NOVEL SULFONES AND THEIR USE AS NEUROPROTECTIVE AND/OR NEURORESTORATIVE AGENTS
20260042770 · 2026-02-12
Assignee
Inventors
- Delphine Charvin (Gex, FR)
- Serge Mignani (Chatenay-Malabry, FR)
- Frédéric MIEGE (LYON, FR)
- Vincent Rodeschini (Mions, FR)
- Yves RIBEILL (DURHAM, NC, US)
Cpc classification
C07D295/10
CHEMISTRY; METALLURGY
A61P25/28
HUMAN NECESSITIES
C07D405/12
CHEMISTRY; METALLURGY
A61K31/496
HUMAN NECESSITIES
C07D413/12
CHEMISTRY; METALLURGY
A61P35/00
HUMAN NECESSITIES
International classification
A61K31/496
HUMAN NECESSITIES
A61K31/4995
HUMAN NECESSITIES
Abstract
A compound of general formula (I)
##STR00001## or a pharmaceutically acceptable salt and/or solvate thereof, and the process for manufacturing the compound of general formula (I). Also, a pharmaceutical composition that includes a compound of general formula (I), and the use of compounds of general formula (I) as neuroprotective and/or neurorestorative agents, in particular for use in the treatment of neurological disorders.
Claims
1-15. (canceled)
16. A compound of formula (I) ##STR00131## or a pharmaceutically acceptable salt and/or solvate thereof; wherein: W represents CH or N; R.sup.A, R.sup.B, R.sup.C and R.sup.D each independently represents hydrogen, F, Cl, CH.sub.3, CF.sub.3, CHF.sub.2, or CH.sub.2F, provided that at least one among R.sup.A, R.sup.B, R.sup.C and R.sup.D does not represent hydrogen; R.sup.1 represents hydrogen or (C.sub.1-C.sub.8) alkyl, wherein the alkyl is optionally substituted by at least one OH, (C.sub.1-C.sub.3) alkoxy, or F; and R.sup.2, R.sup.3 and R.sup.4 represents hydrogen; or R.sup.1 and R.sup.4 form together CH.sub.2OCH.sub.2 or CH.sub.2CH.sub.2, wherein the CH.sub.2CH.sub.2 is optionally substituted by at least one F, OH, or OCH.sub.3; and R.sup.2 and R.sup.3 each represents hydrogen; R.sup.7 represents hydrogen, OH, halogen, (C.sub.1-C.sub.8) alkyl, cycloalkyl, (C.sub.1-C.sub.8) alkyl-O, cycloalkyl-O, cycloalkyl-(C.sub.1-C.sub.8) alkyl-O, heterocycloalkyl-O, R.sup.11O(C.sub.1-C.sub.8) alkyl-O, R.sup.11R.sup.12N(C.sub.1-C.sub.8) alkyl-O, (R.sup.11O)(R.sup.12)N(C.sub.1-C.sub.8) alkyl-O, R.sup.11R.sup.12N(C.sub.1-C.sub.8) alkyl-, R.sup.11O(C.sub.1-C.sub.8) alkyl-, NR.sup.11R.sup.12, CN, CO.sub.2H, CO.sub.2R.sup.11, CONH.sub.2, CON(R.sup.11)H, heterocycloalkyl, or heteroaryl; wherein R.sup.11 and R.sup.12 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; wherein the alkyl or cycloalkyl in R.sup.7 is optionally substituted by at least one F, Cl, OH, O, (C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8) alkyl-O, heterocycloalkyl, aryl, or heteroaryl; wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, (C.sub.1-C.sub.8) alkyl, CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3, CN, OH, O, .fwdarw.O, (C.sub.1-C.sub.8) alkoxy, NR.sup.13R.sup.14, R.sup.13R.sup.14N(C.sub.1-C.sub.8) alkyl-, R.sup.13O.sub.2C(C.sub.1-C.sub.8) alkyl-, CO.sub.2H, R.sup.13R.sup.14NC(O), R.sup.13ONR.sup.14, or (C.sub.1-C.sub.8) alkyl-CO.sub.2; wherein R.sup.13 and R.sup.14 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; Z represents CH, CR.sup.8 or N; wherein R.sup.8 represents (C.sub.1-C.sub.4) alkyl, F, Cl, CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3, CN, OH, or (C.sub.1-C.sub.4) alkoxy; or Z represents CR.sup.8 and R.sup.7 and R.sup.8 form together with the carbon atoms to which they are bound a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by at least one F, OH, O, .fwdarw.O, (C.sub.1-C.sub.8) alkyl, CF.sub.3, HO.sub.2CCH.sub.2, (C.sub.1-C.sub.4) alkyl-CO.sub.2CH.sub.2, R.sup.15R.sup.16NCH.sub.2, aryl, or aryl-(C.sub.1-C.sub.8) alkyl-, wherein R.sup.15 and R.sup.16 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; R.sup.5 represents hydrogen, (C.sub.1-C.sub.8) alkyl, CH.sub.3 substituted by one to three (C.sub.1-C.sub.8) alkyl groups, cycloalkyl, heterocycloalkyl, aryl, or cycloalkyl-(C.sub.1-C.sub.8) alkyl; wherein the alkyl or cycloalkyl in R.sup.5 is optionally substituted by at least one F, Cl, (C.sub.1-C.sub.8) alkyl, CF.sub.3, OCF.sub.3, CN, OH, O, (C.sub.1-C.sub.8) alkoxy, NR.sup.17R.sup.18, CO.sub.2H, R.sup.17R.sup.18NC(O), R.sup.17ONR.sup.18, heterocycloalkyl, aryl, or heteroaryl; wherein R.sup.17 and R.sup.18 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; and wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, (C.sub.1-C.sub.8) alkyl, CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3, CN, OH, O, .fwdarw.O, (C.sub.1-C.sub.8) alkoxy, NR.sup.19R.sup.20, CO.sub.2H, R.sup.19R.sup.20NC(O), R.sup.19ONR.sup.20, (C.sub.1-C.sub.8) alkyl-CO.sub.2, R.sup.19R.sup.20N(C.sub.1-C.sub.8) alkyl-, R.sup.19O.sub.2C(C.sub.1-C.sub.8) alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl-(C.sub.1-C.sub.8) alkyl-; wherein R.sup.19 and R.sup.20 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; R.sup.6 represents hydrogen, (C.sub.1-C.sub.8) alkyl, CH.sub.3 substituted by one to three (C.sub.1-C.sub.8) alkyl groups, cycloalkyl, heterocycloalkyl, aryl, or cycloalkyl-(C.sub.1-C.sub.8) alkyl; wherein the alkyl or cycloalkyl in R.sup.6 is optionally substituted by at least one F, Cl, (C.sub.1-C.sub.8) alkyl, CF.sub.3, OCF.sub.3, CN, OH, O, (C.sub.1-C.sub.8) alkoxy, NR.sup.21R.sup.22, CO.sub.2H, R.sup.21R.sup.22NC(O), R.sup.21ONR.sup.22, heterocycloalkyl, aryl, or heteroaryl; wherein R.sup.21 and R.sup.22 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; and wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, (C.sub.1-C.sub.8) alkyl, CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3, CN, OH, O, .fwdarw.O, (C.sub.1-C.sub.8) alkoxy, NR.sup.23R.sup.24, CO.sub.2H, R.sup.23R.sup.24NC(O), R.sup.23ONR.sup.24, (C.sub.1-C.sub.8) alkyl-CO.sub.2, R.sup.23R.sup.24N(C.sub.1-C.sub.8) alkyl-, R.sup.23O.sub.2C(C.sub.1-C.sub.8) alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl-(C.sub.1-C.sub.8) alkyl-; wherein R.sup.23 and R.sup.24 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; or R.sup.5 and R.sup.6 form together with the carbon atom to which they are bound a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by at least one F, Cl, (C.sub.1-C.sub.8) alkyl, CF.sub.3, OCF.sub.3, CN, OH, O, .fwdarw.O, (C.sub.1-C.sub.8) alkoxy, NR.sup.25R.sup.26, CO.sub.2H, (C.sub.1-C.sub.8) alkyl-CO.sub.2, R.sup.25R.sup.26NC(O), R.sup.21ONR.sup.26, R.sup.25R.sup.26N(C.sub.1-C.sub.8) alkyl-, R.sup.21O.sub.2C(C.sub.1-C.sub.8) alkyl-, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C.sub.1-C.sub.8) alkyl-, heterocycloalkyl-(C.sub.1-C.sub.8) alkyl-, aryl-(C.sub.1-C.sub.8) alkyl-, heteroaryl-(C.sub.1-C.sub.8) alkyl-, aryl-cycloalkyl-, cycloalkyl-O, heterocycloalkyl-O, aryl-O, heteroaryl-O, cycloalkyl-(C.sub.1-C.sub.8) alkyl-O, heterocycloalkyl-(C.sub.1-C.sub.8) alkyl-O, aryl-(C.sub.1-C.sub.8) alkyl-O, heteroaryl-(C.sub.1-C.sub.8) alkyl-O, cycloalkyl-NR.sup.25, heterocycloalkyl-NR.sup.25, aryl-NR.sup.25, heteroaryl-NR.sup.25, cycloalkyl-(C.sub.1-C.sub.8) alkyl-NR.sup.25, heterocycloalkyl-(C.sub.1-C.sub.8) alkyl-NR.sup.25, aryl-(C.sub.1-C.sub.8) alkyl-NR.sup.25, heteroaryl-(C.sub.1-C.sub.8) alkyl-NR.sup.25, benzylidene, heteroarylidene, aryl-(C.sub.1-C.sub.8) alkyl-ylidene-, or heteroaryl-(C.sub.1-C.sub.8) alkyl-ylidene-; wherein R.sup.25 and R.sup.26 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; and wherein the heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylidene is optionally substituted at least one F, Cl, (C.sub.1-C.sub.8) alkyl, CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3, CN, OH, O, .fwdarw.O, (C.sub.1-C.sub.8) alkoxy, NR.sup.27R.sup.28, CO.sub.2H, R.sup.27R.sup.28NC(O), R.sup.27ONR.sup.28, (C.sub.1-C.sub.8) alkyl-CO.sub.2, R.sup.27R.sup.28N(C.sub.1-C.sub.8) alkyl-, R.sup.27O.sub.2C(C.sub.1-C.sub.8) alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl-(C.sub.1-C.sub.8) alkyl-; wherein R.sup.27 and R.sup.28 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; and R.sup.9 represents hydrogen, (C.sub.1-C.sub.8) alkyl, CH.sub.3 substituted by one to three (C.sub.1-C.sub.8) alkyl groups, cycloalkyl, heterocycloalkyl, aryl, or cycloalkyl-(C.sub.1-C.sub.8) alkyl; wherein the alkyl or cycloalkyl in R.sup.9 is optionally substituted by at least one F, Cl, (C.sub.1-C.sub.8) alkyl, CF.sub.3, OCF.sub.3, CN, OH, O, (C.sub.1-C.sub.8) alkoxy, NR.sup.29R.sup.30, CO.sub.2H, R.sup.29R.sup.30NC(O), R.sup.29ONR.sup.30, heterocycloalkyl, aryl, or heteroaryl; wherein R.sup.29 and R.sup.30 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; and wherein the heterocycloalkyl, aryl, or heteroaryl is optionally substituted by at least one F, Cl, (C.sub.1-C.sub.8) alkyl, CF.sub.3, OCF.sub.3, CN, OH, O, .fwdarw.O, (C.sub.1-C.sub.8) alkoxy, NR.sup.31R.sup.32, CO.sub.2H, R.sup.31R.sup.32NC(O), R.sup.31ONR.sup.32, (C.sub.1-C.sub.8) alkyl-CO.sub.2, R.sup.23R.sup.24N(C.sub.1-C.sub.8) alkyl-, R.sup.23O.sub.2C(C.sub.1-C.sub.8) alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl-(C.sub.1-C.sub.8) alkyl-; wherein R.sup.31 and R.sup.32 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl.
17. The compound according to claim 16, wherein at least one among R.sup.A, R.sup.B, R.sup.C and R.sup.D represents hydrogen.
18. The compound according to claim 17, wherein at least one among R.sup.A and R.sup.C represents hydrogen.
19. The compound according to claim 16, wherein at least one among R.sup.A, R.sup.B and R.sup.D represents F or Cl.
20. The compound according to claim 19, wherein at least one among R.sup.B and R.sup.D represents F or Cl.
21. The compound according to claim 20, wherein R.sup.B and R.sup.D each independently represents F or Cl.
22. The compound according to claim 16, wherein R.sup.1 and R.sup.4 form together CH.sub.2OCH.sub.2.
23. The compound according to claim 16, wherein R.sup.1 and R.sup.4 form together CH.sub.2CH.sub.2, wherein the CH.sub.2CH.sub.2 is optionally substituted by at least one F, OH, or OCH.sub.3.
24. The compound according to claim 16, wherein R.sup.1 represents methyl, ethyl, CF.sub.3, or CH.sub.3OCH.sub.2.
25. The compound according to claim 16, wherein R.sup.7 represents hydrogen, OH, or halogen; or wherein R.sup.7 represents (C.sub.1-C.sub.8) alkyl-O or cycloalkyl-O, wherein the alkyl or cycloalkyl is optionally substituted by at least one F, Cl, OH, (C.sub.1-C.sub.8) alkoxy, or aryl.
26. The compound according to claim 25, wherein R.sup.7 represents OH, Cl, OCH.sub.3, or HOCH.sub.2CH.sub.2O.
27. The compound according to claim 16, wherein R.sup.5 and R.sup.6 each independently represents (C.sub.1-C.sub.8) alkyl or aryl-(C.sub.1-C.sub.8) alkyl-, and R.sup.9 represents hydrogen.
28. The compound according to claim 27, wherein R.sup.5 and R.sup.6 each independently represents methyl, ethyl, n-propyl, 2-phenylethyl-, or 3-phenylpropyl-.
29. The compound according to claim 16, wherein R.sup.6 represents (C.sub.1-C.sub.8) alkyl, cycloalkyl-(C.sub.1-C.sub.8)-alkyl, or aryl, and R.sup.5 and R.sup.9 each represents hydrogen.
30. The compound according to claim 29, wherein R.sup.6 represents i-propyl, n-propyl, tert-butyl, i-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl-CH.sub.2, or phenyl.
31. The compound according to claim 16, wherein R.sup.5 and R.sup.6 form together with the carbon atom to which they are bound a cycloalkyl or heterocycloalkyl, and R.sup.9 represents hydrogen.
32. The compound according to claim 16, wherein R.sup.5 and R.sup.6 form together with the carbon atom to which they are bound a cyclobutyl, cyclopentyl, cyclohexyl, oxetane, 1-phenyl-4-piperidyl, 1-(2-phenylethyl)-4-piperidyl, or 1-[2-(4-fluorophenyl)ethyl]-4-piperidyl, and R.sup.9 represents hydrogen.
33. The compound according to claim 16, wherein said compound is selected from the group consisting of: TABLE-US-00007 001 [4-[5-(1-ethylpropylsulfonyl)-2-methoxy-phenyl]piperazin- 1-yl]-[4-fluoro-2-(trifluoromethyl)phenyl]methanone 002 [4-(5-cyclopentylsulfonyl-2-methoxy-phenyl)piperazin-1- yl]-[4-fluoro-2-(trifluoromethyl)phenyl]methanone 003 [4-(5-cyclohexylsulfonyl-2-methoxy-phenyl)piperazin-1- yl]-[4-fluoro-2-(trifluoromethyl)phenyl]methanone 004 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-(5- cyclopentylsulfonyl-2-methoxy-phenyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 005 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-(1- ethylpropylsulfonyl)-2-methoxy-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 006 (2-chloro-4-fluoro-phenyl)-[rac-(3S)-4-(5- cyclopentylsulfonyl-2-methoxy-phenyl)-3-methyl-piperazin-1- yl]methanone 007 (2-chloro-4-fluoro-phenyl)-[rac-(3S)-4-[5-(1- ethylpropylsulfonyl)-2-methoxy-phenyl]-3-methyl-piperazin-1- yl]methanone 008 (2-chloro-4-fluoro-phenyl)-[4-(5-isopropylsulfonyl-2- methoxy-phenyl)piperazin-1-yl]methanone 009 (2-chloro-4-fluoro-phenyl)-[4-[5- (cyclopropylmethylsulfonyl)-2-methoxy-phenyl]piperazin-1- yl]methanone 010 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-(5- cyclobutylsulfonyl-2-methoxy-phenyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 011 (2-chloro-4-fluoro-phenyl)-[4-[2-methoxy-5-(oxetan-3- ylsulfonyl)phenyl]piperazin-1-yl]methanone 012 (2-chloro-4-fluoro-phenyl)-[4-[5- (cyclobutylmethylsulfonyl)-2-methoxy-phenyl]piperazin-1- yl]methanone 013 (2-chloro-4-fluoro-phenyl)-[4-[5- (cyclopentylmethylsulfonyl)-2-methoxy-phenyl]piperazin-1- yl]methanone 014 [(1S,5R)-8-(5-benzylsulfonyl-2-methoxy-phenyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro- phenyl)methanone 015 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-(2,2- dimethylpropylsulfonyl)-2-methoxy-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 016 (2-chloro-4-fluoro-phenyl)-[rac-(3S)-4-[2-methoxy-5-[rac- (1S)-1-methylpropyl]sulfonyl-phenyl]-3-methyl-piperazin-1- yl]methanone 017 [4-fluoro-2-(trifluoromethyl)phenyl]-[rac-(3S)-4-[2- methoxy-5-[rac-(1S)-1-methylpropyl]sulfonyl-phenyl]-3-methyl- piperazin-1-yl]methanone 018 [4-fluoro-2-(trifluoromethyl)phenyl]-[4-(5-isobutylsulfonyl- 2-methoxy-phenyl)piperazin-1-yl]methanone 019 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-(2- cyclopentylethylsulfonyl)-2-methoxy-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 020 [(1S,5R)-8-(5-butylsulfonyl-2-methoxy-phenyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro- phenyl)methanone 021 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-(2- ethylbutylsulfonyl)-2-methoxy-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 022 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[2-methoxy-5- [(1SR)-1-methylpropyl]sulfonyl-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 023 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[2-methoxy-5- [(1SR)-1-methyl-3-phenyl-propyl]sulfonyl-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 024 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[2-methoxy-5- [(1SR)-1-methyl-4-phenyl-butyl]sulfonyl-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 025 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-[(1SR)-1-ethyl-3- phenyl-propyl]sulfonyl-2-methoxy-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 026 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-[(1SR)-1-ethyl-4- phenyl-butyl]sulfonyl-2-methoxy-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 027 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[2-methoxy-5-[(1- phenyl-4-piperidyl)sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan- 3-yl]methanone 028 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[2-methoxy-5-[[1-(2- phenylethyl)-4-piperidyl]sulfonyl]phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 029 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-[[1-[2-(4- fluorophenyl)ethyl]-4-piperidyl]sulfonyl]-2-methoxy-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 030 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[2-hydroxy-5-[(1- phenyl-4-piperidyl)sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan- 3-yl]methanone 031 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[2-hydroxy-5-[[1-(2- phenylethyl)-4-piperidyl]sulfonyl]phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 032 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-(2,2- dimethylpropylsulfonyl)-2-hydroxy-3-methyl-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 033 [(1S,5R)-8-[3-chloro-5-(2,2-dimethylpropylsulfonyl)-2- hydroxy-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4- fluoro-phenyl)methanone 034 [(1S,5R)-8-[3-chloro-5-(2,2-dimethylpropylsulfonyl)-2-(2- hydroxyethoxy)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2- chloro-4-fluoro-phenyl)methanone 035 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[2,3-dichloro-5-(2,2- dimethylpropylsulfonyl)phenyl]-3,8-diazabicyclo[3.2.1]octan-3- yl]methanone 036 [(1S,5R)-8-[3-chloro-5-(2,2-dimethylpropylsulfonyl)-2- methyl-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4- fluoro-phenyl)methanone and pharmaceutically acceptable salts and/or solvates thereof.
34. A pharmaceutical composition comprising a compound according to claim 16 and at least one pharmaceutically acceptable carrier.
35. A process for manufacturing the compound according to claim 16, comprising a step of reacting: a compound of formula (II) ##STR00132## wherein: Z, R.sup.5, R.sup.6, R.sup.7 and R.sup.9 are as defined above, and X represents halide or CF.sub.3SO.sub.3, with a compound of formula (III) ##STR00133## wherein W, R.sup.A-R.sup.D and R.sup.1-R.sup.4 are as defined above, in presence of a base and a metal catalyst; thereby obtaining the compound of formula (I) or the pharmaceutically acceptable salt and/or solvate thereof.
Description
DETAILED DESCRIPTION
Compound
[0052] An object of the present invention is a compound of formula (I)
##STR00003## [0053] or a pharmaceutically acceptable salt and/or solvate thereof; [0054] wherein [0055] W represents CH or N; [0056] R.sup.A, R.sup.B, R.sup.C and R.sup.D each independently represents hydrogen, F, Cl, CH.sub.3, CF.sub.3, CHF.sub.2 or CH.sub.2F, [0057] provided that at least one among R.sup.A, R.sup.B, R.sup.C and R.sup.D does not represent hydrogen; [0058] R.sup.1 represents hydrogen or (C.sub.1-C.sub.8) alkyl, wherein the alkyl is optionally substituted by at least one OH, (C.sub.1-C.sub.3) alkoxy or F; and R.sup.2, R.sup.3 and R.sup.4 represents hydrogen; [0059] or R.sup.1 and R.sup.4 form together CH.sub.2OCH.sub.2 or CH.sub.2CH.sub.2, wherein the CH.sub.2CH.sub.2 is optionally substituted by at least one F, OH or OCH.sub.3; and R.sup.2 and R.sup.3 each represents hydrogen; [0060] R.sup.7 represents hydrogen, OH, halogen, (C.sub.1-C.sub.8) alkyl, cycloalkyl, (C.sub.1-C.sub.8) alkyl-O, cycloalkyl-O, cycloalkyl-(C.sub.1-C.sub.8) alkyl-O, heterocycloalkyl-O, R.sup.11O(C.sub.1-C.sub.8) alkyl-O, R.sup.11R.sup.12N(C.sub.1-C.sub.8)alkyl-O, (R.sup.11O)(R.sup.12)N(C.sub.1-C.sub.8)alkyl-O, R.sup.11R.sup.12N(C.sub.1-C.sub.8) alkyl-, R.sup.11O(C.sub.1-C.sub.8) alkyl-, NR.sup.11R.sup.12, CN, CO.sub.2H, CO.sub.2R.sup.11, CONH.sub.2, CON(R.sup.11)H, heterocycloalkyl, or heteroaryl; wherein R.sup.11 and R.sup.12 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; [0061] wherein the alkyl or cycloalkyl in R.sup.7 is optionally substituted by at least one F, Cl, OH, O, (C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8) alkyl-O, heterocycloalkyl, aryl or heteroaryl; [0062] wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, (C.sub.1-C.sub.8) alkyl, CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3, CN, OH, O, .fwdarw.O, (C.sub.1-C.sub.8) alkoxy, NR.sup.13R.sup.14, R.sup.13R.sup.14N(C.sub.1-C.sub.8) alkyl-, R.sup.13O.sub.2C(C.sub.1-C.sub.8) alkyl-, CO.sub.2H, R.sup.13R.sup.14NC(O), R.sup.13ONR.sup.14, or (C.sub.1-C.sub.8) alkyl-CO.sub.2; wherein R.sup.13 and R.sup.14 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; [0063] Z represents CH, CR.sup.8 or N; [0064] wherein R.sup.8 represents (C.sub.1-C.sub.4) alkyl, F, Cl, CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3, CN, OH or (C.sub.1-C.sub.4) alkoxy; [0065] or Z represents CR.sup.8 and R.sup.7 and R.sup.8 form together with the carbon atoms to which they are bound a cycloalkyl or heterocycloalkyl, [0066] wherein the cycloalkyl or heterocycloalkyl is optionally substituted by at least one F, OH, O, .fwdarw.O, (C.sub.1-C.sub.8) alkyl, CF.sub.3, HO.sub.2CCH.sub.2, (C.sub.1-C.sub.4) alkyl-CO.sub.2CH.sub.2, R.sup.15R.sup.16NCH.sub.2, aryl, or aryl-(C.sub.1-C.sub.8) alkyl-, wherein R.sup.15 and R.sup.16 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; [0067] R.sup.5 represents hydrogen, (C.sub.1-C.sub.8) alkyl, CH.sub.3 substituted by one to three (C.sub.1-C.sub.8) alkyl groups, cycloalkyl, heterocycloalkyl, aryl, or cycloalkyl-(C.sub.1-C.sub.8) alkyl; [0068] wherein the alkyl or cycloalkyl in R.sup.5 is optionally substituted by at least one F, Cl, (C.sub.1-C.sub.8) alkyl, CF.sub.3, OCF.sub.3, CN, OH, O, (C.sub.1-C.sub.8) alkoxy, NR.sup.17R.sup.18, CO.sub.2H, R.sup.17R.sup.18NC(O), R.sup.17ONR.sup.18, heterocycloalkyl, aryl or heteroaryl; wherein R.sup.17 and R.sup.18 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; [0069] wherein the heterocycloalkyl, aryl or heteroaryl (i.e., any heterocycloalkyl, aryl or heteroaryl that is represented by R.sup.5 or that is part of any substituent thereof) is optionally substituted by at least one F, Cl, (C.sub.1-C.sub.8) alkyl, CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3, CN, OH, O, .fwdarw.O, (C.sub.1-C.sub.8) alkoxy, NR.sup.19R.sup.20, CO.sub.2H, R.sup.19R.sup.20NC(O), R.sup.19ONR.sup.20, (C.sub.1-C.sub.8) alkyl-CO.sub.2, R.sup.19R.sup.20N(C.sub.1-C.sub.8) alkyl-, R.sup.19O.sub.2C(C.sub.1-C.sub.8) alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl-(C.sub.1-C.sub.8) alkyl-; wherein R.sup.19 and R.sup.20 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; [0070] R.sup.6 represents hydrogen, (C.sub.1-C.sub.8) alkyl, CH.sub.3 substituted by one to three (C.sub.1-C.sub.8) alkyl groups, cycloalkyl, heterocycloalkyl, aryl, or cycloalkyl-(C.sub.1-C.sub.8) alkyl; [0071] wherein the alkyl or cycloalkyl in R.sup.6 is optionally substituted by at least one F, Cl, (C.sub.1-C.sub.8) alkyl, CF.sub.3, OCF.sub.3, CN, OH, O, (C.sub.1-C.sub.8) alkoxy, NR.sup.21R.sup.22, CO.sub.2H, R.sup.21R.sup.22NC(O), R.sup.21ONR.sup.22, heterocycloalkyl, aryl or heteroaryl; wherein R.sup.21 and R.sup.22 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; [0072] wherein the heterocycloalkyl, aryl or heteroaryl (i.e., any heterocycloalkyl, aryl or heteroaryl that is represented by R.sup.6 or that is part of any substituent thereof) is optionally substituted by at least one F, Cl, (C.sub.1-C.sub.8) alkyl, CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3, CN, OH, O, .fwdarw.O, (C.sub.1-C.sub.8) alkoxy, NR.sup.23R.sup.24, CO.sub.2H, R.sup.23R.sup.24NC(O), R.sup.23ONR.sup.24, (C.sub.1-C.sub.8) alkyl-CO.sub.2, R.sup.23R.sup.24N(C.sub.1-C.sub.8) alkyl-, R.sup.23O.sub.2C(C.sub.1-C.sub.8) alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl-(C.sub.1-C.sub.8) alkyl-; wherein R.sup.23 and R.sup.24 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; [0073] or R.sup.5 and R.sup.6 form together with the carbon atom to which they are bound a cycloalkyl or heterocycloalkyl, [0074] wherein the cycloalkyl or heterocycloalkyl (i.e., the cycloalkyl or heterocycloalkyl that is formed by R.sup.5, R.sup.6 and the carbon atom to which they are bound) is optionally substituted by at least one F, Cl, (C.sub.1-C.sub.8) alkyl, CF.sub.3, OCF.sub.3, CN, OH, O, .fwdarw.O, (C.sub.1-C.sub.8) alkoxy, NR.sup.25R.sup.26, CO.sub.2H, (C.sub.1-C.sub.8) alkyl-CO.sub.2, R.sup.25R.sup.26NC(O), R.sup.25ONR.sup.26, R.sup.25R.sup.26N(C.sub.1-C.sub.8) alkyl-, R.sup.25O.sub.2C(C.sub.1-C.sub.8) alkyl-, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C.sub.1-C.sub.8) alkyl-, heterocycloalkyl-(C.sub.1-C.sub.8) alkyl-, aryl-(C.sub.1-C.sub.8) alkyl-, heteroaryl-(C.sub.1-C.sub.8) alkyl-, aryl-cycloalkyl-, cycloalkyl-O, heterocycloalkyl-O, aryl-O, heteroaryl-O, cycloalkyl-(C.sub.1-C.sub.8) alkyl-O, heterocycloalkyl-(C.sub.1-C.sub.8) alkyl-O, aryl-(C.sub.1-C.sub.8) alkyl-O, heteroaryl-(C.sub.1-C.sub.8) alkyl-O, cycloalkyl-NR.sup.25, heterocycloalkyl-NR.sup.25, aryl-NR.sup.25, heteroaryl-NR.sup.25, cycloalkyl-(C.sub.1-C.sub.8) alkyl-NR.sup.25, heterocycloalkyl-(C.sub.1-C.sub.8) alkyl-NR.sup.25, aryl-(C.sub.1-C.sub.8) alkyl-NR.sup.25, heteroaryl-(C.sub.1-C.sub.8) alkyl-NR.sup.25, benzylidene, heteroarylidene, aryl-(C.sub.1-C.sub.8) alkyl-ylidene- or heteroaryl-(C.sub.1-C.sub.8) alkyl-ylidene-; [0075] wherein R.sup.25 and R.sup.26 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; [0076] wherein the heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylidene (i.e., any heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylidene that is part of any substituent of the heterocycloalkyl formed by R.sup.5, R.sup.6 and the nitrogen atom to which they are bound) is optionally substituted at least one F, Cl, (C.sub.1-C.sub.8) alkyl, CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3, CN, OH, O, .fwdarw.O, (C.sub.1-C.sub.8) alkoxy, NR.sup.27R.sup.28, CO.sub.2H, R.sup.27R.sup.28NC(O), R.sup.27ONR.sup.28, (C.sub.1-C.sub.8) alkyl-CO.sub.2, R.sup.27R.sup.28N(C.sub.1-C.sub.8) alkyl-, R.sup.27O.sub.2C(C.sub.1-C.sub.8) alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl-(C.sub.1-C.sub.8) alkyl-; wherein R.sup.27 and R.sup.28 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; [0077] R.sup.9 represents hydrogen, (C.sub.1-C.sub.8) alkyl, CH.sub.3 substituted by one to three (C.sub.1-C.sub.8) alkyl groups, cycloalkyl, heterocycloalkyl, aryl, or cycloalkyl-(C.sub.1-C.sub.8) alkyl; [0078] wherein the alkyl or cycloalkyl in R.sup.9 is optionally substituted by at least one F, Cl, (C.sub.1-C.sub.8) alkyl, CF.sub.3, OCF.sub.3, CN, OH, O, (C.sub.1-C.sub.8) alkoxy, NR.sup.29R.sup.30, CO.sub.2H, R.sup.29R.sup.30NC(O), R.sup.29ONR.sup.30, heterocycloalkyl, aryl or heteroaryl; wherein R.sup.29 and R.sup.30 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; [0079] wherein the heterocycloalkyl, aryl or heteroaryl (i.e., any heterocycloalkyl, aryl or heteroaryl that is represented by R.sup.9 or that is part of any substituent thereof) is optionally substituted by at least one F, Cl, CF.sub.3, OCF.sub.3, CN, OH, O, .fwdarw.O, (C.sub.1-C.sub.8) alkoxy, NR.sup.31R.sup.32, CO.sub.2H, R.sup.31R.sup.32NC(O), R.sup.31ONR.sup.32, (C.sub.1-C.sub.8) alkyl-CO.sub.2, R.sup.23R.sup.24N(C.sub.1-C.sub.8) alkyl-, R.sup.23O.sub.2C(C.sub.1-C.sub.8) alkyl-, heterocycloalkyl, heteroaryl, aryl, or aryl-(C.sub.1-C.sub.8) alkyl-; wherein R.sup.31 and R.sup.32 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl.
[0080] In any one of the following embodiments directed to specific limitations to the structure of the compounds of formula (I), any alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylidene may independently be optionally substituted as indicated under formula (I) herein, unless otherwise specified.
[0081] According to one preferred embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof; wherein: [0082] W represents CH or N; [0083] R.sup.A, R.sup.B, R.sup.C and R.sup.D each independently represents hydrogen, F, Cl, CH.sub.3, CF.sub.3, CHF.sub.2 or CH.sub.2F, [0084] provided that at least one among R.sup.A, R.sup.B, R.sup.C and R.sup.D does not represent hydrogen; [0085] R.sup.1 represents hydrogen or (C.sub.1-C.sub.8) alkyl, wherein the alkyl is optionally substituted by at least one OH, (C.sub.1-C.sub.3) alkoxy or F; and R.sup.2, R.sup.3 and R.sup.4 represents hydrogen; [0086] or R.sup.1 and R.sup.4 form together CH.sub.2OCH.sub.2 or CH.sub.2CH.sub.2, wherein the CH.sub.2CH.sub.2 is optionally substituted by at least one F, OH or OCH.sub.3; and R.sup.2 and R.sup.3 each represents hydrogen; [0087] R.sup.7 represents hydrogen, OH, halogen, (C.sub.1-C.sub.8) alkyl, cycloalkyl, (C.sub.1-C.sub.8) alkyl-O, cycloalkyl-O, cycloalkyl-(C.sub.1-C.sub.8) alkyl-O, heterocycloalkyl-O, R.sup.11O(C.sub.1-C.sub.8) alkyl-O, R.sup.11R.sup.12N(C.sub.1-C.sub.8) alkyl-O or (R.sup.11O)(R.sup.12)N(C.sub.1-C.sub.8) alkyl-O; wherein R.sup.11 and R.sup.12 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; [0088] wherein the alkyl or cycloalkyl is optionally substituted by at least one F, Cl, heterocycloalkyl, aryl or heteroaryl; [0089] wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3, CN, OH, (C.sub.1-C.sub.8) alkoxy, NR.sup.13R.sup.14, CO.sub.2H, R.sup.13R.sup.14NC(O), or R.sup.13ONR.sup.14; wherein R.sup.13 and R.sup.14 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; [0090] Z represents CH or N; [0091] or Z represents CR.sup.8 and R.sup.7 and R.sup.8 form together with the carbon atoms to which they are bound a cycloalkyl or heterocycloalkyl, [0092] wherein the cycloalkyl or heterocycloalkyl is optionally substituted by at least one F, OH, CF.sub.3, HO.sub.2CCH.sub.2, (C.sub.1-C.sub.4) alkyl-CO.sub.2CH.sub.2, or R.sup.15R.sup.16NCH.sub.2, wherein R.sup.15 and R.sup.16 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; [0093] R.sup.5 represents hydrogen, (C.sub.1-C.sub.8) alkyl, CH.sub.3 substituted by one to three (C.sub.1-C.sub.8) alkyl groups, cycloalkyl or cycloalkyl-(C.sub.1-C.sub.8) alkyl; [0094] wherein the alkyl or cycloalkyl is optionally substituted by at least one F, Cl, CF.sub.3, OCF.sub.3, CN, OH, (C.sub.1-C.sub.8) alkoxy, NR.sup.17R.sup.18, CO.sub.2H, R.sup.17R.sup.18NC(O), R.sup.17ONR.sup.18, heterocycloalkyl, aryl or heteroaryl; wherein R.sup.17 and R.sup.18 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; [0095] wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3, CN, OH, (C.sub.1-C.sub.8) alkoxy, NR.sup.19R.sup.20, CO.sub.2H, R.sup.19R.sup.20NC(O), or R.sup.19ONR.sup.20; wherein R.sup.19 and R.sup.20 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; [0096] R.sup.6 represents hydrogen, (C.sub.1-C.sub.8) alkyl, CH.sub.3 substituted by one to three (C.sub.1-C.sub.8) alkyl groups, cycloalkyl or cycloalkyl-(C.sub.1-C.sub.8) alkyl; [0097] wherein the alkyl or cycloalkyl is optionally substituted by at least one F, Cl, CF.sub.3, OCF.sub.3, CN, OH, (C.sub.1-C.sub.8) alkoxy, NR.sup.21R.sup.22, CO.sub.2H, R.sup.21R.sup.22NC(O), R.sup.21ONR.sup.22, heterocycloalkyl, aryl or heteroaryl; wherein R.sup.21 and R.sup.22 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; [0098] wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3, CN, OH, (C.sub.1-C.sub.8) alkoxy, NR.sup.23R.sup.24, CO.sub.2H, R.sup.23R.sup.24NC(O), or R.sup.23ONR.sup.24; wherein R.sup.23 and R.sup.24 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; [0099] or R.sup.5 and R.sup.6 form together with the carbon atom to which they are bound a cycloalkyl or heterocycloalkyl, [0100] wherein the cycloalkyl or heterocycloalkyl is optionally substituted by at least one F, Cl, CF.sub.3, OCF.sub.3, CN, OH, (C.sub.1-C.sub.8) alkoxy, NR.sup.25R.sup.26, CO.sub.2H, R.sup.25R.sup.26NC(O), R.sup.25ONR.sup.26, heterocycloalkyl, aryl, heteroaryl, heterocycloalkyl-(C.sub.1-C.sub.8) alkyl-, aryl-(C.sub.1-C.sub.8) alkyl-, heteroaryl-(C.sub.1-C.sub.8) alkyl-, cycloalkyl-(C.sub.1-C.sub.8) alkyl-O, aryl-(C.sub.1-C.sub.8) alkyl-O, heteroaryl-(C.sub.1-C.sub.8) alkyl-O, cycloalkyl-(C.sub.1-C.sub.8) alkyl-NR.sup.25, aryl-(C.sub.1-C.sub.8) alkyl-NR.sup.25, heteroaryl-(C.sub.1-C.sub.8) alkyl-NR.sup.25, benzylidene, heteroarylidene, aryl-(C.sub.1-C.sub.8) alkyl-ylidene- or heteroaryl-(C.sub.1-C.sub.8) alkyl-ylidene-; [0101] wherein R.sup.25 and R.sup.26 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; [0102] wherein the heterocycloalkyl, aryl, heteroaryl, benzylidene or heteroarylidene is optionally substituted at least one F, Cl, CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3, CN, OH, (C.sub.1-C.sub.8) alkoxy, NR.sup.27R.sup.28, CO.sub.2H, R.sup.27R.sup.28NC(O), or R.sup.27ONR.sup.28; wherein R.sup.27 and R.sup.28 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; [0103] R.sup.9 represents hydrogen, (C.sub.1-C.sub.8) alkyl, CH.sub.3 substituted by one to three (C.sub.1-C.sub.8) alkyl groups, cycloalkyl or cycloalkyl-(C.sub.1-C.sub.8) alkyl; [0104] wherein the alkyl or cycloalkyl is optionally substituted by at least one F, Cl, CF.sub.3, OCF.sub.3, CN, OH, (C.sub.1-C.sub.8) alkoxy, NR.sup.29R.sup.30, CO.sub.2H, R.sup.29R.sup.30NC(O), R.sup.29ONR.sup.30, heterocycloalkyl, aryl or heteroaryl; wherein R.sup.29 and R.sup.30 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; [0105] wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted by at least one F, Cl, CF.sub.3, OCF.sub.3, CN, OH, (C.sub.1-C.sub.8) alkoxy, NR.sup.31R.sup.32, CO.sub.2H, R.sup.31R.sup.32NC(O), or R.sup.31ONR.sup.32; wherein R.sup.31 and R.sup.32 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl.
[0106] According to one embodiment, W represents CH.
[0107] According to one embodiment, at least one among R.sup.A, R.sup.B, R.sup.C and R.sup.D represents hydrogen. In one embodiment, exactly one among R.sup.A, R.sup.B, R.sup.C and R.sup.D represents hydrogen. In one embodiment, exactly two among R.sup.A, R.sup.B, R.sup.C and R.sup.D represents hydrogen. In one embodiment, exactly three among R.sup.A, R.sup.B, R.sup.C and R.sup.D represents hydrogen.
[0108] In one embodiment, at least one among R.sup.A and R.sup.C represents hydrogen. In one particular embodiment, R.sup.A represents hydrogen. In one particular embodiment, R.sup.C represents hydrogen.
[0109] According to one embodiment, at least one among R.sup.A, R.sup.B and R.sup.D represents F or Cl. In one embodiment, at least one among R.sup.B and R.sup.D represents F or Cl. In one particular embodiment, R.sup.B and R.sup.D each independently represents F or Cl. In one particular embodiment, R.sup.B represents F. In one particular embodiment, R.sup.B represents Cl. In one particular embodiment, R.sup.D represents F. In one particular embodiment, R.sup.D represents Cl. In one preferred embodiment, R.sup.B represents F. In one preferred embodiment, R.sup.D represents Cl. In one further preferred embodiment, R.sup.B represents F and R.sup.D represents Cl.
[0110] As defined under formula (I) hereinabove, R.sup.1 may represents (C.sub.1-C.sub.8) alkyl, wherein the alkyl is optionally substituted by at least one OH, (C.sub.1-C.sub.3) alkoxy or F, i.e., the (C.sub.1-C.sub.8) alkyl in R.sup.1 is optionally substituted by at least one group, and the group may be OH, (C.sub.1-C.sub.3) alkoxy or F. According to one embodiment, R.sup.1 represents (C.sub.1-C.sub.8) alkyl, wherein the alkyl is optionally substituted by at least one group selected from OH, (C.sub.1-C.sub.3) alkoxy and F.
[0111] According to one embodiment, R.sup.1 represents hydrogen or (C.sub.1-C.sub.8) alkyl, wherein the alkyl is optionally substituted by at least one OH, (C.sub.1-C.sub.3) alkoxy or F; and R.sup.2, R.sup.3 and R.sup.4 represents hydrogen. In one embodiment, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 represents hydrogen.
[0112] According to one embodiment, R.sup.1 and R.sup.4 form together CH.sub.2OCH.sub.2 or CH.sub.2CH.sub.2. In one embodiment, R.sup.1 and R.sup.4 form together CH.sub.2CH.sub.2. In one embodiment, the CH.sub.2CH.sub.2 is optionally substituted by at least one F, OH or OCH.sub.3. In one embodiment, the CH.sub.2CH.sub.2 is not substituted.
[0113] According to one embodiment, R.sup.1 represents methyl, ethyl, CF.sub.3 or methoxymethyl (CH.sub.3OCH.sub.2). In one embodiment, R.sup.1 represents methyl, ethyl or CF.sub.3. In one embodiment, R.sup.1 represents methoxymethyl (CH.sub.3OCH.sub.2).
[0114] According to one embodiment, R.sup.7 represents hydrogen, OH, halogen, (C.sub.1-C.sub.8) alkyl, cycloalkyl, (C.sub.1-C.sub.8) alkyl-O, cycloalkyl-O, cycloalkyl-(C.sub.1-C.sub.8) alkyl-O, heterocycloalkyl-O, R.sup.11O(C.sub.1-C.sub.8) alkyl-O, R.sup.11R.sup.12N(C.sub.1-C.sub.8) alkyl-O or (R.sup.11O)(R.sup.12)N(C.sub.1-C.sub.8) alkyl-O; wherein R.sup.11 and R.sup.12 each independently represents hydrogen or (C.sub.1-C.sub.8) alkyl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted as defined under formula (I) hereinabove.
[0115] According to one embodiment, R.sup.7 represents hydrogen, OH or halogen. In one embodiment, R.sup.7 represents hydrogen. In one preferred embodiment, R.sup.7 represents hydroxyl (OH). In one embodiment, R.sup.7 represents halogen. In one particular embodiment, R.sup.7 represents F or Cl. In one particular embodiment, R.sup.7 represents F. In one particular preferred embodiment, R.sup.7 represents Cl.
[0116] In one preferred embodiment, R.sup.7 does not represent hydrogen.
[0117] According to one embodiment, R.sup.7 represents (C.sub.1-C.sub.8) alkyl-O (i.e., (C.sub.1-C.sub.8) alkoxy), or cycloalkyl-O. In one embodiment, the alkyl or cycloalkyl is optionally substituted by at least one F, Cl, OH, (C.sub.1-C.sub.8) alkoxy or aryl. In one particular embodiment, R.sup.7 represents OCH.sub.3 (methoxy) or HOCH.sub.2CH.sub.2O.
[0118] According to one embodiment, R.sup.7 represents (C.sub.1-C.sub.8) alkyl-O (i.e., (C.sub.1-C.sub.8) alkoxy). In one embodiment, the alkyl is optionally substituted by at least one F or Cl. In one particular embodiment, the halogen is F. In one embodiment, R.sup.7 represents OCH.sub.3 (methoxy), OCH.sub.2CH.sub.3 or OCF.sub.3.
[0119] According to one embodiment, R.sup.7 represents cycloalkyl-O. In one embodiment, R.sup.7 represents cyclobutyl-O.
[0120] According to one embodiment, R.sup.7 represents (C.sub.1-C.sub.8) alkyl-O (i.e., (C.sub.1-C.sub.8) alkoxy), wherein the alkyl is optionally substituted by at least one OH or (C.sub.1-C.sub.8) alkoxy, i.e., RO(C.sub.1-C.sub.8) alkyl-O wherein R represents H or (C.sub.1-C.sub.8) alkyl. In one embodiment, R.sup.7 represents HOCH.sub.2CH.sub.2O or CH.sub.3OCH.sub.2CH.sub.2O.
[0121] According to one embodiment, R.sup.7 represents (C.sub.1-C.sub.8) alkyl-O (i.e., (C.sub.1-C.sub.8) alkoxy), wherein the alkyl is optionally substituted by at least one aryl. In one embodiment, the aryl is not substituted. In one embodiment, R.sup.7 represents phenyl-CH.sub.2O.
[0122] According to one embodiment, R.sup.7 represents (C.sub.1-C.sub.8) alkyl-O (i.e., (C.sub.1-C.sub.8) alkoxy), wherein the alkyl is optionally substituted by at least one heteroaryl. In one embodiment, the heteroaryl is not substituted. In one embodiment, R.sup.7 represents heteroaryl-CH.sub.2O.
[0123] According to one embodiment, R.sup.7 represents (C.sub.1-C.sub.8) alkyl-O (i.e., (C.sub.1-C.sub.8) alkoxy), wherein the alkyl is optionally substituted by at least one heterocycloalkyl. In one embodiment, R.sup.7 represents heterocycloalkyl-(C.sub.1-C.sub.8) alkyl-O, i.e., the alkyl is substituted by exactly one heterocycloalkyl. In one embodiment, the heterocycloalkyl is not substituted.
[0124] In one preferred embodiment, R.sup.7 represents Cl, OH, OCH.sub.3, HOCH.sub.2CH.sub.2O, CH.sub.3 (methyl).
[0125] According to one embodiment, Z represents CH or N; or Z represents CR.sup.8 and R.sup.7 and R.sup.8 form together with the carbon atoms to which they are bound a cycloalkyl or heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted as defined under formula (I) hereinabove. In other words, in this embodiment, R.sup.8 represent hydrogen, except where R.sup.7 and R.sup.8 form together with the carbon atoms to which they are bound a cycloalkyl or heterocycloalkyl.
[0126] According to one embodiment, Z represents CH or N. In one embodiment, Z represents CH. In one embodiment, Z represents N.
[0127] According to one preferred embodiment, Z represents CR.sup.8; wherein R.sup.8 represents (C.sub.1-C.sub.4) alkyl, F, Cl, CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3, CN, OH or (C.sub.1-C.sub.4) alkoxy. In one embodiment, R.sup.8 represents methyl, ethyl, F, Cl, CF.sub.3, CN or OH. In one preferred embodiment, R.sup.8 represents methyl or Cl.
[0128] According to another embodiment, Z represents CR.sup.8 and R.sup.7 and R.sup.8 form together with the carbon atoms to which they are bound a cycloalkyl or heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted as defined under formula (I) herein.
[0129] In one preferred embodiment, Z represents CR.sup.8 and R.sup.7 and R.sup.8 form together with the carbon atoms to which they are bound an heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted as defined under formula (I) herein.
[0130] According to one embodiment, R.sup.5 and R.sup.6 each independently represents (C.sub.1-C.sub.8) alkyl and R.sup.9 represents hydrogen. In one preferred embodiment, R.sup.5 and R.sup.6 each independently represents methyl or ethyl.
[0131] According to one preferred embodiment, R.sup.5 and R.sup.6 each independently represents (C.sub.1-C.sub.8) alkyl or aryl-(C.sub.1-C.sub.8) alkyl-. In one preferred embodiment, R.sup.5 and R.sup.6 each independently represents methyl, ethyl, n-propyl, 2-phenylethyl- or 3-phenylpropyl. In one further preferred embodiment, R.sup.9 represents hydrogen.
[0132] According to one embodiment, R.sup.6 represents (C.sub.1-C.sub.8) alkyl or aryl and R.sup.5 and R.sup.9 each represents hydrogen. In one embodiment, R.sup.6 represents propyl (e.g., isopropyl), tert-butyl or phenyl.
[0133] In one embodiment, R.sup.6 represents (C.sub.1-C.sub.8) alkyl and R.sup.5 and R.sup.9 each represents hydrogen. In one preferred embodiment, R.sup.6 represents propyl (e.g., isopropyl) or tert-butyl.
[0134] According to one preferred embodiment, R.sup.6 represents (C.sub.1-C.sub.8) alkyl, cycloalkyl-(C.sub.1-C.sub.8)-alkyl or aryl. In one preferred embodiment, R.sup.6 represents i-propyl, n-propyl, tert-butyl, i-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl-CH.sub.2 or phenyl. In one further preferred embodiment, R.sup.5 and/or R.sup.9 represents hydrogen.
[0135] According to one embodiment, R.sup.6 represents aryl and R.sup.5 and R.sup.9 each represents hydrogen. In one embodiment, R.sup.6 represents phenyl.
[0136] According to one embodiment, R.sup.5 represents hydrogen.
[0137] According to one embodiment, R.sup.5 represents (C.sub.1-C.sub.8) alkyl. In one embodiment, R.sup.5 represents methyl or ethyl.
[0138] According to one embodiment, R.sup.6 represents (C.sub.1-C.sub.8) alkyl. In one embodiment, R.sup.6 represents methyl or ethyl.
[0139] According to one embodiment, R.sup.6 represents aryl. In one embodiment, R.sup.6 represents phenyl.
[0140] According to one embodiment, R.sup.9 represents hydrogen or (C.sub.1-C.sub.8) alkyl. In one embodiment, R.sup.9 represents (C.sub.1-C.sub.8) alkyl. In one particular embodiment, R.sup.9 represents (C.sub.1-C.sub.4) alkyl. In one preferred embodiment, R.sup.9 represents hydrogen.
[0141] According to one embodiment, R.sup.5 and R.sup.6 form together with the carbon atom to which they are bound a cycloalkyl or heterocycloalkyl and R.sup.9 represents hydrogen. In one preferred embodiment, R.sup.5 and R.sup.6 form together with the carbon atom to which they are bound a cyclobutyl, cyclopentyl, cyclohexyl or oxetane.
[0142] In one preferred embodiment, R.sup.5 and R.sup.6 form together with the carbon atom to which they are bound a cyclobutyl, cyclopentyl, cyclohexyl, oxetane, 1-phenyl-4-piperidyl, 1-(2-phenylethyl)-4-piperidyl or 1-[2-(4-fluorophenyl)ethyl]-4-piperidyl.
[0143] According to one embodiment, R.sup.5 and R.sup.6 form together with the carbon atom to which they are bound a cycloalkyl. In one embodiment, R.sup.5 and R.sup.6 form together with the carbon atom to which they are bound a cyclobutyl, cyclopentyl or cyclohexyl.
[0144] According to one embodiment, R.sup.5 and R.sup.6 form together with the carbon atom to which they are bound a heterocycloalkyl. In one embodiment, R.sup.5 and R.sup.6 form together with the carbon atom to which they are bound an oxetane.
[0145] According to one embodiment, at least one heterocycloalkyl present in the compound of formula (I) is a water-solubilizing group, i.e., the presence of this group in the molecule increases the solubility thereof in water, compared with the same molecule not comprising the heterocycloalkyl.
[0146] According to one embodiment, the compound of formula (I) is a compound of formula (I-a)
##STR00004## [0147] or a pharmaceutically acceptable salt and/or solvate thereof; [0148] wherein W, R.sup.B, R.sup.D, Z, R.sup.1-R.sup.4 and R.sup.5-R.sup.7 are as defined under formula (I) herein.
[0149] In one embodiment, W in formula (I-a) represents CH.
[0150] In one embodiment, R.sup.B and R.sup.D in formula (I-a) each independently represents F or Cl. In one particular embodiment, R.sup.B represents F, R.sup.D represents Cl.
[0151] According to one embodiment, the compound of formula (I) is selected from the compounds of Table 1 below, and pharmaceutically acceptable salts and/or solvates thereof.
TABLE-US-00003 TABLE 1 Cpd Structure Name 001
[0152] All references herein to a compound of the invention (e.g., compound of formula (I)) include references to salts, solvates, multi component complexes and liquid crystals thereof. All references herein to a compound of the invention include references to polymorphs and crystal habits thereof. All references herein to a compound of the invention include references to isotopically-labelled compounds thereof, including deuterated compounds thereof. All references herein to a compound of the invention include references to stereoisomers thereof. All references herein to a compound of the invention include references to pharmaceutically acceptable prodrugs thereof.
[0153] In particular, the compounds of the invention may be in the form of pharmaceutically acceptable salts. According to one embodiment, the compound of the invention is a pharmaceutically acceptable salt.
[0154] Pharmaceutically acceptable salts include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinafoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)-morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. When a compound contains an acidic group as well as a basic group the compound may also form internal salts, and such compounds are within the scope of the invention. When a compound contains a hydrogen-donating heteroatom (e.g., NH), the invention also encompasses salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.
[0155] Pharmaceutically acceptable salts of compounds of the invention may be prepared by one or more of these methods: (i) by reacting the compound with the desired acid; (ii) by reacting the compound with the desired base; (iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound or by ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using the desired acid; and/or (iv) by converting one salt of the compound to another by reaction with an appropriate acid or by means of a suitable ion exchange column. All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.
[0156] In particular, the compounds of the invention may be in the form of pharmaceutically acceptable solvates. According to one embodiment, the compound of the invention is a pharmaceutically acceptable solvate. According to one embodiment, the compound of the invention is a pharmaceutically acceptable salt and solvate.
[0157] In particular, the compounds of the invention may include at least one asymmetric center(s) and thus may exist as different stereoisomeric forms. Accordingly, all references herein to a compound of the invention include all possible stereoisomers and include not only the racemic compounds, but the individual enantiomers and their non-racemic mixtures as well. Non-racemic mixtures may comprise any amounts of each distinct stereoisomer, for example one stereoisomer may be preponderant (e.g., a 90/10 or 80/20 mixture), or the enantiomeric ratio may be close to a racemic mixture (e.g., a 40/60 mixture). When a compound is desired as a single enantiomer, such single enantiomer may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be carried out by any suitable method known in the art.
Pharmaceutical Composition
[0158] Another object of the present invention is a composition comprising a compound according to the invention, as described herein. According to one embodiment, the composition further comprises at least one pharmaceutically acceptable carrier, so that the composition is a pharmaceutical composition as defined herein.
[0159] In a first embodiment, the pharmaceutical composition comprises the compound according to the invention as sole therapeutic agent. In a second embodiment, the pharmaceutical composition further comprises at least another therapeutic agent such as, for example, a therapeutic agent suitable for treating a neurological disorder.
[0160] Another object of the present invention is a medicament comprising a compound according to the invention, as described herein.
Kit
[0161] Another object of the present invention is a kit of parts (in short kit) comprising a compound or composition according to the invention, as described herein. According to one embodiment, the kit comprises a manufacture such as, for example, a package or a container. According to one embodiment, the kit comprises instructions for use. The kit may be promoted, distributed, or sold as a unit for performing the methods of the present invention.
[0162] According to one embodiment, the kit comprises: a pharmaceutical composition comprising the compound according to the invention, and another separate pharmaceutical composition comprising at least another therapeutic agent such as, for example, a therapeutic agent suitable for treating a neurological disorder.
Medical Use of the Compound
[0163] Another object of the present invention is a compound or a composition according to the invention, as described herein, for use as a medicament.
[0164] Another object of the present invention is a compound or a composition according to the invention, as described herein, for use in the treatment of a neurological disorder.
[0165] Another object of the present invention is a method for treating a neurological disorder in a subject in need thereof. Another object of the present invention is the use of a compound or a composition according to the invention, as described herein, in the manufacture of a medicament for the treatment of a neurological disorder. Another object of the present invention is the use of a compound or a composition according to the invention, as described herein, for treating a neurological disorder.
[0166] According to one embodiment, the method or the use comprises a step of administering to a subject a therapeutically effective amount of a compound, a composition or a medicament according to the invention, as described herein.
[0167] According to one embodiment, the neurological disorder to be treated by the method or the use of the invention is: [0168] a disease or a disorder associated with defective neurogenesis such as, for example, Hirschsprung disease, schizophrenia, Ataxia telangiectasia, age-related decline of nervous system performance, or a neurodevelopmental disorder; [0169] a neurodegenerative disease or disorder, such as, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Fronto-temporal dementia, retinal neurodegenerative diseases, neuro-ophthalmic diseases, neurotrophic keratitis, Charcot-Marie-Tooth disease, Spinal Muscular Atrophy, epilepsy (e.g., an epilepsy disorder, or a seizure disorder, or a chronic neurological disorder presenting with epilepsy), dementia, age-related decline of nervous system performance, a prion disease, Creutzfeldt-Jacob disease, Multiple System Atrophy (Shy Drager Syndrome), Multiple sclerosis, or Guillain-Barre syndrome; [0170] a disease or a disorder associated with nerve injury or neurotoxicity, such as, for example, head injury, brain damage, traumatic brain injury, peripheral nerve injury, traumatic peripheral nerve injury, peripheral neuropathy, nerve transplantation complications, spinal cord injury, traumatic spinal cord injury, severance of nerves or nerve damage, severance of cerebrospinal nerve cord, a damage to brain or nerve cells, syringomyelia, optic neuropathy, trauma, stroke, ischemia, stroke, ischemic stroke, neurotoxicity caused by alcohol or substance abuse (e.g., ecstasy, methamphetamine etc.), or aphasia; [0171] a neurodevelopmental disorder, such as, for example, Rett syndrome, X-linked mental retardation, fragile X syndrome, Down's syndrome, Autism Spectrum Disorder, Hirschsprung's disease, Tourette syndrome, childhood learning disorder, an attention deficit disorder, Attention Deficit Hyperactivity Disorder (ADHD), Angelman syndrome, micropreemie, schizophrenia, Language disorder, preterm birth, perinatal arterial ischemic stroke, spina bifida, mental retardation, nonsyndromic X-linked mental retardation, Ondine syndrome, or WAGR syndrome; [0172] a neuropsychiatric disorder such as, for example, depression, Major Depressive Disorder, schizophrenia, schizophrenic form disorder, schizoaffective disorder, delusional disorder, anxiety, anxiety disorders, panic disorder, phobias, an obsessive-compulsive disorder, a post-traumatic stress disorder, a bipolar disorder, anorexia nervosa, bulimia nervosa, anhedonia, apathy, dementia, substance-induced dementia, a motor and/or tic disorder characterized by motor and/or vocal tics (e.g., Tourette's disorder), a substance use behavior, addiction, mood disorders, suicidality, cancer-related psychiatric symptoms, Alzheimer's disease, Huntington's disease, Fronto-temporal dementia, or a reward deficiency syndrome (RDS); [0173] a movement disorder, such as, for example, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, a motor and tic disorder characterized by motor and/or vocal tics (e.g., Tourette's disorder), an ataxia, ataxias muscular rigidity (spasticity), Charcot-Marie-Tooth disease, Spinal Muscular Atrophy, Werdnig-Hoffmann disease, or chronic proximal spinal muscular atrophy; [0174] a pain disorder, such as, for example, neuralgia, trigeminal neuralgia, chronic pain, inflammatory pain, pain associated with arthritis, fibromyalgia, back pain, cancer-associated pain, pain associated with digestive disease, pain associated with Crohn's disease, pain associated with autoimmune disease, pain associated with endocrine disease, pain associated with diabetic neuropathy, phantom limb pain, spontaneous pain, chronic post-surgical pain, chronic, temporomandibular pain, causalgia, post-herpetic neuralgia, AIDS-related pain, complex regional pain syndromes type I and II, trigeminal neuralgia, chronic back pain, pain associated with spinal cord injury, pain associated with drug intake and recurrent acute pain, neuropathic pain, or inappropriate neuronal activity resulting in neurodysthesia in a disease such as diabetes, an MS and a motor neuron disease; [0175] an ophthalmic disease or an ocular disorder such as, for example, a retinal disorder, retinal neurodegenerative diseases, Retinitis Pigmentosa, Non-Arthritic Anterior Ischemic Optic Neuropathy (NAION), macular degeneration, age-related macular degeneration, glaucoma, diabetic retinopathy, optic neuropathy and retinal degeneration, neuro-ophthalmic diseases, age-related cataract, primary open-angle glaucoma (POAG), retinal ganglion cell damage, ocular hypertension, ischemic optic neuropathy, macular telangiectasia, cystoid macular edema, Macular Telangiectasia Type 2, neurotrophic keratitis, or strabismus; [0176] a disorder of the enteric system or a gastro-intestinal disorder, such as, for example, a disorder of intestinal motility, constipation, Hirschsprung's disease, Inflammatory Bowel Disease, Intestinal Neuronal Dysplasia, ulcerative colitis, Achalasia, Esophageal spasm, duodenal ulcer, Zollinger-Ellison Syndrome, hypersecretion of gastric acid, malabsorptive disorder or intestinal inflammation; [0177] a progressive muscular dystrophy, such as, for example, Duchenne, Becker, Emery-Dreifuss, Landowy-Dejerine, scapulohumeral, limb-girdle, Von Graefe-Fuchs, oculopharyngeal, myotonic and congenital, a congenital or acquired myopathy, Charcot-Marie-Tooth disease, Werdnig-Hoffmann disease, or chronic proximal spinal muscular atrophy; [0178] a disease or a disorder associated with defective long-term or short-term memory, such as, for example, memory loss, benign forgetfulness, or Alzheimer's disease; [0179] an autoimmune disorder such as, for example, multiple sclerosis, autoimmune encephalomyelitis, autoimmune encephalitis, autoimmune hemolytic anemia, chronic lymphocytic leukemia, Churg-Strauss syndrome, anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, Thyroid-associated orbitopathy, autoimmune thyroiditis, Guillain-Barr syndrome, or autoimmune thrombocytopenic purpura; [0180] a neuro-ontological disease or disorder such as, for example, cochlear sensory cell damage, defective auditory perception, hearing loss, or tinnitus; [0181] a sleep disorder, such as, for example, narcolepsy, restless leg syndrome, Obstructive sleep apnea, chronic insomnia disorder, paradoxical sleep deprivation or REM sleep deprivation; [0182] a cerebrovascular disease or a neurovascular disease, such as, for example, early brain injury (EBI) after subarachnoid hemorrhage (SAH), cerebral ischemia, stroke, hypoxic-ischemic brain injury, perinatal arterial ischemic stroke, or neovascular Age-related macular degeneration (nvAMD); [0183] a substance abuse disorder, such as, for example, substance dependence, substance abuse and the sequalae of substance abuse dependence, substance-induced psychological disorder, substance withdrawal and substance-induced dementia or amnestic disorder; [0184] a neuronal reaction to viral infection, Trypanosoma infection, a neurological deficit associated with AIDS, obesity, temporomandibular joint dysfunction, aphasia, Bell's palsy, encephalitis, a kidney disease or renal dysfunction, phaeochromocytoma, a metabolic syndrome, cancer, eczema, thrombocytopenia; hypoplasia; disseminated intravascular coagulation (DIC); myelodysplasia; immune thrombocytopenic purpura (ITP), HIV induced ITP, a neuro-oncological disease or disorder, neuro-immunological disease or disorder, multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), type I neurofibromatosis, Scleroderma, an epidermal and stromal wound healing disorder and/or a scarring disorder; or [0185] a disease or disorder associated with aging and/or senescence.
[0186] According to one embodiment, the neurological disorder is epilepsy, such as, for example, Dravet syndrome, benign Rolandic epilepsy, frontal lobe epilepsy, infantile spasms, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy, childhood absence epilepsy (e.g. pyknolepsy), febrile seizures, progressive myoclonus epilepsy of Lafora, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, Generalized Epilepsy with Febrile Seizures (GEFS+), Severe Myoclonic, Epilepsy of Infancy (SMEI), Benign Neonatal Familial Convulsions (BFNC), West Syndrome, Ohtahara Syndrome, early myoclonic encephalopathies, migrating partial epilepsy, infantile epileptic encephalopathies, Tuberous Sclerosis Complex (TSC), focal cortical dysplasia, Type I Lissencephaly, Miller-Dieker Syndrome, Angelman's syndrome, Fragile X syndrome, epilepsy in autism spectrum disorders, epilepsy in subcortical band heterotopia, epilepsy in Walker-Warburg syndrome, epilepsy in Alzheimer's disease, post-traumatic epilepsy, progressive myoclonus epilepsies, reflex epilepsy, Rasmussen's syndrome, temporal lobe epilepsy, limbic epilepsy, status epilepticus, abdominal epilepsy, massive bilateral myoclonus, catamenial epilepsy, Jacksonian seizure disorder, Unverricht-Lundborg disease, or photosensitive epilepsy.
[0187] According to one embodiment, the composition or the medicament according to the invention, as described herein, is to be administered to a subject, and may be formulated using methods well-known in the art. Non-limiting examples of forms adapted for administration include solutions (such as, for example, sterile aqueous solutions), gels, dispersions, emulsions, suspensions and solid forms suitable for using to prepare solutions or suspensions upon the addition of a liquid prior to use (such as, for example, powder or liposomal forms).
[0188] The composition or the medicament according to the invention, as described herein, may be administered using administration route well-known in the art such as, for example, parenterally, orally, by inhalation, spray, rectally, nasally, or via an implanted reservoir.
[0189] It will be however understood that the total daily usage of the compound, the composition or the medicament will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disease being treated and the severity of the disease; activity of the compound employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific therapeutic agent employed; the duration of the treatment; drugs used in combination or coincidental with the specific therapeutic agent employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. The total dose required for each treatment may be administered by multiple doses or in a single dose.
[0190] In one embodiment, the dosage of the compound is about 0.01 to 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be about 0.05 to 0.5, about 0.5 to 5 or about 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing from about 1.0 to 1000 milligrams of the active ingredient, particularly about 1.0, about 5.0, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0, and about 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
[0191] According to a first embodiment, the composition or the medicament according to the invention, as described herein, is to be administered as sole therapeutic agent. According to a second embodiment, the composition or the medicament according to the invention, as described herein, is to be administered before at least another therapeutic agent, concomitantly with at least another therapeutic agent, and/or after at least another therapeutic agent. In one embodiment, the other therapeutic agent is suitable for treating a neurological disorder.
[0192] Another object of the present invention is a method of promoting neuronal cell's survival and/or neuronal cell's functions. Another object of the present invention is a compound or a composition according to the invention, as described herein, for use in promoting neuronal cell's survival and/or neuronal cell's functions. According to one embodiment, the method or the use comprises a step of contacting a neuronal cell with a therapeutically effective amount of a compound, a composition or a medicament according to the invention, as described herein. The method or the use may be in vitro, ex vivo or in vivo.
[0193] Another object of the present invention is a method of rescuing neuronal cell's functions after the neuronal cell has been subjected to insults, events, or conditions detrimental to neuronal cell's functions. Another object of the present invention is a compound or a composition according to the invention, as described herein, for use in rescuing neuronal cell's functions after the neuronal cell has been subjected to insults, events, or conditions detrimental to neuronal cell's functions. Such insults, events, or conditions include, without limitation, neuronal stress, for instance, caused by hypoxia or ischemia; traumatic injuries; and exposure to toxic molecules, for instance, to abnormal misfolded proteins, protein aggregates, excitotoxins, reactive oxygen species, endoplasmic reticulum stressors, mitochondrial stressors, Golgi apparatus antagonists and the like. According to one embodiment, the method or the use comprises a step of contacting a neuronal cell with a therapeutically effective amount of a compound, a composition or a medicament according to the invention, as described herein. The method or the use may be in vitro, ex vivo or in vivo.
[0194] Another object of the present invention is a method of binding or modulating GFR1 using a compound or a composition according to the invention, as described herein. Another object of the present invention is a compound or a composition according to the invention, as described herein, for binding or modulating GFR1. According to one preferred embodiment, the compound or a composition is for activating GFR1. In one embodiment, GFR1 is human GFR1, preferably with SEQ ID NO: 1.
[0195] Another object of the present invention is a method of activating the GFR1/RET signaling pathway using a compound or a composition according to the invention, as described herein. Another object of the present invention is a compound or a composition according to the invention, as described herein, for activating the GFR1/RET signaling pathway.
[0196] Another object of the present invention is a method of detecting GFR1 in a sample, using a compound or a composition according to the invention, as described herein. Another object of the present invention is a compound or a composition according to the invention, as described herein, for detecting GFR1 in a sample. In one embodiment, GFR1 is human GFR1, preferably with SEQ ID NO: 1. In one embodiment, the compound according to the invention may be fused to a detectable label, such as, e.g., a fluorophore or any other moiety that can re-emit light upon light excitation, a radiolabel, a contrast agent and the like.
Manufacturing Process
Synthesis of the compound
[0197] The compound according to the invention, as described herein, may be manufactured by means of synthetic methods well-known in the art.
[0198] Another object of the present invention is a process for manufacturing a compound of the invention, as described herein. According to one embodiment, the process is a Buchwald-Hartwig amination.
[0199] According to one embodiment, the process comprises a step of reaction of: [0200] a compound of formula (II)
##STR00041## [0201] wherein Z, R.sup.5, R.sup.6, R.sup.7 and R.sup.9 are as defined under formula (I) herein and X represents halide or CF.sub.3SO.sub.3, [0202] with a compound of formula (III)
##STR00042## [0203] wherein W, R.sup.A-R.sup.D and R.sup.1-R.sup.4 are as defined under formula (I) herein, [0204] in presence of a base and a metal catalyst; thereby obtaining the compound of the invention.
[0205] In one embodiment, the base is cesium carbonate (Cs.sub.2CO.sub.3), sodium carbonate (Na.sub.2CO.sub.3) or potassium carbonate (K.sub.2CO.sub.3). In one particular embodiment, the base is cesium carbonate (Cs.sub.2CO.sub.3). In one embodiment, the base is sodium tert-butanoate (t-BuONa), potassium tert-butanoate (t-BuOK) or potassium phosphate. In one particular embodiment, the base is sodium tert-butanoate (t-BuONa).
[0206] In one embodiment, the catalyst is a palladium catalyst. In one particular embodiment, the catalyst is a Pd(OAc).sub.2 and rac-BINAP (2,2-bis(diphenylphosphino)-1,1-binaphtyle) system. In one particular embodiment, the catalyst is XPhos-Pd-G3.
[0207] In one embodiment, X represents halide. In one particular embodiment, X represents Br.
[0208] In one embodiment, the reaction is carried out in a solvent. In one particular embodiment, the solvent is toluene. In one embodiment, the reaction is carried out at reflux.
[0209] According to another embodiment, the process comprises: [0210] (a-1) a step of reaction of [0211] a compound of formula (II)
##STR00043## [0212] wherein Z, R.sup.5, R.sup.6, R.sup.7 and R.sup.9 are as defined under formula (I) herein and X represents halide or CF.sub.3SO.sub.3, [0213] with a mono-protected piperazine (i.e., a piperazine wherein only one of the NH groups is protected by means of a protecting group R.sup.P) of the following formula (MPP),
##STR00044## [0214] wherein R.sup.1-R.sup.4 are as defined under formula (I) herein; [0215] in presence of a base and a metal catalyst; [0216] thereby obtaining a compound of formula (IV)
##STR00045## [0217] wherein Z, R.sup.1-R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.9 are as defined under formula (I) herein and R.sup.P is the protecting group; then [0218] (a-2) a step of deprotection of the compound of formula (IV); [0219] thereby obtaining a compound of formula (V)
##STR00046## [0220] wherein Z, R.sup.1-R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.9 are as defined under formula (I) herein; and [0221] (a-3) a step of reaction of the compound of formula (V) with a compound of formula (VI)
##STR00047## [0222] wherein W and R.sup.A-R.sup.D are as defined under formula (I) herein, [0223] in presence of a peptide coupling agent and a base; [0224] thereby obtaining the compound of the invention.
[0225] In one embodiment, the base and/or the catalyst at step (a-1) are as described hereinabove under step (a-1). In one embodiment, X represents halide. In one particular embodiment, X represents Br.
[0226] The protecting group may be any protecting group known in the art such as, for example, tert-butyloxycarbonyl (Boc). The protective group may be removed at step (a-2) by any method known in the art appropriate to the nature of the protective group, such as, for example, addition of a strong Bronsted acid (e.g., hydrochloric acid [HCl]).
[0227] The peptide coupling agent at step (a-3) may be any peptide coupling agent known in the art such as, for example, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU).
[0228] The base at step (a-3) may be any base known in the art such as, for example, an amine base. According to one embodiment, the amine is triethylamine (Et.sub.3N) or diisopropylethylamine (iPr.sub.2NEt).
[0229] In one embodiment, the reaction at step (a-3) is carried out in a solvent. In one particular embodiment, the solvent is dimethylformamide (DMF) and/or tetrahydrofuran (THF). In one particular embodiment, the solvent is dichloroethane (DCE) and/or acetonitrile (MeCN). In one embodiment, the reaction is carried out at room temperature (RT).
[0230] In one embodiment, the process further comprises a work-up step (b). In one embodiment, the work-up step (b) comprises a step of extraction by a solvent. In one particular embodiment, the solvent is ethyl acetate (EtOAc). In one particular embodiment, the solvent is water or a 1N HCl solution. In one particular embodiment, the solvent is dichloromethane (DCM). In one embodiment, the work-up step (b) comprises a step of filtration. In one particular embodiment, the filtration is over Celite In one embodiment, the work-up step (b) comprises a step of concentration under reduced pressure.
[0231] In one embodiment, the process further comprises a purification step (c). In one embodiment, the purification step (c) comprises a purification by chromatography. In one particular embodiment, the chromatography is flash chromatography (FC) (e.g., cHex/EtOAc gradient), preparative thin-layer chromatography (PTLC) or semi-preparative high-performance liquid chromatography (HPLC).
Synthetic Intermediates
[0232] Another object of the present invention is a compound of formula (II)
##STR00048## [0233] wherein Z, R.sup.5, R.sup.6, R.sup.7 and R.sup.9 are as defined under formula (I) herein and X represents halide or CF.sub.3SO.sub.3.
[0234] Another object of the present invention is a compound of formula (III)
##STR00049## [0235] wherein W, R.sup.A-R.sup.D and R.sup.1-R.sup.4 are as defined under formula (I) herein.
[0236] Another object of the present invention is a compound of formula (IV)
##STR00050## [0237] wherein Z, R.sup.1-R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.9 are as defined under formula (I) herein and R.sup.P is a protecting group (e.g., Boc).
[0238] Another object of the present invention is a compound of formula (V)
##STR00051## [0239] wherein Z, R.sup.1-R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.9 are as defined under formula (I) herein.
EXAMPLES
[0240] The present invention is further illustrated by the following examples.
Example 1: Synthesis of the Compounds
General Material and Methods
Abbreviations
[0241] List of abbreviations: [0242] Ac: acetyl [0243] Ar: argon [0244] BINAP: (2,2-bis(diphenylphosphino)-1,1-binaphthyl) [0245] cHex: cyclohexane [0246] DCM: dichloromethane [0247] DMF: dimethylformamide [0248] Et: ethyl [0249] FC: flash chromatography [0250] m-CPBA: meta-chloroperbenzoic acid [0251] MTBE: methyl tert-butyl ether [0252] PTLC: preparative thin-layer chromatography [0253] RT: room temperature [0254] TBTU: 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate [0255] TFA: trifluoroacetic acid [0256] THF: tetrahydrofuran [0257] XPhos: dicyclohexyl[2,4,6-tris(propan-2-yl)[1,1-biphenyl]-2-yl]phosphane
Analytical Methods
[0258] .sup.1H NMR spectra (400 MHz) and .sup.19F NMR spectra (376 MHz) were recorded with a Bruker ULTRASHIELD 400 spectrometer. Processing and analyses of the spectra were performed with MestReNova. Data appear in the following order: chemical shifts in ppm which were referenced to the internal solvent signal, multiplicity, coupling constant J in Hertz and number of protons.
[0259] Reversed-phase HPLC/MS analyses were carried out with a Waters Alliance 2795 HPLC equipped with an autosampler, an inline membrane degasser, a column oven 10 (T=45 C.), a UV detector, and a ZQ quadrupole mass detector working in ionization electrospray mode. Analyzed compounds (0.1 to 0.3 mg) were solubilized in a minimum amount of DMSO completed with acetonitrile (total volume: 1 mL). Standard analytical parameters: flow rate: 1 mL/min, V.sub.inj.: 5 L. Acidic conditions: Waters XSelect CSH C18 column (3.5 m, 2.115 50 mm). Gradient: (H.sub.2O+0.04% v/v HCO.sub.2H (10 mM))/ACN from 95/5 to 0/100 in 2.5 min. Alkaline conditions: Waters Xbridge C18 column (3.5 m, 2.150 mm). Gradient: (H.sub.2O+0.06% v/v NH.sub.3 (aq.) (10 mM))/ACN from 95/5 to 0/100 in 2.5 min.
General Synthetic Methods
General Protocol 1 (GP-1): Thiol Alkylation
[0260] To a solution of 3-bromo-4-methoxy benzenethiol in DMF, were added the alkylhalide or pseudo-halide and K.sub.2CO.sub.3. The mixture was stirred the required time at the required temperature. The reaction mixture was partitioned between water and MTBE. The layers were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were washed (brine), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc gradient) to afford the required thioether.
General Protocol 2 (GP-2): Thioether Oxidation
[0261] To a solution of thioether from GP-1 in DCM at 0 C., was added m-CPBA. The mixture was stirred at RT for the required time. Aq. Sat. Na.sub.2S.sub.2O.sub.3, aq. sat. NaHCO.sub.3 and EtOAc were added. The mixture was vigorously stirred for 10 min. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (brine), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc gradient) to afford the required sulfone.
General Protocol 3 (GP-3): Buchwald Coupling Using Pd(OAc).SUB.2./Rac-BINAP
[0262] A microwave reaction vial was charged with the arylbromide from GP-2, the required piperazine, Cs.sub.2CO.sub.3, Pd(OAc).sub.2 and rac-BINAP. The vial was flushed with argon and degassed toluene was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating-block for the required time. After cooling down to RT, EtOAc was added and the suspension as filtered over Celite (EtOAc rinses). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc gradient) or PTLC to afford the required product.
General Protocol 4 (GP-4): Buchwald Coupling Using XPhos-Pd-G3
[0263] A microwave reaction vial was charged with the arylbromide from GP-2 the required piperazine, t-BuONa and XPhos-Pd-G3. The vial was flushed with argon and degassed toluene was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating-block for the required time. After cooling down to RT, EtOAc was added and the suspension was filtered over Celite (EtOAc rinses). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc gradient) or PTLC to afford the required product.
Synthesis of Intermediate Compounds
Synthesis of thioethers using GP-1
2-bromo-4-(1-ethylpropylsulfanyl)-1-methoxy-benzene (I-001)
##STR00052##
[0264] Using GP-1, I-001 was obtained as a colorless oil in 99% yield using 3-bromo-4-methoxy benzenethiol (156 mg, 712 mol, 1 equiv.), 3-bromopentane (215 mg, 1.42 mmol, 2 equiv.) and K.sub.2CO.sub.3 (197 mg, 1.42 mmol, 2 equiv.) in DMF (2.1 mL) at RT for 16 h. .sup.1H NMR (400 MHz, Chloroform-d) 7.65 (d, J=2.2 Hz, 1H), 7.37 (dd, J=8.5, 2.2 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 3.91 (s, 3H), 2.84 (p, J=6.3 Hz, 1H), 1.82-1.39 (m, 4H), 1.03 (t, J=7.4 Hz, 6H). MS (ESI.sup.+): [M+H].sup.+ 289.0/291.0.
2-bromo-4-cyclopentylsulfanyl-1-methoxy-benzene (I-002)
##STR00053##
[0265] Using GP-1, I-002 was obtained as a light yellow oil in 80% yield using 3-bromo-4-methoxy benzenethiol (560 mg, 2.56 mmol, 1 equiv.), iodocyclopentane (442 L, 3.83 mmol, 1.5 equiv.) and K.sub.2CO.sub.3 (530 mg, 3.83 mmol, 1.5 equiv.) in DMF (13 mL) at RT for 4 h. .sup.1H NMR (400 MHz, Chloroform-d) 7.54 (d, J=2.2 Hz, 1H), 7.25 (dd, J=8.5, 2.2 Hz, 1H), 6.74 (d, J=8.5 Hz, 1H), 3.80 (s, 3H), 3.43-3.32 (m, 1H), 1.95-1.83 (m, 2H), 1.75-1.62 (m, 2H), 1.58-1.43 (m, 4H). MS (ESI.sup.+): [M+H].sup.+ 287.0/289.0.
2-bromo-4-cyclohexylsulfanyl-1-methoxy-benzene (I-003)
##STR00054##
[0266] Using GP-1, I-003 was obtained as a light yellow oil in 50% yield using 3-bromo-4-methoxy benzenethiol (124 mg, 566 mol, 1 equiv.), iodocyclohexane (110 L, 849 mol, 1.5 equiv.) and K.sub.2CO.sub.3 (117 mg, 849 mol, 1.5 equiv.) in DMF (2.3 mL) at RT for 60 h. .sup.1H NMR (400 MHz, Chloroform-d) 7.67 (d, J=2.2 Hz, 1H), 7.37 (t, J=2.0 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 3.91 (s, 3H), 3.03-2.82 (m, 1H), 2.05-1.87 (m, 2H), 1.85-1.72 (m, 2H), 1.69-1.58 (m, 1H), 1.41-1.15 (m, 5H). MS (ESI.sup.+): [M+H].sup.+ 301.0/303.0.
2-bromo-4-(cyclopropylmethylsulfanyl)-1-methoxy-benzene (I-004)
##STR00055##
[0267] Using GP-1, I-004 was obtained as a light yellow oil in 87% yield using 3-bromo-4-methoxy benzenethiol (120 mg, 548 mol, 1 equiv.), (bromomethyl)cyclopropane (80 L, 0.82 mmol, 1.5 equiv.) and K.sub.2CO.sub.3 (114 mg, 822 mol, 1.5 equiv.) in DMF (2.7 mL) at RT for 4 h. .sup.1H NMR (400 MHz, DMSO-d6) 7.40 (d, J=2.3 Hz, 1H), 7.20 (dd, J=8.6, 2.2 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 3.65 (s, 3H), 2.66 (d, J=7.0 Hz, 2H), 0.80-0.69 (m, 1H), 0.36-0.25 (m, 2H), 0.05-0.06 (m, 2H). MS (ESI.sup.+): [M+H].sup.+ 273.0/275.0.
2-bromo-4-(cyclopropylmethylsulfanyl)-1-methoxy-benzene (I-005)
##STR00056##
[0268] Using GP-1, I-005 was obtained as a light yellow oil in 71% yield using 3-bromo-4-methoxy benzenethiol (170 mg, 776 mol, 1 equiv.), bromocyclobutane (98 L, 1.2 mmol, 1.5 equiv.) and K.sub.2CO.sub.3 (161 mg, 1.16 mmol, 1.5 equiv.) in DMF (3.9 mL) at 80 C. for 16 h. Purified by FC (cHex/EtOAc=90/10 to 60/40). .sup.1H NMR (400 MHz, Chloroform-d) 7.53 (d, J=2.2 Hz, 1H), 7.24 (d, J=2.2 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 3.88 (s, 3H), 3.75 (p, J=7.8 Hz, 1H), 2.42-2.31 (m, 2H), 2.05-1.87 (m, 4H). MS (ESI.sup.+): [M+H].sup.+ 273.0/275.0.
3-(3-bromo-4-methoxy-phenyl)sulfanyloxetane (I-006)
##STR00057##
[0269] Using GP-1, I-006 was obtained as a light yellow oil in 69% yield using 3-bromo-4-methoxy benzenethiol (150 mg, 685 mol, 1 equiv.), 3-bromooxetane (78 L, 1.03 mmol, 1.5 equiv.) and K.sub.2CO.sub.3 (141 mg, 1.03 mmol, 1.5 equiv.) in DMF (3.4 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=90/10 to 60/40). .sup.1H NMR (400 MHz, Chloroform-d) 7.54 (d, J=2.2 Hz, 1H), 7.28 (dd, J=8.6, 2.4 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 4.95 (t, J=7.0 Hz, 2H), 4.61 (t, J=6.5 Hz, 2H), 4.40-4.27 (m, 1H), 3.89 (s, 3H). MS (ESI.sup.+): [M+H].sup.+ 275.0/277.0.
2-bromo-4-(cyclobutylmethylsulfanyl)-1-methoxy-benzene (I-007)
##STR00058##
[0270] Using GP-1, I-007 was obtained as a colorless oil in 64% yield using 3-bromo-4-methoxy benzenethiol (120 mg, 548 mol, 1 equiv.), (bromomethyl)cyclobutane (92 L, 0.82 mmol, 1.5 equiv.) and K.sub.2CO.sub.3 (114 mg, 0.82 mmol, 1.5 equiv.) in DMF (2.7 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=90/10 to 60/40). .sup.1H NMR (400 MHz, Chloroform-d) 7.57 (d, J=2.2 Hz, 1H), 7.29 (dd, J=8.5, 2.3 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H), 3.88 (s, 3H), 2.89 (d, J=7.6 Hz, 2H), 2.46 (hept, J=7.6 Hz, 1H), 2.15-2.02 (m, 2H), 1.90-1.75 (m, 2H), 1.75-1.63 (m, 2H). MS (ESI.sup.+): [M+H].sup.+ 287.0/289.0.
2-bromo-4-(cyclopentylmethylsulfanyl)-1-methoxy-benzene (I-008)
##STR00059##
[0271] Using GP-1, I-008 was obtained as a colorless oil in 30% yield using 3-bromo-4-methoxy benzenethiol (120 mg, 548 mol, 1 equiv.), (bromomethyl)cyclobutane (103 L, 822 mol, 1.5 equiv.) and K.sub.2CO.sub.3 (114 mg, 822 mol, 1.5 equiv.) in DMF (2.7 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=90/10 to 60/40). .sup.1H NMR (400 MHz, Chloroform-d) 7.58 (d, J=2.3 Hz, 1H), 7.30 (dd, J=8.5, 2.3 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 3.88 (s, 3H), 2.84 (d, J=7.3 Hz, 2H), 2.05 (hept, J=7.6 Hz, 1H), 1.89-1.76 (m, 2H), 1.63-1.50 (m, 4H), 1.33-1.18 (m, 2H). MS (ESI.sup.+): [M+H].sup.+ 301.0/303.0.
4-benzylsulfanyl-2-bromo-1-methoxy-benzene (I-009)
##STR00060##
[0272] Using GP-1, I-009 was obtained as a colorless oil in 100% yield using 3-bromo-4-methoxy benzenethiol (170 mg, 776 mol, 1 equiv.), benzyl bromide (142 L, 1.16 mmol, 1.5 equiv.) and K.sub.2CO.sub.3 (161 mg, 1.16 mmol, 1.5 equiv.) in DMF (3.9 mL) at RT for 1 h. Purified by FC (cHex/EtOAc=90/10 to 60/40). .sup.1H NMR (400 MHz, Chloroform-d) 7.55 (d, J=2.2 Hz, 1H), 7.45-7.24 (m, 5H), 7.22 (d, J=2.1 Hz, 1H), 6.79 (d, J=8.5 Hz, 1H), 4.03 (s, 2H), 3.89 (s, 3H). MS (ESI.sup.+): [M+H].sup.+ 309.0/311.0.
2-bromo-4-(2,2-dimethylpropylsulfanyl)-1-methoxy-benzene (I-010)
##STR00061##
[0273] Using GP-1, I-010 was obtained as a colorless oil in 22% yield using 3-bromo-4-methoxy benzenethiol (170 mg, 776 mol, 1 equiv.), 1-bromo-2,2-dimethylpropane (147 L, 1.16 mmol, 1.5 equiv.) and K.sub.2CO.sub.3 (161 mg, 1.16 mmol, 1.5 equiv.) in DMF (3.9 mL) at RT for 1 h. Purified by FC (cHex/EtOAc=90/10 to 60/40). .sup.1H NMR (400 MHz, Chloroform-d) 7.58 (d, J=2.3 Hz, 1H), 7.31 (dd, J=8.6, 2.3 Hz, 1H), 6.80 (d, J=8.5 Hz, 1H), 3.87 (s, 3H), 2.82 (s, 2H), 1.01 (s, 9H). MS (ESI.sup.+): [M+H].sup.+ 289.0/291.0.
2-bromo-4-isopropylsulfanyl-1-methoxy-benzene (I-011)
##STR00062##
[0274] Using GP-1, I-011 was obtained as a colorless oil in 42% yield using 3-bromo-4-methoxy benzenethiol (120 mg, 548 mol, 1 equiv.), 1-Bromo-2,2-dimethylpropane (77 L, 0.82 mmol, 1.5 equiv.) and K.sub.2CO.sub.3 (114 mg, 822 mol, 1.5 equiv.) in DMF (2.7 mL) at RT for 4 h. Purified by FC (cHex/EtOAc=90/10 to 60/40). .sup.1H NMR (400 MHz, Chloroform-d) 7.57 (d, J=2.2 Hz, 1H), 7.28 (dd, J=8.5, 2.2 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 3.81 (s, 3H), 3.13 (hept, J=6.7 Hz, 1H), 1.17 (d, J=6.6 Hz, 6H). MS (ESI.sup.+): [M+H].sup.+ 261.0/263.0.
2-bromo-4-isobutylsulfanyl-1-methoxy-benzene (I-023)
##STR00063##
[0275] Using GP-1, I-023 was obtained as a colorless oil in 65% yield using 3-bromo-4-methoxy-benzenethiol (219 mg, 999 mol, 1 equiv.), 1-bromo-2-methylpropane (120 L, 1.10 mmol, 1.1 equiv.) and K.sub.2CO.sub.3 (145 mg, 1.05 mmol, 1.05 equiv.) in DMF (9.1 mL) at RT for 5 h. Purified by FC (cHex/EtOAc=100/0 to 80/20). .sup.1H NMR (400 MHz, Chloroform-d) 7.58 (d, J=2.3 Hz, 1H), 7.30 (dd, J=8.5, 2.3 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 3.88 (s, 3H), 2.72 (d, J=6.9 Hz, 2H), 1.80 (hept, J=13.4, 6.7 Hz, 1H), 1.01 (d, J=6.7 Hz, 6H). MS (ESI.sup.+): [M+H].sup.+ 275.0/277.0.
2-bromo-1-methoxy-4-(1-methylbutylsulfanyl)benzene (I-025)
##STR00064##
[0276] Using GP-1, I-025 was obtained as a colorless oil in 88% yield using 3-bromo-4-methoxy-benzenethiol (1.37 g, 6.27 mmol, 1 equiv.), 2-bromopentane (1.16 mL, 9.41 mmol, 1.5 equiv.) and K.sub.2CO.sub.3 (1.30 g, 9.41 mmol, 1.5 equiv.) in DMF (25 mL) at RT for 5 h. Desired product I-025 was contaminated by 10% of disulfide and was used for the further reaction without further purification. .sup.1H NMR (400 MHz, Chloroform-d) 7.64 (d, J=2.2 Hz, 1H), 7.35 (ddd, J=8.5, 4.6, 2.2 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 3.89 (d, J=1.3 Hz, 4H), 3.13-2.96 (m, 1H), 1.51-1.38 (m, 3H), 1.22 (d, J=6.7 Hz, 3H), 0.95-0.86 (m, 3H). MS (ESI.sup.+): [M+H].sup.+ 288.9/290.9.
2-bromo-4-(2-cyclopentylethylsulfanyl)-1-methoxy-benzene (I-032)
##STR00065##
[0277] Using GP-1, I-032 was obtained as a colorless oil in 26% yield using 3-bromo-4-methoxy-benzenethiol (270 mg, 1.23 mmol, 1 equiv.), 2-bromoethylcyclopentane (0.21 mL, 1.5 mmol, 1.2 equiv.) and K.sub.2CO.sub.3 (255 mg, 1.85 mmol, 1.5 equiv.) in DMF (6.2 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=95/5 to 60/40). .sup.1H NMR (400 MHz, Chloroform-d) 7.57 (d, J=2.2 Hz, 1H), 7.29 (dd, J=8.5, 2.3 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 3.88 (s, 3H), 2.87-2.80 (m, 2H), 1.94-1.82 (m, 1H), 1.80-1.72 (m, 2H), 1.61-1.47 (m, 6H), 1.12-1.01 (m, 2H). MS (ESI.sup.+): [M+H].sup.+ 315.0/317.0.
2-bromo-4-butylsulfanyl-1-methoxy-benzene (I-033)
##STR00066##
[0278] Using GP-1, I-033 was obtained as a colorless oil in 53% yield using 3-bromo-4-methoxy-benzenethiol (150 mg, 0.685 mmol, 1 equiv.), 1-bromobutane (0.11 mL, 1.03 mmol, 1.5 equiv.) and K.sub.2CO.sub.3 (142 mg, 1.03 mmol, 1.5 equiv.) in DMF (3.4 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=90/10 to 60/40). .sup.1H NMR (400 MHz, Chloroform-d) 7.58 (d, J=2.2 Hz, 1H), 7.30 (dd, J=8.5, 2.3 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 3.88 (s, 3H), 2.87-2.78 (m, 2H), 1.61-1.55 (m, 2H), 1.49-1.36 (m, 2H), 0.91 (t, J=7.3 Hz, 3H). MS (ESI.sup.+): [M+H].sup.+ 275.0/277.0.
2-bromo-4-(2-ethylbutylsulfanyl)-1-methoxy-benzene (I-034)
##STR00067##
[0279] Using GP-1, I-034 was obtained as a colorless oil in 90% yield using 3-bromo-4-methoxy-benzenethiol (170 mg, 0.776 mmol, 1 equiv.), 3-(bromomethyl)pentane (0.16 mL, 1.2 mmol, 1.5 equiv.) and K.sub.2CO.sub.3 (161 mg, 1.16 mmol, 1.5 equiv.) in DMF (3.9 mL) at RT for 16 h. Purified by FC (cHex/EtOAc=90/10 to 60/40). .sup.1H NMR (400 MHz, Chloroform-d) 7.57 (d, J=2.3 Hz, 1H), 7.29 (dd, J=8.5, 2.3 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H), 3.87 (s, 3H), 2.84-2.79 (m, 2H), 1.48-1.38 (m, 5H), 0.88-0.83 (m, 6H). MS (ESI.sup.+): [M+H].sup.+ 303.0/305.0.
2-bromo-1-methoxy-4-sec-butylsulfanyl-benzene (I-035)
##STR00068##
[0280] Using GP-1, I-035 was obtained as a colorless oil in 53% yield using 3-bromo-4-methoxy-benzenethiol (150 mg, 0.684 mmol, 1 equiv.), 2-bromobutane (0.11 mL, 1.0 mmol, 1.5 equiv.) and K.sub.2CO.sub.3 (142 mg, 1.03 mmol, 1.5 equiv.) in DMF (3.4 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=90/10 to 60/40). .sup.1H NMR (400 MHz, Chloroform-d) 7.64 (d, J=2.2 Hz, 1H), 7.35 (dd, J=8.5, 2.2 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 3.89 (s, 3H), 3.05-2.94 (m, 1H), 1.67-1.56 (m, 1H), 1.53-1.40 (m, 1H), 1.22 (d, J=6.8 Hz, 3H), 1.00 (t, J=7.4 Hz, 3H). MS (ESI.sup.+): [M+H].sup.+ 275.0/277.0.
2-bromo-1-methoxy-4-(1-methyl-3-phenyl-propyl)sulfanyl-benzene (I-036)
##STR00069##
[0281] Using GP-1, I-036 was obtained as a colorless oil in 40% yield using 3-bromo-4-methoxy-benzenethiol (200 mg, 0.913 mmol, 1 equiv.), (1-methyl-3-phenyl-propyl) methanesulfonate (250 mg, 1.10 mmol, 1.2 equiv.) and K.sub.2CO.sub.3 (189 mg, 1.37 mmol, 1.5 equiv.) in DMF (4.6 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=100/0 to 70/30). .sup.1H NMR (400 MHz, Chloroform-d) 7.63 (d, J=2.2 Hz, 1H), 7.38-7.26 (m, 3H), 7.22-7.12 (m, 3H), 6.83-6.75 (m, 1H), 3.89 (s, 3H), 3.04 (h, J=6.8 Hz, 1H), 2.81-2.70 (m, 2H), 2.01-1.68 (m, 2H), 1.29-1.25 (d, J=6.8 Hz, 3H).
2-bromo-1-methoxy-4-(1-methyl-4-phenyl-butyl)sulfanyl-benzene (I-037)
##STR00070##
[0282] Using GP-1, I-037 was obtained as a colorless oil in 40% yield using 3-bromo-4-methoxy-benzenethiol (150 mg, 0.684 mmol, 1 equiv.), (1-methyl-3-phenyl-butyl) methanesulfonate (199 mg, 0.821 mmol, 1.2 equiv.) and K.sub.2CO.sub.3 (142 mg, 1.03 mmol, 1.5 equiv.) in DMF (4.6 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=100/0 to 70/30). .sup.1H NMR (400 MHz, Chloroform-d) 7.62 (d, J=2.2 Hz, 1H), 7.35-7.27 (m, 3H), 7.23-7.03 (m, 3H), 6.80 (d, J=8.5 Hz, 1H), 3.89 (s, 3H), 3.05 (h, J=6.7 Hz, 1H), 2.66-2.56 (m, 2H), 1.88-1.69 (m, 2H), 1.67-1.46 (m, 2H), 1.22 (d, J=6.7 Hz, 3H).
2-bromo-4-(1-ethyl-3-phenyl-propyl)sulfanyl-1-methoxy-benzene (I-038)
##STR00071##
[0283] Using GP-1, I-038 was obtained as a colorless oil in 40% yield using 3-bromo-4-methoxy-benzenethiol (200 mg, 0.913 mmol, 1 equiv.), (1-methyl-3-phenyl-propyl) methanesulfonate (265 mg, 1.10 mmol, 1.2 equiv.) and K.sub.2CO.sub.3 (189 mg, 1.37 mmol, 1.5 equiv.) in DMF (4.6 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=100/0 to 70/30). .sup.1H NMR (400 MHz, Chloroform-d) 7.63 (d, J=2.2 Hz, 1H), 7.37-7.26 (m, 3H), 7.23-7.13 (m, 3H), 6.81 (d, J=8.4 Hz, 1H), 3.89 (s, 3H), 2.94-2.68 (m, 3H), 1.94-1.72 (m, 2H), 1.69-1.51 (m, 2H), 1.01 (t, J=7.4 Hz, 3H).
2-bromo-4-(1-ethyl-4-phenyl-butyl)sulfanyl-1-methoxy-benzene (I-039)
##STR00072##
[0284] Using GP-1, I-039 was obtained as a colorless oil in 40% yield using 3-bromo-4-methoxy-benzenethiol (87 mg, 0.40 mmol, 1.2 equiv.), (1-ethyl-4-phenyl-butyl) methanesulfonate (85 mg, 0.33 mmol, 1.0 equiv.) and K.sub.2CO.sub.3 (69 mg, 0.50 mmol, 1.5 equiv.) in DMF (1.7 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=100/0 to 70/30). .sup.1H NMR (400 MHz, Chloroform-d) 7.53 (d, J=2.2 Hz, 1H), 7.26-7.16 (m, 3H), 7.16-7.04 (m, 3H), 6.71 (d, J=8.5 Hz, 1H), 3.81 (s, 3H), 2.79 (p, J=6.4 Hz, 1H), 2.53 (t, J=7.6 Hz, 2H), 1.84-1.62 (m, 2H), 1.57-1.38 (m, 4H), 0.90 (t, J=7.3 Hz, 3H).
Synthesis of Sulfones Using GP-2
2-bromo-4-(1-ethylpropylsulfonyl)-1-methoxy-benzene (I-012)
##STR00073##
[0285] Using GP-2, I-012 was obtained as a colorless oil in 96% yield using I-001 (200 mg, 285 mol, 1 equiv.) and m-CPBA (70% wet, 371 mg, 1.51 mmol, 2.2 equiv.) in DCM (3.4 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=95/5 to 50/50). .sup.1H NMR (400 MHz, Chloroform-d) 8.07 (d, J=2.2 Hz, 1H), 7.83 (dd, J=8.6, 2.2 Hz, 1H), 7.03 (d, J=8.7 Hz, 1H), 4.01 (s, 3H), 2.80 (tt, J=7.2, 4.8 Hz, 1H), 1.97-1.81 (m, 2H), 1.80-1.63 (m, 2H), 1.03 (t, J=7.5 Hz, 6H). MS (ESI.sup.+): [M+H].sup.+ 321.0/323.0.
2-bromo-4-cyclopentylsulfonyl-1-methoxy-benzene (I-013)
##STR00074##
[0286] Using GP-2, I-013 was obtained as a colorless oil in 94% yield using I-002 (590 mg, 332 mol, 1 equiv.) and m-CPBA (70% wet, 1.01 g, 4.52 mmol, 2.2 equiv.) in DCM (3.4 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=95/5 to 50/50). .sup.1H NMR (400 MHz, Chloroform-d) 8.09 (d, J=2.3 Hz, 1H), 7.84 (dd, J=8.6, 2.3 Hz, 1H), 7.02 (d, J=8.7 Hz, 1H), 4.00 (s, 3H), 3.48 (tt, J=8.8, 7.2 Hz, 1H), 2.15-1.99 (m, 2H), 1.97-1.72 (m, 4H), 1.69-1.56 (m, 2H). MS (ESI.sup.+): [M+H].sup.+ 319.0/321.0.
2-bromo-4-cyclohexylsulfonyl-1-methoxy-benzene (I-014)
##STR00075##
[0287] Using GP-2, I-014 was obtained as a colorless oil in 94% yield using I-003 (100 mg, 332 mol, 1 equiv.) and m-CPBA (70% wet, 275 g, 1.23 mmol, 3.7 equiv.) in DCM (2.2 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=95/5 to 50/50). .sup.1H NMR (400 MHz, Chloroform-d) 8.03 (d, J=2.2 Hz, 1H), 7.78 (dd, J=8.6, 2.2 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 3.98 (s, 3H), 2.87 (tt, J=12.1, 3.4 Hz, 1H), 2.13-2.01 (m, 2H), 1.95-1.81 (m, 2H), 1.39 (qd, J=12.3, 3.4 Hz, 2H), 1.28-1.09 (m, 4H). MS (ESI.sup.+): [M+H].sup.+ 333.0/335.0.
2-bromo-4-(cyclopropylmethylsulfonyl)-1-methoxy-benzene (I-015)
##STR00076##
[0288] Using GP-2, I-015 was obtained as a colorless oil in 76% yield using I-004 (130 mg, 476 mol, 1 equiv.) and m-CPBA (70% wet, 258 mg, 1.05 mmol, 2.2 equiv.) in DCM (2.4 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=95/5 to 50/50). .sup.1H NMR (400 MHz, Chloroform-d) 8.11 (d, J=2.3 Hz, 1H), 7.86 (dd, J=8.6, 2.2 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 3.99 (s, 3H), 3.01 (d, J=7.2 Hz, 2H), 1.09-0.94 (m, 1H), 0.66-0.53 (m, 2H), 0.22-0.09 (m, 2H). MS (ESI.sup.+): [M+H].sup.+ 305.0/306.9.
2-bromo-4-cyclobutylsulfonyl-1-methoxy-benzene (I-016)
##STR00077##
[0289] Using GP-2, I-016 was obtained as a colorless oil in 66% yield using I-005 (150 mg, 549 mol, 1 equiv.) and m-CPBA (70% wet, 298 mg, 1.21 mmol, 2.2 equiv.) in DCM (2.7 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=95/5 to 50/50). .sup.1H NMR (400 MHz, Chloroform-d) 8.03 (d, J=2.2 Hz, 1H), 7.79 (dd, J=8.6, 2.3 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 3.97 (s, 3H), 3.84-3.73 (m, 1H), 2.61-2.48 (m, 2H), 2.25-2.13 (m, 2H), 2.05-1.91 (m, 2H). MS (ESI.sup.+): [M+H].sup.+ 304.9/307.0.
3-(3-bromo-4-methoxy-phenyl)sulfonyloxetane (I-017)
##STR00078##
[0290] Using GP-2, I-017 was obtained as a colorless oil in 69% yield using I-006 (130 mg, 472 mol, 1 equiv.) and m-CPBA (70% wet, 256 mg, 1.04 mmol, 2.2 equiv.) in DCM (2.4 mL) at RT for 16 h. Purified by FC (cHex/EtOAc=95/5 to 50/50). .sup.1H NMR (400 MHz, Chloroform-d) 8.07 (d, J=2.2 Hz, 1H), 7.85 (dd, J=8.7, 2.3 Hz, 1H), 7.03 (d, J=8.7 Hz, 1H), 4.96-4.89 (m, 2H), 4.80 (t, J=7.7 Hz, 2H), 4.44 (tt, J=8.1, 6.2 Hz, 1H), 3.99 (s, 3H). MS (ESI.sup.+): [M+H].sup.+ 307.0/309.0.
2-bromo-4-(cyclobutylmethylsulfonyl)-1-methoxy-benzene (I-018)
##STR00079##
[0291] Using GP-2, I-018 was obtained as a colorless oil in 54% yield using I-007 (100 mg, 348 mol, 1 equiv.) and m-CPBA (70% wet, 119 mg, 766 mol, 2.2 equiv.) in DCM (1.7 mL) at RT for 16 h. Purified by FC (cHex/EtOAc=95/5 to 50/50). .sup.1H NMR (400 MHz, Chloroform-d) 8.03 (d, J=2.3 Hz, 1H), 7.79 (dd, J=8.7, 2.3 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 3.97 (s, 3H), 3.18 (d, J=7.3 Hz, 2H), 2.68 (tt, J=15.6, 7.7 Hz, 1H), 2.12-2.01 (m, 2H), 1.98-1.68 (m, 4H). MS (ESI.sup.+): [M+H].sup.+ 319.0/320.9.
2-bromo-4-(cyclopentylmethylsulfonyl)-1-methoxy-benzene (I-019)
##STR00080##
[0292] Using GP-2, I-019 was obtained as a colorless oil in 100% yield using I-008 (50 mg, 166 mol, 1 equiv.) and m-CPBA (70% wet, 90 mg, 0.37 mmol, 2.2 equiv.) in DCM (0.8 mL) at RT for 16 h. Purified by FC (cHex/EtOAc=95/5 to 50/50). .sup.1H NMR (400 MHz, Chloroform-d) 8.04 (d, J=2.3 Hz, 1H), 7.80 (dd, J=8.6, 2.3 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 3.96 (s, 3H), 3.10 (d, J=6.8 Hz, 2H), 2.28-2.15 (m, 1H), 1.92-1.81 (m, 2H), 1.66-1.47 (m, 4H), 1.26-1.14 (m, 2H). MS (ESI.sup.+): [M+H].sup.+ 332.9/335.0.
4-benzylsulfonyl-2-bromo-1-methoxy-benzene (I-020)
##STR00081##
[0293] Using GP-2, I-020 was obtained as a colorless oil in 100% yield using I-009 (240 mg, 776 mol, 1 equiv.) and m-CPBA (70% wet, 421 mg, 1.70 mmol, 2.2 equiv.) in DCM (3.9 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=95/5 to 50/50). .sup.1H NMR (400 MHz, Chloroform-d) 7.76 (d, J=2.3 Hz, 1H), 7.49 (dd, J=8.6, 2.3 Hz, 1H), 7.38-7.27 (m, 3H), 7.13-7.07 (m, 2H), 6.86 (d, J=8.7 Hz, 1H), 4.29 (s, 2H), 3.95 (s, 3H). MS (ESI.sup.+): [M+H].sup.+ 341.0/342.9.
2-bromo-4-(2,2-dimethylpropylsulfonyl)-1-methoxy-benzene (I-021)
##STR00082##
[0294] Using GP-2, I-021 was obtained as a colorless oil in 72% yield using I-010 (50 mg, 173 mol, 1 equiv.) and m-CPBA (70% wet, 94 mg, 0.38 mmol, 2.2 equiv.) in DCM (0.9 mL) at RT for 16 h. Purified by FC (cHex/EtOAc=95/5 to 50/50). .sup.1H NMR (400 MHz, Chloroform-d) 8.08 (d, J=2.3 Hz, 1H), 7.84 (dd, J=8.7, 2.3 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 3.98 (s, 3H), 3.01 (s, 2H), 1.19 (s, 9H). MS (ESI.sup.+): [M+H].sup.+ 321.0/322.9.
2-bromo-4-isopropylsulfonyl-1-methoxy-benzene (I-022)
##STR00083##
[0295] Using GP-2, I-022 was obtained as a colorless oil in 67% yield using I-011 (60 mg, 230 mol, 1 equiv.) and m-CPBA (70% wet, 125 mg, 505 mol, 2.2 equiv.) in DCM (1.5 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=95/5 to 50/50). .sup.1H NMR (400 MHz, Chloroform-d) 8.04 (d, J=2.3 Hz, 1H), 7.80 (dd, J=8.6, 2.3 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 3.98 (s, 3H), 3.22-3.11 (m, 1H), 1.29 (d, J=6.8 Hz, 6H). MS (ESI.sup.+): [M+H].sup.+ 293.0/295.0.
2-bromo-1-methoxy-4-(1-methylbutylsulfonyl)benzene (I-026)
##STR00084##
[0296] Using GP-2, I-026 was obtained as a colorless oil in 80% yield using I-025 (1.64 g, 5.68 mmol, 1 equiv.) and m-CPBA (70% wet, 3.08 g, 12.5 mmol, 2.2 equiv.) in DCM (28 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=95/5 to 60/40). .sup.1H NMR (400 MHz, Chloroform-d) 8.04 (d, J=2.2 Hz, 1H), 7.80 (dd, J=8.6, 2.2 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 3.99 (s, 3H), 3.01 (dqd, J=10.4, 6.9, 3.6 Hz, 1H), 1.92 (dddd, J=12.7, 9.5, 5.7, 3.2 Hz, 1H), 1.53-1.31 (m, 2H), 1.29-1.22 (m, 4H), 0.91 (t, J=7.2 Hz, 3H). MS (ESI.sup.+): [M+H].sup.+ 320.9/323.0.
2-bromo-4-(2-cyclopentylethylsulfonyl)-1-methoxy-benzene (I-040)
##STR00085##
[0297] Using GP-2, I-040 was obtained as a colorless oil in 66% yield using I-032 (100 mg, 0.317 mmol, 1 equiv.) and m-CPBA (70% wet, 172 mg, 0.697 mmol, 2.2 equiv.) in DCM (1.6 mL) at RT for 1 h. Purified by FC (cHex/EtOAc=95/5 to 50/50). .sup.1H NMR (400 MHz, Chloroform-d) 8.07 (d, J=2.2 Hz, 1H), 7.83 (dd, J=8.6, 2.3 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 3.99 (s, 3H), 3.12-3.04 (m, 2H), 1.84-1.69 (m, 5H), 1.62-1.40 (m, 4H), 1.11-1.00 (m, 2H). MS (ESI.sup.+): [M+H].sup.+ 347.0/349.0.
2-bromo-4-butylsulfonyl-1-methoxy-benzene (I-041)
##STR00086##
[0298] Using GP-2, I-041 was obtained as a colorless oil in 36% yield using I-033 (100 mg, 0.363 mmol, 1 equiv.) and m-CPBA (70% wet, 197 mg, 0.800 mmol, 2.2 equiv.) in DCM (1.8 mL) at RT for 16 h. Purified by FC (cHex/EtOAc=95/5 to 50/50). .sup.1H NMR (400 MHz, Chloroform-d) 1H NMR (400 MHz, Chloroform-d) 8.07 (d, J=2.3 Hz, 1H), 7.83 (dd, J=8.7, 2.3 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 3.99 (s, 3H), 3.11-3.03 (m, 2H), 1.74-1.64 (m, 2H), 1.50-1.30 (m, 2H), 0.90 (t, J=7.4 Hz, 3H). MS (ESI.sup.+): [M+H].sup.+ 307.0/308.9.
2-bromo-4-(2-ethylbutylsulfonyl)-1-methoxy-benzene (I-042)
##STR00087##
[0299] Using GP-2, I-042 was obtained as a colorless oil in 73% yield using I-034 (235 mg, 0.775 mmol, 1 equiv.) and m-CPBA (70% wet, 420 mg, 1.70 mmol, 2.2 equiv.) in DCM (3.9 mL) at RT for 16 h. Purified by FC (cHex/EtOAc=95/5 to 50/50). .sup.1H NMR (400 MHz, Chloroform-d) 1H NMR (400 MHz, Chloroform-d) 8.07 (d, J=2.3 Hz, 1H), 7.83 (dd, J=8.6, 2.3 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 3.98 (s, 3H), 3.00 (d, J=6.0 Hz, 2H), 1.89 (hept, J=6.1 Hz, 1H), 1.48-1.41 (m, 4H), 0.83 (t, J=7.4 Hz, 6H). MS (ESI.sup.+): [M+H].sup.+ 335.0/337.0.
2-bromo-1-methoxy-4-sec-butylsulfonyl-benzene (I-043)
##STR00088##
[0300] Using GP-2, I-043 was obtained as a colorless oil in 72% yield using I-035 (50 mg, 0.182 mmol, 1 equiv.) and m-CPBA (70% wet, 98 mg, 0.40 mmol, 2.2 equiv.) in DCM (0.9 mL) at RT for 16 h. Purified by FC (cHex/EtOAc=95/5 to 50/50). .sup.1H NMR (400 MHz, Chloroform-d) 1H NMR (400 MHz, Chloroform-d) 8.04 (d, J=2.2 Hz, 1H), 7.80 (dd, J=8.6, 2.2 Hz, 1H), 7.01 (d, J=8.6 Hz, 1H), 3.99 (s, 3H), 2.98-2.87 (m, 1H), 2.07-1.94 (m, 1H), 1.49-1.36 (m, 1H), 1.27 (d, J=6.9 Hz, 3H), 0.99 (t, J=7.5 Hz, 3H). MS (ESI.sup.+): [M+H].sup.+ 306.9/308.9.
2-bromo-1-methoxy-4-(1-methyl-3-phenyl-propyl)sulfonyl-benzene (I-044)
##STR00089##
[0301] Using GP-2, I-044 was obtained as a colorless oil in 58% yield using I-036 (156 mg, 0.444 mmol, 1 equiv.) and m-CPBA (70% wet, 274 mg, 1.11 mmol, 2.2 equiv.) in DCM (2.2 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=95/5 to 50/50). .sup.1H NMR (400 MHz, Chloroform-d) 8.00 (d, J=2.2 Hz, 1H), 7.76 (dd, J=8.6, 2.3 Hz, 1H), 7.31-7.24 (m, 2H), 7.24-7.17 (m, 1H), 7.14-7.08 (m, 2H), 6.98 (d, J=8.7 Hz, 1H), 3.98 (s, 3H), 3.00 (dqd, J=9.5, 6.9, 3.7 Hz, 1H), 2.82 (ddd, J=14.3, 9.3, 5.3 Hz, 1H), 2.60 (ddd, J=13.9, 8.9, 7.5 Hz, 1H), 2.29 (dddd, J=13.2, 9.3, 7.5, 3.7 Hz, 1H), 1.80-1.64 (m, 1H), 1.32 (d, J=6.9 Hz, 3H).
2-bromo-1-methoxy-4-(1-methyl-4-phenyl-butyl)sulfonyl-benzene (I-045)
##STR00090##
[0302] Using GP-2, I-045 was obtained as a colorless oil in 50% yield using I-037 (185 mg, 0.506 mmol, 1 equiv.) and m-CPBA (70% wet, 308 mg, 1.25 mmol, 2.5 equiv.) in DCM (2.5 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=95/5 to 50/50). .sup.1H NMR (400 MHz, Chloroform-d) 8.00 (d, J=2.2 Hz, 1H), 7.76 (dd, J=8.6, 2.3 Hz, 1H), 7.31-7.24 (m, 2H), 7.24-7.17 (m, 1H), 7.14-7.08 (m, 2H), 6.98 (d, J=8.7 Hz, 1H), 3.99 (s, 3H), 3.10-2.90 (m, 1H), 2.70-2.50 (m, 2H), 2.02-1.93 (m, 1H), 1.90-1.52 (m, 2H), 1.51-1.39 (m, 1H), 1.35-1.21 (m, 3H).
2-bromo-4-(1-ethyl-3-phenyl-propyl)sulfonyl-1-methoxy-benzene (I-046)
##STR00091##
[0303] Using GP-2, I-046 was obtained as a colorless oil in 75% yield using I-038 (228 mg, 0.624 mmol, 1 equiv.) and m-CPBA (70% wet, 384 mg, 1.56 mmol, 2.2 equiv.) in DCM (3.1 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=95/5 to 50/50). .sup.1H NMR (400 MHz, Chloroform-d) 8.01 (d, J=2.3 Hz, 1H), 7.77 (dd, J=8.7, 2.2 Hz, 1H), 7.31-7.23 (m, 2H), 7.22-7.15 (m, 1H), 7.14-7.07 (m, 2H), 6.98 (d, J=8.7 Hz, 1H), 3.99 (s, 3H), 2.89-2.74 (m, 2H), 2.67 (ddd, J=13.9, 9.5, 6.6 Hz, 1H), 2.14 (dddd, J=14.6, 9.5, 6.6, 5.1 Hz, 1H), 1.97-1.82 (m, 2H), 1.69 (dp, J=14.7, 7.4 Hz, 1H), 1.00 (t, J=7.5 Hz, 3H).
2-bromo-4-(1-ethyl-4-phenyl-butyl)sulfonyl-1-methoxy-benzene (I-047)
##STR00092##
[0304] Using GP-2, I-047 was obtained as a colorless oil in 38% yield using I-039 (61 mg, 0.16 mmol, 1 equiv.) and m-CPBA (70% wet, 98 mg, 0.40 mmol, 2.5 equiv.) in DCM (0.8 mL) at RT for 2 h. Purified by FC (cHex/EtOAc=95/5 to 50/50). .sup.1H NMR (400 MHz, Chloroform-d) 8.01 (d, J=2.3 Hz, 1H), 7.72 (dd, J=8.6, 2.2 Hz, 1H), 7.30-7.25 (m, 2H), 7.21-7.04 (m, 3H), 6.95 (d, J=8.7 Hz, 1H), 3.98 (s, 3H), 2.81 (dt, J=6.8, 4.5 Hz, 1H), 2.59 (t, J=6.9 Hz, 2H), 1.99-1.57 (m, 6H), 0.97 (t, J=7.5 Hz, 3H).
Synthesis of Common Intermediate Piperazines I-028 to I-031
tert-butyl 4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazine-1-carboxylate (Boc-I-028)
##STR00093##
[0305] To a solution of 4-fluoro-2-(trifluoromethyl)benzoic acid (12.0 g, 57.7 mmol, 1 equiv.) in THF (180 mL) at RT, was added TBTU (18.5 g, 57.7 mmol, 1 equiv.). The mixture was stirred 15 min at RT, and a solution of tert-butyl piperazine-1-carboxylate (12.9 g, 69.2 mmol, 1.2 equiv.) and Et.sub.3N (12.1 mL, 86.5 mmol, 1.5 equiv.) in THF (60 mL) was added dropwise. The mixture was stirred at RT for 60 h. The reaction mixture was concentrated under reduced pressure. The reaction mixture was partitioned between 1N HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc(2*). The combined organic extracts were washed (as. 1N HCl, aq. sat. NaHCO.sub.3, brine), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure to afford 23.1 g (100%) of tert-butyl 4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazine-1-carboxylate (Boc-I-028) as a brown oil that solidifies upon standing. .sup.1H NMR (400 MHz, Chloroform-d) 7.43 (dd, J=8.6, 2.1 Hz, 1H), 7.34-7.28 (m, 2H), 3.90-3.65 (m, 2H), 3.62-3.44 (m, 2H), 3.35 (dd, J=6.4, 4.0 Hz, 2H), 3.15 (dd, J=6.5, 4.0 Hz, 2H), 1.46 (s, 9H). MS (ESI.sup.+): [M+H].sup.+ 377.1.
[4-fluoro-2-(trifluoromethyl)phenyl]-piperazin-1-yl-methanone (I-028)
##STR00094##
[0306] To a solution of crude tert-butyl 4-(4-fluoro-2-(trifluoromethyl)benzoyl)piperazine-1-carboxylate Boc-I-028 (23.1 g, 57.9 mmol, 1 equiv.) in dioxane (25 mL) at RT, was added HCl (4M solution in dioxane, 75.0 mL, 300 mmol, 5 equiv.). The mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and DCM. K.sub.2CO.sub.3(s) was added portionwise until pH >11. The layers were separated and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (120 g column, dry load, DCM/MeOH=98/2 to 80/20) to afford 13.6 g (83%) of [4-fluoro-2-(trifluoromethyl)phenyl]-piperazin-1-yl-methanone I-028 as an orange solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.41 (dd, J=8.8, 2.4 Hz, 1H), 7.32 (qd, J=8.4, 5.6 Hz, 2H), 3.87-3.69 (m, 2H), 3.15 (t, J=5.1 Hz, 2H), 2.94 (t, J=5.2 Hz, 2H), 2.76 (tq, J=12.1, 6.1, 5.0 Hz, 2H). MS (ESI.sup.+): [M+H].sup.+ 277.4.
tert-butyl 4-(2-chloro-4-fluoro-benzoyl)piperazine-1-carboxylate (Boc-I-029)
##STR00095##
[0307] To a solution of 2-chloro-4-fluorobenzoic acid (5.00 g, 28.6 mmol, 1 equiv.) in THF (89 mL) at RT, was added TBTU (9.20 g, 28.6 mmol, 1 equiv.). The mixture was stirred 15 min at RT, and a solution of tert-butyl piperazine-1-carboxylate (6.40 g, 34.4 mmol, 1.2 equiv.) and Et.sub.3N (6.0 mL, 43 mmol, 1.5 equiv.) in THF (30 mL) was added dropwise. The mixture was stirred at RT for 60 h. The reaction mixture was concentrated under reduced pressure. The reaction mixture was partitioned between 1N HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc(2*). The combined organic extracts were washed (aq. 1N HCl, aq. sat. NaHCO.sub.3, brine), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure to afford 10.2 g (100%) of tert-butyl 4-(2-chloro-4-fluoro-benzoyl)piperazine-1-carboxylate (Boc-I-029) as an orange oil. .sup.1H NMR (400 MHz, Chloroform-d) 7.32-7.29 (m, 1H), 7.18 (dd, J=8.5, 2.5 Hz, 1H), 7.07 (td, J=8.3, 2.5 Hz, 1H), 3.92-3.79 (m, 1H), 3.73 (dt, J=13.2, 5.7 Hz, 1H), 3.63-3.50 (m, 2H), 3.48-3.34 (m, 2H), 3.34-3.10 (m, 2H), 1.48 (s, 9H). MS (ESI.sup.+): [M+H].sup.+ 343.1/345.1.
(2-chloro-4-fluoro-phenyl)-piperazin-1-yl-methanone (I-029)
##STR00096##
[0308] To a solution of crude tert-butyl 4-(2-chloro-4-fluoro-benzoyl)piperazine-1-carboxylate Boc-I-029 (10.2 g, 28.6 mmol, 1 equiv.) in dioxane (37 mL) at RT, was added HCl (4M solution in dioxane, 37 mL, 148 mmol, 5 equiv.). The mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and DCM. K.sub.2CO.sub.3(s) was added portionwise until pH >11. The layers were separated and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (80 g column, dry load, DCM/MeOH=98/2 to 80/20) to afford 5.24 g (72%) of (2-chloro-4-fluoro-phenyl)-piperazin-1-yl-methanone I-029 as an orange solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.41 (dd, J=8.8, 2.4 Hz, 1H), 7.32 (qd, J=8.4, 5.6 Hz, 2H), 3.87-3.69 (m, 2H), 3.15 (t, J=5.1 Hz, 2H), 2.94 (t, J=5.2 Hz, 2H), 2.80-2.70 (m, 2H). MS (ESI.sup.+): [M+H].sup.+ 243.1/245.1.
tert-butyl 3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Boc-I-030)
##STR00097##
[0309] To a solution of 2-chloro-4-fluorobenzoic acid (9.87 g, 56.5 mmol, 1.2 equiv.) in DMF (118 mL) at RT, was added TBTU (18.1 g, 56.5 mmol, 1.2 equiv.). The mixture was stirred 15 min at RT, and a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10.0 g, 47.1 mmol, 1 equiv.) and Et.sub.3N (9.8 mL, 71 mmol, 1.5 equiv.) in THF (118 mL) was added dropwise. The mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure. The reaction mixture was partitioned between aq. sat. NH.sub.4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc(2*). The combined organic extracts were washed (aq. sat. NH.sub.4Cl, aq. sat. NaHCO.sub.3, brine), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure to afford 21.3 g (76% pure, 93%) of tert-butyl 3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Boc-I-030) as an orange oil. .sup.1H NMR (400 MHz, Chloroform-d) 7.33 (dd, J=8.5, 5.9 Hz, 0.5H), 7.23-7.09 (m, 1.5H), 7.09-6.97 (m, 1H), 4.54-4.40 (m, 1H), 4.33 (s, 1H), 4.23-4.01 (m, 1H), 3.56-3.17 (m, 1H), 3.17-2.93 (m, 2H), 2.11-1.70 (m, 4H), 1.47 (s, 9H). MS (ESI.sup.+): [M+H].sup.+ 369.1/371.1.
(2-chloro-4-fluoro-phenyl)-(3,8-diazabicyclo[3.2.1]octan-3-yl)methanone (I-030)
##STR00098##
[0310] To a solution of crude tert-butyl 3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Boc-I-030 (21.3 g, 76% pure, 43.9 mmol, 1 equiv.) in dioxane (55 mL) at RT, was added HCl (4M solution in dioxane, 55 mL, 220 mmol, 5 equiv.). The mixture was stirred at RT for 60 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and DCM. K.sub.2CO.sub.3(s) was added portionwise until pH >11. The layers were separated and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (220 g column, dry load, DCM/MeOH (7N NH.sub.3)=99/1 to 95/5) to afford 10.3 g (88%) of (2-chloro-4-fluoro-phenyl)-(3,8-diazabicyclo[3.2.1]octan-3-yl)methanone I-030 as a white solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.32 (dd, J=8.5, 5.9 Hz, 0.5H), 7.20-7.15 (m, 0.5H), 7.15-7.10 (m, 1H), 7.09-6.98 (m, 1H), 4.47-4.37 (m, 1H), 3.69-3.56 (m, 1H), 3.44-3.34 (m, 1.5H), 3.22 (d, J=11.9 Hz, 0.5H), 3.10-2.98 (m, 2H), 1.95-1.48 (m, 4H). MS (ESI.sup.+): [M+H].sup.+ 269.1/271.0.
tert-butyl 4-(2-chloro-4-fluoro-benzoyl)-2-methyl-piperazine-1-carboxylate (Boc-I-031)
##STR00099##
[0311] To a solution of 2-chloro-4-fluorobenzoic acid (10.5 g, 59.9 mmol, 1.2 equiv.) in THF (120 mL) at RT, was added TBTU (19.2 g, 59.9 mmol, 1 equiv.). The mixture was stirred 15 min at RT, and a solution of tert-butyl 2-methylpiperazine-1-carboxylate (10.0 g, 49.9 mmol, 1 equiv.) and Et.sub.3N (6.5 mL, 37 mmol, 0.75 equiv.) in THF (120 mL) was added dropwise. The mixture was stirred at RT for 60 h. The reaction mixture was concentrated under reduced pressure. The reaction mixture was partitioned between aq. sat. NH.sub.4Cl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc(2*). The combined organic extracts were washed (aq. sat. NH.sub.4Cl, aq. sat. NaHCO.sub.3, brine), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (220 g column, dry load, cHex/EtOAc=90/10 to 50/50) to afford 16.8 g (94%) of tert-butyl 4-(2-chloro-4-fluoro-benzoyl)-2-methyl-piperazine-1-carboxylate (Boc-I-031) as a white solid. .sup.1H NMR (400 MHz, Chloroform-d, multiple sets of rotamers) 7.36-7.21 (m, 1H), 7.20-7.09 (m, 1H), 7.08-6.97 (m, 1H), 4.67-4.13 (m, 2H), 3.99-3.74 (m, 1H), 3.41-3.23 (m, 1H), 3.23-2.83 (m, 3H), 1.44 (s, 9H), 1.29-0.97 (m, 3H). MS (ESI.sup.+): [M+H].sup.+ 357.0/359.0.
(2-chloro-4-fluoro-phenyl)-(3-methylpiperazin-1-yl)methanone (I-031)
##STR00100##
[0312] To a solution of crude tert-butyl 4-(2-chloro-4-fluoro-benzoyl)-2-methyl-piperazine-1-carboxylate Boc-I-031 (16.8 g, 47.1 mmol, 1 equiv.) in DCM (235 mL) at 0 C., was added TFA (72 mL, 941 mmol, 20 equiv.). The mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and DCM at 0 C. K.sub.2CO.sub.3(s) was added portionwise until pH >11. The layers were separated and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (80 g column, dry load, DCM/MeOH (7N NH.sub.3)=99/1 to 90/10) to afford 9.8 g (81%) of (2-chloro-4-fluoro-phenyl)-(3-methylpiperazin-1-yl)methanone I-031 as a white solid. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.32 (ddd, J=8.6, 5.9, 1.3 Hz, 0.5H), 7.25 (ddd, J=8.5, 5.9, 1.4 Hz, 0.5H), 7.21-7.13 (m, 1H), 7.09-7.01 (m, 1H), 4.69-4.56 (m, 1H), 3.31-2.75 (m, 5H), 2.51 (m, 1H), 1.15 (dd, J=6.3, 2.4 Hz, 1.5H), 0.98 (dd, J=6.3, 4.5 Hz, 1.5H). MS (ESI.sup.+): [M+H].sup.+ 257.1/259.1.
Synthesis of Intermediates Required for Final Products 016 and 017
1-(5-isobutylsulfonyl-2-methoxy-phenyl)-2-methyl-piperazine (I-027)
##STR00101##
[0313] A microwave reaction vial was charged with the sulfone I-026 (1.53 g, 4.77 mmol, 1 equiv.), commercial tert-butyl 3-methylpiperazine-1-carboxylate (1.15 g, 5.73 mmol, 1.2 equiv.), Cs.sub.2CO.sub.3 (4.66 g, 14.3 mmol, 3 equiv.), Pd(OAc).sub.2 (107 mg, 477 mol, 0.1 equiv.) and rac-BINAP (297 mg, 477 mol, 0.1 equiv.). The vial was flushed with argon and degassed toluene (24 mL) was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating-block for 16 h. After cooling down to RT, EtOAc was added and the suspension was filtered over Celite (EtOAc rinses). The filtrate was concentrated under reduced pressure. The residue was directly treated with HCl (4M solution in dioxane, 1.68 mL, 6.72 mmol, 10 equiv.). The mixture was stirred at RT for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and DCM. NaOH 2M was added dropwise until pH >11. The layers were separated and the aqueous phase was extracted with DCM (2*). The combined organic extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry load, DCM/MeOH (7N NH.sub.3)=99/1 to 95/5) to afford 160 mg (9% over two steps) of I-027 as a yellow oil. .sup.1H NMR (400 MHz, Chloroform-d) 7.55 (dd, J=8.6, 2.3 Hz, 1H), 7.42 (d, J=2.3 Hz, 1H), 6.97 (d, J=8.6 Hz, 1H), 3.93 (s, 3H), 3.65-3.51 (m, 1H), 3.25 (ddd, J=11.2, 5.0, 2.1 Hz, 1H), 3.21-3.14 (m, 1H), 3.14-2.94 (m, 3H), 2.84-2.71 (m, 2H), 1.95-1.87 (m, 1H), 1.54-1.27 (m, 3H), 1.25 (d, J=6.9 Hz, 4H), 0.93 (dd, J=6.4, 1.3 Hz, 3H), 0.89 (t, J=7.2 Hz, 3H). MS (ESI.sup.+): [M+H].sup.+ 341.1.
Synthesis of Intermediates Required for Final Product 018
[4-fluoro-2-(trifluoromethyl)phenyl]-[4-(5-isobutylsulfanyl-2-methoxy-phenyl)piperazin-1-yl]methanone (I-024)
##STR00102##
[0314] A microwave reaction vial was charged with the thioether I-023 (180 mg, 654 mol, 1 equiv.), piperazine I-028 (271 mg, 981 mol, 1.5 equiv.), Cs.sub.2CO.sub.3 (426 mg, 1.31 mmol, 2 equiv.), Pd(OAc).sub.2 (15 mg, 67 mol, 0.1 equiv.) and rac-BINAP (50 mg, 81 mol, 0.12 equiv.). The vial was flushed with Ar and degassed toluene (3.4 mL) was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating-block for 4 h30. After cooling down to RT, EtOAc was added and the suspension was filtered over Celite (EtOAc rinses). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=100/0 to 30/70) affording I-024 in 83% yield. .sup.1H NMR (400 MHz, Chloroform-d) 7.43 (dd, J=8.9, 2.5 Hz, 1H), 7.38 (dd, J=8.6, 5.3 Hz, 1H), 7.32 (td, J=8.3, 2.6 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.97-6.89 (m, 1H), 6.80 (d, J=8.4 Hz, 1H), 4.04-3.91 (m, 2H), 3.85 (s, 3H), 3.43-3.30 (m, 2H), 3.20-3.06 (m, 2H), 3.05-2.88 (m, 2H), 2.73 (d, J=6.8 Hz, 2H), 1.81 (hept, J=6.7 Hz, 1H), 1.01 (d, J=6.7 Hz, 6H). .sup.19F NMR (376 MHz, Chloroform-d) 60.24, 109.44. MS (ESI.sup.+): [M+H].sup.+ 471.1.
Synthesis of Intermediates Required for Final Product 027, 028 & 029
tert-butyl 4-(3-bromo-4-methoxy-phenyl)sulfonylpiperidine-1-carboxylate (I-048)
##STR00103##
[0315] To a solution of 3-bromo-4-methoxy benzenethiol (1.38 g, 6.31 mmol, 1.05 equiv.) in MeCN (30 mL) at RT, were added t-Butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (1.68 g, 6.01 mmol, 1 equiv.) and K.sub.2CO.sub.3 (1.25 g, 9.02 mmol, 1.5 equiv.). The mixture was stirred at 80 C. for 16 h. After cooling down to RT, the suspension was filtered over fritted glass and the filtrate was concentrated under reduced pressure. The residue was solubilized in DCM (26 mL) at 0 C. and m-CPBA (70% wet, 9.36 g, 41.7 mmol, 7 equiv.) was added. The mixture was stirred at RT for 16 h. Aq. sat. Na.sub.2S.sub.2O.sub.3, aq. sat. NaHCO.sub.3 and EtOAc were added. The mixture was vigorously stirred for 10 min. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (brine), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=95/5 to 50/50) affording I-048 in 36% yield. .sup.1H NMR (400 MHz, Chloroform-d) 8.03 (d, J=2.2 Hz, 1H), 7.78 (dd, J=8.7, 2.3 Hz, 1H), 7.02 (d, J=8.7 Hz, 1H), 4.23 (s, 2H), 3.99 (s, 3H), 3.01 (tt, J=12.1, 3.6 Hz, 1H), 2.66 (s, 2H), 1.98 (d, J=12.9 Hz, 2H), 1.59 (dd, J=12.4, 4.9 Hz, 2H), 1.44 (s, 9H). MS (ESI.sup.+): [M+H].sup.+ 434.1/436.1.
tert-butyl 4-[3-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-methoxy-phenyl]sulfonylpiperidine-1-carboxylate (I-049)
##STR00104##
[0316] A microwave reaction vial was charged with the sulfone I-048 (500 mg, 1.15 mmol, 1 equiv.), piperazine I-030 (371 mg, 1.38 mmol, 1.2 equiv.), Cs.sub.2CO.sub.3 (1.12 g, 3.45 mmol, 3 equiv.), Pd(OAc).sub.2 (25.8 mg, 115 mol, 0.1 equiv.) and rac-BINAP (108 mg, 172 mol, 0.15 equiv.). The vial was flushed with Ar and degassed toluene (5.8 mL) was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating-block for 16 h. After cooling down to RT, EtOAc was added and the suspension was filtered over Celite (EtOAc rinses). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=90/10 to 0/100) affording I-049 in 76% yield. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.45-7.32 (m, 1.5H), 7.24-7.12 (m, 2.5H), 7.12-7.00 (m, 1H), 6.97 (d, J=8.5 Hz, 1H), 4.56-4.45 (m, 1H), 4.35-4.25 (m, 1H), 4.25-4.15 (m, 2H), 4.06 (s, 1H), 3.94 & 3.93 (s, 3H), 3.67 & 3.50 (d, J=12.4 Hz, 1H), 3.33-3.23 (m, 1H), 3.20-3.07 (m, 1H), 3.02-2.90 (m, 1H), 2.64 (s, 2H), 2.00-1.85 (m, 4.5H), 1.75-1.65 (m, 0.5H), 1.60-1.50 (m, 3H), 1.43 (s, 9H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.21, 109.33. MS (ESI.sup.+): [M+H].sup.+ 622.3/624.3.
(2-chloro-4-fluoro-phenyl)-[8-[2-methoxy-5-(4-piperidylsulfonyl)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone; hydrochloride (I-050)
##STR00105##
[0317] To a solution of I-049 (544 mg, 0.874 mmol, 1.00 equiv.) diluted in DCM (4.3 mL) at RT, was added HCl 4N in dioxane (4.37 mL, 17.5 mmol, 20.0 equiv.). The resulting solution was stirred at RT for 2 h. The reaction was concentrated under reduced pressure to afford I-050 in 100% yield. .sup.1H NMR (400 MHz, DMSO-d6, 2 sets of rotamers) 9.19 & 9.16 (s, 1H), 8.71 & 8.67 (s, 1H), 7.65-7.40 (m, 2H), 7.39-7.25 (m, 2H), 7.21 (d, J=8.6 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H), 4.43-4.23 (m, 2H), 3.89 (s, 3H), 3.55-3.25 (m, 4H), 3.18-2.92 (m, 2H), 2.84 (q, J=12.0 Hz, 2H), 2.05-1.55 (m, 8H). .sup.19F NMR (376 MHz, DMSO-d6, 2 sets of rotamers) 110.01, 110.22. MS (ESI.sup.+): [MCl].sup.+522.1/523.9.
Synthesis of Intermediates Required for Final Product 030 & 031
2-bromo-4-(4-piperidylsulfonyl)phenol (I-051)
##STR00106##
[0318] To a solution of I-048 (406 mg, 0.935 mmol, 1.00 equiv.) in DCM (4.7 mL) at RT, was added BBr.sub.3 (1.0 M solution in DCM, 1.87 mL, 1.87 mmol, 2 equiv. The resulting solution was stirred at RT for 30 h. Water was added dropwise and the pH of the aqueous phase was adjusted to 11 using 2N NaOH. Both phases were concentrated under reduced pressure. The residue was dissolved in DCM/MeOH (50/50) and the resulting suspension was filtered over Celite. The filtrate was concentrated under reduced pressure. The residue was purified by FC (DCM/MeOH=99/1 to 80/20) affording I-051 in 97% yield. .sup.1H NMR (400 MHz, DMSO-d6) 7.85 (d, J=2.3 Hz, 1H), 7.65 (dd, J=8.6, 2.3 Hz, 1H), 7.17 (d, J=8.6 Hz, 1H), 3.61-3.47 (m, 1H), 3.30-3.25 (m, 4H), 2.08-1.94 (m, 2H), 1.78-1.51 (m, 2H).MS (ESI.sup.+): [M+H].sup.+ 320.0/322.0.
1-[4-(3-bromo-4-hydroxy-phenyl)sulfonyl-1-piperidyl]-2,2,2-trifluoro-ethanone (I-052)
##STR00107##
[0319] To a solution of I-051 (298 mg, 0.93 mmol, 1.00 equiv.) and Et.sub.3N (0.26 mL, 1.9 mmol, 2 equiv.) in DCM (4.7 mL) at RT, was added trifluoroacetic anhydride (0.19 mL, 1.4 mmol, 1.5 equiv.). The mixture was stirred at RT for 2 h. HCl 1N was added. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with HCl 1N, aq. sat. NaHCO.sub.3 and brine, dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=95/5 to 0/100) affording I-052 in 39% yield. .sup.1H NMR (400 MHz, Chloroform-d) 8.00 (d, J=2.2 Hz, 1H), 7.73 (dd, J=8.6, 2.2 Hz, 1H), 7.19 (d, J=8.6 Hz, 1H), 6.19 (s, 1H), 4.63 (d, J=13.8 Hz, 1H), 4.14 (d, J=7.1 Hz, 1H), 3.14 (dddd, J=12.3, 8.5, 6.1, 3.3 Hz, 2H), 2.90-2.73 (m, 1H), 2.14 (t, J=15.7 Hz, 2H), 1.90-1.69 (m, 2H). .sup.19F NMR (376 MHz, Chloroform-d) 6-69.0. MS (ESI.sup.+): [M+H].sup.+ 416.0/418.0.
1-[4-[3-bromo-4-(methoxymethoxy)phenyl]sulfonyl-1-piperidyl]-2,2,2-trifluoro-ethanone (I-053)
##STR00108##
[0320] To a solution of I-052 (165 mg, 0.353 mmol, 1.00 equiv.) and iPr.sub.2EtN (0.18 mL, 1.1 mmol, 3 equiv.) in DCM (1.8 mL) at RT, was added chloromethyl methyl ether (0.05 mL, 0.7 mmol, 2 equiv.). The mixture was stirred at RT for 2 h. HCl 1N was added. The aqueous phase was extracted with DCM. The combined organic layers were washed with HCl 1N and brine, dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure affording I-053 in 95% yield as a colorless oil. .sup.1H NMR (400 MHz, Chloroform-d) 8.05 (d, J=2.3 Hz, 1H), 7.75 (dd, J=8.7, 2.3 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 5.35 (s, 2H), 4.63 (d, J=13.9 Hz, 1H), 4.14 (d, J=14.2 Hz, 1H), 3.54 (s, 3H), 3.26-3.04 (m, 2H), 2.80 (t, J=12.1 Hz, 1H), 2.22-2.03 (m, 2H), 1.87-1.66 (m, 2H)..sup.19F NMR (376 MHz, Chloroform-d) 69.0. MS (ESI.sup.+): [M+H].sup.+ 460.0/461.9.
1-[4-[3-[3-(2-chloro-4-fluoro-benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-(methoxymethoxy)phenyl]sulfonyl-1-piperidyl]-2,2,2-trifluoro-ethanone (I-054)
##STR00109##
[0321] A microwave reaction vial was charged with the sulfone I-053 (155 mg, 0.337 mmol, 1 equiv.), piperazine I-030 (109 mg, 0.404 mmol, 1.2 equiv.), Cs.sub.2CO.sub.3 (329 mg, 1.01 mmol, 3 equiv.), Pd(OAc).sub.2 (11.3 mg, 50.5 mol, 0.15 equiv.) and rac-BINAP (62.9 mg, 101 mol, 0.30 equiv.). The vial was flushed with Ar and degassed toluene (5.7 mL) was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating-block for 4 h. After cooling down to RT, EtOAc was added and the suspension was filtered over Celite (EtOAc rinses). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=90/10 to 0/100) affording I-054 in 52% yield. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.43-7.33 (m, 1.5H), 7.25-7.13 (m, 3.5H), 7.12-6.99 (m, 1H), 5.32-5.25 (m, 2H), 4.67-4.46 (m, 2H), 4.33 (s, 1H), 4.15-4.05 (m, 1H), 3.72-3.42 (m, 4H), 3.35-3.25 (m, 1H), 3.20-3.05 (m, 3H), 2.78 (t, J=12.7 Hz, 1H), 2.04 (s, 7H), 1.79-1.58 (m, 2H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 69.0, 109.06, 109.20. MS (ESI.sup.+): [M+H].sup.+ 648.2/650.1.
(2-chloro-4-fluoro-phenyl)-[8-[2-(methoxymethoxy)-5-(4-piperidylsulfonyl)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-055)
##STR00110##
[0322] To a solution of sulfone I-054 (130 mg, 0.177 mmol, 1 equiv.) in THF/MeOH/H.sub.2O (3/1/1, 2 mL) at RT, was added LiOH (21 mg, 0.88 mmol, 5 equiv.). The mixture was stirred at RT for 1 h. Water and DCM were added. The layers were separated and the aqueous phase was extracted with DCM. The combined organic layers were dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure affording I-055 in 76% yield. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.40-7.32 (m, 1.5H) 7.23-7.12 (m, 3.5H), 7.12-7.00 (m, 1H), 5.29-5.23 (m, 2H), 4.58-4.45 (m, 1H), 4.32 (s, 1H), 4.08 (s, 1H), 3.70-3.45 (m, 4H), 3.28 (d, J=12.9 Hz, 1H), 3.22-3.09 (m, 3H), 2.96 (tt, J=12.2, 3.6 Hz, 1H), 2.55 (td, J=12.4, 2.6 Hz, 2H), 2.11-1.88 (m, 5.5H), 1.70-1.60 (s, 0.5H), 1.58-1.50 (m, 3H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.17, 109.31. MS (ESI.sup.+): [M+H].sup.+ 552.2/554.1.
(2-chloro-4-fluoro-phenyl)-[8-[2-(methoxymethoxy)-5-[(1-phenyl-4-piperidyl)sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-056)
##STR00111##
[0323] A microwave reaction vial was charged with the amine I-055 (50 mg, 0.068 mmol, 1 equiv.), bromobenzene (13 mg, 0.082 mmol, 1.2 equiv.), Cs.sub.2CO.sub.3 (55.3 mg, 0.170 mmol, 2.5 equiv.), Pd(OAc).sub.2 (3.1 mg, 14 mol, 0.2 equiv.) and rac-BINAP (16.9 mg, 27.2 mol, 0.40 equiv.). The vial was flushed with Ar and degassed toluene (0.7 mL) was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating-block for 16 h. After cooling down to RT, EtOAc was added and the suspension was filtered over Celite (EtOAc rinses). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=90/10 to 0/100) affording I-056 in 62% yield. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.50-7.30 (m, 5H), 7.25-7.18 (m, 4H), 7.10-7.00 (m, 1H), 6.95-6.85 (m, 1H), 5.38-5.18 (m, 2H), 4.60-4.48 (m, 1H), 4.33 (s, 1H), 4.09 (s, 1H), 3.80-3.70 (m, 1H), 3.70-3.48 (m, 4H), 3.52 (d, J=3.8 Hz, 3H), 3.29 (d, J=13.0 Hz, 1H), 3.15 (t, J=10.5 Hz, 1H), 3.05-2.90 (m, 1H), 2.72-2.60 (m, 2H), 2.20-1.90 (m, 3.5H), 1.90-1.70 (m, 2H), 1.70-1.60 (m, 0.5H)..sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.13, 109.27. MS (ESI.sup.+): [M+H].sup.+ 628.2/630.2.
(2-chloro-4-fluoro-phenyl)-[8-[2-(methoxymethoxy)-5-[[1-(2-phenylethyl)-4-piperidyl]sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-057)
##STR00112##
[0324] To a solution of amine I-055 (50 mg, 0.068 mmol, 1 equiv.) in DCM (0.7 mL), were added acetic acid (7.8 L, 0.13 mmol, 2 equiv.), phenylacetaldehyde (15.8 L, 0.136 mmol, 2 equiv.) and NaBH(Oac).sub.3 (14 mg, 0.068 mmol, 1 equiv). The mixture was stirred at RT for 16 h. Sat. aq. NaHCO.sub.3 and DCM were added. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (DCM/MeOH=99/1 to 90/10) affording I-057 in 80% yield. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.41-7.30 (m, 3H), 7.23-7.14 (m, 6H), 7.12-6.96 (m, 2H), 5.34-5.19 (m, 2H), 4.56-4.45 (m, 1H), 4.32 (s, 1H), 4.08 (s, 1H), 3.70-3.45 (m, 4H), 3.30 & 3.27 (s, 1H), 3.20-2.97 (m, 3H), 2.97-2.42 (m, 7H), 2.12-1.85 (m, 5.5H), 1.75-1.60 (m, 2.5H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.17, 109.31. MS (ESI+): [M+H].sup.+ 656.2/658.2.
Synthesis of Intermediates Required for Final Product 032
4-(2,2-dimethylpropylsulfanyl)-1-methoxy-2-methyl-benzene (I-058)
##STR00113##
[0325] To a solution of 4-methoxy-3-methyl-benzenethiol (350 mg, 2.27 mmol, 1 equiv.) in dry DMF (2.3 mL) at RT, was added sodium hydride (60% in grease, 109 mg, 2.73 mmol, 1.2 equiv). The mixture was stirred at RT for 30 min and 1-bromo-2,2-dimethylpropane (0.34 mL, 2.73 mmol, 1.2 equiv). The mixture was stirred at 80 C. for 1 h. After cooling down to RT, water and MTBE were added. The layers were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were washed (brine), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=99/1 to 90/10) affording I-058 in 89% yield. .sup.1H NMR (400 MHz, Chloroform-d) 7.17-7.11 (m, 2H), 6.66 (d, J=8.2 Hz, 1H), 3.73 (s, 3H), 2.75 (s, 2H), 2.11 (s, 3H), 0.94 (s, 9H). MS (ESI.sup.+): [M+H].sup.+ 225.1.
4-(2,2-dimethylpropylsulfonyl)-1-methoxy-2-methyl-benzene (I-059)
##STR00114##
[0326] To a solution of I-058 (453 mg, 2.02 mmol, 1 equiv.) in DCM (10 mL) at 0 C., was added m-CPBA (70% wet, 1.10 g, 4.44 mmol, 2.2 equiv.). The mixture was stirred at RT for 1 h. Aq. sat. Na.sub.2S.sub.2O.sub.3, aq. sat. NaHCO.sub.3 and EtOAc were added. The mixture was vigorously stirred for 10 min. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (brine), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=95/5 to 50/50) affording I-059 in 86% yield. .sup.1H NMR (400 MHz, Chloroform-d) 7.73 (dd, J=8.6, 2.5 Hz, 1H), 7.65 (dd, J=2.4, 0.9 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H), 3.90 (s, 3H), 3.01 (s, 2H), 2.26 (s, 3H), 1.17 (s, 9H). MS (ESI.sup.+): [M+H].sup.+ 257.1.
4-(2,2-dimethylpropylsulfonyl)-2-methyl-phenol (I-060)
##STR00115##
[0327] To a solution of I-059 (550 mg, 1.74 mmol, 1 equiv.) in DCM (5 mL) at 0 C., was added BBr.sub.3 (1.0M in DCM, 5.2 mL, 5.2 mmol, 3 equiv.). The mixture was stirred at RT for 16 h. Water was added dropwise and the layers were separated. The aqueous phase was extracted with DCM. The combined organic extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=98/2 to 75/25) affording I-060 in 71% yield. .sup.1H NMR (400 MHz, Chloroform-d) 1H NMR (400 MHz, Chloroform-d) 7.67 (dd, J=2.4, 0.9 Hz, 1H), 7.63 (dd, J=8.4, 2.4 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 5.44 (s, 1H), 3.01 (s, 2H), 2.30 (s, 3H), 1.17 (s, 9H). MS (ESI.sup.+): [M+H].sup.+ 243.1.
2-bromo-4-(2,2-dimethylpropylsulfonyl)-6-methyl-phenol (I-061)
##STR00116##
[0328] To a solution of I-060 (300 mg, 1.24 mmol, 1 equiv.) in DMF (6.2 mL) at RT, was added N-bromosuccinimide (242 mg, 1.36 mmol, 1.1 equiv.). The mixture was stirred at RT for 1 h. Water and EtOAc were added and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=97/3 to 70/30) affording I-061 in 80% yield. .sup.1H NMR (400 MHz, Chloroform-d) 1H NMR (400 MHz, Chloroform-d) 7.90-7.87 (m, 1H), 7.64-7.59 (m, 1H), 6.04 (s, 1H), 3.00 (s, 2H), 2.36 (s, 3H), 1.19 (s, 9H). MS (ESI.sup.+): [M+H].sup.+ 321.0/323.0.
1-bromo-5-(2,2-dimethylpropylsulfonyl)-2-(methoxymethoxy)-3-methyl-benzene (I-062)
##STR00117##
[0329] To a solution of I-061 (320 mg, 0.996 mmol, 1.00 equiv.) and Et.sub.3N (0.28 mL, 2.0 mmol, 2 equiv.) in DCM (4 mL) at RT, was added chloromethyl methyl ether (0.11 mL, 1.5 mmol, 2 equiv.). The mixture was stirred at RT for 2 h. Sat. aq. NH.sub.4Cl and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed (water, brine), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=97/3 to 70/30) affording I-062 in 70% yield. .sup.1H NMR (400 MHz, Chloroform-d) 7.95 (d, J=2.3 Hz, 1H), 7.68 (d, J=2.3 Hz, 1H), 5.14 (s, 2H), 3.64 (s, 3H), 3.00 (s, 2H), 2.42 (s, 3H), 1.21 (s, 9H). MS (ESI.sup.+): [M+H].sup.+ 365.0/367.0.
(2-chloro-4-fluoro-phenyl)-[8-[5-(2,2-dimethylpropylsulfonyl)-2-(methoxymethoxy)-3-methyl-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone (I-063)
##STR00118##
[0330] A microwave reaction vial was charged with the sulfone I-062 (255 mg, 0.698 mmol, 1 equiv.), piperazine I-030 (225 mg, 0.834 mmol, 1.2 equiv.), t-BuONa (201 mg, 2.09 mmol, 3 equiv.) and XPhos-Pd-G3 (59.1 mg, 69.8 mol, 0.1 equiv.). The vial was flushed with Ar and degassed toluene (5.7 mL) was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating-block for 2 h. After cooling down to RT, EtOAc was added and the suspension was filtered over Celite (EtOAc rinses). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=96/4 to 60/40) affording I-063 in 26% yield. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.32 (s, 1H), 7.23-7.01 (m, 4H), 5.17-5.10 (m, 2H), 4.56-4.48 (m, 1H), 4.30 (s, 1H), 4.08 (s, 1H), 3.62-3.38 (m, 4H), 3.22 (d, J=12.9 Hz, 1H), 3.14 (t, J=12.1 Hz, 1H), 2.98 (s, 2H), 2.36 (s, 3H), 2.03-1.85 (m, 3.5H), 1.77-1.67 (m, 0.5H), 1.18 (s, 9H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.11, 109.26. MS (ESI.sup.+): [M+H].sup.+ 553.1/555.1.
Synthesis of Intermediates Required for Final Product 033
2-chloro-4-(2,2-dimethylpropylsulfanyl)-1-methoxy-benzene (I-064)
##STR00119##
[0331] To a solution of 3-chloro-4-methoxy-benzenethiol (500 mg, 2.86 mmol, 1 equiv.) in dry DMF (2.9 mL) at RT, was added sodium hydride (60% in grease, 137 mg, 3.43 mmol, 1.2 equiv). The mixture was stirred at RT for 30 min and 1-bromo-2,2-dimethylpropane (0.43 mL, 3.44 mmol, 1.2 equiv). The mixture was stirred at 80 C. for 1 h. After cooling down to RT, water and MTBE were added. The layers were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were washed (brine), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=99/1 to 90/10) affording I-064 in 92% yield. .sup.1H NMR (400 MHz, Chloroform-d) 7.44 (d, J=2.3 Hz, 1H), 7.29 (dd, J=8.5, 2.3 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 3.90 (s, 3H), 2.85 (s, 2H), 1.04 (s, 9H). MS (ESI.sup.+): [M+H].sup.+ 245.1/247.1.
2-chloro-4-(2,2-dimethylpropylsulfonyl)-1-methoxy-benzene (I-065)
##STR00120##
[0332] To a solution of I-064 (640 mg, 2.59 mmol, 1 equiv.) in DCM (13 mL) at 0 C., was added m-CPBA (70% wet, 1.40 g, 5.69 mmol, 2.2 equiv.). The mixture was stirred at RT for 1 h. Aq. sat. Na.sub.2S.sub.2O.sub.3, aq. sat. NaHCO.sub.3 and EtOAc were added. The mixture was vigorously stirred for 10 min. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (brine), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=95/5 to 50/50) affording I-065 in 98% yield. .sup.1H NMR (400 MHz, Chloroform-d) 7.94 (d, J=2.3 Hz, 1H), 7.82 (dd, J=8.7, 2.3 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 4.01 (s, 3H), 3.04 (s, 2H), 1.21 (s, 9H). MS (ESI.sup.+): [M+H].sup.+ 277.0/279.0.
2-chloro-4-(2,2-dimethylpropylsulfonyl)phenol (I-066)
##STR00121##
[0333] To a solution of I-065 (739 mg, 2.54 mmol, 1 equiv.) in DCM (5 mL) at 0 C., was added BBr.sub.3 (1.0M in DCM, 5.1 mL, 5.1 mmol, 2 equiv.). The mixture was stirred at RT for 16 h. Water was added dropwise and the layers were separated. The aqueous phase was extracted with DCM. The combined organic extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=95/5 to 50/50) affording I-066 in 92% yield. 1H NMR (400 MHz, Chloroform-d) 7.94 (d, J=2.2 Hz, 1H), 7.76 (dd, J=8.6, 2.2 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 6.17 (s, 1H), 3.04 (s, 2H), 1.21 (s, 9H). MS (ESI.sup.+): [M+H].sup.+ 263.0/265.0.
2-bromo-6-chloro-4-(2,2-dimethylpropylsulfonyl)phenol (I-067)
##STR00122##
[0334] To a solution of I-066 (624 mg, 2.30 mmol, 1 equiv.) in DMF (11.5 mL) at RT, was added N-bromosuccinimide (451 mg, 2.53 mmol, 1.1 equiv.). The mixture was stirred at RT for 1 h. Water and EtOAc were added and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=95/5 to 50/50) affording I-067 in 94% yield. .sup.1H NMR (400 MHz, Chloroform-d) 1H NMR (400 MHz, Chloroform-d) 8.00 (d, J=2.1 Hz, 1H), 7.90 (d, J=2.1 Hz, 1H), 6.40 (s, 1H), 3.04 (s, 2H), 1.23 (s, 9H).
1-bromo-3-chloro-5-(2,2-dimethylpropylsulfonyl)-2-(methoxymethoxy)benzene (I-068)
##STR00123##
[0335] To a solution of I-067 (740 mg, 2.17 mmol, 1.00 equiv.) and Et.sub.3N (0.60 mL, 4.3 mmol, 2 equiv.) in DCM (8.7 mL) at RT, was added chloromethyl methyl ether (0.25 mL, 3.2 mmol, 2 equiv.). The mixture was stirred at RT for 2 h. Sat. aq. NH.sub.4Cl and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed (water, brine), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=97/3 to 70/30) affording I-068 in 62% yield. .sup.1H NMR (400 MHz, Chloroform-d) 8.04 (d, J=2.2 Hz, 1H), 7.92 (d, J=2.2 Hz, 1H), 5.29 (s, 2H), 3.73 (s, 3H), 3.04 (s, 2H), 1.25 (s, 9H). MS (ESI.sup.+): [M+H].sup.+ 384.9/386.9.
[8-[3-chloro-5-(2,2-dimethylpropylsulfonyl)-2-(methoxymethoxy)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro-phenyl)methanone (I-069)
##STR00124##
[0336] A microwave reaction vial was charged with the sulfone I-068 (260 mg, 0.674 mmol, 1 equiv.), piperazine I-030 (235 mg, 0.876 mmol, 1.3 equiv.), t-BuONa (194 mg, 2.02 mmol, 3 equiv.) and XPhos-Pd-G3 (57.1 mg, 67.4 mol, 0.1 equiv.). The vial was flushed with Ar and degassed toluene (5.7 mL) was added. The vial was sealed and the reaction was stirred at reflux in a preheated heating-block for 2 h. After cooling down to RT, EtOAc was added and the suspension was filtered over Celite (EtOAc rinses). The filtrate was concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=96/4 to 60/40) affording I-069 in 53% yield. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.55-7.50 (m, 1H), 7.39 (dd, J=8.5, 5.8 Hz, 0.5H), 7.27-7.15 (m, 2.5H), 7.15-7.01 (m, 1H), 5.27-5.18 (m, 2H), 4.60-4.49 (m, 1H), 4.40 (s, 1H), 4.20 & 4.19 (s, 1H), 3.70-3.42 (m, 4H), 3.34-3.12 (m, 2H), 3.02 (s, 2H), 2.05-1.87 (m, 3.5H), 1.72-1.65 (m, 0.5H), 1.22 (s, 9H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 108.93, 109.08. MS (EST+): [M+H].sup.+ 573.1/575.1.
Synthesis of Intermediates Required for Final Product 035
1-bromo-2,3-dichloro-5-iodo-benzene (1-070)
##STR00125##
[0337] 3-bromo-4,5-dichloroaniline (617 mg, 2.56 mmol, 1 equiv.) was added to a solution of H.sub.2SO.sub.4 (0.41 mL, 7.7 mmol, 3 equiv.) in water (9.5 mL). The mixture was stirred at 80 C. for 10 min before being cooled down to 5 C. A solution of NaNO.sub.2 (177 mg, 2.56 mmol, 1 equiv.) in water (1.1 mL) was added dropwise. The mixture was stirred at RT for 1 h and a solution of KI (425 mg, 2.56 mmol, 1 equiv.) in water (1.1 mL) was added dropwise. The resulting mixture was stirred at RT for 30 min and at 40 C. for 30 min. EtOAc was added and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=99/1 to 80/20) affording I-070 in 62% yield. .sup.1H NMR (400 MHz, Chloroform-d) 7.88 (d, J=2.0 Hz, 1H), 7.76 (d, J=1.9 Hz, 1H).
1-bromo-2,3-dichloro-5-(2,2-dimethylpropylsulfanyl)benzene (I-071)
##STR00126##
[0338] A MW vial was charged with I-070 (500 mg, 1.42 mmol, 1 equiv.) and XantPhos-Pd-G3 (135 mg, 0.142 mmol, 0.1 equiv.). The vial was flushed with Ar and degassed toluene (7.1 mL) was added. iPr.sub.2NEt (495 L, 3.84 mmol, 2 equiv.) and 2,2-dimethylpropane-1-thiol (172 L, 1.42 mmol, 1 equiv.) were added. The vial was sealed and the reaction was stirred at 100 C. in a preheated heating-block for 1 h. After cooling down to RT, the reaction mixture was concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=100/0 to 80/20) affording I-071 in 66% yield. .sup.1H NMR (400 MHz, Chloroform-d) 7.47 (d, J=2.2 Hz, 1H), 7.35 (d, J=2.2 Hz, 1H), 2.87 (s, 2H), 1.06 (s, 9H).
1-bromo-2,3-dichloro-5-(2,2-dimethylpropylsulfonyl)benzene (I-072)
##STR00127##
[0339] Using GP-2, I-072 was obtained as a white solid in 72% yield using I-071 (308 mg, 939 mol, 1 equiv.) and m-CPBA (70% wet, 509 mg, 2.07 mmol, 2.2 equiv.) in DCM (4.7 mL) at RT for 1 h. Purified by FC (cHex/EtOAc=100/0 to 70/30). .sup.1H NMR (400 MHz, Chloroform-d) 8.08 (d, J=2.0 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 3.04 (s, 2H), 1.23 (s, 9H). MS (ESI.sup.+): [M+H].sup.+ 358.9/360.9.
Synthesis of Intermediates Required for Final Product 036
1-bromo-3-chloro-5-iodo-2-methyl-benzene (I-073)
##STR00128##
[0340] 3-bromo-5-chloro-4-methylaniline (363 mg, 1.65 mmol, 1 equiv.) was added to a solution of H.sub.2SO.sub.4 (0.26 mL, 4.9 mmol, 3 equiv.) in water (6.1 mL). The mixture was stirred at 80 C. for 10 min before being cooled down to 5 C. A solution of NaNO.sub.2 (114 mg, 1.65 mmol, 1 equiv.) in water (0.7 mL) was added dropwise. The mixture was stirred at RT for 1 h and a solution of KI (273 mg, 1.65 mmol, 1 equiv.) in water (0.7 mL) was added dropwise. The resulting mixture was stirred at RT for 30 min and at 40 C. for 30 min. EtOAc was added and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=100/0 to 70/30) affording I-073 in 32% yield. .sup.1H NMR (400 MHz, Chloroform-d) 7.80 (d, J=1.7 Hz, 1H), 7.66 (d, J=1.7 Hz, 1H), 2.47 (s, 3H).
1-bromo-3-chloro-5-(2,2-dimethylpropylsulfanyl)-2-methyl-benzene (I-074)
##STR00129##
[0341] A MW vial was charged with I-073 (174 mg, 0.525 mmol, 1 equiv.) and XantPhos-Pd-G3 (50 mg, 0.052 mmol, 0.1 equiv.). The vial was flushed with Ar and degassed toluene (2.6 mL) was added. iPr.sub.2NEt (183 L, 1.05 mmol, 2 equiv.) and 2,2-dimethylpropane-1-thiol (63.6 L, 0.525 mmol, 1 equiv.) were added. The vial was sealed and the reaction was stirred at 100 C. in a preheated heating-block for 1.5 h. After cooling down to RT, the reaction mixture was concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc=100/0 to 80/20) affording I-074 in 58% yield. .sup.1H NMR (400 MHz, Chloroform-d) 7.43 (d, J=1.9 Hz, 1H), 7.28 (d, J=1.9 Hz, 1H), 2.86 (s, 2H), 2.46 (s, 3H), 1.05 (s, 9H).
1-bromo-3-chloro-5-(2,2-dimethylpropylsulfonyl)-2-methyl-benzene (I-075)
##STR00130##
[0342] Using GP-2, I-075 was obtained as a white solid in 67% yield using I-074 (93.0 mg, 302 mol, 1 equiv.) and m-CPBA (70% wet, 164 mg, 0.665 mmol, 2.2 equiv.) in DCM (1.5 mL) at RT for 16 h. Purified by FC (cHex/EtOAc=100/0 to 70/30). .sup.1H NMR (400 MHz, Chloroform-d) 8.00 (d, J=1.8 Hz, 1H), 7.86 (d, J=1.8 Hz, 1H), 3.03 (s, 2H), 2.60 (s, 3H), 1.22 (s, IOH). MS (ESI.sup.+): [M+H].sup.+ 339.0/341.0.
Synthesis of Final Compounds
Synthetic methods for final compounds
[0343] The synthetic protocols for the final compounds are presented on the following Table 2.
TABLE-US-00004 TABLE 2 Cpd Synthetic protocols Purity 001 According to GP-3, 001 was obtained in 87% yield using aryl bromide >95% I-012 (215 mg, 633 mol, 1 equiv.), piperazine I-028 (211 mg, 736 mol, 1.2 equiv.), Cs.sub.2CO.sub.3 (311 mg, 953 mol, 1.5 equiv.), Pd(OAc).sub.2 (7.1 mg, 32 mol, 0.05 equiv.) and rac-BINAP (24 mg, 38 mol, 0.06 equiv.) in Toluene (3.2 mL) at reflux for 6 h. Purification by FC (cHex/EtOAc = 95/5 to 0/100). 002 According to GP-3, 002 was obtained in 80% yield using aryl bromide >95% I-013 (131 mg, 410 mol, 1 equiv.), piperazine I-028 (136 mg, 493 mol, 1.2 equiv.), Cs.sub.2CO.sub.3 (201 mg, 616 mol, 1.5 equiv.), Pd(OAc).sub.2 (4.6 mg, 21 mol, 0.05 equiv.) and rac-BINAP (15 mg, 25 mol, 0.06 equiv.) in Toluene (2.1 mL) at reflux for 2.5 h. Purification by FC (cHex/EtOAc = 95/5 to 0/100). 003 According to GP-3, 003 was obtained in 20% yield using aryl bromide >95% I-014 (76.0 mg, 228 mol, 1 equiv.), piperazine I-028 (78.0 mg, 274 mol, 1.2 equiv.), Cs.sub.2CO.sub.3 (111 mg, 342 mol, 1.5 equiv.), Pd(OAc).sub.2 (4.6 mg, 21 mol, 0.05 equiv.) and rac-BINAP (8.5 mg, 14 mol, 0.06 equiv.) in Toluene (1.1 mL) at reflux for 18 h. Purification by FC (cHex/EtOAc = 95/5 to 50/50). 004 According to GP-3, 004 was obtained in 47% yield using aryl bromide >95% I-013 (100 mg, 313 mol, 1 equiv.), piperazine I-030 (101 mg, 376 mol, 1.2 equiv.), Cs.sub.2CO.sub.3 (153 mg, 470 mol, 1.5 equiv.), Pd(OAc).sub.2 (4.6 mg, 21 mol, 0.05 equiv.) and rac-BINAP (12 mg, 19 mol, 0.06 equiv.) in Toluene (1.1 mL) at reflux for 5 h. Purification by FC (cHex/EtOAc = 95/5 to 0/100). 005 According to GP-3, 005 was obtained in 54% yield using aryl bromide >95% I-012 (100 mg, 311 mol, 1 equiv.), piperazine I-030 (100 mg, 374 mol, 1.2 equiv.), Cs.sub.2CO.sub.3 (152 mg, 467 mol, 1.5 equiv.), Pd(OAc).sub.2 (3.5 mg, 16 mol, 0.05 equiv.) and rac-BINAP (12 mg, 19 mol, 0.06 equiv.) in Toluene (1.5 mL) at reflux for 12 h. Purification by FC (cHex/EtOAc = 95/5 to 0/100). 006 According to GP-3, 006 was obtained in 11% yield using aryl bromide >95% I-013 (300 mg, 940 mol, 1 equiv.), piperazine I-031 (290 mg, 1.13 mmol, 1.2 equiv.), Cs.sub.2CO.sub.3 (459 mg, 1.41 mmol, 1.5 equiv.), Pd(OAc).sub.2 (11 mg, 47 mol, 0.05 equiv.) and rac-BINAP (35 mg, 56 mol, 0.06 equiv.) in Toluene (4.7 mL) at reflux for 48 h. Purification by FC (cHex/EtOAc = 95/5 to 0/100). 007 According to GP-3, 007 was obtained in 10% yield using aryl bromide >95% I-012 (300 mg, 934 mol, 1 equiv.), piperazine I-031 (288 mg, 1.12 mmol, 1.2 equiv.), Cs.sub.2CO.sub.3 (456 mg, 1.40 mmol, 1.5 equiv.), Pd(OAc).sub.2 (11 mg, 47 mol, 0.05 equiv.) and rac-BINAP (35 mg, 56 mol, 0.06 equiv.) in Toluene (4.7 mL) at reflux for 24 h. Purification by FC (cHex/EtOAc = 95/5 to 0/100). 008 According to GP-3, 008 was obtained in 36% yield using aryl bromide >95% I-022 (45.0 mg, 154 mol, 1 equiv.), piperazine I-029 (45.0 mg, 184 mol, 1.2 equiv.), Cs.sub.2CO.sub.3 (75.0 mg, 230 mol, 1.5 equiv.), Pd(OAc).sub.2 (1.7 mg, 7.7 mol, 0.05 equiv.) and rac-BINAP (5.7 mg, 9.2 mol, 0.06 equiv.) in Toluene (0.8 mL) at reflux for 16 h. Purification by FC (cHex/EtOAc = 95/5 to 0/100). 009 According to GP-3, 009 was obtained in 27% yield using aryl bromide >95% I-015 (110 mg, 360 mol, 1 equiv.), piperazine I-029 (105 mg, 433 mol, 1.2 equiv.), Cs.sub.2CO.sub.3 (176 mg, 541 mol, 1.5 equiv.), Pd(OAc).sub.2 (4.1 mg, 18 mol, 0.05 equiv.) and rac-BINAP (14 mg, 22 mol, 0.06 equiv.) in Toluene (1.8 mL) at reflux for 16 h. Purification by FC (cHex/EtOAc = 95/5 to 0/100) and PTLC (CHex/(EtOAc/EtOH = 3/1) = 1/1). 010 According to GP-4, 010 was obtained in 79% yield using aryl bromide >95% I-016 (110 mg, 360 mol, 1 equiv.), piperazine I-030 (145 mg, 541 mol, 1.5 equiv.), t-BuONa (104 mg, 1.08 mmol, 3 equiv.), XPhos-Pd-G3 (31 mg, 36 mol, 0.1 equiv.) in Toluene (1.8 mL) at reflux for 16 h. Purification by FC (cHex/EtOAc = 95/5 to 0/100). 011 According to GP-4, 011 was obtained in 34% yield using aryl bromide >95% I-017 (50.0 mg, 163 mol, 1 equiv.), piperazine I-029 (60.0 mg, 244 mol, 1.5 equiv.), t-BuONa (47.0 mg, 488 mol, 3 equiv.), XPhos- Pd-G3 (14 mg, 16 mol, 0.1 equiv.) in Toluene (0.8 mL) at reflux for 2 h. Purification by FC (cHex/EtOAc = 95/5 to 0/100). 012 According to GP-4, 012 was obtained in 29% yield using aryl bromide >95% I-018 (60.0 mg, 188 mol, 1 equiv.), piperazine I-029 (68.0 mg, 282 mol, 1.5 equiv.), t-BuONa (54.0 mg, 564 mol, 3 equiv.), XPhos- Pd-G3 (16 mg, 19 mol, 0.1 equiv.) in Toluene (0.9 mL) at reflux for 2 h. Purification by FC (cHex/EtOAc = 95/5 to 0/100). 013 According to GP-4, 013 was obtained in 29% yield using aryl bromide >95% I-019 (60.0 mg, 180 mol, 1 equiv.), piperazine I-029 (66 mg, 270 mol, 1.5 equiv.), t-BuONa (52.0 mg, 540 mol, 3 equiv.), XPhos-Pd-G3 (15 mg, 18 mol, 0.1 equiv.) in Toluene (0.9 mL) at reflux for 2 h. Purification by FC (cHex/EtOAc = 95/5 to 0/100) and PTLC (DCM/MeOH = 95/05). 014 According to GP-4, 014 was obtained in 90% yield using aryl bromide >95% I-020 (100 mg, 293 mol, 1 equiv.), piperazine I-030 (118 mg, 440 mol, 1.5 equiv.), t-BuONa (85.0 mg, 879 mol, 3 equiv.), XPhos-Pd-G3 (25 mg, 29 mol, 0.1 equiv.) in Toluene (1.5 mL) at reflux for 16 h. Purification by FC (cHex/EtOAc = 95/5 to 0/100). 015 According to GP-4, 015 was obtained in 32% yield using aryl bromide >95% I-021 (40 mg, 125 mol, 1 equiv.), piperazine I-030 (50.0 mg, 187 mol, 1.5 equiv.), t-BuONa (36.0 mg, 374 mol, 3 equiv.), XPhos-Pd-G3 (11 mg, 13 mol, 0.1 equiv.) in Toluene (0.6 mL) at reflux for 16 h. Purification by FC (cHex/EtOAc = 95/5 to 0/100) and PTLC (DCM/MeOH = 90/10). 016 To a solution of 2-chloro-4-fluorobenzoic acid (38.5 mg, 220 mol, 1.5 >95% equiv.) in DMF (1.5 mL) at RT, was added TBTU (70.7 mg, 220 mol, 1.5 equiv.). The mixture was stirred 30 min at RT, and a solution of piperazine I-027 (50 mg, 147 mol, 1.00 equiv) and Et.sub.3N (41 L, 294 mol, 2 equiv) in THF (1.5 mL) was added dropwise. The mixture was stirred at RT for 16 h. The reaction mixture was partitioned between EtOAc and aq. sat. NH.sub.4Cl. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (aq. sat. NH.sub.4Cl, aq. sat. NaHCO.sub.3, brine), dried (NaSO4), filtered and concentrated under reduced pressure. The residue was purified by PTLC (cHex/EtOAc = 50/50) and another PTLC (DCM/EtOAc = 90/10) affording 016 in 49% yield. 017 To a solution of 4-fluoro-2-(trifluoromethyl)benzoic acid (45.8 mg, >95% 220 mol, 1.5 equiv.) in DMF (1.5 mL) at RT, was added TBTU (70.7 mg, 220 mol, 1.5 equiv.). The mixture was stirred 30 min at RT, and a solution of piperazine I-027 (50 mg, 147 mol, 1.00 equiv) and triethylamine (41 L, 294 mol, 2 equiv) in THF (1.5 mL) was added dropwise. The mixture was stirred at RT for 16 h. The reaction mixture was partitioned between EtOAc and aq. sat. NH.sub.4Cl. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (aq. sat. NH.sub.4Cl, aq. sat. NaHCO.sub.3, brine), dried (NaSO4), filtered and concentrated under reduced pressure. The residue was purified by PTLC (cHex/EtOAc = 50/50) and another PTLC (DCM/EtOAc = 90/10) affording 017 in 58% yield. 018 To a solution of thioether I-024 (105 m, 223 mol, 1 equiv.) in >95% THF/water (2/1, 2.2 mL) at RT, was added oxone (137 mg, 440 mol, 2 equiv.). After 2 h, more oxone (68 mg, 110 mol, 1 equiv.) was added and the mixture was stirred a further 2 h at RT. Water was added and the product was extracted twice with EtOAc. The combined organics extracts were washed with brine, dried (MgSO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc = 95/5 to 0/100) affording 018 in 9% yield. 019 According to GP-4, 019 was obtained in 22% yield using aryl bromide >95% I-040 (73.0 mg, 210 mol, 1 equiv.), piperazine I-030 (67.8 mg, 252 mol, 1.2 equiv.), t-BuONa (61 mg, 0.63 mmol, 3 equiv.), XPhos- Pd-G3 (8.9 mg, 11 mol, 0.05 equiv.) in Toluene (1.1 mL) at reflux for 2 h. Purification by FC (cHex/EtOAc = 95/5 to 0/100). 020 According to GP-4, 020 was obtained in 78% yield using aryl bromide >95% I-041 (40.0 mg, 130 mol, 1 equiv.), piperazine I-030 (45.5 mg, 169 mol, 1.3 equiv.), t-BuONa (37 mg, 0.39 mmol, 3 equiv.), XPhos- Pd-G3 (11 mg, 13 mol, 0.1 equiv.) in Toluene (0.7 mL) at reflux for 5 h. Purification by FC (cHex/EtOAc = 95/5 to 0/100). 021 According to GP-4, 021 was obtained in 62% yield using aryl bromide >95% I-042 (185 mg, 552 mol, 1 equiv.), piperazine I-030 (193 mg, 717 mol, 1.3 equiv.), t-BuONa (159 mg, 1.65 mmol, 3 equiv.), XPhos-Pd-G3 (47 mg, 55 mol, 0.1 equiv.) in Toluene (2.8 mL) at reflux for 5 h. Purification by FC (cHex/EtOAc = 95/5 to 0/100). 022 According to GP-4, 022 was obtained in 78% yield using aryl bromide >95% I-043 (40.0 mg, 130 mol, 1 equiv.), piperazine I-030 (45.5 mg, 169 mol, 1.3 equiv.), t-BuONa (37.5 mg, 0.391 mmol, 3 equiv.), XPhos-Pd-G3 (11 mg, 13 mol, 0.1 equiv.) in Toluene (0.7 mL) at reflux for 5 h. Purification by FC (cHex/EtOAc = 95/5 to 0/100). 023 According to GP-4, 023 was obtained in 68% yield using aryl bromide >95% I-044 (98.0 mg, 256 mol, 1 equiv.), piperazine I-030 (82.4 mg, 307 mol, 1.2 equiv.), t-BuONa (73.7 mg, 0.767 mmol, 3 equiv.), XPhos-Pd-G3 (11 mg, 13 mol, 0.05 equiv.) in Toluene (2.6 mL) at reflux for 5 h. Purification by FC (cHex/EtOAc = 95/5 to 30/70). 024 According to GP-4, 024 was obtained in 21% yield using aryl bromide >95% I-045 (75.0 mg, 189 mol, 1 equiv.), piperazine I-030 (60.9 mg, 227 mol, 1.2 equiv.), t-BuONa (54.4 mg, 0.566 mmol, 3 equiv.), XPhos-Pd-G3 (8.0 mg, 9.4 mol, 0.05 equiv.) in Toluene (1.9 mL) at reflux for 16 h. Purification by FC (cHex/EtOAc = 95/5 to 30/70). 025 According to GP-4, 025 was obtained in 60% yield using aryl bromide >95% I-046 (100 mg, 252 mol, 1 equiv.), piperazine I-030 (81.1 mg, 302 mol, 1.2 equiv.), t-BuONa (72.6 mg, 0.755 mmol, 3 equiv.), XPhos-Pd-G3 (11 mg, 13 mol, 0.05 equiv.) in Toluene (2.5 mL) at reflux for 2 h. Purification by FC (cHex/EtOAc = 95/5 to 30/70). 026 According to GP-3, 026 was obtained in 82% yield using aryl bromide >95% I-047 (25 mg, 61 mol, 1 equiv.), piperazine I-030 (20 mg, 73 mol, 1.2 equiv.), Cs.sub.2CO.sub.3 (59.4 mg, 182 mol, 3 equiv.), Pd(OAc).sub.2 (1.4 mg, 6.1 mol, 0.1 equiv.) and rac-BINAP (4.6 mg, 7.3 mol, 0.12 equiv.) in Toluene (0.3 mL) at reflux for 16 h. Purification by PTLC (cHex/EtOAc = 70/30). 027 According to GP-4, 027 was obtained in 40% yield using amine >95% hydrochloride I-050 (80.0 mg, 135 mol, 1 equiv.), bromobenzene (21.3 L, 202 mol, 1.5 equiv.), t-BuONa (38.8 mg, 0.403 mmol, 3 equiv.), XPhos-Pd-G3 (11 mg, 13 mol, 0.05 equiv.) in Toluene (0.7 mL) at reflux for 16 h. Purification by PTLC (cHex/EtOAc = 50/50). 028 To a solution of amine hydrochloride I-050 (80.0 mg, 135 mol, 1 >95% equiv.) in DCM (0.7 mL) at RT, were added phenylacetaldehyde (37 mg, 0.31 mmol, 2 equiv.) and NaBH(OAc).sub.3 (65 mg, 0.31 mmol, 2 equiv.). The mixture was stirred at RT for 2 h. Sat. aq. NaHCO.sub.3 and the layers were separated. The aqueous phase was extracted with DCM and the combined organic extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by PTLC (cHex/EtOAc = 50/50) affording 028 in 55% yield. 029 To a solution of amine hydrochloride I-050 (80.0 mg, 135 mol, 1 >95% equiv.) in DCM (0.7 mL) at RT, were added 2-(4- Fluorophenyl)acetaldehyde (42 mg, 0.31 mmol, 2 equiv.) and NaBH(OAc).sub.3 (65 mg, 0.31 mmol, 2 equiv.). The mixture was stirred at RT for 2 h. Sat. aq. NaHCO.sub.3 and the layers were separated. The aqueous phase was extracted with DCM and the combined organic extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The residue was purified by PTLC (cHex/EtOAc = 50/50) affording 029 in 41% yield. 030 To a solution of I-056 (42 mg, 67 mol, 1 equiv.) in DCM (0.7 mL) at >95% RT, was added TFA (0.10 mL, 1.3 mmol, 20 equiv.). The mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by PTLC (CHCl.sub.3/iPrOH = 97/3) affording 030 in 36% yield. 031 To a solution of I-057 (44 mg, 67 mol, 1 equiv.) in DCM (0.7 mL) at >95% RT, was added TFA (0.10 mL, 1.3 mmol, 20 equiv.). The mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by PTLC (DCM/MeOH = 95/5) affording 031 in 49% yield. 032 To a solution of I-063 (100 mg, 181 mol, 1 equiv.) in DCM (0.9 mL) at >95% RT, was added TFA (0.28 mL, 3.6 mmol, 20 equiv.). The mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc = 95/5 to 50/50) affording 032 in 11% yield. 033 To a solution of I-069 (200 mg, 349 mol, 1 equiv.) in DCM (1.7 mL) at >95% RT, was added TFA (0.54 mL, 7.0 mmol, 20 equiv.). The mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by FC (cHex/EtOAc = 95/5 to 50/50) affording 033 in 84% yield. 034 A suspension of 033 (45 mg, 85 mol, 1 equiv.) 2-bromoethanol (15 L, >95% 0.21 mmol, 2.5 equiv.) and K.sub.2CO.sub.3 (35 mg, 0.26 mmol, 3 equiv.) in dry DMF (0.8 mL) was stirred at 50 C. for 16 h. Water was added and the product was extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by PTLC (cHex/EtOAc = 30/70) to afford 034 in 72% yield. 035 According to GP-3, 035 was obtained in 58% yield using aryl bromide >95% I-072 (120 mg, 333 mol, 1 equiv.), piperazine I-030 (107 mg, 400 mol, 1.2 equiv.), Cs.sub.2CO.sub.3 (326 mg, 1.00 mmol, 3 equiv.), Pd(OAc).sub.2 (7.5 mg, 33 mol, 0.10 equiv.) and rac-BINAP (25 mg, 40 mol, 0.12 equiv.) in Toluene (1.7 mL) at reflux for 2 h. Purification by FC (cHex/EtOAc = 92/8 to 20/80) and PTLC (cHex/EtOAc = 50/50). 036 According to GP-3, 036 was obtained in 27% yield using aryl bromide >95% I-075 (69.0 mg, 203 mol, 1 equiv.), piperazine I-030 (65.5 mg, 244 mol, 1.2 equiv.), Cs.sub.2CO.sub.3 (199 mg, 0.609 mmol, 3 equiv.), Pd(OAc).sub.2 (4.6 mg, 20 mol, 0.10 equiv.) and rac-BINAP (15 mg, 24 mol, 0.12 equiv.) in Toluene (1.0 mL) at reflux for 2 h. Purification by FC (cHex/EtOAc = 94/6 to 40/60) and PTLC (cHex/EtOAc = 70/30).
Analytical Data for the Final Compounds
[0344] The analytical data for the final compounds are presented on the following Table 3.
TABLE-US-00005 TABLE 3 Cpd Description 001 White solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.58 (dd, J = 8.5, 2.2 Hz, 1H), 7.46 (dd, J = 8.8, 2.5 Hz, 1H), 7.43-7.31 (m, 3H), 7.00 (d, J = 8.6 Hz, 1H), 4.05 (ddd, J = 13.3, 6.4, 3.4 Hz, 1H), 4.00-3.90 (m, 4H), 3.38 (t, J = 5.1 Hz, 2H), 3.22 (ddd, J = 10.1, 6.4, 3.5 Hz, 1H), 3.14 (ddd, J = 11.5, 7.1, 3.5 Hz, 1H), 3.08-2.93 (m, 2H), 2.77 (tt, J = 7.1, 4.8 Hz, 1H), 1.95-1.80 (m, 2H), 1.75-1.60 (m, 2H), 1.01 (t, J = 7.5 Hz, 6H). .sup.19F NMR (376 MHz, Chloroform-d) 60.3, 109.2. MS (ESI.sup.+): [M + H].sup.+ 517.2. 002 Brown solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.61 (dd, J = 8.5, 2.2 Hz, 1H), 7.46 (dd, J = 8.8, 2.5 Hz, 1H), 7.43-7.31 (m, 3H), 7.00 (d, J = 8.6 Hz, 1H), 4.04 (ddd, J = 13.2, 6.4, 3.6 Hz, 1H), 4.00-3.92 (m, 4H), 3.57-3.42 (m, 1H), 3.38 (t, J = 5.1 Hz, 2H), 3.22 (ddd, J = 10.2, 6.5, 3.7 Hz, 1H), 3.14 (ddd, J = 11.5, 7.1, 3.6 Hz, 1H), 3.08- 2.93 (m, 2H), 2.12-2.00 (m, 2H), 1.95-1.84 (m, 2H), 1.84-1.70 (m, 2H), 1.68-1.60 (m, 2H). .sup.19F NMR (376 MHz, Chloroform-d) 60.2, 109.2. MS (ESI.sup.+): [M + H].sup.+ 515.1. 003 White solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.55 (dd, J = 8.5, 2.2 Hz, 1H), 7.44 (dd, J = 8.8, 2.5 Hz, 1H), 7.38 (m, 1H), 7.36-7.31 (m, 1H), 7.30 (d, J = 2.3 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 4.06-3.90 (m, 5H), 3.36 (t, J = 5.1 Hz, 2H), 3.24-3.09 (m, 2H), 3.05-2.94 (m, 2H), 2.85 (tt, J = 12.2, 3.5 Hz, 1H), 2.05 (d, J = 12.4 Hz, 2H), 1.85 (d, J = 12.3 Hz, 2H), 1.43-1.34 (m, 2H), 1.29-1.11 (m, 4H). .sup.19F NMR (376 MHz, Chloroform-d) 60.3, 109.2. MS (ESI.sup.+): [M + H].sup.+ 529.1. 004 Yellow solid. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.47 & 7.45 (t, J = 1.8 Hz, 1H), 7.37 & 7.21 (dd, J = 8.4, 6.0 Hz, 1H), 7.26-7.23 (m, 1H), 7.19- 7.12 (m, 1H), 7.08 & 7.03 (td, J = 8.2, 2.5 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 4.55- 4.45 (m, 1H), 4.30 (t, J = 8.0 Hz, 1H), 4.10-4.04 (m, 1H), 3.94 & 3.93 (s, 3H), 3.67 & 3.50 (d, J = 12.6, Hz, 1H), 3.47-3.38 (m, 1H), 3.30 & 3.27 (d, J = 4.9 Hz, 1H), 3.13 (t, J = 10.9 Hz, 1H), 2.10-1.79 (m, 8H), 1.79-1.67 (m, 2H), 1.67-1.57 (m, 2H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.26, 109.38. MS (ESI.sup.+): [M + H].sup.+ 507.1/509.1. 005 Yellow solid. .sup.1H NMR (400 MHz, Chloroform-d, multiple sets of rotamers) 7.47 (m, 1H), 7.45-7.15 (m, 3H), 7.08 (dtd, J = 18.7, 8.2, 2.4 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 4.55 & 4.51 (d, J = 4.0 Hz, 1H), 4.38-4.28 (m, 1H), 4.14-4.04 (m, 1H), 3.96 & 3.95 (s, 3H), 3.70 & 3.53 (d, J = 12.0 Hz, 1H), 3.32 & 3.29 (d, J = 5.8 Hz, 1H), 3.19- 3.12 (m, 1H), 2.80-2.72 (m, 1H), 2.16-1.60 (m, 8H), 1.02-0.98 (m, 6H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.26, 109.37. MS (ESI.sup.+): [M + H].sup.+ 509.1/511.1. 006 Yellow solid. .sup.1H NMR (400 MHz, Chloroform-d, multiple sets of rotamers) 7.64- 7.52 (m, 1H), 7.47-7.28 (m, 2H), 7.23-7.14 (m, 1H), 7.12-7.02 (m, 1H), 7.01-6.90 (m, 1H), 4.23-3.67 (m, 6H), 3.58-2.75 (m, 5H), 2.12-1.59 (m, 8H), 1.06-0.76 (m, 3H). .sup.19F NMR (376 MHz, Chloroform-d, multiple sets of rotamers) 109.27, 109.33, 109.34. MS (ESI.sup.+): [M + H].sup.+ 495.0/497.0. 007 Yellow solid. .sup.1H NMR (400 MHz, Chloroform-d, multiple sets of rotamers) 7.63- 7.54 (m, 1H), 7.45-7.29 (m, 2H), 7.19 (ddd, J = 11.1, 8.5, 2.4 Hz, 1H), 7.07 (tdt, J = 8.0, 4.6, 2.5 Hz, 1H), 6.97 (dd, J = 8.5, 4.8 Hz, 1H), 4.24-3.68 (m, 6H), 3.59-2.72 (m, 5H), 1.94-1.79 (m, 2H), 1.73-1.58 (m, 2H), 1.05-0.93 (m, 8H), 0.81 (t, J = 6.5 Hz, 1H). .sup.19F NMR (376 MHz, Chloroform-d) 109.27, 109.33, 109.35. MS (ESI.sup.+): [M + H].sup.+ 497.2/499.1. 008 White solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.57 (dd, J = 8.5, 2.2 Hz, 1H), 7.32 (dd, J = 5.4, 3.9 Hz, 2H), 7.18 (dd, J = 8.5, 2.5 Hz, 1H), 7.07 (td, J = 8.3, 2.5 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 3.99 (t, J = 5.1 Hz, 2H), 3.96 (s, 3H), 3.56-3.44 (m, 1H), 3.44-3.34 (m, 1H), 3.16 (d, 3H), 3.12-3.07 (m, 1H), 3.04-2.90 (m, 1H), 1.28 (d, J = 6.8 Hz, 6H). .sup.19F NMR (376 MHz, Chloroform-d) 109.20. MS (ESI.sup.+): [M + H].sup.+ 455.1/457.1. 009 Yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.62 (dd, J = 8.4, 2.1 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.32 (dd, J = 8.5, 5.8 Hz, 1H), 7.18 (dd, J = 8.5, 2.4 Hz, 1H), 7.07 (td, J = 8.3, 2.4 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 4.05-3.97 (m, 2H), 3.96 (s, 3H), 3.52-3.33 (m, 2H), 3.23-3.06 (m, 3H), 2.99 (d, J = 7.2 Hz, 3H), 1.01 (tt, J = 8.3, 5.0 Hz, 1H), 0.62-0.48 (m, 2H), 0.23-0.05 (m, 2H). .sup.19F NMR (376 MHz, Chloroform-d) 109.18. MS (ESI.sup.+): [M + H].sup.+ 467.1/469.1. 010 White solid. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.46-7.41 (m, 1H), 7.36 (dd, J = 8.5, 5.8 Hz, 1H), 7.21 (p, J = 3.0 Hz, 1H), 7.19-7.12 (m, 1H), 7.06 (dtd, J = 18.8, 8.2, 2.4 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 4.55-4.45 (m, 1H), 4.34- 4.24 (m, 1H), 4.06 (s, 1H), 3.93 (s, 3H), 3.75 (p, J = 8.3 Hz, 1H), 3.70-3.46 (m, 1H), 3.28 (dd, J = 13.1, 5.2 Hz, 1H), 3.13 (t, J = 11.0 Hz, 1H), 2.60-2.45 (m, 2H), 2.22- 2.09 (m, 2H), 2.05-1.87 (m, 5H), 1.66-1.59 (m, 1H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.26, 109.37. MS (ESI.sup.+): [M + H].sup.+ 493.1/495.1. 011 White solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.59 (dd, J = 8.6, 2.2 Hz, 1H), 7.36-7.30 (m, 2H), 7.18 (dd, J = 8.5, 2.4 Hz, 1H), 7.07 (td, J = 8.3, 2.4 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 4.93 (t, J = 6.7 Hz, 2H), 4.78 (t, J = 7.7 Hz, 2H), 4.49-4.37 (m, 1H), 4.05-3.97 (m, 2H), 3.96 (s, 3H), 3.55-3.32 (m, 2H), 3.21-2.97 (m, 4H). .sup.19F NMR (376 MHz, Chloroform-d) 109.10. MS (ESI.sup.+): [M + H].sup.+ 469.0/479.0. 012 Yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.57 (dd, J = 8.4, 2.2 Hz, 1H), 7.37-7.29 (m, 2H), 7.18 (dd, J = 8.5, 2.4 Hz, 1H), 7.07 (td, J = 8.3, 2.5 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 4.05-3.97 (m, 2H), 3.95 (s, 3H), 3.44 (dd, J = 27.2, 7.2 Hz, 2H), 3.22-2.95 (m, 6H), 2.71 (p, J = 7.7 Hz, 1H), 2.05 (q, J = 8.9 Hz, 2H), 1.94-1.68 (m, 4H). .sup.19F NMR (376 MHz, Chloroform-d) 109.18. MS (ESI.sup.+): [M + H].sup.+ 481.1/483.1. 013 White solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.60 (dd, J = 8.5, 2.2 Hz, 1H), 7.36 (d, J = 2.2 Hz, 1H), 7.33 (dd, J = 8.5, 5.9 Hz, 1H), 7.18 (dd, J = 8.5, 2.5 Hz, 1H), 7.07 (td, J = 8.2, 2.5 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 4.03-3.96 (m, 2H), 3.96 (s, 3H), 3.52-3.34 (m, 2H), 3.24-2.96 (m, 6H), 2.25 (dq, J = 15.4, 7.7 Hz, 1H), 1.89 (dd, J = 12.5, 7.5 Hz, 2H), 1.68-1.57 (m, 3H), 1.25-1.15 (m, 3H). .sup.19F NMR (376 MHz, Chloroform-d) 109.19. MS (ESI.sup.+): [M + H].sup.+ 495.2/497.1. 014 Yellow solid. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.37-7.27 (m, 3H), 7.26-7.01 (m, 6H), 6.89 (d, J = 8.5 Hz, 1H), 6.73-6.70 (m, 1H), 4.42 (dd, J = 12.9, 7.2 Hz, 1H), 4.28-4.25 (m, 2H), 4.09-3.97 (m, 1H), 3.91 (s, 3H), 3.90-3.81 (m, 1H), 3.59-3.35 (m, 1H), 3.15 (dd, J = 12.9, 5.7 Hz, 1H), 3.05 (t, J = 13.8 Hz, 1H), 1.85-1.64 (m, 4H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.27, 109.36. MS (ESI.sup.+): [M + H].sup.+ 529.1/531.1. 015 White solid. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.49-7.45 (m, 1H), 7.36 (dd, J = 8.5, 5.9 Hz, 1H), 7.21 (dd, J = 8.5, 2.4 Hz, 1H), 7.18-7.13 (m, 1H), 7.06 (dtd, J = 18.8, 8.2, 2.4 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 4.56-4.46 (m, 1H), 4.38-4.28 (m, 1H), 4.08 (s, 1H), 3.93 (s, 3H), 3.70-3.47 (m, 1H), 3.29 (dd, J = 13.0, 5.9 Hz, 1H), 3.13 (t, J = 11.7 Hz, 1H), 3.00 (s, 2H), 2.10-1.83 (m, 4H), 1.15 (s, 9H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.27, 109.38. MS (ESI.sup.+): [M + H].sup.+ 509.2/511.2. 016 White solid. .sup.1H NMR (400 MHz, Chloroform-d, multiple sets of diastereoisomers) 7.61-7.56 (m, 1H), 7.43-7.30 (m, 2H), 7.22-7.16 (m, 1H), 7.11-7.04 (m, 1H), 7.01- 6.96 (m, 1H), 4.22-3.92 (m, 4H), 3.88-3.71 (m, 2H), 3.58-3.28 (m, 3H), 3.20-2.77 (m, 3H), 1.94-1.85 (m, 1H), 1.51-1.23 (m, 8H), 1.03-0.81 (m, 7H). .sup.19F NMR (376 MHz, Chloroform-d, multiple sets of diastereoisomers) 109.27, 109.33, 109.34. MS (ESI.sup.+): [M + H].sup.+ 497.0/499.0. 017 White solid. .sup.1H NMR (400 MHz, Chloroform-d, multiple sets of diastereoisomers) 7.64-7.57 (m, 1H), 7.46-7.29 (m, 4H), 7.01-6.96 (m, 1H), 4.35-3.90 (m, 4H), 3.85- 3.41 (m, 2H), 3.39-3.25 (m, 2H), 3.22-2.75 (m, 3H), 1.94-1.84 (m, 1H), 1.50-1.23 (m, 7H), 1.00-0.78 (m, 7H). .sup.19F NMR (376 MHz, Chloroform-d, multiple sets of diastereoisomers) 60.30, 60.31, 60.32, 60.49, 109.19, 109.23, 109.25, 109.30. MS (ESI.sup.+): [M + H].sup.+ 531.1. 018 Brown solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.60 (dd, J = 8.5, 2.2 Hz, 1H), 7.44 (dd, J = 8.8, 2.5 Hz, 1H), 7.42-7.29 (m, 3H), 6.98 (d, J = 8.6 Hz, 1H), 4.05-3.90 (m, 5H), 3.37 (t, J = 5.1 Hz, 2H), 3.24-3.10 (m, 2H), 3.05-2.92 (m, 4H), 2.23 (dp, J = 13.3, 6.7 Hz, 1H), 1.06 (d, J = 6.7 Hz, 6H). .sup.19F NMR (376 MHz, Chloroform-d) 60.2, 109.2. MS (ESI.sup.+): [M + H].sup.+ 503.1. 019 White solid. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.47 (d, J = 8.0 Hz, 1H), 7.37 (dd, J = 8.5, 5.8 Hz, 1H), 7.25-7.20 (m, 1H), 7.18-7.12 (m, 1H), 7.11-7.01 (m, 1H), 6.97 (d, J = 8.5 Hz, 1H), 4.51 (t, J = 10.9 Hz, 1H), 4.36-4.27 (m, 1H), 4.07 (s, 1H), 3.94 (s, 3H), 3.70-3.48 (m, 1H), 3.29 (dd, J = 13.0, 6.1 Hz, 1H), 3.13 (t, J = 11.5 Hz, 1H), 3.08-2.99 (m, 2H), 2.11-1.87 (m, 4H), 1.80-1.61 (m, 6H), 1.62-1.57 (m, 2H), 1.49-1.43 (m, 1H), 1.11-0.97 (m, 2H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.25, 109.35. MS (ESI.sup.+): [M + H].sup.+ 535.1/537.1. 020 White solid. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.49-7.44 (m, 1H), 7.37 (dd, J = 8.5, 5.9 Hz, 1H), 7.25-7.13 (m, 2H), 7.06 (dtd, J = 19.0, 8.3, 2.4 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 4.55-4.46 (m, 1H), 4.31 (dd, J = 12.8, 6.3 Hz, 1H), 4.07 (s, 1H), 3.93 (s, 3H), 3.71-3.47 (m, 1H), 3.29 (dd, J = 13.1, 6.9 Hz, 1H), 3.13 (t, J = 11.9 Hz, 1H), 3.08-3.00 (m, 2H), 2.11-1.87 (m, 4H), 1.69-1.61 (m, 2H), 1.37 (h, J = 7.3 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.25, 109.36. MS (ESI.sup.+): [M + H].sup.+ 495.1/497.1. 021 White solid. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.47 (dt, J = 8.5, 1.8 Hz, 1H), 7.25-7.17 (m, 2H), 7.17-7.12 (m, 1H), 7.06 (dtd, J = 18.8, 8.3, 2.4 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 4.55-4.46 (m, 1H), 4.36-4.27 (m, 1H), 4.11- 4.04 (m, 1H), 3.94 (s, 3H), 3.59 (dd, J = 64.1, 12.3 Hz, 1H), 3.29 (dd, J = 13.1, 6.9 Hz, 1H), 3.13 (t, J = 11.3 Hz, 1H), 2.98 (d, J = 5.9 Hz, 2H), 2.06-1.88 (m, 3H), 1.81 (p, J = 6.2 Hz, 1H), 1.67-1.59 (m, 1H), 1.49-1.35 (m, 4H), 0.80 (d, J = 8.0 Hz, 6H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.25, 109.36. MS (ESI.sup.+): [M + H].sup.+ 523.2/525.2. 022 White solid. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.46-7.42 (m, 1H), 7.36 (dd, J = 8.5, 5.9 Hz, 1H), 7.21 (p, J = 2.9 Hz, 1H), 7.19-7.13 (m, 1H), 7.06 (dtd, J = 18.8, 8.3, 2.5 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 4.55-4.46 (m, 1H), 4.34-4.26 (m, 1H), 4.06 (s, 1H), 3.93 (s, 3H), 3.70-3.47 (m, 1H), 3.28 (dd, J = 13.1, 5.1 Hz, 1H), 3.13 (t, J = 10.9 Hz, 1H), 2.89 (dqd, J = 10.4, 6.8, 3.7 Hz, 1H), 2.08-1.89 (m, 4H), 1.66-1.59 (m, 1H), 1.46-1.34 (m, 1H), 1.24 (dd, J = 6.9, 2.6 Hz, 3H), 0.96 (t, J = 7.5, 1.4 Hz, 3H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.26, 109.37. MS (ESI.sup.+): [M + H].sup.+ 495.1/497.1. 023 White solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.47-7.35 (m, 1H), 7.31-7.00 (m, 9H), 6.97 (d, J = 8.4 Hz, 1H), 4.59-4.45 (m, 1H), 4.37-4.21 (m, 1H), 4.11- 4.01 (m, 1H), 3.96 (s, 3H), 3.72-3.64 (m, 0.5H), 3.59-3.45 (m, 0.5H), 3.39-3.23 (m, 1H), 3.23-3.06 (m, 1H), 3.06-2.91 (m, 1H), 2.87-2.77 (m, 1H), 2.66-2.50 (m, 1H), 2.37-2.19 (m, 1H), 2.10-1.83 (m, 3.5H), 1.78-1.63 (m, 1.5H), 1.42- 1.23 (m, 3H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.25, 109.36. MS (ESI.sup.+): [M + H].sup.+ 571.1/573.1. 024 White solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.50-7.26 (m, 2H), 7.25-6.98 (m, 8H), 6.94 (d, J = 8.5 Hz, 1H), 4.60-4.44 (m, 1H), 4.39-4.18 (m, 1H), 4.04 (s, 1H), 3.94 & 3.93 (s, 3H), 3.78-3.60 (m, 0.5H), 3.58-3.46 (m, 0.5H), 3.37-3.21 (m, 1H), 3.21-3.05 (m, 1H), 3.05-2.89 (m, 1H), 2.70-2.46 (m, 2H), 2.13-1.83 (m, 3.5H), 1.83-1.50 (m, 3.5H), 1.51-1.29 (m, 1H), 1.30-1.18 (m, 3H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.25, 109.36. MS (ESI.sup.+): [M + H].sup.+ 585.1/587.2. 025 White solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.46-7.40 (m, 1H), 7.40-7.32 (m, 0.5H), 7.26-6.91 (m, 9.5H), 4.56-4.43 (m, 1H), 4.31-4.21 (m, 1H), 4.10- 3.98 (m, 1H), 3.97-3.90 (m, 3H), 3.73-3.60 (m, 0.5H), 3.54-3.44 (m, 0.5H), 3.31- 3.22 (m, 1H), 3.19-3.05 (m, 1H), 2.86-2.57 (m, 3H), 2.24-2.06 (m, 1H), 2.06- 1.80 (m, 5.5H), 1.75-1.58 (m, 1.5H), 1.05-0.91 (m, 3H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.26, 109.37. MS (ESI.sup.+): [M + H].sup.+ 585.1/587.2. 026 White solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.42-7.33 (m, 1.5H), 7.26-6.98 (m, 8.5H), 6.93 (d, J = 8.5 Hz, 1H), 4.57-4.43 (m, 1H), 4.32-4.21 (m, 1H), 4.08- 3.99 (m, 1H), 3.94 (s, 3H), 3.72-3.61 (m, 0.5H), 3.54-3.44 (m, 0.5H), 3.34-3.22 (m, 1H), 3.12 (t, J = 11.0 Hz, 1H), 2.84-2.74 (m, 1H), 2.63-2.50 (m, 2H), 2.12- 1.58 (m, 10H), 0.99-0.87 (m, 3H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.25, 109.36. MS (ESI.sup.+): [M + H].sup.+ 599.2/601.2. 027 .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.48 (d, J = 8.5 Hz, 1H), 7.40 (dd, J = 8.5, 5.9 Hz, 0.5H), 7.28-7.22 (m, 3.5H), 7.22-7.14 (m, 1H), 7.14- 7.02 (m, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.94-6.84 (m, 3H), 4.54 (dd, J = 13.3, 6.3 Hz, 1H), 4.39-4.28 (m, 1H), 4.17-4.04 (m, 1H), 4.03-3.89 (m, 3H), 3.77 (d, J = 12.4 Hz, 2H), 3.72-3.51 (m, 1H), 3.32 (d, J = 13.6 Hz, 1H), 3.16 (t, J = 10.8 Hz, 1H), 3.08-2.94 (m, 1H), 2.75-2.62 (m, 2H), 2.17-1.62 (m, 8H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.23, 109.35. MS (ESI.sup.+): [M + H].sup.+ 598.3/600.2. 028 White solid. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.39-7.33 (m, 1H), 7.30 (dd, J = 8.5, 5.8 Hz, 0.5H), 7.23-7.20 (m, 1H), 7.19-7.16 (m, 1H), 7.16-7.11 (m, 2.5H), 7.11-7.05 (m, 3H), 6.99 (dtd, J = 18.8, 8.3, 2.5 Hz, 1H), 6.89 (dd, J = 8.6, 1.3 Hz, 1H), 4.53-4.39 (m, 1H), 4.28-4.17 (m, 1H), 4.08-3.97 (m, 1H), 3.93-3.81 (m, 3H), 3.65-3.37 (m, 1H), 3.29-3.15 (m, 1H), 3.12-3.04 (m, 1H), 3.04-2.94 (m, 2H), 2.85-2.73 (m, 1H), 2.72-2.61 (m, 2H), 2.57-2.42 (m, 2H), 2.02-1.54 (m, 10H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.26, 109.38. MS (ESI.sup.+): [M + H].sup.+ 626.3/628.3. 029 .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.39-7.33 (m, 1H), 7.30 (dd, J = 8.5, 5.8 Hz, 0.5H), 7.16-6.92 (m, 5.5H), 6.92-6.84 (m, 3H), 4.44 (dd, J = 13.0, 6.0 Hz, 1H), 4.28-4.18 (m, 1H), 4.06-3.95 (m, 1H), 3.92-3.80 (m, 3H), 3.66-3.39 (m, 1H), 3.22 (d, J = 12.8 Hz, 1H), 3.06 (t, J = 10.4 Hz, 1H), 3.02-2.91 (m, 2H), 2.78 (t, J = 12.3 Hz, 1H), 2.68-2.58 (m, 2H), 2.51-2.38 (m, 2H), 1.99- 1.55 (m, 10H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 109.24, 109.36, 117.22, 117.23. MS (ESI.sup.+): [M + H].sup.+ 644.3/646.3. 030 Off-white solid. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.58 (dd, J = 8.4, 2.1 Hz, 1H), 7.42-7.34 & 7.26-7.15 (m, 5H), 7.14-7.01 (m, 2H), 6.97- 6.80 (m, 4H), 4.64 (d, J = 12.9 Hz, 1H), 3.89-3.71 (m, 3H), 3.70-3.61 & 3.57- 3.41 (m, 2H), 3.34-3.17 (m, 2H), 3.06-2.89 (m, 1H), 2.67 (t, J = 12.0 Hz, 2H), 2.24-1.96 & 1.88-1.71 (m, 8H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 108.72, 108.86. MS (ESI.sup.+): [M + H].sup.+ 584.2/586.2. 031 White solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.55 (dd, J = 8.4, 2.1 Hz, 1H), 7.41-7.32 & 7.25-7.23 (m, 3H), 7.30-7.27 (m, 1H), 7.23-7.03 (m, 6H), 6.92 (br s, 1H), 4.64 (d, J = 12.2 Hz, 1H), 3.84-3.74 (m, 1H), 3.70-3.59 & 3.57-3.41 (m, 2H), 3.33-3.21 (m, 2H), 3.07 (d, J = 11.4 Hz, 2H), 2.86 (t, J = 12.5 Hz, 1H), 2.79-2.67 (m, 2H), 2.62-2.48 (m, 2H), 2.25-1.91 & 1.77-1.60 (m, 10H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 108.75, 108.89. MS (ESI.sup.+): [M + H].sup.+ 612.2/614.1. 032 White solid. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.49-7.46 (m, 1H), 7.40-7.36 (m, 0.5H), 7.30-7.28 (m, 0.5H), 7.25-6.99 (m, 4H), 4.67- 4.59 (m, 1H), 3.75-3.69 (m, 1H), 3.66-3.43 (m, 2H), 3.30-3.22 (m, 2H), 2.97 (s, 2H), 2.31 (s, 3H), 2.17-1.98 (m, 3.5H), 1.75-1.68 (m, 0.5H), 1.16 (s, 9H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 108.81, 108.94. MS (ESI.sup.+): [M + H].sup.+ 509.0/511.0. 033 White solid. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.59 & 7.58 (m, 1H), 7.43-7.36 (m, 0.5H), 7.27-7.15 (m, 2.5H), 7.14-7.03 (m, 1H), 6.68 (br s, 1H), 4.63-4.55 (m, 1H), 4.22-4.13 (m, 1H), 3.97-3.87 (m, 1H), 3.77-3.47 (m, 1H), 3.33-3.26 (m, 1H), 3.25-3.16 (m, 1H), 3.01 (s, 2H), 2.20-1.90 (m, 3.5H), 1.76-1.65 (m, 0.5H), 1.20 (s, 9H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 108.87, 109.01. MS (ESI.sup.+): [M + H].sup.+ 529.0/531.0. 034 White solid. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.65-7.20 (m, 1H), 7.43-7.33 (m, 0.5H), 7.35-7.30 (m, 1H), 7.27-7.16 (m, 1.5H), 7.15- 7.03 (m, 1H), 4.63 & 4.59 (s, 1H), 4.46-4.17 (m, 4H), 4.13-3.98 (m, 1H), 3.85- 3.75 (m, 2H), 3.75-3.50 (m, 1H), 3.35 & 3.32 (s, 1H), 3.27-3.17 (m, 1H), 3.02 (s, 2H), 2.15-1.90 (m, 3.5H), 1.74-1.63 (m, 0.5H), 1.22 (s, 9H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 108.80, 109.94. MS (ESI.sup.+): [M + H].sup.+ 573.1/575.1/577.1 035 White solid. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.67-7.57 (m, 1H), 7.44-7.34 (m, 0.5H), 7.31-7.27 (m, 1H), 7.26-7.02 (m, 2.5H), 4.69- 4.53 (m, 1H), 4.22-4.11 (m, 1H), 4.00-3.89 (m, 1H), 3.79-3.69 (m, 0.5H), 3.63- 3.53 (m, 0.5H), 3.41-3.29 (m, 1H), 3.29-3.14 (m, 1H), 3.01 (s, 2H), 2.24-1.86 (m, 3.5H), 1.79-1.65 (m, 0.5H), 1.24-1.15 (m, 9H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 108.96, 109.09,. MS (ESI.sup.+): [M + H].sup.+ 547.1/549.1. 036 White solid. .sup.1H NMR (400 MHz, Chloroform-d, 2 sets of rotamers) 7.60-7.54 (m, 1H), 7.43-7.33 (m, 0.5H), 7.26-7.00 (m, 3.5H), 4.68-4.50 (m, 1H), 3.98- 3.83 (m, 1H), 3.76-3.58 (m, 1.5H), 3.58-3.47 (m, 0.5H), 3.37-3.15 (m, 2H), 3.00 (s, 2H), 2.55-2.40 (m, 3H), 2.16-1.87 (m, 3.5H), 1.75-1.62 (m, 0.5H), 1.19 (s, 9H). .sup.19F NMR (376 MHz, Chloroform-d, 2 sets of rotamers) 108.97, 109.11. MS (ESI.sup.+): [M + H].sup.+ 527.1/529.1.
Example 2: Biological Activity of the Compounds
[0345] The purpose of this experiment was to evaluate the GFR1-RET activity of the compounds 001-036 according to the invention.
Materials and Methods
[0346] The compounds were tested for their activating activity of Elk1 signaling using the previously developed reporter-gene-based system in cells expressing GFR1-RET (MG87 murine fibroblast stably transfected with PathDetect Elk-1, GFR1, and RET) disclosed in Sidorova, Y. A. et al.: Persephin signaling through GFR1: The potential for the treatment of Parkinson's disease. Molecular and Cellular Neuroscience, July 2010, Vol. 44, pp. 223-232. DOI: 10.1016/j.mcn.2010.03.009. For EC.sub.50 determination, a dose-response test was performed using 6 concentrations of each tested compound. Dose-response curves were fitted using the sigmoidal dose-response (variable slope) analysis in GraphPad Prism program (Graph Pad Inc) and EC.sub.50 of agonist/activator activity was calculated. Dose-response experiments were all performed in duplicate, two times independently.
Results
[0347] The results are presented on Table 4 below (* means 50 M>EC.sub.50>10 M, ** means 1 M<EC.sub.50<10 M, *** means EC.sub.50<1 M).
TABLE-US-00006 TABLE 4 Luciferase Cpd Name assay EC.sub.50 001 [4-[5-(1-ethylpropylsulfonyl)-2-methoxy- * phenyl]piperazin-1-yl]-[4-fluoro-2- (trifluoromethyl)phenyl]methanone 002 [4-(5-cyclopentylsulfonyl-2-methoxy-phenyl)piperazin-1- * yl]-[4-fluoro-2-(trifluoromethyl)phenyl]methanone 003 [4-(5-cyclohexylsulfonyl-2-methoxy-phenyl)piperazin-1- * yl]-[4-fluoro-2-(trifluoromethyl)phenyl]methanone 004 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-(5- ** cyclopentylsulfonyl-2-methoxy-phenyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 005 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-(1- ** ethylpropylsulfonyl)-2-methoxy-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 006 (2-chloro-4-fluoro-phenyl)-[rac-(3S)-4-(5- ** cyclopentylsulfonyl-2-methoxy-phenyl)-3-methyl- piperazin-1-yl]methanone 007 (2-chloro-4-fluoro-phenyl)-[rac-(3S)-4-[5-(1- ** ethylpropylsulfonyl)-2-methoxy-phenyl]-3-methyl- piperazin-1-yl]methanone 008 (2-chloro-4-fluoro-phenyl)-[4-(5-isopropylsulfonyl-2- * methoxy-phenyl)piperazin-1-yl]methanone 009 (2-chloro-4-fluoro-phenyl)-[4-[5- ** (cyclopropylmethylsulfonyl)-2-methoxy-phenyl]piperazin- 1-yl]methanone 010 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-(5- ** cyclobutylsulfonyl-2-methoxy-phenyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 011 (2-chloro-4-fluoro-phenyl)-[4-[2-methoxy-5-(oxetan-3- * ylsulfonyl)phenyl]piperazin-1-yl]methanone 012 (2-chloro-4-fluoro-phenyl)-[4-[5- * (cyclobutylmethylsulfonyl)-2-methoxy-phenyl]piperazin- 1-yl]methanone 013 (2-chloro-4-fluoro-phenyl)-[4-[5- ** (cyclopentylmethylsulfonyl)-2-methoxy-phenyl]piperazin- 1-yl]methanone 014 [(1S,5R)-8-(5-benzylsulfonyl-2-methoxy-phenyl)-3,8- * diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro- phenyl)methanone 015 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-(2,2- ** dimethylpropylsulfonyl)-2-methoxy-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 016 (2-chloro-4-fluoro-phenyl)-[rac-(3S)-4-[2-methoxy-5-[rac- ** (1S)-1-methylpropyl]sulfonyl-phenyl]-3-methyl-piperazin- 1-yl]methanone 017 [4-fluoro-2-(trifluoromethyl)phenyl]-[rac-(3S)-4-[2- ** methoxy-5-[rac-(1S)-1-methylpropyl]sulfonyl-phenyl]-3- methyl-piperazin-1-yl]methanone 018 [4-fluoro-2-(trifluoromethyl)phenyl]-[4-(5- * isobutylsulfonyl-2-methoxy-phenyl)piperazin-1- yl]methanone 019 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-(2- ** cyclopentylethylsulfonyl)-2-methoxy-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 020 [(1S,5R)-8-(5-butylsulfonyl-2-methoxy-phenyl)-3,8- ** diazabicyclo[3.2.1]octan-3-yl]-(2-chloro-4-fluoro- phenyl)methanone 021 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-(2- ** ethylbutylsulfonyl)-2-methoxy-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 022 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[2-methoxy-5- ** [(1SR)-1-methylpropyl]sulfonyl-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 023 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[2-methoxy-5- ** [(1SR)-1-methyl-3-phenyl-propyl]sulfonyl-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 024 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[2-methoxy-5- ** [(1SR)-1-methyl-4-phenyl-butyl]sulfonyl-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 025 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-[(1SR)-1-ethyl- ** 3-phenyl-propyl]sulfonyl-2-methoxy-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 026 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-[(1SR)-1-ethyl- ** 4-phenyl-butyl]sulfonyl-2-methoxy-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 027 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[2-methoxy-5-[(1- *** phenyl-4-piperidyl)sulfonyl]phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 028 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[2-methoxy-5-[[1- ** (2-phenylethyl)-4-piperidyl]sulfonyl]phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 029 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-[[1-[2-(4- ** fluorophenyl)ethyl]-4-piperidyl]sulfonyl]-2-methoxy- phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone 030 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[2-hydroxy-5-[(1- *** phenyl-4-piperidyl)sulfonyl]phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 031 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[2-hydroxy-5-[[1- ** (2-phenylethyl)-4-piperidyl]sulfonyl]phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 032 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[5-(2,2- ** dimethylpropylsulfonyl)-2-hydroxy-3-methyl-phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 033 [(1S,5R)-8-[3-chloro-5-(2,2-dimethylpropylsulfonyl)-2- *** hydroxy-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2- chloro-4-fluoro-phenyl)methanone 034 [(1S,5R)-8-[3-chloro-5-(2,2-dimethylpropylsulfonyl)-2-(2- ** hydroxyethoxy)phenyl]-3,8-diazabicyclo[3.2.1]octan-3- yl]-(2-chloro-4-fluoro-phenyl)methanone 035 (2-chloro-4-fluoro-phenyl)-[(1S,5R)-8-[2,3-dichloro-5- *** (2,2-dimethylpropylsulfonyl)phenyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methanone 036 [(1S,5R)-8-[3-chloro-5-(2,2-dimethylpropylsulfonyl)-2- *** methyl-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-(2- chloro-4-fluoro-phenyl)methanone
[0348] The above results clearly evidence that the tested compounds 001-036 have significant GFR1-RET activity. Thus, the compounds of the invention are useful as neuroprotective and neurorestorative agents. The tested compounds 001-036 are well-representing the class of the compounds of formula (I).