Claims
- 1) A compound of the formula
- 2. A compound of the formula
- 3. A compound or salt according to claim 1 of the formula:
- 4. A compound or salt according to claim 1 of the formula:
- 5. A compound or salt according to claim 4 wherein
R1 is hydrogen, halogen, C1-C2alkyl or C1-C2alkoxy; Ra is selected from hydrogen, halogen, C1-C6 alkyl, C1 C6alkoxy, haloalkyl, haloalkoxy, hydroxy C1-C6alkyl, mono- or di-(C1-C6)alkylamino, mono- or di-(C1-C6) alkyl3amino(C1-C6)alkyl where each alkyl3 may be substituted by mono- or di-(C1-C6)alkylamino, heterocycloalkyl(C1-C6)alkyl, heterocycloalkyl(C1-C6)alkylamino, and heterocycloalkyl which may be substituted by C1-C6alkyl; Rb is selected from hydrogen, halogen, hydroxy, methyl, and ethyl, and W is phenyl, pyridyl, thienyl, or pyrimidinyl, each of which is substituted with Rd, Rd′, and Rd″, where Rd, Rd′, and Rd″ are independently selected from hydrogen, halogen, hydroxy, haloalkyl, haloalkoxy di(C1-C6)alkylamino(C1-C6)alkoxy, C1-C6 alkyl, C1-C6 alkoxy, mono- or di-(C1-C6)alkylamino, C1-C6 alkylamino (C1-C6)alkoxy, C3-C7 cycloalkylamino(C1-C6)alkoxy, and heteroaryl(C1-C6)alkoxy.
- 6. A compound or salt of claim 5 wherein Rd, Rd′, and Rd are independently hydrogen, fluorine or hydroxyl.
- 7. A compound or salt according to claim 5, wherein W is phenyl carrying Rd, Rd′, and Rd″ where one of Rd, Rd′, and Rd″ is hydrogen and the other two are independently hydrogen, haloalkyl, haloalkoxy C1-C6 alkyl, C1-C6 alkoxy, mono- or di-(C1-C6)alkylamino, C1-C6 alkylamino(C1-C6)alkoxy, C3-C7 cycloalkylamino(C1-C6)alkoxy, or heteroaryl(C1-C6)alkoxy.
- 8. A compound or salt of claim 7 wherein Ra is hydrogen, hydroxy(C1-C6)alkyl, 4-(C1-C6)alkyl-[1,4]diazepan-1-yl(C1-C6)alkyl, 4-(C1-C6)alkyl-piperazin-1-yl(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkyl((C1-C6)alkyl)amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkylamino(C1-C6)alkyl, or pyrrolidin-1-yl or piperidin-1-yl(C1-C6)alkylamino (C1-C6)alkyl.
- 9. A compound or salt according to claim 1 of the formula:
- 10. A compound or salt of claim 7 wherein Ra is hydroxymethyl.
- 11. A compound or salt according to claim 1 of the formula:
- 12. A compound or salt according to claim 1 of the formula:
- 13. A compound or salt according to claim 1 of the formula:
- 14. A compound or salt according to claim 1 of the formula:
- 15. A compound or salt according to claim 1 of the formula:
- 16. A compound or salt according to claim 1 of the formula:
- 17. A compound or salt according to claim 4 wherein Rb is hydrogen; and W is phenyl or thienyl each of which is substituted with Rd, Rd′, and Rd″ where Rd, Rd′, and Rd″ are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, haloalkyl, haloalkoxy, hydroxy, amino, and C1-C6 alkyl substituted with 0-2 R6, C1-C6 alkoxy substituted with 0-2 R6, —NH(C1-6 alkyl) substituted with 0-2 R6, —N(C1-C6 alkyl)(C1-C6 alkyl) wherein each alkyl is independently substituted with 0-2 R6, —XR7, and Y;
X at each occurrence is independently selected from the group consisting of —CH2—, —CHR8—, —O—, —NH—, and —NR8—; R6 at each occurrence is independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)(C1-C6 alkyl), —NH—(C1-C6 alkyl-Y), —N(C1-C6 alkyl)-(C1-C6 alkyl-Y), —NH—(C1-C6 alkyl-N(C1-C6 alkyl)(C1-C6 alkyl)), —N(C1-C6 alkyl)-(C1-C6 alkyl-N(C1-C6 alkyl)(C1-C6 alkyl)), morpholinyl, pyrrolidinyl, piperidinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, —S(O)m(C1-C6 alkyl), haloalkyl, haloalkoxy, —CO(C1-C6 alkyl), —CONH(C1-C6 alkyl), CON(C1-C6 alkyl)(C1-C6 alkyl), —XR7, and Y; wherein
m is 0, 1, or 2; R7 and R8 at each occurrence are independently C1-C8 alkyl, wherein R7 and R8 are substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of oxo, hydroxy, halogen, amino, cyano, nitro, haloalkyl, haloalkoxy, C1-C6 alkoxy, —NH(C1-C6 alkyl), and —N(C1-C6 alkyl)(C1-C6 alkyl); and Y at each occurrence is independently selected from 5- to 8-membered carbocycles or heterocycles, which are saturated, partially unsaturated, or aromatic and contain zero, one or two heteroatom(s) selected from N, O, and S, and which carbocycles or heterocycles may be further substituted with one or more substituents selected from halogen, oxo, hydroxy, amino, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, and mono- or di C1-C6 alkylamino.
- 18. A compound or salt according to claim 17 wherein Ra and Rb are hydrogen or Ra is hydroxymethyl and Rb is hydrogen.
- 19. A compound according to claim 1, which selected from
1-[[2-(2-Fluoro-4-hydroxyphenyl)-4-quinolinyl]carbonyl]pyrrolidine; 1-[[6-Fluoro-2-(4-fluorophenyl)-4-quinolinyl]carbonyl]-pyrrolidine; 1-[[6-Fluoro-2-(3,4-difluorophenyl)-4-quinolinyl]carbonyl]-pyrrolidine; 1-[[2-(4-Fluorophenyl)-4-quinolinyl]carbonyl]pyrrolidine; and 1-[[2-(2,4-Difluorophenyl)-4-quinolinyl]carbonyl]pyrrolidine; and the pharmaceutically acceptable salts thereof.
- 20. A compound according to claim 1, which is selected from 1-[[2-(3-Chloro-4-fluorophenyl)-4-quinolinyl]carbonyl]pyrrolidine;
1-[[6-Fluoro-2-(3-thienyl)-4-quinolinyl]carbonyl]-pyrrolidine; 1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]pyrrolidine; 1-[[2-(2-Fluorophenyl)-4-quinolinyl]carbonyl]-pyrrolidine; 1-[[(6-Fluoro-2-phenyl)-4-quinolinyl]carbonyl]pyrrolidine; 1-[[2-[3-(3-n-propylamino-1-propoxy)phenyl]-4-quinolinyl]carbonyl]pyrrolidine; 1-[[2-(2,5-Difluorophenyl)-4-quinolinyl]carbonyl]pyrrolidine; 1-[[2-[3-(3-cyclopropylamino-1-propoxy)phenyl]-4-quinolinyl]carbonyl]pyrrolidine; 1-[[2-(3-Hydroxyphenyl)-4-quinolinyl]carbonyl]pyrrolidine; 1-[[(6-Chloro-2-phenyl)-4-quinolinyl]carbonyl]pyrrolidine; 1-[[2-[4-(3-n-propylamino-1-propoxy)phenyl]-4-quinolinyl]carbonyl]pyrrolidine; and 1-[[6-Chloro-2-(2-fluorophenyl)-4-quinolinyl]carbonyl]pyrrolidine; and the pharmaceutically acceptable salts thereof.
- 21. A compound according to claim 1, which is selected from
1-[[2-[3-(2-n-Propylamino-1-ethoxy)phenyl]-4-quinolinyl]carbonyl]pyrrolidine; 1-[[2-[4-(3-Ethylamino-1-propoxy)phenyl]-4-quinolinyl]carbonyl]pyrrolidine; 1-[[2-[4-(3-n-Butylamino-1-propoxy)phenyl]-4-quinolinyl]carbonyl]pyrrolidine; 1-[[2-(3-Fluoro-4-hydroxyphenyl)-4-quinolinyl]carbonyl]pyrrolidine; 1-[[2-[3-(2-Methylamino-1-ethoxy)phenyl]-4-quinolinyl]carbonyl]pyrrolidine; 1-[[2-(2-Fluoro-4-methoxyphenyl)-4-quinolinyl]carbonyl]pyrrolidine; 1-[[2-[3-(3-N-Pyrrolidinyl-1-propoxy)phenyl]-4-quinolinyl]carbonyl]pyrrolidine; 1-[[2-(3-Methoxyphenyl)-4-quinolinyl]carbonyl]pyrrolidine; 1-[[2-[4-(3-i-propylamino-1-propoxy)phenyl]-4-quinolinyl]carbonyl]pyrrolidine; and 1-[[2-[3-(2-Imdazolyl-1-ethoxy)phenyl]-4-quinolinyl]carbonyl]-pyrrolidine; and the pharmaceutically acceptable salts thereof.
- 22. A compound according to claim 1, which is selected from
1-[[2-(3-Fluoro-4-methoxyphenyl)-4-quinolinyl]carbonyl]pyrrolidine; 1-[[2-(2-Methylphenyl)-4-quinolinyl]carbonyl]-pyrrolidine; 1-[[2-[4-(3-piperidinylamino-1-propoxy)phenyl]-4-quinolinyl]carbonyl]pyrrolidine; 1-[[2-(4-(3-Diethylamino-1-propoxy)phenyl]-4-quinolinyl]carbonyl]pyrrolidine; (R)-1-[[6-Fluoro-2-(4-fluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; (R)-1-[[2-(4-Fluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (R)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; (R)-1-[(6-Chloro-2-phenyl-4-quinolinyl)carbonyl]-2-hydroxymethylpyrrolidine; and (R)-1-[[2-(3-Chloro-4-fluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; and the pharmaceutically acceptable salts thereof.
- 23. A compound according to claim 1, which is selected from
(R)-1-[[6-Fluoro-2-(3,4-difluorophenyl)-4-quinolinyl)carbonyl]-2-hydroxymethylpyrrolidine; (R)-1-[[2-(4-Methoxyphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; (R)-1-[[6-Fluoro-2-(4-fluorophenyl)-4-quinolinyl)carbonyl]-2-hydroxymethyl-pyrrolidine; (R)-1-[[2-(3-Methoxyphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (R)-1-[(6-Fluoro-2-phenyl-4-quinolinyl)carbonyl]-2-hydroxymethyl-pyrrolidine; (R)-1-[[2-(2-Fluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (R)-1-[[2-(2-Methylphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (R)-1-[[6-Fluoro-2-(2-fluorophenyl)-4-quinolinyl)carbonyl]-2-hydroxymethyl-pyrrolidine; (R)-1-[[6-Fluoro-2-(3-thienyl)-4-quinolinyl)carbonyl]-2-hydroxymethyl-pyrrolidine; and (R)-1-[[2-Phenyl-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; and the pharmaceutically acceptable salts thereof.
- 24. A compound according to claim 1, which is selected from
(R)-1-[[2-(2-Fluoro-4-hydroxyphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (R)-1-[[2-(2,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (R)-1-([2-(2-Fluoro-4-ethoxyphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (R)-1-[[2-(2,6-Difluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (R)-1-[[6-Bromo-2-phenyl-4-quinolinyl)carbonyl]-2-hydroxymethyl-pyrrolidine; (R)-1-[[2-[2-Fluoro-4-(3-bromo-1-propoxy)phenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (R)-1-[[2-(2-Fluoro-4-methoxyphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; (R)-1-[[2-(2,5-Difluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; (R)-1-[[6-Methoxy-2-phenyl-4-quinolinyl)carbonyl]-2-hydroxymethylpyrrolidine; (R)-1-[[6-Chloro-2-(2-fluoro-4-methoxyphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; (R)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(2-diethylamino-1-ethyl-1-methyl-aminomethyl)pyrrolidine; and (R)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(N-ethylpiperazinyl)methyl)pyrrolidine; and the pharmaceutically acceptable salts thereof.
- 25. A compound according to claim 1, which is selected from
(R)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(2-diethylamino-1-ethyl-1-ethyl-aminomethyl)pyrrolidine; (R)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(2-diethylaminoethyl)-aminomethyl)pyrrolidine; (R)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(2-dimethylamino-1-ethyl-1-methyl-aminomethyl)pyrrolidine; (R)-1-[[2-(4-Fluorophenyl)-4-quinolinyl]carbonyl]-2-(2-dimethylaminoethyl)aminomethyl)pyrrolidine; (R)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(N-methylhomopiperazinyl)methyl)pyrrolidine; (R)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(N-methylpiperazinyl)methyl)pyrrolidine; (R)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(N-piperidinylethylaminomethyl)pyrrolidine; (R)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(N-pyrrolidinylethylaminomethyl)pyrrolidine; (R)-1-[(2-phenyl-4-quinolinyl)carbonyl]-2-hydroxymethyl pyrrolidine; and 1-[[2-(4-Fluorophenyl)-4-quinolinyl]carbonyl]-3-hydroxy-pyrrolidine; and the pharmaceutically acceptable salts thereof.
- 26. A compound according to claim 1, which is selected from
1-[(2-phenylthieno[3,2-b]pyridyl)carbonyl]-pyrrolidine; (R)-1-[(2-phenylthieno[3,2-b]pyridyl)carbonyl]-2-hydroxymethyl-pyrrolidine; and 1-[(2-phenyl-1,6-naphthyridinyl)carbonyl]-pyrrolidine; and the pharmaceutically acceptable salts thereof.
- 27. A compound according to claim 1, which is selected from
(S)-1-[[6-Fluoro-2-(4-fluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; (S)-1-[[2-(4-Fluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (S)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; (S)-1-[(6-Chloro-2-phenyl-4-quinolinyl)carbonyl]-2-hydroxymethylpyrrolidine; and (S)-i-[[2-(3-Chloro-4-fluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; and the pharmaceutically acceptable salts thereof.
- 28. A compound according to claim 1, which is selected from
(S)-1-[[6-Fluoro-2-(3,4-difluorophenyl)-4-quinolinyl)carbonyl]-2-hydroxymethylpyrrolidine; (S)-1-[[2-(4-Methoxyphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; (S)-1-[[6-Fluoro-2-(4-fluorophenyl)-4-quinolinyl)carbonyl]-2-hydroxymethyl-pyrrolidine; (S)-1-[[2-(3-Methoxyphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (S)-1-[(6-Fluoro-2-phenyl-4-quinolinyl)carbonyl]-2-hydroxymethyl-pyrrolidine; (S)-1-[[2-(2-Fluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (S)-1-[(2-(2-Methylphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (S)-1-[(6-Fluoro-2-(2-fluorophenyl)-4-quinolinyl)carbonyl]-2-hydroxymethyl-pyrrolidine; (S)-1-([6-Fluoro-2-(3-thienyl)-4-quinolinyl)carbonyl]-2-hydroxymethyl-pyrrolidine; and (S)-1-[[2-Phenyl-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; and the pharmaceutically acceptable salts thereof.
- 29. A compound according to claim 1, which is selected from
(-S)-1-[[2-(2-Fluoro-4-hydroxyphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (S)-1-[[2-(2,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (S)-1-[[2-(2-Fluoro-4-ethoxyphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (S)-1-[[2-(2,6-Difluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (S)-1-[[6-Bromo-2-phenyl-4-quinolinyl)carbonyl]-2-hydroxymethyl-pyrrolidine; (S)-1-[[2-[2-Fluoro-4-(3-bromo-1-propoxy)phenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (S)-1-[[2-(2-Fluoro-4-methoxyphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; (S)-1-[[2-(2,5-Difluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; (S)-1-[[6-Methoxy-2-phenyl-4-quinolinyl)carbonyl]-2-hydroxymethylpyrrolidine; (S)-1-[[6-Chloro-2-(2-fluoro-4-methoxyphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; (S)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(2-diethylamino-1-ethyl-1-methyl-aminomethyl)pyrrolidine; and (S)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(N-ethylpiperazinyl)methyl)pyrrolidine; and the pharmaceutically acceptable salts thereof.
- 30. A compound according to claim 1, which is selected from (S)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(2-diethylamino-1-ethyl-1-ethyl-aminomethyl)pyrrolidine;
(S)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(2-diethylaminoethyl)-aminomethyl)pyrrolidine; (S)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(2-dimethylamino-1-ethyl-1-methyl-aminomethyl)pyrrolidine; (S)-1-[[2-(4-Fluorophenyl)-4-quinolinyl]carbonyl]-2-(2-dimethylaminoethyl)aminomethyl)pyrrolidine; (S)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(N-methylhomopiperazinyl)methyl)pyrrolidine; (S)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(N-methylpiperazinyl)methyl)pyrrolidine; (S)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(N-piperidinylethylaminomethyl)pyrrolidine; (S)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(N-pyrrolidinylethylaminomethyl)pyrrolidine; (S)-1-[(2-phenyl-4-quinolinyl)carbonyl]-2-hydroxymethyl pyrrolidine; and (S)-1-[(2-phenylthieno[3,2-b]pyridyl)carbonyl]-2-hydroxymethyl-pyrrolidine; and the pharmaceutically acceptable salts thereof.
- 31. A compound according to claim 1, which is selected from
(±)-1-[[6-Fluoro-2-(4-fluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; (±)-1-[[2-(4-Fluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (±)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; (±)-1-[(6-Chloro-2-phenyl-4-quinolinyl)carbonyl]-2-hydroxymethylpyrrolidine; and (±)-1-[[2-(3-Chloro-4-fluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; and the pharmaceutically acceptable salts thereof.
- 32. A compound according to claim 1, which is selected from
(±)-1-[[6-Fluoro-2-(3,4-difluorophenyl)-4-quinolinyl)carbonyl]-2-hydroxymethylpyrrolidine; (±)-1-[[2-(4-Methoxyphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; (±)-1-[[6-Fluoro-2-(4-fluorophenyl)-4-quinolinyl)carbonyl]-2-hydroxymethyl-pyrrolidine; (±)-1-[[2-(3-Methoxyphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (±)-1-[(6-Fluoro-2-phenyl-4-quinolinyl)carbonyl]-2-hydroxymethyl-pyrrolidine; (±)-1-[[2-(2-Fluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (±)-1-[[2-(2-Methylphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (±)-1-[[6-Fluoro-2-(2-fluorophenyl)-4-quinolinyl)carbonyl]-2-hydroxymethyl-pyrrolidine; (±)-1-[[6-Fluoro-2-(3-thienyl)-4-quinolinyl)carbonyl]-2-hydroxymethyl-pyrrolidine; and (±)-1-[[2-Phenyl-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; and the pharmaceutically acceptable salts thereof.
- 33. A compound according to claim 1, which is selected from
(±)-1-[[2-(2-Fluoro-4-hydroxyphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (±)-1-[[2-(2,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (±)-1-[(2-(2-Fluoro-4-ethoxyphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (±)-1-[[2-(2,6-Difluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (±)-1-[[6-Bromo-2-phenyl-4-quinolinyl)carbonyl]-2-hydroxymethyl-pyrrolidine; (±)-1-[[2-[2-Fluoro-4-(3-bromo-1-propoxy)phenyl)-4-quinolinyl]carbonyl]-2-hydroxymethyl-pyrrolidine; (±)-1-[[2-(2-Fluoro-4-methoxyphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; (±)-1-[[2-(2,5-Difluorophenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; (±)-1-[[6-Methoxy-2-phenyl-4-quinolinyl)carbonyl]-2-hydroxymethylpyrrolidine; (±)-1-[[6-Chloro-2-(2-fluoro-4-methoxyphenyl)-4-quinolinyl]carbonyl]-2-hydroxymethylpyrrolidine; (±)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(2-diethylamino-1-ethyl-1-methyl-aminomethyl)pyrrolidine; and (±)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(N-ethylpiperazinyl)methyl)pyrrolidine; and the pharmaceutically acceptable salts thereof.
- 34. A compound according to claim 1, which is selected from (±)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(2-diethylamino-1-ethyl-1-ethyl-aminomethyl)pyrrolidine;
(±)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(2-diethylaminoethyl)-aminomethyl)pyrrolidine; (±)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(2-dimethylamino-1-ethyl-1-methyl-aminomethyl)pyrrolidine; (±)-1-[[2-(4-Fluorophenyl)-4-quinolinyl]carbonyl]-2-(2-dimethylaminoethyl)aminomethyl)pyrrolidine; (±)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(N-methylhomopiperazinyl)methyl)pyrrolidine; (±)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(N-methylpiperazinyl)methyl)pyrrolidine; (±)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(N-piperidinylethylaminomethyl)pyrrolidine; (±)-1-[[2-(3,4-Difluorophenyl)-4-quinolinyl]carbonyl]-2-(N-pyrrolidinylethylaminomethyl)pyrrolidine; (±)-1-[(2-phenyl-4-quinolinyl)carbonyl]-2-hydroxymethyl pyrrolidine; and (±)-1-[(2-phenylthieno[3,2-b]pyridyl)carbonyl]-2-hydroxymethyl-pyrrolidine; and the pharmaceutically acceptable salts thereof.
- 35. A compound according to claim 1 for use in therapeutic treatment of a disease or disorder associated with pathogenic agonism, inverse agonism or antagonism of the GABAA receptor.
- 36. A pharmaceutical composition comprising a compound or salt according to claim 1 combined with at least one pharmaceutically acceptable carrier or excipient.
- 37. A method for the treatment of a disease or disorder associated with pathogenic agonism, inverse agonism or antagonism of the GABAA receptor, said method comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a compound or salt of claim 1.
- 38. A method according to claim 32 wherein the disease or disorder associated with pathogenic agonism, inverse agonism or antagonism of the GABAA receptor is anxiety, depression, a sleep disorder, or cognitive impairment.
- 39. The use of a compound or salt according to claim 1 for the manufacture of a medicament for the treatment of a disease or disorder associated with pathogenic agonism, inverse agonism or antagonism of the GABAA receptor.
- 40. The use of a compound or salt according to claim 1 for the manufacture of a medicament for the treatment of anxiety, depression, sleep disorders, or cognitive impairment.
- 41. A method for localizing GABAA receptors in a tissue sample comprising:
contacting with the sample a detectably-labeled compound or salt of claim 1 under conditions that permit binding of the compound to GABAA receptors, washing the sample to remove unbound compound, and detecting the bound compound.
- 42. A method of inhibiting the binding of a benzodiazepine compound to a GABAA receptor, said method comprising contacting a compound or salt of claim 1 with cells expressing such a receptor in the presence of the benzodiazepine, wherein the compound is present at a concentration sufficient to inhibit the binding a benzodiazepine compound to a GABAA receptor in vitro.
- 43. A method for altering the signal-transducing activity of GABAA receptors, said method comprising exposing cells expressing such receptors to a compound or salt according to claim 1 at a concentration sufficient to inhibit RO15-1788 binding to cells expressing a cloned human GABAA receptor in vitro.
- 44. A packaged pharmaceutical composition comprising the pharmaceutical composition of claim 30 in a container and instructions for using the composition to treat a patient suffering from a disorder responsive to agonism, inverse agonism or antagonism of the GABAA receptor.
- 45. The packaged pharmaceutical composition of claim 39, wherein said patient is suffering from anxiety, depression, a sleep disorder, or cognitive impairment.
- 46. A compound or salt according to claim 1 wherein in a assay of GABAA receptor binding the compound exhibits an IC50 of 1 micromolar or less.
- 47. A compound or salt according to claim 1 wherein in a assay of GABAA receptor binding the compound exhibits an IC50 of 100 nanomolar or less.
- 48. A compound or salt according to claim 1 wherein in a assay of GABAA receptor binding the compound exhibits an IC50 of 10 nanomolar or less.
- 49. A compound or salt according to claim 1 of the formula:
- 50. A compound or salt according to claim 1 of the formula:
- 51. A compound or salt according to claim 1 of the formula:
- 52. A compound or salt of claim 7 wherein Ra is hydrogen, hydroxymethyl, [(2-diethylamino-ethyl)-methyl-amino]methyl, or [(2-Diethylamino-ethyl)-methyl-amino]methyl.
- 53. A compound or salt according to claim 5, wherein W is phenyl carrying Rd, Rd′, and Rd″ where one of Rd, Rd′, and Rd″ is hydrogen and the other two are independently hydrogen, halogen, hydroxy, C1-C6 alkylamino(C1-C6)alkoxy, C1-C6 or alkoxy.
- 54. A method for preparing a compound of claim 1.
Parent Case Info
[0001] This application claims priority from U.S. Provisional Application Ser. No. 60/225,552, filed Aug. 16, 2000.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60225552 |
Aug 2000 |
US |
Continuations (1)
|
Number |
Date |
Country |
Parent |
09931549 |
Aug 2001 |
US |
Child |
10429107 |
May 2003 |
US |