U.S. patent application number 15/115327 was filed with the patent office on 2017-01-05 for macrocycles with hetrocyclic p2' groups as factor xia inhibitors.
The applicant listed for this patent is BRISTOL-MYERS SQUIBB COMPANY. Invention is credited to James R. Corte, Indawati De Lucca, Andrew K. Dilger, William R. Ewing, Tianan Fang, Michael J. Orwat, Kumar Balashanmuga Pabbisetty, Donald J.P. Pinto, Leon M. Smith, II, Yufeng Wang, Ruth R. Wexler, Wu Yang, Yeheng Zhu.
Application Number | 20170002006 15/115327 |
Document ID | / |
Family ID | 52484570 |
Filed Date | 2017-01-05 |
United States Patent
Application |
20170002006 |
Kind Code |
A1 |
Corte; James R. ; et
al. |
January 5, 2017 |
MACROCYCLES WITH HETROCYCLIC P2' GROUPS AS FACTOR XIA
INHIBITORS
Abstract
The present invention provides compounds of Formula (I): or
stereoisomers, tautomers, or pharmaceutically acceptable salts
thereof, wherein all the variables are as defined herein. These
compounds are selective factor XIa inhibitors or dual inhibitors of
FXIa and plasma kallikrein. This invention also relates to
pharmaceutical compositions comprising these compounds and methods
of treating thromboembolic and/or inflammatory disorders using the
same. ##STR00001##
Inventors: |
Corte; James R.;
(Lawrenceville, NJ) ; De Lucca; Indawati;
(Pennington, NJ) ; Fang; Tianan; (Levittown,
PA) ; Yang; Wu; (Princeton Junction, NJ) ;
Wang; Yufeng; (North Brunswick, NJ) ; Dilger; Andrew
K.; (Ewing, NJ) ; Pabbisetty; Kumar Balashanmuga;
(Piscataway, NJ) ; Ewing; William R.; (Yardley,
PA) ; Zhu; Yeheng; (Stockton, NJ) ; Wexler;
Ruth R.; (Belle Mead, NJ) ; Pinto; Donald J.P.;
(Churchville, PA) ; Orwat; Michael J.; (New Hope,
PA) ; Smith, II; Leon M.; (Somerset, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BRISTOL-MYERS SQUIBB COMPANY |
Princeton |
NJ |
US |
|
|
Family ID: |
52484570 |
Appl. No.: |
15/115327 |
Filed: |
January 30, 2015 |
PCT Filed: |
January 30, 2015 |
PCT NO: |
PCT/US2015/013654 |
371 Date: |
July 29, 2016 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
61933942 |
Jan 31, 2014 |
|
|
|
62058293 |
Oct 1, 2014 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
9/00 20180101; A61P 11/00 20180101; C07D 487/08 20130101; A61P
27/00 20180101; A61P 43/00 20180101; C07D 471/18 20130101; C07D
471/08 20130101; C07D 403/06 20130101; A61P 7/02 20180101; A61P
7/00 20180101; C07D 403/14 20130101; A61P 13/12 20180101 |
International
Class: |
C07D 471/18 20060101
C07D471/18; C07D 487/08 20060101 C07D487/08 |
Claims
1. A compound of Formula (I): ##STR00532## or a stereoisomer, a
tautomer, a pharmaceutically acceptable salt thereof, wherein: ring
A is independently selected from 6-membered aryl and 5- to
6-membered heterocyclyl, wherein said aryl and heterocyclyl are
optionally substituted with, where valence allows, one or more
R.sup.4; ring B is 5- to 10-membered heterocyclyl optionally
substituted with, where valence allows, one or more R.sup.3 or 5-
to 10-membered heterocyclyl comprising carbon atoms and 1-4
heteroatoms selected from N, NR.sup.3c, O, and S(O).sub.p and
optionally substituted with, where valence allows, one or more
R.sup.3; G.sup.1 is independently selected from C.sub.3-10
carbocyclyl and 5- to 10-membered heterocyclyl, wherein said
carbocyclyl and heterocyclyl are optionally substituted with, where
valence allows, one or more R.sup.8; X is independently selected
from C.sub.4-8 alkylene and C.sub.4-8 alkenylene, wherein said
alkylene and alkenylene are substituted with R.sup.1 and R.sup.2;
alternatively one or more of the carbon atoms of said alkylene and
alkenylene may be replaced by O, C.dbd.O, S(.dbd.O).sub.p,
S(.dbd.O).sub.pNH, and NR.sup.15; Y is independently selected from
--CR.sup.13NH--, --NHC(.dbd.O)--, --C(.dbd.O)NH--,
--S(.dbd.O).sub.pNH--, --NHS(.dbd.O).sub.p--, and C.sub.1-2
alkylene; R.sup.1 and R.sup.2 are independently selected from H, D,
halogen, haloalkyl, C.sub.1-6 alkyl (optionally substituted with
R.sup.6), hydroxyl, and alkoxy optionally substituted with R.sup.6,
and C.sub.3-6 cycloalkyl optionally substituted with R.sup.6;
optionally, when R.sup.1 and R.sup.2 are attached to the same
carbon atom, together they form an oxo group or C.sub.3-6
cycloalkyl; optionally, when R.sup.1 and R.sup.2 are attached to
carbon atoms adjacent to each other, together they form a bond or
carbocyclyl; optionally, R.sup.1 and R.sup.15 or R.sup.2 and
R.sup.15 taken together form a ring; R.sup.3 is independently
selected from H, NO.sub.2, .dbd.O, halogen, haloalkyl, C.sub.1-4
alkyl (optionally substituted with R.sup.6), C.sub.2-4 alkenyl
(optionally substituted with R.sup.6), C.sub.2-4 alkynyl
(optionally substituted with R.sup.6), CN,
--(CH.sub.2).sub.n--OR.sup.5, --(CH.sub.2).sub.n--NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(.dbd.O)R.sup.5,
--(CH.sub.2).sub.n--C(.dbd.O)OR.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(.dbd.O)OR.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(.dbd.O)R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(N--CN)NHR.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(NH)NHR.sup.5,
--(CH.sub.2).sub.n--N.dbd.CR.sup.9NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(.dbd.O)NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(.dbd.O)NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(.dbd.S)NR.sup.9C(.dbd.O)R.sup.5,
--(CH.sub.2).sub.n--S(.dbd.O).sub.pR.sup.5,
--(CH.sub.2).sub.n--S(.dbd.O).sub.pNR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9S(.dbd.O).sub.pNR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9S(.dbd.O).sub.pR.sup.5,
--(CH.sub.2).sub.n--C.sub.3-10 carbocyclyl and
--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
carbocyclyl and heterocyclyl are optionally substituted with
R.sup.6; optionally, two adjacent R.sup.3 groups on the
heterocyclyl may form a ring optionally substituted with R.sup.6;
R.sup.3c is independently selected from H, haloalkyl, C.sub.1-4
alkyl (optionally substituted with R.sup.6),
--(CH.sub.2).sub.1-2--OH, C(.dbd.O)C.sub.1-4 alkyl,
--(CH.sub.2).sub.0-2--C(.dbd.O)OH, --C(.dbd.O)OC.sub.1-4 alkyl,
S(.dbd.O).sub.pC.sub.1-6 alkyl, --(CH.sub.2).sub.n--C.sub.3-10
carbocyclyl and --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl,
wherein said carbocyclyl and heterocyclyl are optionally
substituted with R.sup.6; R.sup.4 is independently selected from H,
OH, NH.sub.2, halogen, CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy, --CH.sub.2OH, --C(.dbd.O)OH,
--CH.sub.2C(.dbd.O)OH, --CO.sub.2(C.sub.1-4 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-4 alkyl),
--C(.dbd.O)N(C.sub.1-4 alkyl).sub.2, --S(.dbd.O).sub.2C.sub.1-4
alkyl, --S(.dbd.O).sub.2NH.sub.2, C.sub.3-6 cycloalkyl, aryl, and
5- to 6-membered heterocyclyl, wherein said cycloalkyl, aryl and
heterocyclyl are optionally substituted with R.sup.6; R.sup.5 is
independently selected from H, C.sub.1-4 alkyl (optionally
substituted with halogen, hydroxyl, alkoxy, carboxy,
hydroxycarbonyl, alkoxycarbonyl, amino, substituted amino),
--(CH.sub.2).sub.n--C.sub.3-10 carbocyclyl and
--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
carbocyclyl and heterocyclyl are optionally substituted with
R.sup.6; alternatively, R.sup.5 and R.sup.5 together with the
nitrogen atom to which they are both attached form a heterocyclic
ring optionally substituted with R.sup.6, R.sup.6 is independently
selected from H, --(CH.sub.2).sub.n--OH, .dbd.O,
--(CH.sub.2).sub.nNH.sub.2, --(CH.sub.2).sub.nCN, halogen,
C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)NH.sub.2,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--C.sub.3-10 carbocyclyl, --(CH.sub.2).sub.n-4-
to 10-membered heterocyclyl, and --O-4- to 10-membered
heterocyclyl, wherein said carbocyclyl and heterocyclyl are
optionally substituted with R.sup.10; R.sup.7 is independently
selected from H, hydroxyl, alkoxy, halogen, amino,
C.sub.1-3haloalkyl, and C.sub.1-3 alkyl; R.sup.8 is independently
selected from H, halogen, --(CH.sub.2).sub.nCN, C.sub.1-6 alkyl,
amino, aminoalkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy,
alkylcarbonyl, carboxyl, carboxyl ester, amide,
haloalkylaminocarbonyl, arylalkylaminocarbonyl,
haloalkylaminocarbonyl, alkoxycarbonylamino,
haloalkylcarbonylamino, arylamino, heteroarylamino,
arylalkylcarbonyl, aryloxy, heteroaryloxy, alkylthio,
alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfonamide,
--(CH.sub.2).sub.n-aryl, --(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl,
and --(CH.sub.2).sub.n-4- to 12-membered heterocyclyl, wherein said
aryl, cycloalkyl, and heterocyclyl are optionally substituted with
R.sup.10; alternatively, two adjacent R.sup.8 groups taken together
form a heterocyclic ring optionally substituted with R.sup.10;
R.sup.9 is H or C.sub.1-6 alkyl; R.sup.10 is independently selected
from H, C.sub.1-6 alkyl (optionally substituted with R.sup.11),
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl (optionally substituted
with R.sup.11), --(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl
(optionally substituted with R.sup.11), --(CH.sub.2).sub.n--O-4- to
10-membered heterocyclyl (optionally substituted with R.sup.11),
halogen, --(CH.sub.2).sub.nCN, NO.sub.2, .dbd.O,
C(.dbd.O)NR.sup.12R.sup.12, --(CH.sub.2).sub.11C(.dbd.O)OR.sup.12,
Si(C.sub.1-4 alkyl).sub.3, --(CH.sub.2).sub.n--OR.sup.12,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12, --S(.dbd.O).sub.pC.sub.1-6
alkyl, NR.sup.12S(.dbd.O).sub.pC.sub.1-6 alkyl,
S(.dbd.O).sub.pNR.sup.12R.sup.12, and C(.dbd.NOH)NH.sub.2;
R.sup.11, at each occurrence, is independently selected from H,
halogen, C.sub.1-5 alkyl, --(CH.sub.2).sub.n--OH, C.sub.3-6
cycloalkyl, phenyl, and heterocyclyl; R.sup.12, at each occurrence,
is independently selected from H, C.sub.1-5 alkyl optionally
substituted with R.sup.11, C.sub.3-6 cycloalkyl, phenyl, and
heterocyclyl, or R.sup.12 and R.sup.12 together with the nitrogen
atom to which they are both attached form a heterocyclic ring
optionally substituted with C.sub.1-4alkyl; R.sup.13 is,
independently at each occurrence, selected from H, C.sub.1-4
haloalkyl, C.sub.1-4 alkyl, C(.dbd.O)OH, C(.dbd.O)O(C.sub.1-4
alkyl), C(.dbd.O)O(CH.sub.2).sub.2O(C.sub.1-4 alkyl),
C(.dbd.O)O(C.sub.1-4 haloalkyl), CH.sub.2C(.dbd.O)OH,
CH.sub.2C(.dbd.O)O(C.sub.1-4 alkyl), C(.dbd.O)NH.sub.2,
C(.dbd.O)NH(C.sub.1-4 alkyl), C(.dbd.O)N(C.sub.1-4 alkyl).sub.2,
and --C(.dbd.O)NH(C.sub.1-4 alkoxy); R.sup.15 is H or C.sub.1-6
alkyl; n, at each occurrence, is an integer independently selected
from 0, 1, 2, 3, and 4; and p, at each occurrence, is an integer
independently selected from 0, 1, and 2.
2. The compound of claim 1 having Formula (IIa): ##STR00533## or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt
thereof, wherein: ring A is independently selected from 6-membered
aryl and 5- to 6-membered heterocyclyl; ring B is 5- to 10-membered
heterocyclyl or 5- to 10-membered heterocyclyl comprising carbon
atoms and 1-4 heteroatoms selected from N, NR.sup.3c, O, and
S(O).sub.p; G.sup.1 is independently selected from C.sub.3-6
carbocyclyl and 5- to 10-membered heterocyclyl, wherein said
carbocyclyl and heterocyclyl are substituted with 1-4 R.sup.8; W is
independently selected from (CR.sup.1R.sup.2).sub.1-2, O, NH, and
N(C.sub.1-4 alkyl); Y is independently selected from
--CR.sup.13NH--, --NHC(.dbd.O)-- and --C(.dbd.O)NH--; R.sup.1 and
R.sup.2 are independently selected from H, halogen, haloalkyl,
C.sub.1-4 alkyl (optionally substituted with R.sup.6), hydroxyl,
and alkoxy (optionally substituted with R.sup.6), and C.sub.3-5
cycloalkyl optionally substituted with R.sup.6; R.sup.3 is
independently selected from H, halogen, C.sub.1-4 alkyl (optionally
substituted with R.sup.6), CN, --(CH.sub.2).sub.n--OR.sup.5,
--(CH.sub.2).sub.n--NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(.dbd.O)R.sup.5, and
--(CH.sub.2).sub.n--C(.dbd.O)OR.sup.5; R.sup.3c is independently
selected from H, haloalkyl, C.sub.1-4 alkyl (optionally substituted
with R.sup.6), --(CH.sub.2).sub.0-2--OH, C(.dbd.O)C.sub.1-4 alkyl,
--(CH.sub.2).sub.0-2--C(.dbd.O)OH, --C(.dbd.O)OC.sub.1-4 alkyl,
S(.dbd.O).sub.pC.sub.1-6 alkyl, --(CH.sub.2).sub.n--C.sub.3-10
carbocyclyl and --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl,
wherein said carbocyclyl and heterocyclyl are optionally
substituted with R.sup.6; R.sup.4 is independently selected from H,
OH, halogen, CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4
alkoxy, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-4 alkyl),
--C(.dbd.O)N(C.sub.1-4 alkyl).sub.2, C.sub.3-6 cycloalkyl, aryl,
and 5- to 6-membered heterocyclyl, wherein said cycloalkyl, aryl
and heterocyclyl are optionally substituted with R.sup.6; R.sup.5
is independently selected from H, C.sub.1-4 alkyl (optionally
substituted with halogen, hydroxyl, alkoxy, carboxy,
alkoxycarbonyl, amino, substituted amino), C.sub.3-10 carbocyclyl
and 4- to 10-membered heterocyclyl, wherein said carbocyclyl and
heterocyclyl are optionally substituted with R.sup.6; R.sup.6 is
independently selected from H, OH, .dbd.O,
--(CH.sub.2).sub.nNH.sub.2, --(CH.sub.2).sub.nCN, halogen,
C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--C(.dbd.O)NH.sub.2,
--(CH.sub.2).sub.n--C.sub.3-10 carbocyclyl, --(CH.sub.2).sub.n-4-
to 10-membered heterocyclyl, and --(CH.sub.2).sub.n-4- to
10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl
are optionally substituted with R.sup.10; R.sup.7 is independently
selected from H, hydroxyl, halogen, C.sub.1-2haloalkyl, and
C.sub.1-2alkyl; R.sup.8 is independently selected from H, halogen,
CN, NH.sub.2, C.sub.1-6 alkyl, haloalkyl, haloalkylcarbonylamino,
arylamino, heteroarylamino, hydroxycarbonyl,
haloalkylaminocarbonyl, arylalkylcarbonyl, alkylcarbonyl, alkoxy,
haloalkoxy, --(CH.sub.2).sub.n-aryl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, and --(CH.sub.2).sub.n-4- to 12-membered heterocyclyl,
wherein said aryl, cycloalkyl, and heterocyclyl are optionally
substituted with R.sup.10; alternatively, two adjacent R.sup.8
groups and G.sub.1 form a fused heterocyclic group selected from
##STR00534## R.sup.9 is H or C.sub.1-6 alkyl; R.sup.10 is
independently selected from H, C.sub.1-6 alkyl (optionally
substituted with R.sup.11), C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
aryl (optionally substituted with R.sup.11),
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl (optionally substituted
with R.sup.11), --(CH.sub.2).sub.n--O-4- to 10-membered
heterocyclyl (optionally substituted with R.sup.11), F, Cl, Br,
--(CH.sub.2).sub.nCN, NO.sub.2, .dbd.O, C(.dbd.O)NR.sup.12R.sup.12,
--(CH.sub.2).sub.nC(.dbd.O)OR.sup.12, Si(C.sub.1-4 alkyl).sub.3,
--(CH.sub.2).sub.n--OR.sup.12, --(CH.sub.2).sub.nNR.sup.12R.sup.12,
and --S(.dbd.O).sub.pC.sub.1-6 alkyl,
NR.sup.12S(.dbd.O).sub.pC.sub.1-6 alkyl, and
S(.dbd.O).sub.pNR.sup.12R.sup.12; R.sup.10' is independently
selected from H, C.sub.1-6 alkyl (optionally substituted with
R.sup.11), aryl, --(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl
(optionally substituted with R.sup.11), and
--(CH.sub.2).sub.n--O-4- to 10-membered heterocyclyl (optionally
substituted with R.sup.11); R.sup.11, at each occurrence, is
independently selected from H, halogen, C.sub.1-5 alkyl,
--(CH.sub.2).sub.n--OH, C.sub.3-6 cycloalkyl, and phenyl; R.sup.12,
at each occurrence, is independently selected from H, C.sub.1-5
alkyl optionally substituted with R.sup.11, C.sub.3-6 cycloalkyl,
phenyl, and heterocyclyl, or R.sup.12 and R.sup.12 together with
the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
R.sup.13 is, independently at each occurrence, selected from H,
CF.sub.3, C(.dbd.O)OH, C(.dbd.O)O(C.sub.1-4 alkyl), and
--C(.dbd.O)NH.sub.2(C.sub.1-4 alkoxy); n, at each occurrence, is an
integer independently selected from 0, 1, 2, 3, and 4; and p, at
each occurrence, is an integer independently selected from 0, 1,
and 2.
3. The compound of claim 2 having Formula (IIb): ##STR00535## or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt
thereof, wherein: ring A is independently selected from phenyl and
5- to 6-membered heterocyclyl; ring B is 5- to 10-membered
heterocyclyl or 5- to 6-membered heterocyclyl comprising carbon
atoms and 1-4 heteroatoms selected from N, NR.sup.3c, O, and
S(O).sub.p; W is independently selected from
(CR.sup.1R.sup.2).sub.1-2, O, NH, and N(C.sub.1-4 alkyl); Y is
independently selected from --CH.sub.2NH--, --NHC(.dbd.O)-- and
--C(.dbd.O)NH--; G.sup.3 is independently selected from N and
CR.sup.8a; G.sup.4 is independently selected from N and CR.sup.8e;
R.sup.1 and R.sup.2 are independently selected from H, D, halogen,
CF.sub.3, C.sub.1-6 alkyl, and hydroxyl; R.sup.3 is independently
selected from H, halogen, C.sub.1-4alkyl (optionally substituted
with R.sup.6), CN, --(CH.sub.2).sub.n--OR.sup.5,
--(CH.sub.2).sub.n--NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(.dbd.O)R.sup.5, and
--(CH.sub.2).sub.n--C(.dbd.O)OR.sup.5; R.sup.3c is independently
selected from H, haloalkyl, C.sub.1-4 alkyl (optionally substituted
with R.sup.6), --(CH.sub.2).sub.1-2--OH, C(.dbd.O)C.sub.1-4 alkyl,
--(CH.sub.2).sub.1-2--C(.dbd.O)OH, --C(.dbd.O)OC.sub.1-4 alkyl,
S(.dbd.O).sub.pC.sub.1-6 alkyl, --(CH.sub.2).sub.n--C.sub.3-10
carbocyclyl and --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl,
wherein said carbocyclyl and heterocyclyl are optionally
substituted with R.sup.6; R.sup.4 is independently selected from H,
OH, F, Cl, Br, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3, CN,
C(.dbd.O)NH.sub.2, C.sub.3-6 cycloalkyl, aryl, and 5- to 6-membered
heterocyclyl, wherein said cycloalkyl, aryl and heterocyclyl are
optionally substituted with R.sup.6; R.sup.5 is independently
selected from H, and C.sub.1-4 alkyl optionally substituted with
halogen and hydroxyl; R.sup.6 is independently selected from H,
--(CH.sub.2).sub.n--OH, .dbd.O, NH.sub.2, --(CH.sub.2).sub.n--CN,
halogen, C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, and
--O--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
cycloalkyl and heterocyclyl are optionally substituted with
R.sup.10; R.sup.7 is independently selected from H, F, Cl, Br,
CF.sub.3, and CH.sub.3; R.sup.8a is independently selected from H,
F, Cl, Br, I, --(CH.sub.2).sub.nCN, --(CH.sub.2).sub.nNH.sub.2,
C.sub.1-2alkyl, C.sub.1-2haloalkyl, OH, OC.sub.1-2alkyl,
OC.sub.1-2haloalkyl, C(.dbd.O)OH, C(.dbd.O)OC.sub.1-3alkyl,
C(.dbd.O)NH.sub.2, C(.dbd.O)NHC.sub.1-2haloalkyl,
C(.dbd.O)NHarylalkyl, C(.dbd.O)C.sub.1-3alkyl,
NHC(.dbd.O)OC.sub.1-2alkyl, NHC(.dbd.O)C.sub.1-2haloalkyl, NH-aryl,
NH-heteroaryl, aryl, C.sub.3-6 cycloalkyl, and 4- to 12-membered
heterocyclyl, wherein said aryl, cycloalkyl and heterocyclyl is
optionally substituted with R.sup.10; R.sup.8b is independently
selected from H and F; R.sup.8c is independently selected from H,
F, Cl, methyl, ethyl, isopropyl, OCHF.sub.2, and OCH.sub.3;
R.sup.8d is independently selected from H, F, and Cl; R.sup.8e is
independently selected from H, F, and Cl; R.sup.10 is independently
selected from H, C.sub.1-6 alkyl (optionally substituted with
R.sup.11), C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl (optionally
substituted with R.sup.11), --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl (optionally substituted with R.sup.11),
--(CH.sub.2).sub.n--O-4- to 10-membered heterocyclyl (optionally
substituted with R.sup.11), F, Cl, Br, CN, NO.sub.2, .dbd.O,
CONR.sup.12R.sup.12, (CH.sub.2).sub.nC(.dbd.O)OR.sup.12,
Si(C.sub.1-4 alkyl).sub.3, --(CH.sub.2).sub.n--OR.sup.12, and
--(CH.sub.2).sub.n--NR.sup.12R.sup.12, --S(.dbd.O).sub.pC.sub.1-6
alkyl, NR.sup.12S(.dbd.O).sub.pC.sub.1-6 alkyl, and
S(.dbd.O).sub.pNR.sup.12R.sup.12; R.sup.11, at each occurrence, is
independently selected from H, halogen, C.sub.1-5 alkyl,
--(CH.sub.2).sub.n--OH, C.sub.3-6 cycloalkyl, and phenyl; R.sup.12,
at each occurrence, is independently selected from H, C.sub.1-5
alkyl optionally substituted with R.sup.11, C.sub.3-6 cycloalkyl,
phenyl, and heterocyclyl, or R.sup.12 and R.sup.12 together with
the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl; n, at
each occurrence, is an integer independently selected from 0, 1,
and 2; and p, at each occurrence, is an integer independently
selected from 0, 1, and 2.
4. The compound of claim 3 or a stereoisomer, a tautomer, a
pharmaceutically acceptable salt thereof, wherein: ring A is
independently selected from phenyl and 5- to 6-membered
heterocyclyl; ring B is 5- to 6-membered heteroaryl comprising
carbon atoms and 1-4 heteroatoms selected from N and NR.sup.3c; W
is independently selected from (CR.sup.1R.sup.2).sub.1-2, O, NH,
and N(C.sub.1-4 alkyl); Y is independently selected from
--CH.sub.2NH--, --NHC(.dbd.O)-- and --C(.dbd.O)NH--; G.sup.3 is
CR.sup.8a; G.sup.4 is CR.sup.8e; R.sup.1 and R.sup.2 are
independently selected from H, D, halogen, CF.sub.3, C.sub.1-6
alkyl, and hydroxyl; R.sup.3 is independently selected from H,
halogen, C.sub.1-4alkyl (optionally substituted with R.sup.6), CN,
--(CH.sub.2).sub.n--OR.sup.5, --(CH.sub.2).sub.n--C(.dbd.O)R.sup.5,
and --(CH.sub.2).sub.n--C(.dbd.O)OR.sup.5; R.sup.3c is
independently selected from H, haloalkyl, C.sub.1-4 alkyl
(optionally substituted with R.sup.6), --(CH.sub.2).sub.1-2--OH,
C(.dbd.O)C.sub.1-4 alkyl, --(CH.sub.2).sub.1-2--C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-4 alkyl, S(.dbd.O).sub.pC.sub.1-6 alkyl,
--(CH.sub.2).sub.n--C.sub.3-10 carbocyclyl and
--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
carbocyclyl and heterocyclyl are optionally substituted with
R.sup.6; R.sup.4 is independently selected from H, OH, F, Cl, Br,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3, CN, C(.dbd.O)NH.sub.2,
C.sub.3-6 cycloalkyl, aryl, and 5- to 6-membered heterocyclyl,
wherein said cycloalkyl, aryl and heterocyclyl are optionally
substituted with R.sup.6; R.sup.5 is independently selected from H
and C.sub.1-4 alkyl; R.sup.6 is independently selected from H,
--(CH.sub.2).sub.n--OH, .dbd.O, NH.sub.2, --(CH.sub.2).sub.n--CN,
halogen, C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, and
--O--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
cycloalkyl and heterocyclyl are optionally substituted with
R.sup.10; R.sup.7 is independently selected from H, F, Cl, Br, and
methyl; R.sup.8a is independently selected from H, F, Cl, Br, I,
--(CH.sub.2).sub.nCN, --(CH.sub.2).sub.nNH.sub.2,
CH.sub.3CHF.sub.2, CCH.sub.3F.sub.2, CF.sub.3, OH, OCH.sub.3,
OCF.sub.3, OCHF.sub.2, C(.dbd.O)CH.sub.3, C(.dbd.O)OH,
C(.dbd.O)OCH.sub.3, C(.dbd.O)NH.sub.2, C(.dbd.O)NHCH.sub.2CF.sub.3,
C(.dbd.O)NHCH.sub.2Ph, NHC(.dbd.O)OCH.sub.3, NHC(.dbd.O)CF.sub.3,
##STR00536## R.sup.8b is independently selected from H and F;
R.sup.8c is independently selected from H, F, Cl, methyl, ethyl,
isopropyl, and OCH.sub.3; R.sup.8d is independently selected from
H, F, and Cl; R.sup.8e is independently selected from H, F, and Cl;
R.sup.10 is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl (optionally substituted with R.sup.11),
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl (optionally substituted
with R.sup.11), --(CH.sub.2).sub.n--O-4- to 10-membered
heterocyclyl (optionally substituted with R.sup.11), F, Cl, Br, CN,
NO.sub.2, .dbd.O, CONR.sup.12R.sup.12,
--(CH.sub.2).sub.n--C(.dbd.O)OR.sup.12, Si(C.sub.1-4 alkyl).sub.3,
--(CH.sub.2).sub.p--OR.sup.12,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12, --S(.dbd.O).sub.pC.sub.1-6
alkyl, NR.sup.12S(.dbd.O).sub.pC.sub.1-6 alkyl, and
S(.dbd.O).sub.pNR.sup.12R.sup.12; R.sup.10' is independently
selected from H, C.sub.1-6 alkyl (optionally substituted with
R.sup.11), aryl, --(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl
(optionally substituted with R.sup.11), and
--(CH.sub.2).sub.n--O-4- to 10-membered heterocyclyl (optionally
substituted with R.sup.11); R.sup.11, at each occurrence, is
independently selected from H, halogen, C.sub.1-5 alkyl,
--(CH.sub.2).sub.n--OH, C.sub.3-6 cycloalkyl, and phenyl; R.sup.12,
at each occurrence, is independently selected from H, C.sub.1-5
alkyl optionally substituted with R.sup.11, C.sub.3-6 cycloalkyl,
phenyl, and heterocyclyl, or R.sup.12 and R.sup.12 together with
the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl; n, at
each occurrence, is an integer independently selected from 0, 1,
and 2; and p, at each occurrence, is an integer independently
selected from 0, 1, and 2.
5. The compound of claim 4 having Formula (IIc): ##STR00537## or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt
thereof, wherein: ring A is independently selected from phenyl and
5- to 6-membered heterocyclyl; ring B is 5- to 6-membered
heteroaryl comprising carbon atoms and 1-3 heteroatoms selected
from N and NR.sup.3c; W is independently selected from
(CR.sup.1R.sup.2).sub.1-2, O, NH, and N(C.sub.1-4 alkyl); Y is
independently selected from --CH.sub.2NH--, --NHC(.dbd.O)-- and
--C(.dbd.O)NH--; R.sup.1 and R.sup.2 are independently selected
from H, D, F, C.sub.1-4 alkyl, and hydroxyl; R.sup.3 is
independently selected from H, halogen, haloalkyl, C.sub.1-4alkyl
(optionally substituted with R.sup.6), and CN; R.sup.3c is
independently selected from H, haloalkyl, C.sub.1-4 alkyl
(optionally substituted with R.sup.6), --(CH.sub.2).sub.1-2--OH,
C(.dbd.O)C.sub.1-4 alkyl, --(CH.sub.2).sub.1-2--C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-4 alkyl, S(.dbd.O).sub.pC.sub.1-6 alkyl,
--(CH.sub.2).sub.n--C.sub.3-10 carbocyclyl and
--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
carbocyclyl and heterocyclyl are optionally substituted with
R.sup.6; R.sup.4 is independently selected from H, OH, F, Cl, Br,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3, CN; C(.dbd.O)NH.sub.2,
C.sub.3-6 cycloalkyl, aryl, and 5- to 6-membered heterocyclyl;
R.sup.6 is independently selected from H, --(CH.sub.2).sub.n--OH,
.dbd.O, NH.sub.2, --(CH.sub.2).sub.n--CN, halogen, C.sub.1-6 alkyl,
--(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, and
--O--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
cycloalkyl and heterocyclyl are optionally substituted with
R.sup.10; R.sup.8b is independently selected from H and F; R.sup.8c
is independently selected from H, F, Cl, CH.sub.3, and OCH.sub.3;
R.sup.10 is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, --(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl
(optionally substituted with R.sup.11), --(CH.sub.2).sub.n--O-4- to
10-membered heterocyclyl (optionally substituted with R.sup.11), F,
Cl, Br, CN, NO.sub.2, .dbd.O, C(.dbd.O)NR.sup.12R.sup.12,
C(.dbd.O)OR.sup.12, Si(C.sub.1-4 alkyl).sub.3,
--(CH.sub.2).sub.n--OR.sup.12, --(CH.sub.2).sub.nNR.sup.12R.sup.12,
--S(.dbd.O).sub.pC.sub.1-6 alkyl, NR.sup.12S(.dbd.O).sub.pC.sub.1-6
alkyl, and S(.dbd.O).sub.pNR.sup.12R.sup.12; R.sup.11, at each
occurrence, is independently selected from H, halogen, C.sub.1-5
alkyl, --(CH.sub.2).sub.n--OH, C.sub.3-6 cycloalkyl, and phenyl;
R.sup.12, at each occurrence, is independently selected from H,
C.sub.1-5 alkyl, C.sub.3-6 cycloalkyl, phenyl, and heterocyclyl, or
R.sup.12 and R.sup.12 together with the nitrogen atom to which they
are both attached form a heterocyclic ring optionally substituted
with C.sub.1-4alkyl; n, at each occurrence, is an integer
independently selected from 0, 1, and 2; and p, at each occurrence,
is an integer independently selected from 0, 1, and 2.
6. The compound of claim 5 having Formula (IId): ##STR00538## or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt
thereof, wherein: ---- is an optional bond; ring A is independently
selected from phenyl and 5- to 6-membered heterocyclyl; W is
independently selected from CHR.sup.1a, O, NH, and N(C.sub.1-4
alkyl); G.sup.5 is independently selected from CH.sub.2 and
NR.sup.3c; G.sup.6 is independently selected from CH.sub.2 and
NR.sup.3c; provided when G.sup.5 is CH.sub.2, G.sup.6 is NR.sup.3c;
when G.sup.5 is NR.sup.3c, G.sup.6 is CH.sub.2 and only one
R.sup.3c is present on the ring; Y is independently selected from
--NHC(.dbd.O)-- and --C(.dbd.O)NH--; R.sup.1 is independently
selected from H and C.sub.1-4 alkyl; R.sup.1a is independently
selected from H, D, F, CH.sub.3, and OH; R.sup.2 is independently
selected from H, D, and OH; R.sup.3c is independently selected from
H, haloalkyl, C.sub.1-4alkyl (optionally substituted with R.sup.6),
--(CH.sub.2).sub.0-2--OH, C(.dbd.O)C.sub.1-4 alkyl,
--(CH.sub.2).sub.0-2--C(.dbd.O)OH, --C(.dbd.O)OC.sub.1-4 alkyl,
S(.dbd.O).sub.pC.sub.1-6 alkyl, phenyl optionally substituted with
R.sup.6, 5- to 6-membered heterocyclyl optionally substituted with
R.sup.6, and 5- to 6-membered heteroaryl optionally substituted
with R.sup.6; R.sup.4 is independently selected from H, OH, F, Cl,
Br, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3, CN, and
C(.dbd.O)NH.sub.2; R.sup.6 is independently selected from H,
--(CH.sub.2).sub.n--OH, .dbd.O, NH.sub.2, --(CH.sub.2).sub.n--CN,
halogen, C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, and
--O--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
cycloalkyl and heterocyclyl are optionally substituted with
R.sup.10; R.sup.8b is independently selected from H and F; R.sup.8c
is independently selected from H, F, Cl, CH.sub.3, and OCH.sub.3;
R.sup.10 is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), aryl,
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl (optionally substituted
with R.sup.11), --(CH.sub.2).sub.n--O-4- to 10-membered
heterocyclyl (optionally substituted with R.sup.11), F, Cl, Br, CN,
NO.sub.2, .dbd.O, C(.dbd.O)NR.sup.12R.sup.12; C(.dbd.O)OR.sup.12,
Si(C.sub.1-4 alkyl).sub.3, --(CH.sub.2).sub.n--OR.sup.12,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12; S(.dbd.O).sub.pC.sub.1-6
alkyl, NR.sup.12S(O).sub.pC.sub.1-6 alkyl, and
S(.dbd.O).sub.pNR.sup.12R.sup.12; R.sup.11, at each occurrence, is
independently selected from H, halogen, C.sub.1-5 alkyl,
--(CH.sub.2).sub.n--OH, C.sub.3-6 cycloalkyl, and phenyl; R.sup.12,
at each occurrence, is independently selected from H, C.sub.1-5
alkyl, C.sub.3-6 cycloalkyl, phenyl, and heterocyclyl, or R.sup.12
and R.sup.12 together with the nitrogen atom to which they are both
attached form a heterocyclic ring optionally substituted with
C.sub.1-4alkyl; n, at each occurrence, is an integer independently
selected from 0, 1, and 2; and p, at each occurrence, is an integer
independently selected from 0, 1, and 2.
7. The compound of claim 6 having Formula (IIe): ##STR00539## or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt
thereof, wherein: ring A is independently selected from
##STR00540## R.sup.1 is independently selected from H and C.sub.1-4
alkyl; R.sup.1a is independently selected from H, D, F, CH.sub.3,
and OH; R.sup.2 is independently selected from H, D, and OH;
R.sup.3c is independently selected from H, CHF.sub.2, CD.sub.3,
CH.sub.3, CH.sub.2CH.sub.2OH, CH.sub.2C(.dbd.O)OH,
SO.sub.2CH.sub.3, phenyl optionally substituted with R.sup.6, and
5- to 6-membered heteroaryl optionally substituted with R.sup.6;
R.sup.4 is independently selected from H, F, and C(.dbd.O)NH.sub.2;
R.sup.6 is independently selected from H, --(CH.sub.2).sub.n--OH,
.dbd.O, NH.sub.2, --(CH.sub.2).sub.n--CN, halogen, C.sub.1-6 alkyl,
--(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, and
--O--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
cycloalkyl and heterocyclyl are optionally substituted with
R.sup.10; R.sup.8b is independently selected from H and F; R.sup.8c
is independently selected from H, F, Cl, CH.sub.3, and OCH.sub.3;
R.sup.10 is independently selected from H, CF.sub.3, CHF.sub.2,
CH.sub.2F, aryl, --(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl
(optionally substituted with R.sup.11), heteroaryl (optionally
substituted with R.sup.11), --(CH.sub.2).sub.n--O-4- to 10-membered
heterocyclyl (optionally substituted with R.sup.11), F, Cl, Br, CN,
NO.sub.2, .dbd.O, C(.dbd.O)NR.sup.12R.sup.12,
--(CH.sub.2).sub.n--C(.dbd.O)OR.sup.12, Si(C.sub.1-4 alkyl).sub.3,
--(CH.sub.2).sub.n--OR.sup.12,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12, --S(.dbd.O).sub.pC.sub.1-6
alkyl, NR.sup.12S(.dbd.O).sub.pC.sub.1-6 alkyl, and
S(.dbd.O).sub.pNR.sup.12R.sup.12; R.sup.11, at each occurrence, is
independently selected from H, halogen, C.sub.1-5 alkyl,
--(CH.sub.2).sub.n--OH, C.sub.3-6 cycloalkyl, and phenyl; R.sup.12,
at each occurrence, is independently selected from H, C.sub.1-5
alkyl, C.sub.3-6 cycloalkyl, phenyl, and heterocyclyl, or R.sup.12
and R.sup.12 together with the nitrogen atom to which they are both
attached form a heterocyclic ring optionally substituted with
C.sub.1-4alkyl; and n, at each occurrence, is an integer
independently selected from 0, 1, and 2.
8. The compound of claim 6 having Formula (IIf): ##STR00541## or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt
thereof, wherein: ring A is independently selected from
##STR00542## R.sup.1 is independently selected from H and C.sub.1-4
alkyl; R.sup.1a is independently selected from H, D, F, CH.sub.3,
and OH; R.sup.2 is independently selected from H, D, and OH;
R.sup.3c is independently selected from H, CHF.sub.2, CD.sub.3,
CH.sub.3, SO.sub.2CH.sub.3, phenyl optionally substituted with
R.sup.6, and 5- to 6-membered heterocyclyl optionally substituted
with R.sup.6, 5- to 6-membered heteroaryl optionally substituted
with R.sup.6; R.sup.4 is independently selected from H and F;
R.sup.6 is independently selected from OH, .dbd.O, NH.sub.2, CN,
halogen, C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, and
--O--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
cycloalkyl and heterocyclyl are optionally substituted with
R.sup.10; R.sup.8b is independently selected from H and F; R.sup.8c
is independently selected from H, F, Cl, CH.sub.3, and OCH.sub.3;
R.sup.10 is independently selected from H, CF.sub.3, CHF.sub.2,
C(CH.sub.3).sub.2OH, aryl, --(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl
(optionally substituted with R.sup.11), --(CH.sub.2).sub.n--O-4- to
10-membered heterocyclyl (optionally substituted with R.sup.11), F,
Cl, Br, CN, NO.sub.2, .dbd.O, C(.dbd.O)NR.sup.12R.sup.12,
C(.dbd.O)OR.sup.12, Si(C.sub.1-4 alkyl).sub.3,
--(CH.sub.2).sub.n--OR.sup.12,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12, --S(.dbd.O).sub.pC.sub.1-6
alkyl, NR.sup.12S(.dbd.O).sub.pC.sub.1-6 alkyl, and
S(.dbd.O).sub.pNR.sup.12R.sup.12; R.sup.11, at each occurrence, is
independently selected from H, halogen, C.sub.1-5 alkyl,
--(CH.sub.2).sub.n--OH, C.sub.3-6 cycloalkyl, and phenyl; R.sup.12,
at each occurrence, is independently selected from H, C.sub.1-5
alkyl, C.sub.3-6 cycloalkyl, phenyl, and heterocyclyl, or R.sup.12
and R.sup.12 together with the nitrogen atom to which they are both
attached form a heterocyclic ring optionally substituted with
C.sub.1-4alkyl; and n, at each occurrence, is an integer
independently selected from 0, 1, and 2.
9. The compound of claim 6 having Formula (IIg): ##STR00543## or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt
thereof, wherein: ring A is independently selected from
##STR00544## R.sup.1 is independently selected from H and C.sub.1-4
alkyl; R.sup.1a is independently selected from H, F, CH.sub.3, and
OH; R.sup.2 is independently selected from H and OH; R.sup.3c is
independently selected from H, CHF.sub.2, CD.sub.3, and CH.sub.3;
R.sup.4 is independently selected from H and F; R.sup.8b is
independently selected from H and F; R.sup.8c is independently
selected from H, F, Cl, CH.sub.3, and OCH.sub.3; R.sup.10 is
independently selected from H, CF.sub.3, CHF.sub.2, aryl,
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl (optionally substituted
with R.sup.11), --(CH.sub.2).sub.n--O-4- to 10-membered
heterocyclyl (optionally substituted with R.sup.11), F, Cl, Br, CN,
NO.sub.2, .dbd.O, C(.dbd.O)NR.sup.12R.sup.12, C(.dbd.O)OR.sup.12,
Si(C.sub.1-4 alkyl).sub.3, --(CH.sub.2).sub.n--OR.sup.12,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12, --S(.dbd.O).sub.pC.sub.1-6
alkyl, NR.sup.12S(.dbd.O).sub.pC.sub.1-6 alkyl, and
S(.dbd.O).sub.pNR.sup.12R.sup.12; R.sup.11, at each occurrence, is
independently selected from H, halogen, C.sub.1-5 alkyl,
--(CH.sub.2).sub.n--OH, C.sub.3-6 cycloalkyl, and phenyl; R.sup.12,
at each occurrence, is independently selected from H, C.sub.1-5
alkyl, C.sub.3-6 cycloalkyl, phenyl, and heterocyclyl, or R.sup.12
and R.sup.12 together with the nitrogen atom to which they are both
attached form a heterocyclic ring optionally substituted with
C.sub.1-4alkyl; and n, at each occurrence, is an integer
independently selected from 0, 1, and 2.
10. The compound of claim 2 having Formula (IIIb): ##STR00545## or
a stereoisomer, a tautomer, a pharmaceutically acceptable salt
thereof, wherein: ring A is independently selected from phenyl and
5- to 6-membered heterocyclyl; G.sup.1 is independently selected
from aryl, C.sub.3-6cycloalkyl and 5- to 6-membered heterocyclyl,
wherein said aryl, cycloalkyl and heterocyclyl are substituted with
1-4 R.sup.8; G.sup.2 is independently selected from N and
CR.sup.3b; G.sup.7 is independently selected from N and CR.sup.3;
G.sup.8 is independently selected from N and CR.sup.3; provided at
least one of G.sup.2, G.sup.6, and G.sup.7 is N; R.sup.1 and
R.sup.2 are independently selected from H, halogen, CF.sub.3,
C.sub.1-6 alkyl, and hydroxyl; R.sup.3 is independently selected
from H, halogen, haloalkyl, C.sub.1-4alkyl (optionally substituted
with R.sup.6), C.sub.2-4alkenyl (optionally substituted with
R.sup.6), CN, NO.sub.2, --(CH.sub.2).sub.n--OR.sup.5,
--(CH.sub.2).sub.n--NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(.dbd.O)OR.sup.5,
--(CH.sub.2).sub.n--NHC(.dbd.O)OR.sup.5,
--(CH.sub.2).sub.n--NHC(.dbd.O)R.sup.5,
--(CH.sub.2).sub.n--NHC(N--CN)NHR.sup.5,
--(CH.sub.2).sub.n--NHC(NH)NHR.sup.5,
--(CH.sub.2).sub.n--N.dbd.CHNR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NHC(.dbd.O)NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(.dbd.O)NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NHC(S)NR.sup.9C(.dbd.O)R.sup.5,
--(CH.sub.2).sub.n--S(.dbd.O).sub.pC.sub.1-6 alkyl optionally
substituted with R.sup.11,
--(CH.sub.2).sub.n--S(.dbd.O).sub.pNR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NHS(.dbd.O).sub.pNR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NHS(.dbd.O).sub.pC.sub.1-6 alkyl optionally
substituted with R.sup.11, --(CH.sub.2).sub.n--C.sub.3-10
carbocyclyl and --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl,
wherein said carbocyclyl and heterocyclyl are optionally
substituted with R.sup.6; optionally, two adjacent R.sup.3 groups
on the carbocyclyl and heterocyclyl may form a ring optionally
substituted with R.sup.6; R.sup.3a is independently selected from H
and halogen; R.sup.3b is independently selected from H, halogen,
methyl, and CN; R.sup.4 is independently selected from H, OH, F,
Cl, Br, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3, CN, C.sub.3-6
cycloalkyl, aryl, and 5- to 6-membered heterocyclyl, wherein said
cycloalkyl, aryl and heterocyclyl are optionally substituted with
R.sup.6; R.sup.5 is independently selected from H, C.sub.1-4 alkyl
(optionally substituted with halogen, hydroxyl, alkoxy, carboxy,
alkoxycarbonyl, amino, substituted amino),
--(CH.sub.2).sub.n--C.sub.3-10 carbocyclyl and
--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
carbocyclyl and heterocyclyl are optionally substituted with
R.sup.6; R.sup.6 is independently selected from
--(CH.sub.2).sub.n--OH, .dbd.O, NH.sub.2, --(CH.sub.2).sub.n--CN,
halogen, C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, and
--O--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
cycloalkyl and heterocyclyl are optionally substituted with
R.sup.10; R.sup.7 is independently selected from H, F, Cl, and
methyl; R.sup.8 is independently selected from H, halogen, CN,
NH.sub.2, C.sub.1-6 alkyl, haloalkyl, alkylcarbonyl, alkoxy,
haloalkoxy, aryl, C.sub.3-6 cycloalkyl, and 4- to 12-membered
heterocyclyl, wherein said aryl, cycloalkyl, and heterocyclyl are
optionally substituted with R.sup.10; R.sup.10 is independently
selected from H, C.sub.1-6 alkyl (optionally substituted with
R.sup.11), C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl (optionally substituted
with R.sup.11), --(CH.sub.2).sub.n--O-4- to 10-membered
heterocyclyl (optionally substituted with R.sup.11), F, Cl, Br, CN,
NO.sub.2, .dbd.O, C(.dbd.O)NR.sup.12R.sup.12, C(.dbd.O)OR.sup.12,
Si(C.sub.1-4 alkyl).sub.3, --(CH.sub.2).sub.n--OR.sup.12,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12, --S(.dbd.O).sub.pC.sub.1-6
alkyl, NR.sup.12S(.dbd.O).sub.pC.sub.1-6 alkyl, and
S(.dbd.O).sub.pNR.sup.12R.sup.12; R.sup.11, at each occurrence, is
independently selected from H, halogen, C.sub.1-5 alkyl,
--(CH.sub.2).sub.n--OH, C.sub.3-6 cycloalkyl, and phenyl; R.sup.12,
at each occurrence, is independently selected from H, C.sub.1-5
alkyl, C.sub.3-6 cycloalkyl, phenyl, and heterocyclyl, or R.sup.12
and R.sup.12 together with the nitrogen atom to which they are both
attached form a heterocyclic ring optionally substituted with
C.sub.1-4alkyl; n, at each occurrence, is an integer independently
selected from 0, 1, and 2; and p, at each occurrence, is an integer
independently selected from 0, 1, and 2.
11. The compound of claim 10, having Formula (IVa): ##STR00546## or
a stereoisomer, a tautomer, a pharmaceutically acceptable salt
thereof, wherein: ring A is independently selected from
##STR00547## R.sup.1 and R.sup.2 are independently selected from H,
F, C.sub.1-4 alkyl, and OH; R.sup.1a, at each occurrence, is
independently selected from H, F, CH.sub.3, and OH; R.sup.3 is
independently selected from H, F, Cl, Br, I, C.sub.2-4alkenyl
(optionally substituted C(.dbd.O)OH), CN, and
--(CH.sub.2).sub.n--OH; R.sup.4 is independently selected from H,
OH, F, OC.sub.1-4 alkyl, C.sub.1-4 alkyl, CN, C.sub.3-6 cycloalkyl,
aryl, and 5- to 6-membered heterocyclyl, wherein said cycloalkyl,
aryl and heterocyclyl are optionally substituted with R.sup.6;
R.sup.6 is independently selected from OH, NH.sub.2, halogen,
C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl, .dbd.O, C.sub.3-6 cycloalkyl,
4- to 10-membered heterocyclyl, and --O-4- to 10-membered
heterocyclyl, wherein said cycloalkyl and heterocyclyl are
optionally substituted with R.sup.10; R.sup.8a is independently
selected from H, F, Cl, Br, CN, OCH.sub.3, OCF.sub.3, CH.sub.3,
C(.dbd.O)CH.sub.3, CF.sub.3, OCHF.sub.2, NHC(.dbd.O)C.sub.1-4
alkyl, aryl, C.sub.3-6 cycloalkyl, and 4- to 12-membered
heterocyclyl, wherein said aryl, cycloalkyl, and heterocyclyl are
optionally substituted with R.sup.10; R.sup.8b is independently
selected from H and F; R.sup.8c is independently selected from H,
F, Cl, CH.sub.3, and OCH.sub.3; R.sup.10 is independently selected
from C.sub.1-6 alkyl, --C.sub.3-6 cycloalkyl, F, Cl, Br, CF.sub.3,
CHF.sub.2, CN, and OC.sub.1-5 alkyl; and n, at each occurrence, is
an integer independently selected from 0, 1, and 2.
12. The compound of claim 3, or a stereoisomer, a tautomer, a
pharmaceutically acceptable salt thereof, wherein: ring A is
independently selected from ##STR00548## ring B is independently
selected from ##STR00549## W is independently selected from
CHR.sup.1a, O, NH, and N(C.sub.1-4 alkyl); R.sup.1 is independently
selected from H and C.sub.1-4 alkyl; R.sup.1a is independently
selected from H F, CH.sub.3, and hydroxyl; R.sup.2 is independently
selected from H and hydroxyl; R.sup.3 is independently selected
from H, .dbd.O, F, CHF.sub.2, CF.sub.3, OCF.sub.3, OCHF.sub.2,
CH.sub.3, CN, --(CH.sub.2).sub.0-2--OH, OC.sub.1-4 alkyl,
C(.dbd.O)C.sub.1-4 alkyl, --(CH.sub.2).sub.0-1--C(.dbd.O)OH,
--C(.dbd.O)OC.sub.1-4 alkyl, --S(.dbd.O).sub.2C.sub.1-4 alkyl, and
--NHC(.dbd.O)OC.sub.1-4 alkyl; R.sup.3c is independently selected
from H, CF.sub.2H, CF.sub.3, C.sub.1-4 alkyl, and CD.sub.3; R.sup.4
is independently selected from H and F; R.sup.8b is independently
selected from H and F; R.sup.8c is independently selected from H
and Cl; R.sup.10 is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), aryl,
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl (optionally substituted
with R.sup.11), --(CH.sub.2).sub.n--O-4- to 10-membered
heterocyclyl, F, Cl, Br, CN, C(.dbd.O)NR.sup.12R.sup.12,
Si(C.sub.1-4 alkyl).sub.3, and --(CH.sub.2).sub.n--OR.sup.12;
R.sup.11, at each occurrence, is independently selected from H,
halogen, and C.sub.1-5 alkyl; and n, at each occurrence, is an
integer independently selected from 0, 1, 2, 3, and 4.
13. The compound of claim 2, or a stereoisomer, a tautomer, a
pharmaceutically acceptable salt thereof, wherein: ring A is
independently selected from ##STR00550## ring B is independently
selected from ##STR00551## G.sup.1 is independently selected from
##STR00552## ##STR00553## ##STR00554## ##STR00555## ##STR00556##
##STR00557## ##STR00558## ##STR00559## ##STR00560## ##STR00561##
##STR00562## ##STR00563## ##STR00564## W is independently selected
from CHR.sup.1, O, NH, and N(C.sub.1-4 alkyl); Y is independently
selected from --NH--, --NHC(.dbd.O)-- and --C(.dbd.O)NH--; R.sup.1
and R.sup.2 are independently selected from H, F, C.sub.1-4 alkyl,
and hydroxyl; R.sup.3 is independently selected from H, .dbd.O, F,
CHF.sub.2, CF.sub.3, OCF.sub.3, OCHF.sub.2, CH.sub.3, CN,
--(CH.sub.2).sub.0-2--OH, OC.sub.1-4 alkyl, C(.dbd.O)C.sub.1-4
alkyl, --(CH.sub.2).sub.0-1--C(.dbd.O)OH, --C(.dbd.O)OC.sub.1-4
alkyl, --S(.dbd.O).sub.2C.sub.1-4 alkyl, and
--NHC(.dbd.O)OC.sub.1-4 alkyl; R.sup.3c is independently selected
from H, CF.sub.2H, CF.sub.3, C.sub.1-4 alkyl, and CD.sub.3; R.sup.4
is independently selected from H, F, and C.sub.1-4 alkyl; and
R.sup.7 is H.
14. The compound of claim 4 having Formula (V): ##STR00565## or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt
thereof, wherein: ring A is independently selected from phenyl and
5- to 6-membered heterocyclyl; W is independently selected from
CHR.sup.1a, O, NH, and N(C.sub.1-4 alkyl); R.sup.1 is independently
selected from H and C.sub.1-4 alkyl; R.sup.1a is independently
selected from H, F, CH.sub.3, and hydroxyl; R.sup.2 is
independently selected from H and hydroxyl; R.sup.3 is
independently selected from H, haloalkyl, C.sub.1-4alkyl
(optionally substituted with R.sup.6), F, CN, C(.dbd.O)C.sub.1-4
alkyl, C(.dbd.O)OH, C(.dbd.O)OC.sub.1-4 alkyl,
--S(.dbd.O).sub.2C.sub.1-4alkyl, and --NHC(.dbd.O)OC.sub.1-4 alkyl;
R.sup.4 is independently selected from H, OH, F, Cl, Br, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, CF.sub.3, and CN; R.sup.5 is independently
selected from H, C.sub.1-4 alkyl (optionally substituted with
halogen, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, amino,
substituted amino), --(CH.sub.2).sub.n--C.sub.3-10 carbocyclyl and
--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
carbocyclyl and heterocyclyl are optionally substituted with
R.sup.6; R.sup.6 is independently selected from
--(CH.sub.2).sub.n--OH, .dbd.O, NH.sub.2, --(CH.sub.2).sub.n--CN,
halogen, C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, and
--O--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
cycloalkyl and heterocyclyl are optionally substituted with
R.sup.10; R.sup.7 is independently selected from H, F, Cl, and
methyl; R.sup.8b is independently selected from H and F; R.sup.8c
is independently selected from H, F, Cl, CH.sub.3, and OCH.sub.3;
R.sup.10 is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, --(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl
(optionally substituted with R.sup.11), --(CH.sub.2).sub.n--O-4- to
10-membered heterocyclyl (optionally substituted with R.sup.11), F,
Cl, Br, CN, NO.sub.2, .dbd.O, C(.dbd.O)NR.sup.12R.sup.12,
C(.dbd.O)OR.sup.12, Si(C.sub.1-4 alkyl).sub.3,
--(CH.sub.2).sub.n--OR.sup.12, and
--(CH.sub.2).sub.n--NR.sup.12R.sup.12; R.sup.11, at each
occurrence, is independently selected from H, halogen, C.sub.1-5
alkyl, --(CH.sub.2).sub.n--OH, C.sub.3-6 cycloalkyl, and phenyl;
R.sup.12, at each occurrence, is independently selected from H,
C.sub.1-5 alkyl, C.sub.3-6 cycloalkyl, phenyl, and heterocyclyl, or
R.sup.12 and R.sup.12 together with the nitrogen atom to which they
are both attached form a heterocyclic ring optionally substituted
with C.sub.1-4alkyl; n, at each occurrence, is an integer
independently selected from 0, 1, and 2; and p, at each occurrence,
is an integer independently selected from 0, 1, and 2.
15. A pharmaceutical composition comprising one or more compounds
according to claim 1 and a pharmaceutically acceptable carrier or
diluent.
16. A method for the treatment and/or prophylaxis of a
thromboembolic disorder, comprising: administering to a patient in
need thereof a therapeutically effective amount of a compound of
claim 1, or a stereoisomer, a tautomer, or a pharmaceutically
acceptable salt thereof, wherein the thromboembolic disorder is
selected from arterial cardiovascular thromboembolic disorders,
venous cardiovascular thromboembolic disorders, and thromboembolic
disorders in the chambers of the heart or in the peripheral
circulation.
17. A method according to claim 16, wherein the thromboembolic
disorder is selected from unstable angina, an acute coronary
syndrome, atrial fibrillation, myocardial infarction, 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.
18. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is entitled to priority pursuant to 35
U.S.C. .sctn.119(e) to U.S. provisional patent application Nos.
61/933,942, filed on Jan. 31, 2014 and 62/058,293, filed on Oct. 1,
2014, which are incorporated herein in their entireties.
FIELD OF THE INVENTION
[0002] The present invention relates generally to novel macrocyclic
compounds, and their analogues thereof, which are factor XIa
inhibitors or dual inhibitors of factor XIa and plasma kallikrein,
compositions containing them, and methods of using them, for
example, for the treatment or prophylaxis of thromboembolic
disorders, or for the treatment of retinal vascular permeability
associated with diabetic retinopathy and diabetic macular
edema.
BACKGROUND OF THE INVENTION
[0003] Thromboembolic diseases remain the leading cause of death in
developed countries despite the availability of anticoagulants such
as warfarin (COUMADIN.RTM.), heparin, low molecular weight heparins
(LMWH), and synthetic pentasaccharides and antiplatelet agents such
as aspirin and clopidogrel (PLAVIX.RTM.). The oral anticoagulant
warfarin, inhibits the post-translational maturation of coagulation
factors VII, IX, X and prothrombin, and has proven effective in
both venous and arterial thrombosis. However, its usage is limited
due to its narrow therapeutic index, slow onset of therapeutic
effect, numerous dietary and drug interactions, and a need for
monitoring and dose adjustment. Thus discovering and developing
safe and efficacious oral anticoagulants for the prevention and
treatment of a wide range of thromboembolic disorders has become
increasingly important.
[0004] One approach is to inhibit thrombin generation by targeting
the inhibition of coagulation factor XIa (FXIa). Factor XIa is a
plasma serine protease involved in the regulation of blood
coagulation, which is initiated in vivo by the binding of tissue
factor (TF) to factor VII (FVII) to generate factor VIIa (FVIIa).
The resulting TF:FVIIa complex activates factor IX (FIX) and factor
X (FX) that leads to the production of factor Xa (FXa). The
generated FXa catalyzes the transformation of prothrombin into
small amounts of thrombin before this pathway is shut down by
tissue factor pathway inhibitor (TFPI). The process of coagulation
is then further propagated via the feedback activation of Factors
V, VIII and XI by catalytic amounts of thrombin. (Gailani, D. et
al., Arterioscler. Thromb. Vasc. Biol., 27:2507-2513 (2007).) The
resulting burst of thrombin converts fibrinogen to fibrin that
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, 17:S1-S5 (2003)).
Therefore, factor XIa plays a key role in propagating this
amplification loop and is thus an attractive target for
anti-thrombotic therapy.
[0005] An alternative way of initiation of coagulation is operative
when blood is exposed to artificial surfaces. This process is also
termed contact activation. Surface absorption of factor XII leads
to a conformational change in the factor XII molecule, thereby
facilitating activation to proteolytic active factor XII molecules
(factor XIIa and factor XIIf). Factor XIIa (or XIIf) has a number
of target proteins, including plasma prekallikrein and factor
XI.
[0006] Plasma prekallikrein is a zymogen of a trypsin-like serine
protease and is present in plasma at 35 to 50 .mu.g/mL. The gene
structure is similar to that of factor XI. Overall, the amino acid
sequence of plasma kallikrein has 58% homology to factor XI. Plasma
kallikrein is thought to play a role in a number of inflammatory
disorders. The major inhibitor of plasma kallikrein is the serpin
C1 esterase inhibitor. Patients who present with a genetic
deficiency in C1 esterase inhibitor suffer from hereditary
angioedema (HAE) which results in intermittent swelling of face,
hands, throat, gastrointestinal tract and genitals. Blisters formed
during acute episodes contain high levels of plasma kallikrein
which cleaves high molecular weight kininogen liberating bradykinin
leading to increased vascular permeability. Treatment with a large
protein plasma kallikrein inhibitor has been shown to effectively
treat HAE by preventing the release of bradykinin which causes
increased vascular permeability (Lehmann, A., "Ecallantide (DX-88),
a plasma kallikrein inhibitor for the treatment of hereditary
angioedema and the prevention of blood loss in on-pump
cardiothoracic surgery", Expert Opin. Biol. Ther., 8:1187-1199
(2008)).
[0007] The plasma kallikrein-kinin system is abnormally abundant in
patients with advanced diabetic macular edema. It has been recently
published that plasma kallikrein contributes to retinal vascular
dysfunctions in diabetic rats (Clermont, A. et al., "Plasma
kallikrein mediates retinal vascular dysfunction and induces
retinal thickening in diabetic rats", Diabetes, 60:1590-1598
(2011)). Furthermore, administration of the plasma kallikrein
inhibitor ASP-440 ameliorated both retinal vascular permeability
and retinal blood flow abnormalities in diabetic rats. Therefore, a
plasma kallikrein inhibitor should have utility as a treatment to
reduce retinal vascular permeability associated with diabetic
retinopathy and diabetic macular edema. Other complications of
diabetes such as cerebral hemorrhage, nephropathy, cardiomyopathy
and neuropathy, all of which have associations with plasma
kallikrein may also be considered as targets for a plasma
kallikrein inhibitor.
[0008] To date, no small molecule synthetic plasma kallikrein
inhibitor has been approved for medical use. The large protein
plasma kallikrein inhibitors present risks of anaphylactic
reactions, as has been reported for Ecallantide. Thus there remains
a need for compounds that inhibit plasma kallikrein, that do not
induce anaphylaxis and that are orally available. Furthermore, the
molecules in the known art feature a highly polar and ionizable
guanidine or amidine functionality. It is well known that such
functionalities may be limiting to gut permeability and therefore
to oral availability.
SUMMARY OF THE INVENTION
[0009] The present invention provides novel macrocyclic compounds,
their analogues, including stereoisomers, tautomers,
pharmaceutically acceptable salts, or solvates thereof, which are
useful as selective factor XIa inhibitors or dual inhibitors of
factor XIa and plasma kallikrein.
[0010] The present invention also provides processes and
intermediates for making the compounds of the present
invention.
[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
stereoisomers, tautomers, pharmaceutically acceptable salts, or
solvates thereof.
[0012] The compounds of the invention may be used in the treatment
and/or prophylaxis of thromboembolic disorders.
[0013] The compounds of the invention may be used in the treatment
of retinal vascular permeability associated with diabetic
retinopathy and diabetic macular edema.
[0014] The compounds of the present invention may be used in
therapy.
[0015] The compounds of the present invention may be used for the
manufacture of a medicament for the treatment and/or prophylaxis of
a thromboembolic disorder.
[0016] The compounds of the invention can be used alone, in
combination with other compounds of the present invention, or in
combination with one or more, preferably one to two other
agent(s).
[0017] These and other features of the invention will be set forth
in expanded form as the disclosure continues.
DETAILED DESCRIPTION OF THE INVENTION
I. Compounds of the Invention
[0018] In one aspect, the present invention provides, inter alia,
compounds of Formula (I):
##STR00002##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0019] ring A is independently selected from 6-membered aryl and 5-
to 6-membered heterocyclyl, wherein said aryl and heterocyclyl are
optionally substituted with, where valence allows, one or more
R.sup.4;
[0020] ring B is 5- to 10-membered heterocyclyl optionally
substituted with, where valence allows, one or more R.sup.3 or 5-
to 10-membered heterocyclyl comprising carbon atoms and 1-4
heteroatoms selected from N, NR.sup.3c, O, and S(O).sub.p and
optionally substituted with, where valence allows, one or more
R.sup.3;
[0021] G.sup.1 is independently selected from C.sub.3-10
carbocyclyl and 5- to 10-membered heterocyclyl, wherein said
carbocyclyl and heterocyclyl are optionally substituted with, where
valence allows, one or more R.sup.8;
[0022] X is independently selected from C.sub.4-8 alkylene and
C.sub.4-8 alkenylene, wherein said alkylene and alkenylene are
substituted with R.sup.1 and R.sup.2; alternatively one or more of
the carbon atoms of said alkylene and alkenylene may be replaced by
O, C.dbd.O, S(.dbd.O).sub.p, S(.dbd.O).sub.pNH, and NR.sup.15;
[0023] Y is independently selected from --CR.sup.13NH--,
--NHC(.dbd.O)--, --C(.dbd.O)NH--, --S(.dbd.O).sub.pNH--,
--NHS(.dbd.O).sub.p--, and C.sub.1-2 alkylene;
[0024] R.sup.1 and R.sup.2 are independently selected from H, D,
halogen, haloalkyl, C.sub.1-6 alkyl (optionally substituted with
R.sup.6), hydroxyl, and alkoxy optionally substituted with R.sup.6,
and C.sub.3-6 cycloalkyl optionally substituted with R.sup.6;
optionally, when R.sup.1 and R.sup.2 are attached to the same
carbon atom, together they form an oxo group or C.sub.3-6
cycloalkyl; optionally, when R.sup.1 and R.sup.2 are attached to
carbon atoms adjacent to each other, together they form a bond or
carbocyclyl; optionally, R.sup.1 and R.sup.15 or R.sup.2 and
R.sup.15 taken together form a ring;
[0025] R.sup.3 is independently selected from H, NO.sub.2, .dbd.O,
halogen, haloalkyl, C.sub.1-4 alkyl (optionally substituted with
R.sup.6), C.sub.2-4 alkenyl (optionally substituted with R.sup.6),
C.sub.2-4 alkynyl (optionally substituted with R.sup.6), CN,
--(CH.sub.2).sub.n--OR.sup.5, --(CH.sub.2).sub.n--NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(.dbd.O)R.sup.5,
--(CH.sub.2).sub.n--C(.dbd.O)OR.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(.dbd.O)OR.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(.dbd.O)R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(N--CN)NHR.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(NH)NHR.sup.5,
--(CH.sub.2).sub.n--N.dbd.CR.sup.9NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(.dbd.O)NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(.dbd.O)NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(.dbd.S)NR.sup.9C(.dbd.O)R.sup.5,
--(CH.sub.2).sub.n--S(.dbd.O).sub.pR.sup.5,
--(CH.sub.2).sub.n--S(.dbd.O).sub.pNR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9S(.dbd.O).sub.pNR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9S(.dbd.O).sub.pR.sup.5,
--(CH.sub.2).sub.n--C.sub.3-10 carbocyclyl and
--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
carbocyclyl and heterocyclyl are optionally substituted with
R.sup.6; optionally, two adjacent R.sup.3 groups on the
heterocyclyl may form a ring optionally substituted with
R.sup.6;
[0026] R.sup.3c is independently selected from H, haloalkyl,
C.sub.1-4 alkyl (optionally substituted with R.sup.6),
--(CH.sub.2).sub.1-2--OH, C(.dbd.O)C.sub.1-4 alkyl,
--(CH.sub.2).sub.0-2--C(.dbd.O)OH, --C(.dbd.O)OC.sub.1-4 alkyl,
S(.dbd.O).sub.pC.sub.1-6 alkyl, --(CH.sub.2).sub.n--C.sub.3-10
carbocyclyl and --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl,
wherein said carbocyclyl and heterocyclyl are optionally
substituted with R.sup.6;
[0027] R.sup.4 is independently selected from H, OH, NH.sub.2,
halogen, CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4
alkoxy, --CH.sub.2OH, --C(.dbd.O)OH, --CH.sub.2C(.dbd.O)OH,
--CO.sub.2(C.sub.1-4 alkyl), --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NH(C.sub.1-4 alkyl), --C(.dbd.O)N(C.sub.1-4
alkyl).sub.2, --S(.dbd.O).sub.2C.sub.1-4 alkyl,
--S(.dbd.O).sub.2NH.sub.2, C.sub.3-6 cycloalkyl, aryl, and 5- to
6-membered heterocyclyl, wherein said cycloalkyl, aryl and
heterocyclyl are optionally substituted with R.sup.6;
[0028] R.sup.5 is independently selected from H, C.sub.1-4 alkyl
(optionally substituted with halogen, hydroxyl, alkoxy, carboxy,
hydroxycarbonyl, alkoxycarbonyl, amino, substituted amino),
--(CH.sub.2).sub.n--C.sub.3-10 carbocyclyl and
--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
carbocyclyl and heterocyclyl are optionally substituted with
R.sup.6; alternatively, R.sup.5 and R.sup.5 together with the
nitrogen atom to which they are both attached form a heterocyclic
ring optionally substituted with R.sup.6;
[0029] R.sup.6 is independently selected from H,
--(CH.sub.2).sub.n--OH, .dbd.O, --(CH.sub.2).sub.nNH.sub.2,
--(CH.sub.2).sub.nCN, halogen, C.sub.1-6 alkyl,
--(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)NH.sub.2,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--C.sub.3-10 carbocyclyl, --(CH.sub.2).sub.n-4-
to 10-membered heterocyclyl, and --O-4- to 10-membered
heterocyclyl, wherein said carbocyclyl and heterocyclyl are
optionally substituted with R.sup.10;
[0030] R.sup.7 is independently selected from H, hydroxyl, alkoxy,
halogen, amino, C.sub.1-3haloalkyl, and C.sub.1-3 alkyl;
[0031] R.sup.8 is independently selected from H, halogen,
--(CH.sub.2).sub.nCN, C.sub.1-6 alkyl, amino, aminoalkyl,
haloalkyl, hydroxyl, alkoxy, haloalkoxy, alkylcarbonyl, carboxyl,
carboxyl ester, amide, haloalkylaminocarbonyl,
arylalkylaminocarbonyl, haloalkylaminocarbonyl,
alkoxycarbonylamino, haloalkylcarbonylamino, arylamino,
heteroarylamino, arylalkylcarbonyl, aryloxy, heteroaryloxy,
alkylthio, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
sulfonamide, --(CH.sub.2).sub.n-aryl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, and --(CH.sub.2).sub.n-4- to 12-membered heterocyclyl,
wherein said aryl, cycloalkyl, and heterocyclyl are optionally
substituted with R.sup.10;
[0032] alternatively, two adjacent R.sup.8 groups taken together
form a heterocyclic ring optionally substituted with R.sup.10;
[0033] R.sup.9 is H or C.sub.1-6 alkyl;
[0034] R.sup.10 is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl (optionally substituted with R.sup.11),
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl (optionally substituted
with R.sup.11), --(CH.sub.2).sub.n--O-4- to 10-membered
heterocyclyl (optionally substituted with R.sup.11), halogen,
--(CH.sub.2).sub.nCN, NO.sub.2, .dbd.O, C(.dbd.O)NR.sup.12R.sup.12,
--(CH.sub.2).sub.nC(.dbd.O)OR.sup.12, Si(C.sub.1-4 alkyl).sub.3,
--(CH.sub.2).sub.n--OR.sup.12,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12, --S(.dbd.O).sub.pC.sub.1-6
alkyl, NR.sup.12S(.dbd.O).sub.pC.sub.1-6 alkyl,
S(.dbd.O).sub.pNR.sup.12R.sup.12, and C(.dbd.NOH)NH.sub.2;
[0035] R.sup.11, at each occurrence, is independently selected from
H, halogen, C.sub.1-5 alkyl, --(CH.sub.2).sub.n--OH, C.sub.3-6
cycloalkyl, phenyl, and heterocyclyl;
[0036] R.sup.12, at each occurrence, is independently selected from
H, C.sub.1-5 alkyl optionally substituted with R.sup.11, C.sub.3-6
cycloalkyl, phenyl, and heterocyclyl, or R.sup.12 and R.sup.12
together with the nitrogen atom to which they are both attached
form a heterocyclic ring optionally substituted with
C.sub.1-4alkyl;
[0037] R.sup.13 is, independently at each occurrence, selected from
H, C.sub.1-4 haloalkyl, C.sub.1-4 alkyl, C(.dbd.O)OH,
C(.dbd.O)O(C.sub.1-4 alkyl), C(.dbd.O)O(CH.sub.2).sub.2O(C.sub.1-4
alkyl), C(.dbd.O)O(C.sub.1-4 haloalkyl), CH.sub.2C(.dbd.O)OH,
CH.sub.2C(.dbd.O)O(C.sub.1-4 alkyl), C(.dbd.O)NH.sub.2,
C(.dbd.O)NH(C.sub.1-4 alkyl), C(.dbd.O)N(C.sub.1-4 alkyl).sub.2,
and --C(.dbd.O)NH(C.sub.1-4 alkoxy);
[0038] R.sup.15 is H or C.sub.1-6 alkyl;
[0039] n, at each occurrence, is an integer independently selected
from 0, 1, 2, 3, and 4; and
[0040] p, at each occurrence, is an integer independently selected
from 0, 1, and 2.
[0041] In another aspect, the present invention provides compounds
of Formula (I) or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, wherein:
[0042] ring A is independently selected from a 6-membered aryl and
a 5- to 6-membered heterocycle, wherein said aryl and heterocycle
are optionally substituted with, where valence allows, one or more
R.sup.4;
[0043] ring B is a 5- to 10-membered heterocycle optionally
substituted with, where valence allows, one or more R.sup.3;
[0044] G.sup.1 is independently selected from a C.sub.3-10
carbocycle and a 5- to 10-membered heterocycle, wherein said
carbocycle and heterocycle are optionally substituted with, where
valence allows, one or more R.sup.8;
[0045] X is independently selected from C.sub.4-8 alkylene and
C.sub.4-8 alkenylene, wherein said alkylene and alkenylene are
substituted with R.sup.1 and R.sup.2; alternatively one or more of
the carbon atoms of said alkylene and alkenylene may be replaced by
O, C.dbd.O, S(.dbd.O).sub.p, S(.dbd.O).sub.pNH, NH, and N(C.sub.1-4
alkyl);
[0046] Y is independently selected from --CR.sup.13NH--,
--NHC(.dbd.O)--, --C(.dbd.O)NH--, --S(.dbd.O).sub.pNH--,
--NHS(.dbd.O).sub.p--, and C.sub.1-2 alkylene;
[0047] R.sup.1 and R.sup.2 are independently selected from H,
halogen, haloalkyl, C.sub.1-6 alkyl (optionally substituted with
R.sup.6), hydroxyl, and alkoxy (optionally substituted with
R.sup.6), and C.sub.3-6 cycloalkyl optionally substituted with
R.sup.6; optionally, when R.sup.1 and R.sup.2 are attached to the
same carbon atom, together they form an oxo group or C.sub.3-6
cycloalkyl; optionally, when R.sup.1 and R.sup.2 are attached to
carbon atoms adjacent to each other, together they form a bond or a
carbocycle;
[0048] R.sup.3 is independently selected from H, NO.sub.2, .dbd.O,
halogen, haloalkyl, C.sub.1-4 alkyl (optionally substituted with
R.sup.6), C.sub.2-4 alkenyl (optionally substituted with R.sup.6),
C.sub.2-4 alkynyl (optionally substituted with R.sup.6), CN,
--(CH.sub.2).sub.n--OR.sup.5, --(CH.sub.2).sub.n--NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(.dbd.O)R.sup.5,
--(CH.sub.2).sub.n--C(.dbd.O)OR.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(.dbd.O)OR.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(.dbd.O)R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(N--CN)NHR.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(NH)NHR.sup.5,
--(CH.sub.2).sub.n--N.dbd.CR.sup.9NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(.dbd.O)NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(.dbd.O)NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(.dbd.S)NR.sup.9C(.dbd.O)R.sup.5,
--(CH.sub.2).sub.n--S(.dbd.O).sub.pC.sub.1-6 alkyl optionally
substituted with R.sup.11,
--(CH.sub.2).sub.n--S(.dbd.O).sub.pNR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9S(.dbd.O).sub.pNR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9S(.dbd.O).sub.pC.sub.1-6 alkyl
optionally substituted with R.sup.11,
--(CH.sub.2).sub.n--C.sub.3-10 carbocycle and --(CH.sub.2).sub.n-4-
to 10-membered heterocycle, wherein said carbocycle and heterocycle
are optionally substituted with R.sup.6; optionally, two adjacent
R.sup.3 groups on the carbocycle and heterocycle may form a ring
optionally substituted with R.sup.6;
[0049] R.sup.4 is independently selected from H, OH, NH.sub.2,
halogen, CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4
alkoxy, --CH.sub.2OH, --C(.dbd.O)OH, --CH.sub.2C(.dbd.O)OH,
--CO.sub.2(C.sub.1-4 alkyl), --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NH(C.sub.1-4 alkyl), --C(.dbd.O)N(C.sub.1-4
alkyl).sub.2, --S(.dbd.O).sub.2C.sub.1-4 alkyl,
S(.dbd.O).sub.2NH.sub.2, C.sub.3-6 cycloalkyl, aryl, and 5- to
6-membered heterocycle, wherein said cycloalkyl, aryl and
heterocycle are optionally substituted with R.sup.6;
[0050] R.sup.5 is independently selected from H, C.sub.1-4 alkyl
(optionally substituted with halogen, hydroxyl, alkoxy, carboxy,
alkoxycarbonyl, amino, substituted amino),
--(CH.sub.2).sub.n--C.sub.3-10 carbocycle and --(CH.sub.2).sub.n-4-
to 10-membered heterocycle, wherein said carbocycle and heterocycle
are optionally substituted with R.sup.6; alternatively, R.sup.5 and
R.sup.5 together with the nitrogen atom to which they are both
attached form a heterocyclic ring optionally substituted with
R.sup.6;
[0051] R.sup.6 is independently selected from H,
--(CH.sub.2).sub.n--OH, .dbd.O, --(CH.sub.2).sub.nNH.sub.2,
--(CH.sub.2).sub.nCN, halogen, C.sub.1-6 alkyl,
--(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--C.sub.3-10 carbocycle, --(CH.sub.2).sub.n-4- to
10-membered heterocycle, and --O-4- to 10-membered heterocycle,
wherein said carbocycle and heterocycle are optionally substituted
with R.sup.10;
[0052] R.sup.7 is independently selected from H, hydroxyl, alkoxy,
halogen, amino, and C.sub.1-3 alkyl;
[0053] R.sup.8 is independently selected from H, halogen, CN,
NH.sub.2, C.sub.1-6 alkyl, haloalkyl, haloalkylcarbonylamine,
alkylcarbonyl, hydroxyl, alkoxy, haloalkoxy,
--(CH.sub.2).sub.n-aryl, --(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl,
and --(CH.sub.2).sub.n-4- to 6-membered heterocycle, wherein said
aryl, cycloalkyl, and heterocycle are optionally substituted with
R.sup.10;
[0054] alternatively, two adjacent R.sup.8 groups form a
heterocyclic ring optionally substituted with R.sup.10;
[0055] R.sup.9 is H or C.sub.1-6 alkyl;
[0056] R.sup.10 is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, --(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl
(optionally substituted with R.sup.11), --(CH.sub.2).sub.n--O-4- to
10-membered heterocycle (optionally substituted with R.sup.11),
halogen, CN, NO.sub.2, .dbd.O, C(.dbd.O)NR.sup.12R.sup.12,
C(.dbd.O)OH, Si(C.sub.1-4 alkyl).sub.3,
--(CH.sub.2).sub.n--OR.sup.12,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12, and C(.dbd.NOH)NH.sub.2;
[0057] R.sup.11, at each occurrence, is independently selected from
H, halogen, C.sub.1-5 alkyl, --(CH.sub.2).sub.n--OH, C.sub.3-6
cycloalkyl, phenyl, and heterocycle;
[0058] R.sup.12, at each occurrence, is independently selected from
H, C.sub.1-5 alkyl, C.sub.3-6 cycloalkyl, phenyl, and heterocycle,
or R.sup.12 and R.sup.12 together with the nitrogen atom to which
they are both attached form a heterocyclic ring optionally
substituted with C.sub.1-4alkyl;
[0059] R.sup.13 is, independently at each occurrence, selected from
H, halogen, C.sub.1-4 haloalkyl, CO.sub.2H, CO.sub.2(C.sub.1-4
alkyl), CO.sub.2(CH.sub.2).sub.2O(C.sub.1-4 alkyl),
CO.sub.2(C.sub.1-4 haloalkyl),
CO.sub.2(CH.sub.2).sub.2SO.sub.2(C.sub.1-4 alkyl),
CH.sub.2CO.sub.2H, CH.sub.2CO.sub.2(C.sub.1-4 alkyl), CONH.sub.2,
CONH(C.sub.1-4 alkyl), CON(C.sub.1-4 alkyl).sub.2, --CONH(C.sub.1-4
alkoxy), --CO.sub.2(CH.sub.2).sub.2O(C.sub.1-4 alkyl),
--CO.sub.2(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--CONH(CH.sub.2).sub.2O(C.sub.1-4 alkyl),
--CONH(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2, --CON(C.sub.1-4
alkyl)(CH.sub.2).sub.2O(C.sub.1-4 alkyl), --CON(C.sub.1-4
alkyl)(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkyl,
--CONHBn, --CONH(OBn), --(CO).sub.0-1(CH.sub.2).sub.0-3--C.sub.3-6
carbocycle, and
--(CH.sub.2).sub.0-1--(CO).sub.0-1--(V).sub.0-1--(CH.sub.2).sub.0-2-(4-
to 6-membered heterocycle comprising carbon atoms and 1-4
heteroatoms selected from N, NH, N(C.sub.1-4 alkyl), O, and
S(O).sub.p), wherein said carbocycle and heterocycle are
substituted with 0-2 R.sup.14;
[0060] R.sup.14 is, independently at each occurrence, selected from
the group consisting of: halogen, OH, CHF.sub.2, CF.sub.3,
C.sub.1-4 alkoxy, CH.sub.2OH, CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl),
CONH.sub.2, and C.sub.1-4 alkyl;
[0061] V is independently selected from O, NH and N(C.sub.1-4
alkyl);
[0062] n, at each occurrence, is an integer independently selected
from 0, 1, 2, 3, and 4; and
[0063] p, at each occurrence, is an integer independently selected
from 0, 1, and 2.
[0064] In another aspect, the present invention provides compounds
of Formula (I) or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, wherein:
[0065] ring A is independently selected from a 6-membered aryl and
a 5- to 6-membered heterocycle, wherein said aryl and heterocycle
are optionally substituted with, where valence allows, one or more
R.sup.4;
[0066] ring B is a 5- to 10-membered heterocycle optionally
substituted with, where valence allows, one or more R.sup.3;
[0067] G.sup.1 is independently selected from a C.sub.3-10
carbocycle and a 5- to 10-membered heterocycle, wherein said
carbocycle and heterocycle are optionally substituted with, where
valence allows, one or more R.sup.8;
[0068] X is independently selected from C.sub.4-8 alkylene and
C.sub.4-8 alkenylene, wherein said alkylene and alkenylene are
substituted with R.sup.1 and R.sup.2; alternatively one or more of
the carbon atoms of said alkylene and alkenylene may be replaced by
O, C.dbd.O, S(O).sub.p, S(O).sub.pNH, NH, and N(C.sub.1-4
alkyl);
[0069] Y is independently selected from --NH--C(O)-- and
--C(O)--NH--;
[0070] R.sup.1 and R.sup.2 are independently selected from H,
halogen, haloalkyl, C.sub.1-6 alkyl (optionally substituted with
R.sup.6), hydroxyl, and alkoxy (optionally substituted with
R.sup.6), and C.sub.3-6 cycloalkyl optionally substituted with
R.sup.6; optionally, when R.sup.1 and R.sup.2 are attached to the
same carbon atom, together they form an oxo group or
C.sub.3-6cycloalkyl;
optionally, when R.sup.1 and R.sup.2 are attached to carbon atoms
adjacent to each other, together they form a bond or a
carbocycle;
[0071] R.sup.3 is independently selected from H, NO.sub.2, .dbd.O,
halogen, haloalkyl, C.sub.1-4alkyl (optionally substituted with
R.sup.6), C.sub.2-4alkenyl (optionally substituted with R.sup.6),
C.sub.2-4alkynyl (optionally substituted with R.sup.6), CN,
--(CH.sub.2).sub.n--OR.sup.5, --(CH.sub.2).sub.n--NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(O)OR.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(O)OR.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(O)R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(N--CN)NHR.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(NH)NHR.sup.5,
--(CH.sub.2).sub.n--N.dbd.CR.sup.9NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(O)NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(O)NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(S)NR.sup.9C(O)R.sup.5,
--(CH.sub.2).sub.n--S(O).sub.pR.sup.12,
--(CH.sub.2).sub.n--S(O).sub.pNR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9S(O).sub.pNR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9S(O).sub.pR.sup.12,
--(CH.sub.2).sub.n--C.sub.3-10 carbocycle and --(CH.sub.2).sub.n-4-
to 10-membered heterocycle, wherein said carbocycle and heterocycle
are optionally substituted with R.sup.6; optionally, two adjacent
R.sup.3 groups on the carbocycle and heterocycle may form a ring
optionally substituted with R.sup.6;
[0072] R.sup.4 is independently selected from H, OH, NH.sub.2,
halogen, CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4
alkoxy, --CH.sub.2OH, --CO.sub.2H, --CH.sub.2CO.sub.2H,
--CO.sub.2(C.sub.1-4 alkyl), --C(O)NH.sub.2, --C(O)NH(C.sub.1-4
alkyl), --C(O)N(C.sub.1-4 alkyl).sub.2, S(O).sub.2NH.sub.2,
C.sub.3-6 cycloalkyl, aryl, and 5- to 6-membered heterocycle,
wherein said cycloalkyl, aryl and heterocycle are optionally
substituted with R.sup.6;
[0073] R.sup.5 is independently selected from H, C.sub.1-4 alkyl
(optionally substituted with halogen, hydroxyl, alkoxy, carboxy,
alkoxycarbonyl, amino, substituted amino),
--(CH.sub.2).sub.n--C.sub.3-10 carbocycle and --(CH.sub.2).sub.n-4-
to 10-membered heterocycle, wherein said carbocycle and heterocycle
are optionally substituted with R.sup.6; alternatively, R.sup.5 and
R.sup.5 together with the nitrogen atom to which they are both
attached form a heterocyclic ring optionally substituted with
R.sup.6;
[0074] R.sup.6 is independently selected from H,
--(CH.sub.2).sub.n--OH, .dbd.O, --(CH.sub.2).sub.nNH.sub.2,
--(CH.sub.2).sub.nCN, halogen, C.sub.1-6 alkyl,
--(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--C.sub.3-10 carbocycle, --(CH.sub.2).sub.n-4- to
10-membered heterocycle, and --O-4- to 10-membered heterocycle,
wherein said carbocycle and heterocycle are optionally substituted
with R.sup.10;
[0075] R.sup.7 is independently selected from H, hydroxyl, alkoxy,
halogen, amino, and C.sub.1-3 alkyl;
[0076] R.sup.8 is independently selected from H, halogen, CN,
NH.sub.2, C.sub.1-6 alkyl, haloalkyl, haloalkylcarbonylamine,
alkylcarbonyl, alkoxy, haloalkoxy, --(CH.sub.2).sub.n-aryl,
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl, and --(CH.sub.2).sub.n-4-
to 6-membered heterocycle;
[0077] R.sup.9 is H or C.sub.1-6 alkyl;
[0078] R.sup.10 is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, --(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl
(optionally substituted with R.sup.11), --O-4- to 10-membered
heterocycle (optionally substituted with R.sup.11), F, Cl, Br, CN,
NO.sub.2, .dbd.O, CO.sub.2H, --(CH.sub.2).sub.n--OC.sub.1-5 alkyl,
--(CH.sub.2).sub.n--OR.sup.11, and
--(CH.sub.2).sub.n--NR.sup.11R.sup.11;
[0079] R.sup.11, at each occurrence, is independently selected from
H, C.sub.1-5 alkyl, --(CH.sub.2).sub.n--OH, C.sub.3-6 cycloalkyl,
and phenyl, or R.sup.11 and R.sup.11 together with the nitrogen
atom to which they are both attached form a heterocyclic ring
optionally substituted with C.sub.1-4alkyl;
[0080] R.sup.12 is C.sub.1-6 alkyl optionally substituted with
R.sup.11;
[0081] n, at each occurrence, is an integer independently selected
from 0, 1, 2, 3, and 4; and
[0082] p, at each occurrence, is an integer independently selected
from 0, 1, and 2.
[0083] In another aspect, the present invention provides compounds
of Formula (II):
##STR00003##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0084] ring A is independently selected from a 6-membered aryl and
a 5- to 6-membered heterocycle, wherein said aryl and heterocycle
are substituted with 1-4 R.sup.4;
[0085] ring B is a 5- to 10-membered heterocycle substituted with
1-4 R.sup.3;
[0086] G.sup.1 is independently selected from a C.sub.3-10
carbocycle and a 5- to 10-membered heterocycle, wherein said
carbocycle and heterocycle are substituted with 1-4 R.sup.8;
[0087] Y is independently selected from --NH--C(O)-- and
--C(O)--NH--;
[0088] R.sup.1 and R.sup.2 are independently selected from H,
halogen, haloalkyl, C.sub.1-4 alkyl (optionally substituted with
R.sup.6), hydroxyl, and alkoxy (optionally substituted with
R.sup.6), and C.sub.3-5 cycloalkyl optionally substituted with
R.sup.6;
[0089] R.sup.3 is independently selected from H, .dbd.O, halogen,
haloalkyl, C.sub.1-4alkyl (optionally substituted with R.sup.6),
C.sub.2-4 alkenyl (optionally substituted with R.sup.6), C.sub.2-4
alkynyl (optionally substituted with R.sup.6), CN, NO.sub.2,
--(CH.sub.2).sub.n--OR.sup.5, --(CH.sub.2).sub.n--NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(O)OR.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(O)OR.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(O)R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(N--CN)NHR.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(NH)NHR.sup.5,
--(CH.sub.2).sub.n--N.dbd.CR.sup.9NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(O)NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(O)NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9C(S)NR.sup.9C(O)R.sup.5,
--(CH.sub.2).sub.n--S(O).sub.pR.sup.12,
--(CH.sub.2).sub.n--S(O).sub.pNR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9S(O).sub.pNR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NR.sup.9S(O).sub.pR.sup.12,
--(CH.sub.2).sub.n--C.sub.3-10 carbocycle and --(CH.sub.2).sub.n-4-
to 10-membered heterocycle, wherein said carbocycle and heterocycle
are optionally substituted with R.sup.6; optionally, two adjacent
R.sup.3 groups on the carbocycle and heterocycle may form a ring
optionally substituted with R.sup.6;
[0090] R.sup.4 is independently selected from H, OH, halogen, CN,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy,
--C(O)NH.sub.2, --C(O)NH(C.sub.1-4 alkyl), --C(O)N(C.sub.1-4
alkyl).sub.2, C.sub.3-6 cycloalkyl, aryl, and 5- to 6-membered
heterocycle, wherein said cycloalkyl, aryl and heterocycle are
optionally substituted with R.sup.6;
[0091] R.sup.5 is independently selected from H, C.sub.1-4 alkyl
(optionally substituted with halogen, hydroxyl, alkoxy, carboxy,
alkoxycarbonyl, amino, substituted amino), C.sub.3-10 carbocycle
and 4- to 10-membered heterocycle, wherein said carbocycle and
heterocycle are optionally substituted with R.sup.6; alternatively,
R.sup.5 and R.sup.5 together with the nitrogen atom to which they
are both attached form a heterocyclic ring optionally substituted
with R.sup.6;
[0092] R.sup.6 is independently selected from OH, .dbd.O,
--(CH.sub.2).sub.nNH.sub.2, --(CH.sub.2).sub.nCN, halogen,
C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--C.sub.3-10 carbocycle, --(CH.sub.2).sub.n-4- to
10-membered heterocycle, and --(CH.sub.2).sub.n-4- to 10-membered
heterocycle, wherein said carbocycle and heterocycle are optionally
substituted with R.sup.10;
[0093] R.sup.7 is independently selected from H, hydroxyl, alkoxy,
halogen, methyl, ethyl, and isopropyl;
[0094] R.sup.8 is independently selected from H, halogen, CN,
NH.sub.2, C.sub.1-6 alkyl, haloalkyl, alkylcarbonyl, alkoxy,
haloalkoxy, --(CH.sub.2).sub.n-aryl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, and --(CH.sub.2).sub.n-4- to 6-membered
heterocycle;
[0095] R.sup.9 is H or C.sub.1-6 alkyl;
[0096] R.sup.10 is independently selected from C.sub.1-6 alkyl
(optionally substituted with R.sup.11), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, --(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl, --O-4-
to 10-membered heterocycle (optionally substituted with R.sup.11),
F, Cl, Br, CN, NO.sub.2, .dbd.O, CO.sub.2H,
--(CH.sub.2).sub.n--OC.sub.1-5 alkyl,
--(CH.sub.2).sub.n--OR.sup.11, and
--(CH.sub.2).sub.n--NR.sup.11R.sup.11;
[0097] R.sup.11, at each occurrence, is independently selected from
H, C.sub.1-5 alkyl, --(CH.sub.2).sub.n--OH, C.sub.3-6 cycloalkyl,
and phenyl, or R.sup.11 and R.sup.11 together with the nitrogen
atom to which they are both attached form a heterocyclic ring
optionally substituted with C.sub.1-4alkyl;
[0098] R.sup.12 is C.sub.1-6 alkyl optionally substituted with
R.sup.11;
[0099] n, at each occurrence, is an integer independently selected
from 0, 1, 2, 3, and 4; and
[0100] p, at each occurrence, is an integer independently selected
from 0, 1, and 2.
[0101] In another aspect, the present invention provides compounds
of Formula (II), or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, wherein:
[0102] ring A is independently selected from
##STR00004##
[0103] ring B is
##STR00005##
[0104] ---- is an optional bond;
[0105] G.sup.1 is independently selected from
##STR00006##
[0106] Y is --C(O)NH--;
[0107] R.sup.1 and R.sup.2 are independently selected from H and
C.sub.1-4 alkyl;
[0108] R.sup.3 is independently selected from H, F, C.sub.1-4
alkyl, haloalkyl, and --NHC(O)OC.sub.1-4 alkyl; provided only one
R.sup.3 is present on the ring, and
[0109] R.sup.4 is independently selected from H, and C.sub.1-4
alkyl; and
[0110] R.sup.7 is H.
[0111] In another aspect, the present invention provides compounds
of Formula (IIa):
##STR00007##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0112] ring A is independently selected from 6-membered aryl and 5-
to 6-membered heterocyclyl;
[0113] ring B is 5- to 10-membered heterocyclyl or 5- to
10-membered heterocyclyl comprising carbon atoms and 1-4
heteroatoms selected from N, NR.sup.3c, O, and S(O).sub.p;
[0114] G.sup.1 is independently selected from C.sub.3-6 carbocyclyl
and 5- to 10-membered heterocyclyl, wherein said carbocyclyl and
heterocyclyl are substituted with 1-4 R.sup.8;
[0115] W is independently selected from (CR.sup.1R.sup.2).sub.1-2,
O, NH, and N(C.sub.1-4 alkyl);
[0116] Y is independently selected from --CR.sup.13NH--,
--NHC(.dbd.O)-- and --C(.dbd.O)NH--;
[0117] R.sup.1 and R.sup.2 are independently selected from H, D,
halogen, haloalkyl, C.sub.1-4 alkyl (optionally substituted with
R.sup.6), hydroxyl, and alkoxy (optionally substituted with
R.sup.6), and C.sub.3-5 cycloalkyl optionally substituted with
R.sup.6;
[0118] R.sup.3 is independently selected from H, halogen, C.sub.1-4
alkyl (optionally substituted with R.sup.6), CN,
--(CH.sub.2).sub.n--OR.sup.5, --(CH.sub.2).sub.n--NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(.dbd.O)R.sup.5, and
--(CH.sub.2).sub.n--C(.dbd.O)OR.sup.5;
[0119] R.sup.3c is independently selected from H, haloalkyl,
C.sub.1-4 alkyl (optionally substituted with R.sup.6),
--(CH.sub.2).sub.1-2--OH, C(.dbd.O)C.sub.1-4 alkyl,
--(CH.sub.2).sub.1-2--C(.dbd.O)OH, --C(.dbd.O)OC.sub.1-4 alkyl,
S(.dbd.O).sub.pC.sub.1-6 alkyl, --(CH.sub.2).sub.n--C.sub.3-10
carbocyclyl and --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl,
wherein said carbocyclyl and heterocyclyl are optionally
substituted with R.sup.6;
[0120] R.sup.4 is independently selected from H, OH, halogen, CN,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-4 alkyl),
--C(.dbd.O)N(C.sub.1-4 alkyl).sub.2, C.sub.3-6 cycloalkyl, aryl,
and 5- to 6-membered heterocyclyl, wherein said cycloalkyl, aryl
and heterocyclyl are optionally substituted with R.sup.6;
[0121] R.sup.5 is independently selected from H, C.sub.1-4 alkyl
(optionally substituted with halogen, hydroxyl, alkoxy, carboxy,
alkoxycarbonyl, amino, substituted amino), C.sub.3-10 carbocyclyl
and 4- to 10-membered heterocyclyl, wherein said carbocyclyl and
heterocyclyl are optionally substituted with R.sup.6;
[0122] R.sup.6 is independently selected from H, OH, .dbd.O,
--(CH.sub.2).sub.nNH.sub.2, --(CH.sub.2).sub.nCN, halogen,
C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--C(.dbd.O)NH.sub.2,
--(CH.sub.2).sub.n--C.sub.3-10 carbocyclyl, --(CH.sub.2).sub.n-4-
to 10-membered heterocyclyl, and --(CH.sub.2).sub.n-4- to
10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl
are optionally substituted with R.sup.10;
[0123] R.sup.7 is independently selected from H, hydroxyl, halogen,
C.sub.1-2haloalkyl, and C.sub.1-2alkyl;
[0124] R.sup.8 is independently selected from H, halogen, CN,
NH.sub.2, C.sub.1-6 alkyl, haloalkyl, haloalkylcarbonylamino,
arylamino, heteroarylamino, hydroxycarbonyl,
haloalkylaminocarbonyl, arylalkylcarbonyl, alkylcarbonyl, alkoxy,
haloalkoxy, --(CH.sub.2).sub.n-aryl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, and --(CH.sub.2).sub.n-4- to 12-membered heterocyclyl,
wherein said aryl, cycloalkyl, and heterocyclyl are optionally
substituted with R.sup.10; alternatively, two adjacent R.sup.8
groups and G.sub.1 form a fused heterocyclic group selected
from
##STR00008##
[0125] R.sup.9 is H or C.sub.1-6 alkyl;
[0126] R.sup.10 is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl (optionally substituted with R.sup.11),
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl (optionally substituted
with R.sup.11), --(CH.sub.2).sub.n--O-4- to 10-membered
heterocyclyl (optionally substituted with R.sup.11), F, Cl, Br,
--(CH.sub.2).sub.nCN, NO.sub.2, .dbd.O, C(.dbd.O)NR.sup.12R.sup.12,
--(CH.sub.2).sub.nC(.dbd.O)OR.sup.12, Si(C.sub.1-4 alkyl).sub.3,
--(CH.sub.2).sub.n--OR.sup.12,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12, and
--S(.dbd.O).sub.pC.sub.1-6 alkyl, NR.sup.12S(.dbd.O).sub.pC.sub.1-6
alkyl, and S(.dbd.O).sub.pNR.sup.12R.sup.12;
[0127] R.sup.10' is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), aryl,
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl (optionally substituted
with R.sup.11), and --(CH.sub.2).sub.n--O-4- to 10-membered
heterocyclyl (optionally substituted with R.sup.11);
[0128] R.sup.11, at each occurrence, is independently selected from
H, halogen, C.sub.1-5 alkyl, --(CH.sub.2).sub.n--OH, C.sub.3-6
cycloalkyl, and phenyl;
[0129] R.sup.12, at each occurrence, is independently selected from
H, C.sub.1-5 alkyl optionally substituted with R.sup.11, C.sub.3-6
cycloalkyl, phenyl, and heterocyclyl, or R.sup.12 and R.sup.12
together with the nitrogen atom to which they are both attached
form a heterocyclic ring optionally substituted with
C.sub.1-4alkyl;
[0130] R.sup.13 is, independently at each occurrence, selected from
H, CF.sub.3, C(.dbd.O)OH, C(.dbd.O)O(C.sub.1-4 alkyl), and
--C(.dbd.O)NH.sub.2(C.sub.1-4 alkoxy);
[0131] n, at each occurrence, is an integer independently selected
from 0, 1, 2, 3, and 4; and
[0132] p, at each occurrence, is an integer independently selected
from 0, 1, and 2.
[0133] In another aspect, the present invention provides compounds
of Formula (IIb):
##STR00009##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0134] ring A is independently selected from phenyl and 5- to
6-membered heterocyclyl;
[0135] ring B is 5- to 10-membered heterocyclyl or 5- to 6-membered
heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected
from N, NR.sup.3c, O, and S(O).sub.p;
[0136] W is independently selected from (CR.sup.1R.sup.2).sub.1-2,
O, NH, and N(C.sub.1-4 alkyl);
[0137] Y is independently selected from --CH.sub.2NH--,
--NHC(.dbd.O)-- and --C(.dbd.O)NH--;
[0138] G.sup.3 is independently selected from N and CR.sup.8a;
[0139] G.sup.4 is independently selected from N and CR.sup.8e;
[0140] R.sup.1 and R.sup.2 are independently selected from H, D,
halogen, CF.sub.3, C.sub.1-6 alkyl, and hydroxyl;
[0141] R.sup.3 is independently selected from H, halogen,
C.sub.1-4alkyl (optionally substituted with R.sup.6), CN,
--(CH.sub.2).sub.n--OR.sup.5, --(CH.sub.2).sub.n--NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(.dbd.O)R.sup.5, and
--(CH.sub.2).sub.n--C(.dbd.O)OR.sup.5;
[0142] R.sup.3c is independently selected from H, haloalkyl,
C.sub.1-4 alkyl (optionally substituted with R.sup.6),
--(CH.sub.2).sub.1-2--OH, C(.dbd.O)C.sub.1-4 alkyl,
--(CH.sub.2).sub.1-2--C(.dbd.O)OH, --C(.dbd.O)OC.sub.1-4 alkyl,
S(.dbd.O).sub.pC.sub.1-6 alkyl, --(CH.sub.2).sub.n--C.sub.3-10
carbocyclyl and --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl,
wherein said carbocyclyl and heterocyclyl are optionally
substituted with R.sup.6;
[0143] R.sup.4 is independently selected from H, OH, F, Cl, Br,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3, CN, C(.dbd.O)NH.sub.2,
C.sub.3-6 cycloalkyl, aryl, and 5- to 6-membered heterocyclyl,
wherein said cycloalkyl, aryl and heterocyclyl are optionally
substituted with R.sup.6;
[0144] R.sup.5 is independently selected from H, and C.sub.1-4
alkyl optionally substituted with halogen and hydroxyl;
[0145] R.sup.6 is independently selected from H,
--(CH.sub.2).sub.n--OH, .dbd.O, NH.sub.2, --(CH.sub.2).sub.n--CN,
halogen, C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, and
--O--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
cycloalkyl and heterocyclyl are optionally substituted with
R.sup.10;
[0146] R.sup.7 is independently selected from H, F, Cl, Br,
CF.sub.3, and CH.sub.3;
[0147] R.sup.8a is independently selected from H, F, Cl, Br, I,
--(CH.sub.2).sub.nCN, --(CH.sub.2).sub.nNH.sub.2, C.sub.1-2alkyl,
C.sub.1-2haloalkyl, OH, OC.sub.1-2alkyl, OC.sub.1-2haloalkyl,
C(.dbd.O)OH, C(.dbd.O)OC.sub.1-3alkyl, C(.dbd.O)NH.sub.2,
C(.dbd.O)NHC.sub.1-2haloalkyl, C(.dbd.O)NHarylalkyl,
C(.dbd.O)C.sub.1-3alkyl, NHC(.dbd.O)OC.sub.1-2alkyl,
NHC(.dbd.O)C.sub.1-2haloalkyl, NH-aryl, NH-heteroaryl, aryl,
C.sub.3-6 cycloalkyl, and 4- to 12-membered heterocyclyl, wherein
said aryl, cycloalkyl and heterocyclyl is optionally substituted
with R.sup.10;
[0148] R.sup.8b is independently selected from H and F;
[0149] R.sup.8c is independently selected from H, F, Cl, methyl,
ethyl, isopropyl, OCHF.sub.2, and OCH.sub.3;
[0150] R.sup.8d is independently selected from H, F, and Cl;
[0151] R.sup.8e is independently selected from H, F, and Cl;
[0152] R.sup.10 is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl (optionally substituted with R.sup.11),
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl (optionally substituted
with R.sup.11), --(CH.sub.2).sub.n--O-4- to 10-membered
heterocyclyl (optionally substituted with R.sup.11), F, Cl, Br, CN,
NO.sub.2, .dbd.O, CONR.sup.12R.sup.12,
--(CH.sub.2).sub.nC(.dbd.O)OR.sup.12, Si(C.sub.1-4 alkyl).sub.3,
--(CH.sub.2).sub.n--OR.sup.12, and
--(CH.sub.2).sub.n--NR.sup.12R.sup.12, --S(.dbd.O).sub.pC.sub.1-6
alkyl, NR.sup.12S(.dbd.O).sub.pC.sub.1-6 alkyl, and
S(.dbd.O).sub.pNR.sup.12R.sup.12;
[0153] R.sup.11, at each occurrence, is independently selected from
H, halogen, C.sub.1-5 alkyl, --(CH.sub.2).sub.n--OH, C.sub.3-6
cycloalkyl, and phenyl;
[0154] R.sup.12, at each occurrence, is independently selected from
H, C.sub.1-5 alkyl optionally substituted with R.sup.11, C.sub.3-6
cycloalkyl, phenyl, and heterocyclyl, or R.sup.12 and R.sup.12
together with the nitrogen atom to which they are both attached
form a heterocyclic ring optionally substituted with
C.sub.1-4alkyl;
[0155] n, at each occurrence, is an integer independently selected
from 0, 1, and 2; and
[0156] p, at each occurrence, is an integer independently selected
from 0, 1, and 2.
[0157] In another aspect, the present invention provides compounds
of Formula (IIb), or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, wherein:
[0158] ring A is independently selected from phenyl and 5- to
6-membered heterocyclyl;
[0159] ring B is 5- to 6-membered heteroaryl comprising carbon
atoms and 1-4 heteroatoms selected from N and NR.sup.3c;
[0160] W is independently selected from (CR.sup.1R.sup.2).sub.1-2,
O, NH, and N(C.sub.1-4 alkyl); Y is independently selected from
--CH.sub.2NH--, --NHC(.dbd.O)-- and --C(.dbd.O)NH--;
[0161] G.sup.3 is CR.sup.8a;
[0162] G.sup.4 is CR.sup.8e;
[0163] R.sup.1 and R.sup.2 are independently selected from H, D,
halogen, CF.sub.3, C.sub.1-6 alkyl, and hydroxyl;
[0164] R.sup.3 is independently selected from H, halogen,
C.sub.1-4alkyl (optionally substituted with R.sup.6), CN,
--(CH.sub.2).sub.n--OR.sup.5, --(CH.sub.2).sub.n--C(.dbd.O)R.sup.5,
and --(CH.sub.2).sub.n--C(.dbd.O)OR.sup.5;
[0165] R.sup.3c is independently selected from H, haloalkyl,
C.sub.1-4 alkyl (optionally substituted with R.sup.6),
--(CH.sub.2).sub.1-2--OH, C(.dbd.O)C.sub.1-4 alkyl,
--(CH.sub.2).sub.1-2--C(.dbd.O)OH, --C(.dbd.O)OC.sub.1-4 alkyl,
S(.dbd.O).sub.pC.sub.1-6 alkyl, --(CH.sub.2).sub.n--C.sub.3-10
carbocyclyl and --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl,
wherein said carbocyclyl and heterocyclyl are optionally
substituted with R.sup.6;
[0166] R.sup.4 is independently selected from H, OH, F, Cl, Br,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3, CN, C(.dbd.O)NH.sub.2,
C.sub.3-6 cycloalkyl, aryl, and 5- to 6-membered heterocyclyl,
wherein said cycloalkyl, aryl and heterocyclyl are optionally
substituted with R.sup.6;
[0167] R.sup.5 is independently selected from H and C.sub.1-4
alkyl;
[0168] R.sup.6 is independently selected from H,
--(CH.sub.2).sub.n--OH, .dbd.O, NH.sub.2, --(CH.sub.2).sub.n--CN,
halogen, C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, and
--O--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
cycloalkyl and heterocyclyl are optionally substituted with
R.sup.10;
[0169] R.sup.7 is independently selected from H, F, Cl, Br, and
methyl;
[0170] R.sup.8a is independently selected from H, F, Cl, Br, I,
--(CH.sub.2).sub.nCN, --(CH.sub.2).sub.nNH.sub.2,
CH.sub.3CHF.sub.2, CCH.sub.3F.sub.2, CF.sub.3, OH, OCH.sub.3,
OCF.sub.3, OCHF.sub.2, C(.dbd.O)CH.sub.3, C(.dbd.O)OH,
C(.dbd.O)OCH.sub.3, C(.dbd.O)NH.sub.2, C(.dbd.O)NHCH.sub.2CF.sub.3,
C(.dbd.O)NHCH.sub.2Ph, NHC(.dbd.O)OCH.sub.3,
NHC(.dbd.O)CF.sub.3,
##STR00010##
[0171] R.sup.8b is independently selected from H and F;
[0172] R.sup.8c is independently selected from H, F, Cl, methyl,
ethyl, isopropyl, and OCH.sub.3;
[0173] R.sup.8d is independently selected from H, F, and Cl;
[0174] R.sup.8e is independently selected from H, F, and Cl;
[0175] R.sup.10 is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl (optionally substituted with R.sup.11),
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl (optionally substituted
with R.sup.11), --(CH.sub.2).sub.n--O-4- to 10-membered
heterocyclyl (optionally substituted with R.sup.11), F, Cl, Br, CN,
NO.sub.2, .dbd.O, CONR.sup.12R.sup.12,
--(CH.sub.2).sub.n--C(.dbd.O)OR.sup.12, Si(C.sub.1-4 alkyl).sub.3,
--(CH.sub.2).sub.n--OR.sup.12,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12, --S(.dbd.O).sub.pC.sub.1-6
alkyl, NR.sup.12S(.dbd.O).sub.pC.sub.1-6 alkyl, and
S(.dbd.O).sub.pNR.sup.12R.sup.12;
[0176] R.sup.10' is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), aryl,
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl (optionally substituted
with R.sup.11), and --(CH.sub.2).sub.n--O-4- to 10-membered
heterocyclyl (optionally substituted with R.sup.11);
[0177] R.sup.11, at each occurrence, is independently selected from
H, halogen, C.sub.1-5 alkyl, --(CH.sub.2).sub.n--OH, C.sub.3-6
cycloalkyl, and phenyl;
[0178] R.sup.12, at each occurrence, is independently selected from
H, C.sub.1-5 alkyl optionally substituted with R.sup.11, C.sub.3-6
cycloalkyl, phenyl, and heterocyclyl, or R.sup.12 and R.sup.12
together with the nitrogen atom to which they are both attached
form a heterocyclic ring optionally substituted with
C.sub.1-4alkyl;
[0179] n, at each occurrence, is an integer independently selected
from 0, 1, and 2; and
[0180] p, at each occurrence, is an integer independently selected
from 0, 1, and 2.
[0181] In another aspect, the present invention provides compounds
of Formula (IIc):
##STR00011##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0182] ring A is independently selected from phenyl and 5- to
6-membered heterocyclyl;
[0183] ring B is 5- to 6-membered heteroaryl comprising carbon
atoms and 1-3 heteroatoms selected from N and NR.sup.3c;
[0184] W is independently selected from (CR.sup.1R.sup.2).sub.1-2,
O, NH, and N(C.sub.1-4 alkyl);
[0185] Y is independently selected from --CH.sub.2NH--,
--NHC(.dbd.O)-- and --C(.dbd.O)NH--;
[0186] R.sup.1 and R.sup.2 are independently selected from H, D, F,
C.sub.1-4 alkyl, and hydroxyl;
[0187] R.sup.3 is independently selected from H, halogen,
haloalkyl, C.sub.1-4alkyl (optionally substituted with R.sup.6),
and CN;
[0188] R.sup.3c is independently selected from H, haloalkyl,
C.sub.1-4 alkyl (optionally substituted with R.sup.6),
--(CH.sub.2).sub.1-2--OH, C(.dbd.O)C.sub.1-4 alkyl,
--(CH.sub.2).sub.1-2--C(.dbd.O)OH, --C(.dbd.O)OC.sub.1-4 alkyl,
S(.dbd.O).sub.pC.sub.1-6 alkyl, --(CH.sub.2).sub.n--C.sub.3-10
carbocyclyl and --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl,
wherein said carbocyclyl and heterocyclyl are optionally
substituted with R.sup.6;
[0189] R.sup.4 is independently selected from H, OH, F, Cl, Br,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3, CN; C(.dbd.O)NH.sub.2,
C.sub.3-6 cycloalkyl, aryl, and 5- to 6-membered heterocyclyl;
[0190] R.sup.6 is independently selected from H,
--(CH.sub.2).sub.n--OH, .dbd.O, NH.sub.2, --(CH.sub.2).sub.n--CN,
halogen, C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, and
--O--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
cycloalkyl and heterocyclyl are optionally substituted with
R.sup.10;
[0191] R.sup.8b is independently selected from H and F;
[0192] R.sup.8c is independently selected from H, F, Cl, CH.sub.3,
and OCH.sub.3;
[0193] R.sup.10 is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, --(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl
(optionally substituted with R.sup.11), --(CH.sub.2).sub.n--O-4- to
10-membered heterocyclyl (optionally substituted with R.sup.11), F,
Cl, Br, CN, NO.sub.2, .dbd.O, C(.dbd.O)NR.sup.12R.sup.12,
C(.dbd.O)OR.sup.12, Si(C.sub.1-4 alkyl).sub.3,
--(CH.sub.2).sub.n--OR.sup.12,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12, --S(.dbd.O).sub.pC.sub.1-6
alkyl, NR.sup.12S(.dbd.O).sub.pC.sub.1-6 alkyl, and
S(.dbd.O).sub.pNR.sup.12R.sup.12;
[0194] R.sup.11, at each occurrence, is independently selected from
H, halogen, C.sub.1-5 alkyl, --(CH.sub.2).sub.n--OH, C.sub.3-6
cycloalkyl, and phenyl;
[0195] R.sup.12, at each occurrence, is independently selected from
H, C.sub.1-5 alkyl, C.sub.3-6 cycloalkyl, phenyl, and heterocyclyl,
or R.sup.12 and R.sup.12 together with the nitrogen atom to which
they are both attached form a heterocyclic ring optionally
substituted with C.sub.1-4alkyl;
[0196] n, at each occurrence, is an integer independently selected
from 0, 1, and 2; and
[0197] p, at each occurrence, is an integer independently selected
from 0, 1, and 2.
[0198] In another aspect, the present invention provides compounds
of Formula (IId):
##STR00012##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0199] ---- is an optional bond;
[0200] ring A is independently selected from phenyl and 5- to
6-membered heterocyclyl;
[0201] W is independently selected from CHR.sup.1a, O, NH, and
N(C.sub.1-4 alkyl);
[0202] G.sup.5 is independently selected from CH.sub.2 and
NR.sup.3c;
[0203] G.sup.6 is independently selected from CH.sub.2 and
NR.sup.3c;
[0204] provided when G.sup.5 is CH.sub.2, G.sup.6 is NR.sup.3c;
when G.sup.5 is NR.sup.3c, G.sup.6 is CH.sub.2 and only one
R.sup.3c is present on the ring;
[0205] Y is independently selected from --NHC(.dbd.O)-- and
--C(.dbd.O)NH--;
[0206] R.sup.1 is independently selected from H and C.sub.1-4
alkyl;
[0207] R.sup.1a is independently selected from H, D, F, CH.sub.3,
and OH;
[0208] R.sup.2 is independently selected from H, D, and OH;
[0209] R.sup.3c is independently selected from H, haloalkyl,
C.sub.1-4alkyl (optionally substituted with R.sup.6),
--(CH.sub.2).sub.1-2--OH, C(.dbd.O)C.sub.1-4 alkyl,
--(CH.sub.2).sub.1-2--C(.dbd.O)OH, --C(.dbd.O)OC.sub.1-4 alkyl,
S(.dbd.O).sub.pC.sub.1-6 alkyl, phenyl optionally substituted with
R.sup.6, 5- to 6-membered heterocyclyl optionally substituted with
R.sup.6, and 5- to 6-membered heteroaryl optionally substituted
with R.sup.6;
[0210] R.sup.4 is independently selected from H, OH, F, Cl, Br,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3, CN, and
C(.dbd.O)NH.sub.2;
[0211] R.sup.6 is independently selected from H,
--(CH.sub.2).sub.n--OH, .dbd.O, NH.sub.2, --(CH.sub.2).sub.n--CN,
halogen, C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, and
--O--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
cycloalkyl and heterocyclyl are optionally substituted with
R.sup.10;
[0212] R.sup.8b is independently selected from H and F;
[0213] R.sup.8c is independently selected from H, F, Cl, CH.sub.3,
and OCH.sub.3;
[0214] R.sup.10 is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), aryl,
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl (optionally substituted
with R.sup.11), --(CH.sub.2).sub.n--O-4- to 10-membered
heterocyclyl (optionally substituted with R.sup.11), F, Cl, Br, CN,
NO.sub.2, .dbd.O, C(.dbd.O)NR.sup.12R.sup.12, C(.dbd.O)OR.sup.12,
Si(C.sub.1-4 alkyl).sub.3, --(CH.sub.2).sub.n--OR.sup.12, and
--(CH.sub.2).sub.n--NR.sup.12R.sup.12, --S(.dbd.O).sub.pC.sub.1-6
alkyl, NR.sup.12S(.dbd.O).sub.pC.sub.1-6 alkyl, and
S(.dbd.O).sub.pNR.sup.12R.sup.12;
[0215] R.sup.11, at each occurrence, is independently selected from
H, halogen, C.sub.1-5 alkyl, --(CH.sub.2).sub.n--OH, C.sub.3-6
cycloalkyl, and phenyl;
[0216] R.sup.12, at each occurrence, is independently selected from
H, C.sub.1-5 alkyl, C.sub.3-6 cycloalkyl, phenyl, and heterocyclyl,
or R.sup.12 and R.sup.12 together with the nitrogen atom to which
they are both attached form a heterocyclic ring optionally
substituted with C.sub.1-4alkyl;
[0217] n, at each occurrence, is an integer independently selected
from 0, 1, and 2; and
[0218] p, at each occurrence, is an integer independently selected
from 0, 1, and 2.
[0219] In another aspect, the present invention provides compounds
of Formula (IIe):
##STR00013##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0220] ring A is independently selected from
##STR00014##
[0221] R.sup.1 is independently selected from H and C.sub.1-4
alkyl;
[0222] R.sup.1a is independently selected from H, D, F, CH.sub.3,
and OH;
[0223] R.sup.2 is independently selected from H, D, and OH;
[0224] R.sup.3c is independently selected from H, CHF.sub.2,
CD.sub.3, CH.sub.3, CH.sub.2CH.sub.2OH, CH.sub.2C(.dbd.O)OH,
SO.sub.2CH.sub.3, phenyl optionally substituted with R.sup.6, and
5- to 6-membered heteroaryl optionally substituted with
R.sup.6;
[0225] R.sup.4 is independently selected from H, F, and
C(.dbd.O)NH.sub.2;
[0226] R.sup.6 is independently selected from H,
--(CH.sub.2).sub.n--OH, .dbd.O, NH.sub.2, --(CH.sub.2).sub.n--CN,
halogen, C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, and
--O--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
cycloalkyl and heterocyclyl are optionally substituted with
R.sup.10;
[0227] R.sup.8b is independently selected from H and F;
[0228] R.sup.8c is independently selected from H, F, Cl, CH.sub.3,
and OCH.sub.3;
[0229] R.sup.10 is independently selected from H, CF.sub.3,
CHF.sub.2, CH.sub.2F, aryl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl (optionally substituted with R.sup.11), heteroaryl
(optionally substituted with R.sup.11), --(CH.sub.2).sub.n--O-4- to
10-membered heterocyclyl (optionally substituted with R.sup.11), F,
Cl, Br, CN, NO.sub.2, .dbd.O, C(.dbd.O)NR.sup.12R.sup.12,
--(CH.sub.2).sub.n--C(.dbd.O)OR.sup.12, Si(C.sub.1-4 alkyl).sub.3,
--(CH.sub.2).sub.n--OR.sup.12,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12, --S(.dbd.O).sub.pC.sub.1-6
alkyl, NR.sup.12S(.dbd.O).sub.pC.sub.1-6 alkyl, and
S(.dbd.O).sub.pNR.sup.12R.sup.12;
[0230] R.sup.11, at each occurrence, is independently selected from
H, halogen, C.sub.1-5 alkyl, --(CH.sub.2).sub.n--OH, C.sub.3-6
cycloalkyl, and phenyl;
[0231] R.sup.12, at each occurrence, is independently selected from
H, C.sub.1-5 alkyl, C.sub.3-6 cycloalkyl, phenyl, and heterocyclyl,
or R.sup.12 and R.sup.12 together with the nitrogen atom to which
they are both attached form a heterocyclic ring optionally
substituted with C.sub.1-4alkyl; and
[0232] n, at each occurrence, is an integer independently selected
from 0, 1, and 2.
[0233] In another aspect, the present invention provides compounds
of Formula (IIf):
##STR00015##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0234] ring A is independently selected from
##STR00016##
[0235] R.sup.1 is independently selected from H and C.sub.1-4
alkyl;
[0236] R.sup.1a is independently selected from H, D, F, CH.sub.3,
and OH;
[0237] R.sup.2 is independently selected from H, D, and OH;
[0238] R.sup.3c is independently selected from H, CHF.sub.2,
CD.sub.3, CH.sub.3, SO.sub.2CH.sub.3, phenyl optionally substituted
with R.sup.6, and 5- to 6-membered heterocyclyl optionally
substituted with R.sup.6, 5- to 6-membered heteroaryl optionally
substituted with R.sup.6;
[0239] R.sup.4 is independently selected from H and F;
[0240] R.sup.6 is independently selected from OH, .dbd.O, NH.sub.2,
CN, halogen, C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, and
--O--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
cycloalkyl and heterocyclyl are optionally substituted with
R.sup.10;
[0241] R.sup.8b is independently selected from H and F;
[0242] R.sup.8c is independently selected from H, F, Cl, CH.sub.3,
and OCH.sub.3;
[0243] R.sup.10 is independently selected from H, CF.sub.3,
CHF.sub.2, C(CH.sub.3).sub.2OH, aryl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl (optionally substituted with R.sup.11),
--(CH.sub.2).sub.n--O-4- to 10-membered heterocyclyl (optionally
substituted with R.sup.11), F, Cl, Br, CN, NO.sub.2, .dbd.O,
C(.dbd.O)NR.sup.12R.sup.12, C(.dbd.O)OR.sup.12, Si(C.sub.1-4
alkyl).sub.3, --(CH.sub.2).sub.n--OR.sup.12,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12, --S(.dbd.O).sub.pC.sub.1-6
alkyl, NR.sup.12S(.dbd.O).sub.pC.sub.1-6 alkyl, and
S(.dbd.O).sub.pNR.sup.12R.sup.12;
[0244] R.sup.11, at each occurrence, is independently selected from
H, halogen, C.sub.1-5 alkyl, --(CH.sub.2).sub.n--OH, C.sub.3-6
cycloalkyl, and phenyl;
[0245] R.sup.12, at each occurrence, is independently selected from
H, C.sub.1-5 alkyl, C.sub.3-6 cycloalkyl, phenyl, and heterocyclyl,
or R.sup.12 and R.sup.12 together with the nitrogen atom to which
they are both attached form a heterocyclic ring optionally
substituted with C.sub.1-4alkyl; and
[0246] n, at each occurrence, is an integer independently selected
from 0, 1, and 2.
[0247] In another aspect, the present invention provides compounds
of Formula (IIf): or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, wherein:
[0248] ring A is independently selected from
##STR00017##
[0249] R.sup.1 is independently selected from H and C.sub.1-4
alkyl;
[0250] R.sup.1a is independently selected from H, D, F, CH.sub.3,
and OH;
[0251] R.sup.2 is independently selected from H, D, and OH;
[0252] R.sup.3a is independently selected from H, CHF.sub.2,
CD.sub.3, CH.sub.3, SO.sub.2CH.sub.3, phenyl optionally substituted
with R.sup.6, and heterocyclyl selected from
##STR00018##
[0253] R.sup.4 is independently selected from H and F;
[0254] R.sup.6 is independently selected from H, OH, OC.sub.1-4
alkyl, CN, F, Cl, and C.sub.1-4 alkyl;
[0255] R.sup.8b is independently selected from H and F;
[0256] R.sup.8c is independently selected from H, F, Cl, CH.sub.3,
and OCH.sub.3;
[0257] R.sup.10 is independently selected from H, CF.sub.3,
CHF.sub.2, C(CH.sub.3).sub.2OH, aryl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl (optionally substituted with R.sup.11),
--(CH.sub.2).sub.n--O-4- to 10-membered heterocyclyl (optionally
substituted with R.sup.11), F, Cl, Br, CN, NO.sub.2, .dbd.O,
C(.dbd.O)NR.sup.12R.sup.12, C(.dbd.O)OR.sup.12, Si(C.sub.1-4
alkyl).sub.3, --(CH.sub.2).sub.n--OR.sup.12,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12, --S(.dbd.O).sub.pC.sub.1-6
alkyl, NR.sup.12S(.dbd.O).sub.pC.sub.1-6 alkyl, and
S(.dbd.O).sub.pNR.sup.12R.sup.12;
[0258] R.sup.11, at each occurrence, is independently selected from
H, halogen, C.sub.1-5 alkyl, --(CH.sub.2).sub.n--OH, C.sub.3-6
cycloalkyl, and phenyl;
[0259] R.sup.12, at each occurrence, is independently selected from
H, C.sub.1-5 alkyl, C.sub.3-6 cycloalkyl, phenyl, and heterocyclyl,
or R.sup.12 and R.sup.12 together with the nitrogen atom to which
they are both attached form a heterocyclic ring optionally
substituted with C.sub.1-4alkyl; and
[0260] n, at each occurrence, is an integer independently selected
from 0, 1, and 2.
[0261] In another aspect, the present invention provides compounds
of Formula (IIg):
##STR00019##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0262] ring A is independently selected from
##STR00020##
[0263] R.sup.1 is independently selected from H and C.sub.1-4
alkyl;
[0264] R.sup.1a is independently selected from H, F, CH.sub.3, and
OH;
[0265] R.sup.2 is independently selected from H and OH;
[0266] R.sup.3c is independently selected from H, CHF.sub.2,
CD.sub.3, and CH.sub.3;
[0267] R.sup.4 is independently selected from H and F;
[0268] R.sup.8b is independently selected from H and F;
[0269] R.sup.8c is independently selected from H, F, Cl, CH.sub.3,
and OCH.sub.3;
[0270] R.sup.10 is independently selected from H, CF.sub.3,
CHF.sub.2, aryl, --(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl
(optionally substituted with R.sup.11), --(CH.sub.2).sub.n--O-4- to
10-membered heterocyclyl (optionally substituted with R.sup.11), F,
Cl, Br, CN, NO.sub.2, .dbd.O, C(.dbd.O)NR.sup.12R.sup.12,
C(.dbd.O)OR.sup.12, Si(C.sub.1-4 alkyl).sub.3,
--(CH.sub.2).sub.n--OR.sup.12,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12, --S(.dbd.O).sub.pC.sub.1-6
alkyl, NR.sup.12S(.dbd.O).sub.pC.sub.1-6 alkyl, and
S(.dbd.O).sub.pNR.sup.12R.sup.12;
[0271] R.sup.11, at each occurrence, is independently selected from
H, halogen, C.sub.1-5 alkyl, --(CH.sub.2).sub.n--OH, C.sub.3-6
cycloalkyl, and phenyl;
[0272] R.sup.12, at each occurrence, is independently selected from
H, C.sub.1-5 alkyl, C.sub.3-6 cycloalkyl, phenyl, and heterocyclyl,
or R.sup.12 and R.sup.12 together with the nitrogen atom to which
they are both attached form a heterocyclic ring optionally
substituted with C.sub.1-4alkyl; and
[0273] n, at each occurrence, is an integer independently selected
from 0, 1, and 2.
[0274] In another aspect, the present invention provides compounds
of Formula (IIIa):
##STR00021##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0275] ring A is independently selected from phenyl and a 5- to
6-membered heterocycle;
[0276] G.sup.1 is independently selected from aryl,
C.sub.3-6cycloalkyl and a 5- to 6-membered heterocycle, wherein
said aryl, cycloalkyl and heterocycle are substituted with 1-4
R.sup.8;
[0277] G.sup.2 is N;
[0278] R.sup.1 and R.sup.2 are independently selected from H,
halogen, CF.sub.3, C.sub.1-6 alkyl, and hydroxyl;
[0279] R.sup.3 is independently selected from H, halogen,
haloalkyl, C.sub.1-4alkyl (optionally substituted with R.sup.6),
C.sub.2-4alkenyl (optionally substituted with R.sup.6), CN,
NO.sub.2, --(CH.sub.2).sub.n--OR.sup.5,
--(CH.sub.2).sub.n--NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(.dbd.O)OR.sup.5,
--(CH.sub.2).sub.n--NHC(.dbd.O)OR.sup.5,
--(CH.sub.2).sub.n--NHC(.dbd.O)R.sup.5,
--(CH.sub.2).sub.n--NHC(N--CN)NHR.sup.5,
--(CH.sub.2).sub.n--NHC(NH)NHR.sup.5,
--(CH.sub.2).sub.n--N.dbd.CHNR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NHC(.dbd.O)NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(.dbd.O)NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NHC(S)NR.sup.9C(.dbd.O)R.sup.5,
--(CH.sub.2).sub.n--S(.dbd.O).sub.pC.sub.1-6 alkyl optionally
substituted with R.sup.11,
--(CH.sub.2).sub.n--S(.dbd.O).sub.pNR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NHS(.dbd.O).sub.pNR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NHS(.dbd.O).sub.pC.sub.1-6 alkyl optionally
substituted with R.sup.11, --(CH.sub.2).sub.n--C.sub.3-10
carbocycle and --(CH.sub.2).sub.n-4- to 10-membered heterocycle,
wherein said carbocycle and heterocycle are optionally substituted
with R.sup.6; optionally, two adjacent R.sup.3 groups on the
carbocycle and heterocycle may form a ring optionally substituted
with R.sup.6;
[0280] R.sup.3c is independently selected from H and halogen;
[0281] R.sup.3b is independently selected from H, halogen, methyl,
and CN;
[0282] R.sup.4 is independently selected from H, OH, F, Cl, Br,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3, CN, C.sub.3-6
cycloalkyl, aryl, and 5- to 6-membered heterocycle, wherein said
cycloalkyl, aryl and heterocycle are optionally substituted with
R.sup.6;
[0283] R.sup.5 is independently selected from H, C.sub.1-4 alkyl
(optionally substituted with halogen, hydroxyl, alkoxy, carboxy,
alkoxycarbonyl, amino, substituted amino),
--(CH.sub.2).sub.n--C.sub.3-10 carbocycle and --(CH.sub.2).sub.n-4-
to 10-membered heterocycle, wherein said carbocycle and heterocycle
are optionally substituted with R.sup.6;
[0284] R.sup.6 is independently selected from
--(CH.sub.2).sub.n--OH, .dbd.O, NH.sub.2, --(CH.sub.2).sub.n--CN,
halogen, C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, --(CH.sub.2).sub.n-4- to 10-membered heterocycle, and
--O--(CH.sub.2).sub.n-4- to 10-membered heterocycle, wherein said
cycloalkyl and heterocycle are optionally substituted with
R.sup.10;
[0285] R.sup.7 is independently selected from H, F, Cl, and
methyl;
[0286] R.sup.8 is independently selected from H, halogen, CN,
NH.sub.2, C.sub.1-6 alkyl, haloalkyl, alkylcarbonyl, alkoxy,
haloalkoxy, aryl, C.sub.3-6 cycloalkyl, and 4- to 6-membered
heterocycle, wherein said aryl, cycloalkyl, and heterocycle are
optionally substituted with R.sup.10;
[0287] R.sup.10 is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, --(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl
(optionally substituted with R.sup.11), --(CH.sub.2).sub.n--O-4- to
10-membered heterocycle (optionally substituted with R.sup.11), F,
Cl, Br, CN, NO.sub.2, .dbd.O, C(.dbd.O)NR.sup.12R.sup.12,
C(.dbd.O)OR.sup.12, Si(C.sub.1-4 alkyl).sub.3,
--(CH.sub.2).sub.n--OR.sup.12, and
--(CH.sub.2).sub.n--NR.sup.12R.sup.12;
[0288] R.sup.11, at each occurrence, is independently selected from
H, halogen, C.sub.1-5 alkyl, --(CH.sub.2).sub.n--OH, C.sub.3-6
cycloalkyl, and phenyl;
[0289] R.sup.12, at each occurrence, is independently selected from
H, C.sub.1-5 alkyl, C.sub.3-6 cycloalkyl, phenyl, and heterocycle,
or R.sup.12 and R.sup.12 together with the nitrogen atom to which
they are both attached form a heterocyclic ring optionally
substituted with C.sub.1-4alkyl;
[0290] n, at each occurrence, is an integer independently selected
from 0, 1, and 2; and
[0291] p, at each occurrence, is an integer independently selected
from 0, 1, and 2.
[0292] In another aspect, the present invention provides compounds
of Formula (IIIb):
##STR00022##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0293] ring A is independently selected from phenyl and 5- to
6-membered heterocyclyl;
[0294] G.sup.1 is independently selected from aryl,
C.sub.3-6cycloalkyl and 5- to 6-membered heterocyclyl, wherein said
aryl, cycloalkyl and heterocyclyl are substituted with 1-4
R.sup.8;
[0295] G.sup.2 is independently selected from N and CR.sup.3b;
[0296] G.sup.7 is independently selected from N and CR.sup.3;
[0297] G.sup.8 is independently selected from N and CR.sup.3;
[0298] provided at least one of G.sup.2, G.sup.6, and G.sup.7 is
N;
[0299] R.sup.1 and R.sup.2 are independently selected from H,
halogen, CF.sub.3, C.sub.1-6 alkyl, and hydroxyl;
[0300] R.sup.3 is independently selected from H, halogen,
haloalkyl, C.sub.1-4alkyl (optionally substituted with R.sup.6),
C.sub.2-4alkenyl (optionally substituted with R.sup.6), CN,
NO.sub.2, --(CH.sub.2).sub.n--OR.sup.5,
--(CH.sub.2).sub.n--NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(.dbd.O)OR.sup.5,
--(CH.sub.2).sub.n--NHC(.dbd.O)OR.sup.5,
--(CH.sub.2).sub.n--NHC(.dbd.O)R.sup.5,
--(CH.sub.2).sub.n--NHC(N--CN)NHR.sup.5,
--(CH.sub.2).sub.n--NHC(NH)NHR.sup.5,
--(CH.sub.2).sub.n--N.dbd.CHNR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NHC(.dbd.O)NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(.dbd.O)NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NHC(S)NR.sup.9C(.dbd.O)R.sup.5,
--(CH.sub.2).sub.n--S(.dbd.O).sub.pC.sub.1-6 alkyl optionally
substituted with R.sup.11,
--(CH.sub.2).sub.n--S(.dbd.O).sub.pNR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NHS(.dbd.O).sub.pNR.sup.5R.sup.5,
--(CH.sub.2).sub.n--NHS(.dbd.O).sub.pC.sub.1-6 alkyl optionally
substituted with R.sup.11, --(CH.sub.2).sub.n--C.sub.3-10
carbocyclyl and --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl,
wherein said carbocyclyl and heterocyclyl are optionally
substituted with R.sup.6; optionally, two adjacent R.sup.3 groups
on the carbocyclyl and heterocyclyl may form a ring optionally
substituted with R.sup.6;
[0301] R.sup.3a is independently selected from H and halogen;
[0302] R.sup.3b is independently selected from H, halogen, methyl,
and CN;
[0303] R.sup.4 is independently selected from H, OH, F, Cl, Br,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3, CN, C.sub.3-6
cycloalkyl, aryl, and 5- to 6-membered heterocyclyl, wherein said
cycloalkyl, aryl and heterocyclyl are optionally substituted with
R.sup.6;
[0304] R.sup.5 is independently selected from H, C.sub.1-4 alkyl
(optionally substituted with halogen, hydroxyl, alkoxy, carboxy,
alkoxycarbonyl, amino, substituted amino),
--(CH.sub.2).sub.n--C.sub.3-10 carbocyclyl and
--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
carbocyclyl and heterocyclyl are optionally substituted with
R.sup.6;
[0305] R.sup.6 is independently selected from
--(CH.sub.2).sub.n--OH, .dbd.O, NH.sub.2, --(CH.sub.2).sub.n--CN,
halogen, C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, and
--O--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
cycloalkyl and heterocyclyl are optionally substituted with
R.sup.10;
[0306] R.sup.7 is independently selected from H, F, Cl, and
methyl;
[0307] R.sup.8 is independently selected from H, halogen, CN,
NH.sub.2, C.sub.1-6 alkyl, haloalkyl, alkylcarbonyl, alkoxy,
haloalkoxy, aryl, C.sub.3-6 cycloalkyl, and 4- to 12-membered
heterocyclyl, wherein said aryl, cycloalkyl, and heterocyclyl are
optionally substituted with R.sup.10;
[0308] R.sup.10 is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, --(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl
(optionally substituted with R.sup.11), --(CH.sub.2).sub.n--O-4- to
10-membered heterocyclyl (optionally substituted with R.sup.11), F,
Cl, Br, CN, NO.sub.2, .dbd.O, C(.dbd.O)NR.sup.12R.sup.12,
C(.dbd.O)OR.sup.12, Si(C.sub.1-4 alkyl).sub.3,
--(CH.sub.2).sub.n--OR.sup.12,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12, --S(.dbd.O).sub.pC.sub.1-6
alkyl, NR.sup.12S(.dbd.O).sub.pC.sub.1-6 alkyl, and
S(.dbd.O).sub.pNR.sup.12R.sup.12;
[0309] R.sup.11, at each occurrence, is independently selected from
H, halogen, C.sub.1-5 alkyl, --(CH.sub.2).sub.n--OH, C.sub.3-6
cycloalkyl, and phenyl;
[0310] R.sup.12, at each occurrence, is independently selected from
H, C.sub.1-5 alkyl, C.sub.3-6 cycloalkyl, phenyl, and heterocyclyl,
or R.sup.12 and R.sup.12 together with the nitrogen atom to which
they are both attached form a heterocyclic ring optionally
substituted with C.sub.1-4alkyl;
[0311] n, at each occurrence, is an integer independently selected
from 0, 1, and 2; and
[0312] p, at each occurrence, is an integer independently selected
from 0, 1, and 2.
[0313] In another aspect, the present invention provides compounds
of Formula (IVb):
##STR00023##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0314] ring A is independently selected from
##STR00024##
[0315] R.sup.1 and R.sup.2 are independently selected from H, F,
C.sub.1-4 alkyl, and OH;
[0316] R.sup.1a, at each occurrence, is independently selected from
H, F, CH.sub.3, and OH;
[0317] R.sup.3 is independently selected from H, F, Cl, Br, I,
C.sub.2-4alkenyl (optionally substituted C(.dbd.O)OH), CN, and
--(CH.sub.2).sub.n--OH;
[0318] R.sup.4 is independently selected from H, OH, F, OC.sub.1-4
alkyl, C.sub.1-4 alkyl, CN, C.sub.3-6 cycloalkyl, aryl, and 5- to
6-membered heterocyclyl, wherein said cycloalkyl, aryl and
heterocyclyl are optionally substituted with R.sup.6;
[0319] R.sup.6 is independently selected from OH, NH.sub.2,
halogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl, .dbd.O, C.sub.3-6 cycloalkyl,
4- to 10-membered heterocyclyl, and --O-4- to 10-membered
heterocyclyl, wherein said cycloalkyl and heterocyclyl are
optionally substituted with R.sup.10;
[0320] R.sup.8a is independently selected from H, F, Cl, Br, CN,
OCH.sub.3, OCF.sub.3, CH.sub.3, C(.dbd.O)CH.sub.3, CF.sub.3,
OCHF.sub.2, NHC(.dbd.O)C.sub.1-4 alkyl, aryl, C.sub.3-6 cycloalkyl,
and 4- to 12-membered heterocyclyl, wherein said aryl, cycloalkyl,
and heterocyclyl are optionally substituted with R.sup.10;
[0321] R.sup.8b is independently selected from H and F;
[0322] R.sup.8c is independently selected from H, F, Cl, CH.sub.3,
and OCH.sub.3;
[0323] R.sup.10 is independently selected from C.sub.1-6 alkyl,
--C.sub.3-6 cycloalkyl, F, Cl, Br, CF.sub.3, CHF.sub.2, CN, and
OC.sub.1-5 alkyl; and
[0324] n, at each occurrence, is an integer independently selected
from 0, 1, and 2.
[0325] In another aspect, the present invention provides compounds
of Formula (IIb), or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, wherein:
[0326] ring A is independently selected from
##STR00025##
[0327] ring B is independently selected from
##STR00026##
[0328] W is independently selected from CHR.sup.1a, O, NH, and
N(C.sub.1-4 alkyl);
[0329] R.sup.1 is independently selected from H and C.sub.1-4
alkyl;
[0330] R.sup.1a is independently selected from H F, CH.sub.3, and
hydroxyl;
[0331] R.sup.2 is independently selected from H and hydroxyl;
[0332] R.sup.3 is independently selected from H, .dbd.O, F,
CHF.sub.2, CF.sub.3, OCF.sub.3, OCHF.sub.2, CH.sub.3, CN,
--(CH.sub.2).sub.0-2--OH, OC.sub.1-4 alkyl, C(.dbd.O)C.sub.1-4
alkyl, --(CH.sub.2).sub.0-1--C(.dbd.O)OH, --C(.dbd.O)OC.sub.1-4
alkyl, --S(.dbd.O).sub.2C.sub.1-4 alkyl, and
--NHC(.dbd.O)OC.sub.1-4 alkyl;
[0333] R.sup.3c is independently selected from H, CF.sub.2H,
CF.sub.3, C.sub.1-4 alkyl, and CD.sub.3;
[0334] R.sup.4 is independently selected from H and F;
[0335] R.sup.8b is independently selected from H and F;
[0336] R.sup.8c is independently selected from H and Cl;
[0337] R.sup.10 is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), aryl,
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl (optionally substituted
with R.sup.11), --(CH.sub.2).sub.n--O-4- to 10-membered
heterocyclyl, F, Cl, Br, CN, C(.dbd.O)NR.sup.12R.sup.12,
Si(C.sub.1-4 alkyl).sub.3, and --(CH.sub.2).sub.n--OR.sup.12;
[0338] R.sup.11, at each occurrence, is independently selected from
H, halogen, and C.sub.1-5 alkyl; and
[0339] n, at each occurrence, is an integer independently selected
from 0, 1, 2, 3, and 4; and
[0340] other variables are as defined in Formula (IVb) above.
[0341] In another aspect, the present invention provides compounds
of Formula (IIc), or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, wherein:
[0342] ring A is independently selected from
##STR00027##
[0343] ring B is independently selected from,
##STR00028##
[0344] W is independently selected from CHR.sup.1a, O, NH, and
N(C.sub.1-4 alkyl);
[0345] R.sup.1 is independently selected from H and C.sub.1-4
alkyl;
[0346] R.sup.1a is independently selected from H F, CH.sub.3, and
hydroxyl;
[0347] R.sup.2 is independently selected from H and hydroxyl;
[0348] R.sup.3 is independently selected from H, .dbd.O, F,
CHF.sub.2, CF.sub.3, OCF.sub.3, OCHF.sub.2, CH.sub.3, CN,
--(CH.sub.2).sub.0-2--OH, OC.sub.1-4 alkyl, C(.dbd.O)C.sub.1-4
alkyl, --(CH.sub.2).sub.0-1--C(.dbd.O)OH, --C(.dbd.O)OC.sub.1-4
alkyl, --S(.dbd.O).sub.2C.sub.1-4 alkyl, and
--NHC(.dbd.O)OC.sub.1-4 alkyl;
[0349] R.sup.3c is independently selected from H, CF.sub.2H,
CF.sub.3, C.sub.1-4 alkyl, and CD.sub.3;
[0350] R.sup.4 is independently selected from H and F;
[0351] R.sup.8b is independently selected from H and F;
[0352] R.sup.8c is independently selected from H and Cl;
[0353] R.sup.10 is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), aryl,
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl (optionally substituted
with R.sup.11), --(CH.sub.2).sub.n--O-4- to 10-membered
heterocyclyl, F, Cl, Br, CN, C(.dbd.O)NR.sup.12R.sup.12,
Si(C.sub.1-4 alkyl).sub.3, and --(CH.sub.2).sub.n--OR.sup.12;
[0354] R.sup.11, at each occurrence, is independently selected from
H, halogen, and C.sub.1-5 alkyl; and
[0355] n, at each occurrence, is an integer independently selected
from 0, 1, 2, 3, and 4; and
[0356] other variables are as defined in Formula (IIc) above.
[0357] In another aspect, the present invention provides compounds
of Formula (IIa), or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, wherein:
[0358] ring A is independently selected from
##STR00029##
[0359] ring B is independently selected from
##STR00030##
[0360] G.sup.1 is independently selected from
##STR00031## ##STR00032## ##STR00033## ##STR00034## ##STR00035##
##STR00036## ##STR00037## ##STR00038## ##STR00039##
##STR00040##
[0361] W is independently selected from CHR.sup.1, O, NH, and
N(C.sub.1-4 alkyl);
[0362] Y is independently selected from --NH--, --NHC(.dbd.O)-- and
--C(.dbd.O)NH--;
[0363] R.sup.1 and R.sup.2 are independently selected from H, F,
C.sub.1-4 alkyl, and hydroxyl;
[0364] R.sup.3 is independently selected from H, .dbd.O, F,
CHF.sub.2, CF.sub.3, OCF.sub.3, OCHF.sub.2, CH.sub.3, CN,
--(CH.sub.2).sub.0-2--OH, OC.sub.1-4 alkyl, C(.dbd.O)C.sub.1-4
alkyl, --(CH.sub.2).sub.0-1--C(.dbd.O)OH, --C(.dbd.O)OC.sub.1-4
alkyl, --S(.dbd.O).sub.2C.sub.1-4 alkyl, and
--NHC(.dbd.O)OC.sub.1-4 alkyl;
[0365] R.sup.3c is independently selected from H, CF.sub.2H,
CF.sub.3, C.sub.1-4 alkyl, and CD.sub.3;
[0366] R.sup.4 is independently selected from H, F, and C.sub.1-4
alkyl; and
[0367] R.sup.7 is H; and
[0368] other variables are as defined in Formula (IIa) above.
[0369] In another aspect, the present invention provides compounds
of Formula (V):
##STR00041##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0370] ring A is independently selected from phenyl and a 5- to
6-membered heterocyclyl;
[0371] W is independently selected from CHR.sup.1a, O, NH, and
N(C.sub.1-4 alkyl);
[0372] R.sup.1 is independently selected from H and C.sub.1-4
alkyl;
[0373] R.sup.1a is independently selected from H and F;
[0374] R.sup.2 is independently selected from H and hydroxyl;
[0375] R.sup.3 is independently selected from H, haloalkyl, and
C.sub.1-4alkyl (optionally substituted with R.sup.6), F, CN,
C(.dbd.O)C.sub.1-4 alkyl, C(.dbd.O)OH,
--S(.dbd.O).sub.2C.sub.1-4alkyl, and --NHC(.dbd.O)OC.sub.1-4
alkyl;
[0376] R.sup.4 is independently selected from H, OH, F, Cl, Br,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3, and CN;
[0377] R.sup.5 is independently selected from H, C.sub.1-4 alkyl
(optionally substituted with halogen, hydroxyl, alkoxy, carboxy,
alkoxycarbonyl, amino, substituted amino),
--(CH.sub.2).sub.n--C.sub.3-10 carbocyclyl and
--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
carbocyclyl and heterocyclyl are optionally substituted with
R.sup.6;
[0378] R.sup.6 is independently selected from
--(CH.sub.2).sub.n--OH, .dbd.O, NH.sub.2, --(CH.sub.2).sub.n--CN,
halogen, C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, and
--O--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
cycloalkyl and heterocyclyl are optionally substituted with
R.sup.10;
[0379] R.sup.7 is independently selected from H, F, Cl, and
methyl;
[0380] R.sup.8b is independently selected from H and F;
[0381] R.sup.8c is independently selected from H, F, Cl, CH.sub.3,
and OCH.sub.3;
[0382] R.sup.10 is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, --(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl
(optionally substituted with R.sup.11), --(CH.sub.2).sub.n--O-4- to
10-membered heterocyclyl (optionally substituted with R.sup.11), F,
Cl, Br, CN, NO.sub.2, .dbd.O, C(.dbd.O)NR.sup.12R.sup.12,
C(.dbd.O)OR.sup.12, Si(C.sub.1-4 alkyl).sub.3,
--(CH.sub.2).sub.n--OR.sup.12, and
--(CH.sub.2).sub.n--NR.sup.12R.sup.12;
[0383] R.sup.11, at each occurrence, is independently selected from
H, halogen, C.sub.1-5 alkyl, --(CH.sub.2).sub.n--OH, C.sub.3-6
cycloalkyl, and phenyl;
[0384] R.sup.12, at each occurrence, is independently selected from
H, C.sub.1-5 alkyl, C.sub.3-6 cycloalkyl, phenyl, and heterocyclyl,
or R.sup.12 and R.sup.12 together with the nitrogen atom to which
they are both attached form a heterocyclic ring optionally
substituted with C.sub.1-4alkyl; and
[0385] n, at each occurrence, is an integer independently selected
from 0, 1, and 2; and
[0386] p, at each occurrence, is an integer independently selected
from 0, 1, and 2.
[0387] In another aspect, the present invention provides compounds
of Formula (VI):
##STR00042##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0388] ring A is independently selected from phenyl and a 5- to
6-membered heterocyclyl;
[0389] W is independently selected from (CR.sup.1R.sup.2).sub.1-2,
O, NH, and N(C.sub.1-4 alkyl);
[0390] Y is independently selected from --NH--, --NHC(.dbd.O)-- and
--C(.dbd.O)NH--;
[0391] R.sup.1 and R.sup.2 are independently selected from H,
halogen, CF.sub.3, C.sub.1-6 alkyl, and hydroxyl;
[0392] R.sup.3 is independently selected from H, haloalkyl, and
C.sub.1-4alkyl (optionally substituted with R.sup.6),
--(CH.sub.2).sub.0-2--OH, C(.dbd.O)C.sub.1-4 alkyl,
--(CH.sub.2).sub.0-2--C(.dbd.O)OH, and --C(.dbd.O)OC.sub.1-4 alkyl;
only one R.sup.3c is present on the ring;
[0393] R.sup.4 is independently selected from H, OH, F, Cl, Br,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CF.sub.3, CN, C.sub.3-6
cycloalkyl, aryl, and 5- to 6-membered heterocyclyl, wherein said
cycloalkyl, aryl and heterocyclyl are optionally substituted with
R.sup.6;
[0394] R.sup.5 is independently selected from H, C.sub.1-4 alkyl
(optionally substituted with halogen, hydroxyl, alkoxy, carboxy,
alkoxycarbonyl, amino, substituted amino),
--(CH.sub.2).sub.n--C.sub.3-10 carbocyclyl and
--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
carbocyclyl and heterocyclyl are optionally substituted with
R.sup.6;
[0395] R.sup.6 is independently selected from
--(CH.sub.2).sub.n--OH, .dbd.O, NH.sub.2, --(CH.sub.2).sub.n--CN,
halogen, C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl, --(CH.sub.2).sub.n--C.sub.3-6
cycloalkyl, --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, and
--O--(CH.sub.2).sub.n-4- to 10-membered heterocyclyl, wherein said
cycloalkyl and heterocyclyl are optionally substituted with
R.sup.10;
[0396] R.sup.7 is independently selected from H, F, and methyl;
[0397] R.sup.8a is independently selected from H, F, Cl, Br, CN,
OCH.sub.3, OCF.sub.3, CH.sub.3, C(.dbd.O)CH.sub.3, CHF.sub.2,
CF.sub.3, CCH.sub.3F.sub.2, OCHF.sub.2, aryl, C.sub.3-6 cycloalkyl,
and 4- to 6-membered heterocyclyl optionally substituted with
R.sup.10;
[0398] R.sup.8b is independently selected from H and F;
[0399] R.sup.8c is independently selected from H, F, Cl, CH.sub.3,
and OCH.sub.3;
[0400] R.sup.10 is independently selected from H, C.sub.1-6 alkyl
(optionally substituted with R.sup.11), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, --(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl
(optionally substituted with R.sup.11), --(CH.sub.2).sub.n--O-4- to
10-membered heterocyclyl (optionally substituted with R.sup.11), F,
Cl, Br, CN, NO.sub.2, .dbd.O, CONR.sup.12R.sup.12,
C(.dbd.O)OR.sup.12, Si(C.sub.1-4 alkyl).sub.3,
--(CH.sub.2).sub.n--OR.sup.12, and
--(CH.sub.2).sub.n--NR.sup.12R.sup.12;
[0401] R.sup.11, at each occurrence, is independently selected from
H, halogen, C.sub.1-5 alkyl, --(CH.sub.2).sub.n--OH, C.sub.3-6
cycloalkyl, and phenyl;
[0402] R.sup.12, at each occurrence, is independently selected from
H, C.sub.1-5 alkyl, C.sub.3-6 cycloalkyl, phenyl, and heterocyclyl,
or R.sup.12 and R.sup.12 together with the nitrogen atom to which
they are both attached form a heterocyclic ring optionally
substituted with C.sub.1-4alkyl;
[0403] n, at each occurrence, is an integer independently selected
from 0, 1, and 2; and
[0404] p, at each occurrence, is an integer independently selected
from 0, 1, and 2.
[0405] In one embodiment, G.sup.1 is independently selected from
the group consisting of
##STR00043##
wherein R.sup.8 is, independently at each occurrence, selected from
the group consisting of H, halogen, CN, C.sub.1-6 alkyl, haloalkyl,
alkoxy, haloalkoxy, and 4- to 6-membered heterocyclyl.
[0406] In another embodiment, G.sup.1 is
##STR00044##
wherein R.sup.8 is, independently at each occurrence, selected from
the group consisting of H, halogen, CN, methyl, ethyl, CF.sub.3
CHF.sub.2, OMe, OEt, OCF.sub.3, OCHF.sub.2, aryl, C.sub.3-6
cycloalkyl, and 4- to 6-membered heterocyclyl.
[0407] In another embodiment, G.sup.1 is
##STR00045##
and selected from the group consisting of
##STR00046##
[0408] In another embodiment, G.sup.1 is
##STR00047##
wherein R.sup.8a is independently selected from the group
consisting of H, F, OCH.sub.3, OCHF.sub.2, and
##STR00048##
[0409] In another embodiment, R.sup.8b is independently selected
from the group consisting of H, F and Cl.
[0410] In another embodiment, R.sup.8b is independently selected
from the group consisting of H and F.
[0411] In another embodiment, R.sup.8c is Cl.
[0412] In another embodiment, G.sup.1 is
##STR00049##
selected from the group consisting of
##STR00050##
[0413] In another embodiment, G.sup.1 is
##STR00051##
[0414] In one embodiment, the present invention provides compounds
of Formulae (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf),
(IIg), (IIIa), (IIIb), (IVb), (V), and (VI) or stereoisomers,
tautomers, pharmaceutically acceptable salts, solvates, or prodrugs
thereof, wherein ring A is independently selected from the group
consisting of imidazole, oxadiazole, pyridine, pyridinone,
pyridazine, pyridazinone, and phenyl.
[0415] In another embodiment,
##STR00052##
is independently selected from the group consisting of
##STR00053##
[0416] In another embodiment,
##STR00054##
is independently selected from the group consisting of
##STR00055##
[0417] In another embodiment,
##STR00056##
is independently selected from the group consisting of
##STR00057##
[0418] In still another embodiment,
##STR00058##
is independently selected from the group consisting of
##STR00059##
[0419] In another embodiment,
##STR00060##
[0420] In another embodiment,
##STR00061##
[0421] In another embodiment,
##STR00062##
[0422] In another embodiment,
##STR00063##
[0423] In another embodiment,
##STR00064##
[0424] In another embodiment,
##STR00065##
[0425] In another embodiment,
##STR00066##
[0426] In another embodiment, ring B is independently selected
from
##STR00067##
[0427] In another embodiment, ring B is independently selected from
z,
##STR00068##
[0428] In another embodiment, ring B is independently selected
from,
##STR00069##
[0429] In another embodiment, ring B is
##STR00070##
wherein R.sup.3c is independently selected from H, CHF.sub.2,
CD.sub.3, CH.sub.3, and SO.sub.2CH.sub.3.
[0430] In another embodiment, R.sup.1 is independently selected
from the group consisting of H, OH, F, and C.sub.1-4 alkyl.
[0431] In another embodiment, R.sup.1 is independently selected
from the group consisting of H and methyl, ethyl, and
isopropyl.
[0432] In one embodiment, R.sup.2 is, independently at each
occurrence, selected from the group consisting of H and C.sub.1-4
alkyl.
[0433] In another embodiment, R.sup.2 is, independently at each
occurrence, selected from the group consisting of H and methyl.
[0434] In another embodiment, one of R.sup.1 and R.sup.2 is H and
the other is methyl;
[0435] In another embodiment, R.sup.1 and R.sup.2 together are
.dbd.O;
[0436] In one embodiment, Ring B is 5-membered heteroaryl
comprising carbon atoms and heteroatoms selected from N and
NR.sup.3c; R.sup.3 is independently selected from H, halogen,
C.sub.1-4 alkyl (optionally substituted with R.sup.6), CN,
--(CH.sub.2).sub.n--OR.sup.5, --(CH.sub.2).sub.n--NR.sup.5R.sup.5,
--(CH.sub.2).sub.n--C(.dbd.O)R.sup.5, and
--(CH.sub.2).sub.n--C(.dbd.O)OR.sup.5; R.sup.3c is independently
selected from H, haloalkyl, C.sub.1-4 alkyl (optionally substituted
with R.sup.6), --(CH.sub.2).sub.1-2--OH, C(.dbd.O)C.sub.1-4 alkyl,
--(CH.sub.2).sub.1-2--C(.dbd.O)OH, --C(.dbd.O)OC.sub.1-4 alkyl,
S(.dbd.O).sub.pC.sub.1-6 alkyl, --(CH.sub.2).sub.n--C.sub.3-10
carbocyclyl and --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl,
wherein said carbocyclyl and heterocyclyl are optionally
substituted with R.sup.6; R.sup.5 is independently selected from H,
C.sub.1-4 alkyl (optionally substituted with halogen, hydroxyl,
alkoxy, carboxy, alkoxycarbonyl), --(CH.sub.2).sub.n--C.sub.3-10
carbocyclyl and --(CH.sub.2).sub.n-4- to 10-membered heterocyclyl,
wherein said carbocyclyl and heterocyclyl are optionally
substituted with R.sup.6; R.sup.6 is independently selected from
OH, .dbd.O, --(CH.sub.2).sub.nNH.sub.2, --(CH.sub.2).sub.nCN,
halogen, C.sub.1-6 alkyl, --(CH.sub.2).sub.n--C(.dbd.O)OH,
--(CH.sub.2).sub.n--C(.dbd.O)OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--OC.sub.1-4 alkyl,
--(CH.sub.2).sub.n--C.sub.3-10 carbocyclyl, --(CH.sub.2).sub.n-4-
to 10-membered heterocyclyl, and --(CH.sub.2).sub.n-4- to
10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl
are optionally substituted with R.sup.10.
[0437] In another aspect, the present invention provides a compound
selected from any subset list of compounds exemplified in the
present application.
[0438] In another aspect, the present invention provides a compound
selected from: [0439]
(9R,13S)-13-(4-{5-chloro-2-[(pyrimidin-2-yl)amino]phenyl}-6-oxo-1,6-dihyd-
ropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]-
octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0440] ethyl
2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricycl-
o
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-d-
ihydropyrimidin-4-yl}phenyl)-1H-pyrazol-1-yl]acetate; [0441]
2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricycl-
o
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-d-
ihydropyrimidin-4-yl}phenyl)-1H-pyrazol-1-yl]acetic acid; [0442]
2-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)acetonitrile; [0443]
(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2-
,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0444]
(9R,13S)-13-{4-[5-chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,-
6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.s-
up.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;
[0445]
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-4,5,8-triazatricyclo[13.3-
.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one; [0446]
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carboxylic acid; [0447]
(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-5-chloro-6-oxo-1,6-dihydropyrimid-
in-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca--
1(18),2(6),4,14,16-pentaen-8-one; [0448]
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1,3-thiazol-5-yl)phenyl]-6-oxo-1,6-d-
ihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricycl-
o [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one;
[0449]
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0450]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-
-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraaz-
atricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate; [0451]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0452]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-
-6-oxo-1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraa-
zatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate; [0453]
(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricy-
clo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0454]
(9S,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetr-
aazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0455]
(9R,13S)-13-{4-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-6-oxo-1,6-dih-
ydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,-
6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;
[0456]
(9R,13S)-13-{4-[3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl]-6-oxo-1,6--
ihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;
[0457]
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.-
3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0458]
(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-
-yl]-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-
-1(18),2(6),4,14,16-pentaen-8-one; [0459]
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0460]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0461]
(9R)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6--
dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]-
octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0462]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7-triazatr-
icyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one;
[0463]
(10R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophen-
yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,
8-diazatricyclo[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-o-
ne trifluoroacetate; [0464]
1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triaza-
tricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-
-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-1,2,3-triazole-4-carbonitri-
le; [0465]
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-
-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-
-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0466]
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,-
7-triazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0467]
1-(4-chloro-3-fluoro-2-{1-[(9R,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-ox-
o-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentae-
n-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbo-
nitrile; [0468]
1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triaza-
tricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-
-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitrile;
[0469]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-
-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3-
,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0470]
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8-diazatricyclo[13.3.1.-
0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one; [0471]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0472]
(9R,13S)-13-{4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-oxo-1-
,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7-triazatri-
cyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one;
[0473]
(9R,13S)-13-(4-{5-chloro-2-[4-(pyrimidin-2-yl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,-
7-triazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0474]
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4,10-dimethyl-3,8-diazatricyclo[13.-
3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one; [0475]
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-5-methoxy-10-methyl-3,8-diazatricyc-
lo[13.3.1.0.sup.27] nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one;
[0476]
(10R,14S)-5-chloro-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazo-
l-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8-diazatricycl-
o[13.3.1.0.sup.2,7] nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one;
[0477]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,16-tetraazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0478]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazat-
ricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaene-16-carboxam-
ide; [0479]
1-(4-chloro-2-{1-[(9R,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-oxo-3,4,7-t-
riazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxamide; [0480]
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7-triazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0481]
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0482]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0483]
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-t-
etraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one;
trifluoroacetate; [0484]
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-t-
etraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0485]
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15--
tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0486]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0487]
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0488]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-
-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0489]
2-[(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoroph-
enyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatri-
cyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic acid
trifluoroacetate; [0490]
2-[(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]p-
henyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tetraazatr-
icyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic acid
trifluoroacetate; [0491]
2-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-o-
xo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.-
3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic acid
trifluoroacetate; [0492]
2-[(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-
-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic acid
trifluoroacetate; [0493]
2-[(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]-
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tetraazat-
ricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic
acid trifluoroacetate; [0494]
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.-
3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0495]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-
-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.-
1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0496] methyl
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6] octadeca-1(18),3,5,14,16-pentaene-4-carboxylate
trifluoroacetate; [0497] methyl
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricy-
clo
[12.3.1.0.sup.2,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate
trifluoroacetate; [0498]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylic acid
trifluoroacetate; [0499]
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricy-
clo[12.3.1.0.sup.2,6]
octadeca-1(18),3,5,14,16-pentaene-4-carboxylic acid
trifluoroacetate; [0500]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,15-tetra-
azatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate; [0501]
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7-
,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0502]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricycl-
o[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one;
[0503]
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-tria-
zatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0504]
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluo-
rophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl(10,11-.sup.2H.sub.-
2)-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0505]
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(
.sup.2H.sub.3)methyl-9-methyl(10,11-.sup.2H.sub.2)-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0506]
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl(10,11-.sup-
.2H.sub.2)-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),-
4,14,16-pentaen-8-one trifluoroacetate; [0507]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl(10,11-.sup.2H.sub.2-
)-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0508]
(10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-
-1,6-dihydropyrimidin-1-yl}-10-methyl-3,8,16-triazatricyclo[13.3.1.0.sup.2-
,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one,
bis-trifluoroacetate; [0509]
(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6-dihyd-
ropyrimidin-1-yl]-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0510]
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihyd-
ropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.-
0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0511]
(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrim-
idin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0.sup.2-
,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0512]
(10R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophen-
yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,
8,16-triazatricyclo[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-
-9-one bis-trifluoroacetate; [0513]
(9R,13S)-3-(difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluoromethy-
l)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,4,7,17-
-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0514]
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-5-(triflu-
oromethyl)-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyc-
lo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one;
[0515]
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8,16-triazatricyclo[13.-
3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one,
bis-trifluoroacetate; [0516]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one;
[0517]
6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(9R,13S-
)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2-
(6),4,14,16-pentaen-13-yl]-3,4-dihydropyrimidin-4-one; [0518]
(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-10-fluoro-9-methyl-3,4,7-tri-
azatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0519]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-
-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-11-fluoro-9-methyl-3,-
4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0520]
(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-10,16-difluoro-3,9-dimethyl-3,4,7-triazatricycl-
o[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one;
[0521]
(9S,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10,16-difluoro-3,9-dimethyl-3,4,7-tr-
iazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0522]
(9R,13S)-13-{4-[5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)ph-
enyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(A.sup.2Ha,f)methyl-9-methyl-3,4,-
7-triazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0523]
6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(9R,13S-
)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]o-
ctadeca-1(18),2(6),4,14,16-pentaen-13-yl]-3,4-dihydropyrimidin-4-one;
[0524]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-
-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7--
triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaene-16-carbonitrile;
[0525]
(9R,13S)-13-(4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraaza-
tricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate; [0526]
(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-
-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,.sup.6]octadeca-
-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate; [0527]
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihyd-
ropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,.s-
up.6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;
[0528]
(13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-
-dihydropyrimidin-1-yl}-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo[12.3.-
1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0529]
(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-
-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tet-
raazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0530]
(9R,13S)-13-{4-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-
-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tet-
raazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0531]
(9R,13S)-3-(difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluoromethy-
l)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,4,7,15-
-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0532]
(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]--
3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6-
),4,14,16-pentaen-8-one; [0533]
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(4-methyl-1H-1,2,3-triazol-1-yl)pheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-t-
etraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0534]
(9R,13S)-13-(4-{5-chloro-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}-6--
oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0535]
(9R,13S)-13-[4-(3-fluoro-4-methylpyridin-2-yl)-6-oxo-1,6-dihydropyrimidin-
-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(-
18),2(6),4,14,16-pentaen-8-one; [0536]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one;
[0537]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0538]
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluo-
rophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazat-
ricyclo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0539]
(9R,13S)-13-{4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-oxo-1-
,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;
[0540]
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxamide
trifluoroacetate; [0541]
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitrile
trifluoro acetate; [0542]
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-9-oxo-3,8-diazatricyclo[1-
3.3.1.0.sup.2,7]
nonadeca-1(19),2(7),3,5,15,17-hexaene-5-carbonitrile; [0543]
(9R,13S)-13-(4-{5-chloro-2-[4-({3H-[1,2,3]triazolo[4,5-b]pyridin-3-
-yloxy}
methyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-
-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18-
),2(6),4,14,16-pentaen-8-one trifluoroacetate; [0544]
(9R,13S)-13-(4-{5-chloro-2-[4-(hydroxylmethyl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricycl-
o[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0545]
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricycl-
o[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0546]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-
-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.-
3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0547]
(9R,13S)-13-(4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl-
]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0548]
1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tet-
raazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]--
6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitrile
trifluoroacetate; [0549]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl-9-methyl-3,4-
,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0550]
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15--
tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0551]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-
-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0552]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl-9-methyl-3,4-
,7-triazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate; [0553]
(9S,13R)-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-
-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricy-
clo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one;
[0554]
(9R,13R)-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-
-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricy-
clo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one;
[0555]
(9R,13S)-13-{4-[5-chloro-2-(pyridin-3-yl)phenyl]-6-oxo-1,6-dihydropyrimid-
in-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca--
1(18),2(6),4,14,16-pentaen-8-one; [0556]
(9R,13S)-13-(4-{5-chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-y-
l]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4-
,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentae-
n-8-one; [0557]
(9R,13S)-3-(difluoromethyl)-9-methyl-13-(6-oxo-4-{2-[4-(trifluoromethyl)--
1H-1,2,3-triazol-1-yl]phenyl}-1,6-dihydropyrimidin-1-yl)-3,4,7,15-tetraaza-
tricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0558]
(9R,13S)-3-(difluoromethyl)-13-(4-{5-fluoro-2-[4-(trifluoromethyl)-
-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3-
,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0559]
(9R,13S)-13-{4-[5-chloro-2-(4-hydroxy-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-
-1,6-ihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0560]
5-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatri-
cyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1-
,6-dihydropyrimidin-4-yl}phenyl)pyridine-3-carbonitrile; [0561]
(9R,13S)-13-{4-[5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl]-6-
-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.-
3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0562] methyl
4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}benzoate; [0563]
(9R,13S)-13-{4-[3-chloro-6-(4-ethoxy-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo-
[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0564]
(9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluoro-
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatri-
cyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0565]
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2-
,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;
[0566]
(9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluoro-
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl--
3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen--
8-one; [0567]
(9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-
-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetra-
azatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0568]
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}-3-fluorophenyl)-1H-1,2,3-triazole-4-carbonitrile
trifluoroacetate; [0569]
(9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-
-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl-9-m-
ethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,-
16-pentaen-8-one trifluoroacetate; [0570]
1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tet-
raazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]--
6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-1,2,3-triazole-4-carbo-
nitrile trifluoroacetate; [0571]
(9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluoro-
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-
,15-tetraazatricyclo[12.3.1.0
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0572]
(9R,13S)-13-(4-{3-chloro-6-[4-(difluoromethyl)-1H-1,2,3-triazol-1--
yl]-2-fluorophenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9--
methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14-
,16-pentaen-8-one trifluoroacetate; [0573]
(9R,13S)-13-(4-{3-chloro-6-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]-2-f-
luorophenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraa-
zatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0574]
(9R,13S)-13-[4-(3-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dime-
thyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,1-
6-pentaen-8-one; [0575]
4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-y-
l}benzoic acid; [0576]
(9R,13S)-3-(difluoromethyl)-9-methyl-13-{6-oxo-4-[5-(propan-2-yl)-2-[4-(t-
rifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl]-1,6-dihydropyrimidin-1-yl}-3-
,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pent-
aen-8-one; [0577]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl-9-methyl-3,4-
,7,17-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0578]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8-oxo-3,-
4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaene-16-carbonitrile;
[0579]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-
-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,17-tetraaz-
atricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0580]
(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-
-6-oxo-1,6-dihydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraaza-
tricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate; [0581]
(9R,13S)-3-(difluoromethyl)-13-(4-{5-ethyl-2-[4-(trifluoromethyl)-1H-1,2,-
3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15--
tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0582]
(9S,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraa-
zatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0583]
(9R,13S)-13-{5-chloro-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)pheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo-
[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0584]
(9R,13S)-3-(difluoromethyl)-13-(4-{4-fluoro-2-[4-(trifluoromethyl)-1H-1,2-
,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-
-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0585]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,17-tetra-
azatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0586]
(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyri-
midin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0587]
(9R,13S)-13-[4-(5-chloro-2-phenylphenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-
-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(-
6),4,14,16-pentaen-8-one; [0588]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,16-
-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0589]
(9R,13S)-13-[4-(5-chloro-1-ethyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimi-
din-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.s-
up.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0590]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0591]
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-o-
xo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.-
1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0592]
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phen-
yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-tri-
azatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate; [0593]
(9R,13S)-13-{4-[5-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one;
[0594]
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0595]
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3-
.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0596]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-fluo-
ro-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo-
[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one;
[0597]
(9R,13S)-13-{5-bromo-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl-
]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[-
12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0598]
(9R,13S)-13-(4-{5-chloro-3-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-
-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-
-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pe-
ntaen-8-one; [0599]
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,8-diazatricyclo[13.3.1.-
0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one; [0600]
(10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-
-1,6-dihydropyrimidin-1-yl}-10-methyl-5,
8-diazatricyclo[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-o-
ne; [0601]
(9R,13S)-13-[4-(6-chloro-1H-1,3-benzodiazol-4-yl)-6-oxo-1,6-dih-
ydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[-
12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0602]
methyl
4-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-o-
xo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.-
3.1.0.sup.2,6]
octadeca-1(18),2,5,14,16-pentaen-4-yl]piperidine-1-carboxylate;
[0603]
(9R,13S)-13-(4-{4-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-
-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0604]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-meth-
yl-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo-
[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one;
[0605]
(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-
,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6)-
,4,14,16-pentaen-8-one; [0606]
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(4-phenyl-1H-1,2,3-triazol-1-yl)pheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo-
[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0607]
N-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}-3-fluorophenyl)carbamate trifluoroacetate;
[0608]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetr-
aazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-15-ium-15-olate;
[0609]
(9R,13S)-13-(4-{5-chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl-
]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,-
7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0610]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-3-yl)-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6] octadeca-1(18),2,5,14,16-pentaen-8-one;
[0611]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-3-(pyridin-3-yl)-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one;
[0612]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.-
3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0613]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyr-
idin-3-yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,-
4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-penta-
en-8-one; [0614]
(9R,13S)-13-(5-bromo-4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol--
1-yl]pyridin-3-yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-m-
ethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,-
16-pentaen-8-one; [0615]
(9R,13S)-13-(4-{5-chloro-4-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-
-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-
-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pe-
ntaen-8-one; [0616]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3-phenyl-3,4,7,15-tetraazat-
ricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0617]
(9R,13S)-13-(4-{4,5-Dichloro-2-[4-(trifluoromethyl)-1H-1,2,3-triaz-
ol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-meth-
yl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16--
pentaen-8-one; [0618]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1-methyl-1H-imidazol-5-yl)-3,4,7,15-
-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one;
[0619]
4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-y-
l}-N-(2,2,2-trifluoroethyl)benzamide; [0620]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),3,14,16-pentaen-8-one; [0621]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-5,9-dimethyl-4,5,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),3,14,16-pentaen-8-one;
[0622]
(9R,13S)-13-[4-(1-benzyl-5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrim-
idin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0623]
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-5-methyl-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0624]
(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-pyrazol-3-yl)phenyl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2-
,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0625]
(9R,13S)-13-{4-[5-chloro-2-(1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyr-
imidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octad-
eca-1(18),2(6),4,14,16-pentaen-8-one; [0626]
(9R,13S)-13-[4-(5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl-
]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]o-
ctadeca-1(18),2(6),4,14,16-pentaen-8-one; [0627]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-4-(6-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tet-
raazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one; [0628]
(10R,14S)-3-chloro-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1--
yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-5,
8-diazatricyclo[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-o-
ne; [0629]
(9R,13S)-13-{4-[5-chloro-2-(1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-d-
ihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0630]
N-benzyl-4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatric-
yclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,-
6-dihydropyrimidin-4-yl}benzamide; [0631]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-2-yl)-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6] octadeca-1(18),2,5,14,16-pentaen-8-one;
[0632]
1-(4-chloro-3-fluoro-2-{1-[(9R,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-ox-
o-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-p-
entaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carbon-
itrile; [0633]
1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tet-
raazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]--
6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-pyrazole-4-carbonitril-
e; [0634]
(9R,13S)-13-{4-[5-chloro-2-(1-propyl-1H-pyrazol-4-yl)phenyl]-6-o-
xo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.-
1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0635]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-4-yl)-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6] octadeca-1(18),2,5,14,16-pentaen-8-one;
[0636]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-3-(pyridin-4-yl)-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one;
[0637]
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-1H-imidazole-4-carbonitrile; [0638]
N-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tet-
raazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]--
6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamide;
[0639]
(9R,13S)-13-(4-{5-chloro-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]phenyl}-6-oxo-
-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.-
0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0640]
(9R,13S)-13-{4-[5-(difluoromethoxy)-2-[4-(trifluoromethyl)-1H-1,2,3-triaz-
ol-1-yl]phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-meth-
yl-3,4,7,15-tetraazatricyclo[12.3.1.0
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0641]
(9R,13S)-3-(difluoromethyl)-13-(4-{5-methoxy-2-[4-(trifluoromethyl)-1H-1,-
2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,1-
5-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0642]
(9R,13S)-13-(4-{5-chloro-2-[1-(2-methylpropyl)-1H-pyrazol-4-yl]phenyl}-6--
oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0643]
(9R,13S)-13-{4-[2-(1-benzyl-1H-pyrazol-4-yl)-5-chlorophenyl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2-
,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0644]
(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0645]
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-fluoro-10-methyl-5,8,16-triazatri-
cyclo[13.3.1.0.sup.2,7] nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one;
[0646]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyridin-2-yl)-9-methyl-3-
,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-
-8-one; [0647]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(difluoromethyl)-9-methyl-3,4,7,15-
-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one; [0648]
(9R,13S)-13-{4-[5-chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1-
,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0649]
(9R,13S)-13-(4-{5-chloro-2-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricycl-
o[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one;
[0650]
3-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-o-
xo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.-
3.1.0.sup.2,6] octadeca-1(18),2,5,14,16-pentaen-4-yl]benzonitrile;
[0651]
(9R,13S)-13-{4-[5-chloro-2-(5-methyl-1H-imidazol-1-yl)phenyl]-6-oxo-1,6-d-
ihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;
[0652]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1H-pyrazol-3-yl)-3,4,7,15-tetraazat-
ricyclo [12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one;
[0653]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-tetraazatr-
icyclo[12.3.1.0.sup.2,6] octadeca-1(18),2,5,14,16-pentaen-8-one;
[0654]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-4-(pyrazin-2-yl)-3,4,7,15-t-
etraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one; [0655]
(9R,13S)-13-[4-(2-Amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-
-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0656]
(9R,13S)-13-(4-{3-chloro-6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-fluorop-
henyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatric-
yclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one;
[0657]
(9R,13S)-13-[4-(5-chloro-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]--
3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]oct-
adeca-1(18),2(6),4,14,16-pentaen-8-one; [0658]
(9R,13S)-13-[4-(6-chloro-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl-
]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]o-
ctadeca-1(18),2(6),4,14,16-pentaen-8-one; [0659]
(14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl-
}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,8,16-triazatricyclo[13.3.1.-
0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
trifluoroacetate; [0660]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-
-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-4-(6-oxo-1,6-dihydro-
pyridazin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),-
2,5,14,16-pentaen-8-one; [0661]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyrazin-2-yl)-9-methyl-3-
,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-
-8-one; [0662]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-methoxypyridin-4-yl)-9-
-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,1-
6-pentaen-8-one; [0663]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8-oxo-3,-
4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaene-17-carbonitrile;
[0664]
(9R,13S)-13-{4-[5-chloro-2-(4-methyl-1H-imidazol-1-yl)phenyl]-6-ox-
o-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0665]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-hydroxypyridin-4-yl)-9-
-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,1-
6-pentaen-8-one; [0666]
(9R,13S)-13-{4-[5-chloro-2-(1,3-oxazol-2-yl)phenyl]-6-oxo-1,6-dihydropyri-
midin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octade-
ca-1(18),2(6),4,14,16-pentaen-8-one; [0667]
(9R,13S)-13-(4-{5-chloro-2-[(pyrazin-2-yl)amino]phenyl}-6-oxo-1,6-dihydro-
pyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]oc-
tadeca-1(18),2(6),4,14,16-pentaen-8-one; [0668]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(4-hydroxypyrimidin-5-yl)-9-methyl-
-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-penta-
en-8-one; [0669] ethyl
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-3-methyl-1H-pyrazole-4-carboxylate;
[0670]
(9R,13S)-13-{4-[5-chloro-2-(3,4-dimethyl-1H-pyrazol-1-yl)phenyl]-6-oxo-1,-
6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.s-
up.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0671] ethyl
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carboxylate; [0672]
(9R,13S)-13-[4-(5-chloro-2-hydroxyphenyl)-6-oxo-1,6-dihydropyrimidin-1-yl-
]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2-
(6),4,14,16-pentaen-8-one; [0673]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl}--
6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12-
.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0674]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-4-methanesulfonyl-9-methyl-3,4,7,15-tetraazatri-
cyclo [12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one;
[0675]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-methanesulfonyl-9-methyl-3,4,7,15-tetraazatri-
cyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one;
[0676]
(9R,13S)-13-(4-{2,3-difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl-
]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,-
7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-
-8-one; [0677] methyl
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-1H-imidazole-4-carboxylate; [0678]
(9R,13S)-13-[4-(2,5-dichlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9--
dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,-
14,16-pentaen-8-one; [0679]
(9R,13R)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate; [0680]
(9R,13S)-13-(4-{2,3-difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triaz-
ol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl--
9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,-
14,16-pentaen-8-one; [0681]
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-1H-imidazole-4-carboxylic acid; [0682]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0683]
(10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-
-1,6-dihydropyrimidin-1-yl}-10-methyl-3,5,8-triazatricyclo[13.3.1.0.sup.2,-
7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one; [0684]
(9R,13S)-13-{4-[5-chloro-1-(2-hydroxyethyl)-1H-indazol-7-yl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0685]
(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimid-
in-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.su-
p.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0686]
(9R,13S)-13-{4-[5-chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0687]
(9R,13S)-13-[4-(6-chloro-1-methyl-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrim-
idin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0688]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-4-(6-hydroxypyridin-3-yl)-9-methyl-3,4,7,15-tet-
raazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one; [0689]
(9R,13S)-13-{4-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,-
6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatric-
yclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one;
[0690]
(9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]-
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatri-
cyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one;
[0691]
(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-
-yl]-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(-
6),4,14,16-pentaen-8-one; [0692]
(9R,13S)-13-{4-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,6-dihyd-
ropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]-
octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0693]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-hydroxypyridin-4-yl)-9-methyl-3-
,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-
-8-one; [0694]
(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-
-yl]-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,-
6]octadeca-1(18),2,5,14,16-pentaen-8-one; [0695]
(9R,13S)-13-{4-[5-chloro-2-(pyridazin-4-yl)phenyl]-6-oxo-1,6-dihydropyrim-
idin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadec-
a-1(18),2(6),4,14,16-pentaen-8-one; [0696]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-4-(2-hydroxypyrimidin-5-yl)-9-methyl-3,4,7,15-t-
etraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one; [0697]
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol--
1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,8,17-triazatricy-
clo[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one;
[0698]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(piperidin-4-yl)-3,4,7,15-tetraazatr-
icyclo[12.3.1.0.sup.2,6] octadeca-1(18),2,5,14,16-pentaen-8-one;
[0699]
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}-3-fluorophenyl)-1H-pyrazole-4-carbonitrile;
[0700]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-4-(1H-imidazol-4-yl)-9-methyl-3,4,7,15-tetraaza-
tricyclo [12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one;
[0701]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1H-1,2,4-triazol-5-yl)-3,4,7,15-tet-
raazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one; [0702]
N-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatri-
cyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1-
,6-dihydropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamide; [0703]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-hydroxypyridin-3-yl)-9-methyl-3-
,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-
-8-one; [0704]
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-3-(1H-pyrazol-3-yl)-3,4,7,15-tetraazat-
ricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0705]
(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-
-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(-
18),2(6),4,14,16-pentaen-8-one; [0706]
(9R,13S)-13-(4-{5-chloro-2-[(pyrimidin-4-yl)amino]phenyl}-6-oxo-1,6-dihyd-
ropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]-
octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0707]
(9R,13S)-13-{4-[2-(aminomethyl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidi-
n-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0708]
(9R,13S)-13-{4-[5-chloro-2-(pyridin-2-yl)phenyl]-6-oxo-1,6-dihydropyrimid-
in-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca--
1(18),2(6),4,14,16-pentaen-8-one; [0709]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-3-yl)-9-methyl-3-
,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-
-8-one; [0710]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(6-methoxypyrimidin-4-yl)-9-methyl-
-3,4,7,15-tetraazatricyclo[12.3.1.0
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0711]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyrimidin-4-yl)-9-methyl-
-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-penta-
en-8-one; [0712]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-hydroxypyrimidin-4-yl)-9-methyl-
-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-penta-
en-8-one; [0713]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-4-yl)-9-methyl-3-
,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-
-8-one; [0714]
(9R,13S)-13-{4-[5-chloro-2-(4-methylphenyl)phenyl]-6-oxo-1,6-dihydropyrim-
idin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadec-
a-1(18),2(6),4,14,16-pentaen-8-one; [0715]
(9R,13S)-13-{4-[5-chloro-2-(3-chlorophenyl)phenyl]-6-oxo-1,6-dihydropyrim-
idin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadec-
a-1(18),2(6),4,14,16-pentaen-8-one; [0716]
(9R,13S)-13-{4-[5-chloro-2-(3-methoxyphenyl)phenyl]-6-oxo-1,6-dihydropyri-
midin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octade-
ca-1(18),2(6),4,14,16-pentaen-8-one; [0717]
(9R,13S)-13-{4-[5-chloro-2-(2-methylphenyl)phenyl]-6-oxo-1,6-dihydropyrim-
idin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadec-
a-1(18),2(6),4,14,16-pentaen-8-one; [0718]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethoxy)phenyl]phenyl}-6-oxo-1,6--
dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0719]
(9R,13S)-13-{4-[5-chloro-2-(2-chlorophenyl)phenyl]-6-oxo-1,6-dihydropyrim-
idin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadec-
a-1(18),2(6),4,14,16-pentaen-8-one; [0720]
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)phenyl]phenyl}-6-oxo-1,6-d-
ihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0721]
(9R,13S)-13-(4-{5-chloro-2-[4-(propan-2-ylsulfanyl)phenyl]phenyl}-6-oxo-1-
,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0722]
4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)benzene-1-sulfonamide; [0723]
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethoxy)phenyl]phenyl}-6-oxo-1,6-d-
ihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0724]
N-[3-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricycl-
o
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-d-
ihydropyrimidin-4-yl}phenyl)phenyl]methanesulfonamide; [0725]
3-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)benzonitrile; [0726]
(9R,13S)-13-(4-{5-chloro-2-[3-(trifluoromethoxy)phenyl]phenyl}-6-oxo-1,6--
dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0727]
(9R,13S)-13-{4-[5-chloro-2-(3-methanesulfonylphenyl)phenyl]-6-oxo-1,6-dih-
ydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,-
6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0728] methyl
4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)benzoate; [0729]
(9R,13S)-13-{4-[5-chloro-2-(3-methylphenyl)phenyl]-6-oxo-1,6-dihydropyrim-
idin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadec-
a-1(18),2(6),4,14,16-pentaen-8-one; [0730]
4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)benzonitrile; [0731]
(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-indol-5-yl)phenyl]-6-oxo-1,6-dihy-
dropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0732]
(9R,13S)-13-{4-[5-chloro-2-(isoquinolin-5-yl)phenyl]-6-oxo-1,6-dihydropyr-
imidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octad-
eca-1(18),2(6),4,14,16-pentaen-8-one; [0733] methyl
3-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)benzoate; [0734]
N-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricycl-
o
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-d-
ihydropyrimidin-4-yl}phenyl)phenyl]methanesulfonamide; [0735]
(9R,13S)-13-(4-{5-chloro-2-[3-(trifluoromethyl)phenyl]phenyl}-6-oxo-1,6-d-
ihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; [0736]
(9R,13S)-13-{4-[5-chloro-2-(4-methoxyphenyl)phenyl]-6-oxo-1,6-dihydropyri-
midin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octade-
ca-1(18),2(6),4,14,16-pentaen-8-one; [0737]
(9R,13S)-13-{4-[5-chloro-2-(4-chlorophenyl)phenyl]-6-oxo-1,6-dihydropyrim-
idin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadec-
a-1(18),2(6),4,14,16-pentaen-8-one; [0738]
(9R,13S)-13-{4-[5-chloro-2-(pyridin-4-yl)phenyl]-6-oxo-1,6-dihydropyrimid-
in-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca--
1(18),2(6),4,14,16-pentaen-8-one; [0739]
(9R,13S)-13-{4-[5-chloro-2-(isoquinolin-7-yl)phenyl]-6-oxo-1,6-dihydropyr-
imidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octad-
eca-1(18),2(6),4,14,16-pentaen-8-one; [0740]
(9R,13S)-13-{4-[5-chloro-2-(pyrimidin-5-yl)phenyl]-6-oxo-1,6-dihydropyrim-
idin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadec-
a-1(18),2(6),4,14,16-pentaen-8-one; [0741] ethyl
2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricycl-
o
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-d-
ihydropyrimidin-4-yl}phenyl)-1H-pyrazol-1-yl]acetate; [0742]
(9R,13S)-13-{4-[5-chloro-2-(1-ethyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dih-
ydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,-
6]octadeca-1(18),2(6),4,14,16-pentaen-8-one; and [0743]
(9R,13S)-13-(4-{5-chloro-2-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]phenyl}-6--
oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one.
[0744] In another embodiment, the compounds of the present
invention have Factor XIa or plasma kallikrein Ki values.ltoreq.10
.mu.M.
[0745] In another embodiment, the compounds of the present
invention have Factor XIa or plasma kallikrein Ki values.ltoreq.1
.mu.M.
[0746] In another embodiment, the compounds of the present
invention have Factor XIa or plasma kallikrein Ki values.ltoreq.0.5
.mu.M.
[0747] In another embodiment, the compounds of the present
invention have Factor XIa or plasma kallikrein Ki values.ltoreq.0.1
.mu.M.
II. Other Embodiments of the Invention
[0748] In another embodiment, the present invention provides a
composition comprising at least one of the compounds of the present
invention or a stereoisomer, a tautomer, a pharmaceutically
acceptable salt, or a solvate thereof.
[0749] 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, a tautomer, a pharmaceutically acceptable salt,
or a solvate, thereof.
[0750] 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, a tautomer, a pharmaceutically acceptable salt, or a
solvate thereof.
[0751] In another embodiment, the present invention provides a
process for making a compound of the present invention.
[0752] In another embodiment, the present invention provides an
intermediate for making a compound of the present invention.
[0753] In another embodiment, the present invention provides a
pharmaceutical composition further comprising additional
therapeutic agent(s). In a preferred embodiment, the present
invention provides pharmaceutical composition, wherein the
additional therapeutic agent(s) are an anti-platelet agent or a
combination thereof. Preferably, the anti-platelet agent(s) are
clopidogrel and/or aspirin, or a combination thereof.
[0754] In another embodiment, the present invention provides a
method for the treatment and/or prophylaxis of a thromboembolic
disorder comprising administering to a patient in need of such
treatment and/or prophylaxis a therapeutically effective amount of
at least one of the compounds of the present invention or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a
solvate thereof.
[0755] In another embodiment, the present invention provides a
compound of the present invention or a stereoisomer, a tautomer, a
pharmaceutically acceptable salt, or a solvate thereof, for use in
therapy.
[0756] In another embodiment, the present invention provides a
compound of the present invention or a stereoisomer, a tautomer, a
pharmaceutically acceptable salt, or a solvate thereof, for use in
therapy for the treatment and/or prophylaxis of a thromboembolic
disorder.
[0757] In another embodiment, the present invention also provides
the use of a compound of the present invention or a stereoisomer, a
tautomer, a pharmaceutically acceptable salt, or a solvate thereof,
for the manufacture of a medicament for the treatment and/or
prophylaxis of a thromboembolic disorder.
[0758] In another embodiment, the present invention provides a
method for treatment and/or prophylaxis of a thromboembolic
disorder, comprising: administering to a patient in need thereof a
therapeutically effective amount of a first and second therapeutic
agent, wherein the first therapeutic agent is a compound of the
present invention or a stereoisomer, a tautomer, a pharmaceutically
acceptable salt, or a solvate thereof, and the second therapeutic
agent is at least one agent selected from a factor Xa inhibitor
such as apixaban, rivaroxaban, betrixaban, edoxaban, an
anti-coagulant agent, an anti-platelet agent, a thrombin inhibiting
agent such as dabigatran, a thrombolytic agent, and a fibrinolytic
agent. Preferably, the second therapeutic agent is at least one
agent selected from warfarin, unfractionated heparin, low molecular
weight heparin, synthetic pentasaccharide, hirudin, argatroban,
aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate,
droxicam, diclofenac, eribaxaban, sulfinpyrazone, piroxicam,
ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab,
melagatran, desulfatohirudin, tissue plasminogen activator,
modified tissue plasminogen activator, anistreplase, urokinase, and
streptokinase. Preferably, the second therapeutic agent is at least
one anti-platelet agent. Preferably, the anti-platelet agent(s) are
clopidogrel and/or aspirin, or a combination thereof.
[0759] The thromboembolic disorder includes arterial cardiovascular
thromboembolic disorders, venous cardiovascular thromboembolic
disorders, arterial cerebrovascular thromboembolic disorders, and
venous cerebrovascular thromboembolic disorders. Examples of the
thromboembolic disorder include, but are not limited to, 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.
[0760] In another embodiment, the present invention provides a
method for the treatment and/or prophylaxis of an inflammatory
disorder comprising: administering to a patient in need of such
treatment and/or prophylaxis a therapeutically effective amount of
at least one of the compounds of the present invention or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a
solvate thereof. Examples of the inflammatory disorder include, but
are not limited to, sepsis, acute respiratory distress syndrome,
and systemic inflammatory response syndrome.
[0761] In another embodiment, the present invention provides a
method for the prophylaxis of a disease or condition in which
plasma kallikrein activity is implicated comprising administering
to a patient in need of such treatment and/or prophylaxis a
therapeutically effective amount of at least one of the compounds
of the present invention or a stereoisomer, a tautomer, a
pharmaceutically acceptable salt, or a solvate thereof.
[0762] The disease or condition in which plasma kallikrein activity
is implicated includes, but not limited to, impaired visual acuity,
diabetic retinopathy, diabetic macular edema, hereditary
angioedema, diabetes, pancreatitis, nephropathy, cardio myopathy,
neuropathy, inflammatory bowel disease, arthritis, inflammation,
septic shock, hypotension, cancer, adult respiratory distress
syndrome, disseminated intravascular coagulation, and
cardiopulmonary bypass surgery.
[0763] 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.
[0764] 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 and/or prophylaxis of a thromboembolic
disorder.
[0765] 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 embodiments. It is also to be understood that each
individual element of the embodiments is its own independent
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.
III. Chemistry
[0766] Throughout the specification and the appended claims, a
given chemical formula or name shall encompass all stereo and
optical isomers and racemates thereof where such isomers exist.
Unless otherwise indicated, all chiral (enantiomeric and
diastereomeric) and racemic forms are within the scope of the
invention. Many geometric isomers of C.dbd.C double bonds, C.dbd.N
double bonds, ring systems, and the like can also be present in the
compounds, and all such stable isomers are contemplated in the
present invention. Cis- and trans-(or E- and Z-) geometric isomers
of the compounds of the present invention are described and may be
isolated as a mixture of isomers or as separated isomeric forms.
The present compounds can be isolated in optically active or
racemic forms. Optically active forms may be prepared by resolution
of racemic forms or by synthesis from optically active 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 may be separated by conventional
methods, for example, by chromatography or fractional
crystallization. Depending on the process conditions the end
products of the present invention are obtained either in free
(neutral) or salt form. Both the free form and the salts of these
end products are within the scope of the invention. If so desired,
one form of a compound may be converted into another form. A free
base or acid may be converted into a salt; a salt may be converted
into the free compound or another salt; a mixture of isomeric
compounds of the present invention may be separated into the
individual isomers. Compounds of the present invention, free form
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.
[0767] The term "stereoisomer" refers to isomers of identical
constitution that differ in the arrangement of their atoms in
space. Enantiomers and diastereomers are examples of stereoisomers.
The term "enantiomer" refers to one of a pair of molecular species
that are mirror images of each other and are not superimposable.
The term "diastereomer" refers to stereoisomers that are not mirror
images. The term "racemate" or "racemic mixture" refers to a
composition composed of equimolar quantities of two enantiomeric
species, wherein the composition is devoid of optical activity.
[0768] The symbols "R" and "S" represent the configuration of
substituents around a chiral carbon atom(s). The isomeric
descriptors "R" and "S" are used as described herein for indicating
atom configuration(s) relative to a core molecule and are intended
to be used as defined in the literature (IUPAC Recommendations
1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).
[0769] The term "chiral" refers to the structural characteristic of
a molecule that makes it impossible to superimpose it on its mirror
image. The term "homochiral" refers to a state of enantiomeric
purity. The term "optical activity" refers to the degree to which a
homochiral molecule or nonracemic mixture of chiral molecules
rotates a plane of polarized light.
[0770] As used herein, the term "alkyl" or "alkylene" is intended
to include both branched and straight-chain saturated aliphatic
hydrocarbon groups having the specified number of carbon atoms. For
example, "C.sub.1 to C.sub.10 alkyl" or "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 to C.sub.6 alkyl"
or "C.sub.1-C.sub.6 alkyl" denotes alkyl having 1 to 6 carbon
atoms.
[0771] Alkyl group can be unsubstituted or substituted with at
least one hydrogen being replaced by another chemical group.
Example alkyl groups include, but are not limited to, methyl (Me),
ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g.,
n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl,
neopentyl). When "C.sub.0 alkyl" or "C.sub.0 alkylene" is used, it
is intended to denote a direct bond. "Alkyl" also includes
deuteroalkyl such as CD.sub.3.
[0772] "Alkenyl" or "alkenylene" is intended to include hydrocarbon
chains of either straight or branched configuration having one or
more, preferably one to three, carbon-carbon double bonds that may
occur in any stable point along the chain. For example, "C.sub.2 to
C.sub.6 alkenyl" or "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; such as ethenyl, propenyl, butenyl, pentenyl, and
hexenyl.
[0773] "Alkynyl" or "alkynylene" is intended to include hydrocarbon
chains of either straight or branched configuration having one or
more, preferably one to three, carbon-carbon triple bonds that may
occur in any stable point along the chain. For example, "C.sub.2 to
C.sub.6 alkynyl" or "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, and
hexynyl.
[0774] The term "alkoxy" or "alkyloxy" refers to an --O-alkyl
group. "C.sub.1 to C.sub.6 alkoxy" or "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. Example alkoxy groups
include, but are not limited to, methoxy, ethoxy, propoxy (e.g.,
n-propoxy and isopropoxy), and t-butoxy. Alkoxy also includes
deuteroalkoxy such as OCD.sub.3. 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-- and ethyl-S--.
[0775] "Halo" or "halogen" includes fluoro, chloro, bromo, and
iodo. "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
halogens. 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" that 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.
[0776] "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 to C.sub.6
haloalkoxy" or "C.sub.1-6 haloalkoxy", is intended to include
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6 haloalkoxy
groups. Examples of haloalkoxy include, but are not limited to,
trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy.
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--, and pentafluoroethyl-S--.
[0777] The term "amino", as used herein, refers to --NH.sub.2.
[0778] The term "substituted amino", as used herein, refers to the
defined terms below having the suffix "amino" such as "arylamino",
"alkylamino", "arylamino", etc.
[0779] The term "alkoxycarbonyl", as used herein, refers to an
alkoxy group attached to the parent molecular moiety through a
carbonyl group.
[0780] The term "alkoxycarbonylamino", as used herein, refers to an
--NHR wherein R is an alkoxycarbonyl group.
[0781] The term "alkylamino", as used herein refers to --NHR,
wherein R is an alkyl group.
[0782] The term "alkylcarbonyl", as used herein, refers to an alkyl
group attached to the parent molecular moiety through a carbonyl
group.
[0783] The term "alkylcarbonylamino", as used herein, refers to
--NHR wherein R is an alkylcarbonyl group.
[0784] The term "aminosulfonyl", as used herein, refers to
--SO.sub.2NH.sub.2.
[0785] The term "arylalkyl", as used herein, refers to an alkyl
group substituted with one, two, or three aryl groups.
[0786] The term "arylamino", as used herein, refers to --NHR
wherein R is an aryl group.
[0787] The term "arylcarbonyl", as used herein, refers to an aryl
group attached to the parent molecular moiety through a carbonyl
group.
[0788] The term "arylcarbonylamino", as used herein refers to --NHR
wherein R is an arylcarbonyl group.
[0789] The term "cyano", as used herein, refers to --CN.
[0790] The term "cycloalkylamino", as used herein, refers to --NHR
wherein R is a cycloalkyl group.
[0791] The term "cycloalkylcarbonyl", as used herein, refers to a
cycloalkyl group attached to the parent molecular moiety through a
carbonyl group.
[0792] The term "cycloalkylcarbonylamino", as used herein, refers
to --NHR wherein R is a cycloalkylcarbonyl group.
[0793] The term "cycloalkyloxy", as used herein, refers to a
cycloalkyl group attached to the parent molecular moiety through an
oxygen atom.
[0794] The term "dialkylamino", as used herein, refers to NR.sub.2,
wherein each R is an alkyl group. The two alkyl groups are the same
or different.
[0795] The term "haloalkoxy", as used herein, refers to a haloalkyl
group attached to the parent molecular moiety through an oxygen
atom.
[0796] The term "haloalkyl", as used herein, refers to an alkyl
group substituted by one, two, three, or four halogen atoms.
[0797] The term "haloalkylamino", as used herein, refers to --NHR
wherein R is a haloalkyl group.
[0798] The term "carbonyl" refers to C(.dbd.O) or C(O).
[0799] The term "carboxyl" or "carboxyl" refers to C(.dbd.O)OH.
[0800] The terms "carboxyl ester" and "oxycarbonyl" refer to the
groups --C(O)O-alkyl, --C(O)O-substituted alkyl, --C(O)O-alkenyl,
--C(O)O-substituted alkenyl, --C(O)O-alkynyl, C(O)O-substituted
alkynyl, --C(O)O-cycloalkyl, --C(O)O-substituted cycloalkyl,
--C(O)O-aryl, --C(O)O-substituted aryl, --C(O)O-heteroaryl,
--C(O)O-substituted heteroaryl, --C(O)O-heterocyclic, and
--C(O)O-substituted heterocyclic.
[0801] The term "aminoacyl" or "amide", or the prefix "carbamoyl",
"carboxamide", "substituted carbamoyl" or "substituted carboxamide"
refers to the group --C(O)NRR where each R is independently
selected from the group consisting of hydrogen, alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,
heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic.
[0802] The term "haloalkylcarbonyl", as used herein, refers to a
haloalkyl group attached to the parent molecular moiety through a
carbonyl group.
[0803] The term "haloalkylcarbonylamino", as used herein, refers to
--NHR wherein R is a haloalkylcarbonyl group.
[0804] The terms "alkylcarbonyl" refer to an alkyl or substituted
alkyl bonded to a carbonyl.
[0805] The term "alkoxycarbonyl", as used herein, refers to an
alkoxy group attached to the parent molecular moiety through a
carbonyl group.
[0806] The term "hydroxy" or "hydroxyl" refers to OH.
[0807] As used herein the term "thiol" means --SH. A thiol may be
substituted with a substituent disclosed herein, in particular
alkyl(thioalkyl), aryl(thioaryl), or alkoxy(thioalkoxy).
[0808] As used herein the term "sulfonyl", used alone or linked to
other terms such as alkylsulfonyl or arylsulfonyl, refers to the
divalent radicals --SO.sub.2--. In aspects of the invention a
sulfonyl group, the sulfonyl group may be attached to a substituted
or unsubstituted hydroxyl, alkyl group, ether group, alkenyl group,
alkynyl group, aryl group, cycloalkyl group, cycloalkenyl group,
cycloalkynyl group, heterocyclic group, carbohydrate, peptide, or
peptide derivative.
[0809] The term "cycloalkyl" refers to cyclized alkyl groups,
including mono-, bi- or poly-cyclic ring systems. "C.sub.3 to
C.sub.7 cycloalkyl" or "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, and norbornyl.
Branched cycloalkyl groups such as 1-methylcyclopropyl and
2-methylcyclopropyl are included in the definition of
"cycloalkyl".
[0810] As used herein, "carbocycle", "carbocyclyl", or "carbocyclic
residue" 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 hydrocarbon ring, any of which
may be saturated, partially unsaturated, unsaturated or aromatic.
Examples of such carbocyclyls include, but are not limited to,
cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,
cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,
cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,
[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),
[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,
adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shown
above, bridged rings are also included in the definition of
carbocyclyl (e.g., [2.2.2]bicyclooctane). Preferred carbocyclyls,
unless otherwise specified, are cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, phenyl, and indanyl. When the term
"carbocyclyl" is used, it is intended to include "aryl". A bridged
ring occurs when one or more carbon atoms link two non-adjacent
carbon atoms. Preferred bridges are one or two carbon atoms. It is
noted that a bridge always converts a monocyclic ring into a
tricyclic ring. When a ring is bridged, the substituents recited
for the ring may also be present on the bridge.
[0811] As used herein, the term "bicyclic carbocyclyl" or "bicyclic
carbocyclic group" is intended to mean a stable 9- or 10-membered
carbocyclic ring system that 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.
[0812] "Aryl" groups refer to monocyclic or polycyclic aromatic
hydrocarbons, including, for example, phenyl, naphthyl, and
phenanthranyl. Aryl moieties are well known and described, for
example, in Lewis, R. J., ed., Hawley's Condensed Chemical
Dictionary, 13th Edition, John Wiley & Sons, Inc., New York
(1997).
[0813] "C.sub.6 or C.sub.10 aryl" or "C.sub.6-10 aryl" refers to
phenyl and naphthyl. Unless otherwise specified, "aryl", "C.sub.6
or C.sub.10 aryl" or "C.sub.6-10 aryl" or "aromatic residue" may be
unsubstituted or substituted with 1 to 5 groups, preferably 1 to 3
groups, OH, OCH.sub.3, Cl, F, Br, I, CN, NO.sub.2, NH.sub.2,
N(CH.sub.3)H, N(CH.sub.3).sub.2, CF.sub.3, OCF.sub.3,
C(.dbd.O)CH.sub.3, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CO.sub.2H, and
CO.sub.2CH.sub.3.
[0814] The term "benzyl", as used herein, refers to a methyl group
on which one of the hydrogen atoms is replaced by a phenyl group,
wherein said phenyl group may optionally be substituted with 1 to 5
groups, preferably 1 to 3 groups, OH, OCH.sub.3, Cl, F, Br, I, CN,
NO.sub.2, NH.sub.2, N(CH.sub.3)H, N(CH.sub.3).sub.2, CF.sub.3,
OCF.sub.3, C(.dbd.O)CH.sub.3, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CO.sub.2H, and
CO.sub.2CH.sub.3.
[0815] As used herein, the term "heterocycle", "heterocyclyl" or
"heterocyclic ring" is intended to mean a stable 3-, 4-, 5-, 6-, or
7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-,
13-, or 14-membered polycyclic heterocyclic ring that is saturated,
partially unsaturated, or fully unsaturated, and that contains
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 (i.e., N.fwdarw.O and
S(O).sub.p, wherein p is 0, 1 or 2). The nitrogen atom may be
substituted or unsubstituted (i.e., N or NR wherein R is H or
another substituent, if defined). The heterocyclic ring may be
attached to its pendant group at any heteroatom or carbon atom that
results in a stable structure. The heterocyclic rings described
herein may be substituted on carbon or on a nitrogen atom if the
resulting compound is stable. A nitrogen in the heterocyclyl may
optionally be quaternized. It is preferred that when the total
number of S and O atoms in the heterocyclyl 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 heterocyclyl is not more
than 1. When the term "heterocyclyl" is used, it is intended to
include heteroaryl.
[0816] Examples of heterocyclyls include, but are not limited to,
acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl,
benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl,
benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl,
carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran,
furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, imidazolopyridinyl, indolenyl, indolinyl,
indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,
isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,
isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl,
isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl,
oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl,
phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,
phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl,
4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl,
pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl,
pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl,
pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl,
2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,
quinoxalinyl, quinuclidinyl, 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,
thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,
thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
Also included are fused ring and spiro compounds containing, for
example, the above heterocyclyls.
[0817] Examples of 5- to 10-membered heterocyclyls 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.
[0818] Examples of 5- to 6-membered heterocyclyls 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 heterocyclyls.
[0819] As used herein, the term "bicyclic heterocyclyl" "bicyclic
heterocyclyl" 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 heterocyclyl, a 6-membered heterocyclyl or a
carbocyclyl (provided the first ring is not benzo when the second
ring is a carbocyclyl).
[0820] 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 heterocyclyl 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 heterocyclyl is not more than 1.
[0821] 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-tetrahydroquinolinyl, 2,3-dihydrobenzofuranyl, chromanyl,
1,2,3,4-tetrahydroquinoxalinyl, and
1,2,3,4-tetrahydroquinazolinyl.
[0822] As used herein, the term "aromatic heterocyclic group" or
"heteroaryl" is intended to mean stable monocyclic and polycyclic
aromatic hydrocarbons that include at least one heteroatom ring
member such as sulfur, oxygen, or nitrogen. Heteroaryl groups
include, without limitation, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl,
imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl,
benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl,
tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl,
carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and
benzodioxane. Heteroaryl groups are substituted or unsubstituted.
The nitrogen atom is substituted or unsubstituted (i.e., N or NR
wherein R is H or another substituent, if defined). The nitrogen
and sulfur heteroatoms may optionally be oxidized (i.e., N.fwdarw.O
and S(O).sub.p, wherein p is 0, 1 or 2).
[0823] Bridged rings are also included in the definition of
heterocyclyl. A bridged ring occurs when one or more atoms (i.e.,
C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.
Examples of bridged rings 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.
[0824] The term "counterion" is used to represent a negatively
charged species such as chloride, bromide, hydroxide, acetate, and
sulfate.
[0825] When a dotted ring is used within a ring structure, this
indicates that the ring structure may be saturated, partially
saturated or unsaturated.
[0826] As referred to herein, the term "substituted" means that at
least one hydrogen atom is replaced with a non-hydrogen group,
provided that normal valencies are maintained and that the
substitution results in a stable compound. When a substituent is
keto (i.e., .dbd.O), then 2 hydrogens on the atom are replaced.
Keto substituents are not present on aromatic moieties. When a ring
system (e.g., carbocyclic or heterocyclic) is said to be
substituted with a carbonyl group or a double bond, it is intended
that the carbonyl group or double bond be part (i.e., within) of
the ring. Ring double bonds, as used herein, are double bonds that
are formed between two adjacent ring atoms (e.g., C.dbd.C, C.dbd.N,
or N.dbd.N).
[0827] 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.
[0828] 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 groups, then said group may optionally be
substituted with up to three R groups, and at each occurrence R is
selected independently from the definition of R. Also, combinations
of substituents and/or variables are permissible only if such
combinations result in stable compounds.
[0829] 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 in 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.
[0830] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms that 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,
and/or other problem or complication, commensurate with a
reasonable benefit/risk ratio.
[0831] 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.
[0832] The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound that 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 Edition, Mack Publishing Company, Easton, Pa. (1990), the
disclosure of which is hereby incorporated by reference.
[0833] 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:
[0834] a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985),
and Widder, K. et al., eds., Methods in Enzymology, 112:309-396,
Academic Press (1985);
[0835] b) Bundgaard, H., Chapter 5: "Design and Application of
Prodrugs", A Textbook of Drug Design and Development, pp. 113-191,
Krosgaard-Larsen, P. et al., eds., Harwood Academic Publishers
(1991);
[0836] c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);
[0837] d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988);
and
[0838] e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).
[0839] Compounds containing a carboxy group can form
physiologically hydrolyzable esters that 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.1-6alkyl,
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.1-6alkoxycarbonyloxy-C.sub.1-6alkyl (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.
[0840] Preparation of prodrugs is well known in the art and
described in, for example, King, F. D., ed., Medicinal Chemistry:
Principles and Practice, The Royal Society of Chemistry, Cambridge,
UK (1994); Testa, B. et al., Hydrolysis in Drug and Prodrug
Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and
Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C. G., ed., The
Practice of Medicinal Chemistry, Academic Press, San Diego, Calif.
(1999).
[0841] The present invention is intended to include all isotopes of
atoms occurring in the present compounds. Isotopes include those
atoms having the same atomic number but different mass numbers. By
way of general example and without limitation, isotopes of hydrogen
include deuterium and tritium. Deuterium has one proton and one
neutron in its nucleus and that has twice the mass of ordinary
hydrogen. Deuterium can be represented by symbols such as ".sup.2H"
or "D". The term "deuterated" herein, by itself or used to modify a
compound or group, refers to replacement of one or more hydrogen
atom(s), which is attached to carbon(s), with a deuterium atom.
Isotopes of carbon include .sup.13C and .sup.14C.
[0842] Isotopically-labeled compounds of the invention can
generally be prepared by conventional techniques known to those
skilled in the art or by processes analogous to those described
herein, using an appropriate isotopically-labeled reagent in place
of the non-labeled reagent otherwise employed. Such compounds have
a variety of potential uses, e.g., as standards and reagents in
determining the ability of a potential pharmaceutical compound to
bind to target proteins or receptors, or for imaging compounds of
this invention bound to biological receptors in vivo or in
vitro.
[0843] "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.
[0844] 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. The
solvent molecules in the solvate may be present in a regular
arrangement and/or a non-ordered arrangement. The solvate may
comprise either a stoichiometric or nonstoichiometric amount of the
solvent molecules. "Solvate" encompasses both solution-phase and
isolable solvates. Exemplary solvates include, but are not limited
to, hydrates, ethanolates, methanolates, and isopropanolates.
Methods of solvation are generally known in the art.
[0845] Abbreviations as used herein, 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, "N" for normal,
"M" for molar, "mmol" for millimole or millimoles, "min" for minute
or minutes, "h" for hour or hours, "rt" for room temperature, "RT"
for retention time, "RBF" for round bottom flask, "atm" for
atmosphere, "psi" for pounds per square inch, "conc." for
concentrate, "RCM" for ring-closing metathesis, "sat" or "sat'd"
for saturated, "SFC" for supercritical fluid chromatography "MW"
for molecular weight, "mp" for melting point, "ee" for enantiomeric
excess, "MS" or "Mass Spec" for mass spectrometry, "ESI" for
electrospray ionization mass spectroscopy, "HR" for high
resolution, "HRMS" for high resolution mass spectrometry, "LCMS"
for liquid chromatography mass spectrometry, "HPLC" for high
pressure liquid chromatography, "RP HPLC" for reverse phase HPLC,
"TLC" or "tlc" for thin layer chromatography, "NMR" for nuclear
magnetic resonance spectroscopy, "nOe" for nuclear Overhauser
effect 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, and ".alpha.",
".beta.", "R", "S", "E", and "Z" are stereochemical designations
familiar to one skilled in the art. [0846] Me methyl [0847] Et
ethyl [0848] Pr propyl [0849] i-Pr isopropyl [0850] Bu butyl [0851]
i-Bu isobutyl [0852] t-Bu tert-butyl [0853] Ph phenyl [0854] Bn
benzyl [0855] Boc or BOC tert-butyloxycarbonyl [0856] Boc.sub.2O
di-tert-butyl dicarbonate [0857] AcOH or HOAc acetic acid [0858]
AlCl.sub.3 aluminum chloride [0859] AIBN azobisisobutyronitrile
[0860] aqueous aq [0861] BBr.sub.3 boron tribromide [0862]
BCl.sub.3 boron trichloride [0863] BEMP
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphor-
ine [0864] BOP reagent
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate [0865] Burgess reagent
1-methoxy-N-triethylammoniosulfonyl-methanimidate [0866] Cbz
carbobenzyloxy [0867] DCM or CH.sub.2Cl.sub.2 dichloromethane
[0868] CH.sub.3CN or ACN acetonitrile [0869] CDCl.sub.3
deutero-chloroform [0870] CHCl.sub.3 chloroform [0871] mCPBA or
m-CPBA meta-chloroperbenzoic acid [0872] Cs.sub.2CO.sub.3 cesium
carbonate [0873] Cu(OAc).sub.2 copper (II) acetate [0874] CuI
copper(I) iodide [0875] CuSO.sub.4 copper(II) sulfate [0876]
Cy.sub.2NMe N-cyclohexyl-N-methylcyclohexanamine [0877] DBU
1,8-diazabicyclo[5.4.0]undec-7-ene [0878] DCE 1,2-dichloroethane
[0879] DEA diethylamine [0880] Dess-Martin
1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-beniziodoxol-3-(1H)-one
[0881] DIC or DIPCDI diisopropylcarbodiimide [0882] DIEA, DIPEA or
Hunig's base diisopropylethylamine [0883] DMAP
4-dimethylaminopyridine [0884] DME 1,2-dimethoxyethane [0885] DMF
dimethyl formamide [0886] DMSO dimethyl sulfoxide [0887] cDNA
complimentary DNA [0888] Dppp
(R)-(+)-1,2-bis(diphenylphosphino)propane [0889] DuPhos
(+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene [0890] EDC
N-(3-dimethylaminopropyl)-Y-ethylcarbodiimide [0891] EDCI
N-(3-dimethylaminopropyl)-Y-ethylcarbodiimide hydrochloride [0892]
EDTA ethylenediaminetetraacetic acid [0893] (S,S)-EtDuPhosRh(I)
(+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)rho-
dium(I) trifluoromethanesulfonate [0894] Et.sub.3N or TEA
triethylamine [0895] EtOAc ethyl acetate [0896] Et.sub.2O diethyl
ether [0897] EtOH ethanol [0898] GMF glass microfiber filter [0899]
Grubbs II
(1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro
(phenylmethylene)(triycyclohexylphosphine)ruthenium [0900] HCl
hydrochloric acid [0901] HATU
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0902] HEPES
4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid [0903] Hex
hexane [0904] HOBt or HOBT 1-hydroxybenzotriazole [0905]
H.sub.2O.sub.2 hydrogen peroxide [0906] H.sub.2SO.sub.4 sulfuric
acid [0907] IBX 2-iodoxybenzoic acid [0908] InCl.sub.3 Indium(III)
chloride [0909] Jones reagent CrO.sub.3 in aqueous H.sub.2SO.sub.4,
2 M [0910] K.sub.2CO.sub.3 potassium carbonate [0911]
K.sub.2HPO.sub.4 potassium phosphate dibasic [0912] K.sub.3PO.sub.4
potassium phosphate tribasic [0913] KOAc potassium acetate [0914]
K.sub.3PO.sub.4 potassium phosphate [0915] LAH lithium aluminum
hydride [0916] LG leaving group [0917] LiOH lithium hydroxide
[0918] MeOH methanol [0919] MgSO.sub.4 magnesium sulfate [0920]
MsOH or MSA methylsulfonic acid [0921] NaCl sodium chloride [0922]
NaH sodium hydride [0923] NaHCO.sub.3 sodium bicarbonate [0924]
Na.sub.2CO.sub.3 sodium carbonate [0925] NaOH sodium hydroxide
[0926] Na.sub.2SO.sub.3 sodium sulfite [0927] Na.sub.2SO.sub.4
sodium sulfate [0928] NBS N-bromosuccinimide [0929] NCS
N-chlorosuccinimide [0930] NH.sub.3 ammonia [0931] NH.sub.4Cl
ammonium chloride [0932] NH.sub.4OH ammonium hydroxide [0933]
NH.sub.4COOH ammonium formate [0934] NMM N-methylmorpholine [0935]
OTf triflate or trifluoromethanesulfonate [0936]
Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone)dipalladium(0) [0937]
Pd(OAc).sub.2 palladium(II) acetate [0938] Pd/C palladium on carbon
[0939] Pd(dppf)Cl.sub.2
[1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) [0940]
Ph.sub.3PCl.sub.2 triphenylphosphine dichloride [0941] PG
protecting group [0942] POCl.sub.3 phosphorus oxychloride [0943]
i-PrOH or IPA isopropanol [0944] PS Polystyrene [0945] rt room
temperature [0946] SEM-Cl 2-(trimethysilyl)ethoxymethyl chloride
[0947] SiO.sub.2 silica oxide [0948] SnCl.sub.2 tin(II) chloride
[0949] TBAI tetra-n-butylammonium iodide [0950] TBN t-butyl nitrite
[0951] TFA trifluoroacetic acid [0952] THF tetrahydrofuran [0953]
TMSCHN.sub.2 trimethylsilyldiazomethane [0954] T3P.RTM. propane
phosphonic acid anhydride [0955] TRIS tris (hydroxymethyl)
aminomethane [0956] pTsOH p-toluenesulfonic acid
[0957] The compounds of the present invention can be prepared in a
number of ways known to one skilled in the art of organic
synthesis, which are described in more detail in Section VI.
IV. Biology
[0958] 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
thromboembolic disorders and include acute coronary syndrome,
unstable angina, myocardial infarction, atrial fibrillation,
thrombosis in the cavity of the heart, 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, stents, artificial heart valves, and hemodialysis
membranes.
[0959] Some conditions contribute to the risk of developing
thrombosis. For example, alterations of the vessel wall, changes in
the flow of blood, and alterations in the composition of the
vascular compartment. These risk factors are collectively known as
Virchow's triad. (Colman, R. W. et al., eds., Hemostasis and
Thrombosis, Basic Principles and Clinical Practice, Fifth Edition,
p. 853, Lippincott Williams & Wilkins (2006)).
[0960] Antithrombotic agents are frequently given to patients at
risk of developing thromboembolic disease because of the presence
of one or more predisposing risk factors from Virchow's triad to
prevent formation of an occlusive thrombus (primary prevention).
For example, in an orthopedic surgery setting (e.g., hip and knee
replacement), an antithrombotic agent is frequently administered
prior to a surgical procedure. The antithrombotic agent
counterbalances the prothrombotic stimulus exerted by vascular flow
alterations (stasis), potential surgical vessel wall injury, as
well as changes in the composition of the blood due to the acute
phase response related to surgery. Another example of the use of an
antithrombotic agent for primary prevention is dosing with aspirin,
a platelet activation inhibitor, in patients at risk for developing
thrombotic cardiovascular disease. Well recognized risk factors in
this setting include age, male gender, hypertension, diabetes
mellitus, lipid alterations, and obesity.
[0961] Antithrombotic agents are also indicated for secondary
prevention, following an initial thrombotic episode. For example,
patients with mutations in factor V (also known as factor V Leiden)
and additional risk factors (e.g., pregnancy), are dosed with
anticoagulants to prevent the reoccurrence of venous thrombosis.
Another example entails secondary prevention of cardiovascular
events in patients with a history of acute myocardial infarction or
acute coronary syndrome. In a clinical setting, a combination of
aspirin and clopidogrel (or other thienopyridines) may be used to
prevent a second thrombotic event.
[0962] Antithrombotic agents are also given to treat the disease
state (i.e., by arresting its development) after it has already
started. For example, patients presenting with deep vein thrombosis
are treated with anticoagulants (i.e., heparin, warfarin, or LMWH)
to prevent further growth of the venous occlusion. Over time, these
agents also cause a regression of the disease state because the
balance between prothrombotic factors and
anticoagulant/profibrinolytic pathways is changed in favor of the
latter. Examples on the arterial vascular bed include the treatment
of patients with acute myocardial infarction or acute coronary
syndrome with aspirin and clopidogrel to prevent further growth of
vascular occlusions and eventually leading to a regression of
thrombotic occlusions.
[0963] Thus, antithrombotic agents are used widely for primary and
secondary prevention (i.e., prophylaxis or risk reduction) of
thromboembolic disorders, as well as treatment of an already
existing thrombotic process. Drugs that inhibit blood coagulation,
or anticoagulants, are "pivotal agents for prevention and treatment
of thromboembolic disorders" (Hirsh, J. et al., Blood, 105:453-463
(2005)).
[0964] An alternative way of initiation of coagulation is operative
when blood is exposed to artificial surfaces (e.g., during
hemodialysis, "on-pump" cardiovascular surgery, vessel grafts,
bacterial sepsis), on cell surfaces, cellular receptors, cell
debris, DNA, RNA, and extracellular matrices. This process is also
termed contact activation. Surface absorption of factor XII leads
to a conformational change in the factor XII molecule, thereby
facilitating activation to proteolytic active factor XII molecules
(factor XIIa and factor XIIf). Factor XIIa (or XIIf) has a number
of target proteins, including plasma prekallikrein and factor XI.
Active plasma kallikrein further activates factor XII, leading to
an amplification of contact activation. Alternatively, the serine
protease prolylcarboxylpeptidase can activate plasma kallikrein
complexed with high molecular weight kininogen in a multiprotein
complex formed on the surface of cells and matrices (Shariat-Madar
et al., Blood, 108:192-199 (2006)). Contact activation is a surface
mediated process responsible in part for the regulation of
thrombosis and inflammation, and is mediated, at least in part, by
fibrinolytic-, complement-, kininogen/kinin-, and other humoral and
cellular pathways (for review, Coleman, R., "Contact Activation
Pathway", Hemostasis and Thrombosis, pp. 103-122, Lippincott
Williams & Wilkins (2001); Schmaier, A. H., "Contact
Activation", Thrombosis and Hemorrhage, pp. 105-128 (1998)). The
biological relevance of the contact activation system for
thromboembolic diseases is supported by the phenotype of factor XII
deficient mice. More specifically, factor XII deficient mice were
protected from thrombotic vascular occlusion in several thrombosis
models as well as stroke models and the phenotype of the XII
deficient mice was identical to XI deficient mice (Renne et al., J.
Exp. Med., 202:271-281 (2005); Kleinschmitz et al., J. Exp. Med.,
203:513-518 (2006)). The fact that factor XI is down-stream from
factor XIIa, combined with the identical phenotype of the XII and
XI deficient mice suggest that the contact activation system could
play a major role in factor XI activation in vivo.
[0965] Factor XI is a zymogen of a trypsin-like serine protease and
is present in plasma at a relatively low concentration. Proteolytic
activation at an internal R369-1370 bond yields a heavy chain (369
amino acids) and a light chain (238 amino acids). The latter
contains a typical trypsin-like catalytic triad (H413, D464, and
S557). Activation of factor XI by thrombin is believed to occur on
negatively charged surfaces, most likely on the surface of
activated platelets. Platelets contain high affinity (0.8 nM)
specific sites (130-500/platelet) for activated factor XI. After
activation, factor XIa remains surface bound and recognizes factor
IX as its normal macromolecular substrate. (Galiani, D., Trends
Cardiovasc. Med., 10:198-204 (2000)).
[0966] In addition to the feedback activation mechanisms described
above, thrombin activates thrombin activated fibrinolysis inhibitor
(TAFI), a plasma carboxypeptidase that cleaves C-terminal lysine
and arginine residues on fibrin, reducing the ability of fibrin to
enhance tissue-type plasminogen activator (tPA) dependent
plasminogen activation. In the presence of antibodies to FXIa, clot
lysis can occur more rapidly independent of plasma TAFI
concentration. (Bouma, B. N. et al., Thromb. Res., 101:329-354
(2001).) Thus, inhibitors of factor XIa are expected to be
anticoagulant and profibrinolytic.
[0967] Further evidence for the anti-thromboembolic effects of
targeting factor XI is derived from mice deficient in factor XI. It
has been demonstrated that complete fXI deficiency protected mice
from ferric chloride (FeCl.sub.3)-induced carotid artery thrombosis
(Rosen et al., Thromb. Haemost., 87:774-777 (2002); Wang et al., J.
Thromb. Haemost., 3:695-702 (2005)). Also, factor XI deficiency
rescues the perinatal lethal phenotype of complete protein C
deficiency (Chan et al., Amer. J. Pathology, 158:469-479 (2001)).
Furthermore, baboon cross-reactive, function blocking antibodies to
human factor XI protect against baboon arterial-venous shunt
thrombosis (Gruber et al., Blood, 102:953-955 (2003)). Evidence for
an antithrombotic effect of small molecule inhibitors of factor XIa
is also disclosed in published U.S. Patent Publication No.
2004/0180855 A1. Taken together, these studies suggest that
targeting factor XI will reduce the propensity for thrombotic and
thromboembolic diseases.
[0968] Genetic evidence indicates that factor XI is not required
for normal homeostasis, implying a superior safety profile of the
factor XI mechanism compared to competing antithrombotic
mechanisms. In contrast to hemophilia A (factor VIII deficiency) or
hemophilia B (factor IX deficiency), mutations of the factor XI
gene causing factor XI deficiency (hemophilia C) result in only a
mild to moderate bleeding diathesis characterized primarily by
postoperative or posttraumatic, but rarely spontaneous hemorrhage.
Postoperative bleeding occurs mostly in tissue with high
concentrations of endogenous fibrinolytic activity (e.g., oral
cavity, and urogenital system). The majority of the cases are
fortuitously identified by preoperative prolongation of aPTT
(intrinsic system) without any prior bleeding history.
[0969] The increased safety of inhibition of XIa as an
anticoagulation therapy is further supported by the fact that
Factor XI knock-out mice, which have no detectable factor XI
protein, undergo normal development, and have a normal life span.
No evidence for spontaneous bleeding has been noted. The aPTT
(intrinsic system) is prolonged in a gene dose-dependent fashion.
Interestingly, even after severe stimulation of the coagulation
system (tail transection), the bleeding time is not significantly
prolonged compared to wild-type and heterozygous litter mates.
(Gailani, D., Frontiers in Bioscience, 6:201-207 (2001); Gailani,
D. et al., Blood Coagulation and Fibrinolysis, 8:134-144 (1997).)
Taken together, these observations suggest that high levels of
inhibition of factor XIa should be well tolerated. This is in
contrast to gene targeting experiments with other coagulation
factors, excluding factor XII.
[0970] In vivo activation of factor XI can be determined by complex
formation with either C1 inhibitor or alpha 1 antitrypsin. In a
study of 50 patients with acute myocardial infarction (AMI),
approximately 25% of the patients had values above the upper normal
range of the complex ELISA. This study can be viewed as evidence
that at least in a subpopulation of patients with AMI, factor XI
activation contributes to thrombin formation (Minnema, M. C. et
al., Arterioscler. Thromb. Vasc. Biol., 20:2489-2493 (2000)). A
second study establishes a positive correlation between the extent
of coronary arteriosclerosis and factor XIa in complex with alpha 1
antitrypsin (Murakami, T. et al., Arterioscler. Thromb. Vasc.
Biol., 15:1107-1113 (1995)). In another study, Factor XI levels
above the 90th percentile in patients were associated with a
2.2-fold increased risk for venous thrombosis (Meijers, J. C. M. et
al., N. Engl. J. Med., 342:696-701 (2000)).
[0971] Also, it is preferred to find new compounds with improved
activity in in vitro clotting assays, compared with known serine
protease inhibitors, such as the activated partial thromboplastin
time (aPTT) or prothrombin time (PT) assay. (for a description of
the aPTT and PT assays see, Goodnight, S. H. et al., "Screening
Tests of Hemostasis", Disorders of Thrombosis and Hemostasis: A
Clinical Guide, Second Edition, pp. 41-51, McGraw-Hill, New York
(2001)).
[0972] It is also desirable and preferable to find compounds with
advantageous and improved characteristics compared with known
serine protease inhibitors, in one or more of the following
categories that 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 that 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.
[0973] Pre-clinical studies demonstrated significant antithrombotic
effects of small molecule factor XIa inhibitors in rabbit and rat
model of arterial and venous thrombosis, at doses that preserved
hemostasis. (Wong P. C. et al., Journal of Thrombosis and
Thrombolysis, 32(2):129-137 (August 2011); Schumacher, W. et al.,
Journal of Thrombosis and Haemostasis, 3(Suppl. 1):P1228 (2005);
Schumacher, W. A. et al., Eur. J. Pharmacol., 167-174 (2007)).
Furthermore, it was observed that in vitro prolongation of the aPTT
by specific XIa inhibitors is a good predictor of efficacy in our
thrombosis models. Thus, the in vitro aPTT test can be used as a
surrogate for efficacy in vivo. Pre-clinical and clinical studies
using FXI antisense (ASO) has been shown to be effective in various
venous and arterial thrombosis models, comparable to warfarin or
enoxaparin without increased bleeding (Bueller et al., DOI:
10.1056/NEJMoa1405760 (2014)).
[0974] As used herein, the term "patient" encompasses all mammalian
species.
[0975] As used herein, "treating" or "treatment" cover the
treatment of a disease-state in a mammal, particularly in a human,
and include: (a) inhibiting the disease-state, i.e., arresting it
development; and/or (b) relieving the disease-state, i.e., causing
regression of the disease state.
[0976] As used herein, "prophylaxis" is the protective treatment of
a disease state to reduce and/or minimize the risk and/or reduction
in the risk of recurrence of a disease state by administering to a
patient a therapeutically effective amount of at least one of the
compounds of the present invention or a or a stereoisomer, a
tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
Patients may be selected for prophylaxis therapy based on factors
that are known to increase risk of suffering a clinical disease
state compared to the general population. For prophylaxis
treatment, conditions of the clinical disease state may or may not
be presented yet. "Prophylaxis" treatment can be divided into (a)
primary prophylaxis and (b) secondary prophylaxis. Primary
prophylaxis is defined as treatment to reduce or minimize the risk
of a disease state in a patient that has not yet presented with a
clinical disease state, whereas secondary prophylaxis is defined as
minimizing or reducing the risk of a recurrence or second
occurrence of the same or similar clinical disease state.
[0977] As used herein, "prevention" cover the preventive treatment
of a subclinical disease-state in a mammal, particularly in a
human, aimed at reducing the probability of the occurrence of a
clinical disease-state. Patients are selected for preventative
therapy based on factors that are known to increase risk of
suffering a clinical disease state compared to the general
population.
[0978] As used herein, "risk reduction" covers therapies that lower
the incidence of development of a clinical disease state. As such,
primary and secondary prevention therapies are examples of risk
reduction.
[0979] "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 to inhibit factor XIa
and/or plasma kallikrein and/or to prevent or treat the disorders
listed herein. When applied to a combination, the term refers to
combined amounts of the active ingredients that result in the
preventive or therapeutic effect, whether administered in
combination, serially, or simultaneously.
[0980] The term "thrombosis", as used herein, refers to formation
or presence of a thrombus (pl. thrombi); clotting within a blood
vessel that 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 that 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 "thromboembolic
disorders" entails both "thrombotic" and "embolic" disorders
(defined above).
[0981] The term "thromboembolic disorders" as used herein includes
arterial cardiovascular thromboembolic disorders, venous
cardiovascular or cerebrovascular thromboembolic disorders, and
thromboembolic disorders in the chambers of the heart or in the
peripheral circulation. 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 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. The medical implants or devices include, but
are not limited to: prosthetic valves, artificial valves,
indwelling catheters, stents, blood oxygenators, shunts, vascular
access ports, ventricular assist devices and artificial hearts or
heart chambers, and vessel grafts. The procedures include, but are
not limited to: cardiopulmonary bypass, percutaneous coronary
intervention, and hemodialysis. In another embodiment, the term
"thromboembolic disorders" includes acute coronary syndrome,
stroke, deep vein thrombosis, and pulmonary embolism.
[0982] In another embodiment, the present invention provides a
method for the treatment of a thromboembolic disorder, wherein the
thromboembolic disorder is selected from unstable angina, an acute
coronary syndrome, atrial fibrillation, myocardial infarction,
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. In another embodiment,
the present invention provides a method for the treatment of a
thromboembolic disorder, wherein the thromboembolic disorder is
selected from acute coronary syndrome, stroke, venous thrombosis,
atrial fibrillation, and thrombosis resulting from medical implants
and devices.
[0983] In another embodiment, the present invention provides a
method for the primary prophylaxis of a thromboembolic disorder,
wherein the thromboembolic disorder is selected from unstable
angina, an acute coronary syndrome, atrial fibrillation, 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. In another embodiment, the present invention
provides a method for the primary prophylaxis of a thromboembolic
disorder, wherein the thromboembolic disorder is selected from
acute coronary syndrome, stroke, venous thrombosis, and thrombosis
resulting from medical implants and devices.
[0984] In another embodiment, the present invention provides a
method for the secondary prophylaxis of a thromboembolic disorder,
wherein the thromboembolic disorder is selected from unstable
angina, an acute coronary syndrome, atrial fibrillation, recurrent
myocardial infarction, 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. In another embodiment, the present invention
provides a method for the secondary prophylaxis of a thromboembolic
disorder, wherein the thromboembolic disorder is selected from
acute coronary syndrome, stroke, atrial fibrillation and venous
thrombosis.
[0985] 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.
[0986] 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.
[0987] Thromboembolic disorders are frequently associated with
patients with atherosclerosis. Risk factors for atherosclerosis
include but are not limited to male gender, age, hypertension,
lipid disorders, and diabetes mellitus. Risk factors for
atherosclerosis are at the same time risk factors for complications
of atherosclerosis, i.e., thromboembolic disorders.
[0988] Similarly, arterial fibrillation is frequently associated
with thromboembolic disorders. Risk factors for arterial
fibrillation and subsequent thromboembolic disorders include
cardiovascular disease, rheumatic heart disease, nonrheumatic
mitral valve disease, hypertensive cardiovascular disease, chronic
lung disease, and a variety of miscellaneous cardiac abnormalities
as well as thyrotoxicosis.
[0989] Diabetes mellitus is frequently associated with
atherosclerosis and thromboembolic disorders. Risk factors for the
more common type 2 include but are not limited to are family
history, obesity, physical inactivity, race/ethnicity, previously
impaired fasting glucose or glucose tolerance test, history of
gestational diabetes mellitus or delivery of a "big baby",
hypertension, low HDL cholesterol, and polycystic ovary
syndrome.
[0990] Risk factors for congenital thrombophilia include gain of
function mutations in coagulation factors or loss of function
mutations in the anticoagulant- or fibrinolytic pathways.
[0991] Thrombosis has been associated with a variety of tumor
types, e.g., pancreatic cancer, breast cancer, brain tumors, lung
cancer, ovarian cancer, prostate cancer, gastrointestinal
malignancies, and Hodgkins or non-Hodgkins lymphoma. Recent studies
suggest that the frequency of cancer in patients with thrombosis
reflects the frequency of a particular cancer type in the general
population (Levitan, N. et al., Medicine (Baltimore), 78(5):285-291
(1999); Levine M. et al., N. Engl. J. Med., 334(11):677-681 (1996);
Blom, J. W. et al., JAMA, 293(6):715-722 (2005)). Hence, the most
common cancers associated with thrombosis in men are prostate,
colorectal, brain, and lung cancer, and in women are breast, ovary,
and lung cancer. The observed rate of venous thromboembolism (VTE)
in cancer patients is significant. The varying rates of VTE between
different tumor types are most likely related to the selection of
the patient population. Cancer patients at risk for thrombosis may
possess any or all of the following risk factors: (i) the stage of
the cancer (i.e., presence of metastases), (ii) the presence of
central vein catheters, (iii) surgery and anticancer therapies
including chemotherapy, and (iv) hormones and antiangiogenic drugs.
Thus, it is common clinical practice to dose patients having
advanced tumors with heparin or low molecular heparin to prevent
thromboembolic disorders. A number of low molecular heparin
preparations have been approved by the FDA for these
indications.
[0992] There are three main clinical situations when considering
the prevention of VTE in a medical cancer patient: (i) the patient
is bedridden for prolonged periods of time; (ii) the ambulatory
patient is receiving chemotherapy or radiation; and (iii) the
patient is with indwelling central vein catheters. Unfractionated
heparin (UFH) and low molecular weight heparin (LMWH) are effective
antithrombotic agents in cancer patients undergoing surgery.
(Mismetti, P. et al., British Journal of Surgery, 88:913-930
(2001).)
A. In Vitro Assays
[0993] The effectiveness of compounds of the present invention as
inhibitors of the coagulation Factors XIa, VIIa, IXa, Xa, XIIa,
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 or
fluorogenic 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
pNA (para nitroaniline), which was monitored spectrophotometrically
by measuring the increase in absorbance at 405 nm, or the release
of AMC (amino methylcoumarin), 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 or fluorescence change 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 the
inhibitory constant, K.sub.i.
[0994] 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; JT Baker or Fisher Scientific).
Determinations were made using purified human Factor XIa at a final
concentration of 25-200 pM (Haematologic Technologies) and the
synthetic substrate S-2366 (pyroGlu-Pro-Arg-pNA; Chromogenix or
AnaSpec) at a concentration of 0.0002-0.001 M.
[0995] Factor VIIa determinations were made in 0.005 M calcium
chloride, 0.15 M sodium chloride, 0.05 M HEPES buffer containing
0.1% PEG 8000 at a pH of 7.5. Determinations were made using
purified human Factor VIIa (Haematologic Technologies) or
recombinant human Factor VIIa (Novo Nordisk) at a final assay
concentration of 0.5-10 nM, recombinant soluble tissue factor at a
concentration of 10-40 nM and the synthetic substrate
H-D-Ile-Pro-Arg-pNA (S-2288; Chromogenix or BMPM-2; AnaSpec) at a
concentration of 0.001-0.0075 M.
[0996] Factor IXa determinations were made in 0.005 M calcium
chloride, 0.1 M sodium chloride, 0.0000001 M Refludan (Berlex),
0.05 M TRIS base and 0.5% PEG 8000 at a pH of 7.4. Refludan was
added to inhibit small amounts of thrombin in the commercial
preparations of human Factor IXa. 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-Ph'Gly-Arg-AMC; CenterChem) at a concentration of
0.0004-0.0005 M.
[0997] Factor Xa determinations were made in 0.1 M sodium phosphate
buffer at a pH of 7.5 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
0.0002-0.00035 M.
[0998] Factor XIIa determinations were made in 0.05 M HEPES buffer
at pH 7.4 containing 0.145 M NaCl, 0.05 M KCl, and 0.1% PEG 8000.
Determinations were made using purified human Factor XIIa at a
final concentration of 4 nM (American Diagnostica) and the
synthetic substrate SPECTROZYME.RTM. #312
(H-D-CHT-Gly-L-Arg-pNA.2AcOH; American Diagnostica) at a
concentration of 0.00015 M.
[0999] Plasma kallikrein determinations were made in 0.1 M sodium
phosphate buffer at a pH of 7.5 containing 0.1-0.2 M sodium
chloride and 0.5% PEG 8000. Determinations were made using purified
human plasma kallikrein (Enzyme Research Laboratories) at a final
assay concentration of 200 pM and the synthetic substrate S-2302
(H-(D)-Pro-Phe-Arg-pNA; Chromogenix) at a concentration of
0.00008-0.0004 M.
[1000] Thrombin determinations were made in 0.1 M sodium phosphate
buffer at a pH of 7.5 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 or AnaSpec) at a
concentration of 0.0002-0.0004 M.
[1001] The Michaelis constant, K.sub.m, for substrate hydrolysis by
each protease, was determined at 25.degree. C. or 37.degree. C. in
the absence of inhibitor. 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 or fluorescence change versus time) were measured.
The following relationships were used to calculate K.sub.i
values:
(Vmax*S)/(K.sub.m+S);
(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
v.sub.s/v.sub.o=A+((B-A)/1+((IC.sub.50/(I).sub.n))); and
K.sub.i=IC.sub.50/(1+S/K.sub.m) for a competitive inhibitor
where:
[1002] v.sub.o is the velocity of the control in the absence of
inhibitor;
[1003] v.sub.s is the velocity in the presence of inhibitor;
[1004] V.sub.max is the maximum reaction velocity;
[1005] I is the concentration of inhibitor;
[1006] A is the minimum activity remaining (usually locked at
zero);
[1007] B is the maximum activity remaining (usually locked at
1.0);
[1008] n is the Hill coefficient, a measure of the number and
cooperativity of potential inhibitor binding sites;
[1009] IC.sub.50 is the concentration of inhibitor that produces
50% inhibition under the assay conditions;
[1010] K.sub.i is the dissociation constant of the enzyme inhibitor
complex;
[1011] S is the concentration of substrate; and
[1012] K.sub.m is the Michaelis constant for the substrate.
[1013] 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 FXIa
versus protease P=K.sub.i for protease P/K.sub.i for FXIa).
Compounds with selectivity ratios>20 are considered
selective.
[1014] The effectiveness of compounds of the present invention as
inhibitors of coagulation can be determined using a standard or
modified clotting assay. An increase in the plasma clotting time in
the presence of inhibitor is indicative of anticoagulation.
Relative clotting time is the clotting time in the presence of an
inhibitor divided by the clotting time in the absence of an
inhibitor. The results of this assay may be expressed as
IC1.5.times. or IC2.times., the inhibitor concentration required to
increase the clotting time by 1.5 time or 2 times, respectively,
relative to the clotting time in the absence of the inhibitor. The
IC1.5.times. or IC2.times. is found by linear interpolation from
relative clotting time versus inhibitor concentration plots using
inhibitor concentration that spans the IC1.5.times. or
IC2.times..
[1015] Clotting times are determined using citrated normal human
plasma as well as plasma obtained from a number of laboratory
animal species (e.g., rat, or rabbit). A compound is diluted into
plasma beginning with a 10 mM DMSO stock solution. The final
concentration of DMSO is less than 2%. Plasma clotting assays are
performed in an automated coagulation analyzer (Sysmex,
Dade-Behring, Ill.). Similarly, clotting times can be determined
from laboratory animal species or humans dosed with compounds of
the invention.
[1016] Activated Partial Thromboplastin Time (aPTT) is determined
using ACTIN.RTM. (Dade-Behring, Ill.) following the directions in
the package insert. Plasma (0.05 mL) is warmed to 37.degree. C. for
1 minute. ACTIN.RTM. (0.05 mL) is added to the plasma and incubated
for an additional 2 to 5 minutes. Calcium chloride (25 mM, 0.05 mL)
is added to the reaction to initiate coagulation. The clotting time
is the time in seconds from the moment calcium chloride is added
until a clot is detected.
[1017] Prothrombin Time (PT) is determined using thromboplastin
(Innovin, Dade-Behring, Ill.) following the directions in the
package insert. Plasma (0.05 mL) is warmed to 37.degree. C. for 1
minute. Thromboplastin (0.1 mL) is added to the plasma to initiate
coagulation. The clotting time is the time in seconds from the
moment thromboplastin is added until a clot is detected.
[1018] Chymotrypsin 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; JT Baker or Fisher Scientific).
Determinations were made using purified human chymotrypsin at a
final concentration of 0.2-2 nM (Calbiochem) and the synthetic
substrate S-2586 (Methoxy-Succinyl-Arg-Pro-Tyr-pNA; Chromogenix) at
a concentration of 0.0005-0.005 M.
[1019] Trypsin determinations were made in 0.1 M sodium phosphate
buffer at a pH of 7.5 containing 0.2 M sodium chloride and 0.5% PEG
8000. Determinations were made using purified human trypsin (Sigma)
at a final assay concentration of 0.1-1 nM and the synthetic
substrate S-2222 (Bz-Ile-Glu (gamma-OMe, 50%)-Gly-Arg-pNA;
Chromogenix) at a concentration of 0.0005-0.005 M.
[1020] The exemplified Examples disclosed below were tested in the
Factor XIa assay described above and found having Factor XIa
inhibitory activity. A range of Factor XIa inhibitory activity (Ki
values) of .ltoreq.10 .mu.M (10000 nM) was observed.
[1021] The exemplified Examples disclosed below were tested in the
Plasma Kallikrein assay described above, with some Examples having
both Factor XIa and Plasma Kallikrein inhibitory activity. For
those Examples where the Plasma Kallikrein inhibitory activity was
observed as Ki values of .ltoreq.10 .mu.M (10000 nM), the
inhibitory activity is reported.
B. In Vivo Assays
[1022] 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 Arteriovenous Shunt
Thrombosis Models.
[1023] a. In Vivo Electrically-Induced Carotid Artery Thrombosis
(ECAT) Model
[1024] The rabbit ECAT model, described by Wong et al. (J.
Pharmacol. Exp. Ther., 295:212-218 (2000)), 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 or after the
initiation of thrombosis. Drug treatment prior to initiation of
thrombosis is used to model the ability of test agents to prevent
and reduce the risk of thrombus formation, whereas dosing after
initiation is used to model the ability to treat existing
thrombotic disease. 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 the 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.).
[1025] b. In Vivo Rabbit Arteriovenous (AV) Shunt Thrombosis
Model
[1026] The rabbit AV shunt model, described by Wong et al. (Wong,
P. C. et al., J. Pharmacol. Exp. Ther. 292:351-357 (2000)), 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 that 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.).
[1027] The anti-inflammatory effect of these compounds can be
demonstrated in an Evans Blue dye extravasation assay using
C1-esterase inhibitor deficient mice. In this model, mice are dosed
with a compound of the present invention, Evans Blue dye is
injected via the tail vein, and extravasation of the blue dye is
determined by spectrophotometric means from tissue extracts.
[1028] The ability of the compounds of the current invention to
reduce or prevent the systemic inflammatory response syndrome, for
example, as observed during on-pump cardiovascular procedures, can
be tested in in vitro perfusion systems, or by on-pump surgical
procedures in larger mammals, including dogs and baboons. Read-outs
to assess the benefit of the compounds of the present invention
include for example reduced platelet loss, reduced platelet/white
blood cell complexes, reduced neutrophil elastase levels in plasma,
reduced activation of complement factors, and reduced activation
and/or consumption of contact activation proteins (plasma
kallikrein, factor XII, factor XI, high molecular weight kininogen,
C1-esterase inhibitors).
[1029] The compounds of the present invention may also be useful as
inhibitors of additional serine proteases, notably human thrombin,
human plasma kallikrein and human plasmin. Because of their
inhibitory action, these compounds are indicated for use in the
prevention or treatment of physiological reactions, including blood
coagulation, fibrinolysis, blood pressure regulation and
inflammation, and wound healing catalyzed by the aforesaid class of
enzymes. Specifically, the compounds have utility as drugs for the
treatment of diseases arising from elevated thrombin activity of
the aforementioned serine proteases, such as myocardial infarction,
and as reagents used as anticoagulants in the processing of blood
to plasma for diagnostic and other commercial purposes.
V. Pharmaceutical Compositions, Formulations and Combinations
[1030] 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.
[1031] The term "pharmaceutical composition" means a composition
comprising a compound of the invention in combination with at least
one additional pharmaceutically acceptable 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, 18th Edition
(1990).
[1032] 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.
[1033] 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 about 1000 mg/kg of body weight, preferably
between about 0.01 to about 100 mg/kg of body weight per day, and
most preferably between about 0.1 to about 20 mg/kg/day.
Intravenously, the most preferred doses will range from about 0.001
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.
[1034] Compounds of this invention can also be administered by
parenteral administration (e.g., intra-venous, intra-arterial,
intramuscularly, or subcutaneously. When administered intra-venous
or intra-arterial, the dose can be given continuously or
intermittent. Furthermore, formulation can be developed for
intramuscularly and subcutaneous delivery that ensure a gradual
release of the active pharmaceutical ingredient. In one embodiment,
the pharmaceutical composition is a solid formulation, e.g., a
spray-dried composition, which may be used as is, or whereto the
physician or the patient adds solvents, and/or diluents prior to
use.
[1035] 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.
[1036] 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, e.g., oral tablets, capsules, elixirs, and syrups,
and consistent with conventional pharmaceutical practices.
[1037] 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.
[1038] 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.
[1039] Compounds of the present invention may also be coupled with
soluble polymers as targetable drug carriers. Such polymers can
include polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamidephenol,
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. Solid dispersions are
also called solid-state dispersions. In some embodiments, any
compound described herein is formulated as a spray dried dispersion
(SDD). An SDD is a single phase amorphous molecular dispersion of a
drug in a polymer matrix. It is a solid solution prepared by
dissolving the drug and a polymer in a solvent (e.g., acetone,
methanol or the like) and spray drying the solution. The solvent
rapidly evaporates from droplets which rapidly solidifies the
polymer and drug mixture trapping the drug in amorphous form as an
amorphous molecular dispersion.
[1040] 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.
[1041] 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.
[1042] Liquid dosage forms for oral administration can contain
coloring and flavoring to increase patient acceptance.
[1043] 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 bisulfate, 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.
[1044] Suitable pharmaceutical carriers are described in
Remington's Pharmaceutical Sciences, Mack Publishing Company, a
standard reference text in this field.
[1045] Where the compounds of this invention are combined with
other anticoagulant agents, for example, a daily dosage may be
about 0.1 to about 100 milligrams of the compound of the present
invention and about 0.1 to about 100 milligrams 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
about 300 milligrams per dosage unit, and the second anti-coagulant
in an amount of about 1 to about 500 milligrams per dosage
unit.
[1046] 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
about 300 milligrams of the compound of the present invention and
about 50 to about 150 milligrams of the anti-platelet agent,
preferably about 0.1 to about 4 milligrams of the compound of the
present invention and about 1 to about 3 milligrams of antiplatelet
agents, per kilogram of patient body weight.
[1047] Where the compounds of the present invention are
administered in combination with thrombolytic agent, typically a
daily dosage may be about 0.1 to about 100 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 thrombolytic agent when administered alone may be
reduced by about 50-80% when administered with a compound of the
present invention.
[1048] 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.
[1049] 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.
[1050] In another embodiment, the present invention provides a
pharmaceutical composition further comprising additional
therapeutic agent(s) selected from 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, phospodiesterase 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.
[1051] In another embodiment, the present invention provides a
pharmaceutical composition further comprising additional
therapeutic agent(s) selected from an antiarrhythmic 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.
[1052] 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.
[1053] In another embodiment, the present invention provides a
pharmaceutical composition wherein the additional therapeutic agent
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, renin
inhibitors (aliskiren) and vasopepsidase inhibitors, an
antiarrythmic agent selected from I.sub.Kur inhibitors, an
anticoagulant selected from thrombin inhibitors, antithrombin-III
activators, heparin co-factor II activators, other factor XIa
inhibitors, other kallikrein inhibitors, plasminogen activator
inhibitor (PAI-1) antagonists, thrombin activatable fibrinolysis
inhibitor (TAFI) inhibitors, factor VIIa inhibitors, factor IXa
inhibitors, and factor Xa inhibitors, or an antiplatelet agent
selected from GPIIb/IIIa blockers, GP Ib/IX blockers, protease
activated receptor 1 (PAR-1) antagonists, protease activated
receptor4 (PAR-4) antagonists, prostaglandin E2 receptor EP3
antagonists, collagen receptor antagonists, phosphodiesterase-III
inhibitors, P2Y.sub.1 receptor antagonists, P2Y.sub.12 antagonists,
thromboxane receptor antagonists, cyclooxygense-1 inhibitors, and
aspirin, or a combination thereof.
[1054] In another embodiment, the present invention provides
pharmaceutical composition, wherein the additional therapeutic
agent(s) are an anti-platelet agent or a combination thereof.
[1055] In another embodiment, the present invention provides a
pharmaceutical composition, wherein the additional therapeutic
agent is the anti-platelet agent clopidogrel.
[1056] The compounds of the present invention can be administered
alone or in combination with one or more additional therapeutic
agents. 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.
[1057] Compounds that can be administered in combination with the
compounds of the present invention include, but are not limited to,
anticoagulants, anti-thrombin agents, anti-platelet agents,
fibrinolytics, hypolipidemic agents, antihypertensive agents, and
anti-ischemic agents.
[1058] 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 LOVENOX.RTM.), 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.RTM., 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.
[1059] 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
granule-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
(PAR-1) antagonists (e.g., E-5555, SCH-530348, SCH-203099,
SCH-529153 and SCH-205831), and pharmaceutically acceptable salts
or prodrugs thereof.
[1060] Other examples of suitable anti-platelet agents for use in
combination with the compounds of the present invention, with or
without aspirin, are ADP (adenosine diphosphate) receptor
antagonists, preferably antagonists of the purinergic receptors
P2Y.sub.1 and P2Y.sub.12, with P2Y.sub.12 being even more
preferred. Preferred P2Y.sub.12 receptor antagonists include
clopidogrel, ticlopidine, prasugrel, ticagrelor, and cangrelor, and
pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine
and clopidogrel are also preferred compounds since they are known
to be more gentle than aspirin on the gastrointestinal tract in
use. Clopidogrel is an even more preferred agent.
[1061] A preferred example is a triple combination of a compound of
the present invention, aspirin, and another anti-platelet agent.
Preferably, the anti-platelet agent is clopidogrel or prasugrel,
more preferably clopidogrel.
[1062] 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 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, 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 a-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.
[1063] 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.
[1064] Examples of suitable cholesterol/lipid lowering agents and
lipid profile therapies for use in combination with the compounds
of the present invention include HMG-CoA reductase inhibitors
(e.g., pravastatin, lovastatin, simvastatin, fluvastatin,
atorvastatin, rosuvastatin, and other statins), low-density
lipoprotein (LDL) receptor activity modulators (e.g., HOE-402,
PCSK9 inhibitors), bile acid sequestrants (e.g., cholestyramine and
colestipol), nicotinic acid or derivatives thereof (e.g.,
NIASPAN.RTM.), GPR109B (nicotinic acid receptor) modulators,
fenofibric acid derivatives (e.g., gemfibrozil, clofibrate,
fenofibrate and benzafibrate) and other peroxisome
proliferator-activated receptors (PPAR) alpha modulators, PPARdelta
modulators (e.g., GW-501516), PPARgamma modulators (e.g.,
rosiglitazone), compounds that have multiple functionality for
modulating the activities of various combinations of PPARalpha,
PPARgamma and PPARdelta, probucol or derivatives thereof (e.g.,
AGI-1067), cholesterol absorption inhibitors and/or Niemann-Pick
C1-like transporter inhibitors (e.g., ezetimibe), cholesterol ester
transfer protein inhibitors (e.g., CP-529414), squalene synthase
inhibitors and/or squalene epoxidase inhibitors or mixtures
thereof, acyl coenzyme A: cholesteryl acyltransferase (ACAT) 1
inhibitors, ACAT2 inhibitors, dual ACAT1/2 inhibitors, ileal bile
acid transport inhibitors (or apical sodium co-dependent bile acid
transport inhibitors), microsomal triglyceride transfer protein
inhibitors, liver-X-receptor (LXR) alpha modulators, LXRbeta
modulators, LXR dual alpha/beta modulators, FXR modulators, omega 3
fatty acids (e.g., 3-PUFA), plant stanols and/or fatty acid esters
of plant stanols (e.g., sitostanol ester used in BENECOL.RTM.
margarine), endothelial lipase inhibitors, and HDL functional
mimetics which activate reverse cholesterol transport (e.g., apoAI
derivatives or apoAI peptide mimetics).
[1065] The compounds of the present invention can also be combined
with soluble guanylate cyclase inhibitors, Chymase inhibitors, ROMK
inhibitors, ACE inhibitors, ATII inhibitors, ATR inhibitors, NEP
inhibitors and other compounds to treat heart failure.
[1066] 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
thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasma kallikrein. Such
compounds may be provided in a commercial kit, for example, for use
in pharmaceutical research involving thrombin, Factor VIIa, IXa,
Xa, XIa, and/or plasma kallikrein. 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 experimentor 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.
[1067] The compounds of the present invention may also be used in
diagnostic assays involving thrombin, Factor VIIa, IXa, Xa, XIa,
and/or plasma kallikrein. For example, the presence of thrombin,
Factor VIIa, IXa, Xa XIa, and/or plasma kallikrein in an unknown
sample could be determined by addition of the relevant chromogenic
substrate, for example S2366 for Factor XIa, 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 XIa was present.
[1068] Extremely potent and selective compounds of the present
invention, those having K.sub.i values less than or equal to 0.001
.mu.M against the target protease and greater than or equal to 0.1
.mu.M against the other proteases, may also be used in diagnostic
assays involving the quantitation of thrombin, Factor VIIa, IXa,
Xa, XIa, and/or plasma kallikrein in serum samples. For example,
the amount of Factor XIa in serum samples could be determined by
careful titration of protease activity in the presence of the
relevant chromogenic substrate, S2366, with a potent Factor XIa
inhibitor of the present invention.
[1069] 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 and/or inflammatory
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 and/or inflammatory
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.
[1070] 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.
[1071] 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.
[1072] 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).
[1073] Other features of the invention will become apparent in the
course of the following descriptions of exemplary embodiments that
are given for illustration of the invention and are not intended to
be limiting thereof. The following Examples have been prepared,
isolated and characterized using the methods disclosed herein.
VI. General Synthesis Including Schemes
[1074] The compounds of the present invention may be synthesized by
many methods available to those skilled in the art of organic
chemistry (Maffrand, J. P. et al., Heterocycles, 16(1):35-37
(1981)). General synthetic schemes for preparing compounds of the
present invention are described below. These schemes are
illustrative and are not meant to limit the possible techniques one
skilled in the art may use to prepare the compounds disclosed
herein. Different methods to prepare the compounds of the present
invention will be evident to those skilled in the art.
Additionally, the various steps in the synthesis may be performed
in an alternate sequence in order to give the desired compound or
compounds.
[1075] Examples of compounds of the present invention prepared by
methods described in the general schemes are given in the
intermediates and examples section set out hereinafter. Preparation
of homochiral examples may be carried out by techniques known to
one skilled in the art. For example, homochiral compounds may be
prepared by separation of racemic products by chiral phase
preparative HPLC. Alternatively, the example compounds may be
prepared by methods known to give enantiomerically enriched
products. These include, but are not limited to, the incorporation
of chiral auxiliary functionalities into racemic intermediates
which serve to control the diastereoselectivity of transformations,
providing enantio-enriched products upon cleavage of the chiral
auxiliary.
[1076] 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 or
solvent mixture 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.
[1077] 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 et al.
(Protective Groups in Organic Synthesis, Fourth Edition,
Wiley-Interscience (2006)).
[1078] Representative pyrimidinone compounds 1a of this invention
can be prepared as described in Scheme 1. Using a modified
procedure described by Xiao (Organic Letters, 11:1421 (2009)),
suitably substituted pyrimidin-4-ol derivatives 1b can be coupled
with an appropriately substituted macrocycle amine 1c in the
presence of HATU and DBU in a solvent such as CH.sub.3CN to provide
pyrimidinone compounds 1a. When ring A is a SEM-protected imidazole
ring, an additional deprotection step employing 4N HCl in dioxane
or TFA in DCM is used to afford compounds of this invention.
##STR00071##
[1079] Scheme 2 describes the synthesis of suitably substituted
pyrimidin-4-ol derivatives 1b. Suzuki-Miyaura coupling between
6-chloropyrimidin-4-ol (2a) and an appropriately substituted
heteroaryl boronic acid or ester 2c in the presence of a base such
as Hunig's base or potassium phosphate tribasic, in a solvent
mixture, such as toluene and ethanol, or THF, using a precatalyst
such as Pd(PPh.sub.3).sub.4 or 2nd generation XPhos provides 1b.
Alternatively, when 4-chloro-6-methoxypyrimidine 2b is used, an
additional deprotection step, employing aqueous HBr at elevated
temperatures, is required to provide pyrimidin-4-ol derivatives
1b.
##STR00072##
[1080] Intermediates for preparation of compounds of the present
invention wherein ring A and B are a 6-membered heterocyclyl
(example--pyridine) can be derived from appropriately substituted
aldehydes 3a according to the general method outlined in Scheme 3.
Condensation of aldehyde 3a (X.dbd.N, Y.dbd.Z=M=CH) prepared
according to a modified procedure described by Negi (Synthesis, 991
(1996)), with (S)-2-methylpropane-2-sulfinamide in the presence of
anhydrous copper sulfate or cesium carbonate in a solvent such as
DCM gives the sulfinimine 3b (Ellman, J., J. Org. Chem., 64:1278
(1999)). Using a modified procedure described by Kuduk (Tetrahedron
Letters, 45:6641 (2004)), suitably substituted Grignard reagents,
for example allylmagnesium bromide, can be added to sulfinimine 3b
to give a sulfinamide 3c, as a mixture of diastereomers which can
be separated at various stages of the sequence. The
diastereoselectivity for the addition of allylmagnesium bromide to
sulfinimine 3b can be improved by employing indium(III) chloride
according to a modified procedure of Xu (Xu, M-H, Organic Letters,
10(6):1259 (2008)). Suzuki-Miyaura coupling between
4-chloropyridine 3c and an appropriately substituted heteroaryl
boronic acid or ester 3e in the presence of a base such as
potassium phosphate, in a solvent mixture, such as DMSO and
H.sub.2O, or DMF, using a precatalyst such as
Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 complex provides 3g.
Alternatively, the Suzuki-Miyaura coupling between boronic acid 3d
and an appropriately substituted heteroaryl halide 3f can be used
to prepare 3g. Protecting group interconversion can be accomplished
in two steps to give 3h. Alternatively, the protecting group
interconversion can take place initially on 3c followed by the
Suzuki-Miyaura coupling. The aniline 3h can then be coupled with an
appropriately substituted carboxylic acid 3i using T3P.RTM. and a
base, such as pyridine, to give the amide 3j. Using a modified
procedure described by Lovely (Tetrahedron Letters, 44:1379
(2003)), 3j, following pretreatment with p-toluenesulfonic acid to
form the pyridinium ion, can be cyclized via ring-closing
metathesis using a catalyst, such as Second Generation Grubbs
Catalyst in a suitable solvent, such as DCM, DCE, or toluene at
elevated temperature, to give the pyridine-containing macrocycle
3k. The alkene can be reduced with hydrogen over either palladium
on carbon or platinum oxide, and subsequent deprotection with TFA
in DCM or 4M HCl in dioxane provides amine 3l. Compounds of the
formula 3l can be converted to compounds in this invention
according to Scheme 1.
##STR00073## ##STR00074##
[1081] Methods for synthesis of a large variety of substituted
pyridine compounds useful as starting materials for the preparation
of compounds of the present invention are well known in the art and
have been extensively reviewed. (For examples of methods useful for
the preparation of pyridine starting materials see: Kroehnke, F.,
Synthesis, 1 (1976); Abramovitch, R. A., ed., "Pyridine and Its
Derivatives", The Chemistry of Heterocyclic Compounds, 14(Suppl.
1-4), John Wiley & Sons, New York (1974); Boulton, A. J. et
al., eds., Comprehensive Heterocyclic Chemistry, 2:165-524,
Pergamon Press, New York (1984); McKillop, A., ed., Comprehensive
Heterocyclic Chemistry, 5:1-300, Pergamon Press, New York
(1996)).
[1082] In cases where suitably substituted boronic acids are not
commercially available, a modification to this approach may be
adopted wherein a heteroaryl halide is subjected to a palladium
mediated coupling with a diboron species such as bis(pinacolato)
diboron or bis(neopentyl glycolato)diboron to provide the
corresponding 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane or the
5,5-dimethyl-[1,3,2]dioxaborolane intermediates using the method of
Ishiyama, T. et al. (J. Org. Chem., 60(23):7508-7510 (1995)).
Alternately, this same intermediate can be prepared by reaction of
the intermediate halide with the corresponding dialkoxyhydroborane
as described by Murata et al. (J. Org. Chem., 62(19):6458-6459
(1997)). The boron pinacolate intermediates can be used in place of
boronic acids for coupling to the aryl/heteroaryl halides or
triflates or the boron pinacolate intermediate can be converted to
the boronic acids. Alternately, the corresponding boronic acids can
be prepared by metal-halogen exchange of the aryl/heteroaryl
halide, quenching with a trialkoxyborate reagent, and aqueous
workup to provide the boronic acids (Miyaura, N. et al., Chem.
Rev., 95:2457 (1995)).
[1083] It is also realized that the scope of intermediate synthesis
can be further extended outside the use of Suzuki-Miyaura coupling
methodology since the precursor heteroaryl halides or triflates
described above are also precursors for Stille, Negishi, Hiyama,
and Kumada-type cross coupling methodologies (Tsuji, J., Transition
Metal Reagents and Catalysts: Innovations in Organic Synthesis,
John Wiley & Sons (2000); Tsuji, J., Palladium Reagents and
Catalysts: Innovations in Organic Synthesis, John Wiley & Sons
(1996)).
[1084] Intermediates for preparation of compounds of the present
invention wherein ring A is an imidazole ring, can be prepared from
an appropriately N-protected allylglycine (4a) according to the
general method outlined in Scheme 4 (Contour-Galcera et al.,
Bioorg. Med. Chem. Lett., 11(5):741-745 (2001)). Condensation of 4a
with a suitably substituted alpha-bromo-ketone bearing a heteroaryl
group (4b) in the presence of a suitable base such as potassium
bicarbonate, potassium carbonate or cesium carbonate in a suitable
solvent such as DMF provides a keto ester intermediate which can be
cyclized to afford an imidazole (4c) by heating in the presence of
excess ammonium acetate in a solvent such as toluene or xylene.
This latter transformation can be conveniently carried out on small
scale at 160.degree. C. in a microwave reactor or on larger scale
by refluxing the mixture while removing water via a Dean-Stark
trap. The resulting imidazole intermediate (4c) is then protected
by treatment with SEM-Cl in the presence of a base such as sodium
hydride or dicyclohexylmethylamine in a solvent such as THF or DCM.
The resulting heteroaryl bromide (4d) is then converted to the
corresponding amino-heterocyclyl (4e) by heating in a sealed vessel
with excess ammonium hydroxide, in the presence of copper iodide, a
base such as potassium carbonate and a catalytic amount of proline
in DMSO as solvent. Acylation of 4e with the appropriate alkenoic
acid and a coupling agent such as T3P.RTM. or BOP reagent, or
alternately, by treatment with an alkenoic acid chloride in the
presence of a base such as TEA, DIPEA, or pyridine provides diene
4f, which undergoes ring closing metathesis by heating in dilute
solution in the presence of p-toluene sulfonic acid and Second
Generation Grubbs Catalyst in a suitable solvent such as DCM or DCE
to provide the corresponding macrocycle (4g). Alternately, the RCM
can be run in a microwave at elevated temperatures without pTsOH.
Reduction of the double bond followed by bromination with NBS at
room temperature affords 4h. Suzuki-Miyaura coupling with
methylboronic acid or tetramethylstannane and removal of the
protecting group (PG), provides intermediate 4i. Intermediate 4i
can be converted to compounds of the present invention following
the steps described in Scheme 1.
##STR00075## ##STR00076##
[1085] Scheme 5 describes the intermediates in the present
invention where ring B is a heterocyclyl (example--pyrazole).
Chloropyridine 3b undergoes protecting group interconversion to
provide 5a which can be coupled to 4-nitropyrazoles 5b upon heating
with a Pd(II) salt such as Pd(OAc).sub.2 in the presence of a
phosphine ligand and a base such as potassium carbonate in a
solvent such as DMF or DMA, as described by Sames (Goikhman, R.,
Jacques, T. L. and Sames, D., J. Am. Chem. Soc., 131:3042 (2009)).
Zinc/HOAc reduction of the nitropyrazole, 5c, followed by amidation
with an appropriately substituted carboxylic acid, 5d, provides 5e.
Macrocyclization is then accomplished via ring-closing metathesis
using the Grubb's second generation ruthenium catalyst to yield 5f.
Hydrogenation of the resulting olefin and protecting group cleavage
yields amine 5g. Compounds of the formulae 5g can be converted to
compounds in this invention upon coupling with an appropriately
substituted pyrimidin-4-ol derivative, 1b, according to Scheme
1.
##STR00077## ##STR00078##
[1086] Compounds in this invention bearing alternate regiochemical
pyrazole substitution can be synthesized as shown in Scheme 6. When
R is an appropriate protective group
(example--trimethylsilylethoxymethyl), deprotection of 6a to 6b can
be followed by alkylation with an alkyl halide under basic
conditions, upon reaction with a boronic acid in the presence of
Cu(II) salts such as Cu(OAc).sub.2, or upon reaction with an aryl
iodide in the presence of CuI and a diamine ligand. In most cases,
the alkylation proceeds to give solely the product shown in 6c. In
select cases, products with the pyrazole regiochemistry shown in
Scheme 5 are formed as a minor component.
[1087] Compounds in this invention bearing alternate regiochemical
pyrazole substitution can be synthesized as shown in Scheme 6. When
R is an appropriate protective group
(example--trimethylsilylethoxymethyl), deprotection of 6a to 6b can
be followed by alkylation with an alkyl halide under basic
conditions, upon reaction with a boronic acid in the presence of
Cu(II) salts such as Cu(OAc).sub.2, or upon reaction with an aryl
iodide in the presence of CuI and a diamine ligand. In most cases,
the alkylation proceeds to give solely the product shown in 6c. In
select cases, products with the pyrazole regiochemistry shown in
Scheme 5 are formed as a minor component.
##STR00079##
[1088] Intermediates for preparation of compounds of the present
invention wherein R.sup.1a is --F can be prepared according to
Scheme 7. Olefin 5f can be subjected to hydrofluorination, yielding
as many as four isomeric alkyl fluorides. Following separation of
the isomers, deprotection of the amine protecting group is
accomplished by the action of either TFA or HCl, as previously
shown in Schemes 3-5. The intermediate 7a and 7b can be elaborated
to compounds of this invention according to the procedure described
in Scheme 1.
##STR00080##
[1089] Intermediates for preparation of compounds of the present
invention corresponding to Formula V can be prepared according to
Scheme 8. Chloropyridine 5a is reacted with aqueous hydrazine to
generate substituted hydrazine 8a. This hydrazine can be cyclized
upon treatment with .alpha.-cyanoketones 8b to yield aminopyrazoles
8c. These intermediates (8c) can be elaborated to compounds of this
invention according to the procedures described in Schemes 1 and
3.
##STR00081##
[1090] Scheme 9 describes the synthesis of suitably substituted
pyrimidin-4-ol derivatives where G.sup.1 is a substituted phenyl.
Aniline 9a can be converted to a suitably substituted triazole 9b
in a one pot, two step sequence. Specifically, the aniline 9a is
converted to the aryl azide in situ followed by cycloaddition with
a suitably substituted alkyne in the presence of a copper catalyst,
such as Cu.sub.2O, to provide 9b. Demethylation of 9b according to
Scheme 2 provides the pyrimidin-4-ol derivatives 9c. When R.sup.10
is a trimethylsilyl group, the silyl moiety can be converted to a
chloride at elevated temperature with NCS in the presence of silica
gel. Aniline 9a can be converted to the iodide 9d with p-TsOH,
NaNO.sub.2, and Nat Subjecting iodide 9d to a variety of
N-arylation or Suzuki-Miyaura couplings, followed by demethylation
according to Scheme 2, gives additional pyrimidin-4-ol derivatives
9e. When R.sup.8 is tetrazole, intermediate 9g can be prepared by
first treatment of the aniline 9a with trimethoxymethane and sodium
azide followed by demethylation according to Scheme 2.
##STR00082##
[1091] Scheme 10 describes the synthesis of suitably substituted
pyrimidin-4-ol derivatives where R.sup.8 is a thiadiazole. Bromide
10a can be converted to acetyl compound 10b by coupling with
1-(trimethylsilyl)ethanone with Pd catalyst. 10b can react with
ethyl hydrazinecarboxylate to form 10c, which upon treatment with
SOCl.sub.2 to give thiadiazole compound 10d. Intermediate 10e can
be obtained by demethylation of 10d according to Scheme 2.
##STR00083##
[1092] Representative synthesis of compounds in this invention
where ring A is methoxy-pyridine is outlined in Scheme 11.
Benzaldehyde 11a which was used in a Horner-Wadsworth-Emmons
reaction with (S)-tert-butyl
(1-(dimethoxyphosphoryl)-2-oxohex-5-en-3-yl)carbamate (synthesis
previously described) to afford 11b. Then, enone 11b was converted
into key intermediate 11e by treatment with NH.sub.4OAc and
separated by chiral chromatography to 11d1 and 11d2. Methylation of
chiral separation product 11d2 gave 2-methyoxy pyridine 11e. Zn
mediated reduction of nitro group afforded aniline 11f. Coupling of
aniline 11f with the 2-methylbut-3-enoic acid by methods known in
the art of synthesis resulted in formation of 11g. The following
ring closing metathesis formed two isomers 11h1 and 11h2.
Hydrogenation and deprotection of 11h1 and 11h2 gave the crucial
intermediate 11l1 and 11l2 which can be coupled to afford compounds
of this invention.
##STR00084## ##STR00085##
[1093] The corresponding pyridone compounds of this invention can
also be prepared by the methodologies outlined in Schemes 12 to
14.
##STR00086## ##STR00087##
##STR00088##
##STR00089##
[1094] Other azole containing compounds of this invention can also
be accessed via the schematic shown in Scheme 15 by following the
procedure outlined for the pyridine/one ring systems.
##STR00090##
[1095] Purification of intermediates and final products was carried
out via either normal or reverse phase chromatography. Normal phase
chromatography was carried out using pre-packed SiO.sub.2
cartridges eluting with either gradients of hexanes and EtOAc or
DCM and MeOH unless otherwise indicated. Reverse phase preparative
HPLC was carried out using C18 columns eluting with gradients of
Solvent A (90% water, 10% MeOH, 0.1% TFA) and Solvent B (10% water,
90% MeOH, 0.1% TFA, UV 220 nm) or with gradients of Solvent A (90%
water, 10% ACN, 0.1% TFA) and Solvent B (10% water, 90% ACN, 0.1%
TFA, UV 220 nm) or with gradients of Solvent A (98% water, 2% ACN,
0.05% TFA) and Solvent B (98% ACN, 2% water, 0.05% TFA, UV 220 nm)
(or) SunFire Prep C18 OBD 5.mu. 30.times.100 mm, 25 min gradient
from 0-100% B. A=H.sub.2O/ACN/TFA 90:10:0.1. B=ACN/H.sub.2O/TFA
90:10:0.1
[1096] Unless otherwise stated, analysis of final products was
carried out by reverse phase analytical HPLC.
[1097] Method A: Waters SunFire column (3.5 .mu.m C18,
3.0.times.150 mm). Gradient elution (0.5 mL/min) from 10-100%
Solvent B for 12 min and then 100% Solvent B for 3 min was used.
Solvent A is (95% water, 5% acetonitrile, 0.05% TFA) and Solvent B
is (5% water, 95% acetonitrile, 0.05% TFA, UV 254 nm).
[1098] Method B: Waters Acquity UPLC BEH C18, 2.1.times.50 mm,
1.7-.mu.m particles; Mobile Phase A: 5:95 acetonitrile:water with
10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water
with 10 mM ammonium acetate; Temperature: 50.degree. C.; Gradient:
0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow:
1.11 mL/min.
[1099] Method C: Waters Acquity UPLC BEH C18, 2.1.times.50 mm,
1.7-.mu.m particles; Mobile Phase A: 5:95 acetonitrile:water with
0.1% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.1% TFA;
Temperature: 50.degree. C.; Gradient: 0-100% B over 3 minutes, then
a 0.75-minute hold at 100% B; Flow: 1.11 mL/min
[1100] Method X: ZORBAX.RTM. SB C18 column (4.6.times.75 mm).
Gradient elution (2.5 mL/min) from 0-100% Solvent B for 8 min and
then 100% Solvent B for 2 min was used. Solvent A is (90% water,
10% MeOH, 0.02% H.sub.3PO.sub.4) and Solvent B is (10% water, 90%
MeOH, 0.02% H.sub.3PO.sub.4, UV 220 nm).
Intermediate 1
Preparation of
N-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide
##STR00091##
[1101] 1A. Preparation of
N-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide
[1102] Et.sub.3N (2.1 mL, 15.3 mmol) was added to a solution of
4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (3 g, 12.7 mmol) and
TFAA (2.2 mL, 15.3 mmol) in DCM (100 mL). The solution was stirred
for 1 h at rt. The solution was then concentrated to about 15 mL
volume and purified by normal phase silica gel chromatography
(hexanes-EtOAc gradient) to yield
N-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroaceta-
mide (4 g, 12.06 mmol, 95% yield) as a white powder.
1B. Preparation of
N-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide
[1103] A clear, orange solution of
N-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide
(3.2 g, 9.65 mmol) in HOAc (20 ml) and 48% aq HBr (5.5 ml, 48.2
mmol) was warmed to 60.degree. C. for 1.5 h. The reaction was
cooled to rt and the solvents were removed in vacuo. EtOAc (100 mL)
and sat aq NaHCO.sub.3 were added to the residue. The aqueous layer
was then extracted twice with EtOAc (50 mL). The combined organic
layers were dried with MgSO.sub.4 and concentrated. The residue was
triturated with Et.sub.2O and filtered to yield
N-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide
(1.2 g, 3.78 mmol, 39.2% yield) as a white powder.
Intermediate 2
Preparation of (R)-2-methylbut-3-enoic acid
##STR00092##
[1104] 2A. Preparation of
(R)-4-benzyl-3-((R)-2-methylbut-3-enoyl)oxazolidin-2-one
[1105] To the solution of 2-methylbut-3-enoic acid (5.59 g, 55.9
mmol) and NMM (6.14 mL, 55.9 mmol) in THF (62 mL) at 0.degree. C.
was added pivaloyl chloride (6.87 mL, 55.9 mmol) dropwise. The
reaction mixture was cooled down to -78.degree. C., and stirred for
.about.2 h. In a separate flask: To the solution of
(R)-4-benzyloxazolidin-2-one (8.25 g, 46.6 mmol) in THF (126 mL) at
-78.degree. C. was added 2.5 M nBuLi in hexane (20.49 mL, 51.2
mmol) dropwise. After 35 min, this reaction was transferred via
cannula to the first reaction. The reaction mixture was stirred at
-78.degree. C. for 2 h, then the cold bath was removed, and the
reaction was quenched with sat NH.sub.4Cl. The reaction was diluted
with water and extracted with EtOAc (3.times.). The combined
organic layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated to give a yellow oil (15 g).
Purification by silica gel chromatography afforded
(R)-4-benzyl-3-((R)-2-methylbut-3-enoyl)oxazolidin-2-one (6.59 g,
55%) as a colorless oil. MS(ESI) m/z: 282.1 (M+Na).sup.+. .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. 7.36-7.19 (m, 5H), 6.03-5.93 (m,
1H), 5.23-5.10 (m, 2H), 4.69-4.63 (m, 1H), 4.51-4.43 (m, 1H),
4.23-4.15 (m, 2H), 3.29 (dd, J=13.5, 3.3 Hz, 1H), 2.79 (dd, J=13.5,
9.6 Hz, 1H), 1.35 (d, J=6.9 Hz, 3H) ppm. The other diastereomer
(R)-4-benzyl-3-((S)-2-methylbut-3-enoyl)oxazolidin-2-one (4.6 g,
38%) was also obtained as a white solid. MS(ESI) m/z: 260.1
(M+H).sup.+.
2B. Preparation of (R)-2-methylbut-3-enoic acid
[1106] To a clear colorless solution of
(R)-4-benzyl-3-((R)-2-methylbut-3-enoyl) oxazolidin-2-one (6.05 g,
23.33 mmol) in THF (146 mL) at 0.degree. C. was added dropwise 30%
aq H.sub.2O.sub.2 (9.53 mL, 93 mmol) followed by 2 N LiOH (23.33
mL, 46.7 mmol). After 30 min, the reaction was quenched with 25 mL
of sat Na.sub.2SO.sub.3 and 25 mL of sat NaHCO.sub.3. The reaction
was then concentrated to remove the THF. The residue was diluted
with water and extracted with CHCl.sub.3 (3.times.). The aqueous
layer was acidified with conc. HCl to pH .about.3 and then it was
extracted with EtOAc (3.times.). The EtOAc layers were combined,
washed with brine, dried over MgSO.sub.4, filtered and concentrated
to afford (R)-2-methylbut-3-enoic acid (2.15 g, 92%) as a colorless
oil. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 10.84 (br. s., 1H),
5.94 (ddd, J=17.4, 10.1, 7.4 Hz, 1H), 5.22-5.13 (m, 2H), 3.23-3.15
(m, 1H), 1.31 (d, J=7.2 Hz, 3H) ppm.
Intermediate 3
Preparation of 6-(3-chloro-2-fluorophenyl)pyrimidin-4-ol
##STR00093##
[1108] A microwave vial containing 6-chloropyrimidin-4-ol (0.100 g,
0.766 mmol), (3-chloro-2-fluorophenyl)boronic acid (0.534 g, 3.06
mmol), and Pd(PPh.sub.3).sub.4 (0.089 g, 0.077 mmol) was purged
with Ar for several min. Then degassed toluene (1.53 mL) and EtOH
(1.53 mL) were added followed by DIEA (0.54 mL, 3.06 mmol). The
vial was capped and the reaction was microwaved at 120.degree. C.
for 1 h. The resulting clear, orange solution was allowed to cool
to rt and a precipitate formed. The yellow solid was removed by
filtration, rinsing with 1:1 toluene/EtOH. A precipitate formed in
the filtrate. The solid was collected by filtration, rinsed with
cold 1:1 toluene/EtOH, air-dried, and dried under vacuum to give
6-(3-chloro-2-fluorophenyl)pyrimidin-4-ol (0.0357 g, 21% yield) as
a white solid. MS(ESI) m/z: 225.1 (M+H).sup.+ and 227.1
(M+2+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.71
(br. s., 1H), 8.31 (d, J=1.1 Hz, 1H), 7.87 (ddd, J=8.0, 7.2, 1.7
Hz, 1H), 7.74-7.69 (m, 1H), 7.36 (td, J=8.0, 1.1 Hz, 1H), 6.72 (br.
s, 1H). .sup.19F NMR (471 MHz, DMSO-d.sub.6) .delta. -117.48.
Intermediate 4
Preparation of 6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol,
hydrobromide
##STR00094##
[1109] 4A. Preparation of
4-(3-chloro-2,6-difluorophenyl)-6-methoxypyrimidine
[1110] A flask containing 4-chloro-6-methoxypyrimidine (1.0 g, 6.92
mmol), (3-chloro-2,6-difluorophenyl)boronic acid (1.996 g, 10.38
mmol), and 2nd generation XPhos precatalyst (0.272 g, 0.346 mmol)
was purged with Ar for several min, then degassed THF (13.84 mL)
and degassed 0.5 M K.sub.3PO.sub.4 (27.7 mL, 13.84 mmol) were
added. The resulting cloudy, pink reaction mixture was stirred
vigorously at rt. After 2 h, the reaction was diluted with water
and extracted with EtOAc (2.times.). The organic layers were
combined and washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated to give an orange-brown residue weighing
1.5 g. Purification by normal phase chromatography gave
4-(3-chloro-2,6-difluorophenyl)-6-methoxypyrimidine (0.242 g, 13.6%
yield) as an off-white solid. MS(ESI) m/z: 257.0 (M+H).sup.+ and
259.0 (M+2+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.86
(d, J=1.1 Hz, 1H), 7.68-7.63 (m, 1H), 7.17 (td, J=9.0, 1.8 Hz, 1H),
7.10-7.08 (m, 1H), 4.07 (s, 3H). .sup.19F NMR (471 MHz, CD.sub.3OD)
.delta. -115.84 (d, J=4.3 Hz), -116.49 (d, J=5.7 Hz).
4B. Preparation of
6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol
[1111] A clear, yellow solution of
4-(3-chloro-2,6-difluorophenyl)-6-methoxypyrimidine (0.240 g, 0.935
mmol) in AcOH (9.35 mL) and 48% aq HBr (5.29 mL, 46.8 mmol) was
warmed to 85.degree. C. After 1 h, the reaction was cooled to rt
and then it was concentrated to give a yellow solid. Et.sub.2O (10
mL) was added resulting in a suspension. The solid was collected by
filtration, rinsed with Et.sub.2O, air-dried, and then dried under
vacuum to give 6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol (0.258
g, 85% yield) as an off-white solid. MS(ESI) m/z: 243.0 (M+H).sup.+
and 245.0 (M+2+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.33 (d, J=1.1 Hz, 1H), 7.77 (td, J=8.7, 5.6 Hz, 1H), 7.32
(td, J=9.1, 1.7 Hz, 1H), 6.63 (d, J=0.6 Hz, 1H). .sup.19F NMR (471
MHz, DMSO-d.sub.6) .delta. -113.79 (d, J=4.3 Hz), -113.88 (d, J=5.7
Hz).
Intermediate 5
Preparation of 6-(5-chloro-2-fluorophenyl)pyrimidin-4-ol
##STR00095##
[1112] 5A. Preparation of
4-(5-chloro-2-fluorophenyl)-6-methoxypyrimidine
[1113] A microwave vial containing 4-chloro-6-methoxypyrimidine
(0.290 g, 2.007 mmol), (5-chloro-2-fluorophenyl)boronic acid (0.35
g, 2.007 mmol) and Na.sub.2CO.sub.3 (0.213 g, 2.007 mmol) in DME
(10 mL), EtOH (1.250 mL) and water (1.250 mL) was purged with
N.sub.2 for several min. Then PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2
adduct (0.082 g, 0.100 mmol) was added and the vial was capped. The
reaction was heated in a microwave at 100.degree. C. for 1 h. The
reaction mixture was then diluted with water and extracted with
EtOAc. The organic layer was washed with brine and then
concentrated to give an orange-brown residue. Purification by
normal phase chromatography gave
4-(5-chloro-2-fluorophenyl)-6-methoxypyrimidine (400 mg, 84% yield)
as white crystals. MS(ESI) m/z: 239.3 (M+H).sup.+. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.86 (s, 1H), 8.16 (dd, J=6.7, 2.8 Hz,
1H), 7.39 (ddd, J=8.8, 4.2, 2.9 Hz, 1H), 7.28-7.23 (m, 1H), 7.12
(dd, J=10.8, 8.8 Hz, 1H), 4.04 (s, 3H).
5B. Preparation of 6-(5-chloro-2-fluorophenyl)pyrimidin-4-ol
[1114] A clear, yellow solution of
4-(5-chloro-2-fluorophenyl)-6-methoxypyrimidine (300 mg, 1.257
mmol) in AcOH (12.57 mL) and 48% aq HBr (7 mL, 61.9 mmol) was
warmed to 85.degree. C. After 0.5 h, the reaction was cooled to rt
and concentrated under high vacuum to dryness. To the residue was
added sat NaHCO.sub.3 carefully to give a suspension. The solid was
collected by filtration, rinsed with water, a small amount of
acetone and air dried to give
6-(5-chloro-2-fluorophenyl)pyrimidin-4-ol (140 mg, 36.5% yield) as
a white solid. MS(ESI) m/z: 225.2 (M+H).sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 12.73 (br. s., 1H), 8.33 (d, J=0.9 Hz,
1H), 7.99 (dd, J=6.6, 2.9 Hz, 1H), 7.61 (ddd, J=6.6, 4.3, 2.1 Hz,
1H), 7.43 (dd, J=11.1, 8.9 Hz, 1H), 6.76 (s, 1H).
Intermediate 6
Preparation of
(S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)
boronic acid
##STR00096##
[1115] 6A. Preparation of
4-chloro-2-[(E)-2-[(S)-2-methylpropane-2-sulfinyl]ethenyl]pyridine
[1116] To a solution of S-(-)-t-butyl-sulfinamide (0.856 g, 7.06
mmol) in DCM (14.1 mL) was added sequentially CuSO.sub.4 (2.481 g,
15.54 mmol) and 4-chloropicolinaldehyde (1.0 g, 7.06 mmol). The
resulting white suspension was stirred at rt. After 3 h, the brown
suspension was filtered through CELITE.RTM., eluting with DCM, to
give a clear brown filtrate. Concentration of the filtrate gave a
brown oil weighing 1.85 g. Purification by normal phase
chromatography gave 1.31 g of
4-chloro-2-[(E)-2-[(S)-2-methylpropane-2-sulfinyl]ethenyl]pyridine
as a clear, yellow oil. MS(ESI) m/z: 245.0 (M+H).sup.+.
6B. Preparation of
(S)--N--((S)-1-(4-chloropyridin-2-yl)but-3-enyl)-2-methylpropane-2-sulfin-
amide
[1117] To a cooled (0-5.degree. C.) mixture of InCl.sub.3 (13.56 g,
61.3 mmol) in THF (170 mL) was added dropwise over 30 min 1 M
allylmagnesium bromide in Et.sub.2O (62 mL, 61.3 mmol). The
reaction was allowed to warm to rt. After 1 h at rt, a solution of
chloro-2-[(E)-2-[(S)-2-methylpropane-2-sulfinyl]ethenyl]pyridine
(10 g, 40.9 mmol) in EtOH (170 mL) was added. After 3 h, the
reaction was concentrated under vacuum at 50-55.degree. C. The
crude material was partitioned between EtOAc (200 mL) and water (50
mL) and the layers were separated. The aqueous layer was extracted
with EtOAc (2.times.50 mL). The organic layers were combined and
washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered
and concentrated to give
(S)--N--((S)-1-(4-chloropyridin-2-yl)but-3-enyl)-2-methylpropane-2-sulfin-
amide (13.5 g, 106%) as a yellow oil. MS(ESI) m/z: 287.2
(M+H).sup.+.
6C. Preparation of (S)-tert-butyl
1-(4-chloropyridin-2-yl)but-3-enylcarbamate
[1118]
(S)--N--((S)-1-(4-Chloropyridin-2-yl)but-3-enyl)-2-methylpropane-2--
sulfinamide (75 g, 261 mmol) was dissolved in MeOH (1500 mL). 6 N
aq HCl (750 mL, 4.5 mol) was added. The reaction was stirred at rt
for 3 h and then was concentrated. The residue was diluted with
water (2 L), washed with EtOAc (500 mL). The aqueous layer was
basified with sat Na.sub.2CO.sub.3 solution and then extracted with
EtOAc (3.times.1 L). The combined organic layers were washed with
water (1 L) and brine (1 L), dried over Na.sub.2SO.sub.4, filtered
and concentrated under vacuum at 50-55.degree. C. to give crude
product (43 g, 90%). MS(ESI) m/z: 183.2 (M+H).sup.+. The crude
product (42 g, 230 mmol) was dissolved in DCM (420 mL) and
Et.sub.3N (32.1 mL, 230 mmol) was added followed by dropwise
addition of Boc.sub.2O (53.4 mL, 230 mmol). The reaction was
stirred at rt for 3 h. The reaction was diluted with DCM (1 L),
washed with water (500 mL) and brine (500 mL). The organic layer
was dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
crude product was then purified using silica gel chromatography to
give (S)-tert-butyl 1-(4-chloropyridin-2-yl)but-3-enylcarbamate (61
g, 86%) as a pale yellow solid. MS(ESI) m/z: 283.2 (M+H).sup.+.
6D. Preparation of
(S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronic
acid trifluoroacetate
[1119] To a solution of
5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (1.198 g, 5.30
mmol) and (S)-tert-butyl
1-(4-chloropyridin-2-yl)but-3-enylcarbamate (1.0 g, 3.54 mmol),
prepared as described in Intermediate 23, in DMSO (10 mL) was added
KOAc (1.041 g, 10.61 mmol) and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2
adduct (0.289 g, 0.354 mmol). The reaction was purged with Ar for
10 min. The reaction mixture was then sealed and stirred for 12 h
at 85.degree. C. The reaction mixture was cooled to rt and then it
was diluted with EtOAc and washed with water. The aqueous layer was
extracted with EtOAc. The organic layers were combined and was
washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Purification by reverse phase chromatography afforded
the
(S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronic
acid trifluoroacetate (1.1 g, 77%) as a white solid. MS(ESI) m/z:
293.2 (M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.54
(d, J=5.8 Hz, 1H), 8.11 (s, 1H), 8.02 (dd, J=5.8, 0.6 Hz, 1H), 5.79
(ddt, J=17.1, 10.2, 7.1 Hz, 1H), 5.11-5.03 (m, 2H), 4.86 (t, J=7.0
Hz, 1H), 2.69-2.55 (m, 2H), 1.40 (br. s., 9H) ppm.
Intermediate 7
Preparation of
6-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
##STR00097##
[1120] 7A. Preparation of
N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide
[1121] To a cooled (-10.degree. C.) suspension of
4-chloro-3-fluoroaniline (10.67 g, 73.3 mmol) and Na.sub.2CO.sub.3
(13.21 g, 125 mmol) in Et.sub.2O (300 mL) was added dropwise TFAA
(12.23 mL, 88 mmol). The mixture was allowed to warm to rt
overnight. The mixture was diluted with hexane (300 mL) and
filtered. The filtrate was washed with ice water, 10% aq
NaHCO.sub.3, and brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated to give
N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide (17 g, 96%
yield), as a pale, yellow solid. MS(ESI) m/z: 242.1
(M+H).sup.+.
7B. Preparation of
(3-chloro-2-fluoro-6-(2,2,2-trifluoroacetamido)phenyl)boronic
acid
[1122] To a cooled (-78.degree. C.) clear, colorless solution of
N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide (0.500 g,
2.070 mmol) in THF (8.28 mL) was added dropwise 2.5 M nBuLi in
hexane (1.74 mL, 4.35 mmol) over 15 min keeping the internal
temperature below -65.degree. C. The resulting clear, yellow
solution was stirred at -78.degree. C. for 10 min. The reaction was
allowed to warm to -50.degree. C. over 1 h. The reaction was then
cooled to -78.degree. C. and B(O-i-Pr).sub.3 (1.051 mL, 4.55 mmol)
was added dropwise. The reaction was stirred at -78.degree. C. for
30 min and then the ice bath was removed and the reaction was
allowed to warm to rt and stirred at rt for 1 h. After this time,
the reaction was cooled to -5.degree. C. and then quenched with the
dropwise addition of 1.0 M HCl (5 mL) followed by the addition of
water (5 mL). The resulting cloudy yellow reaction mixture was
stirred at rt for 45 min. The reaction was diluted with EtOAc and
the layers were separated. The organic layer was washed with brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated to give a
pale, orange solid. The solid was partitioned between THF (10 mL)
and 0.5 M HCl (20 mL) and stirred vigorously for 4 h. The layers
were then separated and the clear, colorless aqueous layer was
concentrated to give
(3-chloro-2-fluoro-6-(2,2,2-trifluoroacetamido)phenyl)boronic acid
(0.1599 g, 34.2% yield) as a white solid. MS(ESI) m/z: 189.9
[M+H].sup.+.
7C. Preparation of
4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline
[1123] 4-Chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline was
prepared according to the procedures described in Intermediate 3
using (3-chloro-2-fluoro-6-(2,2,2-trifluoroacetamido)phenyl)boronic
acid. MS(ESI) m/z: 253.9 (M+H).sup.+. .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 8.82 (d, J=1.1 Hz, 1H), 7.18 (dd, J=8.8, 8.3
Hz, 1H), 7.01 (dd, J=3.0, 1.1 Hz, 1H), 6.61 (dd, J=8.9, 1.5 Hz,
1H), 4.04 (s, 3H). .sup.19F NMR (471 MHz, CD.sub.3OD) .delta.
-119.92 (s, 1F).
7D. Preparation of
4-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine
trifluoroacetate
[1124] In a microwave vial,
4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (0.045 g,
0.177 mmol) in CH.sub.3CN (1.8 mL), cooled to 0.degree. C., was
added isoamylnitrite (0.036 mL, 0.266 mmol), followed by the
dropwise addition of TMSN.sub.3 (0.035 mL, 0.266 mmol). Gas
evolution was observed. After 5 min, the cold bath was removed, and
the reaction was allowed to warm to rt. After 1 h,
trimethylsilylacetylene (0.076 mL, 0.532 mmol) was added. The
septum was replaced with a microwave cap and sealed. The reaction
was heated in a microwave at 120.degree. C. for a total of 4 h. The
reaction was concentrated almost to dryness and then purified by
reverse phase chromatography to give
4-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine
(27 mg, 0.088 mmol) as a clear glass. MS(ESI) m/z: 306.3
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.74 (d,
J=0.4 Hz, 1H), 7.80 (d, J=0.9 Hz, 1H), 7.77-7.69 (m, 2H), 7.38 (dd,
J=8.6, 1.5 Hz, 1H), 6.88 (s, 1H), 4.06 (s, 3H). .sup.19F NMR (376
MHz, CDCl.sub.3) .delta. -76.02 (s), -112.27 (s).
7E. Preparation of
6-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
[1125]
6-(3-Chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
was prepared according to the procedures in described in
Intermediate 5 for the synthesis of
6-(5-chloro-2-fluorophenyl)pyrimidin-4-ol, by replacing
4-(5-chloro-2-fluorophenyl)-6-methoxypyrimidine with
4-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine-
. MS(ESI) m/z: 292.3 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.20 (d, J=1.1 Hz, 1H), 8.06 (d, J=0.7 Hz, 1H), 7.89-7.81
(m, 1H), 7.80 (d, J=0.9 Hz, 1H), 7.54 (dd, J=8.6, 1.5 Hz, 1H), 6.52
(s, 1H).
Intermediate 8
Preparation of
6-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
##STR00098##
[1126] 8A. Preparation of
4-chloro-2-(6-methoxypyrimidin-4-yl)aniline
[1127] 4-Chloro-2-(6-methoxypyrimidin-4-yl)aniline was synthesized
according to the procedure described in Intermediate 5, by
replacing (5-chloro-2-fluorophenyl)boronic acid with
4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.
MS(ESI) m/z: 236.3 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.78 (s, 1H), 7.49 (d, J=2.4 Hz, 1H), 7.15 (dd, J=8.6, 2.4
Hz, 1H), 6.99 (d, J=0.9 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 4.02 (s,
3H).
8B. Preparation of
6-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
[1128] 6-(5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
was synthesized according to the procedures described for the
synthesis of
6-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol,
by replacing 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline
with 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline. MS(ESI) m/z:
274.3 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.51
(d, J=0.9 Hz, 1H), 8.35 (d, J=1.1 Hz, 1H), 7.92 (d, J=1.1 Hz, 1H),
7.88 (d, J=2.4 Hz, 1H), 7.83-7.78 (m, 1H), 7.74-7.69 (m, 1H), 6.39
(d, J=0.9 Hz, 1H).
Intermediate 9
Preparation of
6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol
##STR00099##
[1129] 9A. Preparation of
4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
##STR00100##
[1131] In a 20 mL microwave vial was added 2-bromo-4-chloroaniline
(3 g, 14.53 mmol),
4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxabo-
rolane (5.53 g, 21.80 mmol), KOAc (3.66 g, 37.3 mmol),
Pd(dppf)Cl.sub.2--CH.sub.2Cl.sub.2 adduct (0.32 g, 0.44 mmol) and
DMSO (9 mL). The resulting suspension was purged with N.sub.2,
capped and heated at 80.degree. C. for 22 h. The reaction was
cooled to rt. Water was added to dissolve the salts, then the
reaction was filtered. The remaining solid was suspended in DCM and
the insoluble solid was filtered. The filtrate was concentrated and
then purified by normal phase chromatography to give
4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.15 g,
86% yield) as a white solid. MS(ESI) m/z: 172.3
(M-C.sub.6H.sub.10+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.54 (d, J=2.6 Hz, 1H), 7.13 (dd, J=8.8, 2.6 Hz, 1H), 6.52
(d, J=8.6 Hz, 1H), 4.72 (br. s., 2H), 1.34 (s, 12H).
9B. Preparation of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline
##STR00101##
[1133] A RBF containing 4-chloro-6-methoxypyrimidine (3.13 g, 21.62
mmol), 4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(7.31 g, 21.62 mmol), Na.sub.2CO.sub.3 (2.29 g, 21.62 mmol), DME
(86 ml), EtOH (10.81 ml) and water (10.81 ml) was equipped with a
condenser. The mixture was purged with Ar for several min then
Pd(dppf)Cl.sub.2--CH.sub.2Cl.sub.2 adduct (1.77 g, 2.16 mmol) was
added. The reaction was heated at 90.degree. C. for 5 h. The
reaction was cooled to rt, diluted with water and extracted with
EtOAc. The organic layer was washed with brine, concentrated and
purified by normal phase chromatography to give
4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (2.86 g, 56.1% yield)
as yellow solid. MS(ESI) m/z: 236.0 (M+H).sup.+. .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 8.78 (d, J=1.1 Hz, 1H), 7.49 (d, J=2.5 Hz,
1H), 7.15 (dd, J=8.8, 2.5 Hz, 1H), 6.99 (d, J=1.1 Hz, 1H), 6.67 (d,
J=8.8 Hz, 1H), 5.89 (br. s., 2H), 4.03 (s, 3H).
9C. Preparation of
4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxy-
pyrimidine
##STR00102##
[1135] To a solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline
(1.5 g, 6.36 mmol) in ACN (90 ml) at 0.degree. C. was added
3-methylbutyl nitrite (1.28 ml, 9.55 mmol), followed by the
dropwise addition of TMSN.sub.3 (1.26 ml, 9.55 mmol). Gas evolution
was observed. After 10 min, the ice bath was removed, and the
reaction was allowed to warm to rt. After 1 h,
ethynyltrimethylsilane (2.72 ml, 19.09 mmol) and Cu.sub.2O (0.09 g,
0.64 mmol) were added and the reaction was stirred for an
additional 1 h. The reaction was partitioned in EtOAc and sat
NH.sub.4Cl, and the layers were separated. The organic layer was
washed with brine, dried over MgSO.sub.4, filtered and
concentrated. Purification by normal phase chromatography gave
4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxy-
pyrimidine (2.13 g, 5.92 mmol, 93% yield) as a yellow solid.
MS(ESI) m/z: 360.3 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.71 (d, J=1.1 Hz, 1H), 7.82 (d, J=2.2 Hz, 1H), 7.61-7.56
(m, 1H), 7.54-7.48 (m, 2H), 6.20 (d, J=1.1 Hz, 1H), 3.92 (s, 3H),
0.32-0.28 (m, 9H).
9D. Preparation of
4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine
##STR00103##
[1137] To a solution of
4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxy-
pyrimidine (1.56 g, 4.33 mmol) in ACN (28.9 ml) was added NCS (2.03
g, 15.17 mmol) and silica gel (6.51 g, 108 mmol). The reaction was
stirred at 80.degree. C. for 1 h. Then, the reaction was filtered
to remove the silica gel and the collected silica gel was washed
with EtOAc. The filtrate was washed with water (2.times.), brine
and concentrated. Purification by normal phase chromatography gave
4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine
(0.90 g, 64.5% yield) as a yellow foam. MS(ESI) m/z: 322.3
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.70 (d,
J=1.1 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.66-7.55 (m, 2H), 7.50 (d,
J=8.6 Hz, 1H), 6.52 (d, J=0.9 Hz, 1H), 3.98 (s, 3H).
9E. Preparation of
6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol
##STR00104##
[1139] To a solution of
4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine
(900 mg, 2.79 mmol) in AcOH (6 ml) was added 48% aq HBr (3 ml, 26.5
mmol). The mixture was stirred at 85.degree. C. for 1 h. The
reaction was concentrated to dryness and then partitioned between
EtOAc and sat NaHCO.sub.3. The mixture was separated and the
aqueous layer was extracted with EtOAc (2.times.). The organic
layers were combined, concentrated, and then the residue was
purified by normal phase chromatography to give a white solid. The
solid was suspended in Et.sub.2O, filtered and washed with
Et.sub.2O to give
6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]
pyrimidin-4-ol (610 mg, 70.9% yield) as a white solid. MS(ESI) m/z:
308.3 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.96
(s, 1H), 7.74-7.67 (m, 2H), 7.62 (dd, J=8.5, 2.3 Hz, 1H), 7.47 (d,
J=8.4 Hz, 1H), 6.44 (d, J=0.9 Hz, 1H).
Intermediate 10
Preparation of
6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)
pyrimidin-4-ol
##STR00105##
[1140] 10A. Preparation of
N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide
[1141] To a suspension of 4-chloro-3-fluoroaniline (10.67 g, 73.3
mmol) and Na.sub.2CO.sub.3 (24.5 g, 125 mmol) in Et.sub.2O (300 mL)
at -10.degree. C. under N.sub.2 was added TFAA (12.23 mL, 88 mmol)
dropwise. The mixture was allowed to warm to rt and then stirred
for 18 h. The reaction mixture was diluted with hexane (300 mL) and
filtered. The filtrate was washed with ice water, 10% aq
NaHCO.sub.3, and brine, dried over Na.sub.2SO.sub.4, and
concentrated. A pale yellow solid obtained as
N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide (17 g, 96%
yield). MS(ESI) m/z: 242.1 (M+H).sup.+.
10B. Preparation of (6-amino-3-chloro-2-fluorophenyl)boronic
acid
[1142] To a cooled (-78.degree. C.) clear, colorless solution of
N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide (5 g, 20.70
mmol) in THF (69.0 ml) was added dropwise 2.5 M BuLi in hexane
(16.56 ml, 41.4 mmol) over 15 min, keeping the internal temperature
below -60.degree. C. The resulting clear, yellow solution was
stirred at -78.degree. C. for 10 min, then the reaction was allowed
to warm to -50.degree. C. over 1 h. The resulting clear brown
solution was cooled to -78.degree. C. and then B(O-iPr).sub.3
(10.51 ml, 45.5 mmol) was added dropwise. The reaction was stirred
at -78.degree. C. for 10 min, and then the ice bath was removed and
the reaction was allowed to warm to rt. The resulting orange
suspension was stirred at rt for 2 h, then cooled in ice bath and
quenched with 1 N HCl (40 ml). The reaction mixture was warmed to
40.degree. C. for 1 h and then cooled to rt. The reaction was
diluted with EtOAc and the layers were separated. The organic layer
was washed with brine and concentrated. Purification by normal
phase chromatography afforded
(6-amino-3-chloro-2-fluorophenyl)boronic acid (3 g, 76.6% yield).
MS(ESI) m/z: 190.1 (M+H).sup.+.
10C. Preparation of
4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline
[1143] Reaction was done in a 350 ml pressure bottle. A solution of
4-chloro-6-methoxypyrimidine (1.784 g, 12.34 mmol),
(6-amino-3-chloro-2-fluorophenyl)boronic acid (3.3 g, 12.34 mmol)
in toluene (25 ml) and EtOH (25 ml) was purged with N.sub.2 for
several min. DIEA (4.31 ml, 24.68 mmol) followed by
Pd(Ph.sub.3P).sub.4 (1.426 g, 1.234 mmol) were added. The flask was
capped and the reaction was heated at 120.degree. C. for 2 h, then
cooled to rt, and concentrated. Purification by normal phase
chromatography afforded
4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (2 g, 45.2%
yield) as a yellow solid. MS(ESI) m/z: 254.0 (M+H).sup.+.
10D. Preparation of
4-(3-chloro-2-fluoro-6-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)--
6-methoxypyrimidine
##STR00106##
[1145] To a cooled (0.degree. C.), clear, yellow solution of
4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (2.1 g, 8.28
mmol) in ACN (118 ml) was added isoamylnitrite (1.67 ml, 12.42
mmol), followed by the dropwise addition of TMSN.sub.3 (1.63 ml,
12.42 mmol). After 10 min, the cold bath was removed, and the
reaction was allowed to warm to rt. After 2 h,
ethynyltrimethylsilane (3.54 ml, 24.84 mmol) and Cu.sub.2O (0.118
g, 0.83 mmol) were added, and the reaction was stirred at rt for
1.5 h. The reaction was then diluted with EtOAc and washed with sat
NH.sub.4Cl, brine, dried over MgSO.sub.4, filtered and concentrated
to give a brown oil. Purification by normal phase chromatography
afforded
4-(3-chloro-2-fluoro-6-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)--
6-methoxypyrimidine (2.71 g, 87% yield) as a brown solid. MS(ESI)
m/z: 378.1 (M+H).sup.+.
10E. Preparation of
4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxyp-
yrimidine
##STR00107##
[1147] In a RBF equipped with stirring bar and condenser was added
4-(3-chloro-2-fluoro-6-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)--
6-methoxypyrimidine (2.71 g, 7.17 mmol), NCS (3.35 g, 25.1 mmol),
and silica gel (10.77 g, 179 mmol), followed by ACN (47.8 ml). The
reaction was heated at 80.degree. C. for 1 h, and then cooled to
rt. The reaction was filtered, and the filtrate was concentrated.
The residue was redissolved in EtOAc and washed with sat
NaHCO.sub.3, water, brine, and concentrated. Purification by normal
phase chromatography afforded
4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxyp-
yrimidine (1.05 g, 43.0% yield) as a yellow solid. MS(ESI) m/z:
340.0 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.68
(d, J=0.7 Hz, 1H), 7.71-7.62 (m, 2H), 7.37 (dd, J=8.6, 1.8 Hz, 1H),
6.84 (s, 1H), 4.02 (s, 3H).
10F. Preparation of
6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)
pyrimidin-4-ol
##STR00108##
[1149] A clear, yellow solution of
4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxyp-
yrimidine (1.05 g, 3.09 mmol) in HOAc (15.43 ml) and 48% aq HBr
(17.46 ml, 154 mmol) was warmed to 65.degree. C. for 3 h, and then
cooled to rt and concentrated. The yellow gum was suspended in
EtOAc and washed with sat NaHCO.sub.3 (2.times.), brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. To the residue was
added Et.sub.2O (10 ml), and the resulting suspension was sonicated
then filtered. The solid was rinsed with Et.sub.2O (2 ml),
air-dried with suction to afford
6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-
-ol (0.79 g, 78% yield) as a white solid. MS(ESI) m/z: 326.3
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.35 (s,
1H), 8.08 (d, J=0.7 Hz, 1H), 7.85 (dd, J=8.7, 7.6 Hz, 1H), 7.54
(dd, J=8.6, 1.5 Hz, 1H), 6.57 (s, 1H).
Intermediate 11
Preparation of
6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-
pyrimidin-4-ol
##STR00109##
[1150] 11A. Preparation of
4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-
-6-methoxypyrimidine
[1151] To a cooled (0.degree. C.), clear, yellow solution of
4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (0.2 g, 0.79
mmol) in ACN (11.26 ml) was added isoamylnitrite (0.16 mL, 1.18
mmol), followed by the dropwise addition of TMSN.sub.3 (0.16 mL,
1.18 mmol). After 10 min, the cold bath was removed, and the
reaction was allowed to warm to rt. After 2 h, Cu.sub.2O (0.011 g,
0.079 mmol) was added. 3,3,3-Trifluoroprop-1-yne (0.5 mL, 0.79
mmol) gas was bubbled in through the reaction for 5 min, then the
reaction was capped and stirred at rt. After 1 h, the reaction was
diluted with EtOAc and washed with sat NH.sub.4Cl, brine, dried
over MgSO.sub.4, filtered and concentrated to give a brown oil.
Purification by normal phase chromatography afforded
4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-
-6-methoxypyrimidine (0.24 g, 81% yield) as a yellow solid. MS(ESI)
m/z: 374.3 (M+H).sup.+.
11B. Preparation of
6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-
pyrimidin-4-ol
[1152] A clear, yellow solution of
4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-
-6-methoxypyrimidine (0.1 g, 0.268 mmol) in HOAc (1.34 ml) and 48%
aq HBr (1.51 ml, 13.38 mmol) was warmed to 65.degree. C. for 3 h,
and then cooled to rt and concentrated. The yellow gum was
suspended with EtOAc, washed with sat NaHCO.sub.3 (2.times.),
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated. To
the residue was added Et.sub.2O (3 ml) and the resulting suspension
was sonicated, then filtered. The solid was rinsed with Et.sub.2O
(2 ml), air-dried with suction to afford
6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-
pyrimidin-4-ol (0.07 g, 72.7% yield) as a white solid. MS(ESI) m/z:
360.0 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.84
(s, 1H), 8.03 (br. s., 1H), 7.91-7.84 (m, 1H), 7.58 (dd, J=8.8, 1.5
Hz, 1H), 6.61 (br. s., 1H).
Intermediate 12
Preparation of
1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-
-4-carbonitrile
##STR00110##
[1153] 12A. Preparation of
1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-
-4-carboxamide
[1154] To a cooled (0.degree. C.), clear, yellow solution of
4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (1 g, 3.94
mmol) in ACN (56.3 ml) was added isoamylnitrite (0.79 ml, 5.91
mmol), followed by the dropwise addition of TMSN.sub.3 (0.79 ml,
5.91 mmol). After 10 min, the cold bath was removed, and the
reaction was allowed to warm to rt and stirred at rt for 1 h. Next,
propiolamide (0.817 g, 11.83 mmol) and Cu.sub.2O (0.056 g, 0.394
mmol) were added. After 1 h, the yellow cloudy reaction was diluted
with EtOAc, and washed with sat NH.sub.4Cl, brine, dried over
MgSO.sub.4, filtered and concentrated to give a yellow solid. DCM
(10 ml) was added and the resulting mixture was sonicated. The
suspension was filtered and the solid was air-dried. A yellow solid
obtained as
1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-
-4-carboxamide (1.003 g, 73.0% yield). MS(ESI) m/z: 349.0
(M+H).sup.+.
12B. Preparation of
1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-
-4-carbonitrile
[1155] To a suspension of
1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-
-4-carboxamide (1.003 g, 2.88 mmol) in EtOAc (13 ml) was added TEA
(1.20 ml, 8.63 mmol), followed by the dropwise addition of T3P.RTM.
(50% in EtOAc) (5.14 ml, 8.63 mmol). The reaction was microwaved at
120.degree. C. for 30 min and then it was cooled to rt. The
reaction was diluted with EtOAc, washed with sat NaHCO.sub.3,
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated to
afford a brown solid. Purification by normal phase chromatography
afforded
1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-
-4-carbonitrile (0.815 g, 86% yield) as a yellow solid. MS(ESI)
m/z: 331.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.62 (d, J=1.1 Hz, 1H), 8.21 (s, 1H), 7.72 (dd, J=8.6, 7.5 Hz, 1H),
7.39 (dd, J=8.6, 1.8 Hz, 1H), 6.89 (dd, J=1.9, 1.2 Hz, 1H), 4.03
(s, 3H).
12C. Preparation of
1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-
-4-carbonitrile
[1156] To a suspension of
1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-
-4-carbonitrile (0.81 g, 2.449 mmol) in ACN (16.33 ml) was added
TMSI (2.00 ml, 14.70 mmol) at rt then the clear solution was heated
to 50.degree. C. After 18 h, the reaction was cooled to rt. The
reaction was poured into a 10% Na.sub.2S.sub.2O.sub.3 solution and
extracted with EtOAc (3.times.). The combined organic layers were
washed with sat NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated to give a residue. The residue was
suspended in DCM (20 ml), filtered, and the solid was rinsed with
DCM, and air-dried to afford
1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-
-4-carbonitrile (0.73 g, 94% yield) as a white solid. MS(ESI) m/z:
317.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.97
(s, 1H), 8.04 (s, 1H), 7.91-7.85 (m, 1H), 7.58 (dd, J=8.8, 1.5 Hz,
1H), 6.62 (s, 1H). .sup.19F NMR (376 MHz, CD.sub.3OD) .delta.
-114.93 (s, 1F).
Intermediate 13
Preparation of
6-(5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
hydrobromide
##STR00111##
[1157] 13A. Preparation of
4-(5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrim-
idine
[1158] To a cooled (0.degree. C.), clear, yellow solution of
4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (0.100 g, 0.42 mmol) in
ACN (6.06 ml) was added isoamylnitrite (0.086 ml, 0.64 mmol),
followed by the dropwise addition of TMSN.sub.3 (0.084 ml, 0.64
mmol). After 10 min, the cold bath was removed, and the reaction
was allowed to warm to rt and the reaction was stirred at rt for 1
h. Next, ethynylcyclopropane (0.120 g, 1.27 mmol) and Cu.sub.2O
(6.07 mg, 0.042 mmol) were added. The flask was equipped with a
reflux condenser and the reaction was heated to 50.degree. C. for 1
h, then the reaction was cooled to rt. The reaction was diluted
with DCM and washed with sat NH.sub.4Cl, brine, dried over
MgSO.sub.4, filtered and concentrated to give a brown oil.
Purification by normal phase chromatography then reverse phase
chromatography afforded
4-(5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrim-
idine (0.024 g, 17.3% yield) as a yellow oil. MS(ESI) m/z: 328.1
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.75 (d,
J=0.9 Hz, 1H), 7.79 (d, J=2.2 Hz, 1H), 7.61-7.56 (m, 1H), 7.51-7.47
(m, 1H), 7.29 (s, 1H), 6.35 (d, J=0.9 Hz, 1H), 3.96 (s, 3H), 1.96
(tt, J=8.4, 5.0 Hz, 1H), 1.02-0.95 (m, 2H), 0.88-0.81 (m, 2H).
13B. Preparation of
6-(5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)
pyrimidin-4-ol hydrobromide
[1159] A clear, yellow solution of
4-(5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrim-
idine (0.024 g, 0.073 mmol) in HOAc (0.73 ml) and 48% aq HBr (0.41
ml, 3.66 mmol) was warmed to 65.degree. C. for 3 h, and then cooled
to rt and concentrated. The yellow gum was suspended in EtOAc and
washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. To the residue was added Et.sub.2O (3 ml), sonicated,
and filtered. The solid was rinsed with Et.sub.2O (2 ml), air-dried
with suction to afford
6-(5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
hydrobromide (0.03 g, 100% yield) as a yellow solid. MS(ESI) m/z:
314.0 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.67
(d, J=0.7 Hz, 1H), 8.22 (s, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.82 (dd,
J=8.6, 2.2 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 6.48 (d, J=0.9 Hz, 1H),
2.11-2.01 (m, 1H), 1.11-1.04 (m, 2H), 0.91-0.84 (m, 2H).
Intermediate 14
Preparation of
6-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimi-
din-4-ol
##STR00112##
[1160] 14A. Preparation of
4-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-met-
hoxypyrimidine
[1161] To a cooled (0.degree. C.), clear, yellow solution of
4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (0.100 g, 0.39
mmol) in ACN (5.6 ml) was added isoamylnitrite (0.079 ml, 0.59
mmol), followed by the dropwise addition of TMSN.sub.3 (0.078 ml,
0.59 mmol). After 10 min, the cold bath was removed, and the
reaction was allowed to warm to rt. After 1 h, ethynylcyclopropane
(0.112 g, 1.18 mmol) and Cu.sub.2O (5.64 mg, 0.039 mmol) were
added. The flask was equipped with a reflux condenser and the
reaction was heated to 50.degree. C. for 1 h, then the reaction was
cooled to rt. The reaction was diluted with DCM and washed with sat
NH.sub.4Cl, brine, dried over MgSO.sub.4, filtered and concentrated
to give a brown oil. Purification by normal phase chromatography
afforded
4-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-met-
hoxypyrimidine (0.05 g, 36.7% yield) as a yellow oil. MS(ESI) m/z:
346.0 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.69
(d, J=0.9 Hz, 1H), 7.63 (dd, J=8.6, 7.5 Hz, 1H), 7.35 (dd, J=8.6,
1.5 Hz, 1H), 7.30 (s, 1H), 6.76 (t, J=1.2 Hz, 1H), 4.00 (s, 3H),
1.90 (tt, J=8.4, 5.0 Hz, 1H), 0.98-0.91 (m, 2H), 0.82-0.76 (m,
2H).
14B. Preparation of
6-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)
pyrimidin-4-ol
[1162] A clear, yellow solution of
4-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-met-
hoxypyrimidine (0.05 g, 0.145 mmol) in HOAc (1.45 ml) and 48% aq
HBr (0.82 ml, 7.23 mmol) was warmed to 65.degree. C. for 3 h, and
then the reaction was cooled to rt and concentrated. Purification
by reverse phase chromatography afforded
6-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimi-
din-4-ol (0.04 g, 83% yield) as a yellow solid. MS(ESI) m/z: 332.0
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.09 (d,
J=0.9 Hz, 1H), 7.91 (s, 1H), 7.82 (dd, J=8.6, 7.7 Hz, 1H), 7.49
(dd, J=8.8, 1.5 Hz, 1H), 6.50-6.47 (m, 1H), 1.97 (tt, J=8.5, 5.1
Hz, 1H), 1.01-0.95 (m, 2H), 0.81-0.75 (m, 2H). .sup.19F NMR (376
MHz, CD.sub.3OD) .delta. -115.39 (s).
Intermediate 15
Preparation of
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol
##STR00113##
[1163] 15A. Preparation of
4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methox-
ypyrimidine
##STR00114##
[1165] To a solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline
(1.0 g, 4.24 mmol), prepared as described in Intermediate 9B, in
ACN (60.6 ml) at 0.degree. C. was added 3-methylbutyl nitrite (0.86
ml, 6.36 mmol) followed by the dropwise addition of TMSN.sub.3
(0.84 ml, 6.36 mmol). Gas evolution was observed. After 10 min, the
ice bath was removed, and the reaction was allowed to warm to rt.
After 2 h, Cu.sub.2O (61 mg, 0.42 mmol) was added followed by a
slow bubbling of 3,3,3-trifluoroprop-1-yne gas over a period of 5
min. After an additional 10 min, the reaction was partitioned
between DCM and sat NH.sub.4Cl and then the layers were separated.
The organic layer was washed with brine, dried over MgSO.sub.4,
filtered and concentrated. Purification by normal phase
chromatography gave
4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methox-
ypyrimidine (1.46 g, 97% yield) as a yellow solid. MS(ESI) m/z:
356.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.62
(d, J=1.1 Hz, 1H), 8.00 (d, J=0.7 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H),
7.66-7.60 (m, 1H), 7.52 (d, J=8.6 Hz, 1H), 6.60 (d, J=1.1 Hz, 1H),
3.98 (s, 3H). .sup.19F NMR (376 MHz, CDCl.sub.3) .delta. -61.10
(s).
15B. Preparation of
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}
pyrimidin-4-ol
##STR00115##
[1167] To a solution of
4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methox-
ypyrimidine (1.46 g, 4.10 mmol) in AcOH (10 ml) was added 48% aq
HBr (5 ml, 44.2 mmol). The mixture was stirred at 85.degree. C. for
1 h. The reaction was concentrated to dryness and then partitioned
between EtOAc and sat NaHCO.sub.3. The layers were separated and
the aqueous layer was extracted with EtOAc (2.times.). The organic
layers were combined and washed with sat NaHCO.sub.3, brine, dried
over MgSO.sub.4, filtered and the solvent was reduced under vacuum
until some solid started to form. The resulting suspension was
triturated with Et.sub.2O. The solid was filtered and washed with
Et.sub.2O to give
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol (1 g, 71.3% yield) as a pale yellow solid. MS(ESI) m/z: 342.0
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.83 (d,
J=0.7 Hz, 1H), 7.99 (d, J=0.9 Hz, 1H), 7.87 (d, J=2.2 Hz, 1H),
7.79-7.72 (m, 1H), 7.70-7.62 (m, 1H), 6.45 (d, J=0.9 Hz, 1H).
.sup.19F NMR (376 MHz, CD.sub.3OD) .delta. -62.61 (s).
Intermediate 16
Preparation of
6-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin--
4-ol
##STR00116##
[1168] 16A. Preparation of
{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazol-4-yl}met-
hanol
##STR00117##
[1170]
{1-[4-Chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazol-4--
yl}methanol (0.44 g, 52.5% yield) was prepared in a similar manner
as the procedure described for the preparation of
4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxy-
pyrimidine, as described in Intermediate 9C, by replacing
ethynyltrimethylsilane with propargyl alcohol (0.38 ml, 6.36 mmol).
MS(ESI) m/z: 318.3 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.66 (d, J=1.1 Hz, 1H), 7.77 (d, J=2.2 Hz, 1H), 7.63 (s,
1H), 7.61-7.55 (m, 1H), 7.51-7.46 (m, 1H), 6.42 (d, J=1.1 Hz, 1H),
4.77 (d, J=5.9 Hz, 2H), 3.93 (s, 3H).
16B. Preparation of
1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbal-
dehyde
##STR00118##
[1172] To a solution of
{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazol-4-yl}met-
hanol (95 mg, 0.3 mmol) in DMSO (1 mL) was added IBX (92 mg, 0.33
mmol) and the reaction was stirred at rt for 14 h. Water and sat
NaHCO.sub.3 were added and the mixture was extracted with EtOAc
(2.times.). The organic layers were combined, concentrated and
purified by normal phase chromatography to give
1-[4-chloro-2-(6-methoxy
pyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbaldehyde (82 mg, 87%
yield) as a white solid. MS(ESI) m/z: 316.3 (M+H).sup.+. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 10.16 (s, 1H), 8.62 (d, J=1.1 Hz,
1H), 8.21 (s, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.64 (dd, J=8.5, 2.3 Hz,
1H), 7.53 (d, J=8.4 Hz, 1H), 6.59 (d, J=1.1 Hz, 1H), 3.97 (s,
3H).
16C. Preparation of
4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxy-
pyrimidine
##STR00119##
[1174] To a solution of
1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbal-
dehyde (427 mg, 1.35 mmol) in DCM (30 ml) was added DAST (0.54 ml,
4.1 mmol) and the reaction was stirred overnight at rt. The
reaction was quenched with water and extracted with DCM. The
organic layer was concentrated and purified by normal phase
chromatography to give
4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxy-
pyrimidine (441 mg, 97% yield) as a yellow solid. MS(ESI) m/z:
338.3 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.65
(d, J=0.9 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.62 (dd,
J=8.5, 2.3 Hz, 1H), 7.55-7.47 (m, 1H), 6.89 (t, J=54.6 Hz, 1H),
6.52 (d, J=1.1 Hz, 1H), 4.03-3.87 (m, 3H). .sup.19F NMR (376 MHz,
CDCl.sub.3) .delta. -112.40 (s).
16D. Preparation of
6-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}
pyrimidin-4-ol
##STR00120##
[1176]
6-{5-Chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyri-
midin-4-ol (370 mg, 88% yield) was prepared in a similar manner as
the procedure described for the preparation of
6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol,
as described in Intermediate 9E, by replacing
4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine
with
4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-me-
thoxypyrimidine (441 mg, 1.31 mmol). MS(ESI) m/z: 324.3
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.04 (s,
1H), 7.86 (s, 1H), 7.71 (d, J=2.2 Hz, 1H), 7.67-7.61 (m, 1H), 7.51
(d, J=8.6 Hz, 1H), 6.92 (t, J=54.6 Hz, 1H), 6.43 (d, J=0.7 Hz, 1H).
.sup.19F NMR (376 MHz, CDCl.sub.3) .delta. -112.69 (s).
Intermediate 17
Preparation of
6-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol
##STR00121##
[1177] 17A. Preparation of
4-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-methoxypyrimid-
ine
[1178] 4-Chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (300
mg, 1.183 mmol) dissolved in AcOH (3 mL) was added
trimethoxymethane (377 mg, 3.55 mmol), stirred at rt. After 30 min,
NaN.sub.3 (231 mg, 3.55 mmol) was added and stirred at rt for 16 h.
To the reaction mixture was added water and a precipitate formed.
The mixture was filtered to collect the solid residue, and filtrate
was extracted with EtOAc, and the organic later was washed with
brine, dried over MgSO.sub.4, filtered and concentrated to give a
crude solid, which was then combined with original solid residue
collected. The crude material was purified by normal phase
chromatography to afford
4-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-6-methoxypyrim-
idine (367 mg, 100% yield). MS(ESI) m/z: 307.08 (M+H).sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.78 (s, 1H), 8.59 (d,
J=1.1 Hz, 1H), 7.71 (dd, J=8.7, 7.4 Hz, 1H), 7.38 (dd, J=8.6, 1.8
Hz, 1H), 6.86 (dd, J=1.9, 1.2 Hz, 1H), 3.98 (s, 3H).
17B. Preparation of
6-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol
[1179] To a solution of
4-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-6-methoxypyrimidine
(50 mg, 0.163 mmol), NaI (244 mg, 1.630 mmol) dissolved in ACN (1.6
ml) was added TMSCl (0.2 ml, 1.630 mmol). The resulting reaction
mixture was stirred at rt for 23 h. To the reaction mixture was
added CELITE.RTM., the slurry was filtered and the collected
organics were concentrated to yield a crude solid. Purification by
normal phase chromatography, followed by trituration with
Et.sub.2O, afforded
6-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol
(46 mg, 96% yield) as a white solid. MS(ESI) m/z: 293.08
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.75 (s,
1H), 8.40 (s, 1H), 8.28 (dd, J=8.7, 7.6 Hz, 1H), 7.97 (dd, J=8.7,
1.7 Hz, 1H), 7.02 (s, 1H).
Intermediate 18
Preparation of
1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbon-
itrile
##STR00122##
[1180] 18A. Preparation of
1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbox-
amide
##STR00123##
[1182]
1-[4-Chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4--
carboxamide (300 mg, 80% yield) was prepared in a similar manner as
the procedure described for the preparation of
4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-methoxypyrimidine, as described in Intermediate 9C, by
replacing ethynyltrimethylsilane with prop-2-ynamide (176 mg, 2.55
mmol). MS(ESI) m/z: 331.4 (M+H).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.66 (d, J=0.7 Hz, 1H), 8.16 (s, 1H), 7.76 (d,
J=2.4 Hz, 1H), 7.62 (dd, J=8.5, 2.3 Hz, 1H), 7.51 (d, J=8.6 Hz,
1H), 7.05 (br. s., 1H), 6.53 (d, J=0.9 Hz, 1H), 5.66 (br. s., 1H),
3.97 (s, 3H).
18B. Preparation of
1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbon-
itrile
##STR00124##
[1184] To a suspension of
1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbox-
amide (91 mg, 0.28 mmol) and TEA (115 .mu.l, 0.83 mmol) in EtOAc
(6.88 ml) was added T3P.RTM. (50% in EtOAc) (0.49 ml, 0.83 mmol)
dropwise. The reaction was microwaved at 120.degree. C. for 1 h.
Additional TEA (115 .mu.l, 0.83 mmol) and T3P.RTM. (50% in EtOAc)
(0.49 ml, 0.83 mmol) were added and the reaction was microwaved at
120.degree. C. for an additional 30 min. The reaction was diluted
with EtOAc and washed with water, sat NaHCO.sub.3, brine, dried
over MgSO.sub.4, filtered, and concentrated. Purification by normal
phase chromatography gave
1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbon-
itrile (91 mg, 100% yield) as a white solid. MS(ESI) m/z: 313.3
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.62 (d,
J=0.9 Hz, 1H), 8.17 (s, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.65 (dd,
J=8.5, 2.3 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 6.65 (d, J=1.1 Hz, 1H),
4.00 (s, 3H).
18C. Preparation of
1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbon-
itrile
##STR00125##
[1186] To a suspension of
1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbon-
itrile (91 mg, 0.29 mmol) in ACN (3 mL) was added TMSI (0.2 mL,
1.47 mmol) at rt and the solution was heated at 50.degree. C. for
15 h. The reaction was poured into 10% Na.sub.2S.sub.2O.sub.3 and
sat NaHCO.sub.3 then extracted with EtOAc (3.times.). The combined
organic layers were washed with brine. On standing, a solid
precipitated out from the organic layer. The solid was filtered and
rinsed with EtOAc and air-dried to give
1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbon-
itrile (60 mg, 69.0% yield) as a white solid. MS(ESI) m/z: 299.3
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.22 (s,
1H), 7.91 (s, 1H), 7.72 (d, J=2.2 Hz, 1H), 7.66 (dd, J=8.5, 2.3 Hz,
1H), 7.49 (d, J=8.4 Hz, 1H), 6.55 (s, 1H).
Intermediate 19
Preparation of
(9R,13S)-13-amino-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15--
tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-on-
e
##STR00126##
[1187] 19A. Preparation of
4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole
[1188] To a solution of 4-nitro-1H-pyrazole (5.0 g, 44.2 mmol) in
THF (100 mL) at 0.degree. C. was added
N-cyclohexyl-N-methylcyclohexanamine (0.948 mL, 4.43 mmol) followed
by dropwise addition of SEM-Cl (12.55 mL, 70.7 mmol). The reaction
mixture was then allowed to gradually warm to rt and stirred
overnight. The reaction mixture was concentrated and purified by
normal phase chromatography to yield
4-nitro-14(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole as clear
oil (2.4 g, 21% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
8.31 (s, 1H), 8.10 (s, 1H), 5.46 (s, 2H), 3.67-3.55 (m, 2H),
0.99-0.90 (m, 2H), 0.05-0.03 (m, 9H).
19B. Preparation of (S)-benzyl
(1-(4-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrid-
in-2-yl)but-3-en-1-yl)carbamate
[1189] To a N.sub.2 flushed pressure vial was added (S)-benzyl
(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate, prepared as
described in Intermediate 23, (1.9 g, 6.00 mmol),
4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole, prepared
as described in Intermediate 41A, (1.6 g, 6.60 mmol),
di(adamant-1-yl)(butyl)phosphine (0.323 g, 0.90 mmol), PvOH (0.209
mL, 1.80 mmol) and K.sub.2CO.sub.3 (2.48 g, 17.9 mmol). To the
above mixture was then added N,N-dimethylacetamide (45 mL) and the
vial was purged with N.sub.2 for 5 min. To this mixture was then
added Pd(OAc).sub.2 (0.135 g, 0.600 mmol). The reaction mixture was
again purged with N.sub.2. The vial was sealed and heated in
microwave at 120.degree. C. for 1 h. The reaction mixture was
cooled to rt and partitioned between 10% aqueous LiCl (15 mL) and
EtOAc (30 mL). The aqueous layer was extracted with EtOAc
(2.times.20 mL) and the combined organic layers were washed with
brine (15 mL) and dried over MgSO.sub.4. The crude product was then
purified using normal phase chromatography to yield (S)-benzyl
(1-(4-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrid-
in-2-yl)but-3-en-1-yl)carbamate (1.92 g, 58% yield) as a brown oil.
MS(ESI) m/z: 524.2 (M+H).sup.+.
19C. Preparation of
(S)-benzyl(1-(4-(4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol--
5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate
[1190] A solution of (S)-benzyl
(1-(4-(4-nitro-14(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridi-
n-2-yl)but-3-en-1-yl)carbamate (1.92 g, 3.68 mmol), prepared as
described in Intermediate 41B, in MeOH (20 mL) and AcOH (2 mL) was
heated at 40.degree. C. To the above clear solution was then slowly
added Zn (0.481 g, 7.35 mmol, in 3 portions (50:25:25%)) and
allowed to stir at the same temperature for 5 min. The reaction
mixture was monitored by LCMS and once complete, to the cooled
reaction mixture was added 2.0 g of K.sub.2CO.sub.3 (1 g for 1 mL
AcOH) and 2 mL water. The reaction mixture was stirred for 5 min
then filtered over a pad of CELITE.RTM. and concentrated to yield
the crude product. The crude product was then partitioned between
EtOAc (30 mL) and sat NaHCO.sub.3 (15 mL) solution. The organic
layers are separated and dried over MgSO.sub.4, filtered and
concentrated. The crude product was then purified using normal
phase chromatography to yield (5)-benzyl
(1-(4-(4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrid-
in-2-yl)but-3-en-1-yl)carbamate (1.15 g, 63% yield) as pale yellow
oil. MS(ESI) m/z: 494.4 (M+H).sup.+.
19D. Preparation of benzyl
((S)-1-(4-(4-((R)-2-methylbut-3-enamido)-1-((2-(trimethylsilyl)ethoxy)met-
hyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate
[1191] To a N.sub.2 flushed, 3-necked, 250 mL RBF was added a
solution (S)-benzyl
(1-(4-(4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrid-
in-2-yl)but-3-en-1-yl)carbamate (1.15 g, 2.33 mmol), prepared as
described in Example 41C, and EtOAc (15 mL). The solution was
cooled to -10.degree. C. and (R)-2-methylbut-3-enoic acid, as
prepared in Intermediate 2, (350 mg, 3.49 mmol), pyridine (0.564
mL, 6.99 mmol) and T3P.RTM. (2.77 mL, 4.66 mmol) were added. The
cooling bath was removed and the solution was allowed to warm to rt
and then stir over a period of 20 h. Water (20 mL) and EtOAc (20
mL) were added and the mixture was stirred for 30 min. The organic
phase was separated and the aqueous layer was extracted with EtOAc
(20 mL). The combined organic extracts were washed with brine (15
mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. Purification by normal phase chromatography eluting with a
gradient of hexanes/EtOAc gave benzyl
((S)-1-(4-(4-((R)-2-methylbut-3-enamido)-1-((2-(trimethylsilyl)ethoxy)
methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (1.12
g, 79% yield). MS(ESI) m/z: 576.4 [M+H].sup.+.
19E. Preparation of benzyl
N-[(9R,10E,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)
ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),-
2(6),4,10,14,16-hexaen-13-yl]carbamate
[1192] To a N.sub.2 flushed, 250 mL, 3-necked, RBF was added a
solution of benzyl
((5)-1-(4-(4-((R)-2-methylbut-3-enamido)-1-((2-(trimethylsilyl)eth-
oxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate
(1.12 g, 1.945 mmol), prepared as described in Intermediate 41D, in
DCE (18 mL). The solution was sparged with Ar for 15 min. Second
Generation Grubbs Catalyst (662 mg, 0.778 mmol) was added in one
portion. The reaction mixture was heated at 120.degree. C. in
microwave for 30 min. After cooling to rt, the solvent was removed
and the residue was purified by normal phase chromatography eluting
with a gradient of DCM/MeOH to yield benzyl
N-[(9R,10E,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl-
}-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,1-
6-hexaen-13-yl]carbamate (477 mg, 42% yield) as a tan solid.
MS(ESI) m/z: 548.3 [M+H].sup.+.
19F. Preparation of
(9R,13S)-13-amino-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15--
tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-on-
e
[1193] Pd/C (0.93 g, 0.871 mmol) was added to a 250 mL Parr
hydrogenation flask containing a solution of benzyl
N-[(9R,10E,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)
ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),-
2(6),4,10,14,16-hexaen-13-yl]carbamate (477 mg, 0.871 mmol),
prepared as described in Intermediate 41E, in EtOH (20 mL). The
flask was purged with N.sub.2 and pressurized to 55 psi of H.sub.2
and allowed to stir for 4 h. The reaction was filtered through a
pad of CELITE.RTM. and concentrated to yield
(9R,13S)-13-amino-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}--
3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pen-
taen-8-one (245 mg, 64% yield) as a tan solid. MS(ESI) m/z: 416.4
[M+H].sup.+.
Intermediate 20
Preparation of
6-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol
##STR00127##
[1194] 20A. Preparation of
4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-methoxypyrimidine
[1195] To a solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline
(0.507 g, 2.151 mmol) dissolved in AcOH (5.4 ml) was added
trimethoxymethane (0.685 g, 6.45 mmol) and the resulting solution
was stirred at rt for 30 min. After that time NaN.sub.3 (0.420 g,
6.45 mmol) was added and the reaction mixture was stirred at rt for
16 h. Water was added to form a precipitate. The precipitate was
collected by filtration, and filtrate was extracted with EtOAc,
which was then washed with brine, dried over MgSO.sub.4, filtered
and concentrated to give a crude solid. The combined solid residue
was purified by normal phase chromatography to afford
4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-methoxypyrimidine (0.59
g, 95% yield) as an off-white solid. MS(ESI) m/z: 289.08
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.76 (s,
1H), 8.62 (d, J=0.9 Hz, 1H), 7.74 (d, J=2.2 Hz, 1H), 7.66 (dd,
J=8.5, 2.3 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 6.65 (d, J=1.1 Hz, 1H),
3.99 (s, 3H).
20B. Preparation of
6-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol
[1196] To a solution of
4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-methoxypyrimidine (0.59
g, 2.044 mmol), NaI (3.06 g, 20.44 mmol) in ACN (20.44 ml) was
added TMSCl (2.6 ml, 20.44 mmol), and the reaction was stirred at
rt for 16 h. CELITE.RTM. was added to the reaction mixture, the
slurry was filtered, and concentrated to give a crude solid
mixture. The solid was purified by normal phase chromatography,
then recrystallized from EtOAc to give
6-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol (370
mg, 66% yield) as a white solid. MS(ESI) m/z: 275.08 (M+H).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.62 (br. s., 1H),
9.72 (s, 1H), 7.97 (d, J=0.7 Hz, 1H), 7.92 (d, J=2.2 Hz, 1H),
7.87-7.83 (m, 1H), 7.82-7.78 (m, 1H), 6.48 (d, J=0.7 Hz, 1H).
Intermediate 21
Preparation of
6-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)p-
yrimidin-4-ol
##STR00128##
[1197] 21A. Preparation of
(1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazol-
-4-yl)methanol
[1198] To a cooled (0.degree. C.), clear, yellow solution of
4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (1.058 g, 4.17
mmol) in ACN (59.6 ml) was added isoamylnitrite (0.84 ml, 6.26
mmol), followed by the dropwise addition of TMSN.sub.3 (0.82 ml,
6.26 mmol). After 10 min, the cold bath was removed, and the
reaction was allowed to warm to rt. Propargyl alcohol (0.75 ml,
12.51 mmol) and Cu.sub.2O (0.060 g, 0.42 mmol) were added. After 1
h, the reaction was diluted with EtOAc and washed with sat
NH.sub.4Cl, brine, dried over MgSO.sub.4, filtered and concentrated
to give a brown oil. The crude product was purified by normal phase
chromatography to give
(1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazol-
-4-yl)methanol (0.8 g, 57.1% yield) as a yellow foam. MS(ESI) m/z:
336.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.65
(d, J=1.1 Hz, 1H), 7.69-7.62 (m, 2H), 7.37 (dd, J=8.6, 1.5 Hz, 1H),
6.81 (t, J=1.2 Hz, 1H), 4.76 (d, J=5.9 Hz, 2H), 4.00 (s, 3H), 2.18
(t, J=6.1 Hz, 1H).
21B. Preparation of
1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-
-4-carbaldehyde
[1199] To the solution of
(1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazol-
-4-yl)methanol (0.8 g, 2.38 mmol) in DMSO (9.53 ml) was added IBX
(0.734 g, 2.62 mmol), and the reaction was stirred at rt. After 18
h, water and sat NaHCO.sub.3 were added and the reaction mixture
was extracted with EtOAc (2.times.). The organic layers were
combined and dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Purification by normal phase chromatography afforded
1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-
-4-carbaldehyde (0.64 g, 80% yield) as a white solid. MS(ESI) m/z:
334.4 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.12
(s, 1H), 8.60 (d, J=1.1 Hz, 1H), 8.25 (s, 1H), 7.71 (dd, J=8.6, 7.5
Hz, 1H), 7.39 (dd, J=8.6, 1.8 Hz, 1H), 6.88 (dd, J=1.8, 1.1 Hz,
1H), 4.01 (s, 3H).
21C. Preparation of
4-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)--
6-methoxypyrimidine
[1200] To the solution of
1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-
-4-carbaldehyde (0.3 g, 0.9 mmol) in DCM (24 ml) was added DAST
(0.54 ml, 4.09 mmol). The reaction was stirred at rt for 22 h. To
the reaction was added water and the resulting mixture was
extracted with DCM. The organic layer was washed with brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated. Purification by
normal phase chromatography afforded
4-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)--
6-methoxypyrimidine (0.256 g, 80% yield) as a white solid. MS(ESI)
m/z: 356.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.62 (d, J=0.9 Hz, 1H), 7.94 (t, J=1.3 Hz, 1H), 7.69 (dd, J=8.6,
7.5 Hz, 1H), 7.39 (dd, J=8.6, 1.8 Hz, 1H), 7.00-6.69 (m, 2H), 4.00
(s, 3H).
21D. Preparation of
6-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)p-
yrimidin-4-ol
[1201] A clear, yellow solution of
4-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)--
6-methoxypyrimidine (0.256 g, 0.72 mmol) in HOAc (3.6 ml) and 48%
aq HBr (4.07 ml, 36.0 mmol) was warmed to 65.degree. C. for 3 h,
and then the reaction was cooled to rt and concentrated. The yellow
gum was suspended in EtOAc and washed with sat NaHCO.sub.3
(2.times.), brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was suspended in Et.sub.2O (3 ml),
sonicated, and filtered. The solid was rinsed with Et.sub.2O (2
ml), air-dried with suction to afford
6-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)p-
yrimidin-4-ol (0.23 g, 94% yield) as a yellow solid. MS(ESI) m/z:
342.0 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.56
(t, J=1.4 Hz, 1H), 8.05 (d, J=0.9 Hz, 1H), 7.86 (dd, J=8.6, 7.7 Hz,
1H), 7.57 (dd, J=8.7, 1.7 Hz, 1H), 6.98 (t, J=54.0 Hz, 1H), 6.58
(t, J=1.2 Hz, 1H). .sup.19F NMR (376 MHz, CD.sub.3OD) .delta.
-114.68 (s), -115.20 (s).
Intermediate 22
Preparation of
6-(5-chloro-1-methyl-1H-indazol-7-yl)pyrimidin-4-ol
##STR00129##
[1202] 22A. Preparation of
7-bromo-5-chloro-1-methyl-1H-indazole
[1203] To a solution of 7-bromo-5-chloro-1H-indazole (5.0 g, 21.60
mmol) and K.sub.2CO.sub.3 (14.93 g, 108 mmol) in DMSO (24.91 ml)
was added CH.sub.3I (1.62 ml, 25.9 mmol) at rt. The reaction
mixture was stirred at rt overnight. Reaction was diluted with
water and the resulting solid filtered through a Buchner funnel,
washed with water, and dried under vacuum. The regioisomers were
separate by normal phase chromatography eluting with a gradient of
hexanes/EtOAc with the 1st isomer to elute off of the column being
7-bromo-5-chloro-1-methyl-1H-indazole (2.83 g, 53.4%) as confirmed
by .sup.1H NMR and a negative NOE. MS(ESI) m/z: 245 (M+H).sup.+ and
247 (M+2+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.12-8.09 (m, 1H), 7.88 (d, J=1.8 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H),
4.32 (s, 3H).
22B. Preparation of
5-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-inda-
zole
[1204] To a stirring solution of
7-bromo-5-chloro-1-methyl-1H-indazole (1.0 g, 4.07 mmol) in dioxane
(20.37 ml) at rt was added
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.190
g, 4.68 mmol) and KOAc (1.839 g, 18.74 mmol). The reaction was
purged with Ar (3.times.). Pd(dppf)Cl.sub.2 DCM complex (0.266 g,
0.326 mmol) was added, the reaction was again purged with Ar, and
heated to 90.degree. C. After stirring overnight, the reaction
mixture was cooled to rt, diluted with water, extracted with EtOAc
(3.times.), washed with water, brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The crude residue was purified by
normal phase column chromatography eluting with a gradient of
hexanes/EtOAc to give
5-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-inda-
zole (0.47 g, 39.4% yield) an oil which slowly solidified upon
standing. MS(ESI) m/z: 293.0 (M+H).sup.+ and 295.0 (M+2+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.94 (s, 1H), 7.80 (d,
J=2.2 Hz, 1H), 7.71 (d, J=2.2 Hz, 1H), 4.23 (s, 3H), 1.40 (s,
12H).
22C. Preparation of
5-chloro-7-(6-methoxypyrimidin-4-yl)-1-methyl-1H-indazole
[1205] To a large microwave vial was added
4-chloro-6-methoxypyrimidine (0.201 g, 1.391 mmol),
5-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-inda-
zole (0.407 g, 1.391 mmol), and 2 M aqNa.sub.2CO.sub.3 (0.70 ml,
1.391 mmol) in DME (5.56 ml)/EtOH (0.696 ml). The mixture was
purged with Ar for several min, PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2
adduct (0.114 g, 0.139 mmol) added and then heated at 90.degree. C.
After 4 h, the reaction mixture was cooled to rt, diluted with
water, and extracted with EtOAc. The organic layer washed with
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated to
give an orange-brown residue. The crude material was purified by
normal phase column chromatography eluting with a gradient of
hexanes/EtOAc to give
5-chloro-7-(6-methoxypyrimidin-4-yl)-1-methyl-1H-indazole (0.382,
100%) as a solid. MS(ESI) m/z: 275.1 (M+H).sup.+ and 277.1
(M+2+H).sup.+.
22D. Preparation of
6-(5-chloro-1-methyl-1H-indazol-7-yl)pyrimidin-4-ol
[1206] A clear, yellow solution of
5-chloro-7-(6-methoxypyrimidin-4-yl)-1-methyl-1H-indazole (0.382 g,
1.391 mmol) in AcOH (3 ml) and 48% aq HBr (1.639 ml, 14.49 mmol)
was warmed to 85.degree. C. After 3 h, the reaction mixture was
concentrated. The residue was dissolved in EtOAc and washed with
sat NaHCO.sub.3. The aqueous layer was extracted with additional
EtOAc, washed with brine, dried over Na.sub.2SO.sub.4, filtered,
and concentrated. The resulting solid was suspended with Et.sub.2O,
filtered, and dried under vacuum to give
6-(5-chloro-1-methyl-1H-indazol-7-yl)pyrimidin-4-ol (0.085 g,
23.5%) as a white solid. MS(ESI) m/z: 261.0 (M+H).sup.+ and 263.0
(M+2+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.78
(br. s., 1H), 8.32 (s, 1H), 8.13 (s, 1H), 7.97 (d, J=1.8 Hz, 1H),
7.46-7.36 (m, 1H), 6.66 (s, 1H), 3.87 (s, 3H).
Intermediate 23
Preparation of tert-butyl
N-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]carbamate
##STR00130##
[1207] 23A. Preparation of
4-chloro-2-[(E)-2-[(S)-2-methylpropane-2-sulfinyl]ethenyl]pyridine
[1208] To a solution of S-(-)-t-butyl-sulfinamide (0.856 g, 7.06
mmol) in DCM (14.13 mL) was added sequentially CuSO.sub.4 (2.481 g,
15.54 mmol) and 4-chloropicolinaldehyde (1.0 g, 7.06 mmol). The
white suspension was stirred at rt. After 3 h, the brown suspension
was filtered through CELITE.RTM., eluting with DCM, to give a clear
brown filtrate. Concentration gave crude product as a brown oil
weighing 1.85 g. Purification by normal phase chromatography gave
tert-butyl N-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]carbamate
(1.31 g) as a clear, yellow oil. MS(ESI) m/z: 245.0
(M+H).sup.+.
23B. Preparation of
(R)--N-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sul-
finamide
[1209] To a cooled (0-5.degree. C.) mixture of InCl.sub.3 (13.56 g,
61.3 mmol) in THF (170 mL) was added dropwise over 30 min 1 M
allylmagnesium bromide in Et.sub.2O (62 mL, 61.3 mmol). The
reaction was allowed to warm to rt. After 1 h, a solution of
4-chloro-2-[(E)-2-[(S)-2-methylpropane-2-sulfinyl]ethenyl]pyridine
(10 g, 40.9 mmol) in EtOH (170 mL) was added to the reaction
mixture. After 2-3 h, the reaction was concentrated under vacuum at
50-55.degree. C. The crude material was partitioned between EtOAc
(200 ml) and water (50 ml) and the layers were separated. The
aqueous layer was extracted with EtOAc (2.times.50 ml). The organic
layers were combined and washed with brine (100 ml), dried over
Na.sub.2SO.sub.4, filtered and concentrated to give
(R)--N-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sul-
finamide (13.5 g, 106%) as a yellow oil. MS(ESI) m/z: 287.2
(M+H).sup.+.
23C. Preparation of
(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-amine
[1210]
(R)--N-[(1S)-1-(4-Chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-
-2-sulfinamide (75 g, 261 mmol) was dissolved in MeOH (1500 mL). 6
N HCl (750 ml, 4.5 mol) was added. The reaction was stirred at rt
for 2-3 h and then was concentrated. The residue was diluted with
water (2 L), washed with EtOAc (500 ml). The aqueous layer was
basified with sat aq Na.sub.2CO.sub.3, then extracted into EtOAc
(3.times.1 L). The combined organic layers were washed with water
(1 L) and brine (1 L), dried over Na.sub.2SO.sub.4, filtered and
conc. under vacuum at 50-55.degree. C. to give
(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-amine (43 g, 90%). MS(ESI)
m/z: 183.2 (M+H).sup.+.
23D. Preparation of tert-butyl
N-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]carbamate
[1211] (1S)-1-(4-Chloropyridin-2-yl)but-3-en-1-amine (42 g, 230
mmol) was dissolved in DCM (420 mL), Et.sub.3N (32.1 mL, 230 mmol)
was added followed by dropwise addition of BOC.sub.2O (53.4 mL, 230
mmol). The reaction was stirred at rt for 2-3 h. The reaction was
diluted with excess DCM (1 L), washed with water (500 ml) and brine
(500 ml). The organic layer was dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The crude product was purified using
silica gel chromatography to give tert-butyl
N-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]carbamate (61 g, 86%)
as a pale yellow solid. MS(ESI) m/z: 283.2 (M+H).sup.+. .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 8.44 (d, 1H), 7.26-7.16 (dd, 2H),
5.69-5.61 (m, 1H), 5.59 (bs, 1H), 5.07-5.03 (m, 2H), 4.76 (bs, 1H),
2.62-2.55 (m, 2H), 1.42 (s, 9H).
Intermediate 24
Preparation of tert-butyl
N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate
##STR00131##
[1212] 24A. Preparation of
(R)--N-[(1E)-(3-bromophenyl)methylidene]-2-methylpropane-2-sulfinamide
[1213] To 3-bromobenzaldehyde (7.8 g, 42.2 mmol) was added
(R)-2-methylpropane-2-sulfinamide (5.11 g, 42.2 mmol),
Cs.sub.2CO.sub.3 (20.60 g, 63.2 mmol) in DCM (211 ml) and the
resulting reaction mixture was stirred for 5 days. The reaction
mixture was then partitioned with brine (50 ml) and DCM (50 ml).
The aqueous layer was extracted with DCM (2.times.50 ml). The
combined organic layers were washed with brine (25 ml), dried
(Na.sub.2SO.sub.4), filtered and concentrated. Purification by
normal phase chromatography using hexanes and EtOAc as eluents gave
(R)--N-[(1E)-(3-bromophenyl)methylidene]-2-methylpropane-2-sulfinamide
(11.8 g, 97%) as an amber oil. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.53 (s, 1H), 8.02 (t, J=1.8 Hz, 1H), 7.74 (dt, J=7.7, 1.2
Hz, 1H), 7.64 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.36 (t, J=7.8 Hz,
1H), 1.34-1.22 (m, 9H). MS(ESI) m/z: 290 (M+H).sup.+.
24B. Preparation of
(R)--N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamid-
e
[1214] To
(R)--N-[(1E)-(3-bromophenyl)methylidene]-2-methylpropane-2-sulfi-
namide (11.8 g, 40.9 mmol) in THF (190 ml), in a 3 neck flask,
cooled to 0.degree. C., was added allyl bromide (3.90 ml, 45.0
mmol) and In (6.58 g, 57.3 mmol). After stirred at rt for 18 h, the
reaction was heated to 50.degree. C. for 6 h, then stirred at rt
for 18 h. The reaction mixture was filtered through CELITE.RTM. and
the filtrate was quenched with water (100 ml). A thick clear
gelatinous material formed in the aqueous layer. The organics were
extracted with EtOAc (4.times.75 ml). The combined organic layer
was washed with brine, dried with MgSO.sub.4, filtered and
concentrated to give
(R)--N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamid-
e as a clear oil (9.6 g, 71%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.48 (t, J=1.8 Hz, 1H), 7.41 (dt, J=7.6, 1.6 Hz, 1H),
7.26-7.18 (m, 2H), 5.79-5.66 (m, 1H), 5.23-5.16 (m, 2H), 4.46 (ddd,
J=8.1, 5.6, 2.0 Hz, 1H), 3.69 (s, 1H), 2.63-2.53 (m, 1H), 2.53-2.40
(m, 1H), 1.23-1.19 (m, 9H).
24C. Preparation of tert-butyl
N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate
##STR00132##
[1216] To
(R)--N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]-2-methylpropane-2-s-
ulfinamide (9.6 g, 29.1 mmol) in MeOH (300 ml) was added conc. HCl
(4 ml). After 3 h, the reaction was concentrated and the residue
was dissolved in DCM (300 ml), cooled to 0.degree. C., and then TEA
(16.20 ml, 116 mmol) and Boc.sub.2O (6.75 ml, 29.1 mmol) in DCM (20
ml) were added. After 18 h, additional Boc.sub.2O (1 g) was added
and the reaction was stirred 4 h. The reaction was quenched with
water (100 ml) and extracted with DCM (3.times.50 ml). The combined
organic layers were washed with brine (50 ml), dried
(Na.sub.2SO.sub.4), filtered and concentrated. Purification by
normal phase chromatography using hexanes and EtOAc as eluents gave
tert-butyl N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (7.3 g,
77%) as a white solid. MS(ESI) m/z: 326.08 (M+H).sup.+.
Intermediate 25
Preparation of
N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]carbamate
##STR00133##
[1217] 25A. Preparation of
(R)--N-[(1E)-(3-bromo-5-fluorophenyl)methylidene]-2-methylpropane-2-sulfi-
namide
[1218] To 3-bromo-5-fluorobenzaldehyde (25 g, 123 mol) dissolved in
DCM (200 mL) was added (R)-2-methylpropane-2-sulfinamide (14.96 g,
123 mol) and Cs.sub.2CO.sub.3 (40.2 g, 123 mol). The reaction
mixture was stirred at rt overnight. After this time, the reaction
mixture was filtered and concentrated to give a yellow oil. The
yellow oil was purified using a 120 g silica gel ISCO column eluted
with hexanes and EtOAc to give
(R)--N-[(1E)-(3-bromo-5-fluorophenyl)methylidene]-2-methylpropane-2-sulfi-
namide (35 g, 93%) as a yellow oil. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.58-8.55 (m, 1H), 8.05-7.98 (m, 1H),
7.84-7.76 (m, 2H), 1.20 (s, 9H). LCMS m/z 306.1 (M+H).
25B. Preparation of
(R)--N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]-2-methylpropane-2-s-
ulfinamide
[1219]
N-[(1E)-(3-Bromo-5-fluorophenyl)methylidene]-2,2-dimethylpropanamid-
e (35 g, 114 mol) was dissolved in THF (500 mL) in a large 3 neck
RB flask and flushed with Ar. The solution was cooled to 0.degree.
C. and In powder (18.4 g, 160 mol) was added followed by dropwise
addition of allylbromide (15.2 g, 126 mol). The reaction was
stirred at 0.degree. C. for 2 h, then the ice bath was removed and
the reaction mixture was stirred at rt overnight. The reaction was
quenched with water (2 L) and the gelatinous material was filtered
through CELITE.RTM.. The filtrate was concentrated to an oily mass.
The crude material was dissolved in water (2 L) and the organics
were extracted with EtOAc (4.times.200 mL), dried over MgSO.sub.4,
filtered and concentrated to give an oil. The oily liquid was
purified via a silica gel ISCO column and eluted with DCM/MeOH to
afford
(R)--N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]-2-methylp-
ropane-2-sulfinamide (34.9 g, 88% yield) as a semi solid mass. LCMS
m/z 348.2 (M+H). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
7.44-7.38 (m, 2H), 7.26-7.20 (m, 1H), 5.79-5.65 (m, 1H), 5.46-5.42
(m, 1H), 5.04-4.98 (m, 2H), 4.41-4.34 (m, 1H), 2.69-2.59 (m, 1H),
2.49-2.43 (m, 1H), 1.09 (s, 9H).
25C. Preparation of
N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]carbamate
[1220] To a cooled 0.degree. C. solution of
(R)--N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]-2-methylpropane-2-s-
ulfinamide (21.9 g, 100 mol) dissolved in MeOH (100 mL) was added
conc. HCl (50 mL) dropwise and then the reaction was stirred at
0.degree. C. for 48 h. After this time, the reaction mixture was
concentrated to give a white solid mass. The residue was dissolved
in water (1 L) and the organics were extracted with EtOAc
(2.times.200 mL), dried over MgSO.sub.4, filtered and concentrated
to a brown oil (11.5 g). The aqueous layer was basified with NaOH
and the organics were extracted with EtOAc (2.times.300 mL), dried
over MgSO.sub.4, filtered and concentrated to a brown oil (18 g).
The combined oils were dissolved in DCM (500 mL) and to this was
added Boc.sub.2O (22 g) followed by TEA (15 mL) and the reaction
mixture was stirred at rt overnight. The reaction mixture was
concentrated and purified via a 330 g silica gel Isco column
eluting with hexanes and EtOAc to give a white solid. The white
solid was triturated with hexanes and the precipitate was collected
by filtration to give
N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]carbamate (29.5 g,
87% yield).
Intermediate 26
Preparation of
N-[(1S)-1-(5-bromopyridin-3-yl)but-3-en-1-yl]carbamate
##STR00134##
[1221] 26A. Preparation of
(R)--N-[(1E)-(5-chloropyridin-3-yl)methylidene]-2-methylpropane-2-sulfina-
mide
[1222] 5-Bromonicotinaldehyde (6.6 g, 35.9 mmol) was dissolved in
DCM (200 mL). To the solution was added Cs.sub.2CO.sub.3 (11.68 g,
35.9 mmol) and (R)-2-methylpropane-2-sulfinamide (4.34 g, 35.9 mol)
and then the reaction mixture was stirred at rt overnight. The
inorganics were filtered and the filtrate was concentrated to
afford
(R)--N-[(1E)-(5-chloropyridin-3-yl)methylidene]-2-methylpropane-2-sulfina-
mide as an oil (10.4 g, 100% yield). LCMS m/z=291.3.
26B. Preparation of
(R)--N-[(1S)-1-(5-chloropyridin-3-yl)but-3-en-1-yl]-2-methylpropane-2-sul-
finamide
[1223] To a solution of
(R)--N-[(1E)-(5-chloropyridin-3-yl)methylidene]-2-methylpropane-2-sulfina-
mide (10.36 g, 35.8 mmol) in THF (150 mL) at 0.degree. C. was added
powdered In (5.76 g, 50.2 mmol) followed by allylbromide (3.72 mL,
43.0 mmol). The reaction mixture was sealed and was stirred
vigorously at 0.degree. C. for 1 h and then warmed to rt and
stirred overnight. The reaction gradually turned from pale yellow
to greenish yellow to dark greenish yellow with the indium metal
forming fine particles. LCMS of the greenish black heterogenous
solution showed the desired product peak and mass. The solution was
filtered through a pad of CELITE.RTM. and washed with EtOAc. The
solution was concentrated to afford a yellow solid mass. The solids
were dissolved in MeOH (100 mL) and a solution of 4 N HCl in
dioxane (25 mL) was added. The resultant solution was stirred at
rt. After 6 h, conc. HCl (1 mL) was added and stirring was
continued for 1 h. The reaction mixture was concentrated to give a
yellow solid. The solid was dissolved in a mixture of THF and
dioxane and DCM (1:1:1, 200 mL). To this solution was added TEA (20
mL) followed by Boc.sub.2O (8.1 g, 37.1 mmol) and the reaction
mixture was stirred overnight. LCMS confirmed the desired product
formation. To the reaction mixture was added water (200 mL) and the
mixture was filtered through a pad of CELITE.RTM. and washed with
EtOAc (200 mL). The aqueous layer was extracted with EtOAc
(2.times.100 mL). The combined organic layer was dried over
MgSO.sub.4, filtered and concentrated to give a reddish brown oil.
The crude material was purified via a 80 g silica gel ISCO column
and eluted with hexanes and EtOAc.
(R)--N-[(1S)-1-(5-Chloropyridin-3-yl)but-3-en-1-yl]-2-methylpropane-2-sul-
finamide was obtained as a pale yellow semi solid mass (4.3 g,
36.7% yield). LCMS m/z 327.1 (M+H). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.61-8.59 (m, 1H), 8.51-8.48 (m, 1H), 7.77-7.74
(m, 1H), 5.76-5.63 (m, 1H), 5.23-5.14 (m, 2H), 5.00-4.84 (m, 1H),
4.83-4.70 (m, 1H), 2.60-2.44 (m, 2H), 1.48-1.35 (m, 9H).
Intermediate 27
Preparation of tert-butyl
N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]carbamate
##STR00135##
[1224] 27A. Preparation of
(R)--N-[(1E)-(2-bromopyridin-4-yl)methylidene]-2-methylpropane-2-sulfinam-
ide
##STR00136##
[1226] To a stirred suspension of (R)-2-methylpropane-2-sulfinamide
(13.03 g, 108 mmol) and Cs.sub.2CO.sub.3 (52.5 g, 161 mmol) in DCM
(400 ml) was added 2-bromopyridine-4-carbaldehyde (20 g, 108 mmol)
over 10 min. The reaction mixture was then stirred for 18.5 h at
rt. The reaction mixture was concentrated and the residue was
diluted with EtOAc (50 ml) and washed with brine (3.times.20 ml).
The organic layer was dried over MgSO.sub.4, filtered and the
filtrate concentrated. The residue was purified by normal phase
chromatography using hexanes and EtOAc as eluents to afford
(R)--N-[(1E)-(2-bromopyridin-4-yl)methylidene]-2-methylpropane-2-sulfinam-
ide (27.2 g, 87%) as a white solid. MS(ESI) m/z: 289-291.0
(M+H).sup.+.
27B. Preparation of
(R)--N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]-2-methylpropane-2-sulf-
onamide
##STR00137##
[1228] To a solution of
(R)--N-[(1E)-(2-bromopyridin-4-yl)methylidene]-2-methylpropane-2-sulfinam-
ide (0.73 g, 2.52 mmol) and In (0.435 g, 3.79 mmol) in THF (6 ml)
was slowly added 3-bromoprop-1-ene (0.458 g, 3.79 mmol) and
resulting solution was heated at 60.degree. C. for 18 h. The
reaction mixture was cooled, filtered through CELITE.RTM. and the
filtrate was concentrated. To the residue was added EtOAc (100 ml)
and 5% aq NaHCO.sub.3 (1 L) and an emulsion formed immediately. The
suspension was filtered through paper. The organic layer was washed
with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified by normal phase
chromatography using hexanes and EtOAc as eluents to afford (0.62
g, 74%) of
(R)--N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]-2-methylpropane-2-sulf-
onamide as a yellow liquid. MS(ESI) m/z: 331-333.0 (M+H).sup.+.
27C. Preparation of tert-butyl
N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]carbamate
##STR00138##
[1230] To a solution of
(R)--N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]-2-methylpropane-2-sulf-
inamide (1.38 g, 4.17 mmol) in MeOH (10 ml) was added 4 N HCl in
dioxane (5.21 mL, 20.83 mmol). The reaction mixture was stirred for
1.5 h at rt, then was concentrated. To the resulting residue was
added ACN (10 ml), TEA (5.8 ml, 41.7 mmol) and Boc.sub.2O (1.818 g,
8.33 mmol). After 18 h, the reaction mixture was concentrated and
the residue was taken up in EtOAc, washed with water, brine, dried
over MgSO.sub.4, filtered and concentrated. The resulting residue
was purified by normal phase chromatography using hexanes and EtOAc
as eluents to afford tert-butyl
N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]carbamate (0.80 g,
58.7%) as a pale yellow oil. MS(ESI) m/z: 324-326.1
(M+H).sup.+.
Intermediate 28
Preparation of
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0.sup.2,6-
] octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00139##
[1231] 28A. Preparation of
(S)--N-[(1E)-(6-chloropyridin-2-yl)methylidene]-2-methylpropane-2-sulfina-
mide
[1232] To a solution of (S)-2-methylpropane-2-sulfinamide (1.712 g,
14.13 mmol) in DCM (61.4 mL) was added Cs.sub.2CO.sub.3 (6.91 g,
21.19 mmol) and 6-chloropicolinaldehyde (2.0 g, 14.13 mmol). The
resulting white suspension was stirred at rt. After 17 h, the
reaction was filtered. The filtrate was diluted with EtOAc (100 ml)
and washed with brine (3.times.50 mL). The organic layer was dried
over MgSO.sub.4, filtered and concentrated to give
(S)--N-[(1E)-(6-chloropyridin-2-yl)methylidene]-2-methylpropane-2-sulfina-
mide (3.58 g, 100%) as a yellow oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.65 (s, 1H), 7.99-7.94 (m, 1H), 7.79 (t, J=7.7
Hz, 1H), 7.45 (dd, J=7.9, 0.7 Hz, 1H), 1.28 (s, 10H).
28B. Preparation of
(S)--N-[(1S)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sul-
finamide, and
28C. Preparation of
(S)--N-[(1R)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sul-
finamide
[1233] To a mixture of
(S)--N-[(1E)-(6-chloropyridin-2-yl)methylidene]-2-methylpropane-2-sulfina-
mide (1.73 g, 7.07 mmol) and In (0.92 g, 10.60 mmol) in THF (17.7
ml) was slowly added 3-bromoprop-1-ene (0.92 g, 10.60 mmol). The
reaction was heated at 60.degree. C. overnight. The reaction
mixture was cooled to rt, filtered through CELITE.RTM. and the
filtrate was concentrated. The resulting residue was purified by
normal phase chromatography, using hexanes and EtOAc, which gave a
5.6:1 of
(S)--N-[(1S)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sul-
finamide:(S)--N-[(1R)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropa-
ne-2-sulfinamide (2.42 g, 58%) as a brown semi-solid. MS(ESI) m/z:
287.4 (M+H).sup.+.
28D. Preparation of
(S)-2-methyl-N-[(1R)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]-
but-3-en-1-yl]propane-2-sulfinamide (Diastereomer A), and
28E. Preparation of
(S)-2-methyl-N-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]-
but-3-en-1-yl]propane-2-sulfinamide (Diastereomer B)
[1234] To a N.sub.2 flushed pressure vial was added 5.6:1 of
(S)--N-[(1S)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sul-
finamide:
(S)--N-[(1R)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylprop-
ane-2-sulfinamide (2.18 g, 7.60 mmol), 1-methyl-4-nitro-1H-pyrazole
(0.966 g, 7.60 mmol), prepared as described in Intermediate 32A,
di(adamant-1-yl)(butyl)phosphine (0.954 g, 2.66 mmol), PvOH (0.300
ml, 2.58 mmol), K.sub.2CO.sub.3 (3.62 g, 26.2 mmol), Pd(OAc).sub.2
(0.341 g, 1.52 mmol) and DMF (15.2 mL). The vial was purged with
Ar. The vial was sealed and heated at 120.degree. C. overnight. The
reaction mixture was cooled to rt, partitioned between water and
EtOAc, and the layers were separated. The aqueous layer was
extracted with EtOAc (3.times.) and the organic layers were
combined and concentrated. The crude product was purified using
normal phase chromatography followed a second purification by
reverse phase chromatography to give
(S)-2-methyl-N-[(1R)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]-
but-3-en-1-yl]propane-2-sulfinamide (Diastereomer A) (0.275 g,
13%), MS(ESI) m/z: 274.4 (M+H).sup.+; and
(S)-2-methyl-N-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]-
but-3-en-1-yl]propane-2-sulfinamide (Diastereomer B) (1.2 g, 57%);
MS(ESI) m/z: 274.4 (M+H).sup.+.
28F. Preparation of tert-butyl
N-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl-
]carbamate
[1235]
(1S)-1-(6-(1-Methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-
-amine (Diastereomer B) (1.2 g, 3.18 mmol) was dissolved in MeOH (5
mL) and dioxane (25 ml). 4 N HCl in dioxane (4.8 ml, 19.1 mmol) was
added. The reaction was stirred at rt for 3 h and then was
concentrated. The residue was coevaporated with toluene, dissolved
in DCM (40 mL), and cooled to 0.degree. C. TEA (4.43 mL, 31.8 mmol)
was added followed by BOC.sub.2O (0.738 mL, 3.18 mmol). The
reaction was stirred at 0.degree. C. for 15 min and then the
reaction was allowed to warm to rt. After 2 h, the reaction was
diluted with DCM, washed with sat NaHCO.sub.3, brine, and
concentrated. Purification by normal phase chromatography gave
tert-butyl
N-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl-
]carbamate (393 mg, 33% yield) as an orange oil. MS(ESI) m/z: 374.5
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.19 (s,
1H), 7.84 (t, J=7.8 Hz, 1H), 7.55 (d, J=7.7 Hz, 1H), 7.38 (d, J=7.7
Hz, 1H), 5.77-5.58 (m, 1H), 5.40 (br. s., 1H), 5.13-5.01 (m, 2H),
4.92 (d, J=6.8 Hz, 1H), 3.86 (s, 3H), 2.71-2.51 (m, 2H), 1.43 (s,
9H).
28G. Preparation of tert-butyl
N-[(1S)-1-[6-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl-
]carbamate
[1236] To a solution of tert-butyl
N-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)
pyridin-2-yl]but-3-en-1-yl]carbamate (393 mg, 1.05 mmol) in MeOH
(6.4 mL) was added AcOH (0.64 mL). The reaction mixture was heated
to 45.degree. C. then Zn powder (206 mg, 3.16 mmol) was added
portionwise. After 1 h, additional Zn (198 mg) was added. Upon
completion of the reaction, the mixture was cooled to rt,
partitioned between DCM and sat NaHCO.sub.3, and the layers were
separated. The aqueous layer was extracted with DCM (2.times.). The
organic layers were combined and washed with brine, dried over
MgSO.sub.4, filtered and concentrated to give tert-butyl
N-[(1S)-1-[6-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl-
]carbamate (343 mg, 95% yield) as a yellow foam. MS(ESI) m/z: 344.5
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.74 (t,
J=7.8 Hz, 1H), 7.39 (dd, J=7.8, 0.8 Hz, 1H), 7.25-7.18 (m, 1H),
7.14 (d, J=7.7 Hz, 1H), 5.70 (ddt, J=17.1, 10.2, 7.0 Hz, 1H), 5.46
(d, J=6.8 Hz, 1H), 5.13-4.99 (m, 2H), 4.89 (d, J=6.8 Hz, 1H), 4.01
(s, 3H), 2.71-2.53 (m, 2H), 1.49-1.30 (m, 9H).
28H. Preparation of tert-butyl
N-[(1S)-1-(6-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyr-
idin-2-yl)but-3-en-1-yl]carbamate
[1237] To tert-butyl
N-[(1S)-1-[6-(4-amino-1-methyl-1H-pyrazol-5-yl)
pyridin-2-yl]but-3-en-1-yl]carbamate (343 mg, 0.999 mmol) in EtOAc
(3.33 ml) was added a solution of (R)-2-methylbut-3-enoic acid
(0.150 g, 1.498 mmol), prepared as described in Intermediate 2, in
EtOAc (1 ml). The mixture was cooled to 0.degree. C. and pyridine
(0.24 ml, 3.0 mmol) was added, followed by the addition of a
solution of 50% T3P.RTM. in EtOAc (1.19 ml, 1.50 mmol). After 2 h,
the reaction was partitioned between sat NaHCO.sub.3 and EtOAc, and
the layers were separated. The aqueous layer was extracted with
EtOAc (2.times.). The organic layers were combined and washed with
brine and then concentrated. Purification by normal phase
chromatography gave tert-butyl
N-[(1S)-1-(6-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyr-
idin-2-yl) but-3-en-1-yl]carbamate (360 mg, 85%) as a yellow solid.
MS(ESI) m/z: 426.5 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.35 (br. s., 1H), 8.30 (s, 1H), 7.82 (t, J=7.8 Hz, 1H),
7.40 (d, J=7.9 Hz, 1H), 7.32-7.19 (m, 1H), 6.01 (ddd, J=17.4, 10.0,
7.6 Hz, 1H), 5.78-5.57 (m, 1H), 5.35-5.04 (m, 5H), 4.91 (br. s.,
1H), 4.06 (s, 3H), 3.26-3.06 (m, 1H), 2.81-2.54 (m, 2H), 1.54-1.30
(m, 12H).
[1238] 28I. Preparation of tert-butyl
N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
[1239] A solution of tert-butyl
N-[(1S)-1-(6-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyr-
idin-2-yl) but-3-en-1-yl]carbamate (140 mg, 0.329 mmol) in EtOAc
(25 ml) was purged with Ar for 20 min. Second Generation Grubbs
Catalyst (0.112 g, 0.132 mmol) was added and the reaction mixture
was heated at 80.degree. C. overnight. The reaction mixture was
cooled to rt and concentrated. Purification by normal phase
chromatography and then by reverse phase chromatography was done.
The fractions containing the desired product were made basic (pH
.about.8) with sat NaHCO.sub.3 and then concentrated. The residue
was partitioned between water and EtOAc, and the layers were
separated. The aqueous layer was extracted with DCM (3.times.) and
EtOAc (3.times.). The organic layers were combined and washed with
brine, dried MgSO.sub.4, filtered and concentrated to give
tert-butyl
N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (96 mg,
66% yield). MS(ESI) m/z: 398.2 (M+H).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 11.12 (br. s., 1H), 8.08 (s, 1H), 7.84 (t,
J=7.9 Hz, 1H), 7.39 (dd, J=7.9, 0.7 Hz, 1H), 7.32-7.24 (m, 1H),
5.98-5.83 (m, 1H), 5.55 (dd, J=15.7, 7.4 Hz, 1H), 5.41 (d, J=6.6
Hz, 1H), 5.04 (m, 1H), 4.10-4.03 (m, 3H), 3.15 (quin, J=7.3 Hz,
1H), 2.84-2.56 (m, 2H), 1.51-1.32 (m, 12H).
28J. Preparation of tert-butyl
N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate,
and
28K. Preparation of tert-butyl
N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-2(6),4-dien-13-yl]carbamate
[1240] A solution of tert-butyl
N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (0.096
g, 0.024 mmol) in EtOH (4 ml) was hydrogenated at 20 psi H.sub.2 in
the presence of PtO.sub.2 (20 mg) for 20 h. The mixture was
filtered, washing with MeOH and EtOAc. The filtrate was
concentrated and then purified by reverse phase chromatography to
give, following neutralization of the fractions and extraction,
tert-butyl
N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-2(6),4-dien-13-yl]carbamate (20 mg, 20.4% yield), MS(ESI)
m/z: 406.2 (M+H).sup.+; and tert-butyl
N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (68 mg, 70.5%
yield), MS(ESI) m/z: 400.2 (M+H).sup.+.
28L. Preparation of
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[1241] To a solution of tert-butyl
N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.035 g,
0.088 mmol) in DCM (0.5 ml) was added TFA (0.2 mL, 2.60 mmol).
After stirring for 1 h, the reaction mixture was concentrated to
dryness, and coevaporated with CH.sub.3CN. The residue was
neutralized by dissolving in MeOH, passing through NaHCO.sub.3
cartridge (StratoSpheres SPE; 500 mg, 0.90 mmol loading), and the
filtrate concentrated to give
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one (15 mg, 57% yield) as
clear glass. MS(ESI) m/z: 300.5 (M+H).sup.+.
Intermediate 29
Preparation of
(9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00140##
[1242] 29A. Preparation of tert-butyl
N-[(1S)-1-[3-fluoro-5-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl]but-3-en-1-
-yl]carbamate
[1243] To tert-butyl
N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]carbamate (0.19 g,
0.552 mmol), 1-methyl-4-nitro-1H-pyrazole (0.070 g, 0.552 mmol),
di(adamantan-1-yl)(butyl)phosphine (0.059 g, 0.166 mmol), pivalic
acid (0.019 ml, 0.166 mmol), K.sub.2CO.sub.3 (0.229 g, 1.656 mmol)
was added DMF (1.1 ml), and the mixture was purged with Ar.
Pd(OAc).sub.2 (0.025 g, 0.110 mmol) was added and the reaction was
heated at 120.degree. C. for 18 h. The reaction was partitioned
between water (15 ml) and EtOAc (30 ml). The aqueous layer was
extracted with EtOAc (2.times.20 ml). The combined organic layers
was washed with brine (15 ml), dried over MgSO.sub.4, filtered and
concentrated. The residue was purified by normal phase
chromatography using hexanes and EtOAc as eluents to give
tert-butyl
N-[(1S)-1-[3-fluoro-5-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl]but-3-en-1-
-yl]carbamate (0.123 g, 57%) as a yellow oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.23-8.17 (m, 1H), 7.22-7.16 (m, 1H), 7.10 (s,
1H), 7.01 (dt, J=8.5, 1.9 Hz, 1H), 5.76-5.60 (m, 1H), 5.22-5.11 (m,
2H), 4.90 (br. s., 1H), 4.78 (br. s., 1H), 3.78-3.69 (m, 3H),
2.60-2.48 (m, 2H), 1.41 (br. s., 9H).
29B. Preparation of tert-butyl
N-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl]but-3-en-1-
-yl]carbamate
[1244] To tert-butyl
N-[(1S)-1-[3-fluoro-5-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl]but-3-en-1-
-yl]carbamate (0.123 g, 0.315 mmol) dissolved in acetone (5
ml)/water (1 ml), cooled to 0.degree. C., and NH.sub.4Cl (0.084 g,
1.575 mmol) and Zn (0.206 g, 3.15 mmol) were added. The ice bath
was removed. After 3 h, the reaction was filtered and filtrate was
partitioned between water (10 ml) and EtOAc (30 ml). The aqueous
layer was extracted with EtOAc (2.times.20 ml). The combined
organic layers was washed with brine (10 ml), dried over
MgSO.sub.4, filtered and concentrated. The residue was purified by
normal phase chromatography using DCM and 0-10% MeOH as eluents to
give tert-butyl
N-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl]but-3-en-1-
-yl]carbamate (0.105 g, 92%). MS(ESI) m/z: 361.08 (M+H).sup.+.
29C. Preparation of tert-butyl
N-[(1S)-1-(3-fluoro-5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-
-5-yl}phenyl)but-3-en-1-yl]carbamate
[1245] To tert-butyl
N-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl]but-3-en-1-
-yl]carbamate (0.105 g, 0.291 mmol) in EtOAc (0.58 ml) was added
(R)-2-methylbut-3-enoic acid (0.035 g, 0.350 mmol), prepared as
described in Intermediate 2, in 0.3 ml EtOAc. The mixture was
cooled to 0.degree. C. and Hunig's Base (0.153 ml, 0.874 mmol)
followed by a solution of 50% T3P.RTM. in EtOAc (0.347 ml, 0.583
mmol) were added. After 4 h, the reaction was partitioned with sat
NaHCO.sub.3 (5 ml) and
[1246] EtOAc (5 ml). The aqueous layer was extracted with EtOAc
(2.times.10 ml). The combined organic layers was washed with brine
(5 ml), dried over MgSO.sub.4, filtered and concentrated. The
residue was purified by normal phase chromatography using hexanes
and EtOAc as eluents to give the desired product (53.0 mg, 41%) as
a yellow foam. MS(ESI) m/z: 443.5 (M+H).sup.+.
29D. Preparation of tert-butyl
N-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.-
0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
[1247] A solution of tert-butyl
N-[(1S)-1-(3-fluoro-5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-
-5-yl}phenyl)but-3-en-1-yl]carbamate (0.053 g, 0.120 mmol) in
degassed DCE (10 ml) was heated to 120.degree. C. for 30 min in a
microwave in the presence of Second Generation Grubbs Catalyst
(0.041 g, 0.048 mmol). The reaction mixture was directly purified
by normal phase chromatography using hexanes and EtOAc as eluents
to give tert-butyl
N-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
(27.0 mg, 54%) as a dark solid. MS(ESI) m/z: 415.4 (M+H).sup.+.
29E. Preparation of
(9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[1248] A solution of tert-butyl
N-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.-
0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
(0.027 g, 0.065 mmol) in EtOH (3 ml) was hydrogenated in the
presence of PtO.sub.2 (5 mg) for 6 h. After this time, the reaction
was filtered through CELITE.RTM. and the filtrate was concentrated
to tert-butyl
N-[(9R,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0.su-
p.2,6] octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (19 mg).
The Boc protecting group was removed by dissolving the material in
3 ml of 50% TFA/DCM. After 2 h, the reaction mixture was
concentrated and the residue was taken up in DCM and MeOH, and
filtered through a basic cartridge. Concentration of the filtrate
afforded
(9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0.su-
p.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one (19 mg, 92%) as a
dark solid. MS(ESI) m/z: 317.4 (M+H).sup.+.
Intermediate 30
Preparation of
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00141##
[1249] 30A. Preparation of
1-(difluoromethyl)-4-nitro-1H-pyrazole
[1250] Cs.sub.2CO.sub.3 (14.41 g, 44.2 mmol) was suspended in a
solution of 4-nitro-1H-pyrazole (5.00 g, 44.2 mmol) and DMF (40
mL). After heating to 120.degree. C. for 5 min, solid sodium
2-chloro-2,2-difluoroacetate (13.48 g, 88 mmol) was added in 10
equal portions over 20 min. The reaction was complete after 10 min
of additional heating. The mixture was added to a separatory funnel
containing 100 mL water and extracted with Et.sub.2O (2.times.50
mL). The combined organic layers were concentrated. Purification by
normal-phase chromatography eluting with a gradient of
hexanes/EtOAc yielded 1-(difluoromethyl)-4-nitro-1H-pyrazole (6.99
g, 42.9 mmol, 97% yield) as a clear, colorless oil. .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 8.58 (s, 1H), 8.22 (s, 1H), 7.39-7.05
(t, J=60 Hz, 1H).
30B. Preparation of (S)-tert-butyl
(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-
-yl)carbamate
[1251] To a N.sub.2 flushed, 500 mL RBF was added (S)-tert-butyl
(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate, prepared as
described in Intermediate 23, (10 g, 35.4 mmol),
1-(difluoromethyl)-4-nitro-1H-pyrazole, prepared as described in
Intermediate 30A, (6.34 g, 38.9 mmol) and dioxane (100 mL). The
solution was bubbled with N.sub.2 for 5 min and Pd(OAc).sub.2 (0.40
g, 1.7 mmol), di(adamantan-1-yl)(butyl)phosphine (1.27 g, 3.5
mmol), K.sub.2CO.sub.3 (14.7 g, 106 mmol) and PvOH (1.08 g, 10.61
mmol) were added. The reaction mixture was bubbled with N.sub.2 for
5 min, then heated to 100.degree. C. for 3 h. Water (200 mL) was
added. The reaction mixture was then extracted with EtOAc
(2.times.200 mL). The combined organic extracts were washed with
water (200 mL), brine (200 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated. Purification by normal phase
chromatography eluting with a gradient of hexanes/EtOAc afforded
(S)-tert-butyl
(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-
-yl)carbamate (12.91 g, 31.5 mmol, 89% yield) as a yellowish oil.
MS(ESI) m/z: 410.4 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.80 (dd, J=5.1, 0.7 Hz, 1H), 8.36 (s, 1H), 7.34 (s, 1H),
7.31 (dd, J=5.1, 1.5 Hz, 1H), 7.27-6.91 (t, J=58 Hz, 1H), 5.79-5.63
(m, 1H), 5.16-5.03 (m, 2H), 4.92 (d, J=5.9 Hz, 1H), 2.67 (t, J=6.4
Hz, 2H), 1.46 (br. s., 9H).
30C. Preparation of (S)-tert-butyl
(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-
-yl)carbamate
[1252] To a 100 mL, 3-necked RBF was added a solution of
(S)-tert-butyl
(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-
-yl)carbamate (0.78 g, 1.90 mmol) in MeOH (12 mL) and a solution of
NH.sub.4Cl (1.02 g, 19 mmol) in water (3 mL). To the solution was
added Fe (0.53 g, 9.49 mmol). The reaction mixture was heated to
65.degree. C. for 3 h. Water (50 mL) was added. After cooling to
rt, the mixture was filtered through a CELITE.RTM. pad and rinsed
with MeOH (200 mL). The filtrate was concentrated. The residue was
partitioned between EtOAc (100 mL) and water (100 mL). The organic
phase was separated, washed with water (100 mL), brine (100 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
Purification by normal phase chromatography eluting with a gradient
of DCM/MeOH yielded (S)-tert-butyl
(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-
-yl)carbamate (0.585 g, 1.54 mmol, 81% yield) as an oil. MS(ESI)
m/z: 380.1 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.70 (dd, J=5.0, 0.7 Hz, 1H), 7.43 (s, 1H), 7.36 (s, 1H), 7.32 (dd,
J=5.1, 1.5 Hz, 1H), 7.28-6.97 (t, J=58 Hz, 1H), 5.80-5.66 (m, 1H),
5.65-5.53 (m, 1H), 5.13-5.03 (m, 2H), 4.87 (br. s., 1H), 3.22 (br.
s., 2H), 2.65 (t, J=6.5 Hz, 2H), 1.52-1.37 (m, 9H).
30D. Preparation of tert-butyl
((5)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5--
yl)pyridin-2-yl)but-3-en-1-yl)carbamate
[1253] To a N.sub.2 flushed, 3-necked, 250 mL RBF was added a
solution of (S)-tert-butyl
(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-
-yl)carbamate (5 g, 13.18 mmol) and EtOAc (50 mL). The solution was
cooled to -10.degree. C. and (R)-2-methylbut-3-enoic acid, as
prepared in Intermediate 2, (1.72 g, 17.13 mmol), pyridine (4.26
mL, 52.7 mmol), and T3P.RTM. (23.54 mL, 39.5 mmol) were added. The
cooling bath was removed and the solution was allowed to warm to rt
and then stir over a period of 20 h. Water (30 mL) and EtOAc (30
mL) were added and the mixture was stirred for 30 min. The organic
phase was separated and the aqueous layer was extracted with EtOAc
(30 mL). The combined organic extracts were washed with brine (50
mL), dried over Na.sub.2SO.sub.4, filtered and concentrated.
Purification by normal phase chromatography eluting with a gradient
of hexanes/EtOAc gave tert-butyl
((5)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5--
yl)pyridin-2-yl)but-3-en-1-yl)carbamate (5.69 g, 12.33 mmol, 94%
yield). MS(ESI) m/z: 462.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.75 (dd, J=5.0, 0.6 Hz, 1H), 8.37 (s, 1H),
7.32 (t, J=59 Hz, 1H), 7.28 (br. s., 1H), 7.20 (s, 1H), 5.97-5.85
(m, 1H), 5.78-5.65 (m, 1H), 5.56-5.44 (m, 1H), 5.28-5.19 (m, 2H),
5.12 (d, J=2.0 Hz, 2H), 4.91-4.82 (m, 1H), 3.20-3.11 (m, 1H),
2.72-2.62 (m, 2H), 1.48-1.43 (s, 9H), 1.33 (d, J=6.8 Hz, 3H).
30E. Preparation of tert-butyl
N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,.sup.6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carba-
mate
[1254] To a N.sub.2 flushed, 2 L, 3-necked, RBF was added a
solution of tert-butyl
((S)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5--
yl)pyridin-2-yl)but-3-en-1-yl)carbamate (3 g, 6.50 mmol) in EtOAc
(1300 mL). The solution was sparged with Ar for 15 min. Second
Generation Grubbs Catalyst (1.38 g, 1.63 mmol) was added in one
portion. The reaction mixture was heated to reflux for 24 h. After
cooling to rt, the solvent was removed and the residue was purified
by normal phase chromatography eluting with a gradient of DCM/MeOH
to yield tert-butyl
N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,.sup.6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carba-
mate (2.13 g, 4.91 mmol, 76% yield) as a tan solid. MS(ESI) m/z:
434.4 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.71
(d, J=5.1 Hz, 1H), 7.78 (s, 1H), 7.44-7.40 (m, 1H), 7.36 (br. s.,
1H), 7.27 (t, J=58 Hz, 1H), 6.87 (s, 1H), 6.49-6.39 (m, 1H), 5.78
(s, 1H), 4.80 (br. s., 2H), 3.18-3.08 (m, 1H), 3.08-2.98 (m, 1H),
2.06-1.93 (m, 1H), 1.51 (s, 9H), 1.19 (d, J=6.6 Hz, 3H).
30F. Preparation of tert-butyl
N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,.sup.6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
[1255] Pd/C (0.60 g, 0.570 mmol) was added to a 250 mL Parr
hydrogenation flask containing a solution of tert-butyl
N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,.sup.6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carba-
mate (2.46 g, 5.68 mmol) in EtOH (100 mL). The flask was purged
with N.sub.2 and pressurized to 55 psi of H.sub.2 allowed to stir
for 18 h. The reaction was filtered through CELITE.RTM. and
concentrated to yield tert-butyl
N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,.sup.6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(2.17 g, 88% yield) as a tan solid. MS(ESI) m/z: 436.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.32 (s, 1H), 8.71 (d,
J=5.0 Hz, 1H), 7.96 (t, J=58 Hz, 1H), 7.43 (s, 1H), 7.32 (d, J=4.8
Hz, 1H), 7.22 (d, J=7.3 Hz, 1H), 4.66 (d, J=8.3 Hz, 1H), 2.62 (br.
s., 1H), 1.88 (d, J=12.8 Hz, 1H), 1.77-1.59 (m, 2H), 1.42-1.28 (m,
9H), 1.15 (d, J=18.2 Hz, 2H), 0.83 (d, J=7.0 Hz, 3H).
Example 30G
Preparation of
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[1256] 4 N HCl in dioxane (3.88 mL, 15.5 mmol) was added to a
solution of tert-butyl
N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,.sup.6]
octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (2.25 g, 5.2
mmol) in MeOH (10 mL). The reaction was allowed to stir at rt for 2
h. The reaction was cooled in an ice bath, and 7 N NH.sub.3 in MeOH
(13.3 mL, 93.0 mmol) was added. After 5 min, the reaction was
diluted with CH.sub.2Cl.sub.2 (80 mL) and the solid that formed was
filtered. The filtrate was concentrated to yield
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (1.3 g,
3.88 mmol, 75% yield). MS(ESI) m/z: 336.3 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.33 (s, 1H), 8.71 (d, J=5.0 Hz,
1H), 7.94 (t, J=58 Hz, 1H), 7.85 (s, 1H), 7.40 (s, 1H), 7.32 (d,
J=5.0 Hz, 1H), 4.01 (dd, J=10.2, 5.1 Hz, 1H), 2.63-2.53 (m, 1H),
1.90-1.69 (m, 2H), 1.53-1.36 (m, 2H), 1.16-1.00 (m, 1H), 0.85 (d,
J=7.0 Hz, 3H).
Intermediate 31
Preparation of
(9R,13S)-13-amino-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one, hydrochloride
##STR00142##
[1257] 31A. Preparation of tert-butyl
N-[(1S)-1-[3-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carba-
mate
[1258] To tert-butyl
N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (2 g, 6.13 mmol),
1-methyl-4-nitro-1H-pyrazole (0.779 g, 6.13 mmol),
di(adamantan-1-yl)(butyl) phosphine (0.659 g, 1.839 mmol), pivalic
acid (0.213 ml, 1.839 mmol), K.sub.2CO.sub.3 (2.54 g, 18.39 mmol)
was added DMF (9 ml). The mixture was purged with Ar for 10 min and
Pd(OAc).sub.2 (0.275 g, 1.226 mmol) was added. The reaction was
heated at 120.degree. C. for 15 h. The reaction was partitioned
between water (50 ml) and EtOAc (50 ml) and solution was filtered
through paper and the layers were separated. The aqueous layer was
extracted with EtOAc (2.times.50 ml). The combined organic layers
were washed with brine (50 ml), dried over MgSO.sub.4, filtered and
concentrated. The residue was purified by normal phase
chromatography using hexanes and EtOAc as eluents to afford
(S)-tert-butyl
(1-(3-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl)but-3-en-1-yl)carbamate
(1.186 g, 3.18 mmol, 51.9% yield) as a yellow oil. MS(ESI) m/z:
371.1 (M-H).sup.+.
31B. Preparation of tert-butyl
N-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)phenyl]
but-3-en-1-yl]carbamate
[1259] To tert-butyl
N-[(1S)-1-[3-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carba-
mate (0.097 g, 0.260 mmol) in acetone (5 ml)/water (1 ml), cooled
to 0.degree. C., was added NH.sub.4Cl (0.070 g, 1.302 mmol) and Zn
(0.170 g, 2.60 mmol). The ice bath was removed. After 3 h, the
reaction was filtered and the filtrate was partitioned between
water (10 ml) and EtOAc (30 ml). The aqueous layer was extracted
with EtOAc (2.times.20 ml). The combined organic layers were washed
with brine (10 ml), dried over MgSO.sub.4, filtered and
concentrated. The residue was purified by normal phase
chromatography using DCM and 0-10% MeOH as eluents to afford
tert-butyl
N-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carba-
mate (76.6 mg, 86%). MS(ESI) m/z: 343.2 (M+H).sup.+.
31C. Preparation of tert-butyl
N-[(1S)-1-(3-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}phe-
nyl)but-3-en-1-yl]carbamate
[1260] To tert-butyl
N-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carba-
mate (0.076 g, 0.222 mmol) in EtOAc (0.58 ml) was added
(R)-2-methylbut-3-enoic acid (0.027 g, 0.266 mmol), prepared as
described in Intermediate 2, in 0.3 mL EtOAc. The mixture was
cooled to 0.degree. C. and Hunig's Base (0.116 ml, 0.666 mmol)
followed by a solution of 50% T3P.RTM. in EtOAc (0.264 ml, 0.444
mmol) were added. After 3 h, the reaction was partitioned with sat
NaHCO.sub.3 (5 ml) and EtOAc (5 ml). The aqueous layer was
extracted with EtOAc (2.times.10 ml). The combined organic layers
were washed with brine (5 ml), dried over MgSO.sub.4, filtered and
concentrated. The residue was purified by normal phase
chromatography using hexanes and EtOAc as eluents to afford
tert-butyl
N-[(1S)-1-(3-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}phe-
nyl)but-3-en-1-yl]carbamate (69 mg, 73%) as a yellow oil. MS(ESI)
m/z: 425.2 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.04 (s, 1H), 7.52-7.45 (m, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.26-7.18
(m, 2H), 7.05 (br. s., 1H), 5.96-5.85 (m, 1H), 5.69 (ddt, J=17.0,
10.1, 7.0 Hz, 1H), 5.21-5.09 (m, 4H), 4.95 (br. s., 1H), 4.77 (br.
s., 1H), 3.76 (s, 3H), 3.07 (quin, J=7.2 Hz, 1H), 2.61-2.48 (m,
2H), 1.45-1.38 (m, 9H), 1.30 (d, J=7.0 Hz, 3H).
31D. Preparation of tert-butyl
N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
[1261] A solution of tert-butyl
N-[(1S)-1-(3-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}phe-
nyl)but-3-en-1-yl]carbamate (0.069 g, 0.163 mmol) in degassed DCE
(10 ml) was heated to 120.degree. C. for 30 min in a microwave in
the presence of Second Generation Grubbs Catalyst (0.055 g, 0.065
mmol). The reaction mixture was directly purified by normal phase
chromatography twice using hexanes and EtOAc as eluents to afford
desired tert-butyl
N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
(33 mg, 51.2%) as a dark solid. MS(ESI) m/z: 397.1 (M+H).sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.61-7.52 (m, 1H),
7.46-7.40 (m, 1H), 7.33-7.25 (m, 1H), 7.20 (d, J=7.5 Hz, 1H), 6.93
(br. s., 1H), 6.83 (s, 1H), 5.63 (ddd, J=15.1, 9.4, 5.6 Hz, 1H),
5.18 (br. s., 1H), 4.89 (dd, J=15.2, 8.8 Hz, 1H), 4.69 (br. s.,
1H), 3.93-3.86 (m, 3H), 3.09-2.99 (m, 1H), 2.69-2.58 (m, 1H),
2.17-2.08 (m, 1H), 1.53-1.32 (m, 9H), 1.18 (d, J=6.8 Hz, 3H).
31E. Preparation of tert-butyl
N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
[1262] A solution of tert-butyl
N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
(0.089 g, 0.224 mmol) in EtOH (5 ml) was hydrogenated under a
H.sub.2 atmosphere at 55 psi for 3 h. The reaction mixture was
filtered through small plug of CELITE.RTM. and rinsed with
EtOH/MeOH/DCM to give tert-butyl
N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octa-
deca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (89 mg, 99%) as a
white solid. MS(ESI) m/z: 399.4 (M+H).sup.+. .sup.1H NMR (400 MHz
CDCl.sub.3) .delta. 7.53-7.43 (m, 2H), 7.43-7.36 (m, 1H), 7.29 (s,
1H), 6.44 (s, 1H), 4.90 (br. s., 1H), 4.68 (br. s., 1H), 3.98 (s,
3H), 2.44 (br. s., 1H), 1.93 (d, J=7.7 Hz, 1H), 1.85-1.63 (m, 2H),
1.42 (br. s., 9H), 1.28-1.19 (m, 2H), 1.07 (d, J=6.8 Hz, 3H), 0.96
(br. s., 1H).
31F. Preparation of
(9R,13S)-13-amino-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one hydrochloride
##STR00143##
[1264] tert-Butyl
N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (88 mg, 0.221
mmol) was deprotected with 4 N HCl in dioxane (3 ml) for 5 h. The
reaction was concentrated to afford (70 mg, 95%) of
(9R,13S)-13-amino-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one hydrochloride as a dark
solid. MS(ESI) m/z: 299.08 (M+H).sup.+. .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 7.81 (s, 1H), 7.77-7.70 (m, 1H), 7.70-7.58 (m,
3H), 4.46 (dd, J=12.0, 4.5 Hz, 1H), 4.19-4.07 (m, 3H), 3.45-3.26
(m, 1H), 2.75-2.59 (m, 1H), 2.21-2.09 (m, 1H), 1.99-1.86 (m, 2H),
1.58 (td, J=14.3, 8.3 Hz, 1H), 1.29-1.17 (m, 1H), 1.03 (d, J=6.9
Hz, 3H), 0.94-0.82 (m, 1H).
Intermediate 32
Preparation of
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
] octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00144##
[1265] 32A. Preparation of 1-methyl-4-nitro-1H-pyrazole
[1266] To a solution of 4-nitro-1H-pyrazole (2.5 g, 22.11 mmol) in
THF (50 mL) was added NaH (0.973 g, 24.32 mmol) and the mixture was
stirred at rt for 5 min. To this suspension was then added
CH.sub.3I (1.382 mL, 22.11 mmol) and stirred at rt overnight. The
reaction mixture was then diluted with EtOAc (2.times.25 mL) and
washed with brine (25 mL). The organic layer was concentrated,
followed by purification using normal phase chromatography to yield
1-methyl-4-nitro-1H-pyrazole as white solid (1.9 g, 80% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.12 (s, 1H), 8.06
(s, 1H), 3.97 (s, 3H).
32B. Preparation of (S)-tert-butyl
(1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbam-
ate
[1267] To a N.sub.2 flushed pressure vial was added (S)-tert-butyl
(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate, prepared as
described in Intermediate 23, (3.0 g, 10.61 mmol),
1-methyl-4-nitro-1H-pyrazole (1.348 g, 10.61 mmol),
di(adamant-1-yl)(butyl) phosphine (1.141 g, 3.18 mmol), PvOH (0.369
ml, 3.18 mmol), K.sub.2CO.sub.3 (4.40 g, 31.8 mmol) and DMF (21
mL). The reaction mixture was purged with N.sub.2 for 5 min and
Pd(OAc).sub.2 (0.476 g, 2.122 mmol) was added. The reaction mixture
was purged with N.sub.2. The vial was sealed and heated at
120.degree. C. for 4 h. The reaction mixture was cooled to rt and
partitioned between 10% aqueous LiCl (15 mL) and EtOAc (30 mL). The
aqueous layer was extracted with EtOAc (2.times.20 mL) and the
combined organic layers were washed with brine (15 mL), dried over
MgSO.sub.4, filtered and concentrated. The crude product was then
purified using normal phase chromatography to yield (S)-tert-butyl
(1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbam-
ate (1.2 g, 29% yield) as a brown oil. MS(ESI) m/z: 374.4
(M+H).sup.+.
32C. Preparation of (S)-tert-butyl
(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbam-
ate
[1268] A solution of (S)-tert-butyl
(1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbam-
ate (1.2 g, 3.21 mmol) in MeOH (10 mL) and AcOH (1 mL) was heated
to 40.degree. C. To the above clear solution was then slowly added
Zn (0.420 g, 6.43 mmol) in 3 portions (50:25:25%) and stirred at
40.degree. C. for 5 min. The reaction mixture was monitored by LCMS
and once complete, the solution was cooled to rt, and
K.sub.2CO.sub.3 and 1 mL water were added. The reaction mixture was
stirred for 5 min, then filtered through a pad of CELITE.RTM. and
concentrated to yield the crude product. The crude product was
partitioned between EtOAc (30 mL) and sat NaHCO.sub.3 (15 mL). The
organic layers were separated and dried over MgSO.sub.4. The crude
product was purified using normal phase chromatography to yield
(S)-tert-butyl
(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbam-
ate (0.88 g, 76% yield) as pale brown oil. MS(ESI) m/z: 344.4
(M+H).sup.+.
32D. Preparation of tert-butyl
((5)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-
-2-yl)but-3-en-1-yl)carbamate
[1269] To a N.sub.2 flushed, 3-necked, 250 mL RBF was added a
solution of (S)-tert-butyl
(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbam-
ate (620 mg, 1.805 mmol) and EtOAc (15 mL). The solution was cooled
to -10.degree. C. and (R)-2-methylbut-3-enoic acid, as prepared in
Intermediate 2, (271 mg, 2.71 mmol), pyridine (0.437 mL, 5.42 mmol)
and T3P.RTM. (2.149 mL, 3.61 mmol) were added. The cooling bath was
removed and the solution was allowed to warm to rt and then stir
over a period of 20 h. Water (15 mL) and EtOAc (15 mL) were added
and the mixture was stirred for 30 min. The organic phase was
separated and the aqueous layer was extracted with EtOAc (15 mL).
The combined organic extracts were washed with brine (15 mL), dried
over Na.sub.2SO.sub.4, filtered and concentrated. Purification by
normal phase chromatography eluting with a gradient of
hexanes/EtOAc gave tert-butyl
((S)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-
-2-yl)but-3-en-1-yl)carbamate (0.26 g, 34% yield). MS(ESI) m/z:
426.5 [M+H].sup.+.
32E. Preparation of tert-butyl
N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
[1270] To a N.sub.2 flushed, 250 mL, 3-necked RBF was added a
solution of tert-butyl
((5)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-
-2-yl)but-3-en-1-yl)carbamate (266 mg, 0.625 mmol) in DCE (18 mL).
The solution was sparged with Ar for 15 min. Second Generation
Grubbs Catalyst (213 mg, 0.250 mmol) was added in one portion. The
reaction mixture was heated to 120.degree. C. in microwave for 30
min. After cooling to rt, the solvent was removed and the residue
was purified by normal phase chromatography eluting with a gradient
of DCM/MeOH to yield tert-butyl
N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (60 mg,
23% yield) as a tan solid. MS(ESI) m/z: 398.4 [M+H].sup.+.
32F. Preparation of tert-butyl
N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
[1271] Pd/C (0.016 g, 0.015 mmol) was added to a 100 mL Parr
hydrogenation flask containing a solution of tert-butyl
N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (60 mg,
0.151 mmol) in EtOH (6 mL). The flask was purged with N.sub.2 and
pressurized to 55 psi of H.sub.2 and allowed to stir for 5 h. The
reaction was filtered through a pad of CELITE.RTM. and concentrated
to yield tert-butyl
N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (48 mg, 76%
yield) as a tan solid. MS(ESI) m/z: 400.5 [M+H].sup.+.
32G. Preparation of
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[1272] To a solution of tert-butyl
N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (48 mg, 0.120
mmol) in DCM (2.5 mL) was added TFA (0.6 mL, 7.79 mmol) and the
reaction was stirred at rt for 1.5 h. The reaction mixture was then
concentrated to give
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.su-
p.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one bis
trifluoroacetate (63 mg, 94% yield) as a brown solid which was then
dissolved in MeOH (1 mL) to give a clear, brown solution. The
solution was added to a pre-rinsed AGILENT.RTM. StratoSpheres SPE
PL-HCO.sub.3 MP Resin cartridge. Gravity filtration, eluting with
MeOH, gave a clear, slightly yellow filtrate. Concentration
provided
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one (25 mg, 93%) as a pale
yellow solid. MS(ESI) m/z: 300.4 [M+H].sup.+.
Intermediate 33
Preparation of
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,15-tetraazatricy-
clo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00145##
[1273] 33A. Preparation of
1-(.sup.2H.sub.3)methyl-4-nitro-1H-pyrazole
[1274] DIAD (5.59 mL, 28.7 mmol) was added to a solution of
4-nitro-1H-pyrazole (2.5 g, 22.11 mmol), CD.sub.3OD (0.898 mL,
22.11 mmol), and Ph.sub.3P (resin bound) (8.84 g, 26.5 mmol) in THF
(40 ml) and stirred overnight. The reaction was quenched with
water, extracted with EtOAc, washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The crude product was
purified by normal phase chromatography eluting with a gradient of
DCM/MeOH to afford 1-(.sup.2H.sub.3)methyl-4-nitro-1H-pyrazole
(1.92 g, 14.76 mmol, 66.7% yield) as a white solid. MS(ESI) m/z:
131.0 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.13
(d, J=0.4 Hz, 1H), 8.05 (s, 1H).
33B. Preparation of tert-butyl
N-[(1S)-1-{4-[1-(.sup.2H.sub.3)methyl-4-nitro-1H-pyrazol-5-yl]pyridin-2-y-
l}but-3-en-1-yl]carbamate
[1275] To a large microwave vial were added (S)-tert-butyl
(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate (2.61 g, 9.22
mmol), 1-(.sup.2H.sub.3)methyl-4-nitro-1H-pyrazole (1.0 g, 7.69
mmol), di(adamantan-1-yl)(butyl)phosphine (0.413 g, 1.15 mmol),
K.sub.2CO.sub.3 (3.19 g, 23.06 mmol), pivalic acid (0.268 ml, 2.306
mmol) and DMF (15.37 ml). The reaction was purged with Ar for 10
min, Pd(OAc).sub.2 (0.173 g, 0.769 mmol) was added, the vial
sealed, and stirred at 115.degree. C. overnight. The reaction was
then partitioned between EtOAc and H.sub.2O. The aqueous layer was
extracted with EtOAc (2.times.). The combined organic layer was
washed with brine, dried over MgSO.sub.4, filtered and
concentrated. The residue was purified by normal phase
chromatography eluting with a gradient of hexanes/EtOAc to give
tert-butyl
N-[(1S)-1-{4-[1-(.sup.2H.sub.3)methyl-4-nitro-1H-pyrazol-5-yl]pyridin-2-y-
l}but-3-en-1-yl]carbamate (1.49 g, 3.96 mmol, 51.5% yield) as a
lavender foam. MS(ESI) m/z: 377.0 (M+H).sup.+. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.77 (d, J=4.8 Hz, 1H), 8.21 (s, 1H), 7.26
(s, 1H), 7.23 (dd, J=5.1, 1.5 Hz, 1H), 5.78-5.65 (m, 1H), 5.55 (d,
J=6.8 Hz, 1H), 5.14-5.03 (m, 2H), 4.89 (d, J=6.8 Hz, 1H), 2.66 (t,
J=6.6 Hz, 2H), 1.44 (s, 9H).
33C. Preparation of tert-butyl
N-[(1S)-1-{4-[4-amino-1-(.sup.2H.sub.3)methyl-1H-pyrazol-5-yl]pyridin-2-y-
l}but-3-en-1-yl]carbamate
[1276] tert-Butyl
N-[(1S)-1-{4-[1-(.sup.2H.sub.3)methyl-4-nitro-1H-pyrazol-5-yl]pyridin-2-y-
l}but-3-en-1-yl]carbamate (1.45 g, 3.85 mmol) was dissolved in
acetone (15 ml)/water (3 ml), cooled to 0.degree. C. NH.sub.4Cl
(1.030 g, 19.26 mmol) and Zn (2.52 g, 38.5 mmol) were added and the
ice bath was removed. After 1 h, the reaction was filtered and
filtrate partitioned with water (30 ml) and EtOAc (50 ml). The
aqueous layer was extracted with EtOAc (2.times.50 ml). The
combined organic layers were washed with brine (20 ml), dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified by
normal phase eluting with a gradient of DCM/MeOH chromatography to
afford tert-butyl
N-[(1S)-1-{4-[4-amino-1-(.sup.2H.sub.3)methyl-1H-pyrazol-5-yl]pyridin-2-y-
l}but-3-en-1-yl]carbamate (0.62 g, 46.5%). MS(ESI) m/z: 347.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.67 (dd,
J=5.1, 0.7 Hz, 1H), 7.26-7.23 (m, 2H), 7.21 (dd, J=5.1, 1.5 Hz,
1H), 5.79-5.66 (m, 1H), 5.58 (d, J=7.3 Hz, 1H), 5.11-5.05 (m, 2H),
4.86 (q, J=6.6 Hz, 1H), 2.64 (t, J=6.7 Hz, 2H), 1.44 (s, 9H).
33D. Preparation of tert-butyl
N-[(1S)-1-{4-[1-(.sup.2H.sub.3)methyl-4-[(2R)-2-methylbut-3-enamido]-1H-p-
yrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate
[1277] (R)-2-Methylbut-3-enoic acid (233 mg, 2.327 mmol),
tert-butyl
N-[(1S)-1-{4-[4-amino-1-(.sup.2H.sub.3)methyl-1H-pyrazol-5-yl]pyridin-2-y-
l}but-3-en-1-yl]carbamate (620 mg, 1.79 mmol), pyridine (0.433 ml,
5.37 mmol) in EtOAc (17.900 ml) was cooled to -10.degree. C. under
Ar. T3P.RTM. (50% wt in EtOAc) (2.13 ml, 3.58 mmol) was added
dropwise and then the reaction mixture was gradually warmed up to
rt. After 3.5 h, the reaction mixture was diluted with EtOAc,
washed with 1.5 M K.sub.2HPO.sub.4 followed by brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The crude product was
then purified by normal phase chromatography eluting with a
gradient of hexanes/EtOAc to give tert-butyl
N-[(1S)-1-{4-[1-(.sup.2H.sub.3)methyl-4-[(2R)-2-methylbut-3-enamido]-1H-p-
yrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate (529 mg, 1.234
mmol, 69.0% yield) as a yellow foam. MS(ESI) m/z: 429.2
(M+H).sup.+.
33E. Preparation of tert-butyl
N-[(9R,10E,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-oxo-3,4,7,15-tetraazat-
ricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carba-
mate
[1278] Five large microwave vials were charged in equal amounts
with the following: tert-butyl
N-[(1S)-1-{4-[1-(.sup.2H.sub.3)methyl-4-[(2R)-2-methylbut-3-enamido]-1H-p-
yrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate (0.51 g, 1.190
mmol) in degassed DCE (90 ml) was irradiated at 120.degree. C. for
30 min in the presence of Second Generation Grubbs Catalyst (0.404
g, 0.476 mmol). The reactions were combined, concentrated, and the
residue purified by normal phase column chromatography eluting with
a gradient of hexanes/EtOAc to give tert-butyl
N-[(9R,10E,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-oxo-3,4,7,15-tetraazat-
ricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carba-
mate (0.124 g, 26.0%) as a brown solid. MS(ESI) m/z: 401.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.66 (d,
J=5.1 Hz, 1H), 7.52 (s, 1H), 7.19 (d, J=4.8 Hz, 1H), 6.80 (s, 1H),
6.37 (d, J=7.5 Hz, 1H), 5.68 (t, J=11.2 Hz, 1H), 4.82-4.63 (m, 2H),
3.12-2.93 (m, 2H), 1.93 (q, J=11.1 Hz, 1H), 1.48 (s, 9H), 1.15 (d,
J=5.9 Hz, 3H).
33F. Preparation of tert-butyl
N-[(9R,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricy-
clo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
[1279] PtO.sub.2 (6.80 mg, 0.030 mmol) was added to a stirring
solution of tert-butyl
N-[(9R,10E,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-oxo-3,4,7,15-tetraazat-
ricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (0.120 g,
0.300 mmol) in EtOH (10 ml). The suspension was subjected to a
H.sub.2 atmosphere (55 psi) for 1 h. The catalyst was filtered off
through a plug of CELITE.RTM. and the filtrate concentrated to give
tert-butyl
N-[(9R,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricy-
clo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.104 g, 86%).
MS(ESI) m/z: 403.2 (M+H).sup.+.
33G. Preparation of
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,15-tetraazatricy-
clo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[1280] 4 M HCl in dioxane (1.62 ml) was added to a stirring
solution of tert-butyl
N-[(9R,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricy-
clo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(0.100 g, 0.248 mmol) in MeOH (3 ml) and stirred overnight. The
reaction mixture was concentrated to dryness and placed under high
vacuum. The hydrochloride salt was free based by dissolution in
MeOH, passed through a resin bound NaHCO.sub.3 cartridge
(StratoSpheres SPE; 500 mg, 0.90 mmol loading) and filtrate
concentrated to give
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,15-tetraazatricy-
clo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one.
MS(ESI) m/z: 303.4 (M+H).sup.+.
Intermediate 34
Preparation of
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,17-tetraazatricy-
clo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00146##
[1282]
(9R,13S)-13-Amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,17-tetraaz-
atricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one was prepared in a similar
manner as
(9R,13S)-13-amino-3-c(.sup.2H.sub.3)methyl-9-methyl-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one,
as described in Intermediate 33, replacing (S)-tert-butyl
(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate, described in
Intermediate 23, with (S)-tert-butyl
(1-(2-bromopyridin-4-yl)but-3-en-1-yl)carbamate, described in
Intermediate 27. MS(ESI) m/z: 303.3 (M+H).sup.+. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.70 (d, J=5.3 Hz, 1H), 7.58 (s, 1H),
7.50-7.42 (m, 2H), 4.14-4.05 (m, 1H), 2.72 (td, J=6.7, 3.5 Hz, 1H),
2.06-1.94 (m, 2H), 1.65-1.50 (m, 2H), 1.41-1.26 (m, 1H), 1.02 (d,
J=6.8 Hz, 3H), 0.70-0.53 (m, 1H).
Intermediate 35
Preparation of
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00147##
[1283] 35A. Preparation of tert-butyl
N-[(1S)-1-{3-[1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl]phenyl}but-3-en--
1-yl]carbamate
[1284] To a solution of (S)-tert-butyl
(1-(3-bromophenyl)but-3-en-1-yl)carbamate (4.0 g, 12.29 mmol),
prepared as described in Intermediate 24, in DMF (40.9 ml), was
added 1-(difluoromethyl)-4-nitro-1H-pyrazole (2.20 g, 13.49 mmol),
di(adamantan-1-yl)(butyl) phosphine (0.659 g, 1.839 mmol),
K.sub.2CO.sub.3 (5.08 g, 36.8 mmol) and pivalic acid (0.427 ml,
3.68 mmol). The resulting solution was purged with Ar for 10 min.
Pd(OAc).sub.2 (0.275 g, 1.226 mmol) was added and the reaction
mixture was stirred at 115.degree. C. for 4 h. The reaction was
cooled to rt, quenched with water (50 mL) and extracted with EtOAc
(3.times.50 mL). The combined organic layers were washed with brine
(50 mL), dried (MgSO.sub.4), filtered, and concentrated. The
residue was purified by normal phase column chromatography eluting
with a gradient of heptane/EtOAc to give tert-butyl
N-[(1S)-1-{3-[1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl]phenyl}but-3-en--
1-yl]carbamate (4.0 g, 80.0%). MS(ESI) m/z: 407 (M-H).sup.-.
35B. Preparation of tert-butyl
N-[(1S)-1-{3-[4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl]phenyl}but-3-en--
1-yl]carbamate
[1285] tert-Butyl
N-[(1S)-1-{3-[1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl]phenyl}but-3-en--
1-yl]carbamate (4.0 g, 9.79 mmol) was dissolved in acetone (100
ml)/H.sub.2O (24 ml) and then cooled to 0.degree. C. To the
solution was added NH.sub.4Cl (2.62 g, 49.0 mmol) and Zn (6.40 g,
98 mmol) and the ice bath was removed. After 2 h, the reaction
mixture was filtered and filtrate partitioned between water (30 ml)
and EtOAc (50 ml). The aqueous layer was extracted with EtOAc
(2.times.50 ml). The combined organic phase was washed with brine
(20 ml), dried (MgSO.sub.4), filtered, and concentrated. The
residue was purified by normal phase chromatography eluting with a
gradient of DCM/MeOH to give of tert-butyl
N-[(1S)-1-{3-[4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl]phenyl}but-3-en--
1-yl]carbamate (3.33 g, 8.80 mmol, 90%) as a yellow oil. MS(ESI)
m/z: 379.2 (M+H).sup.+.
35C. Preparation of tert-butyl
N-[(1S)-1-{3-[1-(difluoromethyl)-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazo-
l-5-yl]phenyl}but-3-en-1-yl]carbamate
[1286] To a solution of tert-butyl
N-[(1S)-1-{3-[4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl]phenyl}but-3-en--
1-yl]carbamate (3.3 g, 8.72 mmol) in EtOAc (20 ml) at 0.degree. C.
was added (R)-2-methylbut-3-enoic acid (1.048 g, 10.46 mmol),
prepared as described in Intermediate 2, in EtOAc (10 ml), pyridine
(2.116 ml, 26.2 mmol), and T3P.RTM./50% EtOAc (10.38 ml, 17.44
mmol). After 4 h, the reaction was diluted with EtOAc, and washed
with a solution of K.sub.2HPO.sub.4, followed by brine. The organic
layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated.
The residue was purified normal phase column chromatography eluting
with a gradient of hexanes/EtOAc to give tert-butyl
N-[(1S)-1-{3-[1-(difluoromethyl)-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazo-
l-5-yl]phenyl}but-3-en-1-yl]carbamate (3.10 g, 6.73 mmol, 77%
yield) as a yellow foam. MS(ESI) m/z: 461.2 (M+H).sup.+.
35D. Preparation of tert-butyl
N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12-
.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
[1287] To a solution of tert-butyl
N-[(1S)-1-{3-[1-(difluoromethyl)-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazo-
l-5-yl]phenyl}but-3-en-1-yl]carbamate (3.0 g, 6.51 mmol) in
degassed DCM (800 mL), was added Second Generation Grubbs Catalyst
(2.212 g, 2.61 mmol) and the reaction was heated to 40.degree. C.
After stirring overnight, the mixture was concentrated and the
residue was purified by normal phase column chromatography eluting
with a gradient of hexanes/EtOAc to give tert-butyl
N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12-
.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
(1.8 g, 63.9%). MS(ESI) m/z: 433.2 (M+H).sup.+.
35E. Preparation of tert-butyl
N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
[1288] To a solution of tert-butyl
N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12-
.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
(1.3 g, 3.01 mmol) in EtOH (50 ml) was added PtO.sub.2 (0.102 g,
0.451 mmol) and the reaction was hydrogenated at 55 psi for 4 h.
The reaction mixture was filtered through a plug of CELITE.RTM. and
the filtrate concentrated to give tert-butyl
N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(0.973 g, 74.5%). MS(ESI) m/z: 435.2 (M+H).sup.+.
35F. Preparation of
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[1289] To a solution of tert-butyl
N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(0.973 g, 2.239 mmol) in DCM (50 ml) was added TFA (5.18 ml, 67.2
mmol). After 3 h, the reaction mixture was concentrated to dryness.
The residue was partitioned between sat NaHCO.sub.3 and EtOAc. The
aqueous phase was extracted with EtOAc (3.times.), washed with
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated to
give
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.619 g,
83%). MS(ESI) m/z: 335 (M+H).sup.+.
Intermediate 36
Preparation of
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00148##
[1290] 36A. Preparation of tert-butyl
N-[(1S)-1-{3-[1-(.sup.2H.sub.3)methyl-4-nitro-1H-pyrazol-5-yl]phenyl}but--
3-en-1-yl]carbamate
[1291] To a solution of tert-butyl
N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (3.8 g, 11.65
mmol) in DMF (35 ml), was added
1-(.sup.2H.sub.3)methyl-4-nitro-1H-pyrazole (1.667 g, 12.81 mmol),
di(adamantan-1-yl)(butyl)phosphine (0.626 g, 1.747 mmol),
K.sub.2CO.sub.3 (4.83 g, 34.9 mmol) and pivalic acid (0.406 ml,
3.49 mmol). The reaction was purged with Ar and Pd(OAc).sub.2
(0.262 g, 1.165 mmol) was added. The reaction was heated to
115.degree. C. After 4 h, the reaction was diluted with 1:1
EtOAc/water (50 ml) and filtered through paper to remove Pd solids.
The filtrate was extracted with EtOAc (2.times.50 ml). The combined
organic layer was washed with water (20 ml), brine (20 ml), dried
(MgSO.sub.4), filtered and concentrated. The residue was purified
by normal phase chromatography twice using hexanes and EtOAc as
eluents to afford
tert-butyl-N-[(1S)-1-{3-[1-(.sup.2H.sub.3)methyl-4-nitro-1H-pyrazol-5-yl]-
phenyl}but-3-en-1-yl]carbamate (1.89 g, 43.2%) as a brown oil.
MS(ESI) m/z: 374.4 (M-H).sup.+.
36B. Preparation of tert-butyl
N-[(1S)-1-{3-[4-amino-1-(.sup.2H.sub.3)methyl-1H-pyrazol-5-yl]phenyl}but--
3-en-1-yl]carbamate
[1292] To a cooled (0.degree. C.) solution of tert-butyl
N-[(1S)-1-{3-[1-(.sup.2H.sub.3)methyl-4-nitro-1H-pyrazol-5-yl]phenyl}but--
3-en-1-yl]carbamate (1.89 g, 5.03 mmol), dissolved in acetone (40
ml)/water (12 ml) was added NH.sub.4Cl (1.346 g, 25.2 mmol) and Zn
(3.29 g, 50.3 mmol). The ice bath was removed and the solution was
allowed to warm to rt. After 3 h, the reaction was filtered through
paper and the filtrate was partitioned between water (20 ml) and
EtOAc (75 ml). The aqueous layer was extracted with EtOAc
(2.times.50 ml). The combined organic layers were washed with brine
(25 ml), dried (MgSO.sub.4), filtered and concentrated. The residue
was purified by normal phase chromatography using hexanes and EtOAc
and then DCM/0-10% MeOH as eluents to afford tert-butyl
N-[(1S)-1-{3-[4-amino-1-(.sup.2H.sub.3)methyl-1H-pyrazol-5-yl]phenyl}but--
3-en-1-yl]carbamate (0.84 g, 48.3%) as a light brown foam. MS(ESI)
m/z: 346.5 (M+H).sup.+.
36C. Preparation of tert-butyl
N-[(1S)-1-{3-[1-(.sup.2H.sub.3)methyl-4-[(2R)-2-methylbut-3-enamido]-1H-p-
yrazol-5-yl]phenyl}but-3-en-1-yl]carbamate
[1293] To tert-butyl
N-[(1S)-1-{3-[4-amino-1-(.sup.2H.sub.3)methyl-1H-pyrazol-5-yl]phenyl}but--
3-en-1-yl]carbamate (0.7 g, 2.026 mmol) in EtOAc (6 ml) was added
(R)-2-methylbut-3-enoic acid (0.26 g, 2.63 mmol), prepared as
described in Intermediate 2, in 1 mL EtOAc. The mixture was cooled
to 0.degree. C. and pyridine (0.49 ml, 6.08 mmol) followed by a
solution of 50% T3P.RTM. in EtOAc (2.41 ml, 4.05 mmol) were added.
After 1 h, the reaction was partitioned with sat NaHCO.sub.3 (30
ml) and EtOAc (50 ml). The aqueous layer was extracted with EtOAc
(2.times.50 ml). The combined organic layers were washed with brine
(25 ml), dried (MgSO.sub.4), filtered and concentrated. The residue
was purified by normal phase chromatography using hexanes and EtOAc
as eluents to afford tert-butyl
N-[(1S)-1-{3-[1-(.sup.2H.sub.3)methyl-4-[(2R)-2-methylbut-3-enamido]-1H-p-
yrazol-5-yl]phenyl}but-3-en-1-yl]carbamate (0.69 g, 81%) as a rose
oil. MS(ESI) m/z: 428.5 (M+H).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.07-7.93 (m, 1H), 7.53-7.44 (m, 1H), 7.37 (d,
J=7.9 Hz, 1H), 7.28-7.09 (m, 3H), 5.89 (ddd, J=17.4, 9.9, 7.9 Hz,
1H), 5.76-5.60 (m, 1H), 5.25-5.11 (m, 4H), 5.07 (d, J=7.0 Hz, 1H),
4.77 (br. s., 1H), 3.08 (quin, J=7.2 Hz, 1H), 2.62-2.47 (m, 2H),
1.41 (br. s., 9H), 1.30 (s, 3H).
36D. Preparation of tert-butyl
N-[(9R,10E,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-oxo-3,4,7-triazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
[1294] To a degassed DCM (200 ml) solution of tert-butyl
N-[(1S)-1-{3-[1-(.sup.2H.sub.3)methyl-4-[(2R)-2-methylbut-3-enamido]-1H-p-
yrazol-5-yl]phenyl}but-3-en-1-yl]carbamate (0.699 g, 1.635 mmol)
was added Second Generation Grubbs Catalyst (0.555 g, 0.654 mmol)
and the resulting solution was heated to 40.degree. C. for 24 h.
The reaction mixture was concentrated and the residue was purified
by normal phase chromatography using DCM and 0-10% MeOH as eluents
to afford tert-butyl
N-[(9R,10E,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-oxo-3,4,7-triazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
(0.511 g, 78%) as a dark solid. MS(ESI) m/z: 400.2 (M+H).sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.65-7.56 (m, 1H),
7.51-7.44 (m, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.23 (d, J=7.7 Hz, 1H),
6.85 (s, 1H), 6.68 (s, 1H), 5.66 (ddd, J=15.2, 9.3, 5.6 Hz, 1H),
5.20-5.06 (m, 1H), 4.94 (dd, J=15.3, 8.5 Hz, 1H), 4.78-4.66 (m,
1H), 3.08-2.99 (m, 1H), 2.71-2.58 (m, 1H), 2.23-2.12 (m, 1H), 1.43
(br. s., 9H), 1.25-1.19 (m, 3H).
36E. Preparation of tert-butyl
N-[(9R,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
[1295] To a EtOH (20 ml) solution of tert-butyl
N-[(9R,10E,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-oxo-3,4,7-triazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
(0.40 g, 1.001 mmol) was added PtO.sub.2 (0.023 g, 0.100 mmol). The
reaction vessel was purged with H.sub.2 and the reaction mixture
was then hydrogenated at 55 psi. After 1.5 h under pressure, the
reaction mixture was then allowed to sit overnight under N.sub.2.
The reaction was then filtered through CELITE.RTM. rinsing with DCM
and EtOH. The filtrate was concentration of the afforded tert-butyl
N-[(9R,13S)-3-(.sup.2H.sub.3)methyl9-methyl-8-oxo-3,4,7-triazatricyclo[12-
.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(0.38 g, 95%) as a brown solid. MS(ESI) m/z: 402.5 (M+H).sup.+.
36F. Preparation of
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00149##
[1297] To a dioxane (2 ml) and MeOH (2 ml) solution of tert-butyl
N-[(9R,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(0.38 g, 0.946 mmol) was added 4 N HCl in dioxane (2 ml). After 4
h, the reaction was concentrated to near dryness. The dry residue
was dissolved in MeOH/DCM and filtered through 500 mg basic
cartridge and the filtrate was concentrated to afford
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.28
g, 98%) as a gray solid. MS(ESI) m/z: 302.5 (M+H).sup.+.
Intermediate 37
Preparation of
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00150##
[1298] 37A. Preparation of (S)-tert-butyl
(1-(2-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-4-yl)but-3-en-1-
-yl)carbamate
[1299] To a large microwave vial was added (S)-tert-butyl
(1-(2-bromopyridin-4-yl)but-3-en-1-yl)carbamate (1.5 g, 4.58 mmol),
prepared as described for Intermediate 27,
1-(difluoromethyl)-4-nitro-1H-pyrazole (0.822 g, 5.04 mmol),
prepared as described for Intermediate 30A, DMF (15.3 mL),
di(adamantan-1-yl)(butyl)phosphine (0.247 g, 0.688 mmol),
K.sub.2CO.sub.3 (1.901 g, 13.75 mmol) and pivalic acid (0.160 mL,
1.375 mmol). The mixture was purged with Ar for 15 min.
Pd(OAc).sub.2 (0.103 g, 0.458 mmol) was added, the vial sealed and
stirred at 115.degree. C. After 4 h, the reaction was quenched with
water (50 mL) and extracted with EtOAc (3.times.50 mL). The
combined organic layers were washed with brine (50 mL), dried
(MgSO.sub.4), filtered, and concentrated to give a dark brown oil.
The crude product was purified by normal phase chromatography using
heptane and EtOAc as eluents to give (S)-tert-butyl
(1-(2-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-4-yl)but-3-en-1-
-yl)carbamate (973 mg, 52%) as a orange solid. MS(ESI) m/z: 410.1
(M+H).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.73 (d,
J=5.2 Hz, 1H), 8.38 (s, 1H), 7.74 (br. s., 1H), 7.63-7.48 (m, 1H),
7.44-7.37 (m, 1H), 5.69 (ddt, J=17.0, 10.1, 7.0 Hz, 1H), 5.24-5.17
(m, 2H), 2.62-2.50 (m, 2H), 1.45 (s, 9H).
37B. Preparation of (S)-tert-butyl
(1-(2-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-4-yl)but-3-en-1-
-yl)carbamate
[1300] (S)-tert-Butyl
(1-(2-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-4-yl)but-3-en-1-
-yl)carbamate (0.974 g, 2.379 mmol) was dissolved in acetone (15
mL)/water (3 mL), cooled to 0.degree. C., and NH.sub.4Cl (0.636 g,
11.90 mmol) and Zn (1.555 g, 23.79 mmol) were added. After stirring
overnight at rt, the reaction mixture was filtered through a plug
of CELITE.RTM. and the filtrate was concentrated. The residue was
partitioned with water (30 mL) and EtOAc (50 mL). The aqueous layer
was extracted with EtOAc (2.times.50 mL). The combined organic
layers were washed with brine (20 mL) and dried (MgSO.sub.4). The
product was carried forward as is. MS(ESI) m/z: 380.1
(M+H).sup.+.
37C. Preparation of tert-butyl
((S)-1-(2-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5--
yl)pyridin-4-yl)but-3-en-1-yl)carbamate
[1301] To a stirring solution of (S)-tert-butyl
(1-(2-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-4-yl)but-3-en-1-
-yl)carbamate (0.900 g, 2.372 mmol) in EtOAc (7.91 mL) at 0.degree.
C., (R)-2-methylbut-3-enoic acid (0.309 g, 3.08 mmol) in EtOAc
(0.50 mL) T3P.RTM./50% EtOAc (2.82 mL, 4.74 mmol) and pyridine
(0.576 mL, 7.12 mmol) were added. After 5 h, the reaction mixture
concentrated and purified by normal phase chromatography using
hexanes and EtOAc as eluents to afford tert-butyl
((S)-1-(2-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5--
yl)pyridin-4-yl)but-3-en-1-yl)carbamate (680 mg, 62.1%) as an oil.
MS(ESI) m/z: 462.2 (M+H).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3-d)
.delta. 10.74 (br. s., 1H), 8.60 (s, 1H), 8.57 (d, J=5.2 Hz, 1H),
7.84 (s, 1H), 7.58-7.42 (m, 1H), 7.23-7.20 (m, 1H), 6.00 (ddd,
J=17.3, 10.1, 8.1 Hz, 1H), 5.72-5.62 (m, 1H), 5.36-5.31 (m, 2H),
5.21-5.15 (m, 2H), 3.22 (quin, J=7.2 Hz, 1H), 2.59-2.47 (m, 2H),
1.48-1.37 (m, 12H).
37D. Preparation of tert-butyl
N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,17-tetraazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
[1302] 3 large microwave vials received equal portions of the
following: tert-butyl
((S)-1-(2-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5--
yl)pyridin-4-yl)but-3-en-1-yl)carbamate (0.680 g, 1.473 mmol) in
degassed DCE (61.4 mL) in the presence of Second Generation Grubbs
Catalyst (0.500 g, 0.589 mmol) was irradiated to 120.degree. C. for
30 min in a .mu.wave. The reaction mixture was concentrated and
purified by normal phase chromatography using hexanes and EtOAc as
eluents to give tert-butyl
N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,17-tetraazatricyc-
lo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (158 mg,
24.7%) as a brown film. MS(ESI) m/z: 434.2 (M+H).sup.+. .sup.1H NMR
(500 MHz, CDCl.sub.3-d) .delta. 8.69 (d, J=5.0 Hz, 1H), 8.05-7.89
(m, 1H), 7.83 (s, 1H), 7.10 (s, 1H), 6.77 (br. s., 1H), 5.73 (ddd,
J=15.2, 9.7, 5.1 Hz, 1H), 5.13-5.05 (m, 2H), 3.19-3.10 (m, 1H),
2.73 (d, J=12.7 Hz, 1H), 2.24-2.15 (m, 1H), 1.46 (br. s., 9H),
1.30-1.24 (m, 4H).
37E. Preparation of tert-butyl
N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,17-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
[1303] PtO.sub.2 (8.28 mg, 0.036 mmol) was added to a solution of
tert-butyl
N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,17-tetraazatricyc-
lo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (0.158 g,
0.365 mmol) in EtOH (10 mL) and subjected to a H.sub.2 atmosphere
(55 psi). After 3 h, the catalyst was filtered through a pad of
CELITE.RTM. and filtrate concentrated to give tert-butyl
N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,17-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate.
MS(ESI) m/z: 436.1 (M+H).sup.+.
37F. Preparation of
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[1304] tert-Butyl
N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,17-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(0.159 g, 0.365 mmol) was dissolved in MeOH (0.50 mL) and treated
with 4 M HCl in dioxane (1.83 mL, 7.30 mmol). After stirring for 14
h, the reaction mixture was concentrated to dryness. The amine HCl
salt was free based by dissolving in MeOH and passing through 2
consecutive NaHCO.sub.3 cartridges. The filtrate was concentrated
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.085 g,
69%). MS(ESI) m/z: 336.1 (M+H).sup.+.
Intermediate 38
Preparation of
(10R,14S)-14-amino-10-methyl-3,8-diazatricyclo[13.3.1.0.sup.27]
nonadeca-1(19),2,4,6,15,17-hexaen-9-one
##STR00151##
[1305] 38A. Preparation of
{3-[(1S)-1-{[(tert-butoxy)carbonyl]amino}but-3-en-1-yl]phenyl}
boronic acid
[1306] To a solution of tert-butyl
N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate, prepared as
described in Intermediate 24, (2.36 g, 7.23 mmol) in dioxane (50
ml), was added 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane)
(1.798 g, 7.96 mmol), and KOAc (2.130 g, 21.70 mmol). The mixture
was purged with Ar and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct
(0.295 g, 0.362 mmol) was added. The reaction mixture was heated to
90.degree. C. for 18 h, then quenched with water (20 ml) and
extracted with EtOAc (3.times.30 ml). The combined organic layers
were washed with brine (20 ml), dried (Na.sub.2SO.sub.4), filtered
and concentrated. The residue was absorbed on CELITE.RTM. and
charged to a 100 g reverse phase cartridge which was eluted with a
25 min gradient from 10-100% Solvent B (Solvent A: 90% H.sub.2O-10%
MeCN-0.05% TFA; Solvent B: 90% MeCN-10% H.sub.2O-0.05% TFA) to give
{3-[(1S)-1-{[(tert-butoxy)carbonyl]amino}but-3-en-1-yl]phenyl}boronic
acid as a tan solid. MS(ESI) m/z: 292.08 (M+H).sup.+.
38B. Preparation of tert-butyl N-[(1S)-1-[3-(3-aminopyridin-2-yl)
phenyl]but-3-en-1-yl]carbamate
[1307]
{3-[(1S)-1-{[(tert-Butoxy)carbonyl]amino}but-3-en-1-yl]phenyl}boron-
ic acid (0.36 g, 1.236 mmol), 2-bromopyridin-3-amine (0.214 g,
1.236 mmol), and 2 M aq Na.sub.2CO.sub.3 (3.09 ml, 6.18 mmol) were
added to dioxane (8 ml) and purged with a stream of Ar for 10 min.
Pd(PPh.sub.3).sub.4 (0.143 g, 0.124 mmol) was added and the
reaction mixture was irradiated in microwave at 120.degree. C. for
30 min. The reaction was quenched with water (20 ml) and extracted
with EtOAc (3.times.30 ml). The combined organic layers were washed
with brine (15 ml), dried (MgSO.sub.4), filtered and concentrated.
The residue was purified via Isco 40 g column eluting with
DCM/0-10% MeOH to give a tan foam (0.352 g (84%). The reaction
mixture was filtered and concentrated and the residue was purified
by normal phase chromatography using DCM and 0-10% MeOH as eluents
to afford tert-butyl
N-[(1S)-1-[3-(3-aminopyridin-2-yl)phenyl]but-3-en-1-yl]carbamate
(0.352 g, 84%) as a tan solid. MS(ESI) m/z: 340.5 (M+H).sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.13 (dd, J=4.1, 1.9 Hz,
1H), 7.62-7.54 (m, 2H), 7.44 (t, J=7.6 Hz, 1H), 7.26 (s, 2H),
7.12-7.00 (m, 2H), 5.82-5.57 (m, 1H), 5.23-5.02 (m, 1H), 4.91 (br.
s., 1H), 4.80 (br. s., 1H), 3.82 (br. s., 2H), 2.81-2.41 (m, 2H),
1.51-1.34 (m, 9H).
38C. Preparation of tert-butyl
N-[(1S)-1-(3-{3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3-en--
1-yl]carbamate
[1308] To a cooled (0.degree. C.) EtOAc (6 mL) solution of
tert-butyl
N-[(1S)-1-[3-(3-minopyridin-2-yl)phenyl]but-3-en-1-yl]carbamate
(0.334 g, 1.03 mmol) was added (R)-2-methylbut-3-enoic acid (0.135
g, 1.348 mmol), prepared as described in Intermediate 2, in 1 ml
EtOAc, pyridine (0.252 ml, 3.11 mmol) and the dropwise addition of
a 50% EtOAc solution of T3P.RTM. (1.235 ml, 2.074 mmol). After 1 h,
the reaction was partitioned between sat NaHCO.sub.3 (30 ml) and
EtOAc (50 ml). The aqueous layer was extracted with EtOAc
(2.times.50 ml). The combined organic layers were washed with brine
(25 ml) dried (MgSO.sub.4), filtered and concentrated. The residue
was purified by normal phase chromatography using hexanes and EtOAc
as eluents to afford tert-butyl
N-[(1S)-1-(3-{3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3-en--
1-yl]carbamate (0.334 g, 76%) as a tan solid. MS(ESI) m/z: 428.5
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.71 (dd,
J=8.3, 1.2 Hz, 1H), 8.41 (dd, J=4.6, 1.5 Hz, 1H), 7.60 (br. s.,
1H), 7.49-7.42 (m, 2H), 7.42-7.36 (m, 2H), 7.29 (dd, J=8.4, 4.8 Hz,
1H), 5.84-5.62 (m, 2H), 5.16-5.02 (m, 4H), 4.92 (br. s., 1H), 4.80
(br. s., 1H), 3.04 (quin, J=7.3 Hz, 1H), 2.62-2.48 (m, 2H),
1.51-1.35 (m, 9H), 1.32-1.25 (m, 3H).
38D. Preparation of tert-butyl
N-[(10R,11E,14S)-10-methyl-9-oxo-3,8-diazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamat-
e trifluoroacetate
[1309] To a in degassed DCE (20 ml) solution of tert-butyl
N-[(1S)-1-(3-{3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3-en--
1-yl]carbamate (0.15 g, 0.356 mmol) was added Second Generation
Grubbs Catalyst (0.121 g, 0.142 mmol) and the resulting solution
was heated to 120.degree. C. for 30 min in a microwave. The
reaction was concentrated, and the residue purified by normal phase
chromatography, then reverse phase preparative HPLC
(PHENOMENEX.RTM. Luna Axia C18 5.mu. 30.times.100 mm column, 8-min
gradient; Solvent A: 30% MeOH-70% H.sub.2O-0.1% TFA; Solvent B: 90%
MeOH-10% H.sub.2O-0.1% TFA) to afford tert-butyl
N-[(10R,11E,14S)-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0.sup.27]
nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate
trifluoroacetate (71 mg, 39%) as a clear residue. MS(ESI) m/z:
394.5 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.73
(d, J=4.4 Hz, 1H), 8.44 (d, J=7.9 Hz, 1H), 7.99-7.89 (m, 1H),
7.69-7.59 (m, 1H), 7.59-7.48 (m, 2H), 7.17-7.08 (m, 1H), 5.84-5.67
(m, 1H), 4.67-4.53 (m, 1H), 4.53-4.38 (m, 1H), 3.28-3.17 (m, 1H),
2.77-2.66 (m, 1H), 2.04 (q, J=11.4 Hz, 1H), 1.46 (br. s., 9H),
1.18-1.09 (m, 3H).
38E. Preparation of tert-butyl
N-[(10R,14S)-10-methyl-9-oxo-3,8-diazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate
[1310] To a EtOH (5 ml) solution of tert-butyl
N-[(10R,11E,14S)-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0.sup.2,7]nonad-
eca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate (0.37 g, 0.940
mmol) (free base was prepared as in Example 38D) was added
PtO.sub.2 (21 mg) and the reaction mixture was purged with H.sub.2
and was hydrogenated at 20-30 psi for 4 h. The reaction was
filtered through CELITE.RTM. and the filtrate was concentrated to
afford tert-butyl
N-[(10R,14S)-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0.sup.2,7]nonadeca--
1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate (0.37 g, 99%) as a dark
solid. MS(ESI) m/z: 396.3 (M+H).sup.+.
38F. Preparation of
(10R,14S)-14-amino-10-methyl-3,8-diazatricyclo[13.3.1.0.sup.2,7]
nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
[1311] tert-Butyl
N-[(10R,14S)-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0.sup.2,7]nonadeca--
1(19),2 (7),3,5,15,17-hexaen-14-yl]carbamate (0.18 g, 0.455 mmol)
was dissolved in 4 N HCl in dioxane (2 ml) and MeOH (2 ml). After 2
h, the reaction was concentrated, the residue was dissolved in
DCM/MeOH and free-based by passing through a 500 mg basic cartridge
(2.times.). Concentration of the filtrate afforded
(10R,14S)-14-amino-10-methyl-3,8-diazatricyclo[13.3.1.0.sup.2,7]nonadeca--
1(19),2(7),3,5,15,17-hexaen-9-one (0.11 g, 49%) as a dark brown
film. MS(ESI) m/z: 296.3 (M+H).sup.+.
Intermediate 39
Preparation of
(10R,14S)-14-amino-10-methyl-3,8,16-triazatricyclo[13.3.1.0.sup.2,7]nonad-
eca-1(19),2(7),3,5,15,17-hexaen-9-one
##STR00152##
[1312] 39A. Preparation of (S)-tert-butyl
(1-(3-amino-[2,4'-bipyridin]-2'-yl)but-3-en-1-yl)carbamate
[1313] To a solution of
(S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronic
acid trifluoroacetate (0.60 g, 1.477 mmol) in dioxane (12 ml) was
added 2-bromopyridin-3-amine (0.256 g, 1.477 mmol) and 2 M aq
Na.sub.2CO.sub.3 (3.69 ml, 7.39 mmol). The reaction mixture was
purged with a stream of Ar for 10 min. Pd(PPh.sub.3).sub.4 (0.171
g, 0.148 mmol) was added and the mixture irradiated at 120.degree.
C. for 30 min. The reaction was partitioned between water and
EtOAc. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude material was
purified by normal phase column chromatography eluting with a
gradient of DCM/MeOH to give (S)-tert-butyl
(1-(3-amino-[2,4'-bipyridin]-2'-yl)but-3-en-1-yl)carbamate (0.500
g, 99% yield) as a brown oil. MS(ESI) m/z: 341.1 (M+H).sup.+.
39B. Preparation of tert-butyl
((S)-1-(3-((R)-2-methylbut-3-enamido)-[2,4'-bipyridin]-2'-yl)but-3-en-1-y-
l)carbamate
[1314] A solution of (R)-2-methylbut-3-enoic acid (0.191 g, 1.909
mmol), prepared as described in Intermediate 2, (S)-tert-butyl
(1-(3-amino-[2,4'-bipyridin]-2'-yl)but-3-en-1-yl)carbamate (0.500
g, 1.469 mmol), and pyridine (0.356 ml, 4.41 mmol) in EtOAc (14.69
ml) was cooled down to 0.degree. C. under Ar followed by addition
of T3P.RTM. (50% wt in EtOAc) (1.75 ml, 2.94 mmol), then the
reaction mixture was gradually warmed up to rt. After stirring
overnight, the mixture was diluted with EtOAc, washed with 1.5 M
K.sub.2HPO.sub.4 followed by brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The crude product was then purified by
normal phase chromatography eluting with a gradient of
hexanes/EtOAc to give tert-butyl
((S)-1-(3-((R)-2-methylbut-3-enamido)-[2,4'-bipyridin]-2'-yl)but-3-en-1-y-
l)carbamate (0.458 g, 73.8% yield) as a yellow foam. MS(ESI) m/z:
423.2 (M+H).sup.+.
39C. Preparation of tert-butyl
N-[(10R,11E,14S)-10-methyl-9-oxo-3,8,16-triazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamat-
e, bis-trifluoroacetate
[1315] tert-Butyl
((S)-1-(3-((R)-2-methylbut-3-enamido)-[2,4'-bipyridin]-2'-yl)but-3-en-1-y-
l)carbamate (100 mg, 0.237 mmol) in degassed DCE (14.79 ml) in the
presence of Second Generation Grubbs Catalyst (0.080 g, 0.095 mmol)
was irradiated at 120.degree. C. for 30 min. The reaction mixture
was concentrated and purified by reverse phase chromatography to
give the tert-butyl
N-[(10R,11E,14S)-10-methyl-9-oxo-3,8,16-triazatricyclo[13.3.1.0.sup.2,7]n-
onadeca-1(19),2 (7),3,5,11,15,17-heptaen-14-yl]carbamate,
bis-trifluoroacetate (39 mg, 26.5% yield) as brown oil. MS(ESI)
m/z: 395.2 (M+H).sup.+.
39D. Preparation of tert-butyl
N-[(10R,14S)-10-methyl-9-oxo-3,8,16-triazatricyclo[13.3.1.0.sup.2,7]nonad-
eca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate
[1316] PtO.sub.2 (2.245 mg, 9.89 .mu.mol) was added to a stirring
solution of tert-butyl
N-[(10R,11E,14S)-10-methyl-9-oxo-3,8,16-triazatricyclo[13.3.1.0.sup.2,7]n-
onadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate,
bis-trifluoroacetate (0.039 g, 0.099 mmol) in EtOH (10 ml) and
subjected to a H.sub.2 atmosphere (55 psi). After 4 h, the reaction
mixture was filtered through a pad of CELITE.RTM. and the filtrate
concentrated to give tert-butyl
N-[(10R,14S)-10-methyl-9-oxo-3,8,16-triazatricyclo[13.3.1.0.sup.2,7]nonad-
eca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate. MS(ESI) m/z: 397.2
(M+H).sup.+.
39E. Preparation of
(10R,14S)-14-amino-10-methyl-3,8,16-triazatricyclo[13.3.1.0.sup.27]
nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
[1317] TFA (0.15 mL, 1.967 mmol) was added to a solution of
tert-butyl
N-[(10R,14S)-10-methyl-9-oxo-3,8,16-triazatricyclo[13.3.1.0.sup.2,7]nonad-
eca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate (0.039 g, 0.098
mmol) in DCM (2.0 ml). After stirring for 4 h, the reaction mixture
was concentrated to dryness, and placed under high vacuum for 12 h.
The residue was neutral by dissolving in MeOH, passing through
NaHCO.sub.3 cartridge (StratoSpheres SPE; 500 mg, 0.90 mmol
loading), and concentrating the filtrate to give
(10R,14S)-14-amino-10-methyl-3,8,16-triazatricyclo[13.3.1.0.sup.2,7]nonad-
eca-1(19),2(7),3,5,15,17-hexaen-9-one. MS(ESI) m/z: 297.5
(M+H).sup.+.
Intermediate 40
Preparation of
(9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00153##
[1318] 40A. Preparation of
1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-1H-pyrazole
[1319] To a solution of 4-nitro-1H-pyrazole (4.0 g, 35.4 mmol) in
DMF (50 mL) was added Cs.sub.2CO.sub.3 (12.68 g, 38.9 mmol) and
(2-bromoethoxy)(tert-butyl)dimethylsilane (8.35 mL, 38.9 mmol). The
resulting suspension was heated to 60.degree. C. for 2 h. The
reaction mixture was then diluted with EtOAc (2.times.25 mL) and
washed with 10% LiCl solution (25 mL). The organic layer was
concentrated, and the residue purified using normal phase
chromatography to yield
1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-1H-pyrazole as
white solid (8.6 g, 85% yield). MS(ESI) m/z: 272.4 (M+H).sup.+.
40B. Preparation of (S)-tert-butyl
(1-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-1H-pyrazol-5-yl)-
pyridin-2-yl)but-3-en-1-yl)carbamate
[1320] To a N.sub.2 flushed pressure vial was added (S)-tert-butyl
(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate, prepared as
described in Intermediate 23, (3.0 g, 10.61 mmol),
1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-1H-pyrazole,
prepared as described in Intermediate 40A, (2.88 g, 10.61 mmol),
di(adamant-1-yl)(butyl)phosphine (0.571 g, 1.59 mmol), PvOH (0.369
ml, 3.18 mmol), K.sub.2CO.sub.3 (4.40 g, 31.8 mmol), and DMF (20
mL). The vial was purged with N.sub.2 for 5 min and Pd(OAc).sub.2
(0.238 g, 1.061 mmol) was added. The reaction mixture was again
briefly purged with N.sub.2. The vial was sealed and heated at
120.degree. C. for 4 h. The reaction mixture was cooled to rt and
partitioned between 10% aqueous LiCl (15 mL) and EtOAc (30 mL). The
aqueous layer was extracted with EtOAc (2.times.20 mL) and the
combined organic layers were washed with brine (15 mL), dried over
MgSO.sub.4, filtered and concentrated. The crude product was
purified using normal phase chromatography to yield (S)-tert-butyl
(1-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-1H-pyrazol-5-yl)-
pyridin-2-yl)but-3-en-1-yl)carbamate (1.4 g, 25% yield) as a brown
oil. MS(ESI) m/z: 518.3 (M+H).sup.+.
40C. Preparation of (S)-tert-butyl
(1-(4-(4-amino-1-(2-((tert-butyldimethylsilyl)oxy)
ethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate
[1321] A solution of (S)-tert-butyl
(1-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-1H-pyrazol-5-yl)-
pyridin-2-yl)but-3-en-1-yl)carbamate (2.4 g, 4.64 mmol) in MeOH (25
mL) and CH.sub.3COOH (2.5 mL) was heated to 40.degree. C. To the
resulting clear solution was then slowly added Zn (0.606 g, 9.27
mmol, in 3 portions (50:25:25%)) and the reaction was stirred at
40.degree. C. for 5 min. Additional Zn was added to the reaction.
The reaction mixture was monitored by LCMS and once complete, to
the cooled reaction mixture was then added 2.5 g of K.sub.2CO.sub.3
(1 g for 1 mL AcOH) and 2.5 mL water. The reaction mixture was then
stirred for 5 min. The reaction mixture was then filtered over a
pad of CELITE.RTM. and concentrated to yield the crude product. The
crude product was partitioned between EtOAc (40 mL) and sat
NaHCO.sub.3 (20 mL). The organic layers were separated, dried over
MgSO.sub.4, filtered and concentrated. The crude product was
purified using normal phase chromatography to yield (S)-tert-butyl
(1-(4-(4-amino-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-5-yl)-
pyridin-2-yl)but-3-en-1-yl)carbamate (1.9 g, 80% yield) as pale
brown oil. MS(ESI) m/z: 488.6 (M+H).sup.+.
40D. Preparation of tert-butyl
((5)-1-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((R)-2-methylbut-3-
-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate
[1322] To a N.sub.2 flushed, 3-necked, 250 mL RBF was added
(S)-tert-butyl
(1-(4-(4-amino-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-5-yl)-
pyridin-2-yl)but-3-en-1-yl)carbamate (1.9 g, 3.90 mmol) and EtOAc
(25 mL). The solution was cooled to -10.degree. C. and
(R)-2-methylbut-3-enoic acid, as prepared in Intermediate 2, (390
mg, 3.90 mmol), pyridine (0.630 mL, 7.79 mmol) and T3P.RTM. (3.48
mL, 5.84 mmol) were added. The cooling bath was removed and the
solution was allowed to warm to rt and then stirred for 20 h. Water
(20 mL) and EtOAc (20 mL) were added and the mixture was stirred
for 30 min. The organic phase was separated and the aqueous layer
was extracted with EtOAc (20 mL). The combined organic extracts
were washed with brine (15 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated. Purification by normal phase
chromatography eluting with a gradient of hexanes/EtOAc gave
((5)-1-(4-(1-(2-((tert-butyldimethylsilyl)oxy)
ethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-e-
n-1-yl)carbamate (0.68 g, 28% yield). MS(ESI) m/z: 570.1
[M+H].sup.+.
40E. Preparation of tert-butyl
N-[(9R,10E,13S)-3-{2-[(tert-butyldimethylsilyl)oxy]
ethyl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-
-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
[1323] To a N.sub.2 flushed, 250 mL, 3-necked, RBF was added a
solution of tert-butyl
0)-1-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((R)-2-methylbut-3-e-
namido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (680
mg, 1.193 mmol) in EtOAc (56 mL). The solution was sparged with Ar
for 15 min. Second Generation Grubbs Catalyst (253 mg, 0.298 mmol)
was added in one portion. The reaction mixture was heated to reflux
temperature for overnight. After cooling to rt, the solvent was
removed and the residue was purified by normal phase chromatography
eluting with a gradient of DCM/MeOH to yield tert-butyl
N-[(9R,10E,13S)-3-{2-[(tert-butyldimethylsilyl)oxy]
ethyl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-
-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (400 mg, 61% yield)
as a tan solid. MS(ESI) m/z: 542.6 [M+H].sup.+.
40F. Preparation of tert-butyl
N-[(9R,13S)-3-{2-[(tert-butyldimethylsilypoxy]ethyl}-9-methyl-8-oxo-3,4,7-
,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen--
13-yl]carbamate
[1324] Pd/C (0.078 g, 0.074 mmol) was added to a 250 mL Parr
hydrogenation flask containing a solution of tert-butyl
N-[(9R,10E,13S)-3-{2-[(tert-butyldimethylsilyl)oxy]
ethyl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-
-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (400 mg, 0.738 mmol)
in EtOH (20 mL). The flask was purged with N.sub.2 and pressurized
to 55 psi of H.sub.2 and allowed to stir for 4 h. The reaction was
filtered through a pad of CELITE.RTM. and concentrated to yield
tert-butyl
N-[(9R,13S)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-9-methyl-8-oxo-3,4,-
7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-
-13-yl]carbamate (375 mg, 92% yield) as a tan solid. MS(ESI) m/z:
544.6 [M+H].sup.+.
40G.
(9R,13S)-13-Amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyc-
lo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[1325] To a solution of tert-butyl
N-[(9R,13S)-3-{2-[(tert-butyldimethylsilypoxy]ethyl}-9-methyl-8-oxo-3,4,7-
,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen--
13-yl]carbamate (375 mg, 0.690 mmol) in MeOH (5 mL) was added 4 N
HCl in dioxane (5 mL, 20.0 mmol) and the reaction mixture was
stirred at rt for 1 h. The reaction mixture was then concentrated
to give
(9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one, bis
hydrochloride (220 mg, 96% yield) as a pale yellow solid which was
then dissolved in MeOH (4 mL) to give a clear, pale yellow
solution. The solution was added to a pre-rinsed AGILENT.RTM.
StratoSpheres SPE PL-HCO.sub.3 MP Resin cartridge. Gravity
filtration, eluting with MeOH, gave a clear, slightly yellow
filtrate. Concentration provided
(9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one (170 mg,
96%) as a pale yellow solid. MS(ESI) m/z: 330.5 [M+H].sup.+.
Intermediate 41
Preparation of
(9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00154##
[1326] 41A. Preparation of tert-butyl
N-[(1S)-1-[3-fluoro-5-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl]but-3-en-1-
-yl]carbamate
[1327] To a DMF (1 ml) solution of tert-butyl
N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]carbamate (0.19 g,
0.552 mmol), prepared as described in Intermediate 25, was added
1-methyl-4-nitro-1H-pyrazole (0.070 g, 0.552 mmol),
di(adamantan-1-yl)(butyl) phosphine (0.059 g, 0.166 mmol), pivalic
acid (0.019 ml, 0.166 mmol), K.sub.2CO.sub.3 (0.229 g, 1.656 mmol)
and Pd(OAc).sub.2 (0.025 g, 0.110 mmol). The reaction mixture was
purged with Ar, and heated at 120.degree. C. After 18 h, the
reaction was partitioned between water (15 ml) and EtOAc (30 ml).
The aqueous layer was extracted with EtOAc (2.times.20 ml). The
combined organic layers were washed with brine (15 ml), dried
(MgSO.sub.4), filtered and concentrated. The residue was purified
by normal phase chromatography and was eluted with hexanes and
EtOAc to afford tert-butyl
N-[(1S)-1-[3-fluoro-5-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl]but-3-en-1-
-yl]carbamate as a yellow oil (0.123 g, 57%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.23-8.17 (m, 1H), 7.22-7.16 (m, 1H), 7.10 (s,
1H), 7.01 (dt, J=8.5, 1.9 Hz, 1H), 5.76-5.60 (m, 1H), 5.22-5.11 (m,
2H), 4.90 (br. s., 1H), 4.78 (br. s., 1H), 3.78-3.69 (m, 3H),
2.60-2.48 (m, 2H), 1.41 (br. s., 9H).
41B. Preparation of tert-butyl
N-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl]but-3-en-1-
-yl]carbamate
[1328] tert-Butyl
N-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl]but-3-en-1-
-yl]carbamate (0.123 g, 0.315 mmol) was dissolved in acetone (5
ml)/water (1 ml), cooled to 0.degree. C., and NH.sub.4Cl (0.084 g,
1.575 mmol) and Zn (0.206 g, 3.15 mmol) were added. The ice bath
was removed and the reaction mixture was warmed to rt. After 3 h,
the reaction was filtered and partitioned between water (10 ml) and
EtOAc (30 ml). The aqueous layer was extracted with EtOAc
(2.times.20 ml). The combined organic layers were washed with brine
(10 ml), dried (MgSO.sub.4), filtered and concentrated. The residue
was purified by normal phase chromatography and was eluted with
hexanes and EtOAc to afford tert-butyl
N-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl]but-3-en-1-
-yl]carbamate (0.105 g, 92%). MS(ESI) m/z: 361.08 (M+H).sup.+.
41C. Preparation of tert-butyl
N-[(1S)-1-(3-fluoro-5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-
-5-yl}phenyl)but-3-en-1-yl]carbamate
[1329] To tert-butyl
N-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl]
but-3-en-1-yl]carbamate (0.105 g, 0.291 mmol) was added EtOAc (0.6
ml), (R)-2-methylbut-3-enoic acid (0.035 g, 0.350 mmol), prepared
as described in Intermediate 2, in 0.3 ml EtOAc. The reaction
mixture was cooled to 0.degree. C., and a 50% EtOAc solution of
T3P.RTM. (0.347 ml, 0.583 mmol) and Hunig's Base (0.153 ml, 0.874
mmol) were added. After 4 h, the reaction was partitioned between
sat NaHCO.sub.3 (5 ml) and EtOAc (5 ml). The aqueous layer was
extracted with EtOAc (2.times.10 ml). The combined organic layers
were washed with brine (5 ml), dried (MgSO.sub.4), filtered and
concentrated. The residue was purified by normal phase
chromatography and was eluted with hexanes and EtOAc to give
tert-butyl
N-[(1S)-1-(3-fluoro-5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-
-5-yl}phenyl)but-3-en-1-yl]carbamate as a yellow foam (53 mg, 41%).
MS(ESI) m/z: 443.5 (M+H).sup.+.
41D. Preparation of tert-butyl
N-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.-
0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
[1330] To a degassed DCE (10 ml) solution of tert-butyl
N-[(1S)-1-(3-fluoro-5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-
-5-yl}phenyl)but-3-en-1-yl]carbamate (0.053 g, 0.120 mmol) was
added Second Generation Grubbs Catalyst (0.041 g, 0.048 mmol) and
the reaction mixture was heated to 120.degree. C. for 30 min in a
microwave. The reaction mixture was directly purified by normal
phase chromatography eluting with hexanes and EtOAc to afford
tert-butyl
N-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.-
0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate as
a dark solid (27 mg, 54%). MS(ESI) m/z: 415.4 (M+H).sup.+.
41E. Preparation of
(9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00155##
[1332] To an EtOH (3 ml) solution of tert-butyl
N-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.-
0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
(0.027 g, 0.065 mmol) was added PtO.sub.2 (5 mg). The reaction
mixture was purged with H.sub.2 and was then hydrogenated at 55
psi. After 6 h, the reaction mixture was filtered through
CELITE.RTM. and concentrated to give 19 mg of a dark solid MS(ESI)
m/z: 417.08 (M+H).sup.+. The dark solid residue was dissolved in
50% TFA/DCM (3 ml). After 3 h, the reaction mixture was
concentrated, the residue was dissolved in DCM/MeOH, passed through
a basic cartridge and concentrated to give
(9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0.su-
p.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one a dark solid (19
mg, 92%). MS(ESI) m/z: 317.4 (M+H).sup.+.
Intermediate 42
Preparation of
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0.sup.2,6-
] octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00156##
[1333] 42A. Preparation of tert-butyl
N-[(1S)-1-[2-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl-
]carbamate
[1334] To a large microwave vial was added tert-butyl
N-[(1S)-1-(2-bromopyridin-4-yl) but-3-en-1-yl]carbamate (1.0 g,
3.06 mmol), prepared as described in Intermediate 27,
1-methyl-4-nitro-1H-pyrazole (0.427 g, 3.36 mmol), dioxane (10 ml),
di(adamantan-1-yl)(butyl)phosphine (0.164 g, 0.458 mmol),
K.sub.2CO.sub.3 (1.267 g, 9.17 mmol) and pivalic acid (0.106 ml,
0.917 mmol). The reaction was purged with Ar. Pd(OAc).sub.2 (0.069
g, 0.306 mmol) was added and the reaction was stirred at
100.degree. C. After 4 h, heating was stopped and the reaction was
stirred at rt for 72 h. The reaction was quenched with water (20
ml) and extracted with EtOAc (3.times.50 ml). The combined organic
layers were washed with brine (20 ml), dried (MgSO.sub.4),
filtered, and concentrated. The residue was purified by normal
phase chromatography using heptanes and EtOAc as eluents to give
tert-butyl N-[(1S)-1-[2-(1-methyl-4-nitro-1H-pyrazol-5-yl)
pyridin-4-yl]but-3-en-1-yl]carbamate (0.62 g, 54%) as a white foam.
MS(ESI) m/z: 374.08 (M+H).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 8.73 (d, J=5.2 Hz, 1H), 8.28-8.15 (m, 1H), 7.66-7.54 (m,
1H), 7.43-7.34 (m, 1H), 5.76-5.63 (m, 1H), 5.26-5.16 (m, 2H), 4.99
(br. s., 1H), 4.83 (br. s., 1H), 3.97-3.85 (m, 3H), 2.66-2.46 (m,
2H), 1.45 (br. s., 9H).
42B. Preparation of tert-butyl
N-[(1S)-1-[2-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl-
]carbamate
[1335] To a cooled (0.degree. C.) acetone (40 ml)/water (12 ml)
solution of tert-butyl
N-[(1S)-1-[2-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl-
]carbamate (0.62 g, 1.660 mmol) was added NH.sub.4Cl (0.444 g, 8.30
mmol) and Zn (1.086 g, 16.60 mmol). The ice bath was removed and
the reaction was stirred 18 h. The reaction was filtered through
paper and partitioned with water (20 ml) and EtOAc (75 ml). The
aqueous layer was extracted with EtOAc (2.times.50 ml). The
combined organic layers were washed with brine (25 ml), dried
(MgSO.sub.4), filtered and concentrated. The residue was purified
by normal phase chromatography using DCM and 0-10% MeOH as eluents
to give tert-butyl
N-[(1S)-1-[2-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl-
]carbamate (0.46 g, 60%). MS(ESI) m/z: 344.5 (M+H).sup.+.
42C. Preparation of tert-butyl
N-[(1S)-1-(2-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyr-
idin-4-yl)but-3-en-1-yl]carbamate
[1336] To tert-butyl
N-[(1S)-1-[2-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl-
]carbamate (0.6 g, 1.747 mmol) was added (R)-2-methylbut-3-enoic
acid (0.189 g, 1.893 mmol), prepared as described in Intermediate
2, in EtOAc (5.8 ml), cooled to 0.degree. C. Pyridine (0. 0.424 ml,
5.24 mmol) and a 50% EtOAc solution of T3P.RTM. (2.080 ml, 3.49
mmol) were added. After 24 h, the reaction was partitioned between
sat NaHCO.sub.3 (10 ml) and EtOAc (20 ml). The aqueous layer was
extracted with EtOAc (2.times.20 ml). The combined organic layers
were washed with brine (10 ml), dried (MgSO.sub.4), filtered and
concentrated. The residue was purified by normal phase
chromatography using hexanes and EtOAc as eluents to give
tert-butyl
N-[(1S)-1-(2-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyr-
idin-4-yl)but-3-en-1-yl]carbamate (0.35 g, 47%). MS(ESI) m/z: 426.1
(M+H).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 10.23 (br.
s., 1H), 8.70-8.56 (m, 1H), 8.35 (d, J=1.1 Hz, 1H), 7.56-7.44 (m,
1H), 7.25-7.14 (m, 1H), 6.03 (ddd, J=17.2, 10.2, 8.0 Hz, 1H),
5.39-5.17 (m, 3H), 5.03-4.63 (m, 2H), 4.14-4.08 (m, 3H), 3.22
(quin, J=7.2 Hz, 1H), 2.66-2.49 (m, 1H), 1.84-1.72 (m, 1H),
1.50-1.40 (m, 9H), 1.42-1.37 (m, 3H), 1.06-0.93 (m, 1H).
42D. Preparation of tert-butyl
N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
[1337] To a degassed DCE (20 ml) solution of tert-butyl
N-[(1S)-1-(2-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}
pyridin-4-yl)but-3-en-1-yl]carbamate (0.160 g, 0.376 mmol) was
added Second Generation Grubbs Catalyst (0.096 g, 0.113 mmol) and
the reaction mixture was heated to 120.degree. C. for 30 min in a
microwave. The reaction mixture was concentrated and the residue
was purified by normal phase chromatography using DCM and MeOH as
eluents to afford desired product (29 mg, 19%) as a green film.
MS(ESI) m/z: 398.3 (M+H).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 8.71 (d, J=4.7 Hz, 1H), 7.58 (s, 1H), 7.23 (d, J=13.8 Hz,
1H), 7.03-6.94 (m, 1H), 6.61 (s, 1H), 5.82-5.71 (m, 1H), 5.19-5.09
(m, 2H), 4.75 (br. s., 1H), 4.15-4.09 (m, 3H), 3.19-3.10 (m, 1H),
2.67 (br. s., 1H), 2.28-2.15 (m, 2H), 1.54-1.39 (m, 9H), 1.34-1.28
(m, 3H).
42E. Preparation of
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00157##
[1339] To an EtOH (3 mL) solution of tert-butyl
N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (29 mg,
0.073 mmol) was added PtO.sub.2 (4 mg). The reaction mixture was
purged with H.sub.2, then was hydrogenated at 55 psi. After 3 h,
the reaction mixture was filtered through a 0.4504 filter and
concentrated to afford a dark solid (MS(ESI) m/z: 400.3
(M+H).sup.+). The dark solid residue was dissolved in 4 N HCl in
dioxane (1 ml) and MeOH (1 ml). After 3 h, the mixture was
concentrated and resultant HCl salt was dissolved in DCM/MeOH and
passed through a basic cartridge to afford
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one as a dark solid (21 mg,
96%). MS(ESI) m/z: 300.2 (M+H).sup.+.
Intermediate 43
Preparation of
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00158##
[1340] 43A. Preparation of (S)-tert-butyl
(1-(5-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-3-yl)but-3-en-1-
-yl)carbamate
[1341] To a large microwave vial was added (S)-tert-butyl
(1-(5-bromopyridin-3-yl)but-3-en-1-yl)carbamate (1.0 g, 3.06 mmol),
prepared a described in Intermediate 26,
1-(difluoromethyl)-4-nitro-1H-pyrazole (0.548 g, 3.36 mmol), DMF
(10.19 ml), di(adamantan-1-yl)(butyl)phosphine (0.164 g, 0.458
mmol), K.sub.2CO.sub.3 (1.267 g, 9.17 mmol) and pivalic acid (0.106
ml, 0.917 mmol). The reaction mixture was purged with Ar. After 10
min, Pd(OAc).sub.2 (0.069 g, 0.306 mmol) was added, the vessel
sealed, and stirred at 115.degree. C. After 4 h, the reaction was
quenched with H.sub.2O (50 mL) and extracted with EtOAc (3.times.50
mL). The combined organic phase was washed with brine (50 mL),
dried (MgSO.sub.4), filtered, and concentrated. The crude material
was purified by normal phase chromatography eluting with a gradient
of heptane/EtOAc to give (S)-tert-butyl
(1-(5-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-3-yl)but-3-en-1-
-yl)carbamate (1.25 g, 100%). MS(ESI) m/z: 410.2 (M+H).sup.+.
43B. Preparation of (S)-tert-butyl
(1-(5-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-3-yl)but-3-en-1-
-yl)carbamate
[1342] (S)-tert-Butyl
(1-(5-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-3-yl)but-3-en-1-
-yl)carbamate (1.27 g, 3.10 mmol) was dissolved in acetone (15
ml)/water (3 ml), cooled to 0.degree. C., and NH.sub.4Cl (0.830 g,
15.51 mmol) and Zn (2.028 g, 31.0 mmol) were added. The ice bath
was removed. After 2 h, the reaction mixture was filtered and
filtrate partitioned with water (30 ml) and EtOAc (50 ml). The
aqueous layer was extracted with EtOAc (2.times.50 ml). The
combined organic phase was washed with brine (20 ml), dried
(MgSO.sub.4), filtered, and concentrated. The residue was purified
by normal phase chromatography eluting with a gradient of DCM/MeOH
to give (S)-tert-butyl
(1-(5-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-3-yl)but-3-en-1-
-yl)carbamate (0.720 g, 61.2% yield) as a solid. MS(ESI) m/z: 380
(M+H).sup.+.
43C. Preparation of tert-butyl
((5)-1-(5-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5--
yl)pyridin-3-yl)but-3-en-1-yl)carbamate
[1343] A solution of (S)-tert-butyl
(1-(5-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-3-yl)but-3-en-1-
-yl)carbamate (0.720 g, 1.898 mmol) in EtOAc (20 ml) was cooled to
0.degree. C. and (R)-2-methylbut-3-enoic acid (0.228 g, 2.277
mmol), prepared as described in Intermediate 2, in EtOAc (10 ml),
pyridine (0.460 ml, 5.69 mmol), and T3P.RTM. (50% wt in EtOAc)
(2.259 ml, 3.80 mmol) were added. After 6 h, the reaction was
partitioned with 1.5 M K.sub.2PO.sub.4 (50 mL) and EtOAc (50 mL).
The aqueous layer was extracted with EtOAc (2.times.20 mL). The
combined organic phase was washed with brine (50 mL), dried
(MgSO.sub.4), filtered, and concentrated. The residue was purified
by normal chromatography eluting with a gradient of hexanes/EtOAc
to give tert-butyl
((5)-1-(5-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5--
yl)pyridin-3-yl)but-3-en-1-yl)carbamate (0.386 g, 44.1% yield) as a
yellow foam. MS(ESI) m/z: 462.2 (M+H).sup.+.
43D. Preparation of tert-butyl
N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,16-tetraazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
[1344] To a RBF was added tert-butyl
((5)-1-(5-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5--
yl)pyridin-3-yl)but-3-en-1-yl)carbamate (0.190 g, 0.412 mmol),
pTsOH (0.086 g, 0.453 mmol), and degassed DCE (103 ml). The clear
yellow solution was warmed to 40.degree. C. and degassed with Ar
for 1 h. Second Generation Grubbs Catalyst (0.140 g, 0.165 mmol)
was added and reaction stirred at 40.degree. C. overnight.
Additional Second Generation Grubbs Catalyst (0.2 eq.) was added
and stirring continued. After stirring for a total of 48 h, the
reaction mixture was cooled to rt, washed with sat NaHCO.sub.3,
brine, dried over MgSO.sub.4, filtered, and concentrated. The crude
product was purified by normal phase chromatography eluting with a
gradient of DCM/MeOH to give tert-butyl
N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,16-tetraazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
(0.020 g, 11.2%) as a brown oil. MS(ESI) m/z: 434.3
(M+H).sup.+.
43E. Preparation of tert-butyl
N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,16-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
[1345] To an EtOH (3 mL) solution of tert-butyl
N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,16-tetraazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
(0.020, 0.046 mmol) was added PtO.sub.2 (1.048 mg, 4.61 .mu.mol)
and the reaction was purged with H.sub.2. The reaction mixture was
subjected to a H.sub.2 atmosphere (55 psi). After 2 h, the catalyst
was filtered off through a plug of CELITE.RTM. and the filtrate
concentrated to give tert-butyl
N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,16-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate.
MS(ESI) m/z: 436.2 (M+H).sup.+.
43F. Preparation of
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[1346] tert-Butyl
N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,16-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(0.020 g, 0.046 mmol) was dissolved in 4 N HCl in dioxane (0.230
ml, 0.919 mmol). A minimum amount of MeOH was added to aid
dissolution. After 1 h, the reaction mixture was concentrated to
dryness. The residue was dissolved in MeOH, passed through a
NaHCO.sub.3 cartridge (StratoSpheres SPE; 500 mg, 0.90 mmol
loading), concentrated to give
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one.
MS(ESI) m/z: 336.2 (M+H).sup.+.
Intermediate 44
Preparation of 6-(2-bromo-5-chlorophenyl)pyrimidin-4-ol
##STR00159##
[1347] 44A. Preparation of
4-(2-bromo-5-chlorophenyl)-6-methoxypyrimidine
[1348] To a suspension of
4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (100 mg, 0.424 mmol)
and TsOH.H.sub.2O (97 mg, 0.509 mmol) in CH.sub.3CN (20 mL) was
added CuBr.sub.2 (9.48 mg, 0.042 mmol). Then t-butyl nitrite (0.067
mL, 0.509 mmol) was added followed by tetrabutylammonium bromide
(274 mg, 0.849 mmol) and the reaction was stirred at rt. After 2 h,
water was added and the mixture was extracted with CH.sub.2Cl.sub.2
(2.times.). The organic layers were combined, dried over
MgSO.sub.4, filtered, and concentrated. Purification by normal
phase chromatography gave
4-(2-bromo-5-chlorophenyl)-6-methoxypyrimidine (115 mg, 90% yield)
as a white solid. MS(ESI) m/z: 299.2 (M+H).sup.+. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.88 (d, J=1.1 Hz, 1H), 7.61 (d, J=8.6 Hz,
1H), 7.56 (d, J=2.6 Hz, 1H), 7.30-7.24 (m, 1H), 7.04 (d, J=1.1 Hz,
1H), 4.05 (s, 3H).
44B. Preparation of 6-(2-bromo-5-chlorophenyl)pyrimidin-4-ol
[1349] 6-(2-Bromo-5-chlorophenyl)pyrimidin-4-ol was prepared
according to the procedures described in Intermediate 5 for the
synthesis of 6-(5-chloro-2-fluorophenyl) pyrimidin-4-ol, by
replacing 6-(5-chloro-2-fluorophenyl)pyrimidin-4-ol with
4-(2-bromo-5-chlorophenyl)-6-methoxypyrimidine. MS(ESI) m/z: 285.2
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.19 (s,
1H), 7.72 (d, J=8.6 Hz, 1H), 7.52 (d, J=2.6 Hz, 1H), 7.41 (dd,
J=8.6, 2.6 Hz, 1H), 6.21 (s, 1H).
Example 45
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[(pyrimidin-2-yl)amino]phenyl}-6-oxo-1,6-dihyd-
ropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00160##
[1351]
(9R,13S)-13-(4-{5-Chloro-2-[(pyrimidin-2-yl)amino]phenyl}-6-oxo-1,6-
-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.su-
p.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one, 2 trifluoroacetate
(2.75 mg, 19% yield) was prepared in a similar manner as the
procedure described in Example 314, by replacing 4-bromopyrimidine
hydrochloride (6.78 mg, 0.035 mmol) with 2-bromopyrimidine (5.51
mg, 0.035 mmol). MS(ESI) m/z: 582.5 (M+H).sup.+. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 9.12 (s, 1H), 8.74 (d, J=5.1 Hz, 1H),
8.46-8.42 (m, 3H), 7.73 (s, 1H), 7.66 (d, J=2.6 Hz, 1H), 7.54-7.48
(m, 2H), 7.43 (dd, J=8.9, 2.5 Hz, 1H), 6.85 (t, J=5.0 Hz, 1H), 6.79
(s, 1H), 6.06 (dd, J=12.7, 4.3 Hz, 1H), 4.05 (s, 3H), 2.78-2.67 (m,
1H), 2.42-2.31 (m, 1H), 2.16-2.02 (m, 2H), 1.69-1.44 (m, 2H), 1.02
(d, J=6.8 Hz, 3H), 0.80-0.63 (m, 1H). Analytical HPLC (Method A):
RT=8.33 min, 97.9% purity; Factor XIa Ki=2,000 nM.
Example 46
Preparation of ethyl
2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricycl-
o[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-1H-pyrazol-1-yl]acetate
##STR00161##
[1353] Ethyl
2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricycl-
o
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-d-
ihydropyrimidin-4-yl}phenyl)-1H-pyrazol-1-yl]acetate
trifluoroacetate (3.67 mg, 15% yield) was prepared in a similar
manner as the procedure described in Example 49, by replacing
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
with ethyl
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-
acetate (13.67 mg, 0.049 mmol). MS(ESI) m/z: 641.5 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.96 (s, 1H), 8.74 (d,
J=5.3 Hz, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 7.56-7.52 (m, 2H),
7.51-7.49 (m, 3H), 7.45 (s, 1H), 6.41 (s, 1H), 6.00 (dd, J=12.7,
4.1 Hz, 1H), 4.94 (s, 2H), 4.18 (q, J=7.1 Hz, 2H), 4.05 (s, 3H),
2.76-2.66 (m, 1H), 2.40-2.28 (m, 1H), 2.14-2.03 (m, 2H), 1.67-1.42
(m, 2H), 1.24 (t, J=7.2 Hz, 3H), 1.02 (d, J=6.8 Hz, 3H), 0.80-0.65
(m, 1H). Analytical HPLC (Method A): RT=7.92 min, 99.6% purity;
Factor XIa Ki=25 nM, Plasma Kallikrein Ki=7,000 nM.
Example 47
Preparation of
2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricycl-
o[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-1H-pyrazol-1-yl]acetic acid
##STR00162##
[1355]
2-[4-(4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazat-
ricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-
-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazol-1-yl]acetic acid
trifluoroacetate (8.6 mg, 35% yield) was also isolated from Example
46. MS(ESI) m/z: 613.5 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.94 (s, 1H), 8.75 (d, J=5.3 Hz, 1H), 7.74 (s,
1H), 7.60 (s, 1H), 7.56-7.48 (m, 5H), 7.46 (s, 1H), 6.45 (d, J=0.4
Hz, 1H), 6.00 (dd, J=12.5, 4.2 Hz, 1H), 4.90 (s, 2H), 4.05 (s, 3H),
2.75-2.66 (m, 1H), 2.33 (tt, J=12.7, 4.5 Hz, 1H), 2.14-2.03 (m,
2H), 1.66-1.42 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.82-0.66 (m, 1H).
Analytical HPLC (Method A): RT=6.68 min, 99.0% purity; Factor XIa
Ki=12 nM, Plasma Kallikrein Ki=6,000 nM.
Example 48
Preparation of
2-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)acetonitrile
##STR00163##
[1357]
2-(4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatric-
yclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,-
6-dihydropyrimidin-4-yl}phenyl)acetonitrile trifluoroacetate (2.2
mg, 11% yield) was prepared in a similar manner as the procedure
described in Example 49, by replacing
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (9.52
mg, 0.049 mmol). MS(ESI) m/z: 528.35 (M+H).sup.+. .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 9.04 (br. s., 1H), 8.74 (d, J=5.2 Hz, 1H),
7.73 (s, 1H), 7.59-7.49 (m, 5H), 6.65 (s, 1H), 6.06 (d, J=9.6 Hz,
1H), 4.18-4.08 (m, 2H), 4.06 (s, 3H), 2.78-2.68 (m, 1H), 2.42-2.33
(m, 1H), 2.16-2.03 (m, 2H), 1.68-1.58 (m, 1H), 1.55-1.45 (m, 1H),
1.02 (d, J=6.9 Hz, 3H), 0.79-0.65 (m, 1H). Analytical HPLC (Method
C): RT=1.46 min, 100% purity; Factor XIa Ki=16 nM, Plasma
Kallikrein Ki=850 nM.
Example 49
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2-
,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00164##
[1359] To a degassed solution of
(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-
,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6)-
,4,14,16-pentaen-8-one (15 mg, 0.024 mmol), prepared as described
in Example 211,
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(7.61 mg, 0.037 mmol), and K.sub.2CO.sub.3 (8.43 mg, 0.061 mmol) in
1,4-dioxane (0.6 ml) and water (0.2 ml) was added
Pd(Ph.sub.3P).sub.4 (2.82 mg, 2.440 .mu.mol). The reaction was
microwaved at 120.degree. C. for 0.5 h, and then cooled to rt and
concentrated. Purification by reverse phase chromatography afforded
(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2-
,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (7.9
mg, 47% yield) as an off-white solid. MS(ESI) m/z: 569.6
(M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.97 (s,
1H), 8.75 (d, J=5.2 Hz, 1H), 7.73 (s, 1H), 7.59 (s, 1H), 7.55-7.52
(m, 2H), 7.50-7.45 (m, 3H), 7.33 (s, 1H), 6.40 (d, J=0.6 Hz, 1H),
6.02 (dd, J=12.7, 3.9 Hz, 1H), 4.05 (s, 3H), 3.84 (s, 3H),
2.75-2.68 (m, 1H), 2.39-2.30 (m, 1H), 2.13-2.02 (m, 2H), 1.66-1.45
(m, 2H), 1.02 (d, J=7.2 Hz, 3H), 0.78-0.65 (m, 1H). Analytical HPLC
(Method A): RT=7.01 min, 98.4% purity; Factor XIa Ki=14 nM, Plasma
Kallikrein Ki=930 nM.
Example 50
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,-
6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.s-
up.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00165##
[1361]
(9R,13S)-13-{4-[5-Chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)phenyl]-6--
oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (11.3 mg, 49% yield) was prepared in a similar
manner as the procedure described in Example 49, by replacing
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
with
1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(10.84 mg, 0.049 mmol). MS(ESI) m/z: 583.5 (M+H).sup.+. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.95 (s, 1H), 8.73 (d, J=5.1 Hz, 1H),
7.73-7.69 (m, 2H), 7.55-7.47 (m, 4H), 7.33 (d, J=8.4 Hz, 1H), 6.24
(d, J=0.7 Hz, 1H), 5.97 (dd, J=12.7, 4.3 Hz, 1H), 4.05 (s, 3H),
3.81 (s, 3H), 2.76-2.65 (m, 1H), 2.39-2.28 (m, 1H), 2.13-1.97 (m,
2H), 1.90 (s, 3H), 1.66-1.42 (m, 2H), 1.01 (d, J=6.8 Hz, 3H),
0.80-0.63 (m, 1H). Analytical HPLC (Method A): RT=7.15 min, 99.6%
purity; Factor XIa Ki=270 nM, Plasma Kallikrein Ki=5,200 nM.
Example 51
Preparation of
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-4,5,8-triazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
##STR00166##
[1362] 51A. Preparation of 5-bromopyridazin-4-amine
[1363] tert-Butyl N-(5-bromopyridazin-4-yl)carbamate (400 mg, 1.183
mmol) in DCM (15 mL) was added TFA (4.56 mL, 59.2 mmol). The
reaction was stirred at rt overnight. Concentration gave
5-bromopyridazin-4-amine.trifluoroacetate as a dark brownish solid.
MS(ESI) m/z: 174.2 (M+H).sup.+.
51B. Preparation of
(10R,14S)-14-amino-10-methyl-4,5,8-triazatricyclo[13.3.1.0.sup.27]
nonadeca-1(19),2,4,6,15,17-hexaen-9-one
[1364]
(10R,14S)-14-Amino-10-methyl-4,5,8-triazatricyclo[13.3.1.0.sup.2,7]-
nonadeca-1(19),2,4,6,15,17-hexaen-9-one was prepared in a similar
manner as the procedure described in Intermediate 38, by replacing
2-bromopyridin-3-amine with 5-bromopyridazin-4-amine. MS(ESI) m/z:
297.5 (M+H).sup.+.
51C. Preparation of
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-4,5,8-triazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
[1365]
(10R,14S)-14-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-
-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-4,5,8-triazatricycl-
o[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
trifluoroacetate (3.8 mg, 32.7% yield) was prepared in a similar
manner as the procedure described in Example 56 by using
(10R,14S)-14-amino-10-methyl-4,5,8-triazatricyclo[13.3.1.0.sup.2,7]nonade-
ca-1(19),2,4,6,15,17-hexaen-9-one (4.5 mg, 0.015 mmol). .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 9.42 (s, 1H), 9.14 (s, 1H), 8.82-8.77
(m, 1H), 8.42 (s, 1H), 7.90-7.84 (m, 1H), 7.81 (s, 1H), 7.77-7.72
(m, 1H), 7.70-7.65 (m, 1H), 7.65-7.61 (m, 2H), 7.30-7.24 (m, 1H),
6.45 (d, J=0.7 Hz, 1H), 5.77 (dd, J=12.9, 4.3 Hz, 1H), 2.70-2.59
(m, 1H), 2.36-2.23 (m, 1H), 2.13-2.00 (m, 1H), 2.00-1.89 (m, 1H),
1.67-1.35 (m, 2H), 1.26-1.13 (m, 1H), 1.07 (d, J=6.8 Hz, 3H).
MS(ESI) m/z: 621.0 (M+H).sup.+. Analytical HPLC (Method A): RT=8.24
min, purity=100%; Factor XIa Ki=5 nM, Plasma Kallikrein Ki=18
nM.
Example 52
Preparation of
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carboxylic acid
##STR00167##
[1367] To a solution of ethyl
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihyd-
ropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carboxylate trifluoroacetate
(7 mg, 0.011 mmol) in THF (56 .mu.l) was added a solution of
LiOH.H.sub.2O (4.7 mg, 0.112 mmol) in water (56 .mu.l). To the
resulting cloudy mixture was added MeOH (1 drop). The reaction was
stirred vigorously at rt for 3.5 h. The solution was acidified to
pH 5 with 1.0 N HCl and then purified by reverse phase
chromatography to give
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihyd-
ropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carboxylic acid
trifluoroacetate (0.0024 g, 30% yield) as a white solid. MS(ESI)
m/z: 599.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3CN) .delta.
8.73-8.66 (m, 2H), 8.17 (s, 1H), 7.94 (s, 1H), 7.81 (d, J=2.2 Hz,
1H), 7.73-7.62 (m, 3H), 7.61-7.55 (m, 1H), 7.47-7.38 (m, 2H), 6.16
(d, J=0.9 Hz, 1H), 5.98 (dd, J=12.7, 3.9 Hz, 1H), 4.02 (s, 3H),
2.65 (m, 1H), 2.30-2.19 (m, 1H), 2.15-2.02 (m, 1H), 1.64-1.39 (m,
2H), 0.98 (d, J=6.8 Hz, 3H), 0.61 (m, 1H). Analytical HPLC (Method
A): SunFire, RT=6.48 min, 99.3% purity; Factor XIa Ki=5 nM, Plasma
Kallikrein Ki=2,400 nM.
Example 53
Preparation of
(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-5-chloro-6-oxo-1,6-dihydropyrimid-
in-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca--
1(18),2(6),4,14,16-pentaen-8-one
##STR00168##
[1368] 53A. Preparation of
6-(2-bromo-5-chlorophenyl)-5-chloropyrimidin-4-ol
[1369] To a suspension of 6-(2-bromo-5-chlorophenyl)pyrimidin-4-ol,
prepared as described in Intermediate 44, (40 mg, 0.140 mmol) in
MeCN (1401 .mu.l) was added NCS (20.58 mg, 0.154 mmol). The
reaction was heated at 60.degree. C. for 4 h. The reaction mixture
was concentrated and the crude residue was purified using normal
phase chromatography to yield
6-(2-bromo-5-chlorophenyl)-5-chloropyrimidin-4-ol (42 mg, 94%) as a
white solid. MS(ESI) m/z: 320.9 (M+H).sup.+.
53B. Preparation of
(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-5-chloro-6-oxo-1,6-dihydropyrimid-
in-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca--
1(18),2(6),4,14,16-pentaen-8-one
[1370]
(9R,13S)-13-[4-(2-Bromo-5-chlorophenyl)-5-chloro-6-oxo-1,6-dihydrop-
yrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]oct-
adeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (8.3 mg,
41.1% yield) was prepared in a similar manner as the procedure
described in Example 56, by using
6-(2-bromo-5-chlorophenyl)-5-chloropyrimidin-4-ol (8.6 mg, 0.027
mmol) and
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one (8 mg, 0.027 mmol),
prepared as described in Intermediate 32. MS(ESI) m/z: 603.0
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.99 (s,
1H), 8.75 (d, J=5.1 Hz, 1H), 7.75 (s, 1H), 7.70 (d, J=8.6 Hz, 1H),
7.54 (dd, J=5.1, 1.5 Hz, 1H), 7.50 (s, 1H), 7.45-7.38 (m, 2H), 6.06
(dd, J=12.4, 4.1 Hz, 1H), 4.05 (s, 3H), 2.72 (td, J=6.7, 3.1 Hz,
1H), 2.45-2.31 (m, 1H), 2.19-2.03 (m, 2H), 1.70-1.43 (m, 2H), 1.02
(d, J=7.0 Hz, 3H), 0.73 (br. s., 1H). Analytical HPLC (Method A):
RT=9.24 min, 100% purity; Factor XIa Ki=8 nM, Plasma Kallikrein
Ki=1,200 nM.
Example 54
Preparation of
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1,3-thiazol-5-yl)phenyl]-6-oxo-1,6-d-
ihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricycl-
o [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00169##
[1371] 54A. Preparation of
4-(3-chloro-2-fluoro-6-iodophenyl)-6-methoxypyrimidine
[1372] 4-Chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline,
prepared as described in Intermediate 10C (1 g, 3.94 mmol) in ACN
(26.3 ml) was cooled to 0.degree. C. and pTsOH.H.sub.2O (1.875 g,
9.86 mmol) was added followed by addition of NaNO.sub.2 (0.544 g,
7.88 mmol) and NaI (1.477 g, 9.86 mmol) in water (13.14 ml). After
1 h, the reaction was warmed to rt and stirred overnight. After
this time, the reaction was partially concentrated to remove the
ACN and NaHCO.sub.3 was then added to neutralize the solution. The
resulting solution was extracted with EtOAc. The combined organic
layer was washed with sat Na.sub.2S.sub.2O.sub.3 and brine, dried
over MgSO.sub.4, filtered, and concentrated to yield a solid, which
was purified by normal phase chromatography to give
4-(3-chloro-2-fluoro-6-iodophenyl)-6-methoxypyrimidine (0.934 g,
65% yield). MS(ESI) m/z: 365.2 (M+H).sup.+.
54B. Preparation of
6-(3-chloro-2-fluoro-6-iodophenyl)pyrimidin-4-ol
[1373] 6-(3-Chloro-2-fluoro-6-iodophenyl)pyrimidin-4-ol was
prepared according to the procedures as described in Intermediate
4B for the synthesis of
6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol, by replacing
4-(3-chloro-2,6-difluorophenyl)-6-methoxypyrimidine, prepared as
described in Intermediate 4A, with
4-(3-chloro-2-fluoro-6-iodophenyl)-6-methoxypyrimidine. MS(ESI)
m/z: 350.8 (M+H).sup.+.
54C. Preparation of
(9R,13S)-13-[4-(3-chloro-2-fluoro-6-iodophenyl)-6-oxo-1,6-dihydropyrimidi-
n-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
[1374]
(9R,13S)-13-[4-(3-Chloro-2-fluoro-6-iodophenyl)-6-oxo-1,6-dihydropy-
rimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one was prepared
in a similar manner as the procedure described in Example 56, using
6-(3-chloro-2-fluoro-6-iodophenyl)pyrimidin-4-ol (62.7 mg, 0.179
mmol) and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (60
mg, 0.179 mmol), prepared as described in Intermediate 30. MS(ESI)
m/z: 667.1 (M+H).sup.+.
54D. Preparation of
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1,3-thiazol-5-yl)phenyl]-6-oxo-1,6-d-
ihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricycl-
o [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[1375] To a microwave tube was added
(9R,13S)-13-[4-(3-chloro-2-fluoro-6-iodophenyl)-6-oxo-1,6-dihydropyrimidi-
n-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (20 mg, 0.030 mmol),
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (9.47 mg,
0.045 mmol), K.sub.3PO.sub.4 (29.9 .mu.l, 0.090 mmol) and THF (299
.mu.l). The solution was bubbled through with Ar for several min
then (DtBPF)PdCl.sub.2 (0.974 mg, 1.495 .mu.mol) was added. The
reaction was sealed and heated at 90.degree. C. overnight. The
solution was cooled to rt and Ar was again bubbled through the
solution for several minutes and additional
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (9.47 mg,
0.045 mmol) and Pd(PPh.sub.3).sub.4 (3.46 mg, 2.99 .mu.mol) were
added. The solution was heated in a microwave at 120.degree. C. for
30 min. The solution was then filtered and the residue was purified
by reverse phase chromatography to give
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1,3-thiazol-5-yl)phenyl]-6-oxo-1,6-d-
ihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricycl-
o [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.67
mg, 2.9%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.02 (s, 1H),
8.95 (s, 1H), 8.77 (d, J=5.1 Hz, 1H), 7.80 (s, 1H), 7.74 (s, 1H),
7.72-7.60 (m, 3H), 7.59-7.50 (m, 2H), 7.46 (dd, J=8.4, 1.3 Hz, 1H),
6.55 (s, 1H), 6.05 (dd, J=12.9, 4.3 Hz, 1H), 2.71 (dt, J=6.6, 3.3
Hz, 1H), 2.40-2.26 (m, 1H), 2.12-1.97 (m, 2H), 1.70-1.41 (m, 2H),
1.00 (d, J=7.0 Hz, 3H), 0.66 (br. s., 1H). MS(ESI) m/z: 625.9
(M+H).sup.+. Analytical HPLC (Method A): RT=8.51 min, purity=96.4%;
Factor XIa Ki=1.7 nM, Plasma Kallikrein Ki=230 nM.
Example 55
Preparation of
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00170##
[1376] 55A. Preparation of 1-methyl-4-nitro-1H-pyrazole
[1377] To a solution of 4-nitro-1H-pyrazole (2.5 g, 22.11 mmol) in
THF (50 mL) was added NaH (0.973 g, 24.32 mmol) and the mixture was
stirred at rt for 5 min. To this suspension was added MeI (1.382
mL, 22.11 mmol) and the resulting solution was stirred at rt
overnight. The reaction mixture was then diluted with EtOAc and
washed with brine. The organic layer was concentrated, followed by
purification using normal phase chromatography to yield
1-methyl-4-nitro-1H-pyrazole as a white solid (1.9 g, 80%). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.12 (s, 1H), 8.06 (s, 1H),
3.97 (s, 3H).
55B. Preparation of (S)-tert-butyl
(1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbam-
ate
[1378] To a pressure vial was added (S)-tert-butyl
1-(4-chloropyridin-2-yl)but-3-enylcarbamate, prepared as described
in Intermediate 23, (3.0 g, 10.61 mmol),
1-methyl-4-nitro-1H-pyrazole (1.348 g, 10.61 mmol),
di(adamant-1-yl)(butyl)phosphine (1.141 g, 3.18 mmol), pivalic acid
(0.369 mL, 3.18 mmol) and K.sub.2CO.sub.3 (4.40 g, 31.8 mmol). To
the above mixture was added DMF (21 mL) and the vial was purged and
evacuated (3.times.) with Ar. To this mixture was added
Pd(OAc).sub.2 (0.476 g, 2.122 mmol). The vial was sealed and heated
at 120.degree. C. overnight. The reaction mixture was cooled to rt,
filtered and partitioned between 10% aqueous LiCl (15 mL) and EtOAc
(30 mL). The aqueous layer was extracted with EtOAc (2.times.20 mL)
and the combined organic layers were washed with brine (15 mL),
dried over MgSO.sub.4, filtered and concentrated. The crude product
was then purified using normal phase chromatography to yield
(S)-tert-butyl
(1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbam-
ate (1.2 g, 29% yield) as a brown oil. MS(ESI) m/z: 374.4
(M+H).sup.+.
55C. Preparation of (S)-tert-butyl
(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbam-
ate
[1379] A solution of (S)-tert-butyl
(1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbam-
ate (1.2 g, 3.21 mmol) in MeOH (10 mL) and CH.sub.3COOH (1 ml) was
heated to 60.degree. C. To the above clear solution was then slowly
added Zn (0.420 g, 6.43 mmol) and the solution was allowed to stir
at 60.degree. C. for an additional 15 min. The reaction mixture was
then filtered through CELITE.RTM. and concentrated to yield crude
product. The crude product was then purified using normal phase
chromatography to yield (5)-tert-butyl
(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbam-
ate (0.88 g, 76% yield) as a pale brown oil. MS(ESI) m/z: 344.4
(M+H).sup.+.
55D. Preparation of tert-butyl
((5)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-
-2-yl)but-3-en-1-yl)carbamate
[1380] To a solution of
(R)-4-benzyl-3-((R)-2-methylbut-3-enoyl)oxazolidin-2-one (385 mg,
3.84 mmol), prepared as described in Intermediate 2A,
(S)-tert-butyl
(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbam-
ate (880 mg, 2.56 mmol) and pyridine (0.620 mL, 7.69 mmol) in EtOAc
(40 mL) at -10.degree. C. under Ar was added T3P.RTM. (50% wt in
EtOAc) (3.05 mL, 5.12 mmol) dropwise. The reaction mixture was
stirred at -10.degree. C. and was allowed to gradually warm up to
rt. The reaction mixture was stirred at rt for 2 h, then diluted
with EtOAc and washed with sat aq NaHCO.sub.3 and brine. The
organic layers were pooled together, dried over MgSO.sub.4,
filtered and concentrated. The crude product was then purified
using normal phase chromatography to yield tert-butyl
((5)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-
-2-yl)but-3-en-1-yl)carbamate (0.6 g, 52% yield) as a yellow oil.
MS(ESI) m/z: 426.5 (M+H).sup.+.
55E. Preparation of tert-butyl
N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
[1381] A solution of tert-butyl
((5)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-
-2-yl)but-3-en-1-yl)carbamate (600 mg, 1.410 mmol) in DCE (18 mL)
was purged with Ar (3.times.). Second Generation Grubbs Catalyst
(480 mg, 0.564 mmol) was added and Ar was again bubbled into the
reaction mixture and evacuated (3.times.). The reaction mixture was
then heated at 120.degree. C. in a microwave vial for 30 min. The
reaction mixture was then concentrated and the crude residue was
purified using normal phase chromatography to yield tert-butyl
N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (118 mg,
20% yield) as a brown oil. MS(ESI) m/z: 398.5 (M+H).sup.+.
55F. Preparation of tert-butyl
N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
[1382] To a degassed solution of tert-butyl
N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl] carbamate (118
mg, 0.297 mmol) in EtOH (12 mL) was added Pd/C (31.6 mg, 0.030
mmol) and the reaction mixture was then stirred under H.sub.2 at 55
psi for 5 h. The reaction mixture was then filtered though
CELITE.RTM. and concentrated to yield tert-butyl
N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate. (92 mg, 72%)
as a brown oil. MS(ESI) m/z: 400.4 (M+H).sup.+.
55G. Preparation of
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one,
dihydrochloride
[1383] To a solution of tert-butyl
N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (92 mg, 0.230
mmol) in MeOH (3 mL) was added 4 M HCl in dioxane (3 mL, 12 mmol)
and the reaction was stirred at rt for 1.5 h. The reaction mixture
was concentrated to yield
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one dihydrochloride (86 mg)
as yellow solid. MS(ESI) m/z: 300.4 (M+H).sup.+.
55H. Preparation of
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0-
.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[1384]
(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12-
.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate was prepared according to the procedure described
in Example 56, by using
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one dihydrochloride and
6-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol,
prepared as described in Intermediate 7. MS(ESI) m/z: 574.3
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.82 (s,
1H), 8.73 (d, J=5.3 Hz, 1H), 8.19 (d, J=1.1 Hz, 1H), 7.85 (dd,
J=8.6, 7.7 Hz, 1H), 7.78 (d, J=1.1 Hz, 1H), 7.70 (s, 1H), 7.56-7.50
(m, 2H), 7.49 (s, 1H), 6.53 (s, 1H), 5.98 (dd, J=12.8, 4.2 Hz, 1H),
4.05 (s, 3H), 2.70 (td, J=6.7, 3.2 Hz, 1H), 2.27 (ddt, J=12.7, 8.5,
4.3 Hz, 1H), 2.14-1.92 (m, 2H), 1.66-1.53 (m, 1H), 1.46 (ddd,
J=15.1, 10.0, 5.3 Hz, 1H), 1.00 (d, J=7.0 Hz, 3H), 0.68 (m., 1H).
Analytical HPLC (method A): RT=6.41 min, purity=93%; Factor XIa
Ki=1.0 nM, Plasma Kallikrein Ki=24 nM.
Example 56
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00171##
[1386] To a scintillation vial containing
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol (22.8 mg, 0.067 mmol), prepared as described in Intermediate
15, HATU (33.0 mg, 0.087 mmol) in anhydrous ACN (0.5 mL) was added
DBU (15 mL, 0.100 mmol). After 30 min, a solution of
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one (20 mg, 0.067 mmol),
prepared as described in Intermediate 32, in 0.5 ml CH.sub.3CN and
DMF (0.1 ml) was added. The resulting solution was stirred at rt
for 2 h then purified by reverse phase chromatography to give
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (26.98 mg, 53.1% yield) as a white solid. MS(ESI)
m/z: 624.3 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.81 (d, J=0.7 Hz, 1H), 8.75 (s, 1H), 8.70 (d, J=5.3 Hz, 1H), 7.89
(d, J=2.4 Hz, 1H), 7.77-7.72 (m, 1H), 7.72-7.66 (m, 2H), 7.53 (dd,
J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 6.43 (s, 1H), 6.02-5.93 (m, 1H),
4.04 (s, 3H), 2.70 (td, J=6.7, 3.3 Hz, 1H), 2.27 (tt, J=12.7, 4.4
Hz, 1H), 2.12-1.94 (m, 2H), 1.66-1.52 (m, 1H), 1.45 (ddd, J=15.0,
9.8, 5.0 Hz, 1H), 1.00 (d, J=7.0 Hz, 3H), 0.69 (br. s., 1H).
.sup.19F NMR (376 MHz, CD.sub.3OD) .delta. -62.54 (s), -77.44 (s).
Analytical HPLC (Method A): RT=11.02 min, purity=96.7%; Factor XIa
Ki=1.4 nM, Plasma Kallikrein Ki=24 nM.
Example 57
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00172##
[1387] 57A. Preparation of 2-ethylbut-3-enoic acid
##STR00173##
[1389] To a dry flask was added 2 M DIA in THF (8.28 mL, 58.1 mmol)
and THF (50 mL). The reaction was cooled to -78.degree. C. and 1.6
M nBuLi in hexanes (23.23 mL, 58.1 mmol) was added dropwise. The
reaction was stirred at -78.degree. C. for 30 min. But-3-enoic acid
(2.00 g, 23.23 mmol) was added to the reaction and the reaction was
stirred at -78.degree. C. for 30 min. After this time, EtI (5.44 g,
34.8 mmol) was added. The reaction was slowly warmed to rt and
stirred at rt overnight. The reaction was then quenched with sat
NH.sub.4Cl (3 mL). The pH of the reaction was adjusted to <4
using 1 N HCl. The reaction was then extracted with EtOAc
(2.times.30 mL). The combined organic layer was washed with water
(20 mL) and brine (20 mL), dried over MgSO.sub.4, filtered and
concentrated. The residue was purified using ISCO system (0-60%
EtOAc/Hex gradient) to give 2-ethylbut-3-enoic acid (450 mg, 2.37
mmol, 10.2% yield) as a clear liquid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 5.89-5.75 (m, 1H), 5.22-5.18 (m, 1H), 5.16 (s,
1H), 2.95 (q, J=7.5 Hz, 1H), 1.83 (dt, J=13.9, 7.2 Hz, 1H), 1.61
(dt, J=13.6, 7.4 Hz, 1H), 0.95 (t, J=7.4 Hz, 3H).
57B. Preparation of tert-butyl
((1S)-1-(4-(4-(2-ethylbut-3-enamido)-1-methyl-1H-pyrazol-5-yl)pyridin-2-y-
l)but-3-en-1-yl)carbamate
##STR00174##
[1391] To a RBF was added (S)-tert-butyl
(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbam-
ate, prepared as described in Intermediate 32C, (1000 mg, 2.91
mmol), EtOAc (20 mL), 2-ethylbut-3-enoic acid (332 mg, 2.91 mmol),
and pyridine (0.71 mL, 8.74 mmol). The solution was cooled in a
brine/ice bath and 50% T3P.RTM. (2.60 mL, 4.37 mmol) was added. The
reaction was stirred at 0.degree. C. for 10 min and then at rt for
60 min. The reaction was diluted with EtOAc (30 mL) and washed with
sat NaHCO.sub.3 (20 mL), water (30 mL) and brine (30 mL). The
organic layer was separated, dried over MgSO.sub.4, filtered and
concentrated. The residue was purified using ISCO system (0-100%
EtOAc/Hex gradient) to give tert-butyl
((1S)-1-(4-(4-(2-ethylbut-3-enamido)-1-methyl-1H-pyrazol-5-yl)pyridin-2-y-
l)but-3-en-1-yl)carbamate (1.10 g, 2.50 mmol, 86% yield) as a
diastereomer mixture as a yellow solid. MS(ESI) m/z: 440.0
(M+H).sup.+.
57C. Preparation of tert-butyl
N-[(9R,10E,13S)-9-ethyl-3-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
##STR00175##
[1393] To a microwave vial was added tert-butyl
41S)-1-(4-(4-(2-ethylbut-3-enamido)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl-
)but-3-en-1-yl)carbamate (500 mg, 1.138 mmol) and DCE (12 mL). The
reaction was purged with Ar for 1 min. Then Second Generation
Grubbs Catalyst (386 mg, 0.455 mmol) was added to the solution. The
reaction was sealed and heated in microwave at 120.degree. C. for
30 min. The reaction was concentrated and the residue was purified
using ISCO system (0-10% MeOH/CH.sub.2Cl.sub.2 gradient). Two
products were isolated. The fast eluting product was tert-butyl
N-[(9R,10E)-9-ethyl-3-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (75 mg,
0.182 mmol, 16.0% yield), MS(ESI) m/z: 412.2 (M+H).sup.+ which was
carried forward and the slow eluting product was the other
diastereomer, tert-butyl
N-[(9S,10E)-9-ethyl-3-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (75 mg,
0.182 mmol, 16.0% yield), MS(ESI) m/z: 412.2 (M+H).sup.+.
57D. Preparation of tert-butyl
N-[(9R,13S)-9-ethyl-3-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
##STR00176##
[1395] To a 3-neck RBF was added tert-butyl
N-[(9R,10E)-9-ethyl-3-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl] carbamate (115
mg, 0.279 mmol), EtOH (10 mL) and PtO.sub.2 (31.7 mg, 0.140 mmol).
The reaction was stirred under a H.sub.2 atmosphere (balloon
pressure) for 1 h. The reaction was carefully filtered through
CELITE.RTM. and concentrated. The residue was purified using ISCO
system (0-10% MeOH/CH.sub.2Cl.sub.2 gradient) to give tert-butyl
N-[(9R,13S)-9-ethyl-3-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (75 mg,
0.181 mmol, 64.9% yield) as a light brown solid. MS(ESI) m/z: 414.2
(M+H).sup.+.
57E. Preparation of
(9R,13S)-13-amino-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00177##
[1397] To a RBF was added tert-butyl
N-[(9R,13S)-9-ethyl-3-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (75 mg,
0.181 mmol), dioxane (3 mL), 4 N HCl (18.14 mmol) and MeOH (0.5
mL). The reaction was stirred at rt for 5 min. The reaction was
concentrated and the residue was purified using reverse phase
preparative HPLC to give
(9R,13S)-13-amino-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one, trihydrochloride.
The product was dissolved in MeOH (1 mL) to give a clear, brown
solution. The solution was added to a pre-rinsed AGILENT.RTM.
StratoSpheres SPE PL-HCO.sub.3 MP Resin cartridge. Gravity
filtration, eluting with MeOH, gave a clear, slightly brown
filtrate. Concentration provided
(9R,13S)-13-amino-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (75 mg, 0.177 mmol,
98% yield) as a beige solid. MS(ESI) m/z: 314.2 (M+H).sup.+.
57F. Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00178##
[1399]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-9-ethyl-3-methyl-3,4,7,15-tetraazatricycl-
o[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (5 mg, 6.82 .mu.mol, 26.3% yield) was prepared in
a similar manner as the procedure described in Example 56 by using
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(8 mg, 0.026 mmol), prepared as described in Intermediate 9, and
(9R)-13-amino-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one (8 mg, 0.026 mmol).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.87 (s, 1H), 8.72 (d,
J=5.1 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.64 (dd,
J=8.5, 2.3 Hz, 1H), 7.59 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.46 (s,
1H), 7.36 (dd, J=5.1, 1.5 Hz, 1H), 6.37 (s, 1H), 6.06 (dd, J=12.5,
4.6 Hz, 1H), 4.03 (s, 3H), 2.46-2.36 (m, 1H), 2.26-2.12 (m, 1H),
2.03-1.92 (m, 2H), 1.69-1.56 (m, 2H), 1.45 (d, J=4.8 Hz, 1H),
1.32-1.20 (m, 1H), 0.86 (t, J=7.4 Hz, 3H), 0.69-0.57 (m, 1H);
MS(ESI) m/z: 604.2 (M+H).sup.+. Analytical HPLC (Method A): RT=7.23
min, purity=97.0%; Factor XIa Ki=0.36 nM, Plasma Kallikrein Ki=37
nM.
Example 58
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricy-
clo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00179##
[1400] 58A. Preparation of 2-isopropylbut-3-enoic acid
##STR00180##
[1402] To a flame-dry RBF was added 2 M DIA in THF (3.64 ml, 25.6
mmol) and THF (58.1 ml). The reaction was cooled to -78.degree. C.
and 1.6 M nBuLi in hexane (15.97 ml, 25.6 mmol) was added. The
reaction was stirred at -78.degree. C. for 30 min. But-3-enoic acid
(0.990 ml, 11.62 mmol) was added and the reaction was stirred for
additional 30 min. Then at -78.degree. C., iPrI (1.74 ml, 17.42
mmol) was added and the reaction was slowly warmed to rt over 2 h
and then stirred at rt overnight. The reaction was quenched with
sat NH.sub.4Cl (15 ml). The pH of the solution was adjusted to
<4 using 1 N HCl. The reaction was extracted with EtOAc
(3.times.30 mL). The combined EtOAc layer was washed with brine (40
mL), dried over MgSO.sub.4, filtered and concentrated. The residue
was purified using ISCO system (0-50% EtOAc/Hex gradient) to give
2-isopropylbut-3-enoic acid (800 mg, 6.24 mmol, 53.7% yield) as a
clear liquid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.98-5.65
(m, 1H), 5.33-5.05 (m, 2H), 2.73 (t, J=8.8 Hz, 1H), 2.08-1.95 (m,
1H), 1.09-0.74 (m, 6H).
58B. Preparation of tert-butyl
((1S-[1-(4-{1-methyl-4-[2-(propan-2-yl)but-3-enamido]-1H-pyrazol-5-yl}pyr-
idin-2-yl)but-3-en-1-yl]carbamate
##STR00181##
[1404] To a RBF was added (S)-tert-butyl
(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbam-
ate, prepared as described in Intermediate 32C, (765 mg, 2.228
mmol), EtOAc (20 mL), 2-isopropylbut-3-enoic acid (286 mg, 2.228
mmol), and pyridine (0.540 mL, 6.68 mmol). The solution was cooled
in a brine/ice bath and 50% T3P.RTM. (1.989 mL, 3.34 mmol) was
added. The reaction was stirred at 0.degree. C. for 10 min and then
at rt for 60 min. Reaction was diluted with EtOAc (30 mL) and
washed with sat NaHCO.sub.3 (20 mL), water (30 mL) and brine (30
mL). The organic layer was separated, dried over MgSO.sub.4,
filtered and concentrated. The residue was purified using ISCO
system (0-100% EtOAc/Hex gradient) to give tert-butyl
((1S)-1-(4-(4-(2-isopropylbut-3-enamido)-1-methyl-1H-pyrazol-5-yl)pyridin-
-2-yl)but-3-en-1-yl)carbamate (850 mg, 1.874 mmol, 84% yield) as a
diastereomer mixture as a yellow solid. MS(ESI) m/z: 454.2
(M+H).sup.+.
58C1 and 58C2. Preparation of tert-butyl
N-[(9S,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[-
12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate,
and tert-butyl
N-[(9R,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15
tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-1-
3-yl]carbamate
##STR00182##
[1406] To a microwave vial was added tert-butyl
41S)-1-(4-(4-(2-isopropylbut-3-enamido)-1-methyl-1H-pyrazol-5-yl)pyridin--
2-yl)but-3-en-1-yl)carbamate (250 mg, 0.551 mmol) and DCE (15 mL).
The reaction was purged with Ar for 1 min. Then Second Generation
Grubbs Catalyst (187 mg, 0.220 mmol) was added. The reaction was
sealed and heated at microwave at 120.degree. C. for 60 min. The
reaction was then concentrated and the residue was purified using
reverse phase preparative HPLC to give 58C1, tert-butyl
N-[(9S,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
trifluoroacetate (50 mg, 0.093 mmol, 16.8% yield), (ESI) m/z: 426.2
(M+H).sup.+, which has a shorter retention time and 58C2,
tert-butyl
N-[(9R,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[-
12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
trifluoroacetate (50 mg, 0.093 mmol, 16.8% yield), MS(ESI) m/z:
426.2 (M+H).sup.+ which had a longer retention time.
58D. Preparation of tert-butyl
N-[(9R,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
##STR00183##
[1408] To a 3-neck RBF was added tert-butyl
N-[(9S,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[-
12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
trifluoroacetate (20 mg, 0.037 mmol), EtOH (3 mL) and PtO.sub.2
(4.21 mg, 0.019 mmol). The reaction was stirred under a H.sub.2
atmosphere (balloon pressure) for 1 h. The reaction was carefully
filtered through CELITE.RTM. and the filtrate was concentrated to
give tert-butyl
N-[(9R,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(12 mg, 0.028 mmol, 76% yield). MS(ESI) m/z: 428.2 (M+H).sup.+.
58E. Preparation of
(9R,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00184##
[1410] To a round RBF flask was added tert-butyl
N-[(9R,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(20 mg, 0.047 mmol), dioxane (3 mL), 4 N HCl in dioxane (0.14 mL,
4.68 mmol) and MeOH (0.5 mL). The reaction was stirred at rt for 5
min. The reaction was concentrated and the residue was purified
using reverse phase preparative HPLC to give
(9R,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
hydrochloride. The product was added to a pre-rinsed AGILENT.RTM.
StratoSpheres SPE PL-HCO.sub.3 MP Resin cartridge. Gravity
filtration, eluting with MeOH, gave a clear, slightly brown
filtrate. Concentration provided
(9R,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (7 mg,
0.016 mmol, 34.3% yield) as a solid. MS(ESI) m/z: 328.2
(M+H).sup.+.
58F. Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricy-
clo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00185##
[1412]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraaz-
atricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (6 mg,
8.03 .mu.mol, 40.4% yield) was prepared in a similar manner as the
procedure described in Example 56 by using
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(6.12 mg, 0.020 mmol), prepared as described in Intermediate 9, and
(9R,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (6.5 mg,
0.020 mmol). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.75 (s,
1H), 8.69 (d, J=5.1 Hz, 1H), 8.07-8.01 (m, 1H), 7.82-7.78 (m, 1H),
7.71-7.66 (m, 1H), 7.65 (s, 1H), 7.60-7.57 (m, 1H), 7.52-7.47 (m,
1H), 7.36 (dd, J=5.1, 1.5 Hz, 1H), 6.41 (d, J=0.7 Hz, 1H), 6.09
(dd, J=12.4, 4.3 Hz, 1H), 4.04 (s, 3H), 2.16 (tt, J=12.6, 4.2 Hz,
1H), 2.06-1.71 (m, 5H), 1.60-1.48 (m, 1H), 1.03 (dd, J=6.4, 3.7 Hz,
6H), 0.82 (q, J=11.4 Hz, 1H); MS(ESI) m/z: 618.2 (M+H).sup.+.
Analytical HPLC (Method A): RT=11.50 min, purity=98.0%; Factor XIa
Ki=56 nM, Plasma Kallikrein Ki=3,300 nM.
Example 59
[1413]
(9S,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraaz-
atricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
##STR00186##
59A. Preparation of tert-butyl
N-[(9S,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
##STR00187##
[1415] To a 3-neck RBF was added tert-butyl
N-[(9R,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[-
12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
trifluoroacetate (15 mg, 0.028 mmol), prepared as described in
Example 58C2, EtOH (3 mL) and PtO.sub.2 (3.16 mg, 0.014 mmol). The
reaction was stirred under a H.sub.2 atmosphere (balloon pressure)
for 1 h. The reaction was carefully filtered through CELITE.RTM.
and the filtrate was concentrated to give tert-butyl
N-[(9S,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(10 mg, 0.023 mmol, 84% yield) as a brown solid. MS(ESI) m/z: 618.2
(M+H).sup.+.
59B. Preparation of
(9S,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00188##
[1417] To a RBF was added tert-butyl
N-[(9S,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(20 mg, 0.047 mmol), dioxane (3 mL), 4 N HCl in dioxane (0.142 mL,
4.68 mmol) and MeOH (0.5 mL). The reaction was stirred at rt for 5
min. The reaction was concentrated and the residue was purified
using reverse phase preparative HPLC to give
(9S,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
hydrochloride. The product was added to a pre-rinsed AGILENT.RTM.
StratoSpheres SPE PL-HCO.sub.3 MP Resin cartridge. Gravity
filtration, eluting with MeOH, gave a clear, slightly brown
filtrate. Concentration provided
(9S,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (1.5 mg,
3.43 .mu.mol, 7.34% yield) as a beige solid. MS(ESI) m/z: 328.2
(M+H).sup.+.
59C. Preparation of
(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricy-
clo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00189##
[1419]
(9S,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraaz-
atricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (0.6 mg,
0.778 .mu.mol, 21.23% yield) was prepared in a similar manner as
the procedure described in Example 56 by using
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(1.129 mg, 3.66 .mu.mol), prepared as described in Intermediate 9,
and
(9S,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (1.2 mg,
3.66 .mu.mol). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.80 (s,
1H), 8.76 (d, J=5.1 Hz, 1H), 8.38-8.36 (m, 1H), 7.92 (d, J=2.2 Hz,
1H), 7.79-7.75 (m, 1H), 7.73 (s, 1H), 7.70-7.65 (m, 1H), 7.55 (dd,
J=5.1, 1.5 Hz, 1H), 7.52 (s, 1H), 6.40 (s, 1H), 5.98 (d, J=9.2 Hz,
1H), 4.08 (s, 3H), 2.46-2.27 (m, 2H), 2.17-2.01 (m, 3H), 1.87-1.67
(m, 3H), 1.43 (br. s., 1H), 0.97 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.4
Hz, 3H); MS(ESI) m/z: 618.2 (M+H).sup.+. Analytical HPLC (Method
A): RT=11.52 min, purity=95.0%; Factor XIa Ki=3.5 nM, Plasma
Kallikrein Ki=370 nM.
Example 60
Preparation of
(9S,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetr-
aazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00190##
[1421] (9S,13
S)-13-{4-[3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-o-
xo-1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (0.8 mg, 1.013 .mu.mol, 3.32% yield) was prepared
in a similar manner as the procedure described in Example 56 by
using
6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)
pyrimidin-4-ol (12.43 mg, 0.031 mmol) prepared as described in
Intermediate 10 and
(9S,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one (10 mg,
0.031 mmol). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.80 (s,
1H), 8.75 (d, J=5.1 Hz, 1H), 8.27 (s, 1H), 7.87-7.83 (m, 1H), 7.69
(s, 1H), 7.56-7.49 (m, 2H), 7.48 (s, 1H), 6.61 (s, 1H), 6.01 (d,
J=8.8 Hz, 1H), 4.06 (s, 3H), 2.33-2.24 (m, 1H), 2.13-1.99 (m, 3H),
2.14-1.97 (m, 4H), 1.83-1.69 (m, 2H), 1.42 (br. s., 1H), 1.33-1.23
(m, 1H), 0.94 (d, J=6.8 Hz, 3H), 0.89 (d, J=6.4 Hz, 3H); MS(ESI)
m/z: 636.2 (M+H).sup.+. Analytical HPLC (Method A): RT=11.266 min,
purity=95.0%; Factor XIa Ki=0.53 nM, Plasma Kallikrein Ki=40
nM.
Example 61
Preparation of
(9R,13S)-13-{4-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-6-oxo-1,6-dih-
ydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,-
6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
##STR00191##
[1422] 61A. Preparation of
2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2--
dioxaborolane
##STR00192##
[1424] To a dry RBF was added
1-chloro-4-(difluoromethyl)-2-fluorobenzene (180 mg, 0.997 mmol)
and THF (3 mL). The reaction was cooled to -78.degree. C. and 2 M
LDA in THF (0.498 mL, 0.997 mmol) was added dropwise. The reaction
turned to dark red immediately after the addition. The reaction was
stirred at -78.degree. C. for 5 min and
2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (371 mg, 1.994
mmol) was added in one portion. The reaction was stirred at
-78.degree. C. for 20 min. The colored changed to pale yellow. The
reaction was partitioned between EtOAc (30 mL) and water (20 mL).
The organic layer was separated, washed with water (20 mL) and
brine (20 mL), dried over MgSO.sub.4, filtered and concentrated.
The residue was purified using ISCO system (0-30% EtOAc/Hex
gradient) to give
2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2--
dioxaborolane (125 mg, 0.408 mmol, 40.9% yield) as a light brown
oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.45 (t, J=7.8 Hz,
1H), 7.29 (d, J=8.4 Hz, 1H), 7.10-6.74 (m, 1H), 1.31 (s, 12H).
61B. Preparation of
4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-methoxypyrimidine
##STR00193##
[1426] To a microwave vial was added
2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2--
dioxaborolane (120 mg, 0.391 mmol), 4-chloro-6-methoxypyrimidine
(56.6 mg, 0.391 mmol), toluene (2 mL), EtOH (1 mL) and 2 M
Na.sub.2CO.sub.3 (0.587 mL, 1.174 mmol). The reaction was purged
with Ar and Pd(PPh.sub.3).sub.4 (45 mg, 0.039 mmol) was added. The
reaction was sealed and stirred in a microwave at 120.degree. C.
for 1 h. The reaction was partitioned between EtOAc (20 mL) and
water (20 mL). The organic layer was separated, washed with water
(10 mL) and brine (15 mL), dried over MgSO.sub.4, filtered and
concentrated. The residue was purified using ISCO system (0-30%
EtOAc/Hex gradient) to give
4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-methoxypyrimidine
(40 mg, 0.139 mmol, 35.4% yield) as a white solid. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.88 (d, J=0.9 Hz, 1H), 7.64-7.57 (m, 1H),
7.56-7.50 (m, 1H), 7.11-6.76 (m, 2H), 4.06 (s, 3H).
61C. Preparation of 6-(3-chloro-6-(difluoromethyl)-2
fluorophenyl)pyrimidin-4-ol
##STR00194##
[1428] To a RBF was added
4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-methoxypyrimidine
(40 mg, 0.139 mmol), AcOH (0.5 mL) and 48% HBr (0.784 mL, 6.93
mmol). The reaction was stirred at 85.degree. C. for 45 min. Then
toluene (25 mL) was added and the reaction was concentrated. The
residue was then partitioned between EtOAc (25 mL) and sat aq
NaHCO.sub.3 (25 mL). The organic layer was separated, washed with
water (15 mL) and brine (15 mL), dried over MgSO.sub.4, filtered
and concentrated. The residue was purified using ISCO system
(0-100% EtOAc/Hex gradient) to give
6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrimidin-4-ol (36
mg, 0.131 mmol, 95% yield) as a white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 13.25 (br. s., 1H), 8.28 (s, 1H), 7.70-7.57 (m,
1H), 7.53 (d, J=8.4 Hz, 1H), 7.16-6.79 (m, 1H), 6.72 (br. s.,
1H).
61D. Preparation of
(9R,13S)-13-{4-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-6-oxo-1,6-dih-
ydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,-
6] octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
##STR00195##
[1430]
(9R,13S)-13-{4-[3-Chloro-6-(difluoromethyl)-2-fluorophenyl]-6-oxo-1-
,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
(3.1 mg, 4.44 .mu.mol, 7.38% yield) was prepared in a similar
manner as the procedure described in Example 56 using
6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrimidin-4-ol (16.51
mg, 0.060 mmol). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.78 (d,
J=5.3 Hz, 1H), 7.80-7.74 (m, 2H), 7.60 (d, J=8.6 Hz, 1H), 7.56 (dd,
J=5.3, 1.5 Hz, 1H), 7.53 (s, 1H), 7.16-6.84 (m, 1H), 6.67 (s, 1H),
6.08 (dd, J=12.8, 4.2 Hz, 1H), 4.08 (s, 3H), 2.75 (td, J=6.8, 3.2
Hz, 1H), 2.40 (tt, J=12.7, 4.6 Hz, 1H), 2.19-2.05 (m, 2H),
1.71-1.60 (m, 1H), 1.53 (ddd, J=15.0, 9.9, 5.5 Hz, 1H), 1.05 (d,
J=7.0 Hz, 3H), 0.76 (br. s., 1H); MS(ESI) m/z: 557.1 (M+H).sup.+.
Analytical HPLC (Method A): RT=7.516 min, purity=96.0%; Factor XIa
Ki=2.5 nM, Plasma Kallikrein Ki=45 nM.
Example 62
Preparation of
(9R,13S)-13-{4-[3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl]-6-oxo-1,6--
ihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
##STR00196##
[1431] 62A. Preparation of
1-chloro-4-(1,1-difluoroethyl)-2-fluorobenzene
##STR00197##
[1433] To a sealed tube was added
1-(4-chloro-3-fluorophenyl)ethanone (1 g, 5.79 mmol),
CH.sub.2Cl.sub.2 (10 mL) and DAST (2.297 mL, 17.38 mmol). The
reaction was sealed and stirred at 45.degree. C. for 8 h. The
reaction was carefully quenched with cold sat NaHCO.sub.3 over 30
min until the pH was greater than 7. The organic layer was
separated, washed with water, dried over MgSO.sub.4, filtered and
concentrated. The reside was purified using ISCO system (0-10%
EtOAC/Hex gradient) to give
1-chloro-4-(1,1-difluoroethyl)-2-fluorobenzene (300 mg, 1.54 mmol,
26.6% yield) as a light brown liquid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.49-7.42 (m, 1H), 7.32-7.27 (m, 1H), 7.25-7.20
(m, 1H), 1.90 (t, J=18.2 Hz, 3H).
62B. Preparation of
2-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3-
,2-dioxaborolane
##STR00198##
[1435] To a dry RBF was added
1-chloro-4-(1,1-difluoroethyl)-2-fluorobenzene (230 mg, 1.182 mmol)
and THF (3 mL). The reaction was cooled to -78.degree. C. and 2 M
LDA solution (0.71 mL, 1.418 mmol) was added dropwise. The reaction
turned to red after the addition. The reaction was stirred at
-78.degree. C. for 5 min and then
2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (440 mg, 2.364
mmol) was added in one portion. The reaction was stirred at
-78.degree. C. for additional 20 min. The color changed to pale
yellow. The reaction was partitioned between EtOAc (30 mL) and
water (20 mL). The organic layer was separated, washed with water
(20 mL) and brine (20 mL), dried over MgSO.sub.4, filtered and
concentrated. The residue was purified using ISCO system (0-30%
EtOAc/Hex gradient) to give
2-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3-
,2-dioxaborolane (330 mg, 1.030 mmol, 87% yield) as a clear oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.43 (t, J=7.9 Hz, 1H),
7.18 (d, J=8.4 Hz, 1H), 1.93 (t, J=18.3 Hz, 3H), 1.38 (s, 12H).
62C. Preparation of
4-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)-6-methoxypyrimidine
##STR00199##
[1437] To a microwave vial was added
2-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3-
,2-dioxaborolane (325 mg, 1.014 mmol), 4-chloro-6-methoxypyrimidine
(147 mg, 1.014 mmol), toluene (4 mL), EtOH (2 mL) and 2 M
Na.sub.2CO.sub.3 (1.52 mL, 3.04 mmol). The reaction was purged with
Ar and Pd(PPh.sub.3).sub.4 (116.7 mg, 0.101 mmol) was added. The
reaction was sealed and stirred in microwave at 120.degree. C. for
1 h. The reaction was partitioned between EtOAc (20 mL) and water
(20 mL). The organic layer was separated, washed with water (10 mL)
and brine (15 mL), dried over MgSO.sub.4, filtered and
concentrated. The residue was purified using ISCO system (0-30%
EtOAc/Hex gradient) to give
4-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)-6-methoxypyrimidine
(40 mg, 0.132 mmol, 13.03% yield) as a white solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.84 (d, J=1.1 Hz, 1H), 7.52 (d,
J=7.3 Hz, 1H), 7.36 (dd, J=8.6, 1.3 Hz, 1H), 6.81 (s, 1H), 4.05 (s,
3H), 1.91 (t, J=18.6 Hz, 3H); MS(ESI) m/z: 303.0, 305.0
(M+H).sup.+.
62D. Preparation of
6-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)pyrimidin-4-ol
##STR00200##
[1439] To a RBF was added
4-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)-6-methoxypyrimidine
(35 mg, 0.116 mmol), AcOH (0.5 mL) and HBr (0.654 mL, 5.78 mmol).
The reaction was stirred at 85.degree. C. for 45 min. Then toluene
(25 mL) was added and the reaction was concentrated. The residue
was partitioned between EtOAc (25 mL) and sat NaHCO.sub.3 (25 mL).
The organic layer was separated, washed with water (15 mL) and
brine (15 mL), dried over MgSO.sub.4, filtered and concentrated.
The residue was purified using ISCO system (0-100% EtOAc/Hex
gradient) to give
6-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)pyrimidin-4-ol (28
mg, 0.097 mmol, 84% yield) as a white solid. MS(ESI) m/z: 289,
291.0 (M+H).sup.+.
62E. Preparation of
(9R,13S)-13-{4-[3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl]-6-oxo-1,6--
ihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
##STR00201##
[1441]
(9R,13S)-13-{4-[3-Chloro-6-(1,1-difluoroethyl)-2-fluorophenyl]-6-ox-
o-1,6-ihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.-
0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (30 mg, 0.042 mmol, 69.9% yield) was prepared in a
similar manner as the procedure described in Example 56 by
replacing
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol with
6-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)pyrimidin-4-ol
(22.2 mg, 0.06 mmol). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.99 (br. s., 1H), 8.74 (d, J=4.2 Hz, 1H), 7.78 (s, 1H), 7.65 (t,
J=7.8 Hz, 1H), 7.58 (d, J=3.7 Hz, 1H), 7.50-7.39 (m, 2H), 6.53 (s,
1H), 6.01 (d, J=9.9 Hz, 1H), 4.02 (s, 3H), 2.67 (br. s., 1H),
2.43-2.31 (m, 1H), 2.06 (br. s., 2H), 1.89 (t, J=18.6 Hz, 3H),
1.66-1.53 (m, 1H), 1.45 (br. s., 1H), 0.98 (d, J=6.8 Hz, 3H), 0.73
(br. s., 1H); MS(ESI) m/z: 636.2 (M+H).sup.+. Analytical HPLC
(Method A): RT=11.078 min, purity=96.0%; Factor XIa Ki=16 nM,
Plasma Kallikrein Ki=240 nM.
Example 63
Preparation of
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00202##
[1443] To
6-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-
-ol (0.018 g, 0.060 mmol), prepared as described in Intermediate 7,
was added HATU (0.030 g, 0.078 mmol) and a solution of DBU (0.014
mL, 0.090 mmol) in CH.sub.3CN (0.5 ml). After 30 min,
(9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0.su-
p.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.019 g, 0.060
mmol), prepared as described in Intermediate 29, was added. After
18 h, the reaction was diluted with DMF, filtered and concentrated.
The residue was purified by reverse phase HPLC using
PHENOMENEX.RTM. Luna 5U 30.times.100 mm (10:90 ACN/H.sub.2O to
90:10 AcN/H.sub.2O, 0.1% TFA) (20% B start 10 min gradient). The
desired fractions were concentrated and freeze-dried to afford
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phen-
yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-16-fluoro-3,9-dimethyl-3,4,7-triazatr-
icyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(4.5 mg, 12%) as a white solid. MS(ESI) m/z: 591.3 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.25 (s, 1H), 8.20 (d,
J=1.1 Hz, 1H), 7.91-7.84 (m, 1H), 7.84-7.77 (m, 2H), 7.60-7.49 (m,
3H), 7.38 (d, J=8.6 Hz, 1H), 7.12 (d, J=9.5 Hz, 1H), 6.59 (s, 1H),
5.79 (dd, J=12.9, 3.2 Hz, 1H), 4.08-4.00 (m, 3H), 2.52 (td, J=6.8,
3.4 Hz, 1H), 2.41-2.29 (m, 1H), 2.15-2.04 (m, 1H), 1.90 (d, J=4.8
Hz, 1H), 1.65-1.45 (m, 2H), 1.29-1.19 (m, 1H), 1.14 (d, J=6.8 Hz,
3H). Analytical HPLC (Method A) RT=7.41 min, purity=95%; Factor XIa
Ki=0.25 nM, Plasma Kallikrein Ki=34 nM.
Example 64
Preparation of
(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-
-yl]-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00203##
[1445] To a solution of
6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol hydrobromide (0.017
g, 0.053 mmol), prepared as described in Intermediate 4, in
CH.sub.3CN (1 ml), was added HATU (0.026 g, 0.068 mmol) and DBU
(0.028 mL, 0.184 mmol). After 1 h,
(9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0.su-
p.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one, (0.019 g, 0.053
mmol), prepared as described in Intermediate 29, was added. After
18 h, the reaction was diluted with DMF, filtered and concentrated.
The residue was purified by reverse phase HPLC, then preparative
LCMS to give
(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-
-yl]-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-
-1(18),2(6),4,14,16-pentaen-8-one (3.4 mg, 11.9%). MS(ESI) m/z:
542.1 (M+H).sup.+. .sup.1H NMR ((500 MHz, DMSO-d.sub.6) .delta.
9.23 (s, 1H), 8.69 (br. s., 1H), 7.84-7.73 (m, 1H), 7.61-7.50 (m,
2H), 7.45 (s, 1H), 7.38-7.32 (m, 1H), 7.29-7.19 (m, 1H), 6.74 (s,
1H), 5.66 (d, J=12.5 Hz, 1H), 3.98 (s, 3H), 2.42 (br. s., 1H),
2.10-1.97 (m, 1H), 1.88 (br. s., 1H), 1.45 (d, J=7.3 Hz, 1H), 1.21
(br. s., 1H), 1.11 (br. s., 1H), 0.97 (d, J=6.4 Hz, 3H). Analytical
HPLC (Method C) RT=1.50 min., purity=99%; Factor XIa Ki=26 nM,
Plasma Kallikrein Ki=450 nM.
Example 65
Preparation of
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0.sup.-
2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00204##
[1447] To
6-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-
-ol (13.07 mg, 0.045 mmol), prepared as described in Intermediate
7, was added HATU (22.14 mg, 0.058 mmol) and a solution of DBU
(0.017 mL, 0.112 mmol) in ACN (0.5 ml). After 30 min,
(9R,13S)-13-amino-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octa-
deca-1(18),2(6),4,14,16-pentaen-8-one, hydrochloride (15 mg, 0.045
mmol), prepared as described in Intermediate 31, was added and the
reaction was stirred for 18 h. The reaction was then diluted with
DMF, filtered and concentrated. The residue was purified by reverse
phase HPLC, then, preparative LCMS to give
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (3.2 mg, 12%).
MS(ESI) m/z: 573.3 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.15 (s, 1H), 8.43-8.32 (m, 2H), 8.00-7.93 (m, 2H), 7.84
(s, 1H), 7.68-7.59 (m, 2H), 7.59-7.50 (m, 2H), 7.41 (s, 1H),
7.28-6.99 (m, 2H), 6.56 (s, 1H), 5.60 (d, J=11.3 Hz, 1H), 4.03-3.90
(m, 3H), 2.32 (br. s., 1H), 1.94-1.79 (m, 2H), 1.41 (d, J=5.2 Hz,
1H), 1.14 (br. s., 2H), 0.96 (d, J=6.4 Hz, 3H). Analytical HPLC
(Method C) RT=1.41 min., purity=98%; Factor XIa Ki=0.23 nM, Plasma
Kallikrein Ki=22 nM.
Example 66
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0.sup.-
2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00205##
[1449] To a 1-dram vial containing a white suspension of
6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol
(0.026 g, 0.084 mmol), prepared as described in Intermediate 9, in
CH.sub.3CN (0.5 ml) was added HATU (0.041 g, 0.109 mmol) and DBU
(0.019 mL, 0.126 mmol). After 30 min,
(9R,13S)-13-amino-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octa-
deca-1(18),2(6),4,14,16-pentaen-8-one (0.025 g, 0.084 mmol),
prepared as described in Intermediate 31, which had been free-based
through a basic cartridge in DCM/MeOH and dried, in CH.sub.3CN/DMF
(0.5 ml) was added. After 18 h, the reaction was diluted with DMF,
filtered and purified by reverse phase HPLC using PHENOMENEX.RTM.
Luna 5U 30.times.100 mm (10:90 MeOH/H.sub.2O to 90:10
MeOH/H.sub.2O, 0.1% TFA) (20% B start 10 min gradient) to afford
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1
H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethy-
l-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentae-
n-8-one (13.9 mg, 28% yield) as a white solid. MS(ESI) m/z: 589.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.37-8.33
(m, 1H), 8.19 (s, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.80-7.72 (m, 2H),
7.67-7.55 (m, 3H), 7.52 (s, 1H), 7.34 (d, J=7.3 Hz, 1H), 6.43 (d,
J=0.7 Hz, 1H), 5.84 (dd, J=13.1, 3.2 Hz, 1H), 4.04 (s, 3H),
2.55-2.46 (m, 1H), 2.41-2.30 (m, 1H), 2.17-2.05 (m, 1H), 1.92-1.84
(m, 1H), 1.66-1.53 (m, 2H), 1.22 (br. s., 1H), 1.16 (d, J=6.8 Hz,
3H). Analytical HPLC (Method A) RT=8.25 min., purity=95%; Factor
XIa Ki=0.1 nM, Plasma Kallikrein Ki=8 nM.
Example 67
Preparation of
(9R)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6--
dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00206##
[1451] Purification of Example 65 by reverse phase HPLC, then,
preparative LCMS also gave
(9R)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6--
dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]-
octadeca-1(18),2(6),4,14,16-pentaen-8-one as the first eluting
diastereomer (1.4 mg, 5.4%). MS(ESI) m/z: 573.3 (M+H).sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6).sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.08 (s, 1H), 8.71 (s, 1H), 8.39 (s, 1H),
8.04-7.94 (m, 1H), 7.86 (s, 1H), 7.70-7.58 (m, 2H), 7.58-7.48 (m,
2H), 7.42 (s, 1H), 7.25-7.03 (m, 2H), 6.61 (s, 1H), 5.60 (d, J=13.1
Hz, 1H), 3.98 (s, 2H), 2.41-2.30 (m, 2H), 1.82 (br. s., 1H), 1.68
(d, J=10.1 Hz, 1H), 1.37 (d, J=11.0 Hz, 1H), 1.11 (br. s., 2H),
1.07 (d, J=6.4 Hz, 3H). Analytical HPLC (Method C) RT=1.39 min.,
purity=100%; Factor XIa Ki=5 nM, Plasma Kallikrein Ki=256 nM.
Example 68
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7-triazatr-
icyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00207##
[1453] To a solution of
6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol
(0.031 g, 0.100 mmol), prepared as described in Intermediate 9, in
CH.sub.3CN (0.8 ml) was added HATU (0.049 g, 0.129 mmol) and DBU
(0.023 mL, 0.149 mmol) After 30 min,
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7-triazatricyclo[1-
2.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one 0.03 g,
0.100 mmol), prepared as described in Intermediate 36, was added
(rinsed in with 0.2 ml DMF). After 18 h, the reaction was diluted
with DMF, filtered and concentrated. The residue was purified by
reverse phase HPLC using PHENOMENEX.RTM. Luna 5U 30.times.100 mm
(10:90 MeOH/H.sub.2O to 90:10 MeOH/H.sub.2O, 0.1% TFA) (25% B
start, 14 min gradient). The desired fractions were concentrated
and freeze-dried to afford
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7-triazatr-
icyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(19.6 mg, 33% yield) as a tan solid. MS(ESI) m/z: 592.4
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.33 (s,
1H), 8.18 (s, 1H), 7.87 (d, J=2.2 Hz, 1H), 7.80-7.71 (m, 2H),
7.68-7.55 (m, 3H), 7.54-7.50 (m, 1H), 7.33 (d, J=7.5 Hz, 1H), 6.42
(s, 1H), 5.83 (dd, J=12.8, 3.1 Hz, 1H), 2.56-2.45 (m, 1H),
2.38-2.29 (m, 1H), 2.18-2.06 (m, 1H), 1.94-1.82 (m, 1H), 1.67-1.52
(m, 2H), 1.22 (br. s., 1H), 1.15 (d, J=6.8 Hz, 3H). Analytical HPLC
(Method A) RT=8.44 min, 95% purity; Factor XIa Ki=0.1 nM, Plasma
Kallikrein Ki=6 nM.
Example 69
Preparation of
(10R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophen-
yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,8-diazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
trifluoroacetate
##STR00208##
[1455] To a solution of
6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]
pyrimidin-4-ol (4.42 mg, 0.014 mmol), prepared as described in
Intermediate 10, in CH.sub.3CN (0.2 ml) was added HATU (6.69 mg,
0.018 mmol) and DBU (3.06 .mu.l, 0.020 mmol). After 30 min,
(10R,14S)-14-amino-10-methyl-3,8-diazatricyclo[13.3.1.0.sup.2,7]
nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one (0.004 g, 0.014 mmol),
prepared as described in Intermediate 38, was added with DMF (0.2
ml). After 18 h, the reaction was diluted with DMF, filtered and
concentrated. The residue was purified by reverse phase HPLC using
PHENOMENEX.RTM. Luna 5U 30.times.100 mm (10:90 ACN/H.sub.2O to
90:10 ACN/H.sub.2O, 0.1% TFA) (20% B start, 14 min gradient) to
afford
(10R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophen-
yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,8-diazatricyclo[13.3.1.0.-
sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one trifluoroacetate
(2 mg, 20% yield) as a white solid. MS(ESI) m/z: 604.4 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.69-8.65 (m, 1H),
8.38-8.30 (m, 2H), 8.00-7.91 (m, 2H), 7.91-7.84 (m, 1H), 7.74 (d,
J=7.9 Hz, 1H), 7.69-7.63 (m, 2H), 7.55 (dd, J=8.6, 1.5 Hz, 1H),
7.36 (d, J=7.7 Hz, 1H), 6.64 (s, 1H), 5.83 (dd, J=12.9, 3.4 Hz,
1H), 2.55 (t, J=6.7 Hz, 1H), 2.40-2.29 (m, 1H), 2.21-2.10 (m, 1H),
1.89 (br. s., 1H), 1.65-1.51 (m, 2H), 1.33 (d, J=9.7 Hz, 1H), 1.15
(d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT=6.32 min.
Purity=100%; Factor XIa Ki=1.1 nM, Plasma Kallikrein Ki=54 nM.
Example 70
Preparation of
1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triaza-
tricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-
-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-1,2,3-triazole-4-carbonitri-
le
##STR00209##
[1457] To a solution of
1-[4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-
-4-carbonitrile (13.0 mg, 0.041 mmol), prepared as described in
Intermediate 12, in CH.sub.3CN (0.4 ml) was added HATU (0.020 g,
0.053 mmol) and DBU (9.28 .mu.l, 0.062 mmol). After 0.5 h,
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (14.0 mg,
0.041 mmol), prepared as described in Intermediate 35, was added
with DMF (0.2 ml). Additional CH.sub.3CN (0.2 ml) and DMF (0.2 ml)
were added to rinse the vials and dissolve reagents. After 18 h,
the reaction was diluted with DMF, filtered and concentrated. The
residue was purified by reverse phase HPLC using PHENOMENEX.RTM.
Luna 5U 30.times.100 mm (10:90 ACN/H.sub.2O to 90:10 ACN/H.sub.2O,
0.1% TFA) (20% B start, 14 min gradient) to afford
1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triaza-
tricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-
-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-1,2,3-triazole-4-carbonitri-
le (6 mg, 24.7% yield) as a white solid. MS(ESI) m/z: 643.3
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.96 (br.
s., 1H), 8.22 (br. s., 1H), 7.90 (d, J=6.8 Hz, 1H), 7.79 (br. s.,
2H), 7.71-7.55 (m, 4H), 7.39 (br. s., 1H), 6.71 (br. s., 1H), 5.84
(d, J=9.9 Hz, 1H), 2.52 (br. s., 1H), 2.37 (br. s., 1H), 2.19-2.01
(m, 1H), 2.01-1.87 (m, 1H), 1.59 (br. s., 2H), 1.23 (br. s., 1H),
1.17 (br. s., 3H). Analytical HPLC (Method A) rt=8.83 min,
purity=99%; Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=4 nM.
Example 71
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-tri-
azatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00210##
[1459] To a solution of
6-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}
pyrimidin-4-ol (0.014 g, 0.043 mmol), prepared as described in
Intermediate 16, in CH.sub.3CN (0.4 ml) was added HATU (0.021 g,
0.056 mmol) and DBU (9.78 .mu.l, 0.065 mmol). After 30 min,
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.14 g, 0.043
mmol), prepared as described in Intermediate 35, was added with DMF
(0.2 ml). Additional CH.sub.3CN (0.2 ml) and DMF (0.2 ml) were
added to rinse vials and dissolve reagents. After 18 h, the
reaction was diluted with DMF, filtered and concentrated. The
residue was purified by reverse phase HPLC using PHENOMENEX.RTM.
Luna 5U 30.times.100 mm (10:90 ACN/H.sub.2O to 90:10 ACN/H.sub.2O,
0.1% TFA) (20% B start, 14 min gradient) to afford
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-tri-
azatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(9.9 mg, 35.7%) as a white solid. MS(ESI) m/z: 641.5 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.53 (t, J=1.3 Hz, 1H),
8.19 (s, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.82-7.72 (m, 3H), 7.68 (s,
1H), 7.65-7.56 (m, 3H), 7.38 (d, J=7.5 Hz, 1H), 7.20-6.81 (m, 1H),
6.42 (d, J=0.7 Hz, 1H), 5.82 (dd, J=12.8, 3.3 Hz, 1H), 2.50 (ddd,
J=10.2, 6.9, 3.4 Hz, 1H), 2.35 (d, J=12.5 Hz, 1H), 2.19-2.08 (m,
1H), 1.97-1.86 (m, 1H), 1.65-1.52 (m, 2H), 1.27-1.20 (m, 1H), 1.16
(d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT=8.79 min,
purity=100%; Factor XIa Ki=0.17 nM, Plasma Kallikrein Ki=46 nM.
Example 72
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,-
7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-on-
e
##STR00211##
[1461] To a solution of
6-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}
pyrimidin-4-ol (0.014 g, 0.043 mmol), prepared as described in
Intermediate 16, in CH.sub.3CN (0.4 ml) was added HATU (0.021 g,
0.056 mmol) and DBU (9.78 .mu.l, 0.065 mmol). After 30 min,
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.13
g, 0.043 mmol) prepared as described in Intermediate 36, was added
with DMF (0.2 ml). Additional CH.sub.3CN (0.2 ml) and DMF (0.4 ml)
were added to dissolve reagents. After 18 h, the reaction was
diluted with DMF, filtered and concentrated. The residue was
purified by reverse phase HPLC using PHENOMENEX.RTM. Luna 5U
30.times.100 mm (10:90 ACN/H.sub.2O to 90:10 ACN/H.sub.2O, 0.1%
TFA) (20% B start, 14 min gradient) to afford
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,-
7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-on-
e (10.5 mg, 39%) as a white solid. MS(ESI) m/z: 608.3 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.52 (t, J=1.3 Hz, 1H),
8.14 (s, 1H), 7.93-7.87 (m, 1H), 7.75 (dd, J=8.5, 2.3 Hz, 2H),
7.72-7.66 (m, 1H), 7.64-7.54 (m, 2H), 7.54-7.50 (m, 1H), 7.35-7.30
(m, 1H), 7.14-6.83 (m, 1H), 6.43 (d, J=0.7 Hz, 1H), 5.83 (dd,
J=13.0, 3.3 Hz, 1H), 2.49 (dt, J=6.9, 3.4 Hz, 1H), 2.40-2.27 (m,
1H), 2.09 (d, J=12.3 Hz, 1H), 1.95-1.84 (m, 1H), 1.67-1.52 (m, 2H),
1.21 (d, J=6.8 Hz, 1H), 1.16 (d, J=6.8 Hz, 3H) Analytical HPLC
(Method A) RT=7.94 min, purity=99%; Factor XIa Ki=0.15 nM, Plasma
Kallikrein Ki=21 nM.
Example 73
Preparation of
1-(4-chloro-3-fluoro-2-{1-[(9R,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-ox-
o-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentae-
n-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbo-
nitrile
##STR00212##
[1463] To a solution of
1-[4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-
-4-carbonitrile (0.010 g, 0.032 mmol), prepared as described in
Intermediate 12, in CH.sub.3CN (0.4 ml) was added HATU (0.016 g,
0.041 mmol) and DBU (7.14 .mu.l, 0.047 mmol). After 30 min,
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7-triazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.095 g,
0.032 mmol), prepared as described in Intermediate 36, was added
with DMF (0.2 ml). Additional CH.sub.3CN (0.2 ml) and DMF (0.2 ml)
were added to dissolve reagents. After 18 h, the reaction was
diluted with DMF, filtered and concentrated. The residue was
purified by reverse phase HPLC using PHENOMENEX.RTM. Luna 5U
30.times.100 mm (10:90 ACN/H.sub.2O to 90:10 ACN/H.sub.2O, 0.1%
TFA) (20% B start, 14 min gradient) to afford
1-(4-chloro-3-fluoro-2-{1-[(9R,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-ox-
o-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitrile (4.7
mg, 24%) as a white solid. MS(ESI) m/z: 601.3 (M+H).sup.+. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.94 (s, 1H), 8.16 (s, 1H), 7.90
(dd, J=8.7, 7.6 Hz, 1H), 7.77 (s, 1H), 7.70-7.56 (m, 3H), 7.56-7.49
(m, 1H), 7.32 (d, J=7.7 Hz, 1H), 6.79-6.66 (m, 1H), 5.85 (dd,
J=12.7, 3.2 Hz, 1H), 2.50 (ddd, J=10.2, 6.7, 3.5 Hz, 1H), 2.39-2.30
(m, 1H), 2.20-2.06 (m, 1H), 1.90 (dd, J=9.6, 4.5 Hz, 1H), 1.69-1.53
(m, 2H), 1.28-1.22 (m, 1H), 1.16 (d, J=6.8 Hz, 3H). Analytical HPLC
(Method A) RT=7.99 min, purity=97%; Factor XIa Ki=0.15 nM, Plasma
Kallikrein Ki=9 nM.
Example 74
Preparation of
1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triaza-
tricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-
-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitrile
##STR00213##
[1465] To a solution of
1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbon-
itrile (0.016 g, 0.054 mmol), prepared as described in Intermediate
18, in CH.sub.3CN (0.4 ml) was added HATU (0.026 g, 0.070 mmol) and
DBU (0.012 mL, 0.080 mmol). After 30 min,
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.018 g,
0.054 mmol), prepared as described in Intermediate 35, was added
with DMF (0.5 ml). After 18 h, the reaction was diluted with DMF,
filtered and concentrated. The residue was purified by reverse
phase HPLC using PHENOMENEX.RTM. Luna 5U 30.times.100 mm (10:90
ACN/H.sub.2O to 90:10 ACN/H.sub.2O, 0.1% TFA) (20% B start, 14 min
gradient) to afford
1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triaza-
tricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-y-
l}phenyl)-1H-1,2,3-triazole-4-carbonitrile (11.7 mg, 34%) as a
white solid. MS(ESI) m/z: 616.2 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.96 (s, 1H), 8.19 (s, 1H), 7.94-7.89 (m, 1H),
7.84-7.74 (m, 4H), 7.72-7.66 (m, 1H), 7.66-7.61 (m, 1H), 7.60-7.55
(m, 1H), 7.40 (d, J=7.5 Hz, 1H), 6.52 (s, 1H), 5.83 (dd, J=12.9,
3.4 Hz, 1H), 2.50 (td, J=6.6, 3.7 Hz, 1H), 2.42-2.31 (m, 1H),
2.17-2.07 (m, 1H), 1.90 (dd, J=10.0, 4.7 Hz, 1H), 1.63-1.53 (m,
2H), 1.28-1.20 (m, 1H), 1.16 (d, J=6.8 Hz, 3H). Analytical HPLC
(Method A) RT=8.82, purity=97%; Factor XIa Ki=0.1 nM, Plasma
Kallikrein Ki=10 nM.
Example 75
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-tr-
iazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00214##
[1467] To a solution of
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}
pyrimidin-4-ol (0.029 g, 0.084 mmol), prepared as described in
Intermediate 15, in CH.sub.3CN (0.8 ml) was added HATU (0.041 g,
0.109 mmol) and DBU (0.019 mL, 0.126 mmol). After 30 min,
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.028 g,
0.084 mmol), prepared as described in Example 35, was added with
DMF (0.4 ml). The reaction was stirred 4 h then was diluted with
DMF, filtered and concentrated. The residue was purified by reverse
phase HPLC using PHENOMENEX.RTM. Luna 5U 30.times.100 mm (10:90
ACN/H.sub.2O to 90:10 ACN/H.sub.2O, 0.1% TFA) (20% B start, 14 min
gradient) to afford
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-tr-
iazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one (18.8 mg, 34%) as a white
solid. MS(ESI) m/z: 659.03 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.81 (d, J=0.7 Hz, 1H), 8.18 (s, 1H), 7.89 (d,
J=2.4 Hz, 1H), 7.82-7.74 (m, 3H), 7.70 (s, 1H), 7.64-7.56 (m, 3H),
7.42-7.36 (m, 1H), 6.49 (d, J=0.7 Hz, 1H), 5.83 (dd, J=12.9, 3.2
Hz, 1H), 2.50 (ddd, J=10.2, 6.8, 3.4 Hz, 1H), 2.35 (d, J=12.3 Hz,
1H), 2.15-2.06 (m, 1H), 1.94-1.85 (m, 1H), 1.65-1.51 (m, 2H),
1.31-1.20 (m, 1H), 1.16 (d, J=6.8 Hz, 3H). Analytical HPLC (Method
A) RT=9.40 min, purity=100%; Factor XIa Ki=0.1 nM, Plasma
Kallikrein Ki=15 nM.
Example 76
Preparation of
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8-diazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
##STR00215##
[1469] To a solution of
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}
pyrimidin-4-ol (0.035 g, 0.102 mmol), prepared as described in
Intermediate 15, in CH.sub.3CN (0.4 ml) was added HATU (0.050 g,
0.132 mmol) and DBU (0.023 mL, 0.152 mmol). After 30 min,
(10R,14S)-14-amino-10-methyl-3,8-diazatricyclo[13.3.1.0.sup.2,7]
nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one (0.030 g, 0.102 mmol),
prepared as described in Intermediate 38, was added with DMF (0.6
ml). After 18 h, the reaction was diluted with DMF, filtered and
concentrated. The residue was purified by preparative LCMS using
(5:95 ACN/H.sub.2O to 95:5 ACN/H.sub.2O, 0.1% TFA) to afford
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8-diazatricyclo[13.3.1.-
0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one (8.6 mg,
11.1%). MS(ESI) m/z: 620.08 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.81-8.72 (m, 1H), 8.59 (d, J=4.3 Hz, 1H), 8.16
(s, 1H), 7.88-7.83 (m, 2H), 7.78-7.65 (m, 4H), 7.58-7.53 (m, 1H),
7.53-7.48 (m, 1H), 7.28 (d, J=7.6 Hz, 1H), 6.43 (s, 1H), 5.88-5.72
(m, 1H), 2.49 (br. s., 1H), 2.27 (d, J=10.4 Hz, 1H), 2.10 (d,
J=10.1 Hz, 1H), 1.85 (d, J=8.9 Hz, 1H), 1.55 (d, J=9.8 Hz, 2H),
1.28 (br. s., 1H), 1.13 (d, J=6.7 Hz, 3H). Analytical HPLC (Method
C) RT=1.55 min, purity=97%; Factor XIa Ki=1.7 nM, Plasma Kallikrein
Ki=130 nM.
Example 77
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0-
.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00216##
[1471] To a solution of
6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol
(0.019 g, 0.060 mmol), prepared as described in Intermediate 9, in
CH.sub.3CN (0.4 ml) was added HATU (0.030 g, 0.078 mmol) and DBU
(0.014 mL, 0.090 mmol). After 30 min,
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one, prepared as described
in Intermediate 42, was added with DMF (0.2 ml). After 18 h, the
reaction was diluted with DMF, filtered and concentrated. The
residue was purified by reverse phase HPLC using PHENOMENEX.RTM.
Luna 5U 30.times.100 mm (10:90 ACN/H.sub.2O to 90:10 ACN/H.sub.2O,
0.1% TFA) (20% B start, 14 min gradient) to afford
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,17-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (11.9
mg, 27%) as an off-white solid. MS(ESI) m/z: 590.3 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. d 8.78-8.70 (m, 1H),
8.41-8.33 (m, 2H), 7.92-7.85 (m, 2H), 7.80-7.73 (m, 1H), 7.71-7.65
(m, 1H), 7.51 (s, 1H), 7.21 (dd, J=5.3, 1.8 Hz, 1H), 6.50-6.42 (m,
1H), 5.77 (dd, J=12.5, 3.1 Hz, 1H), 4.23-4.16 (m, 3H), 2.69-2.58
(m, 1H), 2.41 (dd, J=7.5, 4.2 Hz, 1H), 2.22-2.09 (m, 1H), 2.07-1.96
(m, 1H), 1.74-1.60 (m, 1H), 1.38 (d, J=7.7 Hz, 2H), 1.15 (d, J=7.0
Hz, 3H). Analytical HPLC (Method A) RT=7.38 min, purity=96%; Factor
XIa Ki=0.2 nM, Plasma Kallikrein Ki=23 nM.
Example 78
Preparation of
(9R,13S)-13-{4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-oxo-1-
,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7-triazatri-
cyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00217##
[1473] To
6-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]pyrimidin-4--
ol (0.05 g, 0.142 mmol) and HATU (0.070 g, 0.184 mmol) in a small
vial was added DBU (0.032 mL, 0.213 mmol) in CH.sub.3CN (0.8 ml).
After 30 min,
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7-triazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.043 g,
0.142 mmol), prepared as described in Intermediate 36, was added
and the vial was rinsed with DMF (0.2 ml). After 18 h, the reaction
was diluted with DMF, filtered and purified by reverse phase HPLC
using PHENOMENEX.RTM. Luna 5U 30.times.100 mm (10:90 MeOH/H.sub.2O
to 90:10 MeOH/H.sub.2O, 0.1% TFA) (20% B start, 14 min gradient) to
afford
(9R,13S)-13-{4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-oxo-1-
,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7-triazatri-
cyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(30 mg, 33%) as a white solid. This compound was used in subsequent
reaction and a small amount (4 mg, white solid after freeze-drying)
was isolated by preparative LCMS using (5:95 AcN/H.sub.2O to 95:5
AcN/H.sub.2O, 10 mM NH.sub.4OAc). MS(ESI) m/z: 638.4 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.25 (s, 1H), 8.06 (s,
1H), 7.75 (d, J=2.4 Hz, 1H), 7.68-7.59 (m, 2H), 7.56-7.43 (m, 3H),
7.40-7.36 (m, 1H), 7.21 (d, J=7.5 Hz, 1H), 6.30 (s, 1H), 5.71 (dd,
J=12.7, 3.2 Hz, 1H), 2.43-2.32 (m, 1H), 2.28-2.18 (m, 1H), 1.98 (d,
J=12.3 Hz, 1H), 1.84-1.73 (m, 1H), 1.56-1.41 (m, 2H), 1.10 (br. s.,
1H), 1.03 (d, J=6.8 Hz, 3H). Analytical HPLC (Method C) RT=1.60
min, purity=96%; Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=7
nM.
Example 79
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(pyrimidin-2-yl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,-
7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-on-
e
##STR00218##
[1475]
(9R,13S)-13-{4-[2-(4-Bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-
-oxo-1,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7-tri-
azatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
0.014 g, 0.022 mmol), prepared as described in Example 78,
pyrimidin-2-ylboronic acid (2.59 mg, 0.021 mmol), and 2.0 M aq
Na.sub.2CO.sub.3 (0.033 mL, 0.066 mmol) were added to dioxane (0.6
ml) and the resulting solution was purged with a stream of Ar.
Pd(PPh.sub.3).sub.4 (1.270 mg, 1.099 .mu.mol) was then added and
the mixture was heated to 120.degree. C. in a microwave for 30 min.
The reaction was concentrated and the residue was diluted with DMF,
filtered and reconcentrated. The residue was purified by
preparative LCMS using (5:95 ACN/H.sub.2O to 95:5 ACN/H.sub.2O, 10
mM NH.sub.4OAc) to give
(9R,13S)-13-(4-{5-chloro-2-[4-(pyrimidin-2-yl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,-
7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-on-
e (2.5 mg, 25%). MS(ESI) m/z: 636.08 (M+H).sup.+. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 9.16-9.11 (m, 2H), 9.06 (s, 1H), 8.75-8.65
(m, 1H), 8.02 (s, 1H), 7.85-7.77 (m, 1H), 7.71-7.63 (m, 1H),
7.63-7.58 (m, 2H), 7.45-7.35 (m, 3H), 7.16 (s, 1H), 6.37-6.30 (m,
1H), 5.69 (d, J=9.2 Hz, 1H), 2.35 (s, 1H), 2.18 (d, J=9.9 Hz, 1H),
1.95 (d, J=7.9 Hz, 1H), 1.73 (s, 1H), 1.44 (d, J=9.5 Hz, 2H), 1.19
(m, 1H), 1.02 (d, J=6.8 Hz, 3H). Analytical HPLC (Method C) RT=1.43
min, purity=95%; Factor XIa Ki=1.0 nM, Plasma Kallikrein Ki=150
nM.
Example 80
Preparation of
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4,10-dimethyl-3,8-diazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
##STR00219##
[1476] 80A. Preparation of tert-butyl
N-[(1S)-1-[3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)
phenyl]but-3-en-1-yl]carbamate
[1477] To a RBF was added tert-butyl
N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl] carbamate (2.6 g, 7.97
mmol), 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane (1.980 g,
8.77 mmol), and KOAc (2.347 g, 23.91 mmol) in dioxane (35 ml). The
mixture was purged with Ar for 10 min, then PdCl.sub.2(dppf)-DCM
adduct (0.325 g, 0.398 mmol) was added and the reaction was stirred
at 90.degree. C. for 4 h. The reaction was partitioned between
EtOAc (50 ml) and water (40 ml). The organic layer was separated,
washed with water (15 ml), brine (30 ml), dried over MgSO.sub.4,
filtered and concentrated. The residue was purified by normal phase
chromatography using hexanes and EtOAc as eluents to afford
tert-butyl
N-[(1S)-1-[3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]but-3-en-1-yl]c-
arbamate (2.62 g, 92%) as a white solid. MS(ESI) m/z: 292.08
(M+H).sup.+.
80B. Preparation of tert-butyl
N-[(1S)-1-[3-(3-amino-6-methylpyridin-2-yl)phenyl]but-3-en-1-yl]carbamate
[1478] tert-Butyl
N-[(1S)-1-[3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]but-3-en-1-yl]c-
arbamate (0.67 g, 1.865 mmol), 2-bromo-6-methylpyridin-3-amine
(0.349 g, 1.865 mmol), and 2 M aq Na.sub.2CO.sub.3 (4 mL, 8.00
mmol) were added to dioxane (9 ml) and the solution was purged with
a stream of Ar for 10 min. Pd(PPh.sub.3).sub.4 (0.108 g, 0.093
mmol) was added and the mixture was irradiated in a microwave at
120.degree. C. for 30 min. The reaction was quenched with water (20
ml) and extracted with EtOAc (3.times.30 ml). The combined organic
layers were washed with brine (15 ml), dried (MgSO.sub.4), filtered
and concentrated. The residue was purified by normal phase
chromatography using DCM and 0-10% MeOH as eluents to afford
tert-butyl
N-[(1S)-1-[3-(3-amino-6-methylpyridin-2-yl)phenyl]but-3-en-1-yl]carbamate
(0.94 g, 100%, 70% purity) as a brown oil. MS(ESI) m/z: 354.5
(M+H).sup.+.
80C. Preparation of tert-butyl
N-[(1S)-1-(3-{6-methyl-3-[(2R)-2-methylbut-3-enamido]
pyridin-2-yl}phenyl)but-3-en-1-yl]carbamate
[1479] To a solution of tert-butyl
N-[(1S)-1-[3-(3-amino-6-methylpyridin-2-yl)phenyl]
but-3-en-1-yl]carbamate (0.65 g, 1.83 mmol) in EtOAc (0.58 ml), was
added (R)-2-methylbut-3-enoic acid (0.239 g, 2.391 mmol), prepared
as described in Intermediate 2, in 0.3 ml EtOAc. The resulting
solution was cooled to 0.degree. C. and pyridine (0.446 ml, 5.52
mmol) and a 50% EtOAc solution of T3P.RTM. (2.189 ml, 3.68 mmol)
were added. After 3 h, the reaction was quenched with sat
NaHCO.sub.3 (15 ml) and extracted with EtOAc (3.times.20 ml). The
combined organic layers were washed with brine (15 ml) and dried
(MgSO.sub.4). The mixture was filtered and concentrated and the
residue was purified by normal phase chromatography using DCM and
0-10% MeOH as eluents to afford tert-butyl
N-[(1S)-1-(3-{6-Methyl-3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)-
but-3-en-1-yl] carbamate (0.65 g, 82%) as a tan foam. MS(ESI) m/z:
436.08 (M+H).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.56
(d, J=8.5 Hz, 1H), 7.54-7.46 (m, 2H), 7.42 (s, 1H), 7.37 (d, J=1.4
Hz, 2H), 7.17 (d, J=8.5 Hz, 1H), 5.90-5.67 (m, 2H), 5.22-5.03 (m,
4H), 5.00-4.75 (m, 3H), 3.05 (t, J=7.3 Hz, 1H), 2.62 (br. s. and m,
4H), 1.50-1.39 (m, 9H), 1.28 (d, J=7.2 Hz, 3H).
80D. Preparation of tert-butyl
N-[(10R,11E,14S)-4,10-dimethyl-9-oxo-3,8-diazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamat-
e
[1480] To a solution of tert-butyl
N-[(1S)-1-(3-{6-methyl-3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)-
but-3-en-1-yl]carbamate (0.2 g, 0.459 mmol) in degassed DCE (20 ml)
was added Second Generation Grubbs Catalyst (0.156 g, 0.184 mmol)
and the resulting reaction mixture was heated to 120.degree. C. for
30 min in a microwave. The reaction mixture was directly purified
by normal phase chromatography using DCM and 0-10% MeOH as eluents
to afford tert-butyl
N-[(10R,11E,14S)-4,10-dimethyl-9-oxo-3,8-diazatricyclo[13.3.1.0.sup.2,7]n-
onadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate (0.19 g,
100%) as a dark solid. MS(ESI) m/z: 408.08 (M+H).sup.+.
80E. Preparation of
(10R,14S)-14-amino-4,10-dimethyl-3,8-diazatricyclo[13.3.1.0.sup.2,7]
nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
##STR00220##
[1482] tert-Butyl
N-[(10R,11E,14S)-4,10-dimethyl-9-oxo-3,8-diazatricyclo[13.3.1.0.sup.2,7]
nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate (0.187 g,
0.459 mmol) was hydrogenated in EtOH (3 ml) in the presence of
PtO.sub.2 at 20-30 psi. After 4 h, the reaction mixture was
filtered through CELITE.RTM. and concentrated to afford a dark
solid (MS(ESI) m/z: 410.3 (M+H).sup.+) which was then deprotected
with 4 N HCl in dioxane (2 ml) and MeOH (2 ml). The resultant HCl
salt was dissolved in DCM/MeOH and passed through a basic cartridge
to afford (0.16 g, 118%) of a crude dark solid containing as the
major component,
(10R,14S)-14-amino-4,10-dimethyl-3,8-diazatricyclo[13.3.1.0.sup.2,7]nonad-
eca-1(19),2(7),3,5,15,17-hexaen-9-one, which was used in next step
without purification. MS(ESI) m/z: 310.3 (M+H).sup.+.
80F. Preparation of
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4,10-dimethyl-3,8-diazatricyclo[13.-
3.1.0.sup.2,7] nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
##STR00221##
[1484] To
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-
pyrimidin-4-ol (0.033 g, 0.097 mmol), prepared as described in
Intermediate 15, and HATU (0.048 g, 0.126 mmol) in a small vial was
added DBU (0.022 mL, 0.145 mmol) in ACN (0.4 ml). After 30 min,
(10R,14S)-14-amino-4,10-dimethyl-3,8-diazatricyclo[13.3.1.0.sup.2,7]nonad-
eca-1(19),2(7),3,5,15,17-hexaen-9-one (0.033 g, 0.097 mmol) was
added with DMF (0.2 ml). The reaction was stirred for 18 h. The
reaction was diluted with DMF, filtered and purified by preparative
LCMS using (5:95 ACN/H.sub.2O to 95:5 ACN/H.sub.2O, 10 mM
NH.sub.4OAc) to afford
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4,10-dimethyl-3,8-diazatricyclo[13.-
3.1.0.sup.2,7] nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one (5.8 mg,
7.7% yield) as a white solid. MS(ESI) m/z: 634.4 (M+H).sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.75 (s, 1H), 8.12 (s,
1H), 7.86-7.82 (m, 2H), 7.77-7.64 (m, 3H), 7.62-7.54 (m, 2H), 7.34
(d, J=8.2 Hz, 1H), 7.29 (d, J=7.9 Hz, 1H), 6.43 (s, 1H), 5.86-5.73
(m, 1H), 2.61 (s, 3H), 2.45 (br. s., 1H), 2.26 (d, J=9.5 Hz, 1H),
2.11 (br. s., 1H), 1.82 (br. s., 1H), 1.64-1.49 (m, 2H), 1.28-1.21
(m, 1H), 1.13 (d, J=6.7 Hz, 3H). Analytical HPLC (Method C) RT=1.54
min, purity=97%; Factor XIa Ki=2.2 nM, Plasma Kallikrein Ki=260
nM.
Example 81
Preparation of
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-5-methoxy-10-methyl-3,8-diazatri-
cyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
##STR00222##
[1485] 81A. Preparation of tert-butyl
N-[(1S)-1-[3-(3-amino-5-methoxypyridin-2-yl)phenyl]but-3-en-1-yl]carbamat-
e
[1486] tert-Butyl
N-[(1S)-1-[3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]but-3-en-1-yl]c-
arbamate (0.348 g, 0.969 mmol), 2-bromo-5-methoxypyridin-3-amine
(0.197 g, 0.969 mmol), and 2.0 M aq Na.sub.2CO.sub.3 (2.422 mL,
4.84 mmol) were added to dioxane (8 ml) and the solution was purged
with a stream of Ar for 10 min. Pd(PPh.sub.3).sub.4 (0.056 g, 0.048
mmol) was added and the mixture irradiated in microwave at
120.degree. C. for 30 min. The reaction was quenched with water (20
ml) and extracted with EtOAc (3.times.30 ml). The combined organic
layers were washed with brine (15 ml), dried (MgSO.sub.4), filtered
and concentrated. The residue was purified by normal phase
chromatography using DCM and 0-10% MeOH as eluents to afford
tert-butyl N-[(1S)-1-[3-(3-amino-5-methoxypyridin-2-yl)
phenyl]but-3-en-1-yl]carbamate (0.391 g, 100%) as a tan foam.
MS(ESI) m/z: 370.08 (M+H).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.89 (d, J=2.5 Hz, 1H), 7.60-7.52 (m, 2H), 7.45 (t, J=7.6
Hz, 1H), 7.33-7.29 (m, 1H), 6.62 (d, J=2.5 Hz, 1H), 5.73 (ddt,
J=17.1, 10.1, 7.0 Hz, 1H), 5.21-5.06 (m, 2H), 4.93 (br. s., 1H),
4.81 (br. s., 1H), 3.92-3.86 (m, 4H), 3.77-3.71 (m, 1H), 2.64-2.52
(m, 2H), 1.44 (br. s., 9H).
81B. Preparation of tert-butyl
N-[(1S)-1-(3-{5-methoxy-3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl-
)but-3-en-1-yl]carbamate
[1487] To tert-butyl
N-[(1S)-1-[3-(3-amino-5-methoxypyridin-2-yl)phenyl]but-3-en-1-yl]carbamat-
e (0.358 g, 0.972 mmol) was added (R)-2-methylbut-3-enoic acid
(0.126 g, 1.263 mmol), prepared as described in Intermediate 2, in
EtOAc (3 ml). The resulting solution was cooled to 0.degree. C.
Pyridine (0.236 ml, 2.91 mmol) and a 50% EtOAc solution of T3P.RTM.
(1.157 ml, 1.943 mmol) were added. The reaction was partitioned
between sat NaHCO.sub.3 (10 ml) and EtOAc (20 ml). The aqueous
layer was extracted with EtOAc (2.times.20 ml). The combined
organic layers were washed with brine (25 ml), dried (MgSO.sub.4),
filtered and concentrated. The residue was purified by normal phase
chromatography using heptanes and EtOAc as eluents to afford
tert-butyl
N-[(1S)-1-(3-{5-methoxy-3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl-
)but-3-en-1-yl]carbamate (0.347 g, 79%) as a white foam. MS(ESI)
m/z: 452.08 (M+H).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
8.47 (d, J=2.8 Hz, 1H), 8.16 (d, J=2.8 Hz, 1H), 7.65 (br. s., 1H),
7.53-7.46 (m, 1H), 7.46-7.41 (m, 1H), 7.37 (dt, J=7.5, 1.9 Hz, 2H),
5.86-5.65 (m, 2H), 5.19-5.07 (m, 4H), 4.93 (br. s., 1H), 4.82 (br.
s., 1H), 3.93 (s, 3H), 3.07 (quin, J=7.3 Hz, 1H), 2.62-2.51 (m,
2H), 1.50-1.41 (m, 9H), 1.32-1.29 (m, 3H).
81C. Preparation of tert-butyl
N-[(10R,11E,14S)-5-methoxy-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0.sup-
.2,7]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate
[1488] A solution of tert-butyl
N-[(1S)-1-(3-{5-methoxy-3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl-
)but-3-en-1-yl]carbamate (0.189 g, 0.419 mmol) in degassed DCE (20
ml) in the presence of Second Generation Grubbs Catalyst (0.107 g,
0.126 mmol) was heated to 120.degree. C. for 30 min in a microwave.
The reaction mixture was directly purified by normal phase
chromatography using DCM and 0-10% MeOH as eluents to afford
tert-butyl
N-[(10R,11E,14S)-5-methoxy-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0.sup-
.2,7]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate (0.17
g, 96%) as a dark brown oil. MS(ESI) m/z: 424.1 (M+H).sup.+.
81D. Preparation of
(10R,14S)-14-amino-5-methoxy-10-methyl-3,8-diazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
##STR00223##
[1490] tert-Butyl
N-[(10R,11E,14S)-5-methoxy-10-methyl-9-oxo-3,8-diazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamat-
e (0.177 g, 0.418 mmol) was hydrogenated in EtOH (3 ml) in the
presence of PtO.sub.2 (20 mg) over 8 h. The resultant thick sludge
was filtered through CELITE.RTM. and rinsed with DCM, MeOH and EtOH
to afford 0.121 g of a dark solid. MS(ESI) m/z: 426.4 (M+H).sup.+.
Deprotection was performed with 4 N HCl in dioxane (2 ml) in MeOH
(4 ml) over 3 h. The reaction mixture was concentrated and the
residue was taken up in DCM/MeOH and filtered through a basic
cartridge to give
(10R,14S)-14-amino-5-methoxy-10-methyl-3,8-diazatricyclo[13.3.1.0.sup.2,7-
]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one as a dark solid (0.108
g, 79%). MS(ESI) m/z: 326.4 (M+H).sup.+.
81E. Preparation of
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-5-methoxy-10-methyl-3,8-diazatricyc-
lo [13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
##STR00224##
[1492] To
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-
pyrimidin-4-ol (0.032 g, 0.092 mmol), prepared as described in
Intermediate 15, and HATU (0.046 g, 0.120 mmol) in a small vial was
added DBU (0.021 mL, 0.138 mmol) in ACN (0.4 ml). After 30 min,
(10R,14S)-14-amino-5-methoxy-10-methyl-3,8-diazatricyclo[13.3.1.0.sup.2,7-
] nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one (0.030 g, 0.092 mmol)
was added with DMF (0.4 ml). After 18 h, the reaction was diluted
with DMF, filtered and concentrated. The residue was purified twice
by reverse phase HPLC using PHENOMENEX.RTM. Luna 5U 30.times.100 mm
(10:90 ACN/H.sub.2O to 90:10 ACN/H.sub.2O, 0.1% TFA) (20% B start,
14 min gradient) to afford
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-5-methoxy-10-methyl-3,8-diazatricyc-
lo [13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
(3.7 mg, 4.8%) as a white solid. MS(ESI) m/z: 650.3 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.82 (d, J=0.7 Hz, 1H),
8.39 (d, J=2.6 Hz, 1H), 8.25 (s, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.86
(s, 1H), 7.80-7.74 (m, 1H), 7.71-7.63 (m, 2H), 7.62-7.55 (m, 2H),
7.29 (d, J=7.9 Hz, 1H), 6.47 (d, J=0.7 Hz, 1H), 5.81 (dd, J=13.0,
3.5 Hz, 1H), 4.03-4.01 (m, 3H), 2.60-2.49 (m, 1H), 2.34-2.26 (m,
1H), 2.18-2.08 (m, 1H), 1.94-1.85 (m, 1H), 1.62-1.46 (m, 2H), 1.33
(d, J=9.7 Hz, 1H), 1.15 (d, J=6.8 Hz, 3H). Analytical HPLC (Method
A) RT=8.44, purity=93%; Factor XIa Ki=22 nM, Plasma Kallikrein
Ki=950 nM.
Example 82
Preparation of
(10R,14S)-5-chloro-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazo-
l-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8-diazatricycl-
o[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
##STR00225##
[1493] 82A. Preparation of tert-butyl
N-[(1S)-1-[3-(3-amino-5-chloropyridin-2-yl)phenyl]but-3-en-1-yl]carbamate
[1494] tert-Butyl
N-[(1S)-1-[3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]but-3-en-1-yl]c-
arbamate (0.339 g, 0.944 mmol), 2-bromo-5-chloropyridin-3-amine
(0.196 g, 0.944 mmol), and 2.0 M aq Na.sub.2CO.sub.3 (2.36 mL, 4.72
mmol) were added to dioxane (8 ml) and the resulting solution was
purged with a stream of Ar for 10 min. Pd(PPh.sub.3).sub.4 (0.055
g, 0.047 mmol) was added and the mixture irradiated on microwave at
120.degree. C. for 30 min. The reaction was quenched with water (20
ml) and extracted with EtOAc (3.times.30 ml). The combined organic
layers were washed with brine (15 ml), dried (Na.sub.2SO.sub.4),
filtered and concentrated. The residue was purified by normal phase
chromatography using DCM and 0-10% MeOH as eluents to afford
tert-butyl N-[(1S)-1-[3-(3-amino-5-chloropyridin-2-yl)
phenyl]but-3-en-1-yl]carbamate (0.375 g, 106%) as a tan foam.
MS(ESI) m/z: 374.3 (M+H).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 8.08 (d, J=2.2 Hz, 1H), 7.60-7.52 (m, 2H), 7.48-7.43 (m,
1H), 7.34 (d, J=7.7 Hz, 1H), 7.07 (d, J=1.9 Hz, 1H), 5.72 (ddt,
J=17.1, 10.1, 7.0 Hz, 1H), 5.21-5.09 (m, 2H), 4.93 (br. s., 1H),
4.81 (br. s., 1H), 3.94 (br. s., 2H), 2.63-2.51 (m, 2H), 1.43 (br.
s., 9H).
82B. Preparation of tert-butyl
N-[(1S)-1-(3-{5-chloro-3-[(2R)-2-methylbut-3-enamido]
pyridin-2-yl}phenyl)but-3-en-1-yl]carbamate
[1495] To tert-butyl
N-[(1S)-1-[3-(3-amino-5-chloropyridin-2-yl)phenyl]but-3-en-1-yl]carbamate
(0.358 g, 0.958 mmol) was added (R)-2-methylbut-3-enoic acid (0.125
g, 1.245 mmol), prepared as described in Intermediate 2, in 3 ml
EtOAc, and the resulting solution was cooled to 0.degree. C.
Pyridine (0.232 ml, 2.87 mmol) and a 50% EtOAc solution of T3P.RTM.
(1.140 ml, 1.915 mmol) were then added. After 4 h, the reaction was
partitioned with sat NaHCO.sub.3 (10 ml) and EtOAc (10 ml). The
aqueous layer was extracted with EtOAc (2.times.20 ml). The
combined organic layers were washed with brine (10 ml), dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue was
purified by normal phase chromatography using heptanes and EtOAc as
eluents to give tert-butyl
N-[(1S)-1-(3-{5-chloro-3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)-
but-3-en-1-yl]carbamate (0.31 g, 71%) as a white foam. MS(ESI) m/z:
456.08 (M+H).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.88
(d, J=2.2 Hz, 1H), 8.38 (d, J=2.2 Hz, 1H), 7.65 (br. s., 1H),
7.56-7.49 (m, 1H), 7.45-7.40 (m, 2H), 7.39-7.33 (m, 1H), 5.82-5.66
(m, 2H), 5.21-5.11 (m, 2H), 5.11-5.06 (m, 2H), 4.93 (br. s., 1H),
4.82 (br. s., 1H), 3.08 (quin, J=7.2 Hz, 1H), 2.64-2.50 (m, 2H),
1.46-1.41 (m, 9H), 1.30 (d, J=7.2 Hz, 3H).
82C. Preparation of tert-butyl
N-[(10R,11E,14S)-5-chloro-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0.sup.-
2,7]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate
[1496] A solution of Second Generation Grubbs Catalyst (0.107 g,
0.126 mmol) and tert-butyl
N-[(1S)-1-(3-{5-chloro-3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)-
but-3-en-1-yl]carbamate (0.191 g, 0.419 mmol) in degassed DCE (20
ml) was heated to 120.degree. C. for 30 min in a microwave. The
reaction mixture was concentrated and the crude material was
directly purified by normal phase chromatography using DCM and
0-10% MeOH as eluents to afford tert-butyl
N-[(10R,11E,145)-5-chloro-10-methyl-9-oxo-3,8-diazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamat-
e (0.17 g, 95%) as a dark brown oil. MS(ESI) m/z: 428.2
(M+H).sup.+.
82D. Preparation of
(10R,14S)-14-amino-5-chloro-10-methyl-3,8-diazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
##STR00226##
[1498] tert-Butyl
N-[(10R,11E,14S)-5-chloro-10-methyl-9-oxo-3,8-diazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamat-
e (0.17 g, 0.397 mmol) was hydrogenated in EtOH (3 ml) in the
presence of PtO.sub.2 (20 mg) for 8 h. MS(ESI) m/z: 430.3
(M+H).sup.+. The thick sludge was filtered through CELITE.RTM. and
rinsed with DCM/MeOH/EtOH to afford 0.169 g of a dark solid.
Deprotection was carried out with 4 N HCl in dioxane (2 ml) and
MeOH (2 ml) over 4 h. After this time the solution was concentrated
and the residue was taken up in DCM/MeOH and passed through a basic
cartridge to give
(10R,14S)-14-amino-5-chloro-10-methyl-3,8-diazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one as a
crude product (0.159 g, 121%) that was used `as is`. MS(ESI) m/z:
330.08 (M+H).sup.+.
82E. Preparation of
(10R,14S)-5-chloro-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazo-
l-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8-diazatricycl-
o[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
##STR00227##
[1500] To HATU (0.045 g, 0.118 mmol) and
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol (0.031 g, 0.091 mmol), prepared as described in Intermediate
15, in a small vial was added DBU (0.021 mL, 0.136 mmol) in
CH.sub.3CN (0.4 ml). After 30 min, tert-butyl
N-[(10R,11E,14S)-5-chloro-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0.sup.-
2,7]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate (0.030
g, 0.091 mmol) was added with DMF (0.4 ml). After 18 h, the
reaction was diluted with DMF, filtered and concentrated The
residue was purified twice by reverse phase HPLC using
PHENOMENEX.RTM. Luna 5U 30.times.100 mm (10:90 ACN/H.sub.2O to
90:10 ACN/H.sub.2O, 0.1% TFA) (20% B start, 14 min gradient) to
afford
(10R,14S)-5-chloro-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazo-
l-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8-diazatricycl-
o[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one (3.0
mg, 4.2% yield) as a tan solid. MS(ESI) m/z: 654.3 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.81 (d, J=0.7 Hz, 1H),
8.67-8.62 (m, 1H), 8.23 (s, 1H), 7.93-7.84 (m, 3H), 7.79-7.67 (m,
3H), 7.63-7.54 (m, 1H), 7.29 (d, J=7.9 Hz, 1H), 6.47 (d, J=0.9 Hz,
1H), 5.82 (dd, J=12.9, 3.6 Hz, 1H), 2.58-2.48 (m, 1H), 2.40-2.24
(m, 1H), 2.11 (d, J=9.7 Hz, 1H), 1.99-1.87 (m, 1H), 1.55 (d, J=9.0
Hz, 2H), 1.33 (d, J=9.7 Hz, 1H), 1.15 (d, J=6.8 Hz, 3H). Analytical
HPLC (Method A) RT=9.88 min, purity=98%; Factor XIa Ki=3.5 nM,
Plasma Kallikrein Ki=240 nM.
Example 83
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,16-tetraazatricyclo[12.3.1.0-
.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00228##
[1501] 83A. Preparation of tert-butyl
N-[(1S)-1-[5-(1-methyl-4-nitro-1H-pyrazol-5-yl)
pyridin-3-yl]but-3-en-1-yl]carbamate
[1502] To a solution of tert-butyl
N-[(1S)-1-(5-bromopyridin-3-yl)but-3-en-1-yl] carbamate (1.0 g,
3.06 mmol), prepared as described in Intermediate 26, in dioxane
(10 ml) was added 1-methyl-4-nitro-1H-pyrazole (0.427 g, 3.36
mmol), di(adamantan-1-yl)(butyl)phosphine (0.164 g, 0.458 mmol),
K.sub.2CO.sub.3 (1.267 g, 9.17 mmol) and pivalic acid (0.106 ml,
0.917 mmol). The reaction mixture was purged with Ar. Pd(OAc).sub.2
(0.069 g, 0.306 mmol) was added and the solution was stirred at
100.degree. C. After 4 h, the reaction was quenched with water (20
ml) and extracted with EtOAc (3.times.50 ml). The combined organic
layers were washed with brine (20 ml), dried (MgSO.sub.4),
filtered, and concentrated. The residue was purified by normal
phase chromatography using heptanes and EtOAc as eluents to give
tert-butyl
N-[(1S)-1-[5-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-3-yl]but-3-en-1-yl-
]carbamate (0.85 g, 74%) as a white foam. MS(ESI) m/z: 374.5
(M+H).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.74 (d,
J=1.9 Hz, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.25 (s, 1H), 7.72 (t, J=1.9
Hz, 1H), 5.73 (ddt, J=17.1, 10.2, 7.2 Hz, 1H), 5.26-5.17 (m, 2H),
4.99 (br. s., 1H), 4.93-4.84 (m, 1H), 3.80 (s, 3H), 2.75-2.52 (m,
2H), 1.43 (br. s., 9H).
83B. Preparation of tert-butyl
N-[(1S)-1-[5-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-3-yl]but-3-en-1-yl-
]carbamate
[1503] To a solution of tert-butyl
N-[(1S)-1-[5-(1-methyl-4-nitro-1H-pyrazol-5-yl)
pyridin-3-yl]but-3-en-1-yl]carbamate (0.85 g, 2.276) in acetone (60
ml)/water (15 ml) at 0.degree. C. was added NH.sub.4Cl (0.609 g,
11.38 mmol) and Zn (1.488 g, 22.76 mmol). The ice bath was removed
and the reaction was stirred 18 h. The reaction was filtered
through paper and partitioned between water (20 ml) and EtOAc (75
ml). The aqueous layer was extracted with EtOAc (2.times.50 ml).
The combined organic layers were washed with brine (25 ml), dried
(MgSO.sub.4), filtered, and concentrated. Thr residue was purified
by normal phase chromatography using hexanes and EtOAc as eluents
to give tert-butyl
N-[(1S)-1-[5-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-3-yl]but-3-en-1-yl-
]carbamate (0.64 g, 65% yield). MS(ESI) m/z: 344.5 (M+H).sup.+.
83C. Preparation of tert-butyl
N-[(1S)-1-(5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyr-
idin-3-yl)but-3-en-1-yl]carbamate
[1504] To a solution of tert-butyl
N-[(1S)-1-(5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyr-
idin-3-yl) but-3-en-1-yl]carbamate (0.5 g, 1.45 mmol) in EtOAc (4
ml) was added a solution of (R)-2-methylbut-3-enoic acid (0.189 g,
1.893 mmol), prepared as described in Intermediate 2, in 0.3 ml
EtOAc. The reaction mixture was cooled to 0.degree. C. and pyridine
(0.353 ml, 4.37 mmol) and a 50% EtOAc solution of T3P.RTM. (1.733
ml, 2.91 mmol) were added. After 3 h, the reaction was partitioned
between sat NaHCO.sub.3 (15 ml) and EtOAc (20 ml). The aqueous
layer was extracted with EtOAc (2.times.20 ml). The combined
organic layers were washed with brine (10 ml), dried (MgSO.sub.4),
filtered and concentrated. The residue was purified by normal phase
chromatography using DCM and 0-10% MeOH as eluents to give
tert-butyl
N-[(1S)-1-(5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyr-
idin-3-yl)but-3-en-1-yl]carbamate (0.48 g, 77% yield) as a pink
solid. MS(ESI) m/z: 426.5 (M+H).sup.+. .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 8.66 (d, J=2.2 Hz, 1H), 8.51 (d, J=1.9 Hz, 1H),
7.99 (s, 1H), 7.62 (t, J=2.1 Hz, 1H), 6.95 (br. s., 1H), 5.91 (ddd,
J=17.2, 10.0, 8.0 Hz, 1H), 5.79-5.66 (m, 1H), 5.25-5.13 (m, 4H),
4.95 (br. s., 1H), 4.82 (br. s., 1H), 3.85-3.77 (m, 3H), 3.10
(quin, J=7.2 Hz, 1H), 2.68-2.51 (m, 2H), 1.50-1.37 (m, 9H),
1.37-1.29 (m, 3H).
83D. Preparation of tert-butyl
N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,16-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
[1505] To a solution of tert-butyl
N-[(1S)-1-(5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}
pyridin-3-yl)but-3-en-1-yl]carbamate (0.153 g, 0.36 mmol) in DCM
(90 ml) was added pTsOH.H.sub.2O (0.075 g, 0.396 mmol) and the
mixture was degassed for 10 min, then heated to 40.degree. C. for 1
h. Second Generation Grubbs Catalyst (0.122 g, 0.144 mmol) was
added and the reaction was heated at 40.degree. C. for 24 h. The
reaction was quenched with sat NaHCO.sub.3 (15 ml) and extracted
with DCM (3.times.20 ml). The combined organic layers were washed
with brine (30 ml), dried (MgSO.sub.4), filtered and concentrated.
The residue purified by normal phase chromatography using DCM and
MeOH as eluents to afford tert-butyl
N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,16-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (20 mg,
14%) as a brown solid. MS(ESI) m/z: 398.2 (M+H).sup.+. .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 8.60 (s, 1H), 7.57 (s, 1H), 7.25-7.17
(m, 1H), 6.98 (s, 1H), 6.52 (br. s., 1H), 5.78-5.65 (m, 1H), 5.14
(br. s., 1H), 5.04-4.96 (m, 1H), 4.79 (br. s., 1H), 3.97 (s, 3H),
3.85-3.74 (m, 1H), 3.06 (br. s., 1H), 2.61 (br. s., 4H), 1.46 (br.
s., 9H), 1.30-1.23 (m, 3H).
83E. Preparation of
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,16-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00229##
[1507] tert-Butyl
N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,16-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
(20 mg, 0.050 mmol) was hydrogenated in EtOH (3 ml) in the presence
of PtO.sub.2 (4 mg) at 55 psi. After 4 h, the reaction mixture was
filtered through CELITE.RTM. and concentrated to afford 16 mg of a
dark solid (MS(ESI) m/z: 400.08 (M+H).sup.+ which was then
deprotected with 4 N HCl in dioxane (1 ml) and MeOH (1 ml). After 3
h, the mixture was concentrated and the resultant HCl salt was
dissolved in DCM/MeOH and passed through a basic cartridge to
afford
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,16-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one (15 mg, 100%) as a dark
solid.
83F. Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,16-tetraazatricyclo[12.3.1.0-
.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00230##
[1509] To
6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-
-ol (0.015 g, 0.050 mmol), prepared as described in Intermediate
15, and HATU (0.025 g, 0.065 mmol) in a small vial was added DBU
(0.011 mL, 0.075 mmol) in CH.sub.3CN (0.4 ml). After 30 min,
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,16-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.015 g, 0.050 mmol)
was added with DMF (0.2 ml). After 18 h, the reaction was diluted
with DMF, filtered and purified by reverse phase HPLC using
PHENOMENEX.RTM. Luna 5U 30.times.100 mm (10:90 ACN/H.sub.2O to
90:10 ACN/H.sub.2O, 0.1% TFA) (20% B start, 14 min gradient) to
afford
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,16-tetraazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (4.1 mg, 11%) as
an off-white solid. MS(ESI) m/z: 590.3 (M+H).sup.+. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.83 (d, J=1.8 Hz, 1H), 8.64 (d,
J=2.0 Hz, 1H), 8.42-8.34 (m, 2H), 8.30 (s, 1H), 7.95-7.86 (m, 1H),
7.81-7.72 (m, 1H), 7.69-7.63 (m, 1H), 7.60-7.53 (m, 1H), 6.49-6.42
(m, 1H), 5.79 (dd, J=13.0, 3.1 Hz, 1H), 4.13 (s, 3H), 2.56-2.45 (m,
2H), 2.24-2.14 (m, 1H), 1.89 (br. s., 1H), 1.65-1.53 (m, 2H),
1.23-1.14 (m, 3H), 1.10 (br. s., 1H). Analytical HPLC (Method A)
rt=6.29 min, purity=98%; Factor XIa Ki=0.2 nM, Plasma Kallikrein
Ki=43 nM.
Example 84
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazat-
ricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaene-16-carboxam-
ide
##STR00231##
[1510] 84A. Preparation of
3-bromo-5-[(1E)-{[(R)-2-methylpropane-2-sulfinyl]imino}methyl]
benzamide
[1511] To 3-formylbenzonitrile (3.49 g, 26.6 mmol) in con.
H.sub.2SO.sub.4 (12 ml) was heated to 60.degree. C., NBS (5.68 g,
31.9 mmol) was added in 3 portions. The reaction was stirred for 2
h. The reaction was quenched by pouring into ice water. The product
was filtered off and dried. The collected crude product was used
`as is` in next step. The crude material was combined with
(R)-2-methylpropane-2-sulfinamide (1.382 g, 11.40 mmol),
Cs.sub.2CO.sub.3 (5.57 g, 17.10 mmol) in DCM (57.0 ml) and stirred
18 h. The reaction thickened to a gel, was diluted with DCM and
stirring was resumed for 3 h. The reaction was partitioned between
brine (40 ml) and DCM (50 ml). The insoluble gel was filtered off.
The aqueous layer was extracted with DCM (2.times.20 ml). The
combined organic layers were dried (Na.sub.2SO.sub.4), filtered and
concentrated. The residue was purified by normal phase
chromatography using heptanes and EtOAc as eluents to afford
3-bromo-5-[(1E)-{[(R)-2-methylpropane-2-sulfinyl]imino}methyl]benzamide
(3.3 g). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.58 (s, 1H),
8.42 (s, 1H), 8.34 (br. s., 1H), 8.26 (s, 2H), 7.68 (br. s., 1H),
1.20 (s, 9H).
84B. Preparation of
3-bromo-5-[(1S)-1-{[(R)-2-methylpropane-2-sulfinyl]amino}but-3-en-1-yl]be-
nzamide
[1512] To
3-bromo-5-[(1E)-{[(R)-2-methylpropane-2-sulfinyl]imino}methyl]be-
nzamide (3.3 g, 9.96 mmol) in THF (75 ml) was added In (1.716 g,
14.94 mmol) and 3-bromoprop-1-ene (1.30 ml, 14.94 mmol). The
reaction was stirred at rt. After, 72 h, the reaction became a gray
suspension and LCMS showed it was not complete. An additional 4 g
of In and 2.6 ml of 3-bromoprop-1-ene were added. After an
additional week the reaction was filtered and the filtrate
concentrated to give 4 g of crude
3-bromo-5-[(1S)-1-{[(R)-2-methylpropane-2-sulfinyl]amino}but-3-en-1-yl]be-
nzamide. MS(ESI) m/z: 373-375.1 (M+H).sup.+.
84C. Preparation of tert-butyl
N-[(1S)-1-(3-bromo-5-carbamoylphenyl)but-3-en-1-yl] carbamate
[1513] To
3-bromo-5-[(1S)-1-{[(R)-2-methylpropane-2-sulfinyl]amino}but-3-e-
n-1-yl]benzamide (3.7 g, 9.91 mmol) in (1:1) dioxane/MeOH (50 ml)
was added 15 ml of conc. HCl. The reaction was stirred for 24 h,
then concentrated. The residue was dissolved in DCM (50 ml) and
cooled to 0.degree. C. TEA (8.29 ml, 59.5 mmol) and BOC.sub.2O
(2.301 ml, 9.91 mmol) were added. An additional amount of 1 N NaOH
was added to ensure reaction was basic. After 24 h, the thick
reaction was filtered giving a gummy solid. Both the gummy solid
and filtrate were combined and partitioned between water (100 ml)
and EtOAc (150 ml). The aqueous layer was extracted with EtOAc
(2.times.50 ml). The combined organic layers were washed with brine
(50 ml), dried (Na.sub.2SO.sub.4), filtered and concentrated. The
residue was purified by normal phase chromatography using hexanes
and EtOAc as eluents to afford tert-butyl
N-[(1S)-1-(3-bromo-5-carbamoylphenyl)but-3-en-1-yl]carbamate (0.92
g, 25%). MS(ESI) m/z: 311-313.3 (M+H-t-butyl).sup.+. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.88-7.79 (m, 1H), 7.74 (br. s., 1H),
7.56 (t, J=1.5 Hz, 1H), 6.66 (br. s., 1H), 6.40 (br. s., 1H),
5.74-5.59 (m, 1H), 5.28-5.19 (m, 1H), 5.17-5.12 (m, 1H), 4.71 (br.
s., 1H), 2.57-2.45 (m, 3H), 1.49-1.34 (m, 9H).
84D. Preparation of tert-butyl
N-[(1S)-1-{3-carbamoyl-5-[1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl]phen-
yl}but-3-en-1-yl]carbamate
[1514] To a solution of (S)-tert-butyl
(1-(3-bromo-5-carbamoylphenyl)but-3-en-1-yl)carbamate (0.2 g, 0.542
mmol) in dioxane (3 ml) was added
1-(difluoromethyl)-4-nitro-1H-pyrazole (0.106 g, 0.650 mmol),
di(adamantan-1-yl)(butyl)phosphine (0.029 g, 0.081 mmol),
K.sub.2CO.sub.3 (0.225 g, 1.625 mmol) and pivalic acid (0.019 ml,
0.162 mmol). The reaction was purged with Ar. Afterwards,
Pd(OAc).sub.2 (0.012 g, 0.054 mmol) was added and the reaction was
heated to 100.degree. C. After 18 h, the reaction was partitioned
with water (20 ml) and EtOAc (20 ml) and filtered. The filtrate was
extracted with EtOAc (2.times.20 ml). The combined organic layers
were washed with brine (15 ml), dried (MgSO.sub.4), filtered, and
concentrated. The residue was purified by normal phase
chromatography using heptanes and EtOAc as eluents to afford
tert-butyl
N-[(1S)-1-{3-carbamoyl-5-[1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl]phen-
yl}but-3-en-1-yl] carbamate (0.177 g, 72.4%) as a yellow oil.
MS(ESI) m/z: 450.1 (M-H).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 8.34 (s, 1H), 7.99-7.91 (m, 1H), 7.85-7.77 (m, 1H),
7.58-7.52 (m, 1H), 7.16-6.82 (m, 1H), 6.07 (br. s., 1H), 5.75-5.55
(m, 2H), 5.20-5.08 (m, 2H), 4.96 (br. s., 1H), 4.82 (br. s., 1H),
2.62-2.46 (m, 2H), 1.40 (d, J=7.2 Hz, 9H).
84E. Preparation of tert-butyl
N-[(1S)-1-{3-carbamoyl-5-[1-(difluoromethyl)-4-[(2R)-2-methylbut-3-enamid-
o]-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate
[1515] To tert-butyl
N-[(1S)-1-{3-carbamoyl-5-[1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl]phen-
yl}but-3-en-1-yl]carbamate (0.177 g, 0.392 mmol) in acetone (40
ml)/water (12 ml), cooled to 0.degree. C., was added NH.sub.4Cl
(0.105 g, 1.960 mmol) and Zn (0.256 g, 3.92 mmol). After 18 h at
rt, the reaction was filtered through paper and the filtrate was
partitioned with water (20 ml) and EtOAc (25 ml). The aqueous layer
was extracted with EtOAc (2.times.25 ml). The combined organic
layers were washed with brine (25 ml), dried (MgSO.sub.4) filtered
and concentrated. To the crude yellow oil in EtOAc (3 ml) at
0.degree. C., was added (R)-2-methylbut-3-enoic acid (0.051 g,
0.510 mmol), prepared as described in Intermediate 2, pyridine
(0.095 mL, 1.176 mmol) and a 50% EtOAc solution of T3P.RTM. (0.233
mL, 0.784 mmol). After 24 h, the reaction was partitioned between
sat NaHCO.sub.3 (10 ml) and EtOAc (20 ml). The aqueous layer was
extracted with EtOAc (2.times.20 ml). The combined organic layers
were washed with brine (25 ml), dried (MgSO.sub.4), filtered and
concentrated. The was residue was purified by normal phase
chromatography using hexanes and EtOAc as eluents to afford
tert-butyl
N-[(1S)-1-{3-carbamoyl-5-[1-(difluoromethyl)-4-[(2R)-2-methylbut-3-enamid-
o]-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate (0.113 g, 57%) as
a yellow oil. MS(ESI) m/z: 448.3 (M+H-t-butyl).sup.+.
84F. Preparation of tert-butyl
N-[(9R,10E,13S)-16-carbamoyl-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-tria-
zatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]ca-
rbamate
[1516] To a solution of tert-butyl
N-[(1S)-1-{3-carbamoyl-5-[1-(difluoromethyl)-4-[(2R)-2-methylbut-3-enamid-
o]-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate (0.113 g, 0.224
mmol) in degassed DCE (11 ml) was added Second Generation Grubbs
Catalyst (0.08 g, 0.094 mmol) and the resulting solution was heated
to 120.degree. C. for 30 min in a microwave. The reaction was
directly purified by normal phase chromatography using DCM and
0-10% MeOH as eluents gave tert-butyl
N-[(9R,10E,13S)-16-carbamoyl-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-tria-
zatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]ca-
rbamate (33 mg, 31%) as a tan solid. MS(ESI) m/z: 420.2
(M+H-t-butyl).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.95
(s, 1H), 7.82-7.78 (m, 2H), 7.10 (s, 1H), 5.73 (ddd, J=15.2, 10.5,
4.7 Hz, 1H), 4.65 (d, J=9.5 Hz, 1H), 4.54 (dd, J=15.2, 9.2 Hz, 1H),
3.19-3.09 (m, 1H), 2.70 (dt, J=12.1, 3.5 Hz, 1H), 2.03 (q, J=11.4
Hz, 1H), 1.46 (br. s., 9H), 1.08 (d, J=6.8 Hz, 3H).
84G. Preparation of
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[-
12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaene-16-carboxamide
##STR00232##
[1518] tert-Butyl
N-[(9R,10E,13S)-16-carbamoyl-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-tria-
zatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]ca-
rbamate (0.033 g, 0.069 mmol) was hydrogenated in EtOH (1 ml) in
the presence of PtO.sub.2 (5 mg). After 4 h, the reaction was
filtered through 0.45 .mu.M filter to afford 0.022 g of a tan
solid. MS(ESI) m/z: 422.3 (M+H-t-butyl).sup.+. The intermediate was
deprotected in MeOH (1 ml) with 4 N HCl in dioxane (0.5 ml). After
3 h, the reaction was concentrated. The residue was taken up in
DCM/MeOH and passed through a basic cartridge and concentrated to
afford
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaene-16-carboxamide
(22 mg, 84%) as a brown solid. MS(ESI) m/z: 378.2 (M+H).sup.+.
84H. Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazat-
ricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaene-16-carboxami-
de
##STR00233##
[1520] To
6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-
-ol (0.018 g, 0.058 mmol), prepared as described in Intermediate 9,
and HATU (0.029 g, 0.076 mmol) in a small vial was added DBU (0.013
mL, 0.087 mmol) in ACN (0.4 ml). After 30 min,
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[-
12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaene-16-carboxamide (0.022 g, 0.058
mmol) was added with DMF (0.2 ml). After 18 h, the reaction was
diluted with DMF, filtered and purified by reverse phase HPLC using
PHENOMENEX.RTM. Luna 5U 30.times.100 mm (10:90 ACN/H.sub.2O to
90:10 ACN/H.sub.2O, 0.1% TFA) (20% B start, 14 min gradient) to
afford
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazat-
ricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaene-16-carboxami-
de (10 mg, 25%) as a white solid. MS(ESI) m/z: 668.3 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.36 (s, 1H), 8.30 (s,
1H), 8.04 (s, 1H), 7.96 (s, 1H), 7.91-7.86 (m, 2H), 7.85-7.78 (m,
1H), 7.77-7.71 (m, 1H), 7.70-7.63 (m, 2H), 6.47-6.40 (m, 1H), 5.84
(dd, J=12.9, 3.4 Hz, 1H), 2.52 (ddd, J=10.0, 6.7, 3.5 Hz, 1H),
2.47-2.38 (m, 1H), 2.21-2.11 (m, 1H), 1.98-1.86 (m, 1H), 1.67-1.47
(m, 2H), 1.22 (d, J=6.8 Hz, 1H), 1.16 (d, J=6.8 Hz, 3H). Analytical
HPLC (Method A) RT=7.39 min, purity=98%; Factor XIa Ki=0.1 nM,
Plasma Kallikrein Ki=18 nM.
Example 85
Preparation of
1-(4-chloro-2-{1-[(9R,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-oxo-3,4,7-t-
riazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]--
6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxamide
##STR00234##
[1521] 85A. Preparation of
1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbox-
amide
##STR00235##
[1523] To a suspension of
1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbox-
amide (60 mg, 0.18 mmol) in ACN (1 ml) was added TMSI (12 .mu.L,
0.88 mmol). The solution was heated at 70.degree. C. for 3 h. The
reaction was cooled to rt and poured into a 10%
Na.sub.2S.sub.2O.sub.3 solution. The insoluble yellow solid that
formed was filtered and washed with water to give crude
1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbox-
amide (30 mg, 41.8% yield). MS(ESI) m/z: 317.3 (M+H).sup.+. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.57 (s, 1H), 8.02 (s, 1H), 7.85
(d, J=2.4 Hz, 1H), 7.76-7.71 (m, 1H), 7.70-7.64 (m, 1H), 6.39 (s,
1H).
85B. Preparation of
1-(4-chloro-2-{1-[(9R,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-oxo-3,4,7-t-
riazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]--
6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxamide
[1524] To
1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-
-4-carboxamide (0.004 g, 0.013 mmol) and HATU (6.24 mg, 0.016 mmol)
in a small vial was added DBU (2.86 .mu.l, 0.019 mmol) in
CH.sub.3CN (0.8 ml). After 30 min, solid
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7-triazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.038 g,
0.013 mmol), prepared as described in Intermediate 16, was added
(rinsed with 0.2 ml DMF). The reaction was stirred 18 h, then
diluted with DMF, filtered and concentrated. The residue was
purified by preparative LCMS using (5:95 ACN/H.sub.2O to 95:5
ACN/H.sub.2O, 10 mM NH.sub.4OAc) to afford
1-(4-chloro-2-{1-[(9R,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-oxo--
3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen--
13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxa-
mide (3.1 mg, 38% yield) as a white solid. MS(ESI) m/z: 601.08
(M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.47-8.41
(m, 1H), 8.03 (s, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.67-7.60 (m, 2H),
7.60-7.53 (m, 1H), 7.52-7.41 (m, 2H), 7.41-7.36 (m, 1H), 7.19 (d,
J=7.4 Hz, 1H), 6.37-6.28 (m, 1H), 5.69 (d, J=9.6 Hz, 1H), 4.45 (br.
s., 1H), 2.40-2.34 (m, 1H), 2.27-2.19 (m, 1H), 1.82-1.73 (m, 1H),
1.52-1.41 (m, 2H), 1.15-1.10 (m, 1H), 1.07-1.01 (m, 3H). Analytical
HPLC (Method C) RT=1.31 min, purity=95%; Factor XIa Ki=0.3 nM,
Plasma Kallikrein Ki=60 nM.
Example 86
Preparation of
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00236##
[1525] 86A. Preparation of
4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole
[1526] To a solution of 4-nitro-1H-pyrazole (5.1 g, 45.1 mmol) in
THF (50 mL) at 0.degree. C. was added
N-cyclohexyl-N-methylcyclohexanamine (19.32 mL, 90 mmol) followed
by dropwise addition of SEM-Cl (12 mL, 67.7 mmol). The reaction
mixture was slowly allowed to warm to rt and stirred for 18 h. The
reaction mixture was concentrated and the residue was purified by
normal phase chromatography using hexanes and EtOAc as eluents to
afford 4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole
(4.6 g, 43% yield) as a yellow oil. MS(ESI) m/z: 244 (M-H).sup.+.
.sup.1H NMR (500 MHz, CD.sub.3Cl) .delta. 8.30 (s, 1H), 8.10 (s,
1H), 5.45 (s, 2H), 3.67-3.57 (m, 2H), 1.01-0.90 (m, 2H), 0.04-0.00
(m, 9H).
86B. Preparation of tert-butyl
N-[(1S)-1-[3-(4-nitro-1-{[2-(trimethylsilyl)ethoxy]
methyl}-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate
[1527] To a solution of tert-butyl
N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (0.4 g, 1.226
mmol) in DMF (3.07 ml) was added di(adamantan-1-yl)(butyl)phosphine
(0.066 g, 0.184 mmol),
4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole (0.298 g,
1.226 mmol), K.sub.2CO.sub.3 (0.508 g, 3.68 mmol) and pivalic acid
(0.043 ml, 0.368 mmol). The reaction was purged with Ar for 10 min,
then, Pd(OAc).sub.2 (0.028 g, 0.123 mmol) was added and the
reaction was heated to 115.degree. C. for 3 h. The reaction mixture
was diluted with EtOAc/water and filtered through paper to remove
Pd. The filtrate was extracted (2.times.20 ml) EtOAc. The combined
organic layer was washed with water (15 ml), brine (15 ml), dried
(MgSO.sub.4), filtered and concentrated. The residue was purified
by normal phase chromatography using hexanes and EtOAc as eluents
to afford tert-butyl
N-[(1S)-1-[3-(4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-y-
l)phenyl]but-3-en-1-yl] carbamate (0.315 g, 53%) as a yellow oil.
MS(ESI) m/z: 487.3 (M-H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3Cl)
.delta. 8.23 (s, 1H), 7.53-7.40 (m, 4H), 5.69 (ddt, J=17.1, 10.1,
7.2 Hz, 1H), 5.25 (s, 2H), 5.17-5.10 (m, 2H), 4.90 (br. s., 1H),
4.81 (br. s., 1H), 3.75-3.64 (m, 2H), 2.55 (br. s., 2H), 1.48 (br.
s., 9H), 0.96-0.88 (m, 2H), 0.07-0.02 (m, 9H).
86C. Preparation of tert-butyl
N-[(15)-1-[3-(4-amino-1-{[2-(trimethylsilyl)ethoxy]
methyl}-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate
[1528] tert-Butyl
N-[(1S)-1-[3-(4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-y-
l) phenyl]but-3-en-1-yl]carbamate (0.315 g, 0.645 mmol) was
dissolved in acetone (40 ml)/water (12 ml), cooled to 0.degree. C.
NH.sub.4Cl (0.172 g, 3.22 mmol) and Zn (0.421 g, 6.45 mmol) were
added. The ice bath was removed. After 3 h, the reaction was
partitioned with water (20 ml) and EtOAc (75 ml) and filtered
through paper. The aqueous layer was extracted with EtOAc
(2.times.50 ml). The combined organic layers were washed with brine
(25 ml), dried (MgSO.sub.4), filtered and concentrated. The residue
was purified by normal phase chromatography using hexanes and EtOAc
as eluents to afford tert-butyl
N-[(15)-1-[3-(4-amino-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-y-
l)phenyl]but-3-en-1-yl]carbamate (0.269 g, 91%) as a yellow oil.
MS(ESI) m/z: 459.5 (M-H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.54-7.42 (m, 3H), 7.34-7.28 (m, 2H), 5.72 (ddt, J=17.0,
10.1, 7.0 Hz, 1H), 5.33-5.26 (m, 2H), 5.18-5.07 (m, 2H), 4.95 (br.
s., 1H), 4.81 (br. s., 1H), 3.73-3.60 (m, 2H), 3.03 (br. s., 2H),
2.63-2.52 (m, 2H), 1.50-1.36 (m, 9H), 0.97-0.88 (m, 2H), 0.04-0.03
(m, 9H).
86D. Preparation of tert-butyl
N-[(1S)-1-(3-{4-[(2R)-2-methylbut-3-enamido]-1-{[2-(trimethylsilyl)ethoxy-
]methyl}-1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]carbamate
[1529] To tert-butyl
N-[(1S)-1-[3-(4-amino-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-y-
l)phenyl]but-3-en-1-yl]carbamate (0.269 g, 0.586 mmol) in EtOAc (1
ml) was added (R)-2-methylbut-3-enoic acid (0.076 g, 0.762 mmol),
prepared as described in Intermediate 2, in 1 mL EtOAc and the
solution was cooled to 0.degree. C. To the reaction mixture was
added pyridine (0.142 ml, 1.759 mmol) and 50% EtOAc solution of
T3P.RTM. (0.698 ml, 1.173 mmol). After 1 h, the reaction was
partitioned between sat NaHCO.sub.3 (10 ml) and EtOAc (30 ml). The
aqueous layer was extracted with EtOAc (2.times.20 ml). The
combined organic layers were washed with brine (10 ml), dried
(MgSO.sub.4), filtered and concentrated. The residue was purified
by normal phase chromatography using hexanes and EtOAc as eluents
to afford tert-butyl
N-[(1S)-1-(3-{4-[(2R)-2-methylbut-3-enamido]-1-{[2-(trimethylsilyl)ethoxy-
]methyl}-1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]carbamate (0.241 g,
76%) as a pink oil. MS(ESI) m/z: 541.6 (M-H).sup.+. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.18 (s, 1H), 7.53-7.41 (m, 2H),
7.41-7.35 (m, 2H), 7.18 (br. s., 1H), 5.92 (ddd, J=17.2, 10.1, 7.9
Hz, 1H), 5.81-5.65 (m, 1H), 5.37-5.30 (m, 2H), 5.25-5.10 (m, 4H),
4.93 (br. s., 1H), 4.82-4.73 (m, 1H), 3.75-3.66 (m, 2H), 3.12
(quin, J=7.2 Hz, 1H), 2.63-2.49 (m, 2H), 1.48-1.39 (m, 9H),
1.35-1.31 (m, 3H), 1.00-0.90 (m, 2H), 0.03-0.02 (m, 9H).
86E. Preparation of tert-butyl
N-[(9R,10E,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)
ethoxy]methyl}-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),-
4,10,14,16-hexaen-13-yl]carbamate
[1530] A solution of tert-butyl
N-[(1S)-1-(3-{4-[(2R)-2-methylbut-3-enamido]-1-{[2-(trimethylsilyl)
ethoxy]methyl}-1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]carbamate
(0.241 g, 0.446 mmol) in DCM (55 ml), purged with Ar for 15 min.
Second Generation Grubbs Catalyst (0.151 g, 0.178 mmol) was added
and the reaction was heated to 40.degree. C. After 24 h, the
reaction mixture was concentrated and the residue was purified by
normal phase chromatography using DCM and 0-10% MeOH and then,
again with hexanes and EtOAc as eluents to afford tert-butyl
N-[(9R,10E,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)
ethoxy]methyl}-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),-
4,10,14,16-hexaen-13-yl]carbamate (0.224 g, 98%) as a dark solid.
MS(ESI) m/z: 513.5 (M+H).sup.+.
86F. Preparation of tert-butyl
N-[(9R,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]
methyl}-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-
-pentaen-13-yl]carbamate
[1531] tert-Butyl
N-[(9R,10E,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7-
-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13--
yl]carbamate (0.16 g, 0.312 mmol) was hydrogenated at 55 psi in
EtOH (4 ml), in the presence of PtO.sub.2 (7.09 mg, 0.031 mmol).
After 3 h, the reaction was filtered through CELITE.RTM. and
concentrated to afford tert-butyl
N-[(9R,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)
ethoxy]methyl}-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),-
4,14,16-pentaen-13-yl]carbamate (0.15 g, 93%) desired product as a
gray solid. MS(ESI) m/z: 515.5 (M+H).sup.+.
86G. and 86H. Preparation of
(9R,13S)-13-amino-9-methyl-3-{[2-(trimethylsilyl)ethoxy]
methyl}-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-
-pentaen-8-one, and
(9R,13S)-13-amino-9-methyl-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-
-1(18),2(6),4,14,16-pentaen-8-one
##STR00237##
[1533] tert-Butyl
N-[(9R,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7-tri-
azatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]car-
bamat (0.15 g, 0.291 mmol) was heated in water (10 ml) in a
microwave for 30 min at 150.degree. C. The water was decanted from
a tarry material and freeze-dried to afford a mixture of
(9R,13S)-13-amino-9-methyl-3-{[2-(trimethylsilyl)ethoxy]
methyl}-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(MS(ESI) m/z: 415.5 (M+H).sup.+)) and
(9R,13S)-13-amino-9-methyl-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-
-1(18),2(6),4,14,16-pentaen-8-one one (MS(ESI) m/z: 285.5
(M+H).sup.+) (29 mg) which was carried on to the next step `as
is`.
[1534] 861. Preparation of
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00238##
[1535] To
6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]py-
rimidin-4-ol (0.015 g, 0.046 mmol), prepared as described in
Intermediate 10, and HATU (0.023 g, 0.059 mmol) in a small vial was
added DBU (10.34 .mu.l, 0.069 mmol) in CH.sub.3CN (0.8 ml). After
30 min, the mixture of
(9R,13S)-13-amino-9-methyl-3-{[2-(trimethylsilyl)ethoxy]
methyl}-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-
-pentaen-8-one and
(9R,13S)-13-amino-9-methyl-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-
-1(18),2(6), 4,14,16-pentaen-8-one (13 mg) in DMF (0.8 ml) was
added and the reaction was stirred for 24 h. The reaction was
diluted with DMF, filtered and purified by reverse phase HPLC using
PHENOMENEX.RTM. Luna 5U 30.times.100 mm (10:90 MeOH/H.sub.2O to
90:10 MeOH/H.sub.2O, 0.1% TFA) (25% B start, 14 min gradient) to
afford
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7-triazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (2 mg, 7% yield)
as a white solid. MS(ESI) m/z: 593.4 (M+H).sup.+. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.29 (s, 1H), 8.11 (s, 1H), 7.91-7.82 (m,
2H), 7.70-7.65 (m, 1H), 7.62 (s, 1H), 7.56-7.46 (m, 3H), 7.10 (d,
J=7.5 Hz, 1H), 6.67-6.62 (m, 1H), 5.93-5.86 (m, 1H), 2.65-2.57 (m,
1H), 2.29 (d, J=11.4 Hz, 1H), 2.11 (d, J=10.3 Hz, 1H), 1.98 (br.
s., 1H), 1.65 (d, J=5.9 Hz, 1H), 1.59-1.50 (m, 1H), 1.40 (br. s.,
1H), 1.15 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT=7.38
min, purity=90%; Factor XIa Ki=1.8 nM, Plasma Kallikrein Ki=90
nM.
Example 87
Preparation of
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00239##
[1537]
(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetr-
aazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate was prepared in a similar manner as the procedures
described in Example 56, by using
6-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(0.034 g, 0.116 mmol), prepared as described in Intermediate 7, and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.039 g,
0.116 mmol), prepared as described in Intermediate 30, to yield
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatr-
icyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate. MS(ESI) m/z: 610.2 [M+H].sup.+. .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 8.57 (s, 1H), 8.43 (d, J=5.2 Hz, 1H), 7.87
(d, J=1.1 Hz, 1H), 7.53 (dd, J=8.5, 7.7 Hz, 1H), 7.50-7.41 (m, 3H),
7.39-7.32 (m, 2H), 7.25-7.18 (m, 3H), 6.22 (s, 1H), 5.75-5.65 (m,
1H), 2.43-2.35 (m, 1H), 2.01-1.91 (m, 1H), 1.76-1.64 (m, 8H),
1.32-1.22 (m, 1H), 1.21-1.10 (m, 1H), 0.67 (d, J=7.2 Hz, 3H).
Analytical HPLC (Method A): RT=7.59 min, purity=97.5%; Factor XIa
Ki=0.22 nM, Plasma Kallikrein Ki=42 nM.
Example 88
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00240##
[1539]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetr-
aazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate was prepared in a similar manner as the procedures
described in Example 56, by using
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(0.019 g, 0.062 mmol), prepared as described in Intermediate 9, and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.021 g,
0.062 mmol), prepared as described in Intermediate 30, to yield
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatr-
icyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate. MS(ESI) m/z: 626.2 [M+H].sup.+. .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 8.91-8.83 (m, 1H), 8.78-8.71 (m, 1H), 8.33
(s, 1H), 7.88 (d, J=2.5 Hz, 1H), 7.74 (s, 2H), 7.69-7.67 (m, 1H),
7.65 (s, 1H), 7.63 (t, J=58 Hz, 1H), 7.52-7.50 (m, 1H), 6.36 (d,
J=0.8 Hz, 1H), 6.06-5.95 (m, 1H), 2.76-2.65 (m, 1H), 2.36-2.21 (m,
1H), 2.08-1.93 (m, 2H), 1.63-1.53 (m, 1H), 1.53-1.42 (m, 1H), 0.99
(d, J=6.9 Hz, 3H). Analytical HPLC (Method A): RT=8.87 min,
purity=99.7%; Factor XIa Ki=0.12 nM, Plasma Kallikrein Ki=30
nM.
Example 89
Preparation of
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-t-
etraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one-
; trifluoroacetate
##STR00241##
[1541]
(9R,13S)-13-{4-[3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluor-
ophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,-
7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate was prepared in a similar manner as the procedures
described in Example 56, by using
6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-
-ol (0.025 g, 0.063 mmol), prepared as described in Intermediate
10, and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.021 g,
0.063 mmol), prepared as described in Intermediate 30, to yield
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-t-
etraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate. MS(ESI) m/z: 644.3 [M+H].sup.+. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.92-8.84 (m, 1H), 8.80-8.72 (m, 1H), 8.32
(s, 1H), 7.89-7.82 (m, 1H), 7.75 (s, 1H), 7.74-7.70 (m, 1H), 7.66
(t, J=58 Hz, 1H), 7.54 (d, J=1.5 Hz, 2H), 6.60 (s, 1H), 6.07-5.97
(m, 1H), 2.76-2.65 (m, 1H), 2.36-2.23 (m, 1H), 2.09-1.96 (m, 2H),
1.65-1.42 (m, 2H), 1.00 (d, J=7.0 Hz, 3H). Analytical HPLC (Method
A): RT=8.36 min, purity=98.8%; Factor XIa Ki=0.1 nM, Plasma
Kallikrein Ki=11 nM.
Example 90
Preparation of
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-t-
etraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00242##
[1543]
(9R,13S)-13-{4-[3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluor-
ophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,-
7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate was prepared in a similar manner as the procedures
described in Example 56, by using
6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-
-ol (0.054 g, 0.167 mmol), prepared as described in Intermediate
10, and
(9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.055 g,
0.167 mmol), prepared as described in Intermediate 40. The crude
product was purified by prep HPLC to give
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-t-
etraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate. (45 mg, 34% yield) as tan solid. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.82 (s, 1H), 8.75 (d, J=5.3 Hz, 1H),
8.36-8.32 (m, 1H), 7.87 (dd, J=8.6, 7.7 Hz, 1H), 7.81 (dd, J=5.1,
1.5 Hz, 1H), 7.73 (s, 1H), 7.61-7.53 (m, 2H), 6.00 (dd, J=12.7, 4.3
Hz, 1H), 4.51-4.33 (m, 1H), 4.13-3.86 (m, 2H), 3.39-3.35 (m, 2H),
2.71 (td, J=6.8, 3.1 Hz, 1H), 2.43-2.25 (m, 1H), 2.13-1.97 (m, 1H),
1.68-1.40 (m, 2H), 1.03 (d, J=6.8 Hz, 6H), 0.75 (br. s., 1H).
MS(ESI) m/z: 638.5 [M+H].sup.+. Analytical HPLC (Method A): RT=7.32
min, purity=>95.0%; Factor XIa Ki=0.34 nM, Plasma Kallikrein
Ki=28 nM.
Example 91
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,-
7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-
-8-one trifluoroacetate
##STR00243##
[1545]
(9R,13S)-13-(4-{5-Chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-y-
l]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4-
,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate was prepared in a similar manner as the procedures
described in Example 56, by using
6-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin--
4-ol (0.049 g, 0.152 mmol), prepared as described in Intermediate
16, and
(9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.050 g,
0.152 mmol), prepared as described in Intermediate 40. The crude
product was purified by prep HPLC to yield
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15--
tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-on-
e trifluoroacetate (32 mg, 27% yield) as a white solid. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.75 (s, 1H), 8.69 (d, J=5.1 Hz, 1H),
8.56-8.50 (m, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.79-7.61 (m, 4H), 7.55
(s, 1H), 7.16-6.80 (m, 1H), 6.34 (d, J=0.4 Hz, 1H), 5.95 (dd,
J=12.7, 4.1 Hz, 1H), 4.47-4.28 (m, 2H), 4.09-3.87 (m, 2H), 2.67
(td, J=6.8, 3.0 Hz, 1H), 2.34-2.19 (m, 1H), 2.09-1.91 (m, 2H),
1.65-1.34 (m, 2H), 1.00 (d, J=6.8 Hz, 3H), 0.70 (br. s., 1H).
MS(ESI) m/z: 636.5 [M+H].sup.+. Analytical HPLC (Method A): RT=7.32
min, purity=>95.0%; Factor XIa Ki=2.8 nM, Plasma Kallikrein
Ki=220 nM.
Example 92
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00244##
[1547]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetr-
aazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate was prepared in a similar manner as the procedures
described in Example 56, by using
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(0.042 g, 0.137 mmol), prepared as described in Intermediate 9, and
(9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.045 g,
0.137 mmol), prepared as described in Intermediate 40. The crude
product was purified by prep HPLC to yield
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatr-
icyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(65 mg, 61% yield) as white solid. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.79 (s, 1H), 8.73 (d, J=5.1 Hz, 1H), 8.40-8.30
(m, 1H), 7.88 (d, J=2.2 Hz, 1H), 7.81 (dd, J=5.1, 1.5 Hz, 1H),
7.76-7.70 (m, 2H), 7.67-7.61 (m, 1H), 7.58 (s, 1H), 6.37 (d, J=0.4
Hz, 1H), 5.96 (dd, J=12.5, 4.2 Hz, 1H), 4.46-4.33 (m, 2H),
4.09-3.91 (m, 3H), 3.35 (s, 1H), 2.69 (td, J=6.8, 3.0 Hz, 1H),
2.39-2.24 (m, 1H), 2.12-1.94 (m, 2H), 1.66-1.40 (m, 2H), 1.02 (d,
J=7.0 Hz, 3H), 0.73 (br. s., 1H). MS(ESI) m/z: 620.5 [M+H].sup.+.
Analytical HPLC (Method A): RT=7.29 min, purity=>95.0%; Factor
XIa Ki=1.3 nM, Plasma Kallikrein Ki=130 nM.
Example 93
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00245##
[1549]
(9R,13S)-13-{4-[5-Chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate was prepared in a similar manner as the procedures
described in Example 56, by using
6-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)pyrimidin-4-ol (0.037 g,
0.137 mmol), prepared as described in Intermediate 20, and
(9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.045 g,
0.137 mmol), prepared as described in Intermediate 40. The crude
product was purified by prep HPLC to yield
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (52 mg,
52% yield) as a pale white solid. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 9.42 (s, 1H), 8.68 (d, J=5.1 Hz, 2H), 7.88 (d, J=2.2 Hz,
1H), 7.78-7.72 (m, 2H), 7.67 (d, J=8.4 Hz, 2H), 7.55 (s, 1H), 6.49
(s, 1H), 5.93 (d, J=8.8 Hz, 1H), 4.45-4.29 (m, 2H), 4.08-3.88 (m,
3H), 3.32 (s, 1H), 2.66 (d, J=7.0 Hz, 1H), 2.24 (t, J=13.0 Hz, 1H),
2.08-1.88 (m, 2H), 1.65-1.49 (m, 1H), 1.41 (br. s., 1H), 0.98 (d,
J=6.8 Hz, 3H), 0.67 (br. s., 1H). MS(ESI) m/z: 587.5 [M+H].sup.+.
Analytical HPLC (Method A): RT=6.40 min, purity=>95.0%; Factor
XIa Ki=0.65 nM, Plasma Kallikrein Ki=45 nM.
Example 94
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-
-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-o-
ne trifluoroacetate
##STR00246##
[1551]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,-
4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate was prepared in a similar manner as the procedures
described in Example 56, by using
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol (47 mg, 0.137 mmol), prepared as described in Intermediate
15, and
(9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.045 g,
0.137 mmol), prepared as described in Intermediate 40. The crude
product was purified by prep HPLC to yield
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-
-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-o-
ne (67 mg, 61% yield) as a white solid. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.79 (s, 1H), 8.72 (s, 1H), 8.68-8.61 (m, 1H),
7.88-7.82 (m, 1H), 7.78-7.69 (m, 2H), 7.68-7.61 (m, 2H), 7.54 (s,
1H), 6.40 (s, 1H), 5.93 (dd, J=12.7, 4.1 Hz, 1H), 4.42-4.27 (m,
2H), 4.03-3.86 (m, 2H), 2.65 (dt, J=6.8, 3.3 Hz, 1H), 2.33-2.15 (m,
1H), 2.07-1.87 (m, 2H), 1.64-1.48 (m, 1H), 1.41 (td, J=10.0, 5.2
Hz, 1H), 1.01-0.93 (m, 3H), 0.66 (br. s., 1H). MS(ESI) m/z: 654.5
[M+H].sup.+. Analytical HPLC (Method A): RT=8.10 min,
purity=>95.0%; Factor XIa Ki=1.1 nM, Plasma Kallikrein Ki=130
nM.
Example 95
Preparation of
2-[(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoroph-
enyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatri-
cyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]
acetic acid trifluoroacetate
##STR00247##
[1553] A solution of
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-t-
etraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (0.034 g, 0.053 mmol), prepared as described in
Example 90, in acetone (2 mL) was cooled to 0.degree. C. To this
cooled mixture was then added 2.86 M solution of Jones reagent
(0.037 mL, 0.107 mmol) and the resulting reaction mixture was
allowed to warm to rt over a period of 2 h. The reaction mixture
was then quenched with 0.5 mL of IPA and concentrated. The
resulting residue was purified by prep HPLC purification to afford
2-[(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoroph-
enyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatri-
cyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic
acid trifluoroacetate (8 mg, 19% yield) as a white solid. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.85 (s, 1H), 8.74 (d, J=5.1 Hz,
1H), 8.34 (s, 1H), 7.87 (dd, J=8.6, 7.5 Hz, 1H), 7.72 (s, 1H),
7.61-7.53 (m, 2H), 7.49 (dd, J=5.1, 1.5 Hz, 1H), 6.62 (s, 1H), 6.04
(dd, J=12.3, 4.2 Hz, 1H), 5.27-5.06 (m, 2H), 2.72 (dt, J=6.7, 3.4
Hz, 1H), 2.30 (t, J=12.7 Hz, 1H), 2.15-1.97 (m, 2H), 1.69-1.41 (m,
2H), 1.03 (d, J=7.0 Hz, 3H), 0.71 (br. s., 1H). MS(ESI) m/z: 652.2
[M+H].sup.+. Analytical HPLC (Method A): RT=7.45 min,
purity=>95.0%; Factor XIa Ki=0.11 nM, Plasma Kallikrein Ki=12
nM.
Example 96
Preparation of
2-[(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tetraaza-
tricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic
acid trifluoroacetate
##STR00248##
[1555]
2-[(9R,13S)-13-(4-{5-Chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol--
1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tet-
raazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic
acid was prepared in a similar manned as the procedure described in
Example 95, using
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-
-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-
-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pe-
ntaen-8-one trifluoroacetate (0.024 g, 0.038 mmol), prepared as
described in Example 91, to yield
2-[(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]p-
henyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tetraazatr-
icyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic
acid trifluoroacetate (6 mg, 20% yield) as a white solid. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.83 (s, 1H), 8.72 (d, J=5.1 Hz,
1H), 8.56 (s, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.80-7.74 (m, 1H),
7.72-7.66 (m, 2H), 7.59 (s, 1H), 7.49 (dd, J=5.1, 1.3 Hz, 1H),
7.19-6.86 (m, 1H), 6.38 (s, 1H), 6.03 (dd, J=12.7, 4.3 Hz, 1H),
5.27-5.06 (m, 2H), 2.72 (dt, J=6.6, 3.3 Hz, 1H), 2.34-2.22 (m, 1H),
2.13-1.94 (m, 2H), 1.68-1.40 (m, 2H), 1.03 (d, J=7.0 Hz, 3H), 0.71
(br. s., 1H). MS(ESI) m/z: 650.3 [M+H].sup.+. Analytical HPLC
(Method A): RT=7.52 min, purity=>95.0%; Factor XIa Ki=0.65 nM,
Plasma Kallikrein Ki=78 nM.
Example 97
Preparation of
2-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-o-
xo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.-
3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic acid
trifluoroacetate
##STR00249##
[1557]
2-[(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)pheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic acid
trifluoroacetate was prepared in a similar manned as the procedure
described in Example 95, using
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatr-
icyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (0.038 g, 0.061 mmol), prepared as described in
Example 92, to yield
2-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-o-
xo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.-
3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic acid
trifluoroacetate (8 mg, 17% yield) as a white solid. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.85 (s, 1H), 8.73 (d, J=5.1 Hz, 1H),
8.36 (s, 1H), 7.92-7.88 (m, 1H), 7.79-7.64 (m, 3H), 7.59 (s, 1H),
7.49 (dd, J=5.1, 1.3 Hz, 1H), 6.38 (s, 1H), 6.03 (dd, J=12.5, 4.0
Hz, 1H), 5.27-5.04 (m, 2H), 2.72 (m, 1H), 2.30 (m, 1H), 2.14-1.97
(m, 2H), 1.69-1.42 (m, 2H), 1.03 (d, J=6.8 Hz, 3H), 0.71 (br. s.,
1H). MS(ESI) m/z: 634.3 [M+H].sup.+. Analytical HPLC (Method A):
RT=7.49 min, purity=>95.0%; Factor XIa Ki=0.38 nM, Plasma
Kallikrein Ki=52 nM.
Example 98
Preparation of
2-[(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-
-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic acid
trifluoroacetate
##STR00250##
[1559]
2-[(9R,13S)-13-{4-[5-Chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-o-
xo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.-
3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic acid
trifluoroacetate was prepared in a similar manned as the procedure
described in Example 95, using
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo-
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (0.020 g, 0.034 mmol), prepared as described in
Example 93, to yield
2-[(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-
-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic acid
trifluoroacetate (5.1 mg, 20% yield) as a white solid. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 9.45 (s, 1H), 8.80-8.68 (m, 2H),
7.95-7.90 (m, 1H), 7.83-7.76 (m, 1H), 7.74-7.67 (m, 2H), 7.59 (s,
1H), 7.49 (dd, J=5.1, 1.3 Hz, 1H), 6.53 (s, 1H), 6.01 (dd, J=12.5,
4.0 Hz, 1H), 5.28-5.05 (m, 2H), 2.71 (m, 1H), 2.27 (m, 1H),
2.13-1.95 (m, 2H), 1.66-1.39 (m, 2H), 1.03 (d, J=7.0 Hz, 3H), 0.72
(br. s., 1H). MS(ESI) m/z: 601.3 [M+H].sup.+. Analytical HPLC
(Method A): RT=6.62 min, purity=>95.0%; Factor XIa Ki=0.16 nM,
Plasma Kallikrein Ki=20 nM.
Example 99
Preparation of
2-[(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tetraaza-
tricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic
acid trifluoroacetate
##STR00251##
[1561]
2-[(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-
-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-te-
traazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic
acid trifluoroacetate was prepared in a similar manned as the
procedure described in Example 95, using
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-
-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (0.038 g, 0.058 mmol), prepared as described in
Example 94, to yield
2-[(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]-
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tetraazat-
ricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic
acid trifluoroacetate (7.5 mg, 16% yield) as a white solid. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.84 (s, 1H), 8.80 (s, 1H),
8.73-8.68 (m, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.80-7.75 (m, 1H), 7.71
(m, 2H), 7.58 (s, 1H), 7.49 (dd, J=5.1, 1.3 Hz, 1H), 6.46 (s, 1H),
6.03 (dd, J=12.4, 4.1 Hz, 1H), 5.26-5.06 (m, 2H), 2.77-2.66 (m,
1H), 2.27 (m, 1H), 2.13-1.94 (m, 2H), 1.67-1.40 (m, 2H), 1.02 (d,
J=6.8 Hz, 3H), 0.71 (br. s., 1H). MS(ESI) m/z: 668.3 [M+H].sup.+;
Factor XIa Ki=0.29 nM, Plasma Kallikrein Ki=52 nM.
Example 100
Preparation of
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00252##
[1562] 100A. Preparation of
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]
methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,-
14,16-pentaen-8-one
[1563]
(9R,13S)-13-{4-[3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluor-
ophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)e-
thoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(-
6),4,14,16-pentaen-8-one was prepared in a similar manner as the
procedures described in Example 56, by using
6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-
-ol (0.027 g, 0.083 mmol), prepared as described in Intermediate
10, and benzyl
N-[(9R,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,-
4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-penta-
en-13-yl]carbamate (0.034 g, 0.081 mmol), prepared as described in
Intermediate 41, to yield
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]-
methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,1-
4,16-pentaen-8-one (10 mg, 14% yield) as pale white solid. MS(ESI)
m/z: 723.5 [M+H].sup.+.
100B. Preparation of
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[1564] To a solution of
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]
methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,-
14,16-pentaen-8-one (10 mg, 0.014 mmol), in DCM (0.8 mL) was added
TFA (0.2 mL, 2.60 mmol) and the resulting solution was stirred at
rt for 30 min. The reaction mixture was then concentrated and the
residue was purified by prep HPLC purification to give
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.-
3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (4.8 mg, 46% yield) as a pale pink solid. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.74-8.59 (m, 2H), 8.42-8.30 (m,
1H), 7.99 (s, 1H), 7.88 (dd, J=8.6, 7.7 Hz, 1H), 7.77 (s, 1H), 7.67
(dd, J=5.3, 1.3 Hz, 1H), 7.58 (dd, J=8.6, 1.5 Hz, 1H), 6.65 (s,
1H), 6.07 (d, J=8.4 Hz, 1H), 2.90-2.74 (m, 1H), 2.44-2.18 (m, 2H),
2.14-2.02 (m, 1H), 1.83-1.67 (m, 1H), 1.63-1.47 (m, 1H), 1.11 (d,
J=6.8 Hz, 3H), 1.00 (br. s., 1H). MS(ESI) m/z: 594.5 [M+H].sup.+.
Analytical HPLC (Method A): RT=7.11 min, purity=>95.0%; Factor
XIa Ki=1.6 nM, Plasma Kallikrein Ki=85 nM.
Example 101
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00253##
[1565] 101A. Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)e-
thoxy]
methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2-
(6),4,14,16-pentaen-8-one
[1566]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]met-
hyl}-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,1-
6-pentaen-8-one was prepared in a similar manner as the procedure
described in Example 56, by using
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(0.034 g, 0.110 mmol), prepared as described in Intermediate 9, and
benzyl
N-[(9R,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,-
4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-penta-
en-13-yl]carbamate (0.046 g, 0.110 mmol), prepared as described in
Intermediate 41, to give
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)
ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),-
2(6),4,14,16-pentaen-8-one (12 mg, 14% yield) as pale yellow solid.
MS(ESI) m/z: 706.5 [M+H].sup.+.
101B. Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[1567] To a solution of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]
methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,-
14,16-pentaen-8-one (12 mg, 0.017 mmol) in DCM (0.8 mL) was added
TFA (0.2 mL, 2.60 mmol) and the reaction was stirred at rt for 30
min. The reaction mixture was then concentrated and the residue was
purified by prep HPLC purification to give
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
(5.3 mg, 43% yield) as a pale pink solid. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.72-8.57 (m, 2H), 8.37 (s, 1H), 7.99 (s, 1H),
7.91 (d, J=2.2 Hz, 1H), 7.82-7.72 (m, 2H), 7.70-7.63 (m, 2H), 6.41
(s, 1H), 6.11-5.95 (m, 1H), 2.81 (td, J=6.8, 3.4 Hz, 1H), 2.44-2.17
(m, 2H), 2.15-2.01 (m, 1H), 1.80-1.65 (m, 1H), 1.62-1.46 (m, 1H),
1.11 (d, J=7.0 Hz, 3H), 1.01 (br. s., 1H). MS(ESI) m/z: 576.4
[M+H].sup.+. Analytical HPLC (Method A): RT=6.98 min,
purity=>95.0%; Factor XIa Ki=4.2 nM, Plasma Kallikrein Ki=300
nM.
Example 102
Preparation of methyl
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraaza-
tricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate
trifluoroacetate
##STR00254##
[1568] 102A. Preparation of (S)-tert-butyl
(1-(4-hydrazinylpyridin-2-yl)but-3-en-1-yl) carbamate
[1569] A vial with a Teflon septum cap was charged with a solution
of (S)-tert-butyl (1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate
(2 g, 7.0 mmol), prepared as described in Intermediate 23, and 35%
aq hydrazine (10 mL, 111 mmol, 15.75 equiv) in EtOH (10 mL). The
solution was heated by an aluminum block at 115.degree. C. for 18
h. The reaction was concentrated to give a pink oil. The residue
was purified by normal phase silica gel chromatography to give
(S)-tert-butyl (1-(4-hydrazinylpyridin-2-yl)but-3-en-1-yl)carbamate
(1.67 g, 85% yield) as a yellow, foam. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.22 (d, J=5.7 Hz, 1H), 6.60 (s, 1H), 6.57 (dd,
J=5.5, 2.4 Hz, 1H), 5.79-5.54 (m, 3H), 5.14-4.99 (m, 2H), 4.74-4.62
(m, 1H), 2.59 (t, J=6.7 Hz, 2H), 1.52-1.40 (m, 9H). MS(ESI) m/z:
279.2 (M+H).sup.+.
102B. Preparation of (S)-ethyl
5-amino-1-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)-1-
H-pyrazole-3-carboxylate
[1570] Sodium (Z)-1-cyano-3-ethoxy-3-oxoprop-1-en-2-olate (0.29 g,
1.8 mmol) was suspended in a solution of (S)-tert-butyl
(1-(4-hydrazinylpyridin-2-yl)but-3-en-1-yl) carbamate (0.50 g, 1.8
mmol) in EtOH (15 ml). TFA (0.4 ml, 5.39 mmol, 3 equiv) was added
dropwise and the solid slowly dissolved upon heating to 80.degree.
C. Stirring was continued at 80.degree. C. for 2 h, then the
reaction was cooled to rt. The reaction was concentrated to an oil
and the residue dissolved in EtOAc. The organic layer was washed
with pH=7 phosphate buffer, separated and the organic layer was
concentrated to yield an oil. Purification of the crude oil by
normal phase silica gel chromatography yielded (S)-ethyl
5-amino-1-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)-1-
H-pyrazole-3-carboxylate (0.7 g, 97% yield) as a clear, colorless,
thick oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.71-8.67 (m,
1H), 7.64 (d, J=2.0 Hz, 1H), 7.60 (dd, J=5.4, 2.1 Hz, 1H), 6.20 (s,
1H), 5.79-5.66 (m, 1H), 5.56-5.42 (m, 1H), 5.15-5.06 (m, 3H),
4.93-4.82 (m, 1H), 4.44 (q, J=7.1 Hz, 2H), 4.03 (br. s., 2H), 2.66
(m, 2H), 1.46 (s, 9H), 1.45-1.41 (t, J=7.1 Hz, 3H). MS(ESI) m/z:
402.2 (M+H).sup.+.
102C. Preparation of ethyl
1-(2-((S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)
pyridin-4-yl)-5-((R)-2-methylbut-3-enamido)-1H-pyrazole-3-carboxylate
[1571] To a N.sub.2 flushed, 3-necked, 250 mL RBF was added a
solution (5)-ethyl
5-amino-1-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyrid-
in-4-yl)-1H-pyrazole-3-carboxylate (1.75 g, 4.36 mmol) and EtOAc
(15 mL). The solution was cooled to -10.degree. C. and
(R)-2-methylbut-3-enoic acid (436 mg, 4.36 mmol), as prepared in
Intermediate 2, pyridine (0.705 mL, 8.72 mmol) and T3P.RTM. (3.89
mL, 6.54 mmol) were added. The cooling bath was removed and the
solution was allowed to warm to rt and then stir for 20 h. Water
(20 mL) and EtOAc (20 mL) were added and the mixture was stirred
for 30 min. The organic phase was separated and the aqueous layer
was extracted with EtOAc (20 mL). The combined organic extracts
were washed with brine (15 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated. Purification by normal phase
chromatography eluting with a gradient of DCM/MeOH gave ethyl
1-(2-((S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)-5-((R-
)-2-methylbut-3-enamido)-1H-pyrazole-3-carboxylate (1.81 g, 86%
yield) as a white foaming solid. MS(ESI) m/z: 484.5
[M+H].sup.+.
102D. Preparation of ethyl
(10E,13S)-13-{[(tert-butoxy)carbonyl]amino}-9-methyl-8-oxo-2,3,7,15-tetra-
azatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),3,5,10,14,16-hexaene-4-carboxy-
late
[1572] To a N.sub.2 flushed, 250 mL, 3-necked, RBF was added a
solution of ethyl
1-(2-((S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)-
-5-((R)-2-methylbut-3-enamido)-1H-pyrazole-3-carboxylate (1.81 g,
3.74 mmol) and CH.sub.3SO.sub.3H (0.23 ml, 3.56 mmol) in DCM (30
mL). The resulting solution heated to 40.degree. C. The solution
was sparged with Ar for 15 min. Second Generation Grubbs Catalyst
(253 mg, 0.298 mmol) dissolved in DCM (10 mL) was added dropwise
over a period of 10 min at 40.degree. C. The reaction mixture was
heated at 40.degree. C. for overnight. After cooling to rt, the
solvent was removed and the residue was purified by normal phase
chromatography eluting with a gradient of DCM/MeOH to yield ethyl
(10E,13S)-13-{[(tert-butoxy)carbonyl]amino}-9-methyl-8-oxo-2,3,7,15-tetra-
azatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),3,5,10,14,16-hexaene-4-carboxy-
late (670 mg, 39% yield) as a gray solid. MS(ESI) m/z: 556.5
[M+H].sup.+.
102E. Preparation of ethyl
(13S)-13-{[(tert-butoxy)carbonyl]amino}-9-methyl-8-oxo-2,3,7,15-tetraazat-
ricyclo[12.3.1.0.sup.2,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate
[1573] Pd/C (0.16 g, 0.147 mmol) was added to a 250 mL Parr
hydrogenation flask containing a solution of ethyl
(10E,13S)-13-{[(tert-butoxy)carbonyl]amino}-9-methyl-8-oxo-2,3,7,15-tetra-
azatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),3,5,10,14,16-hexaene-4-carboxy-
late (670 mg, 1.471 mmol) in EtOH (15 mL). The flask was purged
with N.sub.2 and pressurized to 55 psi of H.sub.2 and allowed to
stir overnight. The reaction was filtered through a pad of
CELITE.RTM. and concentrated to yield ethyl
(13S)-13-{[(tert-butoxy)
carbonyl]amino}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate (500 mg, 70%
yield) as a tan solid. MS(ESI) m/z: 458.4 [M+H].sup.+.
102F. Ethyl
(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0.sup.2-
,6] octadeca-1(18),3,5,14,16-pentaene-4-carboxylate, bis
hydrochloride
[1574] To a solution of ethyl
(13S)-13-{[(tert-butoxy)carbonyl]amino}-9-methyl-8-oxo-2,3,7,15-tetraazat-
ricyclo[12.3.1.0.sup.2,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate
(500 mg, 1.093 mmol) in MeOH (5 mL) was added 4 M HCl in dioxane (5
mL, 20.0 mmol) and the resulting solution was stirred at rt for 1
h. The reaction mixture was then concentrated to give ethyl
(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate,
bis hydrochloride (380 mg, 97% yield, mixture of methyl and ethyl
esters) as a pale yellow solid. Additionally, also observed was the
formation of methyl
(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.-
0.sup.2,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate, bis
hydrochloride due to transesterification of the ethyl ester to
methyl ester as MeOH was used as solvent. The mixture of ethyl
(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0.sup.2-
,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate, bis
hydrochloride and methyl
(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.-
0.sup.2,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate, bis
hydrochloride were dissolved in MeOH (4 mL) to give a clear, pale
brown solution. The solution was added to a pre-rinsed AGILENT.RTM.
StratoSpheres SPE PL-HCO.sub.3 MP Resin cartridge. Gravity
filtration, eluting with MeOH, gave a clear, slightly yellow
filtrate. Concentration provided ethyl
(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0.sup.2-
,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate (MS(ESI) m/z:
330.5 [M+H].sup.+) and methyl
(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0.sup.2-
,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate (295 mg, 97%)
carboxylate (MS(ESI) m/z: 344.3 [M+H].sup.+) mixture as a pale
brown solid.
102G. Preparation of methyl
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate
trifluoroacetate
##STR00255##
[1576] Methyl
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6] octadeca-1(18),3,5,14,16-pentaene-4-carboxylate
trifluoroacetate was prepared in a similar manner as the procedure
described in Example 56, using 6-(5-chloro-2-(4-chloro-1
H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (0.035 g, 0.115 mmol),
prepared as described in Intermediate 9, and the mixture of ethyl
(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0.sup.2-
,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate and methyl
(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0.sup.2-
,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate (0.041 g, 0.115
mmol) to yield a mixture of methyl
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate and
ethyl
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate which
were further purified by prep HPLC to yield the desired methyl
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate
trifluoroacetate (7 mg, 8% yield) as white solid. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.95 (s, 1H), 8.74 (d, J=5.3 Hz, 1H), 8.34
(s, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.77-7.70
(m, 1H), 7.68-7.58 (m, 2H), 6.84 (s, 1H), 6.37 (s, 1H), 6.12 (dd,
J=12.4, 5.0 Hz, 1H), 3.94 (s, 3H), 2.84 (br. s., 1H), 2.34-2.12 (m,
2H), 2.08-1.92 (m, 1H), 1.80-1.48 (m, 2H), 0.98 (d, J=6.8 Hz, 3H),
0.45 (br. s., 1H). MS(ESI) m/z: 634.3 [M+H].sup.+. Analytical HPLC
(Method A): RT=9.07 min, purity=>95.0%; Factor XIa Ki=11 nM,
Plasma Kallikrein Ki=360 nM.
Example 103
Preparation of methyl
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricy-
clo
[12.3.1.0.sup.2,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate
trifluoroacetate
##STR00256##
[1578] Methyl
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricy-
clo
[12.3.1.0.sup.2,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate
trifluoroacetate was prepared in a similar manner as the procedure
described in Example 56, by using
6-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin--
4-ol (0.037 g, 0.115 mmol), prepared as described in Intermediate
16, and the mixture of ethyl
(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0.sup.2-
,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate and methyl
(9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0.sup.2-
,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate (0.041 g, 0.115
mmol), prepared as described in Example 102F, to yield a mixture of
methyl
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricy-
clo[12.3.1.0.sup.2,6]
octadeca-1(18),3,5,14,16-pentaene-4-carboxylate and ethyl
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-y-
l]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraaz-
atricyclo[12.3.1.0.sup.2,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate
which was further purified by prep HPLC to yield methyl
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricy-
clo[12.3.1.0.sup.2,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate
trifluoroacetate (7 mg, 8% yield) as white solid. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.95 (s, 1H), 8.75 (d, J=5.3 Hz, 1H),
8.59-8.55 (m, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H),
7.80-7.74 (m, 1H), 7.73-7.68 (m, 1H), 7.64 (dd, J=5.5, 2.0 Hz, 1H),
7.19-6.88 (m, 1H), 6.86 (s, 1H), 6.39 (s, 1H), 6.14 (dd, J=12.5,
5.1 Hz, 1H), 3.97 (s, 3H), 2.85 (d, J=6.8 Hz, 1H), 2.36-2.13 (m,
2H), 2.08-1.92 (m, 1H), 1.77-1.51 (m, 2H), 1.01 (d, J=6.8 Hz, 3H),
0.45 (d, J=13.6 Hz, 1H). MS(ESI) m/z: 650.3 [M+H].sup.+. Analytical
HPLC (Method A): RT=8.98 min, purity=>95.0%; Factor XIa Ki=6.5
nM, Plasma Kallikrein Ki=200 nM.
Example 104
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6] octadeca-1(18),3,5,14,16-pentaene-4-carboxylic acid
trifluoroacetate
##STR00257##
[1580] Ethyl
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,
7,15-tetraazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),3,5,14,16-pentaene-4-carboxylate (0.035 g, 0.054
mmol), prepared as described in Example 102, was hydrolyzed using 2
M LiOH solution (0.08 mL, 0.162 mmol) at rt for 1 h. The reaction
was neutralized using 1 N HCl and concentrated. The crude product
was purified using prep HPLC to yield
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylic acid
trifluoroacetate (20 mg, 48% yield) as a white solid. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.98 (s, 1H), 8.76 (d, J=5.3 Hz, 1H),
8.36 (s, 1H), 7.92 (d, J=2.2 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H),
7.79-7.73 (m, 1H), 7.70-7.63 (m, 2H), 6.85 (s, 1H), 6.40 (d, J=0.7
Hz, 1H), 6.15 (dd, J=12.4, 5.0 Hz, 1H), 2.88 (d, J=8.8 Hz, 1H),
2.38-2.15 (m, 2H), 2.10-1.94 (m, 1H), 1.80-1.52 (m, 2H), 1.01 (d,
J=6.8 Hz, 3H), 0.48 (br. s., 1H). MS(ESI) m/z: 620.3 [M+H].sup.+.
Analytical HPLC (Method A): RT=7.96 min, purity=>95.0%; Factor
XIa Ki=1.7 nM, Plasma Kallikrein Ki=470 nM.
Example 105
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraaza-
tricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylic
acid trifluoro acetate
##STR00258##
[1582] Ethyl
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraaza-
tricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate
(0.035 g, 0.053 mmol), prepared as described in Example 103, was
hydrolyzed using 2 M LiOH (0.079 mL, 0.158 mmol) at rt for 1 h. The
reaction was neutralized using 1 N HCl and concentrated. The crude
product was purified using prep HPLC purification to yield
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricy-
clo[12.3.1.0.sup.2,6]octadeca-1(18),3,5,14,16-pentaene-4-carboxylic
acid trifluoroacetate (10 mg, 24% yield) as a white solid. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.96 (s, 1H), 8.75 (d, J=5.3 Hz,
1H), 8.60-8.55 (m, 1H), 7.93 (d, J=2.2 Hz, 1H), 7.85 (d, J=1.8 Hz,
1H), 7.80-7.74 (m, 1H), 7.73-7.62 (m, 2H), 7.20-6.89 (m, 1H), 6.85
(s, 1H), 6.39 (s, 1H), 6.15 (dd, J=12.5, 4.8 Hz, 1H), 2.93-2.82 (m,
1H), 2.34-2.14 (m, 2H), 2.09-1.95 (m, 1H), 1.77-1.52 (m, 2H), 1.01
(d, J=6.8 Hz, 3H), 0.46 (d, J=10.1 Hz, 1H). MS(ESI) m/z: 636.3
[M+H].sup.+. Analytical HPLC (Method A): RT=7.97 min,
purity=>95.0%; Factor XIa Ki=0.92 nM, Plasma Kallikrein Ki=470
nM.
Example 106
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,15-tetra-
azatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00259##
[1584] To a vial (4 ml) containing a suspension
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(0.028 g, 0.089 mmol), prepared as described in Intermediate 9, in
ACN (1 ml) was added HATU (0.044 g, 0.116 mmol) and DBU (0.020 ml,
0.134 mmol). After 20 min,
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,15-tetraazatricy-
clo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(0.027 g, 0.089 mmol), prepared as described in Intermediate 33, in
DMF (1.0 ml) was added at rt. After 4 h, the crude mixture was
purified by reverse phase chromatography (PHENOMENEX.RTM. Luna Axia
C18 5.mu. 30.times.100 mm column, Solvent A: 20% ACN-80%
H.sub.2O-0.1% TFA; Solvent B: 80% ACN-20% H.sub.2O-0.1% TFA) to
give
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,15-tetra-
azatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (19 mg, 28.6%) as a white solid. MS(ESI) m/z:
593.1 (M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.84
(s, 1H), 8.75 (d, J=5.0 Hz, 1H), 8.36 (s, 1H), 7.91 (d, J=2.5 Hz,
1H), 7.76 (dd, J=8.5, 2.2 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J=8.5 Hz,
1H), 7.56-7.50 (m, 2H), 6.39 (s, 1H), 6.01 (dd, J=12.5, 4.0 Hz,
1H), 2.73 (td, J=6.6, 3.0 Hz, 1H), 2.32 (ddt, J=12.8, 8.6, 4.4 Hz,
1H), 2.13-1.99 (m, 2H), 1.67-1.59 (m, 1H), 1.53-1.45 (m, 1H), 1.03
(d, J=6.9 Hz, 3H), 0.71 (br. s., 1H). Analytical HPLC (Method A):
RT=8.55 min, purity=99.0%; Factor XIa Ki=0.27 nM, Plasma Kallikrein
Ki=27 nM.
Example 107
Preparation of
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7-
,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen--
8-one trifluoroacetate
##STR00260##
[1586] To a vial (4 ml) containing a suspension
6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]pyrimidin-4-
-ol hydrobromide (0.034 g, 0.083 mmol), prepared as described in
Intermediate 10, in ACN (1 ml) was added HATU (0.041 g, 0.107 mmol)
and DBU (0.034 ml, 0.223 mmol). After 30 min,
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,15-tetraazatricy-
clo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(0.027 g, 0.089 mmol), prepared as described in Intermediate 33, in
DMF (1.0 ml) was added at rt. After 2 h, the crude mixture was
purified by reverse phase chromatography (PHENOMENEX.RTM. Luna Axia
C18 5.mu. 30.times.100 mm column, Solvent A: 20% ACN-80%
H.sub.2O-0.1% TFA; Solvent B: 80% ACN-20% H.sub.2O-0.1% TFA) to
give
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7-
,15-tetraazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (20.3
mg, 32.2%) as a white solid. MS(ESI) m/z: 611.2 (M+H).sup.+ and
613.1 (M+2+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.85
(s, 1H), 8.78 (d, J=5.1 Hz, 1H), 8.36 (s, 1H), 7.93-7.87 (m, 1H),
7.75 (s, 1H), 7.60-7.55 (m, 2H), 7.53 (s, 1H), 6.64 (s, 1H), 6.03
(dd, J=12.7, 4.1 Hz, 1H), 2.74 (td, J=6.6, 3.1 Hz, 1H), 2.38-2.29
(m, 1H), 2.14-2.01 (m, 2H), 1.69-1.61 (m, 1H), 1.54-1.46 (m, 1H),
1.05 (d, J=7.0 Hz, 3H), 0.78-0.70 (m, 1H). Analytical HPLC (Method
A): RT=8.66 min, purity=96.8%; Factor XIa Ki=0.1 nM, Plasma
Kallikrein Ki=8 nM.
Example 108
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricycl-
o [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00261##
[1588] To a vial (4 ml) containing a suspension
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(0.023 g, 0.075 mmol), prepared as described in Intermediate 9, in
ACN (1 ml) was added HATU (0.037 g, 0.097 mmol) and DBU (0.017 ml,
0.112 mmol). After 30 min,
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.025 g,
0.075 mmol), prepared as described in Intermediate 35, in DMF (1.0
ml) was added at rt. After stirring overnight, the crude mixture
was concentrated and the residue purified by reverse phase
chromatography (PHENOMENEX.RTM. Luna Axia C18 5.mu. 30.times.100 mm
column, Solvent A: 20% ACN-80% H.sub.2O-0.1% TFA; Solvent B: 80%
ACN-20% H.sub.2O-0.1% TFA) to give
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricycl-
o[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one (11
mg, 22.4%) as a white solid. MS(ESI) m/z: 625.1 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.84 (s, 1H), 8.75 (d,
J=5.0 Hz, 1H), 8.36 (s, 1H), 7.91 (d, J=2.5 Hz, 1H), 7.76 (dd,
J=8.5, 2.2 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.56-7.50
(m, 2H), 6.39 (s, 1H), 6.01 (dd, J=12.5, 4.0 Hz, 1H), 2.73 (td,
J=6.6, 3.0 Hz, 1H), 2.32 (ddt, J=12.8, 8.6, 4.4 Hz, 1H), 2.13-1.99
(m, 2H), 1.67-1.59 (m, 1H), 1.53-1.45 (m, 1H), 1.03 (d, J=6.9 Hz,
3H), 0.71 (br. s., 1H). Analytical HPLC (Method A): RT=10.12 min,
purity=98.0%; Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=16 nM.
Example 109
Preparation of
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-tria-
zatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00262##
[1590] To a vial (4 ml) containing a suspension
6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]pyrimidin-4-
-ol (0.020 g, 0.060 mmol), prepared as described in Intermediate
10, in ACN (1 ml) was added HATU (0.030 g, 0.107 mmol) and DBU
(0.014 ml, 0.090 mmol). After 30 min,
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.020 g,
0.060 mmol), prepared as described in Intermediate 35, in DMF (1.0
ml) was added at rt. After 2 h, the crude mixture was purified by
reverse phase chromatography (PHENOMENEX.RTM. Luna Axia C18 5.mu.
30.times.100 mm column, Solvent A: 20% ACN-80% H.sub.2O-0.1% TFA;
Solvent B: 80% ACN-20% H.sub.2O-0.1% TFA) to give
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-tria-
zatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(7.5 mg, 19.1%) as a white solid. MS(ESI) m/z: 643.1 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.33 (s, 1H), 8.26 (s,
1H), 7.91-7.77 (m, 3H), 7.67-7.49 (m, 4H), 7.41 (d, J=7.7 Hz, 1H),
6.66 (s, 1H), 5.85 (dd, J=12.9, 3.2 Hz, 1H), 2.53 (td, J=6.8, 3.2
Hz, 1H), 2.43-2.34 (m, 1H), 2.21-2.10 (m, 1H), 1.98-1.88 (m, 1H),
1.65-1.53 (m, 2H), 1.29-1.15 (m, 4H). Analytical HPLC (Method A):
RT=10.18 min, purity=98.5%; Factor XIa Ki=0.1 nM, Plasma Kallikrein
Ki=5 nM.
Example 110
[1591] Preparation of
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl(10,11-.sup.2H.sub.2)-3,4,-
7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-
-8-one trifluoroacetate
##STR00263##
110A. Preparation of tert-butyl
N-[(9R,13S)-3,9-dimethyl-8-oxo(10,11-.sup.2H.sub.2)-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
[1592] To a solution of tert-butyl
N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (165 mg,
0.415 mmol), prepared as described in Intermediate 32E, in
CD.sub.3OD (7 ml), under N.sub.2 was added Pd/C (44.2 mg, 0.042
mmol), and the resulting solution was purged and refilled with
N.sub.2, then purged and refilled with D.sub.2 (3.times.). The
solution was stirred at rt at 50 psi D.sub.2 for 29 h. The reaction
mixture was filtered through CELITE.RTM. followed by a syringe
filter. The filtrate was concentrated to dryness and dried further
under vacuum to give tert-butyl
N-[(9R,13S)-3,9-dimethyl-8-oxo(10,11-.sup.2H.sub.2)-3,4,7,15-tetraazatric-
yclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
as a light brown solid. MS(ESI) m/z: 402.3 (M+H).sup.+. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.68 (d, J=5.3 Hz, 1H), 7.49-7.43 (m,
3H), 4.77 (dd, J=11.0, 5.3 Hz, 1H), 4.05 (s, 3H), 2.75-2.65 (m,
1H), 1.94 (br. s., 1H), 1.90-1.80 (m, 1H), 1.73-1.61 (m, 1H), 1.54
(t, J=5.8 Hz, 1H), 1.42 (s, 9H), 0.94 (d, J=6.8 Hz, 3H).
110B. Preparation of
(9R,13S)-13-amino-3,9-dimethyl(10,11-.sup.2H.sub.2)-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[1593] CF.sub.3COOD (0.230 ml, 2.99 mmol) was added to a solution
of tert-butyl
N-[(9R,13S)-3,9-dimethyl-8-oxo(10,11-.sup.2H.sub.2)-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(0.040 g, 0.100 mmol) in CD.sub.2Cl.sub.2 (1 ml, 15.67 mmol) at rt.
After 1 h, the reaction mixture was concentrated. The residue was
dissolved in MeOH and free based by passing through two consecutive
resin bound NaHCO.sub.3 cartridges (StratoSpheres SPE; 500 mg, 0.90
mmol loading) and concentrated.
(9R,13S)-13-Amino-3,9-dimethyl(10,11-.sup.2H.sub.2)-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one,
was carried forward `as is` to next reaction. MS(ESI) m/z: 302.2
(M+H).sup.+.
110C. Preparation of
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl(10,11-.sup.2H.sub.2)-3,4,-
7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-
-8-one trifluoroacetate
[1594] To a vial (4 ml) containing a suspension
6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]pyrimidin-4-
-ol (0.027 g, 0.083 mmol), prepared as described in Intermediate
10, in ACN (1 ml) was added HATU (0.041 g, 0.108 mmol) and DBU
(0.019 ml, 0.124 mmol). After 30 min,
(9R,13S)-13-amino-3,9-dimethyl(10,11-.sup.2H.sub.2)-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one, in
DMF (1.0 ml) was added at rt. After 2 h, the crude mixture was
purified by reverse phase chromatography (PHENOMENEX.RTM. Luna Axia
C18 5.mu. 30.times.100 mm column, Solvent A: 20% ACN-80%
H.sub.2O-0.1% TFA; Solvent B: 80% ACN-20% H.sub.2O-0.1% TFA) to
give
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl(10,11-.sup.2H.sub.2)-3,4,-
7,15-tetraazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (22 mg,
35.9%) as a white solid. MS(ESI) m/z: 610.2 (M+H).sup.+. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.84 (s, 1H), 8.77 (d, J=5.1 Hz,
1H), 8.35 (s, 1H), 7.88 (dd, J=8.7, 7.6 Hz, 1H), 7.74 (s, 1H),
7.61-7.54 (m, 2H), 7.52 (s, 1H), 6.63 (s, 1H), 6.02 (dd, J=12.8,
4.0 Hz, 1H), 4.08 (s, 3H), 2.72 (t, J=6.8 Hz, 1H), 2.36-2.29 (m,
1H), 2.07-2.00 (m, 1H), 1.61 (t, J=6.3 Hz, 1H), 1.47 (d, J=3.7 Hz,
1H), 1.03 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A): RT=7.94
min, purity=99.3%; Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=8
nM.
Example 111
Preparation of
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl(10,11-
-.sup.2H.sub.2)-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),-
2(6),4,14,16-pentaen-8-one trifluoroacetate
##STR00264##
[1595] 111A. Preparation of tert-butyl
N-[(9R,13S)-3-(2H.sub.3)methyl-9-methyl-8-oxo(10,11-.sup.2H.sub.2)3,4,7,1-
5-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-
-yl]carbamate
[1596] tert-Butyl
N-[(9R,10E,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-oxo-3,4,7,15-tetraazat-
ricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carba-
mate (153 mg, 0.382 mmol), prepared as described in Example 33E, in
CD.sub.3OD (7 ml), under N.sub.2 was added Pd/C (0.0382 mmol), the
resulting solution was purged and refilled with N.sub.2, then
refilled with D.sub.2 (3.times.), and stirred at rt at 50 psi
D.sub.2 for 65 h. The reaction mixture was filtered through
CELITE.RTM. followed by a syringe filter. The filtrate was
concentrated to dryness and dried further under vacuum to give
tert-butyl
N-[(9R,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-oxo(10,11-.sup.2H.sub.2)3,-
4,7,15
tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-penta-
en-13-yl]carbamate as a light brown solid (143.4 mg, 88.2%).
MS(ESI) m/z: 405.3 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.68 (d, J=5.1 Hz, 1H), 7.50-7.42 (m, 3H), 4.80-4.73 (m,
1H), 3.61 (q, J=7.0 Hz, 1H), 2.76-2.65 (m, 1H), 1.96-1.80 (m, 1H),
1.72-1.61 (m, 1H), 1.54 (t, J=5.6 Hz, 1H), 1.42 (s, 9H), 1.18 (t,
J=7.0 Hz, 1H), 0.94 (d, J=7.0 Hz, 3H).
111B. Preparation of
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl(10,11-.sup.2H.sub.2)-3-
,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pent-
aen-8-one
[1597] CF.sub.3COOD (0.229 ml, 2.97 mmol) was added to a solution
tert-butyl
N-[(9R,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-oxo(10,11-.sup.2H.sub.2)3,-
4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-penta-
en-13-yl]carbamate (0.040 g, 0.099 mmol) in CD.sub.2Cl.sub.2 (1 ml,
15.67 mmol) at rt. After 1 h, the reaction mixture was concentrated
to dryness. The residue was dissolved in MeOH and free based by
passing through two consecutive resin bound NaHCO.sub.3 cartridges
(StratoSpheres SPE; 500 mg, 0.90 mmol loading) and concentrated.
The product,
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl(10,11-.sup.2H.sub.2)-3-
,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pent-
aen-8-one, was carried forward `as is` to next reaction. MS(ESI)
m/z: 305.2 (M+H).sup.+.
111C. Preparation of
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl(10,11-
-.sup.2H.sub.2)-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),-
2(6),4,14,16-pentaen-8-one trifluoroacetate
[1598] To a vial (4 ml) containing a suspension
6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]pyrimidin-4-
-ol (0.027 g, 0.083 mmol), prepared as described in Intermediate
10, in ACN (1 ml) was added HATU (0.041 g, 0.108 mmol) and DBU
(0.019 ml, 0.124 mmol). After 30 min,
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl
(10,11-.sup.2H.sub.2)-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-
-1(18),2(6),4,14,16-pentaen-8-one (0.025 g, 0.082 mmol) in DMF (1.0
ml) was added at rt. After 2 h, the crude mixture was purified by
reverse phase chromatography (PHENOMENEX.RTM. Luna Axia C18 5.mu.
30.times.100 mm column, Solvent A: 20% ACN-80% H.sub.2O-0.1% TFA;
Solvent B: 80% ACN-20% H.sub.2O-0.1% TFA) to give
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl(10,11-
-.sup.2H.sub.2)-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),-
2(6),4,14,16-pentaen-8-one trifluoroacetate (19.2 mg, 30.8%) as a
white solid. MS(ESI) m/z: 613.2 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.90-8.75 (m, 2H), 8.35 (s, 1H), 7.87 (d, J=7.7
Hz, 1H), 7.76 (br. s., 1H), 7.64-7.52 (m, 3H), 6.63 (s, 1H), 6.00
(d, J=12.1 Hz, 1H), 2.76-2.68 (m, 1H), 2.37-2.29 (m, 1H), 2.08-2.02
(m, 1H), 1.61 (t, J=6.2 Hz, 1H), 1.46 (d, J=4.4 Hz, 1H), 1.03 (d,
J=6.8 Hz, 3H). Analytical HPLC (Method A): RT=7.90 min,
purity=99.1%; Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=8 nM.
Example 112
Preparation of
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl(10,11-.sup-
.2H.sub.2)-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),-
4,14,16-pentaen-8-one trifluoroacetate
##STR00265##
[1599] 112A. Preparation of tert-butyl
N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo(10,11-.sup.2H.sub.2)-3,4,7,-
15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-1-
3-yl]carbamate
[1600] tert-Butyl
N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
(180 mg, 0.415 mmol), prepared as described in Example 30E, in
CD.sub.3OD (7 ml), under N.sub.2 was added Pd/C (0.0415 mmol), the
resulting solution was purged and refilled with N.sub.2 and
refilled with D.sub.2 (3.times.), then stirred at rt at 50 psi
D.sub.2 for 60 h. The reaction mixture was filtered through
CELITE.RTM. followed by a syringe filter. The filtrate was
concentrated to dryness and dried further under vacuum to give
tert-butyl
N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo(10,11-.sup.2H.sub.2)-3,4,7,-
15-tetraazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate as a light
brown solid (167 mg, 88.9%). MS(ESI) m/z: 438.3 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.70 (d, J=5.5 Hz, 1H),
7.79 (s, 1H), 7.72 (s, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.52-7.44 (m,
4H), 3.61 (q, J=7.0 Hz, 1H), 2.69 (t, J=6.8 Hz, 2H), 1.91-1.82 (m,
2H), 1.74-1.64 (m, 2H), 1.53 (t, J=5.8 Hz, 2H), 1.42 (s, 13H),
1.33-1.14 (m, 6H), 0.94 (d, J=7.0 Hz, 6H).
112B. Preparation of
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl(10,11-.sup.2H.sub.2)-3,4,7,-
15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-
-one
[1601] CF.sub.3COOD (0.211 ml, 2.74 mmol) was added to a solution
tert-butyl
N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo(10,11-.sup.2H.sub.2)-3,4,7,-
15-tetraazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.040 g, 0.091
mmol) in CD.sub.2Cl.sub.2 (1 ml, 15.67 mmol) at rt. After 1 h, the
reaction mixture was concentrated to dryness. The residue was
dissolved in MeOH and free based by passing through two consecutive
resin bound NaHCO.sub.3 cartridges (StratoSpheres SPE; 500 mg, 0.90
mmol loading) and concentrated. The product,
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl(10,11-.sup.2H.sub.2)-3,4,7,-
15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-
-one was carried forward as is to next reaction. MS(ESI) m/z: 338.2
(M+H).sup.+.
112C. Preparation of
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl(10,11-.sup-
.2H.sub.2)-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),-
4,14,16-pentaen-8-one trifluoroacetate
[1602] To a vial (4 ml) containing a suspension
6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]pyrimidin-4-
-ol (0.024 g, 0.074 mmol), prepared as described in Intermediate
10, in ACN (1 ml) was added HATU (0.037 g, 0.096 mmol) and DBU
(0.017 ml, 0.111 mmol). After 30 min,
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl(10,11-.sup.2H.sub.2)-3,4,7,-
15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-
-one (0.025 g, 0.074 mmol) in DMF (1.0 ml) was added at rt. After 2
h, the crude mixture was purified by reverse phase chromatography
(PHENOMENEX.RTM. Luna Axia C18 5.mu. 30.times.100 mm column,
Solvent A: 20% ACN-80% H.sub.2O-0.1% TFA; Solvent B: 80% ACN-20%
H.sub.2O-0.1% TFA) to give
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-flu-
orophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl(10-
,11-.sup.2H.sub.2)-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(1-
8),2(6),4,14,16-pentaen-8-one trifluoroacetate (16.8 mg, 29.8%) as
a white solid. MS(ESI) m/z: 646.3 (M+H).sup.+. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.91 (s, 1H), 8.78 (d, J=5.1 Hz, 1H), 8.34
(s, 1H), 7.91-7.85 (m, 1H), 7.83-7.67 (m, 3H), 7.58-7.52 (m, 2H),
6.63 (s, 1H), 6.04 (dd, J=12.8, 4.6 Hz, 1H), 2.73 (quin, J=6.8 Hz,
1H), 2.31 (td, J=12.8, 4.0 Hz, 1H), 2.07-1.99 (m, 1H), 1.59 (t,
J=6.1 Hz, 1H), 1.48 (d, J=4.8 Hz, 1H), 1.01 (d, J=6.8 Hz, 3H).
Analytical HPLC (Method A): RT=8.81 min, purity=100%; Factor XIa
Ki=0.1 nM, Plasma Kallikrein Ki=6 nM.
Example 113
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl(10,11-.sup.2H.sub.2-
)-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-p-
entaen-8-one trifluoroacetate
##STR00266##
[1604]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl(10,11-.sup.2H-
.sub.2)-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one was
prepared in a similar manner as the procedure described in Example
112, by using
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(0.023 g, 0.075 mmol), prepared in Intermediate 9, to give
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl(10,11-.sup.2H.sub.2-
)-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate as a white solid (20.4 mg, 36.3%). MS(ESI) m/z:
628.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.91 (s, 1H),
8.77 (d, J=5.1 Hz, 1H), 8.36 (s, 1H), 7.91 (d, J=2.4 Hz, 1H),
7.83-7.65 (m, 5H), 7.58-7.52 (m, 1H), 6.39 (d, J=0.4 Hz, 1H), 6.03
(dd, J=12.8, 4.6 Hz, 1H), 2.74 (t, J=6.7 Hz, 1H), 2.32 (td, J=12.9,
4.0 Hz, 1H), 2.07-1.98 (m, 1H), 1.59 (t, J=6.2 Hz, 1H), 1.48 (d,
J=4.8 Hz, 1H), 1.02 (d, J=7.0 Hz, 3H). Analytical HPLC (Method A):
RT=8.81 min, purity=99.3%; Factor XIa Ki=0.1 nM, Plasma Kallikrein
Ki=25 nM.
Example 114
Preparation of
(10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-
-1,6-dihydropyrimidin-1-yl}-10-methyl-3,8,16-triazatricyclo[13.3.1.0.sup.2-
,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one,
bis-trifluoroacetate
##STR00267##
[1606] To a vial (4 ml) containing a suspension
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(0.021 g, 0.067 mmol), prepared as described in Intermediate 9, in
ACN (1 ml) was added HATU (0.033 g, 0.088 mmol) and DBU (0.015 ml,
0.101 mmol). After 30 min,
(10R,14S)-14-amino-10-methyl-3,8,16-triazatricyclo[13.3.1.0.sup.2,7]
nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one (0.020 g, 0.067 mmol),
prepared as described in Intermediate 38, in DMF (1.0 ml) was added
at rt. After 4 h, the crude mixture was purified by reverse phase
chromatography (PHENOMENEX.RTM. Luna Axia C18 5.mu. 30.times.100 mm
column, Solvent A: 20% ACN-80% H.sub.2O-0.1% TFA; Solvent B: 80%
ACN-20% H.sub.2O-0.1% TFA) to give
(10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-
-1,6-dihydropyrimidin-1-yl}-10-methyl-3,8,16-triazatricyclo[13.3.1.0.sup.2-
,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one, bis-trifluoroacetate
(3.7 mg, 6.72%) as a white solid. MS(ESI) m/z: 587.1 (M+H).sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.02 (s, 1H), 8.77 (d,
J=4.8 Hz, 1H), 8.66 (d, J=4.8 Hz, 1H), 8.37 (s, 1H), 7.94-7.88 (m,
2H), 7.79-7.74 (m, 2H), 7.71-7.67 (m, 2H), 7.59 (dd, J=8.1, 4.8 Hz,
1H), 6.39 (s, 1H), 6.09 (dd, J=12.8, 5.1 Hz, 1H), 2.76 (br. s.,
1H), 2.28 (t, J=12.8 Hz, 1H), 2.10-2.03 (m, 2H), 1.62-1.53 (m, 2H),
1.01 (d, J=7.0 Hz, 3H), 0.66 (br. s., 1H). Analytical HPLC (Method
A): RT=7.60 min, purity=99.0%; Factor XIa Ki=3.3 nM, Plasma
Kallikrein Ki=200 nM.
Example 115
Preparation of
(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrim-
idin-1-yl]-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00268##
[1608] To a vial (4 ml) containing a suspension
6-(5-chloro-1-methyl-1H-indazol-7-yl)pyrimidin-4-ol (0.017 g, 0.066
mmol), prepared as described in Intermediate 22, in ACN (1 ml) was
added HATU (0.033 g, 0.086 mmol) and DBU (0.015 ml, 0.099 mmol).
After 30 min,
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,15-tetraazatricy-
clo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(0.020 g, 0.066 mmol), prepared as described in Intermediate 33, in
DMF (1.0 ml) was added at rt. After 4 h, the crude mixture was
purified by reverse phase chromatography (PHENOMENEX.RTM. Luna Axia
C18 5.mu. 30.times.100 mm column, Solvent A: 20% ACN-80%
H.sub.2O-0.1% TFA; Solvent B: 80% ACN-20% H.sub.2O-0.1% TFA) to
give
(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrim-
idin-1-yl]-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (7.2 mg, 16.3%) as a white solid. MS(ESI) m/z:
587.1 (M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.10
(s, 1H), 8.81 (d, J=5.3 Hz, 1H), 8.11 (s, 1H), 7.94 (d, J=2.0 Hz,
1H), 7.87 (s, 1H), 7.66 (d, J=5.1 Hz, 1H), 7.59-7.55 (m, 1H), 7.50
(d, J=1.8 Hz, 1H), 6.80 (s, 1H), 6.10 (dd, J=12.4, 4.1 Hz, 1H),
4.01-3.96 (m, 3H), 2.76 (dd, J=6.6, 3.1 Hz, 1H), 2.51-2.46 (m, 1H),
2.22-2.11 (m, 2H), 1.72-1.67 (m, 1H), 1.56 (br. s., 1H), 1.08 (d,
J=7.0 Hz, 3H), 0.85 (br. s., 1H). Analytical HPLC (Method A):
RT=7.41 min, purity=100.0%.; Factor XIa Ki=113 nM.
Example 116
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihyd-
ropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00269##
[1610] To a vial (4 ml) containing a suspension
6-[5-chloro-2-(1H-1,2,3-triazol-1-yl) phenyl]pyrimidin-4-ol (0.016
g, 0.060 mmol), prepared as described in Intermediate 8, in ACN (1
ml) was added HATU (0.030 g, 0.078 mmol) and DBU (0.014 ml, 0.090
mmol). After 30 min
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.020
g, 0.060 mmol), prepared as described in Intermediate 35, in DMF
(1.0 ml) was added at rt. After 4 h, the crude mixture was purified
by reverse phase chromatography (PHENOMENEX.RTM. Luna Axia C18
5.mu. 30.times.100 mm column, Solvent A: 20% ACN-80% H.sub.2O-0.1%
TFA; Solvent B: 80% ACN-20% H.sub.2O-0.1% TFA) to give
(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrim-
idin-1-yl]-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one as a white
solid. MS(ESI) m/z: 591.3 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.22 (d, J=1.8 Hz, 2H), 7.90-7.72 (m, 5H),
7.66-7.50 (m, 4H), 7.41 (d, J=7.5 Hz, 1H), 6.27 (s, 1H), 5.83 (dd,
J=12.9, 3.4 Hz, 1H), 2.57-2.47 (m, 1H), 2.41-2.31 (m, 1H),
2.18-2.06 (m, 1H), 1.90 (dd, J=9.5, 5.1 Hz, 1H), 1.64-1.52 (m, 2H),
1.27-1.11 (m, 4H). Analytical HPLC (Method A): RT=8.82 min,
purity=98.4%; Factor XIa Ki=0.72 nM, Plasma Kallikrein Ki=120
nM.
Example 117
Preparation of
(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrim-
idin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00270##
[1612] To a vial (4 ml) containing a suspension of
6-(5-chloro-1-methyl-1H-indazol-7-yl) pyrimidin-4-ol. (0.016 g,
0.060 mmol), prepared as described in Intermediate 22, in ACN (1
ml) was added HATU (0.030 g, 0.078 mmol) and DBU (0.014 ml, 0.090
mmol). After 30 min
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1-
.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.020 g,
0.060 mmol), prepared as described in Intermediate 35, in DMF (1.0
ml) was added at rt. After 4 h, the crude mixture was purified by
reverse phase chromatography (PHENOMENEX.RTM. Luna Axia C18 5.mu.
30.times.100 mm column, Solvent A: 20% ACN-80% H.sub.2O-0.1% TFA;
Solvent B: 80% ACN-20% H.sub.2O-0.1% TFA) to give
(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrim-
idin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0.sup.2-
,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one (11 mg, 30.2%) as a
white solid. MS(ESI) m/z: 578.2 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.36 (s, 1H), 7.95 (s, 1H), 7.79-7.74 (m, 2H),
7.66 (s, 1H), 7.54-7.38 (m, 4H), 7.34 (d, J=2.0 Hz, 1H), 6.67 (s,
1H), 5.83 (dd, J=13.0, 3.3 Hz, 1H), 3.79 (s, 3H), 2.41-2.32 (m,
2H), 2.11 (d, J=12.5 Hz, 1H), 1.83-1.76 (m, 1H), 1.53-1.45 (m, 2H),
1.16-1.03 (m, 4H). Analytical HPLC (Method A): RT=9.56 min,
purity=100%; Factor XIa Ki=90 nM, Plasma Kallikrein Ki=3,800
nM.
Example 118
Preparation of
(10R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophen-
yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,8,16-triazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
bis-trifluoroacetate
##STR00271##
[1614] To a vial (4 ml) containing a suspension
6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]pyrimidin-4-
-ol (0.028 g, 0.084 mmol), prepared as described in Intermediate
10, in ACN (1 ml) was added HATU (0.042 g, 0.11 mmol) and DBU
(0.019 ml, 0.127 mmol). After 30 min,
10R,145)-14-amino-10-methyl-3,8,16-triazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one (0.025
g, 0.084 mmol), prepared as described in Intermediate 39, in DMF
(1.0 ml) was added at rt. After stirring overnight, the crude
mixture was purified by reverse phase chromatography
(PHENOMENEX.RTM. Luna Axia C18 5.mu. 30.times.100 mm column,
Solvent A: 20% ACN-80% H.sub.2O-0.1% TFA; Solvent B: 80% ACN-20%
H.sub.2O-0.1% TFA) to give, after concentration and lyophilization
(10R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophen-
yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,8,16-triazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one,
bis-trifluoroacetate (13 mg, 17.6%) as a white solid. MS(ESI) m/z:
611.2 (M+H).sup.+ and 613.1 (M+2+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. .sup.1H NMR (500 MHz, CD.sub.3OD-d.sub.4) d
8.98 (s, 1H), 8.86-8.83 (m, 1H), 8.75-8.71 (m, 1H), 8.37 (s, 1H),
7.98 (s, 1H), 7.95-7.87 (m, 2H), 7.79-7.71 (m, 2H), 7.59-7.57 (m,
1H), 6.64 (s, 1H), 6.08 (dd, J=12.4, 5.0 Hz, 1H), 2.77 (br. s.,
1H), 2.35-2.28 (m, 1H), 2.13-2.02 (m, 2H), 1.61-1.55 (m, 2H), 1.29
(d, J=6.9 Hz, 1H), 1.00 (d, J=7.2 Hz, 3H), 0.66 (br. s., 1H).
Analytical HPLC (Method A): RT=7.11 min, purity=97.5%; Factor XIa
Ki=1.4 nM, Plasma Kallikrein Ki=73 nM.
Example 119
Preparation of
(9R,13S)-3-(difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluoromethy-
l)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,4,7,17-
-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-o-
ne
##STR00272##
[1615] 119A. Preparation of
4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
[1616] 2-Bromo-4-methylaniline (3 g, 16.12 mmol),
bis(pinacolato)diboron (6.14 g, 24.19 mmol), KOAc (4.07 g, 41.4
mmol) were added to DMSO (9 mL) under N.sub.2 atm and then degassed
for 10 min. Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2Adduct (0.395 g, 0.484
mmol) was added and the resulting suspension was stirred overnight
at 80.degree. C. The reaction mixture was partitioned between DCM
and water. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated then purified normal
phase chromatography using hexane and EtOAc as eluents to give
4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(3.52 g, 94% yield) as a clear oil which solidified into a white
solid upon standing. MS(ESI) m/z: 152.3
(M-C.sub.6H.sub.10+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3-d)
.delta. 7.43 (d, J=1.8 Hz, 1H), 7.04 (dd, J=8.3, 2.3 Hz, 1H), 6.55
(d, J=8.1 Hz, 1H), 4.60 (br. s., 2H), 2.23-2.20 (m, 3H), 1.38-1.32
(m, 12H).
119B. Preparation of
2-(6-methoxypyrimidin-4-yl)-4-methylaniline
[1617] To a RBF equipped with a reflux condenser containing DME
(42.9 mL), EtOH (5.36 mL) was added 4-chloro-6-methoxypyrimidine
(1.55 g, 10.72 mmol),
4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(2.5 g, 10.72 mmol) and 2 M aq Na.sub.2CO.sub.3 (5.36 mL, 10.72
mmol). The mixture was purged with Ar for 10 min then
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (0.876 g, 1.072 mmol) was
added and the reaction mixture heated at 90.degree. C. After 2 h,
the reaction was diluted with water and extracted with EtOAc. The
organic layer washed with brine and concentrated to give a brown
oil. The crude product was purified by normal phase chromatography
using heptane and EtOAc as eluents to give
2-(6-methoxypyrimidin-4-yl)-4-methylaniline (670 mg, 29%) as a
solid. MS(ESI) m/z: 216.1 (M+H).sup.+. .sup.1H NMR (500 MHz,
CDCl.sub.3-d) .delta. 8.79 (d, J=1.1 Hz, 1H), 7.33 (d, J=1.4 Hz,
1H), 7.08-7.01 (m, 2H), 6.67 (d, J=8.3 Hz, 1H), 5.68 (br. s., 2H),
4.03 (s, 3H), 2.29 (s, 3H).
119C. Preparation of
4-methoxy-6-(5-methyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl-
)pyrimidine
[1618] To a cooled (0.degree. C.), clear, yellow solution of
2-(6-methoxypyrimidin-4-yl)-4-methylaniline (0.670 g, 3.11 mmol) in
ACN (44.5 mL) was added isoamylnitrite (0.63 mL, 4.67 mmol),
followed by dropwise addition of TMSN.sub.3 (0.62 mL, 4.67 mmol).
After 10 min, the cold bath was removed, and the reaction allowed
to warm to rt. After 4.5 h, Cu.sub.2O (0.045 g, 0.311 mmol) was
added. After a few min, 3,3,3-trifluoroprop-1-yne (0.293 g, 3.11
mmol) gas was bubbled into the dark green solution at rt. After 1
h, the reaction was diluted with DCM and washed with sat
NH.sub.4Cl, brine, dried over MgSO.sub.4, filtered and concentrated
to give a brown oil. The crude product was purified by normal phase
chromatography using heptane and EtOAc as eluents to give
4-methoxy-6-(5-methyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl-
)pyrimidine (941 mg, 90%) as a solid. MS(ESI) m/z: 336.1
(M+H).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3-d) .delta. 8.63 (s,
1H), 7.98 (s, 1H), 7.56 (s, 1H), 7.45 (s, 2H), 6.58 (s, 1H), 3.97
(s, 3H), 2.53 (s, 3H).
119D. Preparation of
6-(5-methyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)
pyrimidin-4-ol
[1619] A clear, yellow solution of
4-methoxy-6-(5-methyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl-
)pyrimidine (0.941 g, 2.81 mmol) in AcOH (14.03 mL) and 48% aq HBr
(15.88 mL, 140 mmol) was warmed to 85.degree. C. After 3 h, the
reaction was cooled to rt and concentrated. The yellow gum
dissolved in EtOAc, washed with sat NaHCO.sub.3, brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Et.sub.2O (3 mL) was
added, sonicated, and filtered. The solid rinsed with Et.sub.2O (5
mL), air-dried with suction overnight to afford
6-(5-methyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)py-
rimidin-4-ol (0.609 g, 67.5% yield) as a light yellow solid.
MS(ESI) m/z: 322.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 12.90 (br. s., 1H), 8.06 (s, 1H), 7.93 (d, J=0.7 Hz, 1H),
7.57-7.40 (m, 3H), 6.51 (d, J=0.9 Hz, 1H), 2.53 (s, 3H).
119E. Preparation of
(9R,13S)-3-(difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluoromethy-
l)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,4,7,17-
-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-o-
ne trifluoroacetate
[1620]
(9R,13S)-3-(Difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluor-
omethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,-
4,7,17-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (13 mg, 23%) was prepared in a similar manner as
Example 56, using
6-(5-methyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl-
)pyrimidin-4-ol and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one, prepared
as described in Intermediate 37. MS(ESI) m/z: 640.2 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.67 (s, 1H), 8.62-8.57
(m, 1H), 8.31-8.10 (m, 3H), 8.00-7.83 (m, 2H), 7.69 (s, 2H), 7.45
(d, J=0.9 Hz, 2H), 7.02 (dd, J=5.1, 1.5 Hz, 1H), 6.39 (s, 1H),
5.71-5.62 (m, 1H), 2.60-2.53 (m, 1H), 2.42 (s, 3H), 2.27 (d, J=6.6
Hz, 1H), 2.03-1.93 (m, 2H), 1.56 (dd, J=13.4, 5.1 Hz, 1H),
1.31-1.19 (m, 2H), 1.03 (d, J=6.8 Hz, 3H). Analytical HPLC (Method
A): RT=8.90 min, purity=99%; Factor XIa Ki=1.1 nM, Plasma
Kallikrein Ki=340 nM.
Example 120
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-5-(triflu-
oromethyl)-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyc-
lo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00273##
[1622] A TFA/DMSO solution was prepared by dissolving TFA (10
.mu.L) in DMSO (2.5 mL). To a separate vial containing a mixture of
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihyd-
ropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,.s-
up.6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
(0.0084 g, 0.013 mmol), prepared as described in Example 133, and
Zn(SO.sub.2CF.sub.3).sub.2 (8.31 mg, 0.025 mmol) was added DMSO
(0.25 mL). Next, 0.25 mL of the TFA/DMSO solution was added to give
a clear, yellow solution. Then, 70% aq t-BuOOH (5.21 .mu.l, 0.038
mmol) was added. After 2 h, additional Zn(SO.sub.2CF.sub.3).sub.2
(16.6 mg, 0.050 mmol) was added. After 30 min, additional 70% aq
t-BuOOH (10.4 .mu.l, 0.076 mmol) was added. After 1 h, the reaction
was stopped. MeOH (1.5 mL) was added to the reaction mixture and it
was purified by reverse phase chromatography to provide
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-5-(triflu-
oromethyl)-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(0.0024 g, 30% yield) as a white solid. MS(ESI) m/z: 624.4
(M+H).sup.+, 626.4 (M+2+H).sup.+. A mixture of atropisomers were
observed by .sup.1H NMR and .sup.19F NMR. .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 9.09-9.06 (m, 0.5H), 9.03-9.00 (m, 0.5H), 8.75
(d, J=5.0 Hz, 0.5H), 8.72 (d, J=5.0 Hz, 0.5H), 8.33 (s, 0.5H), 8.25
(s, 0.5H), 7.87 (br. s., 0.5H), 7.80 (br. s., 0.5H), 7.76-7.67 (m,
3H), 7.64 (d, J=2.2 Hz, 0.5H), 7.61 (d, J=2.2 Hz, 0.5H), 7.55-7.48
(m, 2H), 6.06-5.97 (m, 1H), 4.06 (s, 1.5H), 4.05 (s, 1.5H),
2.77-2.68 (m, 1H), 2.33-2.24 (m, 1H), 2.14-1.99 (m, 2H), 1.65-1.56
(m, 1H), 1.56-1.44 (m, 1H), 1.02-0.97 (m, 3H), 0.68-0.55 (m, 1H).
.sup.19F NMR (471 MHz, CD.sub.3OD) .delta. -60.90 (s, 1F), -60.94
(s, 1F). Analytical HPLC (Method A): RT=7.55 min, purity=97.9%;
Factor XIa Ki=110 nM.
Example 121
Preparation of
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,
8,16-triazatricyclo[13.3.1.0.sup.2,7]
nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one,
bis-trifluoroacetate
##STR00274##
[1624] To a vial (4 ml) containing a suspension
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol (0.027 g, 0.078 mmol), prepared as described in Intermediate
15, in ACN (2 ml) was added HATU (0.038 g, 0.101 mmol) and DBU
(0.018 ml, 0.116 mmol). After 30 min,
(10R,14S)-14-amino-10-methyl-3,8,16-triazatricyclo[13.3.1.0.sup.2,7]nonad-
eca-1(19),2(7),3,5,15,17-hexaen-9-one (0.023 g, 0.078 mmol),
prepared as described in Intermediate 39, in ACN (1.0 ml) was added
at rt. After 4 h, the crude mixture was purified by reverse phase
chromatography (PHENOMENEX.RTM. Luna Axia C18 5.mu. 30.times.100 mm
column, Solvent A: 20% ACN-80% H.sub.2O-0.1% TFA; Solvent B: 80%
ACN-20% H.sub.2O-0.1% TFA) to give
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-
-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8,16-triazatric-
yclo[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one,
bis-trifluoroacetate (18 mg, 26.8%) as a white solid. MS(ESI) m/z:
621.2 (M+H).sup.+ and 623.1 (M+2+H).sup.+. .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 8.82 (s, 1H), 8.72 (d, J=0.8 Hz, 1H), 8.63 (d,
J=5.0 Hz, 1H), 8.54 (dd, J=5.0, 1.4 Hz, 1H), 7.80-7.78 (m, 2H),
7.70 (dd, J=8.1, 1.5 Hz, 1H), 7.68-7.64 (m, 1H), 7.61-7.57 (m, 2H),
7.51 (dd, J=8.0, 5.0 Hz, 1H), 6.33 (d, J=0.8 Hz, 1H), 5.95 (dd,
J=12.7, 4.7 Hz, 1H), 2.66-2.61 (m, 1H), 2.13 (t, J=12.7 Hz, 1H),
1.91 (t, J=9.9 Hz, 2H), 1.47-1.39 (m, 2H), 0.87 (d, J=7.2 Hz, 3H).
Analytical HPLC (Method A): RT=8.18 min, purity=98.3%; Factor XIa
Ki=2.8 nM, Plasma Kallikrein Ki=190 nM.
Example 122
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatr-
icyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00275##
[1626] To a vial (4 ml) containing a suspension
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(0.014 g, 0.046 mmol), prepared as described in Intermediate 9, in
ACN (1 ml) was added HATU (0.019 g, 0.051 mmol) and DBU (0.009 ml,
0.060 mmol). After 20 min,
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.0155
g, 0.046 mmol), prepared as described in Intermediate 43, in DMF
(1.0 ml) was added at rt. After 3 h, the crude mixture was purified
by reverse phase (PHENOMENEX.RTM. Luna Axia C18 5.mu. 30.times.100
mm column, Solvent A: 20% ACN-80% H.sub.2O-0.1% TFA; Solvent B: 80%
ACN-20% H.sub.2O-0.1% TFA) to give
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl-
]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,16-te-
traazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(1.7 mg, 5.86%). MS(ESI) m/z: 626 (M+H).sup.+. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.35 (s, 1H), 8.74 (s, 1H), 8.63 (d,
J=1.7 Hz, 1H), 8.60-8.53 (m, 2H), 8.12-7.97 (m, 2H), 7.93-7.86 (m,
2H), 7.85-7.71 (m, 2H), 6.41 (s, 1H), 5.57 (d, J=9.9 Hz, 1H),
2.46-2.39 (m, 1H), 2.04-1.95 (m, 1H), 1.79 (d, J=10.7 Hz, 1H), 1.42
(d, J=6.9 Hz, 1H), 1.24 (br. s., 1H), 0.99 (d, J=6.6 Hz, 4H).
Analytical HPLC (Method C): RT=1.52 min, purity=100.0%; Factor XIa
Ki=0.16 nM, Plasma Kallikrein Ki=34 nM.
Example 123
Preparation of
6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(9R,13S-
)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2-
(6),4,14,16-pentaen-13-yl]-3,4-dihydropyrimidin-4-one
##STR00276##
[1627] 123A. Preparation of
(9R,13S)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-13-amine
[1628] To a solution of
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
dihydrochloride (45 mg, 0.121 mmol), prepared as described in
Intermediate 32, in THF (3022 .mu.l) was added BH.sub.3.THF complex
(1813 .mu.l, 1.813 mmol). The reaction was sealed and heated at
60.degree. C. for 4.5 h. MeOH was added, followed by addition of
1.25 M HCl in MeOH (2 ml). The mixture was sealed and heated at
60.degree. C. for 1 h. Another 0.5 mL of HCl in MeOH was added and
heated at 60.degree. C. for 1 h then cooled down to rt overnight.
Another 0.5 mL of 4 N HCl in dioxane was added and the solution was
heated at 65.degree. C. for 5 h. The reaction mixture was
concentrated. The residue was dissolved in MeOH, purified by
reverse phase prep HPLC. After concentration and passing through
NaHCO.sub.3 cartridge,
(9R,13S)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-
-1(18),2(6),4,14,16-pentaen-13-amine (28 mg, 81%) was obtained as
an colorless oil. MS(ESI) m/z: 286.5 (M+H).sup.+.
123B. Preparation of
6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(9R,13S-
)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2-
(6),4,14,16-pentaen-13-yl]-3,4-dihydropyrimidin-4-one
[1629]
6-[3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(-
9R,13S)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1-
(18),2(6),4,14,16-pentaen-13-yl]-3,4-dihydropyrimidin-4-one
trifluoroacetate (12.5 mg, 30.4% yield) was prepared in a similar
manner as the procedure described in Example 56 by using
(9R,13S)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-
-1(18),2(6),4,14,16-pentaen-13-amine (6.5 mg, 0.020 mmol). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.95 (s, 1H), 8.84 (d, J=5.1 Hz,
1H), 8.35 (s, 1H), 8.09-8.04 (m, 1H), 7.90-7.83 (m, 1H), 7.64 (s,
1H), 7.59-7.53 (m, 2H), 6.62 (s, 1H), 6.17 (dd, J=12.5, 4.8 Hz,
1H), 4.02 (s, 3H), 2.97 (d, J=10.6 Hz, 1H), 2.53 (br. s., 1H),
2.34-2.19 (m, 1H), 2.17-2.05 (m, 1H), 2.04-1.75 (m, 2H), 1.56 (t,
J=12.3 Hz, 1H), 1.23 (br. s., 1H), 0.86 (d, J=7.3 Hz, 3H),
0.75-0.40 (m, 1H). MS(ESI) m/z: 594.2 (M+H).sup.+. Analytical HPLC
(Method A): RT=6.97 min, purity=99.1%; Factor XIa Ki=2 nM, Plasma
Kallikrein Ki=690 nM.
Example 124
Preparation of
(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-10-fluoro-9-methyl-3,4,7-tri-
azatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00277##
[1630] 124A. Preparation of tert-butyl
N-[(9S,13S)-3-(difluoromethyl)-10-fluoro-9-methyl-8-oxo
3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-
-13-yl]carbamate
[1631] Fe.sub.2(C.sub.2O.sub.4).sub.3.6H.sub.2O (2.797 g, 5.78
mmol) was added to a RBF containing H.sub.2O (30 ml). The
suspension was warmed by a water bath (50.degree. C.) to aid
dissolution. After 3 h, the clear yellow solution was cooled to
0.degree. C. and purged with Ar. After 20 min, SELECTFLUOR.RTM.
(2.048 g, 5.78 mmol) in ACN (5 ml) was added followed by dropwise
addition of tert-butyl
N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12-
.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
(0.500 g, 1.156 mmol), prepared as described in Example 35D, in ACN
(10 ml). After 5 min, NaBH.sub.4 (0.350 g, 9.25 mmol) was added in
two separate portions over a 5 min period. After 15 min, the
reaction mixture was allowed to come to rt. After 1 h, the reaction
mixture was quenched with aqueous NH.sub.4OH (28-30%; 15 mL). After
30 min, the reaction mixture was filtered and the collected solids
washed with EtOAc. The combined organics was washed with brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated to give a
crude mixture of isomers. The material was subjected chiral
purification using CHIRALPAK.RTM. IC, 21.times.250 mm, 5.mu., using
10% MeOH/90% CO.sub.2 at 75 ml/min, 150 Bar, 40.degree. C. The
early eluting isomer was assigned as tert-butyl
N-[(9S,13S)-3-(difluoromethyl)-10-fluoro-9-methyl-8-oxo-3,4,7-triazatricy-
clo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(99.5% ee; 38 mg, 7.26%) and the second eluting isomer, tert-butyl
N-[(9R,13S)-3-(difluoromethyl)-11-fluoro-9-methyl-8-oxo-3,4,7-triazatricy-
clo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (99.5% ee; 34
mg, 6.50%). MS(ESI) m/z: 397 (M-tBu).sup.+.
124B.
(9S,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-
-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-10-fluoro-9-methyl-3,4,-
7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[1632] The early eluting isomer tert-butyl
N-[(9S,13S)-3-(difluoromethyl)-10-fluoro-9-methyl-8-oxo-3,4,7-triazatricy-
clo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(0.038 g, 0.084 mmol) was treated with HCl (4.0 M in dioxane)
(0.420 ml, 1.680 mmol). A minimum amount of MeOH was added to aid
dissolution. After 2 h, the reaction mixture was concentrated to
dryness. The residue was dissolved in MeOH and passed through a
NaHCO.sub.3 cartridge (StratoSpheres SPE; 500 mg, 0.90 mmol
loading). The filtrate was concentrated and the free base
temporarily set aside. Separately, flask containing a white
suspension of 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)
pyrimidin-4-ol (0.026 g, 0.084 mmol), prepared as described in
Intermediate 9, in ACN (1.120 ml) was added HATU (0.035 g, 0.092
mmol) and DBU (0.016 ml, 0.109 mmol). After 20 min, the free base
in DMF (1 mL) was added and the resulting suspension was stirred at
rt overnight. The reaction mixture was purified reverse phase
chromatography (SunFire C18 5.mu. 30.times.100 mm column, 10-minute
gradient; Solvent A: 20% ACN-80% H.sub.2O-0.1% TFA; Solvent B: 80%
ACN-20% H.sub.2O-0.1% TFA). The pure fractions were liberated of
organics and the remaining aqueous phase freeze-dried to give
(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-
-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-10-fluoro-9-methyl-3,4,-
7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-on-
e (18.2 mg, 33.3%) as a white solid. MS(ESI) m/z: 643 (M+H).sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.83 (s, 1H), 8.40-8.38
(m, 1H), 7.93 (d, J=2.2 Hz, 1H), 7.80-7.75 (m, 2H), 7.71-7.68 (m,
1H), 7.66-7.62 (m, 3H), 7.54 (d, J=7.7 Hz, 1H), 7.28 (d, J=8.0 Hz,
1H), 6.46 (d, J=0.8 Hz, 1H), 5.92 (dd, J=13.3, 4.5 Hz, 1H),
5.38-5.25 (m, 1H), 3.19-3.14 (m, 1H), 2.48-2.41 (m, 1H), 2.27 (ddt,
J=12.9, 8.7, 4.2 Hz, 1H), 1.85-1.75 (m, 1H), 1.05 (d, J=6.9 Hz,
3H), 0.99-0.83 (m, 1H). Analytical HPLC (Method A): RT=9.3 min,
purity=99.5%; Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=24 nM.
Example 125
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-11-fluoro-9-methyl-3,4,7-tri-
azatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00278##
[1634] The second eluting isomer from Example 124A, tert-butyl
N-[(9R,13S)-3-(difluoromethyl)-11-fluoro-9-methyl-8-oxo-3,4,7-triazatricy-
clo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(0.034 g, 0.075 mmol) was treated with HCl (4.0 M in dioxane)
(0.376 ml, 1.50 mmol). A minimum amount of MeOH was added to aid
dissolution. After 2 h, the reaction mixture was concentrated to
dryness. The residue was dissolved in MeOH and passed through a
NaHCO.sub.3 cartridge (StratoSpheres SPE; 500 mg, 0.90 mmol
loading). The filtrate was concentrated and the free base
temporarily set aside. Separately, a flask containing a white
suspension of
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(0.023 g, 0.075 mmol), prepared as described in Intermediate 9, in
ACN (1.120 ml) was added HATU (0.031 g, 0.083 mmol) and DBU (0.015
ml, 0.098 mmol). After 20 min, the free base in DMF (1 mL) was
added and the resulting suspension was stirred at its overnight.
The reaction mixture was purified reverse phase chromatography
(SunFire C18 5.mu. 30.times.100 mm column, 10-minute gradient;
Solvent A: 20% ACN-80% H.sub.2O-0.1% TFA; Solvent B: 80% ACN-20%
H.sub.2O-0.1% TFA). The pure fractions were concentrated to remove
most of the ACN and the remaining aqueous phase freeze-dried to
give
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-11-fluoro-9-methyl-3,4,7-tri-
azatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(8.9 mg, 18.2%) as a white solid. MS(ESI) m/z: 643 (M+H).sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.35 (s, 1H), 8.20 (s,
1H), 7.88 (d, J=2.5 Hz, 1H), 7.80 (s, 1H), 7.76-7.74 (m, 1H), 7.70
(s, 1H), 7.69-7.60 (m, 3H), 7.57-7.51 (m, 1H), 6.44 (d, J=0.8 Hz,
1H), 6.11 (dd, J=13.1, 2.9 Hz, 1H), 4.55-4.40 (m, 1H), 2.96-2.83
(m, 1H), 2.76-2.69 (m, 1H), 2.47-2.38 (m, 1H), 2.21-2.12 (m, 1H),
2.03-1.92 (m, 1H), 1.26 (d, J=6.6 Hz, 3H). Analytical HPLC (Method
A): 9.41 min, purity=99.5%; Factor XIa Ki=20 nM, Plasma Kallikrein
Ki=2,400 nM.
Example 126
Preparation of
(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-10,16-difluoro-3,9-dimethyl-3,4,7-triazatricycl-
o [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00279##
[1635] 126A. Preparation of
N-[(9S,13S)-10,16-difluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
[1636] Fe.sub.2(C.sub.2O.sub.4).sub.3.6H.sub.2O (2.16 g, 4.46 mmol)
was added to a RBF containing H.sub.2O (30 ml). The suspension was
warmed by a water bath (50.degree. C.) to aid dissolution. After 3
h, the clear yellow solution was cooled to 0.degree. C. and purged
with Ar. After 20 min, SELECTFLUOR.RTM. (1.58 g, 4.46 mmol) in ACN
(5 ml) was added followed by dropwise addition of tert-butyl
N-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
(0.370 g, 0.893 mmol), prepared as described in Intermediate 29D,
in ACN (10 ml). After 5 min, NaBH.sub.4 (0.270 g, 7.14 mmol) was
added in two separate portions over a 5 min period. After 15 min,
the reaction mixture was allowed to warm to rt. After 1 h, the
reaction mixture was quenched with 28-30% aq NH.sub.4OH (15 mL).
After 30 min, the reaction mixture was filtered, solids washed with
EtOAc, organics washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated to give a crude mixture of isomers. The
material was subjected chiral purification using CHIRALPAK.RTM. IC,
21.times.250 mm, 5.mu., using 10% EtOH/90% CO.sub.2 at 45 ml/min,
150 Bar, 40.degree. C. The early eluting isomer was assigned
tert-butyl
N-[(9S,13S)-10,16-difluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(99.5% ee; 68 mg, 17.50%) and the second eluting isomer, tert-butyl
N-[(9R,13S)-11,16-difluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(99.5% ee; 32 mg, 8.3%). 435 (M+H).sup.+.
126B. Preparation of
(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10,16-difluoro-3,9-dimethyl-3,4,-
7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-on-
e
[1637] The early eluting isomer assigned tert-butyl
N-[(9S,13S)-10,16-difluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(0.034 g, 0.078 mmol) was treated with 4. M HCl in dioxane (0.391
ml, 1.570 mmol). A minimum amount of MeOH was added to aid
dissolution. After 2 h, the reaction mixture was concentrated to
dryness. The residue was dissolved in MeOH and passed through a
NaHCO.sub.3 cartridge (StratoSpheres SPE; 500 mg, 0.90 mmol
loading). The filtrate was concentrated and the free base
temporarily set aside. Separately, to a flask containing a white
suspension of 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)
phenyl)pyrimidin-4-ol (0.024 g, 0.078 mmol), prepared as described
in Intermediate 9, in ACN (1.120 ml) was added HATU (0.033 g, 0.086
mmol) and DBU (0.015 ml, 0.102 mmol). After 20 min, the free base
in DMF (1 mL) was added and the resulting suspension was stirred at
rt overnight. The reaction mixture was purified reverse phase
chromatography (SunFire C18 5.mu. 30.times.100 mm column, 10-minute
gradient; Solvent A: 20% ACN-80% H.sub.2O-0.1% TFA; Solvent B: 80%
ACN-20% H.sub.2O-0.1% TFA). The pure fractions were concentrated to
remove most of the ACN and the remaining aqueous phase freeze-dried
to give (9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10,16-difluoro-3,9-dimethyl-3,4,-
7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-on-
e (18.5 mg, 37.5%) as a white solid. MS(ESI) m/z: 643 (M+H).sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.81 (s, 1H), 8.39 (s,
1H), 7.94 (d, J=2.5 Hz, 1H), 7.80-7.76 (m, 1H), 7.72-7.68 (m, 1H),
7.50 (s, 1H), 7.40 (s, 1H), 7.31 (dt, J=9.0, 1.8 Hz, 1H), 7.06-7.02
(m, 1H), 6.44 (s, 1H), 5.91 (dd, J=13.5, 4.4 Hz, 1H), 5.37-5.25 (m,
1H), 4.04 (s, 3H), 3.16 (ddd, J=11.3, 7.1, 3.9 Hz, 1H), 2.48-2.41
(m, 1H), 2.30-2.24 (m, 1H), 1.88-1.77 (m, 1H), 1.05 (d, J=6.9 Hz,
3H), 0.99-0.86 (m, 1H). Analytical HPLC (Method A): RT=8.84 min,
purity=99.5%; Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=12 nM.
Example 127
Preparation of
(9S,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10,16-difluoro-3,9-dimethyl-3,4,-
7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-on-
e
##STR00280##
[1639] The early eluting isomer assigned tert-butyl
N-[(9S,13S)-10,16-difluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(0.034 g, 0.078 mmol), prepared as described in Example 126A was
treated with HCl (4.0 M in dioxane) (0.391 ml, 1.570 mmol). A
minimum amount of MeOH was added to aid dissolution. After 2 h, the
reaction mixture was concentrated to dryness. The residue was
dissolved in MeOH and passed through a NaHCO.sub.3 cartridge
(StratoSpheres SPE; 500 mg, 0.90 mmol loading). The filtrate was
concentrated and the free base temporarily set aside. Separately,
flask containing a white suspension of
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol (0.027 g, 0.078 mmol), prepared as described in Intermediate
15, in ACN (1.120 ml) was added HATU (0.033 g, 0.086 mmol) and DBU
(0.015 ml, 0.102 mmol). After 20 min, the free base in DMF (1 mL)
was added and the resulting suspension was stirred at rt overnight.
The reaction mixture was purified reverse phase chromatography
(SunFire C18 5.mu. 30.times.100 mm column, 10-minute gradient;
Solvent A: 20% ACN-80% H.sub.2O-0.1% TFA; Solvent B: 80% ACN-20%
H.sub.2O-0.1% TFA). The pure fractions were liberated of organics
and the remaining aqueous phase freeze-dried to give
(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-
-oxo-1,6-dihydropyrimidin-1-yl}-10,16-difluoro-3,9-dimethyl-3,4,7-triazatr-
icyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(23 mg, 44.2%) as a white solid. MS(ESI) m/z: 659.2 (M+H).sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.87 (d, J=0.8 Hz, 1H),
8.77 (s, 1H), 7.95 (d, J=2.2 Hz, 1H), 7.82-7.78 (m, 1H), 7.76-7.71
(m, 1H), 7.50 (s, 1H), 7.39 (s, 1H), 7.33-7.28 (m, 1H), 6.99 (dt,
J=9.3, 1.8 Hz, 1H), 6.51 (d, J=0.8 Hz, 1H), 5.91 (dd, J=13.3, 4.5
Hz, 1H), 5.37-5.24 (m, 1H), 4.07-4.02 (m, 3H), 3.15 (ddd, J=11.5,
7.2, 3.9 Hz, 1H), 2.42 (tt, J=13.2, 4.0 Hz, 1H), 2.23 (tt, J=13.0,
4.0 Hz, 1H), 1.85-1.78 (m, 1H), 1.05 (d, J=6.9 Hz, 3H), 0.96-0.87
(m, 1H). Analytical HPLC (Method A): RT=9.26 min, purity=99.7%;
Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=10 nM.
Example 128
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl]-6-
-oxo-1,6-dihydropyrimidin-1-yl}-3-(A.sup.2Ha,f)methyl-9-methyl-3,4,7-triaz-
atricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00281##
[1641]
(9R,13S)-13-{4-[5-Chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phe-
nyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl-3,4-
,7-triazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one (1.68 mg, 15% yield) was
prepared in a similar manner as the procedure described in Example
167, using
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,15-tetraaz-
atricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(5.35 mg, 0.018 mmol), prepared as described in Intermediate 33.
MS(ESI) m/z: 598.3 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.17 (s, 1H), 7.86 (s, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.75
(s, 1H), 7.68 (dd, J=8.4, 2.4 Hz, 1H), 7.59-7.55 (m, 3H), 7.49 (s,
1H), 7.32 (d, J=7.3 Hz, 1H), 6.23 (s, 1H), 5.81 (dd, J=13.1, 3.4
Hz, 1H), 2.53-2.26 (m, 2H), 2.13-1.80 (m, 3H), 1.63-1.49 (m, 2H),
1.27-1.09 (m, 4H), 1.01-0.91 (m, 2H), 0.78-0.69 (m, 2H). Analytical
HPLC (Method A): RT=8.15 min, purity=95.3%; Factor XIa Ki=2 nM,
Plasma Kallikrein Ki=280 nM
Example 129
Preparation of
6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(9R,13S-
)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]o-
ctadeca-1(18),2(6),4,14,16-pentaen-13-yl]-3,4-dihydropyrimidin-4-one
##STR00282##
[1643]
6-[3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(-
9R,13S)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-3,4-dihydropyrimidin-4-one
was prepared in a similar manner as the procedure described in
Example 123 by using
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one, prepared
as described in Intermediate 30. .sup.1H NMR (400 MHz, CD.sub.3OD
.delta. 8.99 (s, 1H), 8.73 (d, J=5.3 Hz, 1H), 8.32 (s, 1H), 8.30
(s, 1H), 7.86 (dd, J=8.6, 7.7 Hz, 1H), 7.57 (s, 1H), 7.56-7.52 (m,
2H), 7.49 (d, J=5.1 Hz, 1H), 6.61 (s, 1H), 6.18 (dd, J=12.5, 5.1
Hz, 1H), 2.67 (d, J=11.7 Hz, 1H), 2.36-2.22 (m, 1H), 2.19-1.99 (m,
3H), 1.82 (br. s., 1H), 1.49 (br. s., 1H), 1.24 (m, 1H), 0.76 (d,
J=7.3 Hz, 3H), 0.45 (br. s., 1H). MS(ESI) m/z: 630.2 (M+H).sup.+.
Analytical HPLC (Method A): RT=11.06 min, purity=99.3%; Factor XIa
Ki=0.8 nM, Plasma Kallikrein Ki=880 nM.
Example 130
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazat-
ricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaene-16-carbonit-
rile
##STR00283##
[1645] To
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)pheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,-
7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaene-16-carboxamide,
described in Example 84, (0.004 g, 5.98 .mu.mol) in ACN (0.3 mL),
cooled to 0.degree. C., was added several drops of pyridine, then
POCl.sub.3 (0.91 mg, 5.98 .mu.mol). After 2 h, the reaction was
concentrated and purified by preparative LCMS to afford
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazat-
ricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaene-16-carboxami-
de (1.7 mg, 43%) as a white solid. MS(ESI) m/z: 650.3 (M+H).sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.39 (s, 1H), 8.71 (s,
1H), 8.56 (s, 1H), 7.95 (d, J=1.4 Hz, 2H), 7.89 (t, J=2.9 Hz, 3H),
7.87-7.80 (m, 2H), 7.77-7.71 (m, 1H), 6.40 (s, 1H), 5.55 (d, J=10.5
Hz, 1H), 1.98-1.79 (m, 2H), 1.52-1.36 (m, 1H), 1.12 (br. s., 1H),
1.04-0.98 (m, 1H), 0.96 (d, J=6.9 Hz, 3H). Analytical HPLC (Method
C) RT=1.76 min., purity=99%; Factor XIa Ki=0.2 nM, Plasma
Kallikrein Ki=29 nM.
Example 131
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00284##
[1646] 131A. Preparation of
6-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}
pyrimidin-4-ol, hydrobromide
[1647] A clear, yellow solution of
4-{5-chloro-2-[4-(trimethylsilyl-1H-1,2,3-triazol-1-yl]
phenyl}-6-methoxypyrimidine (0.027 g, 0.075 mmol), prepared as
described in Intermediate 9, in AcOH (0.75 ml) and 48% aq HBr (0.42
ml, 3.75 mmol) was warmed to 65.degree. C. After 1.5 h, the
reaction was concentrated. MeOH was added and the reaction mixture
concentrated. This was repeated (2.times.) to give an 86:14 mixture
6-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin--
4-ol, hydrobromide and
6-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol,
hydrobromide (0.0294 g, 92% yield) as an off-white solid. MS(ESI)
m/z: 346.0 (M+H).sup.+.
131B. Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricycl-
o [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[1648]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-y-
l]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazat-
ricyclo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (0.0087 g, 16% yield) was prepared in a similar
manner as the procedure described in Example 128, by using
6-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin--
4-ol hydrobromide and
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one, prepared as described
in Intermediate 32. MS(ESI) m/z: 628.4 (M+H).sup.+ and 630.5
(M+2+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.84 (s,
1H), 8.71 (d, J=5.1 Hz, 1H), 8.17 (s, 1H), 7.88 (d, J=2.4 Hz, 1H),
7.72 (dd, J=8.6, 2.4 Hz, 1H), 7.66 (s, 1H), 7.63 (d, J=8.4 Hz, 1H),
7.51 (dd, J=5.2, 1.4 Hz, 1H), 7.48 (s, 1H), 6.13 (s, 1H), 5.98 (dd,
J=12.7, 4.3 Hz, 1H), 4.04 (s, 3H), 2.74-2.66 (m, 1H), 2.32-2.21 (m,
1H), 2.12-1.90 (m, 2H), 1.66-1.53 (m, 1H), 1.53-1.39 (m, 1H), 0.99
(d, J=7.0 Hz, 3H), 0.73-0.58 (m, 1H), 0.29 (m, 9H). .sup.19F NMR
(376 MHz, CD.sub.3OD) .delta. -77.51 (br. s., 1F). Analytical HPLC
(Method X): RT=6.62 min, purity=93.5%; Factor XIa Ki=29 nM, Plasma
Kallikrein Ki=760 nM.
Example 132
Preparation of
(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-
-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,.sup.6]octadeca-
-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
##STR00285##
[1650] To a 1-dram vial containing a white suspension of
6-(3-chloro-2,6-difluorophenyl) pyrimidin-4-ol (0.013 g, 0.054
mmol), prepared as described in Intermediate 4, and HATU (0.027 g,
0.070 mmol) in ACN (0.54 ml) was added DBU (0.012 ml, 0.081 mmol).
The resulting bright yellow solution was stirred at rt for 20 min.
Over time this solution became a dull yellow-orange color. Then a
clear, brown solution of
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one, 2 HCl (0.020 g,
0.054 mmol), prepared as described in Intermediate 32, and DBU
(0.016 ml, 0.107 mmol) in DMF (0.54 ml) was added. After 2.5 h, the
reaction was stopped. Purification by reverse phase chromatography
gave
(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-
-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,.sup.6]octadeca-
-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (0.0152 g, 43%
yield) as an off-white solid. MS(ESI) m/z: 525.1 (M+H).sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.04 (s, 1H), 8.75 (d,
J=5.0 Hz, 1H), 7.73 (s, 1H), 7.63 (ddd, J=9.1, 8.3, 5.5 Hz, 1H),
7.55-7.51 (m, 1H), 7.50 (s, 1H), 7.14 (td, J=9.1, 1.7 Hz, 1H), 6.66
(d, J=0.6 Hz, 1H), 6.10-6.02 (m, 1H), 4.05 (s, 3H), 2.76-2.68 (m,
1H), 2.37 (tt, J=12.8, 4.5 Hz, 1H), 2.15-2.04 (m, 2H), 1.68-1.58
(m, 1H), 1.56-1.45 (m, 1H), 1.02 (d, J=6.9 Hz, 3H), 0.80-0.65 (m,
1H). .sup.19F NMR (471 MHz, CD.sub.3OD) .delta. -77.53 (s), -114.79
(d, J=4.3 Hz), -115.50 (d, J=4.3 Hz). Analytical HPLC (Method A):
RT=7.37 min, purity=99.7%; Factor XIa Ki=33 nM, Plasma Kallikrein
Ki=290 nM.
Example 133
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihyd-
ropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,.s-
up.6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
##STR00286##
[1652]
(9R,13S)-13-{4-[5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-
-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.su-
p.2,.sup.6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (14 mg, 38% yield) was prepared in a similar
manner as the procedure described in Example 132, by replacing
6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol with
6-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl] pyrimidin-4-ol (0.015
g, 0.054 mmol), prepared as described in Intermediate 8. MS(ESI)
m/z: 558.4 (M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
8.83 (s, 1H), 8.71 (d, J=5.0 Hz, 1H), 8.21 (s, 1H), 7.89 (d, J=2.2
Hz, 1H), 7.84 (br. s., 1H), 7.72 (dd, J=8.4, 2.3 Hz, 1H), 7.67 (s,
1H), 7.62 (d, J=8.5 Hz, 1H), 7.51 (dd, J=5.1, 1.5 Hz, 1H), 7.48 (s,
1H), 6.18 (s, 1H), 6.00-5.93 (m, 1H), 4.04 (s, 3H), 2.73-2.66 (m,
1H), 2.31-2.23 (m, 1H), 2.11-1.91 (m, 2H), 1.64-1.54 (m, 1H),
1.51-1.40 (m, 1H), 1.00 (d, J=6.9 Hz, 3H), 0.72-0.59 (m, 1H).
.sup.19F NMR (471 MHz, CD.sub.3OD) .delta. -77.37 (s). Analytical
HPLC (Method A): RT=6.22 min, purity=99.2%; Factor XIa Ki=1.8 nM,
Plasma Kallikrein Ki=110 nM.
Example 134
Preparation of
(13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-
-dihydropyrimidin-1-yl}-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00287##
[1653] 134A. Preparation of tert-butyl
N-[(1S)-1-{4-[4-(but-3-enamido)-1-(difluoromethyl)-1H-pyrazol-5-yl]pyridi-
n-2-yl}but-3-en-1-yl]carbamate
[1654] To a cooled (-5.degree. C.) yellow solution of tert-butyl
N-[(1S)-1-{4-[4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl]pyridin-2-yl}but-
-3-en-1-yl]carbamate (0.608 g, 1.60 mmol), prepared as described in
Intermediate 30C, in EtOAc (10.1 ml) was added but-3-enoic acid
(0.14 ml, 1.60 mmol) and pyridine (0.26 ml, 3.21 mmol). Next,
T3P.RTM. (50% in EtOAc, 1.43 ml, 2.40 mmol) was added dropwise. The
resulting orange solution was allowed to warm to rt. After 2 h, the
reaction was diluted with EtOAc and washed with sat NaHCO.sub.3,
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to
give a yellow foam weighing 0.702 g. Purification by normal phase
chromatography gave tert-butyl
N-[(1S)-1-{4-[4-(but-3-enamido)-1-(difluoromethyl)-1H-pyrazol-5-yl]pyridi-
n-2-yl}but-3-en-1-yl]carbamate (0.374 g, 52% yield) as a white
foam. MS(ESI) m/z: 448.2 (M+H).sup.+. .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 8.65 (d, J=4.7 Hz, 1H), 8.04 (s, 1H), 7.44 (s,
1H), 7.40 (t, J=58.0 Hz, 1H), 7.36 (d, J=4.4 Hz, 1H), 5.92 (ddt,
J=17.1, 10.2, 7.0 Hz, 1H), 5.80 (ddt, J=17.2, 10.2, 6.9 Hz, 1H),
5.19-5.13 (m, 2H), 5.12-5.03 (m, 2H), 4.81-4.75 (m, 1H), 3.08 (d,
J=6.9 Hz, 2H), 2.67-2.59 (m, 1H), 2.54-2.46 (m, 1H), 1.42 (s, 9H).
.sup.19F NMR (471 MHz, CD.sub.3OD) .delta. -93.82 (br. s).
134B. Preparation of tert-butyl
N-[(10E,13S)-3-(difluoromethyl)-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
[1655] A solution of tert-butyl
N-[(1S)-1-{4-[4-(but-3-enamido)-1-(difluoromethyl)-1H-pyrazol-5-yl]pyridi-
n-2-yl}but-3-en-1-yl]carbamate (0.374 g, 0.836 mmol) in DCE (20.89
ml) was purged with Ar (3.times.). To the reaction mixture was
added Second Generation Grubbs Catalyst (0.284 g, 0.334 mmol). The
microwave vial was sealed and the reaction was heated in a
microwave at 115.degree. C. for 1 h. The reaction was cooled to rt
and concentrated. The residue was purified by normal phase
chromatography to give tert-butyl
N-[(10E,13S)-3-(difluoromethyl)-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6] octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
(0.106 g, 30% yield) as a brown residue. MS(ESI) m/z: 420.1
(M+H).sup.+.
134C. Preparation of tert-butyl
N-[(13S)-3-(difluoromethyl)-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
[1656] A clear, orange-brown solution of tert-butyl
N-[(10E,13S)-3-(difluoromethyl)-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
(0.105 g, 0.250 mmol) in EtOH (5.0 ml) was purged with Ar for
several min. Next, 10% Pd/C (0.027 g, 0.025 mmol) was added and the
suspension was pressurized with H.sub.2 gas to 55 psi. After 17 h,
CELITE.RTM. was added. The reaction was filtered through a nylon
filter, eluting with EtOH to give a clear, orange solution. The
filtrate was concentrated to give a clear, orange residue.
Purification by reverse phase chromatography gave, after
neutralization of the fractions with sat NaHCO.sub.3 and
concentration, a white solid. The solid was partitioned between
EtOAc and water, and the layers were separated. The aqueous layer
was extracted with EtOAc. The organic layers were combined and
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated to give tert-butyl
N-[(13S)-3-(difluoromethyl)-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.0518 g,
49% yield) as a white solid. MS(ESI) m/z: 422.1 (M+H).sup.+.
134D. Preparation of
(13S)-13-amino-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one,
bis-hydrochloride
[1657] A clear, colorless solution of tert-butyl
N-[(13S)-3-(difluoromethyl)-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.0518 g,
0.123 mmol) in 4 M HCl in dioxane (1.54 ml, 6.15 mmol) was stirred
at rt. After 5 min, a white precipitate formed. After 1 h, the
reaction was concentrated to give
(13S)-13-amino-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one, bis-hydrochloride
(0.0503 g, 104% yield) as an off-white solid. MS(ESI) m/z: 322.1
(M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.82 (d,
J=5.2 Hz, 1H), 7.72 (s, 1H), 7.59 (dd, J=60.0, 57.2 Hz, 1H), 7.58
(d, J=5.2 Hz, 1H), 7.54 (s, 1H), 4.61 (dd, J=11.1, 5.1 Hz, 1H),
2.45 (ddd, J=12.6, 7.4, 2.3 Hz, 1H), 2.22-2.13 (m, 1H), 2.06-1.99
(m, 1H), 1.87-1.71 (m, 2H), 1.67-1.57 (m, 1H), 1.52-1.42 (m, 1H),
0.84-0.73 (m, 1H). .sup.19F NMR (471 MHz, CD.sub.3OD) .delta.
-89.17 (d, J=228.9 Hz, 1F), -98.00 (d, J=227.5 Hz, 1F).
134E. Preparation of
(13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-
-dihydropyrimidin-1-yl}-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo[12.3.-
1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[1658] To a 1-dram vial containing a yellow suspension of
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(0.016 g, 0.051 mmol), prepared as described in Intermediate 9, and
HATU (0.025 g, 0.066 mmol) in ACN (0.51 ml) was added DBU (0.011
ml, 0.076 mmol). The resulting yellow-orange solution was stirred
at rt for 20 min. Over time the solution became a dull
yellow-orange color. Then a clear, yellow solution of
(13S)-13-amino-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one, bis-hydrochloride
(0.020 g, 0.051 mmol) and DBU (0.015 ml, 0.101 mmol) in DMF (0.51
ml) were added. The reaction was stirred at rt. After 3 h, the
reaction was quenched with sat NH.sub.4Cl. The mixture was
partitioned between EtOAc and water and the layers were separated.
The aqueous layer was extracted with EtOAc (2.times.). The organic
layers were combined and washed with sat NaHCO.sub.3, brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated to give a clear,
yellow residue weighing 0.040 g. Purification by reverse phase
chromatography gave
(13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-
-dihydropyrimidin-1-yl}-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo[12.3.-
1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (0.0175 g, 47% yield) as a white solid. MS(ESI)
m/z: 612.2 (M+H).sup.+ and 614.1 (M+2+H).sup.+. .sup.1H NMR (500
MHz, DMSO-d.sub.6, 60.degree. C.) .delta. 9.28 (s, 1H), 8.78 (d,
J=0.5 Hz, 1H), 8.72 (d, J=5.0 Hz, 1H), 8.64 (s, 1H), 7.91 (d, J=2.2
Hz, 1H), 7.89 (t, J=57.8 Hz, 1H), 7.86 (s, 1H), 7.81-7.78 (m, 1H),
7.72 (d, J=8.5 Hz, 1H), 7.64 (d, J=0.6 Hz, 1H), 7.42 (dd, J=5.1,
1.2 Hz, 1H), 6.32 (d, J=0.8 Hz, 1H), 5.93 (dd, J=12.7, 4.4 Hz, 1H),
2.41-2.36 (m, 1H), 2.29-2.20 (m, 1H), 2.00-1.87 (m, 3H), 1.64-1.53
(m, 1H), 1.44-1.33 (m, 1H), 0.76-0.66 (m, 1H). .sup.19F NMR (471
MHz, DMSO-d.sub.6) .delta. -73.75 (br. s), -90.34 (d, J=227.4 Hz),
-95.01 (d, J=228.9 Hz). Analytical HPLC (Method A): RT=7.78 min,
purity=99.8%.
Example 135
Preparation of
(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatr-
icyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00288##
[1659] 135A. Preparation of tert-butyl
((1S)-1-(4-(1-(difluoromethyl)-4-(2-methylbut-3-enamido)-1H-pyrazol-5-yl)-
pyridin-2-yl)but-3-en-1-yl)carbamate
[1660] To a N.sub.2 flushed, 3-necked, 250 mL RBF was added a
solution of (S)-tert-butyl
(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-
-yl)carbamate (1.8 g, 4.74 mmol), prepared as described in
Intermediate 30C, and EtOAc (20 mL). The solution was cooled to
-10.degree. C. and (.+-.)-2-methylbut-3-enoic acid (0.475 g, 4.74
mmol), pyridine (0.767 mL, 9.49 mmol), and T3P.RTM. (4.24 mL, 7.12
mmol) were added. The cooling bath was removed and the solution was
allowed to warm to rt and then stir over a period of 20 h. Water
(15 mL) and EtOAc (15 mL) were added and the mixture was stirred
for 30 min. The organic phase was separated and the aqueous layer
was extracted with EtOAc (30 mL). The combined organic extracts
were washed with brine (50 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated. Purification by normal phase
chromatography eluting with a gradient of hexanes/EtOAc gave
racemic tert-butyl
((1S)-1-(4-(1-(difluoromethyl)-4-(2-methylbut-3-enamido)-1H-pyrazol-5-yl)-
pyridin-2-yl)but-3-en-1-yl)carbamate (1.7 g, 3.50 mmol, 74% yield).
MS(ESI) m/z: 462.4 [M+H].sup.+.
135B1. Preparation of tert-butyl
N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,.sup.6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]
carbamate, and 135B2. tert-Butyl
N-[(9S,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
[1661] To a N.sub.2 flushed, 500 mL, 3-necked, RBF was added a
solution of tert-butyl
((1S)-1-(4-(1-(difluoromethyl)-4-(2-methylbut-3-enamido)-1H-pyrazol-5-yl)-
pyridin-2-yl)but-3-en-1-yl)carbamate (1.7 g, 3.68 mmol) in EtOAc
(175 mL). The solution was sparged with Ar for 15 min. Second
Generation Grubbs Catalyst (0.782 g, 0.921 mmol) was added in one
portion. The reaction mixture was heated to reflux for 24 h. After
cooling to rt, the solvent was removed and the residue was purified
by normal phase chromatography eluting with a gradient of DCM/MeOH
to yield (separated the diastereomers) tert-butyl
N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,.sup.6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carba-
mate (0.33 g, 0.75 mmol, 20% yield) and tert-butyl
N-[(9S,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
(0.34 g, 0.77 mmol, 21% yield) as a tan solid. Both diastereomers:
MS(ESI) m/z: 434.3 [M+H].sup.+.
135C. Preparation of tert-butyl
N-[(9S,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,.sup.6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
[1662] Pd/C (0.082 g, 0.078 mmol) was added to a 100 mL Parr
hydrogenation flask containing a solution of tert-butyl
N-[(9S,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,.sup.6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carba-
mate (0.33 g, 0.775 mmol) in EtOH (15 mL). The flask was purged
with N.sub.2 and pressurized to 55 psi of H.sub.2 and allowed to
stir for 5 h. The reaction was filtered through CELITE.RTM. and
concentrated to yield tert-butyl
N-[(9S,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,.sup.6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(0.3 g, 0.654 mmol, 84% yield) as a tan solid. MS(ESI) m/z: 436.3
[M+H].sup.+.
135D. Preparation of
(9S,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[1663] 4 N HCl in dioxane (5.00 mL, 20.0 mmol) was added to a
solution of tert-butyl
N-[(9S,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,.sup.6]
octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.300 g, 0.689
mmol) in MeOH (5 mL). The reaction was allowed to stir at rt for 1
h. The reaction was concentrated to yield
(9S,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
bis-hydrochloride (0.24 g, 0.644 mmol, 93% yield) as a brown solid
which was then dissolved in MeOH (1 mL) to give a clear, brown
solution. The solution was added to a pre-rinsed AGILENT.RTM.
StratoSpheres SPE PL-HCO.sub.3 MP Resin cartridge. Gravity
filtration, eluting with MeOH, gave a clear, slightly yellow
filtrate. Concentration provided
(9S,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.18 g,
94%) as a pale yellow solid. MS(ESI) m/z: 336.3 [M+H].sup.+.
135E. Preparation of
(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,-
7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-
-8-one trifluoroacetate
[1664]
(9S,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetr-
aazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate was prepared in a similar manner as the procedures
described in Example 56, by using
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(0.221 g, 0.716 mmol), prepared as described in Intermediate 9, and
(9S,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.021 g,
0.062 mmol) to yield
(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,-
7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-
-8-one trifluoroacetate (0.16 g, 0.205 mmol, 29% yield). .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.85 (s, 1H), 8.75 (d, J=5.1 Hz,
1H), 8.37 (s, 1H), 7.93 (d, J=2.2 Hz, 1H), 7.85-7.75 (m, 3H),
7.72-7.67 (m, 1H), 7.62 (s, 1H), 7.57-7.48 (m, 1H), 6.43 (s, 1H),
6.08 (dd, J=12.9, 4.3 Hz, 1H), 2.41-2.30 (m, 1H), 2.29-2.17 (m,
1H), 2.09-1.90 (m, 2H), 1.68-1.52 (m, 2H), 1.28 (d, J=6.8 Hz, 3H),
0.93-0.81 (m, 1H). MS(ESI) m/z: 626.3 [M+H].sup.+. Analytical HPLC
(Method A): RT=9.03 min, purity=>95.0%; Factor XIa Ki=1.7 nM,
Plasma Kallikrein Ki=35 nM.
Example 136
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00289##
[1665] 136A. Preparation of
4-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine
trifluoroacetate
[1666] To a cooled (0.degree. C.), clear, yellow solution of
4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (0.095 g, 0.403 mmol),
prepared as described in Intermediate 8A, in EtOH (5.0 ml) was
added Hunig's base (0.42 ml, 2.42 mmol). After 10 min, a suspension
of
N'-[(2E)-1,1-dichloropropan-2-ylidene]-4-methylbenzene-1-sulfonohydrazide
(0.242 g, 0.52 mmol) in ACN (3.3 ml) was added dropwise. The
resulting orange solution was allowed to warm to rt. After 23 h,
the reaction was stopped and concentrated to give a dark brown oil.
Purification by reverse phase chromatography gave, after
concentration,
4-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine
trifluoroacetate (0.0499 g, 30% yield) as a clear, yellow oil.
MS(ESI) m/z: 302.1 (M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 8.64 (d, J=1.1 Hz, 1H), 7.88 (d, J=0.8 Hz, 1H), 7.85 (d,
J=2.2 Hz, 1H), 7.73 (dd, J=8.5, 2.2 Hz, 1H), 7.62 (d, J=8.5 Hz,
1H), 6.59 (d, J=1.1 Hz, 1H), 3.97 (s, 3H), 2.33 (d, J=0.8 Hz,
3H).
136B. Preparation of
6-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]
pyrimidin-4-ol
[1667] A clear, yellow solution of
4-(5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine-
, TFA (0.0499 g, 0.12 mmol) in AcOH (1.20 ml) and 48% aq HBr (0.68
ml, 6.00 mmol) was warmed to 85.degree. C. After 1 h, the reaction
was cooled to rt and then was concentrated to give a yellow solid.
The yellow solid was suspended in EtOAc and sat NaHCO.sub.3 was
added. The layers were separated and the aqueous layer was
extracted with EtOAc (2.times.). The organic layers were combined
and washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated to give an off-white solid weighing 0.032 g. The solid
was suspended in EtOAc (1 mL) and sonicated. The solid was
collected by filtration, rinsed with EtOAc, air-dried, and dried
under vacuum to give
6-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol
(0.0144 g, 40% yield) as an off-white solid. MS(ESI) m/z: 288.1
(M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.07 (s,
1H), 7.92 (s, 1H), 7.84 (d, J=2.2 Hz, 1H), 7.71 (dd, J=8.5, 2.5 Hz,
1H), 7.60 (d, J=8.5 Hz, 1H), 6.22 (s, 1H), 2.36 (s, 3H).
136C. Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,-
7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-
-8-one trifluoroacetate
[1668]
(9R,13S)-13-{4-[5-Chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetr-
aazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (0.0070 g, 32% yield) was prepared in a similar
manner as the procedure described in Example 56, by using
6-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol
and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one, prepared
in Intermediate 30. MS(ESI) m/z: 606.3 (M+H).sup.+ and 608.2
(M+2+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.91 (s,
1H), 8.73 (d, J=5.2 Hz, 1H), 7.91 (d, J=0.8 Hz, 1H), 7.88 (d, J=2.5
Hz, 1H), 7.73 (s, 1H), 7.70 (dd, J=8.5, 2.5 Hz, 1H), 7.68-7.67 (m,
1H), 7.65 (t, J=60.0 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.53-7.51 (m,
1H), 6.18 (d, J=0.8 Hz, 1H), 6.02-5.97 (m, 1H), 2.74-2.66 (m, 1H),
2.35-2.24 (m, 4H), 2.08-1.94 (m, 2H), 1.63-1.53 (m, 1H), 1.53-1.42
(m, 1H), 0.99 (d, J=6.9 Hz, 3H), 0.67-0.52 (m, 1H). .sup.19F NMR
(471 MHz, CD.sub.3OD) .delta. -74.24 (s), -75.74 (s), -77.66 (s).
Analytical HPLC (Method A): RT=7.55 min, purity=99.8%; Factor XIa
Ki=2.2 nM, Plasma Kallikrein Ki=630 nM.
Example 137
Preparation of
(9R,13S)-3-(difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluoromethy-
l)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,4,7,15-
-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-o-
ne
##STR00290##
[1670]
(9R,13S)-3-(Difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluor-
omethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,-
4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (11 mg, 24%) was prepared in a similar manner as
Example 56 using
6-(5-methyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-
pyrimidin-4-ol, prepared as described in Example 119D and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one,
prepared as described in Intermediate 30. MS(ESI) m/z: 640.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.85-8.74
(m, 3H), 7.84-7.67 (m, 4H), 7.59-7.53 (m, 3H), 6.47 (s, 1H), 6.05
(dd, J=12.8, 4.4 Hz, 1H), 2.75 (dd, J=6.7, 3.0 Hz, 1H), 2.56 (s,
3H), 2.35-2.27 (m, 1H), 2.10-1.99 (m, 2H), 1.64-1.50 (m, 2H), 1.03
(d, J=6.8 Hz, 3H), 0.65 (br. s., 1H) Analytical HPLC (Method A):
RT=8.85 min, purity=99%; Factor XIa Ki=0.32 nM, Plasma Kallikrein
Ki=132 nM.
Example 138
Preparation of
(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]--
3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6-
),4,14,16-pentaen-8-one
##STR00291##
[1672]
(9R,13S)-13-[4-(2-Bromo-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin--
1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(1-
8),2(6),4,14,16-pentaen-8-one trifluoroacetate (160 mg, 46.8%
yield) was prepared in a similar manner as the procedure described
in Example 56, by replacing
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl-
}pyrimidin-4-ol (22.8 mg, 0.067 mmol), prepared as described in
Intermediate 15, with 6-(2-bromo-5-chlorophenyl)pyrimidin-4-ol (143
mg, 0.501 mmol), prepared as described in Intermediate 44. MS(ESI)
m/z: 567.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
9.04 (s, 1H), 8.75 (d, J=5.3 Hz, 1H), 7.76 (s, 1H), 7.70 (d, J=8.6
Hz, 1H), 7.61-7.54 (m, 2H), 7.50 (s, 1H), 7.38 (dd, J=8.6, 2.4 Hz,
1H), 6.70 (s, 1H), 6.05 (dd, J=12.5, 4.0 Hz, 1H), 4.05 (s, 3H),
2.78-2.66 (m, 1H), 2.44-2.33 (m, 1H), 2.16-2.03 (m, 2H), 1.70-1.43
(m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.82-0.66 (m, 1H). Analytical HPLC
(Method A): RT=8.45 min, 99.9% purity; Factor XIa Ki=23 nM, Plasma
Kallikrein Ki=420 nM.
Example 139
Preparation of
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(4-methyl-1H-1,2,3-triazol-1-yl)
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,-
7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-
-8-one
##STR00292##
[1674]
(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-(4-methyl-1H-1,2,3-triazol-1-yl-
)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,-
7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.0174
g, 62% yield) was prepared in a similar manner as the procedure
described in Example 56, by using
6-[3-chloro-2-fluoro-6-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-
-ol, prepared in Example 137B, and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2 (6),4,14,16-pentaen-8-one,
prepared as described in Intermediate 30. MS(ESI) m/z: 624.3
(M+H).sup.+ and 626.2 (M+2+H).sup.+. .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 9.52 (s, 1H), 8.90 (s, 1H), 8.75 (d, J=5.2 Hz,
1H), 7.89 (d, J=0.8 Hz, 1H), 7.82 (dd, J=8.7, 7.6 Hz, 1H), 7.74 (d,
J=0.8 Hz, 1H), 7.69 (br. s, 1H), 7.65 (t, J=58.0 Hz, 1H), 7.53-7.49
(m, 2H), 6.52 (s, 1H), 6.05-5.99 (m, 1H), 2.77-2.66 (m, 1H),
2.34-2.23 (m, 4H), 2.09-1.95 (m, 2H), 1.64-1.53 (m, 1H), 1.53-1.42
(m, 1H), 0.99 (d, J=7.2 Hz, 3H), 0.69-0.53 (m, 1H). .sup.19F NMR
(471 MHz, CD.sub.3OD) .delta. -74.25 (s), -75.75 (s), -115.22 (s).
Analytical HPLC (Method A): RT=7.54 min, purity=99.8%; Factor XIa
Ki=0.63 nM, Plasma Kallikrein Ki=119 nM.
Example 140
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}-6--
oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00293##
[1675] 140A. Preparation of
4-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-6-methoxypyrimi-
dine
[1676] To a sealable vial was added
4-(2-bromo-5-chlorophenyl)-6-methoxypyrimidine (0.08 g, 0.267
mmol),
1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyr-
azole (0.072 g, 0.294 mmol), 3 M aq KH.sub.2PO.sub.4 (0.27 ml, 0.81
mmol) and THF (2.67 ml). Ar was bubbled through the reaction
mixture for several min and (DtBPF)PdCl.sub.2 (8.70 mg, 0.013 mmol)
was added. The vial was sealed and heated at 90.degree. C. for 15
h. The reaction was cooled to rt, diluted with EtOAc, washed with
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated.
Purification by normal phase chromatography afforded
4-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-6-methoxypyrimi-
dine (0.05 g, 56% yield) as a white solid. MS(ESI) m/z: 337.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.81 (d,
J=0.9 Hz, 1H), 7.69 (s, 1H), 7.54 (d, J=2.2 Hz, 1H), 7.48-7.43 (m,
1H), 7.41-7.35 (m, 2H), 7.17 (t, J=54.0 Hz, 1H), 6.61 (d, J=1.1 Hz,
1H), 3.99 (s, 3H).
140B. Preparation of
6-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)
pyrimidin-4-ol
[1677] A clear solution of
4-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-6-methoxypyrimi-
dine (0.05 g, 0.148 mmol) in HOAc (0.742 ml) and 48% aq HBr (0.84
ml, 7.42 mmol) was warmed to 65.degree. C. After 3 h, the reaction
was cooled to rt and concentrated. The residue was dissolved in
EtOAc, washed with sat NaHCO.sub.3, brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Et.sub.2O (3 ml) was
added and the mixture was sonicated. The solid was collected by
filtration and rinsed with Et.sub.2O (2 ml), air-dried to give
6-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)pyrimidin-4-ol
(0.03 g, 63% yield) as a white solid. MS(ESI) m/z: 323.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.20 (d,
J=1.1 Hz, 1H), 8.05 (s, 1H), 7.61-7.27 (m, 5H), 6.40 (d, J=1.1 Hz,
1H).
140C. Preparation of
(9R,13S)-13-(4-{5-chloro-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[1678]
(9R,13S)-13-(4-{5-Chloro-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricycl-
o[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (10 mg, 32% yield) was prepared in a similar
manner as the procedure described in Example 56, by using
6-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)pyrimidin-4-ol
(14.01 mg, 0.043 mmol). MS(ESI) m/z: 605.2 (M+H).sup.+. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.95 (s, 1H), 8.74 (d, J=5.3 Hz, 1H),
8.04 (s, 1H), 7.72 (s, 1H), 7.60-7.25 (m, 7H), 6.42 (s, 1H), 6.02
(dd, J=12.7, 4.3 Hz, 1H), 4.05 (s, 3H), 2.76-2.66 (m, 1H),
2.39-2.27 (m, 1H), 2.14-1.99 (m, 2H), 1.67-1.42 (m, 2H), 1.02 (d,
J=6.8 Hz, 3H), 0.81-0.65 (m, 1H). Analytical HPLC (Method A):
RT=8.18 min, 98.5% purity; Factor XIa Ki=9 nM, Plasma Kallikrein
Ki=910 nM.
Example 141
Preparation of
(9R,13S)-13-[4-(3-fluoro-4-methylpyridin-2-yl)-6-oxo-1,6-dihydropyrimidin-
-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00294##
[1679] 141A. Preparation of
4-methoxy-6-(tributylstannyl)pyrimidine
[1680] To a RBF was added 4-chloro-6-methoxypyrimidine (3.15 g,
21.79 mmol), 1,1,1,2,2,2-hexabutyldistannane (10.92 mL, 21.79
mmol), toluene (50 mL) and Pd(PPh.sub.3).sub.4 (1.259 g, 1.090
mmol). The reaction was purged with Ar and then stirred at
120.degree. C. overnight. The reaction was then partitioned between
EtOAc (30 ml) and water (25 ml). The organic layer was separated,
washed with sat NaCl (20 ml), dried over MgSO.sub.4, filtered and
concentrated. The crude product was purified using ISCO system
(0-30% EtOAc/Hex gradient) to give
4-methoxy-6-(tributylstannyl)pyrimidine (200 mg, 0.501 mmol, 2.3%
yield) as a clear liquid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.85 (d, J=1.1 Hz, 1H), 6.94 (d, J=1.1 Hz, 1H), 3.97 (s, 3H),
1.60-1.55 (m, 6H), 1.36-1.32 (m, 6H), 1.20-1.13 (m, 6H), 0.96-0.91
(m, 9H); MS(ESI) m/z: 401.1 (M+H).sup.+.
141B. Preparation of
4-(3-fluoro-4-methylpyridin-2-yl)-6-methoxypyrimidine
trifluoroacetate
[1681] To a sealed tube was added 2-bromo-3-fluoro-4-methylpyridine
(25.7 mg, 0.135 mmol), 4-methoxy-6-(tributylstannyl)pyrimidine (45
mg, 0.113 mmol), toluene (1.5 mL) and Pd(PPh.sub.3).sub.4 (13.03
mg, 0.011 mmol). The reaction was purged with Ar and then sealed
and stirred at 120.degree. C. overnight. The reaction was
partitioned between EtOAc (25 ml) and water (20 ml). The organic
layer was separated, washed with sat NaCl (10 ml), dried over
MgSO.sub.4, filtered and concentrated. The crude product was
purified using prep-HPLC to give
4-(3-fluoro-4-methylpyridin-2-yl)-6-methoxypyrimidine
trifluoroacetate (20 mg, 0.060 mmol, 53.2% yield) as a purple salt.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.22 (s, 1H), 8.59 (d,
J=4.2 Hz, 1H), 7.56 (s, 1H), 7.51 (br. s., 1H), 4.23 (s, 3H), 2.51
(s, 3H); MS(ESI) m/z: 220.1 (M+H).sup.+.
141C. Preparation of
6-(3-fluoro-4-methylpyridin-2-yl)pyrimidin-4-ol
[1682] To a RBF was added
4-(3-fluoro-4-methylpyridin-2-yl)-6-methoxypyrimidine (20 mg, 0.060
mmol), AcOH (0.5 mL) and HBr (0.34 mL, 3.00 mmol). The reaction was
stirred at 85.degree. C. for 45 min. Then toluene (25 ml) was added
and the reaction was concentrated. The residue was then partitioned
between EtOAc (25 ml) and sat NaHCO.sub.3 (25 ml). The organic
layer was separated, washed with water (15 ml) and sat NaCl (15
ml), dried over MgSO.sub.4, filtered and concentrated, to give
6-(3-fluoro-4-methylpyridin-2-yl)pyrimidin-4-ol (10 mg, 0.049 mmol,
81% yield) as an oil. MS(ESI) m/z: 206.1 (M+H).sup.+.
141D. Preparation of
(9R,13S)-13-[4-(3-fluoro-4-methylpyridin-2-yl)-6-oxo-1,6-dihydropyrimidin-
-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(-
18),2(6),4,14,16-pentaen-8-one trifluoroacetate
[1683]
(9R,13S)-13-[4-(3-Fluoro-4-methylpyridin-2-yl)-6-oxo-1,6-dihydropyr-
imidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octad-
eca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (14 mg, 22
.mu.mol, 41.4% yield) was prepared in a similar manner as the
procedure described in Example 56 by using
6-(3-fluoro-4-methylpyridin-2-yl)pyrimidin-4-ol (15.3 mg, 0.053
mmol) and
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one (16 mg, 0.053 mmol),
prepared as described in Intermediate 32. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 9.21 (br. s., 1H), 8.76 (d, J=4.4 Hz, 1H), 8.49
(br. s., 1H), 7.77 (s, 1H), 7.66 (br. s., 1H), 7.56 (d, J=3.7 Hz,
1H), 7.52 (s, 1H), 7.15 (br. s., 1H), 6.10 (d, J=9.9 Hz, 1H), 4.07
(s, 3H), 2.74 (d, J=12.3 Hz, 1H), 2.51 (br. s., 3H), 2.40 (br. s.,
1H), 2.13 (br. s., 2H), 1.66 (br. s., 1H), 1.54 (br. s., 1H), 1.04
(d, J=6.8 Hz, 3H), 0.75 (br. s., 1H); MS(ESI) m/z: 488.2
(M+H).sup.+. Analytical HPLC (Method A): RT=6.97 min, purity=97.0%;
Factor XIa Ki=110 nM, Plasma Kallikrein Ki=2,200 nM.
Example 142
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatr-
icyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00295##
[1685]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,17-tetr-
aazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (14.2 mg, 24%) was prepared in a similar manner as
Example 56, by using
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol,
prepared as described in Intermediate 9, and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo[1-
2.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one,
prepared as described in Intermediate 37. MS(ESI) m/z: 626.1
(M+H).sup.+ and 628.1 (M+2+H).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.62 (d, J=5.1 Hz, 1H), 8.35-8.13 (m, 3H), 7.85
(s, 2H), 7.71-7.62 (m, 2H), 7.57-7.53 (m, 1H), 7.09-7.03 (m, 1H),
6.36-6.30 (m, 1H), 5.67-5.63 (m, 1H), 2.59-2.54 (m, 1H), 2.31-2.24
(m, 1H), 2.04-1.94 (m, 2H), 1.59-1.54 (m, 1H), 1.30-1.21 (m, 2H),
1.03 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A): RT=8.54 min,
purity=99%; Factor XIa Ki=0.4 nM, Plasma Kallikrein Ki=90 nM.
Example 143
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0-
.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00296##
[1687]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12-
.3.1.0.sup.2,.sup.6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (9.7 mg, 21% yield) was prepared in a similar
manner as the procedure described in Example 56, by replacing
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol with
6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin--
4-ol (20 mg, 0.065 mmol), prepared as described in Intermediate 9.
MS(ESI) m/z: 590.1 (M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 8.82 (s, 1H), 8.72 (d, J=5.0 Hz, 1H), 8.33 (s, 1H), 7.88
(d, J=2.5 Hz, 1H), 7.73 (dd, J=8.5, 2.2 Hz, 1H), 7.68 (s, 1H), 7.64
(d, J=8.5 Hz, 1H), 7.52-7.49 (m, 1H), 7.49 (s, 1H), 6.36 (s, 1H),
5.98 (dd, J=12.5, 3.7 Hz, 1H), 4.04 (s, 3H), 2.70 (td, J=6.5, 3.0
Hz, 1H), 2.33-2.24 (m, 1H), 2.12-1.95 (m, 2H), 1.65-1.55 (m, 1H),
1.52-1.42 (m, 1H), 1.00 (d, J=6.9 Hz, 3H), 0.74-0.61 (m, 1H).
Analytical HPLC (Method A): RT=11.54 min, purity=99%; Factor XIa
Ki=0.17 nM, Plasma Kallikrein Ki=20 nM.
Example 144
Preparation of
(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00297##
[1689]
(9R,13S)-13-{4-[3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluor-
ophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (9.9 mg, 22% yield) was prepared in a similar
manner as the procedure described in Example 56, by using
6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]pyrimidin-4-
-ol (20 mg, 0.061 mmol), prepared as described in Intermediate 10.
MS(ESI) m/z: 608.1 (M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 8.83 (s, 1H), 8.73 (d, J=5.2 Hz, 1H), 8.32 (s, 1H), 7.85
(dd, J=8.5, 7.7 Hz, 1H), 7.68 (s, 1H), 7.55 (dd, J=8.7, 1.5 Hz,
1H), 7.51 (dd, J=5.2, 1.7 Hz, 1H), 7.49 (s, 1H), 6.60 (s, 1H), 6.00
(dd, J=12.8, 4.0 Hz, 1H), 4.05 (s, 3H), 2.75-2.64 (m, 1H), 2.29 (t,
J=12.9 Hz, 1H), 2.14-1.95 (m, 2H), 1.67-1.55 (m, 1H), 1.52-1.40 (m,
1H), 1.00 (d, J=6.9 Hz, 3H), 0.67 (m., 1H). .sup.19F NMR (471 MHz,
CD.sub.3OD) .delta. -76.98 (s),-115.06 (s). Analytical HPLC (Method
A): RT=11.58 min, purity=98.5%; Factor XIa Ki=0.1 nM, Plasma
Kallikrein Ki=6 nM.
Example 145
Preparation of
(9R,13S)-13-{4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-oxo-1-
,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00298##
[1690] 145A. Preparation of
4-[5-chloro-2-(4-bromo-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine
##STR00299##
[1692]
4-[2-(4-Bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-methoxypyrim-
idine (114 mg, 56.0% yield) was prepared in a similar manner as the
procedure described for the preparation of
4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine-
, as described in Intermediate 9D, by replacing NCS with NBS (346
mg, 1.945 mmol). MS(ESI) m/z: 368.3 (M+H).sup.+. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.69 (d, J=0.9 Hz, 1H), 7.75 (d, J=2.4 Hz,
1H), 7.66 (s, 1H), 7.61 (dd, J=8.5, 2.3 Hz, 1H), 7.49 (d, J=8.4 Hz,
1H), 6.52 (d, J=1.1 Hz, 1H), 3.98 (s, 3H).
145B. Preparation of
6-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]pyrimidin-4-ol
##STR00300##
[1694]
6-[2-(4-Bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]pyrimidin-4-ol
(47 mg, 42.9% yield) was prepared in a similar manner as the
procedure described in Intermediate 9E, by replacing
4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine
with
4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-methoxypyrimi-
dine (114 mg, 0.311 mmol). MS(ESI) m/z: 354.2 (M+H).sup.+. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.01 (s, 1H), 7.76 (s, 1H), 7.73
(d, J=2.2 Hz, 1H), 7.62 (dd, J=8.5, 2.1 Hz, 1H), 7.47 (d, J=8.4 Hz,
1H), 6.42 (s, 1H).
145C. Preparation of
(9R,13S)-13-{4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-oxo-1-
,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00301##
[1696]
(9R,13S)-13-{4-[2-(4-Bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-
-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.-
3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (18.7 mg, 36.3% yield) was prepared in a similar
manner as the procedure described in Example 56, by using
6-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]pyrimidin-4-ol
(23.6 mg, 0.067 mmol). MS(ESI) m/z: 636.3 (M+H).sup.+. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.80 (s, 1H), 8.73 (d, J=5.3 Hz, 1H),
8.37 (s, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.75-7.68 (m, 2H), 7.65-7.60
(m, 1H), 7.53 (dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 6.35 (s, 1H),
5.97 (dd, J=12.7, 4.3 Hz, 1H), 4.05 (s, 3H), 2.75-2.65 (m, 1H),
2.35-2.22 (m, 1H), 2.12-1.95 (m, 2H), 1.66-1.53 (m, 1H), 1.51-1.38
(m, 1H), 1.00 (d, J=7.0 Hz, 3H), 0.77-0.60 (m, 1H). Analytical HPLC
(Method A): RT=10.12 min, purity=96.9%; Factor XIa Ki=0.13 nM,
Plasma Kallikrein Ki=18 nM.
Examples 146 and 147
Preparation of
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxamide
trifluoroacetate, and
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-y-
l}phenyl)-1H-1,2,3-triazole-4-carbonitrile trifluoro acetate
##STR00302##
[1697] 146A. Preparation of
1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbox-
amide, and
147A. Preparation of
1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbon-
itrile
##STR00303##
[1699] To a suspension of
1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbox-
amide (150 mg, 0.45 mmol), prepared as described in Intermediate
18A, in DCM (1 mL) was added TFAA (0.3 mL, 2.12 mmol) at rt and the
reaction was stirred for 1 h. The reaction was concentrated to
dryness, partitioned between sat NaHCO.sub.3 and EtOAc, and the
layers were separated. The aqueous layer was extracted with EtOAc
(2.times.). The combined organic layers were concentrated and then
purified by normal phase chromatography to give
1-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole--
4-carboxamide (80 mg, 53.3% yield). MS(ESI) m/z: 331.3 (M+H).sup.+;
and
1-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbox-
amide (60.5 mg, 21.3% yield) which were used as is in the next
step. MS(ESI) m/z: 331.3.
146B. Preparation of
1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbox-
amide, and
147B. Preparation of
1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbon-
itrile
##STR00304##
[1701] To a suspension of a 1:1 mixture of
1-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbon-
itrile and
1-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazol-
e-4-carboxamide (60.5 mg, 0.194 mmol) in ACN (1 mL) was added TMSI
(12 .mu.L, 0.88 mmol) and the solution was heated at 50.degree. C.
overnight. The reaction was poured into 10% aq
Na.sub.2S.sub.2O.sub.3 s and extracted with EtOAc (3.times.). The
combined organic layers were concentrated to dryness then suspended
in DCM. The insoluble yellow solid was filtered to give a 5:3
mixture of
1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbox-
amide and
1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-
-4-carbonitrile (15 mg) which was used as in is the next step.
MS(ESI) m/z: 317.3, 299.3 (M+H).sup.+. The filtrate was
concentrated then purified by normal phase chromatography to give
1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbon-
itrile (20 mg, 34.6% yield) as a yellow solid. MS(ESI) m/z: 299.3
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.23 (s, 1H), 7.93 (s,
1H), 7.73 (d, J=2.2 Hz, 1H), 7.66 (dd, J=8.4, 2.2 Hz, 1H), 7.49 (d,
J=8.4 Hz, 1H), 6.54 (s, 1H).
146C. Preparation of
1-(4-chloro-2-{1[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12-
.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydr-
opyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxamide
trifluoroacetate, and
147C. Preparation of
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihyd-
ropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitrile
trifluoroacetate
##STR00305##
[1703] To a scintillation vial containing a mixture of
1-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbon-
itrile and
1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazol-
e-4-carboxamide (15 mg, 0.050 mmol) in ACN (1 mL), was added HATU
(24.8 mg, 0.065 mmol) and DBU (11 .mu.L, 0.075 mmol). After 20 min,
a solution of
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one (18.4 mg, 0.061
mmol), prepared as described in Intermediate 32, in ACN (0.5 ml)
and DMF (0.1 ml) was added. The resulting solution was stirred at
rt for 2 h then purified by reverse phase chromatography to give
two products.
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carboxamide
trifluoroacetate (3.8 mg, 10.5% yield) as a white solid. MS(ESI)
m/z: 599.4 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.79 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.56 (s, 1H), 7.88 (d, J=2.4
Hz, 1H), 7.76-7.71 (m, 1H), 7.69-7.64 (m, 2H), 7.51 (dd, J=5.2, 1.4
Hz, 1H), 7.48 (s, 1H), 6.35 (s, 1H), 5.96 (dd, J=12.8, 4.2 Hz, 1H),
4.04 (s, 3H), 2.75-2.63 (m, 1H), 2.33-2.21 (m, 1H), 2.12-1.92 (m,
2H), 1.66-1.53 (m, 1H), 1.52-1.40 (m, 1H), 1.00 (d, J=6.8 Hz, 3H),
0.74-0.60 (m, 1H). Analytical HPLC (Method A): RT=8.06 min,
purity=98.4%; Factor XIa Ki=0.44 nM, Plasma Kallikrein Ki=99
nM.
[1704]
1-(4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatric-
yclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,-
6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitrile
trifluoroacetate (1.7 mg, 4.9% yield) as a white solid. MS(ESI)
m/z: 581.3 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.93 (s, 1H), 8.73 (d, J=4.6 Hz, 2H), 7.90 (d, J=2.4 Hz, 1H),
7.79-7.73 (m, 1H), 7.71-7.67 (m, 2H), 7.51 (dd, J=5.1, 1.5 Hz, 1H),
7.49 (s, 1H), 6.46 (d, J=0.7 Hz, 1H), 5.97 (dd, J=12.7, 4.1 Hz,
1H), 4.05 (s, 3H), 2.70 (m, 1H), 2.34-2.21 (m, 1H), 2.13-1.94 (m,
2H), 1.67-1.53 (m, 1H), 1.52-1.39 (m, 1H), 1.01 (d, J=6.8 Hz, 3H),
0.71 (m, 1H). Analytical HPLC (Method A): RT=10.08 min,
purity=99.2%; Factor XIa Ki=0.11 nM, Plasma Kallikrein Ki=20
nM.
Example 148
Preparation of
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-9-oxo-3,8-diazatricycl-
o[13.3.1.0.sup.2,7]
nonadeca-1(19),2(7),3,5,15,17-hexaene-5-carbonitrile
##STR00306##
[1705] 148A. Preparation of tert-butyl
N-[(10R,14S)-5-bromo-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0.sup.2,7]n-
onadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate
##STR00307##
[1707] tert-Butyl
N-[(10R,14S)-5-bromo-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0.sup.2,7]
nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate was prepared
(0.1 g, 49% yield, dark solid) in a similar manner as Example 81C
replacing 2-bromo-5-methoxypyridin-3-amine with
2,5-dibromopyridin-3-amine. LCMS (M+H).sup.+ 474-476.08.
148B. Preparation of tert-butyl
N-[(10R,14S)-5-cyano-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0.sup.2,7]n-
onadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate
[1708] To tert-butyl
N-[(10R,14S)-5-bromo-10-methyl-9-oxo-3,8-diazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate
(0.1 g, 0.211 mmol) in a microwave tube was added Zn(CN).sub.2
(0.037 g, 0.316 mmol), Zn (4.13 mg, 0.063 mmol) and DMF (2.1 ml).
The mixture was purged with Ar for several min.
Pd(t-Bu.sub.3P).sub.2 (10.77 mg, 0.021 mmol) was added. The
reaction was sealed and heated at 80.degree. C. for 18 h. The
reaction was partitioned with water (10 ml) and EtOAc (30 ml). The
aqueous layer was extracted with EtOAc (2.times.10 ml). The
combined organic layers were washed with brine (10 ml), dried
(MgSO.sub.4), filtered and concentrated. The residue was purified
normal phase chromatography using 100% DCM to 10% MeOH as eluents
to give tert-butyl
N-[(10R,14S)-5-cyano-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0.sup.2,7]n-
onadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate (20 mg, 22.56%
yield). LCMS (M+H).sup.+ 421.3.
148C. Preparation of
(10R,14S)-14-amino-10-methyl-9-oxo-3,8-diazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaene-5-carbonitrile
##STR00308##
[1710] tert-Butyl
N-[(10R,14S)-5-cyano-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0.sup.2,7]
nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate (0.02 g, 0.048
mmol), Example 148B, was deprotected and the free-base was produced
in a similar manner as Example 81D to afford
(10R,14S)-14-amino-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0.sup.2,7]
nonadeca-1(19),2(7),3,5,15,17-hexaene-5-carbonitrile (13 mg, 85%)
as a tan solid. LCMS (M+H).sup.+ 321.3.
148D. Preparation of
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-9-oxo-3,8-diazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaene-5-carbonitrile
[1711] To
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-
pyrimidin-4-ol, described in Intermediate 15, (0.014 g, 0.041 mmol)
and HATU (0.020 g, 0.053 mmol) in a small vial was added DBU (9.17
.mu.l, 0.061 mmol) in ACN (0.2 mL). After 30 min,
(10R,14S)-14-amino-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0.sup.2,7]non-
adeca-1(19),2(7),3,5,15,17-hexaene-5-carbonitrile was added in DMF
(0.4 ml). After 18 h, the reaction was diluted with DMF, filtered
and concentrated. The residue was purified by reverse phase HPLC
using PHENOMENEX.RTM. Luna 5U 30.times.100 mm (10:90 ACN/H.sub.2O
to 90:10 ACN/H.sub.2O, 0.1% TFA) (20% B start, 14 min gradient) to
afford
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-9-oxo-3,8-diazatricyclo[1-
3.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaene-5-carbonitrile
(4.9 mg, 14%) as a white solid. MS(ESI) m/z: 645.4 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.98-8.94 (m, 1H), 8.80
(s, 1H), 8.30-8.24 (m, 1H), 8.18-8.13 (m, 1H), 7.96-7.91 (m, 1H),
7.81-7.76 (m, 2H), 7.74-7.68 (m, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.32
(s, 1H), 6.49-6.46 (m, 1H), 5.81 (dd, J=12.7, 3.4 Hz, 1H), 2.56 (d,
J=7.0 Hz, 1H), 2.31 (d, J=5.1 Hz, 1H), 2.16-2.08 (m, 1H), 1.93 (d,
J=7.3 Hz, 1H), 1.58 (d, J=7.3 Hz, 1H), 1.46 (d, J=6.8 Hz, 1H), 1.37
(br. s., 1H), 1.26-1.21 (m, 1H), 1.17 (s, 3H). Analytical HPLC
(Method A) RT=9.37 min, purity=90%; Factor XIa Ki=1.8 nM, Plasma
Kallikrein Ki=120 nM.
Example 149
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy}-
methyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-
-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4-
,14,16-pentaen-8-one trifluoroacetate
##STR00309##
[1712] 149A. Preparation of
4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypy-
rimidine
##STR00310##
[1714] To a solution of
{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazol-4-yl}met-
hanol (95 mg, 0.3 mmol), prepared as described in Intermediate 16A,
in DCM (6 ml) was added DAST (0.040 mL, 0.300 mmol) and the
reaction was stirred at rt for 2 h. The reaction was quenched with
water, and extracted with DCM. The organic layer was concentrated
and purified by normal phase chromatography to give
4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypy-
rimidine (56 mg, 0.175 mmol, 58.4% yield) as a clear oil. MS(ESI)
m/z: 320.0 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.68 (d, J=1.1 Hz, 1H), 7.77 (d, J=2.2 Hz, 1H), 7.73 (d, J=2.6 Hz,
1H), 7.64-7.57 (m, 1H), 7.53-7.48 (m, 1H), 6.46 (d, J=1.1 Hz, 1H),
5.57 (s, 1H), 5.45 (s, 1H), 3.98-3.87 (m, 3H). .sup.19F NMR (376
MHz, CDCl.sub.3) .delta. -208.23 (s).
149B. Preparation of
6-{2-[4-(bromomethyl)-1H-1,2,3-triazol-1-yl]-5-chlorophenyl}
pyrimidin-4-ol
##STR00311##
[1716] A solution of
4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypy-
rimidine (56 mg, 0.175 mmol) in 33% HBr in AcOH (0.5 ml, 4.14 mmol)
was heated at 85.degree. C. for 1 h. The reaction was concentrated
to half the volume then, 48% aq HBr (0.2 ml) was added and heated
at 85.degree. C. for 1 h. The reaction was concentrated, and the
residue was partitioned between EtOAc and sat NaHCO.sub.3. The
layers were separated and the aqueous layer was extracted with
EtOAc (2.times.). The combined organic layers were concentrated and
purified by normal phase chromatography to give
6-{2-[4-(bromomethyl)-1H-1,2,3-triazol-1-yl]-5-chlorophenyl}pyrimidin-4-o-
l. MS(ESI) m/z: 368.2 (M+H).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.87 (d, J=0.9 Hz, 1H), 7.79 (s, 1H), 7.70 (d,
J=2.2 Hz, 1H), 7.65-7.57 (m, 1H), 7.55-7.46 (m, 1H), 6.38 (d, J=1.1
Hz, 1H), 4.60 (s, 2H).
149C. Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-({3H-[1,2,3]triazolo
[4,5-b]pyridin-3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-di-
hydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2-
,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
##STR00312##
[1718]
(9R,13S)-13-(4-{5-Chloro-2-[4-({3H-[1,2,3]triazolo[4,5-b]pyridin-3--
yloxy}
methyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1--
yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18)-
,2(6),4,14,16-pentaen-8-one trifluoroacetate (12.1 mg, 42.1% yield)
was prepared in a similar manner as the procedure described in
Example 56, by using
6-{2-[4-(bromomethyl)-1H-1,2,3-triazol-1-yl]-5-chlorophenyl}
pyrimidin-4-ol (12.3 mg, 0.033 mmol). MS(ESI) m/z: 704.24
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.23 (s,
1H), 8.82-8.71 (m, 2H), 8.66-8.60 (m, 2H), 8.57 (d, J=8.2 Hz, 1H),
7.89 (d, J=2.4 Hz, 1H), 7.81 (dd, J=8.5, 2.1 Hz, 1H), 7.65-7.59 (m,
2H), 7.56 (dd, J=8.4, 4.4 Hz, 1H), 7.51 (d, J=4.6 Hz, 1H), 7.46 (s,
1H), 6.37 (s, 1H), 5.86 (d, J=11.3 Hz, 1H), 5.77 (s, 2H), 4.03-3.91
(m, 3H), 3.55 (m., 1H), 2.62 (m, 1H), 2.23 (m, 1H), 2.05 (d, J=10.4
Hz, 1H), 1.86-1.73 (m, 1H), 1.41 (m, 1H), 1.29 (m, 1H), 0.85 (d,
J=6.7 Hz, 3H), 0.39 (m., 1H). Analytical HPLC (Method C): RT=1.41
min, purity=95%; Factor XIa Ki=3.4 nM, Plasma Kallikrein Ki=310
nM.
Example 150
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(hydroxylmethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00313##
[1719] 150A. Preparation of
6-{5-chloro-2-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]phenyl}
pyrimidin-4-ol
##STR00314##
[1721] A solution of
{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazol-4-yl}met-
hanol (65 mg, 0.205 mmol), prepared as described in Intermediate
16A, in 33% HBr in AcOH (0.6 ml, 4.97 mmol) was heated at
85.degree. C. for 1 h. The reaction was concentrated to half the
volume, then 48% aq HBr (0.2 ml) was added and heated at 85.degree.
C. for 1 h. The reaction was concentrated, and the residue was
partitioned between EtOAc and sat NaHCO.sub.3. The layers were
separated and the aqueous layer was extracted with EtOAc
(2.times.). The combined organic layers were concentrated and
purified by normal phase chromatography to give
6-{5-chloro-2-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-
-ol (13 mg, 20.9% yield). MS(ESI) m/z: 304.4 (M+H).sup.+. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.99 (s, 1H), 7.76 (s, 2H), 7.59
(dd, J=8.5, 2.3 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 6.18 (s, 1H),
4.83-4.76 (m, 2H).
150B. Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]pheny-
l}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00315##
[1723]
(9R,13S)-13-(4-{5-Chloro-2-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl-
]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (1.5 mg, 4.7% yield) was prepared in a similar
manner as the procedure described in Example 56, by using
6-(5-chloro-2-(4-(hydroxylmethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin--
4-ol (13.19 mg, 0.043 mmol). MS(ESI) m/z: 586.20 (M+H).sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.26 (s, 1H), 8.82 (s,
1H), 8.68 (d, J=4.9 Hz, 1H), 8.23 (s, 1H), 7.89 (d, J=1.8 Hz, 1H),
7.78 (d, J=6.4 Hz, 1H), 7.68-7.61 (m, 2H), 7.56 (d, J=5.2 Hz, 1H),
7.47 (s, 1H), 6.15 (s, 1H), 5.90-5.82 (m, 1H), 4.57 (d, J=4.9 Hz,
2H), 4.00 (s, 3H), 2.68-2.60 (m, 1H), 2.32-2.22 (m, 1H), 2.07 (m,
1H), 1.88-1.78 (m, 1H), 1.50-1.43 (m, 1H), 1.40-1.29 (m, 1H), 0.88
(d, J=6.7 Hz, 3H), 0.46-0.35 (m, 1H). Analytical HPLC (Method C):
RT=1.19 min, purity=92%; Factor XIa Ki=7.3 nM, Plasma Kallikrein
Ki=1,400 nM.
Example 151
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00316##
[1725]
(9R,13S)-13-(4-{5-Chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-y-
l]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazat-
ricyclo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (10 mg, 20.4% yield) was prepared in a similar
manner as the procedure described in Example 56, by using
6-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin--
4-ol (21.62 mg, 0.067 mmol), prepared as described in Intermediate
16. MS(ESI) m/z: 606.2 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.77 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.53 (t,
J=1.3 Hz, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.77-7.72 (m, 1H), 7.69 (s,
1H), 7.68-7.64 (m, 1H), 7.52 (dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H),
7.14-6.84 (m, 1H), 6.35 (s, 1H), 5.97 (dd, J=12.5, 4.2 Hz, 1H),
4.04 (s, 3H), 2.70 (td, J=6.7, 3.1 Hz, 1H), 2.27 (qd, J=8.5, 4.7
Hz, 1H), 2.12-1.92 (m, 2H), 1.65-1.53 (m, 1H), 1.45 (ddd, J=14.6,
9.8, 5.3 Hz, 1H), 1.00 (d, J=6.8 Hz, 3H), 0.69 (m, 1H). .sup.19F
NMR (376 MHz, CD.sub.3OD) .delta. -77.76 (s), -114.46 (s).
Analytical HPLC (Method A): RT=7.81 min, purity=98.7%; Factor XIa
Ki=0.27 nM, Plasma Kallikrein Ki=54 nM.
Example 152
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-
-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.-
3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00317##
[1726] 152A. Preparation of
4-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-methoxypyrim-
idine
##STR00318##
[1728] To a solution of 4-(trifluoromethyl)-1H-pyrazole (34.2 mg,
0.251 mmol) in DMF (698 .mu.l) was added NaH (12.57 mg, 0.314 mmol)
in 2 portions and the reaction was stirred at rt for 30 min.
4-(5-Chloro-2-fluorophenyl)-6-methoxypyrimidine (50 mg, 0.210
mmol), prepared as described in Intermediate 5A, was added and the
solution was stirred at rt for 2 h and then heated at 85.degree. C.
overnight. The reaction mixture was quenched with water and MeOH,
then concentrated. Purification by normal phase chromatography gave
4-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-methoxypyrim-
idine (60 mg, 32.3% yield). MS(ESI) m/z: 355.3 (M+H).sup.+. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.73 (d, J=0.9 Hz, 1H), 7.81 (s,
1H), 7.77 (d, J=2.4 Hz, 1H), 7.70 (s, 1H), 7.59-7.53 (m, 1H),
7.51-7.47 (m, 1H), 6.36 (d, J=1.1 Hz, 1H), 3.98-3.94 (m, 3H).
152B. Preparation of
6-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)
pyrimidin-4-ol
##STR00319##
[1730]
6-{5-Chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}pyrimidin-
-4-ol (23 mg, 25.5% yield) was prepared in a similar manner as the
procedure described in Intermediate 9E, by using
4-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-methoxypyrim-
idine (60 mg, 0.169 mmol). MS(ESI) m/z: 341.3 (M+H).sup.+. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.97 (s, 1H), 7.90 (d, J=0.7 Hz,
1H), 7.82 (s, 1H), 7.70 (d, J=2.2 Hz, 1H), 7.63-7.55 (m, 1H),
7.53-7.47 (m, 1H), 6.27 (d, J=0.9 Hz, 1H).
152C. Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00320##
[1732]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (20 mg, 40.2% yield) was prepared in a similar
manner as the procedure described in Example 56, by using
6-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}pyrimidin-4-ol
(22.76 mg, 0.067 mmol). MS(ESI) m/z: 623.2 (M+H).sup.+. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.85 (s, 1H), 8.71 (d, J=5.1 Hz, 1H),
8.32 (s, 1H), 7.90-7.80 (m, 2H), 7.71-7.64 (m, 2H), 7.62-7.57 (m,
1H), 7.52 (dd, J=5.2, 1.7 Hz, 1H), 7.49 (s, 1H), 6.20 (d, J=0.7 Hz,
1H), 5.98 (dd, J=12.7, 4.3 Hz, 1H), 4.05 (s, 3H), 2.70 (td, J=6.7,
3.2 Hz, 1H), 2.30 (tt, J=12.7, 4.4 Hz, 1H), 2.13-1.94 (m, 2H),
1.68-1.53 (m, 1H), 1.47 (ddd, J=14.9, 9.8, 5.3 Hz, 1H), 1.01 (d,
J=6.8 Hz, 3H), 0.70 (m, 1H). .sup.19F NMR (376 MHz, CD.sub.3OD)
.delta. -57.99 (s), -77.75 (s). Analytical HPLC (Method A): RT=8.98
min, purity=99.1%; Factor XIa Ki=10 nM, Plasma Kallikrein Ki=4,900
nM.
Example 153
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00321##
[1733] 153A. Preparation of
6-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}
pyrimidin-4-ol
##STR00322##
[1735] A solution of
4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypy-
rimidine (35 mg, 0.109 mmol), prepared as described in Example 149A
in ACN (1 mL) was treated with TMSI (75 .mu.L, 0.55 mmol) and
heated at 50.degree. C. for 6 h. The reaction was poured into 10%
aq Na.sub.2S.sub.2O.sub.3. Sat NaHCO.sub.3 was added and the
mixture was extracted with EtOAc (2.times.). The combined organic
layers were washed with brine, concentrated, and purified by normal
phase chromatography to give
6-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimid-
in-4-ol (14 mg, 41.8% yield). MS(ESI) m/z: 306.4 (M+H).sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.98 (s, 1H), 7.84 (d,
J=2.4 Hz, 1H), 7.74 (d, J=2.4 Hz, 1H), 7.62 (dd, J=8.5, 2.3 Hz,
1H), 7.49 (d, J=8.4 Hz, 1H), 6.36 (s, 1H), 5.55 (d, J=48.2 Hz, 1H).
.sup.19F NMR (376 MHz, CDCl.sub.3) .delta. -208.21 (s).
153B. Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl-
}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00323##
[1737]
(9R,13S)-13-(4-{5-Chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]-
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatri-
cyclo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (12 mg, 37% yield) was prepared in a similar
manner as the procedure described in Example 56, by replacing
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol with
6-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}py-
rimidin-4-ol (14 mg, 0.046 mmol). MS(ESI) m/z: 588.3 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.79 (s, 1H), 8.71 (d,
J=5.1 Hz, 1H), 8.35 (d, J=3.1 Hz, 1H), 7.88 (d, J=2.4 Hz, 1H),
7.75-7.70 (m, 1H), 7.68 (s, 1H), 7.66-7.62 (m, 1H), 7.52 (dd,
J=5.3, 1.5 Hz, 1H), 7.48 (s, 1H), 6.29 (s, 1H), 5.96 (dd, J=12.5,
4.2 Hz, 1H), 5.47 (d, J=48.6 Hz, 2H), 4.04 (s, 3H), 2.70 (td,
J=6.7, 3.3 Hz, 1H), 2.33-2.20 (m, 1H), 2.12-1.92 (m, 2H), 1.66-1.53
(m, 1H), 1.52-1.37 (m, 1H), 1.00 (d, J=7.0 Hz, 3H), 0.69 (m, 1H).
.sup.19F NMR (376 MHz, CD.sub.3OD) .delta. -77.74 (s), -207.90 (s).
Analytical HPLC (Method A): RT=7.01 min, purity=98.5%; Factor XIa
Ki=1.4 nM, Plasma Kallikrein Ki=150 nM.
Example 154
Preparation of
1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tet-
raazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]--
6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitrile
trifluoroacetate
##STR00324##
[1739]
1-(4-Chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,-
15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-1-
3-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole-4-carbonit-
rile trifluoroacetate (8 mg, 18% yield) was prepared in a similar
manner as the procedure described in Example 56, by using
1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbon-
itrile (17.81 mg, 0.060 mmol), prepared as described in
Intermediate 18. MS(ESI) m/z: 617.2 (M+H). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.93 (s, 1H), 8.79 (s, 1H), 8.75 (d, J=5.1 Hz,
1H), 7.89 (d, J=2.2 Hz, 1H), 7.81-7.63 (m, 5H), 7.54-7.48 (m, 1H),
6.47 (d, J=0.7 Hz, 1H), 5.99 (dd, J=12.8, 4.4 Hz, 1H), 2.76-2.65
(m, 1H), 2.34-2.22 (m, 1H), 2.09-1.94 (m, 2H), 1.65-1.40 (m, 2H),
0.99 (d, J=6.8 Hz, 3H), 0.71-0.54 (m, 1H). Analytical HPLC (Method
A): RT=9.04 min, purity=99.0%; Factor XIa Ki=0.1 nM, Plasma
Kallikrein Ki=17 nM.
Example 155
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl-9-methyl-
-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pe-
ntaen-8-one trifluoroacetate
##STR00325##
[1741]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl-9-meth-
yl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (11 mg, 30% yield) was prepared in a similar
manner as the procedure described in Example 56, by using
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,15-tetraazatricy-
clo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one (15
mg, 0.050 mmol), prepared as described in Intermediate 33. MS(ESI)
m/z: 627.3 (M+H). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.81
(s, 1H), 8.77-8.66 (m, 2H), 7.89 (d, J=2.2 Hz, 1H), 7.79-7.64 (m,
3H), 7.59-7.51 (m, 1H), 7.49 (s, 1H), 6.44 (s, 1H), 5.97 (dd,
J=12.4, 3.9 Hz, 1H), 2.76-2.62 (m, J=6.5, 3.4, 3.4 Hz, 1H),
2.34-2.21 (m, 1H), 2.12-1.94 (m, 2H), 1.68-1.53 (m, 1H), 1.51-1.39
(m, 1H), 1.00 (d, J=6.8 Hz, 3H), 0.78-0.63 (m, 1H). Analytical HPLC
(Method A): RT=8.64 min, purity=99.4%; Factor XIa Ki=0.14 nM,
Plasma Kallikrein Ki=33 nM.
Example 156
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,-
7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-
-8-one trifluoroacetate
##STR00326##
[1743]
(9R,13S)-13-(4-{5-Chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-y-
l]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4-
,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (22 mg, 57% yield) was prepared in a similar
manner as the procedure described in Example 56, using
6-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}
pyrimidin-4-ol (16.41 mg, 0.051 mmol), prepared as described in
Intermediate 16, and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (17 mg,
0.051 mmol), prepared as described in Intermediate 30. MS(ESI) m/z:
642.3 (M+H). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.84 (s,
1H), 8.72 (d, J=5.1 Hz, 1H), 8.53 (t, J=1.4 Hz, 1H), 7.89 (d, J=2.2
Hz, 1H), 7.81-7.62 (m, 5H), 7.54-7.48 (m, 1H), 6.99 (t, J=54.4 Hz,
1H), 6.35 (d, J=0.7 Hz, 1H), 6.00 (dd, J=12.9, 4.7 Hz, 1H), 2.70
(td, J=6.7, 3.0 Hz, 1H), 2.33-2.19 (m, 1H), 2.08-1.93 (m, 2H),
1.64-1.51 (m, 1H), 1.51-1.39 (m, 1H), 0.99 (d, J=7.0 Hz, 3H),
0.68-0.52 (m, 1H). Analytical HPLC (Method A): RT=10.94 min,
purity=99.0%; Factor XIa Ki=0.22 nM, Plasma Kallikrein Ki=50
nM.
Example 157
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,-
7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-
-8-one trifluoroacetate
##STR00327##
[1745]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,-
4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (20 mg, 50% yield) was prepared in a similar
manner as the procedure described in Example 56, by using
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (17 mg,
0.051 mmol), prepared as described in Intermediate 30. MS(ESI) m/z:
660.3 (M+H). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.81 (d,
J=3.7 Hz, 2H), 8.71 (d, J=5.1 Hz, 1H), 7.89 (d, J=2.2 Hz, 1H),
7.81-7.62 (m, 5H), 7.56-7.46 (m, 1H), 6.44 (s, 1H), 6.00 (dd,
J=12.7, 4.5 Hz, 1H), 2.70 (td, J=6.5, 3.0 Hz, 1H), 2.32-2.20 (m,
1H), 2.10-1.91 (m, 2H), 1.65-1.51 (m, 1H), 1.51-1.39 (m, 1H), 0.99
(d, J=6.8 Hz, 3H), 0.70-0.51 (m, 1H). Analytical HPLC (Method A):
RT=9.74 min, purity=97.8%; Factor XIa Ki=0.1 nM, Plasma Kallikrein
Ki=34 nM.
Example 158
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl-9-methyl-
-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00328##
[1747]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl-9-meth-
yl-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (12 mg,
36% yield) was prepared in a similar manner as the procedure
described in Example 56, by using
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7-triazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (16 mg,
0.053 mmol), prepared as described in Intermediate 36. MS(ESI) m/z:
626.3 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.76
(d, J=0.7 Hz, 1H), 8.10 (s, 1H), 7.86 (d, J=2.2 Hz, 1H), 7.76-7.71
(m, 2H), 7.69-7.63 (m, 1H), 7.60-7.50 (m, 2H), 7.49 (s, 1H),
7.31-7.24 (m, 1H), 6.47 (d, J=0.4 Hz, 1H), 5.81 (dd, J=12.8, 3.3
Hz, 1H), 2.46 (ddd, J=10.3, 6.8, 3.6 Hz, 1H), 2.38-2.23 (m, 1H),
2.13-1.98 (m, 1H), 1.91-1.78 (m, 1H), 1.63-1.47 (m, 2H), 1.27-1.15
(m, 1H), 1.13 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A):
RT=9.06 min, purity=99.2%; Factor XIa Ki=0.1 nM, Plasma Kallikrein
Ki=8 nM.
Example 159
Preparation of
(9S,13R)-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-
-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricy-
clo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00329##
[1748] 159A. Preparation of
(R)--N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide
[1749] To a RBF was added 4-chloropicolinaldehyde (5.0 g, 35.3
mmol), CH.sub.2Cl.sub.2 (100 mL), (R)-2-methylpropane-2-sulfinamide
(5.14 g, 42.4 mmol) and Cs.sub.2CO.sub.3 (34.5 g, 106 mmol). The
reaction was stirred at rt overnight. The reaction was filtered
through CELITE.RTM.. The filtrate was concentrated and the residue
was purified using ISCO system (0-50% EtOAc/Hep gradient) to give
(R)--N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide
(6.36 g, 26.0 mmol, 73.6% yield) as a clear oil. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.71 (s, 1H), 8.67 (dd, J=5.3, 0.4 Hz,
1H), 8.05 (dd, J=2.0, 0.4 Hz, 1H), 7.44 (dd, J=5.3, 2.0 Hz, 1H),
1.33 (s, 9H); MS(ESI) m/z: 245.1 (M+H).sup.+.
159B. Preparation of
(R)--N--((R)-1-(4-chloropyridin-2-yl)but-3-en-1-yl)-2-methylpropane-2-sul-
finamide
[1750] To a RBF was added
(R)--N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide
(6.39 g, 26.1 mmol), THF (40 mL), 3-bromoprop-1-ene (3.39 mL, 39.2
mmol) and In (4.50 g, 39.2 mmol). The reaction was stirred at
60.degree. C. overnight. The reaction was then partitioned between
EtOAc (100 ml) and water (50 ml). The organic layer was separated,
washed with sat NaCl (50 ml), dried over MgSO.sub.4, filtered and
concentrated. The residue was purified using ISCO system (0-100%
EtOAc/Hep gradient) to give
(R)--N--((R)-1-(4-chloropyridin-2-yl)but-3-en-1-yl)-2-methylpropane-2-sul-
finamide (5.67 g, 19.8 mmol, 76% yield) as a clear oil. .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 8.50-8.41 (m, 1H), 7.36-7.30 (m, 1H),
7.26-7.18 (m, 1H), 5.71 (ddt, J=17.1, 10.3, 6.9 Hz, 1H), 5.12-4.99
(m, 2H), 4.77 (d, J=7.4 Hz, 1H), 4.48 (q, J=6.8 Hz, 1H), 2.66-2.51
(m, 2H), 1.30-1.27 (m, 9H); MS(ESI) m/z: 287.1 (M+H).sup.+.
159C. Preparation of (R)-tert-butyl
(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate
[1751] To a RBF was added
(R)--N--((R)-1-(4-chloropyridin-2-yl)but-3-en-1-yl)-2-methylpropane-2-sul-
finamide (5.67 g, 19.77 mmol), MeOH (100 mL) and 4 N HCl in dioxane
(24.71 mL, 99 mmol). The reaction was stirred at rt for 30 min. The
reaction was then concentrated to give a white solid. To this solid
was added CH.sub.2Cl.sub.2 (100 mL), Et.sub.3N (5.51 mL, 39.5 mmol)
and (Boc).sub.2O (5.51 mL, 23.72 mmol). The reaction was stirred at
rt overnight. The reaction was diluted with CH.sub.2Cl.sub.2 (100
ml) and washed with water (100 ml) and sat NaCl (100 ml), dried
over MgSO.sub.4, filtered and concentrated. The residue was
purified using ISCO system (0-50% EtOAc/Hex gradient) to give
(R)-tert-butyl (1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate
(4.92 g, 17.40 mmol, 88% yield) as a clear oil. .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 8.47 (d, J=5.2 Hz, 1H), 7.27 (d, J=1.7 Hz,
1H), 7.21 (dd, J=5.2, 1.9 Hz, 1H), 5.80-5.60 (m, 1H), 5.49 (d,
J=5.8 Hz, 1H), 5.15-5.00 (m, 2H), 4.81 (d, J=6.1 Hz, 1H), 2.67-2.50
(m, 2H), 1.50-1.39 (m, 9H); MS(ESI) m/z: 283.1 (M+H).sup.+.
159D. Preparation of (R)-tert-butyl
(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-
-yl)carbamate
[1752] To a RBF was added (R)-tert-butyl
(1-(4-chloropyridin-2-yl)but-3-en-1-yl) carbamate (2.54 g, 15.56
mmol), di(adamantan-1-yl)(butyl)phosphine (0.507 g, 1.415 mmol),
K.sub.2CO.sub.3 (5.87 g, 42.4 mmol), pivalic acid (0.433 g, 4.24
mmol) and dioxane (50 mL). The reaction mixture was purged with Ar
for 5 min. To this mixture was added Pd(OAc).sub.2 (0.159 g, 0.707
mmol) and the reaction was heated at 100.degree. C. for 4 h. The
reaction was then partitioned with water (200 mL) and EtOAc (200
mL). The organic layer was separated and washed with water (200 mL)
and sat NaCl (200 mL), dried over MgSO.sub.4, filtered and
concentrated to give the crude product which was then purified
using ISCO system (0-60% EtOAc/Hex gradient) to give (R)-tert-butyl
(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-
-yl)carbamate (4.12 g, 10.06 mmol, 71.1% yield) as a yellow oil.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.82-8.78 (m, 1H), 8.36
(s, 1H), 7.34 (s, 1H), 7.32-7.30 (m, 1H), 7.23-6.96 (m, 1H),
5.76-5.65 (m, 1H), 5.59 (d, J=5.8 Hz, 1H), 5.14-5.04 (m, 2H), 4.93
(d, J=5.8 Hz, 1H), 2.67 (t, J=6.1 Hz, 2H), 1.46 (br. s., 9H);
MS(ESI) m/z: 410.1 (M+H).sup.+.
159E. Preparation of (R)-tert-butyl
(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-
-yl)carbamate
[1753] To a round bottom was added (R)-tert-butyl
(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-
-yl)carbamate (4.12 g, 10.06 mmol), Zn (2.63 g, 40.3 mmol) MeOH (40
mL) and AcOH (4 mL). The reaction was heated in at 40.degree. C.
for 10 min. The reaction was then cooled to rt and partitioned
between EtOAc (100 ml) and sat NaHCO.sub.3 (100 ml). The organic
layer was separated, washed with water (100 ml) and sat NaCl (100
ml), dried over MgSO.sub.4, filtered and concentrated. The residue
was purified using ISCO system (0-30% MeOH/CH.sub.2Cl.sub.2
gradient) to give (R)-tert-butyl
(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-
-yl)carbamate (3.37 g, 8.88 mmol, 88% yield) as a yellow oil.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.73-8.68 (m, 1H), 7.43
(s, 1H), 7.36 (s, 1H), 7.33 (d, J=5.0 Hz, 1H), 7.26-7.00 (m, 1H),
5.80-5.67 (m, 1H), 5.59 (br. s., 1H), 5.10 (s, 1H), 5.07 (d, J=4.4
Hz, 1H), 4.88 (d, J=6.1 Hz, 1H), 2.66 (t, J=6.2 Hz, 2H), 1.50-1.40
(m, 9H); MS(ESI) m/z: 380.1 (M+H).sup.+.
159F. Preparation of tert-butyl
((1R)-1-(4-(1-(difluoromethyl)-4-(2-methylbut-3-enamido)-1H-pyrazol-5-yl)-
pyridin-2-yl)but-3-en-1-yl)carbamate
[1754] To a RBF was added (R)-tert-butyl
(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-
-yl)carbamate (3.37 g, 8.88 mmol), EtOAc (20 mL),
2-methylbut-3-enoic acid (0.889 g, 8.88 mmol) and pyridine (1.44
mL, 17.76 mmol). The solution was cooled in an ice bath and
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide
(7.93 mL, 13.32 mmol) was added. The reaction was stirred at
0.degree. C. for 2 h. The reaction was then partitioned between
EtOAc (100 ml) and sat NaHCO.sub.3 (100 ml). The organic layer was
separated, washed with water (100 ml) and brine (100 ml), dried
over MgSO.sub.4, filtered and concentrated. The residue was
purified using ISCO system (0-80% EtOAc/Hex gradient) to give
tert-butyl
((1R)-1-(4-(1-(difluoromethyl)-4-(2-methylbut-3-enamido)-1H-pyrazol-5-yl)-
pyridin-2-yl)but-3-en-1-yl)carbamate (3.33 g, 7.22 mmol, 81% yield)
as a yellow oil. It was a mixture of 2 diastereomers. .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 8.74 (d, J=5.0 Hz, 1H), 8.36 (d,
J=2.2 Hz, 1H), 7.34-7.30 (m, 1H), 7.28-7.24 (m, 1H), 7.22-7.06 (m,
2H), 5.98-5.83 (m, 1H), 5.76-5.65 (m, 1H), 5.51 (br. s., 1H),
5.28-5.18 (m, 2H), 5.15-5.03 (m, 2H), 4.86 (br. s., 1H), 3.22-3.04
(m, 1H), 2.66 (br. s., 2H), 1.50-1.42 (m, 9H), 1.33 (dd, J=7.0, 4.5
Hz, 3H); MS(ESI) m/z: 462.2 (M+H).sup.+.
159G and 159H. Preparation of tert-butyl
N-[(9S,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate,
and tert-butyl
N-[(9R,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
[1755] To a RBF was added tert-butyl
41R)-1-(4-(1-(difluoromethyl)-4-(2-methylbut-3-enamido)-1H-pyrazol-5-yl)p-
yridin-2-yl)but-3-en-1-yl)carbamate (3.33 g, 7.22 mmol) and EtOAc.
Second Generation Grubbs Catalyst (1.531 g, 1.804 mmol) was added
to the reaction. The reaction was refluxed under Ar for 2 days. The
reaction was concentrated. The residue was purified using ISCO
system (0-100% EtOAc/Hex gradient and then 100% EtOAc). Two
diastereomers were separated. The compound that came off the column
first was 159G, tert-butyl
N-[(9S,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]
carbamate (490 mg, 1.13 mmol, 15.7% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.72 (d, J=5.1 Hz, 1H), 7.80 (s, 1H), 7.42 (s,
1H), 7.27 (m, 1H), 7.20 (br. s., 1H), 6.87 (s, 1H), 6.41 (d, J=7.5
Hz, 1H), 5.77 (ddd, J=15.2, 11.0, 4.0 Hz, 1H), 4.89-4.70 (m, 2H),
3.19-3.08 (m, 1H), 3.03 (d, J=12.5 Hz, 1H), 2.03-1.92 (m, 1H), 1.50
(s, 9H), 1.20 (d, J=6.6 Hz, 3H); MS(ESI) m/z: 434.1 (M+H).sup.+.
The compound that came off the column second was 159H, tert-butyl
N-[(9R,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate
(460 mg, 1.06 mmol, 14.7% yield). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.71 (d, J=5.1 Hz, 1H), 7.83 (s, 1H), 7.37 (d, J=5.1 Hz,
1H), 7.26 (d, J=2.6 Hz, 1H), 6.89 (s, 1H), 6.68 (br. s., 1H), 6.28
(br. s., 1H), 5.84-5.69 (m, 1H), 5.47-5.32 (m, 1H), 4.82 (br. s.,
1H), 3.11-2.90 (m, 2H), 2.15-1.98 (m, 1H), 1.52-1.44 (m, 9H), 1.37
(d, J=6.6 Hz, 3H); MS(ESI) m/z: 434.1 (M+H).sup.+.
159I. Preparation of tert-butyl
N-[(9S,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
[1756] To a 3-neck RBF wad added tert-butyl
N-[(9S,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]
carbamate (485 mg, 1.119 mmol), EtOH (35 mL) and PtO.sub.2 (127 mg,
0.559 mmol). The reaction was stirred under a H.sub.2 balloon for 1
h. The reaction was carefully filtered through CELITE.RTM. and the
filtrate was concentrated. The residue was purified using ISCO
system (0-10% MeOH/CH.sub.2Cl.sub.2 gradient) to give tert-butyl
N-[(9S,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(370 mg, 0.850 mmol, 76% yield) as a beige solid. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.75 (d, J=5.1 Hz, 1H), 7.63 (s, 1H), 7.46
(s, 1H), 7.35 (s, 1H), 7.31 (m, J=3.5 Hz, 1H), 6.81 (br. s., 1H),
5.81 (d, J=7.9 Hz, 1H), 4.88 (br. s., 1H), 2.62 (td, J=6.5, 2.6 Hz,
1H), 2.13-1.99 (m, 1H), 1.90-1.77 (m, 1H), 1.69-1.62 (m, 1H),
1.56-1.51 (m, 1H), 1.49-1.41 (m, 9H), 1.31-1.17 (m, 1H), 1.03 (d,
J=6.8 Hz, 3H), 0.41 (d, J=12.1 Hz, 1H); MS(ESI) m/z: 436.1
(M+H).sup.+.
159J. Preparation of
(9S,13R)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[1757] To a RBF was added tert-butyl
N-[(9S,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(370 mg, 0.850 mmol), dioxane (1 mL), MeOH (1 mL) and 4 N HCl (6.37
mL, 25.5 mmol). The reaction was stirred at rt for 1 h. The
reaction was concentrated to give the product as HCl salt. This HCl
salt was dissolved in MeOH and was added to a pre-rinsed
AGILENT.RTM. StratoSpheres SPE PL-HCO.sub.3 MP Resin cartridge.
Gravity filtration, eluting with MeOH, gave a clear, slightly brown
filtrate. Concentration provided
(9S,13R)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (285 mg,
0.850 mmol, 100% yield) as a light brown solid. MS(ESI) m/z: 336.1
(M+H).sup.+.
159K. Preparation of
(9S,13R)-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-
-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricy-
clo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[1758]
(9S,13R)-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-o-
xo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraaz-
atricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (230
mg, 360 .mu.mol, 42.3% yield) was prepared in a similar manner as
the procedure described in Example 56 by using
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(331 mg, 0.850 mmol), prepared as described in Intermediate 9, and
(9S,13R)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (285 mg,
0.850 mmol). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.90 (s,
1H), 8.76 (d, J=5.1 Hz, 1H), 8.35 (s, 1H), 7.90 (d, J=2.4 Hz, 1H),
7.78-7.73 (m, 2H), 7.71 (d, J=0.7 Hz, 1H), 7.68 (t, 1H), 7.65 (s,
1H), 7.55-7.53 (m, 1H), 6.39 (d, J=0.9 Hz, 1H), 6.03 (dd, J=12.8,
4.4 Hz, 1H), 2.73 (td, J=6.5, 3.0 Hz, 1H), 2.31 (tt, J=12.8, 4.3
Hz, 1H), 2.11-1.97 (m, 2H), 1.67-1.44 (m, 2H), 1.01 (d, J=7.0 Hz,
3H), 0.64 (br. s., 1H); MS(ESI) m/z: 626.1 (M+H).sup.+. Analytical
HPLC (Method A): RT=7.96 min, purity=95.0%; Factor XIa Ki=14 nM,
Plasma Kallikrein Ki=880 nM.
Example 160
Preparation of
(9R,13R)-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-
-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricy-
clo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00330##
[1759] 160A. Preparation of tert-butyl
N-[(9R,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]
carbamate
[1760] To a 3-neck RBF wad added tert-butyl
N-[(9R,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]
carbamate (450 mg, 1.038 mmol), EtOH (35 mL) and PtO.sub.2 (118 mg,
0.519 mmol). The reaction was stirred under a H.sub.2 balloon for 1
h. The reaction was carefully filtered through CELITE.RTM. and the
filtrate was concentrated. The residue was purified using ISCO
system (0-10% MeOH/CH.sub.2Cl.sub.2 gradient) to give tert-butyl
N-[(9R,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(300 mg, 0.689 mmol, 66.4% yield) as a beige solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.73 (d, J=5.3 Hz, 1H), 7.69 (s, 1H),
7.40 (d, J=5.1 Hz, 1H), 7.30 (m, J=4.2 Hz, 1H), 6.49 (br. s., 1H),
5.90 (d, J=7.0 Hz, 1H), 4.88 (br. s., 1H), 2.25-2.14 (m, 1H), 2.07
(d, J=9.5 Hz, 1H), 1.91-1.77 (m, 1H), 1.47 (s, 11H), 1.27 (d, J=6.8
Hz, 3H), 0.74 (d, J=11.2 Hz, 1H); MS(ESI) m/z: 436.1
(M+H).sup.+.
160B. Preparation of
(9R,13R)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[1761] To a RBF was added tert-butyl
N-[(9R,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(300 mg, 0.689 mmol), dioxane (1 mL), MeOH (1 mL) and 4 N HCl (6.37
mL, 25.5 mmol). The reaction was stirred at rt for 1 h. The
reaction was concentrated to give the product as HCl salt. This HCl
salt was dissolved in MeOH and was added to a pre-rinsed
AGILENT.RTM. StratoSpheres SPE PL-HCO.sub.3 MP Resin cartridge.
Gravity filtration, eluting with MeOH, gave a clear, slightly brown
filtrate. Concentration provided
(9R,13R)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (220 mg,
0.656 mmol, 95% yield) as a light brown solid. MS(ESI) m/z: 336.1
(M+H).sup.+.
160C. Preparation of
(9R,13R)-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-
-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricy-
clo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[1762]
(9R,13R)-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-o-
xo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraaz-
atricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (140
mg, 219 .mu.mol, 33.4% yield) was prepared in a similar manner as
the procedure described in Example 56 by using
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(255 mg, 0.656 mmol), prepared as described in Intermediate 9, and
(9R,13R)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (225 mg,
0.656 mmol). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.83 (s,
1H), 8.74 (d, J=5.1 Hz, 1H), 8.36 (s, 1H), 7.91 (d, J=2.2 Hz, 1H),
7.79 (s, 1H), 7.78-7.74 (m, 1H), 7.69 (t, 1H), 7.68-7.66 (m, 1H),
7.60 (s, 1H), 7.51 (d, J=4.8 Hz, 1H), 6.42 (d, J=0.7 Hz, 1H), 6.07
(dd, J=12.7, 4.3 Hz, 1H), 2.38-2.28 (m, 1H), 2.25-2.15 (m, 1H),
2.05-1.90 (m, 2H), 1.64-1.50 (m, 2H), 1.27 (d, J=6.8 Hz, 3H), 0.83
(d, J=13.6 Hz, 1H); MS(ESI) m/z: 626.1 (M+H).sup.+. Analytical HPLC
(Method A): RT=10.37 min, purity=97.0%; Factor XIa Ki=18 nM, Plasma
Kallikrein Ki=3,200 nM.
Example 161
[1763] Preparation of
(9R,13S)-13-{4-[5-chloro-2-(pyridin-3-yl)phenyl]-6-oxo-1,6-dihydropyrimid-
in-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00331##
[1764] In a microwave vial was added
(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]--
3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6-
),4,14,16-pentaen-8-one (0.02 g, 0.035 mmol), prepared in Example
138, pyridin-3-ylboronic acid (4.76 mg, 0.039 mmol), 3 M aq
K.sub.3PO.sub.4 (0.035 ml, 0.106 mmol) and THF (1 ml). Ar was
bubbled through the reaction for several min and then
(DtBPF)PdCl.sub.2 (1.15 mg, 1.761 .mu.mol) was added. The reaction
mixture was microwaved at 150.degree. C. for 1 h, cooled to rt, and
concentrated. Purification by reverse phase chromatography afforded
(9R,13S)-13-{4-[5-chloro-2-(pyridin-3-yl)phenyl]-6-oxo-1,6-dihydropyrimid-
in-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca--
1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (3.21 mg, 12%
yield) as a yellow solid. MS(ESI) m/z: 566.2 (M+H).sup.+. .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta. 8.79-8.68 (m, 4H), 8.34 (dt,
J=8.2, 1.7 Hz, 1H), 7.90 (dd, J=8.0, 5.8 Hz, 1H), 7.81 (d, J=2.2
Hz, 1H), 7.71-7.66 (m, 2H), 7.57 (d, J=8.3 Hz, 1H), 7.53-7.47 (m,
2H), 6.52 (d, J=0.5 Hz, 1H), 5.98-5.90 (m, 1H), 4.04 (s, 3H),
2.74-2.64 (m, 1H), 2.30-2.19 (m, 1H), 2.10-1.93 (m, 2H), 1.63-1.53
(m, 1H), 1.50-1.40 (m, 1H), 1.00 (d, J=6.9 Hz, 3H), 0.77-0.61 (m,
1H). Analytical HPLC (Method A): RT=4.22 min, 99.8% purity; Factor
XIa Ki=100 nM, Plasma Kallikrein Ki=5,700 nM.
Example 162
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-y-
l]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4-
,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentae-
n-8-one
##STR00332##
[1765] 162A. Preparation of
6-{5-chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]
phenyl}pyrimidin-4-ol
##STR00333##
[1767]
6-{5-Chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]pheny-
l} pyrimidin-4-ol was prepared by the condensation of an ACN (5 ml)
solution consisting of 6-(2-azido-5-chlorophenyl)pyrimidin-4-ol
(0.9 g, 3.44 mmol) and 2-methylbut-3-yn-2-ol (0.289 g, 3.44 mmol)
in the presence Cu.sub.2O (0.05 g). The product, after ISCO silica
gel chromatography with hexane:EtOAc as eluants, was obtained as an
oil (0.5 g). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.60-8.57
(m, 1H), 7.65-7.59 (m, 1H), 7.56-7.53 (m, 1H), 7.37-7.32 (m, 1H),
6.76-6.72 (m, 1H), 3.95 (s, 3H), 3.43-3.30 (m, 1H), 1.52 (s, 6H).
The oil was then dissolved in AcOH (1 ml) and to this was added 48%
aq HBr (0.5 ml) and the reaction was sealed. The reaction mixture
was heated at 80.degree. C. for 2 h and then concentrated to a
gummy solid and water (10 ml) was added. A solid precipitated and
was collected by decanting the solution. The solid was washed
several times with water and the residue was dissolved in MeOH and
the solution was concentrated to give
6-{5-chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]phenyl}pyri-
midin-4-ol (0.15 g, 13%) as a foam. LCMS m/z=332.1 (M+H).sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 11.51-11.06 (m, 1H),
8.33-8.09 (m, 1H), 7.90-7.78 (m, 1H), 7.71 (t, J=7.9 Hz, 1H),
7.39-7.29 (m, 1H), 6.87-6.68 (m, 1H), 5.80-5.66 (m, 1H), 5.27-5.17
(m, 1H), 2.12 (s, 6H).
162B. Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-y-
l]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4-
,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentae-
n-8-one
[1768]
(9R,13S)-13-(4-{5-Chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triaz-
ol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-met-
hyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-
-pentaen-8-one was prepared (4.2 mg, 21% yield) as a solid via the
coupling of
6-{5-chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]phenyl}pyri-
midin-4-ol (0.01 g, 0.030 mmol) and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.010 g,
0.030 mmol) using the HATU, DBU coupling methodology as described
in Example 56. MS m/z=651.1 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.46-9.40 (m, 1H), 8.88-8.82 (m, 1H),
8.72-8.65 (m, 1H), 8.40-8.36 (m, 1H), 8.01-7.93 (m, 2H), 7.89 (s,
1H), 7.72-7.68 (m, 1H), 7.68-7.61 (m, 1H), 7.46-7.40 (m, 1H),
6.63-6.57 (m, 1H), 5.94-5.85 (m, 1H), 5.70-5.64 (m, 1H), 5.15-5.08
(m, 1H), 2.71-2.61 (m, 1H), 2.56 (s, 3H), 2.35-2.16 (m, 1H),
2.08-2.04 (m, 4H), 2.07-1.79 (m, 1H), 1.56-1.26 (m, 1H), 0.93-0.79
(d, 3H), 0.44-0.24 (m, 1H). Analytical HPLC (Method B): RT=1.75
min, purity=97%; Factor XIa Ki=1 nM, Plasma Kallikrein Ki=230
nM.
Example 163
Preparation of
(9R,13S)-3-(difluoromethyl)-9-methyl-13-(6-oxo-4-{2-[4-(trifluoromethyl)--
1H-1,2,3-triazol-1-yl]phenyl}-1,6-dihydropyrimidin-1-yl)-3,4,7,15-tetraaza-
tricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00334##
[1770]
(9R,13S)-3-(Difluoromethyl)-9-methyl-13-(6-oxo-4-{2-[4-(trifluorome-
thyl)-1H-1,2,3-triazol-1-yl]phenyl}-1,6-dihydropyrimidin-1-yl)-3,4,7,15-te-
traazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one was
prepared (1.6 mg, 6.2% yield) as a solid via the coupling of
6-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}
pyrimidin-4-ol (0.012 g, 0.04 mmol) and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6), 4,14,16-pentaen-8-one (0.013
g, 0.04 mmol) using the HATU, DBU coupling methodology as described
in Example 56. LCMS m/z=626.2 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.46-9.42 (m, 1H), 9.20-9.15 (m, 1H),
8.76-8.67 (m, 2H), 7.89-7.83 (m, 2H), 7.80-7.73 (m, 3H), 7.70-7.64
(m, 1H), 7.46-7.39 (m, 1H), 6.42-6.36 (m, 1H), 5.94-5.86 (m, 1H),
2.70-2.60 (m, 1H), 2.31-2.18 (m, 1H), 2.10-1.94 (m, 1H), 1.88-1.77
(m, 1H), 1.52-1.28 (m, 2H), 0.91-0.82 (d, 3H), 0.49-0.19 (m, 1H).
Analytical HPLC (Method B) RT=1.65 min, purity=96%; Factor XIa
Ki=10 nM, Plasma Kallikrein Ki=5,900 nM.
Example 164
Preparation of
(9R,13S)-3-(difluoromethyl)-13-(4-{5-fluoro-2-[4-(trifluoromethyl)-1H-1,2-
,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-
-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-o-
ne
##STR00335##
[1772]
(9R,13S)-3-(Difluoromethyl)-13-(4-{5-fluoro-2-[4-(trifluoromethyl)--
1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,-
4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one was
prepared (8 mg, 26% yield) as a solid via the coupling of
6-{5-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}pyrimidin-4-ol (0.015 g, 0.05 mmol) and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6), 4,14,16-pentaen-8-one (0.015
g, 0.05 mmol) using the HATU, DBU coupling methodology described in
Example 56. LCMS m/z=644.2 (M+H). .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.80-8.72 (m, 3H), 7.82-7.78 (m, 1H), 7.75-7.70 (m, 2H),
7.66-7.60 (m, 2H), 7.52-7.43 (m, 1H), 6.44-6.41 (m, 1H), 6.01-5.95
(m, 1H), 2.75-2.66 (m, 1H), 2.38-2.25 (m, 1H), 2.08-1.92 (m, 2H),
1.64-1.39 (m, 2H), 1.07-0.95 (d, 3H), 0.79-0.54 (m, 1H). Analytical
HPLC (Method A) RT=8.22 min, purity=99%; Factor XIa Ki=5 nM, Plasma
Kallikrein Ki=1,100 nM.
Example 165
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-hydroxy-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-
-1,6-ihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0-
.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00336##
[1773] 165A. Preparation of
6-(5-chloro-2-(4-hydroxy-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
[1774] To a solution of
6-(5-chloro-2-(4-ethoxy-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol,
hydrobromide (0.027 g, 0.068 mmol) in DCM (1 ml) was added
AlCl.sub.3 (0.090 g, 0.68 mmol). The reaction was microwaved at
100.degree. C. for 10 min, cooled to rt. Next the reaction was
cooled in a dry ice/acetone bath and MeOH (1 ml) was added slowly.
The reaction was allowed to warm to rt and the reaction was stirred
until a solution formed. 1 N HCl (1 ml) was added and the resulting
mixture was concentrated to dryness. Purification by reverse phase
chromatography afforded
6-(5-chloro-2-(4-hydroxy-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(0.012 g, 61.2% yield) as a white solid. MS(ESI) m/z: 290.3
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.11 (s,
1H), 7.82 (d, J=2.4 Hz, 1H), 7.72-7.67 (m, 1H), 7.62-7.57 (m, 1H),
7.44 (s, 1H), 6.27 (d, J=0.7 Hz, 1H).
165B. Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-hydroxy-1H-1,2,3-triazol-1-yl)
phenyl]-6-oxo-1,6-ihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatri-
cyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[1775]
(9R,13S)-13-{4-[5-Chloro-2-(4-hydroxy-1H-1,2,3-triazol-1-yl)phenyl]-
-6-oxo-1,6-ihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12-
.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (1.42 mg, 4.9% yield) was prepared in a similar
manner as the procedure described in Example 162, using
6-(5-chloro-2-(4-hydroxy-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(0.012 g, 0.041 mmol) and
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.012 g, 0.041 mmol)
prepared as described in Intermediate 32. MS(ESI) m/z: 572.3
(M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.88 (s,
1H), 8.72 (d, J=5.2 Hz, 1H), 7.87 (d, J=2.2 Hz, 1H), 7.71-7.68 (m,
2H), 7.59 (d, J=8.5 Hz, 1H), 7.52 (dd, J=5.2, 1.7 Hz, 1H), 7.49 (s,
1H), 7.43 (s, 1H), 6.22 (d, J=0.8 Hz, 1H), 5.98 (dd, J=12.7, 4.1
Hz, 1H), 4.05 (s, 3H), 2.75-2.66 (m, 1H), 2.36-2.25 (m, 1H),
2.11-1.96 (m, 2H), 1.65-1.55 (m, 1H), 1.52-1.41 (m, 1H), 1.00 (d,
J=6.9 Hz, 3H), 0.75-0.61 (m, 1H). Analytical HPLC (Method A):
RT=6.12 min, 97.7% purity; Factor XIa Ki=13 nM, Plasma Kallikrein
Ki=750 nM.
Example 166
Preparation of
5-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)pyridine-3-carbonitrile
##STR00337##
[1777]
5-(4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatric-
yclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,-
6-dihydropyrimidin-4-yl}phenyl)pyridine-3-carbonitrile, 2
trifluoroacetate (1.5 mg, 5% yield) was prepared in a similar
manner as the procedure described in Example 161, by replacing
pyridin-3-ylboronic acid (4.76 mg, 0.039 mmol) with
(5-cyanopyridin-3-yl)boronic acid (5.73 mg, 0.039 mmol). MS(ESI)
m/z: 591.2 (M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
8.84 (d, J=1.9 Hz, 1H), 8.79 (s, 1H), 8.72 (d, J=5.2 Hz, 1H), 8.64
(d, J=2.2 Hz, 1H), 8.08 (t, J=2.1 Hz, 1H), 7.75 (d, J=2.2 Hz, 1H),
7.67-7.62 (m, 2H), 7.54-7.47 (m, 3H), 6.43 (d, J=0.8 Hz, 1H),
6.00-5.94 (m, 1H), 4.04 (s, 3H), 2.74-2.66 (m, 1H), 2.31-2.23 (m,
1H), 2.11-1.94 (m, 2H), 1.64-1.54 (m, 1H), 1.51-1.42 (m, 1H), 1.00
(d, J=6.9 Hz, 3H), 0.75-0.60 (m, 1H). Analytical HPLC (Method A):
RT=6.86 min, 99.5% purity; Factor XIa Ki=58 nM, Plasma Kallikrein
Ki=6,500 nM.
Example 167
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl]-6-
-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.-
3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00338##
[1779]
(9R,13S)-13-{4-[5-Chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phe-
nyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (3.96 mg, 9.6% yield) was prepared in a similar
manner as the procedure described in Example 162, using
6-(5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
hydrobromide (0.022 g, 0.057 mmol), prepared as described in
Intermediate 13 and
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.017 g, 0.057
mmol) prepared as described in Intermediate 32. MS(ESI) m/z: 596.1
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.85 (s,
1H), 8.72 (d, J=5.1 Hz, 1H), 7.88-7.86 (m, 2H), 7.72-7.67 (m, 2H),
7.59 (d, J=8.6 Hz, 1H), 7.51 (dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H),
6.17 (d, J=0.9 Hz, 1H), 5.98 (dd, J=12.7, 4.3 Hz, 1H), 4.04 (s,
3H), 2.75-2.66 (m, 1H), 2.34-2.24 (m, 1H), 2.12-1.93 (m, 3H),
1.66-1.40 (m, 2H), 1.03-0.94 (m, 5H), 0.81-0.58 (m, 3H). Analytical
HPLC (Method A): RT=7.43 min, 98.0% purity; Factor XIa Ki=3.2 nM,
Plasma Kallikrein Ki=210 nM.
Example 168
Preparation of methyl
4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydrop-
yrimidin-4-yl}benzoate
##STR00339##
[1780] 168A. Preparation of methyl
4-chloro-2-(6-methoxypyrimidin-4-yl)benzoate, and
168B. Preparation 4-chloro-2-(6-methoxypyrimidin-4-yl)benzoic
acid
[1781] A suspension of 4-chloro-6-methoxypyrimidine (0.067 g, 0.466
mmol) and (5-chloro-2-(methoxycarbonyl)phenyl)boronic acid (0.1 g,
0.466 mmol) in ACN (1.8 ml) was purged with Ar for several min,
then 2 M Na.sub.2CO.sub.3 aq (0.47 ml, 0.94 mmol) was added,
followed by Pd(Ph.sub.3P).sub.4 (0.027 g, 0.023 mmol). The vial was
capped and microwaved at 130.degree. C. for 0.5 h, then cooled to
rt. The reaction was diluted with EtOAc, washed with brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated. Purification by
normal phase chromatography afforded methyl
4-chloro-2-(6-methoxypyrimidin-4-yl)benzoate (0.086 g, 66% yield)
as a colorless oil. MS(ESI) m/z: 279.0 (M+H).sup.+. The aqueous
layer from the work-up was neutralized with 1 N HCl to afford a
white cloudy suspension. The mixture was filtered, and the solid
was rinsed with water and air-dried to afford
4-chloro-2-(6-methoxypyrimidin-4-yl)benzoic acid (0.026 g, 21%
yield) as a white solid. MS(ESI) m/z: 265.0 (M+H).sup.+.
168C. Preparation of methyl
4-chloro-2-(6-hydroxypyrimidin-4-yl)benzoate
[1782] Methyl 4-chloro-2-(6-hydroxypyrimidin-4-yl)benzoate (0.046
g, 56% yield) was prepared in a similar manner as the procedure
described in Example 140B, by replacing
4-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-6-methoxypyrimi-
dine with methyl 4-chloro-2-(6-methoxypyrimidin-4-yl)benzoate
(0.086 g, 0.309 mmol). MS(ESI) m/z: 265.1 (M+H).sup.+. .sup.1H NMR
(500 MHz, CD.sub.3OD) .delta. 8.19 (d, J=1.1 Hz, 1H), 7.83 (d,
J=8.3 Hz, 1H), 7.62-7.57 (m, 2H), 6.57 (d, J=0.8 Hz, 1H), 3.76 (s,
3H).
168D. Preparation of methyl
4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydrop-
yrimidin-4-yl}benzoate trifluoroacetate
[1783] Methyl
4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}benzoate trifluoroacetate (0.067 g, 58% yield)
was prepared in a similar manner as the procedure described in
Example 56, by using methyl
4-chloro-2-(6-hydroxypyrimidin-4-yl)benzoate (0.046 g, 0.174 mmol),
prepared as described in Example 168C. MS(ESI) m/z: 547.2
(M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.99 (s,
1H), 8.74 (d, J=5.2 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.75 (s, 1H),
7.62 (d, J=1.9 Hz, 1H), 7.59 (dd, J=8.3, 2.2 Hz, 1H), 7.55 (dd,
J=5.2, 1.7 Hz, 1H), 7.50 (s, 1H), 6.62 (s, 1H), 6.07 (dd, J=12.7,
4.1 Hz, 1H), 4.05 (s, 3H), 3.75 (s, 3H), 2.76-2.68 (m, 1H),
2.41-2.33 (m, 1H), 2.14-2.03 (m, 2H), 1.67-1.58 (m, 1H), 1.55-1.45
(m, 1H), 1.02 (d, J=6.9 Hz, 3H), 0.79-0.66 (m, 1H). Analytical HPLC
(Method A): RT=6.69 min, 99.9% purity; Factor XIa Ki=27 nM, Plasma
Kallikrein Ki=650 nM.
Example 169
Preparation of
(9R,13S)-13-{4-[3-chloro-6-(4-ethoxy-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00340##
[1785]
(9R,13S)-13-{4-[3-Chloro-6-(4-ethoxy-1H-1,2,3-triazol-1-yl)-2-fluor-
ophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (22 mg, 41.7% yield) was prepared in a similar
manner as the procedure described in Example 162, using
6-(3-chloro-6-(4-ethoxy-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-
-ol, hydrobromide (0.030 g, 0.072 mmol) and
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.025
g, 0.072 mmol) prepared as described in Intermediate 32. MS(ESI)
m/z: 618.4 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.87 (s, 1H), 8.73 (d, J=5.1 Hz, 1H), 7.82 (t, J=8.1 Hz, 1H), 7.71
(s, 1H), 7.66 (s, 1H), 7.56-7.47 (m, 3H), 6.54 (s, 1H), 6.00 (dd,
J=12.5, 4.0 Hz, 1H), 4.13 (q, J=7.0 Hz, 2H), 4.05 (s, 3H),
2.76-2.65 (m, 1H), 2.36-2.24 (m, 1H), 2.14-1.95 (m, 2H), 1.67-1.54
(m, 1H), 1.53-1.41 (m, 1H), 1.35 (t, J=7.0 Hz, 3H), 1.00 (d, J=6.8
Hz, 3H), 0.77-0.59 (m, 1H). .sup.19F NMR (376 MHz, CD.sub.3OD)
.delta. -77.75 (s), -115.15 (s). Analytical HPLC (Method A):
RT=7.32 min, 99.7% purity; Factor XIa Ki=0.88 nM, Plasma Kallikrein
Ki=95 nM.
Example 170
Preparation of
(9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluoro-
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatri-
cyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00341##
[1787]
(9R,13S)-13-{4-[3-Chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2--
fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetra-
azatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (0.02 g, 42.8% yield) was prepared in a similar
manner as the procedure described in Example 160, by using
6-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimi-
din-4-ol (0.021 g, 0.063 mmol), prepared as described in
Intermediate 14, and
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2 (6),4,14,16-pentaen-8-one (0.022 g, 0.063
mmol) prepared as described in Intermediate 32. MS(ESI) m/z: 614.4
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.85 (s,
1H), 8.74 (d, J=5.1 Hz, 1H), 7.88-7.78 (m, 2H), 7.71 (s, 1H),
7.57-7.47 (m, 3H), 6.51 (s, 1H), 6.00 (dd, J=12.7, 4.1 Hz, 1H),
4.05 (s, 3H), 2.76-2.65 (m, 1H), 2.37-2.24 (m, 1H), 2.14-1.89 (m,
3H), 1.67-1.39 (m, 2H), 1.05-0.90 (m, 5H), 0.77-0.60 (m, 3H).
.sup.19F NMR (376 MHz, CD.sub.3OD) .delta. -77.75 (s), -115.19 (s).
Analytical HPLC (Method A): RT=7.35 min, 99.2% purity; Factor XIa
Ki=0.93 nM, Plasma Kallikrein Ki=95 nM.
Example 171
Preparation of
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2-
,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
##STR00342##
[1789]
(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
(0.016 g, 40.1% yield) was prepared in a similar manner as the
procedure described in Example 162, using
6-(3-chloro-2-fluoro-6-(trifluoromethyl)phenyl)pyrimidin-4-ol
hydrobromide (0.021 g, 0.057 mmol) and
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.02 g, 0.057 mmol)
prepared as described in Intermediate 32. MS(ESI) m/z: 575.3
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.05 (s,
1H), 8.77 (d, J=5.1 Hz, 1H), 7.85-7.79 (m, 1H), 7.75 (s, 1H), 7.66
(d, J=8.6 Hz, 1H), 7.55 (dd, J=5.3, 1.5 Hz, 1H), 7.50 (s, 1H), 6.60
(s, 1H), 6.08 (dd, J=12.7, 4.3 Hz, 1H), 4.06 (s, 3H), 2.77-2.67 (m,
1H), 2.45-2.34 (m, 1H), 2.16-2.04 (m, 2H), 1.70-1.44 (m, 2H), 1.02
(d, J=7.0 Hz, 3H), 0.81-0.64 (m, 1H). .sup.19F NMR (376 MHz,
CD.sub.3OD) .delta. -59.04 (s), -77.76 (s), -115.37 (s). Analytical
HPLC (Method A): RT=8.30 min, 99.3% purity; Factor XIa Ki=12 nM,
Plasma Kallikrein Ki=190 nM.
Example 172
Preparation of
(9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluoro-
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl--
3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen--
8-one
##STR00343##
[1791]
(9R,13S)-13-{4-[3-Chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2--
fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-m-
ethyl-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pe-
ntaen-8-one (5.4 mg, 22.0% yield) was prepared in a similar manner
as the procedure described in Example 160, using
6-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimi-
din-4-ol (0.013 g, 0.040 mmol), prepared as described in
Intermediate 14, and
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7-triazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(0.012 g, 0.040 mmol), prepared as described in Intermediate 36.
MS(ESI) m/z: 616.3 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.17 (s, 1H), 7.84-7.73 (m, 3H), 7.62-7.54 (m, 2H),
7.50-7.46 (m, 2H), 7.32 (d, J=7.5 Hz, 1H), 6.55 (s, 1H), 5.82 (dd,
J=12.8, 3.1 Hz, 1H), 2.52-2.42 (m, 1H), 2.38-2.27 (m, 1H),
2.15-2.03 (m, 1H), 1.97-1.81 (m, 2H), 1.62-1.49 (m, 2H), 1.26-1.10
(m, 4H), 1.00-0.90 (m, 2H), 0.73-0.63 (m, 2H). Analytical HPLC
(Method A): RT=8.18 min, 100% purity; Factor XIa Ki=0.36 nM, Plasma
Kallikrein Ki=45 nM.
Example 173
Preparation of
(9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-
-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetra-
azatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00344##
[1793]
(9R,13S)-13-(4-{3-Chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-t-
riazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (0.0215 g, 56.3% yield) was prepared in a similar
manner as the procedure described in Example 160, using
6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-
pyrimidin-4-ol (0.018 g, 0.050 mmol), prepared as described in
Intermediate 11, and
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.015 g, 0.050 mmol)
prepared as described in Intermediate 32. MS(ESI) m/z: 642.3
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.82 (s,
1H), 8.78 (s, 1H), 8.70 (d, J=5.1 Hz, 1H), 7.91-7.83 (m, 1H), 7.70
(s, 1H), 7.59 (dd, J=8.6, 1.3 Hz, 1H), 7.53 (dd, J=5.2, 1.4 Hz,
1H), 7.48 (s, 1H), 6.65 (s, 1H), 6.00 (dd, J=12.7, 4.1 Hz, 1H),
4.05 (s, 3H), 2.74-2.64 (m, 1H), 2.33-2.22 (m, 1H), 2.12-1.93 (m,
2H), 1.66-1.39 (m, 2H), 1.00 (d, J=7.0 Hz, 3H), 0.75-0.58 (m, 1H).
.sup.19F NMR (376 MHz, CD.sub.3OD) .delta. -62.57 (s), -77.74 (s),
-114.95 (s). Analytical HPLC (Method A): RT=8.64 min, 99.6% purity;
Factor XIa Ki=0.11 nM, Plasma Kallikrein Ki=13 nM.
Example 174
Preparation of
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}-3-fluorophenyl)-1H-1,2,3-triazole-4-carbonitrile
trifluoroacetate
##STR00345##
[1795]
1-(4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatric-
yclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,-
6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-1,2,3-triazole-4-carbonitrile
trifluoroacetate (0.0105 g, 0.015 mmol, 23.13% yield) was prepared
in a similar manner as the procedure described in Example 160,
using
1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-
-4-carbonitrile (0.02 g, 0.063 mmol), prepared as described in
Intermediate 12, and
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.019 g, 0.063 mmol)
prepared as described in Intermediate 32. MS(ESI) m/z: 599.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.93 (s,
1H), 8.78-8.74 (m, 2H), 7.93-7.86 (m, 1H), 7.70 (s, 1H), 7.60 (dd,
J=8.7, 1.4 Hz, 1H), 7.53 (dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H),
6.65 (s, 1H), 5.99 (dd, J=12.4, 3.6 Hz, 1H), 4.05 (s, 3H),
2.75-2.65 (m, 1H), 2.35-2.23 (m, 1H), 2.13-1.95 (m, 2H), 1.67-1.41
(m, 2H), 1.01 (d, J=6.8 Hz, 3H), 0.78-0.60 (m, 1H). .sup.19F NMR
(376 MHz, CD.sub.3OD) .delta. -77.72 (s), -114.94 (s). Analytical
HPLC (Method A): RT=7.85 min, 99.2% purity; Factor XIa Ki=0.1 nM,
Plasma Kallikrein Ki=6 nM.
Example 175
Preparation of
(9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-
-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl-9-m-
ethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,-
16-pentaen-8-one trifluoroacetate
##STR00346##
[1797]
(9R,13S)-13-(4-{3-Chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-t-
riazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl-9-methyl-
-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pe-
ntaen-8-one trifluoroacetate (0.018 g, 44.8% yield) was prepared in
a similar manner as the procedure described in Example 160, using
6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-
pyrimidin-4-ol (0.019 g, 0.053 mmol), prepared as described in
Intermediate 11, and
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,15-tetraazatricy-
clo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
(0.016 g, 0.053 mmol) prepared as described in Intermediate 33.
MS(ESI) m/z: 645.3 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.81 (d, J=0.7 Hz, 1H), 8.78 (s, 1H), 8.71 (d, J=5.1 Hz,
1H), 7.87 (dd, J=8.6, 7.7 Hz, 1H), 7.70 (s, 1H), 7.59 (dd, J=8.7,
1.4 Hz, 1H), 7.53 (dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 6.64 (s,
1H), 6.00 (dd, J=12.7, 4.3 Hz, 1H), 2.75-2.65 (m, 1H), 2.33-2.22
(m, 1H), 2.12-1.92 (m, 2H), 1.66-1.40 (m, 2H), 1.00 (d, J=6.8 Hz,
3H), 0.78-0.60 (m, 1H). .sup.19F NMR (376 MHz, CD.sub.3OD) .delta.
-62.59 (s), -77.76 (s), -114.95 (s). Analytical HPLC (Method A):
RT=8.44 min, 100% purity; Factor XIa Ki=0.11 nM, Plasma Kallikrein
Ki=12 nM.
Example 176
Preparation of
1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tet-
raazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]--
6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-1,2,3-triazole-4-carbo-
nitrile trifluoroacetate
##STR00347##
[1799]
1-(4-Chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,-
15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-1-
3-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-1,2,3-triazole-4-
-carbonitrile trifluoroacetate (9 mg, 20.1% yield) was prepared in
a similar manner as the procedure described in Example 160, using
1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-
-4-carbonitrile (18.89 mg, 0.060 mmol), prepared as described in
Intermediate 12, and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one (20 mg,
0.060 mmol) prepared as described in Intermediate 30. MS(ESI) m/z:
635.2 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.92
(s, 1H), 8.81 (s, 1H), 8.77 (d, J=5.3 Hz, 1H), 7.92-7.85 (m, 1H),
7.81-7.48 (m, 5H), 6.65 (s, 1H), 6.00 (dd, J=12.7, 4.5 Hz, 1H),
2.76-2.65 (m, 1H), 2.34-2.22 (m, 1H), 2.10-1.95 (m, 2H), 1.64-1.41
(m, 2H), 0.99 (d, J=6.8 Hz, 3H), 0.73-0.55 (m, 1H). .sup.19F NMR
(376 MHz, CD.sub.3OD) .delta. -77.28 (s), -90.87--92.15 (m),
-96.05--97.42 (m), -114.86 (s). Analytical HPLC (Method A): RT=9.02
min, 99.6% purity; Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=7
nM.
Example 177
Preparation of
(9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluoro-
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-
,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen--
8-one trifluoroacetate
##STR00348##
[1801]
(9R,13S)-13-{4-[3-Chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2--
fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-
-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pe-
ntaen-8-one trifluoroacetate (7.07 mg, 20.6% yield) was prepared in
a similar manner as the procedure described in Example 160, using
6-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)
pyrimidin-4-ol (0.015 g, 0.045 mmol), prepared as described in
Intermediate 14, and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.015
g, 0.045 mmol) prepared as described in Intermediate 30. MS(ESI)
m/z: 650.5 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.92 (s, 1H), 8.76 (d, J=5.1 Hz, 1H), 7.86-7.47 (m, 7H), 6.50 (s,
1H), 6.04 (dd, J=12.5, 4.4 Hz, 1H), 2.77-2.66 (m, 1H), 2.35-2.24
(m, 1H), 2.10-1.87 (m, 3H), 1.66-1.41 (m, 2H), 1.02-0.89 (m, 5H),
0.73-0.50 (m, 3H). .sup.19F NMR (376 MHz, CD.sub.3OD) .delta.
-77.68 (s), -90.26--91.77 (m), -95.81--97.73 (m), -115.24 (s).
Analytical HPLC (Method A): RT=8.74 min, 99.8% purity; Factor XIa
Ki=0.50 nM, Plasma Kallikrein Ki=120 nM.
Example 178
Preparation of
(9R,13S)-13-(4-{3-chloro-6-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]-2-f-
luorophenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl--
3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pen-
taen-8-one trifluoroacetate
##STR00349##
[1803]
(9R,13S)-13-(4-{3-Chloro-6-[4-(difluoromethyl)-1H-1,2,3-triazol-1-y-
l]-2-fluorophenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-m-
ethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,-
16-pentaen-8-one trifluoroacetate (0.016 g, 46.0% yield) was
prepared in a similar manner as the procedure described in Example
160, using
6-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)p-
yrimidin-4-ol (0.015 g, 0.045 mmol), prepared as described in
Intermediate 21, and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatr-
icyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(15 mg, 0.045 mmol), prepared as described in Intermediate 30.
MS(ESI) m/z: 660.5 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.86 (s, 1H), 8.73 (d, J=5.1 Hz, 1H), 8.52 (t, J=1.4 Hz,
1H), 7.86 (dd, J=8.6, 7.5 Hz, 1H), 7.80-7.48 (m, 5H), 6.96 (t,
J=54.0 Hz, 1H), 6.60 (s, 1H), 6.02 (dd, J=12.5, 4.4 Hz, 1H),
2.76-2.66 (m, 1H), 2.32-2.20 (m, 1H), 2.09-1.92 (m, 2H), 1.65-1.40
(m, 2H), 0.99 (d, J=7.0 Hz, 3H), 0.69-0.52 (m, 1H). .sup.19F NMR
(376 MHz, CD.sub.3OD) .delta. -77.73 (s), -90.24--92.35 (m),
-95.39--97.64 (m), -114.57 (d, J=10.3 Hz), -115.06 (s). Analytical
HPLC (Method A): RT=8.91 min, 99.6% purity; Factor XIa Ki=0.1 nM,
Plasma Kallikrein Ki=16 nM.
Example 179
Preparation of
(9R,13S)-13-(4-{3-chloro-6-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]-2-f-
luorophenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraa-
zatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00350##
[1805]
(9R,13S)-13-(4-{3-Chloro-6-[4-(difluoromethyl)-1H-1,2,3-triazol-1-y-
l]-2-fluorophenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15--
tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (0.015 g, 43.3% yield) was prepared in a similar
manner as the procedure described in Example 160, using
6-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)p-
yrimidin-4-ol (0.016 g, 0.047 mmol), prepared as described in
Intermediate 21, and
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.014 g, 0.047
mmol) prepared as described in Intermediate 32. MS(ESI) m/z: 624.5
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.79 (s,
1H), 8.72 (d, J=5.1 Hz, 1H), 8.52 (t, J=1.3 Hz, 1H), 7.86 (dd,
J=8.6, 7.7 Hz, 1H), 7.70 (s, 1H), 7.59-7.51 (m, 2H), 7.48 (s, 1H),
6.97 (t, J=54.0 Hz, 1H), 6.60 (s, 1H), 5.99 (dd, J=12.7, 4.3 Hz,
1H), 4.05 (s, 3H), 2.75-2.64 (m, 1H), 2.34-2.21 (m, 1H), 2.12-1.93
(m, 2H), 1.66-1.39 (m, 2H), 1.00 (d, J=6.8 Hz, 3H), 0.78-0.59 (m,
1H). .sup.19F NMR (376 MHz, CD.sub.3OD) .delta. -77.74 (s),-114.52
(d, J=8.0 Hz), -115.03 (s). Analytical HPLC (Method A): RT=7.79
min, 99.6% purity; Factor XIa Ki=0.14 nM, Plasma Kallikrein Ki=16
nM.
Example 180
Preparation of
(9R,13S)-13-[4-(3-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dime-
thyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,1-
6-pentaen-8-one
##STR00351##
[1807]
(9R,13S)-13-[4-(3-Chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,-
9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),-
4,14,16-pentaen-8-one trifluoroacetate (3.35 mg, 15% yield) was
prepared in a similar manner as the procedure described in Example
161, by replacing pyridin-3-ylboronic acid (4.76 mg, 0.039 mmol)
with lithium
4-methyl-1-(1-methyl-1H-1,2,3-triazol-4-yl)-2,6,7-trioxa-1-borabicyclo
[2.2.2]octan-1-uide (8.41 mg, 0.039 mmol). MS(ESI) m/z: 489.3
(M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.01 (s,
1H), 8.73 (d, J=5.2 Hz, 1H), 8.08 (t, J=1.7 Hz, 1H), 7.94 (dt,
J=7.5, 1.6 Hz, 1H), 7.73 (s, 1H), 7.54-7.44 (m, 4H), 6.93 (d, J=0.5
Hz, 1H), 6.04 (dd, J=12.5, 4.0 Hz, 1H), 4.05 (s, 3H), 2.76-2.68 (m,
1H), 2.42-2.32 (m, 1H), 2.15-2.02 (m, 2H), 1.67-1.57 (m, 1H),
1.55-1.45 (m, 1H), 1.02 (d, J=6.9 Hz, 3H), 0.81-0.65 (m, 1H).
Analytical HPLC (Method A): RT=7.33 min, 99.0% purity; Factor XIa
Ki=360 nM, Plasma Kallikrein Ki=6,800 nM.
Example 181
Preparation of
4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}benzoic acid
##STR00352##
[1809] To the solution of methyl
4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydrop-
yrimidin-4-yl}benzoate trifluoroacetate (0.02 g, 0.030 mmol),
prepared as described in Example 168, in DCM (0.5 ml) at 0.degree.
C. was added BBr.sub.3 (0.029 ml, 0.30 mmol). The reaction became a
yellow suspension. After 10 min, the cold bath was removed, and the
reaction was stirred at rt. After 18 h, the reaction was cooled to
0.degree. C. and carefully quenched with MeOH. The reaction was
warmed to rt and then concentrated. Purification by reverse phase
chromatography afforded
4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydrop-
yrimidin-4-yl}benzoic acid trifluoroacetate (0.011 g, 56% yield) as
a white solid. MS(ESI) m/z: 533.1 (M+H).sup.+. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 9.00 (s, 1H), 8.74 (d, J=5.1 Hz, 1H), 7.90
(d, J=9.0 Hz, 1H), 7.73 (s, 1H), 7.61-7.56 (m, 2H), 7.53 (dd,
J=5.3, 1.5 Hz, 1H), 7.50 (s, 1H), 6.58 (s, 1H), 6.07 (dd, J=12.8,
4.2 Hz, 1H), 4.05 (s, 3H), 2.77-2.67 (m, 1H), 2.41-2.30 (m, 1H),
2.16-2.00 (m, 2H), 1.68-1.57 (m, 1H), 1.55-1.43 (m, 1H), 1.01 (d,
J=7.0 Hz, 3H), 0.79-0.62 (m, 1H). Analytical HPLC (Method A):
RT=5.54 min, 99.9% purity; Factor XIa Ki=500 nM.
Example 182
Preparation of
(9R,13S)-3-(difluoromethyl)-9-methyl-13-{6-oxo-4-[5-(propan-2-yl)-2-[4-(t-
rifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl]-1,6-dihydropyrimidin-1-yl}-3-
,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pent-
aen-8-one
##STR00353##
[1810] 182A. Preparation of
4-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
[1811]
4-Isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(1.21 g, 99%) was prepared in a similar manner as Example 119A
starting from 2-bromo-4-isopropylaniline. MS(ESI) m/z: 180
(M-C.sub.6H.sub.10+H).sup.+.
182B. Preparation
4-isopropyl-2-(6-methoxypyrimidin-4-yl)aniline
[1812] 4-Isopropyl-2-(6-methoxypyrimidin-4-yl)aniline (511 mg, 46%)
was prepared in a similar manner as Example 119B using
4-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.
MS(ESI) m/z: 244.1 (M+H).sup.+.
182C. Preparation of
4-(5-isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)
phenyl)-6-methoxypyrimidine
[1813]
4-(5-Isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-
-6-methoxypyrimidine (522 mg, 68%) was prepared in a similar manner
as Example 119C using
4-isopropyl-2-(6-methoxypyrimidin-4-yl)aniline. MS(ESI) m/z: 364.1
(M+H).sup.+.
182D. Preparation of
6-(5-isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)
pyrimidin-4-ol
[1814]
6-(5-Isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-
pyrimidin-4-ol (459 mg, 91%) was prepared in a similar manner as
Example 119D using
4-(5-isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-met-
hoxypyrimidine. MS(ESI) m/z: 350.1 (M+H).sup.+. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 12.53 (br. s., 1H), 8.06 (s, 1H), 7.92 (s,
1H), 7.58-7.50 (m, 2H), 7.47-7.44 (m, 1H), 6.54 (s, 1H), 3.15-3.03
(m, 1H), 1.38-1.30 (m, 6H).
182E. Preparation of
(9R,13S)-3-(difluoromethyl)-9-methyl-13-{6-oxo-4-[5-(propan-2-yl)-2-[4-(t-
rifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl]-1,6-dihydropyrimidin-1-yl}-3-
,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pent-
aen-8-one, trifluoroacetate
[1815]
(9R,13S)-3-(Difluoromethyl)-9-methyl-13-{6-oxo-4-[5-(propan-2-yl)-2-
-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl]-1,6-dihydropyrimidin-1-
-yl}-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,1-
6-pentaen-8-one, trifluoroacetate (1.6 mg, 3.4%) was prepared in a
similar manner as Example 56 using
6-(5-isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimi-
din-4-ol (21 mg, 0.060 mmol) and of
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (20 mg,
0.060 mmol), prepared as described in Intermediate 30. MS(ESI) m/z:
668.2 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.39
(s, 1H), 9.17 (s, 1H), 8.76 (s, 1H), 8.70 (d, J=5.2 Hz, 1H),
8.09-7.94 (m, 1H), 7.91-7.80 (m, 1H), 7.73-7.60 (m, 3H), 7.43 (d,
J=4.7 Hz, 1H), 6.39 (s, 1H), 5.90 (d, J=10.2 Hz, 1H), 3.09 (dt,
J=13.9, 6.8 Hz, 1H), 2.64 (d, J=3.3 Hz, 1H), 2.29 (t, J=12.7 Hz,
1H), 2.09-2.01 (m, 1H), 1.87-1.80 (m, 1H), 1.52-1.43 (m, 1H), 1.30
(d, J=6.9 Hz, 5H), 0.87 (d, J=6.9 Hz, 2H), 0.37 (br. s., 1H).
Analytical HPLC (Method C): RT=2.00 min, 100% purity; Factor XIa
Ki=500 nM.
Example 183
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl-9-methyl-
-3,4,7,17-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pe-
ntaen-8-one
##STR00354##
[1817]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl-9-meth-
yl-3,4,7,17-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.068
g, 18.7%) as a white solid, was prepared in a similar manner as the
procedure described in Example 56 by using
6-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-
-4-ol (0.188 g, 0.549 mmol), as described in Intermediate 15, and
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,17-tetraazatricy-
clo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(0.166 g, 0.549 mmol), as described in Intermediate 34. MS(ESI)
m/z: 627.5 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.84 (d, J=0.7 Hz, 1H), 8.72 (d, J=5.1 Hz, 1H), 8.29 (s, 1H), 7.91
(d, J=2.4 Hz, 1H), 7.86 (s, 1H), 7.82-7.76 (m, 1H), 7.74-7.69 (m,
1H), 7.51 (s, 1H), 7.16 (dd, J=5.2, 1.7 Hz, 1H), 6.53 (d, J=0.9 Hz,
1H), 5.78 (dd, J=12.4, 3.0 Hz, 1H), 2.70-2.57 (m, 1H), 2.40 (d,
J=12.8 Hz, 1H), 2.15-2.08 (m, 1H), 2.04-1.94 (m, 1H), 1.64 (d,
J=6.8 Hz, 1H), 1.48-1.32 (m, 2H), 1.15 (d, J=6.8 Hz, 3H).
Analytical HPLC (Method A) RT=8.04 min, purity=95%; Factor XIa
Ki=0.15 nM, Plasma Kallikrein Ki=18 nM.
Example 184
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8-ox-
o-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentae-
ne-16-carbonitrile
##STR00355##
[1819]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8--
oxo-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaene-16-carbonitrile
(8 mg, 13.5%) as a white solid, was prepared in a similar manner as
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazat-
ricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaene-16-carbonitr-
ile, as described in Example 130, by replacing
6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol
with
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol, as described in Intermediate 15. LCMS(ESI) m/z: 684.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.82 (d,
J=0.7 Hz, 1H), 8.32 (s, 1H), 8.03 (s, 1H), 7.90 (d, J=2.4 Hz, 2H),
7.83-7.75 (m, 3H), 7.73-7.43 (m, 2H), 6.48 (d, J=0.4 Hz, 1H), 5.76
(dd, J=13.1, 3.4 Hz, 1H), 2.60-2.42 (m, 2H), 2.17-2.05 (m, 1H),
1.88 (dt, J=7.2, 3.7 Hz, 1H), 1.64-1.53 (m, 1H), 1.42 (d, J=8.1 Hz,
1H), 1.20 (br. s., 1H), 1.13 (d, J=6.8 Hz, 3H). Analytical HPLC
(Method A) RT=9.31 min, purity=98%; Factor XIa Ki=0.10 nM, Plasma
Kallikrein Ki=15 nM.
Example 185
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,17-tetraazatr-
icyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00356##
[1821]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,17-tetraaza-
tricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.16 g, 27%), as a white
solid, was prepared in a similar manner as Example 56, using
6-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl-
)pyrimidin-4-ol (0.308 g, 0.902 mmol), as described in Intermediate
15, and
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.27 g, 0.902
mmol), as described in Intermediate 42. LCMS(ESI) m/z: 624.5
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.84 (d,
J=0.9 Hz, 1H), 8.71 (d, J=5.5 Hz, 1H), 8.29 (s, 1H), 7.91 (d, J=2.2
Hz, 1H), 7.86 (s, 1H), 7.80-7.75 (m, 1H), 7.73-7.70 (m, 1H), 7.51
(s, 1H), 7.16 (dd, J=5.2, 1.7 Hz, 1H), 6.53 (d, J=0.7 Hz, 1H), 5.78
(dd, J=12.5, 3.1 Hz, 1H), 4.18 (s, 3H), 2.69-2.55 (m, 1H), 2.40 (d,
J=11.9 Hz, 1H), 2.11 (dd, J=13.3, 3.6 Hz, 1H), 2.00 (dd, J=14.0,
3.6 Hz, 1H), 1.64 (d, J=7.0 Hz, 1H), 1.50-1.29 (m, 2H), 1.15 (d,
J=6.8 Hz, 3H). Analytical HPLC (Method A) RT=8.07 min, purity=95%;
Factor XIa Ki=0.14 nM, Plasma Kallikrein Ki=18 nM.
Example 186
Preparation of
(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricycl-
o [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00357##
[1822] 186A. Preparation of tert-butyl
N-[(9S,13S)-10-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
##STR00358##
[1824] Fe.sub.2(C.sub.2O.sub.4).sub.3.6H.sub.2O (1.910 g, 3.95
mmol) was dissolved in water (75 mL) then purged with Ar
(3.times.). SELECTFLUOR.RTM. (1398 mg, 3.95 mmol) was added,
followed by tert-butyl
N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6] octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate,
prepared as described in Intermediate 32E (523 mg, 1.32 mmol), in
ACN (75 mL). NaBH.sub.4 (398 mg, 10.53 mmol) was added portionwise
and the solution was stirred at rt for 1 h. The reaction mixture
was quenched with 30% aq NH.sub.4OH (40 ml), extracted with 500 ml
10% MeOH in DCM. The combined organic extracts were washed with
brine, dried over MgSO.sub.4, filtered, concentrated. The residue
was purified by reverse phase chromatography to give a mixture of
tert-butyl
N-[(9S,13S)-10-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
and tert-butyl
N-[(9R,13S)-11-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (130
mg) as a solid. Further purification with chiral reverse phase
chromatography gave tert-butyl
N-[(9S,13S)-10-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (59
mg, 10% yield) as a single isomer as a white solid.
186B. Preparation of
(9S,13S)-13-amino-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00359##
[1826] To a solution of tert-butyl
N-[(9S,13S)-10-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (96
mg, 0.230 mmol) in DCM (2 mL) was added TFA (0.709 mL, 9.20 mmol).
The reaction mixture was stirred at rt for 2 h, then was
concentrated to give
(9S,13S)-13-amino-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate as a pale yellow solid, which was then dissolved
in MeOH, passed through PL-HCO.sub.3 MP SPE 500 mg per 6 ml tube,
and rinsed with MeOH, The filtrate was concentrated to give
(9S,13S)-13-amino-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (72 mg, 99%
yield). MS(ESI) m/z: 318.08 (M+H).sup.+.
186C. Preparation of
(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15--
tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-on-
e trifluoroacetate
[1827]
((9S,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-
-6-oxo-1,6-dihydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraaza-
tricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one) trifluoroacetate (7.7
mg, 39% yield) was prepared in a similar manner as the procedure
described in Example 184, by replacing methyl
(10R,14S)-14-amino-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0.sup.2,7]no-
nadeca-1(19),2(7),3,5,15,17-hexaene-4-carboxylate with
(9S,13S)-13-amino-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one. MS(ESI) m/z:
608.08 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.10
(s, 1H), 8.77 (d, J=5.3 Hz, 1H), 8.36 (s, 1H), 7.91 (d, J=2.4 Hz,
1H), 7.78-7.73 (m, 1H), 7.69-7.64 (m, 1H), 7.56 (d, J=0.9 Hz, 1H),
7.53-7.46 (m, 2H), 6.39 (d, J=0.7 Hz, 1H), 6.25 (dd, J=12.1, 5.9
Hz, 1H), 5.46-5.23 (m, 1H), 4.05 (s, 3H), 3.22-3.11 (m, 1H),
2.36-2.19 (m, 2H), 1.86-1.68 (m, 1H), 1.00 (d, J=6.8 Hz, 3H),
0.75-0.51 (m, 1H) Analytical HPLC (Method A): RT=8.33 min,
purity=>97%; Factor XIa Ki=0.37 nM, Plasma Kallikrein Ki=30
nM.
Example 187
Preparation of
(9R,13S)-3-(difluoromethyl)-13-(4-{5-ethyl-2-[4-(trifluoromethyl)-1H-1,2,-
3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15--
tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-on-
e
##STR00360##
[1828] 187A. Preparation of
4-ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
[1829]
4-Ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(0.638 g, 52%) was prepared in a similar manner as Example 119A
starting from 2-bromo-4-ethylaniline. MS(ESI) m/z: 166.0
(M-C.sub.6H.sub.10+H).sup.+. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 7.44 (d, J=2.2 Hz, 1H), 7.08 (dd, J=8.3, 2.3 Hz, 1H), 6.57
(d, J=8.4 Hz, 1H), 4.60 (br. s., 2H), 1.38-1.33 (m, 12H), 1.27 (s,
2H), 1.21-1.16 (m, 3H).
187B. Preparation 4-ethyl-2-(6-methoxypyrimidin-4-yl)aniline
[1830] 4-Ethyl-2-(6-methoxypyrimidin-4-yl)aniline (611 mg, 60%) was
prepared in a similar manner as Example 119B using
4-ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.
MS(ESI) m/z: 230.1 (M+H).sup.+.
187C. Preparation of
4-(5-ethyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-
pyrimidine
[1831]
4-(5-Ethyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-m-
ethoxypyrimidine (430 mg, 46%) was prepared in a similar manner as
Example 119C using 4-ethyl-2-(6-methoxypyrimidin-4-yl)aniline.
MS(ESI) m/z: 350.1 (M+H).sup.+.
187D. Preparation of
6-(5-isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)
pyrimidin-4-ol
[1832]
6-(5-Ethyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyri-
midin-4-ol (345 mg, 84%) was prepared in a similar manner as
Example 119D using
4-(5-ethyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-m-
ethoxypyrimidine. MS(ESI) m/z: 336.1 (M+H).sup.+. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 12.80 (br. s., 1H), 8.06 (s, 1H), 7.93 (s,
1H), 7.59-7.41 (m, 3H), 6.53 (s, 1H), 2.83 (q, J=7.7 Hz, 2H), 1.34
(t, J=7.6 Hz, 3H).
187E. Preparation of
(9R,13S)-3-(difluoromethyl)-13-(4-{5-ethyl-2-[4-(trifluoromethyl)-1H-1,2,-
3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15--
tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-on-
e trifluoroacetate
[1833]
(9R,13S)-3-(Difluoromethyl)-13-(4-{5-ethyl-2-[4-(trifluoromethyl)-1-
H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4-
,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (0.9 mg, 2.0%) was prepared in a similar manner as
Example 56 using
6-(5-ethyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin--
4-ol (21 mg, 0.060 mmol) and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (20 mg,
0.060 mmol), prepared as described in Intermediate 30. MS(ESI) m/z:
654.2 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.40
(s, 1H), 9.18 (s, 1H), 8.78-8.65 (m, 2H), 8.09-7.93 (m, 1H),
7.90-7.83 (m, 1H), 7.72-7.65 (m, 3H), 7.59 (dd, J=8.2, 1.5 Hz, 1H),
7.43 (d, J=4.9 Hz, 1H), 6.38 (s, 1H), 5.90 (d, J=9.5 Hz, 1H), 2.79
(q, J=7.4 Hz, 2H), 2.69-2.61 (m, 1H), 2.28 (t, J=12.5 Hz, 1H),
2.09-2.00 (m, 1H), 1.89-1.79 (m, 1H), 1.47 (dt, J=12.2, 6.4 Hz,
1H), 1.38-1.23 (m, 4H), 0.88 (d, J=6.7 Hz, 3H), 0.36 (br. s., 1H).
Analytical HPLC (Method C): RT=1.896 min, 100% purity; Factor XIa
Ki=110 nM.
Example 188
Preparation of
(9S,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoropheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraa-
zatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00361##
[1835]
(9S,13S)-13-{4-[3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluor-
ophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15--
tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (9.33
mg, 32% yield) was prepared in a similar manner as the procedure
described in Example 186 by replacing
6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol
with
6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]pyrimidin-4-
-ol, prepared as described in Intermediate 10. MS(ESI) m/z: 626.1
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.10 (s,
1H), 8.78 (d, J=5.1 Hz, 1H), 8.34 (s, 1H), 7.88 (dd, J=8.7, 7.6 Hz,
1H), 7.60-7.54 (m, 2H), 7.53-7.48 (m, 2H), 6.63 (s, 1H), 6.27 (dd,
J=11.8, 6.3 Hz, 1H), 5.44-5.25 (m, 1H), 4.05 (s, 3H), 3.23-3.12 (m,
1H), 2.35-2.21 (m, 2H), 1.85-1.69 (m, 1H), 1.00 (d, J=6.8 Hz, 3H),
0.75-0.52 (m, 1H). Analytical HPLC (Method A): RT=8.41 min,
purity=>99%; Factor XIa Ki=0.15 nM, Plasma Kallikrein Ki=19
nM.
Example 189
Preparation of
(9R,13S)-13-{5-chloro-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00362##
[1836] 189A. Preparation of
5-chloro-6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]
pyrimidin-4-ol
[1837] To a solution of
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(100 mg, 0.325 mmol), prepared as described in Intermediate 9, in
ACN (3.24 mL) was added Palau'chlor (82 mg, 0.389 mmol). The
reaction was stirred at 60.degree. C. for 4 h and then the reaction
was cooled to rt and concentrated. Purification by normal phase
chromatography, using EtOAc/Hex, gave a white solid weighing 0.135
g. Purification by reverse phase chromatography, gave a white
solid. The solid was partitioned between sat NaHCO.sub.3 and EtOAc
and the layers were separated. The aqueous layer was extracted with
EtOAc. The organic layers were combined, dried over MgSO.sub.4,
filtered and concentrated to give
5-chloro-6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]
pyrimidin-4-ol (63 mg, 57%) as a beige solid. MS(ESI) m/z: 342
(M+H).sup.+, 344.1 (M+2+H).sup.+, and 346.0 (M+4+H).sup.+. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.09 (s, 1H), 7.75 (s, 1H),
7.66-7.61 (m, 2H), 7.55-7.50 (m, 1H).
189B. Preparation of
(9R,13S)-13-{5-chloro-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)pheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[1838]
(9R,13S)-13-{5-Chloro-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl-
)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (0.0071 g, 23%) was prepared in a similar manner
as the procedure described in Example 56, by replacing
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol with
5-chloro-6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]p-
yrimidin-4-ol. MS(ESI) m/z: 624 (M+H).sup.+, 626.3 (M+2+H).sup.+,
and 628.2 (M+4+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.15 (s, 1H), 8.83 (s, 1H), 8.75 (s, 1H), 8.63 (d, J=5.0
Hz, 1H), 7.83-7.73 (m, 3H), 7.62 (s, 1H), 7.53 (dd, J=5.1, 1.5 Hz,
1H), 7.40 (s, 1H), 5.88-5.78 (m, 1H), 3.95 (s, 3H), 2.62-2.52 (m,
1H), 2.32-2.21 (m, 1H), 2.08-1.98 (m, 1H), 1.87-1.78 (m, 1H),
1.47-1.36 (m, 1H), 1.33-1.21 (m, 1H), 0.81 (d, J=6.9 Hz, 3H),
0.45-0.29 (m, 1H). Analytical HPLC (Method A): RT=8.03 min,
purity=99.5%; Factor XIa Ki=0.46 nM, Plasma Kallikrein Ki=29
nM.
Example 190
Preparation of
(9R,13S)-3-(difluoromethyl)-13-(4-{4-fluoro-2-[4-(trifluoromethyl)-1H-1,2-
,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-
-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-o-
ne
##STR00363##
[1840]
(9R,13S)-3-(Difluoromethyl)-13-(4-{4-fluoro-2-[4-(trifluoromethyl)--
1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,-
4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one was
prepared (0.72 mg, 6% yield as a solid via the coupling of
6-{4-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}pyrimidin-4-ol (0.006 g, 0.018 mmol) and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6), 4,14,16-pentaen-8-one (0.006
g, 0.018 mmol) using the HATU, DBU coupling methodology as
described in Example 56. LCMS m/z=644.2 (M+H).sup.+. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.83-8.77 (m, 2H), 8.73-8.69 (m, 1H),
7.91-7.86 (m, 1H), 7.75-7.72 (m, 2H), 7.68-7.49 (m, 4H), 6.05-5.96
(m, 1H), 2.75-2.62 (m, 1H), 2.30-2.18 (m, 1H), 2.05-1.94 (m, 2H),
1.64-1.36 (d, 3H), 1.02-0.94 (m, 1H). Analytical HPLC (Method A)
RT=8.75 min, purity=98%; Factor XIa Ki=110 nM.
Example 191
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,17-tetra-
azatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00364##
[1842]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,17-
-tetraazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one (10.8 mg, 18.4%), as a
white solid, was prepared in a similar manner as Example 56, using
6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol
(0.024 g, 0.079 mmol), as described in Intermediate 9, and
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,17-tetraazatricy-
clo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
(0.024 g, 0.079 mmol), as described in Intermediate 34. LCMS(ESI)
m/z: 593.3 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.78-8.69 (m, 1H), 8.42-8.33 (m, 2H), 7.92-7.86 (m, 2H), 7.80-7.74
(m, 1H), 7.69-7.64 (m, 1H), 7.52 (s, 1H), 7.21 (dd, J=5.3, 1.5 Hz,
1H), 6.51-6.43 (m, 1H), 5.77 (dd, J=12.5, 3.3 Hz, 1H), 2.62 (ddd,
J=9.5, 6.7, 3.4 Hz, 1H), 2.48-2.38 (m, 1H), 2.22-2.11 (m, 1H),
2.06-1.97 (m, 1H), 1.69-1.59 (m, 1H), 1.42-1.33 (m, 2H), 1.15 (d,
J=6.8 Hz, 3H). Analytical HPLC (Method A) RT=7.77 min, purity=96%;
Factor XIa Ki=0.19 nM, Plasma Kallikrein Ki=22 nM.
Example 192
Preparation of
(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-
-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00365##
[1843] 192A. Preparation of
6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol
[1844] 6-(3-Chloro-2,6-difluorophenyl)pyrimidin-4-ol hydrobromide,
prepared as described in Intermediate 4, was partitioned between
EtOAc and sat NaHCO.sub.3. The layers were separated and the
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated to give a white solid. The solid was
suspended in Et.sub.2O and sonicated. The solid was collected by
filtration, rinsed with Et.sub.2O, and dried under vacuum to give
6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol as a white solid.
MS(ESI) m/z: 243.0 (M+H).sup.+ and 245.0 (M+2+H).sup.+.
192B. Preparation of
(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-
-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,-
6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
[1845]
(9R,13S)-13-[4-(3-Chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrim-
idin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
(0.0092 g, 30%) was prepared in a similar manner as the procedures
described in Example 56, by using
6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol (10.8 mg, 0.045 mmol)
and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.015 g,
0.045 mmol), prepared as described in Intermediate 30. MS(ESI) m/z:
561.1 (M+H).sup.+ and 563.1 (M+2+H).sup.+. .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 9.09 (s, 1H), 8.77 (d, J=5.0 Hz, 1H), 7.79-7.72
(m, 2.25H), 7.67-7.60 (m, 1.5H), 7.56-7.52 (m, 1.25H), 7.14 (dt,
J=9.1, 1.9 Hz, 1H), 6.67 (s, 1H), 6.11-6.04 (m, 1H), 2.76-2.69 (m,
1H), 2.42-2.33 (m, 1H), 2.13-2.02 (m, 2H), 1.66-1.56 (m, 1H),
1.56-1.46 (m, 1H), 1.01 (d, J=6.9 Hz, 3H), 0.73-0.60 (m, 1H).
.sup.19F NMR (471 MHz, CD.sub.3OD) .delta. -114.75 (d, J=4.3 Hz),
-115.47 (d, J=4.3 Hz), -77.66 (s). Analytical HPLC (Method A):
RT=8.38 min, purity=99.7%; Factor XIa Ki=30 nM, Plasma Kallikrein
Ki=670 nM.
Example 193
Preparation of
(9R,13S)-13-[4-(5-chloro-2-phenylphenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-
-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(-
6),4,14,16-pentaen-8-one
##STR00366##
[1847]
(9R,13S)-13-[4-(5-Chloro-2-phenylphenyl)-6-oxo-1,6-dihydropyrimidin-
-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(-
18),2(6),4,14,16-pentaen-8-one trifluoroacetate (5 mg, 21% yield)
was prepared in a similar manner as the procedure described in
Example 161, by replacing pyridin-3-ylboronic acid (4.76 mg, 0.039
mmol) with phenylboronic acid (4.72 mg, 0.039 mmol). MS(ESI) m/z:
565.4 (M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.92
(s, 1H), 8.72 (d, J=5.0 Hz, 1H), 7.71 (d, J=2.2 Hz, 1H), 7.66 (s,
1H), 7.55-7.50 (m, 2H), 7.48 (s, 1H), 7.41 (d, J=8.3 Hz, 1H),
7.34-7.26 (m, 3H), 7.24-7.20 (m, 2H), 6.08 (d, J=0.8 Hz, 1H), 5.94
(dd, J=12.5, 4.0 Hz, 1H), 4.04 (s, 3H), 2.73-2.65 (m, 1H),
2.34-2.24 (m, 1H), 2.10-1.94 (m, 2H), 1.63-1.54 (m, 1H), 1.52-1.41
(m, 1H), 1.00 (d, J=6.9 Hz, 3H), 0.74-0.59 (m, 1H). Analytical HPLC
(Method A): RT=12.43 min, 98.2% purity; Factor XIa Ki=160 nM,
Plasma Kallikrein Ki=4,700 nM.
Example 194
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,-
7,16-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-
-8-one
##STR00367##
[1849]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,-
4,7,16-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (5 mg, 4.9%) was prepared in a similar manner as
Example 56 using
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-
pyrimidin-4-ol, prepared as described in Intermediate 15, and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo[1-
2.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one,
prepared as described in Intermediate 43. MS(ESI) m/z: 660.2
(M+H).sup.+. .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.84
(d, J=0.7 Hz, 1H), 8.78 (s, 1H), 8.65 (d, J=2.0 Hz, 1H), 8.34 (s,
1H), 8.27 (t, J=1.9 Hz, 1H), 7.92 (d, J=2.2 Hz, 1H), 7.82-7.77 (m,
2H), 7.73-7.70 (m, 1H), 6.50 (d, J=0.7 Hz, 1H), 5.79 (dd, J=12.9,
3.4 Hz, 1H), 2.58-2.48 (m, 2H), 2.22-2.14 (m, 1H), 1.92-1.87 (m,
1H), 1.64-1.57 (m, 2H), 1.17 (d, J=6.8 Hz, 3H), 1.12-1.03 (m, 1H).
Analytical HPLC (Method A): RT=8.10 min, purity=90%; Factor XIa
Ki=0.13 nM, Plasma Kallikrein Ki=66 nM.
Example 195
Preparation of
(9R,13S)-13-[4-(5-chloro-1-ethyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimi-
din-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00368##
[1850] 195A. Preparation of
6-(5-chloro-1-methyl-1H-indazol-7-yl)pyrimidin-4-ol
[1851] 6-(5-Chloro-1-methyl-1H-indazol-7-yl)pyrimidin-4-ol was
prepared in a similar manner as Intermediate 22 replacing MeI with
EtI. MS(ESI) m/z: 275.1 (M+H).sup.+ and 277.1 (M+2+H).sup.+.
195B. Preparation of
(9R,13S)-13-[4-(5-chloro-1-ethyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimi-
din-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.s-
up.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[1852]
(9R,13S)-13-[4-(5-Chloro-1-ethyl-1H-indazol-7-yl)-6-oxo-1,6-dihydro-
pyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one,
trifluoroacetate (10.8 mg, 25%) was prepared in a similar manner as
Example 56 using
6-(5-chloro-1-methyl-1H-indazol-7-yl)pyrimidin-4-ol and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one,
prepared as described in Intermediate 30. MS(ESI) m/z: 593.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.12 (s,
1H), 8.76 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.89 (d, J=2.0 Hz, 1H),
7.83-7.73 (m, 2H), 7.69-7.50 (m, 2H), 7.45-7.41 (m, 1H), 6.73 (s,
1H), 6.12 (dd, J=12.9, 4.3 Hz, 1H), 4.39-4.26 (m, 2H), 2.77-2.72
(m, 1H), 2.44-2.35 (m, 1H), 2.14-2.05 (m, 2H), 1.65-1.50 (m, 2H),
1.23 (t, J=7.2 Hz, 3H), 1.01 (d, J=7.0 Hz, 2H), 0.67 (br. s., 1H).
Analytical HPLC (Method A): RT=8.69 min, purity=>99%; Factor XIa
Ki=110 nM, Plasma Kallikrein Ki=8,400 nM.
Example 196
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyc-
lo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00369##
[1853] 196A. Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3-{[2-(trimethylsilyl)ethox-
y]
methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),-
4,14,16-pentaen-8-one
[1854]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3-{[2-(trimethylsilyl-
)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),-
2(6),4,14,16-pentaen-8-one (760 mg, 0.975 mmol, 74% yield) was
prepared in a similar manner as the procedures described in Example
56, by using
6-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)
pyrimidin-4-ol (0.452 g, 1.323 mmol), prepared as described in
Intermediate 15, and
(9R,13S)-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazat-
ricyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(0.550 g, 1.323 mmol), prepared as described in Intermediate 19.
MS(ESI) m/z: 740.6 [M+H].sup.+.
196B. Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[1855] To a solution of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3-{[2-(trimethylsilyl)ethox-
y]
methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),-
4,14,16-pentaen-8-one (760 mg, 1.027 mmol), in DCM (4.0 mL) was
added TFA (1.0 mL, 12.98 mmol) and the resulting solution was
stirred at rt for 30 min. The reaction mixture was then
concentrated and the residue was purified by prep HPLC purification
to give
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (480 mg, 92% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.26 (s, 1H), 9.21 (s, 1H), 8.63 (br. s.,
1H), 8.49 (br. s., 1H), 7.96 (d, J=1.5 Hz, 1H), 7.87-7.78 (m, 2H),
7.47 (br. s., 1H), 7.24-6.98 (m, 1H), 6.48 (s, 1H), 5.97 (br. s.,
1H), 3.45-3.36 (m, 2H), 2.72 (br. s., 1H), 2.32-2.15 (m, 2H), 1.80
(br. s., 1H), 1.52 (br. s., 1H), 1.38 (br. s., 1H), 0.92 (d, J=6.7
Hz, 3H), 0.59 (br. s., 1H). MS(ESI) m/z: 610.1 [M+H].sup.+.
Analytical HPLC (Method B): RT=1.57 min, purity=97.0%; Factor XIa
Ki=1.9 nM, Plasma Kallikrein Ki=205 nM.
Example 197
Preparation of
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-o-
xo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.-
1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00370##
[1857]
(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)pheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo-
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (6.9 mg, 16% yield) was prepared in a similar
manner as the procedure described in Example 196 by using
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one, prepared as described
in Intermediate 32. MS(ESI) m/z: 575.2 (M+H).sup.+. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 9.46 (br. s., 1H), 8.76 (d, J=8.1 Hz,
2H), 7.91 (d, J=6.8 Hz, 1H), 7.80 (br. s., 1H), 7.62 (d, J=7.0 Hz,
2H), 7.53 (br. s., 1H), 6.70 (br. s., 1H), 5.95 (br. s., 1H), 4.09
(br. s., 3H), 2.71 (br. s., 1H), 2.32 (br. s., 1H), 2.05 (br. s.,
2H), 1.62 (br. s., 1H), 1.46 (br. s., 1H), 1.03 (br. s., 3H), 0.77
(br. s., 1H) Analytical HPLC (Method A): RT=6.71 min,
purity=>99%; Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=8
nM.
Example 198
Preparation of
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-o-
xo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatric-
yclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00371##
[1859]
(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)pheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-tria-
zatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (9.7 mg,
33% yield) was prepared in a similar manner as the procedure
described in Example 196 by using
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1-
.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one, prepared as
described in Intermediate 35. MS(ESI) m/z: 610.3 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.42 (s, 1H), 8.17 (s,
1H), 7.89 (dd, J=8.7, 7.6 Hz, 1H), 7.81-7.75 (m, 2H), 7.65-7.46 (m,
4H), 7.38 (d, J=7.7 Hz, 1H), 6.71 (d, J=0.9 Hz, 1H), 5.81 (dd,
J=12.9, 3.4 Hz, 1H), 2.56-2.44 (m, 1H), 2.40-2.25 (m, 1H),
2.17-2.05 (m, 1H), 1.94-1.82 (m, 1H), 1.63-1.47 (m, 2H), 1.27-1.17
(m, 1H), 1.15 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A):
RT=8.62 min, purity=>99%; Factor XIa Ki=0.1 nM, Plasma
Kallikrein Ki=4 nM.
Example 199
Preparation of
(9R,13S)-13-{4-[5-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatr-
icyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00372##
[1860] 199A. Preparation of
6-(5-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)pyrimidin-4-ol
[1861]
6-(5-Chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)pyrimidin-4-ol
(25 mg, 62%) was prepared in a similar manner as Intermediate 22
replacing MeI with 2-bromo-1,1,1-trifluoroethane. MS(ESI) m/z: 329
(M+H).sup.+ and 331 (M+2+H).sup.+.
199B. Preparation of
(9R,13S)-13-{4-[5-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[1862]
(9R,13S)-13-{4-[5-Chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetr-
aazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (14.5 mg, 25%) was prepared in a similar manner as
Example 56 using
6-(5-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)pyrimidin-4-ol
and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one, prepared
as described in Intermediate 30. MS(ESI) m/z: 647.2 (M+H).sup.+ and
649.2 (M+2+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.17
(s, 1H), 8.74 (d, J=5.1 Hz, 1H), 8.27-8.19 (m, 1H), 7.97 (d, J=2.0
Hz, 1H), 7.84-7.72 (m, 2H), 7.68-7.57 (m, 2H), 7.56-7.51 (m, 1H),
6.77 (s, 1H), 6.14 (dd, J=12.9, 4.3 Hz, 1H), 5.51-5.37 (m, 2H),
2.77-2.70 (m, 1H), 2.45-2.35 (m, 1H), 2.08 (t, J=12.4 Hz, 2H),
1.64-1.51 (m, 2H), 1.00 (d, J=6.8 Hz, 3H), 0.68 (br. s., 1H).
Analytical HPLC (Method A): RT=9.21 min, purity=>99%; Factor XIa
Ki=57 nM, Plasma Kallikrein Ki=1,500 nM.
Example 200
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00373##
[1864]
(9R,13S)-13-{4-[5-Chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (22.1 mg, 44% yield) was prepared in a similar
manner as the procedure described in Example 198 by replacing
6-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol
with 6-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol,
prepare as described in Intermediate 20. MS(ESI) m/z: 593.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.38 (s,
1H), 8.73-8.65 (m, 2H), 7.84 (d, J=2.2 Hz, 1H), 7.79-7.42 (m, 6H),
6.46 (s, 1H), 5.88 (dd, J=12.5, 4.2 Hz, 1H), 2.71-2.58 (m, 1H),
2.32-2.19 (m, 1H), 2.04-1.89 (m, 2H), 1.60-1.47 (m, 1H), 1.45-1.30
(m, 1H), 0.94 (d, J=6.8 Hz, 3H), 0.60 (br. s., 1H). Analytical HPLC
(Method A): RT=7.93 min, purity=>99%; Factor XIa Ki=0.1 nM,
Plasma Kallikrein Ki=10 nM.
Example 201
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3-
.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00374##
[1866]
(9R,13S)-13-{4-[5-Chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricycl-
o[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one (10.5
mg, 40% yield) was prepared in a similar manner as the procedure
described in Example 200 by replacing
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one with
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one, prepare as
described in Intermediate 35. MS(ESI) m/z: 592.3 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.39 (s, 1H), 8.09 (s,
1H), 7.86 (d, J=2.4 Hz, 1H), 7.78-7.42 (m, 7H), 7.34 (d, J=7.5 Hz,
1H), 6.51 (s, 1H), 5.76 (dd, J=12.8, 3.1 Hz, 1H), 2.51-2.38 (m,
1H), 2.36-2.21 (m, 1H), 2.11-1.99 (m, 1H), 1.90-1.77 (m, 1H),
1.58-1.41 (m, 2H), 1.21-1.03 (m, 4H) Analytical HPLC (Method A):
RT=8.50 min, purity=>99%; Factor XIa Ki=0.1 nM, Plasma
Kallikrein Ki=6 nM.
Example 202
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-fluo-
ro-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00375##
[1867] 202A. Preparation of
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-fluoropyrimidin-4-
-ol
[1868] To a solution of
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(100 mg, 0.325 mmol) in CH.sub.3CN (2 mL) was added
SELECTFLUOR.RTM. (115 mg, 0.325 mmol). The mixture was stirred at
rt for 1.5 h then DMF (0.5 ml) was added to solubilize the mixture.
The reaction was heated at 85.degree. C. overnight. The reaction
mixture was purified using reverse phase chromatography. After the
pure fractions were concentrated, the residue was partitioned
between EtOAc and sat NaHCO.sub.3 and the layers were separated.
The aqueous layer was extracted with EtOAc (2.times.). The combined
organic layers were dried with MgSO.sub.4, filtered, and
concentrated to give
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-fluoropyrimidin-4-
-ol (13 mg, 12.3% yield) as an off-white foam. MS(ESI) m/z: 326.1
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.94 (s,
1H), 7.79 (s, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.66 (dd, J=8.5, 2.3 Hz,
1H), 7.49 (d, J=8.6 Hz, 1H).
202B. Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)
phenyl]-5-fluoro-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-t-
etraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[1869]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
5-fluoro-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (3 mg, 10% yield) was prepared in a similar manner
as the procedure described in Example 56, using
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-fluoropyrimidin-4-
-ol. MS(ESI) m/z: 608.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.78-8.68 (m, 1H), 8.41 (s, 1H), 7.86 (d, J=2.4
Hz, 1H), 7.81-7.74 (m, 1H), 7.71 (d, J=8.6 Hz, 2H), 7.52 (dd,
J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 6.00 (dd, J=12.4, 3.9 Hz, 1H),
4.05 (s, 3H), 2.70 (m, 1H), 2.36-2.23 (m, 1H), 2.14-1.96 (m, 2H),
1.67-1.54 (m, 1H), 1.53-1.41 (m, 1H), 1.01 (d, J=7.0 Hz, 3H), 0.68
(m., 1H). .sup.19F NMR (376 MHz, CD.sub.3OD) .delta. -77.46 (s),
-147.07 (s). Analytical HPLC (Method A): RT=9.43 min, purity=93%;
Factor XIa Ki=0.12 nM, Plasma Kallikrein Ki=13 nM.
Example 203
Preparation of
(9R,13S)-13-{5-bromo-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00376##
[1870] 203A. Preparation of
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-fluoropyrimidin-4-
-ol
[1871] To a solution of
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(100 mg, 0.325 mmol) in CH.sub.3CN (2 mL) was added NBS (63.5 mg,
0.357 mmol). The mixture was stirred at rt for 1.5 h. The reaction
was partitioned between DCM and water and the layers were
separated. The aqueous layer was extracted with DCM (2.times.). The
combined organic layers was concentrated and then purified on
normal phase chromatography to give
5-bromo-6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)
pyrimidin-4-ol (117 mg, 93% yield) as white foam. MS(ESI) m/z:
388.0 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.11
(s, 1H), 7.71 (s, 1H), 7.66-7.63 (m, 1H), 7.63-7.62 (m, 1H), 7.53
(d, J=8.4 Hz, 1H).
203B. Preparation of
(9R,13S)-13-{5-bromo-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl-
]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[1872]
(9R,13S)-13-{5-Bromo-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)-
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatri-
cyclo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (4 mg, 13% yield) was prepared in a similar manner
as the procedure described in Example 56, by using
5-bromo-6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4--
ol, prepared as described in Example 203A. MS(ESI) m/z: 670.0
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.87 (s,
1H), 8.73 (d, J=5.1 Hz, 1H), 8.35 (s, 1H), 7.80-7.64 (m, 4H),
7.57-7.45 (m, 2H), 5.99 (dd, J=12.8, 3.7 Hz, 1H), 4.05 (s, 3H),
2.72 (m, 1H), 2.40-2.22 (m, 1H), 2.14-2.00 (m, 2H), 1.69-1.55 (m,
1H), 1.49 (t, J=10.0 Hz, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.69 (m, 1H).
Analytical HPLC (Method A): RT=11.12 min, purity=99%; Factor XIa
Ki=4.6 nM, Plasma Kallikrein Ki=220 nM.
Example 204
Preparation of
(9R,13S)-13-(4-{5-chloro-3-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-
-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-
-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pe-
ntaen-8-one
##STR00377##
[1873] 204A. Preparation of
6-(5-chloro-3-fluoro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)
phenyl)pyrimidin-4-ol
[1874]
6-(5-Chloro-3-fluoro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)p-
henyl) pyrimidin-4-ol was prepared in a similar manner as
Intermediate 15, starting from 2-bromo-4-chloro-6-fluoroaniline
instead of 2-bromo-4-chloroaniline. MS(ESI) m/z: 360.0
(M+H).sup.+.
204B. Preparation of
(9R,13S)-13-(4-{5-chloro-3-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-
-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-
-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pe-
ntaen-8-one trifluoroacetate
[1875]
(9R,13S)-13-(4-{5-Chloro-3-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-t-
riazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,-
7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-
-8-one trifluoroacetate (25 mg, 23.4%) was prepared in a similar
manner as Example 56 using
6-(5-chloro-3-fluoro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-
pyrimidin-4-ol and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one, prepared
as described in Intermediate 30. MS(ESI) m/z: 575.1 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.83 (s, 1H), 8.70 (s,
1H), 8.60 (d, J=5.3 Hz, 1H), 7.72-7.53 (m, 5H), 7.43-7.38 (m, 1H),
6.36 (d, J=0.7 Hz, 1H), 5.89 (dd, J=12.7, 4.5 Hz, 1H), 2.60 (td,
J=6.7, 3.0 Hz, 1H), 2.14 (tt, J=12.8, 4.2 Hz, 1H), 1.98-1.82 (m,
2H), 1.53-1.30 (m, 2H), 0.88 (d, J=7.0 Hz, 3H), 0.51 (br. s., 1H).
Analytical HPLC (Method A): RT=9.04 min, purity=99.5%; Factor XIa
Ki=6.8 nM, Plasma Kallikrein Ki=2,700 nM.
Example 205
Preparation of
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,
8-diazatricyclo[13.3.1.0.sup.2,7]
nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
##STR00378##
[1877]
(10R,14S)-14-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-
-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,8-diazatricyclo[1-
3.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
trifluoroacetate (0.0076 g, 36%) was prepared according to the
procedures described in Example 46 by using
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol, prepared as described in Example 15B,
(10R,14S)-14-amino-10-methyl-5,8-diazatricyclo[13.3.1.0.sup.2,7]nonadeca--
1(19),2(7),3,5,15,17-hexaen-9-one, prepared as described in
Intermediate 38, and 4-bromopyridin-3-amine in Intermediate 38B.
MS(ESI) m/z: 620.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.81 (d, J=0.7 Hz, 1H), 8.77 (s, 2H), 8.29 (s, 1H), 8.08
(d, J=5.7 Hz, 1H), 7.91-7.84 (m, 2H), 7.82-7.60 (m, 4H), 7.42-7.34
(m, 1H), 6.49 (d, J=0.4 Hz, 1H), 5.80 (dd, J=13.0, 3.5 Hz, 1H),
2.64-2.51 (m, 1H), 2.39-2.26 (m, 1H), 2.18-2.06 (m, 1H), 1.99-1.88
(m, 1H), 1.63-1.30 (m, 3H), 1.16 (d, J=6.8 Hz, 3H). Analytical HPLC
(Method A): RT=6.87 min, purity=90%; Factor XIa Ki=0.11 nM, Plasma
Kallikrein Ki=11 nM.
Example 206
Preparation of
(10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-
-1,6-dihydropyrimidin-1-yl}-10-methyl-5,8-diazatricyclo[13.3.1.0.sup.2,7]n-
onadeca-1(19),2(7),3,5,15,17-hexaen-9-one
##STR00379##
[1879]
(10R,14S)-14-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-
-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-5,
8-diazatricyclo[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-o-
ne trifluoroacetate (0.0062 g, 31%) was prepared according to the
procedures described in Example 205 by using
6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol,
prepared as described in Intermediate 9E. MS(ESI) m/z: 586.1
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.70 (d,
J=5.3 Hz, 1H), 8.64 (s, 1H), 8.37-8.28 (m, 2H), 7.93-7.84 (m, 3H),
7.75 (dd, J=8.6, 2.2 Hz, 1H), 7.68-7.61 (m, 3H), 7.43-7.35 (m, 1H),
6.42 (s, 1H), 5.82 (dd, J=13.0, 3.5 Hz, 1H), 2.63-2.52 (m, 1H),
2.41-2.28 (m, 1H), 2.20-2.08 (m, 1H), 1.98-1.87 (m, 1H), 1.65-1.45
(m, 2H), 1.41-1.29 (m, 1H), 1.17 (d, J=7.0 Hz, 3H). Analytical HPLC
(Method A): RT=6.26 min, purity=90%; Factor XIa Ki=0.2 nM, Plasma
Kallikrein Ki=17 nM.
Example 207
Preparation of
(9R,13S)-13-[4-(6-chloro-1H-1,3-benzodiazol-4-yl)-6-oxo-1,6-dihydropyrimi-
din-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00380##
[1880] 207A. Preparation of
6-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imida-
zole
[1881] 4-Bromo-6-chloro-1H-benzo[d]imidazole (0.600 g, 2.59 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.790
g, 3.11 mmol), KOAc (0.763 g, 7.78 mmol) were added to dioxane
(10.9 mL). After bubbling Ar through the solution for 2 min,
Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 complex (0.106 g, 0.130 mmol) was
added and the mixture heated at 110.degree. C. overnight. The
reaction mixture was cooled to rt and partitioned between EtOAc and
water. The organic phase separated and washed with sat NaHCO.sub.3
and brine, dried over MgSO.sub.4, filtered, concentrated to yield a
crude dark solid product which was carried forward to the next
reaction. MS(ESI) m/z: 197.0 (M-C.sub.6H.sub.10+H).sup.+.
207B. Preparation of
6-chloro-4-(6-methoxypyrimidin-4-yl)-1H-benzo[d]imidazole
[1882] 4-Chloro-6-methoxypyrimidine (0.562 g, 3.89 mmol),
6-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imida-
zole (0.722 g, 2.59 mmol) and 2 M aq Na.sub.2CO.sub.3 (0.549 g,
5.18 mmol) in DME (20.74 mL), EtOH (2.59 mL) was purged with Ar for
several min. Then PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (0.212 g,
0.259 mmol) was added and heated to 90.degree. C. After 2 h, the
reaction was cooled to rt, diluted with water and extracted with
EtOAc. The organic layer washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give a brown oil.
The crude material was purified by normal phase chromatography
using EtOAc and MeOH as eluants to give
6-chloro-4-(6-methoxypyrimidin-4-yl)-1H-benzo[d]imidazole (148 mg,
22%). MS(ESI) m/z: 261.1 (M+H).sup.1 and 263.1 (M+2+H).sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.93 (d, J=1.1 Hz, 1H),
8.42 (s, 1H), 8.36 (br. s., 1H), 8.20 (d, J=1.9 Hz, 1H), 7.84 (s,
1H), 4.02 (s, 3H).
207C. Preparation of
6-(6-chloro-1H-benzo[d]imidazol-4-yl)pyrimidin-4-ol
[1883] To a clear solution of
6-chloro-4-(6-methoxypyrimidin-4-yl)-1H-benzo[d]imidazole (0.148 g,
0.568 mmol) in AcOH (2.88 ml) was added 63% aq HBr (0.548 ml, 4.54
mmol) and the reaction mixture was heated to 80.degree. C. After 1
h, the solution was cooled to rt, diluted with EtOAc (10 ml), then
quenched with sat aq NaHCO.sub.3 (20 ml). The aqueous layer was
extracted with EtOAc (3.times.10 ml). The combined organic layer
washed with brine (10 ml), dried over Na.sub.2SO.sub.4, filtered
and concentrated. The crude product was triturated with pet. ether,
filtered, and dried under vacuum to give
6-(6-chloro-1H-benzo[d]imidazol-4-yl)pyrimidin-4-ol as a beige
color solid. MS(ESI) m/z: 247 (M+H).sup.1 and 249 (M+2+H).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.39 (s, 1H), 8.35-8.28
(m, 1H), 8.03 (d, J=2.0 Hz, 1H), 7.78 (d, J=2.2 Hz, 2H).
207D. Preparation of
(9R,13S)-13-[4-(6-chloro-1H-1,3-benzodiazol-4-yl)-6-oxo-1,6-dihydropyrimi-
din-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.s-
up.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[1884]
(9R,13S)-13-[4-(6-Chloro-1H-1,3-benzodiazol-4-yl)-6-oxo-1,6-dihydro-
pyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (0.7 mg, 0.77%) was prepared in a similar manner
as Example 56 using
6-(6-chloro-1H-benzo[d]imidazol-4-yl)pyrimidin-4-ol and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one,
prepared as described in Intermediate 30. MS(ESI) m/z: 565
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.43 (s,
1H), 9.07 (br. s., 1H), 8.76 (d, J=4.6 Hz, 1H), 8.43 (br. s., 1H),
8.10 (d, J=17.7 Hz, 1H), 7.99-7.90 (m, 2H), 7.82-7.73 (m, 2H), 7.44
(d, J=4.6 Hz, 1H), 5.99 (d, J=11.0 Hz, 1H), 2.09 (d, J=8.9 Hz, 1H),
1.98 (br. s., 1H), 1.55 (br. s., 4H), 1.40 (br. s., 1H), 0.90 (d,
J=6.7 Hz, 3H). Analytical HPLC (Method C): RT=1.20 min,
purity=100%; Factor XIa Ki=120 nM.
Example 208
Preparation of methyl
4-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraaza-
tricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-4-yl]piperidin-
e-1-carboxylate
##STR00381##
[1886]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(piperidin-4-yl)-3,4,7,15-tetr-
aazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2,5,14,16-pentaen-8-one, prepared as described in
Example 328 (0.015 g, 0.023 mmol), methyl chloroformate (2.2 mg,
0.023 mmol), and Et.sub.3N (0.016 mL, 0.114 mmol) were dissolved in
THF (1 mL) and stirred at rt for 3 h, then concentrated. The
residue was purified by reverse phase chromatography to give methyl
4-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-o-
xo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.-
3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-4-yl]
piperidine-1-carboxylate (10 mg, 61%) as a white solid. MS(ESI)
m/z: 717.2 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.69-8.64 (m, 1H), 8.63-8.57 (m, 1H), 8.36 (s, 1H), 7.91 (d, J=2.4
Hz, 2H), 7.83 (s, 1H), 7.79-7.72 (m, 1H), 7.68 (s, 1H), 7.67-7.65
(m, 1H), 7.65-7.61 (m, 1H), 6.40 (d, J=0.4 Hz, 1H), 6.11-5.99 (m,
1H), 4.52-4.41 (m, 1H), 4.34-4.22 (m, 2H), 3.74 (s, 3H), 3.17-2.97
(m, 2H), 2.86-2.75 (m, 1H), 2.36-2.13 (m, 4H), 2.13-1.97 (m, 3H),
1.81-1.63 (m, 1H), 1.61-1.48 (m, 1H), 1.09 (d, J=7.0 Hz, 3H).
Analytical HPLC (Method A): RT=7.40 min, purity=99%; Factor XIa
Ki=7 nM, Plasma Kallikrein Ki=460 nM.
Example 209
Preparation of
(9R,13S)-13-(4-{4-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,-
7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-
-8-one
##STR00382##
[1888]
(9R,13S)-13-(4-{4-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,-
4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (4 mg,
20% yield), was prepared as a solid via the coupling of
6-{4-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}pyrimidin-4-ol (0.01 g, 0.028 mmol) and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6), 4,14,16-pentaen-8-one (0.01 g,
0.028 mmol) using the HATU, DBU coupling methodology as described
in Example 56. LCMS m/z=660.2 (M+H). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.87-8.80 (m, 2H), 8.76-8.71 (m, 1H), 7.86-7.83
(m, 2H), 7.82-7.80 (m, 1H), 7.77-7.76 (m, 1H), 7.72-7.66 (m, 2H),
7.55-7.52 (m, 1H), 6.49-6.46 (s, 1H), 6.08-5.99 (m, 1H), 2.78-2.68
(m, 1H), 2.36-2.21 (m, 1H), 2.12-1.99 (m, 3H), 1.69-1.41 (m, 4H),
1.05-0.96 (d, 3H), 0.74-0.54 (m, 1H). Analytical HPLC (Method A)
RT=8.77 min, purity=95%; Factor XIa Ki=48 nM.
Example 210
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-meth-
yl-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00383##
[1889] 210A. Preparation of
4-chloro-2-(6-methoxy-5-methylpyrimidin-4-yl)aniline
[1890] 4-Chloro-2-(6-methoxy-5-methylpyrimidin-4-yl)aniline (230
mg, 73% yield) was prepared in a similar manner as the procedure
described in Intermediate 9B, by replacing
4-chloro-6-methoxypyrimidine with
4-chloro-6-methoxy-5-methylpyrimidine (200 mg, 1.261 mmol). MS(ESI)
m/z: 250.1 (M+H).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
8.68 (s, 1H), 7.15 (dd, J=8.6, 2.6 Hz, 1H), 7.09 (d, J=2.6 Hz, 1H),
6.72 (d, J=8.6 Hz, 1H), 4.25 (br. s., 2H), 4.06 (s, 3H), 2.14 (s,
3H), 1.33-1.20 (m, 12H).
210B. Preparation of
4-(5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-
-5-methylpyrimidine
[1891]
4-(5-Chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-m-
ethoxy-5-methylpyrimidine (70 mg, 20% yield) was prepared in a
similar manner as the procedure described in Intermediate 9C, by
replacing 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline with
4-chloro-2-(6-methoxy-5-methylpyrimidin-4-yl)aniline (230 mg, 0.921
mmol). MS(ESI) m/z: 374.4 (M+H).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.36 (s, 1H), 7.44-7.29 (m, 2H), 7.25 (d, J=2.2
Hz, 1H), 7.12 (s, 1H), 3.76-3.70 (m, 3H), 0.04-0.05 (m, 9H).
210C. Preparation of
4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-5-methylp-
yrimidine
[1892]
4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-5-m-
ethylpyrimidine (29 mg, 46% yield) was prepared in a similar manner
as the procedure described in Intermediate 9D, by replacing
4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxy-
pyrimidine with
4-(5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-
-5-methylpyrimidine (70 mg, 0.187 mmol). MS(ESI) m/z: 336.4
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.60 (s,
1H), 7.61-7.58 (m, 2H), 7.50 (s, 1H), 7.47 (d, J=2.0 Hz, 1H), 4.02
(s, 3H), 1.83 (s, 3H).
210D. Preparation of
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin-4-
-ol
[1893]
6-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrim-
idin-4-ol (10 mg, 36% yield) was prepared in a similar manner as
the procedure described in Intermediate 9E, by replacing
4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine
with
4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-5-me-
thylpyrimidine (29 mg, 0.086 mmol). MS(ESI) m/z: 322.0 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.25 (s, 1H), 7.98 (s,
1H), 7.72 (d, J=2.0 Hz, 1H), 7.71 (d, J=0.4 Hz, 1H), 7.66 (dd,
J=2.1, 0.6 Hz, 1H), 1.79 (s, 3H).
210E. Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)
phenyl]-5-methyl-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-t-
etraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[1894]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
5-methyl-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (8.8 mg, 37% yield) was prepared in a similar
manner as the procedure described in Example 56, by using
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin-4-
-ol (0.010 g, 0.031 mmol). MS(ESI) m/z: 604.1 (M+H).sup.+. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.79-8.70 (m, 2H), 8.27 (s, 1H),
7.78 (s, 1H), 7.77-7.69 (m, 2H), 7.68 (d, J=2.0 Hz, 1H), 7.60 (dd,
J=5.3, 1.5 Hz, 1H), 7.50 (s, 1H), 5.95 (dd, J=12.5, 4.2 Hz, 1H),
4.06 (s, 3H), 2.70 (m, 1H), 2.40-2.29 (m, 1H), 2.13-1.99 (m, 2H),
1.77 (s, 3H), 1.67-1.55 (m, 1H), 1.47 (m, 1H), 1.02 (d, J=6.8 Hz,
3H), 0.77 (m., 1H); Analytical HPLC (Method A): RT=7.79 min,
purity=93%; Factor XIa Ki=3.5 nM, Plasma Kallikrein Ki=240 nM.
Example 211
Preparation of
(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-
,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6)-
,4,14,16-pentaen-8-one
##STR00384##
[1895] 211A. Preparation of
4-(5-chloro-2-iodophenyl)-6-methoxypyrimidine
[1896] The solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline
(2 g, 8.49 mmol), prepared as described in Intermediate 8A, in ACN
(56.6 ml) was cooled to 0.degree. C., then p-TsOH.H.sub.2O (4.04 g,
21.22 mmol) was added. A solution of NaNO.sub.2 (1.171 g, 16.97
mmol) and NaI (3.18 g, 21.22 mmol) in water (28.3 ml) was added
slowly and the reaction turned into a dark brown solution. After a
few min, the reaction turned cloudy. The reaction was stirred at
0.degree. C. for 1 h, then the reaction was warmed to rt. After 18
h, the reaction was quenched with sat NaHCO.sub.3 and extracted
with EtOAc. The organic layer was washed with sat aq
Na.sub.2S.sub.2O.sub.3, brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated to yield a solid. Purification by normal
phase chromatography afforded
4-(5-chloro-2-iodophenyl)-6-methoxypyrimidine (2.13 g, 72% yield)
as a white solid. MS(ESI) m/z: 347.2 (M+H).sup.+. .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 8.87 (d, J=1.1 Hz, 1H), 7.88 (d, J=8.3 Hz,
1H), 7.44 (d, J=2.8 Hz, 1H), 7.11 (dd, J=8.5, 2.8 Hz, 1H), 6.93 (d,
J=1.4 Hz, 1H), 4.06 (s, 3H).
211B. Preparation of 6-(5-chloro-2-iodophenyl)pyrimidin-4-ol
[1897] 6-(5-Chloro-2-iodophenyl)pyrimidin-4-ol (0.24 g, 100% yield)
was prepared in a similar manner as the procedure described in
Example 140B, by replacing
4-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-6-methoxypyrimi-
dine with 4-(5-chloro-2-iodophenyl)-6-methoxypyrimidine (0.25 g,
0.721 mmol), and the reaction time was 1 h at 85.degree. C. MS(ESI)
m/z: 333.0 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.27 (d, J=0.9 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.47 (d, J=2.6 Hz,
1H), 7.21 (dd, J=8.6, 2.6 Hz, 1H), 6.54 (d, J=0.9 Hz, 1H).
211C. Preparation of
(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-
,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6)-
,4,14,16-pentaen-8-one trifluoroacetate
[1898]
(9R,13S)-13-[4-(5-Chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-
-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18-
),2(6),4,14,16-pentaen-8-one trifluoroacetate (125 mg, 68% yield)
was prepared in a similar manner as the procedure described in
Example 56, by using 6-(5-chloro-2-iodophenyl)pyrimidin-4-ol (100
mg, 0.301 mmol). MS(ESI) m/z: 615.4 (M+H).sup.+. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 9.05 (s, 1H), 8.75 (d, J=5.3 Hz, 1H), 7.95
(d, J=8.4 Hz, 1H), 7.74 (s, 1H), 7.54 (dd, J=5.1, 1.5 Hz, 1H),
7.51-7.49 (m, 2H), 7.21 (dd, J=8.5, 2.5 Hz, 1H), 6.60 (s, 1H), 6.07
(dd, J=12.8, 4.4 Hz, 1H), 4.05 (s, 3H), 2.77-2.68 (m, 1H), 2.38
(tt, J=12.7, 4.3 Hz, 1H), 2.16-2.02 (m, 2H), 1.68-1.44 (m, 2H),
1.02 (d, J=6.8 Hz, 3H), 0.79-0.64 (m, 1H). Analytical HPLC (Method
A): RT=8.71 min, 99.6% purity; Factor XIa Ki=12 nM, Plasma
Kallikrein Ki=140 nM.
Example 212
Preparation of
(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(4-phenyl-1H-1,2,3-triazol-1-yl)
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00385##
[1900]
(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-(4-phenyl-1H-1,2,3-triazol-1-yl-
)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
(3 mg, 19% yield) was prepared in a similar manner as the procedure
described in Example 56, by using
6-[3-chloro-2-fluoro-6-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-
-ol (9 mg, 0.024 mmol), prepared as described in Intermediate 9,
and
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one (7.3 mg, 0.024 mmol).
LCMS m/z 650.3 (M+H). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.81-8.77 (m, 1H), 8.62-8.57 (m, 1H), 8.56-8.54 (m, 1H), 7.93-7.87
(m, 1H), 7.84-7.78 (m, 3H), 7.66-7.62 (dd, 1H), 7.61-7.57 (m, 1H),
7.52 (bs, 1H), 7.49-7.44 (m, 2H), 7.43-7.38 (m, 1H), 6.68-6.64 (m,
1H), 5.98-5.94 (m, 1H), 4.07 (s, 3H), 2.75-2.61 (m, 1H), 2.39-2.22
(m, 1H), 2.10-1.99 (m, 2H), 1.65-1.53 (m, 1H), 1.49-1.33 (m, 1H),
1.07-1.00 (d, 3H), 0.86-0.67 (m, 1H); Factor XIa Ki=0.81 nM, Plasma
Kallikrein Ki=28 nM.
Example 213
Preparation of
N-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}-3-fluorophenyl)carbamate trifluoroacetate
##STR00386##
[1901] 213A. Preparation of
N-[4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl]
carbamate
[1902] 4-Chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (0.024
g, 0.095 mmol), was dissolved in DCM (5 ml). To this solution was
added sequentially TEA (1 mL) followed by methyl chloroformate
(8.94 mg, 0.095 mmol) and the solution was stirred at rt. After 2
h, the reaction was concentrated in vacuo to an oil and quenched
with dilute HCl (5 mL). The organics were extracted with EtOAc
(2.times.25 mL), dried with MgSO.sub.4 and evaporated to an oil.
LCMS m/z 312.1 (M+H). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
10.30-10.24 (m, 1H), 8.84-8.81 (m, 1H), 8.00-7.92 (m, 1H),
7.40-7.32 (m, 1H), 7.05-7.01 (m, 1H), 3.98 (s, 3H), 3.67 (s, 3H).
The crude product was taken in a small vial and dissolved in AcOH
(1 mL) and to this was added 48% HBr (0.1 mL) and heated at
80.degree. C. until reaction was complete. The reaction mixture was
concentrated and quenched with water (25 mL), extracted with EtOAc
(2.times.25 mL). The combined organic layers was dried and
evaporated to give
N-[4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl] carbamate
as a white film (13 mg). LCMS m/z 299.1 (M+H).
213B. Preparation of
N-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihyd-
ropyrimidin-4-yl}-3-fluorophenyl)carbamate
[1903]
N-(4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatric-
yclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,-
6-dihydropyrimidin-4-yl}-3-fluorophenyl)carbamate (1.1 mg, 4.21%
yield) was prepared following the procedure described in Example 56
by using
N-[4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl]carbamate
(13 mg, 0.044 mmol),
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one (15 mg, 0.044 mmol).
LCMS m/z 580.1 (M+H). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.39-9.34 (m, 1H), 9.24-9.21 (m, 1H), 9.05-9.02 (m, 1H), 8.74-8.70
(m, 1H), 7.74-7.57 (m, 3H), 7.49 (s, 1H), 6.61-6.55 (m, 1H),
5.99-5.87 (m, 1H), 4.04-3.98 (m, 3H), 3.65-3.59 (m, 3H), 2.70-2.62
(m, 1H), 2.40-2.32 (m, 1H), 2.18-2.09 (m, 1H), 1.96-1.85 (m, 1H),
1.53-1.30 (m, 2H), 0.94-0.87 (m, 3H), 0.56-0.36 (m, 1H). Ortho RT.
1.605 min purity 97%; Factor XIa Ki=110 nM.
Example 214
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetr-
aazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-15-ium-1-
5-olate
##STR00387##
[1905]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetr-
aazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one,
prepared as described in Example 88, was dissolved in EtOAc (2 mL)
and m-CPBA (0.021 g, 0.120 mmol) was added at rt. After stirring
overnight, the reaction was concentrated and purified by reverse
phase chromatography to give
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-ox-
o-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-p-
entaen-15-ium-15-olate (11 mg, 15%) as a white solid. MS(ESI) m/z:
642.2 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.54
(s, 1H), 8.71 (s, 1H), 8.40 (d, J=6.7 Hz, 2H), 7.98-7.86 (m, 3H),
7.85-7.76 (m, 2H), 7.72 (d, J=8.5 Hz, 1H), 7.55 (d, J=5.2 Hz, 1H),
6.32 (s, 1H), 5.49-5.31 (m, 1H), 2.48-2.34 (m, 1H), 2.03-1.92 (m,
1H), 1.82-1.70 (m, 1H), 1.48-1.36 (m, 1H), 1.06 (d, J=6.1 Hz, 3H),
1.01-0.85 (m, 1H). Analytical HPLC (Method C): RT=1.45 min,
purity=100%; Factor XIa Ki=0.35 nM, Plasma Kallikrein Ki=74 nM.
Example 215
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,-
7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-on-
e trifluoroacetate
##STR00388##
[1906] 215A. Preparation of
6-{5-chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}
pyrimidin-4-ol
##STR00389##
[1908] 4-Chloro-2-(6-methoxypyrimidin-4-yl)aniline (0.1 g, 0.424
mmol) was dissolved in ACN (5 mL) and cooled to 0.degree. C. To
this solution was added isopentylnitrite ((0.075 g, 0.636 mmol)
followed by the addition of TMSN.sub.3 (0.073 g, 0.636 mmol). The
reaction mixture was stirred at 0.degree. C. for 0.5 h then allowed
to warm to rt and stirred overnight. To the solution was added
Cu.sub.2O (6.1 mg, 0.042 mmol) followed by 3-ethynylpyridine (0.044
g, 0.424 mmol) and stirred at rt. The reaction turned milky gray to
clear in about 2 min. After 1 h, the reaction was concentrated and
directly purified via a 12 g silica gel ISCO column using
hexane/EtOAc as eluants to give
6-{5-chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4--
ol (0.069 g) as a yellowish orange liquid. LCMS m/z 355.1 (M+H).
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.89-8.86 (m, 1H),
7.91-7.88 (m, 1H), 7.49-7.45 (m, 1H), 7.29 (s, 5H), 7.27-7.20 (m,
2H), 4.10-4.04 (m, 3H). The product was dissolved in AcOH (1 mL)
and 48% aq HBr (0.2 mL) was added, sealed and heated at 80.degree.
C. for 2 h. The reaction was concentrated and quenched with sat
NaHCO.sub.3 (25 mL) and extracted with EtOAc (2.times.25 mL). The
organic extracts were combined, dried over
[1909] MgSO.sub.4, filtered and concentrated to afford
6-{5-chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4--
ol as an oil (0.011 g, 7% yield). LCMS m/z 351.1 (M+H).
215B. Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,-
7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-on-
e trifluoroacetate
[1910]
(9R,13S)-13-(4-{5-Chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl]-
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-
-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate was prepared (3.5 mg, 14.1%) following the
procedure described in Example 56 by using
6-{5-chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4--
ol (12 mg, 0.034 mmol) and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1-
.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one (11 mg, 0.034
mmol). LCMS m/z 668.1 (M+H). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.45-9.41 (m, 1H), 9.13-9.09 (m, 1H), 9.02-8.97 (m, 1H),
8.69-8.62 (m, 1H), 8.53-8.47 (m, 1H), 8.35-8.29 (m, 1H), 7.99-7.95
(m, 2H), 7.93-7.83 (m, 4H), 7.75-7.70 (m, 1H), 7.64-7.59 (m, 1H),
7.55-7.50 (m, 1H), 7.49-7.42 (m, 1H), 7.41-7.32 (m, 1H), 7.29-7.23
(m, 1H), 6.50-6.46 (m, 1H), 5.71-5.59 (m, 1H), 2.55-2.29 (m, 2H),
1.99-1.81 (m, 2H), 1.54-1.39 (m, 1H), 1.28-1.06 (m, 2H), 1.05-0.98
(d, 3H), 0.50-0.31 (m, 1H). Orthogonal RT. 1.652 purity>92%;
Factor XIa Ki=0.48 nM, Plasma Kallikrein Ki=75 nM.
Example 216
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-3-yl)-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
##STR00390##
[1912]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one, prepared as
described in Example 101, (0.09 g, 0.156 mmol),
(1R,2R)--N1,N2-dimethylcyclohexane-1,2-diamine (0.022 g, 0.156
mmol), Cs.sub.2CO.sub.3 (0.102 g, 0.312 mmol), and 3-iodopyridine
(0.032 g, 0.156 mmol) were added to a 5 mL microwave vial. DMF (2
mL) was added and the vial was purged with Ar (3.times.). CuI (2
mg, 10.50 .mu.mol) was added, the vial was sealed with a microwave
vial cap and the reaction was heated in a microwave reactor at
120.degree. C. for 30 min. The reaction was then purified by
reverse phase chromatography to yield
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-3-yl)-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
trifluoroacetate (52 mg, 42% yield) as a tan solid. MS(ESI) m/z:
653.6 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
9.34-9.21 (m, 1H), 8.81-8.73 (m, 1H), 8.72-8.64 (m, 2H), 8.60 (s,
2H), 8.37 (s, 1H), 8.02-7.96 (m, 1H), 7.96-7.89 (m, 1H), 7.87-7.80
(m, 1H), 7.80-7.73 (m, 2H), 7.72-7.63 (m, 1H), 6.47-6.35 (m, 1H),
6.20-6.03 (m, 1H), 2.96-2.82 (m, 1H), 2.42-2.22 (m, 2H), 2.17-2.01
(m, 1H), 1.83-1.70 (m, 1H), 1.70-1.52 (m, 1H), 1.42-1.26 (m, 1H),
1.11 (d, J=7.0 Hz, 3H), 0.97-0.85 (m, 2H). Analytical HPLC (Method
A): RT=6.69 min, purity=97.5%; Factor XIa Ki=0.57 nM, Plasma
Kallikrein Ki=10 nM.
Example 217
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-3-(pyridin-3-yl)-3,4,7,15-tetraazatric-
yclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00391##
[1914]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-(pyridin-3-yl)-3,4,7,15-tetraa-
zatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate was
synthesized as a minor product (24 mg, 19% yield) from the reaction
to generate
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-3-yl)-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one,
Example 216. MS(ESI) m/z: 653.6 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 9.27-9.27 (m, 1H), 9.30-9.21 (m, 1H), 8.63 (s,
6H), 8.39 (s, 1H), 8.17-8.09 (m, 1H), 7.95-7.90 (m, 1H), 7.88-7.83
(m, 1H), 7.82-7.73 (m, 3H), 7.71-7.65 (m, 1H), 6.50-6.37 (m, 1H),
5.95-5.80 (m, 1H), 2.78-2.60 (m, 1H), 2.55-2.39 (m, 1H), 2.15-1.98
(m, 2H), 1.83-1.65 (m, 1H), 1.61-1.44 (m, 2H), 1.32 (d, J=7.0 Hz,
5H). Analytical HPLC (Method A): RT=6.45 min, purity=95%; Factor
XIa Ki=74 nM, Plasma Kallikrein Ki=600 nM.
Example 218
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00392##
[1915] 218A. Preparation of 4-nitro-1-phenyl-1H-pyrazole
[1916] To a 3-neck flask was added 4-nitro-1H-pyrazole (3.0 g, 26.5
mmol), phenylboronic acid (5.18 g, 42.4 mmol), NaOH (1.061 g, 26.5
mmol), CuCl.sub.2 (0.357 g, 2.65 mmol) and MeOH (25 mL). The above
reaction mixture was then refluxed overnight while bubbling air
through it. The solvent was then removed under vacuum and the crude
product was purified by silica gel chromatography to yield
4-nitro-1-phenyl-1H-pyrazole (3.5 g, 17.58 mmol, 66% yield) as a
white solid. MS(ESI) m/z: 190.1 [M+H].sup.+.
218B. Preparation of (S)-tert-butyl
(1-(4-(4-nitro-1-phenyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbam-
ate
[1917] To a N.sub.2 flushed, 500 mL RBF was added (S)-tert-butyl
(1-(4-chloropyridin-2-yl) but-3-en-1-yl)carbamate, prepared as
described in Intermediate 23, (2.5 g, 8.84 mmol),
4-nitro-1-phenyl-1H-pyrazole (1.67 g, 8.84 mmol) and dioxane (50
mL). The solution was bubbled with N.sub.2 for 5 min and
Pd(OAc).sub.2 (0.1 g, 0.442 mmol), di(adamantan-1-yl)(butyl)
phosphine (0.317 g, 0.884 mmol), K.sub.2CO.sub.3 (3.67 g, 26.5
mmol) and PvOH (0.271 g, 0.265 mmol) were added. The reaction
mixture was bubbled with N.sub.2 for 5 min, then heated to
100.degree. C. for 3 h. Water (200 mL) was added. The reaction
mixture was extracted with EtOAc (2.times.200 mL). The combined
organic extracts were washed with water (200 mL), brine (200 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated.
Purification by normal phase chromatography eluting with a gradient
of hexanes/EtOAc afforded (S)-tert-butyl
(1-(4-(4-nitro-1-phenyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbam-
ate (3.0 g, 6.54 mmol, 74% yield) as a slightly yellow oil. MS(ESI)
m/z: 436.5 [M+H].sup.+.
218C. Preparation of
(9R,13S)-13-amino-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[1918]
(9R,13S)-13-Amino-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.-
1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one was prepared
in the similar manner as described in Intermediate 30, by using
(S)-tert-butyl
(1-(4-(4-nitro-1-phenyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbam-
ate. (0.11 g, 0.34 mmol, 90% yield). MS(ESI) m/z: 362.5
[M+H].sup.+.
218D.
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-
-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-phenyl-3,4,7,15-tetraazatricycl-
o[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[1919]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-phenyl-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (0.024 g, 0.030 mmol, 33% yield) was prepared in a
similar manner as the procedures described in Example 56, by using
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(0.028 g, 0.091 mmol), prepared as described in Intermediate 9, and
(9R,13S)-13-amino-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0.su-
p.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.033 g, 0.091
mmol). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.81 (s, 1H), 8.39
(d, J=5.3 Hz, 1H), 8.32 (s, 1H), 7.87 (d, J=2.4 Hz, 2H), 7.76-7.68
(m, 2H), 7.65-7.60 (m, 1H), 7.51-7.38 (m, 5H), 6.66 (dd, J=5.1, 1.5
Hz, 1H), 6.37 (s, 1H), 6.02 (dd, J=12.7, 4.3 Hz, 1H), 3.34 (s, 1H),
2.76 (td, J=6.5, 3.1 Hz, 1H), 2.36-2.23 (m, 1H), 2.18-2.08 (m, 1H),
2.06-1.91 (m, 1H), 1.74-1.56 (m, 1H), 1.55-1.39 (m, 1H), 1.02 (d,
J=7.0 Hz, 3H), 0.65 (br. s., 1H). MS(ESI) m/z: 652.6 [M+H].sup.+.
Analytical HPLC (Method A): RT=9.41 min, purity=>95.0%; Factor
XIa Ki=83 nM, Plasma Kallikrein Ki=2,700 nM.
Example 219
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
pyridin-3-yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methy-
l-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-p-
entaen-8-one
##STR00393##
[1921]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]pyridin-3-yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-met-
hyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-
-pentaen-8-one (4 mg, 3% yield) as a solid was prepared in via the
coupling of
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin-3-yl}pyr-
imidin-4-ol (0.014 g, 0.04 mmol) and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6), 4,14,16-pentaen-8-one (0.014
g, 0.04 mmol) using the HATU, DBU coupling methodology as described
in Example 56. MS m/z=661.2 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 9.30-9.27 (m, 1H), 9.08-9.03 (m, 1H), 8.79 (s,
2H), 8.37-8.33 (m, 1H), 7.78-7.74 (m, 2H), 7.70-7.67 (m, 1H),
7.59-7.51 (m, 1H), 6.14-6.00 (m, 1H), 2.81-2.68 (m, 1H), 2.47-2.29
(m, 1H), 2.16-2.01 (m, 2H), 1.70-1.46 (m, 2H), 1.07-0.96 (d, 3H),
0.75-0.55 (m, 1.H). Analytical HPLC (Method A) RT=11.3 min,
purity=98%; Factor XIa Ki=35 nM, Plasma Kallikrein Ki=7,200 nM.
Example 220
Preparation of
(9R,13S)-13-(5-bromo-4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol--
1-yl]pyridin-3-yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-m-
ethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,-
16-pentaen-8-one
##STR00394##
[1923]
(9R,13S)-13-(5-Bromo-4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-tr-
iazol-1-yl]pyridin-3-yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethy-
l)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6)-
,4,14,16-pentaen-8-one was isolated as a by-product of Example 219
(3 mg, 9% yield) as a solid, via the coupling of
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin-3-yl}pyr-
imidin-4-ol containing
5-bromo-6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin--
3-yl}pyrimidin-4-ol (0.014 g, 0.04 mmol) and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6), 4,14,16-pentaen-8-one (0.014
g, 0.04 mmol) using the HATU, DBU coupling methodology as described
in Example 56. MS m/z=740.4 (M+H).sup.+. Analytical HPLC (Method A)
RT=12.2 min, purity=93%; Factor XIa Ki=250 nM, Plasma Kallikrein
Ki=7,000 nM.
Example 221
Preparation of
(9R,13S)-13-(4-{5-chloro-4-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-
-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-
-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pe-
ntaen-8-one
##STR00395##
[1925]
(9R,13S)-13-(4-{5-Chloro-4-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-t-
riazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,-
7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-
-8-one (4 mg, 15% yield) as a solid was prepared via the coupling
of
6-{5-chloro-4-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-
pyrimidin-4-ol (0.013 g, 0.036 mmol) and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6), 4,14,16-pentaen-8-one (0.012
g, 0.036 mmol) using the HATU, DBU coupling methodology as
previously described. MS m/z=678.1 (M+H). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.88-8.82 (m, 2H), 8.75-8.72 (m, 1H), 8.10-8.04
(m, 1H), 7.76 (s, 2H), 7.72-7.65 (m, 1H), 7.56-7.51 (m, 1H), 6.46
(s, 1H), 6.09-5.96 (m, 1H), 4.07-3.99 (m, 1H), 3.53-3.44 (m, 1H),
2.81-2.64 (m, 1H), 2.37-2.21 (m, 1H), 2.09-1.96 (m, 2H), 1.68-1.42
(m, 2H), 1.02 (d, J=7.0 Hz, 3H); Factor XIa Ki=4.7 nM, Plasma
Kallikrein Ki=1,300 nM.
Example 222
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3-phenyl-3,4,7,15-tetra-
azatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00396##
[1927]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3-phenyl-3,4,7,15-tet-
raazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (4.5 mg,
0.005 mmol, 6% yield) was prepared in a similar manner as the
procedures described in Example 56, by using
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol (0.031 g, 0.091 mmol), prepared as described in Intermediate
15, and
(9R,13S)-13-amino-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0.su-
p.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.033 g, 0.091
mmol), prepared as described in Example 218C. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.80 (d, J=0.9 Hz, 1H), 8.77 (s, 1H), 8.37 (d,
J=5.3 Hz, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.86 (s, 1H), 7.78-7.72 (m,
2H), 7.71-7.66 (m, 1H), 7.50-7.39 (m, 5H), 6.66 (dd, J=5.1, 1.5 Hz,
1H), 6.45 (d, J=0.7 Hz, 1H), 6.03 (dd, J=12.7, 4.3 Hz, 1H), 3.35
(s, 1H), 2.76 (td, J=6.6, 3.1 Hz, 1H), 2.27 (tt, J=12.7, 4.5 Hz,
1H), 2.18-2.06 (m, 1H), 2.05-1.92 (m, 1H), 1.70-1.55 (m, 1H),
1.54-1.41 (m, 1H), 1.03 (d, J=6.8 Hz, 3H), 0.66 (br. s., 1H).
MS(ESI) m/z: 686.6 [M+H].sup.+. Analytical HPLC (Method A):
RT=10.03 min, purity=>95.0%; Factor XIa Ki=48 nM, Plasma
Kallikrein Ki=3,700 nM.
Example 223
Preparation of
(9R,13S)-13-(4-{4,5-dichloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl-
]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4-
,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentae-
n-8-one
##STR00397##
[1929]
(9R,13S)-13-(4-{4,5-Dichloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazo-
l-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-meth-
yl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16--
pentaen-8-one (5 mg, 22% yield) as a solid was prepared via the
coupling of
6-{4,5-dichloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}py-
rimidin-4-ol (0.012 g, 0.03 mmol) and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.011 g,
0.03 mmol) using the HATU, DBU coupling methodology as described in
Example 56. MS m/z=694.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.88-8.83 (m, 2H), 8.75-8.71 (m, 1H), 8.10-8.08
(m, 1H), 8.02 (s, 1H), 7.76 (s, 1H), 7.72-7.69 (m, 1H), 7.56-7.51
(m, 1H), 6.47 (d, J=0.7 Hz, 1H), 6.08-6.00 (m, 1H), 2.80-2.63 (m,
1H), 2.36-2.16 (m, 1H), 2.11-1.96 (m, 2H), 1.67-1.42 (m, 2H),
1.06-0.95 (d, 3H), 0.71-0.53 (m, 1H). Analytical HPLC (Method A)
RT=13.3 min, purity=98%; Factor XIa Ki=11 nM, Plasma Kallikrein
Ki=4,500 nM.
Example 224
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1-methyl-1H-imidazol-5-yl)-3,4,7,15-
-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
##STR00398##
[1931]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1-methyl-1H-imidazol-5-yl)-3,-
4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen--
8-one (21 mg, 18%) as a peach solid was prepared in a similar
manner as the procedure described in Example 216, by using
5-iodo-1-methyl-1H-imidazole. MS(ESI) m/z: 656.2 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.06-9.01 (m, 1H),
8.82-8.77 (m, 1H), 8.70-8.65 (m, 1H), 8.37 (s, 1H), 8.22-8.20 (m,
1H), 7.99-7.97 (m, 1H), 7.97-7.94 (m, 1H), 7.93-7.90 (m, 1H),
7.79-7.74 (m, 1H), 7.70-7.66 (m, 1H), 7.66-7.62 (m, 1H), 6.42-6.38
(m, 1H), 6.17-6.06 (m, 1H), 3.98 (s, 3H), 2.94-2.83 (m, 1H),
2.39-2.22 (m, 2H), 2.12-2.00 (m, 1H), 1.81-1.69 (m, 1H), 1.68-1.54
(m, 1H), 1.13-1.05 (m, 3H), 0.87-0.74 (m, 1H). Analytical HPLC
(Method A): RT=5.81 min, purity=91%; Factor XIa Ki=4.5 nM, Plasma
Kallikrein Ki=220 nM.
Example 225
Preparation of
4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}-N-(2,2,2-trifluoroethyl)benzamide
##STR00399##
[1932] 225A. Preparation of
4-chloro-2-(6-methoxypyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)
benzamide
[1933] To a RBF was added
4-chloro-2-(6-methoxypyrimidin-4-yl)benzoic acid (0.374 g, 1.413
mmol), prepared as described in Example 168B, EtOAc (7.07 ml),
2,2,2-CF.sub.3CH.sub.2NH.sub.2 (0.14 g, 1.413 mmol), and pyridine
(0.229 ml, 2.83 mmol). The solution was cooled in a MeOH/ice bath
and 50% w/w
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide
in EtOAc (1.26 ml, 2.120 mmol) was added. The reaction was allowed
to warm to rt. After 18 h, the reaction was diluted with EtOAc,
washed with sat NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. DCM (.about.10 ml) was added, plus a
few drops of MeOH to afford a yellow suspension. The solid was
filtered off, and the filtrate was purified by normal phase
chromatography to afford
4-chloro-2-(6-methoxypyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)benzamide
(0.155 g, 32% yield) as a white solid. MS(ESI) m/z: 346.4
(M+H).sup.+.
225B. Preparation of
4-chloro-2-(6-hydroxypyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)
benzamide
[1934] To a solution of
4-chloro-2-(6-methoxypyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)
benzamide (0.05 g, 0.145 mmol) in ACN (0.96 ml) was added TMSI
(0.118 ml, 0.868 mmol). The reaction was heated to 50.degree. C.
After 6 h, the reaction was cooled to rt, poured into a 10% aq
Na.sub.2S.sub.2O.sub.3, and extracted with EtOAc (3.times.). The
combined organic layers were washed with sat NaHCO.sub.3, brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated.
Purification by normal phase chromatography afforded
4-chloro-2-(6-hydroxypyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)benzamide
(0.02 g, 42% yield) as a white solid. MS(ESI) m/z: 332.3
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.14 (d,
J=0.9 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.59-7.55 (m, 1H), 7.54-7.49
(m, 1H), 6.63 (d, J=0.9 Hz, 1H), 3.98 (q, J=9.5 Hz, 2H). .sup.19F
NMR (376 MHz, CD.sub.3OD) .delta. -73.22 (s).
225C. Preparation of
4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydrop-
yrimidin-4-yl}-N-(2,2,2-trifluoroethyl)benzamide
trifluoroacetate
[1935]
4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricycl-
o[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-y-
l}-N-(2,2,2-trifluoroethyl)benzamide trifluoroacetate (4.8 mg, 11%
yield) was prepared in a similar manner as the procedure described
in Example 56, by replacing
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol with
4-chloro-2-(6-hydroxypyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)be-
nzamide (0.02 g, 0.060 mmol). MS(ESI) m/z: 614.5 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.95 (s, 1H), 8.73 (d,
J=5.3 Hz, 1H), 7.72-7.71 (m, 2H), 7.59-7.55 (m, 1H), 7.54-7.48 (m,
3H), 6.66 (s, 1H), 6.05 (dd, J=12.5, 4.2 Hz, 1H), 4.08-3.90 (m,
5H), 2.76-2.67 (m, 1H), 2.39-2.28 (m, 1H), 2.15-1.98 (m, 2H),
1.68-1.42 (m, 2H), 1.01 (d, J=7.0 Hz, 3H), 0.79-0.62 (m, 1H).
.sup.19F NMR (376 MHz, CD.sub.3OD) .delta. -73.10 (s), -77.67 (s).
Analytical HPLC (Method A): RT=6.78 min, 98.2% purity; Factor XIa
Ki=23 nM, Plasma Kallikrein Ki=3,400 nM.
Example 226
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0-
.sup.2,6] octadeca-1(18),2(6),3,14,16-pentaen-8-one
##STR00400##
[1936] 226A. Preparation of
N-[(1S)-1-[4-(5-amino-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]but-3-en-1-yl-
]carbamate
[1937] In a microwave vial was added
(S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronic
acid (500 mg, 1.712 mmol), 4-bromo-1-methyl-1H-pyrazol-5-amine (301
mg, 1.712 mmol), (DtBPF)PdCl.sub.2 (55.8 mg, 0.086 mmol), 3 M
K.sub.3PO.sub.4 (1.712 mL, 5.13 mmol), and THF (18 mL). The
reaction mixture was purged with Ar (3.times.), then heated at
130.degree. C. in a microwave for 30 min The reaction mixture was
then cooled to rt, diluted with EtOAc and washed with brine
(2.times.15 mL). The crude product was then subjected to silica gel
chromatography to yield
N-[(1S)-1-[4-(5-amino-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]but-3-en-1-yl-
]carbamate (0.5 g, 1.383 mmol, 81% yield). MS(ESI) m/z: 344.5
(M+H).sup.+.
226B. Preparation of
(9R,13S)-13-amino-5,9-dimethyl-4,5,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),3,14,16-pentaen-8-one
[1938]
(9R,13S)-13-Amino-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0.s-
up.2,6]octadeca-1(18),2(6),3,14,16-pentaen-8-one (83 mg, 0.263
mmol, 88% yield) was prepared in a similar manner as the procedure
described in Intermediate 32, by replacing Intermediate 32C with
N-[(1S)-1-[4-(5-amino-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]but-3-en-1-yl-
]carbamate and continuing through the rest of the sequence as
described in the preparation of Intermediate 32.
226C. Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-5,9-dimethyl-4,5,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),3,14,16-pentaen-8-one
trifluoroacetate
[1939]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12-
.3.1.0.sup.2,6]octadeca-1(18),2(6),3,14,16-pentaen-8-one
trifluoroacetate (24 mg, 0.032 mmol, 34% yield) was prepared in a
similar manner as the procedure described in Example 56 by using
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(28.8 mg, 0.094 mmol), prepared as described in Intermediate 9, and
(9R,13S)-13-amino-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),3,14,16-pentaen-8-one (28.0 mg, 0.094 mmol).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.56 (d, J=5.7 Hz, 2H),
8.37 (s, 1H), 8.05 (br. s., 1H), 7.95 (br. s., 1H), 7.89 (d, J=2.4
Hz, 1H), 7.78-7.71 (m, 1H), 7.69-7.61 (m, 2H), 6.40 (s, 1H), 5.94
(br. s., 1H), 3.82 (s, 3H), 2.88 (d, J=18.3 Hz, 1H), 2.36 (br. s.,
1H), 2.29-2.07 (m, 2H), 1.76 (d, J=7.3 Hz, 1H), 1.55 (br. s., 1H),
1.15 (br. s., 3H), 1.00 (br. s., 1H). MS(ESI) m/z: 590.5
[M+H].sup.+. Analytical HPLC (Method A): RT=7.04 min,
purity=>95.0%; Factor XIa Ki=106 nM.
Example 227
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-5,9-dimethyl-4,5,7,15-tetraazatr-
icyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),3,14,16-pentaen-8-one
##STR00401##
[1941]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-5,9-dimethyl-4,5,7,15-tetraaza-
tricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),3,14,16-pentaen-8-one trifluoroacetate (21 mg,
0.027 mmol, 29% yield) was prepared in a similar manner as the
procedure described in Example 226 by replacing
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
with
6-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-
-4-ol (32.0 mg, 0.094 mmol), prepared as described in Intermediate
15. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.84 (s, 1H),
8.55-8.42 (m, 2H), 8.02 (br. s., 1H), 7.97-7.86 (m, 2H), 7.78-7.71
(m, 1H), 7.70-7.59 (m, 2H), 6.44 (s, 1H), 5.93 (br. s., 1H), 3.79
(s, 3H), 2.99-2.81 (m, 1H), 2.32 (br. s., 1H), 2.26-2.04 (m, 2H),
1.73 (d, J=7.3 Hz, 1H), 1.52 (br. s., 1H), 1.26-1.07 (m, 3H), 0.99
(br. s., 1H). MS(ESI) m/z: 624.5 [M+H].sup.+. Analytical HPLC
(Method A): RT=7.83 min, purity=>95.0%; Factor XIa Ki=97 nM.
Example 228
Preparation of
(9R,13S)-13-[4-(1-benzyl-5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrim-
idin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00402##
[1942] 228A. Preparation of
6-(1-benzyl-5-chloro-1H-indazol-7-yl)pyrimidin-4-ol
[1943] 6-(1-Benzyl-5-chloro-1H-indazol-7-yl)pyrimidin-4-ol (32 mg,
32%) was prepared in a similar manner as Intermediate 22 by
replacing MeI with BnBr. MS(ESI) m/z: 337 (M+H).sup.+ and 339
(M+2+H).sup.+.
228B. Preparation of
(9R,13S)-13-[4-(1-benzyl-5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrim-
idin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[1944]
(9R,13S)-13-[4-(1-Benzyl-5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydr-
opyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.-
3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (4 mg, 9.7%) was prepared in a similar manner as
Example 56 using
6-(1-benzyl-5-chloro-1H-indazol-7-yl)pyrimidin-4-ol and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one,
prepared as described in Intermediate 30. MS(ESI) m/z: 655
(M+H).sup.+ and 657 (M+2+H).sup.+. .sup.1H NMR (400 MHz,
methanol-d.sub.4) d 8.99 (s, 1H), 8.69 (d, J=5.1 Hz, 1H), 8.47-8.39
(m, 1H), 8.28 (d, J=2.0 Hz, 1H), 8.11 (s, 1H), 7.89-7.82 (m, 1H),
7.72 (d, J=13.6 Hz, 2H), 7.41 (d, J=5.1 Hz, 1H), 7.35-7.21 (m, 4H),
6.05-5.94 (m, 1H), 5.65 (s, 2H), 2.65 (d, J=6.2 Hz, 1H), 2.40-2.30
(m, 1H), 2.07-1.92 (m, 2H), 1.56-1.33 (m, 3H), 0.90 (d, J=7.0 Hz,
3H), 0.53 (br. s., 1H). Analytical HPLC (Method A): RT=10.76 min,
purity=>95%; Factor XIa Ki=110 nM.
Example 229
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-5-methyl-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0-
.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00403##
[1945] 229A. Preparation of
6-(5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methylp-
yrimidin-4-ol
[1946]
6-(5-Chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-m-
ethylpyrimidin-4-ol (53 mg, 50% yield) was prepared in a similar
manner as the procedure described in Intermediate 18C, by replacing
1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbon-
itrile with
4-(5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-
-5-methylpyrimidine (0.110 g, 0.294 mmol). MS(ESI) m/z: 560.4
(M+H).sup.+.
229B. Preparation of
6-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin-4-ol
[1947] To a solution of
6-(5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methylp-
yrimidin-4-ol (53 mg, 0.147 mmol) in THF (5 mL) was added 1 M TBAF
in THF (0.162 mL, 0.162 mmol) at rt. After 3 h, the solution was
concentrated and partitioned between EtOAc and water and the layers
were separated. The aqueous layer was extracted with EtOAc
(2.times.). The combined organic layer was concentrated and then
purified by normal phase chromatography to give
6-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin-4-ol
(14 mg, 33% yield) as an orange glass. MS(ESI) m/z: 288.4
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.02 (s,
1H), 7.71 (d, J=0.9 Hz, 1H), 7.64-7.58 (m, 3H), 7.51 (t, J=1.3 Hz,
1H), 1.76 (s, 3H).
229C. Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-5-methyl-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[1948]
(9R,13S)-13-{4-[5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-5-methyl--
6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12-
.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (13 mg, 37% yield) was prepared in a similar
manner as the procedure described in Example 56, by replacing
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol with
6-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin--
4-ol (0.014 g, 0.049 mmol). MS(ESI) m/z: 570.1 (M+H).sup.+. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta.8.89 (s, 1H), 8.76 (d, J=5.5 Hz,
1H), 8.17 (d, J=0.9 Hz, 1H), 7.84 (s, 1H), 7.80-7.71 (m, 3H),
7.70-7.64 (m, 2H), 7.51 (s, 1H), 5.93 (dd, J=12.5, 4.2 Hz, 1H),
4.07 (s, 3H), 2.70 (td, J=6.8, 3.3 Hz, 1H), 2.36 (ddt, J=12.6, 8.4,
4.3 Hz, 1H), 2.14-2.00 (m, 2H), 1.69 (s, 3H), 1.66-1.55 (m, 1H),
1.53-1.39 (m, 1H), 1.03 (d, J=7.0 Hz, 3H), 0.79 (m, 1H). Analytical
HPLC (Method A): RT=6.51 min, purity=99%; Factor XIa Ki=63 nM,
Plasma Kallikrein Ki=2,200 nM.
Example 230
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-pyrazol-3-yl)phenyl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2-
,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00404##
[1950]
(9R,13S)-13-{4-[5-Chloro-2-(1-methyl-1H-pyrazol-3-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
(1.14 mg, 7% yield) was prepared in a similar manner as the
procedure described in Example 49, by replacing
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
with
1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(7.61 mg, 0.037 mmol). MS(ESI) m/z: 569.5 (M+H).sup.+. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.91 (s, 1H), 8.71 (d, J=5.1 Hz, 1H),
7.87 (d, J=2.2 Hz, 1H), 7.67 (s, 1H), 7.61 (dd, J=8.3, 2.3 Hz, 1H),
7.52-7.47 (m, 2H), 7.46-7.42 (m, 2H), 6.26 (d, J=2.0 Hz, 1H), 6.13
(s, 1H), 6.00-5.92 (m, 1H), 4.04 (s, 3H), 3.50 (s, 3H), 2.75-2.66
(m, 1H), 2.35-2.24 (m, 1H), 2.13-1.94 (m, 2H), 1.65-1.42 (m, 2H),
1.00 (d, J=6.8 Hz, 3H), 0.76-0.60 (m, 1H). Analytical HPLC (Method
A): RT=7.34 min, 98.4% purity; Factor XIa Ki=800 nM.
Example 231
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyr-
imidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octad-
eca-1(18),2(6),4,14,16-pentaen-8-one
##STR00405##
[1952] To the solution of 1H-imidazole (8.86 mg, 0.130 mmol) and
(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-
,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6)-
,4,14,16-pentaen-8-one trifluoroacetate (0.02 g, 0.033 mmol),
prepared as described in Example 211, in DMSO (1 ml) was added CuI
(0.62 mg, 3.25 .mu.mol), L-proline (0.75 mg, 6.51 .mu.mol), and
K.sub.2CO.sub.3 (0.013 g, 0.098 mmol). The reaction was heated at
80.degree. C. for 3 h and cooled to rt. Purification by reverse
phase chromatography afforded
(9R,13S)-13-{4-[5-chloro-2-(1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyr-
imidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (11 mg,
43% yield) as a yellow solid. MS(ESI) m/z: 555.5 (M+H).sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 9.19 (s, 1H), 8.77-8.67
(m, 2H), 7.92 (d, J=2.5 Hz, 1H), 7.81-7.75 (m, 1H), 7.73-7.64 (m,
4H), 7.54-7.48 (m, 2H), 6.62 (s, 1H), 6.00-5.91 (m, 1H), 4.04 (s,
3H), 2.74-2.64 (m, 1H), 2.32-2.21 (m, 1H), 2.11-1.92 (m, 2H),
1.64-1.39 (m, 2H), 1.01 (d, J=6.9 Hz, 3H), 0.79-0.63 (m, 1H).
Analytical HPLC (Method A): RT=4.41 min, 99.9% purity; Factor XIa
Ki=23 nM, Plasma Kallikrein Ki=1,100 nM.
Example 232
Preparation of
(9R,13S)-13-[4-(5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl-
]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]o-
ctadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00406##
[1953] 232A. Preparation of
6-(5-chloro-1H-indazol-7-yl)pyrimidin-4-ol
[1954] 6-(5-Chloro-1H-indazol-7-yl)pyrimidin-4-ol (13.8 mg, 17%)
was prepared in a similar manner to Example 207C starting from
7-bromo-5-chloro-1H-indazole instead of
4-bromo-6-chloro-1H-benzo[d]imidazole. MS(ESI) m/z: 247 (M+H).sup.+
and 249 (M+2+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.41 (d, J=0.9 Hz, 1H), 8.15 (s, 1H), 8.02 (d, J=1.8 Hz, 1H), 7.99
(d, J=1.8 Hz, 1H), 7.14 (d, J=0.7 Hz, 1H).
232B. Preparation of
(9R,13S)-13-[4-(5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl-
]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
[1955]
(9R,13S)-13-[4-(5-Chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidi-
n-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (5
mg, 13%) was prepared in a similar manner as Example 56 using
6-(5-chloro-1H-indazol-7-yl)pyrimidin-4-ol and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one, prepared
as described in Intermediate 30. MS(ESI) m/z: 565 (M+H).sup.+ and
567 (M+2+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
13.40 (br. s., 1H), 9.37 (s, 1H), 9.00 (s, 1H), 8.70 (d, J=5.1 Hz,
1H), 8.14 (br. s., 1H), 8.07-8.02 (m, 1H), 7.98 (d, J=1.5 Hz, 1H),
7.93-7.74 (m, 2H), 7.69 (s, 1H), 7.38 (d, J=5.1 Hz, 1H), 7.19 (br.
s., 1H), 5.93 (d, J=9.5 Hz, 1H), 2.65-2.60 (m, 1H), 2.26 (d, J=1.8
Hz, 1H), 2.06-1.91 (m, 2H), 1.49-1.30 (m, 2H), 0.83 (d, J=6.8 Hz,
3H), 0.35 (br. s., 1H). Analytical HPLC (Method A): RT=11.43 min,
purity=>95%; Factor XIa Ki=110 nM, Plasma Kallikrein Ki=4,300
nM.
Example 233
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-4-(6-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tet-
raazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
##STR00407##
[1957]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-4-(6-methoxypyridin-3-yl)-9-methyl-3,4,7,-
15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one was
prepared in a similar manner as the procedure described in Example
216, by using 5-iodo-2-methoxypyridine to give
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-4-(6-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tet-
raazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
trifluoroacetate as a brown solid (12 mg, 23%). MS(ESI) m/z: 683.5
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.74-8.69
(m, 1H), 8.68-8.62 (m, 2H), 8.36 (d, J=7.4 Hz, 2H), 8.21-8.14 (m,
1H), 8.02-7.97 (m, 1H), 7.92 (d, J=2.2 Hz, 1H), 7.75 (d, J=2.5 Hz,
2H), 7.67 (d, J=8.5 Hz, 1H), 7.01-6.94 (m, 1H), 6.41 (d, J=0.8 Hz,
1H), 6.13-6.03 (m, 1H), 4.00 (s, 3H), 2.90-2.81 (m, 1H), 2.38-2.22
(m, 2H), 2.05 (s, 1H), 1.81-1.69 (m, 1H), 1.64-1.52 (m, 1H),
1.40-1.28 (m, 1H), 1.11 (d, J=6.9 Hz, 3H). Analytical HPLC (Method
A): RT=9.08 min, purity=95%; Factor XIa Ki=1.1 nM, Plasma
Kallikrein Ki=16 nM.
Example 234
Preparation of
(10R,14S)-3-chloro-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-5,
8-diazatricyclo[13.3.1.0.sup.2,7]
nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
##STR00408##
[1959]
(10R,14S)-3-Chloro-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-y-
l)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-5,
8-diazatricyclo[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-o-
ne trifluoroacetate (0.0069 g, 44%) was prepared according to the
procedures described in Example 206 by using
(10R,14S)-14-amino-3-chloro-10-methyl-5,8-diazatricyclo[13.3.1.0.sup.2,7]-
nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one, prepared as described
in Intermediate 38, by replacing 2-bromopyridin-3-amine with
4-bromo-5-chloropyridin-3-amine in Intermediate 38B. MS(ESI) m/z:
620.1 (M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD, 60.degree. C.)
.delta. 9.00 (s, 1H), 8.75 (s, 1H), 8.71-8.60 (m, 1H), 8.56 (s,
1H), 8.16 (d, J=2.5 Hz, 1H), 8.03 (dd, J=8.4, 2.3 Hz, 1H),
7.97-7.82 (m, 4H), 7.73 (br. s., 1H), 6.70 (s, 1H), 6.04 (dd,
J=12.8, 3.2 Hz, 1H), 2.73-2.55 (m, 2H), 2.52-2.41 (m, 1H), 2.00 (d,
J=9.1 Hz, 2H), 1.85-1.58 (m, 1H), 1.47 (d, J=6.6 Hz, 3H), 1.45-1.23
(m, 1H). Analytical HPLC (Method A): RT=9.14 min, purity>99%;
Factor XIa Ki=0.29 nM, Plasma Kallikrein Ki=80 nM.
Example 235
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyri-
midin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octade-
ca-1(18),2(6),4,14,16-pentaen-8-one
##STR00409##
[1961]
(9R,13S)-13-{4-[5-Chloro-2-(1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihyd-
ropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]-
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (2.97
mg, 14% yield) was prepared in a similar manner as the procedure
described in Example 49, by replacing
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
with tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate
(14.35 mg, 0.049 mmol). MS(ESI) m/z: 555.5 (M+H).sup.+. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.97 (s, 1H), 8.75 (d, J=5.1 Hz, 1H),
7.70 (s, 1H), 7.57-7.47 (m, 7H), 6.37 (s, 1H), 6.02 (dd, J=12.5,
4.4 Hz, 1H), 4.05 (s, 3H), 2.76-2.67 (m, 1H), 2.39-2.28 (m, 1H),
2.15-1.98 (m, 2H), 1.67-1.43 (m, 2H), 1.01 (d, J=7.0 Hz, 3H),
0.80-0.63 (m, 1H). Analytical HPLC (Method A): RT=6.50 min, 99.7%
purity; Factor XIa Ki=14 nM, Plasma Kallikrein Ki=550 nM.
Example 236
Preparation of
N-benzyl-4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-
-dihydropyrimidin-4-yl}benzamide
##STR00410##
[1963] To a cooled (0.degree. C.) solution of phenylmethanamine
(0.081 ml, 0.741 mmol) in DCE (1.48 ml) was added dropwise a 2.0 M
Al(Me).sub.3 in hexane (0.36 ml, 0.72 mmol). A white plume of gas
formed above the reaction mixture. Gas evolution was observed in
the solution. The resulting clear solution was stirred at 0.degree.
C. for 15 min, and then warmed to rt for 2 h. Next a solution of
methyl
4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydrop-
yrimidin-4-yl}benzoate (0.049 g, 0.074 mmol), prepared as described
in Example 168, in DCE (1 ml) was added and the resulting clear,
yellow reaction was heated to 40.degree. C. After 5 h, the reaction
was cooled to rt and the reaction was added to a cold (0.degree.
C.), vigorously stirred suspension of DCM/sat Rochelle's salt. The
biphasic mixture was stirred for 10-15 min and then the layers were
separated. The aqueous layer was extracted with DCM. The combined
organic layers were washed with 1.0 N HCl, brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. Purification by
reverse phase chromatography afforded
N-benzyl-4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-
-dihydropyrimidin-4-yl}benzamide trifluoroacetate (6 mg, 11% yield)
as a yellow solid. MS(ESI) m/z: 622.6 (M+H).sup.+. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.80 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 7.72
(s, 1H), 7.69 (s, 1H), 7.55-7.49 (m, 4H), 7.34-7.15 (m, 5H), 6.66
(s, 1H), 6.02 (dd, J=12.5, 4.2 Hz, 1H), 4.51-4.39 (m, 2H), 4.05 (s,
3H), 2.78-2.67 (m, 1H), 2.34-2.21 (m, 1H), 2.16-2.05 (m, 1H),
2.03-1.92 (m, 1H), 1.69-1.42 (m, 2H), 1.02 (d, J=6.8 Hz, 3H),
0.77-0.59 (m, 1H). Analytical HPLC (Method A): RT=7.27 min, 97.9%
purity; Factor XIa Ki=23 nM, Plasma Kallikrein Ki=1,600 nM.
Example 237
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-2-yl)-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
##STR00411##
[1965]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-2-yl)-3,4,7,15-tetraa-
zatricyclo[12.3.1.0.sup.2,6] octadeca-1(18),2,5,14,16-pentaen-8-one
was prepared in a similar manner as the procedure described in
Example 216, by using 2-iodopyridine to give
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-2-yl)-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
trifluoroacetate (44 mg, 47%). MS(ESI) m/z: 653.5 (M+H).sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.56-9.54 (m, 1H), 9.54
(s, 1H), 8.80 (s, 1H), 8.73-8.73 (m, 1H), 8.75 (s, 1H), 8.68 (s,
1H), 8.64 (d, J=5.2 Hz, 1H), 8.53 (d, J=4.9 Hz, 1H), 8.12-8.02 (m,
2H), 8.00-7.90 (m, 2H), 7.88-7.81 (m, 1H), 7.81-7.72 (m, 1H), 7.63
(dd, J=5.0, 1.1 Hz, 1H), 7.49-7.39 (m, 1H), 6.39 (s, 1H), 6.12-5.95
(m, 1H), 2.88-2.73 (m, 1H), 2.40-2.22 (m, 2H), 1.92-1.78 (m, 1H),
1.64-1.51 (m, 1H), 1.50-1.37 (m, 1H), 0.95 (d, J=6.7 Hz, 3H),
0.65-0.40 (m, 1H). Analytical HPLC (Method C): RT=1.75 min,
purity=100%; Factor XIa Ki=8 nM, Plasma Kallikrein Ki=150 nM.
Example 238
Preparation of
1-(4-chloro-3-fluoro-2-{1-[(9R,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-ox-
o-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-p-
entaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carbon-
itrile
##STR00412##
[1966] 238A. Preparation of
4-(3-chloro-2-fluoro-6-iodophenyl)-6-methoxypyrimidine
[1967] To a suspension of
4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (2 g, 7.88
mmol) in CH.sub.3CN (90 ml) at 0.degree. C. was added
pTsOH.H.sub.2O (3.75 g, 19.71 mmol) followed by the dropwise
addition of a solution of NaNO.sub.2 (1.088 g, 15.77 mmol) and NaI
(2.95 g, 19.71 mmol) in water (22.5 ml). The reaction was allowed
to warm to rt and stir overnight. The reaction was quenched with
sat NaHCO.sub.3, and extracted with EtOAc. The organic layer was
washed with sat Na.sub.2S.sub.2O.sub.3, brine, dried with
MgSO.sub.4, filtered, and concentrated. Purification by normal
phase chromatography gave
4-(3-chloro-2-fluoro-6-iodophenyl)-6-methoxypyrimidine (2.18 g, 76%
yield) as viscous, yellow oil. MS(ESI) m/z: 365.1 (M+H).sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.92 (d, J=0.9 Hz, 1H),
7.68 (dd, J=8.4, 1.5 Hz, 1H), 7.20 (dd, J=8.5, 7.4 Hz, 1H), 6.78
(s, 1H), 4.07 (s, 3H).
238B. Preparation of
6-(3-chloro-2-fluoro-6-iodophenyl)pyrimidin-4-ol
[1968] To a suspension of
4-(3-chloro-2-fluoro-6-iodophenyl)-6-methoxypyrimidine (0.22 g,
0.603 mmol) in ACN (6.03 ml) was added TMSI (0.411 ml, 3.02 mmol).
The resulting clear, yellow solution was heated to 50.degree. C.
for 15 h. Additional TMSI (0.4 ml) was added and the reaction was
heated 50.degree. C. for 7 h. The reaction was poured into a 10%
Na.sub.2S.sub.2O.sub.3 and sat NaHCO.sub.3, extracted with EtOAc
(2.times.), and a mixture of DCM and MeOH. The organic layers were
combined and concentrated. Purification by normal phase
chromatography gave
6-(3-chloro-2-fluoro-6-iodophenyl)pyrimidin-4-ol (190 mg, 90%
yield) as a yellow glass. MS(ESI) m/z: 351.1 (M+H).sup.+. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.33 (d, J=1.1 Hz, 1H), 7.77 (dd,
J=8.6, 1.5 Hz, 1H), 7.34 (dd, J=8.6, 7.5 Hz, 1H), 6.51 (d, J=0.9
Hz, 1H), 4.85 (br. s., 1H).
238C. Preparation of
1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-pyrazole-4-car-
bonitrile
[1969] To a suspension of 1H-pyrazole-4-carbonitrile (50.5 mg,
0.542 mmol), K.sub.3PO.sub.4 (233 mg, 1.084 mmol) and
6-(3-chloro-2-fluoro-6-iodophenyl)pyrimidin-4-ol (190 mg, 0.542
mmol) in dioxane (0.24 mL) was added
(1R,2R)--N1,N2-dimethylcyclohexane-1,2-diamine (38.6 mg, 0.271
mmol). The vial was then purged with Ar, CuI (5.16 mg, 0.027 mmol)
was added, and the vial was sealed. The reaction mixture was heated
at 80.degree. C. After 16 h, the reaction was cooled to rt,
filtered, and the filtrate was concentrated. Purification by
reverse phase chromatography gave
1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-pyrazole-4-car-
bonitrile (74 mg, 43% yield) as an off-white solid. MS(ESI) m/z:
316.3 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.54
(s, 1H), 8.09 (d, J=0.9 Hz, 1H), 7.97 (s, 1H), 7.80 (dd, J=8.7, 7.8
Hz, 1H), 7.50 (dd, J=8.7, 1.7 Hz, 1H), 6.51 (t, J=1.1 Hz, 1H).
238D. Preparation of
1-(4-chloro-3-fluoro-2-{1-[(9R,13S)-3-(.sup.2H.sub.3)methyl-9-methyl-8-ox-
o-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-p-
entaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carbon-
itrile, trifluoroacetate
[1970]
1-(4-Chloro-3-fluoro-2-{1-[(9R,13S)-3-(.sup.2H.sub.3)methyl-9-methy-
l-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,1-
4,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazole-4--
carbonitrile trifluoroacetate (9.5 mg, 41% yield) was prepared in a
similar manner as the procedure described in Example 56, by using
1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-pyrazole-4-car-
bonitrile (10 mg, 0.032 mmol) and
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,15-tetraazatricy-
clo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(9.58 mg, 0.032 mmol), prepared as described in Intermediate 33.
MS(ESI) m/z: 601.0 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.81 (s, 1H), 8.76 (d, J=5.1 Hz, 1H), 8.46 (s, 1H), 7.94
(s, 1H), 7.80 (dd, J=8.6, 7.7 Hz, 1H), 7.69 (s, 1H), 7.55-7.48 (m,
3H), 6.54 (s, 1H), 6.00 (dd, J=13.0, 4.2 Hz, 1H), 2.70 (dt, J=6.7,
3.2 Hz, 1H), 2.36-2.25 (m, 1H), 2.15-1.95 (m, 2H), 1.67-1.55 (m,
1H), 1.55-1.41 (m, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.72 (m., 1H).
Analytical HPLC (Method A): RT=7.58 min, purity=98.5%; Factor XIa
Ki=2.4 nM, Plasma Kallikrein Ki=1,500 nM.
Example 239
Preparation of
1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tet-
raazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]--
6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-pyrazole-4-carbonitril-
e
##STR00413##
[1972]
1-(4-Chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,-
15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-1-
3-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-pyrazole-4-carbo-
nitrile was prepared in a similar manner as the procedure described
in Example 238, by replacing
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,15-tetraazatricy-
clo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one,
prepared as described in Intermediate 33, with
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one (10.62
mg, 0.032 mmol), prepared as described in Example 30G. MS(ESI) m/z:
634.0 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.86
(s, 1H), 8.78 (d, J=5.1 Hz, 1H), 8.47 (s, 1H), 7.94 (s, 1H),
7.83-7.77 (m, 1H), 7.74 (s, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 7.52
(dd, J=8.7, 1.4 Hz, 2H), 6.55 (s, 1H), 6.01 (dd, J=12.7, 4.1 Hz,
1H), 2.76-2.65 (m, 1H), 2.31 (t, J=13.0 Hz, 1H), 2.10-1.95 (m, 2H),
1.65-1.42 (m, 2H), 1.00 (d, J=7.0 Hz, 3H), 0.67 (m., 1H).
Analytical HPLC (Method A): SunFire, RT=8.75 min, 98.8% purity;
Factor XIa Ki=1.0 nM, Plasma Kallikrein Ki=1,100 nM.
Example 240
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1-propyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2-
,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00414##
[1974]
(9R,13S)-13-{4-[5-Chloro-2-(1-propyl-1H-pyrazol-4-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
(14.3 mg, 62% yield) was prepared in a similar manner as the
procedure described in Example 49, by replacing
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
with
1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(11.52 mg, 0.049 mmol). MS(ESI) m/z: 597.4 (M+H).sup.+. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 9.01 (s, 1H), 8.75 (d, J=5.1 Hz, 1H),
7.74 (s, 1H), 7.58-7.52 (m, 3H), 7.50-7.47 (m, 3H), 7.42 (s, 1H),
6.40 (d, J=0.4 Hz, 1H), 6.02 (dd, J=12.7, 4.3 Hz, 1H), 4.07-4.01
(m, 5H), 2.76-2.67 (m, 1H), 2.40-2.29 (m, 1H), 2.13-2.00 (m, 2H),
1.77 (sxt, J=7.2 Hz, 2H), 1.67-1.43 (m, 2H), 1.02 (d, J=6.8 Hz,
3H), 0.79 (t, J=7.4 Hz, 3H), 0.75-0.66 (m, 1H). Analytical HPLC
(Method A): RT=8.12 min, 100% purity; Factor XIa Ki=35 nM, Plasma
Kallikrein Ki=3,800 nM.
Example 241
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-4-yl)-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
##STR00415##
[1976]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-4-yl)-3,4,7,15-tetraa-
zatricyclo[12.3.1.0.sup.2,6] octadeca-1(18),2,5,14,16-pentaen-8-one
was prepared in a similar manner as the procedure described in
Example 216, by using 4-iodopyridine to give
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-4-yl)-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
trifluoroacetate (29 mg, 30% yield). MS(ESI) m/z: 653.6
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.57 (s,
1H), 8.86 (s, 1H), 8.72 (s, 1H), 8.67 (s, 1H), 8.58 (d, J=4.9 Hz,
1H), 8.04 (br. s., 2H), 7.91-7.82 (m, 2H), 7.80-7.73 (m, 1H),
7.73-7.65 (m, 1H), 7.57 (d, J=5.2 Hz, 1H), 6.31 (s, 1H), 6.01-5.87
(m, 1H), 2.80-2.67 (m, 1H), 2.22 (d, J=7.3 Hz, 2H), 1.80 (br. s.,
1H), 1.59-1.45 (m, 1H), 1.44-1.29 (m, 1H), 0.87 (d, J=7.0 Hz, 3H),
0.59-0.36 (m, 1H). Analytical HPLC (Method C): RT=1.42 min,
purity=98%; Factor XIa Ki=0.58 nM, Plasma Kallikrein Ki=20 nM.
Example 242
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-3-(pyridin-4-yl)-3,4,7,15-tetraazatric-
yclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00416##
[1978]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-(pyridin-4-yl)-3,4,7,15-tetraa-
zatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one was synthesized as a
minor product (2 mg, 2.4%) from the reaction to generate
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-4-yl)-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one,
Example 241. MS(ESI) m/z: 653.6 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.98 (br. s., 1H), 8.74 (br. s., 2H), 8.65
(br. s., 3H), 8.03-7.91 (m, 3H), 7.88-7.66 (m, 5H), 6.41 (br. s.,
1H), 5.91-5.79 (m, 1H), 3.90 (br. s., 1H), 3.45 (br. s., 2H),
2.41-2.30 (m, 2H), 2.10-2.04 (m, 1H), 2.03-1.95 (m, 1H), 1.94-1.81
(m, 2H), 1.67 (br. s., 2H), 1.54 (br. s., 3H), 1.30 (br. s., 4H),
1.21 (br. s., 4H). Analytical HPLC (Method C): RT=1.37 min,
purity=100%; Factor XIa Ki=22 nM, Plasma Kallikrein Ki=470 nM.
Example 243
Preparation of
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-1H-imidazole-4-carbonitrile
##STR00417##
[1980]
1-(4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatric-
yclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,-
6-dihydropyrimidin-4-yl}phenyl)-1H-imidazole-4-carbonitrile
trifluoroacetate (9.7 mg, 37% yield) was prepared in a similar
manner as the procedure described in Example 231, by replacing
1H-imidazole with 1H-imidazole-4-carbonitrile (0.012 g, 0.130
mmol). MS(ESI) m/z: 580.20 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.22 (s, 1H), 8.82 (s, 1H), 8.69 (d, J=5.2
Hz, 1H), 8.29 (s, 1H), 8.04 (s, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.78
(dd, J=8.5, 2.1 Hz, 1H), 7.70-7.66 (m, 2H), 7.59 (d, J=4.9 Hz, 1H),
7.48 (s, 1H), 6.37 (s, 1H), 5.89 (d, J=10.7 Hz, 1H), 4.01 (s, 3H),
2.69-2.61 (m, 1H), 2.39-2.27 (m, 1H), 2.11 (t, J=12.5 Hz, 1H),
1.89-1.80 (m, 1H), 1.53-1.42 (m, 1H), 1.39-1.29 (m, 1H), 0.89 (d,
J=7.0 Hz, 3H), 0.50-0.34 (m, 1H). Analytical HPLC (Method B):
RT=8.12 min, 100% purity; Factor XIa Ki=53 nM, Plasma Kallikrein
Ki=3,400 nM.
Example 244
Preparation of
N-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tet-
raazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]--
6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamide
##STR00418##
[1982]
N-(4-Chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,-
15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-1-
3-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamide
was prepared in a similar manner as the procedure described in
Example 56, using
N-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroaceta-
mide (0.19 g, 0.60 mmol), prepared as described in Intermediate 1,
and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.20 g,
0.60 mmol), prepared as described in Intermediate 30, to give
N-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tet-
raazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-y-
l}phenyl)-2,2,2-trifluoroacetamide (222 mg, 58%) as white powder.
MS(ESI) m/z: 636.5 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 9.23 (s, 1H), 8.89 (s, 1H), 8.56 (d, J=5.1 Hz, 1H),
7.74-7.69 (m, 3H), 7.55 (s, 1H), 7.46-7.39 (m, 1H), 7.24 (d, J=5.1
Hz, 1H), 6.74 (s, 1H), 5.83-5.70 (m, 1H), 2.55-2.40 (m, 1H),
2.27-2.12 (m, 1H), 1.89 (s, 1H), 1.81-1.66 (m, 1H), 1.38-1.24 (m,
1H), 1.24-1.11 (m, 1H), 0.70 (d, J=7.0 Hz, 3H). Analytical HPLC
(Method A): RT=10.89 min, purity=99%; Factor XIa Ki=3.9 nM, Plasma
Kallikrein Ki=260 nM.
Example 245
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]phenyl}-6-oxo-
-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.-
0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00419##
[1984]
(9R,13S)-13-(4-{5-Chloro-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]phenyl}-
-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (15.5 mg, 67% yield) was prepared in a similar
manner as the procedure described in Example 49, by replacing
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
with
1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(11.52 mg, 0.049 mmol). MS(ESI) m/z: 597.4 (M+H).sup.+. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 9.02 (s, 1H), 8.75 (d, J=5.1 Hz, 1H),
7.74 (s, 1H), 7.62 (s, 1H), 7.56 (dd, J=5.2, 1.7 Hz, 1H), 7.54-7.52
(m, 1H), 7.50-7.47 (m, 3H), 7.39 (s, 1H), 6.40 (d, J=0.4 Hz, 1H),
6.02 (dd, J=12.7, 4.3 Hz, 1H), 4.46 (spt, J=6.7 Hz, 1H), 4.05 (s,
3H), 2.76-2.66 (m, 1H), 2.41-2.30 (m, 1H), 2.14-2.00 (m, 2H),
1.67-1.37 (m, 8H), 1.02 (d, J=6.8 Hz, 3H), 0.80-0.64 (m, 1H).
Analytical HPLC (Method A): RT=8.07 min, 100% purity; Factor XIa
Ki=44 nM, Plasma Kallikrein Ki=5,600 nM.
Example 246
Preparation of
(9R,13S)-13-{4-[5-(difluoromethoxy)-2-[4-(trifluoromethyl)-1H-1,2,3-triaz-
ol-1-yl]phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-meth-
yl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16--
pentaen-8-one
##STR00420##
[1986]
(9R,13S)-13-{4-[5-(Difluoromethoxy)-2-[4-(trifluoromethyl)-1H-1,2,3-
-triazol-1-yl]phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)--
9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,-
14,16-pentaen-8-one (13 mg, 60% yield) as a solid was prepared via
the coupling of
6-[5-(difluoromethoxy)-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pheny-
l]pyrimidin-4-ol (0.012 g, 0.03 mmol) and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6] octadeca-1(18),2(6), 4,14,16-pentaen-8-one (0.011
g, 0.03 mmol) using the HATU,DBU coupling methodology as described
in Example 56. MS m/z=692.1 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.39 (s, 1H), 9.22 (s, 1H), 8.78 (s, 1H),
8.70 (d, J=5.2 Hz, 1H), 7.97-7.81 (m, 1H), 7.71-7.64 (m, 2H),
7.59-7.53 (m, 2H), 7.50-7.46 (m, 1H), 7.45-7.41 (m, 1H), 6.47-6.41
(m, 1H), 5.95-5.85 (m, 1H), 2.71-2.59 (m, 1H), 2.35-2.23 (m, 1H),
2.07-1.98 (m, 1H), 1.90-1.74 (m, 1H), 1.52-1.24 (m, 2H), 0.88 (d,
J=6.7 Hz, 3H), 0.46-0.19 (m, 1H). Analytical HPLC (Method B) RT=1.8
min, purity=100%; Factor XIa Ki=110 nM.
Example 247
Preparation of
(9R,13S)-3-(difluoromethyl)-13-(4-{5-methoxy-2-[4-(trifluoromethyl)-1H-1,-
2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,1-
5-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8--
one
##STR00421##
[1988]
(9R,13S)-3-(Difluoromethyl)-13-(4-{5-methoxy-2-[4-(trifluoromethyl)-
-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3-
,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (12 mg,
50% yield) as a solid was prepared via the coupling of
6-{5-methoxy-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}pyrimidin-4-ol (0.012 g, 0.03 mmol) and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6), 4,14,16-pentaen-8-one (0.012
g, 0.03 mmol) using the HATU, DBU coupling methodology as described
in Example 56. MS m/z=656.2 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.16-9.12 (m, 1H), 8.91-8.88 (m, 1H),
8.52-8.48 (m, 1H), 8.47-8.43 (m, 1H), 7.66-7.63 (m, 2H), 7.60-7.55
(m, 1H), 7.46-7.42 (m, 1H), 7.20-7.16 (m, 1H), 7.14-7.10 (m, 1H),
7.05-7.00 (m, 1H), 6.21-6.12 (m, 1H), 5.72-5.54 (m, 1H), 2.46-2.38
(m, 1H), 2.09-1.98 (m, 1H), 1.86-1.69 (m, 1H), 1.63-1.47 (m, 1H),
1.29-1.00 (m, 2H), 0.65-0.58 (d, 3H), 0.20-0.04 (m, 1H). Analytical
HPLC (Method B) RT=1.72 min, purity=100%; Factor XIa Ki=7.7 nM,
Plasma Kallikrein Ki=2,400 nM.
Example 248
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[1-(2-methylpropyl)-1H-pyrazol-4-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00422##
[1990]
(9R,13S)-13-(4-{5-Chloro-2-[1-(2-methylpropyl)-1H-pyrazol-4-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricycl-
o[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (7.6 mg, 32% yield) was prepared in a similar
manner as the procedure described in Example 49, by replacing
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
with
1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(12.20 mg, 0.049 mmol). MS(ESI) m/z: 611.4 (M+H).sup.+. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 9.00 (s, 1H), 8.75 (d, J=5.3 Hz, 1H),
7.72 (s, 1H), 7.57-7.47 (m, 6H), 7.42 (s, 1H), 6.37 (d, J=0.4 Hz,
1H), 6.02 (dd, J=12.8, 4.2 Hz, 1H), 4.05 (s, 3H), 3.91-3.81 (m,
2H), 2.76-2.67 (m, 1H), 2.34 (tt, J=12.7, 4.3 Hz, 1H), 2.14-1.98
(m, 3H), 1.67-1.43 (m, 2H), 1.01 (d, J=6.8 Hz, 3H), 0.83-0.63 (m,
7H). Analytical HPLC (Method A): RT=8.63 min, 100% purity; Factor
XIa Ki=73 nM, Plasma Kallikrein Ki=8,900 nM.
Example 249
Preparation of
(9R,13S)-13-{4-[2-(1-benzyl-1H-pyrazol-4-yl)-5-chlorophenyl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2-
,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00423##
[1992]
(9R,13S)-13-{4-[2-(1-Benzyl-1H-pyrazol-4-yl)-5-chlorophenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0-
.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
(2.68 mg, 11% yield) was prepared in a similar manner as the
procedure described in Example 49, by replacing
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
with
1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(13.86 mg, 0.049 mmol). MS(ESI) m/z: 645.4 (M+H).sup.+. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.95 (s, 1H), 8.67 (d, J=5.1 Hz, 1H),
7.70 (s, 1H), 7.59 (s, 1H), 7.54-7.45 (m, 6H), 7.29-7.19 (m, 3H),
7.09-7.05 (m, 2H), 6.36 (d, J=0.7 Hz, 1H), 6.00 (dd, J=12.7, 4.1
Hz, 1H), 5.27 (s, 2H), 4.02 (s, 3H), 2.77-2.68 (m, 1H), 2.34-2.23
(m, 1H), 2.15-2.05 (m, 1H), 2.01-1.90 (m, 1H), 1.67-1.42 (m, 2H),
1.02 (d, J=6.8 Hz, 3H), 0.76-0.60 (m, 1H). Analytical HPLC (Method
A): RT=8.90 min, 100% purity; Factor XIa Ki=100 nM.
Example 250
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00424##
[1993] 250A. Preparation of
4-(5-chloro-2-ethynylphenyl)-6-methoxypyrimidine
[1994] A flame-dried flask containing
4-(5-chloro-2-iodophenyl)-6-methoxypyrimidine (0.520 g, 1.50 mmol),
prepared as described in Example 211, and Pd(PPh.sub.3).sub.4
(0.087 g, 0.075 mmol) was purged with Ar for several min. Next,
degassed THF (7.50 ml) and tributylstannylacetylene (0.651 ml, 2.25
mmol) were added. The resulting clear, burgundy solution was
stirred at rt. After 15 h, the dark purple reaction was diluted
with EtOAc and washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated to give a purple solid. Purification by
normal phase chromatography, using 0-10% EtOAc/Hex, gave
4-(5-chloro-2-ethynylphenyl)-6-methoxypyrimidine (0.176 g, 48%) as
an off-white solid. MS(ESI) m/z: 244.9 (M+H).sup.+.
250B. Preparation of
4-(5-chloro-2-{1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}
phenyl)-6-methoxypyrimidine
[1995] A sealed vial containing a mixture of TMSN.sub.3 (0.091 ml,
0.61 mmol), 4-(5-chloro-2-ethynylphenyl)-6-methoxypyrimidine (0.050
g, 0.20 mmol), sodium ascorbate (8.10 mg, 0.041 mmol), and
CuSO.sub.4 (3.26 mg, 0.020 mmol) was stirred at 60.degree. C. After
2 h, the dark black reaction was cooled to rt. The mixture was
diluted with EtOAc (15 mL), and the turbid solution was washed
water (3.times.), brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated to give 0.110 g of crude product as a black oil.
Purification by normal phase chromatography using 0-40% EtOAc/Hex,
gave 4-(5-chloro-2-{1-[(trimethylsilyl)
methyl]-1H-1,2,3-triazol-4-yl}phenyl)-6-methoxypyrimidine (0.0191
g, 25%) as a yellow residue. MS(ESI) m/z: 374.0 (M+H).sup.+.
250C. Preparation of
4-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]-6-methoxypyrimidine
[1996] To a cooled (0.degree. C.) clear yellow solution of
4-(5-chloro-2-(1-((trimethylsilyl)
methyl)-1H-1,2,3-triazol-4-yl)phenyl)-6-methoxypyrimidine (0.019 g,
0.051 mmol) in THF (0.508 ml) and water (1.831 .mu.l, 0.102 mmol)
was added dropwise 1.0 M TBAF in THF (0.061 ml, 0.061 mmol). The
reaction was stirred at 0.degree. C. for 1 h and then warmed to rt.
After 2 h, additional 1.0 M TBAF in THF (0.061 ml, 0.061 mmol) was
added. After 51 h, additional 1.0 M TBAF in THF (0.51 ml, 0.51
mmol) was added. After 44 h, the reaction was diluted with EtOAc
and washed with sat NH.sub.4Cl, brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated to give
4-(5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)-6-methoxypyrimidine
(0.015 g, 98%) as a yellow residue. MS(ESI) m/z: 302.0
(M+H).sup.+.
250D. Preparation of
6-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]pyrimidin-4-ol
[1997] A clear, yellow solution of
4-(5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)-6-methoxypyrimidine
(0.015 g, 0.050 mmol) in AcOH (0.50 ml) and 48% aq HBr (0.28 ml,
2.486 mmol) was warmed to 85.degree. C. After 1 h, the reaction was
cooled to rt and then concentrated to give a brown solid. The brown
solid was suspended in EtOAc and filtered to give and off-white
solid. Purification by reverse phase chromatography gave, after
free-basing with sat NaHCO.sub.3,
6-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)
phenyl]pyrimidin-4-ol (0.0090 g, 63%) as a white solid. MS(ESI)
m/z: 288.0 (M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
8.21 (s, 1H), 7.90 (s, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.60 (d, J=2.2
Hz, 1H), 7.58 (dd, J=8.3, 2.2 Hz, 1H), 6.38 (s, 1H), 4.09 (s,
3H).
250E. Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[1998]
(9R,13S)-13-{4-[5-Chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12-
.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (0.0055 g, 25%) was prepared in a similar manner
as the procedure described in Example 56, by replacing
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol with
6-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]pyrimidin--
4-ol. MS(ESI) m/z: 570.1 (M+H).sup.+ and 572.0 (M+2+H).sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.94 (s, 1H), 8.75 (d,
J=5.2 Hz, 1H), 7.90 (s, 1H), 7.74 (s, 1H), 7.70 (d, J=8.3 Hz, 1H),
7.63 (d, J=2.2 Hz, 1H), 7.59-7.54 (m, 2H), 7.50 (s, 1H), 6.40 (d,
J=0.6 Hz, 1H), 6.04-5.99 (m, 1H), 4.08 (s, 3H), 4.05 (s, 3H),
2.76-2.67 (m, 1H), 2.40-2.29 (m, 1H), 2.15-2.01 (m, 2H), 1.68-1.56
(m, 1H), 1.55-1.43 (m, 1H), 1.02 (d, J=7.2 Hz, 3H), 0.79-0.64 (m,
1H). Analytical HPLC (Method A): RT=6.30 min, purity=100%; Factor
XIa Ki=11 nM, Plasma Kallikrein Ki=2,000 nM.
Example 251
Preparation of
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-fluoro-10-methyl-5,8,16-triaza-
tricyclo[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
##STR00425##
[1999] 251A. Preparation of tert-butyl
N-(6-fluoro-4-iodopyridin-3-yl)carbamate
[2000] BuLi (11.31 ml, 28.3 mmol) was added dropwise to a stirred,
cooled (-78.degree. C.) solution of tert-butyl
(6-fluoropyridin-3-yl)carbamate (2 g, 9.42 mmol) and TMEDA (4.27
ml, 28.3 mmol) in Et.sub.2O (47.1 ml). The mixture was allowed to
warm to -10.degree. C. and stirred for 2 h. The mixture was
recooled to -78.degree. C. and a cooled (-10.degree. C.) solution
of I.sub.2 (4.90 g, 19.32 mmol) in Et.sub.2O (25 mL) was added
dropwise. The mixture was allowed to warm to rt and stirred for 2
days. Sat aq NH.sub.4Cl was added and the mixture was extracted
with Et.sub.2O and EtOAc. The combined organic fractions were
washed with Na.sub.2S.sub.2O.sub.3, brine, dried over MgSO.sub.4,
filtered and concentrated to give a brownish oil, which was
purified by normal phase chromatography to give tert-butyl
N-(6-fluoro-4-iodopyridin-3-yl)carbamate (0.859 g, 27% yield).
MS(ESI) m/z: 338.9 (M+H).sup.+.
251B. Preparation of 6-fluoro-4-iodopyridin-3-amine
[2001] To a solution of N-(6-fluoro-4-iodopyridin-3-yl)carbamate
(400 mg, 1.183 mmol) in DCM (15 mL) was added TFA (4.56 mL, 59.2
mmol). The reaction was stirred at rt for 1 h. Concentration gave
6-fluoro-4-iodopyridin-3-amine.trifluoroacetate (551 mg, 100%) as a
pale yellow solid. MS(ESI) m/z: 238.9 (M+H).sup.+.
251C. Preparation of
(10R,14S)-14-amino-4-fluoro-10-methyl-5,8,16-triazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2,4,6,15,17-hexaen-9-one
[2002]
(10R,14S)-14-Amino-4-fluoro-10-methyl-5,8,16-triazatricyclo[13.3.1.-
0.sup.2,7] nonadeca-1(19),2,4,6,15,17-hexaen-9-one was prepared in
a similar manner as the procedure described in Intermediate 39, by
replacing 2-bromopyridin-3-amine with
6-fluoro-4-iodopyridin-3-amine. MS(ESI) m/z: 315.4 (M+H).sup.+.
251D. Preparation of
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-fluoro-10-methyl-5,8,16-triazatri-
cyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
[2003]
(10R,14S)-14-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-
-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-fluoro-10-methyl-5,8,16-tri-
azatricyclo[13.3.1.0.sup.2,7]
nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one trifluoroacetate (7.3
mg, 33.7% yield) was prepared in a similar manner as the procedure
described in Example 56 by using
(10R,14S)-14-amino-4-fluoro-10-methyl-5,8,16-triazatricyclo[13.3.1.0.sup.-
2,7]nonadeca-1(19),2,4,6,15,17-hexaen-9-one (8.8 mg, 0.028 mmol).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.91 (s, 1H), 8.83-8.79
(m, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.13-8.09 (m, 1H), 7.89 (d, J=2.4
Hz, 1H), 7.78-7.65 (m, 3H), 7.48 (dd, J=5.1, 1.8 Hz, 1H), 7.37 (d,
J=2.2 Hz, 1H), 6.42 (d, J=0.7 Hz, 1H), 6.04 (dd, J=12.5, 4.8 Hz,
1H), 2.79-2.65 (m, 1H), 2.27-2.14 (m, 1H), 2.07-1.92 (m, 2H),
1.60-1.37 (m, 2H), 0.95 (d, J=6.8 Hz, 3H), 0.57 (br. s., 1H).
MS(ESI) m/z: 639.0 (M+H).sup.+. Analytical HPLC (Method A): RT=9.64
min, purity=100%; Factor XIa Ki=0.53 nM, Plasma Kallikrein Ki=71
nM.
Example 252
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyridin-2-yl)-9-meth-
yl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pen-
taen-8-one
##STR00426##
[2005]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyridin-2-yl)-9-me-
thyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-p-
entaen-8-one (9.5 mg, 17%) was prepared in a similar manner as the
procedure described in Example 216, by using
2-iodo-6-methoxypyridine (31 mg, 0.131 mmol) and
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.04 g,
0.066 mmol), as described in Example 196. MS(ESI) m/z: 717.4
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.57 (s,
1H), 9.21 (s, 1H), 8.71 (d, J=15.6 Hz, 2H), 8.59 (d, J=5.2 Hz, 1H),
8.03-7.90 (m, 3H), 7.90-7.74 (m, 2H), 7.68-7.49 (m, 2H), 6.83 (d,
J=7.9 Hz, 1H), 6.50 (s, 1H), 6.01 (br. s., 1H), 3.98 (s, 3H), 2.79
(br. s., 1H), 2.38-2.15 (m, 2H), 1.85 (br. s., 1H), 1.58 (br. s.,
1H), 1.42 (br. s., 1H), 0.95 (d, J=6.7 Hz, 3H), 0.57 (br. s., 1H).
Analytical HPLC (Method C): RT=2.07 min, purity=100%; Factor XIa
Ki=23 nM, Plasma Kallikrein Ki=1,100 nM.
Example 253
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(difluoromethyl)-9-methyl-3,4,-
7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8--
one
##STR00427##
[2007]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one,
prepared as described in Example 196, (0.02 g, 0.033 mmol), sodium
2-chloro-2,2-difluoroacetate (50 mg, 0.33 mmol), Cs.sub.2CO.sub.3
(0.021 g, 0.066 mmol), and DMF (2 mL) were added to a 5 mL
microwave vial. The reaction was heated to 130.degree. C. for 30
min in a microwave. The mixture was concentrated to dryness and the
residue was purified by reverse phase chromatography to give
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(difluoromethyl)-9-methyl-3,4,7,15-
-tetraazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2,5,14,16-pentaen-8-one (2 mg, 8%). MS(ESI) m/z:
660.1 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.54
(s, 1H), 9.21 (s, 1H), 8.70 (s, 1H), 8.58 (d, J=4.9 Hz, 1H), 8.41
(s, 1H), 7.96 (br. s., 1H), 7.92-7.68 (m, 4H), 7.53 (d, J=4.9 Hz,
1H), 6.49 (s, 1H), 6.12-5.90 (m, 1H), 2.85-2.69 (m, 1H), 2.24 (d,
J=11.9 Hz, 2H), 1.89-1.76 (m, 1H), 1.63-1.49 (m, 1H), 1.47-1.35 (m,
1H), 0.92 (d, J=6.7 Hz, 3H), 0.61-0.38 (m, 1H). Analytical HPLC
(Method C): RT=1.82 min, purity=100%; Factor XIa Ki=8 nM, Plasma
Kallikrein Ki=360 nM.
Example 254
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1-
,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00428##
[2009]
(9R,13S)-13-{4-[5-Chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl]-6-
-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.-
3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (10 mg, 43% yield) was prepared in a similar
manner as the procedure described in Example 49, by replacing
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
with
1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(11.42 mg, 0.049 mmol). MS(ESI) m/z: 595.4 (M+H).sup.+. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.99 (s, 1H), 8.76 (d, J=5.3 Hz, 1H),
7.73 (s, 1H), 7.64 (s, 1H), 7.57-7.52 (m, 2H), 7.50 (s, 1H),
7.47-7.46 (m, J=1.1 Hz, 2H), 7.33 (d, J=0.7 Hz, 1H), 6.39 (s, 1H),
6.03 (dd, J=12.5, 4.2 Hz, 1H), 4.05 (s, 3H), 3.63-3.56 (m, 1H),
2.76-2.67 (m, 1H), 2.35 (tt, J=12.7, 4.3 Hz, 1H), 2.14-2.01 (m,
2H), 1.67-1.44 (m, 2H), 1.04-0.97 (m, 7H), 0.79-0.64 (m, 1H).
Analytical HPLC (Method A): RT=7.82 min, 99.9% purity; Factor XIa
Ki=8 nM, Plasma Kallikrein Ki=1,700 nM.
Example 255
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00429##
[2010] 255A. Preparation of
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)--
1H-pyrazole
[2011] To a stirred solution of
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100
mg, 0.515 mmol) in DMF (1 ml) were added Cs.sub.2CO.sub.3 (252 mg,
0.773 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate
(0.144 ml, 1.031 mmol) at rt. After stirring at 100.degree. C. for
2 h, the reaction mixture was evaporated to dryness, partitioned
between EtOAc and water, and the layers were separated. The organic
layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated
to afford
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)--
1H-pyrazole (0.111 g, 78% yield). MS(ESI) m/z: 277.4
(M+H).sup.+.
255B. Preparation of
(9R,13S)-13-(4-{5-chloro-2-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]phen-
yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricycl-
o [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[2012]
(9R,13S)-13-(4-{5-Chloro-2-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-y-
l]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazat-
ricyclo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (10.6 mg, 43% yield) was prepared in a similar
manner as the procedure described in Example 49, by replacing
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
with
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)--
1H-pyrazole (13.47 mg, 0.049 mmol), prepared as described in
Example 255A. MS(ESI) m/z: 637.5 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.97 (s, 1H), 8.74 (d, J=5.3 Hz, 1H), 7.74-7.67
(m, 2H), 7.56-7.49 (m, 6H), 6.40 (s, 1H), 6.03 (dd, J=12.7, 4.3 Hz,
1H), 4.92-4.82 (m, 2H), 4.05 (s, 3H), 2.76-2.67 (m, 1H), 2.39-2.28
(m, 1H), 2.14-1.99 (m, 2H), 1.67-1.43 (m, 2H), 1.02 (d, J=7.0 Hz,
3H), 0.79-0.64 (m, 1H). Analytical HPLC (Method A): RT=8.26 min,
99.5% purity; Factor XIa Ki=52 nM, Plasma Kallikrein Ki=5,500
nM.
Example 256
Preparation of
3-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-o-
xo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.-
3.1.0.sup.2,6]
octadeca-1(18),2,5,14,16-pentaen-4-yl]benzonitrile
##STR00430##
[2014]
3-[(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)pheny-
l]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,6]
octadeca-1(18),2,5,14,16-pentaen-4-yl]benzonitrile trifluoroacetate
was prepared in a similar manner as the procedure described in
Example 216, by using 3-iodobenzonitrile (3.97 mg, 0.017 mmol) to
give
3-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-o-
xo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-4-yl]benzonitrile
trifluoroacetate (4.5 mg, 33% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.60 (s, 1H), 8.76-8.65 (m, 2H), 8.60 (d,
J=5.2 Hz, 1H), 8.36 (s, 1H), 8.25 (d, J=8.2 Hz, 1H), 7.93-7.86 (m,
2H), 7.84-7.69 (m, 4H), 7.63 (d, J=4.3 Hz, 1H), 6.34 (s, 1H), 5.98
(br. s., 1H), 2.78 (br. s., 1H), 2.54 (s, 1H), 2.24 (d, J=7.3 Hz,
2H), 1.85 (br. s., 1H), 1.56 (br. s., 1H), 1.41 (br. s., 1H), 0.93
(d, J=6.7 Hz, 3H), 0.55 (br. s., 1H). MS(ESI) m/z: 677.1
[M+H].sup.+. Analytical HPLC (Method B): RT=1.91 min,
purity=100.0%; Factor XIa Ki=2.0 nM, Plasma Kallikrein Ki=30
nM.
Example 257
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(5-methyl-1H-imidazol-1-yl)phenyl]-6-oxo-1,6-d-
ihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
##STR00431##
[2016]
(9R,13S)-13-{4-[5-Chloro-2-(5-methyl-1H-imidazol-1-yl)phenyl]-6-oxo-
-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.-
0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (2.3 mg, 9% yield) was prepared in a similar
manner as the procedure described in Example 231, by replacing
1H-imidazole with 4-methyl-1H-imidazole (10.68 mg, 0.130 mmol).
MS(ESI) m/z: 569.20 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.22 (s, 1H), 8.89 (br. s., 1H), 8.78 (s,
1H), 8.67 (d, J=4.9 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.86 (dd,
J=8.5, 2.1 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.59 (d,
J=4.9 Hz, 1H), 7.50-7.40 (m, 2H), 6.41 (br. s., 1H), 5.86 (d,
J=10.4 Hz, 1H), 4.01 (s, 3H), 2.68-2.60 (m, 1H), 2.32-2.22 (m, 1H),
2.16-2.05 (m, 1H), 2.01 (s, 3H), 1.88-1.76 (m, 1H), 1.52-1.27 (m,
2H), 0.88 (d, J=6.7 Hz, 3H), 0.50-0.37 (m, 1H). Analytical HPLC
(Method B): RT=1.49 min, 100% purity; Factor XIa Ki=7,500 nM.
Example 258
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1H-pyrazol-3-yl)-3,4,7,15-tetraazat-
ricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
##STR00432##
[2018]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1H-pyrazol-3-yl)-3,4,7,15-tet-
raazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
trifluoroacetate was prepared in a similar manner as the procedure
described in Example 216, by using 3-iodo-1-trityl-1H-pyrazole
(18.9 mg, 0.043 mmol) followed by deprotection using 50% TFA in DCM
and Et.sub.3SiH as a scavenger to yield
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1H-pyrazol-3-yl)-3,4,7,15-tetraazat-
ricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
trifluoroacetate (4.8 mg, 3.2 .mu.mol, 6% yield). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.45 (s, 1H), 8.76-8.69 (m, 1H), 8.57
(d, J=4.9 Hz, 1H), 8.31 (s, 1H), 8.10 (br. s., 1H), 7.93 (d, J=2.1
Hz, 1H), 7.88 (s, 1H), 7.82 (dd, J=8.5, 2.1 Hz, 1H), 7.77-7.70 (m,
1H), 7.52 (d, J=4.9 Hz, 1H), 7.30-7.02 (m, 3H), 6.37 (s, 1H), 5.97
(br. s., 1H), 2.76 (br. s., 1H), 2.27 (d, J=10.7 Hz, 2H), 1.84 (br.
s., 1H), 1.55 (br. s., 1H), 1.41 (br. s., 1H), 0.93 (d, J=6.7 Hz,
3H), 0.56 (br. s., 1H). MS(ESI) m/z: 642.3 [M+H].sup.+. Analytical
HPLC (Method B): RT=1.51 min, purity=100.0%; Factor XIa Ki=0.29 nM,
Plasma Kallikrein Ki=18 nM.
Example 259
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-tetraazatr-
icyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
##STR00433##
[2020]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-tetr-
aazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2,5,14,16-pentaen-8-one trifluoroacetate was
prepared in a similar manner as the procedure described in Example
216, by using 5-iodopyrimidine (21.4 mg, 0.104 mmol) to give
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl-
]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-te-
traazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
trifluoroacetate (15 mg, 36%). .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 9.58 (s, 1H), 9.40 (s, 2H), 9.20 (s, 1H), 8.85-8.72 (m,
3H), 8.64 (d, J=5.3 Hz, 1H), 7.98-7.91 (m, 2H), 7.87-7.80 (m, 1H),
7.79-7.73 (m, 1H), 7.65 (dd, J=5.1, 1.3 Hz, 1H), 6.39 (s, 1H), 6.02
(d, J=9.5 Hz, 1H), 2.82 (br. s., 1H), 2.37-2.23 (m, 2H), 1.94-1.80
(m, 1H), 1.58 (br. s., 1H), 1.43 (br. s., 1H), 0.99-0.91 (d, J=7.0
Hz, 3H), 0.56 (br. s., 1H). MS(ESI) m/z: 654.6 [M+H].sup.+.
Analytical HPLC (Method A): RT=7.96 min, purity=>95.0%; Factor
XIa Ki=0.63 nM, Plasma Kallikrein Ki=17 nM.
Example 260
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-4-(pyrazin-2-yl)-3,4,7,-
15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-on-
e
##STR00434##
[2022]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-4-(pyrazin-2-yl)-3,4,-
7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
trifluoroacetate (9.0 mg, 34%) was prepared in a similar manner as
the procedure described in Example 216, by using 2-iodopyrazine
(6.75 mg, 0.033 mmol) and
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (20.0 mg,
0.033 mmol), as described in Example 196. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.60 (s, 1H), 9.33 (s, 1H), 9.22 (s, 1H),
8.76-8.65 (m, 2H), 8.63-8.56 (m, 2H), 7.95 (d, J=16.5 Hz, 2H),
7.88-7.78 (m, 2H), 7.66 (d, J=4.9 Hz, 1H), 7.27-6.98 (m, 1H), 6.49
(s, 1H), 6.03 (d, J=9.5 Hz, 1H), 2.79 (br. s., 1H), 2.37-2.18 (m,
2H), 1.83 (br. s., 1H), 1.56 (br. s., 1H), 1.42 (br. s., 1H), 0.93
(d, J=6.7 Hz, 3H), 0.52 (br. s., 1H). MS(ESI) m/z: 688.0
[M+H].sup.+. Analytical HPLC (Method B): RT=1.923 min,
purity=>100.0%; Factor XIa Ki=2.6 nM, Plasma Kallikrein Ki=54
nM.
Example 261
Preparation of
(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]--
3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]oct-
adeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00435##
[2024]
N-(4-Chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,-
15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-1-
3-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamide,
prepared as described in Example 244, (0.2 g, 0.31 mmol) was
dissolved in 1.25 M HCl in MeOH (5 ml, 6.25 mmol). The reaction was
heated to 75.degree. C. for 1 h, then cooled to rt and concentrated
to dryness. The product was purified by recrystallizing from
CH.sub.3CN--H.sub.2O to give
(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]--
3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]oct-
adeca-1(18),2(6),4,14,16-pentaen-8-one (160 mg, 89%) as a yellow
solid. MS(ESI) m/z: 540.5 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.40 (s, 1H), 9.00 (s, 1H), 8.75 (d, J=5.09
Hz, 1H), 7.96 (t, J=57.75 Hz, 1H), 7.90 (s, 1H), 7.73 (s, 1H), 7.46
(d, J=2.49 Hz, 1H), 7.43 (dd, J=4.92, 0.85 Hz, 1H), 7.14 (dd,
J=8.80, 2.51 Hz, 1H), 6.76 (d, J=8.73 Hz, 1H), 6.70 (s, 1H), 6.43
(s, 2H), 5.95 (dd, 12.17, 3.13 Hz, 1H), 2.67 (m, 1H), 2.34 (tm,
J=12.83 Hz, 1H), 2.08 (tm, J=13.09 Hz, 1H), 1.93 (m, 1H), 1.48 (m,
1H), 1.37 (m, 1H), 0.89 (d, J=6.87 Hz, 3H), 0.39 (br-s, 1H).
Analytical HPLC (Method A): RT=7.75 min, purity=94%; Factor XIa
Ki=170 nM, Plasma Kallikrein Ki=5,700 nM.
Example 262
Preparation of
(9R,13S)-13-(4-{3-chloro-6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-fluorop-
henyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatric-
yclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00436##
[2025] 262A. Preparation of
6-(3-chloro-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-fluorophenyl)pyrimid-
in-4-ol
[2026]
6-(3-Chloro-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-fluorophenyl)p-
yrimidin-4-ol (0.032 g, 85% yield) was prepared in a similar manner
as the procedures described in Example 140A and 140B, by replacing
4-(2-bromo-5-chlorophenyl)-6-methoxypyrimidine (0.08 g, 0.267 mmol)
with 4-(6-bromo-3-chloro-2-fluorophenyl)-6-methoxypyrimidine (0.1
g, 0.315 mmol). MS(ESI) m/z: 341.4 (M+H).sup.+. .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 8.35 (s, 1H), 8.06 (s, 1H), 7.67-7.60 (m,
2H), 7.45 (t, J=59.4 Hz, 1H), 7.40 (dd, J=8.3, 1.4 Hz, 1H), 6.52
(s, 1H).
262B. Preparation of
(9R,13S)-13-(4-{3-chloro-6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-fluorop-
henyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatric-
yclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[2027]
(9R,13S)-13-(4-{3-Chloro-6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-f-
luorophenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraa-
zatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (11.7 mg, 36% yield) was prepared in a similar
manner as the procedure described in Example 56, by replacing
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol (22.8 mg, 0.067 mmol) with
6-(3-chloro-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-fluorophenyl)pyrimid-
in-4-ol (14.79 mg, 0.043 mmol). MS(ESI) m/z: 623.6 (M+H).sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.99 (s, 1H), 8.75 (d,
J=5.2 Hz, 1H), 8.00 (s, 1H), 7.73 (s, 1H), 7.64-7.58 (m, 2H),
7.55-7.28 (m, 4H), 6.51 (s, 1H), 6.04 (dd, J=12.7, 3.9 Hz, 1H),
4.05 (s, 3H), 2.75-2.67 (m, 1H), 2.36 (tt, J=12.7, 4.3 Hz, 1H),
2.13-2.02 (m, 2H), 1.66-1.45 (m, 2H), 1.02 (d, J=7.2 Hz, 3H),
0.83-0.66 (m, 1H). .sup.19F NMR (471 MHz, CD.sub.3OD) .delta.
-77.75 (s), -96.25 (s), -117.96 (s). Analytical HPLC (Method A):
RT=8.18 min, 98.0% purity; Factor XIa Ki=4.5 nM, Plasma Kallikrein
Ki=340 nM.
Example 263
Preparation of
(9R,13S)-13-[4-(5-chloro-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]--
3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]oct-
adeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00437##
[2028] 263A. Preparation of
6-(5-chloro-1H-indol-7-yl)pyrimidin-4-ol
[2029] 6-(5-Chloro-1H-indol-7-yl)pyrimidin-4-ol was prepared in a
similar manner as described for Example 207C by replacing
4-bromo-6-chloro-1H-benzo[d]imidazole with
7-bromo-5-chloro-1H-indole. MS(ESI) m/z: 246 (M+H).sup.+.
263B.
(9R,13S)-13-[4-(5-Chloro-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-
-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,-
6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
[2030]
(9R,13S)-13-[4-(5-Chloro-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimidin--
1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2-
,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate was
prepared (0.61 mg, 1.3%) in a similar manner as described in
Example 56 by using 6-(5-chloro-1H-indol-7-yl)pyrimidin-4-ol and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one, prepared
as described in Intermediate 30. MS(ESI) m/z: 564 (M+H).sup.+ and
566 (M+2+H).sup.+. Analytical HPLC (Method A): RT=9.71 min,
purity=>90%; Factor XIa Ki=4,600 nM.
Example 264
Preparation of
(9R,13S)-13-[4-(6-chloro-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl-
]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]o-
ctadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00438##
[2031] 264A. Preparation of
6-(6-chloro-1H-indazol-4-yl)pyrimidin-4-ol
[2032] 6-(6-Chloro-1H-indazol-4-yl)pyrimidin-4-ol was prepared in a
similar manner as described for Example 207C by replacing
4-bromo-6-chloro-1H-benzo[d]imidazole with
4-bromo-6-chloro-1H-indazole. MS(ESI) m/z: 247 (M+H).sup.+.
264B. Preparation of
(9R,13S)-13-[4-(6-chloro-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl-
]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
[2033]
(9R,13S)-13-[4-(6-Chloro-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrimidi-
n-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (4
mg, 9.4%) was prepared in a similar manner as Example 56 by using
6-(6-chloro-1H-indazol-4-yl)pyrimidin-4-ol and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one,
prepared as described in Intermediate 30. MS(ESI) m/z: 565
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.35 (s,
1H), 9.05 (s, 1H), 8.69 (d, J=5.3 Hz, 1H), 8.53 (s, 1H), 7.90-7.84
(m, 2H), 7.75-7.68 (m, 4H), 7.40-7.35 (m, 2H), 7.02 (s, 1H),
2.62-2.58 (m, 1H), 2.36-2.30 (m, 1H), 2.06-2.01 (m, 1H), 1.93-1.87
(m, 1H), 1.47-1.42 (m, 1H), 1.34-1.29 (m, 1H), 0.83 (d, J=6.8 Hz,
3H). Analytical HPLC (Method A): RT=7.32 min, purity=95%; Factor
XIa Ki=260 nM.
Example 265
Preparation of (14
S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,8,16-triazatricyclo[-
13.3.1.0.sup.2,7] nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
trifluoroacetate
##STR00439##
[2034] 265A. Preparation of
(S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronic
acid, trifluoroacetate
[2035] To a solution of
5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (1.198 g, 5.30
mmol) and (S)-tert-butyl
(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate (1.0 g, 3.54
mmol), prepared as described in Intermediate 23, in DMSO (10 mL)
was added KOAc (1.041 g, 10.61 mmol) under Ar.
PdCl.sub.2(dppf)CH.sub.2Cl.sub.2 adduct (0.289 g, 0.354 mmol) and
the mixture was purged with Ar for an additional 10 min then
stirred at 85.degree. C. After 12 h, the reaction mixture was
diluted with EtOAc and washed with water. The aqueous layer was
extracted with EtOAc. The combined organic layers were washed with
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
dark oil purified by reverse phase chromatography to give, after
concentration and lyophilization,
(S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronic
acid trifluoroacetate (1.05 g, 2.59 mmol, 73.1% yield) as a white
solid. MS(ESI) m/z: 293.2 (M+H).sup.+.
265B. Preparation of (S)-tert-butyl
(1-(3'-amino-[4,4'-bipyridin]-2-yl)but-3-en-1-yl) carbamate
[2036] To a solution of
(S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronic
acid, trifluoroacetate (1.0 g, 2.462 mmol) and
4-bromopyridin-3-amine (0.511 g, 2.95 mmol) in dioxane (17 mL) was
added 2 M aq Na.sub.2CO.sub.3 (4.92 mL, 9.85 mmol). The mixture was
purged with a stream of Ar for 5 min. Pd(PPh.sub.3).sub.4 (0.285 g,
0.246 mmol) was added and the reaction was irradiated at
120.degree. C. for 1 h. The reaction was quenched with water (40
mL) and extracted with EtOAc (2.times.). The combined organic
layers were washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. The crude material was purified by normal phase
column chromatography eluting with a gradient of DCM/MeOH to give
(S)-tert-butyl
(1-(3'-amino-[4,4'-bipyridin]-2-yl)but-3-en-1-yl)carbamate (0.736
g, 88% yield) as a brown oil. MS(ESI) m/z: 341.2 (M+H).sup.+.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.68 (d, J=4.7 Hz, 1H),
8.19 (s, 1H), 8.10 (d, J=5.0 Hz, 1H), 7.35 (s, 1H), 7.29 (dd,
J=5.1, 1.5 Hz, 1H), 7.02 (d, J=5.0 Hz, 1H), 5.79-5.68 (m, 1H),
5.62-5.52 (m, 1H), 5.11-5.04 (m, 2H), 4.90-4.80 (m, 1H), 3.83 (br.
s., 2H), 2.64 (t, J=6.7 Hz, 2H), 1.45 (s, 9H).
265C. Preparation of tert-butyl
((S)-1-(3'-((R)-2-methylbut-3-enamido)-[4,4'-bipyridin]-2-yl)but-3-en-1-y-
l)carbamate
[2037] To a solution of (S)-tert-butyl
(1-(3'-amino-[4,4'-bipyridin]-2-yl)but-3-en-1-yl) carbamate (736
mg, 2.16 mmol) in EtOAc (21.6 mL) was added (R)-2-methylbut-3-enoic
acid (303 mg, 3.03 mmol). After cooling to 0.degree. C., pyridine
(0.525 mL, 6.49 mmol) was added followed by T3P.RTM./50% EtOAc
(2.57 mL, 4.32 mmol) dropwise. The reaction was slowly warmed to rt
overnight. The reaction mixture was diluted with water and
extracted with EtOAc (2.times.). The combined organic layers were
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. The crude material was purified by normal phase
column chromatography eluting with a gradient of DCM/MeOH to give
of tert-butyl
((S)-1-(3'-((R)-2-methylbut-3-enamido)-[4,4'-bipyridin]-2-yl)but-3-en-1-y-
l) carbamate (815 mg, 89%). MS(ESI) m/z: 423.2 (M+H).sup.+. .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. 9.45 (s, 1H), 8.70 (d, J=5.0 Hz,
1H), 8.49 (d, J=5.0 Hz, 1H), 7.24 (br. s., 1H), 7.21 (s, 1H),
7.18-7.14 (m, 2H), 5.80 (ddd, J=17.1, 10.1, 8.3 Hz, 1H), 5.74-5.66
(m, 1H), 5.54-5.48 (m, 1H), 5.15-5.05 (m, 4H), 4.92-4.85 (m, 1H),
3.08 (quin, J=7.2 Hz, 1H), 2.69-2.61 (m, 2H), 1.45 (s, 9H),
1.31-1.28 (m, 3H).
265D. Preparation of tert-butyl
N-[(11E,14S)-10-methyl-9-oxo-5,8,16-triazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamat-
e
[2038] To a solution of
tert-butyl((S)-1-(3'-((R)-2-methylbut-3-enamido)-[4,4'-bipyridin]-2-yl)bu-
t-3-en-1-yl)carbamate (400 mg, 0.947 mmol) in freshly opened and
degassed DCM (500 mL) was added p-TsOH.H.sub.2O (378 mg, 1.988
mmol). A stream of N.sub.2 was bubbled for 10 min before heating
the solution at 40.degree. C. under a nitrogen atmosphere. After 1
h, Second Generation Grubbs Catalyst (201 mg, 0.237 mmol) dissolved
in degassed DCM (20 ml) was added to the reaction mixture dropwise
and heating continued at 40.degree. C. overnight. The reaction
mixture was quenched with 1.5 M K.sub.2HPO.sub.3 (30 mL) followed
by separation of the organic phase and concentration. The crude
residue was purified by reverse phase chromatography and
concentration of product fractions. The residue was dissolved in
MeOH, neutralized by passing through NaHCO.sub.3 resin cartridges
(2.times.) and concentrating the filtrate to afford tert-butyl
N-[(11E,14S)-10-methyl-9-oxo-5,8,16-triazatricyclo[13.3.1.0.sup.2,7]nonad-
eca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate (24.6 mg, 6.59%
yield) as brown film. MS(ESI) m/z: 395 (M+H).sup.+.
265E. Preparation of tert-butyl
N-[(14S)-10-methyl-9-oxo-5,8,16-triazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate
[2039] PtO.sub.2 (0.018 g, 0.079 mmol) was added to a stirring
solution of tert-butyl
N-[(11E,14S)-10-methyl-9-oxo-5,8,16-triazatricyclo[13.3.1.0.sup.2,7]nonad-
eca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate (0.031 g, 0.079
mmol) in EtOH (3 mL) and subjected to a H.sub.2 atmosphere (55 psi)
for 3 h. The catalyst was filtered off through a plug of
CELITE.RTM. and filtrate concentrated to give tert-butyl
N-[(14S)-10-methyl-9-oxo-5,8,16-triazatricyclo[13.3.1.0.sup.2,7]nonadeca--
1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate as a brown film (yield
assumed quantitative). MS(ESI) m/z: 397 (M+H).sup.+.
265F. Preparation of
(14S)-14-amino-10-methyl-5,8,16-triazatricyclo[13.3.1.0.sup.27]
nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
[2040] TFA (0.18 mL, 2.35 mmol) was added to a stirring solution of
tert-butyl
N-[(14S)-10-methyl-9-oxo-5,8,16-triazatricyclo[13.3.1.0.sup.2,7]nonadeca--
1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate (31 mg, 0.078 mmol).
After 6 h, the reaction mixture was concentrated and the residue
placed under vacuum overnight. The residue was dissolved in MeOH,
passed a NaHCO.sub.3 resin cartridge, and concentrated to give
(14S)-14-amino-10-methyl-5,8,16-triazatricyclo[13.3.1.0.sup.2,7]nonadeca--
1(19),2(7),3,5,15,17-hexaen-9-one as a brown film. The material was
carried forward to the next reaction without further purification.
MS(ESI) m/z: 297.3 (M+H).sup.+.
265G. Preparation of
(14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,8,16-triazatricyclo[-
13.3.1.0.sup.2,7]
nonadeca-1(19),2(7),3,5,15,17-hexaen-9-onetrifluoracetate
[2041]
(14S)-14-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]-
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,8,16-triazatricyclo[1-
3.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one,
trifluoroacetate was prepared (10.4 mg, 16.5%) in a similar manner
as Example 56 using (14S)-14-amino-10-methyl-5,8,16-triazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one and
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol, prepared as described in Intermediate 15. The compound
exists as an apparent diastereomeric mixture according to NMR data.
MS(ESI) m/z: 621.2 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.88-8.81 (m, 4H), 8.75-8.69 (m, 3H), 8.07 (br. s., 1H),
8.03 (br. s., 1H), 7.96 (d, J=2.2 Hz, 1H), 7.95-7.93 (m, 1H),
7.84-7.82 (m, 1H), 7.80-7.79 (m, 1H), 7.76-7.73 (m, 2H), 7.59 (dd,
J=5.0, 1.7 Hz, 1H), 7.47 (dd, J=5.1, 1.8 Hz, 1H), 7.27 (s, 1H),
6.49-6.45 (m, 2H), 6.09 (dd, J=12.4, 4.7 Hz, 1H), 5.94-5.83 (m,
2H), 4.61 (dd, J=15.2, 9.7 Hz, 1H), 2.94-2.86 (m, 1H), 2.79-2.70
(m, 1H), 2.26 (s, 1H), 2.03 (d, J=13.0 Hz, 1H), 1.35-1.28 (m, 1H),
1.15 (d, J=6.6 Hz, 3H), 1.00 (d, J=6.8 Hz, 2H). Analytical HPLC
(Method A): RT=5.22 min, purity=98%.
Example 267
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-4-(6-oxo-1,6-dihydropyr-
idazin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5-
,14,16-pentaen-8-one
##STR00440##
[2043]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-4-(6-oxo-1,6-dihydrop-
yridazin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2-
,5,14,16-pentaen-8-one trifluoroacetate (2.8 mg, 10% yield) was
prepared in a similar manner as the procedure described in Example
216, by using 5-iodopyridazin-3(2H)-one (7.28 mg, 0.033 mmol) and
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (20.0 mg,
0.033 mmol), prepared as described in Example 196. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.64 (s, 1H), 9.21 (s, 1H), 8.80 (s,
1H), 8.70 (s, 1H), 8.65 (d, J=2.4 Hz, 1H), 8.59 (d, J=4.9 Hz, 1H),
7.96 (d, J=1.8 Hz, 1H), 7.89 (s, 1H), 7.86-7.76 (m, 2H), 7.63 (d,
J=5.2 Hz, 1H), 7.30-7.00 (m, 1H), 6.48 (s, 1H), 6.00 (br. s., 1H),
2.78 (br. s., 1H), 2.24 (d, J=16.2 Hz, 2H), 1.91-1.76 (m, 1H), 1.55
(br. s., 1H), 1.40 (br. s., 1H), 0.92 (d, J=6.7 Hz, 3H), 0.48 (br.
s., 1H). MS(ESI) m/z: 704.0 [M+H].sup.+. Analytical HPLC (Method
B): RT=1.735 min, purity=98.0%; Factor XIa Ki=0.21 nM, Plasma
Kallikrein Ki=9 nM.
Example 268
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyrazin-2-yl)-9-meth-
yl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pen-
taen-8-one
##STR00441##
[2045]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyrazin-2-yl)-9-me-
thyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-p-
entaen-8-one trifluoroacetate (10.9 mg, 16% yield) was prepared in
a similar manner as the procedure described in Example 216, by
using 2-iodo-6-methoxypyrazine (19.35 mg, 0.082 mmol) and
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (50.0 mg,
0.082 mmol), prepared as described in Example 196. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.54 (s, 1H), 9.19 (s, 1H), 8.78 (s,
1H), 8.73 (s, 1H), 8.66 (s, 1H), 8.56 (d, J=4.9 Hz, 1H), 8.28 (s,
1H), 7.96-7.88 (m, 1H), 7.84-7.75 (m, 2H), 7.61 (d, J=4.6 Hz, 1H),
7.21-6.93 (m, 1H), 6.46 (s, 1H), 6.00 (br. s., 1H), 4.01 (s, 3H),
2.75 (br. s., 1H), 2.31-2.14 (m, 2H), 1.85-1.73 (m, 1H), 1.53 (br.
s., 1H), 1.37 (br. s., 1H), 0.90 (d, J=6.7 Hz, 3H), 0.52 (br. s.,
1H). MS(ESI) m/z: 718.0 [M+H].sup.+. Analytical HPLC (Method B):
RT=2.06 min, purity=100.0%; Factor XIa Ki=9 nM, Plasma Kallikrein
Ki=260 nM.
Example 269
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-methoxypyridin-4-y-
l)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,-
14,16-pentaen-8-one
##STR00442##
[2047]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-methoxypyridin-4-
-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,-
5,14,16-pentaen-8-one (6.6 mg, 19%) was prepared in a similar
manner as the procedure described in Example 216, by using
5-fluoro-4-iodo-2-methoxypyridine (21 mg, 0.082 mmol) and
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.025 g,
0.041 mmol), prepared as described in Example 196. MS(ESI) m/z:
735.4 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.60
(s, 1H), 9.23 (s, 1H), 8.72 (s, 1H), 8.60 (d, J=5.2 Hz, 1H), 8.49
(d, J=1.8 Hz, 1H), 8.43 (d, J=3.1 Hz, 1H), 7.98 (d, J=2.1 Hz, 1H),
7.92 (s, 1H), 7.90-7.80 (m, 2H), 7.64 (d, J=4.9 Hz, 1H), 7.39 (d,
J=5.5 Hz, 1H), 6.51 (s, 1H), 6.12-5.90 (m, 1H), 3.93 (s, 3H), 2.79
(br. s., 1H), 2.27 (d, J=17.7 Hz, 2H), 1.84 (br. s., 1H), 1.57 (br.
s., 1H), 1.49-1.34 (m, 1H), 0.94 (d, J=6.7 Hz, 3H), 0.68-0.41 (m,
1H). Analytical HPLC (Method C): RT=2.09 min, purity=100%; Factor
XIa Ki=7.4 nM, Plasma Kallikrein Ki=280 nM.
Example 270
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8-ox-
o-3,4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentae-
ne-17-carbonitrile
##STR00443##
[2048] 270A. Preparation of tert-butyl
N-[(9R,10E,13S)-17-cyano-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatr-
icyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]
carbamate
##STR00444##
[2050] tert-Butyl
N-[(9R,10E,13S)-17-cyano-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatr-
icyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbam-
ate (0.02 g, 45%), a dark film, was prepared in the same manner as
described for Intermediate 35D, substituting
2-bromo-4-formylbenzonitrile for 3-bromobenzaldehyde. LCMS(ESI)
m/z: 458.6 (M+H).sup.+.
270B. Preparation of tert-butyl
N-[(9R,13S)-17-cyano-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
##STR00445##
[2052] tert-Butyl
N-[(9R,10E,13S)-17-cyano-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatr-
icyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbam-
ate (20 mg, 0.044 mmol) in EtOH (10 ml) was added PtO.sub.2 (0.005
g, 0.022 mmol) and the reaction was hydrogenated at 55 psi for 5 h.
The reaction mixture was filtered through a plug of CELITE.RTM. and
the filtrate concentrated. To the product was added DCM (2 ml), TEA
(6.09 .mu.l, 0.044 mmol) and Dess-Martin periodinane (74.2 mg,
0.175 mmol). After 1 h at rt, the reaction was quenched with sat aq
Na.sub.2S.sub.2O.sub.3, and extracted with EtOAc (2.times.15 ml).
The combined organic layer was washed with brine (10 ml), dried
(MgSO.sub.4), filtered and concentrated to afford tert-butyl
N-[(9R,13S)-17-cyano-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(20 mg 100%). MS(ESI) m/z: 460.5 (M+H).sup.+.
270C. Preparation of
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[-
12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaene-17-carbonitrile
##STR00446##
[2054] To tert-butyl
N-[(9R,13S)-17-cyano-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate
(20 mg, 0.044 mmol) was added dioxane (1 ml) followed by 1 ml of 4
N HCl in dioxane. After 3 h, the reaction was concentrated and
residue dissolved in DCM/MeOH and filtered through a basic
cartridge. Concentration of the filtrate afforded
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[-
12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaene-17-carbonitrile
(12 mg, 80%) as a brown solid. MS(ESI) m/z: 360.4 (M+H).sup.+.
270D. Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8-oxo-3,-
4,7-triazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaene-1-
7-carbonitrile
[2055]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8--
oxo-3,4,7-triazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaene-17-carbonitrile
(2.2 mg, 9.6%) was prepared in a similar manner as described in
Example 56 by using
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[-
12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaene-17-carbonitrile.
MS(ESI) m/z: 683.9 (M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 8.71 (s, 1H), 8.13 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.80
(m, 2H), 7.68-7.61 (m, 3H), 7.58-7.51 (m, 2H), 6.34 (s, 1H), 5.62
(d, J=12.9 Hz, 1H), 2.45-2.34 (m, 1H), 2.22 (br. s., 1H), 2.00 (d,
J=16.2 Hz, 1H), 1.64 (d, J=10.2 Hz, 2H), 1.44 (d, J=7.2 Hz, 1H),
1.06 (d, J=6.6 Hz, 3H), 0.62 (br. s., 1H). Analytical HPLC (Method
C) RT=1.93 min, purity=100% as a mixture of diastereomers; Factor
XIa Ki=0.35 nM, Plasma Kallikrein Ki=84 nM.
Example 271
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-methyl-1H-imidazol-1-yl)phenyl]-6-oxo-1,6-d-
ihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00447##
[2057]
(9R,13S)-13-{4-[5-Chloro-2-(4-methyl-1H-imidazol-1-yl)phenyl]-6-oxo-
-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.-
0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (11.7 mg, 45% yield) was a major product isolated
from the preparation of
(9R,13S)-13-{4-[5-chloro-2-(5-methyl-1H-imidazol-1-yl)phenyl]-6-oxo-1,6-d-
ihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate,
Example 257. MS(ESI) m/z: 569.20 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.23 (s, 1H), 9.14 (br. s., 1H), 8.77 (s,
1H), 8.68 (d, J=4.9 Hz, 1H), 7.94 (d, J=2.1 Hz, 1H), 7.85 (dd,
J=8.4, 2.3 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.59 (d,
J=5.2 Hz, 1H), 7.52-7.47 (m, 2H), 6.60 (s, 1H), 5.90 (d, J=9.8 Hz,
1H), 4.01 (s, 3H), 2.69-2.61 (m, 1H), 2.35-2.24 (m, 4H), 2.16-2.06
(m, 1H), 1.88-1.78 (m, 1H), 1.52-1.42 (m, 1H), 1.38-1.28 (m, 1H),
0.89 (d, J=7.0 Hz, 3H), 0.53-0.38 (m, 1H). Analytical HPLC (Method
C): RT=1.14 min, 100% purity; Factor XIa Ki=90 nM, Plasma
Kallikrein Ki=4,600 nM.
Example 272
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-hydroxypyridin-4-y-
l)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,-
14,16-pentaen-8-one
##STR00448##
[2059]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-methoxypyridin-4-
-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,-
5,14,16-pentaen-8-one, prepared as described in Example 269, (0.02
g, 0.027 mmol) was dissolved in THF (2 mL) and conc. HCl (500
.mu.l, 6.00 mmol) was added and the reaction mixture was heated to
70.degree. C. for 16 h. After this time, the solvents were
concentrated and the residue was purified by reverse phase
chromatography to give
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-hydroxypyridin-4-yl)-9-
-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,1-
6-pentaen-8-one (5.3 mg, 26%). MS(ESI) m/z: 721.2 (M+H).sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.59 (s, 1H), 9.24 (s,
1H), 8.73 (s, 1H), 8.60 (d, J=4.9 Hz, 1H), 8.43 (s, 1H), 8.05 (br.
s., 1H), 7.98 (d, J=1.8 Hz, 1H), 7.92 (s, 1H), 7.90-7.79 (m, 2H),
7.63 (d, J=4.0 Hz, 1H), 6.96 (br. s., 1H), 6.51 (s, 1H), 6.14-5.94
(m, 1H), 2.79 (br. s., 1H), 2.27 (d, J=17.1 Hz, 2H), 1.91-1.77 (m,
1H), 1.64-1.50 (m, 1H), 1.49-1.34 (m, 1H), 0.94 (d, J=6.7 Hz, 3H),
0.64-0.42 (m, 1H). Analytical HPLC (Method C): RT=1.68 min,
purity=100%; Factor XIa Ki=0.73 nM, Plasma Kallikrein Ki=130
nM.
Example 274
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1,3-oxazol-2-yl)phenyl]-6-oxo-1,6-dihydropyri-
midin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octade-
ca-1(18),2(6),4,14,16-pentaen-8-one
##STR00449##
[2061] To a degassed dioxane (1 ml) solution of
(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-
,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one (20 mg, 0.033 mmol),
prepared as described in Example 211, was added
2-(tributylstannyl)oxazole (11.65 mg, 0.033 mmol), followed by
addition of Pd(Ph.sub.3P).sub.4 (3.76 mg, 3.25 .mu.mol). The
reaction was stirred at 90.degree. C. for 2 h, then cooled to rt
and concentrated. Purification by reverse phase chromatography
afforded
(9R,13S)-13-{4-[5-chloro-2-(1,3-oxazol-2-yl)phenyl]-6-oxo-1,6-dihydropyri-
midin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octade-
ca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (2.38 mg, 11%
yield) as a white solid. MS(ESI) m/z: 556.4 (M+H).sup.+. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.89 (s, 1H), 8.74 (d, J=5.1 Hz,
1H), 7.92 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 7.71 (s, 1H), 7.69 (d,
J=2.2 Hz, 1H), 7.65 (dd, J=8.4, 2.2 Hz, 1H), 7.52 (dd, J=5.1, 1.5
Hz, 1H), 7.49 (s, 1H), 7.23 (s, 1H), 6.50 (s, 1H), 6.05 (dd,
J=12.7, 4.1 Hz, 1H), 4.05 (s, 3H), 2.77-2.67 (m, 1H), 2.38-2.27 (m,
1H), 2.15-1.98 (m, 2H), 1.68-1.42 (m, 2H), 1.01 (d, J=7.0 Hz, 3H),
0.77-0.62 (m, 1H). Analytical HPLC (Method A): RT=7.13 min, 99.0%
purity; Factor XIa Ki=100 nM, Plasma Kallikrein Ki=4,500 nM.
Example 275
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[(pyrazin-2-yl)amino]phenyl}-6-oxo-1,6-dihydro-
pyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]oc-
tadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00450##
[2063] A sealed microwave vial containing
(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]--
3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one hydrochloride (0.01 g,
0.017 mmol), prepared as described in Example 313, 2-bromopyrazine
(5.51 mg, 0.035 mmol) and EtOH (1 ml) was heated in a microwave at
150.degree. C. for 30 min, cooled to rt, and concentrated. To the
residue were added Cs.sub.2CO.sub.3 (0.030 g, 0.093 mmol),
Pd(OAc).sub.2 (1.05 mg, 4.66 .mu.mol), Xantphos (5.39 mg, 9.31
.mu.mol), and 2-bromopyrazine (5.51 mg, 0.035 mmol), followed by
dioxane (0.931 ml). The reaction mixture was degassed with Ar for
10 min. The vial was sealed and heated at 85.degree. C. After 4 h,
the reaction was cooled to rt and concentrated. Purification by
reverse phase chromatography afforded
(9R,13S)-13-(4-{5-chloro-2-[(pyrazin-2-yl)amino]phenyl}-6-oxo-1,6-dihydro-
pyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]oc-
tadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (2.95 mg,
20% yield) as a yellow solid. MS(ESI) m/z: 582.5 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.09 (s, 1H), 8.73 (d,
J=5.1 Hz, 1H), 8.23-8.19 (m, 2H), 8.08 (dd, J=2.8, 1.4 Hz, 1H),
7.89 (d, J=2.6 Hz, 1H), 7.73 (s, 1H), 7.67 (d, J=2.6 Hz, 1H), 7.53
(dd, J=5.1, 1.5 Hz, 1H), 7.50 (s, 1H), 7.43 (dd, J=8.9, 2.5 Hz,
1H), 6.77 (s, 1H), 6.02 (dd, J=12.7, 4.3 Hz, 1H), 4.05 (s, 3H),
2.76-2.67 (m, 1H), 2.43-2.32 (m, 1H), 2.15-2.01 (m, 2H), 1.68-1.44
(m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.81-0.65 (m, 1H). Analytical HPLC
(Method A): RT=7.06 min, 94.0% purity; Factor XIa Ki=560 nM.
Example 276
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(4-hydroxypyrimidin-5-yl)-9-me-
thyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-p-
entaen-8-one
##STR00451##
[2065]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(4-hydroxypyrimidin-5-yl)-9--
methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-
-pentaen-8-one trifluoroacetate was prepared in a similar manner as
the procedure described in Example 296, to give
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(4-hydroxypyrimidin-5-yl)-9-methyl-
-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-penta-
en-8-one trifluoroacetate (3.82 mg, 4.44 .mu.mol, 42% yield).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.85 (s, 1H), 8.75 (s,
2H), 8.71 (s, 1H), 8.67-8.62 (m, 1H), 8.27 (s, 1H), 8.00-7.93 (m,
2H), 7.82-7.69 (m, 3H), 6.49 (s, 1H), 6.13 (d, J=9.2 Hz, 1H), 2.87
(br. s., 1H), 2.29 (br. s., 2H), 2.13-2.01 (m, 1H), 1.76 (d, J=10.3
Hz, 1H), 1.59 (br. s., 1H), 1.29 (s, 1H), 1.11 (d, J=7.0 Hz, 3H),
0.91 (br. s., 1H). MS(ESI) m/z: 704.5 [M+H].sup.+. Analytical HPLC
(Method A): RT=7.04 min, purity=>95.0%; Factor XIa Ki=2.4 nM,
Plasma Kallikrein Ki=70 nM.
Example 277
Preparation of ethyl
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihyd-
ropyrimidin-4-yl}phenyl)-3-methyl-1H-pyrazole-4-carboxylate
##STR00452##
[2067] To a suspension of ethyl 3-methyl-1H-pyrazole-4-carboxylate
(3.51 mg, 0.023 mmol), K.sub.3PO.sub.4 (9.79 mg, 0.046 mmol) and
(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-
,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one (14 mg, 0.023 mmol) in
dioxane (0.24 mL) was added
(1R,2R)--N1,N2-dimethylcyclohexane-1,2-diamine (1.619 mg, 0.011
mmol). The mixture was purged with Ar, CuI (0.434 mg, 2.277
.mu.mol) was added, and the vial was sealed. The reaction was
heated at 80.degree. C. and stirred overnight. The solution was
concentrated and the residue purified by reverse phase
chromatography to give ethyl
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihyd-
ropyrimidin-4-yl}phenyl)-3-methyl-1H-pyrazole-4-carboxylate
trifluoroacetate (3.21 mg, 17% yield) as a white solid. MS(ESI)
m/z: 641.2 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.86 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.20 (s, 1H), 7.84 (d, J=2.2
Hz, 1H), 7.68 (s, 1H), 7.67-7.61 (m, 1H), 7.60-7.54 (m, 1H),
7.53-7.47 (m, 2H), 6.20 (s, 1H), 6.02-5.95 (m, 1H), 4.30-4.21 (m,
2H), 4.07-4.01 (m, 3H), 2.70 (td, J=6.7, 3.2 Hz, 1H), 2.36 (s, 3H),
2.33-2.24 (m, 1H), 2.13-1.95 (m, 2H), 1.65-1.53 (m, 1H), 1.51-1.40
(m, 1H), 1.34-1.26 (m, 3H), 1.00 (d, J=7.0 Hz, 3H), 0.69 (m, 1H).
Analytical HPLC (Method A): RT=7.46 min, 94% purity; Factor XIa
Ki=170 nM, Plasma Kallikrein Ki=2,700 nM.
Example 278
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(3,4-dimethyl-1H-pyrazol-1-yl)phenyl]-6-oxo-1,-
6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.s-
up.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00453##
[2069]
(9R,13S)-13-{4-[5-Chloro-2-(3,4-dimethyl-1H-pyrazol-1-yl)phenyl]-6--
oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3-
.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (0.85 mg, 5% yield) was prepared in a similar
manner as the procedure described in Example 277, by replacing
ethyl 3-methyl-1H-pyrazole-4-carboxylate with
3,4-dimethyl-1H-pyrazole (2.189 mg, 0.023 mmol). MS(ESI) m/z: 583.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.91 (s,
1H), 8.72 (d, J=5.1 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.68 (s, 1H),
7.60 (dd, J=8.6, 2.4 Hz, 1H), 7.51 (dd, J=5.1, 1.5 Hz, 1H),
7.49-7.46 (m, 2H), 7.39 (s, 1H), 6.02-5.94 (m, 2H), 4.04 (s, 3H),
2.71 (d, J=3.1 Hz, 1H), 2.37-2.24 (m, 1H), 2.14 (s, 3H), 2.00 (s,
3H), 1.93 (s, 1H), 1.66-1.54 (m, 1H), 1.48 (m, 1H), 1.01 (d, J=6.8
Hz, 3H), 0.68 (m, 1H). Analytical HPLC (Method A): RT=6.78 min, 92%
purity; Factor XIa Ki=540 nM.
Example 279
Preparation of ethyl
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihyd-
ropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carboxylate
##STR00454##
[2071] Ethyl
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carboxylate
trifluoroacetate (9.9 mg, 56% yield) was prepared in a similar
manner as the procedure described in Example 277, by replacing
ethyl 3-methyl-1H-pyrazole-4-carboxylate with ethyl
1H-pyrazole-4-carboxylate (3.19 mg, 0.023 mmol). MS(ESI) m/z: 627.1
(M+H).sup.+. .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.86
(s, 1H), 8.72 (d, J=5.3 Hz, 1H), 8.34 (s, 1H), 7.96 (s, 1H), 7.85
(d, J=2.2 Hz, 1H), 7.69 (s, 1H), 7.68-7.64 (m, 1H), 7.61-7.57 (m,
1H), 7.53 (dd, J=5.2, 1.7 Hz, 1H), 7.49 (s, 1H), 6.18 (s, 1H), 5.98
(dd, J=12.7, 4.3 Hz, 1H), 4.28 (q, J=7.1 Hz, 2H), 4.04 (s, 3H),
2.70 (td, J=6.7, 3.3 Hz, 1H), 2.30 (tt, J=12.7, 4.4 Hz, 1H),
2.12-1.94 (m, 2H), 1.66-1.53 (m, 1H), 1.46 (ddd, J=15.0, 9.8, 5.5
Hz, 1H), 1.32 (t, J=7.2 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H), 0.69 (m,
1H). Analytical HPLC (Method A): RT=7.06 min, 99% purity; Factor
XIa Ki=2.2 nM, Plasma Kallikrein Ki=960 nM.
Example 280
Preparation of
(9R,13S)-13-[4-(5-chloro-2-hydroxyphenyl)-6-oxo-1,6-dihydropyrimidin-1-yl-
]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2-
(6),4,14,16-pentaen-8-one
##STR00455##
[2073] The mixture of 1H-imidazole (2.21 mg, 0.033 mmol),
Pd(OAc).sub.2 (0.73 mg, 3.25 .mu.mol) and CuI (0.012 g, 0.065 mmol)
in DMF (1.63 ml) was purged with Ar (3.times.), and then
(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-
,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6)-
,4,14,16-pentaen-8-one (0.02 g, 0.033 mmol), prepared as described
in Example 211, was added. The reaction was sealed and heated at
140.degree. C. After 5 h, the reaction was cooled to rt. The
solution was concentrated and the residue was purified by reverse
phase chromatography afforded
(9R,13S)-13-[4-(5-chloro-2-hydroxyphenyl)-6-oxo-1,6-dihydropyrim-
idin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadec-
a-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (1.76 mg, 9%
yield) as a yellow solid. MS(ESI) m/z: 505.6 (M+H).sup.+. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 9.11 (s, 1H), 8.74 (d, J=5.1 Hz,
1H), 7.84 (d, J=2.6 Hz, 1H), 7.72 (s, 1H), 7.52 (dd, J=5.1, 1.5 Hz,
1H), 7.50 (s, 1H), 7.30 (dd, J=8.8, 2.6 Hz, 1H), 7.07 (s, 1H), 6.90
(d, J=8.8 Hz, 1H), 6.06 (dd, J=12.9, 4.5 Hz, 1H), 4.05 (s, 3H),
2.78-2.68 (m, 1H), 2.35 (tt, J=12.8, 4.3 Hz, 1H), 2.16-2.01 (m,
2H), 1.68-1.45 (m, 2H), 1.01 (d, J=7.0 Hz, 3H), 0.76-0.61 (m, 1H).
Analytical HPLC (Method A): RT=8.47 min, 100% purity; Factor XIa
Ki=57 nM, Plasma Kallikrein Ki=180 nM.
Example 281
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-imidazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatr-
icyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00456##
[2075]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-imidazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricy-
clo[12.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (4 mg, 15% yield) was prepared in a similar manner
as the procedure described in Example 231, by replacing
1H-imidazole with 4-(trifluoromethyl)-1H-imidazole (0.018 g, 0.130
mmol). MS(ESI) m/z: 623.25 (M+H).sup.+. .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 8.84 (s, 1H), 8.70 (d, J=5.2 Hz, 1H), 7.86 (s,
1H), 7.83 (d, J=2.5 Hz, 1H), 7.74 (s, 1H), 7.71-7.66 (m, 2H), 7.58
(d, J=8.5 Hz, 1H), 7.52-7.47 (m, 2H), 6.40 (s, 1H), 5.99 (dd,
J=12.5, 3.4 Hz, 1H), 4.04 (s, 3H), 2.70 (dt, J=6.6, 3.3 Hz, 1H),
2.33-2.23 (m, 1H), 2.12-1.92 (m, 2H), 1.65-1.55 (m, 1H), 1.52-1.41
(m, 1H), 1.01 (d, J=6.9 Hz, 3H), 0.76-0.60 (m, 1H). Analytical HPLC
(Method C): RT=1.58 min, 100% purity; Factor XIa Ki=73 nM, Plasma
Kallikrein Ki=4,700 nM.
Example 282
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-4-methanesulfonyl-9-methyl-3,4,7,15-tetraazatri-
cyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one,
and
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-methanesulfonyl-9-methyl-3,4,7,15-tetraazatri-
cyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00457##
[2077] To a cooled (0.degree. C.), clear, pale pink solution of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
(0.010 g, 0.014 mmol), prepared as described in Example 101, and
pyridine (0.012 ml, 0.145 mmol) was added MsCl (1.1 .mu.l, 0.014
mmol). The reaction was stirred for 30 min at 0.degree. C. and then
the reaction was warmed to rt. After 1 h at rt, TEA (0.020 ml,
0.145 mmol) was added followed by MsCl (1.1 .mu.l, 0.014 mmol).
After 3 h, additional TEA (0.020 ml, 0.145 mmol) was added followed
by the additional of MsCl (5.5 .mu.L, 0.070 mmol). After 1 h, the
reaction was stopped, diluted with EtOAc and washed with 1.5 M
K.sub.2HPO.sub.4, brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated to give a yellow residue. Purification by reverse
phase chromatography, gave after concentration and lyophilization a
1:1 mixture of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-o-
xo-1,6-dihydropyrimidin-1-yl}-4-methanesulfonyl-9-methyl-3,4,7,15-tetraaza-
tricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
trifluoroacetate and
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-methanesulfonyl-9-methyl-3,4,7,15-tetraazatri-
cyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (0.0020 g, 18%) as a white solid. MS(ESI) m/z:
654.0 (M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.87
(s, 1H), 8.79 (s, 1H), 8.67 (d, J=5.2 Hz, 2H), 8.34-8.32 (m, 2H),
8.28 (s, 1H), 7.90-7.87 (m, 4H), 7.75-7.71 (m, 2H), 7.66-7.63 (m,
3H), 7.62-7.60 (m, 1H), 7.55 (dd, J=5.2, 1.7 Hz, 1H), 6.38-6.36 (m,
2H), 6.13-6.06 (m, 1H), 5.99-5.93 (m, 1H), 3.52 (s, 3H), 3.49 (s,
3H), 2.86-2.79 (m, 1H), 2.68-2.61 (m, 1H), 2.32-2.20 (m, 3H),
2.07-1.90 (m, 3H), 1.76-1.64 (m, 1H), 1.62-1.38 (m, 3H), 1.04 (d,
J=6.9 Hz, 3H), 0.98 (d, J=6.9 Hz, 3H), 0.80-0.61 (m, 2H).
Analytical HPLC (Method A): RT=7.98 and 8.11 min, purity=96.9%;
Factor XIa Ki=1.2 nM, Plasma Kallikrein Ki=290 nM.
Example 283
Preparation of
(9R,13S)-13-(4-{2,3-difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl-
]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4-
,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentae-
n-8-one
##STR00458##
[2079]
(9R,13S)-13-(4-{2,3-Difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazo-
l-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-meth-
yl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16--
pentaen-8-one (12 mg, 100% yield) as a solid was prepared via the
coupling of
6-{2,3-difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}py-
rimidin-4-ol (0.007 g, 0.02 mmol) and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6), 4,14,16-pentaen-8-one (0.07 g,
0.02 mmol) using the HATU, DBU coupling methodology as described in
Example 56. MS m/z=662.1 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.34-9.30 (m, 1H), 9.15-9.11 (m, 1H),
8.74-8.71 (m, 1H), 8.63-8.59 (m, 1H), 7.85-7.79 (m, 2H), 7.72-7.67
(m, 1H), 7.64-7.61 (m, 1H), 7.38-7.35 (m, 1H), 6.62-6.58 (m, 1H),
5.88-5.73 (m, 1H), 2.63-2.50 (m, 1H), 2.24-2.10 (m, 1H), 2.02-1.92
(m, 1H), 1.83-1.69 (m, 1H), 1.46-1.16 (m, 2H), 0.84-0.70 (d, 3H),
0.37-0.17 (m, 1H). Analytical HPLC (Method B) RT=1.73 min,
purity=99%; Factor XIa Ki=2 nM, Plasma Kallikrein Ki=570 nM.
Example 284
Preparation of methyl
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihyd-
ropyrimidin-4-yl}phenyl)-1H-imidazole-4-carboxylate
##STR00459##
[2081] Methyl
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-1H-imidazole-4-carboxylate
trifluoroacetate (10 mg, 24% yield) was prepared in a similar
manner as the procedure described in Example 231, by replacing
1H-imidazole with 1H-imidazole-4-carboxylate hydrochloride (0.025
g, 0.195 mmol). MS(ESI) m/z: 613.5 (M+H).sup.+. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.80 (s, 1H), 8.68 (d, J=5.3 Hz, 1H), 8.29
(s, 1H), 8.06 (s, 1H), 7.87 (d, J=2.2 Hz, 1H), 7.72 (dd, J=8.6, 2.4
Hz, 1H), 7.68 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.51 (dd, J=5.1, 1.5
Hz, 1H), 7.49 (s, 1H), 6.47 (s, 1H), 5.96 (dd, J=12.4, 3.9 Hz, 1H),
4.04 (s, 3H), 3.87 (s, 3H), 2.75-2.65 (m, 1H), 2.33-2.22 (m, 1H),
2.11-1.92 (m, 2H), 1.64-1.39 (m, 2H), 1.00 (d, J=6.8 Hz, 3H), 0.67
(br. s., 1H). Analytical HPLC (Method A): RT=6.10 min, 99.9%
purity; Factor XIa Ki=16 nM, Plasma Kallikrein Ki=1,800 nM.
Example 285
Preparation of
(9R,13S)-13-[4-(2,5-dichlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9--
dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,-
14,16-pentaen-8-one
##STR00460##
[2083]
(9R,13S)-13-[4-(2,5-Dichlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl-
]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2-
(6),4,14,16-pentaen-8-one trifluoroacetate (4.3 mg, 13% yield) was
a minor product isolated from the preparation of methyl
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-1H-imidazole-4-carboxylate, Example
284. MS(ESI) m/z: 523.5 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 9.04 (s, 1H), 8.74 (d, J=5.3 Hz, 1H), 7.73 (s,
1H), 7.68 (d, J=2.4 Hz, 1H), 7.55-7.49 (m, 3H), 7.49-7.44 (m, 1H),
6.77 (d, J=0.7 Hz, 1H), 6.06 (dd, J=12.7, 4.1 Hz, 1H), 4.05 (s,
3H), 2.78-2.68 (m, 1H), 2.38 (tt, J=12.8, 4.3 Hz, 1H), 2.16-2.02
(m, 2H), 1.68-1.45 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.70 (br. s.,
1H). Analytical HPLC (Method A): RT=8.29 min, 98.6% purity; Factor
XIa Ki=50 nM, Plasma Kallikrein Ki=770 nM.
Example 286
Preparation of
(9R,13R)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0-
.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
##STR00461##
[2084] 286A. Preparation of
(9R,13R)-13-amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00462##
[2086]
(9R,13R)-13-Amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0.s-
up.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (15 mg, 100%
yield) was prepared in a similar manner as the procedures described
in Intermediate 28, by replacing
(S)-2-methyl-N-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]-
but-3-en-1-yl]propane-2-sulfinamide (Diastereomer B) with
(S)-2-methyl-N-[(1R)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]-
but-3-en-1-yl]propane-2-sulfinamide (Diastereomer A). MS(ESI) m/z:
300.5 (M+H).sup.+.
286B. Preparation of
(9R,13R)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)
phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[2087]
(9R,13R)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12-
.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (7.2 mg, 19% yield) was prepared in a similar
manner as the procedure described in Example 56, by using
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(15.4 mg, 0.050 mmol) and
(9R,13R)-13-amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one, (15 mg, 0.050 mmol),
prepared as described in Example 286A. MS(ESI) m/z: 590.25
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.47 (s,
1H), 8.72 (s, 1H), 8.66 (s, 1H), 7.94 (t, J=7.9 Hz, 1H), 7.90 (d,
J=2.4 Hz, 1H), 7.85-7.79 (m, 1H), 7.77-7.70 (m, 2H), 7.52 (s, 1H),
7.23 (d, J=7.6 Hz, 1H), 6.48 (s, 1H), 5.89 (dd, J=12.4, 2.9 Hz,
1H), 4.10 (s, 3H), 3.91 (s, 1H), 3.08-2.94 (m, 1H), 2.74 (dt,
J=11.4, 5.8 Hz, 1H), 1.70-1.57 (m, 1H), 1.50-1.29 (m, 3H), 1.05 (d,
J=6.7 Hz, 3H), 0.98 (m, 1H). Analytical HPLC (Method B): RT 1.64
min, purity=95%; Factor XIa Ki=1,800 nM.
Example 287
Preparation of
(9R,13S)-13-(4-{2,3-difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl-
]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl-9-methy-
l-3,4,7,17-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-p-
entaen-8-one
##STR00463##
[2089]
(9R,13S)-13-(4-{2,3-Difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazo-
l-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(.sup.2H.sub.3)methyl-9-
-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,1-
4,16-pentaen-8-one (3 mg, 27% yield) as a solid was prepared via
the coupling of
6-{2,3-difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrim-
idin-4-ol (0.005 g, 0.015 mmol) and
(9R,13S)-13-amino-3-(.sup.2H.sub.3)methyl-9-methyl-3,4,7,17-tetraazatricy-
clo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(0.004 g, 0.015 mmol) using the HATU, DBU coupling methodology as
described in Example 56. MS m/z=629.1 (M+H).sup.+. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.30-9.26 (m, 1H), 9.23-9.17 (m, 1H),
8.67-8.61 (m, 1H), 8.58-8.53 (m, 1H), 7.96-7.86 (m, 1H), 7.81-7.74
(m, 2H), 7.45 (s, 1H), 6.98-6.94 (m, 1H), 6.73-6.69 (m, 1H),
5.65-5.48 (m, 1H), 2.55 (s, 1H), 2.44-2.28 (m, 1H), 2.03-1.81 (m,
2H), 1.99-1.76 (m, 2H), 1.53-1.38 (m, 2H), 1.32-1.19 (m, 1H),
1.15-1.06 (d, 3H), 1.01-0.91 (m, 1H). Analytical HPLC (Method B)
RT=1.55 min, purity=94%; Factor XIa Ki=4 nM, Plasma Kallikrein
Ki=520 nM.
Example 288
Preparation of
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-1H-imidazole-4-carboxylic acid
##STR00464##
[2091] To the solution of methyl
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihyd-
ropyrimidin-4-yl}phenyl)-1H-imidazole-4-carboxylate (0.008 g, 9.51
.mu.mol), prepared as described in Example 284, in MeOH (1 ml) was
added 1 N NaOH (0.057 ml, 0.057 mmol). After stirring at rt for 24
h, the reaction was quenched with a few drops of TFA. Purification
by reverse phase chromatography afforded
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihyd-
ropyrimidin-4-yl}phenyl)-1H-imidazole-4-carboxylic acid
trifluoroacetate (4.8 mg, 61% yield) as a white solid. MS(ESI) m/z:
599.5 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.76
(s, 1H), 8.71-8.66 (m, 2H), 8.11 (br. s., 1H), 7.89 (d, J=2.2 Hz,
1H), 7.77-7.72 (m, 1H), 7.70-7.65 (m, 2H), 7.51-7.48 (m, 2H), 6.58
(s, 1H), 5.97 (dd, J=12.5, 4.2 Hz, 1H), 4.04 (s, 3H), 2.75-2.64 (m,
1H), 2.34-2.22 (m, 1H), 2.12-1.93 (m, 2H), 1.65-1.39 (m, 2H), 1.00
(d, J=6.8 Hz, 3H), 0.79-0.62 (m, 1H). Analytical HPLC (Method A):
RT=5.13 min, 99.5% purity; Factor XIa Ki=3.7 nM, Plasma Kallikrein
Ki=450 nM.
Example 289
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0-
.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00465##
[2093]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12-
.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (1.8 mg, 5% yield) was prepared in a similar
manner as the procedure described in Example 56, by using
6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol
(15.4 mg, 0.050 mmol) and
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one, 15 mg, 0.050 mmol),
prepared as described in Intermediate 28. MS(ESI) m/z: 590.25
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.41 (s,
1H), 8.71 (s, 1H), 8.15 (s, 1H), 7.97 (t, J=7.8 Hz, 1H), 7.90 (d,
J=2.4 Hz, 1H), 7.84-7.79 (m, 1H), 7.75 (dd, J=8.1, 6.0 Hz, 2H),
7.52 (s, 1H), 7.20 (d, J=7.9 Hz, 1H), 6.48 (s, 1H), 5.97 (d, J=8.5
Hz, 1H), 4.04 (s, 3H), 3.91 (s, 1H), 2.58 (m, 1H), 2.44-2.31 (m,
1H), 2.09 (d, J=7.6 Hz, 1H), 1.83-1.73 (m, 1H), 1.53-1.39 (m, 2H),
1.23 (m, 1H), 1.00 (d, J=6.7 Hz, 3H). Analytical HPLC (Method B):
RT 1.59 min, purity=93%; Factor XIa Ki=2.3 nM, Plasma Kallikrein
Ki=380 nM.
Example 290
Preparation of
(10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-
-1,6-dihydropyrimidin-1-yl}-10-methyl-3,5,8-triazatricyclo[13.3.1.0.sup.2,-
7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
##STR00466##
[2095]
(10R,14S)-14-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-
-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,5,8-triazatricyclo[13.3.1.0.-
sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one trifluoroacetate
(0.004 g, 28%) was prepared according to the procedures described
in Example 206 by using
(10R,14S)-14-amino-10-methyl-3,5,8-triazatricyclo[13.3.1.0.sup.2-
,7]nonadeca-1(19),2,4,6,15,17-hexaen-9-one, prepared as described
in Intermediate 38, and 4-bromopyrimidin-5-amine in prepared as
described in Intermediate 38B. MS(ESI) m/z: 587.1 (M+H).sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.18 (s, 1H), 8.71 (s,
1H), 8.35-8.31 (m, 2H), 8.01 (s, 1H), 7.87 (d, J=2.4 Hz, 1H),
7.86-7.83 (m, 1H), 7.76-7.71 (m, 1H), 7.67-7.62 (m, 2H), 7.35 (d,
J=7.9 Hz, 1H), 6.42 (d, J=0.7 Hz, 1H), 5.84 (dd, J=13.0, 3.7 Hz,
1H), 2.72-2.59 (m, 1H), 2.40-2.27 (m, 1H), 2.18-2.07 (m, 1H),
2.03-1.94 (m, 1H), 1.68-1.56 (m, 1H), 1.46-1.33 (m, 2H), 1.15 (d,
J=7.0 Hz, 3H). Analytical HPLC (Method A): RT=8.12 min,
purity>99%; Factor XIa Ki=2.4 nM, Plasma Kallikrein Ki=150
nM.
Example 292
Preparation of
(9R,13S)-13-{4-[5-chloro-1-(2-hydroxyethyl)-1H-indazol-7-yl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00467##
[2096] 292A and 292B. Preparation of
7-bromo-5-chloro-1-(2-methoxyethyl)-1H-indazole, and
7-bromo-5-chloro-2-(2-methoxyethyl)-2H-indazole
[2097] To a suspension of 7-bromo-5-chloro-1H-indazole (2.0 g, 8.64
mmol) and K.sub.2CO.sub.3 (5.97 g, 43.2 mmol) in DMSO (9.97 mL) was
added 1-bromo-2-methoxyethane (0.812 mL, 8.64 mmol) at rt under a
blanket of Ar. After 14 h, the reaction mixture was diluted with
water, extracted with EtOAc. The combined organic layer was washed
with water, brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The crude mixture of regioisomers (1:1) was purified
by normal phase chromatography using hexanes and EtOAc as eluants
to afford 7-bromo-5-chloro-1-(2-methoxyethyl)-1H-indazole as the
early eluting isomer (less polar) (0.766 g, 30%) and
7-bromo-5-chloro-2-(2-methoxyethyl)-2H-indazole as the late eluting
isomer (more polar) (1.18 g, 47%).
[2098] 292A. MS(ESI) m/z: 290 (M+H).sup.+ and 292 (M+2+H).sup.+.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.97 (s, 1H), 7.66 (d,
J=1.7 Hz, 1H), 7.56 (d, J=1.9 Hz, 1H), 4.98 (t, J=6.1 Hz, 2H), 3.85
(t, J=6.1 Hz, 2H), 3.34 (s, 3H).
[2099] 292B. MS(ESI) m/z: 290 (M+H).sup.+ and 292 (M+2+H).sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.08 (s, 1H), 7.60 (d,
J=1.5 Hz, 1H), 7.48 (d, J=1.8 Hz, 1H), 4.64-4.59 (m, 2H), 3.89-3.84
(m, 2H), 3.34 (s, 3H).
292C. Preparation of
5-chloro-1-(2-methoxyethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)-1H-indazole
[2100] To a stirring solution of
7-bromo-5-chloro-1-(2-methoxyethyl)-1H-indazole (0.766 g, 2.65
mmol) in dioxane (13.23 mL) at RT was added
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.773
g, 3.04 mmol) and KOAc (1.194 g, 12.17 mmol) and the system was
purged with Ar (3.times.). Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2
complex (0.173 g, 0.212 mmol) was added, the reaction was purged
with Ar, and heated to 90.degree. C.
[2101] After stirring overnight, the reaction mixture was cooled to
rt, diluted with water, extracted with EtOAc (3.times.). The
combined organic layer was washed with water, brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. MS(ESI) m/z: 337
(M+H).sup.+.
292D. Preparation of
5-chloro-1-(2-methoxyethyl)-7-(6-methoxypyrimidin-4-yl)-1H-indazole
[2102] 4-Chloro-6-methoxypyrimidine (0.574 g, 3.97 mmol),
5-chloro-1-(2-methoxyethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)-1H-indazole (0.891 g, 2.65 mmol) and 2 M aq Na.sub.2CO.sub.3
(2.65 mL, 5.29 mmol) were added to DME (17.65 mL)/EtOH (2.206 mL)
and purged with Ar for several min. Pd(dppf)CH.sub.2Cl.sub.2Adduct
(0.216 g, 0.265 mmol) was added and the reaction heated at
90.degree. C. After 14 h, the reaction was diluted with water,
extracted with EtOAc, the organic layer washed with brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated to give a brown
oil. The crude material was purified by normal phase chromatography
using hexanes and EtOAc as eluents to give
5-chloro-1-(2-methoxyethyl)-7-(6-methoxypyrimidin-4-yl)-1H-indazole
(0.777 g, 92% yield) brown oil. MS(ESI) m/z: 319 (M+H).sup.+.
292E. Preparation of
6-(5-chloro-1-(2-hydroxyethyl)-1H-indazol-7-yl)pyrimidin-4-ol
trifluoroacetate
[2103] To a suspension of
5-chloro-1-(2-methoxyethyl)-7-(6-methoxypyrimidin-4-yl)-1H-indazole
(0.300 g, 0.941 mmol) in ACN (3.14 mL) was added TMSI (1 mL, 7.35
mmol) at rt. Then, the clear yellow solution was heated to
50.degree. C. After 4 h, the reaction mixture was cooled to rt,
concentrated and purified by reverse phase chromatography
(PHENOMENEX.RTM. Luna Axia C18 5.mu. 30.times.100 mm column,
10-minute gradient; Solvent A: 30% MeOH-70% H.sub.2O-0.1% TFA;
Solvent B: 90% MeOH-10% H.sub.2O-0.1% TFA) to give
6-(5-chloro-1-(2-hydroxyethyl)-1H-indazol-7-yl)pyrimidin-4-ol
trifluoroacetate (0.127 g, 33.3% yield) as a yellow solid. MS(ESI)
m/z: 291 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.52 (d, J=0.9 Hz, 1H), 8.17 (s, 1H), 7.95 (d, J=2.0 Hz, 1H), 7.47
(d, J=2.0 Hz, 1H), 6.79 (d, J=0.9 Hz, 1H), 4.45 (t, J=5.9 Hz, 2H),
3.80 (t, J=5.9 Hz, 2H).
292F. Preparation of
(9R,13S)-13-{4-[5-chloro-1-(2-hydroxyethyl)-1H-indazol-7-yl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[2104]
(9R,13S)-13-{4-[5-Chloro-1-(2-hydroxyethyl)-1H-indazol-7-yl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (6.6 mg, 29%) was prepared in a similar manner as
Example 56 using
6-(5-chloro-1-(2-hydroxyethyl)-1H-indazol-7-yl)pyrimidin-4-ol
trifluoroacetate and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one, prepared
as described in Intermediate 30. MS(ESI) m/z: 609 (M+H).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.36 (s, 1H), 9.02 (s,
1H), 8.70 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.93 (d, J=2.0 Hz, 1H),
7.85 (s, 1H), 7.69 (s, 1H), 7.40-7.35 (m, 2H), 6.68 (s, 1H), 5.93
(d, J=8.6 Hz, 1H), 4.40-4.28 (m, 2H), 3.50-3.39 (m, 2H), 2.64-2.58
(m, 1H), 2.38-2.30 (m, 1H), 2.11-1.99 (m, 1H), 1.96-1.85 (m, 1H),
1.50-1.39 (m, 1H), 1.36-1.27 (m, 1H), 0.83 (d, J=7.0 Hz, 3H),
0.38-0.28 (m, 1H). Analytical HPLC (Method A): RT=7.16 min,
purity=>95%; Factor XIa Ki=180 nM.
Example 293
Preparation of
(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimid-
in-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00468##
[2105] 293A. Preparation of
5-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole
[2106] To a solution of 7-bromo-5-chloro-1H-indole (0.470 g, 2.039
mmol) in dioxane (10.20 mL) at rt was added
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.595
g, 2.345 mmol) and KOAc (0.921 g, 9.38 mmol), and the system was
purged with Ar (3.times.). Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2complex
(0.133 g, 0.163 mmol) was added and the reaction mixture was again
purged with Ar, and heated to 90.degree. C. After stirring
overnight, the reaction mixture was cooled to rt, diluted with
water, extracted with EtOAc (3.times.), organics washed with water,
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated and
the crude material was carried forward to the next reaction.
MS(ESI) m/z: 278 (M+H).sup.+.
293B. Preparation of
5-chloro-7-(6-methoxypyrimidin-4-yl)-1H-indole
[2107] 4-Chloro-6-methoxypyrimidine (0.391 g, 2.70 mmol),
5-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole
(0.500 g, 1.801 mmol) and 2 M aq Na.sub.2CO.sub.3 (1.801 ml, 3.60
mmol) were added to DME (14.41 mL)/EtOH (1.801 mL) and purged with
Ar for several min. PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2Adduct (0.147
g, 0.180 mmol) was added and heated at 90.degree. C. After 2 h, the
reaction was diluted with water and extracted with EtOAc. The
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The crude material was purified by
normal phase chromatography using hexanes and EtOAc as eluants to
give 5-chloro-7-(6-methoxypyrimidin-4-yl)-1H-indole (0.339 g, 72.5%
yield) as an amber solid. MS(ESI) m/z: 260 (M+H).sup.+. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 11.21 (br. s., 1H), 11.36-11.06 (m,
1H), 8.91 (d, J=1.1 Hz, 1H), 7.77-7.74 (m, 1H), 7.72 (d, J=1.8 Hz,
1H), 7.40-7.38 (m, 1H), 7.30 (d, J=1.1 Hz, 1H), 6.56 (dd, J=3.1,
2.4 Hz, 1H), 4.07 (s, 2H).
293C. Preparation of
6-(5-chloro-1-methyl-1H-indol-7-yl)pyrimidin-4-ol
[2108] MeI (0.212 ml, 3.39 mmol) was added to a suspension of
5-chloro-7-(6-methoxypyrimidin-4-yl)-1H-indole (0.339 g, 1.305
mmol) and K.sub.2CO.sub.3 (0.902 g, 6.53 mmol) in DMSO (5.22 mL) at
rt. After stirring overnight, the reaction mixture was partitioned
between dilute NH.sub.4Cl solution and EtOAc. The organic layer was
washed dilute NaHCO.sub.3 and Na.sub.2S2O.sub.3 solution,
NaHCO.sub.3, brine, then dried over MgSO.sub.4, filtered and
evaporated to dryness. The residue was dissolved in AcOH (5 mL) and
treated with 45% aq HBr i (1.73 mL, 14.36 mmol) and heated to
85.degree. C. After 2 h, the reaction was cooled to rt, then
concentrated to dryness and the material was carried forward to the
reaction. MS(ESI) m/z: 260 (M+H).sup.+.
293D. Preparation of
(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimid-
in-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.su-
p.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[2109]
(9R,13S)-13-[4-(5-Chloro-1-methyl-1H-indol-7-yl)-6-oxo-1,6-dihydrop-
yrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.-
1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (4 mg, 18%) was prepared in a similar manner as
Example 56 using 6-(5-chloro-1-methyl-1H-indol-7-yl)pyrimidin-4-ol
and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one,
prepared as described in Intermediate 30. MS(ESI) m/z: 578
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.36 (s,
1H), 8.98 (s, 1H), 8.70 (d, J=5.1 Hz, 1H), 7.85 (s, 1H), 7.69 (s,
1H), 7.65 (d, J=2.0 Hz, 1H), 7.39-7.35 (m, 2H), 7.03 (d, J=2.0 Hz,
1H), 6.57 (s, 1H), 6.46 (d, J=3.1 Hz, 1H), 5.94-5.90 (m, 1H), 3.53
(s, 3H), 2.63-2.60 (m, 1H), 2.35-2.30 (m, 1H), 2.06-2.02 (m, 1H),
1.95-1.88 (m, 1H), 1.46-1.40 (m, 1H), 1.34-1.28 (m, 1H), 0.82 (d,
J=6.8 Hz, 3H), 0.37-0.29 (m, 1H). Analytical HPLC (Method A):
RT=9.19 min, purity=>95%; Factor XIa Ki=390 nM.
Example 294
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00469##
[2110] 294A. Preparation of
5-chloro-2-(2-methoxyethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)-2H-indazole
[2111]
5-Chloro-2-(2-methoxyethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)-2H-indazole was prepared in a similar manner as Example
292C replacing 7-bromo-5-chloro-1-(2-methoxyethyl)-1H-indazole,
prepared as described in Example 292B with
7-bromo-5-chloro-2-(2-methoxyethyl)-2H-indazole, prepared as
described in Example 292C. MS(ESI) m/z: 337 (M+H).sup.+.
294B. Preparation of
5-chloro-2-(2-methoxyethyl)-7-(6-methoxypyrimidin-4-yl)-2H-indazole
[2112]
5-Chloro-2-(2-methoxyethyl)-7-(6-methoxypyrimidin-4-yl)-2H-indazole
(300 mg, 26%) was prepared in a similar manner as described in
Example 292D using
5-chloro-2-(2-methoxyethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)-2H-indazole. MS(ESI) m/z: 319 (M+H).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.87 (d, J=1.1 Hz, 1H), 8.39 (t, J=1.8 Hz, 2H),
8.09 (s, 1H), 7.75 (d, J=2.0 Hz, 1H), 4.63 (t, J=5.2 Hz, 2H), 4.06
(s, 3H), 3.92-3.88 (m, 2H), 3.35 (s, 3H).
294C. Preparation of
6-(5-chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl)pyrimidin-4-ol
[2113]
6-(5-Chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl)pyrimidin-4-ol, (50
mg, 18%) was prepared in a similar manner as Example 292E using
5-chloro-2-(2-methoxyethyl)-7-(6-methoxypyrimidin-4-yl)-2H-indazole.
MS(ESI) m/z: 291 (M+H).sup.+ and 293 (M+2+H).sup.+. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.71 (s, 1H), 8.46 (s, 1H), 8.22 (d,
J=2.0 Hz, 1H), 8.05 (s, 1H), 8.01 (d, J=1.8 Hz, 1H), 4.65 (t, J=5.2
Hz, 2H), 4.14-4.09 (m, 2H).
294D. Preparation of
(9R,13S)-13-{4-[5-chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl]-6-oxo-1,6-di-
hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[2114]
(9R,13S)-13-{4-[5-Chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatr-
icyclo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate was prepared (2 mg, 8.8%) in a similar manner as
Example 56 using
6-(5-chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl)pyrimidin-4-ol and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one,
prepared as described in Intermediate 30. MS(ESI) m/z: 609
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.36 (s,
1H), 9.00 (s, 1H), 8.69 (d, J=5.1 Hz, 1H), 8.49 (s, 1H), 8.21 (d,
J=2.2 Hz, 1H), 8.03-7.97 (m, 2H), 7.85 (s, 1H), 7.68 (s, 1H), 7.37
(d, J=6.2 Hz, 1H), 5.92-5.89 (m, 1H), 4.48 (t, J=5.3 Hz, 2H), 3.82
(t, J=5.3 Hz, 2H), 2.62-2.59 (m, 1H), 2.34-2.29 (m, 1H), 2.07-2.02
(m, 1H), 1.91-1.87 (m, 1H), 1.47-1.41 (m, 1H), 1.34-1.29 (m, 1H),
0.83 (d, J=6.8 Hz, 3H), 0.38-0.30 (m, 1H). Analytical HPLC (Method
A): RT=7.86 min, purity=>95%; Factor XIa Ki=6,100 nM.
Example 295
Preparation of
(9R,13S)-13-[4-(6-chloro-1-methyl-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrim-
idin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00470##
[2115] 295A. Preparation of
6-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole
[2116]
6-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-
e was prepared in a similar manner as described in Example 293A
replacing 7-bromo-5-chloro-1H-indole with
4-bromo-6-chloro-1H-indazole. MS(ESI) m/z: 197
(M-C.sub.6H.sub.10+H).sup.+.
295B. Preparation of
6-chloro-4-(6-methoxypyrimidin-4-yl)-1H-indazole
[2117] 6-Chloro-4-(6-methoxypyrimidin-4-yl)-1H-indazole (183 mg,
33%) was prepared in a similar manner as described in Example 293B
using
6-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole.
MS(ESI) m/z: 261 (M+H).sup.+.
295C. Preparation of
6-(6-chloro-1-methyl-1H-indazol-4-yl)pyrimidin-4-ol
[2118] MeI (0.12 mL, 1.825 mmol) was added to a suspension of
6-chloro-4-(6-methoxypyrimidin-4-yl)-1H-indazole (0.183 g, 0.702
mmol) and K.sub.2CO.sub.3 (0.485 g, 3.51 mmol) in DMSO (2.81 mL) at
rt. After stirring overnight, the reaction mixture was partitioned
between dilute aq NH.sub.4Cl solution and EtOAc. The organic layer
was washed with dilute NaHCO.sub.3 and Na.sub.2S.sub.2O.sub.3
solution, NaHCO.sub.3, brine, then dried over MgSO.sub.4, filtered,
and evaporated to dryness. This mixture of regioisomers (2:1) was
carried forward to the next reaction. The residue was dissolved in
AcOH (3 mL), treated with 45% aq HBr (0.932 ml, 7.72 mmol), and
heated to 85.degree. C. After 1 h, the reaction mixture was
concentrated to dryness, and the crude reaction mixture was
purified by reverse phase chromatography (PHENOMENEX.RTM. Luna Axia
C18 5.mu. 30.times.100 mm column, 10-minute gradient; Solvent A:
30% ACN-70% H.sub.2O-0.1% TFA; Solvent B: 80% ACN-20% H.sub.2O-0.1%
TFA) to give the desired isomer,
6-(6-chloro-1-methyl-1H-indazol-4-yl) pyrimidin-4-ol (0.127 g,
69.4%) as a white solid and undesired isomer,
6-(6-chloro-2-methyl-2H-indazol-4-yl)pyrimidin-4-ol (0.051 g,
27.9%) as an off-white solid. The methyl group is more downfield
for the undesired isomer than for the desired. MS(ESI) m/z: 261
(M+H).sup.+. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) .delta. 12.69
(br. s., 1H), 8.51 (d, J=0.9 Hz, 1H), 8.37 (d, J=0.7 Hz, 1H),
8.03-7.99 (m, 1H), 7.77-7.74 (m, 1H), 6.99 (d, J=0.9 Hz, 1H), 4.09
(s, 3H).
295D. Preparation of
(9R,13S)-13-[4-(6-chloro-1-methyl-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrim-
idin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[2119]
(9R,13S)-13-[4-(6-Chloro-1-methyl-1H-indazol-4-yl)-6-oxo-1,6-dihydr-
opyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.-
3.1.0.sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate was prepared (1.5 mg, 6.9%) in a similar manner as
Example 56 using 6-(6-chloro-1-methyl-1H-indazol-4-yl)
pyrimidin-4-ol and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one, prepared
as described in Intermediate 30. MS(ESI) m/z: 579 (M+H).sup.+.
Analytical HPLC (Method A): RT=8.40 min, purity=>95%; Factor XIa
Ki=7,400 nM.
Example 296
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-4-(6-hydroxypyridin-3-yl)-9-methyl-3,4,7,15-tet-
raazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
##STR00471##
[2121]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-4-(6-methoxypyridin-3-yl)-9-methyl-3,4,7,-
15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one, prepared
as described in Example 233, was dissolved in THF (1 mL) and HCl
(0.5 mL). The solution was heated to 70.degree. C. for 8 h, then
cooled to rt, concentrated and purified by reverse phase
chromatography to give
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-4-(6-hydroxypyridin-3-yl)-9-methyl-3,4,7,15-tet-
raazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
trifluoroacetate (2.2 mg, 21%). MS(ESI) m/z: 669.3 (M+H).sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.55-9.54 (m, 1H), 9.52
(s, 1H), 8.76-8.65 (m, 2H), 8.58 (d, J=5.2 Hz, 1H), 8.38 (s, 1H),
8.03 (d, J=9.8 Hz, 1H), 7.98 (d, J=2.7 Hz, 1H), 7.92 (d, J=2.1 Hz,
1H), 7.87 (s, 1H), 7.84-7.78 (m, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.56
(d, J=5.2 Hz, 1H), 6.57 (d, J=9.8 Hz, 1H), 6.36 (s, 1H), 6.03-5.90
(m, 1H), 2.33-2.15 (m, 2H), 1.93-1.78 (m, 1H), 1.63-1.50 (m, 1H),
1.49-1.35 (m, 1H), 0.94 (d, J=6.7 Hz, 3H), 0.65-0.49 (m, 1H).
Analytical HPLC (Method C): RT=1.41 min, purity=95%; Factor XIa
Ki=1 nM, Plasma Kallikrein Ki=43 nM.
Example 297
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,6-dihyd-
ropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00472##
[2122] 297A. Preparation of
1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]ethan-1-one
##STR00473##
[2124] A solution of 4-(2-bromo-5-chlorophenyl)-6-methoxypyrimidine
(0.173 g, 0.578 mmol), CeF (0.351 g, 2.310 mmol) in
ClCH.sub.2CH.sub.2Cl (3 mL) was purged with Ar, and
Pd(PPh.sub.3).sub.4 (0.033 g, 0.029 mmol) and
1-(trimethylsilyl)ethanone (0.165 mL, 1.155 mmol) were added. The
reaction mixture was purged with Ar, sealed and heated at
75.degree. C. for 2 days then cooled down to rt. Hexane (1 ml) was
added, reaction mixture was filtered through a pad of CELITE.RTM.,
rinsed with 10 ml EtOAc, filtrate concentrated. Purification by
normal phase chromatography gave
1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl] ethan-1-one (0.057
g, 38% yield). MS(ESI) m/z: 263.08 (M+H).sup.+.
297B. Preparation of
N'-{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]ethenyl}
ethoxycarbohydrazide
##STR00474##
[2126] To a solution of
1-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)ethanone (0.057 g,
0.217 mmol) and ethyl hydrazinecarboxylate (0.022 g, 0.217 mmol) in
EtOH (3 mL) was added 2 drops of conc. aq HCl. The reaction was
heated at 75.degree. C. for 2 h. After this time, the reaction
mixture was concentrated to yield crude solid
N'-{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]ethenyl}ethoxycarbohydr-
azide. MS(ESI) m/z: 349.4 (M+H).sup.+.
297C. Preparation of
4-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-methoxypyrimidine
##STR00475##
[2128] To
N'-{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]ethenyl}
ethoxycarbohydrazide (0.076 g, 0.217 mmol) in a vial was added
SOCl.sub.2 (0.32 ml, 4.34 mmol), and the resulting solution was
stirred at rt for 30 min, then heated at 60.degree. C. for 1 h.
After this time, the solution was cooled to rt. To the reaction
mixture was added MeOH, and the solution was concentrated. The
residue was purified by reverse phase chromatography to afford
4-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-1,2,3-thiadiazole
(0.017 g, 26% yield) as a yellow solid. MS(ESI) m/z: 305.0
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.87 (s,
1H), 8.63 (d, J=1.1 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.76 (d, J=2.0
Hz, 1H), 7.71 (dd, J=8.4, 2.2 Hz, 1H), 6.82 (d, J=1.1 Hz, 1H), 4.02
(s, 3H).
297D. Preparation of
6-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]pyrimidin-4-ol
##STR00476##
[2130]
4-(4-Chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-1,2,3-thiadiazole
(0.059 g, 0.194 mmol) in AcOH (2 ml) was added 48% aq HBr (1.1 ml,
9.68 mmol), and the solution was heated at 85.degree. C. for 1 h
then cooled to rt. The reaction mixture was concentrated. The
residue was dissolved in EtOAc, washed with sat aq NaHCO.sub.3,
brine, dried over MgSO.sub.4, filtered and concentrated to give
6-(5-chloro-2-(1,2,3-thiadiazol-4-yl) phenyl)pyrimidin-4-ol (0.053
g, 94% yield) as an off-white solid. MS(ESI) m/z: 291.0
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.84 (s,
1H), 7.94 (s, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H),
7.55 (dd, J=8.4, 2.2 Hz, 1H), 6.27 (d, J=0.7 Hz, 1H).
297E. Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,6-dihyd-
ropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate
[2131]
(9R,13S)-13-{4-[5-Chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,6-
-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricy-
clo [12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (0.006 g, 7.7%) was prepared according to the
procedures described in Example 56 by using
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one, prepared
as described in Intermediate 30, and
6-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]pyrimidin-4-ol, MS(ESI)
m/z: 609.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD .delta.
8.93 (s, 1H), 8.87 (s, 1H), 8.74 (d, J=5.1 Hz, 1H), 7.82-7.63 (m,
6H), 7.54-7.50 (m, 1H), 6.38 (s, 1H), 6.02 (dd, J=12.8, 4.8 Hz,
1H), 2.78-2.65 (m, 1H), 2.35-2.22 (m, 1H), 2.10-1.96 (m, 2H),
1.65-1.54 (m, 1H), 1.53-1.42 (m, 1H), 0.99 (d, J=7.0 Hz, 3H), 0.63
(br. s., 1H). Analytical HPLC (Method A): RT=8.80 min,
purity>96%; Factor XIa Ki=1.6 nM, Plasma Kallikrein Ki=520
nM.
Example 298
Preparation of
(9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]-
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatri-
cyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00477##
[2132] 298A. Preparation of
4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)
phenyl)-6-methoxypyrimidine
[2133]
4-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-
-6-methoxypyrimidine (42 mg, 25% yield) was prepared in a similar
manner as the procedure described in Example 238C, by replacing
1H-pyrazole-4-carbonitrile with 4-(trifluoromethyl)-1H-pyrazole
(37.3 mg, 0.274 mmol). MS(ESI) m/z: 373.3 (M+H).sup.+. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.68 (d, J=1.1 Hz, 1H), 7.76 (s, 1H),
7.70 (s, 1H), 7.62 (dd, J=8.6, 7.7 Hz, 1H), 7.36 (dd, J=8.7, 1.7
Hz, 1H), 6.78 (t, J=1.2 Hz, 1H), 4.01 (s, 3H).
298B. Preparation of
6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)
phenyl)pyrimidin-4-ol
[2134]
6-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-
pyrimidin-4-ol (0.017 g, 42.1% yield) was prepared in a similar
manner as the procedure described for the preparation of
1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbon-
itrile as described in Intermediate 18C, by replacing
1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbon-
itrile with
4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-6-met-
hoxypyrimidine (0.042 g, 0.113 mmol). MS(ESI) m/z: 359.4
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.36 (d,
J=0.9 Hz, 1H), 8.09 (d, J=1.1 Hz, 1H), 7.85 (s, 1H), 7.81-7.74 (m,
1H), 7.50 (dd, J=8.7, 1.7 Hz, 1H), 6.50 (t, J=1.1 Hz, 1H).
298C. Preparation of
(9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]-
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatri-
cyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[2135]
(9R,13S)-13-(4-{3-Chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-pyrazol-
-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetr-
aazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (13 mg,
37% yield) was prepared in a similar manner as the procedure
described in Example 56, by replacing
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol with
6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phe-
nyl)pyrimidin-4-ol (17 mg, 0.047 mmol). MS(ESI) m/z: 641.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.40 (s,
1H), 8.85 (br. s., 1H), 8.72 (d, J=4.8 Hz, 1H), 8.31 (s, 1H),
7.85-7.74 (m, 2H), 7.69 (s, 1H), 7.55-7.44 (m, 3H), 6.53 (s, 1H),
6.02 (dd, J=12.4, 3.9 Hz, 1H), 4.05 (s, 3H), 2.70 (td, J=6.6, 3.1
Hz, 1H), 2.37-2.22 (m, 1H), 2.15-1.91 (m, 2H), 1.69-1.54 (m, 1H),
1.53-1.39 (m, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.70 (m., 1H).
Analytical HPLC (Method A): RT=8.81 min, purity=99%; Factor XIa
Ki=3.8 nM, Plasma Kallikrein Ki=1,200 nM.
Example 299
Preparation of
(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-
-yl]-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(-
6),4,14,16-pentaen-8-one
##STR00478##
[2136] 299A. Preparation of
(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-
-yl]-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[2137]
(9R,13S)-13-[4-(3-Chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrim-
idin-1-yl]-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraaza-
tricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one (78 mg, 89% yield) was
prepared in a similar manner as the procedures described in Example
56, by using 6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol (0.033
g, 0.137 mmol), prepared as described in Intermediate 4, and
(9R,13S)-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazat-
ricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(0.057 g, 0.137 mmol), prepared as described in Intermediate 19.
MS(ESI) m/z: 641.6 [M+H].sup.+.
299B. Preparation of
(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-
-yl]-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(-
6),4,14,16-pentaen-8-one trifluoroacetate
[2138] To a solution of
(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-
-yl]-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyc-
lo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (78
mg, 0.122 mmol), in DCM (1.6 mL) was added TFA (0.4 mL, 5.19 mmol)
and the resulting solution was stirred at rt for 30 min. The
reaction mixture was then concentrated and the residue was purified
by prep HPLC purification to give
(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyr-
imidin-1-yl]-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate (70 mg, 0.112 mmol, 92% yield). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.31 (s, 1H), 8.95 (s, 1H), 8.57 (br.
s., 1H), 7.92-7.71 (m, 3H), 7.48 (d, J=4.0 Hz, 1H), 7.31 (t, J=8.9
Hz, 1H), 6.70 (s, 1H), 5.99 (br. s., 1H), 2.73 (br. s., 1H), 2.30
(br. s., 2H), 2.01-1.88 (m, 1H), 1.60-1.37 (m, 2H), 0.93 (d, J=6.7
Hz, 3H), 0.64 (br. s., 1H). MS(ESI) m/z: 511.3 [M+H].sup.+.
Analytical HPLC (Method B): RT=1.47 min, purity=94.0%; Factor XIa
Ki=970 nM.
Example 300
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,6-dihyd-
ropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]-
octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00479##
[2140]
(9R,13S)-13-{4-[5-Chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,6-
-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.su-
p.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate
(0.0072 g, 37.8%) was prepared in a similar manner as the procedure
described in Example 297 using
(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one, prepared as described
in Intermediate 32. MS(ESI) m/z: 573.2 (M+H).sup.+. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.98 (s, 1H), 8.85 (s, 1H), 8.76 (d,
J=5.3 Hz, 1H), 7.82 (d, J=8.1 Hz, 1H), 7.78 (s, 1H), 7.76 (d, J=2.2
Hz, 1H), 7.68 (dd, J=8.1, 2.2 Hz, 1H), 7.61 (dd, J=5.3, 1.5 Hz,
1H), 7.52 (s, 1H), 6.40 (s, 1H), 5.99 (dd, J=12.8, 4.4 Hz, 1H),
4.07 (s, 3H), 2.77-2.67 (m, 1H), 2.39-2.27 (m, 1H), 2.14-2.00 (m,
2H), 1.69-1.56 (m, 1H), 1.55-1.41 (m, 1H), 1.03 (d, J=7.0 Hz, 3H),
0.76 (br. s., 1H). Analytical HPLC (Method A): RT=7.46 min,
purity>99%; Factor XIa Ki=1.5 nM, Plasma Kallikrein Ki=280
nM.
Example 301
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-hydroxypyridin-4-yl)-9-meth-
yl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pen-
taen-8-one
##STR00480##
[2142]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-4-yl)-9-me-
thyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-p-
entaen-8-one, prepared as described in Example 323, (0.02 g, 0.027
mmol) was dissolved in THF (2 mL) and HCl (500 .mu.l, 6.00 mmol)
and heated to 70.degree. C. for 16 h. The solvents were
concentrated. The residue was purified by reverse phase
chromatography to give
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-hydroxypyridin-4-yl)-9-methyl-3-
,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-
-8-one. (1.1 mg, 6%). MS(ESI) m/z: 703.0 (M+H).sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 9.58 (s, 1H), 9.33-9.18 (m, 1H),
8.84-8.69 (m, 2H), 8.59 (d, J=4.6 Hz, 1H), 7.98 (br. s., 1H),
7.95-7.79 (m, 3H), 7.71-7.51 (m, 2H), 6.97-6.78 (m, 2H), 6.59-6.47
(m, 1H), 6.04 (br. s., 1H), 2.80 (br. s., 1H), 2.27 (br. s., 2H),
1.97-1.75 (m, 2H), 1.57 (br. s., 1H), 1.42 (br. s., 1H), 0.94 (d,
J=6.7 Hz, 3H), 0.53 (br. s., 1H). Analytical HPLC (Method C):
RT=1.58 min, purity=100%; Factor XIa Ki=0.16 nM, Plasma Kallikrein
Ki=8 nM.
Example 302
Preparation of
(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-
-yl]-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
##STR00481##
[2144]
(9R,13S)-13-[4-(3-Chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrim-
idin-1-yl]-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one trifluoroacetate
(13.7 mg, 0.019 mmol, 33% yield) was prepared in a similar manner
as the procedure described in Example 216, by using
5-iodopyrimidine (24 mg, 0.117 mmol) and
(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimid-
in-1-yl]-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (30 mg,
0.059 mmol), as described in Example 299. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.58 (s, 1H), 9.35 (s, 2H), 9.15 (s, 1H),
8.97 (s, 1H), 8.76 (s, 1H), 8.63 (d, J=4.9 Hz, 1H), 7.92 (s, 1H),
7.74 (td, J=8.7, 5.8 Hz, 1H), 7.61 (d, J=4.9 Hz, 1H), 7.29 (t,
J=9.0 Hz, 1H), 6.69 (s, 1H), 6.01 (d, J=11.6 Hz, 1H), 2.77 (br. s.,
1H), 2.28 (br. s., 2H), 1.99-1.88 (m, 1H), 1.54 (br. s., 1H), 1.43
(br. s., 1H), 0.91 (d, J=6.7 Hz, 3H), 0.55 (br. s., 1H). MS(ESI)
m/z: 589.2 [M+H].sup.+. Analytical HPLC (Method B): RT=1.64 min,
purity=100.0%; Factor XIa Ki=100 nM, Plasma Kallikrein Ki=530
nM.
Example 303
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(pyridazin-4-yl)phenyl]-6-oxo-1,6-dihydropyrim-
idin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadec-
a-1(18),2(6),4,14,16-pentaen-8-one
##STR00482##
[2146] To a degassed solution of
(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-
,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6)-
,4,14,16-pentaen-8-one (20 mg, 0.033 mmol), prepared as described
in Example 211, 4-(tributylstannyl)pyridazine (18.01 mg, 0.049
mmol), CuI (1.24 mg, 6.51 .mu.mol), and CsF (9.88 mg, 0.065 mmol)
in ACN (1 ml) was added Pd(Ph.sub.3P).sub.4 (3.76 mg, 3.25
.mu.mol). After stirring at 45.degree. C. for 2 h, the reaction was
cooled to rt and concentrated. Purification by reverse phase
chromatography afforded
(9R,13S)-13-{4-[5-chloro-2-(pyridazin-4-yl)phenyl]-6-oxo-1,6-dihydropyrim-
idin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadec-
a-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (14.9 mg, 67%
yield). MS(ESI) m/z: 567.35 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.27-9.19 (m, 2H), 9.09 (br. s., 1H), 8.76
(s, 1H), 8.67 (d, J=5.2 Hz, 1H), 7.80 (d, J=1.8 Hz, 1H), 7.74 (dd,
J=8.2, 2.1 Hz, 1H), 7.68-7.56 (m, 4H), 7.48 (s, 1H), 6.50 (s, 1H),
5.92-5.83 (m, 1H), 4.01 (s, 3H), 2.69-2.60 (m, 1H), 2.31-2.22 (m,
1H), 2.14-2.04 (m, 1H), 1.89-1.78 (m, 1H), 1.53-1.42 (m, 1H),
1.38-1.26 (m, 1H), 0.88 (d, J=6.7 Hz, 3H), 0.50-0.32 (m, 1H).
Analytical HPLC (Method C): RT=1.28 min, 100% purity; Factor XIa
Ki=110 nM, Plasma Kallikrein Ki=9,300 nM.
Example 304
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-4-(2-hydroxypyrimidin-5-yl)-9-methyl-3,4,7,15-t-
etraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
##STR00483##
[2148]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-4-(2-hydroxypyrimidin-5-yl)-9-methyl-3,4,-
7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
trifluoroacetate was prepared in a similar manner as the procedure
described in Example 216, by using 5-iodopyrimidin-2-ol (9.63 mg,
0.043 mmol) to give
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-4-(2-hydroxypyrimidin-5-yl)-9-methyl-3,4,7,15-t-
etraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
trifluoroacetate (0.9 mg, 1.032 .mu.mol, 2% yield). .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 9.44 (s, 1H), 8.85-8.66 (m, 4H),
8.55 (d, J=4.9 Hz, 1H), 8.40 (s, 1H), 7.95-7.83 (m, 2H), 7.81-7.66
(m, 2H), 7.53 (d, J=4.6 Hz, 1H), 6.34 (s, 1H), 5.95 (br. s., 1H),
2.74 (br. s., 1H), 2.24 (d, J=14.6 Hz, 2H), 1.80 (br. s., 1H), 1.51
(br. s., 1H), 1.37 (br. s., 1H), 0.89 (d, J=6.4 Hz, 3H), 0.50 (br.
s., 1H). MS(ESI) m/z: 670.2 [M+H].sup.+. Analytical HPLC (Method
B): RT=1.39 min, purity=90.0%; Factor XIa Ki=0.17 nM, Plasma
Kallikrein Ki=14 nM.
Example 305
Preparation of
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,8,17-triazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
##STR00484##
[2149] 305A. Preparation of (S)-tert-butyl
(1-(5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)pyridin-3-yl)but-3-en-1-yl)ca-
rbamate
[2150] To a solution of
5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (2.9 g, 12.84
mmol) and (S)-tert-butyl
(1-(5-bromopyridin-3-yl)but-3-en-1-yl)carbamate (3.0 g, 9.17 mmol)
in toluene (38.8 mL) were added KOAc (2.70 g, 27.5 mmol) and Pd
(dppf) Cl.sub.2 CH.sub.2Cl.sub.2Adduct (0.599 g, 0.733 mmol). The
reaction was purged with Ar for 10 min and then heated at
90.degree. C. for 12 h. The reaction mixture was diluted with EtOAc
and then filtered through CELITE.RTM.. The filtrate was washed with
water, brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. MS(ESI) m/z: 293 (M-C.sub.6H.sub.10+H).sup.+.
305B. Preparation of (S)-tert-butyl
(1-(3'-amino-[3,4'-bipyridin]-5-yl)but-3-en-1-yl)carbamate
[2151] (S)-tert-Butyl
(1-(5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)pyridin-3-yl)but-3-en-1-yl)ca-
rbamate (1.5 g, 4.16 mmol), 4-bromopyridin-3-amine (0.72 g, 4.16
mmol), 4 M NaHCO.sub.3 (3.12 mL, 12.49 mmol) were added to dioxane
(5 mL) and purged with Ar. After 15 min, Pd(PPh.sub.3).sub.4 (0.241
g, 0.208 mmol) was added and the mixture heated at 90.degree. C.
overnight. The reaction mixture was diluted with water (100 ml) and
extracted with EtOAc (2.times.50 ml), washed with brine, dried and
evaporated to a black oil and was carried forward to the next
reaction. MS(ESI) m/z: 341.2 (M+H).sup.+.
305C. Preparation of tert-butyl
((S)-1-(3'-((R)-2-methylbut-3-enamido)-[3,4'-bipyridin]-5-yl)but-3-en-1-y-
l)carbamate
[2152] (R)-2-Methylbut-3-enoic acid (0.576 g, 5.76 mmol),
(S)-tert-butyl
(1-(3'-amino-[3,4'-bipyridin]-5-yl)but-3-en-1-yl)carbamate (1.4 g,
4.11 mmol), pyridine (0.998 ml, 12.34 mmol) in EtOAc (43.8 ml) was
cooled to 0.degree. C. T3P.RTM. (50% wt in EtOAc) (5.23 g, 8.23
mmol) was added and the solution allowed to gradually come to rt.
After 3 h, reaction mixture was concentrated and the residue
purified by normal phase chromatography using EtOAc and MeOH as
eluants to give tert-butyl
((S)-1-(3'-((R)-2-methylbut-3-enamido)-[3,4'-bipyridin]-5-yl)but-3-en-1-y-
l)carbamate (747 mg, 43%) as a brown oil. MS(ESI) m/z: 423.2
(M+H).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 9.38 (br.
s., 1H), 8.66 (s, 1H), 8.57-8.47 (m, 2H), 7.62 (br. s., 1H), 7.44
(br. s., 1H), 7.20 (d, J=4.1 Hz, 1H), 5.86-5.76 (m, 1H), 5.75-5.65
(m, 1H), 5.21-5.10 (m, 3H), 3.71 (d, J=11.0 Hz, 3H), 3.09 (t, J=7.3
Hz, 1H), 2.66-2.46 (m, 2H), 1.44-1.39 (m, 9H), 1.28 (d, J=7.2 Hz,
3H).
305D. Preparation of tert-butyl
N-[(10R,11E,14S)-10-methyl-9-oxo-5,8,17-triazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamat-
e
[2153] tert-Butyl
((S)-1-(3'-((R)-2-methylbut-3-enamido)-[3,4'-bipyridin]-5-yl)but-3-en-1-y-
l)carbamate (0.747 g, 1.768 mmol) and pTsOH (0.689 g, 3.62 mmol)
were added to EtOAc (1040 mL) and heated to 60.degree. C. while
purging with Ar. After 1 h, Second Generation Grubbs Catalyst
(0.600 g, 0.707 mmol) was added and the mixture stirred at
60.degree. C. overnight. The reaction was quenched with sat
NaHCO.sub.3 (150 mL) and extracted with EtOAc (2.times.50 mL). The
combined organic layers were washed with brine (100 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated. The crude material
was purified by normal phase chromatography DCM and MeOH as eluants
to give tert-butyl
N-[(10R,11E,14S)-10-methyl-9-oxo-5,8,17-triazatricyclo[13.3.1.0.sup.2,7]n-
onadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate (0.180 g,
25.8% yield) as a tan solid. MS(ESI) m/z: 395.2 (M+H).sup.+.
305E. Preparation of tert-butyl
N-[(10R,14S)-10-methyl-9-oxo-5,8,17-triazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate
[2154] PtO.sub.2 (10.36 mg, 0.046 mmol) was added to a solution of
tert-butyl
N-[(10R,11E,14S)-10-methyl-9-oxo-5,8,17-triazatricyclo[13.3.1.0.sup.2,7]n-
onadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate (0.180 g,
0.456 mmol) in EtOH (20 mL) and subjected to a H.sub.2 atmosphere
(55 psi). After 3 h, the suspension was filtered through a plug of
CELITE.RTM. and the filtrate concentrated and carried forward to
the next reaction. MS(ESI) m/z: 397.2 (M+H).sup.+.
305F. Preparation of
(10R,14S)-14-amino-10-methyl-5,8,17-triazatricyclo[13.3.1.0.sup.27]
nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one
[2155] TFA (0.70 mL, 9.08 mmol) was added to a stirring solution of
tert-butyl
N-[(10R,14S)-10-methyl-9-oxo-5,8,17-triazatricyclo[13.3.1.0.sup.2,7]nonad-
eca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate (0.180 g, 0.454
mmol) in DCM (5 mL) at rt. After 2 h, the reaction mixture was
concentrated to dryness. The residue was partitioned between EtOAc
and sat NaHCO.sub.3. The aqueous layer was extracted with EtOAc
(2.times.). The combined organic layer was washed with brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated to give
(10R,14S)-14-amino-10-methyl-5,8,17-triazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one (0.037
g, 27.5%) as a brown film. MS(ESI) m/z: 297.2 (M+H).sup.+.
305G. Preparation of
(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]ph-
enyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,8,17-triazatricyclo
[13.3.1.0.sup.2,7]nonadeca-1(19),2,4,6,15,17-hexaen-9-one,
bis-trifluoroacetate
[2156]
(10R,14S)-14-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-
-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-5,8,17-triazatricyc-
lo[13.3.1.0.sup.2,7]nonadeca-1(19),2,4,6,15,17-hexaen-9-one,
bis-trifluoroacetate was prepared (5.2 mg, 11%) in a similar manner
as Example 56 using
(10R,14S)-14-amino-10-methyl-5,8,17-triazatricyclo[13.3.1.0.sup.2,7]nonad-
eca-1(19),2(7),3,5,15,17-hexaen-9-one and
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol, prepared as described in Intermediate 15. MS(ESI) m/z: 621.2
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.69 (s,
1H), 9.19-9.13 (m, 1H), 8.64-8.55 (m, 2H), 8.49 (s, 1H), 8.41-8.38
(m, 1H), 8.03 (s, 1H), 7.87-7.84 (m, 1H), 7.79-7.73 (m, 2H), 7.64
(d, J=4.6 Hz, 1H), 6.42 (s, 1H), 5.51 (d, J=12.8 Hz, 1H), 1.90-1.84
(m, 1H), 1.75-1.67 (m, 1H), 1.39-1.32 (m, 1H), 1.14-1.02 (m, 2H),
0.95-0.85 (m, 3H). Analytical HPLC (Method A): RT=6.96 min,
purity=93%; Factor XIa Ki=0.17 nM, Plasma Kallikrein Ki=25 nM.
Example 306
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(piperidin-4-yl)-3,4,7,15-tetraazatr-
icyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
##STR00485##
[2158]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one, prepared as
described in Example 101, (0.020 g, 0.035 mmol), tert-butyl
4-iodopiperidine-1-carboxylate (11 mg, 0.035 mmol),
Cs.sub.2CO.sub.3 (0.023 g, 0.069 mmol), and DMF (2 mL) were added
to a vial with a Teflon septum-sealed cap. The mixture was heated
to 100.degree. C. for 12 h, at which point it was cooled to rt and
DCM (2 mL) and TFA (1 mL) were added and stirred for 1 h at rt. The
reaction was then concentrated and purified by reverse phase
chromatography to give
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(piperidin-4-yl)-3,4,7,15-tetraazatr-
icyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
trifluoroacetate (3 mg, 14%). MS(ESI) m/z: 659.1 (M+H).sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.42-9.30 (m, 1H), 8.72
(s, 2H), 8.60-8.50 (m, 1H), 7.93 (s, 2H), 7.84 (s, 2H), 7.78-7.72
(m, 1H), 7.48-7.40 (m, 1H), 6.36 (s, 1H), 6.05-5.85 (m, 1H),
4.64-4.45 (m, 1H), 3.17-3.02 (m, 2H), 2.82-2.70 (m, 1H), 1.94-1.75
(m, 1H), 1.62-1.48 (m, 1H), 1.47-1.34 (m, 1H), 0.93 (d, J=7.0 Hz,
3H), 0.70-0.49 (m, 1H). Analytical HPLC (Method C): RT=1.31 min,
purity=100%; Factor XIa Ki=700 nM.
Example 307
Preparation of
1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}-3-fluorophenyl)-1H-pyrazole-4-carbonitrile
##STR00486##
[2160]
1-(4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatric-
yclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,-
6-dihydropyrimidin-4-yl}-3-fluorophenyl)-1H-pyrazole-4-carbonitrile
trifluoroacetate (2 mg, 43% yield) was prepared in a similar manner
as the procedure described in Example 56, by replacing
6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-
-4-ol with
1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-pyra-
zole-4-carbonitrile (2 mg, 6.34 .mu.mol) prepared as described in
Example 238C. MS(ESI) m/z: 598.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.93-8.67 (m, 2H), 8.47 (s, 1H), 7.94 (s, 1H),
7.80 (dd, J=8.6, 7.7 Hz, 1H), 7.70 (s, 1H), 7.57-7.45 (m, 3H), 6.54
(s, 1H), 6.00 (dd, J=12.8, 4.2 Hz, 1H), 4.05 (s, 3H), 2.71 (td,
J=6.6, 3.3 Hz, 1H), 2.37-2.23 (m, 1H), 2.13-1.96 (m, 2H), 1.69-1.55
(m, 1H), 1.54-1.41 (m, 1H), 1.01 (d, J=7.0 Hz, 3H), 0.71 (m, 1H).
Analytical HPLC (Method A): RT=7.58 min, purity=97.1%; Factor XIa
Ki=2 nM, Plasma Kallikrein Ki=1,500 nM.
Example 308
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-4-(1H-imidazol-4-yl)-9-methyl-3,4,7,15-tetraaza-
tricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
##STR00487##
[2162]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-4-(1H-imidazol-4-yl)-9-methyl-3,4,7,15-te-
traazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
trifluoroacetate was prepared in a similar manner as the procedure
described in Example 216, by using 4-iodo-1-trityl-1H-imidazole
(18.9 mg, 0.043 mmol) followed by deprotection using 50% TFA in DCM
and Et.sub.3SiH as scavenger to yield
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-4-(1H-imidazol-4-yl)-9-methyl-3,4,7,15-tetraaza-
tricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
trifluoroacetate (3.3 mg, 3.5 .mu.mol, 7% yield). .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.75 (s, 1H), 8.69-8.62 (m, 1H), 8.37 (s,
1H), 8.24 (s, 1H), 8.03-7.90 (m, 3H), 7.79-7.74 (m, 1H), 7.73-7.66
(m, 2H), 7.55 (br. s., 1H), 6.41 (s, 1H), 6.11 (d, J=9.2 Hz, 1H),
2.88 (d, J=12.1 Hz, 1H), 2.31 (d, J=12.3 Hz, 2H), 2.09 (d, J=12.8
Hz, 1H), 1.74 (br. s., 1H), 1.59 (br. s., 1H), 1.11 (d, J=6.8 Hz,
3H), 0.92 (br. s., 1H). MS(ESI) m/z: 642.2 [M+H].sup.+. Analytical
HPLC (Method A): RT=5.74 min, purity=80.0%; Factor XIa Ki=1.9 nM,
Plasma Kallikrein Ki=180 nM.
Example 309
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1H-1,2,4-triazol-5-yl)-3,4,7,15-tet-
raazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
##STR00488##
[2164]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1H-1,2,4-triazol-5-yl)-3,4,7,-
15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one (9 mg,
33%) as a light brown powder was prepared in a similar manner as
the procedure described in Example 216, by using
5-iodo-1H-1,2,4-triazole. MS(ESI) m/z: 643.1 (M+H).sup.+. .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta. 8.76 (s, 1H), 8.67 (d, J=5.0 Hz,
1H), 8.58-8.48 (m, 1H), 8.41 (s, 1H), 8.36 (s, 1H), 7.98 (s, 1H),
7.91 (d, J=2.2 Hz, 1H), 7.81-7.72 (m, 2H), 7.67 (d, J=8.5 Hz, 1H),
6.40 (s, 1H), 6.18-6.04 (m, 1H), 2.92-2.80 (m, 1H), 2.38-2.22 (m,
2H), 2.13-2.01 (m, 1H), 1.81-1.68 (m, 1H), 1.65-1.52 (m, 1H), 1.10
(d, J=6.9 Hz, 3H), 0.91 (d, J=11.8 Hz, 2H). Analytical HPLC (Method
A): RT=6.27 min, purity=95%; Factor XIa Ki=3 nM, Plasma Kallikrein
Ki=220 nM.
Example 310
Preparation of
N-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamide
##STR00489##
[2165] 310A. Preparation of
N-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide
[2166] TEA (0.71 ml, 5.09 mmol) was added to a solution of
4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (1 g, 4.24 mmol),
prepared as described in Intermediate 8A, and TFAA (0.72 ml, 5.09
mmol) in DCM (25 ml). After stirring at rt for 1 h, the reaction
was diluted with DCM, washed with sat NaHCO.sub.3, brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated. A yellow solid
was obtained as
N-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide
(1.4 g, 99% yield). MS(ESI) m/z: 332.0 (M+H).sup.+.
310B. Preparation of
N-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide
[2167] A clear yellow solution of
N-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide
(1.4 g, 4.22 mmol) in HOAc (10 ml) and 48% aq HBr (2.39 ml, 21.10
mmol) was warmed to 60.degree. C. for 3 h, then cooled to rt, and
the reaction was concentrated. EtOAc (.about.400 ml) was added to
the residue, followed by sat NaHCO.sub.3. The layers were separated
and the organic layer was washed with sat NaHCO.sub.3, brine, dried
over MgSO.sub.4, filtered and concentrated. The residue was
suspended in DCM, and the solid was filtered off. The filtrate was
purified by normal phase chromatography to afford
N-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide
(0.095 g, 7% yield) as a white solid. MS(ESI) m/z: 318.0
(M+H).sup.+.
310C. Preparation of
N-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihyd-
ropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamide
trifluoroacetate
[2168]
N-(4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatric-
yclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,-
6-dihydropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamide
trifluoroacetate (0.113 g, 63% yield) was prepared in a similar
manner as the procedure described in Example 56, by using
N-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide
(0.095 g, 0.301 mmol). MS(ESI) m/z: 600.0 (M+H).sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 12.37 (s, 1H), 9.23 (s, 1H), 9.07
(s, 1H), 8.70 (d, J=5.1 Hz, 1H), 7.96-7.89 (m, 2H), 7.71 (s, 1H),
7.67-7.58 (m, 2H), 7.49 (s, 1H), 6.89 (br. s., 1H), 5.95 (d, J=9.5
Hz, 1H), 4.02 (s, 3H), 2.72-2.62 (m, 1H), 2.44-2.32 (m, 1H),
2.20-2.07 (m, 1H), 1.98-1.85 (m, 1H), 1.58-1.30 (m, 2H), 0.91 (d,
J=6.8 Hz, 3H), 0.58-0.39 (m, 1H). Analytical HPLC (Method A):
RT=9.82 min, 100% purity; Factor XIa Ki=1.7 nM, Plasma Kallikrein
Ki=180 nM.
Example 311
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-hydroxypyridin-3-yl)-9-meth-
yl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pen-
taen-8-one
##STR00490##
[2170]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-3-yl)-9-me-
thyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-p-
entaen-8-one, prepared as described in Example 319, (0.02 g, 0.027
mmol) was dissolved in THF (2 mL) and conc. HCl (500 .mu.l, 6.00
mmol) and heated to 70.degree. C. for 16 h. The reaction was cooled
to rt and the solution were concentrated. The residue was purified
by reverse phase chromatography to give
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-hydroxypyridin-3-yl)-9-methyl-3-
,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-
-8-one (15 mg, 64%). MS(ESI) m/z: 703.2 (M+H).sup.+. .sup.1H NMR
(500 MHz, CD.sub.3OD) .delta. 8.84 (s, 1H), 8.79 (s, 1H), 8.66 (s,
1H), 8.62 (d, J=5.0 Hz, 1H), 8.31 (dd, J=7.4, 1.9 Hz, 1H), 7.97 (s,
1H), 7.93 (d, J=2.2 Hz, 1H), 7.80-7.75 (m, 1H), 7.75-7.68 (m, 2H),
7.48 (dd, J=6.6, 1.9 Hz, 1H), 6.58 (dd, J=7.4, 6.3 Hz, 1H), 6.48
(d, J=0.6 Hz, 1H), 6.16-6.04 (m, 1H), 2.91-2.77 (m, 1H), 2.34-2.21
(m, 2H), 2.11-2.00 (m, 1H), 1.79-1.66 (m, 1H), 1.63-1.51 (m, 1H),
1.10 (d, J=6.9 Hz, 3H), 0.99-0.85 (m, 1H). Analytical HPLC (Method
A): RT=7.36 min, purity=97.6%; Factor XIa Ki=19 nM, Plasma
Kallikrein Ki=800 nM.
Example 312
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-9-methyl-3-(1H-pyrazol-3-yl)-3,4,7,15-tetraazat-
ricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00491##
[2172]
(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]--
6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-(1H-pyrazol-3-yl)-3,4,7,15-tet-
raazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
trifluoroacetate was prepared in a similar manner as the procedure
described in Example 216, by using 3-iodo-1-trityl-1H-pyrazole
(18.9 mg, 0.043 mmol) followed by deprotection using 50% TFA in DCM
and Et.sub.3SiH as scavenger to yield
(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo--
1,6-dihydropyrimidin-1-yl}-4-(1H-imidazol-4-yl)-9-methyl-3,4,7,15-tetraaza-
tricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-8-one
trifluoroacetate (5.3 mg, 3.5 .mu.mol, 7% yield). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 9.31 (s, 1H), 8.69 (s, 1H), 8.58 (s,
1H), 8.52 (d, J=4.9 Hz, 1H), 8.33 (s, 1H), 7.89 (br. s., 2H), 7.78
(d, J=8.5 Hz, 1H), 7.74-7.66 (m, 1H), 7.53 (d, J=4.9 Hz, 1H),
7.24-6.96 (m, 3H), 6.37 (s, 1H), 5.80 (d, J=11.6 Hz, 1H), 3.42-3.33
(m, 1H), 2.29 (br. s., 1H), 1.92 (d, J=11.3 Hz, 1H), 1.79 (br. s.,
1H), 1.48 (d, J=9.8 Hz, 1H), 1.30 (br. s., 1H), 1.14 (d, J=6.7 Hz,
3H), 0.97 (br. s., 1H). MS(ESI) m/z: 642.3 [M+H].sup.+. Analytical
HPLC (Method B): RT=1.48 min, purity=99.0%; Factor XIa Ki=28 nM,
Plasma Kallikrein Ki=720 nM.
Example 313
Preparation of
(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]--
3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6-
),4,14,16-pentaen-8-one
##STR00492##
[2174] To the solution of
N-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihyd-
ropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamide (0.111 g, 0.185
mmol), prepared as described in Example 310, in MeOH (2 ml) was
added 1.25 M HCl in MeOH (0.5 ml, 0.625 mmol). After stirring at
75.degree. C. for 1 h, the reaction was cooled to rt, concentrated
and lyophilized overnight to give
(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-
-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18-
),2(6),4,14,16-pentaen-8-one hydrochloride (0.1 g, 94% yield) as a
yellow solid. From this material, 10 mg was purified by reverse
phase chromatography to afford
(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]--
3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6-
),4,14,16-pentaen-8-one trifluoroacetate. MS(ESI) m/z: 504.4
(M+H).sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.89 (br.
s., 1H), 8.63 (d, J=5.0 Hz, 1H), 7.63 (s, 1H), 7.43-7.38 (m, 2H),
7.33 (s, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.59
(s, 1H), 5.95 (d, J=9.9 Hz, 1H), 3.95 (s, 3H), 2.67-2.60 (m, 1H),
2.31-2.21 (m, 1H), 2.06-1.91 (m, 2H), 1.59-1.34 (m, 2H), 0.92 (d,
J=6.9 Hz, 3H), 0.69-0.54 (m, 1H). Analytical HPLC (Method B):
RT=1.45 min, 100% purity; Factor XIa Ki=57 nM, Plasma Kallikrein
Ki=2,400 nM.
Example 314
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[(pyrimidin-4-yl)amino]phenyl}-6-oxo-1,6-dihyd-
ropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]-
octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00493##
[2176] A mixture of
(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]--
3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6-
),4,14,16-pentaen-8-one hydrochloride (0.01 g, 0.017 mmol),
4-bromopyrimidine hydrochloride (6.78 mg, 0.035 mmol), prepared as
described in Example 313, in EtOH (1 ml) was microwaved at
150.degree. C. for 30 min, cooled to rt and concentrated.
Purification by reverse phase chromatography afforded
(9R,13S)-13-(4-{5-chloro-2-[(pyrimidin-4-yl)amino]phenyl}-6-oxo-1,6-dihyd-
ropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]-
octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (6.3 mg,
45% yield). MS(ESI) m/z: 582.2 (M+H).sup.+. .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 8.88 (s, 1H), 8.61 (d, J=5.2 Hz, 1H), 8.56 (s,
1H), 8.15 (d, J=6.1 Hz, 1H), 7.73-7.67 (m, 2H), 7.62 (s, 1H), 7.48
(dd, J=8.5, 2.5 Hz, 1H), 7.43-7.39 (m, 2H), 6.85 (d, J=6.9 Hz, 1H),
6.61 (s, 1H), 5.89 (d, J=12.9 Hz, 1H), 3.97-3.92 (m, 3H), 2.66-2.59
(m, 1H), 2.28-2.19 (m, 1H), 2.03-1.89 (m, 2H), 1.56-1.34 (m, 2H),
0.92 (d, J=7.2 Hz, 3H), 0.71-0.56 (m, 1H). Analytical HPLC (Method
C): RT=1.16 min, 100% purity; Factor XIa Ki=6,000 nM.
Example 315
Preparation of
(9R,13S)-13-{4-[2-(aminomethyl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidi-
n-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00494##
[2177] 315A. Preparation of tert-butyl
4-chloro-2-(6-hydroxypyrimidin-4-yl)benzylcarbamate
##STR00495##
[2179] In a microwave vial, was taken tert-butyl
2-bromo-4-chlorobenzylcarbamate (0.78 g, 2.43 mmol) and dissolved
in dioxane (10 ml) and the solution was purged with Ar for 0.5 h.
To this solution was then added
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.93
g, 3.64 mmol), followed by KOAc (0.64 g, 6.56 mmol) and
Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2adduct (0.06 g, 0.07 mmol) and the
reaction was sealed. The microwave vial was heated at 80.degree. C.
overnight. LCMS confirmed the formation of desired boronate/boronic
acid and the reaction was cooled to rt. To this was added
chloromethoxypyrimidine (0.351 g, 2.43 mmol) followed by addition
of 2 M aq Na.sub.2CO.sub.3 (3.04 ml) and the reaction mixture was
purged with Ar for 0.5 h followed by the addition of
Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2adduct (0.06 g, 0.07 mmol) and the
reaction was again sealed. The reaction was heated at 120.degree.
C. for 1 h then cooled to rt and the reaction was quenched with
water (100 ml). The organics were extracted with EtOAc (2.times.200
ml), dried and evaporated to a blackish oil. Purified via a 40 g
silica gel ISCO column and eluting with Hex:EtOAc gave pure product
as an oily mass. LCMS m/z=350.08 (M+H).sup.+.
315B. Preparation of tert-butyl
4-chloro-2-(6-hydroxypyrimidin-4-yl)benzylcarbamate
[2180] The tert-butyl
4-chloro-2-(6-methoxypyrimidin-4-yl)benzylcarbamate was taken in a
small vial and to this was added AcOH (1 ml) followed by 48% aq HBr
(0.1 ml), sealed and heated at 80.degree. C. for 1 h. LCMS
confirmed product peak and a mass of 336 (M+H).sup.+. The solution
was cooled and concentrated under a stream of N.sub.2 to a oily
mass and dioxane (3 ml) was added at which point solid
precipitated. The solution was decanted and the residue was
dissolved in DMF (3 ml) and transferred to the dioxane (2 ml)
solution. To this was added Boc.sub.2O (0.1 g) followed by TEA (2
ml) and the solution was stirred at rt overnight. To this solution
was added NaOH solution (1N, 5 ml) and the reaction was stirred at
rt for 0.5 h. After this time, the reaction mixture was extracted
with EtOAc (2.times.50 ml). The combined organic layer was dried
over MgSO.sub.4, filtered and concentrated to a dark brown oil.
Purification via prep HPLC using MeOH/water/TFA gradient afforded
tert-butyl 4-chloro-2-(6-hydroxypyrimidin-4-yl)benzylcarbamate
(0.05 g). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.46-8.32 (m,
1H), 7.54-7.41 (m, 3H), 6.76-6.67 (m, 1H), 4.31 (s, 2H), 1.44 (s,
9H). MS m/z=236.1 (M+H).sup.+.
315C. Preparation of
(9R,13S)-13-{4-[2-(aminomethyl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidi-
n-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
[2181]
(9R,13S)-13-{4-[2-(Aminomethyl)-5-chlorophenyl]-6-oxo-1,6-dihydropy-
rimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1-
.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (4 mg, 42%
yield) was prepared as a solid, via the coupling of
N-{[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]methyl}carbamate
(0.005 g, 0.015 mmol) and
(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6), 4,14,16-pentaen-8-one (0.005
g, 0.015 mmol) using the HATU, DBU coupling methodology described
in Example 56. MS m/z=554.1 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.53-9.43 (m, 1H), 9.11-9.04 (m, 1H),
8.82-8.71 (m, 1H), 8.42-8.23 (m, 1H), 7.98-7.83 (m, 1H), 7.79-7.70
(m, 1H), 7.68-7.59 (m, 1H), 7.37-7.01 (m, 2H), 6.84-6.74 (m, 1H),
6.08-5.91 (m, 1H), 4.19-3.94 (m, 2H), 2.77-2.63 (m, 1H), 2.34-2.22
(m, 1H), 2.13-1.86 (m, 2H), 1.57-1.30 (m, 2H), 0.97-0.74 (d 3H),
0.53-0.27 (m, 1H). Analytical HPLC (Method B) RT=1.17 min,
purity=96%: Factor XIa Ki=43 nM, Plasma Kallikrein Ki=4,900 nM.
Example 316
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(pyridin-2-yl)phenyl]-6-oxo-1,6-dihydropyrimid-
in-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca--
1(18),2(6),4,14,16-pentaen-8-one
##STR00496##
[2183]
(9R,13S)-13-{4-[5-Chloro-2-(pyridin-2-yl)phenyl]-6-oxo-1,6-dihydrop-
yrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]oct-
adeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (13.3 mg,
51% yield) was prepared in a similar manner as the procedure
described in Example 303, by replacing
4-(tributylstannyl)pyridazine with 2-(tributylstannyl)pyridine
(17.96 mg, 0.049 mmol), and the reaction time was 2 h at 45.degree.
C. and then 6 h at 90.degree. C. MS(ESI) m/z: 566.15 (M+H).sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.23 (s, 1H), 8.72 (br.
s., 1H), 8.67 (d, J=4.9 Hz, 1H), 8.52 (d, J=4.0 Hz, 1H), 7.82 (t,
J=7.8 Hz, 1H), 7.72 (s, 1H), 7.67-7.62 (m, 3H), 7.56 (d, J=4.9 Hz,
1H), 7.49-7.36 (m, 3H), 6.25 (s, 1H), 5.86 (d, J=10.1 Hz, 1H), 4.00
(s, 3H), 2.68-2.59 (m, 1H), 2.30-2.21 (m, 1H), 2.14-2.03 (m, 1H),
1.86-1.76 (m, 1H), 1.50-1.40 (m, 1H), 1.37-1.26 (m, 1H), 0.87 (d,
J=7.0 Hz, 3H), 0.52-0.33 (m, 1H). Analytical HPLC (Method C):
RT=1.12 min, 100% purity; Factor XIa Ki=350 nM.
Example 317
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-3-yl)-9-meth-
yl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pen-
taen-8-one
##STR00497##
[2185]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-3-yl)-9-me-
thyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-p-
entaen-8-one was prepared in a similar manner as the procedure
described in Example 216, by using 3-iodo-2-methoxypyridine (39 mg,
0.164 mmol) and
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.05 g,
0.082 mmol), as described in Example 196, to give
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phe-
nyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-3-yl)-9-methyl-3-
,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pentaen-
-8-one trifluoroacetate (49 mg, 71% yield) as a light green solid.
MS(ESI) m/z: 717.5 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 9.47 (s, 1H), 9.24 (d, J=0.8 Hz, 1H), 8.70 (s, 1H), 8.56
(d, J=5.0 Hz, 1H), 8.42 (s, 1H), 8.25 (dd, J=4.8, 1.8 Hz, 1H), 8.20
(dd, J=7.7, 1.7 Hz, 1H), 7.98 (d, J=2.2 Hz, 1H), 7.91 (s, 1H),
7.89-7.81 (m, 2H), 7.58 (dd, J=5.1, 1.5 Hz, 1H), 7.24 (dd, J=7.7,
4.7 Hz, 1H), 6.51 (s, 1H), 6.10-5.95 (m, 1H), 4.02 (s, 3H),
2.84-2.70 (m, 1H), 2.35-2.18 (m, 2H), 1.91-1.75 (m, 1H), 1.63-1.50
(m, 1H), 1.48-1.32 (m, 1H), 0.95 (d, J=7.2 Hz, 3H), 0.69-0.45 (m,
1H). Analytical HPLC (Method A): RT=10.02 min, purity=99.2%; Factor
XIa Ki=18 nM, Plasma Kallikrein Ki=850 nM.
Example 318
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(6-methoxypyrimidin-4-yl)-9-me-
thyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,1-
6-pentaen-8-one
##STR00498##
[2187]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(6-methoxypyrimidin-4-yl)-9--
methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14-
,16-pentaen-8-one trifluoroacetate (0.83 mg, 0.908 .mu.mol, 1%
yield) as a minor product was prepared in a similar manner as the
procedure described in Example 216, by using
4-iodo-6-methoxypyrimidine (19.35 mg, 0.082 mmol) and
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazo-
l-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraaza-
tricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (50 mg,
0.082 mmol), as described in Example 196. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.86 (s, 1H), 8.74 (s, 1H), 8.72 (s, 1H), 8.66
(d, J=5.3 Hz, 1H), 8.59 (s, 1H), 8.07 (s, 1H), 7.95 (d, J=2.4 Hz,
1H), 7.80 (dd, J=8.5, 2.5 Hz, 2H), 7.76-7.70 (m, 1H), 7.45 (s, 1H),
6.50 (s, 1H), 5.93 (d, J=9.0 Hz, 1H), 4.12 (s, 2H), 2.64 (s, 1H),
2.41 (s, 1H), 2.03 (s, 2H), 1.72 (s, 1H), 1.46 (br. s., 2H), 1.34
(d, J=6.8 Hz, 3H), 1.24 (s, 1H). MS(ESI) m/z: 718.3 [M+H].sup.+.
Analytical HPLC (Method A): RT=9.47 min, purity=91.0%; Factor XIa
Ki=280 nM, Plasma Kallikrein Ki=5,200 nM.
Example 319
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyrimidin-4-yl)-9-me-
thyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-p-
entaen-8-one
##STR00499##
[2189]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyrimidin-4-yl)-9--
methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-
-pentaen-8-one trifluoroacetate (5.5 mg, 6.28 .mu.mol, 7% yield) as
a major product was prepared in a similar manner as the procedure
described in Example 216, by using 4-iodo-6-methoxypyrimidine
(19.35 mg, 0.082 mmol) and
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazo-
l-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraaz-
atricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one (50 mg,
0.082 mmol), as described in Example 196. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.86 (d, J=0.9 Hz, 1H), 8.79-8.73 (m, 1H), 8.71
(s, 2H), 8.67 (d, J=5.1 Hz, 1H), 7.99-7.91 (m, 2H), 7.83-7.77 (m,
1H), 7.76-7.70 (m, 2H), 7.43 (d, J=0.9 Hz, 1H), 6.49 (d, J=0.7 Hz,
1H), 6.15 (d, J=8.1 Hz, 1H), 4.11 (s, 3H), 2.88 (d, J=3.3 Hz, 1H),
2.30 (t, J=12.7 Hz, 2H), 2.06 (t, J=11.8 Hz, 1H), 1.82-1.68 (m,
1H), 1.60 (br. s., 1H), 1.10 (d, J=7.0 Hz, 3H), 0.84 (br. s., 1H).
MS(ESI) m/z: 718.3 [M+H].sup.+. Analytical HPLC (Method A): RT=9.90
min, purity=95.0%; Factor XIa Ki=4 nM, Plasma Kallikrein Ki=100
nM.
Example 320
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-hydroxypyrimidin-4-yl)-9-me-
thyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-p-
entaen-8-one
##STR00500##
[2191]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(6-hydroxypyrimidin-4-yl)-9--
methyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-
-pentaen-8-one trifluoroacetate (5.4 mg, 6.47 .mu.mol, 26% yield)
was prepared in a similar manner as the procedure described in
Example 296. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.85 (d,
J=0.9 Hz, 1H), 8.73 (s, 1H), 8.67 (d, J=5.3 Hz, 1H), 8.60 (s, 1H),
8.29 (d, J=0.9 Hz, 1H), 7.97 (s, 1H), 7.94 (d, J=2.4 Hz, 1H),
7.81-7.76 (m, 1H), 7.76-7.69 (m, 2H), 7.00 (d, J=0.7 Hz, 1H), 6.48
(s, 1H), 6.17-6.09 (m, 1H), 2.86 (d, J=3.5 Hz, 1H), 2.35-2.22 (m,
2H), 2.12-1.99 (m, 1H), 1.81-1.53 (m, 3H), 1.09 (d, J=7.0 Hz, 3H),
0.86 (br. s., 1H). MS(ESI) m/z: 704.5 [M+H].sup.+. Analytical HPLC
(Method A): RT=7.47 min, purity=98.0%; Factor XIa Ki=0.2 nM, Plasma
Kallikrein Ki=39 nM.
Example 321
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]
phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-4-yl)-9-meth-
yl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-pen-
taen-8-one
##STR00501##
[2193]
(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1--
yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-4-yl)-9-me-
thyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2,5,14,16-p-
entaen-8-one (4 mg, 6%) was prepared in a similar manner as the
procedure described in Example 216, by using
4-iodo-2-methoxypyridine (39 mg, 0.164 mmol) and
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazo-
l-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraaza-
tricyclo[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
(0.05 g, 0.082 mmol), as described in Example 196. MS(ESI) m/z:
717.1 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.60
(s, 1H), 9.24 (s, 1H), 8.85 (s, 1H), 8.71 (s, 1H), 8.60 (d, J=4.9
Hz, 1H), 8.31 (d, J=5.5 Hz, 1H), 7.98 (s, 1H), 7.92 (s, 1H),
7.90-7.80 (m, 2H), 7.62 (dd, J=18.3, 4.9 Hz, 2H), 7.36 (s, 1H),
6.51 (s, 1H), 6.03 (br. s., 1H), 3.94 (s, 3H), 3.46-3.27 (m, 2H),
2.81 (br. s., 1H), 2.27 (d, J=18.9 Hz, 2H), 1.85 (br. s., 1H), 1.57
(br. s., 1H), 1.42 (br. s., 1H), 0.95 (d, J=6.4 Hz, 3H), 0.54 (br.
s., 1H). Analytical HPLC (Method C): RT=1.81 min, purity=100%;
Factor XIa Ki=0.6 nM, Plasma Kallikrein Ki=17 nM.
Preparation of Examples 322 to 352
[2194] The following compounds were made in a parallel manner using
the following procedure: Reagents were weighed into BIOTAGE.RTM.
0.5-2 mL microwave vials. Stock solutions were made for reagent
addition: Dissolved 472.9 mg core in 18.6 mL 1,4-dioxane (0.04M).
Dissolved 265.7 mg potassium carbonate in 6.2 mL water 0.3 M). To
each microwave vial containing reagent was added Si-DPP-Pd (12.40
mg, 3.72 .mu.mol) via ArgoScoop, 0.600 mL core solution, and 0.200
mL potassium carbonate solution. Queued the reactions to run on the
BIOTAGE.RTM. Initiator (400 W) microwave for 30 min at 120.degree.
C. with 10 seconds of prestirring and using a fixed hold time.
[2195] Upon completion of the microwave run, reaction mixtures were
concentrated, then redissolved in 1.8 mL DMF and filtered through a
45 .mu.M syringe filter. Resulting clear solutions were purified
via preparative LC/MS with the following conditions: Column:
XBridge C18, 19.times.100 mm, 5-.mu.m particles; Mobile Phase A:
5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile
Phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;
Gradient: 40-80% B over 10 min, then a 5-minute hold at 100% B;
Flow: 20 mL/min. Fractions containing the desired product were
combined and dried via centrifugal evaporation. Gradient varied for
each reaction depending on polarity of compound.
[2196] Compound purity was assigned based on the methods below.
[2197] Method A: Column: Waters Acquity UPLC BEH C18, 2.1.times.50
mm, 1.7-.mu.m particles; Mobile Phase A: 5:95 acetonitrile:water
with 10 mM ammonium acetate; Mobile Phase B: 95:5
acetonitrile:water with 10 mM ammonium acetate; Temperature:
50.degree. C.; Gradient: 0-100% B over 3 min, then a 0.75-minute
hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.
[2198] Method B: Column: Waters Acquity UPLC BEH C18, 2.1.times.50
mm, 1.7-.mu.m particles; Mobile Phase A: 5:95 acetonitrile:water
with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5
acetonitrile:water with 0.1% trifluoroacetic acid; Temperature:
50.degree. C.; Gradient: 0-100% B over 3 min, then a 0.75-minute
hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.
Example 322
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-methylphenyl)phenyl]-6-oxo-1,6-dihydropyrim-
idin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadec-
a-1(18),2(6),4,14,16-pentaen-8-one
##STR00502##
[2200] MS(ESI) m/z: 579.1 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.14 (s, 1H), 8.82 (s, 1H), 8.62 (d, J=5.2
Hz, 1H), 7.61 (d, J=2.4 Hz, 1H), 7.57 (s, 1H), 7.53-7.49 (m, 2H),
7.40 (s, 1H), 7.34 (d, J=8.5 Hz, 1H), 7.10-7.03 (m, 4H), 5.99 (s,
1H), 5.79 (d, J=10.1 Hz, 1H), 3.94 (s, 3H), 2.61-2.53 (m, 1H),
2.26-2.17 (m, 4H), 2.07-1.99 (m, 1H), 1.80-1.72 (m, 1H), 1.44-1.35
(m, 1H), 1.31-1.21 (m, 1H), 0.81 (d, J=6.7 Hz, 3H), 0.41-0.26 (m,
1H). Analytical HPLC (Method A): RT=2.02 min, purity=98.7%; Factor
XIa Ki=180 nM.
Example 323
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(3-chlorophenyl)phenyl]-6-oxo-1,6-dihydropyrim-
idin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadec-
a-1(18),2(6),4,14,16-pentaen-8-one
##STR00503##
[2202] MS(ESI) m/z: 599.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.15 (s, 1H), 8.76 (s, 1H), 8.60 (d, J=4.9
Hz, 1H), 7.63 (d, J=2.1 Hz, 1H), 7.59-7.54 (m, 2H), 7.50 (dd,
J=5.2, 0.9 Hz, 1H), 7.43-7.39 (m, 2H), 7.34-7.26 (m, 2H), 7.23 (s,
1H), 7.09 (d, J=7.3 Hz, 1H), 6.16 (s, 1H), 5.79 (d, J=11.0 Hz, 1H),
3.94 (s, 3H), 2.61-2.53 (m, 1H), 2.27-2.17 (m, 1H), 2.07-1.97 (m,
1H), 1.80-1.70 (m, 1H), 1.44-1.34 (m, 1H), 1.31-1.20 (m, 1H), 0.81
(d, J=6.7 Hz, 3H), 0.43-0.29 (m, 1H). Analytical HPLC (Method A):
RT=2.03 min, purity=94.8%; Factor XIa Ki=7,500 nM.
Example 324
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(3-methoxyphenyl)phenyl]-6-oxo-1,6-dihydropyri-
midin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octade-
ca-1(18),2(6),4,14,16-pentaen-8-one
##STR00504##
[2204] MS(ESI) m/z: 595.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.15 (s, 1H), 8.81 (s, 1H), 8.61 (d, J=5.2
Hz, 1H), 7.61 (d, J=2.1 Hz, 1H), 7.58 (s, 1H), 7.55-7.49 (m, 2H),
7.41-7.37 (m, 2H), 7.18 (t, J=7.9 Hz, 1H), 6.80 (dd, J=8.2, 2.1 Hz,
1H), 6.73 (d, J=7.6 Hz, 1H), 6.69 (s, 1H), 6.04 (s, 1H), 5.78 (d,
J=10.1 Hz, 1H), 3.94 (s, 3H), 3.58 (s, 3H), 2.60-2.53 (m, 1H),
2.27-2.18 (m, 1H), 2.07-1.98 (m, 1H), 1.81-1.71 (m, 1H), 1.44-1.34
(m, 1H), 1.31-1.21 (m, 1H), 0.81 (d, J=6.7 Hz, 3H), 0.43-0.29 (m,
1H); Analytical HPLC (Method A): RT=1.91 min, purity=97.5%; Factor
XIa Ki=550 nM.
Example 325
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(2-methylphenyl)phenyl]-6-oxo-1,6-dihydropyrim-
idin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadec-
a-1(18),2(6),4,14,16-pentaen-8-one
##STR00505##
[2206] MS(ESI) m/z: 579.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.20 (s, 1H), 8.91 (s, 1H), 8.68 (d, J=5.2
Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.63-7.55 (m, 3H), 7.46 (s, 1H),
7.31-7.18 (m, 4H), 7.11 (s, 1H), 5.85-5.78 (m, 2H), 4.00 (d, J=3.1
Hz, 3H), 2.67-2.60 (m, 1H), 2.32-2.22 (m, 1H), 2.13-2.03 (m, 1H),
1.95 (d, J=12.8 Hz, 3H), 1.86-1.76 (m, 1H), 1.49-1.39 (m, 1H),
1.37-1.28 (m, 1H), 0.87 (d, J=6.7 Hz, 3H), 0.46-0.31 (m, 1H);
Analytical HPLC (Method A): RT=2.05 min, purity=100%; Factor XIa
Ki=3,900.
Example 326
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethoxy)phenyl]phenyl}-6-oxo-1,6--
dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00506##
[2208] MS(ESI) m/z: 649 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.21 (s, 1H), 8.83 (s, 1H), 8.66 (d, J=4.9
Hz, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.67-7.61 (m, 2H), 7.59 (d, J=4.9
Hz, 1H), 7.51-7.46 (m, 2H), 7.38-7.30 (m, 4H), 6.22 (s, 1H), 5.88
(d, J=10.4 Hz, 1H), 4.01 (s, 3H), 2.69-2.60 (m, 1H), 2.32-2.23 (m,
1H), 2.16-2.06 (m, 1H), 1.86-1.77 (m, 1H), 1.52-1.42 (m, 1H),
1.38-1.28 (m, 1H), 0.88 (d, J=7.0 Hz, 3H), 0.48-0.34 (m, 1H);
Analytical HPLC (Method A): RT=2.14 min, purity=100%; Factor XIa
Ki=640.
Example 327
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(2-chlorophenyl)phenyl]-6-oxo-1,6-dihydropyrim-
idin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadec-
a-1(18),2(6),4,14,16-pentaen-8-one
##STR00507##
[2210] MS(ESI) m/z: 599 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.20 (s, 1H), 8.89 (d, J=5.5 Hz, 1H),
8.70-8.66 (m, 1H), 7.85 (s, 1H), 7.66-7.61 (m, 2H), 7.57 (d, J=4.6
Hz, 1H), 7.52-7.46 (m, 2H), 7.43-7.29 (m, 4H), 5.93, 5.91 (2s, 1H),
5.84 (d, J=11.0 Hz, 1H), 4.01, 4.00 (2s, 3H), 2.66-2.60 (m, 1H),
2.32-2.22 (m, 1H), 2.13-2.04 (m, 1H), 1.85-1.75 (m, 1H), 1.50-1.40
(m, 1H), 1.37-1.27 (m, 1H), 0.87 (d, J=6.7 Hz, 3H), 0.45-0.31 (m,
1H); Analytical HPLC (Method A): RT=2.01 min, purity=100%; Factor
XIa Ki=3,300 nM.
Example 329
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)phenyl]phenyl}-6-oxo-1,6-d-
ihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00508##
[2212] MS(ESI) m/z: 633.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.21 (s, 1H), 8.82 (s, 1H), 8.64 (d, J=4.9
Hz, 1H), 7.74 (d, J=2.1 Hz, 1H), 7.71-7.64 (m, 4H), 7.59 (d, J=4.9
Hz, 1H), 7.53-7.44 (m, 4H), 6.26 (s, 1H), 5.88 (d, J=9.8 Hz, 1H),
4.01 (s, 3H), 2.68-2.59 (m, 1H), 2.32-2.24 (m, 1H), 2.15-2.06 (m,
1H), 1.86-1.77 (m, 1H), 1.51-1.42 (m, 1H), 1.38-1.28 (m, 1H), 0.88
(d, J=6.7 Hz, 3H), 0.48-0.32 (m, 1H); Analytical HPLC (Method A):
RT=2.09 min, purity=100%; Factor XIa Ki=380 nM.
Example 330
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(propan-2-ylsulfanyl)phenyl]phenyl}-6-oxo-1-
,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.-
sup.2,6] octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00509##
[2214] MS(ESI) m/z: 639.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.15 (s, 1H), 8.80 (s, 1H), 8.62 (d, J=5.2
Hz, 1H), 7.65 (d, J=2.1 Hz, 1H), 7.60 (s, 1H), 7.57-7.52 (m, 2H),
7.43-7.38 (m, 2H), 7.25 (d, J=7.9 Hz, 2H), 7.12 (d, J=8.2 Hz, 2H),
6.08 (s, 1H), 5.82 (d, J=9.8 Hz, 1H), 3.96 (s, 3H), 3.49-3.39 (m,
1H), 2.62-2.55 (m, 1H), 2.27-2.17 (m, 1H), 2.10-2.01 (m, 1H),
1.81-1.72 (m, 1H), 1.46-1.36 (m, 1H), 1.33-1.23 (m, 1H), 1.18 (dd,
J=6.6, 2.0 Hz, 6H), 0.83 (d, J=7.0 Hz, 3H), 0.42-0.28 (m, 1H);
Analytical HPLC (Method A): RT=2.25 min, purity=100%; Factor XIa
Ki=400 nM.
Example 331
Preparation of
4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)benzene-1-sulfonamide
##STR00510##
[2216] MS(ESI) m/z: 644 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.21 (s, 1H), 8.85 (s, 1H), 8.69 (d, J=5.2
Hz, 1H), 7.78 (d, J=8.2 Hz, 2H), 7.73 (d, J=2.1 Hz, 1H), 7.67-7.64
(m, 2H), 7.58 (d, J=5.2 Hz, 1H), 7.52-7.40 (m, 6H), 6.25 (s, 1H),
5.89 (d, J=10.7 Hz, 1H), 4.01 (s, 3H), 2.68-2.60 (m, 1H), 2.33-2.24
(m, 1H), 2.15-2.06 (m, 1H), 1.88-1.78 (m, 1H), 1.51-1.42 (m, 1H),
1.39-1.28 (m, 1H), 0.88 (d, J=6.7 Hz, 3H), 0.48-0.33 (m, 1H);
Analytical HPLC (Method A): RT=1.54 min, purity=100%; Factor XIa
Ki=130 nM.
Example 332
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethoxy)phenyl]phenyl}-6-oxo-1,6-d-
ihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00511##
[2218] MS(ESI) m/z: 631 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.21 (s, 1H), 8.86 (s, 1H), 8.67 (d, J=4.9
Hz, 1H), 7.70 (d, J=2.1 Hz, 1H), 7.65 (s, 1H), 7.63-7.57 (m, 2H),
7.49-7.42 (m, 2H), 7.31-7.26 (m, 3H), 7.17-7.11 (m, 2H), 6.17 (s,
1H), 5.88 (d, J=9.8 Hz, 1H), 4.01 (s, 3H), 2.69-2.60 (m, 1H),
2.34-2.24 (m, 1H), 2.16-2.06 (m, 1H), 1.88-1.79 (m, 1H), 1.51-1.42
(m, 1H), 1.39-1.28 (m, 1H), 0.88 (d, J=6.7 Hz, 3H), 0.48-0.33 (m,
1H); Analytical HPLC (Method A): RT=1.97 min, purity=100%; Factor
XIa Ki=180 nM.
Example 333
Preparation of
N-[3-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricycl-
o[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)phenyl]methanesulfonamide
##STR00512##
[2220] MS(ESI) m/z: 658 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.20 (s, 1H), 8.87 (s, 1H), 8.69 (d, J=5.2
Hz, 1H), 7.70 (d, J=2.4 Hz, 1H), 7.66-7.60 (m, 3H), 7.58 (d, J=5.2
Hz, 1H), 7.48-7.44 (m, 2H), 7.38-7.33 (m, 1H), 7.16 (dd, J=8.1, 1.1
Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 7.03 (s, 1H), 6.10 (s, 1H), 5.86
(d, J=9.8 Hz, 1H), 4.01 (s, 3H), 2.80 (s, 3H), 2.70-2.60 (m, 1H),
2.34-2.24 (m, 1H), 2.15-2.05 (m, 1H), 1.88-1.78 (m, 1H), 1.51-1.42
(m, 1H), 1.39-1.28 (m, 1H), 0.89 (d, J=7.0 Hz, 3H), 0.49-0.35 (m,
1H); Analytical HPLC (Method A): RT=1.68 min, purity=100%; Factor
XIa Ki=1,200 nM.
Example 334
Preparation of
3-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)benzonitrile
##STR00513##
[2222] MS(ESI) m/z: 590.3 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.21 (s, 1H), 8.78 (s, 1H), 8.68 (d, J=5.2
Hz, 1H), 7.80 (dd, J=5.3, 2.3 Hz, 1H), 7.74-7.70 (m, 2H), 7.68-7.64
(m, 2H), 7.59-7.51 (m, 4H), 7.47 (s, 1H), 6.31 (s, 1H), 5.86 (d,
J=10.4 Hz, 1H), 4.01 (s, 3H), 2.70-2.59 (m, 1H), 2.33-2.23 (m, 1H),
2.14-2.04 (m, 1H), 1.86-1.77 (m, 1H), 1.51-1.41 (m, 1H), 1.38-1.28
(m, 1H), 0.88 (d, J=7.0 Hz, 3H), 0.50-0.36 (m, 1H); Analytical HPLC
(Method A): RT=1.8 min, purity=100%; Factor XIa Ki=1,600 nM.
Example 335
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[3-(trifluoromethoxy)phenyl]phenyl}-6-oxo-1,6--
dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup-
.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00514##
[2224] MS(ESI) m/z: 649 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.20 (s, 1H), 8.84 (s, 1H), 8.67 (d, J=5.2
Hz, 1H), 7.69 (d, J=2.1 Hz, 1H), 7.67-7.62 (m, 2H), 7.58 (d, J=5.2
Hz, 1H), 7.52 (dt, J=8.1, 3.9 Hz, 2H), 7.47 (s, 1H), 7.36 (d, J=7.9
Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 7.09 (s, 1H), 6.23 (s, 1H), 5.88
(d, J=10.4 Hz, 1H), 4.00 (s, 3H), 2.69-2.60 (m, 1H), 2.33-2.24 (m,
1H), 2.14-2.05 (m, 1H), 1.82-1.72 (m, 1H), 1.51-1.41 (m, 1H),
1.37-1.27 (m, 1H), 0.88 (d, J=7.0 Hz, 3H), 0.49-0.36 (m, 1H);
Analytical HPLC (Method A): RT=2.13 min, purity=100%; Factor XIa
Ki=3,700 nM.
Example 336
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(3-methanesulfonylphenyl)phenyl]-6-oxo-1,6-dih-
ydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,-
6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00515##
[2226] MS(ESI) m/z: 643 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.24, 9.21 (s, 1H), 9.02, 8.79 (2s, 1H),
8.71-8.63 (m, J=14.0, 4.9 Hz, 1H), 8.17-7.43 (m, 9H), 7.07, 6.32
(2s, 1H), 5.99-5.78 (m, 1H), 4.01 (d, J=1.8 Hz, 3H), 3.91, 3.11
(2s, 3H), 2.70-2.59 (m, 1H), 2.41-2.21 (m, 1H), 2.18-2.04 (m, 1H),
1.99-1.75 (m, 1H), 1.54-1.26 (m, 2H), 0.93-0.85 (m, 3H), 0.55-0.35
(m, 1H); Analytical HPLC (Method A): RT=1.65 min, purity=100%;
Factor XIa Ki=1,200 nM.
Example 337
Preparation of methyl
4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihyd-
ropyrimidin-4-yl}phenyl)benzoate
##STR00516##
[2228] MS(ESI) m/z: 623.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.14 (s, 1H), 8.74 (s, 1H), 8.60 (d, J=4.9
Hz, 1H), 7.84 (d, J=8.2 Hz, 2H), 7.66 (d, J=2.1 Hz, 1H), 7.60-7.56
(m, 2H), 7.51 (d, J=5.2 Hz, 1H), 7.45-7.38 (m, 2H), 7.31 (d, J=8.2
Hz, 2H), 6.12 (s, 1H), 5.82-5.75 (m, 1H), 3.94 (s, 3H), 3.80 (s,
3H), 2.61-2.53 (m, 1H), 2.26-2.16 (m, 1H), 2.09-1.97 (m, 1H),
1.80-1.71 (m, 1H), 1.44-1.19 (m, 2H), 0.81 (d, J=6.7 Hz, 3H),
0.42-0.25 (m, 1H); Analytical HPLC (Method A): RT=1.91 min,
purity=98.6%; Factor XIa Ki=750 nM.
Example 338
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(3-methylphenyl)phenyl]-6-oxo-1,6-dihydropyrim-
idin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadec-
a-1(18),2(6),4,14,16-pentaen-8-one
##STR00517##
[2230] MS(ESI) m/z: 579.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.22 (s, 1H), 8.86 (s, 1H), 8.68 (d, J=5.2
Hz, 1H), 7.68 (d, J=2.1 Hz, 1H), 7.65 (s, 1H), 7.62-7.56 (m, 2H),
7.47 (s, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.24-7.18 (m, 1H), 7.13 (d,
J=7.6 Hz, 1H), 7.05 (s, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.09 (s, 1H),
5.85 (d, J=10.4 Hz, 1H), 4.01 (s, 3H), 2.67-2.60 (m, 1H), 2.35-2.22
(m, 4H), 2.14-2.05 (m, 1H), 1.88-1.78 (m, 1H), 1.51-1.42 (m, 1H),
1.38-1.28 (m, 1H), 0.88 (d, J=7.0 Hz, 3H), 0.51-0.37 (m, 1H);
Analytical HPLC (Method A): RT=2.03 min, purity=100%; Factor XIa
Ki=1,400 nM.
Example 339
Preparation of
4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)benzonitrile
##STR00518##
[2232] MS(ESI) m/z: 590.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.22 (s, 1H), 8.79 (s, 1H), 8.67 (d, J=4.9
Hz, 1H), 7.80 (d, J=8.2 Hz, 2H), 7.73 (d, J=2.1 Hz, 1H), 7.69-7.64
(m, 2H), 7.59 (d, J=5.2 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H), 7.47 (s,
1H), 7.43 (d, J=8.5 Hz, 2H), 6.29 (s, 1H), 5.87 (d, J=10.1 Hz, 1H),
4.01 (s, 3H), 2.69-2.60 (m, 1H), 2.33-2.23 (m, 1H), 2.15-2.06 (m,
1H), 1.87-1.78 (m, 1H), 1.52-1.42 (m, 1H), 1.38-1.28 (m, 1H), 0.88
(d, J=6.7 Hz, 3H), 0.49-0.33 (m, 1H); Analytical HPLC (Method A):
RT=1.8 min, purity=100%; Factor XIa Ki=290 nM.
Example 340
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-indol-5-yl)phenyl]-6-oxo-1,6-dihy-
dropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6-
]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00519##
[2234] MS(ESI) m/z: 618.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.20 (s, 1H), 8.90 (s, 1H), 8.68 (d, J=5.2
Hz, 1H), 7.72 (d, J=2.1 Hz, 1H), 7.61 (s, 1H), 7.60-7.55 (m, 2H),
7.47-7.43 (m, 3H), 7.39-7.33 (m, 2H), 6.96 (dd, J=8.5, 1.2 Hz, 1H),
6.40 (d, J=3.1 Hz, 1H), 5.98 (s, 1H), 5.82 (d, J=10.7 Hz, 1H), 4.00
(s, 3H), 3.79 (s, 3H), 2.66-2.59 (m, 1H), 2.33-2.24 (m, 1H),
2.13-2.03 (m, 1H), 1.85-1.77 (m, 1H), 1.49-1.40 (m, 1H), 1.37-1.27
(m, 1H), 0.87 (d, J=7.0 Hz, 3H), 0.45-0.32 (m, 1H); Analytical HPLC
(Method A): RT=2.02 min, purity=100%; Factor XIa Ki=1,300 nM.
Example 341
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(isoquinolin-5-yl)phenyl]-6-oxo-1,6-dihydropyr-
imidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octad-
eca-1(18),2(6),4,14,16-pentaen-8-one
##STR00520##
[2236] MS(ESI) m/z: 616 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.48 (d, J=16.8 Hz, 1H), 9.17 (s, 1H),
8.66-8.58 (m, 2H), 8.43 (br. s., 1H), 8.24 (t, J=9.3 Hz, 1H), 7.90
(t, J=1.8 Hz, 1H), 7.82-7.69 (m, 3H), 7.56-7.51 (m, 2H), 7.48 (dd,
J=8.2, 3.4 Hz, 1H), 7.45-7.38 (m, 2H), 6.00 (d, J=9.5 Hz, 1H), 5.69
(d, J=10.4 Hz, 1H), 3.99 (s, 3H), 2.63-2.57 (m, 1H), 2.19-1.96 (m,
2H), 1.73-1.59 (m, 1H), 1.45-1.34 (m, 1H), 1.31-1.20 (m, 1H), 0.85
(d, J=5.2 Hz, 3H), 0.41-0.28 (m, 1H); Analytical HPLC (Method B):
RT=1.32 min, purity=100%; Factor XIa Ki=6,500 nM.
Example 342
Preparation of methyl
3-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[1-
2.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihyd-
ropyrimidin-4-yl}phenyl)benzoate
##STR00521##
[2238] MS(ESI) m/z: 623.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.21 (s, 1H), 8.80 (s, 1H), 8.65 (d, J=5.2
Hz, 1H), 7.93-7.89 (m, 1H), 7.79 (s, 1H), 7.71 (d, J=2.1 Hz, 1H),
7.66-7.63 (m, 2H), 7.58 (d, J=5.2 Hz, 1H), 7.54-7.46 (m, 4H), 6.23
(s, 1H), 5.86 (d, J=9.8 Hz, 1H), 4.01 (s, 3H), 3.78 (s, 3H),
2.67-2.59 (m, 1H), 2.31-2.22 (m, 1H), 2.14-2.05 (m, 1H), 1.83-1.74
(m, 1H), 1.51-1.41 (m, 1H), 1.37-1.27 (m, 1H), 0.88 (d, J=7.0 Hz,
3H), 0.50-0.36 (m, 1H); Analytical HPLC (Method A): RT=1.87 min,
purity=100%; Factor XIa Ki=2,200 nM.
Example 343
Preparation of
N-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricycl-
o[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)phenyl]methanesulfonamide
##STR00522##
[2240] MS(ESI) m/z: 657.9 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.21 (s, 1H), 8.86 (s, 1H), 8.70 (d, J=5.2
Hz, 1H), 7.70 (d, J=2.4 Hz, 1H), 7.65 (s, 1H), 7.62-7.56 (m, 2H),
7.50-7.42 (m, 2H), 7.30-7.25 (m, 1H), 7.22-7.14 (m, 4H), 6.11 (s,
1H), 5.86 (d, J=8.9 Hz, 1H), 4.01 (s, 3H), 2.99 (s, 3H), 2.68-2.61
(m, 1H), 2.34-2.23 (m, 1H), 2.16-2.06 (m, 1H), 1.88-1.78 (m, 1H),
1.53-1.28 (m, 2H), 0.88 (d, J=7.0 Hz, 3H), 0.51-0.33 (m, 1H);
Analytical HPLC (Method B): RT=1.63 min, purity=97.8%; Factor XIa
Ki=450 nM.
Example 344
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[3-(trifluoromethyl)phenyl]phenyl}-6-oxo-1,6-d-
ihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.-
2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00523##
[2242] MS(ESI) m/z: 633 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.21 (s, 1H), 8.79 (s, 1H), 8.65 (d, J=5.2
Hz, 1H), 7.73-7.64 (m, 4H), 7.61-7.54 (m, 4H), 7.52-7.46 (m, 2H),
6.30 (s, 1H), 5.86 (d, J=10.4 Hz, 1H), 4.01 (s, 3H), 2.67-2.59 (m,
1H), 2.33-2.23 (m, 1H), 2.14-2.05 (m, J=12.1, 12.1 Hz, 1H),
1.82-1.73 (m, 1H), 1.50-1.41 (m, 1H), 1.37-1.27 (m, 1H), 0.88 (d,
J=6.7 Hz, 3H), 0.52-0.38 (m, 1H); Analytical HPLC (Method A):
RT=2.06 min, purity=100%; Factor XIa Ki=4,800 nM.
Example 345
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-methoxyphenyl)phenyl]-6-oxo-1,6-dihydropyri-
midin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octade-
ca-1(18),2(6),4,14,16-pentaen-8-one
##STR00524##
[2244] MS(ESI) m/z: 595 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.22 (s, 1H), 8.89 (s, 1H), 8.69 (d, J=5.2
Hz, 1H), 7.68-7.64 (m, 2H), 7.60-7.56 (m, 2H), 7.47 (s, 1H), 7.41
(d, J=8.2 Hz, 1H), 7.15 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.9 Hz, 2H),
6.08 (s, 1H), 5.87 (d, J=10.1 Hz, 1H), 4.01 (s, 3H), 3.76 (s, 3H),
2.68-2.60 (m, 1H), 2.34-2.26 (m, 1H), 2.16-2.06 (m, 1H), 1.89-1.79
(m, 1H), 1.51-1.42 (m, 1H), 1.39-1.28 (m, 1H), 0.88 (d, J=7.0 Hz,
3H), 0.48-0.35 (m, 1H); Analytical HPLC (Method A): RT=1.89 min,
purity=100%; Factor XIa Ki=350 nM.
Example 346
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(4-chlorophenyl)phenyl]-6-oxo-1,6-dihydropyrim-
idin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadec-
a-1(18),2(6),4,14,16-pentaen-8-one
##STR00525##
[2246] MS(ESI) m/z: 599 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.22 (s, 1H), 8.85 (s, 1H), 8.68 (d, J=4.9
Hz, 1H), 7.70 (d, J=2.1 Hz, 1H), 7.66 (s, 1H), 7.63 (dd, J=8.2, 2.1
Hz, 1H), 7.59 (d, J=5.2 Hz, 1H), 7.48-7.44 (m, 2H), 7.40 (d, J=8.5
Hz, 2H), 7.25 (d, J=8.2 Hz, 2H), 6.19 (s, 1H), 5.88 (d, J=9.8 Hz,
1H), 4.01 (s, 3H), 2.69-2.60 (m, 1H), 2.34-2.25 (m, 1H), 2.15-2.06
(m, 1H), 1.88-1.79 (m, 1H), 1.52-1.42 (m, 1H), 1.39-1.28 (m, 1H),
0.88 (d, J=6.7 Hz, 3H), 0.49-0.34 (m, 1H); Analytical HPLC (Method
B): RT=2 min, purity=95.5%; Factor XIa Ki=220 nM.
Example 347
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(pyridin-4-yl)phenyl]-6-oxo-1,6-dihydropyrimid-
in-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadeca--
1(18),2(6),4,14,16-pentaen-8-one
##STR00526##
[2248] MS(ESI) m/z: 566.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.21 (s, 1H), 8.80 (s, 1H), 8.68 (d, J=5.2
Hz, 1H), 8.55 (d, J=5.8 Hz, 2H), 7.74 (d, J=1.8 Hz, 1H), 7.69 (dd,
J=8.2, 2.1 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J=5.2 Hz, 1H), 7.53 (d,
J=8.2 Hz, 1H), 7.47 (s, 1H), 7.30 (d, J=5.8 Hz, 2H), 6.34 (s, 1H),
5.87 (d, J=10.7 Hz, 1H), 4.01 (s, 3H), 2.69-2.60 (m, 1H), 2.33-2.23
(m, 1H), 2.15-2.06 (m, 1H), 1.88-1.78 (m, 1H), 1.52-1.42 (m, 1H),
1.38-1.28 (m, 1H), 0.88 (d, J=7.0 Hz, 3H), 0.48-0.35 (m, 1H);
Analytical HPLC (Method A): RT=1.52 min, purity=98.9%; Factor XIa
Ki=2,000 nM.
Example 348
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(isoquinolin-7-yl)phenyl]-6-oxo-1,6-dihydropyr-
imidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octad-
eca-1(18),2(6),4,14,16-pentaen-8-one
##STR00527##
[2250] MS(ESI) m/z: 616 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.25 (d, J=7.3 Hz, 2H), 8.73 (s, 1H), 8.60
(d, J=5.2 Hz, 1H), 8.50 (d, J=5.8 Hz, 1H), 8.03 (s, 1H), 7.90 (d,
J=8.5 Hz, 1H), 7.86 (d, J=5.5 Hz, 1H), 7.75 (d, J=1.8 Hz, 1H),
7.70-7.66 (m, 1H), 7.63-7.56 (m, 3H), 7.53 (d, J=4.9 Hz, 1H), 7.45
(s, 1H), 6.22 (s, 1H), 5.82-5.74 (m, 1H), 3.98 (s, 3H), 2.66-2.59
(m, 1H), 2.25-2.16 (m, 1H), 2.07-1.99 (m, 1H), 1.83-1.74 (m, 1H),
1.48-1.38 (m, 1H), 1.35-1.25 (m, 1H), 0.85 (d, J=7.0 Hz, 3H),
0.47-0.32 (m, 1H); Analytical HPLC (Method A): RT=1.77 min,
purity=94.8%; Factor XIa Ki=260 nM, Plasma Kallikrein Ki=3,600
nM.
Example 349
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(pyrimidin-5-yl)phenyl]-6-oxo-1,6-dihydropyrim-
idin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,6]octadec-
a-1(18),2(6),4,14,16-pentaen-8-one
##STR00528##
[2252] MS(ESI) m/z: 567 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.22 (s, 1H), 9.16 (s, 1H), 8.80 (s, 1H),
8.71-8.66 (m, 3H), 7.79 (d, J=2.1 Hz, 1H), 7.73 (dd, J=8.2, 1.8 Hz,
1H), 7.67 (s, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.58 (d, J=4.9 Hz, 1H),
7.48 (s, 1H), 6.46 (s, 1H), 5.89 (d, J=10.4 Hz, 1H), 4.02 (s, 3H),
2.69-2.61 (m, 1H), 2.33-2.23 (m, 1H), 2.16-2.07 (m, J=13.7 Hz, 1H),
1.87-1.78 (m, 1H), 1.52-1.43 (m, 1H), 1.38-1.28 (m, 1H), 0.89 (d,
J=6.7 Hz, 3H), 0.48-0.35 (m, 1H); Analytical HPLC (Method A):
RT=1.4 min, purity=100%; Factor XIa Ki=16 nM, Plasma Kallikrein
Ki=3,000 nM.
Example 350
Preparation of ethyl
2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricycl-
o[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di-
hydropyrimidin-4-yl}phenyl)-1H-pyrazol-1-yl]acetate
##STR00529##
[2254] MS(ESI) m/z: 631.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.25 (s, 1H), 8.84 (s, 1H), 8.67 (d, J=5.2
Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.66-7.46 (m, 6H), 7.43-7.38 (m,
1H), 7.16-7.11 (m, 2H), 7.00 (br. s., 1H), 6.20 (s, 1H), 5.89-5.82
(m, 1H), 4.01 (s, 3H), 2.68-2.60 (m, 1H), 2.33-2.23 (m, 1H),
2.13-2.04 (m, J=7.0 Hz, 1H), 1.86-1.77 (m, 1H), 1.52-1.42 (m, 1H),
1.38-1.28 (m, 1H), 0.89 (d, J=6.7 Hz, 3H), 0.51-0.37 (m, 1H);
Analytical HPLC (Method A): RT=1.99 min, purity=96.9%; Factor XIa
Ki=600 nM.
Example 351
Preparation of
(9R,13S)-13-{4-[5-chloro-2-(1-ethyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dih-
ydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0.sup.2,-
6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00530##
[2256] MS(ESI) m/z: 583.1 (M+H).sup.+; .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.98 (s, 1H), 8.75 (d, J=5.1 Hz, 1H), 7.72 (s,
1H), 7.60 (s, 1H), 7.56-7.52 (m, 2H), 7.49 (s, 1H), 7.48-7.47 (m,
2H), 7.36 (s, 1H), 6.39 (s, 1H), 6.02 (dd, J=12.7, 4.3 Hz, 1H),
4.12 (q, J=7.3 Hz, 2H), 4.05 (s, 3H), 2.76-2.67 (m, 1H), 2.39-2.29
(m, 1H), 2.14-2.00 (m, 2H), 1.67-1.43 (m, 2H), 1.37 (t, J=7.3 Hz,
3H), 1.01 (d, J=6.8 Hz, 3H), 0.79-0.64 (m, 1H); Analytical HPLC
(Method A): RT=1.55 min, purity=95.5%; Factor XIa Ki=96 nM.
Example 352
Preparation of
(9R,13S)-13-(4-{5-chloro-2-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]phenyl}-6--
oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo
[12.3.1.0.sup.2,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one
##STR00531##
[2258] MS(ESI) m/z: 649.3 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 9.24 (s, 1H), 8.95 (s, 1H), 8.62 (d, J=5.2
Hz, 1H), 8.53 (s, 1H), 7.83 (dd, J=8.9, 4.6 Hz, 2H), 7.70 (s, 1H),
7.67-7.56 (m, 5H), 7.49 (s, 1H), 7.36 (t, J=8.7 Hz, 2H), 6.46 (s,
1H), 5.96 (d, J=10.7 Hz, 1H), 4.03 (s, 3H), 2.70-2.62 (m, 1H),
2.38-2.28 (m, 1H), 2.18-2.10 (m, 1H), 1.94-1.85 (m, 1H), 1.54-1.45
(m, 1H), 1.41-1.31 (m, 1H), 0.90 (d, J=6.7 Hz, 3H), 0.51-0.38 (m,
1H); Analytical HPLC (Method A): RT=1.99 min, purity=100%; Factor
XIa Ki=7 nM.
* * * * *