U.S. patent application number 12/826338 was filed with the patent office on 2011-12-29 for 2-pyridyl substituted imidazoles as therapeutic alk5 and/or alk4 inhibitors.
This patent application is currently assigned to EWHA University-Industry Collaboration Foundation. Invention is credited to Chenghua Jin, Dae-Kee Kim, Maddeboina Krishnaiah, Chul-Yong Park, Kota Sudhakar Rao, Yhun Yhong Sheen, Domalapally Sreenu, Vura Bala Subrahmanyam.
Application Number | 20110319406 12/826338 |
Document ID | / |
Family ID | 45219191 |
Filed Date | 2011-12-29 |
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United States Patent
Application |
20110319406 |
Kind Code |
A1 |
Kim; Dae-Kee ; et
al. |
December 29, 2011 |
2-PYRIDYL SUBSTITUTED IMIDAZOLES AS THERAPEUTIC ALK5 AND/OR ALK4
INHIBITORS
Abstract
This invention relates to 2-pyridyl substituted imidazoles which
are inhibitors of the transforming growth factor-.beta.
(TGF-.beta.) type I receptor (ALK5) and/or the activin type I
receptor (ALK4), methods for their preparation, and their use in
medicine, specifically in the treatment and prevention of a disease
state mediated by these receptors.
Inventors: |
Kim; Dae-Kee; (Seoul,
KR) ; Sheen; Yhun Yhong; (Seoul, KR) ; Jin;
Chenghua; (Seoul, KR) ; Park; Chul-Yong;
(Seoul, KR) ; Sreenu; Domalapally; (Seoul, KR)
; Rao; Kota Sudhakar; (Seoul, KR) ; Krishnaiah;
Maddeboina; (Seoul, KR) ; Subrahmanyam; Vura
Bala; (Seoul, KR) |
Assignee: |
EWHA University-Industry
Collaboration Foundation
Seoul
KR
|
Family ID: |
45219191 |
Appl. No.: |
12/826338 |
Filed: |
June 29, 2010 |
Current U.S.
Class: |
514/233.2 ;
514/303; 544/127; 546/119 |
Current CPC
Class: |
A61P 9/12 20180101; A61P
21/00 20180101; A61P 43/00 20180101; A61P 1/18 20180101; A61P 35/02
20180101; A61P 35/04 20180101; A61P 13/08 20180101; A61P 3/10
20180101; A61P 15/00 20180101; A61P 25/00 20180101; A61P 11/00
20180101; C07D 471/04 20130101; A61P 27/02 20180101; A61P 27/06
20180101; A61P 1/04 20180101; A61P 13/12 20180101; A61P 31/18
20180101; A61P 25/28 20180101; A61P 7/02 20180101; A61P 17/00
20180101; A61P 17/02 20180101; A61P 35/00 20180101; A61P 19/02
20180101; A61P 9/10 20180101; A61P 1/16 20180101; A61P 9/04
20180101; A61P 9/00 20180101; A61P 19/10 20180101; A61P 15/10
20180101; A61P 9/08 20180101 |
Class at
Publication: |
514/233.2 ;
546/119; 544/127; 514/303 |
International
Class: |
A61K 31/444 20060101
A61K031/444; A61P 11/00 20060101 A61P011/00; A61P 35/04 20060101
A61P035/04; A61P 25/00 20060101 A61P025/00; C07D 471/04 20060101
C07D471/04; A61K 31/5377 20060101 A61K031/5377 |
Goverment Interests
[0001] This work was supported by National Research Foundation
grant funded by the Korean government (M10870050001-08N7005-00110).
Claims
1. A compound of the formula (I): ##STR00166## wherein: each
R.sup.a is independently H, halo, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.3-6cycloalkyl, OH, --O--C.sub.1-6alkyl,
--O--C.sub.1-6haloalkyl, --O--C.sub.3-6cycloalkyl, NH.sub.2,
--NH--C.sub.1-6alkyl, --NH--C.sub.1-6haloalkyl,
--NH--C.sub.3-6cycloalkyl, --S--C.sub.1-6alkyl,
--S--C.sub.1-6haloalkyl, --S--C.sub.3-6cycloalkyl, CN, or NO.sub.2;
m is 0, 1, 2, 3, or 4; one of A.sup.1 and A.sup.2 is N and the
other is NR.sup.1, wherein R.sup.1 is H, OH, C.sub.1-6alkyl,
C.sub.1-6 haloalkyl, or C.sub.3-6cycloalkyl; X is --NR.sup.2--,
--O--, or --S--, and R.sup.2 is H or C.sub.1-3alkyl; each R.sup.b
is independently H, halo, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-6cycloalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
--(CH.sub.2).sub.q--OR.sup.3, --(CH.sub.2).sub.q--NR.sup.3R.sup.4,
--(CH.sub.2).sub.q--SR.sup.3, --(CH.sub.2).sub.q--NO.sub.2,
--(CH.sub.2).sub.q--CONHOH, --(CH.sub.2).sub.q--CN,
--(CH.sub.2).sub.q--COR.sup.3, --(CH.sub.2).sub.q--CO.sub.2R.sup.3,
--(CH.sub.2).sub.q--CONR.sup.3R.sup.4,
--(CH.sub.2).sub.q-tetrazole, --(CH.sub.2).sub.q--CH.dbd.CH--CN,
--(CH.sub.2).sub.q--CH.dbd.CH--CO.sub.2R.sup.3,
--(CH.sub.2).sub.q--CH.dbd.CH--CONR.sup.3R.sup.4,
--(CH.sub.2).sub.q--CH.dbd.CH-tetrazole,
--(CH.sub.2).sub.q--NHCOR.sup.3,
--(CH.sub.2).sub.q--NHCO.sub.2R.sup.3,
--(CH.sub.2).sub.q--CONHSO.sub.2R.sup.3,
--(CH.sub.2).sub.q--NHSO.sub.2R.sup.3,
--(CH.sub.2).sub.q--C.ident.C--CN,
--(CH.sub.2).sub.q--C.ident.C--CO.sub.2R.sup.3,
--(CH.sub.2).sub.q--C.ident.C--CONR.sup.3R.sup.4,
--(CH.sub.2).sub.q--C.ident.C-tetrazole,
(CH.sub.2).sub.q--SOR.sup.5, --(CH.sub.2).sub.q--SO.sub.2R.sup.5,
or --(CH.sub.2).sub.r--(OR.sup.3).sub.2, wherein R.sup.3 and
R.sup.4 are independently H, C.sub.1-6alkyl, C.sub.1-6haloalkyl, or
C.sub.3-6cycloalkyl; or taken together with the nitrogen atom to
which they are attached form a mono-cyclic ring such as imidazole,
pyrrolidine, piperidine, morpholine, piperazine and homopiperazine;
R.sup.5 is C.sub.1-6alkyl, C.sub.1-6haloalkyl, or
C.sub.3-6cycloalkyl; q is 0, 1, 2, 3, or 4; and r is 1, 2, 3, or 4;
n is 0, 1, 2, 3, 4, or 5; or a pharmaceutically acceptable salt
thereof.
2. The compound of claim 1, which is selected from the group
consisting of:
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1-
H-imidazol-2-yl)methyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-fluoro aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-4-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2,3-difluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3,4-difluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3,5-difluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-chloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-chloro aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-4-chloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2,3-dichloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3,4-dichloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3,5-dichloroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-bromoaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-bromoaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-4-bromoaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-methylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-methylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-4-methylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2,3-dimethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3,4-dimethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3,5-dimethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-ethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-ethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-isopropylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-isopropylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-4-isopropylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-vinylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-vinylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-4-vinylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-ethynylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-methoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-methoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-4-methoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2,3-dimethoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3,4-dimethoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3,5-dimethoxyaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-(methoxymethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-(methoxymethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-4-(methoxymethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-(trifluoromethoxy)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-(trifluoromethoxy)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-4-(trifluoromethoxy)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-(methylthio)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-(methylthio)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-4-(methylthio)aniline;
2-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)benzonitrile;
4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)phthalonitrile;
2-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-n yl)methylamino)benzamide;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)benzamide;
4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)benzamide;
2-(3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-
-imidazol-2-yl)methylamino)phenyl)acetonitrile;
2-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-
-imidazol-2-yl)methylamino)phenyl)acetonitrile;
1-(3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-
-imidazol-2-yl)methylamino)phenyl)ethanone;
1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-
-imidazol-2-yl)methylamino)phenyl)ethanone; Methyl
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)benzoate; Methyl
4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)benzoate;
N-(2-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-
-imidazol-2-yl)methylamino)phenyl)acetamide;
N-(3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-
-imidazol-2-yl)methylamino)phenyl)acetamide;
N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-
-imidazol-2-yl)methylamino)phenyl)acetamide;
N-(2-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-
-imidazol-2-yl)methylamino)phenyl)methanesulfonamide;
N-(3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-
-imidazol-2-yl)methylamino)phenyl)methanesulfonamide;
N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-
-imidazol-2-yl)methylamino)phenyl)methanesulfonamide;
N.sup.1-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-
-1H-imidazol-2-yl)methyl)-N.sup.2,N.sup.2-dimethylbenzene-1,2-diamine;
N.sup.1-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-
-1H-imidazol-2-yl)methyl)-N.sup.3,N.sup.3-dimethylbenzene-1,3-diamine;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-(pyrrolidin-1-yl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-morpholinoaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-morpholinoaniline;
N.sup.3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-
-1H-imidazol-2-yl)methyl)-4-fluoro-N.sup.1,N.sup.1-dimethylbenzene-1,3-dia-
mine;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)--
1H-imidazol-2-yl)methylamino)-5-(dimethylamino)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-4-(dimethylamino)benzonitrile;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-((dimethylamino)methyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-((dimethylamino)methyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-(pyrrolidin-1-ylmethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-(pyrrolidin-1-ylmethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-(morpholinomethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-(morpholinomethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-5-((dimethylamino)methyl)-2-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-((dimethylamino)methyl)-2-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-fluoro-3-(pyrrolidin-1-ylmethyl)aniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-fluoro-3-(morpholinomethyl)aniline;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-4-((dimethylamino)methyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-2-((dimethylamino)methyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-5-((dimethylamino)methyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-4-(pyrrolidin-1-ylmethyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-2-(pyrrolidin-1-ylmethyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-5-(pyrrolidin-1-ylmethyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-4-(morpholinomethyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-2-(morpholinomethyl)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-5-(morpholinomethyl)benzonitrile;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-(2-(dimethylamino)ethylaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-(2-(dimethylamino)ethylaniline;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-ethylpyridin-2-yl)-1H-imi-
dazol-2-yl)methylamino)benzonitrile;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-ethylpyridin-2-yl)-1H-imi-
dazol-2-yl)methyl)-2-fluoroaniline;
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-fluoro-N-methylaniline;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)(methyl)amino)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-n yl)methyl)(methyl)amino)benzamide;
6-(2-benzyl-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-[1,2,4]triazolo[1,-
5-a]pyridine;
6-(2-(2-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-[1,2,4]t-
riazolo[1,5-a]pyridine;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)benzonitrile;
6-(5-(6-methylpyridin-2-yl)-2-(phenoxymethyl)-1H-imidazol-4-yl)-[1,2,4]tr-
iazolo[1,5-a]pyridine;
6-(2-((2-fluorophenoxy)methyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-
-[1,2,4]triazolo[1,5-a]pyridine;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methoxy)benzonitrile;
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methoxy)benzamide;
6-(5-(6-methylpyridin-2-yl)-2-(phenylthiomethyl)-1H-imidazol-4-yl)-[1,2,4-
]triazolo[1,5-a]pyridine; and
6-(2-((2-fluorophenylthio)methyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4--
yl)-[1,2,4]triazolo[1,5-a]pyridine, or a pharmaceutically
acceptable salt thereof.
3. A pharmaceutical composition comprising one or more compounds of
claim 1, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable diluent or carrier.
4-7. (canceled)
Description
TECHNICAL FIELD OF THE INVENTION
[0002] This invention relates to 2-pyridyl substituted imidazoles
which are inhibitors of the transforming growth factor-.beta.
(TGF-.beta.) type I receptor (ALK5) and/or the activin type I
receptor (ALK4), methods for their preparation, and their use in
medicine, specifically in the treatment and prevention of a disease
state mediated by these receptors.
BACKGROUND OF THE INVENTION
[0003] TGF-.beta. denotes a family of proteins, TGF-.beta.1,
TGF-.beta.2 and TGF-.beta.3, which are pleiotropic modulators of
cell proliferation and differentiation, wound healing,
extracellular matrix production and immunosuppression. Other
members of this superfamily include activins, inhibins, bone
morphogenetic proteins, growth and differentiation factors and
Mullerian inhibiting substance.
[0004] TGF-.beta.1 transduces signals through two highly conserved
single transmembrane serine/threonine kinases, the type I (ALK5)
and type II TGF-.beta. receptors. Upon ligand induced
oligomerization, the type II receptor hyperphosphorylates
serine/threonine residues in the GS region of the ALK5, which leads
to activation of the ALK5 by creating a binding site for Smad
proteins. The activated ALK5 in turn phosphorylates Smad2 and Smad3
proteins at the C-terminal SSXS-motif thereby causing their
dissociation from the receptor and heteromeric complex formation
with Smad4. Smad complexes translocate to the nucleus, assemble
with specific DNA-binding co-factors and co-modulators to finally
activate transcription of extracellular matrix components and
inhibitors of matrix-degrading proteases.
[0005] Activins transduce signals in a manner similar to
TGF-.beta.. Activins bind to serine/thereonine kinase, the activin
type II receptor (ActRIIB), and the activated type II receptor
hyperphosphorylates serine/threonine residues in the GS region of
the ALK4. The activated ALK4 in turn phosphorylates Smad2 and
Smad3. The consequent formation of a hetero-Smad complex with Smad4
results in the activin-induced regulation of gene
transcription.
[0006] Numerous experimental animal studies demonstrate an
association between glomerular expression of TGF-.beta. and
fibrosis, including the Thy-1 rat model of proliferative
glomerulonephritis, anti-GBM glomerulonephritis in rabbits, and the
5/6 nephrectomy rat model of focal segmental glomerulosclerosis, as
has been reviewed recently (e.g., Bitzer, M. et al., Kidney Blood
Press. Res. 21: 1-12 (1998)). Neutralizing antibody to TGF-.beta.
improves glomerular histology in the Thy-1 nephritis model (e.g.,
Border, W. A. et al., Nature 346: 371-374 (1990)).
[0007] Hyperglycemic conditions increase TGF-.beta. mRNA and
protein synthesis in both murine proximal tubule cells and human
mesangial cells (e.g., Wahab, N. A. et al., Biochem. 1 316: 985-992
(1996); Rocco, M. V. et al., Kidney Int. 41: 107-114 (1992)).
Diabetic patients with early kidney disease show increased
accumulation of TGF-.beta. mRNA and protein within the glomerulus
(e.g., Yoshioka, K. et al., Lab. Invest. 68: 154-163 (1993)). In
kidneys with chronic renal interstitial fibrosis, the hallmarks are
thickened tubular basement membranes and an expanded interstitial
compartment, with interstitial fibrosis characterized by an
increase in collagens I, III, V, VII, and fibronectin (e.g., Eddy,
A. A., J. Am. Soc. Nephrol. 7: 2495-2508 (1996)).
[0008] TGF-.beta. gene expression and protein production are
increased in a variety of animal models of pulmonary fibrosis
including bleomycin, silica, asbestos, and radiation (e.g., Phan,
S. H. and Kunkel, S. L., Exp. Lung Res. 18: 29-43 (1992); Williams,
A. O. et al., Am. J. Pathol. 142: 1831-1840 (1993); Rube, C. E. et
al., Int. J. Radiat. Oncol. Biol. Phys. 47: 1033-1042 (2000)).
Coincident increase in TGF-.beta.1 protein and collagen gene
expression in adjacent tissue slices from idiopathic pulmonary
fibrosis is observed in human pulmonary fibrotic disease (e.g.,
Broekelmann, T. J. et al., Proc. Natl. Acad. Sci. USA 88: 6642-6646
(1991)). Increased TGF-.beta. production has been documented in
patients with sarcoidosis, pneumoconiosis, asbestosis, and
radiation-induced fibrosis (e.g., Khalil, N. et al., Am. J. Respir.
Cell. Mol. Biol. 14: 131-138 (1996); Jagirdar, J. et al., Environ.
Health Perspect. 105: 1197-1203 (1997)). Anti-TGF-.beta. antibodies
and TGF-.beta.-soluble receptors could partially inhibit fibrosis
in bleomycin-induced lung fibrosis rodent models (e.g., Giri, S. N.
et al., Thorax 48: 959-966 (1993); Wang, Q. et al., Thorax 54:
805-812 (1999)). Tobacco smoke has been implicated as one of the
most important factors that can cause small airway disease followed
by chronic obstructive pulmonary disease (COPD) (e.g., Wright, J.
M. et al., Am. Rev. Respir. Dis. 146: 240-262 (1992)). COPD is a
slowly progressive and irreversible disorder characterized by the
functional abnormality of airway obstruction. TGF-.beta. has been
hypothesized to be involved in airway remodeling found in chronic
airway inflammatory disorders such as COPD (e.g., Takizawa, H. Int.
J. Mol. Med. 1: 367-378 (1998); Ning, W. et al., Proc. Natl. Acad.
Sci. USA 101: 14895-14900 (2004)).
[0009] Hepatic stellate cells (HSC) are the major source of
extracellular matrix proteins in hepatic fibrosis. Extracellular
matrix production by activated hepatic stellate cells is markedly
increased through the action of TGF-.beta.1 (e.g., Friedman, S. L.,
Prog. Liver Dis. 14: 101-130 (1996); Pietrangelo, A., Semin. Liver
Dis. 16: 13-30 (1996)). Transgenic mice that overexpress
TGF-.beta.1 in the liver develop hepatic fibrosis as well as
extrahepatic pathologies such as renal fibrosis (e.g., Sanderson,
N. et al., Proc. Natl. Acad. Sci. USA 92: 2572-2576 (1995)).
[0010] TGF-.beta.1 and its receptors are overexpressed in injured
blood vessels and in fibroproliferative vascular lesions leading to
overproduction of extracellular matrix (e.g., Saltis, J. et al.,
Clin. Exp. Pharmacol. Physiol. 23: 193-200 (1996); McCaffrey, T. A.
et al., J. Clin. Invest. 96: 2667-2675 (1995)).
[0011] Anti-TGF-.beta. antibodies reduce scar formation and improve
the cytoarchitecture of the neodermis in rats (e.g., Shah, M., J.
Cell. Sci. 108: 985-1002 (1995)), improve healing of corneal wounds
in rabbits (e.g., Moller-Pedersen, T., Curr. Eye Res. 17: 736-747
(1998)), and accelerate wound healing of gastric ulcers in rats
(e.g., Ernst, H., Gut 39: 172-175 (1996)).
[0012] Radiation fibrosis is a frequent sequel of therapeutic or
accidental radiation overexposure in normal human tissues.
TGF-.beta.1 plays a central role in the initiation, development,
and persistence of radiation fibrosis, as has been reviewed
recently (e.g., Martin, M. et al., Int. J. Radiat. Oncol. Biol.
Phys. 47: 277-290 (2000)).
[0013] Organ transplantation is complicated in many instances by
chronic rejection and for some organs such as the kidney, it is the
major forms of graft loss. In human patients, chronic rejection of
lung and kidney transplants is associated with increased expression
of TGF-.beta. within the tissue (e.g., El-Gamel, A. et al., Eur J.
Cardiothorac. Surg. 13: 424-430 (1998); Shihab, F. S. et al., J.
Am. Soc. Nephrol. 6: 286-294 (1995)).
[0014] TGF-.beta. is implicated in peritoneal adhesions (e.g.,
Saed, G M. et al., Wound Repair Regeneration 7: 504-510 (1999)).
The peritoneal and sub-dermal fibrotic adhesions could be prevented
by inhibitors of ALK5 and/or ALK4.
[0015] The tumor cells and the stromal cells within the tumors in
late stages of various cancers generally overexpress TGF-.beta..
This leads to stimulation of angiogenesis and cell motility,
suppression of the immune system, and increased interaction of
tumor cells with the extracellular matrix (e.g., Hojo, M. et al.,
Nature 397: 530-534 (1999)). Consequently, the tumor cells become
more invasive and metastasize to distant organs (e.g., Maehara, Y.
et al., J. Clin. Oncol. 17: 607-614 (1999); Picon, A. et al.,
Cancer Epidemiol. Biomarkers Prev. 7: 497-504 (1998)).
[0016] Plasminogen activator inhibitor-1 (PAI-1) is the major
physiological inhibitor of both tissue-type plasminogen activator
and urokinase-type plasminogen activator. Elevated levels of PAI-1
are associated with thrombosis and vascular disease, suggesting
that high plasma PAI-1 may promote a hypercoagulable state by
disrupting the natural balance between fibrinolysis and coagulation
(e.g., Vaughan, D. E., J. Invest. Med. 46: 370-376 (1998)). It is
known that TGF-.beta. stimulates the expression of PAI-1 (e.g.,
Dennler, S. et al., EMBO J. 17: 3091-3100 (1998)). Accordingly,
inhibition of the production of PAI-1 with an inhibitor of the
TGF-.beta. signaling pathway could produce a novel fibrinolytic
therapy.
[0017] Activin signaling and overexpression of activin is linked to
pathological disorders that involve extracellular matrix
accumulation and fibrosis (e.g., Matsuse, T. et al., Am. J. Respir.
Cell Mol. Biol. 13: 17-24 (1995); Inoue, S. et al., Biochem.
Biophys. Res. Comm. 205: 441-448 (1994); Matsuse, T. et al., Am. J.
Pathol. 148: 707-713 (1996); De Bleser et al., Hepatology 26:
905-912 (1997); Pawlowski, J. E., et al., J. Clin. Invest. 100:
639-648 (1997); Sugiyama, M. et al., Gastroenterology 114: 550-558
(1998); Munz, B. et al., EMBO J. 18: 5205-5215 (1999)),
inflammatory responses (e.g., Rosendahl, A. et al., Am. J. Respir.
Cell Mol. Biol. 25: 60-68 (2001), cachexia or wasting (Matzuk, M.
M. et al., Proc. Natl. Acd. Sci. USA 91: 8817-8821 (1994); Coerver,
K. A. et al., Mol. Endocrinol. 10: 534-543 (1996); Cipriano, S. C.
et al., Endocrinology 141: 2319-2327 (2000)), diseases or
pathological responses in the central nervous system (e.g., Logan,
A. et al., Eur. J. Neurosci. 11: 2367-2374 (1999); Logan, A. et
al., Exp. Neurol. 159: 504-510 (1999); Masliah, E. et al.,
Neurochem. Int. 39: 393-400 (2001); De Groot, C. J. A. et al., J.
Neuropathol. Exp. Neurol. 58: 174-187 (1999); John, G R. et al.,
Nat. Med. 8: 1115-1121 (2002)) and hypertension (e.g., Dahly, A. J.
et al., Am. J. Physiol. Regul. Integr. Comp. Physiol. 283: R757-767
(2002)). Studies have shown that TGF-.beta. and activin can act
synergistically to induce extracellular matrix production (e.g.,
Sugiyama, M. et al., Gastroenterology 114; 550-558 (1998)).
[0018] Therefore, it becomes evident that inhibition of ALK5 and/or
ALK4 phosphorylation of Smad2 and Smad3 by the preferred compounds
of this invention could treat and prevent disorders involving these
signaling pathways.
[0019] WO 00/61576 and US 2003/0149277 A1 disclose triarylimidazole
derivatives and their use as ALK5 inhibitors. WO 01/62756 A1
discloses pyridinylimidazole derivatives and their use as ALK5
inhibitors. WO 02/055077 A1 discloses use of imidazolyl cyclic
acetal derivatives as ALK5 inhibitors. WO 03/087304 A2 discloses
tri-substituted heteroaryls and their use as ALK5 and/or ALK4
inhibitors. WO 2005/103028 A1 and U.S. Pat. No. 7,407,958 B2
disclose 2-pyridyl substituted imidazoles as ALK5 and/or ALK4
inhibitors. Especially, one of the representative compounds claimed
in WO 2005/103028 A1 and U.S. Pat. No. 7,407,958 B2, IN-1130,
demonstrated its use in several animal models as ALK5 and/or ALK4
inhibitors. IN-1130 effectively suppressed renal fibrosis induced
by unilateral ureteral obstruction (UUO) in rats (Moon, J.-A. et
al., Kidney Int. 70: 1234-1243 (2006)), ameliorated experimental
autoimmune encephalomyelitis (EAE) in SBE-luc and GFAP-luc mice
immunized with MOG.sub.35-55 (Luo, J. et al., J. Clin. Invest. 117:
3306-3315 (2007)), lessened tunical fibrosis and corrected penile
curvature in rats (Ryu, J.-K. et al., J. Sex. Med. 6: 1284-1296
(2009)), and dramatically reduced tumor volume with an enhanced
immune response in mice treated with murine prostate cancer cell
line Tramp C2 (Lee, G. T. et al., J. Urol. 180: 2660-2667 (2008)).
And, also, US 2008/0319012 A1 discloses 2-pyridyl substituted
imidazoles as ALK5 and/or ALK4 inhibitors. Especially, one of the
representative compounds claimed in US 2008/0319012 A1, IN-1233,
demonstrated its use in several animal models as ALK5 and/or ALK4
inhibitors. IN-1233 effectively prevented the development and
progression of pulmonary arterial hypertension in the monocrotaline
rat model through the inhibition of TGF-.beta. signaling (Long, L.
et al., Circulation 119: 566-576 (2009)) and also prevented
granulation tissue formation after bare metallic stent placement in
a rat urethral model (Kim, J. H. et al., Radiology 255: 75-82
(2010)).
SUMMARY
[0020] Surprisingly, it has now been discovered that a class of
2-pyridyl substituted imidazoles function as potent and selective
inhibitors of ALK5 and/or ALK4 and, therefore, have utility in the
treatment and prevention of various disease states mediated by ALK5
and/or ALK4, such as glomerulonephritis, diabetic nephropathy,
lupus nephritis, hypertension-induced nephropathy, renal
interstitial fibrosis, renal fibrosis resulting from complications
of drug exposure, HIV-associated nephropathy, transplant
nephropathy, liver fibrosis due to all etiologies, hepatic
dysfunction attributable to infections, alcohol-induced hepatitis,
disorders of the biliary tree, pulmonary fibrosis, acute lung
injury, adult respiratory distress syndrome, idiopathic pulmonary
fibrosis, chronic obstructive pulmonary disease, pulmonary disease
due to infectious or toxic agents, post-infarction cardiac
fibrosis, congestive heart failure, dilated cardiomyopathy,
myocarditis, vascular stenosis, hypertension-induced vascular
remodeling, pulmonary arterial hypertension, coronary restenosis,
peripheral restenosis, carotid restenosis, stent-induced
restenosis, atherosclerosis, ocular scarring, corneal scarring,
proliferative vitreoretinopathy, excessive or hypertrophic scar or
keloid formation in the dermis occurring during wound healing
resulting from trauma or surgical wounds, peritoneal and sub-dermal
adhesion, scleroderma, fibrosclerosis, progressive systemic
sclerosis, dermatomyositis, polymyositis, arthritis, osteoporosis,
ulcers, impaired neurological function, male erectile dysfunction,
Peyronie's disease, Dupuytren's contracture, Alzheimer's disease,
Raynaud's syndrome, fibrotic cancers, tumor metastasis growth,
radiation-induced fibrosis, and thrombosis.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] The aforementioned aspects and other features of the present
invention will be explained in the following description, taken in
conjunction with the accompanying drawings, wherein:
[0022] FIG. 1 shows effect of Examples 2, 60, 86, 92, and 94 on the
TGF-.beta.1-induced 3TP-Luc reporter activity in HaCaT-3TP-Luc
cells,
[0023] FIG. 2 shows effect of Examples 2, 60, 86, 92, and 94 on the
TGF-.beta.1-induced 3TP-Luc reporter activity in 4T1-3TP-Luc
cells,
[0024] FIGS. 3A, 3B, 3C, and 3D show effect of Example 60 on the
breast tumor metastasis to the lung in MMTV/c-Neu mice in vivo.
Tumor-bearing MMTV/c-Neu mice were treated intraperitoneally with
either saline (vehicle) or Example 60 (40 mg/kg) every other day
for 3 weeks. (3A). Hematoxylin and eosin (H & E) staining of
mammary tumor and lung tissues. (3B). Number of histologically
detectable metastastic lesions in the lung. Data represents the
mean.+-.SD (n=2 per groups). (3C). Volume of mammary tumor. (3D).
.beta.-Casein mRNA level,
[0025] FIGS. 4A and 4B show effect of Example 60 on the breast
tumor metastasis to the lung in the Balb/c xenograft mice in vivo.
Tumor-bearing Balb/c xenograft mice were treated intraperitoneally
with either saline (vehicle) or Example 60 (40 mg/kg) every other
day for 2.5 weeks. (4A). Number of metastastic nodules on lung
surface (white arrows, left panel). (4B). Volume of primary
tumor.
[0026] Table 1 shows structures and .sup.1H NMR and MS spectral
data of Examples 1-139, and
[0027] Table 2 shows structures and .sup.1H NMR and MS spectral
data of Examples 140-153.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0028] In an embodiment of the present invention, there is provided
a compound of formula (I) or a pharmaceutically acceptable salt
thereof:
##STR00001##
[0029] wherein each R.sup.a is independently H, halo,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.3-6cycloalkyl, OH,
--O--C.sub.1-6alkyl, --O--C.sub.1-6haloalkyl,
--O--C.sub.3-6cycloalkyl, NH.sub.2, --NH--C.sub.1-6alkyl,
--NH--C.sub.1-6haloalkyl, --NH--C.sub.3-6cycloalkyl,
--S--C.sub.1-6alkyl, --S--C.sub.1-6haloalkyl,
--S--C.sub.3-6cycloalkyl, CN, or NO.sub.2;
[0030] m is 0, 1, 2, 3, or 4;
[0031] one of A.sup.1 and A.sup.2 is N and the other is NR.sup.1,
wherein R.sup.1 is H, OH, C.sub.1-6alkyl, C.sub.1-6haloalkyl, or
C.sub.3-6cycloalkyl;
[0032] X is a bond, --(CH.sub.2).sub.p--, --NR.sup.2--, --O--, or
--S--, wherein p is 0 or 1, and R.sup.2 is H or C.sub.1-3alkyl;
[0033] each R.sup.b is independently H, halo, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.3-6cycloalkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, --(CH.sub.2).sub.q--OR.sup.3,
--(CH.sub.2).sub.q--NR.sup.3R.sup.4, --(CH.sub.2).sub.q--SR.sup.3,
--(CH.sub.2).sub.q--NO.sub.2, --(CH.sub.2).sub.q--CONHOH,
--(CH.sub.2).sub.q--CN, --(CH.sub.2).sub.q--COR.sup.3,
--(CH.sub.2).sub.q--CO.sub.2R.sup.3,
--(CH.sub.2).sub.q--CONR.sup.3R.sup.4,
--(CH.sub.2).sub.q-tetrazole, --(CH.sub.2).sub.q--CH.dbd.CH--CN,
--(CH.sub.2).sub.q--CH.dbd.CH--CO.sub.2R.sup.3,
--(CH.sub.2).sub.q--CH.dbd.CH--CONR.sup.3R.sup.4,
--(CH.sub.2).sub.q--CH.dbd.CH-tetrazole,
--(CH.sub.2).sub.q--NHCOR.sup.3,
--(CH.sub.2).sub.q--NHCO.sub.2R.sup.3,
--(CH.sub.2).sub.q--CONHSO.sub.2R.sup.3,
--(CH.sub.2).sub.q--NHSO.sub.2R.sup.3,
--(CH.sub.2).sub.q--C.ident.C--CN,
--(CH.sub.2).sub.q--C.ident.C--CO.sub.2R.sup.3,
--(CH.sub.2).sub.q--C.ident.C--CONR.sup.3R.sup.4,
--(CH.sub.2).sub.q--C.ident.C-tetrazole,
--(CH.sub.2).sub.q--SOR.sup.5, --(CH.sub.2).sub.q--SO.sub.2R.sup.5,
or --(CH.sub.2).sub.r--(OR.sup.3).sub.2, wherein R.sup.3 and
R.sup.4 are independently H, C.sub.1-6alkyl, C.sub.1-6haloalkyl, or
C.sub.3-6cycloalkyl; or taken together with the nitrogen atom to
which they are attached form a mono-cyclic ring such as imidazole,
pyrrolidine, piperidine, morpholine, piperazine and homopiperazine;
R.sup.5 is C.sub.1-6alkyl, C.sub.1-6haloalkyl, or
C.sub.3-6cycloalkyl; q is 0, 1, 2, 3, or 4; and r is 1, 2, 3, or
4;
[0034] n is 0, 1, 2, 3, 4, or 5.
[0035] As used herein, the double bond indicated by the dotted
lines of formula (I), represent the possible tautomeric ring forms
of the compounds falling within the scope of this invention, the
double bond being to the unsubstituted nitrogen.
[0036] Preferably, R.sup.a is C.sub.1-3alkyl or halo.
[0037] Preferably, m is 1 or 2.
[0038] Preferably, one of A.sup.1 and A.sup.2 is N and the other is
NR.sup.1, wherein R.sup.1 is H.
[0039] Preferably, X is --(CH.sub.2).sub.p-- or --NR.sup.2--,
wherein p is 0 and R.sup.2 is H.
[0040] Preferably, R.sup.b is halo, C.sub.1-3alkyl,
C.sub.1-3haloalkyl, C.sub.3-4cycloalkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl, --(CH.sub.2).sub.q--OR.sup.3,
--(CH.sub.2).sub.q--NR.sup.3R.sup.4, --(CH.sub.2).sub.q--SR.sup.3,
--(CH.sub.2).sub.q--CN, --(CH.sub.2).sub.q--COR.sup.3,
--(CH.sub.2).sub.q--CO.sub.2R.sup.3,
--(CH.sub.2).sub.q--CONR.sup.3R.sup.4,
--(CH.sub.2).sub.q--NHCOR.sup.3,
--(CH.sub.2).sub.q--NHSO.sub.2R.sup.3,
--(CH.sub.2).sub.q--SOR.sup.5, or
--(CH.sub.2).sub.q--SO.sub.2R.sup.5, wherein R.sup.3 and R.sup.4
are independently H, C.sub.1-3alkyl, C.sub.1-3haloalkyl, or
C.sub.3-4cycloalkyl; or taken together with the nitrogen atom to
which they are attached form a mono-cyclic ring such as imidazole,
pyrrolidine, piperidine, morpholine, piperazine and homopiperazine;
R.sup.5 is methyl; and q is 0, 1, or 2.
[0041] Preferably, n is 1, 2, or 3.
[0042] Specific compounds of the invention which may be mentioned
include the following and pharmaceutically acceptable salts
thereof: [0043]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)aniline; [0044]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-fluoroaniline; [0045]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-fluoroaniline; [0046]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-4-fluoroaniline; [0047]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2,3-difluoroaniline; [0048]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3,4-difluoroaniline; [0049]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3,5-difluoroaniline; [0050]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-chloroaniline; [0051]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-chloroaniline; [0052]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-4-chloroaniline; [0053]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2,3-dichloroaniline; [0054]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3,4-dichloroaniline; [0055]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3,5-dichloroaniline; [0056]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-bromoaniline; [0057]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-bromoaniline; [0058]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-4-bromoaniline; [0059]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-methylaniline; [0060]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-methylaniline; [0061]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-4-methylaniline; [0062]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2,3-dimethylaniline; [0063]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3,4-dimethylaniline; [0064]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3,5-dimethylaniline; [0065]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-ethylaniline; [0066]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-ethylaniline; [0067]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-isopropylaniline; [0068]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-isopropylaniline; [0069]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-4-isopropylaniline; [0070]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-vinylaniline; [0071]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-vinylaniline; [0072]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-4-vinylaniline; [0073]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-ethynylaniline; [0074]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-methoxyaniline; [0075]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-methoxyaniline; [0076]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-4-methoxyaniline; [0077]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2,3-dimethoxyaniline; [0078]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3,4-dimethoxyaniline; [0079]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3,5-dimethoxyaniline; [0080]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-(methoxymethyl)aniline; [0081]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-(methoxymethyl)aniline; [0082]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-4-(methoxymethyl)aniline; [0083]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-(trifluoromethoxy)aniline; [0084]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-(trifluoromethoxy)aniline; [0085]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-4-(trifluoromethoxy)aniline; [0086]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-(methylthio)aniline; [0087]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-(methylthio)aniline; [0088]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-4-(methylthio)aniline; [0089]
2-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)benzonitrile; [0090]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)benzonitrile; [0091]
4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)benzonitrile; [0092]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)phthalonitrile; [0093]
2-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)benzamide; [0094]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)benzamide; [0095]
4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)benzamide; [0096]
2-(3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-
-imidazol-2-yl)methylamino)phenyl)acetonitrile; [0097]
2-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-
-imidazol-2-yl)methylamino)phenyl)acetonitrile; [0098]
1-(3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-
-imidazol-2-yl)methylamino)phenyl)ethanone; [0099]
1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-
-imidazol-2-yl)methylamino)phenyl)ethanone; [0100] Methyl
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)benzoate; [0101] Methyl
4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)benzoate; [0102]
N-(2-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-
-imidazol-2-yl)methylamino)phenyl)acetamide; [0103]
N-(3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-
-imidazol-2-yl)methylamino)phenyl)acetamide; [0104]
N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-
-imidazol-2-yl)methylamino)phenyl)acetamide; [0105]
N-(2-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-
-imidazol-2-yl)methylamino)phenyl)methanesulfonamide; [0106]
N-(3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-
-imidazol-2-yl)methylamino)phenyl)methanesulfonamide; [0107]
N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-
-imidazol-2-yl)methylamino)phenyl)methanesulfonamide; [0108]
N.sup.1-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-
-1H-imidazol-2-yl)methyl)-N.sup.2,N.sup.2-dimethylbenzene-1,2-diamine;
[0109]
N.sup.1-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridi-
n-2-yl)-1H-imidazol-2-yl)methyl)-N.sup.3,N.sup.3-dimethylbenzene-1,3-diami-
ne; [0110]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-
-yl)-1H-imidazol-2-yl)methyl)-2-(pyrrolidin-1-yl)aniline; [0111]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-morpholinoaniline; [0112]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-morpholinoaniline; [0113]
N.sup.3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-
-1H-imidazol-2-yl)methyl)-4-fluoro-N.sup.1,N.sup.1-dimethylbenzene-1,3-dia-
mine; [0114]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-5-(dimethylamino)benzonitrile; [0115]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-4-(dimethylamino)benzonitrile; [0116]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-((dimethylamino)methyl)aniline; [0117]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-((dimethylamino)methyl)aniline; [0118]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-(pyrrolidin-1-ylmethyl)aniline; [0119]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-(pyrrolidin-1-ylmethyl)aniline; [0120]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-(morpholinomethyl)aniline; [0121]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-(morpholinomethyl)aniline; [0122]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-5-((dimethylamino)methyl)-2-fluoroaniline;
[0123]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-((dimethylamino)methyl)-2-fluoroaniline;
[0124]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-fluoro-3-(pyrrolidin-1-ylmethyl)aniline;
[0125]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-fluoro-3-(morpholinomethyl)aniline; [0126]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-4-((dimethylamino)methyl)benzonitrile;
[0127]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-2-((dimethylamino)methyl)benzonitrile;
[0128]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-5-((dimethylamino)methyl)benzonitrile;
[0129]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-4-(pyrrolidin-1-ylmethyl)benzonitrile;
[0130]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-2-(pyrrolidin-1-ylmethyl)benzonitrile;
[0131]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-5-(pyrrolidin-1-ylmethyl)benzonitrile;
[0132]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-4-(morpholinomethyl)benzonitrile; [0133]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-2-(morpholinomethyl)benzonitrile; [0134]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-5-(morpholinomethyl)benzonitrile; [0135]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-(2-(dimethylamino)ethylaniline; [0136]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-(2-(dimethylamino)ethylaniline; [0137]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-ethylpyridin-2-yl)-1H-imi-
dazol-2-yl)methylamino)benzonitrile; [0138]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-ethylpyridin-2-yl)-1H-imi-
dazol-2-yl)methyl)-2-fluoroaniline; [0139]
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-fluoro-N-methylaniline; [0140]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)(methyl)amino)benzonitrile; [0141]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)(methyl)amino)benzamide; [0142]
6-(2-benzyl-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-[1,2,4]triazolo[1,-
5-a]pyridine; [0143]
6-(2-(2-fluorobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-[1,2,4]t-
riazolo[1,5-a]pyridine; [0144]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)benzonitrile; [0145]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)benzamide; [0146]
6-(5-(6-methylpyridin-2-yl)-2-(phenoxymethyl)-1H-imidazol-4-yl)-[1,2,4]tr-
iazolo[1,5-a]pyridine; [0147]
6-(2-((2-fluorophenoxy)methyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-
-[1,2,4]triazolo[1,5-a]pyridine; [0148]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methoxy)benzonitrile; [0149]
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methoxy)benzamide; [0150]
6-(5-(6-methylpyridin-2-yl)-2-(phenylthiomethyl)-1H-imidazol-4-yl)-[1,2,4-
]triazolo[1,5-a]pyridine; [0151]
6-(2-((2-fluorophenylthio)methyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4--
yl)-[1,2,4]triazolo[1,5-a]pyridine.
[0152] The compounds of the present invention typically are small
organic molecules (non-peptide small molecules), generally less
than about 1,000 daltons in size. Preferred non-peptide small
molecules have molecular weights of less than about 750 daltons,
more preferably less than about 500 daltons.
[0153] Compounds of formula (I) may also be supplied in the form of
a "prodrug" which is designed to release compound of formula (I)
when administered to a subject. Prodrug formed designs are well
known in the art, and depend on the substituents contained in
compound of formula (I). For example, a substituent containing
hydroxyl could be coupled to a carrier which renders the compound
biologically inactive until it is removed by endogenous enzymes or,
for example, by enzymes targeted to a particular receptor or
location in the subject.
[0154] A compound of formula (I) that is acidic in nature (e.g.,
having a carboxyl or phenolic hydroxyl group) can form a
pharmaceutically acceptable salt such as a sodium, potassium,
calcium, or gold salt. Also within the scope of the invention are
salts formed with pharmaceutically acceptable amines such as
ammonia, alkyl amines, hydroxyalkylamines, and N-methylglycamine. A
compound of formula (I) can be treated with an acid to form acid
addition salts. Examples of such acids include hydrochloric acid,
hydrobromic acid, hydroiodic acid, sulfuric acid, methanesulfonic
acid, phosphoric acid, p-bromophenylsulfonic acid, carbonic acid,
succinic acid, citric acid, benzoic acid, oxalic acid, malonic
acid, salicyclic acid, malic acid, fumaric acid, ascorbic acid,
maleic acid, acetic acid, and other mineral and organic acids well
known to those skilled in the art. The acid addition salts can be
prepared by treating a compound of formula (I) in its free base
form with a sufficient amount of an acid (e.g., hydrochloric acid)
to produce an acid addition salt (e.g., a hydrochloride salt). The
acid addition salt can be converted back to its free base form by
treating the salt with a suitable dilute aqueous basic solution
(e.g., sodium hydroxide, sodium bicarbonate, potassium carbonate,
or ammonia).
[0155] Some of the compounds of this invention may be crystallized
or recrystallized from solvents such as aqueous and organic
solvents. In such cases solvates may be formed. This invention
includes within its scope stoichiometric solvates including
hydrates as well as compounds containing variable amounts of water
that may be produced by processes such as lyophilization.
[0156] Compounds of formula (I) may contain one or more asymmetric
centers and thus can exist as enantiomers or diastereomers. It is
to be understood that the invention includes both mixtures and
separate individual isomers of compounds of the formula (I).
Furthermore, certain compounds of formula (I) which contain alkenyl
groups may exist as cis- or trans-isomers. In each instance, the
invention includes both mixtures and separate individual
isomers.
[0157] Compounds of formula (I) may also exist in tautomeric forms
and the invention includes both mixtures and separate individual
tautomers thereof.
[0158] Also included in the invention are radiolabelled derivatives
of compounds of formula (I) which are suitable for biological
studies.
[0159] As used herein, the term "alkyl" group refers to a saturated
aliphatic hydrocarbon group containing 1-6 carbon atoms. An alkyl
group can be straight or branched. Examples of an alkyl group
include, but are not limited to, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. An
alkyl group can be optionally substituted with one or more
substituents such as alkoxy, cycloalkoxy, amino, nitro, carboxy,
cyano, halo, hydroxyl, sulfo, or mercapto.
[0160] As used herein, the term "cycloalkyl" group refers to an
aliphatic carbocyclic ring of 3-6 carbon atoms. Examples of
cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and
cyclohexyl.
[0161] As used herein, the term "haloalkyl" group refers to an
alkyl group containing one or more halogen atoms. Examples of
haloalkyl groups include fluoromethyl, chloromethyl, bromomethyl,
and trifluoromethyl.
[0162] As used herein, the term "halo" group refers to fluorine,
chlorine, bromine, or iodine.
[0163] As used herein, the term "alkenyl" group refers to an
aliphatic carbon group that contains 2-6 carbon atoms and at least
one double bond. Like an alkyl group, an alkenyl group can be
straight or branched. Examples of an alkenyl group include, but are
not limited to, vinyl, allyl, isoprenyl, 2-butenyl, and 2-hexenyl.
An alkenyl group can be optionally substituted with one or more
substituents such as alkoxy, cycloalkoxy, amino, nitro, carboxy,
cyano, halo, hydroxyl, sulfo, or mercapto.
[0164] As used herein, the term "alkynyl" group refers to an
aliphatic carbon group that contains 2-6 carbon atoms and has at
least one triple bond. An alkynyl group can be straight or
branched. Examples of an alkynyl group include, but are not limited
to, ethynyl, propargyl, and butynyl. An alkynyl group can be
optionally substituted with one or more substituents such as
alkoxy, cycloalkoxy, amino, nitro, carboxy, cyano, halo, hydroxyl,
sulfo, or mercapto.
[0165] As used herein, the term "ALK5 and/or ALK4 inhibitor" refers
to a compound, other than inhibitory Smads, e.g. Smad6 and Smad7,
which selectively inhibits the ALK5 and/or ALK4 receptors
preferentially over p38 or type II receptors.
[0166] As used herein, the term "ALK5 and/or ALK4-mediated disease
state" refers to any disease state which is mediated (or modulated)
by ALK5 and/or ALK4, for example, a disease which is modulated by
the inhibition of the phosphorylation of Smad2 and Smad3 in the
TGF-.beta. and/or activin signaling pathways.
[0167] As used herein, the term "ulcers" is used to include, but
not to be limited to, diabetic ulcers, chronic ulcers, gastric
ulcers, and duodenal ulcers.
[0168] Compounds of formula (I) may be prepared by a number of
known methods from commercially available or known starting
materials. If the starting materials are unavailable from a
commercial source, they can be prepared by procedures known in the
art.
##STR00002## ##STR00003##
[0169] In one method, compounds of formula (I) wherein A.sup.1 is N
and A.sup.2 is NH, or A.sup.1 is NH and A.sup.2 is N, and X is
--NH-- are prepared according to Scheme 1. Specifically,
R.sup.a-substituted pyridine-2-carbaldehyde (II) is reacted with
aniline and diphenyl phosphite to give N,P-acetal (III), which can
be further coupled with
[1,2,4]triazolo[1,5-a]pyridine-6-carbaldehyde followed by
hydrolysis in acidic condition to produce a monoketone (IV). The
monoketone (IV) may be oxidized to a diketone (V) with HBr in DMSO.
This diketone (V) can then be condensed with
2,2-dimethoxyacetaldehyde in the presence of ammonium acetate to
yield an acetal-protected imidazole (VI), which can be hydrolyzed
in acidic condition to produce an imidazole-2-carbaldehyde (VII).
The imidazole-2-carbaldehyde (VII) can be coupled with
R.sup.b-substituted aniline (VIII) in the presence of an acid such
as acetic acid to generate an immine, which can be further reduced
with a reducing agent such as sodium borohydride or sodium
triacetoxyborohydride to yield a compound of formula (I). R.sup.a,
R.sup.b, m, and n have been defined as above.
##STR00004##
[0170] In another method, compounds of formula (I) wherein A.sup.1
is N and A.sup.2 is NH, or A.sup.1 is NH and A.sup.2 is N, and X is
--(CH.sub.2).sub.p--, --NR.sup.2--, --O--, or --S--, wherein p is 0
or 1, and R.sup.2 is C.sub.1-3alkyl, are prepared according to
Scheme 2. The diketone (V) can be condensed with an appropriate
R.sup.b-substituted aldehyde (IX) in the presence of ammonium
acetate to yield a compound of formula (I). R.sup.a, R.sup.b, m,
and n have been defined as above.
##STR00005##
[0171] Alternatively, when R.sup.b compounds of formula (I) is
--(CH.sub.2).sub.q--CN, --(CH.sub.2).sub.q--CH.dbd.CH--CN, or
--(CH.sub.2).sub.q--C.ident.C--CN, it can be further functionalized
to form a compound of formula (I) as depicted in Scheme 3. R.sup.a,
R.sup.3, R.sup.4, X, m, and q have been defined as above.
[0172] The resulting compounds of this invention represented by the
formula (I)-(IX) can be separated and purified by appropriate
conventional methods such as column chromatography and
recrystallization.
[0173] Compounds of the invention may be administered by any
suitable route, for example by oral, buccal, sub-lingual, rectal,
vaginal, nasal, topical or parenteral (including intravenous,
intramuscular, subcutaneous and intracoronary) administration.
[0174] The topical formulations of the present invention may be
presented as, for instance, ointments, creams or lotions, eye
ointments and eye or ear drops, impregnated dressings and aerosols,
and may contain appropriate conventional additives such as
preservatives, solvents to assist drug penetration and emollients
in ointments and creams.
[0175] The formulations may also contain compatible conventional
carriers, such as cream or ointment bases and ethanol or oleyl
alcohol for lotions. Such carriers may be present as from about 1%
up to about 98% of the formulation. More usually, they will form up
to about 80% of the formulation.
[0176] For administration to man in the curative or prophylactic
treatment of the disorders identified above, oral, buccal or
sub-lingual dosages of a compound of formula (I) will generally be
in the range of from 50-5000 mg daily for an average adult patient
(70 kg). Thus for a typical adult patient, individual tablets or
capsules contain from 25-500 mg of active compound, in a suitable
pharmaceutically acceptable vehicle or carrier, for administration
in single or multiple doses, once or several times per day. Dosages
for parenteral administration will typically be within the range of
from 25-250 mg per single dose as required. In practice the
physician will determine the actual dosing regimen which will be
most suitable for an individual patient and it will vary with the
age, weight and response of the particular patient. The above
dosages are exemplary of the average case but there can be
individual instances in which higher or lower dosage ranges may be
merited, and such are within the scope of this invention.
[0177] For human use, a compound of formula (I) can be administered
alone, but will generally be administered in admixture with a
pharmaceutical carrier selected with regard to the intended route
of administration and standard pharmaceutical practice. For
example, the compound may be administered orally, buccally or
sublingually, in the form of tablets containing excipients such as
starch or lactose, or in capsules or ovules either alone or in
admixture with excipients, or in the form of elixirs or suspensions
containing flavoring or coloring agents. Such liquid preparations
may be prepared with pharmaceutically acceptable additives such as
suspending agent (e.g. methylcellulose, a semi-synthetic glyceride
such as witepsol or mixtures of glycerides such as a mixture of
apricot kernel oil and PEG-6 esters or mixtures of PEG-8 and
caprylic/capric glycerides). A compound may also be injected
parenterally, for example intravenously, intramuscularly,
subcutaneously or intracoronarily. For parenteral administration,
the compound is best used in the form of a sterile aqueous solution
which may contain other substances, for example, salts, or
monosaccharides such as mannitol or glucose, to make the solution
isotonic with blood.
[0178] Thus, the invention provides in a further aspect a
pharmaceutical composition comprising a compound of formula (I), or
a pharmaceutically acceptable salt or solvate thereof, together
with a pharmaceutically acceptable diluent or carrier therefor.
[0179] The invention also provides a compound of formula (I), or a
pharmaceutically acceptable salt or solvate thereof, or a
pharmaceutical composition containing either entity, for use in
therapy.
[0180] The invention further provides the use of a compound of
formula (I), or a pharmaceutically acceptable salt or solvate
thereof, or a pharmaceutical composition containing either entity,
for the manufacture of a medicament for the treatment of a disease,
mediated by the ALK5 and/or ALK4 receptors in mammals.
[0181] ALK5- and/or ALK4-mediated disease states include, but are
not limited to, glomerulonephritis, diabetic nephropathy, lupus
nephritis, hypertension-induced nephropathy, renal interstitial
fibrosis, renal fibrosis resulting from complications of drug
exposure, HIV-associated nephropathy, transplant nephropathy, liver
fibrosis due to all etiologies, hepatic dysfunction attributable to
infections, alcohol-induced hepatitis, disorders of the biliary
tree, pulmonary fibrosis, acute lung injury, adult respiratory
distress syndrome, idiopathic pulmonary fibrosis, chronic
obstructive pulmonary disease, pulmonary disease due to infectious
or toxic agents, post-infarction cardiac fibrosis, congestive heart
failure, dilated cardiomyopathy, myocarditis, vascular stenosis,
hypertension-induced vascular remodeling, pulmonary arterial
hypertension, coronary restenosis, peripheral restenosis, carotid
restenosis, stent-induced restenosis, atherosclerosis, ocular
scarring, corneal scarring, proliferative vitreoretinopathy,
excessive or hypertrophic scar or keloid formation in the dermis
occurring during wound healing resulting from trauma or surgical
wounds, peritoneal and sub-dermal adhesion, scleroderma,
fibrosclerosis, progressive systemic sclerosis, dermatomyositis,
polymyositis, arthritis, osteoporosis, ulcers, impaired
neurological function, male erectile dysfunction, Peyronie's
disease, Dupuytren's contracture, Alzheimer's disease, Raynaud's
syndrome, fibrotic cancers, tumor metastasis growth,
radiation-induced fibrosis, and thrombosis.
[0182] The invention further provides a method of inhibiting the
TGF-.beta. and/or activin signaling pathways in human, for example,
inhibiting the phosphorylation of Smad2 or Smad3 by ALK5 and/or
ALK4.
[0183] The invention further provides a method of reducing the
accumulation of excess extracellular matrix in human by inhibiting
the TGF-.beta. and/or activin signaling pathways, for example,
inhibiting the phosphorylation of Smad2 or Smad3 by ALK5 and/or
ALK4.
[0184] The invention further provides a method of inhibiting
metastasis of tumor cells in human by inhibiting the TGF-.beta.
signaling pathway.
[0185] The invention further provides a method of treating
carcinomas mediated by an overexpression of TGF-.beta. in human by
inhibiting the TGF-.beta. signaling pathway.
[0186] The present invention is further illustrated in the
following Examples, which should not be taken to limit the scope of
the invention described in the claims. In the Examples,
electrospray ionization mass spectra (ESI-MS) were obtained on a
Q-Tof2 mass spectrometer (Micromass, Manchester, UK).
EXAMPLES
Preparative Example 1
Preparation of
diphenyl(6-methylpyridin-2-yl)(phenylamino)methylphosphonate (a
Compound of the Formula (III) wherein R.sup.a.dbd.CH.sub.3)
[0187] A mixture of 6-methylpyridine-2-carboxaldehyde (2.12 g,
17.50 mmol), aniline (1.63 g, 17.50 mmol), diphenyl phosphite (4.92
g, 21.00 mmol), and zirconyl chloride octahydrate (0.56 g, 1.75
mmol) was stirred at room temperature 1 h. The reaction mixture was
extracted with CH.sub.2Cl.sub.2 (3.times.50 mL), and the
CH.sub.2Cl.sub.2 solution was washed with water (2.times.20 mL),
dried over anhydrous Na.sub.2SO.sub.4, filtered, and evaporated to
dryness under reduced pressure. The residue was purified by MPLC on
silica gel using a mixture of EtOAc and hexane as eluent to give
the titled compound (6.96 g, 92%) as a white solid. .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 7.51 (t, 1H, J=7.8 Hz), 7.38 (dd,
1H, J=7.6, 2.0 Hz), 7.27-7.22 (m, 4H), 7.19-7.15 (m, 2H), 7.14-7.07
(m, 4H), 7.05-7.02 (m, 3H), 6.80-6.74 (m, 3H), 5.53 (pseudo t, 1H,
J=7.4 Hz), 5.36 (dd, 1H, J=21.0, 8.2 Hz), 2.54 (s, 3H).
Preparative Example 2
Preparation of
diphenyl(6-ethylpyridin-2-yl)(phenylamino)methylphosphonate (a
Compound of the Formula (III) wherein
R.sup.a.dbd.CH.sub.2CH.sub.3)
[0188] The titled compound was prepared as described in Preparative
Example 1 by using 6-ethylpyridine-2-carboxaldehyde in place of
6-methylpyridine-2-carboxaldehyde. Yield: 81%; .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 7.55 (t, 1H, J=7.6 Hz), 7.38 (dd, 1H,
J=7.6, 2.0 Hz), 7.26-7.09 (m, 8H), 7.07-7.00 (m, 5H), 5.59 (pseudo
t, 1H, J=7.0 Hz), 5.34 (dd, 1H, J=20.8, 8.0 Hz), 2.82 (q, 2H, J=7.6
Hz), 1.28 (t, 3H, J=7.6 Hz).
Preparative Example 3
Preparation of
2-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-(6-methylpyridin-2-yl)ethanone
(a Compound of the Formula (IV) wherein R.sup.a.dbd.CH.sub.3)
[0189] To a stirred solution of
[1,2,4]triazolo[1,5-a]pyridine-6-carbaldehyde (2.50 g, 17.01 mmol)
(prepared according to the method described in WO 03/087304 A2) and
diphenyl(6-methylpyridin-2-yl)(phenylamino)methylphosphonate (7.32
g, 17.01 mmol) in a mixture of THF (40 mL) and i-PrOH (10 mL) was
added Cs.sub.2CO.sub.3 (7.20 g, 22.11 mmol), and the mixture was
stirred at room temperature overnight. A solution of 3 N HCl (25
mL) was added dropwise to the reaction mixture, and the mixture was
stirred for 1 h. It was then diluted with tert-butyl methyl ether
(40 mL) and extracted with 1 N HCl (2.times.35 mL). The aqueous
extracts were neutralized with 50% KOH until pH 7-8 was reached.
The precipitates were collected by filtration, washed with water,
and dried over P.sub.2O.sub.5 in vacuo to give the titled compound
(3.41 g, 80%) as an off-white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.61 (d, 1H, J=0.8 Hz), 8.31 (s, 1H), 7.88
(dd, 1H, J=7.6, 1.6 Hz), 7.73 (t, 1H, overlapped, J=7.6 Hz), 7.71
(dd, 1H, overlapped, J=9.2, 0.8 Hz), 7.54 (dd, 1H, J=9.2, 1.6 Hz),
7.37 (dd, 1H, J=7.6, 1.6 Hz), 4.62 (s, 2H), 2.67 (s, 3H).
Preparative Example 4
Preparation of
2-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-(6-ethylpyridin-2-yl)ethanone
(a Compound of the Formula (IV) wherein
R.sup.a.dbd.CH.sub.2CH.sub.3)
[0190] The titled compound was prepared as described in Preparative
Example 3 by using
diphenyl(6-ethylpyridin-2-yl)(phenylamino)methylphosphonate in
place of
diphenyl(6-methylpyridin-2-yl)(phenylamino)methylphosphonate.
Yield: 78%; .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.61 (dd,
1H, J=1.6, 0.8 Hz), 8.29 (s, 1H), 7.88 (br d, 1H, J=7.6 Hz), 7.74
(t, 1H, J=7.6 Hz), 7.70 (dd, 1H, J=9.2, 0.8 Hz), 7.54 (dd, 1H,
J=9.2, 1.6 Hz), 7.37 (dd, 1H, J=7.6, 0.8 Hz), 4.62 (s, 2H), 2.93
(q, 2H, J=7.6 Hz), 1.39 (t, 3H, J=7.6 Hz).
Preparative Example 5
Preparation of
1-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(6-methylpyridin-2-yl)ethane-1,2-
-dione (a Compound of the Formula (V) wherein
R.sup.a.dbd.CH.sub.3)
[0191] To a stirred suspension of
2-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-(6-methylpyridin-2-yl)ethanone
(6.20 g, 24.57 mmol) in DMSO (48 mL) was added dropwise HBr (48 wt.
% in water, 5.96 g, 12.4 mL) at 0.degree. C., and the mixture was
heated at 60-70.degree. C. After 2 h, the reaction mixture was
cooled to 0.degree. C., poured onto ice water (20 mL), and basified
to pH 10 with solid K.sub.2CO.sub.3. The mixture was extracted with
CHCl.sub.3 (2.times.250 mL), and the organic phase was washed with
water (2.times.100 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered, and evaporated to dryness under reduced pressure. The
residue was purified by MPLC on silica gel using a mixture of MeOH
and CH.sub.2Cl.sub.2 as eluent to give the titled compound (6.02 g,
92%) as a light yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 9.11 (dd, 1H, J=1.6, 1.2 Hz), 8.47 (s, 1H), 8.14 (dd, 1H,
J=9.2, 1.6 Hz), 8.04 (br d, 1H, J=7.6 Hz), 7.88 (dd, 1H, J=9.2, 1.2
Hz), 7.84 (t, 1H, J=7.8 Hz), 7.42 (br d, 1H, J=8.0 Hz), 2.49 (s,
3H).
Preparative Example 6
Preparation of
1-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(6-ethylpyridin-2-yl)ethane-1,2--
dione (a Compound the of Formula (V) wherein
R.sup.a.dbd.CH.sub.2CH.sub.3)
[0192] The titled compound was prepared as described in Preparative
Example 5 by using
2-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-(6-ethylpyridin-2-yl)ethanone
in place of
2-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-(6-methylpyridin-2-yl)e-
thanone. Yield: 79%; .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
9.11 (dd, 1H, J=1.6, 0.8 Hz), 8.42 (s, 1H), 8.08 (dd, 1H, J=9.2,
1.6 Hz), 7.98 (br d, 1H, J=7.6 Hz), 7.83 (dd, 1H, overlapped,
J=9.2, 0.8 Hz), 7.82 (t, 1H, overlapped, J=7.6 Hz), 7.38 (br d, 1H,
J=7.6 Hz), 2.71 (q, 2H, J=7.6 Hz), 1.08 (t, 3H, J=7.6 Hz).
Preparative Example 7
Preparation of
6-(2-(dimethoxymethyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-[1,2,4]-
triazolo[1,5-a]pyridine (a Compound of the Formula (VI) wherein
R.sup.a.dbd.CH.sub.3)
[0193] A stirred solution of
1-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(6-methylpyridin-2-yl)ethane-1,2-
-dione (6.00 g, 22.49 mmol) in tert-butyl methyl ether (120 mL) was
treated with glyoxal dimethyl acetal (60 wt. % solution in water,
7.8 mL, 44.98 mmol). NH.sub.4OAc (4.33 g, 56.2 mmol) in MeOH (60
mL) was added to it, and the resulting mixture was stirred at room
temperature for 3 h. The pH of the reaction was adjusted to 8 with
saturated aqueous NaHCO.sub.3 solution. The reaction mixture was
extracted with CHCl.sub.3 (2.times.150 mL), and the CHCl.sub.3
solution was washed with water (100 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered, and evaporated to dryness under reduced
pressure. The residue was purified by MPLC on silica gel using a
mixture of MeOH and CH.sub.2Cl.sub.2 as eluent to give the titled
compound (6.13 g, 78%) as a light yellow foam. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 10.54 (br s, 1H), 8.96 (s, 1H), 8.36 (s,
1H), 7.82 (dd, 1H, J=9.2, 1.6 Hz), 7.77 (dd, 1H, J=9.2, 0.8 Hz),
7.47 (t, 1H, J=7.8 Hz), 7.23 (d, 1H, J=7.6 Hz), 7.04 (d, 1H, J=8.0
Hz), 5.57 (s, 1H), 3.48 (s, 6H), 2.58 (s, 3H).
Preparative Example 8
Preparation of
6-(2-(dimethoxymethyl)-5-(6-ethylpyridin-2-yl)-1H-imidazol-4-yl)-[1,2,4]t-
riazolo[1,5-a]pyridine (a Compound of the Formula (VI) wherein
R.sup.a.dbd.CH.sub.2CH.sub.3)
[0194] The titled compound was prepared as described in Preparative
Example 7 by using
1-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(6-ethylpyridin-2-yl)ethane-1,2--
dione in place of
1-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(6-methylpyridin-2-yl)ethane-1,2-
-dione. Yield: 68%; .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
10.67 (br s, 1H), 8.97 (br s, 1H), 8.35 (s, 1H), 7.83 (dd, 1H,
J=9.2, 1.6 Hz), 7.76 (dd, 1H, J=9.2, 0.8 Hz), 7.50 (t, 1H, J=7.8
Hz), 7.25 (br d, 1H, J=7.6 Hz), 7.05 (d, 1H, J=8.0 Hz), 5.56 (s,
1H), 3.46 (s, 6H), 2.83 (q, 2H, J=7.6 Hz), 1.31 (t, 3H, J=7.6
Hz).
Preparative Example 9
Preparation of
4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidaz-
ole-2-carbaldehyde (a Compound of the Formula (VII) wherein
R.sup.a.dbd.CH.sub.3)
[0195]
6-(2-(Dimethoxymethyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-[-
1,2,4]triazolo[1,5-a]pyridine (6.00 g, 17.12 mmol) was dissolved in
1 N HCl (120 mL), and the mixture was heated at 70.degree. C. for 3
h. The reaction mixture was allowed to cool to 0.degree. C., and
then it was neutralized with saturated aqueous NaHCO.sub.3
solution. The mixture was extracted with 10% MeOH in CHCl.sub.3
(3.times.200 mL), and the organic phase was dried over anhydrous
Na.sub.2SO.sub.4, filtered, and evaporated to dryness under reduced
pressure to give the titled compound (4.69 g, 90%) as a light
yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.82 (s,
1H), 9.01 (br s, 1H), 8.41 (s, 1H), 7.85 (dd, 1H, J=9.2, 0.8 Hz),
7.82 (dd, 1H, J=9.2, 1.6 Hz), 7.55 (t, 1H, J=7.8 Hz), 7.33 (br s,
1H), 7.16 (d, 1H, J=8. 0 Hz), 2.60 (s, 3H).
Preparative Example 10
Preparation of
4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-ethylpyridin-2-yl)-1H-imidazo-
le-2-carbaldehyde (a Compound of the Formula (VII) wherein
R.sup.a.dbd.CH.sub.2CH.sub.3)
[0196] The titled compound was prepared as described in Preparative
Example 9 by using
6-(2-(dimethoxymethyl)-5-(6-ethylpyridin-2-yl)-1H-imidazol-4-yl)-[1,2,4]t-
riazolo[1,5-a]pyridine in place of
6-(2-(dimethoxymethyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)-[1,2,4]-
triazolo[1,5-a]pyridine. Yield: 99%; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.86 (t, 1H, J=1.2 Hz), 9.59 (s, 1H), 8.43
(s, 1H), 8.21 (dd, 1H, J=9.2, 1.6 Hz), 7.82 (br d, 1H, J=8.0 Hz),
7.73 (dd, 1H, J=9.2, 0.8 Hz), 7.69 (t, 1H, J=7.8 Hz), 7.08 (br d,
1H, J=7.6 Hz), 2.71 (q, 2H, J=7.6 Hz), 1.16 (t, 3H, J=7.6 Hz).
Preparative Example 11
[0197] Preparation of 3-amino-5-(dimethylamino)benzonitrile (a
compound of the formula (VIII) wherein
R.sup.b=3-cyano-5-dimethylamino). This compound was prepared by the
following 2 steps.
[0198] 3-Bromo-N,N-dimethyl-5-nitroaniline (1.73 g, 7.06 mmol)
(prepared according to the method described in J. Org. Chem. 60:
5091-5103 (2003)), pyridine (24 mL), and CuCN (1.26 g, 2.14 mmol)
were added to a dry sealed tube. The mixture was heated at
220.degree. C. with stirring for 3.5 h. The reaction mixture was
allowed to cool to 100.degree. C., poured into a flask containing a
mixture of aqueous ammonia (100 mL) and water (100 mL), and
extracted with EtOAc (2.times.100 mL). The EtOAc solution was
washed with diluted ammonia solution (100 mL), water (100 mL) and
brine (100 mL) successively, dried over anhydrous Na.sub.2SO.sub.4,
filtered, and evaporated to dryness under reduced pressure. The
residue was purified by MPLC on silica gel using a mixture of EtOAc
and hexane as eluent to give 3-(dimethylamino)-5-nitrobenzonitrile
(0.44 g, 33%) as an orange solid. .sup.1NMR (400 MHz, CDCl.sub.3):
.delta. 7.74 (dd, 1H, J=2.0, 1.2 Hz), 7.65 (t, 1H, J=2.2 Hz), 7.11
(dd, 1H, J=2.4, 1.2 Hz), 3.10 (s, 6H).
[0199] The above nitro compound,
3-(dimethylamino)-5-nitrobenzonitrile (0.42 g, 2.22 mmol) in
methanol (80 mL) was hydrogenated in the presence of 10% Pd/C (0.04
g) under a hydrogen gas atmosphere overnight. The reaction mixture
was filtered through a Celite pad, and the filtrate was evaporated
to dryness under reduced pressure. The residue was purified by MPLC
on silica gel using a mixture of EtOAc and hexane as eluent to give
the titled compound (0.29 g, 80%) as a brown viscous liquid.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 6.35 (dd, 1H, J=2.4, 1.6
Hz), 6.28 (dd, 1H, J=2.0, 1.6 Hz), 6.14 (t, 1H, J=2.2 Hz), 3.76 (br
s, 2H), 2.92 (s, 6H).
Preparative Example 12
[0200] Preparation of 3-((dimethylamino)methyl)-2-fluroaniline (a
compound of the formula (VIII) wherein
R.sup.b=3-(dimethylamino)methyl-2-fluoro). This compound was
prepared by the following 3 steps started with commercially
available 2-fluoro-1-methyl-3-nitrobenzene.
[0201] A stirred solution of 2-fluoro-1-methyl-3-nitrobenzene
(15.80 g, 101.94 mmol) and N-bromosuccinimide (18.14 g, 101.94
mmol) in CCl.sub.4 (400 mL) was treated with benzoyl peroxide (0.37
g, 1.52 mmol). The mixture was heated at reflux temperature
overnight and then cooled to room temperature. The reaction mixture
was filtered, and the filtrate was evaporated to dryness under
reduced pressure. The residue was dissolved in CH.sub.2Cl.sub.2
(100 mL) and filtered again. The filtrate was evaporated to dryness
under reduced pressure, and the residue was purified by MPLC on
silica gel using a mixture of EtOAc and hexane as eluent to give
1-(bromomethyl)-2-fluoro-3-nitrobenzene (8.11 g, 34%) as an
off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.02
(m, 1H), 7.71 (m, 1H), 7.30 (td, 1H, J=8.4, 1.6 Hz), 4.55 (d, 2H,
J=1.6 Hz).
[0202] To a stirred mixture of
1-(bromomethyl)-2-fluoro-3-nitrobenzene (0.70 g, 2.99 mmol) and
dimethylamine hydrochloride (0.48 g, 5.98 mmol) in CH.sub.2Cl.sub.2
(10 mL) was added triethylamine (0.91 g, 8.97 mmol) dropwise. The
mixture was stirred at room temperature for 3 h and evaporated to
dryness under reduced pressure. The residue was diluted with water
(10 mL) and extracted with EtOAc (2.times.25 mL). The EtOAc
solution was washed with water (20 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered, and evaporated to dryness under reduced
pressure. The residue was purified by MPLC on silica gel using a
mixture of EtOAc and hexane as eluent to give
1-(2-fluoro-3-nitrophenyl)-N,N-dimethylmethanamine (0.45 g, 76%) as
a yellow viscous liquid. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.
8.04-7.99 (m, 1H), 7.78-7.73 (m, 1H), 7.37 (td, 1H, J=8.0, 1.0 Hz),
3.64 (d, 2H, J=2.0 Hz), 2.29 (d, 6H, J=0.8 Hz).
[0203] A mixture of the above nitro compound,
1-(2-fluoro-3-nitrophenyl)-N,N-dimethylmethanamine (0.45 g, 1.93
mmol), iron powder (1.35 g, 2.41 mmol), 2 N HCl (1 mL), and ethanol
(5 mL) was heated at reflux temperature with stirring for 2 h.
After cooling to room temperature, the mixture was filtered through
a Celite pad. The filtrate was evaporated to dryness under reduced
pressure, and the residue was diluted with water (10 mL) and
basified with solid K.sub.2CO.sub.3 to pH 10. The aqueous mixture
was extracted with EtOAc (2.times.25 mL), and the EtOAc solution
was dried over anhydrous Na.sub.2SO.sub.4, filtered, and evaporated
to dryness under reduced pressure. The residue was purified by MPLC
on silica gel using a mixture of EtOAc and hexane as eluent to give
the titled compound (0.35 g, 91%) as a white solid. .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 6.88 (td, 1H, J=7.8, 1.0 Hz),
6.72-6.67 (m, 2H), 3.71 (br s, 2H), 3.47 (d, 2H, J=1.6 Hz), 2.27
(s, 6H).
Preparative Example 13
Preparation of 2-fluoro-3-(pyrrolidin-1-ylmethyl)aniline (a
Compound of the Formula (VIII) wherein
R.sup.b=2-fluoro-3-(pyrrolidin-1-ylmethyl))
[0204] To a stirred solution of
1-(bromomethyl)-2-fluoro-3-nitrobenzene (2.00 g, 8.54 mmol) and
pyrrolidine (0.91 g, 12.82 mmol) in CH.sub.2Cl.sub.2 (15 mL) was
added triethylamine (1.72 g, 17.08 mmol) dropwise at 0.degree. C.
The mixture was stirred at room temperature overnight and then
evaporated to dryness under reduced pressure. The residue was
diluted with water (15 mL) and extracted with EtOAc (2.times.30
mL). The EtOAc solution was washed with brine (20 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered, and evaporated to dryness
under reduced pressure. The residue was purified by MPLC on silica
gel using a mixture of EtOAc and hexane as eluent to give
1-(2-fluoro-3-nitrobenzyl)pyrrolidine (1.20 g, 63%) as a viscous
oil. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.02-7.97 (m, 1H),
7.81-7.76 (m, 1H), 7.36 (td, 1H, J=8.0, 1.2 Hz), 3.81 (d, 1H, J=2.0
Hz), 2.62-2.58 (m, 4H), 1.84-1.80 (m, 4H).
[0205] The titled compound was prepared as described in Preparative
Example 12 by using 1-(2-fluoro-3-nitrobenzyl)pyrrolidine in place
of 1-(2-fluoro-3-nitrophenyl)-N,N-dimethylmethanamine. Yield: 80%;
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 6.87 (td, 1H, J=8.0, 0.8
Hz), 6.77 (td, 1H, J=8.0, 2.0 Hz), 6.68-6.64 (m, 1H), 3.67 (d, 2H,
J=1.6 Hz), 2.60-2.57 (m, 4H), 1.82-1.78 (m, 4H).
Preparative Example 14
Preparation of 2-fluoro-3-(morpholinomethyl)aniline (a Compound of
the Formula (VIII) wherein
R.sup.b=2-fluoro-3-(morpholinomethyl))
[0206] A stirred solution of
1-(bromomethyl)-2-fluoro-3-nitrobenzene (2.50 g, 10.6 mmol) and
morpholine (2.78 g, 32.0 mmol) in toluene (24 mL) was heated at
reflux temperature for 2.5 h. The reaction mixture was allowed to
cool to room temperature and then washed with 1 N NaOH (2.times.20
mL). The aqueous layer was extracted with EtOAc (2.times.25 mL),
and the combined toluene solution and EtOAc extracts were dried
over anhydrous Na.sub.2SO.sub.4, filtered, and evaporated to
dryness under reduced pressure. The residue was purified by MPLC on
silica gel using a mixture of EtOAc and hexane as eluent to give
4-(2-fluoro-3-nitrobenzyl)morpholine (1.95 g, 89%) as a light
yellow solid. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.02-7.97
(m, 1H), 7.83-7.78 (m, 1H), 7.36 (td, 1H, J=8.0, 1.0 Hz), 3.70-3.67
(m, 6H), 2.51 (br t, 4H, J=4.6 Hz).
[0207] The titled compound was prepared as described in Preparative
Example 12 by using (4-(2-fluoro-3-nitrobenzyl)morpholine) in place
of 1-(2-fluoro-3-nitrophenyl)-N,N-dimethylmethanamine. Yield: 90%;
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 6.87 (td, 1H, J=8.0, 0.8
Hz), 6.77 (td, 1H, J=8.0, 2.0 Hz), 6.68-6.64 (m, 1H), 3.68 (br t,
4H, J=4.8 Hz), 3.55 (d, 2H, J=1.6 Hz), 2.49 (br t, 4H, J=4.8
Hz).
Preparative Example 15
Preparation of 3-amino-4-((dimethylamino)methyl)benzonitrile (a
Compound of the Formula (VIII) wherein
R.sup.b=5-cyano-2-(dimethylamino)methyl)
[0208] To a stirred mixture of 4-(bromomethyl)-3-nitrobenzonitrile
(5.00 g, 20.74 mmol) (prepared according to the method described in
WO 07/024945 A1) and dimethylamine hydrochloride (2.03 g, 24.89
mmol) in CH.sub.2Cl.sub.2 (70 mL) was added triethylamine (6.30 g,
62.23 mmol) dropwise at 0.degree. C., and the mixture was stirred
at room temperature overnight. The reaction mixture was evaporated
to dryness under reduced pressure, and the residue was diluted with
water (20 mL) and extracted with CH.sub.2Cl.sub.2 (3.times.100 mL).
The CH.sub.2Cl.sub.2 solution was dried over anhydrous
Na.sub.2SO.sub.4, filtered, and evaporated to dryness under reduced
pressure. The residue was purified by MPLC on silica gel using a
mixture of EtOAc and hexane as eluent to give
4-((dimethylamino)methyl)-3-nitrobenzene (3.58 g, 84%) as an orange
solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.15 (br s, 1H),
7.92 (br s, 1H), 7.85 (br d, 1H, J=7.2 Hz), 3.80 (s, 2H), 2.27 (s,
6H).
[0209] The titled compound was prepared as described in Preparative
Example 11 by using 4-((dimethylamino)methyl)-3-nitrobenzonitrile
in place of 3-(dimethylamino)-5-nitrobenzonitrile. Yield: 91%;
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.02 (dd, 1H, J=7.6, 0.4
Hz), 6.91 (dd, 1H, J=7.6, 1.6 Hz), 6.84 (d, 1H, J=1.6 Hz), 5.05 (br
s, 2H), 3.43 (s, 2H), 2.18 (s, 6H).
Preparative Example 16
Preparation of 3-amino-2-((dimethylamino)methyl)benzonitrile (a
Compound of the Formula (VIII) wherein
R.sup.b=3-cyano-2-(dimethylamino)methyl)
[0210] To a stirred mixture of 2-(bromomethyl)-3-nitrobenzonitrile
(1.10 g, 4.56 mmol) (prepared according to the method described in
Tetrahedron 40: 1863-1868 (1984)) and dimethylamine hydrochloride
(0.74 g, 9.13 mmol) in CH.sub.2Cl.sub.2 (15 mL) was added
triethylamine (1.85 g, 18.25 mmol) dropwise at 0.degree. C. The
resulting mixture was stirred at room temperature for 2 h and
evaporated to dryness under reduced pressure. The residue was
diluted with water (10 mL) and extracted with EtOAc (3.times.50
mL). The EtOAc solution was dried over anhydrous Na.sub.2SO.sub.4,
filtered, and evaporated to dryness under reduced pressure. The
residue was purified by MPLC on silica gel using a mixture of EtOAc
and hexane as eluent to give
2-((dimethylamino)methyl)-3-nitrobenzonitrile (0.75 g, 80%) as a
yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.93 (br d,
1H, J=8.0 Hz), 7.85 (dd, 1H, J=8.0, 1.4 Hz), 7.55 (t, 1H, J=8.0
Hz), 3.94 (s, 2H), 2.24 (s, 6H).
[0211] The titled compound was prepared as described in Preparative
Example 11 by using 2-((dimethylamino)methyl)-3-nitrobenzonitrile
in place of 3-(dimethylamino)-5-nitrobenzonitrile. Yield: 93%;
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.15 (t, 1H, J=7.6 Hz),
7.00 (dd, 1H, J=7.6, 0.8 Hz), 6.83 (d, 1H, J=7.6 Hz), 5.06 (br s,
2H), 3.73 (s, 2H), 2.29 (s, 6H).
Preparative Example 17
Preparation of 3-amino-5-((dimethylamino)methyl)benzonitrile (a
Compound of the Formula (VIII) wherein
R.sup.b=3-cyano-5-(dimethylamino)methyl)
[0212] To a stirred mixture of 3-(bromomethyl)-5-nitrobenzonitrile
(1.50 g, 6.22 mmol) (prepared according to the method described in
J. Org. Chem. 55: 1040-1043 (1990)) and dimethylamine hydrochloride
(1.01 g, 12.44 mmol) in CH.sub.2Cl.sub.2 (15 mL) was added
triethylamine (1.88 g, 18.66 mmol) dropwise at 0.degree. C. The
resulting mixture was stirred at room temperature for 3 h and
evaporated to dryness under reduced pressure. The residue was
diluted with water (15 mL) and extracted with EtOAc (3.times.50
mL). The EtOAc solution was dried over anhydrous Na.sub.2SO.sub.4,
filtered, and evaporated to dryness under reduced pressure. The
residue was purified by MPLC on silica gel using a mixture of EtOAc
and hexane as eluent to give
3-((dimethylamino)methyl)-5-nitrobenzonitrile (1.10 g, 87%) as a
viscous liquid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.45 (s,
1H), 8.40 (d, 1H, J=1.6 Hz), 8.01 (s, 1H), 3.59 (s, 2H), 2.30 (s,
6H).
[0213] The titled compound was prepared as described in Preparative
Example 11 by using 3-((dimethylamino)methyl)-5-nitrobenzonitrile
in place of 3-(dimethylamino)-5-nitrobenzonitrile. Yield: 98%;
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 6.96 (m, 1H), 6.88 (br
d, 1H, J=0.8 Hz), 6.80 (dd, 1H, J=2.4, 1.6 Hz), 3.86 (br s, 2H),
3.34 (s, 2H), 2.24 (s, 6H).
Preparative Example 18
Preparation of 3-amino-4-(pyrrolidin-1-ylmethyl)benzonitrile (a
Compound of the Formula (VIII) wherein
R.sup.b=5-cyano-2-(pyrrolidin-1-ylmethyl))
[0214] To a stirred solution of 4-(bromomethyl)-3-nitrobenzonitrile
(5.12 g, 21.57 mmol) and pyrrolidine (1.84 g, 25.88 mmol) in
CH.sub.2Cl.sub.2 (72 mL) was added triethylamine (6.54 g, 64.71
mmol) dropwise at 0.degree. C. The mixture was stirred at room
temperature for 1.5 h and evaporated to dryness under reduced
pressure. The residue was diluted with water (30 mL) and extracted
with CH.sub.2Cl.sub.2 (3.times.100 mL). The CH.sub.2Cl.sub.2
solution was dried over anhydrous Na.sub.2SO.sub.4, filtered, and
evaporated to dryness under reduced pressure. The residue was
purified by MPLC on silica gel using a mixture of EtOAc and hexane
as eluent to give 3-nitro-4-(pyrrolidin-1-ylmethyl)benzonitrile
(2.24 g, 45%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 8.16 (d, 1H, J=1.6 Hz), 7.94 (br d, 1H, J=8.0 Hz), 7.83
(dd, 1H, J=8.0, 1.6 Hz), 3.99 (s, 2H), 2.54 (br s, 4H), 1.79 (m,
4H).
[0215] The titled compound was prepared as described in Preparative
Example 11 by using 3-nitro-4-(pyrrolidin-1-ylmethyl)benzonitrile
in place of 3-(dimethylamino)-5-nitrobenzonitrile. Yield: 91%;
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.06 (d, 1H, J=7.6 Hz),
6.91 (dd, 1H, J=7.6, 1.6 Hz), 6.84 (d, 1H, J=1.6 Hz), 5.08 (br s,
2H), 3.64 (s, 2H), 2.47 (br s, 4H), 1.78 (br s, 4H).
Preparative Example 19
Preparation of 3-amino-2-(pyrrolidin-1-ylmethyl)benzonitrile (a
Compound of the Formula (VIII) wherein
R.sup.b=3-cyano-2-(pyrrolidin-1-ylmethyl))
[0216] To a stirred solution of 2-(bromomethyl)-3-nitrobenzonitrile
(1.10 g, 4.56 mmol) and pyrrolidine (0.65 g, 9.13 mmol) in
CH.sub.2Cl.sub.2 (15 mL) was added triethylamine (1.85 g, 18.25
mmol) dropwise at 0.degree. C. The mixture was stirred at room
temperature for 2 h and evaporated to dryness under reduced
pressure. The residue was diluted with water (10 mL) and extracted
with CH.sub.2Cl.sub.2 (3.times.50 mL). The CH.sub.2Cl.sub.2
solution was dried over anhydrous Na.sub.2SO.sub.4, filtered, and
evaporated to dryness under reduced pressure. The residue was
purified by MPLC on silica gel using a mixture of EtOAc and hexane
as eluent to give 3-nitro-2-(pyrrolidin-1-ylmethyl)benzonitrile
(0.96 g, 91%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 7.90 (d, 1H, J=7.6 Hz), 7.83 (dd, 1H, J=7.6, 0.8 Hz), 7.52
(t, 1H, J=7.6 Hz), 4.14 (s, 2H), 2.52 (br s, 4H), 1.72 (br s,
4H).
[0217] The titled compound was prepared as described in Preparative
Example 11 by using 3-nitro-2-(pyrrolidin-1-ylmethyl)benzonitrile
in place of 3-(dimethylamino)-5-nitrobenzonitrile. Yield: 93%;
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.13 (t, 1H, J=7.8 Hz),
6.99 (dd, 1H, J=7.8, 1.2 Hz), 6.82 (d, 1H, J=8.0 Hz), 5.11 (br s,
2H), 3.91 (s, 2H), 2.58 (br s, 4H), 1.81 (br s, 4H).
Preparative Example 20
Preparation of 3-amino-5-(pyrrolidin-1-ylmethyl)benzonitrile (a
Compound of the Formula (VIII) wherein
R.sup.b=3-cyano-5-(pyrrolidin-1-ylmethyl))
[0218] To a stirred solution of 3-(bromomethyl)-5-nitrobenzonitrile
(1.50 g, 6.22 mmol) and pyrrolidine (0.53 g, 7.46 mmol) in
CH.sub.2Cl.sub.2 (15 mL) was added triethylamine (1.88 g, 18.68
mmol) dropwise at 0.degree. C., and the mixture was stirred at room
temperature overnight. The reaction mixture was evaporated to
dryness under reduced pressure, and the residue was diluted with
water (15 mL) and extracted with EtOAc (3.times.50 mL). The EtOAc
solution was dried over anhydrous Na.sub.2SO.sub.4, filtered, and
evaporated to dryness under reduced pressure. The residue was
purified by MPLC on silica gel using a mixture of EtOAc and hexane
as eluent to give 3-nitro-5-(pyrrolidin-1-ylmethyl)benzonitrile
(1.30 g, 90%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 8.45 (br s, 1H), 8.39 (br t, 1H, J=1.6 Hz), 8.02 (br s,
1H), 3.78 (s, 2H), 2.56 (br s, 4H), 1.84 (br s, 4H).
[0219] The titled compound was prepared as described in Preparative
Example 11 by using 3-nitro-5-(pyrrolidin-1-ylmethyl)benzonitrile
in place of 3-(dimethylamino)-5-nitrobenzonitrile. Yield: 85%;
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 6.99 (pseudo t, 1H,
J=1.6 Hz), 6.94 (pseudo t, 1H, J=1.6 Hz), 6.79 (dd, 1H, J=2.4, 1.6
Hz), 3.87 (br s, 2H), 3.56 (s, 2H), 2.54 (m, 4H), 1.81 (m, 4H).
Preparative Example 21
Preparation of 3-amino-4-(morpholinomethyl)benzonitrile (a Compound
of the Formula (VIII) wherein
R.sup.b=5-cyano-2-(morpholinomethyl))
[0220] To a stirred solution of 4-(bromomethyl)-3-nitrobenzonitrile
(7.12 g, 29.55 mmol) and morpholine (3.09 g, 35.45 mmol) in
CH.sub.2Cl.sub.2 (98 mL) was added triethylamine (8.97 g, 88.64
mmol) dropwise at 0.degree. C. The mixture was stirred at room
temperature for 1.5 h and evaporated to dryness under reduced
pressure. The residue was diluted with water (40 mL) and extracted
with CH.sub.2Cl.sub.2 (3.times.100 mL). The CH.sub.2Cl.sub.2
solution was washed with water (50 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated to dryness under reduced
pressure. The residue was purified by MPLC on silica gel using a
mixture of EtOAc and hexane as eluent to give
4-(morpholinomethyl)-3-nitrobenzonitrile (5.84 g, 80%) as a yellow
solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.12 (s, 1H),
7.83 (br s, 2H), 3.84 (s, 2H), 3.67 (t, 4H, J=4.6 Hz), 2.45 (t, 4H,
J=4.6 Hz).
[0221] The titled compound was prepared as described in Preparative
Example 11 by using 4-(morpholinomethyl)-3-nitrobenzonitrile in
place of 3-(dimethylamino)-5-nitrobenzonitrile. Yield: 78%; .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 7.05 (d, 1H, J=8.0 Hz), 6.92
(dd, 1H, J=8.0, 1.6 Hz), 6.86 (d, 1H, J=1.6 Hz), 5.02 (br s, 2H),
3.68 (br t, 4H, J=4.0 Hz), 3.53 (s, 2H), 2.41 (br s, 4H).
Preparative Example 22
Preparation of 3-amino-2-(morpholinomethyl)benzonitrile (a Compound
of the Formula (VIII) wherein
R.sup.b=3-cyano-2-(morpholinomethyl))
[0222] To a stirred solution of 2-(bromomethyl)-3-nitrobenzonitrile
(1.10 g, 4.56 mmol) and morpholine (0.80 g, 9.13 mmol) in
CH.sub.2Cl.sub.2 (15 mL) was added triethylamine (1.85 g, 18.25
mmol) dropwise at 0.degree. C. The mixture was stirred at room
temperature for 1.5 h and evaporated to dryness under reduced
pressure. The residue was diluted with water (10 mL) and extracted
with CH.sub.2Cl.sub.2 (3.times.50 mL). The CH.sub.2Cl.sub.2
solution was dried over anhydrous Na.sub.2SO.sub.4, filtered, and
evaporated to dryness under reduced pressure. The residue was
purified by MPLC on silica gel using a mixture of EtOAc and hexane
as eluent to give 2-(morpholinomethyl)-3-nitrobenzonitrile (1.02 g,
90%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
7.90 (br d, 1H, J=8.0 Hz), 7.84 (dd, 1H, J=8.0, 1.2 Hz), 7.56 (t,
1H, J=8.0 Hz), 3.99 (s, 2H), 3.60 (br t, 4H, J=4.4 Hz), 2.46 (br s,
4H).
[0223] The titled compound was prepared as described in Preparative
Example 11 by using 2-(morpholinomethyl)-3-nitrobenzonitrile in
place of 3-(dimethylamino)-5-nitrobenzonitrile. Yield: 82%; .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 7.15 (t, 1H, J=7.6 Hz), 7.01 (d,
1H, J=7.6 Hz), 6.83 (d, 1H, J=7.6 Hz), 5.00 (br s, 2H), 3.78 (s,
2H), 3.69 (br s, 4H), 2.50 (br s, 4H).
Preparative Example 23
Preparation of 3-amino-5-(morpholinomethyl)benzonitrile (a Compound
of the Formula (VIII) wherein
R.sup.b=3-cyano-5-(morpholinomethyl))
[0224] To a stirred solution of 3-(bromomethyl)-5-nitrobenzonitrile
(1.50 g, 6.22 mmol) and morpholine (0.65 g, 7.46 mmol) in
CH.sub.2Cl.sub.2 (15 mL) was added triethylamine (1.88 g, 18.66
mmol) dropwise at 0.degree. C. The mixture was stirred at room
temperature overnight and then evaporated to dryness under reduced
pressure. The residue was diluted with water (15 mL) and extracted
with EtOAc (3.times.50 mL). The EtOAc solution was dried over
anhydrous Na.sub.2SO.sub.4, filtered and evaporated to dryness
under reduced pressure. The residue was purified by MPLC on silica
gel using a mixture of EtOAc and hexane as eluent to give
3-(morpholinomethyl)-5-nitrobenzonitrile (0.87 g, 85%) as an
off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.45
(br s, 1H), 8.41 (br s, 1H), 8.01 (br s, 1H), 3.74 (br t, 4H, J=4.4
Hz), 3.64 (s, 2H), 2.48 (br t, 4H, J=4.4 Hz).
[0225] The titled compound was prepared as described in Preparative
Example 11 by using 3-(morpholinomethyl)-5-nitrobenzonitrile in
place of 3-(dimethylamino)-5-nitrobenzonitrile. Yield: 85%; .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 7.00 (br t, 1H, J=1.6 Hz), 6.93
(br s, 1H), 6.81 (dd, 1H, J=2.4, 1.6 Hz), 3.88 (br s, 2H), 3.74 (br
t, 4H, J=4.6 Hz), 3.44 (s, 2H), 2.47 (br s, 4H).
Preparative Example 24
[0226] Preparation of 2-(2-fluorophenoxy)acetaldehyde (a compound
of the formula (IX) wherein R.sup.b=2-fluoro, X.dbd.O). This
compound was prepared by the following 2 steps.
[0227] A stirred mixture of 2-fluorophenol (1.00 g, 8.92 mmol),
2-bromo-1,1-diethoxyethane (1.75 g, 8.92 mmol), and K.sub.2CO.sub.3
(1.47 g, 10.7 mmol) in anhydrous DMF (10 mL) was heated at
110.degree. C. overnight. The reaction mixture was poured into ice
cold water (15 mL) and extracted with EtOAc (2.times.100 mL). The
EtOAc solution was washed with water (25 mL) and brine (25 mL),
dried over anhydrous Na.sub.2SO.sub.4, filtered, and evaporated to
dryness under reduced pressure. The residue was purified by MPLC on
silica gel using a mixture of EtOAc and hexane as eluent to give
1-(2,2-diethoxyethoxy)-2-fluorobenzene (1.65 g, 81%) as a viscous
liquid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.09-6.96 (m,
3H), 6.93-6.87 (m, 1H), 4.85 (t, 1H, J=5.2 Hz), 4.07 (d, 2H, J=5.2
Hz), 3.82-3.74 (m, 2H), 3.69-3.61 (m, 2H), 1.24 (t, 6H, J=7.0
Hz).
[0228] To a stirred solution of
1-(2,2-diethoxyethoxy)-2-fluorobenzene (1.65 g, 7.23 mmol) in a
mixture of 1,4-dioxane (50 mL) and water (40 mL) at 0.degree. C.
was added conc. HCl (17.6 mL), and the mixture was stirred at room
temperature overnight. The reaction mixture was cooled to 0.degree.
C., neutralized with saturated NaHCO.sub.3 solution, and extracted
with EtOAc (2.times.200 mL). The EtOAc solution was dried over
anhydrous Na.sub.2SO.sub.4, filtered, and evaporated to dryness
under reduced pressure. The residue was purified by MPLC on silica
gel using a mixture of EtOAc and hexane as eluent to give the
titled compound (0.78 g, 71%) as a viscous liquid. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 9.87 (s, 1H), 7.12 (ddd, 1H, J=11.4, 8.2,
1.6 Hz), 7.08-7.04 (m, 1H), 7.01-6.95 (m, 1H), 6.91 (td. 1H, J=8.2,
1.6 Hz), 4.63 (s, 2H).
Preparative Example 25
[0229] Preparation of 2-(2-fluorophenylthio)acetaldehyde (a
compound of the formula (IX) wherein R.sup.b=2-fluoro, X.dbd.S).
This compound was prepared by the following 2 steps.
[0230] A mixture of 2-fluorothiophenol (1.00 g, 7.80 mmol),
bromoacetaldehyde diethyl acetal (1.41 mL, 9.36 mmol), and
Cs.sub.2CO.sub.3 (3.05 g, 9.36 mmol) in anhydrous DMF (20 mL) was
stirred under N.sub.2 at room temperature overnight. The reaction
mixture was filtered through a sintered funnel, and the filtrate
was diluted with water (20 mL). The aqueous mixture was extracted
with Et.sub.2O (3.times.100 mL), and the organic phase was dried
over anhydrous MgSO.sub.4, filtered, and evaporated to dryness
under reduced pressure. The residue was purified by MPLC on silica
gel using a mixture of EtOAc and hexane as eluent to give
(2,2-diethoxyethyl)(2-fluorophenyl)sulfane (1.81 g, 95%) as a
viscous liquid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
7.46-7.41 (m, 1H), 7.24-7.18 (m, 1H), 7.09-7.02 (m, 1H), 4.64 (t,
1H, J=5.6 Hz), 3.69-3.61 (m, 2H), 3.56-3.49 (m, 2H), 3.10 (d, 2H,
J=5.6 Hz), 1.17 (t, 6H, J=7.2 Hz).
[0231] To a stirred solution of
(2,2-diethoxyethyl)(2-fluorophenyl)sulfane (1.00 g, 4.09 mmol) in a
mixture of 1,4-dioxane (30 mL) and water (25 mL) at 0.degree. C.
was added conc. HCl (9 mL), and the mixture was stirred at room
temperature for 2 h. The reaction mixture was cooled to 0.degree.
C., neutralized with saturated NaHCO.sub.3 solution, and extracted
with CH.sub.2Cl.sub.2 (3.times.50 mL). The organic phase was washed
with water (50 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered, and evaporated to dryness under reduced pressure to give
the titled compound (0.59 g, 85%) as a viscous liquid, which was
immediately used for the next step without further purification.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.56 (td, 1H, J=3.2, 1.2
Hz), 7.42-7.38 (m, 1H), 7.31-7.25 (m, 1H), 7.12-7.06 (m, 2H), 3.58
(d, 2H, J=3.2 Hz).
Preparative Example 26
[0232] Preparation of 3-(methyl(2-oxoethyl)amino)benzonitrile (a
compound of the formula (IX) wherein R.sup.b=3-cyano, X.dbd.NMe).
This compound was prepared by the following 3 steps started with
commercially available 3-aminobenzonitrile.
[0233] To a stirred solution of 3-aminobenzonitrile (2.50 g, 21.10
mmol) in anhydrous DMSO (30 mL) at 0.degree. C. was added NaH (0.61
g, 25.39 mmol) portionwise, and the mixture was stirred at room
temperature for 20 min and then treated with bromoacetaldehyde
diethyl acetal (4.20 g, 21.10 mmol). After 2 h, to it, saturated
aqueous NH.sub.4Cl (20 mL) was added slowly at 0.degree. C., and
the reaction mixture was extracted with EtOAc (2.times.50 mL). The
EtOAc solution was dried over anhydrous Na.sub.2SO.sub.4, filtered,
and evaporated to dryness under reduced pressure. The residue was
purified by MPLC on silica gel using EtOAc and hexane as eluent to
give 3-(2,2-diethoxyethylamino)benzonitrile (0.86 g, 17%) as a
light orange oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.22
(td, 1H, J=7.8, 0.6 Hz), 6.97 (m, 1H), 6.84-6.81 (m, 2H), 4.67 (t,
1H, J=5.4 Hz), 3.77-3.69 (m, 2H), 3.61-3.53 (m, 2H), 3.24 (d, 2H,
J=5.6 Hz), 1.24 (t, 6H, J=7.0 Hz).
[0234] To a stirred solution of
3-(2,2-diethoxyethylamino)benzonitrile (0.84 g, 3.59 mmol) in
anhydrous DMF (5 mL) at 0.degree. C. was added NaH (0.10 g, 4.30
mmol) portionwise. After 20 min, MeI (0.61 g, 4.30 mmol) was added,
and the mixture was stirred at room temperature for 6 h. The
reaction mixture was cooled to 0.degree. C., and to it, aqueous
NH.sub.4Cl (10 mL) solution was added dropwise. The aqueous mixture
was extracted with CHCl.sub.3 (2.times.30 mL), and the organic
phase was dried over anhydrous Na.sub.2SO.sub.4, filtered, and
evaporated to dryness under reduced pressure. The residue was
purified by MPLC on silica gel using a mixture of EtOAc and hexane
as eluent to give 3-((2,2-diethoxyethyl)(methyl)amino)benzonitrile
(0.65 g, 73%) as a viscous liquid. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.28-7.24 (m, 1H), 6.96-6.93 (m, 3H), 4.60(t,
1H, J=5.2 Hz), 3.76-3.69 (m, 2H), 3.55-3.47 (m, 2H), 3.46 (d, 2H,
J=5.2 Hz), 3.02 (s, 3H), 1.20 (t, 6H, J=7.0 Hz).
[0235] To a stirred solution of
3-((2,2-diethoxyethyl)(methyl)amino)benzonitrile (0.65 g, 2.61
mmol) in anhydrous dioxane (6 mL) at 0.degree. C. was added 1 N HCl
(4.30 mmol) dropwise, and the mixture was stirred at room
temperature for 1 h. The reaction mixture was cooled to 0.degree.
C., neutralized with aqueous NaHCO.sub.3 solution, and extracted
with CHCl.sub.3 (2.times.30 mL). The CHCl.sub.3 solution was dried
over anhydrous Na.sub.2SO.sub.4, filtered, and evaporated to
dryness under reduced pressure to give the titled compound (0.24 g,
52%) as a viscous liquid, which was used for the next step without
further purification. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
9.74 (t, 1H, J=0.8 Hz), 7.29 (ddd, 1H, J=8.8, 7.4, 0.8 HZ), 7.02
(ddd, 1H, J=7.4, 0.8, 1.2 Hz), 6.86 (dd, 1H, J=2.4, 1.2 Hz), 6.82
(ddd, 1H, J=8.8, 2.4, 1.2 Hz) 4.14 (d, 2H, J=0.8 Hz), 3.10 (s,
3H).
Preparative Example 27
[0236] Preparation of 2-((2-fluorophenyl)(methyl)amino)acetaldehyde
(a compound of the formula (IX) wherein R.sup.b=2-fluoro,
X.dbd.NMe). This compound was prepared by the following 3 steps
started with commercially available 2-fluoroaniline.
[0237] A stirred mixture of 2-fluoroaniline (2.00 g, 17.90 mmol),
bromoacetaldehyde dimethyl acetal (3.25 mL, 21.40 mmol), and
Cs.sub.2CO.sub.3 (11.70 g, 35.80 mmol) in anhydrous DMF (10 mL) was
heated to 120.degree. C. overnight. The reaction mixture was
evaporated to dryness under reduced pressure, and the residue was
extracted with Et.sub.2O (2.times.150 mL). The Et.sub.2O solution
was washed with water (4.times.50 mL) and brine (2.times.50 mL),
dried over anhydrous MgSO.sub.4, filtered, and evaporated to
dryness under reduced pressure. The residue was purified by MPLC on
silica gel using a mixture of EtOAc and hexane as eluent to give
N-(2,2-diethoxyethyl)-2-fluoroaniline (2.00 g, 49%) as a colorless
oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.03-6.95 (m, 2H),
6.82-6.77 (m, 1H), 6.71-6.65 (m, 1H), 4.72 (t, 1H, J=5.6 Hz),
3.78-3.71 (m, 2H), 3.62-3.54 (m, 2H), 3.29 (d, 2H, J=5.6 Hz),
1.26-1.22 (m, 6H).
[0238] To a stirred solution of
N-(2,2-diethoxyethyl)-2-fluoroaniline (1.00 g, 4.40 mmol) in
anhydrous DMF (10 mL) at 0.degree. C. was added NaH (0.16 g, 6.60
mmol) portionwise. After 30 min, MeI (0.5 mL, 8.80 mmol) was added,
and the mixture was stirred at room temperature overnight. The
reaction mixture was extracted with EtOAc (2.times.100 mL), and the
EtOAc solution was washed with water (50 mL) and brine (50 mL),
dried over anhydrous Na.sub.2SO.sub.4, filtered, and evaporated to
dryness under reduced pressure to give
N-(2,2-diethoxyethyl)-2-fluoro-N-methylaniline (0.41 g, 38%) as a
colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.05-6.96
(m, 3H), 6.83-6.81 (m, 1H), 4.69 (t, 1H, J=5.2 Hz), 3.72-3.64 (m,
2H), 3.55-3.49 (m, 2H), 3.33 (dd, 2H, J=5.2, 1.2 Hz), 2.97 (s, 3H),
1.19-1.53 (m, 6H).
[0239] To a stirred solution of
N-(2,2-diethoxyethyl)-2-fluoro-N-methylaniline (0.40 g, 1.60 mmol)
in 1,4-dioxane (5 mL) at 0.degree. C. was added 2.5 N HCl (5 mL)
dropwise, and the mixture was stirred at room temperature
overnight. The reaction mixture was cooled to 0.degree. C.,
neutralized with saturated NaHCO.sub.3 solution, and extracted with
CHCl.sub.3 (2.times.50 mL). The CHCl.sub.3 solution was washed with
water (20 mL) and brine (20 mL), dried over Na.sub.2SO.sub.4,
filtered, and evaporated to dryness under reduced pressure to give
the titled compound (0.27 g, 98%) as a colorless oil, which was
used for next step without further purification. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 9.80 (dd, 1H, J=2.4, 1.2 Hz), 7.07-6.89
(m, 4H), 3.91 (dd, 2H, J=1.8, 0.8 Hz), 2.97 (s, 3H).
Practice Example 1
Preparation of
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-vinylaniline (Example 37)
##STR00006##
[0241] To a stirred solution of
4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidaz-
ole-2-carbaldehyde (4.00 g, 13.14 mmol) in 1,2-dichloroethane (240
mL) were added 3-vinylaniline (2.36 g, 19.71 mmol) and AcOH (0.79
g, 13.14 mmol), and the mixture was heated at 80.degree. C. for 2
h. The reaction mixture was cooled to 0.degree. C. and, to it, was
added NaBH(OAc).sub.3 (5.56 g, 26.20 mmol). The mixture was stirred
at 40.degree. C. overnight, and then the pH of the reaction mixture
was adjusted to 7-8 at 0.degree. C. with 10% K.sub.2CO.sub.3
solution. The reaction mixture was extracted with 5% MeOH in
CHCl.sub.3 (2.times.200 mL), and the organic phase was dried over
anhydrous Na.sub.2SO.sub.4, filtered, and evaporated to dryness
under reduced pressure. The residue was purified by MPLC on silica
gel using a mixture of MeOH and CH.sub.2Cl.sub.2 (1:19 (v/v)) as
eluent to give the titled compound (2.89 g, 63%) as a solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.59 (br s, 1H), 8.94
(s, 1H), 8.37 (s, 1H), 7.81 (d, 1H, J=9.2 Hz), 7.77 (d, 1H, J=9.2
Hz), 7.45 (t, 1H, J=7.8 Hz), 7.20 (br d, 1H, overlapped, J=7.6 Hz),
7.15 (t, 1H, overlapped, J=7.8 Hz), 7.00 (d, 1H, J=8.0 Hz), 6.86
(d, 1H, J=7.6 Hz), 6.75 (t, 1H, J=2.0 Hz), 6.63 (dd, 1H,
overlapped, J=17.6, 10.8 Hz), 6.61 (dd, 1H, overlapped, J=8.0, 2.0
Hz), 5.69 (dd, 1H, J=17.6, 0.8 Hz), 5.21 (dd, 1H, J=10.8, 0.8 Hz),
4.55 (s, 2H), 4.39 (br s, 1H), 2.51 (s, 3H); MS (ESI) m/z 408.21
(MH.sup.+).
Practice Example 2
Preparation of
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-vinylaniline hydrochloride (Example 38)
##STR00007##
[0243] A stirred suspension of
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-vinylaniline (1.00 g, 2.45 mmol) in anhydrous
CHCl.sub.3 (12 mL) was heated at 50.degree. C. to give a clear
solution. The CHCl.sub.3 solution was cooled to 0.degree. C. and,
to it, was added 1.0 M HCl in Et.sub.2O (7.36 mL, 7.36 mmol). After
5 min, the precipitates were filtered under N.sub.2 and dried
thoroughly over P.sub.2O.sub.5 in vacuo to give the titled compound
(1.07 g, 98%) as a yellow powder. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.49 (dd, 1H, J=1.6, 0.8 Hz), 8.65 (s, 1H),
7.97 (dd, 1H, J=9.2, 0.8 Hz), 7.86 (dd, 1H, overlapped, J=9.2, 1.6
Hz), 7.85 (t, 1H, overlapped, J=7.8 Hz), 7.65 (d, 1H, J=8.0 Hz),
7.38 (d, 1H, J=7.6 Hz), 7.12 (t, 1H, J=7.8 Hz), 6.91 (t, 1H, J=1.6
Hz), 6.79 (d, 1H, J=7.6 Hz), 6.71 (dd, 1H, J=8.0, 1.6 Hz), 6.64
(dd, 1H, J=17.6, 11.2 Hz), 5.80 (dd, 1H, J=17.6, 0.8 Hz), 5.20 (dd,
1H, J=11.2, 0.8 Hz), 4.79 (s, 2H), 2.51 (s, 3H).
Practice Example 3
Preparation of
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-vinylaniline sulfate (Example 39)
##STR00008##
[0245] To a stirred suspension of
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-3-vinylaniline (100 mg, 0.25 mmol) in anhydrous
EtOH (2 mL) at 0.degree. C. was added 10% H.sub.2SO.sub.4 in
anhydrous EtOH (0.20 mL, 0.37 mmol). The mixture was allowed to
warm to room temperature and stirred for 10 min. The reaction
mixture was diluted with anhydrous Et.sub.2O (8 mL) and stirred for
an additional 10 min. The precipitates were filtered under N.sub.2,
washed with anhydrous Et.sub.2O (4.times.4 mL), and then dried
thoroughly over P.sub.2O.sub.5 in vacuo to give the titled compound
(79 mg, 64%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.40 (dd, 1H, J=1.6, 0.8 Hz), 8.63 (s, 1H), 7.98 (dd, 1H,
J=9.2, 0.8 Hz), 7.84 (t, 1H, J=8.0 Hz), 7.76 (dd, 1H, J=9.2, 1.6
Hz), 7.43 (d, 1H, J=7.6 Hz), 7.40 (d, 1H, J=8.0 Hz), 7.13 (t, 1H,
J=7.8 Hz), 6.80 (br s, 1H), 6.79 (d, 1H, overlapped, J=7.6 Hz),
6.64 (dd, 1H, overlapped, J=17.6, 11.2 Hz), 6.63 (dd, 1H,
overlapped, J=7.6, 2.0 Hz), 5.74 (dd, 1H, J=17.6, 0.8 Hz), 5.21
(dd, 1H, J=11.2, 0.8 Hz), 4.68 (s, 2H), 2.58 (s, 3H).
Practice Example 4
Preparation of
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methylamino)-4-((dimethylamino)methyl)benzonitrile
(Example 116)
##STR00009##
[0247] To a stirred solution of
4-((1,2,4)triazolo(1,5-a)pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidaz-
ole-2-carbaldehyde (0.50 g, 1.64 mmol) in 1,2-dichloroethane (30
mL) were added 3-amino-4-((dimethylamino)methyl)benzonitrile (0.43
g, 2.46 mmol) and AcOH (0.20 g, 3.29 mmol), and the mixture was
heated at 80.degree. C. overnight. The reaction mixture was
concentrated under reduced pressure, and the residue was dissolved
in anhydrous MeOH (30 mL). To a methanolic solution at 0.degree. C.
was added NaBH.sub.4 (0.25 g, 6.57 mmol), and then the mixture was
allowed to warm to room temperature and stirred for an additional 3
h. The pH of the reaction mixture was adjusted to 7-8 at 0.degree.
C. with 1 N HCl, and then MeOH was removed under reduced pressure.
The aqueous mixture was extracted with CH.sub.2Cl.sub.2 (2.times.50
mL), and the CH.sub.2Cl.sub.2 solution was dried over anhydrous
Na.sub.2SO.sub.4, filtered, and evaporated to dryness under reduced
pressure. The residue was purified by MPLC on silica gel using a
mixture of MeOH and CH.sub.2Cl.sub.2 (1:19 (v/v)) as eluent to give
the titled compound (0.60 g, 79%) as a white solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.99 (s, 1H), 8.36 (s, 1H), 7.86 (dd,
1H, J=9.2, 1.6 Hz), 7.78 (dd, 1H, J=9.2, 0.8 Hz), 7.47 (t, 1H,
J=7.6 Hz), 7.23 (br d, 1H, J=7.6 Hz), 7.09 (d, 1H, J=7.6 Hz), 7.01
(d, 1H, J=7.6 Hz), 6.98 (dd, 1H, J=7.6, 1.6 Hz), 6.93 (br s, 1H),
4.59 (s, 2H), 3.63 (s, 2H), 2.53 (s, 3H), 2.33 (s, 6H); MS (ESI)
m/z 464.23 (MH.sup.+).
[0248] The compounds listed in the following Table 1 were prepared
in an analogous manner to those described in the Practice Examples
1-4 above. The mass spectroscopy data of these compounds are
included in the Table 1.
TABLE-US-00001 TABLE 1 Exam- MS (ESI) ple Structure .sup.1H NMR
(ppm) m/z (MH.sup.+) 1 ##STR00010## (400 MHz, CDCl.sub.3) .delta.
10.43 (br s, 1 H), 8.96 (s, 1 H), 8.37 (s, 1 H), 7.82 (dd, 1 H, J =
9.2, 1.6 Hz), 7.77 (dd, 1 H, J = 9.2, 0.8 Hz), 7.45 (t, 1 H, J =
7.6 Hz), 7.25-7.19 (m, 3 H), 7.01 (d, 1 H, J = 7.6 Hz), 6.80 (tt, 1
H, J = 8.0, 1.2 Hz), 6.74-6.72 (m, 2 H), 4.55 (s, 2 H), 2.53 (s, 3
H) 382.19 2 ##STR00011## (400 MHz, CDCl.sub.3) .delta. 11.34 (br s,
1 H), 8.96 (dd, 1 H, J = 1.6, 0.8 Hz), 8.35 (s, 1 H), 7.81 (dd, 1
H, J = 9.2, 1.6 Hz), 7.74 (dd, 1 H, J = 9.2, 0.8 Hz), 7.45 (t, 1 H,
J = 7.6 Hz), 7.23 (d, 1 H, J = 7.6 Hz), 6.97-6.90 (m, 2 H), 6.94
(dd, 1 H, J = 8.0, 1.2 Hz), 6.72 (td, 1 H, J = 8.4, 1.6 Hz),
6.69-6.63 (m, 1 H), 4.51 (s, 2 H), 2.35 (s, 3 H). 400.18 3
##STR00012## (400 MHz, DMSO-d.sub.6) .delta. 9.44 (d, 1 H, J = 0.8
Hz), 8.62 (s, 1 H), 7.96 (dd, 1 H, J = 9.2, 0.8 Hz), 7.83 (t, 1 H,
J = 8.0 Hz), 7.80 (dd, 1 H, J = 9.2, 1.6 Hz), 7.53 (d, 1 H, J = 8.0
Hz), 7.38 (d, 1 H, J = 7.6 Hz), 7.10 (ddd, 1 H, J = 12.0, 8.0, 1.2
Hz), 7.01 (td, 1 H, J = 7.6, 1.2 Hz), 6.88 (br t, 1 H, J = 8.6 Hz),
6.70-6.64 (m, 1 H), 4.75 (s, 2 H), 2.54 (s, 3 H) 4 ##STR00013##
(400 MHz, DMSO-d.sub.6) .delta. 9.40 (dd, 1 H, J = 2.0, 0.8 Hz),
8.64 (s, 1 H), 7.99 (dd, 1 H, J = 9.2, 0.8 Hz), 7.85 (t, 1 H, J =
8.0 Hz), 7.77 (dd, 1 H, J = 9.2, 2.0 Hz), 7.42 (pseudo t, 2 H, J =
7.4 Hz), 7.11 (ddd, 1 H, J = 12.0, 8.0, 1.2 Hz), 7.02 (td, 1 H, J =
7.6, 1.2 Hz), 6.82 (td, 1 H, J = 8.0, 1.2 Hz), 6.71-6.65 (m, 1 H),
4.73 (s, 2 H), 2.59 (s, 3 H) 5 ##STR00014## (400 MHz, CDCl.sub.3)
.delta. 8.94 (t, 1 H, J = 1.4 Hz), 8.36 (s, 1 H), 7.79 (dd, 1 H, J
= 9.2, 1.6 Hz), 7.75 (dd, 1 H, J = 9.2, 0.8 Hz), 7.46 (t, 1 H, J =
7.8 Hz), 7.23 (d, 1 H, J = 8.0 Hz), 7.13-7.07 (m, 1 H), 7.01 (d, 1
H, J = 7.6 Hz), 6.47-6.41 (m, 2 H), 6.37 (dt, 1 H, J = 8.8, 2.4
Hz), 4.49 (s, 2 H), 2.49 (s, 3 H) 400.19 6 ##STR00015## (400 MHz,
CDCl.sub.3) .delta. 8.95 (dd, 1 H, J = 1.6, 1.2 Hz), 8.37 (s, 1 H),
7.80 (dd, 1 H, J = 9.2, 1.6 Hz), 7.76 (dd, 1 H, J = 9.2, 1.2 Hz),
7.46 (t, 1 H, J = 7.6 Hz), 7.23 (d, 1 H, J = 7.6 Hz), 7.01 (d, 1 H,
J = 7.6 Hz), 6.92-6.88 (m, 2 H), 6.65- 6.62 (m, 2 H), 4.49 (s, 2
H), 2.51 (s, 3 H) 400.19 7 ##STR00016## (400 MHz, CDCl.sub.3)
.delta. 8.96 (br s, 1 H), 8.38 (s, 1 H), 7.82 (dd, 1 H, J = 9.2,
1.6 Hz), 7.78 (dd, 1 H, J = 9.2, 0.8 Hz), 7.47 (t, 1 H, J = 7.6
Hz), 7.24 (d, 1 H, J = 7.6 Hz), 7.02 (dd, 1 H, J = 7.6, 0.4 Hz),
6.94-6.88 (m, 1 H), 6.60-6.51 (m, 2 H), 4.71 (br s, 1 H), 4.58 (d,
2 H, J = 3.6 Hz), 2.51 (s, 3 H) 418.18 8 ##STR00017## (400 MHz,
CDCl.sub.3) .delta. 8.94 (t, 1 H, J = 1.4 Hz), 8.38 (s, 1 H), 7.81
(dd, 1 H, overlapped, J = 9.2, 1.6 Hz), 7.78 (dd, 1 H, overlapped,
J = 9.2, 1.2 Hz), 7.47 (t, 1 H, J = 7.8 Hz), 7.24 (d, 1 H, J = 8.0
Hz), 7.03 (d, 1 H, J = 7.6 Hz), 7.04-6.95 (m, 1 H), 6.52 (ddd, 1 H,
J = 12.4, 6.8, 2.8 Hz), 6.42- 6.37 (m, 1 H), 4.48 (s, 2 H), 2.55
(s, 3 H) 418.18 9 ##STR00018## (400 MHz, CDCl.sub.3) .delta. 8.94
(t, 1 H, J = 1.2 Hz), 8.38 (s, 1 H), 7.81 (dd, 1 H, overlapped, J =
9.2, 1.6 Hz), 7.79 (dd, 1 H, overlapped, J = 9.2, 1.2 Hz), 7.47 (t,
1 H, J = 7.8 Hz), 7.24 (d, 1 H, J = 8.0 Hz), 7.03 (d, 1 H, J = 7.6
Hz), 6.24-6.19 (m, 3 H), 4.71 (br s, 1 H), 4.50 (s, 2 H), 2.55 (s,
3 H) 418.18 10 ##STR00019## (400 MHz, CDCl.sub.3) .delta. 8.97 (br
s, 1 H), 8.37 (s, 1 H), 7.82 (dd, 1 H, J = 9.2, 1.6 Hz), 7.77 (dd,
1 H, J = 9.2, 1.0 Hz), 7.46 (t, 1 H, J = 7.6 Hz), 7.29 (dd, 1 H, J
= 7.6, 1.6 Hz), 7.23 (br d, 1 H, J = 7.6 Hz), 7.14 (td, 1 H, J =
8.4, 1.6 Hz), 7.01 (dd, 1 H, J = 7.6, 0.4 Hz), 6.75 (dd, 1 H, J =
8.8, 1.4 Hz), 6.72 (td, 1 H, J = 8.4, 1.6 Hz), 5.01 (br s, 1 H),
4.60 (br s, 2 H), 2.50 (s, 3 H) 416.16 11 ##STR00020## (400 MHz,
DMSO-d.sub.6) .delta. 9.43 (s, 1 H), 8.61 (s, 1 H), 7.95 (dd, 1 H,
J = 9.2, 0.8 Hz), 7.82 (t, 1 H, overlapped, J = 7.8 Hz), 7.81 (dd,
1 H, overlapped, J = 9.2, 2.0 Hz), 7.49 (d, 1 H, J = 8.0 Hz), 7.36
(d, 1 H, J = 7.6 Hz), 7.32 (dd, 1 H, J = 7.8, 1.4 Hz), 7.17 (td, 1
H, J = 8.4, 1.2 Hz), 6.87 (dd, 1 H, J = 8.4, 1.2 Hz), 6.69 (td, 1
H, J = 7.8, 1.4 Hz), 6.15 (br s, 1 H), 4.76 (s, 2 H), 2.55 (s, 3 H)
12 ##STR00021## (400 MHz, CDCl.sub.3) .delta. 8.95 (t, 1 H, J = 1.6
Hz), 8.37 (s, 1 H), 7.81 (dd, 1 H, J = 9.2, 1.6 Hz), 7.77 (dd, 1 H,
J = 9.2, 1.2 Hz), 7.47 (t, 1 H, J = 7.8 Hz), 7.24 (d, 1 H, J = 8.0
Hz), 7.10 (t, 1 H, J = 8.0 Hz), 7.02 (d, 1 H, J = 7.6 Hz), 6.75
(ddd, 1 H, J = 8.0, 2.0, 0.8 Hz), 6.69 (t, 1 H, J = 2.0 Hz), 6.57
(dd, 1 H, J = 8.0, 2.4, 0.8 Hz), 4.51 (s, 2 H), 2.52 (s, 3 H)
416.16 13 ##STR00022## (400 MHz, DMSO-d.sub.6) .delta. 9.45 (dd, 1
H, J = 1.6, 0.8 Hz), 8.63 (s, 1 H), 7.97 (dd, 1 H, J = 9.2, 0.8
Hz), 7.85 (t, 1 H, J = 8.0 Hz), 7.81 (dd, 1 H, J = 9.2, 1.6 Hz),
7.56 (d, 1 H, J = 8.4 Hz), 7.39 (d, 1 H, J = 7.6 Hz), 7.15 (t, 1 H,
J = 8.0 Hz), 6.80 (t, 1 H, J = 2.2 Hz), 6.71-6.65 (m, 2 H), 4.71
(s, 2 H), 2.54 (s, 3 H) 14 ##STR00023## (400 MHz, CDCl.sub.3)
.delta. 8.95 (t, 1 H, J = 1.4 Hz), 8.38 (s, 1 H), 7.81 (dd, 1 H,
overlapped, J = 9.2, 1.4 Hz), 7.78 (dd, 1 H, overlapped, J = 9.2,
1.2 Hz), 7.47 (t, 1 H, J = 7.6 Hz), 7.23 (br, d, 1 H, J = 7.6 Hz),
7.16 (m, 2 H), 7.02 (br d, 1 H, J = 7.6 Hz), 6.65 (m, 2 H), 4.51
(s, 2 H) 2.54 (s, 3 H) 416.16 15 ##STR00024## (400 MHz, CDCl.sub.3)
.delta. 11.02 (br s, 1 H), 8.97 (s, 1 H), 8.36 (s, 1 H), 7.81 (dd,
1 H, J = 9.2, 1.6 Hz), 7.75 (dd, 1 H, J = 9.2, 0.8 Hz), 7.46 (t, 1
H, J = 8.0 Hz), 7.24 (d, 1 H, J = 8.0 Hz), 7.03 (t, 1 H,
overlapped, J = 8.0 Hz), 7.00 (d, 1 H, over- lapped, J = 8.0 Hz),
6.85 (dd, 1 H, J = 8.0, 1.6 Hz), 6.63 (dd, 1 H, J = 8.0, 1.6 Hz),
5.15 (t, 1 H, J = 5.6 Hz), 4.57 (d, 2 H, J = 5.6 Hz), 2.43 (s, 3 H)
450.12 16 ##STR00025## (400 MHz, CDCl.sub.3) .delta. 8.94 (t, 1 H,
J = 1.2 Hz), 8.37 (s, 1 H), 7.80 (dd, 1 H, overlapped, J = 9.2, 1.6
Hz), 7.77 (dd, 1 H, overlapped, J = 9.2, 1.2 Hz), 7.47 (t, 1 H, J =
8.0 Hz), 7.24 (br d, 1 H, J = 8.0 Hz), 7.20 (d, 1 H, J = 8.8 Hz),
7.03 (d, 1 H, J = 8.0 Hz), 6.77 (d, 1 H, J = 2.8 Hz), 6.53 (dd, 1
H, J = 8.8, 2.8 Hz), 4.47 (s, 2 H), 2.51 (s, 3 H) 450.12 17
##STR00026## (400 MHz, CDCl.sub.3/CD.sub.3OD) .delta. 8.90 (s, 1
H), 8.24 (s, 1 H), 7.71 (dd, 1 H, J = 9.2, 1.6 Hz), 7.64 (dd, 1 H,
J = 9.2, 0.8 Hz), 7.45 (t, 1 H, J = 7.6 Hz), 7.16 (br d, 1 H, J =
7.6 Hz), 6.99 (d, 1 H, J = 7.6 Hz), 6.57 (t, 1 H, J = 1.6 Hz), 6.51
(d, 2 H, J = 1.6 Hz), 4.36 (s, 2 H), 2.45 (s, 3 H) 450.12 18
##STR00027## (400 MHz, CDCl.sub.3) .delta. 10.94 (br s, 1 H), 8.97
(br s, 1 H), 8.36 (s, 1 H), 7.82 (d, 1 H, J = 9.2 Hz), 7.75 (d, 1
H, J = 9.2 Hz), 7.45 (t, 1 H, over- lapped, J = 7.8 Hz), 7.43 (dd,
1 H, J = 8.0, 1.6 Hz), 7.21 (d, 1 H, J = 8.0 Hz), 7.16 (td, 1 H, J
= 8.4, 1.2 Hz), 6.99 (d, 1 H, J = 7.6 Hz), 6.71 (dd, 1 H, J = 8.4,
1.2 Hz), 6.63 (td, 1 H, J = 8.0, 1.6 Hz), 4.99 (t, 1 H, J = 5.6
Hz), 4.57 (d, 2 H, J = 5.6 Hz), 2.44 (s, 3 H) 460.11 19
##STR00028## (400 MHz, DMSO-d.sub.6) .delta. 9.43 (dd, 1 H, J =
1.6, 0.8 Hz), 8.62 (s, 1 H), 7.96 (dd, 1 H, J = 9.2, 0.8 Hz), 7.83
(t, 1 H, J = 7.6 Hz), 7.80 (dd, 1 H, J = 9.2, 1.6 Hz), 7.50 (d, 1
H, J = 7.6 Hz), 7.48 (dd, 1 H, J = 8.0, 1.6 Hz), 7.37 (d, 1 H, J =
7.6 Hz), 7.21 (td, 1 H, J = 7.6, 1.6 Hz), 6.87 (dd, 1 H, J = 8.0,
1.2 Hz), 6.63 (td, 1 H, J = 7.6, 1.2 Hz), 6.04 (br s 1 H), 4.78 (s,
2 H), 2.55 (s, 3 H) 20 ##STR00029## (400 MHz, CDCl.sub.3) .delta.
8.89 (br s, 1 H), 8.30 (s, 1 H), 7.75 (dd, 1 H, J = 9.2, 1.6 Hz),
7.69 (d, 1 H, J = 9.2 Hz), 7.44 (br t, 1 H, J = 7.6 Hz), 7.12 (br
d, 1 H, J = 7.6 Hz), 7.00 (d, 1 H, J = 8.0 Hz), 6.97 (t, 1 H,
overlapped, J = 8.0 Hz), 6.82-6.78 (m, 2 H), 6.58 (ddd, 1 H, J =
8.2, 2.4, 0.8 Hz), 4.41 (s, 2 H), 2.49 (s, 3 H) 460.11 21
##STR00030## (400 MHz, DMSO-d.sub.6) .delta. 9.44 (d, 1 H, J = 0.8
Hz), 8.61 (s, 1 H), 7.95 (dd, 1 H, J = 9.2, 0.8 Hz), 7.83 (t, 1 H,
J = 7.8 Hz), 7.82 (dd, 1 H, J = 9.2, 1.6 Hz), 7.50 (d, 1 H, J = 8.0
Hz), 7.37 (d, 1 H, J = 7.6 Hz), 7.08 (t, 1 H, J = 8.0 Hz), 6.94 (t,
1 H, J = 2.0 Hz), 6.79 (ddd, 1 H, J = 7.6, 2.0, 0.8 Hz), 6.71 (ddd,
1 H, J = 8.4, 2.0, 0.8 Hz), 4.63 (s, 2 H), 2.55 (s, 3 H) 22
##STR00031## (400 MHz, CDCl.sub.3) .delta. 8.94 (br s, 1 H), 8.38
(s, 1 H), 7.82-7.77 (m, 2 H), 7.46 (t, 1 H, J = 7.6 Hz), 7.29 (m, 2
H), 7.21 (d, 1 H, J = 7.6 Hz), 7.02 (d, 1 H, J = 7.6 Hz), 6.61 (m,
2 H), 4.51 (s, 2 H), 4.44 (br s, 1 H), 2.54 (s, 3 H) 460.11 23
##STR00032## (400 MHz, CDCl.sub.3) .delta. 8.97 (s, 1 H), 8.37 (s,
1 H), 7.83 (dd, 1 H, J = 9.2, 1.6 Hz), 7.78 (dd, 1 H, J = 9.2, 0.8
Hz), 7.46 (t, 1 H, J = 7.8 Hz), 7.23 (br d, 1 H, J = 7.6 Hz), 7.14
(t, 1 H, overlapped, J = 8.0 Hz), 7.12 (d, 1 H, overlapped, J = 7.6
Hz), 7.01 (d, 1 H, J = 8.0 Hz), 6.76 (td, 1 H, J = 7.6, 0.8 Hz),
6.69 (d, 1 H, J = 7.6 Hz), 4.61 (s, 2 H), 2.54 (s, 3 H), 2.26 (s, 3
H) 396.21 24 ##STR00033## (400 MHz, CDCl.sub.3) .delta. 8.96 (dd, 1
H, J = 1.6, 1.2 Hz), 8.37 (s, 1 H), 7.82 (dd, 1 H, J = 9.2, 1.6
Hz), 7.78 (dd, 1 H, J = 9.2, 1.2 Hz), 7.46 (t, 1 H, J = 7.8 Hz),
7.22 (br d, 1 H, J = 8.0 Hz), 7.11 (t, 1 H, J = 7.8 Hz), 7.01 (d, 1
H, J = 7.6 Hz), 6.63 (dt, 1 H, J = 7.6, 0.8 Hz), 6.57-6.53 (m, 2
H), 4.55 (s, 2 H), 2.54 (s, 3 H), 2.29 (s, 3 H) 396.21 25
##STR00034## (400 MHz, DMSO-d.sub.6) .delta. 9.45 (dd, 1 H, J =
1.6, 0.8 Hz), 8.63 (s, 1 H), 7.97 (dd, 1 H, J = 9.2, 0.8 Hz), 7.83
(t, 1 H, J = 8.0 Hz), 7.81 (dd, 1 H, J = 9.2, 1.6 Hz), 7.56 (d, 1
H, J = 8.0 Hz), 7.37 (d, 1 H, J = 8.0 Hz), 7.02 (t, 1 H, J = 7.8
Hz), 6.60 (s, 1 H), 6.54 (dd, 1 H, J = 8.0, 2.0 Hz), 6.49 (d, 1 H,
J = 7.6 Hz), 4.69 (s, 2 H), 2.52 (s, 3 H), 2.21 (s, 3 H) 26
##STR00035## (400 MHz, CDCl.sub.3) .delta. 8.96 (t, 1 H, J = 1.2
Hz), 8.37 (s, 1 H), 7.82 (d d, 1 H, J = 9.2, 1.6 Hz), 7.77 (dd, 1
H, J = 9.2, 0.8 Hz), 7.45 (t, 1 H, J = 7.8 Hz), 7.22 (br d, 1 H, J
= 8.0 Hz), 7.03 (m, 2 H), 7.02 (d, 1 H, overlapped, J = 7.6 Hz),
6.65 (m, 2 H), 4.53 (s, 2 H), 2.53 (s, 3 H), 2.25 (s, 3 H) 396.21
27 ##STR00036## (400 MHz, CDCl.sub.3) .delta. 8.97 (s, 1 H), 8.37
(s, 1 H), 7.83 (dd, 1 H, J = 9.2, 1.6 Hz), 7.78 (dd, 1 H, J = 9.2,
0.8 Hz), 7.45 (t, 1 H, J = 7.8 Hz), 7.22 (br d, 1 H, J = 7.6 Hz),
7.03 (t, 1 H, overlapped, J = 7.8 Hz), 7.02 (d, 1 H, overlapped, J
= 8.0 Hz), 6.69 (d, 1 H, J = 7.6 Hz), 6.58 (d, 1 H, J = 8.0 Hz),
4.59 (s, 2 H), 2.54 (s, 3 H), 2.31 (s, 3 H), 2.17 (s, 3 H) 410.23
28 ##STR00037## (400 MHz, CDCl.sub.3) .delta. 8.96 (d, 1 H, J = 1.2
Hz), 8.37 (s, 1 H), 7.82 (dd, 1 H, J = 9.2, 1.6 Hz), 7.77 (dd, 1 H,
J = 9.2, 0.8 Hz), 7.45 (t, 1 H, J = 7.6 Hz), 7.22 (br d, 1 H, J =
8.0 Hz), 7.00 (d, 1 H, J = 7.6 Hz), 6.98 (d, 1 H, J = 8.0 Hz), 6.57
(d, 1 H, J = 2.4 Hz), 6.50 (dd, 1 H, J = 8.0, 2.4 Hz), 4.53 (s, 2
H), 2.54 (s, 3 H), 2.20 (s, 3 H), 2.16 (s, 3 H) 410.23 29
##STR00038## (400 MHz, CDCl.sub.3) .delta. 8.95 (dd, 1 H, J = 1.6,
1.2 Hz), 8.36 (s, 1 H), 7.79 (dd, 1 H, J = 9.2, 1.6 Hz), 7.74 (dd,
1 H, J = 9.2, 1.2 Hz), 7.45 (t, 1 H, J = 7.8 Hz), 7.22 (d, 1 H, J =
8.0 Hz), 6.99 (d, 1 H, J = 7.6 Hz), 6.44 (br s, 1 H), 6.31 (s, 2
H), 4.49 (s, 2 H), 2.48 (s, 3 H), 2.21 (s, 6 H) 410.23 30
##STR00039## (400 MHz, CDCl.sub.3) .delta. 8.97 (br s, 1 H), 8.37
(s, 1 H), 7.83 (dd, 1 H, J = 9.2, 1.6 Hz), 7.78 (dd, 1 H, J = 9.2,
0.8 Hz), 7.46 (t, 1 H, J = 7.8 Hz), 7.23 (br d, 1 H, J = 7.6 Hz),
7.16-7.11 (m, 2 H), 7.01 (d, 1 H, J = 7.6 Hz), 6.80 (td, 1 H, J =
7.6, 1.2 Hz), 6.71 (dd, 1 H, J = 8.4, 1.2 Hz), 4.60 (s, 2 H), 2.60
(q, 2 H, J = 7.6 Hz), 2.52 (s, 3 H), 1.32 (t, 3 H, J = 7.6 Hz)
410.23 31 ##STR00040## (400 MHz, CDCl.sub.3) .delta. 8.96 (d, 1 H,
J = 1.2 Hz), 8.37 (s, 1 H), 7.82 (dd, 1 H, J = 9.2, 1.6 Hz), 7.77
(dd, 1 H, J = 9.2, 1.2 Hz), 7.45 (t, 1 H, J = 7.8 Hz), 7.22 (br d,
1 H, J = 8.0 Hz), 7.14 (t, 1 H, J = 7.8 Hz), 7.01 (d, 1 H, J = 7.6
Hz), 6.66 (dd, 1 H, J = 7.6, 0.8 Hz), 6.58 (d, 1 H, J = 2.0 Hz),
6.55 (dd, 1 H, J = 7.6, 2.0 Hz), 4.55 (s, 2 H), 2.58 (q, 2 H, J =
7.6 Hz), 2.53 (s, 3 H), 1.21 (t, 3 H, J = 7.6 Hz) 410.23 32
##STR00041## (400 MHz, DMSO-d.sub.6) .delta. 9.45 (dd, 1 H, J =
1.6, 0.8 Hz), 8.63 (s, 1 H), 7.97 (dd, 1 H, J = 9.2, 0.8 Hz), 7.83
(t, 1 H, J = 8.0 Hz), 7.81 (dd, 1 H, J = 9.2, 1.6 Hz), 7.57 (d, 1
H, J = 8.0 Hz), 7.37 (d, 1 H, J = 8.0 Hz), 7.05 (t, 1 H, J = 7.6
Hz), 6.64 (d, 1 H, J = 1.6 Hz), 6.57-6.52 (m, 2 H), 4.71 (s, 2 H),
2.53 (s, 3 H), 2.50 (q, 2 H, J = 7.6 Hz), 1.14 (t, 3 H, J = 7.6 Hz)
33 ##STR00042## (400 MHz, CDCl.sub.3) .delta. 8.97 (br s, 1 H),
8.37 (s, 1 H), 7.82 (dd, 1 H, J = 9.2, 1.6 Hz), 7.76 (dd, 1 H, J =
9.2, 0.8 Hz), 7.45 (t, 1 H, J = 7.8 Hz), 7.23 (br d, 1 H,
overlapped, J = 8.0 Hz), 7.21 (dd, 1 H, overlapped, J = 7.6, 1.6
Hz), 7.12 (td, 1 H, J = 7.6, 1.6 Hz), 7.00 (d, 1 H, J = 7.6 Hz),
6.83 (td, 1 H, J = 7.6, 1.2 Hz), 6.71 (dd, 1 H, J = 8.0, 1.2 Hz),
4.58 (s, 2 H), 3.00 (heptet, 1 H, J = 6.8 Hz), 2.50 (s, 3 H), 1.31
(d, 6 H, J = 6.8 Hz) 424.24 34 ##STR00043## (400 MHz, CDCl.sub.3)
.delta. 8.96 (dd, 1 H, J = 1.4, 0.8 Hz), 8.35 (s, 1 H), 7.79 (dd, 1
H, J = 9.2, 1.4 Hz), 7.73 (dd, 1 H, J = 9.2, 0.8 Hz), 7.44 (t, 1 H,
J = 7.8 Hz), 7.21 (d, 1 H, J = 7.6 Hz), 7.11 (t, 1 H, J = 7.8 Hz),
6.99 (dd, 1 H, J = 7.8, 0.4 Hz), 6.67 (d, 1 H, J = 7.6 Hz), 6.57
(t, 1 H, J = 2.4 Hz), 6.50 (ddd, 1 H, J = 8.0, 2.4, 0.8 Hz), 4.51
(s, 2 H), 2.80 (heptet, 1 H, J = 6.8 Hz), 2.47 (s, 3 H), 1.20 (d, 6
H, J = 6.8 Hz) 424.24 35 ##STR00044## (400 MHz, CDCl.sub.3) .delta.
8.96 (t, 1 H, J = 1.2 Hz), 8.36 (s, 1 H), 7.81 (dd, 1 H, J = 9.2,
1.6 Hz), 7.75 (d, 1 H, J = 9.2 Hz), 7.44 (t, 1 H, J = 7.8 Hz), 7.21
(d, 1 H, J = 8.0 Hz), 7.06 (m, 2 H), 6.99 (d, 1 H, J = 7.6 Hz),
6.64 (m, 2 H), 4.50 (s, 2 H), 2.80 (heptet, 1 H, J = 6.8 Hz), 2.48
(s, 3 H), 1.19 (d, 6 H, J = 6.8 Hz) 424.24 36 ##STR00045## (400
MHz, CDCl.sub.3) .delta. 8.96 (br s, 1 H), 8.35 (s, 1 H), 7.80 (dd,
1 H, J = 9.2, 1.6 Hz), 7.73 (dd, 1 H, J = 9.2, 0.8 Hz), 7.44 (t, 1
H, J = 7.8 Hz), 7.28 (dd, 1 H, J = 7.6, 1.2 Hz), 7.22 (br d, 1 H, J
= 8.0 Hz), 7.15 (td, 1 H, J = 7.8, 1.2 Hz), 6.99 (d, 1 H, J = 7.6
Hz), 6.79 (dd, 1 H, over- lapped, J = 17.2, 11.2 Hz), 6.78 (td, 1
H, over- lapped, J = 7.6, 0.8 Hz), 6.68 (dd, 1 H, J = 8.2, 1.0 Hz),
5.62 (dd, 1 H, J = 17.2, 1.4 Hz), 5.34 (dd, 1 H, J = 11.2, 1.4 Hz),
4.53 (s, 2 H), 2.45 (s, 3 H) 408.21
37 ##STR00046## (400 MHz, CDCl.sub.3) .delta. 10.59 (br s, 1 H),
8.94 (s, 1 H), 8.37 (s, 1 H), 7.81 (d, 1 H, J = 9.2 Hz), 7.77 (d, 1
H, J = 9.2 Hz), 7.45 (t, 1 H, J = 7.8 Hz), 7.20 (br d, 1 H,
overlapped, J = 7.6 Hz), 7.15 (t, 1 H, overlapped, J = 7.8 Hz),
7.00 (d, 1 H, J = 8.0 Hz), 6.86 (d, 1 H, J = 7.6 Hz), 6.75 (t, 1 H,
J = 2.0 Hz), 6.63 (dd, 1 H, over- lapped, J = 17.6, 10.8 Hz), 6.61
(dd, 1 H, over- lapped, J = 8.0, 2.0 Hz), 5.69 (dd, 1 H, J = 17.6,
0.8 Hz), 5.21 (dd, 1 H, J = 10.8, 0.8 Hz), 4.55 (s, 2 H), 4.39 (br
s, 1 H), 2.51 (s, 3 H) 408.21 38 ##STR00047## (400 MHz,
DMSO-d.sub.6) .delta. 9.49 (dd, 1 H, J = 1.6, 0.8 Hz), 8.65 (s, 1
H), 7.97 (dd, 1 H, J = 9.2, 0.8 Hz), 7.86 (dd, 1 H, overlapped, J =
9.2, 1.6 Hz), 7.85 (t, 1 H, overlapped, J = 7.8 Hz), 7.65 (d, 1 H,
J = 8.0 Hz), 7.38 (d, 1 H, J = 7.6 Hz), 7.12 (t, 1 H, J = 7.8 Hz),
6.91 (t, 1 H, J = 1.6 Hz), 6.79 (d, 1 H, J = 7.6 Hz), 6.71 (dd, 1
H, J = 8.0, 1.6 Hz), 6.64 (dd, 1 H, J = 17.6, 11.2 Hz), 5.80 (dd, 1
H, J = 17.6, 0.8 Hz), 5.20 (dd, 1 H, J = 11.2, 0.8 Hz), 4.79 (s, 2
H), 2.51 (s, 3 H) 39 ##STR00048## (400 MHz, DMSO-d.sub.6) .delta.
9.40 (dd, 1 H, J = 1.6, 0.8 Hz), 8.63 (s, 1 H), 7.98 (dd, 1 H, J =
9.2, 0.8 Hz), 7.84 (t, 1 H, J = 8.0 Hz), 7.76 (dd, 1 H, J = 9.2,
1.6 Hz), 7.43 (d, 1 H, J = 7.6 Hz), 7.40 (d, 1 H, J = 8.0 Hz), 7.13
(t, 1 H, J = 7.8 Hz), 6.80 (br s, 1 H), 6.79 (d, 1 H, overlapped, J
= 7.6 Hz), 6.64 (dd, 1 H, overlapped, J = 17.6, 11.2 Hz), 6.63 (dd,
1 H, overlapped, J = 7.6, 2.0 Hz), 5.74 (dd, 1 H, J = 17.6, 0.8
Hz), 5.21 (dd, 1 H, J = 11.2, 0.8 Hz), 4.68 (s, 2 H), 2.58 (s, 3 H)
40 ##STR00049## (400 MHz, CDCl.sub.3) .delta. 10.39 (br s, 1 H),
8.96 (s, 1 H), 8.37 (s, 1 H), 7.82 (dd, 1 H, J = 9.2, 1.6 Hz), 7.78
(dd, 1 H, J = 9.2, 0.8 Hz), 7.45 (t, 1 H, J = 7.6 Hz), 7.28 (m, 2
H), 7.22 (br d, 1 H, J = 7.6 Hz), 7.01 (d, 1 H, J = 7.6 Hz), 6.69
(m, 2 H), 6.61 (dd, 1 H, J = 17.6, 10.8 Hz), 5.55 (dd, 1 H, J =
17.6, 0.8 Hz), 5.05 (dd, 1 H, J = 10.8, 0.8 Hz), 4.56, (s, 2 H),
2.53 (s, 3 H) 408.21 41 ##STR00050## (400 MHz, CDCl.sub.3) .delta.
8.94 (t, 1 H, J = 1.2 Hz), 8.35 (s, 1 H), 7.77 (dd, 1 H, J = 9.2,
1.2 Hz), 7.72 (d, 1 H, J = 9.2 Hz), 7.46 (t, 1 H, J = 7.8 Hz), 7.23
(d, 1 H, J = 8.0 Hz), 7.07 (t, 1 H, J = 7.8 Hz), 6.99 (d, 1 H, J =
7.6 Hz), 6.86 (d, 1 H, J = 7.6 Hz), 6.73 (br s, 1 H), 6.61 (br d, 1
H, J = 8.0 Hz), 4.45 (s, 2 H), 2.98 (s, 1 H), 2.42 (s, 3 H) 406.18
42 ##STR00051## (400 MHz, CDCl.sub.3) .delta. 8.98 (br s, 1 H),
8.37 (s, 1H), 7.83 (dd, 1 H, J = 9.2, 1.6 Hz), 7.78 (dd, 1 H, J =
9.2, 0.8 Hz), 7.45 (t, 1 H, J = 7.6 Hz), 7.22 (br d, 1 H, J = 7.6
Hz), 7.00 (d, 1 H, J = 7.6 Hz), 6.87 (td, 1 H, J = 7.6, 1.6 Hz),
6.84 (dd, 1 H, J = 8.0, 1.6 Hz), 6.77 (td, 1 H, J = 7.8, 1.6 Hz),
6.69 (dd, 1 H, J = 7.8, 1.6 Hz), 4.58 (s, 2 H), 3.91 (s, 3 H), 2.53
(s, 3 H) 412.21 43 ##STR00052## (400 MHz, CDCl.sub.3) .delta. 8.95
(br s, 1 H), 8.37 (s, 1 H), 7.81 (dd, 1 H, J = 9.2, 1.6 Hz), 7.76
(dd, 1 H, J = 9.2, 0.8 Hz), 7.45 (t, 1 H, J = 7.6 Hz), 7.22 (d, 1
H, J = 7.6 Hz), 7.11 (t, 1 H, J = 8.0 Hz), 7.01 (d, 1 H, J = 7.6
Hz), 6.36-6.31 (m, 2 H), 6.27 (t, 1 H, J = 2.4 Hz), 4.52 (s, 2 H),
3.75 (s, 3 H), 2.51 (s, 3 H) 412.21 44 ##STR00053## (400 MHz,
CDCl.sub.3) .delta. 8.96 (br s, 1 H), 8.37 (s, 1 H), 7.82 (dd, 1 H,
J = 9.2, 1.6 Hz), 7.77 (dd, 1 H, J = 9.2, 0.8 Hz), 7.45 (t, 1 H, J
= 7.8 Hz), 7.22 (br d, 1 H, J = 7.6 Hz), 7.01 (br d, 1 H, J = 8.0
Hz), 6.80 (m, 2 H), 6.70 (m, 2 H), 4.50 (s, 2 H), 3.74 (s, 3 H),
2.53 (s, 3 H) 412.21 45 ##STR00054## (400 MHz, CDCl.sub.3) .delta.
8.96 (br s, 1 H), 8.34 (s, 1 H), 7.80 (dd, 1 H, J = 9.2, 1.6 Hz),
7.72 (d, 1 H, J = 9.2 Hz), 7.42 (t, 1 H, J = 7.6 Hz), 7.20 (br d, 1
H, J = 7.6 Hz), 6.96 (d, 1 H, J = 7.6 Hz), 6.88 (td, 1 H, J = 8.2,
0.4 Hz), 6.36 (d, 1 H, overlapped, J = 8.0 Hz), 6.34 (d, 1 H, over-
lapped, J = 8.2 Hz), 4.52 (s, 2 H), 3.84 (s, 3 H), 3.81 (s, 3 H),
2.43 (s, 3 H) 442.22 46 ##STR00055## (400 MHz, CDCl.sub.3) .delta.
8.94 (dd, 1 H, J = 1.6, 0.8 Hz), 8.34 (s, 1 H), 7.78 (dd, 1 H, J =
9.2, 1.6 Hz), 7.72 (dd, 1 H, J = 9.2, 0.8 Hz), 7.44 (t, 1 H, J =
8.0 Hz), 7.21 (br d, 1 H, J = 8.0 Hz), 6.99 (d, 1 H, J = 8.0 Hz),
6.71 (d, 1 H, J = 8.4 Hz), 6.30 (d, 1 H, J = 2.4 Hz), 6.19 (dd, 1
H, J = 8.4, 2.4 Hz), 4.46 (s, 2 H), 3.78 (s, 3 H), 3.76 (s, 3 H),
2.47 (s, 3 H) 442.22 47 ##STR00056## (400 MHz, CDCl.sub.3) .delta.
10.43 (br s, 1 H), 8.94 (s, 1 H), 8.37 (s, 1 H), 7.81 (d, 1 H, J =
9.2 Hz), 7.77 (d, 1 H, J = 9.2 Hz), 7.45 (t, 1 H, J = 7.6 Hz), 7.20
(d, 1 H, J = 7.6 Hz), 7.01 (d, 1 H, J = 7.6 Hz), 5.96 (t, 1 H, J =
2.0 Hz), 5.92 (d, 2 H, J = 2.0 Hz), 4.52 (d, 2 H, J = 2.8 Hz), 4.41
(br s, 1 H), 3.75 (s, 6 H), 2.54 (s, 3 H) 442.22 48 ##STR00057##
(400 MHz, CDCl.sub.3) .delta. 8.97 (br s, 1 H), 8.37 (s, 1 H), 7.83
(dd, 1 H, J = 9.2, 1.6 Hz), 7.77 (dd, 1 H, J = 9.2, 0.8 Hz), 7.45
(t, 1 H, J = 7.6 Hz), 7.23 (td, 1 H, overlapped, J = 7.6, 1.6 Hz),
7.22 (br d, 1 H, overlapped, J = 7.6 Hz) 7.12 (dd, 1 H, J = 7.6,
1.6 Hz), 7.01 (d, 1 H, J = 8.0 Hz), 6.77-6.73 (m, 2 H), 4.63 (s, 2
H), 4.60 (s, 2 H), 3.42 (s, 3 H), 2.53 (s, 3 H) 426.22 49
##STR00058## (400 MHz, CDCl.sub.3) .delta. 8.96 (br s, 1 H), 8.37
(s, 1 H), 7.82 (dd, 1 H, J = 9.2, 1.6 Hz), 7.78 (dd, 1 H, J = 9.2,
0.8 Hz), 7.45 (t, 1 H, J = 7.6 Hz), 7.21 (t, 1 H, overlapped, J =
8.0 Hz), 7.20 (br d, 1 H, overlapped, J = 7.6 Hz), 7.01 (d, 1 H, J
= 7.6 Hz), 6.76 (d, 1 H, overlapped, J = 8.0 Hz), 6.75 (d, 1 H,
overlapped, J = 1.6 Hz), 6.67-6.64 (m, 1 H), 4.56 (s. 2 H), 4.40
(s, 2 H), 3.38 (s, 3 H), 2.54 (s, 3 H) 426.22 50 ##STR00059## (400
MHz, CDCl.sub.3) .delta. 10.36 (br s, 1 H), 8.95 (s, 1 H), 8.37 (s,
1 H), 7.82 (br d, 1 H, J = 9.2 Hz), 7.78 (br d, 1 H, J = 9.2 Hz),
7.45 (t, 1 H, J = 7.6 Hz), 7.20 (br d, 1 H, overlapped, J = 7.6
Hz), 7.19 (d, 2 H, overlapped, J = 8.4 Hz), 7.01 (d, 1 H, J = 7.6
Hz), 6.71 (d, 2 H, J = 8.4 Hz), 4.55 (s, 2 H), 4.40 (br s, 1 H),
4.34 (s, 2 H), 3.34 (s, 3 H), 2.53 (s, 3 H) 426.22 51 ##STR00060##
(400 MHz, CDCl.sub.3) .delta. 10.42 (br s, 1 H), 8.96 (br s, 1 H),
8.37 (s, 1 H), 7.82 (d, 1 H, J = 9.2 Hz), 7.78 (d, 1 H, J = 9.2
Hz), 7.45 (t, 1 H, J = 7.8 Hz), 7.25-7.18 (m, 2 H), 7.15 (td, 1 H,
J = 7.8, 1.2 Hz), 7.01 (d, 1 H, J = 7.6 Hz), 6.81 (dd, 1 H, J =
8.0, 1.2 Hz), 6.76 (td, 1 H, J = 7.8, 1.6 Hz), 4.85 (t, 1 H, J =
5.6 Hz), 4.61 (d, 2 H, J = 5.6 Hz), 2.52 (s, 3 H) 466.18 52
##STR00061## (400 MHz, CDCl.sub.3) .delta. 8.94 (br s, 1 H), 8.37
(s, 1 H), 7.80 (dd, 1 H, J = 9.2, 1.6 Hz), 7.77 (dd, 1 H, J = 9.2,
0.8 Hz), 7.46 (t, 1 H, J = 7.8 Hz), 7.23 (br d, 1 H, J = 8.0 Hz),
7.19 (t, 1 H, J = 8.2 Hz), 7.02 (d, 1 H, J = 7.6 Hz), 6.64-6.60 (m,
2 H), 6.55 (br s, 1 H), 4.62 (br s, 1 H), 4.52 (s, 2 H), 2.52 (s, 3
H) 466.18 53 ##STR00062## (400 MHz, CDCl.sub.3) .delta. 8.95 (s, 1
H), 8.38 (s, 1 H), 7.81 (dd, 1 H, J = 9.2, 1.6 Hz), 7.78 (dd, 1 H,
J = 9.2, 0.8 Hz), 7.46 (t, 1 H, J = 7.8 Hz), 7.23 (d, 1 H, J = 8.0
Hz), 7.08 (m, 2 H), 7.02 (d, 1 H, J = 7.6 Hz), 6.70 (m, 2 H), 4.53
(s, 2 H), 2.54 (s, 3 H) 466.18 54 ##STR00063## (400 MHz,
CDCl.sub.3) .delta. 11.34 (br s, 1 H), 8.99 (s, 1 H), 8.34 (s, 1
H), 7.83 (br d, 1 H, J = 9.2 Hz), 7.72 (br d, 1 H, J = 9.2 Hz),
7.43 (t, 1 H, J = 7.8 Hz), 7.35 (dd, 1 H, J = 7.6, 1.6 Hz), 7.21
(br d, 1 H, J = 7.6 Hz), 7.12 (td, 1 H, J = 7.8, 1.6 Hz), 6.95 (d,
1 H, J = 8.0 Hz), 6.70 (td, 1 H, J = 7.6, 1.2 Hz), 6.65 (dd, 1 H, J
= 8.0, 1.2 Hz), 5.49 (br t, 1 H, J = 4.8 Hz), 4.55 (d, 2 H, J = 4.8
Hz), 2.33 (s, 3 H), 2.32 (s, 3 H) 428.18 55 ##STR00064## (400 MHz,
CDCl.sub.3) .delta. 11.06 (br s, 1 H), 8.94 (s, 1 H), 8.35 (s, 1
H), 7.78 (dd, 1 H, J = 9.2, 1.2 Hz), 7.74 (d, 1 H, J = 9.2 Hz),
7.45 (t, 1 H, J = 7.8 Hz), 7.21 (br d, 1 H, J = 8.0 Hz), 7.07 (t, 1
H, J = 7.8 Hz), 6.99 (d, 1 H, J = 7.6 Hz), 6.64 (dd, 1 H, J = 7.6,
2.0 Hz), 6.54 (t, 1 H, J = 1.6 Hz), 6.42 (dd, 1 H, J = 8.0, 1.6
Hz), 4.47 (s, 2 H) 4.42 (br s, 1 H), 2.45 (s, 3 H), 2.40 (s, 3 H)
428.19 56 ##STR00065## (400 MHz, DMSO-d.sub.6) .delta. 9.43 (br s,
1 H), 8.62 (s, 1 H), 7.97 (dd, 1 H, J = 9.2, 0.8 Hz), 7.84 (t, 1 H,
J = 7.6 Hz), 7.80 (dd, 1 H, J = 9.2, 1.6 Hz), 7.51 (d, 1 H, J = 7.6
Hz), 7.38 (d, 1 H, J = 7.6 Hz), 7.08 (t, 1 H, J = 7.8 Hz), 6.62 (t,
1 H, J = 2.0 Hz), 6.55 (d, 1 H, J = 7.6 Hz), 6.51 (dd, 1 H, J =
8.0, 2.0 Hz), 4.68 (s, 2 H), 2.55 (s, 3 H), 2.41 (s, 3 H) 57
##STR00066## (400 MHz, DMSO-d.sub.6) .delta. 9.40 (dd, 1 H, J =
1.6, 0.8 Hz), 8.63 (s, 1 H), 7.98 (d, 1 H, J = 9.6 Hz), 7.84 (t, 1
H, J = 7.6 Hz), 7.77 (dd, 1 H, J = 9.6, 1.6 Hz), 7.43 (d, 1 H, J =
7.6 Hz), 7.40 (d, 1 H, J = 7.6 Hz), 7.08 (t, 1 H, J = 8.0 Hz), 6.60
(t, 1 H, J = 2.0 Hz), 6.56 (d, 1 H, J = 8.0 Hz), 6.48 (dd, 1 H, J =
8.0, 2.0 Hz), 4.65 (s, 2 H), 2.58 (s, 3 H), 2.40 (s, 3 H) 58
##STR00067## (400 MHz, CDCl.sub.3) .delta. 11.08 (br s, 1 H), 8.94
(s, 1 H), 8.35 (s, 1 H), 7.78 (dd, 1 H, J = 9.2, 1.6 Hz), 7.73 (d,
1 H, J = 9.2 Hz), 7.45 (t, 1 H, J = 7.8 Hz), 7.21 (br d, 1 H, J =
8.0 Hz), 7.17 (m, 2 H), 6.99 (d, 1 H, J = 7.6 Hz), 6.60 (m, 2 H),
4.46 (s, 2 H), 2.45 (s, 3 H), 2.37 (s, 3 H) 428.18 59 ##STR00068##
(400 MHz, CDCl.sub.3) .delta. 8.98 (br s, 1 H), 8.36 (s, 1 H), 7.83
(dd, 1 H, J = 9.2, 1.6 Hz), 7.76 (dd, 1 H, J = 9.2, 0.8 Hz), 7.47
(t, 1 H, J = 7.8 Hz), 7.40 (br d, 1 H, overlapped, J = 7.6 Hz),
7.38 (t, 1 H, J = 7.8 Hz), 7.25 (br d, 1 H, J = 8.0 Hz), 7.00 (d, 1
H, J = 7.6), 6.80 (d, 1 H, J = 8.4 Hz), 6.75 (td, 1 H, J = 8.0, 0.8
Hz), 5.32 (br t, 1 H, J = 5.6 Hz), 4.62 (d, 2 H, J = 5.6 Hz), 2.41
(s, 3 H) 407.19 60 ##STR00069## (400 MHz, CDCl.sub.3) .delta. 8.94
(t, 1 H, J = 1.2 Hz), 8.38 (s, 1 H), 7.80 (dd, 1 H, J = 9.2, 0.8
Hz), 7.77 (dd, 1 H, J = 9.2, 1.6 Hz), 7.55 (t, 1 H, J = 8.0 Hz),
7.31 (d, 1 H, J = 8.0 Hz), 7.25 (t, 1 H, J = 8.0 Hz), 7.08 (d, 1 H,
J = 8.0 Hz), 7.02 (dt, 1 H, J = 7.6, 1.2 Hz), 6.96-6.92 (m, 2 H),
4.56 (s, 2 H), 2.62 (s, 3 H) 407.19 61 ##STR00070## (400 MHz,
DMSO-d.sub.6) .delta. 9.47 (d, 1 H, J = 0.8 Hz), 8.66 (s, 1 H),
7.97 (dd, 1 H, J = 9.2, 0.8 Hz), 7.87 (t, 1 H, overlapped, J = 7.8
Hz), 7.85 (dd, 1 H, overlapped, J = 9.2, 1.6 Hz), 7.63 (d, 1 H, J =
7.6 Hz), 7.40 (d, 1 H, J = 8.0 Hz), 7.33 (t, 1 H, J = 7.8 Hz), 7.16
(t, 1 H, J = 1.6 Hz), 7.11 (dd, 1 H, J = 8.4, 1.6 Hz), 7.06 (br d,
1 H, J = 7.6 Hz), 4.79 (s, 2 H), 2.53 (s, 3 H) 62 ##STR00071## (400
MHz, DMSO-d.sub.6) .delta. 9.39 (br s, 1 H), 8.64 (s, 1 H), 7.99
(d, 1 H, J = 9.2 Hz), 7.87 (t, 1 H, J = 7.6 Hz), 7.77 (dd, 1 H, J =
9.2, 1.6 Hz), 7.45 (d, 1 H, overlapped, J = 7.6 Hz), 7.44 (d, 1 H,
overlapped, J = 7.6 Hz), 7.34 (t, 1 H, J = 8.0 Hz), 7.10 (d, 1 H, J
= 2.0 Hz), 7.07 (d, 1 H, over- lapped, J = 7.6 Hz), 7.04 (dd, 1 H,
overlapped, J = 8.0, 2.0 Hz), 4.70 (s, 2 H), 2.60 (s, 3 H) 63
##STR00072## (400 MHz, CDCl.sub.3) .delta. 8.93 (t, 1 H, J = 1.2
Hz), 8.37 (s, 1 H), 7.79 (dd, 1 H, overlapped, J = 9.2, 1.6 Hz),
7.76 (dd, 1 H, overlapped, J = 9.2, 0.8 Hz), 7.48 (t, 1 H, J = 7.8
Hz), 7.43 (m, 2 H), 7.24 (d, 1 H, J = 8.0 Hz), 7.03 (d, 1 H, J =
7.6 Hz), 6.68 (m, 2 H), 5.12 (br s, 1 H), 4.54 (d, 2 H, J = 4.0
Hz), 2.51 (s, 3 H) 407.19 64 ##STR00073## (400 MHz, CDCl.sub.3)
.delta. 8.99 (br s, 1 H), 8.35 (s, 1 H), 7.84 (dd, 1 H, J = 9.2,
1.6 Hz), 7.74 (dd, 1 H, J = 9.2, 0.8 Hz), 7.50 (t, 1 H, J = 7.8
Hz), 7.37 (t, 1 H, J = 8.2 Hz), 7.27 (br d, 1 H, J = 7.6 Hz), 7.05
(d, 1 H, J = 8.8 Hz), 7.01 (d, 1 H, over- lapped, J = 8.0 Hz), 6.98
(d, 1 H, overlapped, J = 7.6 Hz), 5.94 (br t, 1 H, J = 5.6 Hz),
4.66 (d, 2 H, J = 5.6 Hz), 2.30 (s, 3 H) 432.19 65 ##STR00074##
(400 MHz, CDCl.sub.3) .delta. 9.04 (dd, 1 H, J = 1.6, 0.8 Hz), 8.48
(br s, 1 H), 8.33 (s, 1 H), 7.84 (dd, 1 H, J = 9.2, 1.6 Hz), 7.72
(d, 1 H, J = 9.2 Hz), 7.41 (t, 1 H, J = 7.8 Hz), 7.37 (dd, 1 H, J =
7.6, 1.2 Hz), 7.29 (td, 1 H, J = 8.4, 1.2 Hz), 7.21 (br d, 1 H, J =
8.0 Hz), 6.92 (d, 1 H, J = 7.6 Hz), 6.83 (d, 1 H, J = 8.4 Hz), 6.62
(td, 1 H, J = 8.0, 1.0 Hz), 6.25 (br s, 2 H), 4.59 (d, 2 H, J = 5.2
Hz), 2.32 (s, 3 H) 425.20 66 ##STR00075## (400 MHz, CD.sub.3OD)
.delta. 9.06 (br s, 1 H), 8.34 (s, 1 H), 7.83 (br d, 1 H, J = 9.2
Hz), 7.71 (d, 1 H, J = 9.2 Hz), 7.59-7.55 (m, 2 H), 7.22-7.18 (m, 2
H), 7.15 (dt, 1 H, J = 7.6, 2.0 Hz), 7.10 (dd, 1 H, J = 8.4, 0.8
Hz), 6.86 (ddd, 1 H, J = 7.6, 2.0, 0.8 Hz), 4.51 (s, 2 H), 2.50 (s,
3 H) 425.20 67 ##STR00076## (400 MHz, CDCl.sub.3/CD.sub.3OD)
.delta. 9.03 (br s, 1 H), 8.32 (s, 1 H), 7.81 (dd, 1 H, J = 9.2,
1.6 Hz), 7.70 (dd, 1 H, J = 9.2, 0.8 Hz), 7.67 (m, 2 H), 7.55 (t, 1
H, J = 7.6 Hz), 7.26 (br d, 1 H, J = 7.6 Hz), 7.09 (d, 1 H, J = 7.6
Hz), 6.71 (m, 2 H), 4.52 (s, 2 H), 2.51 (s, 3 H) 425.20 68
##STR00077## (400 MHz, CDCl.sub.3) .delta. 10.76 (br s, 1 H), 8.94
(br s, 1 H), 8.37 (s, 1 H), 7.81 (br d, 1 H, J = 9.2 Hz), 7.76 (br
d, 1 H, J = 9.2 Hz), 7.46 (t, 1 H, J = 7.6 Hz), 7.21 (br d, 1 H, J
= 7.6 Hz), 7.20-7.15 (m, 1 H), 7.01 (d, 1 H, J = 7.6 Hz), 6.69 (dd,
1 H, J = 7.6, 0.8 Hz), 6.62-6.40 (m, 2 H), 4.53 (br s, 1 H,
overlapped), 4.52 (br s, 2 H, over- lapped), 3.65 (s, 2 H), 2.50
(s, 3 H) 421.21 69 ##STR00078## (400 MHz, CDCl.sub.3) .delta. 10.78
(br s, 1 H), 8.94 (br s, 1 H), 8.36 (s, 1 H), 7.80 (dd, 1 H, J =
9.2, 1.2 Hz), 7.76 (d, 1 H, J = 9.2 Hz), 7.46 (t, 1 H, J = 7.8 Hz),
7.22 (br d, 1 H, J = 7.6 Hz), 7.11 (d, 2 H, J = 8.4 Hz), 7.01 (d, 1
H, J = 8.0 Hz), 6.67 (d, 2 H, J = 8.4), 4.50 (br s, 3 H), 3.61 (s,
2 H), 2.49 (s, 3 H) 421.21 70 ##STR00079## (400 MHz, CDCl.sub.3)
.delta. 11.09 (br s, 1 H), 8.92 (s, 1 H), 8.35 (s, 1 H), 7.79 (d, 1
H, J = 9.2 Hz), 7.74 (d, 1 H, J = 9.2 Hz), 7.44 (t, 1 H, J = 7.8
Hz), 7.30 (d, 1 H, J = 7.6 Hz), 7.26-7.24 (m, 1 H), 7.23 (t, 1 H,
overlapped, J = 7.8 Hz), 7.19 (br d, 1 H, J = 8.0 Hz), 7.00 (d, 1
H, J = 8.0 Hz), 6.86 (dd, 1 H, J = 8.0, 1.8 Hz), 4.68 (br s, 1 H),
4.52 (d, 2 H, J = 5.2 Hz), 2.53 (s, 3 H), 2.47 (s, 3 H) 424.21 71
##STR00080## (400 MHz, CDCl.sub.3) .delta. 8.96 (t, 1 H, J = 1.4
Hz), 8.37 (s, 1 H), 7.81 (d, 2 H, J = 8.8 Hz), 7.79- 7.76 (m, 2 H),
7.54 (t, 1 H, J = 7.8 Hz), 7.30 (d, 1 H, J = 8.0 Hz), 7.07 (d, 1 H,
J = 7.6 Hz), 6.70 (d, 2 H, J = 8.8 Hz), 4.63 (s, 2 H), 2.59 (s, 3
H), 2.48 (s, 3 H) 424.21 72 ##STR00081## (400 MHz, CDCl.sub.3)
.delta. 8.94 (br s, 1 H), 8.34 (s, 1 H), 7.77 (dd, 1 H, J = 9.2,
1.6 Hz), 7.72 (dd, 1 H, J = 9.2, 0.8 Hz), 7.44 (t, 1 H, J = 7.8
Hz), 7.39 (dt, 1 H, J = 7.6, 1.2 Hz), 7.32 (dd, 1 H, J = 2.4, 1.6
Hz), 7.22 (d, 1 H, overlapped, J = 8.0 Hz), 7.19 (t, 1 H,
overlapped, J = 8.0 Hz), 6.98 (d, 1 H, J = 7.6 Hz), 6.81 (ddd, 1 H,
J = 8.0, 2.4, 0.8 Hz), 4.49 (s, 2 H), 3.84 (s, 3 H), 2.43 (s, 3 H)
440.20 73 ##STR00082## (400 MHz, CDCl.sub.3) .delta. 10.52 (br s, 1
H), 8.94
(s, 1 H), 8.37 (s, 1 H), 7.89 (m, 2 H), 7.81 (br d, 1 H, J = 9.6
Hz), 7.78 (br d, 1 H, J = 9.6 Hz), 7.46 (t, 1 H, J = 8.0 Hz), 7.21
(d, 1 H, J = 8.0 Hz), 7.02 (d, 1 H, J = 8.0 Hz), 6.68 (m, 2 H),
4.90 (t, 1 H, J = 5.6 Hz), 4.58 (d, 2 H, J = 5.6 Hz), 3.85 (s, 3
H), 2.51 (s, 3 H) 440.20 74 ##STR00083## (400 MHz, DMSO-d.sub.6)
.delta. 12.56 (br s, 1 H), 9.58 (s, 1 H), 9.36 (s, 1 H), 8.50 (s, 1
H), 8.00 (br d, 1 H, J = 9.2 Hz), 7.82 (d, 1 H, J = 9.2 Hz), 7.71
(t, 1 H, J = 7.8 Hz), 7.44 (br s, 1 H), 7.16 (d, 1 H, overlapped, J
= 8.0 Hz), 7.15 (d, 1 H, over- lapped, J = 7.6 Hz), 7.03 (td, 1 H,
J = 7.6, 1.2 Hz), 6.81 (d, 1 H, J = 7.6 Hz), 6.61 (td, 1 H, J =
7.6, 1.2 Hz), 5.65 (t, 1 H, J = 6.0 Hz), 4.45 (d, 2 H, J = 6.0 Hz),
2.47 (br s, 3 H), 2.09 (s, 3 H) 439.22 75 ##STR00084## (400 MHz,
DMSO-d.sub.6) .delta. 8.97 (br s, 1 H), 8.35 (s, 1 H), 7.79 (dd, 1
H, J = 9.2, 1.6 Hz), 7.73 (d, 1 H, J = 9.2 Hz), 7.46 (t, 1 H, J =
7.8 Hz), 7.38 (br s, 1 H), 7.24 (d, 1 H, J = 8.0 Hz), 7.15 (br s, 1
H), 7.09 (t, 1 H, J = 8.0 Hz), 7.01 (d, 1 H, J = 7.6 Hz), 6.69 (br
d, 1 H, J = 8.0 Hz), 6.41 (dd, 1 H, J = 8.0, 1.6 Hz), 4.50 (s, 2
H), 2.51 (s, 3 H), 2.13 (s, 3 H) 439.22 76 ##STR00085## (400 MHz,
DMSO-d.sub.6) .delta. 8.96 (br s, 1 H), 8.37 (s, 1 H), 7.81 (dd, 1
H, J = 9.2, 1.6 Hz), 7.76 (dd, 1 H, J = 9.2, 0.8 Hz), 7.46 (t, 1 H,
J = 7.8 Hz), 7.27 (m, 2 H), 7.23 (d, 1 H, J = 8.0 Hz), 7.10 (br s,
1 H), 7.01 (d, 1 H, J = 7.6 Hz), 6.66 (m, 2 H), 4.50 (s, 2 H), 2.53
(s, 3 H), 2.13 (s, 3 H) 439.22 77 ##STR00086## (400 MHz,
CD.sub.3OD) .delta. 9.18 (dd, 1 H, J = 1.6, 0.8 Hz), 8.41 (s, 1 H),
7.87 (dd, 1 H, J = 9.2, 1.6 Hz), 7.75 (dd, 1 H, J = 9.2, 0.8 Hz),
7.66 (t, 1 H, J = 7.8 Hz), 7.38 (br d, 1 H, J = 7.6 Hz), 7.20 (dd,
1 H, J = 7.8, 1.4 Hz), 7.16 (d, 1 H, overlapped, J = 7.6 Hz), 7.15
(td, 1 H, over- lapped, J = 8.0, 1.6 Hz), 6.82 (dd, 1 H, J = 8.0,
1.2 Hz), 6.71 (td, 1 H, J = 8.0, 1.4 Hz), 4.59 (s, 2 H), 3.05 (s, 3
H), 2.48 (s, 3 H) 475.19 78 ##STR00087## (400 MHz, CDCl.sub.3)
.delta. 8.92 (br s, 1 H), 8.35 (s, 1 H), 7.78 (dd, 1 H, J = 9.2,
1.6 Hz), 7.73 (dd, 1 H, J = 9.2, 0.8 Hz), 7.46 (t, 1 H, J = 7.6
Hz), 7.21 (br d, 1 H, J = 7.6 Hz), 7.11 (t, 1 H, over- lapped, J =
8.2 Hz), 7.10 (br s, 1 H, overlapped), 7.01 (d, 1 H, J = 7.6 Hz),
6.58 (t, 1 H, J = 2.0 Hz), 6.54 (ddd, 1 H, J = 8.2, 2.0, 0.8 Hz),
6.49 (ddd, 1 H, J = 8.2, 2.0, 0.8 Hz), 4.50 (s, 2 H), 2.94 (s, 3
H), 2.51 (s, 3 H) 475.19 79 ##STR00088## (400 MHz, CDCl.sub.3)
.delta. 8.93 (br s, 1 H), 8.38 (s, 1 H), 7.80 (dd, 1 H, J = 9.2,
1.6 Hz), 7.76 (d, 1 H, J = 9.2 Hz), 7.46 (t, 1 H, J = 7.8 Hz), 7.22
(br d, 1 H, J = 8.0 Hz), 7.09 (d, 2 H, J = 8.8 Hz), 7.02 (d, 1 H, J
= 7.6 Hz), 6.67 (d, 2 H, J = 8.8 Hz), 6.34 (br s, 1 H), 4.52 (br s,
3 H), 2.93 (s, 3 H), 2.54 (s, 3 H) 475.19 80 ##STR00089## (400 MHz,
CDCl.sub.3) .delta. 8.99 (s, 1 H), 8.36 (s, 1 H), 7.83 (dd, 1 H, J
= 9.2, 1.6 Hz), 7.77 (dd, 1 H, J = 9.2, 0.8 Hz), 7.45 (t, 1 H, J =
7.8 Hz), 7.23 (br d, 1 H, J = 7.6 Hz), 7.10 (dd, 1 H, J = 8.0, 1.2
Hz), 7.02 (td, 1 H, overlapped, J = 7.6, 1.2 Hz), 7.00 (d, 1 H,
overlapped, J = 8.0 Hz), 6.78 (td, 1 H, J = 7.6, 1.2 Hz), 6.72 (dd,
1 H, J = 8.0, 1.2 Hz), 4.58 (s, 2 H), 2.73 (s, 6 H), 2.50 (s, 3 H)
425.20 81 ##STR00090## (400 MHz, DMSO-d.sub.6) .delta. 9.47 (dd, 1
H, J = 1.6, 0.8 Hz), 8.63 (s, 1 H), 7.97 (dd, 1 H, J = 9.1, 0.8
Hz), 7.87 (t, 1 H, J = 7.8 Hz), 7.84 (dd, 1 H, J = 9.2, 1.6 Hz),
7.59 (br d, 1 H, overlapped, J = 8.0 Hz), 7.58 (d, 1 H, J = 7.6
Hz), 7.41 (d, 1 H, J = 7.6 Hz), 7.29 (t, 1 H, J = 7.4 Hz), 6.99
(dd, 1 H, J = 7.6, 0.8 Hz), 6.89 (t, 1 H, J = 7.4 Hz), 4.81 (s, 2
H), 3.10 (s, 6 H), 2.56 (s, 3 H) 82 ##STR00091## (400 MHz,
CDCl.sub.3) .delta. 8.97 (s, 1 H), 8.36 (s, 1 H), 7.80 (dd, 1 H, J
= 9.2, 1.6 Hz), 7.75 (d, 1 H, J = 9.2 Hz), 7.45 (t, 1 H, J = 7.8
Hz), 7.23 (d, 1 H, J = 8.0 Hz), 7.07 (t, 1 H, J = 8.2 Hz), 7.00 (d,
1 H, J = 7.6 Hz), 6.24 (d, 1 H, J = 8.0 Hz), 6.14 (br s, 2 H), 4.55
(s, 2 H), 2.90 (s, 6 H), 2.52 (s, 3 H) 425.21 83 ##STR00092## (400
MHz, DMSO-d.sub.6) .delta. 9.48 (dd, 1 H, J = 1.6, 0.8 Hz), 8.64
(s, 1 H), 7.97 (dd, 1 H, J = 9.2, 0.8 Hz), 7.86 (t, 1 H,
overlapped, J = 7.8 Hz), 7.85 (dd, 1 H, overlapped, J = 9.2, 1.6
Hz), 7.62 (d, 1 H, J = 8.0 Hz), 7.39 (d, 1 H, J = 7.6 Hz), 7.28 (t,
1 H, J = 8.2 Hz), 7.17 (br s, 1 H), 6.98 (br d, 1 H, J = 8.0 Hz),
6.81 (br d, 1 H, J = 8.4 Hz), 4.78 (s, 2 H), 3.09 (s, 6 H), 2.52
(s, 3 H) 84 ##STR00093## (400 MHz, CDCl.sub.3) .delta. 10.41 (br s,
1 H), 8.99 (s, 1 H), 8.36 (s, 1 H), 7.84 (dd, 1 H, J = 9.2, 1.2
Hz), 7.76 (d, 1 H, J = 9.2 Hz), 7.45 (t, 1 H, J = 7.8 Hz), 7.23 (br
s, 1 H), 7.10 (dd, 1 H, J = 7.6, 1.2 Hz), 7.00 (td, 1 H,
overlapped, J = 7.6, 1.2 Hz), 6.99 (d, 1 H, overlapped, J = 7.6
Hz), 6.77 (td, 1 H, J = 7.6, 1.2 Hz), 6.72 (d, 1 H, J = 8.0 Hz),
4.58 (s, 2 H), 3.12 (br s, 4 H), 2.51 (s, 3 H), 1.98 (br s, 4 H)
451.22 85 ##STR00094## (400 MHz, DMSO-d.sub.6) .delta. 9.47 (dd, 1
H, J = 2.0, 0.8 Hz), 8.63 (s, 1 H), 7.97 (dd, 1 H, J = 9.2, 0.8
Hz), 7.87 (t, 1 H, J = 7.8 Hz), 7.84 (dd, 1 H, J = 9.2, 2.0 Hz),
7.60 (d, 1 H, J = 8.0 Hz), 7.57 (d, 1 H, J = 8.0 Hz), 7.41 (d, 1 H,
J = 7.6 Hz), 7.30 (td, 1 H, J = 7.8, 0.8 Hz), 7.02 (dd, 1 H, J =
7.8, 1.2 Hz), 6.88 (td, 1 H, J = 8.0, 1.2 Hz), 4.82 (s, 2 H), 3.72
(br s, 4 H), 2.55 (s, 3 H), 2.17 (m, 4 H) 86 ##STR00095## (400 MHz,
CDCl.sub.3) .delta. 8.96 (s, 1 H), 8.37 (s, 1 H), 7.82 (dd, 1 H, J
= 9.2, 1.6 Hz), 7.78 (dd, 1 H, J = 9.2, 1.2 Hz), 7.48 (t, 1 H, J =
7.6 Hz), 7.25 (br d, 1 H, J = 7.6 Hz), 7.09 (dd, 1 H, J = 8.0, 1.6
Hz), 7.05 (td, 1 H, overlapped, J = 7.6, 1.6 Hz), 7.02 (d, 1 H,
overlapped, J = 7.6 Hz), 6.80 (td, 1 H, J = 7.6, 1.2 Hz), 6.71 (dd,
1 H, J = 8.0, 1.2 Hz), 4.57 (s, 2 H), 3.90 (br t, 4 H, J = 4.6 Hz),
2.96 (br t, 4 H, J = 4.6 Hz), 2.54 (s, 3 H) 467.22 87 ##STR00096##
(400 MHz, DMSO-d.sub.6) .delta. 9.46 (dd, 1 H, J = 1.6, 0.8 Hz),
8.64 (s, 1 H), 7.96 (dd, 1 H, J = 9.2, 0.8 Hz), 7.84 (t, 1 H, J =
7.8 Hz), 7.82 (dd, 1 H, J = 9.2, 1.6 Hz), 7.57 (d, 1 H, J = 8.0
Hz), 7.38 (d, 1 H, J = 7.6 Hz), 7.06 (dd, 1 H, J = 7.6, 1.2 Hz),
6.98 (td, 1 H, J = 7.8, 1.2 Hz), 6.82 (dd, 1 H, J = 7.8, 1.2 Hz),
6.70 (td, 1 H, J = 7.6, 1.2 Hz), 4.80 (s, 2 H), 3.84 (br t, 4 H, J
= 4.4 Hz), 2.89 (br t, 4 H, J = 4.4 Hz), 2.53 (s, 3 H) 88
##STR00097## (400 MHz, CDCl.sub.3) .delta. 8.96 (t, 1 H, J = 1.2
Hz), 8.37 (s, 1 H), 7.82-7.76 (m, 2 H), 7.48 (t, 1 H, J = 7.6 Hz),
7.24 (br d, 1 H, J = 7.6 Hz), 7.12 (t, 1 H, J = 8.0 Hz), 7.03 (d, 1
H, J = 7.6 Hz), 6.39 (dd, 1 H, J = 8.0, 1.6 Hz), 6.34 (t, 1 H, J =
2.0 Hz), 6.29 (dd, 1 H, J = 8.0, 2.0 Hz), 4.56 (s, 2 H), 3.85-3.82
(m, 4 H), 3.15-3.12 (m, 4 H), 2.56 (s, 3 H) 467.23 89 ##STR00098##
(400 MHz, DMSO-d.sub.6) .delta. 9.47 (dd, 1 H, J = 1.6, 0.8 Hz),
8.64 (s, 1 H), 7.97 (dd, 1 H, J = 9.2, 0.8 Hz), 7.85 (t, 1 H, J =
8.0 Hz), 7.84 (dd, 1 H, J = 9.2, 1.6 Hz), 7.60 (d, 1 H, J = 8.0
Hz), 7.39 (d, 1 H, J = 8.0 Hz), 7.17 (t, 1 H, J = 8.0 Hz), 6.86 (br
s, 1 H), 6.76 (br s, 1 H), 6.59 (br d, 1 H, J = 7.6 Hz), 4.76 (s, 2
H), 3.92 (br s, 4 H), 3.34 (br s, 4 H), 2.52 (s, 3 H) 90
##STR00099## (400 MHz, CDCl.sub.3) .delta. 8.95 (t, 1 H, J = 1.2
Hz), 8.35 (s, 1 H), 7.78 (dd, 1 H, J = 9.2, 1.6 Hz), 7.70 (dd, 1 H,
J = 9.2, 1.2 Hz), 7.43 (t, 1 H, J = 7.8 Hz), 7.21 (d, 1 H, J = 8.0
Hz), 6.94 (d, 1 H, J = 7.6 Hz), 6.80-6.73 (m, 1 H), 6.14 (br d, 1
H, J = 7.6 Hz), 6.00-5.95 (m, 1 H), 4.49 (s, 2 H), 2.79 (s, 6 H),
2.31 (s, 3 H) 443.21 91 ##STR00100## (400 MHz, DMSO-d.sub.6)
.delta. 9.49 (dd, 1 H, J = 1.6, 0.8 Hz), 8.63 (s, 1 H), 7.97 (dd, 1
H, J = 9.2, 0.8 Hz), 7.85 (dd, 1 H, overlapped, J = 9.2, 1.6 Hz),
7.84 (t, 1 H, overlapped, J = 8.0 Hz), 7.60 (d, 1 H, J = 8.0 Hz),
7.39 (br s, 1 H, overlapped), 7.38 (d, 1 H, overlapped, J = 8.0
Hz), 7.24 (pseudo t, 1 H, J = 9.8 Hz), 6.97 (br s, 1 H), 4.86 (s, 2
H), 3.10 (s, 6 H), 2.52 (s, 3 H) 92 ##STR00101## (400 MHz,
CDCl.sub.3) .delta. 8.94 (t, 1 H, J = 1.2 Hz), 8.38 (s, 1 H), 7.80
(dd, 1 H, overlapped, J = 9.2, 1.6 Hz), 7.78 (dd, 1 H, overlapped,
J = 9.2, 1.2 Hz), 7.49 (t, 1 H, J = 7.6 Hz), 7.25 (d, 1 H, J = 7.6
Hz), 7.04 (d, 1 H, J = 7.6 Hz), 6.38 (dd, 1 H, J = 2.4, 1.2 Hz),
6.30 (t, 1 H, J = 1.6 Hz), 6.18 (t, 1 H, J = 2.2 Hz), 4.53 (s, 2
H), 2.92 (s, 6 H), 2.56 (s, 3 H) 450.21 93 ##STR00102## (400 MHz,
DMSO-d.sub.6) .delta. 9.44 (dd, 1 H, J = 2.0, 0.8 Hz), 8.63 (s, 1
H), 7.97 (dd, 1 H, J = 9.2, 0.8 Hz), 7.85 (t, 1 H, J = 7.8 Hz),
7.81 (dd, 1 H, J = 9.2, 2.0 Hz), 7.55 (d, 1 H, J = 8.0 Hz), 7.40
(d, 1 H, J = 7.6 Hz), 6.47 (s, 2 H), 6.37 (br s, 1 H), 4.73 (s, 2
H), 2.90 (s, 6 H), 2.55 (s, 3 H) 94 ##STR00103## (400 MHz,
CDCl.sub.3) .delta. 8.96 (t, 1 H, J = 1.6 Hz), 8.38 (s, 1 H), 7.82
(dd, 1 H, J = 9.2, 1.6 Hz), 7.79 (dd, 1 H, J = 9.2, 0.8 Hz), 7.53
(t, 1 H, J = 7.8 Hz), 7.31 (d, 1 H, J = 8.0 Hz), 7.08-7.03 (m, 3
H), 6.87 (d, 1 H, J = 1.6 Hz), 5.44 (br s, 1 H), 4.55 (s, 2 H),
2.74 (s, 6 H), 2.58 (s, 3 H) 450.21 95 ##STR00104## (400 MHz,
DMSO-d.sub.6) .delta. 9.44 (dd, 1 H, J = 1.6, 0.8 Hz), 8.64 (s, 1
H), 7.99 (dd, 1 H, J = 9.2, 0.8 Hz), 7.84 (t, 1 H, overlapped, J =
7.8 Hz), 7.82 (dd, 1 H, J = 9.2, 0.8 Hz), 7.51 (d, 1 H, J = 8.0
Hz), 7.39 (d, 1 H, J = 7.6 Hz), 7.15 (dd, 2 H, overlapped, J = 7.6,
0.8 Hz), 7.14 (d, 1 H, overlapped, J = 1.2 Hz), 4.79 (s, 2 H), 2.71
(s, 6 H), 2.56 (s, 3 H) 96 ##STR00105## (400 MHz, CDCl.sub.3)
.delta. 10.57 (br s, 1 H), 8.97 (s, 1 H), 8.34 (s, 1 H), 7.82 (dd,
1 H, J = 9.2, 1.2 Hz), 7.74 (d, 1 H, J = 9.2 Hz), 7.43 (t, 1 H, J =
7.8 Hz), 7.21 (br s, 1 H, overlapped), 7.17 (td, 1 H, J = 8.0, 1.6
Hz), 7.01 (dd, 1 H, J = 7.6, 1.6 Hz), 6.98 (d, 1 H, J = 7.6 Hz),
6.72-6.66 (m, 2 H), 4.61 (s, 2 H), 3.54 (s, 2 H), 2.51 (s, 3 H),
2.28 (s, 6 H) 439.23 97 ##STR00106## (400 MHz, DMSO-d.sub.6)
.delta. 10.03 (br s, 1 H), 9.48 (dd, 1 H, J = 1.6, 0.8 Hz), 8.62
(s, 1 H), 7.95 (dd, 1 H, J = 9.2, 0.8 Hz), 7.87-7.82 (m, 2 H), 7.64
(d, 1 H, J = 7.6 Hz), 7.38 (d, 1 H, J = 7.6 Hz), 7.33-7.27 (m, 2
H), 6.95 (br s, 1 H), 6.78-6.74 (m, 2 H), 4.81 (s, 2 H), 4.43 (s, 2
H), 2.77 (s, 6 H), 2.52 (s, 3 H) 98 ##STR00107## (400 MHz,
CDCl.sub.3) .delta. 9.02 (br s, 1 H), 8.35 (s, 1 H), 7.82 (dd, 1 H,
J = 9.2, 1.6 Hz), 7.74 (dd, 1 H, J = 9.2, 0.8 Hz), 7.46 (t, 1 H, J
= 7.6 Hz), 7.27 (br d, 1 H, J = 7.6 Hz), 7.13 (t, 1 H, J = 7.8 Hz),
7.00 (d, 1 H, J = 7.6 Hz), 6.90 (br s, 1 H), 6.67 (d, 1 H, J = 7.6
Hz), 6.61 (dd, 1 H, J = 8.0, 2.0 Hz), 4.54 (s, 2 H), 3.48 (s, 2 H),
2.51 (s, 3 H), 2.30 (s, 6 H) 439.23 99 ##STR00108## (400 MHz,
DMSO-d.sub.6) .delta. 10.69 (br s, 1 H), 9.48 (dd, 1 H), J = 1.6,
0.8 Hz), 8.63 (s, 1 H), 7.96 (dd, 1 H, J = 9.2, 0.8 Hz), 7.84 (t, 1
H, J = 8.0 Hz), 7.83 (dd, 1 H, J = 9.2, 1.6 Hz), 7.61 (d, 1 H, J =
8.0 Hz), 7.37 (d, 1 H, J = 8.0 Hz), 7.21 (t, 1 H, J = 8.2 Hz), 7.09
(br s, 1 H), 6.85 (dd, 1 H, overlapped, J = 8.4, 2.2 Hz), 6.82 (d,
1 H, J = 8.0 Hz), 4.76 (s, 2 H), 4.16 (d, 1 H, J = 4.8 Hz), 2.66
(d, 6 H, J = 4.4 Hz), 2.51 (s, 3 H) 100 ##STR00109## (400 MHz,
CDCl.sub.3) .delta. 10.40 (br s, 1 H), 8.98 (s, 1 H), 8.35 (s, 1
H), 7.83 (d, 1 H, J = 9.2 Hz), 7.75 (d, 1 H, J = 9.2 Hz), 7.43 (t,
1 H, J = 7.6 Hz), 7.20 (br s, 1 H, overlapped), 7.15 (td, 1 H, J =
8.0, 1.6 Hz), 7.04 (d, 1 H, J = 8.0 Hz), 6.98 (d, 1 H, J = 7.6 Hz),
6.69 (pseudo t, 2 H, J = 7.2 Hz), 4.58 (s, 2 H), 3.72 (s, 2 H),
2.56 (br s, 4 H), 2.50 (s, 3 H), 1.80 (br s, 4 H) 465.25 101
##STR00110## (400 MHz, DMSO-d.sub.6) .delta. 10.29 (br s, 1 H),
9.47 (t, 1 H, J = 0.8 Hz), 8.62 (s, 1 H), 7.95 (d, 1 H, J = 9.2
Hz), 7.87-7.83 (m, 2 H), 7.65 (d, 1 H, J = 8.0 Hz), 7.38 (br d, 2
H, J = 7.6 Hz), 7.27 (td, 1 H, J = 8.0, 1.2 Hz), 6.75 (t, 1 H,
overlapped, J = 7.6 Hz), 6.72 (d, 1 H, overlapped, J = 7.6 Hz),
4.82 (s, 2 H), 4.47 (s, 2 H), 3.44 (br s, 2 H), 3.17 (br s, 2 H),
2.52 (s, 3 H), 2.04 (br s, 2 H), 1.94 (br s, 2 H) 102 ##STR00111##
(400 MHz, CDCl.sub.3) .delta. 9.04 (s, 1 H), 8.35 (s, 1 H), 7.83
(dd, 1 H, J = 9.2, 1.6 Hz), 7.73 (d, 1 H, J = 9.2 Hz), 7.47 (t, 1
H, J = 7.8 Hz), 7.28 (br d, 1 H, J = 7.6 Hz), 7.11 (t, 1 H, J = 7.8
Hz), 7.00 (d, 1 H, J = 8.0 Hz), 6.95 (br s, 1 H), 6.68 (d, 1 H, J =
7.6 Hz), 6.60 (dd, 1 H, J = 8.0, 2.0 Hz), 4.54 (s, 2 H), 3.65 (s, 2
H), 2.61 (br s, 4 H), 2.51 (s, 3 H), 1.78-1.75 (m, 4 H) 465.25 103
##STR00112## (400 MHz, DMSO-d.sub.6) .delta. 10.93 (br s, 1 H),
9.48 (dd, 1 H, J = 1.2, 1.6 Hz), 8.63 (s, 1 H), 7.96 (dd, 1 H, J =
9.2, 0.8 Hz), 7.86-7.81 (m, 2 H), 7.61 (d, 1 H, J = 8.0 Hz), 7.37
(d, 1 H, J = 7.6 Hz), 7.19 (t, 1 H, J = 7.8 Hz), 7.15 (br s, 1 H),
6.86-6.81 (m, 2 H), 4.76 (s, 2 H), 4.22 (d, 2 H, J = 5.6 Hz), 3.29
(m, 2 H), 3.00 (m, 2 H), 2.51 (s, 3 H), 1.92 (m, 2 H), 1.82 (m, 2
H) 104 ##STR00113## (400 MHz, CDCl.sub.3) .delta. 10.35 (br s, 1
H), 8.97 (s, 1 H), 8.36 (s, 1 H), 7.83 (d, 1 H, J = 9.2 Hz), 7.76
(d, 1 H, J = 9.2 Hz), 7.44 (t, 1 H, J = 7.6 Hz), 7.21 (br s, 1 H,
overlapped), 7.19 (td, 1 H, J = 7.6, 1.6 Hz), 7.04 (dd, 1 H, J =
7.6, 1.6 Hz), 6.99 (d, 1 H, J = 7.6 Hz), 6.73-6.68 (m, 2 H), 4.57
(s, 2 H), 3.71 (br s, 4 H), 3.63 (s, 2 H), 2.50 (br s, 7 H) 481.25
105 ##STR00114## (400 MHz, DMSO-d.sub.6) .delta. 9.46 (s, 1 H),
8.62 (s, 1 H), 7.96 (dd, 1 H, J = 9.2, 0.8 Hz), 7.85 (t, 1 H,
overlapped, J = 8.0 Hz), 7.83 (dd, 1 H, over- lapped, J = 9.2, 1.6
Hz), 7.60 (d, 1 H, J = 8.0 Hz), 7.38 (br d, 2 H, J = 8.0 Hz), 7.29
(td, 1 H, J = 8.0, 1.2 Hz), 6.75 (t, 1 H, overlapped, J = 8.0 Hz),
6.74 (d, 1 H, overlapped, J = 8.0 Hz), 4.82 (s, 2 H), 4.45 (s, 2
H), 3.93 (br s, 4 H), 3.34 (br s, 4 H), 2.53 (s, 3 H) 106
##STR00115## (400 MHz, CDCl.sub.3) .delta. 10.78 (br s, 1 H), 8.97
(s, 1 H), 8.35 (s, 1 H), 7.81 (dd, 1 H, J = 9.2, 1.6 Hz), 7.74 (d,
1 H, J = 9.2 Hz), 7.45 (t, 1 H, J = 7.8 Hz), 7.23 (br s, 1 H, 7.13
(t, 1 H, J = 7.8 Hz), 7.00 (d, 1 H, J = 7.6 Hz), 6.79 (br s, 1 H),
6.71 (d, 1 H, J = 7.6 Hz), 6.59 (dd, 1 H, J = 8.0, 1.6 Hz), 4.53
(s, 2 H), 4.44 (br s, 1 H), 3.66 (m, 4 H), 3.45 (s, 2 H), 2.49 (s,
3 H), 2.44 (br s, 4 H) 481.25 107 ##STR00116## (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. 9.36 (dd, 1 H, J = 1.8, 1.0 Hz),
8.62 (s, 1 H), 7.95 (dd, 1 H, J = 9.4, 1.0 Hz), 7.87 (t, 1 H, J =
7.8 Hz), 7.82 (dd, 1 H, J = 9.4, 1.8 Hz), 7.48 (d, 1 H, J = 8.0
Hz), 7.42 (d, 1 H, J = 7.6 Hz), 7.28 (t, 1 H, J = 7.8 Hz), 6.90 (br
s, 1 H), 6.86-6.82 (m, 2 H), 4.68 (s, 2 H Hz), 4.23 (s, 2 H), 3.70
(br s, 4 H), 3.22 (br s, 2 H), 3.14 (br s, 2 H), 2.58 (s, 3 H) 108
##STR00117## (400 MHz, CDCl.sub.3) .delta. 9.06 (s, 1 H), 8.34 (s,
1 H), 7.84 (dd, 1 H, J = 9.2, 1.6 Hz), 7.72 (d, 1 H, J = 9.2 Hz),
7.48 (t, 1 H, J = 7.6 Hz), 7.32 (br s, 1 H), 7.18 (br s, 1 H), 7.00
(d, 1 H, J = 7.6 Hz), 6.90 (dd, 1 H, J = 11.2, 8.0 Hz), 6.55-6.51
(m, 1 H), 4.78 (br s, 1 H), 4.59 (d, 2 H, J = 6.4 Hz), 3.54 (s, 2
H), 2.50 (s, 3 H), 2.34 (s, 6 H) 457.22
109 ##STR00118## (400 MHz, DMSO-d.sub.6) .delta. 10.73 (br s, 1 H),
9.46 (t, 1 H, J = 1.2 Hz), 8.62 (s, 1 H), 7.96 (dd, 1 H, J = 9.2,
0.8 Hz), 7.84 (dd, 1 H, overlapped, J = 9.2, 1.6 Hz), 7.82 (t, 1 H,
overlapped, J = 7.8 Hz), 7.55 (d, 1 H, J = 8.0 Hz), 7.37 (dd, 1 H,
overlapped, J = 8.2, 2.0 Hz), 7.36 (d, 1 H, J = 7.6 Hz), 7.18 (dd,
1 H, J = 11.8, 8.2 Hz), 6.82- 6.78 (m, 1 H), 4.79 (s, 2 H), 4.17
(br s, 2 H), 2.64 (d, 6 H, J = 1.6 Hz), 2.52 (s, 3 H) 110
##STR00119## (400 MHz, CDCl.sub.3) .delta. 8.99 (br s, 1 H), 8.36
(s, 1 H), 7.83 (dd, 1 H, J = 9.2, 1.6 Hz), 7.76 (d, 1 H, J = 9.2
Hz), 7.46 (t, 1 H, J = 7.8 Hz), 7.24 (br s, 1 H), 6.99 (d, 1 H,
overlapped, J = 8.0 Hz), 6.95 (t, 1 H, overlapped, J = 8.0 Hz),
6.76- 6.70 (m, 2 H), 4.73 (br s, 1 H), 4.56 (d, 2 H, J = 5.6 Hz),
3.60 (s, 2 H), 2.50 (s, 3 H), 2.36 (s, 6 H) 457.23 111 ##STR00120##
(400 MHz, DMSO-d.sub.6) .delta. 10.62 (br s, 1 H), 9.46 (s, 1 H),
8.62 (s, 1 H), 7.96 (d, 1 H, J = 9.2 Hz), 7.84 (t, 1 H, overlapped,
J = 8.0 Hz), 7.83 (d, 1 H, overlapped, J = 9.2 Hz), 7.57 (d, 1 H, J
= 8.0 Hz), 7.37 (d, 1 H, J = 8.0 Hz), 7.10 (t, 1 H, J = 7.6 Hz),
7.02 (t, 1 H, J = 7.6 Hz), 6.93 (pseudo t, 1 H, J = 6.6 Hz), 4.78
(s, 2 H), 4.30 (d, 2 H, J = 4.8 Hz), 2.72 (d, 6 H, J = 4.4 Hz),
2.53 (s, 3 H) 112 ##STR00121## (400 MHz, CDCl.sub.3) .delta. 11.11
(br s, 1 H), 8.98 (s, 1 H), 8.35 (s, 1 H), 7.81 (dd, 1 H, J = 9.2,
1.6 Hz), 7.73 (d, 1 H, J = 9.2 Hz), 7.44 (t, 1 H, J = 7.8 Hz), 7.23
(br s, 1 H), 6.97 (d, 1 H, J = 8.0 Hz), 6.91 (t, 1 H, J = 8.0 Hz),
6.75 (td, 1 H, J = 8.0, 1.2 Hz), 6.65 (td, 1 H, J = 8.0, 1.2 Hz),
4.66 (br s, 1 H), 4.51 (d, 2 H, J = 5.6 Hz), 3.66 (s, 2 H), 2.59
(br s, 4 H), 2.42 (s, 3 H), 1.81-1.75 (m, 4 H) 483.24 113
##STR00122## (400 MHz, DMSO-d.sub.6) .delta. 10.84 (br s, 1 H),
9.46 (s, 1 H), 8.62 (s, 1 H), 7.95 (d, 1 H, J = 9.2 Hz), 7.84 (t, 1
H, J = 7.8 Hz), 7.83 (dd, 1 H, J = 9.2, 1.6 Hz), 7.57 (d, 1 H, J =
8.0 Hz), 7.36 (d, 1 H, J = 7.6 Hz), 7.08 (t, 1 H, J = 7.8 Hz),
7.03-6.96 (m, 2 H), 4.77 (s, 2 H), 4.36 (d, 2 H, J = 5.2 Hz), 3.39
(m, 2 H), 3.07 (m, 2 H), 2.53 (s, 3 H), 2.03- 1.87 (m, 4 H) 114
##STR00123## (400 MHz, CDCl.sub.3) .delta. 8.97 (s, 1 H), 8.36 (s,
1 H), 7.82 (dd, 1 H, J = 9.2, 2.0 Hz), 7.76 (dd, 1 H, J = 9.2, 0.8
Hz), 7.46 (t, 1 H, J = 7.6 Hz), 7.23 (br d, 1 H, J = 7.6 Hz), 7.00
(d, 1 H, J = 7.6 Hz), 6.95 (t, 1 H, J = 8.0 Hz), 6.76 (t, 1 H, J =
7.6 Hz), 6.70 (td, 1 H, J = 8.0, 1.6 Hz), 4.67 (br s, 1 H), 4.54
(d, 2 H, J = 4.8 Hz), 3.73 (m, 4 H), 3.59 (s, 2 H), 2.53 (br s, 4
H), 2.47 (s, 3 H) 499.24 115 ##STR00124## (400 MHz, DMSO-d.sub.6)
.delta. 11.18 (br s, 1 H), 9.46 (dd, 1 H, J = 1.6, 1.2 Hz), 8.62
(s, 1 H), 7.96 (dd, 1 H, J = 9.2, 0.8 Hz), 7.84 (t, 1 H, over-
lapped, J = 7.8 Hz), 7.83 (dd, 1 H, overlapped, J = 9.2, 1.6 Hz),
7.57 (d, 1 H, J = 7.6 Hz), 7.37 (d, 1 H, J = 8.0 Hz), 7.10 (t, 1 H,
J = 7.8 Hz), 7.05-6.99 (m, 2 H), 4.78 (s, 2 H), 4.34 (s, 2 H), 3.93
(br s, 2 H), 3.81 (br t, 2 H, J = 11.8 Hz) 3.29 (br s, 2 H), 3.13
(br s, 2 H), 2.53 (s, 3 H) 116 ##STR00125## (400 MHz, CDCl.sub.3)
.delta. 8.99 (s, 1 H), 8.36 (s, 1 H), 7.86 (dd, 1 H, J = 9.2, 1.6
Hz), 7.78 (dd, 1 H, J = 9.2, 0.8 Hz), 7.47 (t, 1 H, J = 7.6 Hz),
7.23 (br d, 1 H, J = 7.6 Hz), 7.09 (d, 1 H, J = 7.6 Hz), 7.01 (d, 1
H, J = 7.6 Hz), 6.98 (dd, 1 H, J = 7.6, 1.6 Hz), 6.93 (br s, 1 H),
4.59 (s, 2 H), 3.63 (s, 2 H), 2.53 (s, 3 H), 2.33 (s, 6 H) 464.23
117 ##STR00126## (400 MHz, DMSO-d.sub.6) .delta. 9.45 (dd, 1 H, J =
1.6, 0.8 Hz), 8.60 (s, 1 H), 7.94 (dd, 1 H, J = 9.2, 0.8 Hz), 7.85
(t, 1 H, overlapped, J = 7.6 Hz), 7.84 (dd, 1 H, overlapped, J =
9.2, 1.6 Hz), 7.57 (d, 1 H, J = 7.6 Hz), 7.52 (d, 1 H, J = 8.0 Hz),
7.39 (d, 1 H, J = 7.6 Hz), 7.30 (br s, 1 H), 7.19-7.17 (m, 2 H),
4.79 (s, 2 H), 4.48 (s, 2 H), 2.78 (s, 6 H), 2.55 (s, 3 H) 118
##STR00127## (400 MHz, DMSO-d.sub.6) .delta. 12.70 (br s, 1 H),
9.54 (s, 1 H), 8.50 (s, 1 H), 7.99 (dd, 1 H, J = 9.2, 2.0 Hz), 7.83
(dd, 1 H, J = 9.2, 0.8 Hz), 7.72 (t, 1 H, J = 7.8 Hz), 7.52 (br s,
1 H), 7.32 (t, 1 H, J = 7.6 Hz), 7.17-7.13 (m, 2 H), 7.07 (d, 1 H,
J = 8.0 Hz), 7.02 (dd, 1 H, J = 7.6, 0.8 Hz), 4.48 (d, 2 H, J = 5.6
Hz), 3.68 (s, 2 H), 2.47 (s, 3 H), 2.23 (s, 6 H) 464.23 119
##STR00128## (400 MHz, DMSO-d.sub.6) .delta. 9.48 (t, 1 H, J = 1.2
Hz), 8.60 (s, 1 H), 7.92 (dd, 1 H, J = 9.2, 1.2 Hz), 7.86 (dd, 1 H,
overlapped, J = 9.2, 1.6 Hz), 7.85 (t, 1 H, overlapped, J = 8.0
Hz), 7.64 (d, 1 H, J = 8.0 Hz), 7.49 (t, 1 H, J = 7.8 Hz), 7.37 (d,
1 H, J = 8.0 Hz), 7.24 (dd, 1 H, J = 7.6, 0.8 Hz), 7.10 (dd, 1 H, J
= 8.0, 0.8 Hz), 4.81 (s, 2 H), 4.61 (s, 2 H), 2.89 (s, 6 H), 2.52
(s, 3 H) 120 ##STR00129## (400 MHz, CDCl.sub.3) .delta. 9.01 (s, 1
H), 8.36 (s, 1 H), 7.83 (dd, 1 H, J = 9.2, 1.6 Hz), 7.76 (dd, 1 H,
J = 9.2, 0.8 Hz), 7.49 (t, 1 H, J = 7.6 Hz), 7.28 (br d, 1 H, J =
7.6 Hz), 7.15 (br s, 1 H), 7.03 (d, 1 H, J = 7.6 Hz), 6.94 (s, 1
H), 6.82 (dd, 1 H, J = 2.0, 1.2 Hz), 4.86 (br s, 1 H), 4.55 (d, 2
H, J = 5.6 Hz), 3.48 (s, 2 H), 2.54 (s, 3 H), 2.32 (s, 6 H) 464.23
121 ##STR00130## (400 MHz, DMSO-d.sub.6) .delta. 10.77 (br s, 1 H),
9.46 (dd, 1 H, J = 1.6, 0.8 Hz), 8.60 (s, 1 H), 7.94 (dd, 1 H, J =
9.2, 0.8 Hz), 7.85 (dd, 1 H, overlapped, J = 9.2, 1.6 Hz), 7.84 (t,
1 H, overlapped, J = 7.8 Hz), 7.55 (d, 1 H, J = 7.6 Hz), 7.36 (d, 1
H, overlapped, J = 8.0 Hz), 7.35 (s, 1 H, overlapped), 7.23 (br s,
2 H), 4.71 (s, 2 H), 4.22 (s, 2 H), 2.67 (s, 6 H), 2.53 (s, 3 H)
122 ##STR00131## (400 MHz, CDCl.sub.3) .delta. 10.40 (br s, 1 H),
8.96 (s, 1 H), 8.36 (s, 1 H), 7.84 (dd, 1 H, J = 9.2, 1.6 Hz), 7.77
(d, 1 H, J = 9.2 Hz), 7.46 (t, 1 H, J = 7.6 Hz), 7.24 (br d, 1 H, J
= 7.6 Hz), 7.09 (d, 1 H, J = 7.6 Hz), 7.00 (d, 1 H, J = 7.6 Hz),
6.96 (dd, 1 H, J = 7.6, 1.6 Hz), 6.86 (br s, 1 H), 4.55 (s, 2 H),
3.74 (s, 2 H), 2.54 (br s, 4 H), 2.51 (s, 3 H), 1.81 (br s, 4 H)
490.25 123 ##STR00132## (400 MHz, DMSO-d.sub.6) .delta. 10.47 (br
s, 2 H), 9.46 (s, 1 H), 8.61 (s, 1 H), 7.95 (dd, 1 H, J = 9.2, 0.4
Hz), 7.86 (t, 1 H, overlapped, J = 7.6 Hz), 7.85 (dd, 1 H,
overlapped, J = 9.2, 1.2 Hz), 7.60 (d, 1 H, J = 7.6 Hz), 7.59 (d, 1
H, J = 8.0 Hz), 7.39 (d, 1 H, J = 7.6 Hz), 7.32 (br s, 1 H), 7.18
(dd, 1 H, J = 7.6, 1.6 Hz), 7.14 (d, 1 H, J = 1.6 Hz), 4.82 (s, 2
H), 4.53 (s, 2 H), 3.23 (br s, 4 H), 2.55 (s, 3 H), 1.99 (br s, 4
H) 124 ##STR00133## (400 MHz, DMSO-d.sub.6) .delta. 12.71 (br s, 1
H), 9.52 (s, 1 H), 8.50 (s, 1 H), 7.98 (dd, 1 H, J = 9.2, 1.6 Hz),
7.83 (d, 1 H, J = 9.2 Hz), 7.71 (t, 1 H, J = 7.8 Hz), 7.51 (br s, 1
H), 7.37 (t, 1 H, J = 5.2 Hz), 7.31 (t, 1 H, J = 8.0 Hz), 7.16 (d,
1 H, J = 7.6 Hz), 7.05 (d, 1 H, J = 8.0 Hz), 7.00 (dd, 1 H, J =
8.0, 1.2 Hz), 4.47 (d, 2 H, J = 5.2 Hz), 3.87 (s, 2 H), 2.51 (br s,
4 H), 2.47 (s, 3 H), 1.74 (br s, 4 H) 490.25 125 ##STR00134## (400
MHz, DMSO-d.sub.6/D.sub.2O) .delta. 9.41 (dd, 1 H, J = 1.6, 0.8
Hz), 8.61 (s, 1 H), 7.94 (dd, 1 H, J = 9.2, 0.8 Hz), 7.89 (t, 1 H,
J = 7.8 Hz), 7.84 (dd, 1 H, J = 9.2, 1.6 Hz), 7.55 (d, 1 H, J = 8.0
Hz), 7.50 (t, 1 H, J = 7.6 Hz), 7.42 (d, 1 H, J = 7.6 Hz), 7.25
(dd, 1 H, J = 7.6, 0.8 Hz), 7.09 (d, 1 H, J = 7.6 Hz), 4.78 (s, 2
H), 4.64 (s, 2 H), 3.45 (br s, 4 H), 2.58 (s, 3 H), 2.06 (br s, 4
H) 126 ##STR00135## (400 MHz, CDCl.sub.3) .delta. 8.99 (s, 1 H),
8.36 (s, 1 H), 7.82 (dd, 1 H, J = 9.2, 1.6 Hz), 7.77 (d, 1 H, J =
9.2 Hz), 7.48 (t, 1 H, J = 7.6 Hz), 7.27 (br d, 1 H, J = 7.6 Hz),
7.13 (br s, 1 H), 7.03 (d, 1 H, J = 7.6 Hz), 6.97 (br s, 1 H), 6.81
(dd, 1 H, J = 2.4, 1.2 Hz), 4.81 (br s, 1 H), 4.54 (d, 2 H, J = 5.6
Hz), 3.62 (s, 2 H), 2.57 (br s, 4 H), 2.54 (s, 3 H), 1.79 (br s, 4
H) 490.25 127 ##STR00136## (400 MHz, DMSO-d.sub.6) .delta. 10.96
(br s 1 H), 9.45 (dd, 1 H, J = 1.6, 0.8 Hz), 8.60 (s, 1 H), 7.94
(dd, 1 H, J = 9.2, 0.8 Hz), 7.84 (dd, 1 H, over- lapped, J = 9.2,
1.6 Hz), 7.83 (t, 1 H, overlapped, J = 7.8 Hz), 7.54 (d, 1 H, J =
8.0 Hz), 7.39 (br s, 1 H), 7.36 (d, 1 H, J = 7.6 Hz), 7.26 (s, 1
H), 7.21 (dd, 1 H, J = 2.0, 1.6 Hz), 4.72 (s, 2 H), 4.29 (s, 2 H),
3.02 (br s, 4 H), 2.53 (s, 3 H), 1.95 (br s, 2 H), 1.84 (br s, 2 H)
128 ##STR00137## (400 MHz, CDCl.sub.3) .delta. 8.97 (s, 1 H), 8.37
(s, 1 H), 7.84 (dd, 1 H, J = 9.2, 1.6 Hz), 7.79 (dd, 1 H, J = 9.2,
1.2 Hz), 7.49 (t, 1 H, J = 7.8 Hz), 7.29 (br d, 1 H, J = 8.0 Hz),
7.12 (d, 1 H, J = 7.6 Hz), 7.03 (d, 1 H, J = 7.6 Hz), 6.99 (dd, 1
H, J = 7.6, 1.6 Hz), 6.93 (br s, 1 H), 4.57 (s, 2 H), 3.75 (br s, 4
H, overlapped), 3.72 (s, 2 H, overlapped), 2.55 (br s, 7 H) 506.25
129 ##STR00138## (400 MHz, DMSO-d.sub.6) .delta. 9.45 (d, 1 H, J =
0.4 Hz), 8.61 (s, 1 H), 7.96 (d, 1 H, J = 9.2 Hz), 7.86 (t, 1 H,
overlapped, J = 8.0 Hz), 7.85 (dd, 1 H, overlapped, J = 9.2, 1.6
Hz), 7.60 (d, 1 H, J = 8.0 Hz), 7.57 (d, 1 H, J = 8.0 Hz), 7.39 (d,
1 H, J = 8.0 Hz), 7.19 (s, 1 H), 7.17 (dd, 1 H, overlapped, J =
8.0, 1.2 Hz), 4.82 (s, 2 H), 4.52 (s, 2 H), 3.91 (br s, 4 H), 3.32
(br s, 4 H), 2.55 (s, 3 H) 130 ##STR00139## (400 MHz, DMSO-d.sub.6)
.delta. 12.70 (br s, 1 H), 9.48 (br s, 1 H), 8.50 (s, 1 H), 7.95
(dd, 1 H, J = 9.2, 1.6 Hz), 7.84 (d, 1 H, J = 9.2 Hz), 7.71 (t, 1
H, J = 7.6 Hz), 7.44 (br s, 1 H), 7.34 (t, 1 H, J = 8.0 Hz), 7.28
(t, 1 H, J = 5.6 Hz), 7.16 (d, 1 H, J = 7.6 Hz), 7.07 (d, 1 H, J =
8.4 Hz), 7.03 (dd, 1 H, J = 7.6, 1.2 Hz), 4.49 (d, 2 H, J = 5.6
Hz), 3.76 (s, 2 H), 3.58 (m, 4 H), 2.48 (s, 3 H), 2.41 (br s, 4 H)
506.24 131 ##STR00140## (400 MHz, DMSO-d.sub.6) .delta. 9.46 (d, 1
H, J = 0.8 Hz), 8.60 (s, 1 H), 7.94 (dd, 1 H, J = 9.2, 0.8 Hz),
7.85 (t, 1 H, overlapped, J = 7.6 Hz), 7.84 (dd, 1 H, overlapped, J
= 9.2, 1.6 Hz), 7.60 (d, 1 H, J = 7.6 Hz), 7.47 (t, 1 H, J = 8.0
Hz), 7.37 (d, 1 H, J = 8.0 Hz), 7.22 (dd, 1 H, J = 7.6, 0.8 Hz),
7.08 (d, 1 H, J = 8.0 Hz), 4.82 (s, 2 H), 4.57 (s, 2 H), 3.95 (br
t, 4 H, J = 4.4 Hz), 3.40 (br s, 4 H), 2.53 (s, 3 H) 132
##STR00141## (400 MHz, CDCl.sub.3) .delta. 8.97 (s, 1 H), 8.38 (s,
1 H), 7.82 (dd, 1 H, J = 9.2, 1.6 Hz), 7.78 (dd, 1 H, J = 9.2, 0.8
Hz), 7.48 (t, 1 H, J = 7.6 Hz), 7.28 (br d, 1 H, J = 7.6 Hz), 7.06
(br s, 1 H, over- lapped), 7.04 (d, 1 H, J = 7.6 Hz), 7.01 (s, 1
H), 6.84 (dd, 1 H, J = 2.0, 1.2 Hz), 4.79 (br s, 1 H), 4.54 (d, 2
H, J = 7.6 Hz), 3.70 (m, 4 H), 3.48 (s, 2 H), 2.55 (s, 3 H), 2.47
(br s, 4 H) 506.24 133 ##STR00142## (400 MHz, DMSO-d.sub.6) .delta.
9.45 (dd, 1 H, J = 1.6, 0.8 Hz), 8.61 (s, 1 H), 7.95 (dd, 1 H, J =
9.2, 0.8 Hz), 7.85 (t, 1 H, overlapped, J = 7.6 Hz), 7.84 (dd, 1 H,
overlapped, J = 9.2, 1.6 Hz), 7.54 (d, 1 H, J = 7.6 Hz), 7.43 (br
s, 1 H), 7.37 (d, 1 H, J = 7.6 Hz), 7.28 (s, 1 H), 7.23 (dd, 1 H, J
= 2.2, 1.4 Hz), 4.74 (s, 2 H), 4.28 (s, 2 H), 3.83 (br s, 4 H),
3.81 (br s, 2 H), 3.08 (br s, 2 H), 2.54 (s, 3 H) 134 ##STR00143##
(400 MHz, CDCl.sub.3) .delta. 8.98 (s, 1 H), 8.36 (s, 1 H), 7.83
(dd, 1 H, J = 9.2, 1.6 Hz), 7.76 (dd, 1 H, J = 9.2, 0.8 Hz), 7.45
(t, 1 H, J = 7.8 Hz), 7.23 (br d, 1 H, J = 7.6 Hz), 7.13 (td, 1 H,
J = 8.0, 1.2 Hz), 7.04 (dd, 1 H, J = 8.0, 1.2 Hz), 6.99 (d, 1 H, J
= 8.0 Hz), 6.72 (d, 1 H, overlapped, J = 7.6 Hz), 6.71 (td, 1 H,
overlapped, J = 8.0, 1.2 Hz), 4.56 (s, 2 H), 2.81 (t, 2 H, J = 6.4
Hz), 2.63 (t, 2 H, J = 6.4 Hz), 2.52 (s, 3 H), 2.36 (s, 6 H) 453.25
135 ##STR00144## (400 MHz, DMSO-d.sub.6/D.sub.2O) .delta. 9.40 (dd,
1 H, J = 1.8, 0.8 Hz), 8.63 (s, 1 H), 7.96 (dd, 1 H, J = 9.2, 0.8
Hz), 7.86 (t, 1 H, J = 7.8 Hz), 7.82 (dd, 1 H, J = 9.2, 1.8 Hz),
7.48 (d, 1 H, J = 8.0 Hz), 7.41 (d, 1 H, J = 7.6 Hz), 7.17-7.12 (m,
2 H), 6.75-671 (m, 2 H), 4.73 (s, 2 H), 3.32 (br t, 2 H, J = 8.4
Hz), 3.02 (br t, 2 H, J = 8.4 Hz), 2.90 (s, 6 H), 2.58 (s, 3 H) 136
##STR00145## (400 MHz, CDCl.sub.3) .delta. 9.08 (s, 1 H), 8.32 (s,
1 H), 7.83 (dd, 1 H, J = 9.2, 1.6 Hz), 7.68 (d, 1 H, J = 9.2 Hz),
7.47 (t, 1 H, J = 7.6 Hz), 7.34 (br d, 1 H, J = 7.6 Hz), 7.04 (t, 1
H, J = 7.6 Hz), 6.99 (dd, 1 H, J = 7.6, 0.4 Hz), 6.66 (br s, 1 H),
6.53- 6.49 (m, 2 H), 4.48 (s, 2 H), 2.89-2.83 (m 4 H), 2.56 (s, 6
H), 2.48 (s, 3 H) 453.25 137 ##STR00146## (400 MHz, DMSO-d.sub.6)
.delta. 10.47 (br s, 1 H), 9.49 (t, 1 H, J = 0.8 Hz), 8.63 (s, 1
H), 7.97 (dd, 1 H, J = 9.2, 0.8 Hz), 7.85 (dd, 1 H, overlapped, J =
9.2, 1.2 Hz), 7.84 (t, 1 H, overlapped, J = 7.8 Hz), 7.64 (d, 1 H,
J = 8.0 Hz), 7.37 (d, 1 H, J = 7.6 Hz), 7.10 (t, 1 H, J = 8.0 Hz),
6.81 (br s, 1 H), 6.66 (dd, 1 H, J = 8.0, 1.6 Hz), 6.58 (d, 1 H, J
= 8.0 Hz), 4.75 (s, 2 H), 3.30-3.25 (m, 2 H), 2.94-2.89 (m, 2 H),
2.77 (d, 6 H, J = 4.8 Hz), 2.51 (s, 3 H) 138 ##STR00147## (400 MHz,
CDCl.sub.3) .delta. 10.40 (br s, 1 H), 8.94 (s, 1 H), 8.38 (s, 1
H), 7.83 (dd, 1 H, J = 9.2, 1.2 Hz), 7.80 (dd, 1 H, J = 9.2, 0.8
Hz), 7.49 (t, 1 H, J = 7.8 Hz), 7.30-7.27 (m, 1 H), 7.24 (d, 1 H, J
= 8.0 Hz), 7.06 (dt, 1 H, over- lapped, J = 7.6, 1.2 Hz), 7.05 (d,
1 H, overlapped, J = 7.6 Hz), 6.94-6.93 (m, 2 H), 4.72 (t, 1 H, J =
5.2 Hz), 4.54 (d, 2 H, J = 5.2 Hz), 2.82 (q, 2 H, J = 7.6 Hz), 1.31
(t, 3 H, J = 7.6 Hz) 421.21 139 ##STR00148## (400 MHz, CDCl.sub.3)
.delta. 10.37 (br s, 1 H), 8.96 (s, 1 H), 8.38 (s, 1 H), 7.84 (dd,
1 H, J = 9.2, 1.2 Hz), 7.79 (dd, 1 H, J = 9.2, 0.8 Hz), 7.48 (t, 1
H, J = 7.8 Hz), 7.22 (d, 1 H, J = 8.0 Hz), 7.06- 7.00 (m, 3 H),
6.80 (td, 1 H, J = 8.0, 1.2 Hz), 6.76-6.70 (m, 1 H), 4.62 (br s, 1
H, overlapped), 4.60 (s, 2 H), 2.80 (q, 2 H, J = 7.6 Hz), 1.29 (t,
3H, J = 7.6 Hz) 414.20
Practice Example 5
Preparation of
N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)-2-fluoro-N-methylaniline (Example 140)
##STR00149##
[0250] To a stirred solution of
1-((1,2,4)triazolo(1,5-a)pyridin-6-yl)-2-(6-methylpyridin-2-yl)ethane-1,2-
-dione (0.20 g, 0.75 mmol) in a mixture of tert-butyl methyl ether
(10 mL) and MeOH (8 mL) were added
2-((2-fluorophenyl)(methyl)amino)acetaldehyde (190 mg, 1.13 mmol)
and NH.sub.4OAc (0.15 g, 1.88 mmol), and the mixture was stirred at
room temperature for 2 h. The pH of the mixture was adjusted to 8
with saturated aqueous NaHCO.sub.3 solution. After removal of the
solvent, the reaction mixture was extracted with CHCl.sub.3
(2.times.100 mL), and the CHCl.sub.3 solution was washed with water
(20 mL) and brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered, and evaporated to dryness under reduced pressure. The
residue was purified by MPLC on silica gel using a mixture of MeOH
and CH.sub.2Cl.sub.2 (1:19 (v/v)) as eluent to give the titled
compound (90 mg, 32%) as a pale yellow solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.97 (br s, 1H), 8.37 (s, 1H), 7.82 (dd, 1H,
J=9.2, 1.6 Hz), 7.78 (dd, 1H, J=9.2, 1.2 Hz), 7.49 (t, 1H, J=7.8
Hz), 7.25 (br d, 1H, J=7.6 Hz), 7.14-7.06 (m, 3H), 7.04 (d, 1H,
J=7.6 Hz), 7.00-6.94 (m, 1H), 4.44 (s, 2H), 2.91 (s, 3H), 2.58 (s,
3H); MS (ESI) m/z 414.20 (MH.sup.+).
Practice Example 6
Preparation of
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)benzonitrile (Example 145)
##STR00150##
[0252] To a stirred solution of
1-((1,2,4)triazolo(1,5-a)pyridin-6-yl)-2-(6-methylpyridin-2-yl)ethane-1,2-
-dione (4.00 g, 15.02 mmol) in a mixture of tert-butyl methyl ether
(30 mL) and MeOH (30 mL) were added 3-(fomylmethyl)benzonitrile
(prepared according to the method described in WO 02/096875 A1)
(6.54 g, 45.07 mmol) and NH.sub.4OAc (11.58 g, 150.24 mmol), and
the mixture was stirred at room temperature for 90 min. The pH of
the mixture was adjusted to 8 with saturated aqueous NaHCO.sub.3
solution. After removal of solvent, the mixture was extracted with
EtOAc (2.times.150 mL), and the EtOAc solution was washed with
water (50 mL) and brine (50 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered, and evaporated to dryness under reduced
pressure. The residue was purified by MPLC on silica gel using a
mixture of MeOH and CH.sub.2Cl.sub.2 (1:19 (v/v)) as eluent to give
the titled compound (1.92 g, 33%) as a yellow solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 12.70 (br s, 1H), 9.53 (br s, 1H),
8.49 (s, 1H), 7.96 (dd, 1H, J=9.2, 1.8 Hz), 7.84 (d, 1H, J=2.0 Hz),
7.82 (d, 1H, J=9.2 Hz), 7.74-7.71 (m, 2H), 7.69 (t, 1H, overlapped,
J=7.6 Hz), 7.56 (t, 1H, J=7.8 Hz), 7.47 (br s, 1H), 7.15 (d, 1H,
J=7.6 Hz), 4.18 (s, 2H), 2.47 (s, 3H); MS (ESI) m/z 392.18
(MH.sup.+).
Practice Example 7
Preparation of
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)benzamide (Example 147)
##STR00151##
[0254] To a stirred solution of
3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-im-
idazol-2-yl)methyl)benzonitrile (41 mg, 0.10 mmol) in EtOH (2 mL)
were added 28% H.sub.2O.sub.2 (13.9 mL, 0.11 mmol) and 1N NaOH
(0.39 mL, 0.39 mmol) at room temperature. The mixture was heated to
at 60.degree. C. for 1 h and then, to it, was added 1 N HCl at
0.degree. C. to adjust pH 7-8. After removal of the solvent, the
residue was extracted with CH.sub.2Cl.sub.2 (2.times.15 mL). The
CH.sub.2Cl.sub.2 solution was washed with water (5 mL) and brine (5
mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and
evaporated to dryness under reduced pressure. The residue was
purified by MPLC on silica gel using a mixture of MeOH and
CH.sub.2Cl.sub.2 (1:9 (v/v)) as eluent to give the titled compound
(15 mg, 35%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.93 (br s, 1H), 8.32 (s, 1H), 7.77 (s, 1H), 7.76 (dd, 1H,
overlapped, J=9.2, 1.6 Hz), 7.69 (d, 1H, J=9.2 Hz), 7.56 (d, 1H,
J=8.0 Hz), 7.44 (t, 1H, J=7.6 Hz), 7.39 (d, 1H, J=7.6 Hz), 7.26 (t,
1H, J=8.0 Hz), 7.21 (d, 1H, J=7.6 Hz), 6.98 (d, 1H, J=7.6 Hz), 6.60
(br s, 1H), 6.27 (br s, 1H), 4.15 (s, 2H), 2.44 (s, 3H); MS (ESI)
m/z 410.19 (MH.sup.+).
[0255] The compounds listed in the following Table 2 were prepared
in an analogous manner to those described in the Practice Examples
5-7 above. The mass spectroscopy data of these compounds are
included in the Table 2.
TABLE-US-00002 TABLE 2 Exam- MS (ESI) ple Structure .sup.1H NMR
(ppm) m/z (MH.sup.+) 140 ##STR00152## (400 MHz, CDCl.sub.3) .delta.
8.97 (br s, 1 H), 8.37 (s, 1 H), 7.82 (dd, 1 H, J = 9.2, 1.6 Hz),
7.78 (dd, 1 H, J = 9.2, 1.2 Hz), 7.49 (t, 1 H, J = 7.8 Hz), 7.25
(br d, 1 H, J = 7.6 Hz), 7.14-7.06 (m, 3 H), 7.04 (d, 1 H, J = 7.6
Hz), 7.00- 6.94 (m, 1 H), 4.44 (s, 2 H), 2.91 (s, 3 H), 2.58 (s, 3
H) 414.20 141 ##STR00153## (400 MHz, CDCl.sub.3) .delta. 8.93 (s, 1
H), 8.37 (s, 1 H), 7.80-7.78 (m, 2 H), 7.48 (t, 1 H, J = 7.6 Hz),
7.35-7.30 (m, 1 H), 7.24 (br d, 1 H, J = 8.0 Hz), 7.08-7.05 (m, 3
H), 7.02 (d, 1 H, J = 7.6 Hz), 4.67 (s, 2 H), 3.14 (s, 3 H), 2.50
(s, 3 H) 421.20 142 ##STR00154## (400 MHz, CDCl.sub.3/CD.sub.3OD)
.delta. 8.86 (dd, 1 H, J = 1.6, 1.2 Hz), 8.18 (s, 1 H), 7.62 (dd, 1
H, J = 9.2, 1.6 Hz), 7.57 (dd, 1 H, J = 9.2, 1.2 Hz), 7.43 (t, 1 H,
J = 8.0 Hz), 7.24 (dd, 1 H, J = 2.4, 1.6 Hz), 7.14 (t, 1 H,
overlapped, J = 8.0 Hz), 7.13 (d, 1 H, overlapped, J = 8.0 Hz),
7.04 (ddd, 1 H, J = 8.0, 1.2, 0.8 Hz), 6.97 (d, 1 H, J = 7.6 Hz),
6.83 (ddd, 1 H, J = 8.0, 2.4, 0.8 Hz), 4.54 (s, 2 H), 2.99 (s, 3
H), 2.38 (s, 3 H) 439.22 143 ##STR00155## (400 MHz, CDCl.sub.3)
.delta. 8.94 (br s, 1 H), 8.36 (s, 1 H), 7.81 (dd, 1 H, J = 9.2,
1.6 Hz), 7.77 (dd, 1 H, J = 9.2, 0.8 Hz), 7.44 (t, 1 H, J = 7.8
Hz), 7.40-7.28 (m, 5 H), 7.20 (br d, 1 H, J = 8.0 Hz), 6.99 (d, 1
H, J = 7.6 Hz), 4.21 (s, 2 H), 2.51 (s, 3 H) 367.18 144
##STR00156## (400 MHz, CDCl.sub.3) .delta. 8.93 (t, 1 H, J = 1.2
Hz), 8.37 (s, 1 H), 7.80 (dd, 1 H, overlapped, J = 9.2, 1.6 Hz),
7.77 (dd, 1 H, overlapped, J = 9.2, 0.8 Hz), 7.46 (t, 1 H, J = 7.8
Hz), 7.39 (td, 1 H, J = 7.6, 1.6 Hz), 7.31-7.25 (m, 1 H), 7.21 (br
d, 1 H, J = 8.0 Hz), 7.14 (td, 1 H, overlapped, J = 7.6, 1.2 Hz),
7.10 (dd, 1 H, J = 8.4, 1.2 Hz), 7.02 (br d, 1 H, J = 7.6 Hz), 4.24
(s, 2 H), 2.55 (s, 3 H) 385.17 145 ##STR00157## (400 MHz,
DMSO-d.sub.6) .delta. 12.70 (br s, 1 H), 9.53 (br s, 1 H), 8.49 (s,
1 H), 7.96 (dd, 1 H, J = 9.2, 1.8 Hz), 7.84 (d, 1 H, J = 2.0 Hz),
7.82 (d, 1 H, J = 9.2 Hz), 7.74-7.71 (m, 2 H), 7.69 (t, 1 H,
overlapped, J = 7.6 Hz), 7.56 (t, 1 H, J = 7.8 Hz), 7.47 (br s, 1
H), 7.15 (d, 1 H, J = 7.6 Hz), 4.18 (s, 2 H), 2.47 (s, 3 H) 392.18
146 ##STR00158## (400 MHz, DMSO-d.sub.6) .delta. 9.51 (dd, 1 H, J =
1.6, 0.8 Hz), 8.65 (s, 1 H), 8.08 (br s, 1 H), 7.97 (dd, 1 H,
overlapped, J = 9.2, 0.8 Hz), 7.95 (br d, overlapped, 1 H, J = 8.0
Hz), 7.87 (dd, 1 H, J = 9.2, 1.6 Hz), 7.85-7.79 (m, 2 H), 7.63 (dd,
1 H, overlapped, J = 7.6, 1.2 Hz), 7.61 (t, 1 H, overlapped, J =
7.6 Hz), 7.36 (d, 1 H, J = 7.6 Hz), 4.55 (s, 2 H), 2.50 (s, 3 H)
147 ##STR00159## (400 MHz, CDCl.sub.3) .delta. 8.93 (br s, 1 H),
8.32 (s, 1 H), 7.77 (s, 1 H), 7.76 (dd, 1 H, overlapped, J = 9.2,
1.6 Hz), 7.69 (d, 1 H, J = 9.2 Hz), 7.56 (d, 1 H, J = 8.0 Hz), 7.44
(t, 1 H, J = 7.6 Hz), 7.39 (d, 1 H, J = 7.6 Hz), 7.26 (t, 1 H, J =
8.0 Hz), 7.21 (d, 1 H, J = 7.6 Hz), 6.98 (d, 1 H, J = 7.6 Hz), 6.60
(br s, 1 H), 6.27 (br s, 1 H), 4.15 (s, 2 H), 2.44 (s, 3 H) 410.19
148 ##STR00160## (400 MHz, CDCl.sub.3) .delta. 8.94 (s, 1 H), 8.37
(s, 1 H), 7.77-7.72 (m, 2 H), 7.51 (t, 1 H, J = 7.6 Hz), 7.32-7.25
(m, 3 H), 7.06 (d, 1 H, J = 7.6 Hz), 7.00 (t, 1 H, overlapped, J =
7.6 Hz), 6.97 (d, 2 H, overlapped, J = 8.0 Hz), 5.22 (s, 2 H), 2.54
(s, 3 H) 383.17 149 ##STR00161## (400 MHz, CDCl.sub.3) .delta. 8.95
(t, 1 H, J = 1.2 Hz), 8.38 (s, 1 H), 7.80 (dd, 1 H, J = 9.2, 0.8
Hz), 7.77 (dd, 1 H, J = 9.2, 1.2 Hz), 7.56 (t, 1 H, J = 8.0 Hz),
7.31 (d, 1 H, J = 7.6 Hz), 7.19 (td, 1 H, J = 8.0, 1.6 Hz), 7.14-
7.06 (m, 3 H), 7.01-6.95 (m, 1 H), 5.34 (s, 2 H), 2.64 (s, 3 H)
401.17 150 ##STR00162## (400 MHz, CDCl.sub.3/CD.sub.3OD) .delta.
8.94 (dd, 1 H, J = 1.6, 1.2 Hz), 8.32 (s, 1 H), 7.78 (dd, 1 H, J =
9.2, 1.6 Hz), 7.73 (dd, 1 H, J = 9.2, 1.2 Hz), 7.52 (t, 1 H, J =
7.8 Hz), 7.42- 7.37 (m, 1 H), 7.31-7.26 (m, 3 H), 7.25 (br d, 1 H,
overlapped, J = 8.0 Hz), 7.07 (d, 1 H, J = 7.6 Hz), 5.23 (s, 2 H),
2.55 (s, 3 H) 408.17 151 ##STR00163## (400 MHz,
CDCl.sub.3/CD.sub.3OD) .delta. 8.94 (t, 1 H, J = 1.6 Hz), 8.31 (s,
1 H), 7.76 (dd, 1 H, J = 9.2, 1.6 Hz), 7.70 (dd, 1 H, J = 9.2, 0.8
Hz), 7.51-7.47 (m, 2 H), 7.42 (ddd, 1 H, J = 8.0, 2.4, 1.2 Hz),
7.31 (t, 1 H, J = 8.0 Hz), 7.23 (d, 1 H, J = 7.6 Hz), 7.12 (ddd, 1
H, J = 8.0, 2.4, 0.8 Hz), 7.04 (d, 1 H, J = 7.6 Hz), 5.22 (s, 2 H),
2.51 (s, 3 H) 426.18 152 ##STR00164## (400 MHz, CDCl.sub.3) .delta.
8.89 (t, 1 H, J = 1.4 Hz), 8.35 (s, 1 H), 7.76-7.19 (m, 2 H), 7.45
(t, 1 H, J = 7.8 Hz), 7.39- 7.36 (m, 2 H), 7.30-7.26 (m, 2 H),
7.23-7.19 (m, 2 H), 7.01 (d, 1 H, J =7.6 Hz), 4.26 (s, 2 H), 2.49
(s, 3 H) 399.15 153 ##STR00165## (400 MHz, CDCl.sub.3) .delta. 8.86
(br s, 1 H), 8.37 (s, 1 H), 7.78 (dd, 1 H, J = 9.2, 0.8 Hz), 7.72
(dd, 1 H, J = 9.2, 1.6 Hz), 7.54-7.48 (m, 2 H), 7.31-7.27 (m, 1 H),
7.25 (br d, 1 H, J = 8.0 Hz), 7.13-7.08 (m, 2 H), 7.06 (d, 1 H, J =
8.0 Hz), 4.30 (s, 2 H), 2.64 (s, 3 H) 417.15
[0256] Biological Data
[0257] The biological activity of the compounds of the invention
may be assessed using the following assays:
[0258] Cell-Free Assay for Evaluating Inhibition of ALK5 Kinase
Phosphorylation of Smad3
[0259] The His-tagged, constitutively active ALK5 (T204D) and Smad3
full protein were expressed in insect cells using the Invitrogen
BacNBlue baculovirus expression system. Expressed proteins were
purified with Qiagen Ni--NTA resin column. The purified smad3
protein 200 ng was mixed with 100 .mu.L of 0.1 M sodium bicarbonate
coating buffer and coated into Flash-Plates by pipetting. Plates
were covered and incubated at 4.degree. C. for 16 h. Then, the
plates were washed 3 times with 200 .mu.L of coating buffer and
allowed to block in 1% BSA in PBS at room temperature for 1 h. The
purified ALK5 protein 100 ng was mixed with 100 .mu.L of reaction
buffer containing 20 mM Tris-HCl (pH 7.4), 5 mM MgCl.sub.2, 1 mM
CaCl.sub.2, 1 mM DTT, 1 .mu.M ATP and 2 .mu.Ci
.gamma.-.sup.32p-ATP, and 1 .mu.L of each test compound of formula
(I) prepared in 100% DMSO solution at different concentrations. The
assay was then initiated with the addition of ALK5 reaction mixture
into Smad3-coated Flash-Plates, followed by incubation at
30.degree. C. for 3 h. After incubation, the assay buffer was
removed and washed 3 times with 200 .mu.L of 10 mM sodium
pyrophosphate solution. Then, the Flash-Plates were air-dried and
counted on a Packard TopCount.
[0260] Compounds of formula (I) typically exhibited IC.sub.50
values of less than 1 .mu.M; some exhibited IC.sub.50 values of
less than 0.1 .mu.M; and some even exhibited IC.sub.50 values less
than 10 nM.
[0261] Cell-Free Assay for Evaluating Inhibition of ALK4 Kinase
Phosphorylation of Smad3 Inhibition of the ALK4 kinase
phosphorylation of Smad3 by test compounds of formula (I) can be
determined in a similar manner to that described above for ALK5
inhibition except that a similarly His-tagged ALK4 is used in place
of the His-tagged, constitutively active ALK5.
[0262] Compounds of formula (I) typically exhibited IC.sub.50
values of less than 1 .mu.M; some exhibited IC.sub.50 values of
less than 0.1 .mu.M.
[0263] Assay for Evaluating Cellular Inhibition of TGF-.beta.
Signaling
[0264] 4T103Tp-Luc stable cells or HaCaT-3TP-Lux stable cells that
have p3TP-Lux (neo) expression plasmid were seeded and treated with
TGF-.beta.1 in 0.2% FBS (2 ng/mL) in the presence or absence of
each test compounds of formula (I) at approximately 60-70%
confluence for 20 h. Cell lysates were used to measure luciferase
activity. Data were normalized by measuring concentration of total
protein.
[0265] Compounds of formula (I) typically exhibited IC.sub.50
values of less than 1 .mu.M; some exhibited IC.sub.50 values of
less than 0.1 .mu.M; and some even exhibited IC.sub.50 values of
less than 10 nM.
[0266] Evaluation of Anti-Metastatic Activity of Example 60 in
Vivo
[0267] Tumor-bearing MMTV/c-Neu mice were treated either saline
(vehicle) or example 60 (40 mg/kg, in 100 .mu.L saline) by
intraperitoneal injection every other day for 3 weeks. The tumor
size was measured using calipers, and the tumor volumes were
calculated by using the following equation:
Tumor volume=(0.5236).times.(width).sup.2.times.(length)
[0268] After sacrifice, mammary tumor and lung tissues were
analyzed by hematoxylin and eosin (H & E) staining. In the
Balb/c xenograft model, 4T1 cells (1.times.10.sup.4 in 100 .mu.L
PBS) were transplanted into the left thoracic mammary fat pads of
10-weeks-old female Balb/c mice, and mice were randomized into two
group (n=6 per groups). Ten days after transplantation,
tumor-bearing Balb/c mice were administered either saline (vehicle)
or example 60 (40 mg/kg, in 100 .mu.L saline) by intraperitoneal
injection every other day for 2.5 weeks. The tumor size was
measured using calipers, and metastastic nodules on the left lobe
surface of lungs were visualized by india ink injection into the
trachea and counted.
* * * * *