Amido compounds and their use as pharmaceuticals
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Abstract
The present invention relates to inhibitors of 11-β hydroxyl steroid dehydrogenase type 1, antagonists of the mineralocorticoid receptor (MR), and pharmaceutical compositions thereof. The compounds of the invention can be useful in the treatment of various diseases associated with expression or activity of 11-β hydroxyl steroid dehydrogenase type 1 and/or diseases associated with aldosterone excess.
55 Citations
25 Claims
-
1. A compound having Formula Va:
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25)
-
2. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cy is aryl optionally substituted by 1, 2, 3, 4 or 5 —
- W—
X—
Y—
Z.
- W—
-
3. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cy is aryl optionally substituted by 1, 2 or 3 halo, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, or C1-4 haloalkoxy.
-
4. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cy is aryl optionally substituted by 1, 2 or 3 halo, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, or C1-4 haloalkoxy.
-
5. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R1 and R2 together with the C atom to which they are attached form a cyclopropyl group.
-
6. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein —
- W—
X—
Y—
Z is halo, cyano, C1-4 cyanoalkyl, nitro, C1-8 alkyl, C2-8 alkenyl, C1-8 haloalkyl, C1-4 alkylthio, C1-4 haloalkylthio, C1-8 alkoxy, C2-8 alkenyloxy, C1-4 haloalkoxy, OH, (C1-4 alkoxy)-C1-4 alkyl, amino, C1-4 alkylamino, C2-8 dialkylamino, OC(O)NRcRd, NRcC(O)Rd, NRcC(O)ORa, NRcS(O)2Rd, C(O)ORa, C(O)Ra, C(O)NRaNRcRd, S(O)2Rd, SRd, C(O)NRcRd, C(S)NRcRd, aryloxy, heteroaryloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, arylalkyloxy, heteroarylalkyloxy, cycloalkylalkyloxy, heterocycloalkylalkyloxy, heteroaryloxyalkyl, aryloxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, or heterocycloalkylalkyl;wherein each of said C1-8 alkyl, C2-8 alkenyl, C1-8 haloalkyl, C1-4 alkylthio, C1-4 haloalkylthio, C1-8 alkoxy, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, heteroaryloxyalkyl, aryloxy, heteroaryloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, arylalkyloxy, heteroarylalkyloxy, cycloalkylalkyloxy, heterocycloalkylalkyloxy, heteroaryloxyalkyl, aryloxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, or 3 halo, cyano, nitro, hydroxyl-(C1-6 alkyl), aminoalkyl, dialkylaminoalkyl, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C1-4 alkoxy, C1-4 haloalkoxy, OH, ORa, (C1-4 alkoxy)-C1-4 alkyl, amino, C1-4 alkylamino, C2-8 dialkylamino, C(O)NRcRd, C(O)ORa, C(O)Ra, (cyclocalkylalkyl)-C(O)—
, NRcC(O)Rd, NRcC(O)ORa, NRcS(O)2Rd, C(S)NRcRd, S(O)2Rd, SRd, (C1-4 alkyl)sulfonyl, arylsulfonyl, aryl optionally substituted by halo, heteroaryl, cycloalkylalkyl, cycloalkyl, or heterocycloalkyl.
- W—
-
7. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein W—
- X—
Y—
Z is halo, cyano, C1-4 cyanoalkyl, nitro, C1-8 alkyl, C1-8 alkenyl, C1-8 haloalkyl, C1-10 alkoxy, C1-4 haloalkoxy, OH, C1-8 alkoxyalkyl, amino, C1-4 alkylamino, C2-8 dialkylamino, OC(O)NRcRd, NRcC(O)Rd, NRcC(O)ORa, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, heteroaryloxyalkyl, aryloxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, or heterocycloalkylalkyl;wherein each of said C1-8 alkyl, C1-8 alkenyl, C1-8 haloalkyl, C1-8 alkoxy, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, heteroaryloxyalkyl, aryloxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, or 3 halo, cyano, nitro, hydroxyl-(C1-6 alkyl), aminoalkyl, dialkylaminoalkyl, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, OH, C1-8 alkoxyalkyl, amino, C1-4 alkylamino, C2-8 dialkylamino, C(O)NRcRd, C(O)ORa, NRcC(O)Rd, NRcS(O)2Rd, (C1-4 alkyl)sulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl.
- X—
-
8. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein —
- W—
X—
Y—
Z is halo, cyano, C1-4 cyanoalkyl, nitro, C1-4 nitroalkyl, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, OH, (C1-4 alkoxy)-C1-4 alkyl, amino, C1-4 alkylamino, C2-8 dialkylamino, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl.
- W—
-
9. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein —
- W—
X—
Y—
Z is halo, C1-4 alkyl, or C1-4 alkoxy.
- W—
-
10. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein:
-
—
W—
X′
—
Y′
—
Z′
is halo, OH, cyano, CHO, COOH, C(O)O—
(C1-4 alkyl), C(O)—
(C1-4 alkyl), SO2—
(C1-4 alkyl), C1-4 alkyl, C1-4 alkoxy or —
L—
R7, wherein said C1-4 alkyl or C1-4 alkoxy is optionally substituted by one or more halo, OH, COOH or C(O)O—
(C1-4 alkyl);L is absent, O, CH2, NHSO2, N[C(O)—
(C1-4 alkyl)]; andR7 is aryl or heteroaryl, each is optionally substituted by 1, 2, or 3 halo, OH, cyano, CHO, COOH, C(O)O—
(C1-4 alkyl), C(O)—
(C1-4 alkyl), SO2—
(C1-4 alkyl), SO2—
NH(C1-4 alkyl), C1-4 alkyl, C1-4 alkoxy, C1-4 haoalkyl, C1-4 hydroxyalkyl, aryl, heteroaryl or aryloxy.
-
-
11. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein —
- W′
—
X′
—
Y′
—
Z′
is halo;
C1-4 alkyl;
C1-4 haloalkyl;
OH;
C1-4 alkoxy;
C1-4 haloalkoxy;
hydroxyalkyl;
alkoxyalkyl;
aryl;
heteroaryl;
aryl substituted by halo, C1-4 alkyl, C1-4 alkoxy, aryl, heteroaryl, or aryloxy;
or heteroaryl substituted by halo, C1-4 alkyl, C1-4 alkoxy, aryl, or heteroaryl.
- W′
-
12. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein —
- W″
—
X″
—
Y″
—
Z″
is halo, cyano, C1-4 cyanoalkyl, nitro, C1-4 nitroalkyl, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkoxy, OH, (C1-4 alkoxy)-C1-4 alkyl, amino, C1-4 alkylamino, C2-8 dialkylamino, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl.
- W″
-
13. A compound of claim 1 having Formula VII:
-
14. A compound of claim 13 having Formula VIII:
-
15. A compound of claim 1 selected from:
-
1′
-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1-({1-[4-(Pyridin-2-yloxy)phenyl]cyclopropyl}carbonyl)-3H-spirol[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(4-Chlorophenyl)cyclobutyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;
1′
-{[1-(4-Methylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(4-Methoxyphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(2,4-Dichlorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidine];1′
-{[1-(6-Phenylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one; and1′
-{[1-(4-Pyrrolidin-1-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;or pharmaceutically acceptable salt thereof.
-
-
16. A compound of claim 1 selected from:
-
1′
-{[1-(6-Pyrrolidin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(2-Oxo-1,3-oxazolidin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(2-Oxopyrrolidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(Pyridin-4-ylmethoxy)phenyl]cyclopropyl}-carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(Pyridin-2-ylmethoxy)phenyl]cyclopropyl}-carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(4-Pyridin-4-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(4-Cyclopropylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(2-Fluoro-4-pyridin-2-ylphenyl)cyclopropyl]-carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{4-[(E)-2-(4-Methylphenyl)vinyl]phenyl}-cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(2-Pyridin-2-ylethoxy)phenyl]cyclopropyl}-carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{4-[(E)-2-Pyridin-4-ylvinyl]phenyl}cyclopropyl)-carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(3,5-Dimethylisoxazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(1-Methyl-1H-pyrazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4′
-(Methylsulfonyl)biphenyl-4-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(1H-1,2,4-Triazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(1-Hydroxycyclopentyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(1-Hydroxycyclobutyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(4-Hydroxytetrahydro-2H-pyran-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(2-Amino-1,3-thiazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(2-Methyl-1,3-thiazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(2-Ethyl-1,3-thiazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(1,3-Thiazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[trans-1-(4-Chlorophenyl)-3-hydroxycyclobutyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[cis-1-(4-Chlorophenyl)-3-fluorocyclobutyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(2-Oxo-1,3-oxazolidin-3-yl)phenyl]cyclobutyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-Pyridin-4-ylcyclobutyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(4-Pyridin-4-ylphenyl)cyclobutyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;N,N-Dimethyl-4-[5-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxamide;1′
-[(1-{6-[4-(Methylsulfonyl)piperazin-1-yl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{6-[4-(2-Fluorophenyl)piperazin-1-yl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[6-(3,3-Difluoropyrrolidin-1-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{6-[3-Hydroxypyrrolidin-1-yl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;N-{1-[5-(1-{[3-Oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)pyridin-2-yl]pyrrolidin-3-yl}acetamide;1′
-({1-[6-(1,3-Dihydro-2H-isoindol-2-yl)pyridin-3-yl]cyclo-propyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[6-(3,4-Dihydro-isoquinolin-2(1H)-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(6-Morpholin-4-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[6-(4-Hydroxypiperidin-1-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;N-{4-[5-(1-{[3-Oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)pyridin-2-yl]phenyl}acetamide;1′
-({1-[6-(2-Fluorophenyl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[6-(1-Benzothien-3-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(2,3′
-Bipyridin-5-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[6-(1-Methyl-1H-indol-5-yl)pyridine-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{6-[3-(Trifluoromethoxy)phenyl]pyridine-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[6-(3-Thienyl)pyridine-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{6-[3-(Trifluoromethyl)phenyl]pyridine-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[6-(1-Methyl-1H-pyrazol-4-yl)pyridine-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(6-Chloropyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[6-(Benzyloxy)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-Quinolin-3-ylcyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;or pharmaceutically acceptable salt thereof.
-
-
17. A compound of claim 1 selected from:
-
4-(1-{[3-Oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)benzonitrile;1′
-{[1-(3-(Hydroxymethyl)phenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(4-Bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(Pyrrolidin-1-ylcarbonyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;4-(1-{[3-Oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)benzohydrazide;N-Methyl-4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)benzamide;4-(1-{[3-Oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)benzenecarbothioamide;1′
-[(1-{4-[2-(Trifluoromethyl)-1H-imidazol-4-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(1-Methyl-1H-pyrazol-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;N-Cyclopropyl-4′
-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)biphenyl-4-carboxamide;1′
-[(1-{4-[5-(Trifluoromethyl)-1H-1,2,4-triazol-3-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(1-Methyl-1H-tetrazol-5-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(2-Amino-1,3-oxazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(4-Pyrimidin-5-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(6-Fluoropyridin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(6-Pyrrolidin-1-ylpyridin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;N-Cyclopropyl-5-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide;N-Methyl-5-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide;1′
-({1-[4-(Methylsulfonyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{4-[(Trifluoromethyl)thio]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(4-Chloro-2-fluorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(2-Oxopyridin-1(2H)-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;Methyl 4-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate;1′
-[(1-{4-[4-(Methylsulfonyl)-2-oxopiperazin-1-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;7-Fluoro-1′
-[(1-{4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}cyclopropyl)carbonyl]spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;N-[4-(1-{[3-Oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]cyclopropanecarboxamide;N-[4-(1-{[3-Oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]benzenesulfonamide;Methyl allyl[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]carbamate;1′
-({1-[4-(1H-1,2,4-Triazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-Quinolin-6-ylcyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-Pyridin-4-ylcyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-Quinolin-4-ylcyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-Quinolin-2-ylcyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-Pyridin-2-ylcyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(1,3-Benzothiazol-2-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(Pyrrolidin-1-ylmethyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;[4-(1-{[3-Oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]cyclopropyl acetic acid;1′
-({1-[4-(3-Thienyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(2-Fluoro-4-pyridin-4-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;5-Methoxy-1′
-{[1-(4-methylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(4-Methylphenyl)cyclopropyl]carbonyl}-3-oxo-3H-spiro[2-benzofuran-1,3′
-pyrrolidine]-5-carbonitrile;1′
-({1-[3′
-(Hydroxymethyl)biphenyl-4-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one; and1′
-({1-[2′
-(Methylthio)biphenyl-4-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;or pharmaceutically acceptable salt thereof.
-
-
18. A compound of claim 1 selected from:
-
1′
-({1-[4-(2-Oxoimidazolidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{4-[4-Isopropyl-2-oxo-1,3-oxazolidin-3-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[2-Fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[2-Fluoro-4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;Methyl 3-oxo-4-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate;1′
-[(1-{6-[4-(Cyclopropyl carbonyl)piperazin-1-yl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{6-[4-(Pyridin-4-yloxy)piperidin-1-yl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{6-[3-(Pyridin-4-yloxy)pyrrolidin-1-yl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(6-Methoxypyridin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;[4′
-(1-{[3-Oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)biphenyl-3-yl]acetonitrile;1′
-({1-[4-(6-Aminopyridin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(6-Hydroxypyridin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(5-Methylpyridin-2-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{4-[(Pyridin-2-yloxy)methyl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{4-[(Pyridin-3-yloxy)methyl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{4-[(Pyridin-4-yloxy)methyl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;3-(1-{[3-Oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)benzonitrile;1′
-[(1-Biphenyl-3-ylcyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(1-Naphthyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one1′
-[(1-Quinolin-6-ylcyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{4-[(5-Methylisoxazol-3-yl)methoxy]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(2-Pyridin-3-yl-1,3-thiazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{4-[5-(Trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(4-tert-Butyl-1,3-thiazol-2-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(4-Chlorophenyl)-1,3-thiazol-2-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
,1″
-[1,4-Phenylenebis(cyclopropane-1,1-diylcarbonyl)]bis(3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one);1′
-[(1-Pyridin-3-ylcyclobutyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(4-Chlorophenyl)cyclobutyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;or pharmaceutically acceptable salt thereof.
-
-
19. A compound of claim 1 selected from:
-
Ethyl 4-[5-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxylate;1′
-[(1-{6-[4-(ethylsulfonyl)piperazin-1-yl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro-[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[6-(4-Methylpiperazin-1-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[6-(4-Phenylpiperazin-1-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{6-[4-(3-Methylbutanoyl)piperazin-1-yl]pyridin-3-yl}cyclopropylcarbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{6-[4-(Cyclopropylmethyl)piperazin-1-yl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[6-(2,5-Dihydro-1H-pyrrol-1-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(6-Piperidin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(4-Methyl-2-oxopiperazin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(4-Acetyl-2-oxo-piperazin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;tert-Butyl 4-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate;1′
-({1-[4-(4-Isobutyrylpiperazin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{4-[4-(Cyclopropyl carbonyl)piperazin-1-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{4-[4-(Methylsulfonyl)piperazin-1-yl]phenyl}cyclopropyl carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(4-Methylpiperazin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;N-Methyl-N-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]cyclopropanecarboxamide;N-[4-(1-{[3-Oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]acetamide;1′
-({1-[4-(2-Oxopyrrolidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(2-Oxo-1,3-oxazolidin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(1H-Pyrazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(2-Oxopiperidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;2-Methyl-3-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]imidazolidine-2,4-dione;1′
-{[1-(4-Morpholin-4-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-Pyridin-3-ylcyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;N-Methyl-4-[5-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)pyridin-2-yl]benzamide;N,N-Dimethyl-4-[5-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)pyridin-2-yl]benzamide;1′
-[(1-{6-[4-(Methylsulfonyl)phenyl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-{[1-(4-Methoxyphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(Pyridin-2-yloxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(Pyridin-3-ylmethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(Isoquinolin-1-ylmethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;Methyl 4-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]-3,6-dihydropyridine-(2H)-carboxylate;Ethyl 4-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate;1′
-({1-[4-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{4-[1-(3-Methylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;5-Hydroxy-1′
-{[1-(4-methylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one; and1′
-({1-[4-(Pyrrolidin-1-ylmethyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;or pharmaceutically acceptable salt thereof.
-
-
20. A compound of claim 1 selected from:
-
1′
-{[1-(4-Chlorophenyl)cyclo-pentyl]carbonyl}-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;Methyl 4-[5-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxylate;N,N-Dimethyl-4-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclo-propyl)phenyl]piperazine-1-carboxamide;Methyl 4-[3-fluoro-4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclo-propyl)phenyl]piperazine-1-carboxylate;1′
-({1-[2-Fluoro-4-(4-propionylpiperazin-1-yl)phenyl]cyclo-propyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[2-Fluoro-4-(4-isobutyrylpiperazin-1-yl)phenyl]cyclo-propyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{4-[4-(Cyclopropyl carbonyl)piperazin-1-yl]-2-fluoro-phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(4-Acetylpiperazin-1-yl)-2-fluorophenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;4-[3-Fluoro-4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]-N,N-dimethylpiperazine-1-carboxamide;1′
-({1-[4-(4-Hydroxypiperidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;N,N-Dimethyl-1-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclo-propyl)phenyl]piperidine-4-carboxamide;Methyl 4-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]piperidine-1-carboxylate;Ethyl 4-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]piperidine-1-carboxylate;1′
-({1-[4-(1-Acetylpiperidin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(1-Isobutyrylpiperidin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(1-Propionylpiperidin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{4-[1-(3-Methylbutanoyl)piperidin-4-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;Methyl 4-hydroxy-4-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclo-propyl)phenyl]piperidine-1-carboxylate;Ethyl 4-hydroxy-4-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclo-propyl)phenyl]piperidine-1-carboxylate;Isopropyl 4-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclo-propyl)phenyl]piperazine-1-carboxylate;1′
-[(1-{4-[6-(Pyrrolidin-1-ylcarbonyl)pyridin-3-yl]phenyl}cyclo-propyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;N-Ethyl-N-methyl-5-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclo-propyl)phenyl]pyridine-2-carboxamide;N,N-Diethyl-5-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclo-propyl)phenyl]pyridine-2-carboxamide;tert-Butyl {4-[5-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclo-propyl)pyridin-2-yl]phenyl}carbamate; andN,N-Dimethyl-1-[5-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclo-propyl)pyridin-2-yl]piperidine-4-carboxamide;or pharmaceutically acceptable salt thereof.
-
-
21. A compound of claim 1 selected from:
-
1′
-({1-[2-Fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(2-Oxoazetidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[2-Fluoro-4-(2-oxoazetidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;Propyl 4-[5-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxylate;Isobutyl 4-[5-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxylate;Isopropyl 4-[5-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxylate;Ethyl 4-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate;Propyl 4-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate;Isobutyl 4-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate;1′
-[(1-{4-[4-(Cyclopropylacetyl)piperazin-1-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{4-[4-(Cyclopropylacetyl)piperazin-1-yl]-2-fluorophenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{4-[4-(3-Methylbutanoyl)piperazin-1-yl]phenyl}cyclopropyl)carbonyl]-3H-2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{2-Fluoro-4-[4-(3-methylbutanoyl)piperazin-1-yl]phenyl}cyclopropyl)carbonyl]-3H -spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{4-[4-(Tetrahydro-2H-pyran-4-ylcarbonyl)piperazin-1-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;Ethyl 4-[3-fluoro-4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate;Propyl 4-[3-fluoro-4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate;4-[3-Fluoro-4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]-N-methylpiperazine-1-carboxamide;1′
-({1-[2-Fluoro-4-(4-isobutyrylpiperazin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-[(1-{4-[4-(Cyclopropylacetyl)piperazin-1-yl]-2-fluorophenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;N,N-Dimethyl-5-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide;N-Ethyl-5-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide;N-Isopropyl-5-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide;5-[3-Fluoro-4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]-N-methylpyridine-2-carboxamide;5-[3-Fluoro-4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]-N-ethylpyridine-2-carboxamide;5-[3-Fluoro-4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]-N-i-propylpyridine-2-carboxamide;5-[3-Fluoro-4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]-N,N-dimethylpyridine-2-carboxamide;6-[3-Fluoro-4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]-N-methylnicotinamide;6-[3-Fluoro-4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]-N,N-dimethylnicotinamide;N-Methyl-6-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]nicotinamide;N,N-Dimethyl-6-[4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]nicotinamide;1′
-({1-[4-(1-Isobutyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[4-(1-Propionyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[6-(2-Oxoazetidin-1-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;Methyl [3-fluoro-4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]carbamate;1′
-[(1-{4-[4-(Cyclopropylcarbonyl)piperazin-1-yl]phenyl}cyclobutyl)carbonyl]-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[2-Fluoro-4-(1H-1,2,3-triazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[2-Fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[2-Fluoro-4-(1H-1,2,4-triazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;1′
-({1-[2-Fluoro-4-(4H-1,2,4-triazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-3-one;N-Ethyl-5-[3-fluoro-4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide; and5-[3-Fluoro-4-(1-{[3-oxo-1′
H,3H-spiro[2-benzofuran-1,3′
-pyrrolidin]-1′
-yl]carbonyl}cyclopropyl)phenyl]-N-isopropylpyridine-2-carboxamide;
or pharmaceutically acceptable salt thereof.
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22. A method of treating a disease in a patient, wherein said disease is obesity, diabetes, glucose intolerance, insulin resistance, hyperglycemia, hyperlipidemia, glaucoma, hypertension, osteoporosis, inflammation, renal disease, atherosclerosis, arteriosclerosis, coronary artery disease, thrombosis, angina, peripheral vascular disease, vascular wall damage, stroke, dyslipidemia, hyperlipoproteinaemia, diabetic dyslipidemia, mixed dyslipedemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome, or general aldosterone-related target organ damage, comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or pharmaceutically acceptable salt thereof.
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23. A composition comprising a compound of claim 1, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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24. A method for treating metabolic syndrome in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or pharmaceutically acceptable salt thereof.
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25. A method for treating type 2 diabetes in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or pharmaceutically acceptable salt thereof.
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2. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cy is aryl optionally substituted by 1, 2, 3, 4 or 5 —
Specification
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Current AssigneeIncyte Corporation, Incyte Holdings Corporation (Incyte Corporation), Incyte Holdings Corporation And Incyte Corporation
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Original AssigneeIncyte Corporation
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InventorsXu, Meizhong, Zhuo, Jincong, Metcalf, Brian W., Zhang, Colin, Yao, Wenqing, Qian, Ding-Quan, He, Chunhong
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Primary Examiner(s)McKane; Joseph K.
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Assistant Examiner(s)Kosack; Joseph R.
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Application NumberUS11/122,309Publication NumberTime in Patent Office944 DaysField of Search514/409, 514/370, 514/380, 514/383, 548/525, 548/247, 548/190, 548/265.8, 548/383, 548/409US Class Current514/370CPC Class CodesA61K 31/407 condensed with other hetero...A61K 31/4439 containing a five-membered ...A61P 11/04 for throat disordersA61P 13/12 of the kidneysA61P 19/10 for osteoporosisA61P 25/28 for treating neurodegenerat...A61P 27/02 Ophthalmic agentsA61P 27/06 Antiglaucoma agents or mioticsA61P 29/00 Non-central analgesic, anti...A61P 3/00 Drugs for disorders of the ...A61P 3/04 Anorexiants; Antiobesity ag...A61P 3/06 AntihyperlipidemicsA61P 3/08 for glucose homeostasis pan...A61P 3/10 for hyperglycaemia, e.g. an...A61P 43/00 Drugs for specific purposes...A61P 5/48 of the pancreatic hormonesA61P 5/50 for increasing or potentiat...A61P 7/00 Drugs for disorders of the ...A61P 7/02 Antithrombotic agents; Anti...A61P 9/00 Drugs for disorders of the ...A61P 9/04 : Inotropic agents, i.e. stim...A61P 9/10 : for treating ischaemic or a...A61P 9/12 : AntihypertensivesA61P 9/14 : Vasoprotectives; Antihaemor...C07D 207/06 : with radicals, containing o...C07D 207/08 : with hydrocarbon radicals, ...C07D 207/10 : with hetero atoms or with c...C07D 207/12 : Oxygen or sulfur atomsC07D 207/14 : Nitrogen atoms not forming ...C07D 207/16 : Carbon atoms having three b...C07D 207/27 : with substituted hydrocarbo...C07D 209/08 : with only hydrogen atoms or...C07D 209/42 : Carbon atoms having three b...C07D 209/44 : Iso-indoles; Hydrogenated i...C07D 209/52 : condensed with a ring other...C07D 209/62 : Naphtho [c] pyrroles; Hydro...C07D 209/70 : containing carbocyclic ring...C07D 211/16 : with acylated ring nitrogen...C07D 211/18 : with substituted hydrocarbo...C07D 211/22 : by oxygen atomsC07D 211/34 : with hydrocarbon radicals, ...C07D 211/46 : having a hydrogen atom as t...C07D 211/48 : having an acyclic carbon at...C07D 211/52 : having an aryl radical as t...C07D 211/58 : attached in position 4C07D 211/64 : having an aryl radical as t...C07D 211/66 : having a hetero atom as the...C07D 211/70 : with only hydrogen atoms, h...C07D 213/38 : having only hydrogen or hyd...C07D 217/06 : with the ring nitrogen atom...C07D 217/26 : Carbon atoms having three b...C07D 221/20 : Spiro-condensed ring systemsC07D 295/185 : from aliphatic carboxylic a...C07D 333/34 : Sulfur atomsC07D 401/04 : directly linked by a ring-m...C07D 401/06 : linked by a carbon chain co...C07D 401/10 : linked by a carbon chain co...C07D 401/14 : containing three or more he...C07D 403/04 : directly linked by a ring-m...C07D 405/04 : directly linked by a ring-m...C07D 405/14 : containing three or more he...C07D 413/10 : linked by a carbon chain co...C07D 413/14 : containing three or more he...C07D 417/04 : directly linked by a ring-m...C07D 471/04 : Ortho-condensed systemsC07D 471/10 : Spiro-condensed systemsC07D 487/04 : Ortho-condensed systemsC07D 487/08 : Bridged systemsC07D 487/10 : Spiro-condensed systemsC07D 491/10 : Spiro-condensed systemsC07D 491/107 : with only one oxygen atom a...C07D 491/20 : Spiro-condensed systemsC07D 493/10 : Spiro-condensed systemsC07D 495/04 : Ortho-condensed systemsC07D 498/20 : Spiro-condensed systemsC07D 513/10 : Spiro-condensed systems