U.S. patent application number 12/494057 was filed with the patent office on 2010-01-14 for certain thienopyrimidine derivatives as phosphodiesterase 10 inhibitors.
This patent application is currently assigned to Memory Pharmaceuticals Corporation. Invention is credited to Mark Phillip Arrington, Allen Hopper, Ruiping Liu, Ashok Tehim.
Application Number | 20100010017 12/494057 |
Document ID | / |
Family ID | 36128394 |
Filed Date | 2010-01-14 |
United States Patent
Application |
20100010017 |
Kind Code |
A1 |
Liu; Ruiping ; et
al. |
January 14, 2010 |
CERTAIN THIENOPYRIMIDINE DERIVATIVES AS PHOSPHODIESTERASE 10
INHIBITORS
Abstract
Certain thienopyrimidine derivatives are useful for the
inhibition of PDE10 enzymes, and thus are useful for treating
psychiatric or neurological syndromes, e.g., psychoses,
obsessive-compulsive disorder and/or Parkinson's disease, as well
as, for example, treating a disease state modulated by PDE10
activity.
Inventors: |
Liu; Ruiping; (Huntington,
NY) ; Arrington; Mark Phillip; (Westwood, NJ)
; Hopper; Allen; (Glen Rock, NJ) ; Tehim;
Ashok; (Ridgewood, NJ) |
Correspondence
Address: |
DARBY & DARBY P.C.
P.O. BOX 770, Church Street Station
New York
NY
10008-0770
US
|
Assignee: |
Memory Pharmaceuticals
Corporation
Montvale
NJ
|
Family ID: |
36128394 |
Appl. No.: |
12/494057 |
Filed: |
June 29, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11317907 |
Dec 22, 2005 |
7576080 |
|
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12494057 |
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60638179 |
Dec 23, 2004 |
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Current U.S.
Class: |
514/260.1 |
Current CPC
Class: |
A61P 3/04 20180101; A61P
7/12 20180101; A61P 25/08 20180101; A61P 25/18 20180101; A61P 25/14
20180101; A61P 43/00 20180101; A61P 25/28 20180101; A61P 25/00
20180101; C07D 495/04 20130101; A61P 3/10 20180101; A61P 25/22
20180101; A61P 25/16 20180101 |
Class at
Publication: |
514/260.1 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61P 25/28 20060101 A61P025/28; A61P 25/00 20060101
A61P025/00; A61P 7/12 20060101 A61P007/12 |
Claims
1.-62. (canceled)
63. A method of selectively inhibiting PDE10 enzyme in a patient in
need thereof comprising administering to said patient an effective
amount of at least one chemical entity chosen from compounds of
Formula I: ##STR00145## and pharmaceutically acceptable salts,
solvates, chelates, non-covalent complexes, prodrugs, and mixtures
thereof, wherein R.sup.1 is chosen from: (i) C.sub.6-10 aryl; (ii)
substituted C.sub.6-10 aryl chosen from mono-, di-, and
tri-substituted aryl wherein the substituents are independently
chosen from halo, C.sub.1-8 alkyl, halogenated C.sub.1-8 alkyl,
C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy, hydroxy C.sub.1-8
alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8 alkylamino,
di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl, C.sub.1-8
alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, and thio; (iii)
heterocyclyl; (iv) substituted heterocyclyl chosen from mono-, di-,
and tri-substituted heterocyclyl wherein the substituents are
independently chosen from halo, C.sub.1-8 alkyl, halogenated
C.sub.1-8 alkyl, C.sub.1-4alkoxy, halogenated C.sub.1-4 alkoxy,
hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8
alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl,
C.sub.1-8 alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, oxo, and thio; (v)
heteroaryl; and (vi) substituted heteroaryl chosen from mono-, di-,
and tri-substituted heteroaryl wherein the substituents are
independently chosen from halo, C.sub.1-8 alkyl, halogenated
C.sub.1-8 alkyl, C.sub.1-4alkoxy, halogenated C.sub.1-4 alkoxy,
hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8
alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl,
C.sub.1-8 alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, oxo, and thio;
R.sup.2 is chosen from C.sub.2-4 hydroxyalkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkenylene-R.sup.5, C.sub.2-4 alkynyl, C.sub.2-4
alkynylene-R.sup.5, --O-arylene-Y--R.sup.5,
--X(CR.sup.3R.sup.4).sub.nYR.sup.5 and
--(CR.sup.6R.sup.7).sub.mYR.sup.5 where: X is chosen from --O--,
--S-- and --NR.sup.9-- where R.sup.9 is chosen from H, C.sub.1-8
alkyl; and C.sub.3-8 cycloalkyl, substituted C.sub.1-8 alkyl; and
substituted C.sub.3-8 cycloalkyl, wherein the substituents on the
alkyl and cycloalkyl groups are independently chosen from halo,
C.sub.1-4-alkyl, C.sub.1-4-alkoxy, and oxo; Y is chosen from a
covalent bond, --O--, --S-- and --NR.sup.9--; n is chosen from 2,
3, 4, and 5; m is chosen from 2, 3, 4, and 5; R.sup.3 and R.sup.4
are each independently chosen from: (i) H; (ii) halo; (iii)
C.sub.1-12 alkyl; (iv) C.sub.2-12 alkenyl; (V) C.sub.2-12 alkynyl;
(vi) C.sub.3-12 cycloalkyl; (vii) substituted C.sub.1-12 alkyl
chosen from mono-, di-, and tri-substituted C.sub.1-12 alkyl and
wherein the substituents are independently chosen from halo,
hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, nitro,
cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; (viii)
substituted C.sub.2-12 alkenyl chosen from mono-, di-, and
tri-substituted C.sub.2-12 alkenyl wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; (ix) substituted C.sub.2-12 alkynyl
chosen from mono-, di-, and tri-substituted C.sub.2-12 alkynyl
wherein the substituents are independently chosen from halo,
hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, nitro,
cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; and (x)
substituted C.sub.3-12 cycloalkyl chosen from mono-, di-, and
tri-substituted C.sub.3-12 cycloalkyl wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkyl amino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; R.sup.6 and R.sup.7 are independently
chosen from (i) H; (ii) halo; (iii) C.sub.1-12 alkyl; (iv)
C.sub.2-12 alkenyl; (V) C.sub.2-12 alkynyl; (vi) C.sub.3-12
cycloalkyl; (vii) substituted C.sub.1-12 alkyl chosen from mono-,
di-, and tri-substituted C.sub.1-12 alkyl wherein the substituents
are independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; (viii) substituted C.sub.2-12 alkenyl
chosen from mono-, di-, and tri-substituted C.sub.2-12 alkenyl
wherein the substituents are independently chosen from halo,
hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, nitro,
cyano, carboxy, amino, C.sub.1-4 alkylamino, di-C.sub.1-4-alkyl
amino, C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; (ix) substituted C.sub.2-12 alkynyl
chosen from mono-, di-, and tri-substituted C.sub.2-12 alkynyl
wherein the substituents are independently chosen from halo,
hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, nitro,
cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; and (x)
substituted C.sub.3-12 cycloalkyl chosen from mono-, di-, and
tri-substituted C.sub.3-12 cycloalkyl wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; and R.sup.5 is chosen from C.sub.6-10
aryl, substituted C.sub.6-10 aryl, Het, substituted Het, C.sub.6-10
aryl-C.sub.1-8 alkyl, substituted C.sub.6-10 aryl-C.sub.1-8 alkyl,
Het-C.sub.1-8 alkyl, and substituted Het-C.sub.1-8 alkyl, wherein
the alkyl portions of C.sub.6-10 aryl-C.sub.1-8 alkyl and
Het-C.sub.1-8 alkyl are optionally substituted by oxo and wherein:
substituted C.sub.6-10 aryl is chosen from mono-, di-, and
tri-substituted C.sub.6-10 aryl wherein the substituents are
independently chosen from (1) C.sub.1-8 alkyl, (2) C.sub.3-8
cycloalkyl, (3) C.sub.4-8 cycloalkylalkyl, (4) C.sub.1-8 alkoxy,
(5) C.sub.3-8 cycloalkoxy, (6) C.sub.4-8 cycloalkylalkoxy, (7)
halo, (8) amino, (9) cyano, (10) hydroxyl, (11) nitro, (12)
C.sub.1-8 halogenated alkyl, (13) C.sub.1-8 halogenated alkoxy,
(14) C.sub.1-8 hydroxyalkyl, (15) C.sub.2-8 hydroxyalkoxy, (16)
C.sub.3-8 alkenyloxy, (17) C.sub.1-8 alkylamino, (18) di-C.sub.1-8
alkylamino, (19) carboxy, (20) alkoxycarbonyl, (21) carboxamido,
(22) aminocarbonyl, (23) hydroxyaminocarbonyl, (24)
alkylaminocarbonyl, (25) dialkylaminocarbonyl, (26) urea, (27)
hydroxyurea, (28) alkylurea, (29) dialkylaminoalkylcarbonyl, (30)
aminocarbonylalkylaminocarbonyl, (31) acylamido, (32)
HCO--NH--NH--CO--, (33) NH.sub.2NHCO--, (34) NH.sub.2NHCONH--, (35)
acyloxy, (36) C.sub.1-8 alkylthio, (37) C.sub.1-8 alkylsulphinyl,
(38) C.sub.1-8 alkylsulphonyl, (39) C.sub.1-8 alkylsulphonamido,
(40) (alkylsuphonyl).sub.2-amino-, (41) thiol, (42) aminosulfonyl,
(43) alkylaminosulfonyl, 44) C.sub.6-10 aryl, (45) substituted
C.sub.6-10 aryl chosen from mono-, di-, and trisubstituted
C.sub.6-10 aryl wherein the substituents are independently chosen
from C.sub.1-8 alkyl, halogenated C.sub.1-8 alkyl, C.sub.1-4
alkoxy, halogenated C.sub.1-4 alkoxy, C.sub.1-8 hydroxyalkyl,
C.sub.2-8 hydroxyalkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8
alkylamino, C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl,
C.sub.1-8 alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9,
cyano, hydroxyl, nitro, and thio; (46) heterocyclyl; (47)
substituted heterocyclyl chosen from mono-, di-, and trisubstituted
heterocyclyl wherein the substituents are independently chosen from
halo, C.sub.1-8 alkyl, halogenated C.sub.1-8 alkyl, C.sub.1-4
alkoxy, halogenated C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl,
hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8
alkylamino, C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl,
C.sub.1-8 alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9,
cyano, hydroxyl, nitro, oxo, and thio; (48) heterocyclyl-carbonyl;
and (49) heterocyclyl-carbonyl chosen from mono-, di-, and
trisubstituted heterocyclyl-carbonyl wherein the substituents are
independently chosen from halo, C.sub.1-8 alkyl, halogenated
C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy,
hydroxy C.sub.1-8 alkyl hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8
alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl,
C.sub.1-8 alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, oxo, and thio; and
Het is chosen from heterocyclyl, substituted heterocyclyl chosen
from mono-, di-, and tri-substituted heterocyclyl, heteroaryl, and
substituted heteroaryl chosen from mono-, di-, and tri-substituted
heteroaryl, wherein the substituents are independently chosen from
(1) C.sub.1-8 alkyl, (2) C.sub.3-8 cycloalkyl, (3) C.sub.4-8
cycloalkylalkyl, (4) C.sub.1-8 alkoxy, (5) C.sub.3-8 cycloalkoxy,
(6) C.sub.4-8 cycloalkylalkoxy, (7) halo, (8) amino, (9) cyano,
(10) hydroxyl, (11) nitro, (12) C.sub.1-8 halogenated alkyl, (13)
C.sub.1-8 halogenated alkoxy, (14) C.sub.1-8 hydroxyalkyl, (15)
C.sub.2-8 hydroxyalkoxy, (16) C.sub.3-8 alkenyloxy, (17) C.sub.1-8
alkylamino, (18) di-C.sub.1-8 alkylamino, (19) carboxy, (20)
alkoxycarbonyl, (21) carboxamido, (22) aminocarbonyl, (23)
hydroxyaminocarbonyl, (24) alkylaminocarbonyl, (25)
dialkylaminocarbonyl, (26) urea, (27) hydroxyurea, (28) alkylurea,
(29) dialkylaminoalkylcarbonyl, (30)
aminocarbonylalkylaminocarbonyl, (31) acylamido, (32)
HCO--NH--NH--CO--, (33) NH.sub.2NHCO--, (34) NH.sub.2NHCONH--, (35)
acyloxy, (36) C.sub.1-8 alkylthio, (37) C.sub.1-8 alkylsulphinyl,
(38) C.sub.1-8 alkylsulphonyl, (39) C.sub.1-8 alkylsulphonamido,
(40) (alkylsuphonyl).sub.2-amino-, (41) thiol, (42) aminosulfonyl,
(43) alkylaminosulfonyl, (44) oxo, (45) C.sub.6-20 aryl, (46)
substituted C.sub.6-20 aryl chosen from mono-, di-, and
tri-substituted C.sub.6-20 aryl wherein the substituents are
independently chosen from halo, C.sub.1-8 alkyl, halogenated
C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy,
C.sub.1-8 hydroxyalkyl, C.sub.2-8 hydroxyalkoxy, amino, C.sub.1-8
alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl,
C.sub.1-8 alkylsuphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, and thio, (47)
heterocyclyl, (48) substituted heterocyclyl chosen from mono-, di-,
and trisubstituted heterocyclyl wherein the substituents are
independently chosen from halo, C.sub.1-8 alkyl, halogenated
C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy,
hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8 alkoxy amino, C.sub.1-8
alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl,
C.sub.1-8 alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, oxo, and thio,
(49) heteroaryl, (50) substituted heteroaryl chosen from mono-,
di-, and trisubstituted heteroaryl wherein the substituents are
independently chosen from halo, C.sub.1-8 alkyl, halogenated
C.sub.1-8 alkyl C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy,
hydroxy C.sub.1-8 alkyl, hydroxy C.sub.1-8 alkoxy, amino, C.sub.1-8
alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl,
C.sub.1-8 alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sub.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, oxo, and thio,
(51) heterocyclyl-carbonyl, (52) substituted heterocyclyl-carbonyl
chosen from mono-, di-, and trisubstituted heterocyclyl-carbonyl
wherein the substituents are independently chosen from halo,
C.sub.1-8 alkyl, halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy,
halogenated C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy
C.sub.2-8 alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8
alkylamino, C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl,
C.sub.1-8 alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9,
cyano, hydroxyl, nitro, oxo, and thio, (53) heteroaryl-carbonyl,
and (54) substituted heteroaryl-carbonyl chosen from mono-, di-,
and trisubstituted heteroaryl-carbonyl wherein the substituents are
independently chosen from halo, C.sub.1-8 alkyl, halogenated
C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy,
hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8
alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl,
C.sub.1-8 alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, oxo, and thio, and
R.sup.9 is chosen from H, C.sub.1-8 alkyl, C.sub.3-8 cycloalkyl,
substituted C.sub.1-8 alkyl chosen from mono-, di-, and
trisubstituted C.sub.1-8 alkyl, and substituted C.sub.3-8
cycloalkyl chosen from mono-, di-, and trisubstituted C.sub.3-8
cycloalkyl wherein the substituents are independently chosen from
halo, C.sub.1-4-alkyl, C.sub.1-4-alkoxy, and oxo; and provided that
the compound of Formula I is not chosen from: (i) when R.sup.1 is
4-methylphenyl, then R.sup.2 is not
--O-p-phenylene-O--(CH.sub.2)phenyl,
--O-p-phenylene-NH--C(O)-thiophen-2-yl,
--O--(CH.sub.2).sub.2--O-(phenyl),
--NH(CH.sub.2).sub.2-(4-hydroxyphenyl),
--O--(CH.sub.2).sub.2-(1,3-dioxoisoindolin-1-yl),
--NH(CH.sub.2).sub.2-(2-oxo-imidazolidin-1-yl),
--NH(CH.sub.2).sub.2-(3,4,-dimethoxyphenyl),
--S(CH.sub.2).sub.2-phenyl, --NH(CH.sub.2).sub.2-phenyl,
--NH(CH.sub.2).sub.2-morpholin-4-yl,
--NH(CH.sub.2).sub.2-thiophen-2-yl,
--NH(CH.sub.2).sub.2-(3,4-methylenedioxyphenyl),
--NH(CH.sub.2).sub.3-morpholinyl, or --S(CH.sub.2).sub.3-phenyl;
(ii) 2-methoxy-4-[[[2-[(5-phenylthieno[2,3-d]pyrimidin
yl)amino]ethyl]imino]-methyl]-phenol; (iii)
4,4'-[1,3-phenylenebis(oxy)bis[5-(4-chlorophenyl)-thieno[2,3-d]pyrimidine-
-; (iv) when R.sup.1 is phenyl, then R.sup.2 is not
--O-p-phenylene-NH--C(O)-3, -4-dimethoxyphenyl,
--O--(CH.sub.2).sub.2--O-(4-methylphenyl),
--O--(CH.sub.2).sub.2--Ophenyl,
--O--(CH.sub.2).sub.2-(3-bromophenyl),
--NH--(CH.sub.2).sub.2--NH(3-CF.sub.3-pyridin-2-yl),
--S--(CH.sub.2).sub.2--O-(3-methylphenyl),
--S--(CH.sub.2).sub.2--O-(4-Fphenyl),
--S--(CH.sub.2).sub.2--O-(2,4-dichlorophenyl),
--NH--(CH.sub.2).sub.2--NH(4-CF.sub.3-pyrimidin-2-yl),
--NH--(CH.sub.2).sub.2--O-(3-acetylaminophenyl),
--S--(CH.sub.2).sub.3-phenyl,
--S--(CH.sub.2).sub.4-(1,3-dioxoisoindolin-1-yl),
--NH--(CH.sub.2).sub.3-morpholin-4-yl,
--NH--(CH.sub.2).sub.3-imidazol-1-yl,
--NH--(CH.sub.2).sub.3-(2-oxo-pyrrolidin-1-yl),
--N(CH.sub.3)--(CH.sub.2).sub.2-pyridin-2-yl,
--NH--(CH.sub.2).sub.2-pyridin-2-yl,
--S--(CH.sub.2).sub.2-(1,3-dioxoisoindolin-1-yl,
--S--(CH.sub.2).sub.2-phenyl,
--NH--(CH.sub.2).sub.2-(2-chlorophenyl),
--NH--(CH.sub.2).sub.2-morpholin-4-yl,
--NH--(CH.sub.2).sub.2-(3,4-dimethoxyphenyl),
--NH--(CH.sub.2).sub.2-thiophen-2-yl, or
--NH--(CH.sub.2).sub.2-phenyl; (v) when R.sup.1 is 4-fluorophenyl,
then R.sup.2 is not chosen from
--O--(CH.sub.2).sub.2--O-(2-chlorophenyl),
--O--(CH.sub.2).sub.2--O-(4-fluorophenyl),
--S--(CH.sub.2).sub.3-phenyl, --NH--(CH.sub.2).sub.3-phenyl,
--NH--(CH.sub.2).sub.2-phenyl,
--NH--(CH.sub.2).sub.3-morpholin-4-yl,
--NH--(CH.sub.2).sub.3-(2-oxo-pyrrolidin-1-yl),
--NH--(CH.sub.2).sub.2-morpholin-4-yl,
--S--(CH.sub.2).sub.2-phenyl, --NH--(CH.sub.2).sub.2-azepan-1-yl,
--S--(CH.sub.2).sub.2-morpholin-4-yl,
--NH--(CH.sub.2).sub.2-(3,4-methylenedioxyphenyl),
--NH--(CH.sub.2).sub.2-thiophen-2-yl, and
--NH--(CH.sub.2).sub.2-(3,4-ethylenedioxyphenyl); (vi) when R.sup.1
is 4-chlorophenyl, then R.sup.2 is not chosen from
--O-p-phenylene-O--CH.sub.2-phenyl,
--O--(CH.sub.2).sub.2--O-(4-methylphenyl),
--S--(CH.sub.2).sub.4-(1,3-dioxoisoindolin-1-yl),
--S--(CH.sub.2).sub.3-phenyl, --S--(CH.sub.2).sub.2-phenyl,
--NH--(CH.sub.2).sub.3-imidazol-1-yl,
--NH--(CH.sub.2).sub.3-morpholin-4-yl,
--NH--(CH.sub.2).sub.2-morpholin-4-yl,
--NH--(CH.sub.2).sub.2-azepan-1-yl,
--S--(CH.sub.2).sub.2-(1,3-dioxoisoindolin-1-yl),
--NH--(CH.sub.2).sub.2-(3,4-methylenedioxyphenyl),
--NH--(CH.sub.2).sub.2-phenyl,
--NH--(CH.sub.2).sub.2-thiophen-2-yl,
--NH--(CH.sub.2).sub.2-(3,4-ethylenedioxyphenyl),
--S--(CH.sub.2).sub.4-(1,3-dioxoisoindolin-1-yl),
--NH(CH.sub.2).sub.3-(2-oxo-pyrrolidin-1-yl), and
--NH(CH.sub.2).sub.2-(3,4,-dimethoxyphenyl); (vii) when R.sup.1 is
3-methylphenyl, then R.sup.2 is not
--O--(CH.sub.2).sub.2--O-(phenyl); (viii) when R.sup.1 is
3-thiophen-2-yl, then R.sup.2 is not chosen from
--NH--(CH.sub.2).sub.2-morpholin-4-yl,
--NH--(CH.sub.2).sub.3-morpholin-4-yl,
--NH--(CH.sub.2).sub.2-phenyl, and
--NH--(CH.sub.2).sub.2-(3,4-dimethoxyphenyl); (ix) when R.sup.1 is
4-methoxyphenyl, then R.sup.2 is not chosen from
--S--(CH.sub.2).sub.3-phenyl,
--NH--(CH.sub.2).sub.2-morpholin-4-yl,
--NH--(CH.sub.2).sub.2--(CH.sub.3).sub.2-morpholin-4-yl,
--NHCH.sub.2C(CH.sub.3).sub.2-morpholin-4-yl,
--N(CH.sub.3)--(CH.sub.2).sub.2-(3,4-dimethoxyphenyl),
--S--(CH.sub.2).sub.2-phenyl, and
--NH--(CH.sub.2).sub.2-(3,4-methylenedioxyphenyl); (x) when R.sup.1
is 3,4-dimethylphenyl, then R.sup.2 is not chosen from
--O-p-phenylene-O--CH.sub.2-phenyl, --S--(CH.sub.2).sub.3-phenyl,
--S--(CH.sub.2).sub.3-morpholin-4-yl, --S--(CH.sub.2).sub.2-phenyl,
--NH--(CH.sub.2).sub.3-(4-hydroxyphenyl),
--O--(CH.sub.2).sub.2-(1,3-dioxoisoindolin-1-yl),
--NH--(CH.sub.2).sub.2-morpholin-4-yl,
--NH--(CH.sub.2).sub.3-morpholin-4-yl,
--NH--(CH.sub.2).sub.2-(3,4-methylenedioxyphenyl),
--S--(CH.sub.2).sub.2-phenyl, --NH--(CH.sub.2).sub.2-phenyl,
--NH--(CH.sub.2).sub.2-thiophen-2-yl, and
--NH--(CH.sub.2).sub.2-(3,4-methylenedioxyphenyl); (xi) when
R.sup.1 is 4-bromophenyl, then R.sup.2 is not chosen from
--(CH.sub.2).sub.3-phenyl, --S--(CH.sub.2).sub.3-morpholin-4-yl,
--S--(CH.sub.2).sub.2-phenyl, --S--(CH.sub.2).sub.3-phenyl,
--NH--(CH.sub.2).sub.3-morpholin-4-yl,
--NH--(CH.sub.2).sub.3-(2-oxo-pyrrolidin-1-yl), and
--NH--(CH.sub.2).sub.2-(3,4-ethylenedioxyphenyl); and (xii) when
R.sup.1 is 4-biphenyl, then R.sup.2 is not
--NH--(CH.sub.2).sub.2-(3,4-ethylenedioxyphenyl); (xiii) when
R.sup.1 is 2,3-dihydro-1,4-benzodioxin-2-yl, then R.sup.2 is not
NH(CH.sub.2).sub.2-phenyl, and (xiv)
5-(2-chlorophenyl)-4-[4-(phenylmethoxy)phenoxy]-thieno[2,3-d]pyrimidine.
64-81. (canceled)
82. The method of claim 63 wherein the patient is suffering from a
psychiatric or neurological syndrome.
83. The method of claim 63 wherein the patient is suffering from
bipolar disorder, schizophrenia, obsessive-compulsive disorder,
Parkinson's disease, Alzheimer's disease, multiple sclerosis,
Huntington's disease, a disorder affecting the function of the
basal ganglia, diabetes or obesity.
84. The method of claim 63, wherein said patient is suffering from
memory and/or cognitive impairment associated with Parkinson's
disease, Alzheimer's disease, dementia, epilepsy, multiple
sclerosis, or Huntington's disease.
Description
[0001] This application claims priority to U.S. provisional
application No. 60/638,179, filed on Dec. 23, 2004.
[0002] Provided are certain thienopyrimidines, methods of preparing
such compounds, compositions containing such compounds, and methods
of use thereof.
[0003] Neurotransmitters and hormones, as well as other types of
extracellular signals such as light and odors, create intracellular
signals by altering the amounts of cyclic nucleotide monophosphates
(cAMP and cGMP) within cells. These intracellular messengers alter
the functions of many intracellular proteins. Cyclic AMP regulates
the activity of cAMP-dependent protein kinase (PKA). PKA
phosphorylates and regulates the function of many types of
proteins, including ion channels, enzymes, and transcription
factors. Downstream mediators of cGMP signaling also include
kinases and ion channels. In addition to actions mediated by
kinases, cAMP and cGMP bind directly to some cellular proteins and
directly regulate their activity.
[0004] Cyclic nucleotides are produced from the actions of adenylyl
cyclase and guanylyl cyclase which convert ATP to cAMP and GTP to
cGMP, respectively. Extracellular signals, often through the
actions of G protein-coupled receptors, regulate the activity of
the cyclases. Alternatively, the amount of cAMP and cGMP may be
altered by regulating the activity of the enzymes that degrade
cyclic nucleotides. Cell homeostasis is maintained by the rapid
degradation of cyclic nucleotides after stimulus-induced increases.
The enzymes that degrade cyclic nucleotides are called 3',5'-cyclic
nucleotide-specific phosphodiesterases (PDEs).
[0005] Eleven PDE gene families (PDE1-PDE11) have been identified
so far, based on their distinct amino acid sequences, catalytic and
regulatory characteristics, and sensitivity to small molecule
inhibitors. These PDE families are coded for by 21 genes; and
further multiple splice variants are transcribed from many of these
genes. Expression patterns of each of the gene families are
distinct. PDEs differ with respect to their affinity for cAMP and
cGMP. Activities of different PDEs are regulated by different
signals. For example, PDE1 is stimulated by Ca.sup.2+/calmodulin,
PDE2 activity is stimulated by cGMP, PDE3 is inhibited by cGMP,
PDE4 is cAMP specific and is specifically inhibited by rolipram,
PDE5 is cGMP-specific and PDE6 is expressed in retina. Less is
known about the expression patterns and functional attributes of
the higher number PDEs (7 through 11).
[0006] PDE10 sequences were first identified by using
bioinformatics and sequence information from other PDE gene
families (Fujishige et al., J. Biol. Chem. 274:18438-18445, 1999;
Loughney, K. et al., Gene 234:109-117, 1999; Soderling, S. et al.,
Proc. Natl. Acad. Sci. USA 96:7071-7076, 1999). PDE10 is defined as
a unique gene family based on its amino acid sequence, functional
properties and tissue distribution. The human PDE10 gene is large,
over 200 kb, with up to 24 exons coding for each of the splice
variants. The amino acid sequence is characterized by two GAF
domains (which bind cGMP), a catalytic region, and alternatively
spliced N and C termini. Numerous splice variants are possible
because of at least 3 alternative exons encoding the N and 2 for
the C-termini. PDE10A1, a splice variant of PDE10, is a 779 amino
acid protein that hydrolyzes both cAMP and cGMP. The K.sub.m values
for cAMP and cGMP are 0.05 and 3.0 micromolar, respectively. In
addition to human variants, several variants with high homology
have been isolated from both rat and mouse tissues and sequence
banks.
[0007] PDE10 transcripts were initially detected in RNA from human
testis and brain. Immunohistochemical analysis identified specific
brain regions enriched in PDE10. The basal ganglia express the
highest amounts of PDE10. Specifically, striatal neurons in the
olfactory tubercle, caudate nucleus and nucleus accumbens are
enriched in PDE10 (Seeger, T. F. et al., Brain Res. 2003, Sept. 26,
985(2):113-26). Western blots did not reveal the expression of
PDE10 in other brain tissues, although immunoprecipitation of the
PDE10 complex was possible in hippocampal and cortical tissues.
This suggests that the expression level of PDE10 in these other
tissues is 100-fold less than in striatal neurons. Expression in
hippocampus is limited to the cell bodies, whereas PDE10is
expressed in terminals, dendrites and axons of striatal
neurons.
[0008] The tissue distribution of PDE10 indicates that PDE10
inhibitors may play an important role in the basal ganglia. PDE10
selective inhibitors could be used to raise levels of cAMP and/or
cGMP within cells that express the PDE10 enzyme, especially neurons
that comprise the basal ganglia. Selective PDE10 inhibition could
lead to altered basal ganglia function and may be effective in
treating a variety of neuropsychiatric conditions involving the
basal ganglia.
[0009] Provided is at least one chemical entity chosen from
compounds of Formula I:
##STR00001##
and pharmaceutically acceptable salts, solvates, chelates,
non-covalent complexes, prodrugs, and mixtures thereof, wherein
R.sup.1 is chosen from: [0010] (i) C.sub.6-10 aryl; [0011] (ii)
substituted C.sub.6-10 aryl chosen from mono-, di-, and
tri-substituted aryl wherein the substituents are independently
chosen from halo, C.sub.1-8 alkyl, halogenated C.sub.1-8 alkyl,
C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy, hydroxy C.sub.1-8
alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8 alkylamino,
di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl, C.sub.1-8
alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, and thio; [0012]
(iii) heterocyclyl; [0013] (iv) substituted heterocyclyl chosen
from mono-, di-, and tri-substituted heterocyclyl wherein the
substitutents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio; [0014] (v) heteroaryl; and [0015]
(vi) substituted heteroaryl chosen from mono-, di-, and
tri-substituted heteroaryl wherein the substitutents are
independently chosen from halo, C.sub.1-8 alkyl, halogenated
C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy,
hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8
alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl,
C.sub.1-8 alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, oxo, and thio;
[0016] R.sup.2 is chosen from C.sub.2-4 hydroxyalkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkenylene-R.sup.5, C.sub.2-4 alkynyl, C.sub.2-4
alkynylene-R.sup.5, --O-arylene-Y--R.sup.5,
--X(CR.sup.3R.sup.4).sub.nYR.sup.5 and
--(CR.sup.6R.sup.7).sub.mYR.sup.5 where: [0017] X is chosen from
--O--, --S-- and --NR.sup.9-- where R.sup.9 is chosen from H,
C.sub.1-8 alkyl; and C.sub.3-8 cycloalkyl, substituted C.sub.1-8
alkyl; and substituted C.sub.3-8 cycloalkyl, wherein the
substituents on the alkyl and cycloalkyl groups are independently
chosen from halo, C.sub.1-4-alkyl, C.sub.1-4-alkoxy, and oxo;
[0018] Y is chosen from a covalent bond, --O--, --S-- and
--NR.sup.9--; [0019] n is chosen from 2, 3, 4, and 5; [0020] m is
chosen from 2, 3, 4, and 5; [0021] R.sup.3 and R.sup.4 are each
independently chosen from: [0022] (i) H; [0023] (ii) halo; [0024]
(iii) C.sub.1-12 alkyl; [0025] (iv) C.sub.2-12 alkenyl; [0026] (v)
C.sub.2-12 alkynyl; [0027] (vi) C.sub.3-12 cycloalkyl; [0028] (vii)
substituted C.sub.1-12 alkyl chosen from mono-, di-, and
tri-substituted C.sub.1-12 alkyl and wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; [0029] (viii) substituted C.sub.2-12
alkenyl chosen from mono-, di-, and tri-substituted C.sub.2-12
alkenyl wherein the substituents are independently chosen from
halo, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
nitro, cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; [0030] (ix)
substituted C.sub.2-12 alkynyl chosen from mono-, di-, and
tri-substituted C.sub.2-12 alkynyl wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; and [0031] (x) substituted C.sub.3-12
cycloalkyl chosen from mono-, di-, and tri-substituted C.sub.3-12
cycloalkyl wherein the substituents are independently chosen from
halo, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
nitro, cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; [0032]
R.sup.6 and R.sup.7 are independently chosen from [0033] (i) H;
[0034] (ii) halo; [0035] (iii) C.sub.1-12 alkyl; [0036] (iv)
C.sub.2-12 alkenyl; [0037] (v) C.sub.2-12 alkynyl; [0038] (vi)
C.sub.3-12 cycloalkyl; [0039] (vii) substituted C.sub.1-12 alkyl
chosen from mono-, di-, and tri-substituted C.sub.1-12 alkyl
wherein the substituents are independently chosen from halo,
hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, nitro,
cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; [0040]
(viii) substituted C.sub.2-12 alkenyl chosen from mono-, di-, and
tri-substituted C.sub.2-12 alkenyl wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; [0041] (ix) substituted C.sub.2-12
alkynyl chosen from mono-, di-, and tri-substituted C.sub.2-12
alkynyl wherein the substituents are independently chosen from
halo, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
nitro, cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; and [0042]
(x) substituted C.sub.3-12 cycloalkyl chosen from mono-, di-, and
tri-substituted C.sub.3-12 cycloalkyl wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; and [0043] R.sup.5 is chosen from
C.sub.6-10 aryl, substituted C.sub.6-10 aryl, Het, substituted Het,
C.sub.6-10 aryl-C.sub.1-8 alkyl, substituted C.sub.6-10
aryl-C.sub.1-8 alkyl, Het-C.sub.1-8 alkyl, and substituted
Het-C.sub.1-8 alkyl, wherein the alkyl portions of C.sub.6-10
aryl-C.sub.1-8 alkyl and Het-C.sub.1-8 alkyl are optionally
substituted by oxo and wherein: [0044] substituted C.sub.6-10 aryl
is chosen from mono-, di-, and tri-substituted C.sub.6-10 aryl
wherein the substituents are independently chosen from [0045] (1)
C.sub.1-8 alkyl, [0046] (2) C.sub.3-8 cycloalkyl, [0047] (3)
C.sub.4-8 cycloalkylalkyl, [0048] (4) C.sub.1-8 alkoxy, [0049] (5)
C.sub.3-8 cycloalkoxy, [0050] (6) C.sub.4-8 cycloalkylalkoxy,
[0051] (7) halo (such as F or Cl), [0052] (8) amino, [0053] (9)
cyano, [0054] (10) hydroxyl, [0055] (b 11) nitro, [0056] (12)
C.sub.1-8 halogenated alkyl, [0057] (13) C.sub.1-8 halogenated
alkoxy, [0058] (14) C.sub.1-8 hydroxyalkyl, [0059] (15) C.sub.2-8
hydroxyalkoxy, [0060] (16) C.sub.3-8 alkenyloxy, [0061] (17)
C.sub.1-8 alkylamino, [0062] (18) di-C.sub.1-8 alkylamino, [0063]
(19) carboxy, [0064] (20) alkoxycarbonyl, [0065] (21) carboxamido,
[0066] (22) aminocarbonyl, [0067] (23) hydroxyaminocarbonyl, [0068]
(24) alkylaminocarbonyl, [0069] (25) dialkylaminocarbonyl, [0070]
(26) urea, [0071] (27) hydroxyurea, [0072] (28) alkylurea, [0073]
(29) dialkylaminoalkylcarbonyl, [0074] (30)
aminocarbonylalkylaminocarbonyl, [0075] (31) acylamido, [0076] (32)
HCO--NH--NH--CO--, [0077] (33) NH.sub.2NHCO--, [0078] (34)
NH.sub.2NHCONH--, [0079] (35) acyloxy, [0080] (36) C.sub.1-8
alkylthio, [0081] (37) C.sub.1-8 alkylsulphinyl, [0082] (38)
C.sub.1-8 alkylsulphonyl, [0083] (39) C.sub.1-8 alkylsulphonamido,
[0084] (40) (alkylsuphonyl).sub.2amino-, [0085] (41) thiol, [0086]
(42) aminosulfonyl, [0087] (43) alkylaminosulfonyl, [0088] (44)
C.sub.6-10 aryl, [0089] (45) substituted C.sub.6-10 aryl chosen
from mono-, di-, and trisubstituted C.sub.6-10 aryl wherein the
substituents are independently chosen from C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, C.sub.1-8 hydroxyalkyl, C.sub.2-8 hydroxyalkoxy,
amino, C.sub.1-4 alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8
alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, and thio; [0090] (46) heterocyclyl; [0091] (47)
substituted heterocyclyl chosen from mono-, di-, and trisubstituted
heterocyclyl wherein the substitutents are independently chosen
from halo, C.sub.1-8 alkyl, halogenated C.sub.1-8 alkyl, C.sub.1-4
alkoxy, halogenated C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl,
hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8
alkylamino, C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl,
C.sub.1-8 alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9,
cyano, hydroxyl, nitro, oxo, and thio; [0092] (48)
heterocyclyl-carbonyl; and [0093] (49) heterocyclyl-carbonyl chosen
from mono-, di-, and trisubstituted heterocyclyl-carbonyl wherein
the substituents are independently chosen from halo, C.sub.1-8
alkyl, halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio; and [0094] Het is chosen from
heterocyclyl, substituted heterocyclyl chosen from mono-, di-, and
tri-substituted heterocyclyl, heteroaryl, and substituted
heteroaryl chosen from mono-, di-, and tri-substituted heteroaryl,
wherein the substituents are independently chosen from [0095] (1)
C.sub.1-8 alkyl, [0096] (2) C.sub.3-8 cycloalkyl, [0097] (3)
C.sub.4-8 cycloalkylalkyl, [0098] (4) C.sub.1-8 alkoxy, [0099] (5)
C.sub.3-8 cycloalkoxy, [0100] (6) C.sub.4-8 cycloalkylalkoxy,
[0101] (7) halo, [0102] (8) amino, [0103] (9) cyano, [0104] (10)
hydroxyl, [0105] (b 11) nitro, [0106] (12) C.sub.1-8 halogenated
alkyl, [0107] (13) C.sub.1-8 halogenated alkoxy, [0108] (14)
C.sub.1-8 hydroxyalkyl, [0109] (15) C.sub.2-8 hydroxyalkoxy [0110]
(16) C.sub.3-8 alkenyloxy, [0111] (17) C.sub.1-8 alkylamino, [0112]
(18) di-C.sub.1-8 alkylamino, [0113] (19) carboxy, [0114] (20)
alkoxycarbonyl, [0115] (21) carboxamido, [0116] (22) aminocarbonyl,
[0117] (23) hydroxyaminocarbonyl, [0118] (24) alkylaminocarbonyl,
[0119] (25) dialkylaminocarbonyl, [0120] (26) urea, [0121] (27)
hydroxyurea, [0122] (28) alkylurea, [0123] (29)
dialkylaminoalkylcarbonyl, [0124] (30)
aminocarbonylalkylaminocarbonyl, [0125] (31) acylamido, [0126] (32)
HCO--NH--NH--CO--, [0127] (33) NH.sub.2NHCO--, [0128] (34)
NH.sub.2NHCONH--, [0129] (35) acyloxy, [0130] (36) C.sub.1-8
alkylthio, [0131] (37) C.sub.1-8 alkylsulphinyl, [0132] (38)
C.sub.1-8 alkylsulphonyl, [0133] (39) C.sub.1-8 alkylsulphonamido,
[0134] (40) (alkylsuphonyl).sub.2amino-, [0135] (41) thiol, [0136]
(42) aminosulfonyl, [0137] (43) alkylaminosulfonyl, [0138] (44)
oxo, [0139] (45) C.sub.6-20 aryl, [0140] (46) substituted
C.sub.6-20 aryl chosen from mono-, di-, and tri-substituted
C.sub.6-20 aryl wherein the substituents are independently chosen
from halo, C.sub.1-8 alkyl, halogenated C.sub.1-8 alkyl, C.sub.1-4
alkoxy, halogenated C.sub.1-4 alkoxy, C.sub.1-8 hydroxyalkyl,
C.sub.2-8 hydroxyalkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8
alkylamino, C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl,
C.sub.1-8 alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9,
cyano, hydroxyl, nitro, and thio, [0141] (47) heterocyclyl, [0142]
(48) substituted heterocyclyl chosen from mono-, di-, and
trisubstituted heterocyclyl wherein the substituents are
independently chosen from halo, C.sub.1-8 alkyl, halogenated
C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy,
hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8
alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl,
C.sub.1-8 alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, oxo, and thio,
[0143] (49) heteroaryl, [0144] (50) substituted heteroaryl chosen
from mono-, di-, and trisubstituted heteroaryl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio, [0145] (51) heterocyclyl-carbonyl,
[0146] (52) substituted heterocyclyl-carbonyl chosen from mono-,
di-, and trisubstituted heterocyclyl-carbonyl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio, [0147] (53) heteroaryl-carbonyl,
and [0148] (54) substituted heteroaryl-carbonyl chosen from mono-,
di-, and trisubstituted heteroaryl-carbonyl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio, and [0149] R.sup.9 is chosen from
H, C.sub.1-8 alkyl, C.sub.3-8 cycloalkyl, substituted C.sub.1-8
alkyl chosen from mono-, di-, and trisubstituted C.sub.1-8 alkyl,
and substituted C.sub.3-8 cycloalkyl chosen from mono-, di-, and
trisubstituted C.sub.3-8 cycloalkyl wherein the substituents are
independently chosen from halo, C.sub.1-4-alkyl, C.sub.1-4-alkoxy,
and oxo; and provided that the compound of Formula I is not chosen
from: [0150] (i) when R.sup.1 is 4-methylphenyl, then R.sup.2 is
not --O-p-phenylene-O--(CH.sub.2)phenyl,
--O-p-phenylene-NH--C(O)-thiophen-2-yl,
--O--(CH.sub.2).sub.2--O-(phenyl),
--NH(CH.sub.2).sub.2-(4-hydroxyphenyl),
--O--(CH.sub.2).sub.2-(1,3-dioxoisoindolin-1-yl),
--NH(CH.sub.2).sub.2-(2-oxo-imidazolidin-1-yl),
--NH(CH.sub.2).sub.2-(3,4,-dimethoxyphenyl),
--S(CH.sub.2).sub.2-phenyl, --NH(CH.sub.2).sub.2-phenyl,
--NH(CH.sub.2).sub.2-morpholin-4-yl,
--NH(CH.sub.2).sub.2-thiophen-2-yl,
--NH(CH.sub.2).sub.2-(3,4-methylenedioxyphenyl),
--NH(CH.sub.2).sub.3-morpholin-4-yl, or --S(CH.sub.2).sub.3-phenyl;
[0151] (ii)
2-methoxy-4-[[[2-[(5-phenylthieno[2,3-d]pyrimidin-4-yl)amino]ethyl]imino]-
-methyl]-phenol; [0152] (iii)
4,4'-[1,3-phenylenebis(oxy)bis[5-(4-chlorophenyl)-thieno[2,3-d]pyrimidine-
; [0153] (iv) when R.sup.1 is phenyl, then R.sup.2 is not
--O-p-phenylene-NH--C(O)-3,-4-dimethoxyphenyl,
--O--(CH.sub.2).sub.2--O-(4-methylphenyl),
--O--(CH.sub.2).sub.2--Ophenyl,
--O--(CH.sub.2).sub.2--O(3-bromophenyl),
--NH--(CH.sub.2).sub.2--NH(3-CF.sub.3-pyridin-2-yl),
--S--(CH.sub.2).sub.2--O-(3-methylphenyl),
--S--(CH.sub.2).sub.2--O-(4-Fphenyl),
--S--(CH.sub.2).sub.2--O-(2,4-dichlorophenyl),
--NH--(CH.sub.2).sub.2--NH(4-CF.sub.3-pyrimidin-2-yl),
--NH--(CH.sub.2).sub.2--O-(3-acetylaminophenyl),
--S--(CH.sub.2).sub.3-phenyl,
--S--(CH.sub.2).sub.4-(1,3-dioxoisoindolin-1-yl),
--NH--(CH.sub.2).sub.3-morpholin-4-yl,
--NH--(CH.sub.2).sub.3-imidazol-1-yl,
--NH--(CH.sub.2).sub.3-(2-oxo-pyrrolidin-1-yl),
--N(CH.sub.3)--(CH.sub.2).sub.2-pyridin-2-yl,
--NH--(CH.sub.2).sub.2-pyridin-2-yl,
--S--(CH.sub.2)--(1,3-dioxoisoindolin-1-yl,
--S--(CH.sub.2).sub.2-phenyl,
--NH--(CH.sub.2).sub.2-(2-chlorophenyl),
--NH--(CH.sub.2).sub.2-morpholin-4-yl,
--NH--(CH.sub.2).sub.2-(3,4-dimethoxyphenyl),
--NH--(CH.sub.2).sub.2-thiophen-2-yl, or
--NH--(CH.sub.2).sub.2-phenyl; [0154] (v) when R.sup.1 is
4-fluorophenyl, then R.sup.2 is not chosen from
--O--(CH.sub.2).sub.2--O-(2-chlorophenyl),
--O--(CH.sub.2).sub.2--O-(4-fluorophenyl),
--S--(CH.sub.2).sub.3-phenyl --NH--(CH.sub.2).sub.3-phenyl,
--NH--(CH.sub.2).sub.2-phenyl,
--NH--(CH.sub.2).sub.3-morpholin-4-yl,
--NH--(CH.sub.2).sub.3-(2-oxo-pyrrolidin-1-yl),
--NH--(CH.sub.2).sub.2-morpholin-4-yl,
--S--(CH.sub.2).sub.2-phenyl, --NH--(CH.sub.2).sub.2-azepan-1-yl,
--S--(CH.sub.2).sub.2-morpholin-4-yl,
--NH--(CH.sub.2).sub.2-(3,4-methylenedioxyphenyl),
--NH--(CH.sub.2).sub.2-thiophen-2-yl, and
--NH--(CH.sub.2).sub.2-(3,4-ethylenedioxyphenyl); [0155] (vi) when
R.sup.1 is 4-chlorophenyl, then R.sup.2 is not chosen from
--O-p-phenylene-O--CH.sub.2-phenyl,
--O--(CH.sub.2).sub.2--O-(4-methylphenyl),
--S--(CH.sub.2).sub.4-(1,3-dioxoisoindolin-1-yl),
--S--(CH.sub.2).sub.3-phenyl, --S--(CH.sub.2).sub.2-phenyl,
--NH--(CH.sub.2).sub.3-imidazol-1-yl,
--NH--(CH.sub.2).sub.3-morpholin-4-yl,
--NH--(CH.sub.2).sub.2-morpholin-4-yl,
--NH--(CH.sub.2).sub.2-azepan-1-yl,
--S--(CH.sub.2).sub.2-(1,3-dioxoisoindolin-1-yl),
--NH--(CH.sub.2).sub.2-(3,4-methylenedioxyphenyl),
--NH--(CH.sub.2).sub.2-phenyl,
--NH--(CH.sub.2).sub.2-thiophen-2-yl,
--NH--(CH.sub.2).sub.2-(3,4-ethylenedioxyphenyl),
--S--(CH.sub.2).sub.4-(1,3-dioxoisoindolin-1-yl),
--NH(CH.sub.2).sub.3-(2-oxo-pyrrolidin-1-yl), and
--NH(CH.sub.2).sub.2-(3,4,-dimethoxyphenyl); [0156] (vii) when
R.sup.1 is 3-methylphenyl, then R.sup.2 is not
--O--(CH.sub.2).sub.2--O-(phenyl); [0157] (viii) when R.sup.1 is
3-thiophen-2-yl, then R.sup.2 is not chosen from
--NH--(CH.sub.2).sub.2-morpholin-4-yl,
--NH--(CH.sub.2).sub.3-morpholin, --NH--(CH.sub.2).sub.2-phenyl,
and --NH--(CH.sub.2).sub.2-(3,4-dimethoxyphenyl); [0158] (ix) when
R.sup.1 is 4-methoxyphenyl, then R.sup.2 is not chosen from
--S--(CH.sub.2).sub.3-phenyl,
--NH--(CH.sub.2).sub.2-morpholin-4-yl,
--NH--(CH.sub.2).sub.2--C(CH.sub.3).sub.2-morpholin-4-yl,
--NHCH.sub.2C(CH.sub.3).sub.2-morpholin-4-yl,
--N(CH.sub.3)--(CH.sub.2).sub.2-(3,4-dimethoxyphenyl),
--S--(CH.sub.2).sub.2-phenyl, and
--NH--(CH.sub.2).sub.2-(3,4-methylenedioxyphenyl); [0159] (x) when
R.sup.1 is 3,4-dimethylphenyl, then R.sup.2 is not chosen from
--O-p-phenylene-O--CH.sub.2-phenyl, --S--(CH.sub.2).sub.3-phenyl,
--S--(CH.sub.2).sub.3-morpholin-4-yl, --S--(CH.sub.2).sub.2-phenyl,
--NH--(CH.sub.2).sub.3-(4-hydroxyphenyl),
--O--(CH.sub.2).sub.2-(1,3-dioxoisoindolin-1-yl),
--NH--(CH.sub.2).sub.2-- morpholin-4-yl,
--NH--(CH.sub.2).sub.3-morpholin-4-yl,
--NH--(CH.sub.2).sub.2-(3,4-methylenedioxyphenyl),
--S--(CH.sub.2).sub.2-phenyl, --NH--(CH.sub.2).sub.2-phenyl,
--NH--(CH.sub.2).sub.2-thiophen-2-yl, and
--NH--(CH.sub.2).sub.2-(3,4-methylenedioxyphenyl); [0160] (xi) when
R.sup.1 is 4-bromophenyl, then R.sup.2 is not chosen from
--(CH.sub.2).sub.3-phenyl, --S--(CH.sub.2).sub.3-morpholin-4-yl,
--S--(CH.sub.2).sub.2-phenyl, --S--(CH.sub.2).sub.3-phenyl,
--NH--(CH.sub.2).sub.3-morpholin-4-yl,
--NH--(CH.sub.2).sub.3-(2-oxo-pyrrolidin-1-yl), and
--NH--(CH.sub.2).sub.2-(3,4-ethylenedioxyphenyl); and [0161] (xii)
when R.sup.1 is 4-biphenyl, then R.sup.2 is not
--NH--(CH.sub.2).sub.2-(3,4-ethylenedioxyphenyl); [0162] (xiii)
when R.sup.1 is 2,3-dihydro-1,4-benzodioxin-2-yl, then R.sup.2 is
not NH(CH.sub.2).sub.2-phenyl, and [0163] (xiv)
5-(2-chlorophenyl)-4-[4-(phenylmethoxy)phenoxy]-thieno[2,3-d]pyrimidine.
[0164] Provided is at least one chemical entity chosen from
compounds of Formula I
##STR00002##
and pharmaceutically acceptable salts, solvates, chelates,
non-covalent complexes, prodrugs, and mixtures thereof, wherein
R.sup.1 is chosen from: [0165] (i) C.sub.6-10 aryl; [0166] (ii)
substituted C.sub.6-10 aryl chosen from mono-, di-, and
tri-substituted aryl wherein the substituents are independently
chosen from halo, C.sub.1-8 alkyl, halogenated C.sub.1-8 alkyl,
C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy, hydroxy C.sub.1-8
alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8 alkylamino,
di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl, C.sub.1-8
alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, and thio; [0167]
(iii) heterocyclyl; [0168] (iv) substituted heterocyclyl chosen
from mono-, di-, and tri-substituted heterocyclyl wherein the
substitutents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio; [0169] (v) heteroaryl; and [0170]
(vi) substituted heteroaryl chosen from mono-, di-, and
tri-substituted heteroaryl wherein the substitutents are
independently chosen from halo, C.sub.1-8 alkyl, halogenated
C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy,
hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8
alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl,
C.sub.1-8 alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, oxo, and thio;
[0171] R.sup.2 is chosen from C.sub.2-4 hydroxyalkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkenylene-R.sup.5, C.sub.2-4 alkynyl, C.sub.2-4
alkynylene-R.sup.5, --O-arylene-Y--R.sup.5,
--X(CR.sup.3R.sup.4).sub.nYR.sup.5 and
--(CR.sup.6R.sup.7).sub.mYR.sup.5 where: [0172] X is chosen from
--O--, --S-- and --NR.sup.9--; [0173] Y is chosen from a covalent
bond, --O--, --S-- and --NR.sup.9--; [0174] n is chosen from 2, 3,
4, and 5; [0175] m is chosen from 2, 3, 4, and 5; [0176] R.sup.3
and R.sup.4 are each independently chosen from: [0177] (i) H;
[0178] (ii) halo; [0179] (iii) C.sub.1-12 alkyl; [0180] (iv)
C.sub.2-12 alkenyl; [0181] (v) C.sub.2-12 alkynyl; [0182] (vi)
C.sub.3-12 cycloalkyl; [0183] (vii) substituted C.sub.1-12 alkyl
chosen from mono-, di-, and tri-substituted C.sub.1-12 alkyl and
wherein the substituents are independently chosen from halo,
hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, nitro,
cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; [0184]
(viii) substituted C.sub.2-12 alkenyl chosen from mono-, di-, and
tri-substituted C.sub.2-12 alkenyl wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; [0185] (ix) substituted C.sub.2-12
alkynyl chosen from mono-, di-, and tri-substituted C.sub.2-12
alkynyl wherein the substituents are independently chosen from
halo, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
nitro, cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; and [0186]
(x) substituted C.sub.3-12 cycloalkyl chosen from mono-, di-, and
tri-substituted C.sub.3-12 cycloalkyl wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; [0187] R.sup.6 and R.sup.7 are
independently chosen from [0188] (i) H; [0189] (ii) halo; [0190]
(iii) C.sub.1-12 alkyl; [0191] (iv) C.sub.2-12 alkenyl; [0192] (v)
C.sub.2-12 alkynyl; [0193] (vi) C.sub.3-12 cycloalkyl; [0194] (vii)
substituted C.sub.1-12 alkyl chosen from mono-, di-, and
tri-substituted C.sub.1-12 alkyl wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; [0195] (viii) substituted C.sub.2-12
alkenyl chosen from mono-, di-, and tri-substituted C.sub.2-12
alkenyl wherein the substituents are independently chosen from
halo, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
nitro, cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; [0196] (ix)
substituted C.sub.2-12 alkynyl chosen from mono-, di-, and
tri-substituted C.sub.2-12 alkynyl wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; and [0197] (x) substituted C.sub.3-12
cycloalkyl chosen from mono-, di-, and tri-substituted C.sub.3-12
cycloalkyl wherein the substituents are independently chosen from
halo, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
nitro, cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; [0198]
R.sup.9 is chosen from H, C.sub.1-8 alkyl, C.sub.3-8 cycloalkyl,
substituted C.sub.1-8 alkyl chosen from mono-, di-, and
trisubstituted C.sub.1-8 alkyl, and substituted C.sub.3-8
cycloalkyl chosen from mono-, di-, and trisubstituted C.sub.3-8
cycloalkyl wherein the substituents are independently chosen from
halo, C.sub.1-4-alkyl, C.sub.1-4-alkoxy, and oxo; and [0199]
R.sup.5 is chosen from pyridin-3-yl and pyridin-4-yl, each of which
is optionally substituted with one or two groups chosen from [0200]
(1) C.sub.1-8 alkyl, [0201] (2) C.sub.3-8 cycloalkyl, [0202] (3)
C.sub.4-8 cycloalkylalkyl, [0203] (4) C.sub.1-8 alkoxy, [0204] (5)
C.sub.3-8 cycloalkoxy, [0205] (6) C.sub.4-8 cycloalkylalkoxy,
[0206] (7) halo, [0207] (8) amino, [0208] (9) cyano, [0209] (10)
hydroxyl, [0210] (11) nitro, [0211] (12) C.sub.1-8 halogenated
alkyl, [0212] (13) C.sub.3-8 halogenated alkoxy, [0213] (14)
C.sub.1-8 hydroxyalkyl, [0214] (15) C.sub.2-8 hydroxyalkoxy [0215]
(16) C.sub.3-8 alkenyloxy, [0216] (17) C.sub.1-8 alkylamino, [0217]
(18) di-C.sub.1-8 alkylamino, [0218] (19) carboxy, [0219] (20)
alkoxycarbonyl, [0220] (21) carboxamido, [0221] (22) aminocarbonyl,
[0222] (23) hydroxyaminocarbonyl, [0223] (24) alkylaminocarbonyl,
[0224] (25) dialkylaminocarbonyl, [0225] (26) urea, [0226] (27)
hydroxyurea, [0227] (28) alkylurea, [0228] (29)
dialkylaminoalkylcarbonyl, [0229] (30)
aminocarbonylalkylaminocarbonyl, [0230] (31) acylamido, [0231] (32)
HCO--NH--NH--CO--, [0232] (33) NH.sub.2NHCO--, [0233] (34)
NH.sub.2NHCONH--, [0234] (35) acyloxy, [0235] (36) C.sub.1-8
alkylthio, [0236] (37) C.sub.1-8 alkylsulphinyl, [0237] (38)
C.sub.1-8 alkylsulphonyl, [0238] (39) C.sub.1-8 alkylsulphonamido,
[0239] (40) (alkylsuphonyl).sub.2amino-, [0240] (41) thiol, [0241]
(42) aminosulfonyl, [0242] (43) alkylaminosulfonyl, [0243] (44)
oxo, [0244] (45) C.sub.6-20 aryl, [0245] (46) substituted
C.sub.6-20 aryl chosen from mono-, di-, and tri-substituted
C.sub.6-20 aryl wherein the substituents are independently chosen
from halo, C.sub.1-8 alkyl, halogenated C.sub.1-8 alkyl, C.sub.1-4
alkoxy, halogenated C.sub.1-4 alkoxy, C.sub.1-8 hydroxyalkyl,
C.sub.2-8 hydroxyalkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8
alkylamino, C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl,
C.sub.1-8 alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9,
cyano, hydroxyl, nitro, and thio, [0246] (47) heterocyclyl, [0247]
(48) substituted heterocyclyl chosen from mono-, di-, and
trisubstituted heterocyclyl wherein the substituents are
independently chosen from halo, C.sub.1-8 alkyl, halogenated
C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy,
hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8
alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl,
C.sub.1-8 alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, oxo, and thio,
[0248] (49) heteroaryl, [0249] (50) substituted heteroaryl chosen
from mono-, di-, and trisubstituted heteroaryl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio, [0250] (51) heterocyclyl-carbonyl,
[0251] (52) substituted heterocyclyl-carbonyl chosen from mono-,
di-, and trisubstituted heterocyclyl-carbonyl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4alkoxy, halogenated C.sub.1-4
alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8 alkoxy, amino,
C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8
alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio, [0252] (53) heteroaryl-carbonyl,
and [0253] (54) substituted heteroaryl-carbonyl chosen from mono-,
di-, and trisubstituted heteroaryl-carbonyl wherein the
substituents are independently chosen from halo, C.sub.1-8alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4alkoxy, halogenated C.sub.1-4
alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8alkoxy, amino,
C.sub.1-8 alkylamino, di-C.sub.3-8 alkylamino, C.sub.1-8
alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio.
[0254] Provided is at least one chemical entity chosen from
compounds of Formula I:
##STR00003##
and pharmaceutically acceptable salts, solvates, chelates,
non-covalent complexes, prodrugs, and mixtures thereof, wherein
R.sup.1 is chosen from: [0255] (i) C.sub.6-10 aryl; [0256] (ii)
substituted C.sub.6-10 aryl chosen from mono-, di-, and
tri-substituted aryl wherein the substituents are independently
chosen from halo, C.sub.1-8 alkyl, halogenated C.sub.1-8 alkyl,
C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy, hydroxy C.sub.1-8
alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8 alkylamino,
di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl, C.sub.1-8
alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, and thio; [0257]
(iii) heterocyclyl; [0258] (iv) substituted heterocyclyl chosen
from mono-, di-, and tri-substituted heterocyclyl wherein the
substitutents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio; [0259] (v) heteroaryl; and [0260]
(vi) substituted heteroaryl chosen from mono-, di-, and
tri-substituted heteroaryl wherein the substitutents are
independently chosen from halo, C.sub.1-8 alkyl, halogenated
C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy,
hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8
alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl,
C.sub.1-8 alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, oxo, and thio;
[0261] R.sup.2 is chosen from C.sub.2-4 hydroxyalkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkenylene-R.sup.5, C.sub.2-4 alkynyl, C.sub.2-4
alkynylene-R.sup.5, --O-arylene-Y--R.sup.5,
--X(CR.sup.3R.sup.4).sub.nYR.sup.5 and
--(CR.sup.6R.sup.7).sub.mYR.sup.5 where: [0262] X is chosen from
--O--, --S-- and --NR.sup.9-- where R.sup.9 is chosen from H,
C.sub.1-8 alkyl; and C.sub.3-8 cycloalkyl, substituted C.sub.1-8
alkyl; and substituted C.sub.3-8 cycloalkyl, wherein the
substituents on the alkyl and cycloalkyl groups are independently
chosen from halo, C.sub.1-4-alkyl, C.sub.1-4-alkoxy, and oxo;
[0263] Y is chosen from a covalent bond, --O--, --S-- and
--NR.sup.9--; [0264] n is chosen from 2, 3, 4, and 5; [0265] m is
chosen from 2, 3, 4, and 5; [0266] R.sup.3 and R.sup.4 are each
independently chosen from: [0267] (i) H; [0268] (ii) halo; [0269]
(iii) C.sub.1-12 alkyl; [0270] (iv) C.sub.2-12 alkenyl; [0271] (v)
C.sub.2-12 alkynyl; [0272] (vi) C.sub.3-12 cycloalkyl; [0273] (vii)
substituted C.sub.1-12 alkyl chosen from mono-, di-, and
tri-substituted C.sub.1-12 alkyl and wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; [0274] (viii) substituted C.sub.2-12
alkenyl chosen from mono-, di-, and tri-substituted C.sub.2-12
alkenyl wherein the substituents are independently chosen from
halo, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
nitro, cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; [0275] (ix)
substituted C.sub.2-12 alkynyl chosen from mono-, di-, and
tri-substituted C.sub.2-12 alkynyl wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; and [0276] (x) substituted C.sub.3-12
cycloalkyl chosen from mono-, di-, and tri-substituted C.sub.3-12
cycloalkyl wherein the substituents are independently chosen from
halo, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
nitro, cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; [0277]
R.sup.6 and R.sup.7 are independently chosen from [0278] (i) H;
[0279] (ii) halo; [0280] (iii) C.sub.1-12 alkyl; [0281] (iv)
C.sub.2-12 alkenyl; [0282] (v) C.sub.2-12 alkynyl; [0283] (vi)
C.sub.3-12 cycloalkyl; [0284] (vii) substituted C.sub.1-12 alkyl
chosen from mono-, di-, and tri-substituted C.sub.1-12 alkyl
wherein the substituents are independently chosen from halo,
hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, nitro,
cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; [0285]
(viii) substituted C.sub.2-12 alkenyl chosen from mono-, di-, and
tri-substituted C.sub.2-12 alkenyl wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; [0286] (ix) substituted C.sub.2-12
alkynyl chosen from mono-, di-, and tri-substituted C.sub.2-12
alkynyl wherein the substituents are independently chosen from
halo, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
nitro, cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; and [0287]
(x) substituted C.sub.3-12 cycloalkyl chosen from mono-, di-, and
tri-substituted C.sub.3-12 cycloalkyl wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; [0288] R.sup.9 is chosen from H,
C.sub.1-8 alkyl, C.sub.3-8 cycloalkyl, substituted C.sub.1-8 alkyl
chosen from mono-, di-, and trisubstituted C.sub.1-8 alkyl, and
substituted C.sub.3-8 cycloalkyl chosen from mono-, di-, and
trisubstituted C.sub.3-8 cycloalkyl wherein the substituents are
independently chosen from halo, C.sub.1-4-alkyl, C.sub.1-4-alkoxy,
and oxo; and [0289] R.sup.5 is chosen from pyridin-2-yl and
pyridin-4-yl, each of which is substituted with one or two groups
chosen from [0290] (1) C.sub.1-8 alkyl, [0291] (2) C.sub.3-8
cycloalkyl, [0292] (3) C.sub.4-8 cycloalkylalkyl, [0293] (4)
C.sub.1-8 alkoxy, [0294] (5) C.sub.3-8 cycloalkoxy, [0295] (6)
C.sub.4-8 cycloalkylalkoxy, [0296] (7) halo, [0297] (8) amino,
[0298] (9) cyano, [0299] (10) hydroxyl, [0300] (11) nitro, [0301]
(12) C.sub.2-8 halogenated alkyl, [0302] (13) C.sub.1-8 halogenated
alkoxy, [0303] (14) C.sub.1-8 hydroxyalkyl, [0304] (15) C.sub.2-8
hydroxyalkoxy [0305] (16) C.sub.3-8 alkenyloxy, [0306] (17)
C.sub.1-8 alkylamino, [0307] (18) di-C.sub.1-8 alkylamino, [0308]
(19) carboxy, [0309] (20) alkoxycarbonyl, [0310] (21) carboxamido,
[0311] (22) aminocarbonyl, [0312] (23) hydroxyaminocarbonyl, [0313]
(24) alkylaminocarbonyl, [0314] (25) dialkylaminocarbonyl, [0315]
(26) urea, [0316] (27) hydroxyurea, [0317] (28) alkylurea, [0318]
(29) dialkylaminoalkylcarbonyl, [0319] (30)
aminocarbonylalkylaminocarbonyl, [0320] (31) acylamido, [0321] (32)
HCO--NH--NH--CO--, [0322] (33) NH.sub.2NHCO--, [0323] (34)
NH.sub.2NHCONH--, [0324] (35) acyloxy, [0325] (36) C.sub.1-8
alkylthio, [0326] (37) C.sub.1-8 alkylsulphinyl, [0327] (38)
C.sub.1-8 alkylsulphonyl, [0328] (39) C.sub.1-8 alkylsulphonamido,
[0329] (40) (alkylsuphonyl).sub.2amino-, [0330] (41) thiol, [0331]
(42) aminosulfonyl, [0332] (43) alkylaminosulfonyl, [0333] (44)
oxo, [0334] (45) C.sub.6-20 aryl, [0335] (46) substituted
C.sub.6-20 aryl chosen from mono-, di-, and tri-substituted
C.sub.6-20 aryl wherein the substituents are independently chosen
from halo, C.sub.1-8 alkyl, halogenated C.sub.1-8 alkyl,
C.sub.1-4alkoxy, halogenated C.sub.1-4 alkoxy, hydroxy C.sub.1-8
alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8 alkylamino,
di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl, C.sub.1-8
alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, and thio, [0336]
(47) heterocyclyl, [0337] (48) substituted heterocyclyl chosen from
mono-, di-, and trisubstituted heterocyclyl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8alkoxy,
amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8
alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio, [0338] (49) heteroaryl, [0339] (50)
substituted heteroaryl chosen from mono-, di-, and trisubstituted
hetetoaryl wherein the substituents are independently chosen from
halo, C.sub.1-8 alkyl, halogenated C.sub.1-8 alkyl,
C.sub.1-4alkoxy, halogenated C.sub.1-4 alkoxy, hydroxy C.sub.1-8
alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8 alkylamino,
di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl, C.sub.1-8
alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, oxo, and thio,
[0340] (51) heterocyclyl-carbonyl, [0341] (52) substituted
heterocyclyl-carbonyl chosen from mono-, di-, and trisubstituted
heterocyclyl-carbonyl wherein the substituents are independently
chosen from halo, C.sub.1-8 alkyl, halogenated C.sub.1-8 alkyl,
C.sub.1-4alkoxy, halogenated C.sub.1-4 alkoxy, hydroxy C.sub.1-8
alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8 alkylamino,
di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl, C.sub.1-8
alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, oxo, and thio,
[0342] (53) heteroaryl-carbonyl, and [0343] (54) substituted
heteroaryl-carbonyl chosen from mono-, di-, and trisubstituted
heteroaryl-carbonyl wherein the substituents are independently
chosen from halo, C.sub.1-8 alkyl, halogenated C.sub.1-8 alkyl,
C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy, hydroxy C.sub.1-8
alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8 alkylamino,
di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl, C.sub.1-8
alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, oxo, and thio.
[0344] Provided is at least one chemical entity chosen from
compounds of Formula II:
##STR00004##
and pharmaceutically acceptable salts, solvates, chelates,
non-covalent complexes, prodrugs, and mixtures thereof, wherein
R.sup.1 is chosen from: [0345] (i) C.sub.6-10 aryl; [0346] (ii)
substituted C.sub.6-10 aryl chosen from mono-, di-, and
tri-substituted aryl wherein the substituents are independently
chosen from halo, C.sub.1-8 alkyl, halogenated C.sub.1-8 alkyl,
C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy, hydroxy C.sub.1-8
alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8 alkylamino,
di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl, C.sub.1-8
alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, and thio; [0347]
(iii) heterocyclyl; [0348] (iv) substituted heterocyclyl chosen
from mono-, di-, and tri-substituted heterocyclyl wherein the
substitutents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio; [0349] (v) heteroaryl; and [0350]
(vi) substituted heteroaryl chosen from mono-, di-, and
tri-substituted heteroaryl wherein the substitutents are
independently chosen from halo, C.sub.1-8 alkyl, halogenated
C.sub.1-8 alkyl, C.sub.1-4alkoxy, halogenated C.sub.1-4 alkoxy,
hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8alkoxy, amino, C.sub.1-8
alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl,
C.sub.1-8 alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, oxo, and thio;
[0351] R.sup.2 is chosen from C.sub.2-4 hydroxyalkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkenylene-R.sup.5, C.sub.2-4 alkynyl, C.sub.2-4
alkynylene-R.sup.5, --O-arylene-Y--R.sup.5,
--X(CR.sup.3R.sup.4).sub.nYR.sup.5 and
--(CR.sup.6R.sup.7).sub.mYR.sup.5 where: [0352] X is chosen from
--O--, --S-- and --NR.sup.9-- where R.sup.9 is chosen from H,
C.sub.1-8 alkyl; and C.sub.3-8 cycloalkyl, substituted C.sub.1-8
alkyl; and substituted C.sub.3-8 cycloalkyl, wherein the
substituents on the alkyl and cycloalkyl groups are independently
chosen from halo, C.sub.1-4-alkyl, C.sub.1-4-alkoxy, and oxo;
[0353] Y is chosen from a covalent bond, --O--, --S-- and
--NR.sup.9--; [0354] n is chosen from 2, 3, 4, and 5; [0355] m is
chosen from 2, 3, 4, and 5; [0356] R.sup.3 and R.sup.4 are each
independently chosen from: [0357] (i) H; [0358] (ii) halo; [0359]
(iii) C.sub.1-12 alkyl; [0360] (iv) C.sub.2-12 alkenyl; [0361] (v)
C.sub.2-12 alkynyl; [0362] (vi) C.sub.3-12 cycloalkyl; [0363] (vii)
substituted C.sub.1-12 alkyl chosen from mono-, di-, and
tri-substituted C.sub.1-12 alkyl and wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; [0364] (viii) substituted C.sub.2-12
alkenyl chosen from mono-, di-, and tri-substituted C.sub.2-12
alkenyl wherein the substituents are independently chosen from
halo, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
nitro, cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; [0365] (ix)
substituted C.sub.2-12 alkynyl chosen from mono-, di-, and
tri-substituted C.sub.2-12 alkynyl wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; and [0366] (x) substituted C.sub.3-12
cycloalkyl chosen from mono-, di-, and tri-substituted C.sub.3-12
cycloalkyl wherein the substituents are independently chosen from
halo, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
nitro, cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; [0367]
R.sup.6 and R.sup.7 are independently chosen from [0368] (i) H;
[0369] (ii) halo; [0370] (iii) C.sub.1-12 alkyl; [0371] (iv)
C.sub.2-12 alkenyl; [0372] (v) C.sub.2-12 alkynyl; [0373] (vi)
C.sub.3-12 cycloalkyl; [0374] (vii) substituted C.sub.1-12 alkyl
chosen from mono-, di-, and tri-substituted C.sub.1-12 alkyl
wherein the substituents are independently chosen from halo,
hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, nitro,
cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; [0375]
(viii) substituted C.sub.2-12 alkenyl chosen from mono-, di-, and
tri-substituted C.sub.2-12 alkenyl wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; [0376] (ix) substituted C.sub.2-12
alkynyl chosen from mono-, di-, and tri-substituted C.sub.2-12
alkynyl wherein the substituents are independently chosen from
halo, hydroxy, C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy,
nitro, cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; and [0377]
(x) substituted C.sub.3-12 cycloalkyl chosen from mono-, di-, and
tri-substituted C.sub.3-12 cycloalkyl wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; [0378] R.sup.9 is chosen from H,
C.sub.1-8 alkyl, C.sub.3-8 cycloalkyl, substituted C.sub.1-8 alkyl
chosen from mono-, di-, and trisubstituted C.sub.1-8 alkyl, and
substituted C.sub.3-8 cycloalkyl chosen from mono-, di-, and
trisubstituted C.sub.3-8 cycloalkyl wherein the substituents are
independently chosen from halo, C.sub.1-4-alkyl, C.sub.1-4-alkoxy,
and oxo; [0379] p is chosen from 1, 2, 3, and 4; and [0380] for
each occurrence, R.sup.10 is independently chosen from [0381] (1)
C.sub.2-8 alkyl, [0382] (2) C.sub.3-8 cycloalkyl, [0383] (3)
C.sub.4-8 cycloalkylalkyl, [0384] (4) C.sub.3-8 cycloalkoxy, [0385]
(5) C.sub.4-8 cycloalkylalkoxy, [0386] (6) amino, [0387] (7) cyano,
[0388] (8) nitro, [0389] (9) C.sub.1-8 halogenated alkyl, [0390]
(10) C.sub.1-8 halogenated alkoxy, [0391] (b 11) C.sub.1-8
hydroxyalkyl, [0392] (12) C.sub.2-8 hydroxyalkoxy, [0393] (13)
C.sub.1-8 alkylamino, [0394] (14) di-C.sub.1-8alkylamino, [0395]
(15) carboxy, [0396] (16) alkoxycarbonyl, [0397] (17)
aminocarbonyl, [0398] (18) hydroxyaminocarbonyl, [0399] (19)
alkylaminocarbonyl, [0400] (20) dialkylaminocarbonyl, [0401] (21)
urea, [0402] (22) hydroxyurea, [0403] (23) alkylurea, [0404] (24)
dialkylaminoalkylcarbonyl, [0405] (25)
aminocarbonylalkylaminocarbonyl, [0406] (26) acylamido, [0407] (27)
HCO--NH--NH--CO--, [0408] (28) NH.sub.2NHCO--, [0409] (29)
NH.sub.2NHCONH--, [0410] (30) acyloxy, [0411] (31) C.sub.1-8
alkylthio, [0412] (32) C.sub.1-8 alkylsulphinyl, [0413] (33)
C.sub.1-8 alkylsulphonyl, [0414] (34) C.sub.1-8 alkylsulphonamido,
[0415] (35) (alkylsuphonyl).sub.2-amino-, [0416] (36) thiol, [0417]
(37) aminosulfonyl, [0418] (38) alkylaminosulfonyl, [0419] (39)
C.sub.6-20 aryl, [0420] (40) substituted C.sub.6-20 aryl chosen
from mono-, di-, and tri-substituted C.sub.6-20 aryl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, C.sub.1-8 hydroxyalkyl, C.sub.2-8 hydroxyalkoxy,
amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8
alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, and thio, [0421] (41) heterocyclyl-carbonyl,
[0422] (42) substituted heterocyclyl-carbonyl chosen from mono-,
di-, and trisubstituted heterocyclyl-carbonyl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio, [0423] (43) heteroaryl-carbonyl,
and [0424] (44) substituted heteroaryl-carbonyl chosen from mono-,
di-, and trisubstituted heteroaryl-carbonyl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio.
[0425] Also provided is a pharmaceutical composition comprising at
least one chemical entity described herein and a pharmaceutically
acceptable carrier.
[0426] Also provided is a method of selectively inhibiting PDE10
enzyme in a patient in need thereof comprising administering to
said patient an effective amount of at least one chemical entity
described herein.
[0427] Unless otherwise specified the following terms in the
specification and the claims in this Application have the meanings
given below.
[0428] Halo herein refers to F, Cl, Br, and I, such as F and
Cl.
[0429] Alkyl means a straight-chain or branched-chain aliphatic
hydrocarbon radical. Suitable alkyl groups include, but are not
limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,
tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,
and dodecyl. Other examples of suitable alkyl groups include 1-, 2-
or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl,
1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or
3,3-dimethylbutyl, 1- or 2-ethylbutyl, ethylmethylpropyl,
trimethylpropyl, methylhexyl, dimethylpentyl, ethylpentyl,
ethylmethylbutyl, dimethylbutyl, and the like.
[0430] Alkenyl refers to an unsaturated branched or straight-chain
alkyl group having at least one carbon-carbon double bond derived
by the removal of one hydrogen atom from a single carbon atom of a
parent alkene. The group may be in either the cis or trans
configuration about the double bond(s). Typical alkenyl groups
include, but are not limited to, ethenyl; propenyls such as
prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl),
prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls
such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,
but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl,
buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,
cyclobuta-1,3-dien-1-yl; and the like. In certain embodiments, an
alkenyl group has from 2 to 20 carbon atoms and in other
embodiments, from 2 to 6 carbon atoms. Alkenylene refers to a
divalent alkenyl group.
[0431] Alkynyl refers to an unsaturated branched or straight-chain
alkyl group having at least one carbon-carbon triple bond derived
by the removal of one hydrogen atom from a single carbon atom of a
parent alkyne. Typical alkynyl groups include, but are not limited
to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl;
butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and
the like. In certain embodiments, an alkynyl group has from 2 to 20
carbon atoms and in other embodiments, from 3 to 6 carbon atoms.
Alkynylene refers to a divalent alkynyl group.
[0432] Cycloalkyl herein refers to a non-aromatic monocyclic,
bicyclic, or tricyclic carbocyclic ring, usually having from 3 to 8
ring carbon atoms, for example 4 to 6 ring carbon atoms. The ring
may be saturated or have one or more carbon-carbon double bonds.
Examples of cycloalkyl groups include cyclopropyl, cyclobutyl,
cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,
and cyclooctyl, as well as bridged and caged saturated ring groups
such as norbornane. Other suitable cycloalkyl groups include
spiropentyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl,
spiro[2.4]heptyl, spiro[2.5]octyl, bicyclo[5.1.0]octyl,
spiro[2.6]nonyl, bicyclo[2.2.0]hexyl, spiro[3.3]heptyl, and
bicyclo[4.2.0]octyl.
[0433] In the arylalkyl groups and heteroarylalkyl groups, "alkyl"
refers to a divalent alkylene group having, in certain embodiments,
1 to 4 carbon atoms.
[0434] In the cases where alkyl is a substituent (e.g., alkyl
substituents on aryl and heteroaryl groups) or is part of a
substituent (e.g., in the alkylamino, dialkylamino, hydroxyalkyl,
hydroxyalkoxy, alkylthio, alkylsulphinyl, and alkylsulphonyl
substituents), the alkyl portion usually has 1 to 12 carbon atoms,
for example 1 to 8 carbon atoms, such as 1 to 4 carbon atoms.
[0435] Aryl, as a group or substituent per se or as part of a group
or substituent, refers to an aromatic, monocyclic or bicyclic
carbocyclic radical containing 6 to 14 carbon atoms, such as 6 to
12 carbon atoms, for example 6 to 10 carbon atoms. Suitable aryl
groups include phenyl, naphthyl and biphenyl. Unless otherwise
specified, substituted aryl groups include the above-described aryl
groups which are substituted by at least one time, for example,
one, two, or three times, by a group chosen from halo, alkyl,
hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,
alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy,
cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl,
alkylsulphonyl, phenoxy, and acyloxy (e.g., acetoxy).
[0436] Arylalkyl refers to an aryl-alkyl-radical in which the aryl
and alkyl portions are in accordance with the previous
descriptions. Suitable examples include I-phenethyl, 2-phenethyl,
phenpropyl, phenbutyl, phenpentyl, and naphthylenemethyl.
[0437] Heteroaryl encompasses:
[0438] 5- to 7-membered aromatic, monocyclic rings containing one
or more, for example, from 1 to 4, or in certain embodiments, from
1 to 3, such as 1 or 2, heteroatoms chosen from N, O, and S, with
the remaining ring atoms being carbon;
[0439] bicyclic heterocyclyl rings containing one or more, for
example, from 1 to 4, or in certain embodiments, from 1 to 3, such
as 1 or 2, heteroatoms chosen from N, O, and S, with the remaining
ring atoms being carbon and wherein at least one heteroatom is
present in an aromatic ring, and
[0440] tricyclic heterocyclyl rings containing one or more, for
example, from 1 to 5, or in certain embodiments, from 1 to 4, such
as 1 or 2, heteroatoms chosen from N, O, and S, with the remaining
ring atoms being carbon and wherein at least one heteroatom is
present in an aromatic ring.
[0441] For example, heteroaryl includes a 5- to 7-membered
heterocyclyl, aromatic ring fused to a 5- to 7-membered cycloalkyl
or heterocyclyl ring. For such fused, bicyclic heteroaryl ring
systems wherein only one of the rings contains one or more
heteroatoms, the point of attachment may be at either ring. When
the total number of S and O atoms in the heteroaryl group exceeds
1, those heteroatoms are not adjacent to one another. In certain
embodiments, the total number of S and O atoms in the heteroaryl
group is not more than 2. In certain embodiments, the total number
of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heteroaryl groups include, but are not limited to,
furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl,
pyrimidinyl, indolyl, quinolinyl, naphthyridinyl, azaindolyl (e.g.,
7-azaindolyl), 1,2,3,4,-tetrahydroisoquinolyl, and the like. In
certain embodiments, examples of heteroaryl groups include, but are
not limited to 2-thienyl, 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-,
4-, 5-, 6-, 7- or 8-quinolinyl, 7-azaindolyl, and 1-, 3-, 4-, 5-,
6-, 7- or 8-isoquinolinyl. Unless otherwise specified, substituted
heteroaryl groups refer to the heteroaryl groups described above
which are substituted in one or more places by halo, aryl, alkyl,
alkoxy, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro,
oxo, amino, alkylamino, and dialkylamino. Heteroaryl does not
encompass or overlap with aryl, cycloalkyl, or heterocyclyl, as
defined herein
[0442] Substituted heteroaryl also includes ring systems
substituted with one or more oxide (--O.sup.-) substituents, such
as pyridinyl N-oxides.
[0443] Heteroarylalkyl refers to a heteroaryl-alkyl-group wherein
the heteroaryl and alkyl portions are in accordance with the
previous discussions. Suitable examples are pyridylmethyl,
thienylmethyl, pyrimidinylmethyl, pyrazinylmethyl,
isoquinolinylmethyl, pyridylethyl and thienylethyl.
[0444] By heterocycloalkyl or heterocyclyl is meant a single,
non-aromatic ring, usually with 3 to 7 ring atoms, containing at
least 2 carbon atoms in addition to 1-3 heteroatoms independently
selected from oxygen, sulfur, and nitrogen, as well as combinations
comprising at least one of the foregoing heteroatoms. Heterocyclyl
also includes bicyclic ring systems wherein one non-aromatic ring,
usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in
addition to 1-3 heteroatoms independently selected from oxygen,
sulfur, and nitrogen, as well as combinations comprising at least
one of the foregoing heteroatoms; and the other ring, usually with
3 to 7 ring atoms, optionally contains 1-3 heteroatoms
independently selected from oxygen, sulfur, and nitrogen and is not
aromatic. The ring or rings may be saturated or have one or more
carbon-carbon double bonds. Suitable heterocyclyl groups include,
for example (as numbered from the linkage position assigned
priority 1), 3-tetrahydrofuranyl, piperidinyl, imidazolinyl,
imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, piperazinyl,
oxazolidinyl, and indolinyl. Substituted heterocyclyl also includes
ring systems substituted with one or more oxo (=0) or oxide
(--O.sup.-) substituents, such as piperidinyl N-oxide,
morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and
1,1-dioxo-1-thiomorpholinyl.
[0445] Acyl refers to alkanoyl radicals having 2 to 4 carbon atoms,
such as formyl, acetyl, propionyl, and butanoyl.
[0446] Substituted radicals usually have 1 to 3 substituents, for
example, 1 or 2 substituent, such as 1 substituent.
[0447] Compounds of Formula I include, but are not limited to,
optical isomers of compounds of Formula I, racemates, and other
mixtures thereof. In those situations, the single enantiomers or
diastereomers, i.e., optically active forms, can be obtained by
asymmetric synthesis or by resolution of the racemates. 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 high-pressure
liquid chromatography (HPLC) column. Substantially pure enantiomers
contain no more than 5% w/w of the corresponding opposite
enantiomer, such as no more than 2%, for example, no more than 1%.
In addition, compounds of Formula I include Z- and E-forms (or cis-
and trans-forms) of compounds with carbon-carbon double bonds.
Where compounds of Formula I exists in various tautomeric forms,
chemical entities of the present invention include all tautomeric
forms of the compound.
[0448] Chemical entities of the present invention include compounds
of Formula I and all pharmaceutically acceptable forms thereof.
Pharmaceutically acceptable forms of the compounds recited herein
include pharmaceutically acceptable salts, solvates, crystal forms
(including polymorphs and clathrates), chelates, non-covalent
complexes, prodrugs, and mixtures thereof. In certain embodiments,
the compounds described herein are in the form of pharmaceutically
acceptable salts. Hence, the terms "chemical entity" and "chemical
entities" also encompass pharmaceutically acceptable salts,
solvates, chelates, non-covalent complexes, prodrugs, and
mixtures.
[0449] A polymorph is a solid crystalline phase of a compound with
at least two different arrangements or polymorphic forms of that
compound molecule in the solid state. Polymorphic forms of any
given compound are defined by the same chemical formula or
composition and are as distinct in chemical structure as
crystalline structures of two different chemical compounds.
[0450] Pharmaceutically acceptable salts include those obtained by
reacting the main compound, functioning as a base, with an
inorganic or organic acid to form a salt, for example, salts of
hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic
acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid
and citric acid. Other examples of acid salts that can be obtained
by reaction with inorganic or organic acids: acetates, adipates,
alginates, citrates, aspartates, benzoates, benzenesulfonates,
bisulfates, butyrates, camphorates, digluconates,
cyclopentanepropionates, dodecyl sulfates, ethanesulfonates,
glucoheptanoates, glycerophosphates, hemisulfates, heptanoates,
hexanoates, fumarates, hydrobromides, hydroiodides,
2-hydroxy-ethanesulfonates, lactates, maleates, methanesulfonates,
nicotinates, 2-naphthalenesulfonates, oxalates, palmoates,
pectinates, persulfates, 3-phenylpropionates, picrates, pivalates,
propionates, succinates, tartrates, thiocyanates, tosylates,
mesylates and undecanoates.
[0451] Pharmaceutically acceptable salts also include those in
which the main compound functions as an acid and is reacted with an
appropriate base to form, e.g., sodium, potassium, calcium,
magnesium, ammonium, and choline salts.
[0452] Those skilled in the art will recognize various synthetic
methodologies that may be used to prepare non-toxic
pharmaceutically acceptable addition salts.
[0453] As noted above, prodrugs also fall within the scope of
chemical entities, for example ester or amide derivatives of the
compounds of Formula I. The term "prodrugs" includes any compounds
that become compounds of Formula I when administered to a patient,
e.g., upon metabolic processing of the prodrug. Examples of
prodrugs include, but are not limited to, acetate, formate, and
benzoate and like derivatives of functional groups (such as alcohol
or amine groups) in the compounds of Formula I.
[0454] The term solvate refers to the chemical entity formed by the
interaction of a solvent and a compound. Solvates may also form
when solvent molecules are incorporated into the crystalline
lattice structure of the compound molecule during the
crystallization process. Suitable solvates are pharmaceutically
acceptable solvates, such as hydrates, e.g., monohydrates,
dihydrates, sesquihydrates, and hemihydrates.
[0455] One of ordinary skill in the art will further recognize that
compounds of Formulas I and Ia can exist in different solvate
forms.
[0456] The term chelate refers to the chemical entity formed by the
coordination of a compound to a metal ion at two (or more)
points.
[0457] The term non-covalent complex refers to the chemical entity
formed by the interaction of a compound and another molecule
wherein a covalent bond is not formed between the compound and the
molecule. For example, complexation can occur through van der Waals
interactions, hydrogen bonding, and electrostatic interactions
(also called ionic bonding).
[0458] Provided is at least one chemical entity chosen from
compounds of Formula I:
##STR00005##
and pharmaceutically acceptable salts, solvates, chelates,
non-covalent complexes, prodrugs, and mixtures thereof, wherein
R.sup.1 is chosen from: [0459] (i) C.sub.6-10 aryl; [0460] (ii)
substituted C.sub.6-10 aryl chosen from mono-, di-, and
tri-substituted aryl wherein the substituents are independently
chosen from halo, C.sub.1-8 alkyl, halogenated C.sub.1-8 alkyl,
C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy, hydroxy C.sub.1-8
alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8 alkylamino,
di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl, C.sub.1-8
alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, and thio; [0461]
(iii) heterocyclyl; [0462] (iv) substituted heterocyclyl chosen
from mono-, di-, and tri-substituted heterocyclyl wherein the
substitutents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio; [0463] (v) heteroaryl; and [0464]
(vi) substituted heteroaryl chosen from mono-, di-, and
tri-substituted heteroaryl wherein the substitutents are
independently chosen from halo, C.sub.1-8 alkyl, halogenated
C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy,
hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8
alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl,
C.sub.1-8 alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, oxo, and thio;
[0465] R.sup.2 is chosen from C.sub.2-4 hydroxyalkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkenylene-R.sup.5, C.sub.2-4 alkynyl, C.sub.2-4
alkynylene-R.sup.5, --O-arylene-Y--R.sup.5,
--X(CR.sup.3R.sup.4).sub.nYR.sup.5 and
--(CR.sup.6R.sup.7).sub.mYR.sup.5 where: [0466] X is chosen from
--O--, --S-- and --NR.sup.9--; [0467] Y is chosen from a covalent
bond, --O--, --S-- and --NR.sup.9--; [0468] n is chosen from 2, 3,
4, and 5; [0469] m is chosen from 2, 3, 4, and 5; [0470] R.sup.3
and R.sup.4 are each independently chosen from: [0471] (i) H;
[0472] (ii) halo; [0473] (iii) C.sub.1-12 alkyl; [0474] (iv)
C.sub.2-12 alkenyl; [0475] (v) C.sub.2-12 alkynyl; [0476] (vi)
C.sub.3-12 cycloalkyl; [0477] (vii) substituted C.sub.1-12 alkyl
chosen from mono-, di-, and tri-substituted C.sub.1-12 alkyl and
wherein the substituents are independently chosen from halo,
hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy, nitro,
cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; [0478]
(viii) substituted C.sub.2-12 alkenyl chosen from mono-, di-, and
tri-substituted C.sub.2-12 alkenyl wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; [0479] (ix) substituted C.sub.2-12
alkynyl chosen from mono-, di-, and tri-substituted C.sub.2-12
alkynyl wherein the substituents are independently chosen from
halo, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
nitro, cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; and [0480]
(x) substituted C.sub.3-12 cycloalkyl chosen from mono-, di-, and
tri-substituted C.sub.3-12 cycloalkyl wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; [0481] R.sup.6 and R.sup.7 are
independently chosen from [0482] (i) H; [0483] (ii) halo; [0484]
(iii) C.sub.1-12 alkyl; [0485] (iv) C.sub.2-12 alkenyl; [0486] (v)
C.sub.2-12 alkynyl; [0487] (vi) C.sub.3-12 cycloalkyl; [0488] (vii)
substituted C.sub.1-12 alkyl chosen from mono-, di-, and
tri-substituted C.sub.1-12 alkyl wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; [0489] (viii) substituted C.sub.2-12
alkenyl chosen from mono-, di-, and tri-substituted C.sub.2-12
alkenyl wherein the substituents are independently chosen from
halo, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
nitro, cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; [0490] (ix)
substituted C.sub.2-12 alkynyl chosen from mono-, di-, and
tri-substituted C.sub.2-12 alkynyl wherein the substituents are
independently chosen from halo, hydroxy, C.sub.1-4-alkoxy,
halogenated C.sub.1-4 alkoxy, nitro, cyano, carboxy, amino,
C.sub.1-4 alkylamino, di-C.sub.1-4-alkylamino,
C.sub.1-4-hydroxyalkyl, C.sub.2-4-hydroxyalkoxy,
C.sub.1-4-alkylthio, C.sub.1-4-alkylsulphinyl, and
C.sub.1-4-alkylsulphonyl; and [0491] (x) substituted C.sub.3-12
cycloalkyl chosen from mono-, di-, and tri-substituted C.sub.3-12
cycloalkyl wherein the substituents are independently chosen from
halo, hydroxy, C.sub.1-4-alkoxy, halogenated C.sub.1-4 alkoxy,
nitro, cyano, carboxy, amino, C.sub.1-4 alkylamino,
di-C.sub.1-4-alkylamino, C.sub.1-4-hydroxyalkyl,
C.sub.2-4-hydroxyalkoxy, C.sub.1-4-alkylthio,
C.sub.1-4-alkylsulphinyl, and C.sub.1-4-alkylsulphonyl; and [0492]
R.sup.5 is chosen from C.sub.6-10 aryl, substituted C.sub.6-10
aryl, Het, substituted Het, C.sub.6-10 aryl-C.sub.1-8 alkyl,
substituted C.sub.6-10 aryl-C.sub.1-8 alkyl, Het-C.sub.1-8 alkyl,
and substituted Het-C.sub.1-8 alkyl, wherein the alkyl portions of
C.sub.6-10 aryl-C.sub.1-8 alkyl and Het-C.sub.1-8 alkyl are
optionally substituted by oxo and wherein: [0493] substituted
C.sub.6-10 aryl is chosen from mono-, di-, and tri-substituted
C.sub.6-10 aryl wherein the substituents are independently chosen
from [0494] (1) C.sub.1-8 alkyl, [0495] (2) C.sub.3-8 cycloalkyl,
[0496] (3) C.sub.4-8 cycloalkylalkyl, [0497] (4) C.sub.1-8 alkoxy,
[0498] (5) C.sub.3-8 cycloalkoxy, [0499] (6) C.sub.4-8
cycloalkylalkoxy, [0500] (7) halo (such as F or Cl), [0501] (8)
amino, [0502] (9) cyano, [0503] (10) hydroxyl, [0504] (11) nitro,
[0505] (12) C.sub.1-8 halogenated alkyl, [0506] (13) C.sub.1-8
halogenated alkoxy, [0507] (14) C.sub.1-8 hydroxyalkyl, [0508] (15)
C.sub.2-8 hydroxyalkoxy, [0509] (16) C.sub.3-8 alkenyloxy, [0510]
(17) C.sub.1-8 alkylamino, [0511] (18) di-C.sub.1-8 alkylamino,
[0512] (19) carboxy, [0513] (20) alkoxycarbonyl, [0514] (21)
carboxamido, [0515] (22) aminocarbonyl, [0516] (23)
hydroxyaminocarbonyl, [0517] (24) alkylaminocarbonyl, [0518] (25)
dialkylaminocarbonyl, [0519] (26) urea, [0520] (27) hydroxyurea,
[0521] (28) alkylurea, [0522] (29) dialkylaminoalkylcarbonyl,
[0523] (30) aminocarbonylalkylaminocarbonyl, [0524] (31) acylamido,
[0525] (32) HCO--NH--NH--CO--, [0526] (33) NH.sub.2NHCO--, [0527]
(34) NH.sub.2NHCONH--, [0528] (35) acyloxy, [0529] (36) C.sub.1-8
alkylthio, [0530] (37) C.sub.1-8 alkylsulphinyl, [0531] (38)
C.sub.1-8 alkylsuphonyl, [0532] (39) C.sub.1-8 alkylsulphonamido,
[0533] (40) (alkylsuphonyl).sub.2-amino-, [0534] (41) thiol, [0535]
(42) aminosulfonyl, [0536] (43) alkylaminosulfonyl, [0537] (44)
C.sub.6-10 aryl, [0538] (45) substituted C.sub.6-10 aryl chosen
from mono-, di-, and trisubstituted C.sub.6-10 aryl wherein the
substituents are independently chosen from C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, C.sub.1-8 hydroxyalkyl, C.sub.2-8 hydroxyalkoxy,
amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8
alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, and thio; [0539] (46) heterocyclyl; [0540] (47)
substituted heterocyclyl chosen from mono-, di-, and trisubstituted
heterocyclyl wherein the substitutents are independently chosen
from halo, C.sub.1-8 alkyl, halogenated C.sub.1-8 alkyl, C.sub.1-4
alkoxy, halogenated C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl,
hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8
alkylamino, C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl,
C.sub.1-8 alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9,
cyano, hydroxyl, nitro, oxo, and thio; [0541] (48)
heterocyclyl-carbonyl; and [0542] (49) heterocyclyl-carbonyl chosen
from mono-, di-, and trisubstituted heterocyclyl-carbonyl wherein
the substituents are independently chosen from halo, C.sub.1-8
alkyl, halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio; and [0543] Het is chosen from
heterocyclyl, substituted heterocyclyl chosen from mono-, di-, and
tri-substituted heterocyclyl, heteroaryl, and substituted
heteroaryl chosen from mono-, di-, and tri-substituted heteroaryl,
wherein the substituents are independently chosen from [0544] (1)
C.sub.1-8 alkyl, [0545] (2) C.sub.3-8 cycloalkyl, [0546] (3)
C.sub.4-8 cycloalkylalkyl, [0547] (4) C.sub.1-8 alkoxy, [0548] (5)
C.sub.3-8 cycloalkoxy, [0549] (6) C.sub.4-8 cycloalkylalkoxy,
[0550] (7) halo, [0551] (8) amino, [0552] (9) cyano, [0553] (10)
hydroxyl, [0554] (11) nitro, [0555] (12) C.sub.1-8 halogenated
alkyl, [0556] (13) C.sub.1-8 halogenated alkoxy, [0557] (14)
C.sub.1-8 hydroxyalkyl, [0558] (15) C.sub.2-8 hydroxyalkoxy [0559]
(16) C.sub.3-8 alkenyloxy, [0560] (17) C.sub.1-8 alkylamino, [0561]
(18) di-C.sub.1-8 alkylamino, [0562] (19) carboxy, [0563] (20)
alkoxycarbonyl, [0564] (21) carboxamido, [0565] (22) aminocarbonyl,
[0566] (23) hydroxyaminocarbonyl, [0567] (24) alkylaminocarbonyl,
[0568] (25) dialkylaminocarbonyl, [0569] (26) urea, [0570] (27)
hydroxyurea, [0571] (28) alkylurea, [0572] (29)
dialkylaminoalkylcarbonyl, [0573] (30)
aminocarbonylalkylaminocarbonyl, [0574] (31) acylamido, [0575] (32)
HCO--NH--NH--CO--, [0576] (33) NH.sub.2NHCO--, [0577] (34)
NH.sub.2NHCONH--, [0578] (35) acyloxy, [0579] (36) C.sub.1-8
alkylthio, [0580] (37) C.sub.1-8 alkylsulphinyl, [0581] (38)
C.sub.1-8 alkylsulphonyl, [0582] (39) C.sub.1-8 alkylsulphonamido,
[0583] (40) (alkylsuphonyl).sub.2-amino-, [0584] (41) thiol, [0585]
(42) aminosulfonyl, [0586] (43) alkylaminosulfonyl, [0587] (44)
oxo, [0588] (45) C.sub.6-20 aryl, [0589] (46) substituted
C.sub.6-20 aryl chosen from mono-, di-, and tri-substituted
C.sub.6-20 aryl wherein the substituents are independently chosen
from halo, C.sub.1-8 alkyl, halogenated C.sub.1-8 alkyl, C.sub.1-4
alkoxy, halogenated C.sub.1-4 alkoxy, C.sub.1-8 hydroxyalkyl,
C.sub.2-8 hydroxyalkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8
alkylamino, C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl,
C.sub.1-8 alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9,
cyano, hydroxyl, nitro, and thio, [0590] (47) heterocyclyl, [0591]
(48) substituted heterocyclyl chosen from mono-, di-, and
trisubstituted heterocyclyl wherein the substituents are
independently chosen from halo, C.sub.1-8 alkyl, halogenated
C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy,
hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8
alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl,
C.sub.1-8 alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, oxo, and thio,
[0592] (49) heteroaryl, [0593] (50) substituted heteroaryl chosen
from mono-, di-, and trisubstituted heteroaryl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio, [0594] (51) heterocyclyl-carbonyl,
[0595] (52) substituted heterocyclyl-carbonyl chosen from mono-,
di-, and trisubstituted heterocyclyl-carbonyl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4alkoxy, halogenated C.sub.1-4
alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8 alkoxy, amino,
C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8
alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio, [0596] (53) heteroaryl-carbonyl,
and [0597] (54) substituted heteroaryl-carbonyl chosen from mono-,
di-, and trisubstituted heteroaryl-carbonyl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio, and
[0598] R.sup.9 is chosen from H, C.sub.1-8 alkyl, C.sub.3-8
cycloalkyl, substituted C.sub.1-8 alkyl chosen from mono-, di-, and
trisubstituted C.sub.1-8 alkyl, and substituted C.sub.3-8
cycloalkyl chosen from mono-, di-, and trisubstituted C.sub.3-8
cycloalkyl wherein the substituents are independently chosen from
halo, C.sub.1-4-alkyl, C.sub.1-4-alkoxy, and oxo; and
provided that the compound of Formula I is not chosen from:
[0599] (i) when R.sup.1 is 4-methylphenyl, then R.sup.2 is not
--O-p-phenylene-O--(CH.sub.2)phenyl,
--O-p-phenylene-NH--C(O)-thiophen-2-yl,
--O--(CH.sub.2).sub.2--O-(phenyl),
--NH(CH.sub.2).sub.2-(4-hydroxyphenyl),
--O--(CH.sub.2).sub.2-(1,3-dioxoisoindolin-1-yl),
--NH(CH.sub.2).sub.2-(2-oxo-imidazolidin-1-yl),
--NH(CH.sub.2).sub.2-(3,4,-dimethoxyphenyl),
--S(CH.sub.2).sub.2-phenyl, --NH(CH.sub.2).sub.2-phenyl,
--NH(CH.sub.2).sub.2-morpholin-4-yl,
--NH(CH.sub.2).sub.2-thiophen-2-yl,
--NH(CH.sub.2).sub.2-(3,4-methylenedioxyphenyl),
--NH(CH.sub.2).sub.3-morpholin-4-yl, or
--S(CH.sub.2).sub.3-phenyl;
[0600] (ii)
2-methoxy-4-[[[2-[(5-phenylthieno[2,3-d]pyrimidin-4-yl)amino]ethyl]imino]-
-methyl]-phenol;
[0601] (iii)
4,4'-[1,3-phenylenebis(oxy)bis[5-(4-chlorophenyl)-thieno[2,3-d]pyrimidine-
;
[0602] (iv) when R.sup.1 is phenyl, then R.sup.2 is not
--O-p-phenylene-NH--C(O)-3,-4-dimethoxyphenyl,
--O--(CH.sub.2).sub.2--O-(4-methylphenyl),
--O--(CH.sub.2).sub.2--Ophenyl,
--O--(CH.sub.2).sub.2--O(3-bromophenyl),
--NH--(CH.sub.2).sub.2--NH(3-CF.sub.3-pyridin-2-yl),
--S--(CH.sub.2).sub.2--O-(3-methylphenyl),
--S--(CH.sub.2).sub.2--O-(4-Fphenyl),
--S--(CH.sub.2).sub.2--O-(2,4-dichlorophenyl),
--NH--(CH.sub.2).sub.2--NH(4-CF.sub.3-pyrimidin-2-yl),
--NH--(CH.sub.2).sub.2--O-(3-acetylaminophenyl),
--S--(CH.sub.2).sub.3-phenyl,
--S--(CH.sub.2).sub.4-(1,3-dioxoisoindolin-1-yl),
--NH--(CH.sub.2).sub.3-morpholin-4-yl,
--NH--(CH.sub.2).sub.3-imidazol-1-yl,
--NH--(CH.sub.2).sub.3-(2-oxo-pyrrolidin-1-yl),
--N(CH.sub.3)--(CH.sub.2).sub.2-pyridin-2-yl,
--NH--(CH.sub.2).sub.2-pyridin-2-yl,
--S--(CH.sub.2).sub.2-(1,3-dioxoisoindolin-1-yl,
--S--(CH.sub.2).sub.2-phenyl,
--NH--(CH.sub.2).sub.2-(2-chlorophenyl),
--NH--(CH.sub.2).sub.2-morpholin-4-yl,
--NH--(CH.sub.2).sub.2-(3,4-dimethoxyphenyl),
--NH--(CH.sub.2).sub.2-thiophen-2-yl, or
--NH--(CH.sub.2).sub.2-phenyl; [0603] (v) when R.sup.1 is
4-fluorophenyl, then R.sup.2 is not chosen from
--O--(CH.sub.2).sub.2--O-(2-chlorophenyl),
--O--(CH.sub.2).sub.2--O-(4-fluorophenyl),
--S--(CH.sub.2).sub.3-phenyl, --NH--(CH.sub.2).sub.3-phenyl,
--NH--(CH.sub.2).sub.2-phenyl,
--NH--(CH.sub.2).sub.3-morpholin-4-yl,
--NH--(CH.sub.2).sub.3-(2-oxo-pyrrolidin-1-yl),
--NH--(CH.sub.2).sub.2-morpholin-4-yl,
--S--(CH.sub.2).sub.2-phenyl, --NH--(CH.sub.2).sub.2-azepan-1-yl,
--S--(CH.sub.2).sub.2-morpholin-4-yl,
--NH--(CH.sub.2).sub.2-(3,4-methylenedioxyphenyl),
--NH--(CH.sub.2).sub.2-thiophen-2-yl, and
--NH--(CH.sub.2).sub.2-(3,4-ethylenedioxyphenyl); [0604] (vi) when
R.sup.1 is 4-chlorophenyl, then R.sup.2 is not chosen from
--O-p-phenylene-O--CH.sub.2-phenyl,
--O--(CH.sub.2).sub.2--O-(4-methylphenyl),
--S--(CH.sub.2).sub.4-(1,3-dioxoisoindolin-1-yl),
--S--(CH.sub.2).sub.3-phenyl, --S--(CH.sub.2).sub.2-phenyl,
--NH--(CH.sub.2).sub.3-imidazol-1-yl,
--NH--(CH.sub.2).sub.3-morpholin-4-yl,
--NH--(CH.sub.2).sub.2-morpholin-4-yl,
--NH--(CH.sub.2).sub.2-azepan-1-yl,
--S--(CH.sub.2).sub.2-(1,3-dioxoisoindolin-1-yl),
--NH--(CH.sub.2).sub.2-(3,4-methylenedioxyphenyl),
--NH--(CH.sub.2).sub.2-phenyl,
--NH--(CH.sub.2).sub.2-thiophen-2-yl,
--NH--(CH.sub.2).sub.2-(3,4-ethylenedioxyphenyl),
--S--(CH.sub.2).sub.4-(1,3-dioxoisoindolin-1-yl),
--NH(CH.sub.2).sub.3-(2-oxo-pyrrolidin-1-yl), and
--NH(CH.sub.2).sub.2-(3,4,-dimethoxyphenyl); [0605] (vii) when
R.sup.1 is 3-methylphenyl, then R.sup.2 is not
--O--(CH.sub.2).sub.2--O-(phenyl); [0606] (viii) when R.sup.1 is
3-thiophen-2-yl, then R.sup.2 is not chosen from
--NH--(CH.sub.2).sub.2-morpholin-4-yl,
--NH--(CH.sub.2).sub.3-morpholin-4-yl,
--NH--(CH.sub.2).sub.2-phenyl, and
--NH--(CH.sub.2).sub.2-(3,4-dimethoxyphenyl); [0607] (ix) when
R.sup.1 is 4-methoxyphenyl, then R.sup.2 is not chosen from
--S--(CH.sub.2).sub.3-phenyl,
--NH--(CH.sub.2).sub.2-morpholin-4-yl,
--NH--(CH.sub.2).sub.2--C(CH.sub.3).sub.2-morpholin-4-yl,
--NHCH.sub.2C(CH.sub.3).sub.2-morpholin-4-yl,
--N(CH.sub.3)--(CH.sub.2).sub.2-(3,4-dimethoxyphenyl),
--S--(CH.sub.2).sub.2-phenyl, and
--NH--(CH.sub.2).sub.2-(3,4-methylenedioxyphenyl); [0608] (x) when
R.sup.1 is 3,4-dimethylphenyl, then R.sup.2 is not chosen from
--O-p-phenylene-O--CH.sub.1-phenyl, --S--(CH.sub.2).sub.3-phenyl,
--S--(CH.sub.2).sub.3-morpholin-4-yl, --S--(CH.sub.2).sub.2-phenyl,
--NH--(CH.sub.2).sub.3-(4-hydroxyphenyl),
--O--(CH.sub.2).sub.2-(1,3-dioxoisoindolin-1-yl),
--NH--(CH.sub.2).sub.2-morpholin-4-yl,
--NH--(CH.sub.2).sub.3-morpholin-4-yl,
--NH--(CH.sub.2).sub.2-(3,4-methylenedioxyphenyl),
--S--(CH.sub.2).sub.2-phenyl, --NH--(CH.sub.2).sub.2-phenyl,
--NH--(CH.sub.2).sub.2-thiophen-2-yl, and
--NH--(CH.sub.2).sub.2-(3,4-methylenedioxyphenyl); [0609] (xi) when
R.sup.1 is 4-bromophenyl, then R.sup.2 is not chosen from
--(CH.sub.2).sub.3-phenyl, --S--(CH.sub.2).sub.3-morpholin-4-yl,
--S--(CH.sub.2).sub.2-phenyl, --S--(CH.sub.2).sub.3-phenyl,
--NH--(CH.sub.2).sub.3-morpholin-4-yl,
--NH--(CH.sub.2).sub.3-(2-oxo-pyrrolidin-1-yl), and
--NH--(CH.sub.2).sub.2-(3,4-ethylenedioxyphenyl); and [0610] (xii)
when R.sup.1 is 4-biphenyl, then R.sup.2 is not
--NH--(CH.sub.2).sub.2-(3,4-ethylenedioxyphenyl); [0611] (xiii)
when R.sup.1 is 2,3-dihydro-1,4-benzodioxin-2-yl, then R.sup.2 is
not NH(CH.sub.2).sub.2-phenyl; and [0612] (xiv)
5-(2-chlorophenyl)-4-[4-(phenylmethoxy)phenoxy]-thieno[2,3-d]pyrimidine.
[0613] In certain embodiments, R.sup.1 is chosen from aryl,
substituted aryl, heterocyclyl, substituted heterocyclyl,
heteroaryl, and substituted heteroaryl.
[0614] In certain embodiments, R.sup.1 is chosen from aryl and
substituted aryl wherein substituted aryl is chosen from mono-,
di-, and tri-substituted aryl. In certain embodiments, R.sup.1 is
chosen from phenyl and substituted phenyl wherein substituted
phenyl is chosen from mono-, di-, and tri-substituted phenyl. In
certain embodiments, R.sup.1 is chosen from phenyl and phenyl
substituted with one or more (such as one, two, or three) halo
(such as fluoro). In some embodiments, R.sup.1 is chosen from
phenyl and 4-F-phenyl.
[0615] In certain embodiments, R.sup.1 is chosen from heterocyclyl,
substituted heterocyclyl, heteroaryl, and substituted heteroaryl.
In certain embodiments, R.sup.1 is chosen from optionally
substituted furanyl (e.g., optionally substituted furan-2-yl),
optionally substituted pyridinyl (e.g., pyridin-4-yl, pyridin-3-yl,
pyridin-2-yl, any of which is optionally substituted), optionally
substituted pyrimidinyl (e.g., optionally substituted
5-pyrimidin-2-yl), optionally substituted pyrazinyl (e.g.,
optionally substituted 5-pyrazin-2-yl), and optionally substituted
thiazolyl (e.g., optionally substituted 1,3-thiazol-2-yl).
[0616] In certain embodiments, R.sup.1 is chosen from optionally
substituted furanyl (e.g., optionally substituted furan-2-yl),
optionally substituted pyridinyl (e.g., pyridin-4-yl, pyridin-3-yl,
pyridin-2-yl, any of which is optionally substituted), and
optionally substituted thiazolyl (e.g., optionally substituted
1,3-thiazol-2-yl).
[0617] In certain embodiments, R.sup.1 is chosen from
5-chloro-furan-2-yl, furan-2-yl, pyridin-4-yl, pyridin-3-yl,
pyridin-2-yl, 1,3-thiazol-2-yl, 5-pyrimidin-2-yl and
5-pyrazin-2-yl.
[0618] In certain embodiments, R.sup.1 is chosen from furan-2-yl,
pyridin-4-yl, pyridin-3-yl, 1,3-thiazol-2-yl, and
5-pyrimidin-2-yl.
[0619] In certain embodiments, R.sup.2 is chosen from
--O-arylene-Y--R.sup.5, --X(CR.sup.3R.sup.4).sub.nYR.sup.5 and
--(CR.sup.6R.sup.7).sub.mYR.sup.5.
[0620] In certain embodiments, R.sup.2 is --O-arylene-Y--R.sup.5.
In certain embodiments, R.sup.2 is --O-phenylene-Y--R.sup.5. In
certain embodiments, the --O and --YR.sup.5 substituents attached
the phenylene group are meta-substituted.
[0621] In certain embodiments, R.sup.2 is
--X(CR.sup.3R.sup.4).sub.nY--R.sup.5.
[0622] In certain embodiments, R.sup.2 is
--(CR.sup.6R.sup.7).sub.mYR.sup.5.
[0623] In certain embodiments, X is --NH--. In certain embodiments,
X is --O--.
[0624] In certain embodiments, Y is a bond. In certain embodiments,
Y is --O--. In certain embodiments, Y is --NH--.
[0625] In certain embodiments, n is chosen from 3, 4, and 5. In
certain embodiments, n is chosen from 2 and 3. In certain
embodiments, n is 3. In certain embodiments, n is 2.
[0626] In certain embodiments, m is chosen from 3, 4, and 5.
[0627] In certain embodiments, R.sup.3 and R.sup.4 are
independently chosen from H, CH.sub.3, and F. In certain
embodiments, R.sup.3 and R.sup.4 are H.
[0628] In certain embodiments, R.sup.6 and R.sup.7 are
independently chosen from H, CH.sub.3, and F. In certain
embodiments, R.sup.6 and R.sup.7 are H;
[0629] In certain embodiments, --(CR.sup.6R.sup.7).sub.mY--R.sup.5
is --(CH.sub.2).sub.4--O--R.sup.5.
[0630] In certain embodiments, --X(CR.sup.3R.sup.4).sub.nY--R.sup.5
is chosen from --NH--(CH.sub.2).sub.3--O--R.sup.5,
--NH--(CH.sub.2).sub.2--NH--R.sup.5,
--O--(CH.sub.2).sub.2--O--R.sup.5,
--O--(CH.sub.2).sub.3--O--R.sup.5,
--O--CH.sub.2--C(CH.sub.3).sub.2--CH.sub.2--O--R.sup.5, and
--NH--(CH.sub.2).sub.2--O--R.sup.5. In certain embodiments,
--X(CR.sup.3R.sup.4).sub.nY--R.sup.5 is chosen from
--NH--(CH.sub.2).sub.3--O--R.sup.5,
--NH--(CH.sub.2).sub.2--NH--R.sup.5,
--O--(CH.sub.2).sub.3--O--R.sup.5, and
--NH--(CH.sub.2).sub.2--O--R.sup.5. In certain embodiments,
--X(CR.sup.3R.sup.4).sub.nY--R.sup.5 is chosen from
--NH--(CH.sub.2).sub.3--O--R.sup.5 and
--O--(CH.sub.2).sub.3--O--R.sup.5.
[0631] In certain embodiments, --X(CR.sup.3R.sup.4).sub.nYR.sup.5
is --NH--(CH.sub.2).sub.3--R.sup.5 (i.e. Y is a covalent bond).
[0632] In certain embodiments, R.sup.9 is chosen from H, C.sub.1-4
alkyl; and C.sub.1-8 cycloalkyl, substituted C.sub.1-4 alkyl chosen
from mono-, di-, and tri-substituted C.sub.1-4 alkyl; and
substituted C.sub.3-8 cycloalkyl chosen from mono-, di-, and
tri-substituted C.sub.3-8 cycloalkyl, wherein the substituents on
the alkyl and cycloalkyl groups are independently chosen from halo,
C.sub.1-4-alkyl, C.sub.1-4-alkoxy, and oxo.
[0633] In certain embodiments, R.sup.5 is chosen from pyridin-3-yl
and pyridin-4-yl, each of which is optionally substituted with one
or two groups chosen from [0634] (1) C.sub.1-8 alkyl, [0635] (2)
C.sub.1-8 cycloalkyl, [0636] (3) C.sub.4-8 cycloalkylalkyl, [0637]
(4) C.sub.1-8 alkoxy, [0638] (5) C.sub.3-8 cycloalkoxy, [0639] (6)
C.sub.4-8 cycloalkylalkoxy, [0640] (7) halo, [0641] (8) amino,
[0642] (9) cyano, [0643] (10) hydroxyl, [0644] (11) nitro, [0645]
(12) C.sub.1-8 halogenated alkyl, [0646] (13) C.sub.1-8 halogenated
alkoxy, [0647] (14) C.sub.1-8 hydroxyalkyl, [0648] (15) C.sub.2-8
hydroxyalkoxy [0649] (16) C.sub.3-8 alkenyloxy, [0650] (17)
C.sub.1-8 alkylamino, [0651] (18) di-C.sub.1-8 alkylamino, [0652]
(19) carboxy, [0653] (20) alkoxycarbonyl, [0654] (21) carboxamido,
[0655] (22) aminocarbonyl, [0656] (23) hydroxyaminocarbonyl, [0657]
(24) alkylaminocarbonyl, [0658] (25) dialkylaminocarbonyl, [0659]
(26) urea, [0660] (27) hydroxyurea, [0661] (28) alkylurea, [0662]
(29) dialkylaminoalkylcarbonyl, [0663] (30)
aminocarbonylalkylaminocarbonyl, [0664] (31) acylamido, [0665] (32)
HCO--NH--NH--CO--, [0666] (33) NH.sub.2NHCO--, [0667] (34)
NH.sub.2NHCONH--, [0668] (35) acyloxy, [0669] (36) C.sub.1-8
alkylthio, [0670] (37) C.sub.1-8 alkylsulphinyl, [0671] (38)
C.sub.1-8 alkylsulphonyl, [0672] (39) C.sub.1-8 alkylsulphonamido,
[0673] (40) (alkylsuphonyl).sub.2amino-, [0674] (41) thiol, [0675]
(42) aminosulfonyl, [0676] (43) alkylaminosulfonyl, [0677] (44)
oxo, [0678] (45) C.sub.6-20 aryl, [0679] (46) substituted
C.sub.6-20 aryl chosen from mono-, di-, and tri-substituted
C.sub.6-2 aryl wherein the substituents are independently chosen
from halo, C.sub.1-8 alkyl, halogenated C.sub.1-8 alkyl, C.sub.1-4
alkoxy, halogenated C.sub.1-4 alkoxy, C.sub.1-8 hydroxyalkyl,
C.sub.2-8 hydroxyalkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8
alkylamino, C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl,
C.sub.1-8 alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9,
cyano, hydroxyl, nitro, and thio, [0680] (47) heterocyclyl, [0681]
(48) substituted heterocyclyl chosen from mono-, di-, and
trisubstituted heterocyclyl wherein the substituents are
independently chosen from halo, C.sub.1-8 alkyl, halogenated
C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy,
hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8
alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl,
C.sub.1-8 alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, oxo, and thio,
[0682] (49) heteroaryl, [0683] (50) substituted heteroaryl chosen
from mono-, di-, and trisubstituted heteroaryl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio, [0684] (51) heterocyclyl-carbonyl,
[0685] (52) substituted heterocyclyl-carbonyl chosen from mono-,
di-, and trisubstituted heterocyclyl-carbonyl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio, [0686] (53) heteroaryl-carbonyl,
and [0687] (54) substituted heteroaryl-carbonyl chosen from mono-,
di-, and trisubstituted heteroaryl-carbonyl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio.
[0688] In certain embodiments, R.sup.5 is chosen from pyridin-2-yl
and pyridin-4-yl, each of which is substituted with one or two
groups chosen from [0689] (1) C.sub.1-8 alkyl, [0690] (2) C.sub.3-8
cycloalkyl, [0691] (3) C.sub.4-8 cycloalkylalkyl, [0692] (4)
C.sub.1-8 alkoxy, [0693] (5) C.sub.3-8 cycloalkoxy, [0694] (6)
C.sub.4-8 cycloalkylalkoxy, [0695] (7) halo, [0696] (8) amino,
[0697] (9) cyano, [0698] (10) hydroxyl, [0699] (11) nitro, [0700]
(12) C.sub.2-8 halogenated alkyl, [0701] (13) C.sub.1-8 halogenated
alkoxy, [0702] (14) C.sub.1-8 hydroxyalkyl, [0703] (15) C.sub.2-8
hydroxyalkoxy [0704] (16) C.sub.3-8 alkenyloxy, [0705] (17)
C.sub.1-8 alkylamino, [0706] (18) di-C.sub.1-8 alkylamino, [0707]
(19) carboxy, [0708] (20) alkoxycarbonyl, [0709] (21) carboxamido,
[0710] (22) aminocarbonyl, [0711] (23) hydroxyaminocarbonyl, [0712]
(24) alkylaminocarbonyl, [0713] (25) dialkylaminocarbonyl, [0714]
(26) urea, [0715] (27) hydroxyurea, [0716] (28) alkylurea, [0717]
(29) dialkylaminoalkylcarbonyl, [0718] (30)
aminocarbonylalkylaminocarbonyl, [0719] (31) acylamido, [0720] (32)
HCO--NH--NH--CO--, [0721] (33) NH.sub.2NHCO--, [0722] (34)
NH.sub.2NHCONH--, [0723] (35) acyloxy, [0724] (36) C.sub.1-8
alkylthio, [0725] (37) C.sub.1-8 alkylsulphinyl, [0726] (38)
C.sub.1-8 alkylsulphonyl, [0727] (39) C.sub.1-8 alkylsulphonamido,
[0728] (40) (alkylsuphonyl).sub.2-amino-, [0729] (41) thiol, [0730]
(42) aminosulfonyl, [0731] (43) alkylaminosulfonyl, [0732] (44)
oxo, [0733] (45) C.sub.6-20 aryl, [0734] (46) substituted
C.sub.6-20 aryl chosen from mono-, di-, and tri-substituted
C.sub.6-20 aryl wherein the substituents are independently chosen
from halo, C.sub.1-8 alkyl, halogenated C.sub.1-8 alkyl, C.sub.1-4
alkoxy, halogenated C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl,
hydroxy C.sub.2-8 alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8
alkylamino, C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl,
C.sub.1-8 alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9,
cyano, hydroxyl, nitro, and thio, [0735] (47) heterocyclyl, [0736]
(48) substituted heterocyclyl chosen from mono-, di-, and
trisubstituted heterocyclyl wherein the substituents are
independently chosen from halo, C.sub.1-8 alkyl, halogenated
C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated C.sub.1-4 alkoxy,
hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8alkoxy, amino, C.sub.1-8
alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8 alkylsulphinyl,
C.sub.1-8 alkylsulphonyl, C.sub.1-8 alkylsulphonamido, --COR.sup.9,
--CSR.sup.9, --SR.sup.9, cyano, hydroxyl, nitro, oxo, and thio,
[0737] (49) heteroaryl, [0738] (50) substituted heteroaryl chosen
from mono-, di-, and trisubstituted heteroaryl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio, [0739] (51) heterocyclyl-carbonyl,
[0740] (52) substituted heterocyclyl-carbonyl chosen from mono-,
di-, and trisubstituted heterocyclyl-carbonyl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4alkoxy, halogenated C.sub.1-4
alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8alkoxy, amino,
C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8
alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio, [0741] (53) heteroaryl-carbonyl,
and [0742] (54) substituted heteroaryl-carbonyl chosen from mono-,
di-, and trisubstituted heteroaryl-carbonyl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio.
[0743] Provided is at least one chemical entity chosen from
compounds of Formula II:
##STR00006##
and pharmaceutically acceptable salts, solvates, chelates,
non-covalent complexes, prodrugs, and mixtures thereof, wherein
R.sup.1, X, Y, n, R.sup.3, R.sup.4, and R.sup.9 are as described
for compounds of Formula I and wherein
[0744] p is chosen from 1, 2, 3, and 4;
[0745] for each occurrence, R.sup.10 is independently chosen from
[0746] (1) C.sub.2-8 alkyl, [0747] (2) C.sub.3-8 cycloalkyl, [0748]
(3) C.sub.4-8 cycloalkylalkyl, [0749] (4) C.sub.3-8 cycloalkoxy,
[0750] (5) C.sub.4-8 cycloalkylalkoxy, [0751] (6) amino, [0752] (7)
cyano, [0753] (8) nitro, [0754] (9) C.sub.1-8 halogenated alkyl,
[0755] (10) C.sub.1-8 halogenated alkoxy, [0756] (11) C.sub.1-8
hydroxyalkyl, [0757] (12) C.sub.2-8 hydroxyalkoxy, [0758] (13)
C.sub.1-8 alkylamino, [0759] (14) di-C.sub.1-8alkylamino, [0760]
(15) carboxy, [0761] (16) alkoxycarbonyl, [0762] (17)
aminocarbonyl, [0763] (18) hydroxyaminocarbonyl, [0764] (19)
alkylaminocarbonyl, [0765] (20) dialkylaminocarbonyl, [0766] (21)
urea, [0767] (22) hydroxyurea, [0768] (23) alkylurea, [0769] (24)
dialkylaminoalkylcarbonyl, [0770] (25)
aminocarbonylalkylaminocarbonyl, [0771] (26) acylamido, [0772] (27)
HCO--NH--NH--CO--, [0773] (28) NH.sub.2NHCO--, [0774] (29)
NH.sub.2NHCONH--, [0775] (30) acyloxy, [0776] (31) C.sub.1-8
alkylthio, [0777] (32) C.sub.1-8 alkylsulphinyl, [0778] (33)
C.sub.1-8 alkylsulphonyl, [0779] (34) C.sub.1-8 alkylsulphonamido,
[0780] (35) (alkylsuphonyl).sub.2amino-, [0781] (36) thiol, [0782]
(37) aminosulfonyl, [0783] (38) alkylaminosulfonyl, [0784] (39)
C.sub.6-20 aryl, [0785] (40) substituted C.sub.6-20 aryl chosen
from mono-, di-, and tri-substituted C.sub.6-20 aryl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4alkoxy, halogenated
C.sub.1-4alkoxy, C.sub.1-8 hydroxyalkyl, C.sub.2-8 hydroxyalkoxy,
amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino, C.sub.1-8
alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, and thio, [0786] (41) heterocyclyl-carbonyl,
[0787] (42) substituted heterocyclyl-carbonyl chosen from mono-,
di-, and trisubstituted heterocyclyl-carbonyl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio, [0788] (43) heteroaryl-carbonyl,
and [0789] (44) substituted heteroaryl-carbonyl chosen from mono-,
di-, and trisubstituted heteroaryl-carbonyl wherein the
substituents are independently chosen from halo, C.sub.1-8 alkyl,
halogenated C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogenated
C.sub.1-4 alkoxy, hydroxy C.sub.1-8 alkyl, hydroxy C.sub.2-8
alkoxy, amino, C.sub.1-8 alkylamino, di-C.sub.1-8 alkylamino,
C.sub.1-8 alkylsulphinyl, C.sub.1-8 alkylsulphonyl, C.sub.1-8
alkylsulphonamido, --COR.sup.9, --CSR.sup.9, --SR.sup.9, cyano,
hydroxyl, nitro, oxo, and thio.
[0790] In certain embodiments, [0791] R.sup.1 is chosen from [0792]
aryl (such as phenyl), [0793] substituted aryl chosen from mono-,
di-, and trisubstituted aryl wherein the substitutent is halo (such
as F, e.g., phenyl substituted by fluoro), [0794] heterocyclyl, and
[0795] substituted heterocyclyl, such as optionally substituted
heterocyclyl chosen from optionally substituted furanyl, optionally
substituted pyridinyl, optionally substituted pyrimidinyl,
optionally substituted pyrazinyl, and optionally substituted
thiazolyl, such as heterocyclyl chosen from 5-chloro-furan-2-yl,
furan-2-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl,
1,3-thiazol-2-yl, 5-pyrazin-2-yl, and 5-pyrimidin-2-yl; [0796]
R.sup.2 is --X(CR.sup.3R.sup.4).sub.nY--R.sup.5; [0797]
--X(CR.sup.3R.sup.4).sub.nY-- is chosen from
--NH--(CH.sub.2).sub.3--O--, --NH--(CH.sub.2).sub.2--NH--,
--O--(CH.sub.2).sub.2--O--, --O--(CH.sub.2).sub.3--O--,
--O--CH.sub.2--C(CH.sub.3).sub.2--CH.sub.2--O--, and
--NH--(CH.sub.2).sub.2--O--, and in certain embodiments,
--X(CR.sup.3R.sup.4).sub.nY-- is chosen from
--NH--(CH.sub.2).sub.3--O-- and --O--(CH.sub.2).sub.3--O--; [0798]
R.sup.3, R.sup.4, R.sup.6, and R.sup.7 are independently chosen
from H, CH.sub.3, and F, and in certain embodiments, R.sup.3,
R.sup.4, R.sup.6, and R.sup.7 are H; [0799] X is chosen from O and
NR.sup.9, and in certain embodiments, X is chosen from O and NH,
[0800] Y is chosen from O and NR.sup.9, and in certain embodiments,
Y is chosen from O and NH, and in yet other certain embodiments, Y
is O; and [0801] R.sup.5 is chosen from [0802] phenyl, [0803]
benzyl, [0804] benzoyl, [0805] benzothiadiazolyl, [0806] pyrazolyl,
[0807] benzisothiazolyl, [0808] dihydroindolyl, [0809] pyridinyl,
[0810] substituted phenyl chosen from mono-, di-, and
tri-substituted phenyl wherein the substituents are independently
chosen from alkyl-CO--NH-- (e.g., CH.sub.3--CO--NH--,
CH.sub.3CH.sub.2--CO--NH-- and cyclopropyl-CO--NH--),
NH.sub.2--CO--NH--, alkyl-NH--CO--NH--, NH.sub.2--NH--CO--NH--,
OH--NH--CO--NH--, NH.sub.2--CO--, NH.sub.2--NH--CO--, HO--NH--CO--,
alkyl-NH--CO--, (alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--, HCO--NH--NH--CO--,
alkyl-SO.sub.2--NH--, (alkyl-SO.sub.2).sub.2N--, nitro, alkyl
(e.g., ethyl), alkoxy (e.g., methoxy), halogenated alkoxy (e.g.,
trifluoromethoxy), cyano, alkoxycarbonyl (e.g., methoxycarbonyl),
triazolyl, halo (e.g., F), amino, carboxy,
methylpiperazinyloxycarbonyl, and morpholinylcarbonyl, [0811]
substituted benzyl chosen from mono-, di-, and tri-substituted
benzyl wherein the substituents are independently chosen from
alkyl-CO--NH-- (e.g., CH.sub.3--CO--NH--,
CH.sub.3CH.sub.2--CO--NH-- and cyclopropyl-CO--NH--),
NH.sub.2--CO--NH--, alkyl-NH--CO--NH--, NH.sub.2--NH--CO--NH--,
OH--NH--CO--NH--, NH.sub.2--CO--, NH, --NH--CO--, HO--NH--CO--,
alkyl-NH--CO--, (alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--HCO--NH--NH--CO--, alkyl-SO.sub.2--NH--,
(alkyl-SO.sub.2).sub.2N--, nitro, alkyl (e.g., ethyl), alkoxy
(e.g., methoxy), halogenated alkoxy (e.g., trifluoromethoxy),
cyano, alkoxycarbonyl (e.g., methoxycarbonyl), triazolyl, halo
(e.g., F), amino, carboxy, methylpiperazinyloxycarbonyl, and
morpholinylcarbonyl, [0812] substituted benzoyl chosen from mono-,
di-, and tri-substituted benzoyl wherein the substituents are
independently chosen from alkyl-CO--NH-- (e.g., CH.sub.3--CO--NH--,
CH.sub.3CH.sub.2--CO--NH-- and cyclopropyl-CO--NH--),
NH.sub.2--CO--NH--, alkyl-NH--CO--NH--, NH.sub.2--NH--CO--NH--,
OH--NH--CO--NH--, NH.sub.2--CO--, NH.sub.2--NH--CO--, HO--NH--CO--,
alkyl-NH--CO--, (alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--, HCO--NH--NH--CO--,
alkyl-SO.sub.2--NH--, (alkyl-SO.sub.2).sub.2N--, nitro, alkyl
(e.g., ethyl), alkoxy (e.g., methoxy), halogenated alkoxy (e.g.,
trifluoromethoxy), cyano, alkoxycarbonyl (e.g., methoxycarbonyl),
triazolyl, halo (e.g., F), amino, carboxy,
methylpiperazinyloxycarbonyl, and morpholinylcarbonyl, [0813]
substituted benzothiadiazolyl chosen from mono-, di-, and
tri-substituted benzothiadiazolyl wherein the substituents are
independently chosen from alkyl-CO--NH-- (e.g., CH.sub.3--CO--NH--,
CH.sub.3CH.sub.2--CO--NH-- and cyclopropyl-CO--NH--),
NH.sub.2--CO--NH--, alkyl-NH--CO--NH--, NH.sub.2--NH--CO--NH--,
OH--NH--CO--NH--, NH.sub.2--CO--, NH.sub.2--NH--CO--, HO--NH--CO--,
alkyl-NH--CO--, (alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--, HCO--NH--NH--CO--,
alkyl-SO.sub.2--NH--, (alkyl-SO.sub.2).sub.2N--, nitro, alkyl
(e.g., ethyl), alkoxy (e.g., methoxy), halogenated alkoxy (e.g.,
trifluoromethoxy), cyano, alkoxycarbonyl (e.g., methoxycarbonyl),
triazolyl, halo (e.g., F), amino, carboxy,
methylpiperazinyloxycarbonyl, and morpholinylcarbonyl, [0814]
substituted pyrazolyl chosen from mono-, di-, and tri-substituted
pyrazolyl wherein the substituents are independently chosen from
alkyl-CO--NH-- (e.g., CH.sub.3--CO--NH--,
CH.sub.3CH.sub.2--CO--NH-- and cyclopropyl-CO--NH--),
NH.sub.2--CO--NH--, alkyl-NH--CO--NH--, NH.sub.2--NH--CO--NH--,
OH--NH--CO--NH--, NH.sub.2--CO--, NH.sub.2--NH--CO--, HO--NH--CO--,
alkyl-NH--CO--, (alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--, HCO--NH--NH--CO--,
alkyl-SO.sub.2--NH--, (alkyl-SO.sub.2).sub.2N--, nitro, alkyl
(e.g., ethyl), alkoxy (e.g., methoxy), halogenated alkoxy (e.g.,
trifluoromethoxy), cyano, alkoxycarbonyl (e.g., methoxycarbonyl),
triazolyl, halo (e.g., F), amino, carboxy,
methylpiperazinyloxycarbonyl, and morpholinylcarbonyl, [0815]
substituted benzisothiazolyl chosen from mono-, di-, and
tri-substituted benzisothiazolyl wherein the substituents are
independently chosen from alkyl-CO--NH-- (e.g., CH.sub.3--CO--NH--,
CH.sub.3CH.sub.2--CO--NH-- and cyclopropyl-CO--NH--),
NH.sub.2--CO--NH--, alkyl-NH--CO--NH--, NH.sub.2--NH--CO--NH--,
OH--NH--CO--NH--, NH.sub.2--CO--, NH.sub.2--NH--CO--, HO--NH--CO--,
alkyl-NH--CO--, (alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--, HCO--NH--NH--CO--,
alkyl-SO.sub.2--NH--, (alkyl-SO.sub.2).sub.2N--, nitro, alkyl
(e.g., ethyl), alkoxy (e.g., methoxy), halogenated alkoxy (e.g.,
trifluoromethoxy), cyano, alkoxycarbonyl (e.g., methoxycarbonyl),
triazolyl, halo (e.g., F), amino, carboxy,
methylpiperazinyloxycarbonyl, and morpholinylcarbonyl, [0816]
substituted dihydroindolyl chosen from mono-, di-, and
tri-substituted dihydroindolyl wherein the substituents are
independently chosen from alkyl-CO--NH-- (e.g., CH.sub.3--CO--NH--,
CH.sub.3CH.sub.2--CO--NH-- and cyclopropyl-CO--NH--),
NH.sub.2--CO--NH--, alkyl-NH--CO--NH--, NH.sub.2--NH--CO--NH--,
OH--NH--CO--NH--, NH.sub.2--CO--, NH.sub.2--NH--CO--, HO--NH--CO--,
alkyl-NH--CO--, (alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-N--H--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--, HCO--NH--NH--CO--,
alkyl-SO.sub.2--NH--, (alkyl-SO.sub.2).sub.2N--, nitro, alkyl
(e.g., ethyl), alkoxy (e.g., methoxy), halogenated alkoxy (e.g.,
trifluoromethoxy), cyano, alkoxycarbonyl (e.g., methoxycarbonyl),
triazolyl, halo (e.g., F), amino, carboxy,
methylpiperazinyloxycarbonyl, and morpholinylcarbonyl, and [0817]
substituted pyridinyl chosen from mono-, di-, and tri-substituted
pyridinyl wherein the substituents are independently chosen from
alkyl-CO--NH-- (e.g., CH.sub.3--CO--NH--,
CH.sub.3CH.sub.2--CO--NH-- and cyclopropyl-CO--NH--),
NH.sub.2--CO--NH--, alkyl-NH--CO--NH--, NH.sub.2--NH--CO--NH--,
OH--NH--CO--NH--, NH.sub.2--CO--, NH.sub.2--NH--CO--, HO--NH--CO--,
alkyl-NH--CO--, (alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--HCO--NH--NH--CO--, alkyl-SO.sub.2--NH--,
(alkyl-SO.sub.2).sub.2N--, nitro, alkyl (e.g., ethyl), alkoxy
(e.g., methoxy), halogenated alkoxy (e.g., trifluoromethoxy),
cyano, alkoxycarbonyl (e.g., methoxycarbonyl), triazolyl, halo
(e.g., F), amino, carboxy, methylpiperazinyloxycarbonyl, and
morpholinylcarbonyl; and [0818] in certain embodiments, R.sup.5 is
chosen from phenyl and substituted phenyl wherein substituted
phenyl is chosen from mono-, di-, and tri-substituted phenyl and
wherein the substituents are independently chosen from
alkyl-CO--NH-- (e.g., CH.sub.3--CO--NH--,
CH.sub.3CH.sub.2--CO--NH-- and cyclopropyl-CO--NH--),
NH.sub.2--CO--NH--, alkyl-NH--CO--NH--, NH.sub.2--NH--CO--NH--,
OH--NH--CO--NH--, NH.sub.2--CO--, NH.sub.2--NH--CO--, HO--NH--CO--,
alkyl-NH--CO--, (alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--HCO--NH--NH--CO--, alkyl-SO.sub.2--NH--,
(alkyl-SO.sub.2).sub.2N--, nitro, alkyl (e.g., ethyl), alkoxy
(e.g., methoxy), halogenated alkoxy (e.g., trifluoromethoxy),
cyano, alkoxycarbonyl (e.g., methoxycarbonyl), triazolyl, halo
(e.g., F), amino, carboxy, methylpiperazinyloxycarbonyl, and
morpholinylcarbonyl.
[0819] In certain embodiments, [0820] R.sup.1 is chosen from [0821]
aryl (such as phenyl), [0822] aryl (such as phenyl) substituted by
halo (such as F), and [0823] heterocyclyl, [0824] substituted
heterocyclyl, such as optionally substituted heterocyclyl chosen
from optionally substituted furanyl, optionally substituted
pyridinyl, and optionally substituted thiazolyl, such as
heterocyclyl chosen from furan-2-yl, pyridin-4-yl, pyridin-3-yl,
pyridin-2-yl, and 1,3-thiazol-2-yl; [0825] R.sup.2 is
--X(CR.sup.3R.sup.4).sub.nY--R'; [0826]
--X(CR.sup.3R.sup.4).sub.nY-- is chosen from
--NH--(CH.sub.2).sub.3--O--, --NH--(CH.sub.2).sub.2--NH--,
--O--(CH.sub.2).sub.3--O--, and --NH--(CH.sub.2).sub.2--O--, and in
certain embodiments, --X(CR.sup.3R.sup.4).sub.nY-- is chosen from
--NH--(CH.sub.2).sub.3--O-- and --O--(CH.sub.2).sub.3--O--; [0827]
R.sup.3, R.sup.4, R.sup.6, and R.sup.7 are independently chosen
from H, CH.sub.3, and F, and in certain embodiments, R.sup.3,
R.sup.4, R.sup.6, and R.sup.7 are H; [0828] X is chosen from O and
NR.sup.9, and in certain embodiments, X is chosen from O and NH;
[0829] Y is chosen from O and NR.sup.9, and in certain embodiments,
Y is chosen from O and NH, and in yet other certain embodiments, Y
is O; [0830] the subscript n is chosen from 2 and 3, and in certain
embodiments, the subscript n is 3; [0831] R.sup.5 is chosen from
[0832] phenyl, [0833] benzyl, [0834] benzoyl, [0835]
benzothiadiazolyl, [0836] pyrazolyl, [0837] benzisothiazolyl,
[0838] dihydroindolyl, [0839] pyridinyl, [0840] substituted phenyl
chosen from mono-, di-, and tri-substituted phenyl wherein the
substituents are independently chosen from alkyl-CO--NH-- (e.g.,
CH.sub.3--CO--NH--, CH.sub.3CH.sub.2--CO--NH-- and
cyclopropyl-CO--NH--), NH.sub.2--CO--NH--, alkyl-NH--CO--NH--,
NH.sub.2--NH--CO--NH--, OH--NH--CO--NH--, NH.sub.2--CO--,
NH.sub.2--NH--CO--, HO--NH--CO--, alkyl-NH--CO--,
(alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--, HCO--NH--NH--CO--,
alkyl-SO.sub.2--NH--, (alkyl-SO.sub.2).sub.2N--, nitro, alkyl
(e.g., ethyl), alkoxy (e.g., methoxy), halogenated alkoxy (e.g.,
trifluoromethoxy), cyano, alkoxycarbonyl (e.g., methoxycarbonyl),
triazolyl, halo (e.g., F), amino, carboxy,
methylpiperazinyloxycarbonyl, and morpholinylcarbonyl, [0841]
substituted benzyl chosen from mono-, di-, and tri-substituted
benzyl wherein the substituents are independently chosen from
alkyl-CO--NH-- (e.g., CH.sub.3--CO--NH--,
CH.sub.3CH.sub.2--CO--NH-- and cyclopropyl-CO--NH--),
NH.sub.2--CO--NH--, alkyl-NH--CO--NH--, NH.sub.2--NH--CO--NH--,
OH--NH--CO--NH--, NH.sub.2--CO--, NH.sub.2--NH--CO--, HO--NH--CO--,
alkyl-NH--CO--, (alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--HCO--NH--NH--CO--, alkyl-SO.sub.2--NH--,
(alkyl-SO.sub.2).sub.2N--, nitro, alkyl (e.g., ethyl), alkoxy
(e.g., methoxy), halogenated alkoxy (e.g., trifluoromethoxy),
cyano, alkoxycarbonyl (e.g., methoxycarbonyl), triazolyl, halo
(e.g., F), amino, carboxy, methylpiperazinyloxycarbonyl, and
morpholinylcarbonyl, [0842] substituted benzoyl chosen from mono-,
di-, and tri-substituted benzoyl wherein the substituents are
independently chosen from alkyl-CO--NH-- (e.g., CH.sub.3--CO--NH--,
CH.sub.3CH.sub.2--CO--NH-- and cyclopropyl-CO--NH--),
NH.sub.2--CO--NH--, alkyl-NH--CO--NH--, NH.sub.2--NH--CO--NH--,
OH--NH--CO--NH--, NH.sub.2--CO--, NH.sub.2--NH--CO--, HO--NH--CO--,
alkyl-NH--CO--, (alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--, HCO--NH--NH--CO--,
alkyl-SO.sub.2--NH--, (alkyl-SO.sub.2).sub.2N--, nitro, alkyl
(e.g., ethyl), alkoxy (e.g., methoxy), halogenated alkoxy (e.g.,
trifluoromethoxy), cyano, alkoxycarbonyl (e.g., methoxycarbonyl),
triazolyl, halo (e.g., F), amino, carboxy,
methylpiperazinyloxycarbonyl, and morpholinylcarbonyl, [0843]
substituted benzothiadiazolyl chosen from mono-, di-, and
tri-substituted benzothiadiazolyl wherein the substituents are
independently chosen from alkyl-CO--NH-- (e.g., CH.sub.3--CO--NH--,
CH.sub.3CH.sub.2--CO--NH-- and cyclopropyl-CO--NH--),
NH.sub.2--CO--NH--, alkyl-NH--CO--NH--, NH.sub.2--NH--CO--NH--,
OH--NH--CO--NH--, NH.sub.2--CO--, NH.sub.2--NHCO--, HO--NH--CO--,
alkyl-NH--CO--, (alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NHCO--, HCO--NH--NH--CO--, alkyl-SO.sub.2--NH--,
(alkyl-SO.sub.2).sub.2N--, nitro, alkyl (e.g., ethyl), alkoxy
(e.g., methoxy), halogenated alkoxy (e.g., trifluoromethoxy),
cyano, alkoxycarbonyl (e.g., methoxycarbonyl), triazolyl, halo
(e.g., F), amino, carboxy, methylpiperazinyloxycarbonyl, and
morpholinylcarbonyl, [0844] substituted pyrazolyl chosen from
mono-, di-, and tri-substituted pyrazolyl wherein the substituents
are independently chosen from alkyl-CO--NH-- (e.g.,
CH.sub.3--CO--NH--, CH.sub.3CH.sub.2--CO--NH-- and
cyclopropyl-CO--NH--), NH.sub.2--CO--NH--, alkyl-NH--CO--NH--,
NH.sub.2--NH--CO--NH--, OH--NH--CO--NH--, NH.sub.2--CO--,
NH.sub.2--NH--CO--, HO--NH--CO--, alkyl-NH--CO--,
(alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--, HCO--NH--NH--CO--,
alkyl-SO.sub.2--NH--, (alkyl-SO.sub.2).sub.2N--, nitro, alkyl
(e.g., ethyl), alkoxy (e.g., methoxy), halogenated alkoxy (e.g.,
trifluoromethoxy), cyano, alkoxycarbonyl (e.g., methoxycarbonyl),
triazolyl, halo (e.g., F), amino, carboxy,
methylpiperazinyloxycarbonyl, and morpholinylcarbonyl, [0845]
substituted benzisothiazolyl chosen from mono-, di-, and
tri-substituted benzisothiazolyl wherein the substituents are
independently chosen from alkyl-CO--NH-- (e.g., CH.sub.3--CO--NH--,
CH.sub.3CH.sub.2--CO--NH-- and cyclopropyl-CO--NH--),
NH.sub.2--CO--NH--, alkyl-NH--CO--NH--, NH.sub.2--NH--CO--NH--,
OH--NH--CO--NH--, NH.sub.2--CO--, NH.sub.2--NH--CO--, HO--NH--CO--,
alkyl-NH--CO--, (alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--, HCO--NH--NH--CO--,
alkyl-SO.sub.2--NH--, (alkyl-SO.sub.2).sub.2N--, nitro, alkyl
(e.g., ethyl), alkoxy (e.g., methoxy), halogenated alkoxy (e.g.,
trifluoromethoxy), cyano, alkoxycarbonyl (e.g., methoxycarbonyl),
triazolyl, halo (e.g., F), amino, carboxy,
methylpiperazinyloxycarbonyl, and morpholinylcarbonyl, [0846]
substituted dihydroindolyl chosen from mono-, di-, and
tri-substituted dihydroindolyl wherein the substituents are
independently chosen from alkyl-CO--NH-- (e.g., CH.sub.3--CO--NH--,
CH.sub.3CH.sub.2--CO--NH-- and cyclopropyl-CO--NH--),
NH.sub.2--CO--NH--, alkyl-NH--CO--NH--, NH.sub.2--NH--CO--NH--,
OH--NH--CO--NH--, NH.sub.2--CO--, NH.sub.2--NH--CO--, HO--NH--CO--,
alkyl-NH--CO--, (alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--, HCO--NH--NH--CO--,
alkyl-SO.sub.2--NH--, (alkyl-SO.sub.2).sub.2N--, nitro, alkyl
(e.g., ethyl), alkoxy (e.g., methoxy), halogenated alkoxy (e.g.,
trifluoromethoxy), cyano, alkoxycarbonyl (e.g., methoxycarbonyl),
triazolyl, halo (e.g., F), amino, carboxy,
methylpiperazinyloxycarbonyl, and morpholinylcarbonyl, and [0847]
substituted pyridinyl chosen from mono-, di-, and tri-substituted
pyridinyl wherein the substituents are independently chosen from
alkyl-CO--NH-- (e.g., CH.sub.3--CO--NH--,
CH.sub.3CH.sub.2--CO--NH-- and cyclopropyl-CO--NH--),
NH.sub.2--CO--NH--, alkyl-NH--CO--NH--, NH.sub.2--NH--CO--NH--,
OH--NH--CO--NH--, NH.sub.2--CO--, NH.sub.2--NH--CO--, HO--NH--CO--,
alkyl-NH--CO--, (alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--HCO--NH--NH--CO--, alkyl-SO.sub.2--NH--,
(alkyl-SO.sub.2).sub.2N--, nitro, alkyl (e.g., ethyl), alkoxy
(e.g., methoxy), halogenated alkoxy (e.g., trifluoromethoxy),
cyano, alkoxycarbonyl (e.g., methoxycarbonyl), triazolyl, halo
(e.g., F), amino, carboxy, methylpiperazinyloxycarbonyl, and
morpholinylcarbonyl; and [0848] in certain embodiments, R.sup.5 is
chosen from phenyl and substituted phenyl wherein substituted
phenyl is chosen from mono-, di-, and tri-substituted phenyl and
wherein the substituents are independently chosen from
alkyl-CO--NH-- (e.g., CH.sub.3--CO--NH--,
CH.sub.3CH.sub.2--CO--NH-- and cyclopropyl-CO--NH--),
NH.sub.2--CO--NH--, alkyl-NH--CO--NH--, NH.sub.2--NH--CO--NH--,
OH--NH--CO--NH--, NH.sub.2--CO--, NH.sub.2--NH--CO--, HO--NH--CO--,
alkyl-NH--CO--, (alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--, HCO--NH--NH--CO--,
alkyl-SO.sub.2--NH--, (alkyl-SO.sub.2).sub.2N--, nitro, alkyl
(e.g., ethyl), alkoxy (e.g., methoxy), halogenated alkoxy (e.g.,
trifluoromethoxy), cyano, alkoxycarbonyl (e.g., methoxycarbonyl),
triazolyl, halo (e.g., F), amino, carboxy,
methylpiperazinyloxycarbonyl, and morpholinylcarbonyl.
[0849] In certain embodiments, R.sup.1 is chosen from phenyl,
furanyl, pyridinyl, pyrimidinyl, thiazolyl, substituted phenyl,
substituted furanyl, substituted pyridinyl, substituted
pyrimidinyl, and substituted thiazolyl, and R.sup.2 is
--X(CR.sup.3R.sup.4).sub.nYR.sup.5.
[0850] In certain embodiments, R.sup.1 is chosen from furanyl,
pyridinyl, thiazolyl, phenyl, and phenyl substituted by halo, and
R.sup.2 is --X(CR.sup.3R.sup.4).sub.nYR.sup.5.
[0851] In certain embodiments, R.sup.1 is chosen from phenyl and
phenyl substituted by halo, and R.sup.2 is
--X(CR.sup.3R.sup.4).sub.nYR.sup.5.
[0852] In certain embodiments, R.sup.1 is chosen from phenyl,
furanyl, pyridinyl, thiazolyl, substituted phenyl, substituted
furanyl, substituted pyridinyl, and substituted thiazolyl, and
R.sup.2 is chosen from --NH--(CH.sub.2).sub.3--O--R.sup.5,
--NH--(CH.sub.2).sub.2--NH--R.sup.5,
--O--(CH.sub.2).sub.3--O--R.sup.5, and
--NH--(CH.sub.2).sub.2--O--R.sup.5.
[0853] In certain embodiments, R.sup.1 is chosen from phenyl,
phenyl substituted by halo, furanyl, pyridinyl, and thiazolyl, and
R.sup.2 is chosen from --NH--(CH.sub.2).sub.3--O--R.sup.5,
--NH--(CH.sub.2).sub.2--NH--R.sup.5,
--O--(CH.sub.2).sub.3--O--R.sup.5, and
--NH--(CH.sub.2).sub.2--O--R.sup.5.
[0854] In certain embodiments, R.sup.1 is chosen from phenyl and
phenyl substituted by halo, and R.sup.2 is chosen from
--NH--(CH.sub.2).sub.3--O--R.sup.5,
--NH--(CH.sub.2).sub.2--NH--R.sup.5,
--O--(CH.sub.2).sub.3--O--R.sup.5, and
--NH--(CH.sub.2).sub.2--O--R.sup.5.
[0855] In certain embodiments, R.sup.1 is chosen from phenyl,
furanyl, pyridinyl, or thiazolyl, substituted phenyl, substituted
furanyl, substituted pyridinyl, and substituted thiazolyl, and
R.sup.2 is chosen from NH--(CH.sub.2).sub.3--O--R.sup.5 and
--O--(CH.sub.2).sub.3--O--R.sup.5.
[0856] In certain embodiments, R.sup.1 is chosen from phenyl,
phenyl substituted by halo, furanyl, pyridinyl, and thiazolyl, and
R.sup.2 is chosen from NH--(CH.sub.2).sub.3--O--R.sup.5 and
--O--(CH.sub.2).sub.3--O--R.sup.5.
[0857] In certain embodiments, R.sup.1 is chosen from phenyl and
phenyl substituted by halo, and R.sup.2 is chosen from
NH--(CH.sub.2).sub.3--O--R.sup.5 and
--O--(CH.sub.2).sub.3--O--R.sup.5.
[0858] In certain embodiments, R.sup.1 is chosen from phenyl,
furanyl, pyridinyl, and thiazolyl, which in each case is
unsubstituted or substituted, and R.sup.2 is
--O--(CH.sub.2).sub.3--O--R.sup.5.
[0859] In certain embodiments, R.sup.1 is chosen from phenyl,
phenyl substituted by halo, furanyl, pyridinyl, and thiazolyl, and
R.sup.2 is --O--(CH.sub.2).sub.3--O--R.sup.5.
[0860] In certain embodiments, R.sup.1 is chosen from phenyl and
phenyl substituted by halo, and R.sup.2 is
--O--(CH.sub.2).sub.3--O--R.sup.5.
[0861] In certain embodiments, R.sup.1 is chosen from phenyl,
furanyl, pyridinyl, and thiazolyl, substituted phenyl, substituted
furanyl, substituted pyridinyl, and substituted thiazolyl; R.sup.2
is chosen from NH--(CH.sub.2).sub.3--O--R.sup.5 and
--O--(CH.sub.2).sub.3--O--R.sup.5; and R.sup.5 is chosen from
phenyl, benzyl, benzoyl), benzothiadiazolyl, pyridinyl, substituted
phenyl, substituted benzyl, substituted benzoyl), substituted
benzothiadiazolyl, and substituted pyridinyl.
[0862] In certain embodiments, R.sup.1 is chosen from phenyl,
phenyl substituted by halo, furanyl, pyridinyl, and thiazolyl;
R.sup.2 is chosen from NH--(CH.sub.2).sub.3--O--R.sup.5 and
--O--(CH.sub.2).sub.3--O--R.sup.5, and R.sup.5 is chosen from
phenyl, benzyl, benzoyl), benzothiadiazolyl, and pyridinyl,
substituted phenyl, substituted benzyl, substituted benzoyl),
substituted benzothiadiazolyl, and substituted pyridinyl.
[0863] In certain embodiments, R.sup.1 is chosen from phenyl and
phenyl substituted by halo; R.sup.2 is chosen from
NH--(CH.sub.2).sub.3--O--R.sup.5 or
--O--(CH.sub.2).sub.3--O--R.sup.5; and R.sup.5 is chosen from
phenyl, benzyl, benzoyl), benzothiadiazolyl, pyridinyl, substituted
phenyl, substituted benzyl, substituted benzoyl), substituted
benzothiadiazolyl, and substituted pyridinyl.
[0864] In certain embodiments, R.sup.1 is chosen from phenyl,
furanyl, pyridinyl, and thiazolyl, substituted phenyl, substituted
furanyl, substituted pyridinyl, and substituted thiazolyl; R.sup.2
is chosen from NH--(CH.sub.2).sub.3--O--R.sup.5 and
--O--(CH.sub.2).sub.3--O--R.sup.5, and R.sup.5 is chosen from
phenyl and pyridinyl, which in each case is substituted by
alkyl-CO--NH-- (e.g., CH.sub.3--CO--NH--,
CH.sub.3CH.sub.2--CO--NH-- or cyclopropyl-CO--NH--),
NH.sub.2--CO--NH--, alkyl-NH--CO--NH--, NH.sub.2--NH--CO--NH--,
OH--NH--CO--NH--, NH.sub.2--CO--, NH.sub.2--NH--CO--, HO--NH--CO--,
alkyl-NH--CO--, (alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--, HCO--NH--NH--CO--,
alkyl-SO.sub.2--NH--, (alkyl-SO.sub.2).sub.2N--, nitro, alkoxy
(e.g., methoxy), halogenated alkoxy (e.g., trifluoromethoxy),
cyano, alkoxycarbonyl (e.g., methoxycarbonyl), triazolyl, halo
(e.g., F), amino, carboxy, methylpiperazinyloxycarbonyl, and
morpholinylcarbonyl.
[0865] In certain embodiments, R.sup.1 is chosen from phenyl,
phenyl substituted by halo, furanyl, pyridinyl, and thiazolyl;
R.sup.2 is chosen from NH--(CH.sub.2).sub.3--O--R.sup.5 and
--O--(CH.sub.2), --O--R.sup.5, and R.sup.5 is chosen from phenyl
and pyridinyl, which in each case is substituted by alkyl-CO--NH--
(e.g., CH.sub.3--CO--NH--, CH.sub.3CH.sub.2--CO--NH-- or
cyclopropyl-CO--NH--), NH.sub.2--CO--NH--, alkyl-NH--CO--NH--,
NH.sub.2--NH--CO--NH--, OH--NH--CO--NH--, NH.sub.2--CO--,
NH.sub.2--NH--CO--, HO--NH--CO--, alkyl-NH--CO--,
(alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--, HCO--NH--NH--CO--,
alkyl-SO.sub.2--NH--, (alkyl-SO.sub.2).sub.2N--, nitro, alkoxy
(e.g., methoxy), halogenated alkoxy (e.g., trifluoromethoxy),
cyano, alkoxycarbonyl (e.g., methoxycarbonyl), triazolyl, halo
(e.g., F), amino, carboxy, methylpiperazinyl-oxycarbonyl, and
morpholinylcarbonyl.
[0866] In certain embodiments, R.sup.1 is chosen from phenyl and
phenyl substituted by halo; R.sup.2 is chosen from
NH--(CH.sub.2).sub.3--O--R.sup.5 and
--O--(CH.sub.2).sub.3--O--R.sup.5; and R.sup.5 is chosen from
phenyl and pyridinyl, which in each case is substituted by
alkyl-CO--NH-- (e.g., CH.sub.3--CO--NH--,
CH.sub.3CH.sub.2--CO--NH-- or cyclopropyl-CO--NH--),
NH.sub.2--CO--NH--, alkyl-NH--CO--NH--, NH.sub.2--NH--CO--NH--,
OH--NH--CO--NH--, NH.sub.2--CO--, NH.sub.2--NH--CO--, HO--NH--CO--,
alkyl-NH--CO--, (alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--, HCO--NH--NH--CO--,
alkyl-SO.sub.2--NH--, (alkyl-SO.sub.2).sub.2N--, nitro, alkoxy
(e.g., methoxy), halogenated alkoxy (e.g., trifluoromethoxy),
cyano, alkoxycarbonyl (e.g., methoxycarbonyl), triazolyl, halo
(e.g., F), amino, carboxy, methylpiperazinyloxy-carbonyl, and
morpholinylcarbonyl.
[0867] In certain embodiments, R.sup.1 is chosen from phenyl and
phenyl substituted by halo; R.sup.2 is
NH--(CH.sub.2).sub.2--O--R.sup.5, and R.sup.5 is chosen from phenyl
and phenyl substituted by alkyl-CO--NH--.
[0868] In certain embodiments, R.sup.1 is chosen from phenyl and
phenyl substituted by halo; R.sup.2 is
NH--(CH.sub.2).sub.3--O--R.sup.5, and; R.sup.5 is chosen from
benzyl, benzoyl), and benzothiadiazolyl, substituted benzyl,
substituted benzoyl), and substituted benzothiadiazolyl, which in
each case the substituents are chosen from nitro, alkoxy (e.g.,
methoxy), cyano, halogenated alkoxy (e.g., OCF.sub.3),
alkoxycarbonyl (e.g., methoxycarbonyl), and alkyl-CO--NH-- (e.g.,
acetamido).
[0869] In certain embodiments, R.sup.1 is chosen from phenyl,
furanyl, pyridinyl, thiazolyl, substituted phenyl, substituted
furanyl, substituted pyridinyl, and substituted thiazolyl; R.sup.2
is --O--(CH.sub.2).sub.3--O--R.sup.5, and R.sup.5 is chosen from
phenyl and pyridinyl, which in each case is substituted by
alkyl-CO--NH--(e.g., CH.sub.3--CO--NH--,
CH.sub.3--CH.sub.2--CO--NH-- or cyclopropyl-CO--NH--),
NH.sub.2--CO--NH--, alkyl-NH--CO--NH--, NH.sub.2--NH--CO--NH--,
OH--NH--CO--NH--, NH.sub.2--CO--, NH.sub.2--NH--CO--, HO--NH--CO--,
alkyl-NH--CO--, (alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--, HCO--NH--NH--CO--,
alkyl-SO.sub.2--NH--, (alkyl-SO.sub.2).sub.2N--, nitro, alkoxy
(e.g., methoxy), halogenated alkoxy (e.g., trifluoromethoxy),
cyano, alkoxycarbonyl (e.g., methoxycarbonyl), triazolyl, halo
(e.g., F), amino, carboxy, methylpiperazinyl-oxycarbonyl, and
morpholinylcarbonyl.
[0870] In certain embodiments, R.sup.1 is chosen from phenyl and
halogenated phenyl; R.sup.2 is --O--(CH.sub.2).sub.3O--R.sup.5, and
R.sup.5 is chosen from phenyl and pyridinyl, which in each case is
substituted by alkyl-CO--NH-- (e.g., CH.sub.3--CO--NH--,
CH.sub.3CH.sub.2--CO--NH-- or cyclopropyl-CO--NH--),
NH.sub.2--CO--NH--, alkyl-NH--CO--NH--, NH.sub.2--NH--CO--NH--,
OH--NH--CO--NH--, NH.sub.2--CO--, NH.sub.2--NH--CO--, HO--NH--CO--,
alkyl-NH--CO--, (alkyl).sub.2N--CO--, NH.sub.2-alkylene-NH--CO--,
(alkyl)NH-alkylene-NH--CO--, (alkyl).sub.2N-alkylene-NH--CO--,
NH.sub.2-alkylene-NH--CO--, HCO--NH--NH--CO--,
alkyl-SO.sub.2--NH--, (alkyl-SO.sub.2).sub.2N--, nitro, alkoxy
(e.g., methoxy), halogenated alkoxy (e.g., trifluoromethoxy),
cyano, alkoxycarbonyl (e.g., methoxycarbonyl), triazolyl, halo
(e.g., F), amino, carboxy, methylpiperazinyl-oxycarbonyl, and
morpholinylcarbonyl.
[0871] In certain embodiments, the compound of Formula I is chosen
from: [0872]
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino}prop-
oxy)-phenyl]-acetamide, [0873]
N-(3-nitrobenzyl)-N'-(5-phenylthieno[2,3-d]pyrimidin-4-yl)ethane-1,2-diam-
ine, [0874]
N-(3,4-dimethoxybenzyl)-N'-(5-phenylthieno[2,3-d]pyrimidin-4-yl)ethane-1,-
2-diamine, [0875]
N-(2,1,3-benzothiadiazol-5-ylmethyl)-N'-(5-phenylthieno[2,3-d]pyrimidin-4-
-yl)ethane-1,2-diamine, [0876]
N-{3-[({2-[(5-phenylthieno[2,3-d]pyrimidin-4-yl)amino]ethyl}amino)methyl]-
-phenyl}-acetamide, [0877]
N-{4-[({2-[(5-phenylthieno[2,3-d]pyrimidin-4-yl)amino]ethyl}amino)methyl]-
-phenyl}-acetamide, [0878]
3-(acetylamino)-N-{2-[(5-phenylthieno[2,3-d]pyrimidin-4-yl)amino]-ethyl}b-
enzamide, [0879]
3-[({2-[(5-phenylthieno[2,3-d]pyrimidin-4-yl)amino]ethyl}amino)methyl]-be-
nzonitrile, [0880] Methyl
3-[({2-[(5-phenylthieno[2,3-d]pyrimidin-4-yl)amino]methyl}amino)-methyl]--
benzoate, [0881]
N-(5-phenylthieno[2,3-d]pyrimidin-4-yl)-N'-[3-(trifluoromethoxy)benzyl]et-
hane-1,2-diamine, [0882]
5-(4-fluorophenyl)-4-[3-(3-nitrophenoxy)propoxy]thieno[2,3-d]pyrimidine,
[0883]
N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino}prop-
oxy)-phenyl]-acetamide, [0884]
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]-acetamide, [0885]
N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]-acetamide, [0886]
5-(4-fluorophenyl)-4-{3-[4-(1H-1,2,4-triazol-1-yl)phenoxy]propoxy}thieno[-
2,3-d]pyrimidine, [0887]
4-[3-(4-fluorophenoxy)propoxy]-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine,
[0888] Methyl
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzoate-
, [0889]
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-
aniline, [0890]
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzoic
acid, [0891]
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]-cyclopropanecarboxamide, [0892]
5-(4-fluorophenyl)-4-(3-{3-[(4-methylpiperazin-1-yl)carbonyl]phenoxy}-pro-
poxy)-thieno[2,3-d]pyrimidine, [0893]
5-(4-fluorophenyl)-4-{3-[3-(morpholin-4-ylcarbonyl)phenoxy]propoxy}-thien-
o[2,3-d]pyrimidine, [0894]
N-ethyl-3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-
-benzamide, [0895]
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-N,N-dim-
ethylbenzamide, [0896]
N-[2-(dimethylamino)ethyl]-3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidi-
n-4-yl]oxy}propoxy)benzamide, [0897]
N-(2-amino-2-oxoethyl)-3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4--
yl]oxy}propoxy)benzamide, [0898]
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-N'-form-
ylbenzohydrazide, [0899]
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-N-methy-
lbenzamide, [0900]
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzamid-
e, [0901]
3-(2-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethoxy)-
-N-methylbenzamide, [0902]
N-[3-(2-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethoxy)phenyl-
]-urea, [0903]
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-phen-
yl]urea, [0904]
3-(2-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethoxy)benzamide-
, [0905]
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-
-benzohydrazide, [0906]
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-N-hydro-
xybenzamide, [0907]
4-(2-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethoxy)benzamide
[0908]
N-ethyl-N'-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]o-
xy}propoxy)phenyl]urea, [0909]
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]-methanesulfonamide, [0910]
N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]-methanesulfonamide, [0911]
N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]-N-(methylsulfonyl)methanesulfonamide, [0912]
N-(ethylsulfonyl)-N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl-
]oxy}-propoxy)phenyl]ethanesulfonamide, [0913]
N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]-ethanesulfonamide, [0914]
N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]-N'-methylurea, [0915]
N-ethyl-N'-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}prop-
oxy)-phenyl]-urea, [0916]
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]-ethanesulfonamide, [0917]
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]-N'-methylurea, [0918]
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]-hydrazinecarboxamide, [0919]
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]-N'-hydroxyurea, [0920]
4-{3-[5-(4-fluorophenyl)-thieno[2,3d]pyrimidin-4-yloxy]-propoxy}-benzamid-
e, [0921]
5-{3-[5-(4-fluorophenyl)-thieno[2,3-d]pyrimidin-4-yloxy]-propoxy-
}-nicotinic acid, methyl ester, [0922]
N-{3-[3-(5-furan-2-yl-thieno[2,3d]pyrimidin-4-yloxy)-propoxy]-phenyl}acet-
amide, [0923]
2-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzamid-
e, [0924]
5-{3-[5-(4-fluorophenyl)-thieno[2,3-d]pyrimidin-4-yloxy]-propoxy-
}-nicotinic acid, [0925]
N-(3-{3-[(5-phenylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}phenyl)acetamid-
e, [0926]
N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}prop-
oxy)phenyl]-hydrazinecarboxamide, [0927]
5-{3-[(5-pyridin-4-ylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}pyridine-2-c-
arboxamide, [0928]
5-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pyridine-
-2-carboxamide, [0929]
5-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pyridi-
ne-2-carboxamide, [0930]
5-{3-[(5-pyridin-3-ylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}pyridine-2-c-
arboxamide [0931]
N-methyl-5-{3-[(5-pyridin-4-ylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}-py-
ridine-2-carboxamide, [0932]
5-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-N-methy-
lpyridine-2-carboxamide, [0933]
N-methyl-5-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}propo-
xy)-pyridine-2-carboxamide, [0934]
N-methyl-5-{3-[(5-pyridin-3-ylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}-py-
ridine-2-carboxamide,
[0935] In certain embodiments, the compound of Formula I is chosen
from: [0936]
N-methyl-3-{3-[(5-pyridin-3-ylthieno[2,3-d]pyrimidin-4-yl)oxy]prop-
oxy}benzamide, [0937]
N-methyl-5-(3-{[5-(1,3-thiazol-2-yl)-thieno[2,3-d]pyrimidin-4-yl]amino}-p-
ropoxy)pyridine-2-carboxamide, [0938]
5-(3-{[5-(5-chloro-2-furyl)thieno[2,3-d]pyrimidin-4-yl)amino}propoxy)-N-m-
ethylpyridine-2-carboxamide, [0939]
N-methyl-5-{3-[(5-pyridin-3-ylthieno[2,3-d]pyrimidin-4-yl)amino]propoxy}p-
yridine-2-carboxamide, [0940]
N-methyl-5-{3-[(5-pyridin-2-ylthieno[2,3-d]pyrimidin-4-yl)amino]propoxy}p-
yridine-2-carboxamide, [0941]
N-methyl-5-{3-[(5-pyridin-2-ylthieno[2,3-d]pyrimidin-4-yl)amino]propoxy-}-
nicotinamide, [0942]
5-{3-[(5-pyridin-3-ylthieno[2,3-d]-pyrimidine-4-yl)oxy]propoxy}pyridine-2-
-carboxamide hydroformate, [0943]
5-(4-fluorophenyl)-4-(3-{[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]ox-
y}propoxy)thieno[2,3-d]pyrimidine, [0944]
4-[3-(4-chlorophenoxy)propoxy]-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine,
[0945]
4-[3-(3,5-difluorophenoxy)propoxy]-5-(4-fluorophenyl)thieno[2,3-d]-
pyrimidine, [0946]
4-[3-(3,4-dimethoxyphenoxy)propoxy]-5-(4-fluorophenyl)thieno[2,3-d]pyrimi-
dine, [0947]
4-[3-(1,2-benzisothiazol-3-yloxy)propoxy]-5-(4-fluorophenyl)thieno[2,3-d]-
pyrimidine, [0948]
5-(4-fluorophenyl)-4-(3-phenoxypropoxy)-thieno[2,3-d]pyrimidine,
[0949]
5-(4-fluorophenyl)-4-[3-(3-methoxy-phenoxy)propoxy]thieno[2,3-d]pyrimidin-
e, [0950]
5-(4-fluorophenyl)-4-[3-(3-methyl-phenoxy)propoxy]thieno[2,3-d]p-
yrimidine, [0951]
5-(4-fluorophenyl)-4-{3-[3-(trifluoro-methoxy)phenoxy]propoxy}thieno[2,3--
d]pyrimidine, [0952]
4-[3-(3-ethylphenoxy)propoxy]-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine,
[0953]
5-{3-[(5-pyrimidin-2-ylthieno[2,3-d]pyrimidin-4-yl)amino]propoxy}p-
yridine-2-carboxylic acid hydroformate, [0954]
5-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]amino}propoxy)pyri-
dine-2-carboxylic acid hydroformate, [0955]
5-{3-pyrazin-2-ylthieno[2,3-d]pyrimidin-4-yl)amino]propoxy}pyridine-2-car-
boxylic acid hydroformate, [0956]
4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butan-1-ol, [0957]
4-but-3-en-1-yl-5-(4-fluorophenyl)-thieno[2,3-d]pyrimidine, [0958]
Methyl
5-{4-[5-(4-fluorophenyl)-thieno[2,3-d]pyrimidin-4-yl]butoxy}-nicotinate,
[0959]
5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}nicotin-
ic acid hydroformate, [0960]
5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}-N-methylnicot-
inamide hydroformate, [0961]
5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}nicotinamide
hydroformate, [0962]
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}phenoxy)-phen-
yl]acetamide hydroformate, [0963]
N-[3-(2,2-dimethyl-3-{[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]ox-
y}propoxy)phenyl]acetamide hydroformate, [0964]
N-[3-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3d]pyrimidin-4-yl]oxy}phenoxy)phen-
yl]-acetamide hydroformate, [0965]
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-2,2-dimethyl-
-propoxy)phenyl]acetamide hydroformate, [0966]
5-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-1,3-dih-
ydro-2H-indol-2-one, [0967]
5-{3-[(5-pyridin-3-ylthieno[2,3-d]pyrimidin-4-yl)amino]propoxy}pyridine-2-
-carboxamide hydroformate, [0968]
5-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]amino}propoxy)pyri-
dine-2-carboxamide hydroformate, [0969]
N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino}propyl)phen-
yl]-acetamide, [0970]
N-(3-{3-[(5-pyridin-3-ylthieno[2,3-d]pyrimidin-4-yl)amino]propoxy}phenyl)-
-acetamide, [0971]
N-[3-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]amino}propoxy)--
phenyl]acetamide, [0972]
N-(3-{3-[(5-pyridin-2-ylthieno[2,3-d]pyrimidin-4-yl)amino]propoxy}phenyl)-
-acetamide, [0973]
N-[4-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]amino}propoxy)--
phenyl]acetamide, [0974]
N-(4-{3-[(5-pyridin-3-ylthieno[2,3-d]pyrimidin-4-yl)amino]propoxy}phenyl)-
-acetamide, [0975]
N-[4-(3-{[5-(5-chloro-2-furyl)thieno[2,3-d]pyrimidin-4-yl]amino}propoxy)--
phenyl]acetamide, [0976]
5-(4-fluorophenyl)-4-[3-(3-nitrophenoxy)propoxy]thieno[2,3-d]pyrimidine,
[0977]
N-methyl-4-{3-[(5-pyridin-3-ylthieno[2,3-d]pyrimidin-4-yl)oxy]prop-
oxy}-benzamide, [0978]
N-methyl-5-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}propo-
xy)-nicotinamide, [0979]
N-methyl-5-{3-[(5-pyridin-3-ylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}-ni-
cotinamide, [0980]
N-methyl-3-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}propo-
xy)-benzamide, [0981]
N-[4-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)phe-
nyl]-acetamide, and [0982]
N-(4-{3-[(5-pyridin-3-ylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}phenyl)-a-
cetamide.
[0983] In certain embodiments, the compound of Formula I is chosen
from those listed in Table I:
TABLE-US-00001 TABLE I Cpd # Structure Name 1 ##STR00007##
N-(3-{3-[(5-phenylthieno[2,3- d]pyrimidin-4-yl)amino]-
propoxy}phenyl)-acetamide 2 ##STR00008##
N-[3-(3-{[5-(4-fluorophenyl)- thieno[2,3-d]pyrimidin-4-yl]amino}-
propoxy)phenyl]-acetamide 3 ##STR00009## N-(3-nitrobenzyl)-N'-(5-
phenylthieno[2,3-d]pyrimidin-4- yl)ethane-1,2-diamine 4
##STR00010## N-(3,4-dimethoxybenzyl)-N'-(5-
phenylthieno[2,3-d]pyrimidin-4- yl)ethane-1,2-diamine 5
##STR00011## N-(2,1,3-benzothiadiazol-5-ylmethyl)-
N'-(5-phenylthieno[2,3-d]pyrimidin-4- yl)ethane-1,2-diamine 6
##STR00012## N-{3-[({2-[(5-phenylthieno[2,3-
d]pyrimidin-4-yl)amino]ethyl}- amino)methyl]phenyl}acetamide 7
##STR00013## N-{4-[({2-[(5-phenylthieno[2,3-
d]pyrimidin-4-yl)amino]ethyl}amino)- methyl]phenyl}acetamide 8
##STR00014## 3-(acetylamino)-N-{2-[(5-
phenylthieno[2,3-d]pyrimidin-4- yl)amino]ethyl}benzamide 9
##STR00015## 3-[({2-[(5-phenylthieno[2,3-
d]pyrimidin-4-yl)amino]ethyl}- amino)-methyl]benzonitrile 10
##STR00016## methyl 3-[({2-[(5-phenylthieno[2,3-
d]pyrimidin-4-yl)amino]ethyl}- amino)methyl]benzoate 11
##STR00017## N-(5-phenylthieno[2,3-d]pyrimidin-4-
yl)-N'-[3-(trifluoromethoxy)-benzyl]- ethane-1,2-diamine 12
##STR00018## 5-(4-fluorophenyl)-4-[3-(3-
nitrophenoxy)propoxy]thieno[2,3- d]pyrimidine 13 ##STR00019##
N-[4-(3-{[5-(4- fluorophenyl)thieno[2,3-d]pyrimidin- 4-yl]amino}-
propoxy)phenyl]acetamide 14 ##STR00020##
N-[3-(3-{[5-(4-fluorophenyl)- thieno[2,3-d]pyrimidin-4-
yl]oxy}propoxy)-phenyl]acetamide 15 ##STR00021##
N-[4-(3-{[5-(4-fluorophenyl)- thieno[2,3-d]pyrimidin-4-
yl]oxy}propoxy)-phenyl]acetamide 16 ##STR00022##
5-(4-fluorophenyl)-4-{3-[4-(1H-1,2,4-
triazol-1-yl)phenoxy]-propoxy}- thieno[2,3-d]pyrimidine 17
##STR00023## 4-[3-(4-fluorophenoxy)propoxy]-5-(4-
fluorophenyl)thieno[2,3-d]pyrimidine 18 ##STR00024## methyl
3-(3-{[5-(4-fluorophenyl)- thieno[2,3-d]pyrimidin-4-yl]oxy}-
propoxy)benzoate 19 ##STR00025##
3-(3-{[5-(4-fluorophenyl)-thieno[2,3-
d]pyrimidin-4-yl]oxy}propoxy)- aniline 20 ##STR00026##
3-(3-{[5-(4-fluorophenyl)-thieno[2,3-
d]pyrimidin-4-yl]oxy}propoxy)- benzoic acid 21 ##STR00027##
N-[3-(3-{[5-(4-fluorophenyl)- thieno[2,3-d]pyrimidin-4-
yl]oxy}propoxy)-phenyl]cyclo- propanecarboxamide 22 ##STR00028##
5-(4-fluorophenyl)-4-(3-{3-[(4- methylpiperazin-1-yl)carbonyl]-
phenoxy}-propoxy)thieno[2,3- d]pyrimidine 23 ##STR00029##
5-(4-fluorophenyl)-4-{3-[3- (morpholin-4-ylcarbonyl)-
phenoxy]propoxy}-thieno[2,3- d]pyrimidine 24 ##STR00030##
N-ethyl-3-(3-{[5-(4-fluorophenyl)-
thieno[2,3-d]pyrimidin-4-yl]oxy}- propoxy)benzamide 25 ##STR00031##
3-(3-{[5-(4-fluorophenyl)-thieno[2,3-
d]pyrimidin-4-yl]oxy}propoxy)-N,N- dimethylbenzamide 26
##STR00032## N-[2-(dimethylamino)ethyl]-3-(3-{[5-
(4-fluorophenyl)thieno[2,3- d]pyrimidin-4-yl]oxy}propoxy)-
benzamide 27 ##STR00033## N-(2-amino-2-oxoethyl)-3-(3-{[5-(4-
fluorophenyl)thieno[2,3-d]pyrimidin- 4-yl]oxy}propoxy)-benzamide 28
##STR00034## 3-(3-{[5-(4-fluorophenyl)-thieno[2,3-
d]pyrimidin-4-yl]oxy}propoxy)-N'- formylbenzohydrazide 29
##STR00035## 3-(3-{[5-(4-fluorophenyl)-thieno[2,3-
d]pyrimidin-4-yl]oxy}propoxy)-N- methyl-benzamide 30 ##STR00036##
3-(3-{[5-(4-fluorophenyl-)thieno[2,3-
d]pyrimidin-4-yl]oxy}propoxy)- benzamide 31 ##STR00037##
3-(2-{[5-(4-fluorophenyl)-thieno[2,3-
d]pyrimidin-4-yl]oxy}ethoxy)-N- methylbenzamide 32 ##STR00038##
N-[3-(2-{[5-(4-fluorophenyl)- thieno[2,3-d]pyrimidin-4-
yl]oxy}ethoxy)phenyl]urea 33 ##STR00039##
N-[3-(3-{[5-(4-fluorophenyl)- thieno[2,3-d]pyrimidin-4-
yl]oxy}propoxy)phenyl]urea 34 ##STR00040##
3-(2-{[5-(4-fluorophenyl)-thieno[2,3- d]pyrimidin-4-yl]oxy}ethoxy)-
benzamide 35 ##STR00041## 3-(3-{[5-(4-fluorophenyl)-thieno[2,3-
d]pyrimidin-4-yl]oxy}propoxy)- benzohydrazide 36 ##STR00042##
3-(3-{[5-(4-fluorophenyl)-thieno[2,3-
d]pyrimidin-4-yl]oxy}propoxy)-N- hydroxy-benzamide 37 ##STR00043##
4-(2-{[5-(4-fluorophenyl)-thieno[2,3- d]pyrimidin-4-yl]oxy}ethoxy)-
benzamide 38 ##STR00044## N-ethyl-N'-[3-(3-{[5-(4-
fluorophenyl)thieno[2,3-d]pyrimidin- 4-yl]oxy}propoxy)-phenyl]urea
39 ##STR00045## N-[3-(3-{[5-(4-fluorophenyl)-
thieno[2,3-d]pyrimidin-4- yl]oxy}propoxy)-phenyl]methane-
sulfonamide 40 ##STR00046## N-[4-(3-{[5-(4-fluorophenyl)-
thieno[2,3-d]pyrimidin-4-yl]oxy}- propoxy)phenyl]methansulfonamide
41 ##STR00047## N-[4-(3-{[5-(4-fluorophenyl)-
thieno[2,3-d]pyrimidin-4- yl]oxy}propoxy)-phenyl]-N-
(methylsulfonyl)methansulfonamide 42 ##STR00048##
N-(ethylsulfonyl)-N-[4-(3-{[5-(4-
fluorophenyl)thieno[2,3-d]pyrimidin- 4-yl)oxy}propoxy)phenyl]
ethanesulfonamide 43 ##STR00049## N-[4-(3-{[5-(4-
fluorophenyl)thieno[2,3-d]pyrimidin- 4-yl]oxy}propoxy)-
phenyl]ethanesulfonamide 44 ##STR00050## N-[4-(3-{[5-(4-
fluorophenyl)thieno[2,3-d]pyrimidin- 4-yl]oxy}propoxy)-phenyl]-N'-
methylurea 45 ##STR00051## N-ethyl-N'-[4-(3-{[5-(4-fluoro-
phenyl)thieno[2,3-d]pyrimidin-4- yl]oxy}-propoxy)phenyl]urea 46
##STR00052## N-[3-(3-{[5-(4- fluorophenyl)thieno[2,3-d]pyrimidin-
4-yl]oxy}propoxy)- phenyl]ethanesulfonamide 47 ##STR00053##
N-[3-(3-{[5-(4- fluorophenyl)thieno[2,3-d]pyrimidin-
4-yl]oxy}propoxy)-phenyl]-N'- methylurea 48 ##STR00054##
N-[3-(3-{[5-(4- fluorophenyl)thieno[2,3-d]pyrimidin-
4-yl]oxy}propoxy)- phenyl]hydrazinecarboxamide 49 ##STR00055##
N-[3-(3-{[5-(4- fluorophenyl)thieno[2,3-d]pyrimidin-
4-yl]oxy}propoxy)-phenyl]-N'- hydroxyurea 50 ##STR00056##
4-{3-[5-(4-fluorophenyl)-thieno[2,3d]- pyrimidin-4-yloxy]-propoxy}-
benzamide 51 ##STR00057## 5-{3-[5-(4-fluorophenyl)-thieno[2,3-
d]pyrimidin-4-yloxy]-propoxy}- nicotinic acid methyl ester 52
##STR00058## N-{3-[3-(5-furan-2-yl-thieno[2,3d]-
pyrimidin-4-yloxy)-propoxy]- phenyl}acetamide 53 ##STR00059##
2-(3-{[5-(4-fluorophenyl)thieno[2,3- d]pyrimidin-4-yl]oxy}propoxy)-
benzamide 54 ##STR00060## 5-{3-[5-(4-fluorophenyl)-thieno[2,3-
d]pyrimidin-4-yloxy]-propoxy}- nicotinic acid 55 ##STR00061##
N-(3-{-[(5-phenylthieno[2,3- d]pyrimidin-4-
yl)oxy]propoxy}phenyl)-acetamide 56 ##STR00062## N-[4-(3-{[5-(4-
fluorophenyl)thieno[2,3-d]pyrimidin- 4-yl]oxy}propoxy)-
phenyl]hydrazinecarboxamide 57 ##STR00063##
5-{3-[(5-pyridin-4-ylthieno[2,3- d]pyrimidin-4-
yl)oxy]propoxy}pyridine-2- carboxamide 58 ##STR00064##
5-(3-{[5-(4-fluorophenyl)thieno[2,3- d]pyrimidin-4-
yl]oxy}propoxy)pyridine-2- carboxamide 59 ##STR00065##
5-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3-
d]pyrimidin-4-yl]oxy}propoxy)- pyridine-2-carboxamid 60
##STR00066## 5-{3-[(5-pyridin-3-ylthieno[2,3- d]pyrimidin-4-
yl)oxy]propoxy}pyridine-2- carboxamide 61 ##STR00067##
N-methy1-5-{3-[(5-pyridin-4- ylthieno[2,3-d]pyrimidin-4-yl)oxy]-
propoxy}pyridine-2-carboxamide 62 ##STR00068##
5-(3-{[5-(4-fluorophenyl)thieno[2,3-
d]pyrimidin-4-yl]oxy}propoxy)-N- methylpyridine-2-carboxamide 63
##STR00069## N-methyl-5-(3-{[5-(1,3-thiazol-2-
yl)thieno[2,3-d]pyrimidin-4-yl]oxy}- propoxy)pyridine-2-carboxamide
64 ##STR00070## N-methyl-5-{3-[(5-pyridin-3-
ylthieno[2,3-d]pyrimidin-4-yl)oxy]- propoxy}pyridine-2-carboxamide
65 ##STR00071## N-methyl-3-{3-[(5-pyridin-3-
ylthieno[2,3-d]pyrimidin-4- yl)oxy]propoxy}benzamide 66
##STR00072## N-methyl-5-(3-{[5-(1,3-thiazol-2-yl)-
thieno[2,3-d]pyrimidin-4-yl]amino}- propoxy)pyridine-2-carboxamide
67 ##STR00073## 5-(3-{[5-(5-chloro-2-furyl)thieno[2,3-
d]pyrimidin-4-yl]amino}propoxy)-N- methylpyridine-2-carboxamide 68
##STR00074## N-methyl-5-{3-[(5-pyridin-3-
ylthieno[2,3-d]pyrimidin-4- yl)amino]propoxy}pyridine-2-
carboxamide 69 ##STR00075## N-methyl-5-{3-[(5-pyridin-2-
ylthieno[2,3-d]pyrimidin-4- yl)amino]propoxy}pyridine-2-
carboxamide 70 ##STR00076## N-methyl-5-{3-[(5-pyridin-2-
ylthieno[2,3-d]pyrimidin-4- yl)amino]propoxy}-nicotinamide 71
##STR00077## 5-{3-[(5-pyridin-3-ylthieno[2,3-d]-
pyrimidin-4-yl)oxy]propoxy}pyridine- 2-carboxamide hydroformate 72
##STR00078## 5-(4-fluorophenyl)-4-(3-{[1-methyl-5-
(trifluoromethyl)-1H-pyrazol-3- yl]oxy}propoxy)thieno[2,3-
d]pyrimidine 73 ##STR00079## 4-[3-(4-chlorophenoxy)propoxy]-5-(4-
fluorophenyl)thieno[2,3-d]pyrimidine 74 ##STR00080##
4-[3-(3,5-difluorophenoxy)propoxy]- 5-(4-fluorophenyl)thieno[2,3-
d]pyrimidine 75 ##STR00081## 4-[3-(3,4-
dimethoxyphenoxy)propoxy]-5-(4-
fluorophenyl)thieno[2,3-d]pyrimidine 76 ##STR00082##
4-[3-(1,2-benzisothiazol-3- yloxy)propoxy]-5-(4-
fluorophenyl)thieno[2,3-d]pyrimidine 77 ##STR00083##
5-(4-fluorophenyl)-4-(3- phenoxypropoxy)-thieno[2,3- d]pyrimidine
78 ##STR00084## 5-(4-fluorophenyl)-4-[3-(3-methoxy-
phenoxy)propoxy]thieno[2,3- d]pyrimidine 79 ##STR00085##
5-(4-fluorophenyl)-4-[3-(3-methyl- phenoxy)propoxy]thieno[2,3-
d]pyrimidine 80 ##STR00086## 5-(4-fluorophenyl)-4-{3-[3-(trifluoro-
methoxy)phenoxy]propoxy}thieno[2,3- d]pyrimidine 81 ##STR00087##
4-[3-(3-ethylphenoxy)propoxy]-5-(4-
fluorophenyl)thieno[2,3-d]pyrimidine
82 ##STR00088## 5-{3-[(5-pyrimidin-2-ylthieno[2,3- d]pyrimidin-4-
yl)amino]propoxy}pyridine-2- carboxylic acid hydroformate 83
##STR00089## 5-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3- d]pyrimidin-4-
yl]amino}propoxy)pyridine-2- carboxylic acid hydroformate 84
##STR00090## 5-{3-[(5-pyrazin-2-ylthieno[2,3- d]pyrimidin-4-
yl)amino]propoxy}pyridine-2- carboxylic acid hydroformate 85
##STR00091## 4-[5-(4-fluorophenyl)thieno[2,3-
d]pyrimidin-4-yl]butan-1-ol 86 ##STR00092##
4-but-3-en-1-yl-5-(4-fluorophenyl)- thieno[2,3-d]pyrimidine 87
##STR00093## methyl 5-{4-[5-(4-fluorophenyl)-
thieno[2,3-d]pyrimidin-4-yl]butoxy}- nicotinate 88 ##STR00094##
5-{4-[5-(4-fluorophenyl)thieno[2,3-
d]pyrimidin-4-yl]butoxy}nicotinic acid hydroformate 89 ##STR00095##
5-{4-[5-(4-fluorophenyl)thieno[2,3- d]pyrimidin-4-yl]butoxy}-N-
methylnicotinamide hydroformate 90 ##STR00096##
5-{4-[5-(4-fluorophenyl)thieno[2,3-
d]pyrimidin-4-yl]butoxy}nicotinamide hydroformate 91 ##STR00097##
N-[3-(3-{[5-(4- fluorophenyl)thieno[2,3-d]pyrimidin-
4-yl]oxy}phenoxy)-phenyl]acetamide hydroformate 92 ##STR00098##
N-[3-(2,2-dimethyl-3-{[5-(1,3-thiazol-
2-yl)thieno[2,3-d]pyrimidin-4- yl]oxy}propoxy)phenyl]acetamide
hydroformate 93 ##STR00099## N-[3-(3-{[5-(1,3-thiazol-2-
yl)thieno[2,3-d]pyrimidin-4- yl]oxy}phenoxy)phenyl]-acetamide
hydroformate 94 ##STR00100## N-[3-(3-{[5-(4-
fluorophenyl)thieno[2,3-d]pyrimidin- 4-yl]oxy}-2,2-dimethyl-
propoxy)phenyl]acetamide hydroformate 95 ##STR00101##
5-(3-{[5-(4-fluorophenyl)thieno[2,3-
d]pyrimidin-4-yl]oxy}propoxy)-1,3- dihydro-2H-indol-2-one 96
##STR00102## 5-{3-[(5-pyridin-3-ylthieno[2,3- d]pyrimidin-4-
yl)amino]propoxy}pyridine-2- carboxamide hydroformate 97
##STR00103## 5-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3- d]pyrimidin-4-
yl]amino}propoxy)pyridine-2- carboxamide hydroformate 98
##STR00104## N-[4-(3-{[5-(4- fluorophenyl)thieno[2,3-d]pyrimidin-
4-yl]amino}propyl)phenyl]-acetamide 99 ##STR00105##
N-(3-{3-[(5-pyridin-3-ylthieno[2,3- d]pyrimidin-4-
yl)amino]propoxy}phenyl)acetamide 100 ##STR00106##
N-[3-(3-{[5-(1,3-thiazol-2- yl)thieno[2,3-d]pyrimidin-4-
yl]amino}propoxy)phenyl]acetamide 101 ##STR00107##
N-(3-{3-[(5-pyridin-2-ylthieno[2,3- d]pyrimidin-4-
yl)amino]propoxy}phenyl)acetamide 102 ##STR00108##
N-[4-(3-{[5-(1,3-thiazol-2- yl)thieno[2,3-d]pyrimidin-4-
yl]amino}propoxy)phenyl]acetamide 103 ##STR00109##
N-(4-{3-[(5-pyridin-3-ylthieno[2,3- d]pyrimidin-4-
yl)amino]propoxy}phenyl)acetamide 104 ##STR00110##
N-[4-(3-{[5-(5-chloro-2- furyl)thieno[2,3-d]pyrimidin-4-
yl]amino}propoxy)phenyl]acetamide 105 ##STR00111##
5-(4-fluorophenyl)-4-[3-(3- nitrophenoxy)propoxy]thieno[2,3-
d]pyrimidine 106 ##STR00112## N-methyl-4-{3-[(5-pyridin-3-
ylthieno[2,3-d]pyrimidin-4- yl)oxy]propoxy}-benzamide 107
##STR00113## N-methyl-5-(3-{[5-(1,3-thiazol-2-
yl)thieno[2,3-d]pyrimidin-4- yl]oxy}propoxy)nicotinamide 108
##STR00114## N-methyl-5-{3-[(5-pyridin-3-
ylthieno[2,3-d]pyrimidin-4- yl)oxy]propoxy}nicotinamide 109
##STR00115## N-methyl-3-(3-{[5-(1,3-thiazol-2-
yl)thieno[2,3-d]pyrimidin-4- yl]oxy}propoxy)benzamide 110
##STR00116## N-[4-(3-{[5-(1,3-thiazol-2-
yl)thieno[2,3-d]pyrimidin-4- yl]oxy}propoxy)phenyl]acetamide 111
##STR00117## N-(4-{3-[(5-pyridin-3-ylthieno[2,3- d]pyrimidin-4-
yl)oxy]propoxy}phenyl)acetamide
[0984] Also provided are s pharmaceutical compositions comprising
at least one chemical entity described herein and a
pharmaceutically acceptable carrier and, optionally, another active
agent as discussed below. Also provided is a method of inhibiting a
PDE10 enzyme, e.g., as determined by a conventional assay or one
described herein, either in vitro or in vivo (in an animal, e.g.,
in an animal model, or in a mammal or in a human); a method of
treating a psychiatric or neurological syndrome, e.g., psychoses,
obsessive-compulsive disorder and/or Parkinson's disease; a method
of treating a disease state modulated by PDE10 activity, in a
mammal, e.g., a human, e.g., those disease states mentioned
herein.
[0985] Methods include, but are not limited to, methods of
enhancing cognition in a patient in whom such enhancement is
desired, methods of treating a patient suffering from cognition
impairment or decline, methods of treating a patient having a
disease involving decreased cAMP and/or cGMP levels, methods of
inhibiting PDE10 enzyme activity in a patient, methods of treating
a patient suffering psychoses, in particular schizophrenia or
bipolar disorder, methods of treating a patient suffering from
obsessive-compulsive disorder, methods of treating a patient
suffering from Parkinson's disease. In certain embodiments, the
disease state is one that involves elevated intracellular PDE10
levels or decreased cAMP and/or cGMP levels, e.g., involving
neurological or psychiatric syndromes, especially those states
associated with psychoses, most especially schizophrenia or bipolar
disorder, obsessive-compulsive disorder, and/or Parkinson's
disease. All methods comprise administering to the patient an
effective amount of at least one chemical entity described herein.
In certain embodiments, the patient is human.
[0986] Chemical entities described herein can be made by the
methods depicted in the reaction schemes shown below.
[0987] The starting materials and reagents used in preparing these
compounds are either available from commercial suppliers such as
Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.),
or Sigma (St. Louis, Mo.) or are prepared by methods known to those
skilled in the art following procedures set forth in references
such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes
1-17 (John Wiley and Sons, 1994); Rodd's Chemistry of Carbon
Compounds, Volumes 1-5 and Supplementals (Elsevier Science
Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and
Sons, 2003), March's Advanced Organic Chemistry, (John Wiley and
Sons, 4th Edition) and Larock's Comprehensive Organic
Transformations (VCH Publishers Inc., 1989). Those schemes are
merely illustrative of some methods by which the chemical entities
described herein can be synthesized, and various modifications to
these schemes can be made and will be suggested to one skilled in
the art having referred to this disclosure.
[0988] The starting materials and the intermediates of the reaction
may be isolated and purified if desired using conventional
techniques, including but not limited to filtration, distillation,
crystallization, chromatography and the like. Such materials may be
characterized using conventional means, including physical
constants and spectral data.
[0989] Unless specified to the contrary, the reactions described
herein take place at atmospheric pressure over a temperature range
from about -78.degree. C. to about 150.degree. C., such as from
about 0.degree. C. to about 125.degree. C., for example, at about
room (or ambient) temperature, e.g., about 20.degree. C.
[0990] Compounds of Formula I can be prepared as shown in Scheme 1
below.
##STR00118##
[0991] Treatment of a mixture of a methyl ketone compound of
formula I with cyanoacetic acid ethyl ester and sulfur with
morpholine in a suitable alcoholic solvent such as ethanol provides
a 2-amino-thiophene ethyl ester compound of formula 3. Reaction of
3 with formamide provides a 4-hydroxythieneo[2,3-d]pyrimidine
compound of formula 4. Compound 4 can then be converted to a
compound of Formula I where R.sup.2 is
--O(CR.sup.3R.sup.4).sub.nYR.sup.5 by reacting 4 with
LG(CR.sup.3R.sup.4).sub.nYR.sup.5 where LG is a suitable leaving
group such as halo under conditions well known in the art.
[0992] Alternatively, compound 4 can be first converted to a
compound of formula 5 by treating with a chlorinating agent such as
thionyl chloride and the. Compound 5 is then converted to a
compound of Formula I by treating it with is
HO(CR.sup.3R.sup.4).sub.nYR.sup.5, is
HS(CR.sup.3R.sup.4).sub.nYR.sup.5, or is
NH.sup.2(CR.sup.3R.sup.4).sub.nYR.sup.5 under conditions well known
in the art. Detailed descriptions of such procedures are provided
in the Working examples below.
[0993] Compounds of Formula I wherein R.sup.2 is
--(CR.sup.3R.sup.4).sub.nYR.sup.5 can be prepared by reaction of
compound 5 with the Grignard BrMg--(CR.sup.3R.sup.4).sub.nYR.sup.5
under anhydrous conditions in a polar aprotic solvent (such as THF)
using CuI and/or FeBr.sub.2 as catalysts.
[0994] The optical isomers of compounds of Formula I can be
obtained by resolution of the racemic mixtures according to
conventional processes, for example, by the formation of
diastereomeric salts using an optically active acid or base or
formation of covalent diastereomers. Examples of appropriate acids
are tartaric, diacetyltartaric, dibenzoyltartaric,
ditoluoyltartaric and camphorsulfonic acid. Mixtures of
diastereomers can be separated into their individual diastereomers
on the basis of their physical and/or chemical differences by
methods known to those skilled in the art, for example, by
chromatography or fractional crystallization. The optically active
bases or acids are then liberated from the separated diastereomeric
salts.
[0995] A different process for separation of optical isomers
involves the use of chiral chromatography (e.g., chiral HPLC
columns), with or without conventional derivation, optimally chosen
to maximize the separation of the enantiomers. Suitable chiral HPLC
columns are manufactured by Diacel, e.g., Chiracel O D and Chiracel
O J among many others, all routinely selectable. Enzymatic
separations, with or without derivitization, are also useful. The
optically active compounds of Formula I can likewise be obtained by
utilizing optically active starting materials in chiral syntheses
processes under reaction conditions which do not cause
racemization.
[0996] The compounds can be used in different enriched isotopic
forms, e.g., enriched in the content of .sup.2H, .sup.3H, .sup.11C,
.sup.13C and/or .sup.14C. in certain embodiments, the compounds are
deuterated. Such deuterated forms can be made by the procedure
described in U.S. Pat. Nos. 5,846,514 and 6,334,997. As described
in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration can improve
the efficacy and increase the duration of action of drugs.
[0997] Deuterium substituted compounds can be synthesized using
various methods such as described in: Dean, Dennis C.; Editor.
Recent Advances in the Synthesis and Applications of Radiolabeled
Compounds for Drug Discovery and Development. [In: Curr. Pharm.
Des., 2000; 6(10)] (2000), 110 pp. CAN 133:68895 AN 2000:473538
CAPLUS; Kabalka, George W.; Varma, Rajender S. The Synthesis of
Radiolabeled Compounds via Organometallic Intermediates.
Tetrahedron (1989), 45(21), 6601-21, CODEN: TETRAB ISSN:0040-4020.
CAN 112:20527 AN 1990:20527 CAPLUS; and Evans, E. Anthony.
Synthesis of radiolabeled compounds, J. Radioanal. Chem. (1981),
64(1-2), 9-32. CODEN: JRACBN ISSN:0022-4081, CAN 95:76229 AN
1981:476229 CAPLUS.
[0998] The acid addition salts of the claimed compounds may be
prepared by reaction of the compounds with the appropriate
inorganic or organic acid via any of a number of known methods.
Alternatively, alkali and alkaline earth metal salts are prepared
by reacting the chemical entities described herein with the
appropriate base via a variety of known methods. In certain
embodiments, the salts formed are pharmaceutically acceptable for
administration to mammals. However, pharmaceutically unacceptable
salts of the compounds are suitable as intermediates, for example,
for isolating the compound as a salt and then converting the salt
back to the free base compound by treatment with an alkaline
reagent. The free base can then, if desired, be converted to a
pharmaceutically acceptable acid addition salt.
[0999] The chemical entities described herein can be administered
alone or as an active ingredient of a formulation. Thus, also
provided are pharmaceutical compositions comprising at least one
chemical entity described herein and one or more pharmaceutically
acceptable carriers.
[1000] The chemical entities described herein can be administered
to anyone requiring PDE10 inhibition. Administration may be
accomplished according to patient needs, for example, orally,
nasally, parenterally (subcutaneously, intravenously,
intramuscularly, intrasternally and by infusion) by inhalation,
rectally, vaginally, topically and by ocular administration.
[1001] Various solid oral dosage forms can be used for
administering chemical entities described herein including such
solid forms as tablets, gelcaps, capsules, caplets, granules,
lozenges and bulk powders. The chemical entities described herein
can be administered alone or combined with various pharmaceutically
acceptable carriers, diluents (such as sucrose, mannitol, lactose,
starches) and excipients known in the art, including but not
limited to suspending agents, solubilizers, buffering agents,
binders, disintegrants, preservatives, colorants, flavorants,
lubricants and the like. Time release capsules, tablets and gels
are also advantageous in administering the chemical entities
described herein.
[1002] Various liquid oral dosage forms can also be used for
administering chemical entities described herein, including aqueous
and non-aqueous solutions, emulsions, suspensions, syrups, and
elixirs. Such dosage forms can also contain suitable inert diluents
known in the art such as water and suitable excipients known in the
art such as preservatives, wetting agents, sweeteners, flavorants,
as well as agents for emulsifying and/or suspending the chemical
entities described herein. The chemical entities described herein
may be injected, for example, intravenously, in the form of an
isotonic sterile solution. Other preparations are also
possible.
[1003] Suppositories for rectal administration of the chemical
entities described herein can be prepared by mixing the compound
with a suitable excipient such as cocoa butter, salicylates and
polyethylene glycols. Formulations for vaginal administration can
be in the form of a pessary, tampon, cream, gel, paste, foam, or
spray formula containing, in addition to the active ingredient,
such suitable carriers as are known in the art.
[1004] For topical administration, the pharmaceutical composition
can be in the form of creams, ointments, liniments, lotions,
emulsions, suspensions, gels, solutions, pastes, powders, sprays,
and drops suitable for administration to the skin, eye, ear or
nose. Topical administration may also involve transdermal
administration via means such as transdermal patches.
[1005] Aerosol formulations suitable for administering via
inhalation also can be made. For example, for treatment of
disorders of the respiratory tract, the chemical entities described
herein can be administered by inhalation in the form of a powder
(e.g., micronized) or in the form of atomized solutions or
suspensions. The aerosol formulation can be placed into a
pressurized acceptable propellant.
[1006] Numerous standard references are available that describe
procedures for preparing various formulations suitable for
administering the chemical entities described herein. Examples of
potential formulations and preparations are contained, for example,
in the Handbook of Pharmaceutical Excipients, American
Pharmaceutical Association (current edition); Pharmaceutical Dosage
Forms Tablets (Lieberman, Lachman and Schwartz, editors) current
edition, published by Marcel Dekker, Inc., as well as Remington's
Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current
edition).
[1007] The chemical entities described herein can be administered
as the sole active agent or in combination with other
pharmaceutical agents such as other agents used in the treatment of
psychoses, such as schizophrenia and bipolar disorder,
obsessive-compulsive disorder, Parkinson's disease, cognitive
impairment and/or memory loss, e.g., nicotinic .alpha.-7 agonists,
PDE4 inhibitors, other PDE10 inhibitors, calcium channel blockers,
muscarinic m1 and m2 modulators, adenosine receptor modulators,
ampakines, NMDA-R modulators, mGluR modulators, dopamine
modulators, serotonin modulators, canabinoid modulators, and
cholinesterase inhibitors (e.g., donepezil, rivastigimine, and
galanthanamine). In such combinations, each active ingredient can
be administered either in accordance with their usual dosage range
or a dose below their usual dosage range.
[1008] The chemical entities described herein can be administered
in combination with other pharmaceutical agents used in the
treatment of schizophrenia, e.g., Clozaril, Zyprexa, Risperidone,
and Seroquel. Thus, also provided are methods for treating
schizophrenia, including memory impairment associated with
schizophrenia, comprising administering to a patient,
simultaneously or sequentially, at least one chemical entities
described herein and another agent used in the treatment of
schizophrenia such as Clozaril, Zyprexa, Risperidone, and Seroquel.
In methods using simultaneous administration, the agents can be
present in a combined composition or can be administered
separately. As a result, also provided are compositions comprising
at least one chemical entity described herein and another
pharmaceutical agent used in the treatment of schizophrenia, e.g.,
Clozaril, Zyprexa, Risperidone, and Seroquel. Similarly, also
provided are kits containing a composition comprising at least one
chemical entity described herein and another composition comprising
another pharmaceutical agent used in the treatment of
schizophrenia, e.g., Clozaril, Zyprexa, Risperidone, and
Seroquel.
[1009] In addition, the chemical entities described herein can be
administered in combination with other pharmaceutical agents used
in the treatment bipolar disorder such as Lithium, Zyprexa, or
Depakote. Thus, also provided are methods for treating bipolar
disorder, including treating memory and/or cognitive impairment
associated with the disease, comprising administering to a patient,
simultaneously or sequentially, at least one chemical entity
described herein and another agent used in the treatment of bipolar
disorder such as Lithium, Zyprexa, or Depakote. In methods using
simultaneous administration, the agents can be present in a
combined composition or can be administered separately. As a
result, also provided are compositions comprising a at least one
chemical entity described herein and another pharmaceutical agent
used in the treatment of bipolar disorder such as Lithium, Zyprexa,
or Depakote. Similarly, also provided are kits containing a
composition comprising at least one chemical entity described
herein and another composition comprising another pharmaceutical
agent used in the treatment of bipolar disorder such as Lithium,
Zyprexa, or Depakote.
[1010] Also provided are methods for treating Parkinson's disease,
including treating memory and/or cognitive impairment associated
with Parkinson's disease, comprising administering to a patient,
simultaneously or sequentially, at least one chemical entity
described herein and another agent used in the treatment of
Parkinson's disease such as Levodopa, Parlodel, Permax, Mirapex,
Tasmar, Contan, Kemadin, Artane, and Cogentin. In methods using
simultaneous administration, the agents can be present in a
combined composition or can be administered separately. As a
result, also provided are compositions comprising at least one
chemical entity described herein and another pharmaceutical agent
used in the treatment of Parkinson's disease such as Levodopa,
Parlodel, Permax, Mirapex, Tasmar, Contan, Kemadin, Artane, and
Cogentin. Similarly, also provided are kits comprising a
composition comprising at least one chemical entity described
herein and another composition comprising another pharmaceutical
agent used in the treatment of Parkinson's disease such as
Levodopa, Parlodel, Permax, Mirapex, Tasmar, Contan, Kemadin,
Artane, and Cogentin.
[1011] In addition, also provided are methods for treating memory
and/or cognitive impairment associated with Alzheimer's disease
comprising administering to a patient, simultaneously or
sequentially, at least one chemical entity described herein and
another agent used in the treatment of Alzheimer's disease such as
Reminyl, Cognex, Aricept, Exelon, Akatinol, Neotropin, Eldepryl,
Estrogen and Cliquinol. In methods using simultaneous
administration, the agents can be present in a combined composition
or can be administered separately. As a result, also provided are
compositions comprising at least one chemical entity described
herein and another pharmaceutical agent used in the treatment of
Alzheimer's disease such as Levodopa, Parlodel, Permax, Mirapex,
Tasmar, Contan, Kemadin, Artane, and Cogentin. Similarly, also
provided are kits containing a composition comprising at least one
chemical entity described herein and another composition comprising
another pharmaceutical agent used in the treatment of Alzheimer's
disease such as Levodopa, Parlodel, Permax, Mirapex, Tasmar,
Contan, Kemadin, Artane, and Cogentin.
[1012] Also provided are methods for treating Huntington's disease,
including treating memory and/or cognitive impairment associated
with Huntington's disease, comprising administering to a patient,
simultaneously or sequentially, at least one chemical entity
described herein and another agent used in the treatment of
Huntington's disease such as Amitriptyline, Imipramine,
Despiramine, Nortriptyline, Paroxetine, Fluoxetine, Setraline,
Terabenazine, Haloperidol, Chloropromazine, Thioridazine, Sulpride,
Quetiapine, Clozapine, and Risperidone. In methods using
simultaneous administration, the agents can be present in a
combined composition or can be administered separately. As a
result, also provided are compositions comprising at least one
chemical entity described herein and another pharmaceutical agent
used in the treatment of Huntington's disease such as
Amitriptyline, Imipramine, Despiramine, Nortriptyline, Paroxetine,
Fluoxetine, Setraline, Terabenazine, Haloperidol, Chloropromazine,
Thioridazine, Sulpride, Quetiapine, Clozapine, and Risperidone.
Similarly, also provided are kits containing a composition
comprising at least one chemical entity described herein and
another composition comprising another pharmaceutical agent used in
the treatment of Huntington's disease such as Amitriptyline,
Imipramine, Despiramine, Nortriptyline, Paroxetine, Fluoxetine,
Setraline, Terabenazine, Haloperidol, Chloropromazine,
Thioridazine, Sulpride, Quetiapine, Clozapine, and Risperidone.
[1013] Also provided are methods for treating memory and/or
cognitive impairment associated with dementia comprising
administering to a patient, simultaneously or sequentially, at
least one chemical entity described herein and another agent used
in the treatment of dementia such as Thioridazine, Haloperidol,
Risperidone, Cognex, Aricept, and Exelon. In methods using
simultaneous administration, the agents can be present in a
combined composition or can be administered separately. As a
result, also provided are compositions comprising at least one
chemical entity described herein and another pharmaceutical agent
used in the treatment of dementia such as Thioridazine,
Haloperidol, Risperidone, Cognex, Aricept, and Exelon. Similarly,
also provided are kits containing a composition comprising at least
one chemical entity described herein and another composition
comprising another pharmaceutical agent used in the treatment of
dementia such as Thioridazine, Haloperidol, Risperidone, Cognex,
Aricept, and Exelon.
[1014] Also provided are methods for treating memory and/or
cognitive impairment associated with epilepsy comprising
administering to a patient, simultaneously or sequentially, at
least one chemical entity described herein and another agent used
in the treatment of epilepsy such as Dilantin, Luminol, Tegretol,
Depakote, Depakene, Zarontin, Neurontin, Barbita, Solfeton, and
Felbatol. In methods using simultaneous administration, the agents
can be present in a combined composition or can be administered
separately. As a result, also provided are compositions comprising
at least one chemical entity described herein and another
pharmaceutical agent used in the treatment of epilepsy such as
Dilantin, Luminol, Tegretol, Depakote, Depakene, Zarontin,
Neurontin, Barbita, Solfeton, and Felbatol. Similarly, also
provided are kits containing a composition comprising at least one
chemical entity described herein and another composition comprising
another pharmaceutical agent used in the treatment of epilepsy such
as Dilantin, Luminol, Tegretol, Depakote, Depakene, Zarontin,
Neurontin, Barbita, Solfeton, and Felbatol.
[1015] Also provided are methods for treating memory and/or
cognitive impairment associated with multiple sclerosis comprising
administering to a patient, simultaneously or sequentially, at
least one chemical entity described herein and another agent used
in the treatment of multiple sclerosis such as Detrol, Ditropan XL,
OxyContin, Betaseron, Avonex, Azothioprine, Methotrexate, and
Copaxone. In methods using simultaneous administration, the agents
can be present in a combined composition or can be administered
separately. As a result, also provided are compositions comprising
at least one chemical entity described herein and another
pharmaceutical agent used in the treatment of multiple sclerosis
such as Detrol, Ditropan XL, OxyContin, Betaseron, Avonex,
Azothioprine, Methotrexate, and Copaxone. Similarly, also provided
are kits containing a composition comprising at least one chemical
entity described herein and another composition comprising another
pharmaceutical agent used in the treatment of multiple sclerosis
such as Detrol, Ditropan XL, OxyContin, Betaseron, Avonex,
Azothioprine, Methotrexate, and Copaxone.
[1016] Also provided are chemical entities that inhibit PDE10
enzyme activity. PDE10 inhibitors will raise the levels of cAMP or
cGMP within cells that express PDE10. Inhibition of PDE10 enzyme
activity may be of relevance to diseases caused by deficient
amounts of cAMP or cGMP in cells. Alternatively, PDE10 inhibitors
may be of benefit in cases wherein raising the amount of cAMP or
cGMP above normal levels results in a therapeutic effect.
Inhibitors of PDE10 may be used to treat disorders of the
peripheral and central nervous system, cardiovascular diseases,
cancer, gastro-enterological diseases, endocrinological diseases
and urological diseases. Thus, also provided are methods of
selective inhibition of PDE10 enzymes in animals, e.g., mammals,
for example, humans, wherein such inhibition has a therapeutic
effect, such as where such inhibition may relieve conditions
involving neurological or psychiatric syndromes, such as the loss
of memory or psychoses. Such methods comprise administering to an
animal in need thereof, such as a mammal, for example, a human, an
inhibitory amount of at least one chemical entity described herein,
alone or as part of a formulation.
[1017] Indications that may be treated with PDE10 inhibitors,
either alone or in combination with other drugs, include, but are
not limited to, those diseases thought to be mediated in part by
the basal ganglia, prefrontal cortex and hippocampus. These
indications include psychoses, Parkinson's disease, dementias,
obsessive compulsion disorder, tardive dyskinesia, choreas,
depression, mood disorders, impulsivity, drug addiction, attention
deficit/hyperactivity disorder (ADHD), depression with parkinsonian
states, personality changes with caudate or putamen disease,
dementia and mania with caudate and pallidal diseases, and
compulsions with pallidal disease.
[1018] Psychoses are disorders that affect an individual's
perception of reality. Psychoses are characterized by delusions and
hallucinations. Also provided are methods for treating patients
suffering from all forms of psychoses, including but not limited to
schizophrenia, late-onset schizophrenia, schizoaffective disorders,
prodromal schizophrenia, and bipolar disorders. Treatment may be
for the positive symptoms of schizophrenia as well as for the
cognitive deficits and negative symptoms. Other indications for
PDE10 inhibitors are psychoses resulting from drug abuse (including
amphetamines and PCP), encephalitis, alcoholism, epilepsy, Lupus,
sarcoidosis, brain tumors, multiple sclerosis, dementia with Lewy
bodies, or hypoglycemia. Other psychiatric disorders, like
posttraumatic stress disorder (PTSD), and schizoid personality may
also be treated with PDE10 inhibitors.
[1019] Obsessive-compulsive disorder (OCD) has been linked to
deficits in the frontal-striatal neuronal pathways. (Saxena S. et
al., Br J Psychiatry Suppl. 1998; (35):26-37.) Neurons in these
pathways project to striatal neurons that express PDE10. PDE10
inhibitors cause cAMP to be elevated in these neurons, elevations
in cAMP result in an increase in CREB phosphorylation and thereby
improve the functional state of these neurons. PDE10 inhibitors
should be useful for the indication of OCD. OCD may result, in some
cases, from streptococcal infections that cause autoimmune
reactions in the basal ganglia (Giedd J. N. et al., Am. J.
Psychiatry. 2000 February; 157(2):281-3). Because PDE10 inhibitors
may serve a neuroprotective role, administration of PDE10
inhibitors may prevent the damage to the basal ganglia after
repeated streptococcal infections and thereby prevent the
development of OCD.
[1020] In the brain, the level of cAMP or cGMP within neurons is
believed to be related to the quality of memory, such as long term
memory. Without wishing to be bound to any particular mechanism, it
is proposed that since PDE10 degrades cAMP or cGMP, the level of
this enzyme affects memory in animals, for example, in humans. For
example, a compound that inhibits cAMP phosphodiesterase (PDE) can
thereby increase intracellular levels of cAMP, which in turn
activate a protein kinase that phosphorylates a transcription
factor (cAMP response binding protein), which transcription factor
then binds to a DNA promoter sequence to activate genes that are
important in long term memory. The more active such genes are, the
better is long-term memory. Thus, by inhibiting a
phosphodiesterase, long term memory can be enhanced.
[1021] Dementias are diseases that include memory loss and
additional intellectual impairment separate from memory. Also
provided are methods for treating patients suffering from memory
impairment in all forms of dementia. Dementias are classified
according to their cause and include: neurodegenerative dementias
(e.g., Alzheimer's, Parkinson's disease, Huntington's disease,
Pick's disease), vascular (e.g., infarcts, hemorrhage, cardiac
disorders), mixed vascular and Alzheimer's, bacterial meningitis,
Creutzfeld-Jakob Disease, multiple sclerosis, traumatic (e.g.,
subdural hematoma or traumatic brain injury), infectious (e.g.,
HIV), genetic (down syndrome), toxic (e.g., heavy metals, alcohol,
some medications), metabolic (e.g., vitamin B12 or folate
deficiency), CNS hypoxia, Cushing's disease, psychiatric (e.g.,
depression and schizophrenia), and hydrocephalus.
[1022] The condition of memory impairment is manifested by
impairment of the ability to learn new information and/or the
inability to recall previously learned information. Also provided
are methods for dealing with memory loss separate from dementia,
including mild cognitive impairment (MCI) and age-related cognitive
decline. Also provided are methods of treatment for memory
impairment as a result of disease. Memory impairment is a primary
symptom of dementia and can also be a symptom associated with such
diseases as Alzheimer's disease, schizophrenia, Parkinson's
disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob
disease, HIV, cardiovascular disease, and head trauma as well as
age-related cognitive decline. Also provided are methods for
dealing with memory loss resulting from the use of general
anesthetics, chemotherapy, radiation treatment, post-surgical
trauma, and therapeutic intervention. Thus, in certain embodiments,
also provided are methods of treating patients suffering from
memory impairment due to, for example, Alzheimer's disease,
multiple sclerosis, amylolaterosclerosis (ALS), multiple systems
atrophy (MSA), schizophrenia, Parkinson's disease, Huntington's
disease, Pick's disease, Creutzfeld-Jakob disease, depression,
aging, head trauma, stroke, spinal cord injury, CNS hypoxia,
cerebral senility, diabetes associated cognitive impairment, memory
deficits from early exposure of anesthetic agents, multiinfarct
dementia and other neurological conditions including acute neuronal
diseases, as well as HIV and cardiovascular diseases. Also provided
are agents and/or methods to stimulate the formation of memory in
"normal" subjects (i.e., subjects who do not exhibit an abnormal or
pathological decrease in a memory function), e.g., ageing
middle-aged subjects. Lots of repetition, maybe you want to
consolidate
[1023] In certain embodiments, the chemical entities described
herein are used in the treatment of a class of disorders known as
polyglutamine-repeat diseases. These diseases share a common
pathogenic mutation. The expansion of a CAG repeat, which encodes
the amino acid glutamine, within the genome leads to production of
a mutant protein having an expanded polyglutamine region. For
example, Huntington's disease has been linked to a mutation of the
protein huntingtin. In individuals who do not have Huntington's
disease, huntingtin has a polyglutamine region containing about 8
to 31 glutamine residues. For individuals who have Huntington's
disease, huntingtin has a polyglutamine region with over 37
glutamine residues. Aside from Huntington's disease (HD), other
known polyglutamine-repeat diseases and the associated proteins
are: dentatorubral-pallidoluysian atrophy, DRPLA (atrophin-1);
spinocerebellar ataxia type-1 (ataxin-1); spinocerebellar ataxia
type-2 (ataxin-2); spinocerebellar ataxia type-3 also called
Machado-Joseph disease, MJD (ataxin-3); spinocerebellar ataxia
type-6 (alpha 1a-voltage dependent calcium channel);
spinocerebellar ataxia type-7 (ataxin-7); and spinal and bulbar
muscular atrophy, SBMA, also know as Kennedy disease (androgen
receptor). Thus, also provided are methods of treating a
polyglutamine-repeat disease or CAG repeat expansion disease
comprising administering to a patient, such as a human, a
therapeutically effective amount of a compound. In certain
embodiments, there is provided a method of treating Huntington's
disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA),
spinocerebellar ataxia type-1, spinocerebellar ataxia type-2,
spinocerebellar ataxia type-3 (Machado-Joseph disease),
spinocerebellar ataxia type-6, spinocerebellar ataxia type-7, or
spinal and bulbar muscular atrophy, comprising administering to a
patient, such as a human, a therapeutically effective amount of a
compound.
[1024] The basal ganglia are important for regulating the function
of motor neurons; disorders of the basal ganglia result in movement
disorders. Most prominent among the movement disorders related to
basal ganglia function is Parkinson's disease (Obeso J A et al.,
Neurology, 2004 Jan. 13; 62(1 Suppl 1):S17-30). Other movement
disorders related to dysfunction of the basal ganglia include
tardive dyskinesia, progressive supranuclear palsy and cerebral
palsy, corticobasal degeneration, multiple system atrophy, Wilson
disease, and dystonia, tics, and chorea. In certain embodiments,
PDE10 inhibitors may be used to treat movement disorders related to
dysfunction of basal ganglia neurons.
[1025] PDE10 inhibitors can be used to raise cAMP or cGMP levels
and prevent neurons from undergoing apoptosis. PDE10 inhibitors may
be anti-inflammatory by raising cAMP in glial cells. The
combination of anti-apoptotic and anti-inflammatory properties, as
well as positive effects on synaptic plasticity and neurogenesis,
make these compounds useful to treat neurodegeneration resulting
from any disease or injury, including stroke, spinal cord injury,
Alzheimer's disease, multiple sclerosis, amylolaterosclerosis
(ALS), and multiple systems atrophy (MSA).
[1026] Autoimmune diseases or infectious diseases that affect the
basal ganglia may result in disorders of the basal ganglia
including ADHD, OCD, tics, Tourette's disease, Sydenham chorea. In
addition, any insult to the brain can potentially damage the basal
ganglia including strokes, metabolic abnormalities, liver disease,
multiple sclerosis, infections, tumors, drug overdoses or side
effects, and head trauma. In certain embodiments, PDE10 inhibitors
may be used to stop disease progression or restore damaged circuits
in the brain by a combination of effects including increased
synaptic plasticity, neurogenesis, anti-inflammatory, nerve cell
regeneration and decreased apoptosis
[1027] The growth of some cancer cells is inhibited by cAMP and
cGMP. Upon transformation, cells may become cancerous by expressing
PDE10 and reducing the amount of cAMP or cGMP within cells. In
these types of cancer cells, inhibition of PDE10 activity will
inhibit cell growth by raising cAMP (US20040138249, Pyrrolo (2.1a)
dihydroisoquinolines and their use as phosphodiesterase 10a
inhibitors). In some cases, PDE10 may be expressed in the
transformed, cancerous cell but not in the parent cell line. In
transformed renal carcinoma cells, PDE10 is expressed and PDE10
inhibitors reduce the growth rate of the cells in culture.
Similarly, breast cancer cells are inhibited by administration of
PDE10 inhibitors. Many other types of cancer cells may also be
sensitive to growth arrest by inhibition of PDE10. Therefore,
chemical entities described herein may be used to stop the growth
of cancer cells that express PDE10.
[1028] The chemical entities described herein are also suitable for
use in the treatment of diabetes and related disorders such as
obesity, by focusing on regulation of the cAMP signaling system. By
inhibiting PDE-10A activity, intracellular levels of cAMP and
increased, thereby increasing the release of insulin-containing
secretory granules and, therefore, increasing insulin secretion.
See, e.g., WO 2005/012485.
[1029] Thus, in certain embodiments, there is provided a method of
treating diabetes and related disorders comprising administering to
a patient, such as a mammal, such as a human, a therapeutically
effective amount of at least one chemical entity described herein.
In certain embodiments, there is provided a method of treating type
1 diabetes, type 2 diabetes, Syndrome X, impaired glucose
tolerance, impaired fasting glucose, gestational diabetes,
maturity-onset diabetes of the young (MODY), latent autoimmune
diabetes adult (LADA), associated diabetic dyslipidemia,
hyperglycemia, hyperinsulinemia, dyslipidemia,
hypertriglyceridemia, obesity and insulin resistance, comprising
administering to a patient, such as a mammal, such as a human, a
therapeutically effective amount of at least one chemical entity
described herein.
[1030] The chemical entities described herein may also be
administered in combination with other known therapies for the
treatment of diabetes, including, but not limited to, PPAR ligands
(e.g. agonists, antagonists, such as Rosiglitazone, Troglitazone
and Pioglitazone), insulin secretagogues (for example, sulfonylurea
drugs (such as Glyburide, Glimepiride, Chlorpropamide, Tolbutamide,
and Glipizide) and non-sulfonyl secretagogues),
.quadrature.-glucosidase inhibitors (such as Acarbose, Miglitol,
and Voglibose), insulin sensitizers (such as the PPAR-.quadrature.
agonists, e.g., the glitazones; biguanides, PTP-1B inhibitors,
DPP-IV inhibitors and 11beta-HSD inhibitors), hepatic glucose
output lowering compounds (such as glucagon antagonists and
metaformin, such as Glucophage and Glucophage XR), insulin and
insulin derivatives (both long and short acting forms and
formulations of insulin), and anti-obesity drugs (such as
.quadrature.-3 agonists, CB-1 agonists, neuropeptide Y5 inhibitors,
Ciliary Neurotrophic Factor and derivatives (e.g., Axokine),
appetite suppressants (e.g., Sibutramine), and lipase inhibitors
(e.g., Orlistat)).
[1031] The dosages of the chemical entities described herein depend
upon a variety of factors including the particular syndrome to be
treated, the severity of the symptoms, the route of administration,
the frequency of the dosage interval, the particular compound
utilized, the efficacy, toxicology profile, pharmacokinetic profile
of the compound, and the presence of any deleterious side-effects,
among other considerations.
[1032] The chemical entities described herein are typically
administered at dosage levels and in a mammal customary for PDE10
inhibitors such as those known compounds mentioned above. For
example, the compounds can be administered, in single or multiple
doses, by oral administration at a dosage level of generally
0.001-100 mg/kg/day, for example, 0.01-100 mg/kg/day, such as
0.1-70 mg/kg/day, for example, 0.5-10 mg/kg/day. Unit dosage forms
can contain generally 0.01-1000 mg of active compound, for example,
0.1-50 mg of active compound. For intravenous administration, the
compounds can be administered, in single or multiple dosages, at a
dosage level of, for example, 0.001-50 mg/kg/day, such as 0.00-10
mg/kg/day, for example, 0.01-1 mg/kg/day. Unit dosage forms can
contain, for example, 0.1-10 mg of active compound.
[1033] In carrying out the procedures described herein, it is of
course to be understood that reference to particular buffers,
media, reagents, cells, culture conditions and the like are not
intended to be limiting, but are to be read so as to include all
related materials that one of ordinary skill in the art would
recognize as being of interest or value in the particular context
in which that discussion is presented. For example, it is often
possible to substitute one buffer system or culture medium for
another and still achieve similar, if not identical, results. Those
of skill in the art will have sufficient knowledge of such systems
and methodologies so as to be able, without undue experimentation,
to make such substitutions as will optimally serve their purposes
in using the methods and procedures disclosed herein.
[1034] The present invention will now be further described by way
of the following non-limiting examples. In applying the disclosure
of these examples, it should be kept clearly in mind that other and
different embodiments of the methods disclosed according to the
present invention will no doubt suggest themselves to those of
skill in the relevant art.
[1035] In the foregoing and in the following examples, all
temperatures are set forth uncorrected in degrees Celsius; and,
unless otherwise indicated, all parts and percentages are by
weight.
EXAMPLES
[1036] In order that the invention described herein may be more
readily understood, the following examples are set forth. It should
be understood that these examples are for illustrative purposes
only and are not to be construed as limiting this invention in any
manner.
[1037] All NMR spectra were recorded at 300 MHz on a Bruker
Instruments NMR unless otherwise stated. Coupling constants (J) are
in Hertz (Hz) and peaks are listed relative to TMS (.delta. 0.00
ppm). Microwave reactions were performed using a Personal Chemistry
Optimizer.TM. microwave reactor in 10 mL Personal Chemistry
microwave reactor vials. All reactions were performed with the
fixed hold time ON unless otherwise stated. Sulfonic acid ion
exchange resins (SCX) were purchased from Varian Technologies.
Analytical HPLC was performed on 4.6 mm.times.100 mm Xterra
RP.sub.18 3.5.mu. columns using (i) a gradient of 20/80 to 80/20
water (0.1% formic acid)/acetonitrile (0.1% formic acid) over 6 min
(Method A), (ii) a gradient of 20/80 to 80/20 water (0.1% formic
acid)/acetonitrile (0.1% formic acid) over 8 min (Method B), (iii)
a gradient of 40/80 to 80/40 water (0.1% formic acid)/acetonitrile
(0.1% formic acid) over 6 min (Method C), (iv) a gradient of 40/80
to 80/40 water (0.1% formic acid)/acetonitrile (0.1% formic acid)
over 8 min (Method D), or (v) an isocratic of 80/20 acetonitrile
(0.1% formic acid)/water (0.1% formic acid) over 8 min (Method E).
Preparative HPLC was performed on 30 mm.times.100 mm Xtera Prep
RP.sub.18 5.mu. columns using an 8 min gradient of 95/5 to 20/80
water (0.1% formic acid)/acetonitrile (0.1% formic acid).
Example 1
4-(1-Acetyl-piperidin-4-yl)-2-aminothiophene-3-carboxylic acid
ethyl ester
[1038] [See, e.g., Guetschow, Michael and Neumann, Ulf., J. Med.
Chem, 41, 10, 1729-1740, 1998].
##STR00119##
[1039] A mixture of 1-(4-acetylpiperidino)ethan-1-one (1.020 g,
6.028 mmol), sulfur (0.193 g, 6.03 mmol), cyanoacetic acid ethyl
ester (0.682 g, 6.03 mol) and ethanol (2.00 mL) was treated with
morpholine (0.525 g, 0.00603 mol) dropwise at 45.degree. C. After
12 hours, the reaction mixture was diluted with ethyl acetate (60.0
mL), filtered and washed with of 5% aqueous sodium bicarbonate
(2.times.40 mL). The organic layer was concentrated and purified by
chromatography over silica gel using 2% methanol, 0.02% ammonia,
49% ethyl acetate, and 49% hexanes to give 700 mg (39%) of
4-(1-acetyl-piperidin-4-yl)-2-aminothiophene-3-carboxylic acid
ethyl ester as a light brown solid. MS [M+H] 297.1, .sup.1H NMR
(CDCl.sub.3) .delta. (ppm) 6.10 (b, 2H), 5.85 (s, 1H), 4.85 (d,
J=13.5 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 3.88 (m, 1H), 3.31 (m, 1H),
3.12 (m, 1H), 2.61 (m, 1H), 2.12 (s, 3H), 2.00 (m, 2H), 1.62-1.35
(m, 5H).
[1040] The following compounds were synthesized in a similar manner
using different starting materials: [1041]
4-(Pyridine-4-yl)-2-aminothiophene-3-carboxylic acid ethyl ester,
[1042] 4-(Pyridine-3-yl)-2-aminothiophene-3-carboxylic acid ethyl
ester, [1043] 4-(Pyridine-2-yl)-2-aminothiophene-3-carboxylic acid
ethyl ester, [1044] 4-(Thiazol-2-yl)-2-aminothiophene-3-carboxylic
acid ethyl ester, [1045] 4-(2-Furyl)-2-aminothiophene-3-carboxylic
acid ethyl ester.
Example 2
4-Hydroxy-5-(2-furyl)thieno[2,3-d]pyrimidine
[1046] [See, e.g., Perrissin, Monique; Favre, Marylene; Luu-Duc,
Cuong et al; Eur. J. Med. Chem. Chim. Ther., 19, 5, 420-424,
1984].
##STR00120##
[1047] A mixture of ethyl
2-amino-4-(2-furyl)thiophene-3-carboxylate (1.00 g, 4.21 mmol) and
formamide (10.0 g, 0.2 mol) was warmed by microwave at 200.degree.
C. for 10 minutes. The mixture was concentrated in vacuo at
90.degree. C., diluted with 40 mL of 10% methanol/dichloromethane,
and filtered through a 40 grain silica gel column using 5%
methanol/dichloromethane to wash the material through the column.
The filtrate was again concentrated and the remaining residue was
purified by column chromatography over silica gel using a gradient
elution from 5 to 10% methanol in dichloromethane to give 0.482 g
(52.4%) of 4-hydroxy-5-(2-furyl)thieno[2,3-d]pyrimidine as a brown
solid. MS [M+H] 219.1, .sup.1H NMR (10% CD.sub.3OD/CDCl.sub.3)
.delta. (ppm) 7.90 (s, 1H), 7.50 (s, 1H), 7.45 (d, J=3.3 Hz, 1H),
7.40 (d, J=1.8 Hz, 1H), 5.43 (dd, J=3.3, 1.8 Hz, 1H).
[1048] The following compounds were synthesized in a similar manner
using different starting materials: [1049]
4-Hydroxy-5-(pyridin-4-yl)thieno[2,3-d]pyrimidine, [1050]
4-Hydroxy-5-(pyridin-3-yl)thieno[2,3-d]pyrimidine, [1051]
4-Hydroxy-5-(pyridin-2-yl)thieno[2,3-d]pyrimidine, [1052]
4-Hydroxy-5-(thiazol-2-yl)thieno[2,3-d]pyrimidine, [1053]
4-Hydroxy-5-(1-acetylpiperidin-4-yl)thieno[2,3-d]pyrimidine.
Example 3
4-Chloro-5-(thiazol-2-yl)thieno[2,3-d]pyrimidine
##STR00121##
[1055] A mixture of thionyl chloride (15 ml, 200 mmol),
4-hydroxy-5-(thiazol-2-yl)thieno[2,3-d]pyrimidine (1.44 g, 12 mmol)
and N,N-dimethylformamide (3 mL) was heated at 73.degree. C. for 3
hours and then carefully poured into 200 mL of ice/water. The pH
was adjusted to between 7 and 8 with sodium bicarbonate and then
the product was extracted with ethyl acetate (2.times.450 mL). The
organic fractions were combined, dried (MgSO.sub.4) and
concentrated. The resulting residue was purified by column
chromatography over silica gel using a gradient elution from 10 to
20% ethyl acetate in hexanes to give 0.825 g (53%) of
4-chloro-5-(thiazol-2-yl)thieno[2,3-d]pyrimidine as a brown solid.
MS [M+H] 254.0, .sup.1H NMR (400 MHz, 10% CD.sub.3OD/CDCl.sub.3) 8
(ppm) 8.92 (s, 1H), 8.00 (d, J=3.2 Hz, 1H), 7.85 (s, 1H), 7.55 (d,
J=3.2 Hz, 1H).
[1056] The following compounds were synthesized in a similar manner
using different starting materials: [1057]
4-Chloro-5-(pyridin-4-yl)thieno[2,3-d]pyrimidine, [1058]
4-Chloro-5-(pyridin-3-yl)thieno[2,3-d]pyrimidine, [1059]
4-Chloro-5-(pyridin-2-yl)thieno[2,3-d]pyrimidine, [1060]
4-Chloro-5-(2-furyl)thieno[2,3-d]pyrimidine.
Example 4
2)
N-[3-(3-{[5-(4-Fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino}-propoxy)-
phenyl]acetamide
##STR00122##
[1062] A mixture of
4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine (100 mg, 0.378
mmol), N-[3-(3-amino-propoxy)-phenyl]-acetamide (94 mg, 0.45 mmol),
diisopropylethylamine (147 mg, 1.14 mmol) and N,N-dimethylformamide
(3.0 mL) was warmed to 120.degree. C. for 20 minutes by microwave
irradiation. The solvent was then concentrated in vacuo and the
residue was dissolved in ethyl acetate (50 mL) and washed with of
aqueous sodium bicarbonate (2.times.30 mL). The organic layer was
concentrated in vacuo and purified by column chromatography over
silica gel using 1% methanol in dichloromethane as eluant to give
125 mg (73%) of
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino}propoxy)-
phenyl]acetamide as a white solid. MS [M+H] 437.1, .sup.1H NMR
(CDCl.sub.3) .delta. (ppm) 8.50 (s, 1H), 7.41-7.36 (m, 2H), 7.25
(s, 1H), 7.21 (t, J=8.1 Hz, 1H), 7.07-6.95 (m, 3H), 6.94 (d, J=8.1
Hz, 1H), 6.55 (d, J=8.4 Hz, 1H), 5.01 (b, 1H), 3.89 (t, J=6.0 Hz,
2H), 3.64 (m, 2H), 2.19 (s, 3H), 1.98 (m, 2H).
[1063] The following compounds were synthesized in a similar manner
using different starting materials: [1064] 9)
3-[({2-[(5-phenylthieno[2,3-d]pyrimidin-4-yl)amino]ethyl}amino)methyl]-be-
nzonitrile, MS[M+H] 386.2 [1065] 10) Methyl
3-[({2-[(5-phenylthieno[2,3-d]pyrimidin-4-yl)amino]ethyl}amino)-methyl]be-
nzoate, MS[M+H] 419.2 [1066] 11)
N-(5-phenylthieno[2,3-d]pyrimidin-4-yl)-N'-[3-(trifluoromethoxy)benzyl]et-
hane-1,2-diamine, MS[M+H] 445.2 [1067] 99)
N-(3-{3-[(5-pyridin-3-ylthieno[2,3-d]pyrimidin-4-yl)amino]propoxy}phenyl)-
-acetamide, MS[M+H] 420.1 [1068] 100)
N-[3-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]amino}propoxy)--
phenyl]acetamide, MS[M+H] 426.0 [1069] 101)
N-(3-{3-[(5-pyridin-2-ylthieno[2,3-d]pyrimidin-4-yl)amino]propoxy}phenyl)-
-acetamide, MS[M+H] 420.1 [1070] 102)
N-[4-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]amino}propoxy)--
phenyl]acetamide, MS[M+H] 426.0 [1071] 103)
N-(4-{3-[(5-pyridin-3-ylthieno[2,3-d]pyrimidin-4-yl)amino]propoxy}phenyl)-
-acetamide, MS[M+H] 420.0 [1072] 104)
N-[4-(3-{[5-(5-chloro-2-furyl)thieno[2,3-d]pyrimidin-4-yl]amino}propoxy)--
phenyl]acetamide, MS[M+H] 443.1
Example 5
3)
N-(3-Nitrobenzyl)-N'-(5-phenylthieno[2,3-d]pyrimidin-4-ylethane-1,2-dia-
mine
##STR00123##
[1074] A mixture of
N-(5-phenylthieno[2,3-d]pyrimidin-4-yl)ethane-1,2-diamine
[1075] (Maybridge) (30 mg, 0.11 mmol), 3-nitrobenzaldehyde (18 mg,
0.12 mmol), acetic acid (6 mg, 0.10 mmol) and ethanol (3.0 mL) was
stirred at room temperature for 30 minutes, followed by the
addition of 7.6 mg (0.20 mmol) of sodium borohydride (7.6 mg, 0.20
mmol). The reaction was stirred for an additional 30 minutes and
then water (0.2 mL) and ethyl acetate (20 mL) were added. The
mixture was washed with aqueous sodium bicarbonate solution
(2.times.20 mL) and the organic layer was separated, concentrated,
and purified by column chromatography over silica gel using a
gradient elution from 2.5% to 5% methanol in dichloromethane as
eluant to give 34.2 mg (77%)
N-(3-nitrobenzyl)-N'-(5-phenylthieno[2,3-d]pyrimidin-4-yl)ethane-1,2-diam-
ine as a colorless gum. MS [M+H] 406.2, .sup.1H NMR (CDCl.sub.3)
.delta. (ppm) 8.49 (s, 1H), 8.11 (d, J=6.6 Hz, 1H), 8.06 (s, 1H),
7.50-7.32 (m, 7H), 7.08 (s, 1H), 5.48 (b, 1H), 3.75 (s, 2H), 3.55
(m, 2H), 2.75 (m, 2H).
[1076] The following compounds were synthesized in a similar manner
using different starting materials: [1077] 4)
N-(3,4-dimethoxybenzyl)-N'-(5-phenylthieno[2,3-d]pyrimidin-4-yl)ethane-1,-
2-diamine, MS[M+H] 421.2 [1078] 5)
N-(2,1,3-benzothiadiazol-5-ylmethyl)-N'-(5-phenylthieno[2,3-d]pyrimidin-4-
-yl)ethane-1,2-diamine, MS[M+H] 419.1 [1079] 6)
N-{3-[({2-[(5-phenylthieno[2,3-d]pyrimidin-4-yl)amino]ethyl}amino)methyl]-
-phenyl}acetamide, MS{M+H] 418.2 [1080] 7)
N-{4-[({2-[(5-phenylthieno[2,3-d]pyrimidin-4-yl)amino]ethyl}amino)methyl]-
-phenyl}acetamide, MS[M+H] 418.2
Example 6
N-(3-formylphenyl)acetamide
##STR00124##
[1082] A mixture of N-(3-hydroxymethylphenyl)acetamide (165 mg, 1.0
mmol), celite (165 mg), pyridinium chlorochromate (645 mg, 3.0
mmol), N,N-dimethylformamide (1.0 mL) and dichloromethane (25 mL)
was stirred at room temperature for 24 h. The reaction mixture was
filtered and concentrated in vacuo. The resulting residue was
dissolved in dichloromethane (40 mL) and washed with aqueous sodium
bicarbonate solution (2.times.30 mL). The organic layer was
concentrated and the product purified by chromatography over silica
gel using ethyl acetate/hexanes (1:1) as eluant to give 130 mg
(81%) of N-(3-formylphenyl)acetamide as a brown solid. MS [M+H]
164.2, .sup.1H NMR (CDCl.sub.3) .delta. (ppm) 9.96 (s, 1H), 8.22
(b, 1H), 8.03 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.61 (d, J=6.6 Hz,
1H), 7.47 (t, J=7.8 Hz, 1H), 2.22 (s, A1H).
Example 7
19)
3-(3-{[5-(4-Fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-propoxy)anil-
ine
##STR00125##
[1084]
5-(4-Fluorophenyl)-4-[3-(3-nitrophenoxy)propoxy]thieno[2,3-d]pyrimi-
dine (250 mg, 0.588 mmol) was dissolved in tetrahydrofuran (15 mL)
and added (under an atmosphere of argon) to a suspension of 25 mg
of 10% palladium/carbon in methanol (30 mL) and acetic acid (5 mL).
The mixture was then shaken under 40 psi of hydrogen overnight. The
palladium/carbon was removed by filtration and the filtrate was
concentrated in vacuo. The residue was dissolved in ethyl acetate
(50 mL) and washed with aqueous sodium bicarbonate solution
(2.times.30 mL). The organic layer was separated, concentrated, and
purified by column chromatography over silica gel using 33% ethyl
acetate in hexanes as eluant to give 180 mg (76%) of
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy-
)aniline as a colorless gum. MS [M+H] 396.1, .sup.1H NMR
(CDCl.sub.3) .delta. (ppm) 8.65 (s, 1H), 7.45-7.40 (m, 2H), 7.21
(s, 1H), 7.09-7.00 (m, 3H), 6.30 (d, J=2.1 Hz, 1H), 6.20 (d, J=2.8
Hz, 1H), 6.11 (s, 1H), 4.58 (t, J=6.0 Hz, 2H), 3.69 (t, J=6.0 Hz,
3H), 3.68 (b, 2H), 2.05 (m, 2H).
[1085] The following compounds were synthesized in a similar manner
using different starting materials: [1086]
4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)aniline
Example 8
21)
N-[3-(3-{[5-(4-Fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)ph-
enyl]cyclopropanecarboxamide
##STR00126##
[1088] A mixture of
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)aniline
(10 mg, 0.025 mmol), diisopropylethylamine (13 mg, 0.10 mmol), and
dichloromethane (2 mL) was treated with cyclopropanecarbonyl
chloride (30 mg, 0.028 mmol) and stirred at room temperature for 6
hours. The solvent was removed in vacuo and the remaining residue
was dissolved in ethyl acetate (25 mL), washed with aqueous sodium
bicarbonate solution (2.times.20 mL), and the organic fraction was
separated and concentrated. The product was purified by column
chromatography over silica gel using 1% methanol and 0.01% ammonia
in 1:1 ethyl acetate/hexanes to give 12 mg (quantitative yield) of
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]cyclopropanecarboxamide as a yellow gum. MS [M+H] 464.0, .sup.1H
NMR (CDCl.sub.3) .delta. (ppm) 8.65 (s, 1H), 7.48 (s, 1H),
7.50-7.36 (m, 2H), 7.21 (s, 1H), 7.16 (d, J=8.1 Hz, 1H), 7.10-7.00
(m, 2H), 6.95 (d, J=7.5 Hz, 1H), 6.52 (d, J=8.1 Hz, 1H), 4.58 (t,
J=6.0 Hz, 2H), 3.74 (t, J=6.0 Hz, 2H), 2.05 (m, 2H), 1.67 (m, 1H),
1.20-0.80 (m, 4H).
Example 9
27)
N-(2-Amino-2-oxoethyl)-3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-
-4-yl]oxy}propoxy)benzamide
##STR00127##
[1090] 1,3-Diisopropylcarbodiimide (13.0 mg, 0.10 mmol) was added
to a stirred mixture of
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzoic
acid (21 mg, 0.050 mmol), 2-amino-acetamide hydrochloride (11 mg,
0.10 mmol), 1-hydroxybenzotriazole (6.7 mg, 0.05 mmol),
diisopropylethylamine (40 mg, 0.30 mmol) and
4-dimethylaminopyridine (13 mg, 0.10 mmol) in N,N-dimethylformamide
(1.0 mL). The mixture was stirred at room temperature for 6 hours
and then concentrated in vacuo. The resultant residue was dissolved
in ethyl acetate (30 mL), washed with aqueous sodium bicarbonate
solution (2.times.25 mL) and the organic layer was separated and
concentrated. The product was purified by column chromatography
over silica gel using 5% methanol in 1:1 of ethyl acetate/hexanes
to give 9.6 mg (40%) of
N-(2-amino-2-oxoethyl)-3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4--
yl]oxy}propoxy)benzamide as a white solid. MS [M+H] 481.1, .sup.1H
NMR (CDCl.sub.3) .delta. (ppm) 8.68 (s, 1H), 7.60-7.24 (m, 4H),
7.21 (s, 1H), 7.18-6.95 (m, 3H), 6.90 (d, J=7.8 Hz, 1H), 6.31 (b,
1H), 5.62 (b, 1H), 4.59 (t, J=6.0 Hz, 2H), 4.19, (d, J=5.1 Hz, 2H),
3.74 (t, J=6.0 Hz, 2H), 2.10 (m, 2H).
[1091] The following compounds were synthesized in a similar manner
using different starting materials: [1092] 8)
3-(Acetylamino)-N-{2-[(5-phenylthieno[2,3-d]pyrimidin-4-yl)amino]ethyl}-b-
enzamide. MS[M+H] 432.2 [1093] 22)
5-(4-Fluorophenyl)-4-(3-{3-[(4-methylpiperazin-1-yl)carbonyl]phenoxy}-pro-
poxy)thieno[2,3-d]pyrimidine. MS[M+H] 507.1 [1094] 23)
5-(4-Fluorophenyl)-4-{3-[3-(morpholin-4-ylcarbonyl)phenoxy)propoxy}-thien-
o[2,3-d]pyrimidine. MS[M+H] 494.1 [1095] 24)
N-Ethyl-3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-
-benzamide. MS[M+H] 452.1 [1096] 25)
3-(3-{[5-(4-Fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-N,N-dim-
ethylbenzamide MS[M+H] 452.1 [1097] 26)
N-[2-(Dimethylamino)ethyl]-3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidi-
n-4-yl]oxy}propoxy)benzamide. MS[M+H] 495.1 [1098] 28)
3-(3-{[5-(4-Fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-N'-form-
ylbenzohydrazide. MS[M+H] 467.0
Example 10
35)
3-(3-{[5-(4-Fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzo-
hydrazide
##STR00128##
[1100] Thionyl chloride (13 mg, 0.11 mmol) was added to a solution
of
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzoic
acid (43 mg, 0.101 mmol) in tetrahydrofuran (2.0 mL) with stirring
at 70.degree. C. Stirring continued for one hour at 70.degree. C.
and then the mixture was cooled to 25.degree. C. and added to a
solution of hydrazine (32 mg, 1.0 mmol) in tetrahydrofuran (2.0
mL). The reaction was stirred at room temperature for one hour and
the solvent was then removed in vacuo. The residue was dissolved in
ethyl acetate (30 mL), washed with of aqueous sodium bicarbonate
solution (20 mL), concentrated, and purified by column
chromatography over silica gel using 2% methanol in ethyl acetate
as eluant to give 22 mg (50%) of
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzohyd-
razide as a white solid. MS [M+H] 439.2, .sup.1H NMR (CDCl.sub.3)
.delta. (ppm) 8.65 (s, 1H), 7.50-7.35 (m, 2H), 7.32-7.21 (m, 3H),
7.18 (s, 1H), 7.10-6.97 (m, 2H), 6.94 (d, J=2.7 Hz, 1H), 4.59 (t,
J=6.9 Hz, 2H), 4.11 (s, 2H), 3.74 (t, J=6.0 Hz, 2H), 2.09 (m,
2H).
[1101] The following compound was synthesized in a similar manner
using different starting materials: [1102] 36)
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-N-hydro-
xybenzamide. MS[M+H] 440.2
Example 11
3-Hydroxy-N-methylbenzamide
##STR00129##
[1104] A solution of 3-hydroxybenzoic acid methyl ester (2.00 g,
0.0131 mol), methylamine (0.06 mol) and methanol (30 mL) was heated
to 155.degree. C. for 12 hours in a sealed tube. The solvent was
removed in vacuo and the product was purified by column
chromatography over silica gel using a gradient elution from 5 to
8% methanol in dichloromethane to give 1.20 g (60.4%) of
3-hydroxy-N-methylbenzamide as a yellow solid. MS [M+H] 152.2,
.sup.1H NMR (CDCl.sub.3) .delta. (ppm) 7.55 (s, 1H), 7.30 (d, J=7.8
Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 7.01 (m, 1H), 6.65 (b, 1H), 6.20
(b, 1H), 3.03 (d, J=4.8 Hz, 3H).
[1105] The following compounds were synthesized in a similar manner
using different starting materials: [1106] 3-hydroxybenzamide.
MS[M+H] 138.1 [1107] 5-hydroxynicotinamide. MS[M+H] 139.1 [1108]
5-hydroxy-N-methylnicotinamide. MS[M+H] 153.2 [1109]
5-hydroxy-N-methylpyridine-2-carboxamide. MS[M+S] 153.1 [1110]
5-hydroxypyridine-2-carboxamide. MS[M+S] 139.1
Example 12a
54)
5-{3-[5-(4-Fluorophenyl)-thieno[2,3-d]pyrimidin-4-yloxy]-propoxy}-nico-
tinic acid
##STR00130##
[1112] To a solution of
5-{3-[5-(4-fluorophenyl)-thieno[2,3-d]pyrimidin-4-yloxy]-propoxy}-nicotin-
ic acid methyl ester (100 mg) in dioxane (10 mL) was added 0.80 M
lithium hydroxide in water (2.0 mL). The reaction was stirred at
ambient temperature for 16 hours, then acidified with 1M
hydrochloric acid to pH 3, and the solvent removed under reduced
pressure. The residue was dissolved in 20% methanol/dichloromethane
(40 mL), filtered, and the filtrate was concentrated. The product
was purified by column chromatography over silica gel using 10%
methanol in dichloromethane as eluant to give 90 mg (93%) of
5-{3-[5-(4-fluorophenyl)-thieno[2,3-d]pyrimidin-4-yloxy]-propoxy}-nicotin-
ic acid as a white solid. MS [M+H] 425.9, .sup.1H NMR (CD.sub.3OD)
.delta. (ppm) 8.91 (s, 1H), 8.63 (s, 1H), 8.62 (s, 1H), 8.27 (s,
1H), 7.60-7.45 (m, 3H), 7.10 (t, J=8.7 Hz, 2H), 4.67 (t, J=9.0 Hz,
2H), 3.94 (t, J=9.3 Hz, 2H), 2.22 (t, J=9.0 Hz, 2H).
[1113] The following compound was synthesized in a similar manner
using different starting materials: [1114] 20)
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzoic
acid. MS [M+H] 425.0
Example 12b
88)
5-{4-[5-(4-Fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}nicotinic
acid hydroformate
##STR00131##
[1116] A mixture of
methyl-5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}nicotin-
ate (0.010 g, 0.023 mmol) and potassium hydroxide (0.0112 g, 0.200
mmol) in methanol (0.5 mL) was stirred at room temperature for 12
h. Acetic acid (200 mg, 3.33 mmol) was then added, and the reaction
solvent was removed by evaporation. The product was purified by
column chromatography over silica gel using 5% methanol in
dichloromethane as eluant to afford 8 g (83%)
5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}nico-
tinic acid hydroformate as white solid. MS [M+H]=424.1, LC/MS (EI)
t.sub.R 3.89 min (Method D), .sup.1H NMR (10% MeOD/CDCl.sub.3)
.delta. (ppm) 8.94 (s, 1H), 8.73 (s, 1H), 8.28 (s, 1H), 7.68 (s,
1H), 7.40-7.30 (m, 3H), 7.10 (t, J=8.4 Hz, 2H), 3.84 (t, J=6.3 Hz,
2H), 2.68 (t, J=7.2 Hz, 2H), 1.75-1.59 (m, 2H), 1.59-1.45 (m,
2H)
Example 13
5-(3-Hydroxypropoxy)-N-methylpyridine-2-carboxamide
##STR00132##
[1118] To a mixture of 5-hydroxy-N-methylpyridine-2-carboxamide
(400 mg, 3.0 mmol), 1,3-propanediol (230 mg, 3.0 mmol),
triphenylphosphine (786 mg, 3.0 mmol) and N,N-dimethylformamide
(4.5 ml, 60 mmol) was added diisopropyl azodicarboxylate (606 mg,
3.0 mmol) while stirring at ambient temperature. After 18 hours,
the solvent was removed under reduced pressure and the resulting
residue was taken up in ethyl acetate (40 mL) and filtered. The
filtrate was concentrated and purified by column chromatography
over silica gel using methanol/ethyl acetate (3-4%) to give 488 mg
(80%) of 5-(3-hydroxypropoxy)-N-methylpyridine-2-carboxamide as a
colorless gum. MS [M+H] 211.2, .sup.1H NMR (CDCl.sub.3) .delta.
(ppm) 8.19 (d, J=3.0 Hz, 1H), 8.13 (d, J=8.7 Hz, 1H), 7.83 (b, 1H),
7.28 (m, 1H), 4.21 (t, J=6.3 Hz, 2H), 3.88 (m, 2H), 3.02 (d, J=5.1
Hz), 2.08 (m, 2H).
[1119] The following compounds were synthesized in a similar manner
using different starting materials: [1120]
N-[3-(3-hydroxy-propoxy)-phenyl)-acetamide. MS[M+H] 210.3 [1121]
5-(3-hydroxypropoxy)pyridine-2-carboxamide. MS[M+H] 197.2 [1122]
15)
N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]-acetamide. MS[M+H] 438.2 [1123] 16)
5-(4-fluorophenyl)-4-{3-[4-(1H-1,2,4-triazol-1-yl)phenoxy]propoxy}thieno[-
2,3-d]pyrimidine. MS[M+H] 448.1 [1124] 17)
4-[3-(4-fluorophenoxy)propoxy]-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine.
MS[M+H] 399.1 [1125] 18) methyl
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-benzoat-
e. MS[M+H] 439.1 [1126] 12)
5-(4-fluorophenyl)-4-[3-(3-nitrophenoxy)propoxy]thieno[2,3-d]pyrimidine.
MS[M+H] 426.0 [1127] 29)
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-N-methy-
lbenzamide. MS[M+H] 438.2 [1128] 30)
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzamid-
e. MS[M+H] 424.2 [1129] 31)
3-(2-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethoxy)-N-methyl-
benzamide. MS[M+H] 424.2 [1130] 32)
N-[3-(2-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethoxy)phenyl-
]-urea. MS[M+H] 425.2 [1131] 33)
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]-urea. MS[M+H] 439.2 [1132] 34)
3-(2-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethoxy)benzamide-
. MS[M+H] 410.2 [1133] 50)
4-{3-[5-(4-fluorophenyl)-thieno[2,3d]pyrimidin-4-yloxy]-propoxy}-benzamid-
e. MS[M+H] 424.0 [1134] 37)
4-(2-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl
oxy}ethoxy)benzamide. MS[M+H] 410.1 [1135] 53)
2-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzamid-
e. MS[M+H] 424.1 [1136] 51)
5-{3-[5-(4-fluorophenyl)-thieno[2,3-d]pyrimidin-4-yloxy]-propoxy}-nicotin-
ic acid methyl ester. MS[M+H] 440.0
Example 14
61)
N-Methyl-5-{3-[(5-pyridin-4-ylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}-
pyridine-2-carboxamide
##STR00133##
[1138] 5-(3-Hydroxypropoxy)-N-methylpyridine-2-carboxamide (52 mg,
0.25 mmol) in N,N-dimethylacetamide (2.0 mL, 22 mmol) was treated
with sodium hydride (11 mg, 60%, 0.27 mmol) at ambient temperature.
After 1.5 hours, the mixture was added to a solution of
4-chloro-5-pyridin-4-ylthieno[2,3d]pyrimidine (62 mg, 0.025 mmol)
in N,N-dimethylacetamide (1.0 mL) and the resulting mixture was
stirred at room temperature for 12 hours. The reaction mixture was
then quenched by the addition of acetic acid (0.12 mL, 2.0 mmol)
and the solvent was removed under reduced pressure. The residue was
dissolved in ethyl acetate (50 mL), washed with 5% aqueous sodium
bicarbonate (2.times.30 mL) and the organic layer was concentrated.
The product was purified by silica gel chromatography using 3 to 5%
methanol in ethyl acetate to give 72 mg (68%) of
N-methyl-5-{3-[(5-pyridin-4-ylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}pyr-
idine-2-carboxamide as a white solid. MS [M+H] 422.0, .sup.1H NMR
(CDCl.sub.3) .delta. (ppm) 8.74 (s, 1H), 8.66 (s, 1H), 8.54 (d,
J=3.9 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 8.05 (d, J=2.7 Hz, 1H),
7.90-7.73 (m, 2H), 7.33 (s, 1H), 7.28 (dd, J=7.8, 4.8 Hz, 1H), 7.11
(dd, J=8.7, 2.7 Hz, 1H), 4.62 (t, J=6.0 Hz, 2H), 3.76 (t, J=6.0 Hz,
2H), 3.01 (d, J=4.8 Hz, 3H), 2.13 (t, J=6.0 Hz, 2H).
[1139] The following compounds were synthesized in a similar manner
using different starting materials: [1140]
3-[5-(4-fluorophenyl)-thieno[2,3-d]pyrimidin-4-yloxy]-propan-1-ol.
MS[M+H] 305.2 [1141]
5-(4-fluorophenyl)-4-isopropoxythieno[2,3-d]pyrimidine. MS[M+H]
289.2 [1142] 105)
5-(4-fluorophenyl)-4-[3-(3-nitrophenoxy)propoxy]thieno[2,3-d]pyrimidine.
MS[M+H] 426.1 [1143] 14)
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]-acetamide. MS[M+H] 438.4 [1144]
2-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethanol.
MS[M+H] 291.2 [1145] 52)
N-{3-[3-(5-furan-2-yl-thieno[2,3-d]pyrimidin-4-yloxy)-propoxy)-phenyl}-ac-
etamide. MS[M+H] 410.0 [1146]
N-{3-[3-(4-oxo-5-furan-2-yl-4-oxo-4H-thieno[2,3-d]pyrimidin-1-yl)propoxy]-
-phenyl}acetamide. MS[M+H] 410.1 [1147]
N-{3-[3-(4-oxo-5-phenylthieno[2,3-d]pyrimidin-1(4H)-yl)propoxy]phenyl}-ac-
etamide. MS[M+H] 420.0 [1148] Benzyl
4-(2-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}ethyl)-piperazin-
e-1-carboxylate. MS[M+H] 493.1 [1149] 57)
5-{3-[(5-pyridin-4-ylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}pyridine-2-c-
arboxamide. MS[M+H] 408.1 [1150] 58)
5-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pyridine-
-2-carboxamide. MS[M+H] 425.1 [1151] 59)
5-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pyridi-
ne-2-carboxamide. MS[M+H] 414.1 [1152] 60)
5-{3-[(5-pyridin-3-ylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}pyridine-2-c-
arboxamide. MS[M+H] 408.0 [1153] 62)
5-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-N-methy-
lpyridine-2-carboxamide. MS[M+H] 439.1 [1154] 63)
N-methyl-5-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}propo-
xy)-pyridine-2-carboxamide. MS[M+H] 428.0 [1155]
Diethyl[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]malonate.
MS[M+H] 389.1 [1156] 64)
N-methyl-5-{3-[(5-pyridin-2-ylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}-py-
ridine-2-carboxamide. MS[M+H] 422.1 [1157] 106)
N-methyl-4-{3-[(5-pyridin-3-ylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}-be-
nzamide. MS[M+H] 421.1 [1158] 107)
N-methyl-5-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}propo-
xy)-nicotinamide. MS[M+H] 428.0 [1159] 108)
N-methyl-5-{3-[(5-pyridin-3-ylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}-ni-
cotinamide. MS[M+H] 422.1 [1160] 109)
N-methyl-3-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}propo-
xy)-benzamide. MS[M+H] 427.0 [1161] 110)
N-[4-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)phe-
nyl]-acetamide. MS[M+H] 427.0 [1162] 111)
N-(4-{3-[(5-pyridin-3-ylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}phenyl)-a-
cetamide. MS[M+H] 421.0 [1163] 65)
N-methyl-3-{3-[(5-pyridin-3-ylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}ben-
zamide, MS [M+H]=421.1, LC/MS (EI) t.sub.R 5.42 min (Method B)
[1164] 71)
5-{3-[(5-pyridin-3-ylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}pyridine-2-c-
arboxamide hydroformate, MS [M+H]=408.1, LC/MS (EI) t.sub.R 4.14
min (Method B) [1165] 72)
5-(4-fluorophenyl)-4-(3-{[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]ox-
y}propoxy)thieno[2,3-d]pyrimidine, MS [M+H]=453.1, LC/MS (EI)
t.sub.R 4.32 min (Method E) [1166] 73)
4-[3-(4-chlorophenoxy)propoxy]-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine,
MS [M+H]=415.1, LC/MS (EI) t.sub.R 5.65 min (Method E) [1167] 74)
4-[3-(3,5-difluorophenoxy)propoxy]-5-(4-fluorophenyl)thieno[2,3-d]pyrimid-
ine, MS [M+H]=417.1, LC/MS (EI) t.sub.R 4.82 min (Method E) [1168]
75)
4-[3-(3,4-dimethoxyphenoxy)propoxy]-5-(4-fluorophenyl)thieno[2,3-d]pyrimi-
dine, MS [M+H]=441.2, LC/MS (EI) t.sub.R 3.53 min (Method E) [1169]
76)
4-[3-(1,2-benzisothiazol-3-yloxy)propoxy]-5-(4-fluorophenyl)thieno[2,3-d]-
pyrimidine, MS [M+H]=438.1, LC/MS (EI) t.sub.R 5.89 min (Method E)
[1170] 77)
5-(4-fluorophenyl)-4-(3-phenoxypropoxy)thieno[2,3-d]pyrimidine, MS
[M+H]=356.1, LC/MS (EI) t.sub.R 5.24 min (Method E) [1171] 78)
5-(4-fluorophenyl)-4-[3-(3-methoxyphenoxy)propoxy]thieno[2,3-d]pyrimidine-
, MS [M+H]=411.1, LC/MS (EI) t.sub.R 4.25 min (Method E) [1172] 79)
5-(4-fluorophenyl)-4-[3-(3-methylphenoxy)propoxy]thieno[2,3-d]pyrimidine,
MS [M+H]=395.1, LC/MS (EI) t.sub.R 5.36 min (Method E) [1173] 80)
5-(4-fluorophenyl)-4-{3-[3-(trifluoromethoxy)phenoxy]propoxy}thieno[2,3-d-
]pyrimidine, MS [M+H]=465.1, LC/MS (EI) t.sub.R 5.61 min (Method E)
[1174] 81)
4-[3-(3-ethylphenoxy)propoxy]-5-(4-fluorophenyl)thieno[2,3-d]pyrimidi-
ne, MS [M+H]=409.1, LC/MS (EI) t.sub.R 6.06 min (Method E) [1175]
92)
N-[3-(2,2-dimethyl-3-{([5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]o-
xy}propoxy)phenyl]acetamide hydroformate, MS [M+H]=455.1, LC/MS
(EI) t.sub.R 6.13 min (Method D) [1176] 94)
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-2,2-dimethyl
propoxy)phenyl]acetamide hydroformate, MS [M+H]=466.1, LC/MS (EI)
t.sub.R 7.66 min (Method D).
Example 15
39)
N-[3-(3-{[5-(4-Fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-p-
henyl]methanesulfonamide
##STR00134##
[1178] A solution of
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)aniline
(50 mg, 0.126 mmol) in dichloromethane (1.5 mL) was added to
methanesulfonyl chloride (58 mg, 0.51 mmol) while stirring,
followed by the addition of a solution of diisopropylethylamine (18
mg, 0.14 mmol) in dichloromethane (0.5 mL). Stirring was continued
for 12 hours at room temperature and then the solvent was
evaporated in vacuo. The residue was dissolved in ethyl acetate (30
mL), washed with sodium bicarbonate (2.times.25 mL) and the organic
layer was isolated and concentrated. The product was purified by
silica gel chromatography using 40% ethyl acetate in hexanes to
give 23 mg (40%) of
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]methanesulfonamide as a yellow solid. MS [M+H] 474.7. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. (ppm) 8.65 (s, 1H), 7.42 (m, 2H),
7.23 (t, J=68.0 Hz, 1H), 7.22 (s, 1H), 7.06-7.01 (m, 2H), 6.76 (dd,
J=8.0, 2.0 Hz, 1H), 6.68 (t, J=2.4 Hz, 1H), 6.58 (dd, J=8.0, 2.4
Hz, 1H), 6.32 (b, 1H), 4.58 (t, J=6.0 Hz, 2H), 3.01 (s, 3H), 2.07
(m, 2H).
[1179] The following compounds were synthesized in a similar manner
using different starting materials: [1180] 40)
N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]-methanesulfonamide. MS[M+H] 474.7 [1181] 41)
N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]-N-(methylsulfonyl)methanesulfonamide. MS {M+H] 552.8 [1182] 42)
N-(ethylsulfonyl)-N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl-
]oxy}propoxy)phenyl]ethanesulfonamide. MS[M+H] 580.9 [1183] 46)
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-}propoxy)phen-
yl]-ethanesulfonamide. MS[M+H] 488.2 [1184] 43)
N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]-ethanesulfonamide. MS[M-H] 486.7
Example 16
38)
N-Ethyl-N'-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}p-
ropoxy)phenyl]urea
##STR00135##
[1186] A mixture of
3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)aniline
(25 mg, 0.063 mmol) and diisopropylethylamine (9.0 mg, 0.069 mmol)
in dichloromethane (1.5 mL) was added in three portions over a
period of 30 minutes to a solution of triphosgene (7.0 mg, 0.023
mmol) in dichloromethane (0.5 mL) while stirring at ambient
temperature. Stirring continued for 15 minutes followed by the
addition of ethylamine (0.075 mL, 2M in tetrahydrofuran). The
reaction was stirred for 2 hours, then diluted with dichloromethane
(30 mL) and washed with sodium bicarbonate (2.times.20 mL). The
organic layer was dried (Na.sub.2SO.sub.4), concentrated, and
purified by column chromatography over silica gel using 40% ethyl
acetate in hexanes as eluant to give 15 mg (51%) of
N-ethyl-N'-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}prop-
oxy)phenyl]urea as a white solid. MS [M+H] 467.3. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. (ppm) 8.64 (s, 1H), 7.45-7.38 (m, 2H),
7.21 (s, 1H), 7.18 (t, J=8.0 Hz, 1H), 7.06-7.01 (m, 2H), 6.82 (t,
J=2.4 Hz, 1H), 6.79 (m, 1H), 6.50 (m, 1H), 4.58 (t, J=6.0 Hz, 2H),
3.72 (t, J=6.0 Hz, 2H), 3.30 (q, J=7.2 Hz, 2H), 2.06 (m, 2H), 1.16
(t, J=7.2 Hz, 3H).
[1187] The following compounds were synthesized in a similar manner
using different starting materials: [1188] 44)
N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]-N'-methylurea. MS [M+H] 453.5 [1189] 45)
N-ethyl-N'-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}prop-
oxy)phenyl]urea. MS [M+H] 467.9 [1190] 47)
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)pheny-
l]-N'-methylurea. MS [M+H] 453.3 [1191] 56)
N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-phen-
yl]hydrazinecarboxamide. MS [M+H] 454.6 [1192] 49)
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-phen-
yl]-N'-hydroxyurea. MS [M-H] 453.3 [1193] 48)
N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-phen-
yl]hydrazinecarboxamide. MS [M-H] 452.2
Example 17
66)
N-Methyl-5-(3-[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]aminopr-
opoxy)pyridine-2-carboxamide
##STR00136##
[1195] A mixture of
4-chloro-5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidine (0.050 g, 0.20
mmol), 5-(3-aminopropoxy)-N-methylpyridine-2-carboxamide
trifluoroacetate (0.070 g, 0.22 mmol), potassium carbonate (0.272
g, 1.97 mmol) and N,N-dimethylacetamide (2.4 mL) was heated at
120.degree. C. for 13 h. The solvent was evaporated in vacuo, and
the residue was treated with 5% sodium bicarbonate (20 mL) and
ethyl acetate (20 mL). The precipitate was filtered and washed with
water and ethyl ether. The resulting white solid was purified by
column chromatography over silica gel to give 70 mg (81%)
N-methyl-5-(3-[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl
]aminopropoxy)pyridine-2-carboxamide. MS [M+H]=427, LC/MS (EI)
t.sub.R 3.54 min (Method D), .sup.1H NMR (10% MeOD/CDCl.sub.3)
.delta. (ppm) 10.85 (s, 1H), 8.30 (s, 1H), 8.12 (d, J=2.4 Hz, 1H),
8.00 (d, J=8.7 Hz, 1H), 7.94 (b, 1H), 7.71 (s, 1H), 7.50 (d, J=3.6
Hz, 1H), 7.28 (s, 1H), 7.21 (dd, J=8.7, 3.0 Hz, 1H), 4.15 (t, J=0.6
Hz, 2H), 3.80-3.74 (m, 2H), 2.94 (d, J=0.6 Hz, 3H), 2.24-2.18 (m,
2H).
[1196] The following compounds were synthesized in a similar manner
using different starting materials: [1197] 13)
N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino}propoxy)-ph-
enyl]acetamide. MS[M+H] 437.2 [1198] 67)
5-(3-{[5-(5-chloro-2-furyl)thieno[2,3-d]pyrimidin-4-yl]amino}propoxy)-N-m-
ethylpyridine-2-carboxamide, MS [M+H]=444, LC/MS (EI) t.sub.R 3.91
min (Method D) [1199] 68)
N-methyl-5-{3-[(5-pyridin-3-ylthieno[2,3-d]pyrimidin-4-yl)amino]propoxy}p-
yridine-2-carboxamide, MS [M+H]=421, LC/MS (EI) t.sub.R 5.2 min
(Method B) [1200] 69)
N-methyl-5-{3-[(5-pyridin-2-ylthieno[2,3-d]pyrimidin-4-yl)amino]propoxy}p-
yridine-2-carboxamide, MS [M+H]=421, LC/MS (EI) t.sub.R 5.11 min
(Method B) [1201] 70)
N-methyl-5-{3-[(5-pyridin-2-ylthieno[2,3-d]pyrimidin-4-yl)amino]propoxy}n-
icotinamide, MS [M+H]=421.1, LC/MS (EI) t.sub.R 2.89 min (Method D)
[1202] 82)
5-{3-[(5-pyrimidin-2-ylthieno[2,3-d]pyrimidin-4-yl)amino]propoxy}pyri-
dine-2-carboxylic acid hydroformate, MS [M+H]=409.1, LC/MS (EI)
t.sub.R 4.27 min (Method B) [1203] 83)
5-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]amino}propoxy}pyri-
dine-2-carboxylic acid hydroformate, MS [M+H]=414.1, LC/MS (EI)
t.sub.R 4.95 min (Method B) [1204] 84)
5-{3-[(5-pyrazin-2-ylthieno[2,3-d]pyrimidin-4-yl)amino]propoxy}pyridine-2-
-carboxylic acid hydroformate, MS [M+H]=409.1, LC/MS (EI) t.sub.R
4.11 min (Method B) [1205] 96)
5-{3-[(5-pyridin-3-ylthieno[2,3-d]pyrimidin-4-yl)amino]propoxy}pyridine-2-
-carboxamide hydroformate, MS [M+H]=407.1, LC/MS (EI) t.sub.R 4.12
min (Method B) [1206] 97)
5-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]amino}propoxy)pyri-
dine-2-carboxamide hydroformate, MS [M+H]=413.1, LC/MS (EI) t.sub.R
5.49 min (Method B)
Example 18
87) Methyl
5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}nico-
tinate
##STR00137##
[1208] Diisopropyl azodicarboxylate (0.040 g, 0.20 mmol) was added
to a mixture of 5-hydroxynicotinic acid methyl ester (0.038 g, 0.25
mmol), 4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butan-1-ol
(0.060 g, 0.20 mmol), triphenylphosphine (0.052 g, 0.20 mol) and
tetrahydrofuran (3.0 mL) at room temperature with stirring. After
16 h, the solvent was removed in vacuo. The residue was diluted
with ethyl acetate (50 mL) and washed with sodium bicarbonate
(1.times.40 mL). The organic solution was concentrated and purified
by column chromatography (1.5-5% methanol/dichloromethane) to give
7 mg (8%) methyl
5-(4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxynicotinate
as white solid. MS [M+H]=438.1, LC/MS (EI) t.sub.R 4.63 min (Method
D), .sup.1H NMR (CDCl.sub.3) .delta. (ppm) 9.02 (s, 1H), 8.82 (s,
1H), 8.38 (s, 1H), 7.68 (s, 1H), 7.42-7.35 (m, 2H), 7.34 (s, 1H),
7.20-7.10 (m, 2H), 3.97 (s, 3H), 3.88 (t, J=6.3 Hz, 2H), 2.72 (t,
J=7.2 Hz, 2H), 1.81-1.66 (m, 2H), 1.66-1.53 (m, 2H).
[1209] The following compound was synthesized in a similar manner
using different starting materials: [1210] 95)
5-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)-1,3-dih-
ydro-2H-indol-2-one, MS [M+H]=436.1, LC/MS (EI) t.sub.R 6.98 min
(Method D)
Example 19
89)
5-{4-[5-(4-Fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}-N-methyl
nicotinamide hydroformate
##STR00138##
[1212] Methyl
5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}nicotinate
(0.010 g, 0.023 mmol) and methylamine (0.124 g, 0.004 mol) were
mixed in 1-butanol (2.00 mL) and the resulting mixture subjected to
microwave radiation for 2000 seconds at 170.degree. C., followed by
irradiation for 4000 seconds at 180.degree. C. The solvent was
removed by evaporation, and the product purified by preparative
HPLC to give 2 mg (20%)
5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}-N-methylnicot-
inamide hydroformate as a white solid. MS [M+H]=437.1, LC/MS (EI)
t.sub.R 3.55 min (Method D), .sup.1H NMR (10% MeOD/CDCl.sub.3)
.delta. (ppm) 8.93 (s, 1H), 8.43 (s, 1H), 8.20 (s, 1H), 7.70 (s,
1H), 7.60 (s, 1H), 7.40-7.28 (m, 4H), 7.11 (t, J=8.7 Hz, 2H), 3.84
(t, J=6.0 Hz, 2H), 2.95 (d, J=3.6 Hz, 3H), 2.67 (t, J=7.2 Hz, 2H),
1.75-1.59 (m, 2H), 1.59-1.45 (m, 2H)
Example 20
90)
5-{4-[5-(4-Fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}nicotinamid-
e hydroformate
##STR00139##
[1214] Methyl
5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)butoxy}nicotinate
(0.015 g, 0.034 mmol) and ammonia (3.00 mL, 20%, 0.02 mol) were
mixed in 1-butanol (1.00 mL) and the resulting mixture was heated
at 180.degree. C. for 20 h. The solvent was removed by evaporation,
and the product was purified by preparative HPLC to give 5 mg (36%)
5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}nicotinamide
hydroformate as a white solid. MS [M+H]=423.1, LC/MS (EI) t.sub.R
3.45 min (Method D), .sup.1H NMR (7% MeOD/CDCl.sub.3) .delta. (ppm)
8.92 (s, 1H), 8.50 (s, 1H), 8.25 (s, 1H), 7.62 (s, 1H), 7.40-7.30
(m, 3H), 7.10 (t, J=8.4 Hz, 2H), 3.84 (t, J=6.0 Hz, 2H), 2.66 (t,
J=7.5 Hz, 2H), 1.75-1.58 (m, 2H), 1.59-1.45 (m, 2H).
Example 21
91)
N-[3-(3-[5-(4-Fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxyphenoxy)phen-
yl]acetamide
##STR00140##
[1216] N-[3-(3-hydroxyphenoxy)phenyl]acetamide (0.032 g, 0.13 mmol)
in N,N-dimethylacetamide (2.5 mL) was treated with sodium hydride
(0.0063 g, 0.16 mol) at room temperature over a period of 1.5 h.
4-chloro-4-(4-fluorophenyl)thieno[2,3-d]pyrimidine (0.052 g, 0.20
mmol) was added, and the mixture was stirred at room temperature
for 2 h. The reaction mixture was then treated with acetic acid
(0.2 mL) for 5 min, and the solvent was evaporated in vacuo. The
residue was dissolved in ethylacetate (50 mL) and washed with 5%
solium bicarbonate (2.times.30 mL). The organic layer was
concentrated and the product purified by silica gel chromatography
(15% ethyl acetate/hexane) to afford 20 mg (32%)
N-[3-(3-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxyphenoxy)p-
henyl]acetamide as colorless gum. MS [M+H]=472, LC/MS (EI) t.sub.R
7.57 min (Method D), .sup.1H NMR (CDCl.sub.3) .delta. (ppm) 8.65
(s, 1H), 8.50 (s, 1H), 7.58-7.48 (m, 2H), 7.35 (m, 2H), 7.33-7.27
(m, 3H), 7.25 (s, 1H), 7.21 (s, 1H), 7.09 (t, J=8.7 Hz, 2H),
6.93-6.84 (m, 3H), 6.84-6.74 (m, 2H), 2.17 (s, 3H)
[1217] The following compound was synthesized in a similar manner
using different starting materials: [1218] 93)
N-[3-(3-{[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}phenoxy)phe-
nyl]acetamide hydroformate, MS [M+H]=461, LC/MS (EI) t.sub.R 6.19
min (Method D)
Example 22
86) 4-But-3-en-1-yl-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine
##STR00141##
[1220] 3-Butenylmagnesium bromide (0.0040 mol) was added to a
solution of 4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine
(0.529 g, 0.00200 mol), copper (I) iodide (0.038 g, 0.00020 mol)
and ferrous bromide (0.043 g, 0.00020 mol) in tetrahydrofuran (10
mL) and the resulting mixture was maintained at room temperature
for 5 h, then quenched by the addition of water (10 mL). Ethyl
acetate (50 mL) was added and the mixture was filtered. The
filtrate was washed with a saturated solution of sodium bicarbonate
(40 mL) and the organics were concentrated and purified by silica
gel column chromatography (using 15% ethyl acetate/hexane as
eluent) to afford
4-But-3-en-1-yl-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine as a
white solid in 67% yield.
Example 23
85) 4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butan-1-ol
##STR00142##
[1222] 9-BBN (0.236 g, 0.00193 mol) in tetrahydrofuran (5.00 mL)
was treated with
4-but-3-en-1-yl-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine (0.500 g,
0.00176 mol) in tetrahydrofuran (3.0 mL) at 50.degree. C. for 1 h.
Ethanol (1.0 mL), 6 N sodium hydroxide (0.33 mL) and 30% hydrogen
peroxide (0.67 mL) were then added successively and the resulting
mixture was maintained at 50.degree. C. for 1 h. The reaction was
then cooled to room temperature, diluted with ethyl acetate (50 mL)
and washed with sodium bicarbonate (2.times.30 mL). The organic
layers were combined, concentrated and purified by column
chromatography over silica gel (using ethyl acetate/hexane 1:5-1:1
as an eluent) to afford
4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butan-1-ol as a
white solid in 47% yield.
Example 24
98)
N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino}propyl)p-
henyl]acetamide
[1223] (i)
##STR00143##
[1224] 4-(3-aminopropyl)aniline (0.034 g, 0.23 mmol) was added to a
solution of 4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine
(0.04 g, 0.15 mmol), copper (I) iodide (0.009 g, 0.04 mmol) and
potassium carbonate (0.0626 g, 0.453 mmol) in N,N-dimethylacetamide
(3 mL) and the resulting mixture was subjected to microwave
radiation at 140.degree. C. for 4 hours. The solvent was then
removed by evaporation, and the residue was dissolved in ethyl
acetate (50 mL), filtered, and the organics were washed with a
saturated solution of sodium bicarbonate (30 mL): Concentration and
purification by silica gel column chromatography (using 1-3%
methanol, 0.06% ammonia in 1:1 ethyl acetate/hexane) afforded
N-[3-(4-aminophenyl)propyl]-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-am-
ine as a white solid in 30% yield.
##STR00144##
[1225] A mixture of
N-[3-(4-aminophenyl)propyl]-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-am-
ine (0.014 g, 0.037 mmol) and acetic anhydride (0.01 mL) in
methylene chloride (2.0 mL) was heated to 60.degree. C. for 6 h.
The reaction was allowed to cool to room temperature and
concentrated in vacuo. The residue was then dissolved in ethyl
acetate (30 mL) and the organic layer was washed with sodium
bicarbonate (2.times.25 mL). Concentration, followed by followed by
silica gel column chromatography purification (using 3% methanol in
1:1 ethyl acetate/hexane and ammonia (0.03%) as eluent) afforded
N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino}propyl)phen-
yl]acetamide in 90% yield.
Example 25
55)
N-(3-{3-[(5-phenylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}phenyl)aceta-
mide
[1226] A mixture of 5-phenylthieno[2,3-d]pyrimidin-4(1H)-one (0.023
g, 0.10 mmol), N-[3-(3-bromopropoxy)phenyl]acetamide (0.0274 g,
0.10 mmol), potassium carbonate (0.0418 g, 0.30 mmol) and
N,N-dimethylformamide (1.0 mL) was heated to 90.degree. C. for 6 h.
The reaction was then allowed to cool to room temperature and
concentrated in vacuo. The residue was dissolved in ethyl acetate
(30 mL), water (30 mL) was added, and the organic layer was
separated, Concentration, followed by followed by silica gel column
chromatography purification (using 1.50% methanol in 1:1 ethyl
acetate/hexane and ammonia (0.03%) as eluent) afforded
N-(3-{3-[(5-phenylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}phenyl)acetamid-
e in 66% yield.
N-{4-[3-(4-oxo-5-phenylthieno[2,3-d]pyrimidin-1(4H)-yl)propoxy]phenyl}ace-
tamide was also formed in 12% yield during the reaction.
Example 26
mPDE10A7 Enzyme Activity and Inhibition
[1227] To analyze the enzyme activity, 5 .mu.l of serial diluted
mPDE10A7 (PDE10A7 isoform enzyme) containing lysate were incubated
with equal volumes of diluted (100-fold) fluorescein labeled cAMP
or cGMP for 30 minutes in MDC HE 96-well assay plates at room
temperature. Both the enzyme and the substrates were diluted in the
following assay buffer: Tris/HCl (pH 8.0) 50 mM, MgCl.sub.2 5 mM,
2-mercaptoethanol 4 mM, BSA 0.33 mg/ml. After incubation, the
reaction was stopped by adding 201 of diluted (400-fold) binding
reagents and was incubated for an hour at room temperature. The
plates were counted in an Analyst GT (Molecular Devices) for
fluorescence polarization. An IMAP Assay kit (Molecular Device) was
used to assess enzyme properties of mPDE10A7. Data were analyzed
with SoftMax Pro.
[1228] To check the inhibition profile, 10 .mu.l of serial diluted
compounds were incubated with 30 .mu.l of diluted PDE enzymes in a
96-well polystyrene assay plate for 30 minutes at room temperature.
After incubation, 5 .mu.l of the compound-enzyme mixture were
aliquoted into a MDC HE black plate, mixed with 5 .mu.l of 100-fold
diluted fluorescein labeled substrates (cAMP or cGMP), and
incubated for 30 minutes at room temperature. The reaction was
stopped by adding 20 .mu.l of diluted binding reagents and counted
in an Analyst GT for fluorescence polarization. The data were
analyzed with SoftMax Pro.
[1229] Certain chemical entities described herein show activity
with IC50 values of generally less than 5 .mu.M, and in certain
embodiments, less than 0.5 .mu.M.
Example 27
Apomorphine Induced Deficits in Prepulse Inhibition of the Startle
Response in Rats, an In Vivo Test for Antipsychotic Activity
[1230] The thought disorders that are characteristic of
schizophrenia may result from an inability to filter, or gate,
sensorimotor information. The ability to gate sensorimotor
information can be tested in many animals as well as in humans. A
test that is commonly used is the reversal of apomorphine-induced
deficits in the prepulse inhibition of the startle response. The
startle response is a reflex to a sudden intense stimulus such as a
burst of noise. In this example, rats are exposed to a sudden burst
of noise, at a level of 120 db for 40 msec, e.g. the reflex
activity of the rats is measured. The reflex of the rats to the
burst of noise may be attenuated by preceding the startle stimulus
with a stimulus of lower intensity, at 3 to 12 db above background
(65 db), which will attenuate the startle reflex by 20 to 80%
(Geyer, M. A. and Swerdlow, N. R., Measurement of Startle Response,
Prepulse Inhibition and Habituation, Unit 8.7 in Current Protocols
in Neuroscience, 2003, John Wiley & Sons).
[1231] The prepulse inhibition of the startle reflex, described
above, may be attenuated by drugs that affect receptor signaling
pathways in the CNS. One commonly used drug is the dopamine
receptor agonist apomorphine. Administration of apomorphine will
reduce the inhibition of the startle reflex produced by the
prepulse. Antipsychotic drugs such as haloperidol will prevent
apomorphine from reducing the prepulse inhibition of the startle
reflex. This assay may be used to test the antipsychotic efficacy
of PDE10 inhibitors, as they reduce the apormorphine-induced
deficit in the prepulse inhibition of startle. Therefore, PDE10
inhibitors may be useful in restoring the deficits in sensorimotor
gating that contribute to the thought disorders that characterize
schizophrenia.
[1232] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[1233] While the invention has been illustrated with respect to the
production and of particular compounds, it is apparent that
variations and modifications of the invention can be made without
departing from the spirit or scope of the invention. Upon further
study of the specification, further aspects, objects and advantages
of this invention will become apparent to those skilled in the
art.
* * * * *