; (Yardley, PA) |
Correspondence
Address: |
LOUIS J. WILLE;BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT, P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Assignee: |
Bristol-Myers Squibb
Company
|
Family ID: |
37897422 |
Appl. No.: |
12/507907 |
Filed: |
July 23, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11614131 |
Dec 21, 2006 |
7592331 |
|
|
12507907 |
|
|
|
|
60753786 |
Dec 23, 2005 |
|
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60865475 |
Nov 13, 2006 |
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Current U.S.
Class: |
514/310 ;
540/456; 540/460 |
Current CPC
Class: |
C07D 413/12 20130101;
C07D 273/02 20130101; C07D 217/22 20130101; C07D 255/04 20130101;
C07D 417/12 20130101; C07D 245/04 20130101; C07D 401/12 20130101;
C07D 403/12 20130101 |
Class at
Publication: |
514/310 ;
540/456; 540/460 |
International
Class: |
A61K 31/4725 20060101
A61K031/4725; C07D 245/00 20060101 C07D245/00; A61P 7/02 20060101
A61P007/02 |
Claims
1. A compound of Formula (I): ##STR00455## or stereoisomers,
tautomers, pharmaceutically acceptable salts, or solvates thereof,
wherein: ring A is phenyl or a pyridyl isomer defined by replacing
one of CR.sup.1, CR.sup.2, CR.sup.3, or CR.sup.4 in ring A of
formula (I) with N; ring B is phenyl or a pyridyl isomer defined by
replacing one of CR.sup.8, CR.sup.9, CR.sup.10, or CR.sup.11 in
ring B of formula (I) with N; for the definitions of M and L, as
they are written from left to right, the atom connectivity is in
the order (ring A)-L-M-(ring B); M is --CONH--, --SO.sub.2NH--,
--NHCO--, or --NHSO.sub.2--; when M is --CONH--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)Y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--,
--XC(R.sup.12R.sup.13)Y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--,
--XC(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)Y--; when M is
--SO.sub.2NH--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13).sub.y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--,
--XC(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)Y--; when M is --NHCO--, L
is selected from --C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--;
when M is --NHSO.sub.2--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--; W
is substituted with 0-2 R.sup.14 and is selected from: ##STR00456##
X is O, S(O).sub.p, or NR.sup.16; Y is O or NR.sup.16a; Z is NH, O
or S; R.sup.1 is H, F, Cl, Br, I, C.sub.1-4 alkyl substituted with
0-10H, C.sub.1-4 fluoroalkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, or C.sub.3-6 cycloalkyl;
R.sup.2 is H, F, Cl, Br, I, --(CH.sub.2).sub.sOR.sup.a,
--(CH.sub.2).sub.sSR.sup.b, --(CH.sub.2).sub.sCF.sub.3,
--(CH.sub.2).sub.sOCF.sub.3, --(CH.sub.2).sub.sOCHF.sub.2,
--(CH.sub.2).sub.sOCH.sub.2F, --(CH.sub.2).sub.sCN,
--(CH.sub.2).sub.sNO.sub.2, --(CH.sub.2).sub.sNR.sup.cR.sup.d,
--(CH.sub.2).sub.sC(O)R.sup.a, --(CH.sub.2).sub.sCO.sub.2R.sup.a,
--(CH.sub.2).sub.sNR.sup.cC(O)R.sup.a,
--(CH.sub.2).sub.sC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.sNR.sup.cC(O)OR.sup.b,
--(CH.sub.2).sub.sOC(O)OR.sup.b,
--(CH.sub.2).sub.sNR.sup.cC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.sOC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.sSO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.sNR.sup.cSO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.sNR.sup.cSO.sub.2R.sup.b,
--(CH.sub.2).sub.sNR.sup.cSO.sub.2CF.sub.3,
--(CH.sub.2).sub.sSO.sub.2CF.sub.3,
--(CH.sub.2).sub.sS(O).sub.2R.sup.b, C.sub.1-6 alkyl substituted
with 0-2 R.sup.e, C.sub.1-4 fluoroalkyl, C.sub.2-4 alkenyl
substituted with 0-2 R.sup.e, C.sub.2-4 alkynyl substituted with
0-2 R.sup.e, --(CH.sub.2).sub.sC.sub.3-6 carbocycle substituted
with 0-2 R.sup.f, --(CH.sub.2).sub.s-(5- to 6-membered
heterocycle), --(CH.sub.2).sub.s--NR.sup.c-(5- to 6-membered
heterocycle), or --(CH.sub.2).sub.s--O-(5- to 6-membered
heterocycle); wherein said heterocycle comprises carbon atoms and
1-3 heteroatoms selected from N, NR.sup.c, O, and S(O).sub.p and is
substituted with 0-2 R.sup.g; R.sup.3 is H, F, Cl, Br, I,
--(CH.sub.2).sub.sOR.sup.a, --(CH.sub.2).sub.sSR.sup.b,
--(CH.sub.2).sub.sCF.sub.3, --(CH.sub.2).sub.sOCF.sub.3,
--(CH.sub.2).sub.sOCHF.sub.2, --(CH.sub.2).sub.sOCH.sub.2F,
--(CH.sub.2).sub.sCN, --(CH.sub.2).sub.sNO.sub.2,
--(CH.sub.2).sub.sNR.sup.cR.sup.d, --(CH.sub.2).sub.sC(O)R.sup.a,
--(CH.sub.2).sub.sCO.sub.2R.sup.a,
--(CH.sub.2).sub.sNR.sup.cC(O)R.sup.a,
--(CH.sub.2).sub.sC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.sNR.sup.cC(O)OR.sup.b,
--(CH.sub.2).sub.sOC(O)OR.sup.b,
--(CH.sub.2).sub.sNR.sup.cC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.sOC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.sSO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.sNR.sup.cSO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.sNR.sup.cSO.sub.2R.sup.b,
--(CH.sub.2).sub.sNR.sup.cSO.sub.2CF.sub.3,
--(CH.sub.2).sub.sSO.sub.2CF.sub.3,
--(CH.sub.2).sub.sS(O).sub.2R.sup.b,
--O(CH.sub.2).sub.nCO.sub.2R.sup.a,
--(CH.sub.2).sub.sSO.sub.2NHCOR.sup.b,
--(CH.sub.2).sub.sCONHSO.sub.2R.sup.b, C.sub.1-6 alkyl substituted
with 0-2 R.sup.e, C.sub.1-4 fluoroalkyl, C.sub.2-4 alkenyl
substituted with 0-2 R.sup.e, C.sub.2-4 alkynyl substituted with
0-2 R.sup.e, --O(benzyl substituted with CO.sub.2R.sup.a),
--(CH.sub.2).sub.stetrazolyl, --(CH.sub.2).sub.s--C.sub.3-6
carbocycle substituted with 0-2 R.sup.f1, --(CH.sub.2).sub.s-(5- to
6-membered heterocycle), --(CH.sub.2).sub.s--NR.sup.c-(5- to
6-membered heterocycle), or --(CH.sub.2).sub.s--O-(5- to 6-membered
heterocycle); wherein said heterocycle comprises carbon atoms and
1-3 heteroatoms selected from N, NR.sup.c, O, and S(O).sub.p and is
substituted with 0-2 R.sup.g1; alternatively, R.sup.2 and R.sup.3
may combine to form a 5- to 7-membered carbocycle or heterocycle
comprising: carbon atoms and 0-2 heteroatoms selected from N,
NR.sup.c, O, and S(O).sub.p; wherein said carbocycle and
heterocycle are substituted with 0-3 R.sup.g1; R.sup.4 is H, F, Cl,
Br, I, or C.sub.1-4 alkyl; R.sup.5 is H,
--(CH.sub.2).sub.qOR.sup.a, --(CH.sub.2).sub.qSR.sup.b,
--(CH.sub.2).sub.rCF.sub.3, --(CH.sub.2).sub.qOCF.sub.3,
--(CH.sub.2).sub.qOCHF.sub.2, --(CH.sub.2).sub.qOCH.sub.2F,
--(CH.sub.2).sub.qCN, --(CH.sub.2).sub.qNO.sub.2,
--(CH.sub.2).sub.qNR.sup.cR.sup.d, --(CH.sub.2).sub.sC(O)R.sup.a,
--(CH.sub.2).sub.sCO.sub.2R.sup.a,
--(CH.sub.2).sub.qNR.sup.cC(O)R.sup.a,
--(CH.sub.2).sub.sC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.qNR.sup.cC(O)OR.sup.b,
--(CH.sub.2).sub.qOC(O)OR.sup.b,
--(CH.sub.2).sub.qNR.sup.cC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.qOC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.qSO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.qNR.sup.cSO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.qNR.sup.cSO.sub.2R.sup.b,
--(CH.sub.2).sub.qNR.sup.cSO.sub.2CF.sub.3,
--(CH.sub.2).sub.qSO.sub.2CF.sub.3,
--(CH.sub.2).sub.qS(O).sub.2R.sup.b,
--(CH.sub.2).sub.qSO.sub.2NHCOR.sup.b,
--(CH.sub.2).sub.sCONHSO.sub.2R.sup.b, --O(benzyl substituted with
CO.sub.2R.sup.a), --(CH.sub.2).sub.stetrazolyl, C.sub.1-6 alkyl
substituted with 0-2 R.sup.e, C.sub.2-4 alkenyl substituted with
0-2 R.sup.e, C.sub.2-4 alkynyl substituted with 0-2 R.sup.e,
--(CH.sub.2).sub.s--C.sub.3-6 carbocycle substituted with 0-2
R.sup.f1, or --(CH.sub.2).sub.s-5- to 6-membered heterocycle;
wherein said heterocycle comprises carbon atoms and 1-3 heteroatoms
selected from N, NR.sup.c, O, and S(O).sub.p and is substituted
with 0-2 R.sup.g1; R.sup.6 is H, --(CH.sub.2).sub.rOR.sup.a,
--(CH.sub.2).sub.rSR.sup.b, --(CH.sub.2).sub.sCF.sub.3,
--(CH.sub.2).sub.rOCF.sub.3, --(CH.sub.2).sub.rOCHF.sub.2,
--(CH.sub.2).sub.rOCH.sub.2F, --(CH.sub.2).sub.sCN,
--(CH.sub.2).sub.sNO.sub.2, --(CH.sub.2).sub.rNR.sup.cR.sup.d,
--(CH.sub.2).sub.sC(O)R.sup.a, --(CH.sub.2).sub.sCO.sub.2R.sup.a,
--(CH.sub.2).sub.rNR.sup.cC(O)R.sup.a,
--(CH.sub.2).sub.sC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.rNR.sup.cC(O)OR.sup.b,
--(CH.sub.2).sub.rOC(O)OR.sup.b,
--(CH.sub.2).sub.rNR.sup.cC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.rOC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.rSO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.rNR.sup.cSO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.rNR.sup.cSO.sub.2R.sup.b,
--(CH.sub.2).sub.rNR.sup.cSO.sub.2CF.sub.3,
--(CH.sub.2).sub.rSO.sub.2CF.sub.3,
--(CH.sub.2).sub.rS(O).sub.2R.sup.b,
--(CH.sub.2).sub.rSO.sub.2NHCOR.sup.b,
--(CH.sub.2).sub.sCONHSO.sub.2R.sup.b, C.sub.1-6 alkyl substituted
with 0-2 R.sup.e, C.sub.2-4 alkenyl substituted with 0-2 R.sup.e,
C.sub.2-4 alkynyl substituted with 0-2 R.sup.e,
--(CH.sub.2).sub.s--C.sub.3-6 carbocycle substituted with 0-2
R.sup.f1, or --(CH.sub.2).sub.s-5- to 6-membered heterocycle;
wherein said heterocycle comprises carbon atoms and 1-3 heteroatoms
selected from N, NR.sup.c, O, and S(O).sub.p and is substituted
with 0-2 R.sup.g1; alternatively, R.sup.5 and R.sup.6 can be joined
to form a 2 to 5-membered alkylene chain, which may be substituted
with 0-1 R.sup.f1; R.sup.7 is H or C.sub.1-6 alkyl; alternatively,
R.sup.6 and R.sup.7 can be joined to form a 3-7 membered carbocycle
or heterocycle; wherein said carbocycle may be substituted with 0-2
R.sup.f1; and said heterocycle comprises carbon atoms and 1-3
heteroatoms selected from N, NR.sup.c, O, and S(O).sub.p and is
substituted with 0-2 R.sup.g1; R.sup.8 is H, F, Cl, Br, CN,
CH.sub.2F, CHF.sub.2, --(CH.sub.2).sub.sCF.sub.3,
--(CH.sub.2).sub.sOCF.sub.3, --(CH.sub.2).sub.sSCF.sub.3,
--(CH.sub.2).sub.sOCHF.sub.2, --(CH.sub.2).sub.sOCH.sub.2F,
--(CH.sub.2).sub.sCN, --(CH.sub.2).sub.sNO.sub.2, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, --(CH.sub.2).sub.n--OR.sup.a,
--(CH.sub.2).sub.n--SR.sup.b, --(CH.sub.2).sub.n--NR.sup.cR.sup.d,
--(CH.sub.2).sub.sC(O)R.sup.a, --(CH.sub.2).sub.sCO.sub.2R.sup.a,
--(CH.sub.2).sub.sNR.sup.cC(O)R.sup.a,
--(CH.sub.2).sub.sCONR.sup.cR.sup.d,
--(CH.sub.2).sub.sSO.sub.2R.sup.b,
--(CH.sub.2).sub.sSO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.sNR.sup.cC(O)OR.sup.b,
--(CH.sub.2).sub.sOC(O)OR.sup.b,
--(CH.sub.2).sub.sNR.sup.cC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.sOC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.sNR.sup.cSO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.sNR.sup.cSO.sub.2R.sup.b,
--(CH.sub.2).sub.sNR.sup.cSO.sub.2CF.sub.3,
--(CH.sub.2).sub.sSO.sub.2CF.sub.3,
--O(CH.sub.2).sub.nCO.sub.2R.sup.a,
--(CH.sub.2).sub.sSO.sub.2NHCOR.sup.b,
--(CH.sub.2).sub.sCONHSO.sub.2R.sup.b, --O(benzyl substituted with
CO.sub.2R.sup.a), --(CH.sub.2).sub.stetrazolyl, C.sub.1-6 alkyl
substituted with 0-2 R.sup.e, C.sub.1-4 fluoroalkyl, C.sub.2-4
alkenyl substituted with 0-2 R.sup.e, C.sub.2-4 alkynyl substituted
with 0-2 R.sup.e, --(CH.sub.2).sub.s--C.sub.3-6 carbocycle
substituted with 0-2 .mu.l, or --(CH.sub.2).sub.n-5- to 10-membered
heterocycle comprising: carbon atoms and 1-4 heteroatoms selected
from N, NR.sup.c, O, and S(O).sub.p, wherein said phenyl and
heterocycle are substituted with 0-3 R.sup.g1; R.sup.9, R.sup.10,
and R.sup.11 are, independently at each occurrence, H, F, Cl, Br,
I, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy; R.sup.12 and R.sup.13 are,
independently at each occurrence, H, F, Cl, OR.sup.a, SR.sup.b,
CF.sub.3, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, CN, NO.sub.2,
--NR.sup.cR.sup.d, --C(O)R.sup.a, --CO.sub.2R.sup.a,
--NR.sup.cC(O)R.sup.a, --C(O)NR.sup.cR.sup.d,
--NR.sup.cC(O)OR.sup.b, --NR.sup.cC(O)NR.sup.cR.sup.d,
--OC(O)NR.sup.cR.sup.d, --OC(O)OR.sup.a, --SO.sub.2NR.sup.cR.sup.d,
--NR.sup.cSO.sub.2NR.sup.cR.sup.d, --NR.sup.cSO.sub.2R.sup.b,
--NR.sup.cSO.sub.2CF.sub.3, --SO.sub.2CF.sub.3,
--S(O).sub.2R.sup.b, C.sub.1-6 alkyl substituted with 0-2 R.sup.e,
C.sub.2-4 alkenyl substituted with 0-2 R.sup.e, C.sub.2-4 alkynyl
substituted with 0-2 R.sup.e, --(CH.sub.2).sub.s--C.sub.3-6
carbocycle substituted with 0-2 .mu.l, --(CH.sub.2).sub.s-(5- to
6-membered heterocycle), --NR.sup.c-(5- to 6-membered heterocycle),
or --O-(5- to 6-membered heterocycle); wherein said heterocycle
comprises carbon atoms and 1-3 heteroatoms selected from N,
NR.sup.c, O, and S(O).sub.p and is substituted with 0-2 R.sup.g1;
alternatively, any two R.sup.12 or R.sup.13 attached to either the
same carbon or to two adjacent carbons may combine to form a 3- to
7-membered carbocycle or heterocycle comprising: carbon atoms and
0-3 heteroatoms selected from N, NR.sup.c, O, and S(O).sub.p,
wherein said carbocycle or heterocycle is substituted with 0-3
R.sup.g1; alternately, two R.sup.12 or R.sup.13 on the same carbon
atom can be replaced with oxo; optionally, two R.sup.12 or R.sup.13
on adjacent carbon atoms in L may be replaced with a double or
triple bond between the two carbon atoms; R.sup.14 is,
independently at each occurrence, CN, F, Cl, Br, I, OH,
N(R.sup.17R.sup.17), C.sub.1-3 alkyl, or C.sub.1-3 alkoxy; R.sup.15
is, independently at each occurrence, H, --C(.dbd.NH)NH.sub.2,
N(R.sup.17R.sup.17), --C(R.sup.17R.sup.17)N(R.sup.17R.sup.17),
--CON(R.sup.17R.sup.17), CN, F, Cl, Br, I, OH, C.sub.1-3 alkyl, or
C.sub.1-3 alkoxy; R.sup.16 is, independently at each occurrence, H,
C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, phenyl, benzyl,
--C(O)R.sup.a, --C(O)NR.sup.cR.sup.d, --C(O)OR.sup.b,
--SO.sub.2NR.sup.cR.sup.d, --SO.sub.2CF.sub.3, --S(O).sub.2R.sup.b,
or --(CH.sub.2).sub.s-(5- to 6-membered heterocycle); wherein said
alkyl or cycloalkyl are optionally substituted with 0-2 R.sup.e,
said phenyl and benzyl are optionally substituted with 0-2 R.sup.f
and said heterocycle comprises carbon atoms and 1-3 heteroatoms
selected from N, NR.sup.c, O, and S(O).sub.p and is substituted
with 0-2 R.sup.g; R.sup.16a is, independently at each occurrence,
H, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, phenyl, benzyl,
--C(O)R.sup.a, --C(O)NR.sup.cR.sup.d, --C(O)OR.sup.b,
--SO.sub.2NR.sup.cR.sup.d, --SO.sub.2CF.sub.3, --S(O).sub.2R.sup.b,
or 5- to 6-membered heterocycle; wherein said alkyl or cycloalkyl
are optionally substituted with 0-2 R.sup.e, said phenyl and benzyl
are optionally substituted with 0-2 R.sup.f, and said heterocycle
comprises carbon atoms and 1-3 heteroatoms selected from N,
NR.sup.c, O, and S(O).sub.p and is substituted with 0-2 R.sup.g;
R.sup.17 is, independently at each occurrence, H or Me; R.sup.a is,
independently at each occurrence, H, C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl, phenyl, or benzyl; wherein said alkyl and cycloalkyl
are optionally substituted with 0-2 R.sup.e, and said phenyl and
benzyl are optionally substituted with 0-2 R.sup.f; R.sup.b is,
independently at each occurrence, C.sub.1-4
alkyl, C.sub.3-6 cycloalkyl, phenyl, or benzyl; wherein said alkyl
and cycloalkyl are optionally substituted with 0-2 R.sup.e, and
said phenyl and benzyl are optionally substituted with 0-2 R.sup.f;
R.sup.cC and R.sup.d are, independently at each occurrence, H,
C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, phenyl, or benzyl;
alternatively, R.sup.cC and R.sup.d, when attached to the same
nitrogen atom, combine to form a 4- to 7-membered heterocycle
comprising: carbon atoms and 0-2 additional heteroatoms selected
from N, O, and S(O).sub.p; wherein said heterocycle is substituted
with 0-2 R.sup.g; R.sup.e is, independently at each occurrence, F,
CF.sub.3, OH, or C.sub.1-3 alkoxy; R.sup.f is, independently at
each occurrence, F, Cl, Br, CF.sub.3, OH, C.sub.1-3 alkyl, or
C.sub.1-3 alkoxy; R.sup.f1 is, independently at each occurrence,
R.sup.f, --CO.sub.2R.sup.a, --C(O)NR.sup.cR.sup.d,
--CONHSO.sub.2R.sup.b, or --CH.sub.2CONHSO.sub.2R.sup.b; R.sup.g
is, independently at each occurrence, .dbd.O, F, Cl, Br, CF.sub.3,
OH, C.sub.1-3 alkyl, or C.sub.1-3 alkoxy; R.sup.g1 is,
independently at each occurrence, R.sup.g, --CO.sub.2R.sup.a,
--C(O)NR.sup.cR.sup.d, --CONHSO.sub.2R.sup.b, or
--CH.sub.2CONHSO.sub.2R.sup.b; n, at each occurrence, is selected
from 0, 1, 2, 3, and 4; p, at each occurrence, is selected from 0,
1, and 2; q, at each occurrence is selected from 2 or 3; r, at each
occurrence is selected from 1, 2, or 3; and s, at each occurrence,
is selected from 0, 1, and 2.
2. A compound according to claim 1, wherein the compound is of
Formula (I), or stereoisomers, tautomers, pharmaceutically
acceptable salts, or solvates thereof, wherein: M is --CONH--,
--SO.sub.2NH--, --NHCO--, or --NHSO.sub.2--; when M is --CONH--, L
is selected from --C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)Y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--,
--XC(R.sup.12R.sup.13)Y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--, and
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--; when M is
--SO.sub.2NH--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--;
when M is --NHCO--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--;
when M is --NHSO.sub.2--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--; X
is O, S, or NR.sup.16; Z is NH or O; R.sup.2 is H, F, Cl, Br, I,
OR.sup.a, SR.sup.b, CF.sub.3, OCF.sub.3, OCHF.sub.2, OCH.sub.2F,
CN, NO.sub.2, --NR.sup.cR.sup.d, --C(O)R.sup.a, --CO.sub.2R.sup.a,
--NR.sup.cC(O)R.sup.a, --C(O)NR.sup.cR.sup.d,
--NR.sup.cC(O)OR.sup.b, --NR.sup.cC(O)NR.sup.cR.sup.d,
--OC(O)NR.sup.cR.sup.d, --SO.sub.2NR.sup.cR.sup.d,
--NR.sup.cSO.sub.2NR.sup.cR.sup.d, --NR.sup.cSO.sub.2R.sup.b,
--NR.sup.cSO.sub.2CF.sub.3, --SO.sub.2CF.sub.3,
--S(O).sub.2R.sup.b, C.sub.1-6 alkyl substituted with 0-2 R.sup.e,
C.sub.2-4 alkenyl substituted with 0-2 R.sup.e, C.sub.2-4 alkynyl
substituted with 0-2 R.sup.e, C.sub.3-6 carbocycle substituted with
0-2 R.sup.f, --(CH.sub.2).sub.s-(5- to 6-membered heterocycle),
--NR.sup.c-(5- to 6-membered heterocycle), or --O-(5- to 6-membered
heterocycle); wherein said heterocycle comprises carbon atoms and
1-3 heteroatoms selected from N, NR.sup.c, O, and S(O).sub.p and is
substituted with 0-2 R.sup.g; R.sup.3 is H, F, Cl, Br, I, OR.sup.a,
SR.sup.b, CF.sub.3, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, CN,
NO.sub.2, --NR.sup.cR.sup.d, --C(O)R.sup.a, --CO.sub.2R.sup.a,
--NR.sup.cC(O)R.sup.a, --C(O)NR.sup.cR.sup.d,
--NR.sup.cC(O)OR.sup.b, --NR.sup.cC(O)NR.sup.cR.sup.d,
--OC(O)NR.sup.cR.sup.d, --SO.sub.2NR.sup.cR.sup.d,
--NR.sup.cSO.sub.2NR.sup.cR.sup.d, --NR.sup.cSO.sub.2R.sup.b,
--NR.sup.cSO.sub.2CF.sub.3, --SO.sub.2CF.sub.3,
--S(O).sub.2R.sup.b, --O(CH.sub.2).sub.nCO.sub.2R.sup.a,
--SO.sub.2NHCOR.sup.b, --CONHSO.sub.2R.sup.b, C.sub.1-6 alkyl
substituted with 0-2 R.sup.e, C.sub.2-4 alkenyl substituted with
0-2 R.sup.e, C.sub.2-4 alkynyl substituted with 0-2 R.sup.e,
--O(benzyl substituted with CO.sub.2R.sup.a), or tetrazolyl;
alternatively, R.sup.2 and R.sup.3 may combine to form a 5- to
7-membered carbocycle or heterocycle comprising: carbon atoms and
0-2 heteroatoms selected from N, NR.sup.c, O, and S(O).sub.p;
wherein said carbocycle and heterocycle are substituted with 0-3
R.sup.g; R.sup.5 is H, --CH.sub.2CO.sub.2R.sup.a,
--CH.sub.2C(O)NR.sup.cR.sup.d, --CH.sub.2CH.sub.2CO.sub.2R.sup.a,
--CH.sub.2CH.sub.2C(O)NR.sup.cR.sup.d, --CH.sub.2CH.sub.2OR.sup.a,
--CH.sub.2CH.sub.2CH.sub.2OR.sup.a, --CH.sub.2CONHSO.sub.2R.sup.b,
--CH.sub.2CH.sub.2CONHSO.sub.2R.sup.b, C.sub.1-6 alkyl substituted
with 0-2 R.sup.e, --(CH.sub.2).sub.s--C.sub.3-6 carbocycle
substituted with 0-2 R.sup.f, or --(CH.sub.2).sub.s-5- to
6-membered heterocycle; wherein said heterocycle comprises carbon
atoms and 1-3 heteroatoms selected from N, NR.sup.c, O, and
S(O).sub.p and is substituted with 0-2 R.sup.g; R.sup.6 is H,
--CH.sub.2OR.sup.a, --CH.sub.2CH.sub.2OR.sup.a, CN,
--CO.sub.2R.sup.a, --C(O)NR.sup.cR.sup.d,
--CH.sub.2CO.sub.2R.sup.a, --CH.sub.2C(O)NR.sup.cR.sup.d,
--CONHSO.sub.2R.sup.b, --CH.sub.2CONHSO.sub.2R.sup.b, C.sub.1-6
alkyl substituted with 0-2 R.sup.e, --(CH.sub.2).sub.s--C.sub.3-6
carbocycle substituted with 0-2 R.sup.f, or --(CH.sub.2).sub.s-5-
to 6-membered heterocycle; wherein said heterocycle comprises
carbon atoms and 1-3 heteroatoms selected from N, NR.sup.c, O, and
S(O).sub.p and is substituted with 0-2 R.sup.g; alternatively,
R.sup.5 and R.sup.6 can be joined to form a 2 to 5-membered
alkylene chain, which may be substituted with 0-1 R.sup.f1; R.sup.7
is H or C.sub.1-6 alkyl; alternatively, R.sup.6 and R.sup.7 can be
joined to form a 3-7 membered carbocycle or heterocycle; wherein
said carbocycle may be substituted with 0-2 R.sup.f1; and said
heterocycle comprises carbon atoms and 1-3 heteroatoms selected
from N, NR.sup.c, O, and S(O).sub.p and is substituted with 0-2
R.sup.g1; R.sup.8 is, H, F, Cl, Br, CN, CH.sub.2F, CHF.sub.2,
CF.sub.3, OCF.sub.3, SCF.sub.3, NO.sub.2, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, --(CH.sub.2).sub.n--OR.sup.a,
--(CH.sub.2).sub.n--SR.sup.b, --(CH.sub.2).sub.n--NR.sup.cR.sup.d,
--CONR.sup.cR.sup.d, --SO.sub.2R.sup.b, --SO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.n-phenyl, or --(CH.sub.2).sub.n-5- to 10-membered
heterocycle comprising: carbon atoms and 1-4 heteroatoms selected
from N, O, and S(O).sub.p, wherein said phenyl and heterocycle are
substituted with 0-3 R.sup.g; R.sup.9 is H, F, Cl, Br, J, C.sub.1-4
alkyl, or C.sub.1-4 alkoxy; and R.sup.10 and R.sup.11 are,
independently at each occurrence, H, F, Cl, Br, I, or C.sub.1-4
alkyl.
3. A compound according to claim 1, wherein the compound is of
Formula (I), or stereoisomers, tautomers, pharmaceutically
acceptable salts, or solvates thereof, wherein: ring A is phenyl or
a pyridyl isomer defined by replacing one of CR.sup.1, CR.sup.2,
CR.sup.3, or CR.sup.4 in ring A of formula (I) with N; ring B is
phenyl or a pyridyl isomer defined by replacing one of CR.sup.8,
CR.sup.9, CR.sup.10, or CR.sup.11 in ring B of formula (I) with N;
with the proviso that when ring A is pyridyl, then ring B is not
pyridyl; M is --CONH--, --SO.sub.2NH--, --NHCO--, or
--NHSO.sub.2--; when M is --CONH--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)Y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--,
XC(R.sup.12R.sup.13)Y--, and
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13).sub.y--; when M is
--SO.sub.2NH--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--;
when M is --NHCO--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--;
when M is --NHSO.sub.2--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--; Z
is NH or O; R.sup.4 is H or F; R.sup.10 and R.sup.11 are H; and
R.sup.15 is, independently at each occurrence,
--C(.dbd.NH)NH.sub.2, N(R.sup.17R.sup.17),
--C(R.sup.17R.sup.17)N(R.sup.17R.sup.17), --CON(R.sup.17R.sup.17),
or OH.
4. A compound according to claim 1, wherein the compound is of
Formula (I), or stereoisomers, tautomers, pharmaceutically
acceptable salts, or solvates thereof, wherein: ring A is phenyl;
ring B is phenyl; M is --CONH-- or --NHSO.sub.2--; when M is
--CONH--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)Y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--; when M is
--NHSO.sub.2--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--; W is substituted with
0-2 R.sup.14 and is selected from: ##STR00457## Z is NH; R.sup.1 is
H, Cl, Br, methyl, ethyl, 1-hydroxyethyl, propyl, isopropyl, vinyl,
allyl, 2-propenyl, ethynyl, 1-propynyl, methoxy, ethoxy,
cyclopropyl, cyclobutyl, or cyclopentyl; R.sup.4 is H; R.sup.5 is
H, C.sub.1-4 alkyl, --CH.sub.2CO.sub.2R.sup.a,
--CH.sub.2C(O)NR.sup.cR.sup.d, --CH.sub.2CH.sub.2CO.sub.2R.sup.a,
--CH.sub.2CH.sub.2C(O)NR.sup.cR.sup.d, --CH.sub.2CH.sub.2OR.sup.a,
or --CH.sub.2CH.sub.2CH.sub.2OR.sup.a; R.sup.6 is H,
--CH.sub.2OR.sup.a, --CH.sub.2CH.sub.2OR.sup.a, CN, C.sub.1-4
alkyl, --CO.sub.2R.sup.a, --C(O)NR.sup.cR.sup.d,
--CH.sub.2CO.sub.2R.sup.a, or --CH.sub.2C(O)NR.sup.cR.sup.d;
R.sup.7 is H; R.sup.10 and R.sup.11 are H; and R.sup.15 is,
independently at each occurrence, --C(.dbd.NH)NH.sub.2,
N(R.sup.17R.sup.17), --C(R.sup.17R.sup.17)N(R.sup.17R.sup.17), or
--CONH.sub.2.
5. A compound according to claim 1, wherein the compound is of
Formula (I), or stereoisomers, tautomers, pharmaceutically
acceptable salts, or solvates thereof, wherein: ring A is phenyl;
ring B is phenyl; M is --CONH--; L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)Y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--; W is substituted with
0-2 R.sup.14 and is selected from: ##STR00458## Z is NH; R.sup.1 is
H, Cl, Br, methyl, ethyl, vinyl, 2-propenyl, allyl, ethynyl,
1-propynyl, methoxy, ethoxy, or cyclopropyl; R.sup.4 is H; R.sup.5
is H, C.sub.1-4 alkyl, --CH.sub.2CO.sub.2R.sup.a,
--CH.sub.2C(O)NR.sup.cR.sup.d, --CH.sub.2CH.sub.2CO.sub.2R.sup.a,
--CH.sub.2CH.sub.2C(O)NR.sup.cR.sup.d, --CH.sub.2CH.sub.2OR.sup.a,
or --CH.sub.2CH.sub.2CH.sub.2OR.sup.a; R.sup.6 is H,
--CH.sub.2OR.sup.a, --CH.sub.2CH.sub.2OR.sup.a, CN, C.sub.1-4
alkyl, --CO.sub.2R.sup.a, --C(O)NR.sup.cR.sup.d,
--CH.sub.2CO.sub.2R.sup.a, or --CH.sub.2C(O)NR.sup.cR.sup.d;
R.sup.7 is H; R.sup.8 is H, C.sub.1-6 alkyl, OR.sup.a,
--CONR.sup.cR.sup.d, --SO.sub.2R.sup.b, --SO.sub.2NR.sup.cR.sup.d,
phenyl, or 5- to 6-membered heterocycle comprising: carbon atoms
and 1-3 heteroatoms selected from N, O, and S(O).sub.p, wherein
said phenyl and heterocycle are substituted with 0-3 R.sup.g;
R.sup.9, R.sup.10, and R.sup.11 are H; and R.sup.14 is,
independently at each occurrence, F, Cl, methyl, ethyl, hydroxyl,
or methoxy.
6. A compound according to claim 1, wherein the compound is of
Formula (I), or stereoisomers, tautomers, pharmaceutically
acceptable salts, or solvates thereof, wherein: ring A is phenyl;
ring B is phenyl; M is --CONH--; L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)NR.sup.16C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--,
C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, --OC(R.sup.12R.sup.13)--,
or --C(R.sup.12R.sup.13)Y--; W is selected from: ##STR00459## Y is
O Or NMe, Z is NH; R.sup.1 is H, Cl, Br, methyl, ethyl, vinyl,
2-propenyl, ethynyl, methoxy, or ethoxy; R.sup.2 is H, F, Cl, Br,
--OR.sup.a, --SR.sup.b, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2,
--OCH.sub.2F, CN, NO.sub.2, --NR.sup.cR.sup.d, --C(O)R.sup.a,
--CO.sub.2R.sup.a, --NR.sup.cC(O)R.sup.a, --C(O)NR.sup.cR.sup.d,
--NR.sup.cC(O)OR.sup.b,
--OC(O)OR.sup.b--NR.sup.cC(O)NR.sup.cR.sup.d,
--OC(O)NR.sup.cR.sup.d, --SO.sub.2NR.sup.cR.sup.d,
--NR.sup.cSO.sub.2NR.sup.cR.sup.d, --NR.sup.cSO.sub.2R.sup.b,
--S(O).sub.2R.sup.b, C.sub.1-6 alkyl substituted with 0-2 R.sup.e,
C.sub.1-4 fluoroalkyl, C.sub.2-4 alkenyl substituted with 0-2
R.sup.e, C.sub.2-4 alkynyl substituted with 0-2 R.sup.e,
--C.sub.3-6 carbocycle substituted with 0-2 R.sup.f-(5- to
6-membered heterocycle), --NR.sup.c-(5- to 6-membered heterocycle),
or --O-(5- to 6-membered heterocycle); wherein said heterocycle
comprises carbon atoms and 1-3 heteroatoms selected from N,
NR.sup.c, O, and S(O).sub.p and is substituted with 0-2 R.sup.9;
R.sup.3 is H, F, Cl, Me, OCH.sub.2CO.sub.2H; R.sup.4 is H; R.sup.5
is H, C.sub.1-4 alkyl, --CH.sub.2CO.sub.2R.sup.a, or
--CH.sub.2C(O)NR.sup.cR.sup.d; R.sup.6 is H, C.sub.1-4 alkyl,
--CO.sub.2R.sup.a, --C(O)NR.sup.cR.sup.d,
--CH.sub.2CO.sub.2R.sup.a, or --CH.sub.2C(O)NR.sup.cR.sup.d;
R.sup.7 is H; R.sup.8 is --CONR.sup.cR.sup.d, --SO.sub.2R.sup.b,
--SO.sub.2NR.sup.cR.sup.d, or 4-morpholino; R.sup.9, R.sup.10, and
R.sup.11 are H; R.sup.12 and R.sup.13 are, independently at each
occurrence, H, methyl, ethyl, propyl, isopropyl, cyclopropyl,
t-butyl, methoxy, ethoxy, propoxy, isopropoxy, or cyclopropoxy,
with the proviso that no more than two of R.sup.12 and R.sup.13 in
L are other than H; and R.sup.16 is H, C.sub.1-4 alkyl,
--C(O)R.sup.a, --C(O)NR.sup.cR.sup.d, --C(O)OR.sup.b, or
--S(O).sub.2R.sup.b.
7. A compound according to claim 6, wherein the compound is of
Formula (I), or stereoisomers, tautomers, pharmaceutically
acceptable salts, or solvates thereof, wherein: M is --CONH--; L is
selected from --C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)CH.sub.2--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)O--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)NMe-,
--C(R.sup.12R.sup.13)N(C.dbd.OCH.sub.3)CH.sub.2--,
--C(R.sup.12R.sup.13)NHCH.sub.2--, --C(R.sup.12R.sup.13)CH.sub.2--,
and --OCH.sub.2--; W is selected from: ##STR00460## R.sup.1 is H,
Cl, Br, methyl, ethyl, methoxy, or ethoxy; R.sup.2 is H, Cl, Br,
methyl, ethyl, methoxy, or ethoxy; R.sup.3 is H; R.sup.4 is H;
R.sup.5 is H, methyl, ethyl, or --CH.sub.2CO.sub.2H; R.sup.6 is H,
methyl, ethyl, --CO.sub.2H or --CH.sub.2CO.sub.2H; R.sup.7 is H;
and R.sup.8 is --CONR.sup.cR.sup.d or --SO.sub.2R.sup.b.
8. A compound according to claim 1, wherein the compound is of
Formula (I), or stereoisomers, tautomers, pharmaceutically
acceptable salts, or solvates thereof, wherein: when M is --CONH--;
L is selected from --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, --O(CH.sub.2)--, --O(CH.sub.2).sub.2--,
--O(CH.sub.2).sub.3--, --(CH.sub.2).sub.2O--, --CH(Me)CH.sub.2O--,
--C(Me).sub.2CH.sub.2O--, --CH.sub.2CH(Me)O--, --CH(Et)CH.sub.2O--,
--CH.sub.2CH(Et)O--, --CH.sub.2OCH.sub.2--, --(CH.sub.2).sub.2NMe-,
--(CH.sub.2).sub.3NMe-, --CH.sub.2NHCH.sub.2--, and
--CH.sub.2N(Ac)CH.sub.2--; when M is --NHSO.sub.2--, L is selected
from --(CH.sub.2).sub.2-- and --(CH.sub.2).sub.3--; W is selected
from: ##STR00461## Z is NH; R.sup.1 is H, Cl, Br, C.sub.1-4 alkyl,
or C.sub.1-4 alkoxy; R.sup.2 is H, Cl, Br, C.sub.1-4 alkyl, or
C.sub.1-4 alkoxy; R.sup.3 is H; R.sup.4 is H; R.sup.5 is H,
C.sub.1-4 alkyl, --CH.sub.2CO.sub.2H, or --CH.sub.2CO.sub.2Et;
R.sup.6 is H, C.sub.1-4 alkyl, --CO.sub.2H, --CH.sub.2CO.sub.2H, or
--CH.sub.2CO.sub.2Et; R.sup.7 is H; R.sup.8 is H,
--SO.sub.2(C.sub.1-4 alkyl), or --S(C.sub.1-4 alkyl); R.sup.9 is H;
and R.sup.10 is H.
9. A compound according to claim 8, wherein the compound is of
Formula (I), or stereoisomers, tautomers, pharmaceutically
acceptable salts, or solvates thereof, wherein: W is selected from:
##STR00462## R.sup.1 is H, Cl, Br, methyl, ethyl, methoxy, or
ethoxy; R.sup.2 is H, Cl, Br, methyl, ethyl, methoxy, or ethoxy;
R.sup.5 is H, methyl, ethyl, or --CH.sub.2CO.sub.2H; R.sup.6 is H,
methyl, ethyl, --CO.sub.2H, --CH.sub.2CO.sub.2H, or
--CH.sub.2CO.sub.2Et; and R.sup.8 is H, --SO.sub.2Et,
--SO.sub.2(i-Pr), --SO.sub.2(t-Bu), or --S(i-Pr).
10. A compound according to claim 1, wherein the compound is
selected from the exemplified examples or stereoisomers, tautomers,
pharmaceutically acceptable salts, or solvates thereof.
11. A pharmaceutical composition, comprising: a pharmaceutically
acceptable carrier and a compound of claim 1, or stereoisomers,
tautomers, pharmaceutically acceptable salts, or solvates
thereof.
12. A method for treating a thromboembolic disorder, comprising:
administering to a patient in need thereof a therapeutically
effective amount of a compound of claim 1, or stereoisomers,
tautomers, pharmaceutically acceptable salts, or solvates
thereof.
13. A method according to claim 12, wherein the thromboembolic
disorder is selected from the group consisting of arterial
cardiovascular thromboembolic disorders, venous cardiovascular
thromboembolic disorders, and thromboembolic disorders in the
chambers of the heart or in the peripheral circulation.
14. A method according to claim 12, wherein the thromboembolic
disorder is selected from unstable angina, an acute coronary
syndrome, atrial fibrillation, first myocardial infarction,
recurrent myocardial infarction, ischemic sudden death, transient
ischemic attack, stroke, atherosclerosis, peripheral occlusive
arterial disease, venous thrombosis, deep vein thrombosis,
thrombophlebitis, arterial embolism, coronary arterial thrombosis,
cerebral arterial thrombosis, cerebral embolism, kidney embolism,
pulmonary embolism, and thrombosis resulting from medical implants,
devices, or procedures in which blood is exposed to an artificial
surface that promotes thrombosis.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 11/614,131, filed Dec. 21, 2006, which claims priority benefit
of U.S. provisional application Ser. No. 60/753,786, filed Dec. 23,
2005; and Ser. No. 60/865,475, filed Nov. 13, 2006, the entire
disclosures of which are herein incorporated by reference in their
entirety.
FIELD OF THE INVENTION
[0002] The present invention provides novel macrocycles, and
analogues thereof, which are selective inhibitors of the serine
protease coagulation factor VIIa. This invention also relates to
pharmaceutical compositions comprising these compounds and methods
of using the same.
BACKGROUND OF THE INVENTION
[0003] Factor VII is a plasma serine protease involved in the
initiation of the coagulation cascade. It is present in human blood
at a concentration of approximately 500 ng/mL, with about 1% of the
total amount in the proteolytically active form factor VIIa
(Morrissey, J. H. et al. Blood 1993, 81, 734-744). Factor VIIa
binds with high affinity to its cofactor, tissue factor, in the
presence of calcium ions to form a complex with enhanced
proteolytic activity (Carson, S. D. and Brozna, J. P. Blood Coag.
Fibrinol. 1993, 4, 281-292). Tissue factor is normally expressed in
cells surrounding the vasculature, and is exposed to factor VIIa in
blood by vessel injury or atherosclerotic plaque rupture. Once
formed, the tissue factor/factor VIIa complex initiates blood
coagulation by proteolytic cleavage of factor X to factor Xa,
factor IX to factor IXa and autoactivation of additional factor VII
to VIIa. Factor Xa, generated either directly by tissue
factor/factor VIIa or indirectly through action of factor IXa,
catalyzes the conversion of prothrombin to thrombin. Thrombin
converts fibrinogen to fibrin, which polymerizes to form the
structural framework of a blood clot, and activates platelets,
which are a key cellular component of coagulation (Hoffman, M.
Blood Reviews 2003, 17, S1-S5). In addition, there is evidence that
tissue factor is present in blood, likely in an encrypted form that
is de-encrypted during clot formation. (Giesen, P. L. A. et al.
Proc. Natl. Acad. Sci. 1999, 96, 2311-2315; Himber, J. et al. J.
Thromb. Haemost. 2003, 1, 889-895). The tissue factor/factor VIIa
complex derived from blood borne tissue factor may play an
important role in propagation of the coagulation cascade (clot
growth) and in thrombus formation in the absence of vessel wall
injury (i.e., stasis induced deep vein thrombosis or sepsis). The
source of blood borne tissue factor is an area of active research
(Morrissey, J. H. J. Thromb. Haemost. 2003, 1, 878-880).
[0004] While blood coagulation is essential to the regulation of an
organism's hemostasis, it is also involved in many pathological
conditions. In thrombosis, a blood clot, or thrombus, may form and
obstruct circulation locally, causing ischemia and organ damage.
Alternatively, in a process known as embolism, the clot may
dislodge and subsequently become trapped in a distal vessel, where
it again causes ischemia and organ damage. Diseases arising from
pathological thrombus formation are collectively referred to as
thrombotic or thromboembolic disorders and include acute coronary
syndrome, unstable angina, myocardial infarction, ischemic stroke,
deep vein thrombosis, peripheral occlusive arterial disease,
transient ischemic attack, and pulmonary embolism. In addition,
thrombosis occurs on artificial surfaces in contact with blood,
including catheters and artificial heart valves. Therefore, drugs
that inhibit blood coagulation, or anticoagulants, are "pivotal
agents for prevention and treatment of thromboembolic disorders"
(Hirsh, J. et al. Blood 2005, 105, 453-463).
[0005] Because of its key role in the coagulation cascade,
researchers have postulated that inhibition of factor VIIa could be
used to treat or prevent thrombotic or thromboembolic disease.
(Girard, T. J.; Nicholson, N. S. Curr. Opin. Pharmacol. 2001, 1,
159-163; Lazarus, R. A., et al. Curr. Med. Chem. 2004, 11,
2275-2290; Frederick, R. et al. Curr. Med. Chem. 2005, 12,
397-417.) Several studies have confirmed that various biological
and small molecule inhibitors of factor VIIa have in vivo
antithrombotic efficacy with a low bleeding liability. For
instance, it has been demonstrated that a biological factor VIIa
inhibitor XK1, comprising a hybrid of Factor X light chain and
tissue factor pathway inhibitor first kunitz domain, prevents
thrombus formation in a rat model of arterial thrombosis, with no
change in bleeding time or total blood loss (Szalony, J. A. et al.
J. Thrombosis and Thrombolysis 2002, 14, 113-121). In addition,
small molecule active site directed factor VIIa inhibitors have
demonstrated antithrombotic efficacy in animal models of arterial
thrombosis (Suleymanov, O., et al. J Pharmacology and Experimental
Therapeutics 2003, 306, 1115-1121; Olivero, A. G. et al. J. Biol.
Chem. 2005, 280, 9160-9169; Young, W. B., et al. Bioorg. Med. Chem.
Lett. 2006, 16, 2037-2041; Zbinden, K. G. et al. Bioorg. Med. Chem.
2006, 14, 5357-5369) and venous thrombosis (Szalony, J. A., et al.
Thrombosis Research 2003, 112, 167-174; Arnold, C. S., et al.
Thrombosis Research 2006, 117, 343-349), with little impact on
bleeding time or blood loss. Moreover, the biological factor VIIa
inhibitor recombinant nematode anticoagulant protein c2 (rNAPc2) is
currently under clinical investigation for treatment of acute
coronary syndromes. Results of initial clinical trials demonstrate
that rNAPc2 prevents deep vein thrombosis in patients undergoing
total knee replacement (Lee, A., et al. Circulation 2001, 104,
74-78), reduces systemic thrombin generation in patients undergoing
coronary angioplasty (Moons, A. H. M. J. Am. Coll. Cardiol. 2003,
41, 2147-2153), and reduces magnitude and duration of ischemic
events in patients with acute coronary syndromes (Giugliano, R. P.
et al. World Congress of Cardiology 2006, Barcelona, Poster
#3897).
[0006] Work has accordingly been performed to identify and optimize
factor VIIa inhibitors. For example, U.S. Pat. No. 5,866,542
describes recombinant nematode anticoagulant proteins which inhibit
factor VIIa. U.S. Pat. No. 5,843,442 discloses monoclonal
antibodies or antibody fragments possessing factor VIIa inhibitory
activity, and U.S. Pat. No. 5,023,236 presents tripeptides and
tripeptide derivatives that inhibit factor VIIa.
[0007] While a number of factor VIIa inhibitors have been discussed
in the art, improved inhibitors, especially non-peptide inhibitors,
of serine proteases for the treatment of thromboembolic disorders
are always desirable. The present invention discloses novel
macrocyclic derivatives and analogues thereof, as inhibitors of
coagulation Factor VIIa and, as such, their utility in the
treatment of thromboembolic disorders.
[0008] In addition, it is also desirable to find new compounds with
improved pharmacological characteristics compared with known serine
protease inhibitors. For example, it is preferred to find new
compounds with improved factor VIIa inhibitory activity and
selectivity for factor VIIa versus other serine proteases. Also, it
is preferred to find new compounds with improved activity in in
vitro clotting assays, such as the prothrombin time (PT) assay.
(for a description of the PT assay see, Goodnight, S. H.; Hathaway,
W. E. Screening Tests of Hemostasis. Disorders of Thrombosis and
Hemostasis: a clinical guide, 2.sup.nd edition, McGraw-Hill: New
York, 2001 pp. 41-51). It is also desirable and preferable to find
compounds with advantageous and improved characteristics in one or
more of the following categories, which are given as examples and
are not intended to be limiting: (a) pharmacokinetic properties,
including oral bioavailability, half life, and clearance; (b)
pharmaceutical properties; (c) dosage requirements; (d) factors
which decrease blood concentration peak-to-trough characteristics;
(e) factors that increase the concentration of active drug at the
receptor; (f) factors that decrease the liability for clinical
drug-drug interactions; (g) factors that decrease the potential for
adverse side-effects, including selectivity versus other biological
targets; and (h) factors that improve manufacturing costs or
feasibility.
SUMMARY OF THE INVENTION
[0009] The present invention provides novel macrocycles, and
analogues thereof, which are useful as selective inhibitors of
serine protease enzymes, especially factor VIIa, including
stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof.
[0010] The present invention also provides processes and
intermediates for making the compounds of the present invention or
stereoisomers, tautomers, pharmaceutically acceptable salt,
solvates, or prodrugs thereof.
[0011] The present invention also provides pharmaceutical
compositions comprising a pharmaceutically acceptable carrier and
at least one of the compounds of the present invention or a
stereoisomer, tautomer, pharmaceutically acceptable salt, solvate,
or prodrug thereof.
[0012] The present invention also provides a method for modulation
of the coagulation cascade comprising administering to a host in
need of such treatment a therapeutically effective amount of at
least one of the compounds of the present invention or a
stereoisomer, tautomer, pharmaceutically acceptable salt, solvate,
or prodrug thereof.
[0013] The present invention also provides a method for treating
thrombotic or thromboembolic disorders comprising administering to
a host in need of such treatment a therapeutically effective amount
of at least one of the compounds of the present invention or a
stereoisomer, tautomer, pharmaceutically acceptable salt, solvate,
or prodrug thereof.
[0014] The present invention also provides the compounds of the
present invention or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, for use in
therapy.
[0015] The present invention also provides the use of the compounds
of the present invention or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
for the manufacture of a medicament for the treatment of a
thromboembolic disorder.
[0016] These and other features of the invention will be set forth
in expanded form as the disclosure continues.
DETAILED DESCRIPTION OF THE INVENTION
[0017] In a first aspect, the present invention provides, inter
alia, a compound of Formula (I):
##STR00002##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0018] ring A is phenyl or a pyridyl isomer defined by replacing
one of CR.sup.1, CR.sup.2, CR.sup.3, or CR.sup.4 in ring A of
formula (I) with N;
[0019] ring B is phenyl or a pyridyl isomer defined by replacing
one of CR.sup.8, CR.sup.9, CR.sup.10, or CR.sup.11 in ring B of
formula (I) with N;
[0020] for the definitions of M and L, as they are written from
left to right, the atom connectivity is in the order (ring
A)-L-M-(ring B);
[0021] M is --CONH--, --SO.sub.2NH--, --NHCO--, or
--NHSO.sub.2--;
[0022] when M is --CONH--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)Y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--,
--XC(R.sup.12R.sup.13)Y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--,
--XC(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)Y--;
[0023] when M is --SO.sub.2NH--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--XC(R.sup.12R.sup.13)XC(R.sup.-
12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)Y--;
[0024] when M is --NHCO--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--;
[0025] when M is --NHSO.sub.2--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--;
[0026] W is substituted with 0-2 R.sup.14 and is selected from:
##STR00003##
[0027] X is O, S(O).sub.p, or NR.sup.16;
[0028] Y is O or NR.sup.16a;
[0029] Z is NH, O or S;
[0030] R.sup.1 is H, F, Cl, Br, I, C.sub.1-4 alkyl substituted with
0-1 OH, C.sub.1-4 fluoroalkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, or C.sub.3-6
cycloalkyl;
[0031] R.sup.2 is H, F, Cl, Br, I, --(CH.sub.2).sub.sOR.sup.a,
--(CH.sub.2).sub.sSR.sup.b, --(CH.sub.2).sub.sCF.sub.3,
--(CH.sub.2).sub.sOCF.sub.3, --(CH.sub.2).sub.sOCHF.sub.2,
--(CH.sub.2).sub.sOCH.sub.2F, --(CH.sub.2).sub.sCN,
--(CH.sub.2).sub.sNO.sub.2, --(CH.sub.2).sub.sNR.sup.cR.sup.d,
--(CH.sub.2).sub.sC(O)R.sup.a, --(CH.sub.2).sub.sCO.sub.2R.sup.a,
--(CH.sub.2).sub.sNR.sup.cC(O)R.sup.a,
--(CH.sub.2).sub.sC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.sNR.sup.cC(O)OR.sup.b,
--(CH.sub.2).sub.sOC(O)OR.sup.b,
--(CH.sub.2).sub.sNR.sup.cC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.sOC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.sSO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.sNR.sup.cSO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.sNR.sup.cSO.sub.2R.sup.b,
--(CH.sub.2).sub.sNR.sup.cSO.sub.2CF.sub.3,
--(CH.sub.2).sub.sSO.sub.2CF.sub.3,
--(CH.sub.2).sub.sS(O).sub.2R.sup.b, C.sub.1-6 alkyl substituted
with 0-2 R.sup.e, C.sub.1-4 fluoroalkyl, C.sub.2-4 alkenyl
substituted with 0-2 R.sup.e, C.sub.2-4 alkynyl substituted with
0-2 R.sup.e, --(CH.sub.2).sub.sC.sub.3-6 carbocycle substituted
with 0-2 R.sup.f, --(CH.sub.2).sub.s--O--(5- to 6-membered
heterocycle), --(CH.sub.2).sub.s--NR.sup.c--(5- to 6-membered
heterocycle), or --(CH.sub.2).sub.s--O--(5- to 6-membered
heterocycle); wherein said heterocycle comprises carbon atoms and
1-3 heteroatoms selected from N, NR.sup.c, O, and S(O).sub.p and is
substituted with 0-2 R.sup.g;
[0032] R.sup.3 is H, F, Cl, Br, I, --(CH.sub.2).sub.sOR.sup.a,
--(CH.sub.2).sub.sSR.sup.b, --(CH.sub.2).sub.sCF.sub.3,
--(CH.sub.2).sub.sOCF.sub.3, --(CH.sub.2).sub.sOCHF.sub.2,
--(CH.sub.2).sub.sOCH.sub.2F, --(CH.sub.2).sub.sCN,
--(CH.sub.2).sub.sNO.sub.2, --(CH.sub.2).sub.sNR.sup.cR.sup.d,
--(CH.sub.2).sub.sC(O)R.sup.a, --(CH.sub.2).sub.sCO.sub.2R.sup.a,
--(CH.sub.2).sub.sNR.sup.cC(O)R.sup.a,
--(CH.sub.2).sub.sC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.sNR.sup.cC(O)OR.sup.b,
--(CH.sub.2).sub.sOC(O)OR.sup.b,
--(CH.sub.2).sub.sNR.sup.cC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.sOC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.sSO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.sNR.sup.cSO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.sNR.sup.cSO.sub.2R.sup.b,
--(CH.sub.2).sub.sNR.sup.cSO.sub.2CF.sub.3,
--(CH.sub.2).sub.sSO.sub.2CF.sub.3,
--(CH.sub.2).sub.sS(O).sub.2R.sup.b,
--O(CH.sub.2).sub.nCO.sub.2R.sup.a,
--(CH.sub.2).sub.sSO.sub.2NHCOR.sup.b,
--(CH.sub.2).sub.sCONHSO.sub.2R.sup.b, C.sub.1-6 alkyl substituted
with 0-2 R.sup.e, C.sub.1-4 fluoroalkyl, C.sub.2-4 alkenyl
substituted with 0-2 R.sup.e, C.sub.2-4 alkynyl substituted with
0-2 R.sup.e, --O(benzyl substituted with CO.sub.2R.sup.a),
--(CH.sub.2).sub.stetrazolyl, --(CH.sub.2).sub.s--C.sub.3-6
carbocycle substituted with 0-2 R.sup.f1, --(CH.sub.2).sub.s-(5- to
6-membered heterocycle), --(CH.sub.2).sub.s--NR.sup.c--(5- to
6-membered heterocycle), or --(CH.sub.2).sub.s--O--(5- to
6-membered heterocycle); wherein said heterocycle comprises carbon
atoms and 1-3 heteroatoms selected from N, NR.sup.c, O, and
S(O).sub.p and is substituted with 0-2 R.sup.g1;
[0033] alternatively, R.sup.2 and R.sup.3 may combine to form a 5-
to 7-membered carbocycle or heterocycle comprising: carbon atoms
and 0-2 heteroatoms selected from N, NR.sup.c, O, and S(O).sub.p;
wherein said carbocycle and heterocycle are substituted with 0-3
R.sup.g1;
[0034] R.sup.4 is H, F, Cl, Br, I, or C.sub.1-4 alkyl;
[0035] R.sup.5 is H, --(CH.sub.2).sub.qOR.sup.a,
--(CH.sub.2).sub.qSR.sup.b, --(CH.sub.2).sub.rCF.sub.3,
--(CH.sub.2).sub.qOCF.sub.3, --(CH.sub.2).sub.qOCHF.sub.2,
--(CH.sub.2).sub.qOCH.sub.2F, --(CH.sub.2).sub.qCN,
--(CH.sub.2).sub.qNO.sub.2, --(CH.sub.2).sub.qNR.sup.cR.sup.d,
--(CH.sub.2).sub.sC(O)R.sup.a, --(CH.sub.2).sub.sCO.sub.2R.sup.a,
--(CH.sub.2).sub.qNR.sup.cC(O)R.sup.a,
--(CH.sub.2).sub.sC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.qNR.sup.cC(O)OR.sup.b,
--(CH.sub.2).sub.qOC(O)OR.sup.b,
--(CH.sub.2).sub.qNR.sup.cC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.qOC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.qSO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.qNR.sup.cSO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.qNR.sup.cSO.sub.2R.sup.b,
--(CH.sub.2).sub.qNR.sup.cSO.sub.2CF.sub.3,
--(CH.sub.2).sub.qSO.sub.2CF.sub.3,
--(CH.sub.2).sub.qS(O).sub.2R.sup.b,
--(CH.sub.2).sub.qSO.sub.2NHCOR.sup.b,
--(CH.sub.2).sub.sCONHSO.sub.2R.sup.b, --O(benzyl substituted with
CO.sub.2R.sup.a), --(CH.sub.2).sub.stetrazolyl, C.sub.1-6 alkyl
substituted with 0-2 R.sup.e, C.sub.2-4 alkenyl substituted with
0-2 R.sup.e, C.sub.2-4 alkynyl substituted with 0-2 R.sup.e,
--(CH.sub.2).sub.s--C.sub.3-6 carbocycle substituted with 0-2
R.sup.f1, or --(CH.sub.2).sub.s-5- to 6-membered heterocycle;
wherein said heterocycle comprises carbon atoms and 1-3 heteroatoms
selected from N, NR.sup.c, O, and S(O).sub.p and is substituted
with 0-2 R.sup.g1;
[0036] R.sup.6 is H, --(CH.sub.2).sub.rOR.sup.a,
--(CH.sub.2).sub.rSR.sup.b, --(CH.sub.2).sub.sCF.sub.3,
--(CH.sub.2).sub.rOCF.sub.3, --(CH.sub.2).sub.rOCHF.sub.2,
--(CH.sub.2).sub.rOCH.sub.2F, --(CH.sub.2).sub.sCN,
--(CH.sub.2).sub.sNO.sub.2, --(CH.sub.2).sub.rNR.sup.cR.sup.d,
--(CH.sub.2).sub.sC(O)R.sup.a, --(CH.sub.2).sub.sCO.sub.2R.sup.a,
--(CH.sub.2).sub.rNR.sup.cC(O)R.sup.a,
--(CH.sub.2).sub.sC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.rNR.sup.cC(O)OR.sup.b,
--(CH.sub.2).sub.rOC(O)OR.sup.b,
--(CH.sub.2).sub.rNR.sup.cC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.rOC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.rSO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.rNR.sup.cSO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.rNR.sup.cSO.sub.2R.sup.b,
--(CH.sub.2).sub.rNR.sup.cSO.sub.2CF.sub.3,
--(CH.sub.2).sub.rSO.sub.2CF.sub.3,
--(CH.sub.2).sub.rS(O).sub.2R.sup.b,
--(CH.sub.2).sub.rSO.sub.2NHCOR.sup.b,
--(CH.sub.2).sub.sCONHSO.sub.2R.sup.b, C.sub.1-6 alkyl substituted
with 0-2 R.sup.e, C.sub.2-4 alkenyl substituted with 0-2 R.sup.e,
C.sub.2-4 alkynyl substituted with 0-2 R.sup.e,
--(CH.sub.2).sub.s--C.sub.3-6 carbocycle substituted with 0-2
R.sup.f1, or --(CH.sub.2).sub.s-5- to 6-membered heterocycle;
wherein said heterocycle comprises carbon atoms and 1-3 heteroatoms
selected from N, NR.sup.c, O, and S(O).sub.p and is substituted
with 0-2 R.sup.g1;
[0037] alternatively, R.sup.5 and R.sup.6 can be joined to form a 2
to 5-membered alkylene chain, which may be substituted with 0-1
R.sup.f1;
[0038] R.sup.7 is H or C.sub.1-6 alkyl;
[0039] alternatively, R.sup.6 and R.sup.7 can be joined to form a
3-7 membered carbocycle or heterocycle; wherein said carbocycle may
be substituted with 0-2 R.sup.f1; and said heterocycle comprises
carbon atoms and 1-3 heteroatoms selected from N, NR.sup.c, O, and
S(O).sub.p and is substituted with 0-2 R.sup.g1;
[0040] R.sup.8 is H, F, Cl, Br, CN, CH.sub.2F, CHF.sub.2,
--(CH.sub.2).sub.sCF.sub.3, --(CH.sub.2).sub.sOCF.sub.3,
--(CH.sub.2).sub.sSCF.sub.3, --(CH.sub.2).sub.sOCHF.sub.2,
--(CH.sub.2).sub.sOCH.sub.2F, --(CH.sub.2).sub.sCN,
--(CH.sub.2).sub.sNO.sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, --(CH.sub.2).sub.n--OR.sup.a,
--(CH.sub.2).sub.n--SR.sup.b, --(CH.sub.2).sub.n--NR.sup.cR.sup.d,
--(CH.sub.2).sub.sC(O)R.sup.a, --(CH.sub.2).sub.sCO.sub.2R.sup.a,
--(CH.sub.2).sub.sNR.sup.cC(O)R.sup.a,
--(CH.sub.2).sub.sCONR.sup.CR.sup.d,
--(CH.sub.2).sub.sSO.sub.2R.sup.b,
--(CH.sub.2).sub.sSO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.sNR.sup.cC(O)OR.sup.b,
--(CH.sub.2).sub.sOC(O)OR.sup.b,
--(CH.sub.2).sub.sNR.sup.cC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.sOC(O)NR.sup.cR.sup.d,
--(CH.sub.2).sub.sNR.sup.cSO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.sNR.sup.cSO.sub.2R.sup.b,
--(CH.sub.2).sub.sNR.sup.cSO.sub.2CF.sub.3,
--(CH.sub.2).sub.sSO.sub.2CF.sub.3,
--O(CH.sub.2).sub.nCO.sub.2R.sup.a,
--(CH.sub.2).sub.sSO.sub.2NHCOR.sup.b,
--(CH.sub.2).sub.sCONHSO.sub.2R.sup.b, --O(benzyl substituted with
CO.sub.2R.sup.a), --(CH.sub.2).sub.stetrazolyl, C.sub.1-6 alkyl
substituted with 0-2 R.sup.e, C.sub.1-4 fluoroalkyl, C.sub.2-4
alkenyl substituted with 0-2 R.sup.e, C.sub.2-4 alkynyl substituted
with 0-2 R.sup.e, --(CH.sub.2).sub.s--C.sub.3-6 carbocycle
substituted with 0-2 .mu.l, or --(CH.sub.2).sub.n-5- to 10-membered
heterocycle comprising: carbon atoms and 1-4 heteroatoms selected
from N, NR.sup.c, O, and S(O).sub.p, wherein said phenyl and
heterocycle are substituted with 0-3 R.sup.g1;
[0041] R.sup.9, R.sup.10, and R.sup.11 are, independently at each
occurrence, H, F, Cl, Br, I, C.sub.1-4 alkyl, or C.sub.1-4
alkoxy;
[0042] R.sup.12 and R.sup.13 are, independently at each occurrence,
H, F, Cl, OR.sup.a, SR.sup.b, CF.sub.3, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, CN, NO.sub.2, --NR.sup.cR.sup.d, --C(O)R.sup.a,
--CO.sub.2R.sup.a, --NR.sup.cC(O)R.sup.a, --C(O)NR.sup.cR.sup.d,
--NR.sup.cC(O)OR.sup.b, --NR.sup.cC(O)NR.sup.cR.sup.d,
--OC(O)NR.sup.cR.sup.d, --OC(O)OR.sup.a, --SO.sub.2NR.sup.cR.sup.d,
--NR.sup.cSO.sub.2NR.sup.cR.sup.d, --NR.sup.cSO.sub.2R.sup.b,
--NR.sup.cSO.sub.2CF.sub.3, --SO.sub.2CF.sub.3,
--S(O).sub.2R.sup.b, C.sub.1-6 alkyl substituted with 0-2 R.sup.e,
C.sub.2-4 alkenyl substituted with 0-2 R.sup.e, C.sub.2-4 alkynyl
substituted with 0-2 R.sup.e, --(CH.sub.2).sub.s--C.sub.3-6
carbocycle substituted with 0-2 R.sup.f1, --(CH.sub.2).sub.s-(5- to
6-membered heterocycle), --NR.sup.c-(5- to 6-membered heterocycle),
or --O-(5- to 6-membered heterocycle); wherein said heterocycle
comprises carbon atoms and 1-3 heteroatoms selected from N,
NR.sup.c, O, and S(O).sub.p and is substituted with 0-2
R.sup.g1;
[0043] alternatively, any two R.sup.12 or R.sup.13 attached to
either the same carbon or to two adjacent carbons may combine to
form a 3- to 7-membered carbocycle or heterocycle comprising:
carbon atoms and 0-3 heteroatoms selected from N, NR.sup.c, O, and
S(O).sub.p, wherein said carbocycle or heterocycle is substituted
with 0-3 R.sup.g;
[0044] alternately, two R.sup.12 or R.sup.13 on the same carbon
atom can be replaced with oxo; optionally, two R.sup.12 or R.sup.13
on adjacent carbon atoms in L may be replaced with a double or
triple bond between the two carbon atoms;
[0045] R.sup.14 is, independently at each occurrence, CN, F, Cl,
Br, I, OH, N(R.sup.17R.sup.17), C.sub.1-3 alkyl, or C.sub.1-3
alkoxy;
[0046] R.sup.15 is, independently at each occurrence, H,
--C(.dbd.NH)NH.sub.2, N(R.sup.17R.sup.17),
--C(R.sup.17R.sup.17)N(R.sup.17R.sup.17), --CON(R.sup.17R.sup.17),
CN, F, Cl, Br, I, OH, C.sub.1-3 alkyl, or C.sub.1-3 alkoxy;
[0047] R.sup.16 is, independently at each occurrence, H, C.sub.1-6
alkyl, C.sub.3-6 cycloalkyl, phenyl, benzyl, --C(O)R.sup.a,
--C(O)NR.sup.cR.sup.d, --C(O)OR.sup.b, --SO.sub.2NR.sup.cR.sup.d,
--SO.sub.2CF.sub.3, --S(O).sub.2R.sup.b, or --(CH.sub.2).sub.s-(5-
to 6-membered heterocycle); wherein said alkyl or cycloalkyl are
optionally substituted with 0-2 R.sup.e, said phenyl and benzyl are
optionally substituted with 0-2 R.sup.f and said heterocycle
comprises carbon atoms and 1-3 heteroatoms selected from N,
NR.sup.c, O, and S(O).sub.p and is substituted with 0-2
R.sup.g;
[0048] R.sup.16a is, independently at each occurrence, H, C.sub.1-6
alkyl, C.sub.3-6 cycloalkyl, phenyl, benzyl, --C(O)R.sup.a,
--C(O)NR.sup.cR.sup.d, --C(O)OR.sup.b, --SO.sub.2NR.sup.cR.sup.d,
--SO.sub.2CF.sub.3, --S(O).sub.2R.sup.b, or 5- to 6-membered
heterocycle; wherein said alkyl or cycloalkyl are optionally
substituted with 0-2 R.sup.e, said phenyl and benzyl are optionally
substituted with 0-2 R.sup.f, and said heterocycle comprises carbon
atoms and 1-3 heteroatoms selected from N, NR.sup.c, O, and
S(O).sub.p and is substituted with 0-2 R.sup.g;
[0049] R.sup.17 is, independently at each occurrence, H or Me;
[0050] R.sup.a is, independently at each occurrence, H, C.sub.1-4
alkyl, C.sub.3-6 cycloalkyl, phenyl, or benzyl; wherein said alkyl
and cycloalkyl are optionally substituted with 0-2 R.sup.e, and
said phenyl and benzyl are optionally substituted with 0-2
R.sup.f;
[0051] R.sup.b is, independently at each occurrence, C.sub.1-4
alkyl, C.sub.3-6 cycloalkyl, phenyl, or benzyl; wherein said alkyl
and cycloalkyl are optionally substituted with 0-2 R.sup.e, and
said phenyl and benzyl are optionally substituted with 0-2
R.sup.f;
[0052] R.sup.c and R.sup.d are, independently at each occurrence,
H, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, phenyl, or benzyl;
[0053] alternatively, R.sup.c and R.sup.d, when attached to the
same nitrogen atom, combine to form a 4- to 7-membered heterocycle
comprising: carbon atoms and 0-2 additional heteroatoms selected
from N, O, and S(O).sub.p; wherein said heterocycle is substituted
with 0-2 R.sup.g;
[0054] R.sup.e is, independently at each occurrence, F, CF.sub.3,
OH, or C.sub.1-3 alkoxy;
[0055] R.sup.f is, independently at each occurrence, F, Cl, Br,
CF.sub.3, OH, C.sub.1-3 alkyl, or C.sub.1-3 alkoxy;
[0056] R.sup.f1 is, independently at each occurrence, R.sup.f,
--CO.sub.2R.sup.a, --C(O)NR.sup.cR.sup.d, --CONHSO.sub.2R.sup.b, or
--CH.sub.2CONHSO.sub.2R.sup.b;
[0057] R.sup.g is, independently at each occurrence, .dbd.O, F, Cl,
Br, CF.sub.3, OH, C.sub.1-3 alkyl, or C.sub.1-3 alkoxy;
[0058] R.sup.g1 is, independently at each occurrence, R.sup.g,
--CO.sub.2R.sup.a, --C(O)NR.sup.cR.sup.d, --CONHSO.sub.2R.sup.b, or
--CH.sub.2CONHSO.sub.2R.sup.b;
[0059] n, at each occurrence, is selected from 0, 1, 2, 3, and
4;
[0060] p, at each occurrence, is selected from 0, 1, and 2;
[0061] q, at each occurrence is selected from 2 or 3;
[0062] r, at each occurrence is selected from 1, 2, or 3; and
[0063] s, at each occurrence, is selected from 0, 1, and 2.
[0064] In a second aspect, the present invention includes the
compounds of Formula (I), or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
within the scope of the first aspect wherein:
[0065] M is --CONH--, --SO.sub.2NH--, --NHCO--, or
--NHSO.sub.2--;
[0066] when M is --CONH--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)Y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--,
--XC(R.sup.12R.sup.13)Y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--, and
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--;
[0067] when M is --SO.sub.2NH--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--;
[0068] when M is --NHCO--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--;
[0069] when M is --NHSO.sub.2--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--;
[0070] X is O, S, or NR.sup.16;
[0071] Z is NH or O;
[0072] R.sup.2 is H, F, Cl, Br, I, OR.sup.a, SR.sup.b, CF.sub.3,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, CN, NO.sub.2, --NR.sup.cR.sup.d,
--C(O)R.sup.a, --CO.sub.2R.sup.a, --NR.sup.cC(O)R.sup.a,
--C(O)NR.sup.cR.sup.d, --NR.sup.cC(O)OR.sup.b,
--NR.sup.cC(O)NR.sup.cR.sup.d, --OC(O)NR.sup.cR.sup.d,
--SO.sub.2NR.sup.cR.sup.d, --NR.sup.cSO.sub.2NR.sup.cR.sup.d,
--NR.sup.cSO.sub.2R.sup.b, --NR.sup.cSO.sub.2CF.sub.3,
--SO.sub.2CF.sub.3, --S(O).sub.2R.sup.b, C.sub.1-6 alkyl
substituted with 0-2 R.sup.e, C.sub.2-4 alkenyl substituted with
0-2 R.sup.e, C.sub.2-4 alkynyl substituted with 0-2 R.sup.e,
C.sub.3-6 carbocycle substituted with 0-2 R.sup.f,
--(CH.sub.2).sub.s-(5- to 6-membered heterocycle), --NR.sup.c-(5-
to 6-membered heterocycle), or --O-(5- to 6-membered heterocycle);
wherein said heterocycle comprises carbon atoms and 1-3 heteroatoms
selected from N, NR.sup.c, O, and S(O).sub.p and is substituted
with 0-2 R.sup.g;
[0073] R.sup.3 is H, F, Cl, Br, I, OR.sup.a, SR.sup.b, CF.sub.3,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, CN, NO.sub.2, --NR.sup.cR.sup.d,
--C(O)R.sup.a, --CO.sub.2R.sup.a, --NR.sup.cC(O)R.sup.a,
--C(O)NR.sup.cR.sup.d, --NR.sup.cC(O)OR.sup.b,
--NR.sup.cC(O)NR.sup.cR.sup.d, --OC(O)NR.sup.cR.sup.d,
--SO.sub.2NR.sup.cR.sup.d, --NR.sup.cSO.sub.2NR.sup.cR.sup.d,
--NR.sup.cSO.sub.2R.sup.b, --NR.sup.cSO.sub.2CF.sub.3,
--SO.sub.2CF.sub.3, --S(O).sub.2R.sup.b,
--O(CH.sub.2).sub.nCO.sub.2R.sup.a, --SO.sub.2NHCOR.sup.b,
--CONHSO.sub.2R.sup.b, C.sub.1-6 alkyl substituted with 0-2
R.sup.e, C.sub.2-4 alkenyl substituted with 0-2 R.sup.e, C.sub.2-4
alkynyl substituted with 0-2 R.sup.e, --O(benzyl substituted with
CO.sub.2R.sup.a), or tetrazolyl;
[0074] alternatively, R.sup.2 and R.sup.3 may combine to form a 5-
to 7-membered carbocycle or heterocycle comprising: carbon atoms
and 0-2 heteroatoms selected from N, NR.sup.c, O, and S(O).sub.p;
wherein said carbocycle and heterocycle are substituted with 0-3
R.sup.g;
[0075] R.sup.5 is H, --CH.sub.2CO.sub.2R.sup.a,
--CH.sub.2C(O)NR.sup.cR.sup.d, --CH.sub.2CH.sub.2CO.sub.2R.sup.a,
--CH.sub.2CH.sub.2C(O)NR.sup.cR.sup.d, --CH.sub.2CH.sub.2OR.sup.a,
--CH.sub.2CH.sub.2CH.sub.2OR.sup.a, --CH.sub.2CONHSO.sub.2R.sup.b,
--CH.sub.2CH.sub.2CONHSO.sub.2R.sup.b, C.sub.1-6 alkyl substituted
with 0-2 R.sup.e, --(CH.sub.2).sub.s--C.sub.3-6 carbocycle
substituted with 0-2 R.sup.f, or --(CH.sub.2).sub.s-5- to
6-membered heterocycle; wherein said heterocycle comprises carbon
atoms and 1-3 heteroatoms selected from N, NR.sup.c, O, and
S(O).sub.p and is substituted with 0-2 R.sup.g;
[0076] R.sup.6 is H, --CH.sub.2OR.sup.a,
--CH.sub.2CH.sub.2OR.sup.a, CN, --CO.sub.2R.sup.a,
--C(O)NR.sup.cR.sup.d, --CH.sub.2CO.sub.2R.sup.a,
--CH.sub.2C(O)NR.sup.cR.sup.d, --CONHSO.sub.2R.sup.b,
--CH.sub.2CONHSO.sub.2R.sup.b, C.sub.1-6 alkyl substituted with 0-2
R.sup.e, --(CH.sub.2).sub.s--C.sub.3-6 carbocycle substituted with
0-2 R.sup.f, or --(CH.sub.2).sub.s-5- to 6-membered heterocycle;
wherein said heterocycle comprises carbon atoms and 1-3 heteroatoms
selected from N, NR.sup.c, O, and S(O).sub.p and is substituted
with 0-2 R.sup.g;
[0077] alternatively, R.sup.5 and R.sup.6 can be joined to form a 2
to 5-membered alkylene chain, which may be substituted with 0-1
R.sup.f1;
[0078] R.sup.7 is H or C.sub.1-6 alkyl;
[0079] alternatively, R.sup.6 and R.sup.7 can be joined to form a
3-7 membered carbocycle or heterocycle; wherein said carbocycle may
be substituted with 0-2 R.sup.f1; and said heterocycle comprises
carbon atoms and 1-3 heteroatoms selected from N, NR.sup.c, O, and
S(O).sub.p and is substituted with 0-2 R.sup.g1;
[0080] R.sup.8 is, H, F, Cl, Br, CN, CH.sub.2F, CHF.sub.2,
CF.sub.3, OCF.sub.3, SCF.sub.3, NO.sub.2, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, --(CH.sub.2).sub.n--OR.sup.a,
--(CH.sub.2).sub.n--SR.sup.b, --(CH.sub.2).sub.n--NR.sup.cR.sup.d,
--CONR.sup.CR.sup.d, --SO.sub.2R.sup.b, --SO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.n-phenyl, or --(CH.sub.2).sub.n-5- to 10-membered
heterocycle comprising: carbon atoms and 1-4 heteroatoms selected
from N, O, and S(O).sub.p, wherein said phenyl and heterocycle are
substituted with 0-3 R.sup.g;
[0081] R.sup.9 is H, F, Cl, Br, J, C.sub.1-4 alkyl, or C.sub.1-4
alkoxy; and
[0082] R.sup.10 and R.sup.11 are, independently at each occurrence,
H, F, Cl, Br, I, or C.sub.1-4 alkyl.
[0083] In a third aspect, the present invention includes the
compounds of Formula (I), or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
within the scope of the first or second aspect wherein:
[0084] ring A is phenyl or a pyridyl isomer defined by replacing
one of CR.sup.1, CR.sup.2, CR.sup.3, or CR.sup.4 in ring A of
formula (I) with N;
[0085] ring B is phenyl or a pyridyl isomer defined by replacing
one of CR.sup.8, CR.sup.9, CR.sup.10, or CR.sup.11 in ring B of
formula (I) with N;
[0086] with the proviso that when ring A is pyridyl, then ring B is
not pyridyl;
[0087] M is --CONH--, --SO.sub.2NH--, --NHCO--, or
--NHSO.sub.2--;
[0088] when M is --CONH--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)Y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--,
XC(R.sup.12R.sup.13)Y--, and
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--;
[0089] when M is --SO.sub.2NH--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--;
[0090] when M is --NHCO--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--;
[0091] when M is --NHSO.sub.2--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--;
[0092] Z is NH or O;
[0093] R.sup.4 is H or F;
[0094] R.sup.10 and R.sup.11 are H; and
[0095] R.sup.15 is, independently at each occurrence,
--C(.dbd.NH)NH.sub.2, N(R.sup.17R.sup.17),
--C(R.sup.17R.sup.17)N(R.sup.17R.sup.17), --CON(R.sup.17R.sup.17),
or OH.
[0096] In a fourth aspect, the present invention includes the
compounds of Formula (I), or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
within the scope of the first, second, or third aspect wherein:
[0097] ring A is phenyl;
[0098] ring B is phenyl;
[0099] M is --CONH-- or --NHSO.sub.2--;
[0100] when M is --CONH--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)Y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--;
[0101] when M is --NHSO.sub.2--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--;
[0102] W is substituted with 0-2 R.sup.14 and is selected from:
##STR00004##
[0103] Z is NH;
[0104] R.sup.1 is H, Cl, Br, methyl, ethyl, 1-hydroxyethyl, propyl,
isopropyl, vinyl, allyl, 2-propenyl, ethynyl, 1-propynyl, methoxy,
ethoxy, cyclopropyl, cyclobutyl, or cyclopentyl;
[0105] R.sup.4 is H;
[0106] R.sup.5 is H, C.sub.1-4 alkyl, --CH.sub.2CO.sub.2R.sup.a,
--CH.sub.2C(O)NR.sup.cR.sup.d, --CH.sub.2CH.sub.2CO.sub.2R.sup.a,
--CH.sub.2CH.sub.2C(O)NR.sup.cR.sup.d, --CH.sub.2CH.sub.2OR.sup.a,
or --CH.sub.2CH.sub.2CH.sub.2OR.sup.a;
[0107] R.sup.6 is H, --CH.sub.2OR.sup.a,
--CH.sub.2CH.sub.2OR.sup.a, CN, C.sub.1-4 alkyl, --CO.sub.2R.sup.a,
--C(O)NR.sup.cR.sup.d, --CH.sub.2CO.sub.2R.sup.a, or
--CH.sub.2C(O)NR.sup.cR.sup.d;
[0108] R.sup.7 is H;
[0109] R.sup.10 and R.sup.11 are H; and
[0110] R.sup.15 is, independently at each occurrence,
--C(.dbd.NH)NH.sub.2, N(R.sup.17R.sup.17),
--C(R.sup.17R.sup.17)N(R.sup.17R.sup.17), or --CONH.sub.2.
[0111] In a fifth aspect, the present invention includes the
compounds of Formula (I), or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
within the scope of the first, second, third or fourth aspect
wherein:
[0112] ring A is phenyl;
[0113] ring B is phenyl;
[0114] M is --CONH--;
[0115] L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)Y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--;
[0116] W is substituted with 0-2 R.sup.14 and is selected from:
##STR00005##
[0117] Z is NH;
[0118] R.sup.1 is H, Cl, Br, methyl, ethyl, vinyl, 2-propenyl,
allyl, ethynyl, 1-propynyl, methoxy, ethoxy, or cyclopropyl;
[0119] R.sup.4 is H;
[0120] R.sup.5 is H, C.sub.1-4 alkyl, --CH.sub.2CO.sub.2R.sup.a,
--CH.sub.2C(O)NR.sup.cR.sup.d, --CH.sub.2CH.sub.2CO.sub.2R.sup.a,
--CH.sub.2CH.sub.2C(O)NR.sup.cR.sup.d, --CH.sub.2CH.sub.2OR.sup.a,
or --CH.sub.2CH.sub.2CH.sub.2OR.sup.a;
[0121] R.sup.6 is H, --CH.sub.2OR.sup.a,
--CH.sub.2CH.sub.2OR.sup.a, CN, C.sub.1-4 alkyl, --CO.sub.2R.sup.a,
--C(O)NR.sup.cR.sup.d, --CH.sub.2CO.sub.2R.sup.a, or
--CH.sub.2C(O)NR.sup.cR.sup.d;
[0122] R.sup.7 is H;
[0123] R.sup.8 is H, C.sub.1-6 alkyl, OR.sup.a,
--CONR.sup.cR.sup.d, --SO.sub.2R.sup.b, --SO.sub.2NR.sup.cR.sup.d,
phenyl, or 5- to 6-membered heterocycle comprising: carbon atoms
and 1-3 heteroatoms selected from N, O, and S(O).sub.p, wherein
said phenyl and heterocycle are substituted with 0-3 R.sup.g;
[0124] R.sup.9, R.sup.10, and R.sup.11 are H; and
[0125] R.sup.14 is, independently at each occurrence, F, Cl,
methyl, ethyl, hydroxyl, or methoxy.
[0126] In a sixth aspect, the present invention includes the
compounds of Formula (I), or a stereoisomer, tautomer,
pharmaceutically acceptable salt, solvate, or prodrug form thereof,
within the scope of the first aspect wherein:
[0127] ring A is phenyl;
[0128] ring B is phenyl;
[0129] M is --CONH--;
[0130] L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)NR.sup.16C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13).sub.y--,
C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, --OC(R.sup.12R.sup.13)--,
or --C(R.sup.12R.sup.13).sub.y--;
[0131] W is selected from:
##STR00006##
[0132] Y is O Or NMe,
[0133] Z is NH;
[0134] R.sup.1 is H, Cl, Br, methyl, ethyl, vinyl, 2-propenyl,
ethynyl, methoxy, or ethoxy;
[0135] R.sup.2 is H, F, Cl, Br, --OR.sup.a, --SR.sup.b, --CF.sub.3,
--OCF.sub.3, --OCHF.sub.2, --OCH.sub.2F, CN, NO.sub.2,
--NR.sup.cR.sup.d, --C(O)R.sup.a, --CO.sub.2R.sup.a,
--NR.sup.cC(O)R.sup.a, --C(O)NR.sup.cR.sup.d,
--NR.sup.cC(O)OR.sup.b,
--OC(O)OR.sup.b--NR.sup.cC(O)NR.sup.cR.sup.d,
--OC(O)NR.sup.cR.sup.d, --SO.sub.2NR.sup.cR.sup.d,
--NR.sup.cSO.sub.2NR.sup.cR.sup.d, --NR.sup.cSO.sub.2R.sup.b,
--S(O).sub.2R.sup.b, C.sub.1-6 alkyl substituted with 0-2 R.sup.e,
C.sub.1-4 fluoroalkyl, C.sub.2-4 alkenyl substituted with 0-2
R.sup.e, C.sub.2-4 alkynyl substituted with 0-2 R.sup.e,
--C.sub.3-6 carbocycle substituted with 0-2 R.sup.f, -(5- to
6-membered heterocycle), --NR.sup.c-(5- to 6-membered heterocycle),
or --O-(5- to 6-membered heterocycle); wherein said heterocycle
comprises carbon atoms and 1-3 heteroatoms selected from N,
NR.sup.c, O, and S(O).sub.p and is substituted with 0-2
R.sup.g;
[0136] R.sup.3 is H, F, Cl, Me, OCH.sub.2CO.sub.2H;
[0137] R.sup.4 is H;
[0138] R.sup.5 is H, C.sub.1-4 alkyl, --CH.sub.2CO.sub.2R.sup.a, or
--CH.sub.2C(O)NR.sup.cR.sup.d;
[0139] R.sup.6 is H, C.sub.1-4 alkyl, --CO.sub.2R.sup.a,
--C(O)NR.sup.cR.sup.d, --CH.sub.2CO.sub.2R.sup.a, or
--CH.sub.2C(O)NR.sup.cR.sup.d;
[0140] R.sup.7 is H;
[0141] R.sup.8 is --CONR.sup.cR.sup.d, --SO.sub.2R.sup.b,
--SO.sub.2NR.sup.cR.sup.d, or 4-morpholino;
[0142] R.sup.9, R.sup.10, and R.sup.11 are H;
[0143] R.sup.12 and R.sup.13 are, independently at each occurrence,
H, methyl, ethyl, propyl, isopropyl, cyclopropyl, t-butyl, methoxy,
ethoxy, propoxy, isopropoxy, or cyclopropoxy, with the proviso that
no more than two of R.sup.12 and R.sup.13 in L are other than H;
and
[0144] R.sup.16 is H, C.sub.1-4 alkyl, --C(O)R.sup.a,
--C(O)NR.sup.cR.sup.d, --C(O)OR.sup.b, or --S(O).sub.2R.sup.b.
[0145] In a seventh aspect, the present invention includes the
compounds of Formula (I), or a stereoisomer, tautomer,
pharmaceutically acceptable salt, solvate, or prodrug form thereof,
within the scope of any of the above aspects wherein:
[0146] M is --CONH--;
[0147] L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)CH.sub.2--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)O--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)NMe-,
--C(R.sup.12R.sup.13)N(C.dbd.OCH.sub.3)CH.sub.2--,
--C(R.sup.12R.sup.13)NHCH.sub.2--, --C(R.sup.12R.sup.13)CH.sub.2--,
and --OCH.sub.2--;
[0148] W is selected from:
##STR00007##
[0149] R.sup.1 is H, Cl, Br, methyl, ethyl, methoxy, or ethoxy;
[0150] R.sup.2 is H, Cl, Br, methyl, ethyl, methoxy, or ethoxy;
[0151] R.sup.3 is H;
[0152] R.sup.4 is H;
[0153] R.sup.5 is H, methyl, ethyl, or --CH.sub.2CO.sub.2H;
[0154] R.sup.6 is H, methyl, ethyl, --CO.sub.2H or
--CH.sub.2CO.sub.2H;
[0155] R.sup.7 is H; and
[0156] R.sup.8 is --CONR.sup.cR.sup.d or --SO.sub.2R.sup.b.
[0157] In an eighth aspect, the present invention includes the
compounds of Formula (I), or a stereoisomer, tautomer,
pharmaceutically acceptable salt, solvate, or prodrug form thereof,
within the scope of the first aspect wherein:
[0158] when M is --CONH--; L is selected from --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--, --O(CH.sub.2)--,
--O(CH.sub.2).sub.2--, --O(CH.sub.2).sub.3--,
--(CH.sub.2).sub.2O--, --CH(Me)CH.sub.2O--,
--C(Me).sub.2CH.sub.2O--, --CH.sub.2CH(Me)O--, --CH(Et)CH.sub.2O--,
--CH.sub.2CH(Et)O--, --CH.sub.2OCH.sub.2--, --(CH.sub.2).sub.2NMe-,
--(CH.sub.2).sub.3NMe-, --CH.sub.2NHCH.sub.2--, and
--CH.sub.2N(Ac)CH.sub.2--;
[0159] when M is --NHSO.sub.2--, L is selected from
--(CH.sub.2).sub.2-- and --(CH.sub.2).sub.3--;
[0160] W is selected from:
##STR00008##
[0161] Z is NH;
[0162] R.sup.1 is H, Cl, Br, C.sub.1-4 alkyl, or C.sub.1-4
alkoxy;
[0163] R.sup.2 is H, Cl, Br, C.sub.1-4 alkyl, or C.sub.1-4
alkoxy;
[0164] R.sup.3 is H;
[0165] R.sup.4 is H;
[0166] R.sup.5 is H, C.sub.1-4 alkyl, --CH.sub.2CO.sub.2H, or
--CH.sub.2CO.sub.2Et;
[0167] R.sup.6 is H, C.sub.1-4 alkyl, --CO.sub.2H,
--CH.sub.2CO.sub.2H, or --CH.sub.2CO.sub.2Et;
[0168] R.sup.7 is H;
[0169] R.sup.8 is H, --SO.sub.2(C.sub.1-4 alkyl), or --S(C.sub.1-4
alkyl);
[0170] R.sup.9 is H; and
[0171] R.sup.10 is H.
[0172] In a ninth aspect, the present invention includes the
compounds of Formula (I), or a stereoisomer, tautomer,
pharmaceutically acceptable salt, solvate, or prodrug form thereof,
within the scope of the eighth aspect wherein:
[0173] W is selected from:
##STR00009##
[0174] R.sup.1 is H, Cl, Br, methyl, ethyl, methoxy, or ethoxy;
[0175] R.sup.2 is H, Cl, Br, methyl, ethyl, methoxy, or ethoxy;
[0176] R.sup.5 is H, methyl, ethyl, or --CH.sub.2CO.sub.2H;
[0177] R.sup.6 is H, methyl, ethyl, --CO.sub.2H,
--CH.sub.2CO.sub.2H, or --CH.sub.2CO.sub.2Et; and
[0178] R.sup.8 is H, --SO.sub.2Et, --SO.sub.2(i-Pr),
--SO.sub.2(t-Bu), or --S(i-Pr).
[0179] In a tenth aspect, the present invention provides a compound
selected from the exemplified examples or a stereoisomer, tautomer,
pharmaceutically acceptable salt, solvate, or prodrug thereof.
[0180] In another embodiment the present invention provides
compounds wherein: ring A is phenyl; and ring B is phenyl or a
pyridyl isomer defined by replacing one of CR.sup.8, CR.sup.9,
CR.sup.10, or CR.sup.11 in ring B of formula (I) with N.
[0181] In another embodiment the present invention provides
compounds wherein: ring A is phenyl or a pyridyl isomer defined by
replacing one of CR.sup.1, CR.sup.2, CR.sup.3, or CR.sup.4 in ring
A of formula (I) with N; and ring B is phenyl.
[0182] In another embodiment the present invention provides
compounds wherein: ring A is phenyl; and ring B is phenyl.
[0183] In another embodiment the present invention provides
compounds wherein: M is --CONH--, --SO.sub.2NH--, --NHCO--, or
--NHSO.sub.2--;
[0184] when M is --CONH--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)Y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--,
XC(R.sup.12R.sup.13)Y--, and
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--;
[0185] when M is --SO.sub.2NH--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--;
[0186] when M is --NHCO--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--;
[0187] when M is --NHSO.sub.2--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--.
[0188] In another embodiment the present invention provides
compounds wherein: M is --CONH-- or --NHSO.sub.2--;
[0189] when M is --CONH--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)Y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--;
[0190] when M is --NHSO.sub.2--, L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--.
[0191] In another embodiment the present invention provides
compounds wherein: M is --CONH--; and L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)Y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--,
--XC(R.sup.12R.sup.13)Y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--, and
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--.
[0192] In another embodiment the present invention provides
compounds wherein: M is --CONH--; and L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)--, --C(R.sup.12R.sup.13)Y--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)Y--.
[0193] In another embodiment the present invention provides
compounds wherein: M is --SO.sub.2NH--; and L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--.
[0194] In another embodiment the present invention provides
compounds wherein: M is --NHSO.sub.2--; and L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--.
[0195] In another embodiment the present invention provides
compounds wherein: M is --NHCO--; and L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--.
[0196] In another embodiment the present invention provides
compounds wherein: M is --NHSO.sub.2--; and L is selected from
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
--C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.su-
p.13)--,
--XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--, and
--C(R.sup.12R.sup.13)XC(R.sup.12R.sup.13)C(R.sup.12R.sup.13)--,
[0197] In another embodiment the present invention provides
compounds wherein: W is substituted with 0-2 R.sup.14 and is
selected from:
##STR00010##
[0198] In another embodiment the present invention provides
compounds wherein: W is substituted with 0-2 R.sup.14 and is
selected from:
##STR00011##
[0199] In another embodiment the present invention provides
compounds wherein: W is substituted with 0-2 R.sup.14 and is
selected from:
##STR00012##
[0200] In another embodiment the present invention provides
compounds wherein: W is substituted with 0-2 R.sup.14 and is
selected from:
##STR00013##
[0201] In another embodiment the present invention provides
compounds wherein: W is selected from:
##STR00014##
[0202] In another embodiment the present invention provides
compounds wherein: W is selected from:
##STR00015##
[0203] In another embodiment the present invention provides
compounds wherein: W is selected from:
##STR00016##
[0204] In another embodiment the present invention provides
compounds wherein: W is selected from:
##STR00017##
[0205] In another embodiment the present invention provides
compounds wherein: W is selected from:
##STR00018##
[0206] In another embodiment the present invention provides
compounds wherein: W is selected from:
##STR00019##
[0207] In another embodiment the present invention provides
compounds wherein: X is O, S, or NH.
[0208] In another embodiment the present invention provides
compounds wherein: X is O.
[0209] In another embodiment the present invention provides
compounds wherein: X is S.
[0210] In another embodiment the present invention provides
compounds wherein: X is NR.sup.16.
[0211] In another embodiment the present invention provides
compounds wherein: X is NH.
[0212] In another embodiment the present invention provides
compounds wherein: Y is O, S, NMe, or NH.
[0213] In another embodiment the present invention provides
compounds wherein: Y is O or NR.sup.16a.
[0214] In another embodiment the present invention provides
compounds wherein: Y is O or NMe.
[0215] In another embodiment the present invention provides
compounds wherein: Y is O.
[0216] In another embodiment the present invention provides
compounds wherein: Y is S.
[0217] In another embodiment the present invention provides
compounds wherein: Y is NR.sup.16a.
[0218] In another embodiment the present invention provides
compounds wherein: Y is NMe.
[0219] In another embodiment the present invention provides
compounds wherein: Y is NH.
[0220] In another embodiment the present invention provides
compounds wherein: Z is NH or O.
[0221] In another embodiment the present invention provides
compounds wherein: Z is NH.
[0222] In another embodiment the present invention provides
compounds wherein: R.sup.1 is H, Cl, Br, methyl, ethyl,
1-hydroxyethyl, propyl, isopropyl, vinyl, allyl, 2-propenyl,
ethynyl, 1-propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, or
cyclopentyl.
[0223] In another embodiment the present invention provides
compounds wherein: R.sup.1 is H, Cl, Br, methyl, ethyl, vinyl,
2-propenyl, allyl, ethynyl, 1-propynyl, methoxy, ethoxy, or
cyclopropyl.
[0224] In another embodiment the present invention provides
compounds wherein: R.sup.1 is H, Cl, Br, methyl, ethyl, vinyl,
2-propenyl, ethynyl, methoxy, or ethoxy.
[0225] In another embodiment the present invention provides
compounds wherein: R.sup.1 is H, Cl, Br, methyl, ethyl, methoxy, or
ethoxy;
[0226] In another embodiment the present invention provides
compounds wherein: R.sup.2 is H, F, Cl, Br, I, OR.sup.a, SR.sup.b,
CF.sub.3, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, CN, NO.sub.2,
--NR.sup.cR.sup.d, --C(O)R.sup.a, --CO.sub.2R.sup.a,
--NR.sup.cC(O)R.sup.a, --C(O)NR.sup.cR.sup.d,
--NR.sup.cC(O)OR.sup.b, --NR.sup.cC(O)NR.sup.cR.sup.d,
--OC(O)NR.sup.cR.sup.d, --SO.sub.2NR.sup.cR.sup.d,
--NR.sup.cSO.sub.2NR.sup.cR.sup.d, --NR.sup.cSO.sub.2R.sup.b,
--NR.sup.cSO.sub.2CF.sub.3, --SO.sub.2CF.sub.3,
--S(O).sub.2R.sup.b, C.sub.1-6 alkyl substituted with 0-2 R.sup.e,
C.sub.2-4 alkenyl substituted with 0-2 R.sup.e, C.sub.2-4 alkynyl
substituted with 0-2 R.sup.e, C.sub.3-6 carbocycle substituted with
0-2 R.sup.f, --(CH.sub.2).sub.s-(5- to 6-membered heterocycle),
--NR.sup.c-(5- to 6-membered heterocycle), or --O-(5- to 6-membered
heterocycle); wherein said heterocycle comprises carbon atoms and
1-3 heteroatoms selected from N, NR.sup.c, O, and S(O).sub.p and is
substituted with 0-2 R.sup.g;
[0227] R.sup.3 is H, F, Cl, Br, I, OR.sup.a, SR.sup.b, CF.sub.3,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, CN, NO.sub.2, --NR.sup.cR.sup.d,
--C(O)R.sup.a, --CO.sub.2R.sup.a, --NR.sup.cC(O)R.sup.a,
--C(O)NR.sup.cR.sup.d, --NR.sup.cC(O)OR.sup.b,
--NR.sup.cC(O)NR.sup.cR.sup.d, --OC(O)NR.sup.cR.sup.d,
--SO.sub.2NR.sup.cR.sup.d, --NR.sup.cSO.sub.2NR.sup.cR.sup.d,
--NR.sup.cSO.sub.2R.sup.b, --NR.sup.cSO.sub.2CF.sub.3,
--SO.sub.2CF.sub.3, --S(O).sub.2R.sup.b,
--O(CH.sub.2).sub.nCO.sub.2R.sup.a, --SO.sub.2NHCOR.sup.b,
--CONHSO.sub.2R.sup.b, C.sub.1-6 alkyl substituted with 0-2
R.sup.e, C.sub.2-4 alkenyl substituted with 0-2 R.sup.e, C.sub.2-4
alkynyl substituted with 0-2 R.sup.e, --O(benzyl substituted with
CO.sub.2R.sup.a), or tetrazolyl;
[0228] alternatively, R.sup.2 and R.sup.3 may combine to form a 5-
to 7-membered carbocycle or heterocycle comprising: carbon atoms
and 0-2 heteroatoms selected from N, NR.sup.c, O, and S(O).sub.p;
wherein said carbocycle and heterocycle are substituted with 0-3
R.sup.g.
[0229] In another embodiment the present invention provides
compounds wherein: R.sup.2 is H, F, Cl, Br, I, OR.sup.a, SR.sup.b,
CF.sub.3, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, CN, NO.sub.2,
--NR.sup.cR.sup.d, --C(O)R.sup.a, --CO.sub.2R.sup.a,
--NR.sup.cC(O)R.sup.a, --C(O)NR.sup.cR.sup.d,
--NR.sup.cC(O)OR.sup.b, --NR.sup.cC(O)NR.sup.cR.sup.d,
--OC(O)NR.sup.cR.sup.d, --SO.sub.2NR.sup.cR.sup.d,
--NR.sup.cSO.sub.2NR.sup.cR.sup.d, --NR.sup.cSO.sub.2R.sup.b,
--NR.sup.cSO.sub.2CF.sub.3, --SO.sub.2CF.sub.3,
--S(O).sub.2R.sup.b, C.sub.1-6 alkyl substituted with 0-2 R.sup.e,
C.sub.2-4 alkenyl substituted with 0-2 R.sup.e, C.sub.2-4 alkynyl
substituted with 0-2 R.sup.e, C.sub.3-6 carbocycle substituted with
0-2 R.sup.f, --(CH.sub.2).sub.s-(5- to 6-membered heterocycle),
--NR.sup.c-(5- to 6-membered heterocycle), or --O-(5- to 6-membered
heterocycle); wherein said heterocycle comprises carbon atoms and
1-3 heteroatoms selected from N, NR.sup.c, O, and S(O).sub.p and is
substituted with 0-2 R.sup.g.
[0230] In another embodiment the present invention provides
compounds wherein: R.sup.2 is H, Cl, Br, methyl, ethyl, vinyl,
2-propenyl, ethynyl, methoxy, or ethoxy.
[0231] In another embodiment the present invention provides
compounds wherein: R.sup.2 is H, Cl, Br, methyl, ethyl, methoxy, or
ethoxy.
[0232] In another embodiment the present invention provides
compounds wherein: R.sup.3 is H, F, Cl, Me, OCH.sub.2CO.sub.2H.
[0233] In another embodiment the present invention provides
compounds wherein: R.sup.3 is H.
[0234] In another embodiment the present invention provides
compounds wherein: R.sup.4 is H or F.
[0235] In another embodiment the present invention provides
compounds wherein: R.sup.5 is H, C.sub.1-4 alkyl,
--CH.sub.2CO.sub.2R.sup.a, --CH.sub.2C(O)NR.sup.cR.sup.d,
--CH.sub.2CH.sub.2CO.sub.2R.sup.a,
--CH.sub.2CH.sub.2C(O)NR.sup.cR.sup.d, --CH.sub.2CH.sub.2OR.sup.a,
or --CH.sub.2CH.sub.2CH.sub.2OR.sup.a.
[0236] In another embodiment the present invention provides
compounds wherein: R.sup.5 is H, C.sub.1-4 alkyl,
--CH.sub.2CO.sub.2R.sup.a, or --CH.sub.2C(O)NR.sup.cR.sup.d.
[0237] In another embodiment the present invention provides
compounds wherein: R.sup.5 is H, methyl, ethyl, or
--CH.sub.2CO.sub.2H.
[0238] In another embodiment the present invention provides
compounds wherein: R.sup.6 is H, --CH.sub.2OR.sup.a,
--CH.sub.2CH.sub.2OR.sup.a, CN, C.sub.1-4 alkyl, --CO.sub.2R.sup.a,
--C(O)NR.sup.cR.sup.d, --CH.sub.2CO.sub.2R.sup.a, or
--CH.sub.2C(O)NR.sup.cR.sup.d.
[0239] In another embodiment the present invention provides
compounds wherein: R.sup.6 is H, C.sub.1-4 alkyl,
--CO.sub.2R.sup.a, --C(O)NR.sup.cR.sup.d,
--CH.sub.2CO.sub.2R.sup.a, or --CH.sub.2C(O)NR.sup.cR.sup.d.
[0240] In another embodiment the present invention provides
compounds wherein: R.sup.6 is H, methyl, ethyl, --CO.sub.2H or
--CH.sub.2CO.sub.2H.
[0241] In another embodiment the present invention provides
compounds wherein: R.sup.7 is H.
[0242] In another embodiment the present invention provides
compounds wherein: R.sup.8 is, F, Cl, Br, CN, CH.sub.2F, CHF.sub.2,
CF.sub.3, OCF.sub.3, SCF.sub.3, NO.sub.2, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, --(CH.sub.2).sub.n--OR.sup.a,
--(CH.sub.2).sub.n--SR.sup.b, --(CH.sub.2).sub.n--NR.sup.cR.sup.d,
--CONR.sup.cR.sup.d, --SO.sub.2R.sup.b, --SO.sub.2NR.sup.cR.sup.d,
--(CH.sub.2).sub.n-phenyl, or --(CH.sub.2).sub.n-5- to 10-membered
heterocycle comprising: carbon atoms and 1-4 heteroatoms selected
from N, O, and S(O).sub.p, wherein said phenyl and heterocycle are
substituted with 0-3 R.sup.g.
[0243] In another embodiment the present invention provides
compounds wherein: R.sup.8 is C.sub.1-6 alkyl, OR.sup.a,
--CONR.sup.cR.sup.d, --SO.sub.2R.sup.b, --SO.sub.2NR.sup.cR.sup.d,
phenyl, or 5- to 6-membered heterocycle comprising: carbon atoms
and 1-3 heteroatoms selected from N, O, and S(O).sub.p, wherein
said phenyl and heterocycle are substituted with 0-3 R.sup.g.
[0244] In another embodiment the present invention provides
compounds wherein: R.sup.8 is --CONR.sup.cR.sup.d,
--SO.sub.2R.sup.b, --SO.sub.2NR.sup.cR.sup.d, or 4-morpholino.
[0245] In another embodiment the present invention provides
compounds wherein: R.sup.8 is --CONR.sup.cR.sup.d or
--SO.sub.2R.sup.b.
[0246] In another embodiment the present invention provides
compounds wherein: R.sup.9 is H, F, Cl, Br, I, C.sub.1-4 alkyl, or
C.sub.1-4 alkoxy.
[0247] In another embodiment the present invention provides
compounds wherein: R.sup.9 is H.
[0248] In another embodiment the present invention provides
compounds wherein: R.sup.10 and R.sup.11 are, independently at each
occurrence, H, F, Cl, Br, I, or C.sub.1-4 alkyl.
[0249] In another embodiment the present invention provides
compounds wherein: R.sup.10 and R.sup.11 are H.
[0250] In another embodiment the present invention provides
compounds wherein: R.sup.14 is, independently at each occurrence,
F, Cl, methyl, ethyl, hydroxyl, or methoxy.
[0251] In another embodiment the present invention provides
compounds wherein: R.sup.15 is, independently at each occurrence,
--C(.dbd.NH)NH.sub.2, N(R.sup.17R.sup.17),
--C(R.sup.17R.sup.17)N(R.sup.17R.sup.17), --CON(R.sup.17R.sup.17),
or OH.
[0252] In another embodiment the present invention provides
compounds wherein: R.sup.15 is, independently at each occurrence,
--C(.dbd.NH)NH.sub.2, N(R.sup.17R.sup.17),
--C(R.sup.17R.sup.17)N(R.sup.17R.sup.17), or --CONH.sub.2.
[0253] In another embodiment the present invention provides
compounds wherein: R.sup.16 is H, C.sub.1-4 alkyl, --C(O)R.sup.a,
--C(O)NR.sup.cR.sup.d, --C(O)OR.sup.b, or --S(O).sub.2R.sup.b.
[0254] In another embodiment the present invention provides
compounds wherein: R.sup.16 is, independently at each occurrence, H
or C.sub.1-6 alkyl.
[0255] In another embodiment the present invention provides
compounds wherein: R.sup.16 is H.
[0256] In another embodiment the present invention provides
compounds wherein: R.sup.16 is C.sub.1-6 alkyl.
[0257] In another embodiment the present invention provides
compounds wherein: R.sup.16 is, independently at each occurrence, H
or C.sub.1-6 alkyl.
[0258] In another embodiment the present invention provides
compounds wherein: R.sup.16 is, independently at each occurrence, H
or C.sub.1-6 alkyl.
[0259] In another embodiment the present invention provides
compounds wherein: R.sup.16 is H.
[0260] In another embodiment the present invention provides
compounds wherein: R.sup.16 is C.sub.1-6 alkyl.
[0261] In another embodiment the present invention provides a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and at least one of the compounds of the present invention
or a stereoisomer, tautomer, pharmaceutically acceptable salt,
solvate, or prodrug thereof.
[0262] In another embodiment the present invention provides a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a therapeutically effective amount of at least one of
the compounds of the present invention or a stereoisomer, tautomer,
pharmaceutically acceptable salt, solvate, or prodrug thereof.
[0263] In another embodiment, the present invention provides a
novel process for making one of the compounds of the present
invention or a stereoisomer, tautomer, pharmaceutically acceptable
salt, solvate or prodrug thereof.
[0264] In another embodiment, the present invention provides a
novel intermediate for making one of the compounds of the present
invention or a stereoisomer, tautomer, pharmaceutically acceptable
salt, solvate or prodrug thereof.
[0265] In another embodiment the present invention provides a
method for modulation of the coagulation cascade comprising
administering to a host in need of such treatment a therapeutically
effective amount of at least one of the compounds of the present
invention or a stereoisomer, tautomer, pharmaceutically acceptable
salt, solvate, or prodrug form thereof.
[0266] In another embodiment the present invention provides a
method for treating thrombotic or thromboembolic disorders
comprising: administering to a host in need of such treatment a
therapeutically effective amount of at least one of the compounds
of the present invention or a stereoisomer, tautomer,
pharmaceutically acceptable salt, solvate, or prodrug form
thereof.
[0267] In another embodiment, the thromboembolic disorder is
selected from the group consisting of arterial cardiovascular
thromboembolic disorders, venous cardiovascular thromboembolic
disorders, arterial cerebrovascular thromboembolic disorders, and
venous cerebrovascular thromboembolic disorders.
[0268] In another embodiment, the thromboembolic disorder is
selected unstable angina, an acute coronary syndrome, atrial
fibrillation, first myocardial infarction, recurrent myocardial
infarction, ischemic sudden death, transient ischemic attack,
stroke, atherosclerosis, peripheral occlusive arterial disease,
venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial
embolism, coronary arterial thrombosis, cerebral arterial
thrombosis, cerebral embolism, kidney embolism, pulmonary embolism,
and thrombosis resulting from medical implants, devices, or
procedures in which blood is exposed to an artificial surface that
promotes thrombosis.
[0269] In another embodiment, the present invention provides a
novel method of treating a patient in need of thromboembolic
disorder treatment, comprising: administering a compound of the
present invention or a stereoisomer, tautomer, pharmaceutically
acceptable salt, solvate, or prodrug form thereof in an amount
effective to treat a thromboembolic disorder.
[0270] In another embodiment, the present invention provides a
method, comprising: administering a compound of the present
invention or a stereoisomer, tautomer, pharmaceutically acceptable
salt, solvate, or prodrug form thereof in an amount effective to
treat a thromboembolic disorder.
[0271] In another embodiment, the present invention provides a
pharmaceutical composition further comprising at least one
additional therapeutic agent selected from one or more of potassium
channel openers, potassium channel blockers, calcium channel
blockers, sodium hydrogen exchanger inhibitors, antiarrhythmic
agents, antiatherosclerotic agents, anticoagulants, antithrombotic
agents, prothrombolytic agents, fibrinogen antagonists, diuretics,
antihypertensive agents, ATPase inhibitors, mineralocorticoid
receptor antagonists, phosphodiesterase inhibitors, antidiabetic
agents, anti-inflammatory agents, antioxidants, angiogenesis
modulators, antiosteoporosis agents, hormone replacement therapies,
hormone receptor modulators, oral contraceptives, antiobesity
agents, antidepressants, antianxiety agents, antipsychotic agents,
antiproliferative agents, antitumor agents, antiulcer and
gastroesophageal reflux disease agents, growth hormone agents
and/or growth hormone secretagogues, thyroid mimetics,
anti-infective agents, antiviral agents, antibacterial agents,
antifungal agents, cholesterol/lipid lowering agents and lipid
profile therapies, and agents that mimic ischemic preconditioning
and/or myocardial stunning, or a combination thereof.
[0272] In a preferred embodiment, the present invention provides a
pharmaceutical composition wherein the additional therapeutic
agent(s) is an antihypertensive agent selected from ACE inhibitors,
AT-1 receptor antagonists, beta-adrenergic receptor antagonists,
ETA receptor antagonists, dual ETA/AT-1 receptor antagonists, and
vasopeptidase inhibitors, an antiarrythmic agent selected from IKur
inhibitors, an anticoagulant agent selected from thrombin
inhibitors, antithrombin-III activators, heparin co-factor II
activators, other factor VIIa inhibitors, other plasma kallikrein
inhibitors, plasminogen activator inhibitor (PAI-1) antagonists,
thrombin activatable fibrinolysis inhibitor (TAFI) inhibitors,
factor IXa inhibitors, factor Xa inhibitors, and factor XIa
inhibitors, or an antiplatelet agent selected from GPIIb/IIIa
blockers, protease activated receptor (PAR-1) antagonists,
phosphodiesterase-III inhibitors, P2Y.sub.1 receptor antagonists,
P2Y.sub.12 receptor antagonists, thromboxane receptor antagonists,
cyclooxygense-1 inhibitors, and aspirin, or a combination
thereof.
[0273] In another embodiment, the present invention provides a
pharmaceutical composition further comprising additional
therapeutic agent(s) selected from an anti-arrhythmic agent, an
anti-hypertensive agent, an anti-coagulant agent, an anti-platelet
agent, a thrombin inhibiting agent, a thrombolytic agent, a
fibrinolytic agent, a calcium channel blocker, a potassium channel
blocker, a cholesterol/lipid lowering agent, or a combination
thereof.
[0274] In another embodiment, the present invention provides a
pharmaceutical composition further comprising additional
therapeutic agent(s) selected from warfarin, unfractionated
heparin, low molecular weight heparin, synthetic pentasaccharide,
hirudin, argatroban, aspirin, ibuprofen, naproxen, sulindac,
indomethacin, mefenamate, dipyridamol, droxicam, diclofenac,
sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban,
eptifibatide, abciximab, melagatran, ximelagatran,
disulfatohirudin, tissue plasminogen activator, modified tissue
plasminogen activator, anistreplase, urokinase, and streptokinase,
or a combination thereof.
[0275] In a preferred embodiment, the present invention provides a
pharmaceutical composition, wherein the additional therapeutic
agent(s) are an anti-platelet agent or a combination thereof.
[0276] In a preferred embodiment, the present invention provides a
pharmaceutical composition, wherein the additional therapeutic
agent is the anti-platelet agent selected from clopidogrel and
aspirin, or a combination thereof.
[0277] In a preferred embodiment, the present invention provides a
pharmaceutical composition, wherein the additional therapeutic
agent is the anti-platelet agent clopidogrel.
[0278] In another embodiment, the present invention provides a
compound of the present invention for use in therapy.
[0279] In another embodiment, the present invention also provides
the use of a compound of the present invention for the manufacture
of a medicament for the treatment of a thrombotic or thromboembolic
disorder.
[0280] In another embodiment, the present invention provides a
combined preparation of a compound of the present invention and
additional therapeutic agent(s) for simultaneous, separate or
sequential use in therapy.
[0281] In another embodiment, the present invention provides a
combined preparation of a compound of the present invention and
additional therapeutic agent(s) for simultaneous, separate or
sequential use in treatment of a thrombotic or thromboembolic
disorder.
[0282] In another embodiment, the present invention provides a
novel article of manufacture, comprising: (a) a first container;
(b) a pharmaceutical composition located within the first
container, wherein the composition, comprises: a first therapeutic
agent, comprising: a compound of the present invention; and (c) a
package insert stating that the pharmaceutical composition can be
used for the treatment of a thrombotic or thromboembolic
disorder.
[0283] In another preferred embodiment, the present invention
provides a novel article of manufacture, further comprising: (d) a
second container; wherein components (a) and (b) are located within
the second container and component (c) is located within or outside
of the second container.
[0284] In another embodiment, the present invention provides a
novel article of manufacture, comprising: (a) a first container;
(b) a pharmaceutical composition located within the first
container, wherein the composition, comprises: a first therapeutic
agent, comprising: a compound of the present invention; and (c) a
package insert stating that the pharmaceutical composition can be
used in combination with a second therapeutic agent to treat a
thrombotic or thromboembolic disorder.
[0285] In another preferred embodiment, the present invention
provides a novel article of manufacture, further comprising: (d) a
second container; wherein components (a) and (b) are located within
the second container and component (c) is located within or outside
of the second container.
[0286] The present invention may be embodied in other specific
forms without departing from the spirit or essential attributes
thereof. This invention encompasses all combinations of preferred
aspects of the invention noted herein. It is understood that any
and all embodiments of the present invention may be taken in
conjunction with any other embodiment or embodiments to describe
additional more preferred embodiments. It is also to be understood
that each individual element of the preferred embodiments is its
own independent preferred embodiment. Furthermore, any element of
an embodiment is meant to be combined with any and all other
elements from any embodiment to describe an additional
embodiment.
DEFINITIONS
[0287] The compounds herein described may have asymmetric centers.
Compounds of the present invention containing an asymmetrically
substituted atom may be isolated in optically active or racemic
forms. It is well known in the art how to prepare optically active
forms, such as by resolution of racemic forms or by synthesis using
optically active starting materials or optically active catalysts.
Geometric isomers of double bonds such as olefins and C.dbd.N
double bonds can also be present in the compounds described herein,
and all such stable isomers are contemplated in the present
invention. Cis and trans geometric isomers of the compounds of the
present invention are described and may be isolated as a mixture of
isomers or as separated isomeric forms. All chiral (enantiomeric
and diastereomeric), racemic forms and all geometric isomeric forms
of a structure are intended, unless the specific stereochemistry or
isomeric form is specifically indicated. When no specific mention
is made of the configuration (cis, trans or R or S) of a compound
(or of an asymmetric carbon), then any one of the isomers or a
mixture of more than one isomer is intended. The processes for
preparation can use racemates, enantiomers, or diastereomers as
starting materials. All processes used to prepare compounds of the
present invention and intermediates made therein are considered to
be part of the present invention. When enantiomeric or
diastereomeric products are prepared, they can be separated by
conventional methods, for example, by chromatography or fractional
crystallization. Compounds of the present invention, and salts
thereof, may exist in multiple tautomeric forms, in which hydrogen
atoms are transposed to other parts of the molecules and the
chemical bonds between the atoms of the molecules are consequently
rearranged. It should be understood that all tautomeric forms,
insofar as they may exist, are included within the invention. The
inventive compounds may be in the free or hydrate form.
[0288] Preferably, the molecular weight of compounds of the present
invention is less than about 500, 550, 600, 650, 700, 750, or 800
grams per mole. Preferably, the molecular weight is less than about
800 grams per mole. More preferably, the molecular weight is less
than about 700 grams per mole. Even more preferably, the molecular
weight is less than about 600 grams per mole.
[0289] The term "substituted," as used herein, means that any one
or more hydrogens on the designated atom is replaced with a
selection from the indicated group, provided that the designated
atom's normal valency is not exceeded, and that the substitution
results in a stable compound. When a substituent is keto (i.e.,
.dbd.O), then 2 hydrogens on the atom are replaced. When a ring
system (e.g., carbocyclic or heterocyclic) is said to be
substituted with a carbonyl group or a double bond, it is intended
that the carbon atom of the carbonyl group or one carbon atom of
the double bond be part of (i.e., within) the ring. Ring double
bonds, as used herein, are double bonds that are formed between two
adjacent ring atoms (e.g., C.dbd.C, C.dbd.N, or N.dbd.N).
[0290] In cases wherein there are nitrogen atoms (e.g., amines) on
compounds of the present invention, these may be converted to
N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or
hydrogen peroxides) to afford other compounds of this invention.
Thus, shown and claimed nitrogen atoms are considered to cover both
the shown nitrogen and its N-oxide (N.fwdarw.O) derivative. In
cases wherein there are quarternary carbon atoms on compounds of
the present invention, these can be replaced by silicon atoms,
provided they do not form Si--N or Si--O bond.
[0291] When any variable occurs more than one time in any
constituent or formula for a compound, its definition at each
occurrence is independent of its definition at every other
occurrence. Thus, for example, if a group is shown to be
substituted with 0-3 R.sup.e, then said group may optionally be
substituted with up to three R.sup.e groups and R.sup.e at each
occurrence is selected independently from the definition of
R.sup.e.
[0292] When a bond to a substituent is shown to cross a bond
connecting two atoms in a ring, then such substituent may be bonded
to any atom on the ring. When a substituent is listed without
indicating the atom via which such substituent is bonded to the
rest of the compound of a given formula, then such substituent may
be bonded via any atom in such substituent. Combinations of
substituents and/or variables are permissible only if such
combinations result in stable compounds.
[0293] As used herein, "alkyl" or "alkylene" is intended to include
both branched and straight-chain saturated aliphatic hydrocarbon
groups having the specified number of carbon atoms. For example,
"C.sub.1-10 alkyl" (or alkylene), is intended to include C.sub.1,
C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8,
C.sub.9, and C.sub.10 alkyl groups. Additionally, for example,
"C.sub.1-6 alkyl" denotes alkyl having 1 to 6 carbon atoms. Alkyl
groups can be unsubstituted or substituted so that one or more of
its hydrogens are replaced by another chemical group. Examples of
alkyl include, but are not limited to, methyl (Me), ethyl (Et),
n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl,
n-hexyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl,
3-methylpentyl, 4-methylpentyl, and the like.
[0294] "Alkenyl" or "alkenylene" is intended to include hydrocarbon
chains of either a straight or branched configuration having the
specified number of carbon atoms and one or more unsaturated
carbon-carbon bonds which may occur in any stable point along the
chain. For example, "C.sub.2-6 alkenyl" (or alkenylene), is
intended to include C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6
alkenyl groups. Examples of alkenyl include, but are not limited
to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl,
2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl,
4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and
the like.
[0295] "Alkynyl" or "alkynylene" is intended to include hydrocarbon
chains of either a straight or branched configuration and one or
more carbon-carbon triple bonds which may occur in any stable point
along the chain. For example, "C.sub.2-6 alkynyl" (or alkynylene),
is intended to include C.sub.2, C.sub.3, C.sub.4, C.sub.5, and
C.sub.6 alkynyl groups; such as ethynyl, propynyl, butynyl,
pentynyl, hexynyl and the like.
[0296] The term "cycloalkyl" refers to cyclized alkyl groups,
including mono-, bi- or poly-cyclic ring systems. C.sub.3-7
cycloalkyl is intended to include C.sub.3, C.sub.4, C.sub.5,
C.sub.6, and C.sub.7 cycloalkyl groups. Example cycloalkyl groups
include, but are not limited to, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, norbornyl, and the like. Branched
cycloalkyl groups such as 1-methylcyclopropyl and
2-methylcyclopropyl are included in the definition of
"cycloalkyl".
[0297] "Alkoxy" or "alkyloxy" represents an alkyl group as defined
above with the indicated number of carbon atoms attached through an
oxygen bridge. For example, "C.sub.1-6 alkoxy" (or alkyloxy), is
intended to include C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6 alkoxy groups. Examples of alkoxy include, but are not
limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,
s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Similarly,
"alkylthio" or "thioalkoxy" represents an alkyl group as defined
above with the indicated number of carbon atoms attached through a
sulphur bridge; for example methyl-S--, ethyl-S--, and the
like.
[0298] "Halo" or "halogen" as used herein refers to fluoro, chloro,
bromo, and iodo; and "counterion" is used to represent a small,
negatively charged species such as chloride, bromide, hydroxide,
acetate, sulfate, and the like.
[0299] "Haloalkyl" is intended to include both branched and
straight-chain saturated aliphatic hydrocarbon groups having the
specified number of carbon atoms, substituted with 1 or more
halogen. Examples of haloalkyl include, but are not limited to,
fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl,
pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl,
heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl
also include "fluoroalkyl" which is intended to include both
branched and straight-chain saturated aliphatic hydrocarbon groups
having the specified number of carbon atoms, substituted with 1 or
more fluorine atoms.
[0300] "Haloalkoxy" or "haloalkyloxy" represents a haloalkyl group
as defined above with the indicated number of carbon atoms attached
through an oxygen bridge. For example, "C.sub.1-C.sub.6
haloalkoxy", is intended to include C.sub.1, C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6 haloalkoxy groups. Examples of
haloalkoxy include, but are not limited to, trifluoromethoxy,
2,2,2-trifluoroethoxy, pentafluorothoxy, and the like. Similarly,
"haloalkylthio" or "thiohaloalkoxy" represents a haloalkyl group as
defined above with the indicated number of carbon atoms attached
through a sulphur bridge; for example trifluoromethyl-S--,
pentafluoroethyl-S--, and the like.
[0301] As used herein, "carbocycle" is intended to mean any stable
3, 4, 5, 6, 7, or 8-membered monocyclic or bicyclic or 7, 8, 9, 10,
11, 12, or 13-membered bicyclic or tricyclic ring system consisting
of carbon atoms, any of which may be saturated, partially
unsaturated, or aromatic. Examples of such carbocycles include, but
are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,
[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane
(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl,
indanyl, adamantyl, or tetrahydronaphthyl (tetralin). Preferred
carbocycles, unless otherwise specified, are cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl.
[0302] As used herein, the term "bicyclic carbocycle" or "bicyclic
carbocyclic group" is intended to mean a stable 9 or 10-membered
carbocyclic ring system which contains two fused rings and consists
of carbon atoms. Of the two fused rings, one ring is a benzo ring
fused to a second ring; and the second ring is a 5 or 6 membered
carbon ring which is saturated, partially unsaturated, or
unsaturated. The bicyclic carbocyclic group may be attached to its
pendant group at any carbon atom which results in a stable
structure. The bicyclic carbocyclic group described herein may be
substituted on any carbon if the resulting compound is stable.
Examples of a bicyclic carbocyclic group are, but not limited to,
naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and
indanyl. When the term "carbocycle" is used, it is intended to
include "aryl".
[0303] "Aryl" groups refer to monocyclic or polycyclic aromatic
hydrocarbons, including, for example, phenyl, naphthyl,
phenanthranyl, and the like. Aryl moieties are well known and
described, for example, in Hawley's Condensed Chemical Dictionary
(13 ed.), R. J. Lewis, ed., J. Wiley & Sons, Inc., New York
(1997). Aryl groups can be substituted or unsubstituted.
[0304] As used herein, the term "heterocycle" or "heterocyclic
group" is intended to mean a stable 5, 6, or 7-membered monocyclic
or polycyclic or 7, 8, 9, 10, 11, 12, 13, or 14-membered polycyclic
heterocyclic ring which is saturated, partially unsaturated or
fully unsaturated, and which consists of carbon atoms and 1, 2, 3
or 4 heteroatoms independently selected from the group consisting
of N, O and S; and including any polycyclic group in which any of
the above-defined heterocyclic rings is fused to a benzene ring.
The nitrogen and sulfur heteroatoms may optionally be oxidized to
--NO--, --SO--, or --SO.sub.2--. The heterocyclic ring may be
attached to its pendant group at any heteroatom or carbon atom
which results in a stable structure. The heterocyclic rings
described herein may be substituted on carbon or on a nitrogen atom
if the resulting compound is stable. If specifically noted, a
nitrogen in the heterocycle may optionally be quaternized. It is
preferred that when the total number of S and O atoms in the
heterocycle exceeds 1, then these heteroatoms are not adjacent to
one another. It is preferred that the total number of S and O atoms
in the heterocycle is not more than 1. When the term "heterocycle"
is used, it is intended to include "heteroaryl".
[0305] Examples of heterocycles include, but are not limited to,
2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,
4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl,
6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,
benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl,
4aH-carbazolyl, .alpha.-carbolinyl, chromanyl, chromenyl,
cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,
dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, imidazolopyridinyl,
1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl,
isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl,
isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,
isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl,
oxazolidinylperimidinyl, oxindolyl, phenanthridinyl,
phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl,
phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,
piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,
purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,
pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazole,
pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,
pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,
tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,
thianthrenyl, thiazolyl, thiazolopyridinyl, thienyl,
thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,
triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,
1,3,4-triazolyl, and xanthenyl.
[0306] Preferred 5 to 10 membered heterocycles include, but are not
limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,
pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl,
indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl,
oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl,
thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl,
1H-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl,
benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl,
benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl,
isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl,
isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl,
imidazolopyridinyl, and pyrazolopyridinyl.
[0307] Preferred 5 to 6 membered heterocycles include, but are not
limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,
pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl,
indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl,
oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl,
thiadiazolyl, thiazolyl, triazinyl, and triazolyl. Also included
are fused ring and spiro compounds containing, for example, the
above heterocycles.
[0308] As used herein, the term "bicyclic heterocycle" or "bicyclic
heterocyclic group" is intended to mean a stable 9 or 10-membered
heterocyclic ring system which contains two fused rings and
consists of carbon atoms and 1, 2, 3, or 4 heteroatoms
independently selected from the group consisting of N, O and S. Of
the two fused rings, one ring is a 5 or 6-membered monocyclic
aromatic ring comprising a 5 membered heteroaryl ring, a 6-membered
heteroaryl ring or a benzo ring, each fused to a second ring. The
second ring is a 5 or 6 membered monocyclic ring which is
saturated, partially unsaturated, or unsaturated, and comprises a 5
membered heterocycle, a 6 membered heterocycle or a carbocycle
(provided the first ring is not benzo when the second ring is a
carbocycle).
[0309] The bicyclic heterocyclic group may be attached to its
pendant group at any heteroatom or carbon atom which results in a
stable structure. The bicyclic heterocyclic group described herein
may be substituted on carbon or on a nitrogen atom if the resulting
compound is stable. It is preferred that when the total number of S
and O atoms in the heterocycle exceeds 1, then these heteroatoms
are not adjacent to one another. It is preferred that the total
number of S and O atoms in the heterocycle is not more than 1.
[0310] Examples of a bicyclic heterocyclic group are, but not
limited to, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl,
indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,
1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,
5,6,7,8-tetrahydro-quinoline, 2,3-dihydro-benzofuranyl, chromanyl,
1,2,3,4-tetrahydro-quinoxaline, and
1,2,3,4-tetrahydro-quinazoline.
[0311] As used herein, the term "aromatic heterocyclic group" or
"heteroaryl" is intended to mean a stable monocyclic and polycyclic
aromatic hydrocarbons that include at least one heteroatom ring
member such as sulfur, oxygen, or nitrogen. Preferred heteroaryl
groups are stable 5, 6, or 7-membered monocyclic or 7, 8, 9, or
10-membered bicyclic heterocyclic aromatic rings which consists of
carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected
from the group consisting of N, NH, O and S. It is to be noted that
total number of S and O atoms in the aromatic heterocycle is not
more than 1. Heteroaryl groups include, without limitation,
pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl,
quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,
pyrryl, oxazolyl, oxadiazolyl, benzofuryl, benzothienyl,
benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl
indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl,
carbazolyl, benzimidazolyl, 2,3-dihydrobenzofuranyl,
2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-5-oxide,
2,3-dihydrobenzothienyl-5-dioxide, benzoxazolin-2-on-yl, indolinyl,
benzodioxolanyl, benzodioxane, and the like. Heteroaryl groups can
be substituted or unsubstituted.
[0312] Also included are fused ring and spiro compounds containing,
for example, the above carbocycles or heterocycles.
[0313] Bridged rings are also included in the definition of
carbocycle or heterocycle. A bridged ring occurs when one or more
atoms (i.e., C, O, N, or S) link two non-adjacent carbon or
nitrogen atoms. Preferred bridges include, but are not limited to,
one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen
atoms, and a carbon-nitrogen group. It is noted that a bridge
always converts a monocyclic ring into a tricyclic ring. When a
ring is bridged, the substituents recited for the ring may also be
present on the bridge.
[0314] When a dotted ring is used within a ring structure, this
indicates that the ring structure may be saturated, partially
saturated or unsaturated.
[0315] The term "counterion" is used to represent a small,
negatively charged species such as chloride, bromide, hydroxide,
acetate, and sulfate.
[0316] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0317] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound
is modified by making acid or base salts thereof. Examples of
pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic groups such as amines; and
alkali or organic salts of acidic groups such as carboxylic acids.
The pharmaceutically acceptable salts include the conventional
non-toxic salts or the quaternary ammonium salts of the parent
compound formed, for example, from non-toxic inorganic or organic
acids. For example, such conventional non-toxic salts include those
derived from inorganic acids such as hydrochloric, hydrobromic,
sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared
from organic acids such as acetic, propionic, succinic, glycolic,
stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the
like.
[0318] The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound which
contains a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or
base forms of these compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a
mixture of the two; generally, nonaqueous media like ether, ethyl
acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists
of suitable salts are found in Remington's Pharmaceutical Sciences,
18th ed., Mack Publishing Company, Easton, Pa., 1990, the
disclosure of which is hereby incorporated by reference.
[0319] Isotopically labeled compounds of the present invention,
i.e., wherein one or more of the atoms described are replaced by an
isotope of that atom (e.g., C replaced by .sup.13C or by .sup.14C;
and isotopes of hydrogen include tritium and deuterium), are also
provided herein. Such compounds have a variety of potential uses,
e.g., as standards and reagents in determining the ability of a
potential pharmaceutical to bind to target proteins or receptors,
or for imaging compounds of this invention bound to biological
receptors in vivo or in vitro.
[0320] Compounds of the present invention are, subsequent to their
preparation, preferably isolated and purified to obtain a
composition containing an amount by weight equal to or greater than
98%, preferably 99%, compound of the present invention
("substantially pure"), which is then used or formulated as
described herein. Such "substantially pure" compounds are also
contemplated herein as part of the present invention.
[0321] "Stable compound" and "stable structure" are meant to
indicate a compound that is sufficiently robust to survive
isolation to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent. It is preferred
that compounds of the present invention do not contain a N-halo,
S(O).sub.2H, or S(O)H group.
[0322] In addition, compounds of formula I may have prodrug forms.
Any compound that will be converted in vivo to provide the
bioactive agent (i.e., a compound of formula I) is a prodrug within
the scope and spirit of the invention. Various forms of prodrugs
are well known in the art. For examples of such prodrug
derivatives, see: [0323] a) Design of Prodrugs, edited by H.
Bundgaard, (Elsevier, 1985), and Methods in Enzymology, Vol. 42, at
pp. 309-396, edited by K. Widder, et. al. (Academic Press, 1985);
[0324] b) A Textbook of Drug Design and Development, edited by
Krosgaard-Larsen and H. Bundgaard, Chapter 5, "Design and
Application of Prodrugs," by H. Bundgaard, at pp. 113-191 (1991);
[0325] c) H. Bundgaard, Advanced Drug Delivery Reviews, Vol. 8, p.
1-38 (1992); [0326] d) H. Bundgaard, et al., Journal of
Pharmaceutical Sciences, Vol. 77, p. 285 (1988); and [0327] e) N.
Kakeya, et. al., Chem Phar Bull., Vol. 32, p. 692 (1984).
[0328] Preparation of prodrugs is well known in the art and
described in, for example, Medicinal Chemistry: Principles and
Practice, ed. F. D. King, The Royal Society of Chemistry,
Cambridge, UK, 1994, which is incorporated herein by reference in
its entirety.
[0329] Compounds containing a carboxy group can form
physiologically hydrolyzable esters which serve as prodrugs by
being hydrolyzed in the body to yield formula I compounds per se.
Such prodrugs are preferably administered orally since hydrolysis
in many instances occurs principally under the influence of the
digestive enzymes. Parenteral administration may be used where the
ester per se is active, or in those instances where hydrolysis
occurs in the blood. Examples of physiologically hydrolyzable
esters of compounds of formula I include C.sub.1-6 alkyl,
C.sub.1-6alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,
methoxymethyl, C.sub.1-6 alkanoyloxy-C.sub.1-6alkyl, e.g.
acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl,
C.sub.1-16alkoxycarbonyloxy-C.sub.1-16alkyl, e.g.
methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl,
glycyloxymethyl, phenylglycyloxymethyl,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl and other well known
physiologically hydrolyzable esters used, for example, in the
penicillin and cephalosporin arts. Such esters may be prepared by
conventional techniques known in the art.
[0330] The term "solvate" means a physical association of a
compound of this invention with one or more solvent molecules,
whether organic or inorganic. This physical association includes
hydrogen bonding. In certain instances the solvate will be capable
of isolation, for example when one or more solvent molecules are
incorporated in the crystal lattice of the crystalline solid.
"Solvate" encompasses both solution-phase and isolable solvates.
Exemplary solvates include hydrates, ethanolates, methanolates,
isopropanolates and the like. Methods of solvation are generally
known in the art.
[0331] As used herein, the term "patient" or "host" encompasses all
mammalian species.
[0332] As used herein, "treating" or "treatment" cover the
treatment of a disease-state in a mammal, particularly in a human,
and include: (a) preventing the disease-state from occurring in a
mammal, in particular, when such mammal is predisposed to the
disease-state but has not yet been diagnosed as having it; (b)
inhibiting the disease-state, i.e., arresting it development;
and/or (c) relieving the disease-state, i.e., causing regression of
the disease state.
[0333] "Therapeutically effective amount" is intended to include an
amount of a compound of the present invention that is effective
when administered alone or in combination with other active
ingredients to inhibit factor VIIa or to treat the disorders listed
herein. When applied to a combination, the term refers to combined
amounts of the active ingredients that result in the therapeutic
effect, whether administered in combination, serially or
simultaneously. The combination of compounds is preferably a
synergistic combination. Synergy, as described, for example, by
Chou and Talalay, Adv. Enzyme Regul. 1984, 22:27-55, occurs when
the effect (in this case, anticoagulant effect) of the compounds
when administered in combination is greater than the additive
effect of the compounds when administered alone as a single agent.
In general, a synergistic effect is most clearly demonstrated at
sub-optimal concentrations of the compounds. Synergy can be in
terms of lower cytotoxicity, increased antithrombotic effect, or
some other beneficial effect of the combination compared with the
individual components.
[0334] The term "pharmaceutical composition" means a composition
comprising a compound of the invention in combination with at least
one additional pharmaceutical carrier. A "pharmaceutically
acceptable carrier" refers to media generally accepted in the art
for the delivery of biologically active agents to animals, in
particular, mammals, including, i.e., adjuvant, excipient or
vehicle, such as diluents, preserving agents, fillers, flow
regulating agents, disintegrating agents, wetting agents,
emulsifying agents, suspending agents, sweetening agents, flavoring
agents, perfuming agents, antibacterial agents, antifungal agents,
lubricating agents and dispensing agents, depending on the nature
of the mode of administration and dosage forms. Pharmaceutically
acceptable carriers are formulated according to a number of factors
well within the purview of those of ordinary skill in the art.
These include, without limitation: the type and nature of the
active agent being formulated; the subject to which the
agent-containing composition is to be administered; the intended
route of administration of the composition; and, the therapeutic
indication being targeted. Pharmaceutically acceptable carriers
include both aqueous and non-aqueous liquid media, as well as a
variety of solid and semi-solid dosage forms. Such carriers can
include a number of different ingredients and additives in addition
to the active agent, such additional ingredients being included in
the formulation for a variety of reasons, e.g., stabilization of
the active agent, binders, etc., well known to those of ordinary
skill in the art. Descriptions of suitable pharmaceutically
acceptable carriers, and factors involved in their selection, are
found in a variety of readily available sources such as, for
example, Remington's Pharmaceutical Sciences, 17th ed., 1990, which
is incorporated herein by reference in its entirety.
[0335] Abbreviations used in the Examples are defined as follows:
"1.times." for once, "2.times." for twice, "3.times." for thrice,
".degree. C." for degrees Celsius, "eq" for equivalent or
equivalents, "g" for gram or grams, "mg" for milligram or
milligrams, "L" for liter or liters, "mL" for milliliter or
milliliters, ".mu.L" for microliter or microliters, "M" for molar,
"mmol" for millimole or millimoles, "min" for minute or minutes,
"h" for hour or hours, "rt" for room temperature, "atm" for
atmosphere, "psi" for pounds per square inch, "RT" for retention
time, "sat" or "sat'd" for saturated, "MW" for molecular weight,
"MS" for mass spectrometry, "ESI" for electrospray ionization mass
spectroscopy, "HR" for high resolution, "LC-MS" for liquid
chromatography mass spectrometry, "HPLC" for high pressure liquid
chromatography, "NMR" for nuclear magnetic resonance spectroscopy,
".sup.1H" for proton, ".delta." for delta, "s" for singlet, "d" for
doublet, "t" for triplet, "q" for quartet, "m" for multiplet, "br"
for broad, "Hz" for hertz, "tlc" or "TLC" for thin layer
chromatography, and ".alpha.", ".beta.", "R", "S", "E", and "Z" are
stereochemical designations familiar to one skilled in the art.
[0336] ACN is acetonitrile, [0337] AcOH or HOAc is acetic acid,
[0338] AIBN is azo-bis-isobutyrlnitrile, [0339] 9-BBN is
9-borabicyclo[3.3.1]nonane, [0340] BINAP is
2,2'-bis(diphenylphosphino)-1,1'-binaphthalene, [0341] Bn is
benzyl, [0342] Boc is tert-butyl oxycarbonyl, [0343] BOM is
benzyloxymethyl, [0344] BOP is
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate, [0345] Bu is butyl, [0346] iBu or i-Bu is
isobutyl, [0347] t-Bu is tert-butyl, [0348] Cbz is
carbonylbenzyloxy, [0349] DCE is 1,2-dichloroethane, [0350] DCM or
CH.sub.2Cl.sub.2 is dichloromethane, [0351] DIBAH is
diisobutylaluminum hydride, [0352] DIC is
1,3-diisopropylcarbodiimide, [0353] DIEA is diethylpropyl amine,
[0354] DMAP is dimethylaminopyridine, [0355] DME is dimethyl ether,
[0356] DMF is dimethylformamide, [0357] DMPU is
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, [0358] DMSO is
dimethyl sulfoxide, [0359] DPPA is diphenylphosphoryl azide, [0360]
EDCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride, [0361] Et is ethyl, [0362] EtOH is ethanol, [0363]
EtOAc is ethyl acetate, [0364] Et.sub.2O is diethyl ether [0365]
HEPES is 4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid, [0366]
HOAt or HOAT is 1-hydroxy-7-azabenzotriazole, [0367] HOBt is
1-hydroxybenzotriaole hydrate [0368] LAH is lithium aluminum
hydride [0369] LDA is lithium diisopropylamide, [0370] LiHMDS is
bis(trimethylsilyl)amide, [0371] mCPBA or MCPBA is
meta-chloroperbenzoic acid, [0372] Me is methyl, [0373] MeOH is
methanol, [0374] MsCl is methanesulfonyl chloride, [0375] NaHMDS is
sodium hexamethyldisilazane, [0376] NaOAc is sodium actetate,
[0377] NBS is N-bromosuccinimide, [0378] OAc is acetate, [0379]
Pd.sub.2(dba).sub.3 is tris(dibenzylideneacetone)dipalladium(0),
[0380] Pd(PPh.sub.3).sub.4 is tetraks (triphenylphosphine)
palladium, [0381] Ph is phenyl, [0382] PMDTA is
N,N,N',N',N''-pentamethyldiethylenetriamine, [0383] Pr is propyl,
[0384] PyBOP is benzotriazol-1-yl-oxytripyrrolidinophosphonium
hexafluorophosphate, [0385] iPr or i-Pr is isopropyl, [0386] i-PrOH
or IPA is isopropanol, [0387] TBAF is tetrabutylammoniumfluoride,
[0388] TBAI is tetrabutylammonium iodide, [0389] TBS is
tert-butyldimethylsilyl, [0390] TBSCl is tert-butyldimethylsilyl
chloride, [0391] TEA is triethylamine, [0392] TFA is
trifluoroacetic acid, [0393] TFAA is trifluoroacetic anhydride,
[0394] THF is tetrahydrofuran, [0395] TrCl is trityl chloride,
[0396] TRIS is tris(hydroxymethyl)aminomethane, [0397] Tr is
trityl, [0398] Xantphos is
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
Synthesis
[0399] The compounds of the present invention can be prepared in a
number of ways known to one skilled in the art of organic
synthesis. The compounds of the present invention can be
synthesized using the methods described below, together with
synthetic methods known in the art of synthetic organic chemistry,
or by variations thereon as appreciated by those skilled in the
art. Preferred methods include, but are not limited to, those
described below. The reactions are performed in a solvent
appropriate to the reagents and materials employed and suitable for
the transformations being effected. It will be understood by those
skilled in the art of organic synthesis that the functionality
present on the molecule should be consistent with the
transformations proposed. This will sometimes require a judgment to
modify the order of the synthetic steps or to select one particular
process scheme over another in order to obtain a desired compound
of the invention.
[0400] A particularly useful compendium of synthetic methods which
may be applicable to the preparation of compounds of the present
invention may be found in Larock, R. C. Comprehensive Organic
Transformations, VCH: New York, 1989. It will also be recognized
that another major consideration in the planning of any synthetic
route in this field is the judicious choice of the protecting group
used for protection of the reactive functional groups present in
the compounds described in this invention. An authoritative account
describing the many alternatives to the trained practitioner is
Greene and Wuts (Protective Groups In Organic Synthesis,
Wiley-Interscience, 3nd Edition, 1999). All references cited herein
are hereby incorporated in their entirety herein by reference.
[0401] Compounds having the general Formula (I) can be prepared
according to the general methods shown in the schemes below.
Compounds of formula (I) where Z=NH can be prepared using the
general method shown in Scheme 1. Using the Petasis boronic acid
Mannich reaction (Petasis, N. A., Zavialov, I. A. J. Am. Chem. Soc.
1997, 119, 445-446; Petasis, N. A., Goodman, A., Zavialov, I. A.
Tetrahedron 1997, 53, 16463-16470.), amines 1 are reacted with
glyoxylic acid and phenyl boronic acids 2 to afford arylglycines 3.
This reaction is typically conducted in a solvent such as, but not
limited to, toluene, dichloromethane, 1,2-dichloroethane, methanol,
ethanol, dimethylformamide, or acetonitrile, or appropriate
mixtures thereof. In some cases, mixtures of acetonitrile and
dimethylformamide are preferred. Fluorinated alcohols such as
hexafluoroisopropanol are useful additives that may improve the
rate and or yield of the reaction. If necessary, the reaction is
heated conventionally or in a microwave reactor to achieve a
practical reaction rate.
[0402] The preparation of amines 1 is described below in Scheme 7
and in the experimental procedures for Intermediate 1.
Additionally, preparation of primary amines is well known in the
art of organic synthesis and many primary amines are commercially
available. Preparation of phenylboronic acids 2, which contain a
protected benzylamine (PG=protecting group) is described in the
synthesis of Examples 6, 8, 9, 10, and 11 and in Schemes 8 and 9.
Additionally, preparation of phenylboronic acids 2 can be achieved
through methods known to one skilled in the art of organic
synthesis. The protecting group PG in 2 may be, for instance, a
carbamate such as Boc or Cbz, or as in Examples 6, 8, 9, 10, and
11, the entire PGNR.sup.5CR.sup.6R.sup.7 group may be a nitrile,
which may be deprotected by catalytic hydrogenation to an
unsubstituted benzylamine. The protecting group is removed under
appropriate conditions from arylglycines 3 to provide amino acids
4. Amino acids 4 can be cyclized to macrocycles 5 under conditions
suitable for forming an amide bond between the acid and the amine.
Coupling reagents and conditions can be found in Bodanszky,
"Principles of Peptide Synthesis, Second Edition" Springer Verlag
Ed, Berlin (1993) and in a recent review (Montalbetti, C. A. G. N.,
Falque, V. Tetrahedron 2005, 61, 10819-11046). Coupling reagents
include, but not limited to, CDI, DIC, and EDCI. Optionally, an
intermediate activated ester can be prepared by adding one
equivalent of 1-hydroxybenzotriazole or
1-hydroxy-7-azabenzotriazole. Other coupling reagents include, but
not limited to, BOP or HATU, which are usually reacted in the
presence of a tertiary base such as DIEA or TEA. BOP is a preferred
reagent for preparation of compounds of Formula (I). Addition of
catalytic or stoichiometric DMAP may improve the reaction rate or
yield. The reaction may be conducted in solvents such as, but not
limited to, DCE, DCM, DMF, or mixtures thereof. Finally, it may be
necessary to run the macrocyclization reaction under dilute
conditions (initial concentration of 4<0.1 M) to favor
macrocyclization over dimerization. Depending on the particular
substituent groups present in the final compounds, deprotection
steps may be required before or after the macrocyclization step to
afford compounds of Formula (I).
##STR00020##
[0403] An alternative to the Petasis chemistry, enabling the
synthesis of compounds of Formula (I) where Z is either NH or O is
shown in Scheme 2. This scheme shows an explicit subset of L and M
groups, but the chemistry shown can be readily modified by one
skilled in the art to prepare compounds containing other
combinations of L and M. Starting aldehydes 6 are commercially
available or can be readily prepared by methods known to one
skilled in the art of organic synthesis. The aldehydes are
converted to the cyanohydrins 7 by treatment, for instance, with
potassium cyanide and sodium hydrogensulfite in a mixture of EtOAc
and water. The cyanohydrins are reacted with hydrogen chloride in
methanol, and the intermediate imidates are hydrolyzed to afford
methyl esters 8. The hydroxyl group in 8 is converted to a leaving
group (LG) such as halogen or sulfonate. Chloride and triflate are
preferred LGs for this reaction. Nucleophiles W-ZH are reacted with
9 in a solvent such as DCM or DMF and in presence of a base such as
2,6-lutidine, TEA, or DIEA to afford 10. The protecting group in 10
is removed and 11, containing nucleophilic groups YH is reacted
with phenyl carbamates 12, or their synthetic equivalent isocyanate
or carbamoyl halide to give 13. The methyl ester in 13 is
hydrolyzed and the nitrogen protecting group (PG) is removed to
give amino acids 14. Subsequent cyclization as described in Scheme
1 affords macrocycles 15.
##STR00021## ##STR00022##
[0404] Alternatively to Schemes 1 and 2, as exemplified in Scheme
3, aldehydes 6 can be condensed with trimethylsilylcyanide in
presence of ammonia to give aminonitriles 16. Treatment of 16 with
hydrogen chloride in MeOH, followed by hydrolysis on aqueous workup
gives amino esters 17. Amino esters 17 may be coupled with aryl or
heteroaryl halides or sulfonates W-LG by methods known in the art.
For example, amino esters 17 may be coupled to W-LG in the presence
of a palladium catalyst, an appropriate ligand, for example, BINAP,
using a base such as cesium carbonate to provide esters 18. Esters
18 are a subset of esters 10 in Scheme 2, and can be converted to
compounds of Formula (I) using the subsequent methods described in
Scheme 2.
##STR00023##
[0405] Another alternative for the introduction of the Z group is
shown in Scheme 4. Hydroxy esters 8 are oxidized to keto esters 19,
using, for instance, Swern conditions or MnO.sub.2. Subsequent
reductive amination with primary amines W--NH.sub.2, using, for
instance, sodium cyanoborohydride or sodium triacetoxyborohydride
in a solvent such as DCM or acetonitrile, affords amino esters 18.
As indicated in Schemes 2 and 3, compounds 18 may be converted to
compounds of Formula (I).
##STR00024##
[0406] An important group of synthetic approaches to compounds of
Formula (I) are those based on olefin metathesis, as shown in
Schemes 5 and 6. For reviews of olefin metathesis, see: Trnka, T.
M., Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29, and Connon, S.
J., Blechert, S. Ang. Chem., Int. Ed. 2003, 42, 1900-1923. Scheme 5
shows a cross methathesis strategy, where allyl (m=1) or vinyl
(m=0) derivatives 20 are coupled to vinylacetamide (q=1) or
acrylamide (q=0) derivatives 21 using an olefin methathesis
catalyst, for instance, the Grubb's second generation ruthenium
catalyst (Cl.sub.2(PCy.sub.3)(IMes)Ru.dbd.CHPh). Hydrolysis of the
ester and removal of the amine protecting group affords amino acids
23. Subsequent amide coupling as described in Scheme 1 affords
macrocycles 24. The double bond may be reduced by catalytic
hydrogenation to afford macrocycles 25 with a saturated L
group.
##STR00025## ##STR00026##
[0407] Scheme 6 shows a ring closing methathesis approach, in which
compounds 20 and 21 are first independently deprotected to afford
acids 26 and amines 27. The amine and acid are coupled as described
in Scheme 1. Subsequent ring closing methasis of amide 28 using,
for instance, the Grubb's second generation ruthenium catalyst
(Cl.sub.2(PCy.sub.3)(IMes)Ru.dbd.CHPh), affords macrocycles 24,
which may be hydrogenated as described in Scheme 5.
##STR00027##
[0408] The synthesis of an appropriately protected (di-Boc)
intermediate W-ZH for W=1-aminoisoquinolin-6-yl and Z=NH is
described in the Example section below as Intermediate 1.
4-(N-Boc-aminomethyl)aniline, an appropriately protected
intermediate W--NH.sub.2 for W=4-aminomethylphenyl and Z=NH is
commercially available. 3-Aminobenzamide, an intermediate
W--NH.sub.2 for W=3-carbamoylphenyl and Z=NH is also commercially
available. tert-Butyl (4-aminophenyl)(imino)-methylcarbamate, an
appropriately protected intermediate W--NH.sub.2 for
W=4-amidinophenyl and Z=NH is commercially available. Compounds
containing W=1-aminophthalazin-6-yl and Z=NH can be prepared using
the methods shown in Scheme 3. Synthesis of an appropriately
protected intermediate W-LG is shown below in Scheme 7.
4-Bromobenzoic acid 29 is converted to the acid chloride and
reacted with diethylamine. The resulting diethylbenzamide 30 is
formylated by treatment with lithium tetramethylpiperidide at
-78.degree. C., followed by quenching with DMF. Subsequent
cyclization in refluxing hydrochloric acid provides the
hydroxyphthalide 31. The hydroxyphthalide 31 is refluxed with
hydrazine in ethanol to afford 6-bromophthalazin-1(2H)-one 32.
Treatment with phosphorous oxychloride gives
6-bromo-1-chlorophthalazine 33, which is converted to
1-amino-6-bromophthalazine 34 by reaction with ammonia saturated
ethylene glycol at 130.degree. C. The amine is protected by
reaction with di-tert-butyl dicarbonate and 4-dimethylaminopyridine
in acetonitrile. The resulting bromide 35 can then by coupled to a
phenylglycine ester 17 as described in Scheme 3.
##STR00028##
[0409] Synthesis of benzylamine intermediates for preparation of
compounds of Formula (I) is shown in Schemes 8 and 9. Scheme 8
shows the preparation of benzylamine intermediates where R.sup.5=H.
Nitro fluoride 36 may be treated with thiols to afford sulfides 37.
Compounds 37 can be oxidized with mCPBA to sulfones 38. Subsequent
catalytic hydrogenation affords anilines 39, which are useful
intermediates in the synthesis of macrocycles where M=--CONH-- and
--SO.sub.2NH--. Alternatively, iron/acetic acid reduction of 37 to
aniline 40, followed by borane reduction gives benzylamine 41.
Subsequent protection, for instance, with Cbz-Cl and base, gives
intermediates 42, which are also useful for the synthesis of
macrocycles where M=--CONH-- and --SO.sub.2NH--. Oxidation of the
sulfide to the sulfone can be achieved at a later stage in the
synthesis using mCPBA. Methods for coupling these benzylamine
intermediates to A ring intermediates to afford key intermediates 2
are given in the Examples.
##STR00029##
[0410] Synthesis of benzylamine intermediates with R.sup.5
substituents other than H can be achieved as shown in Scheme 9.
Nitro fluoride 43 may be treated with thiols to afford sulfides.
The acid can then be converted to methyl amides 44 through the acid
chloride. Subsequent reductions with iron/acetic acid and borane
give benzyl amines 46. These may be protected, for instance as the
Cbz derivatives 47, which are useful intermediates in the synthesis
of macrocycles where M=--CONH-- and --SO.sub.2NH--. Oxidation of
the sulfide to the sulfone can be achieved at a later stage in the
synthesis using mCPBA.
##STR00030##
[0411] Scheme 10 depicts an alternate approach to compounds where
Y=O and M=--CONH--; ring closure is accomplished via carbamate
formation. Compounds 48 (prepared according to the Schemes 1-4) are
deprotected (PG' protecting group) to afford acids 49, which in
turn are coupled with amines 50 to afford amides 51. Following
amide bond formation, a second protecting group removal (PG''
protecting group) and the nitro functional group reduction
(reducing conditions, such as H.sub.2, Pd--C or Fe, AcOH) afford
amino alcohols 52. Treatment of these intermediates with phosgene
(or a phosgene equivalent such as triphosgene) to generate the
carbamic chloride intermediate in situ, followed by slow addition
of this intermediate into a basic reaction mixture, such as
triethylamine or Hunig's base in DCM or acetonitrile, effects
macrocyclization to yield compounds 53.
##STR00031##
[0412] The compounds of the instant invention herein described may
have asymmetric centers. For example, the chiral carbon atom in
Formula (I) (indicated with an asterisk below) exists either in the
S or R configuration. Thus, the stereoisomeric configurations of
each compound of Formula (I) are considered part of the invention.
In a preferred stereoisomeric embodiment, the present invention
provides for the R configuration at the indicated chiral carbon for
all embodiments of Formula (I), or tautomers, pharmaceutically
acceptable salts, solvates, or prodrug forms thereof.
##STR00032##
EXAMPLES
[0413] The following Examples have been prepared, isolated and
characterized using the methods disclosed herein. The following
Examples demonstrate a partial scope of the invention and are not
meant to be limiting of the scope of the invention.
[0414] In the following experimental procedures, solution ratios
express a volume relationship, unless stated otherwise. NMR
chemical shifts (.delta.) are reported in parts per million. Flash
chromatography (see Still, W. C. et al. J. Org. Chem. 1978, 43,
2923, for a description of the method). was carried out on ISCO
CombiFlash.TM. systems using prepacked SiO.sub.2 cartridges and
eluting with gradients of the specified solvents. Reverse phase
high pressure liquid chromatography (HPLC) was carried out on C18
HPLC columns using methanol/water gradients containing 0.1%
trifluoroacetic acid.
Intermediate 1:
6-Amino-1-(di-tert-butoxycarbonylamino)isoquinoline
##STR00033##
[0415] Intermediate 1A:
(E)-2-(2-(Dimethylamino)vinyl)-4-nitrobenzonitrile
##STR00034##
[0417] A mixture of 2-methyl-4-nitrobenzonitrile (5.0 g, 31 mmol)
and tert-butoxybis(dimethylamino)methane (12.2 mL, 59 mmol) in dry
DMF (8 mL) was stirred at 70.degree. C. for 2 h under N.sub.2.
After cooling to rt, DMF was removed in vacuo and the crude product
was triturated with hexanes/EtOAc (5:1). The solid was collected by
filtration and washed with hexane to give Intermediate 1A (6.5 g,
97%) as black solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.97
(s, 6H), 5.36 (d, J=13.2 Hz, 1H), 7.16 (d, J=13.6 Hz, 1H), 7.52 (d,
J=8.8 Hz, 1H), 7.60 (m, 1H), 8.11 (d, J=1.8 Hz, 1H).
Intermediate 1B:
2-(2,4-Dimethoxybenzyl)-6-nitroisoquinolin-1(2H)-imine
##STR00035##
[0419] Intermediate 1A (4.6 g, 21.2 mmol) and
2,4-dimethoxylbenzylamine (4.0 mL, 1.25 eq) in DMPU (10 mL) was
heated at 140.degree. C. for 3 h. The solvent was removed by vacuum
distillation and residue treated with hexanes/EtOAc (1:1). The
solid was collected by filtration and washed with hexane to give
Intermediate 1B (4.6 g, 64%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 3.72 (s, 3H), 3.81 (s, 3H), 4.96 (s, 1H), 6.28 (d, J=6.6
Hz, 1H), 6.46 (d, J=7.5 Hz, 1H), 6.58 (d, J=1.8 Hz, 1H), 7.03 (d,
J=8.8 Hz, 1H), 7.27 (d, J=6.2 Hz, 1H), 8.02 (dd, J=9.0, 2.4 Hz,
1H), 8.31 (d, J=2.2 Hz, 1H), 8.43 (d, J=8.4 Hz, 1H).
Intermediate 1C: 6-Nitroisoquinolin-1-amine
##STR00036##
[0421] To a solution of Intermediate 1B (11.9 g, 35 mmol) in
anisole (24 mL) was added TFA (24 mL). The reaction mixture was
stirred at 90.degree. C. for 6 h and the solvent was removed under
reduced pressure. The residue was suspended in MeOH (50 mL) and
then treated with NaHCO.sub.3 (3.3 g, 39 mmol) in water (200 mL).
The mixture was stirred at rt for 15 min and the pH was checked to
be 9-10. The precipitate was collected by filtration and washed
with water to afford Intermediate 1C (6.0 g, 91%). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 7.20 (d, J=5.7 Hz, 1H), 7.36 (s, 2H),
7.95 (d, J=5.7 Hz, 1H), 8.15 (dd, J=9.2, 2.6 Hz, 1H), 8.43 (d,
J=9.2 Hz, 1H), 8.67 (d, J=2.6 Hz, 1H).
Intermediate 1D:
6-Nitro-1-di-tert-butoxycarbonylaminoisoquinoline
##STR00037##
[0423] A solution of Intermediate 1C (25.0 g, 0.132 mol),
di-tert-butyl dicarbonate (63.4 g, 0.29 mol) and DMAP (750 mg,
catalyst) in DMPU (125 mL) was stirred at 70.degree. C. for 30 min.
The reaction was quenched with water (300 mL). The reaction mixture
was diluted with ethyl acetate (500 mL) and washed with water. The
organic layer was separated and the solvent removed under vacuum.
The residue was recrystallized from methanol to give Intermediate
1D (54.0 g, 95.0%) as a solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 1.33 (s, 18H), 7.86 (d, J=5.3 Hz, 1H), 8.15 (d, J=9.2 Hz,
1H), 8.39 (dd, J=9.2, 2.20 Hz, 1H), 8.6 (d, J=5.7 Hz, 1H), 8.82 (d,
J=2.2 Hz, 1H). MS (ESI) m/z 801 (2M+Na).sup.+.
Intermediate 1
[0424] A solution of Intermediate 1D (75.0 g, 0.193 mol) in
methanol/THF (500 mL/500 mL) was hydrogenated with a hydrogen
balloon in the presence of Pd/C (5%, 5 g) for 2.0 h. Filtration of
the Pd/C and concentration gave a solid, which was recrystallized
from methanol to give Intermediate 1 as a white solid (65.7 g,
95.0%). .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 1.33 (m, 18H),
4.18 (s, 2H), 6.89 (d, J=2.2 Hz, 1H), 6.99 (dd, J=9.0, 2.4 Hz, 1H),
7.35 (d, J=6.6 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 8.22 (d, J=5.7 Hz,
1H). MS (ESI) m/z 741 (2M+Na).sup.+.
Example 1
2-(1-Amino-isoquinolin-6-ylamino)-16-oxa-4,11-diaza-tricyclo[15.2.2.1.sup.-
6,10]docosa-1(20),6,8,10(22),17(21),18-hexaene-3,12-dione
trifluoroacetic acid salt
##STR00038##
[0425] 1A: 4-(4-Boronophenoxy)-butyric acid
##STR00039##
[0427] A resealable tube was charged with 4-(4-bromophenoxy)butyric
acid (259 mg, 1.0 mmol),
5,5,5',5'-Tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] (249 mg, 1.1
mmol), potassium acetate (245 mg, 2.5 mmol), and DMSO (2 mL). The
resulting orange suspension was deoxygenated by sparging with
nitrogen gas.
Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloromethane adduct (30 mg, 0.041 mmol) was added, and the tube
was sealed tightly and heated at 80.degree. C. overnight.
Hydrochloric acid (1N) was added, and the mixture was extracted
with EtOAc (2.times.), washed with water (2.times.) and brine
(1.times.), and dried (MgSO.sub.4). The organic layer was
concentrated in vacuo and the residue purified by flash
chromatography (0 to 15% MeOH in DCM) to give the
2,2-dimethyl-1,3-propanediol boronic ester of 1A. This material was
dissolved in diethyl ether and washed with NaOH (2 N, 2.times.).
The aqueous layers were washed with diethyl ether, combined, and
acidified to pH 4 with hydrochloric acid (6 N). The resulting solid
precipitate was collected by filtration to afford 1A (210 mg, 94%)
as a beige solid. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 2.06
(m, 2H), 2.48 (t, J=7.5 Hz, 2H), 4.02 (t, J=6.6 Hz, 2H), 6.88 (br
s, 2H), 7.62 (br d, 2H).
1B: 4-(3-Benzyloxycarbonyl-propoxy)-phenylboronic acid
##STR00040##
[0429] A solution of 1A (200 mg, 0.89 mmol), potassium bicarbonate
(313 mg, 3.1 mmol), and benzyl bromide (0.163 mL, 1.4 mmol) in DMF
(2 mL) was heated at 60.degree. C. for 8 h. The reaction mixture
was concentrated in vacuo and the residue was partitioned between
EtOAc and hydrochloric acid (1 N). The aqueous layer was extracted
with EtOAc (2.times.) and then the combined organics were washed
with water (3.times.) and brine, dried (MgSO.sub.4), and
concentrated in vacuo. The residue was purified by flash
chromatography (30 to 100% EtOAc in hexane) to afford 1B (86 mg,
28%) as a white solid. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
2.08 (m, 2H), 2.56 (t, J=7.0 Hz, 2H), 4.00 (m, 2H), 5.12 (s, 2H),
6.84 (2.times.d, 2H), 7.32 (m, 5H), 7.7-7.5 (2.times.d, 2H).
1C:
4-{4-[(1-Di-tert-butoxycarbonylamino-isoquinolin-6-ylamino)-carboxy-me-
thyl]-phenoxy}-butyric acid benzyl ester
##STR00041##
[0431] A solution of 1B (82 mg, 0.26 mmol), Intermediate 1 (72 mg,
0.20 mmol), and glyoxylic acid monohydrate (22 mg, 0.24 mmol) in
DCE (1 mL) was heated at 100.degree. C. for 10 min in a microwave
reactor. This solution was purified by flash chromatography (0 to
15% MeOH in DCM) to give 1C contaminated with 1B (110 mg, 2.5:1
1C/1B, 68% yield based on content of 1C) as a yellow oil. MS (ESI)
m/z 686.3 (M+H).sup.+.
1D:
4-{4-[(1-Di-tert-butoxycarbonylamino-isoquinolin-6-ylamino)-(3-nitro-b-
enzylcarbamoyl)-methyl]-phenoxy}-butyric acid benzyl ester
##STR00042##
[0433] A solution of 1C (110 mg, 0.16 mmol), 3-nitrobenzylamine
hydrochloride (36 mg, 0.19 mmol), DIEA (0.084 mL, 0.48 mmol), HOAt
(22 mg, 0.16 mmol), and EDCI (62 mg, 0.32 mmol) in a mixture of DCM
(2 mL) and DMF (0.5 mL) was stirred at rt overnight. The reaction
mixture was concentrated in vacuo and the residue was triturated
with water and then purified by flash chromatography (0 to 10% MeOH
in DCM) to give 1D (88 mg, 67%). MS (ESI) m/z 820.3
(M+H).sup.+.
1E:
4-{4-[(3-Amino-benzylcarbamoyl)-(1-di-tert-butoxycarbonylamino-isoquin-
olin-6-ylamino)-methyl]-phenoxy}-butyric acid
##STR00043##
[0435] A solution of 1D (88 mg, 0.11 mmol) in MeOH was hydrogenated
(55 psi) over 10% palladium on carbon (36 mg) for three h. The
reaction mixture was filtered and concentrated in vacuo to give 1E
(73 mg, 97%) as a yellow glass. MS (ESI) m/z 700.3 (M+H).sup.+.
1F:
2-(1-Di-tert-butoxycarbonylamino-isoquinolin-6-ylamino)-16-oxa-4,11-di-
aza-tricyclo[15.2.2.1.sup.6,10]docosa-1(20),6,8,10(22),17(21),18-hexaene-3-
,12-dione
##STR00044##
[0437] A solution of 1E (63 mg, 0.090 mmol), DIEA (0.047 mL, 0.27
mmol), HOAt (12 mg, 0.088 mmol), and EDCI (35 mg, 0.18 mmol) in a
mixture of DCM (10 mL) and DMF (0.5 mL) was stirred at rt
overnight. The reaction mixture was concentrated in vacuo and the
residue was purified by reverse phase HPLC to give 1F. MS (ESI) m/z
682.3 (M+H).sup.+.
Example 1
[0438] A solution of 1F (entire amount from previous step+product
from 2 mg and 4 mg scale pilot reactions) in EtOAc (0.5 mL) and
hydrogen chloride in dioxane (1 mL, 4N) was stirred at rt for 3 h.
The reaction mixture was concentrated in vacuo and the residue was
purified by reverse phase HPLC to give Example 1 (15 mg, 26%) as a
white solid. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 2.03-2.19
(m, 2H), 2.44-2.58 (m, 2H), 3.95 (dd, J=15.38, 3.52 Hz, 1H),
4.03-4.19 (m, 2H), 4.73 (dd, J=15.38, 8.35 Hz, 1H), 5.09 (s, 1H),
5.50 (s, 1H), 6.70 (s, 1H), 6.82 (d, J=7.03 Hz, 1H), 6.93 (d,
J=8.35 Hz, 3H), 7.10-7.20 (m, 3H), 7.29 (d, J=7.03 Hz, 1H), 7.46
(d, J=7.03 Hz, 2H), 7.52 (d, J=7.47 Hz, 1H), 8.05 (d, J=9.23 Hz,
1H), 8.49 (dd, J=7.91, 3.95 Hz, 1H). MS (ESI) m/z 482.3
(M+H).sup.+.
Example 2
2-(1-Amino-isoquinolin-6-ylamino)-4,11-diaza-tricyclo[14.2.2.1.sup.6,10]he-
nicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
trifluoroacetic acid salt
##STR00045##
[0439] 2A:
4-[4-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-phenyl]-butyric
acid
##STR00046##
[0441] A resealable tube was charged with 4-bromophenyl butyric
acid (729 mg, 3.1 mmol),
5,5,5',5'-Tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] (746 mg, 3.3
mmol), potassium acetate (736 mg, 7.5 mmol), and DMSO (4 mL). The
resulting orange suspension was deoxygenated by sparging with
nitrogen gas.
Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloromethane adduct (66 mg, 0.090 mmol) was added, and the tube
was sealed tightly and heated at 80.degree. C. overnight.
Hydrochloric acid (1N) was added, and the mixture was extracted
with EtOAc (2.times.), washed with water (2.times.) and brine
(1.times.), and dried (MgSO.sub.4). The organic layer was
concentrated in vacuo and the residue purified by flash
chromatography (0 to 15% MeOH in DCM) to afford 2A (626 mg, 76%) as
an off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.02
(s, 6H), 1.97 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 2.68 (t, J=7.7 Hz,
2H), 3.76 (s, 4H), 7.18 (d, J=7.9 Hz, 2H), 7.72 (d, J=7.5 Hz,
2H).
2B: 4-(4-Boronophenyl)-butyric acid
##STR00047##
[0443] 2A (343 mg, 1.24 mmol) was added to a mixture of diethyl
ether (10 mL) and NaOH (2 mL, 2 N). The reaction mixture was
stirred at rt for 10 min. The ether layer was separated and then
treated with an additional portion of NaOH for 5 min. The combined
aqueous layers were washed with diethyl ether (2.times.) and
acidified to pH 4 with hydrochloric acid (6 N). The resulting solid
precipitate was collected by filtration to afford 2B contaminated
with 2A (212 mg, 1:1 2B/2A, 43% yield based on content of 2B) as a
beige solid.
2C: 4-(3-Benzyloxycarbonyl-propyl)-phenylboronic acid
##STR00048##
[0445] Using a procedure analogous to that used to prepare 1B, 2B
(212 mg, 1:1 mixture of 2B and 2A) was reacted with benzyl bromide
to afford 2C (90 mg, 69%) as a white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.92 (m, 2H), 2.33 (t, J=7.0 Hz, 2H), 2.62 (t,
2H), 5.08 (s, 2H), 7.11 (d, 2H), 7.25-7.35 (m, 5H), 7.69 (d,
2H).
2D:
4-{4-[(1-Di-tert-butoxycarbonylamino-isoquinolin-6-ylamino)-carboxy-me-
thyl]-phenyl}-butyric acid benzyl ester
##STR00049##
[0447] A solution of 2C (179 mg, 0.60 mmol), Intermediate 1 (179
mg, 0.50 mmol), and glyoxylic acid monohydrate (55 mg, 0.60 mmol)
in acetonitrile (2 mL) and DMF (0.2 mL) was heated at 100.degree.
C. for 10 min in a microwave reactor. The reaction was repeated
twice more on the same scale, and the pooled reaction mixtures were
concentrated in vacuo, triturated with water, and then purified by
flash chromatography (0 to 15% MeOH in DCM) to give 2D (630 mg,
52%) as an orange foam. MS (ESI) m/z 670.4 (M+H).sup.+.
2E:
4-{4-[(1-Di-tert-butoxycarbonylamino-isoquinolin-6-ylamino)-(3-nitro-b-
enzylcarbamoyl)-methyl]-phenyl}-butyric acid benzyl ester
##STR00050##
[0449] Using a procedure analogous to that used to prepare 1D, 2D
(59 mg, 0.089 mmol) was reacted with 3-nitrobenzylamine
hydrochloride to give 2E (56 mg, 80%) as a clear oil. MS (ESI) m/z
804.3 (M+H).sup.+.
2F:
4-{4-[(3-Amino-benzylcarbamoyl)-(1-di-tert-butoxycarbonylamino-isoquin-
olin-6-ylamino)-methyl]-phenyl}-butyric acid
##STR00051##
[0451] Using a procedure analogous to that used to prepare 1E, 2E
(56 mg, 0.070 mmol) was hydrogenated to give 2F (41 mg, 85%) as a
clear glass. MS (ESI) m/z 684.3 (M+H).sup.+.
2G:
2-(1-Di-tert-butoxycarbonylamino-isoquinolin-6-ylamino)-4,11-diaza-tri-
cyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-d-
ione
##STR00052##
[0453] Using a procedure analogous to that used to prepare 1F, 2F
(41 mg) was cyclized to give 2G (11 mg, 24%) as a yellow oil. MS
(ESI) m/z 666.4 (M+H).sup.+.
Example 2
[0454] A solution of 2G (11 mg, 0.016 mmol) was dissolved in 50%
TFA/DCM and stirred for 30 min at rt. The solvent was evaporated
under a stream of nitrogen and the residue was purified by reverse
phase HPLC to give Example 2 (5.3 mg, 57%) as a white solid.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 2.07-2.19 (m, 1H),
2.25-2.42 (m, 3H), 2.61-2.72 (m, 1H), 2.82-2.94 (m, 1H), 4.04 (dd,
J=15.82, 4.39 Hz, 1H), 4.70 (dd, J=16.04, 7.69 Hz, 1H), 5.15 (s,
1H), 6.01 (s, 1H), 6.68 (d, J=2.20 Hz, 1H), 6.72 (d, J=7.91 Hz,
1H), 6.83 (d, J=7.03 Hz, 1H), 6.94 (d, J=7.91 Hz, 1H), 7.11-7.26
(m, 4H), 7.29 (d, J=7.03 Hz, 1H), 7.37 (d, J=7.91 Hz, 1H), 7.58 (d,
J=7.91 Hz, 1H), 8.05 (d, J=9.23 Hz, 1H), 8.72 (dd, J=7.25, 4.61 Hz,
1H). MS (ESI) m/z 466.4 (M+H).sup.+.
Example 3
(R)-2-(1-Amino-isoquinolin-6-ylamino)-4,11-diaza-tricyclo[14.2.2.1.sup.6,1-
0]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
##STR00053##
[0456] A solution of Example 2 (156 mg, 0.269 mmol) in methanol (6
mL) was purified by chiral HPLC in two injections of 2.0 mL each.
The chromatography conditions were the following: Chiralcel OD
column (5 cm ID.times.50 cm L, 20.mu., Chiral Technologies, Inc.),
30% (1:1 ethanol/methanol)/70% heptane as eluent, 50 mL/min flow
rate, and uv detection at 254 nm. The product fractions were
combined with product fractions from an additional separation of
Example 2 (46 mg, free base, 0.099 mmol) to give Example 3 (peak 1,
36 mg, 28%), peak 2 (24 mg, 18%), and a mixture of peaks 1 and 2
(28.5 mg, 22%). Peak 1 analytical data: .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 2.07-2.20 (m, 1H), 2.24-2.44 (m, 3H), 2.60-2.74
(m, 1H), 2.79-2.93 (m, 1H), 4.06 (d, J=16.26 Hz, 1H), 4.63 (d,
J=16.26 Hz, 1H), 5.07 (s, 1H), 6.00 (s, 1H), 6.55 (d, J=2.20 Hz,
1H), 6.66 (d, J=6.15 Hz, 1H), 6.71 (d, J=7.91 Hz, 1H), 6.93 (d,
J=7.47 Hz, 1H), 7.01 (dd, J=9.01, 2.42 Hz, 1H), 7.15 (t, J=7.69 Hz,
1H), 7.15-7.22 (m, 1H), 7.24-7.31 (m, 1H), 7.34 (dd, J=7.69, 1.54
Hz, 1H), 7.50 (d, J=6.15 Hz, 1H), 7.55 (dd, J=7.91, 1.76 Hz, 1H),
7.80 (d, J=9.23 Hz, 1H). MS (ESI) m/z 466.4 (M+H).sup.+. Chiral
analytical HPLC retention times: peak 1, 6.45 min; peak 2, 7.75 min
using the following chromatography conditions: Chiralcel OD column
(4.6 mm ID.times.250 mm L, Chiral Technologies, Inc.), 30% (1:1
ethanol/methanol)/70% heptane as eluent, 1 mL/min flow rate, and uv
detection at 254 nm.
Example 4
2-(1-Amino-isoquinolin-6-ylamino)-4,11-diaza-tricyclo[13.2.2.1.sup.6,10]ic-
osa-1(18),6,8,10(20),15(19),16-hexaene-3,12-dione trifluoroacetic
acid salt
##STR00054##
[0457] 4A: 4-(3-(Benzyloxy)-3-oxopropyl)phenylboronic acid
##STR00055##
[0459] Using a procedure analogous to that used to prepare 1B,
3-(4-boronophenyl)propanoic acid (388 mg, 2.00 mmol) was reacted
with benzyl bromide to afford 4A (355 mg, 62%) as a white solid.
.sup.1H NMR (400 MHz, tetrahydrofuran-d.sub.8) .delta. 2.71 (t,
J=7.9 Hz, 2H), 3.02 (t, J=7.5 Hz, 2H), 5.10 (s, 2H), 7.25-7.35 (m,
5H), 8.12 (d, J=7.9 Hz, 2H).
4B:
2-(1-Di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(4-(3-(benzyl-
oxy)-3-oxopropyl)phenyl)acetic acid
##STR00056##
[0461] Using a procedure analogous to that used to prepare 2D, 4A
(110 mg, 0.387 mmol) was reacted with Intermediate 1 (179 mg, 0.50
mmol), and glyoxylic acid monohydrate (55 mg, 0.60 mmol) to afford
4B (200 mg, 79%) as a yellow solid. MS (ESI) m/z 656.4
(M+H).sup.+.
4C: Benzyl
3-(4-(2-(3-nitrobenzylamino)-1-(1-di-tert-butoxycarbonylaminois-
oquinolin-6-ylamino)-2-oxoethyl)phenyl)propanoate
##STR00057##
[0463] Using a procedure analogous to that used to prepare 1D, 4B
(131 mg, 0.200 mmol) was reacted with 3-nitrobenzylamine
hydrochloride to give 4C (84 mg, 53%) as a clear oil. MS (ESI) m/z
790.5 (M+H).sup.+.
4D:
3-(4-(2-(3-Aminobenzylamino)-1-(1-di-tert-butoxycarbonylaminoisoquinol-
in-6-ylamino)-2-oxoethyl)phenyl)propanoic acid
##STR00058##
[0465] Using a procedure analogous to that used to prepare 1E, 4C
(84 mg, 0.11 mmol) was hydrogenated to give 4D (66 mg, 93%). MS
(ESI) m/z 670.4 (M+H).sup.+.
Example 4
[0466] A solution of 4D (32 mg, 0.048 mmol), DIEA (0.030 mL, 0.17
mmol), HOAt (8 mg, 0.06 mmol), and EDCI (19 mg, 0.099 mmol) in a
mixture of DCM (10 mL) and DMF (0.4 mL) was stirred at rt
overnight. The reaction mixture was concentrated in vacuo and the
residue was purified by reverse phase HPLC (MS (ESI) m/z 652.4
(M+H).sup.+). The residue was dissolved in 50% TFA/DCM (1 mL) and
stirred for 1 h at rt. The solvent was evaporated under a stream of
nitrogen and the residue was purified by reverse phase HPLC to give
Example 4 (4 mg, 15%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
2.60 (t, J=7.03 Hz, 2H), 2.88-3.08 (m, 2H), 3.95 (dd, J=15.82, 3.95
Hz, 1H), 4.77 (dd, J=15.38, 8.79 Hz, 1H), 5.15 (s, 1H), 6.70 (s,
1H), 6.84 (d, J=7.03 Hz, 1H), 6.97 (d, J=7.47 Hz, 1H), 7.08-7.20
(m, 3H), 7.22-7.33 (m, 3H), 7.48 (dd, J=7.91, 1.76 Hz, 1H), 7.53
(d, J=7.91 Hz, 1H), 8.09 (d, J=9.23 Hz, 1H), 8.61 (dd, J=8.35, 3.95
Hz, 1H). MS (ESI) m/z 452.4 (M+H).sup.+.
Example 5
2-(1-Amino-isoquinolin-6-ylamino)-4,11-diaza-tricyclo[15.2.2.1.sup.6,10]do-
cosa-1(20),6,8,10(22),17(21),18-hexaene-3,12-dione trifluoroacetic
acid salt
##STR00059##
[0467] 5A:
5-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)pentanoic
acid
##STR00060##
[0469] Using a procedure analogous to that used to prepare 2A,
5-(4-bromophenyl)pentanoic acid (537 mg, 2.09 mmol) was reacted
with 5,5,5',5'-Tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to
afford 5A (429 mg, 71%) as a white solid. .sup.1H NMR (400 MHz,
tetrahydrofuran-d.sub.8) .delta. 0.99 (s, 6H), 1.55-1.70 (m, 4H),
2.24 (t, J=7.5 Hz, 2H), 2.61 (t, J=7.0 Hz, 2H), 3.73 (s, 4H), 7.12
(d, J=7.9 Hz, 2H), 7.65 (d, J=7.9 Hz, 2H).
5B: 5-(4-boronophenyl)pentanoic acid
##STR00061##
[0471] Using a procedure analogous to that used to prepare 2B, 5A
(429 mg, 1.48 mmol) was reacted with NaOH to afford 5B (250 mg,
76%) as an off-white solid.
5C: 4-(5-(benzyloxy)-5-oxopentyl)phenylboronic acid
##STR00062##
[0473] Using a procedure analogous to that used to prepare 1B, 5B
(250 mg, 1.13 mmol) was reacted with benzyl bromide to afford 5C
(226 mg, 79%) as a clear oil.
5D:
2-(1-Di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(4-(5-(benzyl-
oxy)-5-oxopentyl)phenyl)acetic acid
##STR00063##
[0475] Using a procedure analogous to that used to prepare 2D, 5C
(187 mg, 0.599 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 5D (297 mg, 87%) as an orange solid. MS
(ESI) m/z 684.4 (M+H).sup.+.
5E: Benzyl
5-(4-(2-(3-nitrobenzylamino)-1-(1-di-tert-butoxycarbonylaminois-
oquinolin-6-ylamino)-2-oxoethyl)phenyl)pentanoate
##STR00064##
[0477] A solution of 5D (204 mg, 0.299 mmol), 3-nitrobenzylamine
hydrochloride (68 mg, 0.36 mmol), DIEA (0.16 mL, 0.92 mmol), and
BOP (159 mg, 0.360 mmol) in DMF (several mL) was stirred at rt
overnight. The reaction mixture was concentrated in vacuo and the
residue was triturated with water and then purified by flash
chromatography (0 to 30% MeOH in DCM) to give 5E (220 mg, 90%) as a
yellow foam. MS (ESI) m/z 818.4 (M+H).sup.+.
5F:
5-(4-(2-(3-Aminobenzylamino)-1-(1-di-tert-butoxycarbonylaminoisoquinol-
in-6-ylamino)-2-oxoethyl)phenyl)pentanoic acid
##STR00065##
[0479] Using a procedure analogous to that used to prepare 1E, 5E
(220 mg, 0.269 mmol) was hydrogenated to give 5F (151 mg, 80%) as a
yellow glass. MS (ESI) m/z 698.4 (M+H).sup.+.
Example 5
[0480] Using a procedure analogous to that used to prepare Example
4, 5F (150 mg, 0.215 mmol) was cyclized and deprotected to give
Example 5 (13 mg, 10%) as a white amorphous solid. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 1.50-1.79 (m, 4H), 2.15-2.35 (m, 2H),
2.47-2.70 (m, 2H), 4.07 (dd, J=15.16, 4.61 Hz, 1H), 4.72 (dd,
J=15.16, 7.69 Hz, 1H), 5.12 (s, 1H), 6.00 (s, 1H), 6.65 (s, 1H),
6.81 (d, J=7.03 Hz, 1H), 6.94 (d, J=7.47 Hz, 1H), 7.10-7.22 (m,
4H), 7.29 (d, J=7.03 Hz, 1H), 7.47 (d, J=7.91 Hz, 3H), 8.05 (d,
J=9.23 Hz, 1H), 8.88 (dd, J=7.69, 4.61 Hz, 1H). MS (ESI) m/z 480.4
(M+H).sup.+.
Example 6
2-(1-Amino-isoquinolin-6-ylamino)-7-ethanesulfonyl-4,11-diaza-tricyclo[14.-
2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
trifluoroacetic acid salt
##STR00066##
[0481] 6A: 2-(Ethylsulfonyl)-5-nitrobenzonitrile
##STR00067##
[0483] Ethanethiol (2.8 mL, 38 mmol) was added to a solution of
2-fluoro-5-nitrobenzonitrile (5.00 g, 30.1 mmol) and triethylamine
(9.3 mL, 67 mmol) in DMF (100 mL). The reaction mixture was stirred
for 1 h and then poured into water (500 mL). The resulting
precipitate was isolated by filtration, dissolved in DCM, washed
with water and brine, dried (MgSO.sub.4), and concentrated under
reduced pressure. The residue (6.14 g) was dissolved in DCM (100
mL), cooled to 0.degree. C., and treated with MCPBA (16.0 g, 71
mmol) in one portion. The reaction mixture was allowed to stir at
rt overnight, and then was extracted with sodium bicarbonate
solution (saturated), sodium bisulfite solution (10%), and brine.
The organic layer was dried (MgSO.sub.4) and concentrated under
reduced pressure to afford 6A (5.6 g, 80%) as a pale yellow solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.02 (s, 6H), 1.97 (m,
2H), 2.36 (t, J=7.5 Hz, 2H), 2.68 (t, J=7.7 Hz, 2H), 3.76 (s, 4H),
7.18 (d, J=7.9 Hz, 2H), 7.72 (d, J=7.5 Hz, 2H).
6B: 5-Amino-2-(ethylsulfonyl)benzonitrile
##STR00068##
[0485] A solution of 6A (0.554 g, 2.31 mmol) in MeOH (60 mL) was
hydrogenated (60 psi) over 10% palladium on carbon (99 mg) for 3 h
at rt. The reaction mixture was filtered and concentrated under
reduced pressure to give 6B (464 mg, 96%) as an off-white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.30 (t, J=7.25 Hz, 3H),
3.30 (q, J=7.47 Hz, 2H), 4.62 (s, 2H), 6.89 (dd, J=8.79, 2.64 Hz,
1H), 7.04 (d, J=2.20 Hz, 1H), 7.83 (d, J=8.79 Hz, 1H).
6C:
4-(4-Bromophenyl)-N-(3-cyano-4-(ethylsulfonyl)phenyl)butanamide
##STR00069##
[0487] Oxalyl chloride (0.175 mL, 2.0 mmol) was added slowly
dropwise to a solution of 4-(4-bromophenyl)butyric acid (243 mg,
1.0 mmol) in DCM (3 mL) and DMF (2 drops). The reaction was stirred
for 1 h at rt and then concentrated under reduced pressure. The
residue was coevaporated with toluene and then chloroform to give
the acid chloride as a crude brown oil. A solution of the crude
acid chloride (197 mg, 0.75 mmol) and 6B (106 mg, 0.50 mmol) in DCM
(1 mL) was treated with triethylamine (0.140 mL, 1.0 mmol) and DMAP
(10 mg, 0.08 mmol). The reaction mixture was stirred for 14 h at
rt. DCE (1 mL) was added, and the reaction mixture was heated to
reflux for 30 h. The reaction was cooled to rt, diluted with DCM,
and washed with 1 N HCl, dried (MgSO.sub.4), and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography (EtOAc/hexanes) and then by reverse phase HPLC to
give 6C (83 mg, 38%). MS (ESI) m/z 435.2, 437.2 (M+H).sup.+.
6D:
4-(4-(3-cyano-4-(ethylsulfonyl)phenylamino)-4-oxobutyl)phenylboronic
acid
##STR00070##
[0489] A flask containing 6C (83 mg, 0.19 mmol),
5,5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] (47.6 mg,
0.211 mmol), potassium acetate (83 mg, 0.84 mmol), and
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloromethane adduct (4.4 mg, 0.0060 mmol) was purged with argon.
DMSO (1 mL) was added, and the reaction mixture was degassed with
three cycles of vacuum followed by argon backfill. The reaction
mixture was heated for 2 h at 80.degree. C., cooled to rt, and
diluted with water (100 mL). The aqueous solution was extracted
with diethyl ether (3.times.25 mL), dried (MgSO.sub.4), and
concentrated under reduced pressure. The residue was dissolved in a
mixture of diethyl ether (1 mL), DCM (.about.0.1 mL), and EtOAc
(.about.0.1 mL). Diethanolamine (22 mg, 0.21 mmol) in isopropanol
(0.5 mL) was added, and the reaction mixture was stirred overnight
at rt. The reaction mixture was concentrated, and the residue was
purified by reverse phase HPLC (under the standard acidic
conditions) to give 6D (44 mg, 57%) as a clear oil. MS (ESI) m/z
425.4 (M+CH.sub.3OH--H.sub.2O+H).sup.+.
6E:
2-(1-Di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(4-(4-(3-cyan-
o-4-(ethylsulfonyl)phenylamino)-4-oxobutyl)phenyl)acetic acid
##STR00071##
[0491] Using a procedure analogous to that used to prepare 2D, 6D
(43.6 mg, 0.109 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 6E (42.8 mg, 52%) as a yellow solid. MS
(ESI) m/z 772.3 (M+H).sup.+.
6F:
2-(1-Di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(4-(4-(3-(ami-
nomethyl)-4-(ethylsulfonyl)phenylamino)-4-oxobutyl)phenyl)acetic
acid
##STR00072##
[0493] A solution of 6E (17 mg, 0.022 mmol) in a mixture of
methanol (5 mL) and 1M hydrochloric acid (0.050 mL) was
hydrogenated (60 psi) over 10% palladium on carbon (7 mg) for 17 h.
The reaction mixture was filtered and concentrated under reduced
pressure to give 6F (7.1 mg, 41%) as a yellow solid. MS (ESI) m/z
776.4 (M+H).sup.+.
Example 6
[0494] A solution of 6F (7.1 mg, 0.0092 mmol), DIEA (0.010 mL,
0.057 mmol), and BOP (5.3 mg, 0.012 mmol) in DMF (1.0 mL) was
stirred at rt for 1 h. The reaction mixture was concentrated in
vacuo and purified by reverse phase HPLC. The residue was dissolved
in 50% TFA/DCM (1.5 mL) with 2 drops of water added and stirred for
1.25 h at rt. The solvent was evaporated under a stream of nitrogen
and the residue was purified by reverse phase HPLC to give Example
6 (1.30 mg, 21%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 1.24
(t, J=7.25 Hz, 3H), 2.00-2.15 (m, 1H), 2.28-2.46 (m, 3H), 2.54-2.66
(m, 1H), 2.91-2.97 (m, 1H), 3.32-3.49 (m, 2H), 4.17 (dd, J=16.92,
5.49 Hz, 1H), 5.11 (dd, J=17.36, 6.37 Hz, 1H), 5.18 (s, 1H), 6.68
(dd, J=15.16, 1.54 Hz, 2H), 6.87 (d, J=7.03 Hz, 1H), 6.90 (dd,
J=8.35, 2.20 Hz, 1H), 7.03 (dd, 1H), 7.12 (dd, 1H), 7.16 (dd,
J=9.23, 2.20 Hz, 1H), 7.31 (d, J=7.03 Hz, 1H), 7.38-7.47 (m, 1H),
7.61 (dd, J=7.47, 1.76 Hz, 1H), 7.77 (d, J=8.79 Hz, 1H), 8.04 (d,
J=9.23 Hz, 1H), 8.94 (t, J=5.93 Hz, 1H). MS (ESI) m/z 558.3
(M+H).sup.+.
Example 7
(R)-2-(1-Amino-isoquinolin-6-ylamino)-7-ethanesulfonyl-4,11-diaza-tricyclo-
[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
##STR00073##
[0496] A solution of Example 6 (9 mg, 0.013 mmol) in methanol was
purified by chiral HPLC to give peak 1 (2.6 mg, 34%) and Example 7
(peak 2, 2.4 mg, 32%). The chromatography conditions were the
following: Chiralcel OD-H column (2.5 cm ID.times.25 cm L, Chiral
Technologies, Inc.), 30% (1:1 ethanol/methanol)/70% heptane as
eluent, 15 mL/min flow rate, and uv detection at 254 nm. Peak 2
analytical data: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 1.24 (t,
J=7.51 Hz, 3H), 2.02-2.16 (m, 1H), 2.27-2.48 (m, 3H), 2.55-2.69 (m,
1H), 2.87-3.00 (m, 1H), 3.32-3.47 (m, 2H), 4.21 (d, J=16.84 Hz,
1H), 5.05 (d, J=16.84 Hz, 1H), 5.11 (s, 1H), 6.58 (d, J=2.20 Hz,
1H), 6.64 (d, J=1.46 Hz, 1H), 6.71 (d, J=6.22 Hz, 1H), 6.91 (dd,
J=8.42, 2.20 Hz, 1H), 7.01 (dd, J=8.97, 2.38 Hz, 1H), 7.05-7.16 (m,
2H), 7.40 (d, J=7.69 Hz, 1H), 7.48 (d, J=5.86 Hz, 1H), 7.59 (dd,
J=7.87, 1.65 Hz, 1H), 7.77 (d, J=8.42 Hz, 1H), 7.83 (d, J=9.15 Hz,
1H). MS (ESI) m/z 558.3 (M+H).sup.+. Chiral analytical HPLC
retention times: peak 1, 8.65 min; peak 2, 10.08 min using the
following chromatography conditions: Chiralcel OD column (4.6 mm
ID.times.250 mm L, Chiral Technologies, Inc.), 30% (1:1
ethanol/methanol)/70% heptane as eluent, 1 mL/min flow rate, and uv
detection at 254 nm.
Example 8
2-(1-Amino-isoquinolin-6-ylamino)-7-ethanesulfonyl-20-methyl-4,11-diaza-tr-
icyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12--
dione trifluoroacetic acid salt
##STR00074##
[0497] 8A: 4-(4-Bromo-2-methylphenyl)butanoic acid
##STR00075##
[0499] 9-Borabicyclo[3.3.1]nonane (10 mL, 5 mmol, 0.5N in THF) was
treated with methyl but-3-enoate (0.5 g, 5 mmol) dropwise at rt
under argon. The reaction mixture was stirred for 3 h at rt. A
resealable tube was charged with 5-bromo-2-iodotoluene (1.48 g, 5
mmol), sodium methoxide (853 mg, 15.8 mmol), and
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloromethane adduct (110 mg, 0.15 mmol) in THF (15 mL). After
the hydroboration reaction was complete, it was added to the
resealable tube, and the combined reaction mixture was heated to
70.degree. C. for 4 h, then at rt for several days. The reaction
mixture was diluted with water and extracted with EtOAc (2.times.).
The combined organics were extracted with water and brine, dried
(MgSO.sub.4), and concentrated in vacuo. The residue was purified
by silica gel chromatography (EtOAc/hexane) to give 513 mg of
impure ester. This material was dissolved in THF (3 mL), MeOH (1.5
mL) and 1 M NaOH (3 mL) and heated for 1 h at 80.degree. C. Most of
the solvent was removed in vacuo, 1N HCl (4 mL) was added, and the
mixture was extracted with EtOAc (3.times.). The combined organic
layers were washed with brine, dried (MgSO.sub.4), and concentrated
in vacuo. The residue was purified by reverse phase HPLC to give 8A
(287 mg, 22%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 1.82-1.96 (m, 2H), 2.28 (s, 3H), 2.42 (t, J=7.25 Hz, 2H),
2.57-2.65 (m, 2H), 6.99 (d, J=7.91 Hz, 1H), 7.23-7.26 (m, 1H),
7.27-7.31 (m, 1H).
8B:
4-(4-Bromo-2-methylphenyl)-N-(3-cyano-4-(ethylsulfonyl)phenyl)butanami-
de
##STR00076##
[0501] Oxalyl chloride (0.200 mL, 2.29 mmol) was added dropwise to
a solution of 8A (287 mg, 1.12 mmol) in DCM (4 mL) and DMF (1
drop). The reaction mixture was stirred for 4 h, and then
concentrated in vacuo. The residue was coevaporated with toluene
and then dissolved in toluene (10 mL). 6B (227 mg, 1.08 mmol) was
added, and the reaction mixture was heated to reflux for 2 h. The
reaction mixture was concentrated in vacuo, and the residue was
purified by silica gel chromatography (EtOAc/hexane) to give 6B
(373 mg, 77%) as an off-white solid. MS (ESI) m/z 449.1, 451.1
(M+H).sup.+.
8C:
N-(3-Cyano-4-(ethylsulfonyl)phenyl)-4-(4-(5,5-dimethyl-1,3,2-dioxabori-
nan-2-yl)-2-methylphenyl)butanamide
##STR00077##
[0503] Using a procedure analogous to that used to prepare 2A, 8B
(448 mg, 1.00 mmol) was reacted with
5,5,5',5'-Tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to afford 8C
(425 mg, 88%) as an off-white solid. MS (ESI) m/z 413.1 (M-H).sup.-
for free boronic acid.
8D:
4-(4-(3-cyano-4-(ethylsulfonyl)phenylamino)-4-oxobutyl)-3-methylphenyl-
boronic acid
##STR00078##
[0505] Using a procedure analogous to that used to prepare 2B, 8C
(212 mg, 0.44 mmol) was reacted with NaOH and then purified by
silica gel chromatography (MeOH/DCM) to afford 8D (113 mg, 62%).
.sup.1H NMR (400 MHz, THF-d.sub.8) .delta. 1.21 (t, 3H), 1.94-2.04
(m, 2H), 2.40 (t, J=7.25 Hz, 2H), 2.70 (t, J=7.47 Hz, 2H), 3.31 (q,
J=7.47 Hz, 2H), 7.01 (s, 2H), 7.08 (d, J=7.47 Hz, 1H), 7.53 (d,
J=7.47 Hz, 1H), 7.56 (s, 1H), 7.93 (dd, 1H), 7.99 (d, 1H), 1.00 (d,
J=2.20 Hz, 1H), 9.66 (s, 1H).
8E:
2-(1-Di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(4-(4-(3-cyan-
o-4-(ethylsulfonyl)phenylamino)-4-oxobutyl)-3-methylphenyl)acetic
acid
##STR00079##
[0507] Using a procedure analogous to that used to prepare 2D, 8D
(113 mg, 0.273 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 8E (154 mg, 72%) as an off-white solid.
MS (ESI) m/z 786.3 (M+H).sup.+.
8F: 2-(1-Di-tert-butoxycarbonyl
aminoisoquinolin-6-ylamino)-2-(4-(4-(3-(aminomethyl)-4-(ethylsulfonyl)phe-
nylamino)-4-oxobutyl)-3-methylphenyl)acetic acid
##STR00080##
[0509] Using a procedure analogous to that used to prepare 6F, 8E
(154 mg, 0.196 mmol) was hydrogenated to afford 8F (158 mg, 97%).
MS (ESI) m/z 790.2 (M+H).sup.+.
Example 8
[0510] Using a procedure analogous to that used to prepare Example
6, 8F (158 mg, 0.192 mmol) was cyclized and deprotected to afford
Example 8 (22.6 mg, 17%) as an off-white amorphous solid. NMR and
analytical HPLC are consistent with a 1:1 mixture of atropisomers.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 1.19-1.27 (m, 6H),
1.86-1.98 (m, 2H), 2.12-2.21 (m, 1H), 2.28 (t, J=8.97 Hz, 1H),
2.35-2.49 (m, 4H), 2.65-2.75 (m, 1H), 2.87-2.97 (m, 1H), 3.08-3.19
(m, 2H), 3.34-3.45 (m, 4H), 4.10-4.25 (m, 3H), 5.09 (dd, J=17.03,
5.68 Hz, 1H), 5.13 (s, 1H), 5.14 (s, 1H), 6.64-6.71 (m, 4H),
6.80-6.94 (m, 5H), 6.97 (s, 1H), 7.05 (d, J=7.69 Hz, 1H), 7.09-7.17
(m, 2H), 7.29 (d, J=6.96 Hz, 2H), 7.33-7.38 (m, 1H), 7.41-7.46 (m,
1H), 7.47 (s, 1H), 7.76 (d, J=8.42 Hz, 2H), 8.01 (d, J=4.03 Hz,
1H), 8.02-8.05 (m, 1H), 8.89 (t, J=5.86 Hz, 1H), 8.95 (t, J=6.04
Hz, 1H). MS (ESI) m/z 572.1 (M+H).sup.+.
Example 9
(R)-2-(1-Amino-isoquinolin-6-ylamino)-7-(propane-2-sulfonyl)-4,11-diaza-tr-
icyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12--
dione
##STR00081##
[0511] 9A: 2-(Isopropylsulfonyl)-5-nitrobenzonitrile
##STR00082##
[0513] Using a procedure analogous to that used to prepare 6A,
2-fluoro-5-nitrobenzonitrile (2.50 g, 15.6 mmol) was reacted with
isopropylthiol and oxidized with mCPBA to afford 9A (3.04 g, 91%)
as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.40
(d, J=7.03 Hz, 6H), 3.55-3.76 (m, 1H), 8.38 (d, J=8.35 Hz, 1H),
8.63 (dd, J=8.79, 2.20 Hz, 1H), 8.74 (d, J=2.64 Hz, 1H).
9B: 5-Amino-2-(isopropylsulfonyl)benzonitrile
##STR00083##
[0515] Using a procedure analogous to that used to prepare 6B, 9A
(632 mg, 2.48 mmol) was hydrogenated to give 9B (530 mg, 95%) as a
white solid. MS (ESI) m/z 225.3 (M+H).sup.+.
9C:
4-(4-Bromophenyl)-N-(3-cyano-4-(isopropylsulfonyl)phenyl)butanamide
##STR00084##
[0517] Using a procedure analogous to that used to prepare 8B, 9B
(364 mg, 1.62 mmol) was reacted with 4-(4-bromophenyl)butyric acid
chloride to give 9C (667 mg, 92%). MS (ESI) m/z 449.1, 451.1
(M+H).sup.+.
9D:
N-(3-Cyano-4-(isopropylsulfonyl)phenyl)-4-(4-(5,5-dimethyl-1,3,2-dioxa-
borinan-2-yl)phenyl)butanamide
##STR00085##
[0519] Using a procedure analogous to that used to prepare 2A, 9C
(600 mg, 1.34 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 9D (625
mg, 97%) as a brown foam. MS (ESI) m/z 413.1 (M-H).sup.- for free
boronic acid.
9E:
4-(4-(3-cyano-4-(isopropylsulfonyl)phenylamino)-4-oxobutyl)phenylboron-
ic acid
##STR00086##
[0521] Using a procedure analogous to that used to prepare 2B, 9D
(625 mg, 1.29 mmol) was reacted with NaOH to give 9E (508 mg, 95%)
as a brown foam. MS (ESI) m/z 413.2 (M-H).sup.-.
9F:
2-(1-Di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(4-(4-(3-cyan-
o-4-(isopropylsulfonyl)phenylamino)-4-oxobutyl)phenyl)acetic
acid
##STR00087##
[0523] Using a procedure analogous to that used to prepare 2D, 9E
(100 mg, 0.241 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 9F (74 mg, 47%) as a yellow oil. MS
(ESI) m/z 786.3 (M+H).sup.+.
9G:
2-(1-Di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(4-(4-(3-(ami-
nomethyl)-4-(isopropylsulfonyl)phenylamino)-4-oxobutyl)phenyl)acetic
acid
##STR00088##
[0525] Using a procedure analogous to that used to prepare 6F, 9F
(71 mg, 0.090 mmol) was hydrogenated for 48 h to give 9G (98 mg,
100%) as a yellow glass. MS (ESI) m/z 790.3 (M+H).sup.+.
9H:
2-(1-Amino-isoquinolin-6-ylamino)-7-(propane-2-sulfonyl)-4,11-diaza-tr-
icyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12--
dione trifluoroacetic acid salt
##STR00089##
[0527] Using a procedure analogous to that used to prepare Example
6, 9G (98 mg, 0.090 mmol) was cyclized with BOP. This material was
combined with the product of a 5 mg scale cyclization, deprotected
with trifluoroacetic acid, and purified by HPLC to give 9H (20 mg,
27%). MS (ESI) m/z 572.2 (M+H).sup.+.
Example 9
[0528] Using a procedure analogous to that used to prepare Example
7, with the modification that 25% (1:1 ethanol/methanol)/75%
heptane was used as eluent, 9H (20 mg, 0.029 mmol) was purified by
chiral HPLC to give peak 1 (1.65 mg, 10%) and Example 9 (peak 2,
5.5 mg, 33%). Peak 2 analytical data: .sup.1H NMR (400 MHz,
CD.sub.3OD) 1.19 (d, J=6.59 Hz, 3H), 1.35 (d, J=6.96 Hz, 3H),
2.03-2.15 (m, 1H), 2.26-2.46 (m, 3H), 2.56-2.68 (m, 1H), 2.87-2.98
(m, 1H), 3.56-3.73 (m, 1H), 4.22 (d, J=16.84 Hz, 1H), 5.04 (d,
J=16.84 Hz, 1H), 5.10 (s, 1H), 6.57 (d, J=2.20 Hz, 1H), 6.63 (d,
J=1.83 Hz, 1H), 6.70 (d, J=6.22 Hz, 1H), 6.90 (dd, J=8.60, 2.01 Hz,
1H), 6.99 (dd, J=8.97, 2.38 Hz, 1H), 7.07-7.15 (m, 2H), 7.39 (d,
J=7.69 Hz, 1H), 7.49 (d, J=5.86 Hz, 1H), 7.58 (dd, J=7.69, 1.46 Hz,
1H), 7.74 (d, J=8.79 Hz, 1H), 7.81 (d, J=9.15 Hz, 1H). MS (ESI) m/z
572.1 (M+H).sup.+. Chiral analytical HPLC retention times: peak 1,
7.76 min; peak 2, 9.19 min using the following chromatography
conditions: Chiralcel OD column (4.6 mm ID.times.250 mm L, Chiral
Technologies, Inc.), 30% (1:1 ethanol/methanol)/70% heptane as
eluent, 1 mL/min flow rate, and uv detection at 254 nm.
Example 10
2-(1-Amino-isoquinolin-6-ylamino)-7-(2-methyl-propane-2-sulfonyl)-4,11-dia-
za-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene--
3,12-dione trifluoroacetic acid salt
##STR00090##
[0529] 10A: 2-(tert-Butylsulfonyl)-5-nitrobenzonitrile
##STR00091##
[0531] Using a procedure analogous to that used to prepare 6A,
2-fluoro-5-nitrobenzonitrile (2.50 g, 15.6 mmol) was reacted with
tert-butylthiol and oxidized with mCPBA to afford 10A (3.14 g, 88%)
as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.45
(s, 9H), 7.88 (d, J=8.79 Hz, 1H), 8.37 (dd, J=8.35, 2.64 Hz, 1H),
8.55 (d, J=2.64 Hz, 1H).
10B: 5-Amino-2-(tert-butylsulfonyl)benzonitrile
##STR00092##
[0533] Using a procedure analogous to that used to prepare 6B, 10A
(609 mg, 2.27 mmol) was hydrogenated to give 10B (520 mg, 96%) as a
white solid. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 1.35 (s,
9H), 6.91 (dd, J=8.79, 2.20 Hz, 1H), 7.07 (d, J=2.20 Hz, 1H), 7.66
(d, J=8.79 Hz, 1H).
10C:
4-(4-Bromophenyl)-N-(4-(tert-butylsulfonyl)-3-cyanophenyl)butanamide
##STR00093##
[0535] Using a procedure analogous to that used to prepare 8B, 10B
(250 mg, 1.05 mmol) was reacted with 4-(4-bromophenyl)butyric acid
chloride to give 10C (493 mg, 100%). MS (ESI) m/z 461.2, 463.2
(M+H).sup.+.
10D:
N-(4-(tert-butylsulfonyl)-3-cyanophenyl)-4-(4-(5,5-dimethyl-1,3,2-dio-
xaborinan-2-yl)phenyl)butanamide
##STR00094##
[0537] Using a procedure analogous to that used to prepare 2A, 10C
(430 mg, 0.930 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 10D
(431 mg, 93%) as a brown foam. This crude material was taken on to
the next step.
10E:
4-(4-(4-(tert-Butylsulfonyl)-3-cyanophenylamino)-4-oxobutyl)phenylbor-
onic acid
##STR00095##
[0539] Using a procedure analogous to that used to prepare 2B, 10D
(431 mg, 0.869 mmol) was reacted with NaOH to give 10E (263 mg,
71%) as a brown solid. .sup.1H NMR (400 MHz, THF-d.sub.8) .delta.
1.34 (s, 9H), 1.96-2.07 (m, 2H), 2.35 (t, J=7.25 Hz, 2H), 2.69 (t,
J=7.25 Hz, 2H), 7.09 (s, 1H), 7.16 (d, J=7.91 Hz, 2H), 7.71 (d,
J=8.35 Hz, 2H), 7.92-7.96 (m, 1H), 8.01 (dd, J=2.20 Hz, 1H), 8.23
(d, J=2.20 Hz, 1H), 9.69-9.77 (m, 1H).
10F:
2-(1-Di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(4-(4-(4-(te-
rt-butylsulfonyl)-3-cyanophenylamino)-4-oxobutyl)phenyl)acetic
acid
##STR00096##
[0541] Using a procedure analogous to that used to prepare 2D, 10E
(129 mg, 0.301 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 10F (76 mg, 38%). MS (ESI) m/z 800.4
(M+H).sup.+.
10G:
2-(1-Di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(4-(4-(3-(am-
inomethyl)-4-(tert-butylsulfonyl)phenylamino)-4-oxobutyl)phenyl)acetic
acid
##STR00097##
[0543] Using a procedure analogous to that used to prepare 6F, 10F
(76 mg, 0.095 mmol) was hydrogenated over 20% Pd(OH).sub.2 (64 mg)
for 72 h to give 10G (64 mg, 80%) as a yellow glass. MS (ESI) m/z
804.3 (M+H).sup.+.
Example 10
[0544] Using a procedure analogous to that used to prepare Example
6, 10G (64 mg, 0.076 mmol) was cyclized with BOP and deprotected
with trifluoroacetic acid to give Example 10 (1.58 mg, 3.0%).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 1.36 (s, 9H), 2.02-2.16
(m, 1H), 2.25-2.37 (m, 1H), 2.39-2.49 (m, 2H), 2.58-2.70 (m, 1H),
2.88-2.97 (m, 1H), 4.36 (dd, J=17.57, 4.39 Hz, 1H), 5.19 (s, 1H),
5.25 (dd, J=17.39, 7.14 Hz, 1H), 6.53 (d, J=1.83 Hz, 1H), 6.71 (d,
J=2.56 Hz, 1H), 6.87 (d, J=6.96 Hz, 1H), 6.92 (dd, J=8.42, 2.20 Hz,
1H), 7.14-7.23 (m, 3H), 7.31 (d, J=6.96 Hz, 1H), 7.40 (d, J=8.06
Hz, 1H), 7.60 (d, J=8.05 Hz, 1H), 7.75 (d, J=8.42 Hz, 1H), 8.06 (d,
J=9.15 Hz, 1H), 8.78 (t, 1H). MS (ESI) m/z 586.2 (M+H).sup.+.
Example 11
2-(1-Amino-isoquinolin-6-ylamino)-13-oxa-4,11-diaza-tricyclo[14.2.2.1.sup.-
6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
trifluoroacetic acid salt
##STR00098##
[0545] 11A: (3-Cyanophenyl)-carbamic acid 2-(4-bromophenyl)ethyl
ester
##STR00099##
[0547] Titanium tetra-tert-butoxide (0.080 mL, 0.21 mmol) was added
dropwise to a solution of 3-cyanophenylisocyanate (228 mg, 1.58
mmol) and 2-(4-bromophenyl)ethanol (606 mg, 3.01 mmol) in toluene
(10 mL). A precipitate formed immediately and the reaction was
stirred for 2 h at rt. The reaction was quenched with saturated
ammonium chloride solution and extracted with DCM (3.times.). The
combined organic layers were washed with brine, dried (MgSO.sub.4),
and concentrated in vacuo. The residual solid was triturated with
DCM hexane to give 11A (543 mg, 100%) as a white solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 2.95 (t, J=6.81 Hz, 2H), 4.38 (t,
J=6.81 Hz, 2H), 6.68 (s, 1H), 7.11 (d, J=8.35 Hz, 2H), 7.31-7.35
(m, 1H), 7.38 (t, J=7.91 Hz, 1H), 7.44 (d, J=8.35 Hz, 2H), 7.52 (d,
J=7.03 Hz, 1H), 7.76 (s, 1H).
11B: (3-Cyanophenyl)carbamic acid
2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-phenyl]ethyl ester
##STR00100##
[0549] Using a procedure analogous to that used to prepare 2A, 11A
(516 mg, 1.50 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 11B
(434 mg, 76%). This crude material was taken on to the next
step.
11C: 4-(2-((3-Cyanophenyl)carbamoyloxy)ethyl)phenylboronic acid
##STR00101##
[0551] Using a procedure analogous to that used to prepare 2B, 11B
(434 mg, 1.15 mmol) was reacted with NaOH to give 11C (170 mg, 48%)
as a solid. .sup.1H NMR (400 MHz, THF-d.sub.8) .delta. 2.98 (t,
J=7.03 Hz, 2H), 4.38 (t, J=6.81 Hz, 2H), 7.10 (s, 2H), 7.22 (d,
J=7.91 Hz, 1H), 7.30 (d, J=7.47 Hz, 1H), 7.39 (t, J=7.91 Hz, 1H),
7.68 (d, J=8.35 Hz, 1H), 7.73 (d, J=8.35 Hz, 2H), 7.87 (s, 1H),
9.11 (s, 1H).
11D:
2-(1-Di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(4-(2-((3-cy-
anophenyl)carbamoyloxy)ethyl)phenyl)acetic acid
##STR00102##
[0553] Using a procedure analogous to that used to prepare 2D, 11C
(100 mg, 0.32 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 11D (58 mg, 27%). MS (ESI) m/z 682.2
(M+H).sup.+.
11E:
2-(1-Di-tert-butoxycarbonylaminoisoquinolin-6-ylamino)-2-(4-(2-((3-(a-
minomethyl)phenyl)carbamoyloxy)ethyl)phenyl)acetic acid
##STR00103##
[0555] Using a procedure analogous to that used to prepare 6F, 11D
(58 mg, 0.085 mmol) was hydrogenated to give 11E (39 mg, 64%) as a
yellow glass. MS (ESI) m/z 686.3 (M+H).sup.+.
Example 11
[0556] Using a procedure analogous to that used to prepare Example
6, 11E (39 mg, 0.054 mmol) was cyclized with BOP and deprotected
with trifluoroacetic acid to give Example 11 (8.5 mg, 27%). .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 2.82-3.06 (m, 4H), 4.07 (dd,
J=16.11, 4.03 Hz, 1H), 4.27-4.39 (m, 1H), 5.19 (s, 1H), 6.19 (s,
1H), 6.64-6.76 (m, 2H), 6.85 (d, J=6.96 Hz, 1H), 6.90 (d, J=7.69
Hz, 1H), 7.14 (t, J=7.87 Hz, 1H), 7.20 (dd, J=9.15, 2.56 Hz, 1H),
7.25 (dd, J=7.87, 1.65 Hz, 1H), 7.31 (d, J=6.96 Hz, 1H), 7.33-7.42
(m, 2H), 7.62 (dd, J=8.06, 1.83 Hz, 1H), 8.07 (d, J=9.15 Hz, 1H),
8.69 (s, 1H). MS (ESI) m/z 468.2 (M+H).sup.+.
Example 12
(R)-2-(1-Amino-isoquinolin-6-ylamino)-7-ethanesulfonyl-20-methyl-4,11-diaz-
a-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3-
,12-dione
##STR00104##
[0558] A solution of Example 8 (0.100 g, 0.146 mmol) in methanol
was purified by chiral HPLC to give peak 1 (28 mg, 34%) and Example
12 (peak 2, 29 mg, 35%). The chromatography conditions were the
following: Chiralpak AS column (3.0 cm ID.times.25 cm L, 10 micron,
Chiral Technologies, Inc.), 75% CO.sub.2/25% methanol/0.1%
diethylamine as eluent, 100 bar, 40.degree. C., 65 mL/min flow
rate, and UV detection at 220 nm. Peak 2 analytical data: .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.21-1.33 (m, 3H) 1.87-2.00
(m, 1H) 2.26 (s, 1H) 2.37-2.54 (m, 5H) 2.66-2.76 (m, 1H) 2.89-3.00
(m, 1H) 3.08-3.18 (m, 1H) 3.33-3.51 (m, 3H) 4.23 (t, J=17.36 Hz,
1H) 4.99-5.12 (m, 2H) 6.55-6.62 (m, 1H) 6.64-6.69 (m, 1H) 6.69-6.76
(m, 1H) 6.85-6.95 (m, 1H) 6.97-7.10 (m, 2H) 7.30-7.36 (m, 2H)
7.38-7.51 (m, 2H) 7.77 (d, J=8.79 Hz, 1H) 7.81-7.88 (m, 1H),
mixture of two atropisomers. MS (ESI) m/z 572.10 (M+H).sup.+.
Chiral analytical HPLC retention times: peak 1, 20.00 min; peak 2,
24.99 min using the following chromatography conditions: Whelk-01
(R,R) column (4.6 mm ID.times.250 mm L, 10 micron.), 40% (1:1
ethanol/methanol)/60% heptane/0.1% diethylamine as eluent, 2 mL/min
flow rate, and UV detection at 264 nm.
Example 13
(R)-2-(1-Amino-isoquinolin-6-ylamino)-13-oxa-4,11-diaza-tricyclo[14.2.2.1.-
sup.6,10]henicosa-1(19),6.8.10
(21),16(20),17-hexaene-3,12-dione
##STR00105##
[0559] Example 14
(S)-2-(1-Amino-isoquinolin-6-ylamino)-13-oxa-4,11-diaza-tricyclo[14.2.2.1.-
sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
##STR00106##
[0561] A solution of Example 11 (30 mg, 0.052 mmol) in methanol was
purified by chiral HPLC to give Example 13, peak 1 (9 mg, 37%) and
Example 14, peak 2 (9 mg, 37%). The chromatography conditions were
the following: Chiralcel OD column (2.5 cm ID.times.25 cm L, Chiral
Technologies, Inc.), 30% (1:1 ethanol/methanol)/70% heptane as
eluent, 50 mL/min flow rate, and UV detection at 254 nm. Example
13: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.83-2.97 (m, 2H)
4.10 (d, J=15.82 Hz, 1H) 4.28-4.38 (m, 1H) 4.60-4.73 (m, 2H) 5.11
(s, 1H) 6.20 (s, 1H) 6.58 (d, J=2.20 Hz, 1H) 6.68 (d, J=6.15 Hz,
2H) 6.89 (d, J=7.91 Hz, 1H) 7.03 (dd, J=9.01, 2.42 Hz, 1H) 7.13 (t,
J=7.91 Hz, 1H) 7.24 (dd, J=7.91, 1.76 Hz, 1H) 7.39 (ddd, J=15.16,
7.91, 1.98 Hz, 2H) 7.51 (d, J=6.15 Hz, 1H) 7.58 (dd, J=7.91, 1.76
Hz, 1H) 7.82 (d, J=9.23 Hz, 1H). MS (ESI) m/z 468.05 (M+H).sup.+.
Example 14: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.82-3.00
(m, 2H) 4.10 (d, J=16.26 Hz, 1H) 4.29-4.40 (m, 1H) 4.68 (d, J=16.26
Hz, 2H) 5.10 (s, 1H) 6.20 (s, 1H) 6.58 (d, J=2.20 Hz, 1H) 6.68 (d,
J=6.15 Hz, 2H) 6.89 (d, J=7.47 Hz, 1H) 7.03 (dd, J=9.01, 2.42 Hz,
1H) 7.13 (t, J=7.91 Hz, 1H) 7.24 (dd, J=7.91, 1.76 Hz, 1H) 7.39
(ddd, J=15.16, 7.91, 1.54 Hz, 2H) 7.51 (d, J=6.15 Hz, 1H) 7.58 (dd,
J=7.91, 1.76 Hz, 1H) 7.82 (d, J=9.23 Hz, 1H). MS (ESI) m/z 468.05
(M+H).sup.+. Chiral analytical HPLC retention times: Example 13,
8.18 min; Example 14, 10.94 min using the following chromatography
conditions: Chiralcel OD column (4.6 mm ID.times.250 mm L, Chiral
Technologies, Inc.), 30% (1:1 ethanol/methanol)/70% heptane as
eluent, 1 mL/min flow rate, and UV detection at 254 nm.
Example 15
4-((R)-7-Ethanesulfonyl-3,12-dioxo-4,11-diaza-tricyclo[14.2.2.1.sup.6,10]h-
enicosa-1(19),6,8,10(21),16(20),17-hexaen-2-ylamino)-benzamidine
##STR00107##
[0562] 15A: tert-Butyl 5-amino-2-(ethylsulfonyl)benzylcarbamate
##STR00108##
[0564] A solution of 6A (2.0 g, 8.32 mmol) in MeOH (100 mL) and
hydrochloric acid (1 N, 20 mL) was hydrogenated (60 psi) over 20%
Pd(OH).sub.2 (380 mg) for three days. The reaction mixture was
filtered and hydrogenated twice more for three days each time over
fresh catalyst. The reaction mixture was filtered and then
concentrated in vacuo to give a white solid (2.15 g) after
trituration with ethyl acetate and ether. 1.0 g of the solid was
dissolved in THF (25 mL) and triethylamine (1 mL) and treated with
[2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (0.905 g,
3.67 mmol). The reaction mixture was stirred overnight at rt. The
reaction mixture was concentrated in vacuo and the residue was
extracted twice with DCM and saturated sodium bicarbonate. The
combined organics were extracted with brine, dried, and
concentrated in vacuo. The residue was purified by silica gel
chromatography (gradient from 0 to 50% ethyl acetate in hexanes) to
give 15A (1.07 g, 88%) as a clear oil. MS (ESI) m/z 315.12
(M+H).sup.+.
15B: tert-Butyl
5-(4-(4-bromophenyl)butanamido)-2-(ethylsulfonyl)benzylcarbamate
##STR00109##
[0566] Using a procedure analogous to that used to prepare 6C,
except that pyridine was used in place of triethylamine, 15A (0.314
g, 1.00 mmol) was coupled to 4-(4-bromophenyl)butyric acid to give
15B (0.540 g, 100%) as a white foam. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 1.23-1.31 (m, 3H) 1.41 (s, 9H) 1.97-2.08
(m, 2H) 2.37 (t, J=7.47 Hz, 2H) 2.59-2.70 (m, 2H) 3.11-3.23 (m, 2H)
4.12 (q, J=7.03 Hz, 1H) 4.50 (d, J=6.15 Hz, 2H) 5.60 (t, J=5.93 Hz,
1H) 7.06 (d, J=8.35 Hz, 2H) 7.39 (d, J=8.35 Hz, 2H) 7.45-7.50 (m,
1H) 7.83-7.95 (m, 2H).
15C:
4-(4-(3-((tert-Butoxycarbonylamino)methyl)-4-(ethylsulfonyl)phenylami-
no)-4-oxobutyl)phenylboronic acid
##STR00110##
[0568] Using a procedure analogous to that used to prepare 6D, 15B
(0.541 g, 1.0 mmol) was coupled to
5,5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] (0.249 g, 1.1
mmol) and then hydrolyzed to the free boronic acid to give 15C (334
mg, 82%) as a peach colored foam. MS (ESI) m/z 505.03
(M+H).sup.+.
15D:
2-(4-(4-(3-((tert-Butoxycarbonylamino)methyl)-4-(ethylsulfonyl)phenyl-
amino)-4-oxobutyl)phenyl)-2-(4-cyanophenylamino)acetic acid
##STR00111##
[0570] Using a procedure analogous to that used to prepare 2D, 15C
(0.101 g, 0.20 mmol) was reacted with 4-aminobenzonitrile (0.024 g,
0.2 mmol) and glyoxylic acid monohydrate (0.018 g, 0.2 mmol) to
give, after purification by reverse phase HPLC, 15D (78 mg, 62%) as
a white solid. MS (ESI) m/z 634.9 (M+H).sup.+.
15E:
2-(4-(4-(3-(Aminomethyl)-4-(ethylsulfonyl)phenylamino)-4-oxobutyl)phe-
nyl)-2-(4-cyanophenylamino)acetic acid
##STR00112##
[0572] Hydrogen chloride (4N solution in dioxane, 1 mL, 4 mmol) was
added to a solution of 15D (78 mg, 0.12 mmol) in ethyl acetate (1
mL). The reaction mixture was stirred at rt overnight and then
concentrated to give 15E (65 mg, 100%) as a yellow solid. MS (ESI)
m/z 535.0 (M+H).sup.+.
15F:
4-((R)-7-Ethanesulfonyl-3,12-dioxo-4,11-diaza-tricyclo[14.2.2.1.sup.6-
,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen-2-ylamino)-benzonitrile
##STR00113##
[0574] A solution of 15E (200 mg, 0.37 mmol) in DMF (7 mL) was
added dropwise over 0.5 h to a solution of BOP (331 mg, 0.74 mmol)
and DMAP (226 mg, 1.85 mmol) in DCM (75 mL) at 40.degree. C. The
reaction mixture was heated for an additional 0.5 h and then
concentrated in vacuo and the residue was purified by reverse phase
HPLC to give 81 mg of white solid. This was combined with 31 mg
from a previous run, dissolved in MeOH, and purified by chiral HPLC
to give peak 1 (48 mg, 43%) and 15F (peak 2, 40 mg, 36%). The
preparative chromatography conditions were the following: Chiralcel
OD column (5 cm ID.times.50 cm L, 20 micron, Chiral Technologies,
Inc.), 30% (1:1 ethanol/methanol)/70% heptane as eluent, 50 mL/min
flow rate, and UV detection at 254 nm. Chiral analytical HPLC
retention times: peak 1, 6.15 min; 15F, 8.17 min using the
following chromatography conditions: Chiralcel OD column (4.6 mm
ID.times.250 mm L, 10 micron, Chiral Technologies, Inc.), 30% (1:1
ethanol/methanol)/70% heptane as eluent, 1 mL/min flow rate, and UV
detection at 254 nm. MS (ESI) m/z 517.1 (M+H).sup.+.
Example 15
[0575] 15F (30 mg, 0.058 mmol) was dissolved in a solution of
hydroxylamine in DMSO (3M, 0.400 mL). The reaction mixture was
heated at 70.degree. C. for 3 h. An additional aliquot of
hydroxylamine in DMSO (3M, 0.300 mL) was added, and heating was
continued for 2 h. The reaction mixture was diluted with ethyl
acetate and extracted with water and brine, dried (MgSO.sub.4), and
concentrated in vacuo. Acetic anhydride (0.030 mL, 0.32 mmol) was
added to a solution of the residue dissolved in DCM (3 mL). After
30 min at rt, the reaction mixture was concentrated in vacuo. The
residue was dissolved in MeOH and hydrogenated (50 psi) over 10%
palladium on carbon (37 mg) for 2.5 h. The reaction mixture was
filtered and concentrated in vacuo. The residue was purified by
preparative reverse phase HPLC to give Example 15 (7.3 mg, 19%).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.25 (t, J=7.25 Hz,
3H) 2.00-2.16 (m, 1H) 2.27-2.49 (m, 3H) 2.54-2.69 (m, 1H) 2.87-3.00
(m, 1H) 3.32-3.51 (m, 2H) 4.16 (dd, J=16.70, 5.27 Hz, 1H) 5.00-5.14
(m, 2H) 6.63 (d, J=1.76 Hz, 1H) 6.76 (d, J=8.79 Hz, 2H) 6.90 (dd,
J=8.57, 1.98 Hz, 1H) 7.02 (dd, J=7.91, 2.20 Hz, 1H) 7.11 (dd,
J=7.91, 1.32 Hz, 1H) 7.39 (dd, J=7.91, 1.76 Hz, 1H) 7.52-7.62 (m,
3H) 7.76 (d, J=8.35 Hz, 1H) 8.91 (t, J=5.71 Hz, 1H). MS (ESI) m/z
534.0 (M+H).sup.+.
Example 16
3-[(R)-4-Methyl-3,12-dioxo-7-(propane-2-sulfonyl)-13-oxa-4,11-diaza-tricyc-
lo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen-2-ylamino]-
-benzamide
##STR00114##
[0576] 16A: 2-(Isopropylthio)-5-nitrobenzoic acid
##STR00115##
[0578] Isopropylthiol (3.06 mL, 32.8 mmol) was added to a solution
of 2-fluoro-5-nitrobenzoic acid (5.06 g, 27.3 mmol) and
triethylamine (8.4 mL, 60.3 mmol) in DMF (86 mL). The reaction
mixture was stirred overnight at rt and then most of the DMF was
removed in vacuo. The residual solution was poured into ice water
(500 mL) and the resulting yellow solid was isolated by filtration
to give 16A (6.5 g, 100%).
16B: 2-(Isopropylthio)-N-methyl-5-nitrobenzamide
##STR00116##
[0580] Oxalyl chloride (1.75 mL, 19.6 mmol) was added dropwise to a
suspension of 16A (2.41 g, 10 mmol) in DCM (20 mL) containing DMF
(2 drops) at 0.degree. C. The reaction mixture was warmed to rt and
stirred overnight. The reaction mixture was concentrated in vacuo
and coevaporated twice with toluene. The residue was dissolved in
DCM (25 mL) and added portionwise to a solution of methylamine
hydrochloride (2.03 g, 30.1 mmol) and pyridine (8.1 mL, 100 mmol)
in DCM (25 mL) at 0.degree. C. The reaction mixture was stirred
overnight at rt. The reaction mixture was concentrated in vacuo and
the residue was triturated with water to give 16B (2.08 g, 82%) as
a yellow solid.
16C: 5-Amino-2-(isopropylthio)-N-methylbenzamide
##STR00117##
[0582] A suspension of 16B (1.2 g, 4.7 mmol) in a mixture of
ethanol (30 mL), water (5 mL), and acetic acid (3.3 mL, 5.8 mmol)
was heated by a 115.degree. C. oil bath. Iron powder (1.80 g, 32.2
mmol) was added portionwise over 1 h. The reaction mixture was
cooled to rt, filtered, and washed with ethyl acetate. Sodium
bicarbonate solution was added until it was basic. The reaction
mixture was extracted with ethyl acetate (3.times.) and the
combined organics were washed with saturated sodium bicarbonate and
brine, dried (MgSO.sub.4), and concentrated in vacuo to give 16C
(0.98 g, 93%) as a beige solid. MS (ESI) m/z 225.1 (M+H).sup.+.
16D: 4-(Isopropylthio)-3-((methylamino)methyl)aniline
##STR00118##
[0584] Borane (1M solution in THF, 10 mL, 10 mmol) was added slowly
dropwise to a solution of 16C (0.98 g, 4.37 mmol) in THF (60 mL) at
0.degree. C. The reaction mixture was then heated to 70.degree. C.
overnight. The reaction mixture was cooled in an ice bath and
quenched by cautious addition of hydrochloric acid (2N, 12 mL, 24
mmol). The reaction mixture was refluxed for 2 h and then
concentrated almost to dryness in vacuo. The residue was
coevaporated with methanol (3.times.), diluted with ethyl acetate
and sodium hydroxide solution (2N). The aqueous layer was extracted
with ethyl acetate (3.times.), dried (MgSO.sub.4), and concentrated
in vacuo to give 16D (1.03 g, 100%) as a clear oil. MS (ESI) m/z
211.1 (M+H).sup.+.
16E:
tert-Butyl-(5-amino-2-(isopropylthio)benzyl)(methyl)carbamate
##STR00119##
[0586] Di-tert-butyl dicarbonate (0.665 g, 3.05 mmol) in
acetonitrile (3 mL) was added dropwise to a solution of 16D (560
mg, 2.67 mmol) and DMAP (65 mg, 0.53 mmol) in acetonitrile (5 mL)
at 0.degree. C. The reaction mixture was stirred at rt for 4 h. The
reaction mixture was diluted with water and extracted with DCM
(2.times.). The combined organic layers were washed with brine,
dried (MgSO.sub.4), and concentrated in vacuo. The residue was
purified by silica gel chromatography (gradient from 0 to 30% ethyl
acetate in hexanes) to give 16E (0.48 g, 58%). MS (ESI) m/z 311
(M+H).sup.+.
16F:
{3-[(tert-Butoxycarbonyl-methyl-amino)-methyl]-4-isopropylsulfanyl-ph-
enyl}-carbamic acid phenyl ester
##STR00120##
[0588] Phenyl chloroformate (0.204 mL, 1.62 mmol) was added
dropwise to a solution of 16E (0.48 g, 1.55 mmol) in pyridine
(0.193 mL, 2.38 mmol) and DCM (3.5 mL) at 0.degree. C. The reaction
mixture was stirred at rt for 1 h. The reaction mixture was diluted
with water and extracted with DCM (2.times.). The combined organic
layers were dried (MgSO.sub.4) and concentrated in vacuo. The
residue was purified by silica gel chromatography (gradient from 0
to 50% ethyl acetate in hexanes) to give 16F (0.609 g, 91%) as a
white foam.
16G:
[3-[(tert-Butoxycarbonyl-methyl-amino)-methyl]-4-(propane-2-sulfonyl)-
-phenyl]-carbamic acid phenyl ester
##STR00121##
[0590] mCPBA (.about.77%, 0.819 g, 3.65 mmol) was added slowly to a
solution of 16F (0.586 g, 1.36 mmol) in DCM (20 mL) at 0.degree. C.
The reaction mixture was stirred at rt for 5 h. The reaction
mixture was diluted with DCM and extracted with 10% sodium
bisulfite (2.times.), saturated sodium bicarbonate, and brine. The
organic layer was dried (MgSO.sub.4) and concentrated in vacuo. The
residue was purified by silica gel chromatography (gradient from 0
to 50% ethyl acetate in hexanes) to give 16G (0.655 g, 100%) as a
clear foam MS (ESI) m/z 463.0 (M+H).sup.+.
16H:
[3-[(tert-Butoxycarbonyl-methyl-amino)-methyl]-4-(propane-2-sulfonyl)-
-phenyl]-carbamic acid 2-(4-bromo-phenyl)-ethyl ester
##STR00122##
[0592] Sodium hydride (60% in oil, 60 mg, 1.5 mmol) was added
portionwise to a solution of 4-bromophenethyl alcohol (0.718 g,
3.57) in THF (6 mL) at 0.degree. C. The reaction mixture was cooled
to -40.degree. C., and a solution of 16G (0.550 g, 1.19 mmol) in
THF (5 mL) was added slowly dropwise. The reaction mixture was
slowly warmed to 0.degree. C., and then stirred for 3 h at
0.degree. C. The reaction mixture was diluted with water and
extracted with ethyl acetate. The combined organic layers were
washed with water and brine, dried (MgSO.sub.4) and concentrated in
vacuo. The residue was purified by silica gel chromatography
(gradient from 0 to 50% ethyl acetate in hexanes) to give 16H
(0.503 g, 74%) as a white solid.
16I:
4-(2-(3-((tert-Butoxycarbonyl(methyl)amino)methyl)-4-(isopropylsulfon-
yl)phenylcarbamoyloxy)ethyl)phenylboronic acid
##STR00123##
[0594] Using a procedure analogous to that used to prepare 6D, 16H
(0.653 g, 1.15 mmol) was coupled to
5,5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl](0.286 g, 1.27
mmol) and then hydrolyzed to the free boronic acid to give 16I
(0.330 g, 54%) as a white solid.
16J:
2-(4-(2-(3-((tert-Butoxycarbonyl(methyl)amino)methyl)-4-(isopropylsul-
fonyl)phenylcarbamoyloxy)ethyl)phenyl)-2-(3-carbamoylphenylamino)acetic
acid
##STR00124##
[0596] Using a procedure analogous to that used to prepare 2D, 16I
(0.134 g, 0.25 mmol) was reacted with m-aminobenzamide (0.035 g,
0.26 mmol) and glyoxylic acid monohydrate (0.023 g, 0.25 mmol) to
give, after purification by reverse phase HPLC, 16J (134 mg, 78%)
as a pale yellow foam. MS (ESI) m/z 683.1 (M+H).sup.+.
Example 16
[0597] Hydrogen chloride (4N solution in dioxanes, 1 mL, 4 mmol)
was added to 16J (134 mg, 0.196 mmol) in ethyl acetate (1 mL). The
reaction mixture was stirred at rt overnight. The reaction mixture
was concentrated in vacuo and then coevaporated with toluene. The
residue was then dissolved in DMF (10 mL) and cyclized and purified
by reverse phase HPLC according to the procedure described for 15F.
The resulting white solid was dissolved in MeOH, and purified by
chiral HPLC to give Example 16 (peak 1, 9.8 mg, 9.2%) and peak 2
(7.8 mg, 7.4%). The preparative chromatography conditions were the
following: Chiralcel OD column (5 cm ID.times.50 cm L, 20 micron,
Chiral Technologies, Inc.), 30% (1:1 ethanol/methanol)/70% heptane
as eluent, 50 mL/min flow rate, and UV detection at 254 nm. Example
16: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.20 (d, J=6.59
Hz, 3H) 1.32 (d, J=7.03 Hz, 3H) 2.80-2.99 (m, 2H) 3.46-3.55 (m, 1H)
4.02-4.12 (m, 1H) 4.16 (d, J=17.58 Hz, 1H) 4.78-4.88 (m, 1H)
5.53-5.66 (m, 2H) 6.53 (d, J=2.20 Hz, 1H) 6.82-6.92 (m, 2H)
7.06-7.22 (m, 5H) 7.42 (d, J=7.47 Hz, 1H) 7.67-7.77 (m, 2H). MS
(ESI) m/z 565.1 (M+H).sup.+. Chiral analytical HPLC retention
times: peak 1, 11.56 min; peak 2, 14.01 min using the following
chromatography conditions: Chiralcel OD column (4.6 mm ID.times.250
mm L, 10 micron, Chiral Technologies, Inc.), 30% (1:1
ethanol/methanol)/70% heptane as eluent, 1 mL/min flow rate, and UV
detection at 254 nm.
Example 17
(R)-2-(1-Amino-isoquinolin-6-ylamino)-7-ethanesulfonyl-4-methyl-4,11-diaza-
-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,-
12-dione
##STR00125##
[0598] 17A: tert-Butyl
5-amino-2-(ethylthio)benzyl(methyl)carbamate
##STR00126##
[0600] Using a synthetic sequence analogous to that used to convert
2-fluoro-5-nitrobenzoic acid from 16A to 16E,
2-fluoro-5-nitrobenzoic acid was initially reacted with ethanethiol
and subsequently converted to 17A. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 1.19 (t, J=7.25 Hz, 3H) 1.38-1.57 (m, 9H)
2.70 (q, J=7.47 Hz, 2H) 2.76-2.95 (m, 3H) 3.72 (br. s, 2H)
4.52-4.75 (m, 2H) 6.43-6.59 (m, 2H) 7.27 (d, J=7.91 Hz, 1H).
17B: tert-Butyl
5-(4-(4-bromophenyl)butanamido)-2-(ethylthio)benzyl(methyl)carbamate
##STR00127##
[0602] Oxalyl chloride (0.180 mL, 2.06 mmol) was added dropwise to
a suspension of 4-bromophenylbutanoic acid (0.250 g, 1.03 mmol) in
DCM (3 mL) containing DMF (1 drop) at rt. After 4 h, the reaction
mixture was concentrated in vacuo and coevaporated with toluene.
The residue was dissolved in DCM (2 mL) and added dropwise to a
solution of 17A (0.300 g, 1.01 mmol), DMAP (0.025 g, 0.2 mmol) and
pyridine (1.0 mL, 12.3 mmol) in DCM (2 mL) at rt. The reaction
mixture was stirred overnight at rt. The reaction mixture was
concentrated in vacuo and the residue was triturated with water and
then purified by silica gel chromatography (gradient from 0 to 20%
ethyl acetate in hexanes) to give 17B (0.46 g, 88%) as a clear oil
that solidified on standing. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 1.26 (t, J=7.03 Hz, 3H) 1.33-1.58 (m, 9H) 1.96-2.04 (m,
2H) 2.33 (t, J=7.47 Hz, 2H) 2.63 (t, J=7.47 Hz, 2H) 2.63 (t, J=7.47
Hz, 2H) 2.74-2.93 (m, 3H) 4.56 (br. s., 2H) 6.96-7.02 (m, 0.5H)
7.05 (d, J=8.35 Hz, 2H) 7.13 (br. s., 0.4H) 7.28-7.36 (m, 0.8H)
7.38 (d, J=8.35 Hz, 2H) 7.60-7.72 (m, 0.4H) 7.81-7.98 (m, 0.9H)
8.33 (br. s., 1H).
17C: tert-Butyl
5-(4-(4-bromophenyl)butanamido)-2-(ethylsulfonyl)benzyl(methyl)carbamate
##STR00128##
[0604] Using a procedure analogous to that used for preparation of
16G, 17B (0.460 g, 0.88 mmol) was reacted with mCPBA (0.500 g, 2.23
mmol) to give 17C (0.428 g, 88%) as a white foam. MS (ESI) m/z
555.0 (M+H).sup.+.
17D:
4-(4-(3-((tert-Butoxycarbonyl(methyl)amino)methyl)-4-(ethylsulfonyl)p-
henylamino)-4-oxobutyl)phenylboronic acid
##STR00129##
[0606] Using a procedure analogous to that used to prepare 6D, 17C
(0.428 g, 0.76 mmol) was coupled to
5,5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] (0.202 g,
0.894 mmol) and then hydrolyzed to the free boronic acid to give
17D (0.260 g, 76%) as a white solid. MS (ESI) m/z 519.0
(M+H).sup.+.
17E:
2-(1-(bis(tert-Butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(4-(3-
-((tert-butoxycarbonyl(methyl)amino)methyl)-4-(ethylsulfonyl)phenylamino)--
4-oxobutyl)phenyl)acetic acid
##STR00130##
[0608] Using a procedure analogous to that used to prepare 2D, 17D
(0.130 g, 0.25 mmol) was reacted with Intermediate 1 (0.090 g, 0.25
mmol) and glyoxylic acid monohydrate (0.027 g, 0.29 mmol) to give,
after purification by reverse phase HPLC, 17E (109 mg, 49%). MS
(ESI) m/z 890.1 (M+H).sup.+.
Example 17
[0609] Using a procedure analogous to that used for the final Boc
deprotection and cyclization of Example 16, 17E (109 mg, 0.122
mmol) was deprotected with hydrogen chloride and subsequently
cyclized and purified by reverse phase HPLC to give 11 mg of yellow
foam. This material was dissolved in MeOH, and purified by chiral
HPLC using a Chiralcel OJ column to give Example 17 (peak 1) and
peak 2. Example 17: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm
1.25 (t, J=7.51 Hz, 3H) 1.99-2.10 (m, 1H) 2.23-2.58 (m, 4H)
2.94-3.04 (m, 1H) 3.32-3.49 (m, 2H) 3.43 (s, 3H) 4.12 (d, J=17.57
Hz, 1H) 5.63 (d, J=17.21 Hz, 1H) 5.74 (s, 1H) 6.62 (s, 1H) 6.81 (d,
J=2.20 Hz, 1H) 6.89-6.98 (m, 3H) 7.08-7.12 (m, 1H) 7.17 (dd,
J=9.15, 2.20 Hz, 1H) 7.31 (d, J=6.96 Hz, 1H) 7.40 (dd, J=7.87, 1.65
Hz, 1H) 7.74 (dd, J=8.06, 1.83 Hz, 1H) 7.80 (d, J=8.42 Hz, 1H) 8.03
(d, J=9.15 Hz, 1H). MS (ESI) m/z 572.1 (M+H).sup.+. Chiral
analytical HPLC retention times: peak 1, 28 min; peak 2, 49 min
using the following chromatography conditions: Chiralcel OJ column
(4.6 mm ID.times.250 mm L, 10 micron, Chiral Technologies, Inc.),
40% (1:1 ethanol/methanol)/70% heptane as eluent, 1 mL/min flow
rate, and UV detection at 254 nm.
Example 18
(R)-2-(1-Amino-isoquinolin-6-ylamino)-4-methyl-7-(propane-2-sulfonyl)-4,11-
-diaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexa-
ene-3,12-dione
##STR00131##
[0610] 18A: tert-Butyl
5-(4-(4-bromophenyl)butanamido)-2-(isopropylthio)benzyl(methyl)carbamate
##STR00132##
[0612] Using a procedure analogous to that used for preparation of
17B, 16E (0.418 g, 1.35 mmol) was reacted with
4-bromophenylbutanoic acid (0.340 g, 1.40 mmol) to give 18A (0.642
g, 89%) as a white solid. MS (ESI) m/z 537.0 (M+H).sup.+.
18B: tert-Butyl
5-(4-(4-bromophenyl)butanamido)-2-(isopropylsulfonyl)benzyl(methyl)carbam-
ate
##STR00133##
[0614] Using a procedure analogous to that used for preparation of
16G, 18A (0.642 g, 1.20 mmol) was reacted with mCPBA (0.672 g, 3.00
mmol) to give 18B (0.660 g, 97%) as a white solid. MS (ESI) m/z
568.9 (M+H).sup.+.
18C:
4-(4-(3-((tert-Butoxycarbonyl(methyl)amino)methyl)-4-(isopropylsulfon-
yl)phenylamino)-4-oxobutyl)phenylboronic acid
##STR00134##
[0616] Using a procedure analogous to that used to prepare 6D, 18B
(0.660 g, 1.17 mmol) was coupled to
5,5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] (0.290 g,
1.28 mmol) and then hydrolyzed to the free boronic acid to give 18C
(0.476 g, 80%) as a white solid. MS (ESI) m/z 533.0
(M+H).sup.+.
18D:
2-(1-(bis(tert-Butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(4-(3-
-((tert-butoxycarbonyl(methyl)amino)methyl)-4-(isopropylsulfonyl)phenylami-
no)-4-oxobutyl)phenyl)acetic acid
##STR00135##
[0618] Using a procedure analogous to that used to prepare 2D, 18C
(0.151 g, 0.28 mmol) was reacted with Intermediate 1 (0.101 g, 0.28
mmol) and glyoxylic acid monohydrate (0.026 g, 0.28 mmol) to give,
after purification by reverse phase HPLC, 18D (168 mg, 66%) as a
yellow glass.
Example 18
[0619] Using a procedure analogous to that used for the final Boc
deprotection and cyclization of Example 16, 18D (168 mg, 0.186
mmol) was deprotected with hydrogen chloride to give 142 mg yellow
solid. This was subsequently cyclized in two batches (60 mg and 73
mg) and purified by reverse phase HPLC to give a total 68 mg of
racemic product. 43 mg of this material was dissolved in MeOH, and
purified by chiral HPLC give Example 18 (peak 1, 16.9 mg, 47%) as a
beige solid and peak 2 (15.6 mg, 43%) as a beige solid. The
preparative chromatography conditions were the following: Chiralcel
OD column (0.21 cm ID.times.50 cm L, 10 micron, Chiral
Technologies, Inc.), 25% methanol/70% CO.sub.2/0.1% diethylamine as
eluent, 80 mL/min flow rate, and UV detection at 220 nm. Example
18: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.11-1.19 (m, 3H)
1.24-1.36 (m, 3H) 1.96-2.06 (m, 1H) 2.21-2.55 (m, 3H) 2.62-2.73 (m,
1H) 2.90-3.01 (m, 1H) 3.41 (s, 3H) 3.54-3.68 (m, 1H) 4.10 (d,
J=17.14 Hz, 1H) 5.60 (d, J=17.58 Hz, 1H) 5.64 (s, 1H) 6.57 (s, 1H)
6.66 (d, J=2.20 Hz, 1H) 6.73 (d, J=6.15 Hz, 1H) 6.87-7.00 (m, 3H)
7.01-7.09 (m, 1H) 7.37 (d, J=7.91 Hz, 1H) 7.50 (d, J=5.71 Hz, 1H)
7.69 (d, J=7.91 Hz, 1H) 7.76 (dd, J=8.79, 5.27 Hz, 2H). MS (ESI)
m/z 586.0 (M+H).sup.+. Chiral analytical HPLC retention times: peak
1, 13.94 min; peak 2, 18.41 min using the following chromatography
conditions: Whelk-01(R,R) column (4.6 mm ID.times.150 mm L, 10
micron), 50% (1:1 ethanol/methanol)/50% heptane as eluent/0.1%
diethylamine, 2 mL/min flow rate, and UV detection at 271 nm.
Example 19
(R)-2-(1-Amino-8-fluoro-isoquinolin-6-ylamino)-13-oxa-4,11-diaza-tricyclo[-
14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
##STR00136##
[0620] 19A: (E)-methyl 3-(3-amino-5-fluorophenyl)acrylate
##STR00137##
[0622] A mixture of 1-fluoro-3-iodo-5-nitrobenzene (1.145 g, 4.29
mmol), sodium acetate (0.430 g, 5.24 mmol), palladium(II) acetate
(1.7 mg, 0.0076 mmol), methyl acrylate (0.425 mL, 4.71 mmol), and
1-methyl-2-pyrrolidinone (11 mL) under argon was degassed with
three freeze/pump/thaw cycles. The reaction mixture was heated to
130.degree. C. for 35 min and then at 100.degree. C. for 14 h. The
reaction mixture was diluted with water and saturated sodium
bicarbonate solution and extracted three times with diethyl ether.
The combined organic extracts were washed with saturated sodium
bicarbonate solution, hydrochloric acid (1 N), and brine, dried
(MgSO.sub.4), and concentrated under reduced pressure. The residue
was suspended in a mixture of ethanol (12 mL), water (2.5 mL), and
acetic acid (1.25 mmol) and heated to reflux. Iron powder (0.519 g,
9.28 mmol) was added portionwise over 30 min, and reflux was
continued for an additional 30 min. The reaction mixture was
concentrated under reduced pressure. The residue was partitioned
between ethyl acetate and sodium bicarbonate solution and filtered
through a glass fibre filter to remove a fine grey precipitate. The
aqueous phase was extracted with ethyl acetate (3.times.) and the
organic phase was dried (MgSO.sub.4) and concentrated under reduced
pressure to give 19A (0.328 g, 74%) as a pale yellow solid. LC-MS
m/z: 196.2 (M+H).sup.+.
19B: (E)-Methyl 3-(3-(dibenzylamino)-5-fluorophenyl)acrylate
##STR00138##
[0624] Benzyl bromide (0.440 mL, 3.70 mmol) was added to a solution
of 19A (0.328 g, 1.68 mmol) and DIEA (0.880 mL) in acetonitrile (5
mL). The reaction mixture was heated at 60.degree. C. for 14 h and
then concentrated under reduced pressure. The residual solid was
triturated twice with diethyl ether, dissolved in dichloromethane,
and extracted with hydrochloric acid (1N) and saturated sodium
bicarbonate solution. The organic layer was dried (MgSO.sub.4) and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (gradient from 0 to 15% ethyl acetate in
hexanes) to give 19B (0.468 g, 74%) as a white solid. LC-MS m/z:
376.5 (M+H).sup.+.
19C: (E)-3-(3-(Dibenzylamino)-5-fluorophenyl)acrylic acid
##STR00139##
[0626] Sodium hydroxide (2 mL, 2 mmol, 1.00 N solution) was added
to a solution of 19B (0.467 g, 1.24 mmol) in tetrahydrofuran (2 mL)
and methanol (1 mL). The reaction was heated at 80.degree. C. for 1
h. Hydrochloric acid (1 N) was added and the reaction mixture was
extracted with ethyl acetate (2.times.). The combined organic
layers were dried (MgSO.sub.4) and concentrated under reduced
pressure to give 19C (0.411 g, 91%) as a pale yellow solid. LC-MS
m/z: 362.4 (M+H).sup.+.
19D: 6-(Dibenzylamino)-8-fluoroisoquinolin-1(2H)-one
##STR00140##
[0628] A solution of ethyl chloroformate (0.320 mL, 3.35 mmol) in
acetone (5 mL) was added dropwise to a suspension of 19C (1.013 g,
2.80 mmol) in a mixture of acetone (30 mL) and triethylamine (0.90
mL, 6.4 mmol) at 0.degree. C. The reaction mixture was stirred for
45 min and then a solution of sodium azide (0.350 g, 5.4 mmol) in
water (8 mL) was added dropwise over 1 h. After an additional 1 h,
the reaction was warmed to rt, poured into ice water, and the solid
was isolated by filtration and was washed with water (Do not allow
the solid to dry out). (Caution: this acyl azide intermediate is
potentially explosive and should be handled in small quantities
behind a safety shield.) The solid was dissolved in DCM, dried
(MgSO.sub.4), filtered, and the volume reduced to .about.2 mL with
a stream of nitrogen. Diphenyl ether (2 mL) was added, and the
crude acyl azide solution was used directly. The acyl azide
solution was added slowly dropwise via addition funnel to a
refluxing mixture of diphenyl ether (8.12 g) and tributylamine (2
mL), internal temperature .about.230.degree. C. A flow of dry
nitrogen was maintained through the reaction vessel to a bubbler
during the reaction. Reflux was continued for an additional 1 h,
after which time the majority of the solvent was removed in vacuo.
The residue was cooled to room temperature and hexanes was added.
The solid was collected by filtration and washed with hexanes to
give 19D (0.830 g, 83%) as an off-white solid. LC-MS m/z: 359.4
(M+H).sup.+.
19E: 1-Chloro-6-(Dibenzylamino)-8-fluoroisoquinoline
##STR00141##
[0630] A mixture of 19D (0.622 g, 1.74 mmol) and phosphorous
oxychloride (6 mL) was heated at 100.degree. C. for 1.5 h. The
reaction mixture was concentrated under reduced pressure and
co-evaporated twice with toluene. Ice was added to the residue,
followed by sodium hydroxide (1N solution) until the pH was basic.
The mixture was extracted with methylene chloride (3.times.), and
the combined organic layers were washed with saturated sodium
bicarbonate solution and brine, dried (MgSO.sub.4), and dried in
vacuo to give 19E (0.583 g, 89%) as a yellow solid.
19F: N.sup.6,N.sup.6-Dibenzyl-8-fluoroisoquinoline-1,6-diamine
##STR00142##
[0632] A solution of 19E (0.500 g, 1.33 mmol) in a saturated
solution of ammonia in ethylene glycol (30 mL, prepared from 5 g
NH.sub.3 in 25 g ethylene glycol) was heated to 150.degree. C.
(internal temperature) in a Parr stainless steel autoclave with
internal thermocouple and heating controller, with a 3000 psi
pressure rating and 3000 psi rupture disc. The internal pressure
reached 500 psi, so this reaction cannot be run in a glass reaction
vessel. After 19 h, the reactor was allowed to cool to RT, and then
cooled further in an ice bath. The reaction mixture (still
releasing ammonia gas) was poured into ice water, and the resulting
precipitate was collected by filtration. The filtrate was extracted
with dichloromethane and ethyl acetate and the residue from the
organic extracts was combined with precipitate. This material was
purified by silica gel chromatography (0 to 30% ethyl
acetate/hexanes) to give 19F (328 mg, 69%) as a yellow solid. LC-MS
m/z: 358.08 (M+H).sup.+.
19G:
N.sup.6,N.sup.6-Dibenzyl-N.sup.1,N.sup.1-di-tert-butoxycarbonyl-8-flu-
oroisoquinoline-1,6-diamine
##STR00143##
[0634] Di-tert-butyl dicarbonate (58 mg, 0.266 mmol) was added to a
suspension of 19F (21 mg, 0.059 mmol) and DMAP (5 mg, 0.041 mmol)
in acetonitrile (2 mL). The reaction mixture was stirred overnight
at rt and then concentrated under reduced pressure. The residue was
purified by silica gel chromatography (gradient from 0 to 30% ethyl
acetate in hexanes) to afford 19G (23 mg, 70%) as a clear glass.
LC-MS m/z: 558.3 (M+H).sup.+.
19H:
N.sup.1,N.sup.1-Di-tert-butoxycarbonyl-8-fluoroisoquinoline-1,6-diami-
ne
##STR00144##
[0636] A mixture of 19G (77 mg, 0.14 mmol), 20% palladium(II)
hydroxide on carbon (94 mg) and ethanol (20 mL) was hydrogenated
(55 psi) for 4 h. The reaction mixture was filtered and
concentrated under reduced pressure to give 19H (47 mg, 90%) as a
yellow solid. LC-MS m/z: 378.3 (M+H).sup.+.
19I: 4-bromophenethyl 3-cyanophenylcarbamate
##STR00145##
[0638] 2-(4-Bromophenyl)ethanol (1.2 g, 5.97 mmol) was added to a
solution of 3-cyanophenyl isocyanate (0.475 g, 3.3 mmol) in dry
toluene (20 mL), followed by titanium tetra-tert-butoxide (0.16 mL,
0.42 mmol). The reaction mixture was stirred overnight at rt. The
reaction mixture was quenched by addition of saturated ammonium
chloride solution and extracted with DCM (3.times.). The combined
organics were dried and concentrated in vacuo to give 19I (1.08 g,
95%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 2.96 (t, J=6.81
Hz, 2H) 4.39 (t, J=6.81 Hz, 2H) 6.70 (br. s., 1H) 7.13 (d, J=8.35
Hz, 2H) 7.32-7.43 (m, 2H) 7.45 (d, J=8.35 Hz, 2H) 7.53 (d, J=7.03
Hz, 1H) 7.78 (br. s., 1H).
19J: 4-(2-(3-Cyanophenylcarbamoyloxy)ethyl)phenylboronic acid
##STR00146##
[0640] Using procedures analogous to those used to prepare 2A and
hydrolyze it to 2B, 19I (1.08 g, 2.86 mmol) was coupled to
5,5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] (0.710 g,
3.14 mmol) and then a portion of this material was hydrolyzed to
the free boronic acid to give 19J (0.340 g, 72%, two steps) as a
crude white solid.
19K:
2-(1-(bis(tert-Butoxycarbonyl)amino)-8-fluoroisoquinolin-6-ylamino)-2-
-(4-(2-(3-cyanophenylcarbamoyloxy)ethyl)phenyl)acetic acid
##STR00147##
[0642] Using a procedure analogous to that used to prepare 2D, 19J
(0.048 g, 0.15 mmol) was reacted with 19H (0.054 g, 0.14 mmol) and
glyoxylic acid monohydrate (0.015 g, 0.16 mmol) using a reaction
time of 900 sec to give, after purification by reverse phase HPLC,
19K. MS (ESI) m/z 700.05 (M+H).sup.+.
19L:
2-(4-(2-(3-(Aminomethyl)phenylcarbamoyloxy)ethyl)phenyl)-2-(1-(bis(te-
rt-butoxycarbonyl)amino)-8-fluoroisoquinolin-6-ylamino)acetic
acid
##STR00148##
[0644] Using a procedure analogous to that used to prepare 6F, 19K
(0.030 g, 0.043 mmol) was hydrogenated to give 19L (27 mg, 90%). MS
(ESI) m/z 704.2 (M+H).sup.+.
Example 19
[0645] Using a procedure analogous to that used to prepare 15F,
except that BOP was replaced with PyBOP (40 mg, 0.077 mmol), 19L
(27 mg, 0.038 mmol) was cyclized and purified by reverse phase
HPLC. This material was subsequently deprotected using a procedure
analogous to that used for the final step of Example 1. The
resulting material was dissolved in MeOH, and purified by chiral
HPLC to give peak 1 (4 mg, 22%) and Example 19 (peak 2, 2.5 mg,
14%). The preparative chromatography conditions were the following:
Whelk-01 (R,R) column (2.11 cm ID.times.25 cm L, Regis), 40% (1:1
ethanol/methanol)/60% heptane as eluent, 15 mL/min flow rate, and
UV detection at 254 nm. Example 19: .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 2.83-2.99 (m, 3H) 4.05 (dd, J=16.29, 4.21
Hz, 1H) 4.26-4.35 (m, 1H) 6.17 (s, 1H) 6.59 (br. s., 1H) 6.68 (d,
J=8.05 Hz, 1H) 6.83 (dd, J=7.32, 2.20 Hz, 1H) 6.87-6.98 (m, 2H)
7.14 (t, J=7.69 Hz, 1H) 7.22-7.27 (m, 1H) 7.30 (d, J=7.32 Hz, 1H)
7.32-7.36 (m, 1H) 7.38-7.43 (m, 1H) 7.60 (dd, J=7.87, 1.65 Hz, 1H)
8.66 (br. s., 1H). MS (ESI) m/z 485.97 (M+H).sup.+. Chiral
analytical HPLC retention times: peak 1, 6.47 min; Example 19,
10.43 min using the following chromatography conditions: Whelk-01
(R,R) column (4.6 mm ID.times.250 mm L, 10 micron), 50% (1:1
ethanol/methanol)/50% heptane as eluent, 1 mL/min flow rate, and UV
detection at 254 nm.
Example 20
(R)-2-(1-Amino-8-fluoro-isoquinolin-6-ylamino)-4-methyl-7-(propane-2-sulfo-
nyl)-13-oxa-4,11-diaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21-
),16(20),17-hexaene-3,12-dione
##STR00149##
[0646] 20A:
2-(1-(bis(tert-butoxycarbonyl)amino)-8-fluoroisoquinolin-6-ylamino)-2-(4--
(2-(3-((tert-butoxycarbonyl(methyl)amino)methyl)-4-(isopropylsulfonyl)phen-
ylcarbamoyloxy)ethyl)phenyl)acetic acid
##STR00150##
[0648] Using a procedure analogous to that used to prepare 2D, 16I
(0.160 g, 0.300 mmol) was reacted with 19H (0.113 g, 0.300 mmol)
and glyoxylic acid monohydrate (0.028 g, 0.30 mmol) using a 900 sec
reaction time to give, after purification by reverse phase HPLC,
20A (121 mg, 43%). MS (ESI) m/z 924.1 (M+H).sup.+.
20B:
2-(1-amino-8-fluoroisoquinolin-6-ylamino)-2-(4-(2-(4-(isopropylsulfon-
yl)-3-((methylamino)methyl)phenylcarbamoyloxy)ethyl)phenyl)acetic
acid
##STR00151##
[0650] Using a procedure analogous to that used in the final step
of Example 1, 20A (0.152 g, 0.16 mmol) was deprotected using
hydrogen chloride to give 20B (0.132 g, 100%). MS (ESI) m/z 623.97
(M+H).sup.+.
Example 20
[0651] Using a procedure analogous to that used to prepare 15F,
except that BOP was replaced with PyBOP (172 mg, 0.33 mmol), 20B
(132 mg, 0.16 mmol) was cyclized and purified by reverse phase
HPLC. The resulting material was dissolved in MeOH, and purified by
chiral HPLC to give peak 1 (6.8 mg, 14%) and Example 20 (peak 2,
4.8 mg, 9.6%). The preparative chromatography conditions were the
following: Whelk-01 (R,R) column (2.11 cm ID.times.25 cm L, Regis),
40% (1:1 ethanol/methanol)/60% heptane as eluent, 15 mL/min flow
rate, and UV detection at 254 nm. Example 20: .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 2.83-2.99 (m, 3H) 4.05 (dd, J=16.29, 4.21
Hz, 1H) 4.26-4.35 (m, 1H) 6.17 (s, 1H) 6.59 (br. s., 1H) 6.68 (d,
J=8.05 Hz, 1H) 6.83 (dd, J=7.32, 2.20 Hz, 1H) 6.87-6.98 (m, 2H)
7.14 (t, J=7.69 Hz, 1H) 7.22-7.27 (m, 1H) 7.30 (d, J=7.32 Hz, 1H)
7.32-7.36 (m, 1H) 7.38-7.43 (m, 1H) 7.60 (dd, J=7.87, 1.65 Hz, 1H)
8.66 (br. s., 1H). MS (ESI) m/z 485.97 (M+H).sup.+. Chiral
analytical HPLC retention times: peak 1, 8.35 min; Example 20,
10.21 min using the following chromatography conditions: Whelk-01
(R,R) column (4.6 mm ID.times.250 mm L, 10 micron), 60% (1:1
ethanol/methanol)/40% heptane as eluent, 1 mL/min flow rate, and UV
detection at 254 nm.
Example 21
3-[17-Ethyl-4-methyl-3,12-dioxo-7-(propane-2-sulfonyl)-4,11-diaza-tricyclo-
[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen-2-ylamino]-b-
enzamide trifluoroacetic acid salt
##STR00152##
[0652] 21A: Benzyl 4-(4-bromo-2-ethylphenyl)butanoate
##STR00153##
[0654] Using a procedure analogous to that used to prepare 8A,
benzyl but-3-enoate (3.63 g, 0.020 mmol, reference for preparation:
Cardillo, G.; De Simone, A.; Mingardi, A.; Tomasini, C. Synlett
1995, 11, 1131-2) was reacted with 4-bromo-2-ethyl-iodobenzene
(6.23 g, 0.020 mmol) to give 21A (1.5 g, 21%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 1.18 (t, J=7.69 Hz, 3H) 1.84-1.94 (m,
2H) 2.41 (t, J=7.25 Hz, 2H) 2.55-2.62 (m, 4H) 5.12 (s, 1H) 6.96 (d,
J=7.91 Hz, 1H) 7.22 (dd, J=7.91, 2.20 Hz, 1H) 7.29 (d, J=2.20 Hz,
1H) 7.30-7.40 (m, 5H).
21B: tert-Butyl
5-(4-(4-bromo-2-ethylphenyl)butanamido)-2-(isopropylthio)benzyl(methyl)ca-
rbamate
##STR00154##
[0656] Lithium hydroxide monohydrate (0.176 g, 4.19 mmol) was added
to a solution of 21A (0.504 g, 1.4 mmol) in a mixture of THF (2
mL), water (2 mL), and methanol (several drops). After 1 h,
additional lithium hydroxide was added. The reaction mixture was
concentrated in vacuo to remove most of the THF and methanol,
acidified with hydrochloric acid (1N), and extracted with ethyl
acetate (3.times.). The combined organics were washed with brine,
dried, and concentrated in vacuo to give the acid (0.376 g) as a
clear oil. This material was converted to the acid chloride and
then coupled to aniline 16E (0.434 g, 1.4 mmol) using a procedure
analogous to that described for preparation of 17B, to give 21B
(0.700 g, 89%) as a yellow oil.
21C: tert-Butyl
5-(4-(4-bromo-2-ethylphenyl)butanamido)-2-(isopropylsulfonyl)benzyl(methy-
l)carbamate
##STR00155##
[0658] Using a procedure analogous to that described for the
preparation of 16G, 21B (0.700 g, 1.25 mmol) was reacted with mCPBA
(0.695 g, 3.10 mmol) to give 21C (0.513 g, 69%). MS (ESI) m/z 595,
597.4 (M+H).sup.+.
21D:
4-(4-(3-((tert-Butoxycarbonyl(methyl)amino)methyl)-4-(isopropylsulfon-
yl)phenylamino)-4-oxobutyl)-3-ethylphenylboronic acid
##STR00156##
[0660] Using a procedure analogous to that described for the
preparation of 6D, 21C (0.513 g, 0.86 mmol) was coupled to
5,5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] (0.215 g,
0.952 mmol) and hydrolyzed to give boronic acid 21D (0.278 g, 67%).
MS (ESI) m/z 561.48 (M+H).sup.+.
21E:
2-(4-(4-(3-((tert-Butoxycarbonyl(methyl)amino)methyl)-4-(isopropylsul-
fonyl)phenylamino)-4-oxobutyl)-3-ethylphenyl)-2-(3-carbamoylphenylamino)ac-
etic acid
##STR00157##
[0662] Using a procedure analogous to that used to prepare 2D, 21D
(0.0.168 g, 0.300 mmol) was reacted with 3-aminobenzamide (0.041 g,
0.300 mmol) and glyoxylic acid monohydrate (0.028 g, 0.30 mmol) to
give, after purification by reverse phase HPLC, 21E (134 mg, 63%)
as a foam. MS (ESI) m/z 709.52 (M+H).sup.+.
Example 21
[0663] Using a procedure analogous to that described for the
preparation of 15E, 21D (134 mg, 0.189 mmol) was deprotected with
hydrogen chloride. This material was coevaporated with toluene
(2.times.) and then cyclized using a procedure analogous to that
described for preparation of 15F, with the exception that pyBOP was
substituted for BOP, to give Example 21 (39 mg, 30%) as 2:1 mixture
of two atropisomers. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm
1.00 (t, J=7.51 Hz, 1H) 1.18-1.25 (m, 3H) 1.25-1.40 (m, 5H)
1.87-1.99 (m, 0.5H) 2.04-2.17 (m, 0.5H) 2.19-2.58 (m, 3.5H)
2.68-2.92 (m, 2.5H) 3.10-3.25 (m, 0.6H) 3.53-3.69 (m, 0.7H)
4.05-4.18 (m, 0.6H) 5.55-5.71 (m, 1H) 6.57-6.66 (m, 1H) 6.80 (dd,
J=7.87, 1.65 Hz, 1H) 6.90 (dt, J=8.42, 2.38 Hz, 1H) 6.94-7.03 (m,
1.4H) 7.06 (d, J=8.06 Hz, 0.7H) 7.18-7.36 (m, 3H) 7.37-7.42 (m,
0.4H) 7.47 (d, J=1.46 Hz, 0.5H) 7.74-7.79 (m, 1H). MS (ESI) m/z
591.4 (M+H).sup.+.
Example 22
2-(1-Amino-isoquinolin-6-ylamino)-13-methyl-4,11,13-triaza-tricyclo[15.2.2-
.1.sup.6,10]docosa-1(20),6,8,10(22),17(21),18-hexaene-3,12-dione
trifluoroacetic acid salt
##STR00158##
[0664] 22A: 3-(4-bromophenyl)-N-methylpropanamide
##STR00159##
[0666] EDAC (1.56 g, 8.1 mmol) was added in one portion to
3-(4-bromophenyl)propanoic acid (2.5 g, 7.4 mmol) and HOBt (1.1 g,
8.1 mmol) in DMF (6 mL) and the reaction mixture was stirred for 2
h. The reaction mixture was cooled to 0.degree. C. and NH.sub.2Me
(2.0 M in MeOH, 29 mL, 58 mmol) was added dropwise. The solution
was stirred at 0.degree. C. for 30 min and 10 h at ambient
temperature. The reaction mixture was diluted with water (25 mL),
extracted with diethyl either (3.times.50 mL). The combined
organics were washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated in vacuo to yield 22A (1.7 g, 67%) as an off-white
solid. MS (ESI) m/z 242.22/244.22 (M+H).sup.+.
22B: 3-(4-bromophenyl)-N-methylpropan-1-amine
##STR00160##
[0668] Borane in THF (1.0 M, 28 mL, 28 mmol) was added dropwise to
a solution of 22A (1.6 g, 7.0 mmol) in THF (17.5 mL). After
stirring the reaction mixture for 30 min at 0.degree. C. the
mixture was refluxed for 4 h. Methanol (20 mL) was added to the
mixture at 0.degree. C. followed by the addition of 20 mL 6.0 M HCl
dropwise. After refluxing for 30 min the volatiles were removed in
vacuo. 50% NaOH (12 mL) was added dropwise while maintaining the
temperature below 30.degree. C. The resulting mixture was diluted
with water (100 mL) and extracted with diethyl ether (3.times.100
mL). The organics were combined, washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo to yield 22B (1.57 g,
97%) as a clear oil. MS (ESI) m/z 227.99/229.99 (M+H).sup.+.
22C: 1-(3-(4-bromophenyl)propyl)-3-(3-cyanophenyl)-1-methylurea
##STR00161##
[0670] 3-Isocyanatobenzonitrile (202 mg, 1.4 mmol) was added in one
portion to a solution of 22B (320 mg, 1.4 mmol) in methylene
chloride (10 mL). After stirring overnight the reaction mixture was
concentrated in vacuo and purified by flash chromatography (0 to
100% EtOAc in hexanes) to yield 22C (430 mg, 88%) as a clear oil.
MS (ESI) m/z 371.92/373.92 (M+H).sup.+.
22D: 4-(3-(3-(3-cyanophenyl)-1-methylureido)propyl)phenylboronic
acid
##STR00162##
[0672] Using a procedure analogous to that used to prepare 6D, 22C
(210 mg, 0.54 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 22D
(146 mg, 91%) as a clear oil. MS (ESI) m/z 338.3 (M+H).sup.+.
22E:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(3-(3-
-(3-cyanophenyl)-1-methylureido)propyl)phenyl)acetic acid
##STR00163##
[0674] Using a procedure analogous to that used to prepare 2D, 22D
(146 mg, 0.43 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 22E (124 mg, 41%) as a yellow solid. MS
(ESI) m/z 709.08 (M+H).sup.+.
22F:
2-(4-(3-(3-(3-(aminomethyl)phenyl)-1-methylureido)propyl)phenyl)-2-(1-
-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)acetic
acid
##STR00164##
[0676] Using a procedure analogous to that used to prepare 6F, 22E
(124 mg, 0.18 mmol) was hydrogenated for 14 h to give 22F (95 mg,
76%) as a yellow glass. MS (ESI) m/z 713.20 (M+H).sup.+.
Example 22
[0677] Using a procedure analogous to that used to prepare Example
6, 22F (94 mg, 0.12 mmol) was cyclized with BOP. This material was
deprotected with trifluoroacetic acid, and purified by HPLC to give
Example 22 (8 mg, 13%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
ppm 1.87-2.14 (m, 2H) 2.57-2.78 (m, 2H) 4.06 (dd, J=15.82, 4.39 Hz,
1H) 4.77 (dd, J=16.26, 7.91 Hz, 1H) 5.19-5.19 (m, 1H) 5.34 (s, 1H)
6.69 (d, J=1.76 Hz, 1H) 6.78 (d, J=7.47 Hz, 1H) 6.83 (d, J=7.03 Hz,
1H) 7.08-7.15 (m, J=7.91, 7.91 Hz, 1H) 7.22 (dd, J=9.23, 2.20 Hz,
1H) 7.30 (d, J=7.03 Hz, 1H) 7.32-7.39 (m, 2H) 7.56-7.70 (m, J=8.79
Hz, 2H) 7.73 (d, J=8.35 Hz, 1H) 8.08 (d, J=8.79 Hz, 1H) 8.86 (dd,
J=7.91, 4.39 Hz, 1H). MS (ESI) m/z 495.08 (M+H).sup.+.
Example 23
2-(1-Amino-isoquinolin-6-ylamino)-13-methyl-4,11,13-triaza-tricyclo[14.2.2-
.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
trifluoroacetic acid salt
##STR00165##
[0678] 23A: 2-(4-bromophenyl)-N-methylacetamide
##STR00166##
[0680] Using a procedure analogous to that used to prepare 22A,
2-(4-bromophenyl)acetic acid (1.6 g, 7.0 mmol) was coupled to
methylamine to yield 23A (2.0 g, 75%) as a white solid. MS (ESI)
m/z 228.20/230.20 (M+H).sup.+.
23B: 2-(4-bromophenyl)-N-methylethanamine
##STR00167##
[0682] Using a procedure analogous to that used to prepare 22B, 23A
(1.6 g, 7.0 mmol) was reduced with borane in THF to yield 23B (1.45
g, 97%) as a clear oil. MS (ESI) m/z 214.22/216.22 (M+H).sup.+.
23C: 1-(4-bromophenethyl)-3-(3-cyanophenyl)-1-methylurea
##STR00168##
[0684] Using a procedure analogous to that used to prepare 22C, 23B
(300 mg, 1.4 mmol) was reacted with 3-isocyanatobenzonitrile to
yield 23C (406 g, 81%) as a clear oil. MS (ESI) m/z 358.31/360.29
(M+H).sup.+.
23D: 4-(2-(3-(3-cyanophenyl)-1-methylureido)ethyl)phenylboronic
acid
##STR00169##
[0686] Using a procedure analogous to that used to prepare 6D, 23C
(200 mg, 0.70 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 23D
(165 mg, 91%) as a yellow oil. MS (ESI) m/z 324.03 (M+H).sup.+.
23E:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(2-(3-
-(3-cyanophenyl)-1-methylureido)ethyl)phenyl)acetic acid
##STR00170##
[0688] Using a procedure analogous to that used to prepare 2D, 23D
(164 mg, 0.50 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 23E (128 mg, 44%) as a yellow oil. MS
(ESI) m/z 695.19 (M+H).sup.+.
23F:
2-(4-(2-(3-(3-(aminomethyl)phenyl)-1-methylureido)ethyl)phenyl)-2-(1--
(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)acetic
acid
##STR00171##
[0690] Using a procedure analogous to that used to prepare 6F, 23E
(128 mg, 0.18 mmol) was hydrogenated for 14 h to give 23F (60 mg,
46%) as a yellow glass. MS (ESI) m/z 699.19 (M+H).sup.+.
Example 23
[0691] Using a procedure analogous to that used to prepare Example
6, 23F (60 mg, 0.084 mmol) was cyclized with BOP. This material was
deprotected with trifluoroacetic acid, and purified by HPLC to give
Example 23 (7 mg, 17%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
ppm 2.79-2.96 (m, 2H) 3.05 (s, 3H) 4.02 (dd, J=16.04, 3.74 Hz, 1H)
4.76 (dd, J=16.26, 7.47 Hz, 1H) 4.91 (s, 1H) 5.19 (s, 1H) 5.67 (bs,
1H) 6.66-6.72 (m, J=2.20 Hz, 1H) 6.76-6.89 (m, 3H) 7.05-7.14 (m,
J=7.69, 7.69 Hz, 1H) 7.14-7.25 (m, 2H) 7.29 (d, J=7.03 Hz, 1H)
7.32-7.46 (m, 2H) 7.61-7.73 (m, 1H) 8.05 (d, J=9.23 Hz, 1H)
8.65-8.78 (m, J=2.64 Hz, 1H). MS (ESI) m/z 481.11 (M+H).sup.+.
Example 24
(R)-2-(1-Amino-isoquinolin-6-ylamino)-13-methyl-4,11,13-triaza-tricyclo[14-
.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
trifluoroacetic acid salt
##STR00172##
[0693] Example 23 (100 mg) was purified by chiral HPLC then again
by reverse phase HPLC to give Example 24 (peak 1, 19 mg) and peak 2
(19 mg). The chromatography conditions were the following:
Chiralcel OD-H (2.0 cm.times.25 cm, 5 micron, Chiral Technologies,
Inc.), 30% MeOH/EtOH (1:1)/70% Heptane, 20 mL/min flow rate, and UV
detection at 220 nm. Peak 1 analytical data: .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 2.79-2.95 (m, 2H) 3.05 (s, 3H) 4.04 (d,
J=16.26 Hz, 1H) 4.70 (d, J=16.26 Hz, 1H) 5.13 (s, 1H) 6.60 (d,
J=2.20 Hz, 1H) 6.71 (d, J=6.15 Hz, 1H) 6.77-6.88 (m, 2H) 7.01-7.14
(m, 2H) 7.22 (d, J=7.91 Hz, 1H) 7.34 (d, J=7.47 Hz, 1H) 7.41-7.51
(m, 2H) 7.65 (dd, J=7.91, 1.76 Hz, 1H) 7.88 (d, J=9.23 Hz, 1H). MS
(ESI) m/z 481.2 (M+H).sup.+. Chiral analytical HPLC retention
times: peak 1, 8.05 min; peak 2, 10.45 min using the following
chromatography conditions: Chiral OD (4.6.times.250 mm, 10 micron),
30% (1:1 ethanol methanol)/70% heptane as eluent, 1 mL/min flow
rate and UV detection at 254 nm.
Example 25
(R)-2-(1-Amino-isoquinolin-6-ylamino)-7-ethanesulfonyl-13-methyl-4,11,13-t-
riaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexae-
ne-3,12-dione
##STR00173##
[0694] 25A: phenyl 3-cyano-4-(ethylsulfonyl)phenylcarbamate
##STR00174##
[0696] Phenylchloroformate (0.63 mL, 5 mmol) was added dropwise to
a solution of 6B in methylene chloride (10 mL) and pyridine (0.60
mL, 7.1 mmol) at 0.degree. C. After stirring for 1 h, the reaction
mixture was partitioned between 1.0 M HCl (150 mL) and EtOAc (150
mL). The layers were separated and the organic phase was washed
with saturated NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4 and
concentrated. The crude product was purified by flash
chromatography (0% to 100% EtOAc in hexanes) to yield 25A (1.34 g,
85%) as a white solid. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
ppm 1.32 (t, J=7.45 Hz, 3H) 3.36 (q, J=7.33 Hz, 2H) 7.14-7.21 (m,
J=7.58 Hz, 2H) 7.26-7.31 (m, J=7.45, 7.45 Hz, 1H) 7.37-7.45 (m,
J=7.83, 7.83 Hz, 2H) 7.66 (bs, 1H) 7.83 (dd, J=8.72, 2.15 Hz,
1H).
25B:
1-(4-bromophenethyl)-3-(3-cyano-4-(ethylsulfonyl)phenyl)-1-methylurea
##STR00175##
[0698] A solution of 25A (750 mg, 2.3 mmol) and 23B (486 mg, 4.5
mmol) with potassium carbonate (627 mg, 2.3 mmol) in DMF (6 mL)
were heated at 50.degree. C. for 15 h. The mixture was diluted with
water (100 mL) and extracted with EtOAc (3.times.100 mL). The
organics were washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated. The crude product was purified by flash
chromatography (0% to 100% EtOAc in hexanes) to yield give 25B (950
mg, 93%) as a colorless oil. MS (ESI) m/z 449.89/451.91
(M+H).sup.+.
25C:
4-(2-(3-(3-cyano-4-(ethylsulfonyl)phenyl)-1-methylureido)ethyl)phenyl-
boronic acid
##STR00176##
[0700] Using a procedure analogous to that used to prepare 6D, 25B
(950 mg, 2.1 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 25C
(679 mg, 78%) as an white solid. MS (ESI) m/z 415.93
(M+H).sup.+.
25D:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(2-(3-
-(3-cyano-4-(ethylsulfonyl)phenyl)-1-methylureido)ethyl)phenyl)acetic
acid
##STR00177##
[0702] Using a procedure analogous to that used to prepare 2D, 25C
(277 mg, 0.67 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 25D (460 mg, 88%) as a yellow solid. MS
(ESI) m/z 787.00 (M+H).sup.+.
25E:
2-(4-(2-(3-(3-(aminomethyl)-4-(ethylsulfonyl)phenyl)-1-methylureido)e-
thyl)phenyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)ace-
tic acid
##STR00178##
[0704] A solution of 25D (460 mg, 0.59 mmol) in MeOH (50 mL) with
catalytic Raney Ni was stirred under an atmosphere of H.sub.2 (70
psi) for 20 h. The reaction mixture was filtered through Celite and
concentrated to give 25E (340 mg, 73%) as a yellow oil. MS (ESI)
m/z 790.95 (M+H).sup.+.
Example 25
[0705] BOP (380 mg, 0.86 mmol) and DIEA (0.375 mL, 2.2 mmol) were
20 added to a solution of 25E (340 mg, 0.49 mmol) in
CH.sub.2Cl.sub.2 (100 mL) and stirred for 15 h. The mixture was
concentrated in vacuo. The residue was redissolved in
CH.sub.2Cl.sub.2 (4 mL) and TFA (2 mL) with 5 drops of water and
stirred at 40.degree. C. for 1 h. The mixture was concentrated and
purified by reverse phase HPLC and chiral HPLC to yield peak 1 (3.5
mg) and Example 25 (peak 2, 2.5 mg, 5%) as a white solid. The
chromatography conditions were the following: Chiralcel OD-H (2.0
cm.times.25 cm, 5 micron, Chiral Technologies, Inc.), 24% MeOH/EtOH
(1:1)/75% Heptane, 15 mL/min flow rate, and UV detection at 220 nm.
Peak 2 analytical data .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
ppm 1.22 (t, J=7.45 Hz, 3H) 2.79-2.95 (m, 2H) 3.08 (s, 3H) 3.28 (q,
J=7.45 Hz, 2H) 4.19-4.38 (m, 1H) 4.99-5.14 (m, J=24.25 Hz, 1H) 5.23
(s, 1H) 5.25 (none, 1H) 6.71 (d, J=2.02 Hz, 1H) 6.85 (d, J=7.07 Hz,
1H) 7.01 (s, 1H) 7.10-7.23 (m, J=9.22, 2.40 Hz, 2H) 7.25-7.34 (m,
J=7.07 Hz, 2H) 7.37-7.46 (m, 1H) 7.70 (d, J=8.59 Hz, 2H) 8.06 (d,
J=9.09 Hz, 1H) 8.74-8.85 (m, 1H). MS (ESI) m/z 572.93 (M+H).sup.+.
Chiral analytical HPLC retention times: peak 1, 19.26 min; peak 2,
21.62 min using the following chromatography conditions: Chiral OD
(4.6.times.250 mm, 10 micron), 25% (1:1 ethanol/methanol)/75%
heptane as eluent, 1 mL/min flow rate and UV detection at 254
nm.
Example 26
2-(1-Amino-isoquinolin-6-ylamino)-7-ethanesulfonyl-13-oxa-4,11-diaza-tricy-
clo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dio-
ne trifluoroacetic acid salt
##STR00179##
[0706] 26A: 4-bromophenethyl
3-cyano-4-(ethylsulfonyl)phenylcarbamate
##STR00180##
[0708] NaH (138 mg, 3.45 mmol, 60% dispersion in oil) was added to
a solution of 2-(4-bromophenyl)ethanol (833 mg, 4.1 mmol) in THF (7
mL) at 0.degree. C. and stirred for 10 min. The mixture was cooled
to -40.degree. C. and 25A (500 mg, 1.38 mmol) in THF (7 mL) was
added. After stirring warming to 0.degree. C. over 1 h and stirring
at 0.degree. C. for 3 h the mixture was partitioned between EtOAc
and brine (100 mL each). The layers were separated and the organic
layer was washed with 5% NaOH, brine and concentrated in vacuo. The
crude solid was purified by flash chromatrography (0% to 50% EtOAc
in Hexanes) to yield 26A (600 mg, 99%) as a white solid. .sup.1H
NMR (400 MHz, DMSO-D.sub.6) .delta. ppm 1.12 (t, J=7.47 Hz, 2H)
2.95 (t, J=6.59 Hz, 2H) 3.38 (q, J=7.18 Hz, 2H) 4.36 (t, J=6.59 Hz,
2H) 7.27 (d, J=8.35 Hz, 2H) 7.92 (dd, 1H) 8.00 (d, 1H) 8.08 (d,
J=2.20 Hz, 1H) 10.51 (s, 1H).
26B:
4-(2-(3-cyano-4-(ethylsulfonyl)phenylcarbamoyloxy)ethyl)phenylboronic
acid
##STR00181##
[0710] Using a procedure analogous to that used to prepare 6D, 26A
(600 mg, 2.54 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 26B
(455 mg, 82%) as a white solid. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. ppm 1.24 (t, J=7.47 Hz, 3H) 3.01 (t, J=6.81 Hz, 2H) 3.35
(q, J=7.32 Hz, 2H) 4.42 (t, J=6.59 Hz, 2H) 7.29 (d, J=7.91 Hz, 2H)
7.56 (d, J=7.91 Hz, 2H) 7.86 (dd, J=9.01, 1.98 Hz, 1H) 7.99 (d,
J=8.79 Hz, 1H) 8.11 (d, J=2.20 Hz, 1H) 10.12 (s, 1H).
26C:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(2-(3-
-cyano-4-(ethylsulfonyl)phenylcarbamoyloxy)ethyl)phenyl)acetic
acid
##STR00182##
[0712] Using a procedure analogous to that used to prepare 2D, 26B
(225 mg, 0.57 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 26C (374 mg, 86%) as a yellow solid. MS
(ESI) m/z 773.86 (M+H).sup.+.
26D:
2-(4-(2-(3-(aminomethyl)-4-(ethylsulfonyl)phenylcarbamoyloxy)ethyl)ph-
enyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)acetic
acid
##STR00183##
[0714] Using a procedure analogous to that used to prepare 25E, 26C
(374 mg, 0.21 mmol) was hydrogenated for 15 h to give 26D (270 mg,
72%) as a yellow glass. MS (ESI) m/z 777.93 (M+H).sup.+.
Example 26
[0715] Using a procedure analogous to that used to prepare Example
25, 26D (270 mg, 0.35 mmol) was cyclized with BOP. This material
was deprotected with trifluoroacetic acid, and purified by HPLC to
give Example 26 (40 mg, 21%). .sup.1H NMR (400 MHz, DMSO-D.sub.6)
.delta. ppm 1.12 (t, J=7.25 Hz, 3H) 2.71-2.83 (m, 1H) 2.85-3.01 (m,
1H) 3.27-3.37 (m, 2H) 4.18 (d, J=11.86 Hz, 2H) 4.64-4.75 (m, 1 H)
4.91 (dd, J=16.92, 6.37 Hz, 1H) 5.20 (d, J=6.59 Hz, 1H) 6.55 (d,
J=2.20 Hz, 1H) 6.66 (s, 1H) 6.78-6.89 (m, 2H) 7.02-7.13 (m, 2H)
7.22-7.44 (m, 3H) 7.58 (d, J=7.03 Hz, 1H) 7.63-7.72 (m, 2H) 8.13
(d, J=9.23 Hz, 1H) 8.42 (s, 2H) 9.72 (s, 1H) 12.40 (s, 1H). MS
(ESI) m/z 559.84 (M+H).sup.+.
Example 27
(R)-2-(1-Amino-isoquinolin-6-ylamino)-7-ethanesulfonyl-13-oxa-4,11-diaza-t-
ricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-
-dione
##STR00184##
[0717] Example 26 (60 mg) was purified was purified by chiral HPLC
to give peak 1 (14 mg) and Example 27 (peak 2, 14 mg). The
chromatography conditions were the following: Whelk-O 1 (R,R)
(500.times.21.1 mm ID; 10 micron, Regis Technologies), 60%
MeOH/EtOH (1:1), 40% Heptane, 0.1% DEA, 15 mL/min flow rate, and UV
detection at 254 nm. Peak 2 analytical data: .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 1.22 (t, J=7.42 Hz, 3H) 1.22 (t, J=7.42 Hz,
3H) 2.82-3.01 (m, 2H) 3.32-3.35 (m, 2H) 4.15-4.24 (m, 1H) 4.30 (d,
J=17.04 Hz, 1H) 4.76-4.83 (m, 1H) 5.02 (d, J=17.04 Hz, 1H) 5.13 (s,
1H) 6.59 (d, J=2.20 Hz, 1H) 6.66-6.75 (m, 2H) 6.83 (dd, J=8.52,
1.92 Hz, 1H) 6.99 (dd, J=9.07, 2.47 Hz, 1H) 7.10-7.17 (m, 1H)
7.19-7.25 (m, 1H) 7.43 (dd, J=7.97, 1.37 Hz, 1H) 7.51 (d, J=6.05
Hz, 1H) 7.61 (dd, J=7.70, 1.65 Hz, 1H) 7.73 (d, J=8.24 Hz, 1H) 7.80
(d, J=8.79 Hz, 1H). Chiral analytical HPLC retention times: peak 1,
17.75 min; peak 2, 20.50 min using the following chromatography
conditions: Welko-O1 (R, R) column (250.times.4.6 mm ID; 5 micron,
60% MeOH/EtOH (1:1), 40% Heptane, 0.1% DEA as eluent, 1 mL/min flow
rate and UV detection at 254 nm.
Example 28
3-(7-Ethanesulfonyl-13-methyl-3,12-dioxo-4,11,13-triaza-tricyclo[14.2.2.1.-
sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen-2-ylamino)-benzamide
##STR00185##
[0718] 28A: Benzyl 5-amino-2-(ethylsulfonyl)benzylcarbamate
##STR00186##
[0720] To a solution of 3-(aminomethyl)-4-(ethylsulfonyl)aniline
(1.1 g, 5.1 mmol) in DMF (5 mL) and TEA (2.75 mL) was added benzyl
2,5-dioxopyrrolidin-1-yl carbonate (1.4 g, 5.7 mmol) in DCM (15
mL). The solution was stirred for 18 h before quenching with water
(25 mL). The reaction mixture was extracted with DCM (2.times.30
mL), washed with brine and dried (MgSO.sub.4). The organic layer
was concentrated in vacuo and the residue purified by flash
chromatography (0-100% EtOAc/Hexane) to afford 28A (1.0 g, 59%) as
an oil. MS (ESI) m/z 349.2 (M+H).sup.+.
28B: 3-((benzyloxycarbonylamino)methyl)-4-(ethylsulfonyl)phenyl
phenyl carbamic acid
##STR00187##
[0722] To a solution of 28A (1 g, 3 mmol), DCM (10 mL) and pyridine
(10 mL) at 0.degree. C. was added phenyl chloroformate (0.38 mL, 3
mmol) dropwise over 30 min. The reaction was quenched with 1 N HCl
(50 mL) and extracted with EtOAc (3.times.30 mL). The combined
organics were washed with saturated NaHCO.sub.3, brine and dried
(MgSO.sub.4). The organic layer was concentrated in vacuo and the
residue purified by flash chromatography (0-100% EtoAc/Hexane) to
afford 28B (877 mg, 62%) as an oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 1.25 (t, 3H) 5.06 (d, J=8.35 Hz, 4H)
7.09-7.19 (m, 5H) 7.31-7.36 (m, 5H) 7.42-7.47 (m, 1H) 7.70 (d,
J=8.79 Hz, 1H) 7.83 (d, J=8.35 Hz, 1H).
28C: benzyl 4-bromophenethyl(methyl)carbamate
##STR00188##
[0724] Benzyl chloroformate (0.97 mL, 6.7 mmol) was added dropwise
to a solution of 23B (1.1 g, 5.1 mmol) in CH.sub.2Cl.sub.2 (26 mL)
and triethylamine (1 mL, 7.5 mmol). The reaction mixture was washed
with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo.
Purification by flash chromatography (0% to 50% EtOAc in hexanes)
afforded 28C (1.15 g, 65%) as a clear oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 2.70-2.94 (m, 5H) 3.47 (m, 2H) 5.08 (m, 2H)
6.90-7.12 (m, 2H) 7.26-7.44 (m, 7H).
28D: 4-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)phenylboronic
acid
##STR00189##
[0726] Using a procedure analogous to that used to prepare 6D, 28C
(1.14 g, 3.3 mmol) was
5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 28D (760
mg, 74%) as a white solid. MS (ESI) m/z 313.97 (M+H).sup.+.
28E:
2-(4-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)phenyl)-2-(3-carbamoy-
lphenylamino)acetic acid
##STR00190##
[0728] Using a procedure analogous to that used to prepare 2D, 28D
(400 mg, 1.3 mmol) was reacted with 3-aminobenzamide and glyoxylic
acid monohydrate to afford 28E (661 mg, 76%) as a yellow solid. MS
(ESI) m/z 462.32 (M+H).sup.+.
28F:
2-(3-carbamoylphenylamino)-2-(4-(2-(methylamino)ethyl)phenyl)acetic
acid
##STR00191##
[0730] A solution of 28E (265 mg, 0.39 mmol) and Pd/C (10%, 40 mg)
was stirred under H.sub.2 (1 atm) for 15 h. The reaction was
filtered through Celite and concentrated to yield 28F (126 mg, 99%)
as a yellow oil. MS (ESI) m/z 328.29 (M+H).sup.+.
28G:
2-(4-(2-(3-(3-((benzyloxycarbonylamino)methyl)-4-(ethylsulfonyl)pheny-
l)-1-methylureido)ethyl)phenyl)-2-(3-carbamoylphenylamino)acetic
acid
##STR00192##
[0732] Using a procedure analogous to that used to synthesize 25B,
28F (227 mg, 0.69 mmol) was reacted with 28B to yield 28G (230 mg,
49%) as a yellow solid. MS (ESI) m/z 702.44 (M+H).sup.+.
28H:
2-(4-(2-(3-(3-(aminomethyl)-4-(ethylsulfonyl)phenyl)-1-methylureido)e-
thyl)phenyl)-2-(3-carbamoylphenylamino)acetic acid
##STR00193##
[0734] A solution of 28G (225 mg, 0.32 mmol) in THF/MeOH/EtOAc
(1:1:1) and HCl (1.0 M, 1.5 mL) with Pd/C (50 mg, 10%) was stirred
under H.sub.2 (60 psi) for 20 h. The mixture was filtered through
Celite and concentrated in vacuo to yield 28H (160 mg, 83%). MS
(ESI) m/z 568.3 (M+H).sup.+.
Example 28
[0735] A solution of 28H (160 mg, 0.27 mmol) in DMF (4 mL) was
added dropwise over 2 h to a solution of BOP (235 mg, 0.53 mmol),
DMAP (162 mg, 1.33 mmol) and DIEA (0.23 mL, 1.33 mmol) at
40.degree. C. After stirring an additional 2 h at rt, the mixture
was concentrated in vacuo and purified by reverse phase HPLC to
yield Example 28 (30 mg, 21%) as a white solid. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. ppm 1.22 (t, J=7.15 Hz, 3H) 2.80-2.96 (m,
2H) 3.06 (s, 3H) 3.30 (m, 2H) 4.18-4.40 (m, 1H) 4.89-4.99 (m, 1H)
5.07 (s, 1H) 6.78-6.93 (m, 1H) 7.04-7.22 (m, 5H) 7.27-7.42 (m, 2H)
7.62 (d, J=6.60 Hz, 1H) 7.69 (d, J=8.24 Hz, 1H) 8.82 (s, 1H). MS
(ESI) m/z 550.3 (M+H).sup.+.
Example 29
3-((R)-7-Ethanesulfonyl-13-methyl-3,12-dioxo-4,11,13-triaza-tricyclo[14.2.-
2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen-2-ylamino)-benzami-
de
##STR00194##
[0737] Example 28 (30 mg) was purified by chiral HPLC and then
again by reverse phase HPLC to give peak 1 (5 mg) and Example 28
(peak 2, 5 mg). The chromatography conditions were the following:
Chiralcel AD-H (2.0 cm.times.25 cm, 5 micron, Chiral Technologies,
Inc.), 60% MeOH/EtOH (1:1)/40% Heptane, 15 mL/min flow rate, and UV
detection at 220 nm. Peak 2 analytical data: .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 1.21 (t, J=7.47 Hz, 3H) 2.80-2.94 (m,
J=3.08 Hz, 2H) 3.06 (s, 3H) 3.30 (m, 2H) 4.18-4.40 (m, 1H)
4.91-4.99 (m, 1H) 5.07 (s, 1H) 6.73-6.85 (m, 1H) 6.93-7.20 (m, 5H)
7.26-7.40 (m, J=7.47 Hz, 2H) 7.63 (d, J=6.59 Hz, 1H) 7.69 (d,
J=8.79 Hz, 1H). MS (ESI) m/z 550.21 (M+H).sup.+. Chiral analytical
HPLC retention times: peak 1, 13.42 min; peak 2, 18.30 min using
the following chromatography conditions: Chiral AD (4.6.times.250
mm, 10 micron), 40% (1:1 ethanol/methanol)/60% heptane as eluent, 1
mL/min flow rate and UV detection at 254 nm.
Example 30
2-(1-Amino-isoquinolin-6-ylamino)-20-methyl-13-oxa-4,11-diaza-tricyclo[14.-
2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
trifluoroacetic acid salt
##STR00195##
[0738] 30A: 4-bromo-2-methyl-1-vinylbenzene
##STR00196##
[0740] KF (870 mg, 15 mmol), n-Bu.sub.4NCl (2.77 g, 10 mmol),
Pd(dba).sub.2 (145 mg, 0.25 mmol), molecular sieves (4 Ang, 200 mg,
activated balls), 5-bromo-2-iodo-1-methylbenzene (1.49 g, 5 mmol),
trimethyl(vinyl)silane (2.7 mL, 20 mmol), and toluene (10 mL) were
added to a pressure vessel and sparged with Ar. The vial was sealed
and microwaved at 170.degree. C. for 30 min. The mixture was cooled
to ambient temperature, diluted with hexanes, filtered and
concentrated. The crude oil was purified by flash chromatography
(100% hexanes) to yield 30A (750 mg, 76%) as a clear oil. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. ppm 2.31 (s, 3H) 5.31 (dd,
J=10.99, 1.10 Hz, 1H) 5.62 (dd, J=17.59, 1.10 Hz, 1H) 6.84 (dd,
J=17.04, 10.99 Hz, 1H) 7.26-7.35 (m, 3H).
30B: 2-(4-bromo-2-methylphenyl)ethanol
##STR00197##
[0742] A solution of 30A (1.5 g, 7.6 mmol) in 0.5 M 9-BBN in THF
(40 mL, 20 mmol) was heated at 120.degree. C. in a sealed tube for
15 min in a microwave. The mixture was cooled to 0.degree. C. in a
250 mL Erlenmeyer flask. NaOH (1.0 M, 40 mL) then H.sub.2O.sub.2
(30%, 40 mL) were added slowly dropwise while maintaining the
internal temperature below 30.degree. C. HCl (1.0 M, 40 mL) was
added and the mixture was extracted with Et.sub.2O (2.times.100
mL). The organics were combined, washed with NaHCO.sub.3, brine,
dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude
oil was purified by flash chromatography (0% to 50% hexanes in
EtOAc) to yield 30B (1.05 g, 64%) as a clear oil. .sup.1H NMR (400
MHz, MeOD) .delta. ppm 2.30 (s, 3H) 2.80 (t, J=7.20 Hz, 2H) 3.69
(t, J=7.07 Hz, 2H) 7.06 (d, J=8.08 Hz, 1H) 7.23 (dd, J=8.21, 1.89
Hz, 1H) 7.28-7.31 (m, 1H).
30C: 4-bromo-2-methylphenethyl 3-cyanophenylcarbamate
##STR00198##
[0744] NaH (150 mg, 60% disperson in oil) was added portionwise to
a solution of 30B (570 mg, 2.65 mmol) in THF (26.5 mL) and the
mixture was stirred for 30 min. The solution was cooled to
-78.degree. C. and 3-isocyanatobenzonitrile (382 mg, 2.65 mmol) was
added in one portion. The cooling bath was removed and the reaction
was stirred for 2 h. Water (100 mL) was added to the reaction
mixture and it was extracted with EtOAc (2.times.75 mL). The
organics were combined, washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was
purified by flash chromatography (0 to 100% EtOAc in hexanes) to
yield 30C (590 mg, 62%). .sup.1H NMR (400 MHz, DMSO-D.sub.6)
.delta. ppm 2.30 (s, 3H) 2.92 (t, J=6.95 Hz, 2H) 4.28 (t, J=6.95
Hz, 2H) 7.17 (d, J=8.34 Hz, 1H) 7.32 (dd, J=8.21, 1.89 Hz, 1H) 7.39
(d, J=1.77 Hz, 1H) 7.41-7.55 (m, 2H) 7.70 (d, J=8.08 Hz, 1H) 7.85
(s, 1H) 9.97 (s, 1H).
30D: 4-(2-(3-cyanophenylcarbamoyloxy)ethyl)-3-methylphenylboronic
acid
##STR00199##
[0746] Using a procedure analogous to that used to prepare 6D, 30C
(730 mg, 2.0 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 30D
(420 mg, 64%) as a brown oil. .sup.1H NMR (400 MHz, MeOD) .delta.
ppm 2.29 (s, 3H) 2.94 (t, J=7.07 Hz, 2H) 4.26 (t, J=7.07 Hz, 2H)
7.11 (d, J=7.33 Hz, 1H) 7.24 (d, J=7.58 Hz, 1H) 7.33 (t, J=7.96 Hz,
1H) 7.36-7.52 (m, 2H) 7.56 (d, J=7.83 Hz, 1H) 7.77 (s, 1H).
30E:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(2-(3-
-cyanophenylcarbamoyloxy)ethyl)-3-methylphenyl)acetic acid
##STR00200##
[0748] Using a procedure analogous to that used to prepare 2D, 30D
(420 mg, 1.30 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 30E (308 mg) as a tan solid. MS (ESI)
m/z 696.15 (M+H).sup.+.
30F:
2-(4-(2-(3-(aminomethyl)phenylcarbamoyloxy)ethyl)-3-methylphenyl)-2-(-
1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)acetic
acid
##STR00201##
[0750] Using a procedure analogous to that used to prepare 25E, 30E
(308 mg, 0.44 mmol) was hydrogenated for 15 h and purified by
reverse phase HPLC to give 30F (140 mg, 45%) as a yellow solid. MS
(ESI) m/z 700.15 (M+H).sup.+.
Example 30
[0751] Using a procedure analogous to that used to prepare Example
28, 30F (140 mg, 0.2 mmol) was cyclized with PyBOP instead of BOP,
deprotected with TFA, and purified by reverse phase HPLC to give
Example 30 (40 mg, 42%) as a white solid. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 2.32 (s, 1.5H) 2.48 (s, 1.5H) 2.70-2.88 (m,
1H) 3.04-3.22 (m, 1H) 3.88-4.23 (m, 2H) 4.41-4.61 (m, 1H) 4.64-4.80
(m, 1H) 5.09-5.17 (m, J=3.54 Hz, 1H) 6.09-6.26 (m, J=12.13 Hz, 1H)
6.61-6.72 (m, 2H) 6.72-6.83 (m, J=12.88, 7.07 Hz, 1H) 6.83-6.94 (m,
J=7.58 Hz, 1H) 7.03-7.20 (m, 3H) 7.21-7.33 (m, 2H) 7.36-7.54 (m,
1H) 7.98-8.10 (m, J=9.09, 5.05 Hz, 1H) 8.50-8.70 (m, 1H), mixture
of two atropisomers. MS (ESI) m/z 482.20 (M+H).sup.+.
Example 31
2-(1-Amino-isoquinolin-6-ylamino)-7-ethanesulfonyl-20-methyl-13-oxa-4,11-d-
iaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen-
e-3,12-dione trifluoroacetic acid salt
##STR00202##
[0752] 31A: 4-bromo-2-methylphenethyl
3-cyano-4-(ethylsulfonyl)phenylcarbamate
##STR00203##
[0754] NaH (230 mg, 4.4 mmol, 60% disperson in oil) was added
portionwise to a solution of 30B (490 mg, 2.3 mmol) in THF (12 mL)
and the mixture was stirred for 30 min. The solution was cooled to
-40.degree. C. and 25A (760 mg, 2.3 mmol) was added in one portion.
The cooling bath was removed and the reaction was stirred for 2 h.
The reaction mixture was cooled to -40.degree. C. and quenched by
the addition of NH.sub.4Cl (5 mL, sat. aq.). The resulting mixture
was partitioned between water (50 mL) and EtOAc (100 mL). The
organic phase was washed with brine, dried over Na.sub.2SO.sub.4
and concentrated in vacuo. The crude product was purified by flash
chromoatography (0 to 100% EtOAc in hexanes) to yield 31A (745 mg,
72%) as a white solid. .sup.1H NMR (400 MHz, MeOD) .delta. ppm 1.94
(t, J=7.42 Hz, 3H) 3.11 (s, 3H) 4.19 (q, J=7.15 Hz, 2H) 5.14 (t,
J=6.87 Hz, 2H) 7.99 (d, J=8.24 Hz, 1H) 8.14 (dd, J=7.70, 2.20 Hz,
1H) 8.21 (d, J=1.65 Hz, 1H) 8.72-8.77 (m, 1H) 8.79-8.84 (m, 1H)
8.90 (d, J=2.20 Hz, 1H).
31B:
4-(2-(3-cyano-4-(ethylsulfonyl)phenylcarbamoyloxy)ethyl)-3-methylphen-
ylboronic acid
##STR00204##
[0756] Using a procedure analogous to that used to prepare 6D, 31A
(745 mg, 1.66 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 31B
(468 mg, 68%) as a tan foam. .sup.1H NMR (400 MHz, MeOD) .delta.
ppm 1.25 (t, J=7.33 Hz, 3H) 2.34-2.40 (m, 3H) 3.03 (t, J=6.95 Hz,
2H) 3.35 (q, J=7.33 Hz, 2H) 4.39 (t, J=7.07 Hz, 2H) 7.20 (d, J=7.33
Hz, 1H) 7.30-7.43 (m, 2H) 7.86 (dd, J=8.84, 1.77 Hz, 1H) 7.99 (d,
J=8.84 Hz, 1H) 8.11 (d, J=2.02 Hz, 1H) 10.05 (s, 1H).
31C:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(2-(3-
-cyano-4-(ethylsulfonyl)phenylcarbamoyloxy)ethyl)-3-methylphenyl)acetic
acid
##STR00205##
[0758] Using a procedure analogous to that used to prepare 2D, 31B
(468 mg, 1.1 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 31C (419 mg, 44%) as a pale yellow
solid. MS (ESI) m/z 788.07 (M+H).sup.+.
31D:
2-(4-(2-(3-(aminomethyl)-4-(ethylsulfonyl)phenylcarbamoyloxy)ethyl)-3-
-methylphenyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)a-
cetic acid
##STR00206##
[0760] Using a procedure analogous to that used to prepare 25E, 31C
(419 mg) was hydrogenated for 15 h to give 31D (400 mg, 95%) as a
yellow glass. MS (ESI) m/z 792.43 (M+H).sup.+.
Example 31
[0761] Using a procedure analogous to that used to prepare Example
28, 31D (400 mg, 0.51 mmol) was cyclized with PyBOP instead of BOP,
deprotected with TFA, and purified by reverse phase HPLC to give
Example 31 (100 mg, 35%) as a tan solid. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 1.09-1.24 (m, 3H) 2.27 (s, 2H) 2.49 (s, 2H)
2.67-2.88 (m, 1H) 3.05-3.17 (m, 1H) 3.22-3.28 (m, 2H) 4.05 (d,
J=9.89 Hz, 0.5H) 4.13-4.25 (m, 0.5H) 4.29-4.39 (m, 1H) 5.01-5.12
(m, 2H) 5.14-5.18 (m, J=3.30 Hz, 1H) 6.43 (none, 1H) 6.68 (d,
J=2.75 Hz, 1H) 6.70-6.78 (m, J=5.50 Hz, 1H) 6.78-6.86 (m, 1H)
6.92-7.16 (m, 2.5H) 7.21 (m, 0.5H) 7.44 (m, 0.5H) 7.51 (s, 0.5H)
7.65-7.74 (m, 1H) 7.90-8.02 (m, 1H) 8.76-8.92 (m, J=6.05 Hz, 1H).
MS (ESI) m/z 574.18 (M+H).sup.+.
Example 32
2-(1-Amino-isoquinolin-6-ylamino)-7-ethanesulfonyl-17,20-dimethyl-13-oxa-4-
,11-diaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-h-
exaene-3,12-dione trifluoroacetic acid salt
##STR00207##
[0762] 32A: 5-bromo-1,3-dimethyl-2-vinylbenzene
##STR00208##
[0764] Using a procedure analogous to that used to prepare 30A,
5-bromo-2-iodo-1,3-dimethylbenzene (15.6 g, 48 mmol) was reacted
with trimethyl(vinyl)silane in a pressure vessel at 160.degree. C.
for 1 h to yield 32A (10.0 g, 94%) as a clear oil. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 2.26 (s, 6H) 5.24 (dd, J=17.86, 1.92
Hz, 1H) 5.55 (dd, J=11.54, 2.20 Hz, 1H) 7.18 (s, 2H).
32B: 2-(4-bromo-2,6-dimethylphenyl)ethanol
##STR00209##
[0766] Using a procedure analogous to that used to prepare 30B, 32A
was heated in a pressure vessel with 9-BBN at 100.degree. C. for 10
h to yield 32B (6.7 g, 62%) as a clear oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 2.31 (s, 6H) 2.89 (t, J=7.33 Hz, 2H) 3.73
(t, J=7.33 Hz, 2H) 7.16 (s, 2H).
32C: 4-bromo-2,6-dimethylphenethyl
3-cyano-4-(ethylsulfonyl)phenylcarbamate
##STR00210##
[0768] Using a procedure analogous to that used to prepare 31A, 32B
(400 mg, 1.75 mmol) was reacted with 25A (579 mg, 1.75 mmol) to
give 32C (480 mg, 59%) as a white solid. MS (ESI) m/z 465.1/467.1
(M+H).sup.+.
32D:
4-(2-(3-cyano-4-(ethylsulfonyl)phenylcarbamoyloxy)ethyl)-3,5-dimethyl-
phenylboronic acid
##STR00211##
[0770] Using a procedure analogous to that used to prepare 6D, 32C
(480 mg, 1.0 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 32D
(240 mg, 54%) as a tan solid. MS (ESI) m/z 453.12 (M+Na).sup.+.
32E:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(2-(3-
-cyano-4-(ethylsulfonyl)phenylcarbamoyloxy)ethyl)-3,5-dimethylphenyl)aceti-
c acid
##STR00212##
[0772] Using a procedure analogous to that used to prepare 2D, 32D
(240 mg, 0.56 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 32E (560 mg, 69%) as a yellow solid. MS
(ESI) m/z 802.07 (M+H).sup.+.
32F:
2-(4-(2-(3-(aminomethyl)-4-(ethylsulfonyl)phenylcarbamoyloxy)ethyl)-3-
,5-dimethylphenyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylami-
no)acetic acid
##STR00213##
[0774] Using a procedure analogous to that used to prepare 6F, 32E
(560 mg, 0.70) was hydrogenated for 14 h to give 32F (547 mg, 97%)
as a yellow solid. MS (ESI) m/z 806.12 (M+H).sup.+.
Example 32
[0775] Using a procedure analogous to that used to prepare Example
28, 32F (547 mg, 0.68 mmol) was cyclized with PyBOP instead of BOP,
deprotected with TFA, and purified by reverse phase HPLC to give
Example 32 (139 mg, 35%) as a tan solid. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 1.18 (t, J=7.42 Hz, 3H) 2.26 (s, 3H) 2.48
(s, 3H) 2.87-2.98 (m, 1H) 3.07-3.18 (m, 1H) 3.19-3.28 (m, 2H)
4.03-4.36 (m, 2H) 5.03-5.08 (m, 2H) 5.11 (s, 1H) 6.64 (d, J=13.74
Hz, 2H) 6.68-6.76 (m, 1H) 6.80 (d, J=8.25 Hz, 1H) 6.93 (s, 1H) 7.07
(d, J=9.34 Hz, 1H) 7.20 (d, J=6.60 Hz, 1H) 7.36 (s, 1H) 7.70 (d,
J=8.24 Hz, 1H) 7.94 (d, J=7.70 Hz, 1H) 7.96 (none, 1H) 8.70-8.87
(m, 1H). MS (ESI) m/z 589.21 (M+H).sup.+.
Example 33
(R)-2-(1-Amino-isoquinolin-6-ylamino)-7-ethanesulfonyl-17,20-dimethyl-13-o-
xa-4,11-diaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),-
17-hexaene-3,12-dione
##STR00214##
[0777] Example 32 (139 mg) was purified was purified by chiral HPLC
then again by reverse phase HPLC to give peak 1 (40 mg) and Example
32 (peak 2, 35 mg). The chromatography conditions were the
following: Chiralcel OD-H (2.0 cm.times.25 cm, 5 micron, Chiral
Technologies, Inc.), 40% MeOH/EtOH (1:1)/60% Heptane, 15 mL/min
flow rate, and UV detection at 220 nm. Peak 2 analytical data:
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.27 (s, 3H) 2.48 (s,
3H) 2.86-2.95 (m, J=13.19 Hz, 1H) 3.07-3.20 (m, 1H) 3.21-3.33 (m,
2H) 4.04-4.40 (m, 2H) 4.94-5.02 (m, 2H) 5.05 (s, 1H) 6.60 (d,
J=1.65 Hz, 1H) 6.66 (d, J=1.65 Hz, 1H) 6.71 (d, J=6.60 Hz, 1H) 6.80
(dd, J=8.24, 2.20 Hz, 1H) 6.95 (s, 1H) 7.02 (dd, J=9.07, 1.92 Hz,
1H) 7.33 (s, 1H) 7.40 (d, J=6.05 Hz, 1H) 7.72 (d, J=8.25 Hz, 1H)
7.85 (d, J=9.34 Hz, 1H). MS (ESI) m/z 588.2 (M+H).sup.+. Chiral
analytical HPLC retention times: peak 1, 7.55 min; peak 2, 10.87
min using the following chromatography conditions: Chiral AD
(4.6.times.250 mm, 10 micron), 40% (1:1 ethanol methanol)/60%
heptane/0.1% DEA as eluent, 0.7 mL/min flow rate and UV detection
at 270 nm.
Example 34
[(S)-2-(1-Amino-isoquinolin-6-ylamino)-20-methyl-3,12-dioxo-13-oxa-4,11-di-
aza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen--
5-yl]-acetic acid ethyl ester trifluoroacetic acid salt
##STR00215##
[0778] 34A: (S)-ethyl 3-amino-3-(3-nitrophenyl)propanoate
hydrochloride salt
##STR00216##
[0780] (S)-3-Amino-3-(3-nitrophenyl)propanoic acid (500 mg, 2.4
mmol) was dissolved in 2.0HCl in dioxane (2 mL) and concentrated in
vacuo. In a separate flask thionyl chloride (0.21 mL, 2.8 mmol) was
added to ethanol at -10.degree. C. The ethanolic solution was
stirred for 20 min at -10.degree. C. then added to the HCl salt of
(S)-3-amino-3-(3-nitrophenyl)propanoic acid. The resulting solution
was stirred at ambient temperature for 1 h and at 40.degree. C. for
3 h. The reaction mixture was concentrated in vacuo to yield 34A
(600 mg, 92%) as a white solid. MS (ESI) m/z 239.09
(M+H).sup.+.
34B: (S)-ethyl
3-(benzyloxycarbonylamino)-3-(3-nitrophenyl)propanoate
##STR00217##
[0782] N-(Benzyloxycarbonyloxy)succinimide (1.3 g, 5.2 mmol) was
added to a solution of 34A (1.3 g, 4.7 mmol) and DIEA in
CH.sub.2Cl.sub.2 (20 mL). The resulting solution was stirred for 1
h at ambient temperature then diluted with CH.sub.2Cl.sub.2 (40
mL), washed with ammonium chloride, NaHCO.sub.3, brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was
purified by flash chromatography (0% to 60% EtOAc in hexanes) to
yield 34B (1.49 g, 70%) as a clear oil. MS (ESI) m/z 395.07
(M+Na).sup.+.
34C: (S)-ethyl
3-(3-aminophenyl)-3-(benzyloxycarbonylamino)propanoate
##STR00218##
[0784] Fe (1 g, 18.5 mmol, powder) was added portionwise to a
refluxing solution of 34B (1.38 g, 3.7 mmol) in EtOH (75 mL)/water
(16 mL)/AcOH (4 mL). After refluxing for 1 h, the reaction mixture
was cooled to ambient temperature. The mixture was neutralized with
saturated NaHCO.sub.3, diluted with water and extracted with EtOAc.
The combined organics were washed with brine and concentrated. The
crude solid was purified by flash chromatography (0% to 100% EtOAc
in hexanes) to yield 34C (1.19 g, 94%) as a yellow solid. 343.23
(M+H).sup.+.
34D: (S)-ethyl
3-(benzyloxycarbonylamino)-3-(3-((4-bromo-2-methylphenethoxy)carbonylamin-
o)phenyl)propanoate
##STR00219##
[0786] Phosgene (3.5 mmol, 1.75 mL, 20% in toluene) was added to a
solution of 34C (600 mg, 1.75 mmol) and NaHCO.sub.3 (1.47 g, 17.5
mmol) at 0.degree. C. After stirring for 1 h at rt, the solution
was filtered and concentrated in vacuo. 30B (375 mg, 1.75 mmol) in
THF (20 mL) was added to the crude isocyanate and the solution was
cooled to -45.degree. C. NaH (93 mg) was added in one portion and
the mixture was warmed to 0.degree. C. and stirred for 2 h at
0.degree. C. and 15 h at ambient temperature. Ammonium chloride (5
mL, saturated) was added and the reaction mixture was diluted with
water and extracted with EtOAc. The organics were combined, washed
with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo.
The crude product was purified by flash chromatography (0% to 50%
EtOAc in hexanes) to yield 34D (578 mg, 57%) as a yellow oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.15 (t, J=7.15 Hz,
3H) 2.32 (s, 3H) 2.80-2.87 (m, J=6.87, 6.87 Hz, 2H) 2.93 (t, J=7.15
Hz, 2H) 4.05 (q, J=7.15 Hz, 2H) 4.30 (t, J=7.15 Hz, 2H) 5.02-5.18
(m, 3H) 6.95-7.09 (m, 2H) 7.23-7.37 (m, 10H).
34E:
(S)-4-(2-(3-(1-(benzyloxycarbonylamino)-3-ethoxy-3-oxopropyl)phenylca-
rbamoyloxy)ethyl)-3-methylphenylboronic acid
##STR00220##
[0788] Using a procedure analogous to that used to prepare 6D, 34D
(800 mg, 1.37 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 34E
(530 mg, 70%) as an oily brown solid. .sup.1H NMR (400 MHz, MeOD)
.delta. ppm 1.16 (t, J=7.20 Hz, 3H) 2.36 (s, 3H) 2.67-2.85 (m, 2H)
3.01 (t, J=7.07 Hz, 2H) 4.06 (q, J=7.16 Hz, 2H) 4.31 (t, J=7.07 Hz,
2H) 4.96-5.11 (m, J=12.55, 12.55, 12.55 Hz, 3H) 6.99 (d, J=7.33 Hz,
1H) 7.15-7.25 (m, J=7.83, 7.83 Hz, 3H) 7.31 (s, H) 7.35-7.43 (m,
3H).
34F:
2-(4-(2-(3-((S)-1-(benzyloxycarbonylamino)-3-ethoxy-3-oxopropyl)pheny-
lcarbamoyloxy)ethyl)-3-methylphenyl)-2-(1-(bis(tert-butoxycarbonyl)amino)i-
soquinolin-6-ylamino)acetic acid
##STR00221##
[0790] Using a procedure analogous to that used to prepare 2D, 34E
(400 mg, 0.73 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 34F (670 mg, 96%) as a yellow foam. MS
(ESI) m/z 697.15 (M+H).sup.+.
34G:
2-(4-(2-(3-((S)-1-amino-3-ethoxy-3-oxopropyl)phenylcarbamoyloxy)ethyl-
)-3-methylphenyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamin-
o)acetic acid
##STR00222##
[0792] A solution of 34F (670 mg, 0.96 mmol) in MeOH (60 mL) and
HCl (2.5 mL, 1.0 M aqueous) and Pd/C (60 mg) was stirred under an
atmosphere of H.sub.2 (60 psi) for 8 h. The solution was filtered
and concentrated in vacuo to yield 34G (600 mg, 89%) as a yellow
solid. MS (ESI) m/z 786.4 (M+H).sup.+.
Example 34
[0793] Using a procedure analogous to that used to prepare Example
28, 34F (600 mg, 0.73 mmol) was cyclized with PyBOP instead of BOP,
deprotected with TFA, and purified by reverse phase HPLC to give
Example 34 (50 mg, 23% yield) and its diastereomer (49 mg) as a tan
solids. MS (ESI) m/z 568.12 (M+H).sup.+.
Example 35
[(S)-2-(1-Amino-isoquinolin-6-ylamino)-20-methyl-3,12-dioxo-13-oxa-4,11-di-
aza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen--
5-yl]-acetic acid trifluoroacetic acid salt
##STR00223##
[0795] LiOH (1.0 M, 0.75 mL, aqueous) was added to a solution of
Example 34 (46 mg, 0.08 mmol) in THF (1 mL) and stirred for 30 min
at ambient temperature. The reaction mixture was concentrated in
vacuo and purified by reverse phase HPLC to afford Example 35 (10
mg, 23%) as a white solid. MS (ESI) m/z 539.3 (M+H).sup.+.
Example 36
3-(20-Ethyl-13-methyl-3,12-dioxo-4,11,13-triaza-tricyclo[14.2.2.1.sup.6,10-
]henicosa-1(19),6,8,10(21),16(20),17-hexaen-2-ylamino)-benzamide
##STR00224##
[0796] 36A: 4-bromo-2-ethyl-1-vinylbenzene
##STR00225##
[0798] Using a procedure analogous to that used to prepare 30A,
4-bromo-2-ethyl-1-iodobenzene (2.1 g, 6.9 mmol) was reacted with
trimethyl(vinyl)silane in a pressure vessel at 175.degree. C. for
45 min to yield 36A (1.1 g, 77%) as a clear oil. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 1.03 (t, J=7.58 Hz, 3H) 2.51 (q,
J=7.66 Hz, 2H) 5.15 (dd, J=10.99, 1.14 Hz, 1H) 5.47 (dd, J=17.31,
1.14 Hz, 1H) 6.74 (dd, J=17.43, 11.12 Hz, 1H) 7.08-7.20 (m,
3H).
36B: 2-(4-bromo-2-ethylphenyl)ethanol
##STR00226##
[0800] Using a procedure analogous to that used to prepare 30B, 36A
(1.98 g, 5.1 mmol) was heated in a pressure vessel with 9-BBN at
100.degree. C. for 15 h to yield 36B (0.95 g, 81%) as a clear oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.23 (t, J=7.58 Hz,
3H) 2.66 (q, J=7.58 Hz, 2H) 2.87 (t, J=6.82 Hz, 2H) 3.83 (t, J=6.82
Hz, 2H) 7.06 (d, J=8.08 Hz, 1H) 7.25-7.31 (m, 1H) 7.32-7.37 (m,
1H).
36C: 2-(4-bromo-2-ethylphenyl)-N-methylethanamine
##STR00227##
[0802] Mesyl anhydride (430 mg, 2.46 mmol) was added portionwise to
a solution of 36B (470 mg, 2.05 mmol) in CH.sub.2Cl.sub.2 (10 mL)
and Et.sub.3N (0.57 mL, 4.1 mmol) at 0.degree. C. After stirring
for 15 h at ambient temperature, the mixture was diluted with
CH.sub.2Cl.sub.2 (80 mL), washed with 1.0 M HCl, NaHCO.sub.3,
brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The
crude mesylate was dissolved in EtOAc (20 mL) and methyl amine
(33%, 5 mL) and heated in a pressure tube for 2 h. The reaction
mixture was concentrated in vacuo to afford 36C (500 mg, 99%) as a
yellow oil. MS (ESI) m/z 242.0/244.0 (M+H).sup.+.
36D:
1-(4-bromo-2-ethylphenethyl)-3-(3-cyanophenyl)-1-methylurea
##STR00228##
[0804] A solution of 36C (250 mg, 1.03 mmol) and
3-isocyanatobenzonitrile (164 mg, 1.03 mg) in CH.sub.2Cl.sub.2 (10
mL) was refluxed for 30 min. The solution was concentrated in vacuo
and purified by flash chromatography (0% to 100% EtOAc in hexanes)
to afford 36D (250 mg, 63%) as a yellow solid. MS (ESI) m/z
386.04/388.05 (M+H).sup.+.
36E:
4-(2-(3-(3-cyanophenyl)-1-methylureido)ethyl)-3-ethylphenylboronic
acid
##STR00229##
[0806] Using a procedure analogous to that used to prepare 6D, 36D
(500 mg, 1.3 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 36E
(183 mg, 40%) as a tan foam. MS (ESI) m/z 352.6 (M+H).sup.+.
36F:
2-(3-carbamoylphenylamino)-2-(4-(2-(3-(3-cyanophenyl)-1-methylureido)-
ethyl)-3-ethylphenyl)acetic acid
##STR00230##
[0808] Using a procedure analogous to that used to prepare 2D, 36E
(183 mg, 0.52 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 36F (95 mg, 37%) as a yellow film. MS
(ESI) m/z 500.3 (M+H).sup.+.
36G:
2-(4-(2-(3-(3-(aminomethyl)phenyl)-1-methylureido)ethyl)-3-ethylpheny-
l)-2-(3-carbamoylphenylamino)acetic acid
##STR00231##
[0810] Using a procedure analogous to that used to prepare 6F, 36F
(92 mg, 0.19 mmol) was hydrogenated for 4 h and purified by
preparatory HPLC to yield 36G (91 mg, 98%) as a yellow solid. MS
(ESI) m/z 504.3 (M+H).sup.+.
Example 36
[0811] Using a procedure analogous to that used to prepare Example
28, 36G (91 mg, 0.18 mmol) was cyclized with PyBOP instead of BOP
and purified by reverse phase HPLC to give Example 36 (10 mg, 11%)
as a yellow solid. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm
1.11 (t, J=7.45 Hz, 1.5H) 1.27 (t, J=7.45 Hz, 1.5H) 2.98 (s, 3H)
3.06 (d, J=2.27 Hz, 2H) 3.21 (q, J=7.33 Hz, 2H) 3.66-3.79 (m, 2H)
4.04 (dd, J=16.80, 5.94 Hz, 1H) 4.57-4.74 (m, 1H) 5.00-5.12 (m,
J=5.05 Hz, 1H) 6.73-6.90 (m, J=21.85, 7.20 Hz, 3H) 6.99-7.24 (m,
6H) 7.29-7.40 (m, J=6.32 Hz, 1H) 7.41-7.57 (m, 1H) 7.97 (s, 1H). MS
(ESI) m/z 486.4 (M+H).sup.+.
Example 37
3-(17,20-Diethyl-3,12-dioxo-13-oxa-4,11-diaza-tricyclo[14.2.2.1.sup.6,10]h-
enicosa-1(19),6,8,10(21),16(20),17-hexaen-2-ylamino)-benzamide
##STR00232##
[0812] 37A: 5-bromo-1,3-diethyl-2-iodobenzene
##STR00233##
[0814] A solution of 4-bromo-2,6-diethylaniline (10 g, 44 mmol) in
acetonitrile (20 mL) was added dropwise to a solution of I.sub.2
(33.4 g, 131.6 mmol), tert-butylnitrite (7.4 mL, 65.8 mmol) in
acetonitrile (80 mL), never allowing the internal temperature to
exceed 30.degree. C. After stirring 4 h at ambient temperature,
Na.sub.2SO.sub.3 (100 mL, saturated aqueous) was added and stirred
for 1 h. The mixture was extracted with hexanes (3.times.200 mL).
The organics were combined, washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated. The crude oil was purified by
flash chromatography (100% hexanes) to afford 37A (1.9 g, 13%) as a
red oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.20 (t,
J=7.45 Hz, 6H) 2.77 (q, J=7.58 Hz, 4H) 7.18 (s, 2H).
37B: 5-bromo-1,3-diethyl-2-vinylbenzene
##STR00234##
[0816] Using a procedure analogous to that used to prepare 30A, 37A
(1.9 g, 5.6 mmol) was reacted with trimethyl(vinyl)silane to yield
37B (1.2 g, 90%) as a red oil. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 1.14 (t, J=7.47 Hz, 6H) 2.60 (q, J=7.62 Hz, 4H) 5.21
(dd, J=17.80, 1.98 Hz, 1H) 5.51 (dd, J=11.42, 1.76 Hz, 1H) 6.64
(dd, J=18.02, 11.42 Hz, 1H) 7.18 (s, 2H).
37C: 2-(4-bromo-2,6-diethylphenyl)ethanol
##STR00235##
[0818] Using a procedure analogous to that used to prepare 30B, 37B
(1.2 g, 5 mmol) was heated in a pressure vessel with 9-BBN at
115.degree. C. for 1 h to yield 37C (735 mg, 58%) as an orange oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.21 (t, J=7.58 Hz,
6H) 2.66 (q, J=7.49 Hz, 4H) 2.92 (t, J=7.58 Hz, 2H) 3.66-3.77 (t,
J=7.57 Hz, 2H) 7.17 (s, 2H).
37D: 4-bromo-2,6-diethylphenethyl 3-cyanophenylcarbamate
##STR00236##
[0820] Using a procedure analogous to that used to prepare 30C, 37C
(280 mg, 1.95 mmol) was reacted with 3-isocyanatobenzonitrile to
yield 37D (670 mg, 86%) as an yellow oil. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 1.22 (t, J=7.58 Hz, 6H) 2.73 (q, J=7.58 Hz,
4H) 3.06 (t, J=8.1 Hz, 2H) 4.21 (t, J=8.1 Hz, 2H) 7.19 (s, 2H)
7.32-7.39 (m, 1H) 7.40-7.50 (m, J=8.08, 8.08 Hz, 1H) 7.66 (d,
J=8.34 Hz, 1H) 7.86 (s, 1H).
37E:
4-(2-(3-cyanophenylcarbamoyloxy)ethyl)-3,5-diethylphenylboronic
acid
##STR00237##
[0822] Using a procedure analogous to that used to prepare 6D, 37D
(670 mg, 1.7 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 37E
(278 mg, 45%) as a brown oil. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. ppm 1.16 (t, J=7.45 Hz, 6H) 2.68 (q, J=7.41 Hz, 4H) 3.03
(t, J=7.83 Hz, 2H) 4.14 (t, J=7.82 Hz, 2H) 7.13-7.29 (m, 2H)
7.30-7.45 (m, 2H) 7.59 (d, J=7.83 Hz, 1H) 7.80 (s, 1H) 9.42 (s,
1H).
37F:
2-(3-carbamoylphenylamino)-2-(4-(2-(3-cyanophenylcarbamoyloxy)ethyl)--
3,5-diethylphenyl)acetic acid
##STR00238##
[0824] Using a procedure analogous to that used to prepare 2D, 37E
(80 mg, 0.22 mmol) was reacted with 3-aminobenzamide and glyoxylic
acid monohydrate to afford 37F (81 mg, 70%) as a yellow oil. MS
(ESI) m/z 515.21 (M+H).sup.+.
37G:
2-(4-(2-(3-(aminomethyl)phenylcarbamoyloxy)ethyl)-3,5-diethylphenyl)--
2-(3-carbamoylphenylamino)acetic acid
##STR00239##
[0826] Using a procedure analogous to that used to prepare 6F, 37F
(81 mg, 0.16 mmol) was hydrogenated for 16 h to yield 37G (85 mg,
99%) as a yellow solid. MS (ESI) m/z 519.3 (M+H).sup.+.
Example 37
[0827] Using a procedure analogous to that used to prepare Example
28, 37F (90 mg, 0.15 mmol) was cyclized with PyBOP instead of BOP
and purified by reverse phase HPLC to give Example 37 (5 mg, 6%) as
a white solid. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.11
(t, J=7.45 Hz, 3H) 1.28 (t, J=7.33 Hz, 3H) 2.48-2.81 (m, 2H)
2.83-3.21 (m, 4H) 4.12 (s, 1H) 4.63 (s, 1H) 4.98 (s, 1H) 6.17 (s,
1H) 6.65 (d, J=8.08 Hz, 1H) 6.78-6.95 (m, 2H) 7.03-7.22 (m, 5H)
7.29 (s, 1H) 8.39-8.57 (m, 1H) 8.72 (s, 1H). MS (ESI) m/z 501.3
(M+H).sup.+.
Example 38
(R)-2-(1-Amino-isoquinolin-6-ylamino)-17,20-diethyl-13-oxa-4,11-diaza-tric-
yclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-di-
one
##STR00240##
[0828] 38A:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(2-(3-cya-
nophenylcarbamoyloxy)ethyl)-3,5-diethylphenyl)acetic acid
##STR00241##
[0830] Using a procedure analogous to that used to prepare 2D, 37E
(200 mg, 0.55 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 38A (304 mg, 75%) as a yellow oil. MS
(ESI) m/z 738.22 (M+H).sup.+.
38B:
2-(4-(2-(3-(aminomethyl)phenylcarbamoyloxy)ethyl)-3,5-diethylphenyl)--
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)acetic
acid
##STR00242##
[0832] Using a procedure analogous to that used to prepare 6F, 38A
(304 mg, 0.41 mmol) was hydrogenated and purified by prep HPLC to
yield 38B (150 mg, 49%) as a yellow solid. MS (ESI) m/z 742.5
(M+H).sup.+.
Example 38
[0833] Using a procedure analogous to that used to prepare Example
28, 38B (150 mg, 0.2 mmol) was cyclized with PyBOP instead of BOP,
deprotected with TFA, and purified by reverse phase HPLC to give
racemic Example 38 (20 mg, 27%) as a white solid. The racemate was
purified was purified by chiral HPLC to give peak 1 (5 mg) and
Example 38 (peak 2, 5 mg). The chromatography conditions were the
following: Whelk-O 1 (R,R) (500.times.21.1 mm ID; 10 micron, Regis
Technologies), 40% MeOH/EtOH (1:1), 60% Heptane 15 mL/min flow
rate, and UV detection at 220 nm. Peak 2 analytical data: .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.11 (t, J=7.42 Hz, 3H) 1.30
(t, 3H) 2.50-3.22 (m, 6H) 4.08 (d, J=16.49 Hz, 1H) 4.74 (d, J=15.94
Hz, 1H) 5.10 (s, 1H) 6.19 (s, 1H) 6.59-6.74 (m, 2H) 6.79 (d, J=6.60
Hz, 1H) 6.88 (d, J=7.70 Hz, 1H) 7.00-7.20 (m, 3H) 7.31-7.42 (m, 2H)
7.98 (d, J=9.34 Hz, 1H). MS (ESI) m/z 524.2 (M+H).sup.+. Chiral
analytical HPLC retention times: peak 1, 7.94 min; peak 2, 11.40
min using the following chromatography conditions: Welko-O1 (R, R)
column (250.times.4.6 mm ID; 5 micron, 50% MeOH/EtOH (1:1), 50%
Heptane, 0.1% DEA as eluent, 1 mL/min flow rate and UV detection at
254 nm.
Example 39
[(R)-2-(1-Amino-isoquinolin-6-ylamino)-20-methyl-3,12-dioxo-13-oxa-4,11-di-
aza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen--
5-yl]-acetic acid ethyl ester trifluoroacetic acid salt
##STR00243##
[0834] 39A: (R)-ethyl 3-amino-3-(3-nitrophenyl)propanoate
hydrochloride salt
##STR00244##
[0836] Using a procedure analogous to that used to prepare 34A,
(S)-3-amino-3-(3-nitrophenyl)propanoic acid (2.1 g, 10 mmol) was
reacted with thionyl chloride to afford 39A (2.75 g, 99%) as a
white solid. MS (ESI) m/z 239.08 (M+H).sup.+.
39B: (R)-ethyl
3-(benzyloxycarbonylamino)-3-(3-nitrophenyl)propanoate
##STR00245##
[0838] Using a procedure analogous to that used to prepare 34B, 39A
(2.75 g, 10 mmol) was reacted with
N-(Benzyloxycarbonyloxy)succinimide to afford 39B (3.1 g, 83%) as a
white solid. MS (ESI) m/z 395.13 (M+Na).sup.+.
39C: (R)-ethyl
3-(3-aminophenyl)-3-(benzyloxycarbonylamino)propanoate
##STR00246##
[0840] Using a procedure analogous to that used to prepare 34C, 39B
(3.1 g, 8.3 mmol) was reacted with Fe to afford 39C (2.7 g, 95%) as
a white solid. MS (ESI) m/z 343.35 (M+H).sup.+.
39D: (R)-ethyl
3-(benzyloxycarbonylamino)-3-(3-((4-bromo-2-methylphenethoxy)carbonylamin-
o)phenyl)propanoate
##STR00247##
[0842] Using a procedure analogous to that used to prepare 34D, 39C
(1.12 g, 3.3 mmol) was reacted with 30B (700 mg, 3.3 mmol) to
afford 39D (1.07 g, 56%) as a colorless oil. MS (ESI) m/z
583.13/585.13 (M+H).sup.+.
39E:
(R)-4-(2-(3-(1-(benzyloxycarbonylamino)-3-ethoxy-3-oxopropyl)phenylca-
rbamoyloxy)ethyl)-3-methylphenylboronic acid
##STR00248##
[0844] Using a procedure analogous to that used to prepare 6D, 39D
(1.07 g, 1.84 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 39E
(640 mg, 64%) as a tan foam. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. ppm 1.14 (t, J=7.15 Hz, 3H) 2.65-2.86 (m, 2H) 2.99 (t,
J=7.15 Hz, 2H) 4.05 (q, J=7.15 Hz, 2H) 4.19-4.35 (m, 2H) 4.93-5.14
(m, 3H) 6.98 (d, J=7.70 Hz, 1H) 7.12-7.33 (m, 8H) 7.34-7.45 (m, 2H)
7.45-7.59 (m, 1H) 9.14 (s, 1H)
39F:
2-(4-(2-(3-((R)-1-(benzyloxycarbonylamino)-3-ethoxy-3-oxopropyl)pheny-
lcarbamoyloxy)ethyl)-3-methylphenyl)-2-(1-(bis(tert-butoxycarbonyl)amino)i-
soquinolin-6-ylamino)acetic acid
##STR00249##
[0846] Using a procedure analogous to that used to prepare 2D, 39E
(440 mg, 0.8 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 39F (538 mg, 44%) as a brown oil. MS
(ESI) m/z 920.6 (M+H).sup.+.
39G:
2-(4-(2-(3-((R)-1-amino-3-ethoxy-3-oxopropyl)phenylcarbamoyloxy)ethyl-
)-3-methylphenyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamin-
o)acetic acid
##STR00250##
[0848] Using a procedure analogous to that used to prepare 6F, 39F
(538 mg, 0.58 mmol) was hydrogenated and purified by prep HPLC to
yield 39G (270 mg, 59%) as a yellow film. MS (ESI) m/z 786.4
(M+H).sup.+.
Example 39
[0849] Using a procedure analogous to that used to prepare Example
28, 39F (600 mg, 0.73 mmol) was cyclized, deprotected with TFA, and
purified by reverse phase HPLC to give Example 39 (80 mg, 41%) as a
brown solid. MS (ESI) m/z 568.43 (M+H).sup.+.
Example 40
[(R)-2-(1-Amino-isoquinolin-6-ylamino)-20-methyl-3,12-dioxo-13-oxa-4,11-di-
aza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen--
5-yl]-acetic acid trifluoroacetic acid salt
##STR00251##
[0851] Using a procedure analogous to that used to prepare Example
35, Example 39 (40 mg, 0.07 mmol) was reacted with LiOH, and
purified by reverse phase HPLC to give Example 40 (12 mg, 32%) as a
tan solid. MS (ESI) m/z 539.4 (M+H).sup.+.
Example 41
[(R)-2-(3-Carbamoyl-phenylamino)-20-methyl-3,12-dioxo-13-oxa-4,11-diaza-tr-
icyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen-5-yl]--
acetic acid ethyl ester
##STR00252##
[0852] 41A:
2-(4-(2-(3-((R)-1-(benzyloxycarbonylamino)-3-ethoxy-3-oxopropyl)phenylcar-
bamoyloxy)ethyl)-3-methylphenyl)-2-(3-carbamoylphenylamino)acetic
acid
##STR00253##
[0854] Using a procedure analogous to that used to prepare 2D, 39E
(200 mg, 0.36 mmol) was reacted with 3-aminobenzamide and glyoxylic
acid monohydrate to afford 41A (232 mg, 44%) as a brown oil. MS
(ESI) m/z 697.4 (M+H).sup.+.
41B:
2-(4-(2-(3-((R)-1-amino-3-ethoxy-3-oxopropyl)phenylcarbamoyloxy)ethyl-
)-3-methylphenyl)-2-(3-carbamoylphenylamino)acetic acid
##STR00254##
[0856] Using a procedure analogous to that used to prepare 6F, 41A
(232 mg, 0.33 mmol) was hydrogenated to afford 41B (202 mg, 87%) as
a yellow solid. MS (ESI) m/z 563.2 (M+H).sup.+.
Example 41
[0857] Using a procedure analogous to that used to prepare Example
28, 41B (202 mg, 0.31 mmol) was cyclized with BOP and purified by
reverse phase HPLC to give Example 41 (50 mg, 26%) as a brown
solid. MS (ESI) m/z 545.2 (M+H).sup.+.
Example 42
[(R)-2-(3-Carbamoyl-phenylamino)-20-methyl-3,12-dioxo-13-oxa-4,11-diaza-tr-
icyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen-5-yl]--
acetic acid
##STR00255##
[0859] Using a procedure analogous to that used to prepare Example
35, Example 41 (40 mg, 0.07) was reacted with LiOH, and purified by
reverse phase HPLC to give Example 42 (15 mg, 39%) as a yellow
solid. MS (ESI) m/z 517.2 (M+H).sup.+.
Example 43
3-[20-Ethyl-3,12-dioxo-7-(propane-2-sulfonyl)-13-oxa-4,11-diaza-tricyclo[1-
4.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen-2-ylamino]-4-f-
luoro-benzamide
##STR00256##
[0860] 43A:
[3-[(tert-Butoxycarbonyl-methyl-amino)-methyl]-4-(propane-2-sulfonyl)-phe-
nyl]-carbamic acid 2-(4-bromo-2-ethyl-phenyl)-ethyl ester
##STR00257##
[0862] NaH (190 mg, 4.7 mmol) was added in one portion to a
solution of 16G (547 mg, 1.2 mmol) and 36B (1000 mg, 4.4 mmol) in
THF (20 mL) at -40.degree. C. The reaction was warmed slowly to
ambient temperature over 2 h and stirred for 15 h. The reaction was
quenched with saturated citric acid and diluted with EtOAc. The
mixture was washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated in vacuo. The crude product was purified by flash
chromatography (0% to 100% EtOAc in hexanes) to afford 43A (650 mg,
92%) as a yellow solid. MS (ESI) m/z 597.1/599.1 (M+H).sup.+.
43B:
4-(2-(3-((tert-butoxycarbonyl(methyl)amino)methyl)-4-(isopropylsulfon-
yl)phenylcarbamoyloxy)ethyl)-3-ethylphenylboronic acid
##STR00258##
[0864] Using a procedure analogous to that used to prepare 6D, 43A
(650 mg, 1.1 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 43B
(362 mg, 59%) as a brown oil. MS (ESI) m/z 563.2 (M+H).sup.+.
43C:
2-(4-(2-(3-((tert-butoxycarbonyl(methyl)amino)methyl)-4-(isopropylsul-
fonyl)phenylcarbamoyloxy)ethyl)-3-ethylphenyl)-2-(5-carbamoyl-2-fluorophen-
ylamino)acetic acid
##STR00259##
[0866] Using a procedure analogous to that used to prepare 2D, 43B
(362 mg, 0.65 mmol) was reacted with 3-amino-4-fluorobenzamide and
glyoxylic acid monohydrate to afford 43C (296 mg, 62%) as a yellow
oil. MS (ESI) m/z 729.3 (M+H).sup.+.
Example 43
[0867] HCl (4.0 M in dioxane, 10 mL) was added to a solution 43C
(296 mg, 0.41 mmol) in EtOAc (10 mL) and stirred to 1 h. The
solution was concentrated in vacuo. Using a procedure analogous to
that used to prepare Example 28, the solid was cyclized with BOP
and purified by reverse phase HPLC to give Example 43 (40 mg, 16%)
as an off-white solid which consists of a mixture of atropisomers.
.sup.1H NMR (400 MHz, DMSO-D.sub.6) .delta. ppm 1.71 (t, J=7.70 Hz,
1.5H) 1.94-2.05 (m, 6H) 2.09 (t, J=7.42 Hz, 1.5H) 3.14-3.27 (m,
0.5H) 3.35-3.69 (m, 3H) 3.78-3.99 (m, 2.5H) 4.04 (s, 1.5H) 4.04 (s,
1.5H) 4.17-4.37 (m, 1H) 4.73-5.03 (m, 3H) 5.47-5.64 (m, 1H)
6.25-6.44 (m, J=21.71, 17.31 Hz, 1H) 6.48-6.61 (m, J=5.50 Hz, 1H)
7.04-7.20 (m, 1H) 7.52 (d, J=7.70 Hz, 0.5H) 7.61-7.77 (m, 2H)
7.79-7.95 (m, 2.5H) 8.02-8.16 (m, 1H) 8.22-8.33 (m, 1H) 8.37-8.64
(m, 2H). MS (ESI) m/z 611.20 (M+H).sup.+.
Example 44
3-[(R)-20-Ethyl-3,12-dioxo-7-(propane-2-sulfonyl)-13-oxa-4,11-diaza-tricyc-
lo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen-2-ylamino]-
-4-fluoro-benzamide atropisomer 1
##STR00260##
[0868] Example 45
3-[(R)-20-Ethyl-3,12-dioxo-7-(propane-2-sulfonyl)-13-oxa-4,11-diaza-tricyc-
lo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen-2-ylamino]-
-4-fluoro-benzamide atropisomer 2
##STR00261##
[0870] Example 43 (37 mg) was purified by chiral HPLC to separate
the enantiomers and atropisomers: peak 1 (2.5 mg), peak 2 (3.5 mg),
Example 44 (2.5 mg) and Example 45 (3.5 mg). The chromatography
conditions were the following: Chiralpack AD (250.times.20 mm ID;
10 micron, Chiral Technologies, Inc.), 30% IPA, 30% EtOH, 40%
Heptane, 0.1% DEA, 18 mL/min flow rate, and UV detection at 270 nm.
Peak 3 analytical data: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
ppm 0.99 (t, J=7.70 Hz, 3H) 1.23 (d, J=7.15 Hz, 3H) 1.33 (d, J=6.60
Hz, 3H) 2.39-2.53 (m, J=14.57, 7.42 Hz, 1H) 2.68-2.78 (m, J=13.74
Hz, 1H) 2.81-2.94 (m, 1H) 3.33 (s, 3H) 3.43-3.56 (m, 1H) 3.74-3.88
(m, 1H) 4.08-4.30 (m, 2H) 4.59 (s, 1H) 5.52-5.71 (m, 2H) 6.48 (d,
J=2.20 Hz, 1H) 6.84 (dd, J=8.25, 2.20 Hz, 1H) 6.95-7.04 (m, 2H)
7.07-7.18 (m, 1H) 7.31-7.40 (m, 2H) 7.52-7.62 (m, 1H) 7.74 (d,
J=8.79 Hz, 1H). MS (ESI) m/z 611.3 (M+H).sup.+. Peak 4 analytical
data: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.19-1.40 (m,
9H) 2.67-2.94 (m, 3H) 3.17 (d, J=13.74 Hz, 1H) 3.32 (s, 3H)
3.46-3.60 (m, 1H) 3.76-3.85 (m, 1H) 4.02 (dd, J=10.99, 2.75 Hz, 1H)
4.17 (d, J=17.04 Hz, 1H) 4.59 (s, 1H) 5.54-5.68 (m, 2H). MS (ESI)
m/z 611.3 (M+H).sup.+. Chiral analytical HPLC retention times: peak
1, 7.62 min; peak 2, 11.75 min; peak 3, 15.88 min; peak 4, 21.12
min using the following chromatography conditions: Chiralpack AD
(250.times.4.6 mm ID; 10 micron, Chiral Technologies, Inc.), 30%
IPA, 30% EtOH, 40% Heptane, 0.1% DEA, 1 mL/min flow rate, and UV
detection at 270 nm.
Example 46
3-(20-Ethyl-7-isopropylsulfanyl-4-methyl-3,12-dioxo-13-oxa-4,11-diaza-tric-
yclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen-2-ylamin-
o)-benzamide
##STR00262##
[0871] 46A:
(4-bromo-2-ethylphenethoxy)(tert-butyl)dimethylsilane
##STR00263##
[0873] Imidazole (2.1 g, 30.6 mmol) followed by
tert-butylchlorodimethylsilane (2.5 g, 16.8 mmol) were added to a
solution of 36B (3.5 g, 15.3 mmol) in CH.sub.2Cl.sub.2 (100 mL).
The reaction mixture was stirred for 2 h then washed with water and
brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The
crude product was purified by flash chromatography (0% to 30% EtOAc
in hexanes) to yield 46A (4.3 g, 82%) as a colorless oil. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. ppm -0.02 (s, 6H) 0.86 (s, 9H)
1.20 (t, J=7.42 Hz, 3H) 2.63 (q, J=7.51 Hz, 2H) 2.79 (t, J=7.15 Hz,
2H) 3.74 (t, J=7.15 Hz, 2H) 7.22 (dd, J=7.97, 1.92 Hz, 1H) 7.29 (d,
J=2.20 Hz, 1H).
46B: 4-(2-(tert-butyldimethylsilyloxy)ethyl)-3-ethylphenylboronic
acid
##STR00264##
[0875] n-Butyl Lithium (4.7 mL) was added to a solution of 46A (2.1
g, 6.1 mmol) in THF at -78.degree. C. After stirring to 10 min at
-78.degree. C., trimethyl borate (1.0 mL, 12.3 mmol) was added
dropwise. After warming to ambient temperature, the reaction
mixture was stirred an additional 2 h. HCl (1.0 M, 30 mL, aqueous)
was added to the mixture at -40.degree. C. and stirred at
-20.degree. C. for 30 min. The solution was extracted with diethyl
ether. The combined organics were washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The resulting oil was
purified by flash chromatography (0% to 20% MeOH in
CH.sub.2Cl.sub.2) to yield 46B (0.90 mg, 48%) as a clear oil. MS
(ESI) m/z 307.4 (M-H).sup.-.
46C:
2-(3-carbamoylphenylamino)-2-(3-ethyl-4-(2-hydroxyethyl)phenyl)acetic
acid
##STR00265##
[0877] Using a procedure analogous to that used to prepare 2D, 46B
(1.4 g, 4.1 mmol) was reacted with 3-aminobenzamide and glyoxylic
acid monohydrate to afford 46C (1.25 g, 88%) as a yellow solid. MS
(ESI) m/z 343.3 (M+H).sup.+.
46D:
3-(2-((5-amino-2-(isopropylthio)benzyl)(methyl)amino)-1-(3-ethyl-4-(2-
-hydroxyethyl)phenyl)-2-oxoethylamino)benzamide
##STR00266##
[0879] EDCI (67 mg, 0.35 mmol), HOAt (80 mg, 0.58 mmol) and
triethylamine (0.79 mL, 0.58 mmol) were added to a solution of 46C
(100 mg, 0.3 mmol) and 16D (67 mg, 0.3 mmol) and stirred at
50.degree. C. for 4 h. The reaction mixture was diluted with EtOAc,
washed with water, brine, dried over Na.sub.2SO.sub.4 and
concentrated in vacuo. The crude oil was purified by flash
chromatography (0% to 20% MeOH in CH.sub.2Cl.sub.2) to yield 46D as
a yellow solid. MS (ESI) m/z 535.4 (M+H).sup.+.
Example 46
[0880] Phosgene (0.072 mL, 0.14 mmol, 20% in toluene) was added
dropwise to a solution of 46D (70 mg, 0.13 mmol) in acetonitrile
(20 mL) at 0.degree. C. The mixture was stirred for 30 min at
ambient temperature. DMPU (0.5 mL) was added and the solution was
added via syringe pump over 4 h to a solution of triethylamine
(0.18 mL, 1.3 mmol) in acetonitrile (150 mL) at 40.degree. C. The
solution was concentrated in vacuo, combined with an earlier run
(30 mg 46D) and purified by HPLC to yield two atropisomers: peak 1
(16 mg, 15%) and Example 46 (peak 2, 31 mg, 30%). .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. ppm 1.23 (t, J=6.87 Hz, 6H) 1.30 (t,
J=7.70 Hz, 3H) 2.70-2.90 (m, 4H) 3.19 (s, 3H) 3.18-3.18 (m, 1H)
4.00-4.04 (m, 2H) 5.44 (d, J=17.04 Hz, 1H) 5.63 (s, 1H) 6.07 (d,
J=2.75 Hz, 1H) 6.70 (dd, J=8.24, 2.20 Hz, 1H) 6.95-7.04 (m, 1H)
7.11 (s, 2H) 7.19-7.27 (m, 2H) 7.29-7.36 (m, 2H) 7.52 (s, 1H). MS
(ESI) m/z 561.4 (M+H).sup.+. Analytical HPLC retention times: peak
1, 6.52 min; peak 2, 6.76 min using the following chromatography
conditions: Phenomenex Luna (S-5) C-18 (4.6.times.750 mm, 5
micron), 10% to 90% gradient MeOH in water with 0.2%
H.sub.3PO.sub.4 as eluent, 2.5 mL/min flow rate and UV detection at
220 nm.
Example 47
3-(20-Ethyl-7-isopropylsulfonyl-4-methyl-3,12-dioxo-13-oxa-4,11-diaza-tric-
yclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen-2-ylamin-
o)-benzamide
##STR00267##
[0882] Hydrogen peroxide (50%, 0.2 mL) was added dropwise to a
solution of Example 46 (31 mg, 0.055 mmol) in TFA (0.4 mL) and
water (0.4 mL) at -40.degree. C. The reaction mixture was stirred
for 30 min and 2 h at -20.degree. C. the reaction mixture was
partitioned between EtOAc and sat. NaHCO.sub.3. The organic layer
was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated
in vacuo. The crude material was purified by HPLC to yield Example
47 (6 mg, 18%) as a white solid. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. ppm 1.21 (d, J=7.15 Hz, 3H) 1.27-1.35 (m, 6H) 2.68-2.97 (m,
3H) 3.18 (d, J=13.74 Hz, 1H) 3.28 (s, 3H) 3.42-3.57 (m, 1H) 4.03
(dd, J=10.99, 2.20 Hz, 1H) 4.16 (d, J=17.59 Hz, 1H) 5.54-5.64 (m,
2H) 6.52 (s, 1H) 6.85 (dd, J=8.24, 2.20 Hz, 1H) 6.97 (dd, J=13.19,
7.70 Hz, 2H) 7.03-7.12 (m, 1H) 7.18-7.30 (m, 2H) 7.30-7.37 (m, 1H)
7.53 (s, 1H) 7.73 (d, J=8.24 Hz, 1H). MS (ESI) m/z 593.4
(M+H).sup.+.
Example 48
3-((R)-20-Ethyl-7-isopropylsulfanyl-4-methyl-3,12-dioxo-13-oxa-4,11-diaza--
tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen-2-yl-
amino)-benzamide
##STR00268##
[0883] 48A:
(R)-3-(2-((5-amino-2-(isopropylthio)benzyl)(methyl)amino)-1-(3-ethyl-4-(2-
-hydroxyethyl)phenyl)-2-oxoethylamino)benzamide
##STR00269##
[0885] 46D (660 mg) was separated by chiral HPLC to yield 48A (peak
1, 250 mg) and its entantiomer (peak 2, 250 mg). The chromatography
conditions were the following: Chiralcel OD-H (5.0 cm.times.50 cm,
520 micron, Chiral Technologies, Inc.), MeOH/EtOH (1:1) 0.1% DEA,
50 mL/min flow rate, and UV detection at 220 nm. MS (ESI) m/z 535.5
(M+H).sup.+.
Example 48
[0886] Using a procedure analogous to that used to prepare Example
46, 48A (200 mg, 0.36 mmol) was reacted phosgene and purified by
HPLC to afford Example 48 (peak 1, 38 mg, 18%) and peak 2 (72 mg,
34%) as white solids. Analytical data for peak 1: .sup.1H NMR (400
MHz, CD.sub.30D) .delta. ppm 1.10 (t, J=7.42 Hz, 3H) 1.18-1.28 (m,
J=9.34, 6.60 Hz, 6H) 2.51-2.64 (m, 1H) 2.73 (d, J=14.29 Hz, 1H)
2.81-2.86 (m, 1H) 2.88-2.99 (m, 1H) 3.13-3.18 (m, 1H) 3.18 (s, 3H)
3.94-4.03 (m, 1H) 4.08-4.19 (m, 1H) 5.46 (d, J=17.04 Hz, 1H) 5.64
(s, 1H) 5.94-6.12 (m, 1H) 6.69 (dd, J=7.70, 2.20 Hz, 1H) 7.05 (d,
J=9.34 Hz, 1H) 7.21-7.48 (m, 7H). MS (ESI) m/z 561.6 (M+H)+.
Example 49
3-((R)-20-Ethyl-7-isopropylsulfonyl-4-methyl-3,12-dioxo-13-oxa-4,11-diaza--
tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen-2-yl-
amino)-benzamide
##STR00270##
[0888] Using a procedure analogous to that used to prepare Example
47, Example 48 (40 mg, 0.07 mmol) was reacted with hydrogen
peroxide to afford Example 49 (7 mg, 17%) as a white solid. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. ppm 0.95 (t, J=7.42 Hz, 3H)
1.09-1.24 (m, J=6.87, 1.37 Hz, 6H) 2.34-2.46 (m, 2H) 2.63-2.80 (m,
4H) 3.01-3.13 (m, 2H) 3.22 (s, 3H) 3.40-3.51 (m, 2H) 4.02-4.19 (m,
3H) 4.70-4.81 (m, 2H) 5.52 (d, J=17.04 Hz, 1H) 5.60 (s, 1H) 6.30
(s, 1H) 6.84 (dd, J=8.52, 1.92 Hz, 1H) 6.90 (dd, J=7.97, 1.37 Hz,
1H) 6.95 (s, 1H) 6.99-7.05 (m, 1H) 7.05-7.13 (m, 1H) 7.16-7.24 (m,
2H) 7.30 (d, J=7.70 Hz, 1H) 7.53 (dd, J=7.70, 1.65 Hz, 1H) 7.66 (d,
J=8.25 Hz, 1H) 7.72 (s, 1H) 9.73 (s, 1H). MS (ESI) m/z 593.3
(M+H).sup.+.
Example 50
[(2R,5R)-2-(1-Amino-isoquinolin-6-ylamino)-17,20-dimethyl-3,12-dioxo-13-ox-
a-4,11-diaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),1-
7-hexaen-5-yl]-acetic acid ethyl ester trifluoroacetic acid
salt
##STR00271##
[0889] 50A:
(4-bromo-2,6-dimethylphenethoxy)(tert-butyl)dimethylsilane
##STR00272##
[0891] Using a procedure analogous to that used to prepare 46A, 32B
(3.0 g, 13.1 mmol) was reacted tert-butylchlorodimethylsilane to
afford 50A (3.58 g, 80%) as a clear oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm -0.01 (s, 9H) 2.30 (s, 6H) 2.84 (t, J=7.70
Hz, 2H) 3.66 (t, J=7.70 Hz, 2H) 7.13 (s, 2H).
50B:
4-(2-(tert-butyldimethylsilyloxy)ethyl)-3,5-dimethylphenylboronic
acid
##STR00273##
[0893] Using a procedure analogous to that used to prepare 46B, 50A
(3.58 g, 10.5 mmol) was reacted trimethylborate to afford 50B (1.45
g, 45%) as a white solid. .sup.1H NMR (400 MHz, MeOD) .delta. ppm
-0.03 (s, 6H) 0.85 (s, 9H) 2.33 (s, 6H) 2.92 (t, J=7.15 Hz, 2H)
3.75 (t, J=7.42 Hz, 2H) 7.20 (s, 2H).
50C:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(2-hy-
droxyethyl)-3,5-dimethylphenyl)acetic acid
##STR00274##
[0895] Using a procedure analogous to that used to prepare 2D, 50B
(1.43 g, 4.6 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 50C (1.1 g, 39%) as an orange solid. MS
(ESI) m/z 566.6 (M+H).sup.+.
50D: (3R)-ethyl
3-(2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(2-hyd-
roxyethyl)-3,5-dimethylphenyl)acetamido)-3-(3-nitrophenyl)propanoate
##STR00275##
[0897] EDC (187 mg, 0.97 mmol) and HOAt (132 mg, 0.97 mmol) were
added to a solution of 39A (268 mg, 0.97 mmol) and 50C (500 mg,
0.89 mmol) in DMF (10 mL). Triethylamine (0.36 mL, 2.7 mmol) was
added to the reaction mixture and it was stirred at 50.degree. C.
for 3 h. The reaction mixture was diluted with EtOAc, washed with
water and brine, dried over Na.sub.2SO.sub.4 and concentrated in
vacuo. The crude product was purified by flash chromatography (0%
to 20% MeOH in CH.sub.2Cl.sub.2) to yield 50D (580 mg, 83%) as a
yellow solid. MS (ESI) m/z 786.9 (M+H).sup.+.
50E: (3R)-ethyl
3-(3-aminophenyl)-3-(2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-yl-
amino)-2-(4-(2-hydroxyethyl)-3,5-dimethylphenyl)acetamido)propanoate
##STR00276##
[0899] A solution of 50D (580 mg, 0.74 mmol) in MeOH (30 mL) with
Pd/C (35 mg) was stirred under H.sub.2 (50 psi) for 2 h. The
reaction mixture was filtered and concentrated in vacuo. The crude
solid was purified by flash chromatography (0% to 20% MeOH in
CH.sub.2Cl.sub.2) to afford 50E (400 mg, 72%) as a yellow solid. MS
(ESI) m/z 756.6 (M+H).sup.+.
Example 50
[0900] Phosgene (0.16 mL, 0.32 mmol, 20% in toluene) was added
dropwise to a solution of 50E (200 mg, 0.26 mmol) in acetonitrile
(20 mL) at 0.degree. C. After stirring for 30 min at ambient
temperature, Ar was bubbled through the reaction mixture for 5 min.
The reaction mixture was added dropwise to triethylamine (0.37 mL)
in CH.sub.2Cl.sub.2 (100 mL) at 40.degree. C. over 4 h. The
reaction mixture was stirred at ambient temperature for 15 h,
concentrated in vacuo, dissolved in CH.sub.2Cl.sub.2/TFA (1:1) and
stirred for 1 h. The solution was concentrated in vacuo and
purified by reverse phase HPLC to yield Example 50 (33 mg, 43%) and
its diastereomer (37 mg). .sup.1H NMR (400 MHz, MeOD) .delta. ppm
1.25 (t, J=7.07 Hz, 3H) 2.31 (s, 3H) 2.50 (s, 3H) 2.66-2.81 (m, 1H)
2.82-3.05 (m, 3H) 3.09-3.25 (m, 1H) 4.18 (q, J=7.07 Hz, 2H) 5.06
(s, 1H) 5.26-5.41 (m, 1H) 6.29 (s, 1H) 6.62-6.72 (m, 2H) 6.89 (dd,
J=17.05, 7.45 Hz, 2H) 7.00 (s, 1H) 7.07-7.20 (m, 2H) 7.25 (d,
J=7.07 Hz, 1H) 7.36 (s, 1H) 7.98 (d, J=9.09 Hz, 1H) 8.57 (d, J=7.33
Hz, 1H). MS (ESI) m/z 582.6 (M+H).sup.+.
Example 51
[(2R,5R)-2-(1-Amino-isoquinolin-6-ylamino)-17,20-dimethyl-3,12-dioxo-13-ox-
a-4,11-diaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),1-
7-hexaen-5-yl]-acetic acid, trifluoroacetic acid salt
##STR00277##
[0902] Using a procedure analogous to that used to prepare Example
35, Example 50 (30 mg, 0.05 mmol) was reacted with LiOH, and
purified by reverse phase HPLC to give Example 51 (20 mg, 71%) as a
white solid. .sup.1H NMR (400 MHz, MeOD) .delta. ppm 2.32 (s, 3H)
2.51 (s, 3H) 2.66-2.79 (m, 1H) 2.81-3.00 (m, 2H) 3.09-3.27 (m, 1H)
5.05 (s, 1H) 5.30 (dd, J=10.23, 4.17 Hz, 1H) 6.28 (s, 1H) 6.60-6.77
(m, 2H) 6.89-7.05 (m, 3H) 7.10-7.20 (m, 2H) 7.28 (d, J=7.07 Hz, 1H)
7.36 (s, 1H) 8.00 (d, J=9.09 Hz, 1H). MS (ESI) m/z 545.2
(M+H).sup.+.
Example 52
[2-(1-Amino-isoquinolin-6-ylamino)-17,20-dimethyl-3,12-dioxo-13-oxa-4,11-d-
iaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen-
-4-yl]-acetic acid trifluoroacetic acid salt
##STR00278##
[0903] 52A: 2,2,2-trifluoro-N-(3-nitrobenzyl)acetamide
##STR00279##
[0905] Trifluoroacetic anhydride (1.6 mL, 11.7 mmol) was added to a
solution of (3-nitrophenyl)methanamine hydrochloride (2.0 g, 10.6
mmol) and Et.sub.3N (3.7 mL, 26.6 mmol). The reaction mixture was
diluted with CH.sub.2Cl.sub.2, washed with Na.sub.2CO.sub.3, brine,
dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford 52A
(2.0 g, 76%) as an off-white solid. 247.3 (M-H).sup.-.
52B: tert-butyl
2-(2,2,2-trifluoro-N-(3-nitrobenzyl)acetamido)acetate
##STR00280##
[0907] tert-Butyl 2-bromoacetate was added to a solution of 52A
(950 mg, 3.8 mmol) in DMF (8 mL) with Cs.sub.2CO.sub.3 (1.5 g, 4.6
mmol) and stirred 15 h. The reaction mixture was diluted with
EtOAc, washed with water, brine, dried over Na.sub.2SO.sub.4 and
concentrated in vacuo. The crude product was purified by flash
chromatography (0% to 60% EtOAc in hexanes) to afford 52B (850 mg,
61%) as a clear oil. MS (ESI) m/z 361.3 (M-H).sup.-.
52C: tert-butyl 2-(3-nitrobenzylamino)acetate
##STR00281##
[0909] K.sub.2CO.sub.3 (1.5 g, 11 mmol) was added to a solution of
52B (800 mg, 2.2 mmol) in MeOH/H.sub.2O (2:1, 9 mL) and the mixture
was refluxed for 2 h. Volatiles were removed in vacuo and the
remaining aqueous mixture was extracted with EtOAc. The combined
organics were washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated in vacuo. The crude product was purified by flash
chromatography (0% to 100% EtOAc in hexanes) to yield 52C (275 mg,
47%) as a clear oil. MS (ESI) m/z 267.1 (M+H).sup.+.
52D: tert-butyl
2-(2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(2-hyd-
roxyethyl)-3,5-dimethylphenyl)-N-(3-nitrobenzyl)acetamido)acetate
##STR00282##
[0911] EDCI (142 mg, 0.74), HOAt (101 mg, 0.74 mmol), and
triethylamine (0.18 mL, 1.35 mmol) were added to a solution of 50C
(380 mg, 0.67 mmol) and 52C (197 mg, 0.74 mmol) in that order. The
reaction mixture was stirred at 60.degree. C. for 3 h. The solution
was diluted with EtOAc, washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The crude solid was
purified by flash chromatography (0% to 100% EtOAc in hexanes) to
afford 52D (230 mg, 42%) as a yellow solid. MS (ESI) m/z 814.9
(M+H).sup.+.
52E: tert-butyl
2-(N-(3-aminobenzyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-yl-
amino)-2-(4-(2-hydroxyethyl)-3,5-dimethylphenyl)acetamido)acetate
##STR00283##
[0913] A solution of 52D (230 mg, 0.28 mmol) in MeOH (5 mL) with
Pd/C (15 mg) was stirred under H.sub.2 (60 psi) for 3 h. The
reaction mixture was filtered through Celite and concentrated in
vacuo to afford 52E (200 mg, 90%) as a yellow solid. MS (ESI) m/z
784.85 (M+H).sup.+.
Example 52
[0914] Using a procedure analogous to that used to prepare Example
50, 52E (200 mg, 0.25 mmol) was cyclized, deprotected with TFA, and
purified by reverse phase HPLC to give Example 52 (100 mg, 71%) as
an off-white solid. .sup.1H NMR (400 MHz, MeOD) .delta. ppm 2.39
(s, 3H) 2.49 (s, 3H) 3.77-3.99 (m, 2H) 4.02-4.20 (m, 1H) 4.79 (d,
J=18.69 Hz, 1H) 5.04 (s, 1H) 5.36 (s, 1H) 5.42 (d, J=17.04 Hz, 1H)
6.08 (s, 1H) 6.70 (d, J=7.70 Hz, 1H) 6.89 (d, J=7.70 Hz, 1H)
6.94-7.02 (m, 2H) 7.08-7.25 (m, 3H) 7.32 (d, J=6.60 Hz, 1H) 7.38
(s, 1H) 8.04 (d, J=8.79 Hz, 1H). MS (ESI) m/z 554.5
(M+H).sup.+.
Example 53
[(2R,5R)-2-(1-Amino-isoquinolin-6-ylamino)-17,20-dimethyl-3,12-dioxo-4,11--
diaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexae-
n-5-yl]-acetic acid ethyl ester trifluoroacetic acid salt
##STR00284##
[0915] 53A: 2-(4-bromo-2,6-dimethylphenyl)acetaldehyde
##STR00285##
[0917] Dess-Martin Periodinane (5.2 g, 12.5 mmol) was added
portionwise to a solution of 32B (2.6 g, 11.4 mmol) in
CH.sub.2Cl.sub.2 (60 mL) at 0.degree. C. and the mixture was
stirred at ambient temperature for 2 h. The reaction mixture was
filtered and stirred with NaOH (1.0 M, 40 mL) for 10 min. The
organic layer was washed with brine, dried over Na.sub.2SO.sub.4
and concentrated to yield 53A (2.6 g, 99%) as a light yellow oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 2.24 (s, 6H) 3.71 (d,
J=1.77 Hz, 2H) 7.20-7.20 (m, 2H) 9.66 (t, J=1.89 Hz, 1H).
53B: (E)-tert-butyl 4-(4-bromo-2,6-dimethylphenyl)but-2-enoate
##STR00286##
[0919] tert-Butyl 2-(dimethoxyphosphoryl)acetate (2.5 mL, 12.7
mmol) was added dropwise to a suspension of NaH (490 mg, 12.7 mmol,
60% dispersion in oil) in THF (60 mL) at 0.degree. C. After
stirring for 30 min at ambient temperature a solution of 53A (2.6
g, 11.4 mmol) in THF (10 mL) and stirred for 1 h at ambient
temperature. The reaction mixture was poured into 50 mL saturated
NaHCO.sub.3/400 mL water and extracted with diethyl ether. The
combined organics were dried over Na.sub.2SO.sub.4 and concentrated
in vacuo. The crude solid was purified by flash chromatography (0%
to 50% EtOAc in hexanes) to yield 53B (2.35 g, 63%) as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.44 (s, 9H)
2.22 (s, 6H) 3.43 (dd, J=5.56, 1.77 Hz, 2H) 5.43 (dt, J=15.54,
2.02, 1.89 Hz, 1H) 6.92 (dt, J=15.66, 5.56 Hz, 1H) 7.17 (s,
2H).
53C: (E)-4-(4-bromo-2,6-dimethylphenyl)but-2-enoic acid
##STR00287##
[0921] TFA (10 mL) was added to a solution of 53B (2.35 g) in
CH.sub.2Cl.sub.2 (20 mL) at 0.degree. C. and stirred for 4 h. The
reaction mixture was concentrated to yield 53C (1.95 g, 99%) as an
off-white solid. MS (ESI) m/z 267.2/269.2 (M-H).sup.-.
53D: (R,E)-ethyl
3-(benzyloxycarbonylamino)-3-(3-(4-(4-bromo-2,6-dimethylphenyl)but-2-enam-
ido)phenyl)propanoate
##STR00288##
[0923] BOP (1.3 g, 3.0 mmol) was added to a solution of 53C (675
mg, 2.5 mmol), 39C (1.0 g, 2.75 mmol) and triethylamine (5.0 mmol)
in acetonitrile (25 mL) at 0.degree. C. The mixture was stirred at
0.degree. C. for 2 h and at ambient temperature for 15 h. The
mixture was concentrated in vacuo and purified by flash
chromatography (0% to 60% EtOAc in hexanes) to afford 53D (800 mg,
54%) as a white solid. MS (ESI) m/z 593.3/595.3 (M+H).sup.+.
53E:
(R,E)-4-(4-(3-(1-(benzyloxycarbonylamino)-3-ethoxy-3-oxopropyl)phenyl-
amino)-4-oxobut-2-enyl)-3,5-dimethylphenylboronic acid
##STR00289##
[0925] Using a procedure analogous to that used to prepare 6D, 53D
(1000 mg, 2.2 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 53E
(775 mg, 82%) as a yellow powder. MS (ESI) m/z 559.54
(M+H).sup.+.
53F:
(R)-2-(4-((Z)-4-(3-((R)-1-(benzyloxycarbonylamino)-3-ethoxy-3-oxoprop-
yl)phenylamino)-4-oxobut-2-enyl)-3,5-dimethylphenyl)-2-(1-(bis(tert-butoxy-
carbonyl)amino)isoquinolin-6-ylamino)acetic acid
##STR00290##
[0927] Using a procedure analogous to that used to prepare 2D, 53D
(718 mg, 1.3 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 53E (900 mg, 75%) as an orange foam. MS
(ESI) m/z 930.8 (M+H).sup.+.
53E:
(R)-2-(4-(4-(3-((R)-1-amino-3-ethoxy-3-oxopropyl)phenylamino)-4-oxobu-
tyl)-3,5-dimethylphenyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-
-ylamino)acetic acid
##STR00291##
[0929] A solution of 53D (400 mg, 0.43 mmol) in MeOH (10 mL) and
HCl (0.50 mL, 1.0 M) with Pd/C (80 mg) were stirred under H.sub.2
(60 psi) for 15 h. The reaction mixture was filter and concentrated
to afford 53E (300 mg, 87%) as a yellow solid. MS (ESI) m/z 798.6
(M+H).sup.+.
Example 53
[0930] Using a procedure analogous to that used to prepare Example
28, 53E (300 mg, 0.38 mmol) was cyclized with BOP, deprotected with
TFA, and purified by reverse phase HPLC to give Example 53 (50 mg,
46%) and its diastereomer (12 mg) as a white solids. .sup.1H NMR
(400 MHz, MeOD) .delta. ppm 1.94-2.11 (m, 1H) 2.29 (s, 3H)
2.35-2.49 (m, 3H) 2.52 (s, 3H) 2.67-2.94 (m, 4H) 4.18 (q, J=7.24
Hz, 2H) 5.04 (s, 1H) 5.21-5.35 (m, 1H) 6.28 (s, 1H) 6.62-6.75 (m,
2H) 6.81-6.92 (m, 2H) 6.97 (d, J=7.58 Hz, 1H) 7.09-7.22 (m, 1H)
7.24-7.36 (m, 2H) 8.02 (d, J=9.35 Hz, 1H) 8.59 (d, J=7.33 Hz, 1H).
MS (ESI) m/z 580.6 (M+H).sup.+.
Example 54
[(2R,5R)-2-(1-Amino-isoquinolin-6-ylamino)-17,20-dimethyl-3,12-dioxo-4,11--
diaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexae-
n-5-yl]-acetic acid trifluoroacetic acid salt
##STR00292##
[0932] Using a procedure analogous to that used to prepare Example
35, Example 53 (47 mg, 0.08 mmol) was reacted with LiOH, and
purified by reverse phase HPLC to give Example 54 (28 mg, 63%) as a
white solid. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm
1.96-2.10 (m, 1H) 2.27 (s, 3H) 2.37-2.49 (m, 3H) 2.52 (s, 3H)
2.72-2.91 (m, 4H) 5.04 (s, 1H) 5.24-5.35 (m, 1H) 6.28 (s, 1H) 6.63
(d, J=2.27 Hz, 1H) 6.66-6.74 (m, 1H) 6.81-6.90 (m, 2H) 6.99 (d,
J=7.83 Hz, 1H) 7.09 (dd, J=9.35, 2.27 Hz, 1H) 7.12-7.19 (m, J=7.83,
7.83 Hz, 1H) 7.23 (d, J=7.07 Hz, 1H) 7.34 (s, 1H) 7.95 (d, J=9.09
Hz, 1H) 8.66 (d, J=7.33 Hz, 1H).
Example 55
2-(1-Amino-isoquinolin-6-ylamino)-17-methyl-4,11-diaza-tricyclo[14.2.2.1.s-
up.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
##STR00293##
[0933] 55A: 4-(4-bromo-2-methylphenyl)-4-oxobutanoic acid
##STR00294##
[0935] To a solution of 4-bromo-1-iodo-2-methylbenzene (148 mg, 0.5
mmol) in THF (10 mL) at -25.degree. C. was added isopropylmagnesium
bromide (0.5 mL, 0.5 mmol) and stirred 3 h. Succinic anhydride (55
mg, 0.55 mmol) was added and the reaction was stirred 18 h. The
mixture was quenched with water (10 mL) and washed with 1N NaOH (10
mL), 1N HCl (10 mL), brine (10 mL) and dried (MgSO.sub.4). The
organic layer was concentrated in vacuo and the residue purified by
flash chromatography (0-100% EtOAc/Hexane) to afford 55A (42 mg,
31%) as a crystalline solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 0.98 (t, 3H) 2.42 (q, 2H) 2.73 (t, 2H) 4.10 (t, 2H)
6.82 (d, 1H) 7.02 (d, 1H) 7.09 (t, 2H) 7.15 (t, 1H) 7.36 (d, 1H)
7.58-7.63 (m, 1H).
55B: 4-(4-bromo-2-methylphenyl)butanoic acid
##STR00295##
[0937] To a solution of 55A (542 mg, 2 mmol) in TFA (5 mL) was
added triethylsilane (0.8 mL, 5 mmol) and the mixture heated at
90.degree. C. for 7 h. The reaction was quenched with 1N NaOH (20
mL) and washed with EtOAc (20 mL). Aqueous layer was acidified to
pH 1 with 1N HCl and extracted with EtOAc (2.times.20 mL). The
combined organics were washed with brine (10 mL) and dried
(MgSO.sub.4). The organic layer was concentrated in vacuo and the
residue purified by flash chromatography (0-100% EtOAc/Hexane) to
afford 55B (216 mg, 42%) as an oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 0.98 (t, 3H) 2.42 (q, 2H) 2.73 (t, 2H) 4.10
(t, 2H) 6.82 (d, 1H) 7.02 (d, H) 7.09 (t, 2H) 7.15 (t, 1H) 7.36 (d,
1H) 7.58-7.63 (m, 1H).
55C: 4-(4-bromo-2-methylphenyl)-N-(3-cyanophenyl)butanamide
##STR00296##
[0939] Using a procedure analogous to that used to prepare 6C, 55B
(216 mg, 0.84 mmol) was reacted with 3-aminobenzonitrile to afford
55C (228 mg, 76%) as a solid. MS (ESI) m/z 358.1 (M+H).sup.+.
55D: 4-(4-(3-cyanophenylamino)-4-oxobutyl)-3-methylphenylboronic
acid
##STR00297##
[0941] Using a procedure analogous to that used to prepare 6D, 55C
(200 mg, 0.56 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 55D
(200 mg, 56%) as a solid. MS (ESI) m/z 323.2 (M+H).sup.+.
55E:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(4-(3-
-cyanophenylamino)-4-oxobutyl)-3-methylphenyl)acetic acid
##STR00298##
[0943] Using a procedure analogous to that used to prepare 2D, 55D
(200 mg, 0.623 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 55E (200 mg, 46%) as an oil. MS (ESI)
m/z 694.4 (M+H).sup.+.
55F:
2-(4-(4-(3-(aminomethyl)phenylamino)-4-oxobutyl)-3-methylphenyl)-2-(1-
-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)acetic
acid
##STR00299##
[0945] Using a procedure analogous to that used to prepare 6F, 55E
(220 mg, 0.289 mmol) was hydrogenated for 18 h to give 55F (164 mg,
82%) as a solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta. ppm
1.22-1.28 (m, 18H) 1.93 (q, 2H) 2.31 (s, 3H) 2.40 (t, J=7.25 Hz,
2H) 2.67 (t, 2H) 3.35 (s, 1H) 3.82 (s, 2H) 6.59-6.63 (m, J=1.76 Hz,
1H) 7.10 (t, J=8.35 Hz, 2H) 7.18-7.44 (m, 6H) 7.57 (t, 2H) 7.98 (d,
J=5.71 Hz, 1H).
Example 55
[0946] Using a procedure analogous to that used to prepare Example
6, 55F (200 mg, 0.287 mmol) was cyclized with BOP. This material
was deprotected with trifluoroacetic acid, and purified by reverse
phase HPLC and chiral HPLC to give Example 55 (peak 1, 10 mg, 15%)
and peak 2 (10 mg, 15%). The chromatography conditions were the
following: Whelk-O 1 (R,R) (500.times.21.1 mm ID; 10 micron, Regis
Technologies), 60% MeOH/EtOH (1:1), 40% Heptane, 0.1% DEA, 20
mL/min flow rate, and UV detection at 254 nm. Peak 1 analytical
data: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.00 (m, 1H)
2.18-2.28 (m, 1H) 2.30 (s, 1.5H) 2.34-2.43 (m, 2H) 2.46 (s, 1.5H)
2.48-2.69 (m, 2H) 2.91-3.11 (m, 1H) 4.08 (t, J=16.76 Hz, 1H) 4.64
(dd, J=21.44, 15.94 Hz, 1H) 5.03 (d, Chiral analytical HPLC
retention times: peak 1, 11.22 min; peak 2, 16.00 min using the
following chromatography conditions: Welko-O1 (R, R) column
(250.times.4.6 mm ID; 5 micron, 60% MeOH/EtOH (1:1), 40% Heptane,
0.1% DEA as eluent, 1 mL/min flow rate and UV detection at 254
nm.
Example 56
3-(17-Ethyl-3,12-dioxo-13-oxa-4,11-diaza-tricyclo[14.2.2.1.sup.6,10]henico-
sa-1(19),6,8,10(21),16(20),17-hexaen-2-ylamino)-benzamide
##STR00300##
[0947] 56A: 4-bromo-2-ethylphenethyl 3-cyanophenylcarbamate
##STR00301##
[0949] Using a procedure analogous to that used to prepare 30C, 36B
(687 mg, 3 mmol) was reacted with 3-isocyanatobenzonitrile (432 mg,
3 mmol) to give 56A (630 mg, 57%) as an oil. MS (ESI) m/z 373.2
(M+H).sup.+.
56B: 4-(2-(3-cyanophenylcarbamoyloxy)ethyl)-3-ethylphenylboronic
acid
##STR00302##
[0951] Using a procedure analogous to that used to prepare 6D, 56A
(630 mg, 1.69 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 56B
(350 mg, 61%) as a solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4)
.delta. ppm 0.98 (t, 3H) 2.42 (q, 2H) 2.73 (t, 2H) 4.10 (t, 2H)
6.82 (d, 1H) 7.02 (d, 1H) 7.09 (t, 2H) 7.15 (t, 1H) 7.36 (d, 1H)
7.58-7.63 (m, 1H).
56C:
2-(3-carbamoylphenylamino)-2-(4-(2-(3-cyanophenylcarbamoyloxy)ethyl)--
3-ethylphenyl)acetic acid
##STR00303##
[0953] Using a procedure analogous to that used to prepare 2D, 56B
(175 mg, 0.52 mmol) was reacted with 3-aminobenzamide and glyoxylic
acid monohydrate to afford 56C (175 mg, 72%) as an oil. MS (ESI)
m/z 487.3 (M+H).sup.+.
Example 56
[0954] Using a procedure analogous to that used to prepare 6F, 56C
(175 mg, 0.36 mmol) was hydrogenated for 5 h to give
2-(4-(2-(3-(aminomethyl)phenylcarbamoyloxy)ethyl)-3-ethylphenyl)-2-(3-car-
bamoylphenylamino)acetic acid (170 mg, 97%) as an oil. Using a
procedure analogous to that used to prepare Example 28, the crude
material was cyclized with BOP and purified by HPLC to give Example
56 (13 mg, 8%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.15
(t, J=7.70 Hz, 1H) 1.29 (t, J=7.42 Hz, 2H) 2.55-2.68 (m, 1H)
2.69-2.98 (m, 3H) 3.06-3.26 (m, 1H) 3.93-4.25 (m, 1.6H) 4.37-4.51
(m, 0.4H) 4.55-4.86 (m, 2H) 5.00-5.10 (m, J=5.50 Hz, 1H) 6.19 (s,
1H) 6.66 (d, J=7.70 Hz, 1H) 6.87 (d, J=7.15 Hz, 1H) 6.91-6.98 (m,
1H) 7.07-7.20 (m, 2H) 7.20-7.27 (m, 2H) 7.27-7.36 (m, 2H) 7.40 (s,
1H). MS (ESI) m/z 473.3 (M+H).sup.+.
Example 57
2-(1-Amino-isoquinolin-6-ylamino)-17-ethyl-13-oxa-4,11-diaza-tricyclo[14.2-
.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
trifluoroacetic acid salt
##STR00304##
[0955] 57A:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(2-(3-cya-
nophenylcarbamoyloxy)ethyl)-3-ethylphenyl)acetic acid
##STR00305##
[0957] Using a procedure analogous to that used to prepare 2D, 56B
(175 mg, 0.52 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 57A (186 mg, 52%) as an oil. MS (ESI)
m/z 710.5 (M+H).sup.+.
Example 57
[0958] Using a procedure analogous to that used to prepare 6F, 57A
(180 mg, 0.25 mmol) was hydrogenated for 5 h to give
2-(4-(2-(3-(aminomethyl)phenylcarbamoyloxy)ethyl)-3-ethylphenyl)-2-(1-(bi-
s(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)acetic acid (180
mg) as an oil. Using a procedure analogous to that used to prepare
Example 28, the crude oil was cyclized with BOP, deprotected with
trifluoroacetic acid, and purified by HPLC to give Example 57 (16
mg, 13%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.13 (t,
J=7.70 Hz, 1H) 1.34 (t, J=7.42 Hz, 2H) 2.70-3.01 (m, 3H) 3.09-3.25
(m, 1H) 3.95-4.38 (m, 2H) 4.40-4.83 (m, 2H) 5.10-5.19 (m, 1H) 6.19
(s, 1H) 6.63-6.76 (m, 2H) 6.82-6.93 (m, 2H) 7.07-7.27 (m, 4H)
7.28-7.34 (m, 2H) 7.39-7.55 (m, 1H) 8.00-8.12 (m, 1H) 8.56-8.76 (m,
1H). MS (ESI) m/z 496.3 (M+H).sup.+.
Example 58
3-(13-Methyl-3,12-dioxo-4,11,13-triaza-tricyclo[14.2.2.1.sup.6,10]henicosa-
-1(19),6,8,10(21),16(20),17-hexaen-2-ylamino)-benzamide
##STR00306##
[0959] 58A:
2-(3-carbamoylphenylamino)-2-(4-(2-(3-(3-cyanophenyl)-1-methylureido)ethy-
l)phenyl)acetic acid
##STR00307##
[0961] Using a procedure analogous to that used to prepare 2D, 23D
(170 mg, 0.52 mmol) was reacted with 3-aminobenzamide and glyoxylic
acid monohydrate to afford 58A (157 mg, 64%) as an oil. MS (ESI)
m/z 472.3 (M+H).sup.+.
58B:
2-(4-(2-(3-(3-(aminomethyl)phenyl)-1-methylureido)ethyl)phenyl)-2-(3--
carbamoylphenylamino)acetic acid
##STR00308##
[0963] Using a procedure analogous to that used to prepare 6F, 58A
(245 mg, 0.52 mmol) was hydrogenated for 5 h to give 58B (239 mg,
97%) as an oil. MS (ESI) m/z 476.1 (M+H).sup.+.
Example 58
[0964] Using a procedure analogous to that used to prepare Example
28, 58B (150 mg, 0.316 mmol) was cyclized with BOP and purified by
HPLC to give Example 58 (47 mg, 33%). .sup.1H NMR (400 MHz,
MeOD-d.sub.4) .delta. ppm 2.86 (t, J=5.93 Hz, 3H) 3.05 (s, 3H) 4.03
(d, J=15.82 Hz, 1H) 4.63 (d, 1H) 5.09 (s, 1H) 6.82 (d, J=6.59 Hz,
2H) 6.88-6.94 (m, 1H) 7.16-7.24 (m, 4H) 7.27 (d, 2H) 7.31 (d,
J=7.47 Hz, 1H) 7.46 (d, J=8.35 Hz, 1H) 7.57 (d, J=7.91 Hz, 1H). MS
(ESI) m/z 458.3 (M+H).sup.+.
Example 59
(S)-2-(1-Amino-isoquinolin-6-ylamino)-5,17-dimethyl-13-oxa-4,11-diaza-tric-
yclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-di-
one trifluoroacetic acid salt
##STR00309##
[0965] 59A: (S)-benzyl 1-(3-nitrophenyl)ethylcarbamate
##STR00310##
[0967] Benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.36 g, 5.5 mmol)
was added to a solution of (S)-1-(3-nitrophenyl)ethanamine HCl (1
g, 4.95 mmol) in CH.sub.2Cl.sub.2 (70 mL) and DIEA (2.2 mL, 12.4
mmol) and the reaction mixture was stirred for 1 h. The mixture was
diluted with CH.sub.2Cl.sub.2 (100 mL), washed with NaHCO.sub.3,
brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to
yield 59A (1.76 g, 99%) as a white solid. MS (ESI) m/z 323.02
(M+Na).sup.+.
59B: (S)-benzyl 1-(3-aminophenyl)ethylcarbamate
##STR00311##
[0969] To a refluxing solution of 59A (1.7 g, 5.9 mmol), EtOH (60
mL), water (15 mL) and AcOH (4 mL) was added portion-wise Fe powder
(1.6 g, 29.5 mmol) over 30 min. Mixture was heated for 45 min.
before cooling to ambient temperature and filtering through celite.
Filtration and concentration in vacuo afforded 59B (1.5 g, 94%) as
an oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.43 (d,
J=6.59 Hz, 3H) 5.00-5.17 (m, 2H) 5.40 (d, J=7.47 Hz, 1H) 6.53-6.60
(m, 2H) 6.69 (d, J=7.47 Hz, 1H) 7.11 (t, J=7.69 Hz, 1H) 7.29-7.39
(m, 5H).
59C:
(S)-4-(2-(3-(1-(benzyloxycarbonylamino)ethyl)phenylcarbamoyloxy)ethyl-
)-3-methylphenylbromide
##STR00312##
[0971] Using a procedure analogous to that used to prepare 34D, 59B
(1.5 g 5.5 mmol) was reacted with 30B to give 59C (2.46 g, 9%) as
an oil. MS (ESI) m/z 512.2 (M+H).sup.+.
59D:
(S)-4-(2-(3-(1-(benzyloxycarbonylamino)ethyl)phenylcarbamoyloxy)ethyl-
)-3-methylphenylboronic acid
##STR00313##
[0973] Using a procedure analogous to that used to prepare 6D, 59C
(2.46 g, 4.8 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 59D
(560 mg, 22%) as a solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4)
.delta. ppm 1.25-1.41 (m, J=4.39 Hz, 3H) 2.27 (s, 3H) 2.61 (s, 2H)
2.92 (s, 2H) 4.22 (s, 2H) 4.64 (s, 1H) 6.84-7.56 (m, 12H).
59E:
2-(4-(2-(3-((S)-1-(benzyloxycarbonylamino)ethyl)phenylcarbamoyloxy)et-
hyl)-3-methylphenyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-yla-
mino)acetic acid
##STR00314##
[0975] Using a procedure analogous to that used to prepare 2D, 59D
(280 mg, 0.588 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 59E (313 mg, 63%) as an oil. MS (ESI)
m/z 848.7 (M+H).sup.+.
Example 59
[0976] Using a procedure analogous to that used to prepare 6F, 59E
(313 mg, 0.37 mmol) was hydrogenated for 18 h to give
2-(4-(2-(3-((S)-1-aminoethyl)phenylcarbamoyloxy)ethyl)-3-methylphenyl)-2--
(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)acetic acid
(188 mg) as an oil. Using a procedure analogous to that used to
prepare Example 28, the crude oil (188 mg, 0.26 mmol) was cyclized
with BOP, deprotected with trifluoroacetic acid, and purified by
HPLC to give Example 59 (15 mg, 4%). MS (ESI) m/z 496.3
(M+H).sup.+.
Example 60
2-(1-Amino-isoquinolin-6-ylamino)-4,17-dimethyl-13-oxa-4,11-diaza-tricyclo-
[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
trifluoroacetic acid salt
##STR00315##
[0977] 60A: benzyl methyl(3-nitrobenzyl)carbamate
##STR00316##
[0979] Benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.65 g, 6.6 mmol)
was added to a solution of N-methyl-1-(3-nitrophenyl)methanamine (1
g, 6 mmol) in CH.sub.2Cl.sub.2 (24 mL) and DIEA (2.7 mL, 15 mmol)
and the reaction mixture was stirred for 1 h. The mixture was
diluted with CH.sub.2Cl.sub.2 (100 mL), washed with NH.sub.4Cl,
NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4 and concentrated in
vacuo to yield 60A (1.75 g, 99%) as a white solid. MS (ESI) m/z
301.03 (M+H).sup.+.
60B: benzyl 3-aminobenzyl(methyl)carbamate
##STR00317##
[0981] To a refluxing solution of 60A (1.7 g, 5.8 mmol), EtOH (60
mL), water (15 mL) and AcOH (4 mL) was added portion-wise Fe powder
(1.63 g, 29.0 mmol) over 30 min. The mixture was heated for 45 min.
before cooling to ambient temperature and filtered through celite.
Filtrate concentrated in vacuo to afford 60B (1.5 g, 95%) as an
oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.25-1.41 (m,
J=4.39 Hz, 3H) 2.27 (s, 3H) 2.61 (s, 2H) 2.92 (s, 2H) 4.22 (s, 2H)
4.64 (s, 1H) 6.84-7.56 (m, 12H)
60C:
4-(2-(3-(((benzyloxycarbonyl)(methyl)amino)methyl)phenylcarbamoyloxy)-
ethyl)-3-methylphenylbromide
##STR00318##
[0983] Using a procedure analogous to that used to prepare 34D, 60B
(1.6 g, 5.9 mmol) was reacted with 30B to give 60C (2.0 g, 69%) as
an oil. MS (ESI) m/z 512.2 (M+H).sup.+.
60D:
4-(2-(3-(((benzyloxycarbonyl)(methyl)amino)methyl)phenylcarbamoyloxy)-
ethyl)-3-methylphenylboronic acid
##STR00319##
[0985] Using a procedure analogous to that used to prepare 6D, 60C
(2.9 g, 5.6 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 60D
(720 mg, 28%) as a solid. MS (ESI) m/z 475.3 (M-H).sup.-.
60E:
2-(4-(2-(3-(((benzyloxycarbonyl)(methyl)amino)methyl)phenylcarbamoylo-
xy)ethyl)-3-methylphenyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin--
6-ylamino)acetic acid
##STR00320##
[0987] Using a procedure analogous to that used to prepare 2D, 60D
(350 mg, 0.73 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate 60E (535 mg, 87%) as an oil. MS (ESI) m/z 848.1
(M+H).sup.+.
Example 60
[0988] Using a procedure analogous to that used to prepare 6F, 60E
(535 mg, 0.63 mmol)) was hydrogenated for 18 h to give
2-(1-(bis(tert-butoxycarbonyl)amino)
isoquinolin-6-ylamino)-2-(3-methyl-4-(2-(3-((methylamino)methyl)phenylcar-
bamoyloxy)ethyl)phenyl)acetic acid (350 mg, 77%) as an oil. Using a
procedure analogous to that used to prepare Example 28, the crude
oil was cyclized with BOP, deprotected with trifluoroacetic acid,
and purified by HPLC to give Example 60 (2.88 mg, 1.2%). .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.33 (s, 1.5H) 2.49 (s, 1.5H)
2.65-2.84 (m, 1H) 3.05-3.19 (m, 1H) 3.24 (s, 1.5H) 3.26 (s, 1.5H)
3.81-4.06 (m, 1.5H) 4.32-4.35 (m, 0.5H) 5.28-5.51 (m, 1H) 5.62-5.76
(m, 1H) 5.94-6.04 (m, 1H) 6.69 (d, J=7.91 Hz, 1H) 6.78-6.85 (m, 1H)
6.84-6.94 (m, 2H) 7.07-7.36 (m, 6H) 7.51-7.66 (m, 1H) 8.02 (d,
J=9.23 Hz, 1H). MS (ESI) m/z 496.4 (M+H).sup.+.
Example 61
2-(1-Amino-isoquinolin-6-ylamino)-17-chloro-13-oxa-4,11-diaza-tricyclo[14.-
2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
trifluoroacetic acid salt
##STR00321##
[0989] 61A: 4-bromo-2-chloro-1-vinylbenzene
##STR00322##
[0991] Using a procedure analogous to that used to prepare 30A,
4-bromo-2-chloro-1-iodobenzene (8 g, 25 mmol) was reacted with
trimethyl(vinyl)silane in a pressure vessel at 160.degree. C. for 1
h and worked up in a manner similar as in 30A to yield 61A (5.2 g,
96%) as an oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 5.41
(d, J=11.86 Hz, 1H) 7.02 (dd, J=17.36, 11.21 Hz, 1H) 7.35 (dd, 1H)
7.41 (d, 1H) 7.52 (d, J=1.76 Hz, 1H).
61B: 2-(4-bromo-2-chlorophenyl)ethanol
##STR00323##
[0993] Using a procedure analogous to that used to prepare 30B, 61A
(5 g, 23 mmol) was heated in a pressure vessel with 9-BBN at
100.degree. C. for 10 h and worked up as in 30B to yield 61B (2.9
g, 54%) as an oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
2.95 (t, J=6.59 Hz, 2H) 3.85 (t, J=6.59 Hz, 2H) 7.14 (d, J=7.91 Hz,
1H) 7.33 (dd, J=8.13, 1.98 Hz, 1H) 7.52 (d, J=2.20 Hz, 1H).
61C: tert-butyl 3-isocyanatobenzylcarbamate
##STR00324##
[0995] To a solution of 3-(aminomethyl)aniline (25 g, 205 mmol) and
TEA (80 mL, 451 mmol) in DCM (500 mL) and acetonitrile (200 mL) at
0.degree. C. was added dropwise a solution of di-tert-butyl
dicarbonate (45 g, 205 mmol) in DCM (70 mL). The mixture was
stirred for 1 h before concentrating in vacuo. The residue purified
by flash chromatography (0-100% EtoAc/Hexane) to afford 61C (43 g,
94%) as a crystalline solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 1.42-1.47 (m, 9H) 4.18 (d, J=5.71 Hz, 2H) 6.52-6.65 (m,
3H) 7.07 (t, J=7.91 Hz, 1H).
61D:
4-(2-(3-((tert-butoxycarbonylamino)methyl)phenylcarbamoyloxy)ethyl)-3-
-chlorophenylbromide
##STR00325##
[0997] Using a procedure analogous to that used to prepare 34D, 61C
(1.94 g, 8.73 mmol) was reacted with 61B to give 61D (1.84 g, 50%)
as an oil. MS (ESI) m/z 385.1 (M+H).sup.+.
61E:
4-(2-(3-((tert-butoxycarbonylamino)methyl)phenylcarbamoyloxy)ethyl)-3-
-chlorophenylboronic acid
##STR00326##
[0999] Using a procedure analogous to that used to prepare 6D, 61D
(1.84 g, 3.8 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 61E
(750 mg, 44%) as a solid. MS (ESI) m/z 447.1 (M-H).sup.-.
61F:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(2-(3-
-((tert-butoxycarbonylamino)methyl)phenylcarbamoyloxy)ethyl)-3-chloropheny-
l)acetic acid
##STR00327##
[1001] Using a procedure analogous to that used to prepare 2D, 61E
(350 mg, 0.781 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 61F (547 mg, 86%) as an oil. MS (ESI)
m/z 822.0 (M+2H).sup.+.
Example 61
[1002] 61F (547 mg, 0.67 mmol) was stirred in dioxane (10 mL) and
4M HCl/dioxane (5 mL) at ambient temperature for 6 h and
concentrated to give crude benzyl amine (346 mg, 98%) as an oil.
Using a procedure analogous to that used to prepare Example 28, the
oil was cyclized with BOP before concentrating and purifying by
HPLC to give Example 61 (6.2 mg, 2.0%). MS (ESI) m/z 502.3
(M+H).sup.+.
Example 62
3-(17-Ethoxy-3,12-dioxo-13-oxa-4,11-diaza-tricyclo[14.2.2.1.sup.6,10]henic-
osa-1(19),6,8,10(21),16(20),17-hexaen-2-ylamino)-benzamide
##STR00328##
[1003] 62A: 4-bromo-2-ethoxy-1-nitrobenzene
##STR00329##
[1005] To a solution of 4-bromo-2-fluoro-1-nitrobenzene (3 g, 13.6
mmol) and EtOH (50 mL) was added NaOEt (21% w/w, 50 mL). The
mixture stirred for 2 h before concentrating in vacuo. The residue
purified by flash chromatography (0-100% EtoAc/Hexane) to afford
62A (3 g, 90%) as an oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 1.49 (t, 3H) 4.19 (q, 2H) 7.22 (dd, 2H) 7.71-7.81 (m, 1H).
62B: 4-bromo-2-ethoxyaniline
##STR00330##
[1007] To a refluxing solution of 62A (3.0 g, 12.2 mmol), EtOH (60
mL), water (15 mL) and AcOH (10 mL) was added portion-wise Fe
powder (5 g, 89.3 mmol) over 30 min. The mixture was heated for 1 h
before cooling to ambient temperature and filtering through celite.
The filtrate was concentrated in vacuo to afford 62B (2.5 g, 96%)
as an oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.42 (t,
J=7.03 Hz, 3H) 4.02 (q, J=6.88 Hz, 2H) 6.57 (d, J=7.91 Hz, 1H)
6.85-6.90 (m, 2H).
62C: 4-bromo-2-ethoxy-1-iodobenzene
##STR00331##
[1009] To a solution of 62B (2.5 g, 1.2 mmol) in acetonitrile (30
mL) at 0.degree. C. was added dropwise a solution of iodine (6 g,
2.4 mmol), and t-BuONO (1.44 g, 1.4 mmol) in acetonitrile (100 mL)
over 30 min and stirred 1.5 h. The mixture was quenched with
aqueous Na.sub.2SO.sub.3 while maintaining the temperature
<10.degree. C. After stirring 1 h the mixture was extracted with
hexane (3.times.100 mL). The combined organics were dried
(MgSO.sub.4) before concentrating in vacuo and the residue was
purified by flash chromatography (0-5% EtOAc/Hexane) to afford 62C
(2 g, 53%) as an oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
1.47 (t, J=7.03 Hz, 4H) 4.06 (q, J=7.03 Hz, 2H) 6.83 (dd, J=8.35,
1.76 Hz, 1H) 6.90 (d, J=2.20 Hz, 1H) 7.59 (d, J=8.35 Hz, 1H).
62D: 4-bromo-2-ethoxy-1-vinylbenzene
##STR00332##
[1011] Using a procedure analogous to that used to prepare 30A, 62C
(2 g, 6.1 mmol) was reacted with trimethyl(vinyl)silane in a
pressure vessel at 160.degree. C. for 1 h and worked up in a manner
similar as in 30A to yield 62D (1.4 g, 88%) as an oil. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 1.44 (t, J=7.03 Hz, 3H) 4.02 (q,
J=6.74 Hz, 2H) 5.27 (d, J=10.99 Hz, 1H) 5.74 (d, 1H) 6.92-7.01 (m,
2H) 7.04 (d, 1H) 7.31 (d, J=7.91 Hz, 1H).
62E: 2-(4-bromo-2-ethoxyphenyl)ethanol
##STR00333##
[1013] Using a procedure analogous to that used to prepare 30B, 62D
(700 mg, 3.3 mmol) was heated in a pressure vessel with 9-BBN at
100.degree. C. for 10 h and worked up as in 30B to yield 62E (620
mg, 82%) as solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
1.41 (t, J=6.95 Hz, 3H) 2.85 (t, J=6.32 Hz, 2H) 3.81 (t, J=6.32 Hz,
2H) 4.02 (q, J=7.07 Hz, 2H) 6.96 (s, 1H) 6.99-7.03 (m, 2H).
62F: 4-bromo-2-ethoxyphenethyl 3-cyanophenylcarbamate
##STR00334##
[1015] NaH (346 mg, 8.7 mmol, 60% dispersion in oil) was added in
one portion to a solution of 3-isocyanatobenzonitrile (567 mmol,
3.9 mmol) and 62E (960 mg, 3.9 mmol) in THF (40 mL) and the cooling
bath was removed. After stirring for 2 h at ambient temperature 1.0
N citric acid (50 mL) was added and the mixture was extracted with
diethyl ether. The combined organics were washed with brine, dried
over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue
was purified by flash chromatography (0% to 60% EtOAc in hexanes)
to yield 62F (611 mg, 50%) as a pale, yellow solid. MS (ESI) m/z
411.0/413.0 (M+H).sup.+.
62G: 4-(2-(3-cyanophenylcarbamoyloxy)ethyl)-3-ethoxyphenylboronic
acid
##STR00335##
[1017] Using a procedure analogous to that used to prepare 6D, 62F
(811 mg, 2.1 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 62G
(400 mg, 54%) as a white solid. MS (ESI) m/z 355.2 (M+H).sup.+.
62H:
2-(3-carbamoylphenylamino)-2-(4-(2-(3-cyanophenylcarbamoyloxy)ethyl)--
3-ethoxyphenyl)acetic acid
##STR00336##
[1019] Using a procedure analogous to that used to prepare 2D, 62G
(150 mg, 0.423 mmol) was reacted with 3-aminobenzamide and
glyoxylic acid monohydrate to afford 62H (170 mg, 80%) as an oil.
MS (ESI) m/z 503.2 (M+H).sup.+.
62I:
2-(4-(2-(3-(aminomethyl)phenylcarbamoyloxy)ethyl)-3-ethoxyphenyl)-2-(-
3-carbamoylphenylamino)acetic acid
##STR00337##
[1021] Using a procedure analogous to that used to prepare 6F, 62H
(212 mg, 0.42 mmol) was hydrogenated for 18 hrs to give 62I (190
mg, 89%) as an oil. MS (ESI) m/z 507.3 (M+H).sup.+.
Example 62
[1022] Using a procedure analogous to that used to prepare Example
28, 62I (190 mg, 0.38 mmol) was cyclized with BOP and purified by
HPLC to give Example 62 (23 mg, 13%). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 1.36 (t, J=6.81 Hz, 1.5H) 1.47 (t, J=6.81
Hz, 1.5H) 3.09-3.25 (m, 4H) 3.88-4.28 (m, 4H) 4.98-5.05 (m, J=4.39
Hz, 1H) 6.15-6.30 (m, J=13.18 Hz, 1H) 6.60-6.72 (m, 1H) 6.82-6.96
(m, 3H) 6.98-7.29 (m, 7H). MS (ESI) m/z 489.3 (M+H).sup.+.
Example 63
2-(1-Amino-isoquinolin-6-ylamino)-17-ethoxy-13-oxa-4,11-diaza-tricyclo[14.-
2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
trifluoroacetic acid salt
##STR00338##
[1023] 63A:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(2-(3-cya-
nophenylcarbamoyloxy)ethyl)-3-ethoxyphenyl)acetic acid
##STR00339##
[1025] Using a procedure analogous to that used to prepare 2D, 62G
(250 mg, 0.0706 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 63A (329 mg, 64%) as a solid. MS (ESI)
m/z 726.4 (M+H).sup.+.
63B:
2-(4-(2-(3-(aminomethyl)phenylcarbamoyloxy)ethyl)-3-ethoxyphenyl)-2-(-
1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)acetic
acid
##STR00340##
[1027] Using a procedure analogous to that used to prepare 6F, 63A
(329 mg, 0.45 mmol) was hydrogenated for 18 h to give 63B (300 mg,
91%) as an oil. MS (ESI) m/z 731.4 (M+H).sup.+.
Example 63
[1028] Using a procedure analogous to that used to prepare Example
28, 63B (300 mg, 0.41 mmol) was cyclized with BOP, deprotected with
trifluoroacetic acid, and purified by HPLC to give Example 63 (35
mg, 17%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.34 (t,
J=7.03 Hz, 1.5H) 1.50 (t, J=7.03 Hz, 1.5H) 2.92-3.00 (m, 1H)
3.13-3.26 (m, 1H) 3.89-4.18 (m, 3H) 4.19-4.34 (m, 1H) 5.10-5.19 (m,
1H) 6.22 (m, 1H) 6.59-6.94 (m, 4H) 7.02-7.35 (m, 6H) 7.98-8.12 (m,
1H). MS (ESI) m/z 512.3 (M+H).sup.+.
Example 64
3-((2R,5R)-5,17-Dimethyl-3,12-dioxo-13-oxa-4,11-diaza-tricyclo[14.2.2.1.su-
p.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen-2-ylamino)-benzamide
##STR00341##
[1029] 64A: (R)-benzyl 1-(3-nitrophenyl)ethylcarbamate
##STR00342##
[1031] To a solution of benzyl 2,5-dioxopyrrolidin-1-yl carbonate
(4.95 g, 19.9 mmol) and TEA (10 mL) in DCM (50 mL) was added a
solution of (R)-1-(3-nitrophenyl)ethanamine (3 g, 18 mmol) in DMF
(10 mL). The mixture was stirred 2 h and quenched with water (50
mL). The organic layer was separated and dried (MgSO.sub.4) before
concentrating in vacuo. The residue was purified by flash
chromatography (0-35% EtoAc/Hexane) to afford 64A (5 g, 93%) as an
oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.50 (d, J=6.59
Hz, 3H) 4.87-4.98 (m, 1H) 5.00-5.15 (m, 2H) 7.34 (s, 5H) 7.49 (t,
J=7.69 Hz, 1H) 7.64 (d, J=7.03 Hz, 1H) 8.11 (d, J=7.91 Hz, 1H) 8.17
(s, 1H).
64B: (R)-benzyl 1-(3-aminophenyl)ethylcarbamate
##STR00343##
[1033] To a refluxing solution of 64A (5 g, 16.7 mmol), EtOH (100
mL), water (30 mL) and AcOH (15 mL) was added portion-wise Fe
powder (5 g, 89 mmol) over 30 min. The mixture was heated for 1 h.
before cooling to ambient temperature. and filtering through
celite. The filtrate was concentrated in vacuo to afford 64B (2.7
g, 61%) as an oil. MS (ESI) m/z 271.2 (M+H).sup.+.
64C: (R)-((4-bromo-2-methylphenyl)ethyl)
3-(1-(benzyloxycarbonylamino)ethyl)phenylcarbamate
##STR00344##
[1035] Using a procedure analogous to that used to prepare 34D, 64B
(2.7 g, 10 mmol) was reacted with 30B to give 64C (1.8 g, 72%) as
an oil. MS (ESI) m/z 513.2 (M+H).sup.+.
64D: (R)-3-(1-(benzyloxycarbonylamino)ethyl)aminophenyl
2-(4-boronic acid-2-methylphenyl)ethylcarbamate
##STR00345##
[1037] Using a procedure analogous to that used to prepare 6D, 64C
(1 g, 1.96 mmol) was reacted with
5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] to give 64D
(175 mg, 19%) as a solid. MS (ESI) m/z 475.3 (M+H).sup.+.
64E:
2-(4-(2-(3-((R)-1-(benzyloxycarbonylamino)ethyl)phenylcarbamoyloxy)et-
hyl)-3-methylphenyl)-2-(3-carbamoylphenylamino)acetic acid
##STR00346##
[1039] Using a procedure analogous to that used to prepare 2D, 64D
(175 mg, 0.37 mmol) was reacted with 3-aminobenzamide and glyoxylic
acid monohydrate to afford 64E (175 mg, 70%) as an oil. MS (ESI)
m/z 625.3 (M+H).sup.+.
64F:
2-(4-(2-(3-((R)-1-aminoethyl)phenylcarbamoyloxy)ethyl)-3-methylphenyl-
)-2-(3-carbamoylphenylamino)acetic acid
##STR00347##
[1041] Using a procedure analogous to that used to prepare 6F, 64E
(175 mg, 0.28 mmol) was hydrogenated for 18 h to give 64F (116 mg,
85%) as an oil. MS (ESI) m/z 491.1 (M+H).sup.+.
Example 64
[1042] Using a procedure analogous to that used to prepare Example
28, 64F (116 mg, 0.24 mmol) was cyclized with BOP and purified by
HPLC to give Example 64 (7.39 mg, 13%). MS (ESI) m/z 473.3
(M+H).sup.+. .sup.1H NMR (400 MHz, MeOD-d.sub.4) .delta. ppm 2.86
(t, J=5.93 Hz, 3H) 3.05 (s, 3H) 4.03 (d, J=15.82 Hz, 1H) 4.63 (d,
1H) 5.09 (s, 1H) 6.82 (d, J=6.59 Hz, 2H) 6.88-6.94 (m, 1H)
7.16-7.24 (m, 4H) 7.27 (d, 2H) 7.31 (d, J=7.47 Hz, 1H) 7.46 (d,
J=8.35 Hz, 1H) 7.57 (d, J=7.91 Hz, 1H).
Example 65
(R)-2-(1-Amino-isoquinolin-6-ylamino)-5,17-dimethyl-13-oxa-4,11-diaza-tric-
yclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-di-
one trifluoroacetic acid salt
##STR00348##
[1043] 65A:
2-(4-(2-(3-((R)-1-(benzyloxycarbonylamino)ethyl)phenylcarbamoyloxy)ethyl)-
-3-methylphenyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino-
)acetic acid
##STR00349##
[1045] Using a procedure analogous to that used to prepare 2D, 64D
(175 mg, 0.37 mmol) was reacted with Intermediate 1 and glyoxylic
acid monohydrate to afford 65A (300 mg, 95%) as an oil. MS (ESI)
m/z 848.5 (M+H).sup.+.
65B:
2-(4-(2-(3-((R)-1-aminoethyl)phenylcarbamoyloxy)ethyl)-3-methylphenyl-
)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)acetic
acid
##STR00350##
[1047] Using a procedure analogous to that used to prepare 6F, 65A
(300 mg, 0.35 mmol) was hydrogenated for 18 h to give 65B (220 mg,
88%) as an oil. MS (ESI) m/z 714.2 (M+H).sup.+.
Example 65
[1048] Using a procedure analogous to that used to prepare Example
28, 65B (220 mg, 0.31 mmol) was cyclized with BOP, deprotected with
trifluoroacetic acid, and purified by HPLC to give Example 65 (6.1
mg, 4%). MS (ESI) m/z 496.2 (M+H).sup.+.
Example 66
14-(1-Amino-isoquinolin-6-ylamino)-2-oxa-5,12-diaza-tricyclo[13.2.2.1.sup.-
6,10]icosa-1(18),6(20),7,9,15(19),16-hexaene-4,13-dione
trifluoroacetic acid salt
##STR00351##
[1049] 66A: (3-Amino-benzyl)-carbamic acid benzyl ester
##STR00352##
[1051] To a solution of 3-aminobenzylamine (610 mg, 5 mmol) and TEA
(1.01 g, 10 mmol) in 10 mL of THF at 0.degree. C., was added benzyl
chloroformate (936 mg, 5.5 mmol) dropwise. The mixture was stirred
at rt for 30 min. The reaction was quenched with water and
extracted with EtOAc (3.times.20 mL). The organic layer was washed
with brine, dried (Na.sub.2SO.sub.4) and concentrated. Purification
via flash chromatography (0 to 50% EtOAc in hexanes) gives 66A (911
mg, 71%). MS (ESI) m/z 257.3 (M+H).sup.+.
66B: 3-[2-(4-Bromo-phenoxy)-acetylamino]-benzyl}-carbamic acid
benzyl ester
##STR00353##
[1053] A mixture of 3-bromo phenyoxy acetic acid (222 mg, 0.96
mmol), 66A (246 mg, 0.96 mmol), EDCI (250 mg, 1.3 mmol), HOAt (30
mg, 0.22 mmol), and DIEA (0.5 mL, 3 mmol) in THF (4 mL) was stirred
at rt for 16 h. The reaction was quenched with water, extracted
with EtOAc (3.times.20 mL). The organic layer was washed with
brine, dried (Na.sub.2SO.sub.4) and concentrated. Purification via
flash chromatography (0-50% EtOAc in hexanes) gives 66B. (398 mg,
88%) MS (ESI) m/z 469.1 (M+H).sup.+.
66C:
4-(2-(3-((benzyloxycarbonylamino)methyl)phenylamino)-2-oxoethoxy)phen-
ylboronic acid
##STR00354##
[1055] A sealed tube was charged with 66B (235 mg, 0.5 mmol),
5,5,5',5'-Tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] (135 mg, 0.6
mmol), potassium acetate (98 mg, 1.25 mmol), and DMSO (2 mL). The
resulting orange suspension was deoxygenated by sparging with
nitrogen gas.
Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloromethane adduct (30 mg, 0.041 mmol) was added, and the tube
was sealed and heated at 80.degree. C. for 3 h. The reaction was
quenched with water, then extracted with EtOAc (3.times.20 mL). The
organic layer was washed with brine, dried (Na.sub.2SO.sub.4),
filtered through a pad of silica gel and concentrated. The residue
was purified via reverse phase HPLC to give 66C (157 mg, 72%). MS
(ESI) m/z 435.4 (M+H).sup.+.
66D:
2-(4-(2-(3-((benzyloxycarbonylamino)methyl)phenylamino)-2-oxoethoxy)p-
henyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)acetic
acid
##STR00355##
[1057] A solution of 66C (127 mg, 0.29 mmol), Intermediate 1 (116
mg, 0.32 mmol), and glyoxylic acid monohydrate (33 mg, 0.35 mmol)
in CH.sub.3CN (4 mL)/DMF (0.5 mL) was heated at 65.degree. C. for
16 h in a sealed tube. This mixture was concentrated, then purified
by flash chromatography (0 to 10% MeOH in DCM) to give 66D (152 mg,
68% yield) as a yellow solid. MS (ESI) m/z 806.6 (M+H).sup.+.
66E:
2-(4-(2-(3-(aminomethyl)phenylamino)-2-oxoethoxy)phenyl)-2-(1-(bis(te-
rt-butoxycarbonyl)amino)isoquinolin-6-ylamino)acetic acid
##STR00356##
[1059] To a solution of 66D (152 mg) in 10 mL MeOH, was added 10%
Pd/C (ca. 20 mg). The mixture was hydrogenated at 5 psi for 20 min.
The reaction mixture was filtered, concentrated and purified by
flash chromatography (0 to 25% MeOH in DCM) to give 66E (85 mg,
68%). MS (ESI) m/z 672.4 (M+H).sup.+.
66F:
14-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-oxa-5,1-
2-diaza-tricyclo[13.2.2.1.sup.6,10]icosa-1(18),6(20),7,9,15(19),16-hexaene-
-4,13-dione
##STR00357##
[1061] A solution of 66D (55 mg, 0.082 mmol) in 10 mL DMF was added
to a solution of PyBOP (88 mg, 0.17 mmol), DMAP (49 mg, 0.4 mmol),
and TEA (40 mg, 0.4 mmol) in CH.sub.2Cl.sub.2 (30 mL) dropwise
through syringe pump over 3 h. The solution was stirred at rt for
16 h. The solution was washed with 1M H.sub.3PO.sub.4, sat
NaHCO.sub.3 and brine, dried (Na.sub.2SO.sub.4) and concentrated.
The crude product was purified by flash chromatography (0 to 80%
EtOAc in hexanes) to give 66F (8.5 mg, 16%). MS (ESI) m/z 654.8
(M+H).sup.+.
Example 66
[1062] To a solution of 66F (8.5 mg, 0.013 mmol) in 1 mL
CH.sub.2Cl.sub.2, was added TFA (1 mL). The solution was stirred at
rt for 1 h, then concentrated. Purification by reversed phase HPLC
afforded 5 mg (85%) of Example 66. MS (ESI) m/z 454.5 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 3.78-4.01 (m, 2H)
4.66 (dd, J=15.94, 8.79 Hz, 2H) 4.80-4.88 (m, 1H) 5.06 (s, 1H) 6.68
(d, J=2.20 Hz, 1H) 6.78 (d, J=7.15 Hz, 1H) 6.89-7.05 (m, 3H) 7.12
(t, J=7.70 Hz, 1H) 7.18 (dd, J=9.34, 2.20 Hz, 1H) 7.22 (d, J=7.15
Hz, 1H) 7.38 (dd, J=8.79, 2.20 Hz, 1H) 7.61 (dd, J=8.52, 2.47 Hz,
1H) 8.00 (d, J=9.34 Hz, 1H) 8.30 (s, 1H)
Example 67
2-(1-Amino-isoquinolin-6-ylamino)-14-oxa-4,11-diaza-tricyclo[14.2.2.1.sup.-
6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
trifluoroacetic acid salt
##STR00358##
[1063] 67A: (4-Bromo-benzyloxy)-acetic acid
##STR00359##
[1065] To a flask containing NaH (1 g, 25 mmol) in dry THF (25 mL)
at 0.degree. C., was added a solution of 4-bromobenzyl alcohol
(2.11 g, 11.3 mmol) in dry THF (10 mL). The solution was stirred at
0.degree. C. for 1 h, then a solution of bromoacetic acid (1 g,
7.14 mmol) in dry THF (10 mL) was added. The solution was refluxed
for 3 h, then cooled. A solution of MeOH (1 mL) in water (100 mL)
was added, and mixture was extracted with EtOAc (2.times.20 mL).
The water layer was acidified by 1N HCl to pH=2, then extracted
with EtOAc (2.times.20 mL). The combined organic layer was washed
with brine, dried (Na.sub.2SO.sub.4) and concentrated to give 67A.
(1.66 g, 95%). MS (ESI) m/z 169.0
(M--OCH.sub.2CO.sub.2H).sup.+.
67B: benzyl 3-(2-(4-bromobenzyloxy)acetamido)benzylcarbamate
##STR00360##
[1067] To a solution of 67A (245 mg, 1 mmol) and 66A (268 mg, 1.05
mmol) in DMF (4 mL), was added EDCI (288 mg, 1.5 mmol), HOAt (14
mg, 0.1 mmol) and DIEA (0.54 mL, 3 mmol). The mixture was stirred
rt for 16 h, then was quenched with water and extracted with EtOAc
(3.times.20 mL). The organic layer was washed by brine, dried
(Na.sub.2SO.sub.4) and concentrated. Purification via flash
chromatography (0-40% EtOAc in hexanes) gave 67B (300 mg, 62%). MS
(ESI) m/z 483.3 (M+H).sup.+.
67C:
4-((2-(3-((benzyloxycarbonylamino)methyl)phenylamino)-2-oxoethoxy)met-
hyl)phenylboronic acid
##STR00361##
[1069] 67C (172 mg, 80%) was obtained from 67B (233 mg, 0.48 mmol)
using a procedure similar to that used in the preparation of 66C.
MS (ESI) m/z 430.2 (M-H.sub.2O).sup.+.
67D:
2-(4-((2-(3-((benzyloxycarbonylamino)methyl)phenylamino)-2-oxoethoxy)-
methyl)phenyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)a-
cetic acid
##STR00362##
[1071] 67D (116 mg, 43%) was obtained from 67C (150 mg, 0.33 mmol)
using a procedure similar to that used in the preparation of 66D.
MS (ESI) m/z 820.9 (M+H).sup.+.
67E:
2-(4-((2-(3-(aminomethyl)phenylamino)-2-oxoethoxy)methyl)phenyl)-2-(1-
-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)acetic
acid
##STR00363##
[1073] 67E (79 mg, 82%) was obtained from 67D (116 mg, 0.14 mmol)
using a procedure similar to that used in the preparation of 66E.
MS (ESI) m/z 686.8 (M+H).sup.+.
67F:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-14-oxa-4,1-
1-diaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hex-
aene-3,12-dione
##STR00364##
[1075] 67F (40 mg, 53%) was obtained from 67E (79 mg, 0.115 mmol)
using a procedure similar to that used in the preparation of 66F.
MS (ESI) m/z 668.4 (M+H).sup.+.
Example 67
[1076] Example 67 (20 mg, 79%) was obtained from 67F (40 mg, 0.06
mmol) using a procedure similar to that used in the preparation of
Example 66. MS (ESI) m/z 468.3 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 4.03 (d, J=16.26 Hz, 1H) 4.24 (s, 2H)
4.61-4.81 (m, 3H) 5.25 (s, 1H) 5.36 (s, 1H) 6.71 (d, J=2.20 Hz, 1H)
6.84 (d, J=7.03 Hz, 1H) 6.97 (d, J=7.03 Hz, 1H) 7.16-7.23 (m, 2H)
7.24 (d, J=2.64 Hz, 1H) 7.31 (d, J=7.03 Hz, 1H) 7.42-7.47 (m, 1H)
7.48-7.53 (m, 1H) 7.57-7.62 (m, 1H) 7.81 (dd, J=7.69, 1.98 Hz, 1H)
8.07 (d, J=9.23 Hz, 1H)
Example 68
14-(1-Amino-isoquinolin-6-ylamino)-5,5-dioxo-5.lamda..sup.6-thia-4,12-diaz-
a-tricyclo[13.2.2.1.sup.6,10]icosa-1(18),6(20),7,9,15(19),16-hexaen-13-one
trifluoroacetic acid salt
##STR00365##
[1077] 68A: N-(4-bromophenethyl)-3-cyanobenzenesulfonamide
##STR00366##
[1079] To a solution of 2-(4-bromophenyl)ethanamine (600 mg, 3.13
mmol) and TEA (800 mg, 8 mmol) in THF (10 mL), was added a solution
of 3-cyano-benzenesulfonyl chloride (580 mg, 2.88 mmol) in THF (10
mL) at 0.degree. C. The mixture was stirred at rt for 2 h, quenched
with water, and extracted with EtOAc (3.times.20 mL). The organic
layer was washed with brine, dried (Na.sub.2SO.sub.4) and
concentrated. Purification via flash chromatography (0-50% EtOAc in
hexanes) gives 68A (708 mg, 71%). MS (ESI) m/z 365.3
(M+H).sup.+.
68B: 4-(2-(3-cyanophenylsulfonamido)ethyl)phenylboronic acid
##STR00367##
[1081] 68B (256 mg, 78%) was obtained from 68A (365 mg, 1 mmol)
using a procedure similar to that used in the preparation of 66C.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.73 (t, J=7.03 Hz,
2H) 3.16 (t, J=7.25 Hz, 2H) 6.99-7.24 (m, 2H) 7.48 (d, J=7.47 Hz,
1H) 7.59 (t, J=7.91 Hz, 1H) 7.67 (q, J=7.91 Hz, 1H) 7.91 (d, J=8.35
Hz, 1H) 8.02 (d, J=8.35 Hz, 1H) 8.06 (s, 1H)
68C:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(2-(3-
-cyanophenylsulfonamido)ethyl)phenyl)acetic acid
##STR00368##
[1083] 68C (300 mg, 56%) was obtained from 68B (250 mg, 0.76 mmol)
using a procedure similar to that used in the preparation of 66D.
MS (ESI) m/z 702.3 (M+H).sup.+.
68D:
2-(4-(2-(3-(aminomethyl)phenylsulfonamido)ethyl)phenyl)-2-(1-(bis(ter-
t-butoxycarbonyl)amino)isoquinolin-6-ylamino)acetic acid
##STR00369##
[1085] To a solution of 68C (160 mg) in 10 mL MeOH, was added Pd/C
(50 mg). The mixture was hydrogenated at 60 psi for 60 min. The
mixture was filtered, concentrated and purified by flash
chromatography (0 to 15% MeOH in DCM) to give 68D (108 mg, 66%). MS
(ESI) m/z 706.3 (M+H).sup.+.
68E:
14-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-5,5-dioxo-
-5.lamda..sup.6-thia-4,12-diaza-tricyclo[13.2.2.1.sup.6,10]icosa-1(18),6(2-
0),7,9,15(19),16-hexaen-13-one
##STR00370##
[1087] 68E (18 mg, 32%) was obtained from 68D (58 mg, 0.082 mmol)
using a procedure similar to that used in the preparation of 66F.
MS (ESI) m/z 688.9 (M+H).sup.+.
Example 68
[1088] Example 68 (14 mg, 91%) was obtained from 68E (18 mg, 0.026
mmol) using a procedure similar to that used in the preparation of
Example 66. MS (ESI) m/z 488.3 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 2.62-2.77 (m, 2H) 3.10-3.24 (m, 1H)
3.33-3.44 (m, 1H) 3.90 (dd, J=14.29, 4.40 Hz, 1H) 4.61 (dd,
J=14.29, 8.24 Hz, 1H) 5.06 (s, 1H) 6.70 (s, 1H) 6.80-6.87 (m, 2H)
6.92-6.98 (m, 1H) 7.17 (d, J=6.05 Hz, 1H) 7.21 (dd, J=9.34, 2.20
Hz, 1H) 7.29 (d, J=7.15 Hz, 1H) 7.34 (t, J=7.70 Hz, 1H) 7.46 (d,
J=7.70 Hz, 1H) 7.49 (d, J=7.70 Hz, 1H) 7.66 (d, J=7.70 Hz, 1H) 8.06
(d, J=9.34 Hz, 1H) 8.13 (dd, J=8.24, 4.40 Hz, 1H)
Example 69
2-(1-Amino-isoquinolin-6-ylamino)-11,11-dioxo-11.lamda..sup.6-thia-4,12-di-
aza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen--
3-one trifluoroacetic acid salt
##STR00371##
[1089] 69A:
N-(3-(4-bromophenyl)propyl)-3-cyanobenzenesulfonamide
##STR00372##
[1091] 69A (228 mg, 67%) was obtained from
3-(4-bromophenyl)propan-1-amine (630 mg, 3.31 mmol) using a
procedure similar to that used in the preparation of 68A. MS (ESI)
m/z 365.2 (M+H).sup.+.
69B: 4-(3-(3-cyanophenylsulfonamido)propyl)phenylboronic acid
##STR00373##
[1093] 69B (160 mg, 80%) was obtained from 69A (221 mg, 0.58 mmol)
using a procedure similar to that used in the preparation of 66C.
MS (ESI) m/z 345.2 (M+H).sup.+.
69C:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(3-(3-
-cyanophenylsulfonamido)propyl)phenyl)acetic acid
##STR00374##
[1095] 69C (200 mg, 61%) was obtained from 69B (159 mg, 0.46 mmol)
using a procedure similar to that used in the preparation of 66D.
MS (ESI) m/z 716.5 (M+H).sup.+.
69D:
2-(4-(3-(3-(aminomethyl)phenylsulfonamido)propyl)phenyl)-2-(1-(bis(te-
rt-butoxycarbonyl)amino)isoquinolin-6-ylamino)acetic acid
##STR00375##
[1097] 69D (155 mg, 78%) was obtained from 69C (198 mg, 0.28 mmol)
using a procedure similar to that used in the preparation of 68D.
MS (ESI) m/z 720.6 (M+H).sup.+.
69E:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-11,11-diox-
o-11.lamda..sup.6-thia-4,12-diaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19-
),6,8,10(21),16(20),17-hexaen-3-one
##STR00376##
[1099] 69E (43 mg, 54%) was obtained from 69D (82 mg, 0.114 mmol)
using a procedure similar to that used in the preparation of 66F.
MS (ESI) m/z 702.4 (M+H).sup.+.
Example 69
[1100] Example 69 (23 mg, 88%) was obtained from 69E (30 mg, 0.043
mmol) using a procedure similar to that used in the preparation of
Example 66. MS (ESI) m/z 502.4 (M+H).sup.+. .sup.1H NMR (400 MHz,
DMSO-D.sub.6) .delta. ppm 1.66-1.91 (m, 2H) 1.90-2.05 (m, 2H)
2.68-2.81 (m, 1H) 3.93 (dd, J=14.94, 4.39 Hz, 1H) 4.64 (dd,
J=14.94, 7.91 Hz, 1H) 6.65 (s, 1H) 6.82 (d, J=7.03 Hz, 1H)
6.94-7.01 (m, 2H) 7.10 (d, J=7.47 Hz, 1H) 7.16 (d, J=7.91 Hz, 1H)
7.34 (s, 1H) 7.40 (d, J=5.27 Hz, 1H) 7.42-7.48 (m, 2H) 7.48-7.58
(m, 3H) 7.61-7.71 (m, 2H) 8.15 (d, J=9.23 Hz, 1H) 8.39 (s, 2H) 8.68
(dd, J=7.91, 4.39 Hz, 1H) 12.12-12.36 (m, 1H)
Example 70
2-(1-Amino-isoquinolin-6-ylamino)-14-ethyl-13-oxa-4,11-diaza-tricyclo[14.2-
.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
trifluoroacetic acid salt
##STR00377##
[1101] 70A: 2-(4-bromophenyl)-N-methoxy-N-methylacetamide
##STR00378##
[1103] To a round bottom flask containing N-methyl-N-methoxy amine
hydrochloride (878 mg, 9 mmol) in CH.sub.2Cl.sub.2 (6 mL), a
solution of ClAlMe.sub.2 (9 mL, 1M, 9 mmol) was added at 0.degree.
C. dropwise. The solution was stirred at rt for 30 min. A solution
of ethyl 4-bromophenylacetate (1.09 g, 4.05 mmol) was added
dropwise at 0.degree. C. The solution was stirred at rt for 1 h,
quenched with sat. NH.sub.4Cl, and extracted with EtOAc (3.times.20
mL). The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated. Purification via flash
chromatography (0-50% EtOAc/hexanes) afforded 70A (1.03 g, 80%). MS
(ESI) m/z 258.1 (M+H).sup.+.
70B: 1-(4-bromophenyl)butan-2-one
##STR00379##
[1105] To a round bottom flask contained EtMgCl (10 mL, 2M in THF,
20 mmol) at 0.degree. C., was added a solution of 70A (516 mg, 2
mmol) in 10 mL THF. The solution was stirred at rt for 30 min, then
was quenched with sat. NH.sub.4Cl and extracted with EtOAc
(3.times.20 mL). The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated. Purification via flash
chromatography (0-30% EtOAc/hexanes) afforded 70B (288 mg, 65%). MS
(ESI) m/z 227.1 (M+H).sup.+.
70C: 1-(4-bromophenyl)butan-2-ol
##STR00380##
[1107] To a solution of 70B (478 mg, 2.1 mmol) in 5 mL MeOH at
0.degree. C., was added NaBH.sub.4 (110 mg, 2.98 mmol). The
solution was stirred at rt for 30 min, then was diluted with EtOAc
and washed with H.sub.2O and brine, dried (Na.sub.2SO.sub.4) and
concentrated. Purification via flash chromatography (0-30%
EtOAc/hexanes) afforded 70C (460 mg, 96%). MS (ESI) m/z 221.2
(M-OH).sup.+.
70D: 4-(2-hydroxybutyl)phenylboronic acid
##STR00381##
[1109] 70D (98 mg, 79%) was obtained from 70C (471 mg, 2.06 mmol)
using a procedure similar to that used in the preparation of 66C.
MS (ESI) m/z 177.3 (M-OTBS).sup.+.
70E:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(2-hy-
droxybutyl)phenyl)acetic acid
##STR00382##
[1111] 70E (140 mg, 65%) was obtained from 70D (74 mg, 0.38 mmol)
using a procedure similar to that used in the preparation of 66D.
MS (ESI) m/z 566.6 (M+H).sup.+.
70F:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-[4-(2-hy-
droxy-butyl)-phenyl]-N-(3-nitro-benzyl)-acetamide
##STR00383##
[1113] 70E (140 mg, 0.25 mmol) was mixed with 3-cyanobenzylamine
hydrochloride (57 mg, 0.3 mmol), PyBOP (156 mg, 0.3 mmol), TEA (76
mg, 0.75 mmol) in DMF (3 mL) and stirred at rt for 16 h. The
mixture was diluted with H.sub.2O and extracted with EtOAc
(3.times.20 mL). The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated. Purification via flash
chromatography (0-80% EtOAc/hexanes) afforded 70F (180 mg, 63%). MS
(ESI) m/z 700.8 (M+H).sup.+.
70G:
N-(3-Amino-benzyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6--
ylamino)-2-[4-(2-hydroxy-butyl)-phenyl]-acetamide
##STR00384##
[1115] To a solution of 70F (110 mg in 10 mL MeOH, 0.16 mmol) was
added 10% Pd/C (20 mg). The mixture was hydrogenated at 40 psi for
3 h, then filtered and concentrated to give 70G (107 mg, 100%). MS
(ESI) m/z 670.7 (M+H).sup.+.
70H:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-14-ethyl-1-
3-oxa-4,11-diaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(2-
0),17-hexaene-3,12-dione
##STR00385##
[1117] To a solution of 70G (77 mg, 0.115 mmol) in 20 mL
CH.sub.3CN, was added a solution of COCl.sub.2 (20% in toluene,
0.07 mL, 0.13 mmol) at 0.degree. C. The solution was stirred at rt
for 30 min, then was bubbled with Ar for 5 min. This solution was
added dropwise via a syringe pump over 4 h into a solution of TEA
(110 mg, 1 mmol) in 20 mL CH.sub.3CN at 65.degree. C. The solution
was stirred at rt for 16 h, then concentrated. Purification via
reversed phase preparative HPLC afforded 70H (15 mg, 19%). (ESI)
m/z 696.5 (M+H).sup.+.
Example 70
[1118] Example 70 (3.0 mg, 28%) was obtained from 70H (15 mg, 0.022
mmol) using a procedure similar to that used in the preparation of
Example 66. MS (ESI) m/z 496.3 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 0.88-1.15 (m, 3H) 1.63-1.90 (m, 2H)
2.54-2.75 (m, 1H) 2.92-3.10 (m, 1H) 3.82-4.74 (m, 1H) 4.92-5.11 (m,
2H) 5.09-5.31 (m, 1H) 6.16 (d, J=29.88 Hz, 1H) 6.58-6.84 (m, 2H)
6.83-6.98 (m, 2H) 7.08-7.41 (m, 5H) 7.45-7.71 (m, 2H) 8.06 (t,
J=9.67 Hz, 1H)
Examples 71 and 72
2-(1-Amino-isoquinolin-6-ylamino)-14-ethyl-13-oxa-4,11-diaza-tricyclo[14.2-
.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
trifluoroacetic acid salt, diastereomers 1 and 2, respectively
##STR00386##
[1119] 71A and 72A, diastereomers 1 and 2, respectively:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-14-ethyl-13-ox-
a-4,11-diaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),1-
7-hexaene-3,12-dione
##STR00387##
[1121] Purification of 70H (5 mg) via flash chromatography (0 to
40% EtOAc/hexanes) afforded 71A (1.5 mg), followed by 72A. MS (ESI)
m/z 696.5 (M+H).sup.+, for each intermediate.
Example 71
[1122] Example 71 (0.90 mg) was obtained from 71A (1.5 mg, 0.022
mmol) using a procedure similar to that used in the preparation of
Example 66. MS (ESI) m/z 496.3 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 0.88-1.41 (m, 3H) 1.63-1.88 (m, 2H)
2.58-2.72 (m, 1H) 2.94-3.19 (m, 1H) 3.81 (d, J=15.39 Hz, 1H)
4.91-5.08 (m, 2H) 5.15 (s, 1H) 6.20 (s, 1H) 6.64 (s, 1H) 6.72 (d,
J=8.24 Hz, 1H) 6.79 (d, J=7.15 Hz, 1H) 6.92 (d, J=7.15 Hz, 1H) 7.15
(t, J=7.97 Hz, 1H) 7.20 (d, J=7.70 Hz, 1H) 7.24 (d, J=9.34 Hz, 1H)
7.29 (d, J=7.15 Hz, 1H) 7.37 (d, J=8.25 Hz, 1H) 7.50 (dd, J=10.99,
8.24 Hz, 2H) 8.07 (d, J=9.34 Hz, 1H)
Example 72
[1123] Example 72 (1.98 mg) was obtained from 72A (2.5 mg, 0.022
mmol) using a procedure similar to that used in the preparation of
Example 66. MS (ESI) m/z 496.3 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 0.96-1.39 (m, 3H) 1.63-1.86 (m, 2H)
2.56-2.72 (m, 1H) 2.98-3.10 (m, 1H) 4.13 (dd, J=16.49, 4.95 Hz, 1H)
4.67 (dd, J=16.49, 7.15 Hz, 1H) 4.98-5.12 (m, 1H) 5.20 (s, 1H)
6.09-6.23 (m, 1H) 6.63-6.70 (m, 1H) 6.71-6.76 (m, 1H) 6.85-6.94 (m,
2H) 7.08-7.23 (m, 3H) 7.25-7.35 (m, 2H) 7.43-7.53 (m, 1H) 7.62-7.70
(m, 1H) 8.06 (t, J=9.89 Hz, 1H)
Example 73
2-(1-Amino-isoquinolin-6-ylamino)-15-methyl-13-oxa-4,11-diaza-tricyclo[14.-
2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
trifluoroacetic acid salt
##STR00388##
[1124] 73A: ethyl 2-(4-bromophenyl)propanoate
##STR00389##
[1126] To a solution of LDA (8.66 mL, 2M in
heptane/THF/ethylbenzene, 17.3 mmol) in 30 mL THF at -78.degree.
C., was added a solution of ethyl 4-bromophenylacetate (4.00 g,
16.5 mmol) in 20 mL THF. The mixture was stirred at -78.degree. C.
for 30 min, then a solution of iodomethane (10.7 mL, 2M in methyl
tert-butyl ether, 21.5 mmol) was added. The mixture was stirred for
10 min at -78.degree. C., then was removed from the cooling bath
and stirred for 30 min. The reaction was quenched with sat.
NH.sub.4Cl, then diluted with EtOAc. The organic phase was washed
with water, sat. Na.sub.2SO.sub.3 and brine, dried
(Na.sub.2SO.sub.4) and concentrated. The crude product was purified
by flash chromatography (0 to 10% EtOAc/hexanes gradient) to afford
3.07 g of 73A as a colorless oil. MS (ESI) m/z 257.1, 259.1
(M+H).sup.+.
73B: 2-(4-bromophenyl)propan-1-ol
##STR00390##
[1128] To a solution of 73A (3.06 g, 11.9 mmol) in 50 mL
CH.sub.2Cl.sub.2 at -78.degree. C., was added a solution of
diisobutylaluminum hydride (35.7 mL, 35.7 mmol, IM in hexanes). The
mixture was removed from the cooling bath, stirred 1 h, then
recooled to -50.degree. C. and quenched with EtOAc (2 mL). The
reaction mixture was diluted with H.sub.2O, then extracted with
EtOAc (3.times.). The combined organic extract was washed with
brine, dried (Na.sub.2SO.sub.4), filtered through a 1'' pad of
SiO.sub.2, then concentrated to afford 2.34 g of 73B as a colorless
oil. MS (ESI) m/z 197.1 (M-OH).sup.+.
73C: (2-(4-bromophenyl)propoxy)(tert-butyl)dimethylsilane
##STR00391##
[1130] To a solution of 73B (2.34 g, 10.9 mmol) in 30 mL DMF, was
added imidazole (1.11 g, 16.3 mmol) and tert-butyldimethylsilyl
chloride (1.97 g, 13.1 mmol). The mixture was stirred at rt for 3
h, then was diluted with hexanes. The organic phase was washed with
H.sub.2O (2.times.) and brine, dried (Na.sub.2SO.sub.4) and
concentrated. The product was purified by flash chromatography (0
to 10% EtOAc/hexanes gradient) to afford 2.00 g of 73C as a
colorless oil. MS (ESI) m/z 197.1 (M-OTBS).sup.+.
73D: 4-(1-(tert-butyldimethylsilyloxy)propan-2-yl)phenylboronic
acid
##STR00392##
[1132] To a solution of 73C (100 mg in 2 mL dry THF, 0.3 mmol) at
-78.degree. C. was added n-BuLi (1.6 M, 0.2 mL, 0.32 mmol),
followed by B(OMe).sub.3 (0.1 mL, 0.9 mmol). The solution was
stirred at -78.degree. C. for 2 h. 1N HCl (4 mL) was added, and
stirred 30 min. The mixture was extracted with EtOAc (3.times.20
mL). The organic layer was washed by brine, dried
(Na.sub.2SO.sub.4). Purification through ISCO (0-80% EtOAc in
hexanes) gives 73D (37 mg, 40%). .sup.1H NMR (400 MHz,
Chloroform-d) .delta. ppm -0.03 (d, J=3.52 Hz, 6H) 0.84-0.89 (m,
9H) 1.33 (d, J=7.03 Hz, 3H) 2.92-3.06 (m, 1H) 3.62-3.79 (m, 2H)
7.36 (d, J=7.91 Hz, 2H) 8.16 (d, J=7.91 Hz, 2H)
73E:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(1-hy-
droxypropan-2-yl)phenyl)acetic acid
##STR00393##
[1134] 73E (39 mg, 57%) was obtained from 73D (37 mg, 0.126 mmol)
using a procedure similar to that used in the preparation of 66D.
MS (ESI) m/z 552.5 (M+H).sup.+.
73F:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(1-hy-
droxypropan-2-yl)phenyl)-N-(3-nitrobenzyl)acetamide
##STR00394##
[1136] 73F (32 mg, 99%) was obtained from 73E (26 mg, 0.047 mmol)
using a procedure similar to that used in the preparation of 70F.
MS (ESI) m/z 686.5 (M+H).sup.+.
73G:
N-(3-aminobenzyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-y-
lamino)-2-(4-(1-hydroxypropan-2-yl)phenyl)acetamide
##STR00395##
[1138] 73G (23 mg, 80%) was obtained from 73F (30 mg, 0.044 mmol)
using a procedure similar to that used in the preparation of 70G.
MS (ESI) m/z 656.5 (M+H).sup.+.
73H:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-15-methyl--
13-oxa-4,11-diaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(-
20),17-hexaene-3,12-dione
##STR00396##
[1140] 73H (12 mg, 50%) was obtained from 73G (23 mg, 0.035 mmol)
using a procedure similar to that used in the preparation of 70H.
MS (ESI) m/z 682.5 (M+H).sup.+.
Example 73
[1141] Example 73 (7 mg, 82%) was obtained from 73H (12 mg, 0.018
mmol) using a procedure similar to that used in the preparation of
Example 66. MS (ESI) m/z 482.4. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. ppm 1.20-1.44 (m, 3H) 3.02-3.18 (m, 1H) 3.93-4.19 (m, 2H)
4.24-4.70 (m, 2H) 5.18 (d, J=15.94 Hz, 1H) 6.15 (d, J=30.23 Hz, 1H)
6.62-6.74 (m, 2H) 6.85 (t, J=7.42 Hz, 1H) 6.90 (d, J=7.15 Hz, 1H)
7.13 (t, J=7.70 Hz, 1H) 7.16-7.21 (m, 1H) 7.30 (d, J=6.05 Hz, 2H)
7.38 (d, J=8.25 Hz, 1H) 7.48 (dd, J=12.09, 8.25 Hz, 1H) 7.61 (dd,
J=57.99, 7.97 Hz, 1H) 8.06 (dd, J=9.34, 4.95 Hz, 1H)
Example 74
2-(1-Amino-isoquinolin-6-ylamino)-15,15-dimethyl-13-oxa-4,11-diaza-tricycl-
o[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
trifluoroacetic acid salt
##STR00397##
[1142] 74A: 2-(4-bromophenyl)-2-methylpropan-1-ol
##STR00398##
[1144] According to the procedure for the preparation of 73B,
methyl 2-(4-bromophenyl)-2-methylpropanoate (2.15 g, 8.36 mmol)
afforded 1.93 g of 74A as a colorless oil. MS (ESI) m/z 211.1
(M-OH).sup.+.
74B:
(2-(4-bromophenyl)-2-methylpropoxy)(tert-butyl)dimethylsilane
##STR00399##
[1146] According to the procedure for the preparation of 73C, 74A
(1.93 g, 8.42 mmol) afforded 3.04 g of 74B as a colorless oil. MS
(ESI) m/z 211.1 (M-OTBS).sup.+.
74C:
4-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)phenylboronic
acid
##STR00400##
[1148] 74C (58 mg, 13%) was obtained from 74B (512 mg, 1.49 mmol)
using a procedure similar to that used in the preparation of 73D.
.sup.1H NMR (400 MHz, Chloroform-d) .delta. ppm -0.05-0.02 (m, 6H)
0.87 (d, J=3.52 Hz, 9H) 1.36 (d, J=3.08 Hz, 6H) 3.61 (d, J=3.08 Hz,
2H) 7.53 (dd, J=8.13, 2.86 Hz, 2H) 8.17 (dd, J=7.91, 3.08 Hz,
2H)
74D:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(1-hy-
droxy-2-methylpropan-2-yl)phenyl)acetic acid
##STR00401##
[1150] 74D (59 mg, 56%) was obtained from 74C (58 mg, 0.188 mmol)
using a procedure similar to that used in the preparation of 66D.
MS (ESI) m/z 566.6 (M+H).sup.+.
74E:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(1-hy-
droxy-2-methylpropan-2-yl)phenyl)-N-(3-nitrobenzyl)acetamide
##STR00402##
[1152] 74E (35 mg, 51%) was obtained from 74D (58 mg, 0.104 mmol)
using a procedure similar to that used in the preparation of 70F.
MS (ESI) m/z 700.3 (M+H).sup.+.
74F:
N-(3-aminobenzyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-y-
lamino)-2-(4-(1-hydroxy-2-methylpropan-2-yl)phenyl)acetamide
##STR00403##
[1154] 74F (28 mg, 95%) was obtained from 74E (32 mg, 0.046 mmol)
using a procedure similar to that used in the preparation of 70G.
MS (ESI) m/z 670.7 (M+H).sup.+.
74G:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-15,15-dime-
thyl-13-oxa-4,11-diaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21-
),16(20),17-hexaene-3,12-dione
##STR00404##
[1156] 74G was obtained from 74F (27 mg, 0.04 mmol) using a
procedure similar to that used in the preparation of 70H. MS (ESI)
m/z 696.6 (M+H).sup.+.
Example 74
[1157] Example 74 (9.5 mg) was obtained from 74G using a procedure
similar to that used in the preparation of Example 66. MS (ESI) m/z
496.5 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm
1.43 (d, J=8.35 Hz, 6H) 3.90-4.55 (m, 2H) 4.71-4.99 (m, 2H) 5.19
(s, 1H) 6.12 (s, 1H) 6.64-6.73 (m, 2H) 6.83 (d, J=7.03 Hz, 1H) 6.89
(d, J=7.91 Hz, 1H) 7.13 (t, J=7.69 Hz, 1H) 7.19 (dd, J=9.23, 2.20
Hz, 1H) 7.29 (d, J=7.47 Hz, 1H) 7.36-7.46 (m, 2H) 7.53-7.66 (m, 2H)
8.05 (d, J=9.23 Hz, 1H)
Example 75
2-(1-Amino-isoquinolin-6-ylamino)-15-ethyl-13-oxa-4,11-diaza-tricyclo[14.2-
.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
trifluoroacetic acid salt
##STR00405##
[1158] 75A: ethyl 2-(4-bromophenyl)butanoate
##STR00406##
[1160] To a solution of ethyl 2-(4-bromophenyl)acetate (972 mg, 4
mmol) in 10 mL dry THF at -78.degree. C. was added LDA (2 M, 2 mL,
4 mmol). The solution was warmed to rt and stirred 2 h, then was
recooled to -78.degree. C. EtI (0.52 mL) was added, then the
reaction was stirred rt for 16 h. The reaction was quenched with
sat. NH.sub.4Cl, then extracted with EtOAc (3.times.20 mL). The
organic layer was washed with brine, then dried (Na.sub.2SO.sub.4).
Purification via flash chromatography (0-20% EtOAc in hexanes)
gives 75A (228 mg, 21%). MS (ESI) m/z 271.0 (M+H).sup.+.
75B: 2-(4-bromophenyl)butanoic acid
##STR00407##
[1162] To a solution of 75A (228 mg, 0.85 mmol) in 3 mL THF, was
added aq. LiOH (1M, 2 mL, 2 mmol), and the reaction was stirred at
rt for 16 h. Water (20 mL) was added, then the mixture was
acidified with 1N HCl (pH=2) and extracted with EtOAc (3.times.20
mL). The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated to afford 75B (150 mg, 73%). MS
(ESI) m/z 243.0 (M+H).sup.+.
75C: 2-(4-bromophenyl)butan-1-ol
##STR00408##
[1164] To a solution of 75B (96 mg, 0.4 mmol) in 3 mL THF was added
BH.sub.3 (2M in THF, 0.5 mL, 1 mmol). The solution was stirred at
rt for 16 h. EtOAc (20 mL) was added, and the organic phase was
washed with 1M H.sub.3PO.sub.4, sat. NaHCO.sub.3 and brine, dried
(Na.sub.2SO.sub.4), and concentrated. Purification via flash
chromatography (0-30% EtOAc in hexanes) gives 75C (86 mg, 96%). MS
(ESI) m/z 211.2 (M-H.sub.2O).sup.+.
75D: 4-(1-hydroxybutan-2-yl)phenylboronic acid
##STR00409##
[1166] 75D (74 mg, 68%) was obtained from 75C (128 mg, 0.56 mmol)
using a procedure similar to that used in the preparation of 66C.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 0.79 (t, J=7.25 Hz,
3H) 1.50-1.63 (m, 1H) 1.79-1.91 (m, 1H) 2.56-2.68 (m, 1H) 3.66 (d,
J=7.03 Hz, 2H) 7.20 (d, J=7.91 Hz, 2H) 7.55 (d, J=7.91 Hz, 2H)
75E:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(1-hy-
droxybutan-2-yl)phenyl)acetic acid
##STR00410##
[1168] 75E (94 mg, 44%) was obtained from 75D (74 mg, 0.38 mmol)
using a procedure similar to that used in the preparation of 66D.
MS (ESI) m/z 566.6 (M+H).sup.+.
75F:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(1-hy-
droxybutan-2-yl)phenyl)-N-(3-nitrobenzyl)acetamide
##STR00411##
[1170] 75F (60 mg, 51%) was obtained from 75E (94 mg, 0.17 mmol)
using a procedure similar to that used in the preparation of 70F.
MS (ESI) m/z 700.8 (M+H).sup.+.
75G:
N-(3-aminobenzyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-y-
lamino)-2-(4-(1-hydroxybutan-2-yl)phenyl)acetamide
##STR00412##
[1172] 75G (57 mg, 99%) was obtained from 75F (60 mg, 0.086 mmol)
using a procedure similar to that used in the preparation of 70G.
MS (ESI) m/z 670.7 (M+H).sup.+.
75H:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-15-ethyl-1-
3-oxa-4,11-diaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(2-
0),17-hexaene-3,12-dione
##STR00413##
[1174] 75H (25 mg, 42%) was obtained from 75G (57 mg, 0.085 mmol)
using a procedure similar to that used in the preparation of 70H.
MS (ESI) m/z 696.6 (M+H).sup.+.
Example 75
[1175] Example 75 (17 mg, 94%) was obtained from 75H (25 mg, 0.035
mmol) using a procedure similar to that used in the preparation of
Example 66. MS (ESI) m/z 496.6 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 0.80-0.95 (m, 3H) 1.64-1.92 (m, 2H)
2.73-2.96 (m, 1H) 3.96-4.45 (m, 2H) 4.62-4.86 (m, 2H) 5.18 (d,
J=19.33 Hz, 1H) 6.15 (d, J=36.91 Hz, 1H) 6.63-6.74 (m, 2H) 6.84
(dd, J=7.03, 3.52 Hz, 1H) 6.89 (d, J=7.47 Hz, 1H) 7.09-7.40 (m, 5H)
7.48 (t, J=10.11 Hz, 1H) 7.52-7.73 (m, 1H) 8.06 (dd, J=9.23, 5.27
Hz, 1H).
Example 76
(R)-2-(1-Amino-isoquinolin-6-ylamino)-15-methyl-13-oxa-4,11-diaza-tricyclo-
[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
trifluoroacetic acid salt
##STR00414##
[1176] 76A:
(R)-4-benzyl-3-(2-(4-bromophenyl)acetyl)oxazolidin-2-one
##STR00415##
[1178] To a round bottom flask contained
(R)-4-benzyl-2-oxazolidinone (800 mg, 4.51 mmol) in THF (10 mL),
n-BuLi (2.83 mL, 1.6M, 4.52 mmol) was added at -78.degree. C.,
dropwise. The solution was stirred at -78.degree. C. for 10 min. A
solution of 2-(4-bromophenyl)acetyl chloride (1.0 g, 4.28 mmol) in
10 mL THF was added. The solution was stirred -78.degree. C. for 30
min, and rt for 3 h, and then was quenched with sat. NH.sub.4Cl and
extracted with EtOAc (3.times.20 mL). The organic layer was washed
with brine, dried (Na.sub.2SO.sub.4), and concentrated.
Purification via flash chromatography (0-30% EtOAc in hexanes)
gives 76A (1.29 g, 80%). MS (ESI) m/z 374.1 (M+H).sup.+.
76B:
(R)-4-benzyl-3-((R)-2-(4-bromophenyl)propanoyl)oxazolidin-2-one
##STR00416##
[1180] To a solution of 76A (380 mg, 1.01 mmol) in THF (5 mL) at
-78.degree. C., was added NaHMDS (1.3 mL, 1.0M, 1.3 mmol),
dropwise. The solution was stirred at -78.degree. C. for 3 h. A
solution of MeI (0.62 mL, 10 mmol) in 2 mL THF was added. The
solution was stirred -78.degree. C. for 3 h, and -40.degree. C. for
1 h. The reaction was quenched with sat. NH.sub.4Cl and extracted
with EtOAc (3.times.20 mL). The organic layer was washed with
brine, dried (Na.sub.2SO.sub.4), and concentrated. Purification via
flash chromatography (0-30% EtOAc in hexanes) gives 76B (70 mg,
18%). MS (ESI) m/z 388.3 (M+H).sup.+.
76C: (R)-2-(4-bromophenyl)propanoic acid
##STR00417##
[1182] To a solution of 76B (209 mg, 0.54 mmol) in THF (5 mL) at
0.degree. C., was added H.sub.2O.sub.2 (0.33 mL, 50%, 5.4 mmol)
dropwise, followed by aq. LiOH (1.1 mL, 1.0 M, 1.1 mmol). The
solution was stirred at rt for 2 h. Aq. Na.sub.2SO.sub.3 (1M, 20
mL) was added and stirred rt for 30 min. The aqueous phase was
extracted with CH.sub.2Cl.sub.2 (2.times.10 mL), acidified to pH=2
with 1N HCl, and extracted with EtOAc (3.times.20 mL). The organic
layer was washed with brine, dried (Na.sub.2SO.sub.4) and
concentrated to give 76C (110 mg, 90%). MS (ESI) m/z 229.0
(M+H).sup.+.
76D: (R)-2-(4-bromophenyl)propan-1-ol
##STR00418##
[1184] To a solution of 76C (95 mg, 0.42 mmol) in THF (3 mL) at
0.degree. C., was added BH.sub.3 (1M in THF, 0.4 mL, 4 mmol). The
mixture was stirred rt for 16 h. EtOAc (20 mL) was added, and the
organic phase was washed with 1M H.sub.3PO.sub.4, sat. NaHCO.sub.3
and brine, dried (Na.sub.2SO.sub.4), and concentrated to give 76D
(90 mg, 100%). MS (ESI) m/z 197.0 (M-H.sub.2O+H).sup.+.
76E: (R)-2-(4-boronophenyl)propanoic acid
##STR00419##
[1186] 76E (77 mg, 97%) was obtained from 76D (95 mg, 0.44 mmol)
using a procedure similar to that used in the preparation of 66C.
MS (ESI) m/z 163.1 (M-H.sub.2O+H).sup.+.
76F:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-((R)--
1-hydroxypropan-2-yl)phenyl)acetic acid
##STR00420##
[1188] 76F (200 mg, 87%) was obtained from 76E (77 mg, 0.43 mmol)
using a procedure similar to that used in the preparation of 66D.
MS (ESI) m/z 552.3 (M+H).sup.+.
76G:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-((R)--
1-hydroxypropan-2-yl)phenyl)-N-(3-nitrobenzyl)acetamide
##STR00421##
[1190] 76G (172 mg, 87%) was obtained from 76F (190 mg, 0.34 mmol)
using a procedure similar to that used in the preparation of 70F.
MS (ESI) m/z 686.4 (M+H).sup.+.
76H:
N-(3-aminobenzyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-y-
lamino)-2-(4-((R)-1-hydroxypropan-2-yl)phenyl)acetamide
##STR00422##
[1192] 76H (145 mg, 88%) was obtained from 76G (172 mg, 0.25 mmol)
using a procedure similar to that used in the preparation of 70G.
MS (ESI) m/z 656.4 (M+H).sup.+.
76I:
(R)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-15-met-
hyl-13-oxa-4,11-diaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21)-
,16(20),17-hexaene-3,12-dione
##STR00423##
[1194] 76I (20 mg, 24%) was obtained from 76H (80 mg, 0.122 mmol)
using a procedure similar to that used in the preparation of 70H.
MS (ESI) m/z 682.6 (M+H).sup.+.
Example 76
[1195] Example 76 (13.2 mg, 98%) was obtained from 76I (19 mg,
0.028 mmol) using a procedure similar to that used in the
preparation of Example 70. MS (ESI) m/z 482.3 (M+H).sup.+. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.24-1.45 (m, 3H) 3.01-3.19
(m, 1H) 3.92-4.15 (m, 2H) 4.25-4.86 (m, 2H) 5.18 (d, J=14.94 Hz,
1H) 6.15 (d, J=29.00 Hz, 1H) 6.62-6.74 (m, 2H) 6.82 (t, J=7.47 Hz,
1H) 6.89 (d, J=7.91 Hz, 1H) 7.07-7.23 (m, 3H) 7.25-7.34 (m, 2H)
7.35-7.73 (m, 2H) 8.05 (dd, J=9.23, 4.83 Hz, 1H).
Examples 77 and 78
2-(1-Amino-isoquinolin-6-ylamino)-14-methyl-13-oxa-4,11-diaza-tricyclo[14.-
2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
trifluoroacetic acid salt, diastereomers 1 and 2, respectively
##STR00424##
[1196] 77A: 1-(4-bromophenyl)propan-2-ol
##STR00425##
[1198] To a solution of 4-bromophenylacetone (5.00 g, 23.5 mmol) in
ethanol (100 mL) at 0.degree. C., was added sodium borohydride (976
mg, 25.8 mmol) portionwise over 5 min. The mixture was stirred at
rt for 15 h, then quenched with 5% citric acid. The volatile
solvent was removed in vacuo. The mixture was diluted with water,
the pH was adjusted to 4.5 with 1N HCl, then aqueous phase was
extracted with CH.sub.2Cl.sub.2 (3.times.). The combined organic
was washed with brine, dried (Na.sub.2SO.sub.4), filtered through a
pad of SiO.sub.2 (eluted with 10% EtOAc/CH.sub.2Cl.sub.2) and
concentrated to afford 4.90 g of 77A as a colorless oil. MS (ESI)
m/z 197.1 (M-OH).sup.+.
77B:
(1-(4-bromophenyl)propan-2-yloxy)(tert-butyl)dimethylsilane
##STR00426##
[1200] According to the procedure for the preparation of 73C, 77A
(4.90 g, 22.8 mmol) afforded 6.51 g (87%) of 77B as a colorless
oil. MS (ESI) m/z 197.1 (M-OTBS).sup.+.
77C: 4-(2-(tert-butyldimethylsilyloxy)propyl)phenylboronic acid
##STR00427##
[1202] According to the procedure for the preparation of 73D, 77B
(2.14 g, 6.50 mmol) afforded 1.04 g (54%) of 77C as a colorless
solid. MS (ESI) m/z 295.2 (M+H).sup.+.
77D:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(2-(t-
ert-butyldimethylsilyloxy)propyl)phenyl)acetic acid
##STR00428##
[1204] According to the procedure for the preparation of 66D, 77C
(200 mg, 0.68 mmol) afforded 295 mg (65%) of 77D as an off-white
solid. MS (ESI) m/z 666.4 (M+H).sup.+.
77E:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(2-(t-
ert-butyldimethylsilyloxy)propyl)phenyl)-N-(3-nitrobenzyl)acetamide
##STR00429##
[1206] According to the procedure for the preparation of 70F, 77D
(150 mg, 0.225 mmol) afforded 172 mg (96%) of 77E as a brown glass.
MS (ESI) m/z 800.5 (M+H).sup.+.
77F:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(4-(2-hy-
droxypropyl)phenyl)-N-(3-nitrobenzyl)acetamide
##STR00430##
[1208] To a solution of 77E (172 mg, 0.215 mmol) in 3 mL THF, was
added a solution of TBAF (1M in THF, 1 mL, 1 mmol). The mixture was
stirred at 35.degree. C. for 17 h, then concentrated. The residue
was dissolved in EtOAc, washed with water (2.times.) and brine,
dried (Na.sub.2SO.sub.4) and concentrated. Purification by flash
chromatography (0 to 100% EtOAc/hexanes) afforded 38 mg (26%) of
77F as a yellow glass. MS (ESI) m/z 686.4 (M+H).sup.+.
77G:
N-(3-aminobenzyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-y-
lamino)-2-(4-(2-hydroxypropyl)phenyl)acetamide
##STR00431##
[1210] According to the procedure for the preparation of 70G, 77F
(38 mg, 0.055 mmol) afforded 29 mg (80%) of 77G as a white solid.
MS (ESI) m/z 656.5 (M+H).sup.+.
77H and 77I:
2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-14-methyl-13-o-
xa-4,11-diaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),-
17-hexaene-3,12-dione, diastereomers 1 and 2, respectively
##STR00432##
[1212] According to the procedure for the preparation of 70H, 77G
(29 mg, 0.055 mmol) afforded after flash chromatography (0 to 100%
EtOAc/hexanes) 6.8 mg (23%) of 77H as a colorless residue, followed
by 9.0 mg (30%) of 771 as an orange solid. MS (ESI) m/z 656.5
(M+H).sup.+ for each diastereomer.
Example 77
[1213] According to the procedure for the preparation of Example
66, 77H (6.8 mg) afforded 5.2 mg of Example 77 as a white solid. MS
(ESI) m/z 482.4 (M+H).sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) d
ppm 8.58 (d, J=8.35 Hz, 1H) 8.08 (d, J=9.23 Hz, 1H) 7.50 (t, J=8.57
Hz, 2H) 7.37 (d, J=7.91 Hz, 1H) 7.29 (d, J=7.03 Hz, 1H) 7.25 (d,
J=10.55 Hz, 1H) 7.20 (d, J=7.91 Hz, 1H) 7.14 (t, J=7.91 Hz, 1H)
6.91 (d, J=7.47 Hz, 1H) 6.79 (d, J=7.03 Hz, 1H) 6.71 (d, J=7.91 Hz,
1H) 6.64 (s, 1H) 6.21 (s, 1H) 5.18-5.27 (m, 1H) 5.15 (s, 1H)
4.91-4.99 (m, 1H) 3.86-3.94 (m, 1H) 2.99 (d, J=11.86 Hz, 1H) 2.64
(dd, J=13.18, 11.42 Hz, 1H) 1.40 (d, J=6.59 Hz, 3H).
Example 78
[1214] According to the procedure for the preparation of Example
66, 77I (9.0 mg) afforded 5.2 mg of Example 78 as a white solid. MS
(ESI) m/z 482.4 (M+H).sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) d
ppm 8.77 (t, J=6.15 Hz, 1H) 8.05 (d, J=9.23 Hz, 1H) 7.65 (dd,
J=7.69, 1.54 Hz, 1H) 7.48 (dd, J=7.69, 1.10 Hz, 1H) 7.32 (d, J=7.03
Hz, 1H) 7.28 (dd, J=8.13, 1.54 Hz, 1H) 7.15-7.19 (m, 2H) 7.13 (t,
J=7.69 Hz, 1H) 6.88 (t, J=6.15 Hz, 2H) 6.73 (d, J=1.76 Hz, 1H) 6.66
(d, J=7.91 Hz, 1H) 6.14 (s, 1H) 5.25-5.34 (m, J=17.41, 6.12, 6.12,
2.86 Hz, 1H) 5.20 (s, 1H) 4.67 (dd, J=16.48, 6.81 Hz, 1H) 4.13 (dd,
J=16.48, 5.05 Hz, 1H) 3.04 (dd, J=13.40, 1.98 Hz, 1H) 2.65 (dd,
J=13.18, 11.42 Hz, 1H) 1.41 (d, J=6.59 Hz, 3H).
Example 79
14-(1-Amino-isoquinolin-6-ylamino)-17,18-dimethyl-9-(ethylsulfonyl)-2-oxa--
5,12-diaza-tricyclo[13.2.2.1.sup.6,10]icosa-1(18),6(20),7,9,15(19),16-hexa-
ene-4,13-dione trifluoroacetic acid salt
##STR00433##
[1215] 79A: 2-(4-bromo-2,6-dimethylphenoxy)acetic acid
##STR00434##
[1217] To a suspension of sodium hydride (60%, 437 mg, 10.9 mmol)
in THF (10 mL) at rt, was added a solution of
4-bromo-2,6-dimethylphenol (1.00 g, 4.97 mmol) in THF (10 mL), over
5 min. The reddish suspension was stirred at rt for 10 min, then a
solution of bromoacetic acid (691 mg, 4.97 mmol) in 5 mL THF was
added. The suspension was stirred at rt for 20 h. The volatile
solvent was evaporated in vacuo, then the mixture was diluted with
20 mL H.sub.2O. The pH was adjusted to 7 with 1N HCl, then the
aqueous phase was extracted with Et.sub.2O (2.times.). The aqueous
phase was acidified to pH=2 with 1N HCl, then was extracted with
EtOAc (2.times.). The combined organic extract was washed with
brine, dried (Na.sub.2SO.sub.4) and concentrated to afford 1.10 g
(85%) of 79A as a colorless solid. MS (ESI) m/z 259.0
(M+H).sup.+.
79B: benzyl
5-(2-(4-bromo-2,6-dimethylphenoxy)acetamido)-2-(ethylsulfonyl)benzylcarba-
mate
##STR00435##
[1219] To a solution of 79A (100 mg, 0.386 mmol) and 28A (148 mg,
0.386 mmol) in 2 mL pyridine at -15.degree. C., was added
POCl.sub.3 (0.040 mL, 0.425 mmol), dropwise. The mixture was
stirred at this temperature for 20 min, then was quenched with
water. The mixture was diluted with EtOAc, washed with water
(2.times.), 1N HCl, water, sat. NaHCO.sub.3 and brine, dried
(Na.sub.2SO.sub.4) and concentrated. The crude product was purified
by flash chromatography to afford 222 mg (98%) of 79B as a
colorless oil. MS (ESI) m/z 589.2 (M+H).sup.+.
79C:
4-(2-(3-((benzyloxycarbonylamino)methyl)-4-(ethylsulfonyl)phenylamino-
)-2-oxoethoxy)-3,5-dimethylphenylboronic acid
##STR00436##
[1221] According to the procedure for the preparation of 66C, 79B
(375 mg, 0.636 mmol) afforded following reversed phase preparative
HPLC 302 mg (86%) of 79C as a colorless solid. MS (ESI) m/z 555.3
(M+H).sup.+.
79D:
2-(4-(2-(3-((benzyloxycarbonylamino)methyl)-4-(ethylsulfonyl)phenylam-
ino)-2-oxoethoxy)-3,5-dimethylphenyl)-2-(1-(bis(tert-butoxycarbonyl)amino)-
isoquinolin-6-ylamino)acetic acid
##STR00437##
[1223] According to the procedure for the preparation of 66D, 79C
(150 mg, 0.271 mmol) afforded 205 mg (82%) of 79D as an orange
solid. MS (ESI) m/z 926.5 (M+H).sup.+.
79E:
2-(4-(2-(3-(aminomethyl)-4-(ethylsulfonyl)phenylamino)-2-oxoethoxy)-3-
,5-dimethylphenyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylami-
no)acetic acid
##STR00438##
[1225] To a solution of 79D (190 mg, 0.205 mmol) in 5 mL methanol,
was added 10% Pd--C (30 mg). The reaction was evacuated and flushed
with H.sub.2 (3.times.), then stirred under an atmosphere of
H.sub.2 for 1 h. The reaction was filtered and concentrated to
afford 151 mg (93%) of 79E as an orange solid. MS (ESI) m/z 926.5
(M+H).sup.+.
Example 79
[1226] To a solution of PyBOP (197 mg, 0.379 mmol), DMAP (116 mg,
0.95 mmol) and TEA (0.132 mL, 0.95 mmol) in CH.sub.2Cl.sub.2 (50
mL) at rt, was added a solution of 79E in 5 mL DMF over 4 h via a
syringe pump. The mixture was stirred for at rt for 15 h, then was
concentrated. The material was diluted with EtOAc, washed with
water (2.times.), sat. NaHCO.sub.3 and brine, dried
(Na.sub.2SO.sub.4) and concentrated. The residue was treated with 5
mL TFA. The mixture was stirred for 5 min, then concentrated.
Purification by preparative HPLC afforded 6.5 mg of Example 79 as a
yellow solid. MS (ESI) m/z 574.3 (M+H).sup.+; .sup.1H NMR (400 MHz,
CD.sub.3OD) d ppm 8.68-8.74 (m, 1H) 8.09 (d, J=9.34 Hz, 1H) 7.82
(d, J=8.79 Hz, 1H) 7.38 (s, 1H) 7.32 (d, J=7.15 Hz, 1H) 7.24-7.23
(m, 1H) 7.22 (t, J=2.20 Hz, 1H) 6.98 (s, 1H) 6.88 (d, J=7.15 Hz,
1H) 6.74 (d, J=2.20 Hz, 1H) 5.81 (d, J=1.85 Hz, 1H) 5.11 (s, 1H)
5.05 (dd, J=16.49, 7.15 Hz, 1H) 4.62-4.71 (m, 2H) 4.29 (dd,
J=17.04, 4.95 Hz, 1H) 3.37-3.32 (m, 2H) 2.40 (s, 3H) 2.19 (s, 3H)
1.24 (t, J=7.15 Hz, 3H).
Example 80
14-Acetyl-2-(1-amino-isoquinolin-6-ylamino)-4,11,14-triaza-tricyclo[14.2.2-
.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
trifluoroacetic acid salt
##STR00439##
[1227] 80A: benzyl 2-(4-bromobenzylamino)acetate
##STR00440##
[1229] To a suspension of glycine benzyl ester hydrochloride (2.02
g, 10.0 mmol) and 4-bromobenzaldehyde (1.85 g, 10.0 mmol) in 50 mL
DCE, was added acetic acid (2.9 mL, 50 mmol) and TEA (1.4 mL, 10.0
mmol) to give a clear solution. Sodium triacetoxyborohydride (4.24
g, 20.0 mmol) was added. The suspension was stirred at rt for 17 h.
The mixture was neutralized with sat. NaHCO.sub.3 and extracted
with CH.sub.2Cl.sub.2 (3.times.). The combined organic extract was
washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. The
crude product was purified via flash chromatography (0 to 100%
EtOAc in hexanes) to afford 80A (2.13 g, 64%). MS (ESI) m/z 334.0
(M+H).sup.+.
80B: benzyl 2-(N-(4-bromobenzyl)acetamido)acetate
##STR00441##
[1231] To a solution of 80A (500 mg, 1.50 mmol) in 5 mL
CH.sub.2Cl.sub.2, were added TEA (0.229 mL, 1.65 mmol) and acetic
anhydride (0.156 mL, 1.65 mmol). The mixture was stirred at rt for
2 h, then concentrated. The crude product was purified via flash
chromatography (0 to 100% EtOAc in hexanes) to afford 80B (560 mg,
99%). MS (ESI) m/z 376.0 (M+H).sup.+.
80C: 4-((N-(2-(benzyloxy)-2-oxoethyl)acetamido)methyl)phenylboronic
acid
##STR00442##
[1233] 80C (140 mg, 82%) was obtained from 80B (188 mg, 0.5 mmol)
using a procedure similar to that used in the preparation of 66C.
MS (ESI) m/z 342.2 (M+H).sup.+.
80D:
2-(4-((N-(2-(benzyloxy)-2-oxoethyl)acetamido)methyl)phenyl)-2-(1-(bis-
(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)acetic acid
##STR00443##
[1235] 80D (80 mg, 65%) was obtained from 80C (140 mg, 0.38 mmol)
using a procedure similar to that used in the preparation of 66D.
MS (ESI) m/z 713.2 (M+H).sup.+.
80E: benzyl benzyl
2-(N-(4-(1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)-2-(3--
nitrobenzylamino)-2-oxoethyl)benzyl)acetamido)acetate
##STR00444##
[1237] 80D (280 mg, 0.39 mmol) was mixed with 3-cyanobenzylamine
hydrochloride (116 mg, 0.61 mmol), PyBOP (277 mg, 0.53 mmol), and
TEA (202 mg, 2 mmol) in DMF (3 mL) and stirred at rt for 16 h. The
mixture was diluted with H.sub.2O and extracted with EtOAc
(3.times.20 mL). The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated. Purification via flash
chromatography (0-80% EtOAc/hexanes) afforded 80E (150 mg, 45%). MS
(ESI) m/z 847.5 (M+H).sup.+.
80F:
2-(N-(4-(2-(3-aminobenzylamino)-1-(1-(bis(tert-butoxycarbonyl)amino)i-
soquinolin-6-ylamino)-2-oxoethyl)benzyl)acetamido)acetic acid
##STR00445##
[1239] To a solution of 80E (148 mg, 0.18 mmol) in 10 mL MeOH, was
added 10% Pd/C (20 mg). The mixture was hydrogenated at 40 psi for
3 h, then filtered and concentrated to give 80F (115 mg, 100%). MS
(ESI) m/z 727.7 (M+H).sup.+.
80G:
14-Acetyl-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-ylamino)--
4,11,14-triaza-tricyclo[14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20)-
,17-hexaene-3,12-dione
##STR00446##
[1241] To a solution of BOP (30 mg, 0.065), TEA (0.07 mL, 0.5 mmol)
in 40 mL of CH.sub.2Cl.sub.2, was added a solution of 80F (40 mg,
0.055 mmol) in DMF (8 mL) via a syringe pump over 6 h. The mixture
was stirred r.t over night, then was quenched with sat. NH.sub.4Cl
and extracted with EtOAc (3.times.20 mL). The organic layer was
washed with brine, dried (Na.sub.2SO.sub.4) and concentrated.
Purification via flash chromatography (0-10% MeOH/CH.sub.2Cl.sub.2)
afforded 80G (21 mg, 54%). MS (ESI) m/z 709.5 (M+H).sup.+.
Example 80
[1242] To a solution of 80G (15 mg, 0.021 mmol) in 1 mL
CH.sub.2Cl.sub.2, was added TFA (1 mL). The solution was stirred at
rt for 1 h, then concentrated. Purification by reversed phase HPLC
afforded 4 mg (38%) of Example 80. MS (ESI) m/z 509.1 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.43-2.90 (m, 3H)
3.95-4.24 (m, 3H) 4.34-4.57 (m, 1H) 4.69-4.85 (m, 1H) 5.15-5.26 (m,
2H) 5.76-5.88 (m, H) 6.69 (s, H) 6.80-6.89 (m, 2H) 6.97 (t, J=8.35
Hz, 1H) 7.17-7.24 (m, 2H) 7.27-7.46 (m, 3H) 7.53 (t, J=6.81 Hz, 1H)
7.65-7.78 (m, 1H) 8.06 (d, J=9.23 Hz, 1H).
Example 81
2-(1-Amino-isoquinolin-6-ylamino)-4,11,14-triaza-tricyclo[14.2.2.1.sup.6,1-
0]henicosa-1(19),6,8,10(21),16(20),17-hexaene-3,12-dione
##STR00447##
[1243] 81A: benzyl
2-((4-bromobenzyl)(tert-butoxycarbonyl)amino)acetate
##STR00448##
[1245] To a solution of 80A (500 mg, 1.50 mmol) in 5 mL
CH.sub.2Cl.sub.2, were added TEA (0.229 mL, 1.65 mmol) and
Boc.sub.2O (360 mg, 1.65 mmol). The mixture was stirred at rt for 2
h, then additional Boc.sub.2O (50 mg) was added. The mixture was
stirred an additional 30 min, then was concentrated. The crude
product was purified via flash chromatography (0 to 40% EtOAc in
hexanes) to afford 81A (599 mg, 92%). MS (ESI) m/z 434.1
(M+H).sup.+.
81B: 2-((4-bromobenzyl)(tert-butoxycarbonyl)amino)acetic acid
##STR00449##
[1247] To a solution of 81A (325 mg, 0.75 mmol) in THF (5 mL) was
added LiOH (0.5 mL, 3 mmol). The mixture was stirred rt over night,
then concentrated. Water (20 mL) was added to the residue, and the
organic phase was washed with CH.sub.2Cl.sub.2 (2.times.20 mL). The
aqueous layer was acidified with 1N HCl, and was extracted with
EtOAc (2.times.20 mL). The combined organic layer was washed with
brine, dried (Na.sub.2SO.sub.4) and concentrated to give 81B (262
mg, 100%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.36-1.51
(m, 9H) 3.76-3.99 (m, 2H) 4.44 (d, J=5.71 Hz, 2H) 7.18 (d, J=8.35
Hz, 2H) 7.41-7.49 (m, 2H).
81C:
{[3-(Benzyloxycarbonylamino-methyl)-phenylcarbamoyl]-methyl}-(4-bromo-
-benzyl)-carbamic acid tert-butyl ester
##STR00450##
[1249] 81C (226 mg, 97%) was obtained from 81B (139 mg, 0.40 mmol)
using a procedure similar to that used in the preparation of 67B.
MS (ESI) m/z 582.3 (M+H).sup.+.
81D:
4-(((2-(3-((benzyloxycarbonylamino)methyl)phenylamino)-2-oxoethyl)(te-
rt-butoxycarbonyl)amino)methyl)phenylboronic acid
##STR00451##
[1251] 81D (161 mg, 78%) was obtained from 81C (221 mg, 0.38 mmol)
using a procedure similar to that used in the preparation of 66C.
MS (ESI) m/z 548.5 (M+H).sup.+.
81E:
2-(4-(((2-(3-((benzyloxycarbonylamino)methyl)phenylamino)-2-oxoethyl)-
(tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-(bis(tert-butoxycarbonyl)am-
ino)isoquinolin-6-ylamino)acetic acid
##STR00452##
[1253] 81E (102 mg, 40%) was obtained from 81D (152 mg, 0.28 mmol)
using a procedure similar to that used in the preparation of 66D.
MS (ESI) m/z 919.5 (M+H).sup.+.
81F:
2-(4-(((2-(3-(aminomethyl)phenylamino)-2-oxoethyl)(tert-butoxycarbony-
l)amino)methyl)phenyl)-2-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-6-y-
lamino)acetic acid
##STR00453##
[1255] 81F (30 mg, 39%) was obtained from 81E (90 mg, 0.1 mmol)
using a procedure similar to that used in the preparation of 66E.
MS (ESI) m/z 745.8 (M+H).sup.+.
81G:
2-(1-Amino-isoquinolin-6-ylamino)-3,12-dioxo-4,11,14-triaza-tricyclo[-
14.2.2.1.sup.6,10]henicosa-1(19),6,8,10(21),16(20),17-hexaene-14-carboxyli-
c acid tert-butyl ester
##STR00454##
[1257] 81G (14 mg, 73%) was obtained from 81F (19 mg, 0.024 mmol)
using a procedure similar to that used in the preparation of 66F.
MS (ESI) m/z 767.6 (M+H).sup.+.
Example 81
[1258] Example 81 (3.6 mg, 79%) was obtained from 81G (40 mg, 0.02
mmol) using a procedure similar to that used in the preparation of
Example 66. MS (ESI) m/z 467.2. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. ppm 3.90-3.96 (m, 1H) 4.05-4.14 (m, 3H) 4.20 (d, J=13.18
Hz, 1H) 4.43 (d, J=13.18 Hz, 1H) 4.76 (dd, J=16.48, 7.25 Hz, 1H)
5.28 (s, 1H) 6.07 (s, 1H) 6.68 (d, J=1.76 Hz, 1H) 6.75 (d, J=8.79
Hz, 1H) 6.83 (d, J=7.03 Hz, 1H) 7.03 (d, J=7.47 Hz, 1H) 7.19-7.24
(m, 2H) 7.31 (d, J=7.03 Hz, 1H) 7.49-7.53 (m, 2H) 7.83 (d, J=7.91
Hz, 1H) 8.07 (d, J=9.23 Hz, 1H).
UTILITY
[1259] The compounds of the present invention are inhibitors of
factor VIIa and are useful as anticoagulants for the prevention or
treatment of thromboembolic disorders in mammals. In general, a
thromboembolic disorder is a circulatory disease caused by blood
clots (i.e., diseases involving fibrin formation, platelet
activation, and/or platelet aggregation). The term "thromboembolic
disorders (or conditions)" as used herein includes arterial or
venous cardiovascular or cerebovascular thromboembolic disorders,
and thromboembolic disorders in the chambers of the heart. The term
"thromboembolic disorders" as used herein also includes specific
disorders selected from, but not limited to, unstable angina or
other acute coronary syndromes, atrial fibrillation, first or
recurrent myocardial infarction, ischemic sudden death, transient
ischemic attack, stroke, atherosclerosis, peripheral occlusive
arterial disease, venous thrombosis, deep vein thrombosis,
thrombophlebitis, arterial embolism, coronary and cerebral arterial
thrombosis, cerebral embolism, kidney embolisms, pulmonary
embolisms, and thrombosis resulting from medical implants, devices,
or procedures in which blood is exposed to an artificial surface
that promotes thrombosis. The medical implants or devices include,
but are not limited to: prosthetic valves, artificial valves,
indwelling catheters, stents, blood oxygenators, shunts, vascular
access ports, and vessel grafts. The procedures include, but are
not limited to: cardiopulmonary bypass, percutaneous coronary
intervention, and hemodialysis.
[1260] It is noted that thrombosis includes vessel occlusion (e.g.
after a bypass) and reocclusion (e.g., during or after percutaneous
transluminal coronary angioplasty). The thromboembolic disorders
may result from conditions including but not limited to
atherosclerosis, surgery or surgical complications, prolonged
immobilization, arterial fibrillation, congenital thrombophilia,
cancer, diabetes, effects of medications or hormones, and
complications of pregnancy. The anticoagulant or antithrombotic
effect of compounds of the present invention is believed to be due
to inhibition of coagulation factor VIIa.
[1261] The term "thrombosis", as used herein, refers to formation
or presence of a thrombus (pl. thrombi); clotting within a blood
vessel which may cause ischemia or infarction of tissues supplied
by the vessel. The term "embolism", as used herein, refers to
sudden blocking of an artery by a clot or foreign material which
has been brought to its site of lodgment by the blood current. The
term "thromboembolism", as used herein, refers to obstruction of a
blood vessel with thrombotic material carried by the blood stream
from the site of origin to plug another vessel. The term "stroke",
as used herein, refers to embolic stroke or atherothrombotic stroke
arising from occlusive thrombosis in the carotid communis, carotid
interna, or intracerebral arteries.
[1262] The effectiveness of compounds of the present invention as
inhibitors of the coagulation factors VIIa, IXa, Xa, XIa, plasma
kallikrein or thrombin, can be determined using a relevant purified
serine protease, respectively, and an appropriate synthetic
substrate. The rate of hydrolysis of the chromogenic substrate by
the relevant serine protease was measured both in the absence and
presence of compounds of the present invention. Hydrolysis of the
substrate resulted in the release of para-nitroaniline (pNA), which
was monitored spectrophotometrically by measuring the increase in
absorbance at 405 nM, or the release of aminomethylcoumarin (AMC),
which was monitored spectrofluorometrically by measuring the
increase in emission at 460 nM with excitation at 380 nM. A
decrease in the rate of absorbance change at 405 nM in the presence
of inhibitor is indicative of enzyme inhibition. Such methods are
known to one skilled in the art. The results of this assay are
expressed as inhibitory constant, K.sub.i.
[1263] Factor VIIa determinations were made in 0.005 M calcium
chloride, [1264] 0.15 M sodium chloride, 0.05 M HEPES buffer
containing 0.5% PEG 8000 at a pH of 7.4. Determinations were made
using purified human Factor VIIa (Haematologic Technologies) or
recombinant human Factor VIIa (Novo Nordisk) at a final assay
concentration of 2-5 nM, recombinant soluble tissue factor at a
concentration of 18-35 nM and the synthetic substrate
H-D-Ile-Pro-Arg-pNA (S-2288; Chromogenix or BMPM-2; AnaSpec) at a
concentration of 0.001 M. In general, preferred compounds of the
present invention, such as the particular compounds disclosed in
the above examples, have been identified to be active and exhibit
K.sub.i's of equal to or less than 15 .mu.M in the Factor VIIa
assay, thereby demonstrating the utility of the compounds of the
present invention as especially effective inhibitors of coagulation
Factor VIIa, and thus, as inhibitors of the coagulation cascade and
as anticoagulants for the prevention or treatment of thromboembolic
disorders in mammals. More preferred compounds have K.sub.i's of
equal to or less than 5 .mu.M, preferably equal to or less than 1
.mu.M, more preferably equal to or less than 0.5 .mu.M, even more
preferably equal to or less than 0.1 .mu.M.
[1265] Factor IXa determinations were made in 0.005 M calcium
chloride, 0.1 M sodium chloride, 0.05 M TRIS base and 0.5% PEG 8000
at a pH of 7.4. Determinations were made using purified human
Factor IXa (Haematologic Technologies) at a final assay
concentration of 20-100 nM and the synthetic substrate PCIXA2100-B
(CenterChem) or Pefafluor IXa 3688 (H-D-Leu-Phe-Gly-Arg-AMC;
CenterChem) at a concentration of 0.0004-0.0005 M. In general,
compounds tested in the Factor IXa assay are considered to be
active if they exhibit a K.sub.i of equal to or less than 15
.mu.M.
[1266] Factor Xa determinations were made in 0.1 M sodium phosphate
buffer at a pH of 7.4 containing 0.2 M sodium chloride and 0.5% PEG
8000. Determinations were made using purified human Factor Xa
(Haematologic Technologies) at a final assay concentration of
150-1000 pM and the synthetic substrate S-2222
(Bz-Ile-Glu(gamma-OMe, 50%)-Gly-Arg-pNA; Chromogenix) at a
concentration of 0.0002-0.0003 M. In general, compounds tested in
the Factor Xa assay are considered to be active if they exhibit a
K.sub.i of equal to or less than 15 .mu.M.
[1267] Factor XIa determinations were made in 50 mM HEPES buffer at
pH 7.4 containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000
(polyethylene glycol; J T Baker or Fisher Scientific).
Determinations were made using purified human Factor XIa at a final
concentration of 75-200 .mu.M (Haematologic Technologies) and the
synthetic substrate S-2366 (pyroGlu-Pro-Arg-pNA; Chromogenix) at a
concentration of 0.0002-0.00025 M. In general, compounds tested in
the Factor XIa assay are considered to be active if they exhibit a
K.sub.i of equal to or less than 15 .mu.M.
[1268] Plasma kallikrein determinations were made in 0.1 M sodium
phosphate buffer at a pH of 7.4 containing 0.2 M sodium chloride
and 0.5% PEG 8000. Determinations were made using purified human
kallikrein (Enzyme Research Laboratories) at a final assay
concentration of 200 .mu.M and the synthetic substrate S-2302
(H-(D)-Pro-Phe-Arg-pNA; Chromogenix) at a concentration of
0.00008-0.0004 M. The Km value used for calculation of Ki was
0.00005 to 0.00007 M. In general, compounds tested in the plasma
kallikrein assay are considered to be active if they exhibit a
K.sub.i of equal to or less than 15 .mu.M.
[1269] Thrombin determinations were made in 0.1 M sodium phosphate
buffer at a pH of 7.4 containing 0.2 M sodium chloride and 0.5% PEG
8000. Determinations were made using purified human alpha thrombin
(Haematologic Technologies or Enzyme Research Laboratories) at a
final assay concentration of 200-250 pM and the synthetic substrate
S-2366 (pyroGlu-Pro-Arg-pNA; Chromogenix) at a concentration of
0.0002 M. In general, compounds tested in the thrombin assay are
considered to be active if they exhibit a K.sub.i of equal to or
less than 15 .mu.M.
[1270] The selectivity of a compound may be evaluated by taking the
ratio of the K.sub.i value for a given protease with the K.sub.i
value for the protease of interest (i.e., selectivity for FVIIa
versus protease P=K.sub.i for protease P/K.sub.i for FVIIa).
Compounds with selectivity ratios >20 are considered selective.
Compounds with selectivity ratios >100 are preferred, and
compounds with selectivity ratios >500 are more preferred.
[1271] The Michaelis constant, K.sub.m, for substrate hydrolysis by
each protease was determined at 25.degree. C. using the method of
Lineweaver and Burk. Values of K.sub.i were determined by allowing
the protease to react with the substrate in the presence of the
inhibitor. Reactions were allowed to go for periods of 20-180
minutes (depending on the protease) and the velocities (rate of
absorbance change vs time) were measured. The following
relationship was used to calculate K.sub.i values: [1272]
(v.sub.o-v.sub.s)/v.sub.s=I/(K.sub.i(1+S/K.sub.m)) for a
competitive inhibitor with one binding site; or [1273]
v.sub.s/v.sub.o=A+((B-A)/1+((IC.sub.50/(I).sup.n))) and [1274]
K.sub.i=IC.sub.50/(1+S/K.sub.m) for a competitive inhibitor [1275]
where: [1276] v.sub.o is the velocity of the control in the absence
of inhibitor; [1277] v.sub.s is the velocity in the presence of
inhibitor; [1278] I is the concentration of inhibitor; [1279] A is
the minimum activity remaining (usually locked at zero); [1280] B
is the maximum activity remaining (usually locked at 1.0); [1281] n
is the Hill coefficient, a measure of the number and cooperativity
of potential inhibitor binding sites; [1282] IC.sub.50 is the
concentration of inhibitor that produces 50% inhibition under the
assay conditions; [1283] K.sub.i is the dissociation constant of
the enzyme: inhibitor complex; [1284] S is the concentration of
substrate; and [1285] K.sub.m is the Michaelis constant for the
substrate.
[1286] The effectiveness of compounds of the present invention as
antithrombotic agents can be determined using relevant in vivo
thrombosis models, including In Vivo Electrically-induced Carotid
Artery Thrombosis Models and In Vivo Rabbit Arterio-venous Shunt
Thrombosis Models.
In Vivo Electrically-Induced Carotid Artery Thrombosis (ECAT)
Model:
[1287] The rabbit ECAT model, described by Wong et al. (J Pharmacol
Exp Ther 2000, 295, 212-218), can be used in this study. Male New
Zealand White rabbits are anesthetized with ketamine (50 mg/kg+50
mg/kg/h IM) and xylazine (10 mg/kg+10 mg/kg/h IM). These
anesthetics are supplemented as needed. An electromagnetic flow
probe is placed on a segment of an isolated carotid artery to
monitor blood flow. Test agents or vehicle will be given (i.v.,
i.p., s.c., or orally) prior to the initiation of thrombosis.
Thrombus formation is induced by electrical stimulation of the
carotid artery for 3 min at 4 mA using an external stainless-steel
bipolar electrode. Carotid blood flow is measured continuously over
a 90-min period to monitor thrombus-induced occlusion. Total
carotid blood flow over 90 min is calculated by trapezoidal rule.
Average carotid flow over 90 min is then determined by converting
total carotid blood flow over 90 min to percent of total control
carotid blood flow, which would result if control blood flow had
been maintained continuously for 90 min. The ED.sub.50 (dose that
increased average carotid blood flow over 90 min to 50% of the
control) of compounds are estimated by a nonlinear least square
regression program using the Hill sigmoid E.sub.max equation
(DeltaGraph; SPSS Inc., Chicago, Ill.).
In Vivo Rabbit Arterio-Venous (AV) Shunt Thrombosis Model:
[1288] The rabbit AV shunt model, described by Wong et al. (Wong,
P. C. et al. J Pharmacol Exp Ther 2000, 292, 351-357), can be used
in this study. Male New Zealand White rabbits are anesthetized with
ketamine (50 mg/kg+50 mg/kg/h IM) and xylazine (10 mg/kg+10 mg/kg/h
IM). These anesthetics are supplemented as needed. The femoral
artery, jugular vein and femoral vein are isolated and
catheterized. A saline-filled AV shunt device is connected between
the femoral arterial and the femoral venous cannulae. The AV shunt
device consists of an outer piece of tygon tubing (length=8 cm;
internal diameter=7.9 mm) and an inner piece of tubing (length=2.5
cm; internal diameter=4.8 mm). The AV shunt also contains an
8-cm-long 2-0 silk thread (Ethicon, Somerville, N.J.). Blood flows
from the femoral artery via the AV-shunt into the femoral vein. The
exposure of flowing blood to a silk thread induces the formation of
a significant thrombus. Forty minutes later, the shunt is
disconnected and the silk thread covered with thrombus is weighed.
Test agents or vehicle will be given (i.v., i.p., s.c., or orally)
prior to the opening of the AV shunt. The percentage inhibition of
thrombus formation is determined for each treatment group. The
ID.sub.50 values (dose which produces 50% inhibition of thrombus
formation) are estimated by a nonlinear least square regression
program using the Hill sigmoid E.sub.max equation (DeltaGraph; SPSS
Inc., Chicago, Ill.).
[1289] The compounds of the present invention can be administered
alone or in combination with one or more additional therapeutic
agents. These other agents include, but are not limited to, other
anticoagulant or coagulation inhibitory agents, anti-platelet or
platelet inhibitory agents, or thrombolytic or fibrinolytic
agents.
[1290] By "administered in combination" or "combination therapy" it
is meant that the compound of the present invention and one or more
additional therapeutic agents are administered concurrently to the
mammal being treated. When administered in combination each
component may be administered at the same time or sequentially in
any order at different points in time. Thus, each component may be
administered separately but sufficiently closely in time so as to
provide the desired therapeutic effect.
[1291] Other anticoagulant agents (or coagulation inhibitory
agents) that may be used in combination with the compounds of this
invention include warfarin, heparin (either unfractionated heparin
or any commercially available low molecular weight heparin, for
example LOVANOX.TM.), synthetic pentasaccharide, direct acting
thrombin inhibitors including hirudin and argatroban, as well as
other factor VIIa inhibitors, factor IXa inhibitors, factor Xa
inhibitors (e.g., Arixtra.TM., apixaban, rivaroxaban, LY-517717,
DU-176b, DX-9065a, and those disclosed in WO 98/57951, WO
03/026652, WO 01/047919, and WO 00/076970), factor XIa inhibitors,
and inhibitors of activated TAFI and PAI-1 known in the art.
[1292] The term anti-platelet agents (or platelet inhibitory
agents), as used herein, denotes agents that inhibit platelet
function, for example, by inhibiting the aggregation, adhesion or
granular-content secretion of platelets. Such agents include, but
are not limited to, the various known non-steroidal
anti-inflammatory drugs (NSAIDS) such as acetaminophen, aspirin,
codeine, diclofenac, droxicam, fentaynl, ibuprofen, indomethacin,
ketorolac, mefenamate, morphine, naproxen, phenacetin, piroxicam,
sufentanyl, sulfinpyrazone, sulindac, and pharmaceutically
acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin
(acetylsalicylic acid or ASA), and piroxicam are preferred. Other
suitable platelet inhibitory agents include glycoprotein IIb/IIIa
antagonists (e.g., tirofiban, eptifibatide, abciximab, and
integrelin), thromboxane-A2-receptor antagonists (e.g., ifetroban),
thromboxane-A-synthetase inhibitors, phosphodiesterase-III
(PDE-III) inhibitors (e.g., dipyridamole, cilostazol), and PDE-V
inhibitors (such as sildenafil), protease-activated receptor 1
(PAR1) antagonists (e.g., SCH-530348, SCH-203099, SCH-529153 and
SCH-205831), and pharmaceutically acceptable salts or prodrugs
thereof.
[1293] The term anti-platelet agents (or platelet inhibitory
agents), as used herein, is also intended to include ADP (adenosine
diphosphate) receptor antagonists, preferably antagonists of the
purinergic receptors P.sub.2Y.sub.1 and P.sub.2Y.sub.12, with
P.sub.2Y.sub.12 being even more preferred. Preferred
P.sub.2Y.sub.12 receptor antagonists include ticlopidine and
clopidogrel, prasugrel, and AZD-6140, and pharmaceutically
acceptable salts or prodrugs thereof. Clopidogrel is an even more
preferred agent. Ticlopidine and clopidogrel are also preferred
compounds since they are known to be more gentle than aspirin on
the gastro-intestinal tract in use.
[1294] The term thrombin inhibitors (or anti-thrombin agents), as
used herein, denotes inhibitors of the serine protease thrombin. By
inhibiting thrombin, various thrombin-mediated processes, such as
thrombin-mediated platelet activation (that is, for example, the
aggregation of platelets, and/or the secretion of platelet granule
contents including and/or serotonin) and/or fibrin formation are
disrupted. A number of thrombin inhibitors are known to one of
skill in the art and these inhibitors are contemplated to be used
in combination with the present compounds. Such inhibitors include,
but are not limited to, boroarginine derivatives, boropeptides,
heparins, hirudin and argatroban, dabigatran, AZD-0837, and those
disclosed in WO 98/37075 and WO 02/044145, and pharmaceutically
acceptable salts and prodrugs thereof. Boroarginine derivatives and
boropeptides include N-acetyl and peptide derivatives of boronic
acid, such as C-terminal .alpha.-aminoboronic acid derivatives of
lysine, ornithine, arginine, homoarginine and corresponding
isothiouronium analogs thereof. The term hirudin, as used herein,
includes suitable derivatives or analogs of hirudin, referred to
herein as hirulogs, such as disulfatohirudin.
[1295] The term thrombolytic (or fibrinolytic) agents (or
thrombolytics or fibrinolytics), as used herein, denotes agents
that lyse blood clots (thrombi). Such agents include tissue
plasminogen activator (TPA, natural or recombinant) and modified
forms thereof, anistreplase, urokinase, streptokinase, tenecteplase
(TNK), lanoteplase (nPA), factor VIIa inhibitors, thrombin
inhibitors, inhibitors of factors IXa, Xa, and XIa, PAI-I
inhibitors (i.e., inactivators of tissue plasminogen activator
inhibitors), inhibitors of activated TAFI, alpha-2-antiplasmin
inhibitors, and anisoylated plasminogen streptokinase activator
complex, including pharmaceutically acceptable salts or prodrugs
thereof. The term anistreplase, as used herein, refers to
anisoylated plasminogen streptokinase activator complex, as
described, for example, in European Patent Application No. 028,489,
the disclosure of which is hereby incorporated herein by reference
herein. The term urokinase, as used herein, is intended to denote
both dual and single chain urokinase, the latter also being
referred to herein as prourokinase.
[1296] Examples of suitable anti-arrythmic agents for use in
combination with the present compounds include: Class I agents
(such as propafenone); Class II agents (such as carvadiol and
propranolol); Class III agents (such as sotalol, dofetilide,
amiodarone, azimilide and ibutilide); Class IV agents (such as
ditiazem and verapamil); K.sup.+ channel openers such as I.sub.Ach
inhibitors, and I.sub.Kur inhibitors (e.g., compounds such as those
disclosed in WO01/40231).
[1297] Examples of suitable antihypertensive agents for use in
combination with the compounds of the present invention include
alpha adrenergic blockers; beta adrenergic blockers; calcium
channel blockers (e.g., diltiazem, verapamil, nifedipine,
amlodipine and mybefradil); diuretics (e.g., chlorothiazide,
hydrochlorothiazide, flumethiazide, hydroflumethiazide,
bendroflumethiazide, methylchlorothiazide, trichloromethiazide,
polythiazide, benzthiazide, ethacrynic acid tricrynafen,
chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene,
amiloride, spironolactone); renin inhibitors;
angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril,
lisinopril, fosinopril, enalapril, ceranopril, cilazopril,
delapril, pentopril, quinapril, ramipril, lisinopril), angiotensin
AT-1 receptor antagonists (e.g., irbestatin, losartan, valsartan);
ET-A receptor antagonists (e.g., sitaxsentan, atrsentan and
compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265);
Dual ET-A/AT-1 antagonist (e.g., compounds disclosed in WO
00/01389); neutral endopeptidase (NEP) inhibitors; vasopepsidase
inhibitors (dual ACE/NEP inhibitors, e.g., omapatrilat
gemopatrilat, nitrates) and .beta.-blockers (for example
propanolol, nadolo, or carvedilol).
[1298] Examples of suitable cardiac glycosides for use in
combination with the compounds of the present invention include
digitalis and ouabain.
[1299] Examples of suitable mineralocorticoid receptor antagonists
for use in combination with the compounds of the present invention
include sprionolactone and eplirinone.
[1300] Examples of suitable anti-diabetic agents for use in
combination with the compounds of the present invention include:
biguanides (e.g., metformin); glucosidase inhibitors (e.g.,
acarbose); insulins (including insulin secretagogues or insulin
sensitizers); meglitinides (e.g., repaglinide); sulfonylureas
(e.g., glimepiride, glyburide and glipizide); biguanide/glyburide
combinations (e.g., glucovance), thiozolidinediones (e.g.,
troglitazone, rosiglitazone and pioglitazone), PPAR-alpha agonists,
PPAR-gamma agonists, PPAR alpha/gamma dual agonists, SGLT2
inhibitors, inhibitors of fatty acid binding protein (aP2) such as
those disclosed in WO00/59506, glucagon-like peptide-1 (GLP-1), and
dipeptidyl peptidase IV (DPP4) inhibitors.
[1301] Examples of suitable anti-depressant agents for use in
combination with the compounds of the present invention include
nefazodone and sertraline.
[1302] Examples of suitable anti-inflammatory agents for use in
combination with the compounds of the present invention include:
prednisone; dexamethasone; enbrel; protien tyrosine kinase (PTK)
inhibitors; cyclooxygenase inhibitors (including NSAIDs, and COX-1
and/or COX-2 inhibitors); aspirin; indomethacin; ibuprofen;
prioxicam; naproxen; celecoxib; and/or rofecoxib.
[1303] Examples of suitable anti-osteoporosis agents for use in
combination with the compounds of the present invention include
alendronate and raloxifene.
[1304] Examples of suitable hormone replacement therapies for use
in combination with the compounds of the present invention include
estrogen (e.g., conjugated estrogens) and estradiol.
[1305] Examples of suitable anti-obesity agents for use in
combination with the compounds of the present invention include
orlistat, aP2 inhibitors (such as those disclosed in WO00/59506),
and cannabinoid receptor CB1 antagonists (e.g., rimonabant,
AVE-1625, SR-147778, and CP-945598).
[1306] Examples of suitable anti-anxiety agents for use in
combination with the compounds of the present invention include
diazepam, lorazepam, buspirone, and hydroxyzine pamoate.
[1307] Examples of suitable anti-proliferative agents for use in
combination with the compounds of the present invention include
cyclosporin A, paclitaxel, adriamycin; epithilones, cisplatin, and
carboplatin.
[1308] Cholesterol/lipid lowering agents for use in combination
with the compounds of the present invention include HMG-CoA
reductase inhibitors (lovastatin, simvastatin, pravastatin,
fluvastatin, atorvsatatin, rosuvastatin, and other statins),
sequestrants (cholestyramine and colestipol), nicotonic acid,
fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrate
and benzafibrate), and probucol.
[1309] Examples of suitable anti-ulcer and gastroesophageal reflux
disease agents for use in combination with the compounds of the
present invention include famotidine, ranitidine, and
omeprazole.
[1310] Administration of the compounds of the present invention
(i.e., a first therapeutic agent) in combination with at least one
additional therapeutic agent (i.e., a second therapeutic agent),
preferably affords an efficacy advantage over the compounds and
agents alone, preferably while permitting the use of lower doses of
each. A lower dosage minimizes the potential of side effects,
thereby providing an increased margin of safety. It is preferred
that at least one of the therapeutic agents is administered in a
sub-therapeutic dose. It is even more preferred that all of the
therapeutic agents be administered in sub-therapeutic doses.
Sub-therapeutic is intended to mean an amount of a therapeutic
agent that by itself does not give the desired therapeutic effect
for the condition or disease being treated. Synergistic combination
is intended to mean that the observed effect of the combination is
greater than the sum of the individual agents administered
alone.
[1311] The compounds of the present invention are also useful as
standard or reference compounds, for example as a quality standard
or control, in tests or assays involving the inhibition of plasma
kallikrein, thrombin, factor VIIa, IXa, Xa and/or XIa. Such
compounds may be provided in a commercial kit, for example, for use
in pharmaceutical research involving plasma kallikrein, thrombin,
factor VIIa, IXa, Xa and/or XIa. For example, a compound of the
present invention could be used as a reference in an assay to
compare its known activity to a compound with an unknown activity.
This would ensure the experimenter that the assay was being
performed properly and provide a basis for comparison, especially
if the test compound was a derivative of the reference compound.
When developing new assays or protocols, compounds according to the
present invention could be used to test their effectiveness.
[1312] The compounds of the present invention may also be used in
diagnostic assays involving plasma kallikrein, thrombin, factor
VIIa, IXa, Xa, and/or XIa. For example, the presence of plasma
kallikrein, thrombin, factor VIIa, IXa, Xa and/or XIa in an unknown
sample could be determined by addition of the relevant chromogenic
substrate, for example, S2288 for factor VIIa, to a series of
solutions containing test sample and optionally one of the
compounds of the present invention. If production of pNA is
observed in the solutions containing test sample, but not in the
presence of a compound of the present invention, then one would
conclude factor VIIa was present.
[1313] The present invention also encompasses an article of
manufacture. As used herein, article of manufacture is intended to
include, but not be limited to, kits and packages. The article of
manufacture of the present invention, comprises: (a) a first
container; (b) a pharmaceutical composition located within the
first container, wherein the composition, comprises: a first
therapeutic agent, comprising: a compound of the present invention
or a pharmaceutically acceptable salt form thereof, and, (c) a
package insert stating that the pharmaceutical composition can be
used for the treatment of a thromboembolic disorder (as defined
previously). In another embodiment, the package insert states that
the pharmaceutical composition can be used in combination (as
defined previously) with a second therapeutic agent to treat a
thromboembolic disorder. The article of manufacture can further
comprise: (d) a second container, wherein components (a) and (b)
are located within the second container and component (c) is
located within or outside of the second container. Located within
the first and second containers means that the respective container
holds the item within its boundaries.
[1314] The first container is a receptacle used to hold a
pharmaceutical composition. This container can be for
manufacturing, storing, shipping, and/or individual/bulk selling.
First container is intended to cover a bottle, jar, vial, flask,
syringe, tube (e.g., for a cream preparation), or any other
container used to manufacture, hold, store, or distribute a
pharmaceutical product.
[1315] The second container is one used to hold the first container
and, optionally, the package insert. Examples of the second
container include, but are not limited to, boxes (e.g., cardboard
or plastic), crates, cartons, bags (e.g., paper or plastic bags),
pouches, and sacks. The package insert can be physically attached
to the outside of the first container via tape, glue, staple, or
another method of attachment, or it can rest inside the second
container without any physical means of attachment to the first
container. Alternatively, the package insert is located on the
outside of the second container. When located on the outside of the
second container, it is preferable that the package insert is
physically attached via tape, glue, staple, or another method of
attachment. Alternatively, it can be adjacent to or touching the
outside of the second container without being physically
attached.
[1316] The package insert is a label, tag, marker, etc. that
recites information relating to the pharmaceutical composition
located within the first container. The information recited will
usually be determined by the regulatory agency governing the area
in which the article of manufacture is to be sold (e.g., the United
States Food and Drug Administration). Preferably, the package
insert specifically recites the indications for which the
pharmaceutical composition has been approved. The package insert
may be made of any material on which a person can read information
contained therein or thereon. Preferably, the package insert is a
printable material (e.g., paper, plastic, cardboard, foil,
adhesive-backed paper or plastic, etc.) on which the desired
information has been formed (e.g., printed or applied).
Dosage and Formulation
[1317] The compounds of this invention can be administered in such
oral dosage forms as tablets, capsules (each of which includes
sustained release or timed release formulations), pills, powders,
granules, elixirs, tinctures, suspensions, syrups, and emulsions.
They may also be administered in intravenous (bolus or infusion),
intraperitoneal, subcutaneous, or intramuscular form, all using
dosage forms well known to those of ordinary skill in the
pharmaceutical arts. They can be administered alone, but generally
will be administered with a pharmaceutical carrier selected on the
basis of the chosen route of administration and standard
pharmaceutical practice.
[1318] The dosage regimen for the compounds of the present
invention will, of course, vary depending upon known factors, such
as the pharmacodynamic characteristics of the particular agent and
its mode and route of administration; the species, age, sex,
health, medical condition, and weight of the recipient; the nature
and extent of the symptoms; the kind of concurrent treatment; the
frequency of treatment; the route of administration, the renal and
hepatic function of the patient, and the effect desired. A
physician or veterinarian can determine and prescribe the effective
amount of the drug required to prevent, counter, or arrest the
progress of the thromboembolic disorder.
[1319] By way of general guidance, the daily oral dosage of each
active ingredient, when used for the indicated effects, will range
between about 0.001 to 1000 mg/kg of body weight, preferably
between about 0.01 to 100 mg/kg of body weight per day, and most
preferably between about 0.1 to 20 mg/kg/day. Intravenously, the
most preferred doses will range from about 0.1 to about 10
mg/kg/minute during a constant rate infusion. Compounds of this
invention may be administered in a single daily dose, or the total
daily dosage may be administered in divided doses of two, three, or
four times daily.
[1320] Compounds of this invention can be administered in
intranasal form via topical use of suitable intranasal vehicles, or
via transdermal routes, using transdermal skin patches. When
administered in the form of a transdermal delivery system, the
dosage administration will, of course, be continuous rather than
intermittent throughout the dosage regimen.
[1321] The compounds are typically administered in admixture with
suitable pharmaceutical diluents, excipients, or carriers
(collectively referred to herein as pharmaceutical carriers)
suitably selected with respect to the intended form of
administration, that is, oral tablets, capsules, elixirs, syrups
and the like, and consistent with conventional pharmaceutical
practices.
[1322] For instance, for oral administration in the form of a
tablet or capsule, the active drug component can be combined with
an oral, non-toxic, pharmaceutically acceptable, inert carrier such
as lactose, starch, sucrose, glucose, methyl cellulose, magnesium
stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol
and the like; for oral administration in liquid form, the oral drug
components can be combined with any oral, non-toxic,
pharmaceutically acceptable inert carrier such as ethanol,
glycerol, water, and the like. Moreover, when desired or necessary,
suitable binders, lubricants, disintegrating agents, and coloring
agents can also be incorporated into the mixture. Suitable binders
include starch, gelatin, natural sugars such as glucose or
beta-lactose, corn sweeteners, natural and synthetic gums such as
acacia, tragacanth, or sodium alginate, carboxymethylcellulose,
polyethylene glycol, waxes, and the like. Lubricants used in these
dosage forms include sodium oleate, sodium stearate, magnesium
stearate, sodium benzoate, sodium acetate, sodium chloride, and the
like. Disintegrators include, without limitation, starch, methyl
cellulose, agar, bentonite, xanthan gum, and the like.
[1323] The compounds of the present invention can also be
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamellar vesicles, and
multilamellar vesicles. Liposomes can be formed from a variety of
phospholipids, such as cholesterol, stearylamine, or
phosphatidylcholines.
[1324] Compounds of the present invention may also be coupled with
soluble polymers as targetable drug carriers. Such polymers can
include polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine
substituted with palmitoyl residues. Furthermore, the compounds of
the present invention may be coupled to a class of biodegradable
polymers useful in achieving controlled release of a drug, for
example, polylactic acid, polyglycolic acid, copolymers of
polylactic and polyglycolic acid, polyepsilon caprolactone,
polyhydroxy butyric acid, polyorthoesters, polyacetals,
polydihydropyrans, polycyanoacylates, and crosslinked or
amphipathic block copolymers of hydrogels.
[1325] Dosage forms (pharmaceutical compositions) suitable for
administration may contain from about 1 milligram to about 1000
milligrams of active ingredient per dosage unit. In these
pharmaceutical compositions the active ingredient will ordinarily
be present in an amount of about 0.1-95% by weight based on the
total weight of the composition.
[1326] Gelatin capsules may contain the active ingredient and
powdered carriers, such as lactose, starch, cellulose derivatives,
magnesium stearate, stearic acid, and the like. Similar diluents
can be used to make compressed tablets. Both tablets and capsules
can be manufactured as sustained release products to provide for
continuous release of medication over a period of hours. Compressed
tablets can be sugar coated or film coated to mask any unpleasant
taste and protect the tablet from the atmosphere, or enteric coated
for selective disintegration in the gastrointestinal tract.
[1327] Liquid dosage forms for oral administration can contain
coloring and flavoring to increase patient acceptance.
[1328] In general, water, a suitable oil, saline, aqueous dextrose
(glucose), and related sugar solutions and glycols such as
propylene glycol or polyethylene glycols are suitable carriers for
parenteral solutions. Solutions for parenteral administration
preferably contain a water soluble salt of the active ingredient,
suitable stabilizing agents, and if necessary, buffer substances.
Antioxidizing agents such as sodium bisulfite, sodium sulfite, or
ascorbic acid, either alone or combined, are suitable stabilizing
agents. Also used are citric acid and its salts and sodium EDTA. In
addition, parenteral solutions can contain preservatives, such as
benzalkonium chloride, methyl- or propyl-paraben, and
chlorobutanol.
[1329] Suitable pharmaceutical carriers are described in
Remington's Pharmaceutical Sciences, Mack Publishing Company, a
standard reference text in this field.
[1330] Where the compounds of this invention are combined with
other anticoagulant agents, for example, a daily dosage may be
about 0.1 to 100 milligrams of the compound of the present
invention and about 1 to 7.5 milligrams of the second
anticoagulant, per kilogram of patient body weight. For a tablet
dosage form, the compounds of this invention generally may be
present in an amount of about 5 to 10 milligrams per dosage unit,
and the second anti-coagulant in an amount of about 1 to 5
milligrams per dosage unit.
[1331] Where the compounds of the present invention are
administered in combination with an anti-platelet agent, by way of
general guidance, typically a daily dosage may be about 0.01 to 25
milligrams of the compound of the present invention and about 50 to
150 milligrams of the anti-platelet agent, preferably about 0.1 to
1 milligrams of the compound of the present invention and about 1
to 3 milligrams of antiplatelet agents, per kilogram of patient
body weight.
[1332] Where the compounds of the present invention are
administered in combination with thrombolytic agent, typically a
daily dosage may be about 0.1 to 1 milligrams of the compound of
the present invention, per kilogram of patient body weight and, in
the case of the thrombolytic agents, the usual dosage of the
thrombolyic agent when administered alone may be reduced by about
70-80% when administered with a compound of the present
invention.
[1333] Where two or more of the foregoing second therapeutic agents
are administered with the compound of the present invention,
generally the amount of each component in a typical daily dosage
and typical dosage form may be reduced relative to the usual dosage
of the agent when administered alone, in view of the additive or
synergistic effect of the therapeutic agents when administered in
combination.
[1334] Particularly when provided as a single dosage unit, the
potential exists for a chemical interaction between the combined
active ingredients. For this reason, when the compound of the
present invention and a second therapeutic agent are combined in a
single dosage unit they are formulated such that although the
active ingredients are combined in a single dosage unit, the
physical contact between the active ingredients is minimized (that
is, reduced). For example, one active ingredient may be enteric
coated. By enteric coating one of the active ingredients, it is
possible not only to minimize the contact between the combined
active ingredients, but also, it is possible to control the release
of one of these components in the gastrointestinal tract such that
one of these components is not released in the stomach but rather
is released in the intestines. One of the active ingredients may
also be coated with a material that affects a sustained-release
throughout the gastrointestinal tract and also serves to minimize
physical contact between the combined active ingredients.
Furthermore, the sustained-released component can be additionally
enteric coated such that the release of this component occurs only
in the intestine. Still another approach would involve the
formulation of a combination product in which the one component is
coated with a sustained and/or enteric release polymer, and the
other component is also coated with a polymer such as a low
viscosity grade of hydroxypropyl methylcellulose (HPMC) or other
appropriate materials as known in the art, in order to further
separate the active components. The polymer coating serves to form
an additional barrier to interaction with the other component.
[1335] These as well as other ways of minimizing contact between
the components of combination products of the present invention,
whether administered in a single dosage form or administered in
separate forms but at the same time by the same manner, will be
readily apparent to those skilled in the art, once armed with the
present disclosure.
* * * * *