U.S. patent application number 17/589163 was filed with the patent office on 2022-06-02 for kras g12c inhibitors and methods of using the same.
The applicant listed for this patent is AMGEN INC.. Invention is credited to Kate ASHTON, Shon BOOKER, Victor J. CEE, David John KOPECKY, Brian Alan LANMAN, Patricia LOPEZ, Alexander J. PICKRELL, Anthony B. REED, Christopher M. TEGLEY, Hui-Ling WANG, Kevin C. YANG.
Application Number | 20220168280 17/589163 |
Document ID | / |
Family ID | |
Filed Date | 2022-06-02 |
United States Patent
Application |
20220168280 |
Kind Code |
A1 |
LANMAN; Brian Alan ; et
al. |
June 2, 2022 |
KRAS G12C INHIBITORS AND METHODS OF USING THE SAME
Abstract
Provided herein are KRAS G12C inhibitors, composition of the
same, and methods of using the same. These inhibitors are useful
for treating a number of disorders, including pancreatic,
colorectal, and lung cancers.
Inventors: |
LANMAN; Brian Alan;
(Woodland Hills, CA) ; CEE; Victor J.; (Thousand
Oaks, CA) ; PICKRELL; Alexander J.; (Westlake
Village, CA) ; REED; Anthony B.; (Newbury Park,
CA) ; YANG; Kevin C.; (San Gabriel, CA) ;
KOPECKY; David John; (Washington, DC) ; WANG;
Hui-Ling; (Thousand Oaks, CA) ; LOPEZ; Patricia;
(Woodland Hills, CA) ; ASHTON; Kate; (Westlake
Village, CA) ; BOOKER; Shon; (Sherman Oaks, CA)
; TEGLEY; Christopher M.; (Daly City, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AMGEN INC. |
Thousand Oaks |
CA |
US |
|
|
Appl. No.: |
17/589163 |
Filed: |
January 31, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16675121 |
Nov 5, 2019 |
11285135 |
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17589163 |
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15849905 |
Dec 21, 2017 |
10532042 |
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16675121 |
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62438334 |
Dec 22, 2016 |
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International
Class: |
A61K 31/428 20060101
A61K031/428; A61K 31/496 20060101 A61K031/496; A61K 31/519 20060101
A61K031/519; A61P 35/00 20060101 A61P035/00; A61K 31/5025 20060101
A61K031/5025; A61K 31/502 20060101 A61K031/502; A61K 31/517
20060101 A61K031/517; C07D 275/04 20060101 C07D275/04; C07D 471/08
20060101 C07D471/08; C07D 403/04 20060101 C07D403/04; C07D 401/04
20060101 C07D401/04; C07D 513/04 20060101 C07D513/04; C07D 487/04
20060101 C07D487/04; C07D 417/04 20060101 C07D417/04; C07D 239/80
20060101 C07D239/80; C07D 487/10 20060101 C07D487/10; C07D 471/04
20060101 C07D471/04 |
Claims
1. A compound having a structure of formula (I) ##STR00742##
wherein E.sup.1 and E.sup.2 are each independently N or CR.sup.1;
R.sup.1 is independently H, hydroxy, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.1-6alkoxy, NH--C.sub.1-6alkyl,
N(C.sub.1-6alkyl).sub.2, cyano, or halo; R.sup.2 is halo,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR', N(R').sub.2,
C.sub.2-3alkenyl, C.sub.2-3alkynyl, C.sub.0-3
alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, aryl, heteroaryl, and
each R' is independently H, C.sub.1-6 alkyl, C.sub.1-6haloalkyl,
C.sub.3-14cycloalkyl, C.sub.2-14heterocycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl, or two R' substituents,
together with the nitrogen atom to which they are attached, form a
3-7-membered ring; R.sup.3 is halo, C.sub.1-3alkyl,
C.sub.1-2haloalkyl, C.sub.1-3alkoxy, C.sub.3-4cycloalkyl, C.sub.2-3
alkenyl, C.sub.2-3alkynyl, aryl, or heteroaryl; R.sup.4 is
##STR00743## ring A is a monocyclic 4-7 membered ring or a
bicyclic, bridged, fused, or spiro 6-11 membered ring; L is a bond,
C.sub.1-6alkylene, --O--C.sub.0-5alkylene, --S--C.sub.0-5alkylene,
or --NH--C.sub.0-5 alkylene, and for C.sub.2-6alkylene,
--O--C.sub.2-5alkylene, --S--C.sub.2-5alkylene, and NH--C.sub.2-5
alkylene, one carbon atom of the alkylene group can optionally be
replaced with O, S, or NH; R.sup.4' is H, C.sub.1-6alkyl,
C.sub.2-6alkynyl, C.sub.1-6alkylene-O--C.sub.1-4alkyl,
C.sub.1-6alkylene-OH, C.sub.1-6 haloalkyl, cycloalklyl,
heterocycloalkyl, C.sub.0-3alkylene-C.sub.3-4cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14 heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or selected from ##STR00744##
R.sup.5 and R.sup.6 are each independently H, halo, C.sub.1-6alkyl,
C.sub.2-6alkynyl, C.sub.1-6 alkylene-O--C.sub.1-4alkyl,
C.sub.1-6alkylene-OH, C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine,
C.sub.0-6 alkylene-amide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6 alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl, or cyano, or R.sup.5 and
R.sup.6, together with the atoms to which they are attached, form a
4-6 membered ring; and R.sup.7 is H or C.sub.1-8alkyl, or R.sup.7
and R.sup.5, together with the atoms to which they are attached,
form a 4-6 membered ring; or a pharmaceutically acceptable salt
thereof.
2. A compound having a structure of formula (I) ##STR00745##
wherein E.sup.1 and E.sup.2 are each independently N or CR.sup.1;
R.sup.1 is independently H, hydroxy, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.1-6alkoxy, NH--C.sub.1-6alkyl,
N(C.sub.1-4alkyl).sub.2, cyano, or halo; R.sup.2 is halo,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR', N(R').sub.2,
C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or
C.sub.0-3alkylene-C.sub.2-14heteroaryl, and each R' is
independently H, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-14cycloalkyl, C.sub.2-3alkenyl, C.sub.2-3alkynyl, aryl, or
heteroaryl, or two R' substituents, together with the nitrogen atom
to which they are attached, form a 3-7-membered ring; R.sup.3 is
halo, C.sub.1-3alkyl, C.sub.1-2 haloalkyl, C.sub.1-3alkoxy,
C.sub.3-14cycloalkyl, C.sub.2-3alkenyl, C.sub.2-3alkynyl, aryl, or
heteroaryl; R.sup.4 is ##STR00746## ring A is a monocyclic 4-7
membered ring or a bicyclic, bridged, fused, or spiro 6-11 membered
ring; L is a bond, C.sub.1-6alkylene, --O--C.sub.0-5alkylene,
--S--C.sub.0-5alkylene, or --NH--C.sub.0-5 alkylene, and for
C.sub.2-6alkylene, --O--C.sub.2-5alkylene, --S--C.sub.2-5alkylene,
and NH--C.sub.2-5 alkylene, one carbon atom of the alkylene group
can optionally be replaced with O, S, or NH; R.sup.5 and R.sup.6
are each independently H, halo, C.sub.1-8alkyl, C.sub.2-8alkynyl,
C.sub.1-6 alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine, C.sub.0-6
alkylene-amide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6 alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl, or cyano, or R.sup.5 and
R.sup.6, together with the atoms to which they are attached, form a
4-6 membered ring; and R.sup.7 is H or C.sub.1-6alkyl, or R.sup.7
and R.sup.5, together with the atoms to which they are attached,
form a 4-6 membered ring; or a pharmaceutically acceptable salt
thereof.
3. A compound having a structure of formula (II) ##STR00747##
wherein E.sup.1 and E.sup.2 are each independently N or CR.sup.1; J
is N, NR.sup.10, or CR.sup.10; M is N, NR.sup.13, or CR.sup.13; is
a single or double bond as necessary to give every atom its normal
valence; R.sup.1 is independently H, hydroxy, C.sub.1-6alkyl,
C.sub.1-4haloalkyl, C.sub.1-4alkoxy, NH--C.sub.1-4alkyl,
N(C.sub.1-4alkyl).sub.2, cyano, or halo; R.sup.2 is halo,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR', N(R').sub.2,
C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or
C.sub.0-3alkylene-C.sub.2-14heteroaryl, and each R' is
independently H, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-14cycloalkyl, C.sub.2-14heterocycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl, or two R' substituents,
together with the nitrogen atom to which they are attached, form a
3-7-membered ring; R.sup.3 is halo, C.sub.1-3alkyl,
C.sub.1-2haloalkyl, C.sub.1-3alkoxy, C.sub.3-4cycloalkyl,
C.sub.2-14heterocycloalkyl, C.sub.2-3 alkenyl, C.sub.2-3alkynyl,
aryl, or heteroaryl; R.sup.4 is ##STR00748## ring A is a monocyclic
4-7 membered ring or a bicyclic, bridged, fused, or spiro 6-11
membered ring; L is a bond, C.sub.1-6alkylene,
--O--C.sub.0-5alkylene, --S--C.sub.0-5alkylene, or --NH--C.sub.0-5
alkylene, and for C.sub.2-6alkylene, --O--C.sub.2-5alkylene,
--S--C.sub.2-5alkylene, and NH--C.sub.2-5 alkylene, one carbon atom
of the alkylene group can optionally be replaced with O, S, or NH;
R.sup.4' is H, C.sub.1-8alkyl, C.sub.2-8alkynyl,
C.sub.1-6alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6 haloalkyl, cycloalklyl, heterocycloalkyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14 heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or selected from ##STR00749##
R.sup.5 and R.sup.6 are each independently H, halo, C.sub.1-6alkyl,
C.sub.2-6alkynyl, C.sub.1-6 alkylene-O--C.sub.1-4alkyl,
C.sub.1-6alkylene-OH, C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine,
C.sub.0-6 alkylene-amide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6 alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl, or cyano, or R.sup.5 and
R.sup.6, together with the atoms to which they are attached, form a
4-6 membered ring; R.sup.7 is H or C.sub.1-8alkyl, or R.sup.7 and
R.sup.5, together with the atoms to which they are attached, form a
4-6 membered ring; Q is CR.sup.8R.sup.9, C.dbd.CR.sup.8R.sup.9,
C.dbd.O, C.dbd.S, or C.dbd.NR.sup.8; R.sup.8 and R.sup.9 are each
independently H, C.sub.1-3alkyl, hydroxy, C.sub.1-3alkoxy, cyano,
nitro, or C.sub.3-6cycloalkyl, or R.sup.8 and R.sup.9, taken
together with the carbon atom to which they are attached, can form
a 3-6 membered ring; R.sup.10 is C.sub.1-8alkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.3-14heteroaryl, C.sub.0-3
alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, C.sub.1-6alkoxy,
O--C.sub.0-3 alkylene-C.sub.6-14aryl,
O--C.sub.0-3alkylene-C.sub.3-14heteroaryl, O--C.sub.0-3
alkylene-C.sub.3-14cycloalkyl, O--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, NH--C.sub.1-8alkyl,
N(C.sub.1-8alkyl).sub.2, NH--C.sub.0-3alkylene-C.sub.6-14aryl,
NH--C.sub.0-3alkylene-C.sub.2-14heteroaryl,
NH--C.sub.0-3alkylene-C.sub.3-14cycloalkyl, NH--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, halo, cyano, or
C.sub.1-6alkylene-amine; and R.sup.13 is C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine, or
C.sub.3-14cycloalkyl; or a pharmaceutically acceptable salt
thereof, with the proviso that (1) when J is NR.sup.10, M is N or
CR.sup.13; (2) when M is NR.sup.13, J is N or CR.sup.10; (3) when J
is CR.sup.10, M is N or NR.sup.13; and (4) when M is CR.sup.13, J
is N or NR.sup.10.
4. A compound having a structure of formula (II) ##STR00750##
wherein E.sup.1 and E.sup.2 are each independently N or CR.sup.1; J
is N, NR.sup.10, or CR.sup.10; M is N, NR.sup.13, or CR.sup.13; is
a single or double bond as necessary to give every atom its normal
valence; R.sup.1 is independently H, hydroxy, C.sub.1-4alkyl,
C.sub.1-4haloalkyl, C.sub.1-4alkoxy, NH--C.sub.1-4alkyl,
N(C.sub.1-4alkyl).sub.2, cyano, or halo; R.sup.2 is halo,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR', N(R').sub.2,
C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or
C.sub.0-3alkylene-C.sub.2-14heteroaryl, and each R' is
independently H, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-14cycloalkyl, C.sub.2-14heterocycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl, or two R' substituents,
together with the nitrogen atom to which they are attached, form a
3-7-membered ring; R.sup.3 is halo, C.sub.1-3alkyl, C.sub.1-2
haloalkyl, C.sub.1-3alkoxy, C.sub.3-4cycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl; R.sup.4 is ##STR00751## ring
A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,
or spiro 6-11 membered ring; L is a bond, C.sub.1-6alkylene,
--O--C.sub.0-5alkylene, --S--C.sub.0-5alkylene, or --NH--C.sub.0-5
alkylene, and for C.sub.2-6alkylene, --O--C.sub.2-5alkylene,
--S--C.sub.2-5alkylene, and NH--C.sub.2-5 alkylene, one carbon atom
of the alkylene group can optionally be replaced with O, S, or NH;
R.sup.5 and R.sup.6 are each independently H, halo, C.sub.1-6alkyl,
C.sub.2-6alkynyl, C.sub.1-6 alkylene-O--C.sub.1-4alkyl,
C.sub.1-6alkylene-OH, C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine,
C.sub.0-6 alkylene-amide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6 alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl, or cyano, or R.sup.5 and
R.sup.6, together with the atoms to which they are attached, form a
4-6 membered ring; R.sup.7 is H or C.sub.1-8alkyl, or R.sup.7 and
R.sup.5, together with the atoms to which they are attached, form a
4-6 membered ring; Q is CR.sup.8R.sup.9, C.dbd.CR.sup.8R.sup.9,
C.dbd.O, C.dbd.S, or C.dbd.NR.sup.8; R.sup.8 and R.sup.9 are each
independently H, C.sub.1-3alkyl, hydroxy, C.sub.1-3alkoxy, cyano,
nitro, or C.sub.3-6cycloalkyl, or R.sup.8 and R.sup.9, taken
together with the carbon atom to which they are attached, can form
a 3-6 membered ring; R.sup.10 is C.sub.1-8alkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.3-14heteroaryl, C.sub.0-3
alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, C.sub.1-6alkoxy,
O--C.sub.0-3 alkylene-C.sub.6-14aryl,
O--C.sub.0-3alkylene-C.sub.3-14heteroaryl, O--C.sub.0-3
alkylene-C.sub.3-14cycloalkyl, O--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, NH--C.sub.1-8alkyl,
N(C.sub.1-8alkyl).sub.2, NH--C.sub.0-3alkylene-C.sub.6-14aryl,
NH--C.sub.0-3alkylene-C.sub.2-14heteroaryl,
NH--C.sub.0-3alkylene-C.sub.3-14cycloalkyl, NH--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, halo, cyano, or
C.sub.1-6alkylene-amine; and R.sup.13 is C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine, or
C.sub.3-14cycloalkyl; or a pharmaceutically acceptable salt
thereof, with the proviso that (1) when J is NR.sup.10, M is N or
CR.sup.13; (2) when M is NR.sup.13, J is N or CR.sup.10; (3) when J
is CR.sup.10, M is N or NR.sup.13; and (4) when M is CR.sup.13, J
is N or NR.sup.10.
5. The compound of claim 3 or 4, wherein when Q is C.dbd.O; and
E.sup.1 and E.sup.2 are each CR.sup.1; then either (1) R.sup.10 is
C.sub.1-3alkylene-C.sub.6-14aryl,
C.sub.1-3alkylene-C.sub.3-14heteroaryl,
C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.1-3alkylene-C.sub.2-7heterocycloalkyl, or halo; or (2)
R.sup.13 is C.sub.1-3haloalkyl or C.sub.3-5cycloalkyl.
6. The compound of claim 3 or 4, wherein J is NR.sup.10 and M is
CR.sup.13.
7. The compound of claim 3 or 4, wherein J is CR.sup.10 and M is
NR.sup.13.
8. The compound of claim 3 or 4, wherein J is N and M is
NR.sup.13.
9. The compound of claim 3 or 4, wherein J is NR.sup.10 and M is
N.
10. A compound having a structure of formula (III) or (III'):
##STR00752## wherein E.sup.1 and E.sup.2 are each independently N
or CR.sup.1; R.sup.1 is independently H, hydroxy, C.sub.1-6alkyl,
C.sub.1-4haloalkyl, C.sub.1-4alkoxy, NH--C.sub.1-4alkyl,
N(C.sub.1-4alkyl).sub.2, cyano, or halo; R.sup.2 is halo,
C.sub.1-6alkyl, C.sub.1-haloalkyl, OR', N(R').sub.2,
C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or
C.sub.0-3alkylene-C.sub.2-14heteroaryl, and each R' is
independently H, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-14cycloalkyl, C.sub.2-14heterocycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl, or two R' substituents,
together with the nitrogen atom to which they are attached, form a
3-7-membered ring; R.sup.3 is halo, C.sub.1-3alkyl,
C.sub.1-2haloalkyl, C.sub.1-3alkoxy, C.sub.3-4cycloalkyl,
C.sub.2-14heterocycloalkyl, C.sub.2-3 alkenyl, C.sub.2-3alkynyl,
aryl, or heteroaryl; R.sup.4 is ##STR00753## ring A is a monocyclic
4-7 membered ring or a bicyclic, bridged, fused, or spiro 6-11
membered ring; L is a bond, C.sub.1-6alkylene,
--O--C.sub.0-5alkylene, --S--C.sub.0-5alkylene, or --NH--C.sub.0-5
alkylene, and for C.sub.2-6alkylene, --O--C.sub.2-5alkylene,
--S--C.sub.2-5alkylene, and NH--C.sub.2-5 alkylene, one carbon atom
of the alkylene group can optionally be replaced with O, S, or NH;
R.sup.4' is H, C.sub.1-8alkyl, C.sub.2-8alkynyl,
C.sub.1-6alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6 haloalkyl, cycloalklyl, heterocycloalkyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14 heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or selected from ##STR00754##
R.sup.5 and R.sup.6 are each independently H, halo, C.sub.1-6alkyl,
C.sub.2-6alkynyl, C.sub.1-6 alkylene-O--C.sub.1-4alkyl,
C.sub.1-6alkylene-OH, C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine,
C.sub.0-6 alkylene-amide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6 alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl, or cyano, or R.sup.5 and
R.sup.6, together with the atoms to which they are attached, form a
4-6 membered ring; R.sup.7 is H or C.sub.1-8alkyl, or R.sup.7 and
R.sup.5, together with the atoms to which they are attached, form a
4-6 membered ring; Q is CR.sup.8R.sup.9, C.dbd.CR.sup.8R.sup.9,
C.dbd.O, C.dbd.S, or C.dbd.NR.sup.8; R.sup.8 and R.sup.9 are each
independently H, C.sub.1-6alkyl, hydroxy, C.sub.1-6alkoxy, cyano,
nitro, or C.sub.3-14cycloalkyl, or R.sup.8 and R.sup.9, taken
together with the carbon atom to which they are attached, can form
a 3-6 membered ring; R.sup.10 is C.sub.1-8alkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.3-14heteroaryl, C.sub.0-3
alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, C.sub.1-6alkoxy,
O--C.sub.0-3 alkylene-C.sub.6-14aryl,
O--C.sub.0-3alkylene-C.sub.3-14heteroaryl, O--C.sub.0-3
alkylene-C.sub.3-14cycloalkyl, O--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, NH--C.sub.1-8alkyl,
N(C.sub.1-8alkyl).sub.2, NH--C.sub.0-3alkylene-C.sub.6-14aryl,
NH--C.sub.0-3alkylene-C.sub.2-14heteroaryl,
NH--C.sub.0-3alkylene-C.sub.3-14cycloalkyl, NH--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, halo, cyano, or
C.sub.1-6alkylene-amine; or a pharmaceutically acceptable salt
thereof.
11. A compound having a structure of formula (III) or (III'):
##STR00755## wherein E.sup.1 and E.sup.2 are each independently N
or CR.sup.1; R.sup.1 is independently H, hydroxy, C.sub.1-6alkyl,
C.sub.1-4haloalkyl, C.sub.1-4alkoxy, NH--C.sub.1-4alkyl,
N(C.sub.1-4alkyl).sub.2, cyano, or halo; R.sup.2 is halo,
C.sub.1-6alkyl, C.sub.1-haloalkyl, OR', N(R').sub.2,
C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or
C.sub.0-3alkylene-C.sub.2-14heteroaryl, and each R' is
independently H, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-14cycloalkyl, C.sub.2-14heterocycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl, or two R' substituents,
together with the nitrogen atom to which they are attached, form a
3-7-membered ring; R.sup.3 is halo, C.sub.1-3alkyl,
C.sub.1-2haloalkyl, C.sub.1-3alkoxy, C.sub.3-4cycloalkyl,
C.sub.2-14heterocycloalkyl, C.sub.2-3alkenyl, C.sub.2-3alkynyl,
aryl, or heteroaryl; R.sup.4 is ##STR00756## ring A is a monocyclic
4-7 membered ring or a bicyclic, bridged, fused, or spiro 6-11
membered ring; L is a bond, C.sub.1-6alkylene,
--O--C.sub.0-5alkylene, --S--C.sub.0-5alkylene, or --NH--C.sub.0-5
alkylene, and for C.sub.2-6alkylene, --O--C.sub.2-5alkylene,
--S--C.sub.2-5alkylene, and NH--C.sub.2-5 alkylene, one carbon atom
of the alkylene group can optionally be replaced with O, S, or NH;
R.sup.5 and R.sup.6 are each independently H, halo, C.sub.1-6alkyl,
C.sub.2-6alkynyl, C.sub.1-6 alkylene-O--C.sub.1-4alkyl,
C.sub.1-6alkylene-OH, C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine,
C.sub.0-6 alkylene-amide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6 alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl, or cyano, or R.sup.5 and
R.sup.6, together with the atoms to which they are attached, form a
4-6 membered ring; R.sup.7 is H or C.sub.1-8alkyl, or R.sup.7 and
R.sup.5, together with the atoms to which they are attached, form a
4-6 membered ring; Q is CR.sup.8R.sup.9, C.dbd.CR.sup.8R.sup.9,
C.dbd.O, C.dbd.S, or C.dbd.NR.sup.8; R.sup.8 and R.sup.9 are each
independently H, C.sub.1-6alkyl, hydroxy, C.sub.1-6alkoxy, cyano,
nitro, or C.sub.3-14cycloalkyl, or R.sup.8 and R.sup.9, taken
together with the carbon atom to which they are attached, can form
a 3-6 membered ring; R.sup.10 is C.sub.1-8alkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.3-14heteroaryl, C.sub.0-3
alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, C.sub.1-6alkoxy,
O--C.sub.0-3 alkylene-C.sub.6-14aryl,
O--C.sub.0-3alkylene-C.sub.3-14heteroaryl, O--C.sub.0-3
alkylene-C.sub.3-14cycloalkyl, O--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, NH--C.sub.1-8alkyl,
N(C.sub.1-8alkyl).sub.2, NH--C.sub.0-3alkylene-C.sub.6-14aryl,
NH--C.sub.0-3alkylene-C.sub.2-14heteroaryl,
NH--C.sub.0-3alkylene-C.sub.3-14cycloalkyl, NH--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, halo, cyano, or
C.sub.1-6alkylene-amine; or a pharmaceutically acceptable salt
thereof.
12. The compound of claim 10 or 11, having a structure of formula
(III).
13. The compound of claim 10 or 11, having a structure of formula
(III').
14. The compound of any one of claims 3 to 12, wherein Q is
C.dbd.O.
15. The compound of any one of claims 3 to 12, wherein Q is
C.dbd.S.
16. The compound of any one of claims 3 to 12, wherein Q is
C.dbd.NR.sup.8.
17. The compound of claim 16, wherein R.sup.8 is
C.sub.1-2alkyl.
18. The compound of any one of claims 3 to 12, wherein Q is
CR.sup.8R.sup.9.
19. The compound of any one of claims 3 to 12, wherein Q is
C.dbd.CR.sup.8R.sup.9.
20. The compound of claim 18 or 19, wherein R.sup.8 and R.sup.9,
taken together with the carbon atom to which they are attached,
form a 3-4 membered ring.
21. The compound of claim 18 or 19, wherein R.sup.8 is
C.sub.1-2alkyl, and R.sup.9 is H.
22. A compound having a structure of formula (IV) or (IV'):
##STR00757## wherein E.sup.1 and E.sup.2 are each independently
CR.sup.1 or N; R.sup.1 is independently H, hydroxy, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.1-6alkoxy, NH--C.sub.1-6alkyl,
N(C.sub.1-6alkyl).sub.2, cyano, or halo; R.sup.2 is halo,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR', N(R').sub.2,
C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or
C.sub.0-3alkylene-C.sub.2-14heteroaryl, and each R' is
independently H, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-14cycloalkyl, C.sub.2-14heterocycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl, or two R' substituents,
together with the nitrogen atom to which they are attached, form a
3-7-membered ring; R.sup.3 is halo, C.sub.1-2haloalkyl,
C.sub.1-3alkoxy, C.sub.3-4cycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl; R.sup.4 is ##STR00758## ring
A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,
or spiro 6-11 membered ring; L is a bond, C.sub.1-6alkylene,
--O--C.sub.0-5alkylene, --S--C.sub.0-5alkylene, or --NH--C.sub.0-5
alkylene, and for C.sub.2-6alkylene, --O--C.sub.2-5alkylene,
--S--C.sub.2-5alkylene, and NH--C.sub.2-5alkylene, one carbon atom
of the alkylene group can optionally be replaced with O, S, or NH;
R.sup.4' is H, C.sub.1-8alkyl, C.sub.2-8alkynyl,
C.sub.1-6alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6 haloalkyl, cycloalklyl, heterocycloalkyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14 heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or selected from ##STR00759##
R.sup.5 and R.sup.6 are each independently H, halo, C.sub.1-6alkyl,
C.sub.2-6alkynyl, C.sub.1-6 alkylene-O--C.sub.1-4alkyl,
C.sub.1-6alkylene-OH, C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine,
C.sub.0-6 alkylene-amide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6 alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl, or cyano, or R.sup.5 and
R.sup.6, together with the atoms to which they are attached, form a
4-6 membered ring; R.sup.7 is H or C.sub.1-8alkyl, or R.sup.7 and
R.sup.1, together with the atoms to which they are attached, form a
4-6 membered ring; R.sup.8 is H, C.sub.1-3alkyl, hydroxy,
C.sub.1-3alkoxy, halo, cyano, nitro, C.sub.3-14 cycloalkyl, or
NR.sup.11R.sup.12; R.sup.11 and R.sup.12 are each independently H,
C.sub.1-8alkyl, or C.sub.3-14cycloalkyl; and R.sup.10 is
C.sub.1-8alkyl, C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, C.sub.1-6alkoxy,
O--C.sub.0-3alkylene-C.sub.6-14aryl,
O--C.sub.0-3alkylene-C.sub.2-14heteroaryl,
O--C.sub.0-3alkylene-C.sub.3-14 cycloalkyl,
O--C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
NH--C.sub.1-8alkyl, N(C.sub.1-8alkyl).sub.2,
NH--C.sub.0-3alkylene-C.sub.6-14aryl,
NH--C.sub.0-3alkylene-C.sub.2-14heteroaryl,
N--C.sub.0-3alkylene-C.sub.3-14 cycloalkyl,
N--C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, halo, cyano, or
C.sub.1-6 alkylene-amine; or a pharmaceutically acceptable salt
thereof.
23. A compound having a structure of formula (IV) or (IV'):
##STR00760## wherein E.sup.1 and E.sup.2 are each independently
CR.sup.1 or N; R.sup.1 is independently H, hydroxy, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.1-6alkoxy, NH--C.sub.1-6alkyl,
N(C.sub.1-6alkyl).sub.2, cyano, or halo; R.sup.2 is halo,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR', N(R').sub.2,
C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or
C.sub.0-3alkylene-C.sub.2-14heteroaryl, and each R' is
independently H, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-14cycloalkyl, C.sub.2-14heterocycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl, or two R' substituents,
together with the nitrogen atom to which they are attached, form a
3-7-membered ring; R.sup.3 is halo, C.sub.1-2haloalkyl,
C.sub.1-3alkoxy, C.sub.3-14cycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl; R.sup.4 is ##STR00761## ring
A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,
or spiro 6-11 membered ring; L is a bond, C.sub.1-6alkylene,
--O--C.sub.0-5alkylene, --S--C.sub.0-5alkylene, or --NH--C.sub.0-5
alkylene, and for C.sub.2-6alkylene, --O--C.sub.2-5alkylene,
--S--C.sub.2-5alkylene, and NH--C.sub.2-5 alkylene, one carbon atom
of the alkylene group can optionally be replaced with O, S, or NH;
R.sup.5 and R.sup.6 are each independently H, halo, C.sub.1-6alkyl,
C.sub.2-6alkynyl, C.sub.1-6 alkylene-O--C.sub.1-4alkyl,
C.sub.1-alkylene-OH, C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine,
C.sub.0-6 alkylene-amide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6 alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl, or cyano, or R.sup.5 and
R.sup.6, together with the atoms to which they are attached, form a
4-6 membered ring; R.sup.7 is H or C.sub.1-8alkyl, or R.sup.7 and
R.sup.5, together with the atoms to which they are attached, form a
4-6 membered ring; R.sup.8 is H, C.sub.1-3alkyl, hydroxy,
C.sub.1-3alkoxy, halo, cyano, nitro, C.sub.3-14 cycloalkyl, or
NR.sup.11R.sup.12; R.sup.11 and R.sup.12 are each independently H,
C.sub.1-8alkyl, or C.sub.3-15cycloalkyl; and R.sup.10 is
C.sub.1-8alkyl, C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.3-14heteroaryl, C.sub.0-3
alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, C.sub.1-6alkoxy,
O--C.sub.0-3 alkylene-C.sub.6-14aryl,
O--C.sub.0-3alkylene-C.sub.3-14heteroaryl, O--C.sub.0-3
alkylene-C.sub.3-14cycloalkyl, O--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, NH--C.sub.1-8alkyl,
N(C.sub.1-8alkyl).sub.2, NH--C.sub.0-3alkylene-C.sub.6-14aryl,
NH--C.sub.0-3alkylene-C.sub.2-14heteroaryl,
NH--C.sub.0-3alkylene-C.sub.3-14cycloalkyl, NH--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, halo, cyano, or
C.sub.1-6alkylene-amine; or a pharmaceutically acceptable salt
thereof.
24. The compound of claim 22 or 23, having a structure of formula
(IV).
25. The compound of claim 22 or 23, having a structure of formula
(IV').
26. The compound of any one of claims 22 to 25, wherein E.sup.1 and
E.sup.2 are each CR.sup.1, and R.sup.8 is hydroxy, halo, nitro, or
C.sub.3-6cycloalkyl.
27. The compound of any one of claims 22 to 25, wherein R.sup.8 is
methyl.
28. A compound having a structure of formula (V): ##STR00762##
wherein E.sup.1 and E.sup.2 are each independently CR.sup.1 or N;
R.sup.1 is independently H, hydroxy, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.1-6alkoxy, NH--C.sub.1-6alkyl,
N(C.sub.1-6alkyl).sub.2, cyano, or halo; R.sup.2 is halo,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR', N(R').sub.2,
C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or
C.sub.0-3alkylene-C.sub.2-14heteroaryl, and each R' is
independently H, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-14cycloalkyl, C.sub.2-14heterocycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl, or two R' substituents,
together with the nitrogen atom to which they are attached, form a
3-7-membered ring; R.sup.3 is halo, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.3-14cycloalkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, aryl, or heteroaryl; R.sup.4 is
##STR00763## ring A is a monocyclic 4-7 membered ring or a
bicyclic, bridged, fused, or spiro 6-11 membered ring; L is a bond,
C.sub.1-6alkylene, --O--C.sub.0-5alkylene, --S--C.sub.0-5alkylene,
or --NH--C.sub.0-5 alkylene, and for C.sub.2-6alkylene,
--O--C.sub.2-5alkylene, --S--C.sub.2-5alkylene, and NH--C.sub.2-5
alkylene, one carbon atom of the alkylene group can optionally be
replaced with O, S, or NH; R.sup.4' is H, C.sub.1-8alkyl,
C.sub.2-8alkynyl, C.sub.1-6alkylene-O--C.sub.1-4alkyl,
C.sub.1-6alkylene-OH, C.sub.1-6 haloalkyl, cycloalklyl,
heterocycloalkyl, C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14 heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or selected from ##STR00764##
R.sup.5 and R.sup.6 are each independently H, halo, C.sub.1-6alkyl,
C.sub.2-6alkynyl, C.sub.1-6 alkylene-O--C.sub.1-4alkyl,
C.sub.1-6alkylene-OH, C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine,
C.sub.0-6 alkylene-amide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6 alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl, or cyano, or R.sup.5 and
R.sup.6, together with the atoms to which they are attached, form a
4-6 membered ring; R.sup.7 is H or C.sub.1-8alkyl, or R.sup.7 and
R.sup.5, together with the atoms to which they are attached, form a
4-6 membered ring; and R.sup.10 is C.sub.1-8alkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.3-14heteroaryl, C.sub.0-3
alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, C.sub.1-6alkoxy,
O--C.sub.0-3 alkylene-C.sub.6-14aryl,
O--C.sub.0-3alkylene-C.sub.3-14heteroaryl, O--C.sub.0-3
alkylene-C.sub.3-14cycloalkyl, O--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, NH--C.sub.1-8alkyl,
N(C.sub.1-8alkyl).sub.2, NH--C.sub.0-3alkylene-C.sub.6-14aryl,
NH--C.sub.0-3alkylene-C.sub.2-14heteroaryl,
NH--C.sub.0-3alkylene-C.sub.3-14cycloalkyl, NH--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, halo, cyano, or
C.sub.1-6alkylene-amine; or a pharmaceutically acceptable salt
thereof.
29. A compound having a structure of formula (V): ##STR00765##
wherein E.sup.1 and E.sup.2 are each independently CR.sup.1 or N;
R.sup.1 is independently H, hydroxy, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.1-6alkoxy, NH--C.sub.1-6alkyl,
N(C.sub.1-6alkyl).sub.2, cyano, or halo; R.sup.2 is halo,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR', N(R').sub.2,
C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or
C.sub.0-3alkylene-C.sub.2-14heteroaryl, and each R' is
independently H, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-14cycloalkyl, C.sub.2-14heterocycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl, or two R' substituents,
together with the nitrogen atom to which they are attached, form a
3-7-membered ring; R.sup.3 is halo, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.3-14cycloalkyl,
C.sub.2-8alkenyl, C.sub.2-8alkynyl, aryl, or heteroaryl; R.sup.4 is
##STR00766## ring A is a monocyclic 4-7 membered ring or a
bicyclic, bridged, fused, or spiro 6-11 membered ring; L is a bond,
C.sub.1-6alkylene, --O--C.sub.0-5alkylene, --S--C.sub.0-5alkylene,
or --NH--C.sub.0-5alkylene, and for C.sub.2-6alkylene,
--O--C.sub.2-5alkylene, --S--C.sub.2-5alkylene, and
NH--C.sub.2-5alkylene, one carbon atom of the alkylene group can
optionally be replaced with O, S, or NH; R.sup.5 and R.sup.6 are
each independently H, halo, C.sub.1-6alkyl, C.sub.2-6alkynyl,
C.sub.1-6 alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine, C.sub.0-6
alkylene-amide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6 alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl, or cyano, or R.sup.5 and
R.sup.6, together with the atoms to which they are attached, form a
4-6 membered ring; R.sup.7 is H or C.sub.1-8alkyl, or R.sup.7 and
R.sup.5, together with the atoms to which they are attached, form a
4-6 membered ring; and R.sup.10 is C.sub.1-8alkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.3-14heteroaryl, C.sub.0-3
alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, C.sub.1-6alkoxy,
O--C.sub.0-3 alkylene-C.sub.6-14aryl,
O--C.sub.0-3alkylene-C.sub.3-14heteroaryl, O--C.sub.0-3
alkylene-C.sub.3-14cycloalkyl, O--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, NH--C.sub.1-8alkyl,
N(C.sub.1-8alkyl).sub.2, NH--C.sub.0-3alkylene-C.sub.6-14aryl,
NH--C.sub.0-3alkylene-C.sub.2-14heteroaryl,
NH--C.sub.0-3alkylene-C.sub.3-14cycloalkyl, NH--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, halo, cyano, or C.sub.1-6
alkylene-amine; or a pharmaceutically acceptable salt thereof.
30. The compound of any one of claims 1 to 29, wherein each of
E.sup.1 and E.sup.2 is CR.sup.1.
31. The compound of any one of claims 1, 2, 3, 4, 6 to 29 wherein
E.sup.1 is CR.sup.1 and E.sup.2 is N.
32. The compound of any one of claims 1, 2, 3, 4, 6 to 29, wherein
E.sup.1 is N and E.sup.2 is CR.sup.1.
33. The compound of any one of claims 1, 2, 3, 4, 6 to 29, wherein
each of E.sup.1 and E.sup.2 is N.
34. The compound of any one of claims 1, 2, 3, 4, 6 to 33, wherein
R.sup.10 is C.sub.1-6alkyl, aryl, heteroaryl, C.sub.3-14cycloalkyl,
C.sub.2-15heterocycloalkyl, C.sub.1-4alkoxy,
O--C.sub.0-3alkylene-C.sub.6-14aryl,
O--C.sub.0-3alkylene-C.sub.2-14heteroaryl,
O--C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
O--C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
NH--C.sub.1-8alkyl, N(C.sub.1-8alkyl).sub.2,
NH--C.sub.0-3alkylene-C.sub.3-14aryl,
NH--C.sub.0-3alkylene-C.sub.2-14heteroaryl,
NH--C.sub.0-3alkylene-C.sub.3-14cycloalkyl, or
NH--C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl.
35. The compound of claim 28 or 29, wherein E.sup.1 and E.sup.2 are
each CR.sup.1, and R.sup.10 is C.sub.1-3alkylene-C.sub.6-14aryl,
C.sub.1-3alkylene-C.sub.2-14heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.1-3alkylene-C.sub.2-14heterocycloalkyl, or halo.
36. The compound of any one of claims 3 to 33, wherein R.sup.10 is
C.sub.1-8alkyl.
37. The compound of any one of claims 3 to 33, wherein R.sup.10 is
C.sub.0-3alkylene-C.sub.6-14aryl.
38. The compound of any one of claims 3 to 34, wherein R.sup.10 is
C.sub.0-3alkylene-C.sub.3-14heteroaryl.
39. The compound of any one of claims 3 to 35, wherein R.sup.10 is
C.sub.0-3alkylene-C.sub.3-14cycloalkyl.
40. The compound of any one of claims 3 to 24, 26, 27, and 30 to
33, wherein R.sup.10 is
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl.
41. The compound of any one of claims 3 to 33, wherein R.sup.10 is
C.sub.0-6alkylene-amine.
42. The compound of any one of claims 3 to 33, wherein R.sup.10 is
selected from the group consisting of i-Pr, t-Bu, phenyl, benzyl,
OCH.sub.3, Cl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
##STR00767## ##STR00768## ##STR00769## ##STR00770##
43. The compound of any one of claims 3 to 33, wherein R.sup.10
comprises ortho-substituted aryl, ortho-substituted heteroaryl, or
2-substituted cyclohexyl.
44. The compound of claim 43, wherein R.sup.10 is selected from the
group consisting of ##STR00771##
45. The compound of any one of claims 1 to 44, wherein R.sup.1 is
H.
46. The compound of any one of claims 1 to 44, wherein R.sup.1 is
F.
47. The compound of any one of claims 1 to 44, wherein R.sup.1 is
methyl.
48. The compound of any one of claims 1 to 47, wherein R.sup.2 is
aryl.
49. The compound of any one of claims 1 to 47, wherein R.sup.2 is
heteroaryl.
50. The compound of any one of claims 1 to 47, wherein R.sup.2 is
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidine,
pyrrolidine, azetidine, phenyl, naphthyl, pyridyl, indazolyl,
indolyl, azaindolyl, indolinyl, benzotriazolyl, benzoxadiazolyl,
imidazolyl, cinnolinyl, imidazopyridyl, pyrazolopyridyl,
quinolinyl, isoquinolinyl, quinazolinyl, quinazolinonyl,
indolinonyl, isoindolinonyl, tetrahydronaphthyl,
tetrahydroquinolinyl, or tetrahydroisoquinolinyl.
51. The compound of any one of claims 1 to 47, wherein R.sup.2 is
selected from the group consisting of Cl, Br, CF.sub.3, OCH.sub.3,
OCH.sub.2CH.sub.3, phenyl ##STR00772## ##STR00773## ##STR00774##
##STR00775## ##STR00776## ##STR00777## ##STR00778##
52. The compound of any one of claims 1 to 47, wherein R.sup.2 is
selected from the group consisting of bromine, ##STR00779##
53. The compound of any one of claims 1 to 52, wherein R.sup.3 is
halo.
54. The compound of claim 53, wherein R.sup.3 is Cl.
55. The compound of any one of claims 1 to 52, wherein R.sup.3 is
C.sub.1-2alkyl.
56. The compound of claim 55, wherein R.sup.3 is methyl.
57. The compound of any one of claims 1 to 52, wherein R.sup.3 is
C.sub.1-2haloalkyl.
58. The compound of claim 57, wherein R.sup.3 is CF.sub.3.
59. The compound of any one of claims 1 to 58, wherein R.sup.4 is
##STR00780##
60. The compound of claim 59, wherein ring A is ##STR00781##
61. The compound ofany one of claims 1 to 58, wherein R.sup.4 is
##STR00782##
62. The compound of claim 61, wherein ring A is selected from the
group consisting of ##STR00783## ##STR00784##
63. The compound of any one of claims 1 to 58, wherein R.sup.4 is
##STR00785##
64. The compound of any one of claims 1 to 58, wherein R.sup.4 is
##STR00786##
65. The compound of claim 64, wherein ring A is selected from the
group consisting of ##STR00787##
66. The compound of any one of claims 59 to 65, wherein
##STR00788## is selected from the group consisting of ##STR00789##
##STR00790## ##STR00791## ##STR00792## ##STR00793## ##STR00794##
##STR00795## ##STR00796##
67. The compound of any one of claims 59 to 66, wherein L is a
bond.
68. The compound of any one of claims 59 to 66, wherein L is
C.sub.1-2alkylene.
69. The compound of claim 59, 60, 62, 63, or 66, wherein L is
O.
70. The compound of claim 59, 60, 62, 63, or 66, wherein L is
S.
71. The compound of claim 59, 61, 64, 65, or 66, wherein L is
NH.
72. The compound of any one of claims 1 to 59, 61, 63, 64 and 66,
wherein ring A comprises piperidinyl, piperazinyl, pyrrolidinyl, or
azetidinyl.
73. The compound of claim 72, wherein ring A comprises
piperidinyl.
74. The compound of any one of claims 1 to 59, 61, 63, 64 and 65,
wherein R.sup.5 is H or halo.
75. The compound of any one of claims 1 to 59, 61, 63, 64 and 65,
wherein R.sup.5 is H, Br, Cl, F, CN, CH.sub.3, CF.sub.3,
CH.sub.2Br, CH.sub.2OH, CH.sub.2CH.sub.2OH,
CH.sub.2OCH.sub.2phenyl, cyclopropyl, phenyl, CH.sub.2phenyl,
CH.sub.2OCH.sub.3, CH.sub.2N(CH.sub.3).sub.2,
CH.sub.2N(CH.sub.2CH.sub.3).sub.2, CH.sub.2CO.sub.2H,
CH.sub.2CO.sub.2CH.sub.3, CH.sub.2NHC(O)CH.sub.3,
CH.sub.2C(O)NHCH.sub.3, CH.sub.2OC(O)CH.sub.3, or ##STR00797##
76. The compound of any one of claims 1 to 65 and 67 to 75, wherein
R.sup.6 is H, C.sub.1-3alkyl, C.sub.1-3alkylene-O--C.sub.1-2alkyl,
C.sub.1-3alkylene-OH, C.sub.1-3haloalkyl, C.sub.1-3alkylene-amine,
C.sub.0-3alkylene-amide, C.sub.0-1alkylene C(O)OC.sub.1-3alkyl,
C.sub.0-1alkylene-C.sub.2-7heterocycloalkyl,
C.sub.0-1alkylene-C.sub.3-8cycloalkyl, or
C.sub.0-3alkylene-C.sub.6-14aryl.
77. The compound of claim 76, wherein R.sup.6 is
C.sub.1-3alkylene-amine or C.sub.1-3 alkylene-amide and is selected
from the group consisting of CH.sub.2NH.sub.2,
CH(CH.sub.3)NH.sub.2, CH(CH.sub.3).sub.2NH.sub.2,
CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
CH.sub.2NHCH.sub.3, C(O)NHCH.sub.3, C(O)N(CH.sub.3).sub.2,
CH.sub.2C(O)NHphenyl, CH.sub.2NHC(O)CH.sub.3,
CH.sub.2NHCH.sub.2CH.sub.2OH, CH.sub.2NHCH.sub.2CO.sub.2H,
CH.sub.2NH(CH.sub.3)CH.sub.2CO.sub.2CH.sub.3,
CH.sub.2NHCH.sub.2CH.sub.2OCH.sub.3,
CH.sub.2NH(CH.sub.3)CH.sub.2CH.sub.2OCH.sub.3,
CH.sub.2NH(CH.sub.3)CH.sub.2C(O)N(CH.sub.3).sub.2,
CH.sub.2NH(CH.sub.3)CH.sub.2C(O)NHCH.sub.3, CH.sub.2NMe.sub.2,
CH.sub.2NH(CH.sub.3)CH.sub.2CH.sub.2OH,
CH.sub.2NH(CH.sub.3)CH.sub.2CH.sub.2F,
CH.sub.2N.sup.+(CH.sub.3).sub.3, CH.sub.2NHCH.sub.2CHF.sub.2,
CH.sub.2NHCH.sub.2CH.sub.3 ##STR00798## ##STR00799##
78. The compound of any one of claims 1 to 65 and 67 to 75, wherein
R.sup.6 is phenyl, cyclopropyl, CH.sub.3, CF.sub.3,
CH.sub.2CH.sub.3, CH.sub.2NH.sub.2, CH(CH.sub.3)NH.sub.2,
CH(CH.sub.3).sub.2NH.sub.2, CH.sub.2Cl, CH.sub.2Br,
CH.sub.2OCH.sub.3, CH.sub.2Ophenyl, CH.sub.2OH, CO.sub.2H,
CO.sub.2CH.sub.2CH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2OH,
CH.sub.2CH.sub.2N(CH.sub.3).sub.2, CH.sub.2NHCH.sub.3,
C(O)NHCH.sub.3, C(O)N(CH.sub.3).sub.2, CH.sub.2C(O)NHphenyl,
CH.sub.2CHF.sub.2, CH.sub.2F, CHF.sub.2, CH.sub.2NHC(O)CH.sub.3,
CH.sub.2NHCH.sub.2CH.sub.2OH, CH.sub.2NHCH.sub.2CO.sub.2H,
CH.sub.2NH(CH.sub.3)CH.sub.2CO.sub.2CH.sub.3,
CH.sub.2NHCH.sub.2CH.sub.2OCH.sub.3,
CH.sub.2NH(CH.sub.3)CH.sub.2CH.sub.2OCH.sub.3,
CH.sub.2NH(CH.sub.3)CH.sub.2C(O)N(CH.sub.3).sub.2,
CH.sub.2NH(CH.sub.3)CH.sub.2C(O)NHCH.sub.3, CH.sub.2CH.sub.2CCH,
CH.sub.2NMe.sub.2, CH.sub.2NH(CH.sub.3)CH.sub.2CH.sub.2OH,
CH.sub.2NH(CH.sub.3)CH.sub.2CH.sub.2F,
CH.sub.2N.sup.+(CH.sub.3).sub.3, CH.sub.2NHCH.sub.2CHF.sub.2,
CH.sub.2NHCH.sub.2CH.sub.3, ##STR00800## ##STR00801##
##STR00802##
79. The compound of any one of claims 1 to 65 and 67 to 73, wherein
R.sup.5 and R.sup.6 together are ##STR00803##
80. The compound of any one of claims 1 to 65 and 67 to 73, wherein
each of R.sup.5 and R.sup.6 is H.
81. The compound of any one of claims 1 to 58 and 63 to 80, wherein
R.sup.7 is H.
82. The compound of any one of claims 1 to 58 and 63 to 80, wherein
R.sup.7 is methyl.
83. The compound of any one of claims 1 to 58, 63 to 65, 67-73 and
76 to 78, wherein R.sup.7 and R.sup.5 together are --CH.sub.2-- or
--C(O)CH.sub.2--.
84. The compound of any one of claims 1 to 58, wherein R.sup.4 is
selected from the group consisting of ##STR00804## ##STR00805##
##STR00806## ##STR00807##
85. A compound as recited in Table 1.
86. The compound of any one of claims 1 to 85 in the form of a
pharmaceutically acceptable salt.
87. A pharmaceutical formulation comprising the compound of any one
of claims 1 to 86 and a pharmaceutically acceptable excipient.
88. A method of inhibiting KRAS G12C in a cell, comprising
contacting the cell with the compound of any one of claims 1 to 86
or the composition of claim 87.
89. A method of treating cancer in a subject comprising
administering to the subject a therapeutically effective amount of
the compound of any one of claims 1 to 86 or the composition of
claim 87.
90. The method of claim 89, wherein the cancer is lung cancer,
pancreatic cancer, or colorectal cancer.
91. A compound having a structure selected from: ##STR00808##
##STR00809## ##STR00810## ##STR00811## ##STR00812##
##STR00813##
92. The compounds of claim 91 in the form of a pharmaceutically
acceptable salt.
93. A pharmaceutical formulation comprising the compounds of claim
91 or 92 and a pharmaceutically acceptable excipient.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
patent application 62/438,334 filed on Dec. 22, 2016, which
specification is hereby incorporated herein by reference in its
entirety for all purposes.
BACKGROUND
[0002] KRAS gene mutations are common in pancreatic cancer, lung
adenocarcinoma, colorectal cancer, gall bladder cancer, thyroid
cancer, and bile duct cancer. KRAS mutations are also observed in
about 25% of patients with NSCLC, and some studies have indicated
that KRAS mutations are a negative prognostic factor in patients
with NSCLC. Recently, V-Ki-ras2 Kirsten rat sarcoma viral oncogene
homolog (KRAS) mutations have been found to confer resistance to
epidermal growth factor receptor (EGFR) targeted therapies in
colorectal cancer; accordingly, the mutational status of KRAS can
provide important information prior to the prescription of TKI
therapy. Taken together, there is a need for new medical treatments
for patients with pancreatic cancer, lung adenocarcinoma, or
colorectal cancer, especially those who have been diagnosed to have
such cancers characterized by a KRAS mutation, and including those
who have progressed after chemotherapy.
SUMMARY
[0003] Provided herein are compound having a structure of formula
(I)
##STR00001##
wherein
[0004] E.sup.1 and E.sup.2 are each independently N or
CR.sup.1;
[0005] R.sup.1 is independently H, hydroxy, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.1-6alkoxy, NH--C.sub.1-6alkyl,
N(C.sub.1-6alkyl).sub.2, cyano, or halo;
[0006] R.sup.2 is halo, C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR',
N(R').sub.2, C.sub.2-3alkenyl, C.sub.2-3alkynyl, C.sub.0-3
alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3 alkylenearyl, or C.sub.0-3 alkyleneheteroaryl, and each
R' is independently H, C.sub.1-6 alkyl, C.sub.1-6haloalkyl,
C.sub.3-14cycloalkyl, C.sub.2-14heterocycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl, or two R' substituents,
together with the nitrogen atom to which they are attached, form a
3-7-membered ring;
[0007] R.sup.3 is halo, C.sub.1-3alkyl, C.sub.1 2haloalkyl,
C.sub.1-3alkoxy, C.sub.3-4cycloalkyl, C.sub.2-3 alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl;
[0008] R.sup.4 is
##STR00002##
[0009] ring A is a monocyclic 4-7 membered ring or a bicyclic,
bridged, fused, or spiro 6-11 membered ring;
[0010] L is a bond, C.sub.1-6alkylene, --O--C.sub.0-5alkylene,
--S--C.sub.0-5alkylene, or --NH--C.sub.0-5 alkylene, and for
C.sub.2-6alkylene, --O--C.sub.2-5alkylene, --S--C.sub.2-5alkylene,
and NH--C.sub.2-5 alkylene, one carbon atom of the alkylene group
can optionally be replaced with O, S, or NH;
[0011] R.sup.4' is H, C.sub.1-6alkyl, C.sub.2-6alkynyl,
C.sub.1-6alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6 haloalkyl, cycloalklyl, heterocycloalkyl,
C.sub.0-3alkylene-C.sub.3-4cycloalkyl, C.sub.0-3alkylene-C.sub.2-14
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or selected from
##STR00003##
[0012] R.sup.5 and R.sup.6 are each independently H, halo,
C.sub.1-6alkyl, C.sub.2-6alkynyl, C.sub.1-6
alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine, C.sub.0-6
alkylene-amide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6 alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl, or cyano, or R.sup.5 and
R.sup.6, together with the atoms to which they are attached, form a
4-6 membered ring; and
[0013] R.sup.7 is H or C.sub.1-8alkyl, or R.sup.7 and R.sup.5,
together with the atoms to which they are attached, form a 4-6
membered ring,
or a pharmaceutically acceptable salt thereof.
[0014] In another embodiment, provided herein are compounds having
a structure of formula (I)
##STR00004##
wherein
[0015] E.sup.1 and E.sup.2 are each independently N or
CR.sup.1;
[0016] R.sup.1 is independently H, hydroxy, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.1-6alkoxy, NH--C.sub.1-6alkyl,
N(C.sub.1-4alkyl).sub.2, cyano, or halo;
[0017] R.sup.2 is halo, C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR',
N(R').sub.2, C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or
C.sub.0-3alkylene-C.sub.2-14heteroaryl, and each R' is
independently H, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-14cycloalkyl, C.sub.2-3alkenyl, C.sub.2-3alkynyl, aryl, or
heteroaryl, or two R' substituents, together with the nitrogen atom
to which they are attached, form a 3-7-membered ring;
[0018] R.sup.3 is halo, C.sub.1-3alkyl, C.sub.1 2haloalkyl,
C.sub.1-3alkoxy, C.sub.3-14cycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl;
[0019] R.sup.4 is
##STR00005##
[0020] ring A is a monocyclic 4-7 membered ring or a bicyclic,
bridged, fused, or spiro 6-11 membered ring;
[0021] L is a bond, C.sub.1-6alkylene, --O--C.sub.0-5alkylene,
--S--C.sub.0-5alkylene, or --NH--C.sub.0-5 alkylene, and for
C.sub.2-6alkylene, --O--C.sub.2-5alkylene, --S--C.sub.2-5alkylene,
and NH--C.sub.2-5 alkylene, one carbon atom of the alkylene group
can optionally be replaced with O, S, or NH;
[0022] R.sup.5 and R.sup.6 are each independently H, halo,
C.sub.1-5alkyl, C.sub.2-5alkynyl, C.sub.1-6
alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine, C.sub.0-6
alkylene-amide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6 alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl, or cyano, or R.sup.5 and
R.sup.6, together with the atoms to which they are attached, form a
4-6 membered ring; and
[0023] R.sup.7 is H or C.sub.1-6alkyl, or R.sup.7 and R.sup.5,
together with the atoms to which they are attached, form a 4-6
membered ring,
or a pharmaceutically acceptable salt thereof.
[0024] Further provided are compounds of formula (II), or a
pharmaceutically acceptable salt thereof:
##STR00006##
wherein E.sup.1 and E.sup.2 are each independently N or CR.sup.1; J
is N, NR.sup.10, or CR.sup.10; M is N, NR.sup.13, or CR.sup.13; is
a single or double bond as necessary to give every atom its normal
valence; R.sup.1 is independently H, hydroxy, C.sub.1-6alkyl,
C.sub.1-4haloalkyl, C.sub.1-4alkoxy, NH--C.sub.1-4alkyl,
N(C.sub.1-4alkyl).sub.2, cyano, or halo; R.sup.2 is halo,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR', N(R').sub.2,
C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or
C.sub.0-3alkylene-C.sub.2-14heteroaryl, and each R' is
independently H, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-14cycloalkyl, C.sub.2-14heterocycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl, or two R' substituents,
together with the nitrogen atom to which they are attached, form a
3-7-membered ring; R.sup.3 is halo, C.sub.1-3alkyl,
C.sub.1-2haloalkyl, C.sub.1-3alkoxy, C.sub.3-4cycloalkyl,
C.sub.2-14heterocycloalkyl, C.sub.2-3 alkenyl, C.sub.2-3alkynyl,
aryl, or heteroaryl;
[0025] R.sup.4
##STR00007##
ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged,
fused, or spiro 6-11 membered ring; L is a bond, C.sub.1-6alkylene,
--O--C.sub.0-5alkylene, --S--C.sub.0-5alkylene, or --NH--C.sub.0-5
alkylene, and for C.sub.2-6alkylene, --O--C.sub.2-5alkylene,
--S--C.sub.2-5alkylene, and NH--C.sub.2-5 alkylene, one carbon atom
of the alkylene group can optionally be replaced with O, S, or NH;
R.sup.4' is H, C.sub.1-8alkyl, C.sub.2-8alkynyl,
C.sub.1-6alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6 haloalkyl, cycloalklyl, heterocycloalkyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14 heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or selected from
##STR00008##
[0026] R.sup.5 and R.sup.6 are each independently H, halo,
C.sub.1-6alkyl, C.sub.2-6alkynyl, C.sub.1-6
alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine, C.sub.0-6
alkylene-amide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6 alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl, or cyano, or R.sup.5 and
R.sup.6, together with the atoms to which they are attached, form a
4-6 membered ring; R.sup.7 is H or C.sub.1-8alkyl, or R.sup.7 and
R.sup.5, together with the atoms to which they are attached, form a
4-6 membered ring; Q is CR.sup.8R.sup.9, C=CR.sup.8R.sup.9,
C.dbd.O, C=S, or C.dbd.NR.sup.8; R.sup.8 and R.sup.9 are each
independently H, C.sub.1-3alkyl, hydroxy, C.sub.1-3alkoxy, cyano,
nitro, or C.sub.3-6cycloalkyl, or R.sup.8 and R.sup.9, taken
together with the carbon atom to which they are attached, can form
a 3-6 membered ring; R.sup.10 is C.sub.1-8alkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.3-14heteroaryl, C.sub.0-3
alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, C.sub.1-6alkoxy,
O--C.sub.0-3 alkylene-C.sub.6-14aryl,
O--C.sub.0-3alkylene-C.sub.3-14heteroaryl, O--C.sub.0-3
alkylene-C.sub.3-14cycloalkyl, O--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, NH--C.sub.1-8alkyl,
N(C.sub.1-8alkyl).sub.2, NH--C.sub.0-3alkylene-C.sub.6-14aryl,
NH--C.sub.0-3alkylene-C.sub.2-14heteroaryl,
NH--C.sub.0-3alkylene-C.sub.3-14cycloalkyl, NH--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, halo, cyano, or
C.sub.1-6alkylene-amine; and R.sup.13 is C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine, or
C.sub.3-14cycloalkyl, or a pharmaceutically acceptable salt
thereof, with the proviso that [0027] (1) when J is NR.sup.10, M is
N or CR.sup.13; [0028] (2) when M is NR.sup.13, J is N or
CR.sup.10; [0029] (3) when J is CR.sup.10, M is N or NR.sup.13; and
[0030] (4) when M is CR.sup.13, J is N or NR.sup.10.
[0031] In some embodiments, when Q is C.dbd.O, and E.sup.1 and
E.sup.2 are each CR.sup.1; then either (1) R.sup.10 is
C.sub.1-3alkylenearyl, C.sub.1-3alkyleneheteroaryl,
C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.1-3alkylene-C.sub.2-7heterocycloalkyl, or halo; or (2)
R.sup.13 is C.sub.1-3haloalkyl or C.sub.3-5cycloalkyl. In various
embodiments, J is NR.sup.10 and M is CR.sup.13. In some
embodiments, J is CR.sup.10 and M is NR.sup.13. In some
embodiments, J is N and M is NR.sup.13. In various embodiments, J
is NR.sup.10 and M is N.
[0032] Further provided are compounds having a structure of formula
(II)
##STR00009##
wherein
[0033] E.sup.1 and E.sup.2 are each independently N or
CR.sup.1;
[0034] J is N, NR.sup.10, or CR.sup.10;
[0035] M is N, NR.sup.13, or CR.sup.13;
[0036] is a single or double bond as necessary to give every atom
its normal valence;
[0037] R.sup.1 is independently H, hydroxy, C.sub.1-4alkyl,
C.sub.1-4haloalkyl, C.sub.1-4alkoxy, NH--C.sub.1-4alkyl,
N(C.sub.1-4alkyl).sub.2, cyano, or halo; R.sup.2 is halo,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR', N(R').sub.2,
C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or
C.sub.0-3alkylene-C.sub.2-14heteroaryl, and each R' is
independently H, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-14cycloalkyl, C.sub.2-14heterocycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl, or two R' substituents,
together with the nitrogen atom to which they are attached, form a
3-7-membered ring; R.sup.3 is halo, C.sub.1-3alkyl, C.sub.1
2haloalkyl, C.sub.1-3alkoxy, C.sub.3-4cycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl;
[0038] R.sup.4 is
##STR00010##
[0039] ring A is a monocyclic 4-7 membered ring or a bicyclic,
bridged, fused, or spiro 6-11 membered ring;
[0040] L is a bond, C.sub.1-6alkylene, --O--C.sub.0-5alkylene,
--S--C.sub.0-5alkylene, or --NH--C.sub.0-5 alkylene, and for
C.sub.2-6alkylene, --O--C.sub.2-5alkylene, --S--C.sub.2-5alkylene,
and NH--C.sub.2-5 alkylene, one carbon atom of the alkylene group
can optionally be replaced with O, S, or NH;
[0041] R.sup.5 and R.sup.6 are each independently H, halo,
C.sub.1-6alkyl, C.sub.2-6alkynyl, C.sub.1-6
alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine, C.sub.0-6
alkylene-amide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6 alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl, or cyano, or R.sup.5 and
R.sup.6, together with the atoms to which they are attached, form a
4-6 membered ring;
[0042] R.sup.7 is H or C.sub.1-8alkyl, or R.sup.7 and R.sup.5,
together with the atoms to which they are attached, form a 4-6
membered ring;
[0043] Q is CR.sup.8R.sup.9, C.dbd.CR.sup.8R.sup.9, C.dbd.O,
C.dbd.S, or C.dbd.NR.sup.B;
[0044] R.sup.8 and R.sup.9 are each independently H,
C.sub.1-3alkyl, hydroxy, C.sub.1-3alkoxy, cyano, nitro, or
C.sub.3-6cycloalkyl, or R.sup.8 and R.sup.9, taken together with
the carbon atom to which they are attached, can form a 3-6 membered
ring;
[0045] R.sup.10 is C.sub.1-8alkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.3-14heteroaryl, C.sub.0-3
alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, C.sub.1-6alkoxy,
O--C.sub.0-3 alkylene-C.sub.6-14aryl,
O--C.sub.0-3alkylene-C.sub.3-14heteroaryl, O--C.sub.0-3
alkylene-C.sub.3-14cycloalkyl, O--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, NH--C.sub.1-8alkyl,
N(C.sub.1-8alkyl).sub.2, NH--C.sub.0-3alkylene-C.sub.6-14aryl,
NH--C.sub.0-3alkylene-C.sub.2-14heteroaryl,
NH--C.sub.0-3alkylene-C.sub.3-14cycloalkyl, NH--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, halo, cyano, or
C.sub.1-6alkylene-amine;
[0046] with the proviso that [0047] (1) when J is NR.sup.10, M is N
or CR.sup.13; [0048] (2) when M is NR.sup.13, J is N or CR.sup.10;
[0049] (3) when J is CR.sup.10, M is N or NR.sup.13; and [0050] (4)
when M is CR.sup.13, J is N or NR.sup.10.
[0051] In some embodiments, when Q is C.dbd.O, and E.sup.1 and
E.sup.2 are each CR.sup.1; then either (1) R.sup.10 is
C.sub.1-3alkylenearyl, C.sub.1-3alkyleneheteroaryl,
C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.1-3alkylene-C.sub.2-7heterocycloalkyl, or halo; or (2)
R.sup.13 is C.sub.1-3haloalkyl or C.sub.3-5cycloalkyl. In various
embodiments, J is NR.sup.10 and M is CR.sup.13. In some
embodiments, J is CR.sup.10 and M is NR.sup.13. In some
embodiments, J is N and M is NR.sup.13. In various embodiments, J
is NR.sup.10 and M is N.
[0052] Further provided are compounds of formula (III) or (III'),
or a pharmaceutically acceptable salt thereof:
##STR00011##
wherein E.sup.1 and E.sup.2 are each independently N or
CR.sup.1;
[0053] R.sup.1 is independently H, hydroxy, C.sub.1-6alkyl,
C.sub.1-4haloalkyl, C.sub.1-4alkoxy, NH--C.sub.1-4alkyl,
N(C.sub.1-4alkyl).sub.2, cyano, or halo;
[0054] R.sup.2 is halo, C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR',
N(R').sub.2, C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or
C.sub.0-3alkylene-C.sub.2-14heteroaryl, and each R' is
independently H, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-14cycloalkyl, C.sub.2-14heterocycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl, or two R' substituents,
together with the nitrogen atom to which they are attached, form a
3-7-membered ring;
[0055] R.sup.3 is halo, C.sub.1-3alkyl, C.sub.1-2haloalkyl,
C.sub.1-3alkoxy, C.sub.3-4cycloalkyl, C.sub.2-14heterocycloalkyl,
C.sub.2-3 alkenyl, C.sub.2-3alkynyl, aryl, or heteroaryl;
[0056] R.sup.4 is
##STR00012##
[0057] ring A is a monocyclic 4-7 membered ring or a bicyclic,
bridged, fused, or spiro 6-11 membered ring;
[0058] L is a bond, C.sub.1-6alkylene, --O--C.sub.0-5alkylene,
--S--C.sub.0-5alkylene, or --NH--C.sub.0-5 alkylene, and for
C.sub.2-6alkylene, --O--C.sub.2-5alkylene, --S--C.sub.2-5alkylene,
and NH--C.sub.2-5 alkylene, one carbon atom of the alkylene group
can optionally be replaced with O, S, or NH;
[0059] R.sup.4' is H, C.sub.1-8alkyl, C.sub.2-8alkynyl,
C.sub.1-6alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6 haloalkyl, cycloalklyl, heterocycloalkyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14 heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or selected from
##STR00013##
[0060] R.sup.5 and R.sup.6 are each independently H, halo,
C.sub.1-6alkyl, C.sub.2-6alkynyl, C.sub.1-6
alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine, C.sub.0-6
alkylene-amide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6 alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl, or cyano, or R.sup.5 and
R.sup.6, together with the atoms to which they are attached, form a
4-6 membered ring;
[0061] R.sup.7 is H or C.sub.1-8alkyl, or R.sup.7 and R.sup.5,
together with the atoms to which they are attached, form a 4-6
membered ring;
[0062] Q is CR.sup.8R.sup.9, C.dbd.CR.sup.8R.sup.9, C.dbd.O,
C.dbd.S, or C.dbd.NR.sup.B;
[0063] R.sup.8 and R.sup.9 are each independently H,
C.sub.1-6alkyl, hydroxy, C.sub.1-6alkoxy, cyano, nitro, or
C.sub.3-14cycloalkyl, or R.sup.8 and R.sup.9, taken together with
the carbon atom to which they are attached, can form a 3-6 membered
ring;
[0064] R.sup.10 is C.sub.1-8alkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.3-14heteroaryl, C.sub.0-3
alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, C.sub.1-6alkoxy,
O--C.sub.0-3 alkylene-C.sub.6-14aryl,
O--C.sub.0-3alkylene-C.sub.3-14heteroaryl, O--C.sub.0-3
alkylene-C.sub.3-14cycloalkyl, O--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, NH--C.sub.1-8alkyl,
N(C.sub.1-8alkyl).sub.2, NH--C.sub.0-3alkylene-C.sub.6-14aryl,
NH--C.sub.0-3alkylene-C.sub.2-14heteroaryl,
NH--C.sub.0-3alkylene-C.sub.3-14cycloalkyl, NH--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, halo, cyano, or
C.sub.1-6alkylene-amine.
[0065] Further provided are compounds of formula (III) or (III'),
or a pharmaceutically acceptable salt thereof:
##STR00014##
wherein
[0066] E.sup.1 and E.sup.2 are each independently N or
CR.sup.1;
[0067] R.sup.1 is independently H, hydroxy, C.sub.1-6alkyl,
C.sub.1-4haloalkyl, C.sub.1-4alkoxy, NH--C.sub.1-4alkyl,
N(C.sub.1-4alkyl).sub.2, cyano, or halo;
[0068] R.sup.2 is halo, C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR',
N(R').sub.2, C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or
C.sub.0-3alkylene-C.sub.2-14heteroaryl, and each R' is
independently H, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-14cycloalkyl, C.sub.2-14heterocycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl, or two R' substituents,
together with the nitrogen atom to which they are attached, form a
3-7-membered ring;
[0069] R.sup.3 is halo, C.sub.1-3alkyl, C.sub.1-2haloalkyl,
C.sub.1-3alkoxy, C.sub.3-4cycloalkyl, C.sub.2-14heterocycloalkyl,
C.sub.2-3 alkenyl, C.sub.2-3alkynyl, aryl, or heteroaryl;
[0070] R.sup.4 is
##STR00015##
ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged,
fused, or spiro 6-11 membered ring;
[0071] L is a bond, C.sub.1-6alkylene, --O--C.sub.0-5alkylene,
--S--C.sub.0-5alkylene, or --NH--C.sub.0-5 alkylene, and for
C.sub.2-6alkylene, --O--C.sub.2-5alkylene, --S--C.sub.2-5alkylene,
and NH--C.sub.2-5 alkylene, one carbon atom of the alkylene group
can optionally be replaced with O, S, or NH;
[0072] R.sup.5 and R.sup.6 are each independently H, halo,
C.sub.1-6alkyl, C.sub.2-6alkynyl, C.sub.1-6
alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine, C.sub.0-6
alkylene-amide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6 alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl, or cyano, or R.sup.5 and
R.sup.6, together with the atoms to which they are attached, form a
4-6 membered ring;
[0073] R.sup.7 is H or C.sub.1-8alkyl, or R.sup.7 and R.sup.5,
together with the atoms to which they are attached, form a 4-6
membered ring;
[0074] Q is CR.sup.8R.sup.9, C.dbd.CR.sup.8R.sup.9, C.dbd.O,
C.dbd.S, or C.dbd.NR.sup.8;
[0075] R.sup.8 and R.sup.9 are each independently H,
C.sub.1-6alkyl, hydroxy, C.sub.1-6alkoxy, cyano, nitro, or
C.sub.3-14cycloalkyl, or R.sup.8 and R.sup.9, taken together with
the carbon atom to which they are attached, can form a 3-6 membered
ring;
[0076] R.sup.10 is C.sub.1-8alkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.3-14heteroaryl, C.sub.0-3
alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, C.sub.1-6alkoxy,
O--C.sub.0-3 alkylene-C.sub.6-14aryl,
O--C.sub.0-3alkylene-C.sub.3-14heteroaryl, O--C.sub.0-3
alkylene-C.sub.3-14cycloalkyl, O--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, NH--C.sub.1-8alkyl,
N(C.sub.1-8alkyl).sub.2, NH--C.sub.0-3alkylene-C.sub.6-14aryl,
NH--C.sub.0-3alkylene-C.sub.2-14heteroaryl,
NH--C.sub.0-3alkylene-C.sub.3-14cycloalkyl, NH--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, halo, cyano, or
C.sub.1-6alkylene-amine.
[0077] In some embodiments, the compounds have a structure of
formula (III). In other embodiments, the compounds have a structure
of formula (III').
[0078] The compounds of formula (II) or (III) as disclosed herein
can have one or more of the following features. In some
embodiments, Q is C.dbd.O. In some embodiments, Q is C.dbd.S. In
some embodiments, Q is C.dbd.NR.sup.8. In various embodiments,
R.sup.8 is C.sub.1-2alkyl. In some embodiments, Q is
CR.sup.8R.sup.9. In various embodiments, Q is
C.dbd.CR.sup.8R.sup.9. In some embodiments, R.sup.8 and R.sup.9,
taken together with the carbon atom to which they are attached,
form a 3-4 membered ring. In some embodiments, R.sup.8 is
C.sub.1-2alkyl, and R.sup.9 is H.
[0079] Also provided are compounds of formula (IV) or (IV'), or a
pharmaceutically acceptable salt thereof:
##STR00016##
E.sup.1 and E.sup.2 are each independently CR.sup.1 or N;
[0080] R.sup.1 is independently H, hydroxy, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.1-6alkoxy, NH--C.sub.1-6alkyl,
N(C.sub.1-6alkyl).sub.2, cyano, or halo;
[0081] R.sup.2 is halo, C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR',
N(R').sub.2, C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or
C.sub.0-3alkylene-C.sub.2-14heteroaryl, and each R' is
independently H, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-14cycloalkyl, C.sub.2-14heterocycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl, or two R' substituents,
together with the nitrogen atom to which they are attached, form a
3-7-membered ring;
[0082] R.sup.3 is halo, C.sub.1-2haloalkyl, C.sub.1-3alkoxy,
C.sub.3-4cycloalkyl, C.sub.2-3alkenyl, C.sub.2-3alkynyl, aryl, or
heteroaryl;
[0083] R.sup.4 is
##STR00017##
[0084] ring A is a monocyclic 4-7 membered ring or a bicyclic,
bridged, fused, or spiro 6-11 membered ring;
[0085] L is a bond, C.sub.1-6alkylene, --O--C.sub.0-5alkylene,
--S--C.sub.0-5alkylene, or --NH--C.sub.0-5 alkylene, and for
C.sub.2-6alkylene, --O--C.sub.2-5alkylene, --S--C.sub.2-5alkylene,
and NH--C.sub.2-5alkylene, one carbon atom of the alkylene group
can optionally be replaced with O, S, or NH;
[0086] R.sup.4' is H, C.sub.1-8alkyl, C.sub.2-8alkynyl,
C.sub.1-6alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6 haloalkyl, cycloalklyl, heterocycloalkyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14 heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or selected from
##STR00018##
[0087] R.sup.5 and R.sup.6 are each independently H, halo,
C.sub.1-6alkyl, C.sub.2-6alkynyl, C.sub.1-6
alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine, C.sub.0-6
alkylene-amide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6 alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl, or cyano, or R.sup.5 and
R.sup.6, together with the atoms to which they are attached, form a
4-6 membered ring;
[0088] R.sup.7 is H or C.sub.1-8alkyl, or R.sup.7 and R.sup.1,
together with the atoms to which they are attached, form a 4-6
membered ring;
[0089] R.sup.8 is H, C.sub.1-3alkyl, hydroxy, C.sub.1-3alkoxy,
halo, cyano, nitro, C.sub.3-14 cycloalkyl, or
NR.sup.11R.sup.12;
[0090] R.sup.11 and R.sup.12 are each independently H,
C.sub.1-8alkyl, or C.sub.3-14cycloalkyl; and
[0091] R.sup.10 is C.sub.1-8alkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, C.sub.1-6alkoxy,
O--C.sub.0-3alkylene-C.sub.6-14aryl,
O--C.sub.0-3alkylene-C.sub.2-14heteroaryl,
O--C.sub.0-3alkylene-C.sub.3-14 cycloalkyl,
O--C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
NH--C.sub.1-8alkyl, N(C.sub.1-8alkyl).sub.2,
NH--C.sub.0-3alkylene-C.sub.6-14aryl,
NH--C.sub.0-3alkylene-C.sub.2-14heteroaryl,
N--C.sub.0-3alkylene-C.sub.3-14 cycloalkyl,
N--C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, halo, cyano, or
C.sub.1-6 alkylene-amine;
[0092] In some embodiments, the compounds disclosed herein have a
structure of formula (IV). In various embodiments, the compounds
disclosed herein have a structure of formula (IV'). In some
embodiments, E.sup.1 and E.sup.2 are each CR.sup.1, and R.sup.8 is
hydroxy, halo, nitro, or C.sub.3-6cycloalkyl.
[0093] In some embodiments, R.sup.8 is methyl.
[0094] Further provided are compounds having a structure of formula
(IV) or (IV'):
##STR00019##
wherein
[0095] E.sup.1 and E.sup.2 are each independently CR.sup.1 or
N;
[0096] R.sup.1 is independently H, hydroxy, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.1-6alkoxy, NH--C.sub.1-6alkyl,
N(C.sub.1-6alkyl).sub.2, cyano, or halo;
[0097] R.sup.2 is halo, C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR',
N(R').sub.2, C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or
C.sub.0-3alkylene-C.sub.2-14heteroaryl, and each R' is
independently H, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-14cycloalkyl, C.sub.2-14heterocycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl, or two R' substituents,
together with the nitrogen atom to which they are attached, form a
3-7-membered ring;
[0098] R.sup.3 is halo, C.sub.1-2haloalkyl, C.sub.1-3alkoxy,
C.sub.3-14cycloalkyl, C.sub.2-3alkenyl, C.sub.2-3alkynyl, aryl, or
heteroaryl;
[0099] R.sup.4 is
##STR00020##
[0100] ring A is a monocyclic 4-7 membered ring or a bicyclic,
bridged, fused, or spiro 6-11 membered ring;
[0101] L is a bond, C.sub.1-6alkylene, --O--C.sub.0-5alkylene,
--S--C.sub.0-5alkylene, or --NH--C.sub.0-5 alkylene, and for
C.sub.2-6alkylene, --O--C.sub.2-5alkylene, --S--C.sub.2-5alkylene,
and NH--C.sub.2-5 alkylene, one carbon atom of the alkylene group
can optionally be replaced with O, S, or NH;
[0102] R.sup.5 and R.sup.6 are each independently H, halo,
C.sub.1-6alkyl, C.sub.2-6alkynyl, C.sub.1-6
alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine, C.sub.0-6
alkylene-amide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6 alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl, or cyano, or R.sup.5 and
R.sup.6, together with the atoms to which they are attached, form a
4-6 membered ring;
[0103] R.sup.7 is H or C.sub.1-8alkyl, or R.sup.7 and R.sup.5,
together with the atoms to which they are attached, form a 4-6
membered ring;
[0104] R.sup.8 is H, C.sub.1-3alkyl, hydroxy, C.sub.1-3alkoxy,
halo, cyano, nitro, C.sub.3-14 cycloalkyl, or
NR.sup.11R.sup.12;
[0105] R.sup.11 and R.sup.12 are each independently H,
C.sub.1-8alkyl, or C.sub.3-15cycloalkyl; and
[0106] R.sup.10 is C.sub.1-8alkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.3-14heteroaryl, C.sub.0-3
alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, C.sub.1-6alkoxy,
O--C.sub.0-3 alkylene-C.sub.6-14aryl,
O--C.sub.0-3alkylene-C.sub.3-14heteroaryl, O--C.sub.0-3
alkylene-C.sub.3-14cycloalkyl, O--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, NH--C.sub.1-8alkyl,
N(C.sub.1-8alkyl).sub.2, NH--C.sub.0-3alkylene-C.sub.6-14aryl,
NH--C.sub.0-3alkylene-C.sub.2-14heteroaryl,
NH--C.sub.0-3alkylene-C.sub.3-14cycloalkyl, NH--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, halo, cyano, or
C.sub.1-6alkylene-amine;
or a pharmaceutically acceptable salt thereof.
[0107] In some embodiments, the compounds disclosed herein have a
structure of formula (IV). In various embodiments, the compounds
disclosed herein have a structure of formula (IV'). In some
embodiments, E.sup.1 and E.sup.2 are each CR.sup.1, and R.sup.8 is
hydroxy, halo, nitro, or C.sub.3-6cycloalkyl.
[0108] In some embodiments, R.sup.8 is methyl.
[0109] Further provided are compounds having a structure of formula
(V), or a pharmaceutically acceptable salt thereof:
##STR00021##
wherein
[0110] E.sup.1 and E.sup.2 are each independently CR.sup.1 or
N;
[0111] R.sup.1 is independently H, hydroxy, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.1-6alkoxy, NH--C.sub.1-6alkyl,
N(C.sub.1-6alkyl).sub.2, cyano, or halo;
[0112] R.sup.2 is halo, C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR',
N(R').sub.2, C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or
C.sub.0-3alkylene-C.sub.2-14heteroaryl, and each R' is
independently H, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-14cycloalkyl, C.sub.2-14heterocycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl, or two R' substituents,
together with the nitrogen atom to which they are attached, form a
3-7-membered ring;
[0113] R.sup.3 is halo, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.1-6alkoxy, C.sub.3-14cycloalkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, aryl, or heteroaryl; R.sup.4 is
##STR00022##
[0114] ring A is a monocyclic 4-7 membered ring or a bicyclic,
bridged, fused, or spiro 6-11 membered ring;
[0115] L is a bond, C.sub.1-6alkylene, --O--C.sub.0-5alkylene,
--S--C.sub.0-5alkylene, or --NH--C.sub.0-5 alkylene, and for
C.sub.2-6alkylene, --O--C.sub.2-5alkylene, --S--C.sub.2-5alkylene,
and NH--C.sub.2-5 alkylene, one carbon atom of the alkylene group
can optionally be replaced with O, S, or NH;
[0116] R.sup.4' is H, C.sub.1-8alkyl, C.sub.2-6alkynyl,
C.sub.1-6alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6 haloalkyl, cycloalklyl, heterocycloalkyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14 heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or selected from
##STR00023##
[0117] R.sup.5 and R.sup.6 are each independently H, halo,
C.sub.1-6alkyl, C.sub.2-6alkynyl, C.sub.1-6
alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine, C.sub.0-6
alkylene-amide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6 alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl, or cyano, or R.sup.5 and
R.sup.6, together with the atoms to which they are attached, form a
4-6 membered ring;
[0118] R.sup.7 is H or C.sub.1-8alkyl, or R.sup.7 and R.sup.5,
together with the atoms to which they are attached, form a 4-6
membered ring; and
[0119] R.sup.10 is C.sub.1-8alkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.3-14heteroaryl, C.sub.0-3
alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, C.sub.1-6alkoxy,
O--C.sub.0-3 alkylene-C.sub.6-14aryl,
O--C.sub.0-3alkylene-C.sub.3-14heteroaryl, O--C.sub.0-3
alkylene-C.sub.3-14cycloalkyl, O--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, NH--C.sub.1-8alkyl,
N(C.sub.1-8alkyl).sub.2, NH--C.sub.0-3alkylene-C.sub.6-14aryl,
NH--C.sub.0-3alkylene-C.sub.2-14heteroaryl,
NH--C.sub.0-3alkylene-C.sub.3-14cycloalkyl, NH--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, halo, cyano, or
C.sub.1-6alkylene-amine; or a pharmaceutically acceptable salt
thereof.
[0120] Further provided are compounds having a structure of formula
(V):
##STR00024##
wherein
[0121] E.sup.1 and E.sup.2 are each independently CR.sup.1 or
N;
[0122] R.sup.1 is independently H, hydroxy, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.1-6alkoxy, NH--C.sub.1-6alkyl,
N(C.sub.1-6alkyl).sub.2, cyano, or halo;
[0123] R.sup.2 is halo, C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR',
N(R').sub.2, C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.6-14aryl, or
C.sub.0-3alkylene-C.sub.2-14heteroaryl, and each R' is
independently H, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-14cycloalkyl, C.sub.2-14heterocycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl, or two R' substituents,
together with the nitrogen atom to which they are attached, form a
3-7-membered ring;
[0124] R.sup.3 is halo, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.1-6alkoxy, C.sub.3-14cycloalkyl, C.sub.2-8alkenyl,
C.sub.2-8alkynyl, aryl, or heteroaryl;
[0125] R.sup.4 is
##STR00025##
[0126] ring A is a monocyclic 4-7 membered ring or a bicyclic,
bridged, fused, or spiro 6-11 membered ring;
[0127] L is a bond, C.sub.1-6alkylene, --O--C.sub.0-5alkylene,
--S--C.sub.0-5alkylene, or --NH--C.sub.0-5alkylene, and for
C.sub.2-6alkylene, --O--C.sub.2-5alkylene, --S--C.sub.2-5alkylene,
and NH--C.sub.2-5alkylene, one carbon atom of the alkylene group
can optionally be replaced with O, S, or NH;
[0128] R.sup.5 and R.sup.6 are each independently H, halo,
C.sub.1-6alkyl, C.sub.2-6alkynyl, C.sub.1-6
alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine, C.sub.0-6
alkylene-amide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6 alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl,
C.sub.0-3alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.2-14heteroaryl, or cyano, or R.sup.5 and
R.sup.6, together with the atoms to which they are attached, form a
4-6 membered ring;
[0129] R.sup.7 is H or C.sub.1-8alkyl, or R.sup.7 and R.sup.1,
together with the atoms to which they are attached, form a 4-6
membered ring; and
[0130] R.sup.10 is C.sub.1-8alkyl,
C.sub.0-3alkylene-C.sub.6-14aryl,
C.sub.0-3alkylene-C.sub.3-14heteroaryl, C.sub.0-3
alkylene-C.sub.3-14cycloalkyl,
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl, C.sub.1-6alkoxy,
O--C.sub.0-3 alkylene-C.sub.6-14aryl,
O--C.sub.0-3alkylene-C.sub.3-14heteroaryl, O--C.sub.0-3
alkylene-C.sub.3-14cycloalkyl, O--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, NH--C.sub.1-8alkyl,
N(C.sub.1-8alkyl).sub.2, NH--C.sub.0-3alkylene-C.sub.6-14aryl,
NH--C.sub.0-3alkylene-C.sub.2-14heteroaryl,
NH--C.sub.0-3alkylene-C.sub.3-14cycloalkyl, NH--C.sub.0-3
alkylene-C.sub.2-14heterocycloalkyl, halo, cyano, or C.sub.1-6
alkylene-amine; or a pharmaceutically acceptable salt thereof.
[0131] The compounds of formula (I), (II), (III), (III'), (IV),
(IV'), or (V) as disclosed herein can have one or more of the
following features. In some embodiments, each of E.sup.1 and
E.sup.2 is CR.sup.1. In other embodiments, E.sup.1 is CR.sup.1 and
E.sup.2 is N. In some embodiments, E.sup.1 is N and E.sup.2 is
CR.sup.1. In various embodiments, each of E.sup.1 and E.sup.2 is
N.
[0132] The compounds of formula (II), (III), (III'), (IV), (IV'),
or (V) as disclosed herein can have one or more of the following
features. In various embodiments, R.sup.10 is C.sub.1-6alkyl, aryl,
heteroaryl, C.sub.3-14cycloalkyl, C.sub.2-14 heterocycloalkyl,
C.sub.1-6alkoxy, O--C.sub.0-6alkylene-C.sub.6-14aryl,
O--C.sub.0-6alkylene-C.sub.2-14 heteroaryl,
O--C.sub.0-6alkylene-C.sub.3-14cycloalkyl,
O--C.sub.0-6alkylene-C.sub.2-14heterocycloalkyl, N--C.sub.1-8alkyl,
N(C.sub.1-8alkyl).sub.2, NH--C.sub.0-6alkylene-C.sub.6-14aryl,
NH--C.sub.0-6alkylene-C.sub.2-14 heteroaryl,
NH--C.sub.0-6alkylene-C.sub.3-14cycloalkyl, or
NH--C.sub.0-6alkylene-C.sub.2-14 heterocycloalkyl. In various
embodiments, R.sup.10 is C.sub.1-8alkyl. In some embodiments,
R.sup.10 is C.sub.0-3alkylene-C.sub.6-14aryl. In some embodiments,
R.sup.10 is C.sub.0-3 alkylene-C.sub.2-14heteroaryl. In some
embodiments, R.sup.10 is C.sub.0-3alkylene-C.sub.3-14 cycloalkyl.
In some embodiments, R.sup.10 is
C.sub.0-3alkylene-C.sub.2-14heterocycloalkyl. In other embodiments,
R.sup.0 is C.sub.0-6alkyleneamine. For example, R.sup.10 can be
i-Pr, t-Bu, phenyl, benzyl, OCH.sub.3, C.sub.1, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl,
##STR00026## ##STR00027## ##STR00028## ##STR00029##
In some embodiments, R.sup.10 comprises an ortho-substituted aryl
ortho-substituted heteroaryl, or 2-substituted cyclohexyl. For
example, R.sup.10 can be
##STR00030##
[0133] The compounds of formula (I), (II), (III), (III'), (IV),
(IV'), or (V) as disclosed herein can have one or more of the
following features. In some embodiments, R.sup.1 is H. In some
embodiments, R.sup.1 is F. In some embodiments, R.sup.1 is
methyl.
[0134] The compounds of formula (I), (II), (III), (III'), (IV),
(IV'), or (V) as disclosed herein can have one or more of the
following features. In various embodiments, R.sup.2 is aryl. In
some embodiments, R.sup.2 is heteroaryl. In various embodiments,
R.sup.2 is phenyl, naphthyl, pyridyl, indazolyl, indolyl,
azaindolyl, indolinyl, benzotriazolyl, benzoxadiazolyl, imidazolyl,
cinnolinyl, imidazopyridyl, pyrazolopyridyl, quinolinyl,
isoquinolinyl, quinazolinyl, quinazolinonyl, indolinonyl,
isoindolinonyl, tetrahydronaphthyl, tetrahydroquinolinyl, or
tetrahydroisoquinolinyl. For example, R.sup.2 can be Cl, Br,
CF.sub.3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
piperidine, pyrrolidine, azetidine, OCH.sub.3, OCH.sub.2CH.sub.3,
phenyl,
##STR00031## ##STR00032## ##STR00033## ##STR00034## ##STR00035##
##STR00036##
In various embodiments, R.sup.2 can be bromine,
##STR00037##
[0135] The compounds of formula (I), (II), (III), (III'), (IV),
(IV'), or (V) as disclosed herein can have one or more of the
following features. In various embodiments, R.sup.3 is halo. In
various embodiments, R.sup.3 is C.sub.1. In some embodiments,
R.sup.3 is C.sub.1-2alkyl. In some embodiments, R.sup.3 is methyl.
In some embodiments, R.sup.3 is C.sub.1-2haloalkyl. In various
embodiments, R.sup.3 is CF.sub.3.
[0136] The compounds of formula (I), (II), (III), (III'), (IV),
(IV'), or (V) as disclosed herein can have one or more of the
following features. In some embodiments, R.sup.4 is
##STR00038##
In various embodiments, R.sup.4 is
##STR00039##
In some embodiments, R.sup.4 is
##STR00040##
In some embodiments, R.sup.4 is
##STR00041##
In some embodiments, R.sup.4 is
##STR00042##
In some embodiments, R.sup.4 is
##STR00043##
In some embodiments, R.sup.4 can be
##STR00044## ##STR00045## ##STR00046## ##STR00047##
In various embodiments R.sup.4' is H, C.sub.1-8alkyl,
C.sub.2-8alkynyl, C.sub.1-6alkylene-O--C.sub.1-4alkyl,
C.sub.1-6alkylene-OH, C.sub.1-6haloalkyl,
C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl,
C.sub.0-3alkylene-C.sub.6-14aryl, or selected from
##STR00048##
In various embodiments,
##STR00049##
can be
##STR00050## ##STR00051## ##STR00052## ##STR00053## ##STR00054##
##STR00055## ##STR00056##
In some embodiments, ring A is
##STR00057##
In some embodiments, ring A comprises piperidinyl, piperazinyl,
pyrrolidinyl, or azetidinyl. In some embodiments, ring A comprises
piperidinyl. In various embodiments, ring A can be
##STR00058## ##STR00059## ##STR00060##
In various embodiments, ring A can be
##STR00061##
[0137] The compounds of formula (I), (II), (III), (III'), (IV),
(IV'), or (V) as disclosed herein can have one or more of the
following features. In some embodiments, L is a bond. In some
embodiments, L is C.sub.1-2alkylene. In various embodiments, L is
O. In some embodiments, L is S. In various embodiments, L is NH. In
some embodiments, R.sup.5 is H or halo. In some embodiments,
R.sup.5 is H, Br, C.sub.1, F, CN, CH.sub.3, CF.sub.3, CH.sub.2Br,
CH.sub.2OH, CH.sub.2CH.sub.2OH, CH.sub.2OCH.sub.2phenyl,
cyclopropyl, phenyl, CH.sub.2phenyl, CH.sub.2OCH.sub.3,
CH.sub.2N(CH.sub.3).sub.2, CH.sub.2N(CH.sub.2CH.sub.3).sub.2,
CH.sub.2CO.sub.2H, CH.sub.2CO.sub.2CH.sub.3,
CH.sub.2NHC(O)CH.sub.3, CH.sub.2C(O)NHCH.sub.3,
CH.sub.2OC(O)CH.sub.3, or
##STR00062##
In some embodiments, R.sup.6 is C.sub.1-6alkyl,
C.sub.1-6alkylene-O--C.sub.1-6alkyl, C.sub.1-6alkylene-OH,
C.sub.1-3haloalkyl, C.sub.1-6alkylene-amine,
C.sub.0-6alkylene-amide, C.sub.0-1alkylene C(O)OC.sub.1-3alkyl,
C.sub.0-1alkylene-C.sub.2-14heterocycloalkyl,
C.sub.0-1alkylene-C.sub.3-14cycloalkyl, or
C.sub.0-3alkylene-C.sub.6-14aryl. In various embodiments, R.sup.6
is C.sub.0-6alkylene-amine or C.sub.0-3alkylene-amide and is
CH.sub.2NH.sub.2, CH(CH.sub.3)NH.sub.2, CH(CH.sub.3).sub.2NH.sub.2,
CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
CH.sub.2NHCH.sub.3, C(O)NHCH.sub.3, C(O)N(CH.sub.3).sub.2,
CH.sub.2C(O)NHphenyl, CH.sub.2NHC(O)CH.sub.3,
CH.sub.2NHCH.sub.2CH.sub.2OH, CH.sub.2NHCH.sub.2CO.sub.2H,
CH.sub.2NH(CH.sub.3)CH.sub.2CO.sub.2CH.sub.3,
CH.sub.2NHCH.sub.2CH.sub.2OCH.sub.3,
CH.sub.2NH(CH.sub.3)CH.sub.2CH.sub.2OCH.sub.3,
CH.sub.2NH(CH.sub.3)CH.sub.2C(O)N(CH.sub.3).sub.2,
CH.sub.2NH(CH.sub.3)CH.sub.2C(O)NHCH.sub.3, CH.sub.2NMe.sub.2,
CH.sub.2NH(CH.sub.3)CH.sub.2CH.sub.2OH,
CH.sub.2NH(CH.sub.3)CH.sub.2CH.sub.2F,
CH.sub.2N.sup.+(CH.sub.3).sub.3, CH.sub.2NHCH.sub.2CHF2,
CH.sub.2NHCH.sub.2CH.sub.3,
##STR00063## ##STR00064## ##STR00065##
In various embodiments, R.sup.6 is phenyl, cyclopropyl, CH.sub.3,
CF.sub.3, CH.sub.2CH.sub.3, CH.sub.2NH.sub.2, CH(CH.sub.3)NH.sub.2,
CH(CH.sub.3).sub.2NH.sub.2, CH.sub.2Cl, CH.sub.2Br,
CH.sub.2OCH.sub.3, CH.sub.2Ophenyl, CH.sub.2OH, CO.sub.2H,
CO.sub.2CH.sub.2CH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2OH,
CH.sub.2CH.sub.2N(CH.sub.3).sub.2, CH.sub.2NHCH.sub.3,
C(O)NHCH.sub.3, C(O)N(CH.sub.3).sub.2, CH.sub.2C(O)NHphenyl,
CH.sub.2CHF.sub.2, CH.sub.2F, CHF.sub.2, CH.sub.2NHC(O)CH.sub.3,
CH.sub.2NHCH.sub.2CH.sub.2OH, CH.sub.2NHCH.sub.2CO.sub.2H,
CH.sub.2NH(CH.sub.3)CH.sub.2CO.sub.2CH.sub.3,
CH.sub.2NHCH.sub.2CH.sub.2OCH.sub.3,
CH.sub.2NH(CH.sub.3)CH.sub.2CH.sub.2OCH.sub.3,
CH.sub.2NH(CH.sub.3)CH.sub.2C(O)N(CH.sub.3).sub.2,
CH.sub.2NH(CH.sub.3)CH.sub.2C(O)NHCH.sub.3, CH.sub.2CH.sub.2CCH,
CH.sub.2NMe.sub.2, CH.sub.2NH(CH.sub.3)CH.sub.2CH.sub.2OH,
CH.sub.2NH(CH.sub.3)CH.sub.2CH.sub.2F,
CH.sub.2N.sup.+(CH.sub.3).sub.3, CH.sub.2NHCH.sub.2CHF.sub.2,
CH.sub.2NHCH.sub.2CH.sub.3,
##STR00066## ##STR00067## ##STR00068##
In various embodiments, R.sup.5 and R.sup.6 together are
##STR00069##
In some embodiments, each of R.sup.5 and R.sup.6 is H. In some
embodiments, R.sup.7 is H. In some embodiments, R.sup.7 is methyl.
In various embodiments, R.sup.7 and R.sup.5 together are
--CH.sub.2-- or --C(O)CH.sub.2--.
[0138] The compounds disclosed herein can be in the form of a
pharmaceutically acceptable salt. The compounds provided can be
formulated into a pharmaceutical formulation comprising a compound
disclosed herein and a pharmaceutically acceptable excipient.
[0139] Also provided is a method of inhibiting KRAS G12C in a cell,
comprising contacting the cell with a compound or composition
disclosed herein. Further provided is a method of treating cancer
in a subject comprising administering to the subject a
therapeutically effective amount of a compound or composition
disclosed herein. In some embodiments, the cancer is lung cancer,
pancreatic cancer, or colorectal cancer.
DETAILED DESCRIPTION
Definitions
[0140] Abbreviations: The following abbreviations may be used
herein:
TABLE-US-00001 AcOH acetic acid aq or aq. Aqueous BOC or Boc
tert-butyloxycarbonyl cpme cyclopentyl methyl ether DCE
1,2-dichloroethane DABCO 1,4-diazabicyclo[2.2.2]octane DCM
Dichloromethane DMA N,N-Dimethylacetamide DMAP
4-dimethylaminopyridine DME 1,2-dimethoxyethane DMF
N,N-dimethylformamide DMSO dimethyl sulfoxide Dppf, DPPF or dppf
1,1'-bis(diphenylphosphino)ferrocene eq or eq. or equiv. Equivalent
ESI or ES electrospray ionization Et Ethyl Et.sub.2O diethyl ether
EtOAc ethyl acetate g Grams h Hour HPLC high pressure liquid
chromatography iPr Isopropyl iP.sub.r2NEt or DIPEA N-ethyl
diisopropylamine (Hunig's base) KHMDS potassium
hexamethyldisilazide KOAc potassium acetate Lawesson's reagent
2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4- dithiadiphosphetane,
2,4-Bis-(4-methoxyphenyl)- 1,3-dithia-2,4-diphosphetane
2,4-disulfide LC MS, LCMS, liquid chromatography mass spectroscopy
LC-MS or LC/MS LG Leaving group (e.g., halogen, mesylate, triflate)
LHMDS or lithium hexamethyldisilazide LiHMDS m/z mass divided by
charge Me Methyl MeCN Acetonitrile MeOH Methanol Met Metal species
for cross-coupling (e.g., MgX, ZnX, SnR.sub.3, SiR.sub.3,
B(OR).sub.2) mg Milligrams min Minutes mL Milliliters MS mass
spectra NaHMDS sodium hexamethyldisilazide NBS N-bromosuccinimide
n-BuLi n-butyllithium NCS N-chlorosuccinimide NMR nuclear magnetic
resonance Pd.sub.2(dba).sub.3
tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl.sub.2.cndot.DCM
[1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium (II),
complex with dichloromethane Pd(PPh.sub.3).sub.4
Tetrakis(triphenylphosphine)palladium(0) Ph Phenyl PR or PG or
protecting group Prot. group rbf round-bottom flask RP-HPLC reverse
phase high pressure liquid chromatography RT or rt room temperature
sat. or satd. saturated SFC supercritical fluid chromatography
SPhos Pd G3 or (2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl)
SPhos G3 [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate
TBAF tetra-n-butylammonium fluoride TBTU
N,N,N',N'-Tetramethyl-O-(benzotriazol-1- yl)uronium
tetrafluoroborate t-BuOH tert-butanol TEA or Et.sub.3N
Trimethylamine TFA trifluoroacetic acid THF Tetrahydrofuran UV
Ultraviolet
[0141] The use of the terms "a," "an," "the," and similar referents
in the context of describing the invention (especially in the
context of the claims) are to be construed to cover both the
singular and the plural, unless otherwise indicated. Recitation of
ranges of values herein merely are intended to serve as a shorthand
method of referring individually to each separate value falling
within the range, unless otherwise indicated herein, and each
separate value is incorporated into the specification as if it were
individually recited herein. The use of any and all examples, or
exemplary language (e.g., "such as") provided herein, is intended
to better illustrate the invention and is not a limitation on the
scope of the invention unless otherwise claimed. No language in the
specification should be construed as indicating any non-claimed
element as essential to the practice of the invention.
[0142] As used herein, the term "alkyl" refers to straight chained
and branched C.sub.1-C.sub.8 hydrocarbon groups, including but not
limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl,
t-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl,
2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl,
4-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,
3,3-dimethylbutyl, and 2-ethybutyl. The term C.sub.m-n means the
alkyl group has "in" to "n" carbon atoms. The term "alkylene"
refers to an alkyl group having a substituent. An alkyl (e.g.,
methyl), or alkylene (e.g., --CH.sub.2--), group can be substituted
with one or more, and typically one to three, of independently
selected, for example, halo, trifluoromethyl, trifluoromethoxy,
hydroxy, alkoxy, nitro, cyano, alkylamino, C.sub.1-8alkyl,
C.sub.2-8alkenyl, C.sub.2-8alkynyl, --NC, amino, --CO.sub.2H,
--CO.sub.2C.sub.1-C.sub.8alkyl, --OCOC.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10 heterocycloalkyl,
C.sub.5-C.sub.10aryl, and C.sub.5-C.sub.10 heteroaryl. The term
"haloalkyl" specifically refers to an alkyl group wherein at least
one, e.g., one to six, or all of the hydrogens of the alkyl group
are substituted with halo atoms.
[0143] The terms "alkenyl" and "alkynyl" indicate an alkyl group
that further includes a double bond or a triple bond,
respectively.
[0144] As used herein, the term "halo" refers to fluoro, chloro,
bromo, and iodo. The term "alkoxy" is defined as --OR, wherein R is
alkyl.
[0145] As used herein, the term "amino" or "amine" interchangeably
refers to a --NR.sup.2 group, wherein each R is, e.g., H or a
substituent. In some embodiments, the amino group is further
substituted to form an ammonium ion, e.g., NR.sub.3.sup.+. Ammonium
moieties are specifically included in the definition of "amino" or
"amine." Substituents can be, for example, an alkyl, alkoxy,
cycloalkyl, heterocycloalkyl, amide, or carboxylate. An R group may
be further substituted, for example, with one or more, e.g., one to
four, groups selected from halo, cyano, alkenyl, alkynyl, alkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, urea, carbonyl,
carboxylate, amine, and amide. An "amide" or "amido" group
interchangeably refers to a group similar to an amine or amino
group but further including a C(O), e.g., --C(O)NR.sup.2. Some
contemplated amino or amido groups (some with optional alkylene
groups, e.g., alkylene-amino, or alkylene-amido) include
CH.sub.2NH.sub.2, CH(CH.sub.3)NH.sub.2, CH(CH.sub.3).sub.2NH.sub.2,
CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
CH.sub.2NHCH.sub.3, C(O)NHCH.sub.3, C(O)N(CH.sub.3).sub.2,
CH.sub.2C(O)NHphenyl, CH.sub.2NHC(O)CH.sub.3,
CH.sub.2NHCH.sub.2CH.sub.2OH, CH.sub.2NHCH.sub.2CO.sub.2H,
CH.sub.2NH(CH.sub.3)CH.sub.2CO.sub.2CH.sub.3,
CH.sub.2NHCH.sub.2CH.sub.2OCH.sub.3,
CH.sub.2NH(CH.sub.3)CH.sub.2CH.sub.2OCH.sub.3,
CH.sub.2NH(CH.sub.3)CH.sub.2C(O)N(CH.sub.3).sub.2,
CH.sub.2NH(CH.sub.3)CH.sub.2C(O)NHCH.sub.3, CH.sub.2CH.sub.2CCH,
CH.sub.2NMe.sub.2, CH.sub.2NH(CH.sub.3)CH.sub.2CH.sub.2OH,
CH.sub.2NH(CH.sub.3)CH.sub.2CH.sub.2F,
CH.sub.2N.sup.+(CH.sub.3).sub.3, CH.sub.2NHCH.sub.2CHF.sub.2,
##STR00070## ##STR00071##
[0146] As used herein, the term "aryl" refers to a C.sub.6-14
monocyclic or polycyclic aromatic group, preferably a C.sub.6-10
monocyclic or bicyclic aromatic group, or C.sub.10-14 polycyclic
aromatic group. Examples of aryl groups include, but are not
limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl,
phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to
C.sub.10-14 bicyclic and tricyclic carbon rings, where one ring is
aromatic and the others are saturated, partially unsaturated, or
aromatic, for example, dihydronaphthyl, indenyl, indanyl, or
tetrahydronaphthyl (tetralinyl). Unless otherwise indicated, an
aryl group can be unsubstituted or substituted with one or more,
and in particular one to four, groups independently selected from,
for example, halo, C.sub.1-8alkyl, C.sub.2-8alkenyl,
C.sub.2-6alkynyl, --CF.sub.3, --OCF.sub.3, --NO.sub.2, --CN, --NC,
--OH, alkoxy, amino, --CO.sub.2H, --CO.sub.2C.sub.1-C.sub.8alkyl,
--OCOC.sub.1-C.sub.8alkyl, C.sub.3-C.sub.10 cycloalkyl,
C.sub.3-C.sub.10 heterocycloalkyl, C.sub.5-C.sub.10aryl, and
C.sub.5-C.sub.10 heteroaryl.
[0147] As used herein, the term "cycloalkyl" refers to a monocyclic
or polycyclic non-aromatic carbocyclic ring, where the polycyclic
ring can be fused, bridged, or spiro. The carbocyclic ring can have
3 to 10 carbon ring atoms. Contemplated carbocyclic rings include,
but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl.
[0148] As used herein, the term "heterocycloalkyl" means a
monocyclic or polycyclic (e.g., bicyclic), saturated or partially
unsaturated, ring system containing 3 or more (e.g., 3 to 12, 4 to
10, 4 to 8, or 5 to 7) total atoms, of which one to five (e.g., 1,
2, 3, 4, or 5) of the atoms are independently selected from
nitrogen, oxygen, and sulfur. Nonlimiting examples of
heterocycloalkyl groups include azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl, dihydropyrrolyl, morpholinyl,
thiomorpholinyl, dihydropyridinyl, oxacycloheptyl,
dioxacycloheptyl, thiacycloheptyl, and diazacycloheptyl.
[0149] Unless otherwise indicated, a cycloalkyl or heterocycloalkyl
group can be unsubstituted or substituted with one or more, and in
particular one to four, groups. Some contemplated substituents
include halo, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-6alkynyl,
--OCF.sub.3, --NO.sub.2, --CN, --NC, --OH, alkoxy, amino,
--CO.sub.2H, --C.sub.02C.sub.1-C.sub.8alkyl,
--OCOC.sub.1-C.sub.8alkyl, C.sub.3-C.sub.10 cycloalkyl,
C.sub.3-C.sub.10 heterocycloalkyl, C.sub.5-C.sub.10aryl, and
C.sub.5-C.sub.10 heteroaryl.
[0150] As used herein, the term "heteroaryl" refers to a monocyclic
or polycyclic ring system (for example, bicyclic) containing one to
three aromatic rings and containing one to four (e.g., 1, 2, 3, or
4) heteroatoms selected from nitrogen, oxygen, and sulfur in an
aromatic ring. In certain embodiments, the heteroaryl group has
from 5 to 20, from 5 to 15, from 5 to 10 ring, or from 5 to 7
atoms. Heteroaryl also refers to C.sub.10-14 bicyclic and tricyclic
rings, where one ring is aromatic and the others are saturated,
partially unsaturated, or aromatic. Examples of heteroaryl groups
include, but are not limited to, furanyl, imidazolyl, isothiazolyl,
isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl,
pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl,
thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl,
benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl,
benzothiazolyl, benzothienyl, benzothiophenyl, benzotriazolyl,
benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl,
indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl,
isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl,
oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl,
pyrrolopyridyl, quinolinyl, quinoxalinyl, quiazolinyl,
thiadiazolopyrimidyl, and thienopyridyl. Unless otherwise
indicated, a heteroaryl group can be unsubstituted or substituted
with one or more, and in particular one to four or one or two,
substituents. Contemplated substituents include halo,
C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, --OCF.sub.3,
--NO.sub.2, --CN, --NC, --OH, alkoxy, amino, --CO.sub.2H,
--CO.sub.2C.sub.1-C.sub.8alkyl, --OCOC.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10 heterocycloalkyl,
C.sub.5-C.sub.10aryl, and C.sub.5-C.sub.10 heteroaryl.
[0151] As used herein, the term Boc refers to the structure
##STR00072##
[0152] As used herein, the term Cbz refers to the structure
##STR00073##
[0153] As used herein, the term Bn refers to the structure
##STR00074##
[0154] As used herein, the term trifluoroacetamide refers to the
structure
##STR00075##
[0155] As used herein, the term trityl refers to the structure
##STR00076##
[0156] As used herein, the term tosyl refers to the structure
##STR00077##
[0157] As used herein, the term Troc refers to the structure
##STR00078##
[0158] As used herein, the term Teoc refers to the structure
##STR00079##
[0159] As used herein, the term Alloc refers to the structure
##STR00080##
[0160] As used herein, the term Fmoc refers to the structure
##STR00081##
Compounds of the Disclosure
[0161] Provided herein are KRAS inhibitors having structures of one
of Formulas I-V, discussed in more detail below.
[0162] The compounds disclosed herein include all pharmaceutically
acceptable isotopically-labeled compounds wherein one or more atoms
of the compounds disclosed herein are replaced by atoms having the
same atomic number, but an atomic mass or mass number different
from the atomic mass or mass number usually found in nature.
Examples of isotopes that can be incorporated into the disclosed
compounds include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorous, fluorine, chlorine, and iodine, such as .sup.2H,
.sup.3H, .sup.11C, .sup.13c .sup.14C, .sup.13N, .sup.15N, .sup.15O,
.sup.17O, .sup.18O, .sup.31P, .sup.32P, .sup.35S, .sup.18F,
.sup.36Cl, .sup.123I, and .sup.125I, respectively. These
radiolabelled compounds could be useful to help determine or
measure the effectiveness of the compounds, by characterizing, for
example, the site or mode of action, or binding affinity to
pharmacologically important site of action. Certain
isotopically-labeled compounds of the disclosure, for example,
those incorporating a radioactive isotope, are useful in drug
and/or substrate tissue distribution studies. The radioactive
isotopes tritium, i.e. .sup.3H, and carbon-14, i.e. .sup.14C, are
particularly useful for this purpose in view of their ease of
incorporation and ready means of detection.
[0163] Substitution with heavier isotopes such as deuterium, i.e.
.sup.2H, may afford certain therapeutic advantages resulting from
greater metabolic stability, for example, increased in vivo
half-life or reduced dosage requirements, and hence are preferred
in some circumstances.
[0164] Substitution with positron emitting isotopes, such as
.sup.11C, .sup.18F, .sup.15O and .sup.13N, can be useful in
Positron Emission Topography (PET) studies for examining substrate
receptor occupancy. Isotopically-labeled compounds of structure (I)
can generally be prepared by conventional techniques known to those
skilled in the art or by processes analogous to those described in
the Preparations and Examples as set out below using an appropriate
isotopically-labeled reagent in place of the non-labeled reagent
previously employed.
[0165] Isotopically-labeled compounds as disclosed herein can
generally be prepared by conventional techniques known to those
skilled in the art or by processes analogous to those described in
the accompanying examples and schemes using an appropriate
isotopically-labeled reagent in place of the non-labeled reagent
previously employed.
[0166] Certain of the compounds as disclosed herein may exist as
stereoisomers (i.e., isomers that differ only in the spatial
arrangement of atoms) including optical isomers and conformational
isomers (or conformers). The compounds disclosed herein include all
stereoisomers, both as pure individual stereoisomer preparations
and enriched preparations of each, and both the racemic mixtures of
such stereoisomers as well as the individual diastereomers and
enantiomers that may be separated according to methods that are
known to those skilled in the art. Additionally, the compounds
disclosed herein include all tautomeric forms of the compounds.
[0167] Certain of the compounds disclosed herein may exist as
atropisomers, which are conformational stereoisomers that occur
when rotation about a single bond in the molecule is prevented, or
greatly slowed, as a result of steric interactions with other parts
of the molecule. The compounds disclosed herein include all
atropisomers, both as pure individual atropisomer preparations,
enriched preparations of each, or a non-specific mixture of each.
Where the rotational barrier about the single bond is high enough,
and interconversion between conformations is slow enough,
separation and isolation of the isomeric species may be
permitted.
[0168] The disclosure provides a compound having a structure of
formula (I)
##STR00082##
wherein E.sup.1 and E.sup.2 are each independently N or CR.sup.1;
R.sup.1 is independently H, hydroxy, C.sub.1-4alkyl,
C.sub.1-4haloalkyl, C.sub.1-4alkoxy, NH--C.sub.1-4alkyl,
N(C.sub.1-4alkyl).sub.2, cyano, or halo; R.sup.2 is halo,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR', N(R').sub.2,
C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, C.sub.0-3alkylenearyl,
or C.sub.0-3alkyleneheteroaryl, and each R' is independently H,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.3-4cycloalkyl,
C.sub.2-3alkenyl, C.sub.2-3alkynyl, aryl, or heteroaryl, or two R'
substituents, together with the nitrogen atom to which they are
attached, form a 3-7-membered ring; R.sup.3 is halo,
C.sub.1-3alkyl, C.sub.1-2haloalkyl, C.sub.1-3alkoxy,
C.sub.3-4cycloalkyl, C.sub.2-3alkenyl, C.sub.2-3alkynyl, aryl, or
heteroaryl; R.sup.4 is
##STR00083##
[0169] ring A is a monocyclic 4-7 membered ring or a bicyclic,
bridged, fused, or spiro 6-11 membered ring; L is a bond,
C.sub.1-6alkylene, --O--C.sub.0-5alkylene, --S--C.sub.0-5alkylene,
or --NH--C.sub.0-5alkylene, and for C.sub.2-6alkylene,
--O--C.sub.2-5alkylene, --S--C.sub.2-5alkylene, and
NH--C.sub.2-5alkylene, one carbon atom of the alkylene group can
optionally be replaced with O, S, or NH; R.sup.4' is H,
C.sub.1-8alkyl, C.sub.2-8alkynyl,
C.sub.1-6alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6haloalkyl, C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, C.sub.0-3alkylenearyl,
or selected from
##STR00084##
R.sup.5 and R.sup.6 are each independently H, halo, C.sub.1-8alkyl,
C.sub.2-8alkynyl, C.sub.1-6alkylene-O--C.sub.1-4alkyl,
C.sub.1-6alkylene-OH, C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine,
C.sub.0-6alkyleneamide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH,
C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, C.sub.0-3alkylenearyl,
or cyano, or R.sup.5 and R.sup.6, together with the atoms to which
they are attached, form a 4-6 membered ring; and R.sup.7 is H or
C.sub.1-3alkyl, or R.sup.7 and R.sup.5, together with the atoms to
which they are attached, form a 4-6 membered ring, or a
pharmaceutically acceptable salt thereof.
[0170] A compound of formula I, can be in the form of formula
(I-A), (I-B), (I-C), or (I-D):
##STR00085##
[0171] The disclosure also provides a compound having a structure
of formula (II)
##STR00086##
wherein E.sup.1 and E.sup.2 are each independently N or CR.sup.1; J
is N, NR.sup.10, or CR.sup.10; M is N, NR.sup.13, or CR.sup.13; is
a single or double bond as necessary to give every atom its normal
valence; R.sup.1 is independently H, hydroxy, C.sub.1-4alkyl,
C.sub.1-4haloalkyl, C.sub.1-4alkoxy, NH--C.sub.1-4alkyl,
N(C.sub.1-4alkyl).sub.2, cyano, or halo; R.sup.2 is halo,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR', N(R').sub.2,
C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, C.sub.0-3alkylenearyl,
or C.sub.0-3alkyleneheteroaryl, and each R' is independently H,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.3-4cycloalkyl,
C.sub.2-3alkenyl, C.sub.2-3alkynyl, aryl, or heteroaryl, or two R'
substituents, together with the nitrogen atom to which they are
attached, form a 3-7-membered ring; R.sup.3 is halo,
C.sub.1-3alkyl, C.sub.1-2haloalkyl, C.sub.1-3alkoxy,
C.sub.3-4cycloalkyl, C.sub.2-3alkenyl, C.sub.2-3alkynyl, aryl or
heteroaryl; R.sup.4 is
##STR00087##
[0172] ring A is a monocyclic 4-7 membered ring or a bicyclic,
bridged, fused, or spiro 6-11 membered ring; L is a bond,
C.sub.1-6alkylene, --O--C.sub.0-5alkylene, --S--C.sub.0-5alkylene,
or --NH--C.sub.0-5alkylene, and for C.sub.2-6alkylene,
--O--C.sub.2-5alkylene, --S--C.sub.2-5alkylene, and
NH--C.sub.2-5alkylene, one carbon atom of the alkylene group can
optionally be replaced with O, S, or NH; R.sup.4' is H,
C.sub.1-8alkyl, C.sub.2-8alkynyl,
C.sub.1-6alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6haloalkyl, C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, C.sub.0-3alkylenearyl,
or selected from
##STR00088##
R.sup.5 and R.sup.6 are each independently H, halo, C.sub.1-8alkyl,
C.sub.2-8alkynyl, C.sub.1-6alkylene-O--C.sub.1-4alkyl,
C.sub.1-6alkylene-OH, C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine,
C.sub.0-6alkyleneamide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH,
C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, C.sub.0-3alkylenearyl,
or cyano, or R.sup.5 and R.sup.6, together with the atoms to which
they are attached, form a 4-6 membered ring; R.sup.7 is H or
C.sub.1-3alkyl, or R.sup.7 and R.sup.5, together with the atoms to
which they are attached, form a 4-6 membered ring; Q is
CR.sup.8R.sup.9, C.dbd.CR.sup.8R.sup.9, C.dbd.O, C.dbd.S, or
C.dbd.NR.sup.8; R.sup.8 and R.sup.9 are each independently H,
C.sub.1-3alkyl, hydroxy, C.sub.1-3alkoxy, cyano, nitro, or
C.sub.3-6cycloalkyl, or R.sup.8 and R.sup.9, taken together with
the carbon atom to which they are attached, can form a 3-6 membered
ring; R.sup.10 is C.sub.1-8alkyl, C.sub.0-3alkylenearyl,
C.sub.0-3alkyleneheteroaryl, C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, C.sub.1-6alkoxy,
O--C.sub.0-3alkylenearyl, O--C.sub.0-3alkyleneheteroaryl,
O--C.sub.0-3alkylene-C.sub.3-8cycloalkyl, O--C.sub.0-3alkylenearyl,
O--C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, NH--C.sub.1-8alkyl,
N(C.sub.1-8alkyl).sub.2, NH--C.sub.0-3alkylenearyl,
NH--C.sub.0-3alkyleneheteroaryl,
NH--C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
NH--C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, halo, cyano, or
C.sub.1-6alkyleneamine; and R.sup.13 is C.sub.1-4alkyl,
C.sub.1-3haloalkyl, C.sub.1-3alkyleneamine, and
C.sub.3-5cycloalkyl, or a pharmaceutically acceptable salt thereof,
with the proviso that (1) when J is NR.sup.10, M is N or CR.sup.13;
(2) when M is NR.sup.13, J is N or CR.sup.10; (3) when J is
CR.sup.10, M is N or NR.sup.13; and (4) when M is CR.sup.13, J is N
or NR.sup.10.
[0173] In various embodiments, J is NR.sup.10 and M is CR.sup.13.
In some embodiments, J is CR.sup.10 and M is NR.sup.13. In some
embodiments, J is CR.sup.10 and M is N. In various embodiments, J
is N and M is NR.sup.13. In some embodiments, J is N and M is
CR.sup.13. Some specifically contemplated R.sup.13 include methyl,
ethyl, propyl, isopropyl, butyl, sec-butyl, trifluormethyl,
CH.sub.2NH.sub.2, and cyclopropyl. In some embodiments, J is
NR.sup.10 and M is N. In some embodiments, when Q is C.dbd.O and
each of E.sup.1 and E.sup.2 is CR.sup.1, then either (1) R.sup.10
is C.sub.1-3alkylenearyl, C.sub.1-3alkyleneheteroaryl,
C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.1-3alkylene-C.sub.2-7heterocycloalkyl, or halo; or (2)
R.sup.13 is C.sub.1-3haloalkyl or C.sub.3-5cycloalkyl.
[0174] A compound of formula II can be in the form of formula
(II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H),
(II-J), (II-K), (II-L), (II-M), (II-N), (II-0), (II-P), or
(II-Q).
##STR00089## ##STR00090## ##STR00091##
[0175] The disclosure also provides a compound having a structure
of formula (III) or formula (III'):
##STR00092##
wherein each R.sup.1 is independently H, hydroxy, C.sub.1-4alkyl,
C.sub.1-4haloalkyl, C.sub.1-4alkoxy, NH--C.sub.1-4alkyl,
N(C.sub.1-4alkyl).sub.2, cyano, or halo; R.sup.2 is halo,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR', N(R').sub.2,
C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, C.sub.0-3alkylenearyl,
or C.sub.0-3alkyleneheteroaryl, and each R' is independently H,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.3-4cycloalkyl,
C.sub.2-3alkenyl, C.sub.2-3alkynyl, aryl, or heteroaryl, or two R'
substituents, together with the nitrogen atom to which they are
attached, form a 3-7-membered ring; R.sup.3 is halo,
C.sub.1-3alkyl, C.sub.1-2haloalkyl, C.sub.1-3alkoxy,
C.sub.3-4cycloalkyl, C.sub.2-3alkenyl, C.sub.2-3alkynyl, aryl, or
heteroaryl; R.sup.4 is
##STR00093##
[0176] ring A is a monocyclic 4-7 membered ring or a bicyclic,
bridged, fused, or spiro 6-11 membered ring; L is a bond,
C.sub.1-6alkylene, --O--C.sub.0-5alkylene, --S--C.sub.0-5alkylene,
or --NH--C.sub.0-5alkylene, and for C.sub.2-6alkylene,
--O--C.sub.2-5alkylene, --S--C.sub.2-5alkylene, and
NH--C.sub.2-5alkylene, one carbon atom of the alkylene group can
optionally be replaced with O, S, or NH; R.sup.4' is H,
C.sub.1-8alkyl, C.sub.2-8alkynyl,
C.sub.1-6alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6haloalkyl, C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, C.sub.0-3alkylenearyl,
or selected from
##STR00094##
R.sup.5 and R.sup.6 are each independently H, halo, C.sub.1-8alkyl,
C.sub.2-8alkynyl, C.sub.1-6alkylene-O--C.sub.1-4alkyl,
C.sub.1-6alkylene-OH, C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine,
C.sub.0-6alkyleneamide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH,
C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, C.sub.0-3alkylenearyl,
or cyano, or R.sup.5 and R.sup.6, together with the atoms to which
they are attached, form a 4-6 membered ring; R.sup.7 is H or
C.sub.1-3alkyl, or R.sup.7 and R.sup.1, together with the atoms to
which they are attached, form a 4-6 membered ring; Q is
CR.sup.8R.sup.9, C.dbd.CR.sup.8R.sup.9, C.dbd.O, C.dbd.S, or
C.dbd.NR.sup.8; each of R.sup.8 and R.sup.9 independently is H,
C.sub.1-3alkyl, hydroxy, C.sub.1-3alkoxy, cyano, nitro, or
C.sub.3-6cycloalklyl, or R.sup.8 and R.sup.9, taken together with
the carbon atom to which they are attached, can form a 3-6 membered
ring; and R.sup.10 is C.sub.1-8alkyl, C.sub.0-3alkylenearyl,
C.sub.0-3alkyleneheteroaryl, C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, C.sub.1-6alkoxy,
C.sub.1-6alkoxy, O--C.sub.0-3alkylenearyl,
O--C.sub.0-3alkyleneheteroaryl,
O--C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
O--C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, NH--C.sub.1-8alkyl,
N(C.sub.1-8alkyl).sub.2, NH--C.sub.0-3alkylenearyl,
NH--C.sub.0-3alkyleneheteroaryl,
NH--C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
NH--C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, halo, cyano, or
C.sub.1-6alkyleneamine, or a pharmaceutically acceptable salt
thereof.
[0177] A compound of formula III can be in the form of formula
(III-A), (III-B), (III-C), or (III-D):
##STR00095##
[0178] A compound of formula III' can be in the form of formula
(III-A'), (III-B'), (III-C'), or (III-D'):
##STR00096##
[0179] The disclosure also provides a compound having a structure
of formula (IV) or formula (IV'):
##STR00097##
wherein E.sup.1 and E.sup.2 are each independently CR.sup.1 or N;
R.sup.1 is independently H, hydroxy, C.sub.1-4alkyl,
C.sub.1-4haloalkyl, C.sub.1-4alkoxy, NH--C.sub.1-4alkyl,
N(C.sub.1-4alkyl).sub.2, cyano, or halo; R.sup.2 is halo,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR', N(R').sub.2,
C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, C.sub.0-3alkylenearyl,
or C.sub.0-3alkyleneheteroaryl, and each R' is independently H,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.3-4cycloalkyl,
C.sub.2-3alkenyl, C.sub.2-3alkynyl, aryl, or heteroaryl, or two R'
substituents, together with the nitrogen atom to which they are
attached, form a 3-7-membered ring; R.sup.3 is halo, C.sub.1
2haloalkyl, C.sub.1-3alkoxy, C.sub.3-4cycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, aryl, or heteroaryl; R.sup.4 is
##STR00098##
ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged,
fused, or spiro 6-11 membered ring; L is a bond, C.sub.1-6alkylene,
--O--C.sub.0-5alkylene, --S--C.sub.0-5alkylene, or
--NH--C.sub.0-5alkylene, and for C.sub.2-6alkylene,
--O--C.sub.2-5alkylene, --S--C.sub.2-5alkylene, and
NH--C.sub.2-5alkylene, one carbon atom of the alkylene group can
optionally be replaced with O, S, or NH; R.sup.4' is H,
C.sub.1-8alkyl, C.sub.2-6alkynyl,
C.sub.1-6alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6haloalkyl, C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, C.sub.0-3alkylenearyl,
or selected from
##STR00099##
R.sup.5 and R.sup.6 are each independently H, halo, C.sub.1-8alkyl,
C.sub.2-6alkynyl, C.sub.1-6alkylene-O--C.sub.1-4alkyl,
C.sub.1-6alkylene-OH, C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine,
C.sub.0-6alkyleneamide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH,
C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, C.sub.0-3alkylenearyl,
or cyano, or R.sup.5 and R.sup.6, together with the atoms to which
they are attached, form a 4-6 membered ring; R.sup.7 is H or
C.sub.1-3alkyl, or R.sup.7 and R.sup.5, together with the atoms to
which they are attached, form a 4-6 membered ring; R.sup.8 is
C.sub.1-3alkyl, hydroxy, C.sub.1-3alkoxy, halo, cyano, nitro,
C.sub.3-6cycloalkyl, or NR.sup.11R.sup.12; R.sup.1 and R.sup.12 are
each independently H, C.sub.1-4alkyl, or C.sub.3-5cycloalkyl; and
R.sup.10 is C.sub.1-8alkyl, C.sub.0-3alkylenearyl,
C.sub.0-3alkyleneheteroaryl, C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, C.sub.1-6alkoxy,
O--C.sub.0-3alkylenearyl, O--C.sub.0-3alkyleneheteroaryl,
O--C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
O--C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, NH--C.sub.1-8alkyl,
N(C.sub.1-8alkyl).sub.2, NH--C.sub.0-3alkylenearyl,
NH--C.sub.0-3alkyleneheteroaryl,
NH--C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
NH--C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, halo, cyano, or
C.sub.1-6alkyleneamine, or a pharmaceutically acceptable salt
thereof. In some embodiments, E.sup.1 and E.sup.2 are each
CR.sup.1, and R.sup.8 is hydroxy, halo, nitro, or
C.sub.3-6cycloalkyl. In some embodiments, R.sup.8 is methyl. The
compound can have a structure of formula (IV-A), (IV'-A), (IV-B),
(IV'-B), (IV-C), (IV'-C), (IV-D), or (IV'-D):
##STR00100##
[0180] Also provided herein are compounds having a structure of
formula (V):
##STR00101##
wherein E.sup.1 and E.sup.2 are each independently CR.sup.1 or N;
R.sup.1 is independently H, hydroxy, C.sub.1-4alkyl,
C.sub.1-4haloalkyl, C.sub.1-4alkoxy, NH--C.sub.1-4alkyl,
N(C.sub.1-4alkyl).sub.2, cyano, or halo; R.sup.2 is halo,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, OR', N(R').sub.2,
C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, C.sub.0-3alkylenearyl,
or C.sub.0-3alkyleneheteroaryl, and each R' is independently H,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.3-4cycloalkyl,
C.sub.2-3alkenyl, C.sub.2-3alkynyl, aryl, or heteroaryl, or two R'
substituents, together with the nitrogen atom to which they are
attached, form a 3-7-membered ring; R.sup.3 is halo,
C.sub.1-3alkyl, C.sub.1 2haloalkyl, C.sub.1-3alkoxy,
C.sub.3-4cycloalkyl, ALA C.sub.2-3alkenyl, C.sub.2-3alkynyl, aryl,
or heteroaryl; R.sup.4
##STR00102##
ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged,
fused, or spiro 6-11 membered ring; L is a bond, C.sub.1-6alkylene,
--O--C.sub.0-5alkylene, --S--C.sub.0-5alkylene, or
--NH--C.sub.0-5alkylene, and for C.sub.2-6alkylene,
--O--C.sub.2-5alkylene, --S--C.sub.2-5alkylene, and
NH--C.sub.2-5alkylene, one carbon atom of the alkylene group can
optionally be replaced with O, S, or NH; R.sup.4' is H,
C.sub.1-8alkyl, C.sub.2-6alkynyl,
C.sub.1-6alkylene-O--C.sub.1-4alkyl, C.sub.1-6alkylene-OH,
C.sub.1-6haloalkyl, C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, C.sub.0-3alkylenearyl,
or selected from
##STR00103##
R.sup.5and R.sup.6 are each independently H, halo, C.sub.1-8alkyl,
C.sub.2-6alkynyl, C.sub.1-6alkylene-O--C.sub.1-4alkyl,
C.sub.1-6alkylene-OH, C.sub.1-6haloalkyl, C.sub.1-6alkyleneamine,
C.sub.0-6alkyleneamide, C.sub.0-3alkylene-C(O)OH,
C.sub.0-3alkylene-C(O)OC.sub.1-4alkyl, C.sub.1-6alkylene-O-aryl,
C.sub.0-3alkylene-C(O)C.sub.1-4alkylene-OH,
C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, C.sub.0-3alkylenearyl,
or cyano, or R.sup.5 and R.sup.6, together with the atoms to which
they are attached, form a 4-6 membered ring; R.sup.7 is H or
C.sub.1-3alkyl, or R.sup.7 and R.sup.5, together with the atoms to
which they are attached, form a 4-6 membered ring; and R.sup.10 is
C.sub.1-8alkyl, C.sub.0-3alkylenearyl, C.sub.0-3alkyleneheteroaryl,
C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, C.sub.1-6alkoxy,
O--C.sub.0-3alkylenearyl, O--C.sub.0-3alkyleneheteroaryl,
O--C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
O--C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, NH--C.sub.1-8alkyl,
N--C.sub.1-8alkyl, NH--C.sub.0-3alkylenearyl,
NH--C.sub.0-3alkyleneheteroaryl,
NH--C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
NH--C.sub.0-3alkylene-C.sub.2-7heterocycloalkyl, halo, cyano, or
C.sub.1-6alkyleneamine; or a pharmaceutically acceptable salt
thereof.
[0181] For compounds of formulas (II), (III), and (III'): In some
embodiments, Q is C.dbd.O. In some embodiments, Q is C.dbd.S. In
some embodiments, Q is C.dbd.NR.sup.B. R.sup.8 can be
C.sub.1-2alkyl, e.g. methyl.
[0182] Q can be CR.sup.8R.sup.9 or C.dbd.CR.sup.8R.sup.9. R.sup.8
and R.sup.9, taken together with the carbon atom to which they are
attached, can form a 3-4 membered ring, e.g., a cyclopropyl ring.
In some embodiments, R.sup.8 is C.sub.1-2alkyl (e.g., methyl), and
R.sup.9 is H.
[0183] For compounds of formulas (II), (III), (III'), (IV), (IV'),
and (V): In various embodiments, R.sup.10 is C.sub.1-4alkyl, aryl,
heteroaryl, C.sub.3-6cycloalkyl, C.sub.3-6heterocycloalkyl,
C.sub.1-4alkoxy, or aryloxy. In various embodiments, R.sup.10 is
C.sub.1-8alkyl, C.sub.1-8alkyl, or C.sub.1-3alkyl. In various
embodiments, R.sup.10 is C.sub.0-3alkylenearyl,
C.sub.0-1alkylenearyl, or phenyl. In various embodiments, R.sup.10
is C.sub.0-3alkyleneheteroaryl, or C.sub.0-1alkyleneheteroaryl, and
the heteoraryl can be, e.g., pyridyl. In various embodiments,
R.sup.10 is C.sub.0-3alkylene-C.sub.3-8cycloalkyl,
C.sub.0-1alkylene-C.sub.3-8cycloalkyl, or C.sub.3-8cycloalkyl, and
the cycloalkyl can be, e.g., cyclohexyl. In various embodiments,
R.sup.10 is C.sub.0-3alkylene-C.sub.3-8heterocycloalkyl or
C.sub.0-1alkylene-C.sub.3-8heterocycloalkyl. In various
embodiments, R.sup.10 is C.sub.0-6alkyleneamine or
C.sub.0-3alkyleneamine or amine. Some specifically contemplated
R.sup.10 include i-Pr, t-Bu, phenyl, benzyl, OCH.sub.3, C.sub.1,
cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl,
##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108##
##STR00109##
R.sup.10 can comprise an ortho-substituted aryl, ortho-substituted
heteroaryl, or 2-substituted cyclohexyl, such as, for example,
##STR00110##
For all Compounds:
[0184] R.sup.1 can be a small moiety. For example, R.sup.1 can be
H, C.sub.1-2alkyl (e.g., methyl), C.sub.1-2haloalkyl (e.g.,
CF.sub.3), or halo (e.g., F). Some specifically contemplated
R.sup.1 include H, F, Me, C.sub.1, and CF.sub.3.
[0185] R.sup.2 can be C.sub.1-3alkyl, C.sub.1-3haloalkyl,
C.sub.1-3alkoxy, C.sub.0-1alkylene-C.sub.3-8cycloalkyl,
C.sub.3-6cycloalkyl, C.sub.0-1alkylenearyl (e.g., aryl), or
C.sub.0-1alkyleneheteroaryl (e.g., heteroaryl). Some specifically
contemplated R.sup.2 groups include phenyl, naphthyl, pyridyl,
indazolyl, indolyl, azaindolyl, indolinyl, benzotriazolyl,
benzoxadiazolyl, imidazolyl, cinnolinyl, imidazopyridyl,
pyrazolopyridyl, quinolinyl, isoquinolinyl, quinazolinyl,
quinazolinonyl, indolinonyl, isoindolinonyl, tetrahydronaphthyl,
tetrahydroquinolinyl, or tetrahydroisoquinolinyl. Some other
specific R.sup.2 include Cl, Br, CF.sub.3, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, piperidine, pyrrolidine, azetidine,
OCH.sub.3, OCH.sub.2CH.sub.3, phenyl,
##STR00111## ##STR00112## ##STR00113## ##STR00114## ##STR00115##
##STR00116## ##STR00117## ##STR00118##
In some embodiments, R.sup.2 is
##STR00119##
[0186] R.sup.3 can be halo (e.g., C.sub.1), C.sub.1-2alkyl (e.g.,
methyl), or C.sub.1-2haloalkyl (e.g., CF.sub.3). Some specifically
contemplated R.sup.3 include C.sub.1, Me, CF.sub.3, OMe, Et,
C.dbd.CH.sub.2, and cyclopropyl.
[0187] L can be a bond, C.sub.1-6alkylene, --O--C.sub.0-5alkylene,
--S--C.sub.0-5alkylene, or --NH--C.sub.0-5alkylene, and for
C.sub.2-6alkylene, --O--C.sub.2-5alkylene, --S--C.sub.2-5alkylene,
and NH--C.sub.2-5alkylene, one carbon atom of the alkylene group
can optionally be replaced with O, S, or NH. For example, L can be
--CH.sub.2--NH-- when a carbon on a C.sub.2 alkylene group is
replaced with NH, or --O--CH.sub.2CH.sub.2--O--, when a carbon on a
O--C.sub.3alkylene group is replaced with a O. Other options with
substitution of C.sub.3, C.sub.4, C.sub.5, or C.sub.6 alkylene with
O, S, or NH are specifically contemplated. In some embodiments, L
is C.sub.1-2alkylene, O, S, or NH. In some embodiments, L is a
bond.
[0188] Ring A is a monocyclic 4-7 membered ring or a bicyclic,
bridged, fused, or spiro 6-11 membered ring. Some specifically
contemplated rings include cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, pyrrolidinyl, piperidinyl, azepanyl, imidazolidinyl,
hexahydropyrimidinyl, hexahydropyridazinyl, tetrahydrofuranyl,
tetrahydrothiofuranyl, azetidinyl, spiroheptyl, spirooctyl,
spirononyl, spirodecyl, diazabicyclodecyl, diazabicyclononyl,
diazabicyclooctyl, diazabicycloheptyl, hexahydropyrrolopyridyl,
octahydropyrrolopyridyl, and octahydropyrrolopyrimidinyl. In
various embodiments, ring A can comprise piperidinyl, piperazinyl,
pyrrolidinyl, or azetidinyl. In some embodiments, ring A comprises
piperidinyl. Ring A can be further substituted with one to three
substituents. Some non-limiting examples of substitutions on ring A
include one to three substituents selected from alkyl, alkenyl,
alkynyl, hydroxyalkyl, carboxylic acid or ester, haloalkyl,
alkylamine, C(O)NH.sub.2, oxo, halo, cyano, and isocyano.
[0189] When R.sup.4 is
##STR00120##
ring A can be, for example,
##STR00121##
More specifically, when R.sup.4 is
##STR00122##
ring A can be, for example,
##STR00123## ##STR00124##
[0190] When R.sup.4 is
##STR00125##
it can more specifically be
##STR00126##
In such embodiments, ring A can be, for example,
##STR00127##
[0191] R.sup.5 and R.sup.6 are substituents on the acrylamide
moiety of the KRAS inhibitors disclosed herein. In some
embodiments, each of R.sup.5 and R.sup.6 is H. Some specifically
contemplated R.sup.5 substituents include H, Br, C.sub.1, F, CN,
CH.sub.3, CF.sub.3, CH.sub.2Br, CH.sub.2OH, CH.sub.2CH.sub.2OH,
CH.sub.2OCH.sub.2phenyl, cyclopropyl, phenyl, CH.sub.2phenyl,
CH.sub.2OCH.sub.3, CH.sub.2N(CH.sub.3).sub.2,
CH.sub.2N(CH.sub.2CH.sub.3).sub.2, CH.sub.2CO.sub.2H,
CH.sub.2CO.sub.2CH.sub.3, CH.sub.2NHC(O)CH.sub.3,
CH.sub.2C(O)NHCH.sub.3, CH.sub.2OC(O)CH.sub.3, or
##STR00128##
[0192] Some specifically contemplated R.sup.6 substituents include
phenyl, cyclopropyl, CH.sub.3, CF.sub.3, CH.sub.2CH.sub.3,
CH.sub.2NH.sub.2, CH(CH.sub.3)NH.sub.2, CH(CH.sub.3).sub.2NH.sub.2,
CH.sub.2Cl, CH.sub.2Br, CH.sub.2OCH.sub.3, CH.sub.2Ophenyl,
CH.sub.2OH, CO.sub.2H, CO.sub.2CH.sub.2CH.sub.3, CH.sub.2CO.sub.2H,
CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2OH,
CH.sub.2CH.sub.2N(CH.sub.3).sub.2, CH.sub.2NHCH.sub.3,
C(O)NHCH.sub.3, C(O)N(CH.sub.3).sub.2, CH.sub.2C(O)NHphenyl,
CH.sub.2CHF.sub.2, CH.sub.2F, CHF.sub.2, CH.sub.2NHC(O)CH.sub.3,
CH.sub.2NHCH.sub.2CH.sub.2OH, CH.sub.2NHCH.sub.2CO.sub.2H,
CH.sub.2NH(CH.sub.3)CH.sub.2CO.sub.2CH.sub.3,
CH.sub.2NHCH.sub.2CH.sub.2OCH.sub.3,
CH.sub.2NH(CH.sub.3)CH.sub.2CH.sub.2OCH.sub.3,
CH.sub.2NH(CH.sub.3)CH.sub.2C(O)N(CH.sub.3).sub.2,
CH.sub.2NH(CH.sub.3)CH.sub.2C(O)NHCH.sub.3, CH.sub.2CH.sub.2CCH,
CH.sub.2NMe.sub.2, CH.sub.2NH(CH.sub.3)CH.sub.2CH.sub.2OH,
CH.sub.2NH(CH.sub.3)CH.sub.2CH.sub.2F,
CH.sub.2N.sup.+(CH.sub.3).sub.3, CH.sub.2NHCH.sub.2CHF.sub.2,
CH.sub.2NHCH.sub.2CH.sub.3,
##STR00129## ##STR00130##
[0193] R.sup.5 and R.sup.6, together with the atoms to which they
are attached, can form a 4-6 membered ring, e.g., a 5- or
6-membered ring. Such rings include R.sup.5 and R.sup.6 together
being
##STR00131##
[0194] In most embodiments, R.sup.7 is H. However, in some
embodiments, R.sup.7 is methyl. In other embodiments, R.sup.7 and
R.sup.5 together are --CH.sub.2-- or --C(O)CH.sub.2--.
[0195] Some specifically contemplated options for the moiety
##STR00132##
include
##STR00133## ##STR00134## ##STR00135## ##STR00136## ##STR00137##
##STR00138## ##STR00139## ##STR00140## ##STR00141##
##STR00142##
[0196] Some specifically contemplated R.sup.4 substituents
include
##STR00143## ##STR00144## ##STR00145## ##STR00146##
[0197] Some specifically contemplated R.sup.4 substituents can
include
##STR00147##
[0198] In another embodiment, the present invention discloses
compounds having a structure selected from:
##STR00148## ##STR00149## ##STR00150## ##STR00151##
##STR00152##
These compounds can be used as intermediates in the process of
making compounds in the present application. These compounds can be
in the form of a pharmaceutically acceptable salt and in a
pharmaceutical formulation with a pharmaceutically acceptable
excipient.
[0199] The following examples are labeled using a classification
system in which the first number refers to the method used to
synthesize the compound, the second number is an identifying
number, and the third number, if present, refers to the compound's
order of elution in a chromatographic separation process. If third
number is absent, the compound is a single compound or mixture of
isomers. The sequential numbering of the Examples is interrupted
and certain Example numbers are intentionally omitted due to
formatting considerations. The "-" denotes that no changes were
made, or no entries are in the relevant box. Specifically
contemplated compounds include those as listed in Table 1:
TABLE-US-00002 TABLE 1 Ex.# Chemical Structure Ex.# Chemical
Structure Ex.# Chemical Structure 1-1 ##STR00153## 1-6 ##STR00154##
1-11 ##STR00155## 1-2 ##STR00156## 1-7 ##STR00157## 1-12
##STR00158## ##STR00159## 1-3 ##STR00160## 1-8 ##STR00161## 1-13
##STR00162## ##STR00163## 1-4 ##STR00164## 1-9 ##STR00165## 1-14
##STR00166## ##STR00167## ##STR00168## ##STR00169## 1-5
##STR00170## 1-10 ##STR00171## 1-15 ##STR00172## 1-16 ##STR00173##
1-19-2 ##STR00174## 2-7 ##STR00175## ##STR00176## ##STR00177##
##STR00178## 1-17 ##STR00179## 1-20 ##STR00180## 2-8 ##STR00181##
##STR00182## 1-18 ##STR00183## 1-21 ##STR00184## 2-9 ##STR00185##
##STR00186## ##STR00187## 1-19 ##STR00188## 1-22 ##STR00189## 2-10
##STR00190## ##STR00191## 1-19-1 ##STR00192## 1-23 ##STR00193##
1-28 ##STR00194## 2-2 ##STR00195## 2-5-2 ##STR00196## 3-1-1
##STR00197## ##STR00198## 2-3 ##STR00199## 2-6 ##STR00200## 3-1-2
##STR00201## ##STR00202## ##STR00203## 2-4 ##STR00204## 2-6-1
##STR00205## 3-2 ##STR00206## ##STR00207## 2-5 ##STR00208## 2-6-2
##STR00209## 3-3 ##STR00210## ##STR00211## 2-5-1 ##STR00212## 3-1
##STR00213## 3-4 ##STR00214## 3-5 ##STR00215## 3-10 ##STR00216##
3-15 ##STR00217## 3-6 ##STR00218## 3-11 ##STR00219## 3-16
##STR00220## 3-7 ##STR00221## 3-12 ##STR00222## 3-17 ##STR00223##
3-8 ##STR00224## 3-13 ##STR00225## 3-18 ##STR00226## 3-9
##STR00227## 3-14 ##STR00228## 3-19 ##STR00229## 3-20 ##STR00230##
3-25 ##STR00231## 4-5 ##STR00232## 3-21 ##STR00233## 4-1
##STR00234## 4-6 ##STR00235## 3-22 ##STR00236## 4-2 ##STR00237##
4-7 ##STR00238## 3-23 ##STR00239## 4-3 ##STR00240## 4-8
##STR00241## 3-24 ##STR00242## 4-4 ##STR00243## 4-9 ##STR00244##
5-1 ##STR00245## 5-6 ##STR00246## 6-2 ##STR00247## 5-2 ##STR00248##
5-7 ##STR00249## 7-1 ##STR00250## ##STR00251## 5-3 ##STR00252## 5-8
##STR00253## 7-2 ##STR00254## ##STR00255## ##STR00256## 5-4
##STR00257## 5-9 ##STR00258## 7-3 ##STR00259## ##STR00260## 5-5
##STR00261## 6-1 ##STR00262## 8-1 ##STR00263## 8-1-1 ##STR00264##
8-3-2 ##STR00265## 8-6-2 ##STR00266## 8-1-2 ##STR00267## 8-4
##STR00268## 9-1 ##STR00269## 8-2 ##STR00270## 8-5 ##STR00271## 9-2
##STR00272## 8-3 ##STR00273## 8-6 ##STR00274## 9-3 ##STR00275##
8-3-1 ##STR00276## 8-6-1 ##STR00277## 9-4 ##STR00278## ##STR00279##
9-5 ##STR00280## 9-10 ##STR00281## 10-1 ##STR00282## 9-6
##STR00283## 9-11 ##STR00284## 10-2 ##STR00285## 9-7-2 ##STR00286##
9-12 ##STR00287## 10-3 ##STR00288## 9-7-1 ##STR00289## 9-13
##STR00290## 10-4 ##STR00291## 9-9 ##STR00292## 9-14 ##STR00293##
10-5 ##STR00294## ##STR00295## 10-6 ##STR00296## 10-11 ##STR00297##
11-2-1 ##STR00298## 10-7 ##STR00299## 10-12 ##STR00300## 11-2-2
##STR00301## 10-8 ##STR00302## 10-13 ##STR00303## 12 ##STR00304##
10-9 ##STR00305## 11-1-1 ##STR00306## 13 ##STR00307## 10-10
##STR00308## 11-1-2 ##STR00309## 14 ##STR00310## 15 ##STR00311##
18-2 ##STR00312## 20 ##STR00313## 16 ##STR00314## 18-3 ##STR00315##
21 ##STR00316## 17-1 ##STR00317## 19-1 ##STR00318## 22 ##STR00319##
17-2 ##STR00320## 19-2 ##STR00321## 23 ##STR00322## 18-1
##STR00323## 19-3 ##STR00324## 24 ##STR00325## 25 ##STR00326## 30
##STR00327## 35 ##STR00328## 26 ##STR00329## 31 ##STR00330## 36
##STR00331## 27 ##STR00332## 32 ##STR00333## 37 ##STR00334##
##STR00335## 28 ##STR00336## 33 ##STR00337## 38 ##STR00338## 29
##STR00339## 34 ##STR00340## NA NA 1-1 ##STR00341## 1-6
##STR00342## 1-11 ##STR00343## 1-2 ##STR00344## 1-7 ##STR00345##
1-12 ##STR00346## ##STR00347## 1-3 ##STR00348## 1-8 ##STR00349##
1-13 ##STR00350## ##STR00351## 1-4 ##STR00352## 1-9 ##STR00353##
1-14 ##STR00354## ##STR00355## ##STR00356## ##STR00357## 1-5
##STR00358## 1-10 ##STR00359## 1-15 ##STR00360## 1-16 ##STR00361##
1-19-2 ##STR00362## 2-7 ##STR00363## ##STR00364## ##STR00365##
##STR00366## 1-17 ##STR00367## 1-20 ##STR00368## 2-8 ##STR00369##
##STR00370## 1-18 ##STR00371## 1-21 ##STR00372## 2-9 ##STR00373##
##STR00374## ##STR00375## 1-19 ##STR00376## 1-22 ##STR00377## 2-10
##STR00378## ##STR00379## 1-19-1 ##STR00380## 1-23 ##STR00381##
1-28 ##STR00382## 2-1 ##STR00383## 2-5-2 ##STR00384## 3-1-1
##STR00385## 2-2 ##STR00386## 2-6 ##STR00387## 3-1-2 ##STR00388##
##STR00389## ##STR00390## 2-3 ##STR00391## 2-6-1 ##STR00392## 3-2
##STR00393## ##STR00394## 2-4 ##STR00395## 2-6-2 ##STR00396## 3-3
##STR00397## ##STR00398## 2-5 ##STR00399## 3-1 ##STR00400## 3-4
##STR00401## ##STR00402## 2-5-1 ##STR00403## 3-10 ##STR00404## 3-15
##STR00405## 3-5 ##STR00406## 3-11 ##STR00407## 3-16 ##STR00408##
3-6 ##STR00409## 3-12 ##STR00410## 3-17 ##STR00411## 3-7
##STR00412## 3-13 ##STR00413## 3-18 ##STR00414## 3-8 ##STR00415##
3-14 ##STR00416## 3-19 ##STR00417## 3-9 ##STR00418## 3-25
##STR00419## 4-5 ##STR00420## 3-20 ##STR00421## 4-1 ##STR00422##
4-6 ##STR00423## 3-21 ##STR00424## 4-2 ##STR00425## 4-7
##STR00426## 3-22 ##STR00427## 4-3 ##STR00428## 4-8 ##STR00429##
3-23 ##STR00430## 4-4 ##STR00431## 4-9 ##STR00432## 3-24
##STR00433## 5-6 ##STR00434## 6-2 ##STR00435## 5-1 ##STR00436## 5-7
##STR00437## 7-1 ##STR00438## ##STR00439## 5-2 ##STR00440## 5-8
##STR00441## 7-2 ##STR00442## ##STR00443## ##STR00444## 5-3
##STR00445## 5-9 ##STR00446## 7-3 ##STR00447## ##STR00448## 5-4
##STR00449## 6-1 ##STR00450## 8-1 ##STR00451## 5-5 ##STR00452##
8-3-2 ##STR00453## 8-6-2 ##STR00454##
8-1-1 ##STR00455## 8-4 ##STR00456## 9-1 ##STR00457## 8-1-2
##STR00458## 8-5 ##STR00459## 9-2 ##STR00460## 8-2 ##STR00461## 8-6
##STR00462## 9-3 ##STR00463## 8-3 ##STR00464## 8-6-1 ##STR00465##
9-4 ##STR00466## ##STR00467## 8-3-1 ##STR00468## 9-10 ##STR00469##
10-1 ##STR00470## 9-5 ##STR00471## 9-11 ##STR00472## 10-2
##STR00473## 9-6 ##STR00474## 9-12 ##STR00475## 10-3 ##STR00476##
9-7-2 ##STR00477## 9-13 ##STR00478## 10-4 ##STR00479## 9-7-1
##STR00480## 9-14 ##STR00481## 10-5 ##STR00482## ##STR00483## 9-9
##STR00484## 10-11 ##STR00485## 11-2-1 ##STR00486## 10-6
##STR00487## 10-12 ##STR00488## 11-2-2 ##STR00489## 10-7
##STR00490## 10-13 ##STR00491## 12 ##STR00492## 10-8 ##STR00493##
11-1-1 ##STR00494## 13 ##STR00495## 10-9 ##STR00496## 11-1-2
##STR00497## 14 ##STR00498## 10-10 ##STR00499## 18-2 ##STR00500##
20 ##STR00501## 15 ##STR00502## 18-3 ##STR00503## 21 ##STR00504##
16 ##STR00505## 19-1 ##STR00506## 22 ##STR00507## 17-1 ##STR00508##
19-2 ##STR00509## 23 ##STR00510## 17-2 ##STR00511## 19-3
##STR00512## 24 ##STR00513## 18-1 ##STR00514## 30 ##STR00515## 35
##STR00516## 25 ##STR00517## 31 ##STR00518## 36 ##STR00519## 26
##STR00520## 32 ##STR00521## 37 ##STR00522## ##STR00523## 27
##STR00524## 33 ##STR00525## 38 ##STR00526## 28 ##STR00527## 34
##STR00528## -- -- 29 ##STR00529## -- -- -- --
Synthesis of Disclosed Compounds
[0200] Compounds as disclosed herein can be synthesized via a
number of specific methods. The examples which outline specific
synthetic routes, and the generic schemes below are meant to
provide guidance to the ordinarily skilled synthetic chemist, who
will readily appreciate that the solvent, concentration, reagent,
protecting group, order of synthetic steps, time, temperature, and
the like can be modified as necessary, well within the skill and
judgment of the ordinarily skilled artisan.
##STR00530## ##STR00531##
[0201] Method 1 synthesis: A compound of Formula (I) as disclosed
herein can be synthesized as outlined in Method 1. An appropriate
aromatic or heteroaromatic acid is reacted with a halogenating
agent in Step 1 to form a halogenated aromatic or heteroaromatic
acid. The acid is then reacted with an amidating agent in Step 2 to
form an amide intermediate. The amide intermediate is then reacted
with a sulfurizing agent in Step 3 to form a thioamide
intermediate. Next, the thioamide intermediate is reacted with an
oxidant in Step 4 to form the thiazole ring as shown. The amine of
the thiazole is then converted to a leaving group in Step 5 using
an activating agent. The leaving group is then replaced with an
R.sup.4 protected group, as shown in Step 6. The R.sup.2 moiety is
then introduced in Step 7 by a cross-coupling reaction with the
appropriate R.sup.2 (protected) reagent with the X halide on the
thiazole intermediate. Then, in Step 8, the R.sup.4 group is
deprotected under appropriate conditions, depending upon the
protecting group used, the R.sup.4 group is then acylated to
introduce the acrylamide moiety as shown, and lastly, R.sup.2 is
deprotected. Appropriate protecting groups and deprotection
reagents are known to those skilled in the art, e.g., as discussed
in Greene's Protective Groups in Organic Synthesis.
[0202] Contemplated halogenating agents include, but are not
limited to, chlorine, bromine, N-chlorosuccinimide, and
N-bromosuccinimide, optionally in the presence of a catalyst, e.g.,
iron or aluminum. The ordinarily skilled synthetic chemist will
readily understand that other halogenating agents and catalysts can
be used.
[0203] Contemplated amidating agents include, but are not limited
to, N, N'-diisopropylcarbodiimide,
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide,
benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate, thionyl chloride, isobutyl chloroformate,
diethyl cyanophosphonate, carbonyl diimidazole, and polyphosphonic
anhydride. The ordinarily skilled synthetic chemist will readily
understand that other amidating agents can be used.
[0204] Contemplated sulfurizing agents include, but are not limited
to, sulfur, phosphorus pentasulfide, and Lawesson's reagent. The
ordinarily skilled synthetic chemist will readily understand that
other sulfurizing agents can be used.
[0205] Contemplated oxidants include, but are not limited to,
hydrogen peroxide, iodobenzene diacetate, t-butyl hydroperoxide,
N-bromosuccinimide, and ammonium peroxodisulfate. The ordinarily
skilled synthetic chemist will readily understand that other
oxidants can be used.
[0206] Contemplated activating agents include, but are not limited
to, sodium nitrite and t-butyl nitrite. The ordinarily skilled
synthetic chemist will readily understand that other activating
agents can be used.
[0207] Contemplated cross-coupling reactions include, but are not
limited to, Suzuki coupling, Negishi coupling, Hiyama coupling,
Kumada coupling, and Stille coupling. The ordinarily skilled
chemist will readily understand that couplings as shown in Method 1
can be performed under a number of conditions.
##STR00532##
[0208] Method 2 synthesis: Method 2 provides an alternative method
for formation of compounds of Formula (I) as disclosed herein.
After halogenation in Step 1, the R.sup.4 protected group is
introduced by reaction with the acid in a coupling reaction in Step
2. The oxo group is transformed to a sulfur using a sulfurizing
agent in Step 3. Then the thiazole ring is formed in the presence
of an oxidant in Step 4. The remaining steps 5-8 are analogous to
steps 7 and 8 in Method 1 described above.
##STR00533##
[0209] Method 3 synthesis: Method 3 provides an alternative method
for formation of compounds of Formula (I) as disclosed herein. The
R.sup.4 group of the isothiazole intermediate is deprotected and
acylated in Step 1 to introduce the acrylamide moiety. The R.sup.2
moiety is then introduced in Step 2 by a cross-coupling reaction
with the appropriate R.sup.2 (protected) reagent with the X halide
on the isothiazole intermediate. Lastly, the R.sup.2 group is
deprotected in Step 3.
##STR00534##
[0210] Method 4 synthesis: Method 4 provides an alternative method
for formation of compounds of Formula (I) as disclosed herein.
After substituting a leaving group on an isothiazole intermediate
with a protected R.sup.4 group, as depicted in Step 1, the R.sup.4
group intermediate is deprotected and acylated in Step 2 to
introduce the acrylamide moiety. The R.sup.2 moiety is introduced
by a cross-coupling reaction in Step 3, as in Method 1, and the
R.sup.2 group is deprotected in Step 4.
##STR00535##
[0211] Method 5 synthesis: Method 5 provides an alternative method
for formation of compounds of Formula (I) as disclosed herein. In
this alternative, the R.sup.2 moiety is first introduced by a
cross-coupling with the X halide on the aromatic or heteroaromatic
amide intermediate shown in Step 1. The amide intermediate is then
reacted with a sulfurizing agent in Step 2 to form a thioamide
intermediate. Oxidation of this intermediate provides the
isothiazole ring in Step 3. The amine group is then converted to a
leaving group in Step 4 and subsequently substituted with a
protected R.sup.4 group in Step 5. Finally, in Step 6, the R.sup.4
group is deprotected and reacted with an acylating agent, and then
the R.sup.2 group is deprotected.
##STR00536##
[0212] Method 6 synthesis: Method 6 provides an alternative method
for formation of compounds of Formula (I) as disclosed herein. In
this alternative, an isothiazole intermediate is reacted with a
metalating agent to activate the X halide. The R.sup.2 group is
then introduced by reacting the activated intermediate with the
appropriate R.sup.2 (protected) reagent. In the last step, the
R.sup.4 group is deprotected and acylated to introduce the
acrylamide moiety.
[0213] Contemplated metalating agents include, but are not limited
to, bis(pinacolato)diboron, magnesium, zinc, hexamethyldistannane,
and n-butyllithium. The ordinarily skilled synthetic chemist will
readily understand that other metalating agents and catalysts can
be used.
##STR00537##
[0214] Method 7 synthesis: Method 7 provides an alternative method
for formation of compounds of Formula (I) as disclosed herein. The
R.sup.2 moiety is first introduced by a cross-coupling with the X
halide on the aromatic or heteroaromatic acid intermediate shown in
Step 1. The acid moiety is then reacted with the appropriate
R.sup.4 (protected) reagent in the presence of an amidating agent
in Step 2. The carbonyl group of the acid derivative is then
converted to a thiocarbonyl group in Step 3 using a sulfurizing
agent. The thioacid derivative is then reacted with an oxidant to
form the isothiazole intermediate in Step 4. Lastly, the R.sup.4
group is deprotected and acylated to introduce the acrylamide
moiety, and the R.sup.2 group is deprotected.
##STR00538##
[0215] Method 8 synthesis: A compound of Formula (II) as disclosed
herein can be synthesized as outlined in Method 8. An appropriate
aromatic or heteroaromatic acid is reacted with an amidating agent
in Step 1 to form a primary amide intermediate. The amide is then
reacted with an isocyanate-forming reagent and a
R.sup.10-substituted amine to form a urea intermediate.
Contemplated isocyanate-forming agents include oxalyl chloride,
thionyl chloride, and phosphorus oxychloride. The urea intermediate
is then reacted with a cyclization agent in Step 3 to form the
quinazolinedione ring shown. Contemplated cyclization agents
include, but are not limited to, bases such as potassium
hexamethyldisilazide, potassium tert-butoxide, sodium hydride, and
phosphazene bases. The R.sup.2 moiety is then introduced in Step 4
by a cross-coupling reaction with the appropriate R.sup.2
(protected) reagent with the X halide on the quinazolinedione
intermediate. An oxo group of the quinazolinedione is then
converted to a leaving group in Step 5 using an activating agent.
Contemplated activating agents include, but are not limited to,
thionyl chloride, triflic anhydride, phosphorus oxychloride, and
phosphorus pentachloride. The leaving group is then replaced with
an R.sup.4 protected group to form a substituted quinazolinone, as
shown in Step 6. The remaining deprotection-acylation-deprotection
sequence shown in Steps 7-9 are analogous to Step 8 in Method
1.
##STR00539##
[0216] Method 9 synthesis: Method 9 provides an alternative method
for formation of compounds of Formula (II) as disclosed herein. An
oxo group of the quinazolinedione is converted to a leaving group
in Step 1. Step 2 involves the introduction of the R.sup.4
(protected) group, deprotection of the R.sup.4 group, and acylation
of the free R.sup.4 group. The R.sup.2 group is introduced in Step
3 by a cross-coupling reaction with the appropriate R.sup.2
(protected) reagent with the X halide on the quinazolinedione
intermediate. Finally, the R.sup.2 group is deprotected.
##STR00540## ##STR00541##
[0217] Method 10 synthesis: A compound of Formula (V) as disclosed
herein can be synthesized as outlined in Method 10. The appropriate
anhydride is reacted with hydrazine to form the phthalazinedione
ring as shown in Step 1. The R.sup.2 moiety is introduced in Step 2
by a cross-coupling reaction with the appropriate R.sup.2 reagent
with the X halide on the quinazolinedione intermediate. The R.sup.2
group is then protected in Step 3. The phthalazinedione ring is
halogenated twice. Contemplated halogenating agent include thionyl
chloride, phosphorus oxychloride, and oxalyl chloride. One of the
halogen groups is then replaced with an R.sup.4 protected group to
form a substituted phthalazine ring, as shown in Step 5. Then, in
Steps 6 and 7, the R.sup.4 group is deprotected under appropriate
conditions, depending upon the protecting group used, and the free
R.sup.4 group is then acylated to introduce the acrylamide moiety.
The R.sup.2 is deprotected in Step 8. Lastly, the R.sup.10 moiety
is introduced in Step 9 by a cross-coupling reaction with the
appropriate R.sup.10 reagent with the X halide on the phthalazine
intermediate.
##STR00542##
[0218] Method 11 synthesis: Method 11 provides an alternative
method for formation of compounds of Formula (II) as disclosed
herein. An oxo group of the quinazolinedione is converted to a
leaving group in Step 1. The R.sup.4 (protected) group is
introduced in Step 2. The R.sup.2 group is introduced in Step 3 by
a cross-coupling reaction with the appropriate R.sup.2 (protected)
reagent with the X halide on the quinazolinedione intermediate.
Lastly, the R.sup.4 group is deprotected and subsequently acylated
in Steps 4 and 5.
Pharmaceutical Compositions, Dosing, and Routes of
Administration
[0219] Also provided herein are pharmaceutical compositions that
includes a compound as disclosed herein, together with a
pharmaceutically acceptable excipient, such as, for example, a
diluent or carrier. Compounds and pharmaceutical compositions
suitable for use in the present invention include those wherein the
compound can be administered in an effective amount to achieve its
intended purpose. Administration of the compound described in more
detail below.
[0220] Suitable pharmaceutical formulations can be determined by
the skilled artisan depending on the route of administration and
the desired dosage. See, e.g., Remington's Pharmaceutical Sciences,
1435-712 (18th ed., Mack Publishing Co, Easton, Pa., 1990).
Formulations may influence the physical state, stability, rate of
in vivo release and rate of in vivo clearance of the administered
agents. Depending on the route of administration, a suitable dose
may be calculated according to body weight, body surface areas or
organ size. Further refinement of the calculations necessary to
determine the appropriate treatment dose is routinely made by those
of ordinary skill in the art without undue experimentation,
especially in light of the dosage information and assays disclosed
herein as well as the pharmacokinetic data obtainable through
animal or human clinical trials.
[0221] The phrases "pharmaceutically acceptable" or
"pharmacologically acceptable" refer to molecular entities and
compositions that do not produce adverse, allergic, or other
untoward reactions when administered to an animal or a human. As
used herein, "pharmaceutically acceptable excipients" includes any
and all solvents, dispersion media, coatings, antibacterial and
antifungal agents, isotonic and absorption delaying agents and the
like. The use of such excipients for pharmaceutically active
substances is well known in the art. Except insofar as any
conventional media or agent is incompatible with the therapeutic
compositions, its use in therapeutic compositions is contemplated.
Supplementary active ingredients also can be incorporated into the
compositions. In exemplary embodiments, the formulation may
comprise corn syrup solids, high-oleic safflower oil, coconut oil,
soy oil, L-leucine, calcium phosphate tribasic, L-tyrosine,
L-proline, L-lysine acetate, DATEM (an emulsifier), L-glutamine,
L-valine, potassium phosphate dibasic, L-isoleucine, L-arginine,
L-alanine, glycine, L-asparagine monohydrate, L-serine, potassium
citrate, L-threonine, sodium citrate, magnesium chloride,
L-histidine, L-methionine, ascorbic acid, calcium carbonate,
L-glutamic acid, L-cystine dihydrochloride, L-tryptophan,
L-aspartic acid, choline chloride, taurine, m-inositol, ferrous
sulfate, ascorbyl palmitate, zinc sulfate, L-camitine,
alpha-tocopheryl acetate, sodium chloride, niacinamide, mixed
tocopherols, calcium pantothenate, cupric sulfate, thiamine
chloride hydrochloride, vitamin A palmitate, manganese sulfate,
riboflavin, pyridoxine hydrochloride, folic acid, beta-carotene,
potassium iodide, phylloquinone, biotin, sodium selenate, chromium
chloride, sodium molybdate, vitamin D3 and cyanocobalamin.
[0222] The compound can be present in a pharmaceutical composition
as a pharmaceutically acceptable salt. As used herein,
"pharmaceutically acceptable salts" include, for example base
addition salts and acid addition salts.
[0223] Pharmaceutically acceptable base addition salts may be
formed with metals or amines, such as alkali and alkaline earth
metals or organic amines. Pharmaceutically acceptable salts of
compounds may also be prepared with a pharmaceutically acceptable
cation. Suitable pharmaceutically acceptable cations are well known
to those skilled in the art and include alkaline, alkaline earth,
ammonium and quaternary ammonium cations. Carbonates or hydrogen
carbonates are also possible. Examples of metals used as cations
are sodium, potassium, magnesium, ammonium, calcium, or ferric, and
the like. Examples of suitable amines include isopropylamine,
trimethylamine, histidine, N,N'-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, dicyclohexylamine,
ethylenediamine, N-methylglucamine, and procaine.
[0224] Pharmaceutically acceptable acid addition salts include
inorganic or organic acid salts. Examples of suitable acid salts
include the hydrochlorides, formates, acetates, citrates,
salicylates, nitrates, phosphates. Other suitable pharmaceutically
acceptable salts are well known to those skilled in the art and
include, for example, formic, acetic, citric, oxalic, tartaric, or
mandelic acids, hydrochloric acid, hydrobromic acid, sulfuric acid
or phosphoric acid; with organic carboxylic, sulfonic, sulfo or
phospho acids or N-substituted sulfamic acids, for example acetic
acid, trifluoroacetic acid (TFA), propionic acid, glycolic acid,
succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid,
fumaric acid, malic acid, tartaric acid, lactic acid, oxalic acid,
gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic
acid, cinnamic acid, mandelic acid, salicylic acid,
4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic
acid, embonic acid, nicotinic acid or isonicotinic acid; and with
amino acids, such as the 20 alpha amino acids involved in the
synthesis of proteins in nature, for example glutamic acid or
aspartic acid, and also with phenylacetic acid, methanesulfonic
acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane
1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic
acid, naphthalene 2-sulfonic acid, naphthalene 1,5-disulfonic acid,
2- or 3-phosphoglycerate, glucose 6-phosphate, N-cyclohexylsulfamic
acid (with the formation of cyclamates), or with other acid organic
compounds, such as ascorbic acid.
[0225] Pharmaceutical compositions containing the compounds
disclosed herein can be manufactured in a conventional manner,
e.g., by conventional mixing, dissolving, granulating,
dragee-making, levigating, emulsifying, encapsulating, entrapping,
or lyophilizing processes. Proper formulation is dependent upon the
route of administration chosen.
[0226] For oral administration, suitable compositions can be
formulated readily by combining a compound disclosed herein with
pharmaceutically acceptable excipients such as carriers well known
in the art. Such excipients and carriers enable the present
compounds to be formulated as tablets, pills, dragees, capsules,
liquids, gels, syrups, slurries, suspensions and the like, for oral
ingestion by a patient to be treated. Pharmaceutical preparations
for oral use can be obtained by adding a compound as disclosed
herein with a solid excipient, optionally grinding a resulting
mixture, and processing the mixture of granules, after adding
suitable auxiliaries, if desired, to obtain tablets or dragee
cores. Suitable excipients include, for example, fillers and
cellulose preparations. If desired, disintegrating agents can be
added. Pharmaceutically acceptable ingredients are well known for
the various types of formulation and may be for example binders
(e.g., natural or synthetic polymers), lubricants, surfactants,
sweetening and flavoring agents, coating materials, preservatives,
dyes, thickeners, adjuvants, antimicrobial agents, antioxidants and
carriers for the various formulation types.
[0227] When a therapeutically effective amount of a compound
disclosed herein is administered orally, the composition typically
is in the form of a solid (e.g., tablet, capsule, pill, powder, or
troche) or a liquid formulation (e.g., aqueous suspension,
solution, elixir, or syrup).
[0228] When administered in tablet form, the composition can
additionally contain a functional solid and/or solid carrier, such
as a gelatin or an adjuvant. The tablet, capsule, and powder can
contain about 1 to about 95% compound, and preferably from about 15
to about 90% compound.
[0229] When administered in liquid or suspension form, a functional
liquid and/or a liquid carrier such as water, petroleum, or oils of
animal or plant origin can be added. The liquid form of the
composition can further contain physiological saline solution,
sugar alcohol solutions, dextrose or other saccharide solutions, or
glycols. When administered in liquid or suspension form, the
composition can contain about 0.5 to about 90% by weight of a
compound disclosed herein, and preferably about 1 to about 50% of a
compound disclosed herein. In one embodiment contemplated, the
liquid carrier is non-aqueous or substantially non-aqueous. For
administration in liquid form, the composition may be supplied as a
rapidly-dissolving solid formulation for dissolution or suspension
immediately prior to administration.
[0230] When a therapeutically effective amount of a compound
disclosed herein is administered by intravenous, cutaneous, or
subcutaneous injection, the composition is in the form of a
pyrogen-free, parenterally acceptable aqueous solution. The
preparation of such parenterally acceptable solutions, having due
regard to pH, isotonicity, stability, and the like, is within the
skill in the art. A preferred composition for intravenous,
cutaneous, or subcutaneous injection typically contains, in
addition to a compound disclosed herein, an isotonic vehicle. Such
compositions may be prepared for administration as solutions of
free base or pharmacologically acceptable salts in water suitably
mixed with a surfactant, such as hydroxypropylcellulose.
Dispersions also can be prepared in glycerol, liquid polyethylene
glycols, and mixtures thereof and in oils. Under ordinary
conditions of storage and use, these preparations can optionally
contain a preservative to prevent the growth of microorganisms.
[0231] Injectable compositions can include sterile aqueous
solutions, suspensions, or dispersions and sterile powders for the
extemporaneous preparation of sterile injectable solutions,
suspensions, or dispersions. In all embodiments the form must be
sterile and must be fluid to the extent that easy syringability
exists. It must be stable under the conditions of manufacture and
storage and must resist the contaminating action of microorganisms,
such as bacteria and fungi, by optional inclusion of a
preservative. The carrier can be a solvent or dispersion medium
containing, for example, water, ethanol, polyol (e.g., glycerol,
propylene glycol, and liquid polyethylene glycol, and the like),
suitable mixtures thereof, and vegetable oils. In one embodiment
contemplated, the carrier is non-aqueous or substantially
non-aqueous. The proper fluidity can be maintained, for example, by
the use of a coating, such as lecithin, by the maintenance of the
required particle size of the compound in the embodiment of
dispersion and by the use of surfactants. The prevention of the
action of microorganisms can be brought about by various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In
many embodiments, it will be preferable to include isotonic agents,
for example, sugars or sodium chloride. Prolonged absorption of the
injectable compositions can be brought about by the use in the
compositions of agents delaying absorption, for example, aluminum
monostearate and gelatin.
[0232] Sterile injectable solutions are prepared by incorporating
the active compounds in the required amount in the appropriate
solvent with various of the other ingredients enumerated above, as
required, followed by filtered sterilization. Generally,
dispersions are prepared by incorporating the various sterilized
active ingredients into a sterile vehicle which contains the basic
dispersion medium and the required other ingredients from those
enumerated above. In the embodiment of sterile powders for the
preparation of sterile injectable solutions, the preferred methods
of preparation are vacuum-drying and freeze-drying techniques which
yield a powder of the active ingredient plus any additional desired
ingredient from a previously sterile-filtered solution thereof.
[0233] Slow release or sustained release formulations may also be
prepared in order to achieve a controlled release of the active
compound in contact with the body fluids in the GI tract, and to
provide a substantially constant and effective level of the active
compound in the blood plasma. For example, release can be
controlled by one or more of dissolution, diffusion, and
ion-exchange. In addition, the slow release approach may enhance
absorption via saturable or limiting pathways within the GI tract.
For example, the compound may be embedded for this purpose in a
polymer matrix of a biological degradable polymer, a water-soluble
polymer or a mixture of both, and optionally suitable surfactants.
Embedding can mean in this context the incorporation of
micro-particles in a matrix of polymers. Controlled release
formulations are also obtained through encapsulation of dispersed
micro-particles or emulsified micro-droplets via known dispersion
or emulsion coating technologies.
[0234] For administration by inhalation, compounds of the present
invention are conveniently delivered in the form of an aerosol
spray presentation from pressurized packs or a nebulizer, with the
use of a suitable propellant. In the embodiment of a pressurized
aerosol, the dosage unit can be determined by providing a valve to
deliver a metered amount. Capsules and cartridges of, e.g.,
gelatin, for use in an inhaler or insufflator can be formulated
containing a powder mix of the compound and a suitable powder base
such as lactose or starch.
[0235] The compounds disclosed herein can be formulated for
parenteral administration by injection (e.g., by bolus injection or
continuous infusion). Formulations for injection can be presented
in unit dosage form (e.g., in ampules or in multidose containers),
with an added preservative. The compositions can take such forms as
suspensions, solutions, or emulsions in oily or aqueous vehicles,
and can contain formulatory agents such as suspending, stabilizing,
and/or dispersing agents.
[0236] Pharmaceutical formulations for parenteral administration
include aqueous solutions of the compounds in water-soluble form.
Additionally, suspensions of the compounds can be prepared as
appropriate oily injection suspensions. Suitable lipophilic
solvents or vehicles include fatty oils or synthetic fatty acid
esters. Aqueous injection suspensions can contain substances which
increase the viscosity of the suspension. Optionally, the
suspension also can contain suitable stabilizers or agents that
increase the solubility of the compounds and allow for the
preparation of highly concentrated solutions. Alternatively, a
present composition can be in powder form for constitution with a
suitable vehicle (e.g., sterile pyrogen-free water) before use.
[0237] Compounds disclosed herein also can be formulated in rectal
compositions, such as suppositories or retention enemas (e.g.,
containing conventional suppository bases). In addition to the
formulations described previously, the compounds also can be
formulated as a depot preparation. Such long-acting formulations
can be administered by implantation (e.g., subcutaneously or
intramuscularly) or by intramuscular injection. Thus, for example,
the compounds can be formulated with suitable polymeric or
hydrophobic materials (for example, as an emulsion in an acceptable
oil) or ion exchange resins, or as sparingly soluble derivatives,
for example, as a sparingly soluble salt.
[0238] In particular, a compound disclosed herein can be
administered orally, buccally, or sublingually in the form of
tablets containing excipients, such as starch or lactose, or in
capsules or ovules, either alone or in admixture with excipients,
or in the form of elixirs or suspensions containing flavoring or
coloring agents. Such liquid preparations can be prepared with
pharmaceutically acceptable additives, such as suspending agents. A
compound also can be injected parenterally, for example,
intravenously, intramuscularly, subcutaneously, or intracoronarily.
For parenteral administration, the compound is best used in the
form of a sterile aqueous solution which can contain other
substances, for example, salts, or sugar alcohols, such as
mannitol, or glucose, to make the solution isotonic with blood.
[0239] For veterinary use, a compound disclosed herein is
administered as a suitably acceptable formulation in accordance
with normal veterinary practice. The veterinarian can readily
determine the dosing regimen and route of administration that is
most appropriate for a particular animal.
[0240] In some embodiments, all the necessary components for the
treatment of KRAS-related disorder using a compound as disclosed
herein either alone or in combination with another agent or
intervention traditionally used for the treatment of such disease
may be packaged into a kit. Specifically, the present invention
provides a kit for use in the therapeutic intervention of the
disease comprising a packaged set of medicaments that include the
compound disclosed herein as well as buffers and other components
for preparing deliverable forms of said medicaments, and/or devices
for delivering such medicaments, and/or any agents that are used in
combination therapy with the compound disclosed herein, and/or
instructions for the treatment of the disease packaged with the
medicaments. The instructions may be fixed in any tangible medium,
such as printed paper, or a computer readable magnetic or optical
medium, or instructions to reference a remote computer data source
such as a world wide web page accessible via the internet.
[0241] A "therapeutically effective amount" means an amount
effective to treat or to prevent development of, or to alleviate
the existing symptoms of, the subject being treated. Determination
of the effective amounts is well within the capability of those
skilled in the art, especially in light of the detailed disclosure
provided herein. Generally, a "therapeutically effective dose"
refers to that amount of the compound that results in achieving the
desired effect. For example, in one preferred embodiment, a
therapeutically effective amount of a compound disclosed herein
decreases KRAS activity by at least 5%, compared to control, at
least 10%, at least 15%, at least 20%, at least 25%, at least 30%,
at least 35%, at least 40%, at least 45%, at least 50%, at least
55%, at least 60%, at least 65%, at least 70%, at least 75%, at
least 80%, at least 85%, or at least 90%.
[0242] The amount of compound administered can be dependent on the
subject being treated, on the subject's age, health, sex, and
weight, the kind of concurrent treatment (if any), severity of the
affliction, the nature of the effect desired, the manner and
frequency of treatment, and the judgment of the prescribing
physician. The frequency of dosing also can be dependent on
pharmacodynamic effects on arterial oxygen pressures. However, the
most preferred dosage can be tailored to the individual subject, as
is understood and determinable by one of skill in the art, without
undue experimentation. This typically involves adjustment of a
standard dose (e.g., reduction of the dose if the patient has a low
body weight).
[0243] While individual needs vary, determination of optimal ranges
of effective amounts of the compound is within the skill of the
art. For administration to a human in the curative or prophylactic
treatment of the conditions and disorders identified herein, for
example, typical dosages of the compounds of the present invention
can be about 0.05 mg/kg/day to about 50 mg/kg/day, for example at
least 0.05 mg/kg, at least 0.08 mg/kg, at least 0.1 mg/kg, at least
0.2 mg/kg, at least 0.3 mg/kg, at least 0.4 mg/kg, or at least 0.5
mg/kg, and preferably 50 mg/kg or less, 40 mg/kg or less, 30 mg/kg
or less, 20 mg/kg or less, or 10 mg/kg or less, which can be about
2.5 mg/day (0.5 mg/kg.times.5 kg) to about 5000 mg/day (50
mg/kg.times.100 kg), for example. For example, dosages of the
compounds can be about 0.1 mg/kg/day to about 50 mg/kg/day, about
0.05 mg/kg/day to about 10 mg/kg/day, about 0.05 mg/kg/day to about
5 mg/kg/day, about 0.05 mg/kg/day to about 3 mg/kg/day, about 0.07
mg/kg/day to about 3 mg/kg/day, about 0.09 mg/kg/day to about 3
mg/kg/day, about 0.05 mg/kg/day to about 0.1 mg/kg/day, about 0.1
mg/kg/day to about 1 mg/kg/day, about 1 mg/kg/day to about 10
mg/kg/day, about 1 mg/kg/day to about 5 mg/kg/day, about 1
mg/kg/day to about 3 mg/kg/day, about 3 mg/day to about 500 mg/day,
about 5 mg/day to about 250 mg/day, about 10 mg/day to about 100
mg/day, about 3 mg/day to about 10 mg/day, or about 100 mg/day to
about 250 mg/day. Such doses may be administered in a single dose
or it may be divided into multiple doses.
Methods of Using KRAS G12C Inhibitors
[0244] The present disclosure provides a method of inhibiting
RAS-mediated cell signaling comprising contacting a cell with an
effective amount of one or more compounds disclosed herein.
Inhibition of RAS-mediated signal transduction can be assessed and
demonstrated by a wide variety of ways known in the art.
Non-limiting examples include a showing of (a) a decrease in GTPase
activity of RAS; (b) a decrease in GTP binding affinity or an
increase in GDP binding affinity; (c) an increase in K off of GTP
or a decrease in K off of GDP; (d) a decrease in the levels of
signaling transduction molecules downstream in the RAS pathway,
such as a decrease in pMEK, pERK, or pAKT levels; and/or (e) a
decrease in binding of RAS complex to downstream signaling
molecules including but not limited to Raf. Kits and commercially
available assays can be utilized for determining one or more of the
above.
[0245] The disclosure also provides methods of using the compounds
or pharmaceutical compositions of the present disclosure to treat
disease conditions, including but not limited to conditions
implicated by G12C KRAS, HRAS or NRAS mutation (e.g., cancer).
[0246] In some embodiments, a method for treatment of cancer is
provided, the method comprising administering an effective amount
of any of the foregoing pharmaceutical compositions comprising a
compound as disclosed herein to a subject in need thereof. In some
embodiments, the cancer is mediated by a KRAS, HRAS or NRAS G12C
mutation. In various embodiments, the cancer is pancreatic cancer,
colorectal cancer or lung cancer. In some embodiments, the cancer
is gall bladder cancer, thyroid cancer, and bile duct cancer.
[0247] In some embodiments the disclosure provides method of
treating a disorder in a subject in need thereof, wherein the said
method comprises determining if the subject has a KRAS, HRAS or
NRAS G12C mutation and if the subject is determined to have the
KRAS, HRAS or NRAS G12C mutation, then administering to the subject
a therapeutically effective dose of at least one compound as
disclosed herein or a pharmaceutically acceptable salt thereof.
[0248] The disclosed compounds inhibit anchorage-independent cell
growth and therefore have the potential to inhibit tumor
metastasis. Accordingly, another embodiment the disclosure provides
a method for inhibiting tumor metastasis, the method comprising
administering an effective amount a compound disclosed herein.
[0249] KRAS, HRAS or NRAS G12C mutations have also been identified
in hematological malignancies (e.g., cancers that affect blood,
bone marrow and/or lymph nodes). Accordingly, certain embodiments
are directed to administration of a disclosed compounds (e.g., in
the form of a pharmaceutical composition) to a patient in need of
treatment of a hematological malignancy. Such malignancies include,
but are not limited to leukemias and lymphomas. For example, the
presently disclosed compounds can be used for treatment of diseases
such as Acute lymphoblastic leukemia (ALL), Acute myelogenous
leukemia (AML), Chronic lymphocytic leukemia (CLL), small
lymphocytic lymphoma (SLL), Chronic myelogenous leukemia (CML),
Acute monocytic leukemia (AMoL) and/or other leukemias. In other
embodiments, the compounds are useful for treatment of lymphomas
such as all subtypes of Hodgkins lymphoma or non-Hodgkins lymphoma.
In various embodiments, the compounds are useful for treatment of
plasma cell malignancies such as multiple myeloma, mantle cell
lymphoma, and Waldenstrom's macroglubunemia.
[0250] Determining whether a tumor or cancer comprises a G12C KRAS,
HRAS or NRAS mutation can be undertaken by assessing the nucleotide
sequence encoding the KRAS, HRAS or NRAS protein, by assessing the
amino acid sequence of the KRAS, HRAS or NRAS protein, or by
assessing the characteristics of a putative KRAS, HRAS or NRAS
mutant protein. The sequence of wild-type human KRAS, HRAS or NRAS
is known in the art, (e.g. Accession No. NP203524).
[0251] Methods for detecting a mutation in a KRAS, HRAS or NRAS
nucleotide sequence are known by those of skill in the art. These
methods include, but are not limited to, polymerase chain
reaction-restriction fragment length polymorphism (PCR-RFLP)
assays, polymerase chain reaction-single strand conformation
polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR
sequencing, mutant allele-specific PCR amplification (MASA) assays,
direct sequencing, primer extension reactions, electrophoresis,
oligonucleotide ligation assays, hybridization assays, TaqMan
assays, SNP genotyping assays, high resolution melting assays and
microarray analyses. In some embodiments, samples are evaluated for
G12C KRAS, HRAS or NRAS mutations by real-time PCR. In real-time
PCR, fluorescent probes specific for the KRAS, HRAS or NRAS G12C
mutation are used. When a mutation is present, the probe binds and
fluorescence is detected. In some embodiments, the KRAS, HRAS or
NRAS G12C mutation is identified using a direct sequencing method
of specific regions (e.g., exon 2 and/or exon 3) in the KRAS, HRAS
or NRAS gene. This technique will identify all possible mutations
in the region sequenced.
[0252] Methods for detecting a mutation in a KRAS, HRAS or NRAS
protein are known by those of skill in the art. These methods
include, but are not limited to, detection of a KRAS, HRAS or NRAS
mutant using a binding agent (e.g., an antibody) specific for the
mutant protein, protein electrophoresis and Western blotting, and
direct peptide sequencing.
[0253] Methods for determining whether a tumor or cancer comprises
a G12C KRAS, HRAS or NRAS mutation can use a variety of samples. In
some embodiments, the sample is taken from a subject having a tumor
or cancer. In some embodiments, the sample is a fresh tumor/cancer
sample. In some embodiments, the sample is a frozen tumor/cancer
sample. In some embodiments, the sample is a formalin-fixed
paraffin-embedded sample. In some embodiments, the sample is a
circulating tumor cell (CTC) sample. In some embodiments, the
sample is processed to a cell lysate. In some embodiments, the
sample is processed to DNA or RNA.
[0254] The disclosure also relates to a method of treating a
hyperproliferative disorder in a mammal that comprises
administering to said mammal a therapeutically effective amount of
a compound as disclosed herein, or a pharmaceutically acceptable
salt thereof. In some embodiments, said method relates to the
treatment of a subject who suffers from a cancer such as acute
myeloid leukemia, cancer in adolescents, adrenocortical carcinoma
childhood, AIDS-related cancers (e.g. Lymphoma and Kaposi's
Sarcoma), anal cancer, appendix cancer, astrocytomas, atypical
teratoid, basal cell carcinoma, bile duct cancer, bladder cancer,
bone cancer, brain stem glioma, brain tumor, breast cancer,
bronchial tumors, Burkitt lymphoma, carcinoid tumor, atypical
teratoid, embryonal tumors, germ cell tumor, primary lymphoma,
cervical cancer, childhood cancers, chordoma, cardiac tumors,
chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia
(CML), chronic myleoproliferative disorders, colon cancer,
colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma,
extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS
cancer, endometrial cancer, ependymoma, esophageal cancer,
esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor,
extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of
bone, gall bladder cancer, gastric cancer, gastrointestinal
carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell
tumor, gestational trophoblastic tumor, hairy cell leukemia, head
and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma,
hypopharyngeal cancer, intraocular melanoma, islet cell tumors,
pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer,
lip and oral cavity cancer, liver cancer, lobular carcinoma in situ
(LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with
occult primary, midline tract carcinoma, mouth cancer multiple
endocrine neoplasia syndromes, multiple myeloma/plasma cell
neoplasm, mycosis fungoides, myelodysplastic syndromes,
myelodysplastic/myeloproliferative neoplasms, multiple myeloma,
merkel cell carcinoma, malignant mesothelioma, malignant fibrous
histiocytoma of bone and osteosarcoma, nasal cavity and paranasal
sinus cancer, nasopharyngeal cancer, neuroblastoma, non-hodgkin
lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and
oral cavity cancer, oropharyngeal cancer, ovarian cancer,
pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus
and nasal cavity cancer, parathyroid cancer, penile cancer,
pharyngeal cancer, pleuropulmonary blastoma, primary central
nervous system (CNS) lymphoma, prostate cancer, rectal cancer,
transitional cell cancer, retinoblastoma, rhabdomyosarcoma,
salivary gland cancer, skin cancer, stomach (gastric) cancer, small
cell lung cancer, small intestine cancer, soft tissue sarcoma,
T-Cell lymphoma, testicular cancer, throat cancer, thymoma and
thymic carcinoma, thyroid cancer, transitional cell cancer of the
renal pelvis and ureter, trophoblastic tumor, unusual cancers of
childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar
cancer, or viral-induced cancer. In some embodiments, said method
relates to the treatment of a non-cancerous hyperproliferative
disorder such as benign hyperplasia of the skin (e. g., psoriasis),
restenosis, or prostate (e. g., benign prostatic hypertrophy
(BPH)).
[0255] In some embodiments, the methods for treatment are directed
to treating lung cancers, the methods comprise administering an
effective amount of any of the above described compound (or a
pharmaceutical composition comprising the same) to a subject in
need thereof. In certain embodiments the lung cancer is a non-small
cell lung carcinoma (NSCLC), for example adenocarcinoma,
squamous-cell lung carcinoma or large-cell lung carcinoma. In some
embodiments, the lung cancer is a small cell lung carcinoma. Other
lung cancers treatable with the disclosed compounds include, but
are not limited to, glandular tumors, carcinoid tumors and
undifferentiated carcinomas.
[0256] The disclosure further provides methods of modulating a G12C
Mutant KRAS, HRAS or NRAS protein activity by contacting the
protein with an effective amount of a compound of the disclosure.
Modulation can be inhibiting or activating protein activity. In
some embodiments, the disclosure provides methods of inhibiting
protein activity by contacting the G12C Mutant KRAS, HRAS or NRAS
protein with an effective amount of a compound of the disclosure in
solution. In some embodiments, the disclosure provides methods of
inhibiting the G12C Mutant KRAS, HRAS or NRAS protein activity by
contacting a cell, tissue, or organ that expresses the protein of
interest. In some embodiments, the disclosure provides methods of
inhibiting protein activity in subject including but not limited to
rodents and mammal (e.g., human) by administering into the subject
an effective amount of a compound of the disclosure. In some
embodiments, the percentage modulation exceeds 25%, 30%, 40%, 50%,
60%, 70%, 80%, or 90%. In some embodiments, the percentage of
inhibiting exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.
[0257] In some embodiments, the disclosure provides methods of
inhibiting KRAS, HRAS or NRAS G12C activity in a cell by contacting
said cell with an amount of a compound of the disclosure sufficient
to inhibit the activity of KRAS, HRAS or NRAS G12C in said cell. In
some embodiments, the disclosure provides methods of inhibiting
KRAS, HRAS or NRAS G12C activity in a tissue by contacting said
tissue with an amount of a compound of the disclosure sufficient to
inhibit the activity of KRAS, HRAS or NRAS G12C in said tissue. In
some embodiments, the disclosure provides methods of inhibiting
KRAS, HRAS or NRAS G12C activity in an organism by contacting said
organism with an amount of a compound of the disclosure sufficient
to inhibit the activity of KRAS, HRAS or NRAS G12C in said
organism. In some embodiments, the disclosure provides methods of
inhibiting KRAS, HRAS or NRAS G12C activity in an animal by
contacting said animal with an amount of a compound of the
disclosure sufficient to inhibit the activity of KRAS, HRAS or NRAS
G12C in said animal. In some embodiments, the disclosure provides
methods of inhibiting KRAS, HRAS or NRAS G12C activity in a mammal
by contacting said mammal with an amount of a compound of the
disclosure sufficient to inhibit the activity of KRAS, HRAS or NRAS
G12C in said mammal. In some embodiments, the disclosure provides
methods of inhibiting KRAS, HRAS or NRAS G12C activity in a human
by contacting said human with an amount of a compound of the
disclosure sufficient to inhibit the activity of KRAS, HRAS or NRAS
G12C in said human. The present disclosure provides methods of
treating a disease mediated by KRAS, HRAS or NRAS G12C activity in
a subject in need of such treatment.
Combination Therapy:
[0258] The present disclosure also provides methods for combination
therapies in which an agent known to modulate other pathways, or
other components of the same pathway, or even overlapping sets of
target enzymes are used in combination with a compound of the
present disclosure, or a pharmaceutically acceptable salt thereof.
In one aspect, such therapy includes but is not limited to the
combination of one or more compounds of the disclosure with
chemotherapeutic agents, therapeutic antibodies, and radiation
treatment, to provide a synergistic or additive therapeutic
effect.
[0259] Many chemotherapeutics are presently known in the art and
can be used in combination with the compounds of the disclosure. In
some embodiments, the chemotherapeutic is selected from the group
consisting of mitotic inhibitors, alkylating agents,
anti-metabolites, intercalating antibiotics, growth factor
inhibitors, cell cycle inhibitors, enzymes, topoisomerase
inhibitors, biological response modifiers, anti-hormones,
angiogenesis inhibitors, and anti-androgens. Non-limiting examples
are chemotherapeutic agents, cytotoxic agents, and non-peptide
small molecules such as Gleevec.RTM. (Imatinib Mesylate),
Kyprolis.RTM. (carfilzomib), Velcade.RTM. (bortezomib), Casodex
(bicalutamide), Iressa.RTM. (gefitinib), and Adriamycin as well as
a host of chemotherapeutic agents. Non-limiting examples of
chemotherapeutic agents include alkylating agents such as thiotepa
and cyclosphosphamide (CYTOXAN.TM.); alkyl sulfonates such as
busulfan, improsulfan and piposulfan; aziridines such as benzodopa,
carboquone, meturedopa, and uredopa; ethylenimines and
methylamelamines including altretamine, triethylenemelamine,
trietylenephosphoramide, triethylenethiophosphaoramide and
trimethylolomelamine; nitrogen mustards such as chlorambucil,
chlornaphazine, cholophosphamide, estramustine, ifosfamide,
mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,
novembichin, phenesterine, prednimustine, trofosfamide, uracil
mustard; nitrosureas such as carmustine, chlorozotocin,
fotemustine, lomustine, nimustine, ranimustine; antibiotics such as
aclacinomysins, actinomycin, authramycin, azaserine, bleomycins,
cactinomycin, calicheamicin, carabicin, carminomycin,
carzinophilin, Casodex.TM., chromomycins, dactinomycin,
daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin,
epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins,
mycophenolic acid, nogalamycin, olivomycins, peplomycin,
potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin,
streptozocin, tubercidin, ubenimex, zinostatin, zorubicin;
anti-metabolites such as methotrexate and 5-fluorouracil (5-FU);
folic acid analogues such as denopterin, methotrexate, pteropterin,
trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine,
thiamiprine, thioguanine; pyrimidine analogs such as ancitabine,
azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine,
doxifluridine, enocitabine, floxuridine, androgens such as
calusterone, dromostanolone propionate, epitiostanol, mepitiostane,
testolactone; anti-adrenals such as aminoglutethimide, mitotane,
trilostane; folic acid replenisher such as frolinic acid;
aceglatone; aldophosphamide glycoside; aminolevulinic acid;
amsacrine; bestrabucil; bisantrene; edatraxate; defofamine;
demecolcine; diaziquone; elfomithine; elliptinium acetate;
etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine;
mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin;
phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide;
procarbazine; PSK; razoxane; sizofiran; spirogermanium; tenuazonic
acid; triaziquone; 2,2',2''-trichlorotriethylamine; urethan;
vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol;
pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide;
thiotepa; taxanes, e.g. paclitaxel and docetaxel; retinoic acid;
esperamicins; capecitabine; and pharmaceutically acceptable salts,
acids or derivatives of any of the above.
[0260] Also included as suitable chemotherapeutic cell conditioners
are anti-hormonal agents that act to regulate or inhibit hormone
action on tumors such as anti-estrogens including for example
tamoxifen, (Nolvadex.TM.), raloxifene, aromatase inhibiting
4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY
117018, onapristone, and toremifene (Fareston); and anti-androgens
such as flutamide, nilutamide, bicalutamide, leuprolide, and
goserelin; chlorambucil; gemcitabine; 6-thioguanine;
mercaptopurine; methotrexate; platinum analogs such as cisplatin
and carboplatin; vinblastine; platinum; etoposide (VP-16);
ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine;
navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda;
ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS
2000; difluoromethylomithine (DMFO).
[0261] Where desired, the compounds or pharmaceutical composition
of the present disclosure can be used in combination with commonly
prescribed anti-cancer drugs such as Herceptin.RTM., Avastin.RTM.,
Erbitux.RTM., Rituxan.RTM., Taxol.RTM., Arimidex.RTM.,
Taxotere.RTM., ABVD, AVICINE, Abagovomab, Acridine carboxamide,
Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin, Alpharadin,
Alvocidib, 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone,
Amonafide, Anthracenedione, Anti-CD22 immunotoxins, Antineoplastic,
Antitumorigenic herbs, Apaziquone, Atiprimod, Azathioprine,
Belotecan, Bendamustine, BIBW 2992, Biricodar, Brostallicin,
Bryostatin, Buthionine sulfoximine, CBV (chemotherapy), Calyculin,
cell-cycle nonspecific antineoplastic agents, Dichloroacetic acid,
Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin,
Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine,
Fosfestrol, ICE chemotherapy regimen, IT-101, Imexon, Imiquimod,
Indolocarbazole, Irofulven, Laniquidar, Larotaxel, Lenalidomide,
Lucanthone, Lurtotecan, Mafosfamide, Mitozolomide, Nafoxidine,
Nedaplatin, Olaparib, Ortataxel, PAC-1, Pawpaw, Pixantrone,
Proteasome inhibitor, Rebeccamycin, Resiquimod, Rubitecan, SN-38,
Salinosporamide A, Sapacitabine, Stanford V, Swainsonine,
Talaporfin, Tariquidar, Tegafur-uracil, Temodar, Tesetaxel,
Triplatin tetranitrate, Tris(2-chloroethyl)amine, Troxacitabine,
Uramustine, Vadimezan, Vinflunine, ZD6126 or Zosuquidar.
[0262] This disclosure further relates to a method for using the
compounds or pharmaceutical compositions provided herein, in
combination with radiation therapy for inhibiting abnormal cell
growth or treating the hyperproliferative disorder in the mammal.
Techniques for administering radiation therapy are known in the
art, and these techniques can be used in the combination therapy
described herein. The administration of the compound of the
disclosure in this combination therapy can be determined as
described herein.
[0263] Radiation therapy can be administered through one of several
methods, or a combination of methods, including without limitation
external-beam therapy, internal radiation therapy, implant
radiation, stereotactic radiosurgery, systemic radiation therapy,
radiotherapy and permanent or temporary interstitial brachytherapy.
The term "brachytherapy," as used herein, refers to radiation
therapy delivered by a spatially confined radioactive material
inserted into the body at or near a tumor or other proliferative
tissue disease site. The term is intended without limitation to
include exposure to radioactive isotopes (e.g. At-211, I-131,
I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive
isotopes of Lu). Suitable radiation sources for use as a cell
conditioner of the present disclosure include both solids and
liquids. By way of non-limiting example, the radiation source can
be a radionuclide, such as 1-125, 1-131, Yb-169, Ir-192 as a solid
source, I-125 as a solid source, or other radionuclides that emit
photons, beta particles, gamma radiation, or other therapeutic
rays. The radioactive material can also be a fluid made from any
solution of radionuclide(s), e.g., a solution of 1-125 or 1-131, or
a radioactive fluid can be produced using a slurry of a suitable
fluid containing small particles of solid radionuclides, such as
Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in a
gel or radioactive micro spheres.
[0264] The compounds or pharmaceutical compositions of the
disclosure can be used in combination with an amount of one or more
substances selected from anti-angiogenesis agents, signal
transduction inhibitors, antiproliferative agents, glycolysis
inhibitors, or autophagy inhibitors.
[0265] Anti-angiogenesis agents, such as MMP-2
(matrix-metalloproteinase 2) inhibitors, MMP-9
(matrix-metalloprotienase 9) inhibitors, and COX-11 (cyclooxygenase
11) inhibitors, can be used in conjunction with a compound of the
disclosure and pharmaceutical compositions described herein.
Anti-angiogenesis agents include, for example, rapamycin,
temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib,
and bevacizumab. Examples of useful COX-II inhibitors include
alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix
metalloproteinase inhibitors are described in WO 96/33172 WO
96/27583 European Patent Publication EP0818442, European Patent
Publication EP1004578, WO 98/07697, WO 98/03516, WO 98/34918, WO
98/34915, WO 98/33768, WO 98/30566, European Patent Publication
606046, European Patent Publication 931788, WO 90/05719, WO
99/52910, WO 99/52889, WO 99/29667, WO 99/007675, European Patent
Publication EP1786785, European Patent Publication No. EP1181017,
United States Publication US20090012085, United States Publication
U.S. Pat. No. 5,863,949, United States Publication U.S. Pat. No.
5,861,510, and European Patent Publication EP0780386, all of which
are incorporated herein in their entireties by reference. Preferred
MMP-2 and MMP-9 inhibitors are those that have little or no
activity inhibiting MMP-1. More preferred, are those that
selectively inhibit MMP-2 and/or AMP-9 relative to the other
matrix-metalloproteinases (i. e., MAP-1, MMP-3, MMP-4, MMP-5,
MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some
specific examples of MMP inhibitors useful in the disclosure are
AG-3340, RO 32-3555, and RS 13-0830.
[0266] The present compounds may also be used in co-therapies with
other anti-neoplastic agents, such as acemannan, aclarubicin,
aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine,
aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole,
ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos),
bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin,
cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030
(Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane,
dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine,
doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil,
HIT diclofenac, interferon alfa, daunorubicin, doxorubicin,
tretinoin, edelfosine, edrecolomab, eflomithine, emitefur,
epirubicin, epoetin beta, etoposide phosphate, exemestane,
exisulind, fadrozole, filgrastim, finasteride, fludarabine
phosphate, formestane, fotemustine, gallium nitrate, gemcitabine,
gemtuzumab zogamicin, gimeracil/oteracil/tegafur combination,
glycopine, goserelin, heptaplatin, human chorionic gonadotropin,
human fetal alpha fetoprotein, ibandronic acid, idarubicin,
(imiquimod, interferon alfa, interferon alfa, natural, interferon
alfa-2, interferon alfa-2a, interferon alfa-2b, interferon alfa-N1,
interferon alfa-.sub.n3, interferon alfacon-1, interferon alpha,
natural, interferon beta, interferon beta-1a, interferon beta-1 b,
interferon gamma, natural interferon gamma-1a, interferon gamma-1b,
interleukin-1 beta, iobenguane, irinotecan, irsogladine,
lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan
sulfate, letrozole, leukocyte alpha interferon, leuprorelin,
levamisole+fluorouracil, liarozole, lobaplatin, lonidamine,
lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone,
miltefosine, mirimostim, mismatched double stranded RNA,
mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin,
naloxone+pentazocine, nartograstim, nedaplatin, nilutamide,
noscapine, novel erythropoiesis stimulating protein, NSC 631570
octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel,
pamidronic acid, pegaspargase, peginterferon alfa-2b, pentosan
polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit
antithymocyte polyclonal antibody, polyethylene glycol interferon
alfa-2a, porfimer sodium, raloxifene, raltitrexed,
rasburiembodiment, rhenium Re 186 etidronate, RII retinamide,
rituximab, romurtide, samarium (153 Sm) lexidronam, sargramostim,
sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin,
tasonermin, tazarotene, tegafur, temoporfin, temozolomide,
teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin,
thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131,
trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate,
triptorelin, tumor necrosis factor alpha, natural, ubenimex,
bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine,
valrubicin, verteporfin, vinorelbine, VIRULIZIN, zinostatin
stimalamer, or zoledronic acid; abarelix; AE 941 (Aetema),
ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015
(Dendreon), cetuximab, decitabine, dexaminoglutethimide,
diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil,
etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant,
galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical),
granulocyte macrophage colony stimulating factor, histamine
dihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran),
interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim,
lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical
Development), HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC
Technology), idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb
(Techniclone), polymorphic epithelial mucin-yttrium 90 MAb
(Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium,
MX 6 (Galderma), nelarabine, nolatrexed, P 30 protein, pegvisomant,
pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan,
satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR
Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate,
thaliblastine, thrombopoietin, tin ethyl etiopurpurin,
tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York
University), melanoma vaccine (Sloan Kettering Institute), melanoma
oncolysate vaccine (New York Medical College), viral melanoma cell
lysates vaccine (Royal Newcastle Hospital), or valspodar.
[0267] The compounds of the invention may further be used with
VEGFR inhibitors. Other compounds described in the following
patents and patent applications can be used in combination therapy:
U.S. Pat. No. 6,258,812, US 2003/0105091, WO 01/37820, U.S. Pat.
No. 6,235,764, WO 01/32651, U.S. Pat. Nos. 6,630,500, 6,515,004,
6,713,485, 5,521,184, 5,770,599, 5,747,498, WO 02/68406, WO
02/66470, WO 02/55501, WO 04/05279, WO 04/07481, WO 04/07458, WO
04/09784, WO 02/59110, WO 99/45009, WO 00/59509, WO 99/61422, U.S.
Pat. No. 5,990,141, WO 00/12089, and WO 00/02871.
[0268] In some embodiments, the combination comprises a composition
of the present invention in combination with at least one
anti-angiogenic agent. Agents are inclusive of, but not limited to,
in vitro synthetically prepared chemical compositions, antibodies,
antigen binding regions, radionuclides, and combinations and
conjugates thereof An agent can be an agonist, antagonist,
allosteric modulator, toxin or, more generally, may act to inhibit
or stimulate its target (e.g., receptor or enzyme activation or
inhibition), and thereby promote cell death or arrest cell
growth.
[0269] Exemplary anti-angiogenic agents include ERBITUX.TM.
(IMC-C225), KDR (kinase domain receptor) inhibitory agents (e.g.,
antibodies and antigen binding regions that specifically bind to
the kinase domain receptor), anti-VEGF agents (e.g., antibodies or
antigen binding regions that specifically bind VEGF, or soluble
VEGF receptors or a ligand binding region thereof) such as
AVASTIN.TM. or VEGF-TRAP.TM., and anti-VEGF receptor agents (e.g.,
antibodies or antigen binding regions that specifically bind
thereto), EGFR inhibitory agents (e.g., antibodies or antigen
binding regions that specifically bind thereto) such as Vectibix
(panitumumab), IRESSA.TM. (gefitinib), TARCEVA.TM. (erlotinib),
anti-Ang1 and anti-Ang2 agents (e.g., antibodies or antigen binding
regions specifically binding thereto or to their receptors, e.g.,
Tie2/Tek), and anti-Tie2 kinase inhibitory agents (e.g., antibodies
or antigen binding regions that specifically bind thereto). The
pharmaceutical compositions of the present invention can also
include one or more agents (e.g., antibodies, antigen binding
regions, or soluble receptors) that specifically bind and inhibit
the activity of growth factors, such as antagonists of hepatocyte
growth factor (HGF, also known as Scatter Factor), and antibodies
or antigen binding regions that specifically bind its receptor
"c-met".
[0270] Other anti-angiogenic agents include Campath, IL-8, B-FGF,
Tek antagonists (Ceretti et al., U.S. Publication No. 2003/0162712;
U.S. Pat. No. 6,413,932), anti-TWEAK agents (e.g., specifically
binding antibodies or antigen binding regions, or soluble TWEAK
receptor antagonists; see, Wiley, U.S. Pat. No. 6,727,225), ADAM
distintegrin domain to antagonize the binding of integrin to its
ligands (Fanslow et al., U.S. Publication No. 2002/0042368),
specifically binding anti-eph receptor and/or anti-ephrin
antibodies or antigen binding regions (U.S. Pat. Nos. 5,981,245;
5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124 and patent
family members thereof), and anti-PDGF-BB antagonists (e.g.,
specifically binding antibodies or antigen binding regions) as well
as antibodies or antigen binding regions specifically binding to
PDGF-BB ligands, and PDGFR kinase inhibitory agents (e.g.,
antibodies or antigen binding regions that specifically bind
thereto).
[0271] Additional anti-angiogenic/anti-tumor agents include:
SD-7784 (Pfizer, USA); cilengitide. (Merck KGaA, Germany, EPO
770622); pegaptanib octasodium, (Gilead Sciences, USA);
Alphastatin, (BioActa, UK); M-PGA, (Celgene, USA, U.S. Pat. No.
5,712,291); ilomastat, (Arriva, USA, U.S. Pat. No. 5,892,112);
emaxanib, (Pfizer, USA, U.S. Pat. No. 5,792,783); vatalanib,
(Novartis, Switzerland); 2-methoxyestradiol, (EntreMed, USA); TLC
ELL-12, (Elan, Ireland); anecortave acetate, (Alcon, USA);
alpha-D148 Mab, (Amgen, USA); CEP-7055, (Cephalon, USA); anti-Vn
Mab, (Crucell, Netherlands) DAC:antiangiogenic, (ConjuChem,
Canada); Angiocidin, (InKine Pharmaceutical, USA); KM-2550, (Kyowa
Hakko, Japan); SU-0879, (Pfizer, USA); CGP-79787, (Novartis,
Switzerland, EP 970070); ARGENT technology, (Ariad, USA);
YIGSR-Stealth, (Johnson & Johnson, USA); fibrinogen-E fragment,
(BioActa, UK); angiogenesis inhibitor, (Trigen, UK); TBC-1635,
(Encysive Pharmaceuticals, USA); SC-236, (Pfizer, USA); ABT-567,
(Abbott, USA); Metastatin, (EntreMed, USA); angiogenesis inhibitor,
(Tripep, Sweden); maspin, (Sosei, Japan); 2-methoxyestradiol,
(Oncology Sciences Corporation, USA); ER-68203-00, (IVAX, USA);
Benefin, (Lane Labs, USA); Tz-93, (Tsumura, Japan); TAN-1120,
(Takeda, Japan); FR-111142, (Fujisawa, Japan, JP 02233610);
platelet factor 4, (RepliGen, USA, EP 407122); vascular endothelial
growth factor antagonist, (Borean, Denmark); bevacizumab (pINN),
(Genentech, USA); angiogenesis inhibitors, (SUGEN, USA); XL 784,
(Exelixis, USA); XL 647, (Exelixis, USA); MAb, alpha5beta3
integrin, second generation, (Applied Molecular Evolution, USA and
MedImmune, USA); gene therapy, retinopathy, (Oxford BioMedica, UK);
enzastaurin hydrochloride (USAN), (Lilly, USA); CEP 7055,
(Cephalon, USA and Sanofi-Synthelabo, France); BC 1, (Genoa
Institute of Cancer Research, Italy); angiogenesis inhibitor,
(Alchemia, Australia); VEGF antagonist, (Regeneron, USA); rBPI 21
and BPI-derived antiangiogenic, (XOMA, USA); PI 88, (Progen,
Australia); cilengitide (pINN), (Merck KGaA, German; Munich
Technical University, Germany, Scripps Clinic and Research
Foundation, USA); cetuximab (INN), (Aventis, France); AVE 8062,
(Ajinomoto, Japan); AS 1404, (Cancer Research Laboratory, New
Zealand); SG 292, (Telios, USA); Endostatin, (Boston Childrens
Hospital, USA); ATN 161, (Attenuon, USA); ANGIOSTATIN, (Boston
Childrens Hospital, USA); 2-methoxyestradiol, (Boston Childrens
Hospital, USA); ZD 6474, (AstraZeneca, UK); ZD 6126, (Angiogene
Pharmaceuticals, UK); PPI 2458, (Praecis, USA); AZD 9935,
(AstraZeneca, UK); AZD 2171, (AstraZeneca, UK); vatalanib (pINN),
(Novartis, Switzerland and Schering AG, Germany); tissue factor
pathway inhibitors, (EntreMed, USA); pegaptanib (Pinn), (Gilead
Sciences, USA); xanthorrhizol, (Yonsei University, South Korea);
vaccine, gene-based, VEGF-2, (Scripps Clinic and Research
Foundation, USA); SPV5.2, (Supratek, Canada); SDX 103, (University
of California at San Diego, USA); PX 478, (ProlX, USA); METASTATIN,
(EntreMed, USA); troponin I, (Harvard University, USA); SU 6668,
(SUGEN, USA); OXI 4503, (OXiGENE, USA); o-guanidines, (Dimensional
Pharmaceuticals, USA); motuporamine C, (British Columbia
University, Canada); CDP 791, (Celltech Group, UK); atiprimod
(pINN), (GlaxoSmithKline, UK); E 7820, (Eisai, Japan); CYC 381,
(Harvard University, USA); AE 941, (Aeterna, Canada); vaccine,
angiogenesis, (EntreMed, USA); urokinase plasminogen activator
inhibitor, (Dendreon, USA); oglufanide (pINN), (Melmotte, USA);
HIF-lalfa inhibitors, (Xenova, UK); CEP 5214, (Cephalon, USA); BAY
RES 2622, (Bayer, Germany); Angiocidin, (InKine, USA); A6,
(Angstrom, USA); KR 31372, (Korea Research Institute of Chemical
Technology, South Korea); GW 2286, (GlaxoSmithKline, UK); EHT 0101,
(ExonHit, France); CP 868596, (Pfizer, USA); CP 564959, (OSI, USA);
CP 547632, (Pfizer, USA); 786034, (GlaxoSmithKline, UK); KRN 633,
(Kirin Brewery, Japan); drug delivery system, intraocular,
2-methoxyestradiol, (EntreMed, USA); anginex, (Maastricht
University, Netherlands, and Minnesota University, USA); ABT 510,
(Abbott, USA); AAL 993, (Novartis, Switzerland); VEGI,
(ProteomTech, USA); tumor necrosis factor-alpha inhibitors,
(National Institute on Aging, USA); SU 11248, (Pfizer, USA and
SUGEN USA); ABT 518, (Abbott, USA); YH16, (Yantai Rongchang,
China); S-3APG, (Boston Childrens Hospital, USA and EntreMed, USA);
MAb, KDR, (ImClone Systems, USA); MAb, alpha5 beta1, (Protein
Design, USA); KDR kinase inhibitor, (Celltech Group, UK, and
Johnson & Johnson, USA); GFB 116, (South Florida University,
USA and Yale University, USA); CS 706, (Sankyo, Japan);
combretastatin A4 prodrug, (Arizona State University, USA);
chondroitinase AC, (IBEX, Canada); BAY RES 2690, (Bayer, Germany);
AGM 1470, (Harvard University, USA, Takeda, Japan, and TAP, USA);
AG 13925, (Agouron, USA); Tetrathiomolybdate, (University of
Michigan, USA); GCS 100, (Wayne State University, USA) CV 247, (Ivy
Medical, UK); CKD 732, (Chong Kun Dang, South Korea); MAb, vascular
endothelium growth factor, (Xenova, UK); irsogladine (INN), (Nippon
Shinyaku, Japan); RG 13577, (Aventis, France); WX 360, (Wilex,
Germany); squalamine (pINN), (Genaera, USA); RPI 4610, (Sirna,
USA); cancer therapy, (Marinova, Australia); heparanase inhibitors,
(InSight, Israel); KL 3106, (Kolon, South Korea); Honokiol, (Emory
University, USA); ZK CDK, (Schering AG, Germany); ZK Angio,
(Schering AG, Germany); ZK 229561, (Novartis, Switzerland, and
Schering AG, Germany); XMP 300, (XOMA, USA); VGA 1102, (Taisho,
Japan); VEGF receptor modulators, (Pharmacopeia, USA);
VE-cadherin-2 antagonists, (ImClone Systems, USA); Vasostatin,
(National Institutes of Health, USA); vaccine, Flk-1, (ImClone
Systems, USA); TZ 93, (Tsumura, Japan); TumStatin, (Beth Israel
Hospital, USA); truncated soluble FLT 1 (vascular endothelial
growth factor receptor 1), (Merck & Co, USA); Tie-2 ligands,
(Regeneron, USA); and, thrombospondin 1 inhibitor, (Allegheny
Health, Education and Research Foundation, USA).
[0272] Autophagy inhibitors include, but are not limited to
chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil.TM.),
bafilomycin A1, 5-amino-4-imidazole carboxamide riboside (AICAR),
okadaic acid, autophagy-suppressive algal toxins which inhibit
protein phosphatases of type 2A or type 1, analogues of cAMP, and
drugs which elevate cAMP levels such as adenosine, LY204002,
N6-mercaptopurine riboside, and vinblastine. In addition, antisense
or siRNA that inhibits expression of proteins including but not
limited to ATG5 (which are implicated in autophagy), may also be
used.
[0273] Additional pharmaceutically active compounds/agents that can
be used in the treatment of cancers and that can be used in
combination with one or more compound of the present invention
include: epoetin alfa; darbepoetin alfa; panitumumab;
pegfilgrastim; palifermin; filgrastim; denosumab; ancestim; AMG
102; AMG 386; AMG 479; AMG 655; AMG 745; AMG 951; and AMG 706, or a
pharmaceutically acceptable salt thereof.
[0274] In certain embodiments, a composition provided herein is
conjointly administered with a chemotherapeutic agent. Suitable
chemotherapeutic agents may include, natural products such as vinca
alkaloids (e.g., vinblastine, vincristine, and vinorelbine),
paclitaxel, epidipodophyllotoxins (e.g., etoposide and teniposide),
antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin,
doxorubicin, and idarubicin), anthracyclines, mitoxantrone,
bleomycins, plicamycin (mithramycin), mitomycin, enzymes (e.g.,
L-asparaginase which systemically metabolizes L-asparagine and
deprives cells which do not have the capacity to synthesize their
own asparagine), antiplatelet agents, antiproliferative/antimitotic
alkylating agents such as nitrogen mustards (e.g., mechlorethamine,
cyclophosphamide and analogs, melphalan, and chlorambucil),
ethylenimines and methylmelamines (e.g., hexaamethylmelaamine and
thiotepa), CDK inhibitors (e.g., seliciclib, UCN-01, P1446A-05,
PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965),
alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine
(BCNU) and analogs, and streptozocin), trazenes-dacarbazinine
(DTIC), antiproliferative/antimitotic antimetabolites such as folic
acid analogs (e.g., methotrexate), pyrimidine analogs (e.g.,
fluorouracil, floxuridine, and cytarabine), purine analogs and
related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin
and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g.,
anastrozole, exemestane, and letrozole), and platinum coordination
complexes (e.g., cisplatin and carboplatin), procarbazine,
hydroxyurea, mitotane, aminoglutethimide, histone deacetylase
(HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan,
suberoyl anilide hydroamic acid, vorinostat, LBH 589, romidepsin,
ACY-1215, and panobinostat), mTor inhibitors (e.g., temsirolimus,
everolimus, ridaforolimus, and sirolimus), KSP (Eg5) inhibitors
(e.g., Array 520), DNA binding agents (e.g., Zalypsis), PI3K delta
inhibitor (e.g., GS-1101 and TGR-1202), PI3K delta and gamma
inhibitor (e.g., CAL-130), multi-kinase inhibitor (e.g., TG02 and
sorafenib), hormones (e.g., estrogen) and hormone agonists such as
leutinizing hormone releasing hormone (LHRH) agonists (e.g.,
goserelin, leuprolide and triptorelin), BAFF-neutralizing antibody
(e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6
(e.g., CNT0328), telomerase inhibitors (e.g., GRN 163L), aurora
kinase inhibitors (e.g., MLN8237), cell surface monoclonal
antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CS1 (e.g.,
elotuzumab), HSP90 inhibitors (e.g., 17 AAG and KOS 953), PI3K/Akt
inhibitors (e.g., perifosine), Akt inhibitor (e.g., GSK-2141795),
PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zamestra.TM.),
anti-CD138 (e.g., BT062), Torcl/2 specific kinase inhibitor (e.g.,
INK128), kinase inhibitor (e.g., GS-1101), ER/UPR targeting agent
(e.g., MKC-3946), cFMS inhibitor (e.g., ARRY-382), JAK1/2 inhibitor
(e.g., CYT387), PARP inhibitor (e.g., olaparib and veliparib
(ABT-888)), BCL-2 antagonist. Other chemotherapeutic agents may
include mechlorethamine, camptothecin, ifosfamide, tamoxifen,
raloxifene, gemcitabine, navelbine, sorafenib, or any analog or
derivative variant of the foregoing.
[0275] The compounds of the present invention may also be used in
combination with radiation therapy, hormone therapy, surgery and
immunotherapy, which therapies are well known to those skilled in
the art.
[0276] In certain embodiments, a pharmaceutical composition
provided herein is conjointly administered with a steroid. Suitable
steroids may include, but are not limited to,
21-acetoxypregnenolone, alclometasone, algestone, amcinonide,
beclomethasone, betamethasone, budesonide, chloroprednisone,
clobetasol, clocortolone, cloprednol, corticosterone, cortisone,
cortivazol, deflazacort, desonide, desoximetasone, dexamethasone,
diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort,
flucloronide, flumethasone, flunisolide, fluocinolone acetonide,
fluocinonide, fluocortin butyl, fluocortolone, fluorometholone,
fluperolone acetate, fluprednidene acetate, fluprednisolone,
flurandrenolide, fluticasone propionate, formocortal, halcinonide,
halobetasol propionate, halometasone, hydrocortisone, loteprednol
etabonate, mazipredone, medrysone, meprednisone,
methylprednisolone, mometasone furoate, paramethasone,
prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate,
prednisolone sodium phosphate, prednisone, prednival, prednylidene,
rimexolone, tixocortol, triamcinolone, triamcinolone acetonide,
triamcinolone benetonide, triamcinolone hexacetonide, and salts
and/or derivatives thereof. In a particular embodiment, the
compounds of the present invention can also be used in combination
with additional pharmaceutically active agents that treat nausea.
Examples of agents that can be used to treat nausea include:
dronabinol; granisetron; metoclopramide; ondansetron; and
prochlorperazine; or a pharmaceutically acceptable salt
thereof.
[0277] The compounds or pharmaceutical compositions of the
disclosure can also be used in combination with an amount of one or
more substances selected from EGFR inhibitors, MEK inhibitors, PI3K
inhibitors, AKT inhibitors, TOR inhibitors, and immune therapies,
including anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1, and
anti-OX40 agents, GITR agonists, CAR-T cells, and BiTEs.
[0278] EGFR inhibitors include, but are not limited to, small
molecule antagonists, antibody inhibitors, or specific antisense
nucleotide or siRNA. Useful antibody inhibitors of EGFR include
cetuximab (Erbitux), panitumumab (Vectibix), zalutumumab,
nimotuzumab, and matuzumab. Small molecule antagonists of EGFR
include gefitinib, erlotinib (Tarceva), and most recently,
lapatinib (TykerB). See e.g., Yan L, et. al., Pharmacogenetics and
Pharmacogenomics In Oncology Therapeutic Antibody Development,
BioTechniques 2005; 39(4): 565-8, and Paez J G, et. al., EGFR
Mutations In Lung Cancer Correlation With Clinical Response To
Gefitinib Therapy, Science 2004; 304(5676): 1497-500.
[0279] Non-limiting examples of small molecule EGFR inhibitors
include any of the EGFR inhibitors described in the following
patent publications, and all pharmaceutically acceptable salts and
solvates of said EGFR inhibitors: European Patent Application EP
520722, published Dec. 30, 1992; European Patent Application EP
566226, published Oct. 20, 1993; PCT International Publication WO
96/33980, published Oct. 31, 1996; U.S. Pat. No. 5,747,498, issued
May 5, 1998; PCT International Publication WO 96/30347, published
Oct. 3, 1996; European Patent Application EP 787772, published Aug.
6, 1997; PCT International Publication WO 97/30034, published Aug.
21, 1997; PCT International Publication WO 97/30044, published Aug.
21, 1997; PCT International Publication WO 97/38994, published Oct.
23, 1997; PCT International Publication WO 97/49688, published Dec.
31, 1997; European Patent Application EP 837063, published Apr. 22,
1998; PCT International Publication WO 98/02434, published Jan. 22,
1998; PCT International Publication WO 97/38983, published Oct. 23,
1997; PCT International Publication WO 95/19774, published Jul. 27,
1995; PCT International Publication WO 95/19970, published Jul. 27,
1995; PCT International Publication WO 97/13771, published Apr. 17,
1997; PCT International Publication WO 98/02437, published Jan. 22,
1998; PCT International Publication WO 98/02438, published Jan. 22,
1998; PCT International Publication WO 97/32881, published Sep. 12,
1997; German Application DE 19629652, published Jan. 29, 1998; PCT
International Publication WO 98/33798, published Aug. 6, 1998; PCT
International Publication WO 97/32880, published Sep. 12, 1997; PCT
International Publication WO 97/32880 published Sep. 12, 1997;
European Patent Application EP 682027, published Nov. 15, 1995; PCT
International Publication WO 97/02266, published Jan. 23, 197; PCT
International Publication WO 97/27199, published Jul. 31, 1997; PCT
International Publication WO 98/07726, published Feb. 26, 1998; PCT
International Publication WO 97/34895, published Sep. 25, 1997; PCT
International Publication WO 96/31510', published Oct. 10, 1996;
PCT International Publication WO 98/14449, published Apr. 9, 1998;
PCT International Publication WO 98/14450, published Apr. 9, 1998;
PCT International Publication WO 98/14451, published Apr. 9, 1998;
PCT International Publication WO 95/09847, published Apr. 13, 1995;
PCT International Publication WO 97/19065, published May 29, 1997;
PCT International Publication WO 98/17662, published Apr. 30, 1998;
U.S. Pat. No. 5,789,427, issued Aug. 4, 1998; U.S. Pat. No.
5,650,415, issued Jul. 22, 1997; U.S. Pat. No. 5,656,643, issued
Aug. 12, 1997; PCT International Publication WO 99/35146, published
Jul. 15, 1999; PCT International Publication WO 99/35132, published
Jul. 15, 1999; PCT International Publication WO 99/07701, published
Feb. 18, 1999; and PCT International Publication WO 92/20642
published Nov. 26, 1992. Additional non-limiting examples of small
molecule EGFR inhibitors include any of the EGFR inhibitors
described in Traxler, P., 1998, Exp. Opin. Ther. Patents
8(12):1599-1625.
[0280] Antibody-based EGFR inhibitors include any anti-EGFR
antibody or antibody fragment that can partially or completely
block EGFR activation by its natural ligand. Non-limiting examples
of antibody-based EGFR inhibitors include those described in
Modjtahedi, H., et al., 1993, Br. J. Cancer 67:247-253; Teramoto,
T., et al., 1996, Cancer 77:639-645; Goldstein et al., 1995, Clin.
Cancer Res. 1:1311-1318; Huang, S. M., et al., 1999, Cancer Res.
15:59(8):1935-40; and Yang, X., et al., 1999, Cancer Res.
59:1236-1243. Thus, the EGFR inhibitor can be monoclonal antibody
Mab E7.6.3 (Yang, 1999 supra), or Mab C225 (ATCC Accession No.
HB-8508), or an antibody or antibody fragment having the binding
specificity thereof.
[0281] MEK inhibitors include, but are not limited to, CI-1040,
AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886,
ARRY-438162, and PD-325901.
[0282] PI3K inhibitors include, but are not limited to, wortmannin,
17-hydroxywortmannin analogs described in WO 06/044453,
4-[2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno-
[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC 0941 and
described in PCT Publication Nos. WO 09/036,082 and WO 09/055,730),
2-Methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]-
quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or
NVP-BEZ 235, and described in PCT Publication No. WO 06/122806),
(S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]py-
rimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one
(described in PCT Publication No. WO 2008/070740), LY294002
(2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one available from
Axon Medchem), PI 103 hydrochloride
(3-[4-(4-morpholinylpyrido-[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol
hydrochloride available from Axon Medchem), PIK 75
(N'-[(1E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-N,2-dimethyl-5-ni-
trobenzenesulfono-hydrazide hydrochloride available from Axon
Medchem), PIK 90
(N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicot-
inamide available from Axon Medchem), GDC-0941 bismesylate
(2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morphol-
in-4-yl-thieno[3,2-d]pyrimidine bismesylate available from Axon
Medchem), AS-252424
(5-[1-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylide-
ne]-thiazolidine-2,4-dione available from Axon Medchem), and
TGX-221
(7-Methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyr-
imidin-4-one available from Axon Medchem), XL-765, and XL-147.
Other PI3K inhibitors include demethoxyviridin, perifosine, CAL101,
PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765,
Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115,
CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.
[0283] AKT inhibitors include, but are not limited to, Akt-1-1
(inhibits Akt1) (Barnett et al. (2005) Biochem. J, 385 (Pt. 2),
399-408); Akt-1-1,2 (inhibits Ak1 and 2) (Barnett et al. (2005)
Biochem. J. 385 (Pt. 2), 399-408); API-59CJ-Ome (e.g., Jin et al.
(2004) Br. J Cancer 91, 1808-12); 1-H-imidazo[4,5-c]pyridinyl
compounds (e.g., WO05011700); indole-3-carbinol and derivatives
thereof (e.g., U.S. Pat. No. 6,656,963; Sarkar and Li (2004) JNutr.
134 (12 Suppl), 3493S-3498S); perifosine (e.g., interferes with Akt
membrane localization; Dasmahapatra et al. (2004) Clin. Cancer Res.
10(15), 5242-52, 2004); phosphatidylinositol ether lipid analogues
(e.g., Gills and Dennis (2004) Expert. Opin. Investig. Drugs 13,
787-97); and triciribine (TCN or API-2 or NCI identifier: NSC
154020; Yang et al. (2004) Cancer Res. 64, 4394-9).
[0284] TOR inhibitors include, but are not limited to, inhibitors
include AP-23573, CCI-779, everolimus, RAD-001, rapamycin,
temsirolimus, ATP-competitive TORC1/TORC2 inhibitors, including
PI-103, PP242, PP30 and Torin 1. Other TOR inhibitors in FKBP12
enhancer; rapamycins and derivatives thereof, including: CCI-779
(temsirolimus), RAD001 (Everolimus; WO 9409010) and AP23573;
rapalogs, e.g. as disclosed in WO 98/02441 and WO 01/14387, e.g.
AP23573, AP23464, or AP23841; 40-(2-hydroxyethyl)rapamycin,
40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also
called CC1779), 40-epi-(tetrazolyt)-rapamycin (also called ABT578),
32-deoxorapamycin, 16-pentynyloxy-32 (S)-dihydrorapanycin, and
other derivatives disclosed in WO 05005434; derivatives disclosed
in U.S. Pat. No. 5,258,389, WO 94/090101, WO 92/05179, U.S. Pat.
Nos. 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, WO
93/111130, WO 94/02136, WO 94/02485, WO 95/14023, WO 94/02136, WO
95/16691, WO 96/41807, WO 96/41807 and U.S. Pat. No. 5,256,790;
phosphorus-containing rapamycin derivatives (e.g., WO 05016252);
4H-1-benzopyran-4-one derivatives (e.g., U.S. Provisional
Application No. 60/528,340).
[0285] Immune therapies include, but are not limited to, anti-PD-1
agents, anti-PDL-1 agents, anti-CTLA-4 agents, anti-LAG1 agents,
and anti-OX40 agents. Exemplary anti-PD-1 antibodies and methods
for their use are described by Goldberg et al., Blood
110(1):186-192 (2007), Thompson et al., Clin. Cancer Res.
13(6):1757-1761 (2007), and Korman et al., International
Application No. PCT/JP2006/309606 (publication no. WO 2006/121168
A1), each of which are expressly incorporated by reference herein.
include: Yervoy.TM. (ipilimumab) or Tremelimumab (to CTLA-4),
galiximab (to B7.1), BMS-936558 (to PD-1), MK-3475 (to PD-1),
AMP224 (to B7DC), BMS-936559 (to B7-H1), MPDL3280A (to B7-H1),
MEDI-570 (to ICOS), AMG557 (to B7H2), MGA271 (to B7H3), IMP321 (to
LAG-3), BMS-663513 (to CD137), PF-05082566 (to CD137), CDX-1127 (to
CD27), anti-OX40 (Providence Health Services), huMAbOX40L (to
OX40L), Atacicept (to TACI), CP-870893 (to CD40), Lucatumumab (to
CD40), Dacetuzumab (to CD40), Muromonab-CD3 (to CD3), Ipilumumab
(to CTLA-4). Immune therapies also include genetically engineered
T-cells (e.g., CAR-T cells) and bispecific antibodies (e.g.,
BiTEs).
[0286] GITR agonists include, but are not limited to, GITR fusion
proteins and anti-GITR antibodies (e.g., bivalent anti-GITR
antibodies), such as, a GITR fusion protein described in U.S. Pat.
No. 6,111,090box.c, European Patent No.: 090505B1, U.S. Pat. No.
8,586,023, PCT Publication Nos.: WO 2010/003118 and 2011/090754, or
an anti-GITR antibody described, e.g., in U.S. Pat. No. 7,025,962,
European Patent No.: 1947183B1, U.S. Pat. Nos. 7,812,135,
8,388,967, 8,591,886, European Patent No.: EP 1866339, PCT
Publication No.: WO 2011/028683, PCT Publication No.: WO
2013/039954, PCT Publication No.: WO2005/007190, PCT Publication
No.: WO 2007/133822, PCT Publication No.: WO2005/055808, PCT
Publication No.: WO 99/40196, PCT Publication No.: WO 2001/03720,
PCT Publication No.: WO99/20758, PCT Publication No.:
WO2006/083289, PCT Publication No.: WO 2005/115451, U.S. Pat. No.
7,618,632, and PCT Publication No.: WO 2011/051726.
[0287] The compounds described herein can be used in combination
with the agents disclosed herein or other suitable agents,
depending on the condition being treated. Hence, in some
embodiments the one or more compounds of the disclosure will be
co-administered with other agents as described above. When used in
combination therapy, the compounds described herein are
administered with the second agent simultaneously or separately.
This administration in combination can include simultaneous
administration of the two agents in the same dosage form,
simultaneous administration in separate dosage forms, and separate
administration. That is, a compound described herein and any of the
agents described above can be formulated together in the same
dosage form and administered simultaneously. Alternatively, a
compound of the disclosure and any of the agents described above
can be simultaneously administered, wherein both the agents are
present in separate formulations. In another alternative, a
compound of the present disclosure can be administered just
followed by and any of the agents described above, or vice versa.
In some embodiments of the separate administration protocol, a
compound of the disclosure and any of the agents described above
are administered a few minutes apart, or a few hours apart, or a
few days apart.
[0288] As one aspect of the present invention contemplates the
treatment of the disease/conditions with a combination of
pharmaceutically active compounds that may be administered
separately, the invention further relates to combining separate
pharmaceutical compositions in kit form. The kit comprises two
separate pharmaceutical compositions: a compound of the present
invention, and a second pharmaceutical compound. The kit comprises
a container for containing the separate compositions such as a
divided bottle or a divided foil packet. Additional examples of
containers include syringes, boxes, and bags. In some embodiments,
the kit comprises directions for the use of the separate
components. The kit form is particularly advantageous when the
separate components are preferably administered in different dosage
forms (e.g., oral and parenteral), are administered at different
dosage intervals, or when titration of the individual components of
the combination is desired by the prescribing health care
professional.
EXAMPLES
Method 1
Example 1-1:
1-(4-(6-(2-bromo-5-hydroxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-y-
l)piperazin-1-yl)prop-2-en-1-one
##STR00543## ##STR00544##
[0290] Step 1: 2-Amino-4-bromo-5-chloro-3-fluorobenzoic acid
(Intermediate A). A mixture of 2-amino-4-bromo-3-fluorobenzoic acid
(3.91 g, 16.71 mmol, Apollo Scientific Ltd., Stockport, UK) and
N-chlorosuccinimide (1.36 mL, 16.7 mmol) in N,N-dimethylformamide
(33 mL) was stirred at 70.degree. C. for 20 h. The reaction mixture
was then allowed to cool to rt, ice water (40 mL) was added, and
the resulting mixture was stirred for 1 h. The resulting
precipitate was collected by filtration, washed with water, and
dried in vacuo to give 2-amino-4-bromo-5-chloro-3-fluorobenzoic
acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.69 (1H, d,
J=2.0 Hz), 6.48-7.23 (2H, br s). .sup.19F NMR (376 MHz,
DMSO-d.sub.6) 6-119.70 (1F, s). m/z (ESI, +ve) 270.0
(M+H).sup.+.
[0291] Step 2: 2-Amino-4-bromo-5-chloro-3-fluorobenzamide
(Intermediate B). Ammonium chloride (1.10 g, 20.6 mmol) and
diisopropylethylamine (5.13 mL, 29.5 mmol) were sequentially added
to a mixture of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid
(Intermediate A, 3.96 g, 14.7 mmol) and TBTU (4.97 g, 15.5 mmol,
Advanced ChemTech, Louisville, Ky., USA) in N,N-dimethylformamide
(30 mL), and the resulting was stirred at rt for 30 min. The
reaction mixture was then added to saturated aqueous sodium
bicarbonate and stirred for 15 min. The resulting precipitate was
collected by filtration, washed with water, and dried in vacuo to
give 2-amino-4-bromo-5-chloro-3-fluorobenzamide. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.03 (1H, br s), 7.72 (1H, d, J=2.0 Hz),
7.47 (1H, br s), 6.86 (2H, s). .sup.19F NMR (376 MHz, DMSO-d.sub.6)
.delta.-120.79 (1F, s). m/z (ESI, +ve) 268.9 (M+H).sup.+.
[0292] Step 3: 2-Amino-4-bromo-5-chloro-3-fluorobenzothioamide
Lawesson's reagent (2.81 g, 6.95 mmol) was added to
2-amino-4-bromo-5-chloro-3-fluorobenzamide (Intermediate B, 3.10 g,
11.59 mmol) in THF (77 mL), and the resulting mixture was stirred
at rt for 1 h. The reaction mixture was then diluted with EtOAc (75
mL) and sequentially washed with aqueous 2 M HCl (50 mL), saturated
aqueous sodium bicarbonate solution (50 mL), and brine (50 mL). The
organic extract was then dried over Na.sub.2SO.sub.4, collected by
filtration, and concentrated in vacuo. Chromatographic purification
of the residue (silica gel, 0-3% MeOH in DCM) provided
2-amino-4-bromo-5-chloro-3-fluorobenzothioamide: .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.93-10.15 (1H, m), 9.63 (1H, br s),
7.28 (1H, d, J=1.96 Hz), 6.34 (2H, s). .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta.-119.52 (1 F, s). m/z (ESI, +ve) 284.8
(M+H).sup.+.
[0293] Step 4: 6-Bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-amine
Hydrogen peroxide (30% by wt. in water, 2.93 mL, 28.7 mmol) was
added dropwise to an ice-cooled solution of
2-amino-4-bromo-5-chloro-3-fluorobenzothioamide (2.71 g, 9.55 mmol)
in pyridine (32 mL), and the resulting mixture was subsequently
allowed to warm to rt and stir for 24 h. Water (50 mL) was added,
and the precipitated solid was collected by filtration, washed with
water, and dried in vacuo to give
6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-amine: .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.12-8.26 (2H, m), 7.95-8.06 (1H,
m). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.-114.32 (1 F, s).
m/z (ESI, +ve) 283.0 (M+H).sup.+.
[0294] Step 5: 6-Bromo-3,5-dichloro-7-fluorobenzo[c]isothiazole
(Intermediate C) To an ice-cooled mixture of
6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-amine (2.47 g, 8.78
mmol), water (12 mL), and concentrated hydrochloric acid (37 wt %,
12 mL, 395 mmol) was slowly added a solution of sodium nitrite
(0.788 g, 11.4 mmol) in water (2.0 mL). The resulting mixture was
stirred at 0.degree. C. for 2.5 h, and a mixture of copper (I)
chloride (1.39 g, 14.1 mmol) in concentrated hydrochloric (37 wt %,
12 mL, 395 mmol) was then added at 0.degree. C. The reaction
mixture was subsequently allowed to warm to rt and stir for 20 h.
The reaction mixture was diluted with water (50 mL), and the
precipitated solid was collected by filtration and dried in vacuo.
The collected material was taken up in (3:1) DCM:MeOH (200 mL) and
sequentially washed with water (200 mL) and brine (100 mL). The
organic layer was then dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. Chromatographic purification of the residue
(silica gel, 0-20% EtOAc in heptane) gave
6-bromo-3,5-dichloro-7-fluorobenzo[c]isothiazole: .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 7.99 (1H, d, J=1.57 Hz). .sup.19F NMR
(376 MHz, DMSO-d.sub.6) .delta.-111.48 (1 F, s). m/z (ESI, +ve)
425.0 (M+H).sup.+.
[0295] Step 6: tert-Butyl
4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxyl-
ate (Intermediate D) A mixture of
6-bromo-3,5-dichloro-7-fluorobenzo[c]isothiazole (Intermediate C,
150 mg, 0.497 mmol) and 1-Boc-piperazine (204 mg, 1.09 mmol) in
N,N-dimethylformamide (2.0 mL) was stirred at rt for 20 h. The
reaction mixture was then adsorbed onto silica gel and
chromatographically purified (silica gel, 0-20% EtOAc in heptane)
to provide tert-butyl
4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxyl-
ate. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.60 (1H, d,
J=1.56 Hz), 3.68-3.79 (4H, m), 3.40-3.51 (4H, m), 1.26 (9H, s). m/z
(ESI, +ve) 451.8 (M+H).sup.+.
[0296] Step 7: tert-Butyl
4-(6-(2-bromo-5-methoxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)p-
iperazine-1-carboxylate A mixture of tert-butyl
4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxyl-
ate (Intermediate D, 111 mg, 0.247 mmol), 2-bromo-5-methoxybenzene
boronic acid (0.114 mL, 0.494 mmol), sodium carbonate (0.041 mL,
0.988 mmol), and tetrakis(triphenylphosphine)palladium (14.3 mg,
0.012 mmol) in 1,4-dioxane (1.6 mL) and water (0.4 mL) was heated
at 90.degree. C. for 21 h. The reaction mixture then concentrated
in vacuo, adsorbed onto silica gel, and purified by column
chromatography (silica gel, 0-20% (3:1) EtOAc/EtOH in heptane) to
furnish tert-butyl
4-(6-(2-bromo-5-methoxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)p-
iperazine-1-carboxylate: m/z (ESI, +ve) 558.1 (M+H).sup.+.
[0297] Step 8:
1-(4-(6-(2-bromo-5-hydroxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-y-
l)piperazin-1-yl)prop-2-en-1-one Hydrogen chloride (4M in
1,4-dioxane, 2.0 mL, 8.0 mmol) was added to a mixture of tert-butyl
4-(6-(2-bromo-5-methoxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)p-
iperazine-1-carboxylate (107 mg, 0.192 mmol) and methanol (2.0 mL),
and the resulting mixture was stirred at rt for 1 h. The reaction
mixture was then concentrated in vacuo to give
6-(2-bromo-5-methoxyphenyl)-5-chloro-7-fluoro-3-(piperazin-1-yl)benzo[c]i-
sothiazole: m/z (ESI, +ve) 458.0 (M+1).sup.+.
[0298] To this material (88 mg) was added N,N-diisopropylethylamine
(0.101 mL, 0.578 mmol) in dichloromethane (2 mL), and the resulting
mixture was cooled to 0.degree. C. Acryloyl chloride (0.26 M in
DCM, 0.75 mL, 0.19 mmol) was added, and the resulting mixture was
stirred at 0.degree. C. for 10 min. The reaction mixture was
concentrated in vacuo to provide
1-(4-(6-(2-bromo-5-methoxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-y-
l)piperazin-1-yl)prop-2-en-1-one: m/z (ESI, +ve) 512.0
(M+H).sup.+.
[0299] For compounds without a methyl ether protecting group, the
crude material was purified at this stage. For compounds bearing a
methyl ether protecting group, the crude material was used in the
next transformation without purification:
[0300] The resulting
1-(4-(6-(2-bromo-5-methoxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-y-
l)piperazin-1-yl)prop-2-en-1-one was taken up in 1,2-dichloroethane
(2.0 mL) and cooled to 0.degree. C. Boron tribromide solution (1.0
M in hexanes, 0.97 mL, 0.97 mmol) was added, and the resulting
mixture was stirred at 0.degree. C. for 1 h. The reaction mixture
was then added to saturated aqueous sodium bicarbonate (2.0 mL) and
extracted with (2:1) DCM/MeOH (10 mL). The organic extract was
dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo.
Chromatographic purification of the residue (silica gel, 0-3% MeOH
in DCM) provided
1-(4-(6-(2-bromo-5-hydroxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-y-
l)piperazin-1-yl)prop-2-en-1-one: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) 6 9.99 (br s, 1H), 8.04 (s, 1H), 7.55 (d, J=8.7 Hz,
1H), 6.81-6.94 (m, 2H), 6.79 (d, J=2.9 Hz, 1H), 6.19 (dd, J=16.7,
2.2 Hz, 1H), 5.77 (dd, J=10.5, 2.2 Hz, 1H), 3.87 (br d, J=19.5 Hz,
4H), 3.63 (br t, J=5.1 Hz, 4H). .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta.-124.16 (1F, s). m/z (ESI, +ve) 498.0
(M+H).sup.+
TABLE-US-00003 TABLE 1(a) Compounds 1-2 to 1-28 were prepared
following the procedure described in Method 1, Steps 1-8, above as
follows: Method Ex.# Chemical Structure Name changes Reagent 1-2
##STR00545## 1-(4-(5-chloro-7- fluoro-6-(1H- indol-3-yl)-2,1-
benzothiazol-3-yl)- 1-piperazinyl)-2- propen-1-one Omit step 8-3
Step 7: (1-(tert- butoxycarbonyl)- 1h-indol-3- yl)boronic acid
(Combi-blocks Inc. San Diego, CA, USA), Step 8-1: TFA/DCM 1-3
##STR00546## 1-(4-(5-chloro-6- (2-fluoro-6- hydroxyphenyl)-
2,1-benzothiazol- 3-yl)-1- piperazinyl)-2- propen-1-one Omit step
8-3 Step 7: (3- methoxynaphthalen- 1-yl)boronic acid,
Cs.sub.2CO.sub.3, 100.degree. C., Step 8-1: TFA/DCM 1-4
##STR00547## 1-(4-(5-chloro-6- (3-methoxy-1- naphthalenyl)-2,1-
benzothiazol-3-yl)- 1-piperazinyl)-2- propen-1-one -- Step 7: (3-
methoxynaphthalen- 1-yl)boronic acid, Cs.sub.2CO.sub.3, 100.degree.
C., Step 8-1: TFA/DCM 1-5 ##STR00548## 1-(4-(5-chloro-6-
(2-fluoro-6- methoxyphenyl)- 2,1-benzothiazol- 3-yl)-1-
piperazinyl)-2- propen-1-one -- Step 7: (2-fluoro-6-
methoxyphenyl)bo- ronic acid, Cs.sub.2CO.sub.3, 100.degree. C.,
Step 8-1: TFA/DCM 1-6 ##STR00549## 1-(4-(5-chloro-6- (2-fluoro-6-
hydroxyphenyl)- 2,1-benzothiazol- 3-yl)-1- piperazinyl)-2-
propen-1-one -- Step 7: (2-fluoro-6- methoxyphenyl)bo- ronic acid,
Cs.sub.2CO.sub.3, 100.degree. C., Step 8-1: TFA/DCM 1-7
##STR00550## 1-((3R)-4-(5- chloro-7-fluoro-6- (3-hydroxy-1-
naphthalenyl)-2,1- benzothiazol-3-yl)- 3-(hydroxymethyl)-
1-piperazinyl)-2- propen-1-one -- Step 6: (3R)-1-(tert-
butoxycarbonyl)-3- (hydroxymethyl)pi- perazine (Synthonix Inc.,
Wake Forest, NC, USA), Step 7: (3- methoxynaphthalen- 1-yl)boronic
acid (Ark Pharm Inc. Arlington Heights, IL, USA), Step 8-1: TFA/DCM
1-8 ##STR00551## 1-4-(5-chloro-7- fluoro-6-(3- hydroxy-1-
naphthalenyl)-2,1- benzothiazol-3-yl)- 3-ethyl-1- piperazinyl)-2-
propen-1-one -- Step 6: tert-butyl 3- ethylpiperazine-1-
carboxylate (Accel Pharmtech LLC, East Brunswick, NJ, USA), Step 7:
(3- methoxynaphthalen- 1-yl)boronic acid (Ark Pharm Inc. Arlington
Heights, IL, USA), Step 8-1: TFA/DCM ##STR00552## 1-9 ##STR00553##
N-(1-(5-chloro-7- fluoro-6-(3- hydroxy-1- naphthalenyl)-2,1-
benzothiazol-3-yl)- 2-methyl-3- azetidinyl)-2- propenamide -- Step
6: tert-butyl (2- methylazetidin-3- yl)carbamate (PharmaBlock,
Nanjing, China), Step 7: (3- methoxynaphthalen- 1-yl)boronic acid
(Ark Pharm Inc. Arlington Heights, IL, USA), Step 8-1: TFA/DCM
##STR00554## ##STR00555## ##STR00556## 1-10 ##STR00557##
1-((3S)-4-(5- chloro-7-fluoro-6- (5-methyl-1H- indazol-4-yl)-2,1-
benzothiazol-3-yl)- 3-methyl-1- piperazinyl)-2- propen-1-one Omit
step 8-3 Step 6: (S)-4-n-boc- 2-methyl piperazine (CNH
Technologies, Inc., Woburn, MA, USA), Step 7: 4-borono-5-methyl-
1h-indazole (Ark Pharm Inc. Arlington Heights, IL, USA.), Step 8-1:
TFA/DCM 1-11 ##STR00558## 1-((3S)-4-(5- chloro-7-fluoro-6-
(3-hydroxy-1- naphthalenyl)-2,1- benzothiazol-3-yl)-
3-(2-hydroxyethyl)- 1-piperazinyl)-2- propen-1-one -- Step 6:
(S)-tert-butyl 3-(2-hydroxyethyl)pi- perazine-1-carboxylate
(Activate Scientific GmbH, Prien, Germany), Step 7: (3-
methoxynaphthalen- 1-yl)boronic acid (Ark Pharm Inc. Arlington
Heights, IL, USA), Step 8-1: TFA/DCM 1-12 ##STR00559##
4-(5-chloro-7- fluoro-6-(3- hydroxy-1- naphthalenyl)-2,1-
benzothiazol-3-yl)- 1-(2-propenoyl)-2- piperazinecarbox- amide --
Step 6: piperazine- 2-carboxamide (Enamine, Kiev, Ukraine), Step 7:
(3- methoxynaphthalen- 1-yl)boronic acid (Ark Pharm Inc. Arlington
Heights, IL, USA), Step 8-1: TFA/DCM ##STR00560## 1-13 ##STR00561##
1-(4-(5-chloro-7- fluoro-6-(2- methoxy-1- naphthalenyl)-2,1-
benzothiazol-3-yl)- 1-piperazinyl)-2- propen-1-one Omit step 8-3
Step 7: (2- methoxynaphthalen- 1-yl)boronic acid, Cs.sub.2CO.sub.3,
100.degree. C., Step 8-1: TFA/DCM 1-14 ##STR00562##
1-(4-(5-chloro-7- fluoro-6-(2- hydroxy-1- naphthalenyl)-2,1-
benzothiazol-3-yl)- 1-piperazinyl)-2- propen-1-one -- Step 7: (2-
methoxynaphthalen- 1-yl)boronic acid, Cs.sub.2CO.sub.3, 100.degree.
C., Step 8-1: TFA/DCM 1-15 ##STR00563## 1-((3S)-4-(5-
chloro-7-fluoro-6- (3-hydroxy-1- naphthalenyl)-2,1-
benzothiazol-3-yl)- 3-(hydroxymethyl)- 1-piperazinyl)-2-
propen-1-one -- Step 6: (3S)-1-boc- 3-(hydroxymethyl)- piperazine
(Combi- blocks Inc., San Diego, CA, USA), Step 7: (3-
methoxynaphthalen- 1-yl)boronic acid, Step 8-1: TFA/DCM 1-16
##STR00564## 1-(4-(5-chloro-7- fluoro-6-(3- hydroxy-1-
naphthalenyl)-2,1- benzothiazol-3-yl)- 2-(hydroxymethyl)-
1-piperazinyl)-2- propen-1-one -- Step 6: tert-butyl 3- (((tert-
butyldimethylsilyl) oxy)methyl)piper- azine-1-carboxylate.sup.i,
Step 7: (3- methoxynaphthalen- 1-yl)boronic acid, Step 8-1: TFA/DCM
##STR00565## 1-17 ##STR00566## 1-((1R,5S)-3-(5- chloro-7-fluoro-6-
(3-hydroxy-1- naphthalenyl)-2,1- benzothiazol-3-yl)- 3,8-
diazabicyclo[3.2.1] octan-8-yl)-2- propen-1-one -- Step 6:
8-boc-3,8- diaza- bicyclo[3.2.1]octane (Chem-Impex International,
Inc. Wood Dale, IL, USA), Step 7: (3- methoxynaphthalen-
1-yl)boronic acid (Ark Pharm Inc. Arlington Heights, IL, USA), Step
8-1: TFA/DCM 1-18 ##STR00567## 1-(4-(5-chloro-7- fluoro-6-(3-
hydroxy-1- naphthalenyl)-2,1- benzothiazol-3-yl)-
3-(hydroxymethyl)- 1-piperazinyl)-2- propen-1-one -- Step 6:
4-n-boc-2- hydroxymethyl- piperazine (AstaTech, Inc., Bristol, PA,
USA), Step 7: (3- methoxynaphthalen- 1-yl)boronic acid (Ark Pharm
Inc. Arlington Heights, IL, USA), Step 8-1: TFA/DCM ##STR00568##
1-19 ##STR00569## 1-((3S)-4-(5- chloro-7-fluoro-6- (3-hydroxy-1-
naphthalenyl)-2,1- benzothiazol-3-yl)- 3-methyl-1- piperazinyl)-2-
propen-1-one -- Step 6: (S)-4-n-boc- 2-methyl piperazine (CNH
Technologies, Inc., Woburn, MA, USA), Step 7: (3-
methoxynaphthalen- 1-yl)boronic acid (Ark Pharm Inc. Arlington
Heights, IL, USA), Step 8-1: TFA/DCM 1-20 ##STR00570##
1-(3-((5-chloro-7- fluoro-6-(3- hydroxy-1- naphthalenyl)-2,1-
benzothiazol-3- yl)amino)-1- azetidinyl)-2- propen-1-one -- Step 6:
1-boc-3- aminoazetidine (Alfa Aesar, Haver Hill, MA, USA), Step 7:
(3- methoxynaphthalen- 1-yl)boronic acid (Ark Pharm Inc. Arlington
Heights, IL, USA), Step 8-1: TFA/DCM 1-21 ##STR00571##
1-((3R)-4-(5- chloro-7-fluoro-6- (3-hydroxy-1- naphthalenyl)-2,1-
benzothiazol-3-yl)- 3-methyl-1- piperazinyl)-2- propen-1-one --
Step 6: (R)-4-n-boc- 2-methyl-piperazine (CNH Technologies, Inc.,
Woburn, MA, USA), Step 7: (3- methoxynaphthalen- 1-yl)boronic acid
(Ark Pharm Inc. Arlington Heights, IL, USA), Step 8-1: TFA/DCM 1-22
##STR00572## N-((3R)-1-(5- chloro-7-fluoro-6- (3-hydroxy-1-
naphthalenyl)-2,1- benzothiazol-3-yl)- 3-pyrrolidinyl)-2-
propenamide Step 6: (3R)-(-)-3- tert- butoxycarbonylamino-
pyrrolidine (Oakwood Products, Inc. Estill, SC, USA), Step 7: (3-
methoxynaphthalen- 1-yl)boronic acid (Ark Pharm Inc. Arlington
Heights, IL, USA), Step 8-1: TFA/DCM 1-23 ##STR00573##
N-((3R)-1-(5- chloro-7-fluoro-6- (3-hydroxy-1- naphthalenyl)-2,1-
benzothiazol-3-yl)- 3-piperidinyl)-2- propenamide Step 6: (R)-tert-
butyl piperidin-3- ylcarbamate (Combi-blocks Inc., San Diego, CA,
USA), Step 7: (3- methoxynaphthalen- 1-yl)boronic acid (Ark Pharm
Inc. Arlington Heights, IL, USA), Step 8-1: TFA/DCM 1-28
##STR00574## 1-(4-(5-chloro-7- fluoro-6-(2-fluoro- 5-hydroxyphen-
yl)benzo[c]iso- thiazol-3- yl)piperazin-1- yl)prop-2-en-1-one Step
7: (2-fluoro-5- methoxyphen- yl)boronic acid (Combi-blocks Inc.,
San Diego, CA, USA), K.sub.2CO.sub.3, Pd(dppf)Cl.sub.2.cndot.DCM,
100.degree. C. Step 8-1: TFA/DCM
Method 2
Example 2-1:
1-(4-(5-chloro-6-(3-hydroxy-1-naphthalenyl)[1,2]thiazolo[3,4-b]pyridin-3--
yl)-1-piperazinyl)-2-propen-1-one
##STR00575## ##STR00576##
[0302] Step 1: 2-Amino-6-bromo-5-chloronicotinic acid.
N-Chlorosuccinimide (2.78 g, 20.8 mmol) was added to a solution of
2-amino-6-bromonicotinic acid (4.51 g, 20.8 mmol, Ark Pharm Inc.
Arlington Heights, Ill., USA) in DMF (75 mL), and the resulting
mixture was heated at 70.degree. C. for 2.5 h. Heating was then
stopped, and stirring was continued for 16 h. The reaction mixture
was subsequently poured into ice water. After the ice had melted,
the resulting slurry was filtered through a fritted glass funnel.
The collected solids were air-dried, providing
2-amino-6-bromo-5-chloronicotinic acid: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.05 (s, 1H), 7.64 (br. s, 2H). m/z (ESI,
+ve) 250.9 (M+H).sup.+.
[0303] Step 2: tert-Butyl
4-(2-amino-6-bromo-5-chloronicotinoyl)piperazine-1-carboxylate. To
a solution of 2-amino-6-bromo-5-chloronicotinic acid (1.12 g, 4.5
mmol) in DMF (14 mL) was added TBTU (1.93 g, 6.0 mmol). After 5
min, the reaction was sequentially treated with 1-Boc-piperazine
(912 mg, 4.9 mmol) and DIPEA (2.33 mL, 13.4 mmol). The resulting
solution was stirred at rt for 25 h, saturated aqueous
NaHCO.sub.3solution (75 mL) was added, and the resulting mixture
was extracted with DCM. The organic layer was separated and
sequentially washed with water (2.times.), dried over anhydrous
sodium sulfate, and concentrated in vacuo. Chromatographic
purification of the residue (silica gel, 0 to 7% MeOH in DCM)
furnished tert-butyl
4-(2-amino-6-bromo-5-chloronicotinoyl)piperazine-1-carboxylate:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.58 (s, 1H), 6.66 (s,
2H), 3.33 (s, 8H), 1.40 (s, 9H). m/z (ESI, +ve) 419.0
(M+H).sup.+.
[0304] Step 3: tert-Butyl
4-(2-amino-6-bromo-5-chloropyridine-3-carbonothioyl)piperazine-1-carboxyl-
ate. Lawesson's reagent (353 mg, 0.87 mmol) was added to a solution
of tert-butyl
4-(2-amino-6-bromo-5-chloronicotinoyl)piperazine-1-carboxylate (610
mg, 1.45 mmol) in THF (7.5 mL), and the resulting solution was
stirred as 50.degree. C. for 2.5 h. The reaction mixture was then
allowed to cool to rt and sequentially treated with water (10 mL)
and aqueous 1 N HCl (4 mL). The resulting mixture was extracted
with EtOAc (2.times.), and the combined extracts were dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo.
Chromatographic purification of the residue (silica gel, 0-6% MeOH
in DCM) provided tert-butyl
4-(2-amino-6-bromo-5-chloropyridine-3-carbonothioyl)piperazine-1-carboxyl-
ate: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.47 (s, 1H), 6.58
(br. s, 2H), 4.30 (ddd, J=13.3, 6.3, 3.3 Hz, 1H), 4.01-4.13 (m,
2H), 3.68-3.77 (m, 1H), 3.51-3.59 (m, 1H), 3.40-3.50 (m, 3H), 1.41
(s, 9H). m/z (ESI, +ve) 434.9 (M+H).sup.+.
[0305] Step 4: tert-Butyl
4-(5,6-dichloroisothiazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate.
NCS (116 mg, 0.87 mmol) was added to a solution of tert-butyl
4-(2-amino-6-bromo-5-chloropyridine-3-carbonothioyl)piperazine-1-carboxyl-
ate (343 mg, 0.79 mmol) in THF (8 mL), and the resulting solution
was stirred at rt for 20 min. A mixture of water (10 mL) and 1 M
aqueous sodium sulfite (5 mL) was then added, and the resulting
mixture was extracted with EtOAc (2.times.). The combined extracts
were dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. Chromatographic purification of the residue
(silica gel, 0 to 4% MeOH in DCM) provided tert-butyl
4-(5,6-dichloroisothiazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate:
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.10 (s, 1H), 3.69-3.80
(m, 4H), 3.50-3.57 (m, 4H), 1.51 (s, 9H). m/z (ESI, +ve) 389.0
(M+H).sup.+.
[0306] Step 5: tert-Butyl
4-(5-chloro-6-(3-methoxynaphthalen-1-yl)isothiazolo[3,4-b]pyridin-3-yl)pi-
perazine-1-carboxylate. A mixture of tert-butyl
4-(5,6-dichloroisothiazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate
(154 mg, 0.36 mmol), (3-methoxynaphthalen-1-yl)boronic acid (287
mg, 1.42 mmol), and cesium carbonate (463 mg, 1.42 mmol) in
1,4-dioxane (8 mL) and water (2 mL) was sparged with argon before
adding tetrakis(triphenylphosphine)palladium (41 mg, 0.04 mmol).
The reaction mixture was again sparged with argon, then heated in a
sealed tube at 100.degree. C. for 25 h. After cooling to rt, the
reaction mixture was diluted with brine (40 mL) and extracted with
EtOAc (2.times.). The combined extracts were dried over sodium
sulfate, filtered, and concentrated in vacuo. Chromatographic
purification of the residue (silica gel, 0-3.5% MeOH in DCM) gave
tert-butyl
4-(5-chloro-6-(3-methoxynaphthalen-1-yl)isothiazolo[3,4-b]pyridin-3-yl)pi-
perazine-1-carboxylate: m/z (ESI, +ve) 511.1 (M+H).sup.+.
[0307] Step 6:
5-Chloro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)isothiazolo[3,4-b-
]pyridine. Trifluoroacetic acid (560 .quadrature.L, 7.6 mmol) was
added to a solution of tert-butyl
4-(5-chloro-6-(3-methoxynaphthalen-1-yl)isothiazolo[3,4-b]pyridin-3-yl)pi-
perazine-1-carboxylate (155 mg, 0.30 mmol) in DCM (6 mL), and the
resulting solution was stirred at rt for 2.3 h, then concentrated
in vacuo. Chromatographic purification of the residue (silica gel,
0-25% MeOH in DCM) furnished
5-chloro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)isothiazolo[3,4-b-
]pyridine as a TFA salt: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 6 8.78
(s, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.46-7.53 (m, 2H), 7.31 (d, J=3.7
Hz, 2H), 7.19 (d, J=2.4 Hz, 1H), 3.95 (s, 3H), 3.76-3.83 (m, 4H),
3.35-3.43 (m, 4H). m/z (ESI, +ve) 411.0 (M+H).sup.+.
[0308] Step 7:
1-(4-(5-Chloro-6-(3-methoxy-1-naphthalenyl)[1,2]thiazolo[3,4-b]pyridin-3--
yl)-1-piperazinyl)-2-propen-1-one. To an ice-cooled slurry of
5-chloro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)isothiazolo[3,4-b-
]pyridine (TFA salt; 100 mg, 0.19 mmol) in DCM (5 mL) was
sequentially added DIPEA (100 DL, 0.57 mmol) and acryloyl chloride
(23 DL, 0.29 mmol). The resulting solution was stirred at 0.degree.
C. for 70 min, and saturated aqueous NaHCO.sub.3solution (15 mL)
was added. The resulting mixture was extracted with DCM (3.times.),
and the combined extracts were dried over sodium sulfate, filtered,
and concentrated in vacuo. Chromatographic purification of the
residue (silica gel, 0 to 7% MeOH in DCM) provided
1-(4-(5-chloro-6-(3-methoxy-1-naphthalenyl)[1,2]thiazolo[3,4-b]pyridin-3--
yl)-1-piperazinyl)-2-propen-1-one: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.73 (s, 1H), 7.93 (d, J=8.2 Hz, 1H),
7.45-7.54 (m, 2H), 7.25-7.39 (m, 2H), 7.19 (d, J=2.5 Hz, 1H), 6.86
(dd, J=16.7, 10.3 Hz, 1H), 6.19 (dd, J=16.7, 2.3 Hz, 1H), 5.77 (dd,
J=10.5, 2.3 Hz, 1H), 3.94 (s, 3H), 3.81-3.94 (m, 4H), 3.69-3.76 (m,
4H). m/z (ESI, +ve) 465.0 (M+H).sup.+.
[0309] Step 8:
1-(4-(5-Chloro-6-(3-hydroxy-1-naphthalenyl)[1,2]thiazolo[3,4-b]pyridin-3--
yl)-1-piperazinyl)-2-propen-1-one. Boron tribromide (1.0 M in
hexanes, 400 QL, 0.40 mmol) was added (dropwise) to an ice-cooled
solution of
1-(4-(5-chloro-6-(3-methoxynaphthalen-1-yl)isothiazolo[3,4-b]pyridin-3-yl-
)piperazin-1-yl)prop-2-en-1-one (37.3 mg, 0.08 mmol) in
1,2-dichloroethane (4 mL), and the resulting mixture was stirred at
0.degree. C. for 2.3 h. Saturated aqueous NaHCO.sub.3 solution (5
mL) was then added, and the resulting mixture was extracted with
(4:1) DCM:MeOH (2.times.). The combined extracts were dried over
sodium sulfate, filtered, and concentrated in vacuo.
Chromatographic purification of the residue (silica gel, 0-6% MeOH
in DCM) provided
1-(4-(5-chloro-6-(3-hydroxy-1-naphthalenyl)[1,2]thiazolo[3,4-b]pyridin-3--
yl)-1-piperazinyl)-2-propen-1-one: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.97 (br. s, 1H), 8.72 (s, 1H), 7.79 (d,
J=8.6 Hz, 1H), 7.42 (t, J=7.1 Hz, 1H), 7.17-7.28 (m, 3H), 7.09 (d,
J=2.1 Hz, 1H), 6.86 (dd, J=16.7, 10.5 Hz, 1H), 6.19 (dd, J=16.7,
2.3 Hz, 1H), 5.74-5.79 (m, 1H), 3.81-3.95 (m, 4H), 3.68-3.76 (in,
4H). M/z (ESI, +ve) 451.0 (M+H).sup.+.
TABLE-US-00004 TABLE 2 Compounds 2-2 to 2-6 were prepared following
the procedure described in Method 2, Steps 1-8, above as follows:
Method Ex.# Chemical Structure Name changes Reagents 2-2
##STR00577## 1-(4-(5-chloro-6- (2-fluoro-6- methoxyphenyl)
[1,2]thiazolo [3,4-b]pyridin-3- yl)-3-methyl-1- piperazinyl)-2-
propen-1-one Omit Step 8 Step 2: 1-Boc-3- methylpiperazine (Accela
ChemBio Inc. San Diego, CA, USA), Step 4: N- bromosuccinimide, Step
5: 2-fluoro-6- methoxyphenyl boronic acid ##STR00578## 2-3
##STR00579## 1-(4-(5-chloro-6- (2-fluoro-6- hydroxyphenyl)
[1,2]thiazolo [3,4-b]pyridin-3- yl)-3-methyl-1- piperazinyl)-2-
propen-1-one -- Step 2: 1-Boc-3- methylpiperazine (Accela ChemBio
Inc. San Diego, CA, USA), Step 4: N- bromosuccinimide, Step 5:
2-fluoro-6- methoxyphenyl boronic acid ##STR00580## 2-4
##STR00581## 1-(4-(5-chloro-6- (3-methoxy-1- naphthalenyl)[1,2]
thiazolo[3,4-b] pyridin-3-yl)-3- methyl-1- piperazinyl)-2-
propen-1-one Omit Step 8 Step 2: 1-Boc-3- methylpiperazine (Accela
ChemBio Inc. San Diego, CA, USA), Step 4: N- bromosuccinimide
##STR00582## 2-5 ##STR00583## 1-(4-(5-chloro-6- (3-hydroxy-1-
naphthalenyl) [1,2]thiazolo[3,4- b]pyridin-3-yl)-3- methyl-1-
piperazinyl)-2- propen-1-one -- Step 2: 1-Boc-3- methylpiperazine
(Accela ChemBio Inc. San Diego, CA, USA), Step 4: N-
bromosuccinimide ##STR00584## 2-6 ##STR00585## 1-(4-(5-chloro-6-
(5-methyl-1H- indazol-4- yl)[1,2]thiazolo [3,4-b]pyridin-3-
yl)-3-methyl-1- piperazinyl)-2- propen-1-one Omit Step 8 Step 2:
1-Boc-3- methylpiperazine (Accela ChemBio Inc. San Diego, CA, USA),
Step 4: N- bromosuccinimide, Step 5: 4-borono-5- methyl-1h-indazole
(Ark Pharm Inc. Arlington Heights, IL, USA) ##STR00586## 2-7
##STR00587## 1-(4-(5-chloro-7- fluoro-6-(3- hydroxy-1-
naphthalenyl)-2,1- benzothiazol-3- yl)-3,5-dimethyl-
1-piperazinyl)-2- propen-1-one -- Step 1: 2-amino-4- bromo-3-
fluorobenzoic acid (Apollo Scientific Ltd., Stockport, UK), Step 2:
1-boc-3,5- dimethylpiperazine (Combi-blocks Inc., San Diego, CA,
USA), Step 7: (3- methoxynaphthalen-1- yl)boronic acid (Ark Pharm
Inc. Arlington Heights, IL, USA), Step 8-1: TFA/DCM ##STR00588##
##STR00589## 2-8 ##STR00590## 1-(4-(5-chloro-7- fluoro-6-(5-
methyl-1H- indazol-4-yl)-2,1- benzothiazol-3- yl)-3-
(difluoromethyl)- 1-piperazinyl)-2- propen-1-one -- Step 1:
2-amino-4- bromo-3- fluorobenzoic acid (Apollo Scientific Ltd.,
Stockport, UK), Step 2: tert-butyl 3- (difluoromethyl)piper-
azine-1-carboxylate (Enamine, Kiev, Ukraine), Step 7: (5-
methyl-1H-indazol-4- yl)boronic acid (Combi-Blocks, Inc.), Step
8-1: TFA/DCM ##STR00591## 2-9 ##STR00592## 1-(4-(5-chloro-7-
fluoro-6-(2-fluoro- 6-hydroxyphenyl)- 2,1-benzothiazol- 3-yl)-3-
(difluoromethyl)- 1-piperazinyl)-2- propen-1-one Step 8-3 performed
prior to steps 8-2 Step 1: 2-amino-4- bromo-3- fluorobenzoic acid
(Apollo Scientific Ltd., Stockport, UK), Step 2: tert-butyl 3-
(difluoromethyl)piper- azine-1-carboxylate (Enamine, Kiev,
Ukraine), Step 7: 2- fluoro-6-methoxy- phenylboronic acid (Accela
ChemBio Inc. San Diego, CA, USA), Step 8-1: TFA/DCM ##STR00593##
2-10 ##STR00594## 1-(4-(5-chloro-7- fluoro-6-(3- hydroxy-1-
naphthalenyl)-2,1- benzothiazol-3- yl)-3-(2- propanyl)-1-
piperazinyl)-2- propen-1-one -- Step 1: 2-amino-4- bromo-3-
fluorobenzoic acid (Apollo Scientific Ltd., Stockport, UK), Step 2:
1-boc-3- isopropyl-piperazine (Ark Pharm Inc. Arlington Heights,
IL, USA), Step 7: (3- methoxynaphthalen-1- yl)boronic acid (Ark
Pharm Inc. Arlington Heights, IL, USA), Step 8-1: TFA/DCM
##STR00595##
Method 3
Example 3-1:
1-(4-(5-Chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3--
yl)piperazin-1-yl)prop-2-en-1-one
##STR00596##
[0311] Step 1:
1-(4-(6-Bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)pro-
p-2-en-1-one. 0.2 M acryloyl chloride in DCM (1.240 mL, 0.248 mmol)
was added to an ice-cooled solution of
6-bromo-5-chloro-7-fluoro-3-(piperazin-1-yl)benzo[c]isothiazole
(Intermediate D, 87 mg, 0.248 mmol) and N,N-diisopropylethylamine
(0.129 mL, 0.744 mmol) in dichloromethane (2.3 mL), and the
resulting mixture was stirred at 0.degree. C. for 10 min. The
mixture was then concentrated in vacuo, and the residue was
sonicated in MeOH (2 mL). The suspended solid was collected by
filtration, washed with MeOH, and dried in vacuo to provide
1-(4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)pro-
p-2-en-1-one: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.13 (1H,
d, J=1.56 Hz), 6.84 (1H, dd, J=10.47, 16.73 Hz), 6.17 (1H, dd,
J=2.35, 16.63 Hz), 5.66-5.82 (1H, m), 3.73-3.93 (4H, m), 3.55-3.67
(4H, m). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.-113.39 (s,
1F). m/z (ESI, +ve) 405.8 (M+H).sup.+.
[0312] Step 2:
1-(4-(5-Chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3--
yl)piperazin-1-yl)prop-2-en-1-one (Intermediate E). A mixture of
1-(4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)pro-
p-2-en-1-one (Intermediate D, 79 mg, 0.20 mmol),
(3-methoxynaphthalen-1-yl)boronic acid (47.3 mg, 0.234 mmol),
tetrakis(triphenylphosphine)palladium (22.5 mg, 0.020 mmol) and
sodium carbonate (83 mg, 0.78 mmol) in water (0.500 mL) and
1,4-dioxane (2.0 mL) was heated at 100.degree. C. for 16 h. The
reaction mixture was then adsorbed onto silica gel and
chromatographically purified (silica gel, 0-3% MeOH in DCM) to give
1-(4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3--
yl) piperazin-1-yl)prop-2-en-1-one: m/z (ESI, +ve) 482.0
(M+H).sup.+.
[0313] Step 3:
1-(4-(5-Chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3--
yl)piperazin-1-yl)prop-2-en-1-one. Boron tribromide (1.0M in
hexanes, 0.664 mL, 0.664 mmol) was added to an ice-cooled solution
of
1-(4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3--
yl)piperazin-1-yl)prop-2-en-1-one (64 mg, 0.13 mmol) in
1,2-dichloroethane (2.0 mL), and the resulting mixture was stirred
at 0.degree. C. for 1 h. The reaction mixture was then added to
saturated aqueous sodium bicarbonate (2.0 mL) and the resulting
mixture was extracted with (2:1) DCM:MeOH (10 mL). The organic
extract was dried over Na.sub.2SO.sub.4, filtered, and concentrated
in vacuo. Chromatographic purification of the residue (silica gel,
0-3% MeOH in DCM) gave
1-(4-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3--
yl)piperazin-1-yl)prop-2-en-1-one: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.90-10.04 (1H, m), 8.10 (1H, s), 7.80 (1H,
d, J=8.41 Hz), 7.43 (1H, ddd, J=1.96, 6.11, 8.17 Hz), 7.16-7.31
(3H, m), 7.07 (1H, d, J=2.35 Hz), 6.87 (1H, dd, J=10.47, 16.73 Hz),
6.19 (1H, dd, J=2.25, 16.73 Hz), 5.77 (1H, dd, J=2.25, 10.47 Hz),
3.88 (4H, br d, J=19.56 Hz), 3.61-3.72 (4H, m). .sup.19F NMR (376
MHz, DMSO-d.sub.6) .delta.-123.78 (s, 1F). m/z (ESI, +ve) 468.0
(M+H).sup.+.
Alternate Synthesis of Intermediate E
##STR00597##
[0315] 1-(4-(5-Chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]
isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one (Intermediate E,
alternative synthesis): To a solution of
6-bromo-3,5-dichloro-7-fluorobenzo[c]isothiazole (Intermediate C,
715 mg, 2.37 mmol) in N,N-dimethylformamide (5.6 mL) was
sequentially added a solution of 1-(piperazin-1-yl)prop-2-en-1-one
bis(2,2,2-trifluoroacetate) (961 mg, 2.61 mmol, eNovation Chemicals
LLC, Bridgewater, N.J., USA) in N,N-dimethylformamide (5.6 mL) and
N,N-diisopropylethylamine (1.243 mL, 7.12 mmol). The resulting
mixture was stirred at rt for 1 h and then heated at 50.degree. C.
for 22 h. After cooling to rt, the reaction mixture was added to
ice water (10 mL), and the resulting precipitate was collected by
filtration and washed with water. The collected solid was adsorbed
onto silica gel and chromatographically purified (silica gel, 0-3%
MeOH in DCM) to furnish
1-(4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)pro-
p-2-en-1-one.
TABLE-US-00005 TABLE 3 Compounds 3-2 to 3-24 were prepared
following the procedure described in Method 3, Steps 1-3, above as
follows: Ex.# Chemical Structure Name Method changes Reagent 3-2
##STR00598## 8-(5-chloro-7- fluoro-3-(4-(2- propenoyl)-1-
piperazinyl)-2,1- benzothiazol-6- yl)-2(1H)- quinolinone Omit step
3 Step 2: 8-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-
yl)quinolin-2(1H)- one (Chem Shuttle, Hayward, CA, USA), S-Phos Pd
G3, aq. K.sub.2CO.sub.3, 1,4-dioxane 3-3 ##STR00599##
1-(4-(5-chloro-7- fluoro-6-(8- isoquinolinyl)-2,1- benzothiazol-3-
yl)-1-piperazinyl)- 2-propen-1-one Omit step 3 Step 2: 8-
boronoisoquinoline (Frontier Scientific, Inc. Logan, UT, USA) 3-4
##STR00600## 5-(5-chloro-7- fluoro-3-(4-(2- propenoyl)-1-
piperazinyl)-2,1- benzothiazol-6- yl)-2(1H)- quinolinone Omit step
3 Step 2: 5-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-
yl)quinolin-2(1h)- one (Ark Pharm Inc. Arlington Heights, IL, USA)
3-5 ##STR00601## 1-(4-(5-chloro-7- fluoro-6-(5- methyl-1H-
indazol-4-yl)-2,1- benzothiazol-3- yl)-1-piperazinyl)-
2-propen-1-one Omit step 3 Step 2: 4-borono-5- methyl-1h-indazole
(Ark Pharm Inc. Arlington Heights, IL, USA) 3-6 ##STR00602##
1-(4-(5-chloro-7- fluoro-6-(2-fluoro- 6-hydroxyphenyl)-
2,1-benzothiazol- 3-yl)-1- piperazinyl)-2- propen-1-one -- Step 2:
2-fluoro-6- methoxy- phenylboronic acid (Accela ChemBio Inc. San
Diego, CA, USA) 3-7 ##STR00603## 1-(4-(5-chloro-6- (2,4-
difluorophenyl)-7- fluoro-2,1- benzothiazol-3- yl)-1-piperazinyl)-
2-propen-1-one Omit step 3 Step 2: (2,4- difluoro- phenyl)boronic
acid (Combi-blocks Inc., San Diego, CA, USA) 3-8 ##STR00604##
1-(4-(5-chloro-7- fluoro-6-(5- hydroxy-2- methylphenyl)-
2,1-benzothiazol- 3-yl)-1- piperazinyl)-2- propen-1-one Omit step 3
Step 2: (5-hydroxy- 2-methylphenyl- boronic acid (Combi-blocks
Inc., San Diego, CA, USA) 3-9 ##STR00605## 1-4-(5-chloro-6-
(2-chloro-5- methoxyphenyl)- 7-fluoro-2,1- benzothiazol-3-
yl)-1-piperazinyl)- 2-propen-1-one Omit step 3 Step 2: 2-chloro-5-
methoxyphenyl boronic acid (Combi-blocks Inc., San Diego, CA, USA)
3-10 ##STR00606## 1-(4-(5-chloro-6- (2,4-difluoro-5-
hydroxyphenyl)-7- fluoro-2,1- benzothiazol-3- yl)-1-piperazinyl)-
2-propen-1-one -- Step 2: 1-boronic acid-2,4-difluoro-5-
methoxy-benzene (Combi-blocks Inc., San Diego, CA, USA) 3-11
##STR00607## 1-(4-(5-chloro-6- (2-chloro-5- hydroxyphenyl)-7-
fluoro-2,1- benzothiazol-3- yl)-1-piperazinyl)- 2-propen-1-one --
Step 2: 2-chloro-5- methoxyphenyl boronic acid (Combi-blocks Inc.,
San Diego, CA, USA) 3-12 ##STR00608## 1-(4-(6-(5-amino-
2-methylphenyl)- 5-chloro-7-fluoro- 2,1-benzothiazol- 3-yl)-1-
piperazinyl)-2- propen-1-one Omit step 3 Step 2: (5-amino-2-
methyl- phenyl)boronic acid (Combi-blocks Inc., San Diego, CA, USA)
3-13 ##STR00609## N-(3-(5-chloro-7- fluoro-3-(4-(2- propenoyl)-1-
piperazinyl)-2,1- benzothiazol-6- yl)-4-methyl- phenyl)acetamide
Omit step 3 Step 2: [5- (acetylamino)-2- methyl- phenyl]boronic
acid (Combi-blocks Inc., San Diego, CA, USA) 3-14 ##STR00610##
1-(4-(6-(5-amino- 2-fluorophenyl)-5- chloro-7-fluoro-
2,1-benzothiazol- 3-yl)-1- piperazinyl)-2- propen-1-one Omit step 3
Step 2: 2-fluoro-5- aminophenyl boronic acid (Combi-blocks Inc.,
San Diego, CA. USA) 3-15 ##STR00611## 1-(4-(6-(5-amino- 2,3-
difluorophenyl)-5- chloro-7-fluoro- 2,1-benzothiazol- 3-yl)-1-
piperazinyl)-2- propen-1-one Omit step 3 Step 2: 3-borono-
4,5-difluoroaniline (Combi-blocks Inc., San Diego, CA, USA) 3-16
##STR00612## 1-(4-(5-chloro-6- (2,3-difluoro-5- hydroxyphenyl)-7-
fluoro-2,1- benzothiazol-3- yl)-1-piperazinyl)- 2-propen-1-one --
Step 2: 2,3-difluoro- 5-methoxy- phenylboronic acid (Combi-blocks
Inc., San Diego, CA, USA) 3-17 ##STR00613## 1-(4-(5-chloro-6-
(2,4-dichloro-5- hydroxyphenyl)-7- fluoro-2,1- benzothiazol-3-
yl)-1-piperazinyl)- 2-propen-1-one -- Step 2: (2,4- dichloro-5-
methoxy- phenyl)boronic acid (Combi-blocks Inc., San Diego, CA,
USA) 3-18 ##STR00614## 1-(4-(5-chloro-6- (2-chloro-4- fluoro-5-
hydroxyphenyl)-7- fluoro-2,1- benzothiazol-3- yl)-1-piperazinyl)-
2-propen-1-one -- Step 2: (2-chloro-4- fluoro-5-methoxy-
phenyl)boronic acid (Combi-blocks Inc., San Diego, CA, USA) 3-19
##STR00615## 1-(4-(6-(5-amino- 2-chlorophenyl)- 5-chloro-7-fluoro-
2,1-benzothiazol- 3-yl)-1- piperazinyl)-2- propen-1-one Omit step 3
Step 2: (5-amino-2- chlorophenyl)boro- nic acid hydrochloride
(Combi-blocks Inc., San Diego, CA, USA) 3-20 ##STR00616##
1-(4-(6-(5-amino- 2,4- dichlorophenyl)- 5-chloro-7-fluoro-
2,1-benzothiazol- 3-yl)-1- piperazinyl)-2- propen-1-one -- Step 2:
(5-amino- 2,4-dichloro- phenyl)boronic acid (Combi-blocks Inc., San
Diego, CA, USA) 3-21 ##STR00617## 1-(4-(5-chloro-7- fluoro-6-(4-(2-
propanyl)-3- pyridinyl)-2,1- benzothiazol-3- yl)-1-piperazinyl)-
2-propen-1-one Omit step 3 Step 2: (4- isopropylpyridin-3-
yl)boronic acid (Combi-Phos Catalysts Inc. Trenton, NJ, USA) 3-22
##STR00618## 1-(4-(5-chloro-6- (2,3-dichloro-5- hydroxyphenyl)-7-
fluoro-2,1- benzothiazol-3- yl)-1-piperazinyl)- 2-propen-1-one --
Step 2: 2-(2,3- dichloro-5- methoxyphenyl)- 4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (Anisyn Inc., Kalamazoo, MI, US) 3-23
##STR00619## 1-(4-(5-chloro-7- fluoro-6- (naphthalen-1-
yl)benzo[c]iso- thiazol-3-yl)piper- azin-1-yl)prop-2- en-1-one Omit
step 3 Step 1-1: TFA/DCM Step 2: (1- naphthalyl)boronic acid,
Cs.sub.2CO.sub.3, 80.degree. C. 3-24 ##STR00620## 1-(4-(5-chloro-7-
fluoro-6-(quinolin- 8-yl)benzo[c]iso- thiazol-3-yl)piper-
azin-1-yl)prop-2- en-1-one Omit step 3 Step 1-1: TFA/DCM Step 2:
8-quinoline boronic acid (Frontier Scientific Inc., Logan UT, USA),
Cs.sub.2CO.sub.3, 80.degree. C. 3-25 ##STR00621## 3-amino-5-(5-
chloro-7-fluoro-3- (4-(2-propenoyl)- 1-piperazinyl)-2,1-
benzothiazol-6- yl)benzonitrile Omit step 3 Step 1-1: TFA/DCM Step
2: (3-amino-5- cyanophenyl)boronic acid (Combi-blocks Inc., San
Diego, CA, USA), S-Phos Pd G3, K.sub.2CO.sub.3, 100.degree. C.
Method 4
Example 4-1:
1-(6-(5-Chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3--
yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one
##STR00622## ##STR00623##
[0317] Step 1: tert-Butyl
6-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]h-
eptane-2-carboxylate. A mixture of
6-bromo-3,5-dichloro-7-fluorobenzo[c]isothiazole (Intermediate C,
169 mg, 0.562 mmol) and 2-Boc-2,6-diazaspiro[3.3]heptane (212 mg,
1.07 mmol, AstaTech, Inc., Bristol, Pa., USA) in DMF (3.5 mL) was
stirred at rt for 5 h. Ice water (5 mL) was added, and the
resulting mixture was stirred for 15 min. The resulting precipitate
was collected by filtration, washed with water, and dried in vacuo
to provide tert-butyl
6-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]h-
eptane-2-carboxylate: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
7.52-7.74 (1H, m), 4.55 (4H, s), 4.09 (4H, s), 1.38 (9H, s).
.sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.-113.55 (1F, s). m/z
(ESI, +ve) 464.0 (M+1).
[0318] Step 2:
1-(6-(6-Bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.-
3]heptan-2-yl)prop-2-en-1-one. Hydrogen chloride solution (4M in
1,4-dioxane, 5.0 mL, 20 mmol) was added to tert-butyl
6-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]h-
eptane-2-carboxylate (249 mg, 0.538 mmol) in methanol (10 mL), and
the resulting mixture was stirred at rt for 2 h. The reaction
mixture was then concentrated in vacuo to provide
6-bromo-5-chloro-7-fluoro-3-(2,6-diazaspiro[3.3]heptan-2-yl)benzo[c]isoth-
iazole: m/z (ESI, +ve) 363.8 (M+1).sup.+.
[0319] To this material was added N,N-diisopropylethylamine (0.281
mL, 1.61 mmol) in dichloromethane (3.0 mL), and the resulting
mixture was cooled to 0.degree. C. Acryloyl chloride (0.2 M in DCM,
2.69 mL, 0.538 mmol) was then added, and the resulting mixture was
stirred at 0.degree. C. for 10 min. The reaction mixture was then
concentrated in vacuo, and the residue was chromatographically
purified (silica gel, 0-10% (3:1) EtOAc/EtOH in DCM) to provide
1-(6-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.-
3]heptan-2-yl)prop-2-en-1-one: .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.65 (1H, d, J=1.4 Hz), 6.25-6.36 (1H, m), 6.10 (1H, dd,
J=17.0, 2.3 Hz), 5.64-5.72 (1H, m), 4.58 (4H, s), 4.47 (2H, s),
4.18 (2H, s). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.-113.54
(1F, s). m/z (ESI, +ve) 418.0 (M+H).sup.+.
[0320] Step 3:
1-(6-(5-Chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3--
yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one. A mixture of
1-(6-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.-
3]heptan-2-yl)prop-2-en-1-one (102 mg, 0.245 mmol),
(3-methoxynaphthalen-1-yl)boronic acid (59.3 mg, 0.294 mmol),
tetrakis(triphenylphosphine)palladium (28.3 mg, 0.024 mmol), and
sodium carbonate (104 mg, 0.979 mmol) in water (0.5 mL) and
1,4-dioxane (2.0 mL) was heated at 100.degree. C. for 1 h. The
reaction mixture was then adsorbed onto silica gel and
chromatographically purified (silica gel, 0-5% MeOH in DCM). The
purified material was sonicated in MeOH, and the suspended solid
was collected by filtration, washed with MeOH, and dried in vacuo
to provide
1-(6-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3--
yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one: .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.93 (1H, d, J=8.4 Hz), 7.67 (1H,
s), 7.45-7.57 (2H, m), 7.23-7.36 (2H, m), 7.16 (1H, d, J=2.5 Hz),
6.27-6.39 (1H, m), 6.11 (1H, dd, J=17.0, 2.2 Hz), 5.65-5.76 (1H,
m), 4.58-4.67 (4H, m), 4.50 (2H, s), 4.22 (2H, s), 3.93 (3H, s).
.sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.-123.88 (1F, s). m/z
(ESI, +ve) 494.0 (M+H).sup.+.
[0321] Step 4:
1-(6-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3--
yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one. Boron
tribromide (1.0 M in hexanes, 0.638 mL, 0.638 mmol) was added to
ice-cooled
1-(6-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3--
yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one (63 mg, 0.128
mmol) in 1,2-dichloroethane (2.0 mL), and the resulting mixture was
stirred at 0.degree. C. for 2 h. The reaction mixture was then
added to saturated aqueous sodium bicarbonate (2.0 mL), and the
resulting mixture was extracted with (2:1) DCM:MeOH (10 mL). The
organic extract was dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. Chromatographic purification of the residue
(silica gel, 0-2% MeOH (with 2M ammonia) in DCM) gave
1-(6-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]iso-
thiazol-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.82-10.04 (1H, m),
7.79 (1H, d, J=8.2 Hz), 7.66 (1H, s), 7.43 (1H, dt, J=8.3, 4.0 Hz),
7.26 (1H, d, J=2.3 Hz), 7.22 (2H, d, J=3.7 Hz), 7.05 (1H, d, J=2.3
Hz), 6.26-6.38 (1H, in), 6.12 (1H, dd, J=16.8, 2.2 Hz), 5.66-5.72
(1H, in), 4.58-4.67 (4H, in), 4.50 (2H, s), 4.22 (2H, s). .sup.19F
NMR (376 MHz, DMSO-d.sub.6) .delta.-123.98 (1F, s). m/z (ESI, +ve)
480.0 (M+H).sup.+.
TABLE-US-00006 TABLE 4 Compounds 4-2 to 4-9 were prepared following
the procedure described in Method 4, Steps 1-4, above as follows:
Ex.# Chemical Structure Name Method changes Reagent 4-2
##STR00624## 1-(6-(6-bromo-5- chloro-7-fluoro- 2,1-benzothiazol-
3-yl)-2,6- diazaspiro[3.3]hept- 2-yl)-2-propen-1- one Omit steps 3
& 4 -- 4-3 ##STR00625## 1-(6-(5-chloro-7- fluoro-6-(3-
methoxy-1- naphthalenyl)-2,1- benzothiazol-3- yl)-2,6-
diazaspiro[3.3]hep- tan-2-yl)-2-propen- 1-one Omit step 4 -- 4-4
##STR00626## N-(1-(6-bromo-5- chloro-7-fluoro- 2,1-benzothiazol-
3-yl)-3- azetidinyl)-2- propenamide Omit steps 3 & 4 Step 1:
3-N- boc-amino- azetidine, HCl salt (Combi-blocks Inc., San Diego,
CA, USA) 4-5 ##STR00627## N-(1-(5-chloro-7- fluoro-6-(3- methoxy-1-
naphthalenyl)-2,1- benzothiazol-3- yl)-3-azetidinyl)- 2-propenamide
Omit step 4 Step 1: 3-N- boc-amino- azetidine, HCl salt
(Combi-blocks Inc., San Diego, CA, USA) 4-6 ##STR00628##
N-(1-(5-chloro-7- fluoro-6-(3- hydroxy-1- naphthalenyl)-2,1-
benzothiazol-3- yl)-3-azetidinyl)- 2-propenamide -- Step 1: 3-N-
boc-amino- azetidine, HCl salt (Combi-blocks Inc., San Diego, CA,
USA) 4-7 ##STR00629## 1-(3-((6-bromo-5- chloro-7-fluoro-
2,1-benzothiazol- 3-yl)amino)-1- azetidinyl)-2- propen-1-one Omit
steps 3 & 4 Step 1: 1-boc-3- aminoazetidine (Alfa Aesar, Haver
Hill, MA, USA) 4-8 ##STR00630## 1-((3R)-3-((6- bromo-5-chloro-7-
fluoro-2,1- benzothiazol-3- yl)amino)-1- piperidinyl)-2-
propen-1-one Omit steps 3 & 4 Step 1: (R)-tert- butyl 3-
aminopiperidine- 1-carboxylate (AstaTech, Inc., Bristol, PA, USA)
4-9 ##STR00631## 1-((3R)-3-((5- chloro-7-fluoro-6- (3-
hydroxynaphthalen- 1-yl)benzo[c] isothiazol-3- yl)amino)piperidin-
1-yl)prop-2-en-1- one -- Step 1: (R)-tert- butyl 3-
aminopiperidine- 1-carboxylate (AstaTech, Inc., Bristol, PA,
USA)
Method 5
Example 5-1:
N-(1-(5-Chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-y-
l)-3-azetidinyl)-N-methyl-2-propenamide
##STR00632## ##STR00633##
[0323] Step 1:
2-Amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzamide. A
mixture of (3-methoxynaphthalen-1-yl)boronic acid (2.04 g, 10.1
mmol), 2-amino-4-bromo-5-chloro-3-fluorobenzamide (Intermediate B
(1.93 g, 7.20 mmol), tetrakis(triphenylphosphine)palladium (0.832
g, 0.720 mmol), sodium carbonate (1.2 mL, 28.8 mmol) in water (9.6
mL), and 1,4-dioxane (38.4 mL) was heated at 90.degree. C. for 2
days. The reaction mixture was then filtered through a pad of
Celite, washing with EtOAc. The filtrate was diluted with saturated
aqueous NaHCO.sub.3 (50 mL) and extracted with EtOAc (3.times.50
mL). The organic extract was washed with brine (30 mL) and dried
over Na.sub.2SO.sub.4. The solution was then filtered and the
filtrated concentrated in vacuo. The residue was suspended in MeOH
(5 mL), and the suspended solid collected by filtration, washed
with MeOH, and dried to give
2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzamide.
Chromatographic purification of the concentrated filtrate (silica
gel, 0% to 100% (3:1) EtOAc-EtOH in heptane) provided additional
2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzamide.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.01-8.17 (m, 1H), 7.92
(d, J=8.2 Hz, 1H), 7.75 (s, 1H), 7.43-7.55 (m, 3H), 7.23-7.34 (m,
2H), 7.10 (d, J=2.5 Hz, 1H), 6.73 (s, 2H), 3.93 (s, 3H). m/z (ESI,
+ve) 345.0 (M+H).sup.+.
[0324] Step 2:
2-Amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzothioamide.
To a solution of
2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzamide
(2.11 g, 6.12 mmol) in tetrahydrofuran (41 mL) was added Lawesson's
reagent (1.49 mL, 3.67 mmol), and the resulting mixture was stirred
at rt for 1 h. The reaction mixture was then diluted with EtOAc (60
mL) and sequentially washed with 2 M HCl (60 mL), saturated aqueous
NaHCO.sub.3 (60 mL), and brine (60 mL). The organic extract was
dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo.
The residue was sonicated in DCM (5 mL), and the resulting
precipitate was collected by filtration, washed with DCM, and dried
in vacuo provide
2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzothioamide.
Chromatographic purification of the filtrate (silica gel, 0% to
100% (3:1) EtOAc-EtOH in heptane) gave additional
2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzothioamide:
m/z (ESI, +ve) 361.0 (M+H).sup.+.
[0325] Step 3:
5-Chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-amine.
Hydrogen peroxide solution (30% in water, 2.2 mL, 21.3 mmol) was
slowly added to an ice-cooled solution of
2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzothioamide
(1.92 g, 5.33 mmol) in pyridine (18 mL). The resulting mixture was
allowed to warm to rt and stir at rt for 18 h. The reaction mixture
was then diluted with water (60 mL), and the resulting precipitate
was collected by filtration, sequentially washed with water and
MeOH, and dried in vacuo to give
5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-amine:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.14 (s, 2H), 7.99-8.03
(m, 1H), 7.93 (d, J=8.3 Hz, 1H), 7.48-7.55 (m, 1H), 7.47 (d, J=2.3
Hz, 1H), 7.31 (d, J=3.9 Hz, 2H), 7.16 (d, J=2.5 Hz, 1H), 3.94 (s,
3H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.-124.71 (s, 1F).
m/z (ESI, +ve) 359.0 (M+H).sup.+.
[0326] Step 4:
3,5-Dichloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazole.
5-Chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-amine
(1.55 g, 4.31 mmol) was added portion-wise over 15 min to a
suspension of copper (II) chloride (0.870 g, 6.47 mmol) and
tert-butyl nitrite (0.77 mL, 6.47 mmol) in acetonitrile (43 mL) at
65.degree. C. The resulting mixture was stirred at 65.degree. C.
for 30 min and then cooled to ambient temperature and diluted with
ice water (50 mL). The precipitated solid was collected by
filtration, washed with water, and dried in vacuo. The residue was
sonicated in DCM (10 mL), and the suspended solid was collected by
filtration, washed with DCM, and dried in vacuo to recover
unreacted
5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazo-
l-3-amine. The filtrate was concentrated in vacuo to give
3,5-dichloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazole.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.98 (s, 1H), 7.96 (d,
J=8.2 Hz, 1H), 7.49-7.56 (m, 2H), 7.28-7.36 (m, 2H), 7.24-7.28 (m,
1H), 3.95 (s, 3H). .sup.19F NMR (376 MHz, DMSO-d.sub.6)
.delta.-122.17 (s, 1F). m/z (ESI, +ve) 378.0 (M+H).sup.+.
[0327] Step 5: tert-Butyl
(1-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl-
)azetidin-3-yl)(methyl)carbamate. A mixture of
3,5-dichloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazole
(100 mg, 0.264 mmol), DIPEA (0.14 mL, 0.793 mmol), and
3-Boc-3-methylaminoazatidine (0.098 mL, 0.529 mmol, Beta Pharma
Scientific, Inc.) in DMF (1.3 mL) was stirred at rt for 18 h. Ice
water (3 mL) was then added, and the resulting mixture was stirred
for 15 min. The precipitated solid was then collected by
filtration, washed with water, and dried in vacuo to furnish
tert-butyl
(1-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl-
)azetidin-3-yl)(methyl)carbamate: m/z (ESI, +ve) 528.0
(M+H).sup.+.
[0328] Step 6:
N-(1-(5-Chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-y-
l)-3-azetidinyl)-N-methyl-2-propenamide. The title compound was
prepared from tert-butyl
(1-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl-
)azetidin-3-yl)(methyl)carbamate (131.1 mg, 0.248 mmol) in three
steps following the procedure reported in Method 1, Step 8: .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 9.89-10.10 (m, 1H), 7.79 (d,
J=8.4 Hz, 1H), 7.73 (s, 1H), 7.43 (ddd, J=8.2, 5.1, 2.9 Hz, 1H),
7.20-7.30 (m, 3H), 7.05 (d, J=2.2 Hz, 1H), 6.81 (dd, J=16.7, 10.5
Hz, 1H), 6.10-6.23 (m, 1H), 5.69-5.81 (m, 1H), 5.37-5.59 (m, 1H),
4.63-4.74 (m, 3H), 4.53-4.61 (m, 1H), 3.14-3.23 (m, 3H). .sup.19F
NMR (376 MHz, DMSO-d.sub.6) .delta.-124.10 (s, 1F). m/z (ESI, +ve)
468.0 (M+H).sup.+.
TABLE-US-00007 TABLE 5 Compounds 5-2 to 5-9 were prepared following
the procedure described in Method 5, Steps 1-6, above as follows:
Ex.# Chemical Structure Name Reagent 5-2 ##STR00634##
N-(1-(5-chloro-7-fluoro-6- (3-hydroxy-1- naphthalenyl)-2,1-
benzothiazol-3-yl)-3- methyl-3-azetidinyl)-2- propenamide Step 5:
3-(Boc- amino)-3- methylazetidine hydrochloride (Advanced
ChemBlocks, Inc., Burlingame, CA, USA) 5-3 ##STR00635##
N-(1-(5-chloro-7-fluoro-6- (3-hydroxy-1- naphthalenyl)-2,1-
benzothiazol-3-yl)-3- (hydroxymethyl)-3- azetidinyl)-2-propenamide
Step 5: tert-butyl 3- (hydroxymethyl) azetidin- 3-ylcarbamate
(Oakwood Products, Inc. Estill, SC, USA) 5-4 ##STR00636##
1-((2S)-4-(5-chloro-7- fluoro-6-(3-hydroxy-1- naphthalenyl)-2,1-
benzothiazol-3-yl)-2- methyl-1-piperazinyl)-2- propen-1-one Step 5:
(S)-1-N-boc- 2-methylpiperazine (Combi-blocks Inc., San Diego, CA,
USA) 5-5 ##STR00637## 1-((1R,5R)-6-(5-chloro-7-
fluoro-6-(3-hydroxy-1- naphthalenyl)-2,1- benzothiazol-3-yl)-2,6-
diazabicyclo[3.2.0]heptan- 2-yl)-2-propen-1-one Step 5: tert-butyl
2,6- diazabicyclo[3.2.0] heptane-2-carboxylate (eNovation Chemicals
LLC, Bridgewater, NJ, USA) 5-6 ##STR00638##
1-((1S,5S)-6-(5-chloro-7- fluoro-6-(3-hydroxy-1- naphthalenyl)-2,1-
benzothiazol-3-yl)-2,6- diazabicyclo[3.2.0]heptan-
2-yl)-2-propen-1-one Step 5: tert-butyl 2,6- diazabicyclo[3.2.0]
heptane-2-carboxylate (eNovation Chemicals LLC, Bridgewater, NJ,
USA) 5-7 ##STR00639## 1-((2R)-4-(5-chloro-7- fluoro-6-(3-hydroxy-1-
naphthalenyl)-2,1- benzothiazol-3-yl)-2- methyl-1-piperazinyl)-2-
propen-1-one Step 5: (R)-1-boc-2- methyl-piperazine (J&W
Pharmlab, LLC, Levittown, PA, USA) 5-8 ##STR00640##
1-(cis-2-(5-chloro-7-fluoro- 6-(3-hydroxy-1- naphthalenyl)-2,1-
benzothiazol-3-yl)-2,6- diazabicyclo[3.2.0]heptan-
6-yl)-2-propen-1-one Step 5: 1-(2,6- diazabicyclo[3.2.0]
heptan-6-yl)prop-2- en-1-one (eNovation Chemicals LLC, Bridgewater,
NJ, USA) ##STR00641## 5-9 ##STR00642## 1-(3-((5-chloro-7-fluoro-6-
(3-hydroxynaphthalen-1- yl)benzo[c]isothiazol-3-
yl)(methyl)amino)azetidin 1-yl)pro-2-en-1-one Step 5: 1-
azetidinecarboxylic acid, 3- (methylamino)-, 1,1- dimethylethyl
ester
Method 6
Example 6-1:
1-(4-(6-(6-Amino-3-chloro-2-pyridinyl)-5-chloro-7-fluoro-2,1-benzothiazol-
-3-yl)-1-piperazinyl)-2-propen-1-one
##STR00643##
[0330] Step 1: tert-Butyl
4-(5-chloro-7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo-
[c]isothiazol-3-yl)piperazine-1-carboxylate. A mixture of
tert-butyl
4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxyl-
ate (Intermediate D, 1.10 g, 2.45 mmol), bis(pinacolato)diboron
(1.86 g, 7.34 mmol), potassium acetate (0.61 mL, 9.8 mmol), and
Pd(dppf)Cl.sub.2.DCM (0.537 g, 0.734 mmol) in 1,4-dioxane (12 mL)
was heated at 100.degree. C. for 40 h. The reaction mixture was
then concentrated in vacuo and chromatographically purified (silica
gel, 0% to 100% (3:1) EtOAc-EtOH in heptane) to provide tert-butyl
4-(5-chloro-7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo-
[c]isothiazol-3-yl)piperazine-1-carboxylate: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.85 (s, 1H), 3.59 (br d, J=4.7 Hz, 4H),
3.44-3.54 (m, 4H), 1.43 (s, 9H), 1.35 (s, 5H), 1.15 (s, 7H).
.sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.-125.11 (s, 1F). m/z
(ESI, +ve) 498.0 (M+H).sup.+.
[0331] Step 2: tert-Butyl
4-(6-(6-amino-3-chloropyridin-2-yl)-5-chloro-7-fluorobenzo[c]isothiazol-3-
-yl)piperazine-1-carboxylate. A mixture of tert-butyl
4-(5-chloro-7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo-
[c]isothiazol-3-yl)piperazine-1-carboxylate (99.5 mg, 0.200 mmol),
SPhos Pd G3 (17.3 mg, 0.020 mmol), 6-bromo-5-chloropyridin-2-amine
(Combi-blocks Inc., San Diego, Calif., USA, 124 mg, 0.6 mmol),
sodium carbonate (85 mg, 0.80 mmol) in water (0.25 mL), and 1,2-DCE
(0.75 mL) was heated at 50.degree. C. for 2 h. The reaction mixture
was concentrated in vacuo and chromatographically purified (silica
gel, 0% to 100% (3:1) EtOAc-EtOH in heptane) to give tert-butyl
4-(6-(6-amino-3-chloropyridin-2-yl)-5-chloro-7-fluorobenzo[c]isothiazol-3-
-yl)piperazine-1-carboxylate: m/z (ESI, +ve) 498.0 (M+H).sup.+.
[0332] Step 3:
1-(4-(6-(6-Amino-3-chloro-2-pyridinyl)-5-chloro-7-fluoro-2,1-benzothiazol-
-3-yl)-1-piperazinyl)-2-propen-1-one. The title compound was
prepared from tert-butyl
4-(6-(6-amino-3-chloropyridin-2-yl)-5-chloro-7-fluorobenzo[c]isothiazol-3-
-yl)piperazine-1-carboxylate (31.6 mg, 0.063 mmol) in two steps
following the procedure reported in Method 1, Step 8: .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.97-8.10 (m, 1H), 7.60 (d, J=8.9
Hz, 1H), 6.86 (dd, J=16.6, 10.6 Hz, 1H), 6.57 (d, J=8.9 Hz, 1H),
6.38 (s, 2H), 6.19 (dd, J=16.8, 2.3 Hz, 1H), 5.71-5.84 (m, 1H),
3.86 (br d, J=19.9 Hz, 4H), 3.63 (br d, J=1.0 Hz, 4H). .sup.19F NMR
(376 MHz, DMSO-d.sub.6) .delta.-126.04 (s, 1F). m/z (ESI, +ve)
452.0 (M+H).sup.+.
TABLE-US-00008 TABLE 6 Compound 6-2 was prepared following the
procedure described in Method 6, Steps 1-3, above as follows: Ex.#
Chemical Structure Name Reagent 6-2 ##STR00644##
1-(4-(5-chloro-6-(3-chloro- 2-pyridinyl)-7-fluoro-2,1-
benzothiazol-3-yl)-1- piperazinyl)-2-propen-1-one Step 2: 2-bromo-
3-chloropyridine
Method 7
Example 7-1:
1-((3R)-4-(5-Chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazo-
l-3-yl)-3-(difluoromethyl)-1-piperazinyl)-2-propen-1-one|1-((3S)-4-(5-chlo-
ro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-3-(difluor-
omethyl)-1-piperazinyl)-2-propen-1-one
##STR00645## ##STR00646##
[0334] Step 1:
2-Amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzoic acid.
Prepared from Intermediate A using a procedure analogous to that
described in Method 1, Step 7: m/z (ESI, +ve) 346.0
(M+H).sup.+.
[0335] Step 2: tert-Butyl
4-(2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzoyl)-3-(difl-
uoromethyl)piperazine-1-carboxylate. A mixture of
2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzoic acid
(0.150 g, 0.434 mmol), TBTU (0.188 g, 0.586 mmol), tert-butyl
3-(difluoromethyl)piperazine-1-carboxylate (0.123 g, 0.521 mmol),
and DIPEA (0.23 mL, 1.302 mmol) in DMF (4 mL) was stirred at
ambient temperature for 3 h. The reaction mixture was then washed
with saturated aqueous NaHCO.sub.3, and the aqueous wash was
extracted with EtOAc. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo.
Chromatographic purification of the residue (silica gel, 0-40%
EtOAc/heptane) provided tert-butyl
4-(2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzoyl)-3-(difl-
uoromethyl)piperazine-1-carboxylate: m/z (ESI, +ve) 586
(M+Na).sup.+.
[0336] Step 3: tert-Butyl
4-(2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)phenylcarbonothi-
oyl)-3-(difluoromethyl)piperazine-1-carboxylate. Lawesson's reagent
(0.041 mL, 0.10 mmol) was added to a solution of tert-butyl
4-(2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzoyl)-3-(difl-
uoromethyl)piperazine-1-carboxylate (0.095 g, 0.168 mmol) in THF (4
mL), and the resulting mixture was stirred at 50.degree. C. for 18
h. The reaction mixture was then concentrated in vacuo and purified
by column chromatography (silica gel, 0-30% EtOAc/heptane) to give
tert-butyl
4-(2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)phenylcarbonothi-
oyl)-3-(difluoromethyl)piperazine-1-carboxylate: m/z (ESI, +ve)
602.2 (M+Na).sup.+.
[0337] Step 4: tert-Butyl
4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)-
-3-(difluoromethyl)piperazine-1-carboxylate. NBS (0.022 g, 0.17
mmol) was added to a solution of tert-butyl
4-(2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)phenylcarbonothi-
oyl)-3-(difluoromethyl)piperazine-1-carboxylate in THF (7 mL), and
the resulting mixture was stirred at ambient temperature for 15
min. The reaction mixture was diluted with water and washed with
10% sodium thiosulfate. The aqueous wash was extracted with EtOAc,
and the combined organic layers were then concentrated in vacuo to
give tert-butyl
4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)-
-3-(difluoromethyl)piperazine-1-carboxylate: m/z (ESI, +ve) 578.2
(M+H).sup.+.
[0338] Step 5:
1-((3R)-4-(5-Chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazo-
l-3-yl)-3-(difluoromethyl)-1-piperazinyl)-2-propen-1-one|1-((3S)-4-(5-chlo-
ro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-3-(difluor-
omethyl)-1-piperazinyl)-2-propen-1-one. Prepared using a procedure
analogous to that described in Method 1, Step 8: .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.13 (br. s., 1H) 8.12 (d, J=2.2 Hz,
1H) 7.80 (d, J=8.2 Hz, 1H) 7.43 (br t, J=7.0 Hz, 1H) 7.20-7.30 (m,
3H) 7.08 (dd, J=5.8, 2.2 Hz, 1H) 6.78-6.91 (m, 1H) 6.27-6.70 (m,
1H) 6.20 (dd, J=16.6, 2.0 Hz, 1H) 5.76-5.84 (m, 1H).sub.4.73-4.87
(m, 1H).sub.4.19-4.72 (m, 2H).sub.3.55-3.90 (m, 3H).sub.3.36-3.47
(m, 1H). m/z (ESI, +ve) 518.0 (M+H).sup.+.
TABLE-US-00009 TABLE 7 Compounds 7-2 and 7-3 were prepared
following the procedure described in Method 7, Steps 1-5, above as
follows: Ex.# Chemical Structure Name Reagent 7-2 ##STR00647##
1-(4-(5-chloro-7-fluoro- 6-(3-hydroxy-1- naphthalenyl)-2,1-
benzothiazol-3-yl)-3- (fluoromethyl)-1- piperazinyl)-2-propen-1-
one Step 2: 3- fluoromethyl- piperazine-1-carboxylic acid
tert-butyl ester (eNovation Chemicals LLC, Bridgewater, NJ, USA)
##STR00648## 7-3 ##STR00649## methyl 1-(5-chloro-7-
fluoro-6-(3-hydroxy-1- naphthalenyl)-2,1- benzothiazol-3-yl)-4-(2-
propenoyl)-2- piperazinecarboxylate Step 2: 4-boc-
piperazine-2-carboxylic acid methyl ester (Combi-blocks Inc., San
Diego, CA, USA) ##STR00650##
Method 8
Example 8-1:
6-Chloro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-pr-
openoyl)-1-piperazinyl)-2(1H)-quinazolinone
##STR00651## ##STR00652##
[0340] Step 1: 4-Bromo-5-chloro-2-fluorobenzamide. A mixture of
4-bromo-5-chloro-2-fluorobenzoic acid (23.3 g, 92 mmol) in thionyl
chloride (67 mL, 0.92 mol) was stirred at 70.degree. C. under a
reflux condenser for 1 h. The reaction mixture was then
concentrated in vacuo, and the residue was taken up in 1,4-dioxane
(200 mL), treated with ammonium hydroxide (30% aqueous, 82 mL, 0.64
mol), and stirred at rt for 15 min. The reaction mixture was
concentrated in vacuo to give 4-bromo-5-chloro-2-fluorobenzamide:
m/z (ESI, +ve) 251.8 (M+H).sup.+.
[0341] Step 2:
4-Bromo-5-chloro-2-fluoro-N-((2-isopropylphenyl)carbamoyl)benzamide.
A mixture of 4-bromo-5-chloro-2-fluorobenzamide (5.90 g, 23.4 mmol)
and oxalyl chloride (1 M in DCM; 12.9 mL, 25.7 mmol) in DCE (100
mL) was stirred under a reflux condenser at 80.degree. C. for 1 h.
The reaction mixture was then cooled to rt and 2-isopropylaniline
(6.62 mL, 46.7 mmol) was added. The resulting mixture was stirred
at rt for 15 min, then cooled to 0.degree. C. The precipitated
solid was removed by filtration, and the collected filtrate was
concentrated in vacuo to give
4-bromo-5-chloro-2-fluoro-N-((2-isopropylphenyl)carbamoyl)benzamide:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.06 (br. s., 1H)
10.31 (s, 1H) 7.97-8.05 (m, 2H) 7.82 (d, J=7.2 Hz, 1H) 7.32-7.38
(m, 1H) 7.14-7.25 (m, 2H) 3.11 (spt, J=6.8 Hz, 1H) 1.24 (d, J=6.8
Hz, 6H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.-113.6 (s, 1
F). m/z (ESI, +ve) 412.7 and 414.6 (M+H).sup.+.
[0342] Step 3:
7-Bromo-6-chloro-1-(2-isopropylphenyl)quinazoline-2,4(1H,3H)-dione
(Intermediate F). KHMDS (1 M in THF, 8.30 mL, 8.30 mmol) was added
to a mixture of
4-bromo-5-chloro-2-fluoro-N-((2-isopropylphenyl)carbamoyl)benzamide
(1.56 g, 3.77 mmol) in THF (19 mL) at -20.degree. C., and the
resulting mixture was allowed to warm to rt over 1 h. The reaction
mixture was then diluted with EtOAc (150 mL) and washed with
saturated aqueous ammonium chloride (2.times.100 mL). The organic
layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated
in vacuo. The residue was suspended in DCM (5 mL), sonicated,
collected by filtration, and dried in vacuo to give
7-bromo-6-chloro-1-(2-isopropylphenyl)quinazoline-2,4(1H,3H)-dione:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.43 (br. s., 1H) 8.29
(s, 1H) 7.55-7.59 (m, 2H) 7.39-7.44 (m, 1H) 7.16 (d, J=7.8 Hz, 1H)
6.75 (s, 1H) 2.59-2.77 (m, 1H) 1.17-1.24 (m, 3H) 1.11 (d, J=6.8 Hz,
3H). m/z (ESI, +ve) 392.9 and 395.0 (M+H).sup.+.
[0343] Step 4:
6-Chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazoline-2,-
4(1H,3H)-dione. A mixture of
7-bromo-6-chloro-1-(2-isopropylphenyl)quinazoline-2,4(1H,3H)-dione
(Intermediate F, 1.17 g, 2.96 mmol),
(2-fluoro-6-methoxyphenyl)boronic acid (2.02 g, 11.9 mmol), SPhos
Pd G3 (0.128 g, 0.148 mmol), and potassium carbonate (2 M in water,
4.45 mL, 8.90 mmol) in DME (30 mL) was stirred at 85.degree. C. for
16 h. The reaction mixture was then diluted with EtOAc (150 mL) and
washed with saturated aqueous NaHCO.sub.3 (3.times.100 mL). The
organic layer was dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. Chromatographic purification of the residue
(silica gel, 0-50% EtOAc in heptane) gave
6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazoline-2,-
4(1H,3H)-dione: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.90
(d, J=1.2 Hz, 1H) 8.11 (d, J=3.3 Hz, 1H) 7.53-7.59 (m, 1H) 7.48
(tt, J=7.0, 2.2 Hz, 1H) 7.38-7.44 (m, 1H) 7.32-7.37 (m, 2H) 6.93
(dd, J=8.4, 4.3 Hz, 1H) 6.86 (t, J=8.7 Hz, 1H) 6.15 (s, 1H) 3.66
(d, J=30 Hz, 3H) 2.73 (dq, J=14.2, 7.0 Hz, 1H) 1.11 (t, J=7.1 Hz,
3H) 1.03 (dd, J=12.7, 6.8 Hz, 3H). .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta.-113.8 (s, 1F)-115.2 (s, 1F). m/z (ESI, +ve)
439.1 (M+H).sup.+.
[0344] Step 5:
4,6-Dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-
-2(1H)-one. To a solution of
6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazoline-2,-
4(1H,3H)-dione (0.395 g, 0.900 mmol) and Et3N (0.753 mL, 5.40 mmol)
in acetonitrile (9 mL) was added phosphorus oxychloride (0.503 mL,
5.40 mmol), and the resulting solution was stirred at 80.degree. C.
for 1.5 h. The reaction mixture was concentrated in vacuo to give
4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-
-2(1H)-one: m/z (ESI, +ve) 457.1 (M+H).sup.+.
[0345] Alternative procedure for Step 5 (used as noted in the table
below): To a stirred mixture of the product from Step 4 (1.0
equiv.), triethylamine (18.0 equiv.), and
1H-benzo[d][1,2,3]triazole (12 equiv.) in acetonitrile (0.07 M) was
added phosphorus oxychloride (6.0 equiv.), and the resulting
reaction mixture was stirred at 80.degree. C. for 3.5 h. The
reaction mixture was then poured slowly into rapidly stirred water
(100 mL) at 10.degree. C. The aqueous suspension was stirred for 15
min before being extracted with EtOAc (100 mL). The organic layer
was washed with brine (100 mL), dried over MgSO.sub.4, filtered,
and concentrated in vacuo to give a benzotriazole adduct
intermediate that was used directly in Step 6.
[0346] Step 6: tert-Butyl
4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)-2-oxo-1,2--
dihydroquinazolin-4-yl)piperazine-1-carboxylate. A solution of
4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-
-2(1H)-one (obtained from Method 8, Step 5), tert-butyl
piperazine-1-carboxylate (0.335 g, 1.80 mmol), and Et.sub.3N (0.753
mL, 5.40 mmol) in DCE (9 mL) was stirred at 60.degree. C. for 20
min. The reaction mixture was diluted with EtOAc (100 mL) and
washed with saturated aqueous NaHCO.sub.3 (3.times.75 mL). The
organic layer was dried over Na.sub.2SO.sub.4 and concentrated in
vacuo. Chromatographic purification of the residue (silica gel,
0-60% (3:1) EtOAc-EtOH in heptane) provided tert-butyl
4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)-2-oxo-1,2--
dihydroquinazolin-4-yl)piperazine-1-carboxylate: m/z (ESI, +ve)
607.3 (M+H).sup.+.
[0347] Note: When (S)-1-(3-methylpiperazin-1-yl)prop-2-en-1-one
2,2,2-trifluoroacetate was used, it was synthesized as follows:
(S)-1-(3-Methylpiperazin-1-yl)prop-2-en-1-one
2,2,2-trifluoroacetate
##STR00653##
[0349] Step 6-a: (S)-tert-Butyl
4-acryloyl-2-methylpiperazine-1-carboxylate. Acryloyl chloride
(1.34 mL, 16.5 mmol) was added to a solution of
(S)-1-boc-2-methyl-piperazine (3.00 g, 15.0 mmol, Boc Sciences,
Shirley, N.Y.) in THF (30.0 mL) at -10.degree. C., and the
resulting mixture was stirred at -10.degree. C. for 5 min.
Triethylamine (6.26 mL, 44.9 mmol) was then slowly added, and the
resulting mixture was stirred at -10.degree. C. for 15 min, then
allowed to warm to rt. The reaction mixture was partitioned between
EtOAc and saturated aqueous NaHCO.sub.3. The aqueous layer was
extracted with EtOAc (3 x), and the organic layers were then
combined, dried over MgSO.sub.4, filtered, and concentrated in
vacuo. Chromatographic purification of the residue (silica gel,
0-100% EtOAc in heptane) furnished (S)-tert-butyl
4-acryloyl-2-methylpiperazine-1-carboxylate: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 6.72-6.85 (m, 1H) 6.10-6.18 (m, 1H) 5.68-5.76
(m, 1H) 4.08-4.32 (m, 2H) 3.68-4.03 (m, 2H) 2.86-3.14 (m, 2H)
2.66-2.80 (m, 1H) 1.38-1.43 (s, 9H) 0.96-1.04 (m, 3H). m/z (ESI,
+ve) 277.3 (M+Na).sup.+.
[0350] Step 6-b: (S)-1-(3-Methylpiperazin-1-yl)prop-2-en-1-one
2,2,2-trifluoroacetate. A mixture of (S)-tert-butyl
4-acryloyl-2-methylpiperazine-1-carboxylate (3.21 g, 12.62 mmol)
and TFA (4.7 mL, 63.1 mmol) in DCM (16 mL) was stirred at rt for 24
h. The reaction mixture was then concentrated in vacuo to give
(S)-1-(3-methylpiperazin-1-yl)prop-2-en-1-one
2,2,2-trifluoroacetate: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.70-8.99 (m, 1H) 6.74-6.91 (m, 1H) 6.12-6.26 (m, 1H) 5.70-5.84 (m,
1H) 4.25-4.44 (m, 1H) 4.07-4.25 (m, 1H) 3.49-3.53 (m, 1H) 3.22-3.32
(m, 2H) 2.92-3.08 (m, 2H) 1.14-1.29 (m, 3H). m/z (ESI, +ve) 155.1
(M+H).sup.+.
[0351] Step 7:
6-Chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin--
1-yl)quinazolin-2(1H)-one. A solution of tert-butyl
4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)-2-oxo-1,2--
dihydroquinazolin-4-yl)piperazine-1-carboxylate (0.594 g, 0.978
mmol) in TFA (4 mL) was stirred at ambient temperature for 30 min.
The reaction mixture was concentrated in vacuo to give
6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin--
1-yl)quinazolin-2(1H)-one: m/z (ESI, +ve) 507.2 (M+H).sup.+.
[0352] Step 8:
4-(4-Acryloylpiperazin-1-yl)-6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-i-
sopropylphenyl)quinazolin-2(1H)-one. To an ice-cooled solution of
6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin--
1-yl)quinazolin-2(1H)-one and DIPEA (0.85 mL, 4.9 mmol) in DCM (10
mL) at 0.degree. C. was added acryloyl chloride (0.079 mL, 0.98
mmol), and the resulting mixture was stirred at 0.degree. C. for 30
min. The reaction mixture was then diluted with EtOAc (100 mL) and
washed with saturated aqueous NaHCO.sub.3 (3.times.75 mL). The
organic layer was dried over Na.sub.2SO.sub.4, decanted, and
concentrated in vacuo. Chromatographic purification of the residue
(silica gel, 0-100% (3:1) EtOAc-EtOH in heptane) gave
4-(4-acryloylpiperazin-1-yl)-6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-i-
sopropylphenyl)quinazolin-2(1H)-one: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.86 (d, J=1.2 Hz, 1H) 7.41-7.54 (m, 2H)
7.29-7.37 (m, 2H) 7.14 (dt, J=7.8, 1.7 Hz, 1H) 6.70-6.79 (m, 2H)
6.58-6.68 (m, 1H) 6.50 (d, J=7.4 Hz, 1H) 6.39 (dd, J=16.8, 1.8 Hz,
1H) 5.75-5.84 (m, 1H) 3.79-4.06 (m, 8H) 3.75 (s, 2H) 3.66 (s, 1H)
2.69 (tt, J=13.4, 6.8 Hz, 1H) 1.20-1.24 (m, 3H) 1.07 (dd, J=6.8,
3.9 Hz, 3H). .sup.19F NMR (377 MHz, CDCl.sub.3) 6-113.05 (s,
1F)-113.55 (s, 1F). m/z (ESI, +ve) 561.2 (M+H).sup.+.
[0353] Step 9:
6-Chloro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-pr-
openoyl)-1-piperazinyl)-2(1H)-quinazolinone. BBr.sub.3 (1 M in DCE,
3.3 mL, 3.3 mmol) was added to an ice-cooled solution of
4-(4-acryloylpiperazin-1-yl)-6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-i-
sopropylphenyl)quinazolin-2(1H)-one (0.372 g, 0.663 mmol) in DCE
(1.7 mL), and the resulting mixture was stirred at 0.degree. C. for
20 min, then allowed to warm to rt and stir at rt for 2 h.
Saturated aqueous NaHCO.sub.3was added to the reaction mixture,
followed by EtOAc (150 mL). The organic layer was separated and
washed with saturated aqueous NaHCO.sub.3 (3.times.100 mL). The
organic layer was then dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. Chromatographic purification of the residue
(silica gel, 0-100% (3:1) EtOAc-EtOH in heptane) provided
6-chloro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-pr-
openoyl)-1-piperazinyl)-2(1H)-quinazolinone: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.06 (br. d., J=15.1 Hz, 1H) 8.03 (d, J=1.2
Hz, 1H) 7.51-7.56 (m, 1H) 7.45 (t, J=7.6 Hz, 1H) 7.33 (tdd, J=7.5,
7.5, 3.8, 1.4 Hz, 1H) 7.14-7.25 (m, 2H) 6.84 (dd, J=16.8, 10.4 Hz,
1H) 6.62-6.74 (m, 2H) 6.14-6.26 (m, 2H) 5.71-5.78 (m, 1H) 3.71-3.99
(m, 8H) 2.52-2.59 (m, 1H) 1.02-1.12 (m, 6H). .sup.19F NMR (377 MHz,
DMSO-d.sub.6) .delta.-113.6 (s, 1F)-114.8 (s, 1F). m/z (ESI, +ve)
547.1 (M+H).sup.+.
TABLE-US-00010 TABLE 8 Compounds 8-2 to 8-6 were prepared following
the procedure described in Method 8, Steps 1-9, above as follows:
Method Starting Ex.# Chemical Structure Name changes material
Reagents 8-2 ##STR00654## 6-chloro-7-(2- fluoro-6- hydroxyphenyl)-
1-(2-(2- propanyl)phenyl)- 4-(4-(2- propenoyl)-1- piperazinyl)
pyrido[2,3- d]pyrimidin- 2(1H)-one Omit Steps 7 and 8 2,5,6-
trichloro- nicotinic acid Step 4: sodium carbonate Step 6:
1-(piperazin-1- yl)prop-2-en-1- one (eNovation Chemicals LLC,
Bridgewater, NJ, USA) 8-3 ##STR00655## 6-chloro-7-(2- fluoro-6-
hydroxyphenyl)- 4-((2S)-2- methyl-4-(2- propenoyl)-1-
piperazinyl)-1- (2-(2- propanyl)phenyl)- 2(1H)- quinazolinone --
4-bromo- 5-chloro- 2- fluoro- benzoic acid Step 6: (S)- tert-butyl
3- methylpiperazine- 1-carboxylate (CNH Technologies, Inc., Woburn,
MA) 8-4 ##STR00656## 6-chloro-1-(2,6- diethylphenyl)-
7-(2-fluoro-6- hydroxyphenyl)- 4-((2,S)-2- methyl-4-(2-
propenoyl)-1- piperazinyl) pyrido [2,3- d]pyrimidin- 2(1H)-one Omit
steps 7 and 8 2,5,6- trichloro- nicotinic acid Step 2: 2,6-
diethylaniline, Step 5: benzotriazole, Step 6: (S)-1- (3-
methylpiperazin- 1-yl)prop-2-en- 1-one 2,2,2- trifluoroacetate (See
Step 6 note for synthesis) 8-5 ##STR00657## 6-chloro-1-(4-
cyclopropyl-3- pyridinyl)-7-(2- fluoro-6- hydroxyphenyl)- 4-(4-(2-
propenoyl)-1- piperazinyl)- 2(1H)- quinazolinone -- 4-bromo-
5-chloro- 2- fluoro- benzoic acid Step 2: 4- cyclopropylpyridin-
3-amine (Combi-Phos Catalysts Inc. Trenton, NJ, USA), 1,4-
dioxane/water. 100.degree. C. 8-6 ##STR00658## 6-chloro-7-(2-
fluoro-6- hydroxyphenyl)- 4-((2S)-2- methyl-4-(2- propenoyl)-1-
piperazinyl)-1- (2-(2- propanyl)phenyl) pyrido[2,3- d]pyrimidin-
2(1H)-one Omit steps 7 and 8 2,5,6- trichloro- nicotinic acid Step
4: sodium carbonate Step 6: (S)-1- (3- methylpiperazin-
1-yl)prop-2-en- 1-one 2,2,2- trifluoroacetate (See Step 6 note for
synthesis)
Method 9
Example 9-1:
6-Chloro-7-(2,3-dichloro-5-hydroxyphenyl)-4-((2S)-2-methyl-4-(2-propenoyl-
)-1-piperazinyl)-1-(2-(2-propanyl)phenyl)-2(1H)-quinazolinone
##STR00659## ##STR00660##
[0355] Step 1:
7-Bromo-4,6-dichloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one. To
a mixture of
7-bromo-6-chloro-1-(2-isopropylphenyl)quinazoline-2,4(1H,3H)-dione
(Intermediate F, 470 mg, 1.194 mmol) and DIPEA (0.623 mL, 3.58
mmol) in acetonitrile (11.4 mL) was added phosphorus oxychloride
(0.915 mL, 5.97 mmol). The resulting mixture was heated at
80.degree. C. for 2 h, then cooled to ambient temperature and
concentrated in vacuo to give
7-bromo-4,6-dichloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one: m/z
(ESI, +ve) 413.0 (M+H).sup.+.
[0356] Step 2:
(S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-bromo-6-chloro-1-(2-isopropyl-
phenyl)quinazolin-2(1H)-one. A mixture of
7-bromo-4,6-dichloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one (492
mg, 1.19 mmol), (S)-4-N-boc-2-methyl piperazine (478 mg, 2.39
mmol), and DIPEA (0.623 mL, 3.58 mmol) in DMF (2.3 mL) was stirred
at rt for 10 min. Ice water (10 mL) was then added, and the
resulting mixture stirred for 15 min. The precipitated solid was
collected by filtration, washed with water, and dried in vacuo to
give (S)-tert-butyl
4-(7-bromo-6-chloro-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-y-
l)-3-methylpiperazine-1-carboxylate: m/z (ESI, +ve) 577.1
(M+H).sup.+.
[0357] TFA (2.0 mL, 26.8 mmol) was added to a solution of
(S)-tert-butyl
4-(7-bromo-6-chloro-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-y-
l)-3-methylpiperazine-1-carboxylate (297 mg, 0.516 mmol) in DCM
(2.0 mL), and the resulting mixture was stirred at rt for 15 min.
Concentration of the resulting mixture in vacuo provided
(S)-7-bromo-6-chloro-1-(2-isopropylphenyl)-4-(2-methylpiperazin-1-yl)quin-
azolin-2(1H)-one: m/z (ESI, +ve) 477.0 (M+H).sup.+.
[0358] Acryloyl chloride (0.258 M in DCM, 4.0 mL, 1.031 mmol) was
added to an ice-cooled mixture of
(S)-7-bromo-6-chloro-1-(2-isopropylphenyl)-4-(2-methylpiperazin-1-yl)quin-
azolin-2(1H)-one and DIPEA (0.269 mL, 1.547 mmol) in DCM (2.0 mL),
and the resulting mixture was stirred at 0.degree. C. for 20 min.
Concentration in vacuo followed by chromatographic purification of
the residue (silica gel, 0-100% (3:1) EtOAc-EtOH in heptane) gave
(S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-bromo-6-chloro-1-(2-isopropyl-
phenyl)quinazolin-2(1H)-one: .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.91-8.08 (m, 1H), 7.49-7.67 (m, 2H), 7.41 (br d, J=5.8 Hz,
1H), 7.21 (br s, 1H), 6.76-6.98 (m, 1H), 6.52-6.67 (m, 1H),
6.09-6.29 (m, 1H), 5.75 (br s, 1H), 4.61-4.96 (m, 1H), 4.23-4.48
(m, 1H), 3.93-4.21 (m, 2H), 3.50-3.77 (m, 1H), 3.33-3.49 (m, 1H),
3.23-3.28 (m, 1H), 2.94-3.24 (m, 1H), 1.27 (br d, J=9.3 Hz, 6H),
1.09 (br s, 3H). m/z (ESI, +ve) 531.1 (M+H).sup.+.
[0359] Step 3:
(S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-chloro-7-(2,3-dichloro-5-meth-
oxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one. A mixture of
(S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-bromo-6-chloro-1-(2-isopropyl-
phenyl)quinazolin-2(1H)-one (120 mg, 0.226 mmol),
2-(2,3-dichloro-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(82 mg, 0.272 mmol), Na.sub.2CO.sub.3 (96 mg, 0.906 mmol), and
Pd(PPh3).sub.4 (26.2 mg, 0.023 mmol) in 1,4-dioxane (1.6 mL) and
water (0.4 mL) was heated at 90.degree. C. for 17 h. The reaction
mixture was then concentrated in vacuo and chromatographically
purified (silica gel, 0-100% (3:1) EtOAc-EtOH in heptane) to
provide
(S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-chloro-7-(2,3-dichloro-5-meth-
oxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one: m/z (ESI,
+ve) 627.0 (M+H).sup.+.
[0360] Step 4:
6-Chloro-7-(2,3-dichloro-5-hydroxyphenyl)-4-((2S)-2-methyl-4-(2-propenoyl-
)-1-piperazinyl)-1-(2-(2-propanyl)phenyl)-2(1H)-quinazolinone.
BBr.sub.3 (1 M in hexanes, 0.32 mL, 0.320 mmol) was added to an
ice-cooled mixture of
(S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-chloro-7-(2,3-dichloro-5-m-
ethoxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one (40 mg,
0.064 mmol) and DCE (1.0 mL), and the resulting mixture was stirred
at 0.degree. C. for 30 min. Saturated aqueous NaHCO.sub.3 (2.0 mL)
was added, and the resulting mixture was extracted with (2:1)
DCM/MeOH (5 mL). The organic extract was dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo.
Chromatographic purification of the residue (silica gel, 0-10% MeOH
in DCM) gave
6-chloro-7-(2,3-dichloro-5-hydroxyphenyl)-4-((2S)-2-methyl-4-(2-propenoyl-
)-1-piperazinyl)-1-(2-(2-propanyl)phenyl)-2(1H)-quinazolinone:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.42 (br d, J=17.0 Hz,
1H), 7.86-8.11 (m, 1H), 7.50-7.63 (m, 1H), 7.47 (br t, J=6.0 Hz,
1H), 7.36 (t, J=7.5 Hz, 1H), 7.15-7.26 (m, 1H), 7.05 (d, J=2.3 Hz,
1H), 6.78-6.96 (m, 1H), 6.44-6.58 (m, 1H), 6.11-6.29 (m, 2H),
5.71-5.82 (m, 1H), 4.68-4.98 (m, 1H), 3.96-4.52 (m, 3H), 3.52-3.85
(m, 2H), 3.34-3.51 (m, 1H), 2.95-3.26 (m, 1H), 1.27-1.41 (m, 3H),
0.95-1.13 (m, 6H). m/z (ESI, +ve) 611.0 (M+H).sup.+.
TABLE-US-00011 TABLE 9 Compounds 9-2 to 9-14 were prepared
following the procedure described in Method 9, Steps 1-4, above as
follows: Method Starting Ex.# Chemical Structure Name changes
material Reagent 9-2 ##STR00661## 7-bromo-6-chloro-
4-((2S)-2-methyl-4- (2-propenoyl)-1- piperazinyl)-1-(2- (2-
propanyl)phenyl)- 2(1H)- quinazolinone Omits Steps 3 and 4
7-bromo-6- chloro-1-(2- isopropyl- phenyl) quinazoline- 2,4(1H,3H)-
dione -- 9-3 ##STR00662## 7-(5-amino-2- chlorophenyl)-6-
chloro-4-((2S)-2- methyl-4-(2- propenoyl)-1- piperazinyl)-1-(2- (2-
propanyl)phenyl)- 2(1H)- quinazolinone Omit Step 4 7-bromo-6-
chloro-1-(2- isopropyl- phenyl) quinazoline- 2,4(1H,3H)- dione Step
3: (5- amino-2- chlorophenyl) boronic acid hydrochloride
(Combi-blocks Inc., San Diego, CA USA) 9-4 ##STR00663## 1-(2-(2-
butanyl)phenyl)-6- chloro-7-(3- hydroxy-1- naphthalenyl)-4-(4-
(2-propenoyl)-1- piperazinyl)-2(1H)- quinazolinone SM prepared
according to Method 8, steps 1- 3 7-bromo-1- (2-(sec-
butyl)phenyl)- 6- chloro- quinazoline- 2,4(1H,3H)- dione Method 8,
Step 2: (2-sec- butylphenyl) amine (Key Organics Inc., Bedford, MA,
USA), Step 2: 1-boc- piperazine, Step 3: (3- methoxy- naphthalen-1-
yl)boronic acid (Ark Pharm Inc. Arlington Heights, IL, USA), SPhos
Pd G3, K.sub.2CO.sub.3, 1,4- dioxane/water, 100.degree. C.
##STR00664## 9-5 ##STR00665## 3-(6-chloro-7-(2- fluoro-6-
hydroxyphenyl)-2- oxo-4-(4-(2- propenoyl)-1- piperazinyl)-1(2H)-
quinazolinyl) benzonitrile SM prepared according to Method 8, steps
1- 3 3-(7-bromo- 6-chloro-2,4- dioxo-3,4- dihydro- quinazolin-
1(2H)- yl) benzonitrile Method 8, Step 2: 3- aminobenzo- nitrile
(Frontier Scientific Services, Inc., Newark, DE, USA), Step 2:
1-boc- piperazine, Step 3: 2- fluoro-6- hydroxyphenyl boronic acid
(Combi-blocks Inc., San Diego, CA, USA), SPhos Pd G3,
K.sub.2CO.sub.3, 1,4- dioxane/water, 100.degree. C. 9-6
##STR00666## 6-chloro-1-(3- cyclopropyl-4- pyridinyl)-7-(2-
fluoro-6- hydroxyphenyl)-4- (4-(2-propenoyl)-1- piperazinyl)-2(1H)-
quinazolinone SM prepared according to Method 8, steps 1- 3
7-bromo-6- chloro-1-(3- cyclopropyl- pyridin-4- yl)quinazoline-
2,4(1H,3H)- dione Method 8, Step 2: 3- cyclopropyl- pyridin-4-amine
(Combi-Phos Catalysts Inc. Trenton, NJ, USA), Step 2: 1-boc-
piperazine, Step 3: 2- fluoro-6- hydroxyphenyl boronic acid
(Combi-blocks Inc., San Diego, CA, USA), SPhos Pd G3,
K.sub.2CO.sub.3, 1,4- dioxane/water, 100.degree. C. 9-7-2
##STR00667## 6-chloro-1-(3- cyclopropyl-4- pyridinyl)-7-(2-
fluoro-6- hydroxyphenyl)-4- ((2S)-2-methyl-4- (2-propenoyl)-1-
piperazinyl)-2(1H)- quinazolinone [2.sup.nd eluting isomer] SM
prepared according to Method 8, steps 1- 3 7-bromo-6- chloro-1-(3-
cyclopropyl- pyridin-4- yl)quinazoline- 2,4(1H,3H)- dione Method 8,
Step 2: 3- cyclopropyl- pyridin-4-amine (Combi-Phos Catalysts Inc.
Trenton, NJ, USA), Step 3: 2-fluoro-6- hydroxyphenyl boronic acid
(Combi-blocks Inc., San Diego, CA, USA), SPhos Pd G3,
K.sub.2CO.sub.3, 1,4- dioxane/water, 100.degree. C. 9-7-1
##STR00668## 6-chloro-1-(3- cyclopropyl-4- pyridinyl)-7-(2-
fluoro-6- hydroxyphenyl)-4- ((2S)-2-methyl-4- (2-propenoyl)-1-
piperazinyl)-2(1H)- quinazolinone [1.sup.st eluting isomer] SM
prepared according to Method 8, steps 1- 3 7-bromo-6- chloro-1-(3-
cyclopropyl- pyridin-4- yl)quinazoline- 2,4(1H,3H)- dione Method 8,
Step 2: 3- cyclopropyl- pyridin-4-amine (Combi-Phos Catalysts Inc.
Trenton, NJ, USA), Step 3: 2-fluoro-6- hydroxyphenyl boronic acid
(Combi-blocks Inc., San Diego, CA, USA), SPhos Pd G3,
K.sub.2CO.sub.3, 1,4- dioxane/water, 100.degree. C. 9-9
##STR00669## 6-chloro-1-(3- cyclopropyl-4- pyridinyl)-7-(5-
methyl-1H-indazol- 4-yl)-4-((2S)-2- methyl-4-(2- propenoyl)-1-
piperazinyl)-2(1H)- quinazolinone SM prepared according to Method
8, steps 1- 3, omit step 4 7-bromo-6- chloro-1-(3- cyclopropyl-
pyridin-4- yl)quinazoline- 2,4(1H,3H)- dione Method 8, Step 2: 3-
cyclopropyl- pyridin-4-amine, (Combi-Phos Catalysts Inc. Trenton,
NJ, USA), Step 3: 4-borono-5- methyl-1h- indazole (Ark- Pharm
Inc.), SPhos Pd G3, K.sub.2CO.sub.3, 1,4- dioxane/water,
100.degree. C. 9-10 ##STR00670## 6-chloro-7-(2,3-
dichlorophenyl)-4- ((2S)-2-methyl-4- (2-propenoyl)-1-
piperazinyl)-1-(2- (2- propanyl)phenyl)- 2(1H)- quinazolinone Omit
Step 4 7-bromo-6- chloro-1-(2- isopropyl- phenyl) quinazoline-
2,4(1H,3H)- dione Step 3: 2,3- dichloro- benzene- boronic acid
(Alfa Aesar, Haver Hill, MA, USA) 9-11 ##STR00671## 6-chloro-7-(2-
dichlorophenyl)-4- ((2S)-2-methyl-4- (2-propenoyl)-1-
piperazinyl)-1-(2- (2- propanyl)phenyl)- 2(1H)- quinazolinone Omit
Step 4 7-bromo-6- chloro-1-(2- isopropyl- phenyl) quinazoline-
2,4(1H,3H)- dione Step 3: 2- chlorobenzene- boronic acid (Alfa
Aesar, Haver Hill, MA, USA) 9-12 ##STR00672## 7-(1H-benzotriazol-
1-yl)-6-chloro-1- (2,6- diethylphenyl)-4- ((2S)-2-methyl-4-
(2-propenoyl)-1- piperazinyl)pyrido [2,3-d]pyrimidin- 2(1H)-one SM
prepared according to Method 8, steps 1- 3. Omit steps 2-2 and 2-
3; compound isolated in step 2-1 2,5,6- trichloro- nicotinic acid
Method 8 Step 2: 2,6- diethylaniline. Step 1: benzotriazole (see
Method 8, step 5 alternate conditions), Step 2-1: (S)-1- (3-
methylpiperazin- 1-yl)prop-2- en-1-one 2,2,2- trifluoroacetate (See
Method 8 Step 6 note for synthesis) 9-13 ##STR00673##
6-chloro-7-(3- hydroxy-1- naphthalenyl)-1-(2- (2-propanyl)
phenyl)-4-(4-(2- propenoyl)-1- piperazinyl)-2(1H)- quinazolinone --
7-bromo-6- chloro-1-(2- isopropyl- phenyl) quinazoline- 2,4(1H,3H)-
dione Step 1: benzotriazole (see Method 8, step 5 alternate
conditions), Step 2-1: tert-butyl piperazine-1- carboxylate Step
2-3: NEt.sub.3 Step 3: SPhos Pd G3, (3- methoxy- naphthalen-1-
yl)boronic acid, DME 9-14 ##STR00674## 6-chloro-1-((1R)- 2,2-
dimethylcyclohexyl)- 7-(2-fluoro-6- hydroxyphenyl)-4-
(4-(2-propenoyl)-1- piperazinyl)pyrido [2,3-d]pyrimidin-
2(1H)-one|6- chloro-1-((1S)-2,2- dimethylcyclohexyl)-
7-(2-fluoro-6- hydroxyphenyl)-4- (4-(2-propenoyl)-1-
piperazinyl)pyrido [2,3-d]pyrimidin- 2(1H)-one SM prepared
according to Method 8, steps 1- 3 Omit steps 2-2, 2-3 and 4 2,5,6-
trichloro- nicotinic acid Method 8 Step 2: 2,2- dimethylcyclo-
hexan-1-amine Step 2(1): 1- (piperazin-1- yl)prop-2-en-1- one
(eNovation Chemicals LLC, Bridgewater, NJ, USA) Step 3: SPhos Pd
G3, 2-fluoro-6- hydroxyphenyl boronic acid Combi-blocks Inc., San
Diego, CA, USA), DME ##STR00675##
Method 10
Example 10-1:
1-(4-(7-Chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(2-methylphenyl)-1-phthalaz-
inyl)-1-piperazinyl)-2-propen-1-one
##STR00676## ##STR00677##
[0362] Step 1: 6,7-Dichloro-2,3-dihydrophthalazine-1,4-dione
(Intermediate G). Hydrazine (0.232 mL, 10.1 mmol) was added to a
mixture of 5,6-dichloroisobenzofuran-1,3-dione (2.00 g, 9.22 mmol,
TCI America, Portland, Oreg., USA) and ethanol (30 mL), and the
resulting mixture was heated at reflux for 2 h before being cooled
to rt. The resulting precipitate was collected by filtration and
washed with water to give
6,7-dichloro-2,3-dihydrophthalazine-1,4-dione: m/z (ESI, +ve) 231.1
(M+H).sup.+.
[0363] Step 2:
6-Chloro-7-(2-fluoro-6-hydroxyphenyl)-2,3-dihydrophthalazine-1,4-dione.
A mixture of 6,7-dichloro-2,3-dihydrophthalazine-1,4-dione
(Intermediate G, 3.80 g, 16.45 mmol),
2-fluoro-6-hydroxyphenylboronic acid (10.26 g, 65.8 mmol,
Combi-blocks Inc., San Diego, Calif., USA), SPhos Pd G3 (1.423 g,
1.645 mmol), and 2M aqueous Na.sub.2CO.sub.3 (32.9 mL, 65.8 mmol)
in DME (60 mL) was stirred at 80.degree. C. for 16 h. The reaction
mixture was cooled to rt and diluted with water (200 mL) and EtOAc
(300 mL). The aqueous layer was separated, acidified with 5 N HCl,
and extracted with EtOAc (300 mL). The combined organic layers were
washed with brine (200 mL), dried over MgSO.sub.4, filtered, and
concentrated in vacuo. The residue was suspended in DCM (50 mL) and
collected by filtration to give
6-chloro-7-(2-fluoro-6-hydroxyphenyl)-2,3-dihydrophthalazine-1,4-dione:
m/z (ESI, +ve) 307.0 (M+H).sup.+.
[0364] Step 3:
6-(2-((tert-Butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-2,3-dihydrop-
hthalazine-1,4-dione. tert-Butyl(chloro)diphenylsilane (2.67 mL,
10.25 mmol) was added to an ice-cooled mixture of
6-chloro-7-(2-fluoro-6-hydroxyphenyl)-2,3-dihydrophthalazine-1,4-dione
(2.62 g, 8.54 mmol) and TEA (4.75 mL, 34.2 mmol) in acetonitrile
(40 mL), and the resulting mixture was stirred at 0.degree. C. for
15 min, then warmed to rt and stirred for 1.5 h. Additional
tert-butyl(chloro)diphenylsilane (2.67 mL, 10.25 mmol) was added,
and the resulting mixture was stirred at rt for 16 h. The reaction
mixture was subsequently diluted with water (300 mL), acidified
with 5 N HCl, and extracted with EtOAc (300 mL). The organic layer
was separated and sequentially washed with brine (250 mL), dried
over MgSO.sub.4, filtered, and concentrated in vacuo. The residue
was taken up in DCM (200 mL), TFA (20 mL) was added, and the
resulting mixture was stirred at rt for 45 min. The reaction
mixture was then diluted with saturated aqueous NaHCO.sub.3 (200
mL) and extracted with DCM (2.times.250 mL). The combined organic
extracts were dried over MgSO.sub.4, filtered, and concentrated in
vacuo to give
6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-2,3-dihydrop-
hthalazine-1,4-dione: m/z (ESI, +ve) 545.2 (M+H).sup.+.
[0365] Step 4:
6-(2-((tert-Butyldiphenylsilyl)oxy)-6-fluorophenyl)-1,4,7-trichlorophthal-
azine. Pyridine (1.45 mL, 17.1 mmol) was added to a mixture of
6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-2,3-dihydrop-
hthalazine-1,4-dione (4.66 g, 8.55 mmol) and phosphorus oxychloride
(6.39 mL, 68.4 mmol), and the resulting mixture was heated at
100.degree. C. for 1.5 h. The reaction mixture was then cooled to
rt and slowly poured into stirred water (300 mL) while maintaining
an internal temperature of <10.degree. C. After stirring for 15
min, the resulting mixture was extracted with EtOAc (400 mL), and
the organic extract was sequentially washed with brine (250 mL),
dried over MgSO.sub.4, filtered, and concentrated in vacuo.
Chromatographic purification of the residue (silica gel, 0-25%
EtOAc in heptane) provided
6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-1,4,7-trichlorophthal-
azine: m/z (ESI, +ve) 581.1 (M+H).sup.+.
[0366] Step 5: tert-Butyl
4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthal-
azin-1-yl)piperazine-1-carboxylate (Intermediate H).
1-Boc-piperazine (5.00 g, 26.9 mmol) was added to a mixture of
6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-1,4,7-trichlorophthal-
azine (5.21 g, 8.95 mmol) and triethylamine (3.77 mL, 26.9 mmol) in
DCM (35 mL), and the resulting mixture was stirred at rt for 19 h.
The reaction mixture was then partitioned between DCM (300 mL) and
saturated aqueous NaHCO.sub.3 (200 mL). The organic layer was
separated, dried over MgSO.sub.4, filtered, and concentrated in
vacuo. Chromatographic purification of the residue (silica gel,
0-50% EtOAc in heptane) gave a mixture of tert-butyl
4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthal-
azin-1-yl)piperazine-1-carboxylate and tert-butyl
4-(7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,6-dichlorophthal-
azin-1-yl)piperazine-1-carboxylate. The individual regioisomers
were isolated by chiral SFC purification (OJ-H column (30.times.250
mm, 5 pm), 15% (20 mM NH.sub.3 in MeOH) in supercritical CO.sub.2),
providing tert-butyl
4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthal-
azin-1-yl)piperazine-1-carboxylate as the second-eluting isomer:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.27 (s, 1H) 8.17 (s, 1H)
7.56-7.61 (m, 4H) 7.40-7.46 (m, 2H) 7.31-7.37 (m, 4H) 6.99-7.07 (m,
1H) 6.77 (t, J=8.61 Hz, 1H) 6.42 (d, J=8.22 Hz, 1H) 3.72-3.77 (m,
4H) 3.53-3.59 (m, 4H) 1.51 (s, 9H) 0.66 (s, 9H). m/z (ESI, +ve)
731.2 (M+H).sup.+.
[0367] Step 6:
6-(2-((tert-Butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichloro-1-(piper-
azin-1-yl)phthalazine. Trifluoroacetic acid (2 mL, 26.8 mmol) was
added to a stirred solution of tert-butyl
4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthal-
azin-1-yl)piperazine-1-carboxylate (Intermediate H, 1.21 g, 1.654
mmol) in DCM (10 mL), and the resulting mixture was stirred at rt
for 1.5 h. The reaction mixture was then diluted with saturated
aqueous NaHCO.sub.3 (75 mL) and extracted with DCM (2.times.100
mL). The combined organic extracts were dried over MgSO.sub.4,
filtered, and concentrated in vacuo to give
6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichloro--
1-(piperazin-1-yl)phthalazine: m/z (ESI, +ve) 631.3
(M+H).sup.+.
[0368] Step 7:
1-(4-(6-(2-((tert-Butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichloropht-
halazin-1-yl)piperazin-1-yl)prop-2-en-1-one. Acryloyl chloride
(0.148 mL, 1.81 mmol) was added to a mixture of
6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichloro-1-(piper-
azin-1-yl)phthalazine (1.04 g, 1.647 mmol) and triethylamine (0.694
mL, 4.94 mmol) in DCM (10 mL), and the resulting mixture was
stirred at rt for 45 min. Saturated aqueous NaHCO.sub.3 (75 mL) was
added, and the resulting mixture was extracted with DCM
(3.times.100 mL). The combined organic extracts were dried over
MgSO.sub.4, filtered, and concentrated in vacuo to give
1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichloropht-
halazin-1-yl)piperazin-1-yl)prop-2-en-1-one: m/z (ESI, +ve) 685.1
(M+H).sup.+.
[0369] Step 8:
1-(4-(4,7-Dichloro-6-(2-fluoro-6-hydroxyphenyl)phthalazin-1-yl)piperazin--
1-yl)prop-2-en-1-one (Intermediate I). TBAF (1 M in THF, 3.3 mL,
3.30 mmol) was added to a solution of
1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichloropht-
halazin-1-yl)piperazin-1-yl)prop-2-en-1-one (1.13 g, 1.648 mmol) in
THF (10 mL), and the resulting mixture was stirred at rt for 15
min. The reaction mixture was concentrated in vacuo, and the
residue was purified by column chromatography (silica gel, 0-100%
EtOAc in heptane) to give
1-(4-(4,7-dichloro-6-(2-fluoro-6-hydroxyphenyl)phthalazin-1-yl)piperazin--
1-yl)prop-2-en-1-one: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
10.26 (br s, 1H) 8.31 (s, 1H) 8.14 (s, 1H) 7.31-7.40 (m, 1H)
6.78-6.92 (m, 3H) 6.17 (dd, J=16.63, 2.35 Hz, 1H) 5.74 (dd,
J=10.37, 2.35 Hz, 1H) 3.79-3.92 (m, 4H) 3.46-3.55 (m, 4H). m/z
(ESI, +ve) 447.0 (M+H).sup.+.
[0370] Step 9:
1-(4-(7-Chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(o-tolyl)phthalazin-1-yl)pi-
perazin-1-yl)prop-2-en-1-one. A mixture of
1-(4-(4,7-dichloro-6-(2-fluoro-6-hydroxyphenyl)phthalazin-1-yl)piperazin--
1-yl)prop-2-en-1-one (Intermediate I, 25 mg, 0.056 mmol),
2-tolylboronic acid (30.4 mg, 0.224 mmol, Frontier Scientific Inc.,
Logan Utah, USA), Pd(PPh.sub.3).sub.4 (6.46 mg, 5.59 .mu.mol, Strem
Chemicals Inc., NewburyPort, Mass., USA), and 2M aqueous
Na.sub.2CO.sub.3 (0.084 mL, 0.168 mmol) in 1,4-dioxane (0.3 mL) was
stirred at 40.degree. C. for 18 h. The reaction mixture was then
diluted with EtOAc (20 mL) and washed with water (15 mL). The
organic layer was separated and sequentially washed with brine (15
mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo.
Chromatographic purification of the residue (silica gel, 0-100%
EtOAc in heptane) furnished
1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(o-tolyl)phthalazin-1-yl)pi-
perazin-1-yl)prop-2-en-1-one: .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.15 (br s, 1H) 8.33 (s, 1H) 7.36-7.45 (m, 2H) 7.24-7.36
(m, 4H) 6.90 (dd, J=16.63, 10.37 Hz, 1H) 6.70-6.80 (m, 2H) 6.18
(dd, J=16.73, 2.25 Hz, 1H) 5.75 (dd, J=10.56, 2.15 Hz, 1H)
3.83-3.97 (m, 4H) 3.47-3.62 (m, 4H) 1.98-2.06 (m, 3H). m/z (ESI,
+ve) 503.1 (M+H).sup.+.
TABLE-US-00012 TABLE 10 Compounds 10-2 to 10-13 were prepared
following the procedure described in Method 10, Steps 1-9, above as
follows: Method Ex.# Chemical Structure Name changes Reagent 10-2
##STR00678## 1-(4-(7-chloro-6-(2- fluoro-6- hydroxyphenyl)-4-(2-
methoxyphenyl) phthalazin- 1-yl)piperazin-1- yl)prop-2-en-1-one --
Step 9: 2- methoxybenzeneboronic acid 10-3 ##STR00679##
1-(4-(7-chloro-4-(5- chloro-2- methylphenyl)-6-(2- fluoro-6-
hydroxyphenyl)-1- phthalazinyl)-1- piperazinyl)-2-propen- 1-one --
Step 9: (5-chloro-2- methylphenyl)boronic acid (Combi-blocks Inc.,
San Diego, CA, USA) 10-4 ##STR00680## 1-(4-(7-chloro-6-(2-
fluoro-6- hydroxyphenyl)-4-(2- (2-propanyl)phenyl)-
1-phthalazinyl)-1- piperazinyl)-2-propen- 1-one -- Step 9: 2-
isopropylphenyl- boronic acid (Alfa Aesar, Haver Hill, MA, USA)
10-5 ##STR00681## 1-(4-(7-chloro-4-(2- ethylphenyl)-6-(2- fluoro-6-
hydroxyphenyl)-1- phthalazinyl)-1- piperazinyl)-2-propen- 1-one --
Step 9: 2- ethylbenzeneboronic acid (Alfa Aesar, Haver Hill, MA,
USA) 10-6 ##STR00682## 1-(4-(7-chloro-6-(2- fluoro-6-
hydroxyphenyl)-4-(4- methyl-3-pyridinyl)-1- phthalazinyl)-1-
piperazinyl)-2-propen- 1-one -- Step 9: 4- methylpyridine-3-
boronic acid pinacol ester (run at 60.degree. C.) 10-7 ##STR00683##
1-(4-(7-chloro-4-(2,6- dimethylphenyl)-6-(2- fluoro-6-
hydroxyphenyl)-1- phthalazinyl)-1- piperazinyl)-2-propen- 1-one --
Step 9: 2,6- dimethylphenylboronic acid (run at 80.degree. C.) 10-8
##STR00684## 1-(4-(7-chloro-6-(2- fluoro-6- hydroxyphenyl)-4-(2-
methyl-3-pyridinyl)-1- phthalazinyl)-1- piperazinyl)-2-propen-
1-one -- Step 9: 2- methylpyridine-3- boronic acid pinacol ester
(Frontier Scientific, Inc. Logan, UT, USA) 10-9 ##STR00685##
1-(4-(7-chloro-6-(2- fluoro-6- hydroxyphenyl)-4- (1H-indol-4-yl)-1-
phthalazinyl)-1- piperazinyl)-2-propen- 1-one -- Step 9:
1H-indol-4-yl- 4-boronic acid 10-10 ##STR00686##
1-(4-(7-chloro-4-(2- cyclopropylphenyl)-6- (2-fluoro-6-
hydroxyphenyl)-1- phthalazinyl)-1- piperazinyl)-2-propen- 1-one --
Step 9: 2- cyclopropylbenzene- boronic acid (Combi-Phos Catalysts,
Inc., Trenton, NJ, USA) 10-11 ##STR00687## 1-(4-(7-chloro-4-(2-
chlorophenyl)-6-(2- fluoro-6- hydroxyphenyl)-1- phthalazinyl)-1-
piperazinyl)-2-propen- 1-one -- Step 9: 2- chlorophenylboronic acid
(Matrix Scientific, Columbia, SC, USA) 10-12 ##STR00688##
1-(4-(7-chloro-6-(2- fluoro-6- hydroxyphenyl)-4-(5-
methyl-1H-indazol-4- yl)-1-phthalazinyl)-1- piperazinyl)-2-propen-
1-one -- Step 9: (5-methyl-1H- indazol-4-yl)boronic acid
(Combi-Blocks, Inc., San Diego, CA, USA) 10-13 ##STR00689##
1-(4-(4,7-dichloro-6- (2-fluoro-6- hydroxyphenyl)-1-
phthalazinyl)-1- piperazinyl)-2-propen- 1-one Omit Step 9 --
Method 11
Example 11-1:
6-chloro-7-(5-methyl-1H-indazol-4-yl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-pr-
openoyl)-1-piperazinyl)-2(1H)-quinazolinone
##STR00690## ##STR00691##
[0372] Step 1:
4-(1H-benzo[d][1,2,3]triazol-1-yl)-7-bromo-6-chloro-1-(2-isopropylphenyl)-
quinazolin-2(1H)-one. Phosphorus oxychloride (1.204 mL, 7.85 mmol)
was added to a stirred mixture of
7-bromo-6-chloro-1-(2-isopropylphenyl)quinazoline-2,4(1H,3H)-dione
(Intermediate F, 515 mg, 1.308 mmol), triethylamine (3.31 mL, 23.55
mmol), and 1H-benzo[d][1,2,3]triazole (2.01 g, 16.87 mmol) in
acetonitrile (15 mL). The reaction mixture was heated to 80.degree.
C. and stirred for 1 h. The reaction mixture was cooled to rt and
filtered. The filtrate was then poured slowly into rapidly stirred
water (150 mL) at .about.10.degree. C. The aqueous suspension was
stirred for 15 min before being extracted two times with EtOAc (150
mL). The organic layers were combined, washed with brine (150 mL),
dried over MgSO.sub.4, filtered, and concentrated in vacuo to give
crude
4-(1H-benzo[d][1,2,3]triazol-1-yl)-7-bromo-6-chloro-1-(2-isopropylphenyl)-
quinazolin-2(1H)-one. m/z (ESI) M+H: 494.0.
[0373] Step 2: tert-butyl
4-(7-bromo-6-chloro-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-y-
l)piperazine-1-carboxylate. tert-Butyl piperazine-1-carboxylate
(268 mg, 1.438 mmol) was added to a stirred mixture of crude
4-(1H-benzo[d][1,2,3]triazol-1-yl)-7-bromo-6-chloro-1-(2-isopropylphenyl)-
quinazolin-2(1H)-one (647 mg, 1.308 mmol) and triethylamine (3.68
mL, 26.2 mmol) in dimethyl sulfoxide (6 mL). The reaction mixture
was stirred at 80.degree. C. for 30 min. The reaction mixture was
diluted with EtOAc (100 mL) and washed with water (75 mL). The
organic layer was separated, washed with brine (75 mL), dried over
MgSO.sub.4, filtered, and concentrated in vacuo. Chromatographic
purification of the residue (silica gel, 0 to 100% EtOAc in
heptane) gave tert-butyl
4-(7-bromo-6-chloro-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-y-
l)piperazine-1-carboxylate. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 7.79 (1H, s) 7.49-7.59 (2H, m) 7.36-7.42 (1H, m) 7.11 (1H,
d, J=7.63 Hz) 6.80 (1H, s) 3.79-3.92 (4H, m) 3.62-3.73 (4H, m) 2.60
(1H, spt, J=6.80 Hz) 1.49-1.54 (9H, m) 1.22 (3H, d, J=6.85 Hz) 1.08
(3H, d, J=6.85 Hz). m/z (ESI) M+H: 561.0.
[0374] Step 3: tert-butyl
4-(6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-2-oxo-1,2--
dihydroquinazolin-4-yl)piperazine-1-carboxylate. tert-Butyl
4-(7-bromo-6-chloro-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-y-
l)piperazine-1-carboxylate (115 mg, 0.205 mmol),
4-borono-5-methyl-1h-indazole (0.144 mL, 0.819 mmol, Ark Pharm
Inc., Arlington Heights, Ill., USA), Sphos Pd G3 (0.016 mL, 0.020
mmol), and sodium carbonate (2 M aqueous, 0.409 mL, 0.819 mmol)
were mixed in 1,2-dimethoxyethane (1 mL) under an argon atmosphere
in a sealed vial. The reaction mixture was stirred at 100.degree.
C. for 24 h. The reaction mixture was cooled to rt and diluted with
EtOAc (50 mL) and water (40 mL). The organic layer was separated,
washed with brine (40 mL), dried over MgSO.sub.4, filtered, and
concentrated in vacuo. Chromatographic purification of the residue
(silica gel, 0 to 50% (3:1 EtOAc/EtOH) in heptane) gave tert-butyl
4-(6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-2-oxo-1,2--
dihydroquinazolin-4-yl)piperazine-1-carboxylate. m/z (ESI) M+H:
613.2.
[0375] Step 4:
6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-4-(piperazin--
1-yl)quinazolin-2(1H)-one. Trifluoroacetic acid (0.5 mL, 6.71 mmol)
was added to a stirred mixture of tert-butyl
4-(6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-2-oxo-1,2--
dihydroquinazolin-4-yl)piperazine-1-carboxylate (78 mg, 0.127 mmol)
in dichloromethane (1 mL). The reaction mixture was stirred at rt
for 1 h. The reaction mixture was concentrated in vacuo to give
crude
6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-4-(piperazin--
1-yl)quinazolin-2(1H)-one. m/z (ESI) M+H: 513.2.
[0376] Step 5:
6-chloro-7-(5-methyl-1H-indazol-4-yl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-pr-
openoyl)-1-piperazinyl)-2(1H)-quinazolinone. Acryloyl chloride
(10.33 .mu.l, 0.127 mmol) was added to a stirred mixture of
6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-4-(piperazin--
1-yl)quinazolin-2(1H)-one (65 mg, 0.127 mmol) and triethylamine
(0.178 mL, 1.267 mmol) in dichloromethane (2 mL) at 0.degree. C.
The reaction mixture was stirred at 0.degree. C. for 20 min.
Additional acryloyl chloride (5.17 .mu.l, 0.064 mmol) was added,
and the reaction mixture was stirred at 0.degree. C. for another 20
min. The reaction mixture was diluted with DCM (25 mL) and quenched
with saturated aqueous sodium bicarbonate (20 mL). The organic
layer was separated, dried over MgSO.sub.4, filtered, and
concentrated in vacuo. Chromatographic purification of the residue
(silica gel, 0 to 80% (3:1 EtOAc/EtOH) in heptane) gave impure
product. Further chromatographic purification of the impure product
(silica gel, 0 to 100% acetone in heptane) gave the separated
diastereomers.
6-chloro-7-(5-methyl-1H-indazol-4-yl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-pr-
openoyl)-1-piperazinyl)-2(1H)-quinazolinone (Example 11-1-1), was
the first diastereomer to elute. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 10.28 (1H, br s) 7.94 (1H, s) 7.35-7.49 (4H,
m) 7.25-7.31 (2H, m) 7.11 (1H, d, J=7.67 Hz) 6.64 (1H, dd, J=16.79,
10.57 Hz) 6.54 (1H, s) 6.41 (1H, dd, J=16.79, 1.87 Hz) 5.81 (1H,
dd, J=10.57, 1.66 Hz) 3.83-4.07 (8H, m) 2.74 (1H, spt, J=6.84 Hz)
2.13 (3H, s) 1.23 (3H, d, J=6.84 Hz) 1.04 (3H, d, J=6.84 Hz). m/z
(ESI) M+H: 567.2. The second diastereomer to elute was further
purified by column chromatography (silica gel, 0 to 80% (3:1
EtOAc/EtOH) in heptane) to give
6-chloro-7-(5-methyl-1H-indazol-4-yl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-pr-
openoyl)-1-piperazinyl)-2(1H)-quinazolinone (Example 11-1-2).
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 10.37 (1H, br s) 7.94
(1H, s) 7.34-7.50 (4H, m) 7.21-7.31 (2H, m) 7.13 (1H, d, J=7.67 Hz)
6.64 (1H, dd, J=16.90, 10.68 Hz) 6.55 (1H, s) 6.41 (1H, dd,
J=16.79, 1.66 Hz) 5.81 (1H, dd, J=10.47, 1.55 Hz) 3.83-4.08 (8H, m)
2.70 (1H, spt, J=6.84 Hz) 2.13 (3H, s) 1.22 (3H, d, J=6.84 Hz) 1.03
(3H, d, J=6.84 Hz). m/z (ESI) M+H: 567.2.
TABLE-US-00013 TABLE 11 Compounds 11-3 and 11-4 were prepared
following the procedure described in Method 11, Steps 1-5, above as
follows: Ex.# Chemical Structure Name Reagent Isomer 11-2-1
##STR00692## 6-chloro-7-(5- methyl-1H-indazol- 4-yl)-4-((2S)-2-
methyl-4-(2- propenoyl)-1- piperazinyl)-1-(2-(2- propanyl)phenyl)-
2(1H)-quinazolinone Step 2: (S)-4-n- boc-2-methyl piperazine (CNH
Technologies, Inc., Woburn, MA, USA), run at room temp overnight.
1.sup.st eluting isomeric mixture 11-2-2 ##STR00693##
6-chloro-7-(5- methyl-1H-indazol- 4-yl)-4-((2S)-2- methyl-4-(2-
propenoyl)-1- piperazinyl)-1-(2-(2- propanyl)phenyl)-
2(1H)-quinazolinone Step 2: (S)-4-n- boc-2-methyl piperazine (CNH
Technologies, Inc., Woburn, MA, USA), run at room temp overnight.
2.sup.nd eluting isomeric mixture
Section 2-Individual Examples
Example 12
1-(4-(7-Chloro-4-cyclopropyl-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)--
1-piperazinyl)-2-propen-1-one
##STR00694## ##STR00695##
[0378] Step 1: tert-Butyl
4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopr-
opylphthalazin-1-yl)piperazine-1-carboxylate. To a 20 mL vial
charged with tert-butyl
4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthal-
azin-1-yl)piperazine-1-carboxylate (Intermediate H, 0.060 g, 0.082
mmol) was added
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (0.033 g, 0.041 mmol) and
2-methyltetrahydrofuran (2.0 mL). The resulting mixture was capped
and stirred at rt for 10 min before cyclopropylzinc bromide (0.5 M
in THF, 0.820 mL, 0.410 mmol; Rieke Metals, Lincoln, Nebr., USA)
was added via syringe. The reaction mixture was heated at
80.degree. C. for 3 h before being cooled to rt and partitioned
between EtOAc (30 mL) and water (10 mL). The aqueous layer was
extracted once more with EtOAc (20 mL). The combined organic layers
were dried over MgSO.sub.4, filtered, and concentrated in vacuo.
The crude product was purified by column chromatography (24 g of
silica gel, 0 to 30% acetone in heptane) to obtain tert-butyl
4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopr-
opylphthalazin-1-yl)piperazine-1-carboxylate. .sup.1H NMR
(CHLOROFORM-d) 6: 8.31-8.38 (m, 1H), 8.15-8.23 (m, 1H), 7.55-7.64
(m, 4H), 7.39-7.47 (m, 2H), 7.29-7.38 (m, 4H), 6.99-7.09 (m, 1H),
6.74-6.85 (m, 1H), 6.36-6.47 (m, 1H), 3.68-3.79 (m, 4H), 3.37-3.51
(m, 4H), 2.37-2.48 (m, 1H), 1.48-1.54 (m, 9H), 1.37-1.45 (m, 1H),
1.30-1.33 (m, 1H), 1.00-1.15 (m, 2H), 0.61-0.71 (m, 9H). m/z (ESI)
M+H: 737.4.
[0379] Step 2:
6-(2-((tert-Butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropy-
l-1-(piperazin-1-yl)phthalazine. Trifluoroacetic acid (0.316 mL,
4.10 mmol) was added to a solution of tert-butyl
4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopr-
opylphthalazin-1-yl)piperazine-1-carboxylate in DCM (0.7 mL). The
resulting mixture was capped and stirred at rt for 30 min. The
reaction mixture was diluted with DCM (10 mL) and basified using
saturated aqueous NaHCO.sub.3 (5 mL). The aqueous layer was
extracted once more with DCM (10 mL). The combined organic layers
were dried over MgSO.sub.4, filtered, and concentrated in vacuo to
obtain
6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropy-
l-1-(piperazin-1-yl)phthalazine. .sup.1H NMR (CHLOROFORM-d)
.delta.: 8.30-8.36 (m, 1H), 8.18-8.24 (m, 1H), 7.55-7.64 (m, 4H),
7.40-7.46 (m, 2H), 7.33 (q, J=7.1 Hz, 4H), 6.97-7.09 (m, 1H),
6.74-6.83 (m, 1H), 6.36-6.46 (m, 1H), 3.45-3.55 (m, 4H), 3.16-3.26
(m, 4H), 2.35-2.49 (m, 1H), 1.37-1.46 (m, 1H), 1.30-1.33 (m, 1H),
1.06-1.12 (m, 2H), 0.61-0.70 (m, 9H). m/z (ESI) M+H: 637.2.
[0380] Step 3:
1-(4-(6-(2-((tert-Butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cycl-
opropylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one. To a 20 mL
vial charged with
6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropy-
l-1-(piperazin-1-yl)phthalazine (0.023 g, 0.036 mmol) was added
triethylamine (16 pl, 0.114 mmol) and dichloromethane (1.0 mL). The
resulting mixture was capped and stirred at rt for 10 min before
acryloyl chloride (4.0 pl, 0.049 mmol) was added via syringe. The
reaction mixture was capped and continued to stir at rt for 20 min.
The reaction was quenched with saturated aqueous NaHCO.sub.3 (3 mL)
and diluted with DCM (10 mL). The aqueous layer was extracted once
more with DCM (5 mL). The combined organic layers were dried over
MgSO.sub.4, filtered, and concentrated in vacuo to obtain
1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cycl-
opropylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one. .sup.1H NMR
(CHLOROFORM-d) .delta.: 8.32-8.38 (m, 1H), 8.16-8.24 (m, 1H),
7.55-7.65 (m, 4H), 7.40-7.48 (m, 2H), 7.31-7.38 (m, 4H), 6.98-7.10
(m, 1H), 6.75-6.84 (m, 1H), 6.60-6.72 (m, 1H), 6.41-6.47 (m, 1H),
6.31-6.40 (m, 1H), 5.72-5.82 (m, 1H), 3.79-4.08 (m, 4H), 3.44-3.62
(m, 4H), 2.38-2.49 (m, 1H), 1.40-1.45 (m, 1H), 1.33-1.37 (m, 1H),
1.04-1.13 (m, 2H), 0.62-0.68 (m, 9H). m/z (ESI) M+H: 691.2.
[0381] Step 4:
1-(4-(7-Chloro-4-cyclopropyl-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-
-1-piperazinyl)-2-propen-1-one. To a 20 mL vial charged with
1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cycl-
opropylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one (0.022 g,
0.032 mmol) was added tetrahydrofuran (2.0 mL) followed by
tetrabutylammonium fluoride (1.0 M solution in THF, 0.070 mL, 0.070
mmol). The vial was capped and stirred at rt for 30 min. The
reaction mixture was concentrated in vacuo. The crude product was
purified by column chromatography (24 g of silica, 0 to 5% MeOH in
DCM) to obtain
1-(4-(7-chloro-4-cyclopropyl-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-
-1-piperazinyl)-2-propen-1-one. .sup.1H NMR (CHLOROFORM-d) 6:
8.30-8.37 (m, 1H), 8.11-8.18 (m, 1H), 7.29-7.38 (m, 1H), 6.96-7.18
(m, 1H), 6.88-6.94 (m, 1H), 6.76-6.85 (m, 1H), 6.59-6.72 (m, 1H),
6.31-6.42 (m, 1H), 5.73-5.84 (m, 1H), 3.73-4.05 (m, 4H), 3.35-3.62
(m, 4H), 2.40-2.52 (m, 1H), 1.35-1.42 (m, 1H), 1.29-1.34 (m, 1H),
1.03-1.14 (m, 2H). m/z (ESI) M+H: 453.2.
Example 13
1-(4-(4-Anilino-7-chloro-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-pi-
perazinyl)-2-propen-1-one
##STR00696## ##STR00697##
[0383] Step 1: tert-Butyl
4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-(phenyl-
amino)phthalazin-1-yl)piperazine-1-carboxylate. To a 20 mL vial
charged with tert-butyl
4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthal-
azin-1-yl)piperazine-1-carboxylate (0.060 g, 0.082 mmol) was added
dimethyl sulfoxide (2.0 mL) followed by aniline (0.075 mL, 0.820
mmol). The vial was capped and refluxed at 80.degree. C. for 3 h.
The reaction was cooled to rt and partitioned between EtOAc (30 mL)
and water (10 mL). The organic layer was separated and washed with
water (2.times.10 mL). The organic layer was dried over MgSO.sub.4,
filtered, and concentrated in vacuo. The crude product was purified
by column chromatography (40 g of silica, 0 to 30% EtOAc in
heptane) to obtain tert-butyl
4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-(phenyl-
amino)phthalazin-1-yl)piperazine-1-carboxylate. .sup.1H NMR
(CHLOROFORM-d) .delta.: 8.17-8.25 (m, 1H), 7.76-7.81 (m, 1H),
7.60-7.69 (m, 5H), 7.50-7.55 (m, 2H), 7.40-7.46 (m, 2H), 7.31-7.37
(m, 5H), 7.06-7.11 (m, 2H), 6.76-6.83 (m, 1H), 6.57-6.66 (m, 1H),
6.39-6.50 (m, 1H), 3.66-3.81 (m, 4H), 3.32-3.43 (m, 4H), 1.51-1.53
(m, 9H), 0.69-0.75 (m, 9H). m/z (ESI) M+H: 788.2.
[0384] Step 2:
7-(2-((tert-Butyldiphenylsilyl)oxy)-6-fluorophenyl)-6-chloro-N-phenyl-4-(-
piperazin-1-yl)phthalazin-1-amine. Analogous to Example 12, step 2,
the reaction of tert-butyl
4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-(phenyl-
amino)phthalazin-1-yl)piperazine-1-carboxylate delivered
7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-6-chloro-N-phenyl-4-(-
piperazin-1-yl)phthalazin-1-amine. .sup.1H NMR (CHLOROFORM-d)
.delta.: 8.19-8.26 (m, 1H), 7.75-7.80 (m, 1H), 7.60-7.68 (m, 5H),
7.49-7.55 (m, 2H), 7.39-7.46 (m, 3H), 7.32-7.37 (m, 5H), 7.02-7.11
(m, 2H), 6.75-6.84 (m, 1H), 6.59-6.67 (m, 1H), 6.43-6.53 (m, 1H),
3.35-3.47 (m, 4H), 3.16-3.27 (m, 4H), 0.70-0.76 (m, 9H). m/z (ESI)
M+H: 688.2.
[0385] Step 3:
1-(4-(6-(2-((tert-Butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-(phe-
nylamino)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one. Analogous
to Example 12, step 3, the reaction of
7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-6-chloro-N-phenyl-4-(-
piperazin-1-yl)phthalazin-1-amine delivered
1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-(phe-
nylamino)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one. .sup.1H
NMR (CHLOROFORM-d) .delta.: 8.16-8.24 (m, 1H), 7.77-7.84 (m, 1H),
7.62-7.67 (m, 4H), 7.52-7.55 (m, 1H), 7.41-7.46 (m, 3H), 7.32-7.38
(m, 6H), 7.02-7.11 (m, 2H), 6.77-6.84 (m, 1H), 6.65-6.71 (m, 1H),
6.46-6.51 (m, 1H), 6.30-6.39 (m, 2H), 5.73-5.81 (m, 1H), 3.86-4.05
(m, 4H), 3.37-3.53 (m, 4H), 0.69-0.75 (m, 9H). m/z (ESI) M+H:
742.3.
[0386] Step 4:
1-(4-(4-Anilino-7-chloro-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-p-
iperazinyl)-2-propen-1-one. Analogous to Example 12, step 4, the
reaction of
1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-(-
phenylamino)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one
delivered
1-(4-(4-anilino-7-chloro-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-p-
iperazinyl)-2-propen-1-one. .sup.1H NMR (CHLOROFORM-d) 6: 7.96-8.09
(m, 2H), 7.46-7.57 (m, 2H), 7.37-7.44 (m, 1H), 7.29-7.33 (m, 1H),
7.20-7.26 (m, 1H), 6.96-7.07 (m, 1H), 6.81-6.87 (m, 1H), 6.70-6.77
(m, 1H), 6.54-6.67 (m, 1H), 6.29-6.41 (m, 1H), 5.68-5.82 (m, 1H),
3.74-3.96 (m, 4H), 3.12-3.43 (m, 4H). m/z (ESI) M+H: 504.2.
Example 14
1-(4-(7-Chloro-4-cyclopentyl-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)--
1-piperazinyl)-2-propen-1-one
##STR00698## ##STR00699##
[0388] Step 1: tert-Butyl
4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclope-
ntylphthalazin-1-yl)piperazine-1-carboxylate. Analogous to Example
12, step 1, the reaction of tert-butyl
4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthal-
azin-1-yl)piperazine-1-carboxylate (Intermediate H) and
cyclopentylzine bromide (0.5 M in THF, Rieke Metals, Lincoln,
Nebr.,) delivered tert-butyl
4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclope-
ntylphthalazin-1-yl)piperazine-1-carboxylate. .sup.1H NMR
(CHLOROFORM-d) .delta.: 8.18-8.22 (m, 1H), 8.12-8.16 (m, 1H),
7.60-7.66 (m, 2H), 7.50-7.56 (m, 2H), 7.39-7.47 (m, 2H), 7.34-7.38
(m, 2H), 7.28-7.33 (m, 2H), 7.09 (br d, J=1.2 Hz, 1H), 6.75-6.82
(m, 1H), 6.37-6.44 (m, 1H), 3.72-3.78 (m, 4H), 3.44-3.51 (m, 4H),
2.03-2.23 (m, 4H), 1.87-1.96 (m, 2H), 1.67-1.79 (m, 3H), 1.51-1.54
(m, 9H), 0.62-0.67 (m, 9H). m/z (ESI) M+H: 765.2.
[0389] Step 2:
6-(2-((tert-Butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopenty-
l-1-(piperazin-1-yl)phthalazine. Analogous to Example 12, step 2,
the reaction of tert-butyl
4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclope-
ntylphthalazin-1-yl)piperazine-1-carboxylate delivered
6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopenty-
l-1-(piperazin-1-yl)phthalazine. .sup.1H NMR (CHLOROFORM-d)
.delta.: 8.17-8.21 (m, 1H), 8.12-8.16 (m, 1H), 7.61-7.66 (m, 2H),
7.51-7.56 (m, 2H), 7.40-7.46 (m, 2H), 7.34-7.38 (m, 2H), 7.29-7.33
(m, 2H), 6.99-7.08 (m, 1H), 6.74-6.82 (m, 1H), 6.37-6.45 (m, 1H),
3.58-3.67 (m, 4H), 3.27-3.36 (m, 4H), 2.18-2.22 (m, 1H), 2.08-2.12
(m, 2H), 1.86-1.91 (m, 3H), 1.69-1.77 (m, 3H), 0.59-0.67 (m, 9H).
m/z (ESI) M+H: 665.2.
[0390] Step 3:
1-(4-(6-(2-((tert-Butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cycl-
opentylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one. Analogous to
Example 12, step 3, the reaction of
6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopenty-
l-1-(piperazin-1-yl)phthalazine delivered
1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cycl-
opentylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one. .sup.1H NMR
(CHLOROFORM-d) .delta.: 8.18-8.25 (m, 1H), 8.13-8.17 (m, 1H),
7.61-7.67 (m, 2H), 7.50-7.57 (m, 2H), 7.39-7.48 (m, 2H), 7.28-7.37
(m, 4H), 6.99-7.10 (m, 1H), 6.75-6.83 (m, 1H), 6.62-6.71 (m, 1H),
6.33-6.43 (m, 2H), 5.73-5.81 (m, 1H), 3.84-4.07 (m, 4H), 3.71-3.82
(m, 1H), 3.49-3.65 (m, 4H), 1.80-1.96 (m, 4H), 1.67-1.77 (m, 4H),
0.62-0.67 (m, 9H). m/z (ESI) M+H: 719.2.
[0391] Step 4:
1-(4-(7-Chloro-4-cyclopentyl-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-
-1-piperazinyl)-2-propen-1-one. Analogous to Example 12, step 4,
the reaction of
1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cycl-
opentylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one delivered
1-(4-(7-chloro-4-cyclopentyl-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-
-1-piperazinyl)-2-propen-1-one. .sup.1H NMR (CHLOROFORM-d) .delta.:
8.10-8.22 (m, 2H), 7.29-7.38 (m, 1H), 6.86-6.93 (m, 1H), 6.77-6.85
(m, 1H), 6.61-6.72 (m, 1H), 6.33-6.44 (m, 1H), 5.74-5.85 (m, 1H),
3.82-4.05 (m, 4H), 3.75-3.82 (m, 1H), 3.40-3.63 (m, 4H), 2.06-2.24
(m, 4H), 1.81-1.96 (m, 2H), 1.67-1.79 (m, 2H). m/z (ESI) M+H:
481.2.
Example 15
1-(4-(7-Chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(1-piperidinyl)-1-phthalazin-
yl)-1-piperazinyl)-2-propen-1-one
##STR00700##
[0393] Step 1: tert-Butyl
4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(piperidin-1-yl)phthalazin-1-y-
l)piperazine-1-carboxylate. To a 20 mL vial charged with tert-butyl
4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthal-
azin-1-yl)piperazine-1-carboxylate (Intermediate H, 0.060 g, 0.082
mmol) was added piperidine (1.0 mL, 10.10 mmol). The vial was
capped and heated at 80.degree. C. for 2 h. The reaction was cooled
to rt and partitioned between EtOAc (30 mL) and water (10 mL). The
organic layer was separated and washed with water (2.times.10 mL).
The combined organic layers were dried over MgSO.sub.4, filtered,
and concentrated in vacuo to obtain tert-butyl
4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(piperidin-1-yl)phthalazin-1-y-
l)piperazine-1-carboxylate. .sup.1H NMR (CHLOROFORM-d) .delta.:
8.09-8.14 (m, 1H), 7.97-8.03 (m, 1H), 7.28-7.35 (m, 1H), 6.75-6.88
(m, 2H), 3.65-3.76 (m, 4H), 3.30-3.44 (m, 8H), 1.72-1.81 (m, 4H),
1.61-1.71 (m, 3H), 1.48-1.53 (m, 9H). m/z (ESI) M+H: 542.2.
[0394] Step 2:
2-(7-Chloro-1-(piperazin-1-yl)-4-(piperidin-1-yl)phthalazin-6-yl)-3-fluor-
ophenol. Analogous to Example 12, step 2, the reaction of
tert-butyl
4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(piperidin-1-yl)phthalazin-1-y-
l)piperazine-1-carboxylate delivered
2-(7-chloro-1-(piperazin-1-yl)-4-(piperidin-1-yl)phthalazin-6-yl)-3-fluor-
ophenol. .sup.1H NMR (CHLOROFORM-d) .delta.: 8.09-8.13 (m, 1H),
7.95-8.03 (m, 1H), 7.28-7.38 (m, 1H), 6.83-6.89 (m, 1H), 6.75-6.82
(m, 1H), 3.39-3.48 (m, 4H), 3.31-3.38 (m, 4H), 3.12-3.21 (m, 4H),
1.75-1.80 (m, 4H), 1.64-1.69 (m, 2H). m/z (ESI) M+H: 442.2.
[0395] Step 3:
1-(4-(7-Chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(1-piperidinyl)-1-phthalazi-
nyl)-1-piperazinyl)-2-propen-1-one. Analogous to Example 12, step
3, the reaction of
2-(7-chloro-1-(piperazin-1-yl)-4-(piperidin-1-yl)phthalazin-6-yl)-3-fluor-
ophenol delivered
1-(4-(7-Chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(1-piperidinyl)-1-phthalazi-
nyl)-1-piperazinyl)-2-propen-1-one. .sup.1H NMR (CHLOROFORM-d)
.delta.: 8.08-8.15 (m, 1H), 7.98-8.05 (m, 1H), 7.29-7.39 (m, 1H),
6.86-6.94 (m, 1H), 6.76-6.85 (m, 1H), 6.59-6.70 (m, 1H), 6.30-6.43
(m, 1H), 5.72-5.84 (m, 1H), 3.77-4.05 (m, 4H), 3.40-3.56 (m, 4H),
3.32-3.38 (m, 4H), 1.73-1.85 (m, 4H), 1.64-1.70 (m, 2H). m/z (ESI)
M+H: 496.2.
Example 16
1-(4-(7-Chloro-6-(2-fluoro-6-hydroxyphenyl)-4-phenoxy-1-phthalazinyl)-1-pi-
perazinyl)-2-propen-1-one
##STR00701##
[0397] Step 1: tert-Butyl
4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-phenoxyphthalazin-1-yl)piperaz-
ine-1-carboxylate. A dry 50 mL rbf was charged with phenol (0.130
g, 1.381 mmol) and tetrahydrofuran (3.0 mL). The mixture was cooled
to 0.degree. C. before potassium t-butoxide (0.153 g, 1.367 mmol)
was added. The mixture was stirred at 0.degree. C. for 10 min
before being warmed tort and stirred for 30 min. tert-Butyl
4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthal-
azin-1-yl)piperazine-1-carboxylate (Intermediate H, 0.100 g, 0.137
mmol) was added, and the resulting mixture was heated at 60.degree.
C. for 2 h. The reaction was cooled to rt and quenched with water.
The resulting mixture was partitioned between EtOAc (30 mL) and
water (15 mL). The aqueous layer was extracted once more with EtOAc
(20 mL). The combined organic layers were dried over MgSO.sub.4,
filtered, and concentrated in vacuo. The crude product was purified
by column chromatography (40 g of silica, 10 to 50% acetone) to
obtain tert-butyl
4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-phenoxyphthalazin-1-yl)piperaz-
ine-1-carboxylate: m/z (ESI) M+H: 551.2.
[0398] Step 2:
2-(7-chloro-4-phenoxy-1-(piperazin-1-yl)phthalazin-6-yl)-3-fluorophenol.
Analogous to Example 12, step 2, the reaction of
4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-phenoxyphthalazin-1-yl)piperaz-
ine-1-carboxylate delivered.
2-(7-chloro-4-phenoxy-1-(piperazin-1-yl)phthalazin-6-yl)-3-fluorophenol.
.sup.1H NMR (CHLOROFORM-d) .delta.: 8.37-8.42 (m, 1H), 8.14-8.19
(m, 1H), 7.37-7.45 (m, 2H), 7.29-7.34 (m, 1H), 7.19-7.25 (m, 2H),
6.89-6.98 (m, 1H), 6.76-6.87 (m, 4H), 3.36-3.45 (m, 4H), 3.13-3.22
(m, 4H). m/z (ESI) M+H: 451.2.
[0399] Step 3:
1-(4-(7-Chloro-6-(2-fluoro-6-hydroxyphenyl)-4-phenoxy-1-phthalazinyl)-1-p-
iperazinyl)-2-propen-1-one. Analogous to Example 12, step 3, the
reaction of
2-(7-chloro-4-phenoxy-1-(piperazin-1-yl)phthalazin-6-yl)-3-fluoropheno-
l delivered
1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-phenoxy-1-phthalazinyl)-1-p-
iperazinyl)-2-propen-1-one. .sup.1H NMR (CHLOROFORM-d) .delta.:
8.41-8.45 (m, 1H), 8.17-8.20 (m, 1H), 7.40-7.45 (m, 2H), 7.28-7.37
(m, 2H), 7.20-7.26 (m, 1H), 6.78-6.87 (m, 2H), 6.59-6.70 (m, 1H),
6.31-6.41 (m, 1H), 5.97-6.06 (m, 1H), 5.74-5.81 (m, 1H), 3.76-4.03
(m, 4H), 3.38-3.53 (m, 4H). m/z (ESI) M+H: 505.2.
Examples 17-1 and 17-2
(2E)-1-(4-(5-Chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-
-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one (Example
17-1) and
(2E)-1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazo-
l-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one (Example
17-2)
##STR00702##
[0401] Step 1: tert-Butyl
4-(5-chloro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-
e-1-carboxylate. A slurry of tert-butyl
4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxyl-
ate (Intermediate D, 459 mg, 1.02 mmol),
(3-methoxynaphthalen-1-yl)boronic acid (823 mg, 4.07 mmol) and
cesium carbonate (1.33 g, 4.07 mmol) in a mixture of 1,4-dioxane (8
mL) and water (2 mL) was degassed with an argon stream.
Tetrakis(triphenylphosphine)palladium (118 mg, 0.10 mmol) was
added, and the mixture was again degassed with an Argon stream. The
reaction mixture was sealed and heated at 100.degree. C. for 23 h.
The reaction was allowed to cool to rt, diluted with brine (60 mL),
and extracted two times with EtOAc. The combined organic layers
were dried over anhydrous sodium sulfate and concentrated. The
residue was purified by silica gel chromatography (eluent: 0-2%
MeOH in DCM) to provide tert-butyl
4-(5-chloro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-
e-1-carboxylate. m/z (ESI) M+H: 528.0.
[0402] Step 2:
5-Chloro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)benzo[c]isothiazo-
le. To a solution of tert-butyl
4-(5-chloro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-
e-1-carboxylate (327 mg, 0.56 mmol) in DCM (6 mL) was added
trifluoroacetic acid (1.04 mL, 13.9 mmol) via syringe. The
resulting yellow solution was stirred at rt for 4 h and then was
concentrated. The residue was purified by silica gel chromatography
(eluent: 0-25% MeOH in DCM) to provide the mono-TFA salt of
5-chloro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)benzo[c]isothiazo-
le. m/z (ESI) M+H: 428.0.
[0403] Step 3:
(2E)-1-(4-(5-Chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazo-
l-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one. To a
solution of
5-chloro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)benzo[c]isothiazo-
le (74 mg of the mono-TFA salt, 0.14 mmol) and
trans-4-dimethylaminocrotonoic acid hydrochloride (38 mg, 0.23
mmol) in DMA (2 mL) was added thionyl chloride (41 Q L, 0.69 mmol)
via syringe. The resulting brown solution was stirred at rt for 2.5
h. The reaction mixture was quenched with water (50 mL) and
extracted with 8:1 DCM/MeOH. The organic layer was dried over
anhydrous sodium sulfate and concentrated. The residue was purified
by silica gel chromatography (eluent: 0-15% MeOH in DCM) to provide
(2E)-1-(4-(5-chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazo-
l-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.10 (s, 1H), 7.94 (d, J=8.4 Hz,
1H), 7.46-7.55 (m, 2H), 7.27-7.35 (m, 2H), 7.19 (d, J=2.5 Hz, 1H),
6.61-6.72 (m, 2H), 3.94 (s, 3H), 3.80-3.93 (m, 4H), 3.62-3.68 (m,
4H), 3.07 (d, J=4.3 Hz, 2H), 2.18 (s, 6H). m/z (ESI) M+H:
539.2.
[0404] Step 4:
(2E)-1-(4-(5-Chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazo-
l-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one. To a
solution of
(2E)-1-(4-(5-chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazo-
l-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one (23.5 mg,
0.044 mmol) in 1,2-dichloroethane (4 mL) at 0.degree. C. was added
boron tribromide (1.0 M in hexanes, 218 DL, 0.22 mmol) dropwise via
syringe. The resulting yellow slurry was stirred at 0.degree. C.
for 2.75 h and then quenched with saturated aqueous NaHCO.sub.3 (4
mL). The mixture was extracted two times with a 4:1 mixture of
DCM/MeOH. The combined organic layers were dried over anhydrous
sodium sulfate and concentrated. The residue was purified by silica
gel chromatography (eluent: 0-18% MeOH in DCM) to provide
(2E)-1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazo-
l-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.97 (s, 1H), 8.10 (s, 1H), 7.80
(d, J=8.4 Hz, 1H), 7.40-7.46 (m, 1H), 7.19-7.30 (m, 3H), 7.07 (d,
J=2.4 Hz, 1H), 6.62-6.71 (m, 2H), 3.80-3.93 (m, 4H), 3.62-3.69 (m,
4H), 3.07 (d, J=4.1 Hz, 2H), 2.17 (s, 6H). m/z (ESI) M+H:
525.0.
Examples 18-1 to 18-3
1-(4-(5-chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-3-yl-
)-1-piperazinyl)-2-(hydroxymethyl)-2-propen-1-one. (Example 18-1)
and
2-(bromomethyl)-1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1--
benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one (Example 18-2) and
1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-y-
l)-1-piperazinyl)-2-(hydroxymethyl)-2-propen-1-one (Example
18-3)
##STR00703##
[0406] Step 1:
1-(4-(5-Chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-3-y-
l)-1-piperazinyl)-2-(hydroxymethyl)-2-propen-1-one. A vial was
charged with a solution of
1-(4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3--
yl)piperazin-1-yl)prop-2-en-1-one (Intermediate O, 29 mg, 0.06
mmol) in tert-butanol (0.4 mL) and water (0.4 mL). Phenol (5.7 mg,
0.06 mmol), DABCO (20.3 mg, 0.18 mmol) and formaldehyde (37%
aqueous solution, 24 QL, 0.24 mmol) were added sequentially. The
resulting solution was sealed and heated at 55.degree. C. for 29 h.
The reaction was cooled to rt and partitioned between water (6 mL)
and 10:1 DCM/MeOH. The organic layer was separated, and the aqueous
layer was extracted two more times with 10:1 DCM/MeOH. The combined
organic layers were dried over anhydrous sodium sulfate and
concentrated. The residue was purified by silica gel chromatography
(eluent: 0-3.5% MeOH in DCM) to provide
1-(4-(5-chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-3-y-
l)-1-piperazinyl)-2-(hydroxymethyl)-2-propen-1-one. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.12 (s, 1H), 7.94 (d, J=8.2 Hz,
1H), 7.47-7.55 (m, 2H), 7.25-7.34 (m, 2H), 7.19 (d, J=2.5 Hz, 1H),
5.43 (br. s, 1H), 5.20 (br. s, 1H), 5.14 (t, J=5.8 Hz, 1H), 4.12
(d, J=5.7 Hz, 2H), 3.94 (s, 3H), 3.78-3.85 (m, 4H), 3.54-3.66 (m,
4H). m/z (ESI) M+H: 512.0.
[0407] Step 2:
2-(Bromomethyl)-1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1--
benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one and
1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-y-
l)-1-piperazinyl)-2-(hydroxymethyl)-2-propen-1-one. To a solution
of
1-(4-(5-chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-3-y-
l)-1-piperazinyl)-2-(hydroxymethyl)-2-propen-1-one (17.1 mg, 0.033
mmol) in 1,2-dichloroethane (4 mL) at 0.degree. C. was added boron
tribromide solution (1.0 M in hexanes, 167 QL, 0.17 mmol) dropwise
via syringe. The resulting slurry was stirred at 0.degree. C. for
40 min before being quenched with saturated aqueous NaHCO.sub.3 (5
mL). The mixture was extracted twice with a 4:1 mixture of
DCM/MeOH. The combined organic layers were dried over anhydrous
sodium sulfate and concentrated. The residue was purified by silica
gel chromatography (eluent: 0-7% MeOH in DCM) to give two
products.
[0408] First-eluting peak:
2-(bromomethyl)-1-(4-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo-
[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.96 (br. s, 1H), 8.13 (s, 1H), 7.80 (d,
J=8.2 Hz, 1H), 7.40-7.47 (m, 1H), 7.19-7.29 (m, 3H), 7.07 (d, J=2.4
Hz, 1H), 5.78 (s, 1H), 5.41 (s, 1H), 4.38 (s, 2H), 3.84-3.93 (m,
4H), 3.62-3.72 (m, 4H). m/z (ESI) M+H: 560.0
[0409] Second-eluting peak:
1-(4-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3--
yl)piperazin-1-yl)-2-(hydroxymethyl)prop-2-en-1-one. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.98 (br. s, 1H), 8.11 (s, 1H),
7.79 (d, J=8.2 Hz, 1H), 7.37-7.48 (m, 1H), 7.17-7.28 (m, 3H), 7.07
(d, J=2.4 Hz, 1H), 5.43 (br. s, 1H), 5.20 (br. s, 1H), 5.07-5.14
(m, 1H), 4.12 (br. s, 2H), 3.78-3.86 (m, 4H), 3.57-3.66 (m, 4H).
m/z (ESI) M+H: 498.0
Examples 19-1 to 19-3
1-(4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)-2,1-benzoth-
iazol-3-yl)-1-piperazinyl)-2-propen-1-one (Example 19-1) and
1-(4-(5-chloro-7-fluoro-6-(5-hydroxy-1-methyl-1H-indazol-7-yl)-2,1-benzot-
hiazol-3-yl)-1-piperazinyl)-2-propen-1-one (Example 19-2) and
1-(4-(5-chloro-7-fluoro-6-(5-hydroxy-2-methyl-2H-indazol-7-yl)-2,1-benzot-
hiazol-3-yl)-1-piperazinyl)-2-propen-1-one (Example 19-3)
##STR00704## ##STR00705## ##STR00706##
[0411] Step 1: tert-butyl
4-(5-chloro-7-fluoro-6-(5-methoxy-1H-indazol-7-yl)benzo[c]isothiazol-3-yl-
)piperazine-1-carboxylate. A slurry of Intermediate D (232 mg, 0.51
mmol),
5-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole
(535 mg, 1.95 mmol, see synthesis below) and cesium carbonate (636
mg, 1.95 mmol) in a mixture of 1,4-dioxane (8 mL) and water (2 mL)
was degassed with an Argon stream.
Tetrakis(triphenylphosphine)palladium (59 mg, 0.05 mmol) was added
and the mixture was again degassed with an Argon stream. The
reaction mixture was sealed and heated at 100.degree. C. for 18 h.
The reaction was allowed to cool to rt and partitioned between
brine (40 mL) and EtOAc. The aqueous later was twice extracted with
EtOAc and the combined organic layers were dried over anhydrous
sodium sulfate and concentrated. The residue was purified by silica
gel chromatography (eluent: 0-4.5% DCM/MeOH) to provide tert-butyl
4-(5-chloro-7-fluoro-6-(5-methoxy-1H-indazol-7-yl)benzo[c]isothiazol-3-yl-
)piperazine-1-carboxylate. LCMS-ESI (POS.) m/z: 518.2 (M+H).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.90 (br. s, 1H), 8.06
(s, 1H), 8.03 (s, 1H), 7.31 (d, J=1.4 Hz, 1H), 6.99 (d, J=2.2 Hz,
1H), 3.83 (s, 3H), 3.61-3.69 (m, 4H), 3.54-3.60 (m, 4H), 1.45 (s,
9H).
##STR00707##
[0412]
5-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazo-
le. A suspension of 7-bromo-5-methoxy-1H-indazole (1.00 g, 4.40
mmol, Ark Pharm Inc. Arlington Heights, Ill., USA), potassium
acetate (1.30 g, 13.2 mmol) and bis(pinocolato)diboron (1.23 g,
4.84 mmol) in 1,4-dioxane (18 mL) was degassed with an Argon
stream. Added
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) complex
with dichloromethane (108 mg, 0.13 mmol) and again degassed with an
Argon stream. The reaction mixture was sealed and heated at
80.degree. C. for 2 d. The reaction was allowed to cool to rt and
partitioned between water (50 mL) and EtOAc. The aqueous layer was
twice extracted with EtOAc and the combined organic layers were
dried over anhydrous sodium sulfate and concentrated. The residue
was purified by silica gel chromatography (eluent: 2-65%
EtOAc/heptane) to provide
5-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole.
LCMS-ESI (POS.) m/z: 275.1 (M+H).sup.+.
[0413] Step 2: tert-butyl
4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)benzo[c]isothi-
azol-3-yl)piperazine-1-carboxylate and tert-butyl
4-(5-chloro-7-fluoro-6-(5-methoxy-2-methyl-2H-indazol-7-yl)benzo[c]isothi-
azol-3-yl)piperazine-1-carboxylate. To a solution of tert-butyl
4-(5-chloro-7-fluoro-6-(5-methoxy-1H-indazol-7-yl)benzo[c]isothiazol-3-yl-
)piperazine-1-carboxylate (115 mg, 0.22 mmol) in THF (5 mL) was
added sodium hydride (60% dispersion in mineral oil, 44.5 mg, 1.1
mmol). After 10 min, iodomethane (69 Q L, 1.1 mmol) was added and
the reaction stirred at rt for an additional 15 min before being
partitioned between saturated aqueous ammonium chloride (10 mL) and
DCM. The aqueous layer was extracted twice with DCM and the
combined organic layers were dried over anhydrous sodium sulfate
and concentrated to afford a mixture of tert-butyl
4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)benzo[c]isothi-
azol-3-yl)piperazine-1-carboxylate and tert-butyl
4-(5-chloro-7-fluoro-6-(5-methoxy-2-methyl-2H-indazol-7-yl)benzo[c]isothi-
azol-3-yl)piperazine-1-carboxylate. The crude mixture was used in
the subsequent step without purification. LCMS-ESI (POS.) m/z:
532.0 (M+H).sup.+.
[0414] Step 3:
5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)-3-(piperazin-1-y-
l)benzo[c]isothiazole (Intermediate J) and
5-chloro-7-fluoro-6-(5-methoxy-2-methyl-2H-indazol-7-yl)-3-(piperazin-1-y-
l)benzo[c]isothiazole (Intermediate K). To a solution of the crude
mixture of mixture of tert-butyl
4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)benzo[c]isothi-
azol-3-yl)piperazine-1-carboxylate and tert-butyl
4-(5-chloro-7-fluoro-6-(5-methoxy-2-methyl-2H-indazol-7-yl)benzo[c]isothi-
azol-3-yl)piperazine-1-carboxylate (143 mg) in DCM (6 mL) was added
trifluoroacetic acid (484 DL, 6.5 mmol) via syringe. The resulting
solution was stirred at rt for 25 min and then was concentrated.
The residue was purified by silica gel chromatography (eluent:
0-25% DCM/MeOH).
[0415] First-eluting peak: The mono-TFA salt of
5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)-3-(piperazin-1-y-
l)benzo[c]isothiazole (Intermediate J). LCMS-ESI (POS.) m/z: 432.0
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.16 (s,
1H), 8.03 (s, 1H), 7.35 (d, J=2.4 Hz, 1H), 6.99 (d, J=2.4 Hz, 1H),
3.84 (s, 3H), 3.67-3.76 (m, 4H), 3.56 (s, 3H), 3.36-3.42 (m,
4H).
[0416] Second-eluting peak: The mono-TFA salt of
5-chloro-7-fluoro-6-(5-methoxy-2-methyl-2H-indazol-7-yl)-3-(piperazin-1-y-
l)benzo[c]isothiazole (Intermediate K). LCMS-ESI (POS.) m/z: 432.0
(M+H).sup.+.
[0417] Step 4:
1-(4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)-2,1-benzot-
hiazol-3-yl)-1-piperazinyl)-2-propen-1-one. To an ice-cooled slurry
of the mono-TFA salt of Intermediate J (108 mg, 0.20 mmol) in DCM
(5 mL) was added DIPEA (104 DL, 0.60 mmol) followed by acryloyl
chloride (24 DL, 0.30 mmol) dropwise via syringe. The resulting
solution was stirred at 0.degree. C. for 3 h and was then quenched
with saturated aqueous NaHCO.sub.3solution (15 mL) and extracted
twice with DCM. The combined organic layers were dried over
anhydrous sodium sulfate and concentrated. The residue was purified
by silica gel chromatography (eluent: 0-7% DCM/MeOH) to provide
1-(4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)-2,1-benzot-
hiazol-3-yl)-1-piperazinyl)-2-propen-1-one. LCMS-ESI (POS.) m/z:
486.0 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.13
(s, 1H), 8.02 (s, 1H), 7.33 (d, J=2.2 Hz, 1H), 6.99 (d, J=2.4 Hz,
1H), 6.85 (dd, J=16.6, 10.6 Hz, 1H), 6.18 (dd, J=16.7, 2.3 Hz, 1H),
5.76 (dd, J=10.5, 2.3 Hz, 1H), 3.85-3.95 (m, 4H), 3.84 (s, 3H),
3.62-3.72 (m, 4H), 3.56 (s, 3H).
[0418] Step 5:
1-(4-(5-chloro-7-fluoro-6-(5-hydroxy-1-methyl-1H-indazol-7-yl)-2,1-benzot-
hiazol-3-yl)-1-piperazinyl)-2-propen-1-one. To an ice-cooled
solution of
1-(4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)benzo[c]iso-
thiazol-3-yl)piperazin-1-yl)prop-2-en-1-one (72.5 mg, 0.15 mmol) in
1,2-dichloroethane (5 mL) was added boron tribromide solution (1.0
M in hexanes, 746 .quadrature.L, 0.75 mmol) dropwise via syringe.
The resulting slurry was stirred at 0.degree. C. for 3.75 h and was
then quenched with saturated aqueous NaHCO.sub.3solution (5 mL) and
extracted twice with a 4:1 mixture of DCM/MeOH. The combined
organic layers were dried over anhydrous sodium sulfate and
concentrated. The residue was purified by silica gel chromatography
(eluent: 0-6% DCM/MeOH) to provide
1-(4-(5-chloro-7-fluoro-6-(5-hydroxy-1-methyl-1H-indazol-7-yl)benzo[c]iso-
thiazol-3-yl)piperazin-1-yl)prop-2-en-1-one. LCMS-ESI (POS.) m/z:
472.0 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.40
(s, 1H), 8.12 (s, 1H), 7.92 (s, 1H), 7.12 (d, J=2.2 Hz, 1H),
6.81-6.91 (m, 2H), 6.18 (dd, J=16.7, 2.5 Hz, 1H), 5.76 (dd, J=10.4,
2.4 Hz, 1H), 3.81-3.94 (m, 4H), 3.62-3.70 (m, 4H), 3.52 (s,
3H).
[0419] For the synthesis of
1-(4-(5-chloro-7-fluoro-6-(5-hydroxy-2-methyl-2H-indazol-7-yl)-2,1-benzot-
hiazol-3-yl)-1-piperazinyl)-2-propen-1-one.
[0420] Using Intermediate K from Step 3, Steps 4 and 5 were
performed as above to deliver
1-(4-(5-chloro-7-fluoro-6-(5-hydroxy-2-methyl-2H-indazol-7-yl)-2,1-benzot-
hiazol-3-yl)-1-piperazinyl)-2-propen-1-one. LCMS-ESI (POS.) m/z:
472.0 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.28
(s, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 6.95 (d, J=2.0 Hz, 1H),
6.77-6.90 (m, 2H), 6.18 (dd, J=16.7, 2.5 Hz, 1H), 5.76 (dd, J=10.4,
2.2 Hz, 1H), 4.03 (s, 3H), 3.80-3.94 (m, 4H), 3.58-3.66 (m,
4H).
Example 20
1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl-
)-1-piperazinyl)-4-hydroxy-2-methylidene-1-butanone
##STR00708##
[0422] Step 1:
4-((tert-butyldiphenylsilyl)oxy)-1-(4-(5-chloro-7-fluoro-6-(3-methoxynaph-
thalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)-2-methylenebutan-1-one-
. To a solution of
4-((tert-butyldiphenylsilyl)oxy)-2-methylenebutanoic acid (101 mg,
0.29 mmol, prepared according to Pihko, P. M., J Org. Chem., 2006,
71, 2538-2541 and Greaney, M. F., Org. Lett., 2007, 9, 1931-1934)
in DCM (2 mL) was added a 2M solution of oxalyl chloride (0.21 mL,
0.43 mmol) at 0.degree. C. followed by a catalytic amount of DMF (5
.quadrature.L). The reaction mixture was allowed to warm to rt and
stirred for 2 h. The reaction mixture was concentrated in vacuo
then diluted with DCM (1 mL) and added to a solution of
5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)benzo[c]-
isothiazole (Intermediate N, 122 mg, 0.29 mmol), triethylamine
(0.20 mL, 1.43 mmol), and DCM (2 mL). The reaction mixture was
allowed to warm to rt and DMAP (2 mg, 0.016 mmol) was added. The
reaction mixture was stirred at rt for 15 h then concentrated in
vacuo and purified by silica gel column chromatography (eluent:
0-50% EtOAc:heptanes) to give
4-((tert-butyldiphenylsilyl)oxy)-1-(4-(5-chloro-7-fluoro-6-(3-methoxynaph-
thalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)-2-methylenebutan-1-one-
. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.06 (s, 1H), 7.94
(d, J=8.0 Hz, 1H), 7.63-7.61 (m, 4H), 7.52-7.49 (m, 2H), 7.47-7.40
(m, 6H), 7.33-7.28 (m, 2H), 7.20-7.19 (m, 1H), 5.37 (s, 1H), 5.24
(s, 1H), 3.94 (s, 3H), 3.83-3.76 (m, 6H), 3.53 (br s, 2H), 3.31 (s,
4H), 1.01 (s, 9H). m/z (ESI) M+H: 764.
[0423] Step 2:
1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-y-
l)-1-piperazinyl)-4-hydroxy-2-methylidene-1-butanone. To a solution
of
4-((tert-butyldiphenylsilyl)oxy)-1-(4-(5-chloro-7-fluoro-6-(3-methoxynaph-
thalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)-2-methylenebutan-1-one
(85 mg, 0.11 mmol) and DCM (2 mL) was added a 2M solution of
BBr.sub.3 (0.28 mL, 0.56 mmol) in DCM at 0.degree. C. The reaction
mixture was quenched with water, concentrated in vacuo and purified
by silica gel column chromatography (elution with 0-50% heptane/3:1
EtOAc:EtOH) to afford
1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothia-
zol-3-yl)-1-piperazinyl)-4-hydroxy-2-methylidene-1-butanone.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.93 (br s, 1H), 8.11
(s, 1H), 7.80 (d, J=12 Hz, 1H), 7.43 (m, 1H), 7.26-7.20 (m, 3H),
7.07 (s, 1H), 5.32 (s, 1H), 5.16 (s, 1H), 3.83 (br s, 4H), 3.63 (br
s, 4H), 3.53 (t, J=8.0 Hz, 2H), 2.42 (t, J=8.0 Hz, 2H). .sup.19FNMR
(377 MHz, DMSO-d.sub.6) .delta.-123.8 (s, 1F). m/z (ESI) M+H:
512.
Example 21
1-(4-(5-chloro-7-fluoro-6-(7-hydroxy-5-quinolinyl)-2,1-benzothiazol-3-yl)--
1-piperazinyl)-2-propen-1-one
##STR00709##
[0425]
1-(4-(5-chloro-7-fluoro-6-(7-hydroxy-5-quinolinyl)-2,1-benzothiazol-
-3-yl)-1-piperazinyl)-2-propen-1-one was made from Intermediate D
by Method 1 using
7-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline
(synthesis below) with the following changes: in Step 7, S-Phos Pd
G3, aqueous potassium carbonate, and DME were used; in Step 8-1,
TFA/DCM was used; in Step 8-2, DCE was used as solvent; and in Step
8-3, boron tribromide solution (1.0 M in DCE) was used to give
1-(4-(5-chloro-7-fluoro-6-(7-hydroxy-5-quinolinyl)-2,1-benzothiazol-3-yl)-
-1-piperazinyl)-2-propen-1-one. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.81 (dd, J=4.2, 1.3 Hz, 1H) 7.72-7.78 (m, 2H) 7.64 (s, 1H)
7.28 (d, J=2.2 Hz, 1H) 7.16 (dd, J=8.4, 4.3 Hz, 1H) 6.56-6.66 (m,
1H) 6.40 (dd, J=16.8, 1.6 Hz, 1H) 5.78-5.87 (m, 1H) 4.01 (br. s.,
2H) 3.89 (br. s., 2H) 3.50-3.60 (m, 4H). .sup.19F NMR (376 MHz,
CDCl.sub.3) 6-121.33 (s, 1 F). MS (ESI, +ve) m z: 469.1
(M+1).sup.+.
##STR00710##
[0426]
7-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline.
A solution of 5-bromo-7-methoxyquinoline (0.407 g, 1.71 mmol,
OxChem, Wood Dale, Ill., USA),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.912
g, 3.59 mmol), PdCl.sub.2(dppf) (0.051 g, 0.070 mmol), and
potassium acetate (0.503 g, 5.13 mmol) in DMF (9 mL) was stirred at
90.degree. C. for 1 h then at 100.degree. C. for 45 min. The
reaction mixture was diluted with EtOAc (100 mL), and washed with
saturated, aqueous sodium bicarbonate (2.times.75 mL). The organic
layer was separated, dried over anhydrous Na.sub.2SO.sub.4, and
concentrated in vacuo. The crude product was adsorbed onto silica
and purified via column chromatography (silica gel, 0-80%
heptane/EtOAc) to give
7-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline.
MS (ESI, +ve) m z: 286.1 (M+1).sup.+.
Example 22
1-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-4-
-(2-propenoyl)-2-piperazinecarboxylic acid
##STR00711##
[0428] To a solution of methyl
4-acryloyl-1-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isoth-
iazol-3-yl)piperazine-2-carboxylate (Example 7-3, 0.022 g, 0.042
mmol) in THF/EtOH (1:1; 6 mL) at 0.degree. C. was added NaOH (5 N
aq.; 1.0 mL, 5.0 mmol), and the resulting mixture was stirred at
0.degree. C. for 5 min. The reaction was acidified with 5 N HCl at
0.degree. C., extracted with EtOAc, and purified by HPLC to afford
1-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)--
4-(2-propenoyl)-2-piperazinecarboxylic acid. m/z (ESI, +ve) 512.0
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.14-3.28
(m, 1H) 3.52-3.87 (m, 3H) 4.15-5.03 (m, 2H) 5.15-5.23 (m, 1H)
5.77-5.83 (m, 1H) 6.13-6.24 (m, 1H) 6.86 (br. s., 1H) 7.06-7.12 (m,
1H) 7.20-7.30 (m, 3H) 7.38-7.49 (m, 1H) 7.76-7.84 (m, 1H) 8.07-8.13
(m, 1H) 9.98 (br. s., 1H) 13.42 (br. s., 1H).
Example 23
1-(4-(5-chloro-6-(5-cyclopropyl-1H-indazol-4-yl)-7-fluoro-2,1-benzothiazol-
-3-yl)-1-piperazinyl)-2-propen-1-one
##STR00712##
[0430] Example 23 was made as described in Method 1 using
(5-cyclopropyl-1H-indazol-4-yl)boronic acid (see synthesis below)
in Step 7, and omitting Step 8-3. m/z (ESI, +ve) 482.0 (M+H).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.92-13.19 (1H, m),
8.02-8.21 (1H, m), 7.47-7.60 (2H, m), 7.02-7.09 (1H, m), 6.80-6.93
(1H, m), 6.15-6.25 (1H, m), 5.71-5.82 (1H, m), 3.80-3.96 (4H, m),
3.60-3.72 (4H, m), 1.55-1.74 (1H, m), 0.72-0.79 (2H, m), 0.58-0.71
(2H, m).
(5-cyclopropyl-1H-indazol-4-yl)boronic acid
##STR00713##
[0432] Step 1: 2-bromo-1-cyclopropyl-4-fluorobenzene. To a 2-L
round bottom flask at ambient temperature was added
2-bromo-4-fluoro-1-iodobenzene (22 g, 73.1 mmol) and
cyclopropylboronic acid (12.6 g, 146 mmol) in cyclopentyl methyl
ether (1.1 L). Na.sub.2CO.sub.3 (2 M aq.; 183 mL) was added, and
the reaction was degassed with N2-gas for 20 minutes. Tetrakis
(8.45 g, 7.31 mmol) was added, and the reaction was degassed again
with N2-gas for 20 minutes. The reaction mixture was then
transferred to a 5-L autoclave under N2-atm and heated to
130.degree. C. for 40 h. The reaction mixture was cooled to ambient
temperature, filtered through a Celite pad, and washed with diethyl
ether (200 mL). To the filtrate was added water (500 mL), and the
organic layer was separated. The aqueous layer was extracted with
diethyl ether (2.times.300 mL), and the combined organic layers
were dried over anhydrous sodium sulfate and evaporated under
reduced pressure. The crude material was adsorbed onto a plug of
silica gel and chromatographically purified (silica gel, 100%
petroleum ether) to provide 2-bromo-1-cyclopropyl-4-fluorobenzene.
GC-MS m/z: 214/216 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.36-7.23 (m, 1H), 6.95 (dt, J=7.0, 1.5 Hz, 2H), 2.09 (ddd, J=13.8,
8.5, 5.4 Hz, 1H), 1.12-0.88 (m, 2H), 0.76-0.50 (m, 2H).
[0433] Step 2: 2-bromo-3-cyclopropyl-6-fluorobenzaldehyde. To a
500-mL round-bottom flask was added
2-bromo-1-cycloproyl-4-fluorobenzene (6.5 g, 30.2 mmol) in
tetrahydrofuran (130 mL) under N2-atm. LDA (18.1 mL, 36.3 mmol, 2 M
in THF, 1.2 equiv) was added dropwise at -78.degree. C. (internal
temperature maintained between -65.degree. C. to -70.degree. C.),
and the reaction mixture was stirred for 1 h. DMF (6 mL) was then
added dropwise to the reaction mixture (internal temperature
maintained between -65.degree. C. to -70.degree. C.), and the
reaction was stirred for a further 3 h at -78.degree. C. The
reaction was quenched with saturated aqueous ammonium chloride
solution (100 mL) and slowly warmed to ambient temperature. The
mixture was diluted with diethyl ether (200 mL), and the organic
layer separated and washed with a brine solution (2.times.50 mL).
The combined organic layers were dried over anhydrous
Na.sub.2SO.sub.4 and evaporated under reduced pressure. The crude
material was adsorbed onto a plug of silica gel and
chromatographically purified (silica gel, 0-2% EtOAc/hexane) to
provide 2-bromo-3-cyclopropyl-6-fluorobenzaldehyde. GC-MS m/z: 242
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.43 (d, J=1.5 Hz, 1H),
7.26-7.12 (m, 1H), 7.06 (t, J=9.3 Hz, 1H), 2.15 (td, J=8.4, 4.3 Hz,
1H), 1.17-0.94 (m, 2H), 0.78-0.52 (m, 2H).
[0434] Step 3: 4-bromo-5-cyclopropyl-1H-indazole. To a 100-mL
sealed tube was added 2-bromo-3-cyclopropyl-6-fluorobenzaldehyde (4
g, 16.5 mmol) and hydrazine hydrate (4.0 mL, 82 mmol) in ethylene
glycol (40 mL). The reaction was stirred for 2 h at 90.degree. C.
and then heated to 150.degree. C. for 16 h. The reaction mixture
was cooled to ambient temperature, and ice cold water (40 mL) and
EtOAc (50 mL) were added. The organic layer was separated and the
aqueous layer was extracted with EtOAc (2.times.40 mL). The
combined organic layers were washed with water (2.times.40 mL) and
brine solution (40 mL), dried over anhydrous aqueous sodium
sulfate, and concentrated in vacuo. The crude material was adsorbed
onto a plug of silica gel and chromatographically purified (silica
gel, 0-20% EtOAc/hexane) to provide
4-bromo-5-cyclopropyl-1H-indazole. The compound was purified by
reverse phase preparative liquid chromatography (YMC: C.sub.18,
150.times.20 mm, 5 pm; mobile phase: 0.1% TFA in water and
acetonitrile; flow rate: 15 mL/min) to afford pure compound. MS
(ESI positive ion) m/z: 237/239.0 (M+1). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 13.31 (s, 1H), 7.97 (s, 1H), 7.46 (d, J=8.6
Hz, 1H), 6.97 (d, J=8.6 Hz, 1H), 2.21 (tt, J=8.5, 5.3 Hz, 1H),
1.24-0.87 (m, 2H), 0.93-0.33 (m, 2H).
[0435] Step 4: 5-cyclopropyl-1H-indazol-4-yl)boronic acid. To a
100-mL round-bottomed flask was added
4-bromo-5-cyclopropyl-1H-indazole (0.62 g, 2.6 mmol) and
bis(pinacolato)diboron (0.996 g, 3.92 mmol) in 1,4-dioxane (25 mL);
potassium acetate (0.77 g, 7.84 mmol) was added, and the reaction
mixture was degassed with N2-gas for 10 minutes. PdCl.sub.2(dppf)
DCM adduct (0.213 g, 0.261 mmol) was added to the reaction mixture;
the reaction mixture was again degassed with N2-gas for 10 minutes
then heated to 100.degree. C. for 16 h. The reaction mixture was
cooled to ambient temperature, filtered through a Celite pad, and
washed with EtOAc (50 mL). The filtrate was concentrated in vacuo,
and the crude material was adsorbed onto a plug of silica gel and
chromatographically purified (silica gel, 0-50% EtOAc/hexane). The
compound was further purified by reverse phase preparative liquid
chromatography (Grace column; 0-70% MeCN/water) to provide
5-cyclopropyl-1H-indazol-4-yl)boronic acid. MS (ESI positive ion)
m/z: 285.2 (M+1). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.88
(s, 1H), 8.13 (q, J=1.3 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 6.83 (dd,
J=8.8, 1.4 Hz, 1H), 2.78-2.60 (m, 1H), 1.38 (d, J=1.4 Hz, 12H),
1.07-0.85 (m, 2H), 0.75-0.48 (m, 2H).
Example 24
1-(4-(5-Chloro-7-fluoro-6-(3-(methylamino)-1-isoquinolinyl)-2,1-benzothiaz-
ol-3-yl)-1-piperazinyl)-2-propen-1-one
##STR00714##
[0437] Step 1:
1-(5-Chloro-7-fluoro-3-(piperazin-1-yl)benzo[c]isothiazol-6-yl)-N-methyli-
soquinolin-3-amine. To a solution of tert-butyl
4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxyl-
ate (Intermediate D, 30 mg, 0.067 mmol) in tetrahydrofuran (0.6 mL)
at 0.degree. C. was added a solution of isopropylmagnesium chloride
(2.0 M solution in tetrahyrdofuran, 0.050 mL, 0.100 mmol). The
mixture was stirred for 5 min before zinc chloride (1.9 M solution
in 2-methyltetrahydrofuran, 0.053 mL, 0.100 mmol) was added, and
the reaction mixture was warmed to rt and stirred for 40 min. The
reaction mixture was then transferred to a vial containing Sphos Pd
G3 (5.76 mg, 6.66 .mu.mol) and tert-butyl
(1-bromoisoquinolin-3-yl)(methyl)carbamate (24.7 mg, 0.073 mmol,
see synthesis below) and heated to 70.degree. C. overnight. The
crude reaction was diluted with sat. aq. NH.sub.4Cl (50 mL) and
EtOAc (50 mL). The organic layer was separated, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification by
silica gel column chromatography eluting with 6-20% MeOH in DCM
afforded
1-(5-chloro-7-fluoro-3-(piperazin-1-yl)benzo[c]isothiazol-6-yl)-N-methyli-
soquinolin-3-amine. m/z (ESI, +ve) 428.1 (M+H).sup.+.
[0438] Synthesis of tert-butyl
(1-bromoisoquinolin-3-yl)(methyl)carbamate: To a solution of
1-bromoisoquinolin-3-amine (200 mg, 0.897 mmol, Maybridge Chemical
Co., Altrincham, UK) in tetrahydrofuran (5 mL) at rt was added
sodium bis(trimethylsilyl)amide (1M solution in tetrahydrofuran,
1.79 mL, 1.79 mmol). The mixture was stirred for 10 min before a
solution of Boc-anhydride (0.208 mL, 0.897 mmol) in THF (1 mL) was
added. The reaction mixture was stirred for 5 min before being
diluted with sat. aq. NH.sub.4Cl (50 mL) and EtOAc (50 mL). The
organic layer was separated, dried over Na.sub.2SO.sub.4, filtered,
and concentrated. Purification by silica gel column chromatography
eluting with 0-20% EtOAc in heptane afforded tert-butyl
(1-bromoisoquinolin-3-yl)carbamate. m/z (ESI, +ve) 345.0
(M+Na).sup.+.
[0439] To a solution of tert-butyl
(1-bromoisoquinolin-3-yl)carbamate (140 mg, 0.433 mmol) in
tetrahydrofuran (3 mL) at rt was added sodium hydride (60%
dispersion in mineral oil, 22.52 mg, 0.563 mmol). The mixture was
stirred for 15 min before methyl iodide (0.033 mL, 0.520 mmol) was
added. After stirring overnight the reaction was diluted with sat.
aq. NH.sub.4Cl (50 mL) and EtOAc (50 mL). The organic layer was
separated, dried over Na.sub.2SO.sub.4, filtered, and concentrated.
Purification by silica gel column chromatography eluting with 0-10%
EtOAc in heptane afforded tert-butyl
(1-bromoisoquinolin-3-yl)(methyl)carbamate. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 8.25 (d, J=8.61 Hz, 1H), 7.88-7.95 (m,
2H), 7.79 (t, J=7.5 Hz, 1H), 7.70 (t, J=7.6 Hz, 1H), 3.42 (s, 3H),
1.54 (s, 9H). m/z (ESI, +ve) 359.1 (M+H).sup.+.
[0440] Step 2:
1-(4-(5-Chloro-7-fluoro-6-(3-(methylamino)-1-isoquinolinyl)-2,1-benzothia-
zol-3-yl)-1-piperazinyl)-2-propen-1-one. Procedure analogous to
Method 1, Step 8-2. Purified by silica gel column chromatography
eluting with 0-14% MeOH in DCM over 15 min. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 7.90 (s, 1H), 7.63 (d, J=8.5 Hz, 1H),
7.43 (t, J=7.4 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 7.05 (t, J=7.4 Hz,
1H), 6.72-6.84 (m, 1H), 6.67 (s, 1H), 6.15-6.28 (m, 1H), 5.68-5.81
(m, 1H), 3.87-3.97 (m, 4H), 3.63 (m, 4H), 2.90 (s, 3H). m/z (ESI,
+ve) 482.0 (M+H).sup.+.
Example 25
1-(4-(6-(3-Amino-1-isoquinolinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-
-1-piperazinyl)-2-propen-1-one
##STR00715##
[0442] Step 1: tert-Butyl
4-(6-(3-((tert-butoxycarbonyl)amino)isoquinolin-1-yl)-5-chloro-7-fluorobe-
nzo[c]isothiazol-3-yl)piperazine-1-carboxylate. Procedure analogous
to Example 25, Step 1, using a solution of 1.3 M isopropylmagnesium
lithium chloride in THF in place of isopropylmagnesium chloride
solution and bis(2-methyl-2-propanyl)
(1-bromo-3-isoquinolinyl)-2-imidodicarbonate (synthesis below) in
place of tert-butyl (1-bromoisoquinolin-3-yl)(methyl)carbamate. m/z
(ESI, +ve) 614.2 (M+H).sup.+.
[0443] Synthesis of bis(2-methyl-2-propanyl)
(1-bromo-3-isoquinolinyl)-2-imidodicarbonate: To a solution of
1-bromoisoquinolin-3-amine (1.0 g, 4.48 mmol, Maybridge Chemical
Co., Altrincham, UK) in DCM (50 mL) at 0.degree. C. was added
Boc-anhydride (3.12 mL, 13.45 mmol) and DMAP (0.055 g, 0.448 mmol).
The reaction was warmed to rt and stirred overnight. The reaction
mixture was then diluted with sat. aq. NH.sub.4Cl (100 mL) and DCM
(50 mL). The organic layer was separated, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification by
silica gel column chromatography eluting with 0-10% EtOAc in
heptane over 15 min afforded bis(2-methyl-2-propanyl)
(1-bromo-3-isoquinolinyl)-2-imidodicarbonate. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 8.36 (d, J=8.5 Hz, 1H), 8.03 (d, J=8.1
Hz, 1H), 7.77-7.92 (m, 3H), 1.44 (s, 18H). m/z (ESI, +ve) 267.0
(M+H).sup.+.
[0444] Step 2:
1-(4-(6-(3-Amino-1-isoquinolinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl-
)-1-piperazinyl)-2-propen-1-one. Procedure analogous to Method 1,
Steps 8-1 and 8-2 with the use of TFA in DCM in place of 4M HCl in
dioxane/MeOH in Step 8-1. Purified by silica gel column
chromatography eluting with 0-12% MeOH in DCM. This material was
then subjected to SFC purification: diol column (21.2.times.250 mm,
5 pm) using 17% (20 mM NH.sub.3 in MeOH) in supercritical CO.sub.2
(total flow rate was 7 g/min) to afford
1-(4-(6-(3-amino-1-isoquinolinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl-
)-1-piperazinyl)-2-propen-1-one. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 7.85 (s, 1H), 7.53 (d, J=8.5 Hz, 1H),
7.39 (t, J=7.6 Hz, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.03 (t, J=7.8 Hz,
1H), 6.82 (s, 1H), 6.71 (dd, J=10.8, 16.8 Hz, 1H), 6.2 (dd, J=1.5,
16.8 Hz, 1H), 5.70 (dd, J=1.5, 10.8 Hz, 1H), 3.82-3.93 (m, 4H),
3.50-3.66 (m, 4H). m/z (ESI, +ve) 468.0 (M+H).sup.+.
Example 26
1-(4-(6-(2-Amino-4-quinolinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-1--
piperazinyl)-2-propen-1-one
##STR00716##
[0446] Step 1: tert-Butyl
4-(5-chloro-7-fluoro-6-(tributylstannyl)benzo[c]isothiazol-3-yl)piperazin-
e-1-carboxylate. A solution of tert-butyl
4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxyl-
ate (Intermediate D, 320 mg, 0.710 mmol),
1,1,1,2,2,2-hexabutyldistannane (824 mg, 1.420 mmol), and
tetrakis(triphenylphosphine)palladium(0) (82 mg, 0.071 mmol, Strem
Chemicals Inc., NewburyPort, Mass., USA) in N,N-dimethylacetamide
(5 mL) was heated in a sealed vial in the microwave at 160.degree.
C. for 40 min. The reaction mixture was diluted with sat. aq.
NaHCO.sub.3 (50 mL), brine (50 mL) and EtOAc (100 mL). The organic
layer separated, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Purification by silica gel column chromatography
eluting with 0-30% EtOAc in heptane afforded tert-butyl
4-(5-chloro-7-fluoro-6-(tributylstannyl)benzo[c]isothiazol-3-yl)piperazin-
e-1-carboxylate. m/z (ESI, +ve) 662.2 (M+H).sup.+.
[0447] Step 2: 2-Methyl-2-propanyl
4-(6-(2-(bis(((2-methyl-2-propanyl)oxy)carbonyl)amino)-4-quinolinyl)-5-ch-
loro-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinecarboxylate. A
solution of di-tert-butyl (4-bromoquinolin-2-yl)-2-imidodicarbonate
(19.2 mg, 0.045 mmol, prepared in analogous fashion to
bis(2-methyl-2-propanyl)
(1-bromo-3-isoquinolinyl)-2-imidodicarbonate in Example 26 using
4-bromoquinolin-2-amine (Ark Pharm Inc. Arlington Heights, Ill.,
USA) as starting material, tert-butyl
4-(5-chloro-7-fluoro-6-(tributylstannyl)benzo[c]isothiazol-3-yl)piperazin-
e-1-carboxylate (20 mg, 0.030 mmol),
tetrakis(triphenylphosphine)palladium(0) (6.99 mg, 6.05 .mu.mol,
Strem Chemicals Inc., NewburyPort, Mass., USA), copper(I) iodide
(1.153 mg, 6.05 .mu.mol) and cesium fluoride (13.79 mg, 0.091 mmol)
in DMF (0.5 mL) was heated in a sealed vial at 60.degree. C. for 30
min. The crude reaction was diluted with sat. aq. NaHCO.sub.3 (50
mL) and EtOAc (100 mL). The organic layer was separated, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification by
silica gel column chromatography eluting with 0-50% EtOAc in
heptane afforded 2-methyl-2-propanyl
4-(6-(2-(bis(((2-methyl-2-propanyl)oxy)carbonyl)amino)-4-quinolinyl)-5-ch-
loro-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinecarboxylate. m/z
(ESI, +ve) 714.2 (M+H).sup.+.
[0448] Step 3:
1-(4-(6-(2-amino-4-quinolinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-1-
-piperazinyl)-2-propen-1-one. Procedure analogous to Method 1,
Steps 8-1 and 8-2 with the use of TFA in DCM in place of 4 M HCl in
dioxane/MeOH in Step 8-1. .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
.delta. 7.90 (s, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.42-7.49 (m, 1H),
7.10 (d, J=8.0 Hz, 1H), 7.03-7.08 (m, J=7.6 Hz, 1H), 6.67-6.81 (m,
2H), 6.19 (dd, J=1.8, 16.6 Hz, 1H), 5.72 (dd, J=1.8, 10.6 Hz, 1H),
3.87-3.93 (m, 4H), 3.56-3.66 (m, 4H). m/z (ESI, +ve) 468.0
(M+H).sup.+.
Example 27
1-(4-(3-(2-Fluoro-6-hydroxyphenyl)-2-methyl-5-(2-(2-propanyl)phenyl)pyrido-
[2,3-d]pyridazin-8-yl)-1-piperazinyl)-2-propen-1-one
##STR00717## ##STR00718##
[0450] Step 1: 6,7-Dihydropyrido[2,3-d]pyridazine-5,8-dione.
Hydrazine (1.26 mL, 40.2 mmol) was added to a stirred solution of
2,3-pyridinedicarboxylic anhydride (4.00 g, 26.8 mmol) in ethanol
(100 mL). The reaction mixture was refluxed for 16 h before being
cooled to rt and concentrated in vacuo to give crude
6,7-dihydropyrido[2,3-d]pyridazine-5,8-dione that was used directly
in the next step. m/z (ESI) M+H: 164.1.
[0451] Step 2: 5,8-Dichloropyrido[2,3-d]pyridazine. Pyridine (4.57
mL, 53.7 mmol) was added to a mixture of crude
6,7-dihydropyrido[2,3-d]pyridazine-5,8-dione (4.38 g, 26.8 mmol) in
phosphorus (v) oxychloride (20.1 mL, 215 mmol). The reaction
mixture was stirred at 100.degree. C. for 2 h. The reaction mixture
was cooled and poured slowly into rapidly stirred water (250 mL) at
-10.degree. C. The aqueous suspension was stirred for 15 min before
being extracted with EtOAc (250 mL). The organic layer was
separated, washed with brine (200 mL), dried over MgSO.sub.4,
filtered, and concentrated in vacuo. Chromatographic purification
of the residue (silica gel, 0 to 100% EtOAc in heptane) gave
5,8-dichloropyrido[2,3-d]pyridazine. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 9.41 (1H, dd, J=4.30, 1.56 Hz) 8.65 (1H, dd,
J=8.41, 1.56 Hz) 8.02 (1H, dd, J=8.41, 4.30 Hz). m/z (ESI) M+H:
200.0.
[0452] Step 3: 3,5-Dichloropyrido[2,3-d]pyridazin-8(7H)-one and
3,8-dichloropyrido[2,3-d]pyridazin-5(6H)-one. N-Chlorosuccinimide
(1268 mg, 9.50 mmol, TCI America, Portland, Oreg., USA) was added
to a stirred solution of 5,8-dichloropyrido[2,3-d]pyridazine (950
mg, 4.75 mmol) in acetic acid (20 mL) and the reaction mixture was
heated to 100.degree. C. for 16 h. Additional N-chlorosuccinimide
(1268 mg, 9.50 mmol, TCI America, Portland, Oreg., USA) was added,
and the reaction mixture was stirred at 100.degree. C. for another
4 h. Additional N-chlorosuccinimide (634 mg, 4.75 mmol, TCI
America, Portland, Oreg., USA) was added, and the reaction mixture
was stirred for another 4 h. The reaction mixture was then diluted
with water (75 mL) and extracted three times with EtOAc (100 mL).
The combined organic layers were washed with brine (150 mL), dried
over MgSO.sub.4, filtered, and concentrated in vacuo.
Chromatographic purification of the residue (silica gel, 0 to 75%
EtOAc in heptane) gave a regioisomeric mixture of
3,5-dichloropyrido[2,3-d]pyridazin-8(7H)-one compound and
3,8-dichloropyrido[2,3-d]pyridazin-5(6H)-one. m/z (ESI) M+H:
215.9.
[0453] Step 4: 3,5,8-Trichloropyrido[2,3-d]pyridazine. Pyridine
(2.024 mL, 23.79 mmol) was added to the regioisomeric mixture of
3,5-dichloropyrido[2,3-d]pyridazin-8(7H)-one and
3,8-dichloropyrido[2,3-d]pyridazin-5(6H)-one (2.57 g, 11.90 mmol)
in phosphorus oxychloride (8.90 mL, 95 mmol). The reaction mixture
was stirred at 100.degree. C. for 1.5 h. The reaction mixture was
cooled and poured slowly into rapidly stirred water (150 mL) at
-10.degree. C. The aqueous suspension was stirred for 15 min before
being extracted with EtOAc (200 mL). The organic layer was
separated, washed with brine (150 mL), dried over MgSO.sub.4,
filtered, and concentrated in vacuo. Chromatographic purification
of the residue (silica gel, 0 to 50% EtOAc in heptane) gave
3,5,8-trichloropyrido[2,3-d]pyridazine. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 9.27 (1H, d, J=2.35 Hz) 8.58 (1H, d, J=2.35
Hz). m/z (ESI) M+H: 233.9.
[0454] Step 5: tert-Butyl
4-(3,5-dichloropyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate.
1-Boc-piperazine (278 mg, 1.494 mmol) was added to a stirred
mixture of 3,5,8-trichloropyrido[2,3-d]pyridazine (292 mg, 1.245
mmol) and triethylamine (0.350 mL, 2.491 mmol) in dimethyl
sulfoxide (5 mL). The reaction mixture was stirred at rt for 3 h
before being diluted with EtOAc (75 mL), and washed with saturated
aqueous sodium bicarbonate (75 mL). The organic layer was
separated, washed with brine (50 mL), dried over MgSO.sub.4,
filtered, and concentrated in vacuo. Chromatographic purification
of the residue (silica gel, 0 to 25% acetone in heptane) gave
tert-butyl
4-(3,5-dichloropyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate,
the first of two regioisomers to elute. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 9.01 (1H, d, J=2.54 Hz) 8.43 (1H, d, J=2.54
Hz) 4.04-4.15 (4H, m) 3.64-3.70 (4H, m) 1.50 (9H, s). m/z (ESI)
M+H: 384.0.
[0455] Step 6: tert-Butyl
4-(3-chloro-5-(2-isopropylphenyl)pyrido[2,3-d]pyridazin-8-yl)piperazine-1-
-carboxylate. tert-Butyl
4-(3,5-dichloropyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate
(199 mg, 0.518 mmol), 2-isopropylphenylboronic acid (93 mg, 0.570
mmol, Alfa Aesar, Haver Hill, Mass., USA),
tetrakis(triphenylphosphine)palladium (59.8 mg, 0.052 mmol, Strem
Chemicals Inc., NewburyPort, Mass., USA), and sodium carbonate (2 M
aqueous, 1.036 mL, 2.072 mmol) were mixed in 1,4-dioxane (4 mL)
under an argon atmosphere. The reaction mixture was stirred at
40.degree. C. for 16 h. The reaction mixture was cooled to rt,
diluted with EtOAc (50 mL), and washed with water (40 mL). The
organic layer was separated, washed with brine (50 mL), dried over
MgSO.sub.4, filtered, and concentrated in vacuo. Chromatographic
purification of the residue (silica gel, 0 to 50% EtOAc in heptane)
gave a mixture of starting material and desired product. The
mixture was re-subjected to the original reaction conditions using
less 2-isopropylphenylboronic acid (56 mg, 0.342 mmol, Alfa Aesar,
Haver Hill, Mass., USA). The mixture was stirred at 40.degree. C.
for 16 h. Additional 2-isopropylphenylboronic acid (28 mg, 0.171
mmol, Alfa Aesar, Haver Hill, Mass., USA) was added, and the
reaction mixture was stirred for another 6 h. The reaction mixture
was cooled to rt, diluted with EtOAc (50 mL), and washed with water
(40 mL). The organic layer was separated, washed with brine (50
mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo.
Chromatographic purification of the residue (silica gel, 0 to 50%
EtOAc in heptane) gave tert-butyl
4-(3-chloro-5-(2-isopropylphenyl)pyrido[2,3-d]pyridazin-8-yl)piperazine-1-
-carboxylate. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.95 (1H,
d, J=2.35 Hz) 7.72 (1H, d, J=2.54 Hz) 7.45-7.53 (2H, m) 7.26-7.33
(1H, m) 7.16-7.21 (1H, m) 4.04-4.23 (4H, m) 3.66-3.73 (4H, m) 2.67
(1H, spt, J=6.75 Hz) 1.48 (9H, s) 1.16 (3H, d, J=6.85 Hz) 1.03 (3H,
d, J=6.85 Hz). m/z (ESI) M+H: 468.2.
[0456] Step 7: tert-Butyl
4-(3-chloro-5-(2-isopropylphenyl)-2-methylpyrido[2,3-d]pyridazin-8-yl)pip-
erazine-1-carboxylate. Methyllithium (1.6 M solution in diethyl
ether, 0.137 mL, 0.219 mmol) was added to a stirred solution of
tert-butyl
4-(3-chloro-5-(2-isopropylphenyl)pyrido[2,3-d]pyridazin-8-yl)piperazine-1-
-carboxylate (93 mg, 0.199 mmol) in tetrahydrofuran (1 mL) at
-78.degree. C. The reaction mixture was stirred at -78.degree. C.
for 5 min before being allowed to warm to 0.degree. C. and stirred
for 30 min. The reaction mixture was cooled back down to
-78.degree. C. and additional methyllithium (1.6 M solution in
diethyl ether, 0.068 mL, 0.109 mmol) was added. The reaction
mixture was stirred at -78.degree. C. for 5 min before being
allowed to warm to 0.degree. C. and stirred for another 15 min. The
reaction mixture was quenched with water (20 mL) and extracted with
EtOAc (30 mL). The organic layer was separated, washed with brine
(20 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo
to give crude tert-butyl
4-(3-chloro-5-(2-isopropylphenyl)-2-methyl-1,2-dihydropyrido[2,3-d]pyrida-
zin-8-yl)piperazine-1-carboxylate. m/z (ESI) M+H: 484.3.
[0457] 4,5-Dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile
(45.0 mg, 0.198 mmol) was added to a stirred mixture of crude
tert-butyl
4-(3-chloro-5-(2-isopropylphenyl)-2-methyl-1,2-dihydropyrido[2,3-d]pyrida-
zin-8-yl)piperazine-1-carboxylate (96 mg, 0.198 mmol) in
dichloromethane (2 mL). The reaction mixture was stirred at rt for
10 min. The reaction mixture was diluted with DCM (30 mL) and
washed with water (20 mL). The organic layer was separated, dried
over MgSO.sub.4, filtered, and concentrated in vacuo.
Chromatographic purification of the residue (silica gel, 0 to 50%
EtOAc in heptane) gave tert-butyl
4-(3-chloro-5-(2-isopropylphenyl)-2-methylpyrido[2,3-d]pyridazin-8-yl)pip-
erazine-1-carboxylate. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
7.72 (1H, s) 7.51-7.55 (2H, m) 7.32-7.37 (1H, m) 7.22-7.27 (1H, m)
4.08-4.25 (4H, m) 3.71-3.79 (4H, m) 2.87 (3H, s) 2.73 (1H, spt,
J=6.68 Hz) 1.54 (9H, s) 1.21 (3H, d, J=6.85 Hz) 1.07 (3H, d, J=6.85
Hz). m/z (ESI) M+H: 482.1.
[0458] Step 8: tert-Butyl
4-(3-(2-fluoro-6-hydroxyphenyl)-5-(2-isopropylphenyl)-2-methylpyrido[2,3--
d]pyridazin-8-yl)piperazine-1-carboxylate. tert-Butyl
4-(3-chloro-5-(2-isopropylphenyl)-2-methylpyrido[2,3-d]pyridazin-8-yl)pip-
erazine-1-carboxylate (78 mg, 0.162 mmol),
(2-fluoro-6-hydroxyphenyl)boronic acid (101 mg, 0.647 mmol,
Combi-Blocks), Sphos Pd G3 (14.00 mg, 0.016 mmol) and sodium
carbonate (2 M aqueous, 0.324 mL, 0.647 mmol) were mixed in
1,2-dimethoxyethane (1 mL) under an argon atmosphere and then
heated at 80.degree. C. for 2.5 h. The reaction mixture was cooled,
diluted with EtOAc (30 mL), and washed with water (25 mL). The
organic layer was separated, washed with brine (25 mL), dried over
MgSO.sub.4, filtered, and concentrated in vacuo. Chromatographic
purification of the residue (silica gel, 0 to 50% EtOAc in heptane)
gave tert-butyl
4-(3-(2-fluoro-6-hydroxyphenyl)-5-(2-isopropylphenyl)-2-methylpyrido[2,3--
d]pyridazin-8-yl)piperazine-1-carboxylate (66 mg, 0.118 mmol, 73.1%
yield). m/z (ESI) M+H: 558.2.
[0459] Step 9:
3-Fluoro-2-(5-(2-isopropylphenyl)-2-methyl-8-(piperazin-1-yl)pyrido[2,3-d-
]pyridazin-3-yl)phenol. Trifluoroacetic acid (0.2 mL, 2.68 mmol)
was added to a stirred solution of tert-butyl
4-(3-(2-fluoro-6-hydroxyphenyl)-5-(2-isopropylphenyl)-2-methylpyrido[2,3--
d]pyridazin-8-yl)piperazine-1-carboxylate (64 mg, 0.115 mmol) in
dichloromethane (0.5 mL). The reaction mixture was stirred at rt
for 30 min. The reaction mixture was diluted with DCM (30 mL) and
quenched with saturated aqueous sodium bicarbonate (20 mL). The
organic layer was separated, dried over MgSO.sub.4, filtered, and
concentrated in vacuo to give crude
3-fluoro-2-(5-(2-isopropylphenyl)-2-methyl-8-(piperazin-1-yl)pyrido[2,3-d-
]pyridazin-3-yl)phenol. m/z (ESI) M+H: 458.1.
[0460] Step 10:
1-(4-(3-(2-Fluoro-6-hydroxyphenyl)-5-(2-isopropylphenyl)-2-methylpyrido[2-
,3-d]pyridazin-8-yl)piperazin-1-yl)prop-2-en-1-one. Acryloyl
chloride (9.45 .mu.l, 0.116 mmol) was added to a stirred mixture of
3-fluoro-2-(5-(2-isopropylphenyl)-2-methyl-8-(piperazin-1-yl)pyrido[2,3-d-
]pyridazin-3-yl)phenol (53 mg, 0.116 mmol) and triethylamine (0.049
mL, 0.348 mmol) in dichloromethane (1 mL) at 0.degree. C. The
reaction mixture was stirred at 0.degree. C. for 10 min. The
reaction mixture was diluted with DCM (25 mL) and quenched with
saturated aqueous sodium bicarbonate (20 mL). The organic layer was
separated, dried over MgSO.sub.4, filtered, and concentrated in
vacuo. Chromatographic purification of the residue (silica gel, 0
to 100% EtOAc in heptane) gave
1-(4-(3-(2-fluoro-6-hydroxyphenyl)-2-methyl-5-(2-(2-propanyl)phenyl)pyrid-
o[2,3-d]pyridazin-8-yl)-1-piperazinyl)-2-propen-1-one. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 9.51 (0.6H, br s) 8.98 (0.4H, br s)
7.63 (0.4H, s) 7.58 (0.6H, s) 7.35-7.43 (2H, m) 7.10-7.26 (3H, m)
6.78 (1H, dd, J=16.63, 8.22 Hz) 6.59-6.71 (2H, m) 6.36 (1H, dd,
J=16.82, 1.57 Hz) 5.78 (1H, dd, J=10.56, 1.37 Hz).sub.4.10-4.38
(4H, m).sub.3.80-4.03 (4H, m).sub.2.60-2.72 (1H, m).sub.2.61 (1.2H,
s) 2.59 (1.8H, s) 0.91-1.08 (6H, m). m/z (ESI) M+H: 512.3.
Example 28
1-(4-(7-Chloro-6-(2-fluoro-6-hydroxyphenyl)-4-((1R)-1-phenylethyl)-1-phtha-
lazinyl)-1-piperazinyl)-2-propen-1-one and
1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-((1S)-1-phenylethyl)-1-phth-
alazinyl)-1-piperazinyl)-2-propen-1-one
##STR00719##
[0462] A mixture of .alpha.-methylbenzylzinc bromide (0.5 M in THF,
492 .mu.l, 0.246 mmol), tetrakis(triphenylphosphine)palladium (5.68
mg, 4.92 .mu.mol, Strem Chemicals Inc., NewburyPort, Mass., USA),
and
1-(4-(4,7-dichloro-6-(2-fluoro-6-hydroxyphenyl)phthalazin-1-yl)piperazin--
1-yl)prop-2-en-1-one (Intermediate I, 22 mg, 0.049 mmol) was
stirred at 60.degree. C. in a sealed vial for 16 h. The reaction
mixture was concentrated and chromatographic purification of the
residue (silica gel, 0 to 100% EtOAc in heptane) gave a mixture of
1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-((1R)-1-phenylethyl)-1-phth-
alazinyl)-1-piperazinyl)-2-propen-1-one and
1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-((1S)-1-phenylethyl)-1-phth-
alazinyl)-1-piperazinyl)-2-propen-1-one. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 8.27 (1H, s) 8.15 (0.33H, s) 8.10 (0.67H,
s) 7.19-7.31 (5H, m) 7.10-7.16 (1H, m) 6.86 (1H, dd, J=16.73, 10.66
Hz) 6.62-6.78 (2H, m) 6.27 (1H, dd, J=16.82, 1.96 Hz) 5.80 (1H, dd,
J=10.66, 1.86 Hz) 4.94-5.01 (1H, m) 3.93-4.03 (4H, m) 3.49-3.60
(4H, m) 1.81 (3H, d, J=7.04 Hz). m/z (ESI) M+H: 517.1.
Example 29
1-(4-(7-Chloro-4-(4-fluorobenzyl)-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazi-
nyl)-1-piperazinyl)-2-propen-1-one
##STR00720##
[0464] 4-Fluorobenzylzinc chloride (0.5 M in THF, 0.089 mL, 0.044
mmol) was added to a stirred mixture of
1-(4-(4,7-dichloro-6-(2-fluoro-6-hydroxyphenyl)phthalazin-1-yl)piperazin--
1-yl)prop-2-en-1-one (Intermediate I, 18 mg, 0.040 mmol) and
tetrakis(triphenylphosphine)palladium (4.65 mg, 4.02 .mu.mol, Strem
Chemicals Inc., NewburyPort, Mass., USA) in tetrahydrofuran (0.1
mL) in a sealed vial under an argon atmosphere. The reaction
mixture was stirred at rt for 2 h before being heated to 40.degree.
C. for 3 h. Additional 4-fluorobenzylzinc chloride (0.089 mL, 0.044
mmol) was added, and the reaction mixture was stirred at 40.degree.
C. for another 16 h. Additional 4-fluorobenzylzinc chloride (0.089
mL, 0.044 mmol) was added, and the reaction mixture was heated to
60.degree. C. and stirred for 6 h. The reaction mixture was
concentrated in vacuo. Chromatographic purification of the residue
(silica gel, 0 to 100% EtOAc in heptane) gave
1-(4-(7-chloro-4-(4-fluorobenzyl)-6-(2-fluoro-6-hydroxyphenyl)-1-phthalaz-
inyl)-1-piperazinyl)-2-propen-1-one. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 8.32 (1H, s) 8.19 (1H, s) 7.26-7.34 (3H,
m) 6.98 (2H, t, J=8.71 Hz) 6.69-6.91 (3H, m) 6.28 (1H, dd, J=16.92,
1.86 Hz) 5.82 (1H, dd, J=10.56, 1.76 Hz) 4.54-4.65 (2H, m) 3.99
(4H, m) 3.58 (4H, m). m/z (ESI) M+H: 521.2.
Examples 30 and 31
2-(1-(4-Acryloyl-1-piperazinyl)-7-chloro-4-phenyl-6-phthalazinyl)-3-fluoro-
phenol (Example 30) and
2-(4-(4-acryloyl-1-piperazinyl)-7-chloro-1-phenyl-6-phthalazinyl)-3-fluor-
ophenol (Example 31)
##STR00721## ##STR00722##
[0466] Step 1: 1,4,6,7-Tetrachlorophthalazine (Intermediate L).
Pyridine (431 .mu.l, 5.28 mmol) was added to a stirred mixture of
6,7-dichloro-2,3-dihydrophthalazine-1,4-dione (Intermediate G, 610
mg, 2.64 mmol) in phosphorus oxychloride (2.4 mL, 26.4 mmol). The
reaction mixture was heated to 100.degree. C. for 2 h then cooled
and poured slowly into rapidly stirred water (75 mL) at -10.degree.
C. The resulting suspension was filtered, and the solid was washed
with water to give 1,4,6,7-tetrachlorophthalazine. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 8.43 (2H, s). m/z (ESI) M+H: 266.9.
[0467] Step 2: tert-Butyl
4-(4,6,7-trichlorophthalazin-1-yl)piperazine-1-carboxylate
(Intermediate M). 1-Boc-piperazine (340 mg, 1.824 mmol) was added
to a stirred mixture of 1,4,6,7-tetrachlorophthalazine
(Intermediate L, 543 mg, 2.027 mmol) and triethylamine (0.846 mL,
6.08 mmol) in dichloromethane (8 mL). The reaction mixture was
stirred at rt for 2 days. Additional 1-boc-piperazine (340 mg,
1.824 mmol) was added, and the reaction mixture was stirred at rt
for another 23 h. The reaction mixture was quenched with saturated
aqueous sodium bicarbonate (20 mL) and extracted with DCM (30 mL).
The organic layer was separated, washed with brine (20 mL), dried
over MgSO.sub.4, filtered, and concentrated in vacuo.
Chromatographic purification of the residue (silica gel, 0 to 50%
EtOAc in heptane) gave tert-butyl
4-(4,6,7-trichlorophthalazin-1-yl)piperazine-1-carboxylate. .sup.1H
NMR (400 MHz, Chloroform-d) .delta. 8.35 (1H, s) 8.12 (1H, s)
3.68-3.75 (4H, m) 3.45-3.52 (4H, m) 1.51 (9H, s). m/z (ESI) M+H:
417.0.
[0468] Step 3: tert-Butyl
4-(6,7-dichloro-4-phenylphthalazin-1-yl)piperazine-1-carboxylate.
tert-Butyl
4-(4,6,7-trichlorophthalazin-1-yl)piperazine-1-carboxylate
(Intermediate M, 95 mg, 0.227 mmol),
tetrakis(triphenylphosphine)palladium (26.3 mg, 0.023 mmol, Strem
Chemicals Inc., NewburyPort, Mass., USA), phenylboronic acid (27.7
mg, 0.227 mmol), and sodium carbonate (2 M aqueous, 0.341 mL, 0.682
mmol) were mixed in 1,4-dioxane (1 mL) in a sealed vial under an
argon atmosphere. The reaction mixture was stirred at 40.degree. C.
for 24 h. Additional tetrakis(triphenylphosphine)palladium (26.3
mg, 0.023 mmol) and phenylboronic acid (13.5 mg, 0.113 mmol) were
added, and the reaction mixture was stirred at 40.degree. C. for
another 24 h. The reaction mixture was quenched with saturated
aqueous sodium bicarbonate (20 mL) and extracted with EtOAc (25
mL). The organic layer was separated, washed with brine (20 mL),
dried over MgSO.sub.4, filtered, and concentrated in vacuo.
Chromatographic purification of the residue (silica gel, 0 to 100%
EtOAc in heptane) gave tert-butyl
4-(6,7-dichloro-4-phenylphthalazin-1-yl)piperazine-1-carboxylate.
.sup.1H NMR (400 MHz, Chloroform-d) .delta. 8.13 (1H, s) 8.07 (1H,
s) 7.62-7.67 (2H, m) 7.50-7.55 (3H, m) 3.65-3.74 (4H, m) 3.44-3.53
(4H, m) 1.47 (9H, s). m/z (ESI) M+H: 459.1.
[0469] Step 4: 6,7-Dichloro-1-phenyl-4-(piperazin-1-yl)phthalazine.
tert-Butyl
4-(6,7-dichloro-4-phenylphthalazin-1-yl)piperazine-1-carboxylate
(68 mg, 0.148 mmol) was stirred in trifluoroacetic acid (1 mL,
13.46 mmol) at rt for 20 min. The reaction mixture was quenched
with saturated aqueous sodium bicarbonate (20 mL) and extracted two
times with DCM (25 mL). The organic layer was separated, dried over
MgSO.sub.4, filtered, and concentrated in vacuo to give crude
6,7-dichloro-1-phenyl-4-(piperazin-1-yl)phthalazine that was used
directly in the next step. m/z (ESI) M+H: 359.0.
[0470] Step 5:
1-(4-(6,7-Dichloro-4-phenylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one-
. Acryloyl chloride (0.013 mL, 0.162 mmol) was added to a stirred
mixture of 6,7-dichloro-1-phenyl-4-(piperazin-1-yl)phthalazine (53
mg, 0.148 mmol) and triethylamine (0.062 mL, 0.443 mmol) in
dichloromethane (1 mL). The reaction mixture was stirred at rt for
30 min. The reaction mixture was quenched with saturated aqueous
sodium bicarbonate (15 mL) and extracted with DCM (20 mL). The
organic layer was separated, dried over MgSO.sub.4, filtered, and
concentrated in vacuo. Chromatographic purification of the residue
(silica gel, 0 to 100% EtOAc in heptane) gave
1-(4-(6,7-dichloro-4-phenylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one-
. .sup.1H NMR (400 MHz, Cloroform-d) .delta. 8.20 (1H, s) 8.14 (1H,
s) 7.66-7.75 (2H, m) 7.54-7.62 (3H, m) 6.66 (1H, dd, J=16.63, 10.37
Hz) 6.37 (1H, dd, J=16.82, 1.96 Hz) 5.78 (1H, dd, J=10.56, 1.96 Hz)
3.85-4.04 (1H, m) 3.53-3.72 (1H, m). m/z (ESI) M+H: 431.2.
[0471] Step 6:
2-(1-(4-Acryloyl-1-piperazinyl)-7-chloro-4-phenyl-6-phthalazinyl)-3-fluor-
ophenol and
2-(4-(4-acryloyl-1-piperazinyl)-7-chloro-1-phenyl-6-phthalazinyl)-3-fluor-
ophenol.
1-(4-(6,7-Dichloro-4-phenylphthalazin-1-yl)piperazin-1-yl)prop-2--
en-1-one (43 mg, 0.104 mmol), 2-fluoro-6-hydroxyphenylboronic acid
(17.84 mg, 0.114 mmol, Combi-Blocks Inc., San Diego, Calif., USA),
Sphos Pd G3 (9.00 mg, 10.40 .mu.mol), and sodium carbonate (2 M
aqueous, 0.156 mL, 0.312 mmol) were mixed in 1,2-dimethoxyethane
(0.5 mL) in a sealed vial under an argon atmosphere. The reaction
mixture was stirred at 60.degree. C. for 3 h. Additional
2-fluoro-6-hydroxyphenylboronic acid (8.92 mg, 0.057 mmol,
Combi-Blocks Inc., San Diego, Calif., USA) and SPhos Pd G3 (9.00
mg, 10.40 .mu.mol) were added, and the reaction mixture was stirred
at 60.degree. C. for another 2 h. The reaction mixture was quenched
with saturated aqueous sodium bicarbonate (15 mL) and extracted
with EtOAc (20 mL). The organic layer was separated, washed with
brine (10 mL), dried over MgSO.sub.4, filtered, and concentrated in
vacuo. Chromatographic purification of the residue (silica gel, 0
to 100% EtOAc in heptane) gave a mixture of the two regioisomeric
products. Reverse phase preparative chromatography (XBridge Prep
C18 5 .mu.m OBD, 150.times.30 mm; 35 to 55% (0.1% TFA in water) in
(0.1% TFA in acetonitrile); flow rate=30 mL/min) gave the separated
regioisomeric products. The fractions containing the individual
regioisomers were neutralized with saturated aqueous sodium
bicarbonate and extracted with DCM, and the organic extracts were
concentrated in vacuo. The separated regioisomers were further
individually purified by column chromatography (silica gel, 0 to
100% EtOAc in heptane).
2-(1-(4-acryloyl-1-piperazinyl)-7-chloro-4-phenyl-6-phthalazinyl)-3-fluor-
ophenol (Example 30), was the first regioisomer to elute from the
reverse phase preparative chromatography. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 8.21 (1H, s) 8.06 (1H, s) 7.62-7.69 (2H, m)
7.45-7.51 (3H, m) 7.24-7.32 (1H, m) 6.81-6.90 (1H, m) 6.75 (1H, t,
J=8.41 Hz) 6.65 (1H, dd, J=16.82, 10.56 Hz) 6.38 (1H, dd, J=16.82,
1.76 Hz) 5.79 (1H, dd, J=10.56, 1.76 Hz) 3.86-4.02 (4H, m)
3.57-3.76 (4H, m). m/z (ESI) M+H: 489.0.
2-(4-(4-acryloyl-1-piperazinyl)-7-chloro-1-phenyl-6-phthalazinyl)-3-fluor-
ophenol (Example 31), was the second regioisomer to elute from the
reverse phase column. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
8.15 (1H, s) 8.12 (1H, s) 7.68-7.73 (2H, m) 7.53-7.58 (3H, m) 7.30
(1H, br td, J=8.22, 6.65 Hz) 6.88 (1H, d, J=8.22 Hz) 6.78 (1H, t,
J=8.61 Hz) 6.57 (1H, dd, J=16.82, 10.56 Hz) 6.28 (1H, dd, J=16.73,
1.66 Hz) 5.71 (1H, dd, J=10.56, 1.56 Hz) 3.78-3.89 (4H, m)
3.51-3.73 (4H, m). m/z (ESI) M+H: 489.1.
Examples 32 and 33
2-(1-(4-Acryloyl-1-piperazinyl)-7-chloro-4-methoxy-6-phthalazinyl)-3-fluor-
ophenol (Example 32) and
2-(4-(4-acryloyl-1-piperazinyl)-7-chloro-1-methoxy-6-phthalazinyl)-3-fluo-
rophenol (Example 33)
##STR00723##
[0473] Examples 32 and 33 were prepared in an analogous method to
Examples 30 and 31 with the exception of Step 3, which was changed
as follows:
[0474] Step 3: tert-Butyl
4-(6,7-dichloro-4-methoxyphthalazin-1-yl)piperazine-1-carboxylate.
tert-Butyl
4-(4,6,7-trichlorophthalazin-1-yl)piperazine-1-carboxylate
(Intermediate M, 198 mg, 0.474 mmol) and sodium methoxide (25%
solution in methanol, 2 mL, 8.75 mmol) were mixed in a sealed vial.
The reaction mixture was stirred at 60.degree. C. for 2 h. The
reaction mixture was quenched with saturated aqueous sodium
bicarbonate (25 mL) and extracted with EtOAc (25 mL). The organic
layer was separated, washed with brine (20 mL), dried over
MgSO.sub.4, filtered, and concentrated in vacuo. Chromatographic
purification of the residue (silica gel, 0 to 50% EtOAc in heptane)
gave tert-butyl
4-(6,7-dichloro-4-methoxyphthalazin-1-yl)piperazine-1-carboxylate.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.29 (1H, s) 8.08 (1H,
s) 4.22 (3H, s) 3.68-3.73 (4H, m) 3.33-3.38 (4H, m) 1.51 (9H, s).
m/z (ESI) M+H: 413.1.
[0475] From step 6: First eluting regioisomer:
2-(1-(4-acryloyl-1-piperazinyl)-7-chloro-4-methoxy-6-phthalazinyl)-3-fluo-
rophenol (Example 32).sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
8.23 (1H, s) 8.11 (1H, s) 7.32 (1H, td, J=8.31, 6.46 Hz) 6.88 (1H,
d, J=8.22 Hz) 6.77-6.83 (1H, m) 6.65 (1H, dd, J=16.82, 10.56 Hz)
6.37 (1H, dd, J=16.82, 1.76 Hz) 5.79 (1H, dd, J=10.47, 1.86 Hz)
4.18 (3H, s) 3.79-4.05 (4H, m) 3.34-3.54 (4H, m). m/z (ESI) M+H:
443.1.
[0476] Second eluting regioisomer:
2-(4-(4-acryloyl-1-piperazinyl)-7-chloro-1-methoxy-6-phthalazinyl)-3-fluo-
rophenol (Example 33).sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
8.32 (1H, s) 8.01 (1H, s) 7.32 (1H, td, J=8.27, 6.55 Hz) 6.89 (1H,
d, J=8.22 Hz) 6.77-6.83 (1H, m) 6.60 (1H, dd, J=17.02, 10.56 Hz)
6.30 (1H, dd, J=16.82, 1.76 Hz) 5.75 (1H, dd, J=10.56, 1.76 Hz)
4.22 (3H, s) 3.67-3.98 (4H, m) 3.25-3.55 (4H, m). m/z (ESI) M+H:
443.1.
Example 34
1-(4-Acryloyl-1-piperazinyl)-4-benzyl-6,7-dichlorophthalazine
##STR00724##
[0478] Example 34 was prepared in an analogous method to Examples
30 and 31 with the exception of step 6, which was omitted, and
Steps 2 and 3, which were changed as follows:
[0479] Steps 2 and 3: tert-Butyl
4-(4-benzyl-6,7-dichlorophthalazin-1-yl)piperazine-1-carboxylate.
Benzylzinc bromide (0.5 M in THF, 1.926 mL, 0.963 mmol) was added
to a sealed vial containing 1,4,6,7-tetrachlorophthalazine
(Intermediate L, 258 mg, 0.963 mmol) and
tetrakis(triphenylphosphine)palladium (111 mg, 0.096 mmol, Strem
Chemicals Inc., NewburyPort, Mass., USA) under an argon atmosphere.
The reaction mixture was stirred at rt for 16 h. 1-Boc-piperazine
(1.79 g, 9.63 mmol) was added, and the reaction mixture was stirred
at 60.degree. C. for 5 h. The reaction mixture was quenched with
saturated aqueous sodium bicarbonate (40 mL) and extracted with
EtOAc (50 mL). The organic layer was separated, washed with brine
(40 mL), dried over MgSO.sub.4, filtered, and concentrated in
vacuo. Chromatographic purification of the residue (silica gel, 0
to 50% EtOAc in heptane) gave tert-butyl
4-(4-benzyl-6,7-dichlorophthalazin-1-yl)piperazine-1-carboxylate.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.11 (1H, s) 8.10 (1H,
s) 7.27-7.35 (4H, m) 7.20-7.25 (1H, m) 4.59 (2H, s) 3.69-3.74 (4H,
m) 3.44-3.49 (4H, m) 1.52 (9H, s). m/z (ESI) M+H: 473.1. m/z (ESI)
M+H: 473.1.
[0480] From step 5:
1-(4-acryloyl-1-piperazinyl)-4-benzyl-6,7-dichlorophthalazine.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 8.13 (1H, s) 8.12
(1H, s) 7.28-7.36 (4H, m) 7.20-7.26 (1H, m) 6.65 (1H, dd, J=16.82,
10.56 Hz) 6.37 (1H, dd, J=16.82, 1.57 Hz) 5.78 (1H, dd, J=10.56,
1.56 Hz) 4.61 (2H, s) 3.83-4.01 (4H, m) 3.48-3.62 (4H, m). m/z
(ESI) M+H: 427.1.
Example 35 and 36
2-(1-(4-Acryloyl-1-piperazinyl)-4-benzyl-7-chloro-6-phthalazinyl)-3-fluoro-
phenol (Example 35) and
2-(4-(4-acryloyl-1-piperazinyl)-1-benzyl-7-chloro-6-phthalazinyl)-3-fluor-
ophenol (Example 36)
##STR00725##
[0482]
1-(4-(4-Benzyl-6,7-dichlorophthalazin-1-yl)piperazin-1-yl)prop-2-en-
-1-one. (Example 34, 35 mg, 0.082 mmol),
2-fluoro-6-hydroxyphenylboronic acid (12.77 mg, 0.082 mmol,
Combi-Blocks Inc., San Diego, Calif., USA), SPhos Pd G3 (7.09 mg,
8.19 .mu.mol), and sodium carbonate (2 M aqueous, 0.123 mL, 0.246
mmol) were mixed in 1,2-dimethoxyethane (0.3 mL) in a sealed vial
under an argon atmosphere. The reaction mixture was stirred at
60.degree. C. for 1 h. The reaction mixture was quenched with
saturated aqueous sodium bicarbonate (15 mL) and extracted with
EtOAc (20 mL). The organic layer was separated, washed with brine
(10 mL), dried over MgSO.sub.4, filtered, and concentrated in
vacuo. Chromatographic purification of the residue (silica gel, 0
to 100% EtOAc in heptane) gave a mixture of the two regioisomeric
products. Reverse phase preparative chromatography (XBridge Prep
C.sub.18 5 pm OBD, 150.times.30 mm; 20 to 90% (0.1% TFA in water)
in (0.1% TFA in acetonitrile); flow rate=30 mL/min) gave the
partially separated regioisomeric products. The fractions
containing the regioisomers were neutralized with saturated aqueous
sodium bicarbonate and extracted with DCM, and the organic extracts
were concentrated in vacuo.
2-(1-(4-acryloyl-1-piperazinyl)-4-benzyl-7-chloro-6-phthalazinyl)-3-fluor-
ophenol (Example 35), was the first regioisomer to elute during
reverse phase preparative chromatography, and contained
approximately 36% of the second regioisomer to elute. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 8.13 (1H, s) 8.11 (1H, s) 7.12-7.37
(6H, m) 6.91 (1H, d, J=8.22 Hz) 6.77 (1H, t, J=8.61 Hz) 6.64 (1H,
dd, J=16.82, 10.56 Hz) 6.37 (1H, dd, J=16.82, 1.76 Hz) 5.79 (1H,
dd, J=10.56, 1.96 Hz) 4.55 (2H, s) 3.34-4.01 (8H, m). m/z (ESI)
M+H: 503.1.
2-(4-(4-acryloyl-1-piperazinyl)-1-benzyl-7-chloro-6-phthalazinyl)-3-fluor-
ophenol (Example 36), was the second regioisomer to elute. .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. 8.12 (1H, s) 8.05 (1H, s)
7.26-7.36 (5H, m) 7.19-7.24 (1H, m) 6.93 (1H, d, J=8.41 Hz) 6.76
(1H, t, J=8.31 Hz) 6.58 (1H, dd, J=16.82, 10.76 Hz) 6.28 (1H, dd,
J=16.82, 1.76 Hz) 5.75 (1H, dd, J=10.56, 1.76 Hz) 4.54 (2H, s)
3.32-3.93 (8H, m). m/z (ESI) M+H: 503.1.
Example 37
1-(4-acryloyl-1-piperazinyl)-4-benzyl-6-chloro-7-(5-methyl-1H-indazol-4-yl-
)phthalazine and
1-(4-acryloyl-1-piperazinyl)-4-benzyl-7-chloro-6-(5-methyl-1H-indazol-4-y-
l)phthalazine
##STR00726##
[0484] Example 37 was prepared in an analogous method to Examples
35 and 36 with 5-methyl-1h-indazol-4-yl boronic acid (Combi-Blocks
Inc., San Diego, Calif., USA) in place of
2-fluoro-6-hydroxyphenylboronic acid. In this embodiment the two
regioisomeric products were not separated. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 8.23 (0.6H, s) 8.22 (0.4H, s) 8.02 (0.4H, s)
8.00 (0.6H, s) 7.19-7.57 (8H, m) 6.68 (0.4H, dd, J=16.82, 10.56 Hz)
6.60 (0.6H, dd, J=16.82, 10.56 Hz) 6.38 (0.4H, dd, J=16.63, 1.76
Hz) 6.32 (0.6H, dd, J=16.82, 1.76 Hz) 5.79 (0.4H, dd, J=10.56, 1.76
Hz) 5.73 (0.6H, dd, J=10.56, 1.76 Hz) 4.67 (1.2H, s) 4.60 (0.8H, s)
3.74-4.06 (4H, m) 3.46-3.70 (4H, m) 2.21 (1.8H, s) 2.06 (1.2H, s).
m/z (ESI) M+H: 523.
Example 38
6-chloro-1-(cyclopropylmethyl)-7-(2-fluoro-6-hydroxyphenyl)-4-(4-(2-propen-
oyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one
##STR00727##
[0486] The starting material for Example 38 was prepared using
Method 8 Steps 1-4 with reagents 2,5,6-trichloronicotinic acid
(Step 1), aminomethylcyclopropane (Step 2),
2-fluoro-6-hydroxyphenylboronic acid (Step 4, Combi-Blocks Inc.,
San Diego, Calif., USA), and sodium carbonate (Step 4).
[0487] Step 1:
7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-6-chloro-1-(cycloprop-
ylmethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.
tert-Butylchlorodiphenylsilane (0.036 mL, 0.139 mmol) was added to
a stirred mixture of
6-chloro-1-(cyclopropylmethyl)-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]p-
yrimidine-2,4(1H,3H)-dione (42 mg, 0.116 mmol) and triethylamine
(0.065 mL, 0.464 mmol) in acetonitrile (0.5 mL). The reaction
mixture was stirred at rt for 1 h. The reaction mixture was
quenched with saturated aqueous NH.sub.4Cl (25 mL) and extracted
with EtOAc (30 mL). The organic layer was separated, washed with
brine (25 mL), dried over MgSO.sub.4, filtered, and concentrated in
vacuo to give crude
7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-6-chloro-1-(cycloprop-
ylmethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione that was used
directly in the next step. m/z (ESI) M+H: 599.8.
[0488] Step 2:
4-(4-acryloylpiperazin-1-yl)-7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluoro-
phenyl)-6-chloro-1-(cyclopropylmethyl)pyrido[2,3-d]pyrimidin-2(1H)-one.
Phosphorus oxychloride (0.087 mL, 0.933 mmol) was added to a
stirred mixture of crude
7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-6-chloro-1-(cycloprop-
ylmethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (70 mg, 0.117
mmol), triethylamine (0.295 mL, 2.099 mmol), and
1H-benzo[d][1,2,3]triazole (167 mg, 1.400 mmol) in acetonitrile (2
mL). The reaction mixture was stirred at 80.degree. C. for 4 h. The
reaction mixture was concentrated in vacuo. The resulting residue
was taken up in 1,2-dichloroethane (2 mL), and triethylamine (0.295
mL, 2.099 mmol) and 1-(piperazin-1-yl)prop-2-en-1-one (32.7 mg,
0.233 mmol, eNovation Chemicals LLC, Bridgewater, N.J., USA) were
added. The reaction mixture was stirred at rt for 16 h. Additional
triethylamine (0.148 mL, 1.050 mmol) and
1-(piperazin-1-yl)prop-2-en-1-one (32.7 mg, 0.233 mmol, eNovation
Chemicals LLC, Bridgewater, N.J., USA) were added, and the reaction
mixture was stirred at rt for 1 h before being heated to 60.degree.
C. and stirred for 4 h. The reaction mixture was diluted with
saturated aqueous NaHCO.sub.3 (40 mL) and extracted with DCM (50
mL). The organic layer was separated, dried over MgSO.sub.4,
filtered, and concentrated in vacuo. The resulting residue was
again taken up in 1,2-dichloroethane (2 mL), and triethylamine
(0.295 mL, 2.099 mmol) and 1-(piperazin-1-yl)prop-2-en-1-one (32.7
mg, 0.233 mmol, eNovation Chemicals LLC, Bridgewater, N.J., USA)
were added. The reaction mixture was stirred at 60.degree. C. for 6
h. The reaction mixture was diluted with saturated aqueous
NaHCO.sub.3 (40 mL) and extracted with DCM (50 mL). The organic
layer was separated, dried over MgSO.sub.4, filtered, and
concentrated in vacuo. Chromatographic purification of the residue
(silica gel, 0 to 100% (3:1 EtOAc/EtOH) in heptane) gave
4-(4-acryloylpiperazin-1-yl)-7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluoro-
phenyl)-6-chloro-1-(cyclopropylmethyl)pyrido[2,3-d]pyrimidin-2(1H)-one
that was taken on in the next step without further purification.
m/z (ESI) M+H: 721.8.
[0489] Step 3:
4-(4-acryloylpiperazin-1-yl)-6-chloro-1-(cyclopropylmethyl)-7-(2-fluoro-6-
-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one. Tetrabutylammonium
fluoride (1.0 M solution in tetrahydrofuran, 0.025 mL, 0.025 mmol)
was added to a stirred mixture of
4-(4-acryloylpiperazin-1-yl)-7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluoro-
phenyl)-6-chloro-1-(cyclopropylmethyl)pyrido[2,3-d]pyrimidin-2(1H)-one
(6 mg, 8.31 .mu.mol) in tetrahydrofuran (0.2 mL). The reaction
mixture was stirred at rt for 20 min before being concentrated in
vacuo. Chromatographic purification of the residue (silica gel, 0
to 100% (3:1 EtOAc/EtOH) in heptane) gave
6-chloro-1-(cyclopropylmethyl)-7-(2-fluoro-6-hydroxyphenyl)-4-(4-(2-prope-
noyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 8.04 (1H, s) 7.26-7.33 (1H, m) 6.82
(1H, d, J=8.29 Hz) 6.71 (1H, t, J=8.91 Hz) 6.51 (1H, dd, J=16.79,
10.57 Hz) 6.30 (1H, dd, J=16.79, 1.45 Hz) 5.72 (1H, dd, J=10.47,
1.55 Hz) 4.15 (2H, br d, J=6.43 Hz) 3.69-3.90 (8H, m) 1.14-1.27
(4H, m) 0.73-0.88 (1H, in). m/z (ESI) M+H: 483.8.
Separated Compound Examples
TABLE-US-00014 [0490] Racemic SM / separation Ex.# Chemical
Structure Name conditions 2-5-1 ##STR00728##
1-((3S)-4-(5-chloro-6-(3- hydroxy-1- naphthalenyl)[1,2]thiazol
o[3,4-b]-pyridin-3-yl)-3- methyl-1-piperazinyl)-2- propen-1-one or
1-((3R)- 4-(5-chloro-6-(3-hydroxy- 1- naphthalenyl)[1,2]thiazol
o[3,4-b]pyridin-3-yl)-3- methyl-1-piperazinyl)-2- propen-1-one 2-5
/ SFC (Chiralpak AD-H, 20 .times. 150 mm, 5 .mu.m, 55%
MeOH/CO.sub.2, 80 mL/min, 100 bar). 2-5-2 ##STR00729##
1-((3R)-4-(5-chloro-6-(3- hydroxy-1- naphthalenyl)[1,2]thiazol
o[3,4-b)pyridin-3-yl)-3- methyl-1-piperazinyl)-2- propen-1-one or
1-((3S)- 4-(5-chloro-6-(3-hydroxy- 1- naphthalenyl)[1,2]thiazol
o[3,4-b]pyridin-3-yl)-3- methyl-1-piperazinyl)-2- propen-1-one 2-5
/ SFC (Chiralpak AD-H, 20 .times. 150 mm, 5 .mu.m, 55%
MeOH/CO.sub.2, 80 mL/min, 100 bar). 2-6-1 ##STR00730##
1-((3S)-4-(5-chloro-6-(5- methyl-1H-indazol-4-
yl)[1,2]thiazolo[3,4- b]pyridin-3-yl)-3-methyl-
1-piperazinyl)-2-propen- 1-one or 1-((3R)-4-(5-
chloro-6-(5-methyl-1H- indazol-4- yl)[1,2]thiazolo[3,4-
b]pyridin-3-yl)-3-methyl- 1-piperazinyl)-2-propen- 1-one 2-6 / SFC
(Phenomenex (S,S)-Whelk-O 1, 250 .times. 20 mm, 3 .mu.m, 50%
MeOH/CO.sub.2 containing 20 mM NH.sub.3, 60 g/min, 102 bar) 2-6-2
##STR00731## 1-((3R)-4-(5-chloro-6-(5- methyl-1H-indazol-4-
yl)[1,2]thiazolo[3,4- b]pyridin-3-yl)-3-methyl-
1-piperazinyl)-2-propen- 1-one or 1-((3S)4-(5-
chloro-6-(5-methyl-1H- indazol-4- yl)[1,2]thiazolo[3,4-
b]pyridin-3-yl)-3-methyl- 1-piperazinyl)-2-propen- 1-one 2-6 / SFC
(Phenomenex (S,S)-Whelk-O 1, 250 .times. 20 mm, 3 .mu.m, 50%
MeOH/CO.sub.2 containing 20 mM NH.sub.3, 60 g/min, 102 bar) 1-19-1
##STR00732## 1-((3S)-4-(5-chloro-7- fluoro-6-(3-hydroxy-1-
naphthalenyl)-2,1- benzothiazol-3-yl)-3- methyl-1-piperazinyl)-2-
propen-1-one 1-19 / SFC (IC 250 .times. 30 mm, 5 .mu.m, 50%
MeOH/CO.sub.2 (w/ 20 mM NH.sub.3), 100 g/min, 100 bar). 1-19-2
##STR00733## 1-((3S)-4-(5-chloro-7- fluoro-6-(3-hydroxy-1-
naphthalenyl)-2,1- benzothiazol-3-yl)-3- methyl-1-piperazinyl)-2-
propen-1-one 1-19 / SFC (IC 250 .times. 30 mm, 5 .mu.m, 50%
MeOH/CO.sub.2 (w/ 20 mM NH.sub.3), 100 g/min, 100 bar). 3-1-1
##STR00734## 1-(4-(5-chloro-7-fluoro-6- (3-hydroxy-1-
naphthalenyl)-2,1- benzothiazol-3-yl)-1- piperazinyl)-2-propen-1-
one 3-1 / SFC (OD-H 250 .times. 21 mm, 5 .mu.m, 40% MeOH/CO.sub.2
(w/ 20 mM NH.sub.3), 60 mL/min, 100 bar). 3-1-2 ##STR00735##
1-(4-(5-chloro-7-fluoro-6- (3-hydroxy-1- naphthalenyl)-2,1-
benzothiazol-3-yl)-1- piperazinyl)-2-propen-1- one 3-1 / SFC (OD-H
250 .times. 21 mm, 5 .mu.m, 40% MeOH/CO.sub.2 (w/ 20 mM NH.sub.3),
60 mL/min, 100 bar). 8-6-1 ##STR00736## 6-chloro-7-(2-fluoro-6-
hydroxyphenyl)-4-((2S)- 2-methyl-4-(2- propenoyl)-1-
piperazinyl)-1-(2-(2- propanyl)phenyl)pyrido[2,
3-d]pyrimidin-2(1H)-one 8-6 / SFC (Chiralpak IC, 150 .times. 30 mm,
5 .mu.m, 30% MeOH/CO.sub.2, (w/ 20 mM NH.sub.3), 120 g/min, 102
bar). 8-6-2 ##STR00737## 6-chloro-7-(2-fluoro-6-
hydroxyphenyl)-4-((2S)- 2-methyl-4-(2- propenoyl)-1-
piperazinyl)-1-(2-(2- propanyl)phenyl)pyrido[2,
3-d]pyrimidin-2(1H)-one 8-6 / SFC (Chiralpak IC, 150 .times. 30 mm,
5 .mu.m, 30% MeOH/CO.sub.2, (w/ 20 mM NH.sub.3), 120 g/min, 102
bar). 8-1-1 ##STR00738## 6-chloro-7-(2-(fluoro-6-
hydroxyphenyl)-1-(2-(2- propanyl)phenyl)-4-(4-(2- propenoyl)-1-
piperazinyl)-2(1H)- quinazolinone 8-1 / SFC (Chiralpak IC, 300
.times. 15 mm, 5 .mu.m, 40% MeOH/CO.sub.2, (w/ 20 mM NH.sub.3), 135
g/min, 188 bar). 8-1-2 ##STR00739## 6-chloro-7-(2-(fluoro-6-
hydroxyphenyl)-1-(2-(2- propanyl)phenyl)-4-(4-(2- propenoyl)-1-
piperazinyl)-2(1H)- quinazolinone 8-1 / SFC (Chiralpak IC, 300
.times. 15 mm, 5 .mu.m, 40% MeOH/CO.sub.2, (w/ 20 mM NH.sub.3), 135
g/min, 188 bar). 8-3-1 ##STR00740## 6-chloro-7-(2-fluoro-6-
hydroxyphenyl)-4-((2S)- 2-methyl-4-(2- propenoyl)-1-
piperazinyl)-1-(2-(2- propanyl)phenyl)-2(1H)- quinazolinone 8-3 /
SFC (Whelk-01 (S,S), 250 .times. 21 mm, 5 .mu.m, 30% EtOH/CO.sub.2
(w/ 20 mM NH.sub.3), 70 g/min, 187 bar). 8-3-2 ##STR00741##
6-chloro-7-(2-fluoro-6- hydroxyphenyl)-4-((2S)- 2-methyl-4-(2-
propenoyl)-1- piperazinyl)-1-(2-(2- propanyl)phenyl)-2(1H)-
quinazolinone 8-3 / SFC (Whelk-01 (S,S), 250 .times. 21 mm, 5
.mu.m, 30% EtOH/CO.sub.2 (w/ 20 mM NH.sub.3), 70 g/min, 187
bar).
TABLE-US-00015 TABLE 12 Analytical Data for General Procedures
LRMS: (ESI, +ve Ex. # ion) m/z NMR 1-1 498.0 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.99 (br s, 1 H), 8.04 (s, 1 H), 7.55 (d, J =
8.7 Hz, 1 H), 6.81-6.94 (m, 2 H), 6.79 (d, J = 2.9 Hz, 1 H), 6.19
(dd, J = 16.7, 2.2 Hz, 1 H), 5.77 (dd, J = 10.5, 2.2 Hz, 1 H), 3.87
(br d, J = 19.5 Hz, 4 H), 3.63 (br t, J = 5.1 Hz, 4 H). .sup.19F
NMR (376 MHz, DMSO-d.sub.6) .delta. -123.78 (s, 1 F). 1-2 441.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.19 (s, 1H), 7.91 (d,
J = 8.4 Hz, 1H), 7.45-7.53 (m, 2H), 7.43 (d, J = 2.4 Hz, 1H), 7.26-
7.35 (m, 2H), 7.10 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 16.7, 10.5
Hz, 1H), 6.18 (dd, J = 16.7, 2.3 Hz, 1H), 5.76 (d, J = 10.3, 2.4
Hz, 1H), 3.93 (s, 3H), 3.81-3.93 (m, 4H), 3.58-3.64 (m, 4H). 1-3
450.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.91 (br. s, 1H),
8.18 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.47 (s, 1H), 7.37-7.43 (m,
1H), 7.24-7.29 (m, 1H), 7.17-7.23 (m, 2H), 7.01 (d, J = 2.4 Hz,
1H), 6.87 (dd, J = 16.7, 10.5 Hz, 1H), 6.19 (dd, J = 16.7, 2.3 Hz,
1H), 5.73-5.79 (m, 1H), 3.82-3.95 (m, 4H), 3.58-3.64 (m, 4H). 1-4
464.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.19 (s, 1H),
7.91 (d, J = 8.4 Hz, 1H), 7.46-7.52 (m, 2H), 7.43 (d, J = 2.4 Hz,
1H), 7.25- 7.36 (m, 2H), 7.10 (d, J = 2.5 Hz, 1H), 6.87 (dd, J =
16.7, 10.5 Hz, 1H), 6.31 (dd, J = 1.9, 16.8 Hz, 1H), 5.74-5.80 (m,
1H), 3.93 (s, 3H), 3.82-3.93 (m, 4H), 3.56-3.63 (m, 4H). 1-5 432.0
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.12 (s, 1H), 7.41-7.49
(m, 1H), 7.41 (s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.80-6.92 (m, 2H),
6.18 (dd, J = 16.8, 2.4 Hz, 1H), 5.75 (dd, J = 10.5, 2.3 Hz, 1H),
3.79-3.93 (m, 4H), 3.75 (s, 3H), 3.53-3.62 (m, 4H). 1-6 418.0
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.98 (br s., 1H), 8.10
(s, 1H), 7.39 (s, 1H), 7.20-7.29 (m, 1H), 6.68-6.90 (m, 3H), 6.17
(dd, J = 16.6, 2.4 Hz, 1H), 5.75 (dd, J = 10.4, 2.4 Hz, 1H),
3.78-3.93 (m, 4H), 3.53-3.58 (m, 4H). 1-7 498 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.79- 10.10 (1 H, m), 8.05-8.12 (1 H, m),
7.77- 7.83 (1 H, m), 7.39-7.48 (1 H, m), 7.21- 7.29 (3 H, m),
7.04-7.09 (1 H, m), 6.76- 6.91 (1 H, m), 6.14-6.24 (1 H, m), 5.74-
5.81 (1 H, m), 5.02-5.30 (1 H, m), 4.08- 4.53 (3 H, m), 3.54-3.81
(6 H, m). 1-8 496 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.83-
10.10 (1 H, m), 8.01-8.07 (1 H, m), 7.77- 7.84 (1 H, m), 7.39-7.47
(1 H, m), 7.19- 7.31 (3 H, m), 7.04-7.10 (1 H, m), 6.80- 6.94 (1 H,
m), 6.15-6.28 (1 H, m), 5.75- 5.83 (1 H, m), 4.38-4.58 (1 H, m),
4.06- 4.27 (2 H, m), 3.51-3.89 (3 H, m), 3.19- 3.29 (1 H, m),
1.58-1.74 (2 H, m), 0.90- 0.99 (3 H, m). 1-9 467.8 .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.85- 10.08 (1 H, m), 8.73-8.90 (1 H,
m), 7.77- 7.83 (1 H, m), 7.72-7.76 (1 H, m), 7.41- 7.47 (1 H, m),
7.21-7.28 (3 H, m), 7.04- 7.09 (1 H, m), 6.15-6.23 (2 H, m), 5.67-
5.72 (1 H, m), 4.90-5.01 (1 H, m), 4.36- 4.58 (2 H, m), 4.16-4.31
(1 H, m), 1.54- 1.62 (3 H, m). 1-10 470 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 13.03- 13.21 (1 H, m), 8.05-8.11 (1 H, m),
7.53- 7.63 (2 H, m), 7.35-7.41 (1 H, m), 6.80- 6.99 (1 H, m),
6.15-6.28 (1 H, m), 5.74- 5.83 (1 H, m), 4.28-4.55 (2 H, m), 4.15-
4.28 (1 H, m), 3.48-3.83 (4 H, m), 2.16- 2.22 (3 H, m), 1.17-1.28
(3 H, m). 1-11 512 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
9.83- 10.06 (1 H, m), 8.19-8.25 (1 H, m), 7.76- 7.85 (1 H, m),
7.38-7.48 (1 H, m), 7.19- 7.30 (3 H, m), 7.03-7.10 (1 H, m), 6.81-
6.95 (1 H, m), 6.15-6.27 (1 H, m), 5.74- 5.81 (1 H, m), 4.73-4.88
(1 H, m), 4.36- 4.59 (2 H, m), 4.13-4.26 (1 H, m), 4.07- 4.14 (1 H,
m), 3.49-3.80 (5 H, m), 1.72- 1.89 (2 H, m). 1-12 511 .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.26- 8.34 (1 H, m), 8.00-8.09 (2
H, m), 7.70- 7.77 (2 H, m), 7.53-7.61 (2 H, m), 7.41- 7.49 (2 H,
m), 7.32-7.41 (2 H, m), 7.18- 7.25 (1 H, m), 5.15-5.27 (1 H, m),
4.31- 4.56 (2 H, m), 3.63-3.91 (2 H, m), 3.42- 3.60 (2 H, m). 1-13
482.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.13 (d, J = 9.1
Hz, 1H), 8.09 (s, 1H), 7.97 (d, J = 6.8 Hz, 1H), 7.62 (d, J = 9.0
Hz, 1H), 7.38-7.44 (m, 2H), 7.22 (d, J = 8.8 Hz, 1H), 6.87 (dd, J =
16.8, 10.6 Hz, 1H), 6.19 (dd, J = 16.8, 2.4 Hz, 1H), 5.77 (dd, J =
10.5, 2.3 Hz, 1H), 3.82-3.94 (m, 4H), 3.87 (s, 3H), 3.63-3.69 (m,
4H). 1-14 468.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.91
(br. s, 1H), 8.07 (s, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.87 (d, J =
7.8 Hz, 1H), 7.27- 7.38 (m, 3H), 7.15 (d, J = 8.2 Hz, 1H), 6.87
(dd, J = 16.6, 10.6 Hz, 1H), 6.19 (dd, J = 16.7, 2.3 Hz, 1H), 5.76
(dd, J = 10.5, 2.3 Hz, 1H), 3.80-3.95 (m, 4H), 3.60-3.67 (m, 4H).
1-15 497.8 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.03- 8.12
(1 H, m), 7.68-7.79 (1 H, m), 7.32- 7.44 (1 H, m), 7.11-7.26 (3 H,
m), 6.98- 7.06 (1 H, m), 6.77-6.91 (1 H, m), 6.13- 6.26 (1 H, m),
5.73-5.83 (1 H, m), 4.08- 4.54 (3 H, m), 3.54-3.80 (7 H, m). 1-16
498.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.88- 10.15 (1 H,
m), 8.08-8.16 (1 H, m), 7.77- 7.83 (1 H, m), 7.40-7.48 (1 H, m),
7.18- 7.30 (3 H, m), 7.05-7.10 (1 H, m), 6.80- 6.92 (1 H, m),
6.15-6.24 (1 H, m), 5.73- 5.80 (1 H, m), 4.58-4.71 (1 H, m), 4.26-
4.43 (1 H, m), 3.99-4.24 (2 H, m), 3.39- 4.00 (6 H, m). 1-17 494.0
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.81- 10.05 (1 H, m),
8.06-8.12 (1 H, m), 7.77- 7.84 (1 H, m), 7.40-7.47 (1 H, m), 7.19-
7.29 (3 H, m), 7.03-7.08 (1 H, m), 6.77- 6.88 (1 H, m), 6.19-6.30
(1 H, m), 5.73- 5.82 (1 H, m), 4.73-4.86 (2 H, m), 3.82- 3.96 (2 H,
m), 3.44-3.52 (2 H, m), 1.88- 2.14 (4 H, m). 1-18 498.0 .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.85- 10.08 (1 H, m), 8.07-8.13 (1
H, m), 7.77- 7.83 (1 H, m), 7.40-7.48 (1 H, m), 7.22- 7.30 (3 H,
m), 7.04-7.09 (1 H, m), 6.76- 6.92 (1 H, m), 6.15-6.25 (1 H, m),
5.74- 5.81 (1 H, m), 5.04-5.29 (1 H, m), 4.10- 4.52 (3 H, m),
3.53-3.78 (5 H, m). 1-19 482.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 9.90-10.04 (1 H, m), 8.02-8.08 (1 H, m), 7.76-7.82 (1
H, m), 7.38-7.46 (1 H, m), 7.20-7.30 (3 H, m), 7.04-7.08 (1 H, m),
6.79-6.95 (1 H, m), 6.14-6.27 (1 H, m), 5.73-5.81 (1 H, m),
4.38-4.55 (3 H, m), 4.28-4.37 (1 H, m), 4.12-4.26 (1 H, m),
3.46-3.83 (2 H, m), 1.15-1.21 (3 H, m) 1-19-1 482.0 .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 9.83-10.08 (1 H, m), 8.04-8.11
(1 H, m), 7.77-7.84 (1 H, m), 7.38-7.48 (1 H, m), 7.19-7.31 (3 H,
m), 7.05-7.10 (1 H, m), 6.81-6.98 (1 H, m), 6.16-6.28 (1 H, m),
5.75-5.83 (1 H, m), 4.40-4.59 (1 H, m), 4.16-4.40 (1 H, m),
3.96-4.07 (1 H, m), 3.48-3.83 (3 H, m), 3.16-3.29 (1 H, m),
1.10-1.31 (3 H, m). 1-19-2 482.0 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 9.83-10.10 (1 H, m), 8.03-8.10 (1 H, m),
7.77-7.83 (1 H, m), 7.38-7.48 (1 H, m), 7.19-7.31 (3 H, m),
7.05-7.10 (1 H, m), 6.81-6.98 (1 H, m), 6.15-6.28 (1 H, m),
5.73-5.83 (1 H, m), 4.39-4.56 (2 H, m), 4.15-4.38 (1 H, m),
3.97-4.10 (1 H, m), 3.48-3.84 (3 H, m), 1.13-1.27 (3 H, m). 1-20
454.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.83- 10.05 (1 H,
m), 9.11-9.35 (1 H, m), 8.02- 8.07 (1 H, m), 7.76-7.83 (1 H, m),
7.40- 7.47 (1 H, m), 7.20-7.28 (3 H, m), 7.02- 7.09 (1 H, m),
6.33-6.46 (1 H, m), 6.11- 6.22 (1 H, m), 5.69-5.78 (1 H, m), 4.69-
4.80 (1 H, m), 4.40-4.49 (1 H, m), 4.31- 4.41 (1 H, m), 4.21-4.30
(1 H, m), 3.99- 4.09 (1 H, m). 1-21 482.0 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.85- 10.10 (1 H, m), 8.04-8.09 (1 H, m),
7.77- 7.83 (1 H, m), 7.40-7.47 (1 H, m), 7.19- 7.30 (3 H, m),
7.05-7.09 (1 H, m), 6.74- 6.99 (1 H, m), 6.09-6.36 (1 H, m), 5.66-
5.88 (1 H, m), 4.39-4.57 (2 H, m), 4.17- 4.39 (1 H, m), 3.96-4.07
(1 H, m), 3.48- 3.83 (3 H, m), 1.10-1.29 (3 H, m). 1-22 468.0
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.87- 10.03 (1 H, m),
8.45-8.66 (1 H, m), 7.94- 8.01 (1 H, m), 7.76-7.83 (1 H, m), 7.39-
7.47 (1 H, m), 7.21-7.29 (3 H, m), 7.01- 7.10 (1 H, m), 6.10-6.25
(2 H, m), 5.59- 5.70 (1 H, m), 4.56-4.68 (1 H, m), 3.99- 4.13 (1 H,
m), 3.75-3.87 (2 H, m), 3.55- 3.66 (1 H, m), 2.35-2.48 (1 H, m),
2.06- 2.21 (1 H, m). 1-23 482.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.85- 10.06 (1 H, m), 8.27-8.35 (1 H, m), 7.95- 8.00 (1 H,
m), 7.76-7.84 (1 H, m), 7.39- 7.48 (1 H, m), 7.20-7.29 (3 H, m),
7.01- 7.10 (1 H, m), 6.23-6.37 (1 H, m), 6.10- 6.20 (1 H, m),
5.58-5.68 (1 H, m), 4.00-4.11 (1 H, m), 3.89-3.99 (1 H, m),
3.67-3.77 (1 H, m), 3.35-3.49 (2 H, m), 1.94-2.07 (2 H, m),
1.77-1.90 (1 H, m), 1.62-1.72 (1 H, m). 2-7 496.2 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.83-10.11 (m, 1H), 7.90-7.95 (m, 1H),
7.76-7.84 (m, 1H), 7.37-7.49 (m, 1H), 7.19-7.31 (m, 3H), 7.06-7.10
(m, 1H), 6.86-7.00 (m, 1H), 6.22-6.31 (m, 1H), 5.78-5.86 (m, 1H),
4.07-4.22 (m, 3H), 3.89-4.01 (m, 1H), 3.71-3.84 (m, 1H), 3.40-3.52
(m, 1H), 1.22-1.34 (m, 6H) 2-8 506.0 .sup.1H NMR (DMSO-d.sub.6)
.delta.: 13.04-13.25 (m, 1H), 8.09-8.15 (m, 1H), 7.55-7.62 (m, 2H),
7.35-7.41 (m, 1H), 6.76-6.94 (m, 1H), 6.36-6.62 (m, 1H), 6.16-6.24
(m, 1H), 5.75-5.83 (m, 1H), 4.59-4.86 (m, 1H), 4.19-4.58 (m, 1H),
3.52-3.92 (m, 3H), 3.40-3.50 (m, 1H), 3.13-3.27 (m, 1H), 2.13-2.21
(m, 3H) 2-9 486.0 .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.08-10.30
(m, 1H), 7.98-8.07 (m, 1H), 7.29-7.39 (m, 1H), 6.72-6.91 (m, 3H),
6.23-6.63 (m, 1H), 6.13-6.24 (m, 1H), 5.74-5.81 (m, 1H), 4.58-4.82
(m, 1H), 4.42-4.57 (m, 1H), 4.17-4.38 (m, 1H), 3.52-3.89 (m, 4H)
2-10 510.0 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.83-10.06 (m, 1H),
7.93-8.06 (m, 1H), 7.75-7.85 (m, 1H), 7.39-7.51 (m, 1H), 7.17-7.32
(m, 3H), 7.00-7.15 (m, 1H), 6.76-6.96 (m, 1H), 6.12-6.30 (m, 1H),
5.68-5.86 (m, 1H), 4.59-4.71 (m, 1H), 4.35-4.47 (m, 1H), 4.06-4.28
(m, 1H), 3.60-4.06 (m, 3H), 3.43-3.58 (m, 1H), 2.08-2.25 (m, 1H),
1.00-1.11 (m, 3H), 0.86-0.97 (m, 3H) 1-28 436.0 .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.63 (s, 1 H) 8.04 (s, 1 H) 7.09-7.24
(m, 1 H) 6.72-6.95 (m, 3 H) 6.12-6.24 (m, 1 H) 5.74-5.77 (m, 1 H)
3.83-3.88 (d, 4 H) 3.52-3.72 (m, 4 H) 2-1 451.0 .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.97 (br. s, 1H), 8.72 (s, 1H), 7.79 (d,
J = 8.6 Hz, 1H), 7.42 (t, J = 7.1 Hz, 1H), 7.17- 7.28 (m, 3H), 7.09
(d, J = 2.1 Hz, 1H), 6.86 (dd, J = 16.7, 10.5 Hz, 1H), 6.19 (dd, J
= 16.7, 2.3 Hz, 1H), 5.74-5.79 (m,
1H), 3.81-3.95 (m, 4H), 3.68-3.76 (m, 4H) 2-2 447.0 .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.58 (d, J = 3.7 Hz, 1H), 7.47-7.55
(m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.96 (t, J = 8.7 Hz, 1H),
6.79-6.93 (m, 1H), 6.13-6.24 (m, 1H), 5.77 (dd, J = 10.5, 2.1 Hz,
1H), 4.26-4.54 (m, 2H), 3.96-4.25 (m, 1H), 3.65-3.84 (m, 2H), 3.76
(d, J = 2.4 Hz, 3H), 3.47-3.64 (m, 2H), 1.19 (s, 3H). 2-3 433.0
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 8.51 (s, 1H),
7.25-7.34 (m, 1H), 6.74-6.93 (m, 1H), 6.65-6.76 (m, 2H), 6.31 (d, J
= 16.4 Hz, 1H), 5.84 (dd, J = 10.6, 1.5 Hz, 1H), 4.41-4.53 (m, 2H),
4.03-4.15 (m, 1H), 3.54-3.88 (m, 4H), 1.30 (d, J = 6.6 Hz, 3H). 2-4
479.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.67 (s, 1H),
7.93 (d, J = 8.2 Hz, 1H), 7.45-7.53 (m, 2H), 7.26-7.37 (m, 2H),
7.19 (d, J = 2.5 Hz, 1H), 6.81-6.95 (m, 1H), 6.15-6.22 (m, 1H),
5.78 (dd, J = 10.4, 2.2 Hz, 1H), 4.39-4.58 (m, 2H), 4.16-4.26 (m,
1H), 3.94 (s, 3H), 3.68-3.84 (m, 2H), 3.48-3.64 (m, 2H), 1.22 (br.
s, 3H). 2-5 465.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.96
(s, 1H), 8.66 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.42 (t, J = 7.0
Hz, 1H), 7.17-7.30 (m, 3H), 7.09 (d, J = 2.4 Hz, 1H), 6.80- 6.94
(m, 1H), 6.14-6.27 (m, 1H), 5.78 (dd, J = 10.6, 2.2 Hz, 1H),
3.97-4.57 (m, 3H), 3.48-3.83 (m, 4H), 1.22 (br. s, 3H). 2-6 453.0
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.11 (br. s, 1H), 8.66
(d, J = 2.3 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.5 Hz,
1H), 6.80-6.93 (m, 1H), 6.16-6.24 (m, 1H), 5.78 (dd, J = 10.5, 2.3
Hz, 1H), 3.97-4.56 (m, 4H), 3.48-3.85 (m, 3H), 2.19 (s, 3H), 1.22
(br s., 3H). 3-1 468.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
9.90- 10.04 (1H, m), 8.10 (1H, s), 7.80 (1H, d, J = 8.41 Hz), 7.43
(1H, ddd, J = 1.96, 6.11, 8.17 Hz), 7.16-7.31 (3H, m), 7.07 (1H, d,
J = 2.35 Hz), 6.87 (1H, dd, J = 10.47, 16.73 Hz), 6.19 (1H, dd, J =
2.25, 16.73 Hz), 5.77 (1H, dd, J = 2.25, 10.47 Hz), 3.88 (4H, br d,
J = 19.56 Hz), 3.61- 3.72 (4H, m). .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -123.78 (s, 1F). 3-2 469 .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 9.43 (br. s., 1 H) 8.12 (d, J = 15.1 Hz, 1
H) 7.77 (d, J = 9.6 Hz, 1 H) 7.66 (d, J = 7.6 Hz, 1 H) 7.59 (d, J =
8.0 Hz, 1 H) 7.45 (s, 1 H) 7.21-7.26 (m, 1 H) 7.03 (br d, J = 10.4
Hz, 1 H) 6.95 (d, J = 15.1 Hz, 1 H) 6.71 (d, J = 9.6 Hz, 1 H)
3.93-4.14 (m, 4 H) 3.52-3.59 (m, 4 H). .sup.19F NMR (376 MHz,
CDCl.sub.3) .delta. -123.91 (s, 1 F). 3-3 453.0 .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.82- 8.88 (1 H, m), 8.52-8.63 (1 H, m),
8.09- 8.22 (2 H, m), 7.89-8.02 (2 H, m), 7.67- 7.74 (1 H, m),
6.80-6.96 (1 H, m), 6.13- 6.25 (1 H, m), 5.72-5.84 (1 H, m), 3.77-
4.03 (4 H, m), 3.56-3.74 (4 H, m). 3-4 469.0 H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.81- 12.11 (1 H, m), 8.05-8.15 (1 H, m),
7.58- 7.67 (1 H, m), 7.42-7.49 (1 H, m), 7.35- 7.42 (1 H, m),
7.14-7.20 (1 H, m), 6.80- 6.93 (1 H, m), 6.44-6.53 (1 H, m), 6.14-
6.24 (1 H, m), 5.72-5.82 (1 H, m), 3.80- 3.95 (4 H, m), 3.61-3.69
(4 H, m). 3-5 456.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
12.99- 13.26 (1 H, m), 8.10-8.14 (1 H, m), 7.54- 7.60 (2 H, m),
7.33-7.40 (1 H, m), 6.81- 6.94 (1 H, m), 6.14-6.25 (1 H, m), 5.74-
5.80 (1 H, m), 3.81-3.95 (4 H, m), 3.62- 3.71 (4 H, m), 2.12-2.20
(3 H, m). 3-6 436.0 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta.
7.84 (d, J = 1.17 Hz, 1H), 7.26 (dt, J = 6.75, 8.27 Hz, 1H),
6.71-6.90 (m, 2H), 6.62-6.71 (m, 1H), 6.25 (dd, J = 1.96, 16.82 Hz,
1H), 5.79 (dd, J = 1.86, 10.66 Hz, 1H), 3.91-4.03 (m, 4H),
3.57-3.71 (m, 4H), 3.33 (s, 1H). .sup.19F NMR (377 MHz,
METHANOL-d.sub.4) .delta. -116.77 (1 F, s), -125.66 (1 F, d, J =
2.6 Hz) 3-7 438.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.08
(s, 1 H), 7.53-7.62 (m, 1 H), 7.47 (td, J = 9.7, 2.5 Hz, 1 H), 7.28
(td, J = 8.5, 2.2 Hz, 1 H), 6.85 (dd, J = 16.7, 10.5 Hz, 1 H), 6.18
(dd, J = 16.7, 2.2 Hz, 1 H), 5.71- 5.79 (m, 1 H), 3.86 (br d, J =
19.6 Hz, 4 H), 3.63 (t, J = 5.2 Hz, 4 H) 3-8 432.2 .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.38 (s, 1 H), 8.02 (s, 1 H), 7.15 (d, J
= 8.4 Hz, 1 H), 6.85 (dd, J = 16.7, 10.5 Hz, 1 H), 6.77 (dd, J =
8.2, 2.5 Hz, 1 H), 6.58 (d, J = 2.5 Hz, 1 H), 6.18 (dd, J = 16.6,
2.3 Hz, 1 H), 5.72-5.80 (m, 1 H), 3.77-3.93 (m, 4 H), 3.62 (t, J =
5.1 Hz, 4 H), 1.94 (s, 3 H). .sup.19F NMR (376 MHz, DMSO-d.sub.6)
.delta. -124.66 (s, 1 F) 3-9 467.8 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.05 (s, 1 H) 7.54 (d, J = 8.8 Hz, 1 H) 7.10
(dd, J = 8.8, 3.1 Hz, 1 H) 7.02-7.07 (m, 1 H) 6.85 (dd, J = 16.7,
10.5 Hz, 1 H) 6.18 (dd, J = 16.7, 2.2 Hz, 1 H) 5.72-5.79 (m, 1 H)
3.86 (br d, J = 19.4 Hz, 4 H) 3.79 (s, 3 H) 3.62 (t, J = 5.1 Hz, 4
H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -123.83 (s, 1 F)
3-10 454.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.09 (s, 1
H), 8.05 (s, 1 H), 7.39 (dd, J = 11.0, 9.6 Hz, 1 H), 6.97 (dd, J =
9.5, 7.1 Hz, 1 H), 6.85 (dd, J = 16.6, 10.4 Hz, 1 H), 6.17 (dd, J =
16.6, 2.2 Hz, 1 H), 5.75 (dd, J = 10.5, 2.2 Hz, 1 H), 3.76-3.95 (m,
4 H), 3.62 (br t, J = 5.1 Hz, 4 H). .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -122.67 (br s, 1 F), -123.60 (d, J = 4.3 Hz,
1 F), -130.52 (d, J = 2.6 Hz, 1 F) 3-11 453.8 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.83- 10.02 (1 H, m), 8.04 (1 H, s), 7.40 (1
H, br d, J = 8.6 Hz), 6.76-7.03 (3 H, m), 6.12-6.22 (1 H, m),
5.69-5.82 (1 H, m), 3.86 (4 H, br d, J = 18.6 Hz), 3.63 (4 H, br d,
J = 4.7 Hz). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -124.09
(s, 1 F) 3-12 431.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.00 (s, 1 H), 6.99 (d, J = 8.2 Hz, 1 H), 6.85 (dd, J = 16.6, 10.4
Hz, 1 H), 6.57 (dd, J = 8.0, 2.0 Hz, 1 H), 6.39 (d, J = 1.8 Hz, 1
H), 6.18 (dd, J = 16.7, 2.2 Hz, 1 H), 5.69- 5.85 (m, 1 H), 4.99 (s,
2 H), 3.86 (br d, J = 19.6 Hz, 4 H), 3.56-3.70 (m, 4 H), 1.88 (s, 3
H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -124.75 (1 F, s)
3-13 473.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.98 (s, 1
H), 8.05 (s, 1 H), 7.54 (br d, J = 8.4 Hz, 1 H), 7.49 (s, 1 H),
7.29 (d, J = 8.4 Hz, 1 H), 6.85 (dd, J = 16.5, 10.5 Hz, 1 H), 6.18
(dd, J = 16.6, 2.0 Hz, 1 H), 5.76 (dd, J = 10.5, 2.1 Hz, 1H), 3.86
(br d, J = 19.8 Hz, 4 H), 3.63 (br t, J = 4.9 Hz, 4 H), 2.03 (s, 3
H), 2.01 (s, 3 H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.
-124.58 (s, 1 F) 3-14 435.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.03 (s, 1 H), 7.01 (t, J = 9.2 Hz, 1 H), 6.85 (dd, J =
16.7, 10.5 Hz, 1 H), 6.62-6.71 (m, 1 H), 6.52 (dd, J = 6.1, 2.7 Hz,
1 H), 6.18 (dd, J = 16.7, 2.2 Hz, 1 H), 5.70- 5.81 (m, 1 H), 5.11
(s, 2 H), 3.86 (br d, J = 19.6 Hz, 4 H), 3.52-3.69 (m, 4 H).
.sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -123.91 (s, 1 F),
-131.17 (s, 1 F) 3-15 453.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.06 (s, 1 H), 6.85 (dd, J = 16.7, 10.5 Hz, 1 H), 6.63
(ddd, J = 13.0, 6.6, 2.5 Hz, 1 H), 6.33 (br d, J = 2.0 Hz, 1 H),
6.18 (dd, J = 16.6, 2.3 Hz, 1 H), 5.71-5.82 (m, 1 H), 5.44 (s, 2
H), 3.76-3.96 (m, 4 H), 3.56- 3.71 (m, 4 H) 3-16 453.9 .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.12 (s, 1 H), 8.08 (s, 1 H), 6.92
(ddd, J = 12.3, 6.5, 2.9 Hz, 1 H), 6.85 (dd, J = 16.6, 10.4 Hz, 1
H), 6.58-6.65 (m, 1 H), 6.18 (dd, J = 16.7, 2.2 Hz, 1 H), 5.72-
5.79 (m, 1 H), 3.78-3.92 (m, 4 H), 3.63 (t, J = 5.2 Hz, 4 H) 3-17
486.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.86 (br s, 1
H), 8.05 (s, 1 H), 7.68 (s, 1 H), 6.96 (s, 1 H), 6.85 (dd, J =
16.6, 10.4 Hz, 1 H), 6.18 (dd, J = 16.6, 2.3 Hz, 1 H), 5.76 (dd, J
= 10.5, 2.2 Hz, 1 H), 3.78- 3.93 (m, 4 H), 3.56-3.68 (m, 4 H).
.sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -123.87 (s, 1 F) 3-18
469.9 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.36- 10.69 (m,
1 H), 8.04 (s, 1 H), 7.55 (d, J = 11.0 Hz, 1 H), 6.98 (d, J = 9.0
Hz, 1 H), 6.85 (dd, J = 16.7, 10.5 Hz, 1 H), 6.18 (dd, J = 16.7,
2.2 Hz, 1 H), 5.70-5.80 (m, 1 H), 3.86 (br d, J = 19.8 Hz, 4 H),
3.62 (br t, J = 5.1 Hz, 4 H). .sup.19F NMR (376 MHz, DMSO-d.sub.6)
.delta. -123.82 (s, 1 F), -132.61 (br s, 1 F) 3-19 451.0 .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 8.01 (s, 1 H), 7.20 (d, J = 8.6
Hz, 1 H), 6.85 (dd, J = 16.7, 10.5 Hz, 1 H), 6.66 (dd, J = 8.6, 2.7
Hz, 1 H), 6.54 (d, J = 2.5 Hz, 1 H), 6.17 (dd, J = 16.7, 2.2 Hz, 1
H), 5.67- 5.82 (m, 1 H), 5.40 (s, 2 H), 3.85 (br d, J = 19.4 Hz, 4
H), 3.54-3.73 (m, 4 H). .sup.19F NMR (376 MHz, DMSO-d.sub.6)
.delta. -124.25 (1 F, s) 3-20 485.0 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.04 (s, 1 H), 7.50 (s, 1 H), 6.85 (dd, J =
16.7, 10.5 Hz, 1 H), 6.79 (s, 1 H), 6.18 (dd, J = 16.7, 1.9 Hz, 1
H), 5.76 (dd, J = 10.6, 1.8 Hz, 1 H), 5.70 (s, 2 H), 3.86 (br d, J
= 19.8 Hz, 4 H), 3.63 (br d, J = 4.9 Hz, 4 H). .sup.19F NMR (376
MHz, DMSO-d.sub.6) .delta. -124.05 (br s, 1 F) 3-21 445.2 .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 8.54 (d, J = 5.4 Hz, 1 H), 8.29
(s, 1 H), 8.02 (s, 1 H), 7.47 (d, J = 5.2 Hz, 1 H), 6.78 (dd, J =
16.7, 10.5 Hz, 1 H), 6.10 (dd, J = 16.7, 2.2 Hz, 1 H), 5.62-5.75
(m, 1 H), 3.71-3.88 (m, 4 H), 3.56 (br t, J = 5.3 Hz, 4 H),
2.49-2.64 (m, 1 H), 1.10 (d, J = 6.8 Hz, 3 H), 1.01 (d, J = 6.8 Hz,
3 H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -123.04 (1 F, s)
3-22 486.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.52 (br s,
1 H), 8.07 (s, 1 H), 7.14 (d, J = 2.7 Hz, 1 H), 6.78-6.93 (m, 2 H),
6.19 (dd, J = 16.7, 2.2 Hz, 1 H), 5.70-5.82 (m, 1 H), 3.79-3.92 (m,
4 H), 3.63 (br t, J = 5.0 Hz, 4 H). .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -124.13 (s, 1 F) 3-23 452.1 .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.03- 8.14 (m, 3 H) 7.41-7.69 (m, 5 H)
6.84- 6.91 (m, 1 H) 6.17-6.22 (m, 1 H) 5.76- 5.79 (m, 1 H)
3.86-3.91 (m, 4 H) 3.65- 3.67 (m, 4 H) 3-24 453 .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.78- 8.87 (m, 1 H) 8.43-8.54 (m, 1 H)
8.04- 8.40 (m, 2 H) 7.45-7.79 (m, 2 H) 7.53- 7.65 (m, 1 H)
6.74-6.98 (m, 1 H) 6.09- 6.26 (m, 1 H) 5.79-5.81 (m, 1 H) 3.83-
3.93 (m, 4 H) 3.52-3.66 (m, 4 H) 3-25 442 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.03 (s, 1 H) 6.81-6.98 (m, 4 H) 6.15-6.20
(m, 1 H) 5.72-5.86 (m, 3 H) 3.83-3.88 (m, 4 H) 3.6-3.62 (m, 4 H)
4-1 480.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.82- 10.04
(1 H, m), 7.79 (1 H, d, J = 8.2 Hz), 7.66 (1 H, s), 7.43 (1 H, dt,
J = 8.3, 4.0 Hz), 7.26 (1 H, d, J = 2.3 Hz), 7.22 (2 H, d, J = 3.7
Hz), 7.05 (1 H, d, J = 2.3 Hz), 6.26-6.38 (1 H, m), 6.12 (1 H, dd,
J = 16.8, 2.2 Hz), 5.66-5.72 (1 H, m), 4.58- 4.67 (4 H, m), 4.50 (2
H, s), 4.22 (2 H, s). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.
-123.98 (1 F, s) 4-2 418.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.65 (1 H, d, J = 1.4 Hz), 6.25-6.36 (1 H, m), 6.10 (1 H,
dd, J = 17.0, 2.3 Hz), 5.64- 5.72 (1 H, m), 4.58 (4 H, s), 4.47 (2
H, s), 4.18 (2 H, s). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.
-113.54 (1 F, s) 4-3 494.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.93 (1
H, d, J = 8.4 Hz), 7.67 (1 H, s), 7.45- 7.57 (2 H, m), 7.23-7.36 (2
H, m), 7.16 (1 H, d, J = 2.5 Hz), 6.27-6.39 (1 H, m), 6.11 (1 H,
dd, J = 17.0, 2.2 Hz), 5.65- 5.76 (1 H, m), 4.58-4.67 (4 H, m),
4.50 (2 H, s), 4.22 (2 H, s), 3.93 (3 H, s). .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -123.88 (1 F, s) 4-4 391.8 .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.93 (1 H, br s), 7.63-7.77 (1 H, m),
6.04-6.33 (2 H, m), 5.60-5.77 (1 H, m), 4.89 (1 H, br d, J = 3.3
Hz), 4.72 (2 H, br dd, J = 8.1, 3.6 Hz), 4.28 (2 H, br dd, J = 8.0,
3.9 Hz). .sup.19F NMR (377 MHz, DMSO-d.sub.6) .delta. -113.24 (1 F,
s) 4-5 468.0 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.92- 9.00 (1
H, m), 7.93 (1 H, d, J = 8.2 Hz), 7.72 (1 H, s), 7.45-7.60 (2 H,
m), 7.25- 7.36 (2 H, m), 7.17 (1 H, d, J = 2.3 Hz), 6.08-6.36 (2 H,
m), 5.69 (1 H, dd, J = 9.8, 2.2 Hz), 4.87-5.01 (1 H, m), 4.69- 4.84
(2 H, m), 4.33 (2 H, br d, J = 3.3 Hz), 3.94 (3 H, s). .sup.19F NMR
(376 MHz, DMSO-d.sub.6) .delta. -123.93 (1 F, s) 4-6 454.0 .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 9.95 (1 H, s), 8.97 (1 H, d, J
= 7.0 Hz), 7.80 (1 H, d, J = 8.2 Hz), 7.72 (1 H, s), 7.39- 7.49 (1
H, m), 7.16-7.32 (3 H, m), 7.05 (1 H, d, J = 2.2 Hz), 6.08-6.36 (2
H, m), 5.65-5.73 (1 H, m), 4.87-5.05 (1 H, m), 4.77 (2 H, td, J =
8.2, 2.6 Hz), 4.33 (2 H, br t, J = 6.2 Hz). .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -124.03 (1 F, s) 4-7 391.8 .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.23- 9.42 (1 H, m), 8.04 (1 H, d, J =
1.0 Hz), 6.37 (1 H, dd, J = 17.0, 10.2 Hz), 6.15 (1 H, dd, J =
17.0, 2.0 Hz), 5.65-5.86 (1 H, m), 4.70 (1 H, br t, J = 8.0 Hz),
4.35- 4.48 (1 H, m), 4.25-4.33 (1 H, m), 4.22 (1 H, br dd, J = 9.0,
4.3 Hz), 3.99 (1 H, br dd, J = 10.3, 4.4 Hz). .sup.19F NMR (376
MHz, DMSO-d.sub.6) .delta. -113.81 (1 F, s) 4-8 420.0 .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.64 (1 H, br s), 8.15 (1 H, br d,
J = 8.8 Hz), 6.58- 6.97 (1 H, m), 5.97-6.27 (1 H, m), 5.58- 5.74 (1
H, m), 4.50 (1 H, br d, J = 11.5 Hz), 3.91 (1 H, br d, J = 13.5
Hz), 3.14- 3.28 (2 H, m), 2.85-2.97 (1 H, m), 2.08- 2.23 (1 H, m),
1.79-1.91 (1 H, m), 1.64- 1.78 (1 H, m), 1.45-1.60 (1 H, m).
.sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -114.17 (1 F, br s)
4-9 482.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.87- 10.07
(1 H, m), 8.50-8.70 (1 H, m), 8.06- 8.23 (1 H, m), 7.70-7.88 (1 H,
m), 7.39- 7.48 (1 H, m), 7.19-7.28 (3 H, m), 7.02- 7.08 (1 H, m),
6.68-6.93 (1 H, m), 6.05- 6.23 (1 H, m), 5.64-5.78 (1 H, m), 4.51-
4.63 (1 H, m), 4.06-4.17 (1 H, m), 3.91- 4.04 (1 H, m), 3.14-3.30
(1 H, m), 2.91- 3.01 (1 H, m), 2.14-2.29 (1 H, m), 1.83- 1.96 (1 H,
m), 1.68-1.82 (1 H, m), 1.49- 1.65 (1 H, m). 5-1 468.0 .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.89- 10.10 (m, 1 H), 7.79 (d, J =
8.4 Hz, 1 H), 7.73 (s, 1 H), 7.43 (ddd, J = 8.2, 5.1, 2.9 Hz, 1 H),
7.20-7.30 (m, 3 H), 7.05 (d, J = 2.2 Hz, 1 H), 6.81 (dd, J = 16.7,
10.5 Hz, 1 H), 6.10-6.23 (m, 1 H), 5.69-5.81 (m, 1 H), 5.37-5.59
(m, 1 H), 4.63-4.74 (m, 3 H), 4.53-4.61 (m, 1 H), 3.14-3.23 (m, 3
H). .sup.19F NMR (376 MHz, DMSO- d.sub.6) .delta. -124.10 (1 F, s)
5-2 468.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.89- 10.09
(m, 1 H), 8.70 (s, 1 H), 7.79 (d, J = 8.2 Hz, 1 H), 7.69 (s, 1 H),
7.39-7.46 (m, 1 H), 7.16-7.31 (m, 3 H), 7.05 (d, J = 2.2 Hz, 1 H),
6.20-6.32 (m, 1 H), 6.08- 6.18 (m, 1 H), 5.65 (dd, J = 10.1, 1.9
Hz, 1 H), 4.57 (dd, J = 8.1, 1.9 Hz, 2 H), 4.40 (br d, J = 8.4 Hz,
2 H), 1.67 (s, 3 H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.
-124.13 (1 F, s) 5-3 484.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.95 (s, 1 H), 8.74 (s, 1 H), 7.79 (d, J = 8.4 Hz, 1 H),
7.70 (s, 1 H), 7.42 (br t, J = 6.6 Hz, 1 H), 7.16-7.28 (m, 3 H),
7.05 (d, J = 2.2 Hz, 1 H), 6.23-6.41 (m, 1 H), 6.07- 6.19 (m, 1 H),
5.66 (dd, J = 10.1, 1.7 Hz, 1 H), 5.36 (br t, J = 5.8 Hz, 1 H),
4.49 (s, 4 H), 3.74 (br d, J = 5.5 Hz, 2 H). .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -124.12 (1 F, s) 5-4 482.1 .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.99 (s, 1 H), 8.02 (s, 1 H), 7.80 (d, J
= 8.1 Hz, 1 H), 7.38-7.52 (m, 1 H), 7.16-7.34 (m, 3 H), 7.07 (s, 1
H), 6.75-6.96 (m, 1 H), 6.11-6.35 (m, 1 H), 5.66-5.90 (m, 1 H),
4.43-4.91 (m, 1 H), 4.07-4.39 (m, 1 H), 3.90-4.05 (m, 1 H),
3.71-3.87 (m, 1 H), 3.61 (br d, J = 9.7 Hz, 1 H), 3.33-3.51 (m, 2
H), 1.36 (br s, 3 H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.
-124.10 (1 F, s) 5-5 480.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.97 (s, 1 H), 7.80 (d, J = 8.3 Hz, 1 H), 7.69 (d, J = 4.4
Hz, 1 H), 7.38-7.49 (m, 1 H), 7.16- 7.29 (m, 3 H), 7.05 (d, J = 1.0
Hz, 1 H), 6.54-6.86 (m, 1 H), 6.14-6.31 (m, 1 H), 5.74-5.80 (m, 1
H), 5.21-5.40 (m, 1 H), 4.96-5.17 (m, 1 H), 4.61-4.73 (m, 1 H),
4.15-4.42 (m, 2 H), 3.55-3.92 (m, 1 H), 2.25-2.47 (m, 1 H),
1.93-2.20 (m, 1 H) 5-6 480.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.97 (s, 1 H), 7.80 (d, J = 8.1 Hz, 1 H), 7.69 (d, J = 4.1
Hz, 1 H), 7.43 (dt, J = 8.1, 4.1 Hz, 1 H), 7.26 (d, J = 2.3 Hz, 1
H), 7.19- 7.25 (m, 2 H), 7.05 (d, J = 2.1 Hz, 1 H), 6.55-6.83 (m, 1
H), 6.23 (ddd, J = 16.5, 7.5, 2.2 Hz, 1 H), 5.79 (br d, J = 2.1 Hz,
1 H), 5.22-5.40 (m, 1 H), 4.96-5.18 (m, 1 H), 4.61-4.72 (m, 1 H),
4.18-4.44 (m, 2 H), 3.57-3.94 (m, 1 H), 2.27-2.45 (m, 1 H),
1.92-2.24 (m, 1 H) 5-7 482.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.97 (1 H, br s), 8.02 (1 H, s), 7.80 (1 H, d, J = 8.5 Hz),
7.35-7.53 (1 H, m), 7.17-7.33 (3 H, m), 7.07 (1 H, d, J = 2.3 Hz),
6.84 (1 H, dd, J = 16.7, 10.5 Hz), 6.19 (1 H, dd, J = 16.8, 1.7
Hz), 5.68-5.83 (1 H, m), 4.43-4.93 (1 H, m), 4.08-4.39 (1 H, m),
3.93-4.05 (1 H, m), 3.79 (1 H, br d, J = 11.6 Hz), 3.54-3.66 (1 H,
m), 3.37- 3.50 (2 H, m), 1.35 (3 H, br s). .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -123.81 (1 F, d, J = 16.5 Hz) 5-8 480.0
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.98 (s, 1 H), 7.86 (br
d, J = 8.7 Hz, 1 H), 7.80 (d, J = 8.1 Hz, 1 H), 7.37-7.53 (m, 1 H),
7.19-7.31 (m, 3 H), 7.06 (br s, 1 H), 6.25- 6.55 (m, 1 H),
6.11-6.24 (m, 1 H), 5.64- 5.82 (m, 1 H), 5.14-5.44 (m, 1 H), 5.03-
5.12 (m, 1 H), 4.24-4.59 (m, 1 H), 3.63- 4.20 (m, 3 H), 2.22-2.48
(m, 2 H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.
-124.17--123.93 (m, 1 F) 5-9 468.0 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.98 (s, 1 H), 8.04 (s, 1 H), 7.80 (d, J =
8.5 Hz, 1 H), 7.38-7.52 (m, 1 H), 7.15-7.35 (m, 3 H), 7.07 (d, J =
2.3 Hz, 1 H), 6.39 (dd, J = 17.0, 10.4 Hz, 1 H), 6.16 (dd, J =
17.0, 2.1 Hz, 1 H), 5.66-5.81 (m, 1 H), 4.94- 5.06 (m, 1 H), 4.67
(br t, J = 8.7 Hz, 1 H), 4.49 (br dd, J = 9.4, 5.3 Hz, 1 H),
4.31-4.43 (m, 1 H), 4.21 (br dd, J = 10.6, 5.2 Hz, 1 H), 3.43 (s, 3
H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -124.00 (s, 1 F)
6-1 452.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.97- 8.10
(m, 1 H), 7.60 (d, J = 8.9 Hz, 1 H), 6.86 (dd, J = 16.6, 10.6 Hz, 1
H), 6.57 (d, J = 8.9 Hz, 1 H), 6.38 (s, 2 H), 6.19 (dd, J = 16.8,
2.3 Hz, 1 H), 5.71-5.84 (m, 1 H), 3.86 (br d, J = 19.9 Hz, 4 H),
3.63 (br d, J = 1.0 Hz, 4 H). .sup.19F NMR (376 MHz, DMSO-d.sub.6)
.delta. -126.04 (1 F, s) 6-2 437.0 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.67- 8.79 (1 H, m), 8.18 (1 H, dd, J = 8.3,
1.0 Hz), 8.10 (1 H, s), 7.61 (1 H, dd, J = 8.2, 4.7 Hz), 6.86 (1 H,
dd, J = 16.6, 10.4 Hz), 6.19 (1 H, dd, J = 16.8, 2.3 Hz), 5.77 (1
H, dd, J = 10.4, 2.3 Hz), 3.79- 3.97 (4 H, m), 3.58-3.73 (4 H, m).
.sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -125.75 (1 F, s) 7-1
518.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.13 (br. s., 1
H) 8.12 (d, J = 2.2 Hz, 1 H) 7.80 (d, J = 8.2 Hz, 1 H) 7.43 (br t,
J = 7.0 Hz, 1 H) 7.20-7.30 (m, 3 H) 7.08 (dd, J = 5.8, 2.2 Hz, 1 H)
6.78-6.91 (m, 1 H) 6.27- 6.70 (m, 1 H) 6.20 (dd, J = 16.6, 2.0 Hz,
1 H) 5.76-5.84 (m, 1 H) 4.73-4.87 (m, 1 H) 4.19-4.72 (m, 2 H)
3.55-3.90 (m, 3 H) 3.36-3.47 (m, 1 H) 7-2 500.0 .sup.1H NMR
(DMSO-d.sub.6) .delta.: 9.73-10.17 (m, 1H), 8.04-8.12 (m, 1H),
7.77-7.84 (m, 1H), 7.39-7.48 (m, 1H), 7.20-7.30 (m, 3H), 7.06-7.10
(m, 1H), 6.77-6.93 (m, 1H), 6.15-6.24 (m, 1H), 5.74-5.83 (m, 1H),
4.57-4.92 (m, 3H), 4.14-4.54 (m, 2H), 3.55-3.87 (m, 3H), 3.21-3.29
(m, 1H) 7-3 526.0 .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.76-10.22
(m, 1H), 8.09-8.14 (m, 1H), 7.77-7.84 (m, 1H), 7.39-7.48 (m, 1H),
7.20-7.29 (m, 3H), 7.04-7.11 (m, 1H), 6.82 (br. s., 1H), 6.14-6.22
(m, 1H), 5.77-5.83 (m, 1H), 3.68-5.36 (m, 4H), 3.60-3.67 (m, 3H)
8-1 547 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.06 (br. d, J
= 15.1 Hz, 1 H) 8.03 (d, J = 1.2 Hz, 1 H) 7.51-7.56 (m, 1 H) 7.45
(t, J = 7.6 Hz, 1 H) 7.33 (tdd, J = 7.5, 7.5, 3.8, 1.4 Hz, 1 H)
7.14-7.25 (m, 2 H) 6.84 (dd, J = 16.8, 10.4 Hz, 1 H) 6.62-6.74 (m,
2 H) 6.14-6.26 (m, 2 H) 5.71-5.78 (m, 1 H) 3.71-3.99 (m, 8 H)
2.52-2.59 (m, 1 H) 1.02-1.12 (m, 6 H). .sup.19F NMR (377 MHz,
DMSO-d.sub.6) .delta. -113.6 (s, 1 F) -114.8 (s, 1 F). 8-2 548.2
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.61 (1 H, br s) 8.17 (1
H, s) 7.49-7.55 (2 H, m) 7.35-7.43 (1 H, m) 7.23-7.30 (1 H, m) 7.09
(1 H, d, J = 7.88 Hz) 6.58-6.72 (3 H, m) 6.41 (1 H, dd, J = 16.79,
1.66 Hz) 5.82 (1 H, dd, J = 10.47, 1.55 Hz) 3.80- 4.15 (8 H, m)
2.71 (1 H, spt, J = 6.84 Hz) 1.23 (3 H, d, J = 6.84 Hz) 1.03 (4 H,
d, J = 6.84 Hz) 8-3 561 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.81 (s, 1 H) 7.35-7.49 (m, 2 H) 7.18-7.32 (m, 1 H) 7.01-7.17 (m, 2
H) 6.67-6.74 (m, 1 H) 6.48-6.65 (m, 3 H) 6.32-6.44 (m, 1 H)
5.77-5.83 (m, 1 H) 4.19-5.14 (m, 3 H) 3.75-3.98 (m, 1 H) 3.41-3.68
(m, 2 H) 2.85-3.28 (m, 1 H) 2.49-2.71 (m, 1 H) 1.34-1.54 (m, 3 H)
1.13-1.21 (m, 3 H) 1.00-1.07 (m, 3 H). .sup.19F NMR (377 MHz,
CDCl.sub.3) .delta. -113.43--113.3 (m, 1 F) -114.3--113.9 (m, 1 F).
8-3-1 561.2 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.82 (s, 1 H)
7.37-7.51 (m, 2 H) 7.21-7.34 (m, 1 H) 7.05-7.20 (m, 2 H) 6.70 (br
d, J = 8.1 Hz, 1 H) 6.52-6.67 (m, 3 H) 6.39 (dd, J = 16.8, 1.7 Hz,
1 H) 5.80 (dd, J = 10.5, 1.6 Hz, 1 H) 4.26-5.00 (m, 3 H) 3.40- 4.00
(m, 3 H) 3.06-3.24 (m, 1 H) 2.52- 2.69 (m, 1 H) 1.20 (d, J = 6.2
Hz, 6 H) 1.04 (br d, J = 6.4 Hz, 3 H). .sup.19F NMR (377 MHz,
CDCl.sub.3) .delta. -113.31 (br d, J = 63.3 Hz, 1 F) -113.99 (br d,
J = 33.8 Hz, 1 F). 8-3-2 561.2 .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.79 (br s, 1 H) 7.35-7.48 (m, 2 H) 7.21-7.32 (m, 1 H)
7.04-7.17 (m, 2 H) 6.68 (d, J = 8.3 Hz, 1 H) 6.49-6.66 (m, 3 H)
6.36 (br d, J = 16.6 Hz, 1 H) 5.78 (dd, J = 10.4, 1.9 Hz, 1 H)
4.29-5.11 (m, 2 H) 3.46-4.02 (m, 3 H) 2.93-3.29 (m, 2 H) 2.49-2.68
(m, 1 H) 1.48 (dd, J = 14.5, 2.1 Hz, 6 H) 1.03 (br d, J = 6.0 Hz, 3
H). .sup.19F NMR (377 MHz, CDCl.sub.3) .delta. -113.32 (br d, J =
9.5 Hz, 1 F) -114.02--113.78 (m, 1 F).
8-4 576 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.58 (s, 1 H)
8.13 (s, 1 H) 7.41-7.50 (m, 1 H) 7.32 (s, 1 H) 7.30 (s, 1 H)
7.22-7.30 (m, 1 H) 6.53-6.75 (m, 3 H) 6.42 (dd, J = 16.8, 1.7 Hz, 1
H) 5.77-5.86 (m, 1 H) 3.53- 5.25 (m, 6 H) 2.98-3.34 (m, 1 H) 2.16-
2.49 (m, 4 H) 1.52 (br d, J = 19.5 Hz, 3 H) 1.07-1.17 (m, 6 H).
.sup.19F NMR (377 MHz, CDCl.sub.3) .delta. -104.8 (br. s., 1 F)
-104.9 (br. s., 1 F). 8-5 546.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.08-10.10 (m, 1 H) 8.47-8.48 (m, 1 H) 8.37 (s, 1H), 8.05
(s, 1H), 7.16-7.26 (m, 1H) 7.04-7.25 (m, 1 H) 6.82-6.90 (m, 1 H)
6.63-6.77 (m, 2 H) 6.30-6.31 (m, 1 H) 6.16-6.21 (m, 1 H) 5.72-5.79
(m, 1 H) 3.84-4.02 (m, 6 H) 3.76-3.81 (m, 2 H), 1.54-1.55 (m, 1 H)
1.23 (s, 2H) 0.74-0.85 (m, 1 H), 0.52-0.69 (m, 1 H) 8-6 562.1
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.62 (1 H, br s)
8.10-8.13 (1 H, m) 7.49-7.56 (2 H, m) 7.35-7.43 (1 H, m) 7.22-7.30
(1 H, m) 7.10 (1 H, br s) 6.54-6.73 (3 H, m) 6.38-6.45 (1 H, m)
5.82 (1 H, dd, J = 10.57, 1.45 Hz) 2.60-5.27 (8 H, m) 1.42- 1.54 (3
H, m) 1.23 (3 H, d, J = 6.84 Hz) 1.03 (3 H, d, J = 6.84 Hz) 9-1
611.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.42 (br d, J =
17.0 Hz, 1 H), 7.86-8.11 (m, 1 H), 7.50-7.63 (m, 1 H), 7.47 (br t,
J = 6.0 Hz, 1 H), 7.36 (t, J = 7.5 Hz, 1 H), 7.15-7.26 (m, 1 H),
7.05 (d, J = 2.3 Hz, 1 H), 6.78-6.96 (m, 1 H), 6.44-6.58 (m, 1 H),
6.11-6.29 (m, 2 H), 5.71-5.82 (m, 1 H), 4.68-4.98 (m, 1 H),
3.96-4.52 (m, 3 H), 3.52-3.85 (m, 2 H), 3.34-3.51 (m, 1 H),
2.95-3.26 (m, 1 H), 1.27-1.41 (m, 3 H), 0.95-1.13 (m, 6 H) 9-2
531.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.91- 8.08 (m, 1
H), 7.49-7.67 (m, 2 H), 7.41 (br d, J = 5.8 Hz, 1 H), 7.21 (br s, 1
H), 6.76-6.98 (m, 1 H), 6.52-6.67 (m, 1 H), 6.09-6.29 (m, 1 H),
5.75 (br s, 1 H), 4.61- 4.96 (m, 1 H), 4.23-4.48 (m, 1 H), 3.93-
4.21 (m, 2 H), 3.50-3.77 (m, 1H), 3.33- 3.49 (m, 1 H), 3.23-3.28
(m, 1 H), 2.94- 3.24 (m, 1 H), 1.27 (br d, J = 9.3 Hz, 6 H), 1.09
(br s, 3 H) 9-3 576.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
7.88- 8.01 (m, 1 H), 7.49-7.61 (m, 1 H), 7.46 (br t, J = 7.6 Hz, 1
H), 7.36 (t, J = 7.3 Hz, 1 H), 7.15-7.25 (m, 1 H), 7.08 (d, J = 8.7
Hz, 1 H), 6.76-6.95 (m, 1 H), 6.57 (dd, J = 8.7, 2.5 Hz, 1 H),
6.17-6.32 (m, 2 H), 6.11-6.16 (m, 1 H), 5.72-5.81 (m, 1 H), 5.40
(br d, J = 10.8 Hz, 2 H), 4.66- 4.99 (m, 1 H), 4.21-4.52 (m, 2 H),
3.94- 4.20 (m, 2 H), 3.53-3.82 (m, 2 H), 3.36- 3.51 (m, 1 H),
1.27-1.40 (m, 3 H), 0.95- 1.12 (m, 6 H) 9-4 593.2 .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.94 (br. s, 1H), 8.10 (s, 1H), 7.72 (d,
J = 8.1 Hz, 1H), 7.43-7.51 (m, 1H), 7.31-7.42 (m, 3H), 7.11-7.27
(m, 4H), 6.68-6.93 (m, 2H), 6.14-6.36 (m, 2H), 5.70-5.83 (m, 1H),
3.72-4.12 (m, 8H), 2.23-2.40 (m, 1H), 1.32-1.65 (m, 2H), 0.95-1.16
(m, 3H), 0.36-0.75 (m, 3H). 9-5 530.2 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.97 (s, 1 H) 7.85-7.90 (m, 2 H) 7.64- 7.72
(m, 2 H) 7.10-7.18 (m, 1 H) 6.73- 6.78 (m, 1 H) 6.57-6.67 (m, 2 H)
6.33 (s, 1 H) 6.10-6.14 (m, 1 H) 5.66-5.72 (m, 1 H) 3.85-3.96 (m, 4
H) 3.48-3.79 (m, 2 H) 3.68-3.75 (m, 2 H) 9-6 546.2 .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.92-10.25 (m, 1 H) 8.44-8.82 (m, 1 H)
8.27-8.40 (m, 1 H) 7.99 (s, 1 H) 7.27-7.28 (m, 1 H) 7.11-7.21 (m, 1
H) 6.72-6.91 (m, 1 H) 6.48-6.71 (m, 2 H) 6.03-6.31 (m, 2 H)
5.48-5.79 (m, 1 H) 3.57 4.16 (m, 8 H) 1.36-1.70 (m, 1 H) 0.21-0.92
(m, 4 H) 9-7 561.2 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta.
8.44-8.56 (m, 1 H) 8.41-8.44 (m, 1 H) 8.00-8.03 (m, 1 H) 7.35-7.37
(m, 1 H) 7.14-7.23 (m, 1 H) 6.75-6.83 (m, 1 H), 6.56-6.66 (m, 2 H)
6.40-6.46 (m, 1 H) 6.25-6.31 (m, 1 H) 5.75-5.82 (m, 1 H) 4.42-4.67
(m, 2 H) 3.59-3.89 (m, 2 H) 1.57-1.70 (m, 1 H) 1.45-1.52 (m, 3 H)
1.27 (s, 4H) 0.80-0.88 (m, 3 H) 9-8 561.2 .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 8.43-8.50 (m, 1 H) 8.30-8.36 (m, 1 H)
7.91-7.97 (m, 1 H) 7.25-7.32 (m, 1 H) 7.07-7.14 (m, 1 H) 6.70-6.78
(m, 1 H) 6.47-6.60 (m, 2 H) 6.33-6.41 (m, 1 H) 6.16-6.26 (m, 1 H)
5.68-5.77 (m, 1 H) 4.32-4.52 (m, 2 H) 3.50-3.81 (m, 2 H) 1.51-1.62
(m, 1 H) 1.36-1.41 (m, 3 H) 1.19 (s, 4 H) 0.74-0.85 (m, 3 H) 9-9
581.2 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 8.48-8.57 (m,
1 H) 8.31-8.41 (m, 1 H) 8.13-8.18 (m, 1 H) 7.38-7.54 (m, 3 H)
7.28-7.40 (m, 1 H) 6.82-6.95 (m, 1 H) 6.45-6.50 (m, 1 H) 6.28-6.38
(m, 1 H) 5.81-5.90 (m, 1 H) 4.47-4.63 (m, 2 H) 4.07-4.25 (m, 1 H)
3.63-3.94 (m, 2 H) 2.13-2.21 (m, 3 H) 1.62-1.75 (m, 1 H) 1.51-1.57
(m, 3 H) 1.27-1.37 (m, 3 H) 0.86-0.95 (m, 3 H) 9-10 597.2 .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 8.01 (br d, J = 18.0 Hz, 1 H),
7.71 (d, J = 8.1 Hz, 1 H), 7.50-7.58 (m, 1 H), 7.39-7.49 (m, 2 H),
7.35 (t, J = 7.4 Hz, 1 H), 7.09- 7.27 (m, 2 H), 6.78-6.97 (m, 1 H),
6.14- 6.29 (m, 2 H), 5.71-5.82 (m, 1 H), 4.70- 4.98 (m, 1 H),
3.98-4.54 (m, 3 H), 3.39- 3.85 (m, 2 H), 2.91-3.29 (m, 1 H), 1.27-
1.41 (m, 3 H), 1.10 (br t, J = 6.2 Hz, 3 H), 0.94-1.07 (m, 3 H)
9-11 561.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.99 (br d,
J = 16.6 Hz, 1 H), 7.49-7.68 (m, 2 H), 7.29-7.48 (m, 4 H),
7.10-7.26 (m, 2 H), 6.76-6.96 (m, 1 H), 6.12-6.31 (m, 2 H),
5.71-5.82 (m, 1 H), 4.68-4.97 (m, 1 H), 3.95-4.51 (m, 3 H),
3.44-3.85 (m, 2 H), 2.92-3.26 (m, 2 H), 1.27-1.41 (m, 3 H),
1.06-1.17 (m, 3 H), 0.92-1.06 (m, 3 H) 9-12 583 .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.35 (s, 1 H) 8.08 (d, J = 8.3 Hz, 1 H)
7.51-7.59 (m, 1 H) 7.34-7.44 (m, 3 H) 7.21 (td, J = 7.7, 0.8 Hz, 1
H) 6.85 (d, J = 8.5 Hz, 1 H) 6.56-6.75 (m, 1 H) 6.45 (dd, J = 16.8,
1.7 Hz, 1 H) 5.81-5.90 (m, 1 H) 4.33-5.25 (m, 3 H) 3.82-4.01 (m, 1
H) 3.05-3.71 (m, 3 H) 2.40-2.58 (m, 2 H) 2.20-2.37 (m, 2 H) 1.57
(br d, J = 18.0 Hz, 3 H) 1.10 (td, J = 7.6, 0.8 Hz, 6 H). 9-13
579.2 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.93 (0.5 H, s)
7.92 (0.5 H, s) 7.69-7.74 (1 H, m) 7.18-7.51 (7 H, m) 7.11-7.16 (1
H, m) 6.88 (1 H, dd, J = 25.82, 2.54 Hz) 6.59- 6.68 (2 H, m) 6.42
(1 H, dd, J = 16.82, 1.76 Hz) 5.82 (1 H, dd, J = 10.56, 1.56 Hz)
3.81-4.11 (8 H, m) 2.65-2.74 (1 H, m) 1.25 (1.5 H, d, J = 6.85 Hz)
1.22 (1.5 H, d, J = 6.85 Hz) 1.13 (1.5 H, d, J = 6.85 Hz) 0.98 (1.5
H, d, J = 6.85 Hz) 9-14 540.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.21 (0.6 H, br s) 10.12 (0.4 H, br s) 8.29- 8.35 (1 H, m)
7.28-7.38 (1 H, m) 6.73- 6.85 (3 H, m) 6.17 (1 H, dd, J = 16.59,
2.28 Hz) 5.74 (1 H, dd, J = 10.37, 2.28 Hz) 5.30-5.38 (0.6 H, m)
5.00-5.06 (0.4 H, m) 3.61-3.96 (8 H, m) 2.90- 3.06 (1 H, m)
1.69-1.83 (1 H, m) 1.15- 1.52 (6 H, m) 0.69-1.04 (6 H, m) 10-1
503.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.15 (1 H, br s)
8.33 (1 H, s) 7.36-7.45 (2 H, m) 7.24-7.36 (4 H, m) 6.90 (1 H, dd,
J = 16.63, 10.37 Hz) 6.70-6.80 (2 H, m) 6.18 (1 H, dd, J = 16.73,
2.25 Hz) 5.75 (1 H, dd, J = 10.56, 2.15 Hz) 3.83-3.97 (4 H, m)
3.47-3.62 (4 H, m) 1.98-2.06 (3 H, m) 10-2 519.2 .sup.1H NMR
(CDCl.sub.3) .delta.: 8.16-8.24 (m, 1H), 7.61-7.67 (m, 1H),
7.43-7.52 (m, 2H), 7.15-7.23 (m, 1H), 7.05-7.13 (m, 1H), 6.92-7.02
(m, 1H), 6.70-6.82 (m, 2H), 6.57-6.69 (m, 1H), 6.30-6.40 (m, 1H),
5.68-5.81 (m, 1H), 3.81-4.03 (m, 4H), 3.49-3.71 (m, 7H), 2.52-2.66
(m, 1H). 10-3 537.0 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta.
8.35 (1 H, s) 7.38-7.42 (1 H, m) 7.37 (1 H, s) 7.31-7.36 (2 H, m)
7.21 (1 H, td, J = 8.31, 6.85 Hz) 6.83 (1 H, dd, J = 16.73, 10.66
Hz) 6.69 (1 H, d, J = 8.41 Hz) 6.63 (1 H, br t, J = 8.80 Hz) 6.24
(1 H, dd, J = 16.82, 1.96 Hz) 5.77 (1 H, dd, J = 10.66, 1.86 Hz)
3.94-4.01 (4 H, m) 3.58-3.66 (4 H, m) 1.99-2.04 (3 H, m) 10-4 531.2
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 8.34 (1 H, s)
7.44-7.51 (2 H, m) 7.34 (1 H, d, J = 4.30 Hz) 7.27-7.32 (1 H, m)
7.15-7.25 (2 H, m) 6.83 (1 H, dd, J = 16.82, 10.56 Hz) 6.66 (1 H,
d, J = 8.22 Hz) 6.57-6.64 (1 H, m) 6.21-6.27 (1 H, m) 5.77 (1 H,
dd, J = 10.66, 1.86 Hz) 3.93-4.02 (4 H, m) 3.56-3.65 (4 H, m)
2.46-2.56 (1 H, m) 0.98-1.13 (6 H, m) 10-5 517.1 .sup.1H NMR (400
MHz, METHANOL-d.sub.4) .delta. 8.44 (1 H, s) 7.46-7.57 (3 H, m)
7.26- 7.44 (3 H, m) 6.94 (1 H, dd, J = 16.73, 10.66 Hz) 6.77 (1 H,
d, J = 8.22 Hz) 6.68- 6.75 (1 H, m) 6.35 (1 H, dd, J = 16.73, 1.86
Hz) 5.88 (1 H, dd, J = 10.76, 1.96 Hz) 4.04-4.12 (4 H, m) 3.67-3.76
(4 H, m) 2.36-2.60 (2 H, m) 1.06 (3 H, q, J = 7.63 Hz) 10-6 504.1
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 8.56 (1 H, br d, J
= 5.09 Hz) 8.51 (1 H, s) 8.42 (1 H, s) 7.49 (1 H, br d, J = 5.09
Hz) 7.43 (1 H, s) 7.22-7.29 (1 H, m) 6.87 (1 H, dd, J = 16.73,
10.66 Hz) 6.72 (1 H, br d, J = 8.41 Hz) 6.67 (1 H, br t, J = 8.71
Hz) 6.28 (1 H, dd, J = 16.73, 1.27 Hz) 5.79-5.84 (1 H, m) 3.98-4.06
(4 H, m) 3.64-3.73 (4 H, m) 2.19 (3 H, s) 10-7 517.2 .sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta. 8.46 (1 H, s) 7.24-7.41 (5 H,
m) 6.93 (1 H, dd, J = 16.82, 10.56 Hz) 6.76 (1 H, d, J = 8.41 Hz)
6.68-6.74 (1 H, m) 6.34 (1 H, dd, J = 16.82, 1.96 Hz) 5.87 (1 H,
dd, J = 10.56, 1.96 Hz) 4.05-4.11 (4 H, m) 3.68-3.76 (4 H, m) 2.02
(3 H, s) 2.00 (3 H, s) 10-8 504.2 .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 8.62 (1 H, dd, J = 4.89, 1.56 Hz) 8.43 (1
H, s) 7.87 (1 H, dd, J = 7.73, 1.47 Hz) 7.48 (1 H, dd, J = 7.63,
5.09 Hz) 7.43 (1 H, s) 7.27 (1 H, td, J = 8.31, 6.85 Hz) 6.89 (1 H,
dd, J = 16.82, 10.56 Hz) 6.74 (1 H, d, J = 8.22 Hz) 6.68 (1 H, t, J
= 8.80 Hz) 6.30 (1 H, dd, J = 16.73, 1.86 Hz) 5.83 (1 H, dd, J =
10.66, 1.86 Hz) 3.99-4.07 (4 H, m) 3.65-3.74 (4 H, m) 2.34 (3 H, s)
10-9 528.2 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 8.33 (1
H, s) 7.75 (1 H, s) 7.52-7.56 (1 H, m) 7.12-7.28 (4 H, m) 6.82 (1
H, dd, J = 16.73, 10.66 Hz) 6.64 (1 H, d, J = 8.41 Hz) 6.55-6.61 (1
H, m) 6.24 (1 H, dd, J = 16.82, 1.96 Hz) 6.14 (1 H, dd, J = 3.33,
0.78 Hz) 5.77 (1 H, dd, J = 10.56, 1.96 Hz) 3.91-4.01 (4 H, m)
3.55-3.63 (4 H, m) 10-10 529.1 .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta. 8.52 (1 H, s) 7.55-7.63 (2 H, m) 7.44-
7.51 (2 H, m) 7.35-7.43 (1 H, m) 7.24 (1 H, t, J = 7.04 Hz) 7.02 (1
H, dd, J = 16.73, 10.66 Hz) 6.83-6.90 (1 H, m) 6.76-6.83 (1 H, m)
6.43 (1 H, dd, J = 16.73, 1.66 Hz) 5.97 (1 H, dd, J = 10.66, 1.66
Hz) 4.13-4.19 (4 H, m) 3.76-3.82 (4 H, m) 1.56-1.70 (1 H, m)
0.70-0.92 (3 H, m) 0.55-0.68 (1 H, m) 10-11 523.1 .sup.1H NMR (400
MHz, METHANOL-d.sub.4) .delta. 8.40 (1 H, s) 7.50-7.70 (4 H, m)
7.42 (1
H, s) 7.22-7.30 (1 H, m) 6.89 (1 H, dd, J = 16.73, 10.66 Hz)
6.63-6.76 (2 H, m) 6.30 (1 H, dd, J = 16.73, 1.86 Hz) 5.83 (1 H,
dd, J = 10.56, 1.96 Hz) 3.98-4.10 (4 H, m) 3.62-3.76 (4 H, m) 10-12
543.1 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 8.45 (1 H, s)
7.63-7.67 (1 H, m) 7.51- 7.54 (1 H, m) 7.44-7.48 (1 H, m) 7.34-
7.37 (1 H, m) 7.21 (1 H, td, J = 8.22, 6.85 Hz) 6.90 (1 H, dd, J =
16.73, 10.66 Hz) 6.58-6.72 (2 H, m) 6.31 (1 H, dd, J = 16.82, 1.96
Hz) 5.84 (1 H, dd, J = 10.56, 1.96 Hz) 4.03-4.08 (4 H, m) 3.69-3.75
(4 H, m) 2.22 (1.25 H, s) 2.20 (1.75 H, s) 10-13 447.0 .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.26 (1 H, br s) 8.31 (1 H, s)
8.14 (1 H, s) 7.31- 7.40 (1 H, m) 6.78-6.92 (3 H, m) 6.17 (1 H, dd,
J = 16.63, 2.35 Hz) 5.74 (1 H, dd, J = 10.37, 2.35 Hz) 3.79-3.92 (4
H, m) 3.46-3.55 (4 H, m) 11-1-1 567.2 .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 10.28 (1 H, br s) 7.94 (1 H, s) 7.35-7.49 (4 H,
m) 7.25-7.31 (2 H, m) 7.11 (1 H, d, J = 7.67 Hz) 6.64 (1 H, dd, J =
16.79, 10.57 Hz) 6.54 (1 H, s) 6.41 (1 H, dd, J = 16.79, 1.87 Hz)
5.81 (1 H, dd, J = 10.57, 1.66 Hz) 3.83-4.07 (8 H, m) 2.74 (1 H,
spt, J = 6.84 Hz) 2.13 (3 H, s) 1.23 (3 H, d, J = 6.84 Hz) 1.04 (3
H, d, J = 6.84 Hz) 11-1-2 567.2 .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 10.37 (1 H, br s) 7.94 (1 H, s) 7.34-7.50 (4 H, m)
7.21-7.31 (2 H, m) 7.13 (1 H, d, J = 7.67 Hz) 6.64 (1 H, dd, J =
16.90, 10.68 Hz) 6.55 (1 H, s) 6.41 (1 H, dd, J = 16.79, 1.66 Hz)
5.81 (1 H, dd, J = 10.47, 1.55 Hz) 3.83-4.08 (8 H, m) 2.70 (1 H,
spt, J = 6.84 Hz) 2.13 (3 H, s) 1.22 (3 H, d, J = 6.84 Hz) 1.03 (3
H, d, J = 6.84 Hz). MS (ESI, +ve) m/z: 567.2 [M + H].sup.+. 11-2-1
581.3 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 8.12-8.21 (m,
1H), 7.30-7.56 (m, 6H), 7.21 (d, J = 7.7 Hz, 1H), 6.80-6.97 (m,
1H), 6.46 (s, 1H), 6.30-6.41 (m, 1H), 5.79-5.94 (m, 1H), 5.02-5.14
(m, 1H), 4.39-4.69 (m, 2H), 4.07-4.30 (m, 1H), 3.67 (s, 2H),
3.21-3.51 (m, 1H), 2.68-2.84 (m, 1H), 2.13 (s, 3H), 1.54 (br d, J =
6.0 Hz, 3H), 1.23 (d, J = 7.1 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H)
11-2-2 581.2 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 8.15
(s, 1H), 7.42-7.58 (m, 4H), 7.30-7.39 (m, 2H), 7.25 (d, J = 7.7 Hz,
1H), 6.81- 6.98 (m, 1H), 6.48 (s, 1H), 6.29-6.41 (m, 1H), 5.87 (dd,
J = 1.35, 10.68 Hz, 1H), 5.02-5.12 (m, 1H), 4.42-4.69 (m, 2H),
4.05-4.29 (m, 1H), 3.65-3.93 (m, 2H), 3.21-3.47 (m, 1H), 2.64-2.79
(m, 1H), 2.15 (s, 3H), 1.53 (br d, J = 6.6 Hz, 3H), 1.23 (br d, J =
6.8 Hz, 3H), 1.06 (d, J = 6.8 Hz, 3H)
TABLE-US-00016 TABLE 13 Analytical Data for Individual Examples
LRMS: (ESI, +ve Ex. # ion) m/z NMR 12 453.2 .sup.1H NMR
(CDCl.sub.3) .delta.: 8.30-8.37 (m, 1H), 8.11-8.18 (m, 1H),
7.29-7.38 (m, 1H), 6.96-7.18 (m, 1H), 6.88-6.94 (m, 1H), 6.76-6.85
(m, 1H), 6.59-6.72 (m, 1H), 6.31-6.42 (m, 1H), 5.73-5.84 (m, 1H),
3.73-4.05 (m, 4H), 3.35-3.62 (m, 4H), 2.40-2.52 (m, 1H), 1.35-1.42
(m, 1H), 1.29-1.34 (m, 1H), 1.03-1.14 (m, 2H). m/z (ESI) M + H:
453.2. 13 504.2 .sup.1H NMR (CDCl.sub.3) .delta.: 7.96-8.09 (m,
2H), 7.46-7.57 (m, 2H), 7.37-7.44 (m, 1H), 7.29-7.33 (m, 1H),
7.20-7.26 (m, 1H), 6.96-7.07 (m, 1H), 6.81-6.87 (m, 1H), 6.70-6.77
(m, 1H), 6.54-6.67 (m, 1H), 6.29-6.41 (m, 1H), 5.68-5.82 (m, 1H),
3.74-3.96 (m, 4H), 3.12-3.43 (m, 4H). 14 481.2. .sup.1H NMR
(CDCl.sub.3) .delta.: 8.10-8.22 (m, 2H), 7.29-7.38 (m, 1H),
6.86-6.93 (m, 1H), 6.77-6.85 (m, 1H), 6.61-6.72 (m, 1H), 6.33-6.44
(m, 1H), 5.74-5.85 (m, 1H), 3.82-4.05 (m, 4H), 3.75-3.82 (m, 1H),
3.40-3.63 (m, 4H), 2.06-2.24 (m, 4H), 1.81-1.96 (m, 2H), 1.67-1.79
(m, 2H). 15 496.2 .sup.1H NMR (CDCl.sub.3) .delta.: 8.08-8.15 (m,
1H), 7.98-8.05 (m, 1H), 7.29-7.39 (m, 1H), 6.86-6.94 (m, 1H),
6.76-6.85 (m, 1H), 6.59-6.70 (m, 1H), 6.30-6.43 (m, 1H), 5.72-5.84
(m, 1H), 3.77-4.05 (m, 4H), 3.40-3.56 (m, 4H), 3.32-3.38 (m, 4H),
1.73-1.85 (m, 4H), 1.64-1.70 (m, 2H) 16 505.2 .sup.1H NMR
(CDCl.sub.3) .delta.: 8.41-8.45 (m, 1H), 8.17-8.20 (m, 1H),
7.40-7.45 (m, 2H), 7.28-7.37 (m, 2H), 7.20-7.26 (m, 1H), 6.78-6.87
(m, 2H), 6.59-6.70 (m, 1H), 6.31-6.41 (m, 1H), 5.97-6.06 (m, 1H),
5.74-5.81 (m, 1H), 3.76-4.03 (m, 4H), 3.38-3.53 (m, 4H). 17-1 539.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.97 (s, 1H), 8.10 (s,
1H), 7.80 (d, J = 8.4 Hz, 1H), 7.40-7.46 (m, 1H), 7.19-7.30 (m,
3H), 7.97 (d, J = 2.4 Hz, 1H), 6.62-6.71 (m, 2H), 3.80-3.93 (m,
4H), 3.62-3.69 (m, 4H), 3.07 (d, J = 4.1 Hz, 2H), 2.17 (s, 6H).
17-2 525.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.97 (s,
1H), 8.10 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.40-7.46 (m, 1H),
7.19-7.30 (m, 3H), 7.97 (d, J = 2.4 Hz, 1H), 6.62-6.71 (m, 2H),
3.80-3.93 (m, 4H), 3.62-3.69 (m, 4H), 3.07 (d, J = 4.1 Hz, 2H),
2.17 (s, 6H). 18-1 512.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.12 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.47-7.55 (m, 2H),
7.25-7.34 (m, 2H), 7.19 (d, J = 2.5 Hz, 1H), 5.43 (br. s, 1H), 5.20
(br. s, 1H), 5.14 (t, J = 5.8 Hz, 1H), 4.12 (d, J = 5.7 Hz, 2H),
3.94 (s, 3H), 3.78-3.85 (m, 4H), 3.54-3.66 (m, 4H). 18-2 560.0
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.96 (br. s, 1H), 8.13
(s, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.40-7.47 (m, 1H), 7.19-7.29 (m,
3H), 7.07 (d, J = 2.4 Hz, 1H), 5.41 (s, 1H), 4.38 (s, 1H), 4.38 (s,
2H), 3.84-3.93 (m, 4H), 3.62-3.72 (m, 4H). 18-3 498.0 .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.98 (br. s, 1H), 8.11 (s, 1H),
7.79 (d, J = 8.2 Hz, 1H), 7.37-7.48 (m, 1H), 7.17-7.28 (m, 3H),
7.07 (d, J = 2.4 Hz, 1H), 5.43 (br. s, 1H), 5.20 (br. s, 1H),
5.07-5.14 (m, 1H), 4.12 (br. s, 2H), 3.78-3.86 (m, 4H), 3.57-3.66
(m, 4H). 19-1 486.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.13 (s, 1H), 8.02 (s, 1H), 7.33 (d, J = 2.2 Hz, 1H), 6.99 (d, J =
2.4 Hz, 1H), 6.85 (dd, J = 16.6, 10.6 Hz, 1H), 6.18 (dd, J = 16.7,
2.3 Hz, 1H), 5.76 (dd, J = 10.5, 2.3 Hz, 1H), 3.85-3.95 (m, 4H),
3.84 (s, 3H), 3.62-3.72 (m, 4H), 3.56 (s, 3H). 19-2 472.0 .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 9.40 (s, 1H), 8.12 (s, 1H),
7.92 (s, 1H), 7.12 (d, J = 2.2 Hz, 1H), 6.81-6.91 (m, 2H), 6.18
(dd, J = 16.7, 2.5 Hz, 1H), 5.76 (dd, J = 10.4, 2.4 Hz, 1H),
3.81-3.94 (m, 4H), 3.62-3.70 (m, 4H), 3.52 (s, 3H). 19-3 472.0
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.28 (s, 1H), 8.11 (s,
1H), 8.01 (s, 1H), 6.95 (d, J = 2.0 Hz, 1H), 6.77-6.90 (m, 2H),
6.18 (dd, J = 16.7, 2.5 Hz, 1H), 5.76 (dd, J = 10.4, 2.2 Hz, 1H),
4.03 (s, 3H), 3.80-3.94 (m, 4H), 3.58-3.66 (m, 4H). 20 512 .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 9.93 (br s, 1H), 8.11 (s, 1H),
7.80 (d, J = 12 Hz, 1H), 7.43 (m, 1H), 7.26-7.20 (m, 3H), 7.07 (s,
1H), 5.32 (s, 1H), 5.16 (s, 1H), 3.83 (br s, 4H), 3.63 (br s, 4H),
3.53 (t, J = 8.0 Hz, 2H), 2.42 (t, J = 8.0 Hz, 2H). .sup.19FNMR
(377 MHz, DMSO-d.sub.6) .delta. -123.8 (s, 1F). 21 469 .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.81 (dd, J = 4.2, 1.3 Hz, 1 H)
7.72-7.78 (m, 2 H) 7.64 (s, 1 H) 7.28 (d, J = 2.2 Hz, 1 H) 7.16
(dd, J = 8.4, 4.3 Hz, 1 H) 6.56-6.66 (m, 1 H) 6.40 (dd, J = 16.8,
1.6 Hz, 1 H) 5.78-5.87 (m, 1 H) 4.01 (br. s, 2 H) 3.89 (br. s, 2 H)
3.50-3.60 (m, 4 H). .sup.19FNMR (376 MHz, CDCl.sub.3) .delta.
-121.33 (s, 1 F). 22 512.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 3.14- 3.28 (m, 1 H) 3.52-3.87 (m, 3 H) 4.15- 5.03 (m, 2 H)
5.15-5.23 (m, 1 H) 5.77- 5.83 (m, 1 H) 6.13-6.24 (m, 1 H) 6.86 (br.
s, 1 H) 7.06-7.12 (m, 1 H) 7.20- 7.30 (m, 3 H) 7.38-7.49 (m, 1 H)
7.76- 7.84 (m, 1 H) 8.07-8.13 (m, 1 H) 9.98 (br. s, 1 H) 13.42 (br.
s, 1 H). 23 482.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
12.92- 13.19 (1 H, m), 8.02-8.21 (1 H, m), 7.47- 7.60 (2 H, m),
7.02-7.09 (1 H, m), 6.80- 6.93 (1 H, m), 6.15-6.25 (1 H, m), 5.71-
5.82 (1 H, m), 3.80-3.96 (4 H, m), 3.60- 3.72 (4 H, m), 1.55-1.74
(1 H, m), 0.72- 0.79 (2 H, m), 0.58-0.71 (2 H, m). 24 482.0 .sup.1H
NMR (400 MHz, METHANOL-d.sub.4) .delta. 7.90 (s, 1H), 7.63 (d, J =
8.5 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H),
7.05 (t, J = 7.4 Hz, 1H), 6.72- 6.84 (m, 1H), 6.67 (s, 1H),
6.15-6.28 (m, 1H), 5.68-5.81 (m, 1H), 3.87-3.97 (m, 4H), 3.63 (m,
4H), 2.90 (s, 3H). 25 468.0 .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
.delta. 7.85 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.39 (t, J = 7.6
Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.82
(s, 1H), 6.71 (dd, J = 10.8, 16.8 Hz, 1H), 6.2 (dd, J = 1.5, 16.8
Hz, 1H), 5.70 (dd, J = 1.5, 10.8 Hz, 1H), 3.82-3.93 (m, 4H),
3.50-3.66 (m, 4H) 26 468.0 .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
.delta. 7.90 (s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.42-7.49 (m, 1H),
7.10 (d, J = 8.0 Hz, 1H), 7.03-7.08 (m, J = 7.6 Hz, 1H), 6.67- 6.81
(m, 2H), 6.19 (dd, J = 1.8, 16.6 Hz, 1H), 5.72 (dd, J = 1.8, 10.6
Hz, 1H), 3.87-3.93 (m, 4H), 3.56-3.66 (m, 4H). 27 512.3 .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 9.51 (0.6 H, br s) 8.98 (0.4 H, br s)
7.63 (0.4 H, s) 7.58 (0.6 H, s) 7.35-7.43 (2 H, m) 7.10- 7.26 (3 H,
m) 6.78 (1 H, dd, J = 16.63, 8.22 Hz) 6.59-6.71 (2 H, m) 6.36 (1 H,
dd, J = 16.82, 1.57 Hz) 5.78 (1 H, dd, J = 10.56, 1.37 Hz)
4.10-4.38 (4 H, m) 3.80- 4.03 (4 H, m) 2.60-2.72 (1 H, m) 2.61 (1.2
H, s) 2.59 (1.8 H, s) 0.91-1.08 (6 H, m) 28 517.1 .sup.1H NMR (400
MHz, METHANOL-d.sub.4) .delta. 8.27 (1 H, s) 8.15 (0.33 H, s) 8.10
(0.67 H, s) 7.19-7.31 (5 H, m) 7.10-7.16 (1 H, m) 6.86 (1 H, dd, J
= 16.73, 10.66 Hz) 6.62-6.78 (2 H, m) 6.27 (1 H, dd, J = 16.82,
1.96 Hz) 5.80 (1 H, dd, J = 10.66, 1.86 Hz) 4.94-5.01 (1 H, m)
3.93-4.03 (4 H, m) 3.49-3.60 (4 H, m) 1.81 (3 H, d, J = 7.04 Hz) 29
521.1 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. 8.32 (1 H, s)
8.19 (1 H, s) 7.26-7.34 (3 H, m) 6.98 (2 H, t, J = 8.71 Hz) 6.69-
6.91 (3 H, m) 6.28 (1 H, dd, J = 16.92, 1.86 Hz) 5.82 (1 H, dd, J =
10.56, 1.76 Hz) 4.54-4.65 (2 H, m) 3.99 (4 H, m) 3.58 (4 H, m) 30
489.0 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.21 (1 H, s)
8.06 (1 H, s) 7.62-7.69 (2 H, m) 7.45-7.51 (3 H, m) 7.24-7.32 (1 H,
m) 6.81-6.90 (1 H, m) 6.75 (1 H, t, J = 8.41 Hz) 6.65 (1 H, dd, J =
16.82, 10.56 Hz) 6.38 (1 H, dd, J = 16.82, 1.76 Hz) 5.79 (1 H, dd,
J = 10.56, 1.76 Hz) 3.86-4.02 (4 H, m) 3.57-3.76 (4 H, m) 31 489.1
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.15 (1 H, s) 8.12 (1 H,
s) 7.68-7.73 (2 H, m) 7.53- 7.58 (3 H, m) 7.30 (1 H, br td, J =
8.22, 6.65 Hz) 6.88 (1 H, d, J = 8.22 Hz) 6.78 (1 H, t, J = 8.61
Hz) 6.57 (1 H, dd, J = 16.82, 10.56 Hz) 6.28 (1 H, dd, J = 16.73,
1.66 Hz) 5.71 (1 H, dd, J = 10.56, 1.56 Hz) 3.78-3.89 (4 H, m)
3.51-3.73 (4 H, m) 32 443.1 .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.23 (1 H, s) 8.11 (1 H, s) 7.32 (1 H, td, J = 8.31, 6.46
Hz) 6.88 (1 H, d, J = 8.22 Hz) 6.77- 6.83 (1 H, m) 6.65 (1 H, dd, J
= 16.82, 10.56 Hz) 6.37 (1 H, dd, J = 16.82, 1.76 Hz) 5.79 (1 H,
dd, J = 10.47, 1.86 Hz) 4.18 (3 H, s) 3.79-4.05 (4 H, m) 3.34- 3.54
(4 H, m) 33 443.1 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.32 (1
H, s) 8.01 (1 H, s) 7.32 (1 H, td, J = 8.27, 6.55 Hz) 6.89 (1 H, d,
J = 8.22 Hz) 6.77- 6.83 (1 H, m) 6.60 (1 H, dd, J = 17.02, 10.56
Hz) 6.30 (1 H, dd, J = 16.82, 1.76 Hz) 5.75 (1 H, dd, J = 10.56,
1.76 Hz) 4.22 (3 H, s) 3.67-3.98 (4 H, m) 3.25- 3.55 (4 H, m) 34
427.1 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.13 (1 H, s)
8.12 (1 H, s) 7.28-7.36 (4 H, m) 7.20-7.26 (1 H, m) 6.65 (1 H, dd,
J = 16.82, 10.56 Hz) 6.37 (1 H, dd, J = 16.82, 1.57 Hz) 5.78 (1 H,
dd, J = 10.56, 1.56 Hz) 4.61 (2 H, s) 3.83-4.01 (4 H, m) 3.48-3.62
(4 H, m). 35 503.1 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.13
(1 H, s) 8.11 (1 H, s) 7.12-7.37 (6 H, m) 6.91 (1 H, d, J = 8.22
Hz) 6.77 (1 H, t, J = 8.61 Hz) 6.64 (1 H, dd, J = 16.82, 10.56 Hz)
6.37 (1 H, dd, J = 16.82, 1.76 Hz) 5.79 (1 H, dd, J = 10.56, 1.96
Hz) 4.55 (2 H, s) 3.34-4.01 (8 H, m) 36 503.1 .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.12 (1 H, s) 8.05 (1 H, s) 7.26-7.36 (5 H, m)
7.19- 7.24 (1 H, m) 6.93 (1 H, d, J = 8.41 Hz) 6.76 (1 H, t, J =
8.31 Hz) 6.58 (1 H, dd, J = 16.82, 10.76 Hz) 6.28 (1 H, dd, J =
16.82, 1.76 Hz) 5.75 (1 H, dd, J = 10.56, 1.76 Hz) 4.54 (2 H, s)
3.32-3.93 (8 H, m) 37 523 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.23 (0.6 H, s) 8.22 (0.4 H, s) 8.02 (0.4 H, s) 8.00 (0.6 H, s)
7.19-7.57 (8 H, m) 6.68 (0.4 H, dd, J = 16.82, 10.56 Hz) 6.60 (0.6
H, dd, J = 16.82, 10.56 Hz) 6.38 (0.4 H, dd, J = 16.63, 1.76 Hz)
6.32 (0.6 H, dd, J = 16.82, 1.76 Hz) 5.79 (0.4 H, dd, J = 10.56,
1.76 Hz) 5.73 (0.6 H, dd, J = 10.56, 1.76 Hz) 4.67 (1.2 H, s) 4.60
(0.8 H, s) 3.74-4.06 (4 H, m) 3.46-3.70 (4 H, m) 2.21 (1.8 H, s)
2.06 (1.2 H, s) 38 483.3 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.04 (1 H, s) 7.26-7.33 (1 H, m) 6.82 (1 H, d, J = 8.29 Hz) 6.71 (1
H, t, J = 8.91 Hz) 6.51 (1 H, dd, J = 16.79, 10.57 Hz) 6.30 (1 H,
dd, J = 16.79, 1.45 Hz) 5.72 (1 H, dd, J = 10.47, 1.55 Hz) 4.15 (2
H, br d, J = 6.43 Hz) 3.69-3.90 (8 H, m) 1.14-1.27 (4 H, m)
0.73-0.88 (1 H, m)
Biological Assay Data
[0491] Coupled Nucleotide Exchange Assay: Purified GDP-bound KRAS
protein (aa 1-169), containing both G12C and C118A amino acid
substitutions and an N-terminal His-tag, was pre-incubated with a
compound dose-response titration for 2 hours in assay buffer (25 mM
HEPES pH 7.4, 10 mM MgCl.sub.2, and 0.01% Triton X-100). Following
compound pre-incubation, purified SOS protein (aa 564-1049) and GTP
(Roche 10106399001) were added to the assay wells and incubated for
an additional hour. To determine the extent of inhibition of
SOS-mediated nucleotide exchange, purified GST-tagged cRAF (aa
1-149), nickel chelate AlphaLISA acceptor beads (PerkinElmer
AL108R), and AlphaScreen glutathione donor beads (PerkinElmer
6765302) were added to the assay wells and incubated for 10
minutes. The assay plates were then read on a PerkinElmer EnVision
Multilabel Reader, using AlphaScreen.RTM. technology, and data were
analyzed using a 4-parameter logistic model to calculate IC.sub.50
values.
[0492] Phospho-ERK1/2 MSD Assay: MIA PaCa-2 (ATCC.RTM.
CRL-1420.TM.) and A549 (ATCC.RTM. CCL-185.TM.) cells were cultured
in RPMI 1640 Medium (ThermoFisher Scientific 11875093) containing
10% fetal bovine serum (ThermoFisher Scientific 16000044) and
1.times. penicillin-streptomycin-glutamine (ThermoFisher Scientific
10378016). Sixteen hours prior to compound treatment, MIA PaCa-2 or
A549 cells were seeded in 96-well cell culture plates at a density
of 25,000 cells/well and incubated at 37.degree. C., 5% CO.sub.2. A
compound dose-response titration was diluted in growth media, added
to appropriate wells of a cell culture plate, and then incubated at
37.degree. C., 5% CO.sub.2 for 4 hours. Following compound
treatment, cells were stimulated with 10 ng/mL EGF (Roche
11376454001) for 10 min, washed with ice-cold Dulbecco's
phosphate-buffered saline, no Ca.sup.2+ or Mg.sup.2+ (ThermoFisher
Scientific 14190144), and then lysed in RIPA buffer (50 mM Tris-HCl
pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl, and 0.5%
sodium dodecyl sulfate) containing protease inhibitors (Roche
4693132001) and phosphatase inhibitors (Roche 4906837001). Cell
lysates were stored frozen at -80.degree. C. overnight.
Phosphorylation of ERK1/2 in compound-treated lysates was assayed
using Phospho-ERK1/2 Whole Cell Lysate kits (Meso Scale Discovery
K151DWD) according to the manufacturer's protocol. Assay plates
were read on a Meso Scale Discovery Sector Imager 6000, and data
were analyzed using a 4-parameter logistic model to calculate
IC.sub.50 values.
TABLE-US-00017 TABLE 15 Biochemical and cellular activity of
compounds Coupled exchange IC.sub.50 p-ERK IC.sub.50 p-ERK
IC.sub.50 Ex. # (.mu.M) (MIA PaCa-2, .mu.M) (A549, .mu.M) 1-1 0.355
2.55 >33.3 1-2 2.38 6.08 >100 1-3 0.610 3.84 >100 1-4
>10 >100 >100 1-5 6.66 -- -- 1-6 2.88 36.2 >100 1-7
0.209 1.86 >100 1-8 0.894 6.07 >100 1-9 5.92 -- -- 1-10 0.381
1.09 11.1 1-11 0.695 8.2 >100 1-12 11.8 -- -- 1-13 >10 -- --
1-14 1.78 5.03 >100 1-15 0.562 4.7 >100 1-16 0.492 4.83
>100 1-17 63.5 -- -- 1-18 0.370 0.559 >33.3 1-19 0.297 1.33
>100 1-19-1 0.115 0.368 >100 1-19-2 5.10 >100 >100 1-20
0.683 4.99 >100 1-21 1.30 4.89 >100 1-22 >250 -- -- 1-23
>250 -- -- 1-28 2.20 -- >100 2-1 0.341 1.89 3.7 2-2 12.7 --
-- 2-3 4.05 6.53 >100 2-4 >250 -- -- 2-5 0.684 5.46 3.7 2-5-1
0.308 1.14 >100 2-5-2 1.35 7.48 3.7 2-6 1.59 2.97 3.7 2-6-1 13.0
-- -- 2-6-2 1.25 1.29 3.7 2-7 1.08 3.87 >33.3 2-8 0.361 0.258
>100 2-9 0.301 0.747 >100 2-10 1.73 3.07 >100 3-1 0.266
3.23 >100 3-1-1 3.00 >100 >100 3-1-2 0.302 2.35 >100
3-2 >250 -- -- 3-3 11.3 -- -- 3-4 >250 -- -- 3-5 0.693 5.26
3.7 3-6 1.05 11.8 >100 3-7 6.98 -- 3-8 1.07 7.05 >100 3-9
3.37 9.25 >33.3 3-10 4.74 66.4 11.1 3-11 0.457 3.06 11.1 3-12
2.56 7.66 >100 3-13 6.49 -- -- 3-14 5.64 -- -- 3-15 4.03 20.1
>100 3-16 2.60 21.3 >100 3-17 5.48 -- -- 3-18 2.60 >100
>100 3-19 0.954 2.03 >33.3 3-20 2.99 9.65 >100 3-21 32.0
-- -- 3-22 0.249 1.12 >33.3 3-23 4.65 13.6 >100 3-24 9.07
23.7 >100 3-25 >250 -- -- 4-1 0.529 2.34 >100 4-2 >250
-- -- 4-3 >250 -- -- 4-4 >250 -- -- 4-5 >250 -- -- 4-6
0.630 10.3 >100 4-7 125 -- -- 4-8 177 -- -- 4-9 >250 -- --
5-1 0.875 2.86 >100 5-2 14.2 -- -- 5-3 14.2 -- -- 5-4 0.610 3.25
>100 5-5 0.341 2.53 >100 5-6 0.883 5.9 >100 5-7 0.815 3.79
>100 5-8 0.433 1.2 >33.3 5-9 0.139 0.822 >100 6-1 0.537
1.3 3.7 6-2 5.31 -- -- 7-1 0.299 0.43 >100 7-2 0.180 0.222
>100 7-3 1.73 5.83 >100 8-1 0.542 0.211 62.3 8-1-1 0.172
0.046 69.8 8-1-2 0.322 0.811 >100 8-2 0.152 0.050 >100 8-3
0.283 0.061 >100 8-3-1 0.282 0.408 >100 8-3-2 0.340 0.028
>100 8-4 0.095 0.017 >33.3 8-5 0.400 2.41 >100 8-6 0.100
0.012 69.9 8-6-2 0.185 0.128 >100 8-6-1 0.066 0.01 >33.3 9-1
0.155 0.052 57.4 9-2 0.289 1.11 74.4 9-3 0.113 0.035 66.1 9-4 0.198
0.023 13 9-5 1.33 3.92 >100 9-6 0.237 3.51 >100 9-7-2 --
0.232 62.0 9-7-1 -- 0.023 14.9 9-9 0.147 0.136 65.6 9-10 0.101
0.117 66.5 9-11 0.093 0.147 64 9-12 1.32 1.29 >100 9-13 0.306
0.078 12.8 9-14 0.129 0.344 >100 10-1 24.5 -- -- 10-2 1.93 36.1
>100 10-3 1.10 9.33 >100 10-4 0.235 3.47 >100 10-5 0.297
3.41 >100 10-6 1.20 6.07 >100 10-7 0.533 9.2 >100 10-8
1.34 12.9 >100 10-9 1.68 33.6 >100 10-10 0.359 6.85 >100
10-11 0.516 14.7 >100 10-12 0.912 22.6 >100 10-13 15.1 -- --
11-1-1 0.231 0.247 42.9 11-1-2 0.151 0.016 21.7 11-2-1 0.219 0.054
10 11-2-2 0.256 0.006 26.4 12 3.34 25.9 >100 13 5.20 >100
>100 14 2.69 -- -- 15 2.56 -- -- 16 2.93 8.62 33.3 17-1 20.6 --
-- 17-2 1.02 2.6 49.1 18-1 23.0 -- -- 18-2 0.760 >100 >100
18-3 24.6 -- -- 19-1 15.2 -- -- 19-2 1.62 4.69 3.7 19-3 115 -- --
20 78.8 -- -- 21 9.41 -- -- 22 0.927 56.1 >100 23 3.29 3.21
>33.3 24 6.20 -- -- 25 0.251 0.786 >100 26 3.90 30.3 >100
27 1.28 12.8 >33.3 28 8.17 -- -- 29 3.76 >100 >100 30 7.51
58 >100 31 123 -- -- 32 28.6 -- -- 33 103 -- -- 34 34.2 -- -- 35
8.01 79.7 >100 36 39.8 -- -- 37 9.07 14.7 >100 38 0.484 1.39
>33.3
[0493] The present invention is described in connection with
preferred embodiments. PP71T, However, it should be appreciated
that the invention is not limited to the disclosed embodiments. It
is understood that, given the description of the embodiments of the
invention herein, various modifications can be made by a person
skilled in the art. Such modifications are encompassed by the
claims below.
* * * * *