Claims
- 1. A compound of Formula I: or a pharmaceutically acceptable salt or prodrug thereof, wherein:X is oxygen or H2; A, D, V, W, Y and Z are independently N or CR1; B is CR2; E is CR3; R1 is independently selected at each occurrence from: (i) hydrogen, halogen, hydroxy, amino, nitro, cyano, —C(═O)NH2 and —COOH; and (ii) L-RA-Q-G, wherein: L is a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)n—, —NRB—, —C(═O)NHRB—, —NHRBC(═O)—, —NRBS(O)n— or —S(O)nNRB—; n is independently chosen at each occurrence from 0, 1 or 2; RA is (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl, (C3-C8)cycloalkynyl, quinazoline, pyridine, oxazole, pyrazine, piperazinyl, pyrimidinyl, morpholinyl each of which is optionally substituted with from 1 to 5 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, (C1-C6)alkyl and halo(C1-C6)alkyl; Q is a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)n—, —CHRB—, —NRB—, —C(═O)NHRB—, —NHRBC(═O)—, —NRBS(O)n— or —S(O)nNRB—; RB is independently selected at each occurrence from hydrogen, (C1-C8)alkyl, (C3-C8)cyclOalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl and (C1-C8)alkyl(C3-C8)cycloalkyl; and G is: hydrogen; or (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl(C1-C8)alkyl, or a 3- to 10-membered carbocyclic, quinazoline, pyridine, oxazole, pyrazine, piperazinyl, pyrimidinyl, morpholinyl, each of which is optionally substituted with from 1 to 5 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, —NH(C1-C8)alkyl, —N((C1-C8)alkyl)2, NHC(═O)(C1-C8)alkyl, —N(C1-C8)alkylC(═O)(alkyl), —NHS(O)s(C1-C8)alkyl, S(O)s(C1-C8)alkyl, —S(O)sNH(C1-C8)alkyl and —S(O)sN((C1-C8)alkyl)2, wherein s is 0, 1 or 2; R2 and R3 are independently selected at each occurrence from: (i) hydrogen, halogen, hydroxy, amino, nitro, cyano, —C(═O)NH2 and —COOH; and (ii) T-RC-U-M, wherein: T is a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)n—, —NRD—, —C(O)NHRD—, —NHRDC(═O)—, —NRDS(O)n— or —S(O)nNRD—; n is independently chosen at each occurrence from 0, 1 or 2; RC is (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or a 3- to 10-membered carbo cyclic, quinazoline, pyridine, oxazole, pyrazine, piperazinyl, pyrimidinyl, morpholinyl, each of which is optionally substituted with from 1 to 5 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, (C1-C6)alkyl and halo(C1-C6)alkyl; U is a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)n—, —CHRD—, —NRD—, —C(═O)NHRD—, —NHRDC(═O)—, —NRDS(O)n— or —S(O)nNRD—; RD is independently selected at each occurrence from hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl and (C1-C8)alkyl(C3-C8)cycloalkyl; and M is: hydrogen; or (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8) alkynyl or a 3- to 10-membered carbocyclic, quinazoline, pyridine, oxazole, pyrazine, piperazinyl, pyrimidinyl, morpholinyl, each of which is optionally substituted with from 1 to 5 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, (C1-C8) alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, —NH(C1-C8)alkyl, —N((C1-C8)alkyl)2, NHC(═O)(C1-C8)alkyl, —N(C1-C8)alkyl C(═O)(alkyl), —NHS(O)s(C1-C8)alkyl, —S(O)s(C1-C8)alkkyl, —S(O)sNH(1-C8)alkyl and —S(O)sN((C1-C8)alkyl)2, wherein s is 0, 1 or 2.
- 2. A compound according to claim 1, wherein Y and Z are both CH, and V and W are both CR1.
- 3. A compound according to claim 2, wherein V, W, Y and Z are all CH.
- 4. A compound according to claim 1, wherein A and D are each independently selected from CH and C-halogen.
- 5. A compound according to claim 1, wherein A and D are both CR1, B is CR2 and E is CR3.
- 6. A compound according to claim 1, wherein R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, nitro, cyano, amino, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy substituted with amino, mono- or di-(C1-C6)alkylamino or (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C2-C6)alkenyl, (C3-C7)cycloalkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkynyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, mono and di(C1-C6)alkylamino, amino(C1-C6)alkyl, and mono- and di(C1-C6)alkylamino(C1-C6)alkyl.
- 7. A compound according to claim 6, wherein:T is a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —S(O)n— or —NRD—; U is a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —S(O)n—, —CHRD or —NRD—, and M is hydrogen; or (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or a 3- to 10-membered carbocyclic, quinazoline, pyridine, oxazole, pyrazine, piperazinyl, pyrimidinyl, morpholinyl, each of which is optionally independently substituted with from 1 to 5 substituents selected from hydroxy, halogen, amino, cyano, nitro, (C1-C6)alkyl, halo(C1-C6) alkyl, (C1-C6)alkoxy, —NH(C1-C6)alkyl and —N((C1-C6) alkyl)2.
- 8. A compound according to claim 1, wherein R1 is independently selected at each occurrence from hydrogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy and difluoromethoxy.
- 9. A compound according to claim 6, wherein R2 and R3 are independently selected from:(i) hydrogen and halogen; and (ii) T-RC, wherein T is a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O— or —S(O)2—; and RC is (C1-C6)alkyl or a 5- to 6-membered carbocyclic, quinazoline, pyridine, oxazole, pyrazine, piperazinyl, pyrimidinyl, morpholinyl, each of which is optionally substituted with from 1 to 3 substituents independently selected from hydroxyl, halogen, cyano, (C1-C6)alkyl and halo(C1-C6)alkyl.
- 10. A compound according to claim 1, wherein Q is a bond, —O— or —NRB—.
- 11. A compound according to claim 1, wherein G is hydrogen or (C1-C6) alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C5-C7)cycloalkyl, (C5-C7)cycloalkyl(C1-C6)alkyl, quinazoline, pyridine, oxazole, pyrazine, piperazinyl, pyrimidinyl, morpholinyl, each of which is optionally substituted with from 1 to 5 substituents independently selected from hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, halogen, amino, cyano and nitro.
- 12. A compound according to claim 1, wherein:RD is independently selected at each occurrence from hydrogen, (C1-C6)alkyl and (C5-C7)cycloalkyl; U is a bond, —O—, —C(═O)—, —CHRD— or —NRD—; and M is: hydrogen; or (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl or a 3- to 10-membered carbocyclic, quinazoline, pyridine, oxazole, pyrazine, piperazinyl, pyrimidinyl, morpholinyl, each of which is optionally substituted with from 1 to 5 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy and halo(C1-C6)alkoxy.
- 13. A compound according to claim 1, wherein at least two of V, W, Y and Z are CR1, and wherein:L is a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O— or —NRB—; RB is hydrogen, (C1-C8)alkyl or (C3-C8)cycloalkyl; Q is a bond; and G is hydrogen.
- 14. A compound according to claim 1, wherein RC is selected from phenyl, oxazolyl, piperazinyl, pyrimidinyl, pyrazinyl, and morpholinyl, each of which is substituted with from 0 to 2 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy and halo(C1-C6)alkoxy.
- 15. A compound according to claim 6, wherein R2 and R3 are independently selected at each occurrence from:trifluoromethoxy, trifluoromethyl, trifluorosulfonyl, hydrogen, halogen, hydroxy, nitro, cyano, amino, haloalkyl, and —COOH; and benzoyl, benzhydryl, phenoxy, benzyloxy, phenyl, oxazolyl, piperazinyl, pyrimidinyl, pyrazinyl, and morpholinyl, each of which is substituted with from 0 to 2 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy and halo(C1-C6) alkoxy.
- 16. A compound according to claim 6, wherein:R1 is independently selected at each occurrence from hydrogen, hydroxy, halogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy and halo(C1-C6)alkoxy; R2 is selected from hydrogen, hydroxy, halogen, (C1-C6)alkyl, halo(C1-C6) alkyl, (C1-C6)alkoxy and halo(C1-C6)alkoxy; and R3 is selected from hydroxy, halogen, cyano, and (C1-C6)alkyl, (C5-C7) cycloalkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6) alkanoyloxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkylaminocarbonyl, (C1-C6) carbamate, (C1-C6) alkylsulfonyl, oxazolyl, pyridinyl, pyrazinyl, phenyl, benzyl, phenoxy, benzyloxy and benzoyl, wherein each is optionally substituted with from 1 to 3 substituents independently selected from hydroxy, halogen, (C1-C6)alkyl, halo(C1-C6) alkyl, (C1-C6)alkoxy and halo(C1-C6) alkoxy.
- 17. A compound according to claim 6, wherein:R1 is independently selected at each occurrence from hydrogen, hydroxy, halogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy and halo(C1-C6)alkoxy; R2 is selected from hydroxy, halogen, cyano, and (C1-C6)alkyl, (C5-C7) cycloalkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6) alkanoyloxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkylaminocarbonyl, (C1-C6) carbamate, (C1-C6) lkylsulfonyl, oxazolyl, pyrimidinyl, pyridinyl, pyrazinyl, phenyl, benzyl, phenoxy, benzyloxy and benzoyl, wherein each is optionally substituted with from 1 to 3 substituents independently selected from hydroxy, halogen, (C1-C6)alkyl, halo(C1-C6) alkyl, (C1-C6) alkoxy and halo(C1-C6)alkoxy; and R3 is selected from hydrogen, hydroxy, halogen, (C1-C6)alkyl, halo(C1-C6) alkyl, (C1-C6)alkoxy and halo(C1-C6)alkoxy.
- 18. A compound according to claim 1, wherein:V, W, Y and Z are all CR1, and R1 is independently selected at each occurrence from hydrogen, halogen, (C1-C6)alkyl, halo(C1-C6)alkyl and (C1-C6)alkoxy; A and D are CR1, wherein R1 is independently selected at each occurrence from hydrogen, halogen, (C1-C6)alkyl, halo(C1-C6)alkyl and (C1-C6)alkoxy; and B and E are CR2 and CR3, respectively, wherein R2 and R3 are independently selected from: (i) hydrogen, halogen and cyano; and (ii) (C1-C6)alkyl, (C3-C7)cycloalkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6) alkylaminocarbonyl, (C1-C6)alkylsulfonyl, oxazolyl, pyrimidinyl, pyridinyl, pyrazinyl, phenyl, benzyl, phenoxy, benzyloxy and benzoyl, wherein each is optionally substituted with 1 to 3 substituents selected from halogen and (C1-C6)alkyl.
- 19. A compound according to claim 1, wherein the compound is selected from:1′-(7-chloro-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(5-n-propylsulfonyl-1H benzimidazol-2-yl) spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(5-cyano-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(5-acetyl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(5-carboxy-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one, methyl ester; 1′-(5′pyrazin-2-yl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-pipendin]-3-one; 1′-(5′pyridin-3-yl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(5-trifluoromethoxy-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(5-methyl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(5-benzoyl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(5-methoxy-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(5-chloro-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(5-fluoro-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(5-methyl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(5-methylsulfonyl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(5-oxazol-2-yl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(5,6-difluoro-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(5-trifluoromethyl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(5,7-dichloro-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(5,6-dimethoxy-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(5-trifluoromethylsulfonyl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(5-(3,5-dimethyl-isoxazol-4-yl)-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; 1′-(5-ethoxy-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one; and.
- 20. A compound according to claim 1, wherein the compound exhibits a Ki of 1 micromolar or less in an NPY5 receptor ligand binding assay.
- 21. A compound according to claim 1, wherein the compound exhibits a Ki of 100 nanomolar or less in an NPY5 receptor ligand binding assay.
- 22. A compound according to claim 1, wherein the compound exhibits a Ki of 10 nanomolar or less in an NPY5 receptor ligand binding assay.
- 23. A pharmaceutical composition comprising a compound according to claim 1, in combination with a physiologically acceptable carrier or excipient.
Parent Case Info
This application claims benefit of Provisional Appln No. 60/254,990 filed Dec. 12, 2000.
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Provisional Applications (1)
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Number |
Date |
Country |
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60/254990 |
Dec 2000 |
US |