U.S. patent application number 12/018573 was filed with the patent office on 2011-07-21 for certain imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of bruton's tyrosine kinase by such compounds.
Invention is credited to Kevin S. Currie, James W. Darrow, Robert W. DeSimone, Scott A. Mitchell, Douglas A. Pippin, Dapeng Qian, Xiaobing Qian, Mark Velleca.
Application Number | 20110177011 12/018573 |
Document ID | / |
Family ID | 34138527 |
Filed Date | 2011-07-21 |
United States Patent
Application |
20110177011 |
Kind Code |
A1 |
Currie; Kevin S. ; et
al. |
July 21, 2011 |
CERTAIN IMIDAZO[1,2-A]PYRAZIN-8-YLAMINES AND METHOD OF INHIBITION
OF BRUTON'S TYROSINE KINASE BY SUCH COMPOUNDS
Abstract
Compounds of Formula I-a ##STR00001## and all
pharmaceutically-acceptable forms thereof, are described herein.
The variables R.sub.1, R.sub.2, R.sub.3, Z.sub.1, Q, and A shown in
Formula I-a are defined herein. Pharmaceutical compositions
containing one or more compounds of Formula I-a, or a
pharmaceutically acceptable form of such compounds, and one or more
pharmaceutically acceptable carriers, excipients, or diluents are
provided herein. Methods of treating patients suffering from
certain diseases responsive to inhibition of tyrosine kinase
activity are also given. In certain embodiments the diseases are
responsive to inhibition of Btk activity and/or B-cell
proliferation. Such methods comprise administering to such patients
an amount of a compound of Formula I-a effective to reduce signs or
symptoms of the disease. These diseases include cancer, an
autoimmune and/or inflammatory disease, or an acute inflammatory
reaction. Thus methods of treatment include administering a
sufficient amount of a compound or salt as provided herein to
decrease the symptoms or slow the progression of these diseases.
Other embodiments include methods of treating other animals,
including livestock and domesticated companion animals, suffering
from a disease responsive to inhibition of kinase activity. Methods
of treatment include administering a compound of Formula I-a as a
single active agent or administering a compound of Formula I-a in
combination with one or more other therapeutic agent. A method for
determining the presence of Btk in a sample, comprising contacting
the sample with a compound or form thereof of Formula I-a under
conditions that permit detection of Btk activity, detecting a level
of Btk activity in the sample, and therefrom determining the
presence or absence of Btk in the sample.
Inventors: |
Currie; Kevin S.; (North
Branford, CT) ; DeSimone; Robert W.; (Durham, CT)
; Mitchell; Scott A.; (East Haven, CT) ; Pippin;
Douglas A.; (Branford, CT) ; Darrow; James W.;
(Wallingford, CT) ; Qian; Xiaobing; (Guilford,
CT) ; Velleca; Mark; (New Haven, CT) ; Qian;
Dapeng; (Guilford, CT) |
Family ID: |
34138527 |
Appl. No.: |
12/018573 |
Filed: |
January 23, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10861791 |
Jun 4, 2004 |
7405295 |
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12018573 |
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60475634 |
Jun 4, 2003 |
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60519311 |
Nov 11, 2003 |
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Current U.S.
Class: |
424/43 ; 514/218;
514/233.2; 514/249 |
Current CPC
Class: |
A61P 29/00 20180101;
C07D 487/04 20130101; A61P 35/00 20180101; A61P 37/02 20180101 |
Class at
Publication: |
424/43 ; 514/249;
514/233.2; 514/218 |
International
Class: |
A61K 31/551 20060101
A61K031/551; A61K 31/4985 20060101 A61K031/4985; A61K 31/5355
20060101 A61K031/5355; A61K 9/12 20060101 A61K009/12; A61P 29/00
20060101 A61P029/00; A61P 35/00 20060101 A61P035/00 |
Claims
1-86. (canceled)
87. A pharmaceutical composition, comprising at least one
pharmaceutically acceptable carrier or excipient and a compound of
Formula 1 ##STR00179## or a pharmaceutically acceptable salt,
hydrate or diastereomer thereof, wherein A is 0 or 1; R.sub.1 is
substituted phenyl wherein the substituent is hydroxy, CHO, --COOH,
--CONH.sub.2, --CONHOH, C.sub.2-C.sub.6 alkenyl, mono-, di- or
tri-substituted C.sub.2-C.sub.6 alkenyl, wherein the substituents
are independently halogen, hydroxy, amino, oxo, --COOH,
--CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl, C.sub.2-C.sub.6
alkynyl, mono-, di- or tri-substituted C.sub.2-C.sub.6 alkynyl,
wherein the substituents are independently halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
C.sub.1-C.sub.6hydroxyalkyl, mono-, di- or tri-substituted
C.sub.1-C.sub.6hydroxyalkyl, wherein the substituents are
independently halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
C.sub.1-C.sub.6hydroxyalkoxy, mono-, di- or tri-substituted
C.sub.1-C.sub.6hydroxyalkoxy, wherein the substituents are
independently halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy, mono-, di-
or tri-substituted
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy, wherein the
substituents are independently halogen, hydroxy, amino, oxo,
--COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy, mono-, di- or
tri-substituted
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy, wherein the
substituents are independently halogen, hydroxy, amino, oxo,
--COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
mono-, di- or tri-substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
wherein the substituents are independently halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy,
mono-, di- or tri-substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy,
wherein the substituents are independently halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl, heterocycloalkyl,
mono-, di- or tri-substituted heterocycloalkyl, wherein the
substituents are independently halogen, hydroxy, amino, oxo,
--COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl, aryl, mono-, di- or
tri-substituted aryl, wherein the substituents are independently
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl, heteroaryl, mono-,
di- or tri-substituted heteroaryl, wherein the substituents are
independently halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
--C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10, mono-, di- or
tri-substituted-C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10, wherein the
substituents are independently halogen, hydroxy, amino, oxo,
--COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11, mono-, di- or
tri-substituted-C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11,
wherein the substituents are independently halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11, mono-, di- or
tri-substituted-C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11,
wherein the substituents are independently halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11, mono-, di- or
tri-substituted-C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11,
wherein the substituents are independently halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10, mono-, di- or
tri-substituted-C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10, wherein the
substituents are independently halogen, hydroxy, amino, oxo,
--COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12, mono-,
di- or
tri-substituted-C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12,
wherein the substituents are independently halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl, -L-G, where L is
C.sub.1-C.sub.2alkylene, mono-, di- or tri-substituted
C.sub.1-C.sub.2alkylene, wherein the substituents are independently
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
C.sub.0-C.sub.2alkylene-O--, mono-, di- or tri-substituted
C.sub.0-C.sub.2alkylene-O--, wherein the substituents are
independently halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl, --(C.dbd.O)--,
--(C.sub.1-C.sub.2alkylene)(C.dbd.O)--, mono-, di- or
tri-substituted --(C.sub.1-C.sub.2alkylene)(C.dbd.O)--, wherein the
substituents are independently halogen, hydroxy, amino, oxo,
--COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl, G is
heterocycloalkyl, mono-, di- or tri-substituted heterocycloalkyl,
wherein the substituents are independently halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
C.sub.3-C.sub.7cycloalkyl, mono-, di- or tri-substituted
C.sub.3-C.sub.7cycloalkyl, wherein the substituents are
independently halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl, aryl, mono-, di- or
tri-substituted aryl, wherein the substituents are independently
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl, heteroaryl, mono-,
di- or tri-substituted heteroaryl, wherein the substituents are
independently halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl, or substituted
heteroaryl wherein the substituent is oxo, --CHO, --COOH,
--CONH.sub.2, --CONHOH, C.sub.2-C.sub.6 alkenyl, mono-, di- or
tri-substituted C.sub.2-C.sub.6 alkenyl, wherein the substituents
are independently halogen, hydroxy, amino, oxo, --COOH,
--CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl, C.sub.2-C.sub.6
alkynyl, mono-, di- or tri-substituted C.sub.2-C.sub.6 alkynyl,
wherein the substituents are independently halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl, C
.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
C.sub.1-C.sub.6hydroxyalkyl, mono-, di- or tri-substituted
C.sub.1-C.sub.6hydroxyalkyl, wherein the substituents are
independently halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
C.sub.1-C.sub.6hydroxyalkoxy, mono-, di- or tri-substituted
C.sub.1-C.sub.6hydroxyalkoxy, wherein the substituents are
independently halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy, mono-, di-
or tri-substituted
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy, wherein the
substituents are independently halogen, hydroxy, amino, oxo,
--COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy, mono-, di- or
tri-substituted
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy, wherein the
substituents are independently halogen, hydroxy, amino, oxo,
--COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
mono-, di- or tri-substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
wherein the substituents are independently halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy,
mono-, di- or tri-substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy,
wherein the substituents are independently halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl, heterocycloalkyl,
mono-, di- or tri-substituted heterocycloalkyl, wherein the
substituents are independently halogen, hydroxy, amino, oxo,
--COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl, aryl, mono-, di- or
tri-substituted aryl, wherein the substituents are independently
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl, heteroaryl, mono-,
di- or tri-substituted heteroaryl, wherein the substituents are
independently halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
--C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10, mono-, di- or
tri-substituted-C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10, wherein the
substituents are independently halogen, hydroxy, amino, oxo,
--COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11, mono-, di- or
tri-substituted-C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11,
wherein the substituents are independently halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11, mono-, di- or
tri-substituted-C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11,
wherein the substituents are independently halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11, mono-, di- or
tri-substituted-C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11,
wherein the substituents are independently halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10, mono-, di- or
tri-substituted-C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10, wherein the
substituents are independently halogen, hydroxy, amino, oxo,
--COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12, mono-,
di- or
tri-substituted-C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12,
wherein the substituents are independently halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl, -L-G, where L is
C.sub.1-C.sub.2alkylene, mono-, di- or tri-substituted
C.sub.1-C.sub.2alkylene, wherein the substituents are independently
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
C.sub.0-C.sub.2alkylene-O--, mono-, di- or tri-substituted
C.sub.0-C.sub.2alkylene-O--, wherein the substituents are
independently halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl, --(C.dbd.O)--,
--(C.sub.1-C.sub.2alkylene)(C.dbd.O)--, mono-, di- or
tri-substituted --(C.sub.1-C.sub.2alkylene)(C.dbd.O)--, wherein the
substituents are independently halogen, hydroxy, amino, oxo,
--COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl, G is
heterocycloalkyl, mono-, di- or tri-substituted heterocycloalkyl,
wherein the substituents are independently halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl,
C.sub.3-C.sub.7cycloalkyl, mono-, di- or tri-substituted
C.sub.3-C.sub.7cycloalkyl, wherein the substituents are
independently halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl, aryl, mono-, di- or
tri-substituted aryl, wherein the substituents are independently
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl, heteroaryl, mono-,
di- or tri-substituted heteroaryl, wherein the substituents are
independently halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, or phenyl, R.sub.10, R.sub.11,
and R.sub.12 are independently hydrogen, hydroxy,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.3-C.sub.10cycloalkyl, or heterocycloalkyl, R.sub.1 is
optionally further substituted with 1 or more substituents which
are independently hydroxy, nitro, cyano, amino, --SO.sub.2NH.sub.2,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkanoyl,
C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4haloalkoxy,
C.sub.1-C.sub.6 alkylthio, C.sub.3-C.sub.7cycloalkyl,
(C.sub.1-C.sub.6 alkoxy)C.sub.0-C.sub.6alkyl, (mono-C.sub.1-C.sub.6
alkylamino)C.sub.0-C.sub.6 alkyl, (di-C.sub.1-C.sub.6
alkylamino)C.sub.0-C.sub.6 alkyl, or C.sub.1-C.sub.6alkoxycarbonyl;
R.sub.2 is C.sub.1-C.sub.7 alkyl,
(C.sub.1-C.sub.6alkoxy)C.sub.0-C.sub.6alkoxy, (heterocycloalkyl)
C.sub.0-C.sub.2alkyl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.0-C.sub.2alkyl,
(phenyl)C.sub.0-C.sub.2alkyl, mono-, di-, or tri-substituted
(phenyl)C.sub.0-C.sub.2alkyl, wherein the substituents are
independently hydroxy, nitro, cyano, amino, halogen,
--SO.sub.2NH.sub.2, oxo, --COOH, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.2-C.sub.6alkanoyl, C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6alkyl, mono-C.sub.1-C.sub.6alkylamino,
di-C.sub.1-C.sub.6alkylamino, mono-C.sub.1-C.sub.6alkylcarboxamide,
di-C.sub.1-C.sub.6alkylcarboxamide, C.sub.1-C.sub.6alkoxycarbonyl,
phenyl, heteroaryl, or --(C.dbd.O)R.sub.13 wherein R.sub.13 is
C.sub.1-C.sub.6alkyl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.0-C.sub.2alkyl,
C.sub.1-C.sub.3haloalkyl, heterocycloalkyl, phenyl, or heteroaryl;
(phenoxy)C.sub.0-C.sub.2alkyl, mono-, di-, or tri-substituted
(phenoxy)C.sub.0-C.sub.2alkyl, wherein the substituents are
independently hydroxy, nitro, cyano, amino, halogen,
--SO.sub.2NH.sub.2, oxo, --COOH, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.2-C.sub.6alkanoyl, C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C
.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkoxy,
aminoC.sub.1-C.sub.6alkyl, mono-C.sub.1-C.sub.6alkylamino,
di-C.sub.1-C.sub.6alkylamino, mono-C.sub.1-C.sub.6alkylcarboxamide,
di-C.sub.1-C.sub.6alkylcarboxamide, C.sub.1-C.sub.6alkoxycarbonyl,
phenyl, heteroaryl, or --(C.dbd.O)R.sub.13 wherein R.sub.13 is
C.sub.1-C.sub.6alkyl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.0-C.sub.2alkyl,
C.sub.1-C.sub.3haloalkyl, heterocycloalkyl, phenyl, or heteroaryl;
(heteroaryl)C.sub.0-C.sub.2alkyl, mono-, di-, or tri-substituted
(heteroaryl)C.sub.0-C.sub.2alkyl, wherein the substituents are
independently hydroxy, nitro, cyano, amino, halogen,
--SO.sub.2NH.sub.2, oxo, --COOH, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.2-C.sub.6alkanoyl, C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6alkyl, mono-C.sub.1-C.sub.6alkylamino,
di-C.sub.1-C.sub.6alkylamino, mono-C.sub.1-C.sub.6alkylcarboxamide,
di-C.sub.1-C.sub.6alkylcarboxamide, C.sub.1-C.sub.6alkoxycarbonyl,
phenyl, heteroaryl, or --(C.dbd.O)R.sub.13 wherein R.sub.13 is
C.sub.1-C.sub.6alkyl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.0-C.sub.2alkyl,
C.sub.1-C.sub.3haloalkyl, heterocycloalkyl, phenyl, or heteroaryl;
Z.sub.1 is ##STR00180## R.sub.4 is Hydrogen, C.sub.1-C.sub.6alkyl,
substituted C.sub.1-C.sub.6alkyl wherein the substituent is
hydroxy, nitro, cyano, amino, halogen, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6 alkyl, mono-C.sub.1-C.sub.6
alkylamino, di-C.sub.1-C.sub.6 alkylamino, or --C(O)R.sub.14
wherein R.sub.14 is C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3haloalkyl, or phenyl; C.sub.3-C.sub.7cycloalkyl,
substituted C.sub.3-C.sub.7cycloalkyl, wherein the substituent is
hydroxy, nitro, cyano, amino, halogen, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6 alkyl, mono-C.sub.1-C.sub.6
alkylamino, di-C.sub.1-C.sub.6 alkylamino, or --C(O)R.sub.14
wherein R.sub.14 is C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3haloalkyl, or phenyl; heterocycloalkyl, substituted
heterocycloalkyl, wherein the substituent is hydroxy, nitro, cyano,
amino, halogen, oxo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6 alkyl, mono-C.sub.1-C.sub.6
alkylamino, di-C.sub.1-C.sub.6 alkylamino, or --C(O)R.sub.14
wherein R.sub.14 is C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3haloalkyl, or phenyl; phenyl, substituted phenyl,
wherein the substituent is hydroxy, nitro, cyano, amino, halogen,
oxo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6 alkyl, mono-C.sub.1-C.sub.6
alkylamino, di-C.sub.1-C.sub.6 alkylamino, or --C(O)R.sub.14
wherein R.sub.14 is C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3haloalkyl, or phenyl; heteroaryl, substituted
heteroaryl, wherein the substituent is hydroxy, nitro, cyano,
amino, halogen, oxo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6 alkyl, mono-C.sub.1-C.sub.6
alkylamino, di-C.sub.1-C.sub.6 alkylamino, or --C(O)R.sub.14
wherein R.sub.14 is C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3haloalkyl, or phenyl; Q is phenyl or pyridyl;
R.sub.3 is hydrogen, halogen, C.sub.1-C.sub.7 alkyl,
heterocycloalkyl, mono-, di-, or tri-substituted heterocycloalkyl,
wherein the substituents are independently hydroxy, nitro, cyano,
amino, halogen, --SO.sub.2NH.sub.2, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6-alkoxy)C.sub.1-C.sub.6
alkoxy, mono-C.sub.1-C.sub.6alkylamino,
di-C.sub.1-C.sub.6alkylamino, aminoC.sub.1-C.sub.6 alkyl, or
--C(O)R.sub.14, C.sub.3-C.sub.7cycloalkyl, mono-, di-, or
tri-substituted C.sub.3-C.sub.7cycloalkyl, wherein the substituents
are independently hydroxy, nitro, cyano, amino, halogen,
--SO.sub.2NH.sub.2, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6-alkoxy)C.sub.1-C.sub.6
alkoxy, mono-C.sub.1-C.sub.6alkylamino,
di-C.sub.1-C.sub.6alkylamino, aminoC.sub.1-C.sub.6 alkyl, or
--C(O)R.sub.14, heteroaryl, mono-, di-, or tri-substituted
heteroaryl, wherein the substituents are independently hydroxy,
nitro, cyano, amino, halogen, --SO.sub.2NH.sub.2, oxo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6-alkoxy)C.sub.1-C.sub.6
alkoxy, mono-C.sub.1-C.sub.6alkylamino,
di-C.sub.1-C.sub.6alkylamino, aminoC.sub.1-C.sub.6 alkyl, or
--C(O)R.sub.14.
88. A pharmaceutical composition of claim 87, wherein the
composition is formulated as an injectable fluid, an aerosol, a
cream, a gel, a tablet, a pill, a capsule, a syrup, ophthalmic
solution, or a transdermal patch.
89. A packaged pharmaceutical composition, comprising a
pharmaceutical composition in a container; and instructions for
using the composition to treat a patient suffering from an disease
responsive to Btk inhibition, wherein the pharmaceutical
composition comprises (a) at least one pharmaceutically acceptable
carrier or excipient and (b) the compound of Formula I-a
##STR00181## or a pharmaceutically acceptable salt, hydrate or
diastereomer thereof, wherein A is chosen from 0 and 1; R.sub.1 is
chosen from phenyl substituted with a group chosen from hydroxy,
--CHO, --COOH, --CONH.sub.2, --CONHOH, C.sub.2-C.sub.6 alkenyl,
substituted C.sub.2-C.sub.6 alkenyl chosen from mono-, di-, and
tri-substituted C.sub.2-C.sub.6 alkenyl wherein the substituents
are independently selected from halogen, hydroxy, amino, oxo,
--COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, C.sub.2-C.sub.6
alkynyl, substituted C.sub.2-C.sub.6 alkynyl chosen from mono-,
di-, and tri-substituted C.sub.2-C.sub.6 alkynyl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.1-C.sub.6hydroxyalkyl, substituted
C.sub.1-C.sub.6hydroxyalkyl chosen from mono-, di-, and
tri-substituted C.sub.1-C.sub.6hydroxyalkyl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.1-C.sub.6hydroxyalkoxy, substituted
C.sub.1-C.sub.6hydroxyalkoxy chosen from mono-, di-, and
tri-substituted C.sub.1-C.sub.6hydroxyalkoxy wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy, substituted
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy chosen from
mono-, di-, and tri-substituted
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy, substituted
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy chosen from
mono-, di-, and tri-substituted
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl
chosen from mono-, di-, and tri-substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy,
substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy
chosen from mono-, di-, and tri-substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, heterocycloalkyl,
substituted heterocycloalkyl chosen from mono-, di-, and
tri-substituted heterocycloalkyl wherein the substituents are
independently selected from halogen, hydroxy, amino, oxo, --COOH,
--CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, aryl, substituted
aryl chosen from mono-, di-, and tri-substituted aryl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, heteroaryl,
substituted heteroaryl chosen from mono-, di-, and tri-substituted
heteroaryl wherein the substituents are independently selected from
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10, substituted
--C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10 chosen from mono-, di-,
and tri-substituted --C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11, substituted
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11 chosen from mono-,
di-, and tri-substituted
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11 wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11, substituted
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11 chosen from
mono-, di-, and tri-substituted
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11 wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11, substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11 chosen from mono-,
di-, and tri-substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11, wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10, substituted
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10 chosen from mono-, di-,
and tri-substituted --C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12,
substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12 chosen
from mono-, di-, and tri-substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12, wherein
the substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, -L-G, where L is
chosen from C.sub.1-C.sub.2alkylene, substituted
C.sub.1-C.sub.2alkylene chosen from mono-, di-, and tri-substituted
C.sub.1-C.sub.2alkylene wherein the substituents are independently
selected from halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.0-C.sub.2alkylene-O--, substituted
C.sub.0-C.sub.2alkylene-O-- chosen from mono-, di-, and
tri-substituted C.sub.0-C.sub.2alkylene-O-- wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, --(C.dbd.O)--,
--(C.sub.1-C.sub.2alkylene)(C.dbd.O)--, and substituted
--(C.sub.1-C.sub.2alkylene)(C.dbd.O)-- chosen from mono-, di-, and
tri-substituted --(C.sub.1-C.sub.2alkylene)(C.dbd.O)-- wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, and G is chosen
from heterocycloalkyl, substituted heterocycloalkyl chosen from
mono-, di-, and tri-substituted heterocycloalkyl, wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.3-C.sub.7cycloalkyl, substituted C.sub.3-C.sub.7cycloalkyl
chosen from mono-, di-, and tri-substituted
C.sub.3-C.sub.7cycloalkyl wherein the substituents are
independently selected from halogen, hydroxy, amino, oxo, --COOH,
--CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
aryl, substituted aryl chosen from mono-, di-, and tri-substituted
aryl wherein the substituents are independently selected from
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, heteroaryl, and
substituted heteroaryl chosen from mono-, di-, and tri-substituted
heteroaryl wherein the substituents are independently selected from
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, and heteroaryl
substituted with a group chosen from hydroxy, --CHO, --COOH,
--CONH.sub.2, --CONHOH, C.sub.2-C.sub.6 alkenyl, substituted
C.sub.2-C.sub.6 alkenyl chosen from mono-, di-, and tri-substituted
C.sub.2-C.sub.6 alkenyl wherein the substituents are independently
selected from halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, C.sub.2-C.sub.6
alkynyl, substituted C.sub.2-C.sub.6 alkynyl chosen from mono-,
di-, and tri-substituted C.sub.2-C.sub.6 alkynyl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.1-C.sub.6hydroxyalkyl, substituted
C.sub.1-C.sub.6hydroxyalkyl chosen from mono-, di-, and
tri-substituted C.sub.1-C.sub.6hydroxyalkyl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.1-C.sub.6hydroxyalkoxy, substituted
C.sub.1-C.sub.6hydroxyalkoxy chosen from mono-, di-, and
tri-substituted C.sub.1-C.sub.6hydroxyalkoxy wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy, substituted
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy chosen from
mono-, di-, and tri-substituted
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy, substituted
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy chosen from
mono-, di-, and tri-substituted
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl
chosen from mono-, di-, and tri-substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy,
substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy
chosen from mono-, di-, and tri-substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, heterocycloalkyl,
substituted heterocycloalkyl chosen from mono-, di-, and
tri-substituted heterocycloalkyl wherein the substituents are
independently selected from halogen, hydroxy, amino, oxo, --COOH,
--CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, aryl, substituted
aryl chosen from mono-, di-, and tri-substituted aryl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, heteroaryl,
substituted heteroaryl chosen from mono-, di-, and tri-substituted
heteroaryl wherein the substituents are independently selected from
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10, substituted
--C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10 chosen from mono-, di-,
and tri-substituted --C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11, substituted
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11 chosen from mono-,
di-, and tri-substituted
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11 wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11, substituted
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11 chosen from
mono-, di-, and tri-substituted
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11 wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11, substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11 chosen from mono-,
di-, and tri-substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11, wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10, substituted
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10 chosen from mono-, di-,
and tri-substituted-C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10 wherein
the substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12,
substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12 chosen
from mono-, di-, and tri-substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12, wherein
the substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, -L-G, where L is
chosen from C.sub.1-C.sub.2alkylene, substituted
C.sub.1-C.sub.2alkylene chosen from mono-, di-, and tri-substituted
C.sub.1-C.sub.2alkylene wherein the substituents are independently
selected from halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.0-C.sub.2alkylene-O--, substituted
C.sub.0-C.sub.2alkylene-O-- chosen from mono-, di-, and
tri-substituted C.sub.0-C.sub.2alkylene-O-- wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, --(C.dbd.O)--,
--(C.sub.1-C.sub.2alkylene)(C.dbd.O)--, and substituted
--(C.sub.1-C.sub.2alkylene)(C.dbd.O)-- chosen from mono-, di-, and
tri-substituted --(C.sub.1-C.sub.2alkylene)(C.dbd.O)-- wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, and G is chosen
from heterocycloalkyl, substituted heterocycloalkyl chosen from
mono-, di-, and tri-substituted heterocycloalkyl, wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.3-C.sub.7cycloalkyl, substituted C.sub.3-C.sub.7cycloalkyl
chosen from mono-, di-, and tri-substituted
C.sub.3-C.sub.7cycloalkyl wherein the substituents are
independently selected from halogen, hydroxy, amino, oxo, --COOH,
--CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, aryl, substituted
aryl chosen from mono-, di-, and tri-substituted aryl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, heteroaryl, and
substituted heteroaryl chosen from mono-, di-, and tri-substituted
heteroaryl wherein the substituents are independently selected from
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, and R.sub.1 is
optionally further substituted with 1 or more substituents
independently chosen from hydroxy, nitro, cyano, amino,
--SO.sub.2NH.sub.2, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkanoyl, C.sub.1-C.sub.4haloalkyl,
C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.3-C.sub.7cycloalkyl, (C.sub.1-C.sub.6
alkoxy)C.sub.0-C.sub.6alkyl, (mono-C.sub.1-C.sub.6
alkylamino)C.sub.0-C.sub.6 alkyl, (di-C.sub.1-C.sub.6
alkylamino)C.sub.0-C.sub.6 alkyl, and
C.sub.1-C.sub.6alkoxycarbonyl; R.sub.2 is chosen from
C.sub.1-C.sub.7 alkyl,
(C.sub.1-C.sub.6alkoxy)C.sub.0-C.sub.6alkoxy,
(heterocycloalkyl)C.sub.0-C.sub.2alkyl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.0-C.sub.2alkyl,
(phenyl)C.sub.0-C.sub.2alkyl, substituted
(phenyl)C.sub.0-C.sub.2alkyl chosen from mono-, di-, and
tri-substituted (phenyl)C.sub.0-C.sub.2alkyl wherein the
substituents are independently chosen from hydroxy, nitro, cyano,
amino, halogen, --SO.sub.2NH.sub.2, oxo, --COOH, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6alkanoyl,
C.sub.1-C.sub.6hydroxyalkyl, C.sub.1-C.sub.3haloalkyl,
C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.6 alkylthio,
(C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkoxy,
aminoC.sub.1-C.sub.6alkyl, mono-C.sub.1-C.sub.6alkylamino,
di-C.sub.1-C.sub.6alkylamino, mono-C.sub.1-C.sub.6alkylcarboxamide,
di-C.sub.1-C.sub.6alkylcarboxamide, C.sub.1-C.sub.6alkoxycarbonyl,
phenyl, heteroaryl, and --(C.dbd.O)R.sub.13 wherein R.sub.13 is
chosen from C.sub.1-C.sub.6alkyl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.0-C.sub.2alkyl,
C.sub.1-C.sub.3haloalkyl, heterocycloalkyl, phenyl, and heteroaryl,
(phenoxy)C.sub.0-C.sub.2alkyl, substituted
(phenoxy)C.sub.0-C.sub.2alkyl chosen from mono-, di-, and
tri-substituted (phenoxy)C.sub.0-C.sub.2alkyl wherein the
substituents are independently chosen from hydroxy, nitro, cyano,
amino, halogen, --SO.sub.2NH.sub.2, oxo, --COOH, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6alkanoyl,
C.sub.1-C.sub.6hydroxyalkyl, C.sub.1-C.sub.3haloalkyl,
C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.6 alkylthio,
(C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkoxy,
aminoC.sub.1-C.sub.6alkyl, mono-C.sub.1-C.sub.6alkylamino,
di-C.sub.1-C.sub.6alkylamino, mono-C.sub.1-C.sub.6alkylcarboxamide,
di-C.sub.1-C.sub.6alkylcarboxamide, C.sub.1-C.sub.6alkoxycarbonyl,
phenyl, heteroaryl, and --(C.dbd.O)R.sub.13 wherein R.sub.13 is
chosen from C.sub.1-C.sub.6alkyl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.0-C.sub.2alkyl,
C.sub.1-C.sub.3haloalkyl, heterocycloalkyl, phenyl, and heteroaryl,
(heteroaryl)C.sub.0-C.sub.2alkyl, and substituted
(heteroaryl)C.sub.0-C.sub.2alkyl chosen from mono-, di-, and
tri-substituted (heteroaryl)C.sub.0-C.sub.2alkyl wherein the
substituents are independently chosen from hydroxy, nitro, cyano,
amino, halogen, --SO.sub.2NH.sub.2, oxo, --COOH, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6alkanoyl,
C.sub.1-C.sub.6hydroxyalkyl, C.sub.1-C.sub.3haloalkyl,
C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.6 alkylthio,
(C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkoxy,
aminoC.sub.1-C.sub.6alkyl, mono-C.sub.1-C.sub.6alkylamino,
di-C.sub.1-C.sub.6alkylamino, mono-C.sub.1-C.sub.6alkylcarboxamide,
di-C.sub.1-C.sub.6alkylcarboxamide, C.sub.1-C.sub.6alkoxycarbonyl,
phenyl, heteroaryl, and --(C.dbd.O)R.sub.13 wherein R.sub.13 is
chosen from C.sub.1-C.sub.6alkyl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.0-C.sub.2alkyl,
C.sub.1-C.sub.3haloalkyl, heterocycloalkyl, phenyl, and heteroaryl;
Z.sub.1 is chosen from ##STR00182## wherein R.sub.4 is chosen from
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl substituted
with 1 or more substituents independently chosen from hydroxy,
nitro, cyano, amino, halogen, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6 alkyl, mono-C.sub.1-C.sub.6
alkylamino, di-C.sub.1-C.sub.6 alkylamino, and --C(O)R.sub.14
wherein R.sub.14 is chosen from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3haloalkyl, and phenyl; C.sub.3-C.sub.7cycloalkyl,
C.sub.3-C.sub.7cycloalkyl substituted with 1 or more substituents
independently chosen from hydroxy, nitro, cyano, amino, halogen,
oxo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6 alkyl, mono-C.sub.1-C.sub.6
alkylamino, di-C.sub.1-C.sub.6 alkylamino, and --C(O)R.sub.14
wherein R.sub.14 is chosen from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3haloalkyl, and phenyl; heterocycloalkyl,
heterocycloalkyl substituted with 1 or more substituents
independently chosen from hydroxy, nitro, cyano, amino, halogen,
oxo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6 alkyl, mono-C.sub.1-C.sub.6
alkylamino, di-C.sub.1-C.sub.6 alkylamino, and --C(O)R.sub.14
wherein R.sub.14 is chosen from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3haloalkyl, and phenyl; phenyl, phenyl substituted
with 1 or more substituents independently chosen from hydroxy,
nitro, cyano, amino, halogen, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6 alkyl, mono-C.sub.1-C.sub.6
alkylamino, di-C.sub.1-C.sub.6 alkylamino, and --C(O)R.sub.14
wherein R.sub.14 is chosen from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3haloalkyl, and phenyl; heteroaryl, heteroaryl
substituted with 1 or more substituents independently chosen from
hydroxy, nitro, cyano, amino, halogen, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6 alkyl, mono-C.sub.1-C.sub.6
alkylamino, di-C.sub.1-C.sub.6 alkylamino, and --C(O)R.sub.14
wherein R.sub.14 is chosen from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3haloalkyl, and phenyl; Q is chosen from phenyl and
pyridyl; and R.sub.3 is chosen from hydrogen, halogen,
C.sub.1-C.sub.7 alkyl, heterocycloalkyl, substituted
heterocycloalkyl chosen from mono-, di-, and tri-substituted
heterocycloalkyl wherein the substituents are independently chosen
from hydroxy, nitro, cyano, amino, halogen, --SO.sub.2NH.sub.2,
oxo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6-alkoxy)C.sub.1-C.sub.6
alkoxy, mono --C.sub.1-C.sub.6alkylamino,
di-C.sub.1-C.sub.6alkylamino, aminoC.sub.1-C.sub.6 alkyl, and
--C(O)R.sub.14, C.sub.3-C.sub.7cycloalkyl, substituted
C.sub.3-C.sub.7cycloalkyl chosen from mono-, di-, and
tri-substituted C.sub.3-C.sub.7cycloalkyl wherein the substituents
are independently chosen from hydroxy, nitro, cyano, amino,
halogen, --SO.sub.2NH.sub.2, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6-alkoxy)C.sub.1-C.sub.6
alkoxy, mono --C.sub.1-C.sub.6alkylamino,
di-C.sub.1-C.sub.6alkylamino, aminoC.sub.1-C.sub.6 alkyl, and
--C(O)R.sub.14, heteroaryl, and substituted heteroaryl chosen from
mono-, di-, and tri-substituted heteroaryl wherein the substituents
are independently chosen from hydroxy, nitro, cyano, amino,
halogen, --SO.sub.2NH.sub.2, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6-alkoxy)C.sub.1-C.sub.6
alkoxy, mono --C.sub.1-C.sub.6alkylamino,
di-C.sub.1-C.sub.6alkylamino, aminoC.sub.1-C.sub.6 alkyl, and
-C(O)R.sub.14.
90. A packaged pharmaceutical composition, comprising a
pharmaceutical composition of claim 87 in a container; and
instructions for using the composition to treat a patient suffering
from an disease responsive to Btk inhibition.
91. The packaged pharmaceutical composition of claim 89 wherein the
disease responsive to Btk inhibition is cancer.
92. The packaged pharmaceutical composition of claim 89 wherein the
disease responsive to Btk inhibition is an autoimmune disease, an
inflammatory disease, or an acute inflammatory reaction.
93. A method for treating a patient having a disease responsive to
inhibition of Btk activity, comprising administering to the patient
an effective amount of the compound of Formula I-a ##STR00183## or
a pharmaceutically acceptable salt, hydrate or diastereomer
thereof, wherein A is chosen from 0 and 1; R.sub.1 is chosen from
phenyl substituted with a group chosen from hydroxy, --CHO, --COOH,
--CONH.sub.2, --CONHOH, C.sub.2-C.sub.6 alkenyl, substituted
C.sub.2-C.sub.6 alkenyl chosen from mono-, di-, and tri-substituted
C.sub.2-C.sub.6 alkenyl wherein the substituents are independently
selected from halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, C.sub.2-C.sub.6
alkynyl, substituted C.sub.2-C.sub.6 alkynyl chosen from mono-,
di-, and tri-substituted C.sub.2-C.sub.6 alkynyl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.1-C.sub.6hydroxyalkyl, substituted
C.sub.1-C.sub.6hydroxyalkyl chosen from mono-, di-, and
tri-substituted C.sub.1-C.sub.6hydroxyalkyl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.1-C.sub.6hydroxyalkoxy, substituted
C.sub.1-C.sub.6hydroxyalkoxy chosen from mono-, di-, and
tri-substituted C.sub.1-C.sub.6hydroxyalkoxy wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy, substituted
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy chosen from
mono-, di-, and tri-substituted
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy, substituted
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy chosen from
mono-, di-, and tri-substituted
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl
chosen from mono-, di-, and tri-substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy,
substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy
chosen from mono-, di-, and tri-substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, heterocycloalkyl,
substituted heterocycloalkyl chosen from mono-, di-, and
tri-substituted heterocycloalkyl wherein the substituents are
independently selected from halogen, hydroxy, amino, oxo, --COOH,
--CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, aryl, substituted
aryl chosen from mono-, di-, and tri-substituted aryl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, heteroaryl,
substituted heteroaryl chosen from mono-, di-, and tri-substituted
heteroaryl wherein the substituents are independently selected from
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10, substituted
--C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10 chosen from mono-, di-,
and tri-substituted --C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11, substituted
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11 chosen from mono-,
di-, and tri-substituted
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11 wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11, substituted
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11 chosen from
mono-, di-, and tri-substituted
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11 wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11, substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11 chosen from mono-,
di-, and tri-substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11, wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10, substituted
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10 chosen from mono-, di-,
and tri-substituted --C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12,
substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12 chosen
from mono-, di-, and tri-substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12, wherein
the substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, -L-G, where L is
chosen from C.sub.1-C.sub.2alkylene, substituted
C.sub.1-C.sub.2alkylene chosen from mono-, di-, and tri-substituted
C.sub.1-C.sub.2alkylene wherein the substituents are independently
selected from halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.0-C.sub.2alkylene-O--, substituted
C.sub.0-C.sub.2alkylene-O-- chosen from mono-, di-, and
tri-substituted C.sub.0-C.sub.2alkylene-O-- wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, --(C.dbd.O)--,
--(C.sub.1-C.sub.2alkylene)(C.dbd.O)--, and substituted
--(C.sub.1-C.sub.2alkylene)(C.dbd.O)-- chosen from mono-, di-, and
tri-substituted --(C.sub.1-C.sub.2alkylene)(C.dbd.O)-- wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, and G is chosen
from heterocycloalkyl, substituted heterocycloalkyl chosen from
mono-, di-, and tri-substituted heterocycloalkyl, wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.3-C.sub.7cycloalkyl, substituted C.sub.3-C.sub.7cycloalkyl
chosen from mono-, di-, and tri-substituted
C.sub.3-C.sub.7cycloalkyl wherein the substituents are
independently selected from halogen, hydroxy, amino, oxo, --COOH,
--CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, aryl, substituted
aryl chosen from mono-, di-, and tri-substituted aryl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH,
--CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, heteroaryl, and
substituted heteroaryl chosen from mono-, di-, and tri-substituted
heteroaryl wherein the substituents are independently selected from
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, and heteroaryl
substituted with a group chosen from hydroxy, --CHO, --COOH,
--CONH.sub.2, --CONHOH, C.sub.2-C.sub.6 alkenyl, substituted
C.sub.2-C.sub.6 alkenyl chosen from mono-, di-, and tri-substituted
C.sub.2-C.sub.6 alkenyl wherein the substituents are independently
selected from halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, C.sub.2-C.sub.6
alkynyl, substituted C.sub.2-C.sub.6 alkynyl chosen from mono-,
di-, and tri-substituted C.sub.2-C.sub.6 alkynyl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.1-C.sub.6hydroxyalkyl, substituted
C.sub.1-C.sub.6hydroxyalkyl chosen from mono-, di-, and
tri-substituted C.sub.1-C.sub.6hydroxyalkyl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.1-C.sub.6hydroxyalkoxy, substituted
C.sub.1-C.sub.6hydroxyalkoxy chosen from mono-, di-, and
tri-substituted C.sub.1-C.sub.6hydroxyalkoxy wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy, substituted
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy chosen from
mono-, di-, and tri-substituted
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy, substituted
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy chosen from
mono-, di-, and tri-substituted
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl
chosen from mono-, di-, and tri-substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy,
substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy
chosen from mono-, di-, and tri-substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, heterocycloalkyl,
substituted heterocycloalkyl chosen from mono-, di-, and
tri-substituted heterocycloalkyl wherein the substituents are
independently selected from halogen, hydroxy, amino, oxo, --COOH,
--CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, aryl, substituted
aryl chosen from mono-, di-, and tri-substituted aryl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, heteroaryl,
substituted heteroaryl chosen from mono-, di-, and tri-substituted
heteroaryl wherein the substituents are independently selected from
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10, substituted
--C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10 chosen from mono-, di-,
and tri-substituted --C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11, substituted
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11 chosen from mono-,
di-, and tri-substituted
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11 wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11, substituted
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11 chosen from
mono-, di-, and tri-substituted
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11 wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11, substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11 chosen from mono-,
di-, and tri-substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11, wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10, substituted
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10 chosen from mono-, di-,
and tri-substituted --C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12,
substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12 chosen
from mono-, di-, and tri-substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12, wherein
the substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, -L-G, where L is
chosen from C.sub.1-C.sub.2alkylene, substituted
C.sub.1-C.sub.2alkylene chosen from mono-, di-, and tri-substituted
C.sub.1-C.sub.2alkylene wherein the substituents are independently
selected from halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.0-C.sub.2alkylene-O--, substituted
C.sub.0-C.sub.2alkylene-O-- chosen from mono-, di-, and
tri-substituted C.sub.0-C.sub.2alkylene-O-- wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, --(C.dbd.O)--,
--(C.sub.1-C.sub.2alkylene)(C.dbd.O)--, and substituted
--(C.sub.1-C.sub.2alkylene)(C.dbd.O)-- chosen from mono-, di-, and
tri-substituted --(C.sub.1-C.sub.2alkylene)(C.dbd.O)-- wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, and G is chosen
from heterocycloalkyl, substituted heterocycloalkyl chosen from
mono-, di-, and tri-substituted heterocycloalkyl, wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.3-C.sub.7cycloalkyl, substituted C.sub.3-C.sub.7cycloalkyl
chosen from mono-, di-, and tri-substituted
C.sub.3-C.sub.7cycloalkyl wherein the substituents are
independently selected from halogen, hydroxy, amino, oxo,
--COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, aryl, substituted
aryl chosen from mono-, di-, and tri-substituted aryl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, heteroaryl, and
substituted heteroaryl chosen from mono-, di-, and tri-substituted
heteroaryl wherein the substituents are independently selected from
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, and R.sub.1 is
optionally further substituted with 1 or more substituents
independently chosen from hydroxy, nitro, cyano, amino,
--SO.sub.2NH.sub.2, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkanoyl, C.sub.1-C.sub.4haloalkyl,
C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.3-C.sub.7cycloalkyl, (C.sub.1-C.sub.6
alkoxy)C.sub.0-C.sub.6alkyl, (mono-C.sub.1-C.sub.6
alkylamino)C.sub.0-C.sub.6 alkyl, (di-C.sub.1-C.sub.6
alkylamino)C.sub.0-C.sub.6 alkyl, and
C.sub.1-C.sub.6alkoxycarbonyl; R.sub.2 is chosen from
C.sub.1-C.sub.7 alkyl,
(C.sub.1-C.sub.6alkoxy)C.sub.0-C.sub.6alkoxy,
(heterocycloalkyl)C.sub.0-C.sub.2alkyl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.0-C.sub.2alkyl,
(phenyl)C.sub.0-C.sub.2alkyl, substituted
(phenyl)C.sub.0-C.sub.2alkyl chosen from mono-, di-, and
tri-substituted (phenyl)C.sub.0-C.sub.2alkyl wherein the
substituents are independently chosen from hydroxy, nitro, cyano,
amino, halogen, --SO.sub.2NH.sub.2, oxo, --COOH, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6alkanoyl,
C.sub.1-C.sub.6hydroxyalkyl, C.sub.1-C.sub.3haloalkyl,
C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.6 alkylthio,
(C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkoxy,
aminoC.sub.1-C.sub.6alkyl, mono-C.sub.1-C.sub.6alkylamino,
di-C.sub.1-C.sub.6alkylamino, mono-C.sub.1-C.sub.6alkylcarboxamide,
di-C.sub.1-C.sub.6alkylcarboxamide, C.sub.1-C.sub.6alkoxycarbonyl,
phenyl, heteroaryl, and --(C.dbd.O)R.sub.13 wherein R.sub.13 is
chosen from C.sub.1-C.sub.6alkyl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.0-C.sub.2alkyl,
C.sub.1-C.sub.3haloalkyl, heterocycloalkyl, phenyl, and heteroaryl,
(phenoxy)C.sub.0-C.sub.2alkyl, substituted
(phenoxy)C.sub.0-C.sub.2alkyl chosen from mono-, di-, and
tri-substituted (phenoxy)C.sub.0-C.sub.2alkyl wherein the
substituents are independently chosen from hydroxy, nitro, cyano,
amino, halogen, --SO.sub.2NH.sub.2, oxo, --COOH, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6alkanoyl,
C.sub.1-C.sub.6hydroxyalkyl, C.sub.1-C.sub.3haloalkyl,
C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.6 alkylthio,
(C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkoxy,
aminoC.sub.1-C.sub.6alkyl, mono-C.sub.1-C.sub.6alkylamino,
di-C.sub.1-C.sub.6alkylamino, mono-C.sub.1-C.sub.6alkylcarboxamide,
di-C.sub.1-C.sub.6alkylcarboxamide, C.sub.1-C.sub.6alkoxycarbonyl,
phenyl, heteroaryl, and --(C.dbd.O)R.sub.13 wherein R.sub.13 is
chosen from C.sub.1-C.sub.6alkyl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.0-C.sub.2alkyl,
C.sub.1-C.sub.3haloalkyl, heterocycloalkyl, phenyl, and heteroaryl,
(heteroaryl)C.sub.0-C.sub.2alkyl, and substituted
(heteroaryl)C.sub.0-C.sub.2alkyl chosen from mono-, di-, and
tri-substituted (heteroaryl)C.sub.0-C.sub.2alkyl wherein the
substituents are independently chosen from hydroxy, nitro, cyano,
amino, halogen, --SO.sub.2NH.sub.2, oxo, --COOH, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6alkanoyl,
C.sub.1-C.sub.6hydroxyalkyl, C.sub.1-C.sub.3haloalkyl,
C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.6 alkylthio,
(C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkoxy,
aminoC.sub.1-C.sub.6alkyl, mono-C.sub.1-C.sub.6alkylamino,
di-C.sub.1-C.sub.6alkylamino, mono-C.sub.1-C.sub.6alkylcarboxamide,
di-C.sub.1-C.sub.6alkylcarboxamide, C.sub.1-C.sub.6alkoxycarbonyl,
phenyl, heteroaryl, and --(C.dbd.O)R.sub.13 wherein R.sub.13 is
chosen from C.sub.1-C.sub.6alkyl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.0-C.sub.2alkyl,
C.sub.1-C.sub.3haloalkyl, heterocycloalkyl, phenyl, and heteroaryl
Z.sub.1 is chosen from ##STR00184## wherein R.sub.4 is chosen from
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyl substituted
with 1 or more substituents independently chosen from hydroxy,
nitro, cyano, amino, halogen, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6 alkyl, mono-C.sub.1-C.sub.6
alkylamino, di-C.sub.1-C.sub.6 alkylamino, and --C(O)R.sub.14
wherein R.sub.14 is chosen from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3haloalkyl, and phenyl; C.sub.3-C.sub.7cycloalkyl,
C.sub.3-C.sub.7cycloalkyl substituted with 1 or more substituents
independently chosen from hydroxy, nitro, cyano, amino, halogen,
oxo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6 alkyl, mono-C.sub.1-C.sub.6
alkylamino, di-C.sub.1-C.sub.6 alkylamino, and --C(O)R.sub.14
wherein R.sub.14 is chosen from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3haloalkyl, and phenyl; heterocycloalkyl,
heterocycloalkyl substituted with 1 or more substituents
independently chosen from hydroxy, nitro, cyano, amino, halogen,
oxo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6 alkyl, mono-C.sub.1-C.sub.6
alkylamino, di-C.sub.1-C.sub.6 alkylamino, and --C(O)R.sub.14
wherein R.sub.14 is chosen from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3haloalkyl, and phenyl; phenyl, phenyl substituted
with 1 or more substituents independently chosen from hydroxy,
nitro, cyano, amino, halogen, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6 alkyl, mono-C.sub.1-C.sub.6
alkylamino, di-C.sub.1-C.sub.6 alkylamino, and --C(O)R.sub.14
wherein R.sub.14 is chosen from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3haloalkyl, and phenyl; heteroaryl, heteroaryl
substituted with 1 or more substituents independently chosen from
hydroxy, nitro, cyano, amino, halogen, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6 alkyl, mono-C.sub.1-C.sub.6
alkylamino, di-C.sub.1-C.sub.6 alkylamino, and --C(O)R.sub.14
wherein R.sub.14 is chosen from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3haloalkyl, and phenyl; Q is chosen from phenyl and
pyridyl; and R.sub.3 is chosen from hydrogen, halogen,
C.sub.1-C.sub.7 alkyl, heterocycloalkyl, substituted
heterocycloalkyl chosen from mono-, di-, and tri-substituted
heterocycloalkyl wherein the substituents are independently chosen
from hydroxy, nitro, cyano, amino, halogen, --SO.sub.2NH.sub.2,
oxo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6-alkoxy)C.sub.1-C.sub.6
alkoxy, mono --C.sub.1-C.sub.6alkylamino,
di-C.sub.1-C.sub.6alkylamino, aminoC.sub.1-C.sub.6 alkyl, and
--C(O)R.sub.14, C.sub.3-C.sub.7cycloalkyl, substituted
C.sub.3-C.sub.7cycloalkyl chosen from mono-, di-, and
tri-substituted C.sub.3-C.sub.7cycloalkyl wherein the substituents
are independently chosen from hydroxy, nitro, cyano, amino,
halogen, --SO.sub.2NH.sub.2, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6-alkoxy)C.sub.1-C.sub.6
alkoxy, mono --C.sub.1-C.sub.6alkylamino,
di-C.sub.1-C.sub.6alkylamino, aminoC.sub.1-C.sub.6 alkyl, and
--C(O)R.sub.14, heteroaryl, and substituted heteroaryl chosen from
mono-, di-, and tri-substituted heteroaryl wherein the substituents
are independently chosen from hydroxy, nitro, cyano, amino,
halogen, --SO.sub.2NH.sub.2, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6-alkoxy)C.sub.1-C.sub.6
alkoxy, mono --C.sub.1-C.sub.6alkylamino,
di-C.sub.1-C.sub.6alkylamino, aminoC.sub.1-C.sub.6 alkyl, and
--C(O)R.sub.14
94. A method for treating a patient having a disease responsive to
inhibition of Btk activity, comprising administering an effective
amount of the pharmaceutical composition according to claim 87 to
the patient.
95. A method for increasing sensitivity of cancer cells to
chemotherapy, comprising administering to a patient undergoing
chemotherapy with a chemotherapeutic agent an amount of the
pharmaceutical composition of claim 87, sufficient to increase the
sensitivity of cancer cells to the chemotherapeutic agent.
96. A pharmaceutical composition of claim 87, wherein in the
compound of formula I, A is 0.
97. A pharmaceutical composition of claim 87, wherein in the
compound of formula I, A is 1.
98. A pharmaceutical composition of claim 87, wherein in the
compound of formula I, R.sub.1 is chosen from phenyl substituted
with hydroxy, --CHO, --COOH, --CONH.sub.2, --CONHOH,
C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl chosen
from mono-, di-, and tri-substituted C.sub.2-C.sub.6 alkenyl
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, C.sub.2-C.sub.6
alkynyl, substituted C.sub.2-C.sub.6 alkynyl chosen from mono-,
di-, and tri-substituted C.sub.2-C.sub.6 alkynyl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.1-C.sub.6hydroxyalkyl, substituted
C.sub.1-C.sub.6hydroxyalkyl chosen from mono-, di-, and
tri-substituted C.sub.1-C.sub.6hydroxyalkyl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.1-C.sub.6hydroxyalkoxy, substituted
C.sub.1-C.sub.6hydroxyalkoxy chosen from mono-, di-, and
tri-substituted C.sub.1-C.sub.6hydroxyalkoxy wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy, substituted
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy chosen from
mono-, di-, and tri-substituted
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy, substituted
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy chosen from
mono-, di-, and tri-substituted
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl
chosen from mono-, di-, and tri-substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy,
substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy
chosen from mono-, di-, and tri-substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, heterocycloalkyl,
substituted heterocycloalkyl chosen from mono-, di-, and
tri-substituted heterocycloalkyl wherein the substituents are
independently selected from halogen, hydroxy, amino, oxo, --COOH,
--CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, aryl, substituted
aryl chosen from mono-, di-, and tri-substituted aryl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, heteroaryl,
substituted heteroaryl chosen from mono-, di-, and tri-substituted
heteroaryl wherein the substituents are independently selected from
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10, substituted
--C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10 chosen from mono-, di-,
and tri-substituted --C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11, substituted
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11 chosen from mono-,
di-, and tri-substituted
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11 wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11, substituted
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11 chosen from
mono-, di-, and tri-substituted
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11 wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11, substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11 chosen from mono-,
di-, and tri-substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11, wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10, substituted
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10 chosen from mono-, di-,
and tri-substituted-C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10 wherein
the substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12,
substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12 chosen
from mono-, di-, and tri-substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12, wherein
the substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, -L-G, where L is
chosen from C.sub.1-C.sub.2alkylene, substituted
C.sub.1-C.sub.2alkylene chosen from mono-, di-, and tri-substituted
C.sub.1-C.sub.2alkylene wherein the substituents are independently
selected from halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.0-C.sub.2alkylene-O--, substituted
C.sub.0-C.sub.2alkylene-O-- chosen from mono-, di-, and
tri-substituted C.sub.0-C.sub.2alkylene-O-- wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, --(C.dbd.O)--,
--(C.sub.1-C.sub.2alkylene)(C.dbd.O)--, and substituted
--(C.sub.1-C.sub.2alkylene)(C.dbd.O)-- chosen from mono-, di-, and
tri-substituted --(C.sub.1-C.sub.2alkylene)(C.dbd.O)-- wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, and G is chosen
from heterocycloalkyl, substituted heterocycloalkyl chosen from
mono-, di-, and tri-substituted heterocycloalkyl, wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.3-C.sub.7cycloalkyl, substituted C.sub.3-C.sub.7cycloalkyl
chosen from mono-, di-, and tri-substituted
C.sub.3-C.sub.7cycloalkyl wherein the substituents are
independently selected from halogen, hydroxy, amino, oxo, --COOH,
--CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, aryl, substituted
aryl chosen from mono-, di-, and tri-substituted aryl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C
.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, heteroaryl,
substituted heteroaryl chosen from mono-, di-, and tri-substituted
heteroaryl wherein the substituents are independently selected from
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, and pyridyl
substituted with hydroxy, --CHO, --COOH, --CONH.sub.2, --CONHOH,
C.sub.2-C.sub.6 alkenyl, substituted C.sub.2-C.sub.6 alkenyl chosen
from mono-, di-, and tri-substituted C.sub.2-C.sub.6 alkenyl
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, C.sub.2-C.sub.6
alkynyl, substituted C.sub.2-C.sub.6 alkynyl chosen from mono-,
di-, and tri-substituted C.sub.2-C.sub.6 alkynyl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.1-C.sub.6hydroxyalkyl, substituted
C.sub.1-C.sub.6hydroxyalkyl chosen from mono-, di-, and
tri-substituted C.sub.1-C.sub.6hydroxyalkyl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.1-C.sub.6hydroxyalkoxy, substituted
C.sub.1-C.sub.6hydroxyalkoxy chosen from mono-, di-, and
tri-substituted C.sub.1-C.sub.6hydroxyalkoxy wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy, substituted
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy chosen from
mono-, di-, and tri-substituted
(mono-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy, substituted
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy chosen from
mono-, di-, and tri-substituted
(di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl
chosen from mono-, di-, and tri-substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy,
substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy
chosen from mono-, di-, and tri-substituted
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, heterocycloalkyl,
substituted heterocycloalkyl chosen from mono-, di-, and
tri-substituted heterocycloalkyl wherein the substituents are
independently selected from halogen, hydroxy, amino, oxo, --COOH,
--CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, aryl, substituted
aryl chosen from mono-, di-, and tri-substituted aryl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, heteroaryl,
substituted heteroaryl chosen from mono-, di-, and tri-substituted
heteroaryl wherein the substituents are independently selected from
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10, substituted
--C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10 chosen from mono-, di-,
and tri-substituted --C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11, substituted
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11 chosen from mono-,
di-, and tri-substituted
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11 wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11, substituted
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11 chosen from
mono-, di-, and tri-substituted
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11 wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11, substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11 chosen from mono-,
di-, and tri-substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11, wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10, substituted
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10 chosen from mono-, di-,
and tri-substituted --C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10
wherein the substituents are independently selected from halogen,
hydroxy, amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12)
substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12 chosen
from mono-, di-, and tri-substituted
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12, wherein
the substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, -L-G, where L is
chosen from C.sub.1-C.sub.2alkylene, substituted
C.sub.1-C.sub.2alkylene chosen from mono-, di-, and tri-substituted
C.sub.1-C.sub.2alkylene wherein the substituents are independently
selected from halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.0-C.sub.2alkylene-O--, substituted
C.sub.0-C.sub.2alkylene-O-- chosen from mono-, di-, and
tri-substituted C.sub.0-C.sub.2alkylene-O-- wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, --(C.dbd.O)--,
--(C.sub.1-C.sub.2alkylene)(C.dbd.O)--, and substituted
--(C.sub.1-C.sub.2alkylene)(C.dbd.O)-- chosen from mono-, di-, and
tri-substituted --(C.sub.1-C.sub.2alkylene)(C.dbd.O)-- wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, and G is chosen
from heterocycloalkyl, substituted heterocycloalkyl chosen from
mono-, di-, and tri-substituted heterocycloalkyl, wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl,
C.sub.3-C.sub.7cycloalkyl, substituted C.sub.3-C.sub.7cycloalkyl
chosen from mono-, di-, and tri-substituted
C.sub.3-C.sub.7cycloalkyl wherein the substituents are
independently selected from halogen, hydroxy, amino, oxo, --COOH,
--CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C
.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, aryl, substituted
aryl chosen from mono-, di-, and tri-substituted aryl wherein the
substituents are independently selected from halogen, hydroxy,
amino, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl,
mono-C.sub.1-C.sub.4alkylamino, di-C.sub.1-C.sub.4alkylamino,
mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, heteroaryl,
substituted heteroaryl chosen from mono-, di-, and tri-substituted
heteroaryl wherein the substituents are independently selected from
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono-C.sub.1-C.sub.4alkylamino,
di-C.sub.1-C.sub.4alkylamino, mono-C.sub.1-C.sub.4alkylcarboxamide,
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl, and wherein R.sub.1
is optionally further substituted with 1 or more substituents
independently chosen from hydroxy, nitro, cyano, amino,
--SO.sub.2NH.sub.2, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkanoyl, C.sub.1-C.sub.4haloalkyl,
C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.3-C.sub.7cycloalkyl, (C.sub.1-C.sub.6
alkoxy)C.sub.0-C.sub.6alkyl, (mono-C.sub.1-C.sub.6
alkylamino)C.sub.0-C.sub.6 alkyl, (di-C.sub.1-C.sub.6
alkylamino)C.sub.0-C.sub.6 alkyl, and
C.sub.1-C.sub.6alkoxycarbonyl.
99. A pharmaceutical composition of claim 87, wherein in the
compound of formula I, R.sub.2 is chosen from
(phenyl)C.sub.0-C.sub.2alkyl, substituted
(phenyl)C.sub.0-C.sub.2alkyl chosen from mono-, di-, and
tri-substituted (phenyl)C.sub.0-C.sub.2alkyl wherein the
substituents are independently chosen from hydroxy, nitro, cyano,
amino, halogen, --SO.sub.2NH.sub.2, oxo, --COOH, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6alkanoyl,
C.sub.1-C.sub.6hydroxyalkyl, C.sub.1-C.sub.3haloalkyl,
C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.6 alkylthio,
(C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkoxy,
aminoC.sub.1-C.sub.6alkyl, mono-C.sub.1-C.sub.6 alkylamino,
di-C.sub.1-C.sub.6 alkylamino,
mono-C.sub.1-C.sub.6alkylcarboxamide,
di-C.sub.1-C.sub.6alkylcarboxamide, C.sub.1-C.sub.6alkoxycarbonyl,
phenyl, heteroaryl, and --(C.dbd.O)R.sub.13 wherein R.sub.13 is
chosen from C.sub.1-C.sub.6alkyl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.0-C.sub.2alkyl,
C.sub.1-C.sub.3haloalkyl, heterocycloalkyl, phenyl, and heteroaryl,
(phenoxy)C.sub.0-C.sub.2alkyl, substituted
(phenoxy)C.sub.0-C.sub.2alkyl chosen from mono-, di-, and
tri-substituted (phenoxy)C.sub.0-C.sub.2alkyl wherein the
substituents are independently chosen from hydroxy, nitro, cyano,
amino, halogen, --SO.sub.2NH.sub.2, oxo, --COOH, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6alkanoyl,
C.sub.1-C.sub.6hydroxyalkyl, C.sub.1-C.sub.3haloalkyl,
C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.6 alkylthio,
(C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkoxy,
aminoC.sub.1-C.sub.6alkyl, mono-C.sub.1-C.sub.6 alkylamino,
di-C.sub.1-C.sub.6 alkylamino,
mono-C.sub.1-C.sub.6alkylcarboxamide,
di-C.sub.1-C.sub.6alkylcarboxamide, C.sub.1-C.sub.6alkoxycarbonyl,
phenyl, heteroaryl, and --(C.dbd.O)R.sub.13 wherein R.sub.13 is
chosen from C.sub.1-C.sub.6alkyl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.0-C.sub.2alkyl,
C.sub.1-C.sub.3haloalkyl, heterocycloalkyl, phenyl, and heteroaryl,
(pyridyl)C.sub.0-C.sub.2alkyl, and substituted
(pyridyl)C.sub.0-C.sub.2alkyl chosen from mono-, di-, and
tri-substituted (pyridyl)C.sub.0-C.sub.2alkyl wherein the
substituents are independently chosen from hydroxy, nitro, cyano,
amino, halogen, --SO.sub.2NH.sub.2, oxo, --COOH, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6alkanoyl,
C.sub.1-C.sub.6hydroxyalkyl, C.sub.1-C.sub.3haloalkyl,
C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.6 alkylthio,
(C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkoxy,
aminoC.sub.1-C.sub.6alkyl, mono-C.sub.1-C.sub.6 alkylamino,
di-C.sub.1-C.sub.6 alkylamino,
mono-C.sub.1-C.sub.6alkylcarboxamide,
di-C.sub.1-C.sub.6alkylcarboxamide, C.sub.1-C.sub.6alkoxycarbonyl,
phenyl, heteroaryl, and --(C.dbd.O)R.sub.13 wherein R.sub.13 is
chosen from C.sub.1-C.sub.6alkyl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.0-C.sub.2alkyl,
C.sub.1-C.sub.3haloalkyl, heterocycloalkyl, phenyl, and
heteroaryl.
100. A pharmaceutical composition of claim 87, wherein in the
compound of formula I, Z.sub.1 is chosen from ##STR00185## and
R.sub.4 is chosen from hydrogen, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.7cycloalkyl.
101. A pharmaceutical composition of claim 87, wherein in the
compound of formula I, R.sub.3 is chosen from hydrogen and methyl.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. provisional
application 60/475,634 filed Jun. 4, 2003, and U.S. provisional
application 60/519,311 filed Nov. 11, 2003, which are hereby
incorporated by reference in their entirety.
FIELD OF INVENTION
[0002] Certain imidazo[1,2-a]pyrazin-8-ylamine and related
compounds, which when appropriately substituted are inhibitors of
tyrosine kinase activity, including Bruton's tyrosine kinase (Btk)
activity, are provided herein. Certa in compounds provided herein
are highly active and/or specific inhibitors of Btk activity.
Pharmaceutical compositions comprising such compounds, and methods
of using certain imidazo[1,2-a]pyrazin-8-ylamine and related
compounds to treat a variety of diseases responsive to inhibition
of Btk activity and/or inhibition of B-cell proliferation, are also
disclosed. Additionally, methods for using such compounds as probes
for the detection and/or localization of Btk in biological samples
are given.
BACKGROUND
[0003] Protein kinases, the largest family of human enzymes,
encompass well over 500 proteins. Kinases play critical roles in
signaling pathways controlling fundamental cellular processes such
as proliferation, differentiation, and death (apoptosis). Abnormal
kinase activity has been implicated in a wide range of diseases,
including multiple cancers and autoimmune and inflammatory
diseases. The multifaceted role of kinases in key cell signaling
pathways provides a significant opportunity to identify novel drugs
targeting kinases and signaling pathways. Diseases mediated by
receptor kinase activity include, but are not limited to, diseases
characterized in part by abnormal levels of cell proliferation
(i.e. tumor growth), programmed cell death (apoptosis), cell
migration and invasion, and angiogenesis associated with tumor
growth.
[0004] Because kinases are key regulators they are ideal drug
design targets. Inhibitors of kinases are among the most important
classes of pharmaceutical compounds known. Highly specific,
cell-permeable inhibitors of one or more individual kinases are
useful for the treatment of various kinase-implicated diseases.
Kinase inhibiting compounds are additionally useful for the
systematic investigation of the cellular function of one or more
kinases, and thus, provide valuable tools for the identification of
various kinases of therapeutic interest.
[0005] Bruton's Tyrosine Kinase (Btk) is a member of the Tec family
of tyrosine kinases, and is a critical regulator of early B-cell
development as well as mature B-cell activation, signaling and
survival.
[0006] B-cell signaling through the B-cell receptor (BCR) leads to
a wide range of biological outputs, which in turn depend on the
developmental stage of the B-cell. The magnitude and duration of
BCR signals must be precisely regulated. Aberrant BCR-mediated
signaling can cause disregulated B-cell proliferation and/or the
formation of pathogenic auto-antibodies leading to multiple
autoimmune and/or inflammatory diseases. Mutation of Btk in humans
results in X-linked agammaglobulinaemia (XLA). This disease is
associated with the impaired maturation of B-cells, diminished
immunoglobulin production, comprised T-cell-independent immune
responses and marked attenuation of the sustained calcium sign upon
BCR stimulation.
[0007] Evidence for the role of Btk in autoimmune and/or
inflammatory disease has been established in Btk-deficient mouse
models. For example, in standard murine preclinical models of
systemic lupus erythematosus (SLE), Btk deficiency has been shown
to result in a marked amelioration of disease progression.
Moreover, Btk deficient mice are also resistant to developing
collagen-induced arthritis and are less susceptible to
Staphylococcus-induced arthritis.
[0008] A large body of evidence supports the role of B-cells and
the humoral immune system in the pathogenesis of autoimmune and/or
inflammatory diseases. Protein-based therapeutics (such as Rituxan)
developed to deplete B-cells, represent an important approach to
the treatment of a number of autoimmune and/or inflammatory
diseases. Because of Btk's role in B-cell activation, inhibitors of
Btk are useful as inhibitors of B-cell mediated pathogenic activity
(such as autoantibody production).
[0009] Btk is also expressed in mast cells and monocytes and has
been shown to be important for the function of these cells. For
example, Btk deficiency in mice is associated with impaired
IgE-mediated mast cell activation (marked diminution of TNF.alpha.
and other inflammatory cytokine release), and greatly reduced
TNF.alpha. production by activated monocytes.
[0010] Thus, inhibition of Btk activity is useful for the treatment
of autoimmune and/or inflammatory diseases such as: SLE, rheumatoid
arthritis, multiple vasculitides, idiopathic thrombocytopenic
purpura (ITP), myasthenia gravis, and asthma. In addition, Btk has
been reported to play a role in apoptosis, thus inhibition of Btk
activity is useful for the treatment of B-cell lymphoma and
leukemia.
[0011] Agents capable of inhibiting Btk kinase activity, are highly
desirable for the treatment of a variety of diseases, including
cancer, an autoimmune and/or inflammatory disease, or an acute
inflammatory reaction. Specific, cell-penetrating, small molecule,
non-peptide antagonists of Btk are of particular value for such
therapies. Such compounds are also useful for the systematic
investigation of the cellular function of Btk, and thus, are
valuable research tools for the identification of cell signalling
proteins of therapeutic interest.
[0012] The present invention fulfills this need, and provides
further related advantages.
SUMMARY
[0013] Inhibitors of kinase activity, which may generally be
described as imidazo[1,2-a]pyrazin-8-ylamines and related
compounds, are disclosed herein. Certain compounds provided herein
are highly active and/or specific inhibitors of Btk (Bruton's
tyrosine kinase) activity.
[0014] One embodiment provides a compound of Formula I-a
##STR00002##
or a pharmaceutically acceptable form thereof.
[0015] Within Formula I-a:
[0016] A is 0 or 1.
[0017] R.sub.1 is phenyl or heteroaryl, each of which is optionally
substituted with one of
[0018] (i) oxo, --CHO, --COOH, --CONH.sub.2, or --CONHOH,
[0019] (ii) C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6hydroxyalkyl, C.sub.1-C.sub.6hydroxyalkoxy, (mono-
or di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy,
heterocycloalkyl, aryl, or heteroaryl,
[0020] (iii) --C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10,
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11,
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11,
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10, or
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12 where
R.sub.10, R.sub.11, and R.sub.12 are independently hydrogen,
hydroxy, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.3-C.sub.10cycloalkyl, or heterocycloalkyl, or
[0021] (iv) -L-G, where L is C.sub.1-C.sub.2alkyl,
C.sub.0-C.sub.2alkoxy, --(C.dbd.O)--, or
--(C.sub.1-C.sub.2alkyl)(C.dbd.O)--, and G is heterocycloalkyl,
C.sub.3-C.sub.7cycloalkyl, aryl, or heteroaryl.
[0022] Each of which (ii), (iii), and (iv) is substituted with 0 to
3 substituents independently chosen from halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl, mono- and
di-C.sub.1-C.sub.4alkylamino, mono- and
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl.
[0023] And, R.sub.1 is substituted with 0 or 1 or more substituents
independently chosen from hydroxy, nitro, cyano, amino,
--SO.sub.2NH.sub.2, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkanoyl, C.sub.1-C.sub.4haloalkyl,
C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.3-C.sub.7cycloalkyl, (C.sub.1-C.sub.6
alkoxy)C.sub.0-C.sub.6alkyl, (mono- and di-C.sub.1-C.sub.6
alkylamino)C.sub.0-C.sub.6 alkyl, and
C.sub.1-C.sub.6alkoxycarbonyl.
[0024] R.sub.2 is C.sub.1-C.sub.7 alkyl,
(C.sub.1-C.sub.6alkoxy)C.sub.0-C.sub.6alkoxy,
(heterocycloalkyl)C.sub.0-C.sub.2alkyl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.0-C.sub.2alkyl, or R.sub.2 is
(phenyl)C.sub.0-C.sub.2alkyl, (phenoxy)C.sub.0-C.sub.2alkyl, or
(heteroaryl)C.sub.0-C.sub.2alkyl, each of which is substituted with
0 to 3 substituents independently chosen from hydroxy, nitro,
cyano, amino, halogen, --SO.sub.2NH.sub.2, oxo, --COOH,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.2-C.sub.6alkanoyl, C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6alkyl, mono- and
di-C.sub.1-C.sub.6alkylamino, mono- and
di-C.sub.1-C.sub.6alkylcarboxamide, C.sub.1-C.sub.6alkoxycarbonyl,
phenyl, and heteroaryl, and --(C.dbd.O)R.sub.13 wherein R.sub.13 is
C.sub.1-C.sub.6alkyl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.0-C.sub.2alkyl,
C.sub.1-C.sub.3haloalkyl, heterocycloalkyl, phenyl, or
heteroaryl.
[0025] Z.sub.1 is
##STR00003##
wherein R.sub.4 is hydrogen, or R.sub.4 is C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl,
each of which is substituted with 0 or 1 or more substituents
independently chosen from hydroxy, nitro, cyano, amino, halogen,
oxo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6 alkyl, mono- and di-C.sub.1-C.sub.6
alkylamino, and --C(O)R.sub.14 wherein R.sub.14 is C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.3haloalkyl, or phenyl.
[0026] Q is phenyl or pyridyl.
[0027] R.sub.3 is hydrogen, C.sub.1-C.sub.7 alkyl, or halogen,
or
[0028] R.sub.3 is heterocycloalkyl, C.sub.3-C.sub.7cycloalkyl, or
heteroaryl, each of which is substituted with from 0 to 3
substituents independently chosen from hydroxy, nitro, cyano,
amino, halogen, --SO.sub.2NH.sub.2, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3halooalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6-alkoxy)C.sub.1-C.sub.6
alkoxy, mono- and di-C.sub.1-C.sub.6alkylamino,
aminoC.sub.1-C.sub.6 alkyl, and --C(O)R.sub.14.
[0029] In certain embodiments compounds of Formula I-a, which
exhibit an IC.sub.50 of 1 micromolar or less, 100 nanomolar or
less, or 10 nanomolar or less in standard biochemical assay for Btk
activity, such as the biochemical assay described in Example 6, are
provided herein. Preferred compounds described herein are highly
active inhibitors of B-cell proliferation. For example certain
compounds described herein exhibit an IC.sub.50 value less than or
equal to 10 micromolar, or an IC.sub.50 value less than or equal to
1 micromolar, or an IC.sub.50 value less than or equal to 500 nM in
the tritiated thymidine incorporation assay for B-cell
proliferation described in Example 8. Preferred compounds described
herein are specific inhibitors of B-cell proliferation, exhibiting
an IC.sub.50 value that is at least 3-fold, preferably 5-fold, and
more preferably 10-fold greater for T-cell proliferation than the
IC.sub.50 for B-cell proliferation. The IC.sub.50 for T-cell
proliferation may be determined via a standard assay for T-cell
proliferation such as the thymidine incorporation assay of Example
9.
[0030] A method for determining the presence of Btk in a sample,
comprising contacting the sample with a compound or form thereof of
Formula I-a under conditions that permit detection of Btk activity,
detecting a level of Btk activity in the sample, and therefrom
determining the presence or absence of Btk in the sample, is also
provided herein.
[0031] Pharmaceutical compositions, comprising one or more
compounds of Formula I-a, or any pharmaceutically acceptable form
thereof, together with at least one pharmaceutically acceptable
carrier or excipient, are provided herein.
[0032] Other embodiments pertain to packaged pharmaceutical
compositions which comprise a pharmaceutical composition,
comprising one or more compounds of Formula I-a or any
pharmaceutically acceptable form thereof, together with at least
one pharmaceutically acceptable carrier or excipient in a container
and with instructions for using the pharmaceutical composition to
treat a patient. Preferably the instructions are for using the
pharmaceutical composition to treat a patient suffering from a
disease responsive to inhibition of Btk activity.
[0033] Still other embodiments pertain to a method of inhibiting
Btk kinase. In certain embodiments the method comprises contacting
a cell or cells expressing Btk, either in vivo or in vitro, with a
compound of Formula I-a or form thereof in an amount sufficient to
detectably inhibit Btk activity in vitro.
[0034] Inhibiting Btk activity can effectively inhibit B-cell
proliferation. Small molecule (less than 600 amu) Btk inhibitors
that are orally bioavailable, such as certain compounds and forms
of Formula I-a, are particularly desirable for this purpose. Thus a
method of inhibiting B-cell proliferation, by contacting cells
expressing Btk, either in vivo or in vitro with a compound having a
molecular weight less than 600 amu in an amount sufficient to
detectably inhibit the activity of Btk in vitro is provided herein.
In certain embodiments the compound will be a heterocyclic
compound, such as a heterocyclic compound having a bicyclic
heterocyclic group. In certain embodiments the compound is a
compound of Formula I-a.
[0035] A method of treating a mammal suffering from at least one
disease responsive to inhibition of Btk activity, by administering
to the mammal an effective amount of a compound that is a highly
active Btk inhibitor in an in vitro assay of Btk activity is
included herein. Preferably the compound is also a specific
inhibitor of B-cell proliferation, exhibiting an IC.sub.50 value
that is at least 3-fold, preferably 5-fold, and more preferably
10-fold greater for T-cell proliferation than the IC.sub.50 value
for B-cell proliferation.
[0036] Methods for treating a patient having a disease responsive
to inhibition of Btk activity and/or responsive to inhibition of
B-cell proliferation, are provided herein. Such methods comprise
administering to the patient an effective amount of a compound or
form thereof of Formula I-a. The patient may be a mammal.
Preferably the patient is a human patient, however methods of
treating non-human patients are included herein. For example in
some embodiments the patient is a companion animal, such as a cat
or dog, or the patient is a livestock animal, such as a horse, cow,
or pig. Particularly included herein are methods in which the
disease responsive to Btk inhibition is cancer, an autoimmune
and/or inflammatory disease, or an acute inflammatory reaction.
[0037] Methods of treatment include administering a compound of
Formula I-a as a single active agent or administering a compound of
Formula I-a in combination with one or more other active
agents.
DETAILED DESCRIPTION
[0038] Certain terms to be used herein are provided prior to
setting forth the invention in detail. Compounds of the present
invention are described using standard nomenclature. Unless defined
otherwise, all technical and scientific terms used herein have the
same meaning as is commonly understood by one of skill in the art
to which this invention belongs.
Chemical Description and Terminology
[0039] Formula I-a includes all subformulae thereof. For example
Formula I-a includes compounds of Formulas 1 to 9.
[0040] Certain compounds are described herein using a general
formula that includes variables, e.g. R.sub.1, R.sub.2, R.sub.3, Q,
Z.sub.1, and A. Unless otherwise specified, each variable within
such a formula is defined independently of other variables. When
any variable occurs more than one time in Formula I-a, its
definition on each occurrence is independent of its definition at
every other occurrence.
[0041] In accordance with the usual meaning of "a" and "the" in
patents, reference to "a" kinase or "the" kinase is inclusive of
one or more kinases. Unless otherwise specified the term
"compounds" includes all pharmaceutically acceptable forms of the
disclosed structures.
[0042] In certain situations, the compounds of Formula I-a may
contain one or more asymmetric elements such as stereogenic
centers, stereogenic axes and the like, e.g. asymmetric carbon
atoms, so that the compounds can exist in different stereoisomeric
forms. These compounds can be, for example, racemates or optically
active forms. For compounds with two or more asymmetric elements,
these compounds can additionally be mixtures of diastereomers. For
compounds having asymmetric centers, it should be understood that
all of the optical isomers and mixtures thereof are encompassed. In
addition, compounds with carbon-carbon double bonds may occur in Z-
and E-forms, with all isomeric forms of the compounds being
included in the present invention. In these situations, the single
enantiomers, i.e., optically active forms, can be obtained by
asymmetric synthesis, synthesis from optically pure precursors, or
by resolution of the racemates. Resolution of the racemates can
also be accomplished, for example, by conventional methods such as
crystallization in the presence of a resolving agent, or
chromatography, using, for example a chiral HPLC column.
[0043] Where a compound exists in various tautomeric forms, the
invention is not limited to any one of the specific tautomers, but
rather includes all tautomeric forms.
[0044] The present invention is intended to include all isotopes of
atoms occurring in the present compounds. Isotopes include those
atoms having the same atomic number but different mass numbers. By
way of general example, and without limitation, isotopes of
hydrogen include tritium and deuterium and isotopes of carbon
include .sup.11C, .sup.13C, and .sup.14C.
[0045] The term "substituted", as used herein, means that any one
or more hydrogens on the designated atom or group is replaced with
a selection from the indicated group, provided that the designated
atom's normal valence is not exceeded. When the substituent is oxo
(i.e., .dbd.O), then 2 hydrogens on the atom are replaced. When
aromatic moieties are substituted by an oxo group, the aromatic
ring is replaced by the corresponding partially unsaturated ring.
For example a pyridyl group substituted by oxo is a pyridone.
Combinations of substituents and/or variables are permissible only
if such combinations result in stable compounds or useful synthetic
intermediates. A stable compound or stable structure is meant to
imply a compound that is sufficiently robust to survive isolation
from a reaction mixture, and subsequent formulation into an
effective therapeutic agent.
[0046] Suitable groups that may be present on a "substituted"
position include, but are not limited to, e.g., halogen; cyano;
hydroxyl; nitro; azido; alkanoyl (such as a C.sub.2-C.sub.6
alkanoyl group such as acyl or the like); carboxamido; alkyl groups
(typically having 1 to about 8 carbon atoms, or 1 to about 6 carbon
atoms); cycloalkyl groups, alkenyl and alkynyl groups (including
groups having one or more unsaturated linkages and from 2 to about
8, or 2 to about 6 carbon atoms); alkoxy groups having one or more
oxygen linkages and from 1 to about 8, or from 1 to about 6 carbon
atoms; aryloxy such as phenoxy; alkylthio groups including those
having one or more thioether linkages and from 1 to about 8 carbon
atoms, or from 1 to about 6 carbon atoms; alkylsulfinyl groups
including those having one or more sulfinyl linkages and from 1 to
about 8 carbon atoms, or from 1 to about 6 carbon atoms;
alkylsulfonyl groups including those having one or more sulfonyl
linkages and from 1 to about 8 carbon atoms, or from 1 to about 6
carbon atoms; aminoalkyl groups including groups having one or more
N atoms and from 1 to about 8, or from 1 to about 6 carbon atoms;
aryl having 6 or more carbons and one or more rings, (e.g., phenyl,
biphenyl, naphthyl, or the like, each ring either substituted or
unsubstituted aromatic); arylalkyl having 1 to 3 separate or fused
rings and from 6 to about 18 ring carbon atoms, with benzyl being
an exemplary arylalkyl group; arylalkoxy having 1 to 3 separate or
fused rings and from 6 to about 18 ring carbon atoms, with
benzyloxy being an exemplary arylalkoxy group; or a saturated,
unsaturated, or aromatic heterocyclic group having 1 to 3 separate
or fused rings with 3 to about 8 members per ring and one or more
N, O, or S atoms, e.g. coumarinyl, quinolinyl, isoquinolinyl,
quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl,
thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl,
indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl,
tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, and
pyrrolidinyl. Such heterocyclic groups may be further substituted,
e.g. with hydroxy, alkyl, alkoxy, halogen or amino.
[0047] A dash ("-") that is not between two letters or symbols is
used to indicate a point of attachment for a substituent. For
example, --CHO is attached through carbon of the carbonyl (C.dbd.O)
group.
[0048] As used herein, "alkyl" includes both branched and straight
chain saturated aliphatic hydrocarbon groups, having the specified
number of carbon atoms, generally from 1 to about 12 carbon atoms.
The term C.sub.1-C.sub.7alkyl as used herein indicates an alkyl
group having from 1 to 7 carbon atoms. When C.sub.0-C.sub.nalkyl is
used herein in conjunction with another group, for example,
(heterocycloalkyl)C.sub.0-C.sub.2alkyl, the indicated group, in
this case heterocycloalkyl, is either directly bound by a single
covalent bond (C.sub.0), or attached by an alkyl chain having the
specified number of carbon atoms, in this case from 1 to 2 carbon
atoms. Examples of alkyl include, but are not limited to, methyl,
ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, t-butyl,
n-pentyl, and sec-pentyl. Alkyl groups described herein typically
have from 1 to about 12 carbons atoms. Preferred alkyl groups are
lower alkyl groups, those alkyl groups having from 1 to about 8
carbon atoms, from 1 to about 6 carbon atoms, or from 1 to about 4
carbons atoms e.g. C.sub.1-C.sub.8, C.sub.1-C.sub.6, and
C.sub.1-C.sub.4alkyl groups.
[0049] "Alkenyl" as used herein, indicates a straight or branched
hydrocarbon chain comprising one or more unsaturated carbon-carbon
bonds, which may occur in any stable point along the chain. Alkenyl
groups described herein typically have from 2 to about 12 carbons
atoms. Preferred alkenyl groups are lower alkenyl groups, those
alkenyl groups having from 2 to about 8 carbon atoms, e.g.
C.sub.2-C.sub.8, C.sub.2-C.sub.6, and C.sub.2-C.sub.4 alkenyl
groups. Examples of alkenyl groups include ethenyl, propenyl, and
butenyl groups.
[0050] "Alkynyl" as used herein, indicates a straight or branched
hydrocarbon chain comprising one or more triple carbon-carbon bonds
that may occur in any stable point along the chain, such as ethynyl
and propynyl. Alkynyl groups described herein typically have from 2
to about 12 carbons atoms. Preferred alkynyl groups are lower
alkynyl groups; those alkynyl groups having from 2 to about 8
carbon atoms, e.g. C.sub.2-C.sub.8, C.sub.2-C.sub.6, and
C.sub.2-C.sub.4 alkynyl groups.
[0051] "Alkoxy" indicates an alkyl group as defined above with the
indicated number of carbon atoms attached through an oxygen bridge
(--O--). Examples of alkoxy include, but are not limited to,
methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy,
t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy,
n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
[0052] In the term "(Alkoxy)alkyl" alkoxy and alkyl are as defined
above and the point of attachment is on the alkyl group. For
example (C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkyl indicates an
alkoxy group having from 1 to about 6 carbon atom attached through
its oxygen atom to an alkyl group having from 1 to about 6 carbon
atoms and further attached to the core molecule through a carbon
atom in the C.sub.1-C.sub.6alkyl portion.
[0053] In the term "(Alkoxy)alkoxy" alkoxy is as defined above and
the point of attachment is on the oxygen of the second listed
alkoxy group. For example
(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.4alkoxy indicates an alkoxy
group have from 1 to about 6 carbon atom attached through its
oxygen atom to an second alkoxy group, this one having, for
example, from 1 to about 4 carbon atoms, and further attached to
the core molecule through an oxygen bridge. Similarly the term
"(alkoxy)(alkoxy)alkoxy" refers to two such alkoxy groups attached
to a third alkoxy, which is further attached to the core molecule
through an oxygen bridge.
[0054] "Alkanoyl" indicates an alkyl group as defined above,
attached through a keto (--(C.dbd.O)--) bridge. Alkanoyl groups
have the indicated number of carbon atoms, with the carbon of the
keto group being included in the numbered carbon atoms. For example
a C.sub.2alkanoyl group is an acetyl group having the formula
CH.sub.3(C.dbd.O)--.
[0055] As used herein, "alkylthio" means alkyl-S--, where the alkyl
group is an alkyl group as defined above having the defined number
of carbon atoms. An exemplary alkylthio group is methylthio.
[0056] As used herein the term "alkoxycarbonyl" indicates an alkoxy
group, as defined above, having the indicated number of carbon
atoms, attached through a keto (--(C.dbd.O)--) bridge. The alkoxy
moiety of the alkoxycarbonyl group has the indicated number of
carbon atoms. The carbon of the keto bridge is not included in this
number. C.sub.3alkoxycarbonyl indicates for example, groups of the
formula CH.sub.3(CH.sub.2).sub.2--O--(C.dbd.O)-- or
(CH.sub.3).sub.2(CH)--O--(C.dbd.O)--.
[0057] As used herein "aminoalkyl" is an alkyl group as defined
herein, having the indicated number of carbon atoms, and
substituted with at least one amino substituent (--NH.sub.2). When
indicated, aminoalkyl groups, like other groups described herein,
may be additionally substituted.
[0058] As used herein, the term "mono- and/or di-alkylamino"
indicates secondary or tertiary alkyl amino groups, wherein the
alkyl groups are as defined above and have the indicated number of
carbon atoms. The point of attachment of the alkylamino group is on
the nitrogen. The alkyl groups are independently chosen. Examples
of mono- and/or di-alkylamino groups include ethylamino,
dimethylamino, and methyl-propyl-amino. "Mono- and/or
di-alkylaminoalkyl" groups are mono- and/or di-alkylamino groups
attached through an alkyl linker having the specified number of
carbon atoms, for example a di-methylaminoethyl group. Tertiary
amino substituents may by designated by nomenclature of the form
N--R--N--R', indicating that the groups R and R' are both attached
to a single nitrogen atom.
[0059] As used herein, the term "mono- and/or di-(alkylamino)allyl"
indicates a mono- and/or di-alkylamino group as defined attached
through an alkyl linker having the specified number of carbon
atoms. Similarly "mono- and/or di-(alkylamino)alkoxy" indicates a
mono- and/or di-alkylamino group as defined attached through an
alkoxy linker having the specified number of carbon atoms.
[0060] As used herein the term "mono- and/or di-alkylcarboxamide"
refers to groups of formula (alkyl.sub.1)-NH--(C.dbd.O)-- and
(alkyl.sub.1)(alkyl.sub.2)-N--(C.dbd.O)-- in which the alkyl.sub.1
and alkyl.sub.2 groups are independently chosen alkyl groups as
defined above having the indicated number of carbon atoms.
"Carboxamide" is a group of the formula --(C.dbd.O)NH.sub.2.
[0061] As used herein, the term "aryl" indicates aromatic groups
containing only carbon in the aromatic ring or rings. Such aromatic
groups may be further substituted with carbon or non-carbon atoms
or groups. Typical aryl groups contain 1 or 2 separate, fused, or
pendant rings and from 6 to about 12 ring atoms, without
heteroatoms as ring members. Where indicated, aryl groups may be
substituted. Such substitution may include fusion to a 5 to
7-membered saturated cyclic group that optionally contains 1 or 2
heteroatoms independently chosen from N, O, and S, to form, for
example, a 3,4-methylenedioxy-phenyl group. Aryl groups include,
for example, phenyl, naphthyl, including 1-naphthyl and 2-naphthyl,
and bi-phenyl.
[0062] "Cycloalkyl" as used herein, indicates a monocyclic or
multicyclic saturated hydrocarbon ring group, having the specified
number of carbon atoms, usually from 3 to about 10 ring carbon
atoms. Monocyclic cycloalkyl groups typically have from 3 to about
8 carbon ring atoms or from 3 to about 7 carbon ring atoms.
Multicyclic cycloalkyl groups may have 2 or 3 fused cycloalkyl
rings or contain bridged or caged cycloalkyl groups. Cycloalkyl
substituents may be pendant to the substituted nitrogen or carbon
atom, or where a substituted carbon atom may have two substituents
a cycloalkyl group may be attached as a spiro group. Examples of
cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl as well as bridged or caged saturated ring groups such
as norbornane or adamantane.
[0063] As used herein "(cycloalkyl)C.sub.0-C.sub.2alkyl indicates a
cycloalkyl groups as defined above either directly attached via a
single covalent bond or attached through an ethylene
(--CH.sub.2CH.sub.2--) or methylene (--CH.sub.2--) linker.
[0064] As used herein "haloalkyl" indicates both branched and
straight-chain alkyl groups having the specified number of carbon
atoms, substituted with 1 or more halogen atoms, generally up to
the maximum allowable number of halogen atoms. Examples of
haloalkyl include, but are not limited to, trifluoromethyl,
difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
[0065] "Haloalkoxy" indicates a haloalkyl group as defined above
attached through an oxygen bridge.
[0066] "Halo" or "halogen" as used herein refers to fluoro, chloro,
bromo, and/or iodo. As used herein, "heteroaryl" indicates a stable
5- to 7-membered monocyclic aromatic ring which contains from 1 to
4, or preferably from 1 to 2, heteroatoms chosen from N, O, and S,
with remaining ring atoms being carbon, or a stable bicyclic or
tricyclic system containing at least one 5 to 7 membered aromatic
ring which contains from 1 to 4, or preferably from 1 to 2,
heteroatoms chosen from N, O, and S, with remaining ring atoms
being carbon. When the total number of S and O atoms in the
heteroaryl group exceeds 1, these heteroatoms are not adjacent to
one another. It is preferred that the total number of S and O atoms
in the heteroaryl group is not more than 2. It is particularly
preferred that the total number of S and O atoms in the aromatic
heterocycle is not more than 1. Examples of heteroaryl groups
include, but are not limited to, oxazolyl, pyranyl, pyrazinyl,
pyrazolopyrimidinyl, pyrazolyl, pyridizinyl, pyridyl, pyrimidinyl,
pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienylpyrazolyl,
thiophenyl, triazolyl, benzo[d]oxazolyl, benzofuranyl,
benzothiazolyl, benzothiophenyl, benzoxadiazolyl,
dihydrobenzodioxynyl, furanyl, imidazolyl, indolyl, and
isoxazolyl.
[0067] The term "heterocycloalkyl" indicates a saturated monocyclic
group containing from 1 to about 3 heteroatoms chosen from N, O,
and S, with remaining ring atoms being carbon, or a saturated
bicyclic ring system having at least one N, O, or S ring atom with
remaining atoms being carbon. Monocyclic heterocycloalkyl groups
have from 4 to about 8 ring atoms, and more typically have from 5
to 7 ring atoms. Bicyclic heterocycloalkyl groups typically have
from about five to about 12 ring atoms. Preferred heterocycloalkyl
groups include monocyclic heterocycloalkyl groups that contain from
5 to 7 ring atoms and 1 or 2 heteroatoms independently chosen from
N, O, and S. Examples of heterocycloalkyl groups include
morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl groups.
[0068] In the term "(heterocycloalkyl)alkyl" the groups
heterocycloalkyl and alkyl are as defined above and the point of
attachment to the core structure is on the alkyl group.
[0069] As used herein "hydroxyalkyl" is an alkyl group as defined
herein, having the indicated number of carbon atoms, and
substituted with at least one hydroxyl substituent (--OH). When
indicated, hydroxyalkyl groups, like other groups described herein,
may be additionally substituted. Similarly the term "hydroxyalkoxy"
indicates an alkoxy group as defined herein, having the indicated
number of carbon atoms, and substituted with at least one hydroxyl
substituent (--OH).
[0070] "Pharmaceutically acceptable forms" of the compounds recited
herein include pharmaceutically acceptable salts, hydrates,
solvates, crystal forms, polymorphs, chelates, non-covalent
complexes, esters, clathrates, prodrugs, and mixtures of such
compounds. Pharmaceutically acceptable salts are a preferred
pharmaceutically acceptable form.
[0071] "Pharmaceutically acceptable salts" include derivatives of
the disclosed compounds wherein the parent compound is modified by
making non-toxic acid or base salts thereof, and further refers to
pharmaceutically acceptable solvates of such compounds and such
salts. Examples of pharmaceutically acceptable salts include, but
are not limited to, mineral or organic acid salts of basic residues
such as amines; alkali or organic salts of acidic residues such as
carboxylic acids; and the like. The pharmaceutically acceptable
salts include the conventional non-toxic salts and the quaternary
ammonium salts of the parent compound formed, for example, from
non-toxic inorganic or organic acids. For example, conventional
non-toxic acid salts include those derived from inorganic acids
such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,
nitric and the like; and the salts prepared from organic acids such
as acetic, propionic, succinic, glycolic, stearic, lactic, malic,
tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,
phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic,
besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isethionic,
HOOC--(CH.sub.2).sub.n--COOH where n is 0-4, and the like. The
pharmaceutically acceptable salts of the present invention can be
synthesized from a parent compound, a basic or acidic moiety, by
conventional chemical methods. Generally, such salts can be
prepared by reacting free acid forms of these compounds with a
stoichiometric amount of the appropriate base (such as Na, Ca, Mg,
or K hydroxide, carbonate, bicarbonate, or the like), or by
reacting free base forms of these compounds with a stoichiometric
amount of the appropriate acid. Such reactions are typically
carried out in water or in an organic solvent, or in a mixture of
the two. Generally, non-aqueous media like ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile are preferred, where
practicable. Lists of additional suitable salts may be found, e.g.,
in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing
Company, Easton, Pa., p. 1418 (1985).
[0072] The term "prodrugs" includes any compounds that become
compounds of Formula I-a when administered to a mammalian subject,
e.g., upon metabolic processing of the prodrug. Examples of
prodrugs include, but are not limited to, acetate, formate and
benzoate and like derivatives of functional groups (such as alcohol
or amine groups) in the compounds of Formula I-a.
[0073] The term "active agent" is used to indicate a compound,
including any pharmaceutically form thereof, or natural product,
which has biological activity. Preferably an "active agent" is a
compound having pharmaceutical utility. For example an active agent
may be a compound of Formula I-a, or an anti-cancer or
anti-inflammatory therapeutic, which is not a compound of Formula
I-a.
[0074] The term "effective amount" of a compound of this invention
means an amount effective, when administered to a human or
non-human patient, to provide a therapeutic benefit such as
amelioration of symptoms, slowing of disease progression, or
prevention of disease e.g., an effective amount may be an amount
sufficient to decrease the symptoms of a disease responsive to Btk
inhibition, and preferably is an amount sufficient to reduce cancer
symptoms, the symptoms of an autoimmune and/or inflammatory
disease, or the symptoms of an acute inflammatory reaction. In some
embodiments an effective amount of a compound described herein is
an amount sufficient to decrease the number of detectable cancerous
cells in an organism, detectably slow or stop the growth of a
cancerous tumor, or more preferably an amount sufficient to shrink
a cancerous tumor. In certain circumstances a patient suffering
from cancer may not present symptoms of being affected. Thus, a
therapeutically effective amount of a compound is also an amount
sufficient to prevent a significant increase or significantly
reduce the detectable level of cancerous cells or cancer markers in
the patient's blood, serum, or tissues. In methods described herein
for treating autoimmune and/or inflammatory diseases or acute
inflammatory reactions, an effective amount may also be an amount
sufficient, when administered to a patient, to detectably slow
progression of the disease, or prevent the patient to whom the
compound is given from presenting symptoms of the autoimmune and/or
inflammatory disease, or acute inflammatory response. In certain
methods described herein for treating autoimmune and/or
inflammatory diseases or acute inflammatory reactions, an effective
amount may also be an amount sufficient to produce a detectable
decrease in the amount of a marker protein or cell type in the
patient's blood or serum. For example, in some embodiments an
effective amount is an amount of a compound described herein
sufficient to significantly decrease the number of B-cells. In
another example, in some embodiments an effective amount is an
amount of a compound described herein sufficient to decrease the
level of anti-acetylcholine receptor antibody in a patient's blood
with the disease myasthenia gravis.
[0075] The term "inhibition" indicates a significant decrease in
the baseline activity of a biological activity or process.
"Inhibition of Btk activity" refers to a decrease in Btk activity
as a direct or indirect response to the presence of a compound of
Formula I-a, relative to the activity of Btk in the absence of the
compound. The decrease in activity may be due to the direct
interaction of the compound with Btk, or due to the interaction of
the compound with one or more other factors that in turn affect Btk
activity. For example, the presence of the compound may decrease
Btk activity by directly binding to the Btk, by causing (directly
or indirectly) another factor to decrease Btk activity, or by
(directly or indirectly) decreasing the amount of Btk present in
the cell or organism.
[0076] Inhibition of Btk activity also refers to observable
inhibition of Btk activity in a standard biochemical assay for Btk
activity, such as the ATP hydrolysis assay of Example 6. Preferred
inhibitors of Btk activity have an IC.sub.50 value less than or
equal to 1 micromolar, more preferably less than or equal to less
than 100 nanomolar, and still more preferably less than or equal to
10 nanomolar.
[0077] Without wishing to be bound to any particular theory it is
believed that the inhibition of Btk activity causes an inhibition
of B-cell proliferation. "Inhibition of B-cell proliferation"
refers to inhibition of proliferation of abnormal B-cells, such as
cancerous B-cells, e.g. lymphoma B-cells and/or inhibition of
normal, non-diseased B-cells. The term "inhibition of B-cell
proliferation" indicates any significant decrease in the number of
B-cells, either in vitro or in vivo. Thus in vitro an inhibition of
B-cell proliferation would be any significant decrease in the
number of B-cells in an in vitro sample contacted with a compound
of Formula I-a as compared to a matched sample not contacted with a
compound of Formula I-a.
[0078] Inhibition of B-cell proliferation also refers to observable
inhibition of B-cell proliferation in a standard thymidine
incorporation assay for B-cell proliferation, such as the assay of
Example 8. Preferred inhibitors of B-cell proliferation have an
IC.sub.50 value less than or equal to 10 micromolar, more
preferably less than or equal to less than 1 micromolar, and still
more preferably less than or equal to 500 nanomolar.
[0079] By "significant" is meant any detectable change that is
statistically significant in a standard parametric test of
statistical significance such as Student's T-test, where
p<0.05.
[0080] A "disease responsive to Btk inhibition" is a disease in
which inhibiting Btk kinase provides a therapeutic benefit such as
an amelioration of symptoms, decrease in disease progression,
prevention or delay of disease onset, or inhibition of aberrant
activity of certain cell-types (monocytes, B-cells, and mast
cells).
Imidazo[1,2-.beta.]Pyrazine Compounds
[0081] In addition to compounds of Formula I-a (above), compounds
of Formula 1
##STR00004##
and the pharmaceutically acceptable form thereof, are also
disclosed.
[0082] Within Formula 1:
[0083] A is 0 or 1.
[0084] R.sub.1 is phenyl or heteroaryl, each of which is
substituted with one of
[0085] (i) oxo, --CHO, --COOH, --CONH.sub.2, or --CONHOH,
[0086] (ii) C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6hydroxyalkyl, C.sub.1-C.sub.6hydroxyalkoxy, (mono-
or di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy,
heterocycloalkyl, aryl, or heteroaryl,
[0087] (iii) --C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10,
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11,
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11,
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10, or
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12 where
R.sub.10, R.sub.11, and R.sub.12 are independently hydrogen,
hydroxy, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.3-C.sub.10cycloalkyl, or heterocycloalkyl, or
[0088] (iv) -L-G, where L is C.sub.1-C.sub.2alkyl,
C.sub.0-C.sub.2alkoxy, --(C.dbd.O)--, or
--(C.sub.1-C.sub.2alkyl)(C.dbd.O)--, and G is heterocycloalkyl,
C.sub.3-C.sub.7cycloalkyl, aryl, or heteroaryl.
[0089] Each of which (ii), (iii), and (iv) is substituted with 0 to
3 substituents independently chosen from halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl, mono- and
di-C.sub.1-C.sub.4alkylamino, mono- and
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl.
[0090] And, R.sub.1 is substituted with 0 or 1 or more substituents
independently chosen from hydroxy, nitro, cyano, amino,
--SO.sub.2NH.sub.2, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkanoyl, C.sub.1-C.sub.4haloalkyl,
C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.3-C.sub.7cycloalkyl, (C.sub.1-C.sub.6
alkoxy)C.sub.0-C.sub.6alkyl, (mono- and di-C.sub.1-C.sub.6
alkylamino)C.sub.0-C.sub.6 alkyl, and
C.sub.1-C.sub.6alkoxycarbonyl.
[0091] R.sub.2 is C.sub.1-C.sub.7 alkyl,
(C.sub.1-C.sub.6alkoxy)C.sub.0-C.sub.6alkoxy,
(heterocycloalkyl)C.sub.0-C.sub.2alkyl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.0-C.sub.2alkyl, or R.sub.2 is
(phenyl)C.sub.0-C.sub.2alkyl, (phenoxy)C.sub.0-C.sub.2alkyl, or
(heteroaryl)C.sub.0-C.sub.2alkyl, each of which is substituted with
0 to 3 substituents independently chosen from hydroxy, nitro,
cyano, amino, halogen, --SO.sub.2NH.sub.2, oxo, --COOH,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.2-C.sub.6alkanoyl, C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6alkyl, mono- and
di-C.sub.1-C.sub.6alkylamino, mono- and
di-C.sub.1-C.sub.6alkylcarboxamide, C.sub.1-C.sub.6alkoxycarbonyl,
phenyl, heteroaryl, and --(C.dbd.O)R.sub.13 wherein R.sub.13 is
C.sub.1-C.sub.6alkyl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.0-C.sub.2alkyl,
C.sub.1-C.sub.3haloalkyl, heterocycloalkyl, phenyl, or
heteroaryl.
[0092] Z.sub.1 is
##STR00005##
wherein R.sub.4 is hydrogen, or R.sub.4 is C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl,
each of which is substituted with 0 or 1 or more substituents
independently chosen from hydroxy, nitro, cyano, amino, halogen,
oxo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6 alkyl, mono- and di-C.sub.1-C.sub.6
alkylamino, and --C(O)R.sub.14 wherein R.sub.14 is C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.3haloalkyl, or phenyl.
[0093] Q is phenyl or pyridyl.
[0094] R.sub.3 is hydrogen, halogen, or C.sub.1-C.sub.7 alkyl,
or
[0095] R.sub.3 is heterocycloalkyl, C.sub.3-C.sub.7cycloalkyl, or
heteroaryl, each of which is substituted with from 0 to 3
substituents independently chosen from hydroxy, nitro, cyano,
amino, halogen, --SO.sub.2NH.sub.2, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3halooalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6-alkoxy)C.sub.1-C.sub.6
alkoxy, mono- and di-C.sub.1-C.sub.6alkylamino,
aminoC.sub.1-C.sub.6 alkyl, and --C(O)R.sub.14.
The Variable A
[0096] Also included herein are compounds of Formula 1 wherein A is
0 and compounds of Formula 1 wherein A is 1.
The Variable R.sub.1
[0097] Further provided herein are compounds of Formula 1 and
pharmaceutically acceptable forms thereof, wherein the variable
R.sub.1 satisfies one or more of the following conditions set forth
in A. to O.
[0098] A. R.sub.1 is phenyl or pyridyl, each of which is
substituted with one of
[0099] (i) oxo, --CHO, --COOH, --CONH.sub.2, or --CONHOH,
[0100] (ii) C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6hydroxyalkyl, C.sub.1-C.sub.6hydroxyalkoxy, (mono-
or di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy,
heterocycloalkyl, aryl, or heteroaryl,
[0101] (iii) --C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10,
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11,
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11,
C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11,
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10, or
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12, where
R.sub.10, R.sub.11, and R.sub.12 are independently hydrogen,
hydroxy, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.3-C.sub.10cycloalkyl, or heterocycloalkyl, or
[0102] (iv) -L-G, where L is C.sub.1-C.sub.2alkyl,
C.sub.0-C.sub.2alkoxy, --(C.dbd.O)--, or
--(C.sub.1-C.sub.2allyl)(C.dbd.O)--, and G is heterocycloalkyl,
C.sub.3-C.sub.7cycloalkyl, aryl, or heteroaryl.
[0103] Each of which (ii), (iii), and (iv) is substituted with 0 to
3 substituents independently chosen from halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl, mono- and
di-C.sub.1-C.sub.4alkylamino, mono- and
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl.
[0104] And, R.sub.1 is substituted with 0 or 1 or more substituents
independently chosen from hydroxy, nitro, cyano, amino,
--SO.sub.2NH.sub.2, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkanoyl, C.sub.1-C.sub.4haloalkyl,
C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.3-C.sub.7cycloalkyl, (C.sub.1-C.sub.6
alkoxy)C.sub.0-C.sub.6alkyl, (mono- and di-C.sub.1-C.sub.6
alkylamino)C.sub.0-C.sub.6 alkyl, and
C.sub.1-C.sub.6alkoxycarbonyl.
[0105] B. R.sub.1 is phenyl or pyridyl, each of which is
substituted with one of oxo, --CHO, --COOH, --CONH.sub.2, or
--CONHOH, and R.sub.1 is substituted with 0 or 1 or more
substituents independently chosen from hydroxy, nitro, cyano,
amino, --SO.sub.2NH.sub.2, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkanoyl, C.sub.1-C.sub.4haloalkyl,
C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.3-C.sub.7cycloalkyl, (C.sub.1-C.sub.6
alkoxy)C.sub.0-C.sub.6alkyl, (mono- and di-C.sub.1-C.sub.6
alkylamino)C.sub.0-C.sub.6 alkyl, and
C.sub.1-C.sub.6alkoxycarbonyl.
[0106] C. R.sub.1 is phenyl or pyridyl, each of which is
substituted with one of oxo, --CHO, --COOH, --CONH.sub.2, or
--CONHOH, and R.sub.1 is substituted with from 0 to 3 substituents
independently chosen from hydroxy, cyano, halogen,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxy, and mono- and
di-C.sub.1-C.sub.4alkylamino.
[0107] D. R.sub.1 is phenyl or pyridyl, each of which is
substituted with one of oxo, --CHO, --COOH, --CONH.sub.2, or
--CONHOH, and R.sub.1 is substituted with from 0 to 3 substituents
independently chosen from hydroxy, cyano, halogen,
C.sub.1-C.sub.2alkyl, and C.sub.1-C.sub.2alkoxy.
[0108] E. R.sub.1 is phenyl or pyridyl, each of which is
substituted with one of (ii) C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.6hydroxyalkoxy, (mono- or
di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy,
heterocycloalkyl, aryl, or heteroaryl.
[0109] Each of which (ii) is substituted with 0 to 3 substituents
independently chosen from halogen, hydroxy, amino, oxo, --COOH,
--CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono- and
di-C.sub.1-C.sub.4alkylamino, mono- and
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl.
[0110] And, R.sub.1 is substituted with 0 or 1 or more substituents
independently chosen from hydroxy, nitro, cyano, amino,
--SO.sub.2NH.sub.2, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkanoyl, C.sub.1-C.sub.4haloalkyl,
C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.3-C.sub.7cycloalkyl, (C.sub.1-C.sub.6
alkoxy)C.sub.0-C.sub.6alkyl, (mono- and di-C.sub.1-C.sub.6
alkylamino)C.sub.0-C.sub.6 alkyl, and
C.sub.1-C.sub.6alkoxycarbonyl.
[0111] F. R.sub.1 is phenyl or pyridyl, each of which is
substituted with one of C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.6hydroxyalkoxy, (mono- or
di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
or
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy,
each of which is substituted with 0 to 3 substituents independently
chosen from halogen, hydroxy, cyano, amino, oxo, --COOH,
--CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl, mono- and
di-C.sub.1-C.sub.4alkylamino, and mono- and
di-C.sub.1-C.sub.4alkylcarboxamide.
[0112] And, R.sub.1 is substituted with from 0 to 3 substituents
independently chosen from hydroxy, cyano, halogen,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxy, and mono- and
di-C.sub.1-C.sub.4alkylamino.
[0113] G. R.sub.1 is phenyl or pyridyl, each of which is
substituted with one of C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.6hydroxyalkoxy, (mono- or
di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
or
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy.
[0114] And, R.sub.1 is substituted with from 0 to 3 substituents
independently chosen from hydroxy, cyano, halogen,
C.sub.1-C.sub.2alkyl, and C.sub.1-C.sub.2alkoxy.
[0115] H. R.sub.1 is phenyl or pyridyl, each of which is
substituted with one of pyrrolidinyl, morpholinyl, thiomorpholinyl,
piperazinyl, piperidinyl, [1,4]diazepanyl, phenyl, imidazolyl, or
5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, each of which is
substituted with 0 to 3 substituents independently chosen from
halogen, hydroxy, cyano, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono- and
di-C.sub.1-C.sub.4alkylamino, and mono- and
di-C.sub.1-C.sub.4alkylcarboxamide.
[0116] And, R.sub.1 is substituted with from 0 to 3 substituents
independently chosen from hydroxy, cyano, halogen,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxy, and mono- and
di-C.sub.1-C.sub.4alkylamino.
[0117] I. R.sub.1 is phenyl or pyridyl, each of which is
substituted with one of pyrrolidinyl, morpholinyl, thiomorpholinyl,
piperazinyl, piperidinyl, [1,4]diazepanyl, phenyl, imidazolyl, or
5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, each of which is
substituted with 0 to 3 substituents independently chosen from
halogen, hydroxy, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkoxycarbonyl, mono- and
di-C.sub.1-C.sub.4alkylamino, and mono- and
di-C.sub.1-C.sub.4alkylcarboxamide.
[0118] And, R.sub.1 is substituted with from 0 to 3 substituents
independently chosen from hydroxy, cyano, halogen,
C.sub.1-C.sub.2alkyl, and C.sub.1-C.sub.2alkoxy.
[0119] J. R.sub.1 is phenyl or pyridyl, each of which is
substituted with one of (iii)
--C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10,
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11,
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11,
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10, or
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12 where
R.sub.10, R.sub.11, and R.sub.12 are independently hydrogen,
hydroxy, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.3-C.sub.7cycloalkyl, or heterocycloalkyl. Each of which (iii)
is substituted with 0 to 3 substituents independently chosen from
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono- and
di-C.sub.1-C.sub.4alkylamino, mono- and
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl.
[0120] And, R.sub.1 is substituted with 0 or 1 or more substituents
independently chosen from hydroxy, nitro, cyano, amino,
--SO.sub.2NH.sub.2, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkanoyl, C.sub.1-C.sub.4haloalkyl,
C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.3-C.sub.7cycloalkyl, (C.sub.1-C.sub.6
alkoxy)C.sub.0-C.sub.6alkyl, (mono- and di-C.sub.1-C.sub.6
alkylamino)C.sub.0-C.sub.6 alkyl, and
C.sub.1-C.sub.6alkoxycarbonyl.
[0121] K. R.sub.1 is phenyl or pyridyl, each of which is
substituted with one of --C.sub.1-C.sub.4alkyl(C.dbd.O)OR.sub.10,
--C.sub.0-C.sub.4alkyl(C.dbd.O)NR.sub.10R.sub.11,
--C.sub.1-C.sub.4alkylNR.sub.10(SO.sub.2)R.sub.11,
--C.sub.0-C.sub.4alkylNR.sub.10(C.dbd.O)R.sub.11,
--C.sub.0-C.sub.4alkyl(SO.sub.2)R.sub.10, or
--C.sub.0-C.sub.4alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12 where
R.sub.10, R.sub.11, and R.sub.12 are independently hydrogen,
hydroxy, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.3-C.sub.10cycloalkyl, pyrrolidinyl, morpholinyl,
thiomorpholinyl, piperazinyl, piperidinyl, or [1,4]diazepanyl, each
of which is substituted with 0 to 3 substituents independently
chosen from halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkoxycarbonyl, mono- and
di-C.sub.1-C.sub.4alkylamino, and mono- and
di-C.sub.1-C.sub.4alkylcarboxamide.
[0122] And, R.sub.1 is substituted with from 0 to 3 substituents
independently chosen from hydroxy, cyano, halogen,
C.sub.1-C.sub.2alkyl, and C.sub.1-C.sub.2alkoxy.
[0123] L. R.sub.1 is phenyl or pyridyl, each of which is
substituted with one of (iv) -L-G, where L is C.sub.1-C.sub.2alkyl,
C.sub.0-C.sub.2alkoxy, --(C.dbd.O)--, or
--(C.sub.1-C.sub.2alkyl)(C.dbd.O)--, and G is heterocycloalkyl,
C.sub.3-C.sub.7cycloalkyl, aryl, or heteroaryl, each of which (iv)
is substituted with 0 to 3 substituents independently chosen from
halogen, hydroxy, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono- and
di-C.sub.1-C.sub.4alkylamino, mono- and
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl.
[0124] And, R.sub.1 is substituted with 0 or 1 or more substituents
independently chosen from hydroxy, nitro, cyano, amino,
--SO.sub.2NH.sub.2, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkanoyl, C.sub.1-C.sub.4haloalkyl,
C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.3-C.sub.7cycloalkyl, (C.sub.1-C.sub.6
alkoxy)C.sub.0-C.sub.6alkyl, (mono- and di-C.sub.1-C.sub.6
alkylamino)C.sub.0-C.sub.6 alkyl, and
C.sub.1-C.sub.6alkoxycarbonyl.
[0125] M. R.sub.1 is phenyl or pyridyl, each of which is
substituted with one of -L-G, where L is C.sub.1-C.sub.2alkyl,
C.sub.0-C.sub.2alkoxy, --(C.dbd.O)--, or
--(C.sub.1-C.sub.2alkyl)(C.dbd.O)--, and G is pyrrolidinyl,
morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl,
[1,4]diazepanyl, phenyl, imidazolyl, or
5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, each of which is
substituted with 0 to 3 substituents independently chosen from
halogen, hydroxy, cyano, amino, oxo, --COOH, --CONH.sub.2,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl, mono- and
di-C.sub.1-C.sub.4alkylamino, and mono- and
di-C.sub.1-C.sub.4alkylcarboxamide.
[0126] And, R.sub.1 is substituted with from 0 to 3 substituents
independently chosen from hydroxy, cyano, halogen,
C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxy, and mono- and
di-C.sub.1-C.sub.4alkylamino.
[0127] N. R.sub.1 is phenyl or pyridyl, each of which is
substituted with one of -L-G, where L is C.sub.1-C.sub.2alkyl,
C.sub.0-C.sub.2alkoxy, --(C.dbd.O)--, or
--(C.sub.1-C.sub.2alkyl)(C.dbd.O)--, and G is pyrrolidinyl,
morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl,
[1,4]diazepanyl, phenyl, imidazolyl, or
5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine, each of which is
substituted with 0 to 3 substituents independently chosen from
halogen, hydroxy, oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkoxycarbonyl, mono- and
di-C.sub.1-C.sub.4alkylamino, and mono- and
di-C.sub.1-C.sub.4alkylcarboxamide.
[0128] And, R.sub.1 is substituted with from 0 to 3 substituents
independently chosen from hydroxy, cyano, halogen,
C.sub.1-C.sub.2alkyl, and C.sub.1-C.sub.2alkoxy.
[0129] O. L is phenyl or pyridyl, each of which is substituted with
one of --CH.sub.2--, --(C.dbd.O)--, or --(CH.sub.2)(C.dbd.O)--, and
G is pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl,
piperidinyl, or [1,4]diazepanyl, each of which is substituted with
0 to 3 substituents independently chosen from halogen, hydroxy,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.2alkyl,
C.sub.1-C.sub.2alkoxy, C.sub.2-C.sub.2alkanoyl,
C.sub.1-C.sub.2alkoxycarbonyl, mono- and
di-C.sub.1-C.sub.2alkylamino, and mono- and
di-C.sub.1-C.sub.2alkylcarboxamide.
[0130] And, R.sub.1 is substituted with from 0 to 3 substituents
independently chosen from hydroxy, halogen, C.sub.1-C.sub.2alkyl,
and C.sub.1-C.sub.2alkoxy.
[0131] Also disclosed herein are compounds and pharmaceutically
acceptable forms of Formula 2:
##STR00006##
[0132] Within Formula 2
[0133] A, R.sub.2, Z.sub.1, Q, and R.sub.3 carry any of the
definitions set forth herein for these variables. For example
R.sub.2 may have the definition set forth for this variable in
Formula I-a, R.sub.2 may have the definition set forth for this
variable in Formula 1, R.sub.2 may have any of the values set forth
for this variable in the claims, or in the subsection titled "the
R.sub.2 variable."
[0134] R is
[0135] (i) oxo, --CHO, --COOH, --CONH.sub.2, or --CONHOH,
[0136] (ii) C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6hydroxyalkyl, C.sub.1-C.sub.6hydroxyalkoxy, (mono-
or di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy,
heterocycloalkyl, aryl, or heteroaryl,
[0137] (iii) --C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10,
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11,
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11,
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10, or
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12 where
R.sub.10, R.sub.11, and R.sub.12 are independently hydrogen,
hydroxy, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.3-C.sub.10cycloalkyl, or heterocycloalkyl, or
[0138] (iv) -L-G, where L is C.sub.1-C.sub.2alkyl,
C.sub.0-C.sub.2alkoxy, --(C.dbd.O)--, or
--(C.sub.1-C.sub.2alkyl)(C.dbd.O)--, and G is heterocycloalkyl,
C.sub.3-C.sub.7cycloalkyl, aryl, or heteroaryl. Each of which (ii),
(iii), and (iv) is substituted with 0 to 3 substituents
independently chosen from halogen, hydroxy, amino, oxo, --COOH,
--CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl,
C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkylthio,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.4alkoxycarbonyl, mono- and
di-C.sub.1-C.sub.4alkylamino, mono- and
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl.
[0139] R.sub.A is 0 or 1 or more substituents independently chosen
from hydroxy, nitro, cyano, amino, --SO.sub.2NH.sub.2, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkanoyl,
C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4haloalkoxy,
C.sub.1-C.sub.6 alkylthio, C.sub.3-C.sub.7cycloalkyl,
(C.sub.1-C.sub.6 alkoxy)C.sub.0-C.sub.6alkyl, (mono- and
di-C.sub.1-C.sub.6 alkylamino)C.sub.0-C.sub.6 alkyl, and
C.sub.1-C.sub.6alkoxycarbonyl.
[0140] Another embodiment includes compounds and pharmaceutically
acceptable forms in which R.sub.1 is a phenyl substituted at the
para position by R, and substituted at any other position by
R.sub.A i.e. the invention provides compounds and pharmaceutically
acceptable forms of Formula 3
##STR00007##
[0141] Within Formula 3
[0142] R.sub.2, Z.sub.1, Q, and R.sub.3 carry any of the
definitions set forth herein for these variables and R and R.sub.A
carry the definitions set forth for these variables for Formula
2.
The R.sub.2 Variable
[0143] Further provided herein are compounds of Formula 1 and
pharmaceutically acceptable forms thereof, wherein the variable
R.sub.2 satisfies one or more of the following conditions.
[0144] A. R.sub.2 is (phenyl)C.sub.0-C.sub.2alkyl,
(phenoxy)C.sub.0-C.sub.2alkyl, or (pyridyl)C.sub.0-C.sub.2alkyl,
each of which is substituted with 0 to 3 substituents independently
chosen from hydroxy, nitro, cyano, amino, halogen,
--SO.sub.2NH.sub.2, oxo, --COOH, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.2-C.sub.6alkanoyl, C.sub.1-C.sub.6hydroxyalkyl,
C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy,
C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6
alkoxy, aminoC.sub.1-C.sub.6alkyl, mono- and di-C.sub.1-C.sub.6
alkylamino, mono- and di-C.sub.1-C.sub.6alkylcarboxamide,
C.sub.1-C.sub.6alkoxycarbonyl, phenyl, heteroaryl, and
--(C.dbd.O)R.sub.13 wherein R.sub.13 is C.sub.1-C.sub.6alkyl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.0-C.sub.2alkyl,
C.sub.1-C.sub.3haloalkyl, heterocycloalkyl, phenyl, or
heteroaryl.
[0145] B. R.sub.2 is (phenyl)C.sub.0-C.sub.2alkyl,
(phenoxy)C.sub.0-C.sub.2alkyl, or (pyridyl)C.sub.0-C.sub.2alkyl,
each of which is substituted with 0 to 3 substituents independently
chosen from hydroxy, cyano, amino, halogen, --SO.sub.2NH.sub.2,
oxo, --COOH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4hydroxyalkyl,
C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy, mono- and
di-C.sub.1-C.sub.6alkylamino, mono- and
di-C.sub.1-C.sub.6alkylcarboxamide, C.sub.1-C.sub.4alkoxycarbonyl,
phenyl, and imidazolyl.
The Z.sub.1 Variable
[0146] Within certain embodiments Z.sub.1 is
##STR00008##
wherein R.sub.4 is hydrogen, C.sub.1-C.sub.6alkyl, or
C.sub.3-C.sub.7cycloalkyl. In some of these embodiments R.sub.4 is
hydrogen or methyl.
The Q Variable
[0147] Additional embodiments, pertain to compounds and
pharmaceutically acceptable forms of Formula 4 and Formula 5
##STR00009##
[0148] Within Formula 4 and 5:
[0149] A, R. R.sub.A, R.sub.1, R.sub.2, Z.sub.1, and R.sub.3 carry
any of the definitions set forth herein for these variables.
[0150] In certain embodiments of Formula 5, R is
[0151] (i) oxo, --CHO, --COOH, --CONH.sub.2, or --CONHOH,
[0152] (ii) C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6hydroxyalkyl, C.sub.1-C.sub.6hydroxyalkoxy, (mono-
or di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy,
heterocycloalkyl, aryl, or heteroaryl,
[0153] (iii) --C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10,
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11,
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11,
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10, or
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12 where
R.sub.10, R.sub.11, and R.sub.12 are independently hydrogen,
hydroxy, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.3-C.sub.10cycloalkyl, or heterocycloalkyl, or
[0154] (iv) -L-G, where L is C.sub.1-C.sub.2alkyl,
C.sub.0-C.sub.2alkoxy, --(C.dbd.O)--, or
--(C.sub.1-C.sub.2alkyl)(C.dbd.O)--, and G is heterocycloalkyl,
C.sub.3-C.sub.7cycloalkyl, aryl, or heteroaryl.
[0155] Each of which (ii), (iii), and (iv) is substituted with 0 to
3 substituents independently chosen from halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl, mono- and
di-C.sub.1-C.sub.4alkylamino, mono- and
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl.
[0156] R.sub.A is 0 or 1 or more substituents independently chosen
from hydroxy, nitro, cyano, amino, --SO.sub.2NH.sub.2, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkanoyl,
C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4haloalkoxy,
C.sub.1-C.sub.6 alkylthio, C.sub.3-C.sub.7cycloalkyl,
(C.sub.1-C.sub.6 alkoxy)C.sub.0-C.sub.6alkyl, (mono- and
di-C.sub.1-C.sub.6 alkylamino)C.sub.0-C.sub.6 alkyl, and
C.sub.1-C.sub.6alkoxycarbonyl.
The R.sub.3 Variable
[0157] R.sub.3 is hydrogen or methyl in certain compounds of the
invention and pharmaceutically acceptable forms described
herein.
[0158] Additional embodiments of the invention pertain to compounds
of Formula 6
##STR00010##
and the pharmaceutically acceptable forms thereof.
[0159] Within Formula 6
[0160] Z.sub.1, R.sub.3 and A variables carry any of the
definitions set forth herein for these variables.
[0161] R.sub.1 is phenyl or heteroaryl, each of which is optionally
substituted with one of
[0162] (i) oxo, --CHO, --COOH, --CONH.sub.2, or --CONHOH,
[0163] (ii) C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6hydroxyalkyl, C.sub.1-C.sub.6hydroxyalkoxy, (mono-
or di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy,
heterocycloalkyl, aryl, or heteroaryl,
[0164] (iii) --C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10,
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11,
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11,
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10, or
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12 where
R.sub.10, R.sub.11, and R.sub.12 are independently hydrogen,
hydroxy, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.3-C.sub.10cycloalkyl, or heterocycloalkyl, or
[0165] (iv) -L-G, where L is C.sub.1-C.sub.2alkyl,
C.sub.0-C.sub.2alkoxy, --(C.dbd.O)--, or
--(C.sub.1-C.sub.2alkyl)(C.dbd.O)--, and G is heterocycloalkyl,
C.sub.3-C.sub.7cycloalkyl, aryl, or heteroaryl.
[0166] Each of which (ii), (iii), and (iv) is substituted with 0 to
3 substituents independently chosen from halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl, mono- and
di-C.sub.1-C.sub.4alkylamino, mono- and
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl.
[0167] And, R.sub.1 is substituted with 0 or 1 or more substituents
independently chosen from hydroxy, nitro, cyano, amino,
--SO.sub.2NH.sub.2, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6alkanoyl, C.sub.1-C.sub.4haloalkyl,
C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.3-C.sub.7cycloalkyl, (C.sub.1-C.sub.6
alkoxy)C.sub.0-C.sub.6alkyl, (mono- and di-C.sub.1-C.sub.6
alkylamino)C.sub.0-C.sub.6 alkyl, and
C.sub.1-C.sub.6alkoxycarbonyl.
[0168] R.sub.5 is isopropyl or t-butyl.
[0169] Other embodiments pertain to compounds and forms thereof of
Formula 7 to Formula 9
##STR00011##
[0170] Within Formula 7 to Formula 9:
[0171] R is
[0172] (i) oxo, --CHO, --COOH, --CONH.sub.2, or --CONHOH,
[0173] (ii) C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6hydroxyalkyl, C.sub.1-C.sub.6hydroxyalkoxy, (mono-
or di-C.sub.1-C.sub.6alkylamino)C.sub.1-C.sub.6alkoxy,
(C.sub.1-C.sub.6alkoxy)(C.sub.1-C.sub.6alkylamino)C.sub.0-C.sub.6alkyl,
(C.sub.1-C.sub.0alkoxy)(C.sub.1-C.sub.6alkoxy)C.sub.1-C.sub.6alkoxy,
heterocycloalkyl, aryl, or heteroaryl,
[0174] (iii) --C.sub.1-C.sub.6alkyl(C.dbd.O)OR.sub.10,
--C.sub.0-C.sub.6alkyl(C.dbd.O)NR.sub.10R.sub.11,
--C.sub.1-C.sub.6alkylNR.sub.10(SO.sub.2)R.sub.11,
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)R.sub.11,
--C.sub.0-C.sub.6alkyl(SO.sub.2)R.sub.10, or
--C.sub.0-C.sub.6alkylNR.sub.10(C.dbd.O)NR.sub.11R.sub.12 where
R.sub.10, R.sub.11, and R.sub.12 are independently hydrogen,
hydroxy, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.3-C.sub.10cycloalkyl, or heterocycloalkyl, or
[0175] (iv) -L-G, where L is C.sub.1-C.sub.2alkyl,
C.sub.0-C.sub.2alkoxy, --(C.dbd.O)--, or
--(C.sub.1-C.sub.2alkyl)(C.dbd.O)--, and G is heterocycloalkyl,
C.sub.3-C.sub.7cycloalkyl, aryl, or heteroaryl.
[0176] Each of which (ii), (iii), and (iv) is substituted with 0 to
3 substituents independently chosen from halogen, hydroxy, amino,
oxo, --COOH, --CONH.sub.2, C.sub.1-C.sub.4alkyl,
C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, C.sub.2-C.sub.4alkanoyl,
C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.4alkoxycarbonyl, mono- and
di-C.sub.1-C.sub.4alkylamino, mono- and
di-C.sub.1-C.sub.4alkylcarboxamide, and phenyl.
[0177] R.sub.A is 0 or 1 or more substituents independently chosen
from hydroxy, nitro, cyano, amino, --SO.sub.2NH.sub.2, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkanoyl,
C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4haloalkoxy,
C.sub.1-C.sub.6alkylthio, C.sub.3-C.sub.7cycloalkyl,
(C.sub.1-C.sub.6 alkoxy)C.sub.0-C.sub.6alkyl, (mono- and
di-C.sub.1-C.sub.6 alkylamino)C.sub.0-C.sub.6 alkyl, and
C.sub.1-C.sub.6alkoxycarbonyl.
[0178] R.sub.5 is isopropyl or t-butyl.
[0179] A, Z.sub.1, and R.sub.3 may carry any of the definitions set
forth above for these variables. It certain embodiments it is
preferred that R.sub.3 is hydrogen or methyl.
Pharmaceutical Preparations
[0180] Compounds, salts, and any other pharmaceutically acceptable
forms of the invention can be administered as the neat chemical,
but are preferably administered as a pharmaceutical composition or
formulation. Accordingly, the invention provides pharmaceutical
formulations comprising a compound or pharmaceutically acceptable
form of Formula I-a, together with one or more pharmaceutically
acceptable carriers, excipients, adjuvants, diluents, or other
ingredients.
[0181] Pharmaceutical carriers must be of sufficiently high purity
and sufficiently low toxicity to render them suitable for
administration to the animal being treated. The carrier can be
inert or it can possess pharmaceutical benefits. The amount of
carrier employed in conjunction with the compound is sufficient to
provide a practical quantity of material for administration per
unit dose of the compound.
[0182] Exemplary pharmaceutically acceptable carriers or components
thereof are sugars, such as lactose, glucose and sucrose; starches,
such as corn starch and potato starch; cellulose and its
derivatives, such as sodium carboxymethyl cellulose, ethyl
cellulose, and methyl cellulose; powdered tragacanth; malt;
gelatin; talc; solid lubricants, such as stearic acid and magnesium
stearate; calcium sulfate; synthetic oils; vegetable oils, such as
peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil;
polyols such as propylene glycol, glycerine, sorbitol, mannitol,
and polyethylene glycol; alginic acid; phosphate buffer solutions;
emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl
sulfate; coloring agents; flavoring agents; tableting agents;
stabilizers; antioxidants; preservatives; pyrogen-free water;
isotonic saline; and phosphate buffer solutions.
[0183] Optional active agents may be included in a pharmaceutical
composition, which do not substantially interfere with the activity
of the compound of the present invention.
[0184] Effective concentrations of one or more of the compounds of
the invention including pharmaceutically acceptable salts, esters
or other derivatives thereof are mixed with a suitable
pharmaceutical carrier, excipients, adjuvant, or vehicle. In
instances in which the compounds exhibit insufficient solubility,
methods for solubilizing compounds may be used. Such methods are
known to those of skill in this art, and include, but are not
limited to, using cosolvents, such as dimethylsulfoxide (DMSO),
using surfactants, such as TWEEN, or dissolution in aqueous sodium
bicarbonate. Derivatives of the compounds, such as salts of the
compounds or prodrugs of the compounds may also be used in
formulating effective pharmaceutical compositions.
[0185] Upon mixing or addition of the compound(s) of the invention,
the resulting mixture may be a solution, suspension, emulsion or
the like. The form of the resulting mixture depends upon a number
of factors, including the intended mode of administration and the
solubility of the compound in the chosen carrier or vehicle. The
effective concentration sufficient for ameliorating the symptoms of
the disease treated and may be empirically determined.
[0186] Compounds of provided herein may be administered orally,
topically, parenterally, intravenously, by intramuscular injection,
by inhalation or spray, sublingually, transdermally, via buccal
administration, rectally, as an ophthalmic solution, or by other
means, in dosage unit formulations.
[0187] Dosage formulations suitable for oral use, include, for
example, tablets, troches, lozenges, aqueous or oily suspensions,
dispersible powders or granules, emulsions, hard or soft capsules,
or syrups or elixirs. Compositions intended for oral use may be
prepared according to any method known to the art for the
manufacture of pharmaceutical compositions and such compositions
may contain one or more agents, such as sweetening agents,
flavoring agents, coloring agents and preserving agents, in order
to provide pharmaceutically elegant and palatable preparations.
Oral formulations contain between 0.1 and 99% of a compound of the
invention and usually at least about 5% (weight %) of a compound of
the present invention. Some embodiments contain from about 25% to
about 50% or from 5% to 75% of a compound of invention.
[0188] Orally administered compositions also include liquid
solutions, emulsions, suspensions, powders, granules, elixirs,
tinctures, syrups, and the like. The pharmaceutically acceptable
carriers suitable for preparation of such compositions are well
known in the art. Oral formulations may contain preservatives,
flavoring agents, sweetening agents, such as sucrose or saccharin,
taste-masking agents, and coloring agents.
[0189] Typical components of carriers for syrups, elixirs,
emulsions and suspensions include ethanol, glycerol, propylene
glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
Syrups and elixirs may be formulated with sweetening agents, for
example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent.
Orally Administered Liquids Formulations
[0190] Compounds of the invention can be incorporated into oral
liquid preparations such as aqueous or oily suspensions, solutions,
emulsions, syrups, or elixirs, for example. Moreover, formulations
containing these compounds can be presented as a dry product for
constitution with water or other suitable vehicle before use. Such
liquid preparations can contain conventional additives, such as
suspending agents (e.g., sorbitol syrup, methyl cellulose,
glucose/sugar, syrup, gelatin, hydroxyethyl cellulose,
carboxymethyl cellulose, aluminum stearate gel, and hydrogenated
edible fats), emulsifying agents (e.g., lecithin, sorbitan
monsoleate, or acacia), non-aqueous vehicles, which can include
edible oils (e.g., almond oil, fractionated coconut oil, silyl
esters, propylene glycol and ethyl alcohol), and preservatives
(e.g., methyl or propyl p-hydroxybenzoate and sorbic acid).
Suspensions
[0191] For a suspension, typical suspending agents include
methylcellulose, sodium carboxymethyl cellulose, AVICEL RC-591,
tragacanth and sodium alginate; typical wetting agents include
lecithin and polysorbate 80; and typical preservatives include
methyl paraben and sodium benzoate.
[0192] Aqueous suspensions contain the active material(s) in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone,
gum tragacanth and gum acacia; dispersing or wetting agents; may be
a naturally-occurring phosphatide, for example, lecithin, or
condensation products of an alkylene oxide with fatty acids, for
example polyoxyethylene stearate, or condensation products of
ethylene oxide with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene
oxide with partial esters derived from fatty acids and a hexitol
such as polyoxyethylene sorbitol substitute, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and hexitol anhydrides, for example polyethylene sorbitan
substitute. The aqueous suspensions may also contain one or more
preservatives, for example ethyl, or n-propyl
p-hydroxybenzoate.
[0193] Oily suspensions may be formulated by suspending the active
ingredients in a vegetable oil, for example peanut oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide palatable oral preparations. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
Emulsions
[0194] Pharmaceutical compositions of the invention may also be in
the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example olive oil or peanut oil, or a mineral
oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally-occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol, anhydrides, for example sorbitan
monoleate, and condensation products of the said partial esters
with ethylene oxide, for example polyoxyethylene sorbitan
monoleate.
Dispersible Powders
[0195] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above.
Tablets and Capsules
[0196] Tablets typically comprise conventional pharmaceutically
compatible adjuvants as inert diluents, such as calcium carbonate,
sodium carbonate, mannitol, lactose and cellulose; binders such as
starch, gelatin and sucrose; disintegrants such as starch, alginic
acid and croscarmelose; lubricants such as magnesium stearate,
stearic acid and talc. Glidants such as silicon dioxide can be used
to improve flow characteristics of the powder mixture. Coloring
agents, such as the FD&C dyes, can be added for appearance.
Sweeteners and flavoring agents, such as aspartame, saccharin,
menthol, peppermint, and fruit flavors, are useful adjuvants for
chewable tablets. Capsules (including time release and sustained
release formulations) typically comprise one or more solid diluents
disclosed above. The selection of carrier components often depends
on secondary considerations like taste, cost, and shelf
stability.
[0197] Such compositions may also be coated by conventional
methods, typically with pH or time-dependent coatings, such that
the subject compound is released in the gastrointestinal tract in
the vicinity of the desired topical application, or at various
times to extend the desired action. Such dosage forms typically
include, but are not limited to, one or more of cellulose acetate
phthalate, polyvinylacetate phthalate, hydroxypropyl
methylcellulose phthalate, ethyl cellulose, Eudragit coatings,
waxes and shellac.
[0198] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin or olive oil.
Injectable and Parenteral Formulations
[0199] Pharmaceutical compositions may be in the form of a sterile
injectable aqueous or oleaginous suspension. This suspension may be
formulated according to the known art using those suitable
dispersing or wetting agents and suspending agents that have been
mentioned above. The sterile injectable preparation may also be
sterile injectable solution or suspension in a non-toxic parentally
acceptable diluent or solvent, for example as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution, and isotonic sodium
chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
are useful in the preparation of injectables.
[0200] Compounds of the invention may be administered parenterally
in a sterile medium. Parenteral administration includes
subcutaneous injections, intravenous, intramuscular, intrathecal
injection or infusion techniques. The compound or compounds of the
invention, depending on the vehicle and concentration used, can
either be suspended or dissolved in the vehicle. Advantageously,
adjuvants such as local anesthetics, preservatives and buffering
agents can be dissolved in the vehicle. In many compositions for
parenteral administration the carrier comprises at least about 90%
by weight of the total composition. Preferred carriers for
parenteral administration include propylene glycol, ethyl oleate,
pyrrolidone, ethanol, and sesame oil.
Suppositories
[0201] Compounds of the invention may also be administered in the
form of suppositories for rectal administration of the drug. These
compositions can be prepared by mixing the drug with a suitable
non-irritating excipient that is solid at ordinary temperatures but
liquid at rectal temperature and will therefore melt in the rectum
to release the drug. Such materials include cocoa butter and
polyethylene glycols.
Topical Formulations
[0202] Compounds of the invention may be formulated for local or
topical application, such as for topical application to the skin
and mucous membranes, such as in the eye, in the form of gels,
creams, and lotions and for application to the eye. Topical
compositions of the present invention may be in any form including,
for example, solutions, creams, ointments, gels, lotions, milks,
cleansers, moisturizers, sprays, skin patches, and the like.
[0203] Such solutions may be formulated as 0.01%-10% isotonic
solutions, pH about 5-7, with appropriate salts. Compounds of the
invention may also be formulated for transdermal administration as
a transdermal patch.
[0204] Topical compositions containing the active compound can be
admixed with a variety of carrier materials well known in the art,
such as, for example, water, alcohols, aloe vera gel, allantoin,
glycerine, vitamin A and E oils, mineral oil, propylene glycol,
PPG-2 myristyl propionate, and the like.
[0205] Other materials suitable for use in topical carriers
include, for example, emollients, solvents, humectants, thickeners
and powders. Examples of each of these types of materials, which
can be used singly or as mixtures of one or more materials, are as
follows:
[0206] Emollients, such as stearyl alcohol, glyceryl
monoricinoleate, glyceryl monostearate, propane-1,2-diol,
butane-1,3-diol, mink oil, cetyl alcohol, iso-propyl isostearate,
stearic acid, iso-butyl palmitate, isocetyl stearate, oleyl
alcohol, isopropyl laurate, hexyl laurate, decyl oleate,
octadecan-2-ol, isocetyl alcohol, cetyl palmitate,
dimethylpolysiloxane, di-n-butyl sebacate, iso-propyl myristate,
iso-propyl palmitate, iso-propyl stearate, butyl stearate,
polyethylene glycol, triethylene glycol, lanolin, sesame oil,
coconut oil, arachis oil, castor oil, acetylated lanolin alcohols,
petroleum, mineral oil, butyl myristate, isostearic acid, palmitic
acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl
oleate, and myristyl myristate; propellants, such as propane,
butane, iso-butane, dimethyl ether, carbon dioxide, and nitrous
oxide; solvents, such as ethyl alcohol, methylene chloride,
iso-propanol, castor oil, ethylene glycol monoethyl ether,
diethylene glycol monobutyl ether, diethylene glycol monoethyl
ether, dimethyl sulphoxide, dimethyl formamide, tetrahydrofuran;
humectants, such as glycerin, sorbitol, sodium
2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate,
and gelatin; and powders, such as chalk, talc, fullers earth,
kaolin, starch, gums, colloidal silicon dioxide, sodium
polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl
ammonium smectites, chemically modified magnesium aluminium
silicate, organically modified montmorillonite clay, hydrated
aluminium silicate, fumed silica, carboxyvinyl polymer, sodium
carboxymethyl cellulose, and ethylene glycol monostearate.
[0207] Compounds of the invention may also be topically
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamellar vesicles, and
multilamellar vesicles. Liposomes can be formed from a variety of
phospholipids, such as cholesterol, stearylamine or
phosphatidylcholines.
Other Formulations
[0208] Other compositions useful for attaining systemic delivery of
the subject compounds include sublingual, buccal and nasal dosage
forms. Such compositions typically comprise one or more of soluble
filler substances such as sucrose, sorbitol and mannitol, and
binders such as acacia, microcrystalline cellulose, carboxymethyl
cellulose, and hydroxypropyl methylcellulose. Glidants, lubricants,
sweeteners, colorants, antioxidants and flavoring agents disclosed
above may also be included.
[0209] Compositions for inhalation typically can be provided in the
form of a solution, suspension or emulsion that can be administered
as a dry powder or in the form of an aerosol using a conventional
propellant (e.g., dichlorodifluoromethane or
trichlorofluoromethane).
Additional Components
[0210] The compositions of the present invention may also
optionally comprise an activity enhancer. The activity enhancer can
be chosen from a wide variety of molecules that function in
different ways to enhance therapeutic effects of compounds of the
invention. Particular classes of activity enhancers include skin
penetration enhancers and absorption enhancers.
[0211] Pharmaceutical compositions of the invention may also
contain additional active agents can be chosen from a wide variety
of molecules, which can function in different ways to enhance the
therapeutic effects of a compound of the invention. These optional
other active agents, when present, are typically employed in the
compositions of the invention at a level ranging from about 0.01%
to about 15%. Some embodiments contain from about 0.1% to about 10%
by weight of the composition. Other embodiments contain from about
0.5% to about 5% by weight of the composition.
Packaged Formulations
[0212] The invention includes packaged pharmaceutical formulations.
Such packaged formulations include a pharmaceutical composition
containing one or more compounds, salts, or other pharmaceutically
acceptable forms thereof, of the invention in a container and
instructions for using the composition to treat a mammal (typically
a human patient). Preferably the instructions are for using the
pharmaceutical composition to treat a patient suffering from a
disease responsive to inhibition of Btk activity and/or inhibition
of B-cell proliferation. The invention includes providing
prescribing information; for example, to a patient or health care
provider, or as a label in a packaged pharmaceutical formulation.
Prescribing information may include for example efficacy, dosage
and administration, contraindication and adverse reaction
information pertaining to the pharmaceutical formulation.
[0213] In all of the foregoing the compounds of the invention can
be administered alone, as mixtures, or in combination with other
active agents.
Methods of Treatment
[0214] Imidazo[1,2-a]pyrazines active as kinase inhibitors, in
particular Btk inhibitors are described herein. These inhibitors
are useful for treating diseases responsive to kinase inhibition,
including diseases responsive to Btk inhibition and/or inhibition
of B-cell proliferation, in mammals. Without wishing to be bound to
any particular theory, it is believed that the interaction of the
compounds of Formula I-a with Btk results in the inhibition of Btk
activity and thus in the pharmaceutical utility of these compounds.
Other kinases that may be affected in addition to Btk include, but
are not limited to, other tyrosine kinases and serine/threonine
kinases.
[0215] Accordingly, the invention includes a method of treating a
mammal, preferably a human, having a disease responsive to
inhibition of Btk activity, comprising administrating to the mammal
having such a disease, an effective amount of a compound of Formula
I-a.
[0216] To the extent that Btk is implicated in any of the
following, alleviation of the disease, disease symptoms,
preventative, and prophylactic treatment is within the scope of
this invention. In addition, as noted above, the compounds of
Formula I-a may also inhibit other kinases, such that alleviation
of disease, disease symptoms, preventative, and prophylactic
treatment of conditions associated with these kinases is also
within the scope of this invention.
[0217] Methods of treatment also include inhibiting Btk activity
and/or inhibiting B-cell proliferation, by inhibiting ATP binding
or hydrolysis by Btk or by some other mechanism, in vivo, in a
patient suffering from a disease responsive to inhibition of Btk
activity, by administering an effective concentration of a compound
of Formula I-a to inhibit Btk activity in vitro. An effective
concentration may be ascertained experimentally, for example by
assaying blood concentration of the compound, or theoretically, by
calculating bioavailability.
Diseases Responsive to Kinase Inhibition
[0218] Certain compounds described herein are useful for treating a
patient suffering from a disease responsive to kinase
inhibition.
[0219] Protein kinases, the largest family of human enzymes, are
now considered to be the largest druggable target class.
Encompassing well over 500 proteins (2% of the human genome),
kinases play critical roles in signaling pathways controlling
fundamental cellular processes such as proliferation,
differentiation, and death (apoptosis). Abnormal kinase activity
has been implicated in a wide range of diseases, including multiple
cancers, autoimmune and/or inflammatory diseases, and acute
inflammatory reactions. The multifaceted role of kinases in key
cell signaling pathways provides a significant opportunity to
identify novel drugs targeting kinases and signaling pathways.
Diseases Responsive to Btk Inhibition
[0220] The invention includes a method of treating a patient having
cancer, an autoimmune and/or inflammatory disease, or an acute
inflammatory reaction, by administering an effective amount of a
compound of Formula I-a.
[0221] In a preferred embodiment, the condition responsive to
inhibition of Btk activity and/or B-cell proliferation is cancer,
an autoimmune and/or inflammatory disease, or an acute inflammatory
reaction.
[0222] Preferably, the conditions, diseases that can be affected
using compounds and compositions according to the invention
include, but are not limited to:
autoimmune and/or inflammatory diseases, including but not limited
to psoriasis, allergy, Crohn's disease, irritable bowel syndrome,
Sjogren's disease, tissue graft rejection, and hyperacute rejection
of transplanted organs, asthma, systemic lupus erythematosus (and
associated glomerulonephritis), dermatomyositis, multiple
sclerosis, scleroderma, vasculitis (ANCA-associated and other
vasculitides), autoimmune hemolytic and thrombocytopenic states,
Goodpasture's syndrome (and associated glomerulonephritis and
pulmonary hemorrhage), atherosclerosis, rheumatoid arthritis,
chronic Idiopathic thrombocytopenic purpura (ITP), Addison's
disease, Parkinson's disease, Alzheimer's disease, diabetes, septic
shock, myasthenia gravis, and the like, acute inflammatory
reactions, including but not limited to skin sunburn, inflammatory
pelvic disease, inflammatory bowel disease, urethritis, uvitis,
sinusitis, pneumonitis, encephalitis, meningitis, myocarditis,
nephritis, osteomyelitis, myositis, hepatitis, gastritis,
enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, and
cholocystitis, and cancer, including but not limited to, B-cell
lymphoma, lymphoma (including Hodgkin's and non-Hodgkins lymphoma),
hairy cell leukemia, multiple myeloma, chronic and acute
myelogenous leukemia, and chronic and acute lymphocytic
leukemia.
[0223] Btk is a known inhibitor of apoptosis in lymphoma B-cells.
Defective apoptosis contributes to the pathogenesis and drug
resistance of human leukemias and lymphomas. Thus, a method of
promoting or inducing apoptosis in cells expressing Btk comprising
contacting the cell with an agent that inhibits Btk activity is
also provided herein.
Combination Therapy
[0224] The invention provides methods of treatment in which a
compound of the invention is the only active agent given to a
patient and also includes methods of treatment in which a compound
of Formula I-a is given to a patient in combination with one or
more additional active agent. Thus in one embodiment the invention
provides a method of treating cancer, an autoimmune and/or
inflammatory disease, or an acute inflammatory reaction, which
comprises administering to a mammal in need thereof an effective
amount of a compound of Formula I-a together with a second active
agent, which is useful for treating an cancer, an autoimmune and/or
inflammatory disease, or an acute inflammatory reaction. For
example the second agent may be an anti-inflammatory agent.
Treatment with the second active agent may be prior to, concomitant
with, or following treatment with a compound of Formula I-a. In
certain embodiments a compound of Formula I-a is combined with
another active agent in a single dosage form. Suitable antitumor
therapeutics that may be used in combination with a compound of
Formula I-a include, but are not limited to chemotherapeutic
agents, for example mitomycin C, carboplatin, taxol, cisplatin,
paclitaxel, etoposide, doxorubicin, or a combination comprising at
least one of the foregoing chemotherapeutic agents.
Radiotherapeutic antitumor agents may also be used, alone or in
combination with chemotherapeutic agents.
[0225] Btk inhibitors are useful as chemosensitizing agents, and,
thus, are useful in combination with other chemotherapeutic drugs,
in particular, drugs that induce apoptosis.
[0226] A method for increasing sensitivity of cancer cells to
chemotherapy, comprising administering to a patient undergoing
chemotherapy a chemotherapeutic agent together with a Btk inhibitor
in an amount sufficient to increase the sensitivity of cancer cells
to the chemotherapeutic agent is also provided herein.
[0227] Examples of other chemotherapeutic drugs that can be used in
combination with Btk inhibitors include topoisomerase I inhibitors
(camptothesin or topotecan), topoisomerase II inhibitors (e.g.
daunomycin and etoposide), alkylating agents (e.g.
cyclophosphamide, melphalan and BCNU), tubulin directed agents
(e.g. taxol and vinblastine), and biological agents (e.g.
antibodies such as anti CD20 antibody, IDEC 8, immunotoxins, and
cytokines).
[0228] Included herein are methods of treatment in which a compound
of Formula I-a in administered in combination with an
anti-inflammatory agent. Anti-inflammatory agents include but are
not limited to NSAIDs, non-specific and COX-2 specific
cyclooxygenase enzyme inhibitors, gold compounds, corticosteroids,
methotrexate, tumor necrosis factor receptor (TNF) receptors
antagonists, immunosuppressants and methotrexate.
[0229] Examples of NSAIDs include, but are not limited to
ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac,
combinations of diclofenac sodium and misoprostol, sulindac,
oxaprozin, diflunisal, piroxicam, indomethacin, etodolac,
fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine,
tolmetin sodium, and hydroxychloroquine. Examples of NSAIDs also
include COX-2 specific inhibitors (i.e., a compound that inhibits
COX-2 with an IC.sub.50 that is at least 50-fold lower than the
IC.sub.50 for COX-1) such as celecoxib, valdecoxib, lumiracoxib,
etoricoxib and/or rofecoxib.
[0230] In a further embodiment, the anti-inflammatory agent is a
salicylate. Salicylates include by are not limited to
acetylsalicylic acid or aspirin, sodium salicylate, and choline and
magnesium salicylates.
[0231] The anti-inflammatory agent may also be a corticosteroid.
For example, the corticosteroid may be cortisone, dexamethasone,
methylprednisolone, prednisolone, prednisolone sodium phosphate,
and prednisone.
[0232] In additional embodiments the anti-inflammatory agent is
therapeutic agent is a gold compound such as gold sodium thiomalate
or auranofin.
[0233] The invention also includes embodiments in which the
anti-inflammatory agent is a metabolic inhibitor such as a
dihydrofolate reductase inhibitor, such as methotrexate or a
dihydroorotate dehydrogenase inhibitor, such as leflunomide.
[0234] Other embodiments of the invention pertain to combinations
in which at least one anti-inflammatory compound is an anti-C5
monoclonal antibody (such as eculizumab or pexelizumab), a TNF
antagonist, such as entanercept, or infliximab, which is an
anti-TNF alpha monoclonal antibody.
[0235] Still other embodiments of the invention pertain to
combinations in which at least one active agent is an
immunosuppressant compound such as methotrexate, leflunomide,
cyclosporine, tacrolimus, azathioprine, or mycophenolate
mofetil.
Dosage Levels
[0236] Dosage levels of the order of from about 0.1 mg to about 140
mg per kilogram of body weight per day are useful in the treatment
of the above-indicated conditions (about 0.5 mg to about 7 g per
patient per day). The amount of active ingredient that may be
combined with the carrier materials to produce a single dosage form
will vary depending upon the host treated and the particular mode
of administration. Dosage unit forms will generally contain between
from about 1 mg to about 500 mg of an active ingredient.
[0237] Frequency of dosage may also vary depending on the compound
used and the particular disease treated. However, for treatment of
most autoimmune and/or inflammatory, a dosage regimen of 4 times
daily or less is preferred and a dosage regimen of 1 or 2 times
daily is particularly preferred.
[0238] It will be understood, however, that the specific dose level
for any particular patient will depend upon a variety of factors
including the activity of the specific compound employed, the age,
body weight, general health, sex, diet, time of administration,
route of administration, and rate of excretion, drug combination
and the severity of the particular disease in the patient
undergoing therapy.
EXAMPLES
Example 1
Exemplary Synthesis of Certain Imidazo[1,2-a]Pyrazin-8-Ylamines
[0239] Step 1. 6,8-dibromoimidazo[1,2-a]pyrazine (3)
##STR00012##
[0240] A mixture of bromoacetaldehyde diethyl acetal (51 grams
(g)), 48% hydrobromic acid (HBr) (11 milliliters (mL)), and water
(11 mL) is heated at 120.degree. C. for 1 hour (hr). The solution
is cooled, poured into a mixture of sodium bicarbonate
(NaHCO.sub.3) (60 g) and isopropyl alcohol (IPA) (200 mL), and
stirred for 0.5 hr. The mixture is filtered, and the filtrate is
treated with 3,5-dibromo-2-aminopyrazine (1) (33 g) and heated
under reflux for 16 hr. The suspension is cooled in ice, treated
with 48% HBr (3 mL) and diethyl ether (60 mL) and filtered to
afford (3) as the hydrobromide salt.
Step 2. (6-Bromo-imidazo[1,2-a]pyrazin-8-yl)-phenyl-amine (4)
##STR00013##
[0241] Tri-o-tolylphosphine (1.1 g) is added to a suspension of
tris(dibenzylideneacetone)dipalladium (1.65 g) in degassed toluene
(50 mL) and the mixture is stirred at room temperature for 15
minutes (min). 6,8-Dibromo-imidazo[1,2-a]pyrazine (5.0 g) is then
added and the mixture is stirred at room temperature for 15 minutes
more. Aniline (1.52 g) is added followed by potassium t-butoxide
(2.84 g) and the mixture is stirred at room temperature for 72 hr.
Water (150 mL) is added and the mixture is extracted with ethyl
acetate (3.times.150 mL), the extracts are washed with water
(1.times.100 mL) and brine (1.times.100 mL), dried over MgSO.sub.4,
and evaporated in vacuo to afford a gum. Trituration with diethyl
ether affords (6-bromo-imidazo[1,2-a]pyrazin-8-yl)-phenyl-amine (4)
as a brown solid.
Step 3.
[6-(3-Amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-phenyl-amine
(5)
##STR00014##
[0242] A mixture of
(6-bromo-imidazo[1,2-a]pyrazin-8-yl)-phenyl-amine (4) (1.9 g),
3-aminophenylboronic acid hemisulfate (1.35 g),
tetrakis(triphenylphosphine) palladium (380 mg), 1M aqueous sodium
carbonate (20 mL), and 1,2-dimethoxyethane (40 mL) is heated at
90.degree. for 16 hr. The mixture is cooled to room temperature,
treated with water (50 mL) and extracted with ethyl acetate
(3.times.80 mL). The extracts are washed with water (1.times.50 mL)
and brine (1.times.50 mL), dried over MgSO.sub.4, and evaporated in
vacuo to afford a gum which is purified by flash chromatography
over silica gel, eluting with ethyl acetate, to afford
[6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-phenyl-amine (5) as
a light brown solid.
Step 4.
4-tert-Butyl-N-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phen-
yl]-benzamide (6)
##STR00015##
[0243] A solution of
[6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-phenyl-amine (5)
(50 mg), 4-tert-butyl-benzoyl chloride (0.83 mL of a 0.2M solution
in toluene), and triethylamine (0.034 mL) in toluene (1 mL) and
N,N,-dimethylformamide (1 mL) is stirred at room temperature for 16
hr. The mixture is purified by preparative thin layer
chromatography over silica gel, eluting with diethyl
ether/dichloromethane (1:1) to afford
4-tert-butyl-N-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-benz-
amide (6) as a cream foam.
Example 2
Synthesis of
N-(4-Tert-Butyl-Phenyl)-3-{8-[4-(Morpholin-4-Carbonyl)-Phenylamino]-Imida-
zo[1,2-a]Pyrazin-6-Yl}-Benzamide
[0244] Step. 1. 4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic
acid (7)
##STR00016##
[0245] A mixture of
4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acid ethyl
ester (30 mmol), 1N aqueous sodium hydroxide (50 mL), and ethanol
(80 mL) is heated at reflux for 1.5 hr. The mixture is cooled and
the ethanol removed in vacuo. The residue is diluted with 1N sodium
hydroxide (30 mL) and washed with ethyl acetate (2.times.100 mL)
The aqueous layer is brought to pH 6 with 3N HCl, and the mixture
filtered to give
4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acid (7) as a
light orange solid.
Step 2.
[4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-phenyl]-morpholin-4--
yl-methanone (8)
##STR00017##
[0246] A mixture of
4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acid (7) (0.16
mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium
hexafluorophosphate (0.16 mmol), and N'N-diisopropylethylamine
(0.48 mmol) is stirred at room temperature for 20 min. under
N.sub.2. Morpholine (0.48 mmol) is added and the mixture is stirred
at room temperature for 16 hr. Water (10 mL) is added and the
mixture extracted with ethyl acetate (2.times.70 mL). The extracts
are subsequently washed with water (2.times.30 mL) and brine
(1.times.30 mL), dried over sodium sulfate, and concentrated in
vacuo. The residue is triturated with diethyl ether to give
[4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-phenyl]-morpholin-4-yl-metha-
none (8) as a cream solid.
Step 3. 3-{8-[4-(Morpholine-4-carbonyl)-phenylamino]-imidazo[1,
2-a]pyrazin-6-yl}-benzoic acid (9)
##STR00018##
[0247] The bromide (8) (2.46 mmol) is dissolved in 10 mL DME
(ethylene glycol, dimethyl ether) in a sealable pressure vessel and
N.sub.2 is bubbled through for 10 min.
Tetrakis(triphenylphosphine)palladium (0.24 mmol) is added and
N.sub.2 is bubbled through the reaction for another 10 minutes.
3-Carboxyphenyl boronic acid (3.1 mmol) and 1N Na.sub.2CO.sub.3
solution (10 mL) are then added, the vessel sealed, and the
reaction heated to 95.degree. C. for 16 hrs. with vigorous
stirring. After cooling to room temperature, the reaction is
acidified to pH 3 with 1N HCl and extracted with ethyl acetate
(3.times.25 mL). The pooled ethyl acetate layers are washed with
brine, dried over sodium sulfate, and the solvent removed in vacuo.
The resulting solid is then dissolved in a minimal volume of
CH.sub.2Cl.sub.2 and precipitated out as a whitish-tan solid by
slow addition of ethyl acetate (5 mL) followed by hexanes (30 mL)
to yield
3-{8-[4-(Morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin--
6-yl}-benzoic acid (9).
Step 4.
N-(4-tert-Butyl-phenyl)-3-{8-[4-(morpholine-4-carbonyl)-phenylami-
no]-imidazo[1,2-a]pyrazin-6-yl}-benzamide (10)
##STR00019##
[0248] A mixture of
3-{8-[4-(Morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}--
benzoic acid (9) (0.23 mmol),
benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium
hexafluorophosphate reagent (0.23 mmol) and
N,N'-diisopropylethylamine (0.77 mmol) is stirred under N.sub.2 for
15 min. in 1 mL DMF. 4-tert-Butyl-phenylamine (0.37 mmol) is added
and the reaction stirred at rt for 8 hrs. The reaction is
partitioned between ethyl acetate (15 mL) and water (15 mL) and the
ethyl acetate layer washed with water (2.times.15 mL) and brine
(1.times.15 mL). The organic layer is dried over sodium sulfate and
the solvent removed in vacuo. The resulting crude oil is dissolved
in 1 ml CH.sub.2Cl.sub.2 and clean yellow solid is precipitated by
slow addition of diethyl ether, yielding the final product, (10)
N-(4-tert-Butyl-phenyl)-3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imid-
azo[1,2-a]pyrazin-6-yl}-benzamide.
Example 3
Synthesis of
N-(3-{8-[4-(4-Acetyl-Piperazin-1-Yl)-Phenylamino]-Imidazo[1,2-a]Pyrazin-6-
-Yl}-Phenyl)-4-Tert-Butyl-Benzamide
[0249] Step 1. 4-(4-Nitro-phenyl)-piperazine-1-carboxylic acid
tert-butyl ester
##STR00020##
[0250] A mixture of 1-fluoro-4-nitrobenzene (20.4 mmol),
piperazine-1-carboxylic acid tert-butyl ester (20.4 mmol),
potassium carbonate (40.8 mmol), and N'N-dimethylformamide (80 mL)
is heated at 60.degree. C. for 3 hrs. The mixture is cooled to room
temperature, treated with water (100 mL), extracted with ethyl
acetate (3.times.80 mL). The extracts are washed with water
(3.times.60 mL) and brine (1.times.75 ml), dried over magnesium
sulfate, and concentrated in vacuo to give
4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester
(11) as a yellow solid.
Step 2. 4-(4-Amino-phenyl)-piperazine-1-carboxylic acid tert-butyl
ester
##STR00021##
[0251] A mixture of 4-(4-nitro-phenyl)-piperazine-1-carboxylic acid
tert-butyl ester (11) (18.9 mmol), 10% palladium-on-carbon (600
mg), ethanol (100 mL), and ethyl acetate (100 mL) is hydrogenated
at room temperature and 40 psi for 2 hrs. The mixture is filtered
through celite, washing with ethyl acetate (2.times.100 mL), and
concentrated in vacuo to give
4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester
(12) as a brown oil.
Step 3.
4-[4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-phenyl]-piperazine-
-1-carboxylic acid tert-butyl ester
##STR00022##
[0252] A mixture of 6,8-dibromoimidazo[1,2-a]pyrazine (12.5 mmol),
4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester
(12) (13.1 mmol), potassium carbonate (25 mmol), acetonitrile (50
mL) and N,N-dimethylacetamide (20 mL) is heated at 65.degree. C.
for 16 hrs. The mixture is cooled to room temperature, treated
water (100 mL), and extracted with ethyl acetate (3.times.80 mL).
The extracts are washed with water (3.times.60 mL) and brine
(1.times.60 mL), dried over magnesium sulfate, and concentrated in
vacuo. The residue is chromatographed over silica gel, eluting with
ethyl acetate, to give
4-[4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-phenyl]-piperazine-1-carbo-
xylic acid tert-butyl ester (13) as a light brown foam.
Step 4.
4-{4-[6-(3-Amino-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-phenyl}-
-piperazine-1-carboxylic acid tert-butyl ester (14)
##STR00023##
[0253] A mixture of
4-(6-bromoimidazo[1,2-a]pyrazin-8-ylamino)benzoic acid ethyl ester
(13) (4.33 mmol), 3-aminophenylboronic acid hemisulfate (5.63
mmol), tetrakis(triphenylphosphine)palladium (0.2 mmol), 1N aqueous
sodium carbonate solution (13 mL), and dimethoxyethane (70 mL) is
heated at 95.degree. C. for 2 days. The mixture is allowed to cool,
treated with water (100 mL), and extracted with ethyl acetate
(3.times.80 mL). The extracts are washed with water (2.times.75 mL)
and brine (1.times.75 mL), dried over magnesium sulfate, and
evaporated in vacuo. The residue is chromatographed over silica
gel, eluting with ethyl acetate, to give
4-{4-[6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-phenyl}-piperaz-
ine-1-carboxylic acid tert-butyl ester (14) as a cream solid.
Step 5.
4-(4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyra-
zin-8-ylamino}-phenyl)-piperazine-1-carboxylic acid tert-butyl
ester (15)
##STR00024##
[0254] An ice-cold solution of
4-{4-[6-(3-Amino-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-phenyl}-piperaz-
ine-1-carboxylic acid tert-butyl ester (14) (2.35 mmol),
triethylamine (3.53 mmol), and tetrahydrofuran (20 mL) is treated
dropwise with a solution of 4-t-butylbenzoyl chloride (2.35 mmol)
in tetrahydrofuran (10 mL). The mixture is stirred at room
temperature for 1 hr. Water (50 mL) is added and the mixture
extracted with ethyl acetate (3.times.70 mL). The extracts are
washed with water (2.times.50 mL) and brine (1.times.50 mL), dried
over magnesium sulfate, and evaporated in vacuo. The residue is
triturated with diethyl ether to give
4-(4-{6-[3-(4-tert-butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-yl-
amino}-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (15)
as a cream solid.
Step 6.
4-tert-Butyl-N-{3-[8-(4-piperazin-1-yl-phenylamino)-imidazo[1,2-a-
]pyrazin-6-yl]-phenyl}-benzamide (16)
##STR00025##
[0255] A mixture of
4-(4-{6-[3-(4-tert-butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-yl-
amino}-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (15)
(2.0 mmol), 1M HCl in diethyl ether (20 mL), and dioxane (60 mL) is
stirred at room temperature for 16 hr. Water (100 mL) is added and
the pH brought to 11 with 1N NaOH. The mixture is extracted with
ethyl acetate (3.times.80 mL), the extracts washed with water
(2.times.70 mL) and brine (1.times.70 mL), dried over magnesium
sulfate, and concentrated in vacuo. The residue is slurried with
diethyl ether and filtered to give
4-tert-butyl-N-{3-[8-(4-piperazin-1-yl-phenylamino)-imidazo[1,2-a]pyrazin-
-6-yl]-phenyl}-benzamide (16) as a cream solid.
Step 7.
N-(3-{8-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-imidazo[1,2-a]p-
yrazin-6-yl}-phenyl)-4-tert-butyl-benzamide (17)
##STR00026##
[0256] A mixture of
4-tert-butyl-N-{3-[8-(4-piperazin-1-yl-phenylamino)-imidazo[1,2-a]pyrazin-
-6-yl]-phenyl}-benzamide (16) (0.55 mmol), triethylamine (1.1
mmol), acetic anhydride (0.60 mmol), and dichloromethane (10 mL) is
stirred at room temperature for 1 hr. Water (30 mL) is added, the
mixture extracted with dichloromethane (2.times.50 mL), the
extracts washed with water (2.times.30 mL) and brine (1.times.30
mL), dried over magnesium sulfate, and concentrated in vacuo. The
residue is triturated with diethyl ether and ethyl acetate to give
N-(3-{8-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-imidazo
[1,2-a]pyrazin-6-yl}-phenyl)-4-tert-butyl-benzamide (17) as a cream
solid.
Example 4
Synthesis of
4-Tert-Butyl-N-(3-{8-[4-(Morpholine-4-Carbonyl)-Phenylamino]-Imidazo[1,2--
A]Pyrazin-6-Yl}-Phenyl)-Benzamide
[0257] Step 1. 4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic
acid ethyl ester (18)
##STR00027##
[0258] A mixture of 6,8-dibromoimidazo[1,2-a]pyrazine (0.18 mol),
4-aminobenzoic acid ethyl ester (2) (0.18 mol), and
N,N-dimethylacetamide (30 mL) is heated at 160.degree. C. for 30
min. The mixture is cooled to room temperature, treated with ethyl
acetate (150 mL), stirred, and filtered to afford an orange/brown
solid. This solid is slurried with ethyl acetate and saturated
sodium bicarbonate solution to give
4-(6-bromoimidazo[1,2-a]pyrazin-8-ylamino)benzoic acid ethyl ester
(18) freebase.
Step 2.
4-[6-(3-Amino-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-benzoic acid
ethyl ester (19)
##STR00028##
[0259] A mixture of
4-(6-bromoimidazo[1,2-a]pyrazin-8-ylamino)benzoic acid ethyl ester
(18) (55.3 mmol), 3-aminophenylboronic acid hemisulfate (72 mmol),
tetrakis(triphenylphosphine)palladium (2.8 mmol), 1N aqueous sodium
carbonate solution (166 mmol), and dimethoxyethane (200 mL) is
heated at reflux for 4 days. The mixture is allowed to cool,
treated with water (200 mL), and extracted with ethyl acetate
(4.times.100 mL). The extracts are washed with water (2.times.150
mL) and brine (1.times.100 mL), dried over magnesium sulfate, and
evaporated in vacuo. The residue is triturated with dichloromethane
and diethyl ether to give
4-[6-(3-aminophenyl)imidazo[1,2-a]pyrazin-8-ylamino]benzoic acid
ethyl ester (19) as a yellow solid.
Step 3.
4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]imidazo[1,2-a]pyrazin--
8-ylamino}-benzoic acid ethyl ester (20)
##STR00029##
[0260] An ice-cold solution of
4-[6-(3-aminophenyl)imidazo[1,2-a]pyrazin-8-ylamino]benzoic acid
ethyl ester (19) (44.2 mmol), triethylamine (66.4 mmol), and
tetrahydrofuran (140 mL) is treated dropwise with a solution of
4-t-butylbenzoyl chloride (44.2 mmol) in tetrahydrofuran (60 mL)
and the mixture is stirred at room temperature for 1 hr. Water (100
mL) is added and the mixture extracted with ethyl acetate
(3.times.100 mL), the extracts are washed with water (2.times.100
mL) and brine (1.times.100 mL), dried over magnesium sulfate and
evaporated in vacuo. The residue is triturated with dichloromethane
to give
4-{6-[3-(4-tert-butyl-benzoylamino)phenyl]imidazo[1,2-a]pyrazin-8-
-ylamino}benzoic acid ethyl ester (20) as a pale orange solid.
Step 4.
4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-
-8-ylamino}-benzoic acid (21)
##STR00030##
[0261] A mixture of
4-{6-[3-(4-tert-butyl-benzoylamino)phenyl]imidazo[1,2-a]pyrazin-8-ylamino-
}benzoic acid ethyl ester (20) (30 mmol), 1N aqueous sodium
hydroxide (50 mL), and ethanol (80 mL) is heated at reflux for 1.5
hrs. The mixture is cooled and the ethanol removed in vacuo. The
residue is diluted with 1N sodium hydroxide (30 mL) and washed with
ethyl acetate (2.times.100 mL). The aqueous layer is brought to pH
6 with 3 N HCl, and the mixture is filtered to give
4-{6-[3-(4-tert-butyl-benzoylamino)phenyl]imidazo[1,2-a]pyrazin-8-ylamino-
}benzoic acid (21) as a cream solid.
Step 5.
4-tert-Butyl-N-(3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imid-
azo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide (22)
##STR00031##
[0262] A mixture of
4-{6-[3-(4-tert-butyl-benzoylamino)phenyl]imidazo[1,2-a]pyrazin-8-ylamino-
}benzoic acid (21) (0.16 mmol),
benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium
hexafluorophosphate (0.16 mmol), and N'N-diisopropylethylamine
(0.48 mmol) is stirred at room temperature for 20 min. Morpholine
(0.48 mmol) is added and the mixture is stirred at room temperature
or 16 hrs. Water (10 mL) is added and the mixture extracted with
ethyl acetate (2.times.70 mL), the extracts are washed with water
(2.times.30 mL) and brine (1.times.30 mL), dried over magnesium
sulfate, and concentrated in vacuo. The residue is triturated with
diethyl ether to give
4-tert-B\butyl-N-(3-{8-[4-(morpholine-4-carbonyl)-phenylamino]imidazo[1,2-
-a]pyrazin-6-yl}-phenyl)benzamide (22) as a cream solid.
Example 5
Additional Imidazo[1,2-a]Pyrazin-8-Ylamines
[0263] The following compounds are synthesized via the procedure
set forth in Examples 1 to 4. In some instances changes in starting
materials and reaction conditions that will be readily apparent to
those skilled in the art of organic synthesis may be required.
[0264] LC-MS data reported in this example is obtained as
follows:
[0265] LC conditions: RP-HPLC is performed on an AGILENT 1100
Binary HPLC system. The column is a Restek Ultra IBD 5 .mu.m
1.0.times.30 mm (Cat. #: 9175331). The Mobile Phase contains
component A, 0.2% Formic Acid/Water), and component B,
Acetonitrile. The following Gradient is used:
TABLE-US-00001 Flow Rate Time (min.) % B (.mu.l/min) 0 10 500 1.8
60 500 2.0 95 500 2.2 95 500 2.4 10 500
[0266] MS conditions: Electrospray MS is performed on a MICROMASS
LCT equipped with a LockSpray source for accurate mass
measurements. Spectra are acquired in positive ion mode from
100-1000 Da at an acquisition rate of 1 spectrum/0.9 s with a 0.1 s
interscan delay. The instrument is tuned for a resolution of 5000
(FWHM). Every 5.sup.th scan is taken from the reference position of
the Lockspray source. Leucine enkephalin (556.2771 [M+H].sup.+) is
used as the reference, or lock mass.
TABLE-US-00002 TABLE I Cmp. Name and MS # Structure Molecular
Formula MW m/z (M.sup.+ 1) 23 ##STR00032## 4-tert-Butyl-N-[3-(8-
phenylamino- imidazo[1,2-a]pyrazin- benzamide MF =
C.sub.29H.sub.27N.sub.5O 461.22 462.21 24 ##STR00033##
4-Isopropyl-N-[3-(8- phenylamino- imidazo[1,2-a]pyrazin-
6-yl)-phenyl]- benzamide MF = C.sub.28H.sub.25N.sub.5O 447.21
448.21 25 ##STR00034## 4-tert-Butyl-N-{3-[8- (pyridin-3-ylamino)-
imidazo[1,2-a]pyrazin- 6-yl]-phenyl}- benzamide MF =
C.sub.28H.sub.26N.sub.6O 462.21 463.07 26 ##STR00035##
4-tert-Butyl-N-{3-[8- (4-methoxy- phenylamino)-
imidazo[1,2-a]pyrazin- 6-yl]-phenyl}- benzamide MF =
C.sub.30H.sub.29N.sub.5O.sub.2 491.23 492.10 27 ##STR00036##
4-tert-Butyl-N-{3-[8- (pyridin-4-ylamino)- imidazo[1,2-a]pyrazin-
6-yl]-phenyl}- benzamide MF = C.sub.28H.sub.26N.sub.6O 462.22
463.19 28 ##STR00037## 4-tert-Butyl-N-{3-[8- (4-fluoro-
phenylamino)- imidazo[1,2-a]pyrazin- 6-yl]-phenyl}- benzamide MF =
C.sub.29H.sub.26FN.sub.5O 479.21 480.10 29 ##STR00038##
4-tert-Butyl-N-{3-[8- (3-fluoro- phenylamino)-
imidazo[1,2-a]pyrazin- 6-yl]-phenyl}- benzamide MF =
C.sub.29H.sub.26FN.sub.5O 479.21 480.10 30 ##STR00039##
4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-
imidazo[1,2-a]pyrazin- 8-ylamino}-benzoic acid MF =
C.sub.30H.sub.27N.sub.5O.sub.3 505.21 506.08 31 ##STR00040##
4-tert-Butyl-N-{3-[8- (3-methoxy- phenylamino)-
imidazo[1,2-a]pyrazin- 6-yl]-phenyl}- benzamide MF =
C.sub.30H.sub.29N.sub.5O.sub.2 491.23 492.08 32 ##STR00041##
4-tert-Butyl-N-{3-[8- (6-methoxy-pyridin-3- ylamino)-imidazo[1,2-
a]pyrazin-6-yl]- phenyl}-benzamide MF =
C.sub.29H.sub.28N.sub.6O.sub.2 492.22 493.08 33 ##STR00042##
3-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-
imidazo[1,2-a]pyrazin- 8-ylamino}-benzoic acid MF =
C.sub.30H.sub.27N.sub.5O.sub.3 505.21 506.25 34 ##STR00043##
4-(6-[3-(4-Isopropyl- benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-
8-ylamino}-benzoic acid MF = C.sub.29H.sub.25N.sub.5O.sub.3 491.19
492.19 35 ##STR00044## 4-tert-Butyl-N-{3-[8- (4-cyano-phenylamino)-
imidazo[1,2-a]pyrazin- 6-yl]-phenyl}- benzamide MF =
C.sub.30H.sub.26N.sub.6O 486.22 487.28 36 ##STR00045##
4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-
imidazo[1,2-a]pyrazin- 8-ylamino}-benzamide MF =
C.sub.30H.sub.28N.sub.6O.sub.2 504.22 505.21
TABLE-US-00003 TABLE II Cmp. MS # Structure NAME MW m/z (M.sup.+1)
37 ##STR00046## 4-tert-Butyl-N-{3-[8-(4- morpholin-4-yl-
phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide
C33H34N6O2 546.27 547.11 38 ##STR00047## 3-{6-[3-(4-tert-Butyl-
benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8- ylamino}-benzoic
acid C30H27N5O3 505.21 506.25 39 ##STR00048##
4-tert-Butyl-N-{3-[8-(3- fluoro-4-methoxy-
phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide
C30H28FN5O2 509.22 510.26 40 ##STR00049## 4-{6-[3-(4-tert-Butyl-
benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8- ylamino}-benzoic
N-Methyl amide C31H30N6O2 518.24 519.21 41 ##STR00050##
4-tert-Butyl-N-{3-[8-(4- piperazin-1-yl- phenylamino)-imidazo[1,2-
a]pyrazin-6-yl]-phenyl}- benzamide C33H35N7O 545.29 546.19 42
##STR00051## 4-tert-Butyl-N-[3-(8-m- tolylamino-imidazo[1,2-
a]pyrazin-6-yl)-phenyl]- benzamide C30H29N5O 475.23 476.22 43
##STR00052## (4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-
imidazo[1,2-a]pyrazin-8- ylamino}-phenyl)-acetic acid methyl ester
C32H31N5O3 533.24 534.22 44 ##STR00053## (4-{6-[3-(4-tert-Butyl-
benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-
ylamino}-phenyl)-acetic acid C31H29N5O3 519.22 520.22 45
##STR00054## 4-tert-Butyl-N-(3-{8-[4- (piperazine-1-carbonyl)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide
C34H35N7O2 573.28 574.85 46 ##STR00055##
4-tert-Butyl-N-(3-{8-[4-(2- methoxy-ethoxymethoxy)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide
C33H35N5O4 565.26 566.25 47 ##STR00056## 4-tert-Butyl-N-(3-[8-(4-
hydroxy-phenylamino)- imidazo[1,2-a]pyrazin-6-yl]-
phenyl}-benzamide C29H27N5O2 477.22 478.22 48 ##STR00057##
4-tert-Butyl-N-{3-[8-(6- piperazin-1-yl-pyridin-3-
ylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide C32H34N8O
546.28 547.24 49 ##STR00058## 4-tert-Butyl-N-(3-{8-[4-(4-
methyl-piperazin-1-yl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)- benzamide C34H37N7O 559.31 560.26 50
##STR00059## 4-tert-Butyl-N-{3-[8-(4- [1,4]diazepan-1-yl-
phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide
C34H37N7O 559.31 561.17 51 ##STR00060## 4-tert-Butyl-N-(3-{8-[4-(4-
oxo-piperidin-1-yl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)- benzamide C34H34N6O2 558.27 559.22 52
##STR00061## (4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-
imidazo[1,2-a]pyrazin-8- ylamino}-benzoylamino)- acetic acid methyl
ester C33H32N6O4 576.24 577.29 53 ##STR00062##
(4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-
imidazo[1,2-a]pyrazin-8- ylamino}-benzoylamino)- acetic acid
C32H30N6O4 562.23 563.26 54 ##STR00063## N-(3-{8-[4-(4-Acetyl-
piperazin-1-yl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)-4- tert-butyl-benzamide C35H37N7O2 587.3
588.31 55 ##STR00064## 4-tert-Butyl-N-(3-{8-[4-(3-
methyl-piperazin-1-yl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)- benzamide C34H37N7O 559.31 560.35 56
##STR00065## 4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-
imidazo[1,2-a]pyrazin-8- ylamino}-benzoic hydroxyl amide C30H28N6O3
520.22 521.26 57 ##STR00066## 4-tert-Butyl-N-{3-[8-(4-
hydroxymethyl- phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}-
benzamide C30H29N5O2 491.23 492.28 58 ##STR00067##
4-tert-Butyl-N-{3-[8-(4- piperazin-1-ylmethyl-
phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide
C34H37N7O 559.31 560.37 59 ##STR00068## 4-{6-[3-(4-Bromo-3-methyl-
benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8- ylamino}-benzoic
acid C27H20BrN5O3 541.07 542.14 60 ##STR00069##
4-tert-Butyl-N-{3-[8-(3- methyl-4-piperazin-1-yl-
phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide
C34H37N7O 559.31 560.35 61 ##STR00070## 4-tert-Butyl-N-(3-{8-[4-(3-
methyl-piperazin-1-yl)- phenylamino}-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)- benzamide C34H37N7O 559.31 560.26 62
##STR00071## 4-tert-Butyl-N-{3-[8-(3- hydroxymethyl-
phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide
C30H29N5O2 491.23 492.28 63 ##STR00072##
4-tert-Butyl-N-(3-{8-[3-(3- methyl-piperazin-1-
ylmethyl)-phenylamino]- imidazo[1,2-a]pyrazin-6-yl}-
phenyl)-benzamide C35H39N7O 573.32 574.4 64 ##STR00073##
4-tert-Butyl-N-(3-{8-[3-(3- methyl-piperazin-1-
ylmethyl)-phenylamino]- imidazo[1,2-a]pyrazin-6-yl}-
phenyl)-benzamide C35H39N7O 573.32 574.35 65 ##STR00074##
4-tert-Butyl-N-(3-{8-[3-(3,5- dimethyl-piperazin-1-
ylmethyl)-phenylamino]- imidazo[1,2-a]pyrazin-
6-yl}-phenyl)-benzamide C36H41N7O 587.33 588.39 66 ##STR00075##
4-tert-Butyl-N-(3-{8-[4-3,5- dimethyl-piperazin-1-yl)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}- phenyl)-benzamide
C35H39N7O 573.32 574.42 67 ##STR00076## 4-({6-[3-(4-tert-Butyl-
benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-
ylamino}-methyl)-benzoic acid C31H29N5O3 519.22 520.4 68
##STR00077## 4-tert-Butyl-N-(3-{8-[4-(3- methyl-piperazin-1-yl)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide
C34H37N7O 559.3 560.47 69 ##STR00078## 4-(1-Hydroxy-1-methyl-
ethyl)-N-[3-(8-phenylamino- imidazo[1,2-a]pyrazin-6-yl)-
phenyl]-benzamide C28H25N5O2 463.2 464.36 70 ##STR00079##
(3-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-
imidazo[1,2-a]pyrazin-8- ylamino}-phenyl)-acetic acid C31H29N5O3
519.22 520.4 71 ##STR00080## N-[3-(8-Phenylamino-
imidazo[1,2-a]pyrazin-6-yl)- phenyl]-terephthalamic acid methyl
ester C27H21N5O3 463.16 464.32 72 ##STR00081## N-[3-(8-Phenylamino-
imidazo[1,2-a]pyrazin-6-yl)- phenyl]-terephthalamic acid C26H19N5O3
449.14 450.36 73 ##STR00082## 2-(4-{6-[3-(4-tert-Butyl-
benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-
ylamino)-phenyl)-propionic acid ethyl ester C34H35N5O3 561.27
562.45 74 ##STR00083## 2-(4-{6-[3-(4-tert-Butyl-
benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8-
ylamino}-phenyl)-propionic acid C32H31N5O3 533.24 534.43 75
##STR00084## 4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-
imidazo[1,2-a]pyrazin-8- ylamino}-2-methoxy- benzoic acid methyl
ester C32H31N5O4 549.23 550.42 76 ##STR00085##
4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-
imidazo[1,2-a]pyrazin-8- ylamino}-2-methoxy- benzoic acid
C31H29N5O4 535.22 536.42 77 ##STR00086## 4-tert-Butyl-N-{3-[8-(3-
methylcarbamoylmethyl- phenylamino)-imidazo[1,2-
a]pyrazin-6-yl]-phenyl}- benzamide C32H32N6O2 532.26 533.4 78
##STR00087## 4-tert-Butyl-N-{3-[8-(4- methylcarbamoylmethyl-
phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide
C32H32N6O2 532.25 533.41 79 ##STR00088## 4-tert-Butyl-N-{3-[8-(4-
cyclooctylcarbamoylmethyl- phenylamino)-imidazo[1,2-
a]pyrazin-6-yl]-phenyl}- benzamide C39H44N6O2 628.35 629.51 80
##STR00089## 4-tert-Butyl-N-[3-(8-{4- [(diisopropylcarbamoyl)-
methyl]-phenylamino}- imidazo[1,2-a]pyrazin-6-yl)-
phenyl]-benzamide C37H42N6O2 602.34 603.49 81 ##STR00090##
4-tert-Butyl-N-{3-[8-(4- carbamoylmethyl- phenylamino)-imidazo[1,2-
a]pyrazin-6-yl]-phenyl}- benzamide C31H30N6O2 518.24 519.48 82
##STR00091## 3-(4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-
imidazo[1,2-a]pyrazin-8- ylamino}-phenyl)-propionic acid C32H31N5O3
533.24 534.22 83 ##STR00092## 4-tert-Butyl-N-(3-{8-[4-(2-
hydroxy-ethyl)- phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)-
benzamide C31H31N5O2 505.25 506.4 84 ##STR00093##
4-tert-Butyl-N-(3-{8-[4-(2- methylamino-ethyl)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide
C32H34N6O 518.3 519.45 85 ##STR00094## 4-tert-Butyl-N-{3-[8-(4-
methylaminomethyl- phenylamino)-imidazo[1,2-
a]pyrazin-6-yl]-phenyl}- benzamide C31H32N6O 504.26 505.43 86
##STR00095## 4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-
imidazo[1,2-a]pyrazin-8- ylamino}-2-hydroxy-benzoic acid C30H27N5O4
521.2 522.31 87 ##STR00096## 4-tert-Butyl-N-(3-{8-[4-(1-
hydroxy-1-methyl-ethyl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)- benzamide C32H33N5O2 519.26 520.27 88
##STR00097## 4-tert-Butyl-N-(3-{8-[4-(2- hydroxy-ethoxy)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide
C31H31N5O3 521.24 522.25 89 ##STR00098##
4-tert-Butyl-N-(3-{8-[4-(4- methyl-piperazine-1-
carbonyl)-phenylamino]- imidazo[1,2-a]pyrazin-6-yl}-
phenyl)-benzamide C35H37N7O2 587.3 588.28 90 ##STR00099##
4-tert-Butyl-N-(3-{8-[4-(2- methylamino-ethoxy)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide
C32H34N6O2 534.27 535.27 91 ##STR00100##
4-tert-Butyl-N-(3-{8-[4-(2- dimethylamino-ethoxy)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide
C33H36N6O2 548.28 549.28 92 ##STR00101## 4-{6-[3-(4-tert-Butyl-
benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8- ylamino}-benzoic
methoxy amide C31H30N6O3 534.23 535.25 93 ##STR00102##
4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-
imidazo[1,2-a]pyrazin-8- ylamino}-benzoic hyrdoxyl methyl amide
C31H30N6O3 534.23 535.25 94 ##STR00103## 4-tert-Butyl-N-(3-{8-[4-
([1,4]diazepane-1-carbonyl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)- benzamide C35H37N7O2 587.3 588.27 95
##STR00104## 4-tert-Butyl-N-(3-{8-[4- (pyrrolidine-1-carbonyl)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide
C34H34N6O2 558.27 559.25 96 ##STR00105## 4-tert-Butyl-N-(3-{8-[4-
(morpholine-4-carbonyl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)- benzamide C34H34N6O3 574.26 575.24 97
##STR00106## 4-tert-Butyl-N-(3-{8-[4- (ethoxyamine-4-carbonyl)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide
C33H34N6O3 548.25 549.22 98 ##STR00107## 4-tert-Butyl-N-(3-{8-[4-
(dimethylamine-4-carbonyl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)- benzamide C32H32N6O2 532.25 533.22 99
##STR00108## 4-tert-Butyl-N-(3-{8-[4- (methylethylamine-4-
carbonyl)-phenylamino]- imidazo[1,2-a]pyrazin-6-yl}-
phenyl)-benzamide C33H34N6O2 546.27 547.24
100 ##STR00109## 4-tert-Butyl-N-(3-{8-[4-(3-
oxo-piperazine-1-carbonyl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)- benzamide C34H33N7O3 587.26 588.28 101
##STR00110## 4-tert-Butyl-N-(3-{8- [N,N,N'-Trimethyl-ethane-
1,2-diamine-4-carbonyl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)- benzamide C35H39N7O2 589.31 590.35 102
##STR00111## 4-tert-Butyl-N-(3-{8-[4-(4- methyl-[1,4]diazepane-1-
carbonyl)-phenylamino]- imidazo[1,2-a]pyrazin-6-yl}-
phenyl)-benzamide C36H39N7O2 601.31 602.32 103 ##STR00112##
4-tert-Butyl-N-(3-{8-[4-(N- methyl ethoxyamine-4-
carbonyl)-phenylamino]- imidazo[1,2-a]pyrazin-6-yl}-
phenyl)-benzamide C33H34N6O3 562.26 563.29 104 ##STR00113##
4-tert-Butyl-N-(3-{8-[4-(4- ethyl-piperazine-1-
carbonyl)-phenylamino]- imidazo[1,2-a]pyrazin-6-yl}-
phenyl)-benzamide C36H39N7O2 601.31 602.38 105 ##STR00114##
4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-
imidazo[1,2-a]pyrazin-8- ylamino}-benzoic benzyl amide C37H34N6O2
595.26 596.32 106 ##STR00115## 4-tert-Butyl-N-(3-{8-[4-(4-
methyl-piperazin-1- ylmethyl)-phenylamino]-
imidazo[1,2-a]pyrazin-6-yl}- phenyl)-benzamide C35H39N7O 573.32
574.39 107 ##STR00116## 4-tert-Butyl-N-(3-{8-[4-(4-
ethyl-piperazin-1-ylmethyl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)- benzamide C36H41N7O 587.33 588.42 108
##STR00117## 4-tert-Butyl-N-{3-[8-(4- [1,4]diazepan-1-ylmethyl-
phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide
C35H39N7O 573.32 574.39 109 ##STR00118##
4-tert-Butyl-N-(3-{8-[4-(3- methyl-piperazin-1-
ylmethyl)-phenylamino]- imidazo[1,2-a]pyrazin-6-yl}-
phenyl)-benzamide C35H39N7O 573.32 574.38 110 ##STR00119##
4-tert-Butyl-N-{3-[8-(4- dimethylaminomethyl-
phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide
C32H34N6O 518.27 519.33 111 ##STR00120## 4-tert-Butyl-N-[3-(8-{4-
[(ethyl-methyl-amino)- methyl]-phenylamino}-
imidazo[1,2-a]pyrazin-6-yl)- phenyl]-benzamide C33H36N6O 532.29
533.33 112 ##STR00121## 4-tert-Butyl-N-{3-[8-(4-
{[(2-methoxy-ethyl)-methyl- amino]-methyl}-
phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide
C34H38N6O2 562.31 563.33 113 ##STR00122##
4-tert-Butyl-N-[3-(8-{4-[(2- methoxy-ethylamino)-
methyl]-phenylamino}- imidazo[1,2-a]pyrazin-6-yl)-
phenyl]-benzamide C33H36N6O2 548.28 549.32 114 ##STR00123##
4-tert-Butyl-N-{3-[8-(4- {[(2-dimethylamino-ethyl)-
methyl-amino]-methyl}- phenylamino)-imidazo[1,2-
a]pyrazin-6-yl]-phenyl}- benzamide C35H41N7O 575.33 576.39 115
##STR00124## N-(3-{8-[4-(4-Acetyl- piperazine-1-carbonyl)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)-4-
tert-butyl-benzamide C36H37N7O3 615.29 616.31 116 ##STR00125##
4-tert-Butyl-N-{3-[8-(4- {[(2-hydroxy-ethyl)-methyl-
amino]-methyl}- phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}-
benzamide C33H36N6O2 548.28 549.32 117 ##STR00126##
4-tert-Butyl-N-[3-(8-{4-[(2- hydroxy-ethylamino)-
methyl]-phenylamino}- imidazo[1,2-a]pyrazin-6-yl)-
phenyl]-benzamide C32H34N6O2 534.27 535.32 118 ##STR00127##
4-tert-Butyl-N-(3-{8-[4-(4- methyl-[1,4]diazepan-1-
ylmethyl)-phenylamino]- imidazo[1,2-a]pyrazin-6-yl}-
phenyl)-benzamide C36H41N7O 587.33 588.37 119 ##STR00128##
N-[3-(8-{4-[2-(Acetyl- methyl-amino)-ethoxy]-
phenylamino}-imidazo[1,2- a]pyrazin-6-yl)-phenyl]-4-
tert-butyl-benzamide C34H36N6O3 576.28 577.32 120 ##STR00129##
4-(4-{6-[3-(4-tert-Butyl- benzoylamino)-phenyl]-
imidazo[1,2-a]pyrazin-8- ylamino}-phenyl)- piperazine-1-carboxylic
acid ethyl ester C36H39N7O3 617.31 618.31 121 ##STR00130##
N-(3-{8-[4-(4-Acetyl- piperazin-1-ylmethyl)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl)-phenyl)-4-
tert-butyl-benzamide C36H39N7O2 601.31 602.26 122 ##STR00131##
4-tert-Butyl-N-{3-[8-(4- imidazol-1-ylmethyl-
phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide
C33H31N7O 541.25 542.27 123 ##STR00132## 4-tert-Butyl-N-{3-[8-(4-
pyrrolidin-1-ylmethyl- phenylamino)-imidazo[1,2-
a]pyrazin-6-yl]-phenyl}- benzamide C34H36N6O 544.29 545.3 124
##STR00133## N-[3-(8-{4-[(Acetyl-methyl- amino)-methyl]-
phenylamino}-imidazo[1,2- a]pyrazin-6-yl)-phenyl]-4-
tert-butyl-benzamide C33H34N6O2 546.27 547.33 125 ##STR00134##
4-tert-Butyl-N-[3-(8-{4- [(methanesulfonyl-methyl- amino)-methyl]-
phenylamino}-imidazo[1,2- a]pyrazin-6-yl)-phenyl]- benzamide
C32H34N6O3S 582.24 583.27 126 ##STR00135##
4-tert-Butyl-N-(3-{8-[4-(3- isopropyl-1-methyl- ureidomethyl)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide
C35H39N7O2 589.31 590.35 127 ##STR00136## 4-Isopropyl-N-(3-{8-[4-
(morpholine-4-carbonyl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)- benzamide C33H32N6O3 560.25 561.28 128
##STR00137## N-{3-[8-(4-{[(2-Hydroxy- ethyl)-methyl-amino]-
carbonyl}-phenylamino)- imidazo[1,2-a]pyrazin-6-yl]-
phenyl}-4-isopropyl- benzamide C32H32N6O3 548.25 549.25 129
##STR00138## N-(3-{8-[4-(Morpholine-4- carbonyl)-phenylamino]-
imidazo[1,2-a]pyrazin-6-yl}- phenyl)-benzamide C30H26N6O3 518.2
519.22 130 ##STR00139## 4-Methyl-N-(3-{8-[4-
(morpholine-4-carbonyl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)- benzamide C31H28N6O3 532.22 533.17 131
##STR00140## 4-Ethyl-N-(3-{8-[4- (morpholine-4-carbonyl)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide
C32H30N6O3 546.23 547.17 132 ##STR00141## 4-Fluoro-N-(3-{8-[4-
(morpholine-4-carbonyl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)- benzamide C30H25FN6O3 536.19 537.21 133
##STR00142## N-(3-{8-[4-(Morpholine-4- carbonyl)-phenylamino]-
imidazo[1,2-a]pyrazin-6-yl}- phenyl)-4-trifluoromethyl- benzamide
C31H25F3N6O3 586.19 587.2 134 ##STR00143##
4-tert-Butyl-N-(3-{8-[4-(5,6- dihydro-8H-imidazo[1,2-
a]pyrazine-7-carbonyl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)- benzamide C36H34N8O2 610.28 611.21 135
##STR00144## 4-tert-Butyl-N-(3-{8-[4-(3- oxo-piperazin-1-ylmethyl)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide
C34H35N7O2 573.28 574.18 136 ##STR00145## 1-(4-{6-[3-(4-tert-Butyl-
benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8- ylamino}-benzyl)-
pyrrolidine-2-carboxylic acid methyl ester C36H38N6O3 602.3 603.39
137 ##STR00146## N-(3-{8-[4-(Morpholine-4- carbonyl)-phenylamino]-
imidazo[1,2-a]pyrazin-6-yl}- phenyl)-terephthalamic acid methyl
ester C32H28N6O5 576.21 577.36 138 ##STR00147##
N-(3-{8-[4-(Morpholine-4- carbonyl)-phenylamino]-
imidazo[1,2-a]pyrazin-6-yl}- phenyl)-terephthalamic acid C31H26N6O5
562.19 563.33 139 ##STR00148## N-(3-{8-[4-(4-Acetyl-
piperazin-1-yl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)-4- ethyl-benzamide C33H33N7O2 559.26 560.25
140 ##STR00149## N-(3-{8-[4-(4-Acetyl- piperazin-1-yl)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)-4-
trifluoromethyl-benzamide C32H28F3N7O2 599.22 600.22 141
##STR00150## 4-tert-Butyl-N-(3-{8-[4-(3- methyl-5,6-dihydro-8H-
[1,2,4]triazolo[4,3-a]pyrazin- 7-ylmethyl)-phenylamino]-
imidazo[1,2-a]pyrazin-6-yl}- phenyl)-benzamide C36H37N9O 611.31
612.41 142 ##STR00151## 4-tert-Butyl-N-(3-{8-{4-(3-
methyl-5,6-dihydro-8H- [1,2,4]triazolo[4,3- a]pyrazine-7-carbonyl)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide
C36H35N9O2 625.29 626.4 143 ##STR00152## N-(3-{8-[4-(4-Acetyl-
piperazin-1-yl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)-4- isopropyl-benzamide C34H35N7O2 573.28
574.38 144 ##STR00153## N-(3-{8-[4-(4-Acetyl-
piperazine-1-carbonyl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)-4- isopropyl-benzamide C35H35N7O3 601.28
602.27 145 ##STR00154## 1-(4-{6-[3-(4-tert-Butyl-
benzoylamino)-phenyl]- imidazo[1,2-a]pyrazin-8- ylamino}-benzyl)-
pyrrolidine-2-carboxylic acid C35H36N6O3 588.28 589.25 146
##STR00155## 4-Isopropyl-N-(3-{8-[4-(3- methyl-5,6-dihydro-8H-
[1,2,4]triazolo[4,3- a]pyrazine-7-carbonyl)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide
C35H33N9O2 611.27 612.26 147 ##STR00156## N-(3-{8-[4-(5,6-Dihydro-
8H-imidazo[1,2-a]pyrazine- 7-carbonyl)-phenylamino]-
imidazo[1,2-a]pyrazin-6-yl}- phenyl)-4-isopropyl- benzamide
C35H32N8O2 596.26 597.26 148 ##STR00157##
4-Isopropyl-N-(3-{8-[4-(3- oxo-piperazine-1-carbonyl)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide
C33H31N7O3 573.24 574.27 149 ##STR00158##
4-Isopropyl-N-(3-{8-[4-(4- methyl-piperazine-1-
carbonyl)-phenylamino]- imidazo[1,2-a]pyrazin-6-yl}-
phenyl)-benzamide C34H35N7O2 573.28 574.29 150 ##STR00159##
4-Isopropyl-N-(3-{8-[4-(3- oxo-piperazin-1-ylmethyl)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide
C33H33N7O2 559.26 560.29 151 ##STR00160## N-(3-{8-[4-(4-Acetyl-
piperazin-1-ylmethyl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)-4- isopropyl-benzamide C35H37N7O2 587.3
588.31 152 ##STR00161## N-(3-{8-[4-(Morpholine-4-
carbonyl)-phenylamino]- imidazo[1,2-a]pyrazin-6-yl}-
phenyl)-isonicotinamide C29H25N7O3 519.2 520.2 153 ##STR00162##
N-(3-{8-[4-(Morpholine-4- carbonyl)-phenylamino]-
imidazo[1,2-a]pyrazin-6-yl}- phenyl)-nicotinamide C29H25N7O3 519.2
520.19 154 ##STR00163## 4-tert-Butyl-N-(3-{8-[4-(2-
morpholin-4-yl-2-oxo- ethyl)-phenylamino]-
imidazo[1,2-a]pyrazin-6-yl}- phenyl)-benzamide C35H36N6O3 588.28
589.28 155 ##STR00164## 4-tert-Butyl-N-(3-{8-[3-(2-
morpholin-4-yl-2-oxo- ethyl)-phenylamino]-
imidazo[1,2-a]pyrazin-6-yl}- phenyl)-benzamide C35H36N6O3 588.28
589.29 156 ##STR00165## 4-Isopropyl-N-{3-[8-(4-
morpholin-4-ylmethyl- phenylamino)-imidazo[1,2-
a]pyrazin-6-yl]-phenyl}- benzamide C33H34N6O2 546.27 547.28 157
##STR00166## 4-tert-Butyl-N-{3-[8-(4- morpholin-4-ylmethyl-
phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamide
C34H36N6O2 560.28 561.43 158 ##STR00167## N-(3-{8-[4-(Morpholine-4-
carbonyl)-phenylamino]- imidazo[1,2-a]pyrazin-6-yl}-
phenyl)-2-phenyl-acetamide C31H28N6O3 532.22 533.21 159
##STR00168## N-(4-tert-Butyl-phenyl)-3- {8-[4-(morpholine-4-
carbonyl)-phenylamino]- imidazo[1,2-a]pyrazin-6-yl}- benzamide
C34H34N6O3 574.27 575.23 160 ##STR00169## N-(3-Chloro-benzyl)-3-{8-
[4-(morpholine-4-carbonyl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-benzamide C31H27ClN6O3 566.18 567.17 161
##STR00170## 4-Cyano-N-(3-{8-[4- (morpholine-4-carbonyl)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide
C31H25N7O3 543.2 544.32 162 ##STR00171## 6-Dimethylamino-N-(3-{8-
[4-(morpholine-4-carbonyl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)- nicotinamide C31H30N8O3 562.24 563.26
163 ##STR00172## N-Methyl-N'-(3-{8-[4- (morpholine-4-carbonyl)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- terephthalamide
C32H29N7O4 575.22 576.25 164 ##STR00173## N,N-Dimethyl-N'-(3-{8-[4-
(morpholine-4-carbonyl)- phenylamino]-imidazo[1,2-
a]pyrazin-6-yl}-phenyl)- terephthalamide C33H31N7O4 589.24 590.26
165 ##STR00174## 4-Acetyl-N-(3-{8-[4- (morpholine-4-carbonyl)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide
C32H28N6O4 560.21 561.25 166 ##STR00175##
4-(1H-Imidazol-2-yl)-N-(3- {8-[4-(morpholine-4-
carbonyl)-phenylamino]- imidazo[1,2-a]pyrazin-6-yl}-
phenyl)-benzamide C33H28N8O3 584.22 585.31 167 ##STR00176##
2-(3-Isopropyl-phenoxy)-N- (3-{8-[4-(morpholine-4-
carbonyl)-phenylamino]- imidazo[1,2-a]pyrazin-6-yl}-
phenyl)-acetamide C34H34N6O4 590.26 591.32 168 ##STR00177##
6-tert-Butyl-N-(3-{8-[4- (morpholine-4-carbonyl)-
phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- nicotinamide
C33H33N7O3 575.26 576.24 169 ##STR00178## 4-(6-{3-[(6-tert-Butyl-
pyridine-3-carbonyl)- amino]-phenyl}- imidazo[1,2a]
pyrazin-8-ylamino)-benzoic acid C29H26N6O3 506.2 507.21
[0267] The compounds disclosed in synthetic Examples 1 to 5 were
tested in the Btk biochemical assay described in Example 6 and
found to exhibit an IC.sub.50 value less than or equal to 1
micromolar certain of these compounds were found to exhibit an
IC.sub.50 value less than or equal to 100 nM, and certain of these
compounds exhibited an IC.sub.50 value less than or equal to 10 nM.
Some of the compounds disclosed in synthetic Examples 1 to 5 were
tested in the B-cell proliferation assay of Example 8 and
determined to exhibit an IC.sub.50 value less than or equal to 10
micromolar, certain of these compounds exhibited an IC.sub.50 value
less than or equal to 1 micromolar, and certain of these compounds
exhibited an IC.sub.50 value less than or equal to 500 nM in this
assay. Certain of these compounds do not inhibit T-cell
proliferation and have IC.sub.50 values greater than or equal to 5
micromolar when assayed under conditions described in Example 9.
The compounds assayed in the Example 8 and Example 9 exhibited
IC.sub.50 values for inhibition of T-cell proliferation that were
at least 3-fold, and in some instances 5-fold, or even 10-fold
greater than the IC.sub.50 values of these compounds for inhibition
of B-cell proliferation.
Example 6
Biochemical Btk Assay
[0268] A generalized procedure for one standard biochemical Btk
Kinase Assay used to test compounds disclosed in this application
is as follows.
[0269] A master mix minus Btk enzyme is prepared containing
1.times. Cell Signaling kinase buffer (25 mM Tris-HCl, pH 7.5, 5 mM
.beta.-glycerophosphate, 2 mM dithiothreitol, 0.1 mM
Na.sub.3VO.sub.4, 10 mM MgCl.sub.2), 0.5 .mu.M Promega PTK
Biotinylated peptide substrate 2, and 0.01% BSA. A master mix plus
Btk enzyme is prepared containing 1.times. Cell Signaling kinase
buffer, 0.5 .mu.M PTK Biotinylated peptide substrate 2, 0.01% BSA,
and 100 ng/well (0.06 mU/well) Btk enzyme. Btk enzyme is prepared
as follows: full length human wildtype Btk (accession number
NM-000061) with a C-terminal V5 and 6.times.His tag was subcloned
into pFastBac vector for making baculovirus carrying this
epitope-tagged Btk. Generation of baculovirus was done based on
Invitrogen's instructions detailed in its published protocol
"Bac-toBac Baculovirus Expression Systems" (Cat. Nos. 10359-016 and
10608-016). Passage 3 virus was used to infect Sf9 cells to
overexpress the recombinant Btk protein. The Btk protein was then
purified to homogeneity using Ni-NTA column. The purity of the
final protein preparation was greater than 95% based on the
sensitive Sypro-Ruby staining. A solution of 200 .mu.M ATP is
prepared in water and adjusted to pH7.4 with 1N NaOH. A quantity of
1.25 .mu.L of compounds in 5% DMSO is transferred to a 96-well 1/2
area Costar polystyrene plate. Compounds are tested singly and with
an 11-point dose-responsive curve (starting concentration is 10
.mu.M; 1:2 dilution). A quantity of 18.75 .mu.L of master mix minus
enzyme (as a negative control) and master mix plus enzyme is
transferred to appropriate wells in 96-well 1/2 area costar
polystyrene plate. 5 .mu.L of 200 .mu.M ATP is added to that
mixture in the 96-well 1/2 area Costar polystyrene plate for final
ATP concentration of 40 .mu.M. The reaction is allowed to incubate
for 1 hour at room temperature. The reaction is stopped with Perkin
Elmer 1.times. detection buffer containing 30 mM EDTA, 20 nM
SA-APC, and 1 nM PT66 Ab. The plate is read using time-resolved
fluorescence with a Perkin Elmer Envision using excitation filter
330 nm, emission filter 665 nm, and 2.sup.nd emission filter 615
nm. IC.sub.50 values are subsequently calculated.
Example 7
Ramos Cell Btk Assay
[0270] Another generalized procedure for a standard cellular Btk
Kinase Assay used to test compounds disclosed in this application
is as follows.
[0271] Ramos cells are incubated at a density of 0.5.times.10.sup.7
cells/ml in the presence of test compound for 1 hr at 37.degree. C.
Cells are then stimulated by incubating with 10 .mu.g/ml anti-human
IgM F(ab).sub.2 for 5 minutes at 37.degree. C. Cells are pelleted,
lysed, and a protein assay is performed on the cleared lysate.
Equal protein amounts of each sample are subject to SDS-PAGE and
western blotting with either anti-phosphoBtk(Tyr223) antibody (Cell
Signaling Technology #3531) to assess Btk autophosphorylation or an
anti-Btk antibody (BD Transduction Labs #611116) to control for
total amounts of Btk in each lysate.
Example 8
B-Cell Proliferation Assay
[0272] B-cells are purified from spleens of 8-16 week old Balb/c
mice using a B-cell isolation kit (Miltenyi Biotech, Cat #
130-090-862). Testing compounds are diluted in 0.25% DMSO and
incubated with 2.5.times.10.sup.5 purified mouse splenic B-cells
for 30 min prior to addition of 10 .mu.g/ml of an anti-mouse IgM
antibody (Southern Biotechnology Associates Cat # 1022-01) in a
final volume of 100 .mu.l. Following 24 hr incubation, 1
.mu.Ci.sup.3H-thymidine is added and plates are incubated an
additional 36 hr prior to harvest using the manufacturer's protocol
for SPA[.sup.3H] thymidine uptake assay system (Amersham
Biosciences # RPNQ 0130). SPA-bead based fluorescence is counted in
a microbeta counter (Wallace Triplex 1450, Perkin Elmer).
Example 9
T Cell Proliferation Assay
[0273] T cells are purified from spleens of 8-16 week old Balb/c
mice using a Pan T cell isolation kit (Miltenyi Biotech, Cat #
130-090-861). Testing compounds are diluted in 0.25% DMSO and
incubated with 2.5.times.10.sup.5 purified mouse splenic T cells in
a final volume of 100 .mu.l in flat clear bottom plates precoated
for 90 min at 37.degree. C. with 10 .mu.g/ml each of anti-CD3 (BD #
553057) and anti-CD28 (BD # 553294) antibodies. Following 24 hr
incubation, 1 .mu.Ci .sup.3H-thymidine is added and plates
incubated an additional 36 hr prior to harvest using the
manufacturer's protocol for SPA[.sup.3H] thymidine uptake assay
system (Amersham Biosciences # RPNQ 0130). SPA-bead based
fluorescence was counted in a microbeta counter (Wallace Triplex
1450, Perkin Elmer).
* * * * *