U.S. patent application number 16/799076 was filed with the patent office on 2021-01-21 for pharmacokinetically improved compounds.
The applicant listed for this patent is SURFACE LOGIX, LLC. Invention is credited to Alessandra Bartolozzi, Stewart Campbell, Hope Foudoulakis, Brian Kirk, Siya Ram, Hemalatha Seshadri, Paul Sweetnam.
Application Number | 20210017166 16/799076 |
Document ID | / |
Family ID | 1000005134521 |
Filed Date | 2021-01-21 |
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United States Patent
Application |
20210017166 |
Kind Code |
A1 |
Bartolozzi; Alessandra ; et
al. |
January 21, 2021 |
PHARMACOKINETICALLY IMPROVED COMPOUNDS
Abstract
The present invention relates to inhibitors of ROCK1 and ROCK2
and methods of modulating the pharmacokinetic and/or
pharmacodynamic properties of such compounds. Also provided are
methods of inhibiting ROCK1 and or ROCK2 that are useful for the
treatment of disease.
Inventors: |
Bartolozzi; Alessandra;
(Somerville, MA) ; Campbell; Stewart; (Framingham,
MA) ; Foudoulakis; Hope; (Framingham, US) ;
Kirk; Brian; (Sudbury, MA) ; Ram; Siya;
(Winchester, MA) ; Sweetnam; Paul; (Marblehead,
MA) ; Seshadri; Hemalatha; (Waltham, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SURFACE LOGIX, LLC |
Cambridge |
MA |
US |
|
|
Family ID: |
1000005134521 |
Appl. No.: |
16/799076 |
Filed: |
February 24, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16040245 |
Jul 19, 2018 |
10570123 |
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16799076 |
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15495019 |
Apr 24, 2017 |
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16040245 |
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15263154 |
Sep 12, 2016 |
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15495019 |
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14581746 |
Dec 23, 2014 |
9440961 |
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15263154 |
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13715644 |
Dec 14, 2012 |
8916576 |
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14581746 |
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11887218 |
Mar 14, 2008 |
8357693 |
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PCT/US06/11271 |
Mar 27, 2006 |
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13715644 |
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60665165 |
Mar 25, 2005 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B82Y 30/00 20130101;
C07D 405/14 20130101; C07D 403/14 20130101; C07D 403/12 20130101;
C07D 413/14 20130101; C07D 401/14 20130101 |
International
Class: |
C07D 413/14 20060101
C07D413/14; B82Y 30/00 20060101 B82Y030/00; C07D 401/14 20060101
C07D401/14; C07D 403/12 20060101 C07D403/12; C07D 403/14 20060101
C07D403/14; C07D 405/14 20060101 C07D405/14 |
Claims
1. A compound of formula I: ##STR00303## or pharmaceutically
acceptable salt or hydrate thereof, wherein: R.sup.1 is selected
from the group consisting of aryl,
--(CH.sub.2).sub.y--NR.sup.13R.sup.14, --X--R.sup.12,
--O--(CH.sub.2).sub.y--CO.sub.2R.sup.12,
--O--(CH.sub.2).sub.y--C(.dbd.O)NR.sup.13R.sup.14,
--O--(CH.sub.2).sub.y-heteroaryl, --O--(CH.sub.2).sub.y-cycloalkyl,
--O--C(.dbd.O)--(CH.sub.2).sub.y--NR.sup.13R.sup.14,
--O--(CH.sub.2).sub.z--NR.sup.13R.sup.14,
--NH--C(.dbd.O)--(CH.sub.2).sub.y--NR.sup.13R.sup.14,
--NH--C(.dbd.O)--X--R.sup.15,
--NH--(CH.sub.2).sub.y--NR.sup.13R.sup.14; R.sup.12 is selected
from the group consisting of C.sub.1-C.sub.6 alkyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), aryl,
aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve
membered heterocyclic ring containing up to 3 heteroatoms, each of
which may be optionally substituted at one or more carbon atoms by
from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and C.sub.1-C.sub.3
perfluoro alkyl; R.sup.13 and R.sup.14 are independently selected
from the group consisting of H, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; or
R.sup.13 and R.sup.14 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7 cycloalkyl, oxo,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; X is
selected from a covalent bond, O, NH, and C.sub.1-C.sub.6 alkyl;
R.sup.1 is selected from the group consisting of H, aryl,
heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered
heterocyclic ring containing up to 3 heteroatoms, each of which may
be optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl, or R.sup.15 is selected from
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --CO.sub.2R.sup.18,
--O--(CH.sub.2).sub.x--CO.sub.2R.sup.18, and
--C(.dbd.O)NR.sup.16R.sup.17; R.sup.16 and R.sup.17 independently
selected from the group consisting of H, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8 alkynyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), aryl,
aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve
membered heterocyclic ring containing up to 3 heteroatoms, each of
which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy, amino,
cyano and C.sub.1-C.sub.3 perfluoro alkyl; or R.sup.16 and R.sup.17
may be taken together form a three to twelve membered heterocyclic
ring having up to 3 heteroatoms which is optionally substituted by
from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6
alkoxy, oxo, hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro
alkyl; R.sup.18 is selected from the group consisting of H, aryl,
aralkyl, heteroaryl, C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; x is selected from
0 to 6; y is selected from 0 to 6; z is selected from 2 to 6; each
R.sup.2 is independently selected from the group consisting of
lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro
lower alkyl; each R.sup.3 is independently selected from the group
consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino,
and perfluoro lower alkyl; R.sup.4 is selected from
--(CH.sub.2).sub.a--NR.sup.43R.sup.44, --Y--R.sup.42,
--O--(CH.sub.2).sub.a--CO.sub.2R.sup.42,
--O--(CH.sub.2).sub.a--C(.dbd.O)NR.sup.43R.sup.44,
--O--(CH.sub.2).sub.a-heteroaryl, --O--(CH.sub.2).sub.a-cycloalkyl,
--O--C(.dbd.O)--(CH.sub.2).sub.a--NR.sup.43R.sup.44,
--O--(CH.sub.2).sub.c--NR.sup.43R.sup.44,
--NH--C(.dbd.O)--(CH.sub.2).sub.a--NR.sup.43R.sup.44,
--NH--C(.dbd.O)--Y--R.sup.45,
--NH--C(.dbd.O)--(CH.sub.2).sub.a--NR.sup.43R.sup.44; R.sup.42 is
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted at one or more carbon atoms
by from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and C.sub.1-C.sub.3
perfluoro alkyl; R.sup.43 and R.sup.44 are independently selected
from the group consisting of H, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.5 alkynyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.46R.sup.47, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; or
R.sup.43 and R.sup.44 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; Y is selected from a covalent
bond, O, NH, and C.sub.1-C.sub.6 alkyl; R.sup.45 is selected from
the group consisting of H, aryl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.46R.sup.47, --CO.sub.2R.sup.48,
--O--(CH.sub.2).sub.b--CO.sub.2R.sup.48, and
--C(.dbd.O)NR.sup.46R.sup.47, R.sup.46 and R.sup.47 independently
selected from the group consisting of H, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.5 alkynyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), aryl,
aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve
membered heterocyclic ring containing up to 3 heteroatoms, each of
which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy, amino,
cyano and C.sub.1-C.sub.3 perfluoro alkyl; or R.sup.46 and R.sup.47
may be taken together form a three to twelve membered heterocyclic
ring having up to 3 heteroatoms which is optionally substituted by
from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6
alkoxy, oxo, hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro
alkyl; R.sup.48 is selected from the group consisting of H, aryl,
aralkyl, heteroaryl, C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; a is selected from
0 to 6; b is selected from 0 to 6; c is selected from 2 to 6;
R.sup.5 is selected from the group consisting of H, C.sub.1-C.sub.6
alkyl, --(CH.sub.2).sub.d--C(.dbd.O)--NR.sup.53R.sup.54,
--C(.dbd.O)--(CH.sub.2).sub.d--NR.sup.53R.sup.54,
--C(.dbd.O)--X--R.sup.55, and
--C(.dbd.O)--(CH.sub.2).sub.d--NR.sup.53R.sup.54; R.sup.53 and
R.sup.54 are independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.56R.sup.57, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.56R.sup.57, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; or
R.sup.53 and R.sup.54 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7 cycloalkyl, oxo,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; R.sup.55
is selected from the group consisting of H, aryl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.56R.sup.57, --CO.sub.2R.sup.58,
--O--(CH.sub.2).sub.e--CO.sub.2R.sup.58, and
--C(.dbd.O)NR.sup.56R.sup.57, R.sup.56 and R.sup.57 independently
selected from the group consisting of H, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8 alkynyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), aryl,
aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve
membered heterocyclic ring containing up to 3 heteroatoms, each of
which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy, amino,
cyano and C.sub.1-C.sub.3 perfluoro alkyl; or R.sup.56 and R.sup.57
may be taken together form a three to twelve membered heterocyclic
ring having up to 3 heteroatoms which is optionally substituted by
from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6
alkoxy, oxo, hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro
alkyl; R.sup.58 is selected from the group consisting of H, aryl,
aralkyl, heteroaryl, C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.56R.sup.57, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; d is selected from
0 to 6; e is selected from 0 to 6; R.sup.6 is selected from the
group consisting of H, C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.r--C(.dbd.O)--NR.sup.63R.sup.64,
--C(.dbd.O)--(CH.sub.2).sub.r--NR.sup.63R.sup.64,
--C(.dbd.O)--X--R.sup.65, and
--C(.dbd.O)--(CH.sub.2).sub.r--NR.sup.63R.sup.64; R.sup.63 and
R.sup.64 are independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.66R.sup.67, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.66R.sup.67, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; or
R.sup.63 and R.sup.64 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7 cycloalkyl, oxo,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; R.sup.65
is selected from the group consisting of H, aryl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.66R.sup.67, --CO.sub.2R.sup.68,
--O--(CH.sub.2).sub.s--CO.sub.2R.sup.68, and
--C(.dbd.O)NR.sup.66R.sup.67, R.sup.66 and R.sup.67 independently
selected from the group consisting of H, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8 alkynyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), aryl,
aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve
membered heterocyclic ring containing up to 3 heteroatoms, each of
which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy, amino,
cyano and C.sub.1-C.sub.3 perfluoro alkyl; or R.sup.66 and R.sup.67
may be taken together form a three to twelve membered heterocyclic
ring having up to 3 heteroatoms which is optionally substituted by
from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6
alkoxy, oxo, hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro
alkyl; R.sup.68 is selected from the group consisting of H, aryl,
aralkyl, heteroaryl, C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.66R.sup.67, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; r is selected from
0 to 6; s is selected from 0 to 6; n is selected from 0 to 4; m is
selected from 0 to 3; and p is selected from 0 and 1.
2-26. (canceled)
Description
RELATED APPLICATIONS
[0001] The present application claims the benefit of U.S.
Provisional Patent Application No. 60/665,165 filed on Mar. 25,
2005 and PCT/US2006/011271 filed on Mar. 27, 2006.
BACKGROUND OF THE INVENTION
[0002] The development of a new pharmaceutical agent requires
careful optimization of the chemical and biological properties of a
lead compound. For example, a successful drug candidate must be
safe and effective for its intended use. Further, the compound must
possess desired pharmacokinetic and pharmacodynamic profiles. This
arduous development process usually requires extensive
experimentation. In many cases, the process for determining the
optimal compound can often require preparation of thousands of
structurally similar compounds.
[0003] Among the properties that can limit the utility of a
potential pharmaceutical agent is the degree to which the compound
is complexed to proteins in vivo. If a high percentage of the
compound present in vivo is non-specifically bound, for example by
components of blood and blood plasma, this leaves only a very small
amount of free compound available to tissue to perform its
therapeutic function. Thus, binding of the compound to various
proteins and other plasma components may require an unacceptably
large dosage of compound to achieve the desired therapeutic
effect.
[0004] Traditional approaches have sought to alter pharmacokinetic
properties.
[0005] The Rho-associated kinase is a key intracellular regulator
of cytoskeletal dynamics and cell motility. Rho-kinase regulates a
number of downstream targets of RhoA through phosphorylation,
including, for example, myosin light chain, the myosin light chain
phosphatase binding subunit and LIM-kinase 2. In smooth muscle
cells Rho-kinase mediates calcium sensitization and smooth muscle
contraction. Inhibition of Rho-kinase blocks 5-HT and phenylephrine
agonist induced muscle contraction. When introduced into non-smooth
muscle cells, Rho kinase induces stress fiber formation and is
required for the cellular transformation mediated by RhoA. Rho
kinase participates in a variety of cellular processes, including
but not limited to Na/H exchange transport system activation,
stress fiber formation, adducin activation. Rho kinase is involved
in physiological processes such as vasoconstriction, bronchial
smooth muscle constriction, vascular smooth muscle and endothelial
cell proliferation, platelet aggregation, and others.
[0006] Inhibition of Rho-kinase activity in animal models has
demonstrated a number of benefits of Rho-kinase inhibitors for the
treatment of human diseases. These include models of cardiovascular
diseases such as hypertension, atherosclerosis, restenosis, cardiac
hypertrophy, ocular hypertension, cerebral ischemia, cerebral
vasospasm, penile erectile dysfunction, central nervous system
disorders such as neuronal degeneration and spinal cord injury, and
in neoplasias where inhibition of Rho-kinase activity has been
shown to inhibit tumor cell growth and metastasis, angiogenesis,
arterial thrombotic disorders such as platelet aggregation and
leukocyte aggregation, asthma, regulation of intraoccular pressure,
and bone resorption. The inhibition of Rho-kinase activity in
patients has benefits for controlling cerebral vasospasms and
ischemia following subarachnoid hemorrhage.
[0007] In mammals, Rho-kinase consists of two isoforms, ROCK1
(ROCK.beta.; p160-ROCK) and ROCK2 (ROCK.alpha.). ROCK1 and ROCK2
are differentially expressed and regulated in specific tissues. For
example, ROCK1 is ubiquitously expressed at relatively high levels,
whereas ROCK2 is preferentially expressed in cardiac and brain
tissues and in a developmental stage specific manner. ROCK1 is a
substrate for cleavage by caspase-3 during apoptosis, whereas ROCK2
is not. Smooth muscle specific basic calponin is phosphorylated
only by ROCK2.
[0008] Further, the physiological roles of the proteins appear to
be distinct. For example, a recent study comparing the ROCK1/+
haploinsufficient mice with wild type littermates indicated that
ROCK1 is critical for the development of cardiac fibrosis, but not
hypertrophy, in response to various pathological conditions and
suggest that signaling pathways leading to the hypertrophic and
profibrotic response of the heart are distinct. However, the lack
of inhibitors specific for ROCK1 or ROCK2 has impeded their
respective roles to otherwise be distinguished.
[0009] Accordingly, there is a need for improved ROCK specific
kinase inhibitors, including kinase inhibitors that specifically
inhibit ROCK1 or ROCK2.
SUMMARY OF THE INVENTION
[0010] The present invention relates to compounds having the
formula I
##STR00001##
or pharmaceutically acceptable salt or hydrate thereof, wherein:
R.sup.1 is selected from the group consisting of aryl,
--(CH.sub.2).sub.y--NR.sup.13R.sup.14, --X--R.sup.12,
--O--(CH.sub.2).sub.y--CO.sub.2R.sup.12,
--O--(CH.sub.2).sub.y--C(.dbd.O)NR.sup.13R.sup.14,
--O--(CH.sub.2).sub.y-heteroaryl, --O--(CH.sub.2).sub.y-cycloalkyl,
--O--C(.dbd.O)--(CH.sub.2).sub.y--NR.sup.13R.sup.14,
--O--(CH.sub.2).sub.z--NR.sup.13R.sup.14,
--NH--C(.dbd.O)--(CH.sub.2).sub.y--NR.sup.13R.sup.14,
--NH--C(.dbd.O)--X--R.sup.15,
--NH--(CH.sub.2).sub.y--NR.sup.13R.sup.14; [0011] R.sup.12 is
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), aryl,
aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve
membered heterocyclic ring containing up to 3 heteroatoms, each of
which may be optionally substituted at one or more carbon atoms by
from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and C.sub.1-C.sub.3
perfluoro alkyl; [0012] R.sup.13 and R.sup.14 are independently
selected from the group consisting of H, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0013]
or R.sup.13 and R.sup.14 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7 cycloalkyl, oxo,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0014] X
is selected from a covalent bond, O, NH, and C.sub.1-C.sub.6 alkyl;
[0015] R.sup.15 is selected from the group consisting of H, aryl,
heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered
heterocyclic ring containing up to 3 heteroatoms, each of which may
be optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl, or R.sup.15 is selected from
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --CO.sub.2R.sup.18,
--O--(CH.sub.2).sub.x--CO.sub.2R.sup.18, and
--C(.dbd.O)NR.sup.16R.sup.17; [0016] R.sup.16 and R.sup.17
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0017] or
R.sup.16 and R.sup.17 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0018] R.sup.18 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; [0019] x is
selected from 0 to 6; [0020] y is selected from 0 to 6; [0021] z is
selected from 2 to 6; each R.sup.2 is independently selected from
the group consisting of lower alkyl, CN, halo, hydroxy, lower
alkoxy, amino, and perfluoro lower alkyl; each R.sup.3 is
independently selected from the group consisting of lower alkyl,
CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
R.sup.4 is selected from --(CH.sub.2).sub.a--NR.sup.43R.sup.44,
--Y--R.sup.42, --O--(CH.sub.2).sub.a--CO.sub.2R.sup.42,
--O--(CH.sub.2).sub.a--C(.dbd.O)NR.sup.43R.sup.44,
--O--(CH.sub.2).sub.a-heteroaryl, --O--(CH.sub.2).sub.a-cycloalkyl,
--O--C(.dbd.O)--(CH.sub.2).sub.a--NR.sup.43R.sup.44,
--O--(CH.sub.2).sub.c--NR.sup.43R.sup.44,
--NH--C(.dbd.O)--(CH.sub.2).sub.a--NR.sup.43R.sup.44,
--NH--C(.dbd.O)--Y--R.sup.45,
--NH--C(.dbd.O)--(CH.sub.2).sub.a--NR.sup.43R.sup.44; [0022]
R.sup.42 is selected from the group consisting of C.sub.1-C.sub.6
alkyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted at one or more carbon atoms
by from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and C.sub.1-C.sub.3
perfluoro alkyl; [0023] R.sup.43 and R.sup.44 are independently
selected from the group consisting of H, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8 alkynyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.46R.sup.47, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0024]
or R.sup.43 and R.sup.44 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0025] Y is selected from a
covalent bond, O, NH, and C.sub.1-C.sub.6 alkyl; [0026] R.sup.45 is
selected from the group consisting of H, aryl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.46R.sup.47, --CO.sub.2R.sup.48,
--O--(CH.sub.2).sub.b--CO.sub.2R.sup.48, and
--C(.dbd.O)NR.sup.46R.sup.47, [0027] R.sup.46 and R.sup.47
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0028] or
R.sup.46 and R.sup.47 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0029] R.sup.48 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; [0030] a is
selected from 0 to 6; [0031] b is selected from 0 to 6; [0032] c is
selected from 2 to 6; R.sup.5 is selected from the group consisting
of H, C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.d--C(.dbd.O)--NR.sup.53R.sup.54,
--C(.dbd.O)--(CH.sub.2).sub.d--NR.sup.53R.sup.54,
--C(.dbd.O)--X--R.sup.55, and
--C(.dbd.O)--(CH.sub.2).sub.d--NR.sup.53R.sup.54; [0033] R.sup.53
and R.sup.54 are independently selected from the group consisting
of H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.56R.sup.57, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.56R.sup.57, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0034]
or R.sup.53 and R.sup.54 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7 cycloalkyl, oxo,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0035]
R.sup.55 is selected from the group consisting of H, aryl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.56R.sup.57, --CO.sub.2R.sup.58,
--O--(CH.sub.2).sub.e--CO.sub.2R.sup.58, and
--C(.dbd.O)NR.sup.56R.sup.57, [0036] R.sup.56 and R.sup.57
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0037] or
R.sup.56 and R.sup.57 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0038] R.sup.58 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.56R.sup.57, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; [0039] d is
selected from 0 to 6; [0040] e is selected from 0 to 6; R.sup.6 is
selected from the group consisting of H, C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.r--C(.dbd.O)--NR.sup.63R.sup.64,
--C(.dbd.O)--(CH.sub.2).sub.r--NR.sup.63R.sup.64,
--C(.dbd.O)--X--R.sup.65, and
--C(.dbd.O)--(CH.sub.2).sub.r--NR.sup.63R.sup.64; [0041] R.sup.63
and R.sup.64 are independently selected from the group consisting
of H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.66R.sup.67, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.66R.sup.67, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0042]
or R.sup.63 and R.sup.64 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7 cycloalkyl, oxo,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0043]
R.sup.65 is selected from the group consisting of H, aryl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.66R.sup.67, --CO.sub.2R.sup.68,
--O--(CH.sub.2).sub.s--CO.sub.2R.sup.68, and
--C(.dbd.O)NR.sup.66R.sup.67, [0044] R.sup.66 and R.sup.67
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0045] or
R.sup.66 and R.sup.67 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0046] R.sup.68 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.66R.sup.67, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alky)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; [0047] r is
selected from 0 to 6; [0048] s is selected from 0 to 6; n is
selected from 0 to 4; m is selected from 0 to 3; and p is selected
from 0 and 1.
[0049] The present invention includes pharmaceutical compositions
comprising the compounds of the invention and a pharmaceutically
acceptable carrier and/or diluents.
[0050] The present invention includes pharmaceutical compositions
comprising a substantially pure compound of the invention, or a
pharmaceutically acceptable salt, stercoisomer, or hydrate thereof,
and a pharmaceutically acceptable excipient and/or diluents.
DESCRIPTION OF DRAWINGS
[0051] FIG. 1 shows various compounds that represent embodiment of
the present invention.
[0052] FIG. 2 shows various compounds that represent embodiment of
the present invention.
[0053] FIG. 3 shows various compounds that represent embodiment of
the present invention.
[0054] FIG. 4 shows various compounds that represent embodiment of
the present invention.
[0055] FIG. 5 shows various compounds that represent embodiment of
the present invention.
[0056] FIG. 6 shows various compounds that represent embodiment of
the present invention.
[0057] FIG. 7 shows various compounds that represent embodiment of
the present invention.
[0058] FIG. 8 shows various compounds that represent embodiment of
the present invention.
[0059] FIG. 9 shows various compounds that represent embodiment of
the present invention.
[0060] FIG. 10 depicts the specific inhibition of ROCK2 by the
compound of Example 82. Inhibition is compared to Y27632, which
inhibits both ROCK1 and ROCK2, as well as PKC.
DETAILED DESCRIPTION
[0061] The present invention relates to compounds having the
formula I
##STR00002##
or pharmaceutically acceptable salt or hydrate thereof, wherein:
R.sup.1 is selected from the group consisting of aryl,
--(CH.sub.2).sub.y--NR.sup.13R.sup.14, --X--R.sup.12,
--O--(CH.sub.2).sub.y--CO.sub.2R.sup.12,
--O--(CH.sub.2).sub.y--C(.dbd.O)NR.sup.13R.sup.14,
--O--(CH.sub.2).sub.y-heteroaryl, --O--(CH.sub.2).sub.y-cycloalkyl,
--O--C(.dbd.O)--(CH.sub.2).sub.y--NR.sup.13R.sup.14,
--O--(CH.sub.2).sub.z--NR.sup.13R.sup.14,
--NH--C(.dbd.O)--(CH.sub.2).sub.y--NR.sup.13R.sup.14,
--NH--C(.dbd.O)--X--R.sup.15,
--NH--(CH.sub.2).sub.y--NR.sup.13R.sup.14; [0062] R.sup.12 is
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), aryl,
aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve
membered heterocyclic ring containing up to 3 heteroatoms, each of
which may be optionally substituted at one or more carbon atoms by
from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and C.sub.1-C.sub.3
perfluoro alkyl; [0063] R.sup.13 and R.sup.14 are independently
selected from the group consisting of H, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0064]
or R.sup.13 and R.sup.14 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7 cycloalkyl, oxo,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0065]
each X is selected from a covalent bond, O, NH, and C.sub.1-C.sub.6
alkyl; [0066] R.sup.15 is selected from the group consisting of H,
aryl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve
membered heterocyclic ring containing up to 3 heteroatoms, each of
which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy, amino,
cyano and C.sub.1-C.sub.3 perfluoro alkyl, or R.sup.15 is selected
from --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --CO.sub.2R.sup.18,
--O--(CH.sub.2).sub.x--CO.sub.2R.sup.18, and
--C(.dbd.O)NR.sup.16R.sup.18; [0067] R.sup.16 and R.sup.17
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0068] or
R.sup.16 and R.sup.17 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0069] R.sup.18 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; [0070] x is
selected from 0 to 6; [0071] y is selected from 0 to 6; [0072] z is
selected from 2 to 6; each R.sup.2 is independently selected from
the group consisting of lower alkyl, CN, halo, hydroxy, lower
alkoxy, amino, and perfluoro lower alkyl; each R.sup.3 is
independently selected from the group consisting of lower alkyl,
CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
R.sup.4 is selected from --(CH.sub.2).sub.a--NR.sup.43R.sup.44,
--Y--R.sup.42, --O--(CH.sub.2).sub.a--CO.sub.2R.sup.42,
--O--(CH.sub.2).sub.a--C(.dbd.O)NR.sup.43R.sup.44,
--O--(CH.sub.2).sub.a-heteroaryl, --O--(CH.sub.2).sub.a-cycloalkyl,
--O--C(.dbd.O)--(CH.sub.2).sub.a--NR.sup.43R.sup.44,
--O--(CH.sub.2).sub.c--NR.sup.43R.sup.44,
--NH--C(.dbd.O)--(CH.sub.2).sub.a--NR.sup.43R.sup.44,
--NH--C(.dbd.O)--Y--R.sup.45,
--NH--C(.dbd.O)--(CH.sub.2).sub.a--NR.sup.43R.sup.44; [0073]
R.sup.42 is selected from the group consisting of C.sub.1-C.sub.6
alkyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted at one or more carbon atoms
by from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and C.sub.1-C.sub.3
perfluoro alkyl; [0074] R.sup.43 and R.sup.44 are independently
selected from the group consisting of H, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8 alkynyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.46R.sup.47, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0075]
or R.sup.43 and R.sup.44 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0076] Y is selected from a
covalent bond, O, NH, and C.sub.1-C.sub.6 alkyl; [0077] R.sup.45 is
selected from the group consisting of H, aryl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.46R.sup.47, --CO.sub.2R.sup.48,
--O--(CH.sub.2).sub.b--CO.sub.2R.sup.48, and
--C(.dbd.O)NR.sup.46R.sup.47, [0078] R.sup.46 and R.sup.47
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0079] or
R.sup.46 and R.sup.47 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0080] R.sup.48 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; [0081] a is
selected from 0 to 6; [0082] b is selected from 0 to 6; [0083] c is
selected from 2 to 6; R.sup.5 is selected from the group consisting
of H, C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.d--C(.dbd.O)--NR.sup.53R.sup.54,
--C(.dbd.O)--(CH.sub.2).sub.d--NR.sup.53R.sup.34,
--C(.dbd.O)--X--R.sup.55, and
--C(.dbd.O)--(CH.sub.2).sub.d--NR.sup.53R.sup.54; [0084] R.sup.53
and R.sup.54 are independently selected from the group consisting
of H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.56R.sup.57, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.56R.sup.57, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0085]
or R.sup.53 and R.sup.54 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7 cycloalkyl, oxo,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0086]
R.sup.55 is selected from the group consisting of H, aryl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.56R.sup.57, --CO.sub.2R.sup.58,
--O--(CH.sub.2).sub.e--CO.sub.2R.sup.58, and
--C(.dbd.O)NR.sup.56R.sup.57, [0087] R.sup.56 and R.sup.57
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0088] or
R.sup.56 and R.sup.57 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0089] R.sup.58 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.56R.sup.57, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; [0090] d is
selected from 0 to 6; [0091] e is selected from 0 to 6; R.sup.6 is
selected from the group consisting of H, C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.r--C(.dbd.O)--NR.sup.63R.sup.64,
--C(.dbd.O)--(CH.sub.2).sub.r--NR.sup.63R.sup.64,
--C(.dbd.O)--X--R.sup.65, and
--C(.dbd.O)--(CH.sub.2).sub.r--NR.sup.63R.sup.64; [0092] R.sup.63
and R.sup.64 are independently selected from the group consisting
of H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.66R.sup.67, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.66R.sup.67, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0093]
or R.sup.63 and R.sup.64 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7 cycloalkyl, oxo,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0094]
R.sup.65 is selected from the group consisting of H, aryl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.66R.sup.67, --CO.sub.2R.sup.68,
--O--(CH.sub.2).sub.s--CO.sub.2R.sup.68, and
--C(.dbd.O)NR.sup.66R.sup.67, [0095] R.sup.66 and R.sup.67
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0096] or
R.sup.66 and R.sup.67 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0097] R.sup.68 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.66R.sup.67, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; [0098] r is
selected from 0 to 6; [0099] s is selected from 0 to 6; n is
selected from 0 to 4; m is selected from 0 to 3; and p is selected
from 0 and 1.
[0100] In preferred embodiments of the invention, R.sup.1 is
selected to be --O--(CH.sub.2).sub.y--C(.dbd.O)NR.sup.13R.sup.14 or
--NH--C(.dbd.O)--(CH.sub.2).sub.y--NR.sup.13R.sup.14.
[0101] In preferred embodiments of the invention, R.sup.4 and
R.sup.5 are independently selected from H and alkyl, and in more
preferably H.
[0102] In a preferred embodiment of the present invention, there is
provided a compound of the formula II or III:
##STR00003##
or pharmaceutically acceptable salt or hydrate thereof, wherein
R.sup.1, R.sup.2, R.sup.3, n and m are as for the compound of the
formula I.
[0103] In a preferred embodiments of the invention, there in
provided a compound of the formula IV,
##STR00004##
or pharmaceutically acceptable salt or hydrate thereof, wherein:
[0104] R.sup.13 and R.sup.14 are independently selected from the
group consisting of H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0105]
or R.sup.13 and R.sup.14 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7 cycloalkyl, oxo,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; X is
selected from a covalent bond, O, NH, and C.sub.1-C.sub.6 alkyl;
[0106] R.sup.16 and R.sup.17 independently selected from the group
consisting of H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.1-C.sub.8 alkynyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0107] or R.sup.16 and R.sup.17
may be taken together form a three to twelve membered heterocyclic
ring having up to 3 heteroatoms which is optionally substituted by
from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6
alkoxy, oxo, hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro
alkyl; each R.sup.2 is independently selected from the group
consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino,
and perfluoro lower alkyl; each R.sup.3 is independently selected
from the group consisting of lower alkyl, CN, halo, hydroxy, lower
alkoxy, amino, and perfluoro lower alkyl; n is selected from 0 to
4; and m is selected from 0 to 3.
[0108] In a preferred embodiments of the invention, there in
provided a compound of the formula IV.sub.a:
##STR00005##
or pharmaceutically acceptable salt or hydrate thereof, wherein:
[0109] R.sup.13 and R.sup.14 are independently selected from the
group consisting of H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0110]
or R.sup.13 and R.sup.14 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0111] R.sup.16 and R.sup.17
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0112] or
R.sup.16 and R.sup.17 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl.
[0113] In a preferred embodiments of the invention, there in
provided a compound of the formula V:
##STR00006##
or pharmaceutically acceptable salt or hydrate thereof, wherein:
R.sup.12 is selected from the group consisting of C.sub.1-C.sub.6
alkyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), aryl,
aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve
membered heterocyclic ring containing up to 3 heteroatoms, each of
which may be optionally substituted at one or more carbon atoms by
from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and C.sub.1-C.sub.3
perfluoro alkyl; each R.sup.2 is independently selected from the
group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy,
amino, and perfluoro lower alkyl; each R.sup.3 is independently
selected from the group consisting of lower alkyl, CN, halo,
hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; n is
selected from 0 to 4; and m is selected from 0 to 3.
[0114] In a preferred embodiments of the invention, there in
provided a compound of the formula V.sub.a:
##STR00007##
or pharmaceutically acceptable salt or hydrate thereof, wherein:
R.sup.1 is selected from the group consisting of C.sub.1-C.sub.6
alkyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), aryl,
aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve
membered heterocyclic ring containing up to 3 heteroatoms, each of
which may be optionally substituted at one or more carbon atoms by
from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and C.sub.1-C.sub.3
perfluoro alkyl;
[0115] In a preferred embodiments of the invention, there in
provided a compound of the formula VI:
##STR00008##
or pharmaceutically acceptable salt or hydrate thereof, wherein:
[0116] R.sup.13 and R.sup.14 are independently selected from the
group consisting of H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.16R.sup.18, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0117]
or R.sup.13 and R.sup.14 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7 cycloalkyl, oxo,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0118]
R.sup.16 and R.sup.17 independently selected from the group
consisting of H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.1-C.sub.8 alkynyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0119] or R.sup.16 and R.sup.17
may be taken together form a three to twelve membered heterocyclic
ring having up to 3 heteroatoms which is optionally substituted by
from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6
alkoxy, oxo, hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro
alkyl; each R.sup.2 is independently selected from the group
consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino,
and perfluoro lower alkyl; each R.sup.3 is independently selected
from the group consisting of lower alkyl, CN, halo, hydroxy, lower
alkoxy, amino, and perfluoro lower alkyl; n is selected from 0 to
4; and m is selected from 0 to 3.
[0120] In a preferred embodiments of the invention, there in
provided a compound of the formula VI.sub.a:
##STR00009##
or pharmaceutically acceptable salt or hydrate thereof, wherein:
[0121] R.sup.13 and R.sup.14 are independently selected from the
group consisting of H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0122]
or R.sup.13 and R.sup.14 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7 cycloalkyl, oxo,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0123]
R.sup.16 and R.sup.17 independently selected from the group
consisting of H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.1-C.sub.8 alkynyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0124] or R.sup.16 and R.sup.17
may be taken together form a three to twelve membered heterocyclic
ring having up to 3 heteroatoms which is optionally substituted by
from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6
alkoxy, oxo, hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro
alkyl.
[0125] In a preferred embodiments of the invention, there in
provided a compound of the formula VII:
##STR00010##
or pharmaceutically acceptable salt or hydrate thereof, wherein:
[0126] R.sup.13 and R.sup.14 are independently selected from the
group consisting of H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0127]
or R.sup.13 and R.sup.14 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0128] R.sup.16 and R.sup.17
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0129] or
R.sup.16 and R.sup.17 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; each R.sup.2 is independently
selected from the group consisting of lower alkyl, CN, halo,
hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; each
R.sup.3 is independently selected from the group consisting of
lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro
lower alkyl; n is selected from 0 to 4; and m is selected from 0 to
3.
[0130] In a preferred embodiments of the invention, there in
provided a compound of the formula VII.sub.a:
##STR00011##
or pharmaceutically acceptable salt or hydrate thereof, wherein:
[0131] R.sup.13 and R.sup.14 are independently selected from the
group consisting of H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0132]
or R.sup.13 and R.sup.14 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0133] R.sup.16 and R.sup.17
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; or R.sup.16 and
R.sup.17 may be taken together form a three to twelve membered
heterocyclic ring having up to 3 heteroatoms which is optionally
substituted by from 1 to 3 substituents independently selected from
halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6, alkenyl,
C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl.
[0134] In a preferred embodiments of the invention, there in
provided a compound of the formula VIII:
##STR00012##
or pharmaceutically acceptable salt or hydrate thereof, wherein:
[0135] X is selected from a covalent bond, O, NH, and
C.sub.1-C.sub.6 alkyl; [0136] R.sup.15 is selected from the group
consisting of H, aryl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a
three to twelve membered heterocyclic ring containing up to 3
heteroatoms, each of which may be optionally substituted by from 1
to 3 substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl, or R.sup.1 is
selected from --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --CO.sub.2R.sup.18,
--O--(CH.sub.2).sub.x--CO.sub.2R.sup.18, and
--C(.dbd.O)NR.sup.16R.sup.17; [0137] R.sup.16 and R.sup.17
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0138] or
R.sup.16 and R.sup.17 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0139] R.sup.18 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; [0140] x is
selected from 0 to 6, each R.sup.2 is independently selected from
the group consisting of lower alkyl, CN, halo, hydroxy, lower
alkoxy, amino, and perfluoro lower alkyl; each R.sup.3 is
independently selected from the group consisting of lower alkyl,
CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
n is selected from 0 to 4; and m is selected from 0 to 3.
[0141] In a preferred embodiments of the invention, there in
provided a compound of the formula VIIIa:
##STR00013##
or pharmaceutically acceptable salt or hydrate thereof, wherein:
[0142] X is selected from a covalent bond, O, NH, and
C.sub.1-C.sub.6 alkyl; [0143] R.sup.15 is selected from the group
consisting of H, aryl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a
three to twelve membered heterocyclic ring containing up to 3
heteroatoms, each of which may be optionally substituted by from 1
to 3 substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl, or R.sup.1 is
selected from --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --CO.sub.2R.sup.18,
--O--(CH.sub.2).sub.x--CO.sub.2R.sup.18, and
--C(.dbd.O)NR.sup.16R.sup.17; [0144] R.sup.16 and R.sup.17
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0145] or
R.sup.16 and R.sup.17 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0146] R.sup.18 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; and [0147] x is
selected from 0 to 6.
[0148] In a preferred embodiments of the invention, there in
provided a compound of the formula IX:
##STR00014##
or pharmaceutically acceptable salt or hydrate thereof, wherein:
R.sup.1 is selected from the group consisting of aryl,
--(CH.sub.2).sub.y--NR.sup.13R.sup.14, --X--R.sup.12,
--O--(CH.sub.2).sub.y--CO.sub.2R.sup.12,
--O--(CH.sub.2).sub.y--C(.dbd.O)NR.sup.13R.sup.14,
--O--(CH.sub.2).sub.y-heteroaryl, --O--(CH.sub.2).sub.y-cycloalkyl,
--O--C(.dbd.O)--(CH.sub.2).sub.y--NR.sup.13R.sup.14,
--O--(CH.sub.2).sub.z--NR.sup.13R.sup.14,
--NH--C(.dbd.O)--(CH.sub.2).sub.y--NR.sup.13R.sup.14,
--NH--C(.dbd.O)--X--R.sup.15,
--NH--(CH.sub.2).sub.y--NR.sup.13R.sup.14; [0149] R.sup.12 is
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), aryl,
aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve
membered heterocyclic ring containing up to 3 heteroatoms, each of
which may be optionally substituted at one or more carbon atoms by
from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and C.sub.1-C.sub.3
perfluoro alkyl; [0150] R.sup.13 and R.sup.14 are independently
selected from the group consisting of H, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0151]
or R.sup.13 and R.sup.14 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0152] X is selected from a
covalent bond, O, NH, and C.sub.1-C.sub.6 alkyl; [0153] R.sup.15 is
selected from the group consisting of H, aryl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl, or R.sup.15 is selected from
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --CO.sub.2R.sup.18,
--O--(CH.sub.2).sub.x--CO.sub.2R.sup.18, and
--C(.dbd.O)NR.sup.16R.sup.17; [0154] R.sup.16 and R.sup.17
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0155] or
R.sup.16 and R.sup.17 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0156] R.sup.18 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; [0157] x is
selected from 0 to 6; [0158] y is selected from 0 to 6; [0159] z is
selected from 2 to 6; each R.sup.2 is independently selected from
the group consisting of lower alkyl, CN, halo, hydroxy, lower
alkoxy, amino, and perfluoro lower alkyl; each R.sup.3 is
independently selected from the group consisting of lower alkyl,
CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
R.sup.43 and R.sup.44 are independently selected from the group
consisting of H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.1-C.sub.8 alkynyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.46R.sup.47, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; or
R.sup.43 and R.sup.44 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0160] R.sup.46 and R.sup.47
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0161] or
R.sup.46 and R.sup.47 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0162] R.sup.48 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; c is selected from
2 to 6; n is selected from 0 to 4; and in is selected from 0 to
3.
[0163] In a preferred embodiments of the invention, there in
provided a compound of the formula X:
##STR00015##
or pharmaceutically acceptable salt or hydrate thereof, wherein:
R.sup.1 is selected from the group consisting of aryl,
--(CH.sub.2).sub.y--NR.sup.13R.sup.14, --X--R.sup.12,
--O--(CH.sub.2).sub.y--CO.sub.2R.sup.12,
--O--(CH.sub.2).sub.y--C(.dbd.O)NR.sup.13R.sup.14,
--O--(CH.sub.2).sub.y-heteroaryl, --O--(CH.sub.2).sub.y-cycloalkyl,
--O--C(.dbd.O)--(CH.sub.2).sub.y--NR.sup.13R.sup.14,
--O--(CH.sub.2).sub.z--NR.sup.13R.sup.14,
--NH--C(.dbd.O)--(CH.sub.2).sub.y--NR.sup.13R.sup.14,
--NH--C(.dbd.O)--X--R.sup.15,
--NH--(CH.sub.2).sub.y--NR.sup.13R.sup.14; [0164] R.sup.12 is
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), aryl,
aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve
membered heterocyclic ring containing up to 3 heteroatoms, each of
which may be optionally substituted at one or more carbon atoms by
from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and C.sub.1-C.sub.3
perfluoro alkyl; [0165] R.sup.13 and R.sup.14 are independently
selected from the group consisting of H, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0166]
or R.sup.13 and R.sup.14 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0167] X is selected from a
covalent bond, O, NH, and C.sub.1-C.sub.6 alkyl; [0168] R.sup.15 is
selected from the group consisting of H, aryl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl, or R.sup.15 is selected from
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --CO.sub.2R.sup.18,
--O--(CH.sub.2).sub.x--CO.sub.2R.sup.18, and
--C(.dbd.O)NR.sup.16R.sup.17; [0169] R.sup.16 and R.sup.17
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0170] or
R.sup.16 and R.sup.17 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0171] R.sup.18 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; [0172] x is
selected from 0 to 6; [0173] y is selected from 0 to 6; [0174] z is
selected from 2 to 6; each R.sup.2 is independently selected from
the group consisting of lower alkyl, CN, halo, hydroxy, lower
alkoxy, amino, and perfluoro lower alkyl; each R.sup.3 is
independently selected from the group consisting of lower alkyl,
CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
R.sup.42 is selected from the group consisting of C.sub.1-C.sub.6
alkyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted at one or more carbon atoms
by from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and C.sub.1-C.sub.3
perfluoro alkyl; [0175] R.sup.46 and R.sup.47 independently
selected from the group consisting of H, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8 alkynyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), aryl,
aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve
membered heterocyclic ring containing up to 3 heteroatoms, each of
which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy, amino,
cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0176] or R.sup.46 and
R.sup.47 may be taken together form a three to twelve membered
heterocyclic ring having up to 3 heteroatoms which is optionally
substituted by from 1 to 3 substituents independently selected from
halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6, alkenyl,
C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; n is selected from 0 to 4; and m
is selected from 0 to 3.
[0177] In a preferred embodiments of the invention, there in
provided a compound of the formula XI:
##STR00016##
or pharmaceutically acceptable salt or hydrate thereof, wherein:
R.sup.1 is selected from the group consisting of aryl,
--(CH.sub.2).sub.y--NR.sup.13R.sup.14, --X--R.sup.12,
--O--(CH.sub.2).sub.y--CO.sub.2R.sup.12,
--O--(CH.sub.2).sub.y--C(.dbd.O)NR.sup.13R.sup.14,
--O--(CH.sub.2).sub.y-heteroaryl, --O--(CH.sub.2).sub.y-cycloalkyl,
--O--C(.dbd.O)--(CH.sub.2).sub.y--NR.sup.13R.sup.14,
--O--(CH.sub.2).sub.z--NR.sup.13R.sup.14,
--NH--C(.dbd.O)--(CH.sub.2).sub.y--NR.sup.13R.sup.14,
--NH--C(.dbd.O)--X--R.sup.15,
--NH--(CH.sub.2).sub.y--NR.sup.13R.sup.14; [0178] R.sup.12 is
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), aryl,
aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve
membered heterocyclic ring containing up to 3 heteroatoms, each of
which may be optionally substituted at one or more carbon atoms by
from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and C.sub.1-C.sub.3
perfluoro alkyl; [0179] R.sup.13 and R.sup.14 are independently
selected from the group consisting of H, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0180]
or R.sup.13 and R.sup.14 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0181] X is selected from a
covalent bond, O, NH, and C.sub.1-C.sub.6 alkyl; [0182] R.sup.15 is
selected from the group consisting of H, aryl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl, or R.sup.1 is selected from
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --CO.sub.2R.sup.18,
--O--(CH.sub.2).sub.x--CO.sub.2R.sup.18, and
--C(.dbd.O)NR.sup.16R.sup.17; [0183] R.sup.16 and R.sup.17
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0184] or
R.sup.16 and R.sup.17 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0185] R.sup.18 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; [0186] x is
selected from 0 to 6; [0187] y is selected from 0 to 6; [0188] z is
selected from 2 to 6; each R.sup.2 is independently selected from
the group consisting of lower alkyl, CN, halo, hydroxy, lower
alkoxy, amino, and perfluoro lower alkyl; each R.sup.3 is
independently selected from the group consisting of lower alkyl,
CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
R.sup.43 and R.sup.44 are independently selected from the group
consisting of H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.1-C.sub.8 alkynyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.46R.sup.47, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; or
R.sup.43 and R.sup.44 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0189] R.sup.46 and R.sup.47
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0190] or
R.sup.46 and R.sup.47 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0191] R.sup.48 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; n is selected from
0 to 4; and m is selected from 0 to 3.
[0192] In a preferred embodiments of the invention, there in
provided a compound of the formula XII:
##STR00017##
or pharmaceutically acceptable salt or hydrate thereof, wherein:
R.sup.1 is selected from the group consisting of aryl,
--(CH.sub.2).sub.y--NR.sup.13R.sup.14, --X--R.sup.12,
--O--(CH.sub.2).sub.y--CO.sub.2R.sup.12,
--O--(CH.sub.2).sub.y--C(.dbd.O)NR.sup.13R.sup.14,
--O--(CH.sub.2).sub.y-heteroaryl, --O--(CH.sub.2).sub.y-cycloalkyl,
--O--C(.dbd.O)--(CH.sub.2).sub.y--NR.sup.13R.sup.14,
--O--(CH.sub.2).sub.z--NR.sup.13R.sup.14,
--NH--C(.dbd.O)--(CH.sub.2).sub.y--NR.sup.13R.sup.14,
--NH--C(.dbd.O)--X--R.sup.15,
--NH--(CH.sub.2).sub.y--NR.sup.13R.sup.14; [0193] R.sup.12 is
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), aryl,
aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve
membered heterocyclic ring containing up to 3 heteroatoms, each of
which may be optionally substituted at one or more carbon atoms by
from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and C.sub.1-C.sub.3
perfluoro alkyl; [0194] R.sup.13 and R.sup.14 are independently
selected from the group consisting of H, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0195]
or R.sup.13 and R.sup.14 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7 cycloalkyl, oxo,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0196] X
is selected from a covalent bond, O, NH, and C.sub.1-C.sub.6 alkyl;
[0197] R.sup.15 is selected from the group consisting of H, aryl,
heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered
heterocyclic ring containing up to 3 heteroatoms, each of which may
be optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl, or R.sup.1 is selected from
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --CO.sub.2R.sup.18,
--O--(CH.sub.2).sub.x--CO.sub.2R.sup.18, and
--C(.dbd.O)NR.sup.16R.sup.17; [0198] R.sup.16 and R.sup.17
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0199] or
R.sup.16 and R.sup.17 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0200] R.sup.18 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; [0201] x is
selected from 0 to 6; [0202] y is selected from 0 to 6; [0203] z is
selected from 2 to 6; each R.sup.2 is independently selected from
the group consisting of lower alkyl, CN, halo, hydroxy, lower
alkoxy, amino, and perfluoro lower alkyl; each R.sup.3 is
independently selected from the group consisting of lower alkyl,
CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
R.sup.4 is selected from --(CH.sub.2).sub.a--NR.sup.43R.sup.44,
--Y--R.sup.42, --O--(CH.sub.2).sub.a--CO.sub.2R.sup.42,
--O--(CH.sub.2).sub.a--C(.dbd.O)NR.sup.43R.sup.44,
--O--(CH.sub.2).sub.a-heteroaryl, --O--(CH.sub.2).sub.a-cycloalkyl,
--O--C(.dbd.O)--(CH.sub.2).sub.a--NR.sup.43R.sup.44,
--O--(CH.sub.2).sub.c--NR.sup.43R.sup.44,
--NH--C(.dbd.O)--(CH.sub.2).sub.a--NR.sup.43R.sup.44,
--NH--C(.dbd.O)--Y--R.sup.43,
--NH--C(.dbd.O)--(CH.sub.2).sub.a--NR.sup.43R.sup.44; [0204]
R.sup.42 is selected from the group consisting of C.sub.1-C.sub.6
alkyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted at one or more carbon atoms
by from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and C.sub.1-C.sub.3
perfluoro alkyl; [0205] R.sup.43 and R.sup.44 are independently
selected from the group consisting of H, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8 alkynyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.46R.sup.47, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0206]
or R.sup.43 and R.sup.44 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0207] Y is selected from a
covalent bond, O, NH, and C.sub.1-C.sub.6 alkyl; [0208] R.sup.45 is
selected from the group consisting of H, aryl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.46R.sup.47, --CO.sub.2R.sup.48,
--O--(CH.sub.2).sub.b--CO.sub.2R.sup.48, and
--C(.dbd.O)NR.sup.46R.sup.47, [0209] R.sup.46 and R.sup.47
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0210] or
R.sup.46 and R.sup.47 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0211] R.sup.48 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.46R.sup.47, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; [0212] a is
selected from 0 to 6; [0213] b is selected from 0 to 6; [0214] c is
selected from 2 to 6; R.sup.5 is selected from the group consisting
of H, C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.d--C(.dbd.O)--NR.sup.53R.sup.54,
--C(.dbd.O)--(CH.sub.2).sub.d--NR.sup.53R.sup.54,
--C(.dbd.O)--X--R.sup.55, and
--C(.dbd.O)--(CH.sub.2).sub.d--NR.sup.53R.sup.54; [0215] R.sup.53
and R.sup.54 are independently selected from the group consisting
of H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.56R.sup.57, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.56R.sup.57, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0216]
or R.sup.53 and R.sup.54 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7 cycloalkyl, oxo,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0217]
R.sup.55 is selected from the group consisting of H, aryl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.56R.sup.57, --CO.sub.2R.sup.58,
--O--(CH.sub.2).sub.e--CO.sub.2R.sup.58, and
--C(.dbd.O)NR.sup.56R.sup.57, [0218] R.sup.56 and R.sup.57
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0219] or
R.sup.56 and R.sup.57 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0220] R.sup.58 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.56R.sup.57, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; [0221] d is
selected from 0 to 6; [0222] e is selected from 0 to 6; R.sup.6 is
selected from the group consisting of H, C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.r--C(.dbd.O)--NR.sup.63R.sup.64,
--C(.dbd.O)--(CH.sub.2).sub.r--NR.sup.63R.sup.64,
--C(.dbd.O)--X--R.sup.65, and
--C(.dbd.O)--(CH.sub.2).sub.r--NR.sup.63R.sup.64; [0223] R.sup.63
and R.sup.64 are independently selected from the group consisting
of H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.66R.sup.67, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.66R.sup.67, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0224]
or R.sup.63 and R.sup.64 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7 cycloalkyl, oxo,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0225]
R.sup.65 is selected from the group consisting of H, aryl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.66R.sup.67, --CO.sub.2R.sup.68,
--O--(CH.sub.2).sub.s--CO.sub.2R.sup.68, and
--C(.dbd.O)NR.sup.66R.sup.67, [0226] R.sup.66 and R.sup.67
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0227] or
R.sup.66 and R.sup.67 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0228] R.sup.68 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.66R.sup.67, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; [0229] r is
selected from 0 to 6; [0230] s is selected from 0 to 6; n is
selected from 0 to 4; m is selected from 0 to 3; and p is selected
from 0 and 1.
[0231] In a preferred embodiments of the invention, there in
provided a compound of the formula XII.sub.a:
##STR00018##
or pharmaceutically acceptable salt or hydrate thereof, wherein:
R.sup.1 is selected from the group consisting of aryl,
--(CH.sub.2).sub.y--NR.sup.13R.sup.14, --X--R.sup.12,
--O--(CH.sub.2).sub.y--CO.sub.2R.sup.12,
--O--(CH.sub.2).sub.y--C(.dbd.O)NR.sup.13R.sup.14,
--O--(CH.sub.2).sub.y-heteroaryl, --O--(CH.sub.2).sub.y-cycloalkyl,
--O--C(.dbd.O)--(CH.sub.2).sub.y--NR.sup.13R.sup.14,
--O--(CH.sub.2).sub.z--NR.sup.13R.sup.14,
--NH--C(.dbd.O)--(CH.sub.2).sub.y--NR.sup.13R.sup.14,
--NH--C(.dbd.O)--X--R.sup.15,
--NH--(CH.sub.2).sub.y--NR.sup.13R.sup.14; [0232] R.sup.12 is
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), aryl,
aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve
membered heterocyclic ring containing up to 3 heteroatoms, each of
which may be optionally substituted at one or more carbon atoms by
from 1 to 3 substituents independently selected from halo,
C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and C.sub.1-C.sub.3
perfluoro alkyl; [0233] R.sup.13 and R.sup.14 are independently
selected from the group consisting of H, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0234]
or R.sup.13 and R.sup.14 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7 cycloalkyl, oxo,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0235] X
is selected from a covalent bond, O, NH, and C.sub.1-C.sub.6 alkyl;
[0236] R.sup.15 is selected from the group consisting of H, aryl,
heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered
heterocyclic ring containing up to 3 heteroatoms, each of which may
be optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl, or R.sup.15 is selected from
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --CO.sub.2R.sup.18,
--O--(CH.sub.2).sub.x--CO.sub.2R.sup.18, and
--C(.dbd.O)NR.sup.16R.sup.17; [0237] R.sup.16 and R.sup.17
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0238] or
R.sup.16 and R.sup.17 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0239] R.sup.18 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; [0240] x is
selected from 0 to 6; [0241] y is selected from 0 to 6; [0242] z is
selected from 2 to 6; each R.sup.2 is independently selected from
the group consisting of lower alkyl, CN, halo, hydroxy, lower
alkoxy, amino, and perfluoro lower alkyl; each R.sup.3 is
independently selected from the group consisting of lower alkyl,
CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
n is selected from 0 to 4; and m is selected from 0 to 3.
[0243] In further preferred embodiments of the invention, there in
provided a compound of the formula XII.sub.a wherein R.sup.1 is
selected from --NR.sup.13R.sup.14, --NH--R.sup.12,
--NH--C(.dbd.O)--(CH.sub.2).sub.y--NR.sup.13R.sup.14,
--NH--C(.dbd.O)--X--R.sup.15, and
--NH--(CH.sub.2).sub.y--NR.sup.13R.sup.14.
[0244] In a preferred embodiments of the invention, there in
provided a compound of the formula XII.sub.b:
##STR00019##
or pharmaceutically acceptable salt or hydrate thereof, wherein:
R.sup.7 is selected from the group consisting of
--(CH.sub.2).sub.y--NR.sup.13R.sup.14, and X--R.sup.15; [0245]
R.sup.13 and R.sup.14 are independently selected from the group
consisting of H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)NR.sup.16R.sup.17, aryl, aralkyl, heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered heterocyclic
ring containing up to 3 heteroatoms, each of which may be
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0246]
or R.sup.13 and R.sup.14 may be taken together form a three to
twelve membered heterocyclic ring having up to 3 heteroatoms which
is optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7 cycloalkyl, oxo,
hydroxy, amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0247] X
is selected from a covalent bond, O, NH, and C.sub.1-C.sub.6 alkyl;
[0248] R.sup.15 is selected from the group consisting of H, aryl,
heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to twelve membered
heterocyclic ring containing up to 3 heteroatoms, each of which may
be optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl, or R.sup.15 is selected from
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 alkyl)-NR.sup.16R.sup.17, --CO.sub.2R.sup.18,
--O--(CH.sub.2).sub.x--CO.sub.2R.sup.18, and
--C(.dbd.O)NR.sup.16R.sup.17; [0249] R.sup.16 and R.sup.17
independently selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.8
alkynyl, --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl),
aryl, aralkyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, a three to
twelve membered heterocyclic ring containing up to 3 heteroatoms,
each of which may be optionally substituted by from 1 to 3
substituents independently selected from halo, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6, alkenyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoro alkyl; [0250] or
R.sup.16 and R.sup.17 may be taken together form a three to twelve
membered heterocyclic ring having up to 3 heteroatoms which is
optionally substituted by from 1 to 3 substituents independently
selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6,
alkenyl, C.sub.1-C.sub.6 alkoxy, oxo, hydroxy, amino, cyano and
C.sub.1-C.sub.3 perfluoro alkyl; [0251] R.sup.18 is selected from
the group consisting of H, aryl, aralkyl, heteroaryl,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
alkyl)-NR.sup.16R.sup.17, --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl), each
of which may be optionally substituted by from 1 to 3 substituents
independently selected from halo, C.sub.1-C.sub.6 alkoxy, hydroxy,
amino, cyano and C.sub.1-C.sub.3 perfluoroalkyl; [0252] x is
selected from 0 to 6; [0253] y is selected from 0 to 6; each
R.sup.2 is independently selected from the group consisting of
lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro
lower alkyl; each R.sup.3 is independently selected from the group
consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino,
and perfluoro lower alkyl; n is selected from 0 to 4; and in is
selected from 0 to 3.
[0254] Preferred compounds according to the present invention
include:
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropylacetami-
de,
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2-methoxyeth-
yl)acetamide,
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(pyridin-3-yl)ac-
etamide,
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-(4-methy-
lpiperazin-1-yl)ethanone,
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-morpholinoethano-
ne,
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-methylacetami-
de,
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N--((R)-pyrroli-
din-3-yl)acetamide,
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N--((S)-pyrrolidin-
-3-yl)acetamide,
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N--((R)-tetrahydro-
furan-3-yl)acetamide,
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-(piperidin-1-yl)-
ethanone,
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-tert-bu-
tylacetamide,
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-ethylacetamide,
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(cyanomethyl)ace-
tamide,
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-cyclobuty-
lacetamide,
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isobutylacetamid-
e,
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2,2,2-trifluo-
roethyl)acetamide,
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-cyclohexylacetam-
ide,
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-neopentylace-
tamide,
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(prop-2-y-
nyl)acetamide,
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-4-methylpiperazine--
1-carboxamide,
3-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-1,1-dimethylurea,
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-methoxyacetamide,
methyl
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenylamino)-2-oxoac-
etate,
1-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-3-(2-(dimethy-
lamino)ethyl)urea,
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-morpholinoacetami-
de,
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-3-(4-isopropylpi-
perazin-1-yl)propanamide,
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)piperidine-4-carboxa-
mide,
2-(3-fluoro-4-(phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(4--
methylpiperazin-1-yl)ethoxy)quinazolin-4-amine,
6-(2-(dimethylamino)ethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-N-(1H-indazol-5-
-yl)-7-methoxyquinazolin-4-amine,
2-(3-fluoro-4-(phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(pyrroli-
din-1-yl)ethoxy)quinazolin-4-amine,
2-(4-(1H-indazol-5-ylamino)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-6-yl-
oxy)-1-(4-methylpiperazin-1-yl)ethanone,
2-[(3-(phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-methoxyethoxy)qu-
inazolin-4-amine,
6-(2-(dimethylamino)ethoxy)-N-(1H-indazol-5-yl)-7-methoxy-2-(3-(phenyl)ph-
enyl)quinazolin-4-amine,
2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(pyrrolidin-1-yl)-
ethoxy)quinazolin-4-amine,
2-((2-(4-(1H-indazol-5-ylamino)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin--
6-yloxy)ethyl)(methyl)amino)-N,N-dimethylacetamide,
2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(4-methylpiperazi-
n-1-yl)ethoxy)quinazolin-4-amine,
2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-morpholinoethoxy)-
quinazolin-4-amine,
2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(4-methyl-1,4-dia-
zepan-1-yl)ethoxy)quinazolin-4-amine,
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(dimethylamino)ethoxy)quinazolin-2-yl-
)phenyl)nicotinamide,
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-methoxyethoxy)quinazolin-2-yl)phenyl)-
nicotinamide,
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(dimethylamino)ethoxy)quinazolin-2-yl-
)phenyl)butyramide,
N-(3-(4-(1H-indazol-5-ylamino)-6-(3-(dimethylamino)propoxy)quinazolin-2-y-
l)phenyl)butyramide,
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(3-morpholinopropoxy)quinazoli-
n-2-yl)phenyl)butyramide,
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(3-morpholinopropoxy)quinazoli-
n-2-yl)phenyl)isonicotinamide,
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(3-morpholinopropoxy)quinazoli-
n-2-yl)phenyl)nicotinamide,
N-(3-(4-(1H-Indazol-5-ylamino)-7-methoxy-6-(2-(pyrrolidin-1-yl)ethoxy)qui-
nazolin-2-yl)phenyl)-2-morpholinoacetamide,
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(dimethylamino)ethoxy)-7-methoxyquina-
zolin-2-yl)phenyl)butyramide,
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(dimethylamino)-2-oxoethoxy)-7-methox-
yquinazolin-2-yl)phenyl)nicotinamide,
N-(3-(4-(1H-Indazol-5-ylamino)-6-(2-(dimethylamino)ethoxy)-7-methoxyquina-
zolin-2-yl)phenyl)nicotinamide,
N-(3-(4-(1H-Indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)quinazolin-2--
yl)phenyl)nicotinamide,
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)quinazolin-2--
yl)phenyl)-2-morpholinoacetamide,
2-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)quinazolin-2--
yl)phenoxy)-N-isopropylacetamide,
N-(3-(4-(1H-Indazol-5-ylamino)-6-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-2--
yl)phenyl)butyramide,
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(piperidin-1-yl)ethoxy)quinazolin-2-y-
l)phenyl)butyramide,
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-methoxyethoxy)quinazolin-2-yl)phenyl)-
butyramide,
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-((2-methoxyethyl)(methyl)amino)ethoxy-
)-quinazolin-2-yl)phenyl)butyramide,
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinaz-
olin-2-yl)phenyl)butyramide,
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(2-oxopyrrolidin-1-yl)ethoxy)quinazol-
in-2-yl)phenyl)butyramide,
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(3-hydroxypyrrolidin-1-yl)ethoxy)quin-
azolin-2-yl)phenyl)butyramide,
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-(2-oxopyrrolidin-1-yl)ethox-
y)quinazolin-2-yl)phenyl)butyramide,
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)quinazolin-2--
yl)phenyl)butyramide,
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)eth-
oxy)quinazolin-2-yl)phenyl)butyramide, and
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-((S)-3-(dimethylamino)pyrrolidin-1-yl-
)ethoxy)-7-methoxyquinazolin-2-yl)phenyl)butyramide.
[0255] It is believed that the R.sup.1 and/or the R.sup.4 group
modulates the pharmacokinetic and/or pharmacodynamic profile of the
compound and may result in improved pharmacokinetic properties
compared to the unmodified, i.e., parent compound. In certain
embodiments, the active agent has improved physicochemical
properties, pharmacokinetics, metabolism, or toxicity profile. In a
preferred embodiment, the active agent has superior solubility,
lower IC.sub.50, and/or is substantially less protein bound in vivo
compared to the compound lacking the R.sup.1 residue.
[0256] Preferably, the compounds of the invention include but are
not limited to inhibitors and activators of proteins and enzymes.
Specifically, the compounds of the present invention may modulate
the function of Rho-Kinase. The compounds of the invention may be
useful in the treatment of cancer, neuronal degeneration
(peripheral or central), spinal cord injury, erectile dysfunction,
atherosclerosis, hypertension, cerebral vasospasm, cerebral
ischemia, restenosis, asthma, glaucoma, asthma, osteoporosis,
fibrotic disease (liver and kidney), Kidney dialysis (epithelial
stability), and neuronal degeneration inflammation.
[0257] The term "heteroatom" as used herein means an atom of any
element other than carbon or hydrogen. Preferred heteroatoms are
boron, nitrogen, oxygen, phosphorus, sulfur and selenium. Most
preferred are nitrogen or oxygen.
[0258] The term "alkyl" refers to the radical of saturated
aliphatic groups, including straight-chain alkyl groups,
branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl
substituted cycloalkyl groups, and cycloalkyl substituted alkyl
groups. In preferred embodiments, a straight chain or branched
chain alkyl has 30 or fewer carbon atoms in its backbone (e.g.,
C.sub.1-C.sub.30 for straight chain, C.sub.3-C.sub.30 for branched
chain), and more preferably 20 or fewer. Likewise, preferred
cycloalkyls have from 3-10 carbon atoms in their ring structure,
and more preferably have 5, 6 or 7 carbons in the ring
structure.
[0259] Unless the number of carbons is otherwise specified, "lower
alkyl" as used herein means an alkyl group, as defined above, but
having from one to six carbons, and more preferably from one to
four carbon atoms. Likewise, "lower alkenyl" and "lower alkynyl"
have similar chain lengths. Preferred alkyl groups are lower
alkyls. In preferred embodiments, a substituent designated herein
as alkyl is a lower alkyl.
[0260] The term "cycloalkyl" refers to saturated, carbocyclic
groups having from 3 to 7 carbons in the ring. Preferred cycloalkyl
groups include cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl.
[0261] The term "aralkyl", as used herein, refers to an alkyl group
substituted with an aryl group (e.g., an aromatic or heteroaromatic
group).
[0262] The terms "alkenyl" and "alkynyl" refer to unsaturated
aliphatic groups analogous in length and possible substitution to
the alkyls described above, but that contain at least one double or
triple bond respectively.
[0263] The term "aryl" as used herein includes 5- and 6-membered
single-ring aromatic groups that may include from zero to four
heteroatoms, for example, benzene, pyrene, pyrrole, furan,
thiophene, imidazole, oxazole, thiazole, triazole, pyrazole,
pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those
aryl groups having heteroatoms in the ring structure may also be
referred to as "aryl heterocycles" or "heteroaromatics." The
aromatic ring can be substituted at one or more ring positions with
such substituents as described above, for example, halogen, azide,
alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl,
amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate,
carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido,
ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic
moieties, --CF.sub.3, --CN, or the like. The term "aryl" also
includes polycyclic ring systems having two or more cyclic rings in
which two or more carbons are common to two adjoining rings (the
rings are "fused rings") wherein at least one of the rings is
aromatic, e.g., the other cyclic rings can be cycloalkyls,
cycloalkenyls, aryls and/or heterocyclic groups.
[0264] The terms "heterocyclyl" or "heterocyclic group" refer to 3-
to 10-membered ring structures, more preferably 5- or 6-membered
rings, whose ring structures include one to four heteroatoms.
Heterocycles can also be polycycles. Heterocyclic groups include,
for example, thiophene, thianthrene, furan, pyran, isobenzofuran,
chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole,
isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine,
indolizine, isoindole, indole, indazole, purine, quinolizine,
isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline,
quinazoline, cinnoline, pteridine, carbazole, carboline,
phenanthridine, acridine, pyrimidine, phenanthroline, phenazine,
phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine,
oxolane, thiolane, oxazole, piperidine, piperazine, morpholine,
lactones, lactams such as azetidinones and pyrrolidinones, sultams,
sultones, and the like. The heterocyclic ring can be substituted at
one or more positions with such substituents as described above, as
for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,
hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,
phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,
ketone, aldehyde, ester, a heterocyclyl, an aromatic or
heteroaromatic moiety, --CF.sub.3, --CN, or the like.
[0265] The terms "polycyclyl" or "polycyclic group" refer to two or
more rings (e.g., cycloalkyls, cycloalkenyls, aryls and/or
heterocyclyls) in which two or more carbons are common to two
adjoining rings, e.g., the rings are "fused rings". Rings that are
joined through non-adjacent atoms are termed "bridged" rings. Each
of the rings of the polycyclic group can be substituted with such
substituents as described above, for example, halogen, alkyl,
aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro,
sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl,
carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde,
ester, a heterocyclyl, an aromatic or heteroaromatic moiety,
--CF.sub.3, --CN, or the like.
[0266] As used herein, the term "nitro" means --NO.sub.2; the term
"halogen" or "halo" designates --F, --Cl, --Br or --I; the term
"sulfhydryl" means --SH; the term "hydroxyl" means --OH; and the
term "sulfonyl" means --SO.sub.2--.
[0267] The terms "amine" and "amino" are art-recognized and refer
to both unsubstituted and substituted amines, e.g., a moiety that
can be represented by the general formula:
##STR00020##
wherein R, R' and R'' each independently represent a group
permitted by the rules of valence, preferably H, alkyl, alkenyl,
alkynyl, aralkyl, aryl, and heterocyclic groups.
[0268] The terms "alkoxyl" or "alkoxy" as used herein refers to an
alkyl group, as defined above, having an oxygen radical attached
thereto. Representative alkoxyl groups include methoxy, ethoxy,
propyloxy, tert-butoxy and the like. The term lower alkoxy refers
to an alkoxy group having from 1 to 6 carbon atoms.
[0269] The term "oxo" as used herein refers to an oxygen atom that
has a double bond to a carbon.
[0270] The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms represent
methyl, ethyl, phenyl, trifluoromethanesulfonyl,
nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl,
respectively. A more comprehensive list of the abbreviations
utilized by organic chemists of ordinary skill in the art appears
in the first issue of each volume of the Journal of Organic
Chemistry; this list is typically presented in a table entitled
Standard List of Abbreviations. The abbreviations contained in said
list, and all abbreviations utilized by organic chemists of
ordinary skill in the art are hereby incorporated by reference.
[0271] As used herein, the definition of each expression, e.g.
alkyl, m, n, R, etc., when it occurs more than once in any
structure, is intended to be independent of its definition
elsewhere in the same structure.
[0272] It will be understood that "substitution" or "substituted
with" includes the implicit proviso that such substitution is in
accordance with permitted valence of the substituted atom and the
substituent, and that the substitution results in a stable
compound, e.g., which does not spontaneously undergo transformation
such as by rearrangement, cyclization, elimination, etc.
[0273] As used herein, the term "substituted" is contemplated to
include all permissible substituents of organic compounds. In a
broad aspect, the permissible substituents include acyclic and
cyclic, branched and unbranched, carbocyclic and heterocyclic,
aromatic and non-aromatic substituents of organic compounds.
Illustrative substituents include, for example, those described
herein above. The permissible substituents can be one or more and
the same or different for appropriate organic compounds. For
purposes of this invention, the heteroatoms such as nitrogen may
have hydrogen substituents and/or any permissible substituents of
organic compounds described herein which satisfy the valences of
the heteroatoms. This invention is not intended to be limited in
any manner by the permissible substituents of organic
compounds.
[0274] The phrase "protecting group" as used herein means temporary
substituents which protect a potentially reactive functional group
from undesired chemical transformations. Examples of such
protecting groups include esters of carboxylic acids, silyl ethers
of alcohols, and acetals and ketals of aldehydes and ketones,
respectively. The field of protecting group chemistry has been
reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 2.sup.nd ed.; Wiley: New York, 1991).
[0275] Certain compounds of the present invention may exist in
particular geometric or stereoisomeric forms. The present invention
contemplates all such compounds, including cis- and trans-isomers,
R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the
racemic mixtures thereof, and other mixtures thereof, as falling
within the scope of the invention. Additional asymmetric carbon
atoms may be present in a substituent such as an alkyl group. All
such isomers, as well as mixtures thereof, are included in this
invention.
[0276] In addition, if, for instance, a particular enantiomer of a
compound of the present invention is desired, it may be prepared by
asymmetric synthesis, or by derivation with a chiral auxiliary,
where the resulting diastereomeric mixture is separated and the
auxiliary group cleaved to provide the pure desired enantiomers.
Alternatively, where the molecule contains a basic functional
group, such as amino, or an acidic functional group, such as
carboxyl, diastereomeric salts are formed with an appropriate
optically-active acid or base, followed by resolution of the
diastereomers thus formed by fractional crystallization or
chromatographic means well known in the art, and subsequent
recovery of the pure enantiomers.
[0277] For purposes of this invention, the chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87,
inside cover.
[0278] The compounds of the invention may be prepared according to
the following synthetic schemes:
##STR00021##
[0279] The general intermediate of formula (VII) may be prepared as
illustrated in Scheme A. As illustrated in Scheme A, anthralamide
(2-aminobenzamide (I)) is coupled with an appropriately substituted
acid chloride of formula (II) in the presence of a base such as
pyridine to give the benzamide (III). The reaction is run in an
aprotic solvent such as chloroform (CHCl.sub.3) at a temperature of
-20 to 50.degree. C., preferably at room temperature for 1-24
hours, preferably for 6 hours. Alternatively the benzamide (III)
may be formed by treatment of the anthralamide (2-aminobenzamide
(I)) with the benzoic acid in the presence of a coupling agent.
Suitable coupling agents include
N-cyclohexyl-N'-(4-diethylaminocyclohexyl)-carbodiimide (DCC),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and
bromotripyrrolidino phosphonium hexafluorophosphate (PyBroP.RTM.),
benzotriazole1-1yl-oxy-tris-pyrrolidino phosphonium
hexafluorophosphate (PyBOP.RTM.) with suitable additives if
necessary which include 1-hydroxybenzotriazole (HOBt) and
3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine.
[0280] Cyclodehydration of compound (III) is carried out under
refluxing basic aqueous conditions using sodium hydroxide (NaOH) as
base, though other bases such as potassium hydroxide (KOH) may also
be used. The reaction of compound (III) is carried out at the
reflux temperature of the mixture for about 1-24 hours, preferably
about 4 hours. When X=OMe (compound VII) it may be necessary to
exchange phenol protecting groups. This can be achieved via methods
known to those skilled in the art.
[0281] The compound (IV) is aromatized to the chloroquinazoline (V)
by treatment with thionyl chloride (SOCl.sub.2) with catalytic
dimethylformamide (DMF). The reaction mixture is heated to reflux
for 1-6 hours preferably 4 hours. Alternatively phosphorous oxy
trichloride (POCl.sub.3) or oxalyl chloride can be used instead of
SOCl.sub.2 to effect this transformation.
[0282] The chloroquinazoline is reacted with an appropriately
protected 5-amino indazole (VI) to give the amino quinazoline
(VII). The reaction is carried out in iso-propanol at 95.degree. C.
for a reaction time of 30 minutes to 2 hours.
##STR00022##
[0283] The protected indazole (VI) can be prepared as depicted in
Scheme B. 5-Nitro-indazole is appropriately protected via methods
known to those skilled in the art, preferably with a tert-butoxy
carbonyl group. The nitro group is the reduced to the amino group
via hydrogenation using a metal catalyst such as Pd/C in an inert
solvent such as methanol (MeOH), 1,2 dimethoxethane (DME), ethanol
(EtOH) or acetic acid (AcOH) or a combination of solvents
preferably in a combination of MeOH and DME. The reaction can be
carried out under balloon pressure or under a pressure of 20-50
pounds per square inch (p.s.i.).
##STR00023##
[0284] Compounds of formula (XII) can be synthesized as depicted in
scheme C. Compound (VII) can undergo selective deprotection of the
O-protecting group functionality to give compound (VII) where X=OH.
This can be done by a variety of methods, which are well known to
those skilled in the art. The phenol (VII) is then alkylated with
an electrophile of formula (X) in the presence of a base such as
potassium carbonate (K.sub.2CO.sub.3), potassium tert-butoxide
(KO.sup.tBu), sodium hydride (NaH), sodium hexamethylsilazide
(NaHMDs) or potassium hexamethylsilazide (KHMDS) preferably
K.sub.2CO.sub.3 to give the ether (XI). The reaction is run in an
inert solvent such as DMF at a temperature of 20-100.degree. C.,
preferably at 30-40.degree. C. The electrophile (X) can be either a
chloride (Y=Cl), bromide, (Y=Br), iodide (Y=I) or other suitable
leaving group though it is preferred to use a bromide. Additives
such as sodium iodide (NaI) or potassium iodide (KI) may be
optionally added to the reaction.
##STR00024##
[0285] Compounds of formula (XVII) may be synthesized as depicted
in Scheme D. A compound of formula (VII) where X=NO.sub.2, may be
reduced to the anilino compound (XIII) via catalytic hydrogenation
in an inert solvent or mixture of solvents such as EtOH, MeOH, THF
or DME preferably a mixture of MeOH and DME. The transformation is
effected by use of a metal catalyst such as palladium on carbon
(Pd/C). The compound of formula (XIII) can be treated with,
preferably at room temperature, with a carboxylic acid of formula
(XIV) in the presence of a coupling agent (e.g., PyBOP, PyBrOP,
dicyclohexylcarbodiimide (DCC),
1-(3'-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), or
1-propanephosphonic acid cyclic anhydride (PPAA)) and a suitable
base (e.g., triethylamine, DMAP, or N-methylmorpholine (NMO)) in a
solvent such as dichloromethane, chloroform, or dimethylformamide.
Optionally, agents such as HOBt maybe added to the reaction.
Alternatively the compound of formula (XVI) may be synthesized via
treatment with an acid chloride of formula (XV) in the presence a
tertiary amine base such as triethylamine or DMAP to give an amide
of formula (XVI). The acid chlorides of formula (XV) are
commercially available or can be prepared from carboxylic acids by
procedures known to those skilled in the art. If necessary the
indazole protecting group can be removed at this point to reveal
the final compounds (XVII) via methods known to those skilled in
the art.
##STR00025##
[0286] Compounds of formula (XX) can be prepared by reacting the
amines of formula (XIII) with a chloroformate of formula (XVI) in
the presence of a base such as triethylamine, DMAP, NMO, or sodium
hydrogen carbonate in a suitable solvent such as dichloromethane,
chloroform, aqueous or anhydrous tetrahydrofuran, or
dimethylformamide or in a combination of such solvents. The
reaction can be run at 0 to 60.degree. C., though room temperature
is preferred. If required the indazole protecting group may be
removed to give compound of formula (XX) by methods known to those
skilled in the art.
##STR00026##
[0287] Ureas of formula (XXV) may be synthesized as depicted in
Scheme F. Treatment of an aniline of formula (XIII) with an
isocyanate of formula (XXI) in an inert solvent such as
CH.sub.2Cl.sub.2 in the presence of an amine base such as
Et.sub.3N, DIEA or NMO to give the urea of formula (XXIV) where
R.sub.8 is a hydrogen. Alternatively, anilines of formula (XIII)
may be treated with 4-nitrophenyl carbonochloridate followed by the
sequential addition of an amine of formula (XXII). The reaction is
run in an inert solvent such as THF, DMF or CH.sub.2Cl.sub.2 in the
presence of an amine base such as Et.sub.3N, DIEA or NMO. Another
option of the synthesis of the ureas of formula (XXIV) is to treat
the anilines of formula (XIII) with a carbamoyl chloride of formula
(XXIII) in the presence of a base such as Et.sub.3N, DIEA or NMO.
If appropriate protecting groups (e.g. indazole) may be removed by
methods known to those skilled in the art.
##STR00027##
[0288] Carbamates of formula (XXVII) may be synthesized as depicted
in Scheme G. Treatment of a phenol of formula (VII) where X=OH with
an isocyanate of formula (XXII) in an inert solvent such as
CH.sub.2Cl.sub.2 in the presence of an amine base such as
Et.sub.3N, DIEA or NMO. Alternatively, phenols of formula (VII)
where X=OH) may be treated with 4-nitrophenyl carbonochloridate
followed by the sequential addition of an amine of formula (XXII).
The reaction is run in an inert solvent such as THF, DMF or
CH.sub.2Cl.sub.2 in the presence of an amine base such as
Et.sub.3N, DIEA or NMO. Another option of the synthesis of the
carbamates of formula (XXVI) is to treat the phenols of formula
(VII) where X=OH) with a carbamoyl chloride of formula (XXIII) in
the presence of a base such as Et.sub.3N, DIEA or NMO. If
appropriate protecting groups (e.g. indazole) may be removed by
methods known to those skilled in the art to give the final
compounds (XXVII).
##STR00028##
[0289] Compounds of general formula (XXXIII) can be synthesized as
depicted in Scheme H. Compound (VII) can undergo selective
deprotection of the O-protecting group (R.sub.1) functionality to
give compound (XXX). This can be done by a variety of methods,
which are well known to those skilled in the art. The phenol (XXX)
is then alkylated with an electrophile of formula (XXIX) in the
presence of a base such as potassium carbonate (K.sub.2CO.sub.3),
potassium tert-butoxide (KO.sup.tBu), sodium hydride (NaH), sodium
hexamethylsilazide (NaHMDs) or potassium hexamethylsilazide (KHMDS)
preferably K.sub.2CO.sub.3 to give the ether (XXXI). The reaction
is run in an inert solvent such as DMF at a temperature of
20-100.degree. C., preferably at 85.degree. C. The electrophile
(XXIX) can be either a chloride (Y=Cl), bromide, (Y=Br), iodide
(Y=I) or other suitable leaving group though it is preferred to use
a bromide. Additives such as sodium iodide (NaI) or potassium
iodide (KI) may be optionally added to the reaction.
[0290] Deprotection of the indazole protecting group, which is well
known by those skilled in the art, gives the desired compounds
(XXXII).
[0291] Practitioners of the art will recognize that subsequent
modification of R.sub.9 may be necessary and can be performed as
depicted in scheme I-J.
##STR00029##
[0292] In Scheme I the chloro compounds of formula (XXXI) where
R.sub.9 is Z--Cl and Z is an appropriate linker is heated in the
presence of an amine of formula (XXXIII) in a suitable solvent such
as DMSO or DMF to give the amine containing compounds (XXXIV).
Additives such as NaI or KI may be optionally added to the
reaction. If appropriate protecting groups may be removed at this
point by methods known to those skilled in the art.
##STR00030##
[0293] In scheme J the acid compounds of formula (XXXI) where
R.sub.9 is Z--CO.sub.2H and Z is an appropriate linker is treated
with an amine of formula (XXXIII) preferably at room temperature,
in the presence of a coupling agent (e.g., PyBOP, PyBrOP.RTM.,
dicyclohexylcarbodiimidc (DCC),
1-(3'-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), or
1-propanephosphonic acid cyclic anhydride (PPAA)) and a suitable
base (e.g., triethylamine, DMAP, or N-methylmorpholine (NMO)) in a
solvent such as dichloromethane, chloroform, or dimethylformamide
to give the amides of formula (XXXVI). Optionally, agents such as
HOBt maybe added to the reaction. If appropriate protecting groups
may be removed at this point by methods known to those skilled in
the art to give the product compounds of formula (XXXVII).
[0294] Practitioners of the art will also recognize that the order
of certain steps in the above schemes (A-L) may be altered.
Further, certain conditions such as solvent, temperature, etc. may
be adjusted as would be recognized by the ordinarily skilled
practitioner.
[0295] Reactive groups not involved in the above process steps can
be protected with standard protecting groups during the reactions
and removed by standard procedures (T. W. Greene & P. G. M.
Wuts, Protecting Groups in Organic Synthesis, Third Edition,
Wiley-Interscience) known to those of ordinary skill in the art.
Presently preferred protecting groups include methyl, benzyl,
acetate and tetrahydropyranyl for the hydroxyl moiety, and BOC,
CBz, trifluoroacetamide and benzyl for the amino moiety, methyl,
ethyl, tert-butyl and benzyl esters for the carboxylic acid moiety.
The preferred protecting groups for the indazole moiety are BOC,
CBz, trifluoroacetamide and benzyl.
[0296] The modification of protein binding is based on surface
technology, i.e. the preparation and screening of surfaces for
their ability to resist adsorption of proteins from solution.
Surfaces which are resistant to adsorption of proteins from
solution are known to one of skill in the art as "protein
resistant" surfaces. Functional groups may be screened to identify
the group(s) present in protein resistant surfaces, as described in
e.g., Chapman et al. Surveying for Surfaces that Resist the
Adsorption of Proteins, J. Am. Chem. Soc. 2000, 122:8303-8304;
Ostuni et al. A Survey of Structure-Property Relationships of
Surfaces that Resist the Adsorption of Protein, Langmuir 2001,
17:5605-5620; Holmlin, et al. Zwitterionic SAMs that Resist
Nonspecific Adsorption of Protein from Aqueous Buffer, Langmuir
2001, 17:2841-2850; and Ostuni et al. Self-Assembled Monolayers
that Resist the Adsorption of Proteins and the Adhesion of
Bacterial and Mammalian Cells, Langmuir 2001, 17:6336-6343.
[0297] In general, protein binding is assessed by measuring the
capacity of molecules of the invention to bind to one or more human
serum components or mimics thereof. In one embodiment, suitable
functional residues may be identified by screening of surfaces
comprising such residues for their ability to resist adsorption of
serum components, including, but not limited to serum proteins, and
preferably human serum proteins. Candidate residues can be screened
directly by attaching them to a solid support and testing the
support for protein resistance. Alternatively, candidate residues
are incorporated into, or linked to molecules of pharmaceutical
interest. Such compounds may be synthesized on a solid support, or
bound to a solid support after synthesis. In a non-limiting example
of a direct binding assay, immobilized candidate functional
residues or molecules incorporating such residues are tested for
their ability to bind serum components. The serum components can be
labeled with a signaling moiety for detection, or a labeled
secondary reagent that binds to such serum components can be
used.
[0298] Surfaces which are resistant to adsorption of proteins from
solution are known as "protein resistant" surfaces. Functional
groups may be screened to identify the group(s) present in protein
resistant surfaces, as described in e.g., Chapman et al. Surveying
for Surfaces that Resist the Adsorption of Proteins, J. Am. Chem.
Soc. 2000, 122:8303-8304; Ostuni et al. A Survey of
Structure-Property Relationships of Surfaces that Resist the
Adsorption of Protein, Langmuir 2001, 17:5605-5620; Holmlin, et al.
Zwitterionic SAMs that Resist Nonspecific Adsorption of Protein
from Aqueous Buffer, Langmuir 2001, 17:2841-2850; and Ostuni et al.
Self-Assembled Monolayers that Resist the Adsorption of Proteins
and the Adhesion of Bacterial and Mammalian Cells, Langmuir 2001,
17:6336-6343.
[0299] Upon identification of a functional residue which provides
such protein resistance, one of skill in the art will readily
determine a suitable chemical skeleton or backbone of a known
biologically or chemically active compound to which the functional
residue may be attached by either substitution of functional group
of the active compound or by replacement of a nonessential
functional group of the active compound. For example, as discussed
above, the presence of a piperazine group on a compound will
indicate that such group may be either replaced or substituted with
an functional residue. One of skill in the art, e.g. a medicinal
chemist, will recognize other suitable groups on known active
compounds which may be replaced or substituted with at least one
functional residue. Accordingly, a combinatorial library of
compounds, may be generated as described infra, wherein the
compounds are modified compounds comprising a conjugate of an
active site of the compound (an essential backbone of a compound
having a particular desired activity), e.g. compound A and at least
one functional residue attached thereto, wherein each conjugate has
a different functional residue attached thereto, e.g. residues
having formula C, wherein each R group is selected from the various
groups described herein. Accordingly, a library may be used to
screen a plurality of different functional residues for improved
pharmacokinetic and/or pharmacodynamic properties including
non-specific protein binding of the modified compound.
[0300] In preferred embodiments, the solid support itself is chosen
or modified to minimize its interaction with the serum components.
Examples of such supports and assay systems are described in
International Application WO 02/48676, WO 03/12392, WO 03/18854, WO
03/54515, herein incorporated by reference. Alternatively, the
molecules of the invention may be mixed with one or more serum
components in liquid phase, and the amount of unbound molecules
determined.
[0301] A direct binding analysis can also be preformed in liquid
phase. For example, test compounds can be mixed with one or more
serum components in liquid phase, and the unbound molecules
determined.
[0302] In an example of a preferred embodiment, molecules having
reduced protein binding are identified as follows: a self-assembled
monolayer of thiol molecules terminated with anhydride groups is
formed at a gold surface. A set of small molecules with amine
groups at one end, and groups that are designed to resist binding
to albumin, for example, at the other end are then attached to the
surface via reaction between the amine and anhydride. The set of
molecules are spotted onto spatially distinct regions on the gold
surface to create an array of molecules that might resist protein
binding. This array is then exposed to a solution containing
albumin that is fluorescently labeled. After a suitable incubation
period, the gold surface is washed and scanned on a fluorescent
scanner. The immobilized chemical groups that bound to albumin will
be identified by the presence of a fluorescent signal; groups that
resist albumin binding will have low fluorescence in that part of
the array. If a fluorescent protein is not available then
antibodies against the protein of interest in combination with
fluorescent secondary antibodies can be used to detect protein
binding to the chemical groups. If an antibody is not available
then a labeless detection method such as surface plasmon resonance
(SPR) or MALDI mass spectrometry can be used to identify the
presence of the protein at individual elements in the array. SPR
also has the advantage of providing kinetic information on the
binding of protein to the chemical groups.
[0303] The use of this system is not limited to albumin; any
protein of pharmacokinetic interest can be tested for binding
potential. For example, blood proteins that bind small molecules,
such as .alpha.-acid glycoprotein (AAG, AGP) and lipoproteins,
could be exposed to the array and protein binding detected.
[0304] In an embodiment of the invention, chemical groups can be
identified that resist binding to P-glycoprotein (PGP) and
therefore have the potential to reduce efflux when appended to a
small molecule therapeutic. This is particularly important for
development of anti-cancer drugs provide effective treatment where
multiple drug resistance (MDR) has developed.
[0305] The method could also be used to identify chemical groups
that resist binding to proteins such as thrombin, anti-thrombin,
and Factor Xa and therefore have the potential to control
coagulation.
[0306] This method would also be useful for identifying groups that
improve therapeutics that are designed as supplemental or
replacement therapies where protein binding and PK properties are
very important, e.g., hormones and their binding proteins, and
steroids and their binding proteins such as testosterone and sex
hormone binding globulin (SHBG).
[0307] The following describes a surface-based method for
identifying groups that can improve the solubility of small
molecules. A self-assembled monolayer of thiol molecules terminated
with maleimide groups is formed at a gold surface. A set of small
molecules with thiol groups at one end, and groups that are
hydrophilic at the other end are then attached to the surface via
reaction between the thiol and maleimide. The set of molecules are
spotted onto spatially distinct regions on the gold surface to
create an array of molecules that might increase the solubility of
a small molecule. Droplets of both polar (e.g., water) and
hydrophobic (e.g., octanol) liquids are then placed onto each
element of the array. The contact angles of the two liquids on each
element are then measured at each element of the array using a
goniometer. Alternatively, the wettability of a particular liquid
at a surface presenting a chemical group can be determined by
measuring the area of the surface covered by a droplet when viewed
from above (high contact angle will yield droplets of small area;
low contact angles cover greater areas). The contact angle of a
liquid on a surface presenting a chemical group is inversely
proportional to the miscibility of that chemical group with that
liquid (solvent). For example, a chemical group for which water has
a high contact angle when it is presented at the surface, such as
methyl (CH.sub.3), has low miscibility with water, i.e., it will
tend to reduce the solubility of a small molecule. Conversely, a
chemical group for which water has a low contact angle when it is
presented at the surface, such as carboxyl (COOH), has high
miscibility with water, i.e., it will tend to increase the
solubility of a small molecule. Sets of chemical groups can
therefore be screened rapidly using contact angles on surfaces to
identify groups that improve solubility or reduce hydrophilicity.
This approach can be used to evaluate the effect on solubility of
chemical groups used according to the invention.
[0308] A common parameter for the ability of a small molecule to
cross the lipid membrane of a cell is log P where P is the
partition coefficient of the compound between octanol and water.
The relative contact angle of a surface presenting chemical groups
for octanol and water therefore offers a rapid, empirical method
for ranking large sets of chemical groups for their potential
effect on the log P of a compound.
[0309] The pH dependence of the solubility of small molecules can
be addressed in this method by measuring the contact angles of
solutions at different pHs. The parameter equivalent to log P in
this case is log D, where D is the distribution coefficient,
defined as the ratio of the sum of the concentrations of all
species of the compound in octanol to the sum of the concentrations
of all species of the compound in water at various pHs. Contact
angles measured at different pHs therefore offer the possibility of
an equivalent measure to log D.
[0310] It will also be useful to screen candidate compounds for
their capacity to be actively transported across cell membranes and
cells, or for their resistance to such transport. For example, it
is well known that pharmaceutically useful anti-cancer molecules
may be limited in their effectiveness due to active transport out
of target tumor cells. Similarly, monolayers of brain capillary
endothelial cells have been observed to unidirectionally transport
vincristine from basal side to apical side, effectively preventing
the anti-cancer agent from entering the central nervous system. In
some instances, chemical groups of value will, in addition to
reducing non-specific protein binding, improve pharmcokinetics by
enhancing passive or active transport towards their site of action,
and/or inhibiting transport from the site of action.
[0311] The brain is one of the most difficult tissues for small
molecules to penetrate. The neurovascular junctions are tight and
contain very few active transporters that are mostly responsible
for clearing small molecules out of the brain. The paracellular
route (between cell junctions) is not available to small molecules,
but only the transcellular route is (through cell membranes).
Classically, molecules to target the brain, such as
benzodiazepines, are hydrophobic to allow them to penetrate cell
membranes. The instant invention is compatible with the search for
chemical groups that confer protein resistant and alleviate the
common problem of excessive protein binding associated with
molecules such as the benzodiazepines; this requires high dosing to
account for the large percentage of binding to serum proteins. The
approaches described earlier for the identification of binders of
PGP will be of help to optimize molecules for improved residence
time in the brain.
[0312] Several model systems are available, employing monolayers of
various cell types, for evaluation of active transport of
pharmaceutically active substances. For example, monolayers of
Caco-2 intestinal epithelial cells can be used to evaluate active
transport of substances between the intestine and the bloodstream.
When plated on a surface which allows the flow of material from
apical to basolateral and vice versa, such cells form a biological
membrane which can be used to simulate physiological absorption and
bio-availability. In another example, mouse brain capillary
endothelial cell (MBEC) lines have been established to evaluate
active transport in and out of the central nervous system. Another
example of such cells is HT29 human colon carcinoma cells. Further,
monolayers expressing particular transporter proteins can be
established using transfected cells. For example, Sasaki et al
(2002) J. Biol. Chem. 8:6497 used a double-transfected Madin-Darby
canine kidney cell monolayer to study transport of organic
anions.
[0313] Alternatives to cell monolayers may of course be utilized to
examine permeability. Alternatives typically comprise a biological
structure capable of active transport and include, but are not
limited to, organs of the digestive tract obtained from lab animals
and reconstituted organs or membranes created in vitro from cells
seeded in an artificial matrix.
[0314] In another aspect, the present invention provides a compound
of the general formula I, wherein the compound is an inhibitor of
Rho-kinase. Rho kinase (ROCK), a serine/threonine kinase, serves as
a target protein for small GTP-binding protein Rho. It serves as an
important mediator of numerous cellular functions, including focal
adhesions, motility, smooth muscle contraction, and cytokinesis. In
smooth muscle, ROCK plays an important role in Ca sensitization and
the control of vascular tone. It modulates the level of
phosphorylation of the myosin II light chain of myosin II, mainly
through inhibition of myosin phosphatase, and contributes to
agonist-induced Ca.sup.2+ sensitization in smooth muscle
contraction.
[0315] Rho kinase is found in two forms, ROCK 1 (ROCK.beta.;
p160-ROCK) and ROCK 2 (ROCK.alpha.). Since for example a
ROCK-mediated pathway plays an important role in vascular smooth
muscle contraction, cell adhesion, and cell motility, it has gained
importance in the pathogenesis of atherosclerosis. ROCK inhibitors
are shown to suppress coronary artery spasms. A long-term
inhibition of ROCK is reported to block the development of coronary
arteriosclerotic lesions.
[0316] ROCK mediated pathways mediate numerous different cellular
functions and ROCK inhibitors can be useful in treatments of
patients in need thereof suffering from cardiovascular diseases
such as hypertension, atherosclerosis, restenosis, cardiac
hypertrophy, ocular hypertension, cerebral ischemia, cerebral
vasospasm, penile erectile dysfunction, central nervous system
disorders such as neuronal degeneration and spinal cord injury, and
in neoplasias where inhibition of Rho-kinase has been shown to
inhibit tumor cell growth and metastasis, angiogenesis, arterial
thrombotic disorders such as platelet aggregation and leukocyte
aggregation, asthma, regulation of intraoccular pressure, and bone
resorption. Such treatment often relies on administering a
therapeutic agent to a patient, wherein the therapeutic agent has a
high specificity for a particular pathway or enzyme which is in
need of regulation in the patient, by the therapeutic agent such as
an enzyme inhibitor. In one aspect of the present invention there
is provided, a compound which is an inhibitor of a Rho kinase
(ROCK), preferably the compound of the present invention is an
inhibitor of ROCK2.
[0317] Methods of determining kinase inhibition are well known in
the art. For example, kinase activity of an enzyme and the
inhibitory capacity of a test compound can be determined by
measuring enzyme specific phosphorylation of a substrate.
Commercial assays and kits can be employed. For example, kinase
inhibition can be determined using an IMAP.RTM. assay (Molecular
Devices). This assay method involves the use of a
fluorescently-tagged peptide substrate. Phosphorylation of the
tagged peptide by a kinase of interest promotes binding of the
peptide to a trivalent metal-based nanoparticle via the specific,
high affinity interaction between the phospho-group and the
trivalent metal. Proximity to the nanoparticle results in increased
fluorescence polarization. Inhibition of the kinase by a kinase
inhibitor prevents phosphorylation of the substrate and thereby
limits binding of the fluorescently-tagged substrate to the
nanoparticle. Such an assay can be compatible with a microwell
assay format, allowing simultaneous determination of IC.sub.50 of
multiple compounds.
[0318] In another aspect of the present invention there is provided
a method of treating a patient suffering from a disease comprising
administering to a patient in need of such treatment a
therapeutically effective amount of a compound of the present
invention, wherein the disease is cardiovascular diseases such as
hypertension, atherosclerosis, restenosis, cardiac hypertrophy,
ocular hypertension, cerebral ischemia, cerebral vasospasm, penile
erectile dysfunction, central nervous system disorders such as
neuronal degeneration and spinal cord injury, and in neoplasias
where inhibition of Rho-kinase has been shown to inhibit tumor cell
growth and metastasis, angiogenesis, arterial thrombotic disorders
such as platelet aggregation and leukocyte aggregation, asthma,
regulation of intraoccular pressure, and bone resorption.
[0319] In another aspect, the present invention provides
pharmaceutically acceptable compositions which comprise a
therapeutically-effective amount of one or more of the compounds of
the present invention, including but not limited to the compounds
described above and those shown in the Figures, formulated together
with one or more pharmaceutically acceptable carriers (additives)
and/or diluents. As described in detail below, the pharmaceutical
compositions of the present invention may be specially formulated
for administration in solid or liquid form, including those adapted
for the following: (1) oral administration, for example, drenches
(aqueous or non-aqueous solutions or suspensions), tablets, e.g.,
those targeted for buccal, sublingual, and systemic absorption,
boluses, powders, granules, pastes for application to the tongue;
(2) parenteral administration, for example, by subcutaneous,
intramuscular, intravenous or epidural injection as, for example, a
sterile solution or suspension, or sustained-release formulation;
(3) topical application, for example, as a cream, ointment, or a
controlled-release patch or spray applied to the skin; (4)
intravaginally or intrarectally, for example, as a pessary, cream
or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8)
nasally.
[0320] The phrase "therapeutically-effective amount" as used herein
means that amount of a compound, material, or composition
comprising a compound of the present invention which is effective
for producing some desired therapeutic effect in at least a
sub-population of cells in an animal at a reasonable benefit/risk
ratio applicable to any medical treatment, e.g. reasonable side
effects applicable to any medical treatment.
[0321] The phrase "pharmaceutically acceptable" is employed hercin
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals with toxicity, irritation, allergic response, or other
problems or complications, commensurate with a reasonable
benefit/risk ratio.
[0322] The phrase "pharmaceutically-acceptable carrier" as used
herein means a pharmaceutically-acceptable material, composition or
vehicle, such as a liquid or solid filler, diluent, excipient,
manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc
stearate, or steric acid), or solvent encapsulating material,
involved in carrying or transporting the subject compound from one
organ, or portion of the body, to another organ, or portion of the
body. Each carrier must be "acceptable" in the sense of being
compatible with the other ingredients of the formulation and not
injurious to the patient. Some examples of materials which can
serve as pharmaceutically-acceptable carriers include: (1) sugars,
such as lactose, glucose and sucrose; (2) starches, such as corn
starch and potato starch; (3) cellulose, and its derivatives, such
as sodium carboxymethyl cellulose, ethyl cellulose and cellulose
acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc;
(8) excipients, such as cocoa butter and suppository waxes; (9)
oils, such as peanut oil, cottonseed oil, safflower oil, sesame
oil, olive oil, corn oil and soybean oil; (10) glycols, such as
propylene glycol; (11) polyols, such as glycerin, sorbitol,
mannitol and polyethylene glycol; (12) esters, such as ethyl oleate
and ethyl laurate; (13) agar; (14) buffering agents, such as
magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16)
pyrogen-free water; (17) isotonic saline; (18) Ringer's solution;
(19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters,
polycarbonates and/or polyanhydrides; and (22) other non-toxic
compatible substances employed in pharmaceutical formulations.
[0323] As set out above, certain embodiments of the present
compounds may contain a basic functional group, such as amino or
alkylamino, and are, thus, capable of forming
pharmaceutically-acceptable salts with pharmaceutically-acceptable
acids. The term "pharmaceutically-acceptable salts" in this
respect, refers to the relatively non-toxic, inorganic and organic
acid addition salts of compounds of the present invention. These
salts can be prepared in situ in the administration vehicle or the
dosage form manufacturing process, or by separately reacting a
purified compound of the invention in its free base form with a
suitable organic or inorganic acid, and isolating the salt thus
formed during subsequent purification. Representative salts include
the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate,
nitrate, acetate, valerate, oleate, palmitate, stearate, laurate,
benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,
succinate, tartrate, napthylate, mesylate, glucoheptonate,
lactobionate, and laurylsulphonate salts and the like. (See, for
example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci.
66:1-19).
[0324] The pharmaceutically acceptable salts of the subject
compounds include the conventional nontoxic salts or quaternary
ammonium salts of the compounds, e.g., from non-toxic organic or
inorganic acids. For example, such conventional nontoxic salts
include those derived from inorganic acids such as hydrochloride,
hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like;
and the salts prepared from organic acids such as acetic,
propionic, succinic, glycolic, stearic, lactic, malic, tartaric,
citric, ascorbic, palmitic, malcic, hydroxymaleic, phenylacetic,
glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic,
fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic,
oxalic, isothionic, and the like.
[0325] In other cases, the compounds of the present invention may
contain one or more acidic functional groups and, thus, are capable
of forming pharmaceutically-acceptable salts with
pharmaceutically-acceptable bases. The term
"pharmaceutically-acceptable salts" in these instances refers to
the relatively non-toxic, inorganic and organic base addition salts
of compounds of the present invention. These salts can likewise be
prepared in situ in the administration vehicle or the dosage form
manufacturing process, or by separately reacting the purified
compound in its free acid form with a suitable base, such as the
hydroxide, carbonate or bicarbonate of a
pharmaceutically-acceptable metal cation, with ammonia, or with a
pharmaceutically-acceptable organic primary, secondary or tertiary
amine. Representative alkali or alkaline earth salts include the
lithium, sodium, potassium, calcium, magnesium, and aluminum salts
and the like. Representative organic amines useful for the
formation of base addition salts include ethylamine, diethylamine,
ethylenediamine, ethanolamine, diethanolamine, piperazine and the
like. (See, for example, Berge et al., supra).
[0326] Wetting agents, emulsifiers and lubricants, such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
release agents, coating agents, sweetening, flavoring and perfuming
agents, preservatives and antioxidants can also be present in the
compositions.
[0327] Examples of pharmaceutically-acceptable antioxidants
include: (1) water soluble antioxidants, such as ascorbic acid,
cysteine hydrochloride, sodium bisulfate, sodium metabisulfite,
sodium sulfite and the like; (2) oil-soluble antioxidants, such as
ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated
hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol,
and the like; and (3) metal chelating agents, such as citric acid,
ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid,
phosphoric acid, and the like.
[0328] Formulations of the present invention include those suitable
for oral, nasal, topical (including buccal and sublingual), rectal,
vaginal and/or parenteral administration. The formulations may
conveniently be presented in unit dosage form and may be prepared
by any methods well known in the art of pharmacy. The amount of
active ingredient which can be combined with a carrier material to
produce a single dosage form will vary depending upon the host
being treated, the particular mode of administration. The amount of
active ingredient which can be combined with a carrier material to
produce a single dosage form will generally be that amount of the
compound which produces a therapeutic effect. Generally, out of one
hundred percent, this amount will range from about 0.1 percent to
about ninety-nine percent of active ingredient, preferably from
about 5 percent to about 70 percent, most preferably from about 10
percent to about 30 percent.
[0329] In certain embodiments, a formulation of the present
invention comprises an excipient selected from the group consisting
of cyclodextrins, celluloses, liposomes, micelle forming agents,
e.g., bile acids, and polymeric carriers, e.g., polyesters and
polyanhydrides; and a compound of the present invention. In certain
embodiments, an aforementioned formulation renders orally
bioavailable a compound of the present invention.
[0330] Methods of preparing these formulations or compositions
include the step of bringing into association a compound of the
present invention with the carrier and, optionally, one or more
accessory ingredients. In general, the formulations are prepared by
uniformly and intimately bringing into association a compound of
the present invention with liquid carriers, or finely divided solid
carriers, or both, and then, if necessary, shaping the product.
[0331] Formulations of the invention suitable for oral
administration may be in the form of capsules, cachets, pills,
tablets, lozenges (using a flavored basis, usually sucrose and
acacia or tragacanth), powders, granules, or as a solution or a
suspension in an aqueous or non-aqueous liquid, or as an
oil-in-water or water-in-oil liquid emulsion, or as an elixir or
syrup, or as pastilles (using an inert base, such as gelatin and
glycerin, or sucrose and acacia) and/or as mouth washes and the
like, each containing a predetermined amount of a compound of the
present invention as an active ingredient. A compound of the
present invention may also be administered as a bolus, electuary or
paste.
[0332] In solid dosage forms of the invention for oral
administration (capsules, tablets, pills, dragees, powders,
granules, trouches and the like), the active ingredient is mixed
with one or more pharmaceutically-acceptable carriers, such as
sodium citrate or dicalcium phosphate, and/or any of the following:
(1) fillers or extenders, such as starches, lactose, sucrose,
glucose, mannitol, and/or silicic acid; (2) binders, such as, for
example, carboxymethylcellulose, alginates, gelatin, polyvinyl
pyrrolidone, sucrose and/or acacia; (3) humectants, such as
glycerol; (4) disintegrating agents, such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate; (5) solution retarding agents,
such as paraffin; (6) absorption accelerators, such as quaternary
ammonium compounds and surfactants, such as poloxamer and sodium
lauryl sulfate; (7) wetting agents, such as, for example, cetyl
alcohol, glycerol monostearate, and non-ionic surfactants; (8)
absorbents, such as kaolin and bentonite clay; (9) lubricants, such
as talc, calcium stearate, magnesium stearate, solid polyethylene
glycols, sodium lauryl sulfate, zinc stearate, sodium stearate,
stearic acid, and mixtures thereof; (10) coloring agents; and (11)
controlled release agents such as crospovidone or ethyl cellulose.
In the case of capsules, tablets and pills, the pharmaceutical
compositions may also comprise buffering agents. Solid compositions
of a similar type may also be employed as fillers in soft and
hard-shelled gelatin capsules using such excipients as lactose or
milk sugars, as well as high molecular weight polyethylene glycols
and the like.
[0333] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared using binder (for example, gelatin or hydroxypropylmethyl
cellulose), lubricant, inert diluent, preservative, disintegrant
(for example, sodium starch glycolate or cross-linked sodium
carboxymethyl cellulose), surface-active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the powdered compound moistened with an inert liquid
diluent.
[0334] The tablets, and other solid dosage forms of the
pharmaceutical compositions of the present invention, such as
dragees, capsules, pills and granules, may optionally be scored or
prepared with coatings and shells, such as enteric coatings and
other coatings well known in the pharmaceutical-formulating art.
They may also be formulated so as to provide slow or controlled
release of the active ingredient therein using, for example,
hydroxypropylmethyl cellulose in varying proportions to provide the
desired release profile, other polymer matrices, liposomes and/or
microspheres. They may be formulated for rapid release, e.g.,
freeze-dried. They may be sterilized by, for example, filtration
through a bacteria-retaining filter, or by incorporating
sterilizing agents in the form of sterile solid compositions which
can be dissolved in sterile water, or some other sterile injectable
medium immediately before use. These compositions may also
optionally contain opacifying agents and may be of a composition
that they release the active ingredient(s) only, or preferentially,
in a certain portion of the gastrointestinal tract, optionally, in
a delayed manner. Examples of embedding compositions which can be
used include polymeric substances and waxes. The active ingredient
can also be in micro-encapsulated form, if appropriate, with one or
more of the above-described excipients.
[0335] Liquid dosage forms for oral administration of the compounds
of the invention include pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active ingredient, the liquid dosage forms may
contain inert diluents commonly used in the art, such as, for
example, water or other solvents, solubilizing agents and
emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, oils (in particular,
cottonseed, groundnut, corn, germ, olive, castor and sesame oils),
glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty
acid esters of sorbitan, and mixtures thereof.
[0336] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, coloring, perfuming and
preservative agents.
[0337] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, and mixtures thereof.
[0338] Formulations of the pharmaceutical compositions of the
invention for rectal or vaginal administration may be presented as
a suppository, which may be prepared by mixing one or more
compounds of the invention with one or more suitable nonirritating
excipients or carriers comprising, for example, cocoa butter,
polyethylene glycol, a suppository wax or a salicylate, and which
is solid at room temperature, but liquid at body temperature and,
therefore, will melt in the rectum or vaginal cavity and release
the active compound.
[0339] Formulations of the present invention which are suitable for
vaginal administration also include pessaries, tampons, creams,
gels, pastes, foams or spray formulations containing such carriers
as are known in the art to be appropriate.
[0340] Dosage forms for the topical or transdermal administration
of a compound of this invention include powders, sprays, ointments,
pastes, creams, lotions, gels, solutions, patches and inhalants.
The active compound may be mixed under sterile conditions with a
pharmaceutically-acceptable carrier, and with any preservatives,
buffers, or propellants which may be required.
[0341] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, excipients, such
as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures
thereof.
[0342] Powders and sprays can contain, in addition to a compound of
this invention, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays can additionally contain
customary propellants, such as chlorofluorohydrocarbons and
volatile unsubstituted hydrocarbons, such as butane and
propane.
[0343] Transdermal patches have the added advantage of providing
controlled delivery of a compound of the present invention to the
body. Such dosage forms can be made by dissolving or dispersing the
compound in the proper medium. Absorption enhancers can also be
used to increase the flux of the compound across the skin. The rate
of such flux can be controlled by either providing a rate
controlling membrane or dispersing the compound in a polymer matrix
or gel.
[0344] Ophthalmic formulations, eye ointments, powders, solutions
and the like, are also contemplated as being within the scope of
this invention.
[0345] Pharmaceutical compositions of this invention suitable for
parenteral administration comprise one or more compounds of the
invention in combination with one or more
pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions, or sterile
powders which may be reconstituted into sterile injectable
solutions or dispersions just prior to use, which may contain
sugars, alcohols, antioxidants, buffers, bacteriostats, solutes
which render the formulation isotonic with the blood of the
intended recipient or suspending or thickening agents.
[0346] Examples of suitable aqueous and nonaqueous carriers which
may be employed in the pharmaceutical compositions of the invention
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils, such as olive oil, and injectable organic
esters, such as ethyl oleate. Proper fluidity can be maintained,
for example, by the use of coating materials, such as lecithin, by
the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0347] These compositions may also contain adjuvants such as
preservatives, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms upon the subject
compounds may be ensured by the inclusion of various antibacterial
and antifungal agents, for example, paraben, chlorobutanol, phenol
sorbic acid, and the like. It may also be desirable to include
isotonic agents, such as sugars, sodium chloride, and the like into
the compositions. In addition, prolonged absorption of the
injectable pharmaceutical form may be brought about by the
inclusion of agents which delay absorption such as aluminum
monostearate and gelatin.
[0348] In some cases, in order to prolong the effect of a drug, it
is desirable to slow the absorption of the drug from subcutaneous
or intramuscular injection. This may be accomplished by the use of
a liquid suspension of crystalline or amorphous material having
poor water solubility. The rate of absorption of the drug then
depends upon its rate of dissolution which, in turn, may depend
upon crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally-administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle.
[0349] Injectable depot forms are made by forming microencapsule
matrices of the subject compounds in biodegradable polymers such as
polyactide-polyglycolide. Depending on the ratio of drug to
polymer, and the nature of the particular polymer employed, the
rate of drug release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the drug in liposomes or microemulsions which are
compatible with body tissue.
[0350] When the compounds of the present invention are administered
as pharmaceuticals, to humans and animals, they can be given per se
or as a pharmaceutical composition containing, for example, 0.1 to
99% (more preferably, 10 to 30%) of active ingredient in
combination with a pharmaceutically acceptable carrier.
[0351] The preparations of the present invention may be given
orally, parenterally, topically, or rectally. They are of course
given in forms suitable for each administration route. For example,
they are administered in tablets or capsule form, by injection,
inhalation, eye lotion, ointment, suppository, etc. administration
by injection, infusion or inhalation; topical by lotion or
ointment; and rectal by suppositories. Oral administrations are
preferred.
[0352] The phrases "parenteral administration" and "administered
parenterally" as used herein means modes of administration other
than enteral and topical administration, usually by injection, and
includes, without limitation, intravenous, intramuscular,
intraarterial, intrathecal, intracapsular, intraorbital,
intracardiac, intradermal, intraperitoncal, transtracheal,
subcutaneous, subcuticular, intraarticulare, subcapsular,
subarachnoid, intraspinal and intrasternal injection and
infusion.
[0353] The phrases "systemic administration," "administered
systemically," "peripheral administration" and "administered
peripherally" as used herein mean the administration of a compound,
drug or other material other than directly into the central nervous
system, such that it enters the patient's system and, thus, is
subject to metabolism and other like processes, for example,
subcutaneous administration.
[0354] These compounds may be administered to humans and other
animals for therapy by any suitable route of administration,
including orally, nasally, as by, for example, a spray, rectally,
intravaginally, parenterally, intracisternally and topically, as by
powders, ointments or drops, including buccally and
sublingually.
[0355] Regardless of the route of administration selected, the
compounds of the present invention, which may be used in a suitable
hydrated form, and/or the pharmaceutical compositions of the
present invention, are formulated into pharmaceutically-acceptable
dosage forms by conventional methods known to those of skill in the
art.
[0356] Actual dosage levels of the active ingredients in the
pharmaceutical compositions of this invention may be varied so as
to obtain an amount of the active ingredient which is effective to
achieve the desired therapeutic response for a particular patient,
composition, and mode of administration, without being toxic to the
patient.
[0357] The selected dosage level will depend upon a variety of
factors including the activity of the particular compound of the
present invention employed, or the ester, salt or amide thereof,
the route of administration, the time of administration, the rate
of excretion or metabolism of the particular compound being
employed, the rate and extent of absorption, the duration of the
treatment, other drugs, compounds and/or materials used in
combination with the particular compound employed, the age, sex,
weight, condition, general health and prior medical history of the
patient being treated, and like factors well known in the medical
arts.
[0358] A physician or veterinarian having ordinary skill in the art
can readily determine and prescribe the effective amount of the
pharmaceutical composition required. For example, the physician or
veterinarian could start doses of the compounds of the invention
employed in the pharmaceutical composition at levels lower than
that required in order to achieve the desired therapeutic effect
and gradually increase the dosage until the desired effect is
achieved.
[0359] In general, a suitable daily dose of a compound of the
invention will be that amount of the compound which is the lowest
dose effective to produce a therapeutic effect. Such an effective
dose will generally depend upon the factors described above.
Generally, oral, intravenous, intracerebroventricular and
subcutaneous doses of the compounds of this invention for a
patient, when used for the indicated analgesic effects, will range
from about 0.0001 to about 100 mg per kilogram of body weight per
day.
[0360] If desired, the effective daily dose of the active compound
may be administered as two, three, four, five, six or more
sub-doses administered separately at appropriate intervals
throughout the day, optionally, in unit dosage forms. Preferred
dosing is one administration per day.
[0361] While it is possible for a compound of the present invention
to be administered alone, it is preferable to administer the
compound as a pharmaceutical formulation (composition).
[0362] The compounds according to the invention may be formulated
for administration in any convenient way for use in human or
veterinary medicine, by analogy with other pharmaceuticals.
[0363] In another aspect, the present invention provides
pharmaceutically acceptable compositions which comprise a
therapeutically-effective amount of one or more of the subject
compounds, as described above, formulated together with one or more
pharmaceutically acceptable carriers (additives) and/or diluents.
As described in detail below, the pharmaceutical compositions of
the present invention may be specialty formulated for
administration in solid or liquid form, including those adapted for
the following: (1) oral administration, for example, drenches
(aqueous or non-aqueous solutions or suspensions), tablets,
boluses, powders, granules, pastes for application to the tongue;
(2) parenteral administration, for example, by subcutaneous,
intramuscular or intravenous injection as, for example, a sterile
solution or suspension; (3) topical application, for example, as a
cream, ointment or spray applied to the skin, lungs, or mucous
membranes; or (4) intravaginally or intrarectally, for example, as
a pessary, cream or foam; (5) sublingually or buccally; (6)
ocularly; (7) transdermally; or (8) nasally.
[0364] The term "treatment" is intended to encompass also
prophylaxis, therapy and cure.
[0365] The patient receiving this treatment is any animal in need,
including primates, in particular humans, and other mammals such as
equines, cattle, swine and sheep; and poultry and pets in
general.
[0366] The compound of the invention can be administered as such or
in admixtures with pharmaceutically acceptable carriers and can
also be administered in conjunction with antimicrobial agents such
as penicillins, cephalosporins, aminoglycosides and glycopeptides.
Conjunctive therapy, thus includes sequential, simultaneous and
separate administration of the active compound in a way that the
therapeutical effects of the first administered one is not entirely
disappeared when the subsequent is administered.
[0367] The addition of the active compound of the invention to
animal feed is preferably accomplished by preparing an appropriate
feed premix containing the active compound in an effective amount
and incorporating the premix into the complete ration.
[0368] Alternatively, an intermediate concentrate or feed
supplement containing the active ingredient can be blended into the
feed. The way in which such feed premixes and complete rations can
be prepared and administered are described in reference books (such
as "Applied Animal Nutrition", W.H. Freedman and CO., San
Francisco, U.S.A., 1969 or "Livestock Feeds and Feeding" O and B
books, Corvallis, Ore., U.S.A., 1977).
[0369] Recently, the pharmaceutical industry introduced
microemulsification technology to improve bioavailability of some
lipophilic (water insoluble) pharmaceutical agents. Examples
include Trimetrine (Dordunoo, S. K., et al., Drug Development and
Industrial Pharmacy, 17(12), 1685-1713, 1991 and REV 5901 (Sheen,
P. C., et al., J Pharm Sci 80(7), 712-714, 1991). Among other
things, microemulsification provides enhanced bioavailability by
preferentially directing absorption to the lymphatic system instead
of the circulatory system, which thereby bypasses the liver, and
prevents destruction of the compounds in the hepatobiliary
circulation.
[0370] In one aspect of invention, the formulations contain
micelles formed from a compound of the present invention and at
least one amphiphilic carrier, in which the micelles have an
average diameter of less than about 100 nm. More preferred
embodiments provide micelles having an average diameter less than
about 50 nm, and even more preferred embodiments provide micelles
having an average diameter less than about 30 nm, or even less than
about 20 nm.
[0371] While all suitable amphiphilic carriers are contemplated,
the presently preferred carriers are generally those that have
Generally-Recognized-as-Safe (GRAS) status, and that can both
solubilize the compound of the present invention and microemulsify
it at a later stage when the solution comes into a contact with a
complex water phase (such as one found in human gastro-intestinal
tract). Usually, amphiphilic ingredients that satisfy these
requirements have HLB (hydrophilic to lipophilic balance) values of
2-20, and their structures contain straight chain aliphatic
radicals in the range of C-6 to C-20. Examples are
polyethylene-glycolized fatty glycerides and polyethylene
glycols.
[0372] Particularly preferred amphiphilic carriers are saturated
and monounsaturated polyethyleneglycolyzed fatty acid glycerides,
such as those obtained from fully or partially hydrogenated various
vegetable oils. Such oils may advantageously consist of tri-. di-
and mono-fatty acid glycerides and di- and mono-polyethyleneglycol
esters of the corresponding fatty acids, with a particularly
preferred fatty acid composition including capric acid 4-10, capric
acid 3-9, lauric acid 40-50, myristic acid 14-24, palmitic acid
4-14 and stearic acid 5-15%. Another useful class of amphiphilic
carriers includes partially esterified sorbitan and/or sorbitol,
with saturated or mono-unsaturated fatty acids (SPAN-series) or
corresponding ethoxylated analogs (TWEEN-series).
[0373] Commercially available amphiphilic carriers are particularly
contemplated, including Gelucire-series, Labrafil, Labrasol, or
Lauroglycol (all manufactured and distributed by Gattefosse
Corporation, Saint Priest, France), PEG-mono-oleate, PEG-di-oleate,
PEG-mono-laurate and di-laurate, Lecithin, Polysorbate 80, etc
(produced and distributed by a number of companies in USA and
worldwide).
[0374] Hydrophilic polymers suitable for use in the present
invention are those which are readily water-soluble, can be
covalently attached to a vesicle-forming lipid, and which are
tolerated in vivo without toxic effects (i.e., are biocompatible).
Suitable polymers include polyethylene glycol (PEG), polylactic
(also termed polylactide), polyglycolic acid (also termed
polyglycolide), a polylactic-polyglycolic acid copolymer, and
polyvinyl alcohol. Preferred polymers are those having a molecular
weight of from about 100 or 120 daltons up to about 5,000 or 10,000
daltons, and more preferably from about 300 daltons to about 5,000
daltons. In a particularly preferred embodiment, the polymer is
polyethyleneglycol having a molecular weight of from about 100 to
about 5,000 daltons, and more preferably having a molecular weight
of from about 300 to about 5,000 daltons. In a particularly
preferred embodiment, the polymer is polyethyleneglycol of 750
daltons (PEG(750)). The polymers used in the present invention have
a significantly smaller molecular weight, approximately 100
daltons, compared to the large MW of 5000 daltons or greater that
used in standard pegylation techniques. Polymers may also be
defined by the number of monomers therein; a preferred embodiment
of the present invention utilizes polymers of at least about three
monomers, such PEG polymers consisting of three monomers
(approximately 150 daltons).
[0375] Other hydrophilic polymers which may be suitable for use in
the present invention include polyvinylpyrrolidone,
polymethoxazoline, polyethyloxazoline, polyhydroxypropyl
methacrylamide, polymethacrylamide, polydimethylacrylamide, and
derivatized celluloses such as hydroxymethylcellulose or
hydroxyethylcellulose.
[0376] In certain embodiments, a formulation of the present
invention comprises a biocompatible polymer selected from the group
consisting of polyamides, polycarbonates, polyalkylenes, polymers
of acrylic and methacrylic esters, polyvinyl polymers,
polyglycolides, polysiloxanes, polyurethanes and co-polymers
thereof, celluloses, polypropylene, polyethylenes, polystyrene,
polymers of lactic acid and glycolic acid, polyanhydrides,
poly(ortho)esters, poly(butic acid), poly(valeric acid),
poly(lactide-co-caprolactone), polysaccharides, proteins,
polyhyaluronic acids, polycyanoacrylates, and blends, mixtures, or
copolymers thereof.
[0377] The release characteristics of a formulation of the present
invention depend on the encapsulating material, the concentration
of encapsulated drug, and the presence of release modifiers. For
example, release can be manipulated to be pH dependent, for
example, using a pH sensitive coating that releases only at a low
pH, as in the stomach, or a higher pH, as in the intestine. An
enteric coating can be used to prevent release from occurring until
after passage through the stomach. Multiple coatings or mixtures of
cyanamide encapsulated in different materials can be used to obtain
an initial release in the stomach, followed by later release in the
intestine. Release can also be manipulated by inclusion of salts or
pore forming agents, which can increase water uptake or release of
drug by diffusion from the capsule. Excipients which modify the
solubility of the drug can also be used to control the release
rate. Agents which enhance degradation of the matrix or release
from the matrix can also be incorporated. They can be added to the
drug, added as a separate phase (i.e., as particulates), or can be
co-dissolved in the polymer phase depending on the compound. In all
cases the amount should be between 0.1 and thirty percent (w/w
polymer). Types of degradation enhancers include inorganic salts
such as ammonium sulfate and ammonium chloride, organic acids such
as citric acid, benzoic acid, and ascorbic acid, inorganic bases
such as sodium carbonate, potassium carbonate, calcium carbonate,
zinc carbonate, and zinc hydroxide, and organic bases such as
protamine sulfate, spermine, choline, ethanolamine, diethanolamine,
and triethanolamine and surfactants such as Tween.RTM. and
Pluronic.RTM.. Pore forming agents which add microstructure to the
matrices (i.e., water soluble compounds such as inorganic salts and
sugars) are added as particulates. The range should be between one
and thirty percent (w/w polymer).
[0378] Uptake can also be manipulated by altering residence time of
the particles in the gut. This can be achieved, for example, by
coating the particle with, or selecting as the encapsulating
material, a mucosal adhesive polymer. Examples include most
polymers with free carboxyl groups, such as chitosan, celluloses,
and especially polyacrylates (as used herein, polyacrylates refers
to polymers including acrylate groups and modified acrylate groups
such as cyanoacrylates and methacrylates).
EXAMPLES
[0379] The invention now being generally described, it will be more
readily understood by reference to the following examples, which
are included merely for purposes of illustration of certain aspects
and embodiments of the present invention, and are not intended to
limit the invention.
[0380] Abbreviations used in the following examples and
preparations include: [0381] Ac.sub.2O Acetic anhydride [0382] AcOH
Acetic acid [0383] Bn Benzyl [0384] Celite.RTM. Diatomaceous earth
[0385] 1,2 DCE 1,2-Dichloroethane [0386] d Doublet [0387] dd Double
Doublet [0388] DIEA Di-isopropylethyl amine [0389] DMAP
4-Dimethylamino Pyridine [0390] DME 1,2 Dimethoxyethane [0391] DMF
Dimethylformamide [0392] DMSO Dimethyl sulfoxide [0393] EDC
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride [0394]
EtOAc Ethyl Acetate [0395] EtOH Ethyl Alcohol or Ethanol [0396]
Et.sub.2O Ethyl Ether [0397] Et.sub.3N Triethylamine [0398] g grams
[0399] HOBt 1-Hydroxybenzotriazole [0400] HPLC High Pressure Liquid
Chromatography [0401] h Hour(s) [0402] hr Hour(s) [0403] m
Multiplet [0404] mins. Minutes [0405] MeOH Methyl Alcohol or
Methanol [0406] min Minute(s) [0407] mmol millimoles [0408] mmole
millimoles [0409] MS Mass Spectrometry [0410] NMR Nuclear Magnetic
Resonance [0411] o/n overnight [0412] .sup.iPrOH Iso-propanol
[0413] PPAA 1-Propanephosphonic Acid Cyclic Anhydride [0414]
PyBOP.RTM. Benzotriazol-1-yl-oxytripyrrolidinophosphonium
hexafluorophosphate [0415] q Quartet [0416] RT (or rt) room
temperature (about 20-25.degree. C.) [0417] s Singlet [0418] sat.
Saturated [0419] t Triplet [0420] TBAF Tetra-Butyl Ammonium
Fluoride [0421] TFA Trifluoroacetic Acid [0422] THF Tetrahydrofuran
[0423] v/v volume/volume [0424] wt/v weight/volume
[0425] Mass spectrometry was conducted by: SynPep Co., 6905 Sierra
Ct. Dublin, Calif. 94568, or it was recorded on an LC-MS: Waters
2695 Separations Module with a Waters ZQ 2000 single quadrapole MS
detector. Unless stated all mass spectrometry was run in ESI
mode.
[0426] .sup.1H NMR spectra were recorded on a Varian 400 MHz
machine using Mercury software.
[0427] Analytical HPLC was run on an Agilent 1100 Series machine
using an YMC ProC18 column (4.6.times.50 mm, 5 .mu.m particle
size). Unless stated the method used was 5-95-10 which refers to a
gradient of 5% of buffer A increased to 95% over 10 minutes with
Buffer B. Buffer A is 0.1% TFA/H.sub.2O and Buffer B is 0.0085%
TFA/MeCN.
[0428] Preparative HPLC was performed on Waters Delta machine (600
and 515 Pumps) using an YMC-Pack ProC18 (150.times.20 mm I.D.)
column using a combination of Buffer A (0.1% TFA/H.sub.2O) and
Buffer B (0.0085% TFA/MeCN) as the mobile phase.
[0429] In sofar the synthesis of the following examples of
compounds of the present invention is not explicitly described in
such example, the synthesis is as described herein in general terms
and the appropriate starting material can be easily selected for
synthesizing the compound of the example.
Example 1
##STR00031##
[0431] To a solution of anthranilamide (7.0 g, 51.41 mmole) in
CHCl.sub.3 (260 mL) was added pyridine (8.13 g, 102.8 mmole, 8.28
mL) followed by slow addition of m-anisoyl chloride (9.20 g, 53.94
mmole, 7.35 mL). The reaction mixture was stirred at ambient
temperature for 6 h and then concentrated in vacuo and subsequently
dried under high vacuum for 4 h to give the product. (13.89 g,
mmol, 100%)
Example 2
2-(3-Methoxyphenyl)quinazolin-4(3H)-one
##STR00032##
[0433] A solution of 2 N NaOH (250 mL) was added to the amide from
example 1 (13.89 g, 51.41 mmole) and the reaction mixture was
refluxed for 4 h. The reaction was cooled to ambient temperature
and then adjusted to pH=7 with 1 N HCl. The resulting solid was
stirred at ambient temperature for 2 h and then filtered. The
filtered solid was washed with water, ether and dried under high
vacuum overnight. The crude product was also azeotroped from MeOH
(1.times.) and toluene (2.times.) and dried under high vacuum for
several hours to give 2-(3-methoxyphenyl)quinazolin-4(3H)-one.
(15.5 g, mmol, %)
Example 3
2-(3-Hydroxyphenyl)quinazolin-4(3H)-one
##STR00033##
[0435] To 2-(3-methoxyphenyl)quinazolin-4(3H)-one (11.6 g, 45.98
mmole) was added of CH.sub.2Cl.sub.2 (120 mL) and the mixture was
cooled to -78.degree. C. Then, a 1 M solution of BBr.sub.3 in
CH.sub.2Cl.sub.2 (60 mL, 60.0 mmol) was added drop wise and the
reaction was stirred at -78.degree. C. for 1 h and then ambient
temperature for 3 h. The reaction was re-cooled to -78.degree. C.
and cautiously quenched with MeOH (20 mL). The ice bath was removed
and the system allowed to stir at ambient temperature for 0.5 h.
The pH was adjusted to 7 with 10% w/w NaHCO.sub.3 solution. The
solid was filtered, washed with ether, dried and then azeotroped
from toluene (3.times.) and dried under high vacuum overnight to
give 2-(3-hydroxyphenyl)quinazolin-4(3H)-one. (11.0 g, mmol,
100%).
Example 4
3-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenyl acetate
##STR00034##
[0437] To 2-(3-hydroxyphenyl)quinazolin-4(3H)-one (11.0 g, 45.98
mmole) was added pyridine (16.06 mL, 15.71 g, 0.199 mmole) followed
by addition of acetic anhydride (145 mL) and the reaction mixture
was heated to 105.degree. C. and stirred for 3.5 h. The reaction
mixture was cooled to ambient temperature and then poured onto
ice-water (800 mL) and stirred for 2 h. The solid was then filtered
and washed with water, ethanol, ether and finally hexane and dried
for several hours under high vacuum to give
3-(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl acetate. (8.4 g, mmol,
65%).
Example 5
3-(4-Chloroquinazolin-2-yl)phenyl acetate
##STR00035##
[0439] To 3-(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl acetate was
added thionyl chloride (100 mL) and DMF (2 mL) and the reaction was
heated to reflux for 4 h. The flask was allowed to cool to RT and
then concentrated in vacuo. The crude product was azeotroped with
toluene (2.times.50 mL), taken up in CH.sub.2Cl.sub.2 (300 mL) and
washed with saturated NaHCO.sub.3 (3.times.50 mL), water
(1.times.50 mL) and brine (1.times.50 mL), dried with MgSO.sub.4
and concentrated in vacuo to give 3-(4-chloroquinazolin-2-yl)phenyl
acetate. (9.77 g, mmol, 100%).
Example 6
tert-Butyl
5-(2-(3-acetoxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carbo-
xylate
##STR00036##
[0441] 3-(4-Chloroquinazolin-2-yl)phenyl acetate (9.77 g, 29.97
mmole) was dissolved in isopropanol (290 mL) and tert-butyl
5-amino-1H-indazole-1-carboxylate (6.99 g, 29.97 mmole) was added.
The solution was heated to 95.degree. C. and stirred for 0.25 h. A
gelatinous formation developed which was manually broken up and
dissolution gradually occurred followed by formation of a yellow
precipitate. The reaction was stirred for an additional 0.25 h,
cooled to ambient temperature and filtered. The filtered solid was
washed with ether and then dried under high vacuum overnight to
give tert-butyl
5-(2-(3-acetoxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
(14.58 g, mmol, 98%)
Example 7
tert-Butyl
5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carbo-
xylate
##STR00037##
[0443] To a solution of give tert-butyl
5-(2-(3-acetoxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(5.85 g, 11.8 mmole) in anhydrous MeOH (400 mL) was added 28%
(wt/v) NH.sub.4OH solution (6.50 mL). The reaction mixture was
stirred at ambient temperature for 48 h. The crude product was
filtered and washed with ether followed by hexane and dried under
high vacuum overnight to give tert-butyl
5-(2-(3-hydroxyphenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
(4.85 g, mmol, 91%).
Example 8
##STR00038##
[0445] To a suspension of anthranilamide (24.0 g, 176.28 mmole) and
3-nitro benzoyl chloride (34.5 g, 186.3 mmole) CHCl.sub.3 (700 ml)
was added pyridine (30 ml) drop wise at RT. The reaction mixture
was stirred at ambient temperature for 8 h. The solvent was removed
in vacuo and residue dried under high vacuum to give the product.
(73 g, mmol, %)
Example 9
2-(3-Nitrophenyl)quinazolin-4(3H)-one
##STR00039##
[0447] A suspension of amide from example 8 (estimated 176.3 mmole)
was taken up in 2 N NaOH (800 mL) and was refluxed for 7 h. The
reaction mixture was cooled to ambient temperature and then pH
adjusted to 7 with 3 N HCl. The suspension was stirred at RT for 2
h, filtered, and the filtered solid washed with water and dried
under high vacuum to give 2-(3-nitrophenyl)quinazolin-4(3H)-one.
(45 g, mmol, 96% from anthranilamide).
Example 10
4-Chloro-2-(3-nitrophenyl)quinazoline
##STR00040##
[0449] To a suspension of 2-(3-nitrophenyl)quinazolin-4(3H)-one
(5.7 g, 21.32 mmole) in thionyl chloride (70 mL) was added of DMF
(2 mL). The reaction mixture was refluxed for 4.5 h. The reaction
was then concentrated in vacuo and residue suspended in a mixture
of CH.sub.2Cl.sub.2 (400 mL) and CHCl.sub.3 (500 mL). The organic
layer was washed with water, saturated NaHCO.sub.3, water, brine,
dried with Na.sub.2SO.sub.4 and concentrated in vacuo. The residue
was dried under high vacuum to afford
4-chloro-2-(3-nitrophenyl)quinazoline as an off-white solid. (6.0
g, mmol, 97%).
Example 11
tert-Butyl
5-(2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxy-
late
##STR00041##
[0451] A suspension of 4-chloro-2-(3-nitrophenyl)quinazoline (6.3
g, 21.9 mmole), tert-butyl 5-amino-1H-indazole-1-carboxylate (5.10
g, 21.9 mmole) in isopropanol (300 mL) was heated at 95.degree. C.
for 1.5 h. The suspension was filtered and the filtered solid was
washed with isopropanol. The product was dried under high vacuum
for several hours to give the desired product tert-butyl
5-(2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
(8.3 g, mmol, 79%).
Example 12
##STR00042##
[0453] A suspension of product tert-butyl
5-(2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(9.0 g, 18.65 mmole) in a mixture of DME/MeOH (300 mL/100 mL) was
hydrogenated in the presence of 10% Pd/C (1.25 g) at RT using a
balloon filled with hydrogen gas. The reaction was stirred for 16 h
and the reaction mixture filtered through Celite.TM.. The pad of
Celite.TM. was washed with a 1:1 mixture of MeOH/CH.sub.2Cl.sub.2
(200 mL). The filtrate was then concentrated in vacuo and dried
under high vacuum overnight to give tert-butyl
5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
(8.8 g, mmol, %).
Example 13
tert-butyl
5-(2-(3-(2-(tert-butoxycarbonyl)acetamido)phenyl)quinazolin-4-y-
lamino)-1H-indazole-1-carboxylate
##STR00043##
[0455] A suspension of 2-(tert-butoxycarbonyl)acetic acid (21 mg,
0.11 mmol), PyBOP.RTM. (57 mg, 0.11 mmol), DIEA (38 .mu.L, 0.22
mmol) in anhydrous CH.sub.2Cl.sub.2 (0.5 mL) was stirred at RT for
10 minutes. This solution of activated acid was added to a
suspension of tert-butyl
5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(100 mg, 0.22 mmol) and anhydrous CH.sub.2Cl.sub.2 (1 mL). The
reaction mixture was stirred at RT for 1 h. Activated and added
another 0.5 equivalent of the acid as described above and stirred
for 1 h. Activated and added another 0.3 equivalents of the acid as
described above. Stirred for and additional hour and diluted with
CH.sub.2Cl.sub.2. Extracted with H.sub.2O (3.times.) and the
organic layer was dried under Na.sub.2SO.sub.4 and concentrated in
vacuo. The residue was purified by flash chromatography on silica
(1:1 EtOAc:Hexanes) to give the desired product tert-butyl
5-(2-(3-(2-(tert-butoxycarbonyl)acetamido)phenyl)quinazolin-4-ylamino)-1H-
-indazole-1-carboxylate.(123 mg, 0.20 mmol, 90%).
Example 14
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-(methylamino)aceta-
mide
##STR00044##
[0457] To tert-butyl
5-(2-(3-(2-(tert-butoxycarbonyl)acetamido)phenyl)quinazolin-4-ylamino)-1H-
-indazole-1-carboxylate (123 mg, 0.20 mmol) was added a solution of
1:1 TFA:CH.sub.2Cl.sub.2 (4 mL) and stirred at RT for 2 h. The
reaction mixture was concentrated in vacuo and the residue was
triturated with ethyl ether to afford 2-methoxyacetyl chloride
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-(dimethylamino)ac-
etamide. (95 mg, 0.22 mmol, 100%)
Example 15
tert-butyl
5-(2-(3-(3-(2-(dimethylamino)ethyl)ureido)phenyl)quinazolin-4-y-
lamino)-1H-indazole-1-carboxylate
##STR00045##
[0459] To a solution of tert-butyl
5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(100 mg, 0.22 mmol) in anhydrous CH.sub.2Cl.sub.2 (2 mL) added
Et.sub.3N (45 mg, 0.44 mmol) and 4-nitrophenyl carbonochloridate
(47 mg 0.23 mmol). The solution was stirred at RT for 2 h. To the
reaction mixture added N,N-dimethylethane-1,2-diamine (36 .mu.L,
0.33 mmol) and stirred for 16 h. Concentrated in vacuo to afford
the crude tert-butyl
5-(2-(3-(3-(2-(dimethylamino)ethyl)ureido)phenyl)quinazolin-4-ylamino)-1H-
-indazole-1-carboxylate.
Example 16
1-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-3-(2-(dimethylamino)-
ethyl)urea
##STR00046##
[0461] To tert-butyl
5-(2-(3-(2-methoxyacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-ca-
rboxylate was added a solution of 1:1 TFA:CH.sub.2Cl.sub.2 (2 mL)
and stirred at RT for 2 h. The reaction mixture was concentrated in
vacuo and the residue was triturated with ethyl ether to get a
yellow solid. Product was purified using prep HPLC (method 15-50_90
mins) to afford
1-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-3-(2-(dimethylamino-
)ethyl)urea. (20 mg, 0.042 mmol)
Example 17
tert-butyl
5-(2-(3-(2-(dimethylamino)acetamido)phenyl)quinazolin-4-ylamino-
)-1H-indazole-1-carboxylate
##STR00047##
[0463] A suspension of 2-(dimethylamino)acetic acid (57 mg, 0.55
mmol), PyBOP.RTM. (286 mg, 0.55 mmol), DIEA (240 .mu.L, 1.38 mmol)
in CH.sub.2Cl.sub.2 (2 mL) was stirred at RT for 10-15 minutes.
This solution of activated acid was added to a suspension of
tert-butyl
5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(500 mg, 1.10 mmol) and CH.sub.2Cl.sub.2 (4 mL). The reaction
mixture was stirred at RT for 1.5 h. Activated another 1.5
equivalent of the acid as described above and stirred for 16 h.
Diluted with more CH.sub.2Cl.sub.2 and extracted with H.sub.2O
(3.times.). Organic layer was dried under Na.sub.2SO.sub.4 and
concentrated in vacuo. The residue was purified by flash
chromatography on silica (9:1 CH.sub.2Cl.sub.2:MeOH) to give the
desired product tert-butyl
5-(2-(3-(2-(dimethylamino)acetamido)phenyl)quinazolin-4-ylamino)-1H-indaz-
ole-1-carboxylate.(570 mg, 1.06 mmol, 96%).
Example 18
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-(dimethylamino)ace-
tamide
##STR00048##
[0465] To tert-butyl
5-(2-(3-(2-(dimethylamino)acetamido)phenyl)quinazolin-4-ylamino)-1H-indaz-
ole-1-carboxylate (560 mg, 1.04 mmol) was added a solution of 1:1
TFA:CH.sub.2Cl.sub.2 (6 mL) and stirred at RT for 2 h. The reaction
mixture was concentrated in vacuo and the residue was triturated
with ethyl ether and drops of CH.sub.2Cl.sub.2 to afford
2-methoxyacetyl chloride
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-(dimethy-
lamino)acetamide. (325 mg, 0.74 mmol, 71%)
Example 19
tert-butyl
5-(2-(3-(2-methoxyacetamido)phenyl)quinazolin-4-ylamino)-1H-ind-
azole-1-carboxylate
##STR00049##
[0467] A suspension of tert-butyl
5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(100 mg, 22.0 mmol), 4-methoxyacetyl chloride (40 .mu.L, 0.44
mmol), Et.sub.3N (61 .mu.L, 0.44 mmol), in CH.sub.2Cl.sub.2 (1 mL)
was stirred at RT temperature for 30 minutes. The reaction was then
concentrated in vacuo and residue was triturated with MeOH and
drops of CH.sub.2Cl.sub.2. The solid was filtered under high vacuum
to afford tert-butyl
5-(2-(3-(2-methoxyacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-ca-
rboxylate. (98 mg, 85%)
Example 20
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-methoxyacetamide
##STR00050##
[0469] To tert-butyl
5-(2-(3-(2-methoxyacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-ca-
rboxylate (95 mg, 0.18 mmol) was added a solution of 1:1
TFA:CH.sub.2Cl.sub.2 (2 mL) and stirred at RT for 2 h. The reaction
mixture was concentrated in vacuo and the residue was triturated
with ethyl ether to get a yellow solid. Product was purified using
prep HPLC (method 25-50_70 mins) to afford 2-methoxyacetyl chloride
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-methoxyacetamide.
(45 mg, 59%)
Example 21
tert-butyl
5-(2-(3-((R)-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamido-
)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
##STR00051##
[0471] To a suspension of tert-butyl
5-(2-(3-aminophenyl)quinazoin-4-ylamino)-1H-indazole-1-carboxylate
(20 mg, 0.044 mmol) and
1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carbonyl chloride (880
.mu.L, 0.088 mmol, 0.1M solution in CH.sub.2Cl.sub.2) was added
Et.sub.3N (12 .mu.L, 0.088 mmol), catalytic amount of DMAP, and
CH.sub.2Cl.sub.2 (1 mL). The reaction mixture was stirred at RT for
2 h after which 2 equivalents each of
1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carbonyl chloride and
Et.sub.3N were added. Continued to stir at ambient temperature for
16 hours. The reaction was concentrated in vacuo and the residue
was purified by flash chromatography on silica (10:1
CH.sub.2Cl.sub.2:MeOH). The product tert-butyl
5-(2-(3-((R)-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamido)phenyl)qu-
inazolin-4-ylamino)-1H-indazole-1-carboxylate was isolated. (130
mg, 46%)
Example 22
tert-butyl
5-(2-(3-((R)-pyrrolidine-2-carboxamido)phenyl)quinazolin-4-ylam-
ino)-1H-indazole-1-carboxylate
##STR00052##
[0473] To a suspension of tert-butyl
5-(2-(3-((R)-1-(2,2,2-trifluoroacetyl)-pyrrolidine-2-carboxamido)phenyl)q-
uinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.15 mmol)
in MeOH (5.7 mL) and H.sub.2O (345 mL) was added K.sub.2CO.sub.3
(108 mg, 0.78 mmol). Reaction mixture was refluxed for 2 h. Cooled
to RT temperature and concentrated in vacuo. The residue was
dissolved in EtOAc and extracted with H.sub.2O (3.times.). Dried
the organic layer under Na.sub.2SO.sub.4 and concentrated in vacuo.
The aqueous layer was basicified with 1 N NaOH, extracted with
CHCl.sub.3 (3.times.), dried under Na.sub.2SO.sub.4 and
concentrated in vacuo. The two organic layers were combined to
afford tert-butyl
5-(2-(3-((R)-pyrrolidine-2-carboxamido)phenyl)quinazolin-4-ylamino)-1H-in-
dazole-1-carboxylate. (65 mg, 79%).
Example 23
(2R)--N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)-phenyl)pyrrolidine-2--
carboxamide
##STR00053##
[0475] To tert-butyl
5-(2-(3-((R)-pyrrolidine-2-carboxamido)phenyl)quinazolin-4-ylamino)-1H-in-
dazole-1-carboxylate (65 mg, 0.12 mmol) was added a solution of 1:1
TFA:CH.sub.2Cl.sub.2 (2 mL) and stirred at RT for 2 h. The reaction
mixture was concentrated in vacuo and the residue was triturated
with ethyl ether to get a yellow solid. Product was purified using
prep HPLC (method 25-50_70 mins) to afford
(2R)--N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)pyrrolidine-2--
carboxamide. (64 mg, 100%).
Example 24
tert-butyl
5-(2-(3-(2-methoxy-2-oxoacetamido)phenyl)quinazolin-4-ylamino)--
1H-indazole-1-carboxylate
##STR00054##
[0477] To a suspension of tert-butyl
5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(85 mg, 0.19 mmol) and methyl 2-chloro-2-oxoacetate (35 .mu.L, 0.38
mmol) in CH.sub.2Cl.sub.2 (1 mL) was added Et.sub.3N (53 uL, 0.38
mmol), and catalytic amount of DMAP. The reaction mixture was
stirred at RT for 3 h. The reaction was concentrated in vacuo and
the residue was purified by flash chromatography on silica (10:1
CH.sub.2Cl.sub.2:MeOH). The product tert-butyl
5-(2-(3-(2-methoxy-2-oxoacetamido)phenyl)quinazolin-4-ylamino)-1H-indazol-
e-1-carboxylate was isolate. (18 mg, 18%)
Example 25
methyl
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenylamino)-2-oxoace-
tate
##STR00055##
[0479] To tert-butyl
5-(2-(3-(2-methoxy-2-oxoacetamido)phenyl)quinazolin-4-ylamino)-1H-indazol-
e-1-carboxylate (18 mg, 0.033 mmol) was added a solution of 1:1
TFA:CH.sub.2Cl.sub.2 (2 mL) and stirred at RT for 2 h. The reaction
mixture was concentrated in vacuo and the residue was triturated
with ethyl ether to get a yellow solid to afford methyl
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenylamino)-2-oxoacetate.
(15 mg, 100%).
Example 26
tert-butyl
5-(2-(3-((S)-2-(tert-butoxycarbonyl)propanamido)phenyl)quinazol-
in-4-ylamino)-1H-indazole-1-carboxylate
##STR00056##
[0481] A suspension of (S)-2-(tert-butoxycarbonyl)propanoic acid
(21 mg, 0.11 mmol), PyBOP.RTM. (57 mg, 0.11 mmol), DIEA (49 .mu.L,
0.28 mmol) in CH.sub.2Cl.sub.2 (0.5 mL) was stirred at RT for 10-15
minutes. This solution of activated acid was added to a suspension
of tert-butyl
5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(100 mg, 0.22 mmol) and CH.sub.2Cl.sub.2 (1 mL). The reaction
mixture was stirred at RT for 1.5 h. Activated another 0.5
equivalent of the acid as described above and it was once again
added to the reaction mixture. Stirred for 16 h, diluted with more
CH.sub.2Cl.sub.2 and extracted with H.sub.2O (3.times.). Organic
layer was dried under Na.sub.2SO.sub.4 and concentrated in vacuo to
give the desired product tert-butyl
5-(2-(3-((S)-2-(tert-butoxycarbonyl)propanamido)phenyl)quinazolin-4-ylami-
no)-1H-indazole-1-carboxylate.(95 mg, 69%).
Example 27
(2S)--N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-aminopropana-
mide
##STR00057##
[0483] To tert-butyl
5-(2-(3-((S)-2-(tert-butoxycarbonyl)propanamido)phenyl)-quinazolin-4-ylam-
ino)-1H-indazole-1-carboxylate (95 mg, 0.15 mmol) was added a
solution of 1:1 TFA:CH.sub.2Cl.sub.2 (2 mL) and stirred at RT for 2
h. The reaction mixture was concentrated in vacuo and the crude
product was purified by prep HPLC (method 10-35_90 mins) to afford
(2S)--N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-aminopropan-
amide. (29 mg, 43%)
Example 28
tert-butyl
5-(2-(3-((S)-1-methylpyrrolidine-2-carboxamido)phenyl)quinazoli-
n-4-ylamino)-1H-indazole-1-carboxylate
##STR00058##
[0485] A suspension of (S)-1-methylpyrrolidine-2-carboxylic acid
monohydrate (14 mg, 0.11 mmol), PyBOP.RTM. (57 mg, 0.11 mmol), DIEA
(49 .mu.L, 0.28 mmol) in CH.sub.2Cl.sub.2 (0.5 mL) was stirred at
RT for 10-15 minutes. This solution of activated acid was added to
a suspension of tert-butyl
5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(100 mg, 0.22 mmol) and CH.sub.2Cl.sub.2 (1 mL). The reaction
mixture was stirred at RT for 1.5 h. Activated another 0.5
equivalent of the acid as described above and it was once again
added to the reaction mixture. Stirred for 16 h, diluted with more
CH.sub.2Cl.sub.2 and extracted with H.sub.2O (3.times.). Organic
layer was dried under Na.sub.2SO.sub.4 and concentrated in vacuo to
give the desired oil product tert-butyl
5-(2-(3-((S)-1-methylpyrrolidine-2-carboxamido)phenyl)-quinazolin-4-ylami-
no)-1H-indazole-1-carboxylate.
Example 29
(2S)--N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-1-methylpyrrol-
idine-2-carboxamide
##STR00059##
[0487] To tert-butyl
5-(2-(3-((S)-1-methylpyrrolidine-2-carboxamido)phenyl)-quinazolin-4-ylami-
no)-1H-indazole-1-carboxylate (22 mmol) was added a solution of 1:1
TFA:CH.sub.2Cl.sub.2 (2 mL) and stirred at RT for 2 h. The reaction
mixture was concentrated in vacuo and the crude product was
purified by prep HPLC (method 10-35_90 mins) to afford
(2S)--N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-1-methylpyrro-
lidine-2-carboxamide. (25 mg, 25%)
Example 30
tert-butyl
5-(2-(3-((R)-2-(tert-butoxycarbonyl)propanamido)phenyl)quinazol-
in-4-ylamino)-1H-indazole-1-carboxylate
##STR00060##
[0489] A suspension of (R)-2-(tert-butoxycarbonyl)propanoic acid
(21 mg, 0.11 mmol), PyBOP.RTM. (57 mg, 0.11 mmol), DIEA (49 .mu.L,
0.28 mmol) in CH.sub.2Cl.sub.2 (0.5 mL) was stirred at RT for 10-15
minutes. This solution of activated acid was added to a suspension
of tert-butyl
5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(100 mg, 0.22 mmol) and CH.sub.2Cl.sub.2 (1 mL). The reaction
mixture was stirred at RT for 1.5 h. Activated another 0.5
equivalent of the acid as described above and it was once again
added to the reaction mixture. Stirred for 16 h, diluted with more
CH.sub.2Cl.sub.2 and extracted with H.sub.2O (3.times.). Organic
layer was dried under Na.sub.2SO.sub.4 and concentrated in vacuo to
give the desired product tert-butyl
5-(2-(3-((R)-2-(tert-butoxycarbonyl)propanamido)phenyl)quinazolin-4-ylami-
no)-1H-indazole-1-carboxylate.(95 mg, 69%).
Example 31
(2R)--N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-aminopropana-
mide
##STR00061##
[0491] To tert-butyl
5-(2-(3-((R)-2-(tert-butoxycarbonyl)propanamido)phenyl)-quinazolin-4-ylam-
ino)-1H-indazole-1-carboxylate (100 mg, 0.16 mmol) was added a
solution of 1:1 TFA:CH.sub.2Cl.sub.2 (2 mL) and stirred at RT for 2
h. The reaction mixture was concentrated in vacuo and the crude
product was purified by prep HPLC (method 10-35_90 mins) to afford
(2R)--N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-aminopropan-
amide. (24 mg, 38%)
Example 32
tert-butyl
5-(2-(3-(2-morpholinoacetamido)phenyl)quinazolin-4-ylamino)-1H--
indazole-1-carboxylate
##STR00062##
[0493] A suspension of 2-morpholinoacetic acid (16 mg, 0.11 mmol),
PyBOP.RTM. (57 mg, 0.11 mmol), DIEA (96 .mu.L, 0.55 mmol) in
CH.sub.2Cl.sub.2 (0.5 mL) was stirred at RT for 10-15 minutes. This
solution of activated acid was added to a suspension of tert-butyl
5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
( ) (100 mg, 0.22 mmol) and CH.sub.2Cl.sub.2 (1 mL). The reaction
mixture was stirred at RT for 1.5 h. Activated another 0.5
equivalent of the acid as described above and it was once again
added to the reaction mixture and stirred for 1.5 h. Added two more
0.5 equivalents of activated acid while stirring 1.5 hr between
each addition. Diluted with more CH.sub.2Cl.sub.2 and extracted
with H.sub.2O (3.times.). Organic layer was dried under
Na.sub.2SO.sub.4 and concentrated in vacuo to give the desired oil
product tert-butyl
5-(2-(3-(2-morpholinoacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-
-carboxylate.
Example 33
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-morpholinoacetamid-
e
##STR00063##
[0495] To tert-butyl
5-(2-(3-((R)-2-(tert-butoxycarbonyl)propanamido)phenyl)-quinazolin-4-ylam-
ino)-1H-indazole-1-carboxylate (100 mg, 0.16 mmol) was added a
solution of 1:1 TFA:CH.sub.2Cl.sub.2 (2 mL) and stirred at RT for 2
h. The reaction mixture was concentrated in vacuo and the crude
product was purified by prep HPLC (method 10-35_90 mins) to afford
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-morpholinoacetami-
de. (24 mg, 38%)
Example 34
tert-butyl
5-(2-(3-(2-chloroacetamido)phenyl)quinazolin-4-ylamino)-1H-inda-
zole-1-carboxylate
##STR00064##
[0497] To a suspension of tert-butyl
5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(1.0 g, 2.21 mmol) in EtOAc:THF:sat'd NaHCO.sub.3 (110 mL: 30 mL:
50 mL) was added 2-chloroacetyl chloride (1 mL, 12.6 mmol) and
stirred at RT for 2.5 hr. The reaction mixture was stirred at RT
for 1.5 h. Another addition of 2-chloroacetyl chloride (0.5 mL) was
added and continued to stir for 2 h. Concentrated in vacuo to
remove volatiles and residue was washed with 5% citric acid
(2.times.50 mL), water (2.times.100 mL), and sat'd NaCl (1.times.50
mL). The organic layer was dried under Na.sub.2SO.sub.4 and
concentrated in vacuo to give the desired product tert-butyl
5-(2-(3-(2-chloroacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-car-
boxylate.(1.02 g, 87%)
Example 35
tert-butyl
5-(2-(3-(3-(4-isopropylpiperazin-1-yl)propanamido)phenyl)quinaz-
olin-4-ylamino)-1H-indazole-1-carboxylate
##STR00065##
[0499] A suspension of tert-butyl
5-(2-(3-(2-chloroacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-car-
boxylate (112 mg, 0.223 mmol), 1-isopropylpiperazine (52 mg, 0.406
mmol), DIEA (51 mg, 0.402 mmol) in DMF (2 mL) was stirred at
75.degree. C. for 4 h. The reaction mixture was cooled to RT and
the residue was poured into ice-water. The resulting white solid
was filtered and dried for several hours under high vacuum. The
crude product was purified by prep TLC using CH.sub.2Cl.sub.2:MeOH,
(9:1) as the mobile phase to afford tert-butyl
5-(2-(3-(3-(4-isopropylpiperazin-1-yl)propanamido)phenyl)quinazolin-4-yla-
mino)-1H-indazole-1-carboxylate. (60 mg, 0.094 mmol, 42%)
Example 36
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-3-(4-isopropylpipera-
zin-1-yl)propanamide
##STR00066##
[0501] To tert-butyl
5-(2-(3-(3-(4-isopropylpiperazin-1-yl)propanamido)phenyl)-quinazolin-4-yl-
amino)-1H-indazole-1-carboxylate (60 mg, 0.094 mmol) was added a
solution of 1:1 TFA:CH.sub.2Cl.sub.2 (4 mL) and stirred at RT for 2
h. The reaction mixture was concentrated in vacuo and the crude
product was purified by prep HPLC (method 10-35_90 mins) to afford
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-3-(4-isopropylpiper-
azin-1-yl)propanamide. (61 mg, 0.11 mmol, 100%).
Example 37
tert-butyl
5-(2-(3-(2-morpholinoacetamido)phenyl)quinazolin-4-ylamino)-1H--
indazole-1-carboxylate
##STR00067##
[0503] To a suspension of tert-butyl
5-(2-(3-(2-chloroacetamido)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-ca-
rboxylate (1.0 g, 1.89 mmol) in DMF:THF (3 mL:4 mL) was added
morpholine (1.8 mL, 20.6 mmol). The reaction mixture was stirred at
RT for 2.5 h. The reaction mixture was concentrated in vacuo to
remove volatiles. The residue was poured into ice-water and the
resulting white solid was filtered and dried for several hours
under high vacuum. The crude product re-crystallized using absolute
EtOH to afford tert-butyl
5-(2-(3-(2-morpholinoacetamido)-phenyl)quinazolin-4-ylamino)-1H-indazole--
1-carboxylate. (830 mg, 75%)
Example 38
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-morpholinoacetamid-
e
##STR00068##
[0505] To tert-butyl
5-(2-(3-((R)-2-(tert-butoxycarbonyl)propanamido)phenyl)-quinazolin-4-ylam-
ino)-1H-indazole-1-carboxylate (805 mg, 1.39 mmol) was added a
solution of 1:1 TFA:CH.sub.2Cl.sub.2 (10 mL) and stirred at RT for
3 h. Added an additional portion of TFA (1.5 mL) and stirred for
another 2 h. The reaction mixture was diluted with ethyl ether (200
mL) and solid was filtered and dried for several hours under high
vacuum to afford
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-morpholinoacetami-
de. (917 mg, 100%)
Example 39
tert-butyl
5-(2-(3-(2-(4-methylpiperazin-1-yl)acetamido)phenyl)quinazolin--
4-ylamino)-1H-indazole-1-carboxylate
##STR00069##
[0507] A suspension of 2-(4-methylpiperazin-1-yl)acetic acid (34
mg, 0.22 mmol), PyBOP.RTM. (11 mg, 0.22 mmol), DIEA (300 .mu.L,
1.72 mmol) in CH.sub.2Cl.sub.2 (0.5 mL) was stirred at RT for 10-15
minutes. This solution of activated acid was added to a suspension
of tert-butyl
5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(100 mg, 0.22 mmol) and CH.sub.2Cl.sub.2 (1 mL). The reaction
mixture was stirred at RT for 1.5 h. Activated another 1 equivalent
of the acid as described above and it was once again added to the
reaction mixture. Stirred for 16 h, diluted with more
CH.sub.2Cl.sub.2 and extracted with H.sub.2O (3.times.). Organic
layer was dried under Na.sub.2SO.sub.4 and concentrated in vacuo to
give the desired product tert-butyl
5-(2-(3-(2-(4-methylpiperazin-1-yl)acetamido)phenyl)quinazolin-4-ylamino)-
-1H-indazole-1-carboxylate.
Example 40
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-(4-methylpiperazin-
-1-yl)acetamide
##STR00070##
[0509] To tert-butyl
5-(2-(3-(2-(4-methylpiperazin-1-yl)acetamido)phenyl)-quinazolin-4-ylamino-
)-1H-indazole-1-carboxylate (22 mmol) was added a solution of 1:1
TFA:CH.sub.2Cl.sub.2 (2 mL) and stirred at RT for 2 h. The reaction
mixture was concentrated in vacuo and the crude product was
purified by prep HPLC (method 10-35_90 mins) to afford
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-(4-methylpiperazi-
n-1-yl)acetamide. (33 mg, 33%)
Example 41
tert-butyl
5-(2-(3-(morpholine-4-carboxamido)phenyl)quinazolin-4-ylamino)--
1H-indazole-1-carboxylate
##STR00071##
[0511] To a suspension of tert-butyl
5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(100 mg, 0.22 mmol) and morpholine-4-carbonyl chloride (51 .mu.L,
0.44 mmol) in CH.sub.2Cl.sub.2 (2 mL) was added Et.sub.3N (61
.mu.L, 0.44 mmol) and catalytic amount of DMAP. The reaction
mixture was stirred at RT for 2 h after which 2 equivalents each of
morpholine-4-carbonyl chloride and Et.sub.3N were added. After 2 h
of stirring another 2 equivalents of both the chloride and
Et.sub.3N were added and continued to stir at ambient temperature
for 16 hours. The reaction was concentrated in vacuo and the
residue was purified by flash chromatography on silica (12:1
CH.sub.2Cl.sub.2:MeOH). The product tert-butyl
5-(2-(3-(morpholine-4-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazol-
e-1-carboxylate was isolated. (80 mg, 65%)
Example 42
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)morpholine-4-carboxam-
ide
##STR00072##
[0513] To tert-butyl
5-(2-(3-(morpholine-4-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazol-
e-1-carboxylate (25 mg, 0.044 mmol) was added a solution of 1:1
TFA:CH.sub.2Cl.sub.2 (2 mL) and stirred at RT for 2 h. The reaction
mixture was concentrated in vacuo and the product triturated with
ethyl ether to afford
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)morpholine-4-carboxa-
mide. (24 mg, 100%)
Example 43
tert-butyl
5-(2-(3-(1-methylpiperazine-4-carboxamido)phenyl)quinazolin-4-y-
lamino)-1H-indazole-1-carboxylate
##STR00073##
[0515] To a suspension of tert-butyl
5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(100 mg, 0.22 mmol) and 4-methylpiperazine-1-carbonyl chloride
hydrochloride (88 mg, 0.44 mmol) in CH.sub.2Cl.sub.2 (2 mL) was
added Et.sub.3N (92 .mu.L, 0.66 mmol) and catalytic amount of DMAP.
The reaction mixture was stirred at RT for 2 h after which 2
equivalents each of 4-methylpiperazine-1-carbonyl chloride
hydrochloride and 3 equivalents of Et.sub.3N were added. Continued
to stir at ambient temperature for 16 hours. The reaction was
concentrated in vacuo and the residue was purified by flash
chromatography on silica (8:1 CH.sub.2Cl.sub.2:MeOH). The product
tert-butyl
5-(2-(3-(1-methylpiperazine-4-carboxamido)phenyl)-quinazolin-4-ylamino)-1-
H-indazole-1-carboxylate was isolated. (160 mg, 100%)
Example 44
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-4-methylpiperazine-1-
-carboxamide
##STR00074##
[0517] To tert-butyl
5-(2-(3-(1-methylpiperazine-4-carboxamido)phenyl)quinazolin-4-ylamino)-1H-
-indazole-1-carboxylate (165 mg, 0.22 mmol) was added a solution of
1:1 TFA:CH.sub.2Cl.sub.2 (6 mL) and stirred at RT for 2 h. The
reaction mixture was concentrated in vacuo and left under high
vacuum for several hours. The crude product was purified by prep
HPLC (method 25-50_70 mins) to afford
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-4-methylp-
iperazine-1-carboxamide. (88 mg, 69%)
Example 45
tert-butyl
5-(2-(3-(3,3-dimethylureido)phenyl)quinazolin-4-ylamino)-1H-ind-
azole-1-carboxylate
##STR00075##
[0519] To a suspension of tert-butyl
5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(75 mg, 0.17 mmol) and dimethylcarbamic chloride (30 .mu.L, 0.33
mmol) in CH.sub.2Cl.sub.2 (2 mL) was added Et.sub.3N (46 .mu.L,
0.33 mmol) and catalytic amount of DMAP. The reaction mixture was
stirred at RT for 2 h after which 2 equivalents each of
dimethylcarbamic chloride and Et.sub.3N were added. After 2 h of
stirring another 2 equivalents of both the chloride and Et.sub.3N
were added. Upon the addition of the third addition of the chloride
and the Et.sub.3N the temperature was raised to 45.degree. C. The
reaction mixture was stirred for 48 h. Concentrated in vacuo and
the residue was purified by flash chromatography on silica (10:1
CH.sub.2Cl.sub.2:MeOH). The product tert-butyl
5-(2-(3-(3,3-dimethylureido)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-c-
arboxylate was isolated. (62 mg, 70%)
Example 46
3-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-1,1-dimethylurea
##STR00076##
[0521] To tert-butyl
5-(2-(3-(3,3-dimethylureido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-ca-
rboxylate (50 mg, 0.10 mmol) was added a solution of 1:1
TFA:CH.sub.2Cl.sub.2 (3 mL) and stirred at RT for 2 h. The reaction
mixture was concentrated in vacuo and left under high vacuum for
several hours. The crude product was triturated with ethyl ether
and the yellow solid was purified by prep HPLC (method 25-50_70
mins) to afford
3-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-1,1-dimethylurea.
(36 mg, 86%)
Example 47
tert-butyl
5-(2-(3-(3-benzylureido)phenyl)quinazolin-4-ylamino)-1H-indazol-
e-1-carboxylate
##STR00077##
[0523] To a suspension of tert-butyl
5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(150 mg, 0.33 mmol) and 1-(isocyanatomethyl)benzene (162 .mu.L,
1.32 mmol) in CH.sub.2Cl.sub.2 (2 mL) was added Et.sub.3N (1.38 mL,
9.9 mmol). The reaction mixture was stirred at RT for 4 h and
concentrated in vacuo. The residue was triturated using MeOH and
drops of CH.sub.2Cl.sub.2 to afford tert-butyl
5-(2-(3-(3-benzylureido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carbox-
ylate. (100 mg, 52%)
Example 48
1-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-3-benzylurea
##STR00078##
[0525] To tert-butyl
5-(2-(3-(3-benzylureido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carbox-
ylate (30 mg, 0.051 mmol) was added a solution of 1:1
TFA:CH.sub.2Cl.sub.2 (2 mL) and stirred at RT for 2 h. The reaction
mixture was concentrated in vacuo and left under high vacuum for
several hours. The crude product was triturated with ethyl ether to
afford
1-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-3-benzylurea.
(25 mg, 100%)
Example 49
tert-butyl
5-(2-(3-(piperidine-4-carboxamido)phenyl)quinazolin-4-ylamino)--
1H-indazole-1-carboxylate
##STR00079##
[0527] A suspension of tert-butyl
5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(126 mg, 0.278 mmol),
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (79 mg, 0.347
mmol), PyBOP.RTM. (212 mg, 0.455 mmol) and DIEA (250 .mu.L, 1.43
mmol) in CH.sub.2Cl.sub.2 (10 mL) was stirred at RT for 72 h.
Reaction mixture was diluted with more CH.sub.2Cl.sub.2 (50 mL) and
extracted with H.sub.2O (3.times.). Organic layer was dried under
Na.sub.2SO.sub.4 and concentrated in vacu. Crude product was
purified by prep TLC to give the desired product tert-butyl
5-(2-(3-(piperidine-4-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazol-
e-1-carboxylate.
Example 50
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)piperidine-4-carboxam-
ide
##STR00080##
[0529] To tert-butyl
5-(2-(3-(piperidine-4-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazol-
e-1-carboxylate (mg, mmol) was added a solution of 1:1
TFA:CH.sub.2Cl.sub.2 (4 mL) and stirred at RT for 2 h. The reaction
mixture was concentrated in vacuo and left under high vacuum for
several hours. The crude product was triturated with ethyl ether to
afford
N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)piperidine-4-carboxa-
mide. (97 mg, 0.21 mmol, 75% over two steps)
Example 51
tert-Butyl
5-(2-(3-(2-tert-butoxy-2-oxoethoxy)phenyl)quinazolin-4-ylamino)-
-1H-indazole-1-carboxylate
##STR00081##
[0531] A mixture of tert-butyl
5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(0.800 g, 1.76 mmol), tert-butyl 2-bromoacetate (130 .mu.L, 0.88
mmol) and K.sub.2CO.sub.3 (0.972 g, 7.04 mmol) in DMF (35 mL) was
heated at 80.degree. C. for 2 h. Upon which additional tert-butyl
2-bromoacetate (130 .mu.L, 0.88 mmol) was added, heating at
80.degree. C. was continued for a further 1.5 h. The mixture was
allowed to cool to RT and concentrated in vacuo. Diluted with
CH.sub.2Cl.sub.2 and extracted with water (3.times.). Dried under
Na.sub.2SO.sub.4 and concentrated in vacuo to give tert-Butyl
5-(2-(3-(2-tert-butoxy-2-oxoethoxy)phenyl)quinazolin-4-ylamino)-1H-indazo-
le-1-carboxylate. (0.950 g, 1.68 mmol, 95%).
Example 52
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic
acid
##STR00082##
[0533] A solution of tert-butyl
5-(2-(3-(2-tert-butoxy-2-oxoethoxy)phenyl)-quinazolin-4-ylamino)-1H-indaz-
ole-1-carboxylate was stirred in CH.sub.2Cl.sub.2 (2 mL) and TFA (2
mL) for 1 h. The volatiles were removed in vacuo and the residue
was triturated with ethyl ether. The crude product was purified
using prep HPLC (method 10-35_90 mins) to afford to give
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid.
(0.43 mg, 0.10 mmol)
Example 53
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropyl-N-methy-
lacetamide
##STR00083##
[0535] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(120 mg, 0.29 mmol), PyBOP.RTM. (150 mg, 0.29 mmol), DIEA (152
.mu.L, 0.87 mmol) in CH.sub.2Cl.sub.2 (5 mL) was stirred at RT for
10-15 minutes. To this solution of activated acid was added
N-methylpropan-2-amine (30 .mu.L, 0.29 mmol). The reaction mixture
was stirred at RT for 3 h and concentrated in vacuo. The crude
product was purified using prep HPLC (method 5-25-50_80 mins) and
was further washed with ethyl ether and drops of CH.sub.2Cl.sub.2
to afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropyl-N-meth-
ylacetamide. (12 mg, 0.025 mmol, 9%)
Example 54
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2-methoxyethyl)a-
cetamide
##STR00084##
[0537] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(100 mg, 0.24 mmol), PyBOP.RTM. (125 mg, 0.24 mmol), DIEA (125
.mu.L, 0.72 mmol) in CH.sub.2Cl.sub.2:DMF (4 mL:0.5 mL) stirred at
RT for 10-15 minutes. To this solution of activated acid was added
2-methoxyethanamine (21 .mu.L, 0.24 mmol) and the reaction mixture
was stirred at RT for 3 h. Concentrated in vacuo and the crude
product was purified using prep HPLC (method 10-35_90 mins) and was
further washed with ethyl ether and drops of CH.sub.2Cl.sub.2 to
afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2-methoxyethyl)-
acetamide.(25 mg, 0.053 mmol, 22%)
Example 55
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(pyridin-3-yl)ace-
tamide
##STR00085##
[0539] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(100 mg, 0.24 mmol), PyBOP.RTM. (125 mg, 0.24 mmol), DIEA (250
.mu.L, 0.44 mmol) in CH.sub.2Cl.sub.2:DMF (4 mL:1 mL) stirred at RT
for 10-15 minutes. To this solution of activated acid was added
3-amino pyridine (23 mg, 0.24 mmol) and the reaction mixture was
stirred at 50.degree. C. for 1.5 h. Concentrated in vacuo and the
crude product was purified using prep HPLC (method 10-35_90 mins)
to afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(pyridin-3-yl)ac-
etamide.(11 mg, 0.023 mmol, 9%)
Example 56
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-(4-methylpiperazi-
n-1-yl)ethanone
##STR00086##
[0541] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(100 mg, 0.24 mmol), PyBOP.RTM. (125 mg, 0.24 mmol), DIEA (125
.mu.L, 0.24 mmol) in CH.sub.2Cl.sub.2 (5 mL) stirred at RT for
10-15 minutes. To this solution of activated acid was added
1-methylpiperazine (27 .mu.L, 0.24 mmol) and the reaction mixture
was stirred at RT for 1.5 h. Concentrated in vacuo and the crude
product was purified using prep HPLC (method 10-35_90 mins) to
afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-(4-methylpiperaz-
in-1-yl)ethanone.(32 mg, 0.065 mmol, 27%)
Example 57
2-chloro-N-(2-(dimethylamino)ethyl)acetamide
##STR00087##
[0543] A suspension of 2-chloroacetic acid (214 mg, 2.27 mmol),
PyBOP.RTM. (1.18, 2.27 mmol), DIEA (1.18 mL, 6.81 mmol) in
CH.sub.2Cl.sub.2 (1 mL) was stirred at RT for 10-15 minutes. This
solution of activated acid was added to a suspension of
N1,N1-dimethylethane-1,2-diamine (249 .mu.L, 2.27 mmol) and
CH.sub.2Cl.sub.2 (4 mL). The reaction mixture was stirred at RT for
1.5 h. Diluted with more CH.sub.2Cl.sub.2 and extracted with
H.sub.2O (3.times.). Organic layer was dried under Na.sub.2SO.sub.4
and concentrated in vacuo to give the desired product
2-chloro-N-(2-(dimethylamino)ethyl)acetamide.
Example 58
tert-butyl
5-(2-(3-(2-(2-(dimethylamino)ethylamino)-2-oxoethoxy)phenyl)qui-
nazolin-4-ylamino)-1H-indazole-1-carboxylate
##STR00088##
[0545] A suspension of tert-butyl
5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(80 mg, 0.18 mmol), 2-chloro-N-(2-(dimethylamino)-ethyl)acetamide
(40 mg, 0.25 mmol), K.sub.2CO.sub.3 (162 mg, 1.17 mmol), in DMF (5
mL). Stirred at RT for 4 h upon which 2 equivalents each of
2-chloro-N-(2-(dimethylamino)-ethyl)acetamide and K.sub.2CO.sub.3
were added. Continued to stir for 16 h. Concentrated in vacuo to
afford the crude tert-butyl
5-(2-(3-(2-(2-(dimethylamino)-ethylamino)-2-oxoethoxy)phenyl)quinazolin-4-
-ylamino)-1H-indazole-1-carboxylate. (0.18 mmol).
Example 59
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2-(dimethylamino-
)ethyl)acetamide
##STR00089##
[0547] To tert-butyl
5-(2-(3-(2-(2-(dimethylamino)ethylamino)-2-oxoethoxy)phenyl)quinazolin-4--
ylamino)-1H-indazole-1-carboxylate (0.18 mmol) was added a solution
of 1:1 TFA:CH.sub.2Cl.sub.2 (2 mL) and stirred at RT for 2 h. The
reaction mixture was concentrated in vacuo and the crude product
was purified by prep HPLC (method 10-35_90 mins) to afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2-(dimethylamin-
o)ethyl)acetamide. (19 mg, 0.039 mmol, 22%).
Example 60
tert-butyl
5-(2-(3-(2-isopropoxy-2-oxoethoxy)phenyl)quinazolin-4-ylamino)--
1H-indazole-1-carboxylate
##STR00090##
[0549] A suspension of tert-butyl
5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(120 mg, 0.26 mmol), isopropyl 2-chloroacetate (45 mL, 0.36 mmol),
K.sub.2CO.sub.3 (125 .mu.L, 0.24 mmol), in DMF (5 mL) stirred at RT
for 2 h. Concentrated in vacuo to afford the crude tert-butyl
5-(2-(3-(2-isopropoxy-2-oxoethoxy)phenyl)quinazolin-4-ylamino)-1H-indazol-
e-1-carboxylate ( ). (0.26 mmol)
Example 61
isopropyl
2-(3-(4-(H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetate
##STR00091##
[0551] To a suspension of tert-butyl
5-(2-(3-(2-isopropoxy-2-oxoethoxy)phenyl)quinazolin-4-ylamino)-1H-indazol-
e-1-carboxylate (0.26 mmol) in 1,4-dioxane (0.5 mL) was added a 4M
solution of hydrogen chloride in 1,4-dioxane (3 mL) and stirred at
RT for 16 h. The reaction mixture was concentrated in vacuo residue
was purified using prep HPLC (method 10-35_90 mins) to afford
isopropyl
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetate. (28
mg, 0.062 mmol, 24%)
Example 62
tert-butyl
5-(2-(3-(oxazol-2-ylmethoxy)phenyl)quinazolin-4-ylamino)-1H-ind-
azole-1-carboxylate
##STR00092##
[0553] A suspension of tert-butyl
5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(100 mg, 0.22 mmol), 2-(chloromethyl)oxazole (31 mg, 0.26 mmol), KI
(44 mg, 0.27 mmol), and K.sub.2CO.sub.3 (122 mg, 0.88 mmol) in dry
DMF (1.5 mL) was stirred at 70.degree. C. for 1 h. The mixture was
poured into water, filtered, dried under high vacuum for several
hours to afford tert-butyl
5-(2-(3-(oxazol-2-ylmethoxy)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-c-
arboxylate.
Example 63
N-(1H-indazol-5-yl)-2-(3-(oxazol-2-ylmethoxy)phenyl)quinazolin-4-amine
##STR00093##
[0555] To tert-butyl
5-(2-(3-(2-(2-(dimethylamino)ethylamino)-2-oxoethoxy)-phenyl)quinazolin-4-
-ylamino)-1H-indazole-1-carboxylate was added a solution of 1:1
TFA:CH.sub.2Cl.sub.2 (3 mL) and stirred at RT for 2 h. The reaction
mixture was concentrated in vacuo and the crude product was
purified by prep HPLC (method 20-45_90 mins) to afford
N-(1H-indazol-5-yl)-2-(3-(oxazol-2-ylmethoxy)phenyl)quinazolin-4-amine.
(12 mg, 0.028 mmol).
Example 64
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-morpholinoethanon-
e
##STR00094##
[0557] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(80 mg, 0.16 mmol), PyBOP.RTM. (46 mg, 0.088 mmol), DIEA (28 .mu.L,
0.16 mmol) in dry CH.sub.2Cl.sub.2:DMF (2:0.1 mL) was stirred at RT
for 15 minutes. To this solution of activated acid was added
morpholine (8.7 mg, 0.10 mmol). After 30 minutes, 1.0 equivalent of
DIEA and 0.55 equivalent of PyBOP.RTM. were added. After stirring
the solution for 15 minutes, 0.65 equivalents of morpholine were
added and the mixture was stirred for an additional 30 minutes. The
solvent was removed in vacuo and the crude product was purified
using prep HPLC (20-45_90 mins) to afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-morpholinoethano-
ne. (13 mg, 0.027 mmol, 17%)
Example 65
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-methylacetamide
##STR00095##
[0559] To a solution of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(80 mg, 0.16 mmol) in dry CH.sub.2Cl.sub.2:DMF (2.0:0.1 mL), added
DIEA (29 .mu.L, 0.16 mmol) and PyBOP.RTM. (46 mg, 0.088 mmol).
After stirring the mixture at RT for 15 minutes, methanamine was
bubbled through the solution for 15 minutes. Added another 1.0
equivalent of DIEA and 0.55 equivalents of PyBOP.RTM. after
stirring the solution for 15 minutes, followed by methanamine
bubbling for an additional 15 minutes. The solvent was removed in
vacuo and the crude material was purified by prep HPLC (method
20-4590 mins) to afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-methylacetamide.
(46 mg, 0.11 mmol, 68%).
Example 66
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N,N-dimethylacetami-
de
##STR00096##
[0561] To a solution of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(80 mg, 0.16 mmol) in dry CH.sub.2Cl.sub.2:DMF (2.0:0.1 mL), added
DIEA (29 .mu.L, 0.16 mmol) and PyBOP.RTM. (46 mg, 0.088 mmol).
After stirring the mixture at RT for 15 minutes, dimethylamine was
bubbled through the solution for 15 minutes. Added another 1.0
equivalent of DIEA and 0.55 equivalents of PyBOP.RTM. after
stirring the solution for 15 minutes, followed by dimethylamine
bubbling for an additional 15 minutes. The solvent was removed in
vacuo and the crude material was purified by prep HPLC (method
20-45_90 mins) to afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N,N-dimethylacetam-
ide (26 mg, 0.059 mmol, 37%).
Example 67
tert-butyl
5-(2-(3-((1-methyl-1H-imidazol-2-yl)methoxy)phenyl)quinazolin-4-
-ylamino)-1H-indazole-1-carboxylate
##STR00097##
[0563] A solution of tert-butyl
5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(50 mg, 0.11 mmol), 2-(chloromethyl)-1-methyl-1H-imidazole (22 mg,
0.13 mmol), KI (22 mg, 0.13 mmol), K.sub.2CO.sub.3 (76 mg, 0.55
mmol) in anhydrous DMF (1.2 mL) was heated at 50.degree. C. for 100
minutes. Added 1.2 equivalents each of
2-(chloromethyl)-1-methyl-1H-imidazole and KI and heated for
another 35 minutes. Added 2.4 equivalents each of
2-(chloromethyl)-1-methyl-1H-imidazole and KI along with 2.0
equivalents of K.sub.2CO.sub.3 and heated for 1 h. The solution was
diluted with CH.sub.2Cl.sub.2 and washed with aqueous saturated
NaCl (2.times.). The organic phase was dried under Na.sub.2SO.sub.4
and concentrated in vacuo to afford tert-butyl
5-(2-(3-((1-methyl-1H-imidazol-2-yl)methoxy)-phenyl)quinazolin-4-ylamino)-
-1H-indazole-1-carboxylate.
Example 68
N-(1H-indazol-5-yl)-2-(3-((1-methyl-1H-imidazol-2-yl)methoxy)phenyl)-quina-
zolin-4-amine
##STR00098##
[0565] To tert-butyl
5-(2-(3-((1-methyl-1H-imidazol-2-yl)methoxy)phenyl)-quinazolin-4-ylamino)-
-1H-indazole-1-carboxylate was added a solution of 1:1
TFA:CH.sub.2Cl.sub.2 (2 mL) and stirred at RT for 2 h. The reaction
mixture was concentrated in vacuo and the crude product was
purified by prep HPLC (method 10-35_90 mins) to afford
N-(1H-indazol-5-yl)-2-(3-((1-methyl-1H-imidazol-2-yl)methoxy)phenyl)-quin-
azolin-4-amine. (5.4 mg, 0.012 mmol).
Example 69
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(cyclopropylmethy-
l)acetamide
##STR00099##
[0567] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(80 mg, 0.16 mmol), PyBOP.RTM. (46 mg, 0.088 mmol), DIEA (28 .mu.L,
0.16 mmol) in dry CH.sub.2Cl.sub.2:DMF (2:0.1 mL) was stirred at RT
for 15 minutes. To this solution of activated acid was added
cyclopropylmethanamine (7.1 mg, 0.10 mmol). After 30 minutes, 1.0
equivalent of DIEA and 0.55 equivalents of PyBOP.RTM. were added.
After stirring the solution for 15 minutes, 0.65 equivalents of
cyclopropylmethanamine were added and the mixture was stirred for
an additional 30 minutes. The solvent was removed in vacuo and the
crude product was purified using prep HPLC (20-45_90 mins) to
afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(cyclopro-
pylmethyl)acetamide. (60 mg, 0.13 mmol, 81%)
Example 70
(3R)-tert-butyl
3-(2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamido)pyrrol-
idine-1-carboxylate
##STR00100##
[0569] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(67 mg, 0.13 mmol), PyBOP.RTM. (37 mg, 0.072 mmol), DIEA (23 .mu.L,
0.13 mmol) in dry CH.sub.2Cl.sub.2:DMF (2:0.1 mL) was stirred at RT
for 15 minutes. To this solution of activated acid was added
(R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (16 mg, 0.084
mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalent
of PyBOP.RTM. were added. After stirring the solution for 15
minutes, 0.65 equivalent of (R)-tert-butyl
3-aminopyrrolidine-1-carboxylate were added and the mixture was
stirred for an additional 30 minutes. The solvent was removed in
vacuo to afford the crude (3R)-tert-butyl
3-(2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamido)pyrrol-
idine-1-carboxylate.
Example 71
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N--((R)-pyrrolidin--
3-yl)acetamide
##STR00101##
[0571] To (3R)-tert-butyl
3-(2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamido)pyrrol-
idine-1-carboxylate was added a solution of 1:1
TFA:CH.sub.2Cl.sub.2 (3 mL) and stirred at RT for 2 h. The reaction
mixture was concentrated in vacuo and the crude product was
purified by prep HPLC (method 10-35_90 mins) to afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N--((R)-pyrrolidin-
-3-yl)acetamide. (45 mg, 0.094 mmol)
Example 72
(3S)-tert-butyl
3-(2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamido)pyrrol-
idine-1-carboxylate
##STR00102##
[0573] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(50 mg, 0.098 mmol), PyBOP.RTM. (28 mg, 0.054 mmol), DIEA (17
.mu.L, 0.098 mmol) in dry CH.sub.2Cl.sub.2:DMF (2:0.1 mL) was
stirred at RT for 15 minutes. To this solution of activated acid
was added (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (16 mg,
0.084 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55
equivalent of PyBOP.RTM. were added. After stirring the solution
for 15 minutes, 0.65 equivalent of (S)-tert-butyl
3-aminopyrrolidine-1-carboxylate were added and the mixture was
stirred for an additional 30 minutes. The solvent was removed in
vacuo to afford the crude (3S)-tert-butyl
3-(2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamido)pyrrol-
idine-1-carboxylate.
Example 73
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N--((S)-pyrrolidin--
3-yl)acetamide
##STR00103##
[0575] To (3S)-tert-butyl
3-(2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamido)pyrrol-
idine-1-carboxylate was added a solution of 1:1
TFA:CH.sub.2Cl.sub.2 (3 mL) and stirred at RT for 2 h. The reaction
mixture was concentrated in vacuo and the crude product was
purified by prep HPLC (method 10-35_90 mins) to afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N--((S)-pyrrolidin-
-3-yl)acetamide. (33 mg, 0.069 mmol)
Example 74
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(1-methylpiperidi-
n-4-yl)acetamide
##STR00104##
[0577] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(70 mg, 0.14 mmol), PyBOP.RTM. (40 mg, 0.077 mmol), DIEA (24 .mu.L,
0.14 mmol) in dry CH.sub.2Cl.sub.2:DMF (2:0.1 mL) was stirred at RT
for 15 minutes. To this solution of activated acid was added
1-methylpiperidin-4-amine (10 mg, 0.091 mmol). After 30 minutes,
1.0 equivalent of DIEA and 0.55 equivalents of PyBOP.RTM. were
added. After stirring the solution for 15 minutes, 0.65 equivalents
of 1-methylpiperidin-4-amine were added and the mixture was stirred
for an additional 30 minutes. The solvent was removed in vacuo and
the crude product was purified using prep HPLC (10-35_90 mins) to
afford
2-(3-(4-(H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(1-methylpiperidi-
n-4-yl)acetamide. (49 mg, 0.097 mmol, 69%)
Example 75
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(tetrahydro-2H-py-
ran-4-yl)acetamide
##STR00105##
[0579] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(70 mg, 0.14 mmol), PyBOP.RTM. (40 mg, 0.077 mmol), DIEA (24 .mu.L,
0.14 mmol) in dry CH.sub.2Cl.sub.2:DMF (2:0.1 mL) was stirred at RT
for 15 minutes. To this solution of activated acid was added
tetrahydro-2H-pyran-4-amine hydrochloride (13 mg, 0.091 mmol).
After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of
PyBOP.RTM. were added. After stirring the solution for 15 minutes,
0.65 equivalents of tetrahydro-2H-pyran-4-amine hydrochloride were
added and the mixture was stirred for an additional 30 minutes. The
solvent was removed in vacuo and the crude product was purified
using prep HPLC (15-40_90 mins) to afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(tetrahydro-2H-p-
yran-4-yl)acetamide. (32 mg, 0.065 mmol, 46%)
Example 76
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N--((R)-tetrahydrof-
uran-3-yl)acetamide
##STR00106##
[0581] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(70 mg, 0.14 mmol), PyBOP.RTM. (40 mg, 0.077 mmol), DIEA (24 .mu.L,
0.14 mmol) in dry CH.sub.2Cl.sub.2:DMF (2:0.1 mL) was stirred at RT
for 15 minutes. To this solution of activated acid was added
(R)-tetrahydrofuran-3-aminium 4-methylbenzenesulfonate (24 mg,
0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55
equivalents of PyBOP.RTM. were added. After stirring the solution
for 15 minutes, 0.65 equivalents of (R)-tetrahydrofuran-3-aminium
4-methylbenzenesulfonate were added and the mixture was stirred for
an additional 30 minutes. The solvent was removed in vacuo and the
crude product was purified using prep HPLC (15-40_90 mins) to
afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N--((R)-tetrahydro-
furan-3-yl)acetamide. (41 mg, 0.085 mmol, 61%).
Example 77
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-(piperidin-1-yl)e-
thanone
##STR00107##
[0583] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(70 mg, 0.14 mmol), PyBOP.RTM. (40 mg, 0.077 mmol), DIEA (24 .mu.L,
0.14 mmol) in dry CH.sub.2Cl.sub.2:DMF (2:0.1 mL) was stirred at RT
for 15 minutes. To this solution of activated acid was added
piperidine (7.7 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent
of DIEA and 0.55 equivalents of PyBOP.RTM. were added. After
stirring the solution for 15 minutes, 0.65 equivalents of
piperidine were added and the mixture was stirred for an additional
30 minutes. The solvent was removed in vacuo and the crude product
was purified using prep HPLC (25-55_90 mins) to afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-(piperidin-1-yl)-
ethanone. (29 mg, 0.061 mmol, 43%).
Example 78
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-tert-butylacetami-
de
##STR00108##
[0585] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(70 mg, 0.14 mmol), PyBOP.RTM. (40 mg, 0.077 mmol), DIEA (24 .mu.L,
0.14 mmol) in dry CH.sub.2Cl.sub.2:DMF (2:0.1 mL) was stirred at RT
for 15 minutes. To this solution of activated acid was added
2-methylpropan-2-amine (6.7 mg, 0.091 mmol). After 30 minutes, 1.0
equivalent of DIEA and 0.55 equivalents of PyBOP.RTM. were added.
After stirring the solution for 15 minutes, 0.65 equivalents of
2-methylpropan-2-amine were added and the mixture was stirred for
an additional 30 minutes. The solvent was removed in vacuo and the
crude product was purified using prep HPLC (25-55_90 mins) to
afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-tert-butylacetam-
ide. (36 mg, 0.061 mmol, 55%).
Example 79
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-ethylacetamide
##STR00109##
[0587] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(70 mg, 0.14 mmol), PyBOP.RTM. (40 mg, 0.077 mmol), DIEA (24 .mu.L,
0.14 mmol) in dry CH.sub.2Cl.sub.2:DMF (2:0.1 mL) was stirred at RT
for 15 minutes. To this solution of activated acid was added
ethanamine hydrochloride (7.4 mg, 0.091 mmol). After 30 minutes,
1.0 equivalent of DIEA and 0.55 equivalents of PyBOP.RTM. were
added. After stirring the solution for 15 minutes, 0.65 equivalents
of ethanamine hydrochloride were added and the mixture was stirred
for an additional 30 minutes. The solvent was removed in vacuo and
the crude product was purified using prep HPLC (15-40_90 mins) to
afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-ethylacetamide.
(19 mg, 0.043 mmol, 31%)
Example 80
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-cyclobutylacetami-
de
##STR00110##
[0589] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(70 mg, 0.14 mmol), PyBOP.RTM. (40 mg, 0.077 mmol), DIEA (24 .mu.L,
0.14 mmol) in dry CH.sub.2Cl.sub.2:DMF (2:0.1 mL) was stirred at RT
for 15 minutes. To this solution of activated acid was added
cyclobutanamine (6.5 mg, 0.091 mmol). After 30 minutes, 1.0
equivalent of DIEA and 0.55 equivalents of PyBOP.RTM. were added.
After stirring the solution for 15 minutes, 0.65 equivalents of
cyclobutanamine were added and the mixture was stirred for an
additional 30 minutes. The solvent was removed in vacuo and the
crude product was purified using prep HPLC (25-50_90 mins) to
afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-cyclobutylacetam-
ide. (36 mg, 0.077 mmol, 55%).
Example 81
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(cyanomethyl)acet-
amide
##STR00111##
[0591] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(70 mg, 0.14 mmol), PyBOP.RTM. (40 mg, 0.077 mmol), DIEA (24 .mu.L,
0.14 mmol) in dry CH.sub.2Cl.sub.2:DMF (2:0.1 mL) was stirred at RT
for 15 minutes. To this solution of activated acid was added
aminoacetonitrile monosulfate (14 mg, 0.091 mmol). After 30
minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP.RTM.
were added. After stirring the solution for 15 minutes, 0.65
equivalents of aminoacetonitrile monosulfate were added and the
mixture was stirred for an additional 30 minutes. The solvent was
removed in vacuo and the crude product was purified using prep HPLC
(15-40_90 mins) to afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(cyanomethyl)ace-
tamide. (12 mg, 0.027 mmol, 19%).
Example 82
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropylacetamid-
e
##STR00112##
[0593] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(70 mg, 0.14 mmol), PyBOP.RTM. (40 mg, 0.077 mmol), DIEA (24 .mu.L,
0.14 mmol) in dry CH.sub.2Cl.sub.2:DMF (2:0.1 mL) was stirred at RT
for 15 minutes. To this solution of activated acid was added
propan-2-amine (5.4 mg, 0.091 mmol). After 30 minutes, 1.0
equivalent of DIEA and 0.55 equivalents of PyBOP.RTM. were added.
After stirring the solution for 15 minutes, 0.65 equivalents of
propan-2-amine were added and the mixture was stirred for an
additional 30 minutes. The solvent was removed in vacuo and the
crude product was purified using prep HPLC (25-50_90 mins) to
afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropylacetami-
de. (40 mg, 0.086 mmol, 61%).
Example 83
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N--(R)-sec-butylace-
tamide
##STR00113##
[0595] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(70 mg, 0.14 mmol), PyBOP.RTM. (40 mg, 0.077 mmol), DIEA (24 .mu.L,
0.14 mmol) in dry CH.sub.2Cl.sub.2:DMF (2:0.1 mL) was stirred at RT
for 15 minutes. To this solution of activated acid was added
(R)-butan-2-amine (6.6 mg, 0.091 mmol). After 30 minutes, 1.0
equivalent of DIEA and 0.55 equivalents of PyBOP.RTM. were added.
After stirring the solution for 15 minutes, 0.65 equivalents of
(R)-butan-2-amine were added and the mixture was stirred for an
additional 30 minutes. The solvent was removed in vacuo and the
crude product was purified using prep HPLC (15-40_90 mins) to
afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N--(R)-s-
ec-butylacetamide. (34 mg, 0.073 mmol, 52%).
Example 84
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamide
##STR00114##
[0597] To a solution of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(70 mg, 0.14 mmol) in dry CH.sub.2Cl.sub.2:DMF (2.0:0.1 mL), added
DIEA (24 .mu.L, 0.14 mmol) and PyBOP.RTM. (40 mg, 0.077 mmol).
After stirring the mixture at RT for 15 minutes, ammonia was
bubbled through the solution for 15 minutes. Added another 1.0
equivalent of DIEA and 0.55 equivalents of PyBOP.RTM. after
stirring the solution for 15 minutes, followed by ammonia bubbling
for an additional 15 minutes. The solvent was removed in vacuo and
the crude material was purified by prep HPLC (method 10-35_90 mins)
to afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamide.
(27 mg, 0.066 mol, 47%).
Example 85
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2,2,2-trifluoroe-
thyl)acetamide
##STR00115##
[0599] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(70 mg, 0.14 mmol), PyBOP.RTM. (40 mg, 0.077 mmol), DIEA (24 .mu.L,
0.14 mmol) in dry CH.sub.2Cl.sub.2:DMF (2:0.1 mL) was stirred at RT
for 15 minutes. To this solution of activated acid was added
2,2,2-trifluoroethanamine (9.0 mg, 0.091 mmol). After 30 minutes,
1.0 equivalent of DIEA and 0.55 equivalents of PyBOP.RTM. were
added. After stirring the solution for 15 minutes, 0.65 equivalents
of 2,2,2-trifluoroethanamine were added and the mixture was stirred
for an additional 30 minutes. The solvent was removed in vacuo and
the crude product was purified using prep HPLC (25-50_90 mins) to
afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2,2,2-trifluoro-
ethyl)acetamide. (16 mg, 0.032 mmol, 23%).
Example 86
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-cyclohexylacetami-
de
##STR00116##
[0601] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (
) (70 mg, 0.14 mmol), PyBOP.RTM. (40 mg, 0.077 mmol), DIEA (24
.mu.L, 0.14 mmol) in dry CH.sub.2Cl.sub.2:DMF (2:0.1 mL) was
stirred at RT for 15 minutes. To this solution of activated acid
was added cyclohexanamine (9.0 mg, 0.091 mmol). After 30 minutes,
1.0 equivalent of DIEA and 0.55 equivalents of PyBOP.RTM. were
added. After stirring the solution for 15 minutes, 0.65 equivalents
of cyclohexanamine were added and the mixture was stirred for an
additional 30 minutes. The solvent was removed in vacuo and the
crude product was purified using prep HPLC (20-50_90 mins) to
afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-cycloh-
exylacetamide. (27 mg, 0.055 mmol, 39%).
Example 87
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2-methylbut-3-yn-
-2-yl)acetamide
##STR00117##
[0603] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(70 mg, 0.14 mmol), PyBOP.RTM. (40 mg, 0.077 mmol), DIEA (24 .mu.L,
0.14 mmol) in dry CH.sub.2Cl.sub.2:DMF (2:0.1 mL) was stirred at RT
for 15 minutes. To this solution of activated acid was added
2-methylbut-3-yn-2-amine (7.6 mg, 0.091 mmol). After 30 minutes,
1.0 equivalent of DIEA and 0.55 equivalents of PyBOP.RTM. were
added. After stirring the solution for 15 minutes, 0.65 equivalents
of 2-methylbut-3-yn-2-amine were added and the mixture was stirred
for an additional 30 minutes. The solvent was removed in vacuo and
the crude product was purified using prep HPLC (20-45_90 mins) to
afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2-methylbut-3-y-
n-2-yl)acetamide. (22 mg, 0.046 mmol, 33%).
Example 88
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-neopentylacetamid-
e
##STR00118##
[0605] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(70 mg, 0.14 mmol), PyBOP.RTM. (40 mg, 0.077 mmol), DIEA (24 .mu.L,
0.14 mmol) in dry CH.sub.2Cl.sub.2:DMF (2:0.1 mL) was stirred at RT
for 15 minutes. To this solution of activated acid was added
2,2-dimethylpropan-1-amine (7.9 mg, 0.091 mmol). After 30 minutes,
1.0 equivalent of DIEA and 0.55 equivalents of PyBOP.RTM. were
added. After stirring the solution for 15 minutes, 0.65 equivalents
of 2,2-dimethylpropan-1-amine were added and the mixture was
stirred for an additional 30 minutes. The solvent was removed in
vacuo and the crude product was purified using prep HPLC (25-50_90
mins) to afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-neopentylacetami-
de. (40 mg, 0.083 mmol, 59%).
Example 89
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(prop-2-ynyl)acet-
amide
##STR00119##
[0607] A suspension of
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid
(70 mg, 0.14 mmol), PyBOP.RTM. (40 mg, 0.077 mmol), DIEA (24 .mu.L,
0.14 mmol) in dry CH.sub.2Cl.sub.2:DMF (2:0.1 mL) was stirred at RT
for 15 minutes. To this solution of activated acid was added
prop-2-yn-1-amine (5.0 mg, 0.091 mmol). After 30 minutes, 1.0
equivalent of DIEA and 0.55 equivalents of PyBOP.RTM. were added.
After stirring the solution for 15 minutes, 0.65 equivalents of
prop-2-yn-1-amine were added and the mixture was stirred for an
additional 30 minutes. The solvent was removed in vacuo and the
crude product was purified using prep HPLC (15-28_90 mins and
0-15_90 mins) to afford
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(prop-2-ynyl)ace-
tamide. (14 mg, 0.031 mmol, 22%).
Example 90
2-Bromo-N-isopropylacetamide
##STR00120##
[0609] A solution of iso-propyl amine (5.0 g, 7.20 mL, 84.6 mmole)
in 63 mL of ethylene dichloride was cooled to -10.degree. C. To
this was added a solution of .alpha.-bromoacetylbromide (8.53 g,
3.68 mL, 42.3 mmole) in 10.5 mL of ethylene dichloride. The
reaction mixture was stirred for 10 mins. The iso-propylammonium
hydrobromide was filtered from the mixture and the filtrate then
concentrated in vacuo to give 2-bromo-N-isopropylacetamide as a
white solid. (5.30 g, 29.4 mmol 70%).
Example 91
tert-Butyl
5-(2-(3-(2-(isopropylamino)-2-oxoethoxy)phenyl)quinazolin-4-yla-
mino)-1H-indazole-1-carboxylate
##STR00121##
[0611] A solution of tert-butyl
5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
(0.3 g, 0.66 mmol), N-isopropylbromoacetamide (0.132 g, 0.726
mmole), and K.sub.2CO.sub.3 (0.183 g, 1.32 mmole) in DMF (3.6 mL)
was heated overnight at 30.degree. C. The crude product was poured
onto ice-water (ca. 50 mL) and the suspension was stirred for
approximately 0.5 h, filtered and dried (Na.sub.2SO.sub.4). The
crude product was recrystallized from absolute EtOH (10 mL) to
afford tert-butyl
5-(2-(3-(2-(isopropylamino)-2-oxoethoxy)-phenyl)quinazolin-4-ylamino)-1H--
indazole-1-carboxylate (0.160 g, mmol, 45%).
Example 92
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropylacetamid-
e
##STR00122##
[0613] A solution of tert-butyl
5-(2-(3-(2-(isopropylamino)-2-oxoethoxy)phenyl)-quinazolin-4-ylamino)-1H--
indazole-1-carboxylate (4.30 g, 7.79 mmole) in TFA (20 mL) and
CH.sub.2Cl.sub.2 (20 mL) was stirred at room temperature for 1 h.
The reaction mixture was concentrated in vacuo, and to the crude
residue was added ca. 50 mL Et.sub.2O. The resulting bright yellow
suspension was stirred for 15 minutes and filtered and dried giving
2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropylacetami-
de trifluroacetate salt. (4.1 g, mmol, %).
Example 93
4,5-Dimethoxy-2-nitrobenzamide
##STR00123##
[0615] To a suspension of 4,5-dimethoxy-2-nitrobenzoic acid (4.95
g, 21.8 mmol) in anhydrous benzene (30 mL) was added SOCl.sub.2
(1.75 mL). The resulting mixture was heated at 75.degree. C. for
3.5 h. The solvent was evaporated under reduced pressure and the
residue was dried under high vacuum. The residue was dissolved in
anhydrous THF (30 mL) and cooled to 0.degree. C. To the cooled
solution was added a saturated solution of ammonia in THF (ca. 50
mL). A precipitate began to form and stirring was continued for 12
hours at RT. The solvent was removed under reduced pressure and the
residue was dried under high vacuum to give
4,5-dimethoxy-2-nitrobenzamide which was used without further
purification (6.0 g). HPLC retention time 4.438 mins.
Example 94
2-Amino-4,5-dimethoxybenzamide
##STR00124##
[0617] A suspension of 4,5-dimethoxy-2-nitrobenzamide (5.8 g, 25.6
mmol) in a 1:1 mixture of DME/MeOH (total volume 200 ml) and 10%
Pd/C (0.7 g) was hydrogenated at RT using a balloon filled with
hydrogen gas. The reaction was stirred for 16 h and the reaction
mixture filtered through Celite.RTM.. The pad of Celite.RTM. was
washed with a 1:1 mixture of MeOH/CH.sub.2Cl.sub.2 (200 mL). The
filtrate was then concentrated in vacuo and dried under high vacuum
overnight to give 2-amino-4,5-dimethoxybenzamide. (5.0 g, 25.5
mmol, 99%). HPLC retention time 2.303 mins.
Example 95
4,5-Di-methoxy-2-(3-fluoro-4-(phenyl)phenyl)benzamide
##STR00125##
[0619] To a solution of 2-amino-4,5-dimethoxybenzamide (3.1 g, 15.8
mmol) in CHCl.sub.3 (100 mL) was added acid chloride (3.41 g, 15.8
mmol) as a solution in CHCl.sub.3 (40 mL) and pyridine (12 mL). The
resulting mixture was stirred at RT for 16 h. The mixture was then
heated at 55.degree. C. for 2 h. The volatiles were removed in
vacuo and the residue was triturated with water/1N HCl resulting in
a solid which was washed with 1N HCl and water. The solid was dried
under vacuum and washed with CH.sub.2Cl.sub.2 and dried under
vacuum to give the desired product which was used directly in the
next step (3.0 g). HPLC retention time 8.33 mins.
Example 96
2-(3-fluoro-4-(phenyl)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one
##STR00126##
[0621] A suspension of the
4,5-Di-methoxy-2-(3-fluoro-4-(phenyl)phenyl)-benzamide (4.25 g) in
2N NaOH (120 mL) was heated at 105.degree. C. for 5 h. The mixture
was allowed to cool to RT. The mixture was neutralized with 6N HCl
with cooling. A solid separated out which was collected via
filtration and washed with Et.sub.2O and hexane to give the desired
product
2-(3-fluoro-4-(phenyl)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one
(4.00 g, 10.6 mmol, 67% over two steps). HPLC retention time 7.9
mins.
Example 97
2-(3-fluoro-4-(phenyl)phenyl)-6-hydroxy-7-methoxyquinazolin-4(3H)-one
##STR00127##
[0623] A mixture of
2-(3-fluoro-4-(phenyl)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one
(3.83 g, 10.2 mmol) and methionine (2.1 g, 14.1 mmol) in
methanesulfonic acid was heated 110.degree. C. for 4 h. Additional
methionine (0.75 g) was added and heating was continued for another
1.5 h. The mixture was allowed to cool to RT and was poured into
ice-water (300 mL). A solid separated out, which was collected via
filtration. The solid was suspended in sat. NaHCO.sub.3 and the
after the effervescence subsided the solid was again collected via
filtration. The solid was washed with water and EtOH to give the
desired product
2-(3-fluoro-4-(phenyl)phenyl)-6-hydroxy-7-methoxyquinazolin-4(3H)-one
(3.2 g, 8.83 mmol, 87%). HPLC retention time 7.06 mins.
Example 98
2-(3-fluoro-4-(phenyl)phenyl)-7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl
acetate
##STR00128##
[0625] A mixture of
2-(3-fluoro-4-(phenyl)phenyl)-6-hydroxy-7-methoxyquinazolin-4(3H)-one
(3.2 g, 8.83 mmol), Ac.sub.2O (40 mL) and pyridine (5 mL) was
heated at 105.degree. C. for 4 h. The mixture was poured onto
ice-water (300 mL). The mixture was stirred for 1 h, upon which the
solid which had formed was collected via filtration. The solid was
washed with water and EtOH and dried under vacuum to give the
desired product
2-(3-fluoro-4-(phenyl)phenyl)-7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl
acetate. MS 405.2 (M+1) HPLC retention time 8.23 mins.
Example 99
4-chloro-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-6-yl
acetate
##STR00129##
[0627] A suspension of
2-(3-fluoro-4-(phenyl)phenyl)-7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl
acetate (3.0 g, 7.42 mmol) in SOCl.sub.2 (60 mL) with DMF (1.4 mL)
was heated at reflux for 5 h. the mixture was allowed to cool to RT
and the volatiles were removed in vacuo. The residue was taken up
in CHCl.sub.3 (300 mL) and washed with water (100 mL), sat.
NaHCO.sub.3 (100 mL), water (100 mL) and brine (100 mL). The
organic layer was dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to give the desired product
4-chloro-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-6-yl
acetate (3.14 g, 7.42 mmol, 100%). HPLC retention time 11.30
minutes (5-95-13 method).
Example 100
tert-butyl
5-(6-acetoxy-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin--
4-ylamino)-1H-indazole-1-carboxylate
##STR00130##
[0629] A mixture of
4-chloro-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-6-yl
acetate (3.14 g, 7.42 mmol) and tert-butyl
5-amino-1H-indazole-1-carboxylate (1.85 g, 7.93 mmol) in IPA (180
mL) was heated at 95.degree. C. for 5 h. The mixture was allowed to
cool to RT and the solid was collected via filtration. The solid
was subjected to flash chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2/MeOH) to give the desired compound tert-butyl
5-(6-acetoxy-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-
-1H-indazole-1-carboxylate (2.70 g, 4.36 mmol, 59%). MS 620.4
(M+1). HPLC retention time 8.10 mins (5-95-13 method).
Example 101
tert-butyl
5-(2-(3-fluoro-4-(phenyl)phenyl)-6-hydroxy-7-methoxyquinazolin--
4-ylamino)-1H-indazole-1-carboxylate
##STR00131##
[0631] A mixture of tert-butyl
5-(6-acetoxy-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-
-1H-indazole-1-carboxylate (2.6 g) and 28% NH.sub.4OH (2.8 mL) in
MeOH (160 mL) was stirred at RT for 24 h. A solid separated out
which was collected via filtration. The solid was triturated with
hexane and dried under vacuum to give the desired compound
tert-butyl
5-(2-(3-fluoro-4-(phenyl)phenyl)-6-hydroxy-7-methoxyquinazolin-4-ylamino)-
-1H-indazole-1-carboxylate (0.6 g). MS 578.4 (M+1). HPLC retention
time 7.66 mins.
Example 102
tert-butyl
5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyqu-
inazolin-4-ylamino)-1H-indazole-1-carboxylate
##STR00132##
[0633] A mixture of tert-butyl
5-(2-(3-fluoro-4-(phenyl)phenyl)-6-hydroxy-7-methoxyquinazolin-4-ylamino)-
-1H-indazole-1-carboxylate (0.61 g, 1.06 mmol), 1-bromo-2-chloro
ethane (0.475 g, 3.31 mmol) and K.sub.2CO.sub.3 (0.533 g, 3.86
mmol) in DMF (5 mL) was heated at 85.degree. C. for 2.5 h. the
mixture was allowed to cool to RT upon which, it was poured into
water. A solid separated out which was collected via filtration and
dried under vacuum. The residue was purified via preparative TLC
(SiO.sub.2, CH.sub.2Cl.sub.2:MeOH 9:1) to give the desired compound
tert-butyl
5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-
-ylamino)-1H-indazole-1-carboxylate (0.37 g, 0.578 mmol, 55%). MS
640.3 (M+1 Cl isotope pattern).
Example 103
2-(3-fluoro-4-(phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(4-methyl-
piperazin-1-yl)ethoxy)quinazolin-4-amine
##STR00133##
[0635] A mixture of
5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-
-ylamino)-1H-indazole-1-carboxylate (0.35 g, 0.55 mmol) and
4-methyl piperazine in DMSO (1.5 mL) was heated at 85.degree. C.
for 3 h. The mixture was allowed to cool to RT, upon which it was
poured into water (100 mL). The solid that formed was collected via
filtration and purified by preparative TLC (SiO.sub.2,
CH.sub.2Cl.sub.2:MeOH 9:1) to give the desired compound. The lower
running spot was isolated and then taken up in CH.sub.2Cl.sub.2 (6
mL) and TFA (5 mL). The mixture was stirred for 2.5 h at RT. The
volatiles were removed in vacuo to give a solid which was
triturated with Et.sub.2O, filtered and dried under vacuum to give
the desired product
2-(3-fluoro-4-(phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(4-methy-
lpiperazin-1-yl)ethoxy)quinazolin-4-amine (0.111 g, 0.184 mmol,
33%). MS 604.5 (M+1). HPLC retention time 5.10 mins.
Example 104
6-(2-(dimethylamino)ethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-N-(1H-indazol-5--
yl)-7-methoxyquinazolin-4-amine
##STR00134##
[0637] To an ice-cold solution of
5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-
-ylamino)-1H-indazole-1-carboxylate (0.26 g, 0.55 mmol) in DMSO (3
mL) was bubbled dimethylamine for 3-4 minutes. The mixture was
heated at 85.degree. C. for 2 h. The mixture was allowed to cool to
RT, upon which it was poured into water (100 mL). The solid that
formed was collected via filtration and purified by preparative TLC
(SiO.sub.2, CH.sub.2Cl.sub.2:MeOH 9:1) to give the desired
compound. The purified compound was taken up in CH.sub.2Cl.sub.2 (5
mL) and TFA (5 mL). The mixture was stirred for 3 h at RT. The
volatiles were removed in vacuo to give a solid which was dried
under vacuum to give the desired product
6-(2-(dimethylamino)ethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-N-(1H-indazol-5-
-yl)-7-methoxyquinazolin-4-amine (0.173 g, 0.315 mmol, 57%). MS
548.5 (M+). HPLC retention time 5.38 mins.
Example 105
2-(3-fluoro-4-(phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(pyrrolid-
in-1-yl)ethoxy)quinazolin-4-amine
##STR00135##
[0639] A mixture of
5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-
-ylamino)-1H-indazole-1-carboxylate (0.200 g, 0.31 mmol) and
pyrrolidine (0.385 g, 5.41 mmol) in DMSO (1.5 mL) was heated at
75.degree. C. for 1.5 h. The mixture was allowed to cool to RT,
upon which it was poured into water (100 mL). The solid that formed
was collected via filtration and purified by preparative TLC
(SiO.sub.2, CH.sub.2Cl.sub.2:MeOH 9:1) to give the desired compound
2-(3-fluoro-4-(phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(pyrroli-
din-1-yl)ethoxy)quinazolin-4-amine (0.15 g, 0.261 mmol, 84%). MS
575.4 (M+1) HPLC retention time 5.40 mins.
Example 106
4,5-Di-methoxy-2-(3-phenyl)pheny)benzamide
##STR00136##
[0641] To a mixture of 2-amino-4,5-dimethoxybenzamide (8.42 g,
38.86 mmole) and pyridine (11.64 g, 147.4 mmole) in CHCl.sub.3 (180
mL) was added 3-phenylbenzoyl chloride (7.23 g, 36.86 mmole) and
the reaction was stirred at RT for 5 h. The volatiles were removed
in vacuo and the product 2-(benzoylamino)-4,5-dimethoxybenzamide
was used immediately without future purification. HPLC retention
time 7.92 mins.
Example 107
2-[(3-phenyl)phenyl]-6,7-dimethoxyquinazolin-4(3H)-one
##STR00137##
[0643] A mixture of 2 N NaOH (185 mL, 370 mmole) and
4,5-di-methoxy-2-(3-phenyl)pheny)benzamide (38.9 mmole) was stirred
under reflux for 16 h. The mixture was cooled and then pH adjusted
to 7 with 1 N HCl. The crude product was filtered from solution,
and the cake was washed with ether, hexane and dried under vacuum
to give 2-[(3-phenyl)phenyl]-6,7-dimethoxyquinazolin-4(3H)-one
(9.97 g, 27.82 mmole, 76% over two steps). HPLC retention time 7.23
mins.
Example 108
2-[(3-phenyl)phenyl]-6-hydroxy-7-methoxyquiazolin-4(3H)-one
##STR00138##
[0645] To a solution of
2-[(3-phenyl)phenyl]-6,7-dimethoxyquinazolin-4(3H)-one (9.97 g,
27.8 mmole) in methanesulfonic acid (100 mL) was added L-methionine
(5.00 g, 33.49 mmoles) and the reaction was stirred at 100.degree.
C. for 24 h. The solution was cooled to RT and poured onto
ice-water (800 mL) and the resulting precipitate was filtered and
washed with water. To the crude product was added ethanol (400 mL)
and the suspension was stirred at 60.degree. C. for 1 h. The
product was then filtered and the cake was washed with ether,
hexane and dried under vacuum to afford
2-[(3-phenyl)phenyl]-6-hydroxy-7-methoxyquiazolin-4(3H)-one (3.84
g, 11.15 mmole, 40%). HPLC retention time 6.37 mins.
Example 109
2-[(3-phenyl)phenyl]-7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl
acetate
##STR00139##
[0647] To a mixture of
2-[(3-phenyl)phenyl]-6-hydroxy-7-methoxyquiazolin-4(3H)-one (3.40
g, 9.87 mmole) in acetic anhydride (40 mL, 43.2 g, 423.16 mmole)
was added pyridine (4 mL, 3.91 g, 49.46 mmole) and the reaction was
stirred at 105.degree. C. for 3 h. The suspension was cooled to RT
and poured onto ice-water (800 mL) and stirred for 20 min. The
crude product was filtered, washed with water and dried under
vacuum to give
2-[(3-phenyl)phenyl]-7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl
acetate (186-036, 3.6 g, 9.32 mmole, 94%). HPLC retention time 7.81
mins.
Example 110
4-chloro-2-[(3-phenyl)phenyl]-7-methoxyquinazolin-6-yl acetate
##STR00140##
[0649] To a mixture of
2-[(3-phenyl)phenyl]-7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl
acetate (3.6 g, 9.32 mmole) in SOCl.sub.2 (40 mL) was added DMF (1
mL) and the reaction was stirred at reflux for 16 h. The mixture
was cooled to RT and then the volatiles were removed in vacuo. The
crude product was dissolved in CHCl.sub.3 (300 mL) and washed with
saturated NaHCO.sub.3 solution (3.times.150 mL), water (2.times.150
mL) and brine (1.times.150 mL) and dried with Na.sub.2SO.sub.4. The
solution was concentrated in vacuo to yield
4-chloro-2-[(3-phenyl)phenyl]-7-methoxyquinazolin-6-yl acetate (4.0
g, 9.88 mmole). HPLC retention time 11.12 mins. (5-95-13
method).
Example 111
tert-butyl
5-(6-acetoxy-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino-
)-1H-indazole-1-carboxylate
##STR00141##
[0651] A mixture of
4-chloro-2-[(3-phenyl)phenyl]-7-methoxyquinazolin-6-yl acetate
(4.00 g, 9.88 mmole), tert-butyl 5-amino-1H-indazole-1-carboxylate
(2.42 g, 10.37 mmole) in iso-propanol (130 mL) was stirred at
95.degree. C. for 2 h. The reaction was cooled to RT and the crude
product was filtered and then washed with ether, iso-propanol, and
hexane and dried under vacuum to give tert-butyl
5-(6-acetoxy-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indaz-
ole-1-carboxylate (4.33 g, 7.20 mmole, 77% over two steps). MS 602
(M+1). HPLC retention time 6.47 mins.
Example 112
5-(2-[(3-phenyl)phenyl]-6-hydroxy-7-methoxyquinazolin-4-ylamino)-1H-indazo-
le-1-carboxylate
##STR00142##
[0653] To a mixture of tert-butyl
5-(6-acetoxy-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indaz-
ole-1-carboxylate (4.30 g, 7.15 mmole) in CH.sub.3OH (300 mL) was
added 28% NH.sub.4OH, and the reaction was stirred at RT for 16 h.
The solution was concentrated in vacuo and the resulting solid was
triturated with toluene and then hexane, followed by filtration to
give tert-butyl
5-(2-[(3-phenyl)phenyl]-6-hydroxy-7-methoxyquinazolin-4-ylamino)-1H-indaz-
ole-1-carboxylate (4.40 g, 7.87 mmole). MS 560 (M+1). HPLC
retention time 7.62 mins.
Example 113
tert-butyl
5-[6-(2-tert-butoxy-2-oxoethoxy)-2-(3-phenyl)phenyl]-7-methoxyq-
uinazolin-4-ylamino)-1H-indazole-1-carboxylate
##STR00143##
[0655] A mixture of tert-butyl
5-(2-[(3-phenyl)phenyl]-6-hydroxy-7-methoxyquinazolin-4-ylamino)-1H-indaz-
ole-1-carboxylate (1.0 g, 1.79 mmole), tert-butylbromoacetate
(0.174 g, 0.132 mL, 0.895 mmole), potassium carbonate (0.99 g, 7.16
mmole) in DMF (20 mL) was stirred at 80.degree. C. for 2 h. Then, a
second portion of tert-butylbromoacetate (0.174 g, 0.132 mL, 0.895
mmole) was added and the reaction for stirred for an additional 2 h
at 80.degree. C. The mixture was cooled to RT and the volatiles
were removed in vacuo. The crude product was partitioned between
dichloromethane and water and the organic layer was dried with
sodium sulfate and concentrated in vacuo. The crude product
tert-butyl
5-[6-(2-tert-butoxy-2-oxoethoxy)-2-(3-phenyl)phenyl]-7-methoxyquinazolin--
4-ylamino)-1H-indazole-1-carboxylate was used immediately without
further purification. MS 618 (M-.sup.tBu+1). HPLC retention time
8.48 mins.
Example 114
2-(4-(1H-indazol-5-ylamino)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-6-ylo-
xy)acetic Acid
##STR00144##
[0657] To tert-butyl
5-[6-(2-tert-butoxy-2-oxoethoxy)-2-(3-phenyl)phenyl]-7-methoxyquinazolin--
4-ylamino)-1H-indazole-1-carboxylate (1.79 mmole) was added TFA (15
mL) at RT, and the solution was stirred for 2 h. The volatiles were
removed in vacuo and the crude product was then triturated with
ether, filtered and dried under vacuum to give
2-(4-(1H-indazol-5-ylamino)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-6-yl-
oxy) acetic acid (0.775 g, 1.50 mmole, 84% over 2 steps). MS 518
(M+1). HPLC retention time 5.95 mins.
Example 115
2-(4-(1H-indazol-5-ylamino)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-6-ylo-
xy)-1-(4-methylpiperazin-1-yl)ethanone
##STR00145##
[0659] To a mixture of
2-(4-(1H-indazol-5-ylamino)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-6-yl-
oxy)acetic acid (0.25 g, 0.48 mmole) in DMF (1 mL)/CH.sub.2Cl.sub.2
(7 mL) was added PyBOP.RTM. (0.25 g, 0.48 mmole), and DIEA (0.186
g, 0.251 mL, 1.44 mmole). The mixture was then stirred for 15
minutes and 1-methylpiperazine (0.048 g, 0.053 mL, 0.48 mmole) was
added and the reaction was stirred at RT for 3 h. The volatiles
were then removed in vacuo. Upon adding CH.sub.2Cl.sub.2, the crude
product precipitated and was subsequently filtered. The cake was
washed with ether, hexane, CH.sub.3OH, CH.sub.2Cl.sub.2 and finally
hexane. The crude product was purified by reverse phase HPLC (25 to
55% CH.sub.3CN/H.sub.2O, 90 minute run time) to yield
2-(4-(1H-indazol-5-ylamino)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-6-yl-
oxy)-1-(4-methylpiperazin-1-yl)ethanone (0.015 g, 5%). MS 600
(M+1). HPLC retention time 5.22 mins.
Example 116
tert-butyl
5-(2-[(3-(phenyl)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazoli-
n-4-ylamino)-1H-indazole-1-carboxylate
##STR00146##
[0661] A mixture of tert-butyl
5-(2-[(3-phenyl)phenyl]-6-hydroxy-7-methoxyquinazolin-4-ylamino)-1H-indaz-
ole-1-carboxylate (0.055 g, 0.098 mmole), 2-bromoethyl methyl ether
(0.031 g, 0.021 mL, 0.226 mmole), K.sub.2CO.sub.3 (0.036 g, 0.26
mmole), and DMF (2.5 mL) was stirred at 85.degree. C. for 3.5 h.
The mixture was poured onto ice-water (200 mL) and the crude
product was filtered. The product was then dissolved in ether and
was washed with water and the organic layer was concentrated in
vacuo. The crude product was purified by preparative TLC
(SiO.sub.2, 7:2.6:0.4 (CH.sub.2Cl.sub.2:EtOAc:CH.sub.3OH) to give
tert-butyl
5-(2-[(3-(phenyl)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamin-
o)-1H-indazole-1-carboxylate (0.110 g). HPLC retention time 7.89
mins.
Example 117
2-[(3-(phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-methoxyethoxy)qui-
nazolin-4-amine
##STR00147##
[0663] TFA (4 mL) was added to tert-butyl
5-(2-[(3-(phenyl)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamin-
o)-1H-indazole-1-carboxylate (0.110 g, mmole) and the reaction was
stirred at RT for 2 h. The solution was concentrated in vacuo and
then azeotroped from hexane (1.times.) The crude product was
triturated with ether and filtered, dried under vacuum to give
2-[(3-(phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-methoxyethoxy)qu-
inazolin-4-amine (0.024 g, 0.046 mmole, 47% over 2 steps). MS 518.4
(M+1). HPLC retention time 6.47 mins.
Example 118
tert-butyl
5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin--
4-ylamino)-1H-indazole-1-carboxylate
##STR00148##
[0665] A mixture of tert-butyl
5-(2-[(3-phenyl)phenyl]-6-hydroxy-7-methoxyquinazolin-4-ylamino)-1H-indaz-
ole-1-carboxylate (1.5 g, 2.68 mmole), 1-bromo-2-chloroethane (1.32
g, 0.76 mL, 9.17 mmole), K.sub.2CO.sub.3 (1.55 g, 11.21 mmole), and
DMF (15 mL) was stirred at 85.degree. C. for 2.5 h. The mixture was
poured onto ice-water and the crude product was filtered. The
product was then dissolved in a mixture of CH.sub.2Cl.sub.2 and
CH.sub.3OH and the solution was concentrated in vacuo to give
tert-butyl
5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-
-1H-indazole-1-carboxylate (1.55 g, 2.49 mmol, 93%). HPLC retention
time 8.22 mins.
Example 119
6-(2-(dimethylamino)ethoxy)-N-(1H-indazol-5-yl)-7-methoxy-2-(3-(phenyl)phe-
nyl)quinazolin-4-amine
##STR00149##
[0667] A solution of tert-butyl
5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-
-1H-indazole-1-carboxylate (0.25 g, 0.40 mmole) in DMSO (3 mL) was
cooled to 0.degree. C. To this was added dimethylamine gas (bubbled
into solution for 15 minutes) and the reaction was slowly heated to
85.degree. C. and stirred for 2 h. The mixture was poured onto
ice-water and the crude product was filtered. The product was then
dissolved in a mixture of CH.sub.2Cl.sub.2 and CH.sub.3OH and the
solution was concentrated in vacuo. The residue was purified via
preparative TLC (SiO.sub.2, 10% CH.sub.2Cl.sub.2/CH.sub.3OH). To
the crude product was added TFA (5 mL) and the reaction was stirred
at RT for 1 h. The solution was concentrated in vacuo and the
residue was triturated with ether, filtered and dried under vacuum
to give
6-(2-(dimethylamino)ethoxy)-N-(1H-indazol-5-yl)-7-methoxy-2-(3-(phenyl)
phenyl)quinazolin-4-amine (0.096 g, 0.18 mmole, 45% over 2 steps).
MS 531 (M+1). HPLC retention time 5.18 mins.
Example 120
2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(pyrrolidin-1-yl)e-
thoxy)quinazolin-4-amine
##STR00150##
[0669] To a mixture of tert-butyl
5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-
-1H-indazole-1-carboxylate (0.25 g, 0.040 mmole) in DMSO (2 mL) was
added pyrrolidine (0.143 g, 0.16 mL, 2.00 mmole) and the reaction
was stirred at 85.degree. C. for 4 h. The mixture was poured onto
ice-water and the crude product was filtered. The product was then
dissolved in a mixture of CH.sub.2Cl.sub.2 and CH.sub.3OH and the
solution was concentrated in vacuo. The residue was purified via
preparative TLC (SiO.sub.2, 10% CH.sub.2Cl.sub.2/CH.sub.3OH) to
give
2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(pyrrolidin-1-yl)-
ethoxy)quinazolin-4-amine (0.042 g, 0.075 mmole, 19%). MS 557
(M+1). HPLC retention time 5.34 mins.
Example 121
2-((2-(4-(1H-indazol-5-ylamino)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-6-
-yloxy)ethyl)(methyl)amino)-N,N-dimethylacetamide
##STR00151##
[0671] To a mixture of tert-butyl
5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-
-1H-indazole-1-carboxylate (0.25 g, 0.40 mmole) in DMSO (2 mL) was
added N,N-dimethyl-2-(methylamino)acetamide (0.232 g, 2.00 mmole)
and the reaction was stirred at 85.degree. C. for 4 h. The mixture
was poured onto ice-water and the crude product was filtered. The
product was then dissolved in a mixture of CH.sub.2Cl.sub.2 and
CH.sub.3OH and the solution was concentrated in vacuo. The residue
was purified via preparative TLC (SiO.sub.2, 10%
CH.sub.2Cl.sub.2/CH.sub.3OH). To the product was added TFA (4 mL)
and the reaction was stirred at RT for 2 h. The solution was
concentrated in vacuo and the residue was triturated with ether,
filtered and dried under vacuum to give
2-((2-(4-(1H-indazol-5-ylamino)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin--
6-yloxy) ethyl)(methyl)amino)-N,N-dimethylacetamide (0.178 g, 0.30
mmole, 74%). MS 602.6 (M+1). HPLC retention time 5.24 mins.
Example 122
tert-butyl
5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)-
ethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
##STR00152##
[0673] To a mixture of tert-butyl
5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-
-1H-indazole-1-carboxylate (0.30 g, 0.44 mmole) in DMSO (2 mL) was
added 1-methylpiperazine (0.903 g, 1.00 mL, 9.02 mmole) and the
reaction was stirred at 85.degree. C. for 3 h. The mixture was
poured onto ice-water (100 mL) and the crude product was filtered.
The product was then dissolved in a mixture of CH.sub.2Cl.sub.2 and
CH.sub.3OH and the solution was concentrated in vacuo. The residue
was purified via preparative TLC (SiO.sub.2, 10%
CH.sub.2Cl.sub.2/CH.sub.3OH-with 0.1% NH.sub.4OH) to give
tert-butyl
5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)qui-
nazolin-4-ylamino)-1H-indazole-1-carboxylate which was taken on to
the next step. HPLC retention time 6.00 mins.
Example 123
2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(4-methylpiperazin-
-1-yl)ethoxy)quinazolin-4-amine
##STR00153##
[0675] TFA (4 mL) was added to
5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)qui-
nazolin-4-ylamino)-1H-indazole-1-carboxylate and the reaction was
stirred at RT for 1.5 h. The solution was concentrated in vacuo and
the crude product was triturated with ether and filtered, dried
under vacuum to give
2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(4-methylpip-
erazin-1-yl)ethoxy)quinazolin-4-amine (0.166 g, 0.283 mmole, 64%
over two steps). MS 586.4 (M+1). HPLC retention time 5.06 mins.
Example 124
2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-morpholinoethoxy)q-
uinazolin-4-amine
##STR00154##
[0677] To a mixture of tert-butyl
5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-
-1H-indazole-1-carboxylate (0.25 g, 0.40 mmole) in DMSO (2 mL) was
added morpholine (1.32 g, 1.33 mL, 15.2 mmole) and the reaction was
stirred at 85.degree. C. for 48 h. The mixture was poured onto
ice-water and the crude product was filtered. The product was then
dissolved in a mixture of CH.sub.2Cl.sub.2 and CH.sub.3OH and the
solution was concentrated in vacuo. The residue was purified via
preparative TLC (SiO.sub.2, 10% CH.sub.2Cl.sub.2/CH.sub.3OH) to
give
2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-morpholinoethoxy)-
quinazolin-4-amine (0.131 g, 0.20 mmole, 50%). MS 572.2 (M+). HPLC
retention time 5.27 mins.
Example 125
tert-butyl
5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4-methyl-1,4-diazepan-1-
-yl)ethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
##STR00155##
[0679] A mixture of tert-butyl
5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-
-1H-indazole-1-carboxylate (0.25 g, 0.402 mmole),
1-methyl-1,4-diazepane (0.23 g, 0.25 mL, 2.00 mmoles) in DMSO was
stirred at 85.degree. C. for 2.5 h. The suspension was poured onto
ice-water, filtered and re-dissolved in a mixture of
CH.sub.2Cl.sub.2 and CH.sub.3OH and the solution was concentrated
in vacuo. The residue was purified via preparative TLC (SiO.sub.2,
10% CH.sub.2Cl.sub.2/CH.sub.3OH-with 0.1% NH.sub.4OH) to give
tert-butyl
5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4-methyl-1,4-diazepan-1-yl)ethoxy-
)quinazolin-4-ylamino)-1H-indazole-1-carboxylate which taken on
directly to the next step. HPLC retention time 5.96 mins.
Example 126
2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(4-methyl-1,4-diaz-
epan-1-yl)ethoxy)quinazolin-4-amine
##STR00156##
[0681] To a solution of
5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4-methyl-1,4-diazepan-1-yl)ethoxy-
)quinazolin-4-ylamino)-1H-indazole-1-carboxylate in
CH.sub.2Cl.sub.2 (2 mL) was added HCl as a 4.0 M solution in 1,4
dioxane (8 mL) and the reaction was stirred at RT for 5 h. The
volatiles were removed in vacuo and the crude product was washed
with hexane and dried under vacuum to yield
2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(4-methyl-1-
,4-diazepan-1-yl)ethoxy)quinazolin-4-amine (0.063 g, 0.105 mmole,
26% over 2 steps.). MS 600.4 (M+1). HPLC retention time 5.01
mins.
Example 127
5-Methoxy-2-nitrobenzamide
##STR00157##
[0683] To a suspension of 5-methoxy-2-nitrobenzoic acid (7.5 g,
38.0 mmol) in anhydrous benzene (50 mL), was added thionyl chloride
(3.8 mL, 52.05 mmol) followed by the addition of anhydrous DMF (0.4
mL). The resulting reaction mixture was refluxed for 5 h, upon
which the volatiles were removed in vacuo. The residue was
dissolved in anhydrous THF (60 mL) and added to an ice-cold
saturated solution of ammonia in THF (60 mL). The resulting
heterogeneous reaction mixture was allowed to warm room temperature
and stirring was continued at RT for 48 h. The s volatiles were
removed in vacuo and the residue was used without further
purification for next step. HPLC retention time 3.29 mins.
Example 128
5-Methoxy-2-aminobenzamide
##STR00158##
[0685] To a suspension of 5-methoxy-2-nitrobenzamide (38.0 mmol) in
methanol (150 mL), was added 10% Pd-C (1.2 g) under an atmosphere
of argon followed by addition of ammonium formate (18.0 g, 285.4
mmole). T resulting reaction mixture was refluxed for 2.5 h, upon
which, the mixture was allowed to cool to RT and was filtered
through a pad of Celite.RTM.. The filtrate was concentrated under
reduced pressure and the residue was washed with water to give a
solid (4.74 g). The filtrate, was extracted with ethyl acetate
(2.times.300 mL), dried (Na.sub.2SO.sub.4), filtered, concentrated
in vacuo and combined with the previous solid. The resulting solid
was dried under vacuum to give 5-methoxy-2-aminobenzamide (4.74 g,
35.7 mmol, 94%). HPLC retention time 3.16 mins.
Example 129
5-Methoxy-2-(3-nitrophenyl)aminobenzamide
##STR00159##
[0687] To a suspension of 2-amino-5-methoxybenzamide (2.42 g, 14.6
mmol) and pyridine (6 mL) in CHCl.sub.3 (120 mL) was added
3-nitrobenzoyl chloride (3.0 g, 16.1 mmol). The resulting mixture
was stirred at RT for 6 h. The volatiles were removed in vacuo and
the resultant solid was washed with Et.sub.2O to give the
5-Methoxy-2-(3-nitrobenzoyl)aminobenzamide (6.15 g) which was taken
directly on to the next step. HPLC retention time 6.58 mins.
Example 130
6-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one
##STR00160##
[0689] A suspension of the amide from the previous step (6.0 g) in
3N NaOH (160 mL) was heated at 100.degree. C. from 9 h. The mixture
was allowed to cool to RT and stirring was continued overnight at
RT. The mixture was neutralized with 6N HCl to pH 7. A solid
precipitated out and was collected via filtration and dried under
vacuum to give the desired product
6-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one (4.0 g, 13.5 mmol,
95%). HPLC retention time 6.721 min.
Example 131
6-hydroxy-2-(3-nitrophenyl)quinazolin-4(3H)-one
##STR00161##
[0691] To a suspension of
6-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one (3.90 g, 13.1
mmol), in CH.sub.2Cl.sub.2 (30 mL) cooled to -78.degree. C. under
an atmosphere of N.sub.2 was added BBr.sub.3 as a 1.0M solution in
CH.sub.2Cl.sub.2 (20 mL, 20.0 mmol). The resulting mixture was
stirred at -78.degree. C. for 1 h, then allowed to warm to RT upon
which it was stirred for a further 3 h. The mixture was re-cooled
to -78.degree. C. and stirred overnight. The reaction was quenched
by the addition of EtOH (60 mL) and allowed to warm to RT. Stirring
was continued for 1 h at RT, upon which a precipitate formed. Sat.
NaHCO.sub.3 solution was added and the yellow solid was collected
via filtration and washed with Et.sub.2O and EtOH and dried under
vacuum to give 6-hydroxy-2-(3-nitrophenyl)quinazolin-4(3H)-one
(2.96 g, 10.5 mmol, 80%). HPLC retention time 5.588 min.
Example 132
2-(3-nitrophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl acetate
##STR00162##
[0693] A mixture of 6-hydroxy-2-(3-nitrophenyl)quinazolin-4(3H)-one
(2.92 g, 10.3 mmol) Ac.sub.2O (30 mL) and pyridine (4 mL) was
heated at 105.degree. C. for 4 h. The mixture was allowed to cool
to RT and was poured into ice-water (300 mL). The resulting slurry
was stirred for 2-3 h at RT, then the solid was collected via
filtration, washed with water, EtOH and Et.sub.2O and dried under
vacuum to give the product
2-(3-nitrophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl acetate (3.35 g,
10.3 mmol, 100%). HPLC retention time 6.559 min.
Example 133
4-chloro-2-(3-nitrophenyl)quinazolin-6-yl acetate
##STR00163##
[0695] A suspension of
2-(3-nitrophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl acetate (3.30 g,
10.1 mmol) in SOCl.sub.2 (65 mL) was added DMF (2 mL). The mixture
was refluxed for 2.5 h, upon which the volatiles were removed in
vacuo. The residue was taken up in CHCl.sub.3 (450 mL) and washed
with sat NaHCO.sub.3 (200 ml) and water (200 mL). The organic layer
was dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to
give the product 4-chloro-2-(3-nitrophenyl)quinazolin-6-yl acetate
(3.53 g, 10.3 mmol). HPLC retention time 9.748 min.
Example 134
tert-butyl
5-(6-acetoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-
-1-carboxylate
##STR00164##
[0697] A mixture of 4-chloro-2-(3-nitrophenyl)quinazolin-6-yl
acetate (1.63 g, 4.74 mmol) and tert-butyl
5-amino-1H-indazole-1-carboxylate (1.16 g, 4.28 mmol) in IPA (80
mL) were heated at 95.degree. C. for 5 h. The mixture was allowed
to cool to RT, the yellow solid was collected via filtration and
washed with Et.sub.2O to give the product tert-butyl
5-(6-acetoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxy-
late (2.14 g, 3.96 mmol, 84%). HPLC retention time 9.649 min.
Example 135
tert-butyl
5-(6-acetoxy-2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-
-1-carboxylate
##STR00165##
[0699] A mixture of tert-butyl
5-(6-acetoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxy-
late (0.84 g, 1.55 mmol) in MeOH (200 mL) was added 10% Pd/C under
an atmosphere of N.sub.2. The mixture was stirred under an
atmosphere of H.sub.2 (balloon pressure) for 48 h at RT. The
mixture was filtered through a pad of Celite.RTM. washing with
MeOH. The volatiles were removed in vacuo to give tert-butyl
5-(6-acetoxy-2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxy-
late (0.811 g, 1.59 mmol). HPLC retention time 5.51 min.
Example 136
tert-butyl
5-(6-acetoxy-2-(3-(nicotinamido)phenyl)quinazolin-4-ylamino)-1H-
-indazole-1-carboxylate
##STR00166##
[0701] A suspension of tert-butyl
5-(6-acetoxy-2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxy-
late (0.50 g, 0.98 mmol), nicotinoyl chloride hydrochloride (0.224
g, 1.26 mmol) and DIEA (0.45 g, 3.48 mmol) in CH.sub.2Cl.sub.2 (15
mL) was stirred at RT for 7 h. The volatiles were removed in vacuo
and the residue was purified by preparative TLC (SiO.sub.2,
CH.sub.2Cl.sub.2:MeOH 9:1) to give the product tert-butyl
5-(6-acetoxy-2-(3-(nicotinamido)phenyl)quinazolin-4-ylamino)-1H-indazole--
1-carboxylate (0.374 g, 0.608 mmol, 62%).
Example 137
tert-butyl
5-(6-hydroxy-2-(3-(nicotinamido)phenyl)quinazolin-4-ylamino)-1H-
-indazole-1-carboxylate
##STR00167##
[0703] A mixture of
5-(6-acetoxy-2-(3-(nicotinamido)phenyl)quinazolin-4-ylamino)-1H-indazole--
1-carboxylate (0.374 g, 0.607 mmol) and 28% NH.sub.4OH (0.45 mL) in
MeOH (50 mL) was stirred at RT for 24 h. The volatiles were removed
in vacuo and the residue was washed with Et.sub.2O to give the
product tert-butyl
5-(6-hydroxy-2-(3-(nicotinamido)phenyl)quinazolin-4-ylamino)-1H-indazole--
1-carboxylate (0.318 g, 0.554 mmol, 91%).
Example 138
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(dimethylamino)ethoxy)quinazolin-2-yl)-
phenyl)nicotinamide
##STR00168##
[0705] A mixture of
5-(6-hydroxy-2-(3-(nicotinamido)phenyl)quinazolin-4-ylamino)-1H-indazole--
1-carboxylate (0.127 g, 0.221 mmol),
2-chloro-N,N-dimethylethanamine (0.065 g, 0.45 mmol) and
K.sub.2CO.sub.3 (0.131 g, 0.948 mmol) in DMF (2 mL) was heated at
70.degree. C. for 2 h. The mixture was diluted with
CH.sub.2Cl.sub.2 (75 mL), washed with water (10 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo.
[0706] The material was taken up in CH.sub.2Cl.sub.2 (2 mL) and TFA
(3 mL) was added. The mixture was stirred at RT for 3 h. The
volatiles were removed in vacuo and the residue was triturated with
Et.sub.2O and dried under vacuum to give the desired product
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(dimethylamino)ethoxy)quinazolin-2-yl-
)phenyl) nicotinamide (0.077 g, 0.141 mmol, 64%). MS 545.3 (M+1).
HPLC retention time 3.67 mins.
Example 139
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-methoxyethoxy)quinazolin-2-yl)phenyl)n-
icotinamide
##STR00169##
[0708] A mixture of tert-butyl
5-(6-hydroxy-2-(3-(nicotinamido)-phenyl)quinazolin-4-ylamino)-1H-indazole-
-1-carboxylate (0.107 g, 0.186 mmol), 1-bromo-2-methoxyethane
(0.056 g, 0.403 mmol) and K.sub.2CO.sub.3 (0.068 g, 0.492 mmol) in
DMF (1 mL) was heated at 70.degree. C. for 2.5 h. the mixture was
allowed to cool to RT upon which, the mixture was diluted with
CH.sub.2Cl.sub.2 (75 mL), washed with water (10 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo.
[0709] The material was taken up in CH.sub.2Cl.sub.2 (2 mL) and TFA
(3 mL) was added. The mixture was stirred at RT for 3 h. The
volatiles were removed in vacuo and the residue was triturated with
Et.sub.2O and dried under vacuum to give the desired product
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-methoxyethoxy)quinazolin-2-yl)phenyl)-
nicotinamide (0.078 g, 0.147 mmol, 79%). MS 532.4 (M+1). HPLC
retention time 4.5 mins.
Example 140
tert-butyl
5-(2-(3-butyramidophenyl)-6-hydroxyquinazolin-4-ylamino)-1H-ind-
azole-1-carboxylate
##STR00170##
[0711] A mixture of tert-butyl
5-(6-acetoxy-2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxy-
late (0.570 g, 1.12 mmol), butryl chloride (0.18 g, 1.69 mmol), and
DIEA (0.65 g, 5.03 mmol) in CH.sub.2Cl.sub.2 (20 mL) was stirred at
RT for 7 h. the volatiles were removed in vacuo and the residue was
triturated with water. The resultant solid was collected by
filtration, washed with water and dried under vacuum.
[0712] The residue was taken up in MeOH (50 mL) and 28% NH.sub.4OH
(0.9 mL) was added. The mixture was stirred at RT for 24 h. The
volatiles were removed in vacuo and the residue was triturated with
MeOH/Et.sub.2O to give the product tert-butyl
5-(2-(3-butyramidophenyl)-6-hydroxyquinazolin-4-ylamino)-1H-indazole-1-ca-
rboxylate (0.354 g, 0.657 mmol, 59%). HPLC retention time 6.342
min.
Example 141
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(dimethylamino)ethoxy)quinazolin-2-yl)-
phenyl)butyramide
##STR00171##
[0714] To a mixture of tert-butyl
5-(2-(3-butyramidophenyl)-6-hydroxyquinazolin-4-ylamino)-1H-indazole-1-ca-
rboxylate (0.107 g, 0.199 mmol), 2-chloro-N,N-dimethylethanamine
hydrochloride (0.065 g, 0.451 mmol), K.sub.2CO.sub.3 (0.065 g,
0.451 mmol) in DMF (1.2 mL) was heated at 70.degree. C. for 2.5 h.
The mixture was allowed to cool to RT upon which, the mixture was
diluted with CH.sub.2Cl.sub.2 (75 mL), washed with water (10 mL),
dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo.
[0715] The material was taken up in CH.sub.2Cl.sub.2 (2 mL) and TFA
(3 mL) was added. The mixture was stirred at RT for 3 h. The
volatiles were removed in vacuo and the residue was triturated with
Et.sub.2O and dried under vacuum to give the desired product
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(dimethylamino)ethoxy)quinazolin-2-yl-
)phenyl) butyramide (0.037 g, 72.6 mol, 36%). MS 510.4 (M+1). HPLC
retention time 5.16 min.
Example 142
N-(3-(4-(1H-indazol-5-ylamino)-6-(3-(dimethylamino)propoxy)quinazolin-2-yl-
)phenyl)butyramide
##STR00172##
[0717] To a mixture of tert-butyl
5-(2-(3-butyramidophenyl)-6-hydroxyquinazolin-4-ylamino)-1H-indazole-1-ca-
rboxylate (0.106 g, 0.197 mmol),
3-chloro-N,N-dimethylpropan-1-amine (0.081 g, 0.451 mmol),
K.sub.2CO.sub.3 (0.065 g, 0.512 mmol) in DMF (1.2 mL) was heated at
70.degree. C. for 2.5 h. The mixture was allowed to cool to RT upon
which, the mixture was diluted with CH.sub.2Cl.sub.2 (75 mL),
washed with water (10 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The material was purified by preparative TLC
(SiO.sub.2, CH.sub.2Cl.sub.2:MeOH 9:1).
[0718] The purified material was taken up in CH.sub.2Cl.sub.2 (2
mL) and TFA (3 mL) was added. The mixture was stirred at RT for 3
h. The volatiles were removed in vacuo and the residue was
triturated with Et.sub.2O and dried under vacuum to give the
desired product
N-(3-(4-(1H-indazol-5-ylamino)-6-(3-(dimethylamino)propoxy)quinazolin-2-y-
l)phenyl) butyramide (0.057 g, 0.109 mmol, 55%). MS 524.6 (M+1).
HPLC retention time.
Example 143
4,5-Dimethoxy-2-(3-nitrophenyl)aminobenzamide
##STR00173##
[0720] To a suspension of 2-amino-4,5-dimethoxybenzamide (5.05 g,
25.7 mmole) and 3-nitro benzoyl chloride (5.2 g, 28.0 mmole)
CHCl.sub.3 (120 ml) was added pyridine (50 ml) drop wise at RT. The
reaction mixture was stirred at RT for 24 h. The solvent was
removed in vacuo and residue was triturated with Et.sub.2O,
filtered and dried under high vacuum to give 4,
5-dimethoxy-2-(3-nitrophenyl)aminobenzamide, which was used
directly in the next step.
Example 144
6,7-Dimethoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one
##STR00174##
[0722] A suspension of 4,
5-dimethoxy-2-(3-nitrophenyl)aminobenzamide (9.5 g) was taken up in
2 N NaOH (200 mL) and was refluxed for 8 h. The reaction mixture
was cooled to RT and left to stand overnight. The pH adjusted to 7
with 3 N HCl and the mixture was filtered. The filtered solid
washed with water and dried under high vacuum to give
6,7-dimethoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one. (6.2 g, 18.9
mmol, 74% over two steps) HPLC retention time 6.15 mins.
Example 145
6-Hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one
##STR00175##
[0724] A mixture of
6,7-dimethoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one (5.72 g, 17.5
mmol) and L-methionine (3.1 g, 20.7 mmol) in methanesulfonic acid
(40 mL) was heated at 100.degree. C. for 4.5 h. An additional
aliquot of L-methionine (0.45 g, 1.36 mmol) and methanesulfonic
acid (10 mL) were added and the mixture was heated for a further 2
h. The mixture was allowed to cool to RT, poured into ice water
(ca. 500 mL) and was neutralized with sat. NaHCO.sub.3 solution. A
solid separated out which was collected by filtration and dried
under vacuum to give the desired
6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one. (7.3 g).
HPLC retention time 5.486 min.
Example 146
Benzyl 3-(benzyloxy)-4-methoxybenzoate
##STR00176##
[0726] To an ice cold mixture of isovanillic acid 1 (4.3 g, 25.5
mmol) and K.sub.2CO.sub.3 (10.5 g, 0.152 mol) in anhydrous DMF (40
mL) was added benzyl bromide (8.7 g, 6.05 mL, 51.1 mmol). The
resulting reaction mixture stirred at RT overnight. An additional
aliquot of benzyl bromide was added (1.0 ml) and stirring was
continued for 1.5 h. The reaction mixture was poured into brine
(100 mL) and the solid was collected via filtration, washed with
water and dried under high vacuum to give benzyl
3-(benzyloxy)-4-methoxybenzoate as a white solid (7.99 g, 23.0
mmol, 90%).
Example 147
Benzyl 5-(benzyloxy)-4-methoxy-2-nitrobenzoate
##STR00177##
[0728] To a solution of benzyl 3-(benzyloxy)-4-methoxybenzoate
(6.32 g, 18.1 mmol) in Ac.sub.2O (62 mL) cooled to -10.degree. C.
under an atmosphere of N.sub.2 was added fuming HNO.sub.3 (1.5 mL,
37.1 mmol) in one portion. Stirring was continued at -10.degree. C.
for 10 minutes, then at RT for 3 hours. The reaction mixture was
carefully poured into ice-water and the pH adjusted to ca. pH=5
with 5N NaOH, sat. NaHCO.sub.3 and 0.5 NaOH. The mixture was
extracted with CH.sub.2Cl.sub.2 (3.times.200 mL). The combined
organics were dried (Na.sub.2SO.sub.4), filtered and concentrated
in vacuo. The residue was azeotroped with heptane to give benzyl
5-(benzyloxy)-4-methoxy-2-nitrobenzoate as red colored oil (6.55 g,
16.7 mmol, 93%).
Example 148
5-(Benzyloxy)-4-methoxy-2-nitrobenzoic acid
##STR00178##
[0730] To a solution of benzyl
5-(benzyloxy)-4-methoxy-2-nitrobenzoate (1.4 g, 3.56 mmol) in EtOH
(10 mL) was added 1N NaOH (4.27 mL, 4.27 mmol). The mixture was
stirred at RT for 1 h, upon which an additional aliquot of NaOH
(4.27 mL, 4.27 mmol) was added. Stirring was continued at RT
overnight. The mixture was diluted with water (20 mL) and washed
with CH.sub.2Cl.sub.2 (2.times.25 mL). The aqueous layer was
acidified to pH=2 with 0.5 N HCl and extracted with EtOAc
(3.times.50 mL). The combined organics were dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give
5-(benzyloxy)-4-methoxy-2-nitrobenzoic acid (1.02 g, 3.37 mmol,
94%).
Example 149
4-Methoxy-5-benzyloxy-2-nitrobenzamide
##STR00179##
[0732] To a suspension of 4-methoxy-5-benzyloxy-2-nitrobenzoic acid
(10.0 g, 33.3 mmol) in anhydrous THF (100 mL) was added oxalyl
chloride (4.90 mL, 56.2 mmol) followed by one drop of anhydrous
DMF. The mixture was stirred at RT for 16 h, upon which the mixture
was poured into water (300 mL) and ammonium hydroxide (50 mL). A
solid was separated out, which was collected by filtration and
dried under vacuo. The solid was taken up in refluxing methanol
(500 mL) and the insoluble solid was collected via filtration and
dried under vacuum to give 4-methoxy-5-benzyloxy-2-nitrobenzamide
(6.50 g, 21.5 mmol, 65%). HPLC retention time 6.154 min.
Example 150
4-Methoxy-5-benzyloxy-2-aminobenzamide
##STR00180##
[0734] A mixture of 4-methoxy-5-benzyloxy-2-nitrobenzamide (6.60 g,
21.9 mmol) and iron powder (8.14 g, 0.146 mot) in acetic
acid/methanol (80 mL/80 mL) was heated at 85.+-.5.degree. C. for
1.5 h. The reaction mixture was allowed to cool to RT and the iron
was removed by filtration, and volatiles were removed in vacuo. The
residue was taken up in sat. sodium bicarbonate and the mixture was
extracted with ethyl acetate (600 mL.times.3). The combined organic
layers were washed with water (1.times.150 mL), brine (1.times.150
mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo
to give 4-methoxy-5-benzyloxy-2-aminobenzamide (5.2 g, 19.1 mmol,
87%). MS 273.2. (M+). HPLC retention time 4.585 min.
Example 151
4-Methoxy-5-benzyloxy-2-(3-nitrobenzoylamino)benzamide
##STR00181##
[0736] To a suspension of 6-methoxy-7-benzyloxy-2-aminobenzamide
(4.86 g, 17.9 mmol) and pyridine (10 mL) in chloroform (600 mL),
was added 3-nitrobenzoyl chloride (3.60 g, 19.4 mmol) slowly. The
resulting reaction mixture was stirred at room temperature for 24
h, upon which the volatiles were removed under reduced pressure,
and resulting residue was dried under vacuum. The residue upon
trituration with Et.sub.2O gave a light yellow colored solid in
quantitative yield (Note: Possesses some pyridine. HCl). HPLC
retention time 8.384 min.
Example 152
6-(Benzyloxy)-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one
##STR00182##
[0738] A suspension of
4-methoxy-5-benzyloxy-2-(3-nitrobenzoylamino) benzamide (8.00 g,
possesses some pyridinc.HCl) in 4N NaOH (200 mL) was heated at
100.+-.5.degree. C. for 10 h. The reaction mixture was allowed to
cool to room temperature and pH was adjusted to 7-7.5 with 6 N HCl.
A solid separated out, which was collected by filtration, washed
with water (100 mL) and dried under vacuum to give
6-(benzyloxy)-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one (3.22
g, 7.99 mmol, 47% over two steps). MS 404 (M+1) HPLC retention time
8.026 min.
Example 153
6-Hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one
##STR00183##
[0740] To a suspension of
6-(benzyloxy)-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one (3.21
g, 7.95 mmol) in trifluoroacetic acid (45 mL) was heated at
75.+-.5.degree. C. for 2.5 h. The volatiles were removed in vacuo
and residue was taken up with sat. NaHCO.sub.3 solution. A light
yellow colored solid separated out, which was collected via
filtration. The solid was washed with water and dried under vacuum
to give 6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one
(2.38 g, 7.60 mmol, 96%). HPLC retention time 5.486 min.
Example 154
7-Methoxy-2-(3-nitrophenyl)-4-oxo-3,4-dihydroquinazolin-6-ylacetate
##STR00184##
[0742] A mixture of
6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one (2.3 g,
7.34 mmol), Ac.sub.2O (40 mL) and pyridine (4 mL) were heated at
105.degree. C. for 3.5 h. The reaction mixture was allowed to cool
and poured into ice-water (ca. 300 mL) and the resulting slurry was
stirred for 2 h. The solid was collected by filtration and washed
with water, EtOH and Et.sub.2O and dried under high vacuum to give
7-methoxy-2-(3-nitrophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl
acetate. (2.6 g, 7.31 mmol, 99%). HPLC retention time 6.24 min.
Example 155
4-Chloro-7-methoxy-2-(3-nitrophenyl)quinazolin-6-ylacetate
##STR00185##
[0744] A mixture of the
7-methoxy-2-(3-nitrophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl
acetate (1.70 g, 4.79 mmol), thionyl chloride (30 mL) and anhydrous
DMF (0.6 mL) were refluxed for 2.5 h. The volatiles were removed in
vacuo and the residue dissolved in CH.sub.2CL.sub.2 (500 mL) and
was washed with water, sat. NaHCO.sub.3, water and brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo to
4-chloro-7-methoxy-2-(3-nitrophenyl)quinazolin-6-yl acetate. (1.6
g, 4.23 mmol, 88%). HPLC retention time 9.75 min.
Example 156
tert-Butyl
5-(6-acetoxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1-
H-indazole-1-carboxylate
##STR00186##
[0746] A mixture of
4-chloro-7-methoxy-2-(3-nitrophenyl)quinazolin-6-yl acetate (1.60
g, 4.23 mmol) and tert-butyl 5-amino-H-indazole-1-carboxylate (1.0
g, 4.28 mmol) were refluxed in anhydrous iso-propanol (60 mL) for 5
h. The mixture was allowed to cool to RT, upon which the solid was
collected via filtration and was washed with Et.sub.2O to give
tert-butyl
5-(6-acetoxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-
-1-carboxylate. (2.2 g, 4.23 mmol, 100%). HPLC retention time=7.75
mins.
Example 157
tert-Butyl
5-(6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1-
H-indazole-1-carboxylate
##STR00187##
[0748] To a suspension of tert-butyl
5-(6-acetoxy-7-methoxy-2-(3-nitrophenyl)-quinazolin-4-ylamino)-1H-indazol-
e-1-carboxylate (1.150 g, 2.01 mmol) in MeOH (100 mL) was added 28%
aq. NH.sub.4OH solution (0.7 mL). The mixture was stirred at RT for
20 h. The solid was collected via filtration and dried under vacuum
to give tert-butyl
5-(6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-
-1-carboxylate. (0.800 g, 1.51 mmol, 75%). HPLC retention time 6.57
mins.
Example 158
tert-butyl
5-(7-methoxy-6-(3-morpholinopropoxy)-2-(3-nitrophenyl)quinazoli-
n-4-ylamino)-1H-indazole-1-carboxylate
##STR00188##
[0750] A mixture of tert-Butyl
5-(6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-
-1-carboxylate (0.70 g, 1.32 mmol), 4-(3-chloropropyl)morpholine
(0.32 g, 1.96 mmol) and K.sub.2CO.sub.3 (1.33 g, 9.62 mmol) in DMF
(10 mL) was heated at 80.degree. C. for 2.5 h. The mixture was
allowed to cool to RT and the volatiles were removed in vacuo. The
crude product was purified by column chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2 97:3 to 94:6 to 90:10) to give the desired
compound tert-butyl
5-(7-methoxy-6-(3-morpholinopropoxy)-2-(3-nitrophenyl)quinazolin-4-ylamin-
o)-1H-indazole-1-carboxylate. HPLC retention time (5.76 min).
Example 159
tert-butyl
5-(2-(3-aminophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoli-
n-4-ylamino)-1H-indazole-1-carboxylate
##STR00189##
[0752] To a mixture of
5-(7-methoxy-6-(3-morpholinopropoxy)-2-(3-nitrophenyl)quinazolin-4-ylamin-
o)-1H-indazole-1-carboxylate (0.215 g) in MeOH (60 mL) was added
Pd/C (0.21 g) and NH.sub.4CO.sub.2 (0.21 g). The mixture was heated
at 60.degree. C. for 40 mins, upon which an additional portion of
NH.sub.4CO.sub.2 (0.095 g) was added, heating was continued for a
further 20 minutes. The mixture was filtered to remove the Pd/C and
the filtrate was concentrated under reduced pressure. The residue
was taken up in CH.sub.2Cl.sub.2 (300 mL) wand was washed with
water and brine. The mixture was dried (Na.sub.2SO.sub.4) and the
volatiles removed in vacuo. The material was combined with an
identical experiment using 0.2 g and the residue was subjected to
preparative TLC (SiO.sub.2, CH.sub.2Cl.sub.2:MeOH 9:1) to give the
desired product tert-butyl
5-(2-(3-aminophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-ylamin-
o)-1H-indazole-1-carboxylate. HPLC retention time 4.67 mins.
Example 160
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-
-2-yl)phenyl)butyramide
##STR00190##
[0754] To a solution of tert-butyl
5-(2-(3-aminophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-ylamin-
o)-1H-indazole-1-carboxylate (0.076 g, 0.121 mmol) in
CH.sub.2Cl.sub.2 (4 mL), DIEA (0.040 g, 0.30 mmol) and butryl
chloride (0.026 g) were added were added. The resulting mixture was
stirred at RT for 2.5 h. The volatiles were removed in vacuo and
the residue was taken up in CH.sub.2Cl.sub.2 (15 mL), washed with
NaHCO.sub.3 solution, water and brine, dried (Na.sub.2SO.sub.4) and
filtered.
[0755] The residue was taken up in CH.sub.2Cl.sub.2 (3 mL) and TFA
(3 mL) was added. The mixture was stirred at RT for 2.5 h. The
volatiles were removed in vacuo and the residue was washed with
Et.sub.2O and hexane. The solid was dried under vacuum to give the
desired product
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(3-morpholinopropoxy)quinazoli-
n-2-yl)phenyl) butyramide (0.066 g, 0.110 mmol, 91%). MS 596.3
(M+1). HPLC retention time 4.60 mins.
Example 161
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-
-2-yl)phenyl)isonicotinamide
##STR00191##
[0757] To a solution of tert-butyl
5-(2-(3-aminophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-ylamin-
o)-1H-indazole-1-carboxylate (0.064 g, 0.102 mmol) in
CH.sub.2Cl.sub.2 (4 mL), DIEA (0.041 g, 0.32 mmol) and
isonicotinoyl chloride (0.022 g, 0.123 mmol) were added were added.
The resulting mixture was stirred at RT for 2.5 h. The volatiles
were removed in vacuo and the residue was taken up in
CH.sub.2Cl.sub.2 (15 mL), washed with NaHCO.sub.3 solution, water
and brine, dried (Na.sub.2SO.sub.4) and filtered.
[0758] The residue was taken up in CH.sub.2Cl.sub.2 (3 mL) and TFA
(3 mL) was added. The mixture was stirred at RT for 2.5 h. The
volatiles were removed in vacuo and the residue was washed with
Et.sub.2O and hexane. The solid was dried under vacuum to give the
desired product
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(3-morpholinopropoxy)quinazoli-
n-2-yl)phenyl)isonicotinamide (0.073 g, 0.098 mmol, 96%). MS 631.3
(M+1). HPLC retention time 3.94 mins
Example 162
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-
-2-yl)phenyl)nicotinamide
##STR00192##
[0760] To a solution of tert-butyl
5-(2-(3-aminophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-ylamin-
o)-1H-indazole-1-carboxylate (0.035 g, 0.056 mmol) in
CH.sub.2Cl.sub.2 (4 mL), DIEA (0.036 g, 0.28 mmol) and
isonicotinoyl chloride hydrochloride (0.013 g, 0.073 mmol) were
added were added. The resulting mixture was stirred at RT for 2.5
h. The volatiles were removed in vacuo and the residue was purified
by preparative TLC (SiO.sub.2 CHCl.sub.3:MeOH 9:1).
[0761] The crude material was taken up in CH.sub.2Cl.sub.2 (2 mL)
and TFA (2.5 mL) was added. The mixture was stirred at RT for 2.5
h. The volatiles were removed in vacuo and the residue was washed
with Et.sub.2O and dried under vacuum to give the desired product
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(3-morpholinopropoxy)quinazoli-
n-2-yl)phenyl) nicotinamide. MS 631.7 (M+1). HPLC retention time
3.779 mins.
Example 163
tert-butyl
5-(6-acetoxy-2-(3-aminophenyl)-7-methoxyquinazolin-4-ylamino)-1-
H-indazole-1-carboxylate
##STR00193##
[0763] To a mixture of tert-butyl
5-(6-acetoxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-
-1-carboxylate (0.40 g, 0.70 mmol) in MeOH (100 mL) was added Pd/C
(0.15 g) under an atmosphere of N.sub.2. The mixture was then
stirred under an atmosphere of H.sub.2 (balloon pressure) for 48 h
at RT. The mixture was filtered through a pad of Celite.RTM.
washing with MeOH. The filtrate was concentrated in vacuo to give
the desired product tert-butyl
5-(6-acetoxy-2-(3-aminophenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-
-1-carboxylate. (0.23 g, 0.43 mmol, 61%). HPLC retention time 5.748
mins.
Example 164
tert-Butyl
5-(6-hydroxy-7-methoxy-2-(3-(2-morpholinoacetamido)phenyl)quina-
zolin-4-ylamino)-1H-indazole-1-carboxylate
##STR00194##
[0765] To a solution of tert-butyl
5-(6-acetoxy-2-(3-aminophenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-
-1-carboxylate (0.538 g, 0.995 mmol) in EtOAc:THF (80 mL:20 mL) was
added sat. NaHCO.sub.3 (30 mL) followed by 2-chloroacetyl chloride
(0.5 mL). The resulting mixture was stirred at RT for 3 h, upon
which an additional aliquot of 2-chloroacetyl chloride (0.5 mL) was
added. The mixture was stirred at RT for a further 2 h. The layers
were separated and the organic layer was washed with 50% citric
acid (2.times.50 mL), water (2.times.100 mL) and brine (1.times.50
mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in
vacuo.
[0766] The crude mixture was dissolved in DMF/THF (10 mL 1:1 v/v)
and morpholine (1.5 mL) was added. The mixture was stirred at RT
for 4 h, upon which it was diluted with water (200 mL) and
extracted with EtOAc (2.times.300 mL). The combined organics were
washed with water (1.times.100 mL), dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo.
[0767] The residue was taken up in MeOH (50 mL) and 28% NH.sub.4OH
(0.8 mL) was added. The subsequent mixture was stirred at RT for 24
h, upon which the volatiles were removed in vacuo to give
tert-butyl
5-(6-hydroxy-7-methoxy-2-(3-(2-morpholinoacetamido)phenyl)quinazolin-4-yl-
amino)-1H-indazole-1-carboxylate (0.330 g, 0.527 mmol, 53% over
three steps). HPLC retention time 5.181 mins.
Example 165
tert-Butyl
5-(6-(2-chloroethoxy)-7-methoxy-2-(3-(2-morpholinoacetamido)phe-
nyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
##STR00195##
[0769] A mixture of tert-butyl
5-(6-hydroxy-7-methoxy-2-(3-(2-morpholinoacetamido)phenyl)quinazolin-4-yl-
amino)-1H-indazole-1-carboxylate (0.330 g, 0.527 mmol),
1-bromo-2-chloroethane (0.287 g, 2.00 mmol) and K.sub.2CO.sub.3
(0.330 g, 2.39 mmol) in DMF (3 mL) was heated at 85.degree. C. for
3 h. The mixture was allowed to cool to RT, upon which it was
diluted with water (200 mL) and the resulting precipitate was
collected via filtration. The solid was taken up in EtOAc (250 mL)
and washed with water (1.times.100 mL) and brine (1.times.100 mL),
dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to
give tert-butyl
5-(6-(2-chloroethoxy)-7-methoxy-2-(3-(2-morpholinoacetamido)-phenyl)quina-
zolin-4-ylamino)-1H-indazole-1-carboxylate which was used without
further purification (0.300 g, 0.436 mmol, 83%). HPLC retention
time 5.842 mins.
Example 166
tert-Butyl
5-(7-methoxy-2-(3-(2-morpholinoacetamido)phenyl)-6-(2-(pyrrolid-
in-1-yl)ethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
##STR00196##
[0771] To a mixture of tert-butyl
5-(6-(2-chloroethoxy)-7-methoxy-2-(3-(2-morpholinoacetamido)phenyl)quinaz-
olin-4-ylamino)-1H-indazole-1-carboxylate (0.280 g, 0.407 mmol) in
DMF (2 mL) and THF (3 mL) was added pyrrolidine (0.8 mL). The
resultant mixture was heated at 85.degree. C. for 2 h, upon which
it was allowed to cool to RT, the volatiles were removed in vacuo
and the residue was taken up in ice-water (200 mL). The resulting
precipitate was collected via filtration and subjected to
preparative TLC (SiO.sub.2, CH.sub.2Cl.sub.2:MeOH 83:17) to give
tert-butyl
5-(7-methoxy-2-(3-(2-morpholinoacetamido)-phenyl)-6-(2-(pyrrolidin-1-yl)e-
thoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.085 g,
0.118 mmol, 29%). HPLC retention time 3.81 minutes.
Example 167
N-(3-(4-(1H-Indazol-5-ylamino)-7-methoxy-6-(2-(pyrrolidin-1-yl)ethoxy)quin-
azolin-2-yl)phenyl)-2-morpholinoacetamide
##STR00197##
[0773] To a mixture of tert-butyl
5-(7-methoxy-2-(3-(2-morpholinoacetamido)-phenyl)-6-(2-(pyrrolidin-1-yl)e-
thoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.085 g,
0.118 mmol) in CH.sub.2Cl.sub.2 (4 mL) was added TFA (6 mL). The
resultant mixture was stirred at RT for 1.25 h, upon which the
volatiles were removed in vacuo and the residue was triturated with
Et.sub.2O to give
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-(pyrrolidin-1-yl)ethoxy)qui-
nazolin-2-yl)phenyl)-2-morpholinoacetamide (0.090 g, 0.112 mmol,
95%). MS 623.2 (M+1). HPLC retention time 3.806 mins.
Example 168
tert-Butyl
5-(6-acetoxy-2-(3-butyramidophenyl)-7-methoxyquinazolin-4-ylami-
no)-1H-indazole-1-carboxylate
##STR00198##
[0775] To a solution of tert-butyl
5-(6-acetoxy-2-(3-aminophenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-
-1-carboxylate (2.51 g, 4.65 mmol) and DIEA (3.08 mL, 17.7 mmol) in
dichloromethane (60 mL) was added butryl chloride (0.72 g, 6.76
mmol). The resulting reaction mixture was stirred at room
temperature for 84 h upon which a solid separated out. The solid
was collected by filtration and dried under vacuum (1.32 g). The
filtrate was concentrated in vacuo and upon trituration with water
gave an additional product (1.0 g). Combination of the two solids
gave tert-butyl
5-(6-acetoxy-2-(3-butyramidophenyl)-7-methoxyquinazolin-4-ylamino)-1H-ind-
azole-1-carboxylate (2.32 g, 3.80 mmol, 82%). HPLC retention time
7.079 min.
Example 169
tert-butyl
5-(2-(3-butyramidophenyl)-6-hydroxy-7-methoxyquinazolin-4-ylami-
no)-1H-indazole-1-carboxylate
##STR00199##
[0777] To a mixture of tert-butyl
5-(6-acetoxy-2-(3-aminophenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-
-1-carboxylate (0.205 g, 0.38 mmol) in CH.sub.2Cl.sub.2 (10 mL) was
added DIEA (0.180 g, 1.4 mmol) and butryl chloride (0.055 g, 0.52
mmol) respectively. The mixture was stirred at RT for 2 h. The
mixture was concentrated in vacuo and taken up in CH.sub.2Cl.sub.2
(60 mL), the organic layer was washed with water and brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo.
[0778] The residue was taken up in MeOH (40 mL) and 28% NH.sub.4OH
(0.25 mL) was added to the mixture. The mixture was stirred at RT
for 24 h. The volatiles were removed in vacuo and the residue was
triturated with Et.sub.2O to give tert-butyl
5-(2-(3-butyramidophenyl)-6-hydroxy-7-methoxyquinazolin-4-ylamino)-1H-ind-
azole-1-carboxylate (0.130 g, 0.24 mmol, 63%). HPLC retention time
6.49 min.
Example 170
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(dimethylamino)ethoxy)-7-methoxyquinaz-
olin-2-yl)phenyl)butyramide
##STR00200##
[0780] To a mixture of tert-butyl
5-(2-(3-butyramidophenyl)-6-hydroxy-7-methoxyquinazolin-4-ylamino)-1H-ind-
azole-1-carboxylate (0.102 g, 0.168 mmol),
2-chloro-N,N-dimethylethanamine hydrochloride (0.053 g, 0.37 mmol)
and K.sub.2CO.sub.3 (0.090 g, 0.65 mmol) in DMF (2.5 mL) was heated
at 85.degree. C. for 3 h. The mixture was allowed to cool to RT and
was concentrated in vacuo. The residue was subjected to preparative
TLC (SiO.sub.2, CH.sub.2Cl.sub.2 9:1).
[0781] After isolation, the product was immediately taken up
CH.sub.2Cl.sub.2 (1 mL) and TFA (2 mL) was added. The mixture was
stirred at RT for 3.5 h, the volatiles were removed in vacuo and
the residue was triturated with Et.sub.2O and dried under vacuum to
give the desired product
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(dimethylamino)
ethoxy)-7-methoxy quinazolin-2-yl)phenyl)butyramide. MS 540.5
(M+1). (HPLC retention time 4.55 mins.
Example 171
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(dimethylamino)-2-oxoethoxy)-7-methoxy-
quinazolin-2-yl)phenyl)nicotinamide
##STR00201##
[0783] To a mixture of tert-butyl
5-(6-hydroxy-7-methoxy-2-(3-(nicotinamido)-phenyl)quinazolin-4-ylamino)-1-
H-indazole-1-carboxylate (0.106 g, 0.175 mmol),
2-chloro-N,N-dimethylacetamide (0.051 g, 0.418 mmol) and
K.sub.2CO.sub.3 (0.053 g, 0.383 mmol) in DMF (2 mL) was heated at
85.degree. C. for 3 h. The mixture was concentrated in vacuo and
the residue subjected to preparative TLC (SiO.sub.2
CH.sub.2Cl.sub.2:MeOH 9:1).
[0784] The product from above was then taken up in CH.sub.2Cl.sub.2
(3 mL) and TFA (2.5 mL) was added. The mixture was stirred at RT
for 3 h. The volatiles were removed in vacuo and the residue was
triturated with Et.sub.2O wand dried under vacuum. The residue was
purified by preparative HPLC (method 10-35-95) to give the desired
product
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(dimethylamino)-2-oxoethoxy)-7-methox-
yquinazolin-2-yl)phenyl) nicotinamide (0.021 g, 35.7 .mu.mol, 20%).
MS 589.3 (M+1). HPLC retention time 4.31 mins.
Example 172
tert-Butyl
5-(6-(2-(dimethylamino)ethoxy)-7-methoxy-2-(3-nitrophenyl)quina-
zolin-4-ylamino)-1H-indazole-1-carboxylate
##STR00202##
[0786] A mixture of tert-butyl
5-(6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-
-1-carboxylate (0.475 g, 0.898 mmol),
2-chloro-N,N-dimethylethanamine (0.28 g, 1.94 mmol) and
K.sub.2CO.sub.3 (1.18 g, 2.54 mmol) in DMF (8 mL) was heated at
85.degree. C. for 3 h. The volatiles were removed in vacuo and the
residue was taken up in CHCl.sub.3/MeOH. The solid was removed via
filtration and the filtrate was concentrated in vacuo. The residue
was purified by column chromatography (SiO.sub.2, CHCl.sub.3/MeOH
93:7 then 90:10) to give tert-butyl
5-(6-(2-(dimethylamino)ethoxy)-7-methoxy-2-(3-nitrophenyl)quinazolin-4-yl-
amino)-1H-indazole-1-carboxylate. (0.087 g, 0.145 mmol, 16%). MS
600.4 (M+1).
Example 173
tert-Butyl
5-(2-(3-aminophenyl)-6-(2-(dimethylamino)ethoxy)-7-methoxyquina-
zolin-4-ylamino)-1H-indazole-1-carboxylate
##STR00203##
[0788] A mixture of tert-butyl
5-(6-(2-(dimethylamino)ethoxy)-7-methoxy-2-(3-nitrophenyl)quinazolin-4-yl-
amino)-1H-indazole-1-carboxylate (0.085 g, 0.142 mmol) and 10% Pd/C
(0.100 g) in MeOH (20 ml) was hydrogenated at RT using a balloon
filled with hydrogen gas. The reaction was heated at 55.degree. C.
for 1 h. The reaction mixture filtered through Celite.RTM. washing
with MeOH. The filtrate was concentrated in vacuo to give
tert-butyl
5-(2-(3-aminophenyl)-6-(2-(dimethylamino)ethoxy)-7-methoxyquinazolin-4-yl-
amino)-1H-indazole-1-carboxylate. (0.065 g, 0.128 mmol, 90%). HPLC
retention time 3.42 mins.
Example 174
N-(3-(4-(1H-Indazol-5-ylamino)-6-(2-(dimethylamino)ethoxy)-7-methoxyquinaz-
olin-2-yl)phenyl)nicotinamide
##STR00204##
[0790] To a mixture of tert-butyl
5-(2-(3-aminophenyl)-6-(2-(dimethylamino)-ethoxy)-7-methoxyquinazolin-4-y-
lamino)-1H-indazole-1-carboxylate (0.067 g, 0.142 mmol) and
di-iso-propylethylamine (0.075 g, 0.58 mmol) in CH.sub.2Cl.sub.2
(20 ml) was added nictinoyl chloride (0.032 g, 0.18 mmol). The
reaction was stirred at RT for 8 h, upon which the volatiles were
removed in vacuo. The residue was dissolved in CH.sub.2Cl.sub.2 (1
mL) and was treated with TFA (2.5 mL). The mixture was stirred at
RT for 2 h, the volatiles were removed in vacuo and the residue was
washed with Et.sub.2O and CH.sub.2Cl.sub.2. Purification was
accomplished using preparative HPLC (10-35-90 method) to give
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(dimethylamino)ethoxy)-7-methoxyquina-
zolin-2-yl)phenyl)nicotinamide. (0.017 g, 29.6 .mu.mol, 21%). MS
575.3 (M+1). HPLC retention time 3.81 mins.
Example 175
tert-Butyl
5-(6-acetoxy-7-methoxy-2-(3-(nicotinamido)phenyl)quinazolin-4-y-
lamino)-1H-indazole-1-carboxylate
##STR00205##
[0792] To a mixture of tert-butyl
5-(6-acetoxy-2-(3-aminophenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-
-1-carboxylate (0.230 g, 0.43 mmol) and di-iso-propylethylamine
(0.180 g, 0.14 mmol) in CH.sub.2Cl.sub.2 (20 ml) was added
nictinoyl chloride (0.097 g, 0.54 mmol). The reaction was stirred
at RT for 6 h, upon which the volatiles were removed in vacuo and
the residue was purified via preparative TLC (SiO.sub.2,
CH.sub.2Cl.sub.2/MeOH 9:1) to give tert-butyl
5-(6-acetoxy-7-methoxy-2-(3-(nicotinamido)phenyl)quinazolin-4-ylamino)-1H-
-indazole-1-carboxylate. (0.168 g, 0.26 mmol, 60%). HPLC retention
time 5.924 mins.
Example 176
tert-Butyl
5-(6-hydroxy-7-methoxy-2-(3-(nicotinamido)phenyl)quinazolin-4-y-
lamino)-1H-indazole-1-carboxylate
##STR00206##
[0794] To a suspension of tert-butyl
5-(6-acetoxy-7-methoxy-2-(3-(nicotinamido)-phenyl)quinazolin-4-ylamino)-1-
H-indazole-1-carboxylate (0.163 g, 0.299 mmol) in MeOH (15 mL) was
added aq. NH.sub.4OH solution (0.12 mL). The mixture was stirred at
RT for 24 h. The volatiles were removed in vacuo and the residue
was triturated with Et.sub.2O and dried under vacuum to give
tert-butyl
5-(6-hydroxy-7-methoxy-2-(3-(nicotinamido)phenyl)-quinazolin-4-ylamino)-1-
H-indazole-1-carboxylate. (0.102 g, 0.188 mmol, 63%). HPLC
retention time 5.04 mins.
Example 177
tert-Butyl
5-(7-methoxy-6-(2-methoxyethoxy)-2-(3-(nicotinamido)phenyl)quin-
azolin-4-ylamino)-1H-indazole-1-carboxylate
##STR00207##
[0796] To a solution of tert-butyl
5-(6-hydroxy-7-methoxy-2-(3-(nicotinamido)-phenyl)quinazolin-4-ylamino)-1-
H-indazole-1-carboxylate (0.108 g, 0.179 mmol),
1-bromo-2-methoxyethane (0.054 g, 0.389 mmol) and K.sub.2CO.sub.3
(0.052 g, 0.449 mmol) in DMF (2 mL) were heated at 85.degree. C.
for 3 h. The mixture was allowed to cool to RT and the volatiles
were removed in vacuo. The residue was purified by preparative tlc
(SiO.sub.2, CH.sub.2Cl.sub.2/MeOH 9:1) to give tert-butyl
5-(7-methoxy-6-(2-methoxyethoxy)-2-(3-(nicotinamido)phenyl)quinazolin-4-y-
lamino)-1H-indazole-1-carboxylate. The material was taken directly
on to the next step. HPLC retention time 5.802 mins.
Example 178
N-(3-(4-(1H-Indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)quinazolin-2-y-
l)phenyl)nicotinamide
##STR00208##
[0798] A solution of tert-butyl
5-(7-methoxy-6-(2-methoxyethoxy)-2-(3-(nicotinamido)phenyl)quinazolin-4-y-
lamino)-1H-indazole-1-carboxylate in CH.sub.2Cl.sub.2 (15 mL) and
TFA (2.2 mL) was stirred at RT for 1 h. The volatiles were removed
in vacuo and the residue was washed with Et.sub.2O to give
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)quinazolin-2--
yl)phenyl)nicotinamide trifluroacetate salt (0.086 g, 0.127 mmol,
71% over two steps). MS 562.4 (M+1). HPLC retention time 4.92
mins.
Example 179
2-Methoxyethyl 4-methoxy-3-(2-methoxyethoxy)benzoate
##STR00209##
[0800] To a mixture of 3-hydroxy-4-methoxy benzoic acid (9.6 g,
57.1 mmol) in DMF (110 mL) cooled to 0.degree. C. under an
atmosphere of N.sub.2 was added K.sub.2CO.sub.3 slowly. The mixture
was stirred for 30 minutes upon which 2-bromoethyl methyl ether
(10.7 mL, 114.2 mmol) was added slowly. The mixture was stirred at
RT for 1 h and then at 80.degree. C. for 12 hours, upon which
another portion of 2-bromoethyl methyl ether (8.0 mL, 85.7 mmol)
was added. Heating was continued for 2 h., upon which TLC indicated
complete reaction. The reaction mixture was allowed to cool to RT
and poured into ice-water. The mixture was extracted with
EtOAc:hexane (4:1 v/v, 3.times.300 mL). The combined extracts were
washed with brine (lx 300 mL), dried (Na.sub.2SO.sub.4), filtered
and concentrated in vacuo to give 2-methoxyethyl
4-methoxy-3-(2-methoxyethoxy)benzoate as a dark colored oil. (15.05
g, 52.9 mmol, 93%). MS 307.3 (M+Na). HPLC retention time 5.80
mins.
Example 180
2-Methoxyethyl 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoate
##STR00210##
[0802] To a solution of 2-methoxyethyl
4-methoxy-3-(2-methoxyethoxy)benzoate (15.05 g, 52.9 mmol) in AcOH
(54 mL) under an atmosphere of N.sub.2 was added conc. HNO.sub.3
(13.5 mL) in one portion. The reaction was stirred at RT for 72 h.
The mixture was poured into ice-water (ca. 800 mL) and extracted
with EtOAc (2.times.400 mL). The combined organics were washed with
water (2.times.200 mL) and brine (lx 200 mL), dried
(Na.sub.2SO.sub.4) and conc. in vacuo. The residue was azeotroped
with heptane (2.times.300 mL) to remove residual AcOH giving
2-methoxyethyl 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoate as a
dark colored oil. (15.5 g, 47.1 mmol, 89%). HPLC retention time
6.24 mins.
Example 181
4-Methoxy-5-(2-methoxyethoxy)-2-nitrobenzoic Acid
##STR00211##
[0804] To a solution of 2-methoxyethyl
4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoate (5.0 g, 15.2 mmol) in
EtOH (40 mL) was added 2N NaOH (40 mL, 76.0 mmol, 5 eq.). The
mixture was stirred at RT for 12 h. The mixture was diluted with
water (100 mL) and washed with CH.sub.2Cl.sub.2 (1.times.100 mL).
The aqueous layer was acidified to pH=1 using 1N HCl (A solid began
to precipitate, this was dissolved by the addition of EtOAc). The
aqueous mixture was extracted with EtOAc (2.times.200 mL). The
combined organics were washed with brine (1.times.100 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give
4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoic acid as an off white
solid (3.55 g, 12.4 mmol, 86%). HPLC retention time 4.94 mins.
Example 182
4-Methoxy-5-(2-methoxyethoxy)-2-nitrobenzamide
##STR00212##
[0806] To a solution of
4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoic acid (3.35 g, 12.4
mmol) under an atmosphere of N.sub.2 in anhydrous THF (50 mL) was
added oxalyl chloride (2.25 mL, 1.7 eq. 25.5 mmol) and two drops of
DMF. The mixture was stirred at RT for 30 minutes, upon which two
more drops of DMF were added and stirring at RT was continued for 1
h. Tlc and HPLC analysis indicated complete formation of the acid
chloride intermediate and the mixture was concentrated in vacuo to
give the acid chloride intermediate as a yellow solid. The solid
was dissolved in anhydrous THF (50 mL) and to this solution was
added a saturated solution of NH.sub.3 in THF (15 mL) via a
cannula. A precipitate began to form and stirring was continued at
RT for 12 h. The mixture was concentrated in vacuo to give
4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzamide as an off-white
solid. (4.5 g, contains some NH.sub.4Cl, the mixture was taken on
directly to the next step). HPLC retention time 8.55 mins.
Example 183
2-Amino-4-methoxy-5-(2-methoxyethoxy)benzamide
##STR00213##
[0808] A mixture of 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzamide
(4.5 g, contains some NH.sub.4Cl) and 10% Pd/C (ca. 0.5 g) in DME
(200 mL) and MeOH (200 mL) was hydrogenated under a balloon of
H.sub.2 at RT for 12 h. The mixture was filtered through a pad of
Celite.RTM. and concentrated in vacuo to give
2-amino-4-methoxy-5-(2-methoxyethoxy)benzamide as an off white
solid (2.8 g, 11.6 mmol). HPLC retention time 2.80 mins.
Example 184
4-Methoxy-5-(2-methoxyethoxy)-(3-nitrophenyl)aminobenzamide
##STR00214##
[0810] To a mixture of
2-amino-4-methoxy-5-(2-methoxyethoxy)benzamide (1.78 g, 7.40 mmol)
and pyridine (2.40 mL, 29.6 mmol) in CHCl.sub.3 (40 mL) was added
3-nitrobenzoyl chloride (1.44 g, 7.8 mmol). The mixture was stirred
at RT for 2.5 h upon which the mixture was concentrated in vacuo to
give the desired product, which was used directly in the next step
without purification.
Example 185
7-Methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazolin-4(3H)-one
##STR00215##
[0812] The crude product from the previous step (7.4 mmol
theoretically) was taken up in 2N NaOH (40 mL) and refluxed for 4
h. the mixture was allowed to cool to RT and neutralized to pH=7
with 6 and 1 N HCl. Upon neutralization a precipitate appeared
which was collected via filtration and washed with Et.sub.2O. The
solid was azeotroped with toluene (2.times.50 mL) to remove any
residual water and dried under high vacuum to give
7-methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazolin-4(3H)-o-
ne as an off white solid (2.60 g, 7.00 mmol, 95% over two steps).
HPLC retention time 6.2 mins.
Example 186
4-Chloro-7-methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazoline
##STR00216##
[0814] To a suspension of
7-methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazolin-4(3H)-one
(1.65 g, 4.46 mmol) in anhydrous THF (30 mL) was added oxalyl
chloride (1.3 mL, 14.7 mmol) and 2 drops of DMF. The mixture was
refluxed for 2 h, upon which the mixture was concentrated in vacuo,
taken up in CHCl.sub.3 (100 mL) and washed with sat. NaHCO.sub.3
(3.times.50 mL), water (2.times.50 mL) and brine (1.times.50 mL).
The organic layer was dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to give
4-chloro-7-methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazoline
(1.18 g, 3.03 mmol, 68%). HPLC retention time 9.55 mins.
Example 187
tert-Butyl
5-(7-methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazolin-4--
ylamino)-1H-indazole-1-carboxylate
##STR00217##
[0816] A mixture of
4-chloro-7-methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazoline
(0.500 g, 1.28 mmol) and 5-amino-1H-indazole-1-carboxylate (0.314
g, 1.34 mmol) in iso-propanol (30 mL) was heated at 95.degree. C.
for 30 minutes and at 95.degree. C. for 8 h. The mixture was
allowed to cool to RT and the solid was collected via filtration.
The cake was washed with iso-propanol and Et.sub.2O, triturated
with CH.sub.2Cl.sub.2 and EtOAc and dried in vacuo to give
tert-Butyl
5-(7-methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazolin-4-ylamino)-1-
H-indazole-1-carboxylate (0.560 g, 0.955 mmol, 71%). MS 587 (M+1).
HPLC retention time 7.21 mins.
Example 188
tert-Butyl
5-(2-(3-aminophenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4--
ylamino)-1H-indazole-1-carboxylate
##STR00218##
[0818] A mixture of tert-butyl
5-(7-methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazolin-4-ylamino)-1-
H-indazole-1-carboxylate (0.560 g, 0.95 mmol) and 10% Pd/C (ca. 0.1
g) in DME (100 mL) and MeOH (100 mL) was hydrogenated under a
balloon of H.sub.2 at RT for 12 h. The mixture was filtered through
a pad of Celite.RTM. and concentrated in vacuo to give tert-butyl
5-(2-(3-aminophenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-1-
H-indazole-1-carboxylate as an off white solid (0.510 g, 0.92 mmol,
97%). HPLC retention time 5.62 mins.
Example 189
tert-butyl
5-(7-methoxy-6-(2-methoxyethoxy)-2-(3-(2-morpholinoacetamido)ph-
enyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
##STR00219##
[0820] A mixture of 2-morpholinoacetic acid (0.034 g, 0.24 mmol),
DIEA (0.165 mL, 0.94 mmol) and PyBOP.RTM. (0.125 g, 0.24 mmol) in
CH.sub.2Cl.sub.2 (1 mL) was stirred at RT for 10 minutes, upon
which it was added to a solution of tert-Butyl
5-(2-(3-aminophenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-1-
H-indazole-1-carboxylate (0.260 g, 0.47 mmol) in CH.sub.2Cl.sub.2
(10 mL). the subsequent was stirred at RT for 1 hr upon which
further aliquots of 2-morpholinoacetic acid (0.034 g, 0.24 mmol)
and PyBOP.RTM. (0.125 g, 0.24 mmol) were added. The resulting
mixture was stirred at RT overnight upon which the mixture was
concentrated in vacuo and taken directly to the next step. HPLC
retention time 5.35 mins.
Example 190
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)quinazolin-2-y-
l)phenyl)-2-morpholinoacetamide
##STR00220##
[0822] To a suspension of tert-butyl
5-(7-methoxy-6-(2-methoxyethoxy)-2-(3-(2-morpholinoacetamido)
phenyl) quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (0.321 g,
0.47 mmol) in CH.sub.2Cl.sub.2 (3 mL) was added TFA (3 mL). The
resulting mixture was stirred at RT for 1.5 h, upon which it was
concentrated in vacuo and the residue purified by preparative HPLC
(10-35-90 method) to give
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)quinazolin-2--
yl)phenyl)-2-morpholinoacetamide trifluoroacetate salt (0.141 g,
0.202 mmol, 43% over two steps). MS 584 (M+1). HPLC retention time
4.40 mins.
Example 191
2-(3-(benzyloxy)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4(3H)-one
##STR00221##
[0824] To mixture of 2-amino-4-methoxy-5-(2-methoxyethoxy)benzamide
(2.20 g, 9.16 mmol) and 3-(benzyloxy)benzoyl chloride (2.50 g, 10.1
mmol) in CHCl.sub.3 (50 mL) was added pyridine 2.9 mL). The mixture
was stirred at RT for 3 h, upon which the volatiles were removed in
vacuo.
[0825] The residue was taken up in 2N NaOH (60 mL) and heated at
reflux overnight. The mixture was allowed to cool to RT, upon which
it was neutralized with 1N HCl to pH=7. The mixture was allowed to
stand for 2 h upon which the precipitate was collected via
filtration. The solid was dried under high vacuum to give
2-(3-(benzyloxy)-phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4(3H)-on-
e (3.28 g, 7.58 mmol, 83%). MS 433 (M+1). HPLC retention time 7.41
mins.
Example 192
2-(3-(benzyloxy)phenyl)-4-chloro-7-methoxy-6-(2-methoxyethoxy)quinazoline
##STR00222##
[0827] To a suspension of
2-(3-(benzyloxy)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4(3H)-one
(3.28 g, 7.58 mmol) in CH.sub.2Cl.sub.2 (100 mL) was added oxalyl
chloride (2.20 mL, 24.8 mmol) and 2 drops of DMF. The mixture was
stirred at RT for 6 h. An additional aliquot of oxalyl chloride
(1.20 mL, 13.5 mmol) was added. Stirring was continued at RT
overnight, upon which the mixture was concentrated in vacuo, taken
up in CHCl.sub.3 (100 mL) and washed with sat. NaHCO.sub.3
(3.times.50 mL), water (2.times.50 mL) and brine (1.times.50 mL).
The organic layer was dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to give
2-(3-(benzyloxy)phenyl)-4-chloro-7-methoxy-6-(2-methoxyethoxy)quinazoline
(1.52 g, 3.37 mmol, 45%). MS 451 (M+1 Cl isotope pattern). HPLC
retention time 10.84 mins. (10-95-13 method).
Example 193
tert-butyl
5-(2-(3-(benzyloxy)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazo-
lin-4-ylamino)-1H-indazole-1-carboxylate
##STR00223##
[0829] A mixture of
2-(3-(benzyloxy)phenyl)-4-chloro-7-methoxy-6-(2-methoxyethoxy)quinazoline
(1.55 g, 3.44 mmol) and tert-butyl
5-amino-1H-indazole-1-carboxylate (0.842 g, 3.61 mmol) in
iso-propanol (100 mL) was heated at 95.degree. C. for 2 h, upon
which the an additional aliquot of tert-butyl
5-amino-1H-indazole-1-carboxylate (0.100 g, 0.43 mmol) was added.
Stirring was continued at 95.degree. C. for a further 3 h upon
which a third aliquot of tert-butyl
5-amino-1H-indazole-1-carboxylate (0.050 g, 0.22 mmol) was added.
Stirring was continued at 95.degree. C. for a further 1 h upon
which the mixture was allowed to cool to RT and the precipitate was
collected via filtration. The solid was washed with iso-propanol
and dried under vacuum to give tert-butyl
5-(2-(3-(benzyloxy)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylam-
ino)-1H-indazole-1-carboxylate (2.35 g, 3.44 mmol, 100%). MS 648
(M+1). HPLC retention time 7.79 mins.
Example 194
tert-Butyl
5-(2-(3-hydroxyphenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin--
4-ylamino)-1H-indazole-1-carboxylate
##STR00224##
[0831] A suspension of tert-butyl
5-(2-(3-(benzyloxy)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylam-
ino)-1H-indazole-1-carboxylate (2.70 g, 4.17 mmol) in MeOH (400 mL)
and DME (200 mL) was added Pd/C (10%, wet, 0.500 g) under an
atmosphere of N.sub.2. The N.sub.2 was exchanged for H.sub.2 and
the mixture was stirred under an atmosphere of H2 (balloon
pressure) overnight. The mixture was filtered through a pad of
Celite.RTM. and the filtrate was concentrated in vacuo to give
tert-Butyl
5-(2-(3-hydroxyphenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-
-1H-indazole-1-carboxylate (2.25 g, 4.04 mmol, 97%). MS 558 (M+1).
HPLC retention time 6.44 mins.
Example 195
tert-butyl
5-(2-(3-(2-(isopropylamino)-2-oxoethoxy)phenyl)-7-methoxy-6-(2--
methoxyethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate
##STR00225##
[0833] To a solution of tert-Butyl
5-(2-(3-hydroxyphenyl)-7-methoxy-6-(2-methoxyethoxy)
quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.400 g, 0.72
mmol) and 2-chloro-N-isopropylacetamide (0.107 g, 0.79 mmol) in DMF
(16 mL) was added K.sub.2CO.sub.3 (0.297 g, 1.44 mmol). The mixture
was heated at 80.degree. C. for 72 h. The mixture was concentrated
in vacuo and taken on directly into the next step. HPLC retention
time 6.76 mins.
Example 196
2-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)quinazolin-2-y-
l)phenoxy)-N-isopropylacetamide
##STR00226##
[0835] The crude tert-butyl
5-(2-(3-(2-(isopropylamino)-2-oxoethoxy)phenyl)-7-methoxy-6-(2-methoxyeth-
oxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate from the
previous step was taken up in CH.sub.2Cl.sub.2 (2 mL) and TFA (5
mL). The mixture was stirred at RT for 2 h. The mixture was
concentrated in vacuo and a portion of the residue was purified by
preparative HPLC (10-35-90, 10-30-90, 0-15-90, 5-20-90 and 20-40-90
methods) to give
2-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)-quinazolin-2-
-yl)phenoxy)-N-isopropylacetamide (0.039 g, 68.4 .mu.mol). MS 557
(M+1). HPLC retention time 5.48 mins.
Example 197
tert-butyl
5-(2-(3-butyramidophenyl)-6-hydroxyquinazolin-4-ylamino)-1H-ind-
azole-1-carboxylate
##STR00227##
[0837] To a solution of tert-butyl
5-(6-acetoxy-2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxy-
late (0.57 g, 1.12 mmol) and DIEA (0.65 g, 5.03 mmol) in
dichloromethane (20 mL) was added butryl chloride (0.180 g, 1.69
mmol). The resulting reaction mixture was stirred at room
temperature for 4 h. The volatiles were removed under reduced
pressure and the residue was triturated with water causing
formation of a precipitate. The solid was collected via filtration
and dried under vacuum. The solid was suspended in anhydrous
methanol (50 mL) and 28% ammonium hydroxide (0.9 mL) was added. The
resulting reaction mixture was stirred at room temperature for 24
h. The volatiles were removed under reduced pressure and the
residue upon trituration with ether gave tert-butyl
5-(2-(3-butyramidophenyl)-6-hydroxyquinazolin-4-ylamino)-1H-indazole-1-ca-
rboxylate (0.354 g, 0.66 mmol, 59% over two steps). HPLC retention
time 6.342 min.
Example 198
tert-butyl
5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)quinazolin-4-ylamin-
o)-1H-indazole-1-carboxylate
##STR00228##
[0839] To a mixture of
5-(2-(3-butyramidophenyl)-6-hydroxyquinazolin-4-ylamino)-1H-indazole-1-ca-
rboxylate (1.50 g, 2.79 mmol) and potassium carbonate (1.64 g, 11.8
mmol) in anhydrous DMF (5 mL) was added 1-bromo-2-chloroethane (1.6
g, 11.2 mmol) The subsequent mixture was heated at 85.degree. C.
for 4 h, upon which it was allowed to cool to RT and it was poured
onto ice-water. A solid was precipitated out, which collected via
filtration and dried under vacuum. The solid was purified via
silica gel column chromatography to give tert-butyl
5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)-quinazolin-4-ylamino)-1H-ind-
azole-1-carboxylate (0.94 g, 1.56 mmol, 60%). HPLC retention time
7.479.
Example 199
N-(3-(4-(1H-Indazol-5-ylamino)-6-(2-(pyrrolidin-1-yl)ethoxy)-quinazolin-2--
yl)phenyl)butyramide
##STR00229##
[0841] To a solution of tert-butyl
5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)quinazolin-4-ylamino)-1H-inda-
zole-1-carboxylate (0.170 g, 0.282 mmol) in DMSO (2 mL) was added
pyrrolidine (0.5 mL). The subsequent mixture was heated at
80.degree. C. for 1.5 h upon which it was allowed to cool to RT and
poured into ice-water (100 mL). A precipitate formed which was
collected via filtration and it was dried under vacuum. The
precipitate was purified via preparative TLC (SiO.sub.2,
CH.sub.2Cl.sub.2:MeOH 8:1).
[0842] The purified solid was taken up in HCl (4M in 1,4 dioxane, 2
mL) and stirred at RT for 2 h. The volatiles were removed in vacuo
to give
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-2--
yl)phenyl)butyramide di-hydrochloride salt (0.120 g, 0.198 mmol,
70% over two steps). MS 536 (M+1). HPLC retention time 4.61
mins.
Example 200
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(piperidin-1-yl)ethoxy)-quinazolin-2-y-
l)phenyl)butyramide
##STR00230##
[0844] To a solution of tert-butyl
5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)quinazolin-4-ylamino)-1H-inda-
zole-1-carboxylate (0.174 g, 0.290 mmol) in DMSO (1.5 mL) was added
piperidine (0.5 mL). The subsequent mixture was heated at
80.degree. C. for 1.5 h upon which it was allowed to cool to RT and
poured into ice-water (100 mL). A precipitate formed which was
collected via filtration and it was dried under vacuum. The
precipitate was purified via preparative TLC (Si.sub.2,
CH.sub.2Cl.sub.2:MeOH 8:1).
[0845] The purified solid was taken up in HCl (4M in 1,4 dioxane, 2
mL) and stirred at RT for 2 h. The volatiles were removed in vacuo
to give
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(piperidin-1-yl)ethoxy)quinazolin-2-y-
l)phenyl)butyramide di-hydrochloride salt (0.085 g, 0.137 mmol, 47%
over two steps). MS 550 (M+1). HPLC retention time 4.67 mins.
Example 201
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-methoxyethoxy)quinazolin-2-yl)phenyl)b-
utyramide
##STR00231##
[0847] A mixture of tert-butyl
5-(2-(3-butyramidophenyl)-6-hydroxyquinazolin-4-ylamino)-1H-indazole-1-ca-
rboxylate (0.167 g, 0.31 mmol), 1-bromo-2-methoxyethane (0.118 g,
0.85 mmol) and K.sub.2CO.sub.3 (0.172 g, 1.25 mmol) in DMF (2 mL)
was heated at 80.degree. C. for 2.5 h. The mixture was allowed to
cool to RT, upon which it was poured into water. A precipitate
formed which was collected via filtration, dried under vacuum and
purified via preparative TLC (SiO.sub.2, CH.sub.2Cl.sub.2:MeOH
95:5).
[0848] The purified solid was taken up in HCl (4M in 1,4 dioxane,
30 mL) and stirred at RT for 4.5 h. The volatiles were removed in
vacuo and the residue was triturated with Et.sub.2O to give
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-methoxyethoxy)
quinazolin-2-yl)phenyl) butyramide hydrochloride (0.091 g, 0.171
mmol, 55% over two steps). MS 497 (M+1). HPLC retention time 5.547
mins.
Example 202
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-((2-methoxyethyl)(methyl)amino)ethoxy)-
quinazolin-2-yl)phenyl)butyramide
##STR00232##
[0850] To a solution of tert-butyl
5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)-quinazolin-4-ylamino)-1H-ind-
azole-1-carboxylate (0.150 g, 0.250 mmol) in DMSO (2 mL) was added
2-methoxy-N-methylethanamine (0.5 mL). The subsequent mixture was
heated at 75.degree. C. for 1.5 h upon which it was allowed to cool
to RT and poured into ice-water (100 mL). A precipitate formed
which was collected via filtration and it was dried under vacuum.
The precipitate was purified via preparative TLC (SiO.sub.2,
CH.sub.2Cl.sub.2:MeOH 8:1). Two compounds were isolated and
combined.
[0851] The combined compounds were taken up in CH.sub.2Cl.sub.2 (2
mL) and HCl (4M in 1,4 dioxane, 25 mL) and stirred at RT for 7 h.
The volatiles were removed in vacuo and the residue was washed with
CH.sub.2Cl.sub.2 and Et.sub.2O. The solid was dried under vacuum to
give
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-((2-methoxyethyl)(methyl)amino)ethoxy-
)-quinazolin-2-yl)phenyl)butyramide di-hydrochloride salt (0.100 g,
0.160 mmol, 64% over two steps). MS 554 (M+1). HPLC retention time
4.52 mins.
Example 203
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(4-methylpiperazin-1-yl)ethoxy)-quinaz-
olin-2-yl)phenyl)butyramide
##STR00233##
[0853] To a solution of tert-butyl
5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)quinazolin-4-ylamino)-1H-inda-
zole-1-carboxylate (0.150 g, 0.250 mmol) in DMSO (2 mL) was added
1-methylpiperazine (0.5 mL). The subsequent mixture was heated at
85.degree. C. for 2 h upon which an additional aliquot of
1-methylpiperazine (0.2 mL). Heating at 85.degree. C. was continued
for a further 1.5 h, upon which the mixture was allowed to cool to
RT and poured into ice-water (100 mL). A precipitate formed which
was collected via filtration and it was dried under vacuum. The
precipitate was purified via preparative TLC (Si.sub.2,
CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH 9:1:0.1) to give two
compounds.
[0854] The combined compounds were taken up in CH.sub.2Cl.sub.2 (2
mL) TFA (4 mL) was added. The resulting mixture was stirred at RT
for 4 h, upon which the volatiles were removed in vacuo. The
residue was neutralized with sat. NaHCO.sub.3 and extracted with
THF (3.times.25 mL). The combined organics were washed with brine
(1.times.20 mL), dried (Na.sub.2SO.sub.4) and purified by
preparative TLC (SiO.sub.2, CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH
9:1:0.1). The purified compound was taken up in CH.sub.2Cl.sub.2 (2
mL) and HCl (4M in 1,4 dioxane, 10 mL) and was stirred at RT for 4
h. The volatiles were removed in vacuo and the residue was
triturated with Et.sub.2O, filtered and dried under vacuum to give
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinaz-
olin-2-yl)phenyl)butyramide di-hydrochloride salt (0.067 g, 0.105
mmol, 42% over two steps). MS 565 (M+1). HPLC retention time 4.30
mins.
Example 204
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(2-oxopyrrolidin-1-yl)ethoxy)-quinazol-
in-2-yl)phenyl)butyramide
##STR00234##
[0856] A mixture of tert-butyl
5-(2-(3-butyramidophenyl)-6-hydroxyquinazolin-4-ylamino)-1H-indazole-1-ca-
rboxylate (0.120 g, 0.186 mmol), 1-(2-bromoethyl)pyrrolidin-2-one
(0.25 g, 1.31 mmol) and K.sub.2CO.sub.3 (0.415 g, 3.0 mmol) in DMF
(1.5 mL) was heated at 75.degree. C. for 5 h. The mixture was
allowed to cool to RT, upon which it was poured into water. A
precipitate formed which was collected via filtration, dried under
vacuum and purified via preparative TLC (SiO.sub.2,
CH.sub.2Cl.sub.2:MeOH 95:5).
[0857] The purified solid was taken up in HCl (4M in 1,4 dioxane,
30 mL) and stirred at RT for 4 h. The volatiles were removed in
vacuo and the residue was washed with CH.sub.2Cl.sub.2 to give
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(2-oxopyrrolidin-1-yl)ethoxy)quinazol-
in-2-yl)phenyl)butyramide hydrochloride (0.025 g, 0.043 mmol, 23%
over two steps). MS 550 (M+1). HPLC retention time 5.30 mins.
Example 205
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(3-hydroxypyrrolidin-1-yl)ethoxy)-quin-
azolin-2-yl)phenyl)butyramide
##STR00235##
[0859] To a solution of tert-butyl
5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)-quinazolin-4-ylamino)-1H-ind-
azole-1-carboxylate (0.143 g, 0.240 mmol) in DMSO (1.5 mL) was
added pyrrolidin-3-ol (0.5 mL). The subsequent mixture was heated
at 75.degree. C. for 1.5 h upon which it was allowed to cool to RT
and poured into ice-water (100 mL). A precipitate formed which was
collected via filtration and it was dried under vacuum. The
precipitate was purified via preparative TLC (SiO.sub.2,
CH.sub.2Cl.sub.2:MeOH NH.sub.4OH 9:1:0.1).
[0860] The purified solid was taken up in MeOH/CH.sub.2Cl.sub.2 (3
mL 1:1) and HCl (4M in 1,4 dioxane, 2 mL) was added. The mixture
was stirred at RT for 4 h. The volatiles were removed in vacuo and
the residue was washed with CH.sub.2Cl.sub.2 to give
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(3-hydroxypyrrolidin-1-yl)ethoxy)quin-
azolin-2-yl)phenyl) butyramide di-hydrochloride salt (0.095 g,
0.153 mmol, 64% over two steps). MS 552 (M+1). HPLC retention time
4.389 mins.
Example 206
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-(2-oxopyrrolidin-1-yl)ethoxy-
)quinazolin-2-yl)phenyl)butyramide
##STR00236##
[0862] A mixture of tert-butyl
5-(2-(3-butyramidophenyl)-6-hydroxy-7-methoxyquinazolin-4-ylamino)-1H-ind-
azole-1-carboxylate (0.200 g, 0.35 mmol),
2-(2-oxopyrrolidin-1-yl)ethyl methanesulfonate (0.300 g, 1.48 mmol)
and K.sub.2CO.sub.3 (0.410 g, 2.97 mmol) in DMF (3 mL) was heated
at 75.degree. C. for 5 h. The mixture was allowed to cool to RT,
upon which it was poured into water 50-80 mL). A precipitate formed
which was collected via filtration, dried under vacuum and purified
via preparative TLC (SiO.sub.2, CH.sub.2Cl.sub.2:MeOH 95:5).
[0863] The purified solid was taken up in CH.sub.2Cl.sub.2/MeOH (3
mL 1:1) and HCl (4M in 1,4 dioxane, 30 mL) was added. The mixture
was stirred at RT for 5 h. The volatiles were removed in vacuo to
give
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-(2-oxopyrrolidin-1-yl)ethox-
y)quinazolin-2-yl)phenyl)butyramide hydrochloride (0.108, 0.176
mmol, 50% over two steps). MS 580 (M+1). HPLC retention time 5.523
mins.
Example 207
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)-quinazolin-2--
yl)phenyl)butyramide
##STR00237##
[0865] A mixture of tert-butyl
5-(2-(3-butyramidophenyl)-6-hydroxy-7-methoxyquinazolin-4-ylamino)-1H-ind-
azole-1-carboxylate (0.176 g, 0.31 mmol), 1-bromo-2-methoxyethane
(0.120 g, 0.86 mmol) and K.sub.2CO.sub.3 (0.120 g, 2.8 mmol) in
DMSO (1.5 mL) was heated at 75.degree. C. for 1.5 h. The mixture
was allowed to cool to RT, upon which it was poured into water. A
precipitate formed which was collected via filtration and dried
under vacuum.
[0866] The solid was taken up CH.sub.2Cl.sub.2 (8 mL) and HCl (4M
in 1,4 dioxane, 18 mL) was added. The subsequent mixture was
stirred at RT for 4 h. The volatiles were removed in vacuo and the
residue was triturated with Et.sub.2O to give
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)quinazolin-2--
yl)phenyl) butyramide hydrochloride (0.09 g, 0.160 mmol, 52% over
two steps). MS 527 (M+1). HPLC retention time 5.71 mins.
Example 208
tert-Butyl
5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)-7-methoxyquinazoli-
n-4-ylamino)-1H-indazole-1-carboxylate
##STR00238##
[0868] To a mixture of tert-butyl
5-(2-(3-butyramidophenyl)-6-hydroxy-7-methoxyquinazolin-4-ylamino)-1H-ind-
azole-1-carboxylate (0.855 g, 1.50 mmol) and potassium carbonate
(0.950 g, 6.87 mmol) in anhydrous DMF (8 mL) was added,
1-bromo-2-chloroethane (0.89 g, 6.20 mmol) and resulting reaction
mixture was stirred at 85.degree. C. for 3.5 h. The mixture was
allowed to cool to room temperature upon which, it was poured into
ice-water. A solid was precipitated out, which was collected via
filtration and dried under vacuum to give tert-butyl
5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)-7-methoxyquinazolin-4-ylamin-
o)-1H-indazole-1-carboxylate (0.864 g, 1.37 mmol, 91%). HPLC
retention time 7.694 min.
Example 209
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)etho-
xy)quinazolin-2-yl)phenyl)butyramide
##STR00239##
[0870] To a solution of tert-butyl
5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)-7-methoxyquinazolin-4-ylamin-
o)-1H-indazole-1-carboxylate (0.170 g, 0.299 mmol) in DMSO (2 mL)
was added 1-methylpiperazine (0.5 mL). The subsequent mixture was
heated at 85.degree. C. for 2.5 h upon which it was allowed to cool
to RT and poured into ice-water (100 mL). A precipitate formed
which was collected via filtration and it was dried under vacuum.
The precipitate was purified via preparative TLC (SiO.sub.2,
CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH 9:1:0.1). The purified compound
was taken up in CH.sub.2Cl.sub.2 (2 mL) and HCl (4M in 1,4 dioxane,
10 mL) and stirred at RT for 4 h. The volatiles were removed in
vacuo and the residue was triturated with Et.sub.2O, filtered and
dried under vacuum to give
N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)eth-
oxy)-quinazolin-2-yl)phenyl) butyramide di-hydrochloride salt
(0.085 g, 0.128 mmol, 43% over two steps). MS 595 (M+1). HPLC
retention time 4.337 mins.
Example 210
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-((S)-3-(dimethylamino)pyrrolidin-1-yl)-
ethoxy)-7-methoxyquinazolin-2-yl)phenyl)butyramide
##STR00240##
[0872] To a solution of tert-butyl
5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)-7-methoxyquinazolin-4-ylamin-
o)-1H-indazole-1-carboxylate (0.180 g, 0.300 mmol) in DMSO (2 mL)
was added (S)--N,N-dimethylpyrrolidin-3-amine (0.5 mL). The
subsequent mixture was heated at 80.degree. C. for 1.5 h upon which
it was allowed to cool to RT and poured into ice-water (100 mL). A
precipitate formed which was collected via filtration and it was
dried under vacuum. The precipitate was purified via preparative
TLC (SiO.sub.2, CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH 9:1:0.1).
[0873] The purified solid was taken up in HCl(4M in 1,4 dioxane, 2
mL) and stirred at RT for 2 h. The volatiles were removed in vacuo
to give
N-(3-(4-(1H-indazol-5-ylamino)-6-(2-((S)-3-(dimethylamino)pyrrolidin-1-yl-
)ethoxy)-7-methoxyquinazolin-2-yl) phenyl) butyramide
di-hydrochloride salt (0.090 g, 0.132 mmol, 44% over two steps). MS
609 (M+1). HPLC retention time 4.30 mins.
Example 211
##STR00241##
[0874] Example 212
##STR00242##
[0875] Example 213
##STR00243##
[0876] Example 214
##STR00244##
[0877] Example 215
##STR00245##
[0878] Example 216
##STR00246##
[0879] Example 217
##STR00247##
[0880] Example 218
##STR00248##
[0881] Example 219
##STR00249##
[0882] Example 220
##STR00250##
[0883] Example 221
##STR00251##
[0884] Example 222
##STR00252##
[0885] Example 223
##STR00253##
[0886] Example 224
##STR00254##
[0887] Example 225
##STR00255##
[0888] Example 226
##STR00256##
[0889] Example 227
##STR00257##
[0890] Example 228
##STR00258##
[0891] Example 229
##STR00259##
[0892] Example 230
##STR00260##
[0893] Example 231
##STR00261##
[0894] Example 232
##STR00262##
[0895] Example 233
##STR00263##
[0896] Example 234
##STR00264##
[0897] Example 235
##STR00265##
[0898] Example 236
##STR00266##
[0899] Example 237
##STR00267##
[0900] Example 238
##STR00268##
[0901] Example 239
##STR00269##
[0902] Example 240
##STR00270##
[0903] Example 241
##STR00271##
[0904] Example 242
##STR00272##
[0905] Example 243
##STR00273##
[0906] Example 244
##STR00274##
[0907] Example 245
##STR00275##
[0908] Example 246
##STR00276##
[0909] Example 247
##STR00277##
[0910] Example 248
##STR00278##
[0911] Example 249
##STR00279##
[0912] Example 250
##STR00280##
[0913] Example 251
##STR00281##
[0914] Example 252
##STR00282##
[0915] Example 253
##STR00283##
[0916] Example 254
##STR00284##
[0917] Example 255
##STR00285##
[0918] Example 256
##STR00286##
[0919] Example 257
##STR00287##
[0920] Example 258
##STR00288##
[0921] Example 259
##STR00289##
[0922] Example 260
##STR00290##
[0923] Example 261
##STR00291##
[0924] Example 262
##STR00292##
[0925] Example 263
##STR00293##
[0926] Example 264
##STR00294##
[0927] Example 265
##STR00295##
[0928] Example 266
##STR00296##
[0929] Example 267
##STR00297##
[0930] Example 268
##STR00298##
[0931] Example 269
##STR00299##
[0932] Example 270
##STR00300##
[0933] Example 271
##STR00301##
[0934] Example 272
##STR00302##
[0935] Example 273
[0936] 1. ROCK Binding Assay
[0937] ROCK-I inhibitory activity can be measured using the ROCK-II
Assay Kit (Molecular Devices, inc.; Sunnyvale, Calif.).
[0938] 2. A functional measure of ROCK activity in cells
MLC Phosphorylation
[0939] Myosin regulatory light chain phosphorylation can be
measures in vascular smooth muscle (VSM) cells. VSM cells are
isolated from the pulmonary artery of newborn calves and used in
the 2nd to 4th passage. Cells are maintained in low glucose DME
(JRH Biosciences) supplemented with 2 mM glutamine, 100 U/ml
penicillin 100 U/ml streptomycin, 10 mM Hepes (Life Technologies),
and 10% fetal bovine serum (Hyclone) in 10% CO.sub.2. Confluent
monolayers are serum-starved for 72 hours in DME containing 0.4%
fetal bovine serum prior to experiments. Quiescent cell monolayers
are dissociated into single cells and plated at low. For
experimental manipulation, cells are plated in DME containing 1%
bovine serum albumin, transferrin (5 .mu.g/ml; Collaborative
Research), human high density lipoprotein (10 .mu.g/ml; Intracel),
20 mM Hepes, sodium pyruvate (110 mg/L), penicillin G (100
units/ml), streptomycin (100 .mu.g/ml) and L-glutamine (0.292
mg/ml). Cells are harvested in ice-cold 10% trichloroacetic acid
supplemented with 10 mM dithiothreitol (Sigma) and centrifuged at
13,000 rpm for 15 minutes at 4.degree. C. The pellets are washed
once with ice cold distilled water, and once with cold acetone.
Samples are then placed in sample buffer (10 M urea [#161-0730,
Bio-Rad], 1.times. Tris-glycine running buffer, 150 mM
dithiothreitol, 0.01% bromophenol blue), soniccated, loaded onto
and run on electrophoretic gels at 6 mA. Proteins are transferred
to nitrocellulose in 1.times. Tris/glycine buffer with 20%
methanol, blocked in three percent bovine serum albumin in Tris
Buffered Saline, and probed with antibodies to detect
phosphorylated isoforms of myosin regulatory light chain (Cell
Signaling Technologies) for two hours at room temperature. Signals
are detected using a horseradish peroxidase-conjugated secondary
antibody (NA-131, Amersham; 1:4000) and Renaissance Enhanced
Luminol Reagent (NEN Life Sciences Products) as a chemiluminescent
substrate. Signal intensity is normalized and analyzed using NIH
Image.
Motility
[0940] Cellular motility can be assessed using a migration assay.
Fluorescently-labeled HT1080 human fibrosarcoma cells are seeded
into a Fluoroblok Transwell 8 .mu.M pore 96-well plate (Becton
Dickenson) at a density of 40,000 cells per well in serum-free,
phenol-free MEM. Compounds are added to the cells in the transwell
inserts at a final concentration of 0.5% dimethylsulfoxide.
Compounds are also added to the bottom wells in phenol-free MEM
containing 10% fetal bovine serum as the chemoattractant. Cells are
incubated at 37.degree. C. for 4 h, and fluorescence is measured
from the bottom of the plate on a fluorescent plate reader
(Analyst, LJL Biosystems).
[0941] 3. Xenograft Studies
Procedures:
[0942] Set up HRLN female nu/nu mice with 1 mm.sup.3 tumor
fragments se in flank [0943] Do a pair match when tumors reach an
average size of 80-120 mg, and begin treatment [0944] Prepare
dosing solutions: [0945] Positive controls (cell line
dependant)--daily, store at room temp [0946] QO1--daily [0947] Body
Weight: qd .times.5 then 2.times./wk to end [0948] Caliper
Measurement: 2.times./wk to end [0949] Endpoint: TGD. Animals are
to be monitored individually. The endpoint of the experiment is a
tumor volume of 1000 mm.sup.3 or 60 days, whichever comes first;
responders can be followed longer. When the endpoint is reached,
the animals are to be euthanized [0950] Report any adverse
reactions or death to TL, PM, RD or CEO immediately [0951] Return
remaining compound & dosing solution to client [0952] Necropsy
one animal/group at endpoint to examine for overt toxicity or
metastasis. [0953] Report to consist of data, stats, graphs
only.
Dosing Instructions:
[0953] [0954] Dosing volume=10 mL/kg (0.2 mL/20 g mouse). Adjust
volume accordingly for body weight. [0955] Stop dosing and monitor
animals if group mean weight loss >20% or >1 animal dies.
Example 274
[0956] Inhibition of ROCK2 by various compounds was determined.
IC.sub.50 values are reported in Table 1. Differential inhibition
of ROCK1 and ROCK2 has also been observed for several of the
compounds as shown in Table 2.
TABLE-US-00001 TABLE 1 Inhibition of ROCK2 Compound Molecular
IC.sub.50 (.mu.M) Compound Molecular IC.sub.50 (.mu.M) (Example #)
Weight (ROCK2) (Example #) Weight (ROCK2) 230 451.523 >3.00E-06
200 549.666 1.40E-08 211 423.467 1.29E-07 200 3.20E-08 231 479.533
>3.00E-06 200 1.70E-08 212 422.482 >1.00E-04 200 1.20E-08 212
>1.00E-05 201 496.560 3.50E-08 213 481.549 >1.00E-04 201
6.80E-08 213 >1.00E-05 201 3.20E-08 232 452.508 >1.00E-04 201
1.10E-08 232 >3.00E-06 201 9.50E-08 233 353.377 2.00E-06 201
1.20E-07 233 2.50E-06 201 5.10E-08 214 436.508 >1.00E-04 201
6.40E-08 214 >1.00E-05 258 492.572 2.55E-07 215 423.470 1.70E-05
258 1.82E-07 215 >1.00E-05 203 564.680 1.20E-08 234 468.507
>1.00E-04 203 1.20E-08 234 >3.00E-06 203 1.20E-08 235 575.660
>1.00E-04 203 9.50E-09 216 446.460 >1.00E-04 204 549.623
1.51E-07 236 647.724 >1.00E-04 204 1.06E-07 217 463.534 3.60E-05
204 6.70E-08 237 500.551 >1.00E-04 205 551.639 1.10E-08 237
>1.00E-04 205 1.20E-08 238 583.638 >1.00E-04 205 8.00E-09 238
>1.00E-04 205 1.30E-08 218 463.534 >1.00E-04 206 579.649
4.80E-08 218 >1.00E-04 206 6.40E-08 219 410.428 2.90E-06 207
526.586 6.10E-08 220 465.507 >1.00E-04 207 4.40E-08 221 423.470
4.90E-05 207 2.90E-08 239 367.403 >1.00E-04 209 594.707 1.60E-08
222 457.486 >1.00E-04 209 1.40E-08 222 >1.00E-04 210 608.733
1.80E-08 223 457.487 >1.00E-04 210 1.00E-08 223 8.30E-06 259
436.508 2.90E-08 224 451.523 5.30E-06 261 625.717 >3.00E-07 225
424.455 1.70E-06 243 523.629 >3.00E-07 240 395.413 2.30E-05 243
4.00E-06 199 535.639 9.60E-09 262 526.586 2.40E-08 199 2.60E-08 265
466.534 6.50E-06 199 1.20E-08 265 7.30E-06 199 1.00E-08 267 353.377
3.90E-06
[0957] Inhibitory activity for Rho kinase was determined for
examples of compounds of the present invention. Inhibition of Rho
kinase can be assayed as described. For each of these compounds
their inhibitory activity for both ROCK 1 and ROCK 2 was
determined. The following tables 2.1, 2.2, 2.3, and 2.4 show
inhibition of Rho kinase, ROCK 1 and ROCK 2, by compounds of the
invention which are based on Example 82 and compounds which are
modified at position 6, position 7, or both positions 6 and 7 of
compounds based on Example 82. The IC50 values (in .mu.M) for each
of these compounds show a selectivity for inhibiting ROCK2.
TABLE-US-00002 TABLE 2.1 Inhibition of ROCK 1 and ROCK 2 with
compounds of the invention based on example 82. IC50 for IC50 for
ROCK 1 ROCK 2 Example (.mu.M) (.mu.M) 272 >10 0.57 54 >10
0.15 55 >10 0.09 84 2.6 0.52
TABLE-US-00003 TABLE 2.2 Inhibition of ROCK 1 and ROCK 2 with
compounds of the invention based on example 82 with modifications
at the 6,7-position. IC50 for IC50 for ROCK 1 ROCK 2 Example
(.mu.M) (.mu.M) 167 >3 0.06 160 >3 0.05
TABLE-US-00004 TABLE 2.3 Inhibition of ROCK 1 and ROCK 2 with
compounds of the invention based on example 82 with modifications
at the 6 position. IC50 for IC50 for ROCK 1 ROCK 2 Example (.mu.M)
(.mu.M) 141 >1 0.04
TABLE-US-00005 TABLE 2.4 Inhibition of ROCK 1 and ROCK 2 with
compounds of thc invcntion bascd on cxamplc 82 with modifications
at the 7 position. IC50 for IC50 for ROCK 1 ROCK 2 Example (.mu.M)
(.mu.M) 263 >3 0.09
INCORPORATION BY REFERENCE
[0958] All of the patents and publications cited herein are hereby
incorporated by reference in their entireties.
EQUIVALENTS
[0959] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. Such equivalents are intended to be encompassed by the
following claims.
* * * * *