U.S. patent application number 15/890436 was filed with the patent office on 2018-06-14 for phthalazinones and isoquinolinones as rock inhibitors.
The applicant listed for this patent is Bristol-Myers Squibb Company. Invention is credited to Peter W. Glunz, Vladimir Ladziata, Mimi L. Quan, Yan Zou.
Application Number | 20180162823 15/890436 |
Document ID | / |
Family ID | 50031626 |
Filed Date | 2018-06-14 |
United States Patent
Application |
20180162823 |
Kind Code |
A1 |
Glunz; Peter W. ; et
al. |
June 14, 2018 |
PHTHALAZINONES AND ISOQUINOLINONES AS ROCK INHIBITORS
Abstract
The present invention provides compounds of Formula (I):
##STR00001## or stereoisomers, tautomers, or pharmaceutically
acceptable salts thereof, wherein all the variables are as defined
herein. These compounds are selective ROCK inhibitors. This
invention also relates to pharmaceutical compositions comprising
these compounds and methods of treating cardiovascular, smooth
muscle, oncologic, neuropathologic, autoimmune, fibrotic, and/or
inflammatory disorders using the same.
Inventors: |
Glunz; Peter W.; (Yardley,
PA) ; Zou; Yan; (Jamison, PA) ; Quan; Mimi
L.; (Yardley, PA) ; Ladziata; Vladimir;
(Ewing, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bristol-Myers Squibb Company |
Princeton |
NJ |
US |
|
|
Family ID: |
50031626 |
Appl. No.: |
15/890436 |
Filed: |
February 7, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14759495 |
Jul 7, 2015 |
9926282 |
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PCT/US2014/011957 |
Jan 17, 2014 |
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15890436 |
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61754007 |
Jan 18, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 9/04 20180101; A61P
9/08 20180101; C07D 403/10 20130101; C07D 417/14 20130101; C07D
413/10 20130101; A61P 9/00 20180101; A61P 9/02 20180101; A61P 35/00
20180101; A61P 27/06 20180101; A61P 19/02 20180101; C07D 405/12
20130101; C07D 491/048 20130101; A61P 21/02 20180101; A61P 25/00
20180101; C07D 237/32 20130101; A61P 43/00 20180101; A61P 11/00
20180101; C07D 417/10 20130101; C07D 217/24 20130101; A61P 15/10
20180101; C07D 413/12 20130101; C07D 513/04 20130101; A61P 21/00
20180101; A61P 37/02 20180101; C07D 403/12 20130101; C07D 401/12
20130101; C07D 401/10 20130101; C07D 487/04 20130101; A61P 9/10
20180101; A61P 27/02 20180101; A61P 19/04 20180101; C07D 417/12
20130101; C07D 405/10 20130101; A61P 11/06 20180101; A61P 25/28
20180101; C07D 471/04 20130101; A61P 9/12 20180101; A61P 29/00
20180101; A61P 1/04 20180101 |
International
Class: |
C07D 237/32 20060101
C07D237/32; C07D 405/10 20060101 C07D405/10; C07D 217/24 20060101
C07D217/24; C07D 417/14 20060101 C07D417/14; C07D 417/12 20060101
C07D417/12; C07D 413/12 20060101 C07D413/12; C07D 405/12 20060101
C07D405/12; C07D 403/12 20060101 C07D403/12; C07D 403/10 20060101
C07D403/10; C07D 401/12 20060101 C07D401/12; C07D 401/10 20060101
C07D401/10; C07D 491/048 20060101 C07D491/048; C07D 487/04 20060101
C07D487/04; C07D 471/04 20060101 C07D471/04; C07D 417/10 20060101
C07D417/10; C07D 413/10 20060101 C07D413/10; C07D 513/04 20060101
C07D513/04 |
Claims
1. A compound of Formula (I): ##STR00790## or a stereoisomer, a
tautomer, a pharmaceutically acceptable salt thereof, wherein: M is
N; L is selected from --CR.sup.4R.sup.4C(O)--, --OC(O)--,
--NR.sup.6C(O)--, and --NR.sup.6--; R.sup.1 is selected from
NR.sup.5R.sup.5, C.sub.3-10 carbocycle and 4- to 15-membered
heterocycle comprising carbon atoms and 1-4 heteroatoms selected
from N, NR.sup.8, O, and S(O).sub.p; wherein said carbocycle and
heterocycle are substituted with 1-4 R.sup.7; R.sup.2, at each
occurrence, is independently selected from halogen, C.sub.1-6
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, C.sub.1-4 haloalkyl,
--OH, --CH.sub.2OH, --OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, CN,
--NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2,
--CO.sub.2H, --CH.sub.2CO.sub.2H, --CO.sub.2(C.sub.1-4 alkyl),
--CO(C.sub.1-4 alkyl), --CH.sub.2NH.sub.2, --CONH.sub.2,
--CONH(C.sub.1-4 alkyl), --CON(C.sub.1-4 alkyl).sub.2,
--OCH.sub.2CO.sub.2H, --NHCO(C.sub.1-4 alkyl),
--NHCO.sub.2(C.sub.1-4 alkyl), --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --C(.dbd.NH)NH.sub.2, carbocycle, and
heterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl,
carbocycle, and heterocycle are substituted with 0-4 R.sup.9;
R.sup.3, at each occurrence, is independently selected from
halogen, C.sub.1-6 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio,
C.sub.1-4 haloalkyl, --CH.sub.2OH, --OCH.sub.2F, --OCHF.sub.2,
--OCF.sub.3, CN, --NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4
alkyl).sub.2, --CO.sub.2H, --CH.sub.2CO.sub.2H,
--CO.sub.2(C.sub.1-4 alkyl), --CO(C.sub.1-4 alkyl),
--CH.sub.2NH.sub.2, --CONH.sub.2, --CONH(C.sub.1-4 alkyl),
--CON(C.sub.1-4 alkyl).sub.2, --OCH.sub.2CO.sub.2H,
--NHCO(C.sub.1-4 alkyl), --NHCO.sub.2(C.sub.1-4 alkyl),
--NHSO.sub.2(C.sub.1-4 alkyl), --SO.sub.2NH.sub.2,
--C(.dbd.NH)NH.sub.2, carbocycle, and heterocycle, wherein said
alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle
are substituted with 0-4 R.sup.9; R.sup.4, at each occurrence, is
independently selected from H, OH, NH.sub.2, CH.sub.2NH.sub.2,
C.sub.1-4 haloalkyl, OCH.sub.2F, OCHF.sub.2, OCF.sub.3,
--NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2, C.sub.1-4
alkoxy, CH.sub.2OH, CH.sub.2O(C.sub.1-4 alkyl), CH.sub.2CO.sub.2H,
CH.sub.2CO.sub.2(C.sub.1-4 alkyl), C.sub.1-4 alkyl, carbocycle, and
heterocycle, wherein said alkyl, alkoxy, haloalkyl, carbocycle, and
heterocycle are substituted with 0-4 R.sup.9; R.sup.5, at each
occurrence, is independently selected from H, C.sub.1-4 alkyl,
--(CR.sup.6R.sup.6).sub.n--C.sub.3-10 carbocycle and
--(CR.sup.6R.sup.6).sub.n-4-10 membered heterocycle comprising
carbon atoms and 1-4 heteroatoms selected from N, NR.sup.8, O, and
S(O).sub.p, wherein said alkyl, carbocycle and heterocycle are
substituted with 1-4 R.sup.7; alternatively, R.sup.5 and R.sup.5
are taken together with the nitrogen atom to which they are
attached to form 4- to 15-membered heterocycle substituted with 1-4
R.sup.7; R.sup.6, at each occurrence, is independently selected
from H and C.sub.1-4 alkyl; R.sup.7, at each occurrence, is
independently selected from H, .dbd.O, NO.sub.2, halogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, CN, OH, CF.sub.3,
--(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.3O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2OH,
--NHCO.sub.2(CH.sub.2).sub.2NH.sub.2,
--NHCO.sub.2(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--NHCO.sub.2CH.sub.2CO.sub.2H, --CH.sub.2NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NR.sup.8R.sup.8, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--CONR.sup.8R.sup.8,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
--NHCO-carbocycle, --NHCO-heterocycle,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkoxyl,
carbocycle, and heterocycle are substituted with 0-4 R.sup.9;
R.sup.8, at each occurrence, is independently selected from H,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
--(CH.sub.2).sub.n--C(O)C.sub.1-4alkyl,
--(CH.sub.2).sub.n--C(O)carbocycle,
--(CH.sub.2).sub.n--C(O)heterocycle,
--(CH.sub.2).sub.n--C(O)NR.sup.aR.sup.a,
--(CH.sub.2).sub.n--C(O)O-alkyl,
--(CH.sub.2).sub.n--C(O)O-carbocycle,
--(CH.sub.2).sub.n--C(O)O-heterocycle,
--(CH.sub.2).sub.n--SO.sub.2alkyl, --(CH.sub.2).sub.n
SO.sub.2carbocycle, --(CH.sub.2).sub.n--SO.sub.2heterocycle,
--(CH.sub.2).sub.n--SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, alkenyl, alkynyl, carbocycle, and heterocycle
are substituted with 0-4 R.sup.9; alternatively, R.sup.8 and
R.sup.8 are taken together with the nitrogen atom to which they are
attached to form 4- to 10-membered heterocycle substituted with 0-4
R.sup.9; R.sup.9, at each occurrence, is independently selected
from halogen, OH, NO.sub.2, CHF.sub.2, CF.sub.3, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CH.sub.2OH, CO(C.sub.1-4 alkyl), CO.sub.2H,
CO.sub.2(C.sub.1-4 alkyl), --(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a, --O(CH.sub.2).sub.ncarbocycle,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CR.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein said
alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
0-4 R.sup.b; R.sup.10 is selected from H and C.sub.1-4 alkyl;
R.sup.a, at each occurrence, is independently selected from H,
C.sub.1-4 alkyl, --(CH.sub.2).sub.nOH, CO(C.sub.1-4 alkyl),
COCF.sub.3, CO.sub.2(C.sub.1-4 alkyl), --CONH.sub.2,
--CONH--C.sub.1-4 alkylene-CO.sub.2(C.sub.1-4 alkyl), C.sub.1-4
alkylene-CO.sub.2(C.sub.1-4 alkyl), R.sup.c, CO.sub.2R.sup.c, and
CONHR.sup.c; alternatively, R.sup.a and R.sup.a are taken together
with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and
heterocycle are substituted with 0-4 R.sup.b; R.sup.b, at each
occurrence, is independently selected from .dbd.O, OH, halogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OCF.sub.3, NH.sub.2, NO.sub.2,
N(C.sub.1-4 alkyl).sub.2, CO(C.sub.1-4 alkyl), CO(C.sub.1-4
haloalkyl), CO.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
alkylene-O(C.sub.1-4 alkyl), --CONH--C.sub.1-4 alkylene-N(C.sub.1-4
alkyl).sub.2, --CONH--C.sub.1-4 alkylene-N (C.sub.1-4 alkyl).sub.2,
--C.sub.1-4 alkylene-O--P(O)(OH).sub.2, --NHCO.sub.2(C.sub.1-4
alkyl), --R.sup.c, COR.sup.c, CO.sub.2R.sup.c, and CONHR.sup.c;
R.sup.c, at each occurrence, is independently selected from
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.n-phenyl, and --(CH.sub.2).sub.n-5- to 6-membered
heterocycle containing carbon atoms and 1-4 heteroatoms selected
from the group consisting of: N, NH, N(C.sub.1-4 alkyl), O, and
S(O).sub.p; wherein each ring moiety is substituted with 0-2
R.sup.d; R.sup.d, at each occurrence, is independently selected
from .dbd.O, halogen, --OH, C.sub.1-4 alkyl, NH.sub.2, NH(C.sub.1-4
alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkoxy, and
--NHCO(C.sub.1-4 alkyl), and heterocycle containing carbon atoms
and 1-4 heteroatoms selected from the group consisting of: N, NH,
N(C.sub.1-4 alkyl), O, and S(O).sub.p; n, at each occurrence, is
independently selected from 0, 1, 2, 3, and 4; p, at each
occurrence, is independently selected from 0, 1, and 2; provided
when L is NHC(O), R.sup.1 is other than ##STR00791## wherein X is N
or a substituted or unsubstituted carbon atom; when L is NR.sup.6,
R.sup.1 is heterocycle substituted with 1-4 R.sup.7;
2. The compound of claim 1, having Formula (II): ##STR00792## or a
stereoisomer, a tautomer, or a pharmaceutically acceptable salt
thereof, wherein: M is N; R.sup.5, at each occurrence, is
independently selected from H, C.sub.1-4 alkyl,
--(CR.sup.6R.sup.6).sub.n--C.sub.3-10 carbocycle, and
--(CR.sup.6R.sup.6).sub.n-4-10 membered heterocycle comprising
carbon atoms and 1-4 heteroatoms selected from N, NR.sup.8, O, and
S(O).sub.p, wherein said alkyl, carbocycle, and heterocycle are
substituted with 1-4 R.sup.7; alternatively, R.sup.5 and R.sup.5
are taken together with the nitrogen atom to which they are
attached to form 4- to 10-membered heterocycle substituted with 1-4
R.sup.7; R.sup.7, at each occurrence, is independently selected
from H, .dbd.O, NO.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4
alkoxy, CN, OH, CF.sub.3, --(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.3O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2OH,
--NHCO.sub.2(CH.sub.2).sub.2NH.sub.2,
--NHCO.sub.2(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--NHCO.sub.2CH.sub.2CO.sub.2H, --CH.sub.2NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NR.sup.8R.sup.8, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--CONR.sup.8R.sup.8,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
--NHCO-carbocycle, --NHCO-heterocycle,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkoxyl,
carbocycle, and heterocycle are substituted with 0-4 R.sup.9;
R.sup.8, at each occurrence, is independently selected from H,
C.sub.1-4 alkyl, C(O)C.sub.1-4alkyl, C(O)carbocycle,
C(O)heterocycle, --(CH.sub.2).sub.n C(O)NR.sup.aR.sup.a,
C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO.sub.2alkyl,
SO.sub.2carbocycle, SO.sub.2heterocycle, SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.9; R.sup.9, at each occurrence, is independently
selected from halogen, OH, NO.sub.2, CHF.sub.2, CF.sub.3, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, CH.sub.2OH, CO.sub.2H, CO.sub.2(C.sub.1-4
alkyl), CONH.sub.2, --(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2)(2-4)NR.sup.aR.sup.a,
--(CR.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein said
alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
0-4 R.sup.b; R.sup.10 is selected from H and C.sub.1-4 alkyl;
R.sup.a, at each occurrence, is independently selected from H,
C.sub.1-4 alkyl, --(CH.sub.2).sub.nOH, CO(C.sub.1-4 alkyl),
COCF.sub.3, CO.sub.2(C.sub.1-4 alkyl), --CONH.sub.2,
--CONH--C.sub.1-4 alkylene-CO.sub.2(C.sub.1-4 alkyl), C.sub.1-4
alkylene-CO.sub.2(C.sub.1-4 alkyl), R.sup.c, CO.sub.2R.sup.c, and
CONHR.sup.c; alternatively, R.sup.a and R.sup.a are taken together
with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and
heterocycle are substituted with 0-4 R.sup.b; R.sup.b, at each
occurrence, is independently selected from .dbd.O, halogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OCF.sub.3, NH.sub.2, NO.sub.2,
N(C.sub.1-4 alkyl).sub.2, CO(C.sub.1-4 alkyl), CO(C.sub.1-4
haloalkyl), CO.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
alkylene-O(C.sub.1-4 alkyl), --CONH--C.sub.1-4 alkylene-N(C.sub.1-4
alkyl).sub.2, --CONH--C.sub.1-4 alkylene-N (C.sub.1-4 alkyl).sub.2,
--C.sub.1-4 alkylene-O--P(O)(OH).sub.2, --NHCO.sub.2(C.sub.1-4
alkyl), --R.sup.c, COR.sup.c, CO.sub.2R.sup.c, and CONHR.sup.c;
R.sup.c, at each occurrence, is independently selected from
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.n-phenyl, and --(CH.sub.2).sub.n-5- to 6-membered
heterocycle containing carbon atoms and 1-4 heteroatoms selected
from the group consisting of: N, NH, N(C.sub.1-4 alkyl), O, and
S(O).sub.p; wherein each ring moiety is substituted with 0-2
R.sup.d; R.sup.d, at each occurrence, is independently selected
from .dbd.O, halogen, --OH, C.sub.1-4 alkyl, NH.sub.2, NH(C.sub.1-4
alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkoxy, and
--NHCO(C.sub.1-4 alkyl), and heterocycle containing carbon atoms
and 1-4 heteroatoms selected from the group consisting of: N, NH,
N(C.sub.1-4 alkyl), O, and S(O).sub.p; n, at each occurrence, is
independently selected from 0, 1, 2, 3, and 4; p, at each
occurrence, is independently selected from 0, 1, and 2.
3. The compound of claim 2, wherein: R.sup.5 is selected from H,
C.sub.1-4 alkyl, --(CH.sub.2).sub.n--C.sub.3-10 cycloalkyl,
--(CH.sub.2).sub.n-aryl, --(CH.sub.2).sub.n-4-10 membered
heterocycle selected from ##STR00793## wherein said alkyl,
cycloalkyl, aryl are substituted with 1-4 R.sup.7.
4. The compound of claim 2, wherein: R.sup.5 and R.sup.5 are taken
together with the nitrogen atom to which they are attached to form
a heterocycle selected from ##STR00794## R.sup.7, at each
occurrence, is independently selected from H, .dbd.O, halogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CN, OH, CF.sub.3,
--(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --CH.sub.2NH.sub.2,
--NHCO(C.sub.1-4 alkyl), --NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NH.sub.2, --NHC(O)NH(C.sub.1-4 alkyl),
--NHC(O)N(C.sub.1-4 alkyl).sub.2, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--CONR.sup.8R.sup.8,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
--NHCO-carbocycle, --NHCO-heterocycle,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkoxyl,
carbocycle, and heterocycle are substituted with 0-4 R.sup.9;
R.sup.8, at each occurrence, is independently selected from H,
C.sub.1-4 alkyl, C(O)C.sub.1-4alkyl, C(O)carbocycle,
C(O)heterocycle, --(CH.sub.2).sub.n--C(O)NR.sup.aR.sup.a,
C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO.sub.2alkyl,
SO.sub.2carbocycle, SO.sub.2heterocycle, SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.9; alternatively, R.sup.8 and R.sup.8 are taken
together with the nitrogen atom to which they are attached to form
4- to 10-membered heterocycle substituted with 0-4 R.sup.9; and
R.sup.9, at each occurrence, is independently selected from
halogen, OH, NO.sub.2, CHF.sub.2, CF.sub.3, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CH.sub.2OH, CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl),
CONH.sub.2, --(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2)(2-4)NR.sup.aR.sup.a,
--(CR.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein said
alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
0-4 R.sup.b; R.sup.a, at each occurrence, is independently selected
from H, C.sub.1-4 alkyl, --(CH.sub.2).sub.nOH, CO(C.sub.1-4 alkyl),
COCF.sub.3, CO.sub.2(C.sub.1-4 alkyl), --CONH.sub.2,
--CONH--C.sub.1-4 alkylene-CO.sub.2(C.sub.1-4 alkyl), C.sub.1-4
alkylene-CO.sub.2(C.sub.1-4 alkyl), R.sup.c, CO.sub.2R.sup.c, and
CONHR.sup.c; alternatively, R.sup.a and R.sup.a are taken together
with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and
heterocycle are substituted with 0-4 R.sup.b; R.sup.b, at each
occurrence, is independently selected from .dbd.O, halogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OCF.sub.3, NH.sub.2, NO.sub.2,
N(C.sub.1-4 alkyl).sub.2, CO(C.sub.1-4 alkyl), CO(C.sub.1-4
haloalkyl), CO.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
alkylene-O(C.sub.1-4 alkyl), --CONH--C.sub.1-4 alkylene-N(C.sub.1-4
alkyl).sub.2, --CONH--C.sub.1-4 alkylene-N (C.sub.1-4 alkyl).sub.2,
--C.sub.1-4 alkylene-O--P(O)(OH).sub.2, --NHCO.sub.2(C.sub.1-4
alkyl), --R.sup.c, COR.sup.c, CO.sub.2R.sup.c, and CONHR.sup.c;
R.sup.c, at each occurrence, is independently selected from
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.n-phenyl, and --(CH.sub.2).sub.n-5- to 6-membered
heterocycle containing carbon atoms and 1-4 heteroatoms selected
from the group consisting of: N, NH, N(C.sub.1-4 alkyl), O, and
S(O).sub.p; wherein each ring moiety is substituted with 0-2
R.sup.d; and R.sup.d, at each occurrence, is independently selected
from .dbd.O, halogen, --OH, C.sub.1-4 alkyl, NH.sub.2, NH(C.sub.1-4
alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkoxy, and
--NHCO(C.sub.1-4 alkyl), and heterocycle containing carbon atoms
and 1-4 heteroatoms selected from the group consisting of: N, NH,
N(C.sub.1-4 alkyl), O, and S(O).sub.p.
5. The compound of claim 1, having Formula (III): ##STR00795## or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt
thereof, wherein: M is N; R.sup.5, at each occurrence, is
independently selected from H, C.sub.1-4 alkyl,
--(CR.sup.6R.sup.6).sub.n--C.sub.3-10 carbocycle, and
--(CR.sup.6R.sup.6).sub.n-4-10 membered heterocycle comprising
carbon atoms and 1-4 heteroatoms selected from N, NR.sup.8, O, and
S(O).sub.p, wherein said alkyl, carbocycle, and heterocycle are
substituted with 1-4 R.sup.7; alternatively, R.sup.5 and R.sup.5
are taken together with the nitrogen atom to which they are
attached to form 4- to 10-membered heterocycle substituted with 1-4
R.sup.7; R.sup.6, at each occurrence, is independently selected
from H and C.sub.1-4 alkyl; R.sup.7, at each occurrence, is
independently selected from H, .dbd.O, NO.sub.2, halogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, CN, OH, CF.sub.3,
--(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.3O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2OH,
--NHCO.sub.2(CH.sub.2).sub.2NH.sub.2,
--NHCO.sub.2(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--NHCO.sub.2CH.sub.2CO.sub.2H, --CH.sub.2NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NR.sup.8R.sup.8, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--CONR.sup.8R.sup.8,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
--NHCO-carbocycle, --NHCO-heterocycle,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkoxyl,
carbocycle, and heterocycle are substituted with 0-4 R.sup.9;
R.sup.8, at each occurrence, is independently selected from H,
C.sub.1-4 alkyl, C(O)C.sub.1-4alkyl, C(O)carbocycle,
C(O)heterocycle, --(CH.sub.2).sub.n--C(O)NR.sup.aR.sup.a,
C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO.sub.2alkyl,
SO.sub.2carbocycle, SO.sub.2heterocycle, SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.9; R.sup.9, at each occurrence, is independently
selected from halogen, OH, NO.sub.2, CHF.sub.2, CF.sub.3, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, CH.sub.2OH, CO.sub.2H, CO.sub.2(C.sub.1-4
alkyl), CONH.sub.2, --(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2)(2-4)NR.sup.aR.sup.a,
--(CR.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein said
alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
0-4 R.sup.b; n, at each occurrence, is independently selected from
0, 1, 2, 3, and 4; and p, at each occurrence, is independently
selected from 0, 1, and 2.
6. The compound of claim 1, wherein: L is --NR.sup.6--; R.sup.1 is
heteroaryl substituted with 1-4 R.sup.7; R.sup.7, at each
occurrence, is independently selected from H, halogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, CN, OH, --(CH.sub.2).sub.n-carbocycle, and
--(CH.sub.2).sub.n-heterocycle, wherein said alkyl, alkoxyl,
carbocycle, and heterocycle are substituted with 0-4 R.sup.9.
7. The compound of claim 6, wherein: L is --NR.sup.6--; and R.sup.1
is selected from ##STR00796##
8. The compound of claim 1, having Formula (IV): ##STR00797## or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt
thereof, wherein: R.sup.1 is selected from NR.sup.5R.sup.5,
C.sub.3-10 carbocycle, and 5- to 10-membered heterocycle, wherein
said carbocycle and heterocycle are substituted with 1-4 R.sup.7;
R.sup.5, at each occurrence, is independently selected from H,
C.sub.1-4 alkyl, --(CR.sup.6R.sup.6).sub.n--C.sub.3-10 carbocycle,
and --(CR.sup.6R.sup.6).sub.n-4-10 membered heterocycle comprising
carbon atoms and 1-4 heteroatoms selected from N, NR.sup.8, O, and
S(O).sub.p, wherein said alkyl, carbocycle, and heterocycle are
substituted with 1-4 R.sup.7; alternatively, R.sup.5 and R.sup.5
are taken together with the nitrogen atom to which they are
attached to form 4- to 10-membered heterocycle substituted with 1-4
R.sup.7; R.sup.6, at each occurrence, is independently selected
from H and C.sub.1-4 alkyl; R.sup.7, at each occurrence, is
independently selected from H, .dbd.O, NO.sub.2, halogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, CN, OH, CF.sub.3,
--(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.3O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2OH,
--NHCO.sub.2(CH.sub.2).sub.2NH.sub.2,
--NHCO.sub.2(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--NHCO.sub.2CH.sub.2CO.sub.2H, --CH.sub.2NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NR.sup.8R.sup.8, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--CONR.sup.8R.sup.8,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
--NHCO-carbocycle, --NHCO-heterocycle,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkoxyl,
carbocycle, and heterocycle are substituted with 0-4 R.sup.9;
R.sup.8, at each occurrence, is independently selected from H,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C(O)C.sub.1-4alkyl,
C(O)carbocycle, C(O)heterocycle,
--(CH.sub.2).sub.n--C(O)NR.sup.aR.sup.a, C(O)O-alkyl,
C(O)O-carbocycle, C(O)O-heterocycle, SO.sub.2alkyl,
SO.sub.2carbocycle, SO.sub.2heterocycle, SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, alkenyl, carbocycle, and heterocycle are
substituted with 0-4 R.sup.9; R.sup.9, at each occurrence, is
independently selected from halogen, OH, NO.sub.2, CHF.sub.2,
CF.sub.3, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CH.sub.2OH, CO.sub.2H,
CO.sub.2(C.sub.1-4 alkyl), CONH.sub.2,
--(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2)(2-4)NR.sup.aR.sup.a,
--(CR.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein said
alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
0-4 R.sup.b; n, at each occurrence, is independently selected from
0, 1, 2, 3, and 4; p, at each occurrence, is independently selected
from 0, 1, and 2.
9. The compound of claim 8, wherein: R.sup.1 is selected from
##STR00798## ##STR00799## R.sup.7, at each occurrence, is
independently selected from H, .dbd.O, NO.sub.2, halogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, CN, OH, CF.sub.3,
--(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.3O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2OH,
--NHCO.sub.2(CH.sub.2).sub.2NH.sub.2,
--NHCO.sub.2(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--NHCO.sub.2CH.sub.2CO.sub.2H, --CH.sub.2NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NR.sup.8R.sup.8, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--CONR.sup.8R.sup.8,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
--NHCO-carbocycle, --NHCO-heterocycle,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkoxyl,
carbocycle, and heterocycle are substituted with 0-4 R.sup.9;
R.sup.8, at each occurrence, is independently selected from H,
C.sub.1-4 alkyl, C(O)C.sub.1-4alkyl, C(O)carbocycle,
C(O)heterocycle, --(CH.sub.2).sub.n--C(O)NR.sup.aR.sup.a,
C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO.sub.2alkyl,
SO.sub.2carbocycle, SO.sub.2heterocycle, SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.9; alternatively, R.sup.8 and R.sup.8 are taken
together with the nitrogen atom to which they are attached to form
4- to 10-membered heterocycle substituted with 0-4 R.sup.9; and
R.sup.9, at each occurrence, is independently selected from
halogen, OH, NO.sub.2, CHF.sub.2, CF.sub.3, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CH.sub.2OH, CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl),
CONH.sub.2, --(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2)(2-4)NR.sup.aR.sup.a,
--(CR.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein said
alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
0-4 R.sup.b; R.sup.a, at each occurrence, is independently selected
from H, C.sub.1-4 alkyl, --(CH.sub.2).sub.nOH, CO(C.sub.1-4 alkyl),
COCF.sub.3, CO.sub.2(C.sub.1-4 alkyl), --CONH.sub.2,
--CONH--C.sub.1-4 alkylene-CO.sub.2(C.sub.1-4 alkyl), C.sub.1-4
alkylene-CO.sub.2(C.sub.1-4 alkyl), R.sup.c, CO.sub.2R.sup.c, and
CONHR.sup.c; alternatively, R.sup.a and R.sup.a are taken together
with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and
heterocycle are substituted with 0-4 R.sup.b; R.sup.b, at each
occurrence, is independently selected from .dbd.O, halogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OCF.sub.3, NH.sub.2, NO.sub.2,
N(C.sub.1-4 alkyl).sub.2, CO(C.sub.1-4 alkyl), CO(C.sub.1-4
haloalkyl), CO.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
alkylene-O(C.sub.1-4 alkyl), --CONH--C.sub.1-4 alkylene-N(C.sub.1-4
alkyl).sub.2, --CONH--C.sub.1-4 alkylene-N (C.sub.1-4 alkyl).sub.2,
--C.sub.1-4 alkylene-O--P(O)(OH).sub.2, --NHCO.sub.2(C.sub.1-4
alkyl), --R.sup.c, COR.sup.c, CO.sub.2R.sup.c, and CONHR.sup.c;
R.sup.c, at each occurrence, is independently selected from
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.n-phenyl, and --(CH.sub.2).sub.n-5- to 6-membered
heterocycle containing carbon atoms and 1-4 heteroatoms selected
from the group consisting of: N, NH, N(C.sub.1-4 alkyl), O, and
S(O).sub.p; wherein each ring moiety is substituted with 0-2
R.sup.d; and R.sup.d, at each occurrence, is independently selected
from .dbd.O, halogen, --OH, C.sub.1-4 alkyl, NH.sub.2, NH(C.sub.1-4
alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkoxy, and
--NHCO(C.sub.1-4 alkyl), and heterocycle containing carbon atoms
and 1-4 heteroatoms selected from the group consisting of: N, NH,
N(C.sub.1-4 alkyl), O, and S(O).sub.p.
10. The compound of claim 8, wherein: R.sup.1 is NR.sup.5R.sup.5;
R.sup.5 and R.sup.5 are taken together with the nitrogen atom to
which they are attached to form 4- to 10-membered heterocycle
substituted with 1-4 R.sup.7; R.sup.7, at each occurrence, is
independently selected from H, .dbd.O, halogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CN, OH, CF.sub.3, --(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl), --NHC(O)NH.sub.2,
--NHC(O)NH(C.sub.1-4 alkyl), --NHC(O)N(C.sub.1-4 alkyl).sub.2,
--NHSO.sub.2(C.sub.1-4 alkyl), --SO.sub.2NH.sub.2,
--SO.sub.2NH(C.sub.1-4 alkyl), --SO.sub.2N(C.sub.1-4 alkyl).sub.2,
--SO.sub.2NH(CH.sub.2).sub.2OH, --SO.sub.2NH(CH.sub.2).sub.2O
(C.sub.1-4 alkyl), --CONH.sub.2, --CONH(C.sub.1-4 alkyl),
--CON(C.sub.1-4 alkyl).sub.2, --CH.sub.2CONH.sub.2,
--(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-carbocycle,
--O(CH.sub.2).sub.n-heterocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkoxyl,
carbocycle, and heterocycle are substituted with 0-4 R.sup.9;
R.sup.8, at each occurrence, is independently selected from H,
C.sub.1-4 alkyl, C(O)C.sub.1-4alkyl, C(O)carbocycle,
C(O)heterocycle, --(CH.sub.2).sub.n--C(O)NR.sup.aR.sup.a,
C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO.sub.2alkyl,
SO.sub.2carbocycle, SO.sub.2heterocycle, SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-cycloalkyl, --(CH.sub.2).sub.n-phenyl, and
--(CH.sub.2).sub.n-heterocycle, wherein said alkyl, carbocycle, and
heterocycle are substituted with 0-4 R.sup.9; and R.sup.9, at each
occurrence, is independently selected from halogen, OH, NO.sub.2,
CHF.sub.2, CF.sub.3, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CH.sub.2OH,
CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl), CONH.sub.2,
--(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2)(2-4)NR.sup.aR.sup.a,
--(CR.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein said
alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
0-4 R.sup.b.
11. A pharmaceutical composition comprising one or more compounds
according to claim 1 and a pharmaceutically acceptable carrier or
diluent.
12. A method for the_prophylaxis and/or treatment of disorders
associated with aberrant Rho kinase activity, 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.
13. The method of claim 12, wherein said disorder is selected from
the group consisting of a cardiovascular disorder, a smooth muscle
related disorder, a fibrotic disease, an inflammatory disease,
neuropathic disorders, oncologic disorders, and an autoimmune
disorder.
14. A method for inhibiting Rho kinase activity, comprising (a)
providing target cells and a composition comprising a compound
described in claim 1; and (b) exposing said target cells to said
composition under conditions such that said composition binds to
said target cells so as to inhibit Rho kinase activity within said
target cells.
Description
CROSS REFERENCES TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. Ser. No.
14/759,495, filed on Jul. 7, 2015 (now allowed) which is a 371 of
International Application No. PCT/US2014/011957, filed on Jan. 17,
2014, which claims the benefit of U.S. Provisional Application Ser.
No. 61/754,007 filed on Jan. 18, 2013 which is incorporated herein
by reference.
FIELD OF THE INVENTION
[0002] The present invention relates generally to novel
phthalazinone and isoquinolinone compounds, and their analogues
thereof, which are inhibitors of Rho kinases, compositions
containing them, and methods of using them, for example, for the
treatment or prophylaxis of disorders associated with aberrant Rho
kinase activity.
BACKGROUND OF THE INVENTION
[0003] Rho-Kinase (ROCK) is a member of the serine-threonine
protein kinase family. ROCK exists in two isoforms, ROCK1 and ROCK2
(Ishizaki, T. et al., EMBO J., 15:1885-1893 (1996)). ROCK has been
identified as an effector molecule of RhoA, a small GTP-binding
protein (G protein) that plays a key role in multiple cellular
signaling pathways. ROCK and RhoA are ubiquitously expressed across
tissues. The RhoA/ROCK signaling pathway is involved in a number of
cellular functions, such as ACTIN.RTM. organization, cell adhesion,
cell migration, and cytokinesis (Riento, K. et al., Nat. Rev. Mol.
Cell Biol., 4:446-456 (2003)). It is also directly involved in
regulating smooth muscle contraction (Somlyo, A. P., Nature,
389:908-911 (1997)). Upon activation of its receptor, RhoA is
activated, and, in turn, it activates ROCK. Activated ROCK
phosphorylates the myosin-binding subunit of myosin light chain
phosphatase, which inhibits activity of the phosphatase and leads
to contraction. Contraction of the smooth muscle in the vasculature
increases blood pressure, leading to hypertension.
[0004] There is considerable evidence in the literature that the
Rho A/ROCK signaling pathway plays an important role in signal
transduction initiated by several vasoactive factors, for example
angiotensin II (Yamakawa, T. et al., Hypertension, 35:313-318
(2000)), urotension II (Sauzeau, V. et al., Circ. Res.,
88:1102-1104 (2001)), endothelin-1 (Tangkijvanich, P. et al.,
Hepatology, 33:74-80 (2001)), serotonin (Shimokawa, H., Jpn. Circ.
J., 64:1-12 (2000)), norepinephrine (Martinez, M. C. et al., Am. J.
Physiol., 279:H1228-H1238 (2000)) and platelet-derived growth
factor (PDGF) (Kishi, H. et al., J. Biochem., 128:719-722 (2000)).
Many of these factors are implicated in the pathogenesis of
cardiovascular disease.
[0005] Additional studies in the literature, some using the known
ROCK inhibitors fasudil (Asano, T. et al., J. Pharmacol. Exp.
Ther., 241:1033-1040 (1987)) or Y-27632 (Uehata, M. et al., Nature,
389:990-994 (1997)) further illustrate the link between ROCK and
cardiovascular disease. For example, ROCK expression and activity
have been shown to be elevated in spontaneously hypertensive rats,
suggesting a link to the development of hypertension in these
animals (Mukai, Y. et al., FASEB J., 15:1062-1064 (2001)). The ROCK
inhibitor Y-27632 (Uehata, M. et al., Nature, ibid.) was shown to
significantly decrease blood pressure in three rat models of
hypertension, including the spontaneously hypertensive rat, renal
hypertensive rat and deoxycortisone acetate salt hypertensive rat
models, while having only a minor effect on blood pressure in
control rats. This reinforces the link between ROCK and
hypertension.
[0006] Other studies suggest a link between ROCK and
atherosclerosis. For example, gene transfer of a dominant negative
form of ROCK suppressed neointimal formation following balloon
injury in porcine femoral arteries (Eto, Y. et al., Am. J. Physiol.
Heart Circ. Physiol., 278:H1744-H1750 (2000)). In a similar model,
ROCK inhibitor Y-27632 also inhibited neointimal formation in rats
(Sawada, N. et al., Circulation, 101:2030-2033 (2000)). In a
porcine model of IL-1 beta-induced coronary stenosis, long term
treatment with the ROCK inhibitor fasudil was shown to
progressively reduce coronary stenosis, as well as promote a
regression of coronary constrictive remodeling (Shimokawa, H. et
al., Cardiovascular Res., 51:169-177 (2001)).
[0007] Additional investigations suggest that a ROCK inhibitor
would be useful in treating other cardiovascular diseases. For
example, in a rat stroke model, fasudil was shown to reduce both
the infarct size and neurologic deficit (Toshima, Y., Stroke,
31:2245-2250 (2000)). The ROCK inhibitor Y-27632 was shown to
improve ventricular hypertrophy, fibrosis and function in a model
of congestive heart failure in Dahl salt-sensitive rats (Kobayashi,
N. et al., Cardiovascular Res., 55:757-767 (2002)).
[0008] Other animal or clinical studies have implicated ROCK in
additional diseases including coronary vasospasm (Shimokawa, H. et
al., Cardiovasc. Res., 43:1029-1039 (1999)), cerebral vasospasm
(Sato, M. et al., Circ. Res., 87:195-200 (2000)),
ischemia/reperfusion injury (Yada, T. et al., J. Am. Coll.
Cardiol., 45:599-607 (2005)), pulmonary hypertension (Fukumoto, Y.
et al., Heart, 91:391-392 (2005)), angina (Shimokawa, H. et al., J.
Cardiovasc. Pharmacol., 39:319-327 (2002)), renal disease (Satoh,
S. et al., Eur. J. Pharmacol., 455:169-174 (2002)) and erectile
dysfunction (Gonzalez-Cadavid, N. F. et al., Endocrine, 23:167-176
(2004)).
[0009] In another study, it has been demonstrated that inhibition
of the RhoA/ROCK signaling pathway allows formation of multiple
competing lamellipodia that disrupt the productive migration of
monocytes (Worthylake, R. A. et al., J. Biol. Chem.,
278:13578-13584 (2003)). It has also been reported that small
molecule inhibitors of Rho Kinase are capable of inhibiting MCP-1
mediated chemotaxis in vitro (Iijima, H., Bioorg. Med. Chem.,
15:1022-1033 (2007)). Due to the dependence of immune cell
migration upon the RhoA/ROCK signaling pathway one would anticipate
inhibition of Rho Kinase should also provide benefit for diseases
such as rheumatoid arthritis, psoriasis, and inflammatory bowel
disease.
[0010] The above studies provide evidence for a link between ROCK
and cardiovascular diseases including hypertension,
atherosclerosis, restenosis, stroke, heart failure, coronary
vasospasm, cerebral vasospasm, ischemia/reperfusion injury,
pulmonary hypertension and angina, as well as renal disease and
erectile dysfunction. Given the demonstrated effect of ROCK on
smooth muscle, ROCK inhibitors may also be useful in other diseases
involving smooth muscle hyper-reactivity, including asthma and
glaucoma (Shimokawa, H. et al., Arterioscler. Thromb. Vase. Biol.,
25:1767-1775 (2005)). Furthermore, Rho-kinase has been indicated as
a drug target for the treatment of various other diseases,
including airway inflammation and hyperresponsiveness (Henry, P. J.
et al., Pulm. Pharmacol Ther., 18:67-74 (2005)), cancer (Rattan, R.
et al., J Neurosci. Res., 83:243-255 (2006); Lepley, D. et al.,
Cancer Res., 65:3788-3795 (2005)), fibrotic diseases (Jiang, C. et
al., nt. J Mol. Sci., 13:8293-8307 (2012); Zhou, L. et al., Am. J.
Nephrol., 34:468-475 (2011)), as well as neurological disorders,
such as spinal-cord injury, Alzheimer's disease, multiple
sclerosis, stroke and neuropathic pain (Mueller, B. K. et al., Nat.
Rev. Drug Disc., 4:387-398 (2005); Sun, X. et al., J.
Neuroimmunol., 180:126-134 (2006)).
[0011] There remains an unmet medical need for new drugs to treat
cardiovascular disease. In the 2012 update of Heart Disease and
Stroke Statistics from the American Heart Association (Circulation,
125:e2-e220 (2012)), it was reported that cardiovascular disease
accounted for 32.8% of all deaths in the U.S., with coronary heart
disease accounting for .about.1 in 6 deaths overall in the U.S.
Contributing to these numbers, it was found that .about.33.5% of
the adult U.S. population was hypertensive, and it was estimated
that in 2010.about.6.6 million U.S. adults would have heart
failure. Therefore, despite the number of medications available to
treat cardiovascular diseases (CVD), including diuretics, beta
blockers, angiotensin converting enzyme inhibitors, angiotensin
blockers and calcium channel blockers, CVD remains poorly
controlled or resistant to current medication for many
patients.
[0012] Although there are many reports of ROCK inhibitors under
investigation (see, for example, US 2012/0122842 A1, US
2010/0041645 A1, US 2008/0161297 A1, and Hu, E. et al., Exp. Opin.
Ther. Targets, 9:715-736 (2005)), fasudil is the only marketed ROCK
inhibitor at this time. An i.v. formulation was approved in Japan
for treatment of cerebral vasospasm. There remains a need for new
therapeutics, including ROCK inhibitors, for the treatment of
cardiovascular diseases, cancer, neurological diseases, renal
diseases, fibrotic diseases, bronchial asthma, erectile
dysfunction, and glaucoma.
SUMMARY OF THE INVENTION
[0013] The present invention provides novel phthalazinone and
isoquinolinone compounds, their analogues, including stereoisomers,
tautomers, pharmaceutically acceptable salts, or solvates thereof,
which are useful as selective inhibitors of Rho kinases.
[0014] The present invention also provides processes and
intermediates for making the compounds of the present
invention.
[0015] 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.
[0016] The compounds of the invention may be used in the treatment
and/or prophylaxis of conditions associated with aberrant ROCK
activity.
[0017] The compounds of the present invention may be used in
therapy.
[0018] The compounds of the present invention may be used for the
manufacture of a medicament for the treatment and/or prophylaxis of
a condition associated with aberrant ROCK activity.
[0019] In another aspect, the present invention is directed to a
method of treating a cardiovascular or related disease which method
comprises administering to a patient in need of such treatment a
compound of the present invention as described above. Examples of
such diseases that may be treated include, for example,
hypertension, atherosclerosis, restenosis, stroke, heart failure,
renal failure, coronary artery disease, peripheral artery disease,
coronary vasospasm, cerebral vasospasm, ischemia/reperfusion
injury, pulmonary hypertension, angina, erectile dysfunction and
renal disease.
[0020] In another aspect, the present invention is directed to a
method of treating diseases involving smooth muscle hyper
reactivity including asthma, erectile dysfunction and glaucoma,
which method comprises administering to a patient in need of such
treatment a compound of the present invention as described
above.
[0021] In another aspect, the present invention is directed to a
method of treating diseases mediated at least partially by Rho
kinase including fibrotic diseases, oncology, spinal-cord injury,
Alzheimer's disease, multiple sclerosis, stroke, neuropathic pain,
rheumatoid arthritis, psoriasis and inflammatory bowel disease,
which method comprises administering to a patient in need of such
treatment a compound of the present invention as described
above.
[0022] In yet additional aspects, the present invention is directed
at pharmaceutical compositions comprising the above-mentioned
compounds, processes for preparing the above-mentioned compounds
and intermediates used in these processes.
[0023] 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).
[0024] 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
[0025] 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:
[0026] M is selected from N and CR.sup.10;
[0027] L is selected from --CR.sup.4R.sup.4C(O)--, --OC(O)--,
--NR.sup.6C(O)--, and --NR.sup.6--;
[0028] R.sup.1 is selected from NR.sup.5R.sup.5, C.sub.3-10
carbocycle and 4- to 15-membered heterocycle comprising carbon
atoms and 1-4 heteroatoms selected from N, NR.sup.8, O, and
S(O).sub.p; wherein said alkyl, carbocycle, and heterocycle are
substituted with 1-4 R.sup.7;
[0029] R.sup.2, at each occurrence, is independently selected from
halogen, C.sub.1-6 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio,
C.sub.1-4 haloalkyl, --OH, --CH.sub.2OH, --OCH.sub.2F,
--OCHF.sub.2, --OCF.sub.3, CN, --NH.sub.2, --NH(C.sub.1-4 alkyl),
--N(C.sub.1-4 alkyl).sub.2, --CO.sub.2H, --CH.sub.2CO.sub.2H,
--CO.sub.2(C.sub.1-4 alkyl), --CO(C.sub.1-4 alkyl),
--CH.sub.2NH.sub.2, --CONH.sub.2, --CONH(C.sub.1-4 alkyl),
--CON(C.sub.1-4 alkyl).sub.2, --OCH.sub.2CO.sub.2H,
--NHCO(C.sub.1-4 alkyl), --NHCO.sub.2(C.sub.1-4 alkyl),
--NHSO.sub.2(C.sub.1-4 alkyl), --SO.sub.2NH.sub.2,
--C(.dbd.NH)NH.sub.2, carbocycle, and heterocycle, wherein said
alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle
are substituted with 0-4 R.sup.9;
[0030] R.sup.3, at each occurrence, is independently selected from
halogen, C.sub.1-6 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio,
C.sub.1-4 haloalkyl, --CH.sub.2OH, --OCH.sub.2F, --OCHF.sub.2,
--OCF.sub.3, CN, --NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4
alkyl).sub.2, --CO.sub.2H, --CH.sub.2CO.sub.2H,
--CO.sub.2(C.sub.1-4 alkyl), --CO(C.sub.1-4 alkyl),
--CH.sub.2NH.sub.2, --CONH.sub.2, --CONH(C.sub.1-4 alkyl),
--CON(C.sub.1-4 alkyl).sub.2, --OCH.sub.2CO.sub.2H,
--NHCO(C.sub.1-4 alkyl), --NHCO.sub.2(C.sub.1-4 alkyl),
--NHSO.sub.2(C.sub.1-4 alkyl), --SO.sub.2NH.sub.2,
--C(.dbd.NH)NH.sub.2, carbocycle, and heterocycle, wherein said
alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle
are substituted with 0-4 R.sup.9;
[0031] R.sup.4, at each occurrence, is independently selected from
H, OH, NH.sub.2, CH.sub.2NH.sub.2, C.sub.1-4 haloalkyl, OCH.sub.2F,
OCHF.sub.2, OCF.sub.3, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4
alkyl).sub.2, C.sub.1-4 alkoxy, CH.sub.2OH, CH.sub.2O(C.sub.1-4
alkyl), CH.sub.2CO.sub.2H, CH.sub.2CO.sub.2(C.sub.1-4 alkyl),
C.sub.1-4 alkyl, carbocycle, and heterocycle, wherein said alkyl,
alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with
0-4 R.sup.9;
[0032] R.sup.5, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --(CR.sup.6R.sup.6).sub.n--C.sub.3-10
carbocycle and --(CR.sup.6R.sup.6).sub.n-4-10 membered heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, carbocycle and
heterocycle are substituted with 1-4 R.sup.7;
[0033] alternatively, R.sup.5 and R.sup.5 are taken together with
the nitrogen atom to which they are attached to form 4- to
15-membered heterocycle substituted with 1-4 R.sup.7;
[0034] R.sup.6, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[0035] R.sup.7, at each occurrence, is independently selected from
H, .dbd.O, NO.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
CN, OH, CF.sub.3, --(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.3O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2OH,
--NHCO.sub.2(CH.sub.2).sub.2NH.sub.2,
--NHCO.sub.2(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--NHCO.sub.2CH.sub.2CO.sub.2H, --CH.sub.2NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NR.sup.8R.sup.8, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--CONR.sup.8R.sup.8,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
--NHCO-carbocycle, --NHCO-heterocycle,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkenyl, alkynyl,
alkoxyl, carbocycle, and heterocycle are substituted with 0-4
R.sup.9;
[0036] R.sup.8, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
--(CH.sub.2).sub.n--C(O)C.sub.1-4alkyl,
--(CH.sub.2).sub.n--C(O)carbocycle,
--(CH.sub.2).sub.n--C(O)heterocycle,
--(CH.sub.2).sub.n--C(O)NR.sup.aR.sup.a,
--(CH.sub.2).sub.n--C(O)O-alkyl,
--(CH.sub.2).sub.n--C(O)O-carbocycle,
--(CH.sub.2).sub.n--C(O)O-heterocycle,
--(CH.sub.2).sub.n--SO.sub.2alkyl, --(CH.sub.2).sub.n
SO.sub.2carbocycle, --(CH.sub.2).sub.n--SO.sub.2heterocycle,
--(CH.sub.2).sub.n--SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.9;
[0037] alternatively, R.sup.8 and R.sup.8 are taken together with
the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle substituted with 0-4 R.sup.9;
[0038] R.sup.9, at each occurrence, is independently selected from
halogen, OH, NO.sub.2, CHF.sub.2, CF.sub.3, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CH.sub.2OH, CO(C.sub.1-4 alkyl), CO.sub.2H,
CO.sub.2(C.sub.1-4 alkyl), --(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a, --O(CH.sub.2).sub.ncarbocycle,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CR.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein said
alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
0-4 R.sup.b;
[0039] R.sup.10 is selected from H and C.sub.1-4 alkyl;
[0040] R.sup.a, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --(CH.sub.2).sub.nOH, CO(C.sub.1-4 alkyl),
COCF.sub.3, CO.sub.2(C.sub.1-4 alkyl), --CONH.sub.2,
--CONH--C.sub.1-4 alkylene-CO.sub.2(C.sub.1-4 alkyl), C.sub.1-4
alkylene-CO.sub.2(C.sub.1-4 alkyl), R.sup.c, CO.sub.2R.sup.c, and
CONHR.sup.c; alternatively, R.sup.a and R.sup.a are taken together
with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and
heterocycle are substituted with 0-4 R.sup.b;
[0041] R.sup.b, at each occurrence, is independently selected from
.dbd.O, OH, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OCF.sub.3,
NH.sub.2, NO.sub.2, N(C.sub.1-4 alkyl).sub.2, CO(C.sub.1-4 alkyl),
CO(C.sub.1-4 haloalkyl), CO.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 alkylene-O(C.sub.1-4 alkyl), --CONH--C.sub.1-4
alkylene-N(C.sub.1-4 alkyl).sub.2, --CONH--C.sub.1-4 alkylene-N
(C.sub.1-4 alkyl).sub.2, --C.sub.1-4 alkylene-O--P(O)(OH).sub.2,
--NHCO.sub.2(C.sub.1-4 alkyl), --R.sup.c, COR.sup.c,
CO.sub.2R.sup.c, and CONHR.sup.c;
[0042] R.sup.c, at each occurrence, is independently selected from
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.n-phenyl, and --(CH.sub.2).sub.n-5- to 6-membered
heterocycle containing carbon atoms and 1-4 heteroatoms selected
from the group consisting of: N, NH, N(C.sub.1-4 alkyl), O, and
S(O).sub.p; wherein each ring moiety is substituted with 0-2
R.sup.d;
[0043] R.sup.d, at each occurrence, is independently selected from
.dbd.O, halogen, --OH, C.sub.1-4 alkyl, NH.sub.2, NH(C.sub.1-4
alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkoxy, and
--NHCO(C.sub.1-4 alkyl), and heterocycle containing carbon atoms
and 1-4 heteroatoms selected from the group consisting of: N, NH,
N(C.sub.1-4 alkyl), O, and S(O).sub.p;
[0044] n, at each occurrence, is independently selected from 0, 1,
2, 3, and 4;
[0045] p, at each occurrence, is independently selected from 0, 1,
and 2;
provided
[0046] 1) when L is NHC(O), R.sup.1 is other than
##STR00003##
wherein X is N or a substituted or unsubstituted carbon atom;
[0047] 2) when L is NR.sup.6, R.sup.1 is heterocycle substituted
with 1-4 R.sup.7.
[0048] In another aspect, the present invention provides compounds
of Formula (I) or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, wherein:
[0049] M is CR.sup.10;
[0050] L is selected from --CR.sup.4R.sup.4C(O)--, --OC(O)--, and
--NR.sup.6C(O)--;
[0051] R.sup.1 is selected from NR.sup.5R.sup.5, C.sub.3-10
carbocycle and 4- to 15-membered heterocycle comprising carbon
atoms and 1-4 heteroatoms selected from N, NR.sup.8, O, and
S(O).sub.p; wherein said alkyl, carbocycle, and heterocycle are
substituted with 1-4 R.sup.7;
[0052] R.sup.3, at each occurrence, is independently selected from
halogen, C.sub.1-6 alkyl, C.sub.1-4 alkoxy;
[0053] R.sup.4 is H;
[0054] R.sup.5, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --(CR.sup.6R.sup.6).sub.n--C.sub.3-10
carbocycle and 4-10 membered heterocycle comprising carbon atoms
and 1-4 heteroatoms selected from N, NR.sup.8, O, and S(O).sub.p,
wherein said alkyl, carbocycle and heterocycle are substituted with
1-4 R.sup.7;
[0055] alternatively, R.sup.5 and R.sup.5 are taken together with
the nitrogen atom to which they are attached to form 4- to
15-membered heterocycle substituted with 1-4 R.sup.7;
[0056] R.sup.7, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, --NR.sup.8R.sup.8,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkoxyl,
carbocycle, and heterocycle are substituted with 0-4 R.sup.9;
[0057] R.sup.8, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[0058] R.sup.9, at each occurrence, is independently selected from
halogen, OH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy;
[0059] R.sup.10 is selected from H and C.sub.1-4 alkyl;
[0060] n, at each occurrence, is independently selected from 0, 1,
2, 3, and 4; and
[0061] p, at each occurrence, is independently selected from 0, 1,
and 2;
[0062] other variables are as defined in Formula (I) above.
[0063] In another aspect, the present invention provides compounds
of Formula (II):
##STR00004##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0064] M is selected from N and CR.sup.10;
[0065] R.sup.5, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --(CR.sup.6R.sup.6).sub.n--C.sub.3-10
carbocycle, and --(CR.sup.6R.sup.6).sub.n-4-10 membered heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, carbocycle, and
heterocycle are substituted with 1-4 R.sup.7;
[0066] alternatively, R.sup.5 and R.sup.5 are taken together with
the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle substituted with 1-4 R.sup.7;
[0067] R.sup.7, at each occurrence, is independently selected from
H, .dbd.O, NO.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
CN, OH, CF.sub.3, --(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.3O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2OH,
--NHCO.sub.2(CH.sub.2).sub.2NH.sub.2,
--NHCO.sub.2(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--NHCO.sub.2CH.sub.2CO.sub.2H, --CH.sub.2NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NR.sup.8R.sup.8, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--CONR.sup.8R.sup.8,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
--NHCO-carbocycle, --NHCO-heterocycle,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkenyl, alkynyl,
alkoxyl, carbocycle, and heterocycle are substituted with 0-4
R.sup.9;
[0068] R.sup.8, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, C(O)C.sub.1-4alkyl, C(O)carbocycle,
C(O)heterocycle, --(CH.sub.2).sub.n C(O)NR.sup.aR.sup.a,
C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO.sub.2alkyl,
SO.sub.2carbocycle, SO.sub.2heterocycle, SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.9;
[0069] R.sup.9, at each occurrence, is independently selected from
halogen, OH, NO.sub.2, CHF.sub.2, CF.sub.3, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CH.sub.2OH, CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl),
CONH.sub.2, --(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2)(2-4)NR.sup.aR.sup.a,
--(C R.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein
said alkyl, alkoxyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.b;
[0070] R.sup.10 is selected from H and C.sub.1-4 alkyl;
[0071] R.sup.a, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --(CH.sub.2).sub.nOH, CO(C.sub.1-4 alkyl),
COCF.sub.3, CO.sub.2(C.sub.1-4 alkyl), --CONH.sub.2,
--CONH--C.sub.1-4 alkylene-CO.sub.2(C.sub.1-4 alkyl), C.sub.1-4
alkylene-CO.sub.2(C.sub.1-4 alkyl), R.sup.c, CO.sub.2R.sup.c, and
CONHR.sup.c; alternatively, R.sup.a and R.sup.a are taken together
with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and
heterocycle are substituted with 0-4 R.sup.b;
[0072] R.sup.b, at each occurrence, is independently selected from
.dbd.O, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OCF.sub.3,
NH.sub.2, NO.sub.2, N(C.sub.1-4 alkyl).sub.2, CO(C.sub.1-4 alkyl),
CO(C.sub.1-4 haloalkyl), CO.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 alkylene-O(C.sub.1-4 alkyl), --CONH--C.sub.1-4
alkylene-N(C.sub.1-4 alkyl).sub.2, --CONH--C.sub.1-4 alkylene-N
(C.sub.1-4 alkyl).sub.2, --C.sub.1-4 alkylene-O--P(O)(OH).sub.2,
--NHCO.sub.2(C.sub.1-4 alkyl), --R.sup.c, COR.sup.c,
CO.sub.2R.sup.c, and CONHR.sup.c;
[0073] R.sup.c, at each occurrence, is independently selected from
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.n-phenyl, and --(CH.sub.2).sub.n-5- to 6-membered
heterocycle containing carbon atoms and 1-4 heteroatoms selected
from the group consisting of: N, NH, N(C.sub.1-4 alkyl), O, and
S(O).sub.p; wherein each ring moiety is substituted with 0-2
R.sup.d;
[0074] R.sup.d, at each occurrence, is independently selected from
.dbd.O, halogen, --OH, C.sub.1-4 alkyl, NH.sub.2, NH(C.sub.1-4
alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkoxy, and
--NHCO(C.sub.1-4 alkyl), and heterocycle containing carbon atoms
and 1-4 heteroatoms selected from the group consisting of: N, NH,
N(C.sub.1-4 alkyl), O, and S(O).sub.p;
[0075] n, at each occurrence, is independently selected from 0, 1,
2, 3, and 4;
[0076] p, at each occurrence, is independently selected from 0, 1,
and 2;
[0077] other variables are as defined in Formula (I) above.
[0078] In another aspect, the present invention provides compounds
of Formula (II) or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, wherein:
[0079] R.sup.5 is selected from H, C.sub.1-4 alkyl,
--(CH.sub.2).sub.n--C.sub.3-10 carbocycle, --(CH.sub.2).sub.n-aryl,
--(CH.sub.2).sub.n-4-10 membered heterocycle selected from
##STR00005##
[0080] wherein said alkyl, cycloalkyl, aryl are substituted with
1-4 R.sup.7; and
[0081] other variables are as defined in Formula (II) above.
[0082] In another aspect, the present invention provides compounds
of Formula (II) or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, wherein:
[0083] R.sup.5 and R.sup.5 are taken together with the nitrogen
atom to which they are attached to form a heterocycle selected
from
##STR00006##
[0084] R.sup.7, at each occurrence, is independently selected from
H, .dbd.O, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CN, OH,
CF.sub.3, --(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --CH.sub.2NH.sub.2,
--NHCO(C.sub.1-4 alkyl), --NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NH.sub.2, --NHC(O)NH(C.sub.1-4 alkyl),
--NHC(O)N(C.sub.1-4 alkyl).sub.2, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--CONR.sup.8R.sup.8,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
--NHCO-carbocycle, --NHCO-heterocycle,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkoxyl,
carbocycle, and heterocycle are substituted with 0-4 R.sup.9;
[0085] R.sup.8, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, C(O)C.sub.1-4alkyl, C(O)carbocycle,
C(O)heterocycle, --(CH.sub.2).sub.n--C(O)NR.sup.aR.sup.a,
C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO.sub.2alkyl,
SO.sub.2carbocycle, SO.sub.2heterocycle, SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.9;
[0086] alternatively, R.sup.8 and R.sup.8 are taken together with
the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle substituted with 0-4 R.sup.9; and
[0087] R.sup.9, at each occurrence, is independently selected from
halogen, OH, NO.sub.2, CHF.sub.2, CF.sub.3, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CH.sub.2OH, CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl),
CONH.sub.2, --(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2)(2-4)NR.sup.aR.sup.a,
--(C R.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein
said alkyl, alkoxyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.b;
[0088] R.sup.a, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --(CH.sub.2).sub.nOH, CO(C.sub.1-4 alkyl),
COCF.sub.3, CO.sub.2(C.sub.1-4 alkyl), --CONH.sub.2,
--CONH--C.sub.1-4 alkylene-CO.sub.2(C.sub.1-4 alkyl), C.sub.1-4
alkylene-CO.sub.2(C.sub.1-4 alkyl), R.sup.c, CO.sub.2R.sup.c, and
CONHR.sup.c; alternatively, R.sup.a and R.sup.a are taken together
with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and
heterocycle are substituted with 0-4 R.sup.b;
[0089] R.sup.b, at each occurrence, is independently selected from
.dbd.O, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OCF.sub.3,
NH.sub.2, NO.sub.2, N(C.sub.1-4 alkyl).sub.2, CO(C.sub.1-4 alkyl),
CO(C.sub.1-4 haloalkyl), CO.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 alkylene-O(C.sub.1-4 alkyl), --CONH--C.sub.1-4
alkylene-N(C.sub.1-4 alkyl).sub.2, --CONH--C.sub.1-4 alkylene-N
(C.sub.1-4 alkyl).sub.2, --C.sub.1-4 alkylene-O--P(O)(OH).sub.2,
--NHCO.sub.2(C.sub.1-4 alkyl), --R.sup.c, COR.sup.c,
CO.sub.2R.sup.c, and CONHR.sup.c;
[0090] R.sup.c, at each occurrence, is independently selected from
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.n-phenyl, and --(CH.sub.2).sub.n-5- to 6-membered
heterocycle containing carbon atoms and 1-4 heteroatoms selected
from the group consisting of: N, NH, N(C.sub.1-4 alkyl), O, and
S(O).sub.p; wherein each ring moiety is substituted with 0-2
R.sup.d; and
[0091] R.sup.d, at each occurrence, is independently selected from
.dbd.O, halogen, --OH, C.sub.1-4 alkyl, NH.sub.2, NH(C.sub.1-4
alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkoxy, and
--NHCO(C.sub.1-4 alkyl), and heterocycle containing carbon atoms
and 1-4 heteroatoms selected from the group consisting of: N, NH,
N(C.sub.1-4 alkyl), O, and S(O).sub.p;
[0092] other variables are as defined in Formula (II) above.
[0093] In another aspect, the present invention provides compounds
of Formula (III):
##STR00007##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0094] M is selected from N and CR.sup.10;
[0095] R.sup.5, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --(CR.sup.6R.sup.6).sub.n--C.sub.3-10
carbocycle, and --(CR.sup.6R.sup.6).sub.n-4-10 membered heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, carbocycle, and
heterocycle are substituted with 1-4 R.sup.7;
[0096] alternatively, R.sup.5 and R.sup.5 are taken together with
the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle substituted with 1-4 R.sup.7;
[0097] R.sup.6, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[0098] R.sup.7, at each occurrence, is independently selected from
H, .dbd.O, NO.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
CN, OH, CF.sub.3, --(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.3O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2OH,
--NHCO.sub.2(CH.sub.2).sub.2NH.sub.2,
--NHCO.sub.2(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--NHCO.sub.2CH.sub.2CO.sub.2H, --CH.sub.2NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NR.sup.8R.sup.8, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--CONR.sup.8R.sup.8,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
--NHCO-carbocycle, --NHCO-heterocycle,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkenyl, alkynyl,
alkoxyl, carbocycle, and heterocycle are substituted with 0-4
R.sup.9;
[0099] R.sup.8, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, C(O)C.sub.1-4alkyl, C(O)carbocycle,
C(O)heterocycle, --(CH.sub.2).sub.n--C(O)NR.sup.aR.sup.a,
C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO.sub.2alkyl,
SO.sub.2carbocycle, SO.sub.2heterocycle, SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.9;
[0100] R.sup.9, at each occurrence, is independently selected from
halogen, OH, NO.sub.2, CHF.sub.2, CF.sub.3, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CH.sub.2OH, CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl),
CONH.sub.2, --(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2)(2-4)NR.sup.aR.sup.a,
--(C R.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein
said alkyl, alkoxyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.b;
[0101] n, at each occurrence, is independently selected from 0, 1,
2, 3, and 4; and
[0102] p, at each occurrence, is independently selected from 0, 1,
and 2;
[0103] other variables are as defined in Formula (I) above.
[0104] In another aspect, the present invention provides compounds
of Formula (I) or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, wherein:
[0105] L is --NR.sup.6--;
[0106] R.sup.1 is heteroaryl substituted with 1-4 R.sup.7;
[0107] R.sup.7, at each occurrence, is independently selected from
H, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CN, OH,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, alkoxyl, carbocycle, and heterocycle are
substituted with 0-4 R.sup.9;
[0108] other variables are as defined in Formula (I) above.
[0109] In another aspect, the present invention provides compounds
of Formula (I) or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, wherein:
[0110] L is --NR.sup.6--;
[0111] R.sup.1 is selected from
##STR00008##
[0112] other variables are as defined in Formula (I) above.
[0113] In still another aspect, the present invention provides
compounds of Formula (IV):
##STR00009##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0114] R.sup.1 is selected from NR.sup.5R.sup.5, C.sub.3-10
carbocycle, and 5- to 10-membered heterocycle, wherein said
carbocycle and heterocycle are substituted with 1-4 R.sup.7;
[0115] R.sup.5, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --(CR.sup.6R.sup.6).sub.n--C.sub.3-10
carbocycle, and --(CR.sup.6R.sup.6).sub.n-4-10 membered heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, carbocycle, and
heterocycle are substituted with 1-4 R.sup.7;
[0116] alternatively, R.sup.5 and R.sup.5 are taken together with
the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle substituted with 1-4 R.sup.7;
[0117] R.sup.6, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[0118] R.sup.7, at each occurrence, is independently selected from
H, .dbd.O, NO.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
CN, OH, CF.sub.3, --(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.3O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2OH,
--NHCO.sub.2(CH.sub.2).sub.2NH.sub.2,
--NHCO.sub.2(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--NHCO.sub.2CH.sub.2CO.sub.2H, --CH.sub.2NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NR.sup.8R.sup.8, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--CONR.sup.8R.sup.8,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
--NHCO-carbocycle, --NHCO-heterocycle,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkenyl, alkynyl,
alkoxyl, carbocycle, and heterocycle are substituted with 0-4
R.sup.9;
[0119] R.sup.8, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C(O)C.sub.1-4alkyl,
C(O)carbocycle, C(O)heterocycle,
--(CH.sub.2).sub.n--C(O)NR.sup.aR.sup.a, C(O)O-alkyl,
C(O)O-carbocycle, C(O)O-heterocycle, SO.sub.2alkyl,
SO.sub.2carbocycle, SO.sub.2heterocycle, SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, alkenyl, carbocycle, and heterocycle are
substituted with 0-4 R.sup.9;
[0120] R.sup.9, at each occurrence, is independently selected from
halogen, OH, NO.sub.2, CHF.sub.2, CF.sub.3, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CH.sub.2OH, CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl),
CONH.sub.2, --(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2)(2-4)NR.sup.aR.sup.a,
--(C R.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein
said alkyl, alkoxyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.b;
[0121] n, at each occurrence, is independently selected from 0, 1,
2, 3, and 4;
[0122] p, at each occurrence, is independently selected from 0, 1,
and 2;
[0123] other variables are as defined in Formula (I) above.
[0124] In still another aspect, the present invention provides
compounds of Formula (IV), or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
wherein:
[0125] R.sup.1 is selected from
##STR00010## ##STR00011##
[0126] R.sup.7, at each occurrence, is independently selected from
H, .dbd.O, NO.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
CN, OH, CF.sub.3, --(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.3O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2OH,
--NHCO.sub.2(CH.sub.2).sub.2NH.sub.2,
--NHCO.sub.2(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--NHCO.sub.2CH.sub.2CO.sub.2H, --CH.sub.2NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NR.sup.8R.sup.8, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--CONR.sup.8R.sup.8,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
--NHCO-carbocycle, --NHCO-heterocycle,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkenyl, alkynyl,
alkoxyl, carbocycle, and heterocycle are substituted with 0-4
R.sup.9;
[0127] R.sup.8, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, C(O)C.sub.1-4alkyl, C(O)carbocycle,
C(O)heterocycle, --(CH.sub.2).sub.n--C(O)NR.sup.aR.sup.a,
C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO.sub.2alkyl,
SO.sub.2carbocycle, SO.sub.2heterocycle, SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.9;
[0128] alternatively, R.sup.8 and R.sup.8 are taken together with
the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle substituted with 0-4 R.sup.9; and
[0129] R.sup.9, at each occurrence, is independently selected from
halogen, OH, NO.sub.2, CHF.sub.2, CF.sub.3, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CH.sub.2OH, CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl),
CONH.sub.2, --(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2)(2-4)NR.sup.aR.sup.a,
--(C R.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein
said alkyl, alkoxyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.b;
[0130] R.sup.a, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --(CH.sub.2).sub.nOH, CO(C.sub.1-4 alkyl),
COCF.sub.3, CO.sub.2(C.sub.1-4 alkyl), --CONH.sub.2,
--CONH--C.sub.1-4 alkylene-CO.sub.2(C.sub.1-4 alkyl), C.sub.1-4
alkylene-CO.sub.2(C.sub.1-4 alkyl), R.sup.c, CO.sub.2R.sup.c, and
CONHR.sup.c; alternatively, R.sup.a and R.sup.a are taken together
with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and
heterocycle are substituted with 0-4 R.sup.b;
[0131] R.sup.b, at each occurrence, is independently selected from
.dbd.O, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OCF.sub.3,
NH.sub.2, NO.sub.2, N(C.sub.1-4 alkyl).sub.2, CO(C.sub.1-4 alkyl),
CO(C.sub.1-4 haloalkyl), CO.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 alkylene-O(C.sub.1-4 alkyl), --CONH--C.sub.1-4
alkylene-N(C.sub.1-4 alkyl).sub.2, --CONH--C.sub.1-4 alkylene-N
(C.sub.1-4 alkyl).sub.2, --C.sub.1-4 alkylene-O--P(O)(OH).sub.2,
--NHCO.sub.2(C.sub.1-4 alkyl), --R.sup.c, COR.sup.c,
CO.sub.2R.sup.c, and CONHR.sup.c;
[0132] R.sup.c, at each occurrence, is independently selected from
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.n-phenyl, and --(CH.sub.2).sub.n-5- to 6-membered
heterocycle containing carbon atoms and 1-4 heteroatoms selected
from the group consisting of: N, NH, N(C.sub.1-4 alkyl), O, and
S(O).sub.p; wherein each ring moiety is substituted with 0-2
R.sup.d; and
[0133] R.sup.d, at each occurrence, is independently selected from
.dbd.O, halogen, --OH, C.sub.1-4 alkyl, NH.sub.2, NH(C.sub.1-4
alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkoxy, and
--NHCO(C.sub.1-4 alkyl), and heterocycle containing carbon atoms
and 1-4 heteroatoms selected from the group consisting of: N, NH,
N(C.sub.1-4 alkyl), O, and S(O).sub.p;
[0134] other variables are as defined in Formula (IV) above.
[0135] In still another aspect, the present invention provides
compounds of Formula (IV), or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
wherein:
[0136] R.sup.1 is NR.sup.5R.sup.5;
[0137] R.sup.5 and R.sup.5 are taken together with the nitrogen
atom to which they are attached to form 4- to 10-membered
heterocycle substituted with 1-4 R.sup.7;
[0138] R.sup.7, at each occurrence, is independently selected from
H, .dbd.O, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CN, OH,
CF.sub.3, --(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl), --NHC(O)NH.sub.2,
--NHC(O)NH(C.sub.1-4 alkyl), --NHC(O)N(C.sub.1-4 alkyl).sub.2,
--NHSO.sub.2(C.sub.1-4 alkyl), --SO.sub.2NH.sub.2,
--SO.sub.2NH(C.sub.1-4 alkyl), --SO.sub.2N(C.sub.1-4 alkyl).sub.2,
--SO.sub.2NH(CH.sub.2).sub.2OH, --SO.sub.2NH(CH.sub.2).sub.2O
(C.sub.1-4 alkyl), --CONH.sub.2, --CONH(C.sub.1-4 alkyl),
--CON(C.sub.1-4 alkyl).sub.2, --CH.sub.2CONH.sub.2,
--(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-carbocycle,
--O(CH.sub.2).sub.n-heterocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkoxyl,
carbocycle, and heterocycle are substituted with 0-4 R.sup.9;
[0139] R.sup.8, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, C(O)C.sub.1-4alkyl, C(O)carbocycle,
C(O)heterocycle, --(CH.sub.2).sub.n--C(O)NR.sup.aR.sup.a,
C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO.sub.2alkyl,
SO.sub.2carbocycle, SO.sub.2heterocycle, SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-cycloalkyl, --(CH.sub.2).sub.n-phenyl, and
--(CH.sub.2).sub.n-heterocycle, wherein said alkyl, carbocycle, and
heterocycle are substituted with 0-4 R.sup.9; and
[0140] R.sup.9, at each occurrence, is independently selected from
halogen, OH, NO.sub.2, CHF.sub.2, CF.sub.3, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CH.sub.2OH, CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl),
CONH.sub.2, --(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2)(2-4)NR.sup.aR.sup.a,
--(C R.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein
said alkyl, alkoxyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.b; and
[0141] other variables are as defined in Formula (IV) above.
[0142] In another aspect, the present invention provides compounds
of Formula (I) or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, wherein:
[0143] M is selected from N and CR.sup.10;
[0144] L is selected from C.sub.1-2 alkylene substituted with 1-2
R.sup.4, wherein one or both carbon atoms and the groups attached
thereto are replaced by O, NR.sup.6, and C(O);
[0145] R.sup.1 is selected from NR.sup.5R.sup.5, C.sub.3-10
carbocycle and 4- to 15-membered heterocycle comprising carbon
atoms and 1-4 heteroatoms selected from N, NR.sup.8, O, and
S(O).sub.p; wherein said alkyl, carbocycle, and heterocycle are
substituted with 1-4 R.sup.7;
[0146] R.sup.2, at each occurrence, is independently selected from
halogen, C.sub.1-6 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio,
C.sub.1-4 haloalkyl, --OH, --CH.sub.2OH, --OCH.sub.2F,
--OCHF.sub.2, --OCF.sub.3, CN, --NH.sub.2, --NH(C.sub.1-4 alkyl),
--N(C.sub.1-4 alkyl).sub.2, --CO.sub.2H, --CH.sub.2CO.sub.2H,
--CO.sub.2(C.sub.1-4 alkyl), --CO(C.sub.1-4 alkyl),
--CH.sub.2NH.sub.2, --CONH.sub.2, --CONH(C.sub.1-4 alkyl),
--CON(C.sub.1-4 alkyl).sub.2, --OCH.sub.2CO.sub.2H,
--NHCO(C.sub.1-4 alkyl), --NHCO.sub.2(C.sub.1-4 alkyl),
--NHSO.sub.2(C.sub.1-4 alkyl), --SO.sub.2NH.sub.2,
--C(.dbd.NH)NH.sub.2, carbocycle, and heterocycle, wherein said
alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle
are substituted with 0-4 R.sup.9;
[0147] R.sup.3, at each occurrence, is independently selected from
halogen, C.sub.1-6 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio,
C.sub.1-4 haloalkyl, --CH.sub.2OH, --OCH.sub.2F, --OCHF.sub.2,
--OCF.sub.3, CN, --NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4
alkyl).sub.2, --CO.sub.2H, --CH.sub.2CO.sub.2H,
--CO.sub.2(C.sub.1-4 alkyl), --CO(C.sub.1-4 alkyl),
--CH.sub.2NH.sub.2, --CONH.sub.2, --CONH(C.sub.1-4 alkyl),
--CON(C.sub.1-4 alkyl).sub.2, --OCH.sub.2CO.sub.2H,
--NHCO(C.sub.1-4 alkyl), --NHCO.sub.2(C.sub.1-4 alkyl),
--NHSO.sub.2(C.sub.1-4 alkyl), --SO.sub.2NH.sub.2,
--C(.dbd.NH)NH.sub.2, carbocycle, and heterocycle, wherein said
alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle
are substituted with 0-4 R.sup.9;
[0148] R.sup.4, at each occurrence, is independently selected from
H, OH, NH.sub.2, CH.sub.2NH.sub.2, C.sub.1-4 haloalkyl, OCH.sub.2F,
OCHF.sub.2, OCF.sub.3, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4
alkyl).sub.2, C.sub.1-4 alkoxy, CH.sub.2OH, CH.sub.2O(C.sub.1-4
alkyl), CH.sub.2CO.sub.2H, CH.sub.2CO.sub.2(C.sub.1-4 alkyl),
C.sub.1-4 alkyl, carbocycle, and heterocycle, wherein said alkyl,
alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with
0-4 R.sup.9;
[0149] R.sup.5, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --(CR.sup.6R.sup.6).sub.n--C.sub.3-10
carbocycle and --(CR.sup.6R.sup.6).sub.n-4-10 membered heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, carbocycle and
heterocycle are substituted with 1-4 R.sup.7;
[0150] alternatively, R.sup.5 and R.sup.5 are taken together with
the nitrogen atom to which they are attached to form 4- to
15-membered heterocycle substituted with 1-4 R.sup.7;
[0151] R.sup.6, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[0152] R.sup.7, at each occurrence, is independently selected from
H, .dbd.O, NO.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
CN, OH, CF.sub.3, --(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.3O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2OH,
--NHCO.sub.2(CH.sub.2).sub.2NH.sub.2,
--NHCO.sub.2(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--NHCO.sub.2CH.sub.2CO.sub.2H, --CH.sub.2NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NR.sup.8R.sup.8, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--CONR.sup.8R.sup.8,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
--NHCO-carbocycle, --NHCO-heterocycle,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkenyl, alkynyl,
alkoxyl, carbocycle, and heterocycle are substituted with 0-4
R.sup.9;
[0153] R.sup.8, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
--(CH.sub.2).sub.n--C(O)C.sub.1-4alkyl,
--(CH.sub.2).sub.n--C(O)carbocycle,
--(CH.sub.2).sub.n--C(O)heterocycle,
--(CH.sub.2).sub.n--C(O)NR.sup.aR.sup.a,
--(CH.sub.2).sub.n--C(O)O-alkyl,
--(CH.sub.2).sub.n--C(O)O-carbocycle,
--(CH.sub.2).sub.n--C(O)O-heterocycle,
--(CH.sub.2).sub.n--SO.sub.2alkyl, --(CH.sub.2).sub.n
SO.sub.2carbocycle, --(CH.sub.2).sub.n--SO.sub.2heterocycle,
--(CH.sub.2).sub.n--SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.9;
[0154] alternatively, R.sup.8 and R.sup.8 are taken together with
the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle substituted with 0-4 R.sup.9;
[0155] R.sup.9, at each occurrence, is independently selected from
halogen, OH, NO.sub.2, CHF.sub.2, CF.sub.3, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CH.sub.2OH, CO(C.sub.1-4 alkyl), CO.sub.2H,
CO.sub.2(C.sub.1-4 alkyl), --(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a, --O(CH.sub.2).sub.ncarbocycle,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CR.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein said
alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
0-4 R.sup.b;
[0156] R.sup.10 is selected from H and C.sub.1-4 alkyl;
[0157] R.sup.a, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --(CH.sub.2).sub.nOH, CO(C.sub.1-4 alkyl),
COCF.sub.3, CO.sub.2(C.sub.1-4 alkyl), --CONH.sub.2,
--CONH--C.sub.1-4 alkylene-CO.sub.2(C.sub.1-4 alkyl), C.sub.1-4
alkylene-CO.sub.2(C.sub.1-4 alkyl), R.sup.c, CO.sub.2R.sup.c, and
CONHR.sup.c; alternatively, R.sup.a and R.sup.a are taken together
with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and
heterocycle are substituted with 0-4 R.sup.b;
[0158] R.sup.b, at each occurrence, is independently selected from
.dbd.O, OH, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OCF.sub.3,
NH.sub.2, NO.sub.2, N(C.sub.1-4 alkyl).sub.2, CO(C.sub.1-4 alkyl),
CO(C.sub.1-4 haloalkyl), CO.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 alkylene-O(C.sub.1-4 alkyl), --CONH--C.sub.1-4
alkylene-N(C.sub.1-4 alkyl).sub.2, --CONH--C.sub.1-4 alkylene-N
(C.sub.1-4 alkyl).sub.2, --C.sub.1-4 alkylene-O--P(O)(OH).sub.2,
--NHCO.sub.2(C.sub.1-4 alkyl), --R.sup.c, COR.sup.c,
CO.sub.2R.sup.c, and CONHR.sup.c;
[0159] R.sup.c, at each occurrence, is independently selected from
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.n-phenyl, and --(CH.sub.2).sub.n-5- to 6-membered
heterocycle containing carbon atoms and 1-4 heteroatoms selected
from the group consisting of: N, NH, N(C.sub.1-4 alkyl), O, and
S(O).sub.p; wherein each ring moiety is substituted with 0-2
R.sup.d;
[0160] R.sup.d, at each occurrence, is independently selected from
.dbd.O, halogen, --OH, C.sub.1-4 alkyl, NH.sub.2, NH(C.sub.1-4
alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkoxy, and
--NHCO(C.sub.1-4 alkyl), and heterocycle containing carbon atoms
and 1-4 heteroatoms selected from the group consisting of: N, NH,
N(C.sub.1-4 alkyl), O, and S(O).sub.p;
[0161] n, at each occurrence, is independently selected from 0, 1,
2, 3, and 4;
[0162] p, at each occurrence, is independently selected from 0, 1,
and 2;
provided
[0163] (1) when L is NHC(O), R.sup.1 is other than
##STR00012##
wherein X is N or a substituted or unsubstituted carbon atom;
[0164] (2) when L is NH, R.sup.1 is other than
##STR00013##
[0165] (3) when L is O, R.sup.1 is other than
##STR00014##
[0166] In another aspect, the present invention provides compounds
of Formula (V):
##STR00015##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0167] L is selected from --CR.sup.4R.sup.4C(O)--, --OC(O)--,
--NR.sup.6C(O)--, and --NR.sup.6--;
[0168] R.sup.1 is selected from NR.sup.5R.sup.5, C.sub.3-10
carbocycle and 4- to 15-membered heterocycle comprising carbon
atoms and 1-4 heteroatoms selected from N, NR.sup.8, O, and
S(O).sub.p; wherein said alkyl, carbocycle, and heterocycle are
substituted with 1-4 R.sup.7;
[0169] R.sup.2, at each occurrence, is independently selected from
halogen, C.sub.1-6 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio,
C.sub.1-4 haloalkyl, --OH, --CH.sub.2OH, --OCH.sub.2F,
--OCHF.sub.2, --OCF.sub.3, CN, --NH.sub.2, --NH(C.sub.1-4 alkyl),
--N(C.sub.1-4 alkyl).sub.2, --CO.sub.2H, --CH.sub.2CO.sub.2H,
--CO.sub.2(C.sub.1-4 alkyl), --CO(C.sub.1-4 alkyl),
--CH.sub.2NH.sub.2, --CONH.sub.2, --CONH(C.sub.1-4 alkyl),
--CON(C.sub.1-4 alkyl).sub.2, --OCH.sub.2CO.sub.2H,
--NHCO(C.sub.1-4 alkyl), --NHCO.sub.2(C.sub.1-4 alkyl),
--NHSO.sub.2(C.sub.1-4 alkyl), --SO.sub.2NH.sub.2,
--C(.dbd.NH)NH.sub.2, carbocycle, and heterocycle, wherein said
alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle
are substituted with 0-4 R.sup.9;
[0170] R.sup.3, at each occurrence, is independently selected from
halogen, C.sub.1-6 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio,
C.sub.1-4 haloalkyl, --CH.sub.2OH, --OCH.sub.2F, --OCHF.sub.2,
--OCF.sub.3, CN, --NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4
alkyl).sub.2, --CO.sub.2H, --CH.sub.2CO.sub.2H,
--CO.sub.2(C.sub.1-4 alkyl), --CO(C.sub.1-4 alkyl),
--CH.sub.2NH.sub.2, --CONH.sub.2, --CONH(C.sub.1-4 alkyl),
--CON(C.sub.1-4 alkyl).sub.2, --OCH.sub.2CO.sub.2H,
--NHCO(C.sub.1-4 alkyl), --NHCO.sub.2(C.sub.1-4 alkyl),
--NHSO.sub.2(C.sub.1-4 alkyl), --SO.sub.2NH.sub.2,
--C(.dbd.NH)NH.sub.2, carbocycle, and heterocycle, wherein said
alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle
are substituted with 0-4 R.sup.9;
[0171] R.sup.4, at each occurrence, is independently selected from
H, OH, NH.sub.2, CH.sub.2NH.sub.2, C.sub.1-4 haloalkyl, OCH.sub.2F,
OCHF.sub.2, OCF.sub.3, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4
alkyl).sub.2, C.sub.1-4 alkoxy, CH.sub.2OH, CH.sub.2O(C.sub.1-4
alkyl), CH.sub.2CO.sub.2H, CH.sub.2CO.sub.2(C.sub.1-4 alkyl),
C.sub.1-4 alkyl, carbocycle, and heterocycle, wherein said alkyl,
alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with
0-4 R.sup.9;
[0172] R.sup.5, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --(CR.sup.6R.sup.6).sub.n--C.sub.3-10
carbocycle and --(CR.sup.6R.sup.6).sub.n-4-10 membered heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, carbocycle and
heterocycle are substituted with 1-4 R.sup.7;
[0173] alternatively, R.sup.5 and R.sup.5 are taken together with
the nitrogen atom to which they are attached to form 4- to
15-membered heterocycle substituted with 1-4 R.sup.7;
[0174] R.sup.6, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[0175] R.sup.7, at each occurrence, is independently selected from
H, .dbd.O, NO.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
CN, OH, CF.sub.3, --(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.3O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2OH,
--NHCO.sub.2(CH.sub.2).sub.2NH.sub.2,
--NHCO.sub.2(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--NHCO.sub.2CH.sub.2CO.sub.2H, --CH.sub.2NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NR.sup.8R.sup.8, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--CONR.sup.8R.sup.8,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
--NHCO-carbocycle, --NHCO-heterocycle,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkenyl, alkynyl,
alkoxyl, carbocycle, and heterocycle are substituted with 0-4
R.sup.9;
[0176] R.sup.8, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
--(CH.sub.2).sub.n--C(O)C.sub.1-4alkyl,
--(CH.sub.2).sub.n--C(O)carbocycle,
--(CH.sub.2).sub.n--C(O)heterocycle,
--(CH.sub.2).sub.n--C(O)NR.sup.aR.sup.a,
--(CH.sub.2).sub.n--C(O)O-alkyl,
--(CH.sub.2).sub.n--C(O)O-carbocycle,
--(CH.sub.2).sub.n--C(O)O-heterocycle,
--(CH.sub.2).sub.n--SO.sub.2alkyl, --(CH.sub.2).sub.n
SO.sub.2carbocycle, --(CH.sub.2).sub.n--SO.sub.2heterocycle,
--(CH.sub.2).sub.n--SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.9;
[0177] alternatively, R.sup.8 and R.sup.8 are taken together with
the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle substituted with 0-4 R.sup.9; R.sup.9, at
each occurrence, is independently selected from halogen, OH,
NO.sub.2, CHF.sub.2, CF.sub.3, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
CH.sub.2OH, CO(C.sub.1-4 alkyl), CO.sub.2H, CO.sub.2(C.sub.1-4
alkyl), --(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a, --O(CH.sub.2).sub.ncarbocycle,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CR.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein said
alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
0-4 R.sup.b;
[0178] R.sup.a, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --(CH.sub.2).sub.nOH, CO(C.sub.1-4 alkyl),
COCF.sub.3, CO.sub.2(C.sub.1-4 alkyl), --CONH.sub.2,
--CONH--C.sub.1-4 alkylene-CO.sub.2(C.sub.1-4 alkyl), C.sub.1-4
alkylene-CO.sub.2(C.sub.1-4 alkyl), R.sup.c, CO.sub.2R.sup.c, and
CONHR.sup.c; alternatively, R.sup.a and R.sup.a are taken together
with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and
heterocycle are substituted with 0-4 R.sup.b;
[0179] R.sup.b, at each occurrence, is independently selected from
.dbd.O, OH, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OCF.sub.3,
NH.sub.2, NO.sub.2, N(C.sub.1-4 alkyl).sub.2, CO(C.sub.1-4 alkyl),
CO(C.sub.1-4 haloalkyl), CO.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 alkylene-O(C.sub.1-4 alkyl), --CONH--C.sub.1-4
alkylene-N(C.sub.1-4 alkyl).sub.2, --CONH--C.sub.1-4 alkylene-N
(C.sub.1-4 alkyl).sub.2, --C.sub.1-4 alkylene-O--P(O)(OH).sub.2,
--NHCO.sub.2(C.sub.1-4 alkyl), --R.sup.c, COR.sup.c,
CO.sub.2R.sup.c, and CONHR.sup.c;
[0180] R.sup.c, at each occurrence, is independently selected from
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.n-phenyl, and --(CH.sub.2).sub.n-5- to 6-membered
heterocycle containing carbon atoms and 1-4 heteroatoms selected
from the group consisting of: N, NH, N(C.sub.1-4 alkyl), O, and
S(O).sub.p; wherein each ring moiety is substituted with 0-2
R.sup.d;
[0181] R.sup.d, at each occurrence, is independently selected from
.dbd.O, halogen, --OH, C.sub.1-4 alkyl, NH.sub.2, NH(C.sub.1-4
alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkoxy, and
--NHCO(C.sub.1-4 alkyl), and heterocycle containing carbon atoms
and 1-4 heteroatoms selected from the group consisting of: N, NH,
N(C.sub.1-4 alkyl), O, and S(O).sub.p;
[0182] n, at each occurrence, is independently selected from 0, 1,
2, 3, and 4;
[0183] p, at each occurrence, is independently selected from 0, 1,
and 2;
provided
[0184] (1) when L is NHC(O), R.sup.1 is other than
##STR00016##
wherein X is N or a substituted or unsubstituted carbon atom;
[0185] (2) when L is NR.sup.6, R.sup.1 is heteroaryl substituted
with 1-4 R.sup.7.
[0186] In another aspect, the present invention provides compounds
of Formula (VI):
##STR00017##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0187] R.sup.5, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --(CR.sup.6R.sup.6).sub.n--C.sub.3-10
carbocycle, and --(CR.sup.6R.sup.6).sub.n-4-10 membered heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.B, O, and S(O).sub.p, wherein said alkyl, carbocycle, and
heterocycle are substituted with 1-4 R.sup.7;
[0188] alternatively, R.sup.5 and R.sup.5 are taken together with
the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle substituted with 1-4 R.sup.7;
[0189] R.sup.7, at each occurrence, is independently selected from
H, .dbd.O, NO.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
CN, OH, CF.sub.3, --(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.3O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2OH,
--NHCO.sub.2(CH.sub.2).sub.2NH.sub.2,
--NHCO.sub.2(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--NHCO.sub.2CH.sub.2CO.sub.2H, --CH.sub.2NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NR.sup.8R.sup.8, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--CONR.sup.8R.sup.8,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
--NHCO-carbocycle, --NHCO-heterocycle,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkenyl, alkynyl,
alkoxyl, carbocycle, and heterocycle are substituted with 0-4
R.sup.9;
[0190] R.sup.8, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, C(O)C.sub.1-4alkyl, C(O)carbocycle,
C(O)heterocycle, --(CH.sub.2).sub.n C(O)NR.sup.aR.sup.a,
C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO.sub.2alkyl,
SO.sub.2carbocycle, SO.sub.2heterocycle, SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.9;
[0191] R.sup.9, at each occurrence, is independently selected from
halogen, OH, NO.sub.2, CHF.sub.2, CF.sub.3, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CH.sub.2OH, CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl),
CONH.sub.2, --(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2)(2-4)NR.sup.aR.sup.a,
--(C R.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein
said alkyl, alkoxyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.b;
[0192] R.sup.a, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --(CH.sub.2).sub.nOH, CO(C.sub.1-4 alkyl),
COCF.sub.3, CO.sub.2(C.sub.1-4 alkyl), --CONH.sub.2,
--CONH--C.sub.1-4 alkylene-CO.sub.2(C.sub.1-4 alkyl), C.sub.1-4
alkylene-CO.sub.2(C.sub.1-4 alkyl), R.sup.c, CO.sub.2R.sup.c, and
CONHR.sup.c; alternatively, R.sup.a and R.sup.a are taken together
with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and
heterocycle are substituted with 0-4 R.sup.b;
[0193] R.sup.b, at each occurrence, is independently selected from
.dbd.O, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OCF.sub.3,
NH.sub.2, NO.sub.2, N(C.sub.1-4 alkyl).sub.2, CO(C.sub.1-4 alkyl),
CO(C.sub.1-4 haloalkyl), CO.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 alkylene-O(C.sub.1-4 alkyl), --CONH--C.sub.1-4
alkylene-N(C.sub.1-4 alkyl).sub.2, --CONH--C.sub.1-4 alkylene-N
(C.sub.1-4 alkyl).sub.2, --C.sub.1-4 alkylene-O--P(O)(OH).sub.2,
--NHCO.sub.2(C.sub.1-4 alkyl), --R.sup.c, COR.sup.c,
CO.sub.2R.sup.c, and CONHR.sup.c;
[0194] R.sup.c, at each occurrence, is independently selected from
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.n-phenyl, and --(CH.sub.2).sub.n-5- to 6-membered
heterocycle containing carbon atoms and 1-4 heteroatoms selected
from the group consisting of: N, NH, N(C.sub.1-4 alkyl), O, and
S(O).sub.p; wherein each ring moiety is substituted with 0-2
R.sup.d;
[0195] R.sup.d, at each occurrence, is independently selected from
.dbd.O, halogen, --OH, C.sub.1-4 alkyl, NH.sub.2, NH(C.sub.1-4
alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkoxy, and
--NHCO(C.sub.1-4 alkyl), and heterocycle containing carbon atoms
and 1-4 heteroatoms selected from the group consisting of: N, NH,
N(C.sub.1-4 alkyl), O, and S(O).sub.p;
[0196] n, at each occurrence, is independently selected from 0, 1,
2, 3, and 4;
[0197] p, at each occurrence, is independently selected from 0, 1,
and 2;
[0198] other variables are as defined in Formula (V) above.
[0199] In another aspect, the present invention provides compounds
of Formula (VI) or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, wherein:
[0200] R.sup.5 is selected from H, C.sub.1-4 alkyl,
--(CH.sub.2).sub.n--C.sub.3-10 carbocycle, --(CH.sub.2).sub.n-aryl,
--(CH.sub.2).sub.n-4-10 membered heterocycle selected from
##STR00018##
[0201] wherein said alkyl, cycloalkyl, aryl are substituted with
1-4 R.sup.7; and
[0202] other variables are as defined in Formula (V) above.
[0203] In another aspect, the present invention provides compounds
of Formula (VI) or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, wherein:
[0204] R.sup.5 and R.sup.5 are taken together with the nitrogen
atom to which they are attached to form a heterocycle selected
from
##STR00019##
[0205] R.sup.7, at each occurrence, is independently selected from
H, .dbd.O, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CN, OH,
CF.sub.3, --(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --CH.sub.2NH.sub.2,
--NHCO(C.sub.1-4 alkyl), --NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NH.sub.2, --NHC(O)NH(C.sub.1-4 alkyl),
--NHC(O)N(C.sub.1-4 alkyl).sub.2, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--CONR.sup.8R.sup.8,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
--NHCO-carbocycle, --NHCO-heterocycle,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkoxyl,
carbocycle, and heterocycle are substituted with 0-4 R.sup.9;
[0206] R.sup.8, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, C(O)C.sub.1-4alkyl, C(O)carbocycle,
C(O)heterocycle, --(CH.sub.2).sub.n--C(O)NR.sup.aR.sup.a,
C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO.sub.2alkyl,
SO.sub.2carbocycle, SO.sub.2heterocycle, SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.9;
[0207] alternatively, R.sup.8 and R.sup.8 are taken together with
the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle substituted with 0-4 R.sup.9; and
[0208] R.sup.9, at each occurrence, is independently selected from
halogen, OH, NO.sub.2, CHF.sub.2, CF.sub.3, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CH.sub.2OH, CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl),
CONH.sub.2, --(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2)(2-4)NR.sup.aR.sup.a,
--(C R.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein
said alkyl, alkoxyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.b;
[0209] R.sup.a, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --(CH.sub.2).sub.nOH, CO(C.sub.1-4 alkyl),
COCF.sub.3, CO.sub.2(C.sub.1-4 alkyl), --CONH.sub.2,
--CONH--C.sub.1-4 alkylene-CO.sub.2(C.sub.1-4 alkyl), C.sub.1-4
alkylene-CO.sub.2(C.sub.1-4 alkyl), R.sup.c, CO.sub.2R.sup.c, and
CONHR.sup.c; alternatively, R.sup.a and R.sup.a are taken together
with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and
heterocycle are substituted with 0-4 R.sup.b;
[0210] R.sup.b, at each occurrence, is independently selected from
.dbd.O, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OCF.sub.3,
NH.sub.2, NO.sub.2, N(C.sub.1-4 alkyl).sub.2, CO(C.sub.1-4 alkyl),
CO(C.sub.1-4 haloalkyl), CO.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 alkylene-O(C.sub.1-4 alkyl), --CONH--C.sub.1-4
alkylene-N(C.sub.1-4 alkyl).sub.2, --CONH--C.sub.1-4 alkylene-N
(C.sub.1-4 alkyl).sub.2, --C.sub.1-4 alkylene-O--P(O)(OH).sub.2,
--NHCO.sub.2(C.sub.1-4 alkyl), --R.sup.c, COR.sup.c,
CO.sub.2R.sup.c, and CONHR.sup.c;
[0211] R.sup.c, at each occurrence, is independently selected from
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.n-phenyl, and --(CH.sub.2).sub.n-5- to 6-membered
heterocycle containing carbon atoms and 1-4 heteroatoms selected
from the group consisting of: N, NH, N(C.sub.1-4 alkyl), O, and
S(O).sub.p; wherein each ring moiety is substituted with 0-2
R.sup.d; and
[0212] R.sup.d, at each occurrence, is independently selected from
.dbd.O, halogen, --OH, C.sub.1-4 alkyl, NH.sub.2, NH(C.sub.1-4
alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkoxy, and
--NHCO(C.sub.1-4 alkyl), and heterocycle containing carbon atoms
and 1-4 heteroatoms selected from the group consisting of: N, NH,
N(C.sub.1-4 alkyl), O, and S(O).sub.p;
[0213] other variables are as defined in Formula (VI) above.
[0214] In another aspect, the present invention provides compounds
of Formula (VII):
##STR00020##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0215] R.sup.5, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --(CR.sup.6R.sup.6).sub.n--C.sub.3-10
carbocycle, and --(CR.sup.6R.sup.6).sub.n-4-10 membered heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, carbocycle, and
heterocycle are substituted with 1-4 R.sup.7;
[0216] alternatively, R.sup.5 and R.sup.5 are taken together with
the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle substituted with 1-4 R.sup.7;
[0217] R.sup.6, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[0218] R.sup.7, at each occurrence, is independently selected from
H, .dbd.O, NO.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
CN, OH, CF.sub.3, --(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.3O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2OH,
--NHCO.sub.2(CH.sub.2).sub.2NH.sub.2,
--NHCO.sub.2(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--NHCO.sub.2CH.sub.2CO.sub.2H, --CH.sub.2NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NR.sup.8R.sup.8, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--CONR.sup.8R.sup.8,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
--NHCO-carbocycle, --NHCO-heterocycle,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkenyl, alkynyl,
alkoxyl, carbocycle, and heterocycle are substituted with 0-4
R.sup.9;
[0219] R.sup.8, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, C(O)C.sub.1-4alkyl, C(O)carbocycle,
C(O)heterocycle, --(CH.sub.2).sub.n--C(O)NR.sup.aR.sup.a,
C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO.sub.2alkyl,
SO.sub.2carbocycle, SO.sub.2heterocycle, SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.9;
[0220] R.sup.9, at each occurrence, is independently selected from
halogen, OH, NO.sub.2, CHF.sub.2, CF.sub.3, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CH.sub.2OH, CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl),
CONH.sub.2, --(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2)(2-4)NR.sup.aR.sup.a,
--(C R.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein
said alkyl, alkoxyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.b;
[0221] n, at each occurrence, is independently selected from 0, 1,
2, 3, and 4; and
[0222] p, at each occurrence, is independently selected from 0, 1,
and 2;
[0223] other variables are as defined in Formula (V) above.
[0224] In another aspect, the present invention provides compounds
of Formula (V) or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, wherein:
[0225] L is --NR.sup.6--;
[0226] R.sup.7, at each occurrence, is independently selected from
H, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CN, OH,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, alkoxyl, carbocycle, and heterocycle are
substituted with 0-4 R.sup.9;
[0227] other variables are as defined in Formula (V) above.
[0228] In another aspect, the present invention provides compounds
of Formula (V) or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, wherein:
[0229] L is --NR.sup.6--; and
[0230] R.sup.1 is selected from
##STR00021##
other variables are as defined in Formula (V) above.
[0231] In still another aspect, the present invention provides
compounds of Formula (VIII):
##STR00022##
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein:
[0232] R.sup.1 is selected from NR.sup.5R.sup.5, C.sub.3-10
carbocycle, and 5- to 10-membered heterocycle, wherein said
carbocycle and heterocycle are substituted with 1-4 R.sup.7;
[0233] R.sup.5, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --(CR.sup.6R.sup.6).sub.n--C.sub.3-10
carbocycle, and --(CR.sup.6R.sup.6).sub.n-4-10 membered heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, carbocycle, and
heterocycle are substituted with 1-4 R.sup.7;
[0234] alternatively, R.sup.5 and R.sup.5 are taken together with
the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle substituted with 1-4 R.sup.7;
[0235] R.sup.6, at each occurrence, is independently selected from
H and C.sub.1-4 alkyl;
[0236] R.sup.7, at each occurrence, is independently selected from
H, .dbd.O, NO.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
CN, OH, CF.sub.3, --(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.3O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2OH,
--NHCO.sub.2(CH.sub.2).sub.2NH.sub.2,
--NHCO.sub.2(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--NHCO.sub.2CH.sub.2CO.sub.2H, --CH.sub.2NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NR.sup.8R.sup.8, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--CONR.sup.8R.sup.8,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
--NHCO-carbocycle, --NHCO-heterocycle,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkenyl, alkynyl,
alkoxyl, carbocycle, and heterocycle are substituted with 0-4
R.sup.9;
[0237] R.sup.8, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C(O)C.sub.1-4alkyl,
C(O)carbocycle, C(O)heterocycle,
--(CH.sub.2).sub.n--C(O)NR.sup.aR.sup.a, C(O)O-alkyl,
C(O)O-carbocycle, C(O)O-heterocycle, SO.sub.2alkyl,
SO.sub.2carbocycle, SO.sub.2heterocycle, SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, alkenyl, carbocycle, and heterocycle are
substituted with 0-4 R.sup.9;
[0238] R.sup.9, at each occurrence, is independently selected from
halogen, OH, NO.sub.2, CHF.sub.2, CF.sub.3, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CH.sub.2OH, CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl),
CONH.sub.2, --(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2)(2-4)NR.sup.aR.sup.a,
--(C R.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein
said alkyl, alkoxyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.b;
[0239] n, at each occurrence, is independently selected from 0, 1,
2, 3, and 4;
[0240] p, at each occurrence, is independently selected from 0, 1,
and 2;
[0241] other variables are as defined in Formula (V) above.
[0242] In still another aspect, the present invention provides
compounds of Formula (VIII), or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
wherein
[0243] R.sup.1 is selected from
##STR00023## ##STR00024##
[0244] R.sup.7, at each occurrence, is independently selected from
H, .dbd.O, NO.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
CN, OH, CF.sub.3, --(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHC.sub.2(C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.3O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2O H,
--NHCO.sub.2(CH.sub.2).sub.2NH.sub.2,
--NHCO.sub.2(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--NHCO.sub.2CH.sub.2CO.sub.2H, --CH.sub.2NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NR.sup.8R.sup.8, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2O
H, --SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--CONR.sup.8R.sup.8,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
--NHCO-carbocycle, --NHCO-heterocycle,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkenyl, alkynyl,
alkoxyl, carbocycle, and heterocycle are substituted with 0-4
R.sup.9;
[0245] R.sup.8, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, C(O)C.sub.1-4alkyl, C(O)carbocycle,
C(O)heterocycle, --(CH.sub.2).sub.n--C(O)NR.sup.aR.sup.a,
C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO.sub.2alkyl,
SO.sub.2carbocycle, SO.sub.2heterocycle, SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-carbocycle, and --(CH.sub.2).sub.n-heterocycle,
wherein said alkyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.9;
[0246] alternatively, R.sup.8 and R.sup.8 are taken together with
the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle substituted with 0-4 R.sup.9; and
[0247] R.sup.9, at each occurrence, is independently selected from
halogen, OH, NO.sub.2, CHF.sub.2, CF.sub.3, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CH.sub.2OH, CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl),
CONH.sub.2, --(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2)(2-4)NR.sup.aR.sup.a,
--(C R.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein
said alkyl, alkoxyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.b;
[0248] R.sup.a, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, --(CH.sub.2).sub.nOH, CO(C.sub.1-4 alkyl),
COCF.sub.3, CO.sub.2(C.sub.1-4 alkyl), --CONH.sub.2,
--CONH--C.sub.1-4 alkylene-CO.sub.2(C.sub.1-4 alkyl), C.sub.1-4
alkylene-CO.sub.2(C.sub.1-4 alkyl), R.sup.c, CO.sub.2R.sup.c, and
CONHR.sup.c; alternatively, R.sup.a and R.sup.a are taken together
with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and
heterocycle are substituted with 0-4 R.sup.b;
[0249] R.sup.b, at each occurrence, is independently selected from
.dbd.O, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, OCF.sub.3,
NH.sub.2, NO.sub.2, N(C.sub.1-4 alkyl).sub.2, CO(C.sub.1-4 alkyl),
CO(C.sub.1-4 haloalkyl), CO.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 alkylene-O(C.sub.1-4 alkyl), --CONH--C.sub.1-4
alkylene-N(C.sub.1-4 alkyl).sub.2, --CONH--C.sub.1-4 alkylene-N
(C.sub.1-4 alkyl).sub.2, --C.sub.1-4 alkylene-O--P(O)(OH).sub.2,
--NHCO.sub.2(C.sub.1-4 alkyl), --R.sup.c, COR.sup.c,
CO.sub.2R.sup.c, and CONHR.sup.c;
[0250] R.sup.c, at each occurrence, is independently selected from
--(CH.sub.2).sub.n--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.n-phenyl, and --(CH.sub.2).sub.n-5- to 6-membered
heterocycle containing carbon atoms and 1-4 heteroatoms selected
from the group consisting of: N, NH, N(C.sub.1-4 alkyl), O, and
S(O).sub.p; wherein each ring moiety is substituted with 0-2
R.sup.d; and
[0251] R.sup.d, at each occurrence, is independently selected from
.dbd.O, halogen, --OH, C.sub.1-4 alkyl, NH.sub.2, NH(C.sub.1-4
alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkoxy, and
--NHCO(C.sub.1-4 alkyl), and heterocycle containing carbon atoms
and 1-4 heteroatoms selected from the group consisting of: N, NH,
N(C.sub.1-4 alkyl), O, and S(O).sub.p;
[0252] other variables are as defined in Formula (VIII) above.
[0253] In still another aspect, the present invention provides
compounds of Formula (VIII), or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
wherein:
[0254] R.sup.1 is NR.sup.5R.sup.5;
[0255] R.sup.5 and R.sup.5 are taken together with the nitrogen
atom to which they are attached to form 4- to 10-membered
heterocycle substituted with 1-4 R.sup.7;
[0256] R.sup.7, at each occurrence, is independently selected from
H, .dbd.O, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CN, OH,
CF.sub.3, --(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl), --NHC(O)NH.sub.2,
--NHC(O)NH(C.sub.1-4 alkyl), --NHC(O)N(C.sub.1-4 alkyl).sub.2,
--NHSO.sub.2(C.sub.1-4 alkyl), --SO.sub.2NH.sub.2,
--SO.sub.2NH(C.sub.1-4 alkyl), --SO.sub.2N(C.sub.1-4 alkyl).sub.2,
--SO.sub.2NH(CH.sub.2).sub.2OH, --SO.sub.2NH(CH.sub.2).sub.2O
(C.sub.1-4 alkyl), --CONH.sub.2, --CONH(C.sub.1-4 alkyl),
--CON(C.sub.1-4 alkyl).sub.2, --CH.sub.2CONH.sub.2,
--(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-carbocycle,
--O(CH.sub.2).sub.n-heterocycle, and --(CH.sub.2).sub.n-heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N,
NR.sup.8, O, and S(O).sub.p, wherein said alkyl, alkoxyl,
carbocycle, and heterocycle are substituted with 0-4 R.sup.9;
[0257] R.sup.8, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl, C(O)C.sub.1-4alkyl, C(O)carbocycle,
C(O)heterocycle, --(CH.sub.2).sub.n--C(O)NR.sup.aR.sup.a,
C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO.sub.2alkyl,
SO.sub.2carbocycle, SO.sub.2heterocycle, SO.sub.2NR.sup.aR.sup.a,
--(CH.sub.2).sub.n-cycloalkyl, --(CH.sub.2).sub.n-phenyl, and
--(CH.sub.2).sub.n-heterocycle, wherein said alkyl, carbocycle, and
heterocycle are substituted with 0-4 R.sup.9; and
[0258] R.sup.9, at each occurrence, is independently selected from
halogen, OH, NO.sub.2, CHF.sub.2, CF.sub.3, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CH.sub.2OH, CO.sub.2H, CO.sub.2(C.sub.1-4 alkyl),
CONH.sub.2, --(CH.sub.2).sub.nNR.sup.aR.sup.a,
--(CH.sub.2).sub.nCONR.sup.aR.sup.a,
--O(CH.sub.2).sub.nheterocycle, --O(CH.sub.2)(2-4)NR.sup.aR.sup.a,
--(C R.sup.10R.sup.10).sub.n-4-10 membered heterocycle, wherein
said alkyl, alkoxyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.b; and
[0259] other variables are as defined in Formula (VIII) above.
[0260] In one embodiment, the present invention provides compounds
of Formulae (I), (II), (III), and (IV), or stereoisomers,
tautomers, pharmaceutically acceptable salts, solvates, or prodrugs
thereof, wherein M is N or CR.sup.10; L is selected from
--CR.sup.4R.sup.4C(O)--, --OC(O)--, and --NR.sup.6C(O--; R.sup.1 is
selected from NR.sup.5R.sup.5, C.sub.3-10 carbocycle and 4- to
12-membered heterocycle comprising carbon atoms and 1-4 heteroatoms
selected from N, NR.sup.8, O, and S(O).sub.p; wherein said alkyl,
carbocycle and heterocycle are substituted with 1-4 R.sup.7.
[0261] In one embodiment, the present invention provides compounds
of Formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII),
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein L is selected from
--CR.sup.4R.sup.4C(O)--, --OC(O)--, and --NR.sup.6C(O)--; R.sup.1
is selected from NR.sup.5R.sup.5, C.sub.3-10 carbocycle and 4- to
12-membered heterocycle comprising carbon atoms and 1-4 heteroatoms
selected from N, NR.sup.8, O, and S(O).sub.p; wherein said alkyl,
carbocycle and heterocycle are substituted with 1-4 R.sup.7.
[0262] In one embodiment, the present invention provides compounds
of Formulae (I), (IV), (V), and (VIII), or stereoisomers,
tautomers, pharmaceutically acceptable salts, solvates, or prodrugs
thereof, wherein L is selected from --NR.sup.6C(O)--, and
--NR.sup.6--; R.sup.1 is 4- to 12-membered heterocycle comprising
carbon atoms and 1-4 heteroatoms selected from N, NR.sup.8, O, and
S(O).sub.p and substituted with 1-4 R.sup.7.
[0263] In one embodiment, the present invention provides compounds
of Formulae (I), (IV), (V), and (VIII), or stereoisomers,
tautomers, pharmaceutically acceptable salts, solvates, or prodrugs
thereof, wherein L is selected from --NR.sup.6C(O)-- or NR.sup.6--;
R.sup.1 is selected from
##STR00025##
[0264] In one embodiment, the present invention provides compounds
of Formulae (I), (IV), (V), and (VIII), or stereoisomers,
tautomers, pharmaceutically acceptable salts, solvates, or prodrugs
thereof, wherein L is --NR.sup.6C(O)--; R.sup.1 is C.sub.3-10
carbocycle substituted with 1-4 R.sup.7.
[0265] In one embodiment, the present invention provides compounds
of Formulae (I), (IV), (V), and (VIII), or stereoisomers,
tautomers, pharmaceutically acceptable salts, solvates, or prodrugs
thereof, wherein L is selected from --NR.sup.6C(O)--; R.sup.1 is
C.sub.3-6 cycloalkyl substituted with 1-4 R.sup.7 or aryl
substituted with 1-4 R.sup.7; R.sup.7, at each occurrence, is
independently selected from H, .dbd.O, halogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CN, OH, CF.sub.3, --(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.3O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2OH,
--NHCO.sub.2(CH.sub.2).sub.2NH.sub.2,
--NHCO.sub.2(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--NHCO.sub.2CH.sub.2CO.sub.2H, --CH.sub.2NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NH.sub.2, --NHC(O)NH(C.sub.1-4 alkyl),
--NHC(O)N(C.sub.1-4 alkyl).sub.2, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl), --CONH.sub.2,
--CONH(C.sub.1-4 alkyl), --CON(C.sub.1-4 alkyl).sub.2,
--CH.sub.2CONH.sub.2, --(CH.sub.2).sub.n-carbocycle,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
and --(CH.sub.2).sub.n-heterocycle comprising carbon atoms and 1-4
heteroatoms selected from N, NR.sup.8, O, and S(O).sub.p, wherein
said alkyl, alkoxyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.9.
[0266] In one embodiment, the present invention provides compounds
of Formulae (I), (IV), (V), and (VIII), or stereoisomers,
tautomers, pharmaceutically acceptable salts, solvates, or prodrugs
thereof, wherein L is selected from --NR.sup.6C(O)--; R.sup.1 is
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, each
substituted with 1-4 R.sup.7; R.sup.7, at each occurrence, is
independently selected from H, .dbd.O, halogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, CN, OH, CF.sub.3, --(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.3O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2OH,
--NHCO.sub.2(CH.sub.2).sub.2NH.sub.2,
--NHCO.sub.2(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--NHCO.sub.2CH.sub.2CO.sub.2H, --CH.sub.2NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NH.sub.2, --NHC(O)NH(C.sub.1-4 alkyl),
--NHC(O)N(C.sub.1-4 alkyl).sub.2, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl), --CONH.sub.2,
--CONH(C.sub.1-4 alkyl), --CON(C.sub.1-4 alkyl).sub.2,
--CH.sub.2CONH.sub.2, --(CH.sub.2).sub.n-carbocycle,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
and --(CH.sub.2).sub.n-heterocycle comprising carbon atoms and 1-4
heteroatoms selected from N, NR.sup.8, O, and S(O).sub.p, wherein
said alkyl, alkoxyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.9.
[0267] In one embodiment, the present invention provides compounds
of Formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII),
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein L is selected from
--CR.sup.4R.sup.4C(O)--, --OC(O)--, and --NR.sup.6C(O)--; R.sup.1
is NR.sup.5R.sup.5; R.sup.5, at each occurrence, is independently
selected from H, C.sub.1-4 alkyl,
--(CR.sup.6R.sup.6).sub.n--C.sub.3-10 carbocycle, and
--(CR.sup.6R.sup.6).sub.n-4-10 membered heterocycle comprising
carbon atoms and 1-4 heteroatoms selected from N, NR.sup.8, O, and
S(O).sub.p, wherein said carbocycle and heterocycle are substituted
with 1-4 R.sup.7.
[0268] In one embodiment, the present invention provides compounds
of Formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII),
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein L is selected from
--CR.sup.4R.sup.4C(O)--, --OC(O)--, and --NR.sup.6C(O)--; R.sup.1
is NR.sup.5R.sup.5; R.sup.5, at each occurrence, is independently
selected from H, C.sub.1-4 alkyl, --(CH.sub.2).sub.n--C.sub.3-10
carbocycle, --(CH.sub.2).sub.n-aryl, --(CH.sub.2).sub.n-4-10
membered heterocycle selected from
##STR00026##
[0269] In one embodiment, the present invention provides compounds
of Formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII),
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein L is selected from
--CR.sup.4R.sup.4C(O)--, --OC(O)--, and --NR.sup.6C(O)--; R.sup.1
is NR.sup.5R.sup.5; R.sup.5 and R.sup.5 are taken together with the
nitrogen atom to which they are attached to form 4- to 10-membered
heterocycle comprising carbon atoms and 1-4 heteroatoms selected
from N, NR.sup.8, O, and S(O).sub.p, wherein said heterocycle is
substituted with 1-4 R.sup.7.
[0270] In one embodiment, the present invention provides compounds
of Formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII),
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein L is selected from
--CR.sup.4R.sup.4C(O)--, --OC(O)--, and --NR.sup.6C(O)--; R.sup.1
is NR.sup.5R.sup.5; R.sup.5 and R.sup.5 are taken together with the
nitrogen atom to which they are attached to form a heterocycle
selected from
##STR00027##
R.sup.7, at each occurrence, is independently selected from H,
.dbd.O, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CN, OH,
CF.sub.3, --(CH.sub.2).sub.n--CO.sub.2H,
--(CH.sub.2).sub.n--CO.sub.2(C.sub.1-4 alkyl),
--(CH.sub.2).sub.n--NR.sup.8R.sup.8, --NHCO(C.sub.1-4 alkyl),
--NHCOCF.sub.3, --NHCO.sub.2(C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.3O (C.sub.1-4 alkyl),
--NHCO.sub.2(CH.sub.2).sub.2OH,
--NHCO.sub.2(CH.sub.2).sub.2NH.sub.2,
--NHCO.sub.2(CH.sub.2).sub.2N(C.sub.1-4 alkyl).sub.2,
--NHCO.sub.2CH.sub.2CO.sub.2H, --CH.sub.2NHCO.sub.2(C.sub.1-4
alkyl), --NHC(O)NH.sub.2, --NHC(O)NH(C.sub.1-4 alkyl),
--NHC(O)N(C.sub.1-4 alkyl).sub.2, --NHSO.sub.2(C.sub.1-4 alkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-4 alkyl),
--SO.sub.2N(C.sub.1-4 alkyl).sub.2, --SO.sub.2NH(CH.sub.2).sub.2OH,
--SO.sub.2NH(CH.sub.2).sub.2O (C.sub.1-4 alkyl), --CONH.sub.2,
--CONH(C.sub.1-4 alkyl), --CON(C.sub.1-4 alkyl).sub.2,
--CH.sub.2CONH.sub.2, --(CH.sub.2).sub.n-carbocycle,
--O(CH.sub.2).sub.n-carbocycle, --O(CH.sub.2).sub.n-heterocycle,
and --(CH.sub.2).sub.n-heterocycle comprising carbon atoms and 1-4
heteroatoms selected from N, NR.sup.8, O, and S(O).sub.p, wherein
said alkyl, alkoxyl, carbocycle, and heterocycle are substituted
with 0-4 R.sup.9.
[0271] In one embodiment, the present invention provides compounds
of Formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII),
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein L is selected from
--CR.sup.4R.sup.4C(O)--, --OC(O)--, and --NR.sup.6C(O)--; R.sup.1
is selected from
##STR00028##
[0272] In one embodiment, the present invention provides compounds
of Formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII),
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein L is selected from
--CR.sup.4R.sup.4C(O)--, --OC(O)--, and --NR.sup.6C(O)--; R.sup.1
is selected from NR.sup.5R.sup.5, C.sub.3-10 carbocycle and 4- to
12-membered heterocycle comprising carbon atoms and 1-4 heteroatoms
selected from N, NR.sup.8, O, and S(O).sub.p; wherein said alkyl,
carbocycle and heterocycle are substituted with 1-4 R.sup.7;
R.sup.5, at each occurrence, is independently selected from H,
C.sub.1-4 alkyl, --(CR.sup.6R.sup.6).sub.n--C.sub.3-10 carbocycle,
and --(CR.sup.6R.sup.6).sub.n-4-10 membered heterocycle comprising
carbon atoms and 1-4 heteroatoms selected from N, NR.sup.8, O, and
S(O).sub.p, wherein said alkyl, carbocycle and heterocycle are
substituted with 1-4 R.sup.7; alternatively, R.sup.5 and R.sup.5
are taken together with the nitrogen atom to which they are
attached to form 4- to 10-membered heterocycle substituted with 1-4
R.sup.7.
[0273] In one embodiment, the present invention provides compounds
of Formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII),
or stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof, wherein L is selected from
--CR.sup.4R.sup.4C(O)--, --OC(O)--, and --NR.sup.6C(O)--; R.sup.1
is selected from C.sub.3-10 carbocycle and 4- to 12-membered
heterocycle comprising carbon atoms and 1-4 heteroatoms selected
from N, NR.sup.8, O, and S(O).sub.p; wherein said carbocycle and
heterocycle are substituted with 1-4 R.sup.7; R.sup.5, at each
occurrence, is independently selected from H, C.sub.1-4 alkyl,
--(CR.sup.6R.sup.6).sub.n--C.sub.3-10 carbocycle substituted with
1-4 R.sup.7, and --(CR.sup.6R.sup.6).sub.n-4-10 membered
heterocycle selected from
##STR00029##
[0274] alternatively, R.sup.5 and R.sup.5 are taken together with
the nitrogen atom to which they are attached to form a heterocycle
selected from
##STR00030##
[0275] In another aspect, the present invention provides a compound
selected from any subset list of compounds exemplified in the
present application.
[0276] In another embodiment, the compounds of the present
invention have ROCK IC.sub.50 values .ltoreq.10 .mu.M.
[0277] In another embodiment, the compounds of the present
invention have ROCK IC.sub.50 values .ltoreq.1 .mu.M.
[0278] In another embodiment, the compounds of the present
invention have ROCK IC.sub.50 values .ltoreq.0.1 .mu.M.
[0279] In another embodiment, the compounds of the present
invention have ROCK IC.sub.50 values .ltoreq.0.05 .mu.M.
[0280] In another embodiment, the compounds of the present
invention have ROCK IC.sub.50 values .ltoreq.0.01 .mu.M.
II. Other Embodiments of the Invention
[0281] 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.
[0282] 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.
[0283] 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.
[0284] In another embodiment, the present invention provides a
process for making a compound of the present invention.
[0285] In another embodiment, the present invention provides an
intermediate for making a compound of the present invention.
[0286] In another embodiment, the present invention provides a
pharmaceutical composition further comprising additional
therapeutic agent(s).
[0287] In another embodiment, the present invention provides a
method for the treatment and/or prophylaxis of a condition
associated with aberrant ROCK activity 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. As used
herein, the term "patient" encompasses all mammalian species.
[0288] 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.
[0289] As used herein, "prophylaxis" or "prevention" covers 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. "Prophylaxis" therapies can be divided into (a) primary
prevention and (b) secondary prevention. Primary prevention is
defined as treatment in a patient that has not yet presented with a
clinical disease state, whereas secondary prevention is defined as
preventing a second occurrence of the same or similar clinical
disease state. 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.
[0290] 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.
II. Chemistry
[0291] 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.
[0292] 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.
[0293] 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)).
[0294] 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.
[0295] 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.
[0296] 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.
[0297] "Alkenyl" or "alkenylene" is intended to include hydrocarbon
chains of either straight or branched configuration having the
specified number of carbon atoms and one or more, preferably one to
two, 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.
Examples of alkenyl include, but are not limited to, ethenyl,
1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl,
3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,
2-methyl-2-propenyl, and 4-methyl-3-pentenyl.
[0298] "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.
[0299] 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. 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--.
[0300] "Halo" or "halogen" includes fluoro (F), chloro (Cl), bromo
(Br), and iodo (I). "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.
[0301] "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--.
[0302] 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 norbomyl.
Branched cycloalkyl groups such as 1-methylcyclopropyl and
2-methylcyclopropyl are included in the definition of
"cycloalkyl".
[0303] As used herein, "carbocycle" 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 carbocycles include, but are not limited to, cyclopropyl,
cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl,
cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl,
cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,
[4.3.0]bicyclononane, [4.4.0]bicyclodecane (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
carbocycle (e.g., [2.2.2]bicyclooctane). Preferred carbocycles,
unless otherwise specified, are cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, phenyl, and indanyl. When the term
"carbocycle" 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.
[0304] As used herein, the term "bicyclic carbocycle" 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.
[0305] "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). "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.
[0306] 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.
[0307] As used herein, the term "heterocycle" or "heterocyclic
group" 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 heterocycle may
optionally be quaternized. It is preferred that when the total
number of S and O atoms in the heterocycle exceeds 1, then these
heteroatoms are not adjacent to one another. It is preferred that
the total number of S and O atoms in the heterocycle is not more
than 1. When the term "heterocycle" is used, it is intended to
include heteroaryl.
[0308] Examples of heterocycles 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 heterocycles.
[0309] Examples of 5- to 10-membered heterocycles include, but are
not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,
pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl,
indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl,
oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl,
thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl,
1H-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl,
benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl,
benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl,
isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl,
isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl,
imidazolopyridinyl, and pyrazolopyridinyl.
[0310] Examples of 5- to 6-membered heterocycles include, but are
not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,
pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl,
indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl,
oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl,
thiadiazolyl, thiazolyl, triazinyl, and triazolyl. Also included
are fused ring and spiro compounds containing, for example, the
above heterocycles.
[0311] As used herein, the term "bicyclic heterocycle" or "bicyclic
heterocyclic group" is intended to mean a stable 9- or 10-membered
heterocyclic ring system which contains two fused rings and
consists of carbon atoms and 1, 2, 3, or 4 heteroatoms
independently selected from the group consisting of N, O and S. Of
the two fused rings, one ring is a 5- or 6-membered monocyclic
aromatic ring comprising a 5-membered heteroaryl ring, a 6-membered
heteroaryl ring or a benzo ring, each fused to a second ring. The
second ring is a 5- or 6-membered monocyclic ring which is
saturated, partially unsaturated, or unsaturated, and comprises a
5-membered heterocycle, a 6-membered heterocycle or a carbocycle
(provided the first ring is not benzo when the second ring is a
carbocycle).
[0312] The bicyclic heterocyclic group may be attached to its
pendant group at any heteroatom or carbon atom which results in a
stable structure. The bicyclic heterocyclic group described herein
may be substituted on carbon or on a nitrogen atom if the resulting
compound is stable. It is preferred that when the total number of S
and O atoms in the heterocycle exceeds 1, then these heteroatoms
are not adjacent to one another. It is preferred that the total
number of S and O atoms in the heterocycle is not more than 1.
[0313] Examples of a bicyclic heterocyclic group are, but not
limited to, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl,
indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,
1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,
5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,
1,2,3,4-tetrahydro-quinoxalinyl, and
1,2,3,4-tetrahydro-quinazolinyl.
[0314] 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).
[0315] Bridged rings are also included in the definition of
heterocycle. A bridged ring occurs when one or more atoms (i.e., C,
O, N, or S) link two non-adjacent carbon or nitrogen atoms.
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.
[0316] The term "counterion" is used to represent a negatively
charged species such as chloride, bromide, hydroxide, acetate, and
sulfate.
[0317] When a dotted ring is used within a ring structure, this
indicates that the ring structure may be saturated, partially
saturated or unsaturated.
[0318] 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).
[0319] 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.
[0320] 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.
[0321] 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.
[0322] 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.
[0323] 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.
[0324] 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.
[0325] 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: [0326] a) Bundgaard, H., ed., Design of Prodrugs,
Elsevier (1985), and Widder, K. et al., eds., Methods in
Enzymology, 112:309-396, Academic Press (1985); [0327] b)
Bundgaard, H., Chapter 5, "Design and Application of Prodrugs",
Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design and
Development, pp. 113-191, Harwood Academic Publishers (1991);
[0328] c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);
[0329] d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and
[0330] e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).
[0331] 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.
[0332] 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.
[0333] 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).
[0334] 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.
[0335] 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.
[0336] "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.
[0337] 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.
[0338] 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, "atm" for atmosphere, "psi" for pounds per
square inch, "conc." for concentrate, "sat" or "saturated" for
saturated, "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, "6" 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. [0339] Me Methyl [0340] Et Ethyl [0341] Pr
Propyl [0342] i-Pr Isopropyl [0343] Bu Butyl [0344] i-Bu Isobutyl
[0345] t-Bu tert-butyl [0346] Ph Phenyl [0347] Bn Benzyl [0348] Boc
tert-butyloxycarbonyl [0349] AcOH or HOAc acetic acid [0350]
AlCl.sub.3 aluminum chloride [0351] AIBN Azobisisobutyronitrile
[0352] BBr.sub.3 boron tribromide [0353] BCl.sub.3 boron
trichloride [0354] BEMP
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphor-
ine [0355] BOP reagent
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate [0356] Burgess reagent
1-methoxy-N-triethylammoniosulfonyl-methanimidate [0357] CBz
Carbobenzyloxy [0358] CH.sub.2Cl.sub.2 Dichloromethane [0359]
CH.sub.3CN or ACN Acetonitrile [0360] CDCl.sub.3 deutero-chloroform
[0361] CHCl.sub.3 Chloroform [0362] mCPBA or m-CPBA
meta-chloroperbenzoic acid [0363] Cs.sub.2CO.sub.3 cesium carbonate
[0364] Cu(OAc).sub.2 copper (II) acetate [0365] Cy.sub.2NMe
N-cyclohexyl-N-methylcyclohexanamine [0366] DBU
1,8-diazabicyclo[5.4.0]undec-7-ene [0367] DCE 1,2 dichloroethane
[0368] DCM dichloromethane [0369] DEA diethylamine [0370]
Dess-Martin
1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-beniziodoxol-3-(1H)-one
[0371] DIC or DIPCDI diisopropylcarbodiimide [0372] DIEA, DIPEA or
diisopropylethylamine Hunig's base [0373] DMAP
4-dimethylaminopyridine [0374] DME 1,2-dimethoxyethane [0375] DMF
dimethyl formamide [0376] DMSO dimethyl sulfoxide [0377] cDNA
complimentary DNA [0378] Dppp
(R)-(+)-1,2-bis(diphenylphosphino)propane [0379] DuPhos
(+)-1,2-bis((2S,5 S)-2,5-diethylphospholano)benzene [0380] EDC
N-(3-dimthylaminopropyl)-N'-ethylcarbodiimide [0381] EDCI
N-(3-dimthylaminopropyl)-N'-ethylcarbodiimide hydrochloride [0382]
EDTA ethylenediaminetetraacetic acid [0383] (S,S)-EtDuPhosRh(I)
(+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)rho-
dium(I) trifluoromethanesulfonate [0384] Et.sub.3N or TEA
triethylamine [0385] EtOAc ethyl acetate [0386] Et.sub.2O diethyl
ether [0387] EtOH Ethanol [0388] GMF glass microfiber filter [0389]
Grubbs (II)
(1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro
(phenylmethylene)(triycyclohexylphosphine)ruthenium [0390] HCl
hydrochloric acid [0391] HATU
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0392] HEPES
4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid [0393] Hex
Hexane [0394] HOBt or HOBT 1-hydroxybenzotriazole [0395]
H.sub.2SO.sub.4 sulfuric acid [0396] K.sub.2CO.sub.3 potassium
carbonate [0397] KOAc potassium acetate [0398] K.sub.3PO.sub.4
potassium phosphate [0399] LAH lithium aluminum hydride [0400] LG
leaving group [0401] LiOH lithium hydroxide [0402] MeOH Methanol
[0403] MgSO.sub.4 magnesium sulfate [0404] MsOH or MSA
methylsulfonic acid [0405] NaCl sodium chloride [0406] NaH sodium
hydride [0407] NaHCO.sub.3 sodium bicarbonate [0408]
Na.sub.2CO.sub.3 sodium carbonate [0409] NaOH sodium hydroxide
[0410] Na.sub.2SO.sub.3 sodium sulfite [0411] Na.sub.2SO.sub.4
sodium sulfate [0412] NBS N-bromosuccinimide [0413] NCS
N-chlorosuccinimide [0414] NH.sub.3 Ammonia [0415] NH.sub.4C.sub.1
ammonium chloride [0416] NH.sub.4OH ammonium hydroxide [0417] OTf
triflate or trifluoromethanesulfonate [0418] Pd.sub.2(dba).sub.3
tris(dibenzylideneacetone)dipalladium(0) [0419] Pd(OAc).sub.2
palladium(II) acetate [0420] Pd/C palladium on carbon [0421]
Pd(dppf)Cl.sub.2
[1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) [0422]
Ph.sub.3PCl.sub.2 triphenylphosphine dichloride [0423] PG
protecting group [0424] POCl.sub.3 phosphorus oxychloride [0425]
i-PrOH or IPA isopropanol [0426] PS polystyrene [0427] SEM-Cl
2-(trimethysilyl)ethoxymethyl chloride [0428] SiO.sub.2 silica
oxide [0429] SnCl.sub.2 tin(II) chloride [0430] TBAI
tetra-n-butylammonium iodide [0431] TEA triethylamine [0432] TFA
trifluoroacetic acid [0433] THF tetrahydrofuran [0434] TMSCHN.sub.2
trimethylsilyldiazomethane [0435] T3P propane phosphonic acid
anhydride [0436] TRIS tris (hydroxymethyl) aminomethane
[0437] The compounds of the present invention can be prepared in a
number of ways known to one skilled in the art of organic
synthesis.
IV. Biology
In Vitro Assays
[0438] The effectiveness of compounds of the present invention as
ROCK inhibitors can be determined in a 30 .mu.L assay containing 20
mM HEPES, pH 7.5, 20 mM MgCl.sub.2, 0.015% Brij-35, 4 mM DTT, 5
.mu.M ATP and 1.5 .mu.M peptide substrate
(FITC-AHA-AKRRRLSSLRA-OH). Compounds were dissolved in DMSO so that
the final concentration of DMSO was <2%, and the reaction was
initiated with Rho kinase variants. After incubation, the reaction
was terminated by the addition of EDTA and the phosphorylated and
non-phosphorylated peptides separated using a LABCHIP.RTM. 3000
Reader (Caliper Life Sciences). Controls consisted of assays that
did not contain compound, and backgrounds consisted of assays that
contained enzyme and substrate but had EDTA from the beginning of
the reaction to inhibit kinase activity. Compounds were tested in
dose-response format, and the inhibition of kinase activity was
calculated at each concentration of compound. The inhibition data
were fit using a curve-fitting program to determine the IC.sub.50;
i.e., the concentration of compound required to inhibit 50% of
kinase activity.
[0439] Representative Examples were tested in the ROCK assay
described above and found having ROCK inhibitory activity. A range
of ROCK inhibitory activity (IC.sub.50 values) of .ltoreq.50 .mu.M
(50000 nM) was observed. Table A below lists the ROCK IC.sub.50
values measured for the following examples. IC.sub.50 ranges
against ROCKs are as follows: +++=0.1-100 nM; ++=101-1000 nM;
+=1001-50000 nM.
TABLE-US-00001 TABLE A Example No. ROCK1 IC.sub.50 (nM) ROCK2
IC.sub.50 (nM) 1 - +++ 2 ++ +++ 3 ++ +++ 4 - ++ 5 - ++ 6 - ++ 7 -
+++ 8 - + 9 + +++ 10 ++ +++ 11 + ++ 12 + + 13 + + 14 + + 15 + + 16
+ + 17 + +++ 18 + + 19 + + 20 + ++ 21 ++ +++ 22 + + 23 ++ +++ 24 ++
+++ 25 ++ +++ 26 + +++ 27 + +++ 28 + ++ 29 + +++ 30 - - 31 + +++ 32
- - 33 +++ +++ 34 + ++ 35 ++ +++ 36 + +++ 37 ++ +++ 38 ++ +++ 39 ++
+++ 40 ++ +++ 41 +++ +++ 42 + +++ 43 + ++ 44 + +++ 45 - +++ 46 +
+++ 47 ++ +++ 48 ++ +++ 49 - +++ 50 +++ +++ 51 + +++ 52 ++ ++ 53
+++ +++ 54 ++ +++ 55 + + 56 + + 57 + + 58 +++ +++ 59 + + 60 +++ +++
61 +++ +++ 62 +++ +++ 63 ++ +++ 64 ++ +++ 65 +++ +++ 66 +++ +++ 67
++ +++ 68 - +++ 69 + ++ 70 + +++ 71 + +++ 72 ++ +++ 73 ++ +++ 73 -
- 74 + +++ 75 +++ +++ 76 +++ +++ 77 +++ +++ 78 ++ +++ 79 +++ +++ 80
+++ +++ 81 + ++ 82 + ++ 83 +++ +++ 84 ++ +++ 85 +++ +++ 86 ++ +++
87 ++ +++ 88 + +++ 89 ++ +++ 90 ++ +++ 91 + +++ 92 ++ +++ 93 +++
+++ 94 +++ +++ 95 +++ +++ 96 ++ +++ 97 ++ ++ 98 +++ +++ 99 +++ +++
100 +++ +++ 101 +++ +++ 102 +++ +++ 103 +++ +++ 104 +++ +++ 105 ++
+++ 106 + +++ 107 +++ +++ 108 ++ +++ 109 +++ +++ 110 +++ +++ 111 ++
++ 112 + ++ 113 ++ ++ 114 ++ +++ 115 +++ +++ 116 +++ +++ 117 +++
+++ 118 ++ +++ 119 ++ +++ 120 +++ +++ 121 ++ +++ 122 +++ +++ 123 ++
+++ 124 ++ +++ 125 +++ +++ 126 ++ +++ 127 +++ +++ 128 +++ +++ 129
+++ +++ 130 +++ +++ 131 +++ +++ 132 +++ +++ 133 ++ +++ 134 ++ +++
135 ++ +++ 136 + +++ 137 +++ +++ 138 +++ +++ 139 +++ +++ 140 +++
+++ 141 +++ +++ 142 +++ +++ 143 + + 144 +++ +++ 145 +++ +++ 146 +++
+++ 147 +++ +++ 148 +++ +++ 149 +++ +++ 150 +++ +++ 151 +++ +++ 152
+++ +++ 153 +++ +++ 154 +++ +++ 155 +++ +++ 156 +++ +++ 157 +++ +++
158 +++ +++ 159 +++ +++ 160 +++ +++ 161 +++ +++ 162 +++ +++ 163 +++
+++ 164 +++ +++ 165 +++ +++ 166 ++ +++ 167 +++ +++ 168 +++ +++ 169
+++ +++ 170 +++ +++ 171 +++ +++ 172 +++ +++ 173 +++ +++ 174 +++ +++
175 +++ +++ 176 +++ +++ 177 +++ +++ 178 ++ +++ 179 +++ +++ 180 +++
+++ 181 ++ +++ 182 +++ +++ 183 +++ +++ 184 +++ +++ 185 +++ +++ 186
++ +++ 187 +++ +++ 188 +++ +++ 189 +++ +++ 190 +++ +++ 191 +++ +++
192 ++ +++ 193 + ++ 194 ++ +++ 195 +++ +++ 196 + ++ 197 +++ +++ 198
+++ +++ 199 +++ +++ 200 +++ +++ 201 +++ +++ 202 +++ +++ 203 ++ +++
204 ++ +++ 205 ++ +++ 206 +++ +++ 207 +++ +++ 208 +++ +++ 209 ++ ++
210 ++ ++ 211 + ++ 212 ++ +++ 213 +++ +++ 214 +++ +++ 215 ++ ++ 216
+ ++ 217 + ++ 218 + ++ 219 +++ +++ 220 +++ +++ 221 ++ ++ 222 +++
+++ 223 +++ +++ 224 +++ +++ 225 +++ +++ 226 +++ +++ 227 ++ +++ 228
+++ +++ 229 +++ +++ 230 +++ +++ 231 ++ +++ 232 ++ +++ 233 ++ ++ 234
++ +++ 235 +++ +++ 236 ++ +++ 237 ++ +++ 238 ++ +++ 239 ++ +++ 240
++ +++ 241 +++ +++ 242 ++ +++ 243 - - 244 +++ +++
245 +++ +++ 246 +++ +++ 247 +++ +++ 248 ++ +++ 249 +++ +++ 250 ++
+++ 251 ++ +++ 252 + ++ 253 + ++ 254 ++ +++ 255 + ++ 256 ++ +++ 257
+ +++ 258 +++ +++ 259 ++ +++ 260 ++ +++ 261 +++ +++ 262 ++ +++ 263
++ +++ 264 +++ +++ 265 +++ +++ 266 +++ +++ 267 ++ +++ 268 +++ +++
269 + +++ 270 +++ +++ 271 +++ +++ 272 +++ +++ 273 ++ +++ 274 +++
+++ 275 +++ +++ 276 + +++ 277 ++ +++ 278 ++ +++ 279 ++ +++ 280 ++
+++ 281 ++ +++ 282 ++ +++ 283 +++ +++ 284 +++ +++ 285 +++ +++ 286
++ +++ 287 +++ +++ 288 +++ +++ 289 +++ +++ 290 +++ +++ 291 ++ +++
292 ++ +++ 293 ++ +++ 294 ++ +++ 295 ++ +++ 296 ++ +++ 297 +++ +++
298 +++ +++ 299 ++ +++ 300 +++ +++ 301 +++ +++ 302 +++ +++ 303 ++
+++ 304 ++ +++ 305 + + 306 ++ +++ 307 ++ +++ 308 +++ +++ 309 +++
+++ 310 ++ +++ 311 +++ +++ 312 ++ +++ 313 +++ +++ 314 +++ +++ 315
+++ +++ 316 ++ +++ 317 +++ +++ 318 +++ +++ 319 +++ +++ 320 +++ +++
321 +++ ++ 322 +++ ++ 323 +++ +++ 324 +++ +++ 325 ++ +++ 326 +++ ++
327 +++ +++ 328 ++ +++ 329 +++ +++ 330 +++ ++ 331 ++ +++ 332 +++
+++ 333 +++ +++ 334 +++ +++ 335 +++ +++ 336 +++ +++ 337 +++ +++ 338
+++ ++ 339 +++ +++ 340 +++ +++ 341 +++ +++ 342 +++ +++ 343 +++ +++
344 +++ +++ 345 ++ +++ 346 + ++ 347 + ++ 348 ++ +++ 349 +++ +++ 350
+++ +++ 351 +++ +++ 352 + ++ 353 ++ +++ 354 +++ +++ 355 + +++ 356
+++ ++ 357 + ++ 358 ++ +++ 359 + +++ 360 + +++ 361 ++ +++ 362 + +++
363 + +++ 364 ++ +++ 365 + 221.80 366 ++ +++ 367 + +++ 368 + +++
369 ++ +++ 370 + +++ 371 ++ ++ 372 ++ ++ 373 +++ +++ 374 +++ +++
375 +++ +++ 376 ++ +++ 377 + +++ 378 +++ +++ 379 ++ +++ 380 ++ +++
381 +++ +++ 382 +++ +++ 383 ++ +++ 384 ++ +++ 385 +++ +++ 386 ++
+++ 387 + +++ 388 ++ +++ 389 ++ +++ 390 ++ +++ 391 ++ +++ 392 +++
+++ 393 +++ +++ 394 ++ +++ 395 +++ +++ 396 ++ +++ 397 + ++ 398 ++
+++ 399 ++ ++ 400 +++ +++ 401 +++ +++ 402 ++ +++ 403 +++ +++ 404
+++ +++ 405 +++ +++ 406 +++ +++ 407 +++ +++ 408 ++ +++ 409 - - 410
- - 411 - - 412 - -
V. Pharmaceutical Compositions, Formulations and Combinations
[0440] 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.
[0441] 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 patient 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).
[0442] 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 disorder.
[0443] 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.
[0444] 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.
[0445] 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.
[0446] 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.
[0447] 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.
[0448] 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.
[0449] Compounds of the present invention may also be coupled with
soluble polymers as targetable drug carriers. Such polymers can
include polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine
substituted with palmitoyl residues. Furthermore, the compounds of
the present invention may be coupled to a class of biodegradable
polymers useful in achieving controlled release of a drug, for
example, polylactic acid, polyglycolic acid, copolymers of
polylactic and polyglycolic acid, polyepsilon caprolactone,
polyhydroxy butyric acid, polyorthoesters, polyacetals,
polydihydropyrans, polycyanoacylates, and crosslinked or
amphipathic block copolymers of hydrogels.
[0450] 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.
[0451] 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.
[0452] Liquid dosage forms for oral administration can contain
coloring and flavoring to increase patient acceptance.
[0453] In general, water, a suitable oil, saline, aqueous dextrose
(glucose), and related sugar solutions and glycols such as
propylene glycol or polyethylene glycols are suitable carriers for
parenteral solutions. Solutions for parenteral administration
preferably contain a water soluble salt of the active ingredient,
suitable stabilizing agents, and if necessary, buffer substances.
Antioxidizing agents such as sodium bisulfite, sodium sulfite, or
ascorbic acid, either alone or combined, are suitable stabilizing
agents. Also used are citric acid and its salts and sodium EDTA. In
addition, parenteral solutions can contain preservatives, such as
benzalkonium chloride, methyl- or propyl-paraben, and
chlorobutanol.
[0454] 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.
[0455] 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 ROCK.
Such compounds may be provided in a commercial kit, for example,
for use in pharmaceutical research involving ROCK. 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.
[0456] 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 cardiovascular 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 cardiovascular 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.
[0457] 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.
[0458] 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.
[0459] 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).
[0460] 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
[0461] The compounds of the present invention may be synthesized by
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.
[0462] 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.
[0463] 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.
[0464] 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, 4th Edition,
Wiley-Interscience (2006)).
##STR00031##
[0465] Scheme 1 shows the synthesis of generic compounds 1e, 1f,
1g, from the common intermediate 1d. Suzuki-Miyaura coupling
between aryl halide 1a and boronic acid or boronate ester (1b) in
the presence of a base such as K.sub.3PO.sub.4 and a catalyst such
as Pd(PPh.sub.3).sub.4 affords intermediate 1c. Cleavage of the
protecting group, such as using TFA or HCl in dioxane when PG=Boc,
affords the arylamine intermediate 1d. Intermediate 1d is converted
to the urea target 1e by treatment with an isocyanate or a carbamic
chloride. Intermediate 1d is converted to the amide target 1f by
treatment with an acid chloride in the presence of a base such as
pyridine or DIEA. Alternatively, Target 1f is prepared by coupling
of intermediate 1d with a carboxylic acid in the presence of a
coupling reagent, such as HATU or BOP, and a base such as DIEA.
Intermediate 1d is converted to the carbamate target 1g by
treatment with a chloroformate in the presence of a base such as
DIEA or TEA.
##STR00032##
[0466] Alternatively, targets 1e-g can be prepared as shown in
Scheme 2. Aryl halide 2a (commercially available or prepared by
literature methods) is converted to the aryl boronic acid or
boronate ester 2b by coupling with bis(pinacolato)diboron in the
presence of a base such a potassium acetate and a catalyst such as
PdCl.sub.2(dppf) in dioxane or DMSO. Suzuki-Miyaura coupling
between aryl halide 1a and boronic acid or boronate ester (2b) in
the presence of a base such as K.sub.3PO.sub.4 and a catalyst such
as Pd(PPh.sub.3).sub.4 affords target compounds 1e-g.
##STR00033##
[0467] Alternatively, target 1e can be prepared as shown in Scheme
3 beginning from isocyanate 3a, which is either commercially
available or can be prepared from the aniline precursor upon
treatment with phosgene (or equivalent) and an appropriate base
such as TEA. Intermediate 3a is reacted with amine (3b) to afford
urea 3c. Suzuki-Miyaura coupling between aryl halide 1a and boronic
acid or boronate ester (3c) in the presence of a base such as
K.sub.3PO.sub.4 and a catalyst such as Pd(PPh.sub.3).sub.4 affords
target compounds 1e.
##STR00034##
[0468] Scheme 4 shows the synthesis of carbamate target 4e,
beginning from chloroformate 4a (either commercially available or
prepared by treatment of an appropriate halophenol with phosgene or
a phosgene equivalent). Intermediate 4a is reacted with an amine
(4b) in the presence of a base such as TEA to afford carbamate 4c.
Aryl halide 4c is converted to the aryl boronic acid or boronate
ester 4d by coupling with bis(pinacolato)diboron in the presence of
a base such a potassium acetate and a catalyst such as
PdCl.sub.2(dppf) in dioxane or DMSO. Suzuki-Miyaura coupling
between aryl halide 1a and boronic acid or boronate ester (4d) in
the presence of a base such as K.sub.3PO.sub.4 and a catalyst such
as Pd(PPh.sub.3).sub.4 affords target compound 4e.
##STR00035##
[0469] Scheme 5 shows the synthesis of amide target 5e, beginning
with boronic acid/ester 5a, which is either commercially available
or is prepared from the aryl halide precursor. Suzuki-Miyaura
coupling between aryl halide 1a and boronic acid or boronate ester
(5a) in the presence of a base such as K.sub.3PO.sub.4 and a
catalyst such as Pd(PPh.sub.3).sub.4 affords intermediate 5b.
Cleavage of the protecting group (PG) by alkaline hydrolysis (or
other reagents as appropriate) affords carboxylic acid 5c. Coupling
of intermediate 5c with amine 5d in the presence of a coupling
reagent, such as HATU or BOP, and a base such as DIEA affords
target 5e.
##STR00036##
[0470] Scheme 6 shows an alternate synthesis to target 5e beginning
from acid 6a. Coupling of intermediate 6a with amine 6b in the
presence of a coupling reagent, such as HATU or BOP, and a base
such as DIEA affords intermediate amide 6c. Aryl halide 6c is
converted to the aryl boronic acid or boronate ester 6d by coupling
with bis(pinacolato)diboron in the presence of a base such a
potassium acetate and a catalyst such as PdCl.sub.2(dppf) in
dioxane or DMSO. Suzuki-Miyaura coupling between aryl halide 1a and
boronic acid or boronate ester (6d) in the presence of a base such
as K.sub.3PO.sub.4 and a catalyst such as Pd(PPh.sub.3).sub.4
affords target compound 5e.
##STR00037##
[0471] Scheme 7 shows the synthesis of target 7b beginning with
intermediate aniline 1d. Aniline 1d is coupled with heteroaryl
halide 7a under thermal S.sub.NAr conditions in the presence of a
base such as DIEA in a solvent such as DMF to afford 7b.
Alternatively, 1d and 7a may be coupled under Buchwald-Hartwig
N-arylation conditions using a base such as Cs.sub.2CO.sub.3, a
catalyst such as Pd.sub.2(dba).sub.3 and an appropriate ligand to
afford 7b.
##STR00038## ##STR00039##
[0472] Scheme 8 shows an alternative synthesis of target 7b,
beginning from intermediate 8a, which is either commercially
available or can be prepared by literature methods. An appropriate
protecting group is introduced by treatment with a base such as
potassium carbonate and a protecting group reagent such as
para-methoxybenzyl chloride to afford 8b. Treatment of aryl bromide
8b with sodium azide, Cu.sub.2O and a ligand such as proline
affords aniline 8c. Aniline 8c is coupled with heteroaryl halide 7a
under thermal S.sub.NAr conditions in the presence of a base such
as DIEA in a solvent such as DMF to afford intermediate 8d.
Alternatively, 8c and 7a may be coupled under Buchwald-Hartwig
N-arylation conditions using a base such as Cs.sub.2CO.sub.3, a
catalyst such as Pd.sub.2(dba).sub.3 and an appropriate ligand to
afford intermediate 8d. Cleavage of the protecting group under
appropriate conditions (TFA in the case of a para-methoxybenzyl
protecting group) affords target 7b.
##STR00040##
[0473] Scheme 9 shows an alternative synthesis of target 7b,
starting from aryl bromide 8b. Coupling of intermediate 8b with
heteroaryl amine 9a under Buchwald-Hartwig N-arylation conditions
using a base such as Cs.sub.2CO.sub.3, a catalyst such as
Pd.sub.2(dba).sub.3 and an appropriate ligand affords intermediate
8d. Cleavage of the protecting group under appropriate conditions
(TFA in the case of a para-methoxybenzyl protecting group) affords
target 7b.
##STR00041##
[0474] Scheme 10 shows the synthesis of intermediate 1a, where
X.dbd.N. Furan-2,5-dione 10a can be converted to intermediate 10b
by treatment with a reagent such as hydrazine. Intermediate 10b is
chlorinated by treatment with a reagent such as POCl.sub.3 to
afford dichloro intermediate 10c. Partial hydrolysis of 10c with a
reagent such as AcOH affords intermediate 1a.
##STR00042##
[0475] Scheme 11 shows the synthesis of intermediate 1a, where
X.dbd.CR. Intermediate 11a is brominated with a reagent such as NBS
to afford intermediate 1a.
[0476] Purification of intermediates and final products was carried
out via either normal or reverse phase chromatography. Normal phase
chromatography was carried out using prepacked 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% H.sub.2O, 10% MeOH, 0.1% TFA) and Solvent B (10% H.sub.2O, 90%
MeOH, 0.1% TFA, UV 220 nm) or with gradients of Solvent A (90%
H.sub.2O, 10% ACN, 0.1% TFA) and Solvent B (10% H.sub.2O, 90% ACN,
0.1% TFA, UV 220 nm) or with gradients of Solvent A (98% H.sub.2O,
2% ACN, 0.05% TFA) and Solvent B (98% ACN, 2% H.sub.2O, 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 (or) Waters XBridge C18, 19.times.200
mm, 5-.mu.m particles; Guard Column: Waters XBridge C18,
19.times.10 mm, 5-.mu.m particles; Solvent A: water with 20-mM
ammonium acetate; Solvent B: 95:5 acetonitrile:water with 20-mM
ammonium acetate; Gradient: 25-65% B over 20 minutes, then a
5-minute hold at 100% B; Flow: 20 mL/min.
[0477] Unless otherwise stated, analysis of final products was
carried out by reverse phase analytical HPLC.
[0478] Method A:
[0479] SunFire C18 column (3.5 m C18, 3.0.times.150 mm). Gradient
elution (1.0 mL/min) from 10-100% Solvent B over 10 min and then
100% Solvent B for 5 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).
[0480] Method B:
[0481] XBridge Phenyl column (3.5 m C18, 3.0.times.150 mm).
Gradient elution (1.0 mL/min) from 10-100% Solvent B over 10 min
and then 100% Solvent B for 5 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).
[0482] Method C:
[0483] Waters 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: 40.degree. C.; Gradient: 0.5 min hold at 0%
B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow:
1 mL/min.
[0484] Method D:
[0485] Waters BEH C18, 2.1.times.50 mm, 1.7-.mu.m particles; Mobile
Phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile
Phase B: 95:5 methanol:water with 10 mM ammonium acetate;
Temperature: 40.degree. C.; Gradient: 0.5 min hold at 0% B, 0-100%
B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 0.5
mL/min.
[0486] Method E:
[0487] Waters BEH C18, 2.1.times.50 mm, 1.7-.mu.m particles; Mobile
Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B:
95:5 acetonitrile:water with 0.05% TFA; Temperature: 50.degree. C.;
Gradient: 0-100% B over 3 minutes; Flow: 1.11 mL/min.
[0488] Method F:
[0489] Waters 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; Flow: 1.11 mL/min.
Intermediate 1:
2-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)acetic acid
##STR00043##
[0490] Intermediate 1A: Ethyl
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate
##STR00044##
[0492] To a vial containing a degassed (3.times. vacuum/Ar) mixture
of ethyl 2-(4-bromophenyl)acetate (1 g, 4.11 mmol),
bis(pinacolato)diboron (1.25 g, 4.94 mmol), and potassium acetate
(1.21 g, 12.3 mmol) in dioxane (10 mL), was added PdCl.sub.2(dppf)
CH.sub.2Cl.sub.2 adduct (0.090 g, 0.123 mmol). The reaction mixture
was degassed, sealed and heated at 110.degree. C. for 16 h. The
mixture was diluted with water, then extracted with EtOAc. The
organic phase was concentrated and purified via flash
chromatography (EtOAc/hexane) to afford 1.1 g (92%) of Intermediate
1A. MS(ESI) m/z: 291.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.84-7.71 (m, 2H), 7.34-7.28 (m, J=8.0 Hz, 2H),
4.15 (q, J=7.0 Hz, 2H), 3.63 (s, 2H), 1.27 (s, 12H), 1.26-1.22 (m,
3H).
Intermediate 1B: Ethyl
2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)acetate
##STR00045##
[0494] To 4-chlorophthalazin-1(2H)-one (200 mg, 1.11 mmol),
Intermediate 1A (386 mg, 1.33 mmol) and K.sub.3PO.sub.4 (588 mg,
2.77 mmol), were added dioxane (9 mL) and water (1 mL). The mixture
was degassed (evacuated and flushed with Ar (5.times.)).
Pd(PPh.sub.3).sub.4 (64.0 mg, 0.055 mmol) was added, then the
mixture was degassed (2.times.). The reaction vial was sealed and
heated in a microwave reactor at 150.degree. C. for 30 min. The
reaction mixture was concentrated and purified via flash
chromatography (EtOAc/hexane) to afford 218 mg (46%) of
Intermediate 1B. MS(ESI) m/z: 309.1 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 12.84 (s, 1H), 8.46-8.28 (m, 1H),
7.99-7.82 (m, 2H), 7.69 (d, J=7.2 Hz, 1H), 7.59-7.54 (m, 2H), 7.45
(d, J=6.6 Hz, 2H), 4.12 (qd, J=7.1, 1.8 Hz, 2H), 3.79 (s, 2H), 1.22
(td, J=7.0, 1.9 Hz, 3H).
Intermediate 1
##STR00046##
[0496] To a solution of Intermediate 1B (210 mg, 0.681 mmol) in
MeOH (5 mL) and THF (5 mL), was added 1M aq. lithium hydroxide
(3.41 mL, 3.41 mmol). The mixture was stirred rt overnight, then
was concentrated. The residue was acidified with TFA, then was
dissolved in DMSO/MeOH, and purified preparative HPLC to afford 170
mg (89%) of Intermediate 1. MS(ESI) m/z: 281.0 (M+H).sup.+; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 12.83 (s, 1H), 8.42-8.21 (m,
1H), 7.99-7.82 (m, 2H), 7.77-7.62 (m, 1H), 7.59-7.50 (m, 2H),
7.49-7.37 (m, J=8.3 Hz, 2H), 3.69 (s, 2H).
Intermediate 2: 5-((4-Methylpiperazin-1-yl)methyl)isoindoline, 3
TFA
##STR00047##
[0497] Intermediate 2A: tert-Butyl di(prop-2-yn-1-yl)carbamate
##STR00048##
[0499] To a solution of 2-propyn-1-amine and N-2-propynyl- (1.110
mL, 10.74 mmol) in THF (20 mL) at rt, was added BOC.sub.2O (2.58 g,
11.81 mmol). To this mixture was added TEA (0.150 mL, 1.074 mmol).
The mixture was stirred at rt for 14 h. The reaction mixture was
concentrated to an oil. The oil was partitioned between 0.2 N HCl
and EtOAc. The organic phase was washed with H.sub.2O, sat.
NaHCO.sub.3 and brine, dried (Na.sub.2SO.sub.4), filtered through a
1'' pad of SiO.sub.2 and concentrated to afford 2.40 g (100%) of
Intermediate 2A as a yellow oil. MS(ESI) m/z: 216.1 (M+H).sup.+;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.17 (br. s., 4H), 2.22
(t, J=2.4 Hz, 2H), 1.48 (s, 9H).
Intermediate 2B: tert-Butyl
5-(hydroxymethyl)isoindoline-2-carboxylate
##STR00049##
[0501] To a degassed (evacuated and flushed with Ar (5.times.))
solution of prop-2-yn-1-ol (0.961 mL, 16.11 mmol) in toluene (5 mL)
at 50.degree. C., were added in 5 portions at 10 minute intervals
Intermediate 2A (1.20 g, 5.37 mmol) in degassed toluene (5 mL) and
Tris(triphenylphosphine)rhodium(I) chloride (0.124 g, 0.134 mmol).
Following the last addition, the brown mixture was stirred at
50.degree. C. for 1.25 h. The reaction mixture was concentrated,
then was co-evaporated with CHCl.sub.3 (2.times.). The crude
product was purified by flash chromatography (0 to 100% ethyl
acetate/hexanes, eluted at 75% EtOAc) to afford 1.15 g (86% yield)
of Intermediate 2B as a white solid. MS(ESI) m/z: 521.3
(M+H).sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.33-7.21
(m, 3H), 4.63 (dd, J=5.6, 3.2 Hz, 4H), 4.60 (s, 2H), 1.52 (s,
9H).
Intermediate 2C: tert-Butyl
5-(((methylsulfonyl)oxy)methyl)isoindoline-2-carboxylate
##STR00050##
[0503] To a solution of Intermediate 2B (500 mg, 2.006 mmol) in DCM
(10 mL) at 0.degree. C., were added DIEA (0.420 mL, 2.407 mmol) and
Ms-Cl (0.172 mL, 2.206 mmol). The mixture was stirred at 0.degree.
C. for 1.5 h. The mixture was diluted with DCM, then was washed
with half sat. NH.sub.4C.sub.1 and brine. The organic phase was
dried (Na.sub.2SO.sub.4) and concentrated to afford 655 mg (100%)
of Intermediate 2C as a brown oil. The material was used in the
following step without further purification. MS(ESI) m/z: 272.0
(M-t-Bu+2H).sup.+.
Intermediate 2D: tert-Butyl
5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate
##STR00051##
[0505] To a solution of Intermediate 2C (657 mg, 2.007 mmol) in
acetone (10 mL) at rt, were added K.sub.2CO.sub.3 (416 mg, 3.01
mmol) and 1-methyl piperazine (0.556 mL, 5.02 mmol). The mixture
was stirred at rt for 2.5 h, then 1 h at 50.degree. C. The mixture
was concentrated, then was partitioned between EtOAc and H.sub.2O.
The aqueous phase was extracted with EtOAc (2.times.). The combined
organic phase was dried (Na.sub.2SO.sub.4) and concentrated to
afford Intermediate 2D as a brown oil. MS(ESI) m/z: 332.2
(M+H).sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.30-7.21
(m, 3H), 4.63 (dd, J=5.5, 2.0 Hz, 4H), 3.53 (s, 2H), 2.50 (br. s.,
8H), 2.27 (s, 3H), 1.52 (s, 9H).
Intermediate 2
##STR00052##
[0507] Intermediate 2D was treated with 4N HCl in dioxane (5 mL,
20.00 mmol) and the resultant suspension was stirred for 1 h, then
was concentrated. The mixture was redissolved in TFA (10 mL) and
was stirred at rt for 20 min. The mixture was concentrated. The
brown oil was coevaporated with DCM (2.times.), ether, MeOH and
CH.sub.3CN to afford 1.36 g (100% yield, .about.85% purity) of
Intermediate 2 as a brown semisolid, which was used as is without
further purification. MS(ESI) m/z: 232.2 (M+H).sup.+; .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 7.49-7.40 (m, 3H), 4.62 (s, 4H), 3.82
(s, 2H), 3.34 (br. s., 4H), 2.89 (s, 3H), 2.90 (br. s, 4H).
Intermediate 3: 4-(4-Aminophenyl)phthalazin-1(2H)-one, TFA salt
##STR00053##
[0508] Intermediate 3A: tert-Butyl
(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate
##STR00054##
[0510] To 4-chlorophthalazin-1(2H)-one (118 mg, 0.653 mmol),
(4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (170 mg, 0.719
mmol) and potassium phosphate (347 mg, 1.634 mmol), were added
dioxane (9 mL) and water (1 mL). The mixture was degassed
(evacuated and flushed with Ar (5.times.)). Pd(PPh.sub.3).sub.4
(37.8 mg, 0.033 mmol) was added, then the mixture was degassed
(2.times.). The reaction vial was sealed and heated in a microwave
reactor at 150.degree. C. for 35 min. The reaction mixture was
concentrated and purified via flash chromatography to afford 150 mg
(68%) of Intermediate 3A. MS(ESI) m/z: 338.1 (M+H).sup.+.
Intermediate 3
##STR00055##
[0512] To Intermediate 3A (150 mg, 0.445 mmol) in CH.sub.2Cl.sub.2
(3 mL), was added TFA (2 mL). The mixture was stirred rt for 2 h,
then was concentrated. The crude product was purified via flash
chromatography, then preparative HPLC to afford 62 mg (59%) of
Intermediate 3. MS(ESI) m/z: 238.1 (M+H).sup.+; .sup.1H NMR (500
MHz, CD.sub.3OD) .delta. 8.44 (dt, J=4.7, 2.3 Hz, 1H), 7.97-7.87
(m, 2H), 7.81-7.75 (m, 1H), 7.71-7.61 (m, 2H), 7.41-7.30 (m,
2H).
Intermediate 4:
2-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(iso-
indolin-2-yl)ethanone
##STR00056##
[0513] Intermediate 4A:
2-(4-Bromo-2-fluorophenyl)-1-(isoindolin-2-yl)ethanone
##STR00057##
[0515] To 2-(4-bromo-2-fluorophenyl)acetic acid (300 mg, 1.287
mmol), isoindoline (0.161 mL, 1.416 mmol), and HATU (587 mg, 1.545
mmol) in DMF (5 mL), was added DIEA (0.450 mL, 2.57 mmol). The
mixture was stirred at rt for 1 h. The resultant heterogeneous
mixture was diluted with EtOAc, then was washed with H.sub.2O, 1 N
HCl, H.sub.2O, sat. NaHCO.sub.3 and brine. The organic phase was
dried (Na.sub.2SO.sub.4), filtered and concentrated. The crude
product was purified by flash chromatography (gradient from 0 to
100% ethyl acetate/hexanes) to afford 147 mg (34%) of Intermediate
4A as a white solid. MS(ESI) m/z: 333.9 (M+H).sup.+; .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.34-7.30 (m, 3H), 7.30-7.22 (m, 4H),
4.89 (s, 2H), 4.83 (s, 2H), 3.73 (s, 2H)
Intermediate 4
##STR00058##
[0517] To a mixture of Intermediate 4A (146 mg, 0.437 mmol),
bis(pinacolato)diboron (133 mg, 0.524 mmol), and potassium acetate
(129 mg, 1.31 mmol) in a reaction vial, was added dioxane (3 mL).
The mixture was degassed (evacuated and flushed with Ar
(3.times.)). PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 adduct (9.6 mg,
0.013 mmol) was added, then reaction mixture was degassed (3.times.
vacuum/Ar). The vial was sealed, then was heated at 110.degree. C.
for 2 h. The reaction mixture was diluted with EtOAc, then was
washed with H.sub.2O and brine. The organic phase was dried
(Na.sub.2SO.sub.4) and concentrated. The crude product was purified
by flash chromatography (gradient from 0 to 50% ethyl
acetate/hexanes) to afford 120 mg (72%) of Intermediate 4 as a
yellow solid. MS(ESI) m/z: 386.1 (M+H).sup.+; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.55 (dd, J=7.5, 0.9 Hz, 1H), 7.50 (d, J=10.1
Hz, 1H), 7.39 (t, J=7.4 Hz, 1H), 7.32-7.22 (m, 4H), 4.84 (s, 4H),
3.80 (s, 2H), 1.33 (s, 12H).
Intermediate 5:
2-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(iso-
indolin-2-yl)ethanone
##STR00059##
[0518] Intermediate 5A:
2-(4-Bromo-3-fluorophenyl)-1-(isoindolin-2-yl)ethanone
##STR00060##
[0520] To a mixture of 2-(4-bromo-3-fluorophenyl)acetic acid (300
mg, 1.287 mmol), isoindoline (0.161 mL, 1.416 mmol), and HATU (734
mg, 1.931 mmol) in DMF (5 mL), was add DIEA (0.450 mL, 2.6 mmol).
The mixture was stirred rt for 18 h. The reaction mixture was
diluted with EtOAc, then was washed with H.sub.2O, 1 N HCl,
H.sub.2O, sat. Na.sub.2CO.sub.3 and brine. The organic phase was
dried (Na.sub.2SO.sub.4), filtered through a 1'' pad of SiO.sub.2
and concentrated. The crude product was purified by flash
chromatography (gradient from 0 to 100% ethyl acetate/hexanes) to
afford 379 mg (88%) of Intermediate 5A as an off-white solid.
MS(ESI) m/z: 333.9 (M+H).sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.50 (dd, J=8.0, 7.4 Hz, 1H), 7.33-7.22 (m, 4H), 7.14 (dd,
J=9.2, 2.0 Hz, 1H), 7.01 (dd, J=8.5, 1.9 Hz, 1H), 4.83 (s, 4H),
3.72 (s, 2H).
Intermediate 5
##STR00061##
[0522] To a mixture of Intermediate 5A (200 mg, 0.598 mmol),
bis(pinacolato)diboron (182 mg, 0.718 mmol), and potassium acetate
(176 mg, 1.80 mmol) in a reaction vial, was added dioxane (5 mL).
The mixture was degassed (evacuated and flushed with Ar
(3.times.)). PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 adduct (13 mg, 0.018
mmol) was added, then the reaction mixture was degassed (3.times.
vacuum/Ar). The vial was sealed, then was heated at 110.degree. C.
for 2 h. Additional catalyst (13 mg) was added and the reaction
mixture was stirred at 110.degree. C. for 2 more hours. The
reaction mixture was cooled to room temperature, then was filtered
and concentrated. The crude product was purified by flash
chromatography (gradient from 0 to 100% ethyl acetate/hexanes) to
afford 208 mg (91%) of Intermediate 5 as a yellow solid. MS(ESI)
m/z: 386.1 (M+H).sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.71 (t, J=6.9 Hz, 1H), 7.35-7.20 (m, 4H), 7.13 (d, J=7.5 Hz, 1H),
7.04 (d, J=10.1 Hz, 1H), 4.83 (s, 2H), 4.77 (s, 2H), 3.78 (s, 2H),
1.35 (s, 12H).
Intermediate 6: 4-Bromoisoquinolin-1(2H)-one
##STR00062##
[0524] To a solution of isoquinolin-1(2H)-one (105 mg, 0.723 mmol)
in DMF (2 mL), was added NBS (142 mg, 0.796 mmol). The mixture was
stirred at rt for 2 h, then was concentrated. The crude product was
purified via preparative HPLC to afford 110 mg (68%) of
Intermediate 6. MS(ESI) m/z: 223.9 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 11.57 (br. s., 1H), 8.24 (dd, J=8.0, 0.8
Hz, 1H), 7.88-7.83 (m, 1H), 7.79-7.75 (m, 1H), 7.61 (ddd, J=8.0,
7.1, 1.1 Hz, 1H), 7.55 (s, 1H).
Intermediate 7: 2-(4-Bromophenyl)-1-(isoindolin-2-yl)ethanone
##STR00063##
[0526] To a mixture of 2-(4-bromophenyl)acetic acid (300 mg, 1.395
mmol), isoindoline (183 mg, 1.535 mmol), and HATU (796 mg, 2.093
mmol) in DMF (5 mL), was add DIEA (0.487 mL, 2.79 mmol). The
mixture was stirred at rt overnight. The reaction mixture was
quenched with water, then extracted with EtOAc. The organic phase
was washed with 10% LiCl, brine, and concentrated. The residue was
purified via flash chromatography (EtOAc/hexane) to afford 390 mg
(88%) of Intermediate 7. MS(ESI) m/z: 316.0 (M+H).sup.+.
Intermediate 8: (4-(2-(Isoindolin-2-yl)acetyl)phenyl)boronic
acid
##STR00064##
[0528] A mixture of Intermediate 7 (30 mg, 0.095 mmol),
bis(pinacolato)diboron (24 mg, 0.095 mmol), and potassium acetate
(27.9 mg, 0.285 mmol) in dioxane (1 mL) was degassed (3.times.
vacuum/Ar). Then PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 adduct (2.083
mg, 2.85 .mu.mol) was added, the reaction mixture was degassed
again (3.times. vacuum/Ar), sealed in a vial and heated at
110.degree. C. for 2 h. The reaction was purified via preparative
HPLC to afford 14 mg (53%) of Intermediate 8. MS(ESI) m/z: 282.1
(M+H).sup.+.
Intermediate 9:
1-(Isoindolin-2-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
nyl)ethanone
##STR00065##
[0530] According to a procedure similar to the preparation of
Intermediate 8, Intermediate 7 (400 mg, 1.27 mmol) afforded after
flash chromatography (0 to 60% EtOAc/hexane gradient) 406 mg (88%)
of Intermediate 9. MS(ESI) m/z: 364.1 (M+H).sup.+; .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 7.82-7.77 (m, J=8.3 Hz, 2H), 7.39-7.33 (m,
J=8.0 Hz, 2H), 7.27 (d, J=0.6 Hz, 3H), 7.27-7.24 (m, 1H), 7.20 (d,
J=6.6 Hz, 1H), 4.84 (s, 2H), 4.77 (s, 2H), 3.81 (s, 2H), 1.38-1.31
(m, 12H).
Intermediate 10:
N-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)indoline-1-carbo-
xamide
##STR00066##
[0531] Intermediate 10A:
N-(4-Bromophenyl)indoline-1-carboxamide
##STR00067##
[0533] A mixture of 1-bromo-4-isocyanatobenzene (300 mg, 1.515
mmol) and indoline (199 mg, 1.667 mmol) in CH.sub.2Cl.sub.2 (5 mL)
was stirred at rt 1 h. The reaction mixture was diluted with EtOAc
(100 mL), then was washed with 1 N HCl, sat. Na.sub.2CO.sub.3, and
brine. The organic phase was dried over Na.sub.2SO.sub.4, then
concentrated. The residue was purified by flash chromatography
(0-60% EtOAc/hexane gradient) to afford 470 mg (98%) of
Intermediate 10A as a yellow foam. MS(ESI) m/z: 317.0 (M+H).sup.+;
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.88 (d, J=8.0 Hz, 1H),
7.49-7.42 (m, 2H), 7.41-7.35 (m, 2H), 7.22-7.17 (m, 2H), 6.99 (td,
J=7.4, 1.1 Hz, 1H), 6.47 (br. s., 1H), 4.15-4.05 (m, 2H), 3.25 (t,
J=8.5 Hz, 2H).
Intermediate 10
##STR00068##
[0535] To a mixture of Intermediate 10A (470 mg, 1.482 mmol),
bis(pinacolato)diboron (452 mg, 1.778 mmol), and potassium acetate
(436 mg, 4.45 mmol) in dioxane (20 mL), was added PdCl.sub.2(dppf)
CH.sub.2Cl.sub.2 adduct (32.5 mg, 0.044 mmol). The reaction mixture
was degassed (3.times. vacuum/Ar), sealed in a vial and heated at
110.degree. C. for 3 h. The reaction was quenched with water,
extracted with EtOAc (2.times.30 mL). The combined organic layer
was washed with brine, dried (Na.sub.2SO.sub.4) and concentrated.
The residue was purified by flash chromatography (0-60%
EtOAc/hexane gradient) to afford 430 mg (80%) of Intermediate 10 as
a white solid. MS(ESI) m/z: 365.1 (M+H).sup.+; .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 7.89 (d, J=8.0 Hz, 1H), 7.81-7.77 (m,
J=8.3 Hz, 2H), 7.52-7.48 (m, 2H), 7.23-7.18 (m, 2H), 7.01-6.94 (m,
1H), 6.56 (s, 1H), 4.17-4.04 (m, 2H), 3.25 (t, J=8.5 Hz, 2H),
1.39-1.32 (m, 12H).
Intermediate 11:
2-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)propanoic acid
##STR00069##
[0536] Intermediate 11A: Ethyl 2-(4-bromophenyl)propanoate
##STR00070##
[0538] To a solution of ethyl 2-(4-bromophenyl)acetate (150 mg,
0.617 mmol) in THF (3 mL) at -78.degree. C., was added 1.5M LDA
(0.514 mL, 0.926 mmol). The mixture was stirred at -78.degree. C.
for 20 min, then iodomethane (175 mg, 1.23 mmol) was added. The
solution was allowed to warm to rt and stirred overnight. The
reaction mixture was concentrated and the residue was purified by
flash chromatography (0-20% EtOAc/hexane gradient) to afford 120 mg
(76%) of Intermediate 11A as a yellow oil. MS(ESI) m/z: 257.0
(M+H).sup.+; .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.47-7.42
(m, 2H), 7.21-7.16 (m, 2H), 4.12 (dddd, J=17.6, 10.4, 7.1, 3.7 Hz,
2H), 3.67 (q, J=7.3 Hz, 1H), 1.48 (d, J=7.2 Hz, 3H), 1.21 (t, J=7.2
Hz, 3H).
Intermediate 11B: Ethyl
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate
##STR00071##
[0540] To a mixture of Intermediate 11A (120 mg, 0.467 mmol),
bis(pinacolato)diboron (142 mg, 0.56 mmol), and potassium acetate
(137 mg, 1.40 mmol) in dioxane (4 mL), was added PdCl.sub.2(dppf)
CH.sub.2Cl.sub.2 adduct (10 mg, 0.014 mmol). The reaction mixture
was degassed (3.times. vacuum/Ar), sealed and heated at 110.degree.
C. for 16 h. The reaction mixture was concentrated and the residue
was purified by flash chromatography (0-30% EtOAc/hexane gradient)
to afford 120 mg (85%) of Intermediate 11B as a yellow oil. MS(ESI)
m/z: 327.2 (M+H).sup.+; .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
7.81-7.75 (m, J=8.3 Hz, 2H), 7.35-7.29 (m, J=8.0 Hz, 2H), 4.11
(dddd, J=17.8, 10.6, 7.1, 3.6 Hz, 2H), 3.77-3.66 (m, 1H), 1.49 (d,
J=7.2 Hz, 3H), 1.37-1.30 (m, 12H), 1.19 (t, J=7.2 Hz, 3H).
Intermediate 11C: Ethyl
2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propanoate
##STR00072##
[0542] To 4-chlorophthalazin-1(2H)-one (70 mg, 0.388 mmol),
Intermediate 11B (118 mg, 0.388 mmol) and potassium phosphate (206
mg, 0.969 mmol), were added dioxane (3 mL) and water (0.333 mL).
The mixture was degassed (evacuated and flushed with Ar
(5.times.)). Pd(PPh.sub.3).sub.4 (22.40 mg, 0.019 mmol) was added,
then the mixture was degassed (2.times.). The reaction vial was
sealed and heated in a microwave reactor at 150.degree. C. for 30
min. The reaction mixture was concentrated and the residue was
purified by flash chromatography (0-80% EtOAc/hexane gradient) to
afford 100 mg (80%) of Intermediate 11C as a yellow foam. MS(ESI)
m/z: 323.1 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
12.84 (s, 1H), 8.41-8.31 (m, 1H), 7.98-7.84 (m, 2H), 7.70 (d, J=7.7
Hz, 1H), 7.57 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 4.20-4.02
(m, 2H), 3.91 (d, J=6.9 Hz, 1H), 1.46 (d, J=7.2 Hz, 3H), 1.17 (t,
J=7.0 Hz, 3H).
Intermediate 11
##STR00073##
[0544] To a solution of Intermediate 11C (100 mg, 0.310 mmol) in
THF (3 mL), was added 1M LiOH (0.620 mL, 0.620 mmol). The mixture
was stirred at rt for 3 h, then was concentrated. The residue was
purified via preparative HPLC to afford 90 mg (99%) of Intermediate
11 as a white solid. MS(ESI) m/z: 295.1 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 12.83 (s, 1H), 8.42-8.23 (m, 1H),
7.99-7.82 (m, 2H), 7.78-7.66 (m, 1H), 7.61-7.52 (m, J=8.0 Hz, 2H),
7.50-7.40 (m, J=8.0 Hz, 2H), 3.80 (q, J=7.2 Hz, 1H), 1.44 (d, J=6.9
Hz, 3H).
Intermediate 12:
6-Methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)indoli-
ne-1-carboxamide
##STR00074##
[0545] Intermediate 12A:
N-(4-Bromophenyl)-6-methoxyindoline-1-carboxamide
##STR00075##
[0547] 1-Bromo-4-isocyanatobenzene (146 mg, 0.737 mmol) was mixed
with 6-methoxyindoline (110 mg, 0.737 mmol) in DCM (3 mL), and
stirred rt 2 h. The reaction mixture was diluted with EtOAc (100
mL), then was washed with 1 N HCl, sat Na.sub.2CO.sub.3, and brine,
dried (Na.sub.2SO.sub.4), and concentrated. The residue was
purified by flash chromatography (gradient 0-50% EtOAc/Hex) to
afford Intermediate 12A (230 mg, 0.662 mmol, 90% yield) as a purple
solid. MS(ESI) m/z: 346.9 (M+H).sup.+; .sup.1H NMR (500 MHz,
chloroform-d) .delta. 7.58 (d, J=2.2 Hz, 1H), 7.43-7.34 (m, 2H),
7.34-7.28 (m, 2H), 7.02 (d, J=8.3 Hz, 1H), 6.60 (br. s., 1H), 6.50
(dd, J=8.1, 2.3 Hz, 1H), 3.98 (t, J=8.5 Hz, 2H), 3.82-3.72 (m, 3H),
3.07 (t, J=8.4 Hz, 2H).
Intermediate 12
##STR00076##
[0549] To a mixture of Intermediate 12A (230 mg, 0.662 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (202
mg, 0.795 mmol), and potassium acetate (195 mg, 1.99 mmol) in
dioxane (20 mL), was added PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 adduct
(14.5 mg, 0.020 mmol). The reaction mixture was degassed (3.times.
vacuum/Ar), sealed in a vial and heated at 110.degree. C. for 3 h.
The mixture was diluted with water, extracted with EtOAc
(2.times.30 mL). The combined organic layer was washed with brine,
dried (Na.sub.2SO.sub.4) and concentrated. The residue was by flash
chromatography (gradient 0-60% EtOAc/Hex) to afford Intermediate 12
(230 mg, 88% yield) as a white solid. MS(ESI) m/z: 395.1
(M+H).sup.+.
Intermediate 13:
4-(4-Bromophenyl)-2-(4-methoxybenzyl)phthalazin-1(2H)-one
##STR00077##
[0551] 4-(4-Bromophenyl)phthalazin-1(2H)-one (1.50 g, 4.98 mmol),
K.sub.2CO.sub.3 (1.38 g, 9.96 mmol) and dry DMF (25 mL) were added
into a round bottom flask. To the above mixture,
1-(chloromethyl)-4-methoxybenzene (1.35 mL, 9.96 mmol) was added
dropwise with stirring at rt over 5 min. Then, the reaction mixture
was stirred at 50.degree. C. for 2 h. The reaction mixture was
cooled to rt, diluted with water (150 mL) and EtOAc (250 mL). The
organic phase was separated, washed with water (3.times.100 mL),
brine (1.times.50 mL), and dried (Na.sub.2SO.sub.4). EtOAc was
removed under reduced pressure and the residue was purified by
flash chromatography (0-50% EtOAc/Hex). The material was
recrystallized from hexanes/EtOAc (7:3; .about.100 mL), washed with
hexanes and dried to afford Intermediate 13 (1.39 g, 66.2% yield)
as a white solid. MS(ESI) m/z: 421.0 (M+H).sup.+; .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. ppm 8.56-8.49 (m, 1H), 7.75 (quind, J=7.4,
1.3 Hz, 2H), 7.69-7.62 (m, 3H), 7.47 (t, J=7.9 Hz, 4H), 6.85 (d,
J=8.6 Hz, 2H), 5.39 (s, 2H), 3.77 (s, 3H).
Intermediate 14:
4-(4-Aminophenyl)-2-(4-methoxybenzyl)phthalazin-1(2H)-one
##STR00078##
[0553] Intermediate 13 (0.500 g, 1.187 mmol), L-proline (0.178 g,
1.543 mmol), and cuprous oxide (0.170 g, 1.19 mmol) were placed
into a 20 mL pressure vial, and DMSO (8 mL) was added. The reaction
mixture was degassed with stirring (3.times. vacuum/Ar), and sodium
azide (0.154 g, 2.37 mmol) was added. The reaction mixture was
degassed again (2.times. vacuum/Ar), and stirred under Ar at
100.degree. C. for 5 h. The reaction mixture was quenched with sat.
NH.sub.4C.sub.1, diluted with EtOAc (200 mL) and water (100 mL).
Organic phase was washed with sat. Na.sub.2CO.sub.3 (2.times.),
water, brine, dried (Na.sub.2SO.sub.4) and concentrated. The
product was purified via flash chromatography (0-80% EtOAc/Hex) to
afford Intermediate 14 (0.386 g, 91% yield) as an off-white solid.
MS(ESI) m/z: 421.0 (M+H).sup.+; .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. ppm 8.54-8.46 (m, 1H), 7.84-7.77 (m, 1H), 7.77-7.66 (m,
2H), 7.50 (d, J=8.6 Hz, 2H), 7.41-7.35 (m, 2H), 6.85 (d, J=8.6 Hz,
2H), 6.80 (d, J=8.6 Hz, 2H), 5.40 (s, 2H), 5.30 (s, 2H), 3.77 (s,
3H)
Intermediate 15:
1-(2-Hydroxy-2-methylpropyl)-1H-indazole-3-carboxylic acid
##STR00079##
[0554] Intermediate 15A: Ethyl
1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxylate
##STR00080##
[0556] To a vial containing ethyl 1H-indazole-3-carboxylate (75 mg,
0.39 mmol) and 2,2-dimethyloxirane (0.088 mL, 0.99 mmol), was added
acetonitrile (1.5 mL). To this mixture was added Cs.sub.2CO.sub.3
(193 mg, 0.591 mmol). The vial was sealed and the mixture was
stirred at 90.degree. C. for 2.5 h. The reaction mixture was
partitioned between EtOAc and H.sub.2O. The aqueous phase was
extracted with EtOAc. The combined organic phase was washed with
brine, dried (Na.sub.2SO.sub.4) and concentrated. The crude product
was purified by flash chromatography (gradient from 0 to 100% ethyl
acetate/hexanes) to afford Intermediate 15A (45 mg, 43.5% yield) as
a colorless oil. MS(ESI) m/z: 263.1 (M+H).sup.+; .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.24 (dt, J=8.3, 0.9 Hz, 1H), 7.58-7.52
(m, 1H), 7.50-7.43 (m, 1H), 7.32 (ddd, J=8.0, 6.9, 0.9 Hz, 1H),
4.52 (q, J=7.2 Hz, 2H), 4.45 (s, 2H), 2.73 (s, 1H), 1.48 (t, J=7.2
Hz, 3H), 1.26 (s, 6H).
Intermediate 15
##STR00081##
[0558] To a solution of Intermediate 15A (45 mg, 0.17 mmol) in THF
(1 mL), was added 1M aq. LiOH (0.20 mL, 0.20 mmol), followed by
MeOH (0.3 mL). The homogeneous mixture was stirred at rt for 1.5 h.
Additional 1M aq. LiOH (0.1 mL, 0.1 mmol) was added and the mixture
was stirred at rt for 14 h. The reaction mixture was partially
evaporated to remove volatile solvents. The solution was diluted
with H.sub.2O, then was acidified with 1 N HCl (.about.0.3 mL). The
aqueous phase was extracted with EtOAc (3.times.). The combined
organic phase was washed with brine, dried (Na.sub.2SO.sub.4) and
concentrated to afford Intermediate 15 (40 mg, 100% yield) as an
off-white solid. MS(ESI) m/z: 235.1 (M+H).sup.+; .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.27 (d, J=8.1 Hz, 1H), 7.59 (d, J=8.4
Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.41-7.31 (m, 1H), 4.48 (s, 2H),
1.30 (s, 6H).
Intermediate 16:
1-(2-Hydroxy-2-methylpropyl)-1H-indole-3-carboxylic acid
##STR00082##
[0559] Intermediate 16A: Methyl
1-(2-hydroxy-2-methylpropyl)-1H-indole-3-carboxylate
##STR00083##
[0561] To a vial containing methyl 1H-indole-3-carboxylate (200 mg,
1.14 mmol) and 2,2-dimethyloxirane (0.254 mL, 2.85 mmol), was added
acetonitrile (3 mL). To this mixture was added Cs.sub.2CO.sub.3
(558 mg, 1.71 mmol). The vial was sealed and the mixture was
stirred at 90.degree. C. for 2.5 h. The reaction mixture was
partitioned between EtOAc and H.sub.2O. The aqueous phase was
extracted with EtOAc. The combined organic phase was washed with
brine, dried (Na.sub.2SO.sub.4) and concentrated. The crude product
was purified by flash chromatography (gradient from 0 to 100% ethyl
acetate/hexanes) to afford Intermediate 16A (274 mg, 1.108 mmol,
97% yield) white solid. MS(ESI) m/z: 248.1 (M+H).sup.+; .sup.1H NMR
(400 MHz, chloroform-d) .delta. 8.26-8.11 (m, 1H), 7.91 (s, 1H),
7.49-7.38 (m, 1H), 7.31-7.23 (m, 2H), 4.13 (s, 2H), 3.91 (s, 3H),
1.48 (s, 1H), 1.29 (s, 6H).
Intermediate 16
##STR00084##
[0563] To a solution of Intermediate 16A (272 mg, 1.10 mmol) in THF
(5 mL), was added 1M aq. LiOH (1.2 mL, 1.2 mmol), followed by MeOH
(1 mL). The homogeneous mixture was stirred at rt for 1.5 h.
Additional 1M aq. LiOH (1.0 mL, 1.0 mmol) was added and the mixture
was stirred at rt for 14 h. The reaction mixture was heated at
50.degree. C. for 24 h, then at 60.degree. C. for 9 h. The reaction
mixture was partially concentrated to remove the organic solvent.
The partially insoluble mixture was diluted with H.sub.2O and was
washed with Et.sub.2O. The organic phase was extracted with
H.sub.2O (2.times.). The combined aqueous phase was acidified to pH
3 with 1 N HCl, then was extracted with EtOAc (3.times.). The
combined organic phase was washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated to afford Intermediate 16 (255
mg, 99% yield) as an off-white solid. MS(ESI) m/z: 234.1
(M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.27-8.20
(m, 1H), 8.01 (s, 1H), 7.49-7.42 (m, 1H), 7.34-7.26 (m, 2H), 4.15
(s, 2H), 1.30 (s, 6H).
Intermediate 17:
1-(2-(Dimethylamino)ethyl)-1H-indazole-3-carboxylic acid
##STR00085##
[0564] Intermediate 18:
2-(2-(Dimethylamino)ethyl)-2H-indazole-3-carboxylic acid
##STR00086##
[0565] Intermediate 17A: Methyl
1-(2-(dimethylamino)ethyl)-1H-indazole-3-carboxylate
Intermediate 17B: Methyl
2-(2-(dimethylamino)ethyl)-2H-indazole-3-carboxylate
##STR00087##
[0567] In a sealed tube, ethyl 1H-indazole-3-carboxylate (50 mg,
0.263 mmol) mixed with 2-bromo-N,N-dimethylethanamine (120 mg,
0.789 mmol), K.sub.2CO.sub.3 (182 mg, 1.314 mmol) in DMF (5 mL),
stirred 80.degree. C. o/n. Concentrated and purified by prep HPLC.
Two fractions were collected, 1st fraction concentrated to afford
Intermediate 17A (29 mg, 45% yield) as a white solid. MS(ESI) m/z:
248.1 (M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.21
(d, J=8.4 Hz, 1H), 7.65-7.59 (m, 1H), 7.58-7.52 (m, 1H), 7.43-7.36
(m, 1H), 4.96 (t, J=6.4 Hz, 2H), 4.06 (s, 3H), 3.81 (t, J=6.4 Hz,
2H), 2.88 (s, 6H).
[0568] 2nd fraction concentrated to afford Intermediate 17B (19 mg,
29% yield) as a white solid. MS(ESI) m/z: 248.1 (M+H).sup.+;
.sup.1H NMR (400 MHz, chloroform-d) .delta. 8.00 (d, J=8.4 Hz, 1H),
7.74 (d, J=8.8 Hz, 1H), 7.44-7.38 (m, 1H), 7.38-7.29 (m, 1H), 5.35
(t, J=6.1 Hz, 2H), 4.06 (s, 3H), 3.80 (t, J=6.1 Hz, 2H), 3.00 (s,
6H).
Intermediate 17
##STR00088##
[0570] Intermediate 17A (28 mg, 0.113 mmol), dissolved in THF (2
mL), add 1M lithium hydroxide (0.283 mL, 0.283 mmol), stirred rt
o/n. Concentrated and acidified with TFA, dissolved in ACN,
purified via prep HPLC to afford Intermediate 17 (23 mg, 87%
yield). MS(ESI) m/z: 234.1 (M+H).sup.+; .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 8.20 (dt, J=8.3, 0.9 Hz, 1H), 7.79-7.73
(m, 1H), 7.57 (ddd, J=8.5, 7.2, 1.1 Hz, 1H), 7.40 (ddd, J=8.1, 7.1,
0.9 Hz, 1H), 4.97-4.91 (m, 2H), 3.89-3.81 (m, 2H), 3.04 (s,
6H).
Intermediate 18
##STR00089##
[0572] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 17b (19 mg) with lithium
hydroxide afforded Intermediate 18 (16 mg, 89%). MS(ESI) m/z:
234.1; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.10 (dt,
J=8.5, 1.0 Hz, 1H), 7.76 (dt, J=8.7, 0.9 Hz, 1H), 7.41 (ddd, J=8.6,
6.7, 1.2 Hz, 1H), 7.34-7.28 (m, 1H), 5.38-5.32 (m, 2H), 3.89-3.81
(m, 2H), 3.02 (s, 6H).
Intermediate 19: 2-(Oxetan-3-ylmethyl)-2H-indazole-3-carboxylic
acid
##STR00090##
[0573] Intermediate 20:
1-(Oxetan-3-ylmethyl)-1H-indazole-3-carboxylic acid
##STR00091##
[0574] Intermediate 19A: Ethyl
2-(oxetan-3-ylmethyl)-2H-indazole-3-carboxylate
Intermediate 19B: Ethyl
1-(oxetan-3-ylmethyl)-1H-indazole-3-carboxylate
##STR00092##
[0576] To a vial containing ethyl 1H-indazole-3-carboxylate (50 mg,
0.263 mmol) in acetonitrile (2 mL), were added
3-(bromomethyl)oxetane (59.5 mg, 0.394 mmol) and Cs.sub.2CO.sub.3
(128 mg, 0.394 mmol). The vial was sealed and the mixture was
stirred at 90.degree. C. for 3 h. Add DCM, filtered, concentrated
and the residue was loaded onto 10 g column, eluted with EtOAc/Hex
(0-60%); collected 1st peak at 20% EtOAc, concentrated to afford
Intermediate 19A (27 mg, 40% yield). MS(ESI) m/z: 261.1
(M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.03 (dt,
J=8.4, 1.2 Hz, 1H), 7.77 (dt, J=8.5, 1.0 Hz, 1H), 7.40-7.33 (m,
1H), 7.33-7.28 (m, 1H), 5.24 (d, J=7.3 Hz, 2H), 4.81 (dd, J=7.9,
6.4 Hz, 2H), 4.67 (t, J=6.3 Hz, 2H), 4.50 (q, J=7.0 Hz, 2H),
3.80-3.64 (m, 1H), 1.51 (t, J=7.0 Hz, 3H).
[0577] Collected 2nd peak at 35% EtOAc was concentrated to afford
Intermediate 19B. (30 mg, 44% yield). MS(ESI) 261.1 (M+H).sup.+;
.sup.1H NMR (400 MHz, chloroform-d) .delta. 8.23 (dt, J=8.3, 0.9
Hz, 1H), 7.54-7.44 (m, 2H), 7.33 (ddd, J=8.1, 6.7, 1.2 Hz, 1H),
4.85-4.76 (m, 4H), 4.59-4.55 (m, 2H), 4.54-4.48 (m, 2H), 3.70 (tt,
J=7.5, 5.8 Hz, 1H), 1.48 (t, J=7.2 Hz, 3H).
Intermediate 19
##STR00093##
[0579] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 19a (27 mg) with lithium
hydroxide afforded Intermediate 19 (24 mg, 99%). MS(ESI) 233.1
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.39
(dt, J=8.6, 1.0 Hz, 1H), 7.91-7.87 (m, 2H), 7.65 (ddd, J=8.5, 5.4,
2.3 Hz, 1H), 5.18 (dd, J=14.1, 8.4 Hz, 1H), 4.97 (dd, J=13.9, 5.3
Hz, 1H), 4.90 (dd, J=11.6, 8.3 Hz, 1H), 4.69 (dd, J=11.6, 5.2 Hz,
1H), 3.86 (d, J=5.3 Hz, 2H), 3.69 (tt, J=8.3, 5.3 Hz, 1H).
Intermediate 20
##STR00094##
[0581] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 19b (30 mg) with lithium
hydroxide afforded Intermediate 20 (22 mg, 82%). MS(ESI) 233.1
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.15
(dt, J=8.2, 1.0 Hz, 1H), 7.71 (dt, J=8.5, 0.8 Hz, 1H), 7.49 (ddd,
J=8.5, 7.2, 1.1 Hz, 1H), 7.32 (ddd, J=8.1, 7.1, 0.9 Hz, 1H),
4.93-4.85 (m, 2H), 4.61 (t, J=6.2 Hz, 2H), 3.76-3.60 (m, 1H).
Intermediate 21:
1-((1-((Benzyloxy)carbonyl)piperidin-4-yl)methyl)-1H-indazole-3-carboxyli-
c acid
##STR00095##
[0582] Intermediate 21A: Methyl
1-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)-1H-indazole-3-carboxyla-
te
##STR00096##
[0584] To a vial containing ethyl 1H-indazole-3-carboxylate (100
mg, 0.526 mmol) in acetonitrile (5 mL), were added benzyl
4-(bromomethyl)piperidine-1-carboxylate (246 mg, 0.789 mmol) and
Cs.sub.2CO.sub.3 (257 mg, 0.789 mmol). The vial was sealed and the
mixture was stirred at 90.degree. C. for 12 h. Concentrated and
purified by prep HPLC. Two fractions were collected, 1st fraction
concentrated to afford Intermediate 21a (80 mg, 37% yield) as a
white solid. MS(ESI) 408.1 (M+H).sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. 9.62 (br. s., 1H), 8.24 (dt, J=8.1, 0.9 Hz,
1H), 7.51-7.43 (m, 2H), 7.40-7.30 (m, 6H), 5.17-5.10 (m, 2H), 4.36
(d, J=7.3 Hz, 2H), 4.30-4.15 (m, 2H), 4.06 (s, 3H), 2.86-2.66 (m,
2H), 2.30 (ddt, J=15.4, 7.8, 3.8 Hz, 1H), 1.67-1.50 (m, 2H), 1.30
(qd, J=12.4, 4.1 Hz, 2H).
Intermediate 21
##STR00097##
[0586] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 21A (80 mg) with lithium
hydroxide afforded Intermediate 21 (46 mg, 60%). MS(ESI) 394.1
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.15
(dt, J=8.2, 1.0 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.46 (ddd, J=8.4,
7.0, 1.1 Hz, 1H), 7.34-7.24 (m, 6H), 4.87 (br. s., 2H), 4.38 (d,
J=7.3 Hz, 2H), 4.11 (d, J=13.6 Hz, 2H), 2.76 (br. s., 2H), 2.25
(ddt, J=15.2, 7.7, 3.9 Hz, 1H), 1.52 (d, J=11.4 Hz, 2H), 1.25 (qd,
J=12.4, 4.4 Hz, 2H).
Intermediate 22:
1-((Tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-3-carboxylic
acid
##STR00098##
[0587] Intermediate 22A: Methyl
1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-3-carboxylate
##STR00099##
[0589] To a vial containing ethyl 1H-indazole-3-carboxylate (150
mg, 0.789 mmol) in DMF (2 mL), were added
4-(bromomethyl)tetrahydro-2H-pyran (212 mg, 1.18 mmol) and
Cs.sub.2CO.sub.3 (385 mg, 1.18 mmol). The vial was sealed and the
mixture was stirred at 90.degree. C. for 3 h. The reaction mixture
was concentrated and purified by prep HPLC. Two fractions were
collected, 1 st fraction was concentrated to afford Intermediate
22A (76 mg, 35% yield) as a white solid. MS(ESI) 275.1 (M+H).sup.+;
.sup.1H NMR (400 MHz, chloroform-d) .delta. 8.23 (dt, J=8.3, 0.9
Hz, 1H), 7.50-7.47 (m, 2H), 7.34 (ddd, J=8.1, 4.6, 3.2 Hz, 1H),
4.37 (d, J=7.5 Hz, 2H), 4.09-3.99 (m, 5H), 3.47-3.33 (m, 2H),
2.46-2.30 (m, 1H), 1.55-1.45 (m, 4H).
Intermediate 22
##STR00100##
[0591] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 22A (78 mg) with lithium
hydroxide afforded Intermediate 22 (66 mg, 89%). MS(ESI) 261.1
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta.
8.21-8.11 (m, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.46 (td, J=7.7, 0.9 Hz,
1H), 7.30 (ddd, J=8.1, 7.1, 0.7 Hz, 1H), 4.37 (d, J=7.3 Hz, 2H),
3.88 (dt, J=11.3, 3.2 Hz, 2H), 3.39-3.33 (m, 2H), 2.29 (dt, J=15.1,
7.6 Hz, 1H), 1.48-1.36 (m, 4H).
Intermediate 23:
1-((3-Methyloxetan-3-yl)methyl)-1H-indazole-3-carboxylic acid
##STR00101##
[0592] Intermediate 23A: Ethyl
1-((3-methyloxetan-3-yl)methyl-1H-indazole-3-carboxylate
##STR00102##
[0594] According to the procedure for preparation of Intermediate
19B, alkylation of ethyl 1H-indazole-3-carboxylate (200 mg) with
3-(bromomethyl)-3-methyloxetane afforded Intermediate 23A (183 mg,
63%). MS(ESI) 275.1 (M+H).sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.26-8.20 (m, 1H), 7.49-7.44 (m, 2H),
7.35-7.28 (m, 1H), 4.80 (d, J=6.2 Hz, 2H), 4.65 (s, 2H), 4.56-4.47
(m, 2H), 4.45-4.36 (m, 2H), 1.48 (t, J=7.2 Hz, 3H), 1.30 (s,
3H).
Intermediate 23
##STR00103##
[0596] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 23A (183 mg) with lithium
hydroxide to afforded Intermediate 23 (145 mg, 88%). MS(ESI) 247.1
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.16
(dt, J=8.3, 1.0 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.46 (ddd, J=8.4,
7.1, 1.0 Hz, 1H), 7.30 (ddd, J=8.1, 7.1, 0.9 Hz, 1H), 4.83 (d,
J=6.2 Hz, 2H), 4.69 (s, 2H), 4.38 (d, J=6.2 Hz, 2H), 1.22 (s,
3H).
Intermediate 24:
1-((Tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxylic acid
##STR00104##
[0597] Intermediate 24A: Ethyl
1-((tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxylate
##STR00105##
[0599] According to the procedure for preparation of Intermediate
19B, alkylation of ethyl 1H-indazole-3-carboxylate (200 mg)
3-(bromomethyl)tetrahydrofuran afforded Intermediate 24A (140 mg,
49%). MS(ESI) 275.2 (M+H).sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.23 (dt, J=8.2, 1.0 Hz, 1H), 7.52-7.41 (m,
2H), 7.35-7.28 (m, 1H), 4.53 (q, J=7.1 Hz, 2H), 4.45 (d, J=7.7 Hz,
2H), 3.97 (td, J=8.4, 5.5 Hz, 1H), 3.80-3.70 (m, 2H), 3.67-3.58 (m,
1H), 3.14-3.00 (m, 1H), 2.01 (dtd, J=12.9, 7.9, 5.6 Hz, 1H),
1.80-1.67 (m, 1H), 1.49 (t, J=7.2 Hz, 3H).
Intermediate 24
##STR00106##
[0601] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 24A (140 mg) with lithium
hydroxide afforded Intermediate 24 (120 mg, 95%). MS(ESI) 247.1
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.11
(d, J=8.4 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.39 (ddd, J=8.4, 7.0,
1.1 Hz, 1H), 7.28-7.19 (m, 1H), 4.40 (d, J=7.5 Hz, 2H), 3.86 (td,
J=8.1, 5.5 Hz, 1H), 3.70-3.61 (m, 2H), 3.56 (dd, J=8.9, 5.4 Hz,
1H), 2.94-2.82 (m, 1H), 2.00-1.84 (m, 1H), 1.75-1.58 (m, 1H).
Intermediate 25:
1-((Tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxylic acid
(enantiomer 1)
##STR00107##
[0602] Intermediate 26:
1-((Tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxylic acid
(enantiomer 2)
##STR00108##
[0604] The enantiomers of Intermediate 24 (64 mg) were separated
via the following conditions:
[0605] Column: CHIRALPAK.RTM. AD-H, 4.6.times.250 mm, 5 t
[0606] Mobile Phase: 15% MeOH/85% CO.sub.2
[0607] Flow Conditions: 2.0 mL/min, 150 Bar, 35.degree. C.
[0608] Detector Wavelength: 220 nm
[0609] Injection Details: 10 .mu.L of .about.1 mg/mL in MeOH
[0610] 1st isomer: Intermediate 25 (24 mg, 38%). MS(ESI) 247.2
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.16
(d, J=8.1 Hz, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.48 (t, J=7.5 Hz, 1H),
7.32 (t, J=7.4 Hz, 1H), 4.49 (d, J=7.7 Hz, 2H), 3.93 (td, J=8.1,
5.5 Hz, 1H), 3.82-3.71 (m, 2H), 3.62 (dd, J=8.9, 5.2 Hz, 1H),
3.05-2.86 (m, 1H), 2.12-1.90 (m, 1H), 1.87-1.66 (m, 1H).
[0611] 2nd isomer: Intermediate 26 (25 mg, 39%). MS(ESI) 247.2
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.16
(d, J=8.1 Hz, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.48 (t, J=7.5 Hz, 1H),
7.32 (t, J=7.4 Hz, 1H), 4.49 (d, J=7.7 Hz, 2H), 3.93 (td, J=8.1,
5.5 Hz, 1H), 3.82-3.71 (m, 2H), 3.62 (dd, J=8.9, 5.2 Hz, 1H),
3.05-2.86 (m, 1H), 2.12-1.90 (m, 1H), 1.87-1.66 (m, 1H).
Intermediate 27: 1-(Oxetan-2-ylmethyl)-1H-indazole-3-carboxylic
acid
##STR00109##
[0612] Intermediate 27A: Ethyl
1-(oxetan-2-ylmethyl)-1H-indazole-3-carboxylate
##STR00110##
[0614] According to the procedure for preparation of Intermediate
19B, alkylation of ethyl 1H-indazole-3-carboxylate (160 mg) with
2-(bromomethyl)oxetane afforded Intermediate 27A (100 mg, 46%).
MS(ESI) 247.2 (M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.21 (dt, J=8.3, 0.9 Hz, 1H), 7.66 (dt, J=8.5, 0.8 Hz, 1H),
7.43 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.36-7.27 (m, 1H), 5.33-5.21
(m, 1H), 4.82-4.66 (m, 2H), 4.64-4.48 (m, 3H), 4.23 (dt, J=9.1, 6.0
Hz, 1H), 2.80-2.64 (m, 1H), 2.64-2.46 (m, 1H), 1.48 (t, J=7.2 Hz,
3H).
Intermediate 27
##STR00111##
[0616] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 27A (100 mg) with lithium
hydroxide afforded Intermediate 27 (90 mg, 99%). MS(ESI) 233.1
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.14
(dt, J=8.3, 1.0 Hz, 1H), 7.80-7.69 (m, 1H), 7.44 (ddd, J=8.4, 7.0,
1.1 Hz, 1H), 7.37-7.25 (m, 1H), 5.25 (dtd, J=7.7, 6.4, 3.7 Hz, 1H),
4.81-4.64 (m, 2H), 4.55 (ddd, J=8.6, 7.3, 5.7 Hz, 1H), 4.28 (dt,
J=9.1, 6.0 Hz, 1H), 2.74 (dtd, J=11.4, 8.2, 6.3 Hz, 1H), 2.61-2.51
(m, 1H).
Intermediate 28: 1-(2-Methoxyethyl)-1H-indazole-3-carboxylic
acid
##STR00112##
[0617] Intermediate 28A: Ethyl
1-(2-methoxyethyl)-1H-indazole-3-carboxylate
##STR00113##
[0619] According to the procedure for preparation of Intermediate
19B, alkylation of ethyl 1H-indazole-3-carboxylate (150 mg) with
1-bromo-2-methoxyethane afforded Intermediate 28A (104 mg, 53%).
MS(ESI) 249.1 (M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.20 (dt, J=8.2, 1.0 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.42
(ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.29 (ddd, J=8.0, 7.0, 0.8 Hz, 1H),
4.63 (t, J=5.5 Hz, 2H), 4.52 (q, J=7.0 Hz, 2H), 3.85 (t, J=5.4 Hz,
2H), 3.26 (s, 3H), 1.48 (t, J=7.0 Hz, 3H).
Intermediate 28
##STR00114##
[0621] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 28A (104 mg) with lithium
hydroxide afforded Intermediate 28 (90 mg, 98%). MS(ESI) 221.1
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.14
(dt, J=8.3, 0.9 Hz, 1H), 7.67 (dt, J=8.6, 0.9 Hz, 1H), 7.45 (ddd,
J=8.5, 7.2, 1.1 Hz, 1H), 7.30 (ddd, J=8.1, 7.0, 0.8 Hz, 1H), 4.64
(t, J=5.2 Hz, 2H), 3.85 (t, J=5.3 Hz, 2H), 3.27-3.20 (m, 3H).
Intermediate 29: 1-(2-Hydroxypropyl)-1H-indazole-3-carboxylic
acid
##STR00115##
[0622] Intermediate 29A: Methyl
1-(2-hydroxypropyl)-1H-indazole-3-carboxylate
##STR00116##
[0624] To a vial containing ethyl 1H-indazole-3-carboxylate (200
mg, 1.052 mmol) in DMF (3 mL), was added 2-methyloxirane (122 mg,
2.103 mmol) and Cs.sub.2CO.sub.3 (411 mg, 1.262 mmol). The vial was
sealed and the mixture was stirred at 80.degree. C. o/n. LC/MS
showed reaction completed. Quenched with water, extracted with
EtOAc, washed organic layer with 10% LiCl, brine, concentrated and
the residue was purified by prep HPLC to afford Intermediate 29A
(35 mg, 14%). MS(ESI) 235.1 (M+H).sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.19 (dt, J=8.2, 1.0 Hz, 1H), 7.95 (s, 1H),
7.58-7.52 (m, 1H), 7.43 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.30 (ddd,
J=8.0, 6.9, 0.9 Hz, 1H), 4.50-4.35 (m, 3H), 4.03-3.94 (m, 3H), 2.93
(s, 2H), 2.85 (d, J=0.4 Hz, 2H), 1.37-1.24 (m, 3H).
Intermediate 29
##STR00117##
[0626] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 29A (35 mg) with lithium
hydroxide afforded Intermediate 29 (25 mg, 81%). MS(ESI) 221.1
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.15
(dt, J=8.2, 1.0 Hz, 1H), 7.73-7.65 (m, 1H), 7.46 (ddd, J=8.4, 7.0,
1.1 Hz, 1H), 7.30 (ddd, J=8.1, 7.0, 0.8 Hz, 1H), 4.48-4.42 (m, 2H),
4.29 (td, J=6.4, 5.4 Hz, 1H), 1.28-1.18 (m, 3H).
Intermediate 30:
1-(3-(Benzyloxy)-2-hydroxypropyl)-1H-indazole-3-carboxylic acid
##STR00118##
##STR00119##
[0628] To a vial containing ethyl 1H-indazole-3-carboxylate (200
mg, 1.052 mmol) in DMF (3 mL), was added
2-((benzyloxy)methyl)oxirane (345 mg, 2.103 mmol) and
Cs.sub.2CO.sub.3 (514 mg, 1.577 mmol). The vial was sealed and the
mixture was stirred at 80.degree. C. o/n. LC/MS showed reaction
completed. Quenched with water, extracted with EtOAc, washed
organic layer with 10% LiCl, brine, concentrated and the residue
was purified by prep HPLC. 1st fraction concentrated to afford
Intermediate 30 (120 mg, 35% yield) as a white solid. MS(ESI) 327.1
(M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.19 (d,
J=8.1 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.46-7.37 (m, 1H), 7.36-7.27
(m, 6H), 4.63-4.57 (m, 2H), 4.51-4.48 (m, 2H), 4.45-4.36 (m, 1H),
3.59-3.41 (m, 4H).
Intermediate 31: 1-(2,3-Dihydroxypropyl)-1H-indazole-3-carboxylic
acid
##STR00120##
##STR00121##
[0630] Intermediate 30 (90 mg, 0.276 mmol) was dissolved in MeOH (3
mL), degassed and add 10% Pd/C (20 mg). Stirred under H2 balloon
for 3 h, filtered and concentrated under vacuum to afford
Intermediate 31 as a colorless oil (58 mg, 89%). MS(ESI) 237.1
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta.
8.17-8.10 (m, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.45 (ddd, J=8.4, 7.1,
1.0 Hz, 1H), 7.29 (ddd, J=8.0, 7.0, 0.8 Hz, 1H), 4.62 (dd, J=14.3,
4.4 Hz, 1H), 4.51 (dd, J=14.3, 7.3 Hz, 1H), 4.16 (dq, J=7.3, 5.0
Hz, 1H), 3.66-3.53 (m, 2H).
Intermediate 32:
1-(2-(2-Methoxyethoxy)ethyl)-1H-indazole-3-carboxylic acid
##STR00122##
[0631] Intermediate 32A: Ethyl
1-(2-(2-methoxyethoxy)ethyl)-1H-indazole-3-carboxylate
##STR00123##
[0633] According to the procedure for preparation of Intermediate
19B, alkylation of ethyl 1H-indazole-3-carboxylate (150 mg) with
1-bromo-2-(2-methoxyethoxy)ethane afforded Intermediate 32A (105
mg, 46%). MS(ESI) 293.2 (M+H).sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.20 (dt, J=8.2, 1.0 Hz, 1H), 7.63-7.57 (m,
1H), 7.42 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.30 (ddd, J=8.1, 7.0, 0.9
Hz, 1H), 4.67 (t, J=5.6 Hz, 2H), 4.53 (q, J=7.3 Hz, 2H), 3.97 (t,
J=5.7 Hz, 2H), 3.56-3.48 (m, 2H), 3.43-3.37 (m, 2H), 3.28 (s, 3H),
1.48 (t, J=7.2 Hz, 3H).
Intermediate 32
##STR00124##
[0635] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 32A (105 mg)) with lithium
hydroxide afforded Intermediate 32 (93 mg, 98%). MS(ESI) 265.1
(M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 8.12
(dt, J=8.2, 0.9 Hz, 1H), 7.72-7.62 (m, 1H), 7.42 (ddd, J=8.4, 7.0,
1.1 Hz, 1H), 7.27 (ddd, J=8.1, 7.0, 0.8 Hz, 1H), 4.62 (t, J=5.4 Hz,
2H), 3.93 (t, J=5.4 Hz, 2H), 3.49-3.43 (m, 2H), 3.37-3.32 (m, 2H),
3.17 (s, 3H).
Intermediate 33:
1-((1-(tert-Butoxycarbonyl)azetidin-3-yl)methyl)-1H-indazole-3-carboxylic
acid
##STR00125##
[0636] Intermediate 33A: Ethyl
1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-1H-indazole-3-carboxylat-
e
##STR00126##
[0638] According to the procedure for preparation of Intermediate
19B, alkylation of ethyl 1H-indazole-3-carboxylate (150 mg) with
tert-butyl 3-(bromomethyl)azetidine-1-carboxylate afforded
Intermediate 33A (180 mg, 48%). MS(ESI) 360.1 (M+H).sup.+; .sup.1H
NMR (400 MHz, chloroform-d) .delta. 8.22 (d, J=8.4 Hz, 1H),
7.56-7.43 (m, 2H), 7.32 (ddd, J=8.0, 6.8, 1.1 Hz, 1H), 4.67 (d,
J=7.7 Hz, 2H), 4.57-4.44 (m, 2H), 4.02 (t, J=8.5 Hz, 2H), 3.80 (dd,
J=8.9, 5.2 Hz, 2H), 3.24 (ddd, J=7.9, 5.1, 2.6 Hz, 1H), 1.48 (t,
J=7.0 Hz, 3H), 1.44 (s, 9H).
Intermediate 33
##STR00127##
[0640] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 33A (180 mg) with lithium
hydroxide afforded Intermediate 33 (155 mg, 93%). MS(ESI) 332.1
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.16
(dt, J=8.2, 1.0 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.50 (ddd, J=8.5,
7.2, 1.1 Hz, 1H), 7.33 (ddd, J=8.0, 7.0, 0.8 Hz, 1H), 4.72 (d,
J=7.3 Hz, 2H), 4.06-3.96 (m, 2H), 3.84 (br. s., 2H), 3.27-3.17 (m,
1H), 1.41 (s, 9H).
Intermediate 34: 1-(2-(Benzyloxy)ethyl)-1H-indazole-3-carboxylic
acid
##STR00128##
[0641] Intermediate 34A: Ethyl
1-(2-(benzyloxy)ethyl)-1H-indazole-3-carboxylate
##STR00129##
[0643] According to the procedure for preparation of Intermediate
19B, alkylation of ethyl 1H-indazole-3-carboxylate (120 mg) with
((2-bromoethoxy)methyl)benzene afforded Intermediate 34A (120 mg,
59%). MS(ESI) 325.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
chloroform-d) .delta. 8.21 (d, J=8.3 Hz, 1H), 7.56 (d, J=8.5 Hz,
1H), 7.40 (d, J=1.4 Hz, 1H), 7.32-7.27 (m, 1H), 7.25-7.20 (m, 3H),
7.11-7.06 (m, 2H), 4.66 (t, J=5.5 Hz, 2H), 4.52 (q, J=7.2 Hz, 2H),
4.40 (s, 2H), 3.93 (t, J=5.4 Hz, 2H), 1.47 (t, J=7.0 Hz, 3H).
Intermediate 34
##STR00130##
[0645] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 34A (120 mg) with lithium
hydroxide afforded Intermediate 34 (100 mg, 91%). MS(ESI) 297.2
(M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 8.15
(dt, J=8.1, 1.0 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.42 (ddd, J=8.5,
7.1, 1.0 Hz, 1H), 7.33-7.25 (m, 1H), 7.20-7.13 (m, 3H), 7.05-6.90
(m, 2H), 4.65 (t, J=5.2 Hz, 2H), 4.37 (s, 2H), 3.91 (t, J=5.1 Hz,
2H).
Intermediate 35: 1-(2-Hydroxyethyl)-1H-indazole-3-carboxylic
acid
##STR00131##
[0647] Intermediate 34 (84 mg, 0.283 mmol) was dissolved in MeOH (2
mL), degassed and add 10% Pd/C (15 mg), stirred under H2 balloon
for 2 h. Filtered and concentrated to afford Intermediate 35 (55
mg, 94%) as a white solid. MS(ESI) 207.1 (M+H).sup.+; .sup.1H NMR
(400 MHz, methanol-d.sub.4) .delta. 8.14 (dt, J=8.3, 1.0 Hz, 1H),
7.72-7.62 (m, 1H), 7.45 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.29 (ddd,
J=8.1, 7.1, 0.9 Hz, 1H), 4.64-4.53 (m, 2H), 4.07-3.97 (m, 2H).
Intermediate 36:
1-(2-(Tetrahydro-2H-pyran-4-yl)ethyl)-1H-indazole-3-carboxylic
acid
##STR00132##
[0648] Intermediate 36A: Ethyl
1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-indazole-3-carboxylate
##STR00133##
[0650] According to the procedure for preparation of Intermediate
19B, alkylation of ethyl 1H-indazole-3-carboxylate (120 mg) with
4-(2-bromoethyl)tetrahydro-2H-pyran afforded Intermediate 36A (90
mg, 47%). MS(ESI) 303.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
chloroform-d) .delta. 8.23 (dt, J=8.3, 1.0 Hz, 1H), 7.54-7.42 (m,
2H), 7.31 (ddd, J=8.0, 5.9, 1.8 Hz, 1H), 4.62-4.43 (m, 4H),
4.01-3.87 (m, 2H), 3.34 (td, J=11.8, 2.1 Hz, 2H), 1.98-1.85 (m,
2H), 1.65 (dd, J=12.9, 1.9 Hz, 2H), 1.54 (dd, J=7.4, 3.6 Hz, 1H),
1.48 (t, J=7.2 Hz, 3H), 1.41-1.29 (m, 2H).
Intermediate 36
##STR00134##
[0652] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 36A (90 mg) with lithium
hydroxide afforded Intermediate 36 (80 mg, 98%). MS(ESI) 275.2
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta.
8.22-8.12 (m, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.45 (ddd, J=8.4, 7.0,
0.9 Hz, 1H), 7.30 (ddd, J=8.1, 7.1, 0.7 Hz, 1H), 4.51 (t, J=7.3 Hz,
2H), 3.96-3.81 (m, 2H), 3.38-3.24 (m, 2H), 1.86 (q, J=7.0 Hz, 2H),
1.72-1.60 (m, 2H), 1.54-1.42 (m, 1H), 1.37-1.24 (m, 2H).
Intermediate 37: 1-(3-(Benzyloxy)propyl)-1H-indazole-3-carboxylic
acid
##STR00135##
[0653] Intermediate 37A: Ethyl
1-(3-(benzyloxy)propyl)-1H-indazole-3-carboxylate
##STR00136##
[0655] According to the procedure for preparation of Intermediate
19B, alkylation of ethyl 1H-indazole-3-carboxylate (120 mg) with
((3-bromopropoxy)methyl)benzene afforded Intermediate 37A (105 mg,
49%). MS(ESI) 339.2 (M+H).sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.22 (dt, J=8.1, 1.0 Hz, 1H), 7.53-7.47 (m,
1H), 7.43-7.37 (m, 1H), 7.37-7.25 (m, 6H), 4.66-4.60 (m, 2H),
4.56-4.48 (m, 2H), 4.43 (s, 2H), 3.40 (t, J=5.7 Hz, 2H), 2.35-2.21
(m, 2H), 1.48 (t, J=7.2 Hz, 3H).
Intermediate 37
##STR00137##
[0657] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 37A (105 mg) with lithium
hydroxide afforded Intermediate 37 (88 mg, 91%). MS(ESI) 339.2
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.15
(d, J=8.4 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.38 (ddd, J=8.4, 7.0,
1.1 Hz, 1H), 7.31-7.20 (m, 7H), 4.54 (t, J=6.7 Hz, 2H), 4.34 (s,
2H), 3.41-3.36 (m, 2H), 2.25-2.10 (m, 2H).
Intermediate 38: 1-(3-Hydroxypropyl)-1H-indazole-3-carboxylic
acid
##STR00138##
[0659] Intermediate 37 (80 mg, 0.258 mmol) was dissolved in MeOH (3
mL), degassed and add 10% Pd/C (20 mg). Stirred under H2 balloon
for 3 h, filtered and concentrated under vacuum to afford
Intermediate 38 as a colorless oil (50 mg, 75%). MS(ESI) 221.1
(M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta.
8.17-8.13 (m, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.46 (ddd, J=8.4, 7.0,
1.1 Hz, 1H), 7.30 (ddd, J=8.0, 7.1, 0.8 Hz, 1H), 4.60 (t, J=6.9 Hz,
2H), 3.55 (t, J=6.1 Hz, 2H), 2.14 (t, J=6.3 Hz, 2H).
Intermediate 39: 1-(3-Methoxypropyl)-1H-indazole-3-carboxylic
acid
##STR00139##
[0660] Intermediate 39A: Ethyl
1-(3-methoxypropyl)-1H-indazole-3-carboxylate
##STR00140##
[0662] According to the procedure for preparation of Intermediate
19B, alkylation of ethyl 1H-indazole-3-carboxylate (80 mg) with
1-bromo-3-methoxypropane afforded Intermediate 39A (50 mg, 45%).
MS(ESI) 263.2 (M+H).sup.+; .sup.1H NMR (500 MHz, chloroform-d)
.delta. 8.21 (d, J=8.3 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.40 (d,
J=1.4 Hz, 1H), 7.32-7.27 (m, 1H), 7.25-7.20 (m, 3H), 7.11-7.06 (m,
2H), 4.66 (t, J=5.5 Hz, 2H), 4.52 (q, J=7.2 Hz, 2H), 4.40 (s, 2H),
3.93 (t, J=5.4 Hz, 2H), 1.47 (t, J=7.0 Hz, 3H).
Intermediate 39
##STR00141##
[0664] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 39A (50 mg) with lithium
hydroxide afforded Intermediate 39 (44 mg, 99%). MS(ESI) 235.1
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.14
(dt, J=8.3, 0.9 Hz, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.49-7.41 (m, 1H),
7.29 (ddd, J=8.1, 7.0, 0.8 Hz, 1H), 4.61-4.54 (m, 2H), 3.28 (t,
J=5.9 Hz, 2H), 3.25 (s, 3H), 2.16 (t, J=6.1 Hz, 2H).
Intermediate 40: 1-(Pyridin-4-ylmethyl)-1H-indazole-3-carboxylic
acid
##STR00142##
[0665] Intermediate 40A: Ethyl
1-(pyridin-4-ylmethyl)-1H-indazole-3-carboxylate
##STR00143##
[0667] According to the procedure for preparation of Intermediate
19B, alkylation of ethyl 1H-indazole-3-carboxylate (70 mg) with
4-(bromomethyl)pyridine afforded Intermediate 40A (50 mg, 48%).
MS(ESI) 282.1 (M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.61-8.42 (m, 2H), 8.26 (dt, J=8.2, 1.1 Hz, 1H), 7.47-7.37
(m, 1H), 7.35-7.31 (m, 1H), 7.31 (d, J=0.7 Hz, 1H), 7.06-6.99 (m,
2H), 5.70 (s, 2H), 4.54 (q, J=7.3 Hz, 2H), 1.48 (t, J=7.2 Hz,
3H).
Intermediate 40
##STR00144##
[0669] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 40A (50 mg) with lithium
hydroxide afforded Intermediate 40 (45 mg, 95%). MS(ESI) 254.1
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta.
8.56-8.44 (m, 2H), 8.28-8.13 (m, 1H), 7.70-7.57 (m, 1H), 7.48 (d,
J=1.3 Hz, 1H), 7.36 (dd, J=8.3, 1.0 Hz, 1H), 7.26-7.15 (m, 2H),
5.84 (s, 2H).
Intermediate 41: 1-(Pyridin-2-ylmethyl)-1H-indazole-3-carboxylic
acid
##STR00145##
[0670] Intermediate 41A: Ethyl
1-(pyridin-2-ylmethyl)-1H-indazole-3-carboxylate
##STR00146##
[0672] According to the procedure for preparation of Intermediate
19B, alkylation of ethyl 1H-indazole-3-carboxylate (70 mg) with
2-(bromomethyl)pyridine afforded Intermediate 41A (88 mg, 85%).
MS(ESI) 282.1 (M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.61-8.54 (m, 1H), 8.24 (dt, J=8.1, 1.0 Hz, 1H), 7.55 (td,
J=7.7, 1.8 Hz, 1H), 7.45 (dt, J=8.5, 0.9 Hz, 1H), 7.38 (ddd, J=8.4,
6.9, 1.2 Hz, 1H), 7.35-7.29 (m, 1H), 7.20-7.14 (m, 1H), 6.92 (d,
J=7.9 Hz, 1H), 5.84 (s, 2H), 4.54 (q, J=7.3 Hz, 2H), 1.49 (t, J=7.2
Hz, 3H).
Intermediate 41
##STR00147##
[0674] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 41A (88 mg) with lithium
hydroxide afforded Intermediate 41 (105 mg, 91%). MS(ESI) 254.1
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.67
(dd, J=5.4, 0.8 Hz, 1H), 8.21 (dt, J=8.1, 1.0 Hz, 1H), 8.12 (td,
J=7.8, 1.8 Hz, 1H), 7.74-7.61 (m, 2H), 7.51 (ddd, J=8.4, 7.1, 1.0
Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.37 (ddd, J=8.1, 7.1, 0.9 Hz,
1H), 5.99 (s, 2H).
Intermediate 42: 1-(Pyridin-3-ylmethyl)-1H-indazole-3-carboxylic
acid
##STR00148##
[0675] Intermediate 42A: Ethyl
1-(pyridin-3-ylmethyl)-1H-indazole-3-carboxylate
##STR00149##
[0677] According to the procedure for preparation of Intermediate
19B, alkylation of ethyl 1H-indazole-3-carboxylate (70 mg) with
3-(bromomethyl)pyridine afforded Intermediate 42A (18 mg, 18%).
MS(ESI) 282.1 (M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.61 (d, J=1.8 Hz, 1H), 8.54 (dd, J=4.8, 1.5 Hz, 1H), 8.25
(dt, J=8.1, 1.0 Hz, 1H), 7.54-7.47 (m, 1H), 7.45-7.30 (m, 3H), 7.22
(ddd, J=7.9, 4.8, 0.8 Hz, 1H), 5.73 (s, 2H), 4.55 (q, J=7.0 Hz,
2H), 1.50 (t, J=7.2 Hz, 3H).
Intermediate 42
##STR00150##
[0679] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 42A (18 mg) with lithium
hydroxide afforded Intermediate 42 (23 mg, 98%). MS(ESI) 254.1
(M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta.
8.94-8.84 (m, 1H), 8.78 (d, J=5.5 Hz, 1H), 8.49-8.37 (m, 1H), 8.18
(dt, J=8.3, 0.8 Hz, 1H), 8.02-7.92 (m, 1H), 7.77 (d, J=8.5 Hz, 1H),
7.52 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.36 (ddd, J=8.1, 7.2, 0.7 Hz,
1H), 5.98 (s, 2H).
Intermediate 43:
6-Fluoro-1-(2-methylprop-1-en-1-yl)-1H-indazole-3-carboxylic
acid
##STR00151##
[0680] Intermediate 44:
6-Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxylic
acid
##STR00152##
##STR00153##
[0682] To a vial containing methyl
6-fluoro-1H-indazole-3-carboxylate (200 mg, 1.030 mmol) in DMF (3
mL), were added 2,2-dimethyloxirane (0.458 mL, 5.15 mmol) and
Cs.sub.2CO.sub.3 (403 mg, 1.236 mmol). The vial was sealed and the
mixture was stirred at 80.degree. C. for 3 h. Quenched with water,
acidified with 1 N HCl. Extracted with EtOAc, the organic layer was
concentrated and loaded on 10 g column, eluted with MeOH/DCM.
Collected two fractions: 1st fraction: 5% MeOH; 2nd fraction: 8%
MeOH.
[0683] 1st fraction afforded Intermediate 43 (26 mg, 11%). MS(ESI)
235.1 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
13.78 (br. s., 1H), 8.05 (dd, J=9.1, 5.5 Hz, 1H), 7.55 (dt, J=9.9,
1.1 Hz, 1H), 7.44-7.32 (m, 1H), 7.21 (td, J=9.3, 2.3 Hz, 1H), 1.93
(d, J=1.1 Hz, 3H), 1.79 (d, J=1.4 Hz, 3H).
[0684] 2nd fraction afforded Intermediate 44 (90 mg, 36%). MS(ESI)
253.1 (M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta.
8.10 (dd, J=9.0, 5.3 Hz, 1H), 7.44 (dd, J=9.5, 2.0 Hz, 1H), 7.08
(td, J=9.1, 2.1 Hz, 1H), 4.39 (s, 2H), 1.24 (s, 6H).
Intermediate 45:
5-Fluoro-1-(2-methylprop-1-en-1-yl)-1H-indazole-3-carboxylic
acid
##STR00154##
[0685] Intermediate 46:
5-Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxylic
acid
##STR00155##
##STR00156##
[0687] To a vial containing methyl
5-fluoro-1H-indazole-3-carboxylate (200 mg, 1.03 mmol) in ACN (3
mL), were added 2,2-dimethyloxirane (0.458 mL, 5.15 mmol) and
Cs.sub.2CO.sub.3 (403 mg, 1.24 mmol). The vial was sealed and the
mixture was stirred at 80.degree. C. for 3 h. Filtered,
concentrated and the residue was loaded onto 10g column, eluted
with EtOAc/Hex (0-60%); collected a 1st fraction at 40% EtOAc. Then
eluted with MeOH/DCM (0-10%); collected a 2nd fraction at 10%
MeOH.
[0688] 2nd fraction concentrated to afford Intermediate 45 (20 mg,
8%). MS(ESI) 235.1 (M+H).sup.+; .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 7.84-7.70 (m, 1H), 7.63 (ddd, J=9.4, 2.5,
0.7 Hz, 1H), 7.29 (dt, J=3.1, 1.5 Hz, 1H), 7.21 (td, J=9.2, 2.4 Hz,
1H), 1.98 (d, J=1.3 Hz, 3H), 1.76 (d, J=1.3 Hz, 3H).
[0689] 1st fraction concentrated to afford Intermediate 46A (130
mg, 48%). MS(ESI) 267.1 (M+H).sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. 7.81-7.76 (m, 1H), 7.58-7.52 (m, 1H), 7.18
(td, J=8.9, 2.4 Hz, 1H), 4.42 (s, 2H), 4.02-3.97 (m, 3H), 1.26 (s,
6H).
Intermediate 46
##STR00157##
[0691] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 46A (130 mg) with lithium
hydroxide afforded Intermediate 46 (115 mg, 93%) as a white solid.
MS(ESI) 253.1 (M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4)
.delta. 7.77-7.68 (m, 2H), 7.32-7.20 (m, 1H), 4.43 (s, 2H),
1.30-1.21 (m, 6H).
Intermediate 47:
1-((Tetrahydro-2H-pyran-2-yl)methyl)-1H-indazole-3-carboxylic
acid
##STR00158##
[0692] Intermediate 47A: Ethyl
1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indazole-3-carboxylate
##STR00159##
[0694] According to the procedure for preparation of Intermediate
19B, alkylation of ethyl 1H-indazole-3-carboxylate (150 mg) with
2-(bromomethyl)tetrahydro-2H-pyran afforded Intermediate 47A (163
mg, 72%). MS(ESI) 267.1 (M+H).sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.20 (dt, J=8.2, 1.0 Hz, 1H), 7.63-7.57 (m,
1H), 7.43 (ddd, J=8.4, 7.1, 1.2 Hz, 1H), 7.31 (ddd, J=8.0, 6.9, 0.9
Hz, 1H), 4.62-4.45 (m, 4H), 4.00-3.81 (m, 2H), 3.33 (td, J=11.6,
2.5 Hz, 1H), 1.91-1.80 (m, 1H), 1.68-1.59 (m, 1H), 1.57-1.44 (m,
6H), 1.42-1.28 (m, 1H).
Intermediate 47
##STR00160##
[0696] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 47A (46 mg) with lithium
hydroxide afforded Intermediate 47 (30 mg, 72%) as a white solid.
MS(ESI) 261.2 (M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4)
.delta. 8.13 (dd, J=8.1, 0.9 Hz, 1H), 7.75-7.62 (m, 1H), 7.52-7.40
(m, 1H), 7.40-7.25 (m, 1H), 4.59-4.41 (m, 2H), 3.94-3.80 (m, 2H),
1.93-1.78 (m, 1H), 1.65 (d, J=11.7 Hz, 1H), 1.59-1.42 (m, 3H),
1.41-1.26 (m, 1H).
Intermediate 48:
1-(2-Hydroxy-2-methylpropyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic
acid
##STR00161##
[0697] Intermediate 48A: Methyl
1-(2-hydroxy-2-methylpropyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate
##STR00162##
[0699] To a vial containing methyl
1H-pyrrolo[2,3-b]pyridine-3-carboxylate (120 mg, 0.681 mmol) in DMF
(3 mL), were added 2,2-dimethyloxirane (0.303 mL, 3.41 mmol) and
Cs.sub.2CO.sub.3 (266 mg, 0.817 mmol). The vial was sealed and the
mixture was stirred at 80.degree. C. for 3 h. Quenched with water,
extracted with EtOAc, concentrated and the residue was loaded onto
10g column, eluted with EtOAc/Hex (0-60%); collected a fraction at
40% EtOAc. Concentrated to afford Intermediate 48A (134 mg, 79%).
MS(ESI) 249.1 (M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.45 (dd, J=7.9, 1.5 Hz, 1H), 8.33 (dd, J=4.7, 1.7 Hz, 1H),
7.99 (s, 1H), 7.24 (dd, J=7.9, 4.6 Hz, 1H), 4.44 (s, 1H), 4.33 (s,
2H), 3.92 (s, 3H), 1.24 (s, 6H).
Intermediate 48
##STR00163##
[0701] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 48A (134 mg) with lithium
hydroxide afforded Intermediate 48 (127 mg, 99%) as a white solid.
MS(ESI) 235.2 (M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4)
.delta. 8.47 (dd, J=7.9, 1.5 Hz, 1H), 8.29 (d, J=4.0 Hz, 1H), 8.14
(s, 1H), 7.23 (dd, J=7.9, 4.8 Hz, 1H), 4.33 (s, 2H), 1.17 (s,
6H).
Intermediate 49:
5-Fluoro-1-((tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxylic
acid
##STR00164##
[0702] Intermediate 49A: Methyl
5-fluoro-1-((tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxylate
##STR00165##
[0704] According to the procedure for preparation of Intermediate
19B, alkylation of ethyl 1H-indazole-3-carboxylate (100 mg) with
3-(bromomethyl)tetrahydrofuran afforded Intermediate 49A (66 mg,
46%). MS(ESI) 279.2 (M+H).sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. 7.87-7.81 (m, 1H), 7.46-7.41 (m, 1H), 7.22
(td, J=8.9, 2.4 Hz, 1H), 4.41 (d, J=7.7 Hz, 2H), 4.06-4.00 (m, 3H),
3.97-3.92 (m, 1H), 3.80-3.67 (m, 2H), 3.60 (dd, J=9.1, 4.7 Hz, 1H),
3.11-2.95 (m, 1H), 2.08-1.96 (m, 1H), 1.74-1.64 (m, 1H).
Intermediate 49
##STR00166##
[0706] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 49A (68 mg) with lithium
hydroxide afforded Intermediate 49 (63 mg, 98%) as a white solid.
MS(ESI) 265.2 (M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4)
.delta. 7.74-7.67 (m, 2H), 7.26 (td, J=8.9, 2.5 Hz, 1H), 4.47 (d,
J=7.7 Hz, 2H), 3.92 (td, J=8.3, 5.5 Hz, 1H), 3.77-3.69 (m, 2H),
3.60 (dd, J=8.8, 5.2 Hz, 1H), 3.01-2.87 (m, 1H), 2.08-1.95 (m, 1H),
1.80-1.69 (m, 1H).
Intermediate 50:
6-Fluoro-1-((tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxylic
acid
##STR00167##
[0707] Intermediate 50A: Methyl
6-fluoro-1-((tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxylate
##STR00168##
[0709] According to the procedure for preparation of Intermediate
19B, alkylation of ethyl 1H-indazole-3-carboxylate (100 mg) with
3-(bromomethyl)tetrahydrofuran afforded Intermediate 50A (68 mg,
47%). MS(ESI) 279.2 (M+H).sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.22-8.15 (m, 1H), 7.18-7.04 (m, 2H), 4.37
(d, J=7.7 Hz, 2H), 4.03 (s, 3H), 3.96 (td, J=8.3, 5.4 Hz, 2H),
3.82-3.72 (m, 2H), 3.61 (dd, J=9.0, 4.8 Hz, 1H), 3.09-2.95 (m, 1H),
2.02 (dtd, J=12.9, 8.0, 5.5 Hz, 1H), 1.74-1.63 (m, 1H).
Intermediate 50
##STR00169##
[0711] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 50A (68 mg) with lithium
hydroxide afforded Intermediate 50 (50 mg, 77%) as a white solid.
MS(ESI) 265.2 (M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4)
.delta. 8.12 (dd, J=8.7, 5.1 Hz, 1H), 7.44 (dd, J=9.4, 1.9 Hz, 1H),
7.10 (td, J=9.1, 2.2 Hz, 1H), 4.43 (d, J=7.7 Hz, 2H), 3.93 (td,
J=8.2, 5.4 Hz, 1H), 3.84-3.71 (m, 2H), 3.61 (dd, J=8.8, 5.5 Hz,
1H), 3.04-2.83 (m, 1H), 2.12-1.93 (m, 1H), 1.84-1.65 (m, 1H).
Intermediate 51:
6-(2-Hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylic
acid
##STR00170##
[0712] Intermediate 51A: Ethyl
6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylic
##STR00171##
[0714] Ethyl 6-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (130
mg, 0.59 mmol) was mixed with aluminum tribromide (787 mg, 2.95
mmol) in EtSH (2 ml) and stirred at rt for 2 h. Cooled to 0.degree.
C., add MeOH dropwise, concentrated, and the residue was loaded
onto 10g column, eluted with EtOAc/Hex (0-40%); collected fraction
at 30% EtOAc, concentrated to afford Intermediate 51A (50 mg, 41%).
MS(ESI) 207.1 (M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4)
.delta. 8.25 (s, 1H), 8.15 (dd, J=2.1, 0.8 Hz, 1H), 7.99 (dd,
J=9.5, 0.7 Hz, 1H), 7.27 (dd, J=9.6, 2.1 Hz, 1H), 4.35 (q, J=7.3
Hz, 2H), 1.40 (t, J=7.2 Hz, 3H).
Intermediate 51B: Ethyl
6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylate
##STR00172##
[0716] To a solution of Intermediate 51A (50 mg, 0.24 mmol) in
acetonitrile (3 ml) and water (0.2 ml) was added K.sub.2CO.sub.3
(134 mg, 0.970 mmol) and 2,2-dimethyloxirane (0.646 ml, 7.27 mmol).
The reaction mixture was heated to 120.degree. C. by MW for 35 min,
LCMS shows the reaction was completed with formation of desired
product. Filtered and purified through prep HPLC to afford
Intermediate 51B (51 mg, 76%). MS(ESI) 279.2 (M+H).sup.+; .sup.1H
NMR (400 MHz, chloroform-d) .delta. 8.35 (s, 1H), 8.34-8.31 (m,
1H), 8.11-8.04 (m, 1H), 7.29 (dd, J=9.6, 2.1 Hz, 1H), 4.39 (q,
J=7.2 Hz, 2H), 3.86 (s, 2H), 1.45-1.39 (m, 9H)
Intermediate 51
##STR00173##
[0718] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 51B (51 mg) with lithium
hydroxide afforded Intermediate 51 (25 mg, 55%) as a white solid.
MS(ESI) 251.2 (M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4)
.delta. 8.33 (dd, J=2.2, 0.6 Hz, 1H), 8.28 (s, 1H), 8.03 (dd,
J=9.6, 0.6 Hz, 1H), 7.37 (dd, J=9.6, 1.9 Hz, 1H), 3.86 (s, 2H),
1.35 (s, 6H)
Intermediate 52:
6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid
##STR00174##
[0719] Intermediate 52A: Ethyl
6-(2-methoxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylate
##STR00175##
[0721] To a vial containing Intermediate 51A (30 mg, 0.145 mmol) in
CH.sub.3CN (3 mL), were added 1-bromo-2-methoxyethane (30.3 mg,
0.218 mmol) and Cs.sub.2CO.sub.3 (95 mg, 0.29 mmol). The vial was
sealed and the mixture was stirred at 70.degree. C. for 3 h. LC/MS
showed reaction completed. Filtered and concentrated. The residue
was loaded onto 10 g column, eluted with EtOAc/Hex (0-50%);
collected fraction at 30% EtOAc, concentrated to afford
Intermediate 52A (25 mg, 65%). MS(ESI) 265.2 (M+H).sup.+; .sup.1H
NMR (500 MHz, methanol-d.sub.4) .delta. 8.35 (dd, J=2.2, 0.5 Hz,
1H), 8.27 (s, 1H), 8.03-7.99 (m, 1H), 7.34 (dd, J=9.6, 2.2 Hz, 1H),
4.35 (q, J=7.2 Hz, 2H), 4.22-4.15 (m, 2H), 3.82-3.74 (m, 2H),
3.50-3.41 (m, 3H), 1.40 (t, J=7.2 Hz, 3H).
Intermediate 52
##STR00176##
[0723] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 52A (25 mg) with lithium
hydroxide afforded Intermediate 52 (12 mg, 54%) as a white solid.
MS(ESI) 237.1 (M+H).sup.+.
Intermediate 53:
6-(2-(Pyrrolidin-1-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic
acid
##STR00177##
[0724] Intermediate 53A: Ethyl
6-(2-(pyrrolidin-1-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylate
##STR00178##
[0726] According to the procedure for preparation of Intermediate
52A, alkylation of Intermediate 51A (36 mg) with
1-(2-bromoethyl)pyrrolidine afforded Intermediate 53A (29 mg, 55%)
as a white solid. MS(ESI) 304.2 (M+H).sup.+; .sup.1H NMR (400 MHz,
chloroform-d) d 8.39-8.25 (m, 3H), 8.07 (d, J=9.5 Hz, 1H), 7.21
(dd, J=9.7, 2.2 Hz, 1H), 4.44-4.38 (m, 3H), 4.38-4.33 (m, 1H),
4.06-3.94 (m, 2H), 3.69-3.62 (m, 2H), 3.05 (d, J=9.7 Hz, 2H), 2.17
(d, J=4.0 Hz, 4H), 1.41 (t, J=7.2 Hz, 3H).
Intermediate 53
##STR00179##
[0728] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 53A (29 mg) with lithium
hydroxide afforded Intermediate 53 (16 mg, 61%) as a white solid.
MS(ESI) 276.2 (M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4)
.delta. 8.41 (d, J=1.5 Hz, 1H), 8.30 (s, 1H), 8.04 (d, J=9.5 Hz,
1H), 7.39 (dd, J=9.6, 2.1 Hz, 1H), 4.47-4.40 (m, 2H), 3.80 (d,
J=7.5 Hz, 2H), 3.76-3.68 (m, 2H), 3.25 (br. s., 2H), 2.21-2.12 (m,
2H), 2.09 (br. s., 2H).
Intermediate 54:
6-(2-(Dimethylamino)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic
acid
##STR00180##
[0729] Intermediate 54A: Ethyl
6-(2-(dimethylamino)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylate
##STR00181##
[0731] According to the procedure for preparation of Intermediate
52A, alkylation of Intermediate 51A (35 mg) with
2-bromo-N,N-dimethylethanamine afforded Intermediate 54A (20 mg,
43%) as a white solid. MS(ESI) 278.2 (M+H).sup.+; .sup.1H NMR (500
MHz, methanol-d.sub.4) .delta. 8.47 (dd, J=2.2, 0.8 Hz, 1H), 8.32
(s, 1H), 8.07 (dd, J=9.6, 0.5 Hz, 1H), 7.42 (dd, J=9.6, 2.2 Hz,
1H), 4.52-4.42 (m, 2H), 4.36 (q, J=7.2 Hz, 2H), 3.70-3.61 (m, 2H),
3.06-2.99 (m, 6H), 1.45-1.35 (m, 3H).
Intermediate 54
##STR00182##
[0733] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 54A (18 mg) with lithium
hydroxide afforded Intermediate 54 (8 mg, 61%) as a white solid.
MS(ESI) 250.2 (M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4)
.delta. 8.47 (dd, J=2.2, 0.6 Hz, 1H), 8.32 (s, 1H), 8.11-8.07 (m,
1H), 7.41 (dd, J=9.6, 2.2 Hz, 1H), 4.49-4.40 (m, 2H), 3.71-3.60 (m,
2H), 3.02 (s, 6H).
Intermediate 55:
6-(2-Morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid
##STR00183##
[0734] Intermediate 55A: Ethyl
6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carboxylate
##STR00184##
[0736] According to the procedure for preparation of Intermediate
52A, alkylation of Intermediate 51A (40 mg) with
4-(2-bromoethyl)morpholine afforded Intermediate 55A (47 mg, 76%)
as a white solid. MS(ESI) 320.3 (M+H).sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.30 (s, 1H), 8.13-8.10 (m, 1H), 8.02 (dd,
J=9.7, 0.7 Hz, 1H), 7.20 (dd, J=9.7, 2.2 Hz, 1H), 4.36 (q, J=7.2
Hz, 2H), 4.11 (t, J=5.6 Hz, 2H), 3.77-3.69 (m, 4H), 2.83 (t, J=5.6
Hz, 2H), 2.61-2.53 (m, 4H), 1.40 (t, J=7.2 Hz, 3H).
Intermediate 55
##STR00185##
[0738] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 55A (47 mg) with lithium
hydroxide afforded Intermediate 55 (58 mg, 97%) as a white solid.
MS(ESI) 320.3 (M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4)
.delta. 8.38 (dd, J=2.2, 0.7 Hz, 1H), 8.32 (s, 1H), 8.09 (dd,
J=9.7, 0.7 Hz, 1H), 7.36 (dd, J=9.7, 2.2 Hz, 1H), 4.51-4.43 (m,
2H), 3.97 (br. s., 4H), 3.72-3.64 (m, 2H), 3.61-3.35 (m, 4H).
Intermediate 56:
5-(2-Hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylic
acid
##STR00186##
[0739] Intermediate 56A: Ethyl
5-hydroxypyrazolo[1,5-a]pyridine-3-carboxylate
##STR00187##
[0741] Ethyl 5-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (300
mg, 1.36 mmol) was mixed with aluminum tribromide (1817 mg, 6.81
mmol) in EtSH (5 ml) and stirred at rt for 3 h. Cooled to 0.degree.
C., add MeOH dropwise, then water. Extracted with EtOAc.
Concentrated and the residue was loaded onto 24 g column, eluted
with EtOAc/Hex (0-40%); collected fraction at 30% EtOAc,
concentrated to afford Intermediate 56A (90 mg, 32%). MS(ESI) 207.2
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.42
(dd, J=7.5, 0.4 Hz, 1H), 8.21 (s, 1H), 7.41-7.27 (m, 1H), 6.67 (dd,
J=7.5, 2.6 Hz, 1H), 4.32 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.2 Hz,
3H).
Intermediate 56B: Ethyl
5-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylate
##STR00188##
[0743] To a solution of Intermediate 56A (22 mg, 0.107 mmol) in
acetonitrile (3 ml) and water (0.2 ml) was added K.sub.2CO.sub.3
(59.0 mg, 0.427 mmol) and 2,2-dimethyloxirane (0.142 ml, 1.600
mmol). The reaction mixture was heated to 120.degree. C. by
microwave for 30 min. Additional 2,2-dimethyloxirane (0.142 ml,
1.60 mmol) was added, and the mixture was stirred at 120.degree. C.
for 30 min. The mixture was concentrated and the residue was loaded
onto 10g column, eluted with EtOAc/Hex (0-40%); collected product
at 30% EtOAc, concentrated to afford Intermediate 56B (27 mg, 91%).
MS(ESI) 279.3 (M+H).sup.+.
Intermediate 56
##STR00189##
[0745] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 56B (27 mg) with lithium
hydroxide afforded Intermediate 56 (19 mg, 78%) as a white solid.
MS(ESI) 251.1 (M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4)
.delta. 8.54-8.42 (m, 1H), 8.25 (s, 1H), 7.42 (d, J=2.6 Hz, 1H),
6.82 (dd, J=7.5, 2.6 Hz, 1H), 3.92 (s, 2H), 1.35 (s, 6H).
Intermediate 57: 5-Methoxypyrazolo[1,5-a]pyridine-3-carboxylic
acid
##STR00190##
[0747] According to the procedure for preparation of Intermediate
17, saponification of ethyl
5-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (19 mg) with lithium
hydroxide afforded Intermediate 57 (16 mg, 97%) as a white solid.
MS(ESI) 193.1 (M+H).sup.+.
Intermediate 58:
5-(2-(Pyrrolidin-1-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic
acid
##STR00191##
[0748] Intermediate 58A: Ethyl
5-(2-(pyrrolidin-1-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylate
##STR00192##
[0750] To a vial containing Intermediate 56A (45 mg, 0.22 mmol) in
DMF (3 mL), were added 1-(2-bromoethyl)pyrrolidine, hydrobromide
(85 mg, 0.33 mmol) and Cs.sub.2CO.sub.3 (213 mg, 0.655 mmol). The
vial was sealed and the mixture was stirred at 70.degree. C. for 16
h. LC/MS showed reaction completed. Filtered and concentrated.
Purified through prep HPLC to afford Intermediate 58A (48 mg, 73%).
MS(ESI) 304.3 (M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4)
.delta. 8.55 (dd, J=7.4, 0.6 Hz, 1H), 8.30 (s, 1H), 7.52 (d, J=2.8
Hz, 1H), 6.86 (dd, J=7.7, 2.8 Hz, 1H), 4.55-4.47 (m, 2H), 4.36 (q,
J=7.0 Hz, 2H), 3.84-3.73 (m, 4H), 3.29-3.19 (m, 2H), 2.21 (br. s.,
2H), 2.08 (br. s., 2H), 1.46-1.33 (m, 3H).
Intermediate 58
##STR00193##
[0752] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 58A (48 mg) with lithium
hydroxide afforded Intermediate 58 (34 mg, 55%) as a white solid.
MS(ESI) 276.3 (M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4)
.delta. ppm 8.54 (1H, dd, J=7.57, 0.69 Hz), 8.29 (1H, s), 7.5 (1H,
d, J=2.75 Hz), 6.85 (1H, dd, J=7.43, 2.75 Hz), 4.44-4.56 (2H, m),
3.71-3.84 (4H, m),3.26-3.28 (2H, m), 2.21 (2H, br. s.), 2.07 (2H,
br. s.).
Intermediate 59:
5-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid
##STR00194##
[0753] Intermediate 59A: Ethyl
5-(2-methoxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylate
##STR00195##
[0755] According to the procedure for preparation of Intermediate
58A, alkylation of Intermediate 56A (35 mg) with
1-bromo-2-methoxyethane afforded Intermediate 59A (37 mg, 82%) as a
white solid. MS(ESI) 265.3 (M+H).sup.+; .sup.1H NMR (500 MHz,
chloroform-d) d 8.31 (dd, J=7.4, 0.5 Hz, 1H), 8.27 (s, 1H), 7.42
(d, J=2.8 Hz, 1H), 6.66 (dd, J=7.4, 2.8 Hz, 1H), 4.35 (q, J=7.0 Hz,
2H), 4.28-4.17 (m, 2H), 3.85-3.74 (m, 2H), 3.51-3.42 (m, 3H), 1.39
(t, J=7.2 Hz, 3H).
Intermediate 59
##STR00196##
[0757] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 59A (37 mg) with lithium
hydroxide afforded Intermediate 59 (28 mg, 85%) as a white solid.
MS(ESI) 237.3 (M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4)
.delta. 8.47 (dd, J=7.6, 0.5 Hz, 1H), 8.26 (s, 1H), 7.44 (d, J=2.6
Hz, 1H), 6.77 (dd, J=7.5, 2.6 Hz, 1H), 4.31-4.19 (m, 2H), 3.90-3.75
(m, 2H), 3.47-3.39 (m, 3H).
Intermediate 60:
5-(2-Morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid
##STR00197##
[0758] Intermediate 60A: Ethyl
5-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carboxylate
##STR00198##
[0760] According to the procedure for preparation of Intermediate
58A, alkylation of Intermediate 56A (40 mg) with
4-(2-bromoethyl)morpholine afforded Intermediate 60A (51 mg, 82%)
as a white solid. MS(ESI) 320.3 (M+H).sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.30 (dd, J=7.5, 0.7 Hz, 1H), 8.25 (s, 1H),
7.40 (d, J=2.6 Hz, 1H), 6.60 (dd, J=7.5, 2.6 Hz, 1H), 4.33 (q,
J=7.0 Hz, 2H), 4.19 (t, J=5.6 Hz, 2H), 3.78-3.67 (m, 4H), 2.83 (t,
J=5.6 Hz, 2H), 2.61-2.53 (m, 4H), 1.37 (t, J=7.2 Hz, 3H).
Intermediate 60
##STR00199##
[0762] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 60A (51 mg) with lithium
hydroxide afforded Intermediate 60 (60 mg, 93%) as a white solid.
MS(ESI) 292.3 (M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4)
.delta. 8.53 (dd, J=7.6, 0.5 Hz, 1H), 8.29 (s, 1H), 7.50 (d, J=2.6
Hz, 1H), 6.83 (dd, J=7.5, 2.6 Hz, 1H), 4.58-4.51 (m, 2H), 4.05 (br.
s., 2H), 3.88 (br. s., 2H), 3.78-3.70 (m, 2H), 3.65-3.48 (m, 2H),
3.45-3.34 (m, 2H).
Intermediate 61:
5-(2-Hydroxypropoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid
##STR00200##
[0763] Intermediate 61A: Ethyl
5-(2-hydroxypropoxy)pyrazolo[1,5-a]pyridine-3-carboxylate
##STR00201##
[0765] To a solution of Intermediate 56A (41 mg, 0.20 mmol) in
acetonitrile (3 ml) and water (0.2 ml) was added K.sub.2CO.sub.3
(137 mg, 0.994 mmol) and 2-methyloxirane (0.417 ml, 5.97 mmol). The
reaction mixture was heated to 120.degree. C. on MW for 30 min.
Reaction is completed. Concentrated and the residue was loaded onto
10 g column, eluted with EtOAc/Hex (0-50%); collected fraction at
30% EtOAc, concentrated to afford Intermediate 61A (26 mg, 50%).
MS(ESI) 265.2 (M+H).sup.+.
Intermediate 61
##STR00202##
[0767] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 61A (26 mg) with lithium
hydroxide afforded Intermediate 61 (21 mg, 82%) as a white solid.
MS(ESI) 265.2 (M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4)
.delta. 8.46 (dd, J=7.6, 0.6 Hz, 1H), 8.27-8.23 (m, 1H), 7.41 (d,
J=2.6 Hz, 1H), 6.84-6.75 (m, 1H), 4.17 (td, J=6.5, 4.0 Hz, 1H),
4.08-3.90 (m, 2H), 1.38-1.23 (m, 3H).
Intermediate 62:
5-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid
##STR00203##
[0768] Intermediate 62A: Methyl
5-(2-(benzyloxy)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylate
##STR00204##
[0770] According to the procedure for preparation of Intermediate
58A, alkylation of methyl
5-hydroxypyrazolo[1,5-a]pyridine-3-carboxylate (43 mg) with
((2-bromoethoxy)methyl)benzene afforded Intermediate 62A (71 mg,
99%). MS(ESI) 327.3 (M+H).sup.+.
Intermediate 62B:
5-(2-(Benzyloxy)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic
acid
##STR00205##
[0772] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 62A (75 mg) with lithium
hydroxide afforded Intermediate 62B (46 mg, 64%) as a white solid.
MS(ESI) 313.2 (M+H).sup.+.
Intermediate 62
##STR00206##
[0774] Intermediate 62B (43 mg, 0.138 mmol) was mixed with MeOH (5
mL), degassed, add 10% Pd/C (ca. 20 mg), stirred under H2 balloon
o/n for 16 h. Filtered and concentrated to afford Intermediate 62
(26 mg, 85%). MS(ESI) 223.2 (M+H).sup.+; .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 8.46 (d, J=7.7 Hz, 1H), 8.25 (s, 1H),
7.42 (d, J=2.6 Hz, 1H), 6.78 (dd, J=7.6, 2.8 Hz, 1H), 4.25-4.14 (m,
2H), 3.97-3.87 (m, 2H).
Intermediate 63:
5-(2-Hydroxy-3-methoxypropoxy)pyrazolo[1,5-a]pyridine-3-carboxylic
acid
##STR00207##
[0775] Intermediate 63A: Ethyl
5-(2-hydroxy-3-methoxypropoxy)pyrazolo[1,5-a]pyridine-3-carboxylate
##STR00208##
[0777] To a solution of Intermediate 56A (38 mg, 0.184 mmol) in
acetonitrile (3 ml) and water (0.2 ml) was added K.sub.2CO.sub.3
(102 mg, 0.737 mmol) and 2-(methoxymethyl)oxirane (487 mg, 5.53
mmol). The reaction mixture was heated to 120.degree. C. on MW for
35 min, LCMS shows the reaction was complete with formation of
desired product. Filtered and purified through prep HPLC to afford
Intermediate 63A (30 mg, 55%). MS(ESI) 295.2 (M+H).sup.+.
Intermediate 63
##STR00209##
[0779] According to the procedure for preparation of Intermediate
17, saponification of Intermediate 63A (60 mg) with lithium
hydroxide afford Intermediate 63 (47 mg, 87%) as a white solid.
MS(ESI) 267.1 (M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4)
.delta. 8.48-8.45 (m, 1H), 8.26 (s, 1H), 7.43 (d, J=2.8 Hz, 1H),
6.78 (dd, J=7.4, 2.8 Hz, 1H), 4.24-4.06 (m, 3H), 3.60-3.53 (m, 2H),
3.46-3.38 (m, 3H).
Intermediate 66: 4-(4-Aminophenyl)isoquinolin-1(2H)-one, TFA
##STR00210##
[0781] To 4-bromoisoquinolin-1(2H)-one (166 mg, 0.741 mmol),
(4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (176 mg, 0.741
mmol) and K.sub.3PO.sub.4 (393 mg, 1.85 mmol), were added dioxane
(9 mL) and water (1 mL). The mixture was degassed (evacuated and
flushed with Ar (5.times.)). Pd(PPh.sub.3).sub.4 (43 mg, 0.037
mmol) was added, then the mixture was degassed (2.times.). The
reaction vial was sealed and heated in a microwave reactor at
150.degree. C. for 40 min. The reaction mixture was concentrated,
then the residue was purified by flash chromatography (0-100%
EtOAc/Hex). The product was dissolved in DCM (2 mL), then was
treated with TFA (1 mL). The mixture was stirred rt for 1 h,
concentrated and purified via preparative HPLC to afford
Intermediate 66 (117 mg, 45% yield). MS(ESI) m/z: 237.1
(M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 8.41
(dd, J=8.0, 0.8 Hz, 1H), 7.70 (ddd, J=8.3, 7.0, 1.5 Hz, 1H),
7.61-7.50 (m, 5H), 7.49-7.42 (m, 2H), 7.14 (s, 1H), 3.35 (s,
1H).
Intermediate 67:
2-(4-(1-Oxo-1,2-dihydroisoquinolin-4-yl)phenyl)acetic acid
##STR00211##
[0782] Intermediate 67A: Ethyl
2-(4-(1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl)acetate
##STR00212##
[0784] To 4-bromoisoquinolin-1(2H)-one (166 mg, 0.741 mmol),
Intermediate 1A (215 mg, 0.741 mmol) and K.sub.3PO.sub.4 (393 mg,
1.85 mmol), were added dioxane (9 mL) and water (1 mL). The mixture
was degassed (evacuated and flushed with Ar (5.times.)).
Pd(PPh.sub.3).sub.4 (43 mg, 0.037 mmol) was added, then the mixture
was degassed (2.times.). The reaction vial was sealed and heated in
a microwave reactor at 150.degree. C. for 40 min. The reaction
mixture was concentrated, then was purified via prep HPLC to afford
Intermediate 67A (21 mg, 9.2% yield). MS(ESI) m/z: 308.1
(M+H).sup.+.
Intermediate 67
##STR00213##
[0786] A solution of Intermediate 67A (21 mg, 0.068 mmol) in THF,
was treated with 1M lithium hydroxide (0.2 ml, 0.200 mmol). The
mixture was stirred rt for 16 h, then was concentrated. The residue
was purified via preparative HPLC to afford Intermediate 67 (13 mg,
68% yield). MS(ESI) m/z: 280.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.40 (br. s., 1H), 11.43 (d, J=5.2 Hz, 1H),
8.30 (dd, J=7.8, 1.0 Hz, 1H), 7.69 (ddd, J=8.1, 7.0, 1.4 Hz, 1H),
7.57-7.49 (m, 2H), 7.42-7.33 (m, 5H), 7.08 (d, J=5.8 Hz, 1H), 3.31
(br. s., 2H).
Intermediate 68: 4-Bromo-6,7-dimethoxyisoquinolin-1 (2H)-one
##STR00214##
[0788] To a solution of 6,7-dimethoxyisoquinolin-1(2H)-one (205 mg,
1.00 mmol) in AcOH (2 mL), was add bromine (192 mg, 1.199 mmol) in
AcOH (1 mL). The mixture was stirred rt for 1 h, then poured onto
ice and extracted with EtOAc. The organic phase was washed with
brine, then was concentrated. The product was purified by flash
chromatography (0-80% EtOAc/Hex) to afford Intermediate 68 (230 mg,
0.81 mmol, 81% yield) as white form. MS(ESI) m/z: 283.9
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.42 (br.
s., 1H), 7.62 (s, 1H), 7.44 (br. s., 1H), 7.13 (s, 1H), 3.94 (s,
3H), 3.89 (s, 3H).
Intermediate 69: 6-Isopropoxyindoline
##STR00215##
[0789] Intermediate 69A: 6-(Benzyloxy)indoline
##STR00216##
[0791] To a solution of 6-(benzyloxy)-1H-indole (580 mg, 2.60 mmol)
in EtOH (5 mL) at 0.degree. C., was added Sodium cyanoborohydride
(326 mg, 5.20 mmol). The mixture was stirred rt for 16 h then was
concentrated. The residue was purified via prep HPLC to afford
Example 69A (280 mg; 32% yield) as a yellow oil. MS(ESI) m/z: 226.1
(M+H).sup.+; .sup.1H NMR (500 MHz, chloroform-d) .delta. 10.54 (br.
s., 2H), 7.46-7.32 (m, 5H), 7.26 (d, J=8.5 Hz, 1H), 7.13 (d, J=2.2
Hz, 1H), 6.99 (dd, J=8.5, 2.2 Hz, 1H), 4.99 (s, 2H), 3.97-3.84 (m,
2H), 3.23 (t, J=7.6 Hz, 2H).
Intermediate 69B: tert-Butyl
6-(benzyloxy)indoline-1-carboxylate
##STR00217##
[0793] To a mixture of Intermediate 69A (270 mg, 1.20 mmol) and
Boc.sub.2O (0.334 mL, 1.44 mmol) in THF at rt, was added cat. DMAP.
The resulting mixture was stirred rt for 16 h, then was
concentrated and. The residue was purified via flash chromatography
(0-50% EtOAc/Hex) to afford Intermediate 69B (150 mg; 39% yield).
MS(ESI) m/z: 326.1 (M+H).sup.+; .sup.1H NMR (500 MHz, chloroform-d)
.delta. 7.54-7.46 (m, 2H), 7.45-7.37 (m, 2H), 7.36-7.31 (m, 1H),
7.04 (d, J=8.0 Hz, 1H), 6.60 (dd, J=8.1, 2.3 Hz, 1H), 5.10 (s, 2H),
4.10-3.91 (m, 2H), 3.04 (t, J=8.7 Hz, 2H), 1.71-1.55 (m, 9H).
Intermediate 69C: tert-Butyl 6-hydroxyindoline-1-carboxylate
##STR00218##
[0795] To a degassed solution of Intermediate 69B (140 mg, 0.43
mmol) in MeOH (5 mL) was added 10% Pd/C (30 mg). The mixture was
stirred under H2 (balloon) for 4 h. The mixture was filtered and
concentrated to afford Intermediate 69C (90 mg; 89% yield) as white
solid. MS(ESI) m/z: 236.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
methanol-d.sub.4) .delta. 7.32-7.12 (m, 1H), 6.93-6.85 (m, 1H),
6.41-6.30 (m, 1H), 3.95-3.85 (m, 2H), 3.01-2.88 (m, 2H), 1.54 (br.
s., 9H).
Intermediate 69D: tert-Butyl 6-isopropoxyindoline-1-carboxylate
##STR00219##
[0797] Intermediate 69C (45 mg, 0.19 mmol) was mixed with
2-iodopropane (163 mg, 0.956 mmol), Cs.sub.2CO.sub.3 (93 mg, 0.287
mmol) in DMF (3 mL). The mixture was stirred at 80.degree. C. for
16 h, then was concentrated. The residue was purified via flash
chromatography (0-40% EtOAc/Hex) to afford Intermediate 69D (35 mg;
66% yield) as colorless foam. MS(ESI) m/z: 277.9 (M+H).sup.+;
.sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 7.50-7.26 (m, 1H),
7.01-6.95 (m, 1H), 6.46 (dd, J=8.3, 2.5 Hz, 1H), 4.50 (dt, J=11.9,
6.0 Hz, 1H), 3.99-3.83 (m, 2H), 3.03-2.92 (m, 2H), 1.64-1.48 (m,
9H), 1.32-1.25 (m, 6H).
Intermediate 69
##STR00220##
[0799] Intermediate 69D (35 mg, 0.13 mmol) was mixed with TFA (0.5
mL) and DCM (1 mL), and stirred rt for 20 min. The mixture was
concentrated to afford Intermediate 69 (36 mg; 99% yield) as a
colorless foam. MS(ESI) m/z: 177.9 (M+H).sup.+; .sup.1H NMR (500
MHz, methanol-d.sub.4) .delta. 7.40-7.31 (m, 1H), 7.05-6.95 (m,
2H), 4.61 (dt, J=12.1, 6.1 Hz, 1H), 3.86 (t, J=7.7 Hz, 2H), 3.24
(t, J=7.7 Hz, 2H), 1.34-1.27 (m, 6H).
Intermediate 70:
1-(Isoindolin-2-yl)-2-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)phenyl)ethanone
##STR00221##
[0800] Intermediate 70A:
2-(4-Bromo-3-methylphenyl)-1-(isoindolin-2-yl)ethanone
##STR00222##
[0802] To a solution of 2-(4-bromo-3-methylphenyl)acetic acid (200
mg, 0.87 mmol), isoindoline (0.109 mL, 0.96 mmol), and DIEA (0.305
mL, 1.75 mmol) in DMF (3 mL), was add HATU (398 mg, 1.05 mmol). The
mixture was stirred at rt for 19 h. The reaction mixture was
diluted with EtOAc, then was washed with H.sub.2O, sat.
Na.sub.2CO.sub.3 and brine. The organic phase was dried
(Na.sub.2SO.sub.4) and concentrated. The crude product was purified
by flash chromatography to afford Intermediate 70A (128 mg, 44%
yield) as an off-white solid. MS(ESI) 329.9 (M+H).sup.+; .sup.1H
NMR (400 MHz, chloroform-d) .delta. 7.48 (d, J=8.1 Hz, 1H),
7.32-7.27 (m, 3H), 7.25-7.20 (m, 2H), 7.01 (dd, J=8.1, 1.8 Hz, 1H),
4.82 (d, J=5.3 Hz, 4H), 3.69 (s, 2H), 2.38 (s, 3H).
Intermediate 70
##STR00223##
[0804] To a degassed (evacuated and flushed with Ar (3.times.))
mixture of Intermediate 70A (128 mg, 0.388 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (118
mg, 0.465 mmol) and potassium acetate (114 mg, 1.16 mmol) in
dioxane (2 mL), was added PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 adduct
(15.8 mg, 0.019 mmol). The mixture was degassed (2.times.), then
the vial was sealed and stirred at 110.degree. C. for 2.5 h. The
reaction mixture was diluted with EtOAc and was washed with
H.sub.2O and brine. The organic phase was dried (Na.sub.2SO.sub.4),
filtered through a 1'' pad of SiO.sub.2 and concentrated. The crude
product was purified by flash chromatography (gradient from 0 to
100% ethyl acetate/hexanes) to afford Intermediate 70 (126 mg, 86%
yield) as a yellow solid. MS(ESI) 378.1 (M+H).sup.+; .sup.1H NMR
(400 MHz, chloroform-d) .delta. 7.73 (d, J=7.7 Hz, 1H), 7.32-7.23
(m, 3H), 7.21-7.10 (m, 3H), 4.82 (s, 2H), 4.75 (s, 2H), 3.75 (s,
2H), 2.52 (s, 3H), 1.32 (s, 12H).
Intermediate 71:
1-(Indolin-1-yl)-2-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)phenyl)ethanone
##STR00224##
[0806] According to the procedure the preparation of Intermediate
70, substituting indoline for isoindoline afforded Intermediate 71.
MS(ESI) 378.1 (M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.26 (d, J=7.9 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.23-7.07
(m, 4H), 7.04-6.96 (m, 1H), 4.01 (t, J=8.5 Hz, 2H), 3.78 (s, 2H),
3.13 (t, J=8.5 Hz, 2H), 2.52 (s, 3H), 1.33 (s, 12H).
Intermediate 72:
2-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(ind-
olin-1-yl)ethanone
##STR00225##
[0808] According to the procedure the preparation of Intermediate
5, substituting indoline for isoindoline afforded Intermediate 72.
MS(ESI) 382.1 (M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.24 (d, J=8.1 Hz, 1H), 7.71 (dd, J=7.5, 6.6 Hz, 1H),
7.23-7.13 (m, 2H), 7.11 (d, J=7.7 Hz, 1H), 7.06-6.99 (m, 2H), 4.03
(t, J=8.5 Hz, 2H), 3.82 (s, 2H), 3.16 (t, J=8.5 Hz, 2H), 1.35 (s,
12H).
Intermediate 73: 4-Bromo-6-methoxyisoquinolin-1(2H)-one
##STR00226##
[0810] To a solution of 6-methoxyisoquinolin-1(2H)-one (112 mg,
0.639 mmol) in DMF (2 mL), was added NBS (137 mg, 0.767 mmol). The
mixture was stirred at rt overnight, then was concentrated. The
residue was purified via prep HPLC to afford Intermediate 73 (120
mg, 74% yield) as white solid. MS(ESI) m/z: 253.9 (M+H).sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.41 (br. s., 1H),
8.16 (d, J=8.8 Hz, 1H), 7.53 (d, J=4.4 Hz, 1H), 7.18 (dd, J=8.8,
2.4 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 3.99-3.87 (m, 3H).
Intermediate 74: 1-(Indolin-6-yloxy)-2-methylpropan-2-ol, TFA
##STR00227##
[0811] Intermediate 74A: tert-Buty
6-(2-hydroxy-2-methylpropoxy)indoline-1-carboxylate
##STR00228##
[0813] To a mixture of Intermediate 69C (12 mg, 0.051 mmol) and
2,2-dimethyloxirane (37 mg, 0.51 mmol) in acetonitrile (1 mL), was
added K.sub.2CO.sub.3 (35 mg, 0.26 mmol) in water (0.1 mL). The
mixture was stirred in a sealed tube at 100.degree. C. for 3 h,
then was concentrated. The residue was purified via flash
chromatography (0-40% EtOAc/Hex) to afford Intermediate 74A (12 mg,
64% yield). MS(ESI) m/z: 308.2 (M+H).sup.+. .sup.1H NMR (500 MHz,
chloroform-d) .delta. 7.61-7.46 (m, 1H), 7.02 (d, J=8.0 Hz, 1H),
6.50 (dd, J=8.1, 2.3 Hz, 1H), 3.99 (t, J=8.3 Hz, 2H), 3.80 (s, 2H),
3.07-2.96 (m, 2H), 1.59 (d, J=18.4 Hz, 9H), 1.33 (s, 6H).
Intermediate 74
##STR00229##
[0815] Intermediate 74A (12 mg, 0.039 mmol) was stirred with TFA
(0.5 mL) and DCM (0.5 mL) for 20 min, then was concentrated to
afford Intermediate 74 (12 mg, 96% yield). MS(ESI) m/z: 208.2
(M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta.
7.41-7.32 (m, 1H), 7.07-6.97 (m, 2H), 3.84 (t, J=7.7 Hz, 2H), 3.81
(s, 2H), 3.24 (t, J=7.7 Hz, 2H), 1.32 (s, 6H).
Intermediate 75: 6-(Pyridin-3-ylmethoxy)indoline, 2TFA
##STR00230##
[0816] Intermediate 75A: tert-Butyl
6-(pyridin-3-ylmethoxy)indoline-1-carboxylate
##STR00231##
[0818] To a solution of pyridin-3-ylmethanol (26.4 mg, 0.242 mmol),
Intermediate 69C (38 mg, 0.162 mmol), and triphenylphosphine (106
mg, 0.404 mmol) in THF (3 mL), was added DEAD (0.064 mL, 0.404
mmol). The reaction was stirred at rt overnight. The mixture was
purified by preparative HPLC to afford Intermediate 75A (42 mg, 59%
yield) as a white solid. MS(ESI) m/z: 327.1 (M+H).sup.+; .sup.1H
NMR (500 MHz, chloroform-d) .delta. 15.42 (br. s., 1H), 8.91 (s,
1H), 8.81 (d, J=5.2 Hz, 1H), 8.35 (d, J=8.0 Hz, 1H), 7.82 (dd,
J=8.0, 5.5 Hz, 1H), 7.63 (br. s., 1H), 7.05 (d, J=8.3 Hz, 1H), 6.54
(d, J=7.2 Hz, 1H), 5.23 (s, 2H), 4.00 (t, J=8.5 Hz, 2H), 3.04 (t,
J=8.5 Hz, 2H), 1.56 (br. s., 9H).
Intermediate 75
##STR00232##
[0820] Intermediate 75A (45 mg, 0.102 mmol) was stirred with TFA (1
mL) and DCM (2 mL) at rt for 20 min, then was concentrated to
afford Intermediate 75 (47 mg, 100% yield) as a yellow oil. MS(ESI)
m/z: 227.1 (M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4)
.delta. 9.01 (s, 1H), 8.85 (d, J=5.5 Hz, 1H), 8.70 (d, J=8.5 Hz,
1H), 8.10 (dd, J=8.0, 5.8 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.24 (d,
J=2.2 Hz, 1H), 7.21 (dd, J=8.5, 2.5 Hz, 1H), 5.40 (s, 2H),
3.94-3.85 (m, 2H), 3.28 (t, J=7.7 Hz, 2H).
Intermediate 76: 6-(Pyridin-2-ylmethoxy)indoline, 2TFA
##STR00233##
[0822] According to the procedure for the preparation of
Intermediate 75, substituting pyridin-2-ylmethanol for
pyridin-3-ylmethanol afforded Intermediate 76. MS(ESI) m/z: 227.1
(M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 8.82
(dd, J=5.5, 0.8 Hz, 1H), 8.48 (td, J=7.8, 1.7 Hz, 1H), 8.07 (d,
J=7.7 Hz, 1H), 7.98-7.82 (m, 1H), 7.46 (d, J=8.5 Hz, 1H), 7.35-7.14
(m, 2H), 5.56-5.39 (m, 2H), 3.93-3.82 (m, 2H), 3.30-3.25 (m,
2H).
Intermediate 77: 6-(Pyridin-4-ylmethoxy)indoline, 2TFA
##STR00234##
[0824] According to the procedure for the preparation of
Intermediate 75, substituting pyridin-4-ylmethanol for
pyridin-3-ylmethanol afforded Intermediate 77. MS(ESI) m/z: 227.1
(M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta.
8.94-8.84 (m, 2H), 8.22-8.15 (m, 2H), 7.48-7.41 (m, 1H), 7.25 (d,
J=2.2 Hz, 1H), 7.21 (dd, J=8.5, 2.5 Hz, 1H), 5.51 (s, 2H),
3.93-3.87 (m, 2H), 3.28 (t, J=7.7 Hz, 2H).
Intermediate 78: (R)-6-((Tetrahydrofuran-3-yl)oxy)indoline, TFA
##STR00235##
[0826] According to the procedure for the preparation of
Intermediate 75, substituting (S)-tetrahydrofuran-3-ol for
pyridin-3-ylmethanol afforded Intermediate 78. MS(ESI) m/z: 206.1
(M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 7.38
(d, J=8.3 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 7.01 (dd, J=8.5, 2.2 Hz,
1H), 5.03 (qd, J=4.0, 1.5 Hz, 1H), 4.02-3.79 (m, 6H), 3.25 (t,
J=7.7 Hz, 2H), 2.32-2.21 (m, 1H), 2.12-2.04 (m, 1H).
Intermediate 79: (S)-6-((Tetrahydrofuran-3-yl)oxy)indoline, TFA
##STR00236##
[0828] According to the procedure for the preparation of
Intermediate 75, substituting (R)-tetrahydrofuran-3-ol for
pyridin-3-ylmethanol afforded Intermediate 79. MS(ESI) m/z: 206.1
(M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta.
7.40-7.35 (m, 1H), 7.08-6.97 (m, 2H), 4.05-3.81 (m, 6H), 3.25 (t,
J=7.7 Hz, 2H), 2.38-2.23 (m, 1H), 2.17-2.03 (m, 1H).
Intermediate 80: (R)-6-((1-Methylpyrrolidin-3-yl)oxy)indoline,
2TFA
##STR00237##
[0830] According to the procedure for the preparation of
Intermediate 75, substituting (S)-1-methylpyrrolidin-3-ol for
pyridin-3-ylmethanol afforded Intermediate 80. MS(ESI) m/z: 219.1
(M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta.
7.46-7.39 (m, 1H), 7.17-7.11 (m, 1H), 7.10-7.03 (m, 1H), 5.24 (br.
s., 1H), 3.98-3.79 (m, 4H), 3.50-3.35 (m, 1H), 3.27 (t, J=7.7 Hz,
2H), 3.01 (br. s., 3H), 2.68 (br. s., 1H), 2.49-2.33 (m, 1H), 2.27
(br. s., 1H).
Intermediate 81: (S)-6-((1-Methylpyrrolidin-3-yl)oxy)indoline,
2TFA
##STR00238##
[0832] According to the procedure for the preparation of
Intermediate 75, substituting (R)-1-methylpyrrolidin-3-ol for
pyridin-3-ylmethanol afforded Intermediate 81. MS(ESI) m/z: 219.1
(M+H).sup.+.
Intermediate 82: 2-(Indolin-6-yloxy)-N,N-dimethylethanamine,
2TFA
##STR00239##
[0834] According to the procedure for the preparation of
Intermediate 75, substituting 2-(dimethylamino)ethanol for
pyridin-3-ylmethanol afforded Intermediate 82. MS(ESI) m/z: 207.2
(M+H).sup.+.
Intermediate 83: 6-((1-Methylpiperidin-4-yl)oxy)indoline, 2TFA
##STR00240##
[0836] According to the procedure for the preparation of
Intermediate 75, substituting 1-methylpiperidin-4-ol for
pyridin-3-ylmethanol afforded Intermediate 83. MS(ESI) m/z: 233.2
(M+H).sup.+.
Intermediate 84: Methyl 2-(indolin-6-yloxy)acetate
##STR00241##
[0838] According to the procedure for the preparation of
Intermediate 69, substituting methyl 2-bromoacetate for
2-iodopropane afforded Intermediate 84. MS(ESI) m/z: 208.1
(M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. 7.38
(d, J=8.5 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 7.02 (dd, J=8.4, 2.3 Hz,
1H), 4.77 (s, 2H), 3.86 (t, J=7.7 Hz, 2H), 3.78-3.75 (m, 3H), 3.24
(t, J=7.7 Hz, 2H).
Intermediate 85: 6-(Oxetan-3-ylmethoxy)indoline, TFA
##STR00242##
[0840] According to the procedure for the preparation of
Intermediate 75, substituting 3-(bromomethyl)oxetane for
pyridin-3-ylmethanol afforded Intermediate 85. MS(ESI) m/z: 206.1
(M+H).sup.+.
Intermediate 86: 6-(2-(Pyrrolidin-1-yl)ethoxy)indoline, 2TFA
##STR00243##
[0842] According to the procedure for the preparation of
Intermediate 69, substituting methyl 1-(2-bromoethyl)pyrrolidine,
hydrobromide for 2-iodopropane afforded Intermediate 86. MS(ESI)
m/z: 233.1 (M+H).sup.+.
Intermediate 87:
1-(6-(2-Hydroxy-2-methylpropoxy)indolin-1-yl)-2-(4-(4,4,5,5-tetramethyl-1-
,3,2-dioxaborolan-2-yl)phenyl)ethanone
##STR00244##
[0843] Intermediate 87A:
2-(4-Bromophenyl)-1-(6-(2-hydroxy-2-methylpropoxy)indolin-1-yl)ethanone
##STR00245##
[0845] To a mixture of 2-(4-bromophenyl)acetic acid (92 mg, 0.43
mmol), Intermediate 74 (138 mg, 0.43 mmol), and HATU (245 mg, 0.644
mmol) in DMF (5 mL), was add DIEA (0.375 mL, 2.15 mmol). The
mixture was stirred rt for 16 h. The reaction mixture was
concentrated and the residue was purified by flash chromatography
(0-80% EtOAc/Hex) to afford Intermediate 87A (162 mg, 93% yield) as
a colorless foam. MS(ESI) m/z: 404.0 (M+H).sup.+; .sup.1H NMR (500
MHz, chloroform-d) .delta. 7.93 (d, J=2.2 Hz, 1H), 7.49-7.44 (m,
2H), 7.20-7.14 (m, J=8.3 Hz, 2H), 7.04 (d, J=8.3 Hz, 1H), 6.60 (dd,
J=8.3, 2.2 Hz, 1H), 4.11-4.02 (m, 2H), 3.77 (s, 2H), 3.72 (s, 2H),
3.10 (t, J=8.4 Hz, 2H), 1.36-1.28 (m, 6H).
Intermediate 87
##STR00246##
[0847] To a mixture of Intermediate 87A (163 mg, 0.403 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (123
mg, 0.484 mmol), and potassium acetate (119 mg, 1.21 mmol) in
dioxane (4 mL), was added PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 adduct
(8.9 mg, 0.012 mmol). The reaction mixture was degassed (3.times.
vacuum/Ar), sealed in a vial and heated at 110.degree. C. for 2 h.
The reaction mixture was diluted with water, then was extracted
with EtOAc. The organic phase was concentrated and the residue was
purified by flash chromatography (0-80% EtOAc/Hex) to afford
Intermediate 87 (178 mg, 98% yield). MS(ESI) m/z: 452.2
(M+H).sup.+; .sup.1H NMR (500 MHz, chloroform-d) .delta. 7.95 (d,
J=2.2 Hz, 1H), 7.81-7.77 (m, J=8.3 Hz, 2H), 7.34-7.30 (m, J=8.0 Hz,
2H), 7.02 (d, J=8.3 Hz, 1H), 6.59 (dd, J=8.1, 2.3 Hz, 1H), 4.05 (t,
J=8.4 Hz, 2H), 3.80 (d, J=13.2 Hz, 4H), 3.07 (t, J=8.3 Hz, 2H),
1.34 (s, 12H), 1.24-1.22 (m, 6H).
Intermediate 88: N,N-Dimethylindoline-6-carboxamide, TFA
##STR00247##
[0848] Intermediate 88A: N,N-Dimethyl-1H-indole-6-carboxamide
##STR00248##
[0850] To a mixture of 1H-indole-6-carboxylic acid (110 mg, 0.683
mmol), dimethylamine, HCl (83 mg, 1.024 mmol), and HATU (389 mg,
1.024 mmol) in DMF (3 mL), was added DIEA (0.596 mL, 3.41 mmol).
The mixture was stirred rt for 2 h, then was concentrated. The
mixture was purified by prep HPLC to afford Intermediate 88A (125
mg, 97% yield). MS(ESI) m/z: 189.0 (M+H).sup.+; .sup.1H NMR (500
MHz, chloroform-d) .delta. 9.56 (br. s., 1H), 7.61 (d, J=8.0 Hz,
1H), 7.38-7.34 (m, 1H), 7.24-7.19 (m, 1H), 7.12 (dd, J=8.1, 1.5 Hz,
1H), 6.53-6.48 (m, 1H), 3.27-3.05 (m, 3H), 2.99 (br. s., 3H).
Intermediate 88
##STR00249##
[0852] To a solution of Intermediate 88A (125 mg, 0.664 mmol) in
AcOH (3 mL) at 0.degree. C. was added Sodium cyanoborohydride (83
mg, 1.328 mmol). The mixture was stirred at 0.degree. C. for 5 min,
warmed to rt and stirred for 5 h. The reaction mixture was made
basic with 20% NaOH at 0.degree. C., then was extracted with DCM
(3.times.70 mL). The organic layer was washed with brine, dried
over Na.sub.2SO.sub.4, concentrated and purified via preparative
HPLC to afford Intermediate 88 (155 mg, 0.509 mmol, 77% yield) as a
yellow oil. MS(ESI) m/z: 191.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
methanol-d.sub.4) .delta. 7.60-7.53 (m, 1H), 7.52-7.46 (m, 2H),
3.89 (t, J=7.8 Hz, 2H), 3.36 (t, J=7.8 Hz, 2H), 3.11 (s, 3H), 3.00
(s, 3H).
Intermediate 89: Indolin-6-yl(4-methylpiperazin-1-yl)methanone,
2TFA
##STR00250##
[0854] According to the procedure for the preparation of
Intermediate 88, substituting 1-methylpiperazine for dimethylamine,
HCl afforded Intermediate 89. MS(ESI) m/z: 246.1 (M+H).sup.+.
Intermediate 90:
(4-Hydroxypiperidin-1-yl)(indolin-5-yl)methanone
##STR00251##
[0856] According to the procedure for the preparation of
Intermediate 88, substituting piperidin-4-ol for dimethylamine, HCl
and 1H-indole-5-carboxylic acid for 1H-indole-6-carboxylic acid
afforded Intermediate 90. MS(ESI) m/z: 247.1 (M+H).sup.+; .sup.1H
NMR (400 MHz, chloroform-d) .delta. 7.16-7.12 (m, 1H), 7.03 (dd,
J=8.0, 1.7 Hz, 1H), 6.51 (d, J=7.9 Hz, 1H), 3.93 (br. s., 1H), 3.84
(tt, J=8.3, 4.0 Hz, 2H), 3.64-3.41 (m, 4H), 3.19 (ddd, J=13.2, 9.5,
3.3 Hz, 2H), 2.99 (t, J=8.5 Hz, 2H), 1.88-1.73 (m, 2H), 1.57-1.41
(m, 2H).
Intermediate 91: (4-Hydroxypiperidin-1-yl)(indolin-6-yl)methanone,
TFA
##STR00252##
[0858] According to the procedure for the preparation of
Intermediate 88, substituting piperidin-4-ol for dimethylamine, HCl
afforded Intermediate 91. MS(ESI) m/z: 247.1 (M+H).sup.+; .sup.1H
NMR (500 MHz, methanol-d.sub.4) .delta. 7.57 (dd, J=7.7, 0.8 Hz,
1H), 7.51-7.47 (m, 2H), 4.16 (br. s., 1H), 3.95-3.88 (m, 3H), 3.60
(br. s., 1H), 3.37 (t, J=7.8 Hz, 3H), 3.28-3.17 (m, 1H), 2.02-1.88
(m, 1H), 1.82 (br. s., 1H), 1.57 (br. s., 1H), 1.46 (br. s.,
1H).
Intermediate 92: Indolin-6-yl(morpholino)methanone, TFA
##STR00253##
[0860] According to the procedure for the preparation of
Intermediate 88, substituting morpholine for dimethylamine, HCl
afforded Intermediate 92. MS(ESI) m/z: 233.1 (M+H).sup.+; .sup.1H
NMR (400 MHz, chloroform-d) .delta. 12.19 (br. s., 3H), 7.42 (d,
J=7.9 Hz, 1H), 7.35 (dd, J=7.8, 1.2 Hz, 1H), 7.20 (s, 1H), 3.93 (t,
J=7.8 Hz, 2H), 3.77 (br. s., 4H), 3.60 (br. s., 2H), 3.42-3.24 (m,
4H).
Intermediate 93: Indolin-5-yl(morpholino)methanone
##STR00254##
[0862] According to the procedure for the preparation of
Intermediate 88, substituting morpholine for dimethylamine, HCl and
1H-indole-5-carboxylic acid for 1H-indole-6-carboxylic acid
afforded Intermediate 93. MS(ESI) m/z: 233.1 (M+H).sup.+; .sup.1H
NMR (400 MHz, chloroform-d) .delta. 7.19 (d, J=1.1 Hz, 1H),
7.11-7.06 (m, 1H), 6.53 (d, J=8.1 Hz, 1H), 4.04 (br. s., 1H),
3.76-3.54 (m, 10H), 3.02 (t, J=8.6 Hz, 2H).
Intermediate 94: 4-(4-Amino-2-methylphenyl)phthalazin-1(2H)-one,
TFA
##STR00255##
[0863] Intermediate 94A: tert-Butyl
(4-bromo-3-methylphenyl)carbamate
##STR00256##
[0865] To a solution of 4-bromo-3-methylaniline (2.0 g, 10.8 mmol)
and Boc.sub.2O (2.82 g, 12.9 mmol) in MeOH (20 mL), was added
sodium carbonate (2.51 g, 23.7 mmol). The mixture was stirred at rt
for 5 h. Additional Boc.sub.2O (0.28 g, 1.3 mmol) was added and the
mixture was stirred at rt for 20 h. The reaction mixture was
filtered to remove inorganic salt. The filtrate was concentrated to
give a white solid, which was suspended in EtOAc (.about.100 mL).
The suspension was filtered through a 1'' pad of SiO.sub.2. The
filtrate was concentrated to afford Intermediate 94A (3.03 g, 98%
yield) as a white solid. MS(ESI) m/z: 307.9 (M+Na).sup.+; .sup.1H
NMR (400 MHz, chloroform-d) .delta. 7.40 (d, J=8.6 Hz, 1H), 7.32
(d, J=1.8 Hz, 1H), 7.02 (dd, J=8.6, 2.6 Hz, 1H), 6.38 (br. s., 1H),
2.36 (s, 3H), 1.51 (s, 9H).
Intermediate 94B: tert-Butyl
(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methylphenyl)carbamate
##STR00257##
[0867] To a vial containing Intermediate 94A (1.5 g, 5.24 mmol),
5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (1.30 g, 5.77
mmol) and potassium acetate (1.54 g, 15.7 mmol), was added dioxane
(15 ml). The mixture was degassed (evacuated and flushed with Ar
(3.times.)), then PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 adduct (0.214
g, 0.262 mmol) was added. The mixture was degassed (3.times.), then
the vial was sealed and heated at 110.degree. C. for 2.5 h. The
reaction mixture was partitioned between EtOAc and H.sub.2O. The
organic phase was washed with H.sub.2O and brine, dried
(Na.sub.2SO.sub.4), filtered through a 1'' pad of SiO.sub.2 and
concentrated. The crude product was purified by flash
chromatography (gradient from 0 to 50% ethyl acetate/hexanes) to
afford Intermediate 94B (1.545 g, 4.84 mmol, 92% yield) as an
orange foam. MS(ESI) m/z: 250.2 (M(boronic acid)-H).sup.-; .sup.1H
NMR (400 MHz, chloroform-d) .delta. 7.67 (d, J=8.1 Hz, 1H), 7.17
(s, 1H), 7.11 (dd, J=8.1, 2.0 Hz, 1H), 6.41 (br. s., 1H), 3.75 (s,
4H), 2.49 (s, 3H), 1.51 (s, 9H), 1.02 (s, 6H).
Intermediate 94C: tert-Butyl
(3-methyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate
##STR00258##
[0869] To 4-chlorophthalazin-1(2H)-one (400 mg, 2.22 mmol),
Intermediate 94B (778 mg, 2.44 mmol) and phosphoric acid, potassium
salt (1175 mg, 5.54 mmol), were added dioxane (6 mL) and water
(0.667 mL). The mixture was degassed (evacuated and flushed with Ar
(5.times.)). Pd(PPh.sub.3).sub.4 (128 mg, 0.111 mmol) was added,
then the mixture was degassed (2.times.). The reaction vial was
sealed and heated in a microwave reactor at 150.degree. C. for 40
min. The reaction mixture was partitioned between EtOAc and
H.sub.2O. The organic phase was washed with H.sub.2O and brine,
dried (Na.sub.2SO.sub.4) and concentrated. The crude product was
purified by flash chromatography (gradient from 0 to 100% ethyl
acetate/hexanes) to afford Intermediate 94C (540 mg, 1.54 mmol, 69%
yield) as a white solid. MS(ESI) m/z: 352.0 (M+H).sup.+; .sup.1H
NMR (400 MHz, methanol-d.sub.4) .delta. 8.46-8.40 (m, 1H),
7.91-7.80 (m, 2H), 7.47-7.35 (m, 3H), 7.20 (d, J=8.1 Hz, 1H), 2.09
(s, 3H), 1.54 (s, 9H).
Intermediate 94
##STR00259##
[0871] To a suspension of Intermediate 94C (540 mg, 1.54 mmol) in
DCM (5 mL), was added TFA (2 mL). The mixture was stirred at rt for
2 h. The reaction mixture was concentrated, then was co-evaporated
with DCM (3.times.) to afford Intermediate 94 (723 mg, 98% yield)
as a solid. MS(ESI) m/z: 252.1 (M+H).sup.+; .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 8.45 (dd, J=7.9, 1.1 Hz, 1H), 7.93-7.82
(m, 2H), 7.48 (d, J=8.1 Hz, 1H), 7.38-7.27 (m, 3H), 2.19 (s,
3H)
Intermediate 95: 4-(Dimethylamino)-N-(indolin-6-yl)benzamide,
2TFA
##STR00260##
[0872] Intermediate 95A: tert-Butyl
6-nitroindoline-1-carboxylate
##STR00261##
[0874] To a mixture of 6-nitroindoline (300 mg, 1.83 mmol) and
Boc.sub.2O (0.509 mL, 2.19 mmol) in THF at rt, was added cat. DMAP.
The resulting mixture was stirred rt o/n. The reaction mixture was
concentrated and the residue was purified by flash chromatography
(0-20% EtOAc/Hex) to afford Intermediate 95A (480 mg, 99% yield).
MS(ESI) m/z: 287.0 (M+Na).sup.+; .sup.1H NMR (500 MHz,
methanol-d.sub.4) .delta. 8.51 (br. s., 1H), 7.81 (dd, J=8.3, 2.2
Hz, 1H), 7.33 (d, J=8.3 Hz, 1H), 4.12-4.02 (m, 2H), 3.25-3.16 (m,
2H), 1.67-1.49 (m, 9H).
Intermediate 95B: tert-Butyl 6-Aminoindoline-1-carboxylate
##STR00262##
[0876] To a degassed mixture of Intermediate 95A (450 mg, 1.70
mmol) in MeOH (10 mL), was add 10% Pd/C. The mixture was stirred rt
for 2 h under H2 (balloon). The reaction mixture was filtered and
concentrated. The residue was purified by flash chromatography
(0-40% EtOAc/Hex) to afford Intermediate 95B (300 mg, 75% yield).
MS(ESI) m/z: 235.1 (M+H).sup.+; .sup.1H NMR (500 MHz, chloroform-d)
.delta. 7.78-7.14 (m, 1H), 6.54-6.42 (m, 2H), 3.90 (br. s., 2H),
3.61-3.40 (m, 2H), 2.96 (t, J=8.5 Hz, 2H), 1.71-1.46 (m, 9H).
Intermediate 95C: tert-Butyl
6-(4-(dimethylamino)benzamido)indoline-1-carboxylate
##STR00263##
[0878] To a mixture of 4-(dimethylamino)benzoyl chloride (22 mg,
0.12 mmol) and Intermediate 95B (23 mg, 0.098 mmol) in DCM (2 mL)
at 0.degree. C., was added DIEA (0.051 mL, 0.30 mmol). The mixture
was stirred rt for 1 h, then was concentrated. The residue was
purified by flash chromatography (0-60% EtOAc/Hex) to afford
Intermediate 95C (17 mg, 45.4% yield). MS(ESI) m/z: 382.2
(M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.17-8.02
(m, 1H), 7.91-7.82 (m, 2H), 7.60 (br. s., 1H), 7.15 (d, J=8.6 Hz,
2H), 4.07-3.97 (m, 2H), 3.19-3.14 (m, 6H), 3.12-3.05 (m, 2H), 1.58
(br. s., 9H)
Intermediate 95
##STR00264##
[0880] Intermediate 95C (17 mg, 0.045 mmol) stirred with TFA and
DCM for 20 min, then was concentrated to afford Intermediate 95 (19
mg). MS(ESI) m/z: 282.1 (M+H).sup.+: .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 7.94-7.85 (m, 3H), 7.76-7.67 (m, 1H),
7.44 (d, J=8.6 Hz, 1H), 6.90-6.81 (m, 2H), 3.93-3.87 (m, 2H), 3.35
(t, J=7.7 Hz, 2H), 3.07 (s, 6H).
Intermediate 96: 4-(4-Amino-2-chlorophenyl)phthalazin-1
(2H)-one
##STR00265##
[0881] Intermediate 96A: tert-Butyl
(4-bromo-3-chlorophenyl)carbamate
##STR00266##
[0883] To a solution of 4-bromo-3-chloroaniline (1.5 g, 7.3 mmol)
and Boc.sub.2O (2.38 g, 10.9 mmol) in MeOH (20 mL), was added
sodium carbonate (1.694 g, 15.98 mmol). The mixture was stirred at
rt for 16 h. The reaction mixture was concentrated. The residue was
suspended in water, then extracted with DCM. The organic phase was
concentrated and the residue was purified by flash chromatography
(0-20% EtOAc/Hex) to afford Intermediate 96A (2.0 g, 6.52 mmol, 90%
yield). .sup.1H NMR (400 MHz, chloroform-d) .delta. 7.64 (d, J=2.4
Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.08 (dd, J=8.7, 2.5 Hz, 1H), 6.46
(br. s., 1H), 1.53-1.51 (m, 9H).
Intermediate 96B: tert-Butyl
(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate
##STR00267##
[0885] A mixture of Intermediate 96A (1.96 g, 6.39 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.79
g, 7.03 mmol), and potassium acetate (1.88 g, 19.2 mmol) in dioxane
(10 mL). Then PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 adduct (0.14 g,
0.19 mmol) was added, the reaction mixture was degassed (3.times.
vacuum/Ar), sealed in a vial and heated at 110.degree. C. for 16 h.
The reaction was quenched with water, extracted with EtOAc,
concentrated and purified through via flash chromatography (0-40%
EtOAc/Hex) to Intermediate 96B (1.40 g, 62% yield). MS(ESI) m/z:
298.1 (M-(t-Bu)+2H).sup.+; .sup.1H NMR (400 MHz, chloroform-d)
.delta. 7.63 (d, J=8.1 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.18 (dd,
J=8.1, 2.0 Hz, 1H), 6.50 (s, 1H), 1.52 (s, 9H), 1.40-1.33 (m,
12H).
Intermediate 96C: tert-Butyl
(3-chloro-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate
##STR00268##
[0887] To 4-chlorophthalazin-1(2H)-one (100 mg, 0.554 mmol),
Intermediate 96B (206 mg, 0.581 mmol) and phosphoric acid,
potassium salt (294 mg, 1.38 mmol), were added dioxane (5 mL) and
water (0.556 mL). The mixture was degassed (evacuated and flushed
with Ar (5.times.)). Pd(PPh.sub.3).sub.4 (32 mg, 0.028 mmol) was
added, then the mixture was degassed (2.times.). The reaction vial
was sealed and heated in a microwave reactor at 150.degree. C. for
30 min. The reaction mixture was concentrated, then purified by
flash chromatography (0-80% EtOAc/Hex) to afford Intermediate 96C
(200 mg, 97% yield). (ESI) m/z: 372.0 (M+H).sup.+.
Intermediate 96
##STR00269##
[0889] Intermediate 96C (200 mg, 0.538 mmol) was stirred with TFA
(2 mL) and DCM (3 ml) at rt for 30 min. The reaction mixture was
concentrated and the residue was purified by flash chromatography
(0-100% EtOAc/Hex) to afford Intermediate 96 (120 mg, 82% yield).
MS(ESI) m/z 272.0 (M+H).sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.73 (s, 1H), 8.36-8.22 (m, 1H), 7.93-7.78 (m, 2H),
7.41-7.24 (m, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.76 (d, J=2.2 Hz, 1H),
6.64 (dd, J=8.4, 2.2 Hz, 1H), 5.75 (s, 1H).
Intermediate 97:
N-(3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)indolin-
e-1-carboxamide
##STR00270##
[0890] Intermediate 97A:
N-(4-Bromo-3-methylphenyl)indoline-1-carboxamide
##STR00271##
[0892] To a solution of 1-bromo-4-isocyanato-2-methylbenzene (111
mg, 0.523 mmol) in CH.sub.2Cl.sub.2 (1 mL), was added indoline
(68.6 mg, 0.576 mmol) in CH.sub.2Cl.sub.2 (1 mL). The mixture was
stirred at rt for 1 h, then was concentrated. The residue was
purified by flash chromatography (0-50% EtOAc/Hex) to afford
Intermediate 97A (170 mg, 0.513 mmol, 98% yield) as a white solid.
MS(ESI) m/z: 331.0 (M+H).sup.+.
Intermediate 97
##STR00272##
[0894] A mixture of Intermediate 97A (170 mg, 0.513 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (143
mg, 0.565 mmol), and potassium acetate (151 mg, 1.54 mmol) in
dioxane (10 mL). PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 adduct (11.27
mg, 0.015 mmol) was added, the reaction mixture was degassed
(3.times. vacuum/Ar), sealed in a vial and heated at 110.degree. C.
for 3 h. The reaction was quenched with water and extracted with
EtOAc. The organic phase was concentrated and the residue was
purified via flash chromatography (0-40% EtOAc/Hex) to afford
Intermediate 97 (100 mg, 0.264 mmol, 51.5% yield). MS(ESI) m/z:
379.1 (M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d) .delta. 7.89
(d, J=7.9 Hz, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H),
7.26-7.16 (m, 3H), 7.01-6.93 (m, 1H), 6.50 (s, 1H), 4.08 (t, J=8.5
Hz, 2H), 3.23 (t, J=8.6 Hz, 2H), 2.54 (s, 3H), 1.35 (s, 12H).
Intermediate 98: Methyl
2-(3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)-1-
H-indazol-1-yl)acetate
##STR00273##
[0895] Intermediate 98A: tert-Butyl
3-((4-bromophenyl)carbamoyl)-1H-indazole-1-carboxylate
##STR00274##
[0897] To a solution of 4-bromoaniline (63.0 mg, 0.366 mmol),
1-(I-butoxycarbonyl)-1H-indazole-3-carboxylic acid (96 mg, 0.366
mmol), and HATU (146 mg, 0.384 mmol) in DMF (3 mL), was added DIEA
(0.32 mL, 1.83 mmol). The reaction mixture was stirred at rt for 16
h, then was diluted with water. The mixture was extracted with
EtOAc. The organic phase was washed with 10% LiCl and brine, then
concentrated. The residue was purified by flash chromatography
(0-20% EtOAc/Hex) to afford Intermediate 98A (118 mg, 77% yield).
MS(ESI) m/z: 416.1 (M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.98 (s, 1H), 8.48 (dt, J=8.0, 0.9 Hz, 1H), 8.12 (d, J=8.6
Hz, 1H), 7.72-7.65 (m, 2H), 7.63-7.56 (m, 1H), 7.54-7.48 (m, 2H),
7.45 (ddd, J=8.1, 7.1, 0.9 Hz, 1H), 1.78 (s, 9H).
Intermediate 98B: N-(4-Bromophenyl)-1H-indazole-3-carboxamide
##STR00275##
[0899] Intermediate 98A (118 mg, 0.283 mmol) was stirred with TFA
(1 mL) and DCM (2 mL) for 30 min at rt, then was concentrated. The
residue was purified by flash chromatography (0-50% EtOAc/Hex) to
afford Intermediate 98B (65 mg, 0.206 mmol, 72.5% yield) as a
yellow solid. MS(ESI) m/z: 316.0 (M+H).sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 13.80 (br. s., 1H), 10.49 (s, 1H), 8.22 (d,
J=8.1 Hz, 1H), 7.99-7.84 (m, 2H), 7.67 (d, J=8.4 Hz, 1H), 7.57-7.49
(m, 2H), 7.46 (ddd, J=8.3, 7.0, 1.0 Hz, 1H), 7.34-7.24 (m, 1H).
Intermediate 98C: Methyl
2-(3-((4-bromophenyl)carbamoyl)-1H-indazol-1-yl)acetate
##STR00276##
[0901] To a vial containing Intermediate 98B (65 mg, 0.21 mmol) in
DMF (3 mL), were added methyl 2-bromoacetate (38 mg, 0.25 mmol) and
K.sub.2CO.sub.3 (43 mg, 0.31 mmol). The vial was sealed and the
mixture was stirred at rt for 3 h. The reaction mixture was
concentrated, then the residue was diluted with water and extracted
with EtOAc. The organic phase was dried over Na.sub.2SO.sub.4 and
concentrated. The residue was purified by flash chromatography
(0-50% EtOAc/Hex) to afford Intermediate 98C (70 mg, 88% yield) as
a yellow solid. MS(ESI) m/z: 388.0 (M+H).sup.+; .sup.1H NMR (400
MHz, chloroform-d) .delta. 8.80 (s, 1H), 8.44 (dt, J=8.1, 1.0 Hz,
1H), 7.70-7.60 (m, 2H), 7.55-7.45 (m, 3H), 7.41-7.32 (m, 2H), 5.20
(s, 2H), 3.79 (s, 3H).
Intermediate 98
##STR00277##
[0903] To a mixture of Intermediate 98C (72 mg, 0.19 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (51.8
mg, 0.204 mmol), and potassium acetate (54.6 mg, 0.556 mmol) in
dioxane (10 mL), was added PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 adduct
(4.1 mg, 5.6 .mu.mol). The reaction mixture was degassed (3.times.
vacuum/Ar), sealed in a vial and heated at 110.degree. C. for 3 h.
The reaction was diluted with water, then was extracted with EtOAc.
The organic phase was concentrated, then the product was purified
by flash chromatography (0-50% EtOAc/Hex) to afford Intermediate 98
(80 mg, 99% yield) as a colorless oil. MS(ESI) m/z: 388.0
(M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.89 (s,
1H), 8.46 (dt, J=8.1, 1.0 Hz, 1H), 7.89-7.82 (m, 2H), 7.81-7.73 (m,
2H), 7.53-7.43 (m, 1H), 7.35 (td, J=8.1, 1.0 Hz, 2H), 5.21 (s, 2H),
3.78 (s, 3H), 1.36 (s, 12H).
Intermediate 99: Methyl
3-(3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)-1-
H-indazol-1-yl)propanoate
##STR00278##
[0905] According to the procedure for the preparation of
Intermediate 98, substituting methyl 3-bromopropanoate for methyl
2-bromoacetate afforded Intermediate 99. MS(ESI) m/z: 450.3
(M+H).sup.+.
Intermediate 100:
1-(3-Hydroxy-3-methylbutyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)phenyl)-1H-indazole-3-carboxamide
##STR00279##
[0906] Intermediate 100A: Methyl
3-(3-((4-bromophenyl)carbamoyl)-1H-indazol-1-yl)propanoate
##STR00280##
[0908] To a vial containing Intermediate 98B (150 mg, 0.474 mmol)
in DMF (3 mL), were added methyl 3-bromopropanoate (95 mg, 0.569
mmol) and K.sub.2CO.sub.3 (98 mg, 0.712 mmol). The vial was sealed
and the mixture was stirred at rt for 3 h. The reaction mixture was
concentrated, and the residue was diluted with water and extracted
with EtOAc. The organic phase was dried over Na.sub.2SO.sub.4 and
concentrated. The residue was purified by flash chromatography
(0-50% EtOAc/Hex) to afford Intermediate 100A (180 mg, 94% yield).
MS(ESI) m/z: 402.2 (M+H).sup.+; .sup.1H NMR (500 MHz, chloroform-d)
.delta. 8.80 (s, 1H), 8.39 (d, J=8.3 Hz, 1H), 7.68-7.63 (m, 2H),
7.56-7.44 (m, 4H), 7.32 (ddd, J=8.0, 6.9, 0.8 Hz, 1H), 4.71 (t,
J=6.9 Hz, 2H), 3.73-3.66 (m, 3H), 3.05 (t, J=6.7 Hz, 2H).
Intermediate 100B:
N-(4-Bromophenyl)-1-(3-hydroxy-3-methylbutyl)-1H-indazole-3-carboxamide
##STR00281##
[0910] Intermediate 100A (85 mg, 0.211 mmol) was treated with 3M
methylmagnesium chloride (0.704 mL, 2.11 mmol) at 0.degree. C. to
afford Intermediate 100B (68 mg, 80% yield) as a colorless oil.
MS(ESI) m/z: 402.1 (M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.84 (s, 1H), 8.40 (dt, J=8.2, 1.0 Hz, 1H), 7.71-7.63 (m,
2H), 7.52-7.40 (m, 4H), 7.31 (ddd, J=8.1, 6.7, 1.1 Hz, 1H),
4.64-4.52 (m, 2H), 2.20-2.09 (m, 2H), 1.34 (s, 6H).
Intermediate 100
##STR00282##
[0912] A mixture of Intermediate 100B (70 mg, 0.17 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (49 mg,
0.191 mmol), and potassium acetate (51 mg, 0.52 mmol) in dioxane
(10 mL). Then PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 adduct (3.8 mg,
5.22 mol) was added, the reaction mixture was degassed (3.times.
vacuum/Ar), sealed in a vial and heated at 110.degree. C. for 3 h.
The reaction progress was quenched with water, extracted with
EtOAc. The organic phase was concentrated and was purified by flash
chromatography (0-50% EtOAc/Hex) to afford Intermediate 100 (78 mg,
100% yield). MS(ESI) m/z: 450.3.
Intermediate 101:
1-((1-(tert-Butoxycarbonyl)piperidin-4-yl)methyl)-1H-indazole-3-carboxyli-
c acid
##STR00283##
[0914] According to the procedure for the preparation of
Intermediate 21, substituting tert-butyl
4-(bromomethyl)piperidine-1-carboxylate, hydrobromide for benzyl
4-(bromomethyl)piperidine-1-carboxylate afforded Intermediate 101.
MS(ESI) m/z: 360.3 (M+H).sup.+; .sup.1H NMR (500 MHz,
methanol-d.sub.4) .delta. 8.14 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.5
Hz, 1H), 7.47-7.40 (m, 1H), 7.31-7.25 (m, 1H), 4.36 (d, J=7.2 Hz,
2H), 4.06-3.97 (m, 2H), 2.66 (br. s., 2H), 2.21 (ddt, J=11.2, 7.5,
3.8 Hz, 1H), 1.53-1.45 (m, 2H), 1.44-1.35 (m, 9H), 1.26-1.17 (m,
2H).
Intermediate 102: 4-(4-Amino-2-methoxyphenyl)phthalazin-1(2H)-one,
TFA
##STR00284##
[0915] Intermediate 102A: tert-Butyl
(4-bromo-3-methoxyphenyl)carbamate
##STR00285##
[0917] To a solution of 4-bromo-3-methoxyaniline, HCl (0.6 g, 2.5
mmol) and Boc.sub.2O (0.824 g, 3.77 mmol) in MeOH (10 mL), was
added sodium carbonate (0.80 g, 7.55 mmol). The mixture was stirred
at rt for 3 h. The reaction mixture was concentrated and the
residue was purified by flash chromatography (0-20% EtOAc/Hex) to
afford Intermediate 102A (550 mg, 72% yield). MS(ESI) m/z: 302.2
(M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d) .delta. 7.39 (d,
J=8.4 Hz, 1H), 7.32 (s, 1H), 6.63 (dd, J=8.5, 2.3 Hz, 1H), 6.49
(br. s., 1H), 3.91 (s, 3H), 1.55-1.48 (m, 9H).
Intermediate 102B: tert-Butyl
(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamat-
e
##STR00286##
[0919] To a mixture of Intermediate 102A (340 mg, 1.13 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (314
mg, 1.24 mmol), and potassium acetate (331 mg, 3.38 mmol) in
dioxane (8 mL), was added PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 adduct
(24.7 mg, 0.034 mmol). The reaction mixture was degassed (3.times.
vacuum/Ar), sealed in a vial and heated at 110.degree. C. for 3 h.
The reaction was diluted with water and extracted with EtOAc. The
organic phase was concentrated and the residue was purified by
flash chromatography (0-50% EtOAc/Hex) to afford Intermediate 102B
(200 mg, 51% yield) as a colorless foam. MS(ESI) m/z: 350.3
(M+H).sup.+; .sup.1H NMR (500 MHz, chloroform-d) .delta. 7.59 (d,
J=8.0 Hz, 1H), 7.18 (br. s., 1H), 6.81 (br. s., 1H), 6.75 (dd,
J=8.1, 1.8 Hz, 1H), 3.81 (s, 3H), 1.54-1.48 (m, 9H), 1.36-1.31 (m,
12H).
Intermediate 102C: tert-Butyl
(3-methoxy-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate
##STR00287##
[0921] To a 5 mL of microwave vial containing solution of
Intermediate 102B (155 mg, 0.443 mmol) in dioxane (3 mL) were added
potassium phosphate tribasic (235 mg, 1.107 mmol), dioxane (3 mL),
water (0.3 mL) and PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 adduct (36.2
mg, 0.044 mmol) at RT. The reaction was purged with nitrogen and
then was heated with microwave at 130.degree. C. for 15 min. The
reaction mixture was concentrated and the residue was purified by
flash chromatography (0-80% EtOAc/Hex) to afford Intermediate 102C
(88 mg, 54% yield). MS(ESI) m/z: 368.2 (M+H).sup.+; .sup.1H NMR
(400 MHz, chloroform-d) .delta. 9.83 (s, 1H), 8.47 (dd, J=7.6, 1.2
Hz, 1H), 7.84-7.63 (m, 2H), 7.48 (s, 1H), 7.45-7.34 (m, 1H), 6.84
(dd, J=8.1, 2.0 Hz, 1H), 6.64 (s, 1H), 3.76 (s, 3H), 1.57 (s,
9H).
Intermediate 102
##STR00288##
[0923] Intermediate 102C (85 mg, 0.231 mmol) was stirred with TFA
(1 ml) and DCM (2 ml) at rt for 30 min, concentrated to give
Intermediate 102 (78 mg, 88% yield). MS(ESI) m/z: 268.2
(M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta.
8.42-8.37 (m, 1H), 7.83 (quind, J=7.3, 1.5 Hz, 2H), 7.50 (d, J=8.0
Hz, 1H), 7.37-7.33 (m, 1H), 7.17 (d, J=1.9 Hz, 1H), 7.14 (dd,
J=8.0, 1.9 Hz, 1H), 3.82-3.76 (m, 3H).
Intermediate 103: 4-(4-Amino-2-ethoxyphenyl)phthalazin-1
(2H)-one
##STR00289##
[0925] According to the procedure for the preparation of
Intermediate 102, substituting 4-bromo-3-ethoxyaniline for
4-bromo-3-methoxyaniline, HCl afforded after flash chromatography
(0-90% EtOAc/Hex) Intermediate 103. MS(ESI) m/z: 282.2 (M+H).sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.57 (s, 1H),
8.33-8.13 (m, 1H), 7.90-7.72 (m, 2H), 7.44-7.33 (m, 1H), 6.95 (d,
J=8.1 Hz, 1H), 6.34 (d, J=1.8 Hz, 1H), 6.26 (dd, J=7.9, 2.0 Hz,
1H), 5.38 (s, 2H), 3.97-3.81 (m, 2H), 0.97 (t, J=7.0 Hz, 3H).
Intermediate 104:
4-(4-Amino-3-methoxyphenyl)phthalazin-1(2H)-one
##STR00290##
[0927] According to the procedure for the preparation of
Intermediate 102, substituting 4-bromo-2-methoxyaniline, HCl for
4-bromo-3-methoxyaniline, HCl afforded after flash chromatography
(0-100% EtOAc/Hex) Intermediate 104. MS(ESI) m/z: 268.2
(M+H).sup.+; .sup.1H NMR (400 MHz, THF) .delta. 11.64 (br. s., 1H),
8.43-8.34 (m, 1H), 7.87-7.81 (m, 1H), 7.77-7.69 (m, 2H), 7.01 (d,
J=1.8 Hz, 1H), 6.91 (dd, J=7.9, 2.0 Hz, 1H), 6.71 (d, J=7.9 Hz,
1H), 3.84 (s, 3H).
Intermediate 105:
4-(4-Amino-3-hydroxyphenyl)phthalazin-1(2H)-one
##STR00291##
[0928] Intermediate 105A: tert-Butyl
(2-methoxy-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate
##STR00292##
[0930] According to the procedure for the preparation of
Intermediate 102C, substituting 4-bromo-2-methoxyaniline, HCl for
4-bromo-3-methoxyaniline, HCl afforded Intermediate 105A.
Intermediate 105
##STR00293##
[0932] To a solution of Intermediate 105A (25 mg, 0.068 mmol) in
DCM (2 mL), was add boron tribromide (0.34 mL, 0.34 mmol). The
mixture was stirred at rt o/n, then was diluted with water and made
basic with Na.sub.2CO.sub.3. The mixture was extracted with EtOAc,
then the organic phase was concentrated. The residue was purified
by flash chromatography (0-100% EtOAc/Hex) to afford Intermediate
105 (8 mg, 46% yield). MS(ESI) m/z: 254.1 (M+H).sup.+; .sup.1H NMR
(400 MHz, methanol-d.sub.4) .delta. 7.21-7.15 (m, 1H), 6.72-6.65
(m, 1H), 6.64-6.57 (m, 2H), 5.72 (d, J=1.8 Hz, 1H), 5.70-5.58 (m,
2H).
Intermediate 106: Methyl
5-amino-2-(4-oxo-3,4-dihydrophthalazin-1-yl)benzoate
##STR00294##
[0933] Intermediate 106A: Methyl
2-bromo-5-((tert-butoxycarbonyl)amino)benzoate
##STR00295##
[0935] To a solution of methyl 5-amino-2-bromobenzoate (0.45 g,
1.96 mmol) and Boc.sub.2O (0.64 g, 2.93 mmol) in MeOH (10 mL), was
added sodium carbonate (0.456 g, 4.30 mmol). The mixture was
stirred at rt for 16 h, then was concentrated. The residue was
diluted with water and extracted with DCM. The organic phase was
concentrated and the residue was purified by flash chromatography
(0-20% EtOAc/Hex) to afford Intermediate 106A (540 mg, 84% yield).
MS(ESI) m/z: 330.1 (M+H).sup.+.
Intermediate 106B: Methyl
5-((tert-butoxycarbonyl)amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)benzoate
##STR00296##
[0937] To a mixture of Intermediate 106A (360 mg, 1.09 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (305
mg, 1.20 mmol), and potassium acetate (321 mg, 3.27 mmol) in
dioxane (3 mL), was added PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 adduct
(24 mg, 0.033 mmol). The reaction mixture was degassed (3.times.
vacuum/Ar), sealed in a vial and heated at 110.degree. C. for 3 h.
The reaction mixture was diluted with water, then extracted with
EtOAc. The organic phase was concentrated and the residue was
purified by flash chromatography (0-40% EtOAc/Hex) to afford
Intermediate 106B (310 mg, 75% yield) as a yellow oil. MS(ESI) m/z:
376.3 (M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm
7.95 (1H, d, J=1.98 Hz), 7.54 (1H, dd, J=8.14, 1.76 Hz), 7.40 (1H,
d, J=7.92 Hz), 7.03 (1H, s), 3.87 (3H, s), 1.50 (9H, s), 1.39 (12H,
s).
Intermediate 106C: Methyl
5-((tert-butoxycarbonyl)amino)-2-(4-oxo-3,4-dihydrophthalazin-1-yl)benzoa-
te
##STR00297##
[0939] To a 5 mL of microwave vial containing a solution of
Intermediate 106B (92 mg, 0.24 mmol) in dioxane (3 mL) were added
4-chlorophthalazin-1(2H)-one (40 mg, 0.22 mmol), potassium
phosphate tribasic (118 mg, 0.554 mmol), water (0.3 mL) and
PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 adduct (18.09 mg, 0.022 mmol) at
RT. The reaction was purged with nitrogen, sealed and then heated
in a microwave reactor at 130.degree. C. for 15 min. The reaction
mixture was diluted with water, then was extracted with EtOAc. The
organic phase was concentrated and the residue was purified by
flash chromatography (0-80% EtOAc/Hex) to afford Intermediate 106C
(38 mg, 43% yield) as a white solid. MS(ESI) m/z: 396.3
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta.
8.44-8.38 (m, 1H), 8.22 (d, J=2.4 Hz, 1H), 7.88-7.76 (m, 3H), 7.42
(d, J=8.4 Hz, 1H), 7.37-7.31 (m, 1H), 3.55 (s, 3H), 1.56 (s,
9H).
Intermediate 106
##STR00298##
[0941] Intermediate 106C (66 mg, 0.17 mmol) was stirred with TFA (1
mL) and DCM (1 mL) at rt for 30 min, then was concentrated. The
residue was purified by flash chromatography (0-90% EtOAc/Hex) to
afford Intermediate 106 (47 mg, 95% yield). MS(ESI) m/z: 296.2
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta.
8.48-8.36 (m, 1H), 7.87-7.75 (m, 2H), 7.46-7.38 (m, 1H), 7.36 (d,
J=2.4 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H), 6.96 (dd, J=8.1, 2.4 Hz,
1H), 3.49 (s, 3H).
Intermediate 107: 4-(4-Amino-3-fluorophenyl)phthalazin-1(2H)-one,
TFA
##STR00299##
[0942] Intermediate 107A: tert-Butyl
(2-fluoro-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate
##STR00300##
[0944] To a vial containing 4-chlorophthalazin-1(2H)-one (100 mg,
0.554 mmol), (4-((tert-butoxycarbonyl)amino)-3-fluorophenyl)boronic
acid (155 mg, 0.609 mmol) and potassium phosphate tribasic (294 mg,
1.38 mmol), were added dioxane (1.8 mL) and water (0.2 mL). The
mixture was degassed (evacuated and flushed with Ar (3.times.)),
then was treated with Pd(Ph.sub.3P).sub.4 (32 mg, 0.028 mmol). The
mixture was degassed (3.times.), then the vial was sealed and
heated in a microwave reactor at 150.degree. C. for 30 min. The
mixture was partitioned between EtOAc and H.sub.2O. The aqueous
phase was extracted with EtOAc. The combined organic phase was
washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. The
crude product was purified by flash chromatography (gradient from 0
to 100% ethyl acetate/hexanes) to afford Intermediate 107A as a
white solid (124 mg, 63% yield). MS(ESI) m/z: 356.1 (M+H).sup.+;
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 8.40-8.48 (m, 1H),
8.06 (t, J=8.36 Hz, 1H), 7.86-7.96 (m, 2H), 7.81-7.86 (m, 1H),
7.35-7.43 (m, 2H), 1.56 (s, 9H); .sup.19F NMR (376 MHz,
methanol-d.sub.4) .delta. -129.38 (s, 1F).
Intermediate 107
##STR00301##
[0946] To a suspension of Intermediate 107A (123 mg, 0.346 mmol) in
DCM (2 mL), was added TFA (2 mL). The resultant yellow solution was
stirred at rt for 1.25 h, then was concentrated to afford
Intermediate 107 (128 mg, 100% yield) as a white solid. MS(ESI)
m/z: 256.1 (M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4)
.delta. 8.39-8.46 (m, 1H), 7.82-7.96 (m, 3H), 7.25 (dd, J=1.98,
11.88 Hz, 1H), 7.19 (dd, J=1.98, 8.14 Hz, 1H), 6.94-7.04 (m,
1H).
Intermediate 108:
4-(4-Amino-2-(hydroxymethyl)phenyl)phthalazin-1(2H)-one
##STR00302##
[0948] To a solution of Intermediate 106C (220 mg, 0.556 mmol) in
THF (1 mL) was added 2.0 M (in THF) lithium borohydride (0.684 mL,
1.37 mmol) at room temperature. The reaction mixture was stirred at
room temperature for 16 h, then was quenched with MeOH and
concentrated. The residue was purified by flash chromatography
(0-90% EtOAc/Hex) to afford tert-butyl
(3-(hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate
(88 mg, 59% yield). The material was stirred with TFA (1 mL) and
DCM (1 mL) for 30 min, then was concentrated. The residue was
purified by flash chromatography (0-20% MeOH/DCM) to afford
Intermediate 108 (88 mg, 59% yield). MS(ESI) m/z: 268.2
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta.
8.48-8.36 (m, 1H), 7.83 (quind, J=7.3, 1.5 Hz, 2H), 7.54-7.41 (m,
1H), 7.23-7.15 (m, 2H), 6.93 (dd, J=7.9, 2.6 Hz, 1H), 4.42 (br. s.,
2H).
Intermediate 109:
1-((Tetrahydrofuran-2-yl)methyl)-1H-indazole-3-carboxylic acid
##STR00303##
[0949] Intermediate 109A: Ethyl
1-((tetrahydrofuran-2-yl)methyl)-1H-indazole-3-carboxylate
##STR00304##
[0951] To a vial containing ethyl 1H-indazole-3-carboxylate (200
mg, 1.05 mmol) in acetonitrile (3 mL), were added
2-(bromomethyl)tetrahydrofuran (226 mg, 1.37 mmol) and
Cs.sub.2CO.sub.3 (514 mg, 1.58 mmol). The vial was sealed and the
mixture was stirred at 70.degree. C. overnight. The reaction
mixture was diluted with water, then was extracted with EtOAc. The
organic phase was with 10% LiCl and brine, then was concentrated.
The residue was purified by flash chromatography (0-60% EtOAc/Hex)
to afford Intermediate 109A (199 mg, 69% yield). MS(ESI) m/z: 275.2
(M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.19 (dt,
J=8.1, 1.0 Hz, 1H), 7.63-7.57 (m, 1H), 7.41 (ddd, J=8.4, 7.0, 1.1
Hz, 1H), 7.29 (ddd, J=8.1, 7.0, 0.9 Hz, 1H), 4.64-4.47 (m, 4H),
4.40 (qd, J=6.3, 4.5 Hz, 1H), 3.81-3.63 (m, 2H), 2.05-1.94 (m, 1H),
1.88-1.64 (m, 3H), 1.48 (t, J=7.2 Hz, 3H).
Intermediate 109
##STR00305##
[0953] To a solution of Intermediate 109A (205 mg, 0.747 mmol) in
THF (3 mL), was added 1M lithium hydroxide (2.242 mL, 2.242 mmol),
stirred at rt overnight. The reaction mixture was concentrated,
then the residue was taken up in water and EtOAc, then acidified
with 1 N HCl. The phases were separated, then the aqueous phase was
extracted with EtOAc (3.times.). The combined organic phase was
washed with brine, dried (Na.sub.2SO.sub.4) and concentrated to
afford Intermediate 109 (175 mg, 95% yield) as a colorless oil.
MS(ESI) m/z: 247.1 (M+H).sup.+; .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 8.15 (dt, J=8.1, 1.0 Hz, 1H), 7.72 (dt,
J=8.6, 0.9 Hz, 1H), 7.47 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.31 (ddd,
J=8.1, 7.0, 0.9 Hz, 1H), 4.65-4.52 (m, 2H), 4.46-4.33 (m, 1H),
3.87-3.62 (m, 2H), 2.16-1.94 (m, 1H), 1.93-1.65 (m, 3H).
Intermediate 110: 4-(4-Aminophenyl)-7-methoxyphthalazin-1(2H)-one,
TFA
##STR00306##
[0954] Intermediate 110A: Ethyl
2-(4-((tert-butoxycarbonyl)amino)benzoyl)-5-methoxybenzoate
##STR00307##
[0956] (4-((tert-Butoxycarbonyl)amino)phenyl)boronic acid (915 mg,
3.86 mmol), ethyl 2-bromo-5-methoxybenzoate (500 mg, 1.930 mmol),
PEPPSI-IPR catalyst (65.8 mg, 0.096 mmol), and Cs.sub.2CO.sub.3
(1886 mg, 5.79 mmol) were placed in a vial. PhCl (10 mL) was added,
and the vial was evacuated and backfilled with CO gas (3.times.).
The mixture was heated with stirring at 80.degree. C. under balloon
of CO for 20 h. Most of PhCl was removed under reduced pressure,
the residue was purified by flash chromatography (0-70% EtOAc/Hex)
to afford Intermediate 110A (308 mg, 40% yield) as an amber oil,
which solidified upon standing. MS(ESI) m/z: 400.2 (M+H).sup.+;
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 9.78 (s, 1H),
7.67-7.57 (m, 2H), 7.48 (d, J=8.4 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H),
7.37 (d, J=2.4 Hz, 1H), 7.26 (dd, J=8.6, 2.6 Hz, 1H), 3.97 (q,
J=7.1 Hz, 2H), 3.88 (s, 3H), 1.48 (s, 9H), 0.98 (t, J=7.2 Hz,
3H).
Intermediate 110B: tert-Butyl
(4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate
##STR00308##
[0958] Intermediate 110A (308 mg, 0.799 mmol) was placed in a
pressure vial, and dioxane (4 mL), and hydrazine hydrate (0.581 mL,
12.0 mmol) were added sequentially. The reaction mixture was
stirred at rt for 15 min, and then at 100.degree. C. for 3 h. The
reaction mixture was diluted with EtOAc (100 mL), washed with water
(3.times.), brine, and dried (Na.sub.2SO.sub.4). The organic phase
was concentrated and the residue was purified by flash
chromatography (5-100% EtOAc/Hex) to afford Intermediate 110B (172
mg, 59% yield) as a white solid. MS(ESI) m/z: 368.1 (M+H).sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 12.69 (s, 1H), 9.56
(s, 1H), 7.71 (d, J=2.9 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.61 (d,
J=8.6 Hz, 2H), 7.49-7.42 (m, 3H), 3.95 (s, 3H), 1.50 (s, 9H).
Intermediate 110
##STR00309##
[0960] Intermediate 110B (172 mg, 0.468 mmol) was dissolved in TFA
(2 mL), and the reaction mixture was stirred at rt for 15 min. TFA
was removed under reduced pressure, the residue triturated with
Et.sub.2O to give Intermediate 110 (171 mg, 96% yield) as an
off-white solid. MS(ESI) m/z: 268.1 (M+H).sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 12.65 (s, 1H), 7.71 (d, J=2.6 Hz,
1H), 7.68 (d, J=9.0 Hz, 1H), 7.46 (dd, J=9.0, 2.9 Hz, 1H), 7.38 (d,
J=8.6 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 3.95 (s, 3H).
Intermediate 111:
N-(4-(3-(Dicyclopropylmethyl)-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-
-pyrazole-4-carboxamide
##STR00310##
[0961] Intermediate 111A:
4-(4-Bromophenyl)-2-(dicyclopropylmethyl)phthalazin-1(2H)-one
##STR00311##
[0963] Ph.sub.3P (4.35 g, 16.60 mmol) was dissolved in dry THF (40
mL), and the stirred reaction mixture was cooled to 0.degree. C.
Afterwards, DIAD (3.23 mL, 16.60 mmol) was added dropwise over 5
min, and the reaction mixture was stirred at 0.degree. C. for 15
min (thick suspension formed). Then, a suspension of
4-(4-bromophenyl)phthalazin-1 (2H)-one (2.000 g, 6.64 mmol) and
dicyclopropylmethanol (0.979 mL, 8.30 mmol) in dry THF (20 mL) was
added, and the reaction mixture was allowed to reach rt, and
stirred at rt for 16 h. The reaction mixture was quenched with MeOH
(5 mL), diluted with EtOAc (250 mL). Then CELITE.RTM. was added,
the solvent was removed under reduced pressure and the residue was
purified flash chromatography (EtOAc/hexane) to afford 1.396 g
(53.2%) of Intermediate 111A as a white solid. MS(ESI) m/z: 395.1
(M+H).sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
8.56-8.47 (m, 1H), 7.85-7.72 (m, 3H), 7.71-7.63 (m, 2H), 7.59-7.48
(m, 2H), 3.81 (t, J=9.2 Hz, 1H), 1.63-1.56 (m, 2H), 0.75-0.63 (m,
2H), 0.57-0.46 (m, 2H), 0.43-0.30 (m, 4H).
Intermediate 111B:
4-(4-Aminophenyl)-2-(dicyclopropylmethyl)phthalazin-1(2H)-one
##STR00312##
[0965] The following reaction was carried out behind the blast
shield. Intermediate 111A (1.396 g, 3.53 mmol), L-Proline (0.529 g,
4.59 mmol), and cuprous oxide (0.505 g, 3.53 mmol) were placed into
a round-bottom flask, and DMSO (20 mL) was added. The reaction
mixture was degassed with stirring (3.times. vacuum/Ar), and sodium
azide (0.459 g, 7.06 mmol) was added. The reaction mixture was
degassed again (2.times. vacuum/Ar), and stirred under Ar at
100.degree. C. for 3 h. The reaction mixture was cooled to rt, was
quenched with NH.sub.4C.sub.1 (std. aq, 10 mL), diluted with EtOAc
(500 mL) and water (200 mL). Organic phase was separated, washed
with Na.sub.2CO.sub.3 (aq. std., 2.times.50 mL), water (1.times.100
mL), brine (1.times.50 mL), dried (Na.sub.2SO.sub.4) and filtered.
EtOAc was removed under reduced pressure and the residue was
purified by flash chromatography (EtOAc/hexane) to afford
Intermediate 111B (0.742 g, 63.4% yield) as an off-white solid.
MS(ESI) m/z: 332.1 (M+H).sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 8.34 (dd, J=8.1, 1.3 Hz, 1H), 7.97-7.81 (m, 3H), 7.34
(d, J=8.4 Hz, 2H), 6.72 (d, J=8.6 Hz, 2H), 5.45 (s, 2H), 3.67 (t,
J=9.0 Hz, 1H), 1.58-1.45 (m, 2H), 0.70-0.60 (m, 2H), 0.55 (dq,
J=9.4, 4.9 Hz, 2H), 0.40-0.29 (m, 2H), 0.18 (dq, J=9.4, 4.9 Hz,
2H).
Intermediate 111
##STR00313##
[0967] 1H-Pyrazole-4-carboxylic acid (0.301 g, 2.69 mmol) was
suspended in DCM (20 mL), and a drop a DMF was added. Then, oxalyl
chloride (2 M in DCM) (5.60 mL, 11.19 mmol) was added dropwise, and
the reaction mixture was stirred for 2 h at rt (reaction mixture
became homogeneous). Then, DCM was removed under reduced pressure,
and the obtained acid chloride (white solid) was used in the
subsequent step. In a separate flask, to a solution of Intermediate
111B (0.742 g, 2.239 mmol) in THF (20 mL), was added Trimethylsilyl
cyanide (2.99 mL, 22.39 mmol). The resultant solution was stirred
at rt for 10 min, and then was treated with a solution of
1H-pyrazole-4-carboxylic acid chloride obtained as described above
in THF (5 mL). The mixture was stirred at 50.degree. C. for 1.5 h.
Afterwards, the reaction mixture was concentrated, then
trifluoroethanol (10 mL) was added. The mixture was stirred at
70.degree. C. for 15 min, and then concentrated. The obtained
reside was purified by flash chromatography (MeOH/DCM) to give
0.781 g (82%) of Intermediate 111. MS(ESI) m/z: 426.1 (M+H).sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 13.29 (br. s., 1H),
10.01 (s, 1H), 8.37 (dd, J=7.5, 1.3 Hz, 1H), 8.27 (br. s., 1H),
7.99-7.87 (m, 4H), 7.87-7.81 (m, 1H), 7.66 (d, J=8.6 Hz, 2H), 3.70
(t, J=9.2 Hz, 1H), 1.61-1.47 (m, 2H), 0.72-0.61 (m, 2H), 0.57 (dq,
J=9.5, 4.8 Hz, 2H), 0.42-0.31 (m, 2H), 0.20 (dq, J=9.6, 4.9 Hz,
2H)
Intermediate 112: 5-Methyl-1-phenyl-1H-1,2,3-triazole-4-carboxylic
acid
##STR00314##
[0968] Intermediate 112A: Ethyl
5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxylate
##STR00315##
[0970] To the solution of aniline (0.33 g, 3.54 mmol) in
acetonitrile (6 mL) at 0.degree. C. was added isoamyl nitrite
(0.524 mL, 3.90 mmol), followed by azidotrimethylsilane (0.513 mL,
3.90 mmol) dropwise. After 5 min, the cold bath removed, and the
reaction was stirred at rt for 10 min, then ethyl but-2-ynoate
(0.795 g, 7.09 mmol) added, and the reaction stirred in a sealed
tube at 80.degree. C. for 20 h, then cooled to rt. The reaction
mixture was concentrated, then the residue was purified via
preparative HPLC to afford Intermediate 112A (50 mg, 6% yield).
MS(ESI) m/z: 232.0 (M+H).sup.+; .sup.1H NMR (400 MHz, chloroform-d)
.delta. 7.63-7.55 (m, 3H), 7.49-7.41 (m, 2H), 4.47 (q, J=7.0 Hz,
2H), 2.60 (s, 3H), 1.45 (t, J=7.2 Hz, 3H).
Intermediate 112
##STR00316##
[0972] Intermediate 112A (36 mg, 0.16 mmol) was mixed with 1M
lithium hydroxide (0.3 mL, 0.3 mmol) in THF (2 mL) and MeOH (2 mL),
stirred rt for 2 h. The reaction mixture was concentrated and the
residue was purified via preparative HPLC to afford Intermediate
112 (26 mg, 82% yield). MS(ESI) m/z: 204.1 (M+H).sup.+; .sup.1H NMR
(400 MHz, methanol-d.sub.4) .delta. 7.70-7.61 (m, 3H), 7.60-7.52
(m, 2H), 2.59-2.54 (m, 3H).
Intermediate 113:
1-(4-Methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic
acid
##STR00317##
[0973] Intermediate 113A: Ethyl
1-(4-methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate
Intermediate 113B: Ethyl
1-(4-methoxyphenyl)-4-methyl-1H-1,2,3-triazole-5-carboxylate
##STR00318##
[0975] To the solution of 4-methoxyaniline (0.31 g, 2.5 mmol) in
acetonitrile (6 mL) at 0.degree. C. was added isoamyl nitrite
(0.372 mL, 2.77 mmol), followed by azidotrimethylsilane (0.364 mL,
2.77 mmol) dropwise. After 5 min, the cold bath removed, and the
reaction was stirred at rt for 10 min, then ethyl but-2-ynoate
(0.564 g, 5.03 mmol) was added, and the reaction stirred in a
sealed tube at 80.degree. C. The reaction was stirred at 80.degree.
C. for 20 h, then cooled to rt. The reaction mixture was
concentrated, then the residue was purified via preparative HPLC to
afford Intermediate 113A (60 mg, 9% yield) and Intermediate 113B
(22 mg, 3% yield).
Intermediate 113A
[0976] MS(ESI) m/z: 262.2 (M+H).sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. 7.36-7.30 (m, 2H), 7.06-7.00 (m, 2H), 4.43
(q, J=7.2 Hz, 2H), 3.86 (s, 3H), 2.53 (s, 3H), 1.42 (t, J=7.2 Hz,
3H).
Intermediate 113B
[0977] MS(ESI) m/z: 262.2 (M+H).sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. 7.37-7.31 (m, 2H), 7.03-6.97 (m, 2H), 4.27
(q, J=7.0 Hz, 2H), 3.87 (s, 3H), 2.62 (s, 3H), 1.25 (t, J=7.2 Hz,
3H).
Intermediate 113
##STR00319##
[0979] Intermediate 113A (60 mg, 0.23 mmol) was mixed with 1M
lithium hydroxide (0.5 mL, 0.5 mmol) in THF (1 mL) and MeOH (1 mL).
The reaction mixture was stirred rt for 3 h. The reaction mixture
was concentrated and the residue was purified via preparative HPLC
to afford Intermediate 113 (48 mg, 90% yield) as a white solid.
MS(ESI) m/z: 234.0 (M+H).sup.+; .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 7.48-7.41 (m, 2H), 7.17-7.11 (m, 2H),
3.88 (s, 3H), 2.52 (s, 3H).
Intermediate 114:
1-(4-Methoxyphenyl)-4-methyl-1H-1,2,3-triazole-5-carboxylic
acid
##STR00320##
[0981] Intermediate 113B (22 mg, 0.084 mmol) was mixed with 1M
lithium hydroxide (0.2 mL, 0.2 mmol) in THF (1 mL) and MeOH (1 mL)
and was stirred at rt for 2 h. The reaction mixture was
concentrated and the residue was acidified with TFA. The mixture
was concentrated and the residue was purified by flash
chromatography (0-20% MeOH/DCM) to afford Intermediate 114. MS(ESI)
m/z: 234.0 (M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4)
.delta. 7.45-7.24 (m, 2H), 7.08-6.90 (m, 2H), 3.87 (s, 3H), 2.58
(s, 3H).
Example 1:
4-(4-(2-(Isoindolin-2-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-on-
e
##STR00321##
[0983] To 4-chlorophthalazin-1(2H)-one (9.9 mg, 0.055 mmol),
Intermediate 8 (14 mg, 0.050 mmol) and potassium phosphate (26.4
mg, 0.125 mmol), were added dioxane (3 mL) and water (0.5 mL). The
mixture was degassed (evacuated and flushed with Ar (5.times.)).
Pd(PPh.sub.3).sub.4 (2.9 mg, 2.5 .mu.mol) was added, then the
mixture was degassed (2.times.). The reaction vial was sealed and
heated in a microwave reactor at 150.degree. C. for 25 min. The
reaction mixture was concentrated, then was purified by preparative
HPLC to afford 4.4 mg (18%) of Example 1. MS(ESI) m/z: 382.20
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.82 (s,
1H), 8.42-8.29 (m, 1H), 7.96-7.84 (m, 2H), 7.77-7.67 (m, 1H),
7.61-7.52 (m, 2H), 7.52-7.43 (m, 2H), 7.41-7.36 (m, 2H), 7.36-7.27
(m, 2H), 4.98 (s, 2H), 4.70 (s, 2H), 3.89 (s, 2H); Analytical HPLC
RT=1.51 min (Method E), 1.52 min (Method F).
Example 2:
4-(4-(2-(5-Fluoroisoindolin-2-yl)-2-oxoethyl)phenyl)phthalazin--
1(2H)-one
##STR00322##
[0985] According a method similar to the preparation of Example 1,
substitution of isoindoline with 5-fluoroisoindoline afforded
Example 2. MS(ESI) m/z: 400.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.82 (s, 1H), 8.38-8.31 (m, 1H), 7.93-7.86
(m, 2H), 7.74-7.69 (m, 1H), 7.66-7.36 (m, 5H), 7.23 (d, J=9.1 Hz,
1H), 7.18-7.10 (m, 1H), 4.95 (d, J=16.8 Hz, 2H), 4.68 (d, J=16.8
Hz, 2H), 3.87 (s, 2H); Analytical HPLC RT=1.53 min (Method E), 1.52
min (Method F).
Example 3:
4-(4-(2-(5-Methoxyisoindolin-2-yl)-2-oxoethyl)phenyl)phthalazin-
-1(2H)-one
##STR00323##
[0987] To a solution of Intermediate 1 (25 mg, 0.089 mmol) in DMF
(3 mL), was added 5-methoxyisoindoline (20 mg, 0.134 mmol), PyBOP
(69.6 mg, 0.134 mmol), and DIEA (0.078 mL, 0.446 mmol). The mixture
was stirred at rt for 2 h, then was purified by preparative HPLC to
afford 28.1 mg (59%) of Example 3. MS(ESI) m/z: 412.2 (M+H).sup.+;
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.82 (s, 1H),
8.36-8.31 (m, 1H), 7.93-7.86 (m, 2H), 7.73-7.68 (m, 1H), 7.55 (d,
J=7.7 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.26 (dd, J=8.3, 4.4 Hz,
1H), 6.95 (d, J=11.6 Hz, 1H), 6.88 (dd, J=8.4, 1.8 Hz, 1H),
4.95-4.86 (m, 2H), 4.69-4.59 (m, 2H), 3.87 (s, 2H), 3.75 (s, 3H);
Analytical HPLC RT=1.61 min (Method E), 1.61 min (Method F).
[0988] The following Examples in Table 1 were made by using the
same procedure as shown in Example 3. Intermediate 1 was coupled
with the appropriate amine. Various coupling reagents could be used
other than the one described in Example 3 such as BOP, PyBop,
EDC/HOBt or HATU.
##STR00324##
TABLE-US-00002 TABLE 1 LC HPLC MS Method, Ex- (M + RT ample R Name
H).sup.+ (min.) .sup.1H NMR 4 ##STR00325## 4-{4-[2-oxo-2-(1,2,3,4-
tetrahydroisoquinolin- 2-yl)ethyl]phenyl}-1,2- dihydrophthalazin-1-
one 396.1 E: 1.56 F: 1.55 (500 MHz, DMSO-d.sub.6) .delta.
12.92-12.70 (m, 1H), 8.34 (dd, J = 5.4, 2.1 Hz, 1H), 7.97-7.84 (m,
2H), 7.75-7.56 (m, 1H), 7.56-7.47 (m, 2H), 7.47-7.34 (m, 2H),
7.25-7.05 (m, 4H), 4.77 (s, 1H), 4.66 (s, 1H), 3.97-3.84 (m, 2H),
3.79 (t, J = 5.9 Hz, 1H), 3.72 (t, J = 5.9 Hz, 1H), 2.79 (t, J =
5.9 Hz, 2H) 5 ##STR00326## 2-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-N-(pyridin- 3-yl)acetamide 357.1 E: 0.95 F: 1.13 (500
MHz, DMSO-d.sub.6) .delta. 12.83 (s, 1H), 10.69 (s, 1H), 8.92 (br.
s., 1H), 8.41-8.30 (m, 2H), 8.19 (d, J = 8.5 Hz, 1H), 7.94-7.83 (m,
2H), 7.75-7.66 (m, 1H), 7.60-7.55 (m, 2H), 7.55 (d, J = 3.6 Hz,
1H), 7.54-7.50 (m, 2H), 3.83 (s, 2H) 6 ##STR00327##
N-benzyl-2-[4-(4-oxo- 3,4-dihydrophthalazin- 1-yl)phenyl]acetamide
370.1 E: 1.50 F: 1.50 (500 MHz, DMSO-d.sub.6) .delta. 12.82 (s,
1H), 8.62 (t, J = 5.5 Hz, 1H), 8.34 (dd, J = 6.3, 2.8 Hz, 1H),
7.95-7.83 (m, 2H), 7.78-7.63 (m, 1H), 7.57-7.51 (m, J = 8.0 Hz,
2H), 7.49- 7.40 (m, J = 8.0 Hz, 2H), 7.36-7.29 (m, 2H), 7.29-7.22
(m, 3H), 4.31 (d, J = 6.1 Hz, 2H), 3.60 (s, 2H) 7 ##STR00328##
2-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-N-(pyridin-
4-yl)acetamide 357.1 E: 0.98 F: 1.13 (500 MHz, DMSO-d.sub.6)
.delta. 12.84 (s, 1H), 11.39 (s, 1H), 8.65 (d, J = 6.3 Hz, 2H),
8.45-8.29 (m, 1H), 7.97 (d, J = 6.6 Hz, 2H), 7.93-7.84 (m, 2H),
7.80-7.65 (m, 1H), 7.63-7.55 (m, J = 8.0 Hz, 2H), 7.55-7.43 (m, J =
8.0 Hz, 2H), 3.93 (s, 2H) 8 ##STR00329## N-benzyl-N-methyl-2-
[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]acetamide 384.1 E:
1.54 F: 1.53 (500 MHz, DMSO-d.sub.6) .delta. 12.83 (br. s., 1H),
8.41-8.29 (m, 1H), 7.96-7.85 (m, 2H), 7.73-7.63 (m, 1H), 7.60-7.14
(m, 9H), 4.81-4.50 (m, 2H), 3.95-3.82 (m, 2H), 3.10- 2.80 (m, 3H) 9
##STR00330## N-(1H-1,3- benzodiazol-2-yl)-2-[4- (4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]acetamide 396.2 E: 1.09 F: 1.34
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.83 (s, 1H), 12.03
(br. s., 1H), 8.37-8.29 (m, 1H), 7.93-7.85 (m, 2H), 7.72- 7.66 (m,
1H), 7.61-7.53 (m, 4H), 7.47 (dd, J = 5.8, 3.3 Hz, 2H), 7.14 (dd, J
= 5.5, 3.0 Hz, 2H), 3.93 (s, 2H) 10 ##STR00331##
N-(1,3-benzoxazol-2- yl)-2-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]acetamide 397.1 E: 1.29 F: 1.31 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.82 (s, 1H), 8.34 (dd, J = 6.2, 2.9 Hz,
1H), 7.94-7.83 (m, 2H), 7.76-7.67 (m, 1H), 7.58-7.45 (m, 5H),
7.26-7.20 (m, 1H), 7.20-7.15 (m, 1H), 3.87 (br. s., 2H) 11
##STR00332## 4-{4-[2-oxo-2-(4- phenylpiperidin-1-
yl)ethyl]phenyl}-1,2- dihydrophthalazin-1- one 424.4 C: 2.63 D:
3.80 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.84 (br. s.,
1H), 8.34 (d, J = 6.1 Hz, 1H), 7.88 (br. s., 2H), 7.68 (d, J = 6.7
Hz, 1H), 7.55 (d, J = 7.9 Hz, 2H), 7.44 (d, J = 7.6 Hz, 2H),
7.32-7.23 (m, 2H), 7.20 (d, J = 6.7 Hz, 3H), 4.58 (d, J = 11.3 Hz,
1H), 4.13 (d, J = 12.8 Hz, 1H), 3.87 (br. s., 2H), 3.13 (t, J =
13.0 Hz, 1H), 2.82-2.71 (m, 1H), 2.66 (t, J = 12.4 Hz, 1H), 1.77
(t, J = 14.5 Hz, 2H), 1.51-1.34 (m, 2H) 12 ##STR00333## 4-{4-[2-(4-
benzylpiperazin-1-yl)- 2-oxoethyl]phenyl}- 1,2-dihydrophthalazin-
1-one 439.4 C: 2.41 D: 3.63 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 12.84 (br. s., 1H), 8.34 (br. s., 1H), 7.89 (d, J = 3.1 Hz,
2H), 7.69 (d, J = 6.4 Hz, 1H), 7.52 (d, J = 7.3 Hz, 2H), 7.39 (d, J
= 7.9 Hz, 2H), 7.35-7.19 (m, 5H), 3.81 (br. s., 2H), 3.57-3.45 (m,
6H), 2.31 (br. s., 4H) 13 ##STR00334## 4-(4-{2-[(2S)-2-
(methoxymethyl) pyrrolidin-2-yl]-2- oxoethyl}phenyl)-1,2-
dihydrophthalazin-1- one 378.4 C: 2.13 D: 3.24 .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 12.84 (br. s., 1H), 8.34 (d, J = 6.1 Hz,
1H), 7.90 (br. s., 2H), 7.70 (d, J = 6.4 Hz, 1H), 7.52 (d, J = 6.1
Hz, 2H), 7.40 (d, J = 7.0 Hz, 2H), 4.08 (br. s., 1H), 3.78-3.68 (m,
2H), 3.23 (br. s., 3H), 2.00-1.76 (m, 5H) 14 ##STR00335##
N-(cyclopropylmethyl)- 2-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]acetamide 334.3 C: 1.94 D: 3.05 .sup.1H NMR (400 MHz,
CD.sub.3OD)/CDCl.sub.3 (1:1)) .delta. 8.43 (dt, J = 4.3, 2.4 Hz,
1H), 7.84-7.64 (m, 3H), 7.55-7.46 (m, 2H), 7.42 (d, J = 8.0 Hz,
2H), 3.59 (s, 2H), 3.05 (d, J = 7.0 Hz, 2H), 0.98-0.81 (m, 1H),
0.50-0.36 (m, 2H), 0.19- 0.07 (m, 2H) 15 ##STR00336##
4-(4-{2-oxo-2-[4- (pyrimidin-2-yl) pipereazin-1-yl]ethyl}
phenyl)-1,2- dihydrophthalazin-1- one 427.4 C: 2.10 D: 3.26 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 12.83 (br. s., 1H), 8.44- 8.28
(m, 3H), 7.89 (d, J = 3.7 Hz, 2H), 7.69 (br. s., 1H), 7.54 (d, J =
7.3 Hz, 2H), 7.43 (d, J = 7.6 Hz, 2H), 6.70-6.62 (m, 1H), 3.89 (br.
s., 2H), 3.72 (br. s., 4H), 3.65 (br. s., 2H), 3.59 (br. s., 2H) 16
##STR00337## 4-(4-{2-[4-(4- methoxyphenyl) piperazin-1-yl]-2-
oxoethyl}phenyl)-1,2- dihydrophthalazin-1- one 455.4 C: 2.23 D:
3.47 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.83 (br. s.,
1H), 8.33 (br. s., 1H), 7.88 (br. s., 2H), 7.68 (br. s., 1H), 7.53
(d, J = 7.9 Hz, 2H), 7.42 (d, J = 7.6 Hz, 2H), 6.95-6.85 (m, 2H),
6.82 (d, J = 8.5 Hz, 2H), 3.88 (br. s., 2H), 3.68 (br. s., 4H),
3.64 (br. s., 2H), 2.96 (br. s., 4H) 17 ##STR00338## 4-{4-[2-(4-
benzylpiperidin-1-yl)- 2-oxoethyl]phenyl}- 1,2-dihydrophthalazin-
1-one 438.4 C: 2.77 D: 4.04 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 12.84 (br. s., 1H), 8.34 (br. s., 1H), 7.90 (d, J = 3.7 Hz,
2H), 7.69 (d, J = 5.8 Hz, 1H), 7.52 (d, J = 7.9 Hz, 2H), 7.39 (d, J
= 7.6 Hz, 2H), 7.30-7.21 (m, 2H), 7.21-7.10 (m, 3H), 4.38 (d, J =
13.1 Hz, 1H), 3.98 (d, J = 11.6 Hz, 1H), 3.80 (br. s., 2H), 2.96
(t, J = 12.4 Hz, 1H), 1.75 (br. s., 1H), 1.56 (br. s., 2H), 0.99
(t, J = 10.2 Hz, 2H) 18 ##STR00339## 2-[4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-N-[(1S,2R)- 2-phenylcyclopropyl]
acetamide 396.4 C: 2.35 D: 3.56 .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 12.84 (br. s., 1H), 8.49 (br. s., 1H), 8.34 (br. s., 1H),
7.90 (d, J = 3.7 Hz, 2H), 7.71 (d, J = 5.5 Hz, 1H), 7.54 (d, J =
7.6 Hz, 2H), 7.44 (d, J = 7.3 Hz, 2H), 7.29-7.21 (m, 2H), 7.19-7.06
(m, 3H), 3.52 (br. s., 2H), 2.85 (br. s., 1H), 1.97 (br. s., 1H),
1.18 (d, J = 5.8 Hz, 2H) 19 ##STR00340## N-cyclobutyl-2-[4-(4-
oxo-3,4- dihydrophthalazin-1- yl)phenyl]acetamide 334.3 C: 1.95 D:
3.11 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.83 (br. s.,
1H), 8.40 (d, J = 6.1 Hz, 1H), 8.33 (br. s., 1H), 7.89 (d, J = 3.4
Hz, 2H), 7.69 (d, J = 6.7 Hz, 1H), 7.51 (d, J = 7.6 Hz, 2H), 7.41
(d, J = 7.9 Hz, 2H), 4.25-4.11 (m, 1H), 3.46 (s, 2H), 2.22- 2.11
(m, 2H), 1.96-1.83 (m, 2H), 1.70-1.55 (m, 2H) 20 ##STR00341##
2-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-N- phenylacetamide
356.3 C: 2.21 D: 3.36 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
12.83 (br. s., 1H), 10.25 (br. s., 1H), 8.33 (br. s., 1H), 7.88 (d,
J = 4.0 Hz, 2H), 7.70 (br. s., 1H), 7.62 (d, J = 7.6 Hz, 2H),
7.59-7.46 (m, 4H), 7.34-7.25 (m, 2H), 7.09-6.99 (m, 1H), 3.76 (br.
s., 2H) 21 ##STR00342## N-(1,3-benzothiazol-6- yl)-2-[4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]acetamide 413.4 C: 1.96 D: 3.20
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.85 (br. s., 1H),
10.65 (br. s., 1H), 9.26 (br. s., 1H), 8.58 (br. s., 1H), 8.33 (br.
s., 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.89 (br. s., 2H), 7.71 (br. s.,
1H), 7.65 (d, J = 9.5 Hz, 1H), 7.55 (br. s., 4H), 3.82 (br. s., 2H)
22 ##STR00343## N-methyl-2-[4-(4-oxo- 3,4-dihydrophthalazin-
1-yl)phenyl]-N- phenylacetamide 370.3 C: 2.25 D: 3.52 .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 12.83 (br. s., 1H), 8.33 (d, J =
6.7 Hz, 1H), 7.89 (br. s., 2H), 7.73-7.62 (m, J = 7.3 Hz, 1H), 7.54
(d, J = 7.3 Hz, 1H), 7.47 (br. s., 3H), 7.39 (d, J = 7.9 Hz, 4H),
7.20 (br. s., 1H), 3.51 (br. s., 2H), 3.21 (br. s., 3H) 23
##STR00344## 4-{4-[2-(2,3-dihydro- 1H-indol-1-yl)-2-
oxoethyl]phenyl}-1,2- dihydrophthalazin-1- one 382.3 C: 2.48 D:
3.67 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.85 (br. s.,
1H), 8.34 (d, J = 7.3 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.96-7.84
(m, 2H), 7.72 (d, J = 7.3 Hz, 1H), 7.59-7.51 (m, 2H), 7.47 (d, J =
7.0 Hz, 2H), 7.24 (d, J = 6.4 Hz, 1H), 7.18-7.10 (m, 1H), 7.00 (t,
J = 6.6 Hz, 1H), 4.26-4.17 (m, 2H), 3.96 (br. s., 2H), 3.20-3.14
(m, J = 9.2 Hz, 2H) 24 ##STR00345## N-(2,3-dihydro-1,4-
benzodioxin-6-yl)-2-[4- (4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]acetamide 414.3 C: 2.13 D: 3.25 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.84 (br. s., 1H), 10.09 (br. s., 1H),
8.39-8.27 (m, 1H), 7.89 (d, J = 2.4 Hz, 2H), 7.74-7.65 (m, 1H),
7.58-7.51 (m, 2H), 7.49 (d, J = 6.7 Hz, 2H), 7.26 (br. s., 1H),
6.99 (d, J = 6.4 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 4.20 (d, J =
6.4 Hz, 4H), 3.70 (br. s., 2H) 25 ##STR00346## 4-[4-(2-{5-[(4-
methylpiperazin-1- yl)methyl]-2,3-dihydro- 1H-isoindol-2-yl}-2-
dihydrophthalazin-1- one 494.3 E: 0.94 F: 1.15 .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 12.82 (s, 1H), 8.37-8.30 (m, 1H),
7.93-7.86 (m, 2H), 7.71 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 7.7 Hz,
2H), 7.47 (d, J = 7.7 Hz, 2H), 7.33-7.25 (m, 2H), 7.23 (d, J = 7.7
Hz, 1H), 4.95 (d, J = 7.4 Hz, 2H), 4.67 (d, J = 4.7 Hz, 2H), 3.87
(s, 2H), 3.46 (d, J = 3.3 Hz, 2H), 2.36 (br. s., 8H), 2.17 (br. s.,
3H) 26 ##STR00347## N-(3-methyl-1,2- oxazol-5-yl)-2-[4-(4- oxo-3,4-
dihydrophthalazin-1- yl)phenyl]acetamide 361.2 C: 2.06 D: 3.11
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.84 (br. s., 1H),
8.33 (br. s., 1H), 7.89 (br. s., 2H), 7.69 (br. s., 1H), 7.56 (d, J
= 7.3 Hz, 2H), 7.48 (d, J = 4.9 Hz, 2H), 6.12 (br. s., 1H), 3.82
(br. s., 2H), 2.17 (br. s., 3H) 27 ##STR00348## N-(5-methyl-1,2-
oxazol-3-yl)-2-[4-(4- oxo-3,4- dihydrophthalazin-1-
yl)phenyl]acetamide 361.2 C: 2.06 D: 3.08 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.84 (br. s., 1H), 11.21 (br. s., 1H), 8.33
(br. s., 1H), 7.89 (d, J = 3.1 Hz, 2H), 7.70 (br. s., 1H), 7.55 (d,
J = 7.3 Hz, 2H), 7.49 (d, J = 7.0 Hz, 2H), 6.62 (br. s., 1H), 3.78
(br. s., 2H), 2.36 (br. s., 3H) 28 ##STR00349## 2-[4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-N-(1,3- thiazol-2-yl)acetamide
363.2 C: 2.07 D: 3.13 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
12.86 (br. s., 1H), 8.36- 8.30 (m, 1H), 7.93-7.86 (m, 2H),
7.73-7.69 (m, 1H), 7.58-7.53 (m, 2H), 7.53-7.48 (m, 2H), 7.42 (d, J
= 3.5 Hz, 1H), 7.09 (br. s., 1H), 3.83 (s, 2H) 29 ##STR00350##
2-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-N-(1,3,4-
thiadiazol-2- yl)acetamide 364.2 C: 1.84 D: 2.87 .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 12.85 (s, 1H), 9.11 (s, 1H), 8.37-8.30
(m, 1H), 7.95-7.85 (m, 2H), 7.74-7.68 (m, 1H), 7.59-7.53 (m, 2H),
7.53-7.48 (m, 2H), 3.92 (s, 2H) 30 ##STR00351##
N-(6-chloropyridazin- 3-yl)-2-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]acetamide 392.2 C: 2.12 D: 3.18 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.86 (br. s., 1H), 11.67 (br. s., 1H), 8.40
(d, J = 9.5 Hz, 1H), 8.36-8.30 (m, 1H), 7.94-7.85 (m, 3H),
7.74-7.66 (m, 1H), 7.60-7.55 (m, 2H), 7.55-7.49 (m, 2H), 3.92 (s,
2H) 31 ##STR00352## N-(5-methyl-1,3,4- thiadiazol-2-yl)-2-[4-
(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]acetamide 378.2 C: 1.81
D: 3.07 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.86 (s, 1H),
12.70 (br. s., 1H), 8.36-8.30 (m, 1H), 7.93-7.85 (m, 2H), 7.75-
7.66 (m, 1H), 7.60-7.53 (m, 2H), 7.53-7.46 (m, 2H), 3.92 (s, 2H),
2.60 (s, 3H) 32 ##STR00353## 4-{4-[2-(5-methyl-2,3-
dihydro-1H-indol-1- yl)-2-oxoethyl] phenyl}-1,2-
dihydrophthalazin-1- one 396.1 A: 9.56 B: 9.14 (500 MHz,
DMSO-d.sub.6) .delta. 12.83 (s, 1H), 8.41-8.29 (m, 1H), 7.96 (d, J
= 8.3 Hz, 1H), 7.91-7.85 (m, 2H), 7.73-7.68 (m, 1H), 7.62-7.52 (m,
J = 8.3 Hz, 2H), 7.48-7.42 (m, J = 8.0 Hz, 2H), 7.05 (s, 1H), 6.95
(d, J = 8.3 Hz, 1H), 4.21 (t, J = 8.5 Hz, 2H), 3.94 (s, 2H), 3.14
(t, J = 8.4 Hz, 2H), 2.25 (s, 3H) 33 ##STR00354##
4-{4-[2-(6-ethoxy-2,3- dihydro-1H-indol-1- yl)-2-oxoethyl]
phenyl}-1,2- dihydrophthalazin-1- one 426.1 A: 9.62 B: 9.23 (500
MHz, DMSO-d.sub.6) .delta. 12.83 (s, 1H), 8.42-8.30 (m, 1H),
7.94-7.84 (m, 2H), 7.80-7.65 (m, 2H), 7.62-7.51 (m, J = 8.0 Hz,
2H), 7.51-7.40 (m, J = 8.3 Hz, 2H), 7.11 (d, J = 8.0 Hz, 1H), 6.56
(dd, J = 8.0, 2.5 Hz, 1H), 4.24 (t, J = 8.3 Hz, 2H), 4.02-3.89 (m,
4H), 3.09 (t, J = 8.3 Hz, 3H), 1.30 (t, J = 7.0 Hz, 3H) 34
##STR00355## 4-{4-[2-oxo-2-[6- tetrahydroquinolin-1-
yl)ethyl]phenyl}-1,2- dihydrophthalazin-1- one 450.2 E: 1.91 F:
1.73 (500 MHz, DMSO-d.sub.6) .delta. 12.81 (s, 1H), 8.37-8.29 (m,
1H), 7.95-7.87 (m, 2H), 7.66 (d, J = 7.7 Hz, 1H), 7.49 (d, J = 7.7
Hz, 3H), 7.33 (br. s., 2H), 7.19 (d, J = 6.9 Hz, 2H), 7.13 (d, J =
7.2 Hz, 1H), 3.99 (s, 2H), 3.75 (t, J = 6.2 Hz, 2H), 2.66 (br. s.,
2H), 1.86 (quin, J = 6.5 Hz, 2H) 35 ##STR00356## 4-(4-{2-oxo-2-[6-
(trifluoromethyl)-2,3- dihydro-1H-indol-1- yl]ethyl}phenyl)-1,2-
dihydrophthalazin-1- one 450.2 E: 1.91 F: 1.96 (500 MHz,
DMSO-d.sub.6) .delta. 12.83 (s, 1H), 8.42-8.30 (m, 2H), 7.98-7.84
(m, 2H), 7.80-7.67 (m, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.48 (d, J =
8.3 Hz, 3H), 7.37 (d, J = 7.7 Hz, 1H), 4.32 (t, J = 8.5 Hz, 2H),
4.01 (s, 2H), 3.29-3.24 (m, 2H) 39 ##STR00357##
4-{4-[2-(3,3-dimethyl- 2,3-dihydro-1H-indol- 1-yl)-2-oxoethyl]
phenyl}-1,2- dihydrophthalazin-1- one 410.15 E: 1.88 F: 1.89 (500
MHz, DMSO-d.sub.6) .delta. 12.85 (br. s., 1H), 8.38-8.32 (m, 1H),
8.06 (d, J = 8.4 Hz, 1H), 7.93-7.86 (m, 2H), 7.76- 7.68 (m, 1H),
7.61-7.53 (m, J = 8.4 Hz, 2H), 7.50-7.44 (m, J = 7.9 Hz, 2H), 7.27
(d, J = 7.4 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.08-7.00 (m, 1H),
3.98 (d, J = 8.9 Hz, 4H), 1.31 (s, 6H) 40 ##STR00358##
4-{4-[2-(2-methyl-2,3- dihydro-1H-indol-1-
yl)-2-oxoethyl] phenyl}-1,2- dihydrophthalazin-1- one 396.15 E:
1.75 F: 1.77 (500 MHz, CD.sub.3OD) .delta. 8.47-8.41 (m, 1H), 8.10
(d, J = 8.4 Hz, 1H), 7.88-7.77 (m, 3H), 7.63-7.55 (m, 3H), 7.49 (d,
J = 7.4 Hz, 2H), 7.25-7.17 (m, 2H), 7.06 (t, J = 7.4 Hz, 1H), 4.05
(d, J = 15.4 Hz, 1H), 3.95 (d, J = 15.9 Hz, 1H), 3.43 (dd, J =
15.6, 8.7 Hz, 1H), 2.72 (d, J = 15.4 Hz, 1H), 1.38 (d, J = 5.9 Hz,
3H), 1.29 (br. s., 1H) 41 ##STR00359## 4-{4-[2-(6-methoxy-
2,3-dihydro-1H-indol- 1-yl)-2-oxoethyl] phenyl}-1,2-
dihydrophthalazin-1- one 412.0 A: 8.50 B: 7.65 (500 MHz,
DMSO-d.sub.6) .delta. 12.83 (s, 1H), 8.45-8.27 (m, 1H), 7.94-7.85
(m, 2H), 7.79-7.67 (m, 2H), 7.63-7.53 (m, J = 8.0 Hz, 2H),
7.52-7.43 (m, J = 8.0 Hz, 2H), 7.13 (d, J = 8.3 Hz, 1H), 6.58 (dd,
J = 8.3, 2.2 Hz, 1H), 4.25 (t, J = 8.4 Hz, 2H), 3.96 (s, 2H), 3.70
(s, 3H), 3.10 (t, J = 8.4 Hz, 2H)
Example 36:
2-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(iso-
indolin-2-yl)ethanone
##STR00360##
[0990] To a vial containing Intermediate 4 (34.8 mg, 0.091 mmol),
4-chlorophthalazin-1(2H)-one (15 mg, 0.083 mmol) and potassium
phosphate (44 mg, 0.21 mmol), were added dioxane (0.9 mL) and water
(0.1 mL). The mixture was degassed (evacuated and flushed with Ar
(3.times.)). To this mixture was added Pd(Ph.sub.3P).sub.4 (4.8 mg,
4.2 mmol). The mixture was degassed (3.times.), then the vial was
sealed. The vial was heated in a microwave reactor at 150.degree.
C. for 25 min. The mixture was concentrated, then was diluted with
4 mL 1:1 DMSO/MeOH. TFA (0.1 mL) was added, then the suspension was
filtered and the solid collected. The solid was washed with
H.sub.2O (.about.5 mL), then MeOH (.about.5 mL), sucked dry and
dried in vacuo to afford 34.8 mg (42%) of Example 36 as a white
solid. MS(ESI) m/z: 400.0 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.89 (s, 1H), 8.38-8.32 (m, 1H), 7.92
(quind, J=7.1, 1.7 Hz, 2H), 7.76-7.71 (m, 1H), 7.51 (t, J=7.8 Hz,
1H), 7.43 (dd, J=10.5, 1.4 Hz, 1H), 7.41-7.37 (m, 3H), 7.35-7.30
(m, 2H), 5.02 (s, 2H), 4.71 (s, 2H), 3.92 (s, 2H); HPLC RT=7.96 min
(Method A), 8.02 min (Method B).
Example 37:
4-(2-Fluoro-4-(2-(isoindolin-2-yl)-2-oxoethyl)phenyl)phthalazin-1
(2H)-one
##STR00361##
[0992] To a vial containing Intermediate 5 (34.8 mg, 0.091 mmol),
4-chlorophthalazin-1(2H)-one (15 mg, 0.083 mmol) and potassium
phosphate (44.1 mg, 0.208 mmol), were added dioxane (0.9 mL) and
water (0.1 mL). The mixture was degassed (evacuated and flushed
with Ar (3.times.)). To this mixture was added Pd(Ph.sub.3P).sub.4
(4.8 mg, 4.15 .mu.mol). The mixture was degassed (3.times.), then
the vial was sealed. The vial was heated in a microwave reactor at
150.degree. C. for 25 min. The reaction mixture separated into two
phases upon cooling. The organic phase was collected and was
purified by preparative HPLC to afford 11.7 mg (35%) of Example 37.
MS(ESI) m/z: 400.2 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 12.94 (br. s., 1H), 8.37-8.29 (m, 1H), 7.92-7.86 (m, 2H),
7.65-7.49 (m, 4H), 7.45-7.28 (m, 4H), 4.99 (s, 2H), 4.71 (s, 2H),
3.93 (s, 2H); HPLC RT=1.56 min (Method E), 1.52 min (Method F).
Example 38:
4-(4-(2-(Isoindolin-2-yl)-2-oxoethyl)phenyl)isoquinolin-1
(2H)-one
##STR00362##
[0994] According to the procedure for the preparation of Example
36, coupling of Intermediate 6 (30 mg, 0.13 mmol) and Intermediate
9 (51 mg, 0.14 mmol) afforded 17 mg (33%) of Example 38. MS(ESI)
m/z: 381.1 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
11.43 (d, J=5.8 Hz, 1H), 8.29 (dd, J=8.1, 1.2 Hz, 1H), 7.69 (td,
J=7.7, 1.4 Hz, 1H), 7.61-7.51 (m, 2H), 7.44-7.35 (m, 6H), 7.33-7.28
(m, 2H), 7.08 (s, 1H), 4.97 (s, 2H), 4.69 (s, 2H), 3.84 (s, 2H);
HPLC RT=8.20 min (Method A), 7.53 min (Method B).
Example 42:
4-(4-(1-(Indolin-1-yl)-1-oxopropan-2-yl)phenyl)phthalazin-1
(2H)-one
##STR00363##
[0996] According to the procedure for the preparation of Example 3,
coupling of Intermediate 11 (13 mg, 0.044 mmol) and indoline (7.9
mg, 0.066 mmol) using HATU afforded 8.2 mg (46%) of Example 42.
MS(ESI) m/z: 396.15 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.85 (s, 1H), 8.38-8.30 (m, 1H), 8.18 (d,
J=8.4 Hz, 1H), 7.92-7.84 (m, 2H), 7.74-7.68 (m, 1H), 7.62-7.55 (m,
J=8.4 Hz, 2H), 7.55-7.49 (m, J=8.4 Hz, 2H), 7.20 (d, J=7.4 Hz, 1H),
7.16 (t, J=7.7 Hz, 1H), 7.02-6.94 (m, 1H), 4.37 (td, J=10.4, 6.4
Hz, 1H), 4.23 (q, J=6.4 Hz, 1H), 3.91-3.75 (m, 1H), 3.16-3.00 (m,
2H), 1.46 (d, J=6.4 Hz, 3H); HPLC RT=1.77 min (Method E), 1.75 min
(Method F).
Example 43:
4-(4-(1-(Isoindolin-2-yl)-1-oxopropan-2-yl)phenyl)phthalazin-1(2H)-one
##STR00364##
[0998] According to the procedure for the preparation of Example 3,
coupling of Intermediate 11 (13 mg, 0.044 mmol) and isoindoline
(7.9 mg, 0.066 mmol) using HATU afforded 9.0 mg (52%) of Example
43. MS(ESI) m/z: 396.15 (M+H).sup.+; .sup.1H NMR (500 MHz, 1:1
CD.sub.3OD/CDCl.sub.3) .delta. 8.49-8.43 (m, 1H), 7.90-7.83 (m,
2H), 7.83-7.78 (m, 1H), 7.61-7.58 (m, 2H), 7.57-7.52 (m, 2H),
7.35-7.23 (m, 4H), 5.04 (d, J=13.9 Hz, 1H), 4.92-4.85 (m, 1H),
4.83-4.77 (m, 1H), 4.66 (d, J=13.9 Hz, 1H), 4.09 (q, J=6.9 Hz, 1H),
1.58 (d, J=6.9 Hz, 3H).
Example 44:
N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-2,3-dihydro-1H-indene-2-ca-
rboxamide
##STR00365##
[0999] Example 44A:
N-(4-Bromophenyl)-2,3-dihydro-1H-indene-2-carboxamide
##STR00366##
[1001] To a solution of 2,3-dihydro-1H-indene-2-carboxylic acid
(141 mg, 0.872 mmol) in DMF (3 mL), were added 4-bromoaniline (150
mg, 0.872 mmol), PyBOP (499 mg, 0.959 mmol), and DIEA (0.457 mL,
2.62 mmol). The mixture was stirred at rt for 16 h. The reaction
mixture was concentrated and the residue was dissolved in EtOAc,
washed with 10% LiCl, 1N HCl and brine. The crude product was
purified via flash chromatography to afford 90 mg (33%) of Example
44A. MS(ESI) m/z: 316.0 (M+H).sup.+.
Example 44B:
N-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,3-dihydro-1H--
indene-2-carboxamide
##STR00367##
[1003] A mixture of Example 44A (62 mg, 0.20 mmol),
bis(pinacolato)diboron (74.7 mg, 0.294 mmol), and potassium acetate
(57.7 mg, 0.588 mmol) in dioxane (3 mL) was degassed (3.times.
vacuum/Ar). PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 adduct (4.3 mg, 5.9
.mu.mol) was added. The reaction mixture was degassed again
(3.times. vacuum/Ar), sealed in a vial and heated at 110.degree. C.
for 2 h. The reaction mixture was filtered and concentrated to
afford 40 mg (56%) of Example 44B, which was used as is in the
following step. MS(ESI) m/z: 364.2 (M+H).sup.+.
Example 44
##STR00368##
[1005] To 4-chlorophthalazin-1(2H)-one (28.3 mg, 0.157 mmol),
Example 44B (40 mg, 0.11 mmol) and potassium phosphate (76 mg, 0.36
mmol), were added dioxane (3 mL) and water (0.5 mL). The mixture
was degassed (evacuated and flushed with Ar (5.times.)).
Pd(PPh.sub.3).sub.4 (8.2 mg, 7.1 .mu.mol) was added, then the
mixture was degassed (2.times.). The reaction vial was sealed and
heated in a microwave reactor at 150.degree. C. for 25 min. The
reaction mixture was concentrated, then was purified by preparative
HPLC to yield 17.1 mg (24%) of Example 44. MS(ESI) m/z: 382.1
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.79 (s,
1H), 10.26 (s, 1H), 8.38-8.31 (m, 1H), 7.93-7.85 (m, 2H), 7.84-7.79
(m, J=8.5 Hz, 2H), 7.76-7.69 (m, 1H), 7.59-7.50 (m, J=8.5 Hz, 2H),
7.24 (dd, J=5.1, 3.4 Hz, 2H), 7.15 (dd, J=5.4, 3.2 Hz, 2H), 3.46
(t, J=8.5 Hz, 1H), 3.21 (dd, J=8.4, 3.2 Hz, 4H); HPLC RT=1.67 min
(Method E), 1.66 min (Method F).
Example 45:
N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-2-(pyridin-4-yl)thiazole-4-
-carboxamide
##STR00369##
##STR00370##
[1007] To a mixture of Intermediate 3 (25 mg, 0.105 mmol),
2-(pyridin-4-yl)thiazole-4-carboxylic acid (44 mg, 0.21 mmol), and
HATU (60 mg, 0.16 mmol) in THF (1 mL), were added DIEA (0.046 mL,
0.26 mmol) and DMF (1 mL). The mixture was stirred at rt for 2 h,
then was concentrated. The crude product was purified via
preparative HPLC to afford 25 mg (36%) of Example 45. MS(ESI) m/z:
426.0 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
12.84 (s, 1H), 10.53 (s, 1H), 8.86 (d, J=4.1 Hz, 2H), 8.73 (s, 1H),
8.44-8.32 (m, 1H), 8.25 (d, J=6.1 Hz, 2H), 8.12-8.02 (m, 2H),
7.97-7.86 (m, 2H), 7.82-7.76 (m, 1H), 7.68-7.60 (m, 2H); HPLC
RT=5.13 min (Method A), 5.69 min (Method B).
[1008] The following Examples in Table 2 were made by using the
same procedure as shown in Example 45. Intermediate 3 was coupled
with the appropriate carboxylic acid. Various coupling reagents
could be used other than the one described in Example 45, such as
BOP, PyBop, EDC/HOBt or T3P.
##STR00371##
TABLE-US-00003 TABLE 2 LC HPLC MS Method, Ex- (M + RT ample R Name
H).sup.+ (min.) .sup.1H NMR 46 ##STR00372## N-[4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-2-phenyl-1,3-
thiazole-4-carboxamide 425.1 E: 1.83 F: 1.88 (500 MHz,
DMSO-d.sub.6) .delta. 12.83 (br. s., 1H), 10.44 (br. s., 1H),
8.58-8.51 (m, 1H), 8.35 (dd, J = 7.6, 1.2 Hz, 1H), 8.18 (dd, J =
7.6, 2.1 Hz, 2H), 8.11-8.04 (m, J = 8.5 Hz, 2H), 8.00-7.86 (m, 2H),
7.78 (d, J = 7.4 Hz, 1H), 7.66- 7.61 (m, J = 8.5 Hz, 2H), 7.61-7.55
(m, 3H) 47 ##STR00373## N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-5-(pyridin-4- yl)-1,3-thiazole-2- carboxamide 426.0 E:
1.11 F: 1.52 (500 MHz, DMSO-d.sub.6) .delta. 12.85 (s, 1H), 10.91
(s, 1H), 8.96 (s, 1H), 8.82 (d, J = 5.8 Hz, 2H), 8.40-8.33 (m, 1H),
8.30 (d, J = 5.8 Hz, 2H), 8.09-8.01 (m, J = 8.5 Hz, 2H), 7.96-7.87
(m, 2H), 7.77 (d, J = 7.4 Hz, 1H), 7.71- 7.63 (m, J = 8.5 Hz, 2H)
48 ##STR00374## N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-2-[4- (trifluoromethyl) phenyl]-1,3-thiazole-4-
carboxamide 493.2 E: 1.98 F: 1.99 (500 MHz, DMSO-d.sub.6) .delta.
12.83 (s, 1H), 10.52 (s, 1H), 8.64 (s, 1H), 8.41 (d, J = 8.3 Hz,
2H), 8.38-8.32 (m, 1H), 8.10-8.03 (m, J = 8.5 Hz, 2H), 7.98-7.86
(m, 4H), 7.81-7.74 (m, 1H), 7.67-7.56 (m, J = 8.5 Hz, 2H) 49
##STR00375## 2-(3,5-difluorophenyl)- N-[4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1,3-thiazole- 4-carboxamide 461.2
E: 1.87 F: 1.88 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.83
(s, 1H), 10.51 (s, 1H), 8.77-8.68 (m, 1H), 8.63 (s, 1H), 8.35 (dd,
J = 7.6, 1.2 Hz, 1H), 8.13-8.02 (m, J = 8.5 Hz, 2H), 7.98-7.85 (m,
2H), 7.81-7.74 (m, 1H), 7.65-7.61 (m, J = 8.5 Hz, 2H), 7.58 (ddd, J
= 11.6, 9.2, 2.3 Hz, 1H), 7.45-7.34 (m, 1H) 50 ##STR00376##
4-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-1,3-thiazole- 2-carboxamide 363.2 E: 1.46 F: 1.47 (500
MHz, DMSO-d.sub.6) .delta. 12.82 (s, 1H), 10.91 (s, 1H), 8.34 (dd,
J = 7.6, 1.5 Hz, 1H), 8.10-8.00 (m, J = 8.8 Hz, 2H), 7.91 (td, J =
7.4, 1.4 Hz, 2H), 7.78-7.70 (m, 2H), 7.63-7.53 (m, J = 8.5 Hz, 2H),
2.53 (s, 3H) 51 ##STR00377## 5-methyl-N-[4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]-4H,5H,6H,
7H-[1,3]thiazolo[5,4-c] pyridine-2-carboxamide 418.2 E: 0.98 F:
1.31 (500 MHz, DMSO-d.sub.6) .delta. 12.82 (s, 1H), 10.92 (s, 1H),
8.34 (d, J = 7.2 Hz, 1H), 8.08-8.00 (m, J = 8.5 Hz, 2H), 7.96-7.84
(m, 2H), 7.74 (d, J = 7.7 Hz, 1H), 7.63-7.54 (m, J = 8.5 Hz, 2H),
3.72 (s, 2H), 2.97-2.92 (m, 2H), 2.83-2.76 (m, 2H), 2.42 (s, 3H) 52
##STR00378## 1-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-1H- imidazole-2- carboxamide 346.2 E: 1.03 F: 1.26 (500
MHz, DMSO-d.sub.6) .delta. 12.81 (s, 1H), 10.55 (s, 1H), 8.38-8.29
(m, 1H), 8.06-7.98 (m, J = 8.5 Hz, 2H), 7.94- 7.86 (m, 2H), 7.75
(d, J = 7.4 Hz, 1H), 7.62-7.53 (m, J = 8.5 Hz, 2H), 7.47 (s, 1H),
7.11 (s, 1H), 4.02 (s, 3H) 53 ##STR00379## N-[4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-4,5,6,7- tetrahydro-1,3-
benzothiazole-2- carboxamide 403.15 E: 1.70 F: 1.71 (500 MHz,
DMSO-d.sub.6) .delta. 12.82 (s, 1H), 10.85 (s, 1H), 8.34 (dd, J =
7.6, 1.2 Hz, 1H), 8.07-8.01 (m, J = 8.5 Hz, 2H), 7.96-7.85 (m, 2H),
7.74 (d, J = 7.4 Hz, 1H), 7.63- 7.53 (m, J = 8.5 Hz, 2H), 2.87 (dt,
J = 15.7, 5.8 Hz, 4H), 1.91-1.77 (m, 4H) 54 ##STR00380##
1-(4-nitrophenyl)-N-[4- (4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]piperidine-4- carboxamide 470.25 E: 1.61 F: 1.62 (500
MHz, DMSO-d.sub.6) .delta. 12.78 (s, 1H), 10.05 (s, 1H), 8.35-8.31
(m, 1H), 7.89 (td, J = 4.6, 1.8 Hz, 2H), 7.79- 7.75 (m, J = 8.5 Hz,
2H), 7.75-7.68 (m, 1H), 7.55-7.47 (m, J = 8.5 Hz, 2H), 7.37-7.29
(m, 4H), 7.27-7.20 (m, 1H), 3.48 (s, 2H), 2.96-2.84 (m, 2H),
2.41-2.29 (m, 1H), 1.98 (t, J = 11.1 Hz, 2H), 1.84-1.75 (m, 2H),
1.75- 1.64 (m, 2H) 55 ##STR00381## 1-acetyl-N-[4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]piperidine-4- carboxamide 391.2
E: 1.06 F: 1.07 (500 MHz, DMSO-d.sub.6) .delta. 12.78 (s, 1H),
10.13 (s, 1H), 8.35-8.30 (m, 1H), 7.96-7.86 (m, 2H), 7.82-7.75 (m,
J = 8.5 Hz, 2H), 7.72 (d, J = 8.5 Hz, 1H), 7.56-7.47 (m, J = 8.5
Hz, 2H), 4.42 (d, J = 13.2 Hz, 1H), 3.89 (d, J = 12.1 Hz, 1H), 3.09
(t, J = 12.0 Hz, 1H), 2.66-2.58 (m, 2H), 1.84 (t, J = 13.1 Hz, 2H),
1.69-1.57 (m, 1H), 1.53- 1.39 (m, 1H) 56 ##STR00382##
1-benzyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]piperidine-4- carboxamide 439.3 E: 1.05 F: 1.15 (500 MHz,
DMSO-d.sub.6) .delta. 12.78 (s, 1H), 10.05 (s, 1H), 8.35-8.31 (m,
1H), 7.89 (td, J = 4.6, 1.8 Hz, 2H), 7.79- 7.75 (m, J = 8.5 Hz,
2H), 7.75-7.68 (m, 1H), 7.55-7.47 (m, J = 8.5 Hz, 2H), 7.37-7.29
(m, 4H), 7.27-7.20 (m, 1H), 3.48 (s, 2H), 2.96-2.84 (m, 2H),
2.41-2.29 (m, 1H), 1.98 (t, J = 11.1 Hz, 2H), 1.84-1.75 (m, 2H),
1.75- 1.64 (m, 2H) 57 ##STR00383## 1-(2-methoxyethyl)-N-
[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]pyrrolidine-3-
carboxamide 393.2 E: 1.01 F: 0.99 (500 MHz, DMSO-d.sub.6) .delta.
10.14 (br. s., 1H), 8.33 (d, J = 7.4 Hz, 1H), 7.94-7.86 (m, 2H),
7.80-7.74 (m, J = 8.3 Hz, 2H), 7.72 (d, J = 7.2 Hz, 1H), 7.57-7.46
(m, J = 8.3 Hz, 2H), 3.45 (t, J = 5.5 Hz, 3H), 3.26 (s, 3H),
3.12-3.03 (m, 1H), 2.96 (br. s., 1H), 2.73 (br. s., 1H), 2.63 (br.
s., 3H), 2.01 (d, J = 6.9 Hz, 2H) 58 ##STR00384##
4-(dimethylamino)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]benzamide 385.3 E: 1.38 F: 1.59 (500 MHz, DMSO-d.sub.6)
.delta. 12.80 (s, 1H), 10.07 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H),
7.97-7.86 (m, 6H), 7.76 (d, J = 7.7 Hz, 1H), 7.55 (d, J = 8.3 Hz,
2H), 6.78 (d, J = 8.8 Hz, 2H), 3.01 (s, 6H) 59 ##STR00385##
1-benzyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]pyrrolidine-3- carboxamide 425.25 E: 1.16 F: 1.26 (500
MHz, DMSO-d.sub.6) .delta. 12.79 (s, 1H), 10.11 (br. s., 1H),
8.39-8.29 (m, 1H), 7.93-7.86 (m, 2H), 7.79- 7.73 (m, J = 8.5 Hz,
2H), 7.72-7.67 (m, 1H), 7.54-7.48 (m, J = 8.5 Hz, 2H), 7.40-7.31
(m, 4H), 7.28 (br. s., 1H), 3.67 (br. s., 2H), 3.14 (br. s., 1H),
2.96 (br. s., 1H), 2.82-2.69 (m, 2H), 2.59 (br. s., 1H), 2.07 (br.
s., 2H) 60 ##STR00386## N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-4-(pyrrolidin- 1-yl)benzamide 411.2 E: 1.76 F: 1.74 (500
MHz, DMSO-d.sub.6) .delta. 12.80 (s, 1H), 10.03 (s, 1H), 8.34 (d, J
= 7.7 Hz, 1H), 7.97 (s, 2H), 7.93-7.86 (m, 4H), 7.77 (d, J = 7.7
Hz, 1H), 7.55 (d, J = 8.3 Hz, 2H), 6.62 (d, J = 8.5 Hz, 2H), 1.99
(br. s., 4H) 61 ##STR00387## N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-4-(piperidin- 1-yl)benzamide 425.25 E: 1.23 F: 1.83 (500
MHz, DMSO-d.sub.6) .delta. 10.11 (s, 1H), 8.34 (d, J = 7.7 Hz, 1H),
7.99-7.86 (m, 6H), 7.76 (d, J = 7.4 Hz, 1H), 7.56 (d, J = 8.3 Hz,
2H), 7.01 (d, J = 8.8 Hz, 2H), 3.34 (br.s., 4H), 1.60 (br. s., 6H)
62 ##STR00388## N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-3-(pyrrolidin- 1-yl)benzamide 411.2 E: 1.55 F: 1.80
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.81 (s, 1H), 10.31
(s, 1H), 8.38-8.32 (m, 1H), 7.97 (d, J = 8.5 Hz, 2H), 7.94-7.85 (m,
2H), 7.76 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.36-7.27
(m, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.07 (s, 1H), 6.75 (dd, J = 8.0,
1.7 Hz, 1H), 3.31 (br.s., 4H), 1.99 (t, J = 6.2 Hz, 4H) 63
##STR00389## 4-(morpholin-4-yl)-N- [4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]benzamide 427.25 E: 1.42 F: 1.46
(500 MHz, DMSO-d.sub.6) .delta. 12.81 (br. s., 1H), 10.18 (s, 1H),
8.34 (d, J = 7.7 Hz, 1H), 8.06-7.86 (m, 6H), 7.80- 7.73 (m, 1H),
7.56 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 3.82-3.71 (m,
4H), 3.29-3.22 (m, 4H) 64 ##STR00390## 4-(4-methylpiperazin-1-
yl)-N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]benzamide
440.25 E: 1.06 F: 1.18 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
12.80 (s, 1H), 10.14 (s, 1H), 8.34 (d, J = 7.4 Hz, 1H), 7.96 (d, J
= 8.3 Hz, 2H), 7.94-7.86 (m, 4H), 7.76 (d, J = 7.7 Hz, 1H), 7.56
(d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.3 Hz, 2H), 2.46 (br. s., 4H),
2.23 (s, 3H) 65 ##STR00391## 4-(1H-imidadzol-1-yl)-N-
[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]benzamide 408.2 E:
1.05 F: 1.29 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.83 (s,
1H), 10.55 (s, 1H), 8.38 (s, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.22
(s, 1H), 8.00-7.86 (m, 7H), 7.76 (d, J = 7.7 Hz, 1H), 7.71 (t, J =
8.0 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.17 (s, 1H) 66 ##STR00392##
3-(dimethylamino)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]benzamide 385.1 E: 1.16 F: 1.64 (500 MHz, DMSO-d.sub.6)
.delta. 12.84 (br. s., 1H), 10.35 (s, 1H), 8.40-8.31 (m, 1H),
8.00-7.86 (m, 4H), 7.76 (d, J = 7.4 Hz, 1H), 7.59 (d, J = 8.4 Hz,
2H), 7.38-7.32 (m, 1H), 7.28-7.23 (m, 2H), 6.95 (dd, J = 8.2, 2.2
Hz, 1H), 2.98 (s, 6H) 67 ##STR00393## N-[4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]benzamide 342.2 E: 1.47 F: 1.47 (500
MHz, DMSO-d.sub.6) .delta. 12.84 (s, 1H), 10.48 (s, 1H), 8.35 (dd,
J = 7.7, 1.2 Hz, 1H), 8.04-7.96 (m, 4H), 7.95- 7.88 (m, 2H),
7.80-7.73 (m, 1H), 7.65-7.52 (m, 5H)
Example 68: 4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl
isoindoline-2-carboxylate
##STR00394##
[1009] Example 68A: 4-Bromophenyl isoindoline-2-carboxylate
##STR00395##
[1011] To a solution of isoindoline (167 mg, 1.401 mmol) and DIEA
(0.445 mL, 2.55 mmol) in CH.sub.2Cl.sub.2 (3 mL), was added
4-bromophenyl carbonochloridate (300 mg, 1.274 mmol). The mixture
was stirred at rt for 1 h, then was quenched with water. The
mixture was diluted with EtOAc (100 mL), then was washed with 1N
HCl, sat Na.sub.2CO.sub.3 and brine, dried over Na.sub.2SO.sub.4,
and concentrated. The crude product was purified via flash
chromatography to afford 310 mg (76%) of Example 68A. MS(ESI) m/z:
318.0 (M+H).sup.+; .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
7.53-7.48 (m, 2H), 7.36-7.29 (m, 4H), 7.13-7.07 (m, 2H), 4.94 (s,
2H), 4.84 (s, 2H).
Example 68B: (4-((Isoindoline-2-carbonyl)oxy)phenyl)boronic
acid
##STR00396##
[1013] A mixture of Example 68A (100 mg, 0.314 mmol),
bis(pinacolato)diboron (104 mg, 0.409 mmol), and potassium acetate
(93 mg, 0.943 mmol) in dioxane (3 mL) was degassed (3.times.
vacuum/Ar). PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 adduct (6.90 mg, 9.43
.mu.mol) was added, then the reaction mixture was degassed again
(3.times. vacuum/Ar), sealed in a vial and heated at 110.degree. C.
for 2 h. The reaction was concentrated and purified via preparative
HPLC to afford 75 mg (84%) of Example 68B. MS(ESI) m/z: 284.1
(M+H).sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.83-7.76
(m, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.40-7.28 (m, 4H), 7.24-7.10 (m,
2H), 4.95 (s, 2H), 4.78 (s, 2H).
Example 68
##STR00397##
[1015] To 4-chlorophthalazin-1(2H)-one (18.24 mg, 0.101 mmol),
Example 68B (26 mg, 0.092 mmol) and potassium phosphate (48.7 mg,
0.230 mmol), were added dioxane (3 mL) and water (0.5 mL). The
mixture was degassed (evacuated and flushed with Ar (5.times.)).
Pd(PPh.sub.3).sub.4 (5.31 mg, 4.59 .mu.mol) was added, then the
mixture was degassed (2.times.). The reaction vial was sealed and
heated in a microwave reactor at 150.degree. C. for 25 min. The
crude product was purified by preparative HPLC to afford 9 mg (20%)
of Example 68. MS(ESI) m/z: 384.2 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 12.86 (s, 1H), 8.45-8.29 (m, 1H), 7.92
(qd, J=7.3, 5.8 Hz, 2H), 7.75-7.69 (m, 1H), 7.67-7.59 (m, 2H),
7.46-7.37 (m, 4H), 7.36-7.28 (m, 2H), 4.96 (s, 2H), 4.76 (s, 2H);
HPLC RT=1.77 min (Method E), 1.78 min (Method F).
Example 69: 4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl
3-phenylpyrrolidine-1-carboxylate
##STR00398##
[1016] Example 69A: 4-Bromophenyl
3-phenylpyrrolidine-1-carboxylate
##STR00399##
[1018] To a mixture of 3-phenylpyrrolidine (141 mg, 0.956 mmol) and
DIEA (0.223 mL, 1.274 mmol) in CH.sub.2Cl.sub.2 (3 mL) at 0.degree.
C., was added 4-bromophenyl carbonochloridate (150 mg, 0.637 mmol).
The mixture was stirred at rt for 1 h. The reaction mixture was
quenched with water and EtOAc (100 mL) was added. The organic phase
was washed with 1N HCl, sat Na.sub.2CO.sub.3 and brine, dried over
Na.sub.2SO.sub.4, concentrated and purified flash chromatography to
afford 210 mg (95%) of Example 69A. MS(ESI) m/z: 345.9 (M+H).sup.+;
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.56-7.44 (m, 2H),
7.40-7.34 (m, 2H), 7.31-7.26 (m, 3H), 7.09-6.99 (m, 2H), 4.12-3.94
(m, 1H), 3.89-3.73 (m, 1H), 3.64 (td, J=10.2, 6.7 Hz, 1H),
3.60-3.40 (m, 3H), 2.36 (ddtd, J=18.5, 12.4, 6.3, 2.6 Hz, 1H),
2.18-2.01 (m, 1H).
Example 69B: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl
3-phenylpyrrolidine-1-carboxylate
##STR00400##
[1020] To a mixture of Example 69A (210 mg, 0.607 mmol),
bis(pinacolato)diboron (185 mg, 0.728 mmol), and potassium acetate
(179 mg, 1.820 mmol) in dioxane (5 mL), was added PdCl.sub.2(dppf)
CH.sub.2Cl.sub.2 adduct (13.31 mg, 0.018 mmol). The reaction
mixture was degassed (3.times. vacuum/Ar), sealed in a vial and
heated at 110.degree. C. for 2 h. The reaction mixture was diluted
with water and extracted with EtOAc. The organic phase was
concentrated, then purified via flash chromatography
(EtOAc/hexanes) to afford 220 mg (92%) of Example 69B. MS(ESI) m/z:
394.2 (M+H).sup.+; .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.86
(dd, J=7.8, 3.7 Hz, 2H), 7.42-7.35 (m, 2H), 7.33-7.26 (m, 3H), 7.22
(t, J=7.0 Hz, 2H), 4.13-3.99 (m, 1H), 3.92-3.77 (m, 1H), 3.72-3.41
(m, 3H), 2.38 (t, J=13.1 Hz, 1H), 2.19-2.07 (m, 1H), 1.37 (s,
12H).
Example 69
##STR00401##
[1022] To 4-chlorophthalazin-1 (2H)-one (28 mg, 0.16 mmol), Example
69B (79 mg, 0.20 mmol) and potassium phosphate (82 mg, 0.39 mmol),
were added dioxane (3 mL) and water (0.33 mL). The mixture was
degassed (evacuated and flushed with Ar (5.times.)).
Pd(PPh.sub.3).sub.4 (9.0 mg, 7.8 .mu.mol) was added, then the
mixture was degassed (2.times.). The reaction vial was sealed and
heated in a microwave reactor at 150.degree. C. for 35 min. The
reaction mixture was concentrated, then was purified by preparative
HPLC to afford 8.2 mg (10%) of the Example 69. MS(ESI) m/z: 412.2
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.85 (s,
1H), 8.35 (d, J=7.4 Hz, 1H), 7.99-7.86 (m, 2H), 7.70 (d, J=7.4 Hz,
1H), 7.62 (dd, J=8.5, 3.9 Hz, 2H), 7.44-7.30 (m, 6H), 7.29-7.19 (m,
1H), 4.13-3.97 (m, 1H), 3.97-3.76 (m, 1H), 3.72-3.59 (m, 1H),
3.55-3.42 (m, 2H), 2.42-2.26 (m, 1H), 2.17-1.99 (m, 1H); HPLC
RT=1.73 min (Method E), 1.74 min (Method F).
Example 70: 4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl
5-methoxyisoindoline-2-carboxylate
##STR00402##
[1023] Example 70A: 4-Bromophenyl
5-methoxyisoindoline-2-carboxylate
##STR00403##
[1025] To a solution of 5-methoxyisoindoline (80 mg, 0.54 mmol) and
DIEA (0.18 mL, 1.02 mmol) in CH.sub.2Cl.sub.2 (3 mL) at 0.degree.
C., was added 4-bromophenyl carbonochloridate (120 mg, 0.51 mmol).
The reaction mixture was stirred rt for 1 h, then was quenched with
water. The mixture was diluted with EtOAc (100 mL). The organic
phase was washed with 1N HCl, sat. Na.sub.2CO.sub.3 and brine,
dried over Na.sub.2SO.sub.4, and concentrated. The crude product
was purified via flash chromatography to afford 112 mg (63%) of
Example 70A. MS(ESI) m/z: 348.0 (M+H).sup.+; .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.55-7.45 (m, 2H), 7.19 (dd, J=12.2, 8.4 Hz,
1H), 7.13-7.03 (m, 2H), 6.88 (dd, J=8.4, 2.3 Hz, 1H), 6.82 (dd,
J=10.5, 1.9 Hz, 1H), 4.87 (d, J=16.2 Hz, 2H), 4.78 (d, J=17.1 Hz,
2H), 3.83 (s, 3H).
Example 70B: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl
5-methoxyisoindoline-2-carboxylate
##STR00404##
[1027] To a mixture of Example 70A (112 mg, 0.322 mmol),
bis(pinacolato)diboron (98 mg, 0.39 mmol), and potassium acetate
(95 mg, 0.97 mmol) in dioxane (10 mL), was added PdCl.sub.2(dppf)
CH.sub.2Cl.sub.2 adduct (7.1 mg, 9.7 .mu.mol). The reaction mixture
was degassed (3.times. vacuum/Ar), sealed in a vial and heated at
110.degree. C. for 2 h. The reaction was diluted with water and
extracted with EtOAc. The organic phase was concentrated and the
residue was purified via flash chromatography to afford 100 mg
(79%) of Example 70B. MS(ESI) m/z: 396.2 (M+H).sup.+; .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 7.85 (d, J=8.3 Hz, 2H), 7.25-7.15 (m,
3H), 6.92-6.80 (m, 2H), 4.89 (d, J=16.5 Hz, 2H), 4.79 (d, J=18.2
Hz, 2H), 3.83 (s, 3H), 1.44-1.32 (m, 12H).
Example 70
##STR00405##
[1029] To 4-chlorophthalazin-1(2H)-one (13 mg, 0.072 mmol), Example
70B (29.9 mg, 0.076 mmol) and potassium phosphate (38.2 mg, 0.180
mmol), were added dioxane (3 mL) and water (0.33 mL). The mixture
was degassed (evacuated and flushed with Ar (5.times.)).
Pd(PPh.sub.3).sub.4 (4.2 mg, 3.6 .mu.mol) was added, then the
mixture was degassed (2.times.). The reaction vial was sealed and
heated in a microwave reactor at 150.degree. C. for 25 min. The
reaction mixture was concentrated, then was purified via
preparative HPLC to afford 9 mg (23%) of Example 70. MS(ESI) m/z:
414.1 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
12.86 (s, 1H), 8.35 (dd, J=7.6, 1.2 Hz, 1H), 7.98-7.88 (m, 2H),
7.76-7.70 (m, 1H), 7.68-7.61 (m, J=8.5 Hz, 2H), 7.43-7.36 (m, J=8.5
Hz, 2H), 7.30 (d, J=8.3 Hz, 1H), 6.99 (br. s., 1H), 6.91 (d, J=8.3
Hz, 1H), 4.92 (s, 1H), 4.87 (s, 1H), 4.72 (s, 1H), 4.68 (s, 1H),
3.81-3.72 (m, 3H); HPLC RT=9.48 min (Method A), 8.98 min (Method
B).
Example 71: 4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl
5-fluoroisoindoline-2-carboxylate
##STR00406##
[1030] Example 71A: 4-Bromophenyl
5-fluoroisoindoline-2-carboxylate
##STR00407##
[1032] To a mixture of 5-fluoroisoindoline (141 mg, 1.03 mmol) and
DIEA (0.326 mL, 1.87 mmol) in CH.sub.2Cl.sub.2 (3 mL) at 0.degree.
C., was added 4-bromophenyl carbonochloridate (220 mg, 0.934 mmol).
The mixture was stirred at rt for 1 h, then was quenched with
water. The mixture was diluted with EtOAc (100 mL), then was washed
with 1N HCl, sat Na.sub.2CO.sub.3 and brine, dried over
Na.sub.2SO.sub.4, and concentrated. The crude product was purified
via flash chromatography (EtOAc/hexanes) to afford 190 mg (61%) of
Example 71A. MS(ESI) m/z: 414.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.56-7.46 (m, 2H), 7.34-7.21 (m, 1H), 7.16-7.07
(m, 2H), 7.05-6.97 (m, 2H), 4.92 (d, J=14.0 Hz, 2H), 4.82 (d,
J=14.0 Hz, 2H).
Example 71B: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl
5-fluoroisoindoline-2-carboxylate
##STR00408##
[1034] To a mixture of Example 71A (182 mg, 0.541 mmol),
bis(pinacolato)diboron (165 mg, 0.65 mmol), and potassium acetate
(159 mg, 1.62 mmol) in dioxane (4 mL), was added PdCl.sub.2(dppf)
CH.sub.2Cl.sub.2 adduct (11.9 mg, 0.016 mmol). The reaction mixture
was degassed (3.times. vacuum/Ar), sealed in a vial and heated at
110.degree. C. for 2 h. The reaction mixture was partitioned
between EtOAc and H.sub.2O. The organic phase was concentrated and
the residue was purified via flash chromatography to afford 150 mg
(72%) of Example 71B. MS(ESI) m/z: 384.2 (M+H).sup.+; .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 7.88-7.83 (m, 2H), 7.28-7.19 (m, 3H),
7.09-6.95 (m, 2H), 4.93 (d, J=14.3 Hz, 2H), 4.82 (d, J=14.0 Hz,
2H), 1.43-1.34 (m, 12H).
Example 71
##STR00409##
[1036] To 4-chlorophthalazin-1(2H)-one (20 mg, 0.11 mmol), Example
71B (44.6 mg, 0.116 mmol) and potassium phosphate (58.8 mg, 0.277
mmol), were added dioxane (3 mL) and water (0.33 mL). The mixture
was degassed (evacuated and flushed with Ar (5.times.)).
Pd(PPh.sub.3).sub.4 (6.4 mg, 5.5 .mu.mol) was added, then the
mixture was degassed (2.times.). The reaction vial was sealed and
heated in a microwave reactor at 150.degree. C. for 25 min. The
reaction mixture was concentrated and the residue purified via
preparative HPLC to afford 5 mg (8%) of Example 71. MS(ESI) m/z:
402.1 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
12.86 (s, 1H), 8.39-8.32 (m, 1H), 7.95-7.89 (m, 2H), 7.75-7.69 (m,
1H), 7.66-7.60 (m, 2H), 7.44-7.35 (m, 4H), 7.29-7.15 (m, 4H), 4.94
(d, J=17.3 Hz, 2H), 4.74 (d, J=17.1 Hz, 2H); HPLC RT=9.62 min
(Method A), 9.15 min (Method B).
Example 72: 4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl
5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate, 2
TFA
##STR00410##
[1037] Example 72A: 4-Bromophenyl
5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate, 2
TFA
##STR00411##
[1039] To a solution of Intermediate 2 (196 mg, 0.849 mmol) and
DIEA (0.297 mL, 1.70 mmol) in CH.sub.2Cl.sub.2 (3 mL) at 0.degree.
C., was added 4-bromophenyl carbonochloridate (200 mg, 0.849 mmol).
The mixture was stirred at rt for 1 h. The reaction mixture was
quenched with water and diluted with EtOAc (100 mL). The organic
phase was washed with 1N HCl, sat Na.sub.2CO.sub.3 and brine, dried
over Na.sub.2SO.sub.4 and concentrated. The crude product was
purified by flash chromatography, followed by preparative HPLC to
afford 280 mg (50%) of Example 72A. MS(ESI) m/z: 430.1 (M+H).sup.+;
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.60-7.51 (m, 2H),
7.49-7.38 (m, 3H), 7.21-7.10 (m, 2H), 4.96 (s, 2H), 4.79 (s, 2H),
4.15 (s, 2H), 3.49 (br. s., 4H), 3.30-3.19 (m, 4H), 2.94 (s,
3H).
Example 72B: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl
5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate
##STR00412##
[1041] To a mixture of Example 72A (70 mg, 0.106 mmol),
bis(pinacolato)diboron (32.4 mg, 0.128 mmol), and potassium acetate
(31.3 mg, 0.319 mmol) in dioxane (10 mL), was added
PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 adduct (2.3 mg, 3.2 .mu.mol). The
reaction mixture was degassed (3.times. vacuum/Ar), sealed in a
vial and heated at 110.degree. C. for 2 h. The reaction was
quenched with water, then extracted with EtOAc. The organic phase
was concentrated to afford 80 mg of Example 72B, which was used as
is in the following step without further purification. MS(ESI) m/z:
478.4 (M+H).sup.+.
Example 72
##STR00413##
[1043] To a vial containing 4-chlorophthalazin-1(2H)-one (22 mg,
0.12 mmol), Example 72B (80 mg, 0.106 mmol) and potassium phosphate
(64.6 mg, 0.305 mmol), were added dioxane (3 mL) and water (0.33
mL). The mixture was degassed (evacuated and flushed with Ar
(5.times.)). Pd(PPh.sub.3).sub.4 (7.0 mg, 6.1 .mu.mol) was added,
then the mixture was degassed (2.times.). The reaction vial was
sealed and heated in a microwave reactor at 150.degree. C. for 25
min. The reaction mixture was concentrated and purified via
preparative HPLC to afford 22 mg (25%) of Example 72. MS(ESI) m/z:
496.2 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
12.86 (s, 1H), 8.43-8.31 (m, 1H), 8.02-7.86 (m, 2H), 7.71 (d, J=7.7
Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.47-7.34 (m, 4H), 7.30 (d, J=7.4
Hz, 1H), 4.95 (s, 2H), 4.76 (br. s., 2H), 3.65 (br. s., 2H), 2.99
(br. s., 4H), 2.77 (br. s., 3H), 2.36 (br. s., 2H); HPLC RT=4.32
min (Method A), 5.17 min (Method B).
Example 73:
4-(4-((5-Phenyloxazol-2-yl)amino)phenyl)phthalazin-1(2H)-one
##STR00414##
[1044] Example 73A: N-(4-Bromophenyl)-5-phenyloxazol-2-amine
##STR00415##
[1046] To a solution of 2-azido-1-phenylethanone (Angew. Chem. Int.
Ed., 46:4489-4491 (2007)) (126 mg, 0.782 mmol) and
1-bromo-4-isothiocyanatobenzene (167 mg, 0.782 mmol) in dioxane (4
mL) at 80.degree. C., was added triphenylphosphine (205 mg, 0.782
mmol). The mixture was stirred at 85.degree. C. for 30 min, then
was cooled to rt. The reaction mixture was concentrated. The solid
was recrystallized from hot CH.sub.3C.sub.1 (.about.5 mL). The
precipitate was suspended in EtOAc (.about.3 mL), filtered and
collected to afford 134 mg (54%) of Example 73A as a white solid.
MS(ESI) m/z: 315.0 (M+H).sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 7.62-7.57 (m, 2H), 7.51-7.46 (m, 2H), 7.46-7.41 (m, 2H),
7.39 (t, J=7.7 Hz, 2H), 7.26 (dt, J=7.4, 1.3 Hz, 1H), 7.24 (s,
1H).
Example 73B:
5-Phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazol--
2-amine
##STR00416##
[1048] To a vial containing Example 73A (136 mg, 0.432 mmol),
bis(pinacolato)diboron (164 mg, 0.647 mmol) and potassium acetate
(127 mg, 1.30 mmol), was added dioxane (2 mL). The mixture was
degassed (evacuated and flushed with Ar (3.times.)).
PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 adduct (17.6 mg, 0.022 mmol) was
added, then the mixture was degassed (2.times.), then was sealed.
The mixture was stirred at 110.degree. C. for 2 h. The reaction
mixture was diluted with EtOAc. The organic phase was washed with
H.sub.2O and brine, dried (Na.sub.2SO.sub.4) and concentrated. The
crude product was purified by flash chromatography (gradient from 0
to 50% ethyl acetate/hexanes) to afford 122 mg (78%) of Example 73B
as a white solid. MS(ESI) m/z: 363.1 (M+H).sup.+; .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.81 (d, J=8.8 Hz, 2H), 7.55 (dd, J=8.3,
1.2 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.43 (s, 1H), 7.42-7.36 (m,
2H), 7.29-7.23 (m, 1H), 7.18 (s, 1H), 1.35 (s, 12H).
Example 73
##STR00417##
[1050] To 4-chlorophthalazin-1(2H)-one (36.7 mg, 0.203 mmol),
Example 73B (67 mg, 0.185 mmol) and potassium phosphate (98 mg,
0.46 mmol) in dioxane (3 mL) and water (0.5 mL), was added
Pd(PPh.sub.3).sub.4 (10.7 mg, 9.25 .mu.mol). The mixture was
degassed (3.times.), then the reaction vial was sealed and heated
in a microwave reactor at 150.degree. C. for 25 min. The crude
product was purified by preparative HPLC to afford 9.7 mg (11%) of
Example 73. MS(ESI) m/z: 381.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.78 (s, 1H), 10.60 (s, 1H), 8.40-8.30 (m,
1H), 7.96-7.87 (m, 2H), 7.84-7.73 (m, 3H), 7.62 (d, J=7.7 Hz, 2H),
7.57 (d, J=8.5 Hz, 2H), 7.51 (s, 1H), 7.45 (t, J=7.7 Hz, 2H),
7.33-7.24 (m, 1H); HPLC RT=8.99 min (Method A), 8.46 min (Method
B).
Example 74: 4-(4-((4-Phenylthiazol-2-yl)amino)phenyl)phthalazin-1
(2H)-one
##STR00418##
[1051] Example 74A: N-(4-Bromophenyl)-4-phenylthiazol-2-amine
##STR00419##
[1053] 2-Bromo-1-phenylethanone (105 mg, 0.528 mmol) and
1-(4-bromophenyl)thiourea (122 mg, 0.528 mmol) were mixed in
glycerol (5 mL) and stirred at 90.degree. C. for 2 h. The reaction
mixture was partitioned between EtOAc and water. The organic phase
was concentrated and purified via flash chromatography
(EtOAc/hexanes) to afford 165 mg (94%) of Example 74A. MS(ESI) m/z:
331.0 (M+H).sup.+; .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
7.87-7.82 (m, 2H), 7.44-7.38 (m, 4H), 7.36-7.31 (m, 1H), 7.29-7.22
(m, 2H), 6.84 (s, 1H).
Example 74B:
4-Phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-
-2-amine
##STR00420##
[1055] To a mixture of Example 74A (160 mg, 0.483 mmol),
bis(pinacolato)diboron (147 mg, 0.580 mmol), and potassium acetate
(142 mg, 1.45 mmol) in dioxane (10 mL), was added PdCl.sub.2(dppf)
CH.sub.2Cl.sub.2 adduct (10.6 mg, 0.014 mmol). The reaction mixture
was degassed (3.times. vacuum/Ar), sealed in a vial and heated at
110.degree. C. for 2 h. The reaction was diluted with water and
extracted with EtOAc. The organic phase was concentrated and the
product purified via flash chromatography to afford 130 mg (71%) of
Example 74B. MS(ESI) m/z: 379.0 (M+H).sup.+.
Example 74
##STR00421##
[1057] To 4-chlorophthalazin-1(2H)-one (18 mg, 0.10 mmol), Example
74B (45.2 mg, 0.120 mmol) and potassium phosphate (53 mg, 0.25
mmol), were added dioxane (3 mL) and water (0.33 mL). The mixture
was degassed (evacuated and flushed with Ar (5.times.)).
Pd(PPh.sub.3).sub.4 (5.8 mg, 5.0 .mu.mol) was added, then the
mixture was degassed (2.times.). The reaction vial was sealed and
heated in a microwave reactor at 150.degree. C. for 35 min. The
reaction mixture was concentrated, then was purified by preparative
HPLC to afford 2.0 mg (3.9%) of Example 74. MS(ESI) m/z: 397.0
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.78 (s,
1H), 10.53 (s, 1H), 8.39-8.31 (m, 1H), 8.01-7.86 (m, 6H), 7.81 (d,
J=7.4 Hz, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.48-7.38 (m, 3H), 7.37-7.30
(m, 1H); HPLC RT=1.85 min (Method E), 1.90 min (Method F).
Example 75:
4-(4-(Benzo[d]oxazol-2-ylamino)phenyl)phthalazin-1(2H)-one
##STR00422##
##STR00423##
[1059] Intermediate 3 (35 mg, 0.100 mmol), 2-chlorobenzo[d]oxazole
(0.015 mL, 0.130 mmol), and DIEA (0.087 mL, 0.498 mmol) were
dissolved in NMP (1 mL) and the reaction mixture was heated in a
capped vial at 150.degree. C. for 18 h. The reaction mixture was
purified by preparative HPLC to afford 5.0 mg (14%) of Example 75.
MS(ESI) m/z: 355.05 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.83 (s, 1H), 10.90 (br. s., 1H), 8.39-8.30
(m, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.93-7.87 (m, 2H), 7.80-7.76 (m,
1H), 7.63 (d, J=8.4 Hz, 2H), 7.51 (dd, J=16.6, 7.7 Hz, 2H),
7.28-7.22 (m, 1H), 7.19-7.14 (m, 1H); HPLC RT=1.58 min (Method E),
1.64 min (Method F).
Example 76:
N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)indoline-1-carboxamide
##STR00424##
##STR00425##
[1061] To 4-chlorophthalazin-1(2H)-one (29 mg, 0.16 mmol),
Intermediate 10 and potassium phosphate (85 mg, 0.40 mmol), were
added dioxane (3 mL) and water (0.33 mL). The mixture was degassed
(evacuated and flushed with Ar (5.times.)). Pd(PPh.sub.3).sub.4
(9.28 mg, 8.03 .mu.mol) was added, then the mixture was degassed
(2.times.). The reaction vial was sealed and heated in a microwave
reactor at 150.degree. C. for 30 min. The reaction mixture was
concentrated and purified via preparative HPLC to afford 6.1 mg
(9.4%) of Example 76. MS(ESI) m/z: 383.1 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 12.81 (s, 1H), 8.74 (s, 1H), 8.34
(dd, J=7.7, 1.2 Hz, 1H), 8.00-7.85 (m, 3H), 7.76 (d, J=8.9 Hz, 3H),
7.53 (d, J=8.4 Hz, 2H), 7.22 (d, J=7.4 Hz, 1H), 7.14 (t, J=7.7 Hz,
1H), 6.92 (t, J=7.4 Hz, 1H), 4.18 (t, J=8.7 Hz, 2H), 3.20 (t, J=8.7
Hz, 2H); HPLC RT=1.65 min (Method E), 1.66 min (Method F).
Example 77:
N-(4-(1-Oxo-1,2-dihydroisoquinolin-4-yl)phenyl)indoline-1-carboxamide
##STR00426##
##STR00427##
[1063] According to the procedure for the preparation of Example
76, coupling of Intermediate 6 (28 mg, 0.125 mmol) and Intermediate
10 (54.6 mg, 0.150 mmol) afforded 7.5 mg (16%) of Example 77.
MS(ESI) m/z: 382.1 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.41 (br. s., 1H), 8.63 (s, 1H), 8.30 (d, J=8.0 Hz, 1H),
7.89 (d, J=8.3 Hz, 1H), 7.75-7.66 (m, 3H), 7.59-7.51 (m, 2H), 7.35
(d, J=8.3 Hz, 2H), 7.21 (d, J=7.4 Hz, 1H), 7.13 (t, J=7.7 Hz, 1H),
7.07 (s, 1H), 6.91 (t, J=7.3 Hz, 1H), 4.17 (t, J=8.5 Hz, 2H), 3.20
(t, J=8.3 Hz, 2H); HPLC RT=1.77 min (Method E), 1.73 min (Method
F).
Example 78:
4-{4-[(Quinazolin-2-yl)amino]phenyl}-1,2-dihydrophthalazin-1-one,
TFA
##STR00428##
##STR00429##
[1065] According to the procedure for the preparation of Example
75, Intermediate 3 (35 mg, 0.100 mmol) was reacted with
2-chloroquinazoline at 150.degree. C. for 40 h to afford 4.1 mg
(8.6%) of Example 78. MS(ESI) m/z: 366.2 (M+H).sup.+; .sup.1H-NMR:
(500 MHz, DMSO-d.sub.6) .delta. ppm 12.78 (s, 1H), 10.14 (s, 1H),
9.37 (s, 1H), 8.38-8.31 (m, 1H), 8.19 (d, J=8.5 Hz, 2H), 7.96 (d,
J=7.7 Hz, 1H), 7.93-7.87 (m, 2H), 7.84-7.78 (m, 2H), 7.72 (d, J=8.3
Hz, 1H), 7.57 (d, J=8.5 Hz, 2H), 7.42 (t, J=7.3 Hz, 1H); HPLC
RT=1.45 min (Method E), 1.70 min (Method F).
Example 79: 4-(4-(Quinazolin-2-ylamino)phenyl)phthalazin-1(2H)-one,
TFA
##STR00430##
[1067] According to the procedure for the preparation of Example
76, coupling of 4-chlorophthalazin-1(2H)-one (25 mg, 0.14 mmol) and
Intermediate 12 (60.0 mg, 0.152 mmol) afforded 2.5 mg (4.3%) of
Example 79. MS(ESI) m/z: 413.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.79 (br. s., 1H), 8.72 (s, 1H), 8.38-8.30
(m, 1H), 8.01-7.86 (m, 2H), 7.76 (d, J=8.5 Hz, 3H), 7.60-7.49 (m,
3H), 7.09 (d, J=8.3 Hz, 1H), 6.49 (dd, J=8.3, 2.5 Hz, 1H), 4.19 (t,
J=8.7 Hz, 2H), 3.72 (s, 3H), 3.12 (t, J=8.5 Hz, 2H); HPLC RT=1.67
min (Method E), 1.67 min (Method F).
Example 80:
6-Methoxy-N-(4-(1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl)indoline-1-carbo-
xamide
##STR00431##
##STR00432##
[1069] According to the procedure for the preparation of Example
76, coupling of Intermediate 6 (29 mg, 0.129 mmol) and Intermediate
12 (61.2 mg, 0.155 mmol) afforded 5.9 mg (11%) of Example 80.
MS(ESI) m/z: 412.2 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.42 (br. s., 1H), 8.63 (s, 1H), 8.30 (d, J=8.0 Hz, 1H),
7.75-7.66 (m, 3H), 7.60-7.51 (m, 3H), 7.35 (d, J=8.5 Hz, 2H),
7.11-7.03 (m, 2H), 6.48 (dd, J=8.1, 2.3 Hz, 1H), 4.18 (t, J=8.5 Hz,
2H), 3.72 (s, 3H), 3.11 (t, J=8.5 Hz, 2H); HPLC RT=1.47 min (Method
E), 1.48 min (Method F).
Example 81:
(R)--N-(2,3-Dihydro-1H-inden-1-yl)-2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl-
)phenyl)acetamide
##STR00433##
##STR00434##
[1071] According to the procedure for the preparation of Example 3,
coupling of Intermediate 1 (25 mg, 0.089 mmol) with
(R)-2,3-dihydro-1H-inden-1-amine (14.3 mg, 0.107 mmol) afforded
13.7 mg (38%) of Example 81. MS(ESI) m/z: 396.2 (M+H).sup.+;
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.83 (s, 1H), 8.53 (d,
J=8.3 Hz, 1H), 8.38-8.32 (m, 1H), 7.94-7.85 (m, 2H), 7.74-7.68 (m,
1H), 7.58-7.52 (m, 2H), 7.50-7.45 (m, 2H), 7.29-7.24 (m, 1H),
7.24-7.14 (m, 3H), 5.29 (q, J=7.8 Hz, 1H), 3.64-3.54 (m, 2H),
2.99-2.90 (m, 1H), 2.86-2.76 (m, 1H), 2.46-2.37 (m, 1H), 1.81 (dq,
J=12.7, 8.4 Hz, 1H); HPLC RT=1.58 min (Method E), 1.60 min (Method
F).
Example 82:
(S)--N-(2,3-Dihydro-1H-inden-1-yl)-2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl-
)phenyl)acetamide
##STR00435##
##STR00436##
[1073] According to the procedure for the preparation of Example 3,
coupling of Intermediate 1 (25 mg, 0.089 mmol) with
(S)-2,3-dihydro-1H-inden-1-amine (14.3 mg, 0.107 mmol) afforded
19.7 mg (56%) of Example 82. MS(ESI) m/z: 396.2 (M+H).sup.+;
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.83 (s, 1H), 8.53 (d,
J=8.3 Hz, 1H), 8.38-8.31 (m, 1H), 7.94-7.86 (m, 2H), 7.75-7.68 (m,
1H), 7.58-7.52 (m, 2H), 7.50-7.45 (m, 2H), 7.28-7.24 (m, 1H),
7.24-7.14 (m, 3H), 5.29 (q, J=7.9 Hz, 1H), 3.65-3.54 (m, 2H),
2.99-2.91 (m, 1H), 2.81 (dt, J=16.0, 8.3 Hz, 1H), 2.46-2.37 (m,
1H), 1.81 (dq, J=12.5, 8.4 Hz, 1H); HPLC RT=1.63 min (Method E),
1.63 min (Method F).
Example 83:
4-(4-(2-(6-(Benzyloxy)indolin-1-yl)-2-oxoethyl)phenyl)phthalazin-1
(2H)-one
##STR00437##
##STR00438##
[1075] According to the procedure for the preparation of Example 3,
coupling of Intermediate 1 (56 mg, 0.20 mmol) with
6-(benzyloxy)indoline (71.2 mg, 0.21 mmol) afforded 38 mg (38%) of
Example 83. MS(ESI) m/z: 488.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.83 (s, 1H), 8.40-8.30 (m, 1H), 7.99-7.81
(m, 3H), 7.76-7.69 (m, 1H), 7.60-7.53 (m, 2H), 7.50-7.44 (m, J=8.0
Hz, 2H), 7.44-7.40 (m, 2H), 7.39-7.34 (m, 2H), 7.34-7.26 (m, 1H),
7.12 (d, J=8.3 Hz, 1H), 6.66 (dd, J=8.1, 2.3 Hz, 1H), 5.05 (s, 2H),
4.24 (t, J=8.5 Hz, 2H), 3.96 (s, 2H), 3.10 (t, J=8.3 Hz, 2H); HPLC
RT=10.56 min (Method A), 9.34 min (Method B).
Example 84
##STR00439##
[1077] Intermediate 13 (50 mg, 0.12 mmol), benzo[d]thiazol-2-amine
(17.8 mg, 0.119 mmol),
di-tert-butyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)ph-
osphine (7.6 mg, 0.016 mmol), Pd.sub.2(dba).sub.3 (3.3 mg, 3.6
.mu.mol) and K.sub.2CO.sub.3 (23 mg, 0.17 mmol) were added in a
pressure vial. The reaction mixture was degassed (3.times.
vacuum/Ar), and then tBuOH (1 mL) and AcOH (1 drop) were added. The
reaction mixture was degassed again, capped, and stirred at
110.degree. C. for 3 h. The reaction mixture was diluted with
MeOH/DMSO, filtered and purified by preparative HPLC to afford
4-(4-(benzo[d]thiazol-2-ylamino)phenyl)-2-(4-methoxybenzyl)phthala-
zin-1(2H)-one (45.9 mg, 79% yield) as a white solid. MS(ESI) m/z:
491.1 (M+H).sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
10.77 (br. s., 1H), 8.38 (br. s., 1H), 7.99 (d, J=7.9 Hz, 2H), 7.92
(d, J=3.3 Hz, 2H), 7.85 (d, J=7.7 Hz, 2H), 7.69-7.56 (m, 3H), 7.35
(d, J=6.2 Hz, 3H), 7.19 (t, J=7.0 Hz, 1H), 6.90 (d, J=7.9 Hz, 2H),
5.32 (br. s., 2H), 3.71 (s, 3H). The residue was dissolved in TFA
(3 mL) and was sealed vial and was heated in a microwave reactor at
150.degree. C. for 30 min. The reaction mixture was evaporated and
was purified by preparative HPLC to afford 2.3 mg (6%) of Example
84. MS(ESI) m/z: 371.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.80 (s, 1H), 10.72 (s, 1H), 8.35 (d,
J=7.4 Hz, 1H), 7.98 (d, J=8.5 Hz, 2H), 7.94-7.89 (m, 2H), 7.85 (d,
J=8.0 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.61
(d, J=8.5 Hz, 2H), 7.36 (t, J=7.7 Hz, 1H), 7.19 (t, J=7.6 Hz, 1H);
HPLC RT=1.68 min (Method E), 1.84 min (Method F).
Example 85:
4-(4-(Phthalazin-1-ylamino)phenyl)phthalazin-1(2H)-one
##STR00440##
[1079] According to the procedure for the preparation of Example
84, Intermediate 13 (50 mg, 0.12 mmol) and 1-chlorophthalazine
(25.3 mg, 0.154 mmol) afforded after coupling and deprotection 6.6
mg (40%) of Example 85. MS(ESI) m/z: 366.1 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 12.81 (s, 1H), 9.39 (s, 1H),
9.20 (s, 1H), 8.65 (d, J=8.0 Hz, 1H), 8.36 (d, J=7.7 Hz, 1H), 8.16
(d, J=8.3 Hz, 2H), 8.09-8.05 (m, 1H), 8.03 (d, J=7.7 Hz, 1H),
8.02-7.97 (m, 1H), 7.96-7.88 (m, 2H), 7.84 (d, J=7.7 Hz, 1H), 7.61
(d, J=8.5 Hz, 2H); HPLC RT=1.07 min (Method E), 1.40 min (Method
F).
Example 86:
4-{4-[(5-Methyl-1,3-benzoxazol-2-yl)amino]phenyl}-1,2-dihydrophthalazin-1-
-one
##STR00441##
[1081] According to the procedure for the preparation of Example
76, coupling of 2-chloro-5-methylbenzo[d]oxazole (25.05 mg, 0.149
mmol) and Intermediate 12 (35 mg, 0.10 mmol) afforded 6.8 mg (18%)
of Example 86. MS(ESI) m/z: 469.2 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 12.80 (br. s., 1H), 8.34 (d, J=7.7 Hz,
1H), 7.97-7.84 (m, 4H), 7.78 (d, J=7.7 Hz, 1H), 7.61 (d, J=8.0 Hz,
2H), 7.38 (d, J=8.0 Hz, 1H), 7.29 (s, 1H), 6.96 (d, J=8.3 Hz, 1H),
2.38 (s, 3H); HPLC RT=1.75 min (Method E), 1.81 min (Method F).
Example 87:
4-(4-((5-Phenyl-1,3,4-thiadiazol-2-yl)amino)phenyl)phthalazin-1(2H)-one
##STR00442##
[1083] Intermediate 14 (50 mg, 0.14 mmol) and
2-chloro-5-phenyl-1,3,4-thiadiazole (33 mg, 0.17 mmol) were
dissolved in dry THF (2 mL). Then, LiHMDS (1 M in THF) (0.364 mL,
0.364 mmol) was added dropwise to the stirred reaction mixture. The
reaction mixture was stirred at 50.degree. C. for 1 h. The reaction
mixture was cooled to rt, quenched with MeOH (1 mL), and
concentrated under reduced pressure. The residue was redissolved in
TFA (3 mL), and stirred at 150.degree. C. for 15 min under
microwave irradiation. TFA was evaporated, then the residue was
purified by prep HPLC to afford 14.1 mg (25%) of Example 87.
MS(ESI) m/z: 498.1 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 12.80 (s, 1H), 10.79 (br. s., 1H), 8.35 (d, J=7.4 Hz,
1H), 7.98-7.87 (m, 4H), 7.85 (d, J=8.0 Hz, 2H), 7.78 (d, J=7.7 Hz,
1H), 7.61 (d, J=8.0 Hz, 2H), 7.56-7.48 (m, 3H); HPLC RT=1.67 min
(Method E), 1.68 min (Method F).
Example 88:
4-(4-((5-Phenylthiazol-2-yl)amino)phenyl)phthalazin-1(2H)-one
##STR00443##
[1085] According to the procedure for the preparation of Example
87, coupling of Intermediate 14 (40 mg, 0.112 mmol) and
2-chloro-5-phenylthiazole (26.3 mg, 0.134 mmol) afforded after TFA
deprotection and HPLC purification 1.3 mg (3%) on Example 88.
MS(ESI) m/z: 397.2 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 12.78 (br. s., 1H), 10.59 (br. s., 1H), 8.34 (d, J=7.2
Hz, 1H), 7.96-7.87 (m, 2H), 7.85-7.76 (m, 3H), 7.74 (s, 1H), 7.56
(d, J=7.7 Hz, 4H), 7.40 (t, J=7.2 Hz, 2H), 7.31-7.24 (m, 1H); HPLC
RT=1.74 min (Method E), 1.95 min (Method F).
[1086] The following Examples in Table 3 were made by using the
same procedure as shown in Example 45. Intermediate 3 was coupled
with the appropriate carboxylic acid. Various coupling reagents
could be used other than the one described in Example 45, such as
BOP, PyBop, EDC/HOBt or T3P.
##STR00444##
TABLE-US-00004 TABLE 3 LC HPLC MS Method, Ex- (M + RT ample R Name
H).sup.+ (min.) .sup.1H NMR 89 ##STR00445## N-[4-(4-oxo-3,4
dihydrophthalazin-1-yl) phenyl]imidazo[1,2-a]
pyridine-2-carboxamide 382.1 A: 5.21 B: 5.58 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.82 (s, 1H), 10.58 (s, 1H), 8.69 (d, J = 6.9 Hz,
1H), 8.63 (s, 1H), 8.35 (dd, J = 7.8, 1.5 Hz, 1H), 8.14-8.03 (m, J
= 8.5 Hz, 2H), 7.91 (quind, J = 7.6, 1.4 Hz, 2H), 7.81-7.74 (m,
1H), 7.71 (d, J = 9.1 Hz, 1H), 7.64-7.57 (m, J = 8.5 Hz, 2H),
7.49-7.42 (m, 1H), 7.10 (t, J = 6.7 Hz, 1H) 90 ##STR00446##
1-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-1H-indole-2- carboxamide 395.1 E: 1.77 F: 1.79 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) d 12.82 (br. s., 1H), 10.54 (br. s.,
1H), 8.39-8.32 (m, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.97-7.85 (m,
2H), 7.77 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.63-7.54
(m, 3H), 7.38 (s, 1H), 7.34-7.30 (m, 1H), 7.19-7.10 (m, 1H),
4.11-4.00 (m, 3H) 91 ##STR00447## N-[4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-2,3-dihydro- 1H-indene-1-
carboxamide 382.1 E: 1.68 F: 1.70 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.79 (s, 1H), 10.47 (s, 1H), 8.37-8.31 (m, 1H),
7.94-7.85 (m, 2H), 7.83 (d, J = 8.5 Hz, 2H), 7.76-7.71 (m, 1H),
7.55 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 6.9 Hz, 1H), 7.28 (d, J =
7.2 Hz, 1H), 7.24- 7.14 (m, 2H), 4.17 (t, J = 7.4 Hz, 1H),
3.13-3.03 (m, 1H), 2.97-2.87 (m, 1H), 2.44-2.24 (m, 2H) 92
##STR00448## N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-4-(1H-1,2,4- triazol-1-yl)benzamide 409.1 E: 1.33 F:
1.33 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s, 1H), 10.56 (s,
1H), 9.46 (s, 1H), 8.39-8.28 (m, 2H), 8.24-8.18 (m, J = 8.5 Hz,
2H), 8.11-8.03 (m, J = 8.5 Hz, 2H), 8.03-7.84 (m, 4H), 7.77 (d, J =
8.0 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H) 93 ##STR00449##
N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-2,1-
benzoxazole-3- carboxamide 383.0 A: 8.48 B: 7.27 .sup.1H NMR (500
MHz, DMSO-d.sub.6) d 12.88-12.80 (m, 1H), 11.33 (br. s., 1H), 8.35
(d, J = 7.2 Hz, 1H), 8.14-8.02 (m, 3H), 7.92 (t, J = 7.0 Hz, 2H),
7.84 (d, J = 6.6 Hz, 1H), 7.76 (d, J = 6.3 Hz, 1H), 7.64 (d, J =
5.8 Hz, 2H), 7.56 (t, J = 6.7 Hz, 1H), 7.36 (t, J = 6.2 Hz, 1H) 94
##STR00450## 6-(dimethylamino)-N-[4- (4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1H-indole-2- carboxamide 424.2 E:
1.23 F: 1.74 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.81 (s, 1H),
11.29 (s, 1H), 10.20 (s, 1H), 8.35 (d, J = 7.4 Hz, 1H), 8.05-7.85
(m, 5H), 7.78 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.49
(d, J = 9.1 Hz, 1H), 7.34 (s, 1H), 6.76 (dd, J = 8.8, 1.9 Hz, 1H),
6.65 (s, 1H), 2.93 (s, 6H) 95 ##STR00451## 2-methyl-N-[4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]imidazo[1,2-a]
pyridine-3-carboxamide 396.1 E: 1.12 F: 1.37 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.82 (s, 1H), 10.11 (s, 1H), 8.96 (d, J = 6.9 Hz,
1H), 8.35 (d, J = 7.4 Hz, 1H), 7.95- 7.86 (m, 4H), 7.78 (d, J = 7.7
Hz, 1H), 7.66-7.58 (m, 3H), 7.47-7.41 (m, 1H), 7.08 (t, J = 6.7 Hz,
1H), 2.68 (s, 3H) 96 ##STR00452## 5-chloro-1-methyl-N-[4-
(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1H-indole-2-
carboxamide 429.1 E: 2.02 F: 2.02 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.82 (s, 1H), 10.61 (s, 1H), 8.35 (d, J = 7.7 Hz,
1H), 8.04-7.87 (m, 4H), 7.81 (s, 1H), 7.76 (d, J = 7.7 Hz, 1H),
7.65 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.37-7.28 (m,
2H), 4.04 (s, 3H) 97 ##STR00453## 5,5-dimethyl-4-oxo-N-[4-
(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-4,5,6,7-
tetrahydro-1H-indole-3- carboxamide 427.2 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) Shift 12.82 (d, J = 5.8 Hz, 2H), 12.11 (br. s., 1H),
8.34 (d, J = 6.1 Hz, 1H), 7.97-7.50 (m, 8H), 2.89 (d, J = 4.3 Hz,
2H), 1.99 (br. s., 2H), 1.21 (br. s., 6H) 98 ##STR00454##
1-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-1H-indazole- 3-carboxamide 396.2 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) Shift 12.83 (s, 1H), 10.58 (s, 1H), 8.35 (d, J = 7.6
Hz, 1H), 8.26 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 8.5 Hz, 2H),
7.98-7.86 (m, 2H), 7.79 (dd, J = 18.6, 8.2 Hz, 2H), 7.59 (d, J =
8.2 Hz, 2H), 7.53 (t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H),
4.23 (s, 3H) 99 ##STR00455## 1-benzyl-N-[4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]-1H-indazole- 3-carboxamide
472.2 .sup.1H NMR (500 MHz, DMSO-d.sub.6) Shift 12.83 (s, 1H),
10.61 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8.28 (d, J = 8.2 Hz, 1H),
8.10 (d, J = 8.2 Hz, 2H), 7.98-7.87 (m, 2H), 7.82 (d, J = 8.5 Hz,
1H), 7.77 (d, J = 7.0 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.50 (t, J
= 7.6 Hz, 1H), 7.41-7.22 (m, 6H), 5.86 (s, 2H) 100 ##STR00456##
5-ethoxy-2-methyl-N-[4- (4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1-benzofuran- 3-carboxamide 440.2 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) Shift 12.83 (s, 1H), 10.29 (s, 1H), 8.35 (d, J = 7.0
Hz, 1H), 7.97-7.84 (m, 4H), 7.77 (d, J = 7.6 Hz, 1H), 7.60 (d, J =
8.2 Hz, 2H), 7.50 (d, J = 8.9 Hz, 1H), 7.20 (s, 1H), 6.92 (d, J =
8.5 Hz, 1H), 4.07 (q, J = 7.0 Hz, 2H), 2.67 (s, 3H), 1.35 (t, J =
6.7 Hz, 3H) 101 ##STR00457## 5-methyl-N-[4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]-1H-indole-2- carboxamide 395.1
.sup.1H NMR (500 MHz, DMSO-d.sub.6) Shift 12.83 (s, 1H), 11.68 (br.
s., 1H), 10.38 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 7.6
Hz, 2H), 7.96-7.84 (m, 3H), 7.78 (d, J = 7.3 Hz, 1H), 7.61 (d, J =
7.3 Hz, 2H), 7.47 (s, 1H), 7.42-7.33 (m, 2H), 7.07 (d, J = 8.5 Hz,
1H), 2.39 (s, 3H) 102 ##STR00458## N-[4-(4-oxo-3,4-
dihydrophthalazin-1-yl) phenyl]pyrazolo[1,5-a] pyrimidine-2-
carboxamide 441.2 .sup.1H NMR (500 MHz, DMSO-d.sub.6) Shift 12.83
(s, 1H), 10.73 (s, 1H), 9.20 (d, J = 6.7 Hz, 1H), 8.74-8.66 (m,
1H), 8.35 (d, J = 7.6 Hz, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.97-7.87
(m, 2H), 7.76 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.27
(s, 1H), 7.25 (dd, J = 7.0, 4.0 Hz, 1H) 103 ##STR00459##
N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl) phenyl]pyrazolo[1,5-a]
pyridine-3-carboxamide 382.0 A: 7.05 B: 6.25 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.81 (s, 1H), 10.15 (s, 1H), 8.91-8.81 (m,
2H), 8.43-8.27 (m, 2H), 8.05-7.87 (m, 4H), 7.78 (d, J = 7.5 Hz,
1H), 7.65-7.53 (m, 3H), 7.14 (t, J = 6.8 Hz, 1H), 6.59-6.45 (m, 1H)
104 ##STR00460## N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)
phenyl]imidazo[1,2-a] pyridine-3-carboxamide .sup.1H NMR (500 MHz,
DMSO-d.sub.6) Shift 12.84 (s, 1H), 10.42 (s, 1H), 9.50 (d, J = 6.7
Hz, 1H), 8.64 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 7.98-7.84 (m, 4H),
7.78 (t, J = 7.5 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 7.57-7.50 (m,
1H), 7.21 (t, J = 6.7 Hz, 1H) 105 ##STR00461##
5-(benzyloxy)-2-methyl- N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1-benzofuran- 3-carboxamide 502.1 C: 3.04 D: 4.07
.sup.1H NMR (500 MHz, DMSO-d.sub.6) Shift 12.84 (s, 1H), 10.29 (s,
1H), 8.35 (d, J = 7.9 Hz, 1H), 7.97-7.84 (m, 4H), 7.76 (d, J = 7.6
Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.9 Hz, 1H), 7.47
(d, J = 7.6 Hz, 2H), 7.39 (t, J = 7.3 Hz, 2H), 7.35-7.27 (m, 2H),
7.01 (d, J = 8.9 Hz, 1H), 5.15 (s, 2H), 2.66 (s, 3H) 106
##STR00462## 5-hydroxy-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-2,3-dihydro-1- benzofuran-2- carboxamide 400.2 C: 1.90
D: 2.96 .sup.1H NMR (500 MHz, DMSO-d.sub.6) Shift 12.81 (s, 1H),
10.29 (s, 1H), 8.91 (br. s., 1H), 8.51-8.25 (m, 1H), 7.94-7.80 (m,
4H), 7.75-7.65 (m, 1H), 7.55 (d, J = 8.5 Hz, 2H), 6.75- 6.62 (m,
2H), 6.53 (d, J = 6.1 Hz, 1H), 5.28 (dd, J = 9.8, 6.7 Hz, 1H),
3.55-3.41 (m, 1H) 107 ##STR00463## 1-ethyl-N-[4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1H-indole-2- carboxamide 409.2 C:
2.81 D: 3.95 .sup.1H NMR (500 MHz, DMSO-d.sub.6) Shift 12.83 (s,
1H), 10.54 (s, 1H), 8.35 (d, J = 7.0 Hz, 1H), 7.99 (d, J = 8.5 Hz,
2H), 7.93-7.87 (m, 2H), 7.80-7.67 (m, 2H), 7.65-7.53 (m, 3H), 7.38
(s, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 4.62
(d, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H) 108 ##STR00464##
4-oxo-N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-5-(propan-2-
yl)-3H,4H-pyrrolo[2,1-f] [1,2,4]triazine-6- carboxamide 441.2 C:
2.08 D: 3.31 .sup.1H NMR (500 MHz, DMSO-d.sub.6) Shift 12.82 (s,
1H), 11.64 (br. s., 1H), 10.21 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H),
8.10 (s, 1H), 7.93-7.84 (m, 5H), 7.76 (d, J = 7.3 Hz, 1H), 7.57 (d,
J = 8.2 Hz, 2H), 4.13-4.00 (m, 1H), 1.36 (d, J = 7.0 Hz, 6H) 109
##STR00465## 4-oxo-N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-4,5,6,7- tetrahydro-1H-indazole- 3-carboxamide 400.3 C:
2.01 D: 3.40 .sup.1H NMR (500 MHz, DMSO-d.sub.6) Shift 12.84 (s,
1H), 12.60 (br. s., 1H), 8.34 (d, J = 6.7 Hz, 1H), 7.96-7.86 (m,
4H), 7.77 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.3 Hz, 2H), 2.92 (br.
s., 2H), 2.67 (br. s., 2H), 2.16-2.07 (m, 2H) 110 ##STR00466##
N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1H-
pyrazolo[3,4-b]pyridine- 3-carboxamide 383.2 C: 1.73 D: 3.01
.sup.1H NMR (500 MHz, DMSO-d.sub.6) Shift 12.83 (s, 1H), 10.78 (s,
1H), 9.51 (s, 1H), 8.45 (d, J = 5.8 Hz, 1H), 8.35 (d, J = 7.6 Hz,
1H), 8.11 (d, J = 8.2 Hz, 2H), 7.96-7.87 (m, 3H), 7.77 (d, J = 7.3
Hz, 1H), 7.69 (d, J = 6.1 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H) 111
##STR00467## 6-methyl-4-oxo-N-[4-(4- oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-4H,5H,6H,7H- furo[2,3-c]pyridine-3- carboxamide 415.1
112 ##STR00468## N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-[1,2,4] triazolo[1,5-a]pyrimidine- 2-carboxamide 384.2
.sup.1H NMR (400 MHz, methanol-d.sub.4) Shift 13.64 (br. s., 1H),
11.90 (s, 1H), 10.34 (dd, J = 6.8, 2.0 Hz, 1H), 9.86 (dd, J = 4.3,
2.0 Hz, 1H), 9.20-9.11 (m, 1H), 8.92 (d, J = 8.5 Hz, 2H), 8.77-8.67
(m, 2H), 8.60-8.54 (m, 1H), 8.47-8.40 (m, 2H), 8.35 (dd, J = 6.8,
4.3 Hz, 1H) 113 ##STR00469## N-[4-(4-oxo-3,4-
dihydrophthalazin-1-yl) phenyl]pyrazolo[1,5-a] pyrimidine-3-
carboxamide 383.1 .sup.1H NMR (400 MHz, methanol-d.sub.4) Shift
13.62 (s, 1H), 10.97 (s, 1H), 10.20 (dd, J = 6.9, 1.6 Hz, 1H), 9.75
(dd, J = 4.1, 1.6 Hz, 1H), 9.57 (s, 1H), 9.18-9.14 (m, 1H), 8.76-
8.68 (m, 4H), 8.61-8.56 (m, 1H), 8.43 (d, J = 8.6 Hz, 2H), 8.17
(dd, J = 7.0, 4.0 Hz, 1H) 114 ##STR00470##
5-chloro-N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-indazole- 3-carboxamide .sup.1H NMR (400 MHz,
methanol-d.sub.4) Shift 13.64 (br. s., 1H), 11.36 (br. s., 1H),
9.19-9.13 (m, 1H), 8.99 (d, J = 1.8 Hz, 1H), 8.90 (d, J = 8.8 Hz,
2H), 8.72 (quind, J = 7.4, 1.5 Hz, 2H), 8.62-8.53 (m, 2H), 8.39 (d,
J = 8.5 Hz, 2H), 8.19 (dd, J = 8.8, 1.8 Hz, 1H) 115 ##STR00471##
N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1,3-
benzothiazole-2- carboxamide 399.1 .sup.1H NMR (400 MHz,
methanol-d.sub.4) Shift 13.64 (s, 1H), 12.14 (s, 1H), 9.19-9.14 (m,
1H), 9.12-9.04 (m, 2H), 8.96-8.90 (m, 2H), 8.78-8.68 (m, 2H),
8.59-8.55 (m, 1H), 8.53-8.41 (m, 5H) 116 ##STR00472##
2-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-4,5,6,7-
tetrahydro-2H-indazole- 3-carboxamide 400.2 .sup.1H NMR (400 MHz,
methanol-d.sub.4) Shift 13.62 (br. s., 1H), 10.99 (s, 1H),
9.20-9.10 (m, 1H), 8.75-8.65 (m, 3H), 8.58-8.53 (m, 1H), 8.47-8.32
(m, 3H), 4.71 (s, 3H), 3.52 (t, J = 5.8 Hz, 2H), 3.39 (t, J = 5.9
Hz, 2H), 2.63-2.45 (m, 4H) 117 ##STR00473## 4-methoxy-N-[4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]-1H-indole-3- carboxamide 411.2
C: 2.30 D: 3.56 .sup.1H NMR (400 MHz, DMSO-d.sub.6) Shift 12.81
(br. s., 1H), 10.84 (s, 1H), 8.39-8.32 (m, 1H), 8.07 (s, 1H), 7.97-
7.87 (m, 4H), 7.81-7.77 (m, 1H), 7.60 (d, J = 8.5 Hz, 2H),
7.23-7.16 (m, 2H), 6.88-6.82 (m, 1H), 4.15 (s, 3H) 118 ##STR00474##
N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1,2-
benzoxazole-3- carboxamide 383.2 C: 2.58 D: 3.82 .sup.1H NMR (400
MHz, DMSO-d.sub.6) Shift 12.83 (br. s., 1H), 11.24 (br. s., 1H),
8.38-8.33 (m, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.8 Hz,
2H), 7.97-7.87 (m, 3H), 7.83- 7.73 (m, 2H), 7.67-7.62 (m, 2H),
7.60-7.54 (m, 1H) 119 ##STR00475## 5-chloro-N-[4-(4-oxo-3,4-
dihydrophthalazin-1-yl) phenyl]-1H-pyrrolo[2,3-
b]pyridine-2-carboxamide 416.1 C: 2.30 D: 3.61 120 ##STR00476##
5-fluoro-N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-pyrrolo [2,3-b]pyridine-3- carboxamide 398.2 C: 2.04
D: 3.43 .sup.1H NMR (400 MHz, DMSO-d.sub.6) Shift 12.80 (br. s.,
1H), 10.09 (s, 1H), 8.60 (s, 1H), 8.37-8.30 (m, 2H), 8.26 (dd, J =
9.4, 2.9 Hz, 1H), 7.99-7.86 (m, 5H), 7.81-7.75 (m, 1H), 7.58 (d, J
= 8.5 Hz, 2H) 121 ##STR00477## 6-methyl-N-[4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]imidazo[1,2-a]
pyrazine-2-carboxamide 397.1 122 ##STR00478## 1-methyl-N-[4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]-1H-indole-3- carboxamide 395.2
123 ##STR00479## 5-methoxy-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-1H-indazole- 3-carboxamide 412.2 C: 2.23 D: 3.50 .sup.1H
NMR (400 MHz, DMSO-d.sub.6) Shift 12.80 (s, 1H), 10.47 (s, 1H),
8.35 (d, J = 6.8 Hz, 1H), 8.10 (d, J = 8.8 Hz, 2H), 7.96-7.86 (m,
2H), 7.78 (d, J = 9.0 Hz, 1H), 7.64 (s, 1H), 7.61-7.55 (m, 3H),
7.12 (d, J = 9.3 Hz, 1H), 3.85 (s, 3H) 124 ##STR00480##
8-chloro-N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]imidazo[1,2-a] pyrazine-2-carboxamide 415.2 C: 2.03 D:
3.25 .sup.1H NMR (400 MHz, DMSO-d.sub.6) Shift 12.82 (br. s., 1H),
10.58 (br. s., 1H), 8.84 (s, 1H), 8.71 (d, J = 4.5 Hz, 1H),
8.38-8.33 (m, 1H), 8.08 (d, J = 8.8 Hz, 2H), 7.92 (qd, J = 7.2, 5.5
Hz, 2H), 7.86 (d, J = 4.5 Hz, 1H), 7.79-7.74 (m, 1H), 7.61 (d, J =
8.5 Hz, 2H) 125 ##STR00481## 5-methoxy-N-[4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]-1H-indole-2- carboxamide 411.3
C: 2.41 D: 3.63 .sup.1H NMR (500 MHz, DMSO-d.sub.6) Shift 12.83
(br. s., 1H), 11.68 (br. s., 1H), 10.39 (br. s., 1H), 8.35 (d, J =
7.6 Hz, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.96-7.86 (m, 2H), 7.78 (d,
J = 7.6 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.42-7.34 (m, 2H), 7.16
(s, 1H), 6.90 (dd, J = 8.7, 1.4 Hz, 1H), 3.79 (s, 3H)
126 ##STR00482## 7-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]imidazo[1,2-a] pyridine-2-carboxamide 396.3 C: 2.30 D:
3.50 .sup.1H NMR (500 MHz, DMSO-d.sub.6) Shift 12.82 (s, 1H), 10.48
(s, 1H), 8.52 (d, J = 7.3 Hz, 1H), 8.48 (s, 1H), 8.34 (d, J = 7.3
Hz, 1H), 8.10 (d, J = 8.5 Hz, 2H), 7.98-7.86 (m, 2H), 7.76 (d, J =
7.9 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.44 (s, 1H), 6.89 (d, J =
7.0 Hz, 1H), 2.40 (s, 3H) 127 ##STR00483## 6-methoxy-1-methyl-N-
[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1H-indole-2-
carboxamide 425.2 C: 2.71 D: 3.82 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) Shift 12.83 (s, 1H), 10.40 (s, 1H), 8.38-8.31 (m,
1H), 7.97 (d, J = 8.5 Hz, 2H), 7.95- 7.86 (m, 2H), 7.77 (d, J = 7.3
Hz, 1H), 7.62-7.54 (m, 3H), 7.34 (s, 1H), 7.07 (s, 1H), 6.80 (dd, J
= 8.9, 2.1 Hz, 1H), 4.01 (s, 3H), 3.86 (s, 3H) 128 ##STR00484##
N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-6-(propan-2-
yloxy)-1H-indole-2- carboxamide 439.3 C: 2.75 D: 3.89 .sup.1H NMR
(500 MHz, DMSO-d.sub.6) Shift 12.83 (s, 1H), 11.54 (br. s., 1H),
10.31 (s, 1H), 8.35 (d, J = 7.9 Hz, 1H), 8.00 (d, J = 8.5 Hz, 2H),
7.96-7.86 (m, 3H), 7.78 (d, J = 7.3 Hz, 1H), 7.60 (d, J = 8.5 Hz,
2H), 7.56 (d, J = 8.5 Hz, 1H), 7.41 (s, 1H), 6.93 (s, 1H), 6.72
(dd, J = 8.5, 1.8 Hz, 1H), 4.58 (dt, J = 12.2, 6.1 Hz, 1H), 1.30
(d, J = 6.1 Hz, 6H) 129 ##STR00485## 7-methoxy-N-[4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]-1H-indole-2- carboxamide 411.3
C: 2.54 D: 3.73 .sup.1H NMR (500 MHz, DMSO-d.sub.6) Shift 12.84 (s,
1H), 11.66 (s, 1H), 10.36 (s, 1H), 8.39-8.32 (m, 1H), 7.98 (d, J =
8.5 Hz, 2H), 7.94-7.86 (m, 2H), 7.78 (d, J = 7.3 Hz, 1H), 7.62 (d,
J = 8.5 Hz, 2H), 7.34 (s, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.03 (t, J
= 7.9 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 3.96 (s, 3H) 130
##STR00486## 5-ethoxy-1-methyl-N-[4- (4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1H-indole-2- carboxamide 439.2 C:
2.70 D: 3.90 .sup.1H NMR (500 MHz, DMSO-d.sub.6) Shift 12.84 (s,
1H), 10.49 (s, 1H), 8.40-8.29 (m, 1H), 7.98 (d, J = 8.5 Hz, 2H),
7.94- 7.86 (m, 2H), 7.80-7.74 (m, 1H), 7.59 (d, J = 8.5 Hz, 2H),
7.49 (d, J = 9.2 Hz, 1H), 7.27 (s, 1H), 7.17 (d, J = 2.1 Hz, 1H),
6.97 (dd, J = 8.9, 2.4 Hz, 1H), 4.05 (q, J = 6.9 Hz, 2H), 4.01 (s,
3H), 1.36 (t, J = 6.9 Hz, 3H) 131 ##STR00487##
2-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-2H-indazole- 3-carboxamide 396.2 C: 2.16 D: 3.47 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) Shift 12.85 (br. s., 1H), 10.86 (br.
s., 1H), 8.35 (d, J = 7.9 Hz, 1H), 8.00-7.84 (m, 5H), 7.76 (t, J =
8.2 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.38 (t, J = 7.5 Hz, 1H),
7.28 (t, J = 7.2 Hz, 1H), 4.38 (s, 3H) 132 ##STR00488##
N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-(propan-2-
yl)-1H-indazole-3- carboxamide 424.3 C: 2.93 D: 4.06 .sup.1H NMR
(500 MHz, DMSO-d.sub.6) Shift 12.84 (s, 1H), 10.29 (s, 1H), 8.35
(d, J = 8.5 Hz, 1H), 8.25 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 8.5 Hz,
2H), 7.98-7.83 (m, 3H), 7.79 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 8.5
Hz, 2H), 7.50 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 5.16
(quin, J = 6.6 Hz, 1H), 1.62 (d, J = 6.4 Hz, 6H) 133 ##STR00489##
N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl) phenyl]imidazo[1,2-a]
pyrazine-2-carboxamide 383.1 C: 1.90 D: 3.05 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) Shift 12.83 (s, 1H), 10.77 (s, 1H), 9.23 (s, 1H),
8.72 (s, 1H), 8.70-8.64 (m, 1H), 8.34 (d, J = 7.9 Hz, 1H), 8.11 (d,
J = 8.5 Hz, 2H), 8.03 (d, J = 4.9 Hz, 1H), 7.95-7.86 (m, 2H), 7.76
(d, J = 7.3 Hz, 1H), 7.59 (d, J = 8.2 Hz, 2H) 134 ##STR00490##
N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-5H,6H,7H,8H-
imidazo[1,2-a]pyridine-2- carboxamide 386.2 C: 1.93 D: 3.21 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) Shift 12.80 (s, 1H), 9.99 (s, 1H), 8.34
(d, J = 6.7 Hz, 1H), 8.03 (d, J = 8.5 Hz, 2H), 7.94-7.84 (m, 2H),
7.78-7.67 (m, 2H), 7.53 (d, J = 8.5 Hz, 2H), 4.09-3.96 (m, 2H),
2.82 (t, J = 6.0 Hz, 2H), 2.01- 1.81 (m, 4H) 135 ##STR00491##
N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1H-
pyrrolo[2,3-b]pyridine-3- carboxamide 382.2 C: 2.03 D: 3.24 .sup.1H
NMR (400 MHz, DMSO-d.sub.6) Shift 12.79 (br. s., 1H), 10.03 (s,
1H), 8.53 (dd, J = 7.9, 1.6 Hz, 1H), 8.49 (s, 1H), 8.39-8.30 (m,
2H), 8.00-7.86 (m, 4H), 7.81-7.76 (m, 1H), 7.62-7.54 (m, 2H), 7.24
(dd, J = 8.0, 4.8 Hz, 1H) 136 ##STR00492## 1-benzyl-N-[4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]-1H-indole-2- carboxamide 471.4
C: 3.12 D: 4.22 .sup.1H NMR (400 MHz, DMSO-d.sub.6) Shift 12.81
(br. s., 1H), 10.60 (s, 1H), 8.39-8.29 (m, 1H), 7.99-7.93 (m, 2H),
7.93-7.85 (m, 2H), 7.82-7.71 (m, 2H), 7.58 (d, J = 8.8 Hz, 3H),
7.47 (s, 1H), 7.34-7.23 (m, 3H), 7.23-7.08 (m, 4H), 5.91 (s, 2H)
137 ##STR00493## 1-(2-hydroxy-2- methylpropyl)-N-[4-(4- oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1H-indazole- 3-carboxamide 454.2 E:
1.64 F: 1.60 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.85 (s, 1H),
10.44 (s, 1H), 8.35 (d, J = 7.7 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H),
8.08 (d, J = 8.0 Hz, 2H), 7.92 (t, J = 8.8 Hz, 2H), 7.87 (d, J =
8.8 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H),
7.48 (t, J = 7.6 Hz, 1H), 7.32 (t, J = 7.3 Hz, 1H), 4.79 (s, 1H),
4.49 (s, 2H), 1.19 (s, 6H) 138 ##STR00494## 1-(2-hydroxy-2-
methylpropyl)-N-[4-(4- oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-indole-3- carboxamide 453.2 E: 1.65 F: 1.66 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) d 12.83 (br. s., 1H), 10.01 (br. s.,
1H), 8.38 (br. s., 1H), 8.35 (d, J = 7.4 Hz, 1H), 8.24 (d, J = 6.9
Hz, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.95-7.86 (m, 2H), 7.80 (d, J =
6.9 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 7.7 Hz, 2H),
7.28-7.12 (m, 2H), 4.85 (br. s., 1H), 4.17 (br. s., 2H), 1.15 (br.
s., 6H) 139 ##STR00495## 2,7-dimethyl-N-[4-(4- oxo-3,4-
dihydrophthalazin-1- yl)phenyl]imidazo[1,2-
a]pyridine-3-carboxamide 410.2 E: 1.09 F: 1.43 140 ##STR00496##
2-ethyl-N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)
phenyl]imidazo[1,2-a] pyrimdine-3- carboxamide 411.2 E: 1.15 F:
1.46 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.83 (s, 1H), 10.33 (s,
1H), 9.25 (dd, J = 6.9, 1.9 Hz, 1H), 8.67 (dd, J = 4.1, 1.9 Hz,
1H), 8.38-8.33 (m, 1H), 7.97-7.87 (m, 4H), 7.79-7.75 (m, 1H), 7.62
(d, J = 8.5 Hz, 2H), 7.22 (dd, J = 6.7, 4.3 Hz, 1H), 3.11 (q, J =
7.5 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H) 141 ##STR00497##
6-methoxy-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]pyrazolo[1,5- a]pyridine-3-carboxamide 412.1 E: 1.41 F:
1.41 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.81 (s, 1H), 10.11 (s,
1H), 8.74 (s, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.35 (dd, J = 7.7, 1.4
Hz, 1H), 8.18 (d, J = 9.6 Hz, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.91
(ddd, J = 9.6, 7.6, 1.5 Hz, 2H), 7.81-7.76 (m, 1H), 7.58 (d, J =
8.5 Hz, 2H), 7.36 (dd, J = 9.6, 2.2 Hz, 1H), 3.88 (s, 3H) 142
##STR00498## 1-[2-(dimethylamino) ethyl]-N-[4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1H-indazole- 3-carboxamide 453.2 E:
1.37 F: 1.41 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.84 (s, 1H),
10.42 (s, 1H), 9.44 (br. s., 1H), 8.36 (d, J = 7.4 Hz, 1H), 8.29
(d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.5 Hz, 2H), 7.96-7.89 (m, 3H),
7.77 (d, J = 8.0 Hz, 1H), 7.67-7.55 (m, 3H), 7.41 (t, J = 7.6 Hz,
1H), 4.96 (br. s., 2H), 3.77 (br. s., 2H), 3.02- 2.85 (m, 6H) 143
##STR00499## 2-(oxetan-3-ylmethyl)-N- [4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-2H-indazole- 3-carboxamide 452.2 E:
1.14 F: 1.14 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.87 (s, 1H),
11.37 (s, 1H), 8.39-8.35 (m, 1H), 8.31 (d, J = 8.5 Hz, 1H), 8.06
(d, J = 8.8 Hz, 1H), 8.02-7.89 (m, 5H), 7.74 (d, J = 7.7 Hz, 1H),
7.70 (d, J = 8.5 Hz, 3H), 5.23-5.15 (m, 2H), 4.97- 4.88 (m, 2H),
4.70 (dd, J = 11.3, 5.0 Hz, 1H), 3.73 (br. s., 2H), 3.68-3.58 (m,
1H) 144 ##STR00500## 1-(oxetan-3-ylmethyl)-N- (4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl)-1H-indazole- 3-carboxamide 452.1 E:
1.15 F: 1.14 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s, 1H),
10.40 (s, 1H), 8.35 (d, J = 7.7 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H),
8.15-8.05 (m, J = 8.3 Hz, 2H), 7.97-7.88 (m, 3H), 7.78 (d, J = 8.0
Hz, 1H), 7.64-7.58 (m, J = 8.5 Hz, 2H), 7.53 (t, J = 7.7 Hz, 1H),
7.35 (t, J = 7.4 Hz, 1H), 4.89 (d, J = 7.2 Hz, 2H), 4.78-4.67 (m,
2H), 4.55 (t, J = 6.1 Hz, 2H), 3.68- 3.56 (m, 1H) 145 ##STR00501##
1-[(3-methyloxetan-3- yl)methyl]-N-[4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]-1H-indazole- 3-carboxamide
466.2 E: 1.63 F: 1.62 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.82
(s, 1H), 10.36 (s, 1H), 8.35 (d, J = 7.4 Hz, 1H), 8.26 (d, J = 8.3
Hz, 1H), 8.13-8.02 (m, J = 8.0 Hz, 2H), 8.00-7.85 (m, 3H), 7.77 (d,
J = 7.7 Hz, 1H), 7.63-7.58 (m, J = 8.0 Hz, 2H), 7.53 (t, J = 7.6
Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 4.80 (br. s., 4H), 4.33 (d, J =
5.8 Hz, 2H), 1.20 (s, 3H) 146 ##STR00502## N-[4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1-(oxolan-3-
ylmethyl)-1H-indazole-3- carboxamide 466.2 E: 1.63 F: 1.64 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s, 1H), 10.46 (s, 1H), 8.35
(d, J = 7.4 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.13-8.04 (m, J =
7.7 Hz, 2H), 7.96-7.87 (m, 3H), 7.78 (d, J = 7.7 Hz, 1H), 7.67-7.57
(m, J = 8.0 Hz, 2H), 7.53 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.3 Hz,
1H), 4.57 (d, J = 7.4 Hz, 2H), 3.86 (d, J = 7.2 Hz, 1H), 3.74-3.64
(m, 2H), 3.59 (br. s., 1H), 3.05-2.94 (m, 1H), 1.95 (dd, J = 11.8,
7.2 Hz, 1H), 1.72 (dd, J = 12.2, 6.5 Hz, 1H) 147 ##STR00503##
1-[3-(benzyloxy)-2- hydroxypropyl]-N-[4-(4- oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1H-indazole- 3-carboxamide 546.2 E:
1.95 F: 1.95 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s, 1H),
10.48 (s, 1H), 8.39-8.33 (m, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.10-
8.05 (m, 2H), 7.98-7.87 (m, 2H), 7.83-7.74 (m, 2H), 7.62-7.58 (m,
2H), 7.48 (ddd, J = 8.3, 7.1, 0.8 Hz, 1H), 7.39-7.35 (m, 4H),
7.35-7.32 (m, 1H), 7.32-7.27 (m, 1H), 5.24 (d, J = 5.5 Hz, 1H),
4.71-4.61 (m, 1H), 4.59- 4.51 (m, 3H), 4.31-4.21 (m, 1H), 3.51 (d,
J = 5.5 Hz, 2H) 148 ##STR00504## N-[4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1-(oxolan-2-
ylmethyl)-1H-indazole-3- carboxamide 466.3 E: 1.84 F: 1.83 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s, 1H), 10.49 (s, 1H),
8.37-8.34 (m, 1H), 8.25 (d, J = 8.3 Hz, 1H), 8.12- 8.07 (m, 2H),
7.97-7.88 (m, 2H), 7.84 (d, J = 8.5 Hz, 1H), 7.80-7.76 (m, 1H),
7.63-7.57 (m, 2H), 7.50 (ddd, J = 8.4, 7.0, 1.1 Hz, 1H), 7.33 (td,
J = 7.5, 0.7 Hz, 1H), 4.62 (d, J = 5.8 Hz, 2H), 4.40 (t, J = 6.3
Hz, 1H), 3.81-3.72 (m, 1H), 3.62 (dt, J = 8.2, 6.8 Hz, 1H),
2.12-1.92 (m, 1H), 1.88-1.79 (m, 2H), 1.78-1.68 (m, 1H) 149
##STR00505## 1-(2,3-dihydroxypropyl)- N-[4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1H-indazole- 3-carboxamide 456.2 E:
1.40 F: 1.38 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s, 1H),
10.49 (s, 1H), 8.38-8.33 (m, 1H), 8.25 (d, J = 8.3 Hz, 1H), 8.12-
8.09 (m, 1H), 8.09-8.07 (m, 1H), 7.97-7.89 (m, 2H), 7.82-7.76 (m,
2H), 7.62-7.58 (m, 2H), 7.49 (ddd, J = 8.4, 7.0, 1.1 Hz, 1H),
7.35-7.30 (m, 1H), 5.04 (d, J = 5.2 Hz, 1H), 4.86 (t, J = 5.6 Hz,
1H), 4.66 (dd, J = 14.2, 3.7 Hz, 1H), 4.48 (dd, J = 14.2, 8.1 Hz,
1H), 4.13-4.03 (m, 1H), 3.53-3.40 (m, 2H) 150 ##STR00506##
1-(oxan-4-ylmethyl)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-indazole- 3-carboxamide 480.0 E: 1.80 F: 1.79 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s, 1H), 10.47 (s, 1H), 8.35
(dd, J = 7.6, 1.2 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H), 8.15-8.05 (m,
J = 8.5 Hz, 2H), 7.94-7.84 (m, 3H), 7.82- 7.74 (m, 1H), 7.63-7.56
(m, J = 8.5 Hz, 2H), 7.55-7.47 (m, 1H), 7.34 (t, J = 7.4 Hz, 1H),
4.48 (d, J = 7.2 Hz, 2H), 3.88-3.76 (m, 2H), 3.29-3.18 (m, 2H),
2.37-2.21 (m, 1H), 1.50-1.26 (m, 4H) 151 ##STR00507##
1-(2-methoxyethyl)-N-[4- (4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-indazole- 3-carboxamide 440.2 E: 1.73 F: 1.73 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s, 1H), 10.49 (s, 1H), 8.35
(dd, J = 7.8, 1.2 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H), 8.13-8.06 (m,
2H), 7.95-7.88 (m, 2H), 7.84 (d, J = 8.5 Hz, 1H), 7.78 (dd, J =
7.8, 1.0 Hz, 1H), 7.64-7.58 (m, 2H), 7.50 (ddd, J = 8.4, 7.2, 1.0
Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 4.75 (t, J = 5.4 Hz, 2H), 3.88
(t, J = 5.2 Hz, 2H), 3.23 (s, 3H) 152 ##STR00508##
1-(oxetan-2-ylmethyl)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-indazole- 3-carboxamide 452.2 E: 1.61 F: 1.61 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s, 1H), 10.50 (s, 1H), 8.35
(dd, J = 7.6, 1.2 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H), 8.14-8.05 (m,
J = 8.5 Hz, 2H), 7.97-7.88 (m, 3H), 7.80- 7.74 (m, 1H), 7.64-7.57
(m, J = 8.5 Hz, 2H), 7.50 (dd, J = 8.5, 1.1 Hz, 1H), 7.34 (t, J =
7.4 Hz, 1H), 5.33-5.15 (m, 1H), 4.90 (dd, J = 14.9, 6.3 Hz, 1H),
4.80 (dd, J = 14.9, 3.9 Hz, 1H), 4.48 (ddd, J = 8.4, 7.0, 5.8 Hz,
1H), 4.30 (dt, J = 9.0, 5.9 Hz, 1H), 2.78-2.72 (m, 1H), 2.60-2.54
(m, 1H) 153 ##STR00509## 1-(2-hydroxypropyl-N- [4-(4-oxo-3,4-
dihydrophthalazin-1- yl)pheyl]-1H-indazole- 3-carboxamide 440.2 E:
1.55 F: 1.55 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.85 (s, 1H),
10.51 (s, 1H), 8.35 (dd, J = 7.8, 1.2 Hz, 1H), 8.24 (d, J = 8.3 Hz,
1H), 8.12-8.06 (m, J = 8.5 Hz, 2H), 7.97-7.87 (m, 2H), 7.83 (d, J =
8.5 Hz, 1H), 7.79-7.75 (m, 1H), 7.62-7.57 (m, J = 8.5 Hz, 2H),
7.53-7.46 (m, 1H), 7.32 (t, J = 7.4 Hz, 1H), 5.02 (d, J = 5.0 Hz,
1H), 4.47 (d, J = 6.1 Hz, 2H), 4.32-4.19 (m, 1H), 1.16 (d, J = 6.3
Hz, 3H) 154 ##STR00510## 1-[2-(2-methoxyethoxy)
ethyl]-N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-indazole- 3-carboxamide 484.3 E: 1.66 F: 1.66 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) d 12.85 (s, 1H), 10.54 (s, 1H), 8.35
(dd, J = 7.8, 1.2 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H), 8.14-8.06 (m,
J = 8.5 Hz, 2H), 8.00-7.89 (m, 2H), 7.86 (d, J = 8.5 Hz, 1H),
7.83-7.75 (m, 1H), 7.65-7.58 (m, J = 8.5 Hz, 2H), 7.51 (t, J = 7.7
Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H), 4.75 (t, J = 5.4 Hz, 2H), 3.96
(t, J = 5.4 Hz, 2H), 3.51 (dd, J = 5.6, 3.7 Hz, 2H), 3.13 (s, 3H)
155 ##STR00511## 1-(2-hydroxyethyl)-N-[4- (4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1H-indazole- 3-carboxamide 426.2 E:
1.43 F: 1.42 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.85 (s, 1H),
10.53 (s, 1H), 8.35 (dd, J = 7.7, 1.4 Hz, 1H), 8.25 (d, J = 8.3 Hz,
1H), 8.13-8.07 (m, J = 8.5 Hz, 2H), 7.97-7.88 (m, 2H), 7.82 (d, J =
8.5 Hz, 1H), 7.80-7.76 (m, 1H), 7.62-7.58 (m, J = 8.5 Hz, 2H),
7.52-7.47 (m, 1H), 7.33 (t, J = 7.4 Hz, 1H), 4.98 (t, J = 5.5 Hz,
1H), 4.62 (t, J = 5.4 Hz, 2H), 3.94 (q, J = 5.5 Hz, 2H) 156
##STR00512## 1-[2-(oxan-4-yl)ethyl]-N- [4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1H-indazole- 3-carboxamide 494.3 E:
1.96 F: 1.92 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.85 (s, 1H),
10.50 (s, 1H), 8.38-8.33 (m, 1H), 8.26 (d, J = 8.3 Hz, 1H), 8.12-
8.07 (m, J = 8.5 Hz, 2H), 7.97-7.89 (m, 2H), 7.85 (d, J = 8.5 Hz,
1H), 7.78 (d, J = 7.4 Hz, 1H), 7.63-7.57 (m, J = 8.5 Hz, 2H), 7.52
(t, J = 7.7 Hz, 1H), 7.34
(t, J = 7.6 Hz, 1H), 4.62 (t, J = 7.4 Hz, 2H), 3.83 (dd, J = 11.3,
3.0 Hz, 2H), 3.25 (t, J = 11.0 Hz, 2H), 1.96-1.87 (m, 2H), 1.67 (d,
J = 12.9 Hz, 2H), 1.53 (ddt, J = 14.4, 7.2, 3.8 Hz, 1H), 1.26 (qd,
J = 12.2, 4.5 Hz, 2H) 157 ##STR00513## 1-[2-(benzyloxy)ethyl]-N-
[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1H-indazole-
3-carboxamide 516.3 E: 2.08 F: 2.11 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.85 (s, 1H), 10.53 (s, 1H), 8.37-8.33 (m, 1H),
8.26 (d, J = 8.0 Hz, 1H), 8.12- 8.07 (m, J = 8.5 Hz, 2H), 7.96-7.84
(m, 3H), 7.78 (d, J = 7.7 Hz, 1H), 7.64-7.58 (m, J = 8.5 Hz, 2H),
7.50 (t, J = 7.7 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.27-7.19 (m,
3H), 7.15-7.10 (m, 2H), 4.81 (t, J = 5.1 Hz, 2H), 4.47 (s, 2H),
3.97 (t, J = 5.2 Hz, 2H) 158 ##STR00514## 6-fluoro-1-(2-hydroxy-2-
methylpropyl)-N-[4-(4- oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-indazole- 3-carboxamide 472.2 E: 1.65 F: 1.66 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) d 12.85 (s, 1H), 10.49 (s, 1H), 8.35
(dd, J = 7.7, 1.4 Hz, 1H), 8.23 (dd, J = 8.8, 5.5 Hz, 1H),
8.09-8.05 (m, J = 8.8 Hz, 2H), 7.97-7.89 (m, 2H), 7.80-7.76 (m,
1H), 7.73 (dd, J = 9.9, 1.9 Hz, 1H), 7.63- 7.58 (m, J = 8.8 Hz,
2H), 7.21 (td, J = 9.1, 1.9 Hz, 1H), 4.45 (s, 2H), 1.19 (s, 6H) 159
##STR00515## 6-fluoro-1-(oxetan-3- ylmethyl)-N-[4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]-1H-indazole- 3-carboxamide
470.3 E: 1.74 F: 1.71 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.85
(s, 1H), 10.48 (s, 1H), 8.41-8.31 (m, 1H), 8.24 (dd, J = 8.9, 5.4
Hz, 1H), 8.15-8.01 (m, J = 8.5 Hz, 2H), 8.01-7.85 (m, 3H), 7.77 (d,
J = 7.7 Hz, 1H), 7.66-7.52 (m, J = 8.5 Hz, 2H), 7.24 (td, J = 9.1,
1.9 Hz, 1H), 4.85 (d, J = 7.4 Hz, 2H), 4.69 (dd, J = 7.7, 6.3 Hz,
2H), 4.54 (t, J = 6.2 Hz, 2H), 3.71-3.54 (m, 1H) 160 ##STR00516##
N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-(pyridin-2-
ylmethyl)-1H-indazole-3- carboxamide 473.3 A: 10.97 B: 10.36
.sup.1H NMR (400 MHz, DMSO-d.sub.6) d 12.82 (s, 1H), 10.59 (s, 1H),
8.62-8.49 (m, 1H), 8.42-8.23 (m, 2H), 8.14-8.04 (m, 2H), 7.94-7.88
(m, 2H), 7.84-7.73 (m, 3H), 7.61- 7.56 (m, 2H), 7.50 (ddd, J = 8.4,
7.0, 1.1 Hz, 1H), 7.38- 7.31 (m, 2H), 7.16 (d, J = 7.9 Hz, 1H),
5.97 (s, 2H) 161 ##STR00517## N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1-(pyridin-3- ylmethyl)-1H-indazole-3- carboxamide 473.3
A: 8.60 B: 9.15 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s,
1H), 10.57 (s, 1H), 8.77 (d, J = 4.1 Hz, 1H), 8.62 (br. s., 1H),
8.42-8.33 (m, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.8 Hz,
2H), 7.98-7.89 (m, 3H), 7.89-7.83 (m, 1H), 7.82-7.74 (m, 1H), 7.60
(d, J = 8.5 Hz, 2H), 7.56-7.49 (m, 2H), 7.37 (t, J = 7.6 Hz, 1H),
5.94 (s, 2H) 162 ##STR00518## 1-[3-(benzyloxy)propyl]-
N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1H-indazole-
3-carboxamide 530.3 E: 2.15 F: 2.14 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.84 (s, 1H), 10.52 (s, 1H), 8.35 (d, J = 7.7 Hz,
1H), 8.26 (d, J = 8.3 Hz, 1H), 8.12- 8.07 (m, J = 8.3 Hz, 2H),
7.97-7.87 (m, 2H), 7.79 (t, J = 9.5 Hz, 2H), 7.62-7.56 (m, J = 8.5
Hz, 2H), 7.50 (t, J = 7.7 Hz, 1H), 7.37-7.27 (m, 6H), 4.67 (t, J =
6.9 Hz, 2H), 4.44 (s, 2H), 3.45 (t, J = 5.9 Hz, 2H), 2.24 (t, J =
6.5 Hz, 2H) 163 ##STR00519## 1-(3-methoxypropyl)-N- [4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1H-indazole- 3-carboxamide 454.2 E:
1.78 F: 1.77 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.84 (s, 1H),
10.53 (s, 1H), 8.35 (d, J = 7.7 Hz, 1H), 8.26 (d, J = 8.3 Hz, 1H),
8.13- 8.06 (m, J = 8.5 Hz, 2H), 7.98-7.89 (m, 2H), 7.79 (t, J = 9.1
Hz, 2H), 7.64-7.57 (m, J = 8.3 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H),
7.34 (t, J = 7.4 Hz, 1H), 4.63 (t, J = 6.9 Hz, 2H), 3.32- 3.29 (m,
2H), 3.22 (s, 3H), 2.18 (t, J = 6.5 Hz, 2H) 164 ##STR00520##
1-(3-hydroxypropyl)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-indazole- 3-carboxamide 440.3 E: 1.48 F: 1.48 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) d 12.84 (s, 1H), 10.52 (s, 1H), 8.35
(d, J = 7.7 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H), 8.15- 8.08 (m, J =
8.3 Hz, 2H), 7.96-7.86 (m, 2H), 7.82 (d, J = 8.5 Hz, 1H), 7.78 (d,
J = 7.7 Hz, 1H), 7.62-7.57 (m, J = 8.3 Hz, 2H), 7.51 (t, J = 7.6
Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 4.70 (t, J = 5.0 Hz, 1H), 4.64
(t, J = 7.0 Hz, 2H), 3.45 (q, J = 5.8 Hz, 2H), 2.09 (t, J = 6.6 Hz,
2H) 165 ##STR00521## N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1-(pyridin-4- ylmethyl)-1H-indazole-3- carboxamide 473.3
E: 1.20 F: 1.58 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.85 (s,
1H), 10.65 (s, 1H), 8.65 (d, J = 5.2 Hz, 2H), 8.32 (d, J = 8.0 Hz,
1H), 8.35 (d, J = 7.4 Hz, 1H), 8.16-8.03 (m, J = 8.3 Hz, 2H), 7.98-
7.89 (m, 2H), 7.84 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H),
7.64-7.58 (m, J = 8.3 Hz, 2H), 7.54 (t, J = 7.7 Hz, 1H), 7.43-7.35
(m, 3H), 6.04 (s, 2H) 166 ##STR00522## N-[4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1H-pyrrolo [3,2-c]pyridine-3-
carboxamide 382.2 E: 0.96 F: 1.03 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 13.18 (br. s., 1H), 12.86 (s, 1H), 10.46 (s, 1H),
9.58 (br. s., 1H), 8.81 (s, 1H), 8.52 (d, J = 6.1 Hz, 1H), 8.35 (d,
J = 8.0 Hz, 1H), 8.05 (d, J = 6.3 Hz, 1H), 8.01-7.97 (m, J = 8.3
Hz, 2H), 7.96-7.87 (m, 2H), 7.78 (d, J = 7.7 Hz, 1H), 7.66-7.60 (m,
J = 8.3 Hz, 2H), 6.57 (br. s., 1H) 167 ##STR00523##
5-fluoro-1-(2-hydroxy-2- methylpropyl)-N-[4-(4- oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1H-indazole- 3-carboxamide 472.2 E:
1.63 F: 1.64 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.85 (s, 1H),
10.49 (s, 1H), 8.35 (d, J = 7.7 Hz, 1H), 8.12-8.05 (m, J = 8.3 Hz,
2H), 7.99-7.90 (m, 3H), 7.86 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 7.7
Hz, 1H), 7.63-7.57 (m, J = 8.3 Hz, 2H), 7.41 (t, J = 9.1 Hz, 1H),
4.81 (s, 1H), 4.49 (s, 2H), 1.19 (s, 6H) 168 ##STR00524##
1-(oxan-2-ylmethyl)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-indazole- 3-carboxamide 480.2 E: 2.04 F: 2.04 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) d 12.85 (s, 1H), 10.53 (s, 1H), 8.35
(d, J = 7.4 Hz, 1H), 8.24 (d, J = 8.3 Hz, 1H), 8.14- 8.08 (m, J =
8.0 Hz, 2H), 7.97-7.87 (m, 2H), 7.87-7.73 (m, 2H), 7.66-7.57 (m, J
= 8.0 Hz, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H),
4.69-4.57 (m, 1H), 4.57- 4.47 (m, 1H), 3.98-3.84 (m, 2H), 3.79 (d,
J = 11.0 Hz, 1H), 3.29-3.18 (m, 1H), 1.88-1.76 (m, 1H), 1.65 (d, J
= 12.4 Hz, 1H), 1.50-1.29 (m, 4H) 169 ##STR00525## 1-(2-hydroxy-2-
methylpropyl)-N-[4-(4- oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-pyrrolo [2,3-b]pyridine-3- carboxamide 454.2 E: 1.41
F: 1.46 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.84 (s, 1H), 10.18
(s, 1H), 8.61 (s, 1H), 8.56 (d, J = 7.7 Hz, 1H), 8.38-8.32 (m, 2H),
8.02-7.95 (m, J = 8.0 Hz, 2H), 7.95-7.85 (m, 2H), 7.79 (d, J = 7.7
Hz, 1H), 7.63-7.55 (m, J = 8.0 Hz, 2H), 7.33-7.23 (m, 1H), 4.30 (s,
2H), 1.11 (s, 6H) 170 ##STR00526## N-[4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1-[3- ylmethyl]-1H-indazole-3-
carboxamide 466.3 E: 1.80 F: 1.80 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.82 (br. s., 1H), 10.46 (br. s., 1H), 8.35 (d, J
= 6.6 Hz, 1H), 8.26 (d, J = 7.4 Hz, 1H), 8.11-8.04 (m, J = 7.7 Hz,
2H), 7.98-7.86 (m, 3H), 7.78 (d, J = 7.2 Hz, 1H), 7.62-7.57 (m, J =
8.0 Hz, 2H), 7.53 (br. s., 1H), 7.35 (br. s., 1H), 4.57 (d, J = 6.3
Hz, 2H), 3.88-3.80 (m, 1H), 3.72-3.64 (m, 2H), 3.60-3.53 (m, 1H),
2.96 (br. s., 1H), 1.94 (br. s., 1H), 1.72 (br. s., 1H) 171
##STR00527## N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1-[oxolan-3- ylmethyl]-1H-indazole-3- carboxamide 466.3
E: 1.80 F: 1.80 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.82 (br.
s., 1H), 10.46 (br. s., 1H), 8.35 (d, J = 6.9 Hz, 1H), 8.26 (d, J =
7.7 Hz, 1H), 8.12-8.03 (m, J = 7.7 Hz, 2H), 7.98-7.84 (m, 3H), 7.78
(d, J = 6.9 Hz, 1H), 7.65-7.57 (m, J = 7.7 Hz, 2H), 7.56-7.46 (m,
1H), 7.39-7.27 (m, 1H), 4.57 (d, J = 6.6 Hz, 2H), 3.88-3.80 (m,
1H), 3.73-3.64 (m, 2H), 3.63- 3.54 (m, 1H), 2.96 (br. s., 1H), 1.94
(br. s., 1H), 1.72 (br. s., 1H) 172 ##STR00528## 6-(2-hydroxy-2-
methylpropoxy)-N-[4-(4- oxo-3,4- dihydrophthalazin-1-yl)
phenyl]pyrazolo[1,5-a] pyridine-3-carboxamide 470.1 E: 1.44 F: 1.44
.sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.84 (br. s., 1H), 10.12
(br. s., 1H), 8.74 (br. s., 1H), 8.55 (br. s., 1H), 8.35 (d, J =
7.2 Hz, 1H), 8.19 (d, J = 9.6 Hz, 1H), 7.99-7.86 (m, 4H), 7.78 (d,
J = 7.4 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 9.6 Hz,
1H), 4.74 (br. s., 1H), 4.12 (br. s., 1H), 3.83 (br. s., 2H), 3.16
(br. s., 2H), 1.23 (br. s., 6H) 173 ##STR00529##
5-fluoro-N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1-(oxolan-3- ylmethyl)-1H-indazole-3- carboxamide 484.2
E: 1.81 F: 1.81 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.82 (br.
s., 1H), 10.50 (br. s., 1H), 8.35 (br. s., 1H), 8.07 (d, J = 6.6
Hz, 2H), 8.03- 7.94 (m, 1H), 7.90 (br. s., 3H), 7.78 (br. s., 1H),
7.60 (d, J = 6.6 Hz, 2H), 7.53-7.39 (m, 1H), 4.58 (br. s., 2H),
3.85 (br. s., 1H), 3.69 (d, J = 8.0 Hz, 2H), 3.57 (br. s., 1H),
2.94 (br. s., 1H), 1.95 (br. s., 1H), 1.71 (br. s., 1H) 174
##STR00530## 6-fluoro-N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1-(oxolan-3- ylmethyl)-1H-indazole-3- carboxamide 484.3
E: 1.83 F: 1.83 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.82 (br.
s., 1H), 10.50 (br. s., 1H), 8.34 (br. s., 1H), 8.26 (br. s., 1H),
8.07 (d, J = 7.2 Hz, 2H), 7.91 (br. s., 2H), 7.83 (d, J = 9.9 Hz,
1H), 7.78 (br. s., 1H), 7.60 (d, J = 6.9 Hz, 2H), 7.24 (t, J = 8.5
Hz, 1H), 4.53 (br. s., 2H), 3.85 (br. s., 1H), 3.75-3.63 (m, 2H),
3.57 (br. s., 1H), 2.94 (br. s., 1H), 1.94 (br. s., 1H), 1.71 (br.
s., 1H) 175 ##STR00531## 6-(2-methoxyethoxy)-N- [4-(4-oxo-3,4-
dihydrophthalazin-1-yl) phenyl]pyrazolo[1,5-a]
pyridine-3-carboxamide 456.2 E: 1.45 F: 1.45 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.81 (br. s., 1H), 10.11 (br. s., 1H), 8.74 (br.
s., 1H), 8.57 (br. s., 1H), 8.35 (br. s., 1H), 8.18 (d, J = 9.4 Hz,
1H), 7.98-7.88 (m, 4H), 7.79 (br. s., 1H), 7.58 (d, J = 5.2 Hz,
2H), 7.37 (d, J = 9.6 Hz, 1H), 4.21 (br. s., 2H), 3.71 (br. s., 2H)
176 ##STR00532## N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)
phenyl]-6-[2-(pyrrolidin- 1-yl)ethoxy]pyrazolo[1,5-
a]pyridine-3-carboxamide 495.3 E: 1.05 F: 1.05 .sup.1H NMR (500
MHz, DMSO-d.sub.6) d 12.81 (s, 1H), 10.12 (s, 1H), 8.75 (s, 1H),
8.63 (s, 1H), 8.35 (dd, J = 7.6, 1.5 Hz, 1H), 8.21 (d, J = 9.6 Hz,
1H), 8.02-7.90 (m, 3H), 7.79- 7.74 (m, 1H), 7.59 (d, J = 8.5 Hz,
2H), 7.39 (dd, J = 9.6, 1.9 Hz, 1H), 4.28 (br. s., 2H), 2.89 (s,
4H), 1.82 (br. s., 4H) 177 ##STR00533## 6-[2-(dimethylamino)
ethoxy]-N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]pyrazolo[1,5- a]pyridine-3-carboxamide 469.2 E: 1.04 F:
1.05 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s, 1H), 10.14 (s,
1H), 8.78 (s, 1H), 8.70 (d, J = 1.7 Hz, 1H), 8.40-8.32 (m, 1H),
8.24 (d, J = 9.6 Hz, 1H), 8.00-7.87 (m, 4H), 7.77 (d, J = 7.7 Hz,
1H), 7.59 (d, J = 8.5 Hz, 2H), 7.41 (dd, J = 9.5, 2.1 Hz, 1H), 4.45
(t, J = 5.0 Hz, 2H), 3.57 (t, J = 4.7 Hz, 2H), 2.96-2.87 (m, 6H)
178 ##STR00534## 5-fluoro-1-(2- methylprop-1-en-1-yl)-N-
[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1H-indazole-
3-carboxamide 454.2 E: 1.71 F: 1.71 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.84 (s, 1H), 10.79 (s, 1H), 8.35 (dd, J = 7.8,
1.5 Hz, 1H), 7.97-7.85 (m, 5H), 7.79-7.74 (m, 1H), 7.63 (d, J = 8.5
Hz, 2H), 7.56 (dd, J = 9.5, 2.3 Hz, 1H), 7.33 (td, J = 9.3, 2.3 Hz,
1H), 7.29- 7.24 (m, 1H), 1.97-1.86 (m, 3H), 1.79 (d, J = 1.1 Hz,
3H) 179 ##STR00535## 6-fluoro-1-(2- methylprop-1-en-1-yl)-N-
[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1H-indazole-
3-carboxamide 454.2 E: 1.71 F: 1.71 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.84 (s, 1H), 10.92 (s, 1H), 8.39-8.31 (m, 1H),
7.96-7.88 (m, 5H), 7.79-7.72 (m, 1H), 7.66-7.59 (m, 2H), 7.54 (dd,
J = 10.2, 1.9 Hz, 1H), 7.27-7.23 (m, 1H), 7.21-7.15 (m, 1H), 1.92
(d, J = 1.4 Hz, 3H), 1.80 (d, J = 1.4 Hz, 3H) 180 ##STR00536##
6-fluoro-5-methoxy-N-[4- (4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1-benzofuran- 2-carboxamide 430.1 E: 1.61 F: 1.61
.sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.83 (s, 1H), 10.71 (s, 1H),
8.40-8.31 (m, 1H), 8.06-7.96 (m, J = 8.5 Hz, 2H), 7.95-7.87 (m,
2H), 7.79 (s, 1H), 7.77-7.70 (m, 2H), 7.63- 7.58 (m, J = 8.8 Hz,
2H), 7.56 (d, J = 8.8 Hz, 1H), 3.92 (s, 3H) 181 ##STR00537##
5-(2-hydroxy-2- methylpropoxy)-N-[4-(4- oxo-3,4-
dihydrophthalazin-1- yl)phenyl]pyrazolo[1,5-
a]pyridine-3-carboxamide 470.1 A: 6.62 B: 5.93 .sup.1H NMR (400
MHz, DMSO-d.sub.6) d 12.81 (s, 1H), 10.03 (s, 1H), 8.75 (s, 1H),
8.69 (d, J = 7.5 Hz, 1H), 8.38-8.30 (m, 1H), 8.02-7.86 (m, 4H),
7.81-7.75 (m, 1H), 7.65-7.53 (m, 3H), 6.82 (dd, J = 7.5, 2.6 Hz,
1H), 1.25 (s, 6H) 182 ##STR00538## 5-methoxy-N-[4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]pyrazolo[1,5-
a]pyridine-3-carboxamide 412.1 E: 1.30 F: 1.37 .sup.1H NMR (500
MHz, DMSO-d.sub.6) d 10.08 (s, 1H), 8.71 (s, 1H), 8.64 (d, J = 7.6
Hz, 1H), 8.33 (d, J = 7.3 Hz, 1H), 7.96- 7.86 (m, 4H), 7.76 (d, J =
7.9 Hz, 1H), 7.64-7.52 (m, 3H), 6.90-6.74 (m, 1H), 3.70-3.57 (m,
3H) 183 ##STR00539## N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)
phenyl]-5-[2-(pyrrolidin- 1-yl)ethoxy]pyrazolo[1,5-
a]pyridine-3-carboxamide 495.2 E: 1.08 F: 1.07 .sup.1H NMR (500
MHz, DMSO-d.sub.6) d 10.08 (br. s., 1H), 8.71 (br. s., 1H), 8.64
(d, J = 7.3 Hz, 1H), 8.33 (d, J = 6.7 Hz, 1H), 7.98-7.83 (m, 4H),
7.75 (d, J = 7.0 Hz, 1H), 7.63- 7.52 (m, 3H), 6.79 (d, J = 4.9 Hz,
1H), 4.20 (br. s., 2H), 3.65-3.42 (m, 4H), 2.87 (d, J = 4.6 Hz,
2H), 1.86 (br. s., 1H), 1.68 (br. s., 4H) 184 ##STR00540##
5-(2-methoxyethoxy)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]pyrazolo[1,5- a]pyridine-3-carboxamide 456.1 E: 1.37 F:
1.35 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s, 1H), 10.07 (s,
1H), 8.71 (s, 1H), 8.65 (d, J = 7.3 Hz, 1H), 8.33 (d, J = 7.3 Hz,
1H), 8.03-7.83 (m, 4H), 7.76 (d, J = 7.3 Hz, 1H), 7.63- 7.47 (m,
3H), 6.80 (d, J = 7.3 Hz, 1H), 4.22 (br. s., 2H), 3.72 (br. s.,
1H), 3.62 (br. s., 1H), 3.58 (d, J = 7.6 Hz, 3H) 185 ##STR00541##
5-(2-hydroxypropoxy)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)
phenyl]pyrazolo[1,5-a] pyridine-3-carboxamide 456.2 E: 1.26 F: 1.26
.sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.84 (s, 1H), 10.07 (s, 1H),
8.80-8.60 (m, 2H), 8.34 (d, J = 7.4 Hz, 1H), 7.97- 7.87 (m, 4H),
7.77 (d, J = 7.7 Hz, 1H), 7.67-7.52 (m, 3H), 6.86-6.75 (m, 1H),
4.11-3.91 (m, 2H), 3.67-3.41 (m, 1H), 1.39-1.14 (m, 3H) 186
##STR00542## 5-(2-hydroxyethoxy)-N- [4-(4-oxo-3,4-
dihydrophthalazin-1-yl) phenyl]pyrazolo[1,5-a]
pyridine-3-carboxamide 412.2 E: 1.15 F: 1.15 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.83 (s, 1H), 10.05 (s, 1H), 8.75 (s, 1H), 8.70
(d, J = 7.4 Hz, 1H), 8.35 (d, J = 7.4 Hz, 1H), 8.03-7.84 (m, 4H),
7.78 (d, J = 7.7 Hz, 1H), 7.64- 7.50 (m, 3H), 6.81 (dd, J = 7.4,
2.7 Hz, 1H), 4.14 (t, J = 4.7 Hz, 2H), 3.79 (d, J
= 4.4 Hz, 2H) 187 ##STR00543## 5-[2-(morpholin-4-
yl)ethoxy]-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]pyrazolo[1,5- a]pyridine-3-carboxamide 511.1 E: 1.30 F:
1.06 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 10.10 (s, 1H), 8.76 (s,
1H), 8.69 (d, J = 7.4 Hz, 1H), 8.35 (d, J = 7.4 Hz, 1H), 8.02- 7.87
(m, 4H), 7.78 (d, J = 7.7 Hz, 1H), 7.63 (br. s., 1H), 7.57 (d, J =
8.1 Hz, 2H), 6.81 (d, J = 5.0 Hz, 1H), 4.23 (t, J = 5.2 Hz, 2H),
2.82-2.73 (m, 2H) 188 ##STR00544## 6-[2-(morpholin-4-yl)
ethoxy]-N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)
phenyl]pyrazolo[1,5-a] pyridine-3-carboxamide 511.1 E: 1.34 F: 1.07
.sup.1H NMR (500 MHz, DMSO-d.sub.6) d 10.13 (br. s., 1H), 8.74 (br.
s., 1H), 8.58 (br. s., 1H), 8.35 (d, J = 7.7 Hz, 1H), 8.17 (d, J =
9.8 Hz, 1H), 7.99-7.87 (m, 4H), 7.78 (d, J = 7.7 Hz, 1H), 7.58 (d,
J = 7.7 Hz, 2H), 7.37 (d, J = 9.8 Hz, 1H), 4.19 (br. s., 2H), 3.59
(br. s., 4H), 2.73 (d, J = 5.0 Hz, 2H) 189 ##STR00545##
5-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-1-phenyl-1H- pyrazole-4-carboxamide 422.2 E: 1.51 F:
1.51 (500 MHz, DMSO-d.sub.6) .delta. ppm 12.84 (s, 1H), 10.10 (s,
1H), 8.51-8.26 (m, 2H), 8.01-7.87 (m, 4H), 7.76 (d, J = 7.7 Hz,
1H), 7.64-7.42 (m, 7H), 2.57 (s, 3H) 190 ##STR00546##
N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-phenyl-5-
(trifluoromethyl)-1H- pyrazole-4-carboxamide 476.3 E: 1.67 F: 1.67
(500 MHz, DMSO-d.sub.6) .delta. ppm 12.85 (s, 1H), 10.78 (s, 1H),
8.35 (br. s., 2H), 7.89 (d, J = 8.1 Hz, 4H), 7.75 (d, J = 7.1 Hz,
1H), 7.67-7.59 (m, 5H), 7.56 (br. s., 2H) 191 ##STR00547##
N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-phenyl-1H-
pyrazole-4-carboxamide 408.3 E: 1.48 F: 1.47 (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.85 (s, 1H), 10.23 (s, 1H), 9.14 (s,
1H), 8.55-8.17 (m, 2H), 7.92 (dd, J = 13.6, 8.2 Hz, 6H), 7.77 (d, J
= 7.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.56 (t, J = 7.9 Hz, 2H),
7.44-7.30 (m, 1H) 192 ##STR00548## 1-methyl-N-[4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]-5-phenyl-1H-
pyrazole-4-carboxamide 422.3 E: 1.38 F: 1.38 (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.81 (s, 1H), 9.97 (s, 1H), 8.33 (d, J =
7.1 Hz, 1H), 8.19 (s, 1H), 7.94 (s, 1H), 7.92- 7.84 (m, 2H), 7.79
(d, J = 8.4 Hz, 2H), 7.72 (d, J = 7.4 Hz, 1H), 7.56-7.43 (m, 6H),
3.71 (s, 3H) 193 ##STR00549## 3-(3-chloro-2- fluorophenyl)-N-[4-(4-
oxo-3,4- dihydrophthalazin-1-yl) phenyl]-4,5-dihydro-1,2-
oxazole-5-carboxamide 463.2 E: 1.69 F: 1.70 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.83 (s, 1H), 10.57 (s, 1H), 8.33 (d, J = 7.1 Hz,
1H), 7.93-7.80 (m, 4H), 7.80- 7.67 (m, 3H), 7.57 (d, J = 8.4 Hz,
2H), 7.34 (t, J = 7.9 Hz, 1H), 5.42-5.32 (m, 1H), 3.81 (d, J = 10.4
Hz, 2H), 3.39 (d, J = 5.7 Hz, 1H) 194 ##STR00550## 5-(2-hydroxy-3-
methoxypropoxy)-N-[4- (4-oxo-3,4- dihydrophthalazin-1-yl)
phenyl]pyrazolo[1,5-a] pyridine-3-carboxamide 486.1 A: 5.99 B: 5.45
.sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.81 (s, 1H), 10.04 (s, 1H),
8.75 (s, 1H), 8.69 (d, J = 7.4 Hz, 1H), 8.36-8.33 (m, 1H),
8.01-7.86 (m, 4H), 7.78 (dd, J = 7.7, 0.8 Hz, 1H), 7.63-7.56 (m,
3H), 6.81 (dd, J = 7.4, 2.8 Hz, 1H), 4.15- 4.09 (m, 1H), 4.05-3.99
(m, 2H), 3.48-3.41 (m, 2H), 3.35-3.30 (m, 3H) 195 ##STR00551##
1-(3-methylphenyl)-N-[4- (4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-imidazole- 4-carboxamide 422.1 A: 8.34 B: 7.46
.sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.81 (s, 1H), 10.20 (s, 1H),
8.45 (s, 1H), 8.48 (s, 1H), 8.35 (d, J = 7.2 Hz, 1H), 8.06 (d, J =
8.8 Hz, 2H), 7.96-7.87 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.66 (s,
1H), 7.61-7.54 (m, 3H), 7.44 (s, 1H), 7.26 (d, J = 7.7 Hz, 1H),
6.51 (s, 1H), 2.41 (s, 3H) 196 ##STR00552## N-[4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-3-phenyl-4,5-
dihydro-1,2-oxazole-5- carboxamide 411.2 E: 1.56 F: 1.58 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s, 1H), 10.50 (s, 1H),
8.36-8.25 (m, 1H), 7.96-7.82 (m, 4H), 7.77-7.66 (m, 3H), 7.55 (d, J
= 8.2 Hz, 2H), 7.52-7.41 (m, 3H), 5.32 (dd, J = 10.4, 7.9 Hz, 1H),
3.79-3.68 (m, 2H) 197 ##STR00553## 1-(2-methoxyphenyl)-N-
[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1H-pyrazole-
4-carboxamide 438.3 E: 1.51 F: 1.51 (500 MHz, DMSO-d.sub.6) .delta.
ppm 12.85 (s, 1H), 10.21 (s, 1H), 8.83 (s, 1H), 8.34 (d, J = 7.1
Hz, 1H), 8.29 (s, 1H), 7.97- 7.85 (m, 4H), 7.76 (d, J = 7.7 Hz,
1H), 7.67 (d, J = 7.1 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.47-7.39
(m, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 3.91
(s, 3H) 198 ##STR00554## 1-(3-chlorophenyl)-N-[4- (4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1H-pyrazole- 4-carboxamide 442.2 E:
1.75 F: 1.75 (500 MHz, DMSO-d.sub.6) .delta. ppm 12.85 (s, 1H),
10.24 (s, 1H), 9.20 (s, 1H), 8.39 (s, 1H), 8.34 (d, J = 7.4 Hz,
1H), 8.01 (br. s., 1H), 7.96-7.87 (m, 5H), 7.77 (d, J = 7.4 Hz,
1H), 7.63- 7.55 (m, 3H), 7.46 (d, J = 8.1 Hz, 1H) 199 ##STR00555##
5-chloro-N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1-phenyl-1H- pyrazole-4-carboxamide 442.2 E: 1.62 F:
1.62 (500 MHz, DMSO-d.sub.6) .delta. ppm 12.85 (s, 1H), 10.31 (s,
1H), 8.47 (s, 1H), 8.35 (d, J = 7.1 Hz, 1H), 7.98-7.84 (m, 4H),
7.76 (d, J = 7.4 Hz, 1H), 7.67-7.54 (m, 7H) 200 ##STR00556##
1-benzyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-1H-pyrazole- 4-carboxamide 422.2 E: 1.44 F: 1.44 (500
MHz, DMSO-d.sub.6) .delta. ppm 12.83 (s, 1H), 10.07 (s, 1H), 8.48
(s, 1H), 8.34 (d, J = 7.4 Hz, 1H), 8.10 (s, 1H), 7.97- 7.84 (m,
4H), 7.75 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.42-7.35
(m, 2H), 7.34-7.27 (m, 3H), 5.40 (s, 2H) 201 ##STR00557##
5-(adamantan-1-yl)-1- methyl-N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-pyrazole- 3-carboxamide 480.3 E: 2.20 F: 2.21 (500
MHz, DMSO-d.sub.6) .delta. ppm 12.83 (s, 1H), 10.16 (s, 1H), 8.34
(d, J = 7.7 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.94-7.85 (m, 2H),
7.75 (d, J = 7.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H), 6.56 (s, 1H),
4.08 (s, 3H), 2.06 (br. s., 3H), 2.00 (br. s., 6H), 1.84-1.65 (m,
6H) 202 ##STR00558## 1-(3-chloro-2- fluorophenyl)-5-methyl-
N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1H-pyrazole-
4-carboxamide 474.2 E: 1.72 F: 1.72 (500 MHz, DMSO-d.sub.6) .delta.
ppm 12.84 (s, 1H), 10.15 (s, 1H), 8.42 (s, 1H), 8.34 (d, J = 7.1
Hz, 1H), 7.98-7.87 (m, 4H), 7.84 (t, J = 7.1 Hz, 1H), 7.76 (d, J =
7.4 Hz, 1H), 7.64 (t, J = 6.9 Hz, 1H), 7.58 (d, J = 8.1 Hz, 2H),
7.46 (t, J = 7.9 Hz, 1H), 2.45 (s, 3H) 203 ##STR00559##
1-(3-methoxyphenyl)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-pyrazole- 4-carboxamide 438.2 E: 1.56 F: 1.64 (500
MHz, DMSO-d.sub.6) .delta. ppm 10.31 (s, 1H), 8.69 (d, J = 2.5 Hz,
1H), 8.39-8.32 (m, 1H), 7.98-7.88 (m, 5H), 7.83 (dd, J = 4.8, 3.4
Hz, 2H), 7.77 (d, J = 7.4 Hz, 1H), 7.66 (d, J = 1.7 Hz, 1H),
7.62-7.56 (m, 2H), 6.64-6.59 (m, 1H), 4.05 (s, 3H) 204 ##STR00560##
1-ethyl-N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-pyrazole- 4-carboxamide 360.2 E: 1.34 F: 1.36 (500
MHz, DMSO-d.sub.6) .delta. ppm 12.82 (s, 1H), 10.17 (s, 1H),
8.35-8.31 (m, 1H), 7.97 (d, J = 8.5 Hz, 2H), 7.94-7.86 (m, 3H),
7.74 (d, J = 7.0 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 6.80 (d, J =
2.4 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.3 Hz, 3H) 205
##STR00561## 1,5-dimethyl-N-[4-(4- oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-pyrazole- 3-carboxamide 360.2 E: 1.30 F: 1.32 (500
MHz, DMSO-d.sub.6) .delta. ppm 12.81 (s, 1H), 10.12 (s, 1H), 8.33
(d, J = 7.0 Hz, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.90 (quin, J = 6.9
Hz, 2H), 7.74 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H), 6.59
(s, 1H), 3.84 (s, 3H), 2.31 (s, 3H) 206 ##STR00562##
5-tert-butyl-1-methyl-N- [4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-pyrazole- 3-carboxamide 402.2 E: 1.68 F: 1.72 (500
MHz, DMSO-d.sub.6) .delta. ppm 12.82 (s, 1H), 10.12 (s, 1H), 8.33
(d, J = 7.0 Hz, 1H), 7.99-7.85 (m, 4H), 7.74 (d, J = 7.3 Hz, 1H),
7.54 (d, J = 8.5 Hz, 2H), 6.59 (s, 1H), 4.03 (s, 3H), 1.36 (s, 9H)
207 ##STR00563## 1-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-5-phenyl-1H- pyrazole-3-carboxamide 422.2 E: 1.70 F:
1.75 (500 MHz, DMSO-d.sub.6) .delta. ppm 12.83 (s, 1H), 10.31 (s,
1H), 8.34 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.94-7.85
(m, 2H), 7.75 (d, J = 7.6 Hz, 1H), 7.64-7.58 (m, 2H), 7.58- 7.51
(m, 4H), 7.52-7.44 (m, 1H), 6.95 (s, 1H), 3.97 (s, 3H) 208
##STR00564## 1-benzyl-5-methyl-N-[4- (4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1H-pyrazole- 3-carboxamide 436.2 E:
1.73 F: 1.76 (500 MHz, DMSO-d.sub.6) .delta. ppm 12.82 (s, 1H),
10.18 (s, 1H), 8.36-8.31 (m, 1H), 7.97 (d, J = 8.5 Hz, 2H),
7.94-7.85 (m, 2H), 7.74 (d, J = 7.3 Hz, 1H), 7.54 (d, J = 8.5 Hz,
2H), 7.40-7.33 (m, 2H), 7.32-7.25 (m, 1H), 7.17 (d, J = 7.3 Hz,
2H), 6.67 (s, 1H), 5.44 (s, 2H), 2.25 (s, 3H) 209 ##STR00565##
1-(3-methylphenyl)-2- oxo-N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]pyrrolidine-3- carboxamide 439.2 E: 1.63 F: 1.66 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s, 1H), 10.52 (s, 1H),
8.47-8.30 (m, 1H), 7.94-7.86 (m, 2H), 7.83-7.78 (m, J = 8.2 Hz,
2H), 7.72 (d, J = 7.3 Hz, 1H), 7.59-7.52 (m, J = 8.5 Hz, 2H),
7.49-7.43 (m, 2H), 7.27 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 7.3 Hz,
1H), 3.95-3.86 (m, 2H), 3.80 (t, J = 8.7 Hz, 1H), 2.48-2.35 (m,
2H), 2.31 (s, 3H) 210 ##STR00566## 1-(4-methylphenyl)-5-
oxo-N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]pyrrolidine-3-
carboxamide 439.2 E: 1.49 F: 1.50 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.81 (s, 1H), 10.44 (s, 1H), 8.43-8.25 (m, 1H),
7.95-7.84 (m, 2H), 7.80-7.74 (m, J = 8.2 Hz, 2H), 7.70 (d, J = 7.0
Hz, 1H), 7.53 (t, J = 8.4 Hz, 4H), 7.24-7.15 (m, J = 8.2 Hz, 2H),
4.09 (t, J = 9.3 Hz, 1H), 3.98 (dd, J = 9.8, 6.1 Hz, 1H), 2.89-2.68
(m, 3H), 2.27 (s, 3H) 211 ##STR00567## 1-(3-chloro-2-
fluorophenyl)-5-oxo-N- [4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]pyrrolidine-3- carboxamide 477.2 E: 1.48 F: 1.49 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s, 1H), 10.44 (s, 1H),
8.40-8.26 (m, 1H), 7.94-7.86 (m, 2H), 7.78 (d, J = 8.5 Hz, 2H),
7.70 (d, J = 7.3 Hz, 1H), 7.59-7.51 (m, 3H), 7.46 (t, J = 6.9 Hz,
1H), 7.28 (t, J = 8.4 Hz, 2H), 4.12- 4.03 (m, 1H), 4.00-3.91 (m,
1H), 2.85-2.63 (m, 3H) 212 ##STR00568## 1-methyl-N-[4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]-1H-pyrazole- 4-carboxamide
346.2 E: 1.09 F: 1.10 (500 MHz, DMSO-d.sub.6) .delta. ppm 12.82 (s,
1H), 10.06 (s, 1H), 8.35-8.32 (m, 1H), 8.31 (s, 1H), 8.04 (s, 1H),
7.93-7.83 (m, 4H), 7.74 (d, J = 7.3 Hz, 1H), 7.55 (d, J = 8.5 Hz,
2H), 3.89 (s, 3H) 213 ##STR00569## 5-methyl-N-[4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]-1-phenyl-1H-
pyrazole-3-carboxamide 422.2 E: 1.73 F: 1.77 (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.83 (s, 1H), 10.24 (s, 1H), 8.35-8.29
(m, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.94-7.83 (m, 2H), 7.74 (d, J =
7.3 Hz, 1H), 7.65-7.61 (m, 2H), 7.60- 7.54 (m, 4H), 7.53-7.48 (m,
1H), 6.82 (s, 1H), 2.35 (s, 3H) 214 ##STR00570## 5-methyl-1-(2-
methylphenyl)-N-[4-(4- oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-pyrazole- 4-carboxamide 436.2 E: 1.64 F: 1.67 (500
MHz, DMSO-d.sub.6) .delta. ppm 12.83 (s, 1H), 10.09 (s, 1H),
8.38-8.31 (m, 2H), 7.98-7.84 (m, 4H), 7.75 (d, J = 7.6 Hz, 1H),
7.56 (d, J = 8.5 Hz, 2H), 7.49-7.42 (m, 2H), 7.39 (t, J = 6.9 Hz,
1H), 7.31 (d, J = 7.6 Hz, 1H), 3.61 (s, 3H), 2.31 (s, 3H) 215
##STR00571## 2-oxo-N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1- phenylpyrrolidine-3- carboxamide 425.1 E: 1.50 F:
1.52 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s, 1H), 10.53 (s,
1H), 8.35-8.30 (m, 1H), 7.94-7.86 (m, 2H), 7.81 (d, J = 8.5 Hz,
2H), 7.72 (d, J = 7.0 Hz, 1H), 7.69-7.62 (m, J = 7.9 Hz, 2H),
7.59-7.52 (m, J = 8.5 Hz, 2H), 7.40 (t, J = 7.9 Hz, 2H), 7.17 (t, J
= 7.3 Hz, 1H), 4.01-3.88 (m, 2H), 3.84-3.77 (m, 1H), 2.48-2.32 (m,
2H) 216 ##STR00572## 1-(2-methoxyphenyl)-2- oxo-N-[4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]pyrrolidine-3- carboxamide 455.1 E:
1.43 F: 1.45 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s, 1H),
10.48 (s, 1H), 8.45-8.25 (m, 1H), 7.93-7.86 (m, 2H), 7.81 (d, J =
8.5 Hz, 2H), 7.74-7.70 (m, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.36-7.29
(m, 1H), 7.22 (dd, J = 7.6, 1.2 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H),
6.98 (t, J = 7.6 Hz, 1H), 3.79 (s, 3H), 3.73-3.67 (m, 2H),
2.41-2.31 (m, 1H) 217 ##STR00573## 5-oxo-N-[4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1- phenylpyrrolidine-3- carboxamide
425 E: 1.93 F: 1.97 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s,
1H), 10.46 (s, 1H), 8.33 (d, J = 7.6 Hz, 1H), 7.93-7.86 (m, 2H),
7.78 (d, J = 7.9 Hz, 2H), 7.70 (d, J = 7.3 Hz, 1H), 7.68-7.62 (m, J
= 8.6 Hz, 2H), 7.57-7.51 (m, J = 8.2 Hz, 2H), 7.38 (t, J = 7.6 Hz,
2H), 7.15 (t, J = 7.3 Hz, 1H), 4.13 (t, J = 9.2 Hz, 1H), 4.01 (dd,
J = 9.8, 5.8 Hz, 1H), 2.95-2.82 (m, 2H), 2.82-2.75 (m, 1H) 218
##STR00574## 5-oxo-N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1-(propan-2- yl)pyrrolidine-3- carboxamide 391.1 E: 1.63
F: 1.66 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 10.35 (s, 1H), 8.41-
8.26 (m, 1H), 8.02-7.82 (m, 2H), 7.80-7.66 (m, 3H), 7.53 (d, J =
8.5 Hz, 2H), 4.14 (dt, J = 13.7, 6.8 Hz, 1H), 3.62 (s, 2H), 3.43
(dd, J = 9.8, 6.1 Hz, 1H), 3.32 (t, J = 7.2 Hz, 1H), 2.62-2.53 (m,
1H), 1.07 (d, J = 7.0 Hz, 3H), 1.08 (d, J = 7.0 Hz, 3H) 219
##STR00575## 3,5-dimethyl-N-[4-(4- oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1-phenyl-1H- pyrazole-4-carboxamide 436.3 E: 1.44 F:
1.53 (500 MHz, DMSO-d.sub.6) .delta. ppm 12.83 (s, 1H), 10.08 (s,
1H), 8.34 (d, J = 6.7 Hz, 1H), 7.96-7.89 (m, 2H), 7.89-7.83 (m,
2H), 7.87 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 7.1 Hz, 1H), 7.61-7.53
(m, 3H), 7.53-7.43 (m, 2H), 2.43 (s, 3H), 2.38 (s, 3H) 220
##STR00576## 1-(2-chlorophenyl)-N-[4- (4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1H-pyrazole- 4-carboxamide 442.1 E:
1.59 F: 1.61 (500 MHz, DMSO-d.sub.6) .delta. ppm 12.82 (s, 1H),
10.19 (s, 1H), 8.81 (s, 1H), 8.38-8.32 (m, 2H), 7.95-7.91 (m, 3H),
7.90- 7.87 (m, 1H), 7.80-7.73 (m, 2H), 7.71-7.67 (m, 1H), 7.60 (d,
J = 8.5 Hz, 2H), 7.58-7.54 (m, 2H) 221 ##STR00577##
N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-phenyl-5-
(propan-2-yl)-1H-1,2,3- triazole-4-carboxamide 451.3 E: 1.84 F:
1.84 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.85 (s,
1H), 10.76 (s, 1H), 8.35 (d, J = 7.4 Hz, 1H), 8.05 (d, J = 8.4 Hz,
2H), 7.98- 7.85 (m, 2H), 7.76 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 3.7
Hz, 3H), 7.59 (d, J = 8.1 Hz, 4H), 3.26-3.18 (m, 1H), 1.33 (d, J =
7.1 Hz, 6H) 222 ##STR00578## 1-(2-fluorophenyl)-5-
methyl-N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1H-1,2,3-
triazole-4-carboxamide 441.2 E: 1.66 F: 1.66 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.84 (s, 1H), 10.80 (s, 1H), 8.34 (d, J = 7.4 Hz,
1H), 8.11-8.02 (m, J = 8.4 Hz, 2H), 7.98-7.87 (m, 2H), 7.83-7.72
(m, 3H), 7.64 (t, J = 9.1 Hz, 1H), 7.60-7.56 (m, J = 8.4 Hz, 2H),
7.52 (t, J = 7.6 Hz, 1H), 3.46-3.34 (m, 1H) 223 ##STR00579##
5-[4-(2-hydroxypropan-2- yl)phenyl]-3-methyl-N- [4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1,2-oxazole-4- carboxamide 481.2 E:
1.47 F: 1.42 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 8.35 (d, J = 6.7
Hz, 1H), 7.91 (t, J = 5.7 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H),
7.81-7.72 (m, 3H), 7.61 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz,
3H), 2.39 (s, 3H), 1.43 (s, 6H) 224 ##STR00580##
5-[4-(hydroxymethyl) phenyl]-3-methyl-N-[4- (4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1,2-oxazole-4- carboxamide 453.2 E:
1.33 F: 1.36 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 10.76 (s, 1H),
8.40- 8.30 (m, 1H), 7.95-7.88 (m, 2H), 7.86-7.73 (m, 5H), 7.60 (d,
J = 8.5 Hz, 2H), 7.50 (d, J = 8.3 Hz, 2H), 5.33 (br. s., 1H), 4.56
(d, J = 4.4 Hz, 2H), 2.40 (s, 3H) 225 ##STR00581##
1-(3-chlorophenyl)-5- ethyl-N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-1,2,3- triazole-4-carboxamide 470.3 E: 1.61 F: 1.61
.sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s, 1H), 10.79 (s, 1H),
8.35 (d, J = 7.6 Hz, 1H), 8.11-8.04 (m, J = 8.2 Hz, 2H), 7.96-7.85
(m, 3H), 7.79-7.69 (m, 3H), 7.68-7.64 (m, 1H), 7.61-7.55 (m, J =
8.5 Hz, 2H), 3.03 (q, J = 7.3 Hz, 2H), 1.09 (t, J = 7.5 Hz, 3H) 226
##STR00582## N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1-phenyl-1H- pyrazole-3-carboxamide 408.1 E: 1.58 F:
1.67 (500 MHz, DMSO-d.sub.6) .delta. ppm 12.85 (s, 1H), 10.38 (s,
1H), 8.68 (d, J = 2.4 Hz, 1H), 8.35 (d, J = 7.7 Hz, 1H), 8.04 (dd,
J = 8.1, 4.4 Hz, 4H), 7.97-7.86 (m, 2H), 7.77 (d, J = 7.7 Hz, 1H),
7.64-7.52 (m, 4H), 7.42 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 2.4 Hz,
1H) 227 ##STR00583## 1-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-1H-pyrazole- 3-carboxamide 346.1 E: 1.07 F: 1.07 (500
MHz, DMSO-d.sub.6) .delta. ppm 12.83 (s, 1H), 10.27 (s, 1H), 8.34
(d, J = 7.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.96-7.83 (m, 3H),
7.75 (d, J = 7.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H), 6.80 (d, J =
2.0 Hz, 1H), 3.98 (s, 3H) 228 ##STR00584## 3-methyl-N-[4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]-1-phenyl-1H-
pyrazole-4-carboxamide 422.2 E: 1.66 F: 1.66 (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.84 (s, 1H), 10.09 (s, 1H), 9.11 (s,
1H), 8.34 (d, J = 8.4 Hz, 1H), 7.97-7.86 (m, 4H), 7.82 (d, J = 8.1
Hz, 2H), 7.76 (d, J = 7.7 Hz, 1H), 7.61-7.51 (m, 4H), 7.41-7.33 (m,
1H) 229 ##STR00585## 1-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-5-propyl-1H- pyrazole-3-carboxamide 388.1 E: 1.49 F:
1.49 (500 MHz, DMSO-d.sub.6) .delta. ppm 12.82 (s, 1H), 10.18 (s,
1H), 8.34 (d, J = 7.1 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.95-7.84
(m, 2H), 7.75 (d, J = 7.1 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 6.60
(s, 1H), 3.87 (s, 3H), 2.65 (t, J = 7.6 Hz, 2H), 1.65 (sxt, J = 7.4
Hz, 2H), 0.97 (t, J = 7.2 Hz, 3H) 230 ##STR00586## N-[4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-2-phenyl-1H-
imidazole-4-carboxamide 408.2 E: 1.23 F: 1.49 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.82 (s, 1H), 10.05 (s, 1H), 8.34 (d, J = 7.6 Hz,
1H), 8.14-8.06 (m, J = 7.6 Hz, 2H), 8.04-7.97 (m, 3H), 7.96-7.87
(m, 2H), 7.77 (d, J = 7.9 Hz, 1H), 7.61-7.54 (m, J = 8.2 Hz, 2H),
7.52 (t, J = 7.5 Hz, 2H), 7.44 (t, J = 7.3 Hz, 1H) 231 ##STR00587##
N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-phenyl-5-
propyl-1H-1,2,3-triazole- 4-carboxamide 451.1 E: 1.93 F: 1.95
.sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.83 (s, 1H), 10.73 (s, 1H),
8.35 (d, J = 7.0 Hz, 1H), 8.10-8.00 (m, J = 8.2 Hz, 2H), 7.96-7.86
(m, 2H), 7.76 (d, J = 7.9 Hz, 1H), 7.71- 7.65 (m, 3H), 7.64-7.61
(m, 2H), 7.60-7.54 (m, J = 8.5 Hz, 2H), 3.00 (t, J = 7.5 Hz, 2H),
1.54-1.42 (m, 2H), 0.76 (t, J = 7.3 Hz, 3H) 232 ##STR00588##
5-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1-[3-
(trifluoromethyl)phenyl]- 1H-1,2,3-triazole-4- carboxamide 491.1 E:
1.92 F: 1.91 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s, 1H),
10.79 (s, 1H), 8.39-8.33 (m, 1H), 8.14 (s, 1H), 8.10-8.02 (m, 4H),
7.96-7.87 (m, 3H), 7.80-7.73 (m, 1H), 7.59 (d, J = 8.5 Hz, 2H) 233
##STR00589## 1-ethyl-N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-imidazole- 5-carboxamide 360.2 E: 1.04 F: 1.18
.sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s, 1H), 10.27 (s, 1H),
8.34 (d, J = 7.3 Hz, 1H), 7.99-7.83 (m, 6H), 7.74 (d, J = 7.6 Hz,
1H), 7.57 (d, J = 8.2 Hz, 2H), 4.36 (q, J = 6.9 Hz, 2H), 1.34 (t, J
= 7.2 Hz, 3H) 234 ##STR00590## N-(1-tert-butyl-3-{[4-(4- oxo-3,4-
dihydrophthalazin-1- yl)phenyl]carbamoyl}-
1H-pyrazol-4-yl)pyridine- 4-carboxamide 508.2 E: 1.41 F: 1.71
1H-NMR: (500 MHz, DMSO-d.sub.6) .delta. ppm 12.87 (s, 1H), 10.59
(s, 1H), 10.28 (s, 1H), 8.81 (d, J = 5.4 Hz, 2H), 8.44 (s, 1H),
8.34 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.95-7.86 (m,
2H), 7.80 (d, J = 5.7 Hz, 2H), 7.74 (d, J = 7.7 Hz, 1H), 7.59 (d, J
= 8.4 Hz, 2H), 1.63 (s, 9H) 235 ##STR00591##
1-tert-butyl-5-methyl-N- [4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-pyrazole- 3-carboxamide 402.2 E: 1.67 F: 1.68 1H-NMR:
(500 MHz, DMSO-d.sub.6) .delta. ppm 12.84 (s, 1H), 9.86 (s, 1H),
7.98-7.85 (m, 4H), 7.75 (d, J = 7.7 Hz, 1H), 7.55 (d, J = 8.4 Hz,
2H), 6.61 (s, 1H), 2.47 (s, 3H), 1.63 (s, 9H) 236 ##STR00592##
N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-phenyl-1H-
pyrazole-5-carboxamide 408.2 E: 1.48 F: 1.44 1H-NMR: (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.85 (s, 1H), 10.81 (s, 1H), 8.40-8.25
(m, 1H), 7.94-7.85 (m, 2H), 7.83-7.76 (m, 3H), 7.70 (d, J = 8.4 Hz,
1H), 7.54 (d, J = 8.4 Hz, 2H), 7.50-7.36 (m, 5H), 7.07 (s, 1H) 237
##STR00593## N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-5-(pyridin-2- yl)-1H-1,2,4-triazole-3- carboxamide 410.2
E: 1.01 F: 1.11 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.86 (s,
1H), 8.78 (d, J = 4.0 Hz, 1H), 8.36 (d, J = 7.1 Hz, 1H), 8.24 (d, J
= 8.1 Hz, 1H), 8.12-8.03 (m, 3H), 7.97-7.88 (m, 2H), 7.78 (d, J =
7.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 3H) 238 ##STR00594##
2-(2,3-dichlorophenyl)-5- methyl-N-[4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-2H-1,2,3- triazole-4-carboxamide
491.2 E: 2.07 F: 1.97 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 10.72
(s, 1H), 8.34 (d, J = 7.1 Hz, 1H), 8.02-7.97 (m, J = 8.4 Hz, 2H),
7.95 (d, J = 8.4 Hz, 1H), 7.93-7.88 (m, 2H), 7.84 (d, J = 8.1 Hz,
1H), 7.74 (d, J = 7.1 Hz, 1H), 7.64 (t, J = 8.1 Hz, 1H), 7.60- 7.56
(m, J = 8.8 Hz, 2H), 3.89 (s, 1H), 2.64-2.57 (m, 3H) 239
##STR00595## 1-(2-cyano-5- methoxyphenyl)-N-[4-(4- oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1H-1,2,4- triazole-3-carboxamide
464.2 E: 1.38 F: 1.30 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 9.39
(s, 1H), 8.34 (d, J = 7.1 Hz, 1H), 8.03 (d, J = 8.4 Hz, 2H), 8.06
(d, J = 8.8 Hz, 1H), 7.97-7.88 (m, 2H), 7.75 (d, J = 7.4 Hz, 1H),
7.64- 7.55 (m, 3H), 7.33 (dd, J = 8.8, 2.4 Hz, 1H), 3.95 (s, 3H)
240 ##STR00596## N-[4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1-(pyridin-2- yl)-1H-1,2,4-triazole-3- carboxamide 410.3
E: 1.08 F: 1.10 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.85 (s,
1H), 8.76 (d, J = 4.4 Hz, 1H), 8.35 (d, J = 7.1 Hz, 1H), 8.23 (d, J
= 7.7 Hz, 1H), 8.05 (d, J = 8.8 Hz, 3H), 7.97-7.87 (m, 2H), 7.77
(d, J = 7.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 3H), 3.90 (s, 1H) 241
##STR00597## 4-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-2-(1,2,3,4- tetrahydroquinolin-1-yl)- 1,3-thiazole-5-
carboxamide 494.1 E: 1.85 F: 2.00 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.80 (br. s., 1H), 9.89 (br. s., 1H), 8.38-8.30
(m, 1H), 7.95-7.88 (m, 3H), 7.84- 7.79 (m, J = 8.5 Hz, 2H),
7.76-7.71 (m, 1H), 7.60-7.51 (m, J = 8.5 Hz, 2H), 7.30-7.20 (m,
2H), 7.13-7.06 (m, 1H), 3.98-3.88 (m, 2H), 2.79 (t, J = 6.3 Hz,
2H), 2.54 (s, 3H), 1.96 (quin, J = 6.2 Hz, 2H) 242 ##STR00598##
2-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-1H-imidazole- 4-carboxamide 346.2 E: 1.07 F: 0.92
.sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.80 (s, 1H), 10.00 (br. s.,
1H), 8.34 (d, J = 7.6 Hz, 1H), 8.03-7.97 (m, J = 8.2 Hz, 2H),
7.94-7.86 (m, 2H), 7.78-7.73 (m, 2H), 7.58- 7.49 (m, J = 8.2 Hz,
2H), 2.38 (s, 3H) 243 ##STR00599## 4-methyl-N-[4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]-2- (phenylamino)-1,3-
thiazole-5-carboxamide 454.2 E: 1.85 F: 2.00 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 9.93 (s, 1H), 8.34 (d, J = 7.9 Hz, 1H), 7.99-7.88
(m, 3H), 7.82 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 7.9 Hz, 1H),
7.64-7.60 (m, J = 8.2 Hz, 2H), 7.58-7.53 (m, J = 8.2 Hz, 2H), 7.35
(t, J = 7.6 Hz, 2H), 7.25 (br. s., 2H), 7.15 (br. s., 2H), 7.05
(br. s., 2H), 2.06 (s, 3H)
Example 244:
3-(Dimethylamino)-N-[4-(1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl]benzamid-
e, TFA
##STR00600##
##STR00601##
[1088] Intermediate 66 (15 mg, 0.043 mmol),
3-(dimethylamino)benzoic acid (14 mg, 0.086 mmol), and HATU (24 mg,
0.064 mmol) were dissolved in DMF (1 mL). DIEA (0.037 mL, 0.21
mmol) was added, then the mixture was stirred at rt for 24 h. The
mixture was concentrated, then was purified by prep HPLC to afford
Example 244 (9 mg, 41% yield). MS(ESI) m/z: 384.1 (M+H).sup.+;
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.43 (d, J=5.8 Hz,
1H), 10.24 (s, 1H), 8.30 (dd, J=8.0, 0.8 Hz, 1H), 7.97-7.86 (m,
2H), 7.77-7.68 (m, 1H), 7.60-7.52 (m, 2H), 7.49-7.39 (m, 2H),
7.36-7.31 (m, 1H), 7.29-7.20 (m, 2H), 7.09 (d, J=5.8 Hz, 1H),
6.99-6.91 (m, 1H), 2.98 (s, 6H); HPLC RT=5.63 min (Method A), 5.22
min (Method B).
Example 245:
4-(Dimethylamino)-N-(4-(1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl)benzamid-
e, formate salt
##STR00602##
[1090] According to the procedure for the preparation of Example
244, coupling of Intermediate 66 (15 mg, 0.043 mmol) and
4-(dimethylamino)benzoic acid (14.15 mg, 0.086 mmol) afforded
Example 245 (2.1 mg, 11% yield). MS(ESI) m/z: 384.2 (M+H).sup.+;
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.42 (d, J=4.4 Hz,
1H), 9.98 (s, 1H), 8.30 (d, J=8.0 Hz, 1H), 7.89 (d, J=8.5 Hz, 4H),
7.71 (t, J=7.6 Hz, 1H), 7.59-7.49 (m, 2H), 7.38 (d, J=7.7 Hz, 2H),
7.08 (d, J=5.0 Hz, 1H), 6.78 (d, J=8.0 Hz, 2H), 3.01 (s, 6H); HPLC
RT=1.51 min (Method E), 1.71 min (Method F).
Example 246:
N-(4-(1-Oxo-1,2-dihydroisoquinolin-4-yl)phenyl)-4,5,6,7-tetrahydrobenzo[d-
]thiazole-2-carboxamide
##STR00603##
[1092] According to the procedure for the preparation of Example
244, coupling of Intermediate 66 (15 mg, 0.043 mmol) and
4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylic acid (12 mg, 0.064
mmol) afforded Example 246 (7.9 mg, 46% yield). MS(ESI) m/z: 402.1
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.51 (br.
s., 1H), 10.86 (br. s., 1H), 8.29 (d, J=7.2 Hz, 1H), 8.02-7.94 (m,
2H), 7.71 (br. s., 1H), 7.58-7.51 (m, 2H), 7.47-7.37 (m, J=7.7 Hz,
2H), 7.10 (br. s., 1H), 2.95-2.81 (m, 4H), 1.85 (br. s., 4H); HPLC
RT=2.02 min (Method E), 2.02 min (Method F).
Example 247:
N-(4-(1-Oxo-1,2-dihydroisoquinolin-4-yl)phenyl)benzo[c]isoxazole-3-carbox-
amide
##STR00604##
[1094] According to the procedure for the preparation of Example
244, coupling of Intermediate 66 (15 mg, 0.043 mmol) and
benzo[c]isoxazole-3-carboxylic acid (10.5 mg, 0.064 mmol) afforded
Example 247 (4 mg, 19% yield). MS(ESI) m/z: 382.0 (M+H).sup.+;
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.46 (br. s., 1H),
11.25 (br. s., 1H), 8.31 (d, J=8.0 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H),
8.00 (d, J=6.9 Hz, 2H), 7.83 (d, J=9.1 Hz, 1H), 7.72 (br. s., 1H),
7.56 (d, J=7.2 Hz, 3H), 7.47 (d, J=6.9 Hz, 2H), 7.39-7.31 (m, 1H),
7.13 (d, J=5.5 Hz, 1H); HPLC RT=8.83 min (Method A), 7.54 min
(Method B).
Example 248:
1-Methyl-N-(4-(1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl)-1H-indole-2-carb-
oxamide
##STR00605##
[1096] According to the procedure for the preparation of Example
244, coupling of Intermediate 66 (15 mg, 0.043 mmol) and
1-methyl-1H-indole-2-carboxylic acid (11.3 mg, 0.064 mmol) afforded
Example 248 (1.4 mg, 8% yield). MS(ESI) m/z: 394.2 (M+H).sup.+;
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.44 (br. s., 1H),
10.44 (br. s., 1H), 8.31 (d, J=7.7 Hz, 1H), 7.92-7.88 (m, J=7.7 Hz,
2H), 7.71 (br. s., 2H), 7.64-7.51 (m, 3H), 7.48-7.40 (m, J=7.7 Hz,
2H), 7.37-7.29 (m, 2H), 7.15 (t, J=7.0 Hz, 1H), 7.10 (br. s., 1H),
4.04 (br. s., 3H); HPLC RT=1.96 min (Method E), 1.94 min (Method
F).
Example 249:
N-(4-(1-Oxo-1,2-dihydroisoquinolin-4-yl)phenyl)-4-(piperidin-1-yl)benzami-
de
##STR00606##
[1098] According to the procedure for the preparation of Example
244, coupling of Intermediate 66 (15 mg, 0.043 mmol) and
4-(piperidin-1-yl)benzoic acid (12 mg, 0.059 mmol) afforded Example
249 (4.8 mg, 26% yield). MS(ESI) m/z: 424.2 (M+H).sup.+; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 11.43 (br. s., 1H), 10.03 (br.
s., 1H), 8.30 (d, J=7.7 Hz, 1H), 7.93-7.85 (m, 4H), 7.75-7.67 (m,
1H), 7.58-7.49 (m, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.08 (s, 1H), 7.00
(d, J=8.3 Hz, 2H), 1.60 (br. s., 6H); HPLC RT=1.39 min (Method E),
1.97 min (Method F).
Example 250:
4-Morpholino-N-(4-(1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl)benzamide
##STR00607##
[1100] According to the procedure for the preparation of Example
244, coupling of Intermediate 66 (13 mg, 0.037 mmol) and
4-morpholinobenzoic acid (11.54 mg, 0.056 mmol) afforded Example
250 (3.7 mg, 22% yield). MS(ESI) m/z: 422.2 (M+H).sup.+; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 11.41 (br. s., 1H), 10.08 (br.
s., 1H), 8.30 (d, J=8.0 Hz, 1H), 8.02-7.86 (m, 4H), 7.71 (t, J=7.4
Hz, 1H), 7.60-7.52 (m, 2H), 7.39 (d, J=8.0 Hz, 2H), 7.11-7.02 (m,
3H), 3.76 (br. s., 4H), 3.27 (br. s., 4H); HPLC RT=1.51 min (Method
E), 1.51 min (Method F).
Example 251:
N-(4-(1-Oxo-1,2-dihydroisoquinolin-4-yl)phenyl)-4-(pyrrolidin-1-yl)benzam-
ide
##STR00608##
[1102] According to the procedure for the preparation of Example
244, coupling of Intermediate 66 (13 mg, 0.037 mmol) and
4-(pyrrolidin-1-yl)benzoic acid (10.65 mg, 0.056 mmol) afforded
Example 251 (0.4 mg, 3% yield). MS(ESI) m/z: 410.2 (M+H).sup.+;
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.95 (br. s., 1H), 8.30
(d, J=7.7 Hz, 1H), 7.89 (d, J=7.7 Hz, 4H), 7.76-7.67 (m, 1H),
7.59-7.51 (m, 2H), 7.37 (d, J=8.0 Hz, 2H), 7.08 (s, 1H), 6.61 (d,
J=8.3 Hz, 2H), 3.90 (s, 1H), 1.99 (br. s., 4H); HPLC RT=1.92 min
(Method E), 1.91 min (Method F).
Example 252:
4-(4-(2-(5-Methoxy-7-methylindolin-1-yl)-2-oxoethyl)phenyl)phthalazin-1(2-
H)-one
##STR00609##
[1104] Intermediate 1 (15 mg, 0.038 mmol),
5-methoxy-7-methylindoline (9.3 mg, 0.057 mmol), and HATU (21.8 mg,
0.057 mmol) were dissolved in DMF (1 mL). The this mixture was
added DIEA (0.017 mL, 0.095 mmol). The mixture was stirred at rt
overnight, then was concentrated. The residue was purified by prep
HPLC to afford Example 252 (11 mg, 65% yield). MS(ESI) m/z: 426.2
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.83 (s,
1H), 8.34 (d, J=6.9 Hz, 1H), 7.98-7.85 (m, 2H), 7.71 (d, J=6.6 Hz,
1H), 7.63-7.54 (m, J=7.4 Hz, 2H), 7.50-7.42 (m, J=7.4 Hz, 2H), 6.72
(br. s., 1H), 6.57 (br. s., 1H), 4.12 (t, J=7.0 Hz, 2H), 4.00 (br.
s., 2H), 3.71 (s, 3H), 2.97 (t, J=6.9 Hz, 2H), 2.13 (s, 3H); HPLC
RT=1.77 min (Method E), 1.76 min (Method F).
Example 253:
4-(4-(2-(7-Bromo-5-(trifluoromethoxy)indolin-1-yl)-2-oxoethyl)phenyl)phth-
alazin-1(2H)-one
##STR00610##
[1106] According to the procedure for the preparation of Example
252, coupling of Intermediate 1 (15 mg, 0.038 mmol) and
7-bromo-5-(trifluoromethoxy)indoline, HCl (18.2 mg, 0.057 mmol)
afforded Example 253 (11 mg, 54% yield). MS(ESI) m/z: 544.1
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.83 (s,
1H), 8.34 (d, J=6.9 Hz, 1H), 8.00-7.82 (m, 2H), 7.71 (d, J=6.9 Hz,
1H), 7.61-7.53 (m, 2H), 7.51-7.43 (m, 3H), 7.40 (br. s., 1H), 4.22
(t, J=7.3 Hz, 2H), 4.06 (s, 2H), 3.15 (t, J=7.2 Hz, 2H); HPLC
RT=2.08 min (Method E), 2.06 min (Method F).
Example 254:
4-(4-(2-(6-Ethoxyindolin-1-yl)-2-oxoethyl)phenyl)isoquinolin-1(2H)-one
##STR00611##
[1108] According to the procedure for the preparation of Example
252, coupling of Intermediate 67 (12 mg, 0.043 mmol) and
6-ethoxyindoline (0.430 mL, 0.086 mmol) afforded Example 254 (10.5
mg, 55% yield). MS(ESI) m/z: 425.2 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 11.44 (br. s., 1H), 8.30 (d, J=7.7 Hz,
1H), 7.75 (br. s., 1H), 7.73-7.66 (m, 1H), 7.54 (d, J=7.7 Hz, 2H),
7.40 (s, 4H), 7.13-7.05 (m, 2H), 6.55 (d, J=8.0 Hz, 1H), 4.23 (t,
J=7.8 Hz, 2H), 3.95 (q, J=6.6 Hz, 2H), 3.91 (br. s., 2H), 3.08 (t,
J=8.0 Hz, 2H), 1.29 (t, J=6.7 Hz, 3H); HPLC RT=1.95 min (Method E),
1.95 min (Method F).
Example 255:
4-(4-(2-(Isoindolin-2-yl)-2-oxoethyl)phenyl)-6,7-dimethoxyisoquinolin-1(2-
H)-one
##STR00612##
[1110] To Intermediate 68 (20 mg, 0.070 mmol), Intermediate 9 (25.6
mg, 0.070 mmol) and K.sub.3PO.sub.4 (37.4 mg, 0.176 mmol), were
added dioxane (3 mL) and water (0.333 mL). The mixture was degassed
(evacuated and flushed with Ar (5.times.)). Pd(PPh.sub.3).sub.4
(4.1 mg, 3.5 .mu.mol) was added, then the mixture was degassed
(2.times.). The reaction vial was sealed and heated in a microwave
reactor at 150.degree. C. for 25 min. The reaction mixture was
concentrated then was purified by prep HPLC to afford Example 255
(7.5 mg, 24% yield). MS(ESI) m/z: 441.2 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 11.30 (br. s., 1H), 7.68 (s, 1H),
7.50-7.33 (m, 6H), 7.31 (br. s., 2H), 6.98 (br. s., 2H), 4.96 (br.
s., 2H), 4.69 (br. s., 2H), 3.95-3.86 (m, 3H), 3.84 (br. s., 2H),
3.72 (s, 3H); HPLC RT=1.62 min (Method E), 1.62 min (Method F).
Example 256:
4-(2-Fluoro-4-(2-(isoindolin-2-yl)-2-oxoethyl)phenyl)isoquinolin-1(2H)-on-
e
##STR00613##
[1112] According to the procedure for the preparation of Example
255, coupling of Intermediate 5 (37 mg, 0.098 mmol) and
4-bromoisoquinolin-1(2H)-one (20 mg, 0.089 mmol) afforded Example
256 (6.6 mg, 18% yield). MS(ESI) m/z: 339.2 (M+H).sup.+; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 11.50 (br. s., 1H), 8.28 (d,
J=8.0 Hz, 1H), 7.69 (t, J=7.4 Hz, 1H), 7.53 (t, J=7.3 Hz, 1H), 7.37
(d, J=4.4 Hz, 3H), 7.34-7.20 (m, 5H), 7.16 (br. s., 1H), 4.98 (br.
s., 2H), 4.70 (br. s., 2H), 3.88 (br. s., 2H); HPLC RT=1.72 min
(Method E), 1.70 min (Method F).
Example 257:
N-(4-(6,7-Dimethoxy-1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl)-6-methoxyin-
doline-1-carboxamide
##STR00614##
[1114] According to the procedure for the preparation of Example
255, coupling of Intermediate 12 (33 mg, 0.084 mmol) and
Intermediate 68 (20 mg, 0.070 mmol) afforded Example 257 (8.9 mg,
27% yield). MS(ESI) m/z: 472.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.28 (br. s., 1H), 8.61 (br. s., 1H), 7.95
(br. s., 1H), 7.74-7.66 (m, 3H), 7.55 (br. s., 1H), 7.40 (d, J=8.0
Hz, 2H), 7.08 (d, J=7.7 Hz, 1H), 7.03-6.93 (m, 2H), 6.48 (d, J=8.0
Hz, 1H), 4.17 (t, J=8.1 Hz, 2H), 3.89 (s, 3H), 3.74 (s, 3H), 3.71
(s, 3H), 3.11 (t, J=8.3 Hz, 2H); HPLC RT=1.71 min (Method E), 1.70
min (Method F).
Example 258:
4-(4-(2-(6-Isopropoxyindolin-1-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one
##STR00615##
[1116] To a solution of Intermediate 1 (12 mg, 0.043 mmol),
Intermediate 69 (12.5 mg, 0.043 mmol), and HATU (24.4 mg, 0.064
mmol) in DMF (1 mL), was add DIEA (0.037 mL, 0.21 mmol). The
mixture was stirred rt for 16 h, then the mixture was purified via
prep HPLC to afford Example 258 (13 mg; 69% yield) as white solid.
MS(ESI) m/z: 440.1 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 12.86 (br. s., 1H), 8.40-8.32 (m, 1H), 7.90 (br. s., 2H),
7.74 (br. s., 2H), 7.60-7.53 (m, 2H), 7.48-7.42 (m, 2H), 7.10 (d,
J=7.2 Hz, 1H), 6.55 (d, J=7.7 Hz, 1H), 4.48 (d, J=5.2 Hz, 1H),
4.28-4.17 (m, 2H), 3.96 (br. s., 2H), 3.09 (br. s., 2H), 1.23 (br.
s., 6H); HPLC RT=1.93 min (Method E), 191 min (Method F).
Example 259:
4-(4-(2-(Indolin-1-yl)-2-oxoethyl)-2-methylphenyl)phthalazin-1(2H)-one
##STR00616##
[1118] According to the procedure for the preparation of Example
76, coupling of 4-chlorophthalazin-1(2H)-one (15 mg, 0.083 mmol)
and Intermediate 71 (34.5 mg, 0.091 mmol), afforded 1.8 mg (5.5%)
of Example 259. MS(ESI) m/z: 396.2 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 12.82 (br. s., 1H), 8.33 (d, J=3.3 Hz,
1H), 8.09 (d, J=8.0 Hz, 1H), 7.87 (d, J=3.3 Hz, 2H), 7.34-7.21 (m,
5H), 7.15 (br. s., 1H), 7.00 (br. s., 1H), 4.23 (t, J=7.8 Hz, 2H),
3.92 (br. s., 2H), 3.19 (br. s., 2H), 2.07 (br. s., 3H); HPLC
RT=1.96 min (Method E), 1.99 min (Method F).
Example 260:
4-(4-(2-(Isoindolin-2-yl)-2-oxoethyl)-2-methylphenyl)phthalazin-1(2H)-one
##STR00617##
[1120] According to the procedure for the preparation of Example
76, coupling of 4-chlorophthalazin-1(2H)-one (15 mg, 0.083 mmol)
and Intermediate 70 (34.5 mg, 0.091 mmol), afforded 10.4 mg (32%)
of Example 260. MS(ESI) m/z: 396.2 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 12.82 (s, 1H), 8.35-8.29 (m, 1H),
7.90-7.81 (m, 2H), 7.41-7.34 (m, 2H), 7.34-7.29 (m, 3H), 7.27 (s,
2H), 7.24-7.20 (m, 1H), 4.98 (s, 2H), 4.70 (s, 2H), 3.84 (s, 2H),
2.07 (s, 3H); HPLC RT=1.70 min (Method E), 1.73 min (Method F).
Example 261:
4-(2-Fluoro-4-(2-(indolin-1-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one
##STR00618##
[1122] According to the procedure for the preparation of Example
76, coupling of 4-chlorophthalazin-1(2H)-one (15 mg, 0.083 mmol)
and Intermediate 72 (34.8 mg, 0.091 mmol), afforded 10.6 mg (31%)
of Example 261. MS(ESI) m/z: 400.2 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 12.98 (br. s., 1H), 8.36-8.30 (m, 1H),
8.08 (d, J=8.3 Hz, 1H), 7.93-7.86 (m, 2H), 7.53 (t, J=7.7 Hz, 1H),
7.47-7.41 (m, 1H), 7.36 (d, J=11.0 Hz, 1H), 7.32 (d, J=7.7 Hz, 1H),
7.26 (d, J=7.2 Hz, 1H), 7.16 (t, J=7.7 Hz, 1H), 7.05-6.97 (m, 1H),
4.24 (t, J=8.5 Hz, 2H), 4.01 (s, 2H), 3.20 (t, J=8.4 Hz, 2H); HPLC
RT=1.81 min (Method E), 1.83 min (Method F).
Example 262:
4-{4-[2-(2,3-Dihydro-1H-isoindol-2-yl)-2-oxoethyl]phenyl}-6-methoxy-1,2-d-
ihydroisoquinolin-1-one
##STR00619##
[1124] According to the procedure for the preparation of Example
76, coupling of Intermediate 73 (25 mg, 0.098 mmol) and
Intermediate 9 (35.7 mg, 0.098 mmol), afforded 14.4 mg (35%) of
Example 262. MS(ESI) m/z: 411.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.30 (br. s., 1H), 8.22 (d, J=8.8 Hz, 1H),
7.41 (s, 4H), 7.38-7.34 (m, 2H), 7.32-7.28 (m, 2H), 7.14 (dd,
J=8.8, 2.5 Hz, 1H), 7.06 (s, 1H), 6.92 (d, J=2.5 Hz, 1H), 4.96 (s,
2H), 4.69 (s, 2H), 3.84 (s, 2H), 3.75 (s, 3H); HPLC RT=1.61 min
(Method E), 1.62 min (Method F).
Example 263:
4-(4-(2-(Isoindolin-2-yl)-2-oxoethyl)-2-methylphenyl)isoquinolin-1(2H)-on-
e
##STR00620##
[1126] According to the procedure for the preparation of Example
255, coupling of Intermediate 70 (32.8 mg, 0.087 mmol) and
4-bromoisoquinolin-1(2H)-one (15 mg, 0.067 mmol) afforded Example
263 (2.1 mg, 8% yield). MS(ESI) m/z: 395.3 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 11.40 (d, J=5.8 Hz, 1H), 8.27 (dd,
J=8.0, 1.1 Hz, 1H), 7.64 (ddd, J=8.3, 7.0, 1.5 Hz, 1H), 7.53-7.48
(m, 1H), 7.40-7.34 (m, 2H), 7.34-7.29 (m, 2H), 7.28 (s, 1H),
7.24-7.19 (m, 1H), 7.18-7.14 (m, 1H), 7.03-6.97 (m, 2H), 4.97 (s,
2H), 4.69 (s, 2H), 3.80 (s, 2H), 2.03 (s, 3H); HPLC RT=1.68 min
(Method E), 1.67 min (Method F).
Example 264:
4-(4-(2-(Indolin-1-yl)-2-oxoethyl)-2-methylphenyl)isoquinolin-1(2H)-one
##STR00621##
[1128] According to the procedure for the preparation of Example
255, coupling of Intermediate 71 (32.8 mg, 0.087 mmol) and
4-bromoisoquinolin-1(2H)-one (15 mg, 0.067 mmol) afforded Example
264 (1.7 mg, 6% yield). MS(ESI) m/z: 395.3 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 11.41 (d, J=4.4 Hz, 1H), 8.28 (dd,
J=8.0, 1.1 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.64 (td, J=7.6, 1.5
Hz, 1H), 7.54-7.47 (m, 1H), 7.28 (s, 1H), 7.25 (d, J=7.4 Hz, 1H),
7.23-7.20 (m, 1H), 7.19-7.16 (m, 1H), 7.16-7.13 (m, 1H), 7.01 (d,
J=7.4 Hz, 3H), 4.23 (t, J=8.7 Hz, 2H), 3.88 (s, 2H), 3.18 (t, J=8.5
Hz, 2H), 2.04 (s, 3H); HPLC RT=1.81 min (Method E), 1.80 min
(Method F).
Example 265:
4-(4-(2-(6-(2-Hydroxy-2-methylpropoxy)indolin-1-yl)-2-oxoethyl)phenyl)pht-
halazin-1(2H)-one
##STR00622##
[1130] According to the procedure for the preparation of Example
258, coupling of Intermediate 1 (10 mg, 0.036 mmol), Intermediate
74 (11.5 mg, 0.036 mmol) afforded Example 265 (13.2 mg, 0.028 mmol,
78% yield). MS(ESI) m/z: 470.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.86 (s, 1H), 8.39-8.30 (m, 1H), 7.93-7.88
(m, 2H), 7.76 (d, J=2.5 Hz, 1H), 7.73-7.68 (m, 1H), 7.60-7.54 (m,
J=8.3 Hz, 2H), 7.50-7.43 (m, J=8.3 Hz, 2H), 7.11 (d, J=8.3 Hz, 1H),
6.57 (dd, J=8.3, 2.5 Hz, 1H), 4.61 (s, 1H), 4.24 (t, J=8.5 Hz, 2H),
3.96 (s, 2H), 3.63 (s, 2H), 3.10 (t, J=8.4 Hz, 2H), 1.18 (s, 6H);
HPLC RT=1.61 min (Method E), 1.61 min (Method F).
Example 266:
N-(4-(6-Methoxy-1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl)indoline-1-carbo-
xamide
##STR00623##
[1132] According to the procedure for the preparation of Example
76, coupling of Intermediate 73 (18 mg, 0.071 mmol) and
Intermediate 10 (28.4 mg, 0.078 mmol) afforded 5.3 mg (17%) of
Example 266. MS(ESI) m/z: 412.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.28 (d, J=6.1 Hz, 1H), 8.64 (s, 1H), 8.22
(d, J=8.8 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.70-7.65 (m, 2H),
7.41-7.35 (m, 2H), 7.21 (d, J=7.2 Hz, 1H), 7.17-7.11 (m, 2H), 7.05
(d, J=6.1 Hz, 1H), 6.94 (d, J=2.5 Hz, 1H), 6.93-6.88 (m, 1H), 4.16
(t, J=8.8 Hz, 2H), 3.77 (s, 3H), 3.19 (t, J=8.5 Hz, 2H); HPLC
RT=1.71 min (Method E), 1.71 min (Method F).
Example 267: 4-(6-Methoxy-1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl
5-methoxyisoindoline-2-carboxylate
##STR00624##
[1134] According to the procedure for the preparation of Example
76, coupling of Intermediate 73 (18 mg, 0.071 mmol) and Example 70B
(28 mg, 0.071 mmol) afforded 11.9 mg (36%) of Example 267. MS(ESI)
m/z: 443.2 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
11.33 (br. s., 1H), 8.23 (d, J=8.8 Hz, 1H), 7.54-7.44 (m, 2H),
7.35-7.26 (m, 3H), 7.15 (dd, J=8.8, 2.5 Hz, 1H), 7.14-7.08 (m, 1H),
6.98 (s, 1H), 6.94-6.86 (m, 2H), 4.89 (s, 1H), 4.85 (s, 1H), 4.71
(s, 1H), 4.66 (s, 1H), 3.77 (d, J=2.2 Hz, 6H); HPLC RT=1.86 min
(Method E), 1.86 min (Method F).
Example 268:
6-Methoxy-N-(4-(6-methoxy-1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl)indoli-
ne-1-carboxamide
##STR00625##
[1136] According to the procedure for the preparation of Example
76, coupling of Intermediate 73 (25 mg, 0.098 mmol) and
Intermediate 12 (42.7 mg, 0.108 mmol) afforded 3.9 mg (9%) of
Example 268. MS(ESI) m/z: 442.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.64 (s, 1H), 8.22 (d, J=8.8 Hz, 1H),
7.74-7.65 (m, J=8.8 Hz, 2H), 7.55 (d, J=2.5 Hz, 1H), 7.42-7.34 (m,
J=8.5 Hz, 2H), 7.14 (dd, J=8.8, 2.5 Hz, 1H), 7.09 (d, J=8.0 Hz,
1H), 7.04 (d, J=6.1 Hz, 1H), 6.94 (d, J=2.5 Hz, 1H), 6.48 (dd,
J=8.3, 2.5 Hz, 1H), 4.17 (t, J=8.5 Hz, 2H), 3.77 (s, 3H), 3.71 (s,
3H), 3.11 (t, J=8.5 Hz, 2H); HPLC RT=1.71 min (Method E), 1.71 min
(Method F).
Example 269: 4-(6-Methoxy-1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl
isoindoline-2-carboxylate
##STR00626##
[1138] According to the procedure for the preparation of Example
76, coupling of Intermediate 73 (18 mg, 0.071 mmol) and Example 68B
(25.9 mg, 0.071 mmol) afforded 7.1 mg (23%) of Example 269. MS(ESI)
m/z: 413.2 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
11.34 (d, J=5.5 Hz, 1H), 8.23 (d, J=9.1 Hz, 1H), 7.53-7.45 (m, 2H),
7.44-7.38 (m, 2H), 7.36-7.33 (m, 3H), 7.16 (dd, J=8.8, 2.5 Hz, 1H),
7.10 (d, J=5.8 Hz, 1H), 6.90 (d, J=2.5 Hz, 1H), 4.94 (s, 2H), 4.75
(s, 2H), 3.77 (s, 3H); HPLC RT=1.88 min (Method E), 1.88 min
(Method F).
[1139] The following Examples in Table 4 were made by using the
same procedure as shown in Example 3. Intermediate 1 was coupled
with the appropriate amine. Various coupling reagents could be used
other than the one described in Example 3 such as BOP, PyBop,
EDC/HOBt or HATU.
##STR00627##
TABLE-US-00005 TABLE 4 LC HPLC MS Method, Ex- (M + RT ample R IUPAC
name H).sup.+ (min.) .sup.1H NMR 270 ##STR00628## 4-(4-{2-oxo-2-[6-
(pyridin-3- ylmethoxy)-2,3- dihydro-1H-indol-1-
yl]ethyl}phenyl)-1,2- dihydrophthalazin-1- one 489.2 E: 1.33 F:
1.65 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.86 (s, 1H), 8.77 (s,
1H), 8.65 (d, J = 4.4 Hz, 1H), 8.38-8.31 (m, 1H), 8.11 (d, J = 8.0
Hz, 1H), 7.92-7.82 (m, 3H), 7.75-7.69 (m, 1H), 7.64 (dd, J = 7.7,
5.2 Hz, 1H), 7.59-7.54 (m, J = 8.3 Hz, 2H), 7.50-7.43 (m, J = 8.0
Hz, 2H), 7.15 (d, J = 8.0 Hz, 1H), 6.69 (dd, J = 8.3, 2.5 Hz, 1H),
5.17 (s, 2H), 4.25 (t, J = 8.4 Hz, 2H), 3.11 (t, J = 8.4 Hz, 2H)
271 ##STR00629## 4-(4-{2-oxo-2-[6- (pyridin-2- ylmethoxy)-2,3-
dihydro-1H-indol-1- yl]ethyl}phenyl)-1,2- dihydrophthalazin-1- one
489.2 E: 1.33 F: 1.70 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.86
(s, 1H), 8.57 (d, J = 4.7 Hz, 1H), 8.40-8.28 (m, 1H), 7.98-7.82 (m,
4H), 7.73 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.50-7.44
(m, 2H), 7.38-7.31 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.66 (dd, J =
8.1, 2.1 Hz, 1H), 5.13 (s, 2H), 4.24 (t, J = 8.4 Hz, 2H), 3.96 (s,
2H), 3.10 (t, J = 8.3 Hz, 2H) 272 ##STR00630## 4-(4-{2-oxo-2-[6-
(pyridin-2- ylmethoxy)-2,3- dihydro-1H-indol-1-
yl]ethyl}phenyl)-1,2- dihydrophthalazin-1- one 489.2 E: 1.30 F:
1.64 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.86 (s, 1H), 8.55 (d,
J = 5.8 Hz, 2H), 8.39-8.27 (m, 1H), 7.95-7.88 (m, 2H), 7.76-7.67
(m, 1H), 7.60-7.54 (m, J = 8.3 Hz, 2H), 7.51- 7.44 (m, J = 8.0 Hz,
2H), 7.41 (d, J = 5.5 Hz, 2H), 7.14 (d, J = 8.3 Hz, 1H), 6.66 (dd,
J = 8.3, 2.5 Hz, 1H), 5.14 (s, 2H), 4.25 (t, J = 8.5 Hz, 2H), 3.96
(s, 2H), 3.10 (t, J = 8.3 Hz, 2H) 273 ##STR00631##
4-(4-{2-oxo-2-[5- (propan-2-yloxy)-2,3- dihydro-1H-indol-1-
yl]ethyl}phenyl)-1,2- dihydrophthalazin-1- one 440.1 A: 9.77 B:
9.24 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.82 (s, 1H), 8.40-
8.31 (m, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.94-7.86 (m, 2H),
7.78-7.69 (m, 1H), 7.60-7.52 (m, J = 8.0 Hz, 2H), 7.51- 7.45 (m, J
= 8.3 Hz, 2H), 6.83 (s, 1H), 6.69 (dd, J = 8.8, 2.5 Hz, 1H),
4.56-4.45 (m, 1H), 4.20 (t, J = 8.4 Hz, 2H), 3.93 (s, 2H),
3.20-3.07 (m, 4H), 1.29-1.19 (m, 6H) 274 ##STR00632##
4-[4-(2-oxo-2-{6- [(3R)-oxolan-3- yloxy]-2,3-dihydro-
1H-indol-1-yl}ethyl) phenyl]-1,2- dihydrophthalazin-1- one 468.2 E:
1.64 F: 1.64 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.86 (s, 1H),
8.38- 8.30 (m, 1H), 7.93-7.85 (m, 2H), 7.79-7.69 (m, 2H), 7.63-
7.52 (m, J = 8.0 Hz, 2H), 7.52-7.42 (m, J = 8.0 Hz, 2H), 7.13 (d, J
= 8.0 Hz, 1H), 6.64-6.50 (m, 1H), 4.93 (br. s., 1H), 4.24 (t, J =
8.4 Hz, 2H), 3.96 (s, 2H), 3.86-3.78 (m, 2H), 3.78-3.70 (m, 2H),
3.10 (t, J = 8.3 Hz, 2H), 2.16 (dd, J = 13.8, 6.1 Hz, 1H),
2.02-1.83 (m, 1H) 275 ##STR00633## 4-[4-(2-oxo-2-{6-
[(3S)-oxolan-3-yloxy]- 2,3-dihydro-1H-indol- 1-yl}ethyl)phenyl]-
1,2-dihydrophthalazin- 1-one 468.2 E: 1.64 F: 1.61 .sup.1H NMR (500
MHz, DMSO-d.sub.6) d 12.86 (s, 1H), 8.38- 8.30 (m, 1H), 7.92-7.87
(m, 2H), 7.77-7.69 (m, 2H), 7.61- 7.52 (m, J = 8.0 Hz, 2H),
7.51-7.42 (m, J = 8.0 Hz, 2H), 7.13 (d, J = 8.3 Hz, 1H), 6.58-6.51
(m, 1H), 4.93 (br. s., 1H), 4.24 (t, J = 8.4 Hz, 2H), 3.96 (s, 2H),
3.88-3.79 (m, 2H), 3.78-3.70 (m, 2H), 3.10 (t, J = 8.4 Hz, 2H),
2.22-2.12 (m, 1H), 2.00-1.89 (m, 1H) 276 ##STR00634##
2-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-N-(4,5,6,7-
tetrahydro-1,2- benzoxazol-3- yl)acetamide 401.2 E: 1.44 F: 1.44
.sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.86 (s, 1H), 11.08 (br. s.,
1H), 8.34 (d, J = 7.2 Hz, 1H), 7.94-7.87 (m, 2H), 7.70 (d, J = 7.7
Hz, 1H), 7.59-7.54 (m, J = 7.7 Hz, 2H), 7.51- 7.44 (m, J = 7.7 Hz,
2H), 3.79 (s, 2H), 2.65-2.57 (m, 2H), 2.44-2.32 (m, 2H), 1.69 (d, J
= 5.8 Hz, 2H), 1.65-1.55 (m, 2H) 277 ##STR00635##
4-{4-[2-(6-{[(3R)-1- methylpyrrolidin-3- yl]oxy}-2,3-dihydro-
1H-indol-1-yl)-2- oxoethyl]phenyl}-1,2- dihydrophthalazin-1- one
481.2 E: 1.40 F: 1.40 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.86
(br. s., 1H), 8.34 (d, J = 6.9 Hz, 1H), 7.93-7.87 (m, 2H),
7.76-7.69 (m, 2H), 7.59-7.55 (m, J = 7.4 Hz, 2H), 7.49-7.41 (m, J =
7.4 Hz, 2H), 7.11 (d, J = 8.3 Hz, 1H), 6.51 (d, J = 8.0 Hz, 1H),
4.75 (br. s., 1H), 4.24 (t, J = 8.3 Hz, 2H), 3.96 (s, 2H), 3.09 (t,
J = 8.1 Hz, 2H), 2.76-2.70 (m, 1H), 2.62 (d, J = 7.4 Hz, 1H), 2.56
(d, J = 10.2 Hz, 1H), 2.40-2.29 (m, 1H), 2.27-2.16 (m, 4H), 1.90
(s, 1H), 1.79-1.69 (m, 1H) 278 ##STR00636## N-(5-tert-butyl-1,2-
oxazol-3-yl)-2-[4-(4- oxo-3,4- dihydrophthalazin-1-
yl)phenyl]acetamide 403.2 E: 1.70 F: 1.74 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.85 (s, 1H), 11.29 (br. s., 1H), 8.43-8.28 (m,
1H), 7.89 (dd, J = 4.8, 3.4 Hz, 2H), 7.69 (d, J = 7.4 Hz, 1H),
7.59-7.53 (m, J = 7.4 Hz, 2H), 7.53- 7.43 (m, J = 7.7 Hz, 2H), 6.60
(s, 1H), 3.90 (s, 1H), 3.78 (s, 2H), 1.28 (s, 9H) 279 ##STR00637##
4-[4-(2-{6-[2- (dimethylamino) ethoxy]-2,3-dihydro-
1H-indol-1-yl}-2- oxoethyl)phenyl]-1,2- dihydrophthalazin-1- one
469.1 E: 1.27 F: 1.27 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.86
(s, 1H), 8.34 (d, J = 6.9 Hz, 1H), 7.90 (d, J = 3.6 Hz, 2H),
7.81-7.69 (m, 2H), 7.61-7.51 (m, J = 7.4 Hz, 2H), 7.50-7.38 (m, J =
7.4 Hz, 2H), 7.12 (d, J = 8.3 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H),
4.24 (t, J = 8.3 Hz, 2H), 4.07-3.95 (m, 4H), 3.10 (t, J = 8.1 Hz,
2H), 2.62 (br. s., 2H), 2.22 (s, 6H) 280 ##STR00638##
N-(dimethyl-1,2- oxazol-3-yl)-2-[4-(4- oxo-3,4-
dihydrophthalazin-1- yl)phenyl]acetamide 375.2 E: 1.29 F: 1.30
.sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.86 (br. s., 1H), 10.51
(br. s., 1H), 8.34 (d, J = 7.2 Hz, 1H), 8.02-7.81 (m, 3H), 7.70 (d,
J = 6.9 Hz, 1H), 7.61-7.54 (m, J = 7.4 Hz, 2H), 7.53- 7.44 (m, J =
7.4 Hz, 2H), 3.80 (s, 2H), 2.30 (s, 3H), 1.78 (s, 3H) 281
##STR00639## 4-{4-[2-(6-{[(3S)-1- methylpyrrolidin-3-
yl]oxy}-2,3-dihydro- 1H-indol-1-yl)-2- oxoethyl]phenyl}-1,2-
dihydrophthalazin-1- one 481.2 E: 1.31 F: 1.34 .sup.1H NMR (500
MHz, DMSO-d.sub.6) d 12.86 (s, 1H), 8.34 (d, J = 6.9 Hz, 1H),
7.96-7.84 (m, 2H), 7.79-7.69 (m, 2H), 7.66-7.54 (m, J = 7.7 Hz,
2H), 7.51-7.42 (m, J = 7.7 Hz, 2H), 7.11 (d, J = 8.0 Hz, 1H), 6.52
(d, J = 8.0 Hz, 1H), 4.76 (br. s., 1H), 4.24 (t, J = 8.3 Hz, 2H),
3.96 (s, 2H), 3.09 (t, J = 8.3 Hz, 2H), 2.78-2.72 (m, 1H), 2.65 (d,
J = 6.9 Hz, 1H), 2.59 (d, J = 10.2 Hz, 1H), 2.39-2.34 (m, 1H),
2.30-2.20 (m, 4H), 1.79-1.69 (m, 1H) 282 ##STR00640##
4-[4-(2-{6-[(1- methylpiperidin-4- yl)oxy]-2,3-dihydro-
1H-indol-1-yl}-2- oxoethyl)phenyl]-1,2- dihydrophthalazin-1- one
495.1 E: 1.35 F: 1.35 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.87
(s, 1H), 9.46 (br. s., 1H), 8.35 (d, J = 6.3 Hz, 1H), 7.95 (s, 1H),
7.91 (d, J = 3.6 Hz, 2H), 7.83 (br. s., 1H), 7.72 (br. s., 1H),
7.63-7.53 (m, J = 7.7 Hz, 2H), 7.50-7.42 (m, J = 7.4 Hz, 2H),
7.19-7.09 (m, 1H), 6.72-6.61 (m, 1H), 4.25 (t, J = 8.0 Hz, 2H),
3.97 (br. s., 2H), 3.31 (d, J = 12.1 Hz, 2H), 3.20-3.04 (m, 4H),
2.89 (s, 2H), 2.82 (br. s., 2H), 2.77 (br. s., 1H), 2.73 (s, 2H),
2.55 (br. s., 1H), 2.20 (d, J = 13.2 Hz, 1H), 2.09-2.00 (m, 1H),
1.99-1.88 (m, 1H), 1.70 (q, J = 12.1 Hz, 1H) 283 ##STR00641##
methyl 2-[(1-{2-[4-(4- oxo-3,4- dihydrophthalazin-1-
yl)phenyl]acetyl}-2,3- dihydro-1H-indol-6- yl)oxy]acetate 470.1 A:
8.46 B: 8.47 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.83 (s, 1H),
8.39- 8.32 (m, 1H), 7.95-7.86 (m, 2H), 7.77-7.70 (m, 2H), 7.61-
7.53 (m, J = 8.3 Hz, 2H), 7.51-7.44 (m, J = 8.3 Hz, 2H), 7.13 (d, J
= 8.0 Hz, 1H), 6.57 (dd, J = 8.3, 2.5 Hz, 1H), 4.72 (s, 2H), 4.25
(t, J = 8.5 Hz, 2H), 3.96 (s, 2H), 3.76-3.59 (m, 3H), 3.10 (t, J =
8.3 Hz, 2H) 284 ##STR00642## 4-(4-{2-[6-(oxetan-3- ylmethoxy)-2,3-
dihydro-1H-indol-1- yl]-2-oxoethyl} phenyl)-1,2-
dihydrophthalazin-1- one 468.2 E: 1.61 F: 1.61 .sup.1H NMR (500
MHz, DMSO-d.sub.6) d 12.86 (br. s., 1H), 8.34 (d, J = 6.1 Hz, 1H),
7.90 (br. s., 2H), 7.78 (br. s., 1H), 7.72 (d, J = 6.6 Hz, 1H),
7.56 (d, J = 6.9 Hz, 2H), 7.46 (d, J = 7.2 Hz, 2H), 7.13 (d, J =
7.2 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 4.68 (br. s., 2H), 4.40 (br.
s., 2H), 4.25 (t, J = 7.6 Hz, 2H), 4.13 (d, J = 5.2 Hz, 2H), 3.97
(br. s., 2H), 3.10 (t, J = 7.3 Hz, 2H), 1.23 (br. s., 1H) 285
##STR00643## 4-{4-[2-(6-nitro-2,3- dihydro-1H-indol-1-
yl)-2-oxoethyl] phenyl}-1,2- dihydrophthalazin-1- one 427.1 E: 1.70
F: 1.65 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.86 (br. s., 1H),
8.84 (br. s., 1H), 8.39-8.30 (m, 1H), 8.02-7.87 (m, 3H), 7.73 (br.
s., 1H), 7.57 (d, J = 7.2 Hz, 2H), 7.54-7.45 (m, 3H), 4.36 (t, J =
8.0 Hz, 2H), 4.03 (br. s., 2H) 286 ##STR00644##
4-[4-(2-oxo-2-{6-[2- (pyrrolidin-1-yl) ethoxy]-2,3-dihydro-
1H-indol-1-yl}ethyl) phenyl]-1,2- dihydrophthalazin-1- one 495.2 E:
1.27 F: 1.31 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.83 (s, 1H),
8.41- 8.28 (m, 1H), 7.94-7.84 (m, 2H), 7.78-7.68 (m, 2H), 7.63-
7.51 (m, J = 8.3 Hz, 2H), 7.49-7.41 (m, J = 8.0 Hz, 2H), 7.11 (d, J
= 8.3 Hz, 1H), 6.58 (dd, J = 8.3, 2.5 Hz, 1H), 4.24 (t, J = 8.4 Hz,
2H), 4.07-3.92 (m, 4H), 3.10 (t, J = 8.4 Hz, 2H), 2.81-2.69 (m,
2H), 1.66 (dt, J = 6.7, 3.1 Hz, 4H) 291 ##STR00645##
N,N-dimethyl-1-{2-[4- (4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]acetyl}-2,3- dihydro-1H-indole-6- carboxamide 453.2 E:
1.53 F: 1.50 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.86 (br. s.,
1H), 8.34 (d, J = 6.3 Hz, 1H), 8.09 (br. s., 1H), 7.91-7.85 (m,
2H), 7.72 (d, J = 6.6 Hz, 1H), 7.62-7.53 (m, J = 7.2 Hz, 2H), 7.50-
7.41 (m, J = 7.2 Hz, 2H), 7.30 (d, J = 7.2 Hz, 1H), 7.03 (d, J =
7.4 Hz, 1H), 4.33-4.21 (m, 2H), 3.98 (br. s., 2H), 3.22 (t, J = 8.1
Hz, 2H), 2.96 (br. s., 3H), 2.89 (br. s., 3H) 292 ##STR00646##
4-(4-{2-[6-(4- methylpiperazine-1- carbonyl)-2,3-dihydro-
1H-indol-1-yl]-2- oxoethyl}phenyl)-1,2- dihydrophthalazin-1- one
508.3 E: 1.33 F: 1.44 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.86
(br. s., 1H), 8.34 (d, J = 6.3 Hz, 1H), 8.08 (br. s., 1H), 7.90
(br. s., 2H), 7.72 (d, J = 6.1 Hz, 1H), 7.60-7.53 (m, J = 7.4 Hz,
2H), 7.51- 7.45 (m, J = 7.4 Hz, 2H), 7.31 (d, J = 7.4 Hz, 1H), 7.01
(d, J = 7.2 Hz, 1H), 4.27 (t, J = 7.8 Hz, 2H), 4.04-3.94 (m, 2H),
3.58 (br. s., 2H), 3.22 (t, J = 7.8 Hz, 2H), 2.32 (br. s., 2H),
2.24 (br. s., 2H), 2.17 (br. s., 3H) 293 ##STR00647## 4-(4-{2-[6-
(morpholine-4- carbonyl)-2,3-dihydro- 1H-indol-1-yl]-2-
oxoethyl}phenyl)-1,2- dihydrophthalazin-1- one 495.2 E: 1.35 F:
1.35 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.83 (s, 1H), 8.37-
8.30 (m, 1H), 8.11 (s, 1H), 7.92-7.86 (m, 2H), 7.74-7.69 (m, 1H),
7.59-7.54 (m, J = 8.3 Hz, 2H), 7.51-7.44 (m, J = 8.0 Hz, 2H), 7.31
(d, J = 7.4 Hz, 1H), 7.04 (dd, J = 7.7, 1.4 Hz, 1H), 4.27 (t, J =
8.5 Hz, 2H), 4.04-3.93 (m, 2H), 3.57 (br. s., 6H), 3.22 (t, J = 8.4
Hz, 2H) 294 ##STR00648## 4-(4-{2-[5-(4- hydroxypiperidine-1-
carbonyl)-2,3-dihydro- 1H-indol-1-yl]-2- oxoethyl}phenyl)-1,2-
dihydrophthalazin-1- one 509.2 E: 1.21 F: 1.27 .sup.1H NMR (500
MHz, DMSO-d.sub.6) d 12.83 (s, 1H), 8.38- 8.31 (m, 1H), 8.09 (d, J
= 8.3 Hz, 1H), 7.94-7.86 (m, 2H), 7.76-7.69 (m, 1H), 7.60-7.54 (m,
J = 8.3 Hz, 2H), 7.50- 7.44 (m, J = 8.0 Hz, 2H), 7.27 (s, 1H), 7.19
(d, J = 8.3 Hz, 1H), 4.76 (d, J = 4.1 Hz, 1H), 4.26 (t, J = 8.5 Hz,
2H), 3.99 (s, 2H), 3.90 (s, 2H), 3.72 (ddt, J = 12.1, 8.1, 3.8 Hz,
1H, 3.25- 3.10 (m, 4H), 1.73 (br. s., 2H), 1.34 (br. s., 2H) 295
##STR00649## 4-(4-{2-[6-(4- hydroxypiperidine-1-
carbonyl)-2,3-dihydro- 1H-indol-1-yl]-2- oxoethyl}phenyl)-1,2-
dihydrophthalazin-1- one 509.2 E: 1.32 F: 1.32 .sup.1H NMR (500
MHz, DMSO-d.sub.6) d 12.83 (s, 1H), 8.40- 8.31 (m, 1H), 8.08 (s,
1H), 7.92-7.86 (m, 2H), 7.75-7.69 (m, 1H), 7.59-7.53 (m, J = 8.0
Hz, 2H), 7.53-7.45 (m, J = 8.0 Hz, 2H), 7.30 (d, J = 7.7 Hz, 1H),
7.00 (dd, J = 7.4, 1.1 Hz, 1H), 4.75 (d, J = 4.1 Hz, 1H), 4.27 (t,
J = 8.4 Hz, 2H), 4.05-3.91 (m, 3H), 3.71 (td, J = 8.0, 4.1 Hz, 1H),
3.51 (s, 1H), 3.22 (t, J = 8.5 Hz, 2H), 3.13 (br. s., 2H), 1.75
(br. s., 1H), 1.68 (br. s., 1H), 1.40 (br. s., 1H), 1.35-1.23 (m,
7H) 296 ##STR00650## 4-(4-{2-[5- (morpholine-4-
carbonyl)-2,3-dihydro- 1H-indol-1-yl]-2- oxoethyl}phenyl)-1,2-
dihydrophthalazin-1- one 495.2 E: 1.38 F: 1.38 .sup.1H NMR (500
MHz, DMSO-d.sub.6) d 12.83 (s, 1H), 8.37- 8.29 (m, 1H), 8.10 (d, J
= 8.0 Hz, 1H), 7.93-7.86 (m, 2H), 7.75-7.70 (m, 1H), 7.61-7.54 (m,
J = 8.0 Hz, 2H), 7.50- 7.45 (m, J = 8.0 Hz, 2H), 7.31 (s, 1H), 7.23
(d, J = 8.3 Hz, 1H), 4.27 (t, J = 8.4 Hz, 2H), 3.99 (s, 2H), 3.59
(br. s., 4H), 3.48 (br. s., 4H), 3.21 (t, J = 8.3 Hz, 2H)
Example 287:
4-(2-Fluoro-4-(2-(indolin-1-yl)-2-oxoethyl)phenyl)isoquinolin-1(2H)-one
##STR00651##
[1141] According to the procedure for the preparation of Example
76, coupling of Intermediate 6 (15 mg, 0.067 mmol) and Intermediate
72 (33.2 mg, 0.087 mmol), afforded 10.6 mg (31%) of Example 287.
MS(ESI) m/z: 399.2 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.55 (br. s., 1H), 8.28 (dd, J=8.1, 1.0 Hz, 1H), 8.08 (d,
J=8.0 Hz, 1H), 7.69 (ddd, J=8.3, 7.1, 1.4 Hz, 1H), 7.58-7.50 (m,
1H), 7.40 (t, J=7.8 Hz, 1H), 7.32-7.27 (m, 1H), 7.27-7.20 (m, 3H),
7.19-7.12 (m, 2H), 7.04-6.97 (m, 1H), 4.23 (t, J=8.5 Hz, 2H), 3.97
(s, 2H), 3.19 (t, J=8.5 Hz, 2H); HPLC RT=1.76 min (Method E), 1.76
min (Method F).
Example 288:
4-(4-(2-(6-(2-Hydroxy-2-methylpropoxy)indolin-1-yl)-2-oxoethyl)phenyl)iso-
quinolin-1(2H)-one
##STR00652##
[1143] According to the procedure for the preparation of Example
76, coupling of Intermediate 6 (20 mg, 0.089 mmol) and Intermediate
87 (40.3 mg, 0.089 mmol), afforded 11.9 mg (28%) of Example 287.
MS(ESI) m/z: 469.3 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.47 (d, J=5.5 Hz, 1H), 8.33-8.27 (m, 1H), 7.76 (d, J=1.9
Hz, 1H), 7.73-7.67 (m, 1H), 7.58-7.51 (m, 2H), 7.40 (s, 4H),
7.13-7.06 (m, 2H), 6.57 (dd, J=8.1, 2.3 Hz, 1H), 4.62 (s, 1H), 4.23
(t, J=8.5 Hz, 2H), 3.91 (d, J=7.2 Hz, 2H), 3.63 (s, 2H), 3.09 (t,
J=8.4 Hz, 2H), 1.18 (s, 6H); HPLC RT=1.70 min (Method E), 1.69 min
(Method F).
Example 289:
4-(4-(2-(6-(2-Hydroxy-2-methylpropoxy)indolin-1-yl)-2-oxoethyl)phenyl)-6--
methoxyisoquinolin-1 (2H)-one
##STR00653##
[1145] According to the procedure for the preparation of Example
76, coupling of Intermediate 73 (22 mg, 0.087 mmol) and
Intermediate 87 (39.1 mg, 0.087 mmol) afforded 12.4 mg (29%) of
Example 289. MS(ESI) m/z: 499.3 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.30 (d, J=5.8 Hz, 1H), 8.23 (d, J=9.1 Hz,
1H), 7.76 (d, J=1.9 Hz, 1H), 7.48-7.37 (m, 4H), 7.23-7.09 (m, 2H),
7.06 (d, J=5.5 Hz, 1H), 6.94 (d, J=2.2 Hz, 1H), 6.57 (dd, J=8.1,
2.3 Hz, 1H), 4.61 (s, 1H), 4.23 (t, J=8.4 Hz, 2H), 3.92 (s, 2H),
3.77 (s, 3H), 3.63 (s, 2H), 3.09 (t, J=8.4 Hz, 2H), 1.17 (s, 6H);
HPLC RT=1.70 min (Method E), 1.70 min (Method F).
Example 290:
2-((1-(2-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)acetyl)indolin-6-yl)-
oxy)acetic acid
##STR00654##
[1147] A mixture of Example 283 (32 mg, 0.068 mmol) and 1M lithium
hydroxide (0.2 mL, 0.200 mmol) in THF (2 mL) was stirred rt for 2
h. The mixture was concentrated, then was purified by prep HPLC to
afford Example 290 (28 mg, 90% yield). MS(ESI) m/z: 456.0
(M+H).sup.+; .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta.
8.50-8.44 (m, 1H), 7.96-7.84 (m, 4H), 7.63-7.58 (m, 2H), 7.57-7.52
(m, 2H), 7.11 (d, J=8.3 Hz, 1H), 6.64 (dd, J=8.3, 2.5 Hz, 1H), 4.62
(s, 2H), 4.27 (t, J=8.4 Hz, 2H), 4.00 (s, 2H), 3.16 (t, J=8.3 Hz,
2H); HPLC RT=7.44 min (Method A), 7.57 min (Method B).
Example 297:
4-(4-(2-(6-(2-Morpholino-2-oxoethoxy)indolin-1-yl)-2-oxoethyl)phenyl)phth-
alazin-1(2H)-one
##STR00655##
[1149] To a solution of Example 290 (8 mg, 0.018 mmol), morpholine
(3.06 mg, 0.035 mmol), and HATU (10.02 mg, 0.026 mmol) in DMF (1
mL), was add DIEA (0.015 mL, 0.088 mmol). The mixture was stirred
rt for 1 h, then was purified by prep HPLC to afford Example 297
(6.1 mg, 64% yield). MS(ESI) m/z: 525.3 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 12.86 (br. s., 1H), 8.34 (d, J=6.1
Hz, 1H), 7.90 (br. s., 2H), 7.73 (br. s., 2H), 7.56 (d, J=6.6 Hz,
2H), 7.46 (d, J=6.9 Hz, 2H), 7.12 (d, J=5.8 Hz, 1H), 6.57 (d, J=8.0
Hz, 1H), 4.75 (br. s., 2H), 4.24 (t, J=7.4 Hz, 2H), 3.96 (br. s.,
2H), 3.59 (br. s., 2H), 3.55 (br. s., 2H), 3.44 (d, J=11.8 Hz, 4H),
3.10 (t, J=7.6 Hz, 2H); HPLC RT=1.45 min (Method E), 1.45 min
(Method F).
Example 298:
2-((1-(2-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)acetyl)indolin-6-yl)-
oxy)acetamide
##STR00656##
[1151] According to the procedure for the preparation of Example
297, coupling of Example 290 (8 mg, 0.018 mmol) and ammonium
chloride (1.9 mg, 0.035 mmol) afforded Example 298 (5.1 mg, 63%
yield). MS(ESI) m/z: 455.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.86 (br. s., 1H), 8.34 (d, J=6.3 Hz, 1H),
7.90 (br. s., 2H), 7.79 (br. s., 1H), 7.73 (d, J=6.6 Hz, 1H), 7.56
(d, J=7.4 Hz, 2H), 7.53-7.45 (m, 3H), 7.35 (br. s., 1H), 7.13 (d,
J=6.3 Hz, 1H), 6.65-6.55 (m, 1H), 4.35 (br. s., 2H), 4.24 (t, J=7.8
Hz, 2H), 3.96 (br. s., 2H), 3.10 (t, J=7.8 Hz, 2H); HPLC RT=1.48
min (Method E), 1.49 min (Method F).
Example 299:
4-(4-(2-(6-(2-(4-Methylpiperazin-1-yl)-2-oxoethoxy)indolin-1-yl)-2-oxoeth-
yl)phenyl)phthalazin-1 (2H)-one
##STR00657##
[1153] According to the procedure for the preparation of Example
297, coupling of Example 290 (8 mg, 0.018 mmol) and
1-methylpiperazine (4.40 mg, 0.044 mmol) afforded Example 299 (1.2
mg, 9% yield). MS(ESI) m/z: 538.4 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 12.87 (br. s., 1H), 9.98 (br. s., 1H),
8.40-8.29 (m, 1H), 7.91 (br. s., 2H), 7.76-7.67 (m, 2H), 7.57 (d,
J=6.9 Hz, 2H), 7.46 (d, J=6.9 Hz, 2H), 7.19-7.09 (m, 1H), 6.59 (d,
J=7.7 Hz, 1H), 4.87 (br. s., 1H), 4.79 (br. s., 1H), 4.39 (br. s.,
1H), 4.26 (br. s., 2H), 4.06 (br. s., 1H), 3.98 (br. s., 2H),
3.17-3.04 (m, 3H), 2.65 (br. s., 3H); HPLC RT=1.30 min (Method E),
1.30 min (Method F).
Example 300:
4-(Dimethylamino)-N-(1-(2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ace-
tyl)indolin-6-yl)benzamide
##STR00658##
[1155] According to the procedure for the preparation of Example 3,
coupling of Intermediate 1 (11 mg, 0.039 mmol), and Intermediate 95
(22 mg, 0.043 mmol) afforded Example 300 (8.6 mg, 40% yield).
MS(ESI) m/z: 544.3 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 12.84 (s, 1H), 9.81 (s, 1H), 8.38-8.31 (m, 1H), 8.01 (d,
J=8.5 Hz, 1H), 7.92-7.81 (m, 4H), 7.76-7.69 (m, 2H), 7.57 (d, J=8.0
Hz, 2H), 7.48 (d, J=8.0 Hz, 3H), 6.75 (d, J=9.1 Hz, 2H), 4.24 (t,
J=8.5 Hz, 2H), 3.96 (s, 2H), 3.19 (t, J=8.4 Hz, 2H), 2.99 (s, 6H);
HPLC RT=1.55 min (Method E), 1.70 min (Method F).
[1156] The following Examples in Table 5 were made by using the
same procedure as shown in Example 45. Intermediate 94 was coupled
with the appropriate carboxylic acid. Various coupling reagents
could be used other than the one described in Example 45, such as
BOP, PyBop, EDC/HOBt or T3P.
##STR00659##
TABLE-US-00006 TABLE 5 HPLC LCMS Method, Ex- (M + RT ample R IUPAC
name H).sup.+ (min.) .sup.1H NMR 301 ##STR00660## 1-(2-hydroxy-2-
methypropyl)-N-[3- methyl-4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-indazole-3- carboxamide 468.2 E: 1.64 F: 1.67 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) d 12.79 (s, 1H), 10.27 (s, 1H),
8.38-8.30 (m, 1H), 8.24 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 1.7 Hz,
1H), 7.90-7.83 (m, 4H), 7.48 (td, J = 7.7, 0.8 Hz, 1H), 7.36-7.25
(m, 3H), 4.77 (s, 1H), 4.48 (s, 2H), 2.11 (s, 3H), 1.20 (s, 6H) 302
##STR00661## 1-(2-hydroxy-2- methylpropyl)-N-[3-
methyl-4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1H-indole-3-
carboxamide 467.1 E: 7.85 F: 7.05 .sup.1H NMR (400 MHz,
methanol-d.sub.4) d 8.48-8.41 (m, 1H), 8.23 (d, J = 7.5 Hz, 1H),
8.15 (s, 1H), 7.93-7.83 (m, 2H), 7.76 (d, J = 1.8 Hz, 1H), 7.71
(dd, J = 8.3, 2.1 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.47-7.40 (m,
1H), 7.34-7.24 (m, 2H), 7.24-7.18 (m, 1H), 4.23 (s, 2H), 2.16 (s,
3H), 1.25 (s, 6H) 303 ##STR00662## 1-[2-(dimethylamino)
ethyl]-N-[3-methyl-4-(4- oxo-3,4- dihydrophthalazin-1-
yl)phenyl]-1H-indazole-3- carboxamide 467.3 E: 1.33 F: 1.53 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) d 12.80 (s, 1H), 10.29 (s, 1H), 9.39
(br. s., 1H), 8.38-8.33 (m, 1H), 8.29 (d, J = 8.0 Hz, 1H),
7.95-7.80 (m, 5H), 7.59 (t, J = 7.7 Hz, 1H), 7.41 (d, J = 7.7 Hz,
1H), 7.35 (d, J = 8.3 Hz, 1H), 7.32-7.25 (m, 1H), 4.96 (t, J = 5.9
Hz, 2H), 3.80 (br. s., 2H), 2.95 (br. s., 6H), 2.12 (s, 3H) 304
##STR00663## 2-[2-(dimethylamino) ethyl]-N-[3-methyl-4-(4- oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-2H-indazole-3- carboxamide 467.2 A:
1.31 B: 1.45 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.80 (s, 1H),
10.93 (s, 1H), 8.41-8.31 (m, 1H), 7.91-7.81 (m, 4H), 7.80- 7.71 (m,
2H), 7.45-7.35 (m, 2H), 7.32-7.24 (m, 2H), 4.84 (t, J = 6.2 Hz,
2H), 2.83 (t, J = 6.3 Hz, 2H), 2.17 (s, 6H), 2.11 (s, 3H) 305
##STR00664## N-[3-methyl-4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-2-(oxetan-3- ylmethyl)-2H-indazole-3- carboxamide 466.2
E: 1.09 F: 1.08 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.84 (s,
1H), 11.28 (s, 1H), 8.38-8.33 (m, 1H), 8.31 (d, J = 8.5 Hz, 1H),
8.06 (d, J = 8.8 Hz, 1H), 8.00-7.93 (m, 1H), 7.92-7.86 (m, 2H),
7.84 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H),
7.43 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 5.16 (dd, J =
13.3, 8.1 Hz, 2H), 5.01-4.87 (m, 2H), 4.70 (dd, J = 11.3, 4.7 Hz,
1H), 3.73 (br. s., 2H), 3.67-3.59 (m, 1H), 2.14 (s, 3H) 306
##STR00665## N-[3-methyl-4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-2,1- benzoxazole-3- carboxamide 397.1 E: 1.68 F: 1.68
.sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.81 (s, 1H), 11.23 (s, 1H),
8.40-8.28 (m, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.96 (s, 1H),
7.90-7.81 (m, 4H), 7.55 (dd, J = 9.2, 6.5 Hz, 1H), 7.40-7.32 (m,
2H), 7.31-7.25 (m, 1H), 2.11 (s, 3H) 307 ##STR00666## benzyl
4-[(3-{[3-methyl- 4-(4-oxo-3,4- dihydrophthalazin-1-yl)
phenyl]carbamoyl}-1H- indazol-1-yl)methyl] piperidine-1-carboxylate
672.2 A: 11.59 B: 9.87 .sup.1H NMR (400 MHz, DMSO-d.sub.6) d 12.79
(s, 1H), 10.34 (s, 1H), 8.37-8.31 (m, 1H), 8.25 (d, J = 8.1 Hz,
1H), 7.96 (d, J = 2.0 Hz, 1H), 7.92-7.82 (m, 4H), 7.51 (ddd, J =
8.4, 7.0, 1.1 Hz, 1H), 7.41-7.23 (m, 7H), 5.06 (s, 2H), 4.48 (d, J
= 7.0 Hz, 2H), 4.02 (d, J = 13.0 Hz, 2H), 2.78 (br. s., 2H),
2.36-2.19 (m, 1H), 2.16-2.03 (m, 3H), 1.51 (d, J = 11.0 Hz, 2H),
1.26 (qd, J = 12.4, 4.1 Hz, 2H) 308 ##STR00667##
5-fluoro-N-[3-methyl-4- (4-oxo-3,4- dihydrophthalazin-1-yl)
phenyl]-1H-pyrrolo[2,3-b] pyridine-3-carboxamide 414.2 E: 1.44 F:
1.44 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.78 (s, 1H), 12.48
(br. s., 1H), 9.98 (s, 1H), 8.58 (d, J = 2.5 Hz, 1H), 8.33 (br. s.,
2H), 8.26 (dd, J = 9.4, 2.8 Hz, 1H), 7.95 (s, 1H), 7.90-7.84 (m,
2H), 7.81 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.30-7.25 (m, 1H),
2.10 (s, 3H) 309 ##STR00668## 7-methoxy-N-[3-methyl- 4-(4-oxo-3,4-
dihydrophthalazin-1- yl)phenyl]-1H-indole-2- carboxamide 425.2 E:
1.72 F: 1.73 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.79 (s, 1H),
11.62 (s, 1H), 10.26 (s, 1H), 8.40-8.21 (m, 1H), 7.90-7.84 (m, 2H),
7.84-7.76 (m, 2H), 7.38-7.23 (m, 4H), 7.03 (t, J = 7.8 Hz, 1H),
6.81 (d, J = 7.7 Hz, 1H), 3.97 (s, 3H), 3.90 (s, 1H), 2.11 (s, 3H)
310 ##STR00669## N-[3-methyl-4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]pyrazolo[1,5-a] pyridine-3-carboxamide 396.2 E: 1.45 F:
1.45 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.78 (s, 1H), 10.06 (s,
1H), 8.90-8.81 (m, 2H), 8.38-8.27 (m, 2H), 7.91- 7.85 (m, 2H), 7.82
(s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.60- 7.52 (m, 1H), 7.30 (d, J =
8.0 Hz, 2H), 7.14 (t, J = 6.9 Hz, 1H), 3.90 (s, 1H), 2.10 (s, 3H)
311 ##STR00670## 2-methyl-N-[3-methyl-4- (4-oxo-3,4-
dihydrophthalazin-1-yl) phenyl]imidazo[1,2-a]
pyridine-3-carboxamide 410.2 E: 1.08 F: 1.40 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.79 (s, 1H), 10.02 (s, 1H), 8.96 (d, J = 6.9 Hz,
1H), 8.33 (d, J = 4.7 Hz, 1H), 7.91-7.84 (m, 2H), 7.76 (s, 1H),
7.71 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.45 (d, J =
7.4 Hz, 1H), 7.36-7.26 (m, 2H), 7.11-7.06 (m, 1H), 2.68 (s, 3H),
2.10 (s, 3H) 312 ##STR00671## N-[3-methyl-4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]imidazo[1,2-a]
pyridine-3-carboxamide 396.2 E: 1.09 F: 1.14 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.79 (s, 1H), 10.31 (s, 1H), 9.51 (d, J = 7.2 Hz,
1H), 8.64 (s, 1H), 8.39-8.29 (m, 1H), 7.87 (dd, J = 4.8, 2.6 Hz,
2H), 7.83-7.73 (m, 3H), 7.54 (t, J = 7.8 Hz, 1H), 7.37-7.26 (m,
2H), 7.20 (t, J = 6.7 Hz, 1H), 2.11 (s, 3H) 313 ##STR00672##
N-[3-methyl-4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-1-(oxan-4- ylmethyl)-1H-indazole-3- carboxamide 494.2 E:
1.86 F: 1.90 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.79 (s, 1H),
10.34 (s, 1H), 8.37-8.30 (m, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.97
(s, 1H), 7.93-7.85 (m, 4H), 7.51 (t, J = 7.4 Hz, 1H), 7.40-7.26 (m,
3H), 4.48 (d, J = 6.9 Hz, 2H), 3.84 (d, J = 10.7 Hz, 2H), 3.29-3.18
(m, 2H), 2.37-2.24 (m, 1H), 2.10 (s, 3H), 1.40 (br. s., 4H) 314
##STR00673## N-[3-methyl-4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-1-[(3- methyloxetan-3- yl)methyl]-1H-indazole-
3-carboxamide 480.3 A: 1.68 B: 1.67 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.79 (br. s., 1H), 10.23 (br. s., 1H), 8.34 (d, J
= 4.4 Hz, 1H), 8.26 (d, J = 8.3 Hz, 1H), 7.93 (br. s., 1H),
7.91-7.82 (m, 4H), 7.53 (t, J = 7.2 Hz, 1H), 7.41-7.27 (m, 3H),
4.80 (br. s., 4H), 4.33 (d, J = 5.0 Hz, 2H), 3.90 (s, 1H), 2.11
(br. s., 3H), 1.20 (br. s., 3H) 325 ##STR00674##
N-[3-methyl-4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-6-[2-
(pyrrolidin-1-yl)ethoxy] pyrazolo[1,5-a]pyridine- 3-carboxamide
509.2 E: 1.18 F: 1.14 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.79
(s, 1H), 10.06 (s, 1H), 8.76 (s, 1H), 8.65 (s, 1H), 8.40-8.30 (m,
1H), 8.23 (d, J = 9.8 Hz, 1H), 7.91-7.85 (m, 2H), 7.83-7.73 (m,
2H), 7.41 (d, J = 9.5 Hz, 1H), 7.32-7.22 (m, 2H), 4.35 (br. s.,
2H), 2.09 (s, 3H), 1.90 (br. s., 4H)
[1157] The following Examples in Table 6 were made by using the
same procedure as shown in Example 45. Intermediate 96 was coupled
with the appropriate carboxylic acid. Various coupling reagents
could be used other than the one described in Example 45, such as
BOP, PyBop, EDC/HOBt or T3P.
##STR00675##
TABLE-US-00007 TABLE 6 HPLC LCMS Method, Ex- (M + RT ample R IUPAC
name H).sup.+ (min.) .sup.1H NMR 315 ##STR00676##
N-[3-chloro-4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-1-(2-hydroxy- 2-methylpropyl)-1H- indazole-3-carboxamide
488.2 E: 1.78 F: 1.78 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.89
(br. s., 1H), 10.62 (s, 1H), 8.40-8.30 (m, 2H), 8.24 (d, J = 8.3
Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.92-7.85 (m, 3H), 7.55 (d, J =
8.3 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.37-7.28 (m, 2H), 4.77 (br.
s., 1H), 4.49 (s, 2H), 1.20 (s, 6H) 316 ##STR00677## tert-butyl
3-[(3-{[3- chloro-4-(4-oxo-3,4- dihydrophthalazin-1-
yl)phenyl]carbamoyl}- 1H-indazol-1-yl)methyl]
azetidine-1-carboxylate 585.2 A: 11.7 B: 9.80 .sup.1H NMR (400 MHz,
methanol-d.sub.4) d 8.48-8.41 (m, 1H), 8.37-8.29 (m, 1H), 8.25 (t,
J = 2.0 Hz, 1H), 7.97- 7.84 (m, 3H), 7.76 (d, J = 8.6 Hz, 1H),
7.62-7.49 (m, 2H), 7.47-7.41 (m, 1H), 7.41-7.32 (m, 1H), 4.79 (d, J
= 7.0 Hz, 2H), 4.07 (t, J = 8.5 Hz, 2H), 3.91 (dd, J = 8.8, 5.3 Hz,
2H), 1.41 (s, 9H) 317 ##STR00678## N-[3-chloro-4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]imidazo[1,2-a]
pyridine-3-carboxamide 416.1 E: 1.15 F: 1.46 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.89 (s, 1H), 10.55 (s, 1H), 9.51 (d, J = 6.9 Hz,
1H), 8.68 (s, 1H), 8.41- 8.26 (m, 1H), 8.18 (s, 1H), 7.93-7.86 (m,
3H), 7.83 (d, J = 9.1 Hz, 1H), 7.65-7.54 (m, 2H), 7.36-7.29 (m,
1H), 7.26 (t, J = 6.9 Hz, 1H) 318 ##STR00679##
N-[3-chloro-4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-1-(oxan-4- ylmethyl)-1H-indazole-3- carboxamide 514.2 E:
1.94 B: 1.95 .sup.1H NMR (500 MHz, DMSO-d.sub.6) d 12.89 (s, 1H),
10.68 (s, 1H), 8.33 (br. s., 2H), 8.26 (d, J = 8.3 Hz, 1H), 8.05
(d, J = 8.3 Hz, 1H), 7.92-7.85 (m, 3H), 7.59-7.49 (m, 2H),
7.40-7.28 (m, 2H), 4.49 (d, J = 6.9 Hz, 2H), 3.90 (s, 1H), 3.84 (d,
J = 11.0 Hz, 2H), 3.29-3.20 (m, 2H), 2.34-2.23 (m, 1H), 1.40 (br.
s., 4H) 319 ##STR00680## N-[3-chloro-4-(4-oxo-
3,4-dihydrophthalazin-1- yl)phenyl]-1-(oxolan-3-
ylmethyl)-1H-indazole-3- carboxamide 500.2 E: 1.77 F: 1.77 .sup.1H
NMR (500 MHz, DMSO-d.sub.6) d 12.89 (s, 1H), 10.66 (s, 1H),
8.39-8.30 (m, 2H), 8.26 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 8.3 Hz,
1H), 7.94-7.85 (m, 3H), 7.62-7.51 (m, 2H), 7.37 (t, J = 7.4 Hz,
1H), 7.33-7.28 (m, 1H), 4.58 (d, J = 7.2 Hz, 2H), 3.92-3.81 (m,
1H), 3.69 (q, J = 8.1 Hz, 2H), 3.64-3.57 (m, 1H), 3.03-2.92 (m,
1H), 1.95 (dd, J = 12.5, 7.0 Hz, 1H), 1.72 (dd, J = 12.4, 6.3 Hz,
1H) 320 ##STR00681## N-[3-chloro-4-(4-oxo- 3,4-dihydrophthalazin-1-
yl)phenyl]-1-[(3- methyloxetan-3- yl)methyl]-1H-indazole-
3-carboxamide 500.2 E: 1.77 F: 1.76 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) d 12.89 (br. s., 1H), 10.55 (br. s., 1H), 8.38-8.31
(m, 1H), 8.30 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.3
Hz, 1H), 7.94- 7.86 (m, 3H), 7.60-7.50 (m, 2H), 7.36 (t, J = 7.6
Hz, 1H), 7.33-7.28 (m, 1H), 4.86-4.77 (m, 4H), 4.37- 4.28 (m, 2H),
1.20 (s, 3H)
Example 321:
1-((1-(4-Hydroxybutyl)piperidin-4-yl)methyl)-N-(3-methyl-4-(4-oxo-3,4-dih-
ydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide
##STR00682##
[1159] To a degassed solution of Example 307 (24 mg, 0.038 mmol) in
THF (2 mL), was added 10% Pd/C (5 mg). The mixture was stirred
under H2 (balloon). The mixture was filtered, then was purified by
prep HPLC to afford Example 321 (20 mg, 0.034 mmol, 88% yield).
MS(ESI) m/z: 565.3 (M+H).sup.+; .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 8.48-8.43 (m, 1H), 8.33 (d, J=8.1 Hz,
1H), 7.91-7.86 (m, 2H), 7.85-7.82 (m, 1H), 7.80 (dd, J=8.3, 1.9 Hz,
1H), 7.73 (d, J=8.6 Hz, 1H), 7.58-7.51 (m, 1H), 7.45-7.40 (m, 1H),
7.39-7.32 (m, 2H), 4.60-4.52 (m, 2H), 3.66-3.56 (m, 2H), 3.41 (d,
J=13.0 Hz, 1H), 3.18-3.07 (m, 1H), 3.05-2.89 (m, 2H), 2.48 (ddt,
J=11.2, 7.5, 3.9 Hz, 1H), 2.22-2.14 (m, 3H), 2.03-1.75 (m, 4H),
1.74-1.51 (m, 4H); HPLC RT=5.67 min (Method A), 6.19 min (Method
B).
Example 322:
1-((1-(4-Hydroxybutyl)piperidin-4-yl)methyl)-N-(4-(4-oxo-3,4-dihydrophtha-
lazin-1-yl)phenyl)-1H-indazole-3-carboxamide
##STR00683##
[1161] Intermediate 3 (23.7 mg, 0.051 mmol) was coupled with
Intermediate 21 (20 mg, 0.051 mmol) according to the procedure for
Example 45 to afford after prep HPLC the amide product (21 mg, 67%
yield). MS(ESI) m/z: 613.2 (M+H).sup.+. The residue (21 mg) was
dissolved in THF (2 mL). To this mixture was added 10% Pd/C (5 mg).
The mixture was stirred under H2 (balloon) for 16 h. The mixture
was filtered and purified by prep HPLC to afford Example 322 (15
mg, 79% yield). MS(ESI) m/z: 551.2 (M+H).sup.+; .sup.1H NMR (400
MHz, methanol-d.sub.4) .delta. 8.46-8.42 (m, 1H), 8.32 (d, J=8.1
Hz, 1H), 8.01-7.95 (m, 2H), 7.92-7.83 (m, 3H), 7.74-7.69 (m, 1H),
7.66-7.61 (m, 2H), 7.52 (td, J=7.7, 0.9 Hz, 1H), 7.37-7.31 (m, 1H),
4.54 (dd, J=6.7, 3.2 Hz, 2H), 3.63-3.55 (m, 2H), 3.41 (d, J=13.0
Hz, 1H), 3.18-3.05 (m, 2H), 3.05-2.87 (m, 2H), 2.55-2.37 (m, 1H),
1.93 (d, J=14.7 Hz, 2H), 1.89-1.76 (m, 2H), 1.75-1.53 (m, 3H); HPLC
RT=5.53 min (Method A), 6.33 min (Method B).
Example 323:
N-(4-(6-Methoxy-1-oxo-1,2-dihydroisoquinolin-4-yl)-3-methylphenyl)indolin-
e-1-carboxamide
##STR00684##
[1163] According to the procedure for the preparation of Example
76, coupling of Intermediate 73 (10 mg, 0.039 mmol) and
Intermediate 97 (14.9 mg, 0.039 mmol), afforded 2.7 mg (15%) of
Example 323. MS(ESI) m/z: 426.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.19 (d, J=5.8 Hz, 1H), 8.55 (s, 1H), 8.21
(d, J=8.8 Hz, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.57 (s, 1H), 7.51 (d,
J=8.0 Hz, 2H), 7.21 (d, J=7.2 Hz, 1H), 7.12 (t, J=7.0 Hz, 3H), 6.96
(d, J=5.8 Hz, 1H), 6.91-6.85 (m, 1H), 6.39 (s, 1H), 4.15 (t, J=8.7
Hz, 2H), 3.70 (s, 3H), 3.19 (t, J=8.5 Hz, 2H), 2.06 (s, 3H); HPLC
RT=1.77 min (Method E), 1.78 min (Method F).
Example 324:
N-(3-Methyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)indoline-1-carboxa-
mide
##STR00685##
[1165] According to the procedure for the preparation of Example
76, coupling of 4-chlorophthalazin-1(2H)-one (20 mg, 0.11 mmol) and
Intermediate 97 (46 mg, 0.12 mmol), afforded 4.4 mg (10%) of
Example 324. MS(ESI) m/z: 397.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.76 (s, 1H), 8.63 (s, 1H), 8.37-8.28 (m,
1H), 7.93-7.83 (m, 3H), 7.61 (s, 1H), 7.57 (d, J=8.3 Hz, 1H),
7.33-7.27 (m, 1H), 7.21 (d, J=7.4 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H),
7.14 (t, J=7.7 Hz, 1H), 6.92 (t, J=7.3 Hz, 1H), 4.17 (t, J=8.4 Hz,
2H), 3.20 (t, J=8.5 Hz, 2H), 2.07 (s, 3H); HPLC RT=1.73 min (Method
E), 1.73 min (Method F).
Example 326:
1-(Azetidin-3-ylmethyl)-N-(3-methyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)p-
henyl)-1H-indazole-3-carboxamide, TFA
##STR00686##
[1166] Example 326A: tert-Butyl
3-((3-((3-methyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamoyl)-1H-
-indazol-1-yl)methyl)azetidine-1-carboxylate
##STR00687##
[1168] To a solution of Intermediate 94 (55 mg, 0.12 mmol),
Intermediate 33 (38 mg, 0.12 mmol), and HATU (45.8 mg, 0.12 mmol)
in DMF (1 mL), was added DIEA (0.1 mL, 0.57 mmol). The mixture was
stirred at rt for 4 h, then was concentrated. The residue was
purified via preparative HPLC to afford Example 326A (45 mg, 70%
yield). MS(ESI) m/z: 565.3 (M+H).sup.+.
Example 326
##STR00688##
[1170] Example 326A (30 mg, 0.053 mmol) was stirred with TFA (0.5
ml) in DCM (1 ml) for 10 min, then was concentrated. The residue
was purified by prep HPLC to afford Example 326 (30 mg, 97% yield).
MS(ESI) m/z: 465.0 (M+H).sup.+; .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 8.53-8.42 (m, 1H), 8.35 (dt, J=8.2, 1.0
Hz, 1H), 7.94-7.86 (m, 2H), 7.85-7.82 (m, 1H), 7.80 (dd, J=8.4, 1.8
Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.56 (ddd, J=8.4, 7.0, 1.1 Hz,
1H), 7.45-7.39 (m, 1H), 7.39-7.33 (m, 2H), 4.82-4.79 (m, 2H),
4.27-4.12 (m, 4H), 3.76-3.61 (m, 1H), 2.19 (s, 3H); HPLC RT=5.38
min (Method A), 5.98 min (Method B).
Example 327:
1-(Azetidin-3-ylmethyl)-N-[3-chloro-4-(4-oxo-3,4-dihydrophthalazin-1-yl)p-
henyl]-1H-indazole-3-carboxamide, TFA
##STR00689##
[1172] Example 316 (24 mg, 0.041 mmol) stirred with TFA (0.5 ml)
and DCM (2 ml) for 10 min, then was concentrated. The residue was
purified via preparative HPLC to afford Example 327 (20 mg, 81%
yield). MS(ESI) m/z: 485.1 (M+H).sup.+; .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 8.49-8.40 (m, 1H), 8.39-8.31 (m, 1H),
8.24-8.17 (m, 1H), 7.96-7.85 (m, 3H), 7.74 (d, J=8.6 Hz, 1H),
7.61-7.48 (m, 2H), 7.46-7.35 (m, 2H), 4.83-4.81 (m, 2H), 4.31-4.10
(m, 4H), 3.67 (t, J=7.8 Hz, 1H); HPLC RT=5.83 min (Method A), 6.83
min (Method B).
Example 328:
2-(3-{[4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl]carbamoyl}-1H-indazol-1-
-yl)acetic acid
##STR00690##
[1174] To 4-chlorophthalazin-1(2H)-one (40.8 mg, 0.226 mmol),
Intermediate 98 (82 mg, 0.188 mmol) and phosphoric acid, potassium
salt (100 mg, 0.47 mmol), were added dioxane (5 mL) and water (0.56
mL). The mixture was degassed (evacuated and flushed with Ar
(5.times.)). Pd(PPh.sub.3).sub.4 (10.9 mg, 9.42 .mu.mol) was added,
then the mixture was degassed (2.times.). The reaction vial was
sealed and heated in a microwave reactor at 150.degree. C. for 25
min. The product was purified by prep HPLC to afford Example 328
(20 mg, 24% yield). MS(ESI) m/z: 440.1 (M+H).sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 12.82 (s, 1H), 10.60 (s, 1H),
8.40-8.32 (m, 1H), 8.28 (d, J=8.1 Hz, 1H), 8.15-8.06 (m, J=8.6 Hz,
2H), 7.97-7.87 (m, 2H), 7.82 (d, J=8.6 Hz, 1H), 7.79-7.74 (m, 1H),
7.63-7.56 (m, J=8.6 Hz, 2H), 7.53 (td, J=7.7, 1.1 Hz, 1H), 7.36 (t,
J=7.6 Hz, 1H), 5.46 (s, 2H); HPLC RT=7.28 min (Method A), 6.64 min
(Method B).
Example 329:
1-((1-Acetylazetidin-3-yl)methyl)-N-(3-chloro-4-(4-oxo-3,4-dihydrophthala-
zin-1-yl)phenyl)-1H-indazole-3-carboxamide
##STR00691##
[1176] Example 327 (10 mg, 0.021 mmol) was mixed with acetic
anhydride (3.2 mg, 0.031 mmol) and TEA (4.17 mg, 0.041 mmol) in
CH.sub.2Cl.sub.2 (1 mL) and stirred at rt o/n. The reaction mixture
was concentrated, then was purified by prep HPLC to afford Example
329 (9.6 mg, 87% yield). MS(ESI) m/z: 527.2 (M+H).sup.+; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 12.89 (s, 1H), 10.62 (br. s.,
1H), 8.38-8.31 (m, 2H), 8.26 (d, J=8.3 Hz, 1H), 8.04 (d, J=8.3 Hz,
1H), 7.98-7.92 (m, 1H), 7.92-7.85 (m, 2H), 7.60-7.50 (m, 2H), 7.37
(t, J=7.2 Hz, 1H), 7.35-7.28 (m, 1H), 7.20 (s, 1H), 7.10 (s, 1H),
7.00 (s, 1H), 4.83 (br. s., 2H), 4.21 (t, J=8.3 Hz, 1H), 4.05 (br.
s., 1H), 3.96-3.86 (m, 1H), 3.79 (br. s., 1H), 3.25 (br. s., 2H),
2.55 (br. s., 2H), 1.74 (s, 3H); HPLC RT=1.55 min (Method E), 1.55
min (Method F).
Example 330:
N-(3-Methyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-((1-methylazeti-
din-3-yl)methyl)-1H-indazole-3-carboxamide
##STR00692##
[1178] To a solution of Example 326 (10 mg, 0.017 mmol) in
CH.sub.2Cl.sub.2 (1 mL), were added TEA (1.7 mg, 0.017 mmol),
followed by formaldehyde (2.8 mg, 0.035 mmol), acetic acid (5.2 mg,
0.086 mmol), and Na(OAc).sub.3BH (7.3 mg, 0.035 mmol). The mixture
was stirred rt for 16 h, then was concentrated and purified by prep
HPLC to afford Example 330 (3.8 mg, 46% yield). MS(ESI) m/z: 479.2
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.79 (s,
1H), 10.30 (s, 1H), 8.34 (d, J=4.7 Hz, 1H), 8.25 (d, J=7.7 Hz, 1H),
7.92-7.77 (m, 4H), 7.52 (t, J=7.4 Hz, 1H), 7.39-7.21 (m, 3H), 4.76
(d, J=6.9 Hz, 2H), 3.14 (br. s., 4H), 3.05-2.96 (m, 1H), 2.25 (br.
s., 3H), 2.10 (s, 3H); HPLC RT=1.35 min (Method E), 1.35 min
(Method F).
Example 331:
3-(3-((4-(4-Pxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamoyl)-1H-indazol-1-
-yl)propanoic acid
Example 332: Methyl
3-(3-((4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamoyl)-1H-indazol-1-
-yl)propanoate
##STR00693##
[1180] According to the procedure for the preparation of Example
76, coupling of 4-chlorophthalazin-1(2H)-one (40.7 mg, 0.225 mmol)
and Intermediate 99 (92 mg, 0.205 mmol), afforded Example 331 (8
mg, 8.5% yield) and Example 332 (42 mg, 43% yield).
Example 331
[1181] MS(ESI) m/z: 454.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.82 (s, 1H), 12.45 (br. s., 1H), 10.45 (s,
1H), 8.41-8.31 (m, 1H), 8.24 (d, J=8.3 Hz, 1H), 8.13-8.05 (m, 2H),
8.00-7.83 (m, 3H), 7.82-7.73 (m, 1H), 7.65-7.57 (m, 2H), 7.52 (ddd,
J=8.4, 7.0, 1.1 Hz, 1H), 7.39-7.29 (m, 1H), 4.77 (t, J=6.7 Hz, 2H),
3.04 (t, J=6.9 Hz, 2H)); HPLC RT=7.51 min (Method A), 6.78 min
(Method B).
Example 332
[1182] MS(ESI) m/z: 468.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.82 (s, 1H), 10.45 (s, 1H), 8.42-8.28 (m,
1H), 8.26-8.20 (m, 1H), 8.12-8.03 (m, 2H), 7.97-7.83 (m, 3H),
7.83-7.73 (m, 1H), 7.67-7.59 (m, 2H), 7.53 (ddd, J=8.5, 7.1, 1.0
Hz, 1H), 7.41-7.28 (m, 1H), 4.81 (t, J=6.7 Hz, 2H), 3.58 (s, 3H),
3.13 (t, J=6.7 Hz, 2H); HPLC RT=8.90 min (Method A), 7.84 min
(Method B).
Example 333:
1-(3-Hydroxy-3-methylbutyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl-
)-1H-indazole-3-carboxamide
##STR00694##
[1184] According to the procedure for the preparation of Example
76, coupling of 4-chlorophthalazin-1(2H)-one (22.6 mg, 0.113 mmol)
and Intermediate 100 (51 mg, 0.125 mmol), afforded Example 333 (5.2
mg, 9.7% yield). MS(ESI) m/z: 468.3 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 12.82 (s, 1H), 10.48 (s, 1H), 8.35 (dd,
J=7.7, 1.4 Hz, 1H), 8.26 (d, J=8.3 Hz, 1H), 8.09 (d, J=8.5 Hz, 2H),
7.97-7.90 (m, 2H), 7.81-7.74 (m, 2H), 7.60 (s, 1H), 7.57-7.48 (m,
1H), 7.34 (t, J=7.6 Hz, 1H), 4.69-4.63 (m, 2H), 4.57 (br. s., 1H),
2.55 (t, J=5.0 Hz, 1H), 2.09-2.00 (m, 2H), 1.21 (s, 6H); HPLC
RT=1.68 min (Method E), 1.68 min (Method F).
Example 334:
1-(2-((2-Hydroxy-2-methylpropyl)amino)-2-oxoethyl)-N-(4-(4-oxo-3,4-dihydr-
ophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide
##STR00695##
[1186] To Example 328 (8 mg, 0.018 mmol),
1-amino-2-methylpropan-2-ol (3.3 mg, 0.036 mmol), and HATU (7.6 mg,
0.020 mmol) in DMF (1 mL), was added DIEA (0.016 mL, 0.091 mmol).
The mixture was stirred at rt for 16 h, then was purified by prep
HPLC to afford Example 334 (6 mg, 64% yield). MS(ESI) m/z: 511.3
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.82 (s,
1H), 10.55 (s, 1H), 8.39-8.34 (m, 1H), 8.27 (d, J=8.0 Hz, 1H), 8.18
(t, J=6.1 Hz, 1H), 8.12-8.03 (m, 2H), 7.98-7.86 (m, 2H), 7.83-7.76
(m, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.63-7.56 (m, 2H), 7.51 (ddd,
J=8.4, 7.0, 1.1 Hz, 1H), 7.42-7.32 (m, 1H), 5.36 (s, 2H), 3.10 (d,
J=6.1 Hz, 2H), 1.10 (s, 6H); HPLC RT=1.42 min (Method E), 1.41 min
(Method F).
Example 335:
1-(2-(((1-Hydroxycyclobutyl)methyl)amino)-2-oxoethyl)-N-(4-(4-oxo-3,4-dih-
ydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide
##STR00696##
[1188] According to the procedure for the preparation of Example
334, coupling of Example 328 (8 mg, 0.018 mmol) and
1-(aminomethyl)cyclobutanol (3.7 mg, 0.036 mmol) afforded Example
335 (2.7 mg, 26% yield). MS(ESI) m/z: 523.3 (M+H).sup.+; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 12.81 (s, 1H), 10.57 (s, 1H),
8.41-8.32 (m, 1H), 8.29-8.21 (m, 2H), 8.14-8.06 (m, 2H), 7.98-7.86
(m, 3H), 7.78 (dd, J=7.8, 1.0 Hz, 1H), 7.75-7.71 (m, 1H), 7.63-7.55
(m, 2H), 7.53-7.47 (m, 1H), 7.40-7.31 (m, 1H), 5.36 (s, 2H), 3.90
(s, 1H), 3.26 (d, J=5.8 Hz, 2H), 2.00-1.86 (m, 4H), 1.70-1.55 (m,
1H), 1.42 (dt, J=11.2, 9.0 Hz, 1H); HPLC RT=1.47 min (Method E),
1.46 min (Method F).
Example 336:
1-(3-((2-Hydroxy-2-methylpropyl)amino)-3-oxopropyl)-N-(4-(4-oxo-3,4-dihyd-
rophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide
##STR00697##
[1190] According to the procedure for the preparation of Example
334, coupling of Example 331 (9 mg, 0.02 mmol) and
1-amino-2-methylpropan-2-ol (3.5 mg, 0.040 mmol) afforded Example
336 (7.4 mg, 65% yield). MS(ESI) m/z: 525.2 (M+H).sup.+; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 12.82 (s, 1H), 10.44 (s, 1H),
8.35 (dd, J=7.8, 1.2 Hz, 1H), 8.23 (d, J=8.3 Hz, 1H), 8.12-8.05 (m,
J=8.5 Hz, 2H), 7.98-7.84 (m, 3H), 7.82 (d, J=8.5 Hz, 1H), 7.78 (dd,
J=7.8, 1.0 Hz, 1H), 7.63-7.58 (m, J=8.5 Hz, 2H), 7.53-7.47 (m, 1H),
7.33 (t, J=7.4 Hz, 1H), 4.79 (t, J=6.7 Hz, 2H), 2.98 (d, J=6.1 Hz,
2H), 2.93-2.86 (m, 2H), 0.92 (s, 6H); HPLC RT=1.46 min (Method E),
1.46 min (Method F).
Example 337:
1-(3-Morpholino-3-oxopropyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)pheny-
l)-1H-indazole-3-carboxamide
##STR00698##
[1192] According to the procedure for the preparation of Example
334, coupling of Example 331 (9 mg, 0.02 mmol) and morpholine (3.5
mg, 0.040 mmol) afforded Example 337 (7.3 mg, 70% yield). MS(ESI)
m/z: 523.2 (M+H).sup.+; .sup.1H NMR 12.82 (s, 1H), 10.46 (s, 1H),
8.40-8.30 (m, 1H), 8.24 (d, J=8.3 Hz, 1H), 8.13-8.05 (m, 2H),
7.98-7.83 (m, 3H), 7.81-7.73 (m, 1H), 7.62-7.58 (m, 2H), 7.51 (ddd,
J=8.3, 7.1, 0.8 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 4.80 (t, J=7.0 Hz,
2H), 3.52-3.37 (m, 8H), 3.09 (t, J=6.9 Hz, 2H); HPLC RT=1.55 min
(Method E), 1.51 min (Method F).
Example 338:
1-(Azetidin-3-ylmethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-
-indazole-3-carboxamide
##STR00699##
[1194] According to the procedure for the preparation of Example
326, coupling of Intermediate 3 and Intermediate 33, followed by
TFA deprotection afforded Example 338. MS(ESI) m/z: 451.1
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.83 (s,
1H), 10.40 (s, 1H), 8.68 (br. s., 1H), 8.52 (br. s., 1H), 8.40-8.34
(m, 1H), 8.29-8.23 (m, 1H), 8.09-8.03 (m, 2H), 7.97-7.85 (m, 3H),
7.80-7.72 (m, 1H), 7.67-7.60 (m, 2H), 7.57 (ddd, J=8.4, 7.0, 1.1
Hz, 1H), 7.41-7.35 (m, 1H), 4.81 (d, J=6.9 Hz, 2H), 4.14-4.02 (m,
2H), 3.99-3.87 (m, 2H); HPLC RT=5.09 min (Method A), 5.73 min
(Method B).
Example 339:
1-((1-Acetylazetidin-3-yl)methyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)-
phenyl)-1H-indazole-3-carboxamide
##STR00700##
[1196] According to the procedure for the preparation of Example
329, acylation of Example 338 (9 mg, 0.016 mmol) with acetic
anhydride afforded Example 339 (5.0 mg, 63% yield). MS(ESI) m/z:
493.3 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
12.85 (s, 1H), 10.46 (s, 1H), 8.35 (d, J=7.7 Hz, 1H), 8.25 (d,
J=8.0 Hz, 1H), 8.11-8.06 (m, J=8.3 Hz, 2H), 7.97-7.90 (m, 3H), 7.78
(d, J=7.7 Hz, 1H), 7.64-7.58 (m, J=8.5 Hz, 2H), 7.54 (t, J=7.7 Hz,
1H), 7.36 (t, J=7.4 Hz, 1H), 4.83 (dd, J=6.9, 4.7 Hz, 2H), 4.21 (t,
J=8.4 Hz, 1H), 4.05 (dd, J=8.1, 5.6 Hz, 1H), 3.97-3.89 (m, 2H),
3.79 (dd, J=9.4, 5.5 Hz, 1H), 3.30-3.19 (m, 1H), 1.74 (s, 3H); HPLC
RT=1.48 min (Method E), 1.47 min (Method F).
Example 340:
1-((1-Methylazetidin-3-yl)methyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)-
phenyl)-1H-indazole-3-carboxamide
##STR00701##
[1198] According to the procedure for the preparation of Example
330, reductive amination of Example 339 (12 mg, 0.021 mmol)
afforded Example 340 (9.1 mg, 90% yield). MS(ESI) m/z: 465.2
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.86 (s,
1H), 10.41 (d, J=13.5 Hz, 1H), 9.82 (br. s., 1H), 8.36 (d, J=7.7
Hz, 1H), 8.30-8.24 (m, 1H), 8.11-8.03 (m, J=8.3 Hz, 2H), 7.98-7.87
(m, 3H), 7.77 (d, J=7.7 Hz, 1H), 7.65-7.60 (m, J=8.3 Hz, 2H), 7.57
(t, J=7.6 Hz, 1H), 7.38 (t, J=7.4 Hz, 1H), 4.84 (t, J=7.3 Hz, 2H),
4.31 (d, J=5.5 Hz, 1H), 4.27-4.14 (m, 1H), 4.03 (d, J=6.9 Hz, 2H),
2.85 (dd, J=16.4, 4.5 Hz, 3H); HPLC RT=1.33 min (Method E), 1.36
min (Method F).
Example 341: Methyl
3-((3-((4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamoyl)-1H-indazol--
1-yl)methyl)azetidine-1-carboxylate
##STR00702##
[1200] According to the procedure for the preparation of Example
329, acylation of Example 338 (8 mg, 0.014 mmol) with methyl
chloroformate afforded Example 341 (5.1 mg, 67% yield). MS(ESI)
m/z: 509.3 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
12.85 (s, 1H), 10.46 (s, 1H), 8.35 (d, J=7.7 Hz, 1H), 8.25 (d,
J=8.0 Hz, 1H), 8.12-8.04 (m, J=8.0 Hz, 2H), 7.97-7.88 (m, 3H), 7.78
(d, J=7.7 Hz, 1H), 7.63-7.59 (m, J=8.0 Hz, 2H), 7.53 (t, J=7.7 Hz,
1H), 7.35 (t, J=7.6 Hz, 1H), 4.82 (d, J=7.2 Hz, 2H), 4.01 (br. s.,
2H), 3.93-3.84 (m, 2H), 3.54 (s, 3H), 3.27-3.14 (m, 1H); HPLC
RT=1.74 min (Method E), 1.74 min (Method F).
Example 342:
N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(piperidin-4-ylmethyl)-1-
H-indazole-3-carboxamide, TFA
##STR00703##
[1202] According to the procedure for the preparation of Example
45, coupling of Intermediate 3 (95 mg, 0.20 mmol) and Intermediate
101 (88 mg, 0.245 mmol), afforded after TFA deprotection Example
342 (78 mg, 79% yield). MS(ESI) m/z: 479.4 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 12.83 (s, 1H), 10.49 (s, 1H), 8.48
(d, J=9.9 Hz, 1H), 8.38-8.34 (m, 1H), 8.27 (d, J=8.0 Hz, 1H), 8.15
(d, J=11.3 Hz, 1H), 8.11-8.07 (m, 2H), 7.94-7.88 (m, 3H), 7.79-7.74
(m, 1H), 7.64-7.59 (m, 2H), 7.54 (ddd, J=8.4, 7.0, 1.1 Hz, 1H),
7.39-7.33 (m, 1H), 4.55 (d, J=6.6 Hz, 2H), 3.27 (d, J=12.4 Hz, 2H),
2.93-2.80 (m, 2H), 2.39-2.27 (m, 1H), 1.71 (d, J=13.8 Hz, 2H),
1.54-1.39 (m, 2H); HPLC RT=8.74 min (Method A), 9.34 min (Method
B).
Example 343:
1-((1-Acetylpiperidin-4-yl)methyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl-
)phenyl)-1H-indazole-3-carboxamide
##STR00704##
[1204] According to the procedure for the preparation of Example
329, acylation of Example 342 (12 mg, 0.020 mmol) with acetic
anhydride afforded Example 343 (8.9 mg, 84% yield). MS(ESI) m/z:
521.3 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
12.85 (s, 1H), 10.52 (s, 1H), 8.35 (d, J=7.4 Hz, 1H), 8.25 (d,
J=8.0 Hz, 1H), 8.14-8.04 (m, J=8.0 Hz, 2H), 7.98-7.87 (m, 3H), 7.78
(d, J=7.4 Hz, 1H), 7.62-7.58 (m, J=7.7 Hz, 2H), 7.52 (t, J=7.6 Hz,
1H), 7.34 (t, J=7.2 Hz, 1H), 4.49 (d, J=6.6 Hz, 2H), 4.37 (d,
J=12.4 Hz, 1H), 3.80 (d, J=13.5 Hz, 1H), 2.96 (t, J=12.9 Hz, 1H),
2.30 (br. s., 1H), 1.97 (s, 3H), 1.50 (t, J=15.5 Hz, 2H), 1.37-1.25
(m, 1H), 1.18 (d, J=12.1 Hz, 1H); HPLC RT=1.61 min (Method E), 1.61
min (Method F).
Example 344: Methyl
4-((3-((4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamoyl)-1H-indazol--
1-yl)methyl)piperidine-1-carboxylate
##STR00705##
[1206] According to the procedure for the preparation of Example
329, acylation of Example 342 (10 mg, 0.017 mmol) with methyl
choroformate afforded Example 344 (4.7 Example 345 (14.8 mg, 5273%
yield). MS(ESI) m/z: 537.3 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.85 (s, 1H), 10.51 (s, 1H), 8.35 (d, J=7.4
Hz, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.12-8.05 (m, J=8.0 Hz, 2H),
7.95-7.87 (m, 3H), 7.78 (d, J=7.7 Hz, 1H), 7.63-7.57 (m, J=7.7 Hz,
2H), 7.51 (t, J=7.6 Hz, 1H), 7.34 (t, J=7.3 Hz, 1H), 4.48 (d, J=6.9
Hz, 2H), 3.96 (br. s., 2H), 3.57 (s, 3H), 2.73 (br. s., 2H), 2.25
(br. s., 1H), 1.47 (br. s., 2H), 1.32-1.19 (m, 2H); HPLC RT=1.83
min (Method F), 1.83 min (Method F).
Example 345:
1-(2-Hydroxy-2-methylpropyl)-N-(3-methoxy-4-(4-oxo-3,4-dihydrophthalazin--
1-yl)phenyl)-1H-indazole-3-carboxamide
##STR00706##
[1208] According to the procedure for the preparation of Example
45, coupling of Intermediate 102 (16 mg, 0.042 mmol) and
Intermediate 15 (9.8 mg, 0.042 mmol), afforded Example 345 (14.8
mg, 73% yield). MS(ESI) m/z: 484.3 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 12.75 (br. s., 1H), 10.37 (br. s., 1H),
8.35-8.28 (m, 1H), 8.24 (d, J=7.2 Hz, 1H), 7.90-7.80 (m, 4H), 7.70
(d, J=7.2 Hz, 1H), 7.48 (br. s., 1H), 7.40-7.28 (m, 3H), 4.79 (br.
s., 1H), 4.49 (br. s., 2H), 3.72 (br. s., 3H), 1.20 (br. s., 6H);
HPLC RT=1.65 min (Method E), 1.66 min (Method F).
Example 346:
N-(3-Ethoxy-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(2-hydroxy-2-me-
thylpropyl)-1H-indazole-3-carboxamide
##STR00707##
[1210] According to the procedure for the preparation of Example
45, coupling of Intermediate 103 (14 mg, 0.050 mmol) and
Intermediate 15 (11.7 mg, 0.050 mmol), afforded Example 346 (22.9
mg, 92% yield). MS(ESI) m/z: 498.3 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 12.74 (br. s., 1H), 10.35 (br. s., 1H),
8.33-8.27 (m, 1H), 8.24 (d, J=7.7 Hz, 1H), 7.92-7.81 (m, 4H), 7.69
(d, J=8.0 Hz, 1H), 7.48 (br. s., 1H), 7.42-7.37 (m, 1H), 7.33 (d,
J=7.7 Hz, 2H), 4.77 (br. s., 1H), 4.49 (br. s., 2H), 4.06 (br. s.,
2H), 1.20 (br. s., 6H), 1.06 (br. s., 3H); HPLC RT=1.76 min (Method
E), 1.76 min (Method F).
Example 347:
N-(3-Ethoxy-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-((tetrahydrofur-
an-3-yl)methyl)-1H-indazole-3-carboxamide
##STR00708##
[1212] According to the procedure for the preparation of Example
45, coupling of Intermediate 103 (11 mg, 0.039 mmol) and
Intermediate 24 (9.6 mg, 0.039 mmol), afforded Example 347 (17.6
mg, 87% yield). MS(ESI) m/z: 510.4 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 12.74 (s, 1H), 10.40 (s, 1H), 8.34-8.24
(m, 2H), 7.90 (s, 1H), 7.86-7.82 (m, 3H), 7.71 (dd, J=8.3, 1.7 Hz,
1H), 7.53 (ddd, J=8.3, 7.1, 1.1 Hz, 1H), 7.43-7.29 (m, 3H), 4.58
(d, J=7.7 Hz, 2H), 4.14-4.00 (m, 2H), 3.87-3.81 (m, 1H), 3.72-3.64
(m, 2H), 3.58 (dd, J=8.8, 5.5 Hz, 1H), 2.96 (s, 1H), 1.94 (s, 1H),
1.72 (d, J=7.4 Hz, 1H), 1.06 (t, J=7.0 Hz, 3H); HPLC RT=1.81 min
(Method E), 1.81 min (Method F).
Example 348:
N-(3-Methoxy-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-((tetrahydrofu-
ran-3-yl)methyl)-1H-indazole-3-carboxamide
##STR00709##
[1214] According to the procedure for the preparation of Example
45, coupling of Intermediate 102 (15 mg, 0.039 mmol) and
Intermediate 24 (9.7 mg, 0.039 mmol), afforded Example 348 (19.1
mg, 97% yield). MS(ESI) m/z: 496.3 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 12.79 (br. s., 1H), 10.48 (br. s., 1H),
8.28 (br. s., 2H), 7.90 (d, J=7.2 Hz, 1H), 7.88-7.81 (m, 3H), 7.73
(br. s., 1H), 7.53 (br. s., 1H), 7.35 (d, J=8.8 Hz, 3H), 4.58 (br.
s., 2H), 3.86 (br. s., 1H), 3.72 (br. s., 3H), 3.68 (br. s., 2H),
3.59 (br. s., 1H), 2.96 (br. s., 1H), 1.94 (br. s., 1H), 1.77-1.65
(m, 1H); HPLC RT=1.71 min (Method E), 1.71 min (Method F).
Example 349: Propan-2-yl
4-[(3-{[4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl]carbamoyl}-1H-indazol--
1-yl)methyl]piperidine-1-carboxylate
##STR00710##
[1216] According to the procedure for the preparation of Example
329, acylation of Example 342 (10 mg, 0.017 mmol) with isopropyl
chloroformate afforded Example 349 (8 mg, 84% yield). MS(ESI) m/z:
565.2 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
12.82 (s, 1H), 10.47 (s, 1H), 8.35 (dd, J=7.7, 1.4 Hz, 1H), 8.25
(d, J=8.3 Hz, 1H), 8.13-8.06 (m, J=8.8 Hz, 2H), 7.97-7.85 (m, 3H),
7.81-7.73 (m, 1H), 7.63-7.58 (m, J=8.5 Hz, 2H), 7.55-7.48 (m, 1H),
7.34 (t, J=7.4 Hz, 1H), 4.75 (quin, J=6.2 Hz, 1H), 4.48 (d, J=7.2
Hz, 2H), 4.07-3.93 (m, 2H), 2.82-2.66 (m, 2H), 2.25 (ddd, J=11.1,
7.4, 3.7 Hz, 1H), 1.48 (d, J=11.0 Hz, 2H), 1.30-1.22 (m, 2H),
1.20-1.10 (m, 6H); HPLC RT=2.04 min (Method E), 2.04 min (Method
F).
Example 350: 2-Fluoroethyl
4-[(3-{[4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl]carbamoyl}-1H-indazol--
1-yl)methyl]piperidine-1-carboxylate
##STR00711##
[1218] According to the procedure for the preparation of Example
329, acylation of Example 342 (10 mg, 0.017 mmol) with
2-fluoroethyl chloroformate afforded Example 350 (8.5 mg, 86%
yield). MS(ESI) m/z: 569.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.82 (br. s., 1H), 10.48 (s, 1H), 8.35 (dd,
J=7.7, 1.4 Hz, 1H), 8.26 (d, J=8.3 Hz, 1H), 8.12-8.05 (m, J=8.5 Hz,
2H), 7.96-7.84 (m, 3H), 7.77 (d, J=7.7 Hz, 1H), 7.65-7.56 (m, J=8.5
Hz, 2H), 7.55-7.48 (m, 1H), 7.34 (t, J=7.6 Hz, 1H), 4.66-4.61 (m,
1H), 4.55-4.51 (m, 1H), 4.49 (d, J=7.2 Hz, 2H), 4.27-4.23 (m, 1H),
4.23-4.15 (m, 1H), 3.99 (d, J=13.2 Hz, 2H), 2.77 (br. s., 1H), 2.73
(s, 1H), 2.27 (ddd, J=11.1, 7.4, 3.7 Hz, 1H), 1.51 (d, J=11.0 Hz,
2H), 1.27 (qd, J=12.4, 4.1 Hz, 2H); HPLC RT=1.93 min (Method E),
1.95 min (Method F).
Example 351: 2,2,2-Trifluoroethyl
4-[(3-{[4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl]carbamoyl}-1H-indazol--
1-yl)methyl]piperidine-1-carboxylate
##STR00712##
[1220] According to the procedure for the preparation of Example
329, acylation of Example 342 (10 mg, 0.017 mmol) with
2,2,2-trifluoroethyl chloroformate afforded Example 351 (6.6 mg,
62% yield). MS(ESI) m/z: 605.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.82 (br. s., 1H), 10.47 (s, 1H), 8.35 (dd,
J=7.7, 1.4 Hz, 1H), 8.26 (d, J=8.3 Hz, 1H), 8.13-8.06 (m, J=8.5 Hz,
2H), 7.98-7.85 (m, 3H), 7.81-7.72 (m, 1H), 7.64-7.56 (m, J=8.5 Hz,
2H), 7.56-7.48 (m, 1H), 7.34 (t, J=7.6 Hz, 1H), 4.68 (q, J=9.1 Hz,
2H), 4.50 (d, J=7.2 Hz, 2H), 3.97 (br. s., 2H), 2.95-2.80 (m, 2H),
2.29 (ddt, J=11.2, 7.5, 3.9 Hz, 1H), 1.65-1.47 (m, 2H), 1.28 (qd,
J=12.3, 4.3 Hz, 2H); HPLC RT=2.02 min (Method E), 2.02 min (Method
F).
Example 352:
N-(2-Methoxy-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-((tetrahydrofu-
ran-3-yl)methyl)-1H-indazole-3-carboxamide
##STR00713##
[1222] According to the procedure for the preparation of Example
45, coupling of Intermediate 104 (15 mg, 0.056 mmol) and
Intermediate 24 (13.8 mg, 0.056 mmol), afforded Example 352 (19.4
mg, 68% yield). MS(ESI) m/z: 496.3 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 12.84 (s, 1H), 9.58 (s, 1H), 8.55 (d,
J=8.3 Hz, 1H), 8.35 (dd, J=7.8, 1.5 Hz, 1H), 8.27 (d, J=8.3 Hz,
1H), 7.95-7.88 (m, 3H), 7.86-7.80 (m, 1H), 7.59-7.51 (m, 1H), 7.38
(t, J=7.4 Hz, 1H), 7.34 (d, J=1.7 Hz, 1H), 7.25 (dd, J=8.1, 1.8 Hz,
1H), 4.65-4.52 (m, 2H), 4.00 (s, 3H), 3.89-3.84 (m, 1H), 3.75 (dd,
J=8.5, 6.9 Hz, 1H), 3.72-3.66 (m, 1H), 3.59 (dd, J=8.5, 5.8 Hz,
1H), 2.99-2.86 (m, 1H), 2.05-1.92 (m, 1H), 1.72 (dd, J=12.9, 6.6
Hz, 1H); HPLC RT=1.82 min (Method E), 1.82 min (Method F).
Example 353:
1-(2-Hydroxy-2-methylpropyl)-N-(2-hydroxy-4-(4-oxo-3,4-dihydrophthalazin--
1-yl)phenyl)-1H-indazole-3-carboxamide
##STR00714##
[1224] According to the procedure for the preparation of Example
45, coupling of Intermediate 105 (8 mg, 0.032 mmol) and
Intermediate 15 (7.4 mg, 0.032 mmol), afforded Example 353 (0.9 mg,
6% yield). MS(ESI) m/z: 470.3 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.80 (s, 1H), 9.59 (s, 1H), 8.53 (d, J=8.3
Hz, 1H), 8.35 (d, J=7.4 Hz, 1H), 8.26 (d, J=8.3 Hz, 1H), 7.98-7.80
(m, 4H), 7.49 (t, J=7.7 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.22-7.16
(m, 1H), 7.11 (dd, J=8.3, 1.4 Hz, 1H), 4.76 (s, 1H), 4.56-4.43 (m,
2H), 1.28-1.15 (m, 6H); HPLC RT=1.60 min (Method E), 1.56 min
(Method F).
Example 354:
N-(2-Hydroxy-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-((tetrahydrofu-
ran-3-yl)methyl)-1H-indazole-3-carboxamide
##STR00715##
[1226] According to the procedure for the preparation of Example
45, coupling of Intermediate 105 (16 mg, 0.063 mmol) and
Intermediate 24 (15.6 mg, 0.063 mmol), afforded Example 354 (4 mg,
13% yield). MS(ESI) m/z: 482.4 (M+H).sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.80 (s, 1H), 10.63 (s, 1H), 9.59 (s, 1H),
8.51 (d, J=8.4 Hz, 1H), 8.37-8.32 (m, 1H), 8.31-8.26 (m, 1H),
7.96-7.87 (m, 3H), 7.86-7.80 (m, 1H), 7.54 (ddd, J=8.4, 7.0, 1.1
Hz, 1H), 7.44-7.33 (m, 1H), 7.17 (d, J=1.8 Hz, 1H), 7.12 (dd,
J=8.3, 1.9 Hz, 1H), 4.67-4.54 (m, 2H), 3.95-3.82 (m, 1H), 3.75 (dd,
J=8.6, 7.0 Hz, 1H), 3.70-3.63 (m, 1H), 3.63-3.50 (m, 1H), 2.96-2.82
(m, 1H), 2.06-1.91 (m, 1H), 1.72 (dt, J=13.5, 6.6 Hz, 1H); HPLC
RT=9.20 min (Method A), 8.67 min (Method B).
Example 355:
N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-((tetr-
ahydrofuran-3-yl)methyl)-1H-indazole-3-carboxamide
##STR00716##
[1227] Example 355A: Methyl
2-(4-oxo-3,4-dihydrophthalazin-1-yl)-5-(1-((tetrahydrofuran-3-yl)methyl)--
1H-indazole-3-carboxamido)benzoate
##STR00717##
[1229] To a mixture of Intermediate 106 (34 mg, 0.12 mmol),
Intermediate 24 (28 mg, 0.12 mmol), and HATU (48.2 mg, 0.127 mmol)
in DMF (2 mL), was added DIEA (0.100 mL, 0.58 mmol). The reaction
mixture was stirred at rt for 16 h, the was concentrated. The
residue was purified by preparative HPLC to afford Example 355A (39
mg, 64% yield). MS(ESI) m/z: 524.4 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 10.71 (s, 1H), 8.70 (d, J=2.2 Hz, 1H),
8.39-8.31 (m, 1H), 8.28 (td, J=5.5, 2.8 Hz, 2H), 7.90 (d, J=8.5 Hz,
1H), 7.88-7.80 (m, 2H), 7.61-7.51 (m, 2H), 7.42-7.34 (m, 1H),
7.32-7.25 (m, 1H), 4.68-4.52 (m, 2H), 3.86 (td, J=8.0, 5.6 Hz, 1H),
3.77-3.63 (m, 2H), 3.63-3.58 (m, 1H), 3.55 (s, 3H), 3.06-2.92 (m,
1H), 2.03-1.87 (m, 1H), 1.78-1.67 (m, 1H).
Example 355
##STR00718##
[1231] To a solution of Example 355A (13.2 mg, 0.025 mmol) in THF
(1 mL) was added lithium borohydride (2M in THF, 0.684 mL, 1.37
mmol) at room temperature. The reaction mixture was stirred at room
temperature for 4 h, then was diluted with MeOH and DMSO and the
solution was purified by preparative HPLC to afford Example 355
(7.6 mg, 58% yield). MS(ESI) m/z: 496.1 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 12.77 (s, 1H), 10.40 (s, 1H),
8.39-8.30 (m, 1H), 8.26 (d, J=8.3 Hz, 1H), 8.22 (d, J=1.9 Hz, 1H),
7.93 (dd, J=8.3, 2.2 Hz, 1H), 7.91-7.83 (m, 3H), 7.55-7.49 (m, 1H),
7.39-7.28 (m, 3H), 4.65-4.52 (m, 2H), 4.35 (br. s., 2H), 3.87-3.81
(m, 1H), 3.73-3.65 (m, 2H), 3.59 (dd, J=8.8, 5.5 Hz, 1H), 3.04-2.93
(m, 1H), 2.04-1.89 (m, 1H), 1.80-1.68 (m, 1H); HPLC RT=1.55 min
(Method E), 1.55 min (Method F).
Example 356:
1-((1-Methylpiperidin-4-yl)methyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl-
)phenyl)-1H-indazole-3-carboxamide
##STR00719##
[1233] According to the procedure for the preparation of Example
330, reductive amination of Example 342 (12 mg, 0.021 mmol)
afforded Example 356 (6.4 mg, 64% yield). MS(ESI) m/z: 493.2
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.82 (s,
1H), 10.47 (s, 1H), 8.42-8.32 (m, 1H), 8.25 (d, J=8.3 Hz, 1H),
8.13-8.05 (m, J=8.5 Hz, 2H), 7.99-7.84 (m, 3H), 7.78 (d, J=8.3 Hz,
1H), 7.65-7.55 (m, J=8.8 Hz, 2H), 7.51 (t, J=7.7 Hz, 1H), 7.34 (t,
J=7.4 Hz, 1H), 4.47 (d, J=7.2 Hz, 2H), 2.83-2.66 (m, 2H), 2.14 (s,
3H), 2.05-1.96 (m, 1H), 1.81 (t, J=11.1 Hz, 2H), 1.52-1.30 (m, 4H);
HPLC RT=1.30 min (Method E), 1.28 min (Method F).
Example 357:
1-(2-Hydroxy-2-methylpropyl)-N-(2-methoxy-4-(4-oxo-3,4-dihydrophthalazin--
1-yl)phenyl)-1H-indazole-3-carboxamide
##STR00720##
[1235] According to the procedure for the preparation of Example
45, coupling of Intermediate 104 (16 mg, 0.060 mmol) and
Intermediate 15 (14 mg, 0.060 mmol), afforded Example 357 (6.1 mg,
20% yield). MS(ESI) m/z: 484.3 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.83 (s, 1H), 9.59 (s, 1H), 8.57 (d, J=8.3
Hz, 1H), 8.35 (dd, J=7.7, 1.4 Hz, 1H), 8.25 (d, J=8.0 Hz, 1H),
7.98-7.78 (m, 4H), 7.54-7.46 (m, 1H), 7.39-7.31 (m, 2H), 7.25 (dd,
J=8.1, 1.8 Hz, 1H), 4.77 (s, 1H), 4.47 (s, 2H), 3.99 (s, 3H), 1.21
(s, 6H); HPLC RT=1.69 min (Method E), 1.70 min (Method F).
Example 358:
N-(2-Fluoro-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(2-hydroxy-2-me-
thylpropyl)-1H-indazole-3-carboxamide
##STR00721##
[1237] To a solution of Intermediate 107 (15 mg, 0.041 mmol),
Intermediate 15 (10.5 mg, 0.045 mmol) and DIEA (0.035 mL, 0.20
mmol) in DMF (1 mL) at rt, was added HATU (17 mg, 0.045 mmol). The
mixture was stirred at rt for 5 days. The reaction mixture was
diluted with MeOH (1 mL), then was filtered and purified by prep
HPLC to afford Example 358 (6.0 mg, 30% yield). MS(ESI) m/z: 472.2
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.90 (s,
1H), 9.85 (s, 1H), 8.29-8.44 (m, 1H), 8.17-8.29 (m, 2H), 7.89-7.99
(m, 2H), 7.88 (d, J=8.80 Hz, 1H), 7.78 (d, J=7.43 Hz, 1H), 7.60
(dd, J=1.65, 11.28 Hz, 1H), 7.46-7.53 (m, 2H), 7.33 (t, J=7.43 Hz,
1H), 4.48 (s, 2H), 1.20 (s, 6H); HPLC RT=1.67 min (Method E), 1.66
min (Method F).
Example 359:
1-(2-Hydroxyethyl)-N-(3-(hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1--
yl)phenyl)-1H-indazole-3-carboxamide
##STR00722##
[1239] According to the procedure of the preparation of Example
355, substituting Intermediate 35 for Intermediate 24 afforded
Example 359. MS(ESI) m/z: 456.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.80 (s, 1H), 10.45 (s, 1H), 8.36-8.30 (m,
1H), 8.27-8.19 (m, 2H), 7.93-7.84 (m, 3H), 7.81 (d, J=8.4 Hz, 1H),
7.49 (t, J=7.6 Hz, 1H), 7.38-7.28 (m, 3H), 4.61 (t, J=5.0 Hz, 2H),
4.34 (br. s., 2H), 3.94 (d, J=5.4 Hz, 2H); HPLC RT=1.31 min (Method
E), 1.31 min (Method F).
Example 360:
1-(2-Hydroxy-2-methylpropyl)-N-(3-(hydroxymethyl)-4-(4-oxo-3,4-dihydropht-
halazin-1-yl)phenyl)-1H-indazole-3-carboxamide
##STR00723##
[1241] According to the procedure of the preparation of Example
355, substituting Intermediate 15 for Intermediate 24 afforded
Example 360. MS(ESI) m/z: 484.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.80 (s, 1H), 10.39 (s, 1H), 8.38-8.28 (m,
1H), 8.23 (d, J=8.1 Hz, 1H), 8.18 (s, 1H), 7.99-7.80 (m, 4H), 7.48
(t, J=7.6 Hz, 1H), 7.38-7.20 (m, 3H), 5.17 (t, J=5.4 Hz, 1H), 4.84
(s, 1H), 4.48 (s, 2H), 4.34 (br. s., 2H), 3.89 (s, 1H), 1.19 (s,
6H); HPLC RT=1.39 min (Method E), 1.40 min (Method F).
Example 361:
N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(2-(te-
trahydro-2H-pyran-4-yl)ethyl)-1H-indazole-3-carboxamide
##STR00724##
[1243] According to the procedure for the preparation of Example
45, coupling of Intermediate 108 (12.5 mg, 0.047 mmol) and
Intermediate 15 (14 mg, 0.051 mmol), afforded Example 361 (13.4 mg,
53% yield). MS(ESI) m/z: 484.3 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.77 (s, 1H), 10.40 (s, 1H), 8.34-8.29 (m,
1H), 8.28-8.19 (m, 2H), 7.97-7.80 (m, 4H), 7.52 (td, J=7.7, 1.1 Hz,
1H), 7.40-7.27 (m, 3H), 5.11 (t, J=5.4 Hz, 1H), 4.61 (t, J=7.4 Hz,
2H), 4.34 (br. s., 2H), 3.85-3.79 (m, 2H), 3.29-3.19 (m, 3H),
1.96-1.85 (m, 2H); HPLC RT=1.63 min (Method E), 1.64 min (Method
F).
Example 362:
N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)pyrazolo[-
1,5-a]pyridine-3-carboxamide
##STR00725##
[1245] According to the procedure for the preparation of Example
45, coupling of Intermediate 108 (13 mg, 0.049 mmol) and
pyrazolo[1,5-a]pyridine-3-carboxylic acid (7.9 mg, 0.049 mmol),
afforded Example 362 (4.1 mg, 20% yield). MS(ESI) m/z: 412.2
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.78 (br.
s., 1H), 10.16 (br. s., 1H), 8.90-8.77 (m, 2H), 8.43-8.24 (m, 2H),
8.04 (br. s., 1H), 7.96-7.81 (m, 3H), 7.55 (t, J=7.5 Hz, 1H),
7.39-7.26 (m, 2H), 7.14 (t, J=6.4 Hz, 1H), 4.33 (br. s., 2H); HPLC
RT=1.28 min (Method E), 1.16 min (Method F).
Example 363:
N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-methyl-
-1H-indazole-3-carboxamide
##STR00726##
[1247] According to the procedure for the preparation of Example
45, coupling of Intermediate 108 (8 mg, 0.030 mmol) and
1-methyl-1H-indazole-3-carboxylic acid (5.3 mg, 0.030 mmol),
afforded Example 363 (7 mg, 55% yield). MS(ESI) m/z: 426.2
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.77 (s,
1H), 10.49 (s, 1H), 8.37-8.29 (m, 1H), 8.28-8.20 (m, 2H), 7.92-7.83
(m, 3H), 7.80 (d, J=8.5 Hz, 1H), 7.53 (ddd, J=8.4, 7.0, 1.1 Hz,
1H), 7.41-7.25 (m, 3H), 5.10 (t, J=5.4 Hz, 1H), 4.34 (br. s., 2H),
4.23 (s, 3H); HPLC RT=1.40 min (Method E), 1.41 min (Method F).
Example 364:
N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-isopro-
pyl-1H-indazole-3-carboxamide
##STR00727##
[1249] According to the procedure for the preparation of Example
45, coupling of Intermediate 108 (8 mg, 0.030 mmol) and
1-isopropyl-1H-indazole-3-carboxylic acid (6.1 mg, 0.030 mmol),
afforded Example 364 (6.9 mg, 51% yield). MS(ESI) m/z: 454.2
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.78 (s,
1H), 10.25 (s, 1H), 8.37-8.30 (m, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.19
(d, J=1.9 Hz, 1H), 8.01-7.92 (m, 1H), 7.91-7.83 (m, 3H), 7.50 (td,
J=7.7, 0.8 Hz, 1H), 7.38-7.28 (m, 3H), 5.25-5.06 (m, 2H), 4.35 (br.
s., 2H), 1.62 (d, J=6.6 Hz, 6H); HPLC RT=1.81 min (Method E), 1.69
min (Method F).
Example 365:
N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)imidazo[1-
,2-a]pyridine-3-carboxamide
##STR00728##
[1251] According to the procedure for the preparation of Example
45, coupling of Intermediate 108 (10 mg, 0.037 mmol) and
imidazo[1,2-a]pyridine-3-carboxylic acid (6.7 mg, 0.041 mmol),
afforded Example 365 (10.7 mg, 68% yield). MS(ESI) m/z: 412.2
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.51 (d,
J=7.0 Hz, 1H), 8.66 (s, 1H), 8.41-8.23 (m, 1H), 8.05 (s, 1H), 7.93
(s, 1H), 7.92-7.83 (m, 3H), 7.78 (d, J=8.9 Hz, 1H), 7.54 (t, J=7.8
Hz, 1H), 7.32 (d, J=7.9 Hz, 2H), 7.21 (t, J=6.7 Hz, 1H), 4.34 (br.
s., 2H), 3.11 (d, J=7.3 Hz, 1H); HPLC RT=0.95 min (Method E), 1.14
min (Method F).
Example 366:
5-Fluoro-N-(3-(hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-
-1-((tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxamide
##STR00729##
[1253] According to the procedure for the preparation of Example
45, coupling of Intermediate 108 (10 mg, 0.037 mmol) and
Intermediate 49 (10.9 mg, 0.041 mmol), afforded Example 366 (8.6
mg, 45% yield). MS(ESI) m/z: 514.2 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 10.43 (s, 1H), 8.32 (d, J=5.2 Hz, 1H),
8.15 (s, 1H), 7.99-7.77 (m, 6H), 7.42 (t, J=9.0 Hz, 1H), 7.36-7.26
(m, 2H), 4.54 (d, J=7.3 Hz, 2H), 4.33 (br. s., 2H), 3.91-3.76 (m,
1H), 3.61-3.51 (m, 1H), 2.99-2.90 (m, 1H), 1.99-1.88 (m, 1H), 1.69
(dq, J=12.7, 6.6 Hz, 1H); HPLC RT=1.52 min (Method E), 1.48 min
(Method F).
Example 367:
N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-((tetr-
ahydrofuran-2-yl)methyl)-1H-indazole-3-carboxamide
##STR00730##
[1255] According to the procedure for the preparation of Example
45, coupling of Intermediate 108 (9.5 mg, 0.036 mmol) and
Intermediate 109 (9.6 mg, 0.039 mmol), afforded Example 367 (13.7
mg, 74% yield). MS(ESI) m/z: 496.2 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 10.46 (s, 1H), 8.41-8.30 (m, 1H),
8.29-8.18 (m, 2H), 8.00-7.78 (m, 4H), 7.50 (t, J=7.6 Hz, 1H),
7.38-7.26 (m, 3H), 4.62 (d, J=5.4 Hz, 2H), 4.41 (quin, J=6.1 Hz,
1H), 4.34 (br. s., 2H), 3.73 (q, J=6.8 Hz, 1H), 3.68-3.56 (m, 1H),
3.44-3.33 (m, 1H), 2.08-1.94 (m, 1H), 1.86-1.71 (m, 3H); HPLC
RT=1.54 min (Method E), 1.66 min (Method F).
Example 368:
6-Fluoro-N-(3-(hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-
-1-((tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxamide
##STR00731##
[1257] According to the procedure for the preparation of Example
45, coupling of Intermediate 108 (9.5 mg, 0.036 mmol) and
Intermediate 50 (10.3 mg, 0.039 mmol), afforded Example 368 (8.6
mg, 47% yield). MS(ESI) m/z: 514.2 (M+H).sup.+; (500 MHz,
DMSO-d.sub.6) .delta. 10.47 (s, 1H), 8.39-8.30 (m, 1H), 8.30-8.17
(m, 2H), 7.96-7.77 (m, 4H), 7.39-7.31 (m, 2H), 7.24 (t, J=8.9 Hz,
1H), 4.63-4.49 (m, 2H), 4.34 (br. s., 2H), 3.88-3.80 (m, 1H),
3.76-3.64 (m, 2H), 3.58 (dd, J=8.6, 5.6 Hz, 1H), 2.95 (dt, J=13.7,
6.8 Hz, 1H), 2.07-1.89 (m, 1H), 1.71 (dq, J=12.9, 6.6 Hz, 1H); HPLC
RT=1.55 min (Method E), 1.76 min (Method F).
Example 369:
1-(2-Hydroxy-2-methylpropyl)-N-(4-(6-methoxy-4-oxo-3,4-dihydrophthalazin--
1-yl)phenyl)-1H-indazole-3-carboxamide
##STR00732##
[1259] According to the procedure for the preparation of Example
45, coupling of Intermediate 110 (15 mg, 0.039 mmol) and
Intermediate 15 (11 mg, 0.047 mmol), afforded Example 369 (0.9 mg,
6% yield). MS(ESI) m/z: 484.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.75 (s, 1H), 10.40 (s, 1H), 8.23 (d,
J=8.3 Hz, 1H), 8.06 (d, J=8.8 Hz, 2H), 7.86 (d, J=8.8 Hz, 1H),
7.76-7.69 (m, 2H), 7.58 (d, J=8.5 Hz, 2H), 7.53-7.42 (m, 2H), 7.32
(t, J=7.6 Hz, 1H), 4.79 (s, 1H), 4.49 (s, 2H), 3.97 (s, 3H), 1.20
(s, 6H); HPLC RT=1.76 min (Method E), 1.64 min (Method F).
Example 370:
N-(4-(6-Methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)imidazo[1,2-a]pyr-
idine-2-carboxamide
##STR00733##
[1261] According to the procedure for the preparation of Example
45, coupling of Intermediate 110 (15 mg, 0.039 mmol) and
Intermediate 15 (7.7 mg, 0.047 mmol), afforded Example 370 (0.5 mg,
3% yield). MS(ESI) m/z: 412.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.74 (s, 1H), 10.51 (s, 1H), 8.64 (d,
J=6.6 Hz, 1H), 8.57 (s, 1H), 8.09 (d, J=8.3 Hz, 2H), 7.76-7.64 (m,
3H), 7.56 (d, J=8.5 Hz, 2H), 7.49 (dd, J=9.1, 2.8 Hz, 1H),
7.43-7.36 (m, 1H), 7.04 (t, J=6.7 Hz, 1H), 3.96 (s, 3H); HPLC
RT=1.18 min (Method E), 1.37 min (Method F).
Example 371:
N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)spiro[indoline-3,4'-piperid-
ine]-1-carboxamide
##STR00734##
[1263]
2-(4-Isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50
mg, 0.204 mmol) and tert-butyl
spiro[indoline-3,4'-piperidine]-1'-carboxylate (58.8 mg, 0.204
mmol) were dissolved in THF (3 mL), and DIEA (0.053 mL, 0.31 mmol)
was added. The reaction mixture was stirred at rt for 1 h. THF was
removed under reduced pressure. To the obtained residue were added
4-chlorophthalazin-1(2H)-one (18.4 mg, 0.102 mmol) and phosphoric
acid, potassium salt (54.1 mg, 0.255 mmol), followed by dioxane (3
mL) and water (0.333 mL). The mixture was degassed (evacuated and
flushed with Ar (3.times.)). Pd(PPh.sub.3).sub.4 (11.8 mg, 10.2
.mu.mol) was added, then the mixture was degassed (2.times.). The
reaction vial was sealed and heated in a microwave reactor at
150.degree. C. for 30 min. The solvent was removed under reduced
pressure, and the residue was treated with TFA (2 mL). The reaction
mixture was stirred for 15 min. TFA was removed under reduced
pressure. The residue was purified by prep HPLC to afford Example
371 (11.9 mg, 25% yield). MS(ESI) m/z: 452.3 (M+H).sup.+; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.83 (s, 1H), 8.90 (br.
s., 1H), 8.81 (s, 1H), 8.35 (d, J=7.4 Hz, 1H), 8.02-7.85 (m, 4H),
7.76 (d, J=8.4 Hz, 3H), 7.55 (d, J=8.4 Hz, 2H), 7.23 (t, J=7.7 Hz,
1H), 7.18 (d, J=7.4 Hz, 1H), 7.06-6.95 (m, 1H), 4.18 (s, 2H),
3.48-3.33 (m, 1H), 3.02 (br. s., 2H), 2.11-1.99 (m, 2H), 1.88 (d,
J=13.8 Hz, 2H); HPLC RT=1.13 min (Method E), 1.09 min (Method
F).
Example 372:
N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(piperidin-4-yl)-1H-1,2,-
3-triazole-4-carboxamide
##STR00735##
[1265] To a mixture of Intermediate 12 (20 mg, 0.084 mmol),
1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-1,2,3-triazole-4-carboxylic
acid (25 mg, 0.084 mmol), HATU (38.5 mg, 0.101 mmol) in DMF (1.5
mL), was added DIEA (0.074 mL, 0.42 mmol). The mixture was stirred
rt for 16 h, then was concentrated. The residue was stirred with
TFA (0.5 mL) in DCM (1 mL) for 30 min, then was concentrated and
purified by prep HPLC to afford Example 372 (9.6 mg, 27% yield).
MS(ESI) m/z: 416.2 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 12.88-12.81 (m, 1H), 10.71 (s, 1H), 8.88 (s, 1H), 8.34 (d,
J=7.4 Hz, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.95-7.85 (m, 2H), 7.75 (d,
J=7.1 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 4.94 (br. s., 1H), 3.46 (d,
J=12.1 Hz, 1H), 3.18-3.04 (m, 2H), 2.38 (d, J=12.8 Hz, 2H), 2.23
(d, J=10.8 Hz, 2H); HPLC RT=0.78 min (Method E), 0.75 min (Method
F).
Example 373:
1-Cyclohexyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-4-
-carboxamide, TFA
##STR00736##
##STR00737##
[1267] Intermediate 111 (25 mg, 0.059 mmol) was suspended in dry
MeCN (1.5 mL), then bromocyclohexane (0.072 mL, 0.588 mmol) was
added, followed by cesium carbonate (96 mg, 0.294 mmol) and the
reaction mixture was heated under microwave irradiation at
150.degree. C. for 30 min. The reaction mixture was cooled to rt,
and most of MeCN was removed under reduced pressure. The obtained
residue was treated TFA (2 mL), and the reaction mixture was
stirred at rt for 15 min. TFA was removed under reduced pressure.
The crude product was purified by preparative HPLC to afford 17.6
mg (57%) of Example 373. MS(ESI) m/z: 414.2 (M+H).sup.+; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.81 (s, 1H), 10.01 (s,
1H), 8.40 (s, 1H), 8.36-8.30 (m, 1H), 8.05 (s, 1H), 7.93-7.84 (m,
4H), 7.75 (d, J=7.6 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H), 4.27-4.14 (m,
1H), 2.10-2.00 (m, 2H), 1.82 (d, J=13.4 Hz, 2H), 1.77-1.60 (m, 3H),
1.41 (q, J=12.9 Hz, 2H), 1.22 (q, J=13.0 Hz, 1H); HPLC RT=1.61 min
(Method E), 1.62 min (Method F).
Example 374:
1-Cyclopentyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole--
4-carboxamide, TFA
##STR00738##
[1269] According to the procedure for the preparation of Example
373, substituting bromocyclopentane for bromocyclohexane afforded
Example 374. MS(ESI) m/z: 400.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.82 (s, 1H), 10.04 (s, 1H), 8.39 (s,
1H), 8.35-8.31 (m, 1H), 8.04 (s, 1H), 7.94-7.88 (m, 2H), 7.86 (d,
J=8.5 Hz, 2H), 7.74 (d, J=7.3 Hz, 1H), 7.55 (d, J=8.5 Hz, 2H), 4.74
(quin, J=6.9 Hz, 1H), 2.17-2.05 (m, 2H), 1.91 (dd, J=12.8, 7.0 Hz,
2H), 1.84-1.74 (m, 2H), 1.71-1.60 (m, 2H); HPLC RT=1.50 min (Method
E), 1.51 min (Method F).
Example 375:
1-(Cyclopropylmethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-p-
yrazole-4-carboxamide, TFA
##STR00739##
[1271] According to the procedure for the preparation of Example
373, substituting (bromomethyl)cyclopropane for bromocyclohexane
afforded Example 375. MS(ESI) m/z: 386.2 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 12.82 (s, 1H), 10.08 (s, 1H),
8.40 (s, 1H), 8.33 (d, J=7.0 Hz, 1H), 8.06 (s, 1H), 7.95-7.82 (m,
4H), 7.74 (d, J=7.3 Hz, 1H), 7.55 (d, J=8.2 Hz, 2H), 4.02 (d, J=7.3
Hz, 2H), 1.32-1.22 (m, 1H), 0.59-0.52 (m, 2H), 0.42-0.34 (m, 2H);
HPLC RT=1.36 min (Method E), 1.36 min (Method F).
Example 376:
N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(2,2,2-trifluoroethyl)-1-
H-pyrazole-4-carboxamide, TFA
##STR00740##
[1273] According to the procedure for the preparation of Example
373, substituting 2,2,2-trifluoroethyl trifluoromethanesulfonate
for bromocyclohexane afforded Example 376. MS(ESI) m/z: 386.2
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.83
(s, 1H), 10.23 (s, 1H), 8.50 (s, 1H), 8.33 (d, J=7.3 Hz, 1H), 8.18
(s, 1H), 7.95-7.82 (m, 4H), 7.74 (d, J=7.6 Hz, 1H), 7.56 (d, J=8.2
Hz, 2H), 5.20 (q, J=9.1 Hz, 2H); HPLC RT=1.34 min (Method E), 1.35
min (Method F).
Example 377:
1-(2-Hydroxy-2-methylpropyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)pheny-
l)-1H-pyrazole-4-carboxamide
##STR00741##
[1275] According to the procedure for the preparation of Example
373, substituting 2,2-dimethyloxirane for bromocyclohexane afforded
Example 377. MS(ESI) m/z: 404.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.84 (s, 1H), 10.10 (s, 1H), 8.36-8.28
(m, 2H), 8.05 (s, 1H), 7.95-7.84 (m, 4H), 7.75 (d, J=7.4 Hz, 1H),
7.55 (d, J=8.4 Hz, 2H), 4.91 (s, 1H), 4.07 (s, 2H), 1.08 (s, 6H);
HPLC RT=0.98 min (Method E), 0.98 min (Method F).
Example 378:
N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(3,3,3-trifluoro-2-hydro-
xypropyl)-1H-pyrazole-4-carboxamide
##STR00742##
[1277] According to the procedure for the preparation of Example
373, substituting 2-(trifluoromethyl)oxirane for bromocyclohexane
afforded Example 378. MS(ESI) m/z: 440.2 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 12.83 (s, 1H), 10.11 (s, 1H),
8.44 (s, 1H), 8.36-8.30 (m, 1H), 8.14 (s, 1H), 7.99-7.84 (m, 5H),
7.75 (d, J=7.4 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 4.53-4.40 (m, 2H),
4.39-4.27 (m, 1H); HPLC RT=1.11 min (Method E), 1.11 min (Method
F).
Example 379:
1-(2-Hydroxy-3-methoxypropyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phen-
yl)-1H-pyrazole-4-carboxamide
##STR00743##
[1279] According to the procedure for the preparation of Example
373, substituting 2-(methoxymethyl)oxirane for bromocyclohexane
afforded Example 379. MS(ESI) m/z: 420.2 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 10.07 (s, 1H), 8.38-8.29 (m,
2H), 8.06 (s, 1H), 7.96-7.84 (m, 4H), 7.75 (d, J=7.4 Hz, 1H), 7.56
(d, J=8.4 Hz, 2H), 4.23 (dd, J=13.8, 3.7 Hz, 1H), 4.13-4.04 (m,
1H), 3.98 (br. s., 1H), 3.31-3.25 (m, 5H); HPLC RT=0.91 min (Method
E), 1.00 min (Method F).
Example 380:
N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(3,3,3-trifluoro-2-hydro-
xy-2-(trifluoromethyl)propyl)-1H-pyrazole-4-carboxamide
##STR00744##
[1281] According to the procedure for the preparation of Example
373, substituting 2,2-bis(trifluoromethyl)oxirane for
bromocyclohexane afforded Example 380. MS(ESI) m/z: 512.2
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.83
(s, 1H), 10.17 (s, 1H), 8.40 (s, 1H), 8.33 (d, J=7.3 Hz, 1H), 8.11
(s, 1H), 7.97-7.81 (m, 4H), 7.74 (d, J=7.6 Hz, 1H), 7.56 (d, J=7.9
Hz, 2H), 4.81 (s, 2H); HPLC RT=1.48 min (Method E), 1.50 min
(Method F).
Example 381:
1-(tert-Butyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-
-4-carboxamide
##STR00745##
[1283] Intermediate 111 (25 mg, 0.059 mmol) was suspended in dry
MeCN (1.5 mL), then 2-bromo-2-methylpropane (0.066 mL, 0.59 mmol)
was added, followed by silver carbonate (81 mg, 0.29 mmol) and the
reaction mixture stirred at 150.degree. C. for 15 min under
microwave irradiation. The reaction mixture was cooled to rt, and
most of MeCN was removed under reduced pressure. The obtained
residue was treated with TFA (2 mL), and the reaction mixture was
stirred at rt for 15 min. TFA was removed under reduced pressure,
the residue was diluted with DMF (2 mL), filtered and purified by
prep HPLC to afford Example 381 (2.6 mg, 11% yield). MS(ESI) m/z:
388.2 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
12.82 (s, 1H), 10.03 (s, 1H), 8.46 (s, 1H), 8.33 (d, J=7.9 Hz, 1H),
8.05 (s, 1H), 7.95-7.88 (m, 2H), 7.86 (d, J=8.5 Hz, 2H), 7.74 (d,
J=7.6 Hz, 1H), 7.55 (d, J=8.5 Hz, 2H), 1.55 (s, 9H); HPLC RT=1.42
min (Method E), 1.44 min (Method F).
Example 382:
N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-propyl-1H-pyrazole-4-car-
boxamide, TFA
##STR00746##
[1285] According to the procedure for the preparation of Example
373, substituting 1-bromopropane for bromocyclohexane afforded
Example 382. MS(ESI) m/z: 374.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.82 (s, 1H), 10.09 (s, 1H), 8.32 (s,
2H), 8.05 (s, 1H), 7.94-7.87 (m, 2H), 7.85 (d, J=8.2 Hz, 2H), 7.73
(d, J=7.6 Hz, 1H), 7.54 (d, J=8.2 Hz, 2H), 4.10 (t, J=6.9 Hz, 2H),
1.79 (sxt, J=7.2 Hz, 2H), 0.81 (t, J=7.3 Hz, 3H); HPLC RT=1.30 min
(Method E), 1.32 min (Method F).
Example 383:
N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(2,2,3,3-tetrafluoroprop-
yl)-1H-pyrazole-4-carboxamide, TFA
##STR00747##
[1287] According to the procedure for the preparation of Example
373, substituting 2,2,3,3-tetrafluoropropyl
trifluoromethanesulfonate for bromocyclohexane afforded Example
383. MS(ESI) m/z: 446.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.83 (s, 1H), 10.22 (s, 1H), 8.46 (s,
1H), 8.33 (d, J=7.6 Hz, 1H), 8.16 (s, 1H), 7.95-7.87 (m, 2H), 7.85
(d, J=8.5 Hz, 2H), 7.73 (d, J=7.6 Hz, 1H), 7.55 (d, J=8.2 Hz, 2H),
6.73-6.25 (m, 1H), 4.99 (t, J=15.0 Hz, 2H); HPLC RT=1.40 min
(Method E), 1.40 min (Method F).
Example 384:
N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(tetrahydro-2H-pyran-4-y-
l)-1H-pyrazole-4-carboxamide
##STR00748##
[1289] According to the procedure for the preparation of Example
373, substituting 4-bromotetrahydro-2H-pyran for bromocyclohexane
afforded Example 384. MS(ESI) m/z: 416.2 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 12.81 (s, 1H), 10.01 (s, 1H),
8.46 (s, 1H), 8.34 (d, J=7.6 Hz, 1H), 8.10 (s, 1H), 7.98-7.85 (m,
4H), 7.76 (d, J=7.6 Hz, 1H), 7.57 (d, J=8.2 Hz, 2H), 4.49 (t,
J=11.3 Hz, 1H), 3.98 (d, J=10.1 Hz, 2H), 3.49 (t, J=11.4 Hz, 1H),
2.10-1.89 (m, 4H); HPLC RT=1.22 min (Method E), 1.22 min (Method
F).
Example 385:
1-(Cyclopropylmethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-p-
yrazole-4-carboxamide, TFA
##STR00749##
[1291] According to the procedure for the preparation of Example
373, substituting bromocyclobutane for bromocyclohexane afforded
Example 385. MS(ESI) m/z: 386.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.81 (s, 1H), 10.02 (s, 1H), 8.46 (s,
1H), 8.34 (d, J=7.3 Hz, 1H), 8.09 (s, 1H), 7.94-7.84 (m, 4H), 7.75
(d, J=7.6 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H), 4.90 (quin, J=8.3 Hz,
1H), 2.49-2.37 (m, 4H), 1.87-1.76 (m, 2H); HPLC RT=1.39 min (Method
E), 1.39 min (Method F).
Example 386:
1-(2,2-Difluoroethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-p-
yrazole-4-carboxamide
##STR00750##
[1293] According to the procedure for the preparation of Example
373, substituting 2,2-difluoroethyl trifluoromethanesulfonate for
bromocyclohexane afforded Example 386. MS(ESI) m/z: 396.2
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.83
(s, 1H), 10.14 (s, 1H), 8.46 (s, 1H), 8.34 (d, J=7.1 Hz, 1H), 8.16
(s, 1H), 7.97-7.85 (m, 4H), 7.76 (d, J=7.4 Hz, 1H), 7.57 (d, J=8.8
Hz, 2H), 6.42 (t, J=54.2 Hz, 1H), 4.73 (td, J=15.2, 3.2 Hz, 2H);
HPLC RT=1.17 min (Method E), 1.17 min (Method F).
Example 387:
1-(2-Hydroxypropyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyr-
azole-4-carboxamide
##STR00751##
[1295] According to the procedure for the preparation of Example
373, substituting 2-methyloxirane for bromocyclohexane afforded
Example 387. MS(ESI) m/z: 396.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.83 (s, 1H), 10.06 (s, 1H), 8.37-8.31
(m, 2H), 8.06 (s, 1H), 7.95-7.86 (m, 4H), 7.75 (d, J=7.4 Hz, 1H),
7.56 (d, J=8.1 Hz, 2H), 5.06 (d, J=4.7 Hz, 1H), 4.15-4.08 (m, 1H),
4.07-3.95 (m, 2H), 1.07 (d, J=6.1 Hz, 3H); HPLC RT=0.99 min (Method
E), 0.99 min (Method F).
Example 388:
1-(4-Chlorophenyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyra-
zole-4-carboxamide
##STR00752##
[1297] Intermediate 111 (20 mg, 0.047 mmol), 1-chloro-4-iodobenzene
(34 mg, 0.141 mmol), salicylaldoxime (6.5 mg, 0.047 mmol) and
cesium carbonate (46 mg, 0.14 mmol) were suspended in DMF (1.5 mL).
The obtained suspension was degassed (3.times. vacuum/Ar), then
copper(I) oxide (1.7 mg, 0.012 mmol) was added. The reaction
mixture was degassed again (2.times. vacuum/Ar) and was stirred
under microwave irradiation at 200.degree. C. for 30 min. The
reaction mixture was cooled to rt, and most of DMF was evaporated.
The obtained residue was treated TFA (2 mL), and the reaction
mixture was stirred at rt for 15 min. TFA was removed under reduced
pressure, the residue was purified by prep HPLC to afford Example
388 (2.2 mg, 10% yield). MS(ESI) m/z: 442.2 (M+H).sup.+; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.82 (s, 1H), 10.22 (s,
1H), 9.13 (s, 1H), 8.37 (s, 1H), 8.34 (d, J=7.6 Hz, 1H), 8.02-7.84
(m, 6H), 7.76 (d, J=7.6 Hz, 1H), 7.61 (dd, J=13.9, 8.4 Hz, 4H);
HPLC RT=1.77 min (Method E), 1.76 min (Method F).
Example 389:
1-(Oxetan-3-yl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazol-
e-4-carboxamide
##STR00753##
[1299] According to the procedure for the preparation of Example
373, substituting 3-bromooxetane for bromocyclohexane afforded
Example 389. MS(ESI) m/z: 388.0 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.84 (s, 1H), 10.12 (s, 1H), 8.54 (s,
1H), 8.37-8.30 (m, 1H), 8.21 (s, 1H), 7.96-7.85 (m, 4H), 7.75 (d,
J=7.4 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 5.65 (quin, J=6.9 Hz, 1H),
5.00-4.93 (m, 2H), 4.93-4.87 (m, 2H); HPLC RT=1.03 min (Method E),
0.94 min (Method F).
Example 390:
N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(tetrahydrofuran-3-yl)-1-
H-pyrazole-4-carboxamide
##STR00754##
[1301] According to the procedure for the preparation of Example
373, substituting 3-bromotetrahydrofuran for bromocyclohexane
afforded Example 390. MS(ESI) m/z: 402.1 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 12.83 (s, 1H), 10.07 (s, 1H),
8.45 (s, 1H), 8.34 (d, J=7.1 Hz, 1H), 8.09 (s, 1H), 7.97-7.85 (m,
4H), 7.75 (d, J=7.7 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 5.10 (br. s.,
1H), 4.06-3.97 (m, 2H), 3.97-3.90 (m, 1H), 3.88-3.78 (m, 1H),
2.48-2.36 (m, 1H), 2.27 (d, J=3.7 Hz, 1H); HPLC RT=1.10 min (Method
E), 1.02 min (Method F).
Example 391:
N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-4-carboxamide,
TFA
##STR00755##
[1303] Intermediate 111 (20 mg, 0.047 mmol) was treated with TFA (2
mL). The reaction mixture was stirred at rt for 15 min. TFA was
removed under reduced pressure, then the residue was purified by
prep HPLC to afford Example 391 (11.6 mg, 53% yield). MS(ESI) m/z:
332.0 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
12.81 (s, 1H), 10.02 (s, 1H), 8.41 (br. s., 1H), 8.34 (d, J=7.3 Hz,
1H), 8.10 (br. s., 1H), 7.96-7.84 (m, 4H), 7.76 (d, J=7.6 Hz, 1H),
7.56 (d, J=7.9 Hz, 2H); HPLC RT=1.01 min (Method E), 1.01 min
(Method F).
Example 392:
1-(Bicyclo[2.2.1]heptan-7-yl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phen-
yl)-1H-pyrazole-4-carboxamide
Example 393:
1-((1S,2S,4R)-Bicyclo[2.2.1]heptan-2-yl)-N-(4-(4-oxo-3,4-dihydrophthalazi-
n-1-yl)phenyl)-1H-pyrazole-4-carboxamide
##STR00756##
[1305] Intermediate 111 (20 mg, 0.047 mmol) was suspended in dry
MeCN (1.5 mL), then (1R,4S)-7-bromobicyclo[2.2.1]heptane (0.060 mL,
0.470 mmol) was added, followed by cesium carbonate (153 mg, 0.470
mmol) and the reaction mixture was heated under microwave
irradiation at 150.degree. C. for 15 min. The reaction mixture was
heated at 175.degree. C. for 30 min (3.times.). The reaction
mixture was cooled to rt, and most of MeCN was removed under
reduced pressure. The obtained residue was treated TFA (2 mL), and
the reaction mixture was stirred at rt for 15 min. TFA was removed
under reduced pressure, the residue was purified by prep HPLC to
afford Example 392 (7.8 mg, 38% yield) and Example 393 (2.5 mg, 13%
yield).
Example 392
[1306] MS(ESI) m/z: 426.0 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.81 (s, 1H), 9.98 (s, 1H), 8.46 (s,
1H), 8.34 (d, J=7.6 Hz, 1H), 8.04 (s, 1H), 7.98-7.87 (m, 4H), 7.76
(d, J=7.3 Hz, 1H), 7.56 (d, J=8.2 Hz, 2H), 4.38-4.29 (m, 1H), 2.47
(br. s., 1H), 2.39 (br. s., 1H), 2.05 (d, J=13.4 Hz, 1H), 1.91-1.83
(m, 1H), 1.75 (d, J=9.8 Hz, 1H), 1.65-1.46 (m, 2H), 1.38-1.30 (m,
1H), 1.21 (d, J=9.2 Hz, 2H); HPLC RT=1.51 min (Method E), 1.52 min
(Method F).
Example 393
[1307] MS(ESI) m/z: 426.0 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 12.81 (br. s., 1H), 9.99 (br. s., 1H),
8.51-8.40 (m, 1H), 8.34 (d, J=7.0 Hz, 1H), 8.07 (br. s., 1H), 7.89
(d, J=7.9 Hz, 4H), 7.76 (d, J=7.0 Hz, 1H), 7.57 (d, J=7.3 Hz, 2H),
4.73 (br. s., 1H), 2.34 (br. s., 1H), 2.08 (d, J=14.3 Hz, 1H), 1.90
(br. s., 1H), 1.78 (br. s., 1H), 1.65-1.47 (m, 2H), 1.46-1.27 (m,
4H); HPLC RT=1.49 min (Method E), 1.49 min (Method F).
Example 394:
5-Methyl-N-(3-methyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-phenyl-
-1H-pyrazole-4-carboxamide
##STR00757##
[1309] Intermediate 94 (50 mg, 0.137 mmol) was dissolved in dry DMF
(2 mL), then 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (55.4
mg, 0.274 mmol) and DIEA (0.143 mL, 0.821 mmol) were added. After
stirring for 5 min at rt, HATU (52 mg, 0.137 mmol) was added, and
the reaction mixture was stirred at 60.degree. C. for 4 h. The
reaction mixture was quenched with MeOH (0.1 mL) was purified by
preparative HPLC to afford Example 394 (18 mg, 29% yield) as an
off-white solid. MS(ESI) m/z: 436.0 (M+H).sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 12.78 (s, 1H), 9.97 (s, 1H), 8.37
(s, 1H), 8.35-8.29 (m, 1H), 7.91-7.84 (m, 2H), 7.79 (d, J=1.8 Hz,
1H), 7.74 (dd, J=8.4, 2.0 Hz, 1H), 7.63-7.54 (m, 4H), 7.54-7.46 (m,
1H), 7.32-7.26 (m, 2H), 2.58 (s, 3H), 2.09 (s, 3H); HPLC RT=8.43
min (Method A), 8.11 min (Method B).
Example 395:
5-(tert-Butyl)-1-methyl-N-(3-methyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)p-
henyl)-1H-pyrazole-3-carboxamide
##STR00758##
[1311] According to the procedure for the preparation of Example
394, coupling of Intermediate 94 (40 mg, 0.109 mmol) with
5-(tert-butyl)-1-methyl-1H-pyrazole-3-carboxylic acid (31.9 mg,
0.175 mmol) 60.degree. C. for 2 days afforded Example 395 (18.2 mg,
39% yield). MS(ESI) m/z: 416.1 (M+H).sup.+; .sup.1H NMR
.sup.1H-NMR: (500 MHz, DMSO-d.sub.6) .delta. ppm 12.77 (s, 1H),
10.00 (s, 1H), 8.35-8.29 (m, 1H), 7.91-7.83 (m, 3H), 7.79 (dd,
J=8.4, 2.0 Hz, 1H), 7.31-7.24 (m, 2H), 6.59 (s, 1H), 4.05 (s, 3H),
2.07 (s, 3H), 1.39 (s, 9H); HPLC RT=13.24 min (Method A), 11.79 min
(Method B).
Example 396:
1-(1,1-Dioxidotetrahydrothiophen-3-yl)-N-(4-(4-oxo-3,4-dihydrophthalazin--
1-yl)phenyl)-1H-pyrazole-4-carboxamide, TFA
##STR00759##
[1313] According to the procedure for the preparation of Example
373, substituting 3-bromotetrahydrothiophene 1,1-dioxide for
bromocyclohexane afforded Example 396. MS(ESI) m/z: 450.1
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.81
(s, 1H), 10.09 (s, 1H), 8.54 (s, 1H), 8.34 (d, J=7.3 Hz, 1H), 8.19
(s, 1H), 7.98-7.84 (m, 4H), 7.76 (d, J=7.6 Hz, 1H), 7.58 (d, J=7.9
Hz, 2H), 5.35 (t, J=7.3 Hz, 1H), 3.78 (dd, J=13.6, 8.4 Hz, 1H),
3.51 (dd, J=13.9, 7.5 Hz, 1H), 3.49-3.38 (m, 1H), 2.73-2.65 (m,
1H), 2.64-2.55 (m, 1H); HPLC RT=1.13 min (Method E), 1.14 min
(Method F).
Example 397:
N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(pyrrolidin-3-yl)-1H-pyr-
azole-4-carboxamide
##STR00760##
[1315] According to the procedure for the preparation of Example
373, substituting tert-butyl 3-bromopyrrolidine-1-carboxylate for
bromocyclohexane afforded Example 397. MS(ESI) m/z: 401.3
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 10.09
(s, 1H), 8.45 (s, 1H), 8.34 (d, J=7.1 Hz, 1H), 8.09 (s, 1H),
7.95-7.83 (m, 5H), 7.74 (d, J=7.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H),
4.96 (br. s., 1H), 3.29 (dd, J=12.1, 7.1 Hz, 1H), 3.17-3.06 (m,
2H), 3.03-2.93 (m, 1H), 2.32-2.22 (m, 1H), 2.15-2.01 (m, 1H); HPLC
RT=0.85 min (Method E), 0.85 min (Method F).
Example 398:
N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(3,3,3-trifluoropropyl)--
1H-pyrazole-4-carboxamide
##STR00761##
[1317] According to the procedure for the preparation of Example
373, substituting 3-bromo-1,1,1-trifluoropropane for
bromocyclohexane afforded Example 398. MS(ESI) m/z: 428.2
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.84
(s, 1H), 10.11 (s, 1H), 8.44 (s, 1H), 8.34 (d, J=7.1 Hz, 1H), 8.13
(s, 1H), 7.95-7.83 (m, 4H), 7.75 (d, J=7.7 Hz, 1H), 7.56 (d, J=8.4
Hz, 2H), 4.46 (t, J=6.6 Hz, 2H), 2.98-2.89 (m, 2H); HPLC RT=1.35
min (Method E), 1.35 min (Method F).
Example 399:
N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(3-(pyrrolidin-1-yl)prop-
yl)-1H-pyrazole-4-carboxamide
##STR00762##
[1319] According to the procedure for the preparation of Example
373, substituting 1-(3-bromopropyl)pyrrolidine, HCl for
bromocyclohexane afforded Example 399. MS(ESI) m/z: 443.3
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.83
(s, 1H), 10.02 (s, 1H), 8.39 (s, 1H), 8.34 (d, J=7.1 Hz, 1H), 8.08
(s, 1H), 7.97-7.85 (m, 4H), 7.76 (d, J=8.1 Hz, 1H), 7.57 (d, J=8.4
Hz, 2H), 4.21 (t, J=6.9 Hz, 2H), 2.43 (br. s., 4H), 2.37 (t, J=7.1
Hz, 2H), 1.97 (quin, J=6.9 Hz, 2H), 1.69 (br. s., 4H); HPLC RT=0.91
min (Method E), 0.90 min (Method F).
Example 400:
5-Methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-phenyl-1H-1,2,3-
-triazole-4-carboxamide
##STR00763##
[1321] To a mixture of Intermediate 12 (15 mg, 0.043 mmol),
Intermediate 112 (9.5 mg, 0.047 mmol), and HATU (18 mg, 0.047 mmol)
in DMF (1.5 mL), was added DIEA (0.037 mL, 0.21 mmol). The mixture
was stirred rt for 3 h, then 50.degree. C. overnight. The mixture
was purified by prep PHLC to afford Example 400 (4.6 mg, 24%
yield). MS(ESI) m/z: 423.1 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.82 (s, 1H), 10.73 (s, 1H), 8.35 (d, J=6.7
Hz, 1H), 8.09-8.03 (m, J=7.9 Hz, 2H), 7.97-7.87 (m, 2H), 7.76 (d,
J=7.3 Hz, 1H), 7.67 (br. s., 5H), 7.61-7.55 (m, J=7.9 Hz, 2H), 2.60
(s, 3H); HPLC RT=1.70 min (Method E), 1.71 min (Method F).
Example 401:
1-(4-Methoxyphenyl)-5-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)pheny-
l)-1H-1,2,3-triazole-4-carboxamide
##STR00764##
[1323] According to the procedure for the preparation of Example
400, coupling of Intermediate 12 (12 mg, 0.034 mmol) and
Intermediate 113 (8.8 mg, 0.038 mmol) afforded Example 401 (1.8 mg,
11% yield). MS(ESI) m/z: 453.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.82 (s, 1H), 10.70 (s, 1H), 8.34 (d, J=7.6
Hz, 1H), 8.05 (d, J=7.9 Hz, 2H), 7.91 (t, J=7.6 Hz, 2H), 7.76 (d,
J=7.9 Hz, 1H), 7.58 (d, J=8.2 Hz, 4H), 7.19 (d, J=8.2 Hz, 2H), 3.86
(s, 3H), 2.56 (s, 3H); HPLC RT=1.69 min (Method E), 1.70 min
(Method F).
Example 402:
1-(4-Methoxyphenyl)-4-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)pheny-
l)-1H-1,2,3-triazole-5-carboxamide
##STR00765##
[1325] According to the procedure for the preparation of Example
400, coupling of Intermediate 12 (12 mg, 0.034 mmol) and
Intermediate 114 (8.8 mg, 0.038 mmol) afforded Example 402 (2.5 mg,
16% yield). MS(ESI) m/z: 453.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.83 (s, 1H), 10.98 (s, 1H), 8.33 (d, J=7.6
Hz, 1H), 7.89 (d, J=4.3 Hz, 2H), 7.76 (d, J=7.9 Hz, 2H), 7.70 (d,
J=7.0 Hz, 1H), 7.58 (d, J=7.9 Hz, 2H), 7.50 (d, J=8.2 Hz, 2H), 7.11
(d, J=8.5 Hz, 2H), 3.80 (s, 3H), 2.45 (s, 3H); HPLC RT=1.44 min
(Method E), 1.45 min (Method F).
Example 403:
5-(Difluoromethoxy)-1-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)pheny-
l)-1H-pyrazole-3-carboxamide
##STR00766##
[1326] Example 403A: Methyl
5-(difluoromethoxy)-1-methyl-1H-pyrazole-3-carboxylate
##STR00767##
[1328] Methyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate (J. Med.
Chem., 54:8174 (2011)) (0.35 g, 2.24 mmol), K.sub.2CO.sub.3 (0.62
g, 4.48 mmol), and sodium chlorodifluoroacetate (0.684 g, 4.48
mmol) were dissolved in DMF (10 ml) and water (1 ml). The reaction
was heated to 130.degree. C. for 20 min. The reaction was diluted
with water (100 mL) and EtOAc (200 mL). The organic phase was
separated, washed with water (5.times.), brine and dried
(Na.sub.2SO.sub.4). EtOAc was removed under reduced pressure and
the residue was purified by flash chromatography: (40 g) 0-80%
EtOAc/Hex. Fractions were combined and concentrated under reduced
pressure to give Example 403A (0.373 g, 81% yield) as a colorless
syrup. MS(ESI) m/z: 207.0 (M+H).sup.+; .sup.1H-NMR: (400 MHz,
CDCl.sub.3) .delta. ppm 6.44 (t, J=1.0 Hz, 1H), 6.46 (t, J=72.2 Hz,
1H), 3.92 (s, 3H), 3.82 (s, 3H); .sup.19F-NMR: (376 MHz,
CDCl.sub.3) .delta. ppm -84.02 (s, 2F).
Example 403B: 5-(Difluoromethoxy)-1-methyl-1H-pyrazole-3-carboxylic
acid
##STR00768##
[1330] Example 403A (0.373 g, 1.809 mmol) was dissolved in THF (7.5
ml) and MeOH (1.5 ml), then LiOH (1 M in water) (5.43 ml, 5.43
mmol) was added. The reaction was heated to 50.degree. C. for 2 h.
The reaction mixture was quenched with TFA (0.418 ml, 5.43 mmol),
and concentrated under reduced pressure. The residue was diluted
with DMSO/MeOH/water and was purified by preparative HPLC.
Fractions were combined and concentrated to afford Example 403B
(0.230 g, 66% yield) as a white solid. MS(ESI) m/z: 192.9
(M+H).sup.+; .sup.1H-NMR: (500 MHz, DMSO-d.sub.6) .delta. ppm 7.30
(t, J=70.4 Hz, 1H), 6.42 (s, 1H), 3.74 (s, 3H); .sup.19F-NMR: (376
MHz, DMSO-d.sub.6) .delta. ppm -84.72 (s, 2F)
Example 403
##STR00769##
[1332] According to the procedure for the preparation of Example
400, coupling of Intermediate 12 (30 mg, 0.064 mmol) and Example
403B (24.8 mg, 0.129 mmol) afforded Example 403 (14.7 mg, 55%
yield). MS(ESI) m/z: 412.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. .sup.1H-NMR: (500 MHz, DMSO-d.sub.6) .delta.
ppm 12.83 (s, 1H), 10.37 (s, 1H), 8.34 (d, J=7.1 Hz, 1H), 7.98 (d,
J=8.4 Hz, 2H), 7.93-7.84 (m, 2H), 7.74 (d, J=7.4 Hz, 1H), 7.56 (d,
J=8.4 Hz, 2H), 7.52-7.14 (m, 1H), 6.58 (s, 1H), 3.81 (s, 3H); HPLC
RT=1.45 min (Method E), 1.45 min (Method F).
Example 404:
1-(3-Methoxyphenyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-1,2-
,3-triazole-4-carboxamide
##STR00770##
[1333] Example 404A: Ethyl
1-(3-methoxyphenyl)-1H-1,2,3-triazole-4-carboxylate
##STR00771##
[1335] To the solution of 3-methoxyaniline (0.3 g, 2.44 mmol) in
acetonitrile (6 mL) at 0.degree. C. was added isoamyl nitrite
(0.327 mL, 2.44 mmol), followed by azidotrimethylsilane (0.320 mL,
2.44 mmol) dropwise. After 5 min, the ice bath removed, and the
reaction mixture was stirred at rt for 10 min, then ethyl
propiolate (0.494 mL, 4.87 mmol) added. The reaction mixture
stirred in a sealed tube at 80.degree. C. for 20 h, then was cooled
to rt. The reaction mixture was concentrated and the residue was
purified by flash chromatography (0-40% EtOAc/Hexanes) to afford
Example 404A. MS(ESI) m/z: 248.0 (M+H).sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.48 (s, 1H), 7.42-7.32 (m, 1H), 7.28 (t,
J=2.2 Hz, 1H), 7.26-7.19 (m, 1H), 6.99-6.88 (m, 1H), 4.38 (q, J=7.0
Hz, 2H), 3.81 (s, 3H), 1.36 (t, J=7.2 Hz, 3H).
Example 404B: 1-(3-Methoxyphenyl)-1H-1,2,3-triazole-4-carboxylic
acid
##STR00772##
[1337] Example 404A (120 mg, 0.485 mmol) mixed with 1M lithium
hydroxide (1.2 mL, 1.2 mmol) in THF (2 mL) and THF (2 mL). The
reaction mixture was stirred at rt for 2 h, then was concentrated.
The residue was purified by flash chromatography (0-20% MeOH/DCM)
to afford Example 404B (100 mg, 94% yield) as a yellow solid.
MS(ESI) m/z: 220.0 (M+H).sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.03 (s, 1H), 7.59-7.43 (m, 3H), 7.08-7.00 (m, 1H), 3.86
(s, 3H).
Example 404
##STR00773##
[1339] According to the procedure for the preparation of Example
400, coupling of Intermediate 12 (10 mg, 0.028 mmol) and Example
404B (6.9 mg, 0.031 mmol) afforded Example 404 (1.9 mg, 15% yield).
MS(ESI) m/z: 439.15 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.90 (s, 1H), 10.88 (s, 1H), 9.59 (s, 1H),
8.42 (d, J=7.6 Hz, 1H), 8.13 (d, J=7.9 Hz, 2H), 7.98 (t, J=7.6 Hz,
2H), 7.83 (d, J=7.3 Hz, 1H), 7.73-7.64 (m, 4H), 7.61 (d, J=7.0 Hz,
1H), 7.19 (d, J=8.2 Hz, 1H), 3.95 (s, 3H); HPLC RT=1.66 min (Method
E), 1.66 min (Method F).
Example 405:
1-(2-Methoxyphenyl)-5-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)pheny-
l)-1H-1,2,3-triazole-4-carboxamide
##STR00774##
[1340] Example 405A: Ethyl
1-(2-methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate
##STR00775##
[1342] To the solution of 2-methoxyaniline (0.30 g, 2.44 mmol) in
acetonitrile (3 mL) at 0.degree. C. was added isoamyl nitrite
(0.360 mL, 2.68 mmol), followed by azidotrimethylsilane (0.352 mL,
2.68 mmol) dropwise. After 5 min, the cold bath removed, and the
reaction mixture was stirred at rt for 10 min, then ethyl
but-2-ynoate (0.546 g, 4.87 mmol) added, and the reaction mixture
was stirred in a sealed tube at 80.degree. C. for 20 h, then cooled
to rt. The reaction mixture was concentrated and the residue was
purified by flash chromatography (0-40% EtOAc/Hexanes) to afford
1st peak at 30% EtOAc and 2nd peak at 35% EtOAc.
[1343] 1st Peak:
[1344] Ethyl
1-(2-methoxyphenyl)-4-methyl-1H-1,2,3-triazole-5-carboxylate (55
mg, 8.6% yield) yellow solid. MS(ESI) m/z: 262.2 (M+H).sup.+;
.sup.1H NMR (400 MHz, chloroform-d) .delta. 7.47 (ddd, J=8.3, 7.6,
1.8 Hz, 1H), 7.40 (dd, J=7.7, 1.8 Hz, 1H), 7.08 (td, J=7.6, 1.2 Hz,
1H), 7.01 (dd, J=8.4, 1.1 Hz, 1H), 4.21 (q, J=7.3 Hz, 2H), 3.74 (s,
3H), 2.62 (s, 3H), 1.16 (t, J=7.2 Hz, 3H).
[1345] 2nd Peak:
[1346] Example 405A (0.177 g, 28% yield) yellow solid. MS(ESI) m/z:
262.2 (M+H).sup.+; .sup.1H NMR .delta. 7.57-7.50 (m, 1H), 7.36 (dd,
J=7.8, 1.7 Hz, 1H), 7.16-7.07 (m, 2H), 4.46 (q, J=7.0 Hz, 2H), 3.80
(s, 3H), 2.42 (s, 3H), 1.45 (t, J=7.2 Hz, 3H).
Example 405B:
1-(2-Methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic
acid
##STR00776##
[1348] Example 405A (177 mg, 0.677 mmol) stirred with 1M LiOH in
THF (2 mL) at rt for 3 h. The reaction mixture was acidified with
TFA, then was concentrated. The residue was purified via
preparative HPLC to afford Example 405B. MS(ESI) m/z: 234.1
(M+H).sup.+; .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta.
7.64-7.57 (m, 1H), 7.40 (dd, J=7.7, 1.5 Hz, 1H), 7.31-7.25 (m, 1H),
7.16 (td, J=7.6, 1.1 Hz, 1H), 3.83 (s, 3H), 2.38 (s, 3H).
Example 405
##STR00777##
[1350] Intermediate 12 (12 mg, 0.051 mmol), Example 405B (13 mg,
0.056 mmol), HATU (21 mg, 0.056 mmol) were mixed in DMF (1.5 mL),
add DIEA (0.044 mL, 0.253 mmol), stirred 45.degree. C. for 4 h. The
reaction mixture was purified by preparative HPLC to afford Example
405 (7.1 mg, 31% yield). MS(ESI) m/z: 453.2 (M+H).sup.+; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 10.68 (s, 1H), 8.35 (d, J=7.4
Hz, 1H), 8.03 (d, J=8.4 Hz, 2H), 7.95-7.91 (m, 2H), 7.77 (d, J=8.1
Hz, 1H), 7.66 (t, J=7.6 Hz, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.50 (d,
J=7.4 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.21 (t, J=7.6 Hz, 1H), 3.82
(s, 3H), 2.39 (s, 3H); HPLC RT=1.67 min (Method E), 1.58 min
(Method F).
Example 406:
1-(2-Methoxyphenyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-1,2-
,3-triazole-4-carboxamide
##STR00778##
[1352] According to the procedure for the preparation of Example
404, substituting 2-methoxyaniline for 3-methoxyaniline afforded
Example 406. MS(ESI) m/z: 439.2 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.87 (s, 1H), 10.77 (s, 1H), 9.04 (s, 1H),
8.35 (d, J=7.4 Hz, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.95-7.90 (m, 2H),
7.76 (d, J=7.7 Hz, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.64-7.56 (m, 3H),
7.36 (d, J=8.4 Hz, 1H), 7.19 (t, J=7.7 Hz, 1H), 3.88 (s, 3H); HPLC
RT=1.51 min (Method E), 1.51 min (Method F).
Example 407:
3-Cyclopropyl-1-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H--
pyrazole-5-carboxamide
##STR00779##
[1354] Intermediate 12, 2 TFA (30 mg, 0.064 mmol) was dissolved in
dry DMF (1 mL), then
3-cyclopropyl-1-methyl-1H-pyrazole-5-carboxylic acid (21.4 mg,
0.129 mmol) and DIEA (0.068 mL, 0.387 mmol) were added. After
stirring for 5 min at rt, HATU (37 mg, 0.097 mmol) was added, and
the reaction mixture was stirred at 60.degree. C. for 3 h. The
reaction mixture was quenched with MeOH (0.1 mL), diluted with DMF,
filtered and purified by preparative HPLC to afford Example 407
(21.7 mg, 87% yield). MS(ESI) m/z: 386.2 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 12.85 (s, 1H), 10.33 (s, 1H), 8.34
(d, J=7.1 Hz, 1H), 7.97-7.83 (m, 4H), 7.73 (d, J=7.7 Hz, 1H), 7.58
(d, J=8.4 Hz, 2H), 6.78 (s, 1H), 3.99 (s, 3H), 1.97-1.83 (m, 1H),
0.96-0.82 (m, 2H), 0.67 (d, J=3.7 Hz, 2H); HPLC RT=1.47 min (Method
E), 1.48 min (Method F).
Example 408:
1-Methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-3-(trifluoromethy-
l)-1H-pyrazole-5-carboxamide
##STR00780##
[1356] Intermediate 12, 2 TFA (30 mg, 0.064 mmol) was dissolved in
dry DMF (1 mL), then
1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (25.0
mg, 0.129 mmol) and DIEA (0.068 mL, 0.387 mmol) were added. After
stirring for 5 min at rt, HATU (36.8 mg, 0.097 mmol) was added, and
the reaction mixture was stirred at 60.degree. C. for 3 h. The
reaction mixture was quenched with MeOH (0.1 mL), diluted with DMF,
filtered and purified by preparative HPLC to afford Example 408
(19.6 mg, 73% yield). MS(ESI) m/z: 414.2 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 12.86 (s, 1H), 10.64 (s, 1H), 8.34
(d, J=7.1 Hz, 1H), 7.98-7.84 (m, 4H), 7.73 (d, J=7.7 Hz, 1H), 7.61
(d, J=8.4 Hz, 2H), 7.54 (s, 1H), 4.18 (s, 3H); HPLC RT=1.68 min
(Method E), 1.68 min (Method F).
Example 409:
N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(2,2,2-trifluoroethyl)-1-
H-pyrazole-3-carboxamide
##STR00781##
[1358] Intermediate 12, 2 TFA (30 mg, 0.064 mmol) was dissolved in
dry DMF (1 mL), then
1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylic acid (25.0 mg,
0.129 mmol) and DIEA (0.068 mL, 0.387 mmol) were added. After
stirring for 5 min at rt, HATU (36.8 mg, 0.097 mmol) was added, and
the reaction mixture was stirred at 60.degree. C. for 3 h. The
reaction mixture was quenched with MeOH (0.1 mL), diluted with DMF,
filtered and purified by preparative HPLC to afford Example 409
(21.2 mg, 79% yield). MS(ESI) m/z: 414.1 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 12.82 (s, 1H), 10.32 (s, 1H), 8.34
(d, J=7.3 Hz, 1H), 8.03 (br. s., 1H), 7.98 (d, J=7.6 Hz, 2H), 7.90
(t, J=7.6 Hz, 2H), 7.75 (d, J=7.3 Hz, 1H), 7.57 (d, J=7.9 Hz, 2H),
6.95 (br. s., 1H), 5.28 (q, J=8.5 Hz, 2H); HPLC RT=1.46 min (Method
E), 1.47 min (Method F).
Example 410:
1-(Difluoromethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyra-
zole-3-carboxamide
##STR00782##
[1360] Intermediate 12, 2 TFA (30 mg, 0.064 mmol) was dissolved in
dry DMF (1 mL), then 1-(difluoromethyl)-1H-pyrazole-3-carboxylic
acid (20.9 mg, 0.129 mmol) and DIEA (0.068 mL, 0.387 mmol) were
added. After stirring for 5 min at rt, HATU (36.8 mg, 0.097 mmol)
was added, and the reaction mixture was stirred at 60.degree. C.
for 3 h. The reaction mixture was quenched with MeOH (0.1 mL),
diluted with DMF, filtered and purified by preparative HPLC to
afford Example 410 (16.6 mg, 67% yield). MS(ESI) m/z: 382.2
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.84 (s,
1H), 10.58 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.34 (d, J=7.1 Hz, 1H),
8.09-7.80 (m, 5H), 7.75 (d, J=7.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H),
7.06 (d, J=2.0 Hz, 1H); HPLC RT=1.34 min (Method E), 1.25 min
(Method F).
Example 411:
1-(2,2-Difluoroethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-p-
yrazole-5-carboxamide
##STR00783##
[1361] Example 411A: Methyl
1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxylate
Example 411B: Methyl
1-(2,2-difluoroethyl)-1H-pyrazole-5-carboxylate
##STR00784##
[1363] Methyl 1H-pyrazole-3-carboxylate (0.500 g, 3.96 mmol) was
dissolved in dry MeCN (30 mL), then 2,2-difluoroethyl
trifluoromethanesulfonate (0.633 mL, 4.76 mmol) was added, followed
by cesium carbonate (1.94 g, 5.95 mmol) and the reaction mixture
was stirred at 60.degree. C. for 2 h. The reaction mixture was
cooled to rt, diluted with EtOAc. Then CELITE.RTM. was added, and
solvent was removed under reduced pressure. The residue was
purified by flash chromatography (solid loading on CELITE.RTM.):
0-60% EtOAc/Hex affording two products.
Example 411A
[1364] (0.271 g, 1.425 mmol, 35.9% yield) as a colorless syrup:
peak 1 eluted at .about.25% EtOAc. MS(ESI) m/z: 190.9 (M+H).sup.+;
.sup.1H-NMR: (400 MHz, CDCl.sub.3) .delta. ppm 7.57 (d, J=2.0 Hz,
1H), 6.89 (d, J=2.0 Hz, 1H), 6.31-5.95 (m, 1H), 4.98 (td, J=13.1,
4.4 Hz, 2H), 3.91 (s, 3H); .sup.19F-NMR: (376 MHz, CDCl.sub.3)
.delta. ppm -122.87 (s, 2F).
Example 411B
[1365] (0.398 g, 2.093 mmol, 52.8% yield) as a colorless syrup:
peak 2 eluted at .about.45% EtOAc. MS(ESI) m/z: 190.9 (M+H).sup.+;
.sup.1H-NMR: (400 MHz, CDCl.sub.3) .delta. ppm 7.51 (d, J=2.4 Hz,
1H), 6.87 (d, J=2.4 Hz, 1H), 6.29-5.94 (m, 1H), 4.55 (td, J=13.4,
4.3 Hz, 2H), 3.94 (s, 3H); .sup.19F-NMR: (376 MHz, CDCl.sub.3)
.delta. ppm -122.42 (s, 2F).
Example 411C: 1-(2,2-Difluoroethyl)-1H-pyrazole-5-carboxylic
acid
##STR00785##
[1367] Example 411A (0.398 g, 2.093 mmol) was dissolved in THF (8.7
ml) and MeOH (1.7 ml), then LiOH (1 M in water) (6.28 ml, 6.28
mmol) was added. The reaction was heated to 50.degree. C. for 2 h.
The reaction mixture was quenched with TFA (0.484 ml, 6.28 mmol),
and concentrated under reduced pressure. The residue was diluted
with DMSO/MeOH/water, and was purified by preparative to afford
Example 411C (0.173 g, 46.9% yield) as a white solid. MS(ESI) m/z:
176.9 (M+H).sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
13.59 (br. s., 1H), 7.64 (d, J=2.0 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H),
6.60-6.12 (m, 1H), 4.98 (td, J=14.5, 4.0 Hz, 2H).
Example 411
##STR00786##
[1369] Intermediate 12, 2 TFA (30 mg, 0.064 mmol) was dissolved in
dry DMF (1 mL), then Example 411C (22.7 mg, 0.129 mmol) and DIEA
(0.068 mL, 0.387 mmol) were added. After stirring for 5 min at rt,
HATU (36.8 mg, 0.097 mmol) was added, and the reaction mixture was
stirred at 60.degree. C. for 3 h. The reaction mixture was quenched
with MeOH (0.1 mL), diluted with DMF, filtered and purified by
preparative HPLC to afford Example 411 (16.6 mg, 67% yield).
MS(ESI) m/z: 396.2 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 12.85 (s, 1H), 10.56 (s, 1H), 8.35 (d, J=7.1 Hz, 1H),
7.98-7.85 (m, 4H), 7.74 (d, J=8.1 Hz, 1H), 7.71 (d, J=1.7 Hz, 1H),
7.61 (d, J=8.4 Hz, 2H), 7.20 (d, J=1.7 Hz, 1H), 6.56-6.25 (m, 1H),
5.03 (td, J=14.6, 3.5 Hz, 2H); HPLC RT=1.38 min (Method E), 1.28
min (Method F).
Example 412:
1-(2,2-Difluoroethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-p-
yrazole-3-carboxamide
##STR00787##
[1370] Example 412A: 1-(2,2-Difluoroethyl)-1H-pyrazole-3-carboxylic
acid
##STR00788##
[1372] Example 411B (0.271 g, 1.43 mmol) was dissolved in THF (5.9
ml) and MeOH (1.2 ml), then LiOH (1 M in water) (4.28 ml, 4.28
mmol) was added. The reaction was heated to 50.degree. C. for 2 h.
The reaction mixture was quenched with TFA (0.329 ml, 4.28 mmol),
and concentrated under reduced pressure. The residue was diluted
with DMSO/MeOH/water, and was purified by preparative HPLC to
afford Example 412A (0.177 g, 71% yield) as a white solid. MS(ESI)
m/z: 176.9 (M+H).sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
12.76 (s, 1H), 7.88 (d, J=2.4 Hz, 1H), 6.75 (d, J=2.4 Hz, 1H),
6.59-6.19 (m, 1H), 4.72 (td, J=15.2, 3.7 Hz, 2H).
Example 412
##STR00789##
[1374] Intermediate 12, 2 TFA (30 mg, 0.064 mmol) was dissolved in
dry DMF (1 mL), then Example 412A (22.7 mg, 0.129 mmol) and DIEA
(0.068 mL, 0.387 mmol) were added. After stirring for 5 min at rt,
HATU (36.8 mg, 0.097 mmol) was added, and the reaction mixture was
stirred at 60.degree. C. for 3 h. The reaction mixture was quenched
with MeOH (0.1 mL), diluted with DMF, filtered and purified by
preparative HPLC to afford Example 412 (23.3 mg, 91% yield).
MS(ESI) m/z: 396.2 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 12.79 (s, 1H), 10.26 (s, 1H), 8.30 (d, J=7.1 Hz, 1H),
7.99-7.81 (m, 5H), 7.71 (d, J=7.7 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H),
6.86 (d, J=2.0 Hz, 1H), 6.58-6.30 (m, 1H), 4.74 (td, J=15.1, 3.2
Hz, 2H); HPLC RT=1.31 min (Method E), 1.31 min (Method F).
* * * * *