U.S. patent application number 10/425310 was filed with the patent office on 2004-02-05 for imidazo-triazines as corticotropin releasing factor antagonists.
Invention is credited to Frietze, William Eric, Gilligan, Paul Joseph, Olson, Richard Eric.
Application Number | 20040023965 10/425310 |
Document ID | / |
Family ID | 22228194 |
Filed Date | 2004-02-05 |
United States Patent
Application |
20040023965 |
Kind Code |
A1 |
Gilligan, Paul Joseph ; et
al. |
February 5, 2004 |
Imidazo-triazines as corticotropin releasing factor antagonists
Abstract
The present invention describes novel imidazo-triazines of
formula I: 1 wherein A and B are N and D is aryl or heteroaryl or
pharmaceutically acceptable salt forms thereof, which are useful as
CRF antagonists.
Inventors: |
Gilligan, Paul Joseph;
(Wilmington, DE) ; Olson, Richard Eric;
(Wilmington, DE) ; Frietze, William Eric; (Kennett
Square, PA) |
Correspondence
Address: |
STEPHEN B. DAVIS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
22228194 |
Appl. No.: |
10/425310 |
Filed: |
April 29, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10425310 |
Apr 29, 2003 |
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10073800 |
Feb 11, 2002 |
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6579876 |
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10073800 |
Feb 11, 2002 |
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09625291 |
Jul 25, 2000 |
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10073800 |
Feb 11, 2002 |
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09624686 |
Jul 25, 2000 |
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6521636 |
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09624686 |
Jul 25, 2000 |
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09344257 |
Jun 25, 1999 |
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6365589 |
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60091515 |
Jul 2, 1998 |
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Current U.S.
Class: |
514/243 ;
514/234.5; 544/112; 544/184 |
Current CPC
Class: |
C07D 487/04 20130101;
C07D 471/04 20130101 |
Class at
Publication: |
514/243 ;
544/184; 514/234.5; 544/112 |
International
Class: |
A61K 031/5377; A61K
031/53; C07D 487/02 |
Claims
What is claimed as new and desired to be secured by Letter Patent
of United States is:
1. A compound of formula (I) 24or a stereoisomer or
pharmaceutically acceptable salt form thereof, wherein: A is N; B
is N; D is an aryl or heteroaryl group attached through an
unsaturated carbon atom; X is selected from the group CH--R.sup.9,
N--R.sup.10, O, S(O).sub.n and a bond; n is 0, 1 or 2; R.sup.1 is
selected from the group C.sub.1-10 alkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl,
--SO.sub.2--C.sub.1-10 alkyl, --SO.sub.2--R.sup.1a, and
--SO.sub.2--R.sup.1b; R.sup.1 is substituted with 0-1 substituents
selected from the group --CN, --S(O).sub.nR.sup.14b, --COR.sup.13a,
--CO.sub.2R.sup.13a, NR.sup.15aCOR.sup.13a, --N(COR.sup.13a).sub.2,
--NR.sup.15aCONR.sup.13aR.sup.16a, NR.sup.15aCO.sub.2R.sup.14b,
--CONR.sup.13aR.sup.16a, 1-morpholinyl, 1-piperidinyl,
1-piperazinyl, and C.sub.3-8 cycloalkyl, wherein 0-1 carbon atoms
in the C.sub.4-8 cycloalkyl is replaced by a group selected from
the group --O--, --S(O).sub.n--, --NR.sup.13a--,
--NC.sub.2R.sup.14b--, --NCOR.sup.14b--, and --NSO.sub.2R.sup.14b
and wherein N.sub.4 in 1-piperazinyl is substituted with 0-1
substituents selected from the group R.sup.13a, CO.sub.2R.sup.14b,
COR.sup.14b and SO.sub.2R.sup.14b; R.sup.1 is also substituted with
0-3 substituents independently selected at each occurrence from the
group R.sup.1a, R.sup.1b, R.sup.1c, C.sub.1-6 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, Br, Cl, F, I, C.sub.1-4 haloalkyl,
--OR.sup.13a, --NR.sup.13aR.sup.16a, C.sub.1-4 alkoxy-C.sub.1-4
alkyl, and C.sub.3-8 cycloalkyl which is substituted with 0-1
R.sup.9 and in which 0-1 carbons of C.sub.4-8 cycloalkyl is
replaced by --O--; provided that R.sup.1 is other than a
cyclohexyl-(CH.sub.2).sub.2-- group; R.sup.1a is aryl and is
selected from the group phenyl, naphthyl, indanyl and indenyl, each
R.sup.1a being substituted with 0-1 --OR.sup.17 and 0-5
substituents independently selected at each occurrence from the
group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, I,
C.sub.1-4 haloalkyl, --CN, nitro, SH, --S(O).sub.nR.sup.18,
--COR.sup.17, --OC(O)R.sup.18, NR.sup.15aCOR.sup.17,
--N(COR.sup.17).sub.2, NR.sup.15aCONR.sup.17aR.sup.- 19a,
NR.sup.15aCO.sub.2R.sup.18, --NR.sup.17aR.sup.19a, and
--CONR.sup.17aR.sup.19a; R.sup.1b is heteroaryl and is selected
from the group pyridyl, pyrimidinyl, triazinyl, furanyl,
quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl,
pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,
benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl,
indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
2,3-dihydrobenzothienyl- -S-oxide,
2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl,
benzodioxolanyl and benzodioxane, each heteroaryl being substituted
on 0-4 carbon atoms with a substituent independently selected at
each occurrence from the group C.sub.1-6 alkyl, C.sub.3-6
cycloalkyl, Br, Cl, F, I, C.sub.1-4 haloalkyl, --CN, nitro,
--OR.sup.17, SH, --S(O).sub.mR.sup.18, --COR.sup.17,
--OC(O)R.sup.18, --NR.sup.15aCOR.sup.17, --N(COR.sup.17).sub.2,
--NR.sup.15aCONR.sup.17aR.- sup.19a, NR.sup.15aCO.sub.2R.sup.18,
--NR.sup.17aR.sup.19a, and --CONR.sup.17aR.sup.19a and each
heteroaryl being substituted on any nitrogen atom with 0-1
substituents selected from the group R.sup.15a, CO.sub.2R.sup.14b,
COR.sup.14b and SO.sub.2R.sup.14b; R.sup.1c is heterocyclyl and is
a saturated or partially saturated heteroaryl, each heterocyclyl
being substituted on 0-4 carbon atoms with a substituent
independently selected at each occurrence from the group C.sub.1-6
alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, I, C.sub.1-4 haloalkyl,
--CN, nitro, --OR.sup.13a, SH, --S(O).sub.nR.sup.14b,
--COR.sup.13a, OC(O)R.sup.14b, NR.sup.15aCOR.sup.13a,
--N(COR.sup.13a).sub.2, --NR.sup.15aCONR.sup.13aR.- sup.16a,
NR.sup.15aCO.sub.2R.sup.14b, NR.sup.13aR.sup.16a, and
--CONR.sup.13aR.sup.16a and each heterocyclyl being substituted on
any nitrogen atom with 0-1 substituents selected from the group
R.sup.13a, CO.sub.2R.sup.14b, COR.sup.14b and SO.sub.2R.sup.14b and
wherein any sulfur atom is optionally monooxidized or dioxidized;
provided that R.sup.1 is other than a --(CH.sub.2).sub.1-4-aryl,
--(CH.sub.2).sub.1-4-heteroaryl, or
--(CH.sub.2).sub.1-4-heterocycle, wherein the aryl, heteroaryl, or
heterocycle group is substituted or unsubstituted; R.sup.2 is
selected from the group C.sub.1-4 alkyl, C.sub.3-8 cycloalkyl,
C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl and is substituted with
0-3 substituents selected from the group --CN, hydroxy, halo and
C.sub.1-4 alkoxy; alternatively R.sup.2, in the case where X is a
bond, is selected from the group --CN, CF.sub.3 and C.sub.2F.sub.5;
R.sup.9 and R.sup.10 are independently selected at each occurrence
from the group H, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl-C.sub.1-14
alkyl and C.sub.3-8 cycloalkyl; R.sup.13 is selected from the group
H, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy-C.sub.1-4
alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl,
aryl, aryl(C.sub.1-4 alkyl)-, heteroaryl and heteroaryl (C.sub.1-4
alkyl)-; R.sup.13a and R.sup.16a are independently selected at each
occurrence from the group H, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, and
C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl; R.sup.14 is selected from the
group C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4
alkoxy-C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl, aryl, aryl(C.sub.1-4 alkyl)-,
heteroaryl and heteroaryl(C.sub.1-4 alkyl)- and benzyl, each benzyl
being substituted on the aryl moiety with 0-1 substituents selected
from the group C.sub.1-4 alkyl, Br, Cl, F, I, C.sub.1-4 haloalkyl,
nitro, C.sub.1-4 alkoxy C.sub.1-4 haloalkoxy, and dimethylamino;
R.sup.14a is selected from the group C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl,
C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl and benzyl, each benzyl being
substituted on the aryl moiety with 0-1 substituents selected from
the group C.sub.1-4 alkyl, Br, Cl, F, I, C.sub.1-4 haloalkyl,
nitro, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, and dimethylamino;
R.sup.14b is selected from the group C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl,
and C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl; R.sup.15 is independently
selected at each occurrence from the group H, C.sub.1-4 alkyl,
C.sub.3-7 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, phenyl
and benzyl, each phenyl or benzyl being substituted on the aryl
moiety with 0-3 groups chosen from the group C.sub.1-4 alkyl, Br,
Cl, F, I, C.sub.1-4 haloalkyl, nitro, C.sub.1-4 alkoxy, C.sub.1-4
haloalkoxy, and dimethylamino; R.sup.15a is independently selected
at each occurrence from the group H, C.sub.1-4 alkyl, C.sub.3-7
cycloalkyl, and C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl; R.sup.17 is
selected at each occurrence from the group H, C.sub.1-6 alkyl,
C.sub.3-10 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl,
C.sub.1-2 alkoxy-C.sub.1-2 alkyl, C.sub.1-4 haloalkyl,
R.sup.14S(O).sub.n--C.sub.1-4 alkyl, and
R.sup.17bR.sup.19bN--C.sub.2-4 alkyl; R.sup.18 and R.sup.19 are
independently selected at each occurrence from the group H,
C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl, C.sub.1-2 alkoxy-C.sub.1-2 alkyl, and
C.sub.1-4 haloalkyl; alternatively, in an NR.sup.17R.sup.19 moiety,
R.sup.17 and R.sup.19 taken together form 1-pyrrolidinyl,
1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N.sub.4 in
1-piperazinyl is substituted with 0-1 substituents selected from
the group R.sup.13, CO.sub.2R.sup.14, COR.sup.14 and
SO.sub.2R.sup.14; alternatively, in an NR.sup.17bR.sup.19b moiety,
R.sup.17b and R.sup.19b taken together form 1-pyrrolidinyl,
1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N.sub.4 in
1-piperazinyl is substituted with 0-1 substituents selected from
the group R.sup.13, CO.sub.2R.sup.14, COR.sup.14 and
SO.sub.2R.sup.14; R.sup.17a and R.sup.19a are independently
selected at each occurrence from the group H, C.sub.1-6 alkyl,
C.sub.3-10 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl and
C.sub.1-4 haloalkyl; aryl is independently selected at each
occurrence from the group phenyl, naphthyl, indanyl and indenyl,
each aryl being substituted with 0-5 substituents independently
selected at each occurrence from the group C.sub.1-6 alkyl,
C.sub.3-6 cycloalkyl, methylenedioxy, C.sub.1-4 alkoxy-C.sub.1-4
alkoxy, --OR.sup.17, Br, Cl, F, I, C.sub.1-4 haloalkyl, --CN,
--NO.sub.2, SH, --S(O).sub.nR.sup.18, --COR.sup.17,
--CO.sub.2R.sup.17, --OC(O)R.sup.18, --NR.sup.15COR.sup.17,
--N(COR.sup.17).sub.2, --NR.sup.15CONR.sup.17R.sup- .19,
--NR.sup.15CO.sub.2R.sup.18, --NR.sup.17R.sup.19, and
--CONR.sup.17R.sup.19 and up to 1 phenyl, each phenyl substituent
being substituted with 0-4 substituents selected from the group
C.sub.1-3 alkyl, C.sub.1-3 alkoxy, Br, Cl, F, I, --CN,
dimethylamino, CF.sub.3, C.sub.2F.sub.5, OCF.sub.3, SO.sub.2Me and
acetyl; heteroaryl is independently selected at each occurence from
the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl,
isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl,
oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl,
isoxazolyl, triazolyl, tetrazolyl, indazolyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide,
indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane,
each heteroaryl being substituted 0-4 carbon atoms with a
substituent independently selected at each occurrence from the
group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, I,
C.sub.1-4 haloalkyl, --CN, nitro, --OR.sup.17, SH,
--S(O).sub.mR.sup.18, --COR.sup.17, --CO.sub.2R.sup.17,
--OC(O)R.sup.18, --NR.sup.15COR.sup.17, --N(COR.sup.17).sub.2,
--NR.sup.15CONR.sup.17R.sup.19, --NR.sup.15CO.sub.2R.sup.18,
--NR.sup.17R.sup.19, and --CONR.sup.17R.sup.19 and each heteroaryl
being substituted on any nitrogen atom with 0-1 substituents
selected from the group R.sup.15, CO.sub.2R.sup.14a, COR.sup.14a
and SO.sub.2R.sup.14a; and, provided that when D is imidazole or
triazole, R.sup.1 is other than unsubstituted C.sub.1-6 linear or
branched alkyl or C.sub.3-6 cycloalkyl.
2. A method of treating affective disorder, anxiety, depression,
headache, irritable bowel syndrome, post-traumatic stress disorder,
supranuclear palsy, immune suppression, Alzheimer's disease,
gastrointestinal diseases, anorexia nervosa or other feeding
disorder, drug addiction, drug or alcohol withdrawal symptoms,
inflammatory diseases, cardiovascular or heart-related diseases,
fertility problems, human immunodeficiency virus infections,
hemorrhagic stress, obesity, infertility, head and spinal cord
traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis,
hypoglycemia or a disorder the treatment of which can be effected
or facilitated by antagonizing CRF, including but not limited to
disorders induced or facilitated by CRF, in mammals, comprising:
administering to the mammal a therapeutically effective amount of a
compound of formula (I): 25or a stereoisomer or pharmaceutically
acceptable salt form thereof, wherein: A is N; B is N; D is an aryl
or heteroaryl group attached through an unsaturated carbon atom; X
is selected from the group CH--R.sup.9, N--R.sup.10, 0, S(O).sub.n
and a bond; n is 0, 1 or 2; R.sup.1 is selected from the group
C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-8
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, C.sub.1-4
alkoxy-C.sub.1-4 alkyl, --SO.sub.2--C.sub.1-10 alkyl,
--SO.sub.2--R.sup.1a, and --SO.sub.2--R.sup.1b; R.sup.1 is
substituted with 0-1 substituents selected from the group --CN,
--S(O).sub.nR.sup.14b, --COR.sup.13a, CO.sub.2R.sup.13a,
--NR.sup.15aCOR.sup.13a, --N(COR.sup.13a).sub.2,
--NR.sup.15aCONR.sup.13a- R.sup.16a, NR.sup.15aCO.sub.2R.sup.14b,
--CONR.sup.13aR.sup.16a, 1-morpholinyl, 1-piperidinyl,
1-piperazinyl, and C.sub.3-8 cycloalkyl, wherein 0-1 carbon atoms
in the C.sub.4-8 cycloalkyl is replaced by a group selected from
the group --O--, --S(O).sub.n--, --NR.sup.13a--,
--NCO.sub.2R.sup.14b--, --NCOR.sup.14b-- and
--NSO.sub.2R.sup.14b--, and wherein N.sub.4 in 1-piperazinyl is
substituted with 0-1 substituents selected from the group
R.sup.13a, CO.sub.2R.sup.14b, COR.sup.14b and SO.sub.2R.sup.14b;
R.sup.1 is also substituted with 0-3 substituents independently
selected at each occurrence from the group R.sup.1a, R.sup.1b,
R.sup.1c, C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
Br, Cl, F, I, C.sub.1-4 haloalkyl, --OR.sup.13a,
--NR.sup.13aR.sup.16a, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, and
C.sub.3-8 cycloalkyl which is substituted with 0-1 R.sup.9 and in
which 0-1 carbons of C.sub.4-8 cycloalkyl is replaced by --O--;
R.sup.1a is aryl and is selected from the group phenyl, naphthyl,
indanyl and indenyl, each R.sup.1a being substituted with 0-5
substituents independently selected at each occurrence from the
group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, I,
C.sub.1-4 haloalkyl, --CN, nitro, --OR.sup.17, SH,
--S(O).sub.nR.sup.18, --COR.sup.17, --OC(O)R.sup.18,
--NR.sup.15aCOR.sup.17, --N(COR.sup.17).sub.2,
--NR.sup.15aCONR.sup.17aR.- sup.19a, --NR.sup.15aCO.sub.2R.sup.18,
NR.sup.17aR.sup.19a, and --CONR.sup.17aR.sup.19a; R.sup.1b is
heteroaryl and is selected from the group pyridyl, pyrimidinyl,
triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl,
thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl,
benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl,
tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl,
2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl- -S-oxide,
2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl,
benzodioxolanyl and benzodioxane, each heteroaryl being substituted
on 0-4 carbon atoms with a substituent independently selected at
each occurrence from the group C.sub.1-6 alkyl, C.sub.3-6
cycloalkyl, Br, Cl, F, I, C.sub.1-4 haloalkyl, --CN, nitro,
--OR.sup.17, SH, --S(O).sub.mR.sup.18, --COR.sup.17,
--OC(O)R.sup.18, --NR.sup.15aCOR.sup.17, --N(COR.sup.17).sub.2,
NR.sup.15aCONR.sup.17aR.su- p.19a,
--NR.sup.15aCO.sub.2R.sup.18--NR.sup.17aR.sup.19a, and
--CONR.sup.17aR.sup.19a and each heteroaryl being substituted on
any nitrogen atom with 0-1 substituents selected from the group
R.sup.15a, CO.sub.2R.sup.14b, COR.sup.14b and SO.sub.2R.sup.14b;
R.sup.1c is heterocyclyl and is a saturated or partially saturated
heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms
with a substituent independently selected at each occurrence from
the group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, I,
C.sub.1-4 haloalkyl, --CN, nitro, --OR.sup.13a, SH,
--S(O).sub.nR.sup.14b, --COR.sup.13a, --OC(O)R.sup.14b,
NR.sup.15aCOR.sup.13a, --N(COR.sup.13a).sub.2,
--NR.sup.15aCONR.sup.13aR.- sup.16a, NR.sup.15aCO.sub.2R.sup.14b,
NR.sup.13aR.sup.16a, and --CONR.sup.13aR.sup.16a and each
heterocyclyl being substituted on any nitrogen atom with 0-1
substituents selected-from the group R.sup.13a, CO.sub.2R.sup.14b,
COR.sup.14b and SO.sub.2R.sup.14b and wherein any sulfur atom is
optionally monooxidized or dioxidized; R.sup.2 is selected from the
group C.sub.1-4 alkyl, C.sub.3-8 cycloalkyl, C.sub.2-4 alkenyl, and
C.sub.2-4 alkynyl and is substituted with 0-3 substituents selected
from the group --CN, hydroxy, halo and C.sub.1-4 alkoxy;
alternatively R.sup.2, in the case where X is a bond, is selected
from the group --CN, CF.sub.3 and C.sub.2F.sub.5; R.sup.9 and
R.sup.10 are independently selected at each occurrence from the
group H, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl-C.sub.1-4 alkyl and
C.sub.3-8 cycloalkyl; R.sup.13 is selected from the group H,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy-C.sub.1-4
alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl,
aryl, aryl(C.sub.1-4 alkyl)-, heteroaryl and heteroaryl (C.sub.1-4
alkyl)-; R.sup.13a and R.sup.16a are independently selected at each
occurrence from the group H, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, and
C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl; R.sup.14 is selected from the
group C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4
alkoxy-C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl, aryl, aryl(C.sub.1-4 alkyl)-,
heteroaryl and heteroaryl(C.sub.1-4 alkyl)- and benzyl, each benzyl
being substituted on the aryl moiety with 0-1 substituents selected
from the group C.sub.1-4 alkyl, Br, Cl, F, I, C.sub.1-4 haloalkyl,
nitro, C.sub.1-4 alkoxy C.sub.1-4 haloalkoxy, and dimethylamino;
R.sup.14a is selected from the group C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl,
C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl and benzyl, each benzyl being
substituted on the aryl moiety with 0-1 substituents selected from
the group C.sub.1-4 alkyl, Br, Cl, F, I, C.sub.1-4 haloalkyl,
nitro, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, and dimethylamino;
R.sup.14b is selected from the group C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl,
and C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl; R.sup.15 is independently
selected at each occurrence from the group H, C.sub.1-4 alkyl,
C.sub.3-7 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, phenyl
and benzyl, each phenyl or benzyl being substituted on the aryl
moiety with 0-3 groups chosen from the group C.sub.1-4 alkyl, Br,
Cl, F, I, C.sub.1-4 haloalkyl, nitro, C.sub.1-4 alkoxy, C.sub.1-4
haloalkoxy, and dimethylamino; R.sup.15a is independently selected
at each occurrence from the group H, C.sub.1-4 alkyl, C.sub.3-7
cycloalkyl, and C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl; R.sup.17 is
selected at each occurrence from the group H, C.sub.1-6 alkyl,
C.sub.3-10 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl,
C.sub.1-2 alkoxy-C.sub.1-2 alkyl, C.sub.1-4 haloalkyl,
R.sup.14S(O).sub.n--C.sub.1-4 alkyl, and
R.sup.17bR.sup.19bN--C.sub.2-4 alkyl; R.sup.18 and R.sup.19 are
independently selected at each occurrence from the group H,
C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl, C.sub.1-2 alkoxy-C.sub.1-2 alkyl, and
C.sub.1-4 haloalkyl; alternatively, in an NR.sup.17R.sup.17 moiety,
R.sup.17 and R.sup.19 taken together form 1-pyrrolidinyl,
1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N.sub.4 in
1-piperazinyl is substituted with 0-1 substituents selected from
the group R.sup.13, CO.sub.2R.sup.14, COR.sup.14 and
SO.sub.2R.sup.14; alternatively, in an NR.sup.17bR.sup.19b moiety,
R.sup.17b and R.sup.19b taken together form 1-pyrrolidinyl,
1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N.sub.4 in
1-piperazinyl is substituted with 0-1 substituents selected from
the group R.sup.13, CO.sub.2R.sup.14, COR.sup.14 and
SO.sub.2R.sup.14; R.sup.17a and R.sup.19a are independently
selected at each occurrence from the group H, C.sub.1-6 alkyl,
C.sub.3-10 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl and
C.sub.1-4 haloalkyl; aryl is independently selected at each
occurrence from the group phenyl, naphthyl, indanyl and indenyl,
each aryl being substituted with 0-5 substituents independently
selected at each occurrence from the group C.sub.1-6 alkyl,
C.sub.3-6 cycloalkyl, methylenedioxy, C.sub.1-4 alkoxy-C.sub.1-4
alkoxy, --OR.sup.17, Br, Cl, F, I, C.sub.1-4 haloalkyl, --CN,
--NO.sub.2, SH, --S(O).sub.nR.sup.18, --COR.sup.17,
--CO.sub.2R.sup.17, --OC(O)R.sup.18, --NR.sup.15COR.sup.17,
--N(COR.sup.17).sub.2, --NR.sup.15CONR.sup.17R.sup.19,
--NR.sup.15CO.sub.2R.sup.18, --NR.sup.17R.sup.19, and
--CONR.sup.17R.sup.19 and up to 1 phenyl, each phenyl substituent
being substituted with 0-4 substituents selected from the group
C.sub.1-3 alkyl, C.sub.1-3 alkoxy, Br, Cl, F, I, --CN,
dimethylamino, CF.sub.3, C.sub.2F.sub.5, OCF.sub.3, SO.sub.2Me and
acetyl; and, heteroaryl is independently selected at each occurence
from the group pyridyl, pyrimidinyl, triazinyl, furanyl,
quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl,
pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,
benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide,
indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane,
each heteroaryl being substituted 0-4 carbon atoms with a
substituent independently selected at each occurrence from the
group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, I,
C.sub.1-4 haloalkyl, --CN, nitro, --OR.sup.17, SH,
--S(O).sub.mR.sup.18, --COR.sup.17, --CO.sub.2R.sup.17,
--OC(O)R.sup.18, --NR.sup.15COR.sup.17, --N(COR.sup.17).sub.2,
--NR.sup.15CONR.sup.17R.sup.19, --NR.sup.15CO.sub.2R.sup.18,
--NR.sup.17R.sup.19, and --CONR.sup.17R.sup.19 and each heteroaryl
being substituted on any nitrogen atom with 0-1 substituents
selected from the group R.sup.15, CO.sub.2R.sup.14a, COR.sup.14a
and SO.sub.2R.sup.14a.
3. A pharmaceutical composition, comprising: a pharmaceutically
acceptable carrier and a therapeutically effective amount of a
compound of formula (I): 26or a stereoisomer or pharmaceutically
acceptable salt form thereof, wherein: A is N; B is N; D is an aryl
or heteroaryl group attached through an unsaturated carbon atom; X
is selected from the group CH--R.sup.9, N--R.sup.10, 0, S(O).sub.n
and a bond; n is 0, 1 or 2; R.sup.1 is selected from the group
C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-8
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, C.sub.1-4
alkoxy-C.sub.1-4 alkyl, --SO.sub.2--C.sub.1-10 alkyl,
--SO.sub.2--R.sup.1a, and --SO.sub.2--R.sup.1b; R.sup.1 is
substituted with 0-1 substituents selected from the group --CN,
--S(O).sub.nR.sup.14b, --COR.sup.13a, --CO.sub.2R.sup.13a,
--NR.sup.15aCOR.sup.13a, --N(COR.sup.13a).sub.2,
--NR.sup.15aCONR.sup.13a- R.sup.16a, NR.sup.15aCO.sub.2R.sup.14b,
--CONR.sup.13aR.sup.16a, 1-morpholinyl, 1-piperidinyl,
1-piperazinyl, and C.sub.3-8 cycloalkyl, wherein 0-1 carbon atoms
in the C.sub.4-8 cycloalkyl is replaced by a group selected from
the group --O--, --S(O).sub.n--, --NR.sup.13a--,
--NCO.sub.2R.sup.14b--, --NCOR.sup.14b-- and
--NSO.sub.2R.sup.14b--, and wherein N.sub.4 in 1-piperazinyl is
substituted with 0-1 substituents selected from the group
R.sup.13a, CO.sub.2R.sup.14b, COR.sup.14b and SO.sub.2R.sup.14b;
R.sup.1 is also substituted with 0-3 substituents independently
selected at each occurrence from the group R.sup.1a, R.sup.1b,
R.sup.1c, C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
Br, Cl, F, I, C.sub.1-4 haloalkyl, --OR.sup.13a,
--NR.sup.13aR.sup.16a, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, and
C.sub.3-8 cycloalkyl which is substituted with 0-1 R.sup.9 and in
which 0-1 carbons of C.sub.4-8 cycloalkyl is replaced by --O--;
R.sup.1a is aryl and is selected from the group phenyl, naphthyl,
indanyl and indenyl, each R.sup.1a being substituted with 0-5
substituents independently selected at each occurrence from the
group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, I,
C.sub.1-4 haloalkyl, --CN, nitro, --OR.sup.17, SH,
--S(O).sub.nR.sup.18, --COR.sup.17, --OC(O)R.sup.18,
--NR.sup.15aCOR.sup.17, --N(COR.sup.17).sub.2,
NR.sup.15aCONR.sup.17aR.su- p.19a, --NR.sup.15aCO.sub.2R.sup.18,
--NR.sup.17aR.sup.19a, and --CONR.sup.17aR.sup.19a; R.sup.1b is
heteroaryl and is selected from the group pyridyl, pyrimidinyl,
triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl,
thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl,
benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl,
tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl,
2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl- -S-oxide,
2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl,
benzodioxolanyl and benzodioxane, each heteroaryl being substituted
on 0-4 carbon atoms with a substituent independently selected at
each occurrence from the group C.sub.1-6 alkyl, C.sub.3-6
cycloalkyl, Br, Cl, F, I, C.sub.1-4 haloalkyl, --CN, nitro,
--OR.sup.17, SH, --S(O).sub.mR.sup.18, --COR.sup.17,
--OC(O)R.sup.18, --NR.sup.15aCOR.sup.17, --N(COR.sup.17).sub.2,
NR.sup.15aCONR.sup.17aR.su- p.19a, --NR.sup.15aCO.sub.2R.sup.18,
--NR.sup.17aR.sup.19a, and --CONR.sup.17aR.sup.19a and each
heteroaryl being substituted on any nitrogen atom with 0-1
substituents selected from the group R.sup.15a, CO.sub.2R.sup.14b,
COR.sup.14b and SO.sub.2R.sup.14b; R.sup.1c is heterocyclyl and is
a saturated or partially saturated heteroaryl, each heterocyclyl
being substituted on 0-4 carbon atoms with a substituent
independently selected at each occurrence from the group C.sub.1-6
alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, I, C.sub.1-4 haloalkyl,
--CN, nitro, --OR.sup.13a, SH, --S(O).sub.nR.sup.14b,
--COR.sup.13a, OC(O)R.sup.14b, --NR.sup.15aCOR.sup.13a,
--N(COR.sup.13a).sub.2, NR.sup.15aCONR.sup.13aR.- sup.16a,
NR.sup.15aCO.sub.2R.sup.14b, NR.sup.13aR.sup.16a, and
--CONR.sup.13aR.sup.16a and each heterocyclyl being substituted on
any nitrogen atom with 0-1 substituents selected from the group
R.sup.13a, CO.sub.2R.sup.14b, COR.sup.14b and SO.sub.2R.sup.14b and
wherein any sulfur atom is optionally monooxidized or dioxidized;
R.sup.2 is selected from the group C.sub.1-4 alkyl, C.sub.3-8
cycloalkyl, C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl and is
substituted with 0-3 substituents selected from the group --CN,
hydroxy, halo and C.sub.1-4 alkoxy; alternatively R.sup.2, in the
case where X is a bond, is selected from the group --CN, CF.sub.3
and C.sub.2F.sub.5; R.sup.9 and R.sup.10 are independently selected
at each occurrence from the group H, C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl-C.sub.1-4 alkyl and C.sub.3-8 cycloalkyl; R.sup.13 is
selected from the group H, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl, aryl, aryl(C.sub.1-4 alkyl)-,
heteroaryl and heteroaryl (C.sub.1-4 alkyl)-; R.sup.13a and
R.sup.16a are independently selected at each occurrence from the
group H, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4
alkoxy-C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, and C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl; R.sup.14 is selected from the group
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy-C.sub.1-4
alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl,
aryl, aryl(C.sub.1-4 alkyl)-, heteroaryl and heteroaryl(C.sub.1-4
alkyl)- and benzyl, each benzyl being substituted on the aryl
moiety with 0-1 substituents selected from the group C.sub.1-4
alkyl, Br, Cl, F, I, C.sub.1-4 haloalkyl, nitro, C.sub.1-4 alkoxy
C.sub.1-4 haloalkoxy, and dimethylamino; R.sup.14a is selected from
the group C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4
alkoxy-C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl and benzyl, each benzyl being
substituted on the aryl moiety with 0-1 substituents selected from
the group C.sub.1-4 alkyl, Br, Cl, F, I, C.sub.1-4 haloalkyl,
nitro, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, and dimethylamino;
R.sup.14b is selected from the group C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl,
and C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl; R.sup.15 is independently
selected at each occurrence from the group H, C.sub.1-4 alkyl,
C.sub.3-7 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, phenyl
and benzyl, each phenyl or benzyl being substituted on the aryl
moiety with 0-3 groups chosen from the group C.sub.1-4 alkyl, Br,
Cl, F, I, C.sub.1-4 haloalkyl, nitro, C.sub.1-4 alkoxy, C.sub.1-4
haloalkoxy, and dimethylamino; R.sup.15a is independently selected
at each occurrence from the group H, C.sub.1-4 alkyl, C.sub.3-7
cycloalkyl, and C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl; R.sup.17 is
selected at each occurrence from the group H, C.sub.1-6 alkyl,
C.sub.3-10 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl,
C.sub.1-2 alkoxy-C.sub.1-2 alkyl, C.sub.1-4 haloalkyl,
R.sup.14S(O).sub.n--C.sub.1-4 alkyl, and
R.sup.17bR.sup.19bN--C.sub.2-4 alkyl; R.sup.18 and R.sup.19 are
independently selected at each occurrence from the group H,
C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl, C.sub.1-2 alkoxy-C.sub.1-2 alkyl, and
C.sub.1-4 haloalkyl; alternatively, in an NR.sup.17R.sup.19 moiety,
R.sup.17 and R.sup.19 taken together form 1-pyrrolidinyl,
1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N.sub.4 in
l-piperazinyl is substituted with 0-1 substituents selected from
the group R.sup.13, CO.sub.2R.sup.14, COR.sup.14 and
SO.sub.2R.sup.14; alternatively, in an NR.sup.17bR.sup.19b moiety,
R.sup.17b and R.sup.19b taken together form 1-pyrrolidinyl,
1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N.sub.4 in
1-piperazinyl is substituted with 0-1 substituents selected from
the group R.sup.13, CO.sub.2R.sup.14, COR.sup.14 and
SO.sub.2R.sup.14; R.sup.17a and R.sup.19a are independently
selected at each occurrence from the group H, C.sub.1-6 alkyl,
C.sub.3-10 cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl and
C.sub.1-4 haloalkyl; aryl is independently selected at each
occurrence from the group phenyl, naphthyl, indanyl and indenyl,
each aryl being substituted with 0-5 substituents independently
selected at each occurrence from the group C.sub.1-6 alkyl,
C.sub.3-6 cycloalkyl, methylenedioxy, C.sub.1-4 alkoxy-C.sub.1-4
alkoxy, --OR.sup.17, Br, Cl, F, I, C.sub.1-4 haloalkyl, --CN,
--NO.sub.2, SH, --S(O).sub.nR.sup.18, --COR.sup.17,
--CO.sub.2R.sup.17, --OC(O)R.sup.18, --NR.sup.15COR.sup.17,
--N(COR.sup.17).sub.2, --NR.sup.15CONR.sup.17R.sup.19,
--NR.sup.15CO.sub.2R.sup.18, --NR.sup.17R.sup.19, and
--CONR.sup.17R.sup.19 and up to 1 phenyl, each phenyl substituent
being substituted with 0-4 substituents selected from the group
C.sub.1-3 alkyl, C.sub.1-3 alkoxy, Br, Cl, F, I, --CN,
dimethylamino, CF.sub.3, C.sub.2F.sub.5, OCF.sub.3, SO.sub.2Me and
acetyl; and, heteroaryl is independently selected at each occurence
from the group pyridyl, pyrimidinyl, triazinyl, furanyl,
quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl,
pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,
benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide,
indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane,
each heteroaryl being substituted 0-4 carbon atoms with a
substituent independently selected at each occurrence from the
group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, I,
C.sub.1-4 haloalkyl, --CN, nitro, --OR.sup.17, SH,
--S(O).sub.mR.sup.18, --COR.sup.17, --CO.sub.2R.sup.17,
--OC(O)R.sup.18, --NR.sup.15COR.sup.17, --N(COR.sup.17).sub.2,
--NR.sup.15CONR.sup.17R.sup.19, --NR.sup.15CO.sub.2R.sup.18,
--NR.sup.17R.sup.19, and --CONR.sup.17R.sup.19 and each heteroaryl
being substituted on any nitrogen atom with 0-1 substituents
selected from the group R.sup.15, CO.sub.2R.sup.14a, COR.sup.14a
and SO.sub.2R.sup.14a.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of pending U.S. application
Ser. No. 10/073,800, filed Feb. 11, 2002, now allowed, which in
turn is a divisional of U.S. application Ser. No. 09/625,291, filed
Jul. 25, 2000, now abandoned, and U.S. application Ser. No.
09/624,686, also filed Jul. 25, 2000, now U.S. Pat. No. 6,521,636,
which in turn are divisionals of U.S. application Ser. No.
09/344,257, filed Jun. 25, 1999, now U.S. Pat. No. 6,365,589, and
which in turn claims priority to provisional U.S. Application
Serial No. 60/091,515, filed Jul. 2, 1998. The disclosure of each
of these priority applications is incorporated herein by reference
in their entirety.
FIELD OF THE INVENTION
[0002] This invention relates to novel imidazo-pyridines,
-pyridazines, and -triazines, pharmaceutical compositions
containing the same and methods of using same in the treatment of
psychiatric disorders and neurological diseases including affective
disorder, anxiety, depression, headache, irritable bowel syndrome,
post-traumatic stress disorder, supranuclear palsy, immune
suppression, Alzheimer's disease, gastrointestinal diseases,
anorexia nervosa or other feeding disorder, drug addiction, drug or
alcohol withdrawal symptoms, inflammatory diseases, cardiovascular
or heart-related diseases, fertility problems, human
immunodeficiency virus infections, hemorrhagic stress, obesity,
infertility, head and spinal cord traumas, epilepsy, stroke,
ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder
the treatment of which can be effected or facilitated by
antagonizing corticotropin releasing factor (CRF), including but
not limited to disorders induced or facilitated by CRF.
BACKGROUND OF THE INVENTION
[0003] Corticotropin releasing factor, a 41 amino acid peptide, is
the primary physiological regulator of proopiomelanocortin
(POMC)-derived peptide secretion from the anterior pituitary gland
[J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W.
Vale et al., Science 213:1394 (1981)]. In addition to its endocrine
role at the pituitary gland, immunohistochemical localization of
CRF has demonstrated that the hormone has a broad extrahypothalamic
distribution in the central nervous system and produces a wide
spectrum of autonomic, electrophysiological and behavioral effects
consistent with a neurotransmitter or neuromodulator role in brain
[W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob,
Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci.
5:3189 (1985)]. There is also evidence that CRF plays a significant
role in integrating the response of the immune system to
physiological, psychological, and immunological stressors [J. E.
Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci.
41:527 (1987)].
[0004] Clinical data provides evidence that CRF has a role in
psychiatric disorders and neurological diseases including
depression, anxiety-related disorders and feeding disorders. A role
for CRF has also been postulated in the etiology and
pathophysiology of Alzheimer's disease, Parkinson's disease,
Huntington's disease, progressive supranuclear palsy and
amyotrophic lateral sclerosis as they relate to the dysfunction of
CRF neurons in the central nervous system [for review see E. B. De
Souza, Hosp. Practice 23:59 (1988)].
[0005] In affective disorder, or major depression, the
concentration of CRF is significantly increased in the cerebral
spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al.,
Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry
144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988);
M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the
density of CRF receptors is significantly decreased in the frontal
cortex of suicide victims, consistent with a hypersecretion of CRF
[C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In
addition, there is a blunted adrenocorticotropin (ACTH) response to
CRF (i.v. administered) observed in depressed patients [P. W. Gold
et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al.,
Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng.
J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human
primates provide additional support for the hypothesis that
hypersecretion of CRF may be involved in the symptoms seen in human
depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)].
There is preliminary evidence that tricyclic antidepressants can
alter CRF levels and thus modulate the numbers of CRF receptors in
brain [Grigoriadis et al., Neuropsychopharmacology 2:53
(1989)].
[0006] There has also been a role postulated for CRF in the
etiology of anxiety-related disorders. CRF produces anxiogenic
effects in animals and interactions between
benzodiazepine/non-benzodiazepine anxiolytics and CRF have been
demonstrated in a variety of behavioral anxiety models [D. R.
Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J.
Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the
putative CRF receptor antagonist .alpha.-helical ovine CRF (9-41)
in a variety of behavioral paradigms demonstrate that the
antagonist produces "anxiolytic-like" effects that are
qualitatively similar to the benzodiazepines [C. W. Berridge and A.
J. Dunn, Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71
(1990)]. Neurochemical, endocrine and receptor binding studies have
all demonstrated interactions between CRF and benzodiazepine
anxiolytics providing further evidence for the involvement of CRF
in these disorders. Chlordiazepoxide attenuates the "anxiogenic"
effects of CRF in both the conflict test [K. T. Britton et al.,
Psychopharmacology 86:170 (1985); K. T. Britton et al.,
Psychopharmacology 94:306 (1988)] and in the acoustic startle test
[N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats.
The benzodiazepine receptor antagonist (Ro15-1788), which was
without behavioral activity alone in the operant conflict test,
reversed the effects of CRF in a dose-dependent manner while the
benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF
[K. T. Britton et al., Psychopharmacology 94:306 (1988)].
[0007] The mechanisms and sites of action through which the
standard anxiolytics and antidepressants produce their therapeutic
effects remain to be elucidated. It has been hypothesized however,
that they are involved in the suppression of the CRF hypersecretion
that is observed in these disorders. Of particular interest is that
preliminary studies examining the effects of a CRF receptor
antagonist .alpha.-helical CRF.sub.9-41) in a variety of behavioral
paradigms have demonstrated that the CRF antagonist produces
"anxiolytic-like" effects qualitatively similar to the
benzodiazepines [for review see G. F. Koob and K. T. Britton, In:
Corticotropin-Releasing Factor: Basic and Clinical Studies of a
Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press
p221 (1990)].
[0008] In view of the above, efficacious and specific antagonists
of CRF are desired as potentially valuable therapeutic agents for
the treatment of psychiatric disorders and neurological diseases.
It is thus desirable to discover new CRF antagonists.
SUMMARY OF THE INVENTION
[0009] Accordingly, one object of the present invention is to
provide novel imidazo-pyridines, -pyridazines, and -triazines,
which are useful as CRF antagonists or pharmaceutically acceptable
salts or prodrugs thereof.
[0010] It is another object of the present invention to provide
pharmaceutical compositions comprising a pharmaceutically
acceptable carrier and a therapeutically effective amount of at
least one of the compounds of the present invention or a
pharmaceutically acceptable salt form thereof.
[0011] It is another object of the present invention to provide a
method for treating psychiatric disorders and neurological diseases
comprising administering to a host in need of such treatment a
therapeutically effective amount of at least one of the compounds
of the present invention or a pharmaceutically acceptable salt form
thereof.
[0012] These and other objects, which will become apparent during
the following detailed description, have been achieved by the
inventors' discovery that compounds of formula I: 2
[0013] or pharmaceutically acceptable salt forms thereof, wherein
R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are defined below, are CRF
antagonists.
DETAILED DESCRIPTION OF THE INVENTION
[0014] [1] Thus, in a first embodiment, the present invention
provides a novel compound of formula I: 3
[0015] or a stereoisomer or pharmaceutically acceptable salt form
thereof, wherein:
[0016] A is N or C--R.sup.7;
[0017] B is N or C--R.sup.8;
[0018] D is an aryl or heteroaryl group attached through an
unsaturated carbon atom;
[0019] X is selected from the group CH--R.sup.9, N--R.sup.10, O,
S(O).sub.n and a bond;
[0020] n is 0, 1 or 2;
[0021] R.sup.1 is selected from the group C.sub.1-10 alkyl,
C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-8 cycloalkyl,
C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, C.sub.1-4 alkoxy-C.sub.1-4
alkyl, --SO.sub.2--C.sub.1-10 alkyl, --SO.sub.2--R.sup.1a, and
--SO.sub.2--R.sup.1b;
[0022] R.sup.1 is substituted with 0-1 substituents selected from
the group --CN, --S(O).sub.nR.sup.14b, --COR.sup.13a,
--CO.sub.2R.sup.13a, --NR.sup.15aCOR.sup.13a,
--N(COR.sup.13a).sub.2, --NR.sup.15aCONR.sup.13a- R.sup.16a,
NR.sup.15aCO.sub.2R.sup.14b, --CONR.sup.13aR.sup.16a,
1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C.sub.3-8
cycloalkyl, wherein 0-1 carbon atoms in the C.sub.4-8 cycloalkyl is
replaced by a group selected from the group --O--, --S(O).sub.n--,
--NR.sup.13a, --NCO.sub.2R.sup.14b, --NCOR.sup.14b-- and
--NSO.sub.2R.sup.14b-- and wherein N.sub.4 in 1-piperazinyl is
substituted with 0-1 substituents selected from the group
R.sup.13a, CO.sub.2R.sup.14b, COR.sup.14b and
SO.sub.2R.sup.14b;
[0023] R.sup.1 is also substituted with 0-3 substituents
independently selected at each occurrence from the group R.sup.1a,
R.sup.1b, R.sup.1c, C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, Br, Cl, F, I, C.sub.1-4 haloalkyl, OR.sup.13a,
--NR.sup.13aR.sup.16a, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, and
C.sub.3-8 cycloalkyl which is substituted with 0-1 R.sup.9 and in
which 0-1 carbons of C.sub.4-8 cycloalkyl is replaced by --O--;
[0024] provided that R.sup.1 is other than a
cyclohexyl-(CH.sub.2).sub.2--- 0 group;
[0025] R.sup.1a is aryl and is selected from the group phenyl,
naphthyl, indanyl and indenyl, each R.sup.1a being substituted with
0-1 --OR.sup.17 and 0-5 substituents independently selected at each
occurrence from the group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl,
Br, Cl, F, I, C.sub.1-4 haloalkyl, --CN, nitro, SH,
--S(O).sub.nR.sup.18, --COR.sup.17, --OC(O)R.sup.18,
--NR.sup.15aCOR.sup.17, --N(COR.sup.17).sub.2,
--NR.sup.15aCONR.sup.17aR.sup.19a, --NR.sup.15aCO.sub.2R.sup.18,
--NR.sup.17aR.sup.19a, and --CONR.sup.17aR.sup.19a;
[0026] R.sup.1b is heteroaryl and is selected from the group
pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl,
isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl,
oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl,
isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide,
indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane,
each heteroaryl being substituted on 0-4 carbon atoms with a
substituent independently selected at each occurrence from the
group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, I,
C.sub.1-4 haloalkyl, --CN, nitro, --OR.sup.17, SH,
--S(O).sub.mR.sup.18, --COR.sup.17, --OC(O)R.sup.18,
--NR.sup.15aCOR.sup.17, --N(COR.sup.17).sub.2,
NR.sup.15aCONR.sup.17aR.su- p.19a, --NR.sup.15aCO.sub.2R.sup.18,
--NR.sup.17aR.sup.19a, and --CONR.sup.17aR.sup.19a and each
heteroaryl being substituted on any nitrogen atom with 0-1
substituents selected from the group R.sup.15a, CO.sub.2R.sup.14b,
COR.sup.14b and SO.sub.2R.sup.14b;
[0027] R.sup.1c is heterocyclyl and is a saturated or partially
saturated heteroaryl, each heterocyclyl being substituted on 0-4
carbon atoms with a substituent independently selected at each
occurrence from the group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl,
Br, Cl, F, I, C.sub.1-4 haloalkyl, --CN, nitro, --OR.sup.13a, SH,
--S(O).sub.nR.sup.14b, --COR.sup.13a, OC(O)R.sup.14b,
--NR.sup.15aCOR.sup.13a, --N(COR.sup.13a).sub.2,
--NR.sup.15aCONR.sup.13aR.sup.16a, --NR.sup.15aCO.sub.2R.sup.14b,
--NR.sup.13aR.sup.16a, and --CONR.sup.13aR.sup.16a and each
heterocyclyl being substituted on any nitrogen atom with 0-1
substituents selected from the group R.sup.13a, CO.sub.2R.sup.14b,
COR.sup.14b and SO.sub.2R.sup.14b and wherein any sulfur atom is
optionally monooxidized or dioxidized;
[0028] provided that R.sup.1 is other than a
--(CH.sub.2).sub.1-4-aryl, --(CH.sub.2).sub.1-4-heteroaryl, or
--(CH.sub.2).sub.1-4-heterocycle, wherein the aryl, heteroaryl, or
heterocycle group is substituted or unsubstituted;
[0029] R.sup.2 is selected from the group C.sub.1-4 alkyl,
C.sub.3-8 cycloalkyl, C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl and
is substituted with 0-3 substituents selected from the group --CN,
hydroxy, halo and C.sub.1-4 alkoxy;
[0030] alternatively R.sup.2, in the case where X is a bond, is
selected from the group --CN, CF.sub.3 and C.sub.2F.sub.5;
[0031] R.sup.7 and R.sup.8 are independently selected at each
occurrence from the group H, Br, Cl, F, I, --CN, C.sub.1-4 alkyl,
C.sub.3-8 cycloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio,
C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl, amino, C.sub.1-4
alkylamino, (C.sub.1-4 alkyl).sub.2amino and phenyl, each phenyl is
substituted with 0-3 groups selected from the group C.sub.1-7
alkyl, C.sub.3-8 cycloalkyl, Br, Cl, F, I, C.sub.1-4 haloalkyl,
nitro, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, C.sub.1-4 alkylthio,
C.sub.1-4 alkyl sulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-6
alkylamino and (C.sub.1-4 alkyl).sub.2amino;
[0032] R.sup.9 and R.sup.10 are independently selected at each
occurrence from the group H, C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl-C.sub.1-4 alkyl and C.sub.3-8 cycloalkyl;
[0033] R.sup.13 is selected from the group H, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, aryl,
aryl(C.sub.1-4 alkyl)-, heteroaryl and heteroaryl (C.sub.1-4
alkyl)-;
[0034] R.sup.13a and R.sup.16a are independently selected at each
occurrence from the group H, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, and
C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl;
[0035] R.sup.14 is selected from the group C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, aryl,
aryl(C.sub.1-4 alkyl)-, heteroaryl and heteroaryl(C.sub.1-4 alkyl)-
and benzyl, each benzyl being substituted on the aryl moiety with
0-1 substituents selected from the group C.sub.1-4 alkyl, Br, Cl,
F, I, C.sub.1-4 haloalkyl, nitro, C.sub.1-4 alkoxy C.sub.1-4
haloalkoxy, and dimethylamino;
[0036] R.sup.14a is selected from the group C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl and benzyl, each
benzyl being substituted on the aryl moiety with 0-1 substituents
selected from the group C.sub.1-4 alkyl, Br, Cl, F, I, C.sub.1-4
haloalkyl, nitro, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, and
dimethylamino;
[0037] R.sup.14b is selected from the group C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl, and C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl;
[0038] R.sup.15 is independently selected at each occurrence from
the group H, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl, phenyl and benzyl, each phenyl or
benzyl being substituted on the aryl moiety with 0-3 groups chosen
from the group C.sub.1-4 alkyl, Br, Cl, F, I, C.sub.1-4 haloalkyl,
nitro, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, and
dimethylamino;
[0039] R.sup.15a is independently selected at each occurrence from
the group H, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, and C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl;
[0040] R.sup.17 is selected at each occurrence from the group H,
C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl, C.sub.1-2 alkoxy-C.sub.1-2 alkyl,
C.sub.1-4 haloalkyl, R.sup.14S(O).sub.n--C.sub.1-4 alkyl, and
R.sup.17bR.sup.19bN--C.sub.2-4 alkyl;
[0041] R.sup.18 and R.sup.19 are independently selected at each
occurrence from the group H, C.sub.1-6 alkyl, C.sub.3-10
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, C.sub.1-2
alkoxy-C.sub.1-2 alkyl, and C.sub.1-4 haloalkyl;
[0042] alternatively, in an NR.sup.17 R.sup.19 moiety, R.sup.17 and
R.sup.19 taken together form 1-pyrrolidinyl, 1-morpholinyl,
1-piperidinyl or 1-piperazinyl, wherein N.sub.4 in 1-piperazinyl is
substituted with 0-1 substituents selected from the group R.sup.13,
CO.sub.2R.sup.14, COR.sup.14 and SO.sub.2R.sup.14;
[0043] alternatively, in an NR.sup.17bR.sup.19b moiety, R.sup.17b
and R.sup.19b taken together form 1-pyrrolidinyl, 1-morpholinyl,
1-piperidinyl or 1-piperazinyl, wherein N.sub.4 in 1-piperazinyl is
substituted with 0-1 substituents selected from the group R.sup.13,
CO.sub.2R.sup.14, COR.sup.14 and SO.sub.2R.sup.14;
[0044] R.sup.17a and R.sup.19a are independently selected at each
occurrence from the group H, C.sub.1-6 alkyl, C.sub.3-10
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl and C.sub.1-4
haloalkyl;
[0045] aryl is independently selected at each occurrence from the
group phenyl, naphthyl, indanyl and indenyl, each aryl being
substituted with 0-5 substituents independently selected at each
occurrence from the group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl,
methylenedioxy, C.sub.1-4 alkoxy-C.sub.1-4 alkoxy, --OR.sup.17, Br,
Cl, F, I, C.sub.1-4 haloalkyl, --CN, --NO.sub.2, SH,
--S(O).sub.nR.sup.18, --COR.sup.17, --CO.sub.2R.sup.17,
--OC(O)R.sup.18, --NR.sup.15COR.sup.17, --N(COR.sup.17).sub.2,
--NR.sup.15CONR.sup.17R.sup.19, --NR.sup.15CO.sub.2R.sup.18,
--NR.sup.17R.sup.19, and --CONR.sup.17R.sup.19 and up to 1 phenyl,
each phenyl substituent being substituted with 0-4 substituents
selected from the group C.sub.1-3 alkyl, C.sub.1-3 alkoxy, Br, Cl,
F, I, --CN, dimethylamino, CF.sub.3, C.sub.2F.sub.5, OCF.sub.3,
SO.sub.2Me and acetyl;
[0046] heteroaryl is independently selected at each occurence from
the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl,
isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl,
oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl,
isoxazolyl, triazolyl, tetrazolyl, indazolyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide,
indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane,
each heteroaryl being substituted 0-4 carbon atoms with a
substituent independently selected at each occurrence from the
group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, I,
C.sub.1-4 haloalkyl, --CN, nitro, --OR.sup.17, SH,
--S(O).sub.mR.sup.18, --COR.sup.17, --CO.sub.2R.sup.17,
--OC(O)R.sup.18, --NR.sup.15COR.sup.17, --N(COR.sup.17).sub.2,
--NR.sup.15CONR.sup.17R.sup.19, --NR.sup.15CO.sub.2R.sup.18,
--NR.sup.17R.sup.19, and --CONR.sup.17R.sup.19 and each heteroaryl
being substituted on any nitrogen atom with 0-1 substituents
selected from the group R.sup.15, CO.sub.2R.sup.14a, COR.sup.14a
and SO.sub.2R.sup.14a; and,
[0047] provided that when D is imidazole or triazole, R.sup.1 is
other than unsubstituted C.sub.1-6 linear or branched alkyl or
C.sub.3-6 cycloalkyl.
[0048] [2] In a preferred embodiment, the present invention
provides a novel compound of formula Ia: 4
[0049] [3] In another preferred embodiment, the present invention
provides a novel compound of formula Ib: 5
[0050] [4] In another preferred embodiment, the present invention
provides a novel compound of formula Ic: 6
[0051] [5] In another preferred embodiment, the present invention
provides a novel compound of formula Id: 7
[0052] [5a] In a more preferred embodiment, the present invention
provides a novel compound of formula Id, wherein:
[0053] X is selected from the group O, S(O).sub.n and a bond;
[0054] n is 0, 1 or 2;
[0055] R.sup.1 is selected from the group C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.3-8 cycloalkyl;
[0056] R.sup.1 is substituted with 0-1 substituents selected from
the group --CN, --S(O).sub.nR.sup.14b, --COR.sup.13a,
--CO.sub.2R.sup.13a, and C.sub.3-8 cycloalkyl, wherein 0-1 carbon
atoms in the C.sub.4-8 cycloalkyl is replaced by a group selected
from the group --O--, --S(O).sub.n--, --NR.sup.13a--,
--NCO.sub.2R.sup.14b--, --NCOR.sup.14b-- and
--NSO.sub.2R.sup.14b--;
[0057] R.sup.1 is also substituted with 0-2 substituents
independently selected at each occurrence from the group R.sup.1a,
R.sup.1b, C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
Br, Cl, F, CF.sub.3, CF.sub.2CF.sub.3, --OR.sup.13a,
--NR.sup.13aR.sup.16a, C.sub.1-2 alkoxy-C.sub.1-2 alkyl, and
C.sub.3-8 cycloalkyl which is substituted with 0-1 R.sup.9 and in
which 0-1 carbons of C.sub.4-8 cycloalkyl is replaced by --O--;
[0058] provided that R.sup.1 is other than a
cyclohexyl-(CH.sub.2).sub.2-- group;
[0059] R.sup.1a is aryl and is selected from the group phenyl and
indanyl, each R.sup.1a being substituted with 0-1 --OR.sup.17 and
0-5 substituents independently selected at each occurrence from the
group C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, C.sub.1-4
haloalkyl, --CN, --S(O).sub.nR.sup.18, --COR.sup.17,
--NR.sup.17aR.sup.19a, and --CONR.sup.17aR.sup.19a;
[0060] R.sup.1b is heteroaryl and is selected from the group
pyridyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl,
pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl,
and indazolyl, each heteroaryl being substituted on 0-4 carbon
atoms with a substituent independently selected at each occurrence
from the group C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F,
CF.sub.3, --CN, --OR.sup.17, --S(O).sub.mR.sup.18, --COR.sup.17,
NR.sup.17aR.sup.19a, and --CONR.sup.17aR.sup.19a and each
heteroaryl being substituted on any nitrogen atom with 0-1
substituents selected from the group R.sup.15a, CO.sub.2R.sup.14b,
COR.sup.14b and SO.sub.2R.sup.14b;
[0061] provided that R.sup.1 is other than a
--(CH.sub.2).sub.1-4-aryl or --(CH.sub.2).sub.1-4-heteroaryl
wherein the aryl or heteroaryl group is substituted or
unsubstituted;
[0062] R.sup.2 is selected from the group C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl and is substituted with
0-1 substituents selected from the group --CN, OH, Cl, F, and
C.sub.1-4 alkoxy;
[0063] R.sup.7 and R.sup.8 are independently selected from the
group H, Br, Cl, F, --CN, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl,
C.sub.1-4 alkoxy, NH.sub.2, C.sub.1-4 alkylamino, and (C.sub.1-4
alkyl).sub.2-amino;
[0064] R.sup.9 is independently selected at each occurrence from
the group H, C.sub.1-4 alkyl and C.sub.3-8 cycloalkyl;
[0065] R.sup.13 is selected from the group C.sub.1-4 alkyl,
C.sub.1-2 haloalkyl, C.sub.1-2 alkoxy-C.sub.1-2 alkyl, C.sub.3-6
cycloalkyl-C.sub.1-2 alkyl, aryl(C.sub.1-2 alkyl)-, and
heteroaryl(C.sub.1-2 alkyl)-;
[0066] R.sup.13a and R.sup.16a are independently selected at each
occurrence from the group H, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, and
C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl;
[0067] R.sup.14 is selected from the group C.sub.1-4 alkyl,
C.sub.1-2 haloalkyl, C.sub.1-2 alkoxy-C.sub.1-2 alkyl, C.sub.3-6
cycloalkyl-C.sub.1-2 alkyl, aryl(C.sub.1-2 alkyl)-, and
heteroaryl(C.sub.1-2 alkyl)-;
[0068] R.sup.14a is selected from the group C.sub.1-4 alkyl,
C.sub.1-2 haloalkyl, C.sub.1-2 alkoxy-C.sub.1-2 alkyl, and
C.sub.3-6 cycloalkyl-C.sub.1-2 alkyl;
[0069] R.sup.14b is selected from the group C.sub.1-4 alkyl,
C.sub.1-2 haloalkyl, C.sub.1-2 alkoxy-C.sub.1-2 alkyl, C.sub.3-6
cycloalkyl, and C.sub.3-6 cycloalkyl-C.sub.1-2 alkyl;
[0070] R.sup.15 is independently selected at each occurrence from
the group H, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl, phenyl and benzyl, each phenyl or
benzyl being substituted on the aryl moiety with 0-3 groups chosen
from the group C.sub.1-4 alkyl, Br, Cl, F, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, and dimethylamino;
[0071] R.sup.15a is independently selected at each occurrence from
the group H, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, and C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl;
[0072] R.sup.17, R.sup.18 and R.sup.19 are independently selected
at each occurrence from the group H, C.sub.1-6 alkyl, C.sub.3-10
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, C.sub.1-2
alkoxy-C.sub.1-2 alkyl, and C.sub.1-4 haloalkyl;
[0073] alternatively, in an NR.sup.17R.sup.19 moiety, R.sup.17 and
R.sup.19 taken together form 1-pyrrolidinyl, 1-morpholinyl,
1-piperidinyl or 1-piperazinyl, wherein N.sub.4 in 1-piperazinyl is
substituted with 0-1 substituents selected from the group R.sup.13,
CO.sub.2R.sup.14, COR.sup.14 and SO.sub.2R.sup.14;
[0074] R.sup.17a and R.sup.19a are independently selected at each
occurrence from the group H, C.sub.1-6 alkyl, C.sub.3-10
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl and C.sub.1-4
haloalkyl;
[0075] aryl is phenyl substituted with 1-4 substituents
independently selected at each occurrence from the group C.sub.1-4
alkyl, C.sub.3-6 cycloalkyl, --OR.sup.17, Br, Cl, F, C.sub.1-4
haloalkyl, --CN, --S(O).sub.nR.sup.18, --COR.sup.17,
--CO.sub.2R.sup.17, --NR.sup.15COR.sup.17,
--NR.sup.15CO.sub.2R.sup.18, --NR.sup.17R.sup.19, and
--CONR.sup.17R.sup.19; and,
[0076] heteroaryl is independently selected at each occurence from
the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl,
isoquinolinyl, thienyl, thiazolyl, indolyl, pyrrolyl, oxazolyl,
benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl,
isoxazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl,
2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide,
2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl,
benzodioxolanyl and benzodioxane, each heteroaryl being substituted
1-4 carbon atoms with a substituent independently selected at each
occurrence from the group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl,
Br, Cl, F, C.sub.1-4 haloalkyl, --CN, --OR.sup.17,
--S(O).sub.mR.sup.18, --COR.sup.17, --CO.sub.2R.sup.17,
--OC(O)R.sup.18, --NR.sup.15COR.sup.17, --N(COR.sup.17).sub.2,
--NR.sup.15CO.sub.2R.sup.18- , --NR.sup.17R.sup.19, and
--CONR.sup.17R.sup.19 and each heteroaryl being substituted on any
nitrogen atom with 0-1 substituents selected from the group
R.sup.15, CO.sub.2R.sup.14a, COR.sup.14a and SO.sub.2R.sup.14a.
[0077] [5b] In an even more preferred embodiment, the present
invention provides a novel compound of formula Id, wherein:
[0078] X is selected from the group O, S and a bond
[0079] R.sup.1 is substituted C.sub.1-6 alkyl;
[0080] R.sup.1 is substituted with 0-1 substituents selected from
the group --CN, --CO.sub.2R.sup.13a, and C.sub.3-8 cycloalkyl,
wherein 0-1 carbon atoms in the C.sub.4-8 cycloalkyl is replaced by
a group selected from the group --O--, --S(O).sub.n--, and
--NR.sup.13a;
[0081] R.sup.1 is also substituted with 0-2 substituents
independently selected at each occurrence from the group R.sup.1a,
R.sup.1b, C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
Br, Cl, F, CF.sub.3, --OR.sup.13a, NR.sup.13aR.sup.16a, C.sub.1-2
alkoxy-C.sub.1-2 alkyl, and C.sub.3-6 cycloalkyl which is
substituted with 0-1 CH.sub.3 and in which 0-1 carbons of C.sub.4-8
cycloalkyl is replaced by --O--;
[0082] provided that R.sup.1 is other than a
cyclohexyl-(CH.sub.2).sub.2-- group;
[0083] R.sup.1a is aryl and is phenyl substituted with 0-1
substituents selected from OCH.sub.3, OCH.sub.2CH.sub.3,
OCH(CH.sub.3).sub.2, OCH.sub.2CH.sub.2CH.sub.3, and OCF.sub.3, and
0-3 substituents independently selected at each occurrence from the
group CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.3, cyclopropyl, Br, Cl, F, CF.sub.3, --CN,
SCH.sub.3, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--C(O)NH.sub.2, --C(O)NHCH.sub.3, and --C(O)N(CH.sub.3).sub.2;
[0084] R.sup.1b is heteroaryl and is selected from the group
furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl,
pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl
being substituted on 0-3 carbon atoms with a substituent
independently selected at each occurrence from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3,
cyclopropyl, OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN,
SCH.sub.3, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--C(O)NH.sub.2, --C(O)NHCH.sub.3, and --C(O)N(CH.sub.3).sub.2 and
each heteroaryl being substituted on any nitrogen atom with 0-1
substituents selected from the group CH.sub.3, CO.sub.2CH.sub.3,
COCH.sub.3 and SO.sub.2CH.sub.3;
[0085] provided that R.sup.1 is other than a
--(CH.sub.2).sub.1-4-aryl or --(CH.sub.2).sub.1-4-heteroaryl
wherein the aryl or heteroaryl group is substituted or
unsubstituted;
[0086] R.sup.2 is selected from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, and
CH.sub.2CH.sub.2CH.sub.3;
[0087] R.sup.7 and R.sup.8 are independently selected from the
group H, CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, and
CH.sub.2CH.sub.2CH.sub.3;
[0088] aryl is phenyl substituted with 2-4 substituents
independently selected at each occurrence from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3,
cyclopropyl, OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN,
SCH.sub.3, SO.sub.2CH.sub.3, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --C(O)NH.sub.2, --C(O)NHCH.sub.3, and
--C(O)N(CH.sub.3).sub.2; and,
[0089] heteroaryl is independently selected at each occurence from
the group pyridyl, indolyl, benzothienyl, 2,3-dihydrobenzofuranyl,
2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide,
2,3-dihydrobenzothienyl-S-dioxide, indolinyl, and
benzoxazolin-2-on-yl, each heteroaryl being substituted on 2-4
carbon atoms with a substituent independently selected at each
occurrence from the group CH.sub.3, CH.sub.2CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3, cyclopropyl,
OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN,
SCH.sub.3, SO.sub.2CH.sub.3, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --C(O)NH.sub.2, --C(O)NHCH.sub.3, and
--C(O)N(CH.sub.3).sub.2 and each heteroaryl being substituted on
any nitrogen atom with 0-1 substituents selected from the group
CH.sub.3, CO.sub.2CH.sub.3, COCH.sub.3 and SO.sub.2CH.sub.3.
[0090] [5c] In a still more preferred embodiment, the present
invention provides a novel compound of formula Id, wherein:
[0091] R.sup.1 is substituted C.sub.1;
[0092] R.sup.1 is substituted with 0-1 substituents selected from
the group --CN, --CO.sub.2CH.sub.3, and
--CO.sub.2CH.sub.2CH.sub.3;
[0093] R.sup.1 is also substituted with 0-2 substituents
independently selected at each occurrence from the group R.sup.1a,
R.sup.1b, CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.3, --(CH.sub.2).sub.3CH.sub.3,
--CH.dbd.CH.sub.2, --CH.dbd.CH(CH.sub.3), --CH.ident.CH,
--CH.ident.C(CH.sub.3), CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3, F, CF.sub.3, cyclopropyl,
CH.sub.3-cyclopropyl, cyclobutyl, CH.sub.3-cyclobutyl, cyclopentyl,
CH.sub.3-cyclopentyl;
[0094] R.sup.1a is phenyl substituted with 0-1 substituents
selected from OCH.sub.3, OCH.sub.2CH.sub.3, and OCF.sub.3, and 0-2
substituents independently selected at each occurrence from the
group CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.3, Br, Cl, F, CF.sub.3, --CN, and
SCH.sub.3;
[0095] R.sup.1b is heteroaryl and is selected from the group
furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl,
pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being
substituted on 0-3 carbon atoms with a substituent independently
selected at each occurrence from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3,
OCH.sub.3, OCH.sub.2CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN,
and SCH.sub.3 and each heteroaryl being substituted on any nitrogen
atom with 0-1 substituents selected from the group CH.sub.3,
CO.sub.2CH.sub.3, COCH.sub.3 and SO.sub.2CH.sub.3;
[0096] provided that R.sup.1 is other than a
--(CH.sub.2).sub.1-4-aryl or --(CH.sub.2).sub.1-4-heteroaryl
wherein the aryl or heteroaryl group is substituted or
unsubstituted;
[0097] R.sup.2 is selected from the group CH.sub.3,
CH.sub.2CH.sub.3, and CH(CH.sub.3).sub.2;
[0098] R.sup.7 and R.sup.8 are independently selected from the
group H and CH.sub.3;
[0099] aryl is phenyl substituted with 2-4 substituents
independently selected at each occurrence from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3,
cyclopropyl, OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN,
SCH.sub.3, SO.sub.2CH.sub.3, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --C(O)NH.sub.2, --C(O)NHCH.sub.3, and
--C(O)N(CH.sub.3).sub.2; and,
[0100] heteroaryl is pyridyl substituted on 2-4 carbon atoms with a
substituent independently selected at each occurrence from the
group CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.3, cyclopropyl, OCH.sub.3,
OCH.sub.2CH.sub.3, OCH(CH.sub.3) 2, OCH.sub.2CH.sub.2CH.sub.3,
OCF.sub.3, Br, Cl, F, CF.sub.3, --CN, SCH.sub.3, SO.sub.2CH.sub.3,
--NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2, --C(O)NH.sub.2,
--C(O)NHCH.sub.3, and --C(O)N(CH.sub.3).sub.2.
[0101] [5d] In a further preferred embodiment, the present
invention provides a novel compound of formula Id, wherein:
[0102] R.sup.1 is substituted (cyclopropyl)-C.sub.1 alkyl or
(cyclobutyl)-C.sub.1 alkyl;
[0103] R.sup.1 is substituted with 0-1 --CN;
[0104] R.sup.1 is also substituted with 0-1 substituents
independently selected at each occurrence from the group R.sup.1a,
R.sup.1b, CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.3, --(CH.sub.2).sub.3CH.sub.3,
--CH.dbd.CH.sub.2, --CH.dbd.CH(CH.sub.3), --CH.ident.CH,
--CH.ident.C(CH.sub.3), --CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3, F, CF.sub.3, cyclopropyl, and
CH.sub.3-cyclopropyl;
[0105] R.sup.1a is phenyl substituted with 0-1 substituents
selected from OCH.sub.3, OCH.sub.2CH.sub.3, and OCF.sub.3, and 0-2
substituents independently selected at each occurrence from the
group CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.3, Br, Cl, F, CF.sub.3, --CN, and
SCH.sub.3;
[0106] R.sup.1b is heteroaryl and is selected from the group
furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, and
pyrazolyl, each heteroaryl being substituted on 0-3 carbon atoms
with a substituent independently selected at each occurrence from
the group CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.3, OCH.sub.3, OCH.sub.2CH.sub.3, OCF.sub.3,
Br, Cl, F, CF.sub.3, --CN, and SCH.sub.3.
[0107] [5e] In another further preferred embodiment, the present
invention provides a novel compound of formula Id, wherein:
[0108] R.sup.1 is (cyclopropyl)C.sub.1 alkyl or
(cyclobutyl)-C.sub.1 alkyl substituted with 1 substituent
independently selected at each occurrence from the group R.sup.1a,
R.sup.1b, CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.3, --(CH.sub.2).sub.3CH.sub.3,
--CH.dbd.CH.sub.2, --CH.dbd.CH(CH.sub.3), --CH.ident.CH,
--CH.ident.C(CH.sub.3), --CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3, F, CF.sub.3, cyclopropyl, and
CH.sub.3-cyclopropyl;
[0109] R.sup.1a is phenyl substituted with 0-2 substituents
independently selected at each occurrence from the group CH.sub.3,
CH.sub.2CH.sub.3, Cl, F, and CF.sub.3;
[0110] R.sup.1b is heteroaryl and is selected from the group
furanyl, thienyl, and isoxazolyl, each heteroaryl being substituted
on 0-2 carbon atoms with a substituent independently selected at
each occurrence from the group CH.sub.3, OCH.sub.3, Cl, F, and
CF.sub.3.
[0111] [5f] In an even further preferred embodiment, the present
invention provides a novel compound of formula Id, wherein:
[0112] R.sup.1 is selected from the group
[0113] R.sup.1 is selected from the group
(cyclopropyl)CH--CH.sub.3, (cyclopropyl)CH--CH.sub.2CH.sub.3,
(cyclopropyl)CH--CH.sub.2OCH.sub.3,
(cyclopropyl)CH--CH.sub.2CH.sub.2CH.sub.3,
(cyclopropyl)CH--CH.sub.2CH.su- b.2OCH.sub.3,
(cyclopropyl).sub.2CH, phenyl(cyclopropyl)CH,
furanyl(cyclopropyl)CH, thienyl(cyclopropyl)CH,
isoxazolyl(cyclopropyl)CH- , (CH.sub.3-furanyl)(cyclopropyl)CH,
(cyclobutyl)CH--CH.sub.3, (cyclobutyl)CH--CH.sub.2CH.sub.3,
(cyclobutyl)CH--CH.sub.2OCH.sub.3,
(cyclobutyl)CH--CH.sub.2CH.sub.2CH.sub.3,
(cyclobutyl)CH--CH.sub.2CH.sub.- 2OCH.sub.3, (cyclobutyl).sub.2CH,
phenyl(cyclobutyl)CH, furanyl(cyclobutyl)CH, thienyl(cyclobutyl)CH,
isoxazolyl(cyclobutyl)CH, and (CH.sub.3-furanyl)(cyclobutyl)CH;
[0114] [5 g] In another further preferred embodiment, the present
invention provides a novel compound-of formula Id, wherein:
[0115] D is phenyl substituted with 2-4 substituents independently
selected at each occurrence from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3,
cyclopropyl, OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.3, OCF.sub.3, Br, Cl, F, and CF.sub.3.
[0116] [5 h] In another further preferred embodiment, the present
invention provides a novel compound of formula Id, wherein:
[0117] D is pyridyl substituted on 2-4 carbon atoms with a
substituent independently selected at each occurrence from the
group CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.3, cyclopropyl, OCH.sub.3,
OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2, OCH.sub.2CH.sub.2CH.sub.3,
OCF.sub.3, Br, Cl, F, and CF.sub.3.
[0118] [5i] In another preferred embodiment, the present invention
provides a novel compound of formula Id, wherein the compound is
selected from the group:
[0119]
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-c]pyri-
dine;
[0120]
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5--
c]pyridine;
[0121]
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-c-
]pyridine;
[0122]
4-(2,4-Dichlorophenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-c]pyr-
idine;
[0123]
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)propy-
l-imidazo[4,5-c]pyridine;
[0124]
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-
-imidazo[4,5-c]pyridine;
[0125]
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-3-(1-methoxy)butyl-imi-
dazo[4,5-c]pyridine;
[0126]
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidaz-
o[4,5-c]pyridine;
[0127]
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo-
[4,5-c]pyridine;
[0128]
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-
-c]pyridine;
[0129]
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)prop-
yl-imidazo[4,5-c]pyridine;
[0130]
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)buty-
l-imidazo[4,5-c]pyridine;
[0131]
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-3-(1-methoxy)butyl-im-
idazo[4,5-c]pyridine;
[0132]
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-d]pyri-
dazine;
[0133]
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5--
d]pyridazine;
[0134]
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-d-
]pyridazine;
[0135]
4-(2,4-Dichlorophenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-d]pyr-
idazine;
[0136]
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)propy-
l-imidazo[4,5-d]pyridazine;
[0137]
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-
-imidazo[4,5-d]pyridazine;
[0138]
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-3-(1-methoxy)butyl-imi-
dazo[4,5-d]pyridazine;
[0139]
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidaz-
o[4,5-d]pyridazine;
[0140]
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo-
[4,5-d]pyridazine;
[0141]
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-
-d]pyridazine;
[0142]
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)prop-
yl-imidazo[4,5-d]pyridazine;
[0143]
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)buty-
l-imidazo[4,5-d]pyridazine;
[0144]
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-3-(1-methoxy)butyl-im-
idazo[4,5-d]pyridazine;
[0145]
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-c]pyri-
dazine;
[0146]
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5--
c]pyridazine;
[0147]
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-c-
]pyridazine;
[0148]
4-(2,4-Dichlorophenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-c]pyr-
idazine;
[0149]
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)propy-
l-imidazo[4,5-c]pyridazine;
[0150]
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-
-imidazo[4,5-c]pyridazine;
[0151]
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-3-(1-methoxy)butyl-imi-
dazo[4,5-c]pyridazine;
[0152]
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidaz-
o[4,5-c]pyridazine;
[0153]
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo-
[4,5-c]pyridazine;
[0154]
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-
-c]pyridazine;
[0155]
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)prop-
yl-imidazo[4,5-c]pyridazine;
[0156]
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)buty-
l-imidazo[4,5-c]pyridazine;
[0157]
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-3-(1-methoxy)butyl-im-
idazo[4,5-c]pyridazine;
[0158]
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-d]tria-
zine;
[0159]
4-(2,4-Dichlorophenyl)-2-ethyl-1-(i-cyclopropyl)propyl-imidazo[4,5--
d]triazine;
[0160]
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo[4,5-d-
]triazine;
[0161]
4-(2,4-Dichlorophenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-d]tri-
azine;
[0162]
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)propy-
l-imidazo[4,5-d]triazine;
[0163]
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-
-imidazo[4,5-d]triazine;
[0164]
4-(2-Chloro-4-trifluoromethylphenyl)-2-ethyl-3-(1-methoxy)butyl-imi-
dazo[4,5-d]triazine;
[0165]
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidaz-
o[4,5-d]triazine;
[0166]
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-1-(1-cyclopropyl)butyl-imidazo-
[4,5-d]triazine;
[0167]
4-(2-Chloro-4-methoxyphenyl)-2-ethyl-3-(1-methoxy)butyl-imidazo[4,5-
-d]triazine;
[0168]
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)prop-
yl-imidazo[4,5-d]triazine;
[0169]
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-1-(1-cyclopropyl)buty-
l-imidazo[4,5-d]triazine; and,
[0170]
4-(2-Methyl-4-methoxy-5-fluorophenyl)-2-ethyl-3-(1-methoxy)butyl-im-
idazo[4,5-d]triazine;
[0171] or a pharmaceutically acceptable salt form thereof.
[0172] [5j] In another more preferred embodiment, the present
invention provides a novel compound of formula Id, wherein:
[0173] R.sup.1 is C.sub.3-8 cycloalkyl;
[0174] R.sup.1 is substituted with 0-1 substituents selected from
the group --CN, --S(O).sub.nR.sup.14b, COR.sup.13a,
--CO.sub.2R.sup.13a, --NR.sup.15aCOR.sup.13a,
--N(COR.sup.13a).sub.2, --NR.sup.15aCONR.sup.13a- R.sup.16a,
--NR.sup.15aCO.sub.2R.sup.14b, --CONR.sup.13aR.sup.16a,
1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C.sub.4-8
cycloalkyl, wherein 0-1 carbon atoms in the C.sub.4-8 cycloalkyl is
replaced by a group selected from the group --O--, --S(O).sub.n--,
--NR.sup.13a--, --NCO.sub.2R.sup.14b--, --NCOR.sup.14b-- and
--NSO.sub.2R.sup.14b--, and wherein N.sub.4 in 1-piperazinyl is
substituted with 0-1 substituents selected from the group
R.sup.13a, CO.sub.2R.sup.14b, COR.sup.14b and SO.sub.2R.sup.14b;
and,
[0175] R.sup.1 is also substituted with 0-3 substituents
independently selected at each occurrence from the group R.sup.1a,
R.sup.1b, R.sup.1c, C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, Br, Cl, F, I, C.sub.1-4 haloalkyl, --OR.sup.13a, C.sub.1-2
alkoxy-C.sub.1-2 alkyl, and NR.sup.13aR.sup.16a.
[0176] [5k] In another even more preferred embodiment, the present
invention provides a novel compound of formula Id, wherein:
[0177] X is selected from the group O, S(O).sub.n and a bond;
[0178] n is 0, 1 or 2;
[0179] R.sup.1 is selected from the group cyclopropyl, cyclobutyl,
and cyclopentyl;
[0180] R.sup.1 is substituted with 0-1 substituents selected from
the group --CN, --S(O).sub.nR.sup.14b, --COR.sup.13a,
--CO.sub.2R.sup.13a, and C.sub.4-8 cycloalkyl, wherein one carbon
atom in the C.sub.4-8 cycloalkyl is replaced by a group selected
from the group --O--, --S(O).sub.n--, --NR.sup.13a--,
--NCO.sub.2R.sup.14b--, --NCOR.sup.14b-- and
--NSO.sub.2R.sup.14b--;
[0181] R.sup.1 is also substituted with 0-2 substituents
independently selected at each occurrence from the group R.sup.1a,
R.sup.1b, C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
Br, Cl, F, CF.sub.3, CF.sub.2CF.sub.3, --OR.sup.13a, C.sub.1-2
alkoxy-C.sub.1-2 alkyl, and --NR.sup.13aR.sup.16a;
[0182] R.sup.1a is aryl and is selected from the group phenyl and
indanyl, each R.sup.1a being substituted with 0-1 --OR.sup.17 and
0-5 substituents independently selected at each occurrence from the
group C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, C.sub.1-4
haloalkyl, --CN, --S(O).sub.nR.sup.18, --COR.sup.17,
--NR.sup.17aR.sup.19a, and CONR.sup.17aR.sup.19a;
[0183] R.sup.1b is heteroaryl and is selected from the group
pyridyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl,
pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl,
and indazolyl, each heteroaryl being substituted on 0-4 carbon
atoms with a substituent independently selected at each occurrence
from the group C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F,
CF.sub.3, --CN, --OR.sup.17, --S(O).sub.mR.sup.18, --COR.sup.17,
--NR.sup.17aR.sup.19a, and --CONR.sup.17aR.sup.19a and each
heteroaryl being substituted on any nitrogen atom with 0-1
substituents selected from the group R.sup.15a, CO.sub.2R.sup.14b,
COR.sup.14b and SO.sub.2R.sup.14b;
[0184] R.sup.2 is selected from the group C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl and is substituted with
0-1 substituents selected from the group --CN, OH, Cl, F, and
C.sub.1-4 alkoxy;
[0185] R.sup.9 is independently selected at each occurrence from
the group H, C.sub.1-4 alkyl and C.sub.3-8 cycloalkyl;
[0186] R.sup.7 and R.sup.8 are independently selected from the
group H, Br, Cl, F, --CN, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl,
C.sub.1-4 alkoxy, NH.sub.2, C.sub.1-4 alkylamino, and (C.sub.1-4
alkyl).sub.2-amino;
[0187] R.sup.13 is selected from the group C.sub.1-4 alkyl,
C.sub.1-2 haloalkyl, C.sub.1-2 alkoxy-C.sub.1-2 alkyl, C.sub.3-6
cycloalkyl-C.sub.1-2 alkyl, aryl(C.sub.1-2 alkyl)-, and
heteroaryl(C.sub.1-2 alkyl)-;
[0188] R.sup.13a and R.sup.16a are independently selected at each
occurrence from the group H, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, and
C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl;
[0189] R.sup.14 is selected from the group C.sub.1-4 alkyl,
C.sub.1-2 haloalkyl, C.sub.1-2 alkoxy-C.sub.1-2 alkyl, C.sub.3-6
cycloalkyl-C.sub.1-2 alkyl, aryl(C.sub.1-2 alkyl)-, and
heteroaryl(C.sub.1-2 alkyl)-;
[0190] R.sup.14a is selected from the group C.sub.1-4 alkyl,
C.sub.1-2 haloalkyl, C.sub.1-2 alkoxy-C.sub.1-2 alkyl, and
C.sub.3-6 cycloalkyl-C.sub.1-2 alkyl;
[0191] R.sup.14b is selected from the group C.sub.1-4 alkyl,
C.sub.1-2 haloalkyl, C.sub.1-2 alkoxy-C.sub.1-2 alkyl, C.sub.3-6
cycloalkyl, and C.sub.3-6 cycloalkyl-C.sub.1-2 alkyl;
[0192] R.sup.15 is independently selected at each occurrence from
the group H, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl, phenyl and benzyl, each phenyl or
benzyl being substituted on the aryl moiety with 0-3 groups chosen
from the group C.sub.1-4 alkyl, Br, Cl, F, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, and dimethylamino;
[0193] R.sup.15a is independently selected at each occurrence from
the group H, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, and C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl;
[0194] R.sup.17, R.sup.18 and R.sup.19 are independently selected
at each occurrence from the group H, C.sub.1-6 alkyl, C.sub.3-10
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, C.sub.1-2
alkoxy-C.sub.1-2 alkyl, and C.sub.1-4 haloalkyl;
[0195] alternatively, in an NR.sup.17R.sup.19 moiety, R.sup.17 and
R.sup.19 taken together form 1-pyrrolidinyl, 1-morpholinyl,
1-piperidinyl or 1-piperazinyl, wherein N.sub.4 in 1-piperazinyl is
substituted with 0-1 substituents selected from the group R.sup.13,
CO.sub.2R.sup.14, COR.sup.14 and SO.sub.2R.sup.14;
[0196] R.sup.17a and R.sup.19a are independently selected at each
occurrence from the group H, C.sub.1-6 alkyl, C.sub.3-10
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl and C.sub.1-4
haloalkyl; aryl is phenyl substituted with 1-4 substituents
independently selected at each occurrence from the group C.sub.1-4
alkyl, C.sub.3-6 cycloalkyl, --OR.sup.17, Br, Cl, F, C.sub.1-4
haloalkyl, --CN, --S(O).sub.nR.sup.18, --COR.sup.17,
--CO.sub.2R.sup.17, --NR.sup.15COR.sup.17,
--NR.sup.15CO.sub.2R.sup.18, --NR.sup.17R.sup.19, and
--CONR.sup.17R.sup.19; and,
[0197] heteroaryl is independently selected at each occurence from
the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl,
isoquinolinyl, thienyl, thiazolyl, indolyl, pyrrolyl, oxazolyl,
benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl,
isoxazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl,
2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide,
2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl,
benzodioxolanyl and benzodioxane, each heteroaryl being substituted
1-4 carbon atoms with a substituent independently selected at each
occurrence from the group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl,
Br, Cl, F, C.sub.1-4 haloalkyl, --CN, --OR.sup.17,
--S(O).sub.mR.sup.18, --COR.sup.17, --CO.sub.2R.sup.17,
--OC(O)R.sup.18, --NR.sup.15COR.sup.17, --N(COR.sup.17).sub.2,
--NR.sup.15CO.sub.2R.sup.18- , --NR.sup.17R.sup.19, and
--CONR.sup.17R.sup.19 and each heteroaryl being substituted on any
nitrogen atom with 0-1 substituents selected from the group
R.sup.15, CO.sub.2R.sup.14a, COR.sup.14a and SO.sub.2R.sup.14a.
[0198] [51] In another still more preferred embodiment, the present
invention provides a novel compound of formula Id, wherein:
[0199] X is selected from the group O, S and a bond
[0200] R.sup.1 is substituted with 0-1 substituents selected from
the group --CN, --CO.sub.2R.sup.13a, and C.sub.4-8 cycloalkyl,
wherein 0-1 carbon atoms in the C.sub.4-8 cycloalkyl is replaced by
a group selected from the group --O--, --S(O).sub.n--, and
--NR.sup.13a--;
[0201] R.sup.1 is also substituted with 0-2 substituents
independently selected at each occurrence from the group R.sup.1a,
R.sup.1b, C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
Br, Cl, F, CF.sub.3, CF.sub.3, --OR.sup.13a, --OH, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3, and --NR.sup.13aR.sup.16a;
[0202] R.sup.1a is aryl and is phenyl substituted with 0-1
substituents selected from OCH.sub.3, OCH.sub.2CH.sub.3,
OCH(CH.sub.3).sub.2, OCH.sub.2CH.sub.2CH.sub.3, and OCF.sub.3, and
0-3 substituents independently selected at each occurrence from the
group CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.3, cyclopropyl, Br, Cl, F, CF.sub.3, --CN,
SCH.sub.3, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--C(O)NH.sub.2, --C(O)NHCH.sub.3, and --C(O)N(CH.sub.3).sub.2;
[0203] R.sup.1b is heteroaryl and is selected from the group
furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl,
pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl
being substituted on 0-3 carbon atoms with a substituent
independently selected at each occurrence from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3,
cyclopropyl, OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN,
SCH.sub.3, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--C(O)NH.sub.2, --C(O)NHCH.sub.3, and --C(O)N(CH.sub.3).sub.2 and
each heteroaryl being substituted on any nitrogen atom with 0-1
substituents selected from the group CH.sub.3, CO.sub.2CH.sub.3,
COCH.sub.3 and SO.sub.2CH.sub.3;
[0204] R.sup.2 is selected from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, and
CH.sub.2CH.sub.2CH.sub.3;
[0205] R.sup.7 and R.sup.8 are independently selected from the
group H, CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, and
CH.sub.2CH.sub.2CH.sub.3;
[0206] aryl is phenyl substituted with 2-4 substituents
independently selected at each occurrence from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3,
cyclopropyl, OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN,
SCH.sub.3, SO.sub.2CH.sub.3, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --C(O)NH.sub.2, --C(O)NHCH.sub.3, and
--C(O)N(CH.sub.3).sub.2; and,
[0207] heteroaryl is independently selected at each occurence from
the group pyridyl, indolyl, benzothienyl, 2,3-dihydrobenzofuranyl,
2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide,
2,3-dihydrobenzothienyl-S-dioxide, indolinyl, and
benzoxazolin-2-on-yl, each heteroaryl being substituted on 2-4
carbon atoms with a substituent independently selected at each
occurrence from the group CH.sub.3, CH.sub.2CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3, cyclopropyl,
OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN,
SCH.sub.3, SO.sub.2CH.sub.3, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --C(O)NH.sub.2, --C(O)NHCH.sub.3, and
--C(O)N(CH.sub.3).sub.2 and each heteroaryl being substituted on
any nitrogen atom with 0-1 substituents selected from the group
CH.sub.3, CO.sub.2CH.sub.3, COCH.sub.3 and SO.sub.2CH.sub.3.
[0208] [5 m] In another further preferred embodiment, the present
invention provides a novel compound of formula Id, wherein:
[0209] R.sup.1 is substituted with 0-2 substituents independently
selected at each occurrence from the group R.sup.1a, R.sup.1b,
CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.3, --(CH.sub.2).sub.3CH.sub.3,
--CH.dbd.CH.sub.2., --CH.dbd.CH(CH.sub.3), --CH--CH,
--CH.ident.C(CH.sub.3), --CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3, F, and CF.sub.3;
[0210] R.sup.1a is phenyl substituted with 0-1 substituents
selected from OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3) 2,
OCH.sub.2CH.sub.2CH.sub.3, and OCF.sub.3, and 0-2 substituents
independently selected at each occurrence from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3, Br,
Cl, F, CF.sub.3, --CN, and SCH.sub.3;
[0211] R.sup.1b is heteroaryl and is selected from the group
furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl,
pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being
substituted on 0-3 carbon atoms with a substituent independently
selected at each occurrence from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3,
OCH.sub.3, OCH.sub.2CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN,
and SCH.sub.3 and each heteroaryl being substituted on any nitrogen
atom with 0-1 substituents selected from the group CH.sub.3,
CO.sub.2CH.sub.3, COCH.sub.3 and SO.sub.2CH.sub.3;
[0212] R.sup.2 is selected from the group CH.sub.3,
CH.sub.2CH.sub.3, and CH(CH.sub.3).sub.2;
[0213] R.sup.7 and R.sup.8 are independently selected from the
group H and CH.sub.3;
[0214] aryl is phenyl substituted with 2-4 substituents
independently selected at each occurrence from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3,
cyclopropyl, OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN,
SCH.sub.3, SO.sub.2CH.sub.3, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --C(O)NH.sub.2, --C(O)NHCH.sub.3, and
--C(O)N(CH.sub.3).sub.2; and,
[0215] heteroaryl is pyridyl substituted on 2-4 carbon atoms with a
substituent independently selected at each occurrence from the
group CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.3, cyclopropyl, OCH.sub.3,
OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2, OCH.sub.2CH.sub.2CH.sub.3,
OCF.sub.3, Br, Cl, F, CF.sub.3, --CN, SCH.sub.3, SO.sub.2CH.sub.3,
--NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2, --C(O)NH.sub.2,
--C(O)NHCH.sub.3, and --C(O)N(CH.sub.3).sub.2.
[0216] [5n] In another even further preferred embodiment, the
present invention provides a novel compound of formula Id,
wherein:
[0217] R.sup.1 is substituted with 0-2 substituents independently
selected at each occurrence from the group R.sup.1a, CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3,
--(CH.sub.2).sub.3CH.sub.3, --CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3, F, and CF.sub.3; and,
[0218] R.sup.1a is phenyl substituted with 0-2 substituents
independently selected at each occurrence from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3, Br,
Cl, F, CF.sub.3, --CN, and SCH.sub.3.
[0219] [5o] In a still further preferred embodiment, the present
invention provides a novel compound of formula Id, wherein:
[0220] D is phenyl substituted with 2-4 substituents independently
selected at each occurrence from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3,
cyclopropyl, OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.3, OCF.sub.3, Br, Cl, F, and CF.sub.3.
[0221] [5p] In another still further preferred embodiment, the
present invention provides a novel compound of formula Id,
wherein:
[0222] D is pyridyl substituted on 2-4 carbon atoms with a
substituent independently selected at each occurrence from the
group CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3) 2,
CH.sub.2CH.sub.2CH.sub.3, cyclopropyl, OCH.sub.3,
OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2, OCH.sub.2CH.sub.2CH.sub.3,
OCF.sub.3, Br, Cl, F, and CF.sub.3.
[0223] [5q] In another more preferred embodiment, the present
invention provides a novel compound of formula Id, wherein:
[0224] R.sup.1 is selected from the group C.sub.1-10 alkyl,
C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-8 cycloalkyl,
C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl and C.sub.1-4 alkoxy-C.sub.1-4
alkyl;
[0225] R.sup.1 is substituted with a C.sub.3-8 cycloalkyl group,
wherein 0-1 carbon atoms in the C.sub.4-8 cycloalkyl group is
replaced by a group selected from the group --O--, --S(O).sub.n--,
--NR.sup.13a--, --NCO.sub.2R.sup.14b--, --NCOR.sup.14b-- and
--NSO.sub.2R.sup.14b--;
[0226] R.sup.1 is also substituted with 0-3 substituents
independently selected at each occurrence from the group R.sup.1a,
R.sup.1b, R.sup.1c, C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, Br, Cl, F, I, C.sub.1-4 haloalkyl, --OR.sup.13a,
--NR.sup.13aR.sup.16a, C.sub.1-2 alkoxy-C.sub.1-2 alkyl, and
C.sub.3-8 cycloalkyl which is substituted with 0-1 R.sup.9 and in
which 0-1 carbons of C.sub.4-8 cycloalkyl is replaced by --O--;
[0227] provided that R.sup.1 is other than a
cyclohexyl-(CH.sub.2).sub.2-- group;
[0228] R.sup.1a is aryl and is selected from the group phenyl,
naphthyl, indanyl and indenyl, each R.sup.1a being substituted with
0-1 --OR.sup.17 and 0-5 substituents independently selected at each
occurrence from the group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl,
Br, Cl, F, I, C.sub.1-4 haloalkyl, --CN, nitro, SH,
--S(O).sub.nR.sup.18, --COR.sup.17, --OC(O)R.sup.18,
NR.sup.15aCOR.sup.17, --N(COR.sup.17).sub.2,
--NR.sup.15aCONR.sup.17aR.sup.19a, NR.sup.15aCO.sub.2R.sup.18,
--NR.sup.17aR.sup.19a, and --CONR.sup.17aR.sup.19a;
[0229] R.sup.1b is heteroaryl and is selected from the group
pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl,
isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl,
oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl,
isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide,
indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane,
each heteroaryl being substituted on 0-4 carbon atoms with a
substituent independently selected at each occurrence from the
group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, I,
C.sub.1-4 haloalkyl, --CN, nitro, --OR.sup.17, SH,
--S(O).sub.mR.sup.18, --COR.sup.17, --OC(O)R.sup.8,
--NR.sup.15aCOR.sup.17, --N(COR.sup.17).sub.2,
NR.sup.15aCONR.sup.17aR.su- p.19a, NR.sup.15aCO.sub.2R.sup.18,
--NR.sup.17aR.sup.19a, and --CONR.sup.17aR.sup.19a and each
heteroaryl being substituted on any nitrogen atom with 0-1
substituents selected from the group R.sup.15a, CO.sub.2R.sup.14b,
COR.sup.14b and SO.sub.2R.sup.14b; and,
[0230] R.sup.1c is heterocyclyl and is a saturated or partially
saturated heteroaryl, each heterocyclyl being substituted on 0-4
carbon atoms with a substituent independently selected at each
occurrence from the group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl,
Br, Cl, F, I, C.sub.1-4 haloalkyl, --CN, nitro, --OR.sup.13a, SH,
--S(O).sub.nR.sup.14b, --COR.sup.13a, OC(O)R.sup.14b,
--NR.sup.15aCOR.sup.13a, --N(COR.sup.13a).sub.2,
--NR.sup.15aCONR.sup.13aR.sup.16a, --NR.sup.15aCO.sub.2R.sup.14b,
--NR.sup.13aR.sup.16a, and --CONR.sup.13aR.sup.16a and each
heterocyclyl being substituted on any nitrogen atom with 0-1
substituents selected from the group R.sup.13a, CO.sub.2R.sup.14b,
COR.sup.14b and SO.sub.2R.sup.14b and wherein any sulfur atom is
optionally monooxidized or dioxidized.
[0231] [5r] In another even more preferred embodiment, the present
invention provides a novel compound of formula Id, wherein:
[0232] X is selected from the group O, S(O).sub.n and a bond;
[0233] n is 0, 1 or 2;
[0234] R.sup.1 is selected from the group C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.3-8 cycloalkyl;
[0235] R.sup.1 is substituted with a C.sub.3-6 cycloalkyl group,
wherein 0-1 carbon atoms in the C.sub.4-6 cycloalkyl group is
replaced by a group selected from the group --O--, --S(O).sub.n--,
and NR.sup.13a--;
[0236] R.sup.1 is also substituted with 0-2 substituents
independently selected at each occurrence from the group R.sup.1a,
R.sup.1b, C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
Br, Cl, F, CF.sub.3, CF.sub.2CF.sub.3, --OR.sup.13a,
--NR.sup.13aR.sup.16a, C.sub.1-2 alkoxy-C.sub.1-2 alkyl, and
C.sub.3-6 cycloalkyl which is substituted with 0-1 R.sup.9 and in
which 0-1 carbons of C.sub.4-8 cycloalkyl is replaced by --O--;
[0237] R.sup.1a is aryl and is selected from the group phenyl and
indanyl, each R.sup.1a being substituted with 0-1 --OR.sup.17 and
0-5 substituents independently selected at each occurrence from the
group C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, C.sub.1-4
haloalkyl, --CN, --S(O).sub.nR.sup.18, --COR.sup.17,
--NR.sup.17aR.sup.19a, and --CONR.sup.17aR.sup.19a;
[0238] R.sup.1b is heteroaryl and is selected from the group
pyridyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl,
pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl,
and indazolyl, each heteroaryl being substituted on 0-4 carbon
atoms with a substituent independently selected at each occurrence
from the group C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F,
CF.sub.3, --CN, --OR.sup.17, S(O).sub.mR.sup.18, --COR.sup.17,
--NR.sup.17aR.sup.19a, and --CONR.sup.17aR.sup.19a and each
heteroaryl being substituted on any nitrogen atom with 0-1
substituents selected from the group R.sup.15a, CO.sub.2R.sup.14b,
COR.sup.14b and SO.sub.2R.sup.14b;
[0239] R.sup.2 is selected from the group C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl and is substituted with
0-1 substituents selected from the group --CN, OH, Cl, F, and
C.sub.1-4 alkoxy;
[0240] R.sup.7 and R.sup.8 are independently selected from the
group H, Br, Cl, F, --CN, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl,
C.sub.1-4 alkoxy, NH.sub.2, C.sub.1-4 alkylamino, and (C.sub.1-4
alkyl).sub.2-amino;
[0241] R.sup.9 is independently selected at each occurrence from
the group H, C.sub.1-4 alkyl and C.sub.3-8 cycloalkyl;
[0242] R.sup.13 is selected from the group C.sub.1-4 alkyl,
C.sub.1-2 haloalkyl, C.sub.1-2 alkoxy-C.sub.1-2 alkyl, C.sub.3-6
cycloalkyl-C.sub.1-2 alkyl, aryl(C.sub.1-2 alkyl)-, and
heteroaryl(C.sub.1-2 alkyl)-;
[0243] R.sup.13a and R.sup.16a are independently selected at each
occurrence from the group H, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, and
C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl;
[0244] R.sup.14 is selected from the group C.sub.1-4 alkyl,
C.sub.1-2 haloalkyl, C.sub.1-2 alkoxy-C.sub.1-2 alkyl, C.sub.3-6
cycloalkyl-C.sub.1-2 alkyl, aryl(C.sub.1-2 alkyl)-, and
heteroaryl(C.sub.1-2 alkyl)-;
[0245] R.sup.14a is selected from the group C.sub.1-4 alkyl,
C.sub.1-2 haloalkyl, C.sub.1-2 alkoxy-C.sub.1-2 alkyl, and
C.sub.3-6 cycloalkyl-C.sub.1-2 alkyl;
[0246] R.sup.14b is selected from the group C.sub.1-4 alkyl,
C.sub.1-2 haloalkyl, C.sub.1-2 alkoxy-C.sub.1-2 alkyl, C.sub.3-6
cycloalkyl, and C.sub.3-6 cycloalkyl-C.sub.1-2 alkyl;
[0247] R.sup.15 is independently selected at each occurrence from
the group H, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl, phenyl and benzyl, each phenyl or
benzyl being substituted on the aryl moiety with 0-3 groups chosen
from the group C.sub.1-4 alkyl, Br, Cl, F, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, and dimethylamino;
[0248] R.sup.15a is independently selected at each occurrence from
the group H, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, and C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl;
[0249] R.sup.17, R.sup.18 and R.sup.19 are independently selected
at each occurrence from the group H, C.sub.1-6 alkyl, C.sub.3-10
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, C.sub.1-2
alkoxy-C.sub.1-2 alkyl, and C.sub.1-4 haloalkyl;
[0250] alternatively, in an NR.sup.17R.sup.19 moiety, R.sup.17 and
R.sup.19 taken together form 1-pyrrolidinyl, 1-morpholinyl,
1-piperidinyl or 1-piperazinyl, wherein N.sub.4 in 1-piperazinyl is
substituted with 0-1 substituents selected from the group R.sup.13,
CO.sub.2R.sup.14, COR.sup.14 and SO.sub.2R.sup.14;
[0251] R.sup.17a and R.sup.19a are independently selected at each
occurrence from the group H, C.sub.1-6 alkyl, C.sub.3-10
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl and C.sub.1-4
haloalkyl;
[0252] aryl is phenyl substituted with 1-4 substituents
independently selected at each occurrence from the group C.sub.1-4
alkyl, C.sub.3-6 cycloalkyl, --OR.sup.17, Br, Cl, F, C.sub.1-4
haloalkyl, --CN, --S(O).sub.nR.sup.18, --COR.sup.17,
--CO.sub.2R.sup.17, --NR.sup.15COR.sup.17,
--NR.sup.15CO.sub.2R.sup.18, --NR.sup.17R.sup.19, and
--CONR.sup.17R.sup.19; and,
[0253] heteroaryl is independently selected at each occurence from
the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl,
isoquinolinyl, thienyl, thiazolyl, indolyl, pyrrolyl, oxazolyl,
benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl,
isoxazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl,
2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide,
2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl,
benzodioxolanyl and benzodioxane, each heteroaryl being substituted
1-4 carbon atoms with a substituent independently selected at each
occurrence from the group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl,
Br, Cl, F, C.sub.1-4 haloalkyl, --CN, --OR.sup.17,
--S(O).sub.mR.sup.18, --COR.sup.17, --CO.sub.2R.sup.17,
--OC(O)R.sup.18, --NR.sup.15COR.sup.17, --N(COR.sup.17).sub.2,
--NR.sup.15CO.sub.2R.sup.18- , --NR.sup.17R.sup.19, and
--CONR.sup.17R.sup.19 and each heteroaryl being substituted on any
nitrogen atom with 0-1 substituents selected from the group
R.sup.15, CO.sub.2R.sup.14a, COR.sup.14a and SO.sub.2R.sup.14a.
[0254] [5s] In another still more preferred embodiment, the present
invention provides a novel compound of formula Id, wherein:
[0255] X is selected from the group O, S and a bond
[0256] R.sup.1 is C.sub.1-6 alkyl;
[0257] R.sup.1 is substituted with a C.sub.3-6 cycloalkyl, wherein
one carbon atom in the C.sub.4-6 cycloalkyl is replaced by a group
selected from the group --O--, --S(O).sub.n--, and
--NR.sup.13a--;
[0258] R.sup.1 is also substituted with 0-2 substituents
independently selected at each occurrence from the group R.sup.1a,
R.sup.1b, C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, F,
CF.sub.3, --OR.sup.13a, --NR.sup.13aR.sup.16a, --CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3, and C.sub.3-6 cycloalkyl which is
substituted with 0-1 CH.sub.3 and in which 0-1 carbons of C.sub.4-8
cycloalkyl is replaced by --O--;
[0259] provided that R.sup.1 is other than a
cyclohexyl-(CH.sub.2).sub.2-- group;
[0260] R.sup.1a is aryl and is phenyl substituted with 0-1
substituents selected from OCH.sub.3, OCH.sub.2CH.sub.3,
OCH(CH.sub.3).sub.2, OCH.sub.2CH.sub.2CH.sub.3, and OCF.sub.3, and
0-3 substituents independently selected at each occurrence from the
group CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.3, cyclopropyl, Br, Cl, F, CF.sub.3, --CN,
SCH.sub.3, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--C(O)NH.sub.2, --C(O)NHCH.sub.3, and --C(O)N(CH.sub.3).sub.2;
[0261] R.sup.1b is heteroaryl and is selected from the group
furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl,
pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl
being substituted on 0-3 carbon atoms with a substituent
independently selected at each occurrence from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3) 2, CH.sub.2CH.sub.2CH.sub.3,
cyclopropyl, OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN,
SCH.sub.3, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--C(O)NH.sub.2, --C(O)NHCH.sub.3, and --C(O)N(CH.sub.3).sub.2 and
each heteroaryl being substituted on any nitrogen atom with 0-1
substituents selected from the group CH.sub.3, CO.sub.2CH.sub.3,
COCH.sub.3 and SO.sub.2CH.sub.3;
[0262] R.sup.2 is selected from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, and
CH.sub.2CH.sub.2CH.sub.3;
[0263] R.sup.7 and R.sup.8 are independently selected from the
group H, CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, and
CH.sub.2CH.sub.2CH.sub.3;
[0264] aryl is phenyl substituted with 2-4 substituents
independently selected at each occurrence from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3,
cyclopropyl, OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN,
SCH.sub.3, SO.sub.2CH.sub.3, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --C(O)NH.sub.2, --C(O)NHCH.sub.3, and
--C(O)N(CH.sub.3).sub.2; and,
[0265] heteroaryl is independently selected at each occurence from
the group pyridyl, indolyl, benzothienyl, 2,3-dihydrobenzofuranyl,
2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide,
2,3-dihydrobenzothienyl-S-dioxide, indolinyl, and
benzoxazolin-2-on-yl, each heteroaryl being substituted on 2-4
carbon atoms with a substituent independently selected at each
occurrence from the group CH.sub.3, CH.sub.2CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3, cyclopropyl,
OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN,
SCH.sub.3, SO.sub.2CH.sub.3, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --C(O)NH.sub.2, --C(O)NHCH.sub.3, and
--C(O)N(CH.sub.3).sub.2 and each heteroaryl being substituted on
any nitrogen atom with 0-1 substituents selected from the group
CH.sub.3, CO.sub.2CH.sub.3, COCH.sub.3 and SO.sub.2CH.sub.3.
[0266] [5t] In another further preferred embodiment, the present
invention provides a novel compound of formula Id, wherein:
[0267] R.sup.1 is (cyclopropyl)C.sub.1 alkyl or (cyclobutyl)C.sub.1
alkyl;
[0268] R.sup.1 is substituted with 1-2 substituents independently
selected at each occurrence from the group R.sup.1a, R.sup.1b,
CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.3, --(CH.sub.2).sub.3CH.sub.3,
--CH.dbd.CH.sub.2, --CH.dbd.CH(CH.sub.3), --CH.ident.CH,
--CH.ident.C(CH.sub.3), --CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3, F, CF.sub.3, cyclopropyl,
CH.sub.3-cyclopropyl, cyclobutyl, CH.sub.3-cyclobutyl, cyclopentyl,
CH.sub.3-cyclopentyl;
[0269] R.sup.1a is phenyl substituted with 0-1 substituents
selected from OCH.sub.3, OCH.sub.2CH.sub.3, and OCF.sub.3, and 0-2
substituents independently selected at each occurrence from the
group CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.3, Br, Cl, F, CF.sub.3, CN, and
SCH.sub.3;
[0270] R.sup.1b is heteroaryl and is selected from the group
furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl,
pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being
substituted on 0-3 carbon atoms with a substituent independently
selected at each occurrence from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3) 2, CH.sub.2CH.sub.2CH.sub.3,
OCH.sub.3, OCH.sub.2CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN,
and SCH.sub.3 and each heteroaryl being substituted on any nitrogen
atom with 0-1 substituents selected from the group CH.sub.3,
CO.sub.2CH.sub.3, COCH.sub.3 and SO.sub.2CH.sub.3;
[0271] R.sup.2 is selected from the group CH.sub.3,
CH.sub.2CH.sub.3, and CH(CH.sub.3).sub.2;
[0272] R.sup.7 and R.sup.8 are independently selected from the
group H and CH.sub.3;
[0273] aryl is phenyl substituted with 2-4 substituents
independently selected at each occurrence from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3,
cyclopropyl, OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN,
SCH.sub.3, SO.sub.2CH.sub.3, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --C(O)NH.sub.2, --C(O)NHCH.sub.3, and
--C(O)N(CH.sub.3).sub.2; and,
[0274] heteroaryl is pyridyl substituted on 2-4 carbon atoms with a
substituent independently selected at each occurrence from the
group CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.3, cyclopropyl, OCH.sub.3,
OCH.sub.2CH.sub.3, OCH(CH.sub.3) 2, OCH.sub.2CH.sub.2CH.sub.3,
OCF.sub.3, Br, Cl, F, CF.sub.3, --CN, SCH.sub.3, SO.sub.2CH.sub.3,
--NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2, --C(O)NH.sub.2,
--C(O)NHCH.sub.3, and --C(O)N(CH.sub.3).sub.2.
[0275] [5u] In another even further preferred embodiment, the
present invention provides a novel compound of formula Id,
wherein:
[0276] R.sup.1 is (cyclopropyl)C.sub.1 alkyl or (cyclobutyl)C.sub.1
alkyl;
[0277] R.sup.1 is substituted with 1-2 substituents independently
selected at each occurrence from the group R.sup.1a, R.sup.1b,
CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.3, --(CH.sub.2).sub.3CH.sub.3,
--CH.dbd.CH.sub.2, --CH.dbd.CH(CH.sub.3), --CH.ident.CH,
--CH.ident.C(CH.sub.3), --CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3, F, CF.sub.3, cyclopropyl, and
CH.sub.3-cyclopropyl;
[0278] R.sup.1a is phenyl substituted with 0-2 substituents
independently selected at each occurrence from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3, Br,
Cl, F, CF.sub.3, --CN, and SCH.sub.3;
[0279] R.sup.1b is heteroaryl and is selected from the group
furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, and
pyrazolyl, each heteroaryl being substituted on 0-3 carbon atoms
with a substituent independently selected at each occurrence from
the group CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.3, OCH.sub.3, OCH.sub.2CH.sub.3, OCF.sub.3,
Br, Cl, F, CF.sub.3, --CN, and SCH.sub.3.
[0280] [5v] In another further preferred embodiment, the present
invention provides a novel compound of formula Id, wherein:
[0281] D is phenyl substituted with 2-4 substituents independently
selected at each occurrence from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3,
cyclopropyl, OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.3, OCF.sub.3, Br, Cl, F, and CF.sub.3.
[0282] [5w] In another further preferred embodiment, the present
invention provides a novel compound of formula Id, wherein: D is
pyridyl substituted on 2-4 carbon atoms with a substituent
independently selected at each occurrence from the group CH.sub.3,
CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.3,
cyclopropyl, OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.3. OCF.sub.3, Br, Cl, F, and CF.sub.3.
[0283] [6] In a second embodiment, the present invention provides a
novel method of treating affective disorder, anxiety, depression,
headache, irritable bowel syndrome, post-traumatic stress disorder,
supranuclear palsy, immune suppression, Alzheimer's disease,
gastrointestinal diseases, anorexia nervosa or other feeding
disorder, drug addiction, drug or alcohol withdrawal symptoms,
inflammatory diseases, cardiovascular or heart-related diseases,
fertility problems, human immunodeficiency virus infections,
hemorrhagic stress, obesity, infertility, head and spinal cord
traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis,
hypoglycemia or a disorder the treatment of which can be effected
or facilitated by antagonizing CRF, including but not limited to
disorders induced or facilitated by CRF, in mammals,
comprising:
[0284] administering to the mammal a therapeutically effective
amount of a compound of formula (I): 8
[0285] or a stereoisomer or pharmaceutically acceptable salt form
thereof, wherein:
[0286] A is N or C--R.sup.7;
[0287] B is N or C--R.sup.8;
[0288] D is an aryl or heteroaryl group attached through an
unsaturated carbon atom;
[0289] X is selected from the group CH--R.sup.9, N--R.sup.10, 0,
S(O).sub.n and a bond;
[0290] n is 0, 1 or 2;
[0291] R.sup.1 is selected from the group C.sub.1-10 alkyl,
C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-8 cycloalkyl,
C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, C.sub.1-4 alkoxy-C.sub.1-4
alkyl, --SO.sub.2--C.sub.1-10 alkyl, --SO.sub.2--R.sup.1a, and
--SO.sub.2--R.sup.1b;
[0292] R.sup.1 is substituted with 0-1 substituents selected from
the group --CN, --S(O)R.sup.14b, --COR.sup.13a, CO.sub.2R.sup.13a,
--NR.sup.15aCOR.sup.13a, --N(COR.sup.13a).sub.2,
--NR.sup.15aCONR.sup.13a- R.sup.16a, --NR.sup.15aCO.sub.2R.sup.14b,
--CONR.sup.13aR.sup.16a, 1-morpholinyl, 1-piperidinyl,
1-piperazinyl, and C.sub.3-8 cycloalkyl, wherein 0-1 carbon atoms
in the C.sub.4-8 cycloalkyl is replaced by a group selected from
the group --O--, --S(O).sub.n--, --NR.sup.13a--,
--NCO.sub.2R.sup.14b--, --NCOR.sup.14b-- and
--NSO.sub.2R.sup.14b--, and wherein N.sub.4 in 1-piperazinyl is
substituted with 0-1 substituents selected from the group
R.sup.13a, CO.sub.2R.sup.14b, COR.sup.14b and
SO.sub.2R.sup.14b;
[0293] R.sup.1 is also substituted with 0-3 substituents
independently selected at each occurrence from the group R.sup.1a,
R.sup.1b, R.sup.1c, C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, Br, Cl, F, I, C.sub.1-4 haloalkyl, --OR.sup.13a,
--NR.sup.13aR.sup.16a, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, and
C.sub.3-8 cycloalkyl which is substituted with 0-1 R.sup.9 and in
which 0-1 carbons of C.sub.4-8 cycloalkyl is replaced by --O--;
[0294] R.sup.1a is aryl and is selected from the group phenyl,
naphthyl, indanyl and indenyl, each R.sup.1a being substituted with
0-5 substituents independently selected at each occurrence from the
group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, I,
C.sub.1-4 haloalkyl, --CN, nitro, --OR.sup.17, SH,
--S(O).sub.nR.sup.18, --COR.sup.17, --OC(O)R.sup.18,
--NR.sup.15aCOR.sup.17, --N(COR.sup.17).sub.2,
--NR.sup.15aCONR.sup.17aR.sup.19a, NR.sup.15aCO.sub.2R.sup.18,
--NR.sup.17aR.sup.19a, and --CONR.sup.17aR.sup.19a;
[0295] R.sup.1b is heteroaryl and is selected from the group
pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl,
isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl,
oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl,
isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide,
indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane,
each heteroaryl being substituted on 0-4 carbon atoms with a
substituent independently selected at each occurrence from the
group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, I,
C.sub.1-4 haloalkyl, --CN, nitro, --OR.sup.17, SH,
--S(O).sub.mR.sup.18, --COR.sup.17, --OC(O)R.sup.18,
NR.sup.15aCOR.sup.17, --N(COR.sup.17).sub.2,
--NR.sup.15aCONR.sup.17aR.su- p.19a, --NR.sup.15aCO.sub.2R.sup.18,
NR.sup.17aR.sup.19a, and --CONR.sup.17aR.sup.19a and each
heteroaryl being substituted on any nitrogen atom with 0-1
substituents selected from the group R.sup.15a, CO.sub.2R.sup.14b,
COR.sup.14b and SO.sub.2R.sup.14b;
[0296] R.sup.1c is heterocyclyl and is a saturated or partially
saturated heteroaryl, each heterocyclyl being substituted on 0-4
carbon atoms with a substituent independently selected at each
occurrence from the group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl,
Br, Cl, F, I, C.sub.1-4 haloalkyl, --CN, nitro, --OR.sup.13a, SH,
--S(O).sub.nR.sup.14b, --COR.sup.13a, OC(O)R.sup.14b,
NR.sup.15aCOR.sup.13a, --N(COR.sup.13a).sub.2--NR.sup.15a-
CONR.sup.13aR.sup.16a, --NR.sup.15aCO.sub.2R.sup.14b,
NR.sup.13aR.sup.16a, and --CONR.sup.13aR.sup.16a and each
heterocyclyl being substituted on any nitrogen atom with 0-1
substituents selected from the group R.sup.13a, CO.sub.2R.sup.14b,
COR.sup.14b and SO.sub.2R.sup.14b and wherein any sulfur atom is
optionally monooxidized or dioxidized;
[0297] R.sup.2 is selected from the group C.sub.1-4 alkyl,
C.sub.3-8 cycloalkyl, C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl and
is substituted with 0-3 substituents selected from the group --CN,
hydroxy, halo and C.sub.1-4 alkoxy;
[0298] alternatively R.sup.2, in the case where X is a bond, is
selected from the group --CN, CF.sub.3 and C.sub.2F.sub.5;
[0299] R.sup.7 and R.sup.8 are independently selected at each
occurrence from the group H, Br, Cl, F, I, --CN, C.sub.1-4 alkyl,
C.sub.3-8 cycloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio,
C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl, amino, C.sub.1-4
alkylamino, (C.sub.1-4 alkyl).sub.2amino and phenyl, each phenyl is
substituted with 0-3 groups selected from the group C.sub.1-7
alkyl, C.sub.3-8 cycloalkyl, Br, Cl, F, I, C.sub.1-4 haloalkyl,
nitro, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, C.sub.1-4 alkylthio,
C.sub.1-4 alkyl sulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-6
alkylamino and (C.sub.1-4 alkyl).sub.2amino;
[0300] R.sup.9 and R.sup.10 are independently selected at each
occurrence from the group H, C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl-C.sub.1-4 alkyl and C.sub.3-8 cycloalkyl;
[0301] R.sup.13 is selected from the group H, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, aryl,
aryl(C.sub.1-4 alkyl)-, heteroaryl and heteroaryl (C.sub.1-4
alkyl)-;
[0302] R.sup.13a and R.sup.16a are independently selected at each
occurrence from the group H, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, and
C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl;
[0303] R.sup.14 is selected from the group C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, aryl,
aryl(C.sub.1-4 alkyl)-, heteroaryl and heteroaryl(C.sub.1-4 alkyl)-
and benzyl, each benzyl being substituted on the aryl moiety with
0-1 substituents selected from the group C.sub.1-4 alkyl, Br, Cl,
F, I, C.sub.1-4 haloalkyl, nitro, C.sub.1-4 alkoxy C.sub.1-4
haloalkoxy, and dimethylamino;
[0304] R.sup.14a is selected from the group C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl and benzyl, each
benzyl being substituted on the aryl moiety with 0-1 substituents
selected from the group C.sub.1-4 alkyl, Br, Cl, F, I, C.sub.1-4
haloalkyl, nitro, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, and
dimethylamino;
[0305] R.sup.14b is selected from the group C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl, and C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl;
[0306] R.sup.15 is independently selected at each occurrence from
the group H, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl, phenyl and benzyl, each phenyl or
benzyl being substituted on the aryl moiety with 0-3 groups chosen
from the group C.sub.1-4 alkyl, Br, Cl, F, I, C.sub.1-4 haloalkyl,
nitro, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, and
dimethylamino;
[0307] R.sup.15a is independently selected at each occurrence from
the group H, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, and C.sub.3-6
cycloalkyl-C.sub.1-16 alkyl;
[0308] R.sup.17 is selected at each occurrence from the group H,
C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl, C.sub.1-2 alkoxy-C.sub.1-2 alkyl,
C.sub.1-4 haloalkyl, R.sup.14S(O).sub.n--C.sub.1-4 alkyl, and
R.sup.17bR.sup.19bN--C.sub.2-4 alkyl;
[0309] R.sup.18 and R.sup.19 are independently selected at each
occurrence from the group H, C.sub.1-6 alkyl, C.sub.3-10
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, C.sub.1-2
alkoxy-C.sub.1-2 alkyl, and C.sub.1-4 haloalkyl;
[0310] alternatively, in an NR.sup.17R.sup.19 moiety, R.sup.17 and
R.sup.19 taken together form 1-pyrrolidinyl, 1-morpholinyl,
1-piperidinyl or 1-piperazinyl, wherein N.sub.4 in 1-piperazinyl is
substituted with 0-1 substituents selected from the group R.sup.13,
CO.sub.2R.sup.14, COR.sup.14 and SO.sub.2R.sup.14;
[0311] alternatively, in an NR.sup.17bR.sup.19b moiety, R.sup.17b
and R.sup.19b taken together form 1-pyrrolidinyl, 1-morpholinyl,
1-piperidinyl or 1-piperazinyl, wherein N.sub.4 in 1-piperazinyl is
substituted with 0-1 substituents selected from the group R.sup.13,
CO.sub.2R.sup.14, COR.sup.14 and SO.sub.2R.sup.14;
[0312] R.sup.17a and R.sup.19a are independently selected at each
occurrence from the group H, C.sub.1-6 alkyl, C.sub.3-10
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl and C.sub.1-4
haloalkyl; aryl is independently selected at each occurrence from
the group phenyl, naphthyl, indanyl and indenyl, each aryl being
substituted with 0-5 substituents independently selected at each
occurrence from the group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl,
methylenedioxy, C.sub.1-4 alkoxy-C.sub.1-14 alkoxy, --OR.sup.17,
Br, Cl, F, I, C.sub.1-4 haloalkyl, --CN, --NO.sub.2, SH,
--S(O).sub.nR.sup.18, --COR.sup.17, --CO.sub.2R.sup.17,
--OC(O)R.sup.18, --NR.sup.15COR.sup.17, --N(COR.sup.17) 2,
--NR.sup.15CONR.sup.17R.sup.19, --NR.sup.15CO.sub.2R.sup.18,
--NR.sup.17R.sup.19, and --CONR.sup.17R.sup.19 and up to 1 phenyl,
each phenyl substituent being substituted with 0-4 substituents
selected from the group C.sub.1-3 alkyl, C.sub.1-3 alkoxy, Br, Cl,
F, I, --CN, dimethylamino, CF.sub.3, C.sub.2F.sub.5, OCF.sub.3,
SO.sub.2Me and acetyl; and,
[0313] heteroaryl is independently selected at each occurence from
the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl,
isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl,
oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl,
isoxazolyl, triazolyl, tetrazolyl, indazolyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide,
indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane,
each heteroaryl being substituted 0-4 carbon atoms with a
substituent independently selected at each occurrence from the
group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, I,
C.sub.1-4 haloalkyl, --CN, nitro, --OR.sup.17, SH,
--S(O).sub.mR.sup.18, --COR.sup.17, --CO.sub.2R.sup.17,
--OC(O)R.sup.18, --NR.sup.15COR.sup.17, --N(COR.sup.17).sub.2,
--NR.sup.15CONR.sup.17R.sup.19,
--NR.sup.15CO.sub.2R.sup.18--NR.sup.17R.sup.19, and
--CONR.sup.17R.sup.19 and each heteroaryl being substituted on any
nitrogen atom with 0-1 substituents selected from the group
R.sup.15, CO.sub.2R.sup.14a, COR.sup.14a and SO.sub.2R.sup.14a.
[0314] [7] In a third embodiment, the present invention provides a
novel pharmaceutical composition, comprising: a pharmaceutically
acceptable carrier and a therapeutically effective amount of a
compound of formula (I): 9
[0315] or a stereoisomer or pharmaceutically acceptable salt form
thereof, wherein:
[0316] A is N or C--R.sup.7;
[0317] B is N or C--R.sup.8;
[0318] D is an aryl or heteroaryl group attached through an
unsaturated carbon atom;
[0319] X is selected from the group CH--R.sup.9, N--R.sup.10, O,
S(O).sub.n and a bond;
[0320] n is 0, 1 or 2;
[0321] R.sup.1 is selected from the group C.sub.1-10 alkyl,
C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-8 cycloalkyl,
C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, C.sub.1-4 alkoxy-C.sub.1-4
alkyl, --SO.sub.2--C.sub.1-10 alkyl, --SO.sub.2--R.sup.1a, and
--SO.sub.2--R.sup.1b;
[0322] R.sup.1 is substituted with 0-1 substituents selected from
the group --CN, --S(O).sub.nR.sup.14b, --COR.sup.13a,
--CO.sub.2R.sup.13a, --NR.sup.15aCOR.sup.13a,
--N(COR.sup.13a).sub.2, --NR.sup.15aCONR.sup.13a- R.sup.16a,
NR.sup.15aCO.sub.2R.sup.14b, --CONR.sup.13aR.sup.16a,
1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C.sub.3-8
cycloalkyl, wherein 0-1 carbon atoms in the C.sub.4-8 cycloalkyl is
replaced by a group selected from the group --O--, --S(O).sub.n--,
--NR.sup.13a--, --NCO.sub.2R.sup.14b--, --NCOR.sup.14b-- and
--NSO.sub.2R.sup.14b--, and wherein N.sub.4 in 1-piperazinyl is
substituted with 0-1 substituents selected from the group
R.sup.13a, CO.sub.2R.sup.14b, COR.sup.14b and
SO.sub.2R.sup.14b;
[0323] R.sup.1 is also substituted with 0-3 substituents
independently selected at each occurrence from the group R.sup.1a,
R.sup.1b, R.sup.1c, C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, Br, Cl, F, I, C.sub.1-4 haloalkyl, --OR.sup.13a,
--NR.sup.13aR.sup.16a, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, and
C.sub.3-8 cycloalkyl which is substituted with 0-1 R.sup.9 and in
which 0-1 carbons of C.sub.4-8 cycloalkyl is replaced by --O--;
[0324] R.sup.1a is aryl and is selected from the group phenyl,
naphthyl, indanyl and indenyl, each R.sup.1a being substituted with
0-5 substituents independently selected at each occurrence from the
group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, I,
C.sub.1-4 haloalkyl, --CN, nitro, --OR.sup.17, SH,
--S(O).sub.nR.sup.18, --COR.sup.17, --OC(O)R.sup.18,
--NR.sup.15aCOR.sup.17, --N(COR.sup.17).sub.2,
NR.sup.15aCONR.sup.17aR.sup.19a, --NR.sup.15aCO.sub.2R.sup.18,
--NR.sup.17aR.sup.19a, and --CONR.sup.17aR.sup.19a;
[0325] R.sup.1b is heteroaryl and is selected from the group
pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl,
isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl,
oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl,
isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide,
indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane,
each heteroaryl being substituted on 0-4 carbon atoms with a
substituent independently selected at each occurrence from the
group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, I,
C.sub.1-4 haloalkyl, --CN, nitro, --OR.sup.17, SH,
--S(O).sub.mR.sup.18, --COR.sup.17, --OC(O)R.sup.18,
--NR.sup.15aCOR.sup.17, --N(COR.sup.17).sub.2,
NR.sup.15aCONR.sup.17aR.su- p.19a, NR.sup.15aCO.sub.2R.sup.18,
--NR.sup.17aR.sup.19a, and --CONR.sup.17aR.sup.19a and each
heteroaryl being substituted on any nitrogen atom with 0-1
substituents selected from the group R.sup.15a, CO.sub.2R.sup.14b,
COR.sup.14b and SO.sub.2R.sup.14b;
[0326] R.sup.1c is heterocyclyl and is a saturated or partially
saturated heteroaryl, each heterocyclyl being substituted on 0-4
carbon atoms with a substituent independently selected at each
occurrence from the group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl,
Br, Cl, F, I, C.sub.1-4 haloalkyl, --CN, nitro, --OR.sup.13a, SH,
--S(O).sub.nR.sup.14b, --COR.sup.13a, OC(O)R.sup.14b,
--NR.sup.15aCOR.sup.13a, --N(COR.sup.13a).sub.2,
--NR.sup.15aCONR.sup.13aR.sup.16a, NR.sup.15aCO.sub.2R.sup.14b,
--NR.sup.13aR.sup.16a, and --CONR.sup.13aR.sup.16a and each
heterocyclyl being substituted on any nitrogen atom with 0-1
substituents selected from the group R.sup.13a, CO.sub.2R.sup.14b,
COR.sup.14b and SO.sub.2R.sup.14b and wherein any sulfur atom is
optionally monooxidized or dioxidized;
[0327] R.sup.2 is selected from the group C.sub.1-4 alkyl,
C.sub.3-8 cycloalkyl, C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl and
is substituted with 0-3 substituents selected from the group --CN,
hydroxy, halo and C.sub.1-4 alkoxy;
[0328] alternatively R.sup.2, in the case where X is a bond, is
selected from the group --CN, CF.sub.3 and C.sub.2F.sub.5;
[0329] R.sup.7 and R.sup.8 are independently selected at each
occurrence from the group H, Br, Cl, F, I, --CN, C.sub.1-4 alkyl,
C.sub.3-8 cycloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio,
C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl, amino, C.sub.1-4
alkylamino, (C.sub.1-4 alkyl).sub.2amino and phenyl, each phenyl is
substituted with 0-3 groups selected from the group C.sub.1-7
alkyl, C.sub.3-8 cycloalkyl, Br, Cl, F, I, C.sub.1-4 haloalkyl,
nitro, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, C.sub.1-4 alkylthio,
C.sub.1-4 alkyl sulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-6
alkylamino and (C.sub.1-4 alkyl).sub.2amino;
[0330] R.sup.9 and R.sup.10 are independently selected at each
occurrence from the group H, C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl-C.sub.1-4 alkyl and C.sub.3-8 cycloalkyl;
[0331] R.sup.13 is selected from the group H, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, aryl,
aryl(C.sub.1-4 alkyl)-, heteroaryl and heteroaryl(C.sub.1-4
alkyl)-;
[0332] R.sup.13a and R.sup.16a are independently selected at each
occurrence from the group H, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, and
C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl;
[0333] R.sup.14 is selected from the group C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, aryl,
aryl(C.sub.1-4 alkyl)-, heteroaryl and heteroaryl(C.sub.1-4 alkyl)-
and benzyl, each benzyl being substituted on the aryl moiety with
0-1 substituents selected from the group C.sub.1-4 alkyl, Br, Cl,
F, I, C.sub.1-4 haloalkyl, nitro, C.sub.1-4 alkoxy C.sub.1-4
haloalkoxy, and dimethylamino;
[0334] R.sup.14a is selected from the group C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl and benzyl, each
benzyl being substituted on the aryl moiety with 0-1 substituents
selected from the group C.sub.1-4 alkyl, Br, Cl, F, I, C.sub.1-4
haloalkyl, nitro, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, and
dimethylamino;
[0335] R.sup.14b is selected from the group C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, C.sub.3-6
cycloalkyl, and C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl;
[0336] R.sup.15 is independently selected at each occurrence from
the group H, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl, phenyl and benzyl, each phenyl or
benzyl being substituted on the aryl moiety with 0-3 groups chosen
from the group C.sub.1-4 alkyl, Br, Cl, F, I, C.sub.1-4 haloalkyl,
nitro, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, and
dimethylamino;
[0337] R.sup.15a is independently selected at each occurrence from
the group H, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, and C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl;
[0338] R.sup.17 is selected at each occurrence from the group H,
C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-6 alkyl, C.sub.1-2 alkoxy-C.sub.1-2 alkyl,
C.sub.1-4 haloalkyl, R.sup.14S(O).sub.n--C.sub.1-4 alkyl, and
R.sup.17bR.sup.19bN--C.sub.2-4 alkyl;
[0339] R.sup.18 and R.sup.19 are independently selected at each
occurrence from the group H, C.sub.1-6 alkyl, C.sub.3-10
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, C.sub.1-2
alkoxy-C.sub.1-2 alkyl, and C.sub.1-4 haloalkyl;
[0340] alternatively, in an NR.sup.17R.sup.19 moiety, R.sup.17 and
R.sup.19 taken together form 1-pyrrolidinyl, 1-morpholinyl,
1-piperidinyl or 1-piperazinyl, wherein N.sub.4 in 1-piperazinyl is
substituted with 0-1 substituents selected from the group R.sup.13,
CO.sub.2R.sup.14, COR.sup.14 and SO.sub.2R.sup.14;
[0341] alternatively, in an NR.sup.17bR.sup.19b moiety, R.sup.17b
and R.sup.19b taken together form 1-pyrrolidinyl, 1-morpholinyl,
1-piperidinyl or 1-piperazinyl, wherein N.sub.4 in 1-piperazinyl is
substituted with 0-1 substituents selected from the group R.sup.13,
CO.sub.2R.sup.14, COR.sup.14 and SO.sub.2R.sup.14;
[0342] R.sup.17a and R.sup.19a are independently selected at each
occurrence from the group H, C.sub.1-6 alkyl, C.sub.3-10
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl and C.sub.1-4
haloalkyl;
[0343] aryl is independently selected at each occurrence from the
group phenyl, naphthyl, indanyl and indenyl, each aryl being
substituted with 0-5 substituents independently selected at each
occurrence from the group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl,
methylenedioxy, C.sub.1-4 alkoxy-C.sub.1-4 alkoxy, --OR.sup.17, Br,
Cl, F, I, C.sub.1-4 haloalkyl, --CN, --NO.sub.2, SH,
--S(O).sub.nR.sup.18, --COR.sup.17, --CO.sub.2R.sup.17,
--OC(O)R.sup.18, --NR.sup.15COR.sup.17, --N(COR.sup.17).sub.2,
--NR.sup.15CONR.sup.17R.sup.19, --NR.sup.15CO.sub.2R.sup.18,
--NR.sup.17R.sup.19, and --CONR.sup.17R.sup.19 and up to 1 phenyl,
each phenyl substituent being substituted with 0-4 substituents
selected from the group C.sub.1-3 alkyl, C.sub.1-3 alkoxy, Br, Cl,
F, I, --CN, dimethylamino, CF.sub.3, C.sub.2F.sub.5, OCF.sub.3,
SO.sub.2Me and acetyl; and,
[0344] heteroaryl is independently selected at each occurence from
the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl,
isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl,
oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl,
isoxazolyl, triazolyl, tetrazolyl, indazolyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide,
indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane,
each heteroaryl being substituted 0-4 carbon atoms with a
substituent independently selected at each occurrence from the
group C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, Br, Cl, F, I,
C.sub.1-4 haloalkyl, --CN, nitro, --OR.sup.17, SH,
--S(O).sub.mR.sup.18, --COR.sup.17, --CO.sub.2R.sup.17,
--OC(O)R.sup.18, --NR.sup.15COR.sup.17, --N(COR.sup.17).sub.2,
--NR.sup.15CONR.sup.17R.sup.19, --NR.sup.15CO.sub.2R.sup.18,
--NR.sup.17R.sup.19, and --CONR.sup.17R.sup.19 and each heteroaryl
being substituted on any nitrogen atom with 0-1 substituents
selected from the group R.sup.15 CO.sub.2R.sup.14a, COR.sup.14a and
SO.sub.2R.sup.14a.
[0345] In another preferred embodiment, R.sup.1 is other than a
cyclohexyl-(CH.sub.2).sub.1, 2, 3, 4, 5, 6, 7, 8, 9, or 10--
group;
[0346] In another preferred embodiment, R.sup.1 is other than an
aryl-(CH.sub.2).sub.1, 2, 3, 4, 5, 6, 7, 8, 9, or 10-- group,
wherein the aryl group is substituted or unsubstituted;
[0347] In another preferred embodiment, R.sup.1 is other than a
heteroaryl-(CH.sub.2).sub.1, 2, 3, 4, 5, 6, 7, 8, 9, or 10-- group,
wherein the heteroaryl group is substituted or unsubstituted;
[0348] In another preferred embodiment, R.sup.1 is other than a
heterocyclyl-(CH.sub.2).sub.1, 2, 3, 4, 5, 6, 7, 8, 9, or 10--
group, wherein the heterocyclyl group is substituted or
unsubstituted;
[0349] In another preferred embodiment, when D is imidazole or
triazole, R.sup.1 is other than unsubstituted C.sub.1, 2, 3, 4, 5,
6, 7, 8, 9, or 10 linear or branched alkyl or C.sub.3, 4, 5, 6, 7,
or 8 cycloalkyl.
[0350] In another preferred embodiment, R.sup.1a is not substituted
with OR.sup.17.
[0351] In fourth embodiment, the present invention provides
intermediate compounds useful in preparation of the CRF antagonist
compounds and processes for making those intermediates, as
described in the following description and claims.
[0352] In a fifth embodiment, the present invention provides CRF
antagonist compounds and labelled derivatives thereof as standards
and reagents in determining the ability of a potential
pharmaceutical to bind to the CRF receptor.
Definitions
[0353] The compounds herein described may have asymmetric centers.
Compounds of the present invention containing an asymmetrically
substituted atom may be isolated in optically active or racemic
forms. It is well known in the art how to prepare optically active
forms, such as by resolution of racemic forms or by synthesis from
optically active starting materials. Many geometric isomers of
olefins, C.dbd.N double bonds, and the like can also be present in
the compounds described herein, and all such stable isomers are
contemplated in the present invention. Cis and trans geometric
isomers of the compounds of the present invention are described and
may be isolated as a mixture of isomers or as separated isomeric
forms. All chiral, diastereomeric, racemic forms and all geometric
isomeric forms of a structure are intended, unless the specific
stereochemistry or isomeric form is specifically indicated. All
processes used to prepare compounds of the present invention and
intermediates made therein are considered to be part of the present
invention.
[0354] The term "substituted," as used herein, means that any one
or more hydrogens on the designated atom is replaced with a
selection from the indicated group, provided that the designated
atom's normal valency is not exceeded, and that the substitution
results in a stable compound. When a substitent is keto (i.e., =O),
then 2 hydrogens on the atom are replaced. Keto substituents are
not present on aromatic moieties.
[0355] 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. Isotopes of carbon include C-13 and
C-14.
[0356] When any variable (e.g., R.sup.6) occurs more than one time
in any constituent or formula for a compound, its definition at
each occurrence is independent of its definition at every other
occurrence. Thus, for example, if a group is shown to be
substituted with 0-2 R.sup.6, then said group may optionally be
substituted with up to two R.sup.6 groups and R.sup.6 at each
occurrence is selected independently from the definition of
R.sup.6. Also, combinations of substituents and/or variables are
permissible only if such combinations result in stable
compounds.
[0357] When a bond to a substituent is shown to cross a bond
connecting two atoms in a ring, then such substituent may be bonded
to any atom on the ring. When a substituent is listed without
indicating the atom via which such substituent is bonded to the
rest of the compound of a given formula, then such substituent may
be bonded via any atom in such substituent. Combinations of
substituents and/or variables are permissible only if such
combinations result in stable compounds.
[0358] As used herein, "alkyl" is intended to include both branched
and straight-chain saturated aliphatic hydrocarbon groups having
the specified number of carbon atoms. Examples of alkyl include,
but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl,
s-butyl, t-butyl, n-pentyl, and s-pentyl. "Haloalkyl" is intended
to include both branched and straight-chain saturated aliphatic
hydrocarbon groups having the specified number of carbon atoms,
substituted with 1 or more halogen (for example --C.sub.vF.sub.w
where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include,
but are not limited to, trifluoromethyl, trichloromethyl,
pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents an
alkyl group as defined above with the indicated number of carbon
atoms attached through an oxygen bridge. Examples of alkoxy
include, but are not limited to, methoxy, ethoxy, n-propoxy,
i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.
"Cycloalkyl" is intended to include saturated ring groups, such as
cyclopropyl, cyclobutyl, or cyclopentyl. Alkenyl" is intended to
include hydrocarbon chains of either a straight or branched
configuration and one or more unsaturated carbon-carbon bonds which
may occur in any stable point along the chain, such as ethenyl and
propenyl. "Alkynyl" is intended to include hydrocarbon chains of
either a straight or branched configuration and one or more triple
carbon-carbon bonds which may occur in any stable point along the
chain, such as ethynyl and propynyl.
[0359] "Halo" or "halogen" as used herein refers to fluoro, chloro,
bromo, and iodo; and "counter-ion" is used to represent a small,
negatively charged species such as chloride, bromide, hydroxide,
acetate, sulfate, and the like.
[0360] "Halo" or "halogen" as used herein refers to fluoro, chloro,
bromo, and iodo; and "counterion" is used to represent a small,
negatively charged species such as chloride, bromide, hydroxide,
acetate, and sulfate.
[0361] As used herein, "carbocycle" or "carbocyclic residue" is
intended to mean any stable 3- to 7-membered monocyclic or bicyclic
or 7-to 13-membered bicyclic or tricyclic, any of which may be
saturated, partially unsaturated, or aromatic. Examples of such
carbocycles include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl,
cyclooctyl, [3.3.0]bicyclooctane, [4.3.--O]bicyclononane,
[4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl,
naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
[0362] As used herein, the term "heterocycle" or "heterocyclic
system" is intended to mean a stable 5-to 7-membered monocyclic or
bicyclic or 7-to 10-membered bicyclic heterocyclic ring which is
saturated partially unsaturated or unsaturated (aromatic), and
which consists of carbon atoms and from 1 to 4 heteroatoms
independently selected from the group consisting of N, O and S and
including any bicyclic group in which any of the above-defined
heterocyclic rings is fused to a benzene ring. The nitrogen and
sulfur heteroatoms may optionally be oxidized. The heterocyclic
ring may be attached to its pendant group at any heteroatom or
carbon atom which results in a stable structure. The heterocyclic
rings described herein may be substituted on carbon or on a
nitrogen atom if the resulting compound is stable. A nitrogen in
the heterocycle may optionally be quaternized. It is preferred that
when the total number of S and O atoms in the heterocycle exceeds
1, then these heteroatoms are not adjacent to one another. It is
preferred that the total number of S and O atoms in the heterocycle
is not more than 1. As used herein, the term "aromatic heterocyclic
system" is intended to mean a stable 5-to 7-membered monocyclic or
bicyclic or 7-to 10-membered bicyclic heterocyclic aromatic ring
which consists of carbon atoms and from 1 to 4 heterotams
independently selected from the group consisting of N, O and S. It
is preferred that the total number of S and O atoms in the aromatic
heterocycle is not more than 1.
[0363] Examples of heterocycles include, but are not limited to,
acridinyl, azocinyl, benzimidazolyl, benzofuranyl,
benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,
benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,
benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl,
chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,
6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahyd- rofuran, furanyl,
furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,
indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl,
pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,
phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,
piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,
pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,
pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,
pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,
quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,
tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Preferred
heterocycles include, but are not limited to, pyridinyl, furanyl,
thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl,
benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl,
benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl. Also
included are fused ring and Spiro compounds containing, for
example, the above heterocycles.
[0364] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0365] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound
is modified by making acid or base salts thereof. Examples of
pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic residues such as amines; and
alkali or organic salts of acidic residues such as carboxylic
acids. The pharmaceutically acceptable salts include the
conventional non-toxic salts or the quaternary ammonium salts of
the parent compound formed, for example, from non-toxic inorganic
or organic acids. For example, such conventional non-toxic salts
include those derived from inorganic acids such as hydrochloric,
hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the
salts prepared from organic acids such as acetic, propionic,
succinic, glycolic, stearic, lactic, malic, tartaric, citric,
ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,
benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,
toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and
isethionic.
[0366] The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound which
contains a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or
base forms of these compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a
mixture of the two; generally, nonaqueous media like ether, ethyl
acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists
of suitable salts are found in Remington's Pharmaceutical Sciences,
17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the
disclosure of which is hereby incorporated by reference.
[0367] "Prodrugs" are intended to include any covalently bonded
carriers which release the active parent drug according to formula
(I) in vivo when such prodrug is administered to a mammalian
subject. Prodrugs of a compound of formula (I) are prepared by
modifying functional groups present in the compound in such a way
that the modifications are cleaved, either in routine manipulation
or in vivo, to the parent compound. Prodrugs include compounds of
formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded
to any group that, when the prodrug or compound of formula (I) is
administered to a mammalian subject, cleaves to form a free
hydroxyl, free amino, or free sulfhydryl group, respectively.
Examples of prodrugs include, but are not limited to, acetate,
formate and benzoate derivatives of alcohol and amine functional
groups in the compounds of formula (I), and the like.
[0368] "Stable compound" and "stable structure" are meant to
indicate a compound that is sufficiently robust to survive
isolation to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent.
[0369] "Substituted" is intended to indicate that one or more
hydrogens on the atom indicated in the expression using
"substituted" is replaced with a selection from the indicated
group(s), provided that the indicated atom's normal valency is not
exceeded, and that the substitution results in a stable compound.
When a substituent is keto (i.e., .dbd.O) group, then 2 hydrogens
on the atom are replaced.
[0370] "Therapeutically effective amount" is intended to include an
amount of a compound of the present invention or an amount of the
combination of compounds claimed effective to inhibit HIV infection
or treat the symptoms of HIV infection in a host. The combination
of compounds is preferably a synergistic combination. Synergy, as
described for example by Chou and Talalay, Adv. Enzyme Regul.
22:27-55 (1984), occurs when the effect (in this case, inhibition
of HIV replication) of the compounds when administered in
combination is greater than the additive effect of the compounds
when administered alone as a single agent. In general, a
synergistic effect is most clearly demonstrated at suboptimal
concentrations of the compounds. Synergy can be in terms of lower
cytotoxicity, increased antiviral effect, or some other beneficial
effect of the combination compared with the individual
components.
[0371] Combinations of substituents and/or variables are
permissible only if such combinations result in stable compounds. A
stable compound or stable structure is meant to imply a compound
that is sufficiently robust to survive isolation to a useful degree
of purity from a reaction mixture, and formulation into an
effective therapeutic agent.
[0372] The term "therapeutically effective amount" of a compound of
this invention means an amount effective to antagonize abnormal
level of CRF or treat the symptoms of affective disorder, anxiety
or depression in a host.
Synthesis
[0373] The compounds of the present invention can be prepared in a
number of ways well known to one skilled in the art of organic
synthesis. The compounds of the present invention can be
synthesized using the methods described below, together with
synthetic methods known in the art of synthetic organic chemistry,
or variations thereon as appreciated by those skilled in the art.
Preferred methods include but are not limited to those methods
described below. Each of the references cited below are hereby
incorporated herein by reference.
[0374] The following abbreviations are used herein:
1 AcOH acetic acid t-BuOK potassium tert-butoxide DEAD diethyl
azodicarboxylate DMSO dimethyl sulfoxide EtOAc ethyl acetate EtOH
ethanol NaHMDS sodium bis (trimethylsilyl) amide PPh.sub.3
triphenylphosphine THF tetrahydrofuran TLC thin layer
chromatography
[0375] 10
[0376] The compounds of this invention of formula (Ia) may be
prepared using the methods shown in Scheme 1. In this procedure the
5-chloro-3,4-diaminopyridazine precursor may be cyclized to the
desired imidazopyridiazines using orthoesters (for R.sup.2--X--=H,
alkyl, alkoxy, etc.), orthocarbonates, carboxylic acids, carboxylic
acid esters, alkyl imidates and other reagents appropriate to the
product desired, and reaction conditions known to those skilled in
the art of organic synthesis. The synthesis of the starting
material where R.sup.8=H, and the chemistry thereof has been
described by Kurashi and Castle (J. Het. Chem. 1964, 1, 42).
[0377] The imidazolepyridazine may then be N-alkylated using, for
example, base promoted conditions (e.g., NaHMDS/R.sup.1-LG, where
LG=halide, sulfonate, or other appropriate leaving group) or
Mitsunobu reaction conditions (e.g., DEAD/PPh.sub.3/R.sup.1--OH).
The compounds of formula (Ia) are then formed by cross coupling
with an appropriate arylboronic acid, arylstannane, or arylzinc
reagent under known conditions In the case where R.sup.1 is a
protecting group such as benzyl, p-methoxybenzyl, or
tetrahydropyranyl (J. Het. Chem. 1968, 5, 13), the group may be
removed and N-alkylation at this point gives compounds of formula
(Ia). 11
[0378] Compounds of formula (Ia) may also be prepared via the
method outlined in Scheme 2. Commercially available
4,5-dibromo-pyridazin-3-one is N and/or O benzylated then cross
coupled in, for example, a Suzuki reaction
(D-B(OH).sub.2/Pd(PPh.sub.3).sub.4/Na.sub.2CO.sub.3) followed by
deprotection. Chlorination using, for example, POCl.sub.3 gives a
chloro-pyridazine which may then be reacted for example, with an
amidine. N-alkylation of the resulting bicyclic compound using the
methods described above affords the desired compounds of formula
(Ia).
[0379] Compounds of formula (Ia) may also be prepared via the
method outlined in Scheme 2b. In this procedure, a
2-chloroacetophenone is condensed with a dialkyl malonate (e.g.,
TiCl.sub.4/CCl.sub.4/pyridine/TH- F) or nitroacetate. The product
from this reaction is treated with hydrazine to give an
intermediate which is oxidized using, for example, DDQ or NBS to
give the pyridazinone intermediate. Chlorination (or bromination)
using POCl.sub.3 (or POBr.sub.3) affords a chloro- (or bromo-)
pyridazine intermediate. This intermediate, where Y=ester in Scheme
2b, may now be converted to the acid (e.g., LiOH/H.sub.2O/MeOH/THF)
and then subjected to conditions such as the Curtius reaction or
modifications thereof (e.g., DPPA, Et.sub.3N, t-BuOH;
TFA/CH.sub.2Cl.sub.2), which transform the acid to an amino group.
Substitution of the halide with an appropriate amine using, for
example, nucleophilic substitution or cross-coupling reactions,
affords an intermediate which can then be converted to the desired
imidazopyridiazines (Ia) by cyclization using orthoesters (for
R.sup.2--X--=H, alkyl, alkoxy, etc.), orthocarbonates, carboxylic
acids, carboxylic acid esters, alkyl imidates and other reagents
appropriate to the product desired, and reaction conditions known
to those skilled in the art of organic synthesis. 12
[0380] The intermediate where Y.dbd.NO.sub.2 in Scheme 2b may be
treated with an appropriate amine using, for example, nucleophilic
substitution conditions. Reduction of the nitro group to the amine
(e.g., Fe/AcOH or sodium dithionite/water/EtOH) affords an
intermediate which can then be converted to the desired
imidazopyridiazines (Ia) by cyclization using orthoesters (for
R.sup.2--X--=H, alkyl, alkoxy, etc.), orthocarbonates, carboxylic
acids, carboxylic acid esters, alkyl imidates and other reagents
appropriate to the product desired, and reaction conditions known
to those skilled in the art of organic synthesis. 13
[0381] The compounds of this invention of formula (Id) may be
prepared using the methods shown in Scheme 3. In this procedure,
the 3,4-diamino-5-nitropyridine precursor may be cyclized to the
desired imidazopyridines using orthoesters (for R.sup.2--X--=H,
alkyl, alkoxy, etc.), orthocarbonates, carboxylic acids, carboxylic
acid esters, alkyl imidates and other reagents appropriate to the
product desired, and reaction conditions known to those skilled in
the art of organic synthesis. The synthesis of the precursor where
R.sup.7 and R.sup.8=H, and the chemistry thereof has been described
by Graboyes and Day (J. Am. Chem. Soc. 1957, 79, 6421). Reduction
of the nitro group using, for example, stannous chloride, provides
the amino compound. Conversion of the amino group to a chloride,
bromide or iodide may now be effected via diazotization of the
amine followed by displacement with halogen anion. The halide
compounds may then be N-alkylated using, for example, base promoted
conditions (e.g., NaHMDS/R.sup.1-LG, where LG=halide, sulfonate, or
other appropriate leaving group) or Mitsunobu reaction conditions
(e.g., DEAD/PPh.sub.3/R.sup.1--OH). Cross coupling with an
appropriate arylboronic acid, arylstannane, or arylzinc reagent
under known conditions to yield compounds of formula (Id). In the
case where R.sup.1 is a protecting group, the group may now be
removed and N-alkylation at this point gives compounds of formula
(Id). 14
[0382] Compounds of Formula (Ib) may be prepared, using the
procedures outlined in Scheme 4. The starting material (where Ra is
lower alkyl, X and R2 are defined above) may be treated with a
compound of the formula D-M (where M=Li, Na, MgBr, MgCl, ZnCl,
CeCl.sub.2 and D is defined above) in the presence of an inert
solvent at reaction temperatures ranging from -80.degree. C. to
250.degree. C. to provide the keto-imidazole. Inert solvents may
include, but are not limited to, dialkyl ethers (preferably diethyl
ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane)
or aromatic hydrocarbons (preferably benzene or toluene).
[0383] The imidazolepyridazine can then be formed by reaction with
hydrazine in an inert solvent. Inert solvents may include, but are
not limited to, alkyl alcohols (1 to 6 carbons), dialkyl ethers
(preferably diethyl ether), cyclic ethers (preferably
tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably
benzene or toluene). Preferred reaction temperatures range from -80
to 120.degree. C.
[0384] The hydroxypyridazine may then be treated with a
halogenating agent to give halo derivatives which may be isolated
or prepared in situ. Halogenating agents include, but are not
limited to, SOCl.sub.2, POCl.sub.3, PCl.sub.3, PCl.sub.5,
POBr.sub.3, PBr.sub.3 or PBr.sub.5. These intermediates may be
treated with a compound of the Formula R.sup.7H in the presence or
absence of a base in an inert solvent. Bases may include, but are
not limited to, alkali metal hydrides (preferably sodium hydride),
alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide
or sodium ethoxide), alkaline earth metal hydrides, alkali metal
dialkylamides (preferably lithium di-isopropylamide), alkali metal
bis(trialkylsilyl)amides (preferably sodium
bis(trimethylsilyl)amid- e), trialkyl amines (preferably
N,N-di-isopropyl-N-ethyl amine or triethylamine), aromatic amines
(preferably pyridine) or alkyl-lithiums in the presence or absence
of salts or complexes of Cu, Ce, Mg, Pd, Ni, Zn, Sn. Inert solvents
may include, but are not limited to, lower alkanenitriles (1 to 6
carbons, preferably acetonitrile), dialkyl ethers (preferably
diethyl ether), cyclic ethers (preferably tetrahydrofuran or
1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide),
N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides
(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides
(preferably dimethylsulfoxide), aromatic hydrocarbons (preferably
benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10
halogens (preferably dichloromethane). Preferred reaction
temperatures range from -20 to 100.degree. C.
[0385] The resulting compounds may then be reacted with an
alkylating agent of the Formula R.sup.1X (where R.sup.1 is defined
above) and X is halo, alkanesulfonyloxy, arylsulfonyloxy or
haloalkane-sulfonyloxy) in the presence or absence of a base in an
inert solvent to provide compounds of Formula (Id). Bases may
include, but are not limited to, alkali metal hydrides (preferably
sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably
sodium methoxide or sodium ethoxide), alkaline earth metal
hydrides, alkali metal dialkylamides (preferably lithium
di-isopropylamide), alkali metal bis(trialkylsilyl)amides
(preferably sodium bis(trimethylsilyl)amide), trialkyl amines
(preferably N,N-di-isopropyl-N-ethyl amine or triethylamine),
aromatic amines (preferably pyridine) or alkyl-lithiums in the
presence or absence of salts or complexes of Cu, Ce, Mg, Pd, Ni,
Zn, Sn. Inert solvents may include, but are not limited to, lower
alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl
ethers (preferably diethyl ether), cyclic ethers (preferably
tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably
dimethylformamide), N,N-dialkylacetamides (preferably
dimethylacetamide), cyclic amides (preferably
N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably
dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or
toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens
(preferably dichloromethane). Preferred reaction temperatures range
from -20 to 100.degree. C.
[0386] Alternatively, alkylation to compounds of Formula (Ib) by
treatment with a azodicarboxylate ester
R.sup.bO.sub.2CN.dbd.NCO.sub.2R.sup.b (where R.sup.b is a lower
alkyl group) and a compound of the Formula R.sup.1OH in the
presence of a triarylphosphine (where aryl is phenyl or furyl, each
optionally substituted by 0 to 3 alkyl groups) in an inert solvent.
Inert solvents may include, but are not limited to, lower
alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl
ethers (preferably diethyl ether), cyclic ethers (preferably
tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably
dimethylformamide), N,N-dialkylacetamides (preferably
dimethylacetamide), cyclic amides (preferably
N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably
dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or
toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens
(preferably dichloromethane). Preferred reaction temperatures range
from -20 to 100.degree. C. 15
[0387] Compounds of Formula (Ib) may also be prepared, using the
procedures outlined in Scheme 5. The starting diester may be
treated with a reducing agent in inert solvent to afford an
aldehyde. Reducing agents include, but are not limited to, alkali
metal or alkaline earth metal borohydrides (preferably lithium or
sodium borohydride), borane, dialkylboranes (such as
di-isoamylborane), alkali metal aluminum hydrides (preferably
lithium aluminum hydride), alkali metal (trialkoxy)aluminum
hydrides, or dialkyl aluminum hydrides (such as di-isobutylaluminum
hydride). Inert solvents may include, but are not limited to, alkyl
alcohols (1 to 6 carbons), dialkyl ethers (preferably diethyl
ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane),
aromatic hydrocarbons (preferably benzene or toluene). Preferred
reaction temperatures range from -80 to 100.degree. C.
[0388] Alternatively, the aldehyde may be prepared by a two step
sequence: treatment with a reducing agent in an inert solvent,
followed by treatment with an oxidizing agent in an inert solvent.
Reducing agents and inert solvents are defined above. Oxidizing
agents include, but are not limited to, combinations of oxalyl
chloride, dimethyl sulfoxide and organic bases, MnO2, KMnO4,
pyridinium dichromate, pyridinium chlorochromate or combinations of
SO.sub.3 and organic bases. Organic bases include, but are not
limited to, trialkyl amines (preferably N,N-di-isopropyl-N-ethyl
amine or triethylamine) or aromatic amines (preferably
pyridine).
[0389] The aldehyde may then be reacted with hydrazine in an inert
solvent to form an imidazole. Inert solvents may include, but are
not limited to, alkyl alcohols (1 to 6 carbons), dialkyl ethers
(preferably diethyl ether), cyclic ethers (preferably
tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably
benzene or toluene). Preferred reaction temperatures range from -80
to 120.degree. C.
[0390] The hydroxy group may then be treated with sulfonylating
agents in the presence or absence of a base to give
alkanesulfonyloxy, arylsulfonyloxy or haloalkylsulfonyloxy
derivatives, which may be isolated or used in situ. Sulfonylating
agents include, but are not limited to, alkanesulfonyl halides or
anhydrides (such as methanesulfonyl chloride or methanesulfonic
acid anhydride), arylsulfonyl halides or anhydrides (such as
p-toluenesulfonyl chloride or anhydride) or haloalkylsulfonyl
halides or anhydrides (preferably trifluoromethanesulfonic
anhydride). Bases may include, but are not limited to, alkali metal
hydrides (preferably sodium hydride), alkali metal alkoxides (1 to
6 carbons)(preferably sodium methoxide or sodium ethoxide),
alkaline earth metal hydrides, alkali metal dialkylamides
(preferably lithium di-isopropylamide), alkali metal
bis(trialkylsilyl)amides (preferably sodium
bis(trimethylsilyl)amide), trialkyl amines (preferably
N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines
(preferably pyridine). Inert solvents may include, but are not
limited to, lower alkanenitriles (1 to 6 carbons, preferably
acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic
ethers (preferably tetrahydrofuran or 1,4-dioxane),
N,N-dialkylformamides (preferably dimethylformamide),
N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides
(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides
(preferably dimethylsulfoxide), aromatic hydrocarbons (preferably
benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10
halogens (preferably dichloromethane).
[0391] The sulfonylated intermediates may then be reacted with
compounds of the formula D-B(OH)2 in the presence of salts or
complexes of Pd, Ni, or Sn, in the presence or absence of a base in
an inert solvent to provide compounds of Formula (Ib). Bases may
include, but are not limited to, alkaline earth metal carbonates,
alkaline earth metal bicarbonates, alkaline earth metal hydroxides,
alkali metal carbonates, alkali metal bicarbonates, alkali metal
hydroxides, alkali metal hydrides (preferably sodium hydride),
alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide
or sodium ethoxide), alkaline earth metal hydrides, alkali metal
dialkylamides (preferably lithium di-isopropylamide), alkali metal
bis(trialkylsilyl)amides (preferably sodium
bis(trimethylsilyl)amid- e), trialkyl amines (preferably
N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines
(preferably pyridine). Inert solvents may include, but are not
limited to, lower alkanenitriles (1 to 6 carbons, preferably
acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic
ethers (preferably tetrahydrofuran or 1,4-dioxane),
N,N-dialkylformamides (preferably dimethylformamide),
N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides
(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides
(preferably dimethylsulfoxide), aromatic hydrocarbons (preferably
benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10
halogens (preferably dichloromethane). 16
[0392] Compounds of Formula (Ib) may also be prepared by the
procedures outlined in Scheme 6. The starting imidazoles may
treated with halogenating agents in an inert solvent to provide a
dihalo-imidazole. Halogenating agents include, but are not limited
to, SOCl.sub.2, POCl.sub.3, PCl.sub.3, PCl.sub.5, POBr.sub.3,
PBr.sub.3 or PBr.sub.5. Inert solvents may include, but are not
limited to, lower alkanenitriles (1 to 6 carbons, preferably
acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic
ethers (preferably tetrahydrofuran or 1,4-dioxane),
N,N-dialkylformamides (preferably dimethylformamide),
N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides
(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides
(preferably dimethylsulfoxide), aromatic hydrocarbons (preferably
benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10
halogens (preferably dichloromethane).
[0393] One halogen may be replaced via treatment with a compound of
Formula R.sup.cM (where R.sup.c is lower alkyl and M may be Li, Na,
MgBr, MgCl, ZnCl, CeCl.sub.2) in an inert solvent, followed by
reaction with a compound of Formula R.sup.7--(C.dbd.O)--Y (where
R.sup.7 is defined above and Y is halogen, lower alkoxy, lower
alkanoyloxy or (R.sup.dO).sub.2(P.dbd.O)O (where R.sup.d is lower
alkyl or phenyl)). The acyl compounds my be protected by reaction
with acetal- or ketal-forming reagents (where Rd or Re are each
lower alkyl, or taken together they form a lower alkylene chain).
These acetal- or ketal-forming reagents may be combinations of
lower alkyl alcohols or diols and acids or trialkylorthoformates
and acids. Such acids may be present in catalytic or stoichiometric
amounts. Such acids include, but are not limited to, alkanoic acids
of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids
(preferably p-toluenesulfonic acid or benzenesulfonic acid),
alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic
acid), hydrochloric acid, sulfuric acid or phosphoric acid. Inert
solvents may include, but are not limited to, alkyl alcohols (1 to
8 carbons, preferably methanol or ethanol), lower alkanenitriles (1
to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably
glyme or diglyme), cyclic ethers (preferably tetrahydrofuran or
1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide),
N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides
(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides
(preferably dimethylsulfoxide), aromatic hydrocarbons (preferably
benzene or toluene) or halocarbons of 1 to 10 carbons and 1 to 10
halogens (preferably chloroform). Preferred reaction temperatures
range from ambient temperature to 150.degree. C.
[0394] Moiety D may be attached by treatment with a compound of
Formula R.sup.cM (where R.sup.c is lower alkyl and M may be Li, Na,
MgBr, MgCl, ZnCl, CeCl.sub.2) in an inert solvent, followed by
reaction with a compound of Formula D-(C.dbd.O)--Y (where D is
defined above and Y is halogen, lower alkoxy, lower alkanoyloxy or
(R.sup.dO).sub.2(P.dbd.O)O (where R.sup.d is lower alkyl or
phenyl)). Inert solvents may include, but are not limited to,
dialkyl ethers (preferably diethyl ether), cyclic ethers
(preferably tetrahydrofuran or 1,4-dioxane), or aromatic
hydrocarbons (preferably benzene or toluene).
[0395] Compounds of Formula (Ib) may finally be prepared by (a)
hydrolysis with an acid, followed by (b) reaction with hydrazine in
an inert solvent. Acids include, but are not limited to, alkanoic
acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic
acids (preferably p-toluenesulfonic acid or benzenesulfonic acid),
alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic
acid), hydrochloric acid, sulfuric acid or phosphoric acid. Inert
solvents may include, but are not limited to, alkyl alcohols (1 to
8 carbons, preferably methanol or ethanol), lower alkanenitriles (1
to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably
glyme or diglyme), cyclic ethers (preferably tetrahydrofuran or
1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide),
N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides
(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides
(preferably dimethylsulfoxide), aromatic hydrocarbons (preferably
benzene or toluene) or halocarbons of 1 to 10 carbons and 1 to 10
halogens (preferably chloroform). Preferred reaction temperatures
for steps (a) or (b) range from ambient temperature to 150.degree.
C.
[0396] If intermediates contain functional groups which are
sensitive to the reaction conditions employed, these groups may be
protected using methods known to those skilled in the art. These
methods include, but are not limited to, those described in
Protective Groups in Organic Synthesis (Greene, Wuts; 2nd ed.,
1991, John Wiley & Sons, Inc.).
[0397] Other features of the invention will become apparent in the
course of the following descriptions of exemplary embodiments which
are given for illustration of the invention and are not intended to
be limiting thereof.
EXAMPLES
[0398] Abbreviations used in the Examples are defined as follows:
"1.times." for once, "2.times." for twice, "3.times." for thrice,
".degree. C" for degrees Celsius, "eq" for equivalent or
equivalents, "g" for gram or grams, "mg" for milligram or
milligrams, "mL" for milliliter or milliliters, ".sup.1H" for
proton, "h" for hour or hours, "M" for molar, "min" for minute or
minutes, "MHz" for megahertz, "MS" for mass spectroscopy, "NMR" for
nuclear magnetic resonance spectroscopy, "rt" for room temperature,
"tlc" for thin layer chromatography, "v/v" for volume to volume
ratio. ".alpha.", ".beta.", "R" and "S" are stereochemical
designations familiar to those skilled in the art.
Example 1
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-d]pyridazine
[0399] Part A: 4,5-dibromo-2-ethyl-1H-imidazole:
[0400] To a solution of 2-ethylimidazole (57.6 g, 0.6 moles) in
CHCl.sub.3 (700 mL) was cooled to 0-5.degree. C. and then added
bromine (76.8 mL, 1.5 moles) dropwise over 60 mins under nitrogen
atmosphere. The mixture was stirred at 5.degree. C. for 60 mins and
then at room temperature for 2 days. TLC (1:10
MeOH/CH.sub.2Cl.sub.2) revealed disappearence of starting material
(Rf=0.25) and showed a new spot (Rf=0.45). The mixture was cooled
back to 0.degree. C. and added dropwise 2N aq. NaOH (750 mL) to
dissolve the yellow solid separated from the mixture. The aq. layer
was separated and extracted the organic layer with 250 mL of 2N
NaOH. The combined aq. extracts was acidified to pH 8.0 using con.
HCl. The cream colored solid separated was filtered, washed with
water and dried in vacuum at 50.degree. C. to afford 55.0 g of
desired product (mp 149-150.degree. C., 36%). .sup.1H NMR
(CDCl.sub.3): .cndot. 1.27-1.3 (t, 3H, CH.sub.3), 2.7-2.8 (q, 2H,
CH.sub.2). Mass spectrum (CI--NH.sub.3): m/z 255.0 (MH.sup.+).
[0401] Part B:
4,5-dibromo-2-ethyl-1-(1-ethyl)propyl-1H-imidazole:
[0402] A mixture of part A material (8.3 g, 0.033 moles),
triphenylphosphine (9.4 g, 0.036 moles) and molecular sieves (10 g)
in THF (100 mL) was cooled to 0 to -5.degree. C. and then added
3-pentanol (3.4 g, 0.039 moles) under nitrogen atmosphere. The
mixture was stirred at 0.degree. C. for 30 mins and then added
disopropylazodicarboxylate (7.2 g, 0.033 moles) dropwise over 20
mis. The mixture was stirred at 0.degree. C. for 2 h followed by
room temperature for 2 days and TLC (1:50 MeOH/CH.sub.2Cl.sub.2)
revealed a new spot at Rf=0.5. The undissolved material was
filtered, washed with dichloromethane and stripped off the solvent
in vacuum to afford yellow liquid. The crude was purified by flash
column chromatography using chloroform as eluent to afford 4.9 g
(46.5%) of colorless oil. .sup.1H NMR (CDCl.sub.3): .cndot.
0.79-0.84 (t, 6H, 2*CH.sub.3), 1.3-1.35 (t, 3H, CH.sub.3),
1.82-2.18 (m, 4H, 2*CH.sub.2), 2.65-2.72 (q, 2H, CH.sub.2), 3.95
(m, 1H, CH). Mass spectrum (CI--NH.sub.3): m/z 325.0
(MH.sup.+).
[0403] Part C:
4-bromo-2-ethyl-1-(1-ethyl)propyl-1H-imidazole-5-carboxalde-
hyde:
[0404] A solution of part B material (3.7 g, 0.0114 moles) in THF
(40.0 mL) was cooled to -78.degree. C. under nitrogen atmosphere
and then added dropwise 1.6 M n-BuLi solution in hexane (7.4 mL,
0.0119 moles) over 30 mins. The mixture was stirred at -78.degree.
C. for 1 h and then added dropwise DMF (2.7 mL, 0.0342 moles) over
15 mins. The mixture was stirred at -78.degree. C. for 60 mins and
quenched with saturated NH.sub.4Cl (10 mL) at -78.degree. C. TLC
(1:50 MeOH/CH.sub.2Cl.sub.2) revealed a new spot at Rf=0.55 along
with disappearence of starting material spot at Rf=0.5. The
reaction mixture was extracted with diethyl ether (3*25 mL), washed
with brine and dried (MgSO.sub.4). The solvent was stripped off in
vacuo to afford 3.6 g of yellow oil which was purified by flash
column chromatography on silica gel using chloroform as eluent to
afford 1.97 g (64% yield) of colorless oil. .sup.1H NMR
(CDCl.sub.3): .cndot. 0.73-0.83 (t, 6H, 2*CH.sub.3), 1.35-1.40 (t,
3H, CH.sub.3), 1.59-2.17 (m, 4H, 2*CH.sub.2), 2.72-2.80 (q, 2H,
CH.sub.2), 3.95 (m, 1H, CH), 9.67 (s, 1H, CHO). Mass spectrum
(CI--NH.sub.3): m/z 275.1 (M+2H).
[0405] Part D:
4-bromo-2-ethyl-1-(1-ethyl)propyl-1H-imidazole-5-carboxalde- hyde
Ethylene Acetal:
[0406] A mixture of part C material (1.75 g, 0.0064 moles) in
benzene (150 mL) was treated with ethylene glycol (1.2 mL, 0.025
moles), pyridine (0.0035 moles) and p-toluenesulfonic acid mono
hydrate (0.0035 moles). The reaction mixture was heated at reflux
in a 20 mL capacity Dean-Stark trap equipped apparatus for 24 h and
TLC (1:50 MeOH/CH.sub.2Cl.sub.2) revealed a new spot at Rf=0.35
(visible under iodine). The reaction mixture was cooled to room
temperature, diluted with EtOAc (50 mL), washed with 10% sodium
bicarbonate, brine and dried (MgSO.sub.4). The solvent was
evaporated under reduced pressure to furnish yellow oil. The crude
was purified by flash column chromatography on silica gel using 25%
ethyl acetate/chloroform mixture to afford 1.96 g (97%) white solid
(mp 70-71.degree. C.). .sup.1H NMR (CDCl.sub.3): .cndot. 0.78-0.89
(t, 6H, 2*CH.sub.3), 1.29-1.36 (t, 3H, CH.sub.3), 1.77-1.90 (m, 4H,
2*CH.sub.2), 2.70-2.73 (q, 2H, CH.sub.2), 3.98-4.3 (m, 5H, CH and
2*CH.sub.2), 5.86 (s, 1H, CH). Mass spectrum (CI--NH.sub.3): m/z
317.1 (M+). Anal. calcd for C.sub.13H.sub.22Br.sub.1N.sub.2O.sub.2:
C, 49.22; H, 6.67; N, 8.83. Found: C, 49.43; H, 6.61; N, 8.78.
[0407] Part E:
4-(2,4-dichlorobenzoyl)-2-ethyl-1-(1-ethyl)propyl-1H-imidaz-
ole-5-carboxaldehyde:
[0408] A solution of part D material (1.08 g, 0.0034 moles) in THF
(20.0 mL) was cooled to -78.degree. C. and then added dropwise 1.6
M n-BuLi in hexane (2.4 mL, 0.004 moles) over 15 mins under
nitrogen atmosphere. The mixture was stirred at -78.degree. C. for
21/2 h and then added a solution of 2,4-dichlorobenzoyl chloride
(0.84 g, 0.004 moles) in THF (5.0 mL) over 15 mins. The mixture was
stirred at -78.degree. C. for 6 h followed by room temperature
overnight and TLC (30:70 EtOAc/hexane) showed a new spot at
Rf=0.43. The mixture was quenched with saturated NH.sub.4Cl (10.0
ml), extracted with ethyl acetate (3*30 mL), washed with brine and
dried (MgSO.sub.4). The solvent was stripped off in vacuo to afford
crude product which was purified by flash column chromatography on
a silica gel using 15% EtOAC/hexane to afford 0.61 g (44% yield) of
desired product as yellow oil. Mass spectrum (CI--NH.sub.3): m/z
411.2 (M+). The acetal was dissolved in acetone (15.0 mL) and
treated with 3.0 M aqeous HCl (30.0 mL) at room temperature. The
reaction mixture was stirred for 24 h at this temperature and TLC
(30:70 EtOAc/hexane) showed a new spot at Rf=0.55. It was then
quenched with saturated NaCl (50.0 ml), extracted with ethyl
acetate (3*50 mL), washed with brine and dried (MgSO.sub.4). The
solvent was removed in vacuum to afford yellow liquid and purified
the crude by flash column chromatography on a silica gel using 15%
EtOAC/hexane to afford 0.28 g (51% yield) of desired product as
yellow solid (mp 85-86.degree. C.). .sup.1H NMR
(CDCl.sub.3):.cndot. 0.785 (m, 6H, 2*CH.sub.3), 1.28-1.33 (t, 3H,
CH.sub.3), 1.90-2.23 (m, 4H, 2*CH.sub.2), 2.74-2.82 (q, 2H,
CH.sub.2), 3.98-4.05 (m, 1H, CH), 7.34-7.37 (d, 1H, aromatic),
7.45-7.46 (d, 1H, aromatic), 7.55-7.58 (d, 1H, aromatic). Mass
spectrum (CI--NH.sub.3): m/z 367 (M+). Anal. calcd for
C.sub.18H.sub.20Cl.sub.2N.sub.2O.sub.2: C, 58.87; H, 5.50; N, 7.64.
Found: C, 58.91; H, 5.60; N, 7.44.
[0409] Part F:
4-(2,4-dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,-
5-d]pyridazine:
[0410] A mixture of part E material (0.110 g, 0.0003 moles) in
ethanol (15 mL) was treated with anhydrous hydrazine (0.125 g,
0.0039 moles) and refluxed under nitrogen for 4 h. TLC (1:10
MeOH/CH.sub.2Cl.sub.2) showed a new spot at Rf=0.6. The solvent was
removed under vacuum and purified the crude by flash column
chromatography on a silica gel using 1:100 MeOH/CH.sub.2Cl.sub.2 to
afford 105 mg (97% yield) of the product as yellow oil and
tituration of the oil with diethyl ether (1.0 mL) gave 65 mg of
white crystalline solid (mp 136-137.degree. C.). .sup.1H NMR
(CDCl.sub.3): .cndot. 0.82-0.87 (t, 6H, 2*CH.sub.3), 1.41-1.46 (t,
3H, CH.sub.3), 2.05-2.21 (m, 4H, 2*CH.sub.2), 2.95-3.03 (q, 2H,
CH.sub.2), 4.16-4.26 (m, 1H, CH), 7.41-7.44 (d, 1H, aromatic),
7.58-7.59 (d, 1H, aromatic), 7.64-7.67 (d, 1H, aromatic), 9.49 (s,
1H, 9 CH). Mass spectrum (CI--NH.sub.3): m/z 363 (M.sup.+). Anal.
calcd for C.sub.18H.sub.20Cl.sub.2N.sub.4: C, 59.51; H, 5.56; N,
15.42. Found: C, 59.53; H, 5.79; N, 14.70.
Example 95
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imidazo[4,5-c]pyrid-
azine
[0411] Part A:
4-Ethoxycarbonyl-5-(2,4-dichlorophenyl)-1,6-dihydropyridazi-
n-3-one:
[0412] A 1M solution of TiCl.sub.4 in CH.sub.2Cl.sub.2 (100 mL) was
slowly added via syringe to anhydrous THF (500 mL) cooled to
-5.degree. C. under N.sub.2 with vigorous stirring. After stirring
for 15 min, a solution of 2,2',4'-trichloroacetophenone (11 g, 49.2
mmol) in THF was added to the mixture, followed by addition of
diethyl malonate (7.4 mL, 48.4 mmol). Pyridine (16.5 mL) was then
added dropwise, and the reaction mixture was stirred for 16 h at
room temperature. The mixture was then partitioned between
Et.sub.2O and water, and the aqueous layer was washed with
Et.sub.2O. Organic extracts were combined and dried over
MgSO.sub.4, filtered and evaporated in vacuo to afford the olefin
as a pale yellow oil.
[0413] To a solution of the olefin in EtOH was added 1.5
equivalents of hydrazine monohydrate and 1.5 equivalents of
diisopropylethylamine. The mixture was refluxed for 4 h, then
evaporated in vacuo. The residue was chromatographed on silica gel
(100% Hexane to 20% EtOAc/Hexane gradient) to yield 5.8 g of a pale
yellow solid. .sup.1H NMR (300 MHz, CDCl.sub.3): .cndot. 9.39 (s,
1H), 7.42-7.26 (m, 3H), 4.23 (quart., 2H), 3.6 (m, 1H), 3.33-3.11
(m, 2H), 1.27 (t, 3H).
[0414] Part B:
3-Bromo-4-ethoxycarbonyl-5-(2,4-dichlorophenyl)pyridazine:
[0415] To a solution of 1.1 g of product from Part A in toluene was
added 2 equivalents of POBr.sub.3 and the mixture was refluxed for
3 h. The reaction mixture was evaporated in vacuo and the residue
was chromatographed on silica gel to yield desired product (100%
Hexane to 15% EtOAc/Hex gradient). Mass spectrum (APcI):
(M+H).sup.+ m/z 374.8 (60%), 376.8 (100%), 378.8 (43%).
[0416] Part C: 4-Amino-3-bromo-5-(2,4-dichlorophenyl)
Pyridazine:
[0417] To a solution of product from Part B in THF was added a
solution of 5 equivalents of LiOH monohydrate in water. A small
amount of MeOH was added to make the mixture homogenous. The
reaction mixture was stirred at room temperature for 3 h. The
mixture was then partitioned between Et.sub.2O and 1N HCl. The
organic extract was dried over MgSO.sub.4, filtered, and evaporated
in vacuo to give the acid.
[0418] To a solution of the acid in t-BuOH was added 1.1
equivalents of both DPPA (diphenyphosphorylazide) and triethyamine.
The reaction mixture was refluxed for 16 h, then concentrated in
vacuo. The residue was partitioned between Et.sub.2O and water. The
organic extract was dried over MgSO.sub.4, filtered, and evaporated
in vacuo. This residue was dissolved in CH.sub.2Cl.sub.2 and
trifluoroacetic acid was added. This solution was stirred at room
temperature for 4 h, then evaporated in vacuo to afford the crude
amine.
[0419] Part D:
4-(2,4-Dichlorophenyl)-2-ethyl-1-(1-cyclopropyl)propyl-imid-
azo[4,5-c]pyridazine:
[0420] To a mixture of the amine in toluene is added
l-cyclopropyl-1-propylamine hydrochloride (1.2 equivalents), sodium
t-butoxide (2.5 equivalents), Pd.sub.2(dba).sub.3 (0.05
equivalents), and BINAP (0.025 equivalents). The reaction mixture
is stirred at 70.degree. C. for 16 h. The mixture is then cooled
and partitioned between Et.sub.2O and water. The organic extract is
dried over MgSO.sub.4, filtered, and evaporated in vacuo. To the
crude residue is added triethylorthopropionate and 1 drop of conc.
HCl and the mixture is refluxed for 3 h then evaporated in vacuo.
To this residue is added o-xylene and p-toluenesulfonic acid, and
this mixture is refluxed for 3 h then evaporated in vacuo. The
residue is chromatographed on silica gel (100% hexane to 40%
EtOAc/Hexane gradient) to yield the title compound.
Example 1121
Synthesis of
2-ethyl-1-(1-ethyl)propyl-4-(2,4,6-trimethylphenyl)-imidazo[4-
,5-d]pyridazine
[0421] Part A:
2-Ethyl-1-(1-ethyl)propyl-4-(2,4,6-trimethylbenzoyl)-1H-imi-
dazole-5-carboxaldehyde: A mixture of Part D material of Example 1
(0.82 g, 0.0030 moles) in THF (20.0 mL) was cooled to -78.degree.
C. and then added dropwise 1.6 M n-BuLi in hexane (2.0 mL, 0.0033
moles) over 15 mins under nitrogen atmosphere. The mixture was
stirred at -78.degree. C. for 3 h and then added a solution of
2,4,6-trimethylbenzoyl chloride (0.60 g, 0.0033 moles) in THF (5.0
mL) over 15 mins. The mixture was stirred at -78.degree. C. for 6 h
followed by room temperature overnight for 16 h and TLC (30:70
EtOAc/hexane) showed both starting material and product had same Rf
values. The mixture was quenched with saturated NH.sub.4Cl (10.0
ml), extracted with ethyl acetate (3*30 mL), washed with brine and
dried (MgSO.sub.4). The solvent was stripped off in vacuo to afford
crude product (1.0 g) as yellow semi solid. Mass spectrum
(APcI-positive): m/z 385.4 (M+H). The acetal was dissolved in
acetone (15.0 mL) and treated with 3.0 M aqeous HCl (30.0 mL) at
room temperature. The reaction mixture was stirred for 24 h at this
temperature and TLC (30:70 EtOAc/hexane) showed a new spot at
Rf=0.55 along with unreacted starting material acetal. Therefore
continued further for 24 h and found to contain still some
unreacted starting material. It was then quenched with saturated
NaCl (50.0 ml), extracted with ethyl acetate (3*50 mL), washed with
brine and dried (MgSO.sub.4). The solvent was removed in vacuum to
afford yellow liquid and purified the crude by flash column
chromatography on a silica gel using dichloromethane as eluent to
afford 0.3 g (29% yield) of desired product as yellow solid (mp
119-120.degree. C.). .sup.1H NMR (CDCl.sub.3): ? 0.779 (m, 6H,
2*CH.sub.3) 1.26-1.31 (t, 3H, CH.sub.3), 1.90-1.95 (m, 4H,
2*CH.sub.2), 2.16-2.31 (2S, 9H, aromatic CH.sub.3), 2.74-2.81 (q,
2H, CH.sub.2), 3.98-4.05 (m, 1H, CH), 6.87 (s, 2H, aromatic), 10.3
(s, 1H, CHO). Mass spectrum (CI--NH.sub.3): m/z 341 (M+H). Anal.
calcd for C.sub.21H.sub.28N.sub.2O.sub.2: C, 74.08; H, 8.30; N,
8.24. Found: C, 74.33; H, 8.41; N, 8.18.
[0422] Part B: Title Compound: A mixture of Part A material of
Example 1121 (0.2 g, 0.00059 moles) in ethanol (15 mL) was treated
with anhydrous hydrazine (0.245 g, 0.0077 moles) and refluxed under
nitrogen for 1 h. TLC (1:50 MeOH/CH.sub.2Cl.sub.2) showed a new
spot at Rf=0.45. The solvent was removed under vacuum and purified
the crude by treatment with ethanol to afford white solid (0.2 g,
mp 164-165.degree. C.). .sup.1H NMR (CDCl.sub.3): ? 0.77-0.82 (t,
6H, 2*CH.sub.3), 1.24-1.29 (t, 3H, CH.sub.3), 1.86-1.92 (m, 4H,
2*CH.sub.2), 2.14 (s, 6H, 2*CH.sub.3), 2.29 (s, 3H, CH.sub.3),
2.68-2.76 (q, 2H, CH.sub.2), 5.52 (bs, 3H, CH&NH.sub.2), 6.85
(s, 2H, aromatic), 8.16 (s, 1H, --CH.dbd.N). Mass spectrum
(CI--NH.sub.3): m/z 355 (M+H). The reaction stopped at hydrazone
stage and failed to cyclize even after 48 h in refluxing ethanol.
The hydrazone (0.16 g, 0.45 mmol) was taken in 10 mL of ethylene
glycol and refluxed for 2 h at 200.degree. C. Mass spectrum
(CI--NH.sub.3): m/z 337 (m+H) revealed desired product and cooled
the reaction mixture to room temp. and diluted with 25 ml of water,
extracted with ethyl acetate (3*15 mL), washed with brine and dried
(MgSO.sub.4). The crude was purified by flash column chromatography
on a silica gel using 1:50 MeOH/CH.sub.2Cl.sub.2 to afford 71 mg
(47% yield) of the product as yellow crystalline solid (mp
151-152.degree. C.). .sup.1H NMR (CDCl.sub.3): ? 0.82-0.87 (t, 6H,
2*CH.sub.3), 1.35-1.41 (t, 3H, CH.sub.3), 2.0 (s, 6H, 2*CH.sub.3),
2.1-2.17 (q, 4H, CH.sub.2), 2.37 (s, 3H, CH.sub.3), 2.92-3.0 (q,
2H, CH.sub.2), 4.16-4.22 (m, 1H, CH), 6.98 (s, 2H, aromatic), 9.46
(s, 1H, 9 CH). Mass spectrum (CI--NH.sub.3): m/z 337 (M+H). Anal.
calcd for C.sub.21H.sub.28N.sub.4: C, 74.96; H, 8.40; N, 16.65.
Found: C, 74.77; H, 8.62; N, 15.42.
Example 1122
4-(2,4-dichloro-5-fluorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-d]py-
ridazine
[0423] Part A:
2-ethyl-1-(1-ethyl)propyl-4-(2,4-dichloro-5-fluorobenzoyl)--
1H-imidazole-5-carboxaldehyde: A mixture of Part D material of
Example 1 (0.82 g, 0.0030 moles) in THF (20.0 mL) was cooled to
-78.degree. C. and then added dropwise 1.6 M n-BuLi in hexane (2.0
mL, 0.0033 moles) over 15 mins under nitrogen atmosphere. The
mixture was stirred at -78.degree. C. for 3 h and then added a
solution of 2,4-dichloro-5-F-benzoyl chloride (0.75 g, 0.0033
moles) in THF (5.0 mL) over 15 mins. The mixture was stirred at
-78.degree. C. for 6 h followed by room temperature overnight for
16 h and TLC (30:70 EtOAc/hexane) showed absence of starting
material (Rf=0.5) and a new spot for the product at Rf=0.64. The
mixture was quenched with saturated NH.sub.4Cl (25.0 ml), extracted
with ethyl ether (3*30 mL), washed with brine and dried
(MgSO.sub.4). The solvent was stripped off in vacuo to afford crude
product (1.5 g) as yellow oil and purified by flash column
chromatography on a silica gel using dichloromethane as eluent to
afford desired product as colorless viscous oil (0.62 g, 48%).
.sup.1H NMR (CDCl.sub.3): ? 0.86-0.91 (t, 6H, 2*CH.sub.3),
1.25-1.30 (t, 3H, CH.sub.3), 1.83-1.92 (q, 4H, 2*CH.sub.2),
2.70-2.75 (q, 2H, CH.sub.2), 2.74-2.81 (q, 2H, CH.sub.2), 4.04-4.18
(m, 4H, 2*OCH.sub.2), 4.41-4.51 (m, 1H, CH), 6.69 (s, 1H, --CH),
7.38-7.31 (d, 1H, aromatic), 7.45-7.47 (d, 1H, aromatic). Mass
spectrum (APcI-positive): m/z 429.2 (M+). The acetal was dissolved
in acetone (15.0 mL) and treated with 3.0 M aqeous HCl (30.0 mL) at
room temperature. The reaction mixture was stirred for 24 h at this
temperature and TLC (30:70 EtOAc/hexane) showed a new spot at
Rf=0.67 along with disappearence of starting material acetal. It
was then quenched with saturated NaCl (50.0 ml), extracted with
ethyl acetate (3*50 mL), washed with brine and dried (MgSO.sub.4).
The solvent was removed in vacuum to afford yellow liquid and
purified the crude by flash column chromatography on a silica gel
using dichloromethane as eluent to afford 0.43 g (80% yield) of
desired product as white solid (mp 70-71.degree. C.). .sup.1H NMR
(CDCl.sub.3): ? 0.79 (m, 6H, 2*CH.sub.3), 1.28-1.33 (t, 3H,
CH.sub.3), 1.90-2.2 (m, 4H, 2*CH.sub.2), 2.74-2.82 (q, 2H,
CH.sub.2), 3.98-4.05 (m, 1H, CH), 7.42-7.45 (d, 1H, aromatic),
7.50-7.52 (d, 1H, aromatic), 10.4 (s, 1H, CHO). Mass spectrum
(CI--NH.sub.3): m/z 385 (M+). Anal. calcd for
C.sub.18H.sub.19N.sub.2O.su- b.2Cl.sub.2F.sub.1: C, 56.12; H, 4.97;
N, 7.27. Found: C, 56.27; H, 4.95; N, 7.12.
[0424] Part B: Title Compound: A mixture of Part A material of
Example 1122 (0.230 g, 0.0006 moles) in ethanol (15 mL) was treated
with anhydrous hydrazine (0.25 g, 0.0077 moles) and refluxed under
nitrogen for 16 h. TLC (1:10 MeOH/CH.sub.2Cl.sub.2) showed a new
spot at Rf=0.6. The solvent was removed under vacuum and purified
the crude by flash column chromatography on a silica gel using 1:50
MeOH/CH.sub.2Cl.sub.2 to afford 194 mg of pale yellow oil and
tituration of the oil with hexane (1.0 mL) gave 59 mg (26%) of
white crystalline solid (mp 85-87.degree. C.). .sup.1H NMR
(CDCl.sub.3): ? 0.82-0.87 (t, 6H, 2*CH.sub.3), 1.42-1.47 (t, 3H,
CH.sub.3), 2.08-2.21 (m, 4H, 2*CH.sub.2), 2.98-3.03 (q, 2H,
CH.sub.2), 4.16-4.26 (m, 1H, CH), 7.53-7.56 (d, 1H, aromatic),
7.62-7.64 (d, 1H, aromatic), 9.50 (s, 1H, 9 CH). Mass spectrum
(CI--NH.sub.3): m/z 381 (M.sup.+) HRMS calcd. for
C.sub.18H.sub.20Cl.sub.2F.sub.1N.sub.4: 381.1048. Found: 381.1057
(M+H).
Example 1123
2-Ethyl-1-(1-ethyl)propyl-4-(2,4-dimethoxybenzoyl)-1H-imidazole-5-carboxal-
dehyde
[0425] A mixture of Part D material of Example 1 (0.82 g, 0.0030
moles) in THF (20.0 mL) was cooled to -78.degree. C. and then added
dropwise 1.6 M n-BuLi in hexane (2.0 mL, 0.0033 moles) over 15 mins
under nitrogen atmosphere. The mixture was stirred at -78.degree.
C. for 3 h and then added a solution of 2,4-dimethoxybenzoyl
chloride (0.66 g, 0.0033 moles) in THF (5.0 mL) over 15 mins. The
mixture was stirred at -78.degree. C. for 6 h followed by room
temperature overnight for 16 h and The mixture was stirred at
-78.degree. C. for 6 h followed by room temperature overnight for
16 h and TLC (30:70 EtOAc/hexane) showed absence of starting
material (Rf=0.5) and a new spot for the product at Rf=0.57. The
mixture was quenched with saturated NH.sub.4Cl (25.0 ml), extracted
with ethyl ether (3*30 mL), washed with brine and dried
(MgSO.sub.4). The solvent was stripped off in vacuo to afford crude
product (1.3 g) as yellow oil and purified by flash column
chromatography on a silica gel using 1:100 methanol/dichloromethane
as eluent to afford desired product as pale yellow viscous oil
(0.39 g, 32%). Mass spectrum (APcI-positive): m/z 403.3
(M+H.sup.+). The acetal was dissolved in acetone (15.0 mL) and
treated with 3.0 M aqeous HCl (30.0 mL) at room temperature. The
reaction mixture was stirred for 24 h at this temperature and TLC
(1:10 MeOH/CH.sub.2Cl.sub.2) showed two new spots at Rf=0.92 &
0.62. It was then quenched with saturated NaCl (50.0 ml), extracted
with ethyl acetate (3*50 mL), washed with brine and dried
(MgSO.sub.4). The solvent was removed in vacuum to afford yellow
liquid and purified the crude by flash column chromatography on a
silica gel using dichloromethane as eluent. to afford 0.17 g of
desired product (Rf=0.62). Mass spectrum (CI--NH.sub.3): m/z 359
(M+H). 7-13-98: The above aldehyde (0.17 g) was dissolved in
ethanol (15.0 mL) and treated with hydrazine (0.25 mL). The mixture
was refluxed overnight and TLC (1:10 MeOH/CH.sub.2Cl.sub.2)
revealed a new spot at Rf=0.49. The solvent was stripped off in
vacuum and purified the crude by flash column chromatography on a
silica gel using (1:50 MeOH/CH.sub.2Cl.sub.2) as eluent to afford
84 mg colorless oil. The oil was crystallized from 1:10
hexane/ether to afford 64 mg of white solid (mp 126-127.degree.
C.). HRMS calcd for C.sub.20H.sub.27N.sub.4O.sub.2: 355.2133.
Found: 355.2121 (M+H).
Example 1124
4-(2,4-dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-7-methylimidazo[4,5-d]pyr-
idazine
[0426] Part A:
4-(2,4-dichlorobenzoyl)-2-ethyl-1-(1-ethyl)propyl-5-(1-hydr-
oxyethyl)-1H-imidazole: A mixture of Part E material of Example 1
(0.587 g, 0.0016 moles) in THF (20 mL) was cooled to -78.degree. C.
and then added dropwise 1.6 M MeLi in ether (1.0 mL, 0.0016 moles)
over 5 mins. The mixture was stirred at -78.degree. C. for 2 h and
then quenched with water (5.0 ml) at -78.degree. C. The reaction
mixture was extracted with ethyl ether (3*30 mL), washed with brine
and stripped off the solvent in vacuum to afford yellow liquid. TLC
(30:70 EtOAc/hexane) showed absence of starting material at Rf=0.69
and a new spot at Rf=0.4. Purified the crude by flash column
chromatography on a silica gel using 10% EtOAC/hexane to afford
0.470 g (77% yield) of desired product as white solid (mp
125-126.degree. C.). Mass spectrum (CI--NH.sub.3): m/z=383
(M.sup.+). Anal. calcd for C.sub.19H.sub.24Cl.sub.2N.sub.2O.sub.2:
C, 59.54; H, 6.31; N, 7.32. Found: C, 59.59; H, 6.28; N, 7.16.
[0427] Part B:
5-Acetyl-4-(2,4-dichlorobenzoyl)-2-ethyl-1-(1-ethyl)propyl--
1H-imidazole A solution of Part A material of Example 1124 (0.4 g,
0.00104 moles) in toluene (10 mL) was treated with MnO.sub.2 (0.91
g, 0.0104 moles) and stirred at 75.degree. C. for 40 h. TLC (30:70
EtOAc/hexane) showed presence of starting material at Rf=0.4 and a
new spot at Rf=0.57. Added additional MnO.sub.2 (0.91 g) and
continued for addtional 20 h at 75.degree. C. &-27-98: TLC
revealed only trace amount of starting material and therefore
cooled the reaction mixture to room temp and filtered through
celite. The filterate was concentrated to afford 0.32 g of
colorless oil and purified the crude by flash column chromatography
on a silica gel using 15% EtOAC/hexane to afford 0.258 g (65%
yield) of desired product as white solid (m.p. 63-64.degree. C.).
Mass spec (CI--NH.sub.3): m/z=381 (M+). Anal. calcd. for
C.sub.19H.sub.22Cl.sub.2N.- sub.2O.sub.2: C, 59.85; H, 5.83; N,
7.36. Found: C, 59.97; H, 5.80; N, 7.12.
[0428] Part C: Title Compound: imidazole A solution of Part B
material of Example 1124 (0.130 g, 0.00034 moles) in ethanol (10
mL) was treated with anhydrous hydrazine (0.142 g, 0.0044 moles)
and refluxed under nitrogen for 3 h. TLC (1:10
MeOH/CH.sub.2Cl.sub.2) showed a new spot at Rf=0.55. The solvent
was removed under vacuum and purified the crude by flash column
chromatography on a silica gel using 50:50 EtOAc/hexane to afford
53 mg (41% yield) of the product as white solid after tituration of
the oil with !diethyl ether (mp 128-129.degree. C.). Mass spectrum
(CI--NH.sub.3): m/z 377 (M+). Anal. calcd. for
C.sub.19H.sub.22Cl.sub.2N.- sub.4: C, 60.48; H, 5.89; N, 14.89.
Found: C, 59.40; H, 5.72; N, 14.46.
Example 1125
4-(2,4-dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-7-propoxyimidazo[4,5-d]py-
ridazine
[0429] Part A: Methyl
4-(2,4-dichlorobenzoyl)-2-ethyl-1-(1-ethyl)propyl-1H-
-imidazole-5-carboxalate: A mixture of Part E material of Example 1
(0.367 g, 0.001 moles) in methanol (60 mL) was treated with NaCN
(Aldrich, 0.245 g, 0.005 moles, 5 equi.), AcOH (Baker, 96 mg;
0.0016 moles, 1.6 equiv.) and MnO.sub.2, activated (Aldich, 1.24 g,
0.021 moles, 21 equiv.). The resulting mixture was stirred at room
temp under nitrogen for 18 h. TLC (1:50 MeOH/CH.sub.2Cl.sub.2)
revealed absence of starting material at Rf=0.8 and showed a new
spot at Rf=0.44. Mass spec. revealed desired product (m/z=397). The
reaction mixture was filtered through celite, washed with methanol,
concentrated in vacuo and the crude was purified by flash column
chromatography on a silica gel using 1:100 MeOH/CH.sub.2Cl.sub.2 as
eluent to afford 320 mg (mp 73-74.degree. C., 81%) of white solid
after crystallization from hexane. Anal. calcd. for
C.sub.19H.sub.22N.sub.2O.sub.3Cl.sub.2: C, 57.44; H, 5.58; N, 7.05.
Found: C, 57.31; H, 5.45; N, 6.85.
[0430] Part B:
4-(2,4-dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,-
5-d]pyridazin-7-one: A mixture of Part A material of example 1125
(0.100 g, 0.00025 moles) in ethanol (10 mL) was treated with
anhydrous hydrazine (0.105 g, 0.0033 moles) and refluxed under
nitrogen for 48 h. TLC (30:70 EtOAc/hexane) showed a new spot at
Rf=0.35. The solvent was removed under vacuum and purified the
crude by flash column chromatography on a silica gel using 15:50
EtOAc/hexane intially and then methanol to afford 70 mg (74% yield)
of the product as white solid after tituration of the oil with
diethyl ether (mp 246-247.degree. C.). Mass spectrum (CI--NH.sub.3)
m/z=379 (M+).
[0431] Part C: Title Compound: A mixture of Part B material of
example 1125 (0.1 g, 0.264 mmol) in benzene (5.0 mL) was treated
with n-Bu.sub.4NBr (8.5 mg, 0.0264 mmol), powdered KOH (15 mg,
0.264 mmol) and 1-iodopropane (0.134 g, 0.79 mmol). The mixture was
stirred at room temp overnight and TLC (1:50 MeOH/CH.sub.2Cl.sub.2)
showed two new spots at Rf=0.73 and Rf=0.46. The reaction mixture
was diluted with EtOAc (10 mL), washed with brine (10 mL), dried
with MgSO.sub.4 and concentrated to a residue. The crude was
purified by flash column chromatography on a silica gel using
dichloromethane as eluent to afford 56 mg (51% yield) of the
N-propyl product as colorless oil. Mass spectrum (CI--NH.sub.3):
m/z=421. Further elution of the column with 1:50
MeOH/CH.sub.2Cl.sub.2 gave 11 mg (10% yield) of oil which was
crystallized from ether to afford 7-propoxy derivative as a white
solid (m.p. 120-121.degree. C.). Mass spec. (CI--NH.sub.3):
m/z=421. HRMS calcd for C.sub.21H.sub.27N.sub.4OCl.- sub.2:
421.1561. Found: 421.1569 (M+H).
Example 1126
7-chloro-4-(2,4-dichlorophenyl)-2-ethyl-1-(1-methyl)butyl-imidazo[4,5-d]py-
ridazine
[0432] Part A:
4,5-dibromo-2-ethyl-1-(1-methyl)butyl-1H-imidazole:
[0433] A mixture of part A material of example 1 (59 g g, 0.233
moles), triphenylphosphine (67.1 g, 0.256 moles) and molecular
sieves (10 g) in THF (715 mL) was cooled to 0 to -5.degree. C. and
then added 2-pentanol (34.79 g, 0.279 moles) under nitrogen
atmosphere. The mixture was stirred at 0.degree. C. for 30 mins and
then added disopropylazodicarboxylate (50.33 g, 0.256 moles)
dropwise over 20 mins. The mixture was stirred at 0.degree. C. for
2 h followed by room temperature for 2 days and TLC (1:50
MeOH/CH.sub.2Cl.sub.2) revealed a new spot at Rf=0.5. The
undissolved material was filtered, washed with dichloromethane and
stripped off the solvent in vacuum to afford yellow liquid. The
crude was purified by flash column chromatography using chloroform
as eluent to afford 41.5 g (55%) of colorless oil. .sup.1H NMR
(CDCl.sub.3): ? 0.91 (t, 3H, 2*CH.sub.3), 1.27 (m, 2H, CH.sub.2),
1.31 (t, 3H, CH.sub.3), 1.53 (d, 3H, CH.sub.3), 1.78 (m, 1H), 2.04
(m, 1H) 2.71 (q, 2H) and 4.34 (m, 1H). Mass spectrum
(CI--NH.sub.3): m/z 325.0 (M+H)
[0434] Part B:
4-bromo-2-ethyl-1-(1-methyl)butyl-1H-imidazole-5-carboxalde-
hyde:
[0435] A solution of imidazole (37.5 g, 0.116 mol) in THF (250 mL)
was cooled to -78.degree. C. and then added dropwise 1.6 M n-BuLi
(76 mL, 0.122 mol) in hexane over 45 mins. The mixture was stirred
at -78.degree. C. for 1 h (brown solution) and then added DMF (27
g, 0.348 moles) dropwise over 30 mins. The mixture was stirred at
-78.degree. C. for 60 mins. The reaction mixture was quenched with
satd. amm. chloride (100 mL) at -78.degree. C. and brought to room
temp. The reaction mixture was extracted with ethyl ether (3*100
mL), washed with brine and dried with anhyd. MgSO.sub.4. The
solvent was evaporated under reduced pressure to afford 31.6 g of
crude yellow oil. The NMR of the crude revealed formation of
4-bromo-2-ethyl-1-(1-methyl)butyl-1H-imidazole along with desired
product in the ratio of 3:7. The TLC of the undesired
4-bromo-2-ethyl-1-(1-methyl)butyl-1H-imidazole is visible under
iodine exposure (Rf=0.45). The crude was purified by flash column
chromatography on a silica gel using 1% MeOH to afford 18.5 g (59%
yield) of colorless oil. Mass spec: m/z=273. Anal. calcd. for
C.sub.11H.sub.17N.sub.2OBr; C, 48.36; H, 6.27, N, 10.25. Found): C,
48.64; H, 6.01; N, 10.00.
[0436] Part C:
4-bromo-2-ethyl-1-(1-methyl)butyl-1H-imidazole-5-carboxalde- hyde
ethylene acetal: A mixture of Part B material of example 1126 (18.5
g, 0.068 moles) in benzene (250 mL) was treated with ethylene
glycol (16.4 g, 0.264 moles), pyridine (2.-7 g, 0.034 moles) and
p-toluenesulfonic acid monohydrate (6.5 g, 0.034 moles). The
reaction mixture was heated at reflux in a 20 mL capacity
Dean-Stark trap equipped apparatus for 36 h. TLC (30:70
EtOAc/hexane) revealed a new spot at Rf=0.42 (visible under iodine)
along with trace amount of starting material (Rf=0.54). The
reaction mixture was cooled to room temperature, diluted with EtOAc
(250 mL), washed with 10% sodium bicarbonate (2*250 mL), brine and
dried (MgSO.sub.4). The solvent was evaporated under reduced
pressure to furnish white solid (20.7 g, mp 69-70.degree. C., 96%).
The crude was very pure by NMR. Mass spectrum (CI--NH.sub.3): m/z
317.1 (M.sup.+). Anal. calcd. for
C.sub.13H.sub.22N.sub.2O.sub.2Br.sub.1; C, 49.22; H, 6.67, N, 8.83.
Found: C, 49.38; H, 6.62; N, 8.68.
[0437] Part D:
4-(2,4-dichlorobenzoyl)-2-ethyl-1-(1-methyl)butyl-1H-imidaz-
ole-5-carboxaldehyde: A solution of Part C material of Example 1126
(2.3 g, 5.6 mmol) in acetone (60 mL) was cooled to 15.degree. C.
and then added 3M aq. HCl (120 mL) over 15 mins. The mixture was
stirred below 30.degree. C. for 24 h. TLC (30:70 EtOAc/hexane)
showed a new spot at Rf=0.58 along with disappearence of starting
material (Rf=0.43). The solvent was removed under vacuum, extracted
with ethyl acetate (3*50 mL), washed with brine and stripped off
the solvent in vacuum to afford yellow liquid (2.4 g). The crude
was purified by flash column chromatography on a silica gel using
dichloromethane as eluent to afford 1.46 g (71% yield) of desired
product as yellow solid (mp 43-44.degree. C.). Anal. calcd for
C.sub.18H.sub.20Cl.sub.2N.sub.2O.sub.2: C, 58.87; H, 5.50; N, 7.64.
Found: C, 58.96; H, 5.34; N, 7.46. Mass spec. (NH.sub.3--CI):
m/z=367.
[0438] Part E: Methyl
4-(2,4-dichlorobenzoyl)-2-ethyl-1-(1-methyl)butyl-1H-
-imidazole-5-carboxalate: A mixture of Part D material of Example
1126 (1.0 g, 0.0027 moles) in methanol (50 mL) was treated with
NaCN (Aldrich, 0.67 g, 0.0136 moles, 5 equi.), AcOH (Baker, 260 mg;
0.00432 moles, 1.6 equiv.) and MnO.sub.2, activated (Aldrich, 3.34
g, 0.057 moles, 21 equiv.). The resulting mixture was stirred at
room temp under nitrogen for 20 h. TLC (30:70 EtOAc/hexane)
revealed absence of starting material at Rf=0.58 and showed a new
spot at Rf=0.4. The reaction mixture was filtered through celite,
washed with methanol, concentrated in vacuo. The residue was
diluted with water, extracted with ethyl acetate, washed with
brine, dried and concentrated in vacuo to afford 0.98 g of yellow
oil. The crude was purified by flash column chromatography on a
silica gel using 30:70 EtOAc/hexane as eluent to afford 910 mg
(85%) of yellow oil. Mass spectrum: m/z=397. Anal. calcd. for
C.sub.19H.sub.22N.sub.2O.sub.3Cl- .sub.2: C, 57.44; H, 5.58; N,
7.05. Found: C, 57.25; H, 5.70; N, 6.80.
[0439] Part F:
4-(2,4-dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,-
5-d]pyridazin-7-one: A mixture of Part E material of Example 1126
(0.460 g, 0.00115 moles) in ethylene glycol (5 mL) was treated with
anhydrous hydrazine (0.48 g, 0.0151 moles) and refluxed under
nitrogen for 4 h. TLC (30:70 EtOAc/hexane) revealed a new spot
(Rf=0.44) along with disappearence of starting material (Rf=0.4).
The reaction mixture was cooled to room temp and poured over 25 mL
of water, extracted with EtOAc (3*15 mL), washed with brine and
dried. The solvent was removed under vacuo and purified the crude
by flash column chromatography on a silica gel using 15%
EtOAc/hexane to afford colorless oil which was crystallized from
hexane to afford 310 mg of white solid (71%, mp 217-18.degree. C.).
Mass spec. (CI--NH.sub.3): m/z=379. Anal. calcd. for
C.sub.18H.sub.20N.sub.4Cl.sub.2O: C, 57.00; H, 5.33; N, 14.77.
Found: C, 57.02; H, 5.35; N, 14.59.
[0440] Part G: Title Compound: A mixture of Part F material of
Example 1126 (0.270 g, 0.0071 moles) in POCl.sub.3 (3.0 mL) was
refluxed under nitrogen for 8 h. TLC (30:70 EtOAc/hexane) revealed
a new spot (Rf=0.48) along with disappearence of starting material
(Rf=0.44) Excess POCl.sub.3 from the reaction mixture was removed
under vacuo, quenched with ice (10 g), extracted with EtOAc (3*15
mL), washed with brine and dried. The solvent was removed under
vacuo and purified the crude by flash column chromatography on a
silica gel using 30% EtOAc/hexane to afford 80 mg of white solid
(28%, mp 124-125.degree. C.). HRMS calcd for
C.sub.18H.sub.20N.sub.4Cl.sub.3: 397.0753. Found: 397.0749
(M+H).
Example 1127
4-(2,4-dichlorophenyl)-2-ethyl-1-(1-methyl)butyl-7-methoxy-imidazo[4,5-d]p-
yridazine
[0441] A mixture of Part G material of Example 1126 (40 mg, 0.1
mmole) in MeOH (3.0 mL) was treated with 25% NaOMe in MeOH (0.065
mL, 0.3 mmole) and refluxed under nitrogen for 6 h. TLC (30:70
EtOAc/hexane) revealed a new spot (Rf=0.35) along with
disappearence of starting material (Rf=0.48). The solvent from the
reaction mixture was removed under vacuo, quenched with water (10
g), extracted with EtOAc (3*15 mL), washed with brine and dried.
The solvent was removed under vacuo and purified the crude by
recrystallizing from hexane to afford 36 mg of white solid (92%, mp
119-120.degree. C.). HRMS calcd for
C.sub.19H.sub.23N.sub.4Cl.sub.3O.s- ub.1: 393.1248. Found: 393.1246
(M+H).
2TABLE 1 17 18 19 20 21 22 23 Ex. # R.sup.1 D 1a (cPr).sub.2CH
phenyl 2 phenyl(cPr)CH phenyl 3 2-furanyl(cPr)CH phenyl 4
3-furan(cPr)CH phenyl 5 2-thienyl(cPr)CH phenyl 6 3-thienyl(cPr)CH
phenyl 7 2-isoxazolyl(cPr)CH phenyl 8 2-(5-CH.sub.3-furanyl)(cPr)CH
phenyl 9 2-(4-CH.sub.3-isoxazolyl)(cPr)CH phenyl 10
cPr-CH(CH.sub.3) phenyl 11 1-cPr-CH(CH.sub.2CH.sub.3) phenyl 12
1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3) phenyl 13
1-cPr-CH(CH.sub.2OCH.sub.3) phenyl 14 1-cPr-CH(CH.sub.2OCH.sub.3)
phenyl 15 (cBu).sub.2CH phenyl 16 phenyl(cBu)CH phenyl 17
2-furanyl(cBu)CH phenyl 18 3-furan(cBu)CH phenyl 19
2-thienyl(cBu)CH phenyl 20 3-thienyl(cBu)CH phenyl 21
2-isoxazolyl(cBu)CH phenyl 22 2-(5-CH.sub.3- furanyl)(cBu)CH phenyl
23 2-(4-CH.sub.3-isoxazolyl)(cBu)CH phenyl 24 cBu-CH(CH.sub.3)
phenyl 25 1-cBu-CH(CH.sub.2CH.sub.3) phenyl 26
1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3) phenyl 27
1-cBu-CH(CH.sub.2OCH.sub.3) phenyl 28 1-cBu-CH(CH.sub.2CH.sub.2OC-
H.sub.3) phenyl 29 (cPr).sub.2CH 2-Cl-4-Meo-phenyl 30 phenyl(cPr)CH
2-Cl-4-Meo-phenyl 31 2-furanyl(cPr)CH 2-Cl-4-Meo-phenyl 32
3-furan(cPr)CH 2-Cl-4-Meo-phenyl 33 2-thienyl(cPr)CH
2-Cl-4-Meo-phenyl 34 3-thienyl(cPr)CH 2-Cl-4-Meo-phenyl 35
2-isoxazolyl(cPr)CH 2-Cl-4-Meo-phenyl 36
2-(5-CH.sub.3-furanyl)(cPr)CH 2-Cl-4-Meo-phenyl 37
2-(4-CH.sub.3-isoxazolyl)(cPr)CH 2-Cl-4-Meo-phenyl 38
cPr-CH(CH.sub.3) 2-Cl-4-Meo-phenyl 39 1-cPr-CH(CH.sub.2CH.sub.3)
2-Cl-4-Meo-phenyl 40 1-cPr-CH(CH.sub.2OCH.sub.3) 2-Cl-4-Meo-phenyl
42 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3) 2-Cl-4-Meo-phenyl 43
(cBu).sub.2CH 2-Cl-4-Meo-phenyl 44 phenyl(cBu)CH 2-Cl-4-Meo-phenyl
45 2-furanyl(cBu)CH 2-Cl-4-Meo-phenyl 46 3-furan(cBu)CH
2-Cl-4-Meo-phenyl 47 2-thienyl(cBu)CH 2-Cl-4-Meo-phenyl 48
3-thienyl(cBu)CH 2-Cl-4-Meo-phenyl 49 2-isoxazolyl(cBu)CH
2-Cl-4-Meo-phenyl 50 2-(5-CH.sub.3-furanyl)(cBu)CH
2-Cl-4-Meo-phenyl 51 2-(4-CH.sub.3-isoxazolyl)(cBu)CH
2-Cl-4-Meo-phenyl 52 cBu-CH(CH.sub.3) 2-Cl-4-Meo-phenyl 53
1-cBu-CH(CH.sub.2CH.sub.3) 2-Cl-4-Meo-phenyl 54
1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3) 2-Cl-4-Meo-phenyl 55
1-cBu-CH(CH.sub.2OCH.sub.3) 2-Cl-4-Meo-phenyl 56
1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3) 2-Cl-4-Meo-phenyl 57
(cPr).sub.2CH 2-Cl-4-CF.sub.3-phenyl 58 phenyl(cPr)CH
2-Cl-4-CF.sub.3-phenyl 59 2-furanyl(cPr)CH 2-Cl-4-CF.sub.3-phenyl
60 3-furan(cPr)CH 2-Cl-4-CF.sub.3-phenyl 61 2-thienyl(cPr)CH
2-Cl-4-CF.sub.3-phenyl 62 3-thienyl(cPr)CH 2-Cl-4-CF.sub.3-phenyl
63 2-isoxazolyl(cPr)CH 2-Cl-4-CF.sub.3-phenyl 64
2-(5-CH.sub.3-furanyl)(cPr)CH 2-Cl-4-CF.sub.3-phenyl 65
2-(4-CH.sub.3-isoxazolyl)(cPr)CH 2-Cl-4-CF.sub.3-phenyl 66
cPr-CH(CH.sub.3) 2-Cl-4-CF.sub.3-phenyl 67
1-cPr-CH(CH.sub.2CH.sub.3) 2-Cl-4-CF.sub.3-phenyl 68
1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3) 2-Cl-4-CF.sub.3-phenyl 69
1-cPr-CH(CH.sub.2OCH.sub.3) 2-Cl-4-CF.sub.3-phenyl 70
1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3) 2-Cl-4-CF.sub.3-phenyl 71
(cBu).sub.2CH 2-Cl-4-CF.sub.3-phenyl 72 phenyl(cBu)CH
2-Cl-4-CF.sub.3-phenyl 73 2-furanyl(cBu)CH 2-Cl-4-CF.sub.3-phenyl
74 3-furan(cBu)CH 2-Cl-4-CF.sub.3-phenyl 75 2-thienyl(cBu)CH
2-Cl-4-CF.sub.3-phenyl 76 3-thienyl(cBu)CH 2-Cl-4-CF.sub.3-phenyl
77 2-isoxazolyl(cBu)CH 2-Cl-4-CF.sub.3-phenyl 78
2-(5-CH.sub.3-furanyl)(cBu)CH 2-Cl-4-CF.sub.3-phenyl 79
2-(4-CH.sub.3-isoxazolyl)(cBu)CH 2-Cl-4-CF.sub.3-phenyl 80
cBu-CH(CH.sub.3) 2-Cl-4-CF.sub.3-phenyl 81
1-cBu-CH(CH.sub.2CH.sub.3) 2-Cl-4-CF.sub.3-phenyl 82
1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3) 2-Cl-4-CF.sub.3-phenyl 83
1-cBu-CH(CH.sub.2OCH.sub.3) 2-Cl-4-CF.sub.3-phenyl 84
1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3) 2-Cl-4-CF.sub.3-phenyl 85
(cPr).sub.2CH 2,4-diCl-phenyl 86 phenyl(cPr)CH 2,4-diCl-phenyl 87
2-furanyl(cPr)CH 2,4-diCl-phenyl 88 3-furan(cPr)CH 2,4-diCl-phenyl
89 2-thienyl(cPr)CH 2,4-diCl-phenyl 90 3-thienyl(cPr)CH
2,4-diCl-phenyl 91 2-isoxazolyl(cPr)CH 2,4-diCl-phenyl 92
2-(5-CH.sub.3-furanyl)(cPr)CH 2,4-diCl-phenyl 93
2-(4-CH.sub.3-isoxazolyl)(cPr)CH 2,4-diCl-phenyl 94
cPr-CH(CH.sub.3) 2,4-diCl-phenyl 95 1-cPr-CH(CH.sub.2CH.sub.3)
2,4-diCl-phenyl 96 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3)
2,4-diCl-phenyl 97 1-cPr-CH(CH.sub.2OCH.sub.3) 2,4-diCl-phenyl 98
1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3) 2,4-diCl-phenyl 99
(cBu).sub.2CH 2,4-diCl-phenyl 100 phenyl(cBu)CH 2,4-diCl-phenyl 101
2-furanyl(cBu)CH 2,4-diCl-phenyl 102 3-furan(cBu)CH 2,4-diCl-phenyl
103 2-thienyl(cBu)CH 2,4-diCl-phenyl 104 3-thienyl(cBu)CH
2,4-diCl-phenyl 105 2-isoxazolyl(cBu)CH 2,4-diCl-phenyl 106
2-(5-CH.sub.3-furanyl)(cBu)CH 2,4-diCl-phenyl 107
2-(4-CH.sub.3-isoxazolyl)(cBu)CH 2,4-diCl-phenyl 108
cBu-CH(CH.sub.3) 2,4-diCl-phenyl 109 1-cBu-CH(CH.sub.2CH.sub.3)
2,4-diCl-phenyl 110 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3)
2,4-diCl-phenyl 111 1-cBu-CH(CH.sub.2OCH.sub.3) 2,4-diCl-phenyl 112
1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3) 2,4-diCl-phenyl 113
(cPr).sub.2CH 2,5-diCl-phenyl 114 phenyl(cPr)CH 2,5-diCl-phenyl 115
2-furanyl(cPr)CH 2,5-diCl-phenyl 116 3-furan(cPr)CH 2,5-diCl-phenyl
117 2-thienyl(cPr)CH 2,5-diCl-phenyl 118 3-thienyl(cPr)CH
2,5-diCl-phenyl 119 2-isoxazolyl(cPr)OH 2,5-diCl-phenyl 120
2-(5-CH.sub.3-furanyl)(cPr)CH 2,5-diCl-phenyl 121
2-(4-CH.sub.3-isoxazolyl)(cPr)CH 2,5-diCl-phenyl 122
cPr-CH(CH.sub.3) 2,5-diCl-phenyl 123 1-cPr-CH(CH.sub.2CH.sub.3)
2,5-diCl-phenyl 124 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3)
2,5-diCl-phenyl 125 1-cPr-CH(CH.sub.2OCH.sub.3) 2,5-diCl-phenyl 126
1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3) 2,5-diCl-phenyl 127
(cBu).sub.2CH 2,5-diCl-phenyl 128 phenyl(cBu)CH 2,5-diCl-phenyl 129
2-furanyl(cBu)CH 2,5-diCl-phenyl 130 3-furan(cBu)CH 2,5-diCl-phenyl
131 2-thienyl(cBu)CH 2,5-diCl-phenyl 132 3-thienyl(cBu)CH
2,5-diCl-phenyl 133 2-isoxazolyl(cBu)CH 2,5-diCl-phenyl 134
2-(5-CH.sub.3-furanyl)(cBu)CH 2,5-diCl-phenyl 135
2-(4-CH.sub.3-isoxazolyl)(cBu)CH 2,5-diCl-phenyl 136
cBu-CH(CH.sub.3) 2,5-diCl-phenyl 137 1-cBu-CH(CH.sub.2CH.sub.3)
2,5-diCl-phenyl 138 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3)
2,5-diCl-phenyl 139 1-cBu-CH(CH.sub.2OCH.sub.3) 2,5-diCl-phenyl 140
1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3) 2,5-diCl-phenyl 141
(cPr).sub.2CH 2-Cl-4-CF.sub.3O-phenyl 142 phenyl(cPr)CH
2-Cl-4-CF.sub.3O-phenyl 143 2-furanyl(cPr)CH
2-Cl-4-CF.sub.3O-phenyl 144 3-furan(cPr)CH 2-Cl-4-CF.sub.3O-phenyl
145 2-thienyl(cPr)CH 2-Cl-4-CF.sub.3O-phenyl 146 3-thienyl(cPr)CH
2-Cl-4-CF.sub.3O-phenyl 147 2-isoxazolyl(cPr)CH
2-Cl-4-CF.sub.3O-phenyl 148 2-(5-CH.sub.3-furanyl)(cPr)CH
2-Cl-4-CF.sub.3O-phenyl 149 2-(4-CH.sub.3-isoxazolyl)(cPr)CH
2-Cl-4-CF.sub.3O-phenyl 150 cPr-CH(CH.sub.3)
2-Cl-4-CF.sub.3O-phenyl 151 1-cPr-CH(CH.sub.2CH.sub.3)
2-Cl-4-CF.sub.3O-phenyl 152 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3)
2-Cl-4-CF.sub.3O-phenyl 153 1-cPr-CH(CH.sub.2OCH.sub.3)
2-Cl-4-CF.sub.3O-phenyl 154 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3)
2-Cl-4-CF.sub.3O-phenyl 155 (cBu).sub.2CH 2-Cl-4-CF.sub.3O-phenyl
156 phenyl(cBu)CH 2-Cl-4-CF.sub.3O-phenyl 157 2-furanyl(cBu)CH
2-Cl-4-CF.sub.3O-phenyl 158 3-furan(cBu)CH 2-Cl-4-CF.sub.3O-phenyl
159 2-thienyl(cBu)CH 2-Cl-4-CF.sub.3O-phenyl 160 3-thienyl(cBu)CH
2-Cl-4-CF.sub.3O-phenyl 161 2-isoxazolyl(cBu)CH
2-Cl-4-CF.sub.3O-phenyl 162 2-(5-CH.sub.3-furanyl)(cBu)CH
2-Cl-4-CF.sub.3O-phenyl 163 2-(4-CF.sub.3-isoxazolyl)(cBu)CH
2-Cl-4-CF.sub.3O-phenyl 164 cBu-CH(CH.sub.3)
2-Cl-4-CF.sub.3O-phenyl 165 1-cBu-CH(CH.sub.2CH.sub.3)
2-Cl-4-CF.sub.3O-phenyl 166 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3)
2-Cl-4-CF.sub.3O-phenyl 167 1-cBu-CH(CH.sub.2OCH.sub.3)
2-Cl-4-CF.sub.3O-phenyl 168 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3)
2-Cl-4-CF.sub.3O-phenyl 169 (cPr).sub.2CH 2-Cl-4-CH.sub.3-phenyl
170 phenyl(cPr)CH 2-Cl-4-CH.sub.3-phenyl 171 2-furanyl(cPr)CH
2-Cl-4-CH.sub.3-phenyl 172 3-furan(cPr)CH 2-Cl-4-CH.sub.3-phenyl
173 2-thienyl(cPr)CH 2-Cl-4-CH.sub.3-phenyl 174 3-thienyl(cPr)CH
2-Cl-4-CH.sub.3-phenyl 175 2-isoxazolyl(cPr)CH
2-Cl-4-CH.sub.3-phenyl 176 2-(5-CH.sub.3-furanyl)(cPr)CH
2-Cl-4-CH.sub.3-phenyl 177 2-(4-CH.sub.3-isoxazolyl)(cPr)CH
2-Cl-4-CH.sub.3-phenyl 178 cPr-CH(CH.sub.3) 2-Cl-4-CH.sub.3-phenyl
179 1-cPr-CH(CH.sub.2CH.sub.3) 2-Cl-4-CH.sub.3-phenyl 180
1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3) 2-Cl-4-CH.sub.3-phenyl 181
1-cPr-CH(CH.sub.2OCH.sub.3) 2-Cl-4-CH.sub.3phenyl 182
1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3) 2-Cl-4-CH.sub.3-phenyl 183
(cBu).sub.2CH 2-Cl-4-CH.sub.3-phenyl 184 phenyl(cBu)CH
2-Cl-4-CH.sub.3-phenyl 185 2-furanyl(cBu)CH 2-Cl-4-CH.sub.3-phenyl
186 3-furan-(cBu)CH 2-Cl-4-CH.sub.3-phenyl 187 2-thienyl(cBu)CH
2-Cl-4-CH.sub.3-phenyl 188 3-thienyl(cBu)CH 2-Cl-4-CH.sub.3-phenyl
189 2-isoxazolyl(cBu)CH 2-Cl-4-CH.sub.3-phenyl 190
2-(5-CH.sub.3-furanyl)(cBu)CH 2-Cl-4-CH.sub.3-phenyl 191
2-(4-CH.sub.3-isoxazolyl)(cBu)CH 2-Cl-4-CH.sub.3-phenyl 192
cBu-CH(CH.sub.3) 2-Cl-4-CH.sub.3-phenyl 193
1-cBu-CH(CH.sub.2CH.sub.3) 2-Cl-4-CH.sub.3-phenyl 194
1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3) 2-Cl-4-CH.sub.3-phenyl 195
1-cBu-CH(CH.sub.2OCH.sub.3) 2-Cl-4-CH.sub.3-phenyl 196
1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3) 2-Cl-4-CH.sub.3-phenyl 197
(cPr).sub.2CH 2-Cl-4-CN-phenyl 198 phenyl(cPr)CH 2-Cl-4-CN-phenyl
199 2-furanyl(cPr)CH 2-Cl-4-CN-phenyl 200 3-furan(cPr)CH
2-Cl-4-CN-phenyl 201 2-thienyl(cPr)CH 2-Cl-4-CN-phenyl 202
3-thienyl(cPr)CH 2-Cl-4-CN-phenyl 203 2-isoxazolyl(cPr)CH
2-Cl-4-CN-phenyl 204 2-(5-CH.sub.3-furanyl)(cPr)CH 2-Cl-4-CN-phenyl
205 2-(4-CH.sub.3-isoxazolyl)(cPr)CH 2-Cl-4-CN-phenyl 206
cPr-CH(CH.sub.3) 2-Cl-4-CN-phenyl 207 1-cPr-CH(CH.sub.2CH.sub.3)
2-Cl-4-CN-phenyl 208 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3)
2-Cl-4-CN-phenyl 209 1-cPr-CH(CH.sub.2OCH.sub.3) 2-Cl-4-CN-phenyl
210 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3 2-Cl-4-CN-phenyl 211
(cBu).sub.2CH 2-Cl-4-CN-phenyl 212 phenyl(cBu)CH 2-Cl-4-CN-phenyl
213 2-furanyl(cBu)CH 2-Cl-4-CN-phenyl 214 3-furan(cBu)CH
2-Cl-4-CN-phenyl 215 2-thienyl(cBu)CH 2-Cl-4-CN-phenyl 216
3-thienyl(cBu)CH 2-Cl-4-CN-phenyl 217 2-isoxazolyl(cBu)CH
2-Cl-4-CN-phenyl 218 2-(5-CH.sub.3-furanyl)(cBu)CH 2-Cl-4-CN-phenyl
219 2-(4-CH.sub.3-isoxazolyl)(cBu)CH 2-Cl-4-CN-phenyl 220
cBu-CH(CH.sub.3) 2-Cl-4-CN-phenyl 221 1-cBu-CH(CH.sub.2CH.sub.3)
2-Cl-4-CN-phenyl 222 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3)
2-Cl-4-CN-phenyl 223 1-cBu-CH(CH.sub.2OCH.sub.3) 2-Cl-4-CN-phenyl
224 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3) 2-Cl-4-CN-phenyl 225
(cPr).sub.2CH 2-CF.sub.3-4-Cl-phenyl 226 phenyl(cPr)CH
2-CF.sub.3-4-Cl-phenyl 227 2-furanyl(cPr)CH 2-CF.sub.3-4-Cl-phenyl
228 3-furan(cPr)CH 2-CF.sub.3-4-Cl-phenyl 229 2-thienyl(cPr)CH
2-CF.sub.3-4-Cl-phenyl 230 3-thienyl(cPr)CH 2-CF.sub.3-4-Cl-phenyl
231 2-isoxazolyl(cPr)CH 2-CF.sub.3-4-Cl-phenyl 232
2-(5-CH.sub.3-furanyl)(cPr)CH 2-CF.sub.3-4-Cl-phenyl 233
2-(4-CH.sub.3-isoxazolyl)(cPr)CH 2-CF.sub.3-4-Cl-phenyl 234
cPr-CH(CH.sub.3) 2-CF.sub.3-4-Cl-phenyl 235
1-cPr-CH(CH.sub.2CH.sub.3) 2-CF.sub.3-4-Cl-phenyl 236
1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3) 2-CF.sub.3-4-Cl-phenyl 237
1-cPr-CH(CH.sub.2OCH.sub.3) 2-CF.sub.3-4-Cl-phenyl 238
1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3) 2-CF.sub.3-4-Cl-phenyl 239
(cBu).sub.2CH 2-CF.sub.3-4-Cl-phenyl 240 phenyl(cBu)CH
2-CF.sub.3-4-Cl-phenyl 241 2-furanyl(cBu)CH 2-CF.sub.3-4-Cl-phenyl
242 3-furan(cBu)CH 2-CF.sub.3-4-Cl-phenyl 243 2-thienyl(cBu)CH
2-CF.sub.3-4-Cl-phenyl 244 3-thienyl(cBu)CH 2-CF.sub.3-4-Cl-phenyl
245 2-isoxazolyl(cBU)CH 2-CF.sub.3-4-Cl-phenyl 246
2-(5-CH.sub.3-furanyl)(cBu)CH 2-CF.sub.3-4-Cl-phenyl 247
2-(4-CH.sub.3-isoxazolyl)(cBu)CH 2-CF.sub.3-4-Cl-phenyl 248
cBu-CH(CH.sub.3) 2-CF.sub.3-4-Cl-phenyl 249
1-cBu-CH(CH.sub.2CH.sub.3) 2-CF.sub.3-4-Cl-phenyl 250
1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3) 2-CF.sub.3-4-Cl-phenyl 251
1-cBu-CH(CH.sub.2OCH.sub.3) 2-CF.sub.3-4-Cl-phenyl 252
1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3) 2-CF.sub.3-4-Cl-phenyl 253
(cPr).sub.2CH 2-CF.sub.3-4-MeO-phenyl 254 phenyl(cPr)CH
2-CF.sub.3-4-MeO-phenyl 255 2-furanyl(cPr)CH
2-CF.sub.3-4-MeO-phenyl 256 3-furan(cPr)CH 2-CF.sub.3-4-MeO-phenyl
257 2-thienyl(cPr)CH 2-CF.sub.3-4-MeO-phenyl 258 3-thienyl(cPr)CH
2-CF.sub.3-4-MeO-phenyl 259 2-isoxazolyl(cPr)CH
2-CF.sub.3-4-MeO-phenyl 260 2-(5-CH.sub.3-furanyl)(cPr)CH
2-CF.sub.3-4-MeO-phenyl 261 2-(4-CH.sub.3-isoxazolyl)(cPr)CH
2-CF.sub.3-4-MeO-phenyl 262 cPr-CH(CH.sub.3)
2-CF.sub.3-4-MeO-phenyl 263 1-cPr-CH(CH.sub.2CH.sub.3)
2-CF.sub.3-4-MeO-phenyl 264 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3)
2-CF.sub.3-4-MeO-phenyl 265 1-cPr-CH(CH.sub.2OCH.sub.3)
2-CF.sub.3-4-MeO-phenyl 266 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3)
2-CF.sub.3-4-MeO-phenyl 267 (cBu).sub.2CH 2-CF.sub.3-4-MeO-phenyl
268 phenyl(cBu)CH 2-CF.sub.3-4-MeO-phenyl 269 2-furanyl(cBu)CH
2-CF.sub.3-4-MeO-phenyl 270 3-furan(cBu)CH 2-CF.sub.3-4-MeO-phenyl
271 2-thienyl(cBu)CH 2-CF.sub.3-4-MeO-phenyl 272 3-thienyl(cBu)CH
2-CF.sub.3-4-MeO-phenyl 273 2-isoxazolyl(cBu)CH
2-CF.sub.3-4-MeO-phenyl 274 2-(5-CH.sub.3-furanyl)(cBu)CH
2-CF.sub.3-4-MeO-phenyl 275 2-(4-CH.sub.3-isoxazolyl)(cBu)CH
2-CF.sub.3-4-MeO-phenyl 276 cBu-CH(CH.sub.3)
2-CF.sub.3-4-MeO-phenyl 277 1-cBu-CH(CH.sub.2CH.sub.3)
2-CF.sub.3-4-MeO-phenyl 278 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3)
2-CF.sub.3-4-MeO-phenyl 279 1-cBu-CH(CH.sub.2OCH.sub.3)
2-CF.sub.3-4-MeO-phenyl 280 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3)
2-CF.sub.3-4-MeO-phenyl 281 (cPr).sub.2CH 2-CF.sub.3-4-n-PrO-phen-
yl 282 phenyl(cPr)CH 2-CF.sub.3-4-n-PrO-phenyl 283 2-furanyl(cPr)CH
2-CF.sub.3-4-n-PrO-phenyl 284 3-furan(cPr)CH
2-CF.sub.3-4-n-PrO-phenyl 285 2-thienyl(cPr)CH
2-CF.sub.3-4-n-PrO-phenyl 286 3-thienyl(cPr)CH
2-CF.sub.3-4-n-PrO-phenyl 287 2-isoxazolyl(cPr)CH
2-CF.sub.3-4-n-PrO-phenyl 288 2-(5-CH.sub.3-furanyl)(cPr)CH
2-CF.sub.3-4-n-PrO-phenyl 289 2-(4-CH.sub.3-isoxazolyl)(cPr)CH
2-CF.sub.3-4-n-PrO-phenyl 290 cPr-CH(CH.sub.3)
2-CF.sub.3-4-n-PrO-phenyl 291 1-cPr-CH(CH.sub.2CH.sub.3)
2-CF.sub.3-4-n-PrO-phenyl 292 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3)
2-CF.sub.3-4-n-PrO-phenyl 293 1-cPr-CH(CH.sub.2OCH.sub.3)
2-CF.sub.3-4-n-PrO-phenyl 294 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3)
2-CF.sub.3-4-n-PrO-phenyl 295 (cBu).sub.2CH
2-CF.sub.3-4-n-PrO-phenyl 296 phenyl(cBu)CH
2-CF.sub.3-4-n-PrO-phenyl 297 2-furanyl(cBu)CH
2-CF.sub.3-4-n-PrO-phenyl 298 3-furan(cBu)CH
2-CF.sub.3-4-n-PrO-phenyl 299 2-thienyl(cBu)CH
2-CF.sub.3-4-n-PrO-phenyl 300 3-thienyl(cBu)CH
2-CF.sub.3-4-n-PrO-phenyl 301 2-isoxazolyl(cBu)CH
2-CF.sub.3-4-n-PrO-phenyl 302 2-(5-CH.sub.3-furanyl)(cBu)CH
2-CF.sub.3-4-n-PrO-phenyl 303 2-(4-CH.sub.3-isoxazolyl)(cBu)CH
2-CF.sub.3-4-n-PrO-phenyl 304 cBu-CH(CH.sub.3)
2-CF.sub.3-4-n-PrO-phenyl 305 1-cBu-CH(CH.sub.2CH.sub.3)
2-CF.sub.3-4-n-PrO-phenyl 306 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3)
2-CF.sub.3-4-n-PrO-phenyl 307 1-cBu-CH(CH.sub.2OCH.sub.3)
2-CF.sub.3-4-n-PrO-phenyl 308 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3)
2-CF.sub.3-4-n-PrO-phenyl 309 (cPr).sub.2CH 2,4-diCF.sub.3-phenyl
310 phenyl(cPr)CH 2,4-diCF.sub.3-phenyl 311 2-furanyl(cPr)CH
2,4-diCF.sub.3-phenyl 312 3-furan(cPr)CH 2,4-diCF.sub.3-phenyl 313
2-thienyl(cPr)CH 2,4-diCF.sub.3-phenyl 314 3-thienyl(cPr)CH
2,4-diCF.sub.3-phenyl 315 2-isoxazolyl(cPr)CH 2,4-diCF.sub.3-phenyl
316 2-(5-CH.sub.3-furanyl)(cPr)CH 2,4-diCF.sub.3-phenyl 317
2-(4-CH.sub.3-isoxazolyl)(cPr)CH 2,4-diCF.sub.3-phenyl 318
cPr-CH(CH.sub.3) 2,4-diCF.sub.3-phenyl 319
1-cPr-CH(CH.sub.2CH.sub.3) 2,4-diCF.sub.3-phenyl 320
1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3) 2,4-diCF.sub.3-phenyl 321
1-cPr-CH(CH.sub.2OCH.sub.3) 2,4-diCF.sub.3-phenyl 322
1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3) 2,4-diCF.sub.3-phenyl 323
(cBu).sub.2CH 2,4-diCF.sub.3-phenyl 324 phenyl(cBu)CH
2,4-diCF.sub.3-phenyl 325 2-furanyl(cBu)CH 2,4-diCF.sub.3-phenyl
326 3-furan(cBu)CH 2,4-diCF.sub.3-phenyl 327 2-thienyl(cBu)CH
2,4-diCF.sub.3-phenyl 328 3-thienyl(cBu)CH 2,4-diCF.sub.3-phenyl
329 2-isoxazolyl(cBu)CH 2,4-diCF.sub.3-phenyl 330
2-(5-CH.sub.3-furanyl)(cBu)CH 2,4-diCF.sub.3-phenyl 331
2-(4-CH.sub.3-isoxazolyl)(cBu)CH 2,4-diCF.sub.3-phenyl 332
cBu-CH(CH.sub.3) 2,4-diCF.sub.3-phenyl 333
1-cBu-CH(CH.sub.2CH.sub.3) 2,4-diCF.sub.3-phenyl 334
1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3) 2,4-diCF.sub.3-phenyl 335
1-cBu-CH(CH.sub.2OCH.sub.3) 2,4-diCF.sub.3-phenyl 336
1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3) 2,4-diCF.sub.3-phenyl 337
(cPr).sub.2CH 2-CF.sub.3-4-F-phenyl 338 phenyl(cPr)CH
2-CF.sub.3-4-F-phenyl 339 2-furanyl(cPr)CH 2-CF.sub.3-4-F-phenyl
340 3-furan(cPr)CH 2-CF.sub.3-4-F-phenyl 341 2-thienyl(cPr)CH
2-CF.sub.3-4-F-phenyl 342 3-thienyl(cPr)CH 2-CF.sub.3-4-F-phenyl
343 2-isoxazolyl(cPr)CH 2-CF.sub.3-4-F-phenyl 344
2-(5-CH.sub.3-furanyl)(cPr)CH 2-CF.sub.3-4-F-phenyl 345
2-(4-CH.sub.3-isoxazolyl)(cPr)CH 2-CF.sub.3-4-F-phenyl 346
cPr-CH(CH.sub.3) 2-CF.sub.3-4-F-phenyl 347
1-cPr-CH(CH.sub.2CH.sub.3) 2-CF.sub.3-4-F-phenyl 348
1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3) 2-CF.sub.3-4-F-phenyl 349
1-cPr-CH(CH.sub.2OCH.sub.3) 2-CF.sub.3-4-F-phenyl 350
1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3) 2-CF.sub.3-4-F-phenyl 351
(cBu).sub.2CH 2-CF.sub.3-4-F-phenyl 352 phenyl(cBu)CH
2-CF.sub.3-4-F-phenyl 353 2-furanyl(cBu)CH 2-CF.sub.3-4-F-phenyl
354 2-furan(cBu)CH 2-CF.sub.3-4-F-phenyl 355 2-thienyl(cBu)CH
2-CF.sub.3-4-F-phenyl 356 3-thienyl(cBu)CH 2-CF.sub.3-4-F-phenyl
357 2-isoxazolyl(cBu)CH 2-CF.sub.3-4-F-phenyl 358
2-(5-CH.sub.3-furanyl)(cBu)CH 2-CF.sub.3-4-F-phenyl 359
2-(4-CH.sub.3-isoxazolyl)(cBu)CH 2-CF.sub.3-4-F-phenyl 360
cBu-CH(CH.sub.3) 2-CF.sub.3-4-F-phenyl 361
1-cBu-CH(CH.sub.2CH.sub.3) 2-CF.sub.3-4-F-phenyl 362
1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3) 2-CF.sub.3-4-F-phenyl 363
1-cBu-CH(CH.sub.2OCH.sub.3) 2-CF.sub.3-4-F-phenyl 364
1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3) 2-CF.sub.3-4-F-phenyl 365
(cPr).sub.2CH 2-CH.sub.3-4-Cl-phenyl 366 phenyl(cPr)CH
2-CH.sub.3-4-Cl-phenyl 367 2-furanyl(cPr)CH 2-CH.sub.3-4-Cl-phenyl
368 3-furan(cPr)CH 2-CH.sub.3-4-Cl-phenyl 369 2-thienyl(cPr)CH
2-CH.sub.3-4-Cl-phenyl 370 3-thienyl(cPr)CH 2-CH.sub.3-4-Cl-phenyl
371 2-isoxazolyl(cPr)CH 2-CH.sub.3-4-Cl-phenyl 372
2-(5-CH.sub.3-furanyl)(cPr)CH 2-CH.sub.3-4-Cl-phenyl 373
2-(4-CH.sub.3isoxazolyl)(cPr)CH 2-CH.sub.3-4-Cl-phenyl 374
cPr-CH(CH.sub.3) 2-CH.sub.3-4-Cl-phenyl 375
1-cPr-CH(CH.sub.2CH.sub.3) 2-CH.sub.3-4-Cl-phenyl 376
1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3) 2-CH.sub.3-4-Cl-phenyl 377
1-cPr-CH(CH.sub.2OCH.sub.3) 2-CH.sub.3-4-Cl-phenyl 378
1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3) 2-CH.sub.3-4-Cl-phenyl 379
(cBu).sub.2CH 2-CH.sub.3-4-Cl-phenyl 380 phenyl(cBu)CH
2-CH.sub.3-4-Cl-phenyl 381 2-furanyl(cBu)CH 2-CH.sub.3-4-Cl-phenyl
382 3-furan(cBu)CH 2-CH.sub.3-4-Cl-phenyl 383 2-thienyl(cBu)CH
2-CH.sub.3-4-Cl-phenyl 384 3-thienyl(cBu)CH 2-CH.sub.3-4-Cl-phenyl
385 2-isoxazolyl(cBu)CH 2-CH.sub.3-4-Cl-phenyl 386
2-(5-CH.sub.3-furanyl)(cBu)CH 2-CH.sub.3-4-Cl-phenyl 387
2-(4-CH.sub.2-isoxazolyl)(cBu)CH 2-CH.sub.3-4-Cl-phenyl 388
cBu-CH(CH.sub.3) 2-CH.sub.3-4-Cl-phenyl 389
1-cBu-CH(CH.sub.2CH.sub.3) 2-CH.sub.3-4-Cl-phenyl 390
1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3) 2-CH.sub.3-4-Cl-phenyl 391
1-cBu-CH(CH.sub.2OCH.sub.3) 2-CH.sub.3-4-Cl-phenyl 392
1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3) 2-CH.sub.3-4-Cl-phenyl 393
(cPr).sub.2CH 2-CH.sub.3-4-MeO-phenyl 394 phenyl(cPr)CH
2-CH.sub.3-4-MeO-phenyl 395 2-furanyl(cPr)CH
2-CH.sub.3-4-MeO-phenyl 396 3-furan(cPr)CH 2-CH.sub.3-4-MeO-phenyl
397 2-thienyl(cPr)CH 2-CH.sub.3-4-MeO-phenyl 398 3-thienyl(cPr)CH
2-CH.sub.3-4-MeO-phenyl 399 2-isoxazolyl(cPr)CH
2-CH.sub.3-4-MeO-phenyl 400 2-(5-CH.sub.3-furanyl)(cPr)CH
2-CH.sub.3-4-MeO-phenyl 401 2-(4-CH.sub.3-isoxazolyl)(cPr)CH
2-CH.sub.3-4-MeO-phenyl 402 cPr-CH(CH.sub.3)
2-CH.sub.3-4-MeO-phenyl 403 1-cPr-CH(CH.sub.2CH.sub.3)
2-CH.sub.3-4-MeO-phenyl 404 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3)
2-CH.sub.3-4-MeO-phenyl 405 1-cPr-CH(CH.sub.2OCH.sub.3)
2-CH.sub.3-4-MeO-phenyl 406 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3)
2-CH.sub.3-4-MeO-phenyl 407 (cBu).sub.2CH 2-CH.sub.3-4-MeO-phenyl
408 phenyl(cBu)CH 2-CH.sub.3-4-MeO-phenyl 409 2-furanyl(cBu)CH
2-CH.sub.3-4-MeO-phenyl 410 3-furan(cBu)CH 2-CH.sub.3-4-MeO-phenyl
411 2-thienyl(cBu)CH 2-CH.sub.3-4-MeO-phenyl 412 3-thienyl(cBu)CH
2-CH.sub.3-4-MeO-phenyl 413 2-isoxazolyl(cBu)CH
2-CH.sub.3-4-MeO-phenyl 414 2-(5-CH.sub.3-furanyl)(cBu)CH
2-CH.sub.3-4-MeO-phenyl 415 2-(4-CH.sub.3-isoxazolyl)(cBu)CH
2-CH.sub.3-4-MeO-phenyl 416 cBu-CH(CH.sub.3)
2-CH.sub.3-4-MeO-phenyl 417 1-cBu-CH(CH.sub.2CH.sub.3)
2-CH.sub.3-4-MeO-phenyl 418 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3)
2-CH.sub.3-4-MeO-phenyl 419 1-cBu-CH(CH.sub.2OCH.sub.3)
2-CH.sub.3-4-MeO-phenyl 420 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3)
2-CH.sub.3-4-MeO-phenyl 421 (cPr).sub.2CH 2,4-diCH.sub.3-phenyl 422
phenyl(cPr)CH 2,4-diCH.sub.3-phenyl 423 2-furanyl(cPr)CH
2,4-diCH.sub.3-phenyl 424 3-furan(CcPr)CH 2,4-diCH.sub.3-phenyl 425
2-thienyl(cPr)CH 2,4-diCH.sub.3-phenyl 426 3-thienyl(cPr)CH
2,4-diCH.sub.3-phenyl 427 2-isoxazolyl(cPr)OH 2,4-diCH.sub.3-phenyl
428 2-(5-CH.sub.3-furanyl)(cPr)CH 2,4-diCH.sub.3-phenyl 429
2-(4-CH.sub.3-isoxazolyl)(cPr)CH 2,4-diCH.sub.3-phenyl 430
cPr-CH(CH.sub.3) 2,4-diCH.sub.3-phenyl 431
1-cPr-CH(CH.sub.2CH.sub.3) 2,4-diCH.sub.3-phenyl 432
1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3) 2,4-diCH.sub.3-phenyl 433
1-cPr-CH(CH.sub.2OCH.sub.3) 2,4-diCH.sub.3-phenyl 434
1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3) 2,4-diCH.sub.3-phenyl 435
(cBu).sub.2CH 2,4-diCH.sub.3-phenyl 436 phenyl(cBu)CH
2,4-diCH.sub.3-phenyl 437 2-furanyl(cBu)CH 2,4-diCH.sub.3-phenyl
438 3-furan(cBu)CH 2,4-diCH.sub.3-phenyl 439 2-thienyl(cBu)CH
2,4-diCH.sub.3-phenyl 440 3-thienyl(cBu)CH 2,4-diCH.sub.3-phenyl
441 2-isoxazolyl(cBu)CH 2,4-diCH.sub.3-phenyl 442
2-(5-CH.sub.3-furanyl)(cBu)CH 2,4-diCH.sub.3-phenyl 443
2-(4-CH.sub.3-isoxazolyl)(cBu)CH 2,4-diCH.sub.3-phenyl 444
cBu-CH(CH.sub.3) 2,4-diCH.sub.3-phenyl 445
1-cBu-CH(CH.sub.2CH.sub.3) 2,4-diCH.sub.3-phenyl 446
1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3) 2,4-diCH.sub.3-phenyl 447
1-cBu-CH(CH.sub.2OCH.sub.3) 2,4-diCH.sub.3-phenyl 448
1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3) 2,4-diCH.sub.3-phenyl 449
(cPr).sub.2CH 2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl 450
phenyl(cPr)CH 2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl 451
2-furanyl(cPr)CH 2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl 452
3-furan(cPr)CH 2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl 453
2-thienyl(cPr)CH 2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl 454
3-thienyl(cPr)CH 2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl 455
2-isoxazolyl(cPr)CH 2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl 456
2-(5-CH.sub.2-furanyl)(cPr)CH 2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl
457 2-(4-CH.sub.3-isoxazolyl)(cPr)CH
2-CH.sub.3-4-(CH.sub.3).sub.2N-phe- nyl 458 cPr-CH(CH.sub.3)
2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl 459
1-cPr-CH(CH.sub.2CH.sub.3) 2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl
460 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3) 2-CH.sub.3-4-(CH.sub.3).su-
b.2N-phenyl 461 1-cPr-CH(CH.sub.2OCH.sub.3)
2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl 462 1-cPr-CH(CH.sub.2CH.sub-
.2OCH.sub.3) 2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl 463
(cBu).sub.2CH 2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl 464
phenyl(cBu)CH 2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl 465
2-furanyl(cBu)CH 2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl 466
3-furan(cBu)CH 2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl 467
2-thienyl(cBu)CH 2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl 468
3-thienyl(cBu)CH 2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl 469
2-isoxazolyl(cBu)CH 2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl 470
2-(5-CH.sub.3-furanyl)(cBu)CH 2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl
471 2-(4-CH.sub.3-isoxazolyl)(cBu)CH
2-CH.sub.3-4-(CH.sub.3).sub.2N-phe- nyl 472 cBu-CH(CH.sub.3)
2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl 473
1-cBu-CH(CH.sub.2CH.sub.3) 2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl
474 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3) 2-CH.sub.3-4-(CH.sub.3).su-
b.2N-phenyl 475 1-cBu-CH(CH.sub.2OCH.sub.3)
2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl 476 1-cBu-CH(CH.sub.2CH.sub-
.2OCH.sub.3) 2-CH.sub.3-4-(CH.sub.3).sub.2N-phenyl 477
(cPr).sub.2CH 2-MeO-4-CH.sub.3-phenyl 478 phenyl(cPr)CH
2-MeO-4-CH.sub.3-phenyl 479 2-furanyl(cPr)CH
2-MeO-4-CH.sub.3-phenyl 480 3-furan(cPr)CH 2-MeO-4-CH.sub.3-phenyl
481 2-thienyl(cPr)CH 2-MeO-4-CH.sub.3-phenyl 482 3-thienyl(cPr)CH
2-MeO-4-CH.sub.3-phenyl 483 2-isoxazolyl(cPr)CH
2-MeO-4-CH.sub.3-phenyl 484 2-(5-CH.sub.3-furanyl)(cPr)CH
2-MeO-4-CH.sub.3-phenyl 485 2-(4-CH.sub.3-isoxazolyl)(cPr)CH
2-MeO-4-CH.sub.3-phenyl 486 cPr-CH(CH.sub.3)
2-MeO-4-CH.sub.3-phenyl 487 1-cPr-CH(CH.sub.2CH.sub.3)
2-MeO-4-CH.sub.3-phenyl 488 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3)
2-MeO-4-CH.sub.3-phenyl 489 1-cPr-CH(CH.sub.2OCH.sub.3)
2-MeO-4-CH.sub.3-phenyl 490 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3)
2-MeO-4-CH.sub.3-phenyl 491 (cBu).sub.2CH 2-MeO-4-CH.sub.3-phenyl
492 phenyl(cBu)CH 2-MeO-4-CH.sub.3-phenyl 493 2-furanyl(cBu)CH
2-MeO-4-CH.sub.3-phenyl 494 3-furan(cBu)CH 2-MeO-4-CH.sub.3-phenyl
495 2-thienyl(cBu)CH 2-MeO-4-CH.sub.3-phenyl 496 3-thienyl(cBu)CH
2-MeO-4-CH.sub.3-phenyl 497 2-isoxazolyl(cBu)CH
2-MeO-4-CH.sub.3-phenyl 498 2-(5-CH.sub.3-furanyl)(cBu)CH
2-MeO-4-CH.sub.3-phenyl 499 2-(4-CH.sub.3-isoxazolyl)(cBu)CH
2-MeO-4-CH.sub.3-phenyl 500 cBu-CH(CH.sub.3)
2-MeO-4-CH.sub.3-phenyl 501 1-cBu-CH(CH.sub.2CH.sub.3)
2-MeO-4-CH.sub.3-phenyl 502 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3)
2-MeO-4-CH.sub.3-phenyl 503 1-cBu-CH(CH.sub.2OCH.sub.3)
2-MeO-4-CH.sub.3-phenyl 504 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3)
2-MeO-4-CH.sub.3-phenyl 505 (cPr).sub.2CH 2-MeO-4-CF.sub.3-phenyl
506 phenyl(cPr)CH 2-MeO-4-CF.sub.3-phenyl 507 2-furanyl(cPr)CH
2-MeO-4-CF.sub.3-phenyl 508 3-furan(cPr)CH 2-MeO-4-CF.sub.3-phenyl
509 2-thienyl(cPr)CH 2-MeO-4-CF.sub.3-phenyl 510 3-thienyl(cPr)CH
2-MeO-4-CF.sub.3-phenyl 511 2-isoxazolyl(cPr)CH
2-MeO-4-CF.sub.3-phenyl 512 2-(5-CH.sub.3furanyl)(cPr)CH
2-MeO-4-CF.sub.3-phenyl 513 2-(4-CH.sub.3-isoxazolyl)(cPr)CH
2-MeO-4-CF.sub.3-phenyl 514 cPr-CH(CH.sub.3)
2-MeO-4-CF.sub.3-phenyl 515 1-cPr-CH(CH.sub.2CH.sub.3)
2-MeO-4-CF.sub.3-phenyl 516 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3)
2-MeO-4-CF.sub.3-phenyl 517 1-cPr-CH(CH.sub.2OCH.sub.3)
2-MeO-4-CF.sub.3-phenyl 518 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3)
2-MeO-4-CF.sub.3-phenyl 519 (cBu).sub.2CH 2-MeO-4-CF.sub.3-phenyl
520 phenyl(cBu)CH 2-MeO-4-CF.sub.3-phenyl 521 2-furanyl(cBu)CH
2-MeO-4-CF.sub.3-phenyl 522 3-furan(cBu)CH 2-MeO-4-CF.sub.3-phenyl
523 2-thienyl(cBu)CH 2-MeO-4-CF.sub.3-phenyl 524 3-thienyl(cBu)CH
2-MeO-4-CF.sub.3-phenyl 525 2-isoxazolyl(cBu)CH
2-MeO-4-CF.sub.3-phenyl 526 2-(5-CH.sub.3-furanyl)(cBu)CH
2-MeO-4-CF.sub.3-phenyl 527 2-(4-CH.sub.3-isoxazolyl)(cBu)CH
2-MeO-4-CF.sub.3-phenyl 528 cBu-CH(CH.sub.3)
2-MeO-4-CF.sub.3-phenyl 529 1-cBu-CH(CH.sub.2CH.sub.3)
2-MeO-4-CF.sub.3-phenyl 530 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3)
2-MeO-4-CF.sub.3-phenyl 531 1-cBu-CH(CH.sub.2OCH.sub.3)
2-MeO-4-CF.sub.3-phenyl 532 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3)
2-MeO-4-CF.sub.3-phenyl 533 (cPr).sub.2CH 2-MeO-4-Cl-phenyl 534
phenyl(cPr)CH 2-MeO-4-Cl-phenyl 535 2-furanyl(cPr)CH
2-MeO-4-Cl-phenyl 536 3-furan(cPr)CH 2-MeO-4-Cl-phenyl 537
2-thienyl(cPr)CH 2-MeO-4-Cl-phenyl 538 3-thienyl(cPr)CH
2-MeO-4-Cl-phenyl 539 2-isoxazolyl(cPr)CH 2-MeO-4-Cl-phenyl 540
2-(5-CH.sub.3-furanyl)(cPr)CH 2-MeO-4-Cl-phenyl 541
2-(4-CH.sub.3-isoxazolyl)(cPr)CH 2-MeO-4-Cl-phenyl 542
cPr-CH(CH.sub.3) 2-MeO-4-Cl-phenyl 543 1-cPr-CH(CH.sub.2CH.sub.3)
2-MeO-4-Cl-phenyl 544 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3)
2-MeO-4-Cl-phenyl 545 1-cPr-CH(CH.sub.2OCH.sub.3) 2-MeO-4-Cl-phenyl
546 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3) 2-MeO-4-Cl-phenyl 547
(cBu).sub.2CH 2-MeO-4-Cl-phenyl 548 phenyl(cBu)CH 2-MeO-4-Cl-phenyl
549 2-furanyl(cBu)CH 2-MeO-4-Cl-phenyl 550 3-furan(cBu)CH
2-MeO-4-Cl-phenyl 551 2-thienyl(cBu)CH 2-MeO-4-Cl-phenyl 552
3-thienyl(cBu)CH 2-MeO-4-Cl-phenyl 553 2-isoxazolyl(cBu)CH
2-MeO-4-Cl-phenyl 554 2-(5-CH.sub.3-furanyl)(cBu)CH
2-MeO-4-Cl-phenyl 555 2-(4-CH.sub.3-isoxazolyl)(cBu)CH
2-MeO-4-Cl-phenyl 556 cBu-CH(CH.sub.3) 2-MeO-4-Cl-phenyl 557
1-cBu-CH(CH.sub.2CH.sub.3) 2-MeO-4-Cl-phenyl 558
1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3) 2-MeO-4-Cl-phenyl 559
1-cBu-CH(CH.sub.2OCH.sub.3) 2-MeO-4-Cl-phenyl 560
1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3) 2-MeO-4-Cl-phenyl 561
(cPr).sub.2CH 2,4-diMeO-phenyl 562 phenyl(cPr)CH 2,4-diMeO-phenyl
563 2-furanyl(cPr)CH 2,4-diMeO-phenyl 564 3-furan(cPr)CH
2,4-diMeO-phenyl 565 2-thienyl(cPr)CH 2,4-diMeO-phenyl 566
3-thienyl(cPr)CH 2,4-diMeO-phenyl 567 2-isoxazolyl(cPr)CH
2,4-diMeO-phenyl 568 2-(5-CH.sub.3-furanyl)(cPr)CH 2,4-diMeO-phenyl
569 2-(4-CH.sub.3-isoxazolyl)(cPr)CH 2,4-diMeO-phenyl 570
cPr-CH(CH.sub.3) 2,4-diMeO-phenyl 571 1-cPr-CH(CH.sub.2CH.sub.3)
2,4-diMeO-phenyl 572 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3)
2,4-diMeO-phenyl 573 1-cPr-CH(CH.sub.2OCH.sub.3) 2,4-diMeO-phenyl
574 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3) 2,4-diMeO-phenyl 575
(cBu).sub.2CH 2,4-diMeO-phenyl 576 phenyl(cBu)CH 2,4-diMeO-phenyl
577 2-furanyl(cBu)CH 2,4-diMeO-phenyl 578 3-furan(cBu)CH
2,4-diMeO-phenyl 579 2-thienyl(cBu)CH 2,4-diMeO-phenyl 580
3-thienyl(cBu)CH 2,4-diMeO-phenyl 581 2-isoxazolyl(cBu)CH
2,4-diMeO-phenyl 582 2-(5-CH.sub.3-furanyl)(cBu)CH 2,4-diMeO-phenyl
583
2-(4-CH.sub.3-isoxazolyl)(cBu)CH 2,4-diMeO-phenyl 584
cBu-CH(CH.sub.3) 2,4-diMeO-phenyl 585 1-cBu-CH(CH.sub.2CH.sub.3)
2,4-diMeO-phenyl 586 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3)
2,4-diMeO-phenyl 587 1-cBu-CH(CH.sub.2OCH.sub.3) 2,4-diMeO-phenyl
588 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3) 2,4-diMeO-phenyl 589
(cPr).sub.2CH 2,4-diCl-6-CH.sub.3-phenyl 590 phenyl(cPr)CH
2,4-diCl-6-CH.sub.3-phenyl 591 2-furanyl(cPr)CH
2,4-diCl-6-CH.sub.3-phenyl 592 3-furan(cPr)CH
2,4-diCl-6-CH.sub.3-phenyl 593 2-thienyl(cPr)CH
2,4-diCl-6-CH.sub.3-phenyl 594 3-thienyl(cPr)CH
2,4-diCl-6-CH.sub.3-phenyl 595 2-isoxazolyl(cPr)CH
2,4-diCl-6-CH.sub.3-phenyl 596 2-(5-CH.sub.3-furanyl)(cPr)CH
2,4-diCl-6-CH.sub.3-phenyl 597 2-(4-CH.sub.3-isoxazolyl)(cPr)CH
2,4-diCl-6-CH.sub.3-phenyl 598 cPr-CH(CH.sub.3)
2,4-diCl-6-CH.sub.3-phenyl 599 1-cPr-CH(CH.sub.2CH.sub.3)
2,4-diCl-6-CH.sub.3-phenyl 600 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3)
2,4-diCl-6-CH.sub.3-phenyl 601 1-cPr-CH(CH.sub.2OCH.sub.3)
2,4-diCl-6-CH.sub.3-phenyl 602 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3-
) 2,4-diCl-6-CH.sub.3-phenyl 603 (cBu).sub.2CH
2,4-diCl-6-CH.sub.3-phenyl 604 phenyl(cBu)CH
2,4-diCl-6-CH.sub.3-phenyl 605 2-furanyl(cBu)CH
2,4-diCl-6-CH.sub.3-phenyl 606 3-furan(cBu)CH
2,4-diCl-6-CH.sub.3-phenyl 607 2-thienyl(cBu)CH
2,4-diCl-6-CH.sub.3-phenyl 608 3-thienyl(cBu)CH
2,4-diCl-6-CH.sub.3-phenyl 609 2-isoxazolyl(cBu)CH
2,4-diCl-6-CH.sub.3-phenyl 610 2-(5-CH.sub.3-furanyl)(cBu)CH
2,4-diCl-6-CH.sub.3-phenyl 611 2-(4-CH.sub.3-isoxazoyl)(cBu)CH
2,4-diCl-6-CH.sub.3-phenyl 612 cBu-CH(CH.sub.3)
2,4-diCl-6-CH.sub.3-phenyl 613 1-cBu-CH(CH.sub.2CH.sub.3)
2,4-diCl-6-CH.sub.3-phenyl 614 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3)
2,4-diCl-6-CH.sub.3-phenyl 615 1-cBu-CH(CH.sub.2OCH.sub.3)
2,4-diCl-6-CH.sub.3-phenyl 616 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3-
) 2,4-diCl-6-CH.sub.3-phenyl 617 (cPr).sub.2CH 2,4-diCl-5-F-phenyl
618 phenyl(cPr)CH 2,4-diCl-5-F-phenyl 619 2-furanyl(cPr)CH
2,4-diCl-5-F-phenyl 620 3-furan(cPr)CH 2,4-diCl-5-F-phenyl 621
2-thienyl(cPr)CH 2,4-diCl-5-F-phenyl 622 3-thienyl(cPr)CH
2,4-diCl-5-F-phenyl 623 2-isoxazolyl(cPr)CH 2,4-diCl-5-F-phenyl 624
2-(5-CH.sub.3-furanyl)(cPr)CH 2,4-diCl-5-F-phenyl 625
2-(4-CH.sub.3-isoxazolyl)(cPr)CH 2,4-diCl-5-F-phenyl 626
cPr-CH(CH.sub.3) 2,4-diCl-5-F-phenyl 627 1-cPr-CH(CH.sub.2CH.sub.-
3) 2,4-diCl-5-F-phenyl 628 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3)
2,4-diCl-5-F-phenyl 629 1-cPr-CH(CH.sub.2OCH.sub.3)
2,4-diCl-5-F-phenyl 630 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3)
2,4-diCl-5-F-phenyl 631 (cBu).sub.2CH 2,4-diCl-5-F-phenyl 632
phenyl(cBu)CH 2,4-diCl-5-F-phenyl 633 2-furanyl(cBu)CH
2,4-diCl-5-F-phenyl 634 3-furan(cBu)CH 2,4-diCl-5-F-phenyl 635
2-thienyl(cBu)CH 2,4-diCl-5-F-phenyl 636 3-thienyl(cBu)CH
2,4-diCl-5-F-phenyl 637 2-isoxazolyl(cBu)CH 2,4-diCl-5-F-phenyl 638
2-(5-CH.sub.3-furanyl)(cBu)CH 2,4-diCl-5-F-phenyl 639
2-(4-CH.sub.3-isoxazolyl)(cBu)CH 2,4-diCl-5-F-phenyl 640
cBu-CH(CH.sub.3) 2,4-diCl-5-F-phenyl 641 1-cBu-CH(CH.sub.2CH.sub.-
3) 2,4-diCl-5-F-phenyl 642 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3)
2,4-diCl-5-F-phenyl 643 1-cBu-CH(CH.sub.2OCH.sub.3)
2,4-diCl-5-F-phenyl 644 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3)
2,4-diCl-5-F-phenyl 645 (cPr).sub.2CH 2,4-diCl-6-MeS-phenyl 646
phenyl(cPr)CH 2,4-diCl-6-MeS-phenyl 647 2-furanyl(cPr)CH
2,4-diCl-6-MeS-phenyl 648 3-furan(cPr)CH 2,4-diCl-6-MeS-phenyl 649
2-thienyl(cPr)CH 2,4-diCl-6-MeS-phenyl 650 3-thienyl(cPr)CH
2,4-diCl-6-MeS-phenyl 651 2-isoxazolyl(cPr)CH 2,4-diCl-6-MeS-phenyl
652 2-(5-CH.sub.3-furanyl)(cPr)CH 2,4-diCl-6-MeS-phenyl 653
2-(4-CH.sub.3-isoxazolyl)(cPr)CH 2,4-diCl-6-MeS-phenyl 654
cPr-CH(CH.sub.3) 2,4-diCl-6-MeS-phenyl 655
1-cPr-CH(CH.sub.2CH.sub.3) 2,4-diCl-6-MeS-phenyl 656
1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3) 2,4-diCl-6-MeS-phenyl 657
1-cPr-CH(CH.sub.2OCH.sub.3) 2,4-diCl-6-MeS-phenyl 658
1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3) 2,4-diCl-6-MeS-phenyl 659
(cBu).sub.2CH 2,4-diCl-6-MeS-phenyl 660 phenyl(cBu)CH
2,4-diCl-6-MeS-phenyl 661 2-furanyl(cBu)CH 2,4-diCl-6-MeS-phenyl
662 3-furan(cBu)CH 2,4-diCl-6-MeS-phenyl 663 2-thienyl(cBu)CH
2,4-diCl-6-MeS-phenyl 664 3-thienyl(cBu)CH 2,4-diCl-6-MeS-phenyl
665 2-isoxazolyl(cBu)CH 2,4-diCl-6-MeS-phenyl 666
2-(5-CH.sub.3-furanyl)(cBu)CH 2,4-diCl-6-MeS-phenyl 667
2-(4-CH.sub.3-isoxazolyl)(cBu)CH 2,4-diCl-6-MeS-phenyl 668
cBu-CH(CH.sub.3) 2,4-diCl-6-MeS-phenyl 669
1-cBu-CH(CH.sub.2CH.sub.3) 2,4-diCl-6-MeS-phenyl 670
1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3) 2,4-diCl-6-MeS-phenyl 671
1-cBu-CH(CH.sub.3OCH.sub.3) 2,4-diCl-6-MeS-phenyl 672
1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3) 2,4-diCl-6-MeS-phenyl 673
(cPr).sub.2CH 2,4-diCl-6-MeO-phenyl 674 phenyl(cPr)CH
2,4-diCl-6-MeO-phenyl 675 2-furanyl(cPr)CH 2,4-diCl-6-MeO-phenyl
676 3-furan(cPr)CH 2,4-diCl-6-MeO-phenyl 677 2-thienyl(cPr)CH
2,4-diCl-6-MeO-phenyl 678 3-thienyl(cPr)CH 2,4-diCl-6-MeO-phenyl
679 2-isoxazolyl(cPr)CH 2,4-diCl-6-MeO-phenyl 680
2-(5-CH.sub.3-furanyl)(cPr)CH 2,4-diCl-6-MeO-phenyl 681
2-(4-CH.sub.3-isoxazolyl)(cPr)CH 2,4-diCl-6-MeO-phenyl 682
cPr-CH(CH.sub.3) 2,4-diCl-6-MeO-phenyl 683
1-cPr-CH(CH.sub.2CH.sub.3) 2,4-diCl-6-MeO-phenyl 684
1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3) 2,4-diCl-6-MeO-phenyl 685
1-cPr-CH(CH.sub.2OCH.sub.3) 2,4-diCl-6-MeO-phenyl 686
1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3) 2,4-diCl-6-MeO-phenyl 687
(cBu).sub.2CH 2,4-diCl-6-MeO-phenyl 688 phenyl(cBu)CH
2,4-diCl-6-MeO-phenyl 689 2-furanyl(cBu)CH 2,4-diCl-6-MeO-phenyl
690 3-furan(cBu)CH 2,4-diCl-6-MeO-phenyl 691 2-thienyl(cBu)CH
2,4-diCl-6-MeO-phenyl 692 3-thienyl(cBu)CH 2,4-diCl-6-MeO-phenyl
693 2-isoxazolyl(cBu)CH 2,4-diCl-6-MeO-phenyl 694
2-(5-CH.sub.3-furanyl)(cBu)CH 2,4-diCl-6-MeO-phenyl 695
2-(4-CH.sub.3-isoxazolyl)(cBu)CH 2,4-diCl-6-MeO-phenyl 696
cBu-CH(CH.sub.3) 2,4-diCl-6-MeO-phenyl 697
1cBu-CH(CH.sub.2CH.sub.3) 2,4-diCl-6-MeO-phenyl 698
1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3) 2,4-diCl-6-MeO-phenyl 699
1-cBu-CH(CH.sub.2OCH.sub.3) 2,4-diCl-6-MeO-phenyl 700
1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3) 2,4-diCl-6-MeO-phenyl 701
(cPr).sub.2CH 2,5-diCl-4-MeO-phenyl 702 phenyl(cPr)CH
2,5-diCl-4-MeO-phenyl 703 2-furanyl(cPr)CH 2,5-diCl-4-MeO-phenyl
704 3-furan(cPr)CH 2,5-diCl-4-MeO-phenyl 705 2-thienyl(cPr)CH
2,5-diCl-4-MeO-phenyl 706 3-thienyl(cPr)CH 2,5-diCl-4-MeO-phenyl
707 2-isoxazolyl(cPr)CH 2,5-diCl-4-MeO-phenyl 708
2-(5-CH.sub.3-furanyl)(cPr)CH 2,5-diCl-4-MeO-phenyl 709
2-(4-CH.sub.3-isoxazolyl)(cPr)CH 2,5-diCl-4-MeO-phenyl 710
cPr-CH(CH.sub.3) 2,5-diCl-4-MeO-phenyl 711
1-cPr-CH(CH.sub.2CH.sub.3) 2,5-diCl-4-MeO-phenyl 712
1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3) 2,5-diCl-4-MeO-phenyl 713
1-cPr-CH(CH.sub.2OCH.sub.3) 2,5-diCl-4-MeO-phenyl 714
1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3) 2,5-diCl-4-MeO-phenyl 715
(cBu).sub.2CH 2,5-diCl-4-MeO-phenyl 716 phenyl(cBu)CH
2,5-diCl-4-MeO-phenyl 717 2-furanyl(cBu)CH 2,5-diCl-4-MeO-phenyl
718 3-furan(cBu)CH 2,5-diCl-4-MeO-phenyl 719 2-thienyl(cBu)CH
2,5-diCl-4-MeO-phenyl 720 3-thienyl(cBu)CH 2,5-diCl-4-MeO-phenyl
721 2-isoxazolyl(cBu)CH 2,5-diCl-4-MeO-phenyl 722
2-(5-CH.sub.3-furanyl)(cBu)CH 2,5-diCl-4-MeO-phenyl 723
2-(4-CH.sub.3-isoxazolyl)cBu)CH 2,5-diCl-4-MeO-phenyl 724
cBu-CH(CH.sub.3) 2,5-diCl-4-MeO-phenyl 725
1-cBu-CH(CH.sub.2CH.sub.3) 2,5-diCl-4-MeO-phenyl 726
1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3) 2,5-diCl-4-MeO-phenyl 727
1-cBu-CH(CH.sub.2OCH.sub.3) 2,5-diCl-4-MeO-phenyl 728
1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3) 2,5-diCl-4-MeO-phenyl 729
(cPr).sub.2CH 2,4,6-triCl-phenyl 730 phenyl(cPr)CH
2,4,6-triCl-phenyl 731 2-furanyl(cPr)CH 2,4,6-triCl-phenyl 732
3-furan(cPr)CH 2,4,6-triCl-phenyl 733 2-thienyl(cPr)CH
2,4,6-triCl-phenyl 734 3-thienyl(cPr)CH 2,4,6-triCl-phenyl 735
2-isoxazol(cPr)CH 2,4,6-triCl-phenyl 736
2-(5-CH.sub.3-furanyl)(cPr)CH 2,4,6-triCl-phenyl 737
2-(4-CH.sub.3-isoxazol)(cPr)CH 2,4,6-triCl-phenyl 738
cPr-CH(CH.sub.3) 2,4,6-triCl-phenyl 739 1-cPr-CH(CH.sub.2CH.sub.3-
) 2,4,6-triCl-phenyl 740 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3)
2,4,6-triCl-phenyl 741 1-cPr-CH(CH.sub.2OCH.sub.3)
2,4,6-triCl-phenyl 742 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3)
2,4,6-triCl-phenyl 743 (cBu).sub.2CH 2,4,6-triCl-phenyl 744
phenyl(cBu)CH 2,4,6-triCl-phenyl 745 2-furanyl(cBu)CH
2,4,6-triCl-phenyl 746 3-furan(cBu)CH 2,4,6-triCl-phenyl 747
2-thienyl(cBu)CH 2,4,6-triCl-phenyl 748 3-thienyl(cBu)CH
2,4,6-triCl-phenyl 749 2-isoxazolyl(cBu)CH 2,4,6-triCl-phenyl 750
2-(5-CH.sub.3-furanyl)(cBu)CH 2,4,6-triCl-phenyl 751
2-(4-CH.sub.3-isoxazolyl)(cBu)CH 2,4,6-triCl-phenyl 752
cBu-CH(CH.sub.3) 2,4,6-triCl-phenyl 753 1-cBu-CH(CH.sub.2CH.sub.3-
) 2,4,6-triCl-phenyl 754 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3)
2,4,6-triCl-phenyl 755 2-cBu-CH(CH.sub.2OCH.sub.3)
2,4,6-triCl-phenyl 756 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3)
2,4,6-triCl-phenyl 757 (cPr).sub.2CH 2-Cl-4-CH.sub.3-5-F-phenyl 758
phenyl(cPr)CH 2-Cl-4-CH.sub.3-5-F-phenyl 759 2-furanyl(cPr)CH
2-Cl-4-CH.sub.3-5-F-phenyl 760 3-furan(cPr)CH
2-Cl-4-CH.sub.3-5-F-phenyl 761 2-thienyl(cPr)CH
2-Cl-4-CH.sub.3-5-F-phenyl 762 3-thienyl(cPr)CH
2-Cl-4-CH.sub.3-5-F-phenyl 763 2-isoxazolyl(cPr)CH
2-Cl-4-CH.sub.3-5-F-phenyl 764 2-(5-CH.sub.3-furanyl)(cPr)CH
2-Cl-4-CH.sub.3-5-F-phenyl 765 2-(4-CH.sub.3isoxazolyl)(cPr)CH
2-Cl-4-CH.sub.3-5-F-phenyl 766 cPr-CH(CH.sub.3)
2-Cl-4-CH.sub.3-5-F-phenyl 767 1-cPr-CH(CH.sub.2CH.sub.3)
2-Cl-4-CH.sub.3-5-F-phenyl 768 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3)
2-Cl-4-CH.sub.3-5-F-phenyl 769 1-cPr-CH(CH.sub.2OCH.sub.3)
2-Cl-4-CH.sub.3-5-F-phenyl 770 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3-
) 2-Cl-4-CH.sub.3-5-F-phenyl 771 (cBu).sub.2CH
2-Cl-4-CH.sub.3-5-F-phenyl 772 phenyl(cBu)CH
2-Cl-4-CH.sub.3-5-F-phenyl 773 2-furanyl(cBu)CH
2-Cl-4-CH.sub.3-5-F-phenyl 774 3-furan(cBu)CH
2-Cl-4-CH.sub.3-5-F-phenyl 775 2-thienyl(cBu)CH
2-Cl-4-CH.sub.3-5-F-phenyl 776 3-thienyl(cBu)CH
2-Cl-4-CH.sub.3-5-F-phenyl 777 2-isoxazol(cBu)CH
2-Cl-4-CH.sub.3-5-F-phenyl 778 2-(5-CH.sub.3-furanyl)(cBu)CH
2-Cl-4-CH.sub.3-5-F-phenyl 779 2-(4-CH.sub.3-isoxazolyl)(cBu)CH
2-Cl-4-CH.sub.3-5-F-phenyl 780 cBu-CH(CH.sub.3)
2-Cl-4-CH.sub.3-5-F-phenyl 781 1-cBu-CH(CH.sub.2CH.sub.3)
2-Cl-4-CH.sub.3-5-F-phenyl 782 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3)
2-Cl-4-CH.sub.3-5-F-phenyl 783 1-cBu-CH(CH.sub.2OCH.sub.3)
2-Cl-4-CH.sub.3-5-F-phenyl 784 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3-
) 2-Cl-4-CH.sub.3-5-F-phenyl 785 (cPr).sub.2CH
2-Cl-4-MeO-5-CH.sub.3-phenyl 786 phenyl(cPr)CH
2-Cl-4-MeO-5-CH.sub.3-phenyl 787 2-furanyl(cPr)CH
2-Cl-4-MeO-5-CH.sub.3-phenyl 788 3-furan(cPr)CH
2-Cl-4-MeO-5-CH.sub.3-phenyl 789 2-thienyl(cPr)CH
2-Cl-4-MeO-5-CH.sub.3-phenyl 790 3-thienyl(cPr)CH
2-Cl-4-MeO-5-CH.sub.3-phenyl 791 2-isoxazol(cPr)CH
2-Cl-4-MeO-5-CH.sub.3-phenyl 792 2-(5-CH.sub.3-furanyl)(cPr)CH
2-Cl-4-MeO-5-CH.sub.3-phenyl 793 2-(4-CH.sub.3-isoxazolyl)(cPr)CH
2-Cl-4-MeO-5-CH.sub.3-phenyl 794 cPr-CH(CH.sub.3)
2-Cl-4-MeO-5-CH.sub.3-phenyl 795 1-cPr-CH(CH.sub.2CH.sub.3)
2-Cl-4-MeO-5-CH.sub.3-phenyl 796 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.-
3) 2-Cl-4-MeO-5-CH.sub.3-phenyl 797 1-cPr-CH(CH.sub.2OCH.sub.3)
2-Cl-4-MeO-5-CH.sub.3-phenyl 798 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub-
.3) 2-Cl-4-MeO-5-CH.sub.3-phenyl 799 (cBu).sub.2CH
2-Cl-4-MeO-5-CH.sub.3-phenyl 800 phenyl(cBu)CH
2-Cl-4-MeO-5-CH.sub.3-phenyl 801 2-furanyl(cBu)CH
2-Cl-4-MeO-5-CH.sub.3-phenyl 802 3-furan(cBu)CH
2-Cl-4-MeO-5-CH.sub.3-phenyl 803 2-thienyl(cBu)CH
2-Cl-4-MeO-5-CH.sub.3-phenyl 804 3-thienyl(cBu)CH
2-Cl-4-MeO-5-CH.sub.3-phenyl 805 2-isoxazolyl(cBu)CH
2-Cl-4-MeO-5-CH.sub.3-phenyl 806 2-(5-CH.sub.3-furanyl)(cBu)CH
2-Cl-4-MeO-5-CH.sub.3-phenyl 807 2-(4-CH.sub.3-isoxazolyl)(cBu)CH
2-Cl-4-MeO-5-CH.sub.3-phenyl 808 cBu-CH(CH.sub.3)
2-Cl-4-MeO-5-CH.sub.3-phenyl 809 1-cBu-CH(CH.sub.2CH.sub.3)
2-Cl-4-MeO-5-CH.sub.3-phenyl 810 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.-
3) 2-Cl-4-MeO-5-CH.sub.3-phenyl 811 1-cBu-CH(CH.sub.2OCH.sub.3)
2-Cl-4-MeO-5-CH.sub.3-phenyl 812 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub-
.3) 2-Cl-4-MeO-5-CH.sub.3-phenyl 813 (cPr).sub.2CH
2-Cl-4-MeO-5-F-phenyl 814 phenyl(cPr)CH 2-Cl-4-MeO-5-F-phenyl 815
2-furanyl(cPr)CH 2-Cl-4-MeO-5-F-phenyl 816 3-furan(cPr)CH
2-Cl-4-MeO-5-F-phenyl 817 2-thienyl(cPr)CH 2-Cl-4-MeO-5-F-phenyl
818 3-thienyl(cPr)CH 2-Cl-4-MeO-5-F-phenyl 819 2-isoxazolyl(cPr)CH
2-Cl-4-MeO-5-F-phenyl 820 2-(5-CH.sub.3-furanyl)(cPr)CH
2-Cl-4-MeO-5-F-phenyl 821 2-(4-CH.sub.3-isoxazolyl)(cPr)CH
2-Cl-4-MeO-5-F-phenyl 822 cPr-CH(CH.sub.3) 2-Cl-4-MeO-5-F-phenyl
823 1-cPr-CH(CH.sub.2CH.sub.3) 2-Cl-4-MeO-5-F-phenyl 824
1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3) 2-Cl-4-MeO-5-F-phenyl 825
1-cPr-CH(CH.sub.2OCH.sub.3) 2-Cl-4-MeO-5-F-phenyl 826
1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3) 2-Cl-4-MeO-5-F-phenyl 827
(cBu).sub.2CH 2-Cl-4-MeO-5-F-phenyl 828 phenyl(cBu)CH
2-Cl-4-MeO-5-F-phenyl 829 2-furanyl(cBu)CH 2-Cl-4-MeO-5-F-phenyl
830 3-furan(cBu)CH 2-Cl-4-MeO-5-F-phenyl 831 2-thienyl(cBu)CH
2-Cl-4-MeO-5-F-phenyl 832 3-thienyl(cBu)CH 2-Cl-4-MeO-5-F-phenyl
833 2-isoxazolyl(cBu)CH 2-Cl-4-MeO-5-F-phenyl 834
2-(5-CH.sub.3-furanyl)(cBu)CH 2-Cl-4-MeO-5-F-phenyl 835
2-(4-CH.sub.3-isoxazolyl)(cBu)CH 2-Cl-4-MeO-5-F-phenyl 836
cBu-CH(CH.sub.3) 2-Cl-4-MeO-5-F-phenyl 837
1-cBu-CH(CH.sub.2CH.sub.3) 2-Cl-4-MeO-5-F-phenyl 838
1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3) 2-Cl-4-MeO-5-F-phenyl 839
1-cBu-CH(CH.sub.2OCH.sub.3) 2-Cl-4-MeO-5-F-phenyl 840
1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3) 2-Cl-4-MeO-5-F-phenyl 841
(cPr).sub.2CH 2-CH.sub.3-4-MeO-5-Cl-phenyl 842 phenyl(cPr)CH
2-CH.sub.3-4-MeO-5-Cl-phenyl 843 2-furanyl(cPr)CH
2-CH.sub.3-4-MeO-5-Cl-phenyl 844 3-furan(cPr)CH
2-CH.sub.3-4-MeO-5-Cl-phenyl 845 2-thienyl(cPr)CH
2-CH.sub.3-4-MeO-5-Cl-phenyl 846 3-thienyl(cPr)CH
2-CH.sub.3-4-MeO-5-Cl-phenyl 847 2-isoxazolyl(cPr)CH
2-CH.sub.3-4-MeO-5-Cl-phenyl 848 2-(5-CH.sub.3-furanyl)(cPr)CH
2-CH.sub.3-4-MeO-5-Cl-phenyl 849 2-(4-CH.sub.3-isoxazolyl)(cPr)CH
2-CH.sub.3-4-MeO-5-Cl-phenyl 850 cPr-CH(CH.sub.3)
2-CH.sub.3-4-MeO-5-Cl-phenyl 851 1-cPr-CH(CH.sub.2CH.sub.3)
2-CH.sub.3-4-MeO-5-Cl-phenyl 852 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.-
3) 2-CH.sub.3-4-MeO-5-Cl-phenyl 853 1-cPr-CH(CH.sub.2OCH.sub.3)
2-CH.sub.3-4-MeO-5-Cl-phenyl 854 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub-
.3) 2-CH.sub.3-4-MeO-5-Cl-phenyl 855 (cBu).sub.2CH
2-CH.sub.3-4-MeO-5-Cl-phenyl 856 phenyl(cBu)CH
2-CH.sub.3-4-MeO-5-Cl-phenyl 857 2-furanyl(cBu)CH
2-CH.sub.3-4-MeO-5-Cl-phenyl 858 3-furan(cBu)CH
2-CH.sub.3-4-MeO-5-Cl-phenyl 859 2-thienyl(cBu)CH
2-CH.sub.3-4-MeO-5-Cl-phenyl 860 3-thienyl(cBu)CH
2-CH.sub.3-4-MeO-5-Cl-phenyl 861 2-isoxazolyl(cBu)CH
2-CH.sub.3-4-MeO-5-Cl-phenyl 862 2-(5-CH.sub.3-furanyl)(cBu)CH
2-CH.sub.3-4-MeO-5-Cl-phenyl 863
2-(4-CH.sub.3-isoxazolyl)(cBu)CH
2-CH.sub.3-4-MeO-5-Cl-phenyl 864 cBu-CH(CH.sub.3)
2-CH.sub.3-4-MeO-5-Cl-phenyl 865 1-cBu-CH(CH.sub.2CH.sub.3)
2-CH.sub.3-4-MeO-5-Cl-phenyl 866 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.-
3) 2-CH.sub.3-4-MeO-5-Cl-phenyl 867 1-cBu-CH(CH.sub.2OCH.sub.3)
2-CH.sub.3-4-MeO-5-Cl-phenyl 868 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub-
.3) 2-CH.sub.3-4-MeO-5-Cl-phenyl 869 (cPr).sub.2CH
2,5-diCH.sub.3-4-MeO-phenyl 870 phenyl(cPr)CH
2,5-diCH.sub.3-4-MeO-phenyl 871 2-furanyl(cPr)CH
2,5-diCH.sub.3-4-MeO-phenyl 872 3-furan(cPr)CH
2,5-diCH.sub.3-4-MeO-phenyl 873 2-thienyl(cPr)CH
2,5-diCH.sub.3-4-MeO-phenyl 874 3-thienyl(cPr)CH
2,5-diCH.sub.3-4-MeO-phenyl 875 2-isoxazolyl(cPr)CH
2,5-diCH.sub.3-4-MeO-phenyl 876 2-(5-CH.sub.3-furanyl)(cPr)CH
2,5-diCH.sub.3-4-MeO-phenyl 877 2-(4-CH.sub.3-isoxazolyl)(cPr)CH
2,5-diCH.sub.3-4-MeO-phenyl 878 cPr-CH(CH.sub.3)
2,5-diCH.sub.3-4-MeO-phenyl 879 1-cPr-CH(CH.sub.2CH.sub.3)
2,5-diCH.sub.3-4-MeO-phenyl 880 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3-
) 2,5-diCH.sub.3-4-MeO-phenyl 881 1-cPr-CH(CH.sub.2OCH.sub.3)
2,5-diCH.sub.3-4-MeO-phenyl 882 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.-
3) 2,5-diCH.sub.3-4-MeO-phenyl 883 (cPr).sub.2CH
2,5-diCH.sub.3-4-MeO-phenyl 884 phenyl(cBu)CH
2,5-diCH.sub.3-4-MeO-phenyl 885 2-furanyl(cBu)CH
2,5-diCH.sub.3-4-MeO-phenyl 886 3-furan(cBu)CH
2,5-diCH.sub.3-4-MeO-phenyl 887 2-thienyl(cBu)CH
2,5-diCH.sub.3-4-MeO-phenyl 888 3-thienyl(cBu)CH
2,5-diCH.sub.3-4-MeO-phenyl 889 2-isoxazolyl(cBu)CH
2,5-diCH.sub.3-4-MeO-phenyl 890 2-(5-CH.sub.3-furanyl)(cBu)CH
2,5-diCH.sub.3-4-MeO-phenyl 891 2-(4-CH.sub.3-isoxazolyl)(cBu)CH
2,5-diCH.sub.3-4-MeO-phenyl 892 cBu-CH(CH.sub.3)
2,5-diCH.sub.3-4-MeO-phenyl 893 1-cBu-CH(CH.sub.2CH.sub.3)
2,5-diCH.sub.3-4-MeO-phenyl 894 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3-
) 2,5-diCH.sub.3-4-MeO-phenyl 895 1-cBu-CH(CH.sub.2OCH.sub.3)
2,5-diCH.sub.3-4-MeO-phenyl 896 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.-
3) 2,5-diCH.sub.3-4-MeO-phenyl 897 (cPr).sub.2CH
2-CH.sub.3-4-MeO-5-F-phenyl 898 phenyl(cPr)CH
2-CH.sub.3-4-MeO-5-F-phenyl 899 2-furantl(cPr)CH
2-CH.sub.3-4-MeO-5-F-phenyl 900 3-furan(cPr)CH
2-CH.sub.3-4-MeO-5-F-phenyl 901 2-thienyl(cPr)CH
2-CH.sub.3-4-MeO-5-F-phenyl 902 3-thienyl(cPr)CH
2-CH.sub.3-4-MeO-5-F-phenyl 903 2-isoxazolyl(cPr)CH
2-CH.sub.3-4-MeO-5-F-phenyl 904 2-(5-CH.sub.3-furanyl)(cPr)CH
2-CH.sub.3-4-MeO-5-F-phenyl 905 2-(4-CH.sub.3-isoxazolyl)(cPr)CH
2-CH.sub.3-4-MeO-5-F-phenyl 906 cPr-CH(CH.sub.3)
2-CH.sub.3-4-MeO-5-F-phenyl 907 1-cPr-CH(CH.sub.2CH.sub.3)
2-CH.sub.3-4-MeO-5-F-phenyl 908 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3-
) 2-CH.sub.3-4-MeO-5-F-phenyl 909 1-cPr-CH(CH.sub.2OCH.sub.3)
2-CH.sub.3-4-MeO-5-F-phenyl 910 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.-
3) 2-CH.sub.3-4-MeO-5-F-phenyl 911 (cBu).sub.2CH
2-CH.sub.3-4-MeO-5-F-phenyl 912 phenyl(cBu)CH
2-CH.sub.3-4-MeO-5-F-phenyl 913 2-furanyl(cBu)CH
2-CH.sub.3-4-MeO-5-F-phenyl 914 3-furan(cBu)CH
2-CH.sub.3-4-MeO-5-F-phenyl 915 2-thienyl(cBu)CH
2-CH.sub.3-4-MeO-5-F-phenyl 916 3-thienyl(cBu)CH
2-CH.sub.3-4-MeO-5-F-phenyl 917 2-isoxazolyl(cBu)CH
2-CH.sub.3-4-MeO-5-F-phenyl 918 2-(5-CH.sub.3-furanyl)(cBu)CH
2-CH.sub.3-4-MeO-5-F-phenyl 919 2-(4-CH.sub.3-isoxazolyl)(cBu)CH
2-CH.sub.3-4-MeO-5-F-phenyl 920 cBu-CH(CH.sub.3)
2-CH.sub.3-4-MeO-5-F-phenyl 921 1-cBu-CH(CH.sub.2CH.sub.3)
2-CH.sub.3-4-MeO-5-F-phenyl 922 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3-
) 2-CH.sub.3-4-MeO-5-F-phenyl 923 1-cBu-CH(CH.sub.2OCH.sub.3)
2-CH.sub.3-4-MeO-5-F-phenyl 924 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.-
3) 2-CH.sub.3-4-MeO-5-F-phenyl 925 (cPr).sub.2CH
2,4,6-triCH.sub.3-phenyl 926 phenyl(cPr)CH 2,4,6-triCH.sub.3-phenyl
927 2-furanyl(cPr)CH 2,4,6-triCH.sub.3-phenyl 928 3-furan(cPr)CH
2,4,6-triCH.sub.3-phenyl 929 2-thienyl(cPr)CH
2,4,6-triCH.sub.3-phenyl 930 3-thienyl(cPr)CH
2,4,6-triCH.sub.3-phenyl 931 2-isoxazolyl(cPr)CH
2,4,6-triCH.sub.3-phenyl 932 2-(5-CH.sub.3-furanyl)(cPr)CH
2,4,6-triCH.sub.3-phenyl 933 2-(4-CH.sub.3-isoxazolyl)(cPr)CH
2,4,6-triCH.sub.3-phenyl 934 cPr-CH(CH.sub.3)
2,4,6-triCH.sub.3-phenyl 935 1-cPr-CH(CH.sub.2CH.sub.3)
2,4,6-triCH.sub.3-phenyl 936 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3)
2,4,6-triCH.sub.3-phenyl 937 1-cPr-CH(CH.sub.2OCH.sub.3)
2,4,6-triCH.sub.3-phenyl 938 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3)
2,4,6-triCH.sub.3-phenyl 939 (cBu).sub.2CH 2,4,6-triCH.sub.3-phenyl
940 phenyl(cBu)CH 2,4,6-triCH.sub.3-phenyl 941 2-furanyl(cBu)CH
2,4,6-triCH.sub.3-phenyl 942 3-furan(cBu)CH
2,4,6-triCH.sub.3-phenyl 943 2-thienyl(cBu)CH
2,4,6-triCH.sub.3-phenyl 944 3-thienyl(cBu)CH
2,4,6-triCH.sub.3-phenyl 945 2-isoxazolyl(cBu)CH
2,4,6-triCH.sub.3-phenyl 946 2-(5-CH.sub.3-furanyl)(cBu)CH
2,4,6-triCH.sub.3-phenyl 947 2-(4-CH.sub.3-isoxazolyl)(cBu)CH
2,4,6-triCH.sub.3-phenyl 948 cBu-CH(CH.sub.3)
2,4,6-triCH.sub.3-phenyl 949 1-cBu-CH(CH.sub.2CH.sub.3)
2,4,6-triCH.sub.3-phenyl 950 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3)
2,4,6-triCH.sub.3-phenyl 951 1-cBu-CH(CH.sub.2OCH.sub.3)
2,4,6-triCH.sub.3-phenyl 952 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3)
2,4,6-triCH.sub.3-phenyl 953 (cPr).sub.2CH 3-pyridyl 954
phenyl(cPr)CH 3-pyridyl 955 2-furanyl(cPr)CH 3-pyridyl 956
3-furan(cPr)CH 3-pyridyl 957 2-thienyl(cPr)CH 3-pyridyl 958
3-thienyl(cPr)CH 3-pyridyl 959 2-isoxazolyl(cPr)CH 3-pyridyl 960
2-(5-CH.sub.3-furanyl)(cPr)CH 3-pyridyl 961
2-(4-CH.sub.3-isoxazolyl)(cPr)CH 3-pyridyl 962 cPr-CH(CH.sub.3)
3-pyridyl 963 1-cPr-CH(CH.sub.2CH.sub.3) 3-pyridyl 964
1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3) 3-pyridyl 965
1-cPr-CH(CH.sub.2OCH.sub.3) 3-pyridyl 966 1-cPr-CH(CH.sub.2CH.sub-
.2OCH.sub.3) 3-pyridyl 967 (cBu).sub.2CH 3-pyridyl 968
phenyl(cBu)CH 3-pyridyl 969 2-furanyl(cBu)CH 3-pyridyl 970
3-furan(cBu)CH 3-pyridyl 971 2-thienyl(cBu)CH 3-pyridyl 972
3-thienyl(cBu)CH 3-pyridyl 973 2-isoxazolyl(cBu)CH 3-pyridyl 974
2-(5-CH.sub.3-furanyl)(cBu)CH 3-pyridyl 975
2-(4-CH.sub.3-isoxazolyl)(cBu)CH 3-pyridyl 976 cBu-CH(CH.sub.3)
3-pyridyl 977 1-cBu-CH(CH.sub.2CH.sub.3) 3-pyridyl 978
1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3) 3-pyridyl 979
1-cBu-CH(CH.sub.2OCH.sub.3) 3-pyridyl 980 1-cBu-CH(CH.sub.2CH.sub-
.2OCH.sub.3) 3-pyridyl 981 (cPr).sub.2CH 2,6-diMeO-pyrid-3-yl 982
phenyl(cPr)CH 2,6-diMeO-pyrid-3-yl 983 2-furanyl(cPr)CH
2,6-diMeO-pyrid-3-yl 984 3-furan(cPr)CH 2,6-diMeO-pyrid-3-yl 985
2-thienyl(cPr)CH 2,6-diMeO-pyrid-3-yl 986 3-thienyl(cPr)CH
2,6-diMeO-pyrid-3-yl 987 2-isoxazolyl(cPr)CH 2,6-diMeO-pyrid-3-yl
988 2-(5-CH.sub.3-furanyl)(cPr)CH 2,6-diMeO-pyrid-3-yl 989
2-(4-CH.sub.3-isoxazolyl)(cPr)CH 2,6-diMeO-pyrid-3-yl 990
cPr-CH(CH.sub.3) 2,6-diMeO-pyrid-3-yl 991 1-cPr-CH(CH.sub.2CH.sub-
.3) 2,6-diMeO-pyrid-3-yl 992 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3)
2,6-diMeO-pyrid-3-yl 993 1-cPr-CH(CH.sub.2OCH.sub.3)
2,6-diMeO-pyrid-3-yl 994 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3)
2,6-diMeO-pyrid-3-yl 995 (cBu).sub.2CH 2,6-diMeO-pyrid-3-yl 996
phenyl(cBu)CH 2,6-diMeO-pyrid-3-yl 997 2-furanyl(cBu)CH
2,6-diMeO-pyrid-3-yl 998 3-furan(cBu)CH 2,6-diMeO-pyrid-3-yl 999
2-thienyl(cBu)CH 2,6-diMeO-pyrid-3-yl 1000 3-thienyl(cBu)CH
2,6-diMeO-pyrid-3-yl 1001 2-isoxazolyl(cBu)CH 2,6-diMeO-pyrid-3-yl
1002 2-(5-CH.sub.3-furanyl)(cBu)CH 2,6-diMeO-pyrid-3-yl 1003
2-(4-CH.sub.3-isoxazolyl)(cBu)CH 2,6-diMeO-pyrid-3-yl 1004
cBu-CH(CH.sub.3) 2,6-diMeO-pyrid-3-yl 1005 1-cBu-CH(CH.sub.2CH.sub-
.3) 2,6-diMeO-pyrid-3-yl 1006 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3)
2,6-diMeO-pyrid-3-yl 1007 1-cBu-CH(CH.sub.2OCH.sub.3)
2,6-diMeO-pyrid-3-yl 1008 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3)
2,6-diMeO-pyrid-3-yl 1009 (cPr).sub.2CH 2,6-diCH.sub.3-pyrid-3-yl
1010 phenyl(cPr)CH 2,6-diCH.sub.3-pyrid-3-yl 1011 2-furanyl(cPr)CH
2,6-diCH.sub.3-pyrid-3-yl 1012 3-furan(cPr)CH
2,6-diCH.sub.3-pyrid-3-yl 1013 2-thienyl(cPr)CH
2,6-diCH.sub.3-pyrid-3-yl 1014 3-thienyl(cPr)CH
2,6-diCH.sub.3-pyrid-3-yl 1015 2-isoxazolyl(cPr)CH
2,6-diCH.sub.3-pyrid-3-yl 1016 2-(5-CH.sub.3-furanyl)(cPr)CH
2,6-diCH.sub.3-pyrid-3-yl 1017 2-(4-CH.sub.3-isoxazolyl)(cPr)CH
2,6-diCH.sub.3-pyrid-3-yl 1018 cPr-CH(CH.sub.3)
2,6-diCH.sub.3-pyrid-3-yl 1019 1-cPr-CH(CH.sub.2CH.sub.3)
2,6-diCH.sub.3-pyrid-3-yl 1020 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3)
2,6-diCH.sub.3-pyrid-3-yl 1021 1-cPr-CH(CH.sub.2OCH.sub.3)
2,6-diCH.sub.3-pyrid-3-yl 1022 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3)
2,6-diCH.sub.3-pyrid-3-yl 1023 (cBu).sub.2CH
2,6-diCH.sub.3-pyrid-3-yl 1024 phenyl(cBu)CH
2,6-diCH.sub.3-pyrid-3-yl 1025 2-furanyl(cBu)CH
2,6-diCH.sub.3-pyrid-3-yl 1026 3-furan(cBu)CH
2,6-diCH.sub.3-pyrid-3-yl 1027 2-thienyl(cBu)CH
2,6-diCH.sub.3-pyrid-3-yl 1028 3-thienyl(cBu)CH
2,6-diCH.sub.3-pyrid-3-yl 1029 2-isoxazolyl(cBu)CH
2,6-diCH.sub.3-pyrid-3-yl 1030 2-(5-CH.sub.3-furanyl)(cBu)CH
2,6-diCH.sub.3-pyrid-3-yl 1031 2-(4-CH.sub.3-isoxazolyl)(cBu)CH
2,6-diCH.sub.3-pyrid-3-yl 1032 cBu-CH(CH.sub.3)
2,6-diCH.sub.3-pyrid-3-yl 1033 1-cBu-CH(CH.sub.2CH.sub.3)
2,6-diCH.sub.3-pyrid-3-yl 1034 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3)
2,6-diCH.sub.3-pyrid-3-yl 1035 1-cBu-CH(CH.sub.2OCH.sub.3)
2,6-diCH.sub.3-pyrid-3-yl 1036 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3)
2,6-diCH.sub.3-pyrid-3-yl 1037 (cPr).sub.2CH
2-CH.sub.3-6-MeO-pyrid-3-yl 1038 phenyl(cPr)CH
2-CH.sub.3-6-MeO-pyrid-3-yl 1039 2-furanyl(cPr)CH
2-CH.sub.3-6-MeO-pyrid-3-yl 1040 3-furan(cPr)CH
2-CH.sub.3-6-MeO-pyrid-3-yl 1041 2-thienyl(cPr)CH
2-CH.sub.3-6-MeO-pyrid-3-yl 1042 3-thienyl(cPr)CH
2-CH.sub.3-6-MeO-pyrid-3-yl 1043 2-isoxazolyl(cPr)CH
2-CH.sub.3-6-MeO-pyrid-3-yl 1044 2-(5-CH.sub.3-firanyl)(cPr)CH
2-CH.sub.3-6-MeO-pyrid-3-yl 1045 2-(4-CH.sub.3-isoxazolyl)(cPr)CH
2-CH.sub.3-6-MeO-pyrid-3-yl 1046 cPr-CH(CH.sub.3)
2-CH.sub.3-6-MeO-pyrid-3-yl 1047 1-cPr-CH(CH.sub.2CH.sub.3)
2-CH.sub.3-6-MeO-pyrid-3-yl 1048 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3-
) 2-CH.sub.3-6-MeO-pyrid-3-yl 1049 1-cPr-CH(CH.sub.2OCH.sub.3)
2-CH.sub.3-6-MeO-pyrid-3-yl 1050 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.-
3) 2-CH.sub.3-6-MeO-pyrid-3-yl 1051 (cBu).sub.2CH
2-CH.sub.3-6-MeO-pyrid-3-yl 1052 phenyl(cBu)CH
2-CH.sub.3-6-MeO-pyrid-3-yl 1053 2-furanyl(cBu)CH
2-CH.sub.3-6-MeO-pyrid-3-yl 1054 3-furan(cBu)CH
2-CH.sub.3-6-MeO-pyrid-3-yl 1055 2-thienyl(cBu)CH
2-CH.sub.3-6-MeO-pyrid-3-yl 1056 3-thienyl(cBu)CH
2-CH.sub.3-6-MeO-pyrid-3-yl 1057 2-isoxazolyl(cBu)CH
2-CH.sub.3-6-MeO-pyrid-3-yl 1058 2-(5-CH.sub.3-furanyl)(cBu)CH
2-CH.sub.3-6-MeO-pyrid-3-yl 1059 2-(4-CH.sub.3-isoxazolyl)(cBu)CH
2-CH.sub.3-6-MeO-pyrid-3-yl 1060 cBu-CH(CH.sub.3)
2-CH.sub.3-6-MeO-pyrid-3-yl 1061 1-cBu-CH(CH.sub.2CH.sub.3)
2-CH.sub.3-6-MeO-pyrid-3-yl 1062 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3-
) 2-CH.sub.3-6-MeO-pyrid-3-yl 1063 1-cBu-CH(CH.sub.2OCH.sub.3)
2-CH.sub.3-6-MeO-pyrid-3-yl 1064 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.-
3) 2-CH.sub.3-6-MeO-pyrid-3-yl 1065 (cPr).sub.2CH
4-CH.sub.3-6-MeO-pyrid-3-yl 1066 phenyl(cPr)CH
4-CH.sub.3-6-MeO-pyrid-3-yl 1067 2-furanyl(cPr)CH
4-CH.sub.3-6-MeO-pyrid-3-yl 1068 3-furan(cPr)CH
4-CH.sub.3-6-MeO-pyrid-3-yl 1069 2-thienyl(cPr)CH
4-CH.sub.3-6-MeO-pyrid-3-yl 1070 3-thienyl(cPr)CH
4-CH.sub.3-6-MeO-pyrid-3-yl 1071 2-isoxazolyl(cPr)CH
4-CH.sub.3-6-MeO-pyrid-3-yl 1072 2-(5-CH.sub.3-furanyl)(cPr)CH
4-CH.sub.3-6-MeO-pyrid-3-yl 1073 2-(4-CH.sub.3-isoxazolyl)(cPr)CH
4-CH.sub.3-6-MeO-pyrid-3-yl 1074 cPr-CH(CH.sub.3)
4-CH.sub.3-6-MeO-pyrid-3-yl 1075 1-cPr-CH(CH.sub.2CH.sub.3)
4-CH.sub.3-6-MeO-pyrid-3-yl 1076 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3-
) 4-CH.sub.3-6-MeO-pyrid-3-yl 1077 1-cPr-CH(CH.sub.2OCH.sub.3)
4-CH.sub.3-6-MeO-pyrid-3-yl 1078 1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.-
3) 4-CH.sub.3-6-MeO-pyrid-3-yl 1079 (cBu).sub.2CH
4-CH.sub.3-6-MeO-pyrid-3-yl 1080 phenyl(cBu)CH
4-CH.sub.3-6-MeO-pyrid-3-yl 1081 2-furanyl(cBu)CH
4-CH.sub.3-6-MeO-pyrid-3-yl 1082 3-furan(cBu)CH
4-CH.sub.3-6-MeO-pyrid-3-yl 1083 2-thienyl(cBu)CH
4-CH.sub.3-6-MeO-pyrid-3-yl 1084 3-thienyl(cBu)CH
4-CH.sub.3-6-MeO-pyrid-3-yl 1085 2-isoxazolyl(cBu)CH
4-CH.sub.3-6-MeO-pyrid-3-yl 1086 2-(5-CH.sub.3-furanyl)(cBu)CH
4-CH.sub.3-6-MeO-pyrid-3-yl 1087 2-(4-CH.sub.3-isoxazolyl)(cBu)CH
4-CH.sub.3-6-MeO-pyrid-3-yl 1088 cBu-CH(CH.sub.3)
4-CH.sub.3-6-MeO-pyrid-3-yl 1089 1-cBu-CH(CH.sub.2CH.sub.3)
4-CH.sub.3-6-MeO-pyrid-3-yl 1090 1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3-
) 4-CH.sub.3-6-MeO-pyrid-3-yl 1091 1-cBu-CH(CH.sub.2OCH.sub.3)
4-CH.sub.3-6-MeO-pyrid-3-yl 1092 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.-
3) 4-CH.sub.3-6-MeO-pyrid-3-yl 1093 (cPr).sub.2CH
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyrid-3-yl 1094 phenyl(cPr)CH
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyrid-3-yl 1095 2-furanyl(cPr)CH
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyrid-3-yl 1096 3-furan(cPr)CH
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyrid-3-yl 1097 2-thienyl(cPr)CH
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyrid-3-yl 1098 3-thienyl(cPr)CH
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyrid-3-yl 1099 2-isoxazolyl(cPr)CH
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyrid-3-yl 1100
2-(5-CH.sub.3-furanyl)(cPr)CH
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyrid-3-yl 1101
2-(4-CH.sub.3-isoxazolyl)(cPr)CH 4-CH.sub.3-6-(CH.sub.3).sub.2N-
-pyrid-3-yl 1102 cPr-CH(CH.sub.3)
4-CH.sub.3-6-(CH.sub.3).sub.2N-py- rid-3-yl 1103
1-cPr-CH(CH.sub.2CH.sub.3) 4-CH.sub.3-6-(CH.sub.3).su-
b.2N-pyrid-3-yl 1104 1-cPr-CH(CH.sub.2CH.sub.2CH.sub.3)
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyrid-3-yl 1105
1-cPr-CH(CH.sub.2OCH.sub.3)
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyrid-3-yl 1106
1-cPr-CH(CH.sub.2CH.sub.2OCH.sub.3) 4-CH.sub.3-6-(CH.sub.3).sub.2-
N-pyrid-3-yl 1107 (cBu).sub.2CH
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyri- d-3-yl 1108 phenyl(cBu)CH
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyrid-3-yl 1109 2-furanyl(cBu)CH
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyrid-3-yl 1110 3-furan(cBu)CH
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyrid-3-yl 1111 2-thienyl(cBu)CH
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyrid-3-yl 1112 3-thienyl(cBu)CH
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyrid-3-yl 1113 2-isoxazolyl(cBu)CH
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyrid-3-yl 1114
2-(5-CH.sub.3-furanyl)(cBu)CH
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyrid-3- -yl 1115
2-(4-CH.sub.3-isoxazolyl)(cBu)CH 4-CH.sub.3-6-(CH.sub.3).s-
ub.2N-pyrid-3-yl 1116 cBu-CH(CH.sub.3)
4-CH.sub.3-6-(CH.sub.3).sub.- 2N-pyrid-3-yl 1117
1-cBu-CH(CH.sub.2CH.sub.3)
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyrid-3-yl 1118
1-cBu-CH(CH.sub.2CH.sub.2CH.sub.3)
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyrid-3- -yl 1119
1-cBu-CH(CH.sub.2OCH.sub.3) 4-CH.sub.3-6-(CH.sub.3).sub.2N-
-pyrid-3-yl 1120 1-cBu-CH(CH.sub.2CH.sub.2OCH.sub.3)
4-CH.sub.3-6-(CH.sub.3).sub.2N-pyrid-3-yl 1121 3-pentyl
2,4,6-(CH.sub.3).sub.3 phenyl 1122 2-pentyl 2,4-Cl.sub.2-5-F-phenyl
1123 3-pentyl 2,4-(MEO().sub.2-phenyl 1124 3-pentyl
2,4-Cl.sub.2-phenyl 1 3-pentyl 2,4-Cl.sub.2-phenyl
[0442] Table 1 shows compounds which may readily be prepared
according to the procedures described herein in the synthetic
schemes and text. The preferred compounds have a core of e.sub.4
with the exception of Examples 95 and 1124, which have cores of
c.sub.4 and f.sub.4 respectively. Example 1 has a melting point of
136-138.degree. C.
Utility
[0443] Compounds of this invention are expected to have utility in
the treatment of inbalances associated with abnormal levels of CRF
in patients suffering from depression, affective disorders, and/or
anxiety.
CRF-R1 Receptor Binding Assay for the Evaluation of Biological
Activity
[0444] The following is a description of the isolation of cell
membranes containing cloned human CRF-R1 receptors for use in the
standard binding assay as well as a description of the assay
itself.
[0445] Messenger RNA was isolated from human hippocampus. The mRNA
was reverse transcribed using oligo (dt) 12-18 and the coding
region was amplified by PCR from start to stop codons The resulting
PCR fragment was cloned into the EcoRV site of pGEMV, from whence
the insert was reclaimed using XhoI+XbaI and cloned into the
XhoI+XbaI sites of vector pm3ar (which contains a CMV promoter, the
SV40 `t` splice and early poly A signals, an Epstein-Barr viral
origin of replication, and a hygromycin selectable marker). The
resulting expression vector, called phchCRFR was transfected in
293EBNA cells and cells retaining the episome were selected in the
presence of 400 .mu.M hygromycin. Cells surviving 4 weeks of
selection in hygromycin were pooled, adapted to growth in
suspension and used to generate membranes for the binding assay
described below. Individual aliquots containing approximately
1.times.10.sup.8 of the suspended cells were then centrifuged to
form a pellet and frozen.
[0446] For the binding assay a frozen pellet described above
containing 293EBNA cells transfected with hCRFR1 receptors is
homogenized in 10 ml of ice cold tissue buffer (50 mM HEPES buffer
pH 7.0, containing 10 mM MgCl.sub.2, 2 mM EGTA, 1 .mu.g/l
aprotinin, 1 .mu.g/ml leupeptin and 1 .mu.g/ml pepstatin). The
homogenate is centrifuged at 40,000.times.g for 12 min and the
resulting pellet rehomogenized in 10 ml of tissue buffer. After
another centrifugation at 40,000.times.g for 12 min, the pellet is
resuspended to a protein concentration of 360 .mu.g/ml to be used
in the assay.
[0447] Binding assays are performed in 96 well plates; each well
having a 300 .mu.l capacity. To each well is added 50 .mu.l of test
drug dilutions (final concentration of drugs range from
10-.sup.10-10-.sup.5 M), 100 .mu.l of .sup.125I-ovine-CRF
(125I-o-CRF) (final concentration 150 pM) and 150 .mu.l of the cell
homogenate described above. Plates are then allowed to incubate at
room temperature for 2 hours before filtering the incubate over
GF/F filters (presoaked with 0.3% polyethyleneimine) using an
appropriate cell harvester. Filters are rinsed 2 times with ice
cold assay buffer before removing individual filters and assessing
them for radioactivity on a gamma counter.
[0448] Curves of the inhibition of .sup.125I-o-CRF binding to cell
membranes at various dilutions of test drug are analyzed by the
iterative curve fitting program LIGAND [P. J. Munson and D.
Rodbard, Anal. Biochem. 107:220 (1980)], which provides Ki values
for inhibition which are then used to assess biological
activity.
[0449] A compound is considered to be active if it has a Ki value
of less than about 10000 nM for the inhibition of CRF.
[0450] Alternatively, tissues and cells which naturally express CRF
receptors can be employed in binding assays analogous to those
described above.
[0451] Inhibition of CRF-Stimulated Adenylate Cyclase Activity
[0452] Inhibition of CRF-stimulated adenylate cyclase activity can
be performed as described by G. Battaglia et al. Synapse 1:572
(1987). Briefly, assays are carried out at 370 C for 10 min in 200
ml of buffer containing 100 mM Tris-HCl (pH 7.4 at 370 C), 10 mM
MgCl.sub.2, 0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine
(IBMX), 250 units/ml phosphocreatine kinase, 5 mM creatine
phosphate, 100 mM guanosine 5'-triphosphate, 100 nM oCRF,
antagonist peptides (concentration range 10.sup.-9 to 10.sup.-6m)
and 0.8 mg original wet weight tissue (approximately 40-60 mg
protein). Reactions are initiated by the addition of 1 mM
ATP/[.sup.32P]ATP (approximately 2-4 mCi/tube) and terminated by
the addition of 100 ml of 50 mM Tris-HCL, 45 mM ATP and 2% sodium
dodecyl sulfate. In order to monitor the recovery of cAMP, 1 .mu.l
of [.sup.3H]cAMP (approximately 40,000 dpm) is added to each tube
prior to separation. The separation of [.sup.32P]cAMP from
[.sup.32P]ATP is performed by sequential elution over Dowex and
alumina columns.
[0453] In Vivo Biological Assay
[0454] The in vivo activity of the compounds of the present
invention can be assessed using any one of the biological assays
available and accepted within the art. Illustrative of these tests
include the Acoustic Startle Assay, the Stair Climbing Test, and
the Chronic Administration Assay. These and other models useful for
the testing of compounds of the present invention have been
outlined in C. W. Berridge and A. J. Dunn Brain Research Reviews
15:71 (1990). Compounds may be tested in any species of rodent or
small mammal.
Dosage and Formulation
[0455] Compounds of this invention can be administered to treat
these abnormalities by means that produce contact of the active
agent with the agent's site of action in the body of a mammal. The
compounds can be administered by any conventional means available
for use in conjunction with pharmaceuticals either as individual
therapeutic agent or in combination of therapeutic agents. They can
be administered alone, but will generally be administered with a
pharmaceutical carrier selected on the basis of the chosen route of
administration and standard pharmaceutical practice.
[0456] The dosage administered will vary depending on the use and
known factors such as pharmacodynamic character of the particular
agent, and its mode and route of administration; the recipient's
age, weight, and health; nature and extent of symptoms; kind of
concurrent treatment; frequency of treatment; and desired effect.
For use in the treatment of said diseases or conditions, the
compounds of this invention can be orally administered daily at a
dosage of the active ingredient of 0.002 to 200 mg/kg of body
weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divided doses one
to four times a day, or in sustained release formulation will be
effective in obtaining the desired pharmacological effect.
[0457] Dosage forms (compositions) suitable for administration
contain from about 1 mg to about 100 mg of active ingredient per
unit. In these pharmaceutical compositions, the active ingredient
will ordinarily be present in an amount of about 0.5 to 95% by
weight based on the total weight of the composition.
[0458] The active ingredient can be administered orally is solid
dosage forms, such as capsules, tablets and powders; or in liquid
forms such as elixirs, syrups, and/or suspensions. The compounds of
this invention can also be administered parenterally in sterile
liquid dose formulations.
[0459] Gelatin capsules can be used to contain the active
ingredient and a suitable carrier such as but not limited to
lactose, starch, magnesium stearate, steric acid, or cellulose
derivatives. Similar diluents can be used to make compressed
tablets. Both tablets and capsules can be manufactured as sustained
release products to provide for continuous release of medication
over a period of time. Compressed tablets can be sugar-coated or
film-coated to mask any unpleasant taste, or used to protect the
active ingredients from the atmosphere, or to allow selective
disintegration of the tablet in the gastrointestinal tract.
[0460] Liquid dose forms for oral administration can contain
coloring or flavoring agents to increase patient acceptance.
[0461] In general, water, pharmaceutically acceptable oils, saline,
aqueous dextrose (glucose), and related sugar solutions and
glycols, such as propylene glycol or polyethylene glycol, are
suitable carriers for parenteral solutions. Solutions for
parenteral administration preferably contain a water soluble salt
of the active ingredient, suitable stabilizing agents, and if
necessary, butter substances. Antioxidizing agents, such as sodium
bisulfite, sodium sulfite, or ascorbic acid, either alone or in
combination, are suitable stabilizing agents. Also used are citric
acid and its salts, and EDTA. In addition, parenteral solutions can
contain preservatives such as benzalkonium chloride, methyl- or
propyl-paraben, and chlorobutanol.
[0462] Suitable pharmaceutical carriers are described in
"Remington's Pharmaceutical Sciences", A. Osol, a standard
reference in the field.
[0463] Useful pharmaceutical dosage-forms for administration of the
compounds of this invention can be illustrated as follows:
Capsules
[0464] A large number of units capsules are prepared by filling
standard two-piece hard gelatin capsules each with 100 mg of
powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6
mg magnesium stearate.
Soft Gelatin Capsules
[0465] A mixture of active ingredient in a digestible oil such as
soybean, cottonseed oil, or olive oil is prepared and injected by
means of a positive displacement was pumped into gelatin to form
soft gelatin capsules containing 100 mg of the active ingredient.
The capsules were washed and dried.
Tablets
[0466] A large number of tablets are prepared by conventional
procedures so that the dosage unit was 100 mg active ingredient,
0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate,
275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg
lactose. Appropriate coatings may be applied to increase
palatability or delayed adsorption.
[0467] The compounds of this invention may also be used as reagents
or standards in the biochemical study of neurological function,
dysfunction, and disease.
[0468] Obviously, numerous modifications and variations of the
present invention are possible in light of the above teachings. It
is therefore to be understood that within the scope of the appended
claims, the invention may be practiced otherwise that as
specifically described herein.
* * * * *