U.S. patent application number 11/214345 was filed with the patent office on 2006-01-19 for heteroaryl substituted fused bicyclic heteroaryl compounds as gabaa receptor ligands.
This patent application is currently assigned to Neurogen Corporation. Invention is credited to Pamela Albaugh, Manuka Ghosh, Alan Hutchison, Guiying Li, Nian Liu, George Maynard, Scott Mitchell, Vinod Singh, Linghong Xie, Jun Yuan.
Application Number | 20060014746 11/214345 |
Document ID | / |
Family ID | 23181185 |
Filed Date | 2006-01-19 |
United States Patent
Application |
20060014746 |
Kind Code |
A1 |
Hutchison; Alan ; et
al. |
January 19, 2006 |
Heteroaryl substituted fused bicyclic heteroaryl compounds as GABAA
receptor ligands
Abstract
This invention relates to heteroaryl substituted fused bicyclic
heteroaryl compounds, such as heteroaryl substituted
imidazopyridines, imidazopyrazines, imidazopyridizines,
imidazopyrimidines, and imidazothiazoles, which may be described by
Formula I or Formula II: ##STR1## The invention is particularly
related to such compounds that bind with high selectivity and high
affinity to the benzodiazepine site of GABA.sub.A receptors. This
invention also relates to pharmaceutical compositions comprising
such compounds and to the use of such compounds in treatment of
certain central nervous system (CNS) diseases. Processes for
preparing compounds of Formula I and Formula II are disclosed. This
invention also relates to the use of benzimidazoles,
pyridylimidazoles and related bicyclic heteroaryl compounds of
Formula I or Formula II in combination with one or more other CNS
agents to potentiate the effects of the other CNS agents.
Additionally this invention relates to the use such compounds as
probes for the localization of GABA.sub.A receptors in tissue
sections.
Inventors: |
Hutchison; Alan; (Madison,
CT) ; Maynard; George; (Clinton, CT) ;
Albaugh; Pamela; (Carmel, IN) ; Xie; Linghong;
(Guilford, CT) ; Yuan; Jun; (Guilford, CT)
; Mitchell; Scott; (East Haven, CT) ; Singh;
Vinod; (Kanpur, IN) ; Ghosh; Manuka; (Madison,
CT) ; Li; Guiying; (Branford, CT) ; Liu;
Nian; (North Branford, CT) |
Correspondence
Address: |
Steven J. Sarussi;McDonnell Boehnen Hulbert & Berghoff
32nd Floor
300 S. Wacker Drive
Chicago
IL
60606
US
|
Assignee: |
Neurogen Corporation
|
Family ID: |
23181185 |
Appl. No.: |
11/214345 |
Filed: |
August 29, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10194852 |
Jul 12, 2002 |
6936617 |
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11214345 |
Aug 29, 2005 |
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60305533 |
Jul 13, 2001 |
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Current U.S.
Class: |
514/248 ;
514/259.1; 514/303; 544/236; 544/281; 546/118 |
Current CPC
Class: |
A61P 25/20 20180101;
C07D 487/04 20130101; C07D 513/04 20130101; A61P 25/28 20180101;
A61P 25/00 20180101; A61P 25/18 20180101; A61P 25/24 20180101; C07D
471/04 20130101; A61P 25/22 20180101; A61P 43/00 20180101; A61P
25/14 20180101 |
Class at
Publication: |
514/248 ;
514/303; 514/259.1; 544/236; 544/281; 546/118 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 471/02 20060101 C07D471/02; A61K 31/519 20060101
A61K031/519; A61K 31/503 20060101 A61K031/503; A61K 31/4745
20060101 A61K031/4745 |
Claims
1. A compound of the formula: ##STR569## or a pharmaceutically
acceptable salt thereof, wherein: Z.sub.1 is nitrogen or CR.sub.1;
Z.sub.2 is nitrogen or CR.sub.2; Z.sub.3 is nitrogen or CR.sub.3;
Z.sub.4 is nitrogen or CR.sub.4; Z.sub.5 is nitrogen or carbon;
Z.sub.6 is nitrogen or carbon; provided that no more than two of
Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4, Z.sub.5, and Z.sub.6 are
nitrogen; R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are independently
selected from: (i) hydrogen, halogen, hydroxy, nitro, cyano, amino,
haloalkyl, and haloalkoxy; (ii) alkyl, alkoxy, cycloalkyl, alkenyl,
alkynyl, (cycloalkyl)alkyl, --NH(R.sub.10),
--N(R.sub.10)(R.sub.11), hydroxyalkyl, aminoalkyl,
(R.sub.10)NHalkyl, (R.sub.10)(R.sub.11)Nalkyl, alkanoyl,
alkoxycarbonyl, alkylsulfonyl, (C.sub.1-C.sub.6)alkylsulfinyl,
alkylthio, mono- and dialkylaminocarbonyl, heterocycloalkyl, aryl,
and heteroaryl, each of which is unsubstituted or substituted with
1, 2, 3, or 4 substituents independently selected from R.sub.20;
(iii) groups of the formula: ##STR570## wherein G is alkyl, --O--,
--C(.dbd.O)--, or CH.sub.2--C(.dbd.O)--, and R.sub.A is cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl, each of which is
unsubstituted or substituted with 1, 2, 3, or 4 of R.sub.20; (iv)
groups of the formula: ##STR571## wherein J is N, CH, or C-alkyl,
and R.sub.B and R.sub.C are each independently selected from the
group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy,
cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, aryl, arylalkyl,
alkanoyl, heteroaryl, and mono and dialkylaminoalkyl, each of which
is unsubstituted or substituted with 1 or 2 substituents
independently chosen from halogen, hydroxy, cyano, amino, nitro,
alkoxy, haloalkoxy, alkyl and haloalkyl; or R.sub.B and R.sub.C and
the atom to which they are attached form a 4- to 10-membered
monocyclic or bicyclic ring, comprising: a) 0, 1, 2 or 3 double
bonds, and b) 0, 1, 2 or 3 of oxo, O, S, SO, SO.sub.2, or
N--R.sub.D, wherein R.sub.D is (1)hydrogen; or (2) Ar.sub.1, alkyl,
cycloalkyl, heterocycloalkyl, or Ar.sub.1alkyl; wherein Ar.sub.1 is
aryl or heteroaryl, each of which is unsubstituted or substituted
with 1 or 2 substituents independently chosen from halogen,
hydroxy, cyano, amino, nitro, alkoxy, and alkyl; and (v)
--OC(.dbd.O)R.sub.E, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHR.sub.E,
--C(.dbd.O)NR.sub.ER.sub.F, --S(O).sub.nR.sub.E,
--S(O).sub.nNH.sub.2, --S(O).sub.nNHR.sub.E,
--S(O).sub.nNR.sub.ER.sub.F, --NHC(.dbd.O)R.sub.E,
--C(.dbd.NR.sub.E)R.sub.F, --HC.dbd.N--OH, --HC.dbd.N(alkoxy),
--HC.dbd.N(alkyl), --NR.sub.EC(.dbd.O)R.sub.F,
--NHS(O).sub.nR.sub.E, and --NR.sub.ES(O).sub.nR.sub.F, wherein n
is 0, 1 or 2; R.sub.E and R.sub.F are independently selected at
each occurrence from alkyl, cycloalkyl, heterocycloalkyl, alkoxy,
mono- and dialkylamino, aryl, and heteroaryl, each of which is
unsubstituted or substituted with 1, 2, or 3 substituents
independently selected from R.sub.30; R.sub.5 represents: (i)
hydrogen, halogen, cyano, or haloalkyl; (ii) alkyl, cycloalkyl,
(cycloalkyl)alkyl, each of which comprises from 0 to 3 double bonds
and/or from 0 to 3 triple bonds, and is unsubstituted or
substituted with 1, 2, or 3 substituents independently selected
from R.sub.30; or (iii) aryl, arylalkyl, heteroaryl, or
heteroarylalkyl, each of which is unsubstituted or substituted with
1, 2, or 3 substituents independently selected from the group
consisting of haloalkyl, amino, --NH(R.sub.10),
--N(R.sub.10)(R.sub.11), carboxamido, (R.sub.10)NHcarbonyl,
(R.sub.10)(R.sub.11)Ncarbonyl, halogen, hydroxy, nitro, cyano,
amino, alkyl, alkoxy, alkoxy substituted with amino or mono- or
dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy,
cycloalkyloxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl,
haloalkoxy, aminoalkyl, and mono- and dialkylaminoalkyl; R.sub.10
and R.sub.1, are independently selected from the group consisting
of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,
aryl, arylalkyl, alkanoyl, and mono and dialkylaminoalkyl; Q
represents --C(R.sub.6)(R.sub.7), --N(alkyl)- or oxygen, wherein
R.sub.6 and R.sub.7 independently represent hydrogen, fluorine, or
alkyl; with the proviso that Q is not oxygen when X.sub.2 is
nitrogen; R.sub.20 is independently selected at each occurrence
from: halogen, hydroxy, nitro, cyano, amino, alky, alkoxy, alkoxy
substituted with amino or mono- or dialkylamino, cycloalkyl,
cycloalkylalkyl, cycloalkyloxy, alkenyl, alkynyl, haloalkyl,
haloalkoxy, mono- and dialkylamino, aminoalkyl, and mono- and
dialkylaminoalkyl; R.sub.30 is independently selected at each
occurrence from: halogen, hydroxy, nitro, cyano, amino, alkyl,
alkoxy; alkoxy substituted with amino or mono- or dialkylamino,
cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkyloxy,
heterocycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, mono-
and dialkylamino, aminoalkyl, and mono- and dialkylaminoalkyl; and
the group: ##STR572## represents a 5 to 7 membered heteroaryl group
containing from 1 to 4 heteroatoms independently selected from
nitrogen, sulfur, and oxygen, unsubstituted or substituted at each
carbon atom by R, and unsubstituted or substituted at each nitrogen
atom available for substitution by R', wherein R is independently
chosen at each occurrence from halogen, amino, alkyl, alkenyl,
alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, haloalkyl,
haloalkoxy, carboxamido, and 3- to 7-membered carbocyclic and
heterocyclic rings, each of which is unsubstituted or substituted
with one or more substituents independently selected from halogen,
oxo, hydroxy, alkyl, and alkoxy; R' is independently chosen at each
occurrence from alkyl, cycloalkyl, cycloalkyl(alkyl), and 3- to
7-membered carbocyclic and heterocyclic rings, each of which
unsubstituted or substituted with one or more substituents
independently selected from halogen, oxo, hydroxy, alkyl, and
alkoxy; X.sub.1 and X.sub.2 independently represent nitrogen,
carbon or CH; Y is nitrogen, carbon, --CH--, --CH.sub.2--, or
absent; and W represents aryl or heteroaryl, each of which is
unsubstituted or substituted with from 0 to 4 groups independently
selected from R.sub.30, --C(.dbd.O)OR.sub.E, --C(.dbd.O)NR.sub.E,
--C(O)R.sub.E, --OR.sub.E and --S(O).sub.mR.sub.E, wherein m is 0,
1, or 2.
2. A compound or salt according to claim 1, wherein R.sub.1,
R.sub.2, R.sub.3, and R.sub.4 are independently selected from: (i)
hydrogen, halogen, hydroxy, nitro, cyano, amino,
halo(C.sub.1-C.sub.6) alkyl, and halo(C.sub.1-C.sub.6)alkoxy, (ii)
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl,
((C.sub.3-C.sub.8)cycloalkyl)(C.sub.1-C.sub.4)alkyl,
--NH(R.sub.10), --N(R.sub.10)(R.sub.11),
hydroxy(C.sub.1-C.sub.6)alkyl, amino(C.sub.1-C.sub.6)alkyl,
(R.sub.10)NH--, (C.sub.1-C.sub.6)alkyl,
(R.sub.10)(R.sub.11)N(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkanoyl, (C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkylsulfonyl, (C.sub.1-C.sub.6)alkylsulfinyl,
(C.sub.1-C.sub.6)alkylthio, mono- and
di(C.sub.1-C.sub.6)alkylaminocarbonyl, and 3- to 8-membered
heterocycloalkyl, aryl, and heteroaryl, each of which is
unsubstituted or substituted with 1, 2, 3, or 4 substituents
independently selected from R.sub.20; (iii) groups of the formula:
##STR573## wherein G is (C.sub.1-C.sub.6)alkyl, --O--,
--C(.dbd.O)--, or --CH.sub.2--C(.dbd.O)--, and R.sub.A is 3- to
8-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each
of which is unsubstituted or substituted with 1, 2, 3, or 4 of
R.sub.20; (iv) groups of the formula: ##STR574## wherein J is N,
CH, or C--(C.sub.1-C.sub.6)alkyl and R.sub.B and R.sub.C are each
independently selected from the group consisting of hydrogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8cycloalkyl)
(C.sub.1-C.sub.4)alkyl, 3- to 8-membered heterocycloalkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.6)alkanoyl, 3- to
8-membered heteroaryl, and mono and
di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl, each of which
is unsubstituted or substituted with 1 or 2 substituents
independently chosen from halogen, hydroxy, cyano, amino, nitro,
C.sub.1-C.sub.6alkoxy, halo(C.sub.1-C.sub.6)alkoxy,
C.sub.1-C.sub.6alkyl and halo(C.sub.1-C.sub.6)alkyl; or R.sub.B and
R.sub.C and the atom to which they are attached form a 4- to
10-membered monocyclic or bicyclic ring, comprising: a) 0, 1, 2 or
3 double bonds, and b) 0, 1, 2 or 3 of oxo; O, S, SO, SO.sub.2, or
N--R.sub.D, wherein R.sub.D is (1) hydrogen; or (2) Ar.sub.1,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl, 3- to
8-membered heterocycloalkyl, or Ar.sub.1(C.sub.1-C.sub.6)alkyl
wherein Ar.sub.1 is aryl or heteroaryl, each of which is
unsubstituted or substituted with 1 or 2 substituents independently
chosen from halogen, hydroxy, cyano, amino, nitro,
C.sub.1-C.sub.6alkoxy, and C.sub.1-C.sub.6alkyl; and (v)
--OC(.dbd.O)R.sub.E, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHR.sub.E,
--C(.dbd.O)NR.sub.ER.sub.F, --S(O).sub.nR.sub.E,
--S(O).sub.nNH.sub.2, --S(O).sub.nNHR.sub.E,
--S(O).sub.nNR.sub.ER.sub.F, --NHC(.dbd.O)R.sub.E,
--C(.dbd.NR.sub.E)R.sub.F, --HC.dbd.N--OH,
--HC.dbd.N(C.sub.1-C.sub.6alkoxy),
--HC.dbd.N(C.sub.1-C.sub.6alkyl), --NR.sub.EC(.dbd.O)R.sub.F,
--NHS(O).sub.nR.sub.E, and --NR.sub.ES(O).sub.nR.sub.F, wherein n
is 0, 1 or 2, R.sub.E and R.sub.F are independently selected at
each occurrence from (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, 3- to 8-membered heterocycloalkyl,
(C.sub.1-C.sub.6)alkoxy, mono- and di(C.sub.1-C.sub.6)alkylamino,
aryl, and 3- to 8-membered heteroaryl, each of which is
unsubstituted or substituted with 1, 2, or 3 substituents
independently selected from R.sub.30; R.sub.5 represents: (i)
hydrogen, halogen or cyano; (ii) (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8cycloalkyl)(C.sub.1-C.sub.4)alkyl, or an analogue
of the foregoing that comprises from 1 to 3 double bonds and/or
from 1 to 3 triple bonds, each of which is unsubstituted or
substituted with 1, 2, or 3 substituents independently selected
from R.sub.30; or (iii) 3- to 8-membered aryl, 3- to 8-membered
aryl(C.sub.1-C.sub.4)alkyl, 3- to 8-membered heteroaryl, or 3- to
8-membered heteroaryl(C.sub.1-C.sub.4)alkyl, each of which is
unsubstituted or substituted with 1, 2, or 3 substituents
independently selected from the group consisting of
halo(C.sub.1-C.sub.6alkyl, amino, --NH(R.sub.10),
--N(R.sub.10)(R.sub.11), carboxamido, (R.sub.10)NHcarbonyl,
(R.sub.10)(R.sub.11)Ncarbonyl, halogen, hydroxy, nitro, cyano,
amino, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy substituted with amino or mono- or
di(C.sub.1-C.sub.6)alkylamino, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.4)alkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.4)alkoxy,
heterocyclo(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, halo(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkoxy, amino(C.sub.1-C.sub.6)alkyl, and mono-
and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl; R.sub.10
and R.sub.1, are independently selected from the group consisting
of (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkylalkyl, aryl, aryl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkanoyl, and mono and
di(C.sub.1-C.sub.6)alkylaminoalkyl; R.sub.20 is independently
selected at each occurrence from the group consisting of halogen,
hydroxy, nitro, cyano, amino, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkoxy substituted with
amino or mono- or di(C.sub.1-C.sub.6)alkylamino,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.4)alkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.4)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, mono- and
di(C.sub.1-C.sub.6)alkylamino, amino(C.sub.1-C.sub.6)alkyl, and
mono- and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl;
R.sub.30 is independently selected at each occurrence from halogen,
hydroxy, nitro, cyano, amino, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkoxy substituted with
amino or mono- or di(C.sub.1-C.sub.6)alkylamino,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.4)alkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.4)alkoxy, 3- to
8-membered heterocycloalkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, halo(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkoxy, mono- and
di(C.sub.1-C.sub.6)alkylamino, amino(C.sub.1-C.sub.6)alkyl, and
mono- and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl; Q
represents C(R.sub.6)(R.sub.7), N(C.sub.1-C.sub.6alkyl) or oxygen,
wherein R.sub.6 and R.sub.7 independently represent hydrogen,
fluorine, or C.sub.1-C.sub.6alkyl; with the proviso that Q is not
oxygen when X.sub.2 is nitrogen; R is independently chosen at each
occurrence from halogen, amino, C.sub.1-C.sub.6alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
C.sub.1-C.sub.6alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8cycloalkyl)(C.sub.1-C.sub.4)alkyl,
halo(C.sub.1-C.sub.6)alkyl, haloalkoxy, carboxamido, and 3- to
7-membered carbocyclic and heterocyclic rings, each of which is
unsubstituted substituted with from 1 to 4 substituents
independently selected from halogen, oxo, hydroxy,
C.sub.1-C.sub.4alkyl, and C.sub.1-C.sub.4alkoxy; R' is
independently chosen at each occurrence from C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl,
C.sub.3-C.sub.8cycloalkyl(C.sub.1-C.sub.4alkyl), and 3- to
7-membered carbocyclic and heterocyclic rings, each of which is
unsubstituted or substituted with from 1 to 4 substituents
independently selected from halogen, oxo, hydroxy,
C.sub.1-C.sub.4alkyl, and C.sub.1-C.sub.4alkoxy; and W represents
3- to 8-membered aryl or heteroaryl, each of which is unsubstituted
or substituted with from 1 to 4 groups independently selected from
R.sub.30, --C(.dbd.O)OR.sub.E, --C(.dbd.O)NR.sub.E, --C(O)R.sub.E,
--OR.sub.E and --S(O).sub.mR.sub.E, wherein m is 0, 1, or 2.
3. A compound or salt according to claim 2 of the formula:
##STR575## wherein X.sub.3 and X.sub.4 are independently selected
from the group consisting of CH, CR, N, O, S, NH, and
N(C.sub.1-C.sub.6)alkyl provided that at least one of X.sub.1,
X.sub.2, X.sub.3, and X.sub.4 is CH or CR; and wherein R is
independently chosen at each occurrence from: halogen, amino,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy,
carboxamido, and 3- to 7-membered carbocyclic or heterocyclic
rings, each of which is unsubstituted or substituted with from 1 to
4 substituents independently selected from halogen, oxo, hydroxy,
(C.sub.1-C.sub.4)alkyl, and --O(C.sub.1-C.sub.4alkyl).
4. A compound or salt according to claim 3, wherein Z.sub.1 is
CR.sub.1, Z.sub.2 is CR.sub.2, Z.sub.3 is CR.sub.3, and Z.sub.4 is
nitrogen.
5. A compound or salt according to claim 3, wherein Z.sub.1 is
CR.sub.1, Z.sub.2 is CR.sub.2, Z.sub.3 is nitrogen, and Z.sub.4 is
CR.sub.4.
6. A compound or salt according to claim 3, wherein Z.sub.1 is
CR.sub.1, Z.sub.2 is nitrogen, Z.sub.3 is CR.sub.3 and Z.sub.4 is
CR.sub.4.
7. A compound or salt according to claim 3, wherein Z.sub.1 is
nitrogen, Z.sub.2 is CR.sub.2, Z.sub.3 is CR.sub.3 and Z.sub.4 is
CR.sub.4.
8. A compound or salt according to claim 3, wherein X.sub.2 is
carbon and Q is oxygen.
9. A compound or salt according to claim 3, wherein X.sub.2 is
carbon and Q is --NH--, or --N(C.sub.1-C.sub.6alkyl)-.
10. A compound or salt according to claim 3 of the formula:
##STR576##
11. A compound or salt according to claim 10, wherein Q is
C(R.sub.6)(R.sub.7).
12. A compound or salt according to claim 11, wherein each R is
independently selected from the group consisting of: (i) hydrogen,
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkoxy; and (ii) phenyl and pyridyl, each of
which is unsubstituted or substituted with from 1 to 3 substituents
independently chosen from halogen, hydroxy, C.sub.1-C.sub.4alkyl,
and C.sub.1-C.sub.4alkoxy; R.sub.1, R.sub.2, R.sub.3, and R.sub.4
are independently selected from: (i) hydrogen, halogen, hydroxy,
nitro, cyano and amino; (ii) (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkanoyl,
(C.sub.1-C.sub.6)alkyl ether, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, 3- to
8-membered heterocycloalkyl, 3- to 8-membered heteroaryl,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, mono and
di(C.sub.1-C.sub.6)alkylamino, amino(C.sub.1-C.sub.6)alkyl, and
mono- and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl, each
of which is unsubstituted or substituted with 1 or substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy; and (iii)
groups of the formula ##STR577## wherein R.sub.A is 5- to
7-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each
of which is unsubstituted or substituted with 1 or 2 substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkoxy; R.sub.5
represents hydrogen, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl, phenyl, benzyl,
thiophenyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, or
pyrimidinyl; R.sub.6 and R.sub.7 independently represent hydrogen,
fluorine, or C.sub.1-C.sub.6 alkyl; and W represents phenyl,
thienyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, isoxazolyl, or
pyrimidinyl, each of which is unsubstituted or substituted with
from 1 to 4 groups independently selected from R.sub.30.
13. A compound or salt according to claim 3 of the formula
##STR578##
14. A compound or salt according to claim 13, wherein Q is
C(R.sub.6)(R.sub.7).
15. A compound or salt according to claim 14, wherein: each R is
independently selected from the group consisting of: (i) hydrogen,
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkoxy; and (ii) phenyl and pyridyl, each of
which is unsubstituted or substituted with from 1 to 3 substituents
independently chosen from halogen, hydroxy, C.sub.1-C.sub.4alkyl,
and C.sub.1-C.sub.4alkoxy; R.sub.1, R.sub.2, R.sub.3, and R.sub.4
are independently selected from: (i) hydrogen, halogen, hydroxy,
nitro, cyano and amino; (ii) (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkanoyl,
(C.sub.1-C.sub.6)alkyl ether, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, 3- to
8-membered heterocycloalkyl, 3- to 8-membered heteroaryl,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, mono and
di(C.sub.1-C.sub.6)alkylamino, amino(C.sub.1-C.sub.6)alkyl, and
mono- and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl, each
of which is unsubstituted or substituted with 1 or substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy; and (iii)
groups of the formula ##STR579## wherein R.sub.A is 5- to
7-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each
of which is unsubstituted or substituted with 1 or 2 substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkoxy; R.sub.5
represents hydrogen, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl, phenyl, benzyl,
thiophenyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, or
pyrimidinyl; R.sub.6 and R.sub.7 independently represent hydrogen,
fluorine, or C.sub.1-C.sub.6alkyl; and W represents phenyl,
thienyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, isoxazolyl, or
pyrimidinyl, each of which is unsubstituted or substituted with
from 1 to 4 groups independently selected from R.sub.30.
16. A compound or salt according to claim 3 of the formula:
##STR580##
17. A compound or salt according to claim 16, wherein Q is
C(R.sub.6)(R.sub.7).
18. A compound or salt according to claim 3 of the formula:
##STR581##
19. A compound or salt according to claim 3 of the formula:
##STR582##
20. A compound or salt according to claim 3 of the formula:
##STR583##
21. A compound or salt according to claim 20, wherein Q is
C(R.sub.6)(R.sub.7).
22. A compound or salt according to claim 2 of the formula:
##STR584##
23. A compound or salt according to claim 22, wherein Q is
C(R.sub.6)(R.sub.7).
24. A compound or salt according to claim 3 of the formula:
##STR585##
25. A compound or salt according to claim 3 of the formula
##STR586##
26. A compound or salt according to claim 3 of the formula:
##STR587##
27. A compound or salt according to claim 3 of the formula:
##STR588##
28. A compound or salt according to claim 27, wherein Q is
C(R.sub.6)(R.sub.7).
29. A compound or salt according to claim 28, wherein: each R is
independently selected from the group consisting of (i) hydrogen,
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl and
halo(C.sub.1-C.sub.6)alkoxy, and (ii) phenyl and pyridyl, each of
which is unsubstituted or substituted with from 1 to 3 substituents
independently chosen from halogen, hydroxy, C.sub.1-C.sub.4alkyl,
and C.sub.1-C.sub.4alkoxy; R.sub.1, R.sub.2, R.sub.3, and R.sub.4
are independently selected from: (i) hydrogen, halogen, hydroxy,
nitro, cyano and amino; (ii) (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkanoyl,
(C.sub.1-C.sub.6)alkyl ether, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, 3- to
8-membered heterocycloalkyl, 3- to 8-membered heteroaryl,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, mono and
di(C.sub.1-C.sub.6)alkylamino, amino(C.sub.1-C.sub.6)alkyl, and
mono- and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl, each
of which is unsubstituted or substituted with 1 or substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy; and (iii)
groups of the formula ##STR589## wherein R.sub.A is 5- to
7-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each
of which is unsubstituted or substituted with 1 or 2 substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkoxy; R.sub.5
represents hydrogen, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl, phenyl, benzyl,
thiophenyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, or
pyrimidinyl; R.sub.6 and R.sub.7 independently represent hydrogen,
fluorine, or C.sub.1-C.sub.6alkyl; and W represents phenyl,
thienyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, isoxazolyl, or
pyrimidinyl, each of which is unsubstituted or substituted with
from 1 to 4 groups independently selected from R.sub.30.
30. A compound or salt according to claim 29, wherein R.sub.5
represents hydrogen, halogen, or (C.sub.1-C.sub.6)alkyl.
31. A compound or salt according to claim 30, wherein R.sub.5
represents hydrogen, halogen, or (C.sub.1-C.sub.6)alkyl; and W
represents phenyl, 2-thiazoyl, or 2-pyridyl, each of which is
unsubstituted or substituted with from 1 to 4 groups independently
selected from R.sub.30.
32. A compound or salt according to claim 31, wherein R.sub.1 and
R.sub.4 are independently selected from hydrogen, halogen, methyl,
ethyl, methoxy, and ethoxy.
33. A compound or salt according to claim 3 of the formula
##STR590##
34. A compound or salt according to claim 33, wherein Q is
C(R.sub.6)(R.sub.7).
35. A compound or salt according to claim 3 of the formula:
##STR591##
36. A compound or salt according to claim 35 wherein Q is
C(R.sub.6)(R.sub.7).
37. A compound or salt according to claim 36, wherein: each R is
independently selected from the group consisting of (i) hydrogen,
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl and
halo(C.sub.1-C.sub.6)alkoxy, and (ii) phenyl and pyridyl, each of
which is unsubstituted or substituted with from 1 to 3 substituents
independently chosen from halogen, hydroxy, C.sub.1-C.sub.4alkyl,
and C.sub.1-C.sub.4alkoxy; R.sub.1, R.sub.2, and R.sub.3 are
independently selected from: (i) hydrogen, halogen, hydroxy, nitro,
cyano and amino; (ii) (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkanoyl,
(C.sub.1-C.sub.6)alkyl ether, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, 3- to
8-membered heterocycloalkyl, 3- to 8-membered heteroaryl,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, mono and
di(C.sub.1-C.sub.6)alkylamino, amino(C.sub.1-C.sub.6)alkyl, and
mono- and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl, each
of which is unsubstituted or substituted with 1 or substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy; and (iii)
groups of the formula ##STR592## wherein R.sub.A is 5- to
7-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each
of which is unsubstituted or substituted with 1 or 2 substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkoxy; R.sub.5
represents hydrogen, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl, phenyl, benzyl,
thiophenyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, or
pyrimidinyl; R.sub.6 and R.sub.7 independently represent hydrogen,
fluorine, or C.sub.1-C.sub.6alkyl; and W represents phenyl,
thienyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, isoxazolyl, or
pyrimidinyl, each of which is unsubstituted or substituted with
from 1 to 4 groups independently selected from R.sub.30.
38. A compound or salt according to claim 37, wherein R.sub.5
represents hydrogen, halogen, or (C.sub.1-C.sub.6)alkyl.
39. A compound or salt according to claim 38, wherein: each R is
independently selected from the group consisting of (i) hydrogen,
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl and
halo(C.sub.1-C.sub.6)alkoxy, and (ii) phenyl and pyridyl, each of
which is unsubstituted or substituted with from 1 to 3 substituents
independently chosen from halogen, hydroxy, C.sub.1-C.sub.4alkyl,
and C.sub.1-C.sub.4alkoxy; R.sub.1, R.sub.2, and R.sub.3 are
independently selected from: (i) hydrogen, halogen, hydroxy, nitro,
cyano and amino; (ii) (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkanoyl,
(C.sub.1-C.sub.6)alkyl ether, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, 3- to
8-membered heterocycloalkyl, 3- to 8-membered heteroaryl,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, mono and
di(C.sub.1-C.sub.6)alkylamino, amino(C.sub.1-C.sub.6)alkyl, and
mono- and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl, each
of which is unsubstituted or substituted with 1 or substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy; and (iii)
groups of the formula ##STR593## wherein R.sub.A is 5- to
7-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each
of which is unsubstituted or substituted with 1 or 2 substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkoxy; R.sub.5
represents hydrogen, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl, phenyl, benzyl,
thiophenyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, or
pyrimidinyl; R.sub.6 and R.sub.7 independently represent hydrogen,
fluorine, or C.sub.1-C.sub.6alkyl; and W represents phenyl,
thienyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, isoxazolyl, or
pyrimidinyl, each of which is unsubstituted or substituted with
from 1 to 4 groups independently selected from R.sub.30.
40. A compound or salt according to claim 39, wherein R.sub.5
represents hydrogen, halogen, or (C.sub.1-C.sub.6)alkyl.
41. A compound or salt according to claim 40, wherein W represents
phenyl, 2-thiazoyl, or 2-pyridyl, each of which is unsubstituted or
substituted with from 1 to 4 groups independently selected from
R.sub.30.
42. A compound or salt according to claim 39 wherein R.sub.1 is
selected from hydrogen, halogen, methyl, ethyl, methoxy, and
ethoxy.
43. A compound or salt according to claim 3 of the formula
##STR594##
44. A compound or salt according to claim 43, wherein Q is
C(R.sub.6)(R.sub.7).
45. A compound or salt according to claim 3 of the formula
##STR595##
46. A compound or salt according to claim 45, wherein Q is
C(R.sub.6)(R.sub.7).
47. A compound or salt according to claim 46, wherein: each R is
independently selected from the group consisting of (i) hydrogen,
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl and
halo(C.sub.1-C.sub.6)alkoxy, and (ii) phenyl and pyridyl, each of
which is unsubstituted or substituted with from 1 to 3 substituents
independently chosen from halogen, hydroxy, C.sub.1-C.sub.4alkyl,
and C.sub.1-C.sub.4alkoxy; R.sub.2, R.sub.3, and R.sub.4 are
independently selected from: (i) hydrogen, halogen, hydroxy, nitro,
cyano and amino; (ii) (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkanoyl,
(C.sub.1-C.sub.6)alkyl ether, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, 3- to
8-membered heterocycloalkyl, 3- to 8-membered heteroaryl,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, mono and
di(C.sub.1-C.sub.6)alkylamino, amino(C.sub.1-C.sub.6)alkyl, and
mono- and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl, each
of which is unsubstituted or substituted with 1 or substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy; and (iii)
groups of the formula ##STR596## wherein R.sub.A is 5- to
7-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each
of which is unsubstituted or substituted with 1 or 2 substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkoxy; R.sub.5
represents hydrogen, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl, phenyl, benzyl,
thiophenyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, or
pyrimidinyl; R.sub.6 and R.sub.7 independently represent hydrogen,
fluorine, or C.sub.1-C.sub.6alkyl; and W represents phenyl,
thienyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, isoxazolyl, or
pyrimidinyl, each of which is unsubstituted or substituted with
from 1 to 4 groups independently selected from R.sub.30.
48. A compound or salt according to claim 47, wherein R.sub.5
represents hydrogen, halogen, or (C.sub.1-C.sub.6)alkyl.
49. A compound or salt according to claim 48, wherein W represents
phenyl, 2-thiazoyl, or 2-pyridyl, each of which is unsubstituted or
substituted with from 1 to 4 groups independently selected from
R.sub.30.
50. A compound or salt according to claim 47 wherein R.sub.1 is
selected from hydrogen, halogen, methyl, ethyl, methoxy, and
ethoxy.
51. A compound or salt according to claim 3 of the formula
##STR597##
52. A compound or salt according to claim 51, wherein Q is
C(R.sub.6)(R.sub.7).
53. A compound or salt according to claim 3 of the formula:
##STR598##
54. A compound or salt according to claim 53, wherein Q is
C(R.sub.6)(R.sub.7).
55. A compound or salt according to claim 54, wherein: each R is
independently selected from the group consisting of (i) hydrogen,
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl and
halo(C.sub.1-C.sub.6)alkoxy, and (ii) phenyl and pyridyl, each of
which is unsubstituted or substituted with from 1 to 3 substituents
independently chosen from halogen, hydroxy, C.sub.1-C.sub.4alkyl,
and C.sub.1-C.sub.4alkoxy; R.sub.1, R.sub.2, and R.sub.4 are
independently selected from: (i) hydrogen, halogen, hydroxy, nitro,
cyano and amino; (ii) (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkanoyl,
(C.sub.1-C.sub.6)alkyl ether, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, 3- to
8-membered heterocycloalkyl, 3- to 8-membered heteroaryl,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, mono and
di(C.sub.1-C.sub.6)alkylamino, amino(C.sub.1-C.sub.6)alkyl, and
mono- and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl, each
of which is unsubstituted or substituted with 1 or substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy; and (iii)
groups of the formula ##STR599## wherein R.sub.A is 5- to
7-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each
of which is unsubstituted or substituted with 1 or 2 substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkoxy; R.sub.5
represents hydrogen, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl, phenyl, benzyl,
thiophenyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, or
pyrimidinyl; R.sub.6 and R.sub.7 independently represent hydrogen,
fluorine, or C.sub.1-C.sub.6 alkyl; and W represents phenyl,
thienyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, isoxazolyl, or
pyrimidinyl, each of which is unsubstituted or substituted with
from 1 to 4 R.sub.30 groups.
56. A compound or salt according to claim 55, wherein R.sub.5
represents hydrogen, halogen, or (C.sub.1-C.sub.6)alkyl.
57. A compound or salt according to claim 56, wherein W represents
phenyl, 2-thiazoyl, or 2-pyridyl, each of which is unsubstituted or
substituted with from 1 to 4 groups independently selected from
R.sub.30.
58. A compound or salt according to claim 55, wherein R.sub.1 is
selected from hydrogen, halogen, methyl, ethyl, methoxy, and
ethoxy.
59. A compound or salt according to claim 3 of the formula:
##STR600##
60. A compound or salt according to claim 59, wherein Q is
C(R.sub.6)(R.sub.7).
61. A compound or salt according to claim 3 of the formula:
##STR601##
62. A compound or salt according to claim 61, wherein Q is
C(R.sub.6)(R.sub.7).
63. A compound or salt according to claim 62, wherein: each R is
independently selected from the group consisting of (i) hydrogen,
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl and
halo(C.sub.1-C.sub.6)alkoxy, and (ii) phenyl and pyridyl, each of
which is unsubstituted or substituted with from 1 to 3 substituents
independently chosen from halogen, hydroxy, C.sub.1-C.sub.4alkyl,
and C.sub.1-C.sub.4alkoxy; R.sub.1, R.sub.3, and R.sub.4 are
independently selected from: (i) hydrogen, halogen, hydroxy, nitro,
cyano and amino; (ii) (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkanoyl,
(C.sub.1-C.sub.6)alkyl ether, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, 3- to
8-membered heterocycloalkyl, 3- to 8-membered heteroaryl,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, mono and
di(C.sub.1-C.sub.6)alkylamino, amino(C.sub.1-C.sub.6)alkyl, and
mono- and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl, each
of which is unsubstituted or substituted with 1 or substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy; and (iii)
groups of the formula ##STR602## wherein R.sub.A is 5- to
7-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each
of which is unsubstituted or substituted with 1 or 2 substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkoxy; R.sub.5
represents hydrogen, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, or
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl, phenyl, benzyl,
thiophenyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, or
pyrimidinyl; R.sub.6 and R.sub.7 independently represent hydrogen,
fluorine, or C.sub.1-C.sub.6 alkyl; and W represents phenyl,
thienyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, isoxazolyl, or
pyrimidinyl, each of which is unsubstituted or substituted with
from 1 to 4 groups independently selected from R.sub.30.
64. A compound or salt according to claim 63, wherein R.sub.5
represents hydrogen, halogen, or (C.sub.1-C.sub.6)alkyl.
65. A compound or salt according to claim 64, wherein W represents
phenyl, 2-thiazoyl, or 2-pyridyl, each of which is unsubstituted or
substituted with from 1 to 4 groups independently selected from
R.sub.30.
66. A compound or salt according to claim 63 wherein R.sub.1 is
selected from hydrogen, halogen, methyl, ethyl, methoxy, and
ethoxy.
67. A compound or salt according to claim 3 of the formula:
##STR603##
68. A compound or salt according to claim 67, wherein Q is
C(R.sub.6)(R.sub.7).
69. A compound or salt according to claim 68, wherein: each R is
independently selected from the group consisting of (i) hydrogen,
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl and
halo(C.sub.1-C.sub.6)alkoxy, and (ii) phenyl and pyridyl, each of
which is unsubstituted or substituted with from 1 to 3 substituents
independently chosen from halogen, hydroxy, C.sub.1-C.sub.4alkyl,
and C.sub.1-C.sub.4alkoxy; R.sub.1, R.sub.2, R.sub.3, and R.sub.4
are independently selected from: (i) hydrogen, halogen, hydroxy,
nitro, cyano and amino; (ii) (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkanoyl,
(C.sub.1-C.sub.6)alkyl ether, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, 3- to
8-membered heterocycloalkyl, 3- to 8-membered heteroaryl,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, mono and
di(C.sub.1-C.sub.6)alkylamino, amino(C.sub.1-C.sub.6)alkyl, and
mono- and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl, each
of which is unsubstituted or substituted with 1 or substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy; and (iii)
groups of the formula ##STR604## wherein R.sub.A is 5- to
7-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each
of which is unsubstituted or substituted with 1 or 2 substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkoxy; R.sub.5
represents hydrogen, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl, phenyl, benzyl,
thiophenyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, or
pyrimidinyl; R.sub.6 and R.sub.7 independently represent hydrogen,
fluorine, or C.sub.1-C.sub.6 alkyl; and W represents phenyl,
thienyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, isoxazolyl, or
pyrimidinyl, each of which is unsubstituted or substituted with
from 1 to 4 R.sub.30 groups.
70. A compound or salt according to claim 69, wherein R.sub.5
represents hydrogen, halogen, or (C.sub.1-C.sub.6)alkyl.
71. A compound or salt according to claim 70, wherein W represents
phenyl, 2-thiazoyl, or 2-pyridyl, each of which is unsubstituted or
substituted with from 1 to 4 groups independently selected from
R.sub.30.
72. A compound or salt according to claim 69, wherein R.sub.1 is
selected from hydrogen, halogen, methyl, ethyl, methoxy, and
ethoxy.
73. A compound of the formula: ##STR605## or a pharmaceutically
acceptable salt thereof wherein: R.sub.1 and R.sub.2 are
independently selected from hydrogen, halogen, nitro, cyano,
haloalkyl, haloalkoxy, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl,
(cycloalkyl)alkyl, mono and dialkylamino, and aminoalkyl; R.sub.5
represents: (i) hydrogen, halogen, cyano, or haloalkyl; (ii) alkyl,
cycloalkyl, (cycloalkyl)alkyl, each of which comprises from 0 to 3
double bonds and/or from 0 to 3 triple bonds, and is unsubstituted
or substituted with 1, 2, or 3 substituents independently selected
from R.sub.30; or (iii) aryl, arylalkyl, heteroaryl, or
heteroarylalkyl, each of which is unsubstituted or substituted with
1, 2, or 3 substituents independently selected from the group
consisting of alkyl, haloalkyl, amino, --NH(R.sub.10),
--N(R.sub.10)(R.sub.11), carboxamido, (R.sub.10)NHcarbonyl,
(R.sub.10)(R.sub.11)Ncarbonyl, halogen, hydroxy, nitro, cyano,
amino, alkoxy, haloalkoxy, alkoxy substituted with amino or mono-
or di-alkylamino, cycloalkyl, (cycloalkyl)alkyl,
(cycloalkyl)alkoxy, heterocycloalkyl, alkenyl, alkynyl, aminoalkyl,
and mono- and di-alkylaminoalkyl; Q represents C(R.sub.6)(R.sub.7),
N(alkyl) or oxygen, wherein R.sub.6 and R.sub.7 independently
represent hydrogen, fluorine, or alkyl; with the proviso that Q is
not oxygen when X.sub.2 is nitrogen; R.sub.10 and R.sub.11 are
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
alkanoyl, and mono and dialkylaminoalkyl; R.sub.30 is independently
selected at each occurrence from halogen, hydroxy, nitro, cyano,
amino, alkyl, alkoxy, alkoxy substituted with amino or mono- or
dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy,
cycloalkyloxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl,
haloalkoxy, mono- and dialkylamino, aminoalkyl, and mono- and
dialkylaminoalkyl; the group: ##STR606## represents a 5 to 7
membered heteroaryl group containing from 1 to 4 heteroatoms
independently selected from nitrogen, sulfur, and oxygen, wherein
the ring is unsubstituted or substituted at each carbon atom by R,
and unsubstituted or substituted at each nitrogen atom available
for substitution by R', wherein R is independently chosen at each
occurrence from halogen, amino, alkyl, alkenyl, alkynyl, alkoxy,
cycloalkyl, (cycloalkyl)alkyl, haloalkyl, haloalkoxy, carboxamido,
and 3- to 7-membered carbocyclic and heterocyclic rings, each of
which is unsubstituted or substituted with one or more substituents
independently selected from halogen, oxo, hydroxy, alkyl, and
alkoxy; R' is independently chosen at each occurrence from alkyl,
cycloalkyl, cycloalkyl(alkyl), and 3- to 7-membered carbocyclic and
heterocyclic rings, each of which is unsubstituted or substituted
with one or more substituents independently selected from halogen,
oxo, hydroxy, alkyl, and alkoxy; X.sub.1 and X.sub.2 independently
represent nitrogen, carbon or CH; Y is nitrogen, carbon, --CH--,
--CH.sub.2--, or absent; and W represents aryl or heteroaryl, each
of which is unsubstituted or substituted with from 1 to 4 groups
independently selected from R.sub.30, --CO.sub.2H,
--C(.dbd.O)OR.sub.E, --C(.dbd.O)NR.sub.E, --C(O)R.sub.E,
--OR.sub.E, and --S(O).sub.mR.sub.E, wherein R.sub.E is
independently selected at each occurrence from alkyl, cycloalkyl,
heterocycloalkyl, alkoxy, mono- and dialkylamino, aryl, and
heteroaryl, each of which is unsubstituted or substituted with 1,
2, or 3 substituents independently selected from R.sub.30, and
wherein m is 0, 1, or 2.
74. A compound or salt according to claim 73, wherein: R.sub.1 and
R.sub.2 are independently selected from hydrogen, halogen, nitro,
cyano, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.3-C.sub.7cycloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, (C.sub.3-C.sub.7)cycloalkyl)
C.sub.1-C.sub.4alkyl, mono and di(C.sub.1-C.sub.6)alkylamino, and
amino(C.sub.1-C.sub.6)alkyl; R.sub.5 represents: (i) hydrogen,
halogen, cyano, or haloalkyl; (ii) (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8cycloalkyl)(C.sub.1-C.sub.4)alkyl, each of which
comprises from 0 to 3 double bonds and/or from 0 to 3 triple bonds,
each of which is unsubstituted or substituted with 1, 2, or 3
substituents independently selected from R.sub.30; or (iii) aryl,
aryl(C.sub.1-C.sub.4)alkyl, 3- to 8-membered heteroaryl, or 3- to
8-membered heteroaryl(C.sub.1-C.sub.4)alkyl, each of which is
unsubstituted or substituted with 1, 2, or 3 substituents
independently selected from the group consisting of
(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, amino,
--NH(R.sub.10), --N(R.sub.10)(R.sub.11), carboxamido,
(R.sub.10)NHcarbonyl, (R.sub.10)(R.sub.11)Ncarbonyl, halogen,
hydroxy, nitro, cyano, amino, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy substituted with amino or mono- or
di(C.sub.1-C.sub.6)alkylamino, halo(C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.4)alkyl,
(C.sub.3-C.sub.8)cycloalkyl (C.sub.1-C.sub.4)alkoxy,
heterocyclo(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, amino(C.sub.1-C.sub.6) alkyl, and mono-
and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl; Q
represents C(R.sub.6)(R.sub.7), N(C.sub.1-C.sub.6alkyl) or oxygen,
wherein R.sub.6 and R.sub.7 independently represent hydrogen,
fluorine, or (C.sub.1-C.sub.6)alkyl; with the proviso that Q is not
oxygen when X.sub.2 is nitrogen; R.sub.10 and R.sub.1, are
independently selected from the group consisting of
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.4)alkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.6)alkanoyl, and mono and
di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl; R.sub.30 is
independently selected at each occurrence from halogen, hydroxy,
nitro, cyano, amino, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkoxy substituted with
amino or mono- or di(C.sub.1-C.sub.6)alkylamino,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.4)alkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.4)alkoxy, 3- to
8-membered heterocyclo(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, mono- and
di(C.sub.1-C.sub.6)alkylamino, amino(C.sub.1-C.sub.6)alkyl, and
mono- and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl; R is
independently chosen at each occurrence from halogen, amino,
C.sub.1-C.sub.6alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, C.sub.1-C.sub.6alkoxy,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8cycloalkyl)(C.sub.1-C.sub.4)alkyl,
halo(C.sub.1-C.sub.6)alkyl, haloalkoxy, carboxamido, and 3- to
7-membered carbocyclic and heterocyclic rings, each of which is
unsubstituted or substituted with from 1 to 4 substituents
independently selected from halogen, oxo, hydroxy,
C.sub.1-C.sub.4alkyl, and C.sub.1-C.sub.4alkoxy; R' is
independently chosen at each occurrence from C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl,
C.sub.3-C.sub.8cycloalkyl(C.sub.1-C.sub.4alkyl), and 3- to
7-membered carbocyclic and heterocyclic rings, each of which is
unsubstituted or substituted with from 1 to 4 substituents
independently selected from halogen, oxo, hydroxy,
C.sub.1-C.sub.4alkyl, and C.sub.1-C.sub.4alkoxy; and W represents
3- to 8-membered aryl or heteroaryl, each of which is unsubstituted
or substituted with from 1 to 4 groups independently selected from
R.sub.30, --C(.dbd.O)OR.sub.E, --C(.dbd.O)NR.sub.E, --C(O)R.sub.E,
--OR.sub.E and --S(O).sub.mR.sub.E, wherein m is 0, 1, or 2.
75. A compound or salt according to claim 74 of the formula
##STR607## wherein R.sub.5 represents hydrogen, halogen, or
(C.sub.1-C.sub.6)alkyl, and R.sub.6 and R.sub.7 independently
represent hydrogen or (C.sub.1-C.sub.6)alkyl.
76. A compound or salt according to claim 75, wherein W represents
phenyl, 2-thiazoyl, or 2-pyridyl, each of which is unsubstituted or
substituted with from 1 to 4 groups independently selected from
R.sub.30.
77. A compound or salt according to claim 76, wherein R.sub.1 and
R.sub.2 are independently selected from hydrogen, halogen, nitro,
cyano, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
heterocycloalkyl, halo(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkoxy, mono and
di(C.sub.1-C.sub.6)alkylamino, amino(C.sub.1-C.sub.6)alkyl, and
mono- and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl.
78. A pharmaceutical composition comprising a compound or salt
according to claim 1 or claim 73 combined with a pharmaceutically
acceptable carrier or excipient.
79. A method for altering the signal-transducing activity of
GABA.sub.A receptors, said method comprising contacting a cell
expressing GABA.sub.A receptors with a solution comprising a
compound or salt according to claim 1 or claim 78 at a
concentration sufficient to detectably alter the electrophysiology
of the cell, wherein a detectable alteration of the
electrophysiology of the cell indicates an alteration of the
signal-transducing activity of GABA.sub.A receptors.
80. A method for altering the signal-transducing activity of
GABA.sub.A receptors, said method comprising contacting cells
expressing GABA.sub.A receptors with a solution comprising a
compound or salt according to claim 1 or claim 78 at a
concentration sufficient to detectably alter the chloride
conductance in vitro of the cell expressing GABA.sub.A
receptors.
81. The method of claim 80 wherein the cell is recombinantly
expressing a heterologous GABA.sub.A receptor and the alteration of
the electrophysiology of the cell is detected by intracellular
recording or patch clamp recording.
82. The method of claim 80 wherein the cell is a neuronal cell that
is contacted in vivo in an animal, the solution is a body fluid,
and the alteration in the electrophysiology of the cell is detected
as a reproducible change in the animal's behavior.
83. The method of claim 82 wherein the animal is a human, the cell
is a brain cell, and the fluid is cerebrospinal fluid.
84. A method for altering the signal-transducing activity of
GABA.sub.A receptors, the method comprising exposing cells
expressing the GABA.sub.A receptors to a compound or salt according
to claim 1 or claim 78 at a concentration sufficient to inhibit
Ro15-1788 binding in vitro to cells expressing a cloned human
GABA.sub.A receptor.
85. A method for the treatment of anxiety, depression, a sleep
disorder, schizophrenia, attention deficit-hyperactivity disorder,
or for the enhancement of memory comprising administering an
effective amount of a compound or salt of claim 1 or claim 78 to a
patient in need thereof.
86. A method for demonstrating the presence of GABA.sub.A receptors
a cell or tissue sample, said method comprising: contacting a cell
or tissue sample with a labeled compound or salt according to claim
1 or claim 78; washing the cell or tissue sample to remove unbound
labeled compound or salt; and detecting the presence of labeled
compound of salt in the cell or tissue sample.
87. The method of claim 86 in which the cell or tissue sample is a
tissue section.
88. The method of claim 86 in which the labeled compound or salt
contains a radioactive label or a directly or indirectly
luminescent label.
89. The method of claim 86 in which each measurement of the amount
of labeled compound or salt in a sample is carried out by viewing
the autoradiograms and the comparison is a comparison of the
exposure density of the autoradiograms.
90. A packaged pharmaceutical composition comprising the
pharmaceutical composition of claim 1 or claim 78 in a container
and further comprising at least one of: instructions for using the
composition to treat a patient suffering from an anxiety disorder,
or instructions for using the composition to treat a patient
suffering from depression, or instructions for using the
composition to treat a patient suffering from a sleeping disorder,
instructions for using the composition to treat a patient suffering
from schizophrenia, or instructions for using the composition to
treat a patient suffering from attention deficit-hyperactivity
disorder.
91. A packaged pharmaceutic composition comprising a pharmaceutical
composition of claim 1 or claim 78 in a container and further
comprising at least one of: instructions for using the composition
to treat a patient suffering from Alzheimer's dementia, or
instructions for using the composition to enhance memory in a
patient.
92. The use of a compound or salt according to claim 1 or claim 78
for the manufacture of a medicament for the treatment of anxiety,
depression, a sleep disorder, schizophrenia, or attention
deficit-hyperactivity disorder.
93. The use of a compound or salt according to claim 1 or claim 78
for the manufacture of a medicament for the enhancement of
memory.
94. A compound according to claim 1 or claim 78 wherein in a assay
of GABA.sub.A receptor binding that determines the displacement of
.sup.3H-Flumazenil from rat cortical tissue in 0.05 M Tris HCl
buffer at 4.degree. C. the compound exhibits an K.sub.i of 1
micromolar or less.
95. A compound according to claim 94 wherein in a assay of
GABA.sub.A receptor binding the compound exhibits an K.sub.i of 100
nanomolar or less.
96. A compound according to claim 94 wherein in a assay of
GABA.sub.A receptor binding the compound exhibits an K.sub.i of 10
nanomolar or less.
Description
FIELD OF THE INVENTION
[0001] This invention relates to heteroaryl substituted fused
bicyclic heteroaryl compounds, such as heteroaryl substituted
imidazopyridines, imidazopyrazines, imidazopyridizines,
imidazopyrimidines, and imidazothiazoles, and more specifically to
such compounds that bind with high selectivity and high affinity to
the benzodiazepine site of GABA.sub.A receptors. This invention
also relates to pharmaceutical compositions comprising such
compounds and to the use of such compounds in treatment of certain
central nervous system (CNS) diseases. This invention also relates
to the use of these heteroaryl substituted imidazopyridines,
imidazopyrazines, imidazopyridizines, imidazopyrimidines, and
imidazothiazoles compounds and related compounds in combination
with one or more other CNS agents to potentiate the effects of the
other CNS agents. Additionally this invention relates to the use
such compounds as probes for the localization of GABA.sub.A
receptors in tissue sections.
BACKGROUND
[0002] The GABA.sub.A receptor superfamily represents one of the
classes of receptors through which the major inhibitory
neurotransmitter, .gamma.-aminobutyric acid, or GABA, acts. Widely,
although unequally, distributed throughout the mammalian brain,
GABA mediates many of its actions through a complex of proteins
called the GABA.sub.A receptor, which causes alteration in chloride
conductance and membrane polarization. In addition to being the
site of neurotransmitter action, a number of drugs including the
anxiolytic and sedating benzodiazepines bind to this receptor. The
GABA.sub.A receptor comprises a chloride channel that generally,
but not invariably, opens in response to GABA, allowing chloride to
enter the cell. This, in turn, effects a slowing of neuronal
activity through hyperpolarization of the cell membrane
potential.
[0003] GABA.sub.A receptors are composed of five protein subunits.
A number of cDNAs for these GABA.sub.A receptor subunits have been
cloned and their primary structures determined. While these
subunits share a basic motif of 4 membrane-spanning helices, there
is sufficient sequence diversity to classify them into several
groups. To date at least 6.alpha., 3.beta., 3.gamma., 1.epsilon.,
1.delta. and 2.rho. subunits have been identified. Native
GABA.sub.A receptors are typically composed of 2.alpha., 2.beta.,
and 1.gamma.. Various lines of evidence (such as message
distribution, genome localization and biochemical study results)
suggest that the major naturally occurring receptor combinations
are .alpha..sub.1.beta..sub.2.gamma..sub.2,
.alpha..sub.2.beta..sub.3.gamma..sub.2,
.alpha..sub.3.beta..sub.3.gamma..sub.2, and
.alpha..sub.5.beta..sub.3.gamma..sub.2 (Mohler et al. Neuroch. Res.
1995; 20(5):631-36).
[0004] The GABA.sub.A receptor binding sites for GABA (2 per
receptor complex) are formed by amino acids from the .alpha. and
.beta. subunits. Amino acids from the .alpha. and .gamma. subunits
together form one benzodiazepine site per receptor. Benzodiazepines
exert their pharmacological actions by interacting with the
benzodiazepine binding sites associated with the GABA.sub.A
receptor. In addition to the benzodiazepine site (sometimes
referred to as the benzodiazepine or BDZ receptor), the GABA.sub.A
receptor contains sites of interaction for several other classes of
drugs. These include a steroid binding site, a picrotoxin site, and
a barbiturate site. The benzodiazepine site of the GABA.sub.A
receptor is a distinct site on the receptor complex that does not
overlap with the site of interaction for other classes of drugs
that bind to the receptor or for GABA (see, e.g., Cooper, et al.,
The Biochemical Basis of Neuropharmacology, 6.sup.th ed., 1991, pp.
145-148, Oxford University Press, New York).
[0005] In a classic allosteric mechanism, the binding of a drug to
the benzodiazepine site increases the affinity of the GABA receptor
for GABA. Benzodiazepines and related drugs that enhance the
ability of GABA to open GABA.sub.A receptor channels are known as
agonists or partial agonists depending on the level of GABA
enhancement. Other classes of drugs, such as .beta.-carboline
derivatives, that occupy the same site and negatively modulate the
action of GABA are called inverse agonists. A third class of
compounds exists which occupy the same site as both the agonists
and inverse agonists and yet have little or no effect on GABA
activity. These compounds will, however, block the action of
agonists or inverse agonists and are thus referred to as GABA.sub.A
receptor antagonists.
[0006] The important allosteric modulatory effects of drugs acting
at the benzodiazepine site were recognized early, and the
distribution of activities at different subtype receptors has been
an area of intense pharmacological discovery. Agonists that act at
the benzodiazepine site are known to exhibit anxiolytic, sedative,
and hypnotic effects, while compounds that act as inverse agonists
at this site elicit anxiogenic, cognition enhancing, and
proconvulsant effects. While benzodiazepines have enjoyed long
pharmaceutical use as anxiolytics, these compounds are known to
exhibit a number of unwanted side effects. These may include
cognitive impairment, sedation, ataxia, potentiation of ethanol
effects, and a tendency for tolerance and drug dependence.
[0007] GABA.sub.A selective ligands may also act to potentiate the
effects of certain other CNS active compounds. For example, there
is evidence that selective serotonin reuptake inhibitors (SSRIs)
may show greater antidepressant activity when used in combination
with GABA.sub.A selective ligands than when used alone.
SUMMARY OF THE INVENTION
[0008] This invention provides compounds of Formula I and Formula
II (shown below), particularly heteroaryl substituted
imidazopyridines, imidazopyrazines, imidazopyridizines,
imidazopyrimidines, and imidazothiazoles that bind to the
benzodiazepine site of GABA.sub.A receptors, including human
GABA.sub.A receptors. Preferred compounds of the invention bind
with high selectivity and/or high affinity to GABA.sub.A receptors.
Preferred compounds act as agonists, antagonists or inverse
agonists of such receptors. As such, they are useful in the
treatment of various CNS disorders.
[0009] The invention further provides compounds pharmaceutical
compositions comprising compounds of Formula I and/or Formula
II.
[0010] The invention provides methods for synthesizing compounds of
Formula I and Formula II.
[0011] The invention further provides methods of treating patients
suffering from certain CNS disorders with an effective amount of a
compound of Formula I and/or Formula II. The patient may be a human
or other mammal. Treatment of humans, domesticated companion
animals (pets) or livestock animals suffering from certain CNS
disorders with an effective amount of a compound of the invention
is encompassed by the invention.
[0012] In a separate aspect, the invention provides methods of
potentiating the actions of other CNS active compounds. These
methods comprise administering an effective amount of a compound of
Formula I and/or Formula II in conjunction with the administration
of another CNS active compound.
[0013] Additionally this invention relates to the use of compounds
of Formula I or Formula II as probes for the localization of
GABA.sub.A receptors in tissue sections.
[0014] Accordingly an embodiment of the invention is directed to
compounds of Formula I ##STR2## and the pharmaceutically acceptable
salts thereof.
[0015] Z.sub.1 (in Formula I) is nitrogen or CR.sub.1; Z.sub.2 is
nitrogen or CR.sub.2; Z.sub.3 is nitrogen or CR.sub.3; Z.sub.4 is
nitrogen or CR.sub.4; Z.sub.5 is nitrogen or carbon; and Z.sub.6 is
nitrogen or carbon; provided that no more than two of Z.sub.1,
Z.sub.2, Z.sub.3, Z.sub.4, Z.sub.5, and Z.sub.6 are nitrogen.
[0016] R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are independently
selected from: [0017] (i) hydrogen, halogen, hydroxy, nitro, cyano,
amino, haloalkyl, and haloalkoxy; [0018] (ii) alkyl, alkoxy,
cycloalkyl, alkenyl, alkynyl, (cycloalkyl)alkyl, --NH(R.sub.10),
--N(R.sub.10)(R.sub.11), hydroxyalkyl, aminoalkyl,
(R.sub.10)NHalkyl, (R.sub.10)(R.sub.11)Nalkyl, alkanoyl,
alkoxycarbonyl, alkylsulfonyl, alkylsulfinyl, alkylthio, mono- and
dialkylaminocarbonyl, heterocycloalkyl, aryl, and heteroaryl, each
of which is unsubstituted or substituted with 1, 2, 3, or 4
substituents independently selected from R.sub.20; [0019] (iii)
groups of the formula: ##STR3## wherein G is alkyl, --O--,
--C(.dbd.O)--, or --CH.sub.2--C(.dbd.O)--, and R.sub.A is
cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is
unsubstituted or substituted with 1, 2, 3, or 4 of R.sub.20; [0020]
(iv) groups of the formula: ##STR4## [0021] wherein J is N, CH, or
C-alkyl, and R.sub.B and R.sub.C are each independently selected
from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
alkoxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, aryl,
arylalkyl, alkanoyl, heteroaryl, and mono and dialkylaminoalkyl,
each of which is unsubstituted or substituted with 1 or 2
substituents independently chosen from halogen, hydroxy, cyano,
amino, nitro, alkoxy, haloalkoxy, alkyl and haloalkyl; or R.sub.B
and R.sub.C and the atom to which they are attached form a 4- to
10-membered monocyclic or bicyclic ring, comprising: a) 0, 1, 2 or
3 double bonds, and b) 0, 1, 2 or 3 of oxo, O, S, SO, SO.sub.2, or
N--R.sub.D, wherein R.sub.D is (1)hydrogen; or (2) Ar.sub.1, alkyl,
cycloalkyl, heterocycloalkyl, or Ar.sub.1alkyl; wherein Ar.sub.1 is
aryl or heteroaryl, each of which is unsubstituted or substituted
with 1 or 2 substituents independently chosen from halogen,
hydroxy, cyano, amino, nitro, alkoxy, and alkyl; and [0022] (v)
--OC(.dbd.O)R.sub.E, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHR.sub.E,
--C(.dbd.O)NR.sub.ER.sub.F, --S(O).sub.nR.sub.E,
--S(O).sub.nNH.sub.2, --S(O).sub.nNHR.sub.E,
--S(O).sub.nNR.sub.ER.sub.F, --NHC(.dbd.O)R.sub.E,
--C(.dbd.NR.sub.E)R.sub.F, --HC.dbd.N--OH, --HC.dbd.N(alkoxy),
--HC.dbd.N(alkyl), --NR.sub.EC(.dbd.O)R.sub.F,
--NHS(O).sub.nR.sub.E, and --NR.sub.ES(O).sub.nR.sub.F, wherein n
is 0, 1 or 2; R.sub.E and R.sub.F are independently selected at
each occurrence from alkyl, cycloalkyl, heterocycloalkyl, alkoxy,
mono- and dialkylamino, aryl, and heteroaryl, each of which is
unsubstituted or substituted with 1, 2, or 3 substituents
independently selected from R.sub.30.
[0023] R.sub.5 represents: (i) hydrogen, halogen, cyano, or
haloalkyl; (ii) alkyl, cycloalkyl, (cycloalkyl)alkyl, each of which
comprises from 0 to 3 double bonds and/or from 0 to 3 triple bonds,
and is unsubstituted or substituted with 1, 2, or 3 substituents
independently selected from R.sub.30; or (iii) aryl, arylalkyl,
heteroaryl, or heteroarylalkyl, each of which is unsubstituted or
substituted with 1, 2, or 3 substituents independently selected
from the group consisting of haloalkyl, amino, --NH(R.sub.10),
--N(R.sub.10)(R.sub.11), carboxamido, (R.sub.10)NHcarbonyl,
(R.sub.10)(R.sub.11)Ncarbonyl, halogen, hydroxy, nitro, cyano,
amino, alkyl, alkoxy, alkoxy substituted with amino or mono- or
dialkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy,
cycloalkyloxy, heterocycloalkyl, alkenyl, alkynyl, haloalkyl,
haloalkoxy, aminoalkyl, and mono- and dialkylaminoalkyl.
[0024] R.sub.10 and R.sub.11 are independently selected from the
group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,
cycloalkylalkyl, aryl, arylalkyl, alkanoyl, and mono and
dialkylaminoalkyl.
[0025] Q represents --C(R.sub.6)(R.sub.7), --N(alkyl)- or oxygen,
wherein R.sub.6 and R.sub.7 independently represent hydrogen,
fluorine, or alkyl; with the proviso that Q is not oxygen when
X.sub.2 is nitrogen.
[0026] R.sub.20 is independently selected at each occurrence from:
halogen, hydroxy, nitro, cyano, amino, alky, alkoxy, alkoxy
substituted with amino or mono- or dialkylamino, cycloalkyl,
cycloalkylalkyl, cycloalkylalkoxy, cycloalkyloxy, alkenyl, alkynyl,
haloalkyl, haloalkoxy, mono- and dialkylamino, aminoalkyl, and
mono- and dialkylaminoalkyl.
[0027] R.sub.30 is independently selected at each occurrence from:
halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy; alkoxy
substituted with amino or mono- or dialkylamino, cycloalkyl,
cycloalkylalkyl, cycloalkylalkoxy, cycloalkyloxy, heterocycloalkyl,
alkenyl, alkynyl, haloalkyl, haloalkoxy, mono- and dialkylamino,
aminoalkyl, and mono- and dialkylaminoalkyl.
[0028] The group: ##STR5## represents a 5 to 7 membered heteroaryl
group containing from 1 to 4 heteroatoms independently selected
from nitrogen, sulfur, and oxygen, unsubstituted or substituted at
each carbon atom by R, and unsubstituted or substituted at each
nitrogen atom available for substitution by R'.
[0029] R, in the above group, is independently chosen at each
occurrence from halogen, amino, alkyl, alkenyl, alkynyl, alkoxy,
cycloalkyl, (cycloalkyl)alkyl, haloalkyl, haloalkoxy, carboxamido,
and 3- to 7-membered carbocyclic and heterocyclic rings, each of
which is unsubstituted or substituted with one or more substituents
independently selected from halogen, oxo, hydroxy, alkyl, and
alkoxy.
[0030] R' is independently chosen at each occurrence from alkyl,
cycloalkyl, cycloalkyl(alkyl), and 3- to 7-membered carbocyclic and
heterocyclic rings, each of which unsubstituted or substituted with
one or more substituents independently selected from halogen, oxo,
hydroxy, alkyl, and alkoxy.
[0031] X.sub.1 and X.sub.2 independently represent nitrogen, carbon
or CH.
[0032] Y is nitrogen, carbon, --CH--, --CH.sub.2--, or absent.
[0033] W represents aryl or heteroaryl, each of which is
unsubstituted or substituted with from 0 to 4 groups independently
selected from R.sub.30, --C(.dbd.O)OR.sub.E, --C(.dbd.O)NR.sub.E,
--C(O)R.sub.E, --OR.sub.E and --S(O).sub.mR.sub.E, wherein m is 0,
1, or 2.
[0034] In another embodiment the invention provides compounds of
Formula II: ##STR6## and the pharmaceutically acceptable salts
thereof.
[0035] R.sub.1 and R.sub.2, in Formula II, are independently
selected from hydrogen, halogen, nitro, cyano, haloalkyl,
haloalkoxy, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl,
(cycloalkyl)alkyl, mono and dialkylamino, and aminoalkyl.
[0036] The remaining variables shown in Formula II, e.g. Q,
R.sub.5, W, X.sub.1, X.sub.2, and Y, carry the definitions set
forth above for compounds of Formula I.
DETAILED DESCRIPTION
Chemical Description and Terminology
[0037] Prior to setting forth the invention in detail, it may be
helpful to provide definitions of certain terms to be used herein.
Compounds of the present invention are generally described using
standard nomenclature. Certain compounds are described herein using
a general formula that includes variables. Unless otherwise
specified, each variable within such a formula is defined
independently of other variables.
[0038] Formula I includes, but is not limited to the subformulae
exemplified as Formula III-Formula XXIV and their pharmaceutically
acceptable acid and base addition salts. Formula II includes, but
is not limited to the subformulae exemplified as Formula XV-Formula
XXVI and their pharmaceutically acceptable acid and base addition
salts.
[0039] 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 or
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio. As used herein, "pharmaceutically acceptable
salts" refers to derivatives of the disclosed compounds wherein the
parent compound is modified by making acid or base salts thereof.
Those skilled in the art will recognize a wide variety of non-toxic
pharmaceutically acceptable addition salts.
[0040] Examples of pharmaceutically acceptable salts include, but
are not limited to, mineral or organic acid salts of basic residues
such as amines; alkali or organic salts of acidic residues such as
carboxylic acids; and the like. The pharmaceutically acceptable
salts include the conventional non-toxic salts 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, hydroiodic, sulfuric,
sulfamic, sulfinic, phosphoric, nitric and the like; and the salts
prepared from organic acids such as alkanoic such as acetic,
HOOC--(CH.sub.2)n-ACOOH where n is 0-4, and the like, tartaric,
maleic, propionic, succinic, glycolic, stearic, lactic, malic,
tartaric, citric, ascorbic, pamoic, malefic, hydroxymaleic,
phenylacetic, glutamic, benzoic, salicylic, sulfanilic,
2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,
ethanesulfonic, ethane disulfonic, oxalic, isethionic,
HOOC--(CH.sub.2)n-COOH where n is 0-4, and the like. 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., p. 1418 (1985).
[0041] The invention includes hydrates of compounds of Formula I
and Formula II.
[0042] The invention includes all crystalline forms of the
compounds of Formula I and Formula II. Certain crystalline forms
may be preferred.
[0043] The present invention also encompasses the acylated prodrugs
of the compounds of Formula I and Formula II. Those skilled in the
art will recognize various synthetic methodologies that may be
employed to prepare non-toxic pharmaceutically acceptable addition
salts and acylated prodrugs of the compounds encompassed by Formula
I and Formula II. The invention further encompasses all enantiomers
and diastereomers of the disclosed compounds. Those of ordinary
skill in the art will readily recognize methods by which mixtures
of enantiomers and diasteromers may be resolved. The definitions of
Formula I and Formula II as used in herein include possible
isomers, such as tautomers and rotamers.
[0044] The compounds herein described may have one or more
asymmetric centers or planes. 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 (racemates), by asymmetric synthesis, or by synthesis from
optically active starting materials. Resolution of the racemates
can be accomplished, for example, by conventional methods such as
crystallization in the presence of a resolving agent, or
chromatography, using, for example a chiral HPLC column. 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 (enantiomeric and
diastereomeric), and racemic forms, as well as all geometric
isomeric forms of a structure are intended, unless the specific
stereochemistry or isomeric form is specifically indicated.
[0045] When any variable 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 to 3 R*, (where R* indicates any variable group
such as R) then said group may optionally be substituted with up to
three R* groups and R* at each occurrence is selected independently
from the definition of R*. Also, combinations of substituents
and/or variables are permissible only if such combinations result
in stable compounds.
[0046] When any group, such as an aryl group, heteroaryl group,
carbocyclic group, heterocyclic group, or monocylic or bicyclic
ring is said to be "substituted by one or more substituents" that
group may contain from 1 to the maximum number of substituents
allowable without exceeding the valency of the atoms of the
substituted group. Preferably such groups are substituted from 1 to
4 substituents, and more preferably such groups are substituted
with from 1 to 3 substituents. Preferably such groups are not
substituted with more that one oxo substituent.
[0047] A dash "-" that is not between two letters or symbols is
used to indicate a point of attachment for a substituent. For
example --C(.dbd.O)NH.sub.2 is attached through the carbon
atom.
[0048] As used herein, "alkyl" is intended to include both branched
and straight-chain saturated aliphatic hydrocarbon groups, having
the specified number of carbon atoms. Thus, the term
C.sub.1-C.sub.6 alkyl as used herein includes alkyl groups
consisting of 1 to 6 carbon atoms. When C.sub.1-C.sub.nalkyl is
used herein in conjunction with another group, for example,
arylC.sub.1-C.sub.4alkyl, the indicated group, in this case aryl,
is attached by an alkyl chain having the specified number of carbon
atoms, in this case from 1 to 4 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. Preferred alkyl
groups are C.sub.1-C.sub.6 and C.sub.1-C.sub.4 alkyl groups.
[0049] "Alkenyl" is intended to include hydrocarbon chains of
either a straight or branched configuration comprising one or more
unsaturated carbon-carbon bonds, which may occur in any stable
point along the chain, such as ethenyl and propenyl.
[0050] "Alkynyl" is intended to include hydrocarbon chains of
either a straight or branched configuration comprising one or more
triple carbon-carbon bonds that may occur in any stable point along
the chain, such as ethynyl and propynyl.
[0051] "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, 2-butoxy, t-butoxy,
n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy,
2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
[0052] "Alkanoyl" represents an alkyl group as defined above with
the indicated number of carbon atoms attached through a carbonyl
bridge.
[0053] "Alkoxycarbonyl" indicates a group of the formula:
##STR7##
[0054] As used herein, the term "mono- and di-alkylamino" includes
secondary (monoalkylamino) or tertiary alkyl amino groups, wherein
the alkyl groups are as defined above and have the indicated number
of carbon atoms. The point of attachment of the alkylamino group is
on the nitrogen. Examples of mono- and di-alkylamino groups include
ethylamino, dimethylamino, methyl-propyl-amino. The term "mono- and
di-alkylaminoalkyl" is used to indicate and alkyl group, as
described above, substituted by a mono- or di-alkylamino group, as
described above. The term "mono- and di-alkylaminocarbonyl" is used
to indicate a mono- or di-alkylamino group, as described above,
attached through a carbonyl bridge.
[0055] As used herein, the term "aminoalkyl" indicates an alkyl
group substituted at the terminal position by NH.sub.2, e.g. a
3-propylamine group.
[0056] As used herein, the term "alkylsulfinyl" includes those
groups having one or more sulfoxide (SO) linkage groups and
typically from 1 to about 8 carbon atoms, more typically 1 to about
6 carbon atoms.
[0057] As used herein, the term "alkylsulfonyl" includes those
groups having one or more sulfonyl (SO.sub.2) linkage groups and
typically from 1 to about 8 carbon atoms, more typically 1 to about
6 carbon atoms.
[0058] As used herein, the term "alkylthio" includes those groups
having one or more thioether linkages and preferably from 1 to
about 8 carbon atoms, more typically 1 to about 6 carbon atoms.
[0059] As used herein, the term "aryl" indicates aromatic groups
containing only carbon in the aromatic ring. Such aromatic groups
may be further substituted with carbon or non-carbon atoms or
groups. Typical aryl groups contain 1 to 3 separate, fused, or
pendant rings and from 6 to about 18 ring atoms, without
heteroatoms as ring members. Specifically preferred aryl groups
include phenyl, naphthyl, including 1-naphthyl and 2-naphthyl, and
biphenyl.
[0060] "Carboxamido" indicates a group of the formula
--C(.dbd.O)NH.sub.2.
[0061] "Cycloalkyl" is intended to include saturated hydrocarbon
ring groups, having the specified number of carbon atoms, usually
from 3 to about 8 ring carbon atoms. Preferred cycloalkyl groups
have from 3 to 7 ring carbon atoms. Examples of cycloalkyl groups
include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl and
bridged or caged saturated ring groups such as norborane or
adamantane and the like.
[0062] In the term "(cycloalkyl)alkyl" cycloalkyl and alkyl are as
defined above, and the point of attachment is on the alkyl group.
This term encompasses, but is not limited to, cyclopropylmethyl,
cyclohexylmethyl, and cyclohexylmethyl. Likewise, in the term
"(cycloalkyl)alkoxy", cycloalkyl and alkoxy are as define above,
and the point of attachment in the oxygen of the alkoxy group. The
term "cycloalkyloxy" indicates a cycloalkyl group, as defined
above, attached through an oxygen bridge.
[0063] "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 atoms. Examples of haloalkyl include, but are not limited
to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and
penta-fluoroethyl.
[0064] "Haloalkoxy" indicates a haloalkyl group as defined above
attached through an oxygen bridge.
[0065] "Halo" or "halogen" as used herein refers to fluoro, chloro,
bromo, or iodo.
[0066] As used herein, the terms "heteroaryl" is intended to
indicate a stable 5- to 7-membered monocyclic or bicyclic or 7- to
10-membered bicyclic heterocyclic ring which contains at least 1
aromatic ring that contains from 1 to 4 heteroatoms selected from
N, O, and S, with remaining ring atoms being carbon. When the total
number of S and O atoms in the heteroaryl group exceeds 1, it is
understood that 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, 2, or 3, more typically 1 or 2. It
is particularly preferred that the total number of S and O atoms in
the aromatic heterocycle is not more than 1.
[0067] Preferred heteroaryl groups include imidazolyl, pyrrolyl,
pyridyl, thiazolyl, pyrazolyl, thiazolyl, pyrimidinyl, and
thienyl.
[0068] The term "heterocycloalkyl" is used to indicate saturated
cyclic groups containing from 1 to about 3 heteroatoms selected
from N, O, and S, with remaining ring atoms being carbon.
[0069] Heterocycloalkyl groups have from 3 to about 8 ring atoms,
and more typically have from 5 to 7 ring atoms. Examples of
heterocycloalkyl groups include morpholinyl, piperazinyl, and
pyrrolidinyl groups.
[0070] As used herein, the term "heterocyclic group" is intended to
include 3 to 7 membered saturated, partially unsaturated, or
aromatic monocyclic groups having at least one atom selected from
N, O or S. The remaining ring atoms are carbon. 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 that 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 atom
in the heterocycle may optionally be quaternized. It is preferred
that the total number of heteroatoms in the heterocyclic groups is
not more than 4 and that the total number of S and O atoms in the
heterocyclic group is not more than 2, more preferably not more
than 1.
[0071] Additional examples of heteroaryl and heterocyclic groups
include, but are not limited to, pyrimidinyl, pyridyl, quinolinyl,
benzothienyl, indolyl, pryidazinyl, pyazinyl, isoindolyl,
isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl,
isoxazolyl, pyrazolyl, oxazolyl, thienyl, thiazolyl, indolizinyl,
indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl,
benzoisoxolyl, dihydro-benzodioxinyl, furanyl, pyrrolyl,
oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl,
imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl,
carbazolyl, beta-carbolinyl, isochromanyl, chromanonyl, chromanyl,
tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl,
isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl,
pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl,
purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl,
pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl,
dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,
dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl,
coumarinyl, isocoumarinyl, chromanyl, tetrahydroquinolinyl,
dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl,
dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl,
benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl
N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl
N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,
quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,
imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl
N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl
N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl
N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl
N-oxide, benzothiopyranyl S-oxide, and benzothiopyranyl
S,S-dioxide.
[0072] The term "oxo" indicates a carbonyl group. When an oxo group
appears as a substituent the allowed valence of the substituted
position is not exceeded.
GABA Receptor Ligands
[0073] The invention includes certain compounds and
pharmaceutically acceptable salts of Formula I (shown above) in
which the variables, e.g. R.sub.1, R.sub.2, R.sub.3, R.sub.4, Q,
and W, carry the following definitions:
[0074] R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are independently
selected from: [0075] (i) hydrogen, halogen, hydroxy, nitro, cyano,
amino, halo(C.sub.1-C.sub.6) alkyl, and
halo(C.sub.1-C.sub.6)alkoxy, [0076] (ii) (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
((C.sub.3-C.sub.8)cycloalkyl)(C.sub.1-C.sub.4)alkyl,
--NH(R.sub.10), --N(R.sub.10)(R.sub.11),
hydroxy(C.sub.1-C.sub.6)alkyl, amino(C.sub.1-C.sub.6)alkyl,
(R.sub.10)NH, (C.sub.1-C.sub.6)alkyl,
(R.sub.10)(R.sub.11)N(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkanoyl, (C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkylsulfonyl, (C.sub.1-C.sub.6)alkylsulfinyl,
(C.sub.1-C.sub.6)alkylthio, mono- and
di(C.sub.1-C.sub.6)alkylaminocarbonyl, and 3- to 8-membered
heterocycloalkyl, aryl, and heteroaryl, each of which is
unsubstituted or substituted with 1, 2, 3, or 4 substituents
independently selected from R.sub.20; [0077] (iii) groups of the
formula: ##STR8## wherein G is (C.sub.1-C.sub.6)alkyl, --O--,
--C(.dbd.O)--, or --CH.sub.2--C(.dbd.O)--, and R.sub.A is 3- to
8-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each
of which is unsubstituted or substituted with 1, 2, 3, or 4 of
R.sub.20; [0078] (iv) groups of the formula: ##STR9## wherein J is
N, CH, or C--(C.sub.1-C.sub.6)alkyl and R.sub.B and R.sub.C are
each independently selected from the group consisting of hydrogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8cycloalkyl)
(C.sub.1-C.sub.4)alkyl, 3- to 8-membered heterocycloalkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.6)alkanoyl, 3- to
8-membered heteroaryl, and mono and
di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl, each of which
is unsubstituted or substituted with 1 or 2 substituents
independently chosen from halogen, hydroxy, cyano, amino, nitro,
C.sub.1-C.sub.6alkoxy, halo(C.sub.1-C.sub.6)alkoxy,
C.sub.1-C.sub.6alkyl and halo(C.sub.1-C.sub.6)alkyl; or R.sub.B and
R.sub.C and the atom to which they are attached form a 4- to
10-membered monocyclic or bicyclic ring, comprising: a) 0, 1, 2 or
3 double bonds, and b) 0, 1, 2 or 3 of oxo, O, S, SO, SO.sub.2, or
N--R.sub.D, wherein RD is (1) hydrogen; or (2) Ar.sub.1,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl, 3- to
8-membered heterocycloalkyl, or Ar.sub.1(C.sub.1-C.sub.6)alkyl
wherein Ar.sub.1 is aryl or heteroaryl, each of which is
unsubstituted or substituted with 1 or 2 substituents independently
chosen from halogen, hydroxy, cyano, amino, nitro,
C.sub.1-C.sub.6alkoxy, and C.sub.1-C.sub.6alkyl; and [0079] (v)
--OC(.dbd.O)R.sub.E, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHR.sub.E,
--C(.dbd.O)NR.sub.ER.sub.F, --S(O).sub.nR.sub.E,
--S(O).sub.nNH.sub.2, --S(O).sub.nNHR.sub.E,
--S(O).sub.nNR.sub.ER.sub.F, --NHC(.dbd.O)R.sub.E,
--C(.dbd.NR.sub.E)R.sub.F, --HC.dbd.N--OH,
--HC.dbd.N(C.sub.1-C.sub.6alkoxy),
--HC.dbd.N(C.sub.1-C.sub.6alkyl), --NR.sub.EC(.dbd.O)R.sub.F,
--NHS(O).sub.nR.sub.E, and --NR.sub.ES(O).sub.nR.sub.F, wherein n
is 0, 1 or 2, where R.sub.E and R.sub.F are independently selected
at each occurrence from (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, 3- to 8-membered heterocycloalkyl,
(C.sub.1-C.sub.6)alkoxy, mono- and di(C.sub.1-C.sub.6)alkylamino,
aryl, and 3- to 8-membered heteroaryl, each of which is
unsubstituted or substituted with 1, 2, or 3 substituents
independently selected from R.sub.30.
[0080] R.sub.5 represents: (i) hydrogen, halogen or cyano; (ii)
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8cycloalkyl)(C.sub.1-C.sub.4)alkyl, or an analogue
of the foregoing that comprises from 1 to 3 double bonds and/or
from 1 to 3 triple bonds, each of which is unsubstituted or
substituted with 1, 2, or 3 substituents independently selected
from R.sub.30; or [0081] (iii) 3- to 8-membered aryl, 3- to
8-membered aryl(C.sub.1-C.sub.4)alkyl, 3- to 8-membered heteroaryl,
or 3- to 8-membered heteroaryl(C.sub.1-C.sub.4)alkyl, each of which
is unsubstituted or substituted with 1, 2, or 3 substituents
independently selected from the group consisting of
halo(C.sub.1-C.sub.6alkyl, amino, --NH(R.sub.10),
--N(R.sub.10)(R.sub.11), carboxamido, (R.sub.10)NHcarbonyl,
(R.sub.10)(R.sub.11)Ncarbonyl, halogen, hydroxy, nitro, cyano,
amino, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy substituted with amino or mono- or
di(C.sub.1-C.sub.6)alkylamino, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.4)alkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.4)alkoxy,
heterocyclo(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, halo(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkoxy, amino(C.sub.1-C.sub.6)alkyl, and mono-
and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl.
[0082] R.sub.10 and R.sub.11, are independently selected from the
group consisting of (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8)cycloalkylalkyl,
aryl, aryl(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkanoyl, and
mono and di(C.sub.1-C.sub.6)alkylaminoalkyl.
[0083] R.sub.20 is independently selected at each occurrence from
the group consisting of halogen, hydroxy, nitro, cyano, amino,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy substituted with amino or mono- or
di(C.sub.1-C.sub.6)alkylamino, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.4)alkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.4)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, mono- and
di(C.sub.1-C.sub.6)alkylamino, amino(C.sub.1-C.sub.6)alkyl, and
mono- and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl.
[0084] R.sub.30 is independently selected at each occurrence from
halogen, hydroxy, nitro, cyano, amino, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkoxy substituted with
amino or mono- or di(C.sub.1-C.sub.6)alkylamino,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.4)alkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.4)alkoxy, 3- to
8-membered heterocycloalkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, halo(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkoxy, mono- and
di(C.sub.1-C.sub.6)alkylamino, amino(C.sub.1-C.sub.6)alkyl, and
mono- and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl.
[0085] Q represents C(R.sub.6)(R.sub.7), N(C.sub.1-C.sub.6alkyl) or
oxygen, wherein R.sub.6 and R.sub.7 independently represent
hydrogen, fluorine, or C.sub.1-C.sub.6alkyl; with the proviso that
Q is not oxygen when X.sub.2 is nitrogen.
[0086] R is independently chosen at each occurrence from halogen,
amino, C.sub.1-C.sub.6alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, C.sub.1-C.sub.6alkoxy,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8cycloalkyl)(C.sub.1-C.sub.4)alkyl,
halo(C.sub.1-C.sub.6)alkyl, haloalkoxy, carboxamido, and 3- to
7-membered carbocyclic and heterocyclic rings, each of which is
unsubstituted substituted with from 1 to 4 substituents
independently selected from halogen, oxo, hydroxy,
C.sub.1-C.sub.4alkyl, and C.sub.1-C.sub.4alkoxy.
[0087] R' is independently chosen at each occurrence from
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl,
C.sub.3-C.sub.8cycloalkyl(C.sub.1-C.sub.4alkyl), and 3- to
7-membered carbocyclic and heterocyclic rings, each of which is
unsubstituted or substituted with from 1 to 4 substituents
independently selected from halogen, oxo, hydroxy,
C.sub.1-C.sub.4alkyl, and C.sub.1-C.sub.4alkoxy.
[0088] W represents 3- to 8-membered aryl or heteroaryl, each of
which is unsubstituted or substituted with from 1 to 4 groups
independently selected from R.sub.30, --C(.dbd.O)OR.sub.E,
--C(.dbd.O)NR.sub.E, --C(O)R.sub.E, --OR.sub.E and
--S(O).sub.mR.sub.E, wherein m is 0, 1, or 2.
[0089] Such compounds will be referred to as compounds of Formula
III. Variables that are not specifically defined in Formula III,
e.g. R.sub.5, carry the values set forth in Formula I.
[0090] The invention further includes compounds and salts of
Formula IV ##STR10## wherein X.sub.3 and X.sub.4 are independently
selected from the group consisting of CH, CR, N, O, S, NH, and
N(C.sub.1-C.sub.6)alkyl provided that at least one of X.sub.1,
X.sub.2, X.sub.3, and X.sub.4 is CH or CR.
[0091] R in Formula IV is independently chosen at each occurrence
from: halogen, amino, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy,
carboxamido, and 3- to 7-membered carbocyclic or heterocyclic
rings, each of which is unsubstituted or substituted with from 1 to
4 substituents independently selected from halogen, oxo, hydroxy,
(C.sub.1-C.sub.4)alkyl, and --O(C.sub.1-C.sub.4alkyl).
[0092] The remaining variables shown in Formula IV, e.g.,
Z.sub.1-Z.sub.6, R.sub.5, and Q carry the definitions given for
compounds of Formula III.
[0093] The invention includes compounds and salts of Formula IV in
which: [0094] Z.sub.1 is CR.sub.1, Z.sub.2 is CR.sub.2, Z.sub.3 is
CR.sub.3, and Z.sub.4 is nitrogen; [0095] Z.sub.1 is CR.sub.1,
Z.sub.2 is CR.sub.2, Z.sub.3 is nitrogen, and Z.sub.4 is CR.sub.4;
[0096] Z.sub.1 is CR.sub.1, Z.sub.2 is nitrogen, Z.sub.3 is
CR.sub.3 and Z.sub.4 is CR.sub.4; or in which [0097] Z.sub.1 is
nitrogen, Z.sub.2 is CR.sub.2, Z.sub.3 is CR.sub.3 and Z.sub.4 is
CR.sub.4.
[0098] The invention includes compounds and salts of Formula IV in
which X.sub.2 is carbon and Q is oxygen. The invention also
includes compounds and salts of Formula IV in which X.sub.2 is
carbon and Q is --NH--, or --N(C.sub.1-C.sub.6alkyl)-. The
invention further includes compounds and salts of Formula IV in
which Q is C(R.sub.6)(R.sub.7).
[0099] The invention is further directed to compounds of Formula
V-Formula XIV shown in Table I. The variables shown in Formula
V-Formula XIV, e.g. Z.sub.1-Z.sub.6, Q, W, R, and R' carry the
definitions set forth in Formula III. In certain preferred
compounds of Formula V-Formula X and Formula XII-Formula XIV these
variables carry the definitions set forth in Formula IV.
TABLE-US-00001 TABLE I ##STR11## Formula V ##STR12## Formula VI
##STR13## Formula VII ##STR14## Formula VIII ##STR15## Formula IX
##STR16## Formula X ##STR17## Formula XI ##STR18## Formula XII
##STR19## Formula XIII ##STR20## Formula XIV
[0100] The invention includes compounds and salts of Formula
V-Formula XIV in which Q is C(R.sub.6)(R.sub.7).
[0101] The invention also pertains to compounds of Formula
V-Formula XIV in which Q is C(R.sub.6)(R.sub.7); R is independently
selected from the group consisting of: (i) hydrogen, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkoxy; and (ii) phenyl and pyridyl, each of
which is unsubstituted or substituted with from 1 to 3 substituents
independently chosen from halogen, hydroxy, C.sub.1-C.sub.4alkyl,
and C.sub.1-C.sub.4alkoxy; and R' is independently chosen at each
occurrence from C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl,
and C.sub.3-C.sub.8cycloalkyl(C.sub.1-C.sub.4alkyl).
[0102] R.sub.1, R.sub.2, R.sub.3, and/are independently selected
from: [0103] (i) hydrogen, halogen, hydroxy, nitro, cyano and
amino; [0104] (ii) (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkanoyl, (C.sub.2-C.sub.6)alkyl ether,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, 3- to
8-membered heterocycloalkyl, 3- to 8-membered heteroaryl,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, mono and
di(C.sub.1-C.sub.6)alkylamino, amino(C.sub.1-C.sub.6)alkyl, and
mono- and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl, each
of which is unsubstituted or substituted with 1 or substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy; and [0105]
(iii) groups of the formula ##STR21## wherein R.sub.A is 5- to
7-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each
of which is unsubstituted or substituted with 1 or 2 substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkoxy.
[0106] R.sub.5, for these embodiments of the invention, represents
hydrogen, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl, phenyl, benzyl,
thiophenyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, or
pyrimidinyl.
[0107] R.sub.6 and R.sub.7 independently represent hydrogen,
fluorine, or C.sub.1-C.sub.6 alkyl.
[0108] W represents phenyl, thienyl, thiazolyl, pyridyl,
imidazolyl, pyrazolyl, isoxazolyl, or pyrimidinyl, each of which is
unsubstituted or substituted with from 1 to 4 groups independently
selected from R.sub.30. R.sub.30 carries the definition set forth
for compounds and salts of Formula III.
[0109] The invention is further directed to compounds and
pharmaceutically acceptable salts of Formula XV-Formula XXIV shown
in Table II. The variables shown in Formula XV-Formula XXIV carry
the definitions set forth in Formula IV. TABLE-US-00002 TABLE II
##STR22## Formula XV ##STR23## Formula XVII ##STR24## Formula XVIII
##STR25## Formula XIX ##STR26## Formula XX ##STR27## Formula XXI
##STR28## Formula XXII ##STR29## Formula XXIII ##STR30## Formula
XXIII ##STR31## Formula XXIV
[0110] Preferred compounds and salts of Formula XV-Formula XXIV are
those wherein Q is C(R.sub.6)(R.sub.7).
[0111] Other preferred compounds and salts of Formula XV-Formula
XXIV are those wherein Q is C(R.sub.6)(R.sub.7); and R is
independently selected from the group consisting of (i) hydrogen,
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl and
halo(C.sub.1-C.sub.6)alkoxy, and (ii) phenyl and pyridyl, each of
which is unsubstituted or substituted with from 1 to 3 substituents
independently chosen from halogen, hydroxy, C.sub.1-C.sub.4alkyl,
and C.sub.1-C.sub.4alkoxy.
[0112] R.sub.1, R.sub.2, R.sub.3, and R.sub.4 in these embodiments
of the invention are independently selected from: [0113] (i)
hydrogen, halogen, hydroxy, nitro, cyano and amino; [0114] (ii)
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkanoyl, (C.sub.1-C.sub.6)alkyl ether,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, 3- to
8-membered heterocycloalkyl, 3- to 8-membered heteroaryl,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, mono and
di(C.sub.1-C.sub.6)alkylamino, amino(C.sub.1-C.sub.6)alkyl, and
mono- and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl, each
of which is unsubstituted or substituted with 1 or substituents
independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy; and [0115]
(iii) groups of the formula ##STR32## [0116] wherein R.sub.A is 5-
to 7-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl,
each of which is unsubstituted or substituted with 1 or 2
substituents independently selected from hydroxy, halogen,
(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkoxy.
[0117] R.sub.5 represents hydrogen, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl, phenyl, benzyl,
thiophenyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, or
pyrimidinyl. Preferably R.sub.5 represents hydrogen, halogen, or
(C.sub.1-C.sub.6)alkyl.
[0118] R.sub.6 and R.sub.7 independently represent hydrogen,
fluorine, or C.sub.1-C.sub.6alkyl.
[0119] W represents phenyl, thienyl, thiazolyl, pyridyl,
imidazolyl, pyrazolyl, isoxazolyl, or pyrimidinyl, each of which is
unsubstituted or substituted with from 1 to 4 groups independently
selected from R.sub.30. Preferably W represents phenyl, 2-thiazoyl,
or 2-pyridyl, each of which is unsubstituted or substituted with
from 1 to 4 groups independently selected from R.sub.30. R.sub.30
carries the definition set forth in Formula III.
[0120] The invention also includes compounds of Formula V-Formula
XXIV wherein R.sub.1 and R.sub.4 are independently selected from
hydrogen, halogen, methyl, ethyl, methoxy, and ethoxy.
[0121] The invention includes compounds of Formula I and Formula II
in which the group represented by ##STR33## represents an
imidazolyl or pyrrolyl group, each of which may be unsubstituted or
substituted at each carbon atom by R, and unsubstituted or
substituted at each nitrogen atom available for substitution by R'
where R, R' and W, carry the definitions set forth above.
[0122] Additionally the invention includes compounds and
pharmaceutically acceptable salts of Formula V-Formula XXIV wherein
R.sub.1 and R.sub.4 are independently chosen from hydrogen,
halogen, C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy,
C.sub.1-C.sub.6alkyl, hydroxyC.sub.1-C.sub.6alkyl, and
C.sub.1-C.sub.6alkoxy. Preferably R.sub.1 and R.sub.4 are
independently chosen from hydrogen, ethyl, methyl, methoxy, and
1-hydroxy-ethyl. In certain preferred embodiments, the invention
includes compounds of Formula V-Formula XXIV in which R.sub.1 and
R.sub.4 are both hydrogen.
[0123] Preferred values of R.sub.2 for compounds and
pharmaceutically acceptable salts of Formula V-Formula XXIV include
hydrogen, cyano, halogen, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.6alkyl,
hydroxyC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, and
heterocycloalkyl. Particularly preferred values of R.sub.2 for
compounds Formula V-Formula XXIV include hydrogen, cyano, bromo,
chloro, methyl, ethyl, methoxy, trifluoromethyl, and
pyrrolidinyl.
[0124] In certain embodiments R.sub.3 for compounds and
pharmaceutically acceptable salts of Formula V-Formula XXIV is
chosen from hydrogen, cyano, halogen, C.sub.1-C.sub.2haloalkyl,
C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkenyl substituted with
hydroxy, mono- and di-C.sub.1-C.sub.6alkylamino,
C.sub.1-C.sub.3alkanoyl, hydroxyC.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkoxy substituted with
hydroxy, heteroaryl, heterocycloalkyl, and phenyl which is
optionally substituted with one or more of halogen,
C.sub.1-C.sub.2alkyl, C.sub.1-C.sub.2alkoxy, and
C.sub.1-C.sub.2haloalkyl. The invention particularly includes
compounds and salts of Formula V-Formula XXIV those wherein R.sub.3
is chosen from hydrogen, chloro, fluoro, bromo, methyl,
methylamino, dimethylamino, 1,3,4-oxadiazolyl, thienyl,
1,3-thiazolyl, pyridyl, acetyl, trifluoromethyl,
3-hydroxy-3-methylbutoxy, 2-hydroxy-2-methyl-3-butenyl, phenyl,
methylphenyl, methoxyphenyl, and trifluormethylphenyl. In certain
preferred embodiments R.sub.3 in compounds and salts of Formula
V-Formula XXIV is chosen from hydrogen, C.sub.1-C.sub.6 alkyl,
acetyl, cyano, and trifluoromethyl.
[0125] The invention particularly includes compounds and salts of
Formula V-Formula XXIV in which R.sub.5 is ethyl or propyl.
[0126] Preferred values of W for compounds and salts of Formula
V-Formula XXIV include phenyl, thiazolyl, pyridyl, and pyrimidinyl,
each of which is unsubstituted or substituted with 1 or 2 groups
independently chosen from halogen, C.sub.1-C.sub.2alkyl,
C.sub.1-C.sub.2alkoxy, and C.sub.1-C.sub.2 haloalkyl. The invention
particularly includes compounds and salts of Formula V-Formula XXIV
in which W is selected from thiazolyl, pyrimidinyl, phenyl,
2-pyridyl, 3-fluorophenyl and 3-fluoro-2-pyridyl.
[0127] As an additional embodiment, invention includes compounds
and pharmaceutically acceptable salts of Formula II (shown above)
in which R.sub.1 and R.sub.2 are independently selected from
hydrogen, halogen, nitro, cyano, halo(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkoxy, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, C.sub.3-C.sub.7cycloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
(C.sub.3-C.sub.7)cycloalkyl) C.sub.1-C.sub.4alkyl, mono and
di(C.sub.1-C.sub.6)alkylamino, and amino(C.sub.1-C.sub.6)alkyl.
[0128] R.sub.5 in this embodiment of the invention represents: (i)
hydrogen, halogen, cyano, or haloalkyl; (ii)
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8cycloalkyl)(C.sub.1-C.sub.4)alkyl, each of which
comprises from 0 to 3 double bonds and/or from 0 to 3 triple bonds,
each of which is unsubstituted or substituted with 1, 2, or 3
substituents independently selected from R.sub.30; or (iii) aryl,
aryl(C.sub.1-C.sub.4)alkyl, 3- to 8-membered heteroaryl, or 3- to
8-membered heteroaryl(C.sub.1-C.sub.4)alkyl, each of which is
unsubstituted or substituted with 1, 2, or 3 substituents
independently selected from the group consisting of
(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, amino,
--NH(R.sub.10), --N(R.sub.10)(R.sub.11), carboxamido,
(R.sub.10)NHcarbonyl, (R.sub.10)(R.sub.11)Ncarbonyl, halogen,
hydroxy, nitro, cyano, amino, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy substituted with amino or mono- or
di(C.sub.1-C.sub.6)alkylamino, halo(C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.4)alkyl,
(C.sub.3-C.sub.8)cycloalkyl (C.sub.1-C.sub.4)alkoxy,
heterocyclo(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, amino(C.sub.1-C.sub.6) alkyl, and mono-
and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl.
[0129] Q represents C(R.sub.6)(R.sub.7), N(C.sub.1-C.sub.6alkyl) or
oxygen, wherein R.sub.6 and R.sub.7 independently represent
hydrogen, fluorine, or (C.sub.1-C.sub.6)alkyl; with the proviso
that Q is not oxygen when X.sub.2 is nitrogen.
[0130] R.sub.10 and R.sub.11 are independently selected from the
group consisting of (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.4)alkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.6)alkanoyl, and mono and
di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl.
[0131] R.sub.30 is independently selected at each occurrence from
halogen, hydroxy, nitro, cyano, amino, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkoxy substituted with
amino or mono- or di(C.sub.1-C.sub.6)alkylamino,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.4)alkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.4)alkoxy, 3- to
8-membered heterocyclo(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, mono- and
di(C.sub.1-C.sub.6)alkylamino, amino(C.sub.1-C.sub.6)alkyl, and
mono- and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl.
[0132] R is independently chosen at each occurrence from halogen,
amino, C.sub.1-C.sub.6alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, C.sub.1-C.sub.6alkoxy,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8cycloalkyl)(C.sub.1-C.sub.4)alkyl,
halo(C.sub.1-C.sub.6)alkyl, haloalkoxy, carboxamido, and 3- to
7-membered carbocyclic and heterocyclic rings, each of which is
unsubstituted or substituted with from 1 to 4 substituents
independently selected from halogen, oxo, hydroxy,
C.sub.1-C.sub.4alkyl, and C.sub.1-C.sub.4alkoxy.
[0133] R' is independently chosen at each occurrence from
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl,
C.sub.3-C.sub.8cycloalkyl(C.sub.1-C.sub.4alkyl), and 3- to
7-membered carbocyclic and heterocyclic rings, each of which is
unsubstituted or substituted with from 1 to 4 substituents
independently selected from halogen, oxo, hydroxy,
C.sub.1-C.sub.4alkyl, and C.sub.1-C.sub.4alkoxy.
[0134] W represents 3- to 8-membered aryl or heteroaryl, each of
which is unsubstituted or substituted with from 1 to 4 groups
independently selected from R.sub.30, --C(.dbd.O)OR.sub.E,
--C(.dbd.O)NR.sub.E, --C(O)R.sub.E, --OR.sub.E and
--S(O).sub.mR.sub.E, wherein m is 0, 1, or 2. R.sub.E carries the
definition set forth for compounds of Formula II. Such compounds
will be referred to as compounds of Formula XV.
[0135] The invention includes compounds and pharmaceutically
acceptable salts of Formula XVI ##STR34## [0136] R.sub.5 in this
embodiment of the invention represents hydrogen, halogen, or
(C.sub.1-C.sub.6)alkyl, and R.sub.6 and R.sub.7 independently
represent hydrogen or (C.sub.1-C.sub.6)alkyl. The remaining
variables shown in Formula XVI, e.g., R.sub.1 and R.sub.2 carry the
definitions set forth in Formula XVI.
[0137] Certain preferred compounds and salts of Formula XVI are
those wherein W represents phenyl, 2-thiazoyl, or 2-pyridyl, each
of which is unsubstituted or substituted with from 1 to 4 groups
independently selected from R.sub.30.
[0138] Other preferred compounds and salts of Formula XVI are those
wherein W represents phenyl, 2-thiazoyl, or 2-pyridyl, each of
which is unsubstituted or substituted with from 1 to 4 groups
independently selected from R.sub.30 and R.sub.1 and R.sub.2 are
independently selected from hydrogen, halogen, nitro, cyano,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
heterocycloalkyl, halo(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkoxy, mono and
di(C.sub.1-C.sub.6)alkylamino, amino(C.sub.1-C.sub.6)alkyl, and
mono- and di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl.
[0139] This invention relates to heteroaryl substituted fused
bicyclic heteroaryl compounds, such as heteroaryl substituted
imidazopyridines, imidazopyrazines, imidazopyridizines,
imidazopyrimidines, and imidazothiazoles, preferred examples of
which bind with high affinity to the benzodiazepine site of
GABA.sub.A receptors, including human GABA.sub.A receptors.
Affinity of a compound of Formula I or Formula II for GABA.sub.A
receptors may be determined using a standard GABA.sub.A receptor
radioligand binding assay such as the assay given in Example 17.
Preferred compounds of Formula I and/or Formula II exhibit a
K.sub.i of less than 1 micromolar in a GABA.sub.A receptor
radioligand binding assay such as the assay given in Example 17, or
more preferably less than 100 nM or most preferably less than 10 nM
in such and assay. Preferred benzimidazole and pyridylimidazole
derivatives that bind with high selectivity to the benzodiazepine
site of GABA.sub.A receptors, including human GABA.sub.A receptors,
are also included in this invention. Without wishing to be bound to
any particular theory, it is believed that the interaction of the
compounds of Formula I and Formula II with the benzodiazepine site
results in the pharmaceutical utility of these compounds.
[0140] The invention further comprises methods of treating patients
in need of such treatment with an amount of a compound of the
invention sufficient to alter the symptoms of a CNS disorder.
Compounds of Formula I and/or Formula II that exhibit agonist or
inverse agonist activity at particular receptor subtypes are
particularly useful for treating certain CNS disorders. For
example, compounds of Formula I and/or Formula II that act as
agonists at .alpha..sub.2.beta..sub.3.gamma..sub.2 and
.alpha..sub.3.beta..sub.3.gamma..sub.2 receptor subtypes are useful
in treating anxiety disorders such as panic disorder, obsessive
compulsive disorder and generalized anxiety disorder; stress
disorders including post-traumatic stress, and acute stress
disorders. Compounds of the inventions that act as agonists at
.alpha..sub.2.beta..sub.3.gamma..sub.2 and
.alpha..sub.3.beta..sub.3.beta..sub.2 receptor subtypes are also
useful in treating depressive or bipolar disorders and in treating
sleep disorders. Compounds of the invention that act as inverse
agonists at the .alpha..sub.5.beta..sub.3.gamma..sub.2 receptor
subtype or .alpha..sub.1.beta..sub.2.gamma..sub.2 and
.alpha..sub.5.beta..sub.3.gamma..sub.2 receptor subtypes are useful
in treating cognitive disorders including those resulting from Down
Syndrome, neurodegenerative diseases such as Alzheimer's disease
and Parkinson's disease, and stroke related dementia. Compounds of
the invention that act as inverse agonists at the
.alpha..sub.5.beta..sub.3.gamma..sub.2 are particularly useful in
treating cognitive disorders through the enhancement of memory, and
particularly short-term memory, in memory-impaired patients.
Compounds of the invention that act as agonists at the
.alpha..sub.1.beta..sub.2.gamma..sub.2 receptor subtype are useful
in treating convulsive disorders such as epilepsy. Compounds that
act as antagonists at the benzodiazepine site are useful in
reversing the effect of benzodiazepine overdose and in treating
drug and alcohol addiction.
[0141] The diseases and/or disorders that can also be treated using
compounds and compositions according to the invention include:
[0142] Depression, e.g. depression, atypical depression, bipolar
disorder, depressed phase of bipolar disorder. [0143] Anxiety, e.g.
general anxiety disorder (GAD), agoraphobia, panic disorder
+/-agoraphobia, social phobia, specific phobia, Post traumatic
stress disorder, obsessive compulsive disorder (OCD), dysthymia,
adjustment disorders with disturbance of mood and anxiety,
separation anxiety disorder, anticipatory anxiety acute stress
disorder, adjustment disorders, cyclothymia. [0144] Sleep
disorders, e.g. sleep disorders including primary insomnia,
circadian rhythm sleep disorder, dyssomnia NOS, parasomnias,
including nightmare disorder, sleep terror disorder, sleep
disorders secondary to depression and/or anxiety or other mental
disorders, substance induced sleep disorder. [0145] Cognition
Impairment, e.g. cognition impairment, memory impairment,
short-term memory impairment, Alzheimer's disease, Parkinson's
disease, mild cognitive impairment (MCI), age-related cognitive
decline (ARCD), stroke, traumatic brain injury, AIDS associated
dementia, and dementia associated with depression, anxiety or
psychosis. [0146] Attention Deficit Disorder, e.g. attention
deficit disorder (ADD), and attention deficit and hyperactivity
disorder (ADHD). [0147] Speech disorders, e.g. stuttering,
including motor tic, clonic stuttering, dysfluency, speech
blockage, dysarthria, Tourete's syndrome or logospasm. [0148]
Psychosis e.g. schizophrenia, hallucinatory disorders
[0149] The invention also provides pharmaceutical compositions
comprising one or more compounds of the invention together with a
pharmaceutically acceptable carrier or excipient, for treating
disorders responsive to GABA.sub.A receptor modulation, e.g.,
treatment of anxiety, depression, sleep disorders or cognitive
impairment by GABA.sub.A receptor modulation. Pharmaceutical
compositions include packaged pharmaceutical compositions
comprising a container holding a therapeutically effective amount
of at least one GABA.sub.A receptor modulator as described supra
and instructions (e.g., labeling) indicating the contained
GABA.sub.A receptor ligand is to be used for treating a disorder
responsive to GABA.sub.A receptor modulation in the patient.
[0150] In a separate aspect, the invention provides a method of
potentiating the actions of other CNS active compounds, which
comprises administering an effective amount of a compound of the
invention in combination with another CNS active compound. Such CNS
active compounds include, but are not limited to the following: for
anxiety, serotonin receptor (e.g. 5-HT.sub.1A) agonists and
antagonists; for anxiety and depression, neurokinin receptor
antagonists or corticotropin releasing factor receptor (CRF.sub.1)
antagonists; for sleep disorders, melatonin receptor agonists; and
for neurodegenerative disorders, such as Alzheimer's dementia,
nicotinic agonists, muscarinic agents, acetylcholinesterase
inhibitors and dopamine receptor agonists. Particularly the
invention provides a method of potentiating the antidepressant
activity of selective serotonin reuptake inhibitors (SSRIs) by
administering an effective amount of a GABA agonist compound of the
invention in combination with an SSRI.
[0151] Combination administration can be carried out in a fashion
analogous to that disclosed in Da-Rocha, et al., J.
Psychopharmacology (1997) 11(3) 211-218; Smith, et al., Am. J.
Psychiatry (1998) 155(10) 1339-45; or Le, et al., Alcohol and
Alcoholism (1996) 31 Suppl. 127-132. Also see, the discussion of
the use of the GABA.sub.A receptor ligand
3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)
methyloxy-1,2,4-triazolo [3,4-a]phthalzine in combination with
nicotinic agonists, muscarinic agonists, and acetylcholinesterase
inhibitors, in PCT International publications Nos. WO 99/47142, WO
99/47171, and WO 99/47131, respectively. Also see in this regard
PCT International publication No. WO 99/37303 for its discussion of
the use of a class of GABA.sub.A receptor ligands,
1,2,4-triazolo[4,3-b]pyridazines, in combination with SSRIs.
[0152] The present invention also pertains to methods of inhibiting
the binding of benzodiazepine compounds, such as Ro15-1788
(flumazenil), or GABA to the GABA.sub.A receptors which methods
involve contacting a solution containing compound of the invention
with cells expressing GABA.sub.A receptors, wherein the compound is
present at a concentration sufficient to inhibit benzodiazepine
binding or GABA binding to GABA.sub.A receptors in vitro. This
method includes inhibiting the binding of benzodiazepine compounds
to GABA.sub.A receptors in vivo, e.g., in a patient given an amount
of a compound of Formula I or Formula II that would be sufficient
to inhibit the binding of benzodiazepine compounds or GABA to
GABA.sub.A receptors in vitro. In one embodiment, such methods are
useful in treating benzodiazepine drug overdose. The amount of a
compound that would be sufficient to inhibit the binding of a
benzodiazepine compound to the GABA.sub.A receptor may be readily
determined via a GABA.sub.A receptor binding assay, such as the
assay described in Example 17. The GABA.sub.A receptors used to
determine in vitro binding may be obtained from a variety of
sources, for example from preparations of rat cortex or from cells
expressing cloned human GABA.sub.A receptors.
[0153] The present invention also pertains to methods for altering
the signal-transducing activity, particularly the chloride ion
conductance of GABA.sub.A receptors, said method comprising
exposing cells expressing such receptors to an effective amount of
a compound of the invention. This method includes altering the
signal-transducing activity of GABA.sub.A receptors in vivo, e.g.,
in a patient given an amount of a compound of Formula I or Formula
II that would be sufficient to alter the signal-transducing
activity of GABA.sub.A receptors in vitro. The amount of a compound
that would be sufficient to alter the signal-transducing activity
of GABA.sub.A receptors may be determined via a GABA.sub.A receptor
signal transduction assay, such as the assay described in Example
18. The cells expressing the GABA receptors in vivo may be, but are
not limited to, neuronal cells or brain cells. Such cells may be
contacted with compounds of the invention through contact with a
body fluid containing the compound, for example through contact
with cerebrospinal fluid. Alteration of the signal-transducing
activity of GABA.sub.A receptors in vitro may be determined from a
detectable change in the electrophysiology of cells expressing
GABA.sub.A receptors, when such cells are contacted with a compound
of the invention in the presence of GABA.
[0154] Intracellular recording or patch-clamp recording may be used
to quantitate changes in electrophysiology of cells. A reproducible
change in behavior of an animal given a compound of the invention
may also be used to indicate that changes in the electrophysiology
of the animal's cells expressing GABA.sub.A receptors has
occurred.
[0155] The GABA.sub.A receptor ligands provided by this invention
and labeled derivatives thereof are also useful as standards and
reagents in determining the ability of a potential pharmaceutical
to bind to the GABA.sub.A receptor. Radiolabeled derivatives the
GABA.sub.A receptor ligands provided by this invention are also
useful as radiotracers for positron emission tomography (PET)
imaging or for single photon emission computerized tomography
(SPECT).
[0156] More particularly compounds of the invention may be used for
demonstrating the presence of GABA.sub.A receptors in cell or
tissue samples. This may be done by preparing a plurality of
matched cell or tissue samples, at least one of which is prepared
as an experimental sample and at least one of which is prepared as
a control sample. The experimental sample is prepared by contacting
(under conditions that permit binding of RO15-1788 to GABA.sub.A
receptors within cell and tissue samples) at least one of the
matched cell or tissue samples that has not previously been
contacted with any compound or salt of the invention with an
experimental solution comprising the detectably-labeled preparation
of the selected compound or salt at the first measured molar
concentration. The control sample is prepared by in the same manner
as the experimental sample and also contains an unlabelled
preparation of the same compound or salt of the invention at a
greater molar concentration.
[0157] The experimental and control samples are then washed to
remove unbound detectably-labeled compound. The amount of remaining
bound detectably-labeled compound is then measured and the amount
of detectably-labeled compound in the experimental and control
samples is compared. A comparison that indicates the detection of a
greater amount of detectable label in the at least one washed
experimental sample than is detected in any of control samples
demonstrates the presence of GABA.sub.A receptors in that
experimental sample.
[0158] The detectably-labeled compound used in this procedure may
be labeled with a radioactive label or a directly or indirectly
luminescent label. When tissue sections are used in this procedure
and the detectably-labeled compound is radiolabeled, the bound,
labeled compound may be detected autoradiographically to generate
an autoradiogram. The amount of detectable label in an experimental
or control sample may be measured by viewing the autoradiograms and
comparing the exposure density of the autoradiograms.
Pharmaceutical Compositions
[0159] The compounds of general Formulas I may be administered
orally, topically, parenterally, by inhalation or spray or rectally
in dosage unit formulations containing conventional non-toxic
pharmaceutically acceptable carriers, adjuvants and vehicles. Oral
administration in the form of a pill, capsule, elixir, syrup,
lozenge, troche, or the like is particularly preferred. The term
parenteral as used herein includes subcutaneous injections,
intradermal, intravascular (e.g., intravenous), intramuscular,
spinal, intrathecal injection or like injection or infusion
techniques. In addition, there is provided a pharmaceutical
formulation comprising a compound of general Formula I and/or a
compound of general Formula II and a pharmaceutically acceptable
carrier. One or more compounds of general Formula I or Formula II
may be present in association with one or more non-toxic
pharmaceutically acceptable carriers and/or diluents and/or
adjuvants and if desired other active ingredients. The
pharmaceutical compositions containing compounds of general Formula
I and/or Formula II may be in a form suitable for oral use, for
example, as tablets, troches, lozenges, aqueous or oily
suspensions, dispersible powders or granules, emulsion, hard or
soft capsules, or syrups or elixirs.
[0160] Compositions intended for oral use may be prepared according
to any method known to the art for the manufacture of
pharmaceutical compositions and such compositions may contain one
or more agents selected from the group consisting of sweetening
agents, flavoring agents, coloring agents and preserving agents in
order to provide pharmaceutically elegant and palatable
preparations. Tablets contain the active ingredient in admixture
with non-toxic pharmaceutically acceptable excipients that are
suitable for the manufacture of tablets. These excipients may be
for example, inert diluents, such as calcium carbonate, sodium
carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or
alginic acid; binding agents, for example starch, gelatin or
acacia, and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monosterate or glyceryl distearate may be
employed.
[0161] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin or olive oil.
[0162] Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone,
gum tragacanth and gum acacia; dispersing or wetting agents may be
a naturally-occurring phosphatide, for example, lecithin, or
condensation products of an alkylene oxide with fatty acids, for
example polyoxyethylene stearate, or condensation products of
ethylene oxide with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene
oxide with partial esters derived from fatty acids and a hexitol
such as polyoxyethylene sorbitol monooleate, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and hexitol anhydrides, for example polyethylene sorbitan
monooleate. The aqueous suspensions may also contain one or more
preservatives, for example ethyl, or n-propyl p-hydroxybenzoate,
one or more coloring agents, one or more flavoring agents, and one
or more sweetening agents, such as sucrose or saccharin.
[0163] Oily suspensions may be formulated by suspending the active
ingredients in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide palatable oral preparations. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0164] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
[0165] Pharmaceutical compositions of the invention may also be in
the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example olive oil or peanut oil, or a mineral
oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally-occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol, anhydrides, for example sorbitan
monoleate, and condensation products of the said partial esters
with ethylene oxide, for example polyoxyethylene sorbitan
monoleate. The emulsions may also contain sweetening and flavoring
agents.
[0166] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and
flavoring and coloring agents. The pharmaceutical compositions may
be in the form of a sterile injectable aqueous or oleaginous
suspension. This suspension may be formulated according to the
known art using those suitable dispersing or wetting agents and
suspending agents which have been mentioned above. The sterile
injectable preparation may also be sterile injectable solution or
suspension in a non-toxic parentally acceptable diluent or solvent,
for example as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's
solution and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For this purpose any bland fixed oil may be
employed including synthetic mono- or diglycerides. In addition,
fatty acids such as oleic acid find use in the preparation of
injectables.
[0167] The compounds of general Formulas I may also be administered
in the form of suppositories, e.g., for rectal administration of
the drug. These compositions can be prepared by mixing the drug
with a suitable non-irritating excipient that is solid at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum to release the drug. Such materials
are cocoa butter and polyethylene glycols.
[0168] Compounds of general Formulas I may be administered
parenterally in a sterile medium. The drug, depending on the
vehicle and concentration used, can either be suspended or
dissolved in the vehicle. Advantageously, adjuvants such as local
anesthetics, preservatives and buffering agents can be dissolved in
the vehicle.
[0169] For administration to non-human animals, the composition may
also be added to the animal feed or drinking water. It will be
convenient to formulate these animal feed and drinking water
compositions so that the animal takes in an appropriate quantity of
the composition along with its diet. It will also be convenient to
present the composition as a premix for addition to the feed or
drinking water.
[0170] Dosage levels of the order of from about 0.1 mg to about 140
mg per kilogram of body weight per day are useful in the treatment
of the above-indicated conditions (about 0.5 mg to about 7 g per
patient per day). The amount of active ingredient that may be
combined with the carrier materials to produce a single dosage form
will vary depending upon the host treated and the particular mode
of administration. Dosage unit forms will generally contain between
from about 1 mg to about 500 mg of an active ingredient.
[0171] Frequency of dosage may also vary depending on the compound
used and the particular disease treated. However, for treatment of
most disorders, a dosage regimen of 4 times daily or less is
preferred. For the treatment of anxiety, depression, or cognitive
impairment a dosage regimen of 1 or 2 times daily is particularly
preferred. For the treatment of sleep disorders a single dose that
rapidly reaches effective concentrations is desirable.
[0172] It will be understood, however, that the specific dose level
for any particular patient will depend upon a variety of factors
including the activity of the specific compound employed, the age,
body weight, general health, sex, diet, time of administration,
route of administration, and rate of excretion, drug combination
and the severity of the particular disease undergoing therapy.
[0173] Preferred compounds of the invention will have certain
pharmacological properties. Such properties include, but are not
limited to high solubility (preferably 500 ng/ml or more) in
aqueous solutions, oral bioavailability, low toxicity, low serum
protein binding, lack of clinically relevant EKG effects, and
desirable in vitro and in vivo half-lifes. Penetration of the blood
brain barrier for compounds used to treat CNS disorders is
necessary, while low brain levels of compounds used to treat
periphereal disorders are often preferred.
[0174] Assays may be used to predict these desirable
pharmacological properties. Assays used to predict bioavailability
include transport across human intestinal cell monolayers,
including Caco-2 cell monolayers. Toxicity to cultured hepatocyctes
may be used to predict compound toxicity. Penetration of the blood
brain barrier of a compound in humans may be predicted from the
brain levels of the compound in laboratory animals given the
compound intravenously.
[0175] Serum protein binding may be predicted from albumin binding
assays. Such assays are described in a review by Oravcova, et al.
(Journal of Chromatography B (1996) volume 677, pages 1-27).
[0176] Compound half-life is inversely proportional to the
frequency of dosage of a compound. In vitro half-lifes of compounds
may be predicted from assays of microsomal half-life as described
by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998)
volume 26, pages 1120-1127).
EXAMPLES
Preparation of Compounds
[0177] A general illustration of the preparation of compounds of
Formula I and Formula XXVI in the present invention is given in
Schemes 1-9. The following abbreviations are used in the reaction
schemes and examples which follow: [0178]
AIBN--2,2'-Azabisisobutronitrile [0179] DIBAL-H--Diisobutylaluminum
hydride [0180] LDA--Lithium diisopropylamide [0181]
NBS--N-bromosuccinamide [0182] NCS--N-chlorosuccinamide [0183]
THF--tetrahydrofuran ##STR35##
[0184] Scheme 1 shows a route for synthesizing chloromethyl or
mesylmethyl fused imidazo compounds used in the preparation of
compounds of Formula I. Step 1 involves reaction of an
alpha-bromoketoester with a 2-aminopyridine, 2-aminopyrmidine,
2-aminopyrazine, 4-aminopyrimidine, 3-aminopyridazine or other
appropriate aminoheteroaromatic to form an imidazo acid ester. The
requisite alpha-bromoketoester is prepared by reaction of the
corresponding alpha-hydroxyester with N-bromosuccinimide (wherein
R'' is alkyl) in carbon tetrachloride in the presence of catalytic
AIBN. Step 1 results in an isomeric mixture when Z, is nitrogen. In
step 2, the imdiazo acid ester is reduced to the corresponding
alcohol using diisobutylaluminum hydride, lithium aluminum hydride
or other appropriate reducing agent. Low yields are often obtained
from Step 2 of Scheme 1 when Z.sub.2 or Z.sub.3 is nitrogen. In
cases where reduction of the fused heteroaromatic ring occurs, the
transformation from imdazo acid ester to alcohol may be
accomplished by hydrolyzing the ester, converting the acid to the
acid chloride and treating the acid chloride with sodium
borohydride or other appropriate reducing agent. In step 3, the
alcohol is converted to the corresponding mesylate or chloride by
reaction with thionyl chloride or methanesulfonyl chloride.
Compounds of Formula I with R.sub.5=H may be obtained by reaction
of 1,1'-dichloroacetone with the appropriate aminoheteroaromatic
compound as shown in Step 2'. Those skilled in the art will
recognize that the starting materials, reagents and reactions in
Scheme 1 can be modified to readily obtain a variety of
intermediates used in preparing compounds of Formula I.
##STR36##
[0185] Scheme 2 illustrates two routes to aryl and heteroaryl
imidazoles which are intermediates in the synthesis of selected
compounds of Formula I and Formula II.
[0186] In the first route, an aryl or heteroaryl aldehyde is
treated with glyoxal and ammonium hydroxide to form the
corresponding aryl or heteroaryl imidazole. The second route,
involving palladium (0) catalyzed cross-coupling, is used when
direct conversion of the aryl or heteroaryl aldehyde to aryl or
heteroaryl imidazole provides low yields, e.g., in the preparation
of 2-(1H-imidazolyl-2-yl)-thiazole. In this route,
methoxymethyl-protected imidazole is treated with butyl lithium
followed by tri-n-butyltin chloride to obtain the corresponding
2-(tri-n-butyltin)-imidazole. The 2-(tri-n-butyltin)-imidazole
intermediate must be handled with care to avoid decomposition.
Subsequent palladium (0) catalyzed coupling with an appropriate
aryl or heteroaryl halide (denoted as ArX in scheme 2) provides the
corresponding 2-aryl or 2-heteroaryl methoxymethyl-protected
imidazole. Removal of the methoxymethyl protecting group with acid
provides the desired aryl or heteroaryl imidazole for use in
preparing compounds of Formula I and Formula II. ##STR37##
[0187] Scheme 3 provides a route for preparing compounds of Formula
I by reacting the appropriate chloromethyl fused imidazo compounds
and aryl or heteroaryl imidazoles. In step 1, a chloromethyl fused
imidazo compound is reacted with an aryl or heteroaryl imidazole in
the presence of an appropriate base to form compounds of Formula I.
Appropriate bases include but are not limited to sodium hydride,
potassium carbonate and cesium carbonate. When R.sub.5=H in Scheme
3, step 1' may be employed to produce a chloromethyl fused imidazo
compound with R.sub.5=Br or Cl. Reaction of the resulting
haloimidazo compound with an aryl or heteroaryl imidazole in step
2' provides compounds of Formula I with R.sub.5=Br or Cl. In step
3', a compound of Formula I with R.sub.5=Br is optionally converted
to a compound of Formula I with R.sub.5=methyl via the action of
tetramethyltin in the presence of palladium (0). Steps 1', 2' and
3' provide a convenient method for preparing compounds of Formula I
wherein Z.sub.2 or Z.sub.3 is nitrogen and R.sub.5 is methyl.
##STR38##
[0188] Scheme 4 provides a method for obtaining compounds of
Formula I with substitution at Z.sub.3. Analogous chemistry can be
used to introduce substitution at Z.sub.1, Z.sub.2, or Z.sub.4. In
this scheme, a compound of Formula I with Z.sub.3=halogen
(preferably bromine) is coupled with an aryl or alkyl tin reagent
in the presence of palladium (0) catalyst to obtain a compound of
Formula I with Z.sub.3=aryl or alkyl. Those skilled in the art will
recognize that suitable aryl or alkyl boronic acids may be used in
place of aryl or alkyl tin reagents in some cases. When Z.sub.2 is
nitrogen and Z.sub.3 is Br or Cl, a nitrogen or oxygen nucleophile
(NuH) can be used to displace Z.sub.3 to obtain compounds of
Formula I with Z.sub.2=nitrogen or oxygen. For example, compounds
of Formula I with Z.sub.2=N and Z.sub.3=alkylamino are readily
produced by this route. ##STR39##
[0189] Scheme 5 is used to prepare compounds of Formula I wherein
R.sub.5 is cyano. In this scheme,
imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester is reacted
with formaldehyde in acetic acid to produce the corresponding
hydroxymethyl derivative. Oxidation of the primary alcohol provides
the aldehyde which is subsequently converted to the oxime and
dehydrated to the nitrile. Selective reduction of the ethyl ester
group in 3-cyano-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl
ester provides the corresponding alcohol which is converted to the
chloromethyl derivative and reacted with an aryl or heteroaryl
imidazole as described in Scheme 3. Those skilled in the art will
recognize that this synthetic route can be readily modified to
incorporate alternate starting materials and reagents to synthesize
many other compounds of Formula I, where R.sub.5=CN and Z.sub.1,
Z.sub.2, Z.sub.3 and Z.sub.4 are CR.sub.1, CR.sub.2, CR.sub.2, and
CR.sub.4. ##STR40##
[0190] Scheme 6 is used to prepare compounds of Formula I wherein
R.sub.5 is trifluoromethyl. In this route, known
3-bromo-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester is
produced by bromination of imidazo[1,2-a]pyridine-2-carboxylic acid
ethyl ester with N-bromosuccinamide. The resulting
3-bromo-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester is
reacted with trifluoromethyltriethylsilane in the presence of
potassium fluoride and copper (I) chloride to obtain the
corresponding 3-trifluoromethyl derivative. This material is
converted to compounds of Formula I as described in Schemes 1 and
3. Those skilled in the art will recognize that this synthetic
route can be readily modified to incorporate alternate starting
materials and reagents to synthesize many other compounds of
Formula I, where R.sub.5=CF.sub.3 and Z.sub.1, Z.sub.2, Z.sub.3 and
Z.sub.4 are CR.sub.1, CR.sub.2, CR.sub.2, and CR.sub.4.
##STR41##
[0191] Scheme 7 shows a method of synthesizing aryl and heteroaryl
pyrazole compounds of Formula I. In this route,
2-(2,2-dimethoxyethyl)-[1,3]dithiane (J. Het. Chem. 1987, 1221) is
reacted with n-butyllithium followed by a chloromethyl fused
imidazo compound to produce the corresponding alkylation product.
Removal of the [1,3]dithiane yields the corresponding ketone acetal
derivative. This material is deprotected to the ketone aldehyde and
reacted in situ to obtain the desired pyrazole compounds of Formula
I. Undesired isomeric pyrazole is separated by chromatography on
silica gel. Those skilled in the art will recognize that this
synthetic route can be readily modified to incorporate alternate
starting materials and reagents to synthesize many other pyrazole
compounds of Formula I, including compounds wherein Z.sub.1,
Z.sub.2, Z.sub.3 and Z.sub.4 are N or CR.sub.1, CR.sub.2, CR.sub.2,
and CR.sub.4. ##STR42##
[0192] Scheme .sub.8 illustrates a route for preparing compounds of
Formula I wherein Z.sub.4 and Z.sub.6 are nitrogen. In this route
an alkyl nitrile is condensed with oxalic acid diethyl ester to
obtain the corresponding 3-alkyl-3-cyano-2-oxo-propionic acid ethyl
ester. Treatment of the 3-alkyl-3-cyano-2-oxo-propionic acid ethyl
ester with hydrazine monohydrate provides the
5-amino-4-alkyl-1H-pyrazole-3-carboxylic acid ethyl ester which is
subsequently reacted with 3-oxo-butyric acid ethyl ester or
equivalent reagent to obtain the
3-alkyl-5-methyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]-pyrimidine-2-carboxyli-
c acid ethyl ester. Reduction of the ethyl ester to the
corresponding alcohol is accomplished using diisobutylaluminum
hydride at low temperature. Further synthetic transformations as
previously described in Schemes 1 and 3 provide compounds of
Formula I with Z.sub.4 and Z.sub.6=nitrogen. Those skilled in the
art will recognize that this synthetic route can be readily
modified to incorporate alternate starting materials and reagents
to synthesize many other compounds of Formula I wherein Z.sub.4 and
Z.sub.6 are nitrogen. ##STR43##
[0193] Scheme 9 provides a method for preparing compounds of
Formula II from 2-aminothiazoles. The various synthetic
transformations involved have previously been described in Schemes
1, 3 and 8.
[0194] The invention is illustrated further by the following
examples, which are not to be construed as limiting the invention
in scope or spirit to the specific procedures described in them.
Those having skill in the art will recognize that the starting
materials may be varied and additional steps employed to produce
compounds encompassed by the present inventions, as demonstrated by
the following examples. Unless otherwise stated starting material
and reagents employed in this synthesis are of standard commercial
grade. In some cases, protection of certain reactive
functionalities may be necessary to achieve some of the above
transformations. In general, such need for protecting groups, as
well as the conditions necessary to attach and remove such groups,
will be apparent to those skilled in the art of organic
synthesis.
Example 1
SYNTHESIS OF 3-FLUORO-(1H-IMIDAZOL-2-YL)BENZENE
[0195] ##STR44##
[0196] Saturated ammonium hydroxide solution (30 mL) is slowly
added to a solution of 3-fluorobenzaldehyde (12.4 g, 100 mmol) and
glyoxal (17.5 mL of 40% wt in water, 120 mmol) in methanol (100 mL)
at ambient temperature. After stirring for 24 hours, most of the
solvent is removed at reduced pressure. Benzene is added and
evaporated to remove residual water. The resulting dark oil is
purified by chromatography on silica gel (2% MeOH/CH.sub.2Cl.sub.2)
to obtain a tan solid. Trituration with ether/hexane provides
3-fluoro-(1H-imidazol-2-yl)benzene as a white solid. LRMS m/z (M+1)
163.2.
Example 2
SYNTHESIS OF 3-CHLORO-4-FLUORO-(1H-IMIDAZOL-2-YL)BENZENE
[0197] ##STR45##
[0198] A mixture of 3-chloro-4-fluoro-benzaldehyde (0.032 mol),
glyoxal (40% in water, 0.038 mol) and ammonium hydroxide (28% in
water, 0.16 mol) in MeOH (60 mL) is stirred at room temperature
overnight. Solvent is removed in vacuo and the residue is
partitioned between water and CH.sub.2Cl.sub.2. The organic layer
is washed with brine, dried (Na.sub.2SO.sub.4), and concentrated.
The residue is purified by column chromatography on silica gel
eluting with CH.sub.2Cl.sub.2/MeOH (95/5) to afford
3-chloro-4-fluoro-(1H-imidazol-2-yl)benzene as a yellow solid.
.sup.1H NMR (CDCl.sub.3) .delta. 7.88 (dd, 1H), 7.70 (m, 1H), 7.19
(t, 1H), 7.17 (s, 2H). LRMS m/z (M+1) 197.0.
Example 3
SYNTHESIS OF 2,3,4-TRIFLUORO-(1H-IMIDAZOL-2-YL)BENZENE
[0199] ##STR46##
[0200] Saturated ammonium hydroxide solution (26 mL) is slowly
added to a solution of 2,3,4-trifluorobenzaldehyde (5.0 g, 31.2
mmol) and glyoxal (10.75 mL of 40% wt in water, 93.7 mmol) in
methanol (100 mL) at ambient temperature. After stirring for 24
hours, most of the solvent is removed at reduced pressure. Benzene
is added and evaporated to remove residual water. The resulting
dark oil is purified by chromatography on silica gel (5%
MeOH/CH.sub.2Cl.sub.2) to obtain a tan solid. Trituration with
ether/hexane provides 2,3,4-trifluoro-(1H-imidazol-2-yl)benzene as
a white solid. LRMS m/z (M+1) 199.10.
Example 4
SYNTHESIS OF 1-ETHOXYMETHYL-2-TRIBUTYLSTANNANYL-1H-IMIDAZOLE
[0201] ##STR47##
[0202] 1.6 M n-BuLi (12.0 mL, 19.2 mmol) is slowly added to a
solution of 1-ethoxymethyl-1H-imidazole [available via the
procedure outlined in Tang, C. C.; Davalian, D.; Huang, P.;
Breslow, R. J. Am. Chem. Soc. 1978, 100, 3918] (2.20 g, 17.4 mmol)
in THF (30 mL) at -78.degree. C. under N.sub.2. The reaction
mixture is stirred at -78.degree. C. for 20 minutes whereupon
tributyl tin chloride (5.7 mL, 20.9 mmol) is added slowly. The
reaction mixture is stirred at -78.degree. C. for 10 minutes and
then warmed to room temperature. After stirring at room temperature
for 1.5 hours, the reaction mixture is concentrated in vacuo. The
residue is triturated with hexanes and filtered, and the filtrate
is concentrated in vacuo. The residue is again triturated with
hexanes and filtered, and the filtrate concentrated in vacuo. The
.sup.1H NMR of the resulting oil indicates a 2:1 mixture of
1-ethoxymethyl-2-tributylstannanyl-1H-imidazole:
1-ethoxymethyl-1H-imidazole. This material is used in the next
reaction (Example 5) without further purification. Selected .sup.1H
NMR resonances (400 MHz, CDCl.sub.3) .delta. 7.21 (s, 1H), 7.14 (s,
1H), 5.24 (s, 2H) ppm.
Example 5
SYNTHESIS OF 2-(1-ETHOXYMETHYL-1H-IMIDAZOL-2-YL)-THIAZOLE
[0203] ##STR48##
[0204] A solution of crude
1-ethoxymethyl-2-tributylstannanyl-1H-imidazole (previous example),
2-bromothiazole (1.05 mL, 11.6 mmol, 1.0 equivalents based on
integration of .sup.1H NMR of crude
1-ethoxymethyl-2-tributylstannanyl-1H-imidazole), and
Pd(PPh.sub.3).sub.4 (0.67 g, 0.58 mmol) in toluene (20 mL) is
stirred at 80.degree. C. for 18 hours. After cooling to room
temperature, the reaction mixture is poured into saturated aqueous
NaHCO.sub.3 and extracted twice with CH.sub.2Cl.sub.2. The combined
extracts are dried over Na.sub.2SO.sub.4 and concentrated in vacuo.
The residue is purified by flash chromatography on silica gel,
eluting with 2:1 hexanes:EtOAc (+0.5% Et.sub.3N). Fractions
containing product are concentrated and subjected again to flash
chromatography on silica gel. Elution with 2:1 hexanes:EtOAc (+0.5%
Et.sub.3N) affords (26%) of
2-(1-ethoxymethyl-1H-imidazol-2-yl)-thiazole as a bright yellow
oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.82 (d, J=3.2 Hz,
1H), 7.33 (d, J=3.2 Hz, 1H), 7.20 (d, J=1.2 Hz, 1H), 7.15 (d, J=1.2
Hz, 1H), 6.03 (s, 2H), 3.56 (q, J=7.2 Hz, 2H), 1.17 (t, J=7.2 Hz,
3H) ppm.
Example 6
SYNTHESIS OF 2-(1H-IMIDAZOL-2-YL)-THIAZOLE
[0205] ##STR49##
[0206] Concentrated HCl (10 ml) is added to a solution of
2-(1-ethoxymethyl-1H-imidazol-2-yl)-thiazole (940 mg, 4.49 mmol) in
24 mL of 1:1 EtOH--H.sub.2O at room temperature. The solution is
stirred at reflux for 3 hours. The reaction mixture is then cooled
to 0.degree. C. and made basic by the addition of about 12 mL of 10
N aqueous NaOH. The mixture is back titrated to approximately pH 4
using concentrated HCl. Solid NaHCO.sub.3 is added to the point of
saturation and approximately pH 8. The mixture is then extracted
twice using a mixture of THF and EtOAc. The combined extracts are
dried over Na.sub.2SO.sub.4 and concentrated to an oily solid,
which is triturated with a small amount of CH.sub.2Cl.sub.2. The
solid is collected by filtration. The filtrate is concentrated, and
the oily solid triturated once more with CH.sub.2Cl.sub.2. The
second resultant solid is collected by filtration and combined with
the solid first obtained. The product,
2-(1H-imidazol-2-yl)-thiazole, is obtained as a slightly off-white
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.04 (br, 1H),
7.87 (d, J=3.2 Hz, 1H), 7.70 (d, J=3.2 Hz, 1H), 7.14 (br, 2H)
ppm.
Example 7
SYNTHESIS OF
3-{1-[(3-PROPYLIMIDAZO[1,2-A]PYRIDIN-2-YL)METHYL]-1H-IMIDAZOL-2-YL}BENZON-
ITRILE
Step 1. Preparation of 3-bromo-2-oxo-hexanoic acid ethyl ester
[0207] ##STR50##
[0208] In a modification of the method described in JCS Perkin
Trans. I 1972, 2584, a mixture of 2-hydroxy-hexanoic acid ethyl
ester (5 g, 31 mmol), N-bromosuccinimide (12 g, 67 mmol) and
catalytic AIBN in anhydrous CCl.sub.4 (60 mL) is refluxed. After
heating for about 20 minutes, the reaction initiates with evolution
of a red-brown gas. After refluxing 4 hours, the resulting mixture
is filtered and the filtrate evaporated at reduced pressure to
obtain 3-bromo-2-oxo-hexanoic acid ethyl ester as a dark
liquid.
Step 2. Preparation of
3-(1-propyl)-imidazolo[1,2-a]pyridine-2-carboxylate
[0209] ##STR51##
[0210] A solution of 3-bromo-2-oxo-hexanoic acid ethyl ester (2.4
g, 10 mmol) in THF (5 mL) is added to a solution of 2-aminopyridine
(940 mg, 10 mmol) in anhydrous THF (5 mL). After 1 hour, ethanol
(50 mL) is added and the solution is heated at reflux with magnetic
stirring for 6 hours. The resulting dark mixture is evaporated at
reduced pressure, diluted with EtOAc (100 mL), washed with
saturated aqueous NaHCO.sub.3 solution (30 mL), water (30 mL),
brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated
at reduced pressure to obtain a yellow-orange solid.
Recrystallization from diethyl ether provides pure
3-(1-propyl)-imidazolo[1,2-a]pyridine-2-carboxylate as a
cream-colored solid. TLC (10% MeOH/CH.sub.2Cl.sub.2) Rf=0.60.
Step 3. Preparation of
2-hydroxymethyl-3-(1-propyl)-imidazolo[1,2-a]pyridine
[0211] ##STR52##
[0212] A solution of LiAlH.sub.4 (1M in THF, 4.0 mL, 4.0 mmol) is
added to a solution of
3-(1-propyl)-imidazolo[1,2-a]pyridine-2-carboxylate (1 g, 4.3 mmol)
in anhydrous THF (50 mL) at 0.degree. C. under nitrogen with
magnetic stirring. The resulting pale yellow solution is stirred at
0.degree. C. for 4 h and then quenched by addition of 75 mL of
EtOAc and 2 mL saturated aqueous Na.sub.2SO.sub.4. The resulting
mixture is stirred for 1 hour at ambient temperature, dried over
anhydrous Na.sub.2SO.sub.4, filtered through celite and evaporated
at reduced pressure to obtain
2-hydroxymethyl-3-(1-propyl)-imidazolo[1,2-a]pyridine as a
colorless film. TLC (10% MeOH/CH.sub.2Cl.sub.2) Rf=0.15.
Step 4. Preparation of
2-chloromethyl-3-(1-propyl)-imidazolo[1,2-a]pyridine
[0213] ##STR53##
[0214] Thionyl chloride (125 mg, 1.06 mmol) is added to a solution
of 2-hydroxymethyl-3-(1-propyl)-imidazolo[1,2-a]pyridine (100 mg,
0.53 mmol) in CH.sub.2Cl.sub.2 (3 mL) at 0.degree. C. under
nitrogen with magnetic stirring. After 1 hour, the reaction is
diluted with EtOAc (20 mL), washed with saturated aqueous
NaHCO.sub.3 (10 mL), water (10 mL) and brine (10 mL). The solution
is then dried over anhydrous sodium sulfate, filtered and
evaporated at reduced pressure to obtain
2-chloromethyl-3-(1-propyl)-imidazolo[1,2-a]pyridine as a colorless
oil. TLC (10% MeOH/CH.sub.2Cl.sub.2) Rf=0.60.
Step 5. Preparation of
3-{1-[(3-propylimidazo[1,2-a]pyridin-2-yl)methyl]-1H-imidazol-2-yl}benzon-
itrile
[0215] ##STR54##
[0216] NaH (13.5 mg of 60% wt., 0.34 mmol) is added to a solution
of 3-cyano-(1H-imidazol-2-yl)benzene (57.2 mg, 0.34 mmol) in
anhydrous DMF (3.5 mL). After 15 minutes,
2-chloromethyl-3-(1-propyl)-imidazolo[1,2-a]pyridine (70.5 mg, 0.34
mmol) is added and the reaction mixture is stirred at ambient
temperature for 18 hours. Concentration at reduced pressure
followed by purification by chromatography on silica gel (5%
MeOH/CHCl.sub.3) provides
3-{1-[(3-propylimidazo[1,2-a]pyridin-2-yl)methyl]-1H-imidazol-2-yl}benzon-
itrile as a light yellow solid. TLC (5% MeOH/CHCl.sub.3) Rf=0.50.
.sup.1H NMR (CDCl.sub.3): 8.13, s (1H); 8.07, d (1H); 7.90, d (1H);
7.71, d (1H); 7.60, d (1H); 7.58, d (1H); 7.20, dd (1H); 7.14, bs
(2H); 6.85, t (1H); 5.32, s (2H); 2.70, t (2H); 1.50, p (2H), 0.90,
t (3H). LRMS m/z (M+1) 342.30.
Example 8
SYNTHESIS OF
6-CHLORO-2-{[2-(3-FLUOROPHENYL)-1H-IMIDAZOL-1-YL]METHYL}-3-PROPYLIMIDAZOL-
[1,2-A]PYRIDINE
[0217] ##STR55##
[0218] Kt-BuO (0.69 mL of 1 M in THF, 0.69 mmol) is added to a
solution of 3-fluoro-(1H-imidazol-2-yl)benzene (88 mg, 0.58 mmol)
in anhydrous DMA (1 mL). After 15 minutes,
2-chloromethyl-6-chloro-3-(1-propyl)-imidazolo[1,2-a]pyridine (140
mg, 0.58 mmol) is added and the reaction mixture is stirred and
heated at 60.degree. C. for 15 minutes. The reaction mixture is
diluted with EtOAc (10 mL), washed with water (3 mL), brine (3 mL),
dried over Na.sub.2SO.sub.4, filtered and evaporated at reduced
pressure to obtain a yellow solid. Sequential chromatography on
silica gel eluting with EtOAc and then 5% MeOH/CH.sub.2Cl.sub.2
provides
6-chloro-2-{[2-(3-fluorophenyl)-1H-imidazol-1-yl]methyl}-3-propylimidazo[-
1,2-a]pyridine as a cream-colored yellow solid. TLC (10%
MeOH/CH.sub.2Cl.sub.2) Rf=0.35.
Example 9
SYNTHESIS OF
'2-{[2-(6-FLUOROPYRIDIN-2-YL)-1H-IMIDAZOL-1-YL]METHYL}-3-(TRIFLUOROMETHYL-
)IMIDAZO[1,2-A]PYRIDINE
Step 1. Preparation of
3-trifluomethyl-imidazolo[1,2-a]pyridine-2-carboxylate
[0219] ##STR56##
[0220] A mixture containing ethyl
3-bromo-imidazolo[1,2-a]pyridine-2-carboxylate (1 g, 3.7 mmol),
triethyltrifluoro-methylsilane (754 mg, 4.09 mmol), copper (I)
iodide (779 mg, 4.09 mmol) and potassium fluoride (238 mg, 4.09
mmol) in anhydrous DMF (4.1 mL) is heated at 80.degree. C. with
magnetic stirring in a pyrex glass sealed tube. After 40 hours, the
resulting dark mixture is poured into a mixture of EtOAc (100 mL)
and water/sat. NH.sub.4Cl solution (50 mL, 1:1). After stirring for
1 h, the mixture is filtered to remove solids. The solids are
washed with EtOAc (20 mL.times.3) and the organic layer of the
combined filtrates is separated, washed with brine (30 mL), dried
over sodium sulfate, filtered and evaporated at reduced pressure to
obtain crude product as a dark oil. Purification by radial
chromatography using a solvent gradient (35%-45% EtOAc/hexane)
provides ethyl
3-trifluomethyl-imidazolo[1,2-a]pyridine-2-carboxylate as a yellow
oil. TLC (35% EtOAc/hexane) Rf=0.28.
Step 2. Preparation of
2-hydroxymethyl-3-trifluomethyl-imidazolo[1,2-a]pyridine
[0221] ##STR57##
[0222] A solution of LiAlH.sub.4 (1M in THF, 0.60 mL, 0.60 mmol) is
added to a solution of
3-trifluomethyl-imidazolo[1,2-a]pyridine-2-carboxylate (110 mg, 0.5
mmol) in anhydrous THF (3 mL) at 0.degree. C. under nitrogen with
magnetic stirring. The resulting pale yellow solution is allowed to
warm to ambient temperature over a 1 hour period and then quenched
by addition of 0.35 mL of 2 M aqueous KOH. The resulting mixture is
extracted with EtOAc (10 mL.times.3) and the combined organic
layers are dried over anhydrous sodium sulfate, filtered and
evaporated at reduced pressure to obtain a pale yellow oil that
solidifies on standing. Purification by radial chromatography
(35-50% EtOAc/hexane) provides
2-hydroxymethyl-3-trifluomethyl-imidazolo[1,2-a]pyridine as a
colorless solid. TLC (5% MeOH/CH.sub.2Cl.sub.2/0.3%
NH.sub.4OH)Rf=0.24.
Step 3. Preparation of
2-chloromethyl-3-trifluomethyl-imidazolo[1,2-a]pyridine
[0223] ##STR58##
[0224] To a solution of
2-hydroxymethyl-3-trifluomethyl-imidazolo[1,2-a]pyridine (70 mg,
0.32 mmol) and anyhydrous triethylamine (72 mg, 0.71 mmol) in
CH.sub.2Cl.sub.2 (3.2 mL) at 0.degree. C. under nitrogen
methanesulfonyl chloride (39 mg, 0.34 mmol) is added with magnetic
stirring. After 1 h, the reaction is diluted with CH.sub.2Cl.sub.2
(30 mL), washed with water (10 mL), dried over anhydrous sodium
sulfate, filtered and evaporated at reduced pressure to obtain
2-chloromethyl-3-trifluomethyl-imidazolo[1,2-a]pyridine as a
colorless solid. TLC (5% MeOH/CH.sub.2Cl.sub.2/0.3%
NH.sub.4OH)Rf=0.75. LRMS m/z (M+1) 235.1.
Step 4. Preparation of
'2-{[2-(6-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl}-3-(trifluoromethyl-
)imidazo[1,2-a]pyridine
[0225] ##STR59##
[0226] A mixture of
2-chloromethyl-3-trifluomethyl-imidazolo[1,2-a]pyridine (93.7 mg,
0.32 mmol), 2-fluoro-6-(1H-imidazol-2-yl)pyridine (104 mg, 0.64
mmol) and cesium carbonate (211 mg, 0.64 mmol) in DMF (3 mL) is
stirred at 50.degree. C. under nitrogen for 8 hours and then at
ambient temperature for 16 hours. The reaction mixture is
partitioned between EtOAc (30 mL) and water (10 mL), the organic
layer is separated, washed with water (10 mL), brine (10 mL), dried
over anhydrous sodium sulfate, filtered and evaporated at reduced
pressure to obtain a pale yellow solid. Purification by radial
chromatography (3% MeOH/CH.sub.2Cl.sub.2/0.1% NH.sub.4OH) provides
'2-{([2-(6-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl}-3-(trifluoromethy-
l)imidazo[1,2-a]pyridine (75.5 mg) as a colorless solid. .sup.1H
NMR (CDCl.sub.3): 8.21 (d, J=6.9 Hz, 1H), 8.10 (m, 1H), 7.82 (dd,
J.sub.1=15.9 Hz, J.sub.2=8.2 Hz, 1H), 7.62 (d, J=9.1 Hz, 1H), 7.34
(m, 1H), 7.17 (d, J=1.1 Hz, 1H), 6.98 (m, 1H), 6.82 (m, 1H), 6.18
(s, 2H). LRMS m/z (M+1) 362.2.
Example 10
SYNTHESIS OF
6-CHLORO-2-[2-(6-FLUORO-PYRIDIN-2-YL)-2H-PYRAZOL-3-YLMETHYL]-3-METHYL-IMI-
DAZO[1,2-A]PYRIDINE
Step 1. Preparation of
6-Chloro-2-[2-(2,2-dimethoxy-ethyl)-[1,3]dithian-2-ylmethyl]-3-methyl-imi-
dazo[1,2-a]pyridine
[0227] ##STR60##
[0228] A solution of n-BuLi in hexanes (1.6 M, 1.4 mL) is added
dropwise at -50.degree. C. to a solution of
2-(2,2-dimethoxy-ethyl)-[1,3]dithiane (450 mg, prepared according
J. Het. Chem, 1987, 1221) in THF. The mixture is then warmed to
-30.degree. C. for 1 hour. After cooling to -50.degree. C. a
solution of 6-chloro-2-chloromethyl-3-methyl-imidazo[1,2-a]pyridine
(300 mg) in 3 mL of THF is added dropwise; the reaction mixture is
then slowly warmed to room temperature. After quenching with
aqueous NH.sub.4Cl solution, the mixture is extracted with ethyl
acetate. The extract is washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated under vacuum. The residue is
purified on flash chromatographic column, eluting with 5% MeOH in
CH.sub.2Cl.sub.2, to give
6-Chloro-2-[2-(2,2-dimethoxy-ethyl)-[1,3]dithian-2-ylmethyl]-3-methyl-imi-
dazo[1,2-a]pyridine. .sup.1H NMR (CDCl.sub.3, ppm): 7.80 (s, 1H);
7.50(d, 1H); 7.05(d, 1H); 4.80(t, 1H); 3.40(m, 8H); 2.75-3.00(m,
4H); 2.40-2.50(m, 5H); 1.80-2.05(m, 2H).
Step 2. Preparation of
6-Chloro-2-[2-(6-fluoro-pyridin-2-yl)-2H-pyrazol-3-ylmethyl]-3-methyl-imi-
dazo[1,2-a]pyridine
[0229] ##STR61##
[0230] A mixture of
6-Chloro-2-[2-(2,2-dimethoxy-ethyl)-[1,3]dithian-2-ylmethyl]-3-methyl-imi-
dazo[1,2-a]pyridine (200 mg), HgCl.sub.2 (200 mg) and CaCO.sub.3
(100 mg) in a mixed solvent (Acetone/CH.sub.2CN/H.sub.2O, 5/5/5 mL)
is stirred at room temperature overnight. Additional HgCl.sub.2
(200 mg) and CaCO.sub.3 (100 mg) are added and then heated at
50.degree. C. for 2 hours. The solvent is evaporated under vacuum,
and the residue is partitioned between CH.sub.2Cl.sub.2 and water.
The organic layer is separated, washed with water, and concentrated
under vacuum. The residue is dissolved in Acetic acid/H.sub.2O
(10/1 mL), and the solution is heated at 50.degree. C. for 0.5
hours. After cooling, 20 mg of (6-Fluoro-pyridin-2-yl)-hydrazine is
added, and the reaction mixture is then heated at 80.degree. C.
overnight. The mixture is evaporated under vacuum, basified with
aqueous NaHCO.sub.3, and extracted with CH.sub.2Cl.sub.2. The
extracted is washed with brine and concentrated. The residue is
purified on a preparative TLC plate, 10% MeOH/CH.sub.2Cl.sub.2 to
give
6-Chloro-2-[2-(6-fluoro-pyridin-2-yl)-2H-pyrazol-3-ylmethyl]-3-methyl-imi-
dazo[1,2-a]pyridine as a white solid. .sup.1H NMR (CDCl.sub.3,
ppm): 7.80-7.90(m, 3H); 7.58(s, 1H); 7.50(d, 1H); 7.11(dd, 1H);
6.80(dd, 1H); 6.08(s, 1H); 4.70(s, 2H); 2.44(s, 3H).
Example 11
SYNTHESIS
1-[3-ETHYL-2-(2-THIAZOL-2-YL-IMIDAZOL-1-YLMETHYL)IMIDAZO[1,2-B]P-
YRIDA-ZIN-6-YL]ETHANONE
[0231] ##STR62##
[0232] A mixture of
6-chloro-3-ethyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-imidazo[1,2-b]pyr-
idazine (100 mg, 0.26 mmol), 1-ethoxyvinyltributylstannane (142 mg,
0.39 mmol) and PdCl.sub.2(Ph.sub.3P).sub.2 (10 mg) in anhydrous
toluene (5 mL) is heated at 110.degree. C. in a sealed tube for 5
hours. On cooling, water (2 mL), and concentrated HCl (2 mL) are
added and the mixture is stirred at room temperature for 2 hours.
The mixture is neutralized with sodium carbonate solution and
extracted with methylene chloride (3.times.15 mL). The combined
organic layers are dried (Na.sub.2SO.sub.4) and the solvent
removed. The residue is purified by PTLC (5% methanol in methylene
chloride) to give
1-[3-ethyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)imidazo[1,2-b]pyridazin--
6-yl]ethanone as a solid. .sup.1H NMR (CDCl.sub.3): 7.95, d (1H);
7.86, d (1H0; 7.70, d (1H); 7.36, d (1H); 7.25, d (1H); 7.11, d
(1H); 6.18, s (2H); 3.10, q (2H); 2.75, s (3H); 1.18, t (3H).
Example 12
SYNTHESIS OF
4-[3-ETHYL-2-(2-THIAZOL-2-YL-IMIDAZOL-1-YLMETHYL)-IMIDAZO[1,2-B]PYRIDAZIN-
-6-YLOXY]-2-METHYL-BUTAN-2-OL
[0233] ##STR63##
[0234] To a solution of 3-methyl-1,3-butandiol (92 mg, 0.88 mmol)
in THF (10 mL) under N.sub.2 at room temperature is added tBuOK (1M
in THF, 0.88 mL, 0.88 mmol). After 5 minutes,
6-chloro-3-ethyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-imidazo[1,2-b]pyr-
idazine (46 mg, 0.12 mmol) is added. The mixture is refluxed for
2.5 hr. On cooling, solvent is removed in vacuo. To the residue is
added saturated NH.sub.4Cl aqueous solution (8 mL) and extracted
with methylene chloride (15.times.3 mL). The organic layers are
combined, dried (Na.sub.2SO.sub.4) and solvent removed. The crude
product is purified by PTLC (10% methanol in methylene chloride) to
give
4-[3-ethyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-imidazo[1,2-b]pyridazin-
-6-yloxy]-2-methyl-butan-2-ol as an oil. .sup.1H NMR (CDCl.sub.3):
7.88, d (1H); 7.73, d (1H); 7.38, d (1H); 7.21, d (1H); 7.08, d
(1H); 6.62, d (1H); 6.02, s (2H); 4.51, t (2H); 2.93, q (2H); 2.21,
t (2H); 1.35, s (6H); 1.05, t (3H).
Example 13
SYNTHESIS OF
5-ETHYL-6-[2-(6-FLUORO-PYRIDIN-2-YL)-IMIDAZOL-1-YLMETHYL]-IMIDAZO[2,1-B]T-
HIAZOLE
Step 1. Preparation of 5-ethyl-imidazo[2,1-b]thiazole-6-carboxylic
acid ethyl ester
[0235] ##STR64##
[0236] A mixture of 2-aminothiazole (2 g, 20 mmol) and
3-bromo-2-oxo-pentanoic acid ethyl ester (4.4 g, 20 mmol) in
ethanol (40 mL) is refluxed for 20 h. The solvent is removed in
vacuo until dryness. The residue is purified by column
chromatography (5% methanol in methylene chloride) to give
5-ethyl-imidazo[2,1-b]thiazole-6-carboxylic acid ethyl ester as an
oil.
Step 2. Preparation of
5-ethyl-6-hydroxymethyl-imidazo[2,1-b]thiazole
[0237] ##STR65##
[0238] Diisobutylaluminum hydride (1M in THF, 11 mL, 11 mmol) is
added to a solution of 5-ethyl-imidazo[2,1-b]thiazole-6-carboxylic
acid ethyl ester (800 mg, 3.6 mmol) in THF (20 mL). The mixture is
stirred at room temperature for 0.5 h. HCl (10%, 2 mL) is added,
and the mixture is stirred for an additional 5 min. The mixture is
neutralized by the addition of sodium hydroxide (2 N) until pH is
above 10 and then extracted with ethyl acetate (3.times.20 mL). The
combined organic layers are dried and solvent removed to give
5-ethyl-6-hydroxymethyl-imidazo[2,1-b]thiazole as a solid.
Step 3. Preparation of
6-chloromethyl-5-ethyl-imidazo[2,1-b]thiazole
[0239] ##STR66##
[0240] Thionyl chloride (2M in methylene chloride, 10 mL) is added
to 5-ethyl-imidazo[2,1-b]thiazol-6-yl)methanol (700 mg, 3.8 mmol)
is added. The mixture is stirred at room temperature for 0.5 h. All
volatile material is removed until dryness to give
6-chloromethyl-5-ethyl-imidazo[2,1-b]thiazole as a solid.
Step 4. Preparation of
5-ethyl-6-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-imidazo[2,1-b]t-
hiazole
[0241] ##STR67##
[0242] A mixture of 6-chloromethyl-5-ethyl-imidazo[2,1-b]thiazole
(120 mg, 0.6 mmol), 2-fluoro-6-(1H-imidazol-2-yl)pyridine (82 mg,
0.6 mmol) and potassium carbonate (278 mg, 2.4 mmol) in DMF (6 mL)
is stirred at room temperature for 48 h. Brine (15 mL) and
methylene chloride (20 mL) are added. The organic layer is
separated and the aqueous layer is extracted with methylene
chloride (2.times.20 mL). The combined organic layers are washed
with brine (3.times.15 mL) and dried. The solvent is removed in
vacuo. The residue is purified by preparative TLC to give 32 mg of
5-ethyl-6-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-imidazo[2-
,1-b]thiazole as an oil. .sup.1H NMR (CDCl.sub.3): 8.10, dd (1H);
7.82, dd (1H); 7.35, d (1H); 7.26, d (1H); 7.12, d (1H); 6.83, dd
(1H); 6.80, d (1H); 5.92, s (2H); 2.90, q (2H); 1.07, t (3H).
Example 14
Additional Compounds of the Invention
[0243] The compounds shown in Tables 1-8 are prepared according to
the methods given in Schemes 1-9 and further illustrated by
Examples 1-13. "X" shown in the table cells indicates the point of
attachment of the group in the structure shown at the top of that
table. TABLE-US-00003 TABLE 1 ##STR68## CMP # Name W R5 R4 R3 13
6-chloro-2-[(2-phenyl-1H- imidazol-1-yl)methyl]-3-
propylimidazo[1,2-a]pyridine ##STR69## ##STR70## H ##STR71## 14
6-chloro-2-{[2-(3- fluorophenyl)-1H-imidazol-1-
yl]methyl}imidazo[1,2- a]pyridine ##STR72## H H ##STR73## 15
6-chloro-2-{[2-(3- chlorophenyl)-1H-imidazol-1-
yl]methyl}imidazo[1,2- a]pyridine ##STR74## H H ##STR75## 16
6-chloro-2-{[2-(3- fluorophenyl)-1H-imidazol-1- yl]methyl}-3-
propylimidazo[1,2-a]pyridine ##STR76## ##STR77## H ##STR78## 17
3-ethyl-2-{[2-(3-fluorophenyl)- 1H-imidazol-1-
yl]methyl}imidazo[1,2- a]pyridine-7-carbonitrile ##STR79##
##STR80## H H 18 3-ethyl-2-{[2-(6-fluoropyridin-
2-yl)-1H-imidazol-1- yl]methyl}imidazo[1,2-
a]pyridine-7-carbonitrile ##STR81## ##STR82## H H 19
3-ethyl-2-[(2-phenyl-1H- imidazol-1- yl)methyl]imidazo[1,2-
a]pyridine ##STR83## ##STR84## H H 20
3-ethyl-2-{[2-(3-fluorophenyl)- 1H-imidazol-1-
yl]methyl}imidazo[1,2- a]pyridine ##STR85## ##STR86## H H 21
3-ethyl-2-{[2-(6-fluoropyridin- 2-yl)-1H-imidazol-1-
yl]methyl}imidazo[1,2- a]pyridine ##STR87## ##STR88## H H 22
7-chloro-2-{[2-(6- fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-3-
propylimidazo[1,2-a]pyridine ##STR89## ##STR90## H H 23
6-chloro-2-{[2-(6- fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-3-
propylimidazo[1,2-a]pyridine ##STR91## ##STR92## H ##STR93## 24
7-chloro-3-ethyl-2-{[2-(6- fluoropyridin-2-yl)-1H- imidazol-1-
yl]methyl}imidazo[1,2- a]pyridine ##STR94## ##STR95## H H 25
7-chloro-3-ethyl-2-{[2-(3- fluorophenyl)-1H-imidazol-1-
yl]methyl}imidazo[1,2- a]pyridine ##STR96## ##STR97## H H 26
3-{1-[(3-propylimidazo[1,2- a]pyridin-2-yl)methyl]-1H-
imidazol-2-yl}benzonitrile ##STR98## ##STR99## H H 27
3-ethyl-6-fluoro-2-{[2-(6- fluoropyridin-2-yl)-1H- imidazol-1-
yl]methyl}imidazo[1,2- a]pyridine ##STR100## ##STR101## H
##STR102## 28 3-ethyl-6-fluoro-2-{[2-(3-
fluorophenyl)-1H-imidazol-1- yl]methyl}imidazo[1,2- a]pyridine
##STR103## ##STR104## H ##STR105## 29 2-{[2-(3-chlorophenyl)-1H-
imidazol-1-yl]methyl}-3-ethyl- 6-fluoroimidazo[1,2-a]pyridine
##STR106## ##STR107## H ##STR108## 30
2-{[2-(2,5-difluorophenyl)-1H- imidazol-1-yl]methyl}-3-ethyl-
6-fluoroimidazo[1,2-a]pyridine ##STR109## ##STR110## H ##STR111##
31 3-{1-[(3-ethylimidazo[1,2- a]pyridin-2-yl)methyl]-1H-
imidazol-2-yl}benzonitrile ##STR112## ##STR113## H H 32
6-bromo-2-{[2-(3- fluorophenyl)-1H-imidazol-1- yl]methyl}-3-
propylimidazo[1,2-a]pyridine ##STR114## ##STR115## H ##STR116## 33
3-ethyl-2-{[2-(3-fluorophenyl)- 1H-imidazol-1-yl]methyl}-6-(5-
methyl-1,3,4-oxadiazol-2- yl)imidazo[1,2-a]pyridine ##STR117##
##STR118## H ##STR119## 34 6-chloro-2-{[2-(6-
fluoropyridin-2-yl)-1H- imidazoi-1-yl]methyl}-3-
methylimidazo[1,2-a]pyridine ##STR120## ##STR121## H ##STR122## 35
6-chloro-2-{[2-(3- fluorophenyl)-1H-imidazol-1- yl]methyl}-3-
methylimidazo[1,2-a]pyridine ##STR123## ##STR124## H ##STR125## 36
6-chloro-3-ethyl-2-{[2-(6- fluoropyridin-2-yl)-1H- imidazol-1-
yl]methyl}imidazo[1,2- a]pyridine ##STR126## ##STR127## H
##STR128## 37 6-chloro-3-ethyl-2-{[2-(3- fluoropyridin-2-yl)-1H-
imidazol-1- yl]methyl}imidazo[1,2- a]pyridine ##STR129## ##STR130##
H ##STR131## 38 2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-
yl]methyl}imidazo{1,2- a]pyridine-3-carbonitrile ##STR132##
##STR133## H H 39 2-{[2-(3-fluoropyridin-2-yl)- 1H-imidazol-1-
yl]methyl}imidazo{1,2- a]pyridine-3-carbonitrile ##STR134##
##STR135## H H 40 2-{[2-(6-fluoropyridin-2-yl)-
1H-imidazol-1-yl]methyl}-3,6- dimethylimidazo[1,2-a]pyridine
##STR136## ##STR137## H ##STR138## 41 2-{[2-(3-fluorophenyl)-1H-
imidazol-1-yl]methyl}-3,6- dimethylimidazo[1,2-a]pyridine
##STR139## ##STR140## H ##STR141## 42
7-ethyl-2-{[2-(6-fluoropyridin- 2-yl)-1H-imidazol-1- yl]methyl}-3-
methylimidazo[1,2-a]pyridine ##STR142## ##STR143## H H 43
7-ethyl-2-{[2-(3-fluorophenyl)- 1H-imidazol-1-yl]methyl}-3-
methylimidazo[1,2-a]pyridine ##STR144## ##STR145## H H 44
5-ethyl-2-{[2-(6-fluoropyridin- 2-yl)-1H-imidazol-1- yl]methyl}-3-
methylimidazo[1,2-a]pyridine ##STR146## ##STR147## ##STR148## H 45
1-(2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-3-
methylimidazo[1,2-a]pyridin-5- yl)ethanol ##STR149## ##STR150##
##STR151## H 46 6-chloro-2-{[2-(2,5- difluorophenyl)-1H-imidazol-1-
yl]methyl}-3- methylimidazo[1,2-a]pyridine ##STR152## ##STR153## H
##STR154## 47 6-chloro-2-{[2-(5-fluoro-2-
methylphenyl)-1H-imidazol-1- yl]methyl}-3-
methylimidazol[1,2-a]pyridine ##STR155## ##STR156## H ##STR157## 48
2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-
3,5,7-trimethylimidazo[1,2- a]pyridine ##STR158## ##STR159##
##STR160## H 49 2-{[2-(3-fluoropyridin-2-yl)-
1H-imidazol-1-yl]methyl}- 3,5,7-trimethylimidazo[1,2- a]pyridine
##STR161## ##STR162## ##STR163## H 50 2-{[2-(6-fluoropyridin-2-yl)-
1H-imidazol-1-yl]methyl}-3- (trifluoromethyl}imidazo[1,2-
a]pyridine ##STR164## ##STR165## H H 51
2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-3-
(trifluoromethyl}imidazo[1,2- a]pyridine ##STR166## ##STR167## H
##STR168## 52 2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-3-
methyl-6- (trifluoromethyl}imidazo[1,2- a]pyridine ##STR169##
##STR170## H ##STR171## 53 3-bromo-2-{[2-(6-
fluoropyridin-2-yl)-1H- imidazol-1- yl]methyl}imidazo[1,2-
a]pyridine ##STR172## ##STR173## H H 54
3-ethyl-2-[(2-pyrimidin-2-yl- 1H-imidazol-1-yl)methyl]-6-
(trifluoromethyl)imidazo[1,2- a]pyridine ##STR174## ##STR175## H
##STR176## 55 3-ethyl-2-{[2-(1,3-thiazol-2-yl)-
1H-imidazol-1-yl]methyl}-6- (trifluoromethyl)imidazo[1,2-
a]pyridine ##STR177## ##STR178## H ##STR179## 56
3-ethyl-2-{[2-(1,3-thiazol-2-yl)- 1H-imidazol-1-yl]methyl}-5-
(ethyl)imidazo[1,2-a]pyridine ##STR180## ##STR181## H H 57
3-etbyl-2-{[2-(1,3-thiazol-2-yl)- 1H-imidazol-1-yl]methyl}-6-
(acetyl)imidazo[1,2-a]pyridine ##STR182## ##STR183## H ##STR184##
58 3-ethyl-2-{[2-(1,3-thiazol-2-yl)- 1H-imidazol-1-yl]methyl}-6-
(bromo)imidazo[1,2-a]pyridine ##STR185## ##STR186## H ##STR187## 59
3-ethyl-2-{[2-(1,3-thiazol-2-yl)- 1H-imidazol-1-yl]methyl}-6-
(thien-2-yl)imidazo[1,2- a]pyridine ##STR188## ##STR189## H
##STR190## 60 3-ethyl-2-{[2-(1,3-thiazol-2-yl)-
1H-imidazol-1-yl]methyl}-6- (1,3-thiazol-2-yl)imidazo[1,2-
a]pyridine ##STR191## ##STR192## H ##STR193## 61
3-ethyl-2-{[2-(1,3-thiazol-2-yl)- 1H-imidazol-1-yl]methyl}-6-
(pyridin-2-yl)imidazo[1,2- a]pyridine ##STR194## ##STR195## H
##STR196## 62 3-ethyl-2-{[2-(1,3-thiazol-2-yl)-
1H-imidazol-1-yl]methyl}-6- (pyridin-4-yl)imidazo[1,2- a]pyridine
##STR197## ##STR198## H ##STR199## 63
3-ethyl-2-{[2-(1,3-thiazol-2-yl)- 1H-imidazol-1-yl]methyl}-6-
(cyano)imidazo[1,2-a]pyridine ##STR200## ##STR201## H ##STR202##
Mass Spec Cmp (Cald./Obs. # R2 1H NMR M + 1) 13 H 350.1/351.2 14 H
326.1/327.1 15 H 342.0/343.1 16 H 368.1/369.2 17 ##STR203##
345.1/346.2 18 ##STR204## 346.6/347.3 19 H 1Hnmr(CDCl3, 400 MHz)-
302.4/303.2 7.85(1H, dd), 7.72-7.70(2H, m), 7.57(1H, dd), 7.49-
7.42(3H, m), 7.19-7.10(1H, m), 7.10(2H, m), 6.83- 6.80(1H, m),
5.35(2H, s), 2.59(2H, q), 0.99(3H, t),A1H, m), 5.35(2H, s),
2.59(2H, q), 0.99(3H, t). 20 H 1Hnmr(CDCl3, 400 MHz)- 320.4/321.3
7.88(1H, dd), 7.58(1H, dd), 7.54-7.42(3H, m), 7.21- 7.10(4H, m),
6.84(1H, t), 5.35(2H, s), 2.65(2H, q), 1.04(3H, t). 21 H
1Hnmr(CDCl3, 400 MHz)- 321.4/322.3 8.13-8.10(1H, m), 7.90- 7.82(2H,
m), 7.57(1H, dd), 7.32(1H, s), 7.17-7.13(1H, m), 7.11(1H, s),
6.87(1H, dd), 6.81(1H, t), 6.08(2H, s), 3.00(2H, q), 1.06(3H, t).
22 ##STR205## free base in CDCl3: 8.12, dd(1H); 7.85, dd(1H); 7.78,
dd(1H); 7.56, dd (1H); 7.32, dd(1H); 7.10, dd(1H); 6.87, dd(1H);
6.77, dd(1H); 2.91, t(2H); 1.45, p(2H), 0.88,t(3H) 369.12/370.19 23
H free base in CDCl3: 8.11, 369.12/371.90 dd(1H); 7.89, d(1H);
7.85, dd(1H); 7.51, d(1H); 7.32, d(1H); 7.26, m(1H);7.11, d (1H);
7.09, dd(1H); 6.04, s (2H); 2.94, t(2H); 1.51, p (2H); 0.84, t(3H);
24 ##STR206## free base in CDCl3: 8.12, dd(1H); 7.86, dd(1H); 7.81,
d(1H); 7.57, d(1H); 7.31, s(1H); 7.12, s(1H); 6.88, dd(1H); 6.80,
dd (1H); 6.07, s(1H); 3.01, q (2H); 1.06, t(3H) 355.10/356.20 25
##STR207## free base in CDCl3: 7.80, d (1H); 7.58, d(1H); 7.44, m
(3H); 7.13, m(3H); 6.82, dd (1H); 5.32, s(2H); 2.64, q (2H);
1.04,(3H) 354.10/355.20 26 H free base in CDCl3: 8.13, s
341.16/342.30 (1H); 8.07, d(1H); 7.90, d (1H); 7.71, d(1H); 7.60, d
(1H); 7.58, d(1H); 7.20, dd (1H); 7.14, bs(2H); 6.85, t (1H); 5.32,
s(2H); 2.70, t (2H); 1.50, p(2H), 0.90, t(3H) 27 H free base in
CDCl3: 8.14, 339.13/3340.20 dd(1H); 7.86, dd(1H); 7.81, m(1H);
7.55, dd(1H); 7.27, m(1H); 7.07, m(2H);
6.88, dd(1H); 6.08, s(2H); 2.98, q(2H); 1.06, t(3H) 28 H free base
in CDCl3: 8.14, 338.13/339.20 dd(1H); 7.86, dd(1H); 7.81, m(1H);
7.55, dd(1H); 7.27, m(1H); 7.08, m(2H); 6.88, dd(1H); 6.08, s(2H);
2.98, q(2H); 1.06, t(3H) 29 H free base in CDCl3: 7.80,
354.10/355.20 (2H); 7.61, m(1H) 7.55, dd(1H); 7.39, d(1H); 7.28,
m(1H); 7.10, m(3H); 5.32, s(1H); 2.65, q(2H); 1.06, (3H) 30 H free
base in CDCl3: 7.86, 356.12/357.20 m(1H); 7.54, dd(1H); 7.35,
m(1H); 7.17, m(5H); 5.21, s(2H); 2.62, q(2H); 1.02, t (3H) 31 H
tartrate salt in CD3OD: 327.15/328.30 8.26, d(1H); 8.06, s(1H);
8.00, d(1H); 7.85, d(1H); 7.69, t(1H); 7.50, d(1H); 7.35, t(1H);
7.29, s(1H); 7.19, S(1H); 6.99, t(1H), 5.46, s(2H)4.50, s(2H);
2.85, q(2H), 1.11, t(3H) 32 H free base in CDCl3: 7.99, d
412.07/415.00 (1H); 7.48, m(4H); 7.24, dd (1H); 7.15, dd(1H); 7.11,
bs (1H); 5.32, s(2H); 2.57, (2H), 1.43, p(2H), 0.84, (3H) 33 H free
base in CDCl3: 8.62, d 402.16/403.40 (1H); 7.77, dd(1H); 7.69,
dd(1H); 7.49, m(3H); 7.15, m(3H); 5.37, s(2H); 2.74, q (2H); 2.66,
s(3H); 1.11, (3H) 34 H 341.7/342.0 35 H 340.7/341.0 36 H
355.8/342.0 37 H 355.8/356.7 38 H 318.32/319.2 39 H Free base in
CDCl3: 8.56, dd(1H); 8.26, dd(1H); 7.67. d(1H); 7.53, t(1H); 7.51-
7.43, m(3H); 7.41-7.29, m(2H), 7.08, t(1H); 5.93, s(2H) 40 H
321.3/322.0 41 H 320.3/321.0 42 H 335.3/336.0 43 ##STR208##
334.3/335.8 44 H 335.3/336.0 45 H 350.3/351.2 46 H free base in
CDCl3: 7.82, d (1H); 7.46, d(1H); 7.28, m (1H); 7.12, m,(5H); 5.20,
s (2H); 2.13, S(3H) 47 H free base in CDCl3: 7.81, d (1H); 7.48,
dd(1H); 7.21, m (2H); 7.16, d,(1H); 7.12, d (1H); 7.06, m(2H);
5.04, s (2H); 2.12, s(3H); 2.05, s (3H) 48 ##STR209## 335.38/336.21
49 ##STR210## 335.38/336.20 50 H 361.1/362.2 51 H 375.32/376.20 52
H 374.34/375.10 53 H 371.0/373.9 54 H 372.35/373.20 55 H
377.39/378.30 56 ##STR211## 337.44/338.20 57 H 337.41/378.3 58 H
free base in CDCl3: 8.00, s (1H); 7.85, dd(1H); 7.45, d(1H); 7.35,
d(1H); 7.25, s (1H); 7.20, d(1H); 7.10, s(1H); 6.10, s(2H), 2.90, q
(2H); 1.00,(3H) 59 H 377.49/380.3 60 H 378.48/379.5 61 H
372.45/373.3 62 H 372.45/373.3 63 H 334.41/335.20
[0244] TABLE-US-00004 TABLE 2 ##STR212## Mass Spec Cmp. (Cald./ #
Name W R5 R3 1H NMR Obs. M + 1) 64 6-chloro-2-{[2-(3-fluorophenyl)-
1H-imidazol-1- yl]methyl}imidazo[1,2- b]pyridazine ##STR213## H Cl
327.1/328.2 65 6-bromo-6-chloro-2-{[2-(3-
fluorophenyl)-1H-imidazol-1- yl]methyl}imidazo[1,2- b]pyridazine
##STR214## Br Cl 405.0/406.0 66 6-chloro-2-{[2-(6-fluoropyridin-
yl)-1H-imidazol-1-yl]methyl}- 3-propylimidazo[1,2- ]pyridazine
##STR215## ##STR216## Cl 370.1/371.2 67 3-bromo-6-chloro-2-{[2-(6-
fluoropyridin-2-yl)-1H- imidazol-1- yl]methyl}imidazo(1,2-
b]pyridazine ##STR217## Br Cl 406.0/407.1 68
2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-3-
propylimidazo[1,2-b]pyridazine ##STR218## ##STR219## H 336.2/337.2
69 2-{[2-(6-fluoropyridin-2-yl)-1H imidazol-1-
yl]methyl]imidazo[1,2- b]pyridazine ##STR220## H H 294.1/295.3 70
3-bromo-6-chloro-2-{[2-(6- chloropyridin-2-yl)-1H- imidazol-1-
yl]methyl}imidazo[1,2- b]pyridazine ##STR221## Br Cl 421.9/423.0 71
6-chloro-2-{[2-(4-chloropyridin- 2-yl)-1H-imidazol-1-yl]methyl}-
3-propylimidazo[1,2- b]pyridazine ##STR222## ##STR223## Cl
386.1/387.2 72 6-chloro-2-{[2-(6-chloropyridin-
2-yl)-1H-imidazol-1-yl]methyl}- 3-propylimidazo[1,2- b]pyridazine
##STR224## ##STR225## Cl 386.1/387.2 73 3-bromo-6-chloro-2-{[2-(4-
chloropyridin-2-yl)-1H- imidazol-1- yl]methyl]imidazo[1,2-
b]pyridazine ##STR226## Br Cl 74 3-{1-[(6-chloro-3-
propylimidazo[1,2-b]pyridazin- 2-yl)methyl]-1H-imidazol-2-
yl}benzonitrile ##STR227## ##STR228## Cl 376.1/377.5 75
6-chloro-2-{[2-(6-chloropyridin- 2-yl)-1H-imidazol-1-yl]methyl}-
3-ethylimidazo[1,2-b]pyridazine ##STR229## ##STR230## Cl
372.1/373.1 76 3-propyl-2-[(2-pyridin-2-yl-1H- imidazol-1-
yl)methyl]imidazo[1,2- b]pyridazine ##STR231## ##STR232## H
318.2/319.4 77 6-chloro-2-{[2-(6-fluoropyridin-
2-yl)-1H-imidazol-1-yl]methyl}- 3-methylimidazo[1,2- ]pyridazine
##STR233## ##STR234## Cl 342.1/343.2 78
6-chloro-2-{[2-(4-chloropyridin- 2-yl)-1H-imidazol-1-yl]methyl}-
3-methylimidazo[1,2- b]pyridazine ##STR235## ##STR236## Cl
358.0/359.1 79 6-chloro-2-{[2-(6-chloropyridin-
2-yl)-1H-imidazol-1-yl]methyl}- 3-methylimidazo[1,2- b]pyridazine
##STR237## ##STR238## Cl 348.0/359.1 80
2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-3-
methylimidazo[1,2-b]pyridazine ##STR239## ##STR240## H 308.1/309.2
81 6-chloro-2-{[2-(4-chloropyridin- 2-yl)-1H-imidazol-1-yl]methyl}-
3-ethylimidazo[1,2-b]pyridazine ##STR241## ##STR242## Cl
372.1/373.1 82 3-ethyl-2-{[2-(6-fluoropyridin- 2-yl)-1H-imidazol-1-
yl]methyl}imidazo[1,2- b]pyridazine ##STR243## ##STR244## H
322.1/323.7 83 3-methyl-2-[(2-pyridin-2-yl-1H- imidazol-1-
yl)methyl]imidazo[1,2- b]pyridazine ##STR245## ##STR246## H
290.1/291.2 84 3-ethyl-2-[(2-pyridin-2-yl-1H- imidazol-1-
yl)methyl]imidazo[1,2- b]pyridazine ##STR247## ##STR248## H
304.1/305.2 85 3-{1-[(6-chloro-3- ethylimidazo[1,2-b]pyridazin-2-
yl)methyl]-1H-imidazol-2- yl}benzonitrile ##STR249## ##STR250## Cl
362.1/363.2 86 3-{1[(3-propylimidazo[1,2-
b]pyridazin-2-yl)methyl]-1H- imidazol-2-yl}benzonitrile ##STR251##
##STR252## H 342.2/343.2 87 6-chloro-2-{[2-(2-fluorophenyl)-
1H-imidazol-1-yl]methyl}-3- propylimidazo[1,2-b]pyridazine
##STR253## ##STR254## Cl 369.1/370.2 88 6-chloro-3-ethyl-2-{[2-(3-
fluorophenyl)-1H-imidazol-1- yl]methyl}imidazo[1,2- b]pyridazine
##STR255## ##STR256## Cl 355.1/356.1 89 2-{1-[(6-chloro-3-
propylimidazo[1,2-b]pyridazin- 2-yl)methyl]-1H-imidazol-2-
yl}benzonitrile ##STR257## ##STR258## Cl 376.1/377.2 90
6-chloro-2-{(2-(2-fluoropyridin- 4-yl)-1H-imidazol-1-yl]methyl}-
3-propylimidazo[1,2- b]pyridazine ##STR259## ##STR260## Cl
370.1/371.2 91 6-chloro-2-{[2-(2-chloropyridin-
3-yl)-1H-imidazol-1-yl]methyl}- 3-propylimidazo[1,2- b]pyridazine
##STR261## ##STR262## Cl 386.1/387.1 92
3-propyl-2-[(2-pyridin-3-yl-1H- imidazol-1- yl)methyl]imidazo[1,2-
]pyridazine ##STR263## ##STR264## H 318.2/319.4 93
6-chloro-3-ethyl-2-{[2-(2- fluorophenyl)-1H-imidazol-1-
yl]methyl}imidazo[1,2- b]pyridazine ##STR265## ##STR266## Cl
355.1/356.2 94 6-chloro-2-{[2-(3-fluoropyridin-
2-yl)-1H-imidazol-1-yl]methyl]- 3-propylimidazo[1,2- b]pyridazine
##STR267## ##STR268## Cl 370.1/371.3 95 6-chloro-3-propyl-2-({2-[2-
(trifluoromethyl)phenyl]-1H- imidazol-1- yl}methyl)imidazo[1,2-
b]pyridazine ##STR269## ##STR270## Cl 419.1/420.2 96
6-chloro-2-{[2-(2- chlorophenyl)-1H-imidazol-1-
yl]methyl}-3-propylimidazo(1,2- b]pyridazine ##STR271## ##STR272##
Cl 385.1/386.2 97 6-chloro-3-methyl-2-({2-[2-
(trifluoromethyl)phenyl]-1H- imidazol-1- yl}methyl)imidazol[1,2-
]pyridazine ##STR273## ##STR274## Cl 391.1/392.2 98
6-chloro-2-({2-[3- (methylsulfonyl)phenyl]-1H-
imidazol-1-yl}methyl)-3- propylimidazo[1,2-b]pyridazine ##STR275##
##STR276## Cl 429.1/430.3 99 6-chloro-3-propyl-2-({2-[5-
(trifluoromethyl)pyridin-2-yl]- 1H-imidazol-1-
yl}methyl)imidazo[1,2- b]pyridazine ##STR277## ##STR278## Cl
420.1/421.3 100 6-chloro-2-{[2-(2-piperidin-1-
ylpyridin-3-yl)-1H-imidazol-1- yl]methyl}-3-propylimidazo[1,2-
]pyridazine ##STR279## ##STR280## Cl 435.2/436.3 101
6-chloro-3-propyl-2-({2-[6- (trifluoromethyl}pyridin-2-yl]-
1H-imidazol-1- yl}methyl)imidazo[1,2- ]pyridazine ##STR281##
##STR282## Cl 420.1/421.2 102 6-{1-[(6-chloro-3-
propylimidazo[1,2-b]pyridazin- 2-yl)methyl]-1H-imidazol-2-
yl}pyridine-2-carbonitrile ##STR283## ##STR284## Cl 377.1/378.1 103
6-chloro-3-propyl-2-[(2-pyrazin- 2-yl-1H-imidazol-1-
yl)methyl]imidazo[1,2- b]pyridazine ##STR285## ##STR286## Cl
353.1/354.2 104 6-chloro-2-{[2-(5-fluoropyridin-
3-yl)-1H-imidazol-1-yl]methyl}- 3-propylimidazo[1,2- b]pyridazine
##STR287## ##STR288## Cl 370.1/371.2 105
6-chloro-3-propyl-2-({2-[3- (trifluoromethyl)phenyl]-1H-
imidazol-1- yl}methyl)imidazo[1,2- b]pyridazine ##STR289##
##STR290## Cl 419.1/420.2 106 6-chloro-2-{[2-(1,5-dimethyl-
1H-pyrazol-3-yl)-1H-imidazol- 1-yl]methyl}-3-
propylimidazo[1,2-b]pyridazine ##STR291## ##STR292## Cl 369.2/370.2
107 6-chloro-2-{[2-(4-chloro-1- methyl-1H-pyrazol-3-yl)-1H-
imidazol-1-yl]methyl]-3- propylimidazo[1,2-b]pyridazine ##STR293##
##STR294## Cl 389.1/390.3 108 2-{1-[(6-chloro-3-
propylimidazo[1,2-b]pyridazin- 2-yl)methyl]-1H-imidazol-2-
yl}isonicotinonitrile ##STR295## ##STR296## Cl 377.1/378.3 109
6-chloro-2-{[2-(2,6- difluorophenyl)-1H-imidazol-1-
yl]methyl}-3-propylimidazo[1,2- b]pyridazine ##STR297## ##STR298##
Cl 387.1/388.2 110 6-chloro-3-propyl-2-[(2-
pyrimidin-2-yl-1H-imidazol-1- yl)methyl]imidazo[1,2- b]pyridazine
##STR299## ##STR300## Cl 353.1/354.5 111 6-{1-[(6-chloro-3-
methylimidazo[1,2-b]pyridazin- 2-yl)methyl]-1H-imidazol-2-
yl}pyridin-2(1H)-one ##STR301## ##STR302## Cl 340.8/341 112
6-chloro-3-methyl-2-[(2- pyrimidin-2-yl-1H-imidazol-1-
yl)methyl]imidazo(1,2- b]pyridazine ##STR303## ##STR304## Cl
325.1/326.1 113 6-chloro-2-{[2-(5-fluoro-2-
methylphenyl)-1H-imidazol-1- yl]methyl}-3-propylimidazo[1,2-
b]pyridazine ##STR305## ##STR306## Cl 383.1/384.2 114
6-chloro-2-{(2-(6-fluoropyridin- 2-yl)-1H-imidazol-1-
yl]methyl}imidazo[1,2- b]pyridazine ##STR307## H Cl 328.7/329.0 115
3,6-dichloro-2-{[2-(6- fluoropyridin-2-yl)-1H- imidazol-1-
yl]methyl}imidazo[1,2- b]pyridazine ##STR308## Cl Cl 362.0/363.1
116 2-{[2-(6-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-3,6-
dimethylimidazo[1,2- b]pyridazine ##STR309## ##STR310## CH.sub.3
322.3/323.2 117 6-{1-[(3,6-dimethylimidazo[1,2-
b]pyridazin-2-yl)methyl]-1H- imidazol-2-yl}pyridine-2- carbonitrile
##STR311## ##STR312## CH.sub.3 free base in CDCl3: 8.47, d(1H);
7.88, t(1H); 7.75, d(1H); 7.62, d (1H); 7.31, d(1H); 7.18, d(1H);
6.85, d(1H); 6.08, s(2H); 2.58, s (3H); 2.60, s(3H) 118
6-{[2-(3-fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-3,6-
dimethylimidazo[1,2- b]pyridazine ##STR313## ##STR314## CH.sub.3
322.3/323.0 119 6-chloro-3-methyl-2-[(2-thien-2- yl-1H-imidazol-1-
yl)methyl]imidazol[1,2- b]pyridazine ##STR315## ##STR316## Cl
329.0/330.1 120 6-chloro-3-ethyl-2-{[2-(3- fluoropyridin-2-yl)-1H-
imidazol-1- yl]methyl}imidazo[1,2- b]pyridazine ##STR317##
##STR318## Cl 356.7/357.7 121 3-ethyl-2-{[2-(3-fluoropyridin-
2-yl)-1H-imidazol-1- yl]methyl}imidazo[1,2- b]pyridazine ##STR319##
##STR320## H 322.1/323.2 122 2-{[2-(6-chloropyridin-2-yl)-1H-
imidazol-1-yl]methyl}-3-ethyl- N,N-dimethylimidazol[1,2-
]pyridazin-6-amine ##STR321## ##STR322## X.sub.5--N(CH.sub.3).sub.2
381.2/382.2 123 2-{[2-(6-chloropyridin-2-yl)-1H-
imidazol-1-yl]methyl}-3-ethyl- N-methylimidazo[1,2-
b]pyridazin-6-amine ##STR323## ##STR324## ##STR325## 367.1/368.2
124 6-chloro-3-ethyl-2-[(2- pyrimidin-2-yl-1H-imidazol-1-
yl)methyl]imidazo[1,2- b]pyridazine ##STR326## ##STR327## Cl
339.7/340.4 125 6-chloro-3-ethyl-2-{[2-(1,3-
thiazol-2-yl)-1H-imidazol-1- yl]methyl}imidazo[1,2- b]pyridazine
##STR328## ##STR329## CH.sub.3 344.8/345.9 126
3-ethyl-2-{[2-(3-fluoropyridin- 2-yl)-1H-imidazol-1-yl]methyl}-
6-methoxyimidazol[1,2- b]pyridazine ##STR330## ##STR331##
--OCH.sub.3 352.1/353.2 127 3-ethyl-2-{[2-(3-fluoropyridin-
2-yl)-1H-imidazol-1-yl]methyl}- 6-(3-hydroxy-3-
methylbutoxy)imidazo[1,2- b]pyridazine ##STR332##
##STR333## ##STR334## free base in CDCl3: 7.88, d(1H); 7.73, d(1H);
7.38, d(1H); 7.21, d (1H); 7.08, d(1H); 6.62, d(1H); 6.02, s(2H);
4.51, t(2H); 2.93, q (2H); 2.21, t(2H); 1.35, s(6H); 1.05,
t(3H)
[0245] TABLE-US-00005 TABLE 3 ##STR335## Mass Spec (Cal./Obs. Cmp#
Name W R5 R2 1H NMR M + 1) 128 3-chloro-2-{[2-(6-
fluoropyridin-2-yl)-1H- imidazol-1-yl]methyl}-7-
methoxyimidazo[1,2- c]pyrimidine ##STR336## ##STR337## ##STR338##
free base in CDCl3: 8.62, s (1H); 8.08, d (1H); 7.82, dd (1H);
7.22, d (1H); 7.19, d (1H); 6.85, dd (1H); 6.68, s (1H); 6.05, s
(2H); 3.95, s (3H) 129 3-chloro-2-{[2-(2,5-
difluorophenyl)-1H-imidazol- 1-yl]methyl)-7- methoxyimidazo[1,2-
c]pyrimidine ##STR339## ##STR340## ##STR341## free base in CDCI3:
8.62. s (1H); 7.32, m (1H); 7.20, s (1H); 7.18, s (1H); 7.12, m
(2H); 6.65, s (2H); 3.92, s (3H) 130 3-chloro-2-{[2-(3-
yl]methyl}-7- methoxyimidazo[1,2- c]pyrimidine ##STR342##
##STR343## ##STR344## 357.7/358.6
[0246] TABLE-US-00006 TABLE 4 ##STR345## Mass Spec (Cal./Obs. Cmp.
# Name W R5 R3 1H NMR M + 1) 131 3-chloro-2-([2-(6-
fluoropyridin-2-yl)-1H- imidazol-1- yl]methyl}imidazo[1,2-
a]pyrazine ##STR346## ##STR347## H free base in CDCl3: 9.01, s
(1H); 8.09, dd (1H); 7.97, m (2H); 7.82, q, (1H); 7.24, s (1H);
7.18, s (1H); 6.83, dd (1H); 6.17, s (2H) 132 3-bromo-2-{[2-(6-
fluoropyridin-2-yl)-1H- imidazol-1- yl]methyl}imidazo[1,2-
a]pyrazine ##STR348## ##STR349## H free base in CDCl3: 9.0, s(1H);
8.10, dd(1H); 8.00, s(2H); 7.85, q(1H); 7.20, s(1H), 7.15, s(1H);
6.85, dd(1H); 6.15, s(2H) 133 3-bromo-2-{[2-(3-
fluoropyridin-2-yl)-1H- imidazol-1- yl]methyl}imidazo[1,2-
a]pyrazine ##STR350## ##STR351## H free base in CDCl3: 9.0, s(1H);
8.45, dd(1H); 8.00, m(2H); 7.55, t(1H); 7.40-7.2, m(3H), 5.95,
s(2H) 134 6-bromo-3-chloro-2-{[2-(6- fluoropyndin-2-yl)-1H-
imidazol-1- yl]methyl}imidazo[1,2- a]pyrazine ##STR352## ##STR353##
##STR354## free base in CDCl3: 8.70, s (1H); 8.15, m (1H); 8.05, m
(1H); 7.25, s(1H); s (1H); 7.20, s (1H), 6.85, dd (1H); 6.15, s
(2H) 135 3-chloro-2-{[2-(6- fluoropyridin-2-yl)-1H-
imidazol-1-yl]methyl)-6- methylimidazo[1,2-a]pyrazine ##STR355##
##STR356## ##STR357## free base in CDCl3: 8.80, s (1H); 8.15, s
(1H); 7.85, m (2H); 7.35, s (1H); 7.20, s (1H), 6.85, dd (1H);
6.10, s (2H) 136 3-chloro-2-{[2-(6- fluoropyridin-2-yl)-1H-
imidazol-1-yl]methyl}-6- methoxyimidazo[1,2- a]pyrazine ##STR358##
##STR359## ##STR360## free base in CDCl3: 8.85, s (1H); 8.05, s
(1H); 7.80, d (1H); 7.65, (1H); 7.15, s (1H); 7.10, s (1H), 6.70, d
(1H); 6.30, s (2H); 3.85, s (3H) 137 3-chloro-6-methoxy-2-{[2-(6-
methoxypyridin-2-yl)-1H- imidazol-1- yl]methyl}imidazo[1,2-
a]pyrazine ##STR361## ##STR362## ##STR363## free base in CDCl3:
8.75, s (1H); 7.80, d (1H); 7.70, t (1H); 7.45, s (1H); 7.15, s
(1H), 7.10, s(1H); 6.70, d (1H); 6.30, s (2H); 3.95, s (3H); 3.85,
s(3H) 138 3-chloro-6-pyrrolidin-1-yl-2-
{[2-(6-pyrrolidin-1-ylpyridin- 2-yl)-1H-imidazol-1-
yl]methyl}imidazo[1,2- a]pyrazine ##STR364## ##STR365## ##STR366##
448.2/449.0 139 2-{[2-(6-fluoropyridin-2-yl)-
1H-imidazol-1-yl]methyl}-3,6- dimethylimidazo[1,2- a]pyrazine
##STR367## ##STR368## ##STR369## 322.35/323.3 140
6-bromo-3-chloro-2-{[2-(1,3- thiazol-2-yl)-1H-imidazol-1-
yl]methyl}imidazo[1,2- a]pyrazine ##STR370## ##STR371## ##STR372##
free base in CDCl3: 8.83, d (1H); 8.04, d (1H); 7.80, d (1H); 7.31,
d (1H); 7.18, s (1H); 7.15, s (1H); 6.16, s (2H) 141
3-bromo-2-{[2-(6- methoxypyridin-2-yl)-1H- imidazol-1-
yl]methyl}imidazo[1,2- a]pyrazine ##STR373## ##STR374## H free base
in CDCl3: 9.00, s (1H); 8.00, m (2H); 7.80, d(1H); 7.65, t (1H);
7.15, s (1H), 7.10, s(1H); 6.70, d (1H); 6.30, s (2H); 3.90, s (3H)
142 3-chloro-2-{[2-(3- fluorophenyl)-1H-imidazol-1- yl]methyl}-6-
methylimidazo[1,2-a]pyrazine ##STR375## ##STR376## ##STR377## free
base in CDCl3: 8.99. d (1H); 7.79, s (1H); 7.53, m (3H); 7.15, m
(3H); 5.38, s (2H); 2.58, s (3H)
[0247] TABLE-US-00007 TABLE 5 ##STR378## Mass Spec (Cald./Obsd.
Cmp. # Name W R5 R2 1H NMR M + 1) 143 2-{[2-(6-fluoropyridin-2-yl)-
1H-imidazol-1-yl]methyl)-3- propylimidazo[1,2- a]pyrimidine
##STR379## ##STR380## H free base in CDCl3: 8.52, dd (1H); 8.20, dd
(1H); 8.13, dd (1H); 7.88, dd (1H); 7.52, d (1H); 7.12, dd (1H);
7.01, m (2H); 6.16, s (1H); 2.99, t (2H); 1.50, p (2H), 0.87, t
(3H) 336.12/337.30 144 3-{1-[(3-propylimidazo[1,2-
a]pyrimidin-2-yl)methyl]-1H- imidazol-2-yl}benzonitrile ##STR381##
##STR382## H free base in CDCl3: 8.57, dd (1H); 8.22, dd (1H);
8.12, d (1H); 8.07, s (1H); 7.72, d (1H); 7.60, t (1H); 7.21,
d(1H); 7.14, d (1H); 6.93, dd (1H); 5.36, s (2H); 2.68, t (2H);
1.49, p (2H), 0.89, t (3H) 342.16/343.20 145 3-bromo-2-{[2-(6-
fluoropyridin-2-yl)-1H- imidazol-1- yl]methyl)imidazo[1,2-
a]pyrimidine ##STR383## ##STR384## H free base in CDCl3: 8.56, dd
(1H); 8.35, dd (1H); 8.09, dd (1H); 7.83, dd (1H); 7.32, s (1H);
7.14, s (1H); 6.99, dd (1H); 6.85, dd (1H); 6.18, s (2H)
372.01/375.00 146 3-ethyl-2-{[2-(6-fluoropyridin-
2-yl)-1H-imidazol-1- yl]methyl}imidazo[1,2- a]pyrimidine ##STR385##
##STR386## H di HCl salt in d6 DMSO: 9.23, dd (1H); 8.87, dd (1H);
8.36, m (2H); 7.93, d (1H); 7.86, d (1H); 7.50, m (2H); 6.19, s
(2H); 3.10, q (2H); 1.10, t (3H) 322.13/323.30 147
3-ethyl-2-{[2-(3- fluorophenyl)-1H-imidazol-1-
yl]methyl}imidazo[1,2- a]pyrimidine ##STR387## ##STR388## H di HCl
salt in d6 DMSO: 9.12, bd (1H); 8.77, bs (1H); 7.93, bm (2H); 7.71,
m (4H); 7.56, m (2H); 7.37, bs (1H); 5.71, s (2H); 2.97, q (2H);
1.10, t (3H) 321.14/322.30 148 3-{1-[(3-ethylimidazo[1,2-
a]pyrimidin-2-yl)methyl]-1H- imidazol-2-yl}benzonitrile ##STR389##
##STR390## H di HCl salt in d6 DMSO: 9.11, d (1H); 8.76, d (1H);
8.49, d (1H); 8.24, d (1H); 8.18, d (1H); 7.92, s (1H); 7.87, t
(1H); 7.79, s (1H); 7.36, t (1H); 5.71, s (2H), 2.99, q (2H) 1.11,
t (3H) 328.14/329.30 149 2-{[2-(6-chloropyridin-2-yl)-
1H-imidazol-1-yl]methyl}-3- ethylimidazo[1,2-a]pyrimidine
##STR391## ##STR392## H di HCl salt in d6 DMSO: 9.18, d (1H); 8.83,
s (1H); 8.36, d (1H); 8.19, t (1H); 7.92, s (1H); 7.81, s (1H);
7.78, d (1H); 7.44, bs (1H), 6.18, s (2H); 3.07, q (2H), 1.08, t
(3H) 338.10/339.20 150 2{[2-(3-chlorophenyl)-1H-
imidazol-1-yl]methyl}-3- ethylimidazo[1,2-a]pyrimidine ##STR393##
##STR394## H di HCl salt in d6 DMSO: 9.08, dd (1H); 8.74, dd (1H);
8.07, dd (1H); 7.90, m (2H); 7.80: m (2H); (1H); 7.34, dd (1H);
5.68, s (2H); 2.98, q (2H); 1.11, t (3H) 337.11/338.20 151
3-ethyl-2-({2-[2- (trifluoromethyl)phenyl]-1H- imidazol-1-
yl}methyl)imidazo[1,2- a]pyrimidine ##STR395## ##STR396## H di HCl
salt in d6 DMSO: 9.05, dd (1H); 8.75, dd (1H); 8.02, m (6H); 7.34,
dd (1H); 5.44, s (2H); 2.74, q (2H); 0.99, t (3H) 371.14/372.20 152
2-{[2-(2-chlorophenyl)-1H- imidazol-1-yl]methyl}-3-
ethylimidazo[1,2-a]pyrimidine ##STR397## ##STR398## H di HCl salt
in d6 DMSO: 9.05, dd (1H); 8.75, dd (1H); 7.96, m (3H); 7.77, d
(2H); 7.60, m (1H); 7.34, dd (1H); 5.52, s (2H); 2.74, q (2H);
1.00, t (3H) 337.11/338.20 153 3-ethyl-2-{[2-(2-
fluorophenyl)-1H-imidazol-1- yl]methyl}imidazo[1,2- a]pyrimidine
##STR399## ##STR400## H di HCl salt in d6 DMSO: 9.20, d (1H); 8.85,
dd (1H); 7.90, m (4H); 7.51, m (3H); 5.66, s (2H); 2.90, q (2H);
1.06, t (3H) 321.14/322.20 154 3-ethyl-2-{[2-(3-fluoropyridin-
2-yl)-1H-imidazol-1- yl]methyl)imidazo[1,2- a]pyrimidine ##STR401##
##STR402## H di HCl salt in d6 DMSO: 9.16, d (1H); 8.81, d (1H);
8.72, d (1H); 8.15, t (1H); 8.01, s (1H); 7.93, s (1H); 7.84, m
(1H); 7.42, dd (1H); 5.66, s (2H); 2.90, q (2H), 1.06, t (3H)
322.13/323.20 155 3-ethyl-2-{[2-(2-fluoropyridin-
4-yl)-1H-imidazol-1- yl]methyl)imidazo[1,2- a]pyrimidine ##STR403##
##STR404## H di HCl salt in d6 DMSO: 9.10, d (1H); 8.75, d (1H);
8.55, d (1H); 7.90, m (3H); 7.79, s (1H); 7.35, dd (1H); 5.76, s
(2H); 3.01, q (2H); 1.12, t (3H) 322.13/323.30 156
6-{1-[(3-ethylimidazo[1,2- a]pyrimidin-2-yl)methyl]-1H-
imidazol-2-yl}pyridine-2- carbonitrile ##STR405## ##STR406## H di
HCl salt in d6 DMSO: 9.23, d (1H); 8.87, d (1H); 8.60, d (1H);
8.34, dd (1H); 8.23, d (1H); 7.87, s (1H); 7.73, s (1H); 7.50, bs
(1H); 6.17, s (2H); 3.08, q (2H), 1.10, t (3H) 329.14/330.20 157
3-ethyl-2-({2-[5- (trifluoromethyl)pyridin-2-yl]- 1H-imidazol-1-
yl}methyl)imidazo[1,2- a]pyrimidine ##STR407## ##STR408## H di HCl
salt in d6 DMSO: 9.21, m (2H); 8.88, d (1H); 8.56, bs (2H); 7.93, s
(1H); 7.78, s (1H); 7.50, m (1H); 6.25, s (2H); 3.06, q (2H); 1.08,
t (3H) 372.13/373.20 158 3-bromo-2-{[2-(3-
fluorophenyl)-1H-imidazol-1- yl]methyl)imidazo[1,2- a]pyrimidine
##STR409## ##STR410## H di HC1 salt in d6 DMSO: 8.79, dd (1H);
8.63, dd (1H); 7.91, s (2H); 7.80, dd (1H); 7.68, m (2H); 7.54, m
(1H); 7.23, dd (1H); 5.61,s (2H); 371.02/374.00 159
3-bromo-2-({2-[6- (trifluoromethyl)pyridin-2-yl]- 1H-imidazol-1-
yl}methyl)imidazo[1,2- a]pyrimidine ##STR411## ##STR412## H di HCl
salt in d6 DMSO: 8.79, dd (1H); 8.62, d (1H); 8.57, dd (1H); 8.41,
t (1H); 8.10, d (1H); 7.98, d (1H); 7.93, s (1H); 7.21, dd (1H);
6.10, s (2H) 422.01/425.10 160 3-bromo-2-{[2-(1,5-dimethyl-
1H-pyrazol-3-yl)-1H- imidazol-1- yl]methyl)imidazo[1,2-
a]pyrimidine ##STR413## ##STR414## H di HCl salt in d6 DMSO: 8.82,
dd (1H); 8.61, dd (1H); 7.85, s (1H); 7.79, s (1H); 7.23, dd (1H);
7.00, s (1H); 3.86, s (3H); 6.77, 2.32, s (2H); 371.05/374.10 161
3-bromo-2-({2-[3- (trifluoromethyl)phenyl]-1H- imidazol-1-
yl}methyl)imidazo[1,2- a]pyrimidine ##STR415## ##STR416## H di HCl
salt in CD3OD: 8.89, dd (1H); 8.82, dd (1H); 8.16, d (1H); 8.06, d
(1H); 7.89, d (1H); 7.86, d (1H); 7.81, d (1H); 7.42, dd (1H);
5.74, s (2H) 421.01/424.30 162 3-bromo-2-{[2-(4-
methoxyphenyl)-1H-imidazol- 1-yllmethyl}imidazo[1,2- a]pyrimidine
##STR417## ##STR418## H di HCl salt in CD3OD: 8.90, dd (1H); 8.81,
dd (1H); 7.71, m (4H); 7.41, dd (1H); 7.21, d (2H); 5.71, s (2H);
3.90, s (3H) 383.04/386.00 163 3-bromo-2-({2-[3-fluoro-5-
(trifluoromethyl)phenyl]-1H- imidazol-1- yl}methyl)imidazo[1,2-
a]pyrimidine ##STR419## ##STR420## H di HCl salt in CD3OD: 8.86, dd
(1H); 8.78, dd (1H); 8.05, d (1H); 8.03, s (1H); 7.91, d (1H);
7.88, d (1H); 7.82, s (1H); 7.40, dd (1H); 5.73, s (2H)
439.01/441.90 164 3-bromo-2-{[2-(3,5- difluorophenyl)-1H-imidazol-
1-yl]methyl}imidazo[1,2- a]pyrimidine ##STR421## ##STR422## H di
HCl salt in CD3OD: 8.89, dd (1H); 8.80, dd (1H); 7.84, d (1H);
7.79, d (1H); 7.59, m (2H); 7.40, m (2H); 5.74, s (2H)
389.01/392.00 165 3-bromo-2-{[2-(2-methyl-1,3-
thiazol-4-yl)-1H-imidazol-1- yl]methyl}imidazo[1,2- a]pyrimidine
##STR423## ##STR424## H di HCl salt in CD3OD: 8.99, dd (1H); 8.87,
dd (1H); 8.41. s (1H); 7.81, s (1H); 7.75, s (1H); 7.51, dd (1H);
6.23, s (2H); 2.80, s (3H); 373.99/377.00 166
2-{[2-(3-fluorophenyl)-1H- imidazol-1-yl]methyl}-3-
methylimidazo[1,2- a]pyrimidine ##STR425## ##STR426## H di HCl salt
in d6 DMSO: 8.95, dd (1H); 8.71, dd (1H); 7.91, m (1H); 7.88, d
(1H); 7.85, d (1H); 7.73, m (2H); 7.56, m (1H); 7.32, m (1H); 5.66,
s (2H); 2.41, s (3H) 307.12/308.20 167 6-{1-[(3-methylimidazo[1,2-
a]pyrimidin-2-yl)methyl]-1H- imidazol-2-yl)pyridine-2- carbonitrile
##STR427## ##STR428## H di HCl salt in d6 DMSO: 9.07, dd (1H);
8.83, dd (1H); 8.53, d (1H); 8.31, dd (1H); 8.18, dd (1H); 7.82, s
(1H); 7.65, s (1H); 7.46, m (1H); 6.11, s (2H); 2.46, s (3H)
315.12/316.20 168 6-{1-[(3-bromoimidazo[1,2-
a]pyrimidin-2-yl)methyl]-1H- imidazol-2-yl}pyridine-2- carbonitrile
##STR429## ##STR430## H di HCl salt in d6 DMSO: 8.80, dd (1H);
8.59, dd (1H); 8.51, d (1H); 8.32, dd (1H); 8.20, d (1H); 7.97, d
(1H); 7.85, s (1H); 7.20, dd (1H); 6.04, s (2H) 379.02/382.00 169
2-{[2-(6-fluoropyridin-2-yl)- 1H-imidazol-1-yl]methyl}-3-
methylimidazo[1,2- a]pyrimidine ##STR431## ##STR432## H di HCl salt
in d6 DMSO: 9.07, dd (1H); 8.82, dd (1H); 8.32, m (2H); 7.90, s
(1H); 7.82, s (1H); 7.46, m (2H); 6.13, s (2H); 2.54, s (3H)
308.12/309.20 170 3-ethyl-2-({2-[6- (trifluoromethyl)pyridin-2-yl]-
1H-imidazol-1- yl}methyl)imidazo[1,2- a]pyrimidine ##STR433##
##STR434## H di HCl salt in d6 DMSO: 9.10, d (1H); 8.77, bs (1H);
8.53, d (1H); 8.37, t (1H); 8.07, d (1H); 7.76, s (1H); 7.64, s
(1H); 7.36, m (1H); 6.17, s (2H), 2.92, q (2H), 1.01, t (3H)
372.13/373.00 171 3-ethyl-2-{[2-(5- methylisoxazol-3-yl)-1H-
imidazol-1- yl]methyl}imidazo[1,2- a]pyrimidine ##STR435##
##STR436## H di HCl salt in d6 DMSO: 9.21, dd (1H); 8.86, dd (1H);
7.86, d (1H); 7.76, s (1H); 7.48, dd (1H); 7.16, s (1H); 6.01, s
(2H); 3.06, q (3H); 2.54, s (3H), 1.11, t (3H) 308.14/309.11 172
3-ethyl-2-{[2-(1,3-thiazol-2- yl)-1H-imidazol-1-
yl]methyl)imidazo[1,2- a]pyrimidine ##STR437## ##STR438## H di HCl
salt in d6 DMSO: 9.28, dd (1H); 896, dd (1H); 8.05, d (1H); 7.95, d
(1H); 7.74, s (1H); 7.59, dd (1H); 7.33, s (1H); 6.20, s (2H);
3.04, q (2H), 1.02, t (3H) 310.10/311.08 173
2-{[2-(2,3-difluorophenyl)- 1H-imidazol-1-yl]methyl}-3-
ethylimidazo[1,2-a]pyrimidine ##STR439## ##STR440## H di HCl salt
in d6 DMSO: 9.01, dd (1H); 8.76, bs (1H); 7.95, s (1H); 7.88, S
(1H); 7.79, m (2H); 7.51, dd (1H); 7.36. dd (1H); 5.64, s (2H);
2.92, q (2H), 1.01, t (3H) 339.13/340.10 174
2-{[2-(3,4-difluorophenyl)- 1H-imidazol-1-yl]methyl}-3-
ethylimidazo[1,2-a]pyrimidine ##STR441## ##STR442## H di HCl salt
in d6 DMSO: 9.13, dd (1H); 8.77, dd (1H); 8.21, t (1H); 7.88, s
(1H); 7.79, m (2H); 7.75, s (1H); 7.38, dd (1H); 5.68, s (2H);
2.98, q (2H), 1.06, t (3H) 339.13/340.08 175
3-ethyl-2-{[2-(6-fluoropyridin- 2-yl)-1H-imidazol-1- yl]methyl}-7-
methylimidazo[1,2- a]pyrimidine ##STR443## ##STR444## ##STR445## di
HCl salt in d6 DMSO: 9.17, dd (1H); 8.33, m (2H); 7.87,s (1H);
7.78, s (1H); 7.52, d (1H); 7.46, d (1H); 6.16, s (2H); 3.02, q
(2H); 2.65, s (3H); 1.06, t (3H) 336.15/337.07 176
3-ethyl-2-{[2-(5-fluoro-2- methylphenyl)-1H-imidazol-1-
yl]methyl}imidazo[1,2- a]pyrimidine ##STR446## ##STR447## H di HCl
salt in d6 DMSO: 9.03, dd (1H); 8.71, dd (1H); 7.89, s (1H); 7.73,
d (1H); 7.44, d (2H); 7.29, dd (1H); 5.50, s (2H); 2.81, q (2H);
2.10, s (3H), 1.04, t (3H) 335.15/336.08 177 2-{[2-(3-chloro-2,5-
difluorophenyl)-1H-imidazol- 1-yl]methyl}-3-ethyl-7-
(trifluoromethyl)imidazo[1,2- a]pyrimidine ##STR448## ##STR449##
##STR450## di HCl salt in d6 DMSO: 8.58, dd (1H); 8.26, bs (1H);
8.31, bs (2H); 7.97, bs (1H); 7.88, bs (1H); 7.47, m (1H); 6.13, s
(2H); 3.06, q (2H); 1.19, t (3H) 178 2-{[2-(2,5-difluorophenyl)-
1H-imidazol-1-yl]methyl}-3- ethylimidazo[1,2-a]pyrimidine
##STR451## ##STR452## H di HCl salt in d6 DMSO: 9.10, d (1H); 8.76,
d (1H); 7.98, dd (1H); 7.94, s (1H); 7.87, s (1H); 762, m (2H);
7.35, dd (1H); 5.64, s (2H); 2.93, q (2H); 1.07, t (3H)
339.13/340.10 179 2-{[2-(3-chloro-2,5- difluorophenyl)-1H-imidazol-
1-yl]methyl}-3- ethylimidazo[1,2-a]pyrimidine ##STR453## ##STR454##
H di HCl salt in d6 DMSO: 9.02, d (1H); 8.70, dd (1H); 8.03, dd
(1H); 7.96, s (1H); 7.91, s (1H); 7.47, t (1H); 7.29, dd (1H);
5.60, s (2H); 2.89, q (2H); 1.03, t (3H) 373.13/374.20 180
3-[1-[(3-ethylimidazo[1,2- a]pyrimidin-2-yl)methyl]-1H-
imidazol-2-yl)-4- fluorobenzonitrile ##STR455## ##STR456## H di HCl
salt in d6 DMSO: 9.00, dd (1H); 8.68, bs (1H); 8.54, dd (1H); 8.27,
m (1H); 7.91, s (1H); 7.88, s (1H); 7.75, t (1H); 7.26, dd (1H);
5.62, s (2H); 2.91, q (2H), 1.06, t (3H) 346.13/347.20
[0248] TABLE-US-00008 TABLE 6 ##STR457## Mass Spec (Cald./Obsd.
Cmp. # Name W R5 R3 R1 R 1H NMR M + 1) 181 3-Propyl-2-[2-(3-fluoro-
phenyl)-imidazol-1-ylmethyl]- 5-methyl-pyrazolo[1,5- a]pyrimidine
##STR458## ##STR459## ##STR460## H H 349.2/350.2 182
3-Propyl-2-[2-(2-fluoro- phenyl)-imidazol-1-ylmethyl]-
5-methyl-pyrazolo[1,5- a]pyrimidine ##STR461## ##STR462##
##STR463## H H 349.2/350.2 183 3-Propyl-2-[2-(4-fluoro-
phenyl)-imidazol-1-ylmethyl]- 5-methyl-pyrazolo[1,5- a]pyrimidine
##STR464## ##STR465## ##STR466## H H 349.2/350.2 184
3-Propyl-2[2-(2,5-difluoro- 5-methyl-pyrazolo[1,5- a]pyrimidine
##STR467## ##STR468## ##STR469## H H 367.2/368.2 185
3-Propyl-2-[2-(3-chloro-4- fluoro-phenyl)-imidazol-1-
ylmethyl]-5-methyl- pyrazolo[1,5-a]pyrimidine ##STR470## ##STR471##
##STR472## H H 383.1/384.2 186 3-Propyl-2-[2-(3-
chlorophenyl)-imidazol-1- ylmethyl]-5-methyl-
pyrazolo[1,5-a]pyrimidine ##STR473## ##STR474## ##STR475## H H
365.1/366.2 187 3-Propyl-2-[2-(3- fluorophenyl)-4-methyl-
imidazol-1-ylmethyl]-5- methyl-pyrazolo[1,5- a]pyrimidine
##STR476## ##STR477## ##STR478## H CH.sub.3 363.2/364.2 188
3-Propyl-2-[2-(2,5- difluorophenyl)-4-methyl-
imidazol-1-ylmethyl]-5- methyl-pyrazolo[1,5- a]pyrimidine
##STR479## ##STR480## ##STR481## H CH.sub.3 381.2/382.2 189
3-Ethyl-2-[2-(3-fluorophenyl)- imidazol-1-ylmethyl]-5-
methyl-7-methoxy- pyrazolo[1,5-a]pyrimidine ##STR482## ##STR483##
##STR484## OCH.sub.3 H 365.2/366.2 190
3-Ethyl-2-[2-(3-chlorophenyl)- methyl-7-methoxy-
imidazol-1-ylmethyl]-5- pyrazolo[1,5-a]pyrimidine ##STR485##
##STR486## ##STR487## OCH.sub.3 H 381.1/382.2 191
3-Ethyl-2-[2-(2,5- difluorophenyl)-imidazol-1-
ylmethyl]-5-methyl-7- methoxy-pyrazolo[1,5- a]pyrimidine ##STR488##
##STR489## ##STR490## OCH.sub.3 H 383.2/384.2 192
3-Ethyl-2-[2-(6-fluoro- pyridin-2-yl)-imidazol-1-
ylmethyl]-5-methyl- pyrazolo[1,5-a]pyrimidine ##STR491## ##STR492##
##STR493## H H Free base in CDCl3: 8.36, d (1H); 8.10, dd (1H);
7.81, q (1H); 7.12, s (1H); 7.07, s (1H); 6.84, dd (1H); 6.57, d
(1H); 6.12, s (2H); 2.71, q (2H); 2.56, s (3H); 1.04, t (3H)
[0249] TABLE-US-00009 TABLE 7 ##STR494## Cmp. # Name W R.sub.5
R.sub.3 MS NMR 193 4-(3-ethyl-2-([2-(1,3-thiazol-2-yl)-
1H-imidazol-1- yl]methyl)imidazo[1,2-a]pyridin-6-
yl)-2-methylbutan-2-ol ##STR495## ##STR496## ##STR497##
1HNMR(CDCl3, 400 MHz)-7.86(d, 1H), 7.67 (s, 1H), 7.48(d,1H),
7.33(d, 1H), 7.25(s, 1H), 7.01(m, 2H), 6.06(s, 2H), 2.90(q, 2H),
2.68(m, 2H), 1.78(m, 2H), 1.31 (s, 6H), 1.00(t, 3H). 194
(3E)-4-(3-ethyl-2-([2-(1,3-thiazol-2- yl)-1H-imidazol-1-
yl]methyl)imidazo[1,2-a]pyridin-6- yl)-2-methylbut-3-en-2-ol
##STR498## ##STR499## ##STR500## 1HNMR(CDCl3, 400 MHz)-7.86(d, 1H),
7.77 (s, 1H), 7.50 (d, 1H), 7.33(d, 1H), 7.25(s, 1H), 7.05 (s, 1H),
6.55 (d, 1H), 6.35(d, 1H), 6.06(s, 2H), 2.90(q, 2H), 1.31(s, 3H),
1.05 (s, 3H), 1.00(t, 3H). 195 3-ethyl-2-[(2-pyrimidin-2-yl-1H-
imidazol-1-yl)methyl]-6-(1,3-thiazol- 2-yl)imidazo[1,2-a]pyridine
##STR501## ##STR502## ##STR503## 382.2 free base in CDCl3: 8.85, d
(2H); 8.64, m(1H); 7.82, d (1H); 7.62, d (2H); 7.40, d (1H); 7.25,
m (3H); 6.13, s (2H); 3.95, q (2H); 1.10, t (3H) 196
3-ethyl-6-pyridin-2-yl-2-[(2- pyrimidin-2-yl-1H-imidazol-1-
yl)methyl]imidazo[1,2-a]pyridine ##STR504## ##STR505## ##STR506##
197 1-{3-ethyl-2-[(2-pyrimidin-2-yl-1H-
imidazol-1-yl)methyl]imidazo[1,2- a]pyridin-6-yl}ethanone
##STR507## ##STR508## ##STR509## free base in CDCl3: 8.84, d (2H);
8.56, m (1H); 7.67, dd (1H); 7.60, dd (1H); 7.23, m (3H); 6.14, s
(2H); 2.92, q (2H); 2.63, s (3H); 1.05, t (3H) 198
6-chloro-3-ethyl-2-[(2-pyrimidin-2- yl-1H-imidazol-1-
yl)methyl]imidazo[1,2-a]pyridine ##STR510## ##STR511## ##STR512## M
+ 1 (339.2) 1HNMR(CDCl3, 400 MHz)-8383 (d, 2H), 7.89 (d, 1H), 7.49
(d, 1H), 7.23 (m, 3H), 7.13 (d, 1H), 6.10 (s, 2H), 2.83(q, 2H),
1.03(t, 3H). 199 3-ethyl-6-(3-methoxypropyl)-2-[(2-
pyrimidin-2-yl-1H-imidazol-1- yl)methyl]imidazo[1,2-a]pyridine
##STR513## ##STR514## ##STR515## free base in CDCl3: 8.84, d (2H);
7.63, s (1H); 7.46, d (1H); 7.22, m (3H); 7.03, dd (1H); 6.14, s
(2H); 3.40, t (2H); 3.32 s (3H); 2.81, q (2H); 2.65, t (2H); 1.85,
m (2H); 1.02, t (3H). 200 3-ethyl-6-fluoro-2-[(2-pyrimidin-2-
yl-1H-imidazol-1- yl)methyl]imidazol[1,2-a]pyridine ##STR516##
##STR517## ##STR518## free base in CDCl3: 8.84, d (2H); 7.80, m
(1H); 7.52, dd (1H); 7.24, m (3H); 7.05, m (1H); 6.14, s (2H);
2.92, q (2H); 0.95, t (3H) 201 6-bromo-3-ethyl-2-[(2-pyrimidin-2-
yl-1H-imidazol-1- yl)methyl]imidazo[1,2-a]pyridine ##STR519##
##STR520## ##STR521## free base in CDC13: 8.84, d (2H); 8.00, m
(1H); 7.48, d (1H); 7.24, m (4H); 6.14, s (2H); 2.92, q (2H); 1.05,
t (3H) 202 3-ethyl-6-fluoro-2-{[2-(1,3-thiazol-2-
yl)-1H-imidazol-1- yl]methyl)imidazo[1,2-a]pyridine ##STR522##
##STR523## ##STR524## free base in CDCl3: 7.86, d (1H); 7.80, m
(1H); 7.55, m (1H); 7.35, d (1H); 7.26, s (1H); 7.09, m (2H); 6.14,
s (2H); 2.95 q (2H); 1.05, t (3H) 203
3-ethyl-6-(2-methylphenyl)-2-[(2- pyrimidin-2-yl-1H-imidazol-1-
yl)methyl]imidazo[1,2-a]pyridine ##STR525## ##STR526## ##STR527##
free base in CDCl3: 8.84, d (2H); 7.87, m (1H); 7.58, d (1H); 7.24,
m (8H); 6.14, s (2H); 2.85, q (2H); 2.29 s (3H); 1.05, t (3H) 204
3-ethyl-6-(2-methoxyphenyl)-2-[(2- pyrimidin-2-yl-1H-imidazol-1-
yl)methyl]imidazo[1,2-a]pyridine ##STR528## ##STR529## ##STR530##
free base in CDCl3: 8.84, d (2H); 8.02, m (1H); 7.58, dd (1H);
7.33, m (3H); 7.20, m (3H); 7.00, m (2H); 6.12, s (2H); 3.83, s
(3H); 2.85, q (2H); 1.05, t (3H) 205
3-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-6-[2-
(trifluoromethyl)phenyl]imidazo[1,2- a]pyridine ##STR531##
##STR532## ##STR533## 449.42 free base in CDCl3: 8.84, d (2H);
7.83, s (1H); 7.75, dd (1H); 7.53, m (3H); 7.38, d (1H); 7.30, s
(1H); 7.22, m (2H); 7.13, dd (1H); 6.15, s (2H); 2.85, q (2H);
1.00, t (3H)
[0250] TABLE-US-00010 TABLE 8 MS Cmp. calc/ # Name W R.sub.5
R.sub.3 1H NMR obs. 206 '1-(3-ethyl-2-{[(2-(1,3-thiazol-2-yl)-
1H-imidazol-1- yl]methyl}imidazo[1,2-b]pyridazin- 6-yl)ethanone
##STR534## ##STR535## ##STR536## free base in CDCl3: 7.95 (d, 1H);
7.88 (d, 1H), 7.69 (d, 1H), 7.35 (d, 1H), 7.26 (d, 1H), 7.13 (d,
1H), 6.18 (s, 2H), 3.09 (q, 2H), 2.75 (s, 3H), 1.18 (t, 3H) 207
4-(3-ethyl-2-{[2-(1,3-thiazol-2-yl)- 1H-imidazol-1-
yl]methyl}imidazo[1,2-b]pyridazin- 6-yl)-2-methylbutan-2-ol
##STR537## ##STR538## ##STR539## free base in CDCl3: 7.87 (d, 1H);
7.79 (d, 1H); 7.35 (d, 1H); 7.22 (d, 1H); 7.08 (d, 1H); 6.91 (d,
1H); 6.09 (s, 2H), 2.92-3.02 (in, 4H); 1.93 (t, 2H); 1.28 (s, 6H);
1.07 (t, 3H) 208 1-{3-ethyl-2-[(2-pyrimidin-2-yl-1H-
imidazol-1-yl)methyl]imidazo[1,2- b]pyridazin-6-yl}ethanone
##STR540## ##STR541## ##STR542## free base in CDCl3: 8.87 (d, 2H);
7.95 (d, 1H); 7.71 (d, 1H); 7.22-7.29 (m, 3H); 6.20 (s, 2H); 3.02
(q, 2H); 2.72 (s, 3H); 1.15 (t, 3H) 209
3-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]imidazo[1,2-
b]pyridazine ##STR543## ##STR544## H free base in CDCl3: 8.83 (d,
2H); 8.30 (d, 1H); 7.86 (d, 1H); 7.20-7.28 (m, 3H); 6.98 (dd, 1H);
6.13 (s, 2H); 2.97 (q, 2H); 1.06 (t, 3H) 210
3-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-6-(1,3-
thiazol-2-yl)imidazo[1,2- b]pyridazine ##STR545## ##STR546##
##STR547## free base in CD3OD: 9.07 (d, 2H); 8.31 (d, 1H); 8.20 (d,
1H); 8.07 (d, 1H); 7.93 (d, 1H); 7.89 (d, 1H); 7.84 (d, 1H); 7.69
(t, 1H); 6.50 (s, 2H); 3.32 (q, 2H); 1.42 (t, 3H) 211
3-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-6-
(trifluoromethyl)imidazo[1,2- b]pyridazine ##STR548## ##STR549##
##STR550## 373.1/ 374.1 212 3-ethyl-6-(2-isopropoxyethoxy)-2-
[(2-pyrimidin-2-yl-1H-imidazol-1-
yl)methyl]imidazo[1,2-b]pyridazine ##STR551## ##STR552## ##STR553##
1H NMR (CDCl3): 8.84 Cd, 2H), 7.77 (d, 1H), 7.22 (m, 3H), 6.68 (d,
1H), 6.07 (s, 2H), 4.44 (t, 2H), 3.80 (t, 2H), 3.67(m, 1H), 2.85
(2H), 1.90 (d, 6H), 1.06 (t, 3H). 407.4/ 408.4 213
3-ethyl-2-[(2-pyrimidin-2-yl-1H-
imidazol-1-yl)methyl]-6-(tetrahydro- 2H-pyran-4-yloxy)imidazo[1,2-
b]pyridazine ##STR554## ##STR555## ##STR556## 1H NMR(CDCl3): 8.85
(d, 2H), 7.72 (d, 1H), 7.23 (m, 3H), 6.64 (d, 1H), 6.08 (s, 2H),
5.16 (m, 1H), 3.97 (m, 2H), 3.62 (m, 2H), 2.84 (q, 2H), 2.09 (m,
2H), 1.86 (m, 2H), 1.07 (t, 3H). 405.4/ 406.4 214
6-(4-chloro-2-methylphenoxy)-3- ethyl-2-[(2-pyrimidin-2-yl-1H-
imidazol-1-yl)methyl]imidazo[1,2- b]pyridazine ##STR557##
##STR558## ##STR559## 1H NMr(CDCl3): 8.81 (d, 2H), 7.83(d, 1H),
7.23 (m, 5H), 7.02 (d, 1H), 6.83 (d, 1H), 6.07 (s, 2H), 2.68 (q,
2H), 2.18 (s, 3H), 0.88 (t, 3H). 445.2/ 446.2 215
3-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-6-{[4-
(trifluoromethyl)benzyl]oxy}imidazo [1,2-b]pyridazine ##STR560##
##STR561## ##STR562## 479.4/ 480.4 216
3-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-6-
(tetrahydrofuran-3- yloxy)imidazo[1,2-b]pyridazine ##STR563##
##STR564## ##STR565## 391.4/ 392.4 217
3-ethyl-2-[(2-pyrimidin-2-yl-1H- imidazol-1-yl)methyl]-6-[4-
(trifluoromethoxy)phenoxy]imidazo [1,2-b]pyridazine ##STR566##
##STR567## ##STR568## free base in CDCl3: 8.82 (d, 2H); 7.86 (d,
1H); 7.20-7.30 (m, 7H); 6.82 (d, 1H); 6.07 (s, 2H); 2.74 (q, 2H);
0.93 (t, 3H)
Example 15
Preparation of Radiolabeled Probe Compounds of the Invention
[0251] The compounds of the invention are prepared as radiolabeled
probes by carrying out their synthesis using precursors comprising
at least one atom that is a radioisotope. The radioisotope is
preferably selected from of at least one of carbon (preferably
.sup.14C), hydrogen (preferably .sup.3H), sulfur (preferably
.sup.35S), or iodine (preferably .sup.125I). Such radiolabeled
probes are conveniently synthesized by a radioisotope supplier
specializing in custom synthesis of radiolabeled probe compounds.
Such suppliers include Amersham Corporation, Arlington Heights,
Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRI
International, Menlo Park, Calif.; Wizard Laboratories, West
Sacramento, Calif.; ChemSyn Laboratories, Lexena, Kans.; American
Radiolabeled Chemicals, Inc., St. Louis, Mo.; and Moravek
Biochemicals Inc., Brea, Calif.
[0252] Tritium labeled probe compounds are also conveniently
prepared catalytically via platinum-catalyzed exchange in tritiated
acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic
acid, or heterogeneous-catalyzed exchange with tritium gas. Such
preparations are also conveniently carried out as a custom
radiolabeling by any of the suppliers listed in the preceding
paragraph using the compound of the invention as substrate. In
addition, certain precursors may be subjected to tritium-halogen
exchange with tritium gas, tritium gas reduction of unsaturated
bonds, or reduction using sodium borotritide, as appropriate.
Example 16
Receptor Autoradiography
[0253] Receptor autoradiography (receptor mapping) is carried out
in vitro as described by Kuhar in sections 8.1.1 to 8.1.9 of
Current Protocols in Pharmacology (1998) John Wiley & Sons, New
York, using radiolabeled compounds of the invention prepared as
described in the preceding Example.
Example 17
Binding Assay
[0254] The high affinity and high selectivity of preferred
compounds of the invention for the benzodiazepine site of the
GABA.sub.A receptor can be confirmed using the binding assay
described by Thomas and Tallman (J. Bio. Chem. 1981; 156:9838-9842,
and J. Neurosci. 1983; 3:433-440).
[0255] Rat cortical tissue is dissected and homogenized in 25
volumes (w/v) of Buffer A (0.05 M Tris HCl buffer, pH 7.4 at
4.degree. C.). The tissue homogenate is centrifuged in the cold
(4.degree. C.) at 20,000.times.g for 20 minutes. The supernatant is
decanted, the pellet rehomogenized in the same volume of buffer,
and centrifuged again at 20,000.times.g. The supernatant of this
centrifugation step is decanted. The resulting pellet may be stored
at -20.degree. C. overnight. The pellet is then thawed and
resuspended in 25 volumes of Buffer A (original wt/vol),
centrifuged at 20,000.times.g and the supernatant decanted. This
wash step is repeated once. The pellet is finally resuspended in 50
volumes of Buffer A.
[0256] Incubations contain 100 .mu.l of tissue homogenate, 100
.mu.l of radioligand, (0.5 nM .sup.3H-Ro15-1788
[.sup.3H-Flumazenil], specific activity 80 Ci/mmol), and test
compound or control (see below), and are brought to a total volume
of 500 .mu.l with Buffer A. Incubations are carried for 30 minutes
at 4.degree. C. and then rapidly filtered through Whatman GFB
filters to separate free and bound ligand. Filters are washed twice
with fresh Buffer A and counted in a liquid scintillation counter.
Nonspecific binding (control) is determined by displacement of
.sup.3H Ro15-1788 with 10 .mu.M Diazepam (Research Biochemicals
International, Natick, Mass.). Data are collected in triplicate,
averaged, and percent inhibition of total specific binding (Total
Specific Binding=Total-Nonspecific) is calculated for each
compound.
[0257] A competition binding curve may obtained with up to 11
points spanning the compound concentration range from 10.sup.-12M
to 10.sup.-5M obtained per curve by the method described above for
determining percent inhibition. K.sub.i values are calculated
according the Cheng-Prussof equation. Each of the compounds
disclosed in Tables 6-8 was tested in this fashion and each was
found to have a K.sub.i of <4 .mu.M. Preferred compounds of the
invention exhibit K.sub.i values of less than 100 nM and more
preferred compounds of the invention exhibit K.sub.i values of less
than 10 nM.
Example 18
Electrophysiology
[0258] The following assay can be used to determine if a compound
of the invention acts as an agonist, an antagonist, or an inverse
agonist at the benzodiazepine site of the GABA.sub.A receptor.
[0259] Assays are carried out as described in White and Gurley
(NeuroReport 6: 1313-1316, 1995) and White, Gurley, Hartnett,
Stirling, and Gregory (Receptors and Channels 3: 1-5, 1995) with
modifications. Electrophysiological recordings are carried out
using the two electrode voltage-clamp technique at a membrane
holding potential of -70 mV. Xenopus Laevis oocytes are
enzymatically isolated and injected with non-polyadenylated cRNA
mixed in a ratio of 4:1:4 for .alpha., .beta. and .gamma. subunits,
respectively. Of the nine combinations of .alpha., .beta. and
.gamma. subunits described in the White et al. publications,
preferred combinations are .alpha..sub.1.beta..sub.2.gamma..sub.2,
.alpha..sub.2.beta..sub.3.gamma..sub.2,
.alpha..sub.3.beta..sub.3.gamma..sub.2, and
.alpha..sub.5.beta..sub.3.gamma..sub.2. Preferably all of the
subunit cRNAs in each combination are human clones or all are rat
clones. The sequence of each of these cloned subunits is available
from GENBANK, e.g., human .alpha..sub.1, GENBANK accession no.
X14766, human .alpha..sub.2, GENBANK accession no. A28100; human
.alpha..sub.3, GENBANK accession no. A28102; human
.alpha..alpha..sub.5, GENBANK accession no. A28104; human
.beta..sub.2, GENBANK accession no. NM 021911; human .beta..sub.3,
GENBANK accession no. M82919 and accession no. Z20136; human
.beta..sub.2, GENBANK accession no. X15376; rat .alpha..sub.1,
GENBANK accession no. L08490, rat .alpha..sub.2, GENBANK accession
no. L08491; rat .alpha..sub.3, GENBANK accession no. L08492; rat
.alpha..sub.5, GENBANK accession no. L08494; rat .beta..sub.2,
GENBANK accession no. X15467; rat .beta..sub.3, GENBANK accession
no. X15468; and rat .gamma..sub.2, GENBANK accession no. L08497.
For each subunit combination, sufficient message for each
constituent subunit is injected to provide current amplitudes of
>10 nA when 1 .mu.M GABA is applied.
[0260] Compounds are evaluated against a GABA concentration that
evokes <10% of the maximal evokable GABA current (e.g. 1 .mu.M-9
.mu.M). Each oocyte is exposed to increasing concentrations of a
compound being evaluated (test compound) in order to evaluate a
concentration/effect relationship. Test compound efficacy is
calculated as a percent-change in current amplitude:
100*((Ic/I)-1), where Ic is the GABA evoked current amplitude
observed in the presence of test compound and I is the GABA evoked
current amplitude observed in the absence of the test compound.
[0261] Specificity of a test compound for the benzodiazepine site
is determined following completion of a concentration/effect curve.
After washing the oocyte sufficiently to remove previously applied
test compound, the oocyte is exposed to GABA+1 .mu.M Ro15-1788,
followed by exposure to GABA+1 .mu.M Ro15-1788+test compound.
Percent change due to addition of compound is calculated as
described above. Any percent change observed in the presence of
RO15-1788 is subtracted from the percent changes in current
amplitude observed in the absence of 1 .mu.M RO15-1788. These net
values are used for the calculation of average efficacy and
EC.sub.50 values by standard methods. To evaluate average efficacy
and EC.sub.50 values, the concentration/effect data are averaged
across cells and fit to the logistic equation.
[0262] It is to be understood that the foregoing describes
preferred embodiments of the present invention and that
modifications may be made therein without departing from the scope
of the present invention as set forth in the following claims.
* * * * *