U.S. patent application number 15/537738 was filed with the patent office on 2019-11-14 for dopamine d2 receptor ligands.
This patent application is currently assigned to The Broad Institute, Inc.. The applicant listed for this patent is The Broad Institute, Inc., Massachusetts Institute of Technology. Invention is credited to Edward Holson, Michael C. Lewis, Michelle Palmer, Jennifer Q. Pan, Edward Scolnick, Florence Fevrier Wagner, Michel Weiwer, Qihong Xu, Yan-Ling Zhang.
Application Number | 20190345105 15/537738 |
Document ID | / |
Family ID | 56127680 |
Filed Date | 2019-11-14 |
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United States Patent
Application |
20190345105 |
Kind Code |
A9 |
Holson; Edward ; et
al. |
November 14, 2019 |
DOPAMINE D2 RECEPTOR LIGANDS
Abstract
The present invention relates to novel dopamine D2 receptor
ligands. The invention further relates to functionally-biased
dopamine D2 receptor ligands and the use of these compounds for
treating or preventing central nervous system and systemic
disorders associated with dysregulation of dopaminergic
activity.
Inventors: |
Holson; Edward; (Newton,
MA) ; Wagner; Florence Fevrier; (Ashland, MA)
; Weiwer; Michel; (Cambridge, MA) ; Scolnick;
Edward; (Wayland, MA) ; Palmer; Michelle;
(Harvard, MA) ; Lewis; Michael C.; (Dedham,
MA) ; Pan; Jennifer Q.; (Acton, MA) ; Zhang;
Yan-Ling; (Lexington, MA) ; Xu; Qihong;
(Newton, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The Broad Institute, Inc.
Massachusetts Institute of Technology |
Cambridge
Cambridge |
MA
MA |
US
US |
|
|
Assignee: |
The Broad Institute, Inc.
Cambridge
MA
Massachusetts Institute of Technology
Cambridge
MA
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20190023656 A1 |
January 24, 2019 |
|
|
Family ID: |
56127680 |
Appl. No.: |
15/537738 |
Filed: |
December 18, 2015 |
PCT Filed: |
December 18, 2015 |
PCT NO: |
PCT/US15/66689 PCKC 00 |
371 Date: |
June 19, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62094510 |
Dec 19, 2014 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 401/14 20130101;
C07D 211/62 20130101; C07D 471/10 20130101; C07D 471/04 20130101;
A61P 25/00 20180101; C07D 413/12 20130101; C07D 211/26 20130101;
C07D 405/14 20130101; C07D 401/12 20130101 |
International
Class: |
C07D 211/26 20060101
C07D211/26; A61P 25/00 20060101 A61P025/00; C07D 211/62 20060101
C07D211/62; C07D 401/12 20060101 C07D401/12; C07D 401/14 20060101
C07D401/14; C07D 405/14 20060101 C07D405/14; C07D 413/12 20060101
C07D413/12; C07D 471/04 20060101 C07D471/04; C07D 471/10 20060101
C07D471/10 |
Claims
1. A compound of Formula I: ##STR00317## or a stereoisomer,
racemate, tautomer, polymorph, hydrate, or solvate thereof, or a
pharmaceutically acceptable salt thereof, wherein: A-B is
C(O)--NR.sup.13, C(O)--CR.sup.11R.sup.12, C(O)--O,
CR.sup.11R.sup.12--NR.sup.13, CR.sup.11R.sup.12--O,
CR.sup.11R.sup.12--C(O), NR.sup.13--C(O),
NR.sup.13--CR.sup.11R.sup.12, O--CR.sup.11R.sup.12, or O--C(O),
wherein CR.sup.11R.sup.12--NR.sup.13 or
NR.sup.13--CR.sup.11R.sup.12 can form a 3- to 6-membered ring, or
A-Z.sup.1--R.sup.5 form a 3- to 6-membered ring, and B is C(O),
CR.sup.11R.sup.12, O, or NR.sup.13, or A-Z.sup.1, together with any
one or two of Z.sup.2 and Z.sup.3, or any one or two of Z.sup.4 and
Z.sup.5, form a 3- to 6-membered ring, wherein the ring and ring G
form a fused or bridged ring structure, and B is C(O),
CR.sup.11R.sup.12, O, or NR.sup.13, or B--Z.sup.6-Cy.sup.1 or
B--Z.sup.6-Cy.sup.2 form a 3- to 6-membered ring, and A is C(O),
CR.sup.11R.sup.12, O, or NR.sup.13, or B--Z.sup.6--R.sup.1 form a
3- to 6-membered ring, and A is C(O), CR.sup.11R.sup.12, O, or
NR.sup.13, or A-B--Z.sup.6-Cy.sup.1 or A-B--Z.sup.6-Cy.sup.2 form a
5- to 8-membered ring, or A-B--Z.sup.6 form a 3- to 6-membered
ring, or B-A-Z.sup.1 form a 3- to 6-membered ring, or B-A-Z.sup.1,
together with any one or two of Z.sup.2 and Z.sup.3, or any one or
two of Z.sup.4 and Z.sup.5, form a 4- to 6-membered ring, wherein
the ring and ring G form a fused or bridged ring structure;
R.sup.11 and R.sup.12 are each independently H, halogen, or
C.sub.1-C.sub.6 alkyl, or R.sup.11 and R.sup.12, together with the
carbon atom to which R.sup.11 and R.sup.12 are bonded, form a 3- to
6-membered ring, provided that when CR.sup.11R.sup.12--NR.sup.13 or
NR.sup.13--CR.sup.11R.sup.12 forms a 3- to 6-membered ring, one of
R.sup.11 and R.sup.12 is absent; R.sup.13 is H, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.3-C.sub.6 heterocycle, C.sub.6-C.sub.10, aryl, heteroaryl
comprising one or two 5- or 6-membered rings and one to four
heteroatoms selected from N, O, and S, C(O)--C.sub.1-C.sub.6 alkyl,
C(O)-phenyl, C(O)O--C.sub.1-C.sub.6 alkyl, C(O)NR.sup.17R.sup.18,
S(O).sub.2--C.sub.1-C.sub.6 alkyl, or S(O).sub.2NR.sup.17R.sup.18,
provided that when CR.sup.11R.sup.12--NR.sup.13 or
NR.sup.13--CR.sup.11R.sup.12 forms a 3- to 6-membered ring,
R.sup.13 is absent; R.sup.17 and R.sup.18 are each independently H,
C.sub.1-C.sub.6 alkyl, or C.sub.6-C.sub.10 aryl; Z.sup.1 is a
carbon atom; R.sup.5 is H, halogen, OH, C.sub.1-C.sub.6 alkyl,
O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F,
NR.sup.17R.sup.18, NR.sup.17C(O)--C.sub.1-C.sub.6 alkyl,
C(O)NR.sup.17R.sup.18, S--C.sub.1-C.sub.6 alkyl,
S(O)--C.sub.1-C.sub.6 alkyl, S(O).sub.2--C.sub.1-C.sub.6 alkyl,
S(O).sub.2NR.sup.17R.sup.18, NR.sup.17S(O).sub.2--C.sub.1-C.sub.6
alkyl, C.sub.6-C.sub.10aryl, phenyl, benzyl, heteroaryl comprising
one 5- or 6-membered ring and one to four heteroatoms selected from
N, O, and S, C.sub.3-C.sub.6 cycloalkyl, or heterocyclyl comprising
one 4- to 6-membered ring and one to four heteroatoms selected from
N, O, and S, or when B-A-Z.sup.1 form a 3- to 6-membered ring,
absent, or A-Z.sup.1--R.sup.5 form a 3- to 6-membered ring, or
Z.sup.1-R.sup.5, together with R.sup.2 and the carbon atom to which
the R.sup.2 is bonded, form a 4- to 6-membered ring, wherein the
ring and ring G form a fused or bridged ring structure, provided
that when A-B is NR.sup.13--C(O), NR.sup.13--CR.sup.11R.sup.12,
O--C(O), then R.sup.5 is not OH, O--C.sub.1-C.sub.6 alkyl,
S--C.sub.1-C.sub.6 alkyl, NR.sup.17R.sup.18,
NR.sup.17C(O)--C.sub.1-C.sub.6 alkyl, or
NR.sup.17S(O).sub.2--C.sub.1-C.sub.6 alkyl; Z.sup.2 is
C(R.sup.2).sub.p or C(O); Z.sup.3 is C(R.sup.2).sub.p; or any one
or two of Z.sup.2 and Z.sup.3, together with A-Z.sup.1 or
B-A-Z.sup.1, form a 3- to 6-membered ring, wherein the ring and
ring G form a fused or bridged ring structure, or when X is
CR.sup.14R.sup.15 or NR.sup.16, Z.sup.3--N--(Z.sup.7).sub.t--X form
a 4- to 6-membered ring; Z.sup.4 is C(R.sup.2).sub.p; Z.sup.5 is
C(R.sup.2).sub.p or C(O); or any one or two of Z.sup.4 and Z.sup.5,
together with A-Z.sup.1 or B-A-Z.sup.1, form a 3- to 6-membered
ring, wherein the ring and ring G form a fused or bridged ring
structure, or when X is CR.sup.14R.sup.15 or NR.sup.16,
Z.sup.4--N--(Z.sup.7).sub.t--X form a 4- to 6-membered ring; p is 1
or 2; each R.sup.2 is independently H, halogen, OH, C.sub.1-C.sub.6
alkyl, CF.sub.3, O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
heterocycle, C.sub.6-C.sub.10 aryl, O--C.sub.6-C.sub.10 aryl,
C(O)--C.sub.1-C.sub.6 alkyl, C(O)NR.sup.17R.sup.18,
NR.sup.17R.sup.18, NR.sup.17C(O)--C.sub.1-C.sub.6 alkyl,
S(O).sub.2NR.sup.17R.sup.18, or
NR.sup.17S(O).sub.2--C.sub.1-C.sub.6 alkyl, or any two R.sup.2
bonded to different carbon atoms, together with the carbon atoms to
which the two R.sup.2 are bonded, form a 4- to 7-membered ring, or
any two R.sup.2 bonded to the same carbon atom, together with the
carbon atom to which the two R.sup.2 are bonded, form a 3- to
6-membered ring, or R.sup.2, together with the carbon atom to which
the R.sup.2 is bonded, and Z.sup.1--R.sup.5, form a 4- to
6-membered ring, wherein the ring and ring G form a fused or
bridged ring structure, provided that when R.sup.2 is bonded to a
carbon atom adjacent to the nitrogen atom in ring G, then R.sup.2
is H, halogen, C.sub.1-C.sub.6 alkyl, CF.sub.3, C.sub.3-C.sub.8
cycloalkyl, C.sub.3-C.sub.8 heterocycloalkyl, C.sub.6-C.sub.10
aryl, C(O)--C.sub.1-C.sub.6 alkyl, C(O)NR.sup.17R.sup.18, or
S(O).sub.2NR.sup.17R.sup.18; Z.sup.6 is a carbon atom; R.sup.1 is H
or C.sub.1-C.sub.6 alkyl, or when A-B--Z.sup.6 form a 3- to
6-membered ring, absent, or B--Z.sup.6-R.sup.1 form a 3- to
6-membered ring; Cy.sup.1 and Cy.sup.2 are each independently H,
C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 aryl, heteroaryl comprising
one or two 5- or 6-membered rings and one to four heteroatoms
selected from N, O, and S, C.sub.3-C.sub.10 cycloalkyl,
C.sub.5-C.sub.13 bicyclic group, or heterocyclyl comprising one or
two 3- to 6-membered rings and one to four heteroatoms selected
from N, O, and S, wherein the aryl, heteroaryl, cycloalkyl,
bicyclic group, and heterocycyl are each independently optionally
substituted with one or more substituents independently selected
from: halogen, CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.8 cycloalkyl, OH, O--C.sub.1-C.sub.6 alkyl,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, C.sub.6-C.sub.10 aryl,
heteroaryl comprising one 5- or 6-membered ring and one to four
heteroatoms selected from N, O, and S, and NR.sup.17R.sup.18, or
A-B--Z.sup.6-Cy.sup.1 or A-B--Z.sup.6-Cy.sup.2 form a 5- to
8-membered ring, or B--Z.sup.6-Cy.sup.1 or B--Z.sup.6-Cy.sup.2 form
a 3- to 6-membered ring; Z.sup.7 is C(R.sup.3).sub.w, or when X is
CR.sup.14R.sup.15 or NR.sup.16, Z.sup.3--N--(Z.sup.7).sub.t--X or
Z.sup.4--N--(Z.sup.7).sub.t--X form a 4- to 6-membered ring, or
when X is CR.sup.14R.sup.15, Z.sup.7--X, together with R.sup.14 or
R.sup.15, form a 3- to 6-membered ring, or when X is NR.sup.16,
Z.sup.7--X, together with R.sup.16, form a 3- to 6-membered ring,
or Z.sup.7--X--Z.sup.8 form a 3- to 6-membered ring, or
Z.sup.7--X--Z.sup.8-Cy.sup.3 form a 4- to 6-membered ring; each w
is independently 1 or 2; t is 1, 2, 3, or 4, provided that when X
is O, S, S(O), S(O).sub.2, or NR.sup.16, then t is not 1; each
R.sup.3 is independently H, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 heterocycle, OH,
O--C.sub.1-C.sub.6 alkyl, S--C.sub.1-C.sub.6 alkyl,
NR.sup.17R.sup.18, C(O)NR.sup.17R.sup.18,
NR.sup.17C(O)--C.sup.1-C.sub.6 alkyl,
NR.sup.17S(O).sub.2--C.sub.1-C.sub.6 alkyl, or
S(O).sub.2NR.sup.17R.sup.18, or any two R.sup.3 bonded to the same
carbon atom, together with the carbon atom to which the two R.sup.3
are bonded, form C.dbd.O, provided that the C.dbd.0 is not directly
bonded to the nitrogen atom in ring G, or any two R.sup.3 bonded to
the same carbon atom or different carbon atoms, together with the
one or two carbon atoms to which the two R.sup.3 are bonded, form a
3- to 6-membered ring, provided that when X is O, S, or NR.sup.16,
then the R.sup.3 in the C(R.sup.3).sub.w directly bonded to X is
not OH, O--C.sub.1-C.sub.6 alkyl, S--C.sub.1-C.sub.6 alkyl,
NR.sup.17R.sup.18, NR.sup.17C(O)--C.sub.1-C.sub.6 alkyl,
NR.sup.17S(O).sub.2--C.sub.1-C.sub.6 alkyl, or
S(O).sub.2NR.sup.17R.sup.18; X is a bond, O, CR.sup.14R.sup.15, S,
S(O), S(O).sub.2, C.dbd.O, or NR.sup.16, or when X is
CR.sup.14R.sup.15 or NR.sup.16, Z.sup.3--N--Z.sup.7--X or
Z.sup.4--N--Z.sup.7--X form a 4- to 6-membered ring, or when X is
CR.sup.14R.sup.15, Z.sup.7--X or Z.sup.8--X, together with R.sup.14
or R.sup.15, form a 3- to 6-membered ring, or when X is NR.sup.16,
Z.sup.7--X or Z.sup.8--X, together with R.sup.16, form a 3- to
6-membered ring, or Z.sup.7--X--Z.sup.8 form a 3- to 6-membered
ring, or Z.sup.7--X--Z.sup.8-Cy.sup.3 form a 4- to 6-membered ring,
or X--Z.sup.8-Cy.sup.3 form a 3- to 6-membered ring; provided that
when X is O, S, S(O), S(O).sub.2, or NR.sup.16, then t is 2, 3, or
4; R.sup.14 and R.sup.15 are each independently, H, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, phenyl, or
heteroaryl comprising one 5- or 6-membered ring and one to four
heteroatoms selected from N, O, and S, or R.sup.14 and R.sup.15,
together with the carbon atom to which R.sup.14 and R.sup.15 are
bonded, form C.sub.3-C.sub.6 cycloalkyl, C.sub.5-C.sub.13 bicyclic
group, or heterocyclyl comprising one or two 3- to 6-membered rings
and one to four heteroatoms selected from N, O, and S, or when
Z.sup.3--N--Z.sup.7--X or Z.sup.4--N--Z.sup.7--X form a 4- to
6-membered ring, absent, or R.sup.14 or R.sup.15, together with
Z.sup.7--X or Z.sup.8--X, form a 3- to 6-membered ring; R.sup.16
is, H, C.sub.1-C.sub.6 alkyl, phenyl, heteroaryl comprising one 5-
or 6-membered ring and one to four heteroatoms selected from N, O,
and S, C(O)--C.sub.1-C.sub.6 alkyl, C(O)-phenyl,
C(O)O--C.sub.1-C.sub.6 alkyl, C(O)NR.sup.17R.sup.18,
S(O).sub.2--C.sub.1-C.sub.6 alkyl, or S(O).sub.2NR.sup.17R.sup.18,
or when Z.sup.3--N--Z.sup.7--X or Z.sup.4--N--Z.sup.7--X form a 4-
to 6-membered ring, absent, or R.sup.16, together with Z.sup.7--X
or Z.sup.8--X, form a 3- to 6-membered ring; Z.sup.8 is
C(R.sup.4).sub.u, or when X is CR.sup.14R.sup.15, Z.sup.8--X,
together with R.sup.14 or R.sup.15, form a 3- to 6-membered ring,
or when X is NR.sup.16, Z.sup.8--X, together with R.sup.16, form a
3- to 6-membered ring, or Z.sup.7--X--Z.sup.8 form a 3- to
6-membered ring, or Z.sup.7--X--Z.sup.8-Cy.sup.3 form a 4- to
6-membered ring, or X--Z.sup.8-Cy.sup.3 form a 3- to 6-membered
ring, or Z.sup.8, together with R.sup.4 and Cy.sup.3, form a 3- to
6-membered ring; each u is independently 1 or 2; n is 0, 1, or 2;
each R.sup.4 is independently H, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 heterocycle, OH,
O--C.sub.1-C.sub.6 alkyl, S--C.sub.1-C.sub.6 alkyl,
NR.sup.17R.sup.18, C(O)NR.sup.17R.sup.18,
NR.sup.17C(O)--C.sub.1-C.sub.6 alkyl,
NR.sup.17S(O).sub.2--C.sub.1-C.sub.6 alkyl, or
S(O).sub.2NR.sup.17R.sup.18, or any two R.sup.4 bonded to the same
carbon atom, together with the carbon atom to which the two R.sup.4
are bonded, form C.dbd.O, or any two R.sup.4 bonded to the same
carbon atom or on different carbon atoms, together with the one or
two carbon atoms to which the two R.sup.4 are bonded, form a 3- to
6-membered ring, or R.sup.4, together with Z.sup.8-Cy.sup.3, form a
3- to 6-membered ring, provided that when X is O, S, or NR.sup.16,
then the R.sup.4 in the C(R.sup.4).sub.n directly bonded to X is
not OH, O--C.sub.1-C.sub.6 alkyl, S--C.sub.1-C.sub.6 alkyl, or
NR.sup.17R.sup.18; and Cy.sup.3 is H, C.sub.1-C.sub.6 alkyl,
C.sub.6-C.sub.10 aryl, heteroaryl comprising one or two 5- or
6-membered rings and one to four heteroatoms selected from N, O,
and S, C.sub.3-C.sub.10 cycloalkyl, C.sub.5-C.sub.13 bicyclic
group, or heterocyclyl comprising one or two 3- to 6-membered rings
and one to four heteroatoms selected from N, O, and S, wherein the
aryl, heteroaryl, cycloalkyl, bicyclic group, and heterocycyl are
each independently optionally substituted with one or more
substituents independently selected from: halogen, CH.sub.2F,
CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, OH, O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, C.sub.6-C.sub.10 aryl, heteroaryl comprising one 5- or
6-membered ring and one to four heteroatoms selected from N, O, and
S, and NR.sup.17R.sup.18, or Z.sup.7--X--Z.sup.8-Cy.sup.3 form a 4-
to 6-membered ring, or X--Z.sup.8-Cy.sup.3 form a 3- to 6-membered
ring, or Z.sup.8-Cy.sup.3, together with R.sup.4, form a 3- to
6-membered ring, provided that when Z.sup.7--X--Z.sup.8 is
(CH.sub.2).sub.1-6, then Cy.sup.3 is not phenyl, which is
optionally substituted, methylenedioxyphenyl,
isoindoline-1,3,-dione, or dihydrobenzofuranyl.
2. (canceled)
3. The compound of claim 1, having Formula II: ##STR00318## or a
stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate
thereof, or a pharmaceutically acceptable salt thereof, wherein z
is 1, 2, 3, 4, 5, 6, 7, or 8.
4. The compound of claim 1, having Formula IV: ##STR00319## or a
stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate
thereof, or a pharmaceutically acceptable salt thereof, wherein:
Cy.sup.1, Cy.sup.2, and Cy.sup.3 are each independently H,
C.sub.1-C.sub.3 alkyl, phenyl, heteroaryl comprising one or two 5-
or 6-membered rings and one to four heteroatoms selected from N, O,
and S, C.sub.5-C.sub.6 cycloalkyl, C.sub.5-C.sub.13 bicyclic group,
or heterocyclyl comprising one or two 3- to 6-membered rings and
one to four heteroatoms selected from N, O, and S, wherein
Cy.sup.1, Cy.sup.2, and Cy.sup.3 are each independently optionally
substituted with one or more substituents independently selected
from halogen, CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6
alkyl, OH, O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, and NR.sup.17R.sup.18; each R.sup.3 is the same and is
selected from H and C.sub.1-C.sub.3 alkyl; R.sup.5 is H or
C.sub.1-C.sub.3 alkyl; R.sup.13 is H or C.sub.1-C.sub.3 alkyl;
R.sup.17 and R.sup.18 are each independently H or C.sub.1-C.sub.3
alkyl; and v is 1, 2, or 3.
5. The compound of claim 1, having Formula V: ##STR00320## or a
stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate
thereof, or a pharmaceutically acceptable salt thereof, wherein:
Cy.sup.1, Cy.sup.2 and Cy.sup.3 are each independently phenyl,
heteroaryl comprising one or two 5- or 6-membered rings and one to
four heteroatoms selected from N, O, and S, or C.sub.5-C.sub.13
bicyclic group, wherein Cy.sup.1, Cy.sup.2, and Cy.sup.3 are each
independently optionally substituted with one or more substituents
independently selected from halogen, CH.sub.2F, CHF.sub.2,
CF.sub.3, C.sub.1-C.sub.6 alkyl, OH, O--C.sub.1-C.sub.6 alkyl,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and NR.sup.17R.sup.18; R.sup.5
is H or C.sub.1-C.sub.3 alkyl; R.sup.11 and R.sup.12 are each
independently H or C.sub.1-C.sub.3 alkyl; R.sup.13 is H,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, or
C(O)--C.sub.1-C.sub.3 alkyl; and R.sup.17 and R.sup.18 are each
independently H or C.sub.1-C.sub.3 alkyl.
6. (canceled)
7. The compound of claim 1, having Formula VI: ##STR00321## or a
stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate
thereof, or a pharmaceutically acceptable salt thereof, wherein:
Cy.sup.1, Cy.sup.2 and Cy.sup.3 are each independently phenyl or
heteroaryl comprising one or two 5- or 6-membered rings and one to
four heteroatoms selected from N, O, and S, wherein Cy.sup.1,
Cy.sup.2, and Cy.sup.3 are each independently optionally
substituted with one or more substituents independently selected
from halogen, CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6
alkyl, OH, O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, and NR.sup.17R.sup.18; m1 and m2 are each independently
is 0, 1, or 2, provided that m1 and m2 are not both 0; and R.sup.17
and R.sup.18 are each independently H or C.sub.1-C.sub.3 alkyl.
8. The compound of claim 1, having Formula VII: ##STR00322## or a
stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate
thereof, or a pharmaceutically acceptable salt thereof, wherein:
Cy.sup.1, Cy.sup.2 and Cy.sup.3 are each independently phenyl,
heteroaryl comprising one or two 5- or 6-membered rings and one to
four heteroatoms selected from N, O, and S, or C.sub.5-C.sub.13
bicyclic group, wherein Cy.sup.1, Cy.sup.2, and Cy.sup.3 are each
independently optionally substituted with one or more substituents
independently selected from halogen, CH.sub.2F, CHF.sub.2,
CF.sub.3, C.sub.1-C.sub.6 alkyl, OH, O--C.sub.1-C.sub.6 alkyl,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and NR.sup.17R.sup.18; R.sup.17
and R.sup.18 are each independently H or C.sub.1-C.sub.3 alkyl; and
o is 1, 2, or 3.
9. The compound of claim 1, having Formula VIII: ##STR00323## or a
stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate
thereof, or a pharmaceutically acceptable salt thereof, wherein:
Cy.sup.1, Cy.sup.2 and Cy.sup.3 are each independently phenyl or
heteroaryl comprising one or two 5- or 6-membered rings and one to
four heteroatoms selected from N, O, and S, wherein Cy.sup.1,
Cy.sup.2, and Cy.sup.3 are each independently optionally
substituted with one or more substituents independently selected
from halogen, CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6
alkyl, OH, O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, and NR.sup.17R.sup.18; and R.sup.17 and R.sup.18 are
each independently H or C.sub.1-C.sub.3 alkyl.
10. (canceled)
11. The compound of claim 1, or a stereoisomer, racemate, tautomer,
polymorph, hydrate, or solvate thereof, or a pharmaceutically
acceptable salt thereof, wherein Cy.sup.1, Cy.sup.2 or Cy.sup.3 is
independently C.sub.6-C.sub.10 aryl, heteroaryl comprising one or
two 5- or 6-membered rings and one to four heteroatoms selected
from N, O, and S, C.sub.3-C.sub.10 cycloalkyl, or C.sub.5-C.sub.13
bicyclic group, wherein the aryl, heteroaryl, cycloalkyl, and
bicyclic group are each independently optionally substituted with
one or more substituents independently selected from halogen,
CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, OH,
O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and
NR.sup.17R.sup.18.
12. (canceled)
13. The compound of claim 1, or a stereoisomer, racemate, tautomer,
polymorph, hydrate, or solvate thereof, or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is H.
14. (canceled)
15. The compound of claim 1, or a stereoisomer, racemate, tautomer,
polymorph, hydrate, or solvate thereof, or a pharmaceutically
acceptable salt thereof, wherein A-B is C(O)--NR.sup.13 or
CR.sup.11R.sup.12--NR.sup.13.
16-18. (canceled)
19. The compound of claim 1, or a stereoisomer, racemate, tautomer,
polymorph, hydrate, or solvate thereof, or a pharmaceutically
acceptable salt thereof, wherein B-A-Z.sup.1 form a 3- to
6-membered ring optionally comprising one to three heteroatoms
selected from N, O, and S.
20-25. (canceled)
26. The compound of claim 1, or a stereoisomer, racemate, tautomer,
polymorph, hydrate, or solvate thereof, or a pharmaceutically
acceptable salt thereof, wherein X is O.
27-33. (canceled)
34. The compound of claim 1, or a stereoisomer, racemate, tautomer,
polymorph, hydrate, or solvate thereof, or a pharmaceutically
acceptable salt thereof, wherein n is 0.
35-48. (canceled)
49. The compound of claim 1, wherein the compound is:
(R)-1-(2-(3-chlorophenoxy)ethyl)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-
piperidine-4-carboxamide,
(S)-1-(2-(3-chlorophenoxy)ethyl)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-
piperidine-4-carboxamide,
(R)-1-(2-(4-chlorophenoxy)ethyl)-N-((4-chlorophenyl)(pyridine-2-yl)methyl-
) piperidine-4-carboxamide,
(S)-1-(2-(4-chlorophenoxy)ethyl)-N-((4-chlorophenyl)(pyridine-2-yl)methyl-
) piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-fluorophenoxy)ethyl-
)piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-fluorophenoxy)ethyl-
)piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(3-fluorophenoxy)ethyl-
)piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(3-fluorophenoxy)ethyl-
)piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-fluorophenoxy)ethyl-
)piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-fluorophenoxy)ethyl-
)piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-(trifluoromethyl)ph-
enoxy)ethyl) piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-(trifluoromethyl)ph-
enoxy)ethyl) piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(3-(trifluoromethyl)ph-
enoxy)ethyl) piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(3-(trifluoromethyl)ph-
enoxy)ethyl) piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-(trifluoromethyl)ph-
enoxy)ethyl) piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-(trifluoromethyl)ph-
enoxy)ethyl) piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-oxopyridin-1(2H)-yl-
)ethyl) piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-oxopyridin-1(2H)-yl-
)ethyl) piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(pyridin-3-yloxy)ethyl-
)piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(pyridin-3-yloxy)ethyl-
)piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-oxopyridin-1(4H)-yl-
)ethyl) piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-oxopyridin-1(4H)-yl-
)ethyl) piperidine-4-carboxamide, (R)--N-((4-chlorophenyl)
(pyridin-2-yl) methyl)-1-(2-(3-methoxyphenoxy) ethyl)
piperidine-4-carboxamide, (S)--N-((4-chlorophenyl) (pyridin-2-yl)
methyl)-1-(2-(3-methoxyphenoxy) ethyl) piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-methoxyphenoxy)ethy-
l) piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-methoxyphenoxy)ethy-
l) piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2,5-difluorophenoxy)e-
thyl) piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2,5-difluorophenoxy)e-
thyl) piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-((2-oxo-1,2,3,4-tetrah-
ydroquinolin-7-yl)oxy)ethyl)piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-((2-oxo-1,2,3,4-tetrah-
ydroquinolin-7-yl)oxy)ethyl)piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(quinolin-7-yloxy)ethy-
l) piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(quinolin-7-yloxy)ethy-
l) piperidine-4-carboxamide, (R)--N-((4-chlorophenyl)
(pyridin-2-yl) methyl)-1-(2-(cyclohexyloxy) ethyl)
piperidine-4-carboxamide, (S)--N-((4-chlorophenyl) (pyridin-2-yl)
methyl)-1-(2-(cyclohexyloxy) ethyl) piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(3-phenylpropyl)piperidin-
e-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(3-phenylpropyl)piperidin-
e-4-carboxamide, (R)-1-(2-(Benzo[d]thiazol-6-yloxy)
ethyl)-N-((4-chlorophenyl)(pyridin-2-yl) methyl)
piperidine-4-carboxamide, (S)-1-(2-(Benzo[d]thiazol-6-yloxy)
ethyl)-N-((4-chlorophenyl)(pyridin-2-yl) methyl)
piperidine-4-carboxamide,
(R)--N-((3-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-(2-(trifluoromethyl)p-
henoxy) ethyl) piperidine-4-carboxamide, (S)--N-((3
-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-(2-(trifluoromethyl)phenoxy)
ethyl) piperidine-4-carboxamide,
(R)-1-(2-(2-chlorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-yl)methyl-
) piperidine-4-carboxamide,
(S)-1-(2-(2-chlorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-yl)methyl-
) piperidine-4-carboxamide,
(R)-1-(2-(2-fluorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-yl)methyl-
) piperidine-4-carboxamide,
(S)-1-(2-(2-fluorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-yl)methyl-
) piperidine-4-carboxamide,
(R)--N-((3-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidin-
e-4-carboxamide,
(S)--N-((3-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidin-
e-4-carboxamide,
(R)--N-((2-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidin-
e-4-carboxamide,
(S)--N-((2-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidin-
e-4-carboxamide,
(R)--N-((4-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidin-
e-4-carboxamide,
(S)--N-((4-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidin-
e-4-carboxamide,
(R)--N-((3-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidin-
e-4-carboxamide,
(S)--N-((3-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidin-
e-4-carboxamide,
(R)--N-((3-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidin-
e-4-carboxamide,
(S)--N-((3-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidin-
e-4-carboxamide,
(R)--N-((2-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidin-
e-4-carboxamide,
(S)--N-((2-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidin-
e-4-carboxamide,
(R)-1-(2-phenoxyethyl)-N-(pyridin-2-yl(pyridin-3-yl)methyl)piperidine-4-c-
arboxamide,
(S)-1-(2-phenoxyethyl)-N-(pyridin-2-yl(pyridin-3-yl)methyl)piperidine-4-c-
arboxamide,
N-(di(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4-carboxamide,
(R)-1-(2-phenoxyethyl)-N-(pyridin-2-yl(4-(trifluoromethyl)phenyl)methyl)
piperidine-4-carboxamide,
(S)-1-(2-phenoxyethyl)-N-(pyridin-2-yl(4-(trifluoromethyl)phenyl)methyl)
piperidine-4-carboxamide,
(R)-1-(2-phenoxyethyl)-N-(pyridin-2-yl(3-(trifluoromethyl)phenyl)methyl)
piperidine-4-carboxamide,
(S)-1-(2-phenoxyethyl)-N-(pyridin-2-yl(3-(trifluoromethyl)phenyl)methyl)
piperidine-4-carboxamide,
(R)-1-(2-phenoxyethyl)-N-(pyridin-2-yl(2-(trifluoromethyl)phenyl)methyl)
piperidine-4-carboxamide,
(S)-1-(2-phenoxyethyl)-N-(pyridin-2-yl(2-(trifluoromethyl)phenyl)methyl)
piperidine-4-carboxamide,
(R)--N-((4-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidi-
ne-4-carboxamide,
(S)--N-((4-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidi-
ne-4-carboxamide,
(R)--N-((3-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidi-
ne-4-carboxamide,
(S)--N-(3-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidin-
e-4-carboxamide,
(R)--N-((2-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide,
(S)--N-((2-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide,
(R)--N-(cyclohexyl(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4-ca-
rboxamide,
(S)--N-(cyclohexyl(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piper-
idine-4-carboxamide,
(R)--N-(2-methyl-1-(pyridin-2-yl)propyl)-1-(2-phenoxyethyl)piperidine-4-c-
arboxamide,
(S)--N-(2-methyl-1-(pyridin-2-yl)propyl)-1-(2-phenoxyethyl)piperidine-4-c-
arboxamide,
(R)--N-((4-chlorophenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-ca-
rboxamide,
(S)--N-((4-chlorophenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piper-
idine-4-carboxamide,
(R)--N-((4-chlorophenyl)(2-fluorophenyl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(2-fluorophenyl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(3-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperid-
ine-4-carboxamide,
(S)--N-((4-chlorophenyl)(3-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperid-
ine-4-carboxamide,
(R)--N-((4-chlorophenyl)(4-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperid-
ine-4-carboxamide,
(S)--N-((4-chlorophenyl)(4-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperid-
ine-4-carboxamide,
(R)--N-((4-chlorophenyl)(2-methoxyphenyl)methyl)-1-(2-phenoxyethyl)piperi-
dine-4-carboxamide,
(S)--N-((4-chlorophenyl)(2-methoxyphenyl)methyl)-1-(2-phenoxyethyl)piperi-
dine-4-carboxamide,
(R)--N-((4-chlorophenyl)(4-methoxyphenyl)methyl)-1-(2-phenoxyethyl)piperi-
dine-4-carboxamide,
(S)--N-((4-chlorophenyl)(4-methoxyphenyl)methyl)-1-(2-phenoxyethyl)piperi-
dine-4-carboxamide,
(R)--N-((4-fluorophenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-ca-
rboxamide,
(S)--N-((4-fluorophenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piper-
idine-4-carboxamide,
(R)--N-((3-methoxyphenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-c-
arboxamide,
(S)--N-(3-methoxyphenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-ca-
rboxamide,
N-(bis(4-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-ca-
rboxamide,
N-(bis(2-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-ca-
rboxamide,
(R)--N-((2-fluorophenyl)(4-fluorophenyl)methyl)-1-(2-phenoxyeth-
yl)piperidine-4-carboxamide,
(S)--N-((2-fluorophenyl)(4-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperid-
ine-4-carboxamide,
(R)--N-((2-fluorophenyl)(3-methoxyphenyl)methyl)-1-(2-phenoxyethyl)piperi-
dine-4-carboxamide,
(S)--N-((2-fluorophenyl)(3-methoxyphenyl)methyl)-1-(2-phenoxyethyl)piperi-
dine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-methyl-1-(2-phenoxyethyl)
piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-methyl-1-(2-phenoxyethyl)
piperidine-4-carboxamide,
(R)--N-((4-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-(trifluoromethyl)ph-
enoxy)ethyl) piperidine-4-carboxamide,
(S)--N-((4-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-(trifluoromethyl)ph-
enoxy)ethyl) piperidine-4-carboxamide,
(R)-1-(2-(2-chlorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)
piperidine-4-carboxamide,
(S)-1-(2-(2-chlorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)
piperidine-4-carboxamide,
(R)-1-(2-(2-fluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)
piperidine-4-carboxamide,
(S)-1-(2-(2-fluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)
piperidine-4-carboxamide,
(R)-1-(2-(benzo[d]thiazol-6-yloxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl-
)methyl)piperidine-4-carboxamide,
(S)-1-(2-(benzo[d]thiazol-6-yloxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl-
)methyl)piperidine-4-carboxamide,
(R)-1-(2-(2,6-difluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)met-
hyl) piperidine-4-carboxamide,
(S)-1-(2-(2,6-difluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)met-
hyl) piperidine-4-carboxamide,
(R)-1-(2-(2,5-difluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)met-
hyl) piperidine-4-carboxamide,
(S)-1-(2-(2,5-difluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)met-
hyl) piperidine-4-carboxamide,
(R)--N-((4-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-methyl-1-phenoxypropan-
-2-yl)piperidine-4-carboxamide,
(S)--N-((4-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-methyl-1-phenoxypropan-
-2-yl)piperidine-4-carboxamide,
(R)-1-(benzofuran-2-ylmethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)pip-
eridine-4-carboxamide,
(S)-1-(benzofuran-2-ylmethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)pip-
eridine-4-carboxamide,
(R)-1-(benzo[d]oxazol-2-ylmethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl-
)piperidine-4-carboxamide,
(S)-1-(benzo[d]oxazol-2-ylmethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl-
)piperidine-4-carboxamide,
(R)-1-((2,3-dihydro-1H-inden-2-yl)methyl)-N-((4-fluorophenyl)(pyridin-2-y-
l)methyl) piperidine-4-carboxamide,
(S)-1-((2,3-dihydro-1H-inden-2-yl)methyl)-N-((4-fluorophenyl)(pyridin-2-y-
l)methyl) piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(3-phenoxypropyl)piperidi-
ne-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(3-phenoxypropyl)piperidi-
ne-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidin-
e-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidin-
e-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-methylpiperidine-4-carbox-
amide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-methylpiperidine-4--
carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-methoxyethyl)piperidin-
e-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-methoxyethyl)piperidin-
e-4-carboxamide,
(R)-1-(2-(2-chlorophenoxy)ethyl)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)
piperidine-4-carboxamide,
(S)-1-(2-(2-chlorophenoxy)ethyl)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)
piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2,6-difluorophenoxy)e-
thyl) piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2,6-difluorophenoxy)e-
thyl) piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-(trifluoromethoxy)p-
henoxy) ethyl) piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-(trifluoromethoxy)p-
henoxy) ethyl) piperidine-4-carboxamide,
(R)--N-((4-fluorophenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-phenoxyethyl)-
piperidine-4-carboxamide,
(S)--N-((4-fluorophenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-phenoxyethyl)-
piperidine-4-carboxamide,
(R)--N-((4-fluorophenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-(2-(trifluoro-
methyl) phenoxy)ethyl) piperidine-4-carboxamide,
(S)--N-((4-fluorophenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-(2-(trifluoro-
methyl) phenoxy)ethyl) piperidine-4-carboxamide,
(R)-1-(2-(2-fluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)-
-4-methylpiperidine-4-carboxamide,
(S)-1-(2-(2-fluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)-
-4-methylpiperidine-4-carboxamide,
(R)-1-(4-chlorophenyl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)met-
hyl)-N-methyl-1-(pyridin-2-yl)methanamine,
(S)-1-(4-chlorophenyl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)met-
hyl)-N-methyl-1-(pyridin-2-yl)methanamine,
(R)-1-(4-chlorophenyl)-N-methyl-1-(pyridin-2-yl)-N-((1-(2-(2-(trifluorome-
thyl) phenoxy)ethyl)piperidin-4-yl)methyl)methanamine,
(S)-1-(4-chlorophenyl)-N-methyl-1-(pyridin-2-yl)-N-((1-(2-(2-(trifluorome-
thyl) phenoxy)ethyl)piperidin-4-yl)methyl)methanamine,
(R)-1-(4-fluorophenyl)-N-methyl-N-((1-(2-phenoxyethyl)piperidin-4-yl)meth-
yl)-1-(pyridin-2-yl)methanamine,
(S)-1-(4-fluorophenyl)-N-methyl-N-((1-(2-phenoxyethyl)piperidin-4-yl)meth-
yl)-1-(pyridin-2-yl)methanamine,
(R)--N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-1-(4-fluoroph-
enyl)-N-methyl-1-(pyridin-2-yl)methanamine,
(S)--N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-1-(4-fluoroph-
enyl)-N-methyl-1-(pyridin-2-yl)methanamine,
(R)-1-(3-methoxyphenyl)-N-methyl-N-((1-(2-phenoxyethyl)piperidin-4-yl)met-
hyl)-1-(pyridin-2-yl)methanamine, (S)-1-(3
-methoxyphenyl)-N-methyl-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1-(-
pyridin-2-yl)methanamine,
(R)--N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-1-(3-methoxyp-
henyl)-N-methyl-1-(pyridin-2-yl)methanamine,
(S)--N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-1-(3-methoxyp-
henyl)-N-methyl-1-(pyridin-2-yl)methanamine,
(R)-1-(4-fluorophenyl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1
-(pyridin-2-yl) methanamine,
(S)-1-(4-fluorophenyl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1-(py-
ridin-2-yl) methanamine,
(R)-1-(4-chlorophenyl)-N-methyl-N-((1-(2-phenoxyethyl)piperidin-4-yl)meth-
yl)-1-(pyridin-2-yl)methanamine,
(S)-1-(4-chlorophenyl)-N-methyl-N-((1-(2-phenoxyethyl)piperidin-4-yl)meth-
yl)-1-(pyridin-2-yl)methanamine,
(R)-1-(3-methoxyphenyl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1-(p-
yridin-2-yl)methanamine, (S)-1-(3
-methoxyphenyl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1-(pyridin-2-
-yl)methanamine,
(R)-1-(4-chlorophenyl)-1-(2-fluorophenyl)-N-((1-(2-phenoxyethyl)piperidin-
e-4-yl) methyl)methanamine,
(S)-1-(4-chlorophenyl)-1-(2-fluorophenyl)-N-((1-(2-phenoxyethyl)piperidin-
e-4-yl) methyl)methanamine,
(R)-1-(2-(benzo[d]thiazol-6-yloxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-y-
l)methyl) piperidine-4-carboxamide,
(S)-1-(2-(benzo[d]thiazol-6-yloxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-y-
l)methyl) piperidine-4-carboxamide,
N-(bis(4-fluorophenyl)methyl)-1-(2-(2-chlorophenoxy)ethyl)piperidine-4-ca-
rboxamide,
N-(bis(2-fluorophenyl)methyl)-1-(2-(2-chlorophenoxy)ethyl)piper-
idine-4-carboxamide,
(R)-1-(2-(2-chlorophenoxy)ethyl)-N-((2-fluorophenyl)(4-fluorophenyl)methy-
l) piperidine-4-carboxamide,
(S)-1-(2-(2-chlorophenoxy)ethyl)-N-((2-fluorophenyl)(4-fluorophenyl)methy-
l) piperidine-4-carboxamide,
(R)-1-(2-(2-chlorophenoxy)ethyl)-N-((2-fluorophenyl)(3-methoxyphenyl)
methyl) piperidine-4-carboxamide,
(S)-1-(2-(2-chlorophenoxy)ethyl)-N-((2-fluorophenyl)(3-methoxyphenyl)
methyl) piperidine-4-carboxamide,
(R)-1-(4-chlorophenyl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)met-
hyl)-1-(2-fluorophenyl)methanamine,
(S)-1-(4-chlorophenyl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)met-
hyl)-1-(2-fluorophenyl)methanamine,
(R)--N-(1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-1-(3-methoxyph-
enyl)-1-(pyridin-2-yl)methanamine,
(S)--N-(1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-1-(3-methoxyph-
enyl)-1-(pyridin-2-yl)methanamine,
(R)-1-(4-chlorophenyl)-N-((1-(2-(2,5-difluorophenoxy)ethyl)piperidin-4-yl-
)methyl)-1-(pyridin-2-yl)methanamine,
(S)-1-(4-chlorophenyl)-N-((1-(2-(2,5-difluorophenoxy)ethyl)piperidin-4-yl-
)methyl)-1-(pyridin-2-yl)methanamine,
(R)-1-(2-(2,5-difluorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-yl)me-
thyl) piperidine-4-carboxamide,
(S)-1-(2-(2,5-difluorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-yl)me-
thyl) piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(3-fluoropyridin-4-yl)methyl)-1-(2-(2-fluoropheno-
xy)ethyl) piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(3-fluoropyridin-4-yl)methyl)-1-(2-(2-fluoropheno-
xy)ethyl) piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(5-fluoropyridin-2-yl)methyl)-1-(2-(2-fluoropheno-
xy)ethyl) piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(5-fluoropyridin-2-yl)methyl)-1-(2-(2-fluoropheno-
xy)ethyl) piperidine-4-carboxamide,
(R)-1-(2-(2-fluorophenoxy)ethyl)-N-(pyridin-2-yl(3-(trifluoromethoxy)phen-
yl) methyl)piperidine-4-carboxamide,
(S)-1-(2-(2-fluorophenoxy)ethyl)-N-(pyridin-2-yl(3-(trifluoromethoxy)phen-
yl) methyl)piperidine-4-carboxamide,
(R)--N-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methyl)-1-(2--
(2-fluoro phenoxy)ethyl)piperidine-4-carboxamide,
(S)--N-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methyl)-1-(2--
(2-fluoro phenoxy)ethyl)piperidine-4-carboxamide,
(R)--N-(benzo[d][1,3]dioxol-5-yl(pyridin-2-yl)methyl)-1-(2-(2-fluoropheno-
xy) ethyl) piperidine-4-carboxamide,
(R)--N-(benzo[d][1,3]dioxol-5-yl(pyridin-2-yl)methyl)-1-(2-(2-fluoropheno-
xy) ethyl) piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(2-fluorophenyl)methyl)-1-(2-(2-fluorophenoxy)eth-
yl) piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(2-fluorophenyl)methyl)-1-(2-(2-fluorophenoxy)eth-
yl) piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-methyl-1-(1-(2-phenoxy
ethyl) piperidin-4-yl)ethan-1-amine,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-methyl-1-(1-(2-phenoxy
ethyl) piperidin-4-yl)ethan-1-amine,
(R)-2-((4-chlorophenyl)(pyridin-2-yl)methyl)-5-(2-phenoxyethyl)octahydro--
1H-pyrrolo[3,4-c]pyridine,
(S)-2-((4-chlorophenyl)(pyridin-2-yl)methyl)-5-(2-phenoxyethyl)octahydro--
1H-pyrrolo[3,4-c]pyridine,
(R)-2-((4-chlorophenyl)((1-(2-phenoxyethyl)piperidin-4-yl)methoxy)
methyl) pyridine,
(S)-2-((4-chlorophenyl)((1-(2-phenoxyethyl)piperidin-4-yl)methoxy)
methyl) pyridine,
(R)-2-((4-chlorophenyl)(pyridin-2-yl)methyl)-5-(2-(2-(trifluoromethyl)phe-
noxy) ethyl)octahydro-1H-pyrrolo[3,4-c]pyridine,
(S)-2-((4-chlorophenyl)(pyridin-2-yl)methyl)-5-(2-(2-(trifluoromethyl)phe-
noxy) ethyl)octahydro-1H-pyrrolo[3,4-c]pyridine,
(R)-1-(4-fluorophenyl)-N-((4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethy-
l) piperidin-4-yl)methyl)-1-(pyridin-2-yl)methanamine,
(S)-1-(4-fluorophenyl)-N-((4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethy-
l) piperidin-4-yl)methyl)-1-(pyridin-2-yl)methanamine,
(R)-1-(benzo[d][1,3]dioxol-5-yl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)met-
hyl)-1-(pyridin-2-yl)methanamine,
(S)-1-(benzo[d][1,3]dioxol-5-yl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)met-
hyl)-1-(pyridin-2-yl)methanamine,
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-phenoxyethyl)piperi-
din-4-yl) methyl) propan-2-amine,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-phenoxyethyl)piper-
idin-4-yl) methyl) propan-2-amine,
(R)-2-((4-chlorophenyl)(pyridin-2-yl)methyl)-7-(2-phenoxyethyl)-2,7-diaza
spiro[3.5]nonane,
(S)-2-((4-chlorophenyl)(pyridin-2-yl)methyl)-7-(2-phenoxyethyl)-2,7-diaza
spiro[3.5]nonane,
(R)-2-((4-chlorophenyl)(pyridin-2-yl)methyl)-8-(2-phenoxyethyl)-2,8-diaza-
spiro[4.5]decane,
(S)-2-((4-chlorophenyl)(pyridin-2-yl)methyl)-8-(2-phenoxyethyl)-2,8-diaza-
spiro[4.5]decane,
(R)-2-((4-chlorophenyl)(pyridin-2-yl)methyl)-8-(2-(2-(trifluoromethyl)phe-
noxy) ethyl)-2,8-diazaspiro[4.5]decane,
(S)-2-((4-chlorophenyl)(pyridin-2-yl)methyl)-8-(2-(2-(trifluoromethyl)phe-
noxy) ethyl)-2,8-diazaspiro[4.5]decane,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-phenoxyethyl)piper-
idin-4-yl) methyl) acetamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-phenoxyethyl)piper-
idin-4-yl) methyl) acetamide,
N-(isoquinolin-1-ylmethyl)-1-(2-(2-methoxyphenoxy)ethyl)piperidine-4-carb-
oxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-methoxyphen-
oxy) ethyl)piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-methoxyphenoxy)
ethyl)piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(4-henoxybutyl)piperidine-
-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(4-henoxybutyl)piperidine-
-4-carboxamide,
(R)--N((4-chlorophenyl)(pyridin-3-yl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-3-yl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide,
(R)--N((4-chlorophenyl)(pyridin-4-yl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-4-yl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide,
(R)-1-(2-phenoxyethyl)-N-(phenyl(pyridin-2-yl)methyl)piperidine-4-carboxa-
mide,
(S)-1-(2-phenoxyethyl)-N-(phenyl(pyridin-2-yl)methyl)piperidine-4-ca-
rboxamide,
(R)-1-(4-chlorophenyl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)met-
hyl)-1-(pyridin-2-yl)methanamine,
(S)-1-(4-chlorophenyl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1-(py-
ridin-2-yl)methanamine,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2,4-difluorophenoxy)
ethyl)piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2,4-difluorophenoxy)
ethyl)piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(5-fluoropyridin-2-yl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(5-fluoropyridin-2-yl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(3-fluoropyridin-4-yl)methyl)-1-(2-phenoxyethyl)p-
iperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(3-fluoropyridin-4-yl)methyl)-1-(2-phenoxyethyl)p-
iperidine-4-carboxamide,
(R)-1-(2-phenoxyethyl)-N-(pyridin-2-yl(3-(trifluoromethoxy)phenyl)
methyl)piperidine-4-carboxamide,
(S)-1-(2-phenoxyethyl)-N-(pyridin-2-yl(3-(trifluoromethoxy)phenyl)
methyl)piperidine-4-carboxamide,
(R)--N-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methyl)-1-(2--
phenoxyethyl)piperidine-4-carboxamide,
(S)--N-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methyl)-1-(2--
phenoxyethyl)piperidine-4-carboxamide,
(R)-1-(4-chlorophenyl)-1-(pyridin-2-yl)-N-((1-(2-(2-(trifluoromethyl)
phenoxy)ethyl)piperidin-4-yl)methyl)methanamine,
(S)-1-(4-chlorophenyl)-1-(pyridin-2-yl)-N-((1-(2-(2-(trifluoromethyl)
phenoxy)ethyl)piperidin-4-yl)methyl)methanamine,
(R)-1-(4-chlorophenyl)-N-((1-(2-(2-fluorophenoxy) ethyl)
piperidin-4-yl) methyl)-1-(pyridin-2-yl) methanamine,
(S)-1-(4-chlorophenyl)-N-((1-(2-(2-fluorophenoxy) ethyl)
piperidin-4-yl) methyl)-1-(pyridin-2-yl) methanamine,
(R)--N-((1-(2-(2-fluorophenoxy) ethyl) piperidin-4-yl)
methyl)-1-(4-fluorophenyl)-1-(pyridin-2-yl) methanamine,
(S)--N-((1-(2-(2-fluorophenoxy) ethyl) piperidin-4-yl)
methyl)-1-(4-fluorophenyl)-1-(pyridin-2-yl) methanamine,
(R)--N((4-chlorophenyl)(2-fluorophenyl)methyl)-1-(2-(2,
5-difluorophenoxy) ethyl) piperidine-4-carboxamide,
(S)--N-((4-chlorophenyl)(2-fluorophenyl)methyl)-1-(2-(2,
5-difluorophenoxy) ethyl) piperidine-4-carboxamide,
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-2,2,2-trifluoro-N-((1-(2-ph-
enoxyethyl)piperidin-4-yl)methyl)ethanamine,
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-2,2,2-trifluoro-N-((1-(2-ph-
enoxyethyl)piperidin-4-yl)methyl)ethanamine,
(R)-2-(4-chlorophenyl)-N-(1-(2-phenoxyethyl)piperidin-4-yl)-2-(pyridin-2--
yl)acetamide,
(S)-2-(4-chlorophenyl)-N-(1-(2-phenoxyethyl)piperidin-4-yl)-2-(pyridin-2--
yl)acetamide,
(R)-2-((4-chlorophenyl)((1-(2-phenoxyethyl)piperidin-4-yl)methoxy)methyl)-
pyridine,
(S)-2-((4-chlorophenyl)((1-(2-phenoxyethyl)piperidin-4-yl)methox-
y)methyl)pyridine, or a stereoisomer, racemate, tautomer,
polymorph, hydrate, or solvate thereof, or a pharmaceutically
acceptable salt thereof.
50. The compound of claim 1, wherein the compound is:
(R)-2-((4-chlorophenyl)((1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-
-4-yl)methoxy)methyl)pyridine;
(S)-2-((4-chlorophenyl)((1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-
-4-yl)methoxy)methyl)pyridine;
(R)--N-((3-methoxyphenyl)(oxazol-4-yl)methyl)-1-(2-phenoxyethyl)piperidin-
e-4-carboxamide;
(S)--N-((3-methoxyphenyl)(oxazol-4-yl)methyl)-1-(2-phenoxyethyl)piperidin-
e-4-carboxamide;
(R)--N-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methyl)-1-(2--
(2,4-difluorophenoxy)ethyl)piperidine-4-carboxamide;
(S)--N-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methyl)-1-(2--
(2,4-difluorophenoxy)ethyl)piperidine-4-carboxamide;
(R)-1-(4-chlorophenyl)-N-methyl-N-((4-methyl-1-(2-phenoxyethyl)piperidin--
4-yl)methyl)-1-(pyridin-2-yl)methanamine;
(S)-1-(4-chlorophenyl)-N-methyl-N-((4-methyl-1-(2-phenoxyethyl)piperidin--
4-yl)methyl)-1-(pyridin-2-yl)methanamine;
(R)-1-(4-chlorophenyl)-N-((1-(2-(4-fluorophenoxy)ethyl)piperidin-4-yl)met-
hyl)-1-(pyridin-2-yl)methanamine;
(S)-1-(4-chlorophenyl)-N-((1-(2-(4-fluorophenoxy)ethyl)piperidin-4-yl)met-
hyl)-1-(pyridin-2-yl)methanamine;
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-(2-fluorophenoxy)e-
thyl)piperidin-4-yl)methyl)propan-2-amine;
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-(2-fluorophenoxy)e-
thyl)piperidin-4-yl)methyl)propan-2-amine;
(R)--N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-N-((3-methoxy-
phenyl)(pyridin-2-yl)methyl)propan-2-amine;
(S)--N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-N-((3-methoxy-
phenyl)(pyridin-2-yl)methyl)propan-2-amine;
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-(4-fluorophenoxy)e-
thyl)piperidin-4-yl)methyl)propan-2-amine;
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-(4-fluorophenoxy)e-
thyl)piperidin-4-yl)methyl)propan-2-amine;
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-2,2,2-trifluoro-N-((1-(2-(2-
-fluorophenoxy)ethyl)piperidin-4-yl)methyl)ethan-1-amine;
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-2,2,2-trifluoro-N-((1-(2-(2-
-fluorophenoxy)ethyl)piperidin-4-yl)methyl)ethan-1-amine;
(R)-1-(4-chlorophenyl)-N-methyl-1-(pyridin-2-yl)-N-((1-(2-(4-(trifluorome-
thyl)phenoxy)ethyl)piperidin-4-yl)methyl)methanamine;
(S)-1-(4-chlorophenyl)-N-methyl-1-(pyridin-2-yl)-N-((1-(2-(4-(trifluorome-
thyl)phenoxy)ethyl)piperidin-4-yl)methyl)methanamine;
(R)-1-(benzo[d][1,3]dioxol-5-yl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidi-
n-4-yl)methyl)-N-methyl-1-(pyridin-2-yl)methanamine;
(S)-1-(benzo[d][1,3
]dioxol-5-yl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-N-me-
thyl-1-(pyridin-2-yl)methanamine; (R)-1-(benzo
[d][1,3]dioxol-5-yl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methy-
l)-1-(pyridin-2-yl)methanamine;
(S)-1-(benzo[d][1,3]dioxol-5-yl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidi-
n-4-yl)methyl)-1-(pyridin-2-yl)methanamine;
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-((2,3-dihydrobenzo[b][1,4]diox-
in-2-yl)methyl)piperidine-4-carboxamide;
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(pyridin-2-yloxy)ethyl-
)piperidine-4-carboxamide;
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(pyridin-2-yloxy)ethyl-
)piperidine-4-carboxamide;
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(pyridin-4-yloxy)ethyl-
)piperidine-4-carboxamide;
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(pyridin-4-yloxy)ethyl-
)piperidine-4-carboxamide;
(R)--N-((3-methoxyphenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-phenoxyethyl-
)piperidine-4-carboxamide;
(S)--N-((3-methoxyphenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-phenoxyethyl-
)piperidine-4-carboxamide;
(R)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-phenoxyethyl)-
piperidine-4-carboxamide;
(S)--N-((4-chlorophenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-phenoxyethyl)-
piperidine-4-carboxamide;
(R)-1-(2-(2,4-difluorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-yl)me-
thyl)piperidine-4-carboxamide;
(S)-1-(2-(2,4-difluorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-yl)me-
thyl)piperidine-4-carboxamide;
(R)--N-((3-methoxyphenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-c-
arboxamide;
(S)--N-((3-methoxyphenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-c-
arboxamide; or a stereoisomer, racemate, tautomer, polymorph,
hydrate, or solvate thereof, or a pharmaceutically acceptable salt
thereof.
51. (canceled)
52. A pharmaceutical composition comprising a compound of claim 1,
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof, and
one or more pharmaceutically acceptable excipients or carriers.
53. A method of modulating D2 receptor activity, comprising
administering a compound of claim 1, or a stereoisomer, racemate,
tautomer, polymorph, hydrate, or solvate thereof, or a
pharmaceutically acceptable salt thereof.
54. (canceled)
55. A method of treating or preventing a disease or disorder in
which modulation of D2 receptors plays a role, comprising
administering to a subject in need thereof, a therapeutically
effective amount of a compound of claim 1, or a stereoisomer,
racemate, tautomer, polymorph, hydrate, or solvate thereof, or a
pharmaceutically acceptable salt thereof, in combination with a
pharmaceutically acceptable excipient or carrier.
56-63. (canceled)
64. A method of treating or preventing a disease or disorder in
which modulation of D2 receptors plays a role, comprising
administering to a subject in need thereof, a therapeutically
effective amount of a compound which is a selective .beta.-arrestin
antagonist.
65. A method of treating or preventing a disease or disorder in
which modulation of D2 receptors plays a role, comprising
administering to a subject in need thereof, a therapeutically
effective amount of a compound which is a .beta.-arrestin
antagonist and a cAMP agonist.
66-71. (canceled)
Description
RELATED APPLICATIONS
[0001] The present application claims priority under 35 U.S.C.
.sctn. 119(e) to U.S. provisional patent application, U.S. Ser. No.
62/094,510, filed Dec. 19, 2014, which is incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates to novel ligands of dopamine
D2 receptors, in particular, functionally selective ligands of
dopamine D2 receptors. The invention also relates to the use of
these compounds in treating or preventing central nervous system
disorders as well as systemic disorders associated with dopamine D2
receptors.
BACKGROUND OF THE INVENTION
[0003] G-protein-coupled receptors (GPCRs), also known as
7-transmembrane receptors, are the single largest class of drug
targets, with more than 800 members in the human genome (Lefkowitz,
Trends in Pharmacological Sciences (2004), 413). Dopamine receptors
represent prototypic examples of GPCRs that mediate
neurotransmission (Mis sale et al., Physiological Reviews (1998),
189). Dopamine is a monoamine neurotransmitter that exerts its
action on neuronal circuitry via dopamine receptors. As
dopaminergic innervations are most prominent in the brain,
dopaminergic dysfunction can critically affect vital central
nervous system (CNS) functions, ranging from voluntary movement,
feeding, reward, affection, sleep, attention, working memory and
learning (Carlsson, Science (2001), 1021, Beaulieu et al.,
Pharmacological Reviews (2011), 182). Apart from CNS functions,
dopamine is also involved in important physiological roles such as
the regulation of olfaction, cardiovascular functions, sympathetic
regulation, hormonal regulation, retinal processes, immune system
and renal function. Dysregulation of dopaminergic neurotransmission
has been associated with multiple neurological and psychiatric
conditions such as Parkinson's disease, Huntington's disease,
attention deficit hyperactivity disorder (ADHD), mood disorders and
schizophrenia (Carlsson, Science (2001), 1021), as well as various
somatic disorders such as hypertension and kidney dysfunction
(Missale et al., Physiological Reviews (1998), 189, Beaulieu et
al., Pharmacological Reviews (2011), 182).
[0004] With the complex array of critical cellular functions
mediated by dopamine receptors, and the multilevel interactions
that are known to occur between dopamine and other extracellular
messengers in the signaling pathways, there remains a need to
better manage dopamine-related pathologic conditions by precise
targeting of post-receptor intracellular signaling modalities,
either directly or through ligand-biased signaling
pharmacology.
[0005] As drug targets, GPCRs known to mediate dopamine functions
can be broadly classified into D1 and D2 class receptors. D1 class
receptors (D1R and D5R) are mostly coupled to Gas and positively
regulate the production of second messenger cAMP and the activity
of protein kinase A (PKA) (Missale et al., Physiological Reviews
(1998), 189). D2 class receptors (D2R, D3R and D4R) couple to
G.alpha.i/o, downregulating cAMP production and PKA activity
(Missale et al., Physiological Reviews (1998), 189). Additionally,
D2 class dopamine receptors also modulate intracellular Ca.sup.2+
levels, resulting in changes in activity of Ca.sup.2+ regulated
signaling proteins such as protein phosphatase calcineurin (Nishi
et al., J. Neurosci. (1997), 17, 8147).
[0006] D2 class dopamine (D2R) receptors are presently the
best-established targets for antipsychotic drugs. Recent studies
suggest that Varrestin 2 deficiency in mice results in reduction of
dopamine-dependent behaviours (Beaulieu et al., Cell (2005), 261).
The connection between .beta.-arrestin 2 and dopamine-associated
behaviours suggests that .beta.-arrestin 2 could be a positive
mediator of dopaminergic synaptic transmission and a potential
pharmacological target for dopamine-related psychiatric disorders
(Beaulieu et al., Cell (2005), 261).
[0007] Currently, all clinically marketed antipsychotics modulate
dopamine by targeting D2R either as antagonists/inverse agonists
(first- and second-generation antipsychotics, for example,
chlorpromazine, clozapine) or partial agonists (third-generation
antipsychotics, with aripiprazole as the sole example of this
ligand class in the clinic). Antagonism of dopamine D2
receptor/.beta.-arrestin 2 interaction has been found to be a
common property of clinically-effective antipsychotics (Masri et
al., Proceedings of the National Academy of Sciences of the United
States of America (2008), 13656).
[0008] Structure-functional selectivity relationship studies of
.beta.-arrestin-biased dopamine D2 receptor agonists, based on the
aripiprazole scaffold, have been conducted (Chen et al., Journal of
Medicinal Chemistry (2012), 7141, Roth et al., US 2013/0137679,
Shonberg et al., Journal of Medicinal Chemistry (2013), 9199).
Known antipsychotics, even those that share a common mechanistic
pathway such as haloperidol, clozapine, and risperidone, show
highly diverse effects on D2R/G protein signaling and are not
selective across GPCR receptors. There remains a lack of clinical
drug candidates that offer highly functionalized targeting of
dopamine D2 receptors that improve the clinical efficacy of
antipsychotics, while at the same time limiting the undesirable
side effects associated with D2-dopaminergic activity.
[0009] Selectively antagonizing the .beta.-arrestin pathway at the
D2 receptor could be sufficient to produce an antipsychotic effect,
while at the same time, reduce potential side effects that could
arise from antagonizing the cAMP pathway. Modulation of the
.beta.-arrestin-2 dependent pathway could lead to modulation of AKT
and GSK3.beta. target genes (Beaulieu et al., Frontiers in
molecular neuroscience (2011), 38.). Development of compounds with
cAMP biased agonist or antagonist or .beta.-arrestin biased agonist
or antagonist activity could offer a functionally selective means
to modulate or treat dopamine-associated disorders, including
Parkinson's disease, Huntington's disease, mood disorders,
schizophrenia, attention deficit hyperactivity disorder (ADHD),
restless legs syndrome (RLS), pituitary disorders such as pituitary
adenoma or pituitary tumor (prolactinoma) or endocrine disorders,
e.g., galactorrhea. Further, development of ligands that exhibit
functional selectivity as agonists, antagonists, and partial
agonists, as well as selectivity against other GPCRs, allows
modulation of activity at the dopamine D2 receptors to be more
finely-tuned to increase selectivity and hence clinical efficacy
and safety in treatment. By increasing selectivity at dopamine D2
receptors while minimising undesirable side-effects, drugs in this
category would also offer greater success potential with patient
acceptance and compliance.
SUMMARY OF THE INVENTION
[0010] The present invention relates to novel compounds that
modulate dopamine D2 receptors. In particular, compounds of the
present invention show functional selectivity at the dopamine D2
receptors and exhibit selectivity downstream of the D2 receptors,
on the .beta.-arrestin pathway and/or on the cAMP pathway.
Compounds of the present invention exhibit different activity
profiles either as agonist, antagonist, inverse agonist, or partial
agonist. As these compounds are functionally selective downstream
of the D2 receptors, they offer more selectivity and functionality
in treatment of diseases or disorders in which dopamine plays a
role, such as central nervous system disorders associated with D2
receptors, while minimizing potential associated side effects. Use
of .beta.-arrestin biased D2 receptor antagonists which selectively
antagonize the .beta.-arrestin pathway may offer a means to treat
psychotic disorders while also minimizing potential undesirable
side-effects associated with D2 receptor activity. Similarly,
biased D2 receptor agonists which selectively activate either the
.beta.-arrestin pathway or the cAMP pathway may also be
advantageous in treatment of disorders associated with dopamine
receptors, such as Parkinson's disease, ADHD and restless leg
syndrome or an endocrine disorder, e.g., galactorrhea, with fewer
side-effects.
[0011] The present invention provides a compound having Formula
I:
##STR00001##
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof,
wherein each of the variables is defined and illustrated in detail
herein.
[0012] The present invention also provides a pharmaceutical
composition comprising a compound of the invention or a
pharmaceutically acceptable salt, stereoisomer, racemate, tautomer,
polymorph, hydrate, or solvate thereof, and one or more
pharmaceutically acceptable excipients or carriers.
[0013] The present invention also provides a method of modulating
D2 receptor activity by administering a selective .beta.-arrestin
antagonist or a pharmaceutically acceptable salt, stereoisomer,
racemate, tautomer, polymorph, hydrate, or solvate thereof.
[0014] The present invention also provides a method of modulating
D2 receptor activity by administering a compound which is a
.beta.-arrestin antagonist and a cAMP agonist, or a
pharmaceutically acceptable salt, stereoisomer, racemate, tautomer,
polymorph, hydrate, or solvate thereof.
[0015] The present invention also provides a method of modulating
D2 receptor activity by administering a compound of the invention
or a pharmaceutically acceptable salt, stereoisomer, racemate,
tautomer, polymorph, hydrate, or solvate thereof.
[0016] The present invention also provides use of a compound of the
invention or a pharmaceutically acceptable salt, stereoisomer,
racemate, tautomer, polymorph, hydrate, or solvate thereof, as a
.beta.-arrestin biased D2 receptor agonist or antagonist. The
present invention also provides use of a compound of the invention
or a pharmaceutically acceptable salt, stereoisomer, racemate,
tautomer, polymorph, hydrate, or solvate thereof, as a cAMP biased
agonist or antagonist. The present invention also provides use of a
compound of the invention or a pharmaceutically acceptable salt,
stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate
thereof, as a .beta.-arrestin biased antagonist and cAMP biased
agonist.
[0017] The present invention also provides a method of treating or
preventing a disease or disorder in which modulation of D2
receptors (e.g., .beta.-arrestin or Gi/cAMP) plays a role by
administering to a subject in need thereof, a therapeutically
effective amount of a selective .beta.-arrestin antagonist, or a
pharmaceutically acceptable salt, stereoisomer, racemate, tautomer,
polymorph, hydrate, or solvate thereof, in combination with a
pharmaceutically acceptable excipient or carrier, such that the
disease or disorder is treated or prevented.
[0018] The present invention also provides a method of treating or
preventing a disease or disorder in which modulation of D2
receptors (e.g., .beta.-arrestin or Gi/cAMP) plays a role by
administering to a subject in need thereof, a therapeutically
effective amount of a compound which is a .beta.-arrestin
antagonist and a cAMP agonist, or a pharmaceutically acceptable
salt, stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, in combination with a pharmaceutically acceptable
excipient or carrier, such that the disease or disorder is treated
or prevented.
[0019] The present invention also provides a method of treating or
preventing a disease or disorder in which modulation of D2
receptors (e.g., .beta.-arrestin or Gi/cAMP) plays a role by
administering to a subject in need thereof, a therapeutically
effective amount of a compound of the invention, or a
pharmaceutically acceptable salt, stereoisomer, racemate, tautomer,
polymorph, hydrate, or solvate thereof, in combination with a
pharmaceutically acceptable excipient or carrier, such that the
disease or disorder is treated or prevented.
[0020] The present invention also provides a method of treating or
preventing a disease or disorder in which modulation of D2
receptors (e.g., .beta.-arrestin or Gi/cAMP) plays a role by
administering to a subject in need thereof, a therapeutically
effective amount of a pharmaceutical composition of the invention,
such that the disease or disorder is treated or prevented.
[0021] The present invention also provides use of a selective
.beta.-arrestin antagonist, or a pharmaceutically acceptable salt,
stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate
thereof, for treating or preventing a disease or disorder in which
modulation of D2 receptors (e.g., .beta.-arrestin or Gi/cAMP) plays
a role in a subject in need thereof.
[0022] The present invention also provides use of a compound which
is a .beta.-arrestin antagonist and a cAMP agonist, or a
pharmaceutically acceptable salt, stereoisomer, racemate, tautomer,
polymorph, hydrate, or solvate thereof, for treating or preventing
a disease or disorder in which modulation of D2 receptors (e.g.,
.beta.-arrestin or Gi/cAMP) plays a role in a subject in need
thereof.
[0023] The present invention also provides use of a compound of the
invention, or a pharmaceutically acceptable salt, stereoisomer,
racemate, tautomer, polymorph, hydrate, or solvate thereof, or use
of a pharmaceutical composition of the invention, for treating or
preventing a disease or disorder in which modulation of D2
receptors (e.g., .beta.-arrestin or Gi/cAMP) plays a role in a
subject in need thereof.
[0024] The present invention also provides use of a selective
.beta.-arrestin antagonist, or a pharmaceutically acceptable salt,
stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate
thereof, in the manufacture of a medicament for the treatment or
prevention of a disease or disorder in which modulation of D2
receptors (e.g., .beta.-arrestin or Gi/cAMP) plays a role in a
subject in need thereof.
[0025] The present invention also provides use of a compound which
is a .beta.-arrestin antagonist and a cAMP agonist, or a
pharmaceutically acceptable salt, stereoisomer, racemate, tautomer,
polymorph, hydrate, or solvate thereof, in the manufacture of a
medicament for the treatment or prevention of a disease or disorder
in which modulation of D2 receptors (e.g., .beta.-arrestin or
Gi/cAMP) plays a role in a subject in need thereof.
[0026] The present invention also provides use of a compound of the
invention, or a pharmaceutically acceptable salt, stereoisomer,
racemate, tautomer, polymorph, hydrate, or solvate thereof, or use
of a pharmaceutical composition of the invention, in the
manufacture of a medicament for the treatment or prevention of a
disease or disorder in which modulation of D2 receptors (e.g.,
.beta.-arrestin or Gi/cAMP) plays a role in a subject in need
thereof.
[0027] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. In the
specification, the singular forms also include the plural unless
the context clearly dictates otherwise. Although methods and
materials similar or equivalent to those described herein can be
used in the practice or testing of the present invention, suitable
methods and materials are described below. All publications, patent
applications, patents and other references mentioned herein are
incorporated by reference. The references cited herein are not
admitted to be prior art to the present invention. In the case of
conflict, the present specification, including definitions, will
control. In addition, the materials, methods and examples are
illustrative only and are not intended to be limiting.
[0028] Other features and advantages of the invention will be
apparent from the following detailed description and claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] The following detailed description, given by way of example,
but not intended to limit the invention solely to the specific
embodiments described, may be understood in conjunction with the
accompanying drawings, in which:
[0030] FIG. 1 shows representative curves for Compounds 35b, 63,
79, 16a, 52 and control compounds Clozapine and Aripiprazole across
the .beta.-arrestin and cAMP cell based assays in agonist and
antagonist modes (see also Table 3).
[0031] FIG. 2 shows pharmacokinetic and brain distribution of
Compound 35b following a single intraperitoneal dose administration
of 10 mg/kg in male C57BL/6 mice.
[0032] FIG. 3 shows positron emission tomography at different doses
of Compound 35b in comparison with Clozapine. The compounds compete
with [.sup.11C]Raclopride.
[0033] FIG. 4 shows the effect of Compound 35b in comparison with
vehicle to attenuate amphetamine induced hyperactivity (AIH) over
time. Compound 35b dose-dependently attenuates AIH in mice and
shows efficacy at 10 and 30 mg/kg. The x-axis shows the time in
minutes.
[0034] FIG. 5 shows the effect of Compound 35b in comparison with
vehicle and Clozapine in the rotarod assay: Compound 35b promotes
significantly less motor impairment than Clozapine at efficacious
doses.
[0035] FIG. 6 shows a heat map representation of binding across
various GPCR receptors for compounds of the invention and control
compounds.
[0036] FIG. 7 is an ortep representation of an X-ray crystal
structure of (S)-(3-methoxyphenyl)(pyridin-2-yl)methanamine
hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
Compounds of the Invention
[0037] The present invention relates to novel ligands of dopamine
D2 receptors. In particular, the invention relates to a compound
having Formula I:
##STR00002##
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof,
wherein:
[0038] A-B is C(O)--NR.sup.13, C(O)--CR.sup.11R.sup.12, C(O)--O,
CR.sup.11R.sup.12--NR.sup.13, CR.sup.11R.sup.12--NR.sup.13,
CR.sup.11R.sup.12--O, CR.sup.11R.sup.12--C(O), NR.sup.13--C(O),
NR.sup.13--CR.sup.11R.sup.12, O--CR.sup.11R.sup.12, or O--C(O),
wherein CR.sup.11R.sup.12--NR.sup.13 or
NR.sup.13--CR.sup.11R.sup.12 can form a 3- to 6-membered ring, or
[0039] A-Z.sup.1-R.sup.5 form a 3- to 6-membered ring, and B is
C(O), CR.sup.11R.sup.12, O, or NR.sup.13, or [0040] A-Z.sup.1,
together with any one or two of Z.sup.2 and Z.sup.3, or any one or
two of Z.sup.4 and Z.sup.5, form a 3- to 6-membered ring, wherein
the ring and ring G form a fused or bridged ring structure, and B
is C(O), CR.sup.11R.sup.12, O, or NR.sup.13, or [0041]
B--Z.sup.6-Cy.sup.1 or B--Z.sup.6-Cy.sup.2 form a 3- to 6-membered
ring, and A is C(O), CR.sup.11R.sup.12, O, or NR.sup.13, or [0042]
B--Z.sup.6--R.sup.1 form a 3- to 6-membered ring, and A is C(O),
CR.sup.11R.sup.12, O, or NR.sup.13, or [0043] A-B--Z.sup.6-Cy.sup.1
or A-B--Z.sup.6-Cy.sup.2 form a 5- to 8-membered ring, or [0044]
A-B--Z.sup.6 form a 3- to 6-membered ring, or [0045] B-A-Z.sup.1
form a 3- to 6-membered ring, or [0046] B-A-Z.sup.1, together with
any one or two of Z.sup.2 and Z.sup.3, or any one or two of Z.sup.4
and Z.sup.5, form a 4- to 6-membered ring, wherein the ring and
ring G form a fused or bridged ring structure;
[0047] R.sup.11 and R.sup.12 are each independently H, halogen, or
C.sub.1-C.sub.6 alkyl, or R.sup.11 and R.sup.12, together with the
carbon atom to which R.sup.11 and R.sup.12 are bonded, form a 3- to
6-membered ring, provided that when CR.sup.11R.sup.12--NR.sup.13 or
NR.sup.13--CR.sup.11R.sup.12 forms a 3- to 6-membered ring, one of
R.sup.11 and R.sup.12 is absent;
[0048] R.sup.13 is H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 heterocycle,
C.sub.6-C.sub.10 aryl, heteroaryl comprising one or two 5- or
6-membered rings and one to four heteroatoms selected from N, O,
and S, C(O)--C.sub.1-C.sub.6 alkyl, C(O)-phenyl,
C(O)O--C.sub.1-C.sub.6 alkyl, C(O)NR.sup.17R.sup.18,
S(O).sub.2--C.sub.1-C.sub.6 alkyl, or S(O).sub.2NR.sup.17R.sup.18,
provided that when CR.sup.11R.sup.12--NR.sup.13 or
NR.sup.13--CR.sup.11R.sup.12 forms a 3- to 6-membered ring,
R.sup.13 is absent;
[0049] R.sup.17 and R.sup.18 are each independently H,
C.sub.1-C.sub.6 alkyl, or C.sub.6-C.sub.10 aryl;
[0050] Z.sup.1 is a carbon atom;
[0051] R.sup.5 is H, halogen, OH, C.sub.1-C.sub.6 alkyl,
O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F,
NR.sup.17R.sup.18, NR.sup.17C(O)--C.sub.1-C.sub.6 alkyl,
C(O)NR.sup.17R.sup.18, S--C.sub.1-C.sub.6 alkyl,
S(O)--C.sub.1-C.sub.6 alkyl, S(O).sub.2--C.sub.1-C.sub.6 alkyl,
S(O).sub.2NR.sup.17R.sup.18, NR.sup.17S(O).sub.2--C.sub.1-C.sub.6
alkyl, C.sub.6-C.sub.10 aryl, phenyl, benzyl, heteroaryl comprising
one 5- or 6-membered ring and one to four heteroatoms selected from
N, O, and S, C.sub.3-C.sub.6 cycloalkyl, or heterocyclyl comprising
one 4- to 6-membered ring and one to four heteroatoms selected from
N, O, and S, or when B-A-Z.sup.1 form a 3- to 6-membered ring,
absent, or [0052] A-Z.sup.1--R.sup.5 form a 3- to 6-membered ring,
or [0053] Z.sup.1--R.sup.5, together with R.sup.2 and the carbon
atom to which the R.sup.2 is bonded, form a 4- to 6-membered ring,
wherein the ring and ring G form a fused or bridged ring structure,
provided that when A-B is NR.sup.13--C(O),
NR.sup.13--CR.sup.11R.sup.12, O--CR.sup.11R.sup.12, or O--C(O),
then R.sup.5 is not OH, O--C.sub.1-C.sub.6 alkyl,
S--C.sub.1-C.sub.6 alkyl, NR.sup.17R.sup.18,
NR.sup.17C(O)--C.sub.1-C.sub.6 alkyl, or
NR.sup.17S(O).sub.2--C.sub.1-C.sub.6 alkyl;
[0054] Z.sup.2 is C(R.sup.2).sub.p or C(O);
[0055] Z.sup.3 is C(R.sup.2).sub.p; or [0056] any one or two of
Z.sup.2 and Z.sup.3, together with A-Z.sup.1 or B-A-Z.sup.1, form a
3- to 6-membered ring, wherein the ring and ring G form a fused or
bridged ring structure, or [0057] when X is CR.sup.14R.sup.15 or
NR.sup.16, Z.sup.3--N--(Z.sup.7).sub.t--X form a 4- to 6-membered
ring;
[0058] Z.sup.4 is C(R.sup.2).sub.p;
[0059] Z.sup.5 is C(R.sup.2).sub.p or C(O); or [0060] any one or
two of Z.sup.4 and Z.sup.5, together with A-Z.sup.1 or B-A-Z.sup.1,
form a 3- to 6-membered ring, wherein the ring and ring G form a
fused or bridged ring structure, or [0061] when X is
CR.sup.14R.sup.15 or NR.sup.16, Z.sup.4--N--(Z.sup.7).sub.t--X form
a 4- to 6-membered ring;
[0062] p is 1 or 2;
[0063] each R.sup.2 is independently H, halogen, OH,
C.sub.1-C.sub.6 alkyl, CF.sub.3, O--C.sub.1-C.sub.6 alkyl,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 heterocycle, C.sub.6-C.sub.10 aryl,
O--C.sub.6-C.sub.10 aryl, C(O)--C.sub.1-C.sub.6 alkyl,
C(O)NR.sup.17R.sup.18, NR.sup.17R.sup.18,
NR.sup.17C(O)--C.sub.1-C.sub.6 alkyl, S(O).sub.2NR.sup.17R.sup.18,
or NR.sup.17S(O).sub.2--C.sub.1-C.sub.6 alkyl, or [0064] any two
R.sup.2 bonded to different carbon atoms, together with the carbon
atoms to which the two R.sup.2 are bonded, form a 4- to 7-membered
ring, or [0065] any two R.sup.2 bonded to the same carbon atom,
together with the carbon atom to which the two R.sup.2 are bonded,
form a 3- to 6-membered ring, or [0066] R.sup.2, together with the
carbon atom to which the R.sup.2 is bonded, and Z.sup.1--R.sup.5,
form a 4- to 6-membered ring, wherein the ring and ring G form a
fused or bridged ring structure, provided that when R.sup.2 is
bonded to a carbon atom adjacent to the nitrogen atom in ring G,
then R.sup.2 is H, halogen, C.sub.1-C.sub.6 alkyl, CF.sub.3,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 heterocycloalkyl,
C.sub.6-C.sub.10 aryl, C(O)--C.sub.1-C.sub.6 alkyl,
C(O)NR.sup.17R.sup.18, or S(O).sub.2NR.sup.17R.sup.18;
[0067] Z.sup.6 is a carbon atom;
[0068] R.sup.1is H or C.sub.1-C.sub.6 alkyl, or when A-B--Z.sup.6
form a 3- to 6-membered ring, absent, or [0069] B--Z.sup.6--R.sup.1
form a 3- to 6-membered ring;
[0070] Cy.sup.1 and Cy.sup.2 are each independently H,
C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 aryl, heteroaryl comprising
one or two 5- or 6-membered rings and one to four heteroatoms
selected from N, O, and S, C.sub.3-C.sub.10 cycloalkyl,
C.sub.5-C.sub.13 bicyclic group, or heterocyclyl comprising one or
two 3- to 6-membered rings and one to four heteroatoms selected
from N, O, and S, wherein the aryl, heteroaryl, cycloalkyl,
bicyclic group, and heterocycyl are each independently optionally
substituted with one or more substituents independently selected
from: [0071] halogen, CH.sub.2F, CHF.sub.2, CF.sub.3,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, OH,
O--C.sub.1-C.sub.6 alkyl, [0072] OCF.sub.3, OCHF.sub.2, OCH.sub.2F,
C.sub.6-C.sub.10 aryl, heteroaryl comprising one 5- or 6-membered
ring and one to four heteroatoms selected from N, O, and S, and
NR.sup.17R.sup.18, or
[0073] A-B--Z.sup.6-Cy.sup.1 or A-B--Z.sup.6-Cy.sup.2 form a 4- to
8-membered ring, or
[0074] B-Z.sup.6-Cy.sup.1 or B--Z.sup.6-Cy.sup.2 form a 3- to
6-membered ring;
[0075] Z.sup.7 is C(R.sup.3).sub.w, or [0076] when X is
CR.sup.14R.sup.15 or NR.sup.16, Z.sup.3--N--(Z.sup.7).sub.t--X or
Z.sup.4--N--(Z.sup.7).sub.t--X form a 4- to 6-membered ring, or
[0077] when X is CR.sup.14R.sup.15, Z.sup.7--X, together with
R.sup.14 or R.sup.15, form a 3- to 6-membered ring, or [0078] when
X is NR.sup.16, Z.sup.7--X, together with R.sup.16, form a 3- to
6-membered ring, or [0079] Z.sup.7--X--Z.sup.8 form a 3- to
6-membered ring, or [0080] Z.sup.7--X--Z.sup.8-Cy.sup.3 form a 4-
to 6-membered ring;
[0081] each w is independently 1 or 2;
[0082] t is 1, 2, 3, or 4, provided that when X is O, S, S(O),
S(O).sub.2, or NR.sup.16, then t is not 1;
[0083] each R.sup.3 is independently H, halogen, C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 heterocycle, OH,
O--C.sub.1-C.sub.6 alkyl, S--C.sub.1-C.sub.6 alkyl,
NR.sup.17R.sup.18, C(O)NR.sup.17R.sup.18,
NR.sup.17C(O)--C.sub.1-C.sub.6 alkyl,
NR.sup.17S(O).sub.2--C.sub.1-C.sub.6 alkyl, or
S(O).sub.2NR.sup.17R.sup.18, or [0084] any two R.sup.3 bonded to
the same carbon atom, together with the carbon atom to which the
two R.sup.3 are bonded, form C.dbd.O, provided that the C.dbd.O is
not directly bonded to the nitrogen atom in ring G, or [0085] any
two R.sup.3 bonded to the same carbon atom or different carbon
atoms, together with the one or two carbon atoms to which the two
R.sup.3 are bonded, form a 3- to 6-membered ring, provided that
when X is O, S, or NR.sup.16, then the R.sup.3 in the
C(R.sup.3).sub.w directly bonded to X is not OH, O--C.sub.1-C.sub.6
alkyl, S--C.sub.1-C.sub.6 alkyl, NR.sup.17R.sup.18,
NR.sup.17C(O)--C.sub.1-C.sub.6 alkyl,
NR.sup.17S(O).sub.2--C.sub.1-C.sub.6 alkyl, or
S(O).sub.2NR.sup.17R.sup.18;
[0086] X is a bond, O, CR.sup.14R.sup.15, S, S(O), S(O).sub.2,
C.dbd.O, or NR.sup.16, or [0087] when X is CR.sup.14R.sup.15 or
NR.sup.16, Z.sup.3--N--Z.sup.7--X or Z.sup.4--N--Z.sup.7--X form a
4- to 6-membered ring, or [0088] when X is CR.sup.14R.sup.15,
Z.sup.7--X or Z.sup.8--X, together with R.sup.14 or R.sup.15, form
a 3- to 6-membered ring, or [0089] when X is NR.sup.16, Z.sup.7--X
or Z.sup.8--X, together with R.sup.16, form a 3- to 6-membered
ring, or [0090] Z.sup.7--X--Z.sup.8 form a 3- to 6-membered ring,
or [0091] Z.sup.7--X--Z.sup.8-Cy.sup.3 form a 4- to 6-membered
ring, or [0092] X--Z.sup.8-Cy.sup.3 form a 3- to 6-membered ring;
provided that when X is O, S, S(O), S(O).sub.2, or NR.sup.16, then
t is 2, 3, or 4;
[0093] R.sup.14 and R.sup.15 are each independently, H, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, phenyl, or
heteroaryl comprising one 5- or 6-membered ring and one to four
heteroatoms selected from N, O, and S, or R.sup.14 and R.sup.15,
together with the carbon atom to which R.sup.14 and R.sup.15 are
bonded, form C.sub.3-C.sub.6 cycloalkyl, C.sub.5-C.sub.13 bicyclic
group, or heterocyclyl comprising one or two 3- to 6-membered rings
and one to four heteroatoms selected from N, O, and S, or when
Z.sup.3--N--Z.sup.7--X or Z.sup.4--N--Z.sup.7--X form a 4- to
6-membered ring, absent, or [0094] R.sup.14 or R.sup.15, together
with Z.sup.7--X or Z.sup.8--X, form a 3- to 6-membered ring;
[0095] R.sup.16 is, H, C.sub.1-C.sub.6 alkyl, phenyl, heteroaryl
comprising one 5- or 6-membered ring and one to four heteroatoms
selected from N, O, and S, C(O)--C.sub.1-C.sub.6 alkyl,
C(O)-phenyl, C(O)O--C.sub.1-C.sub.6 alkyl, C(O)NR.sup.17R.sup.18,
S(O).sub.2--C.sub.1-C.sub.6 alkyl, or S(O).sub.2NR.sup.17R.sup.18,
or when Z.sup.3--N--Z.sup.7--X or Z.sup.4--N--Z.sup.7--X form a 4-
to 6-membered ring, absent, or [0096] R.sup.16, together with
Z.sup.7--X or Z.sup.8--X, form a 3- to 6-membered ring;
[0097] Z.sup.8 is C(R.sup.4).sub.n, or [0098] when X is
CR.sup.14R.sup.15, Z.sup.8--X, together with R.sup.14 or R.sup.15,
form a 3- to 6-membered ring, or [0099] when X is NR.sup.16,
Z.sup.8--X, together with R.sup.16, form a 3- to 6-membered ring,
or [0100] Z.sup.7--X--Z.sup.8 form a 3- to 6-membered ring, or
[0101] Z.sup.7--X--Z.sup.8-Cy.sup.3 form a 4- to 6-membered ring,
or [0102] X--Z.sup.8-Cy.sup.3 form a 3- to 6-membered ring, or
[0103] Z.sup.8, together with R.sup.4 and Cy.sup.3, form a 3- to
6-membered ring;
[0104] each u is independently 1 or 2;
[0105] n is 0, 1, or 2;
[0106] each R.sup.4 is independently H, halogen, C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 heterocycle, OH,
O--C.sub.1-C.sub.6 alkyl, S--C.sub.1-C.sub.6 alkyl,
NR.sup.17R.sup.18, C(O)NR.sup.17R.sup.18,
NR.sup.17C(O)--C.sub.1-C.sub.6 alkyl,
NR.sup.17S(O).sub.2--C.sub.1-C.sub.6 alkyl, or
S(O).sub.2NR.sup.17R.sup.18, or [0107] any two R.sup.4 bonded to
the same carbon atom, together with the carbon atom to which the
two R.sup.4 are bonded, form C.dbd.O, or [0108] any two R.sup.4
bonded to the same carbon atom or on different carbon atoms,
together with the one or two carbon atoms to which the two R.sup.4
are bonded, form a 3- to 6-membered ring, or [0109] R.sup.4,
together with Z.sup.8-Cy.sup.3, form a 3- to 6-membered ring,
provided that when X is O, S, or NR.sup.16, then the R.sup.4 in the
C(R.sup.4).sub.n directly bonded to X is not OH, O--C.sub.1-C.sub.6
alkyl, S--C.sub.1-C.sub.6 alkyl, or NR.sup.17R.sup.18; and
[0110] Cy.sup.3 is H, C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 aryl,
heteroaryl comprising one or two 5- or 6-membered rings and one to
four heteroatoms selected from N, O, and S, C.sub.3-C.sub.10
cycloalkyl, C.sub.5-C.sub.13 bicyclic group, or heterocyclyl
comprising one or two 3- to 6-membered rings and one to four
heteroatoms selected from N, O, and S, wherein the aryl,
heteroaryl, cycloalkyl, bicyclic group, and heterocycyl are each
independently optionally substituted with one or more substituents
independently selected from: [0111] halogen, CH.sub.2F, CHF.sub.2,
CF.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, OH,
O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F,
C.sub.6-C.sub.10 aryl, heteroaryl comprising one 5- or 6-membered
ring and one to four heteroatoms selected from N, O, and S, and
NR.sup.17R.sup.18, or [0112] Z.sup.7--X--Z.sup.8-Cy.sup.3 form a 4-
to 6-membered ring, or [0113] X--Z.sup.8-Cy.sup.3 form a 3- to
6-membered ring, or [0114] Z.sup.8-Cy.sup.3, together with R.sup.4,
form a 3- to 6-membered ring, provided that when
Z.sup.7--X--Z.sup.8 is (CH.sub.2).sub.1-6, then Cy.sup.3 is not
phenyl, which is optionally substituted, methylenedioxyphenyl,
isoindoline-1,3,-dione, or dihydrobenzofuranyl.
[0115] In certain embodiments, a compound of the invention is of
Formula I, or a stereoisomer, racemate, tautomer, polymorph,
hydrate, or solvate thereof, or a pharmaceutically acceptable salt
thereof, wherein:
[0116] A-B is C(O)--NR.sup.13, C(O)--CR.sup.11R.sup.12, C(O)--O.
CR.sup.11R.sup.12--NR.sup.13, CR.sup.11R.sup.12--O,
CR.sup.11R.sup.12, C(O), NR.sup.13--C(O),
NR.sup.13--CR.sup.11R.sup.12, O--CR.sup.11R.sup.12, or O--C(O),
wherein CR.sup.11R.sup.12--NR.sup.13 or NR.sup.13,
CR.sup.11R.sup.12 can form a 3- to 6-membered ring, or [0117]
A-Z.sup.1--R.sup.5 form a 3- to 6-membered ring, and B is C(O),
CR.sup.11R.sup.12, O, or NR.sup.13, or [0118] A--Z.sup.1, together
with any one or two of Z.sup.2 and Z.sup.3, or any one or two of
Z.sup.4 and Z.sup.5, form a 3- to 6-membered ring, wherein the ring
and ring G form a fused or bridged ring structure, and B is C(O),
CR.sup.11R.sup.12, O, or NR.sup.13, or [0119] B--Z.sup.6-Cy.sup.1
or B--Z.sup.6-Cy.sup.2 form a 3- to 6-membered ring, and A is C(O),
CR.sup.11R.sup.12, O, or NR.sup.13, or [0120] B--Z.sup.6--R.sup.1
form a 3- to 6-membered ring, and A is C(O), CR.sup.11R.sup.12, O,
or NR.sup.13, or [0121] A-B--Z.sup.6-Cy.sup.1 or
A-B--Z.sup.6-Cy.sup.2 form a 5- to 8-membered ring, or [0122]
A-B--Z.sup.6 form a 3- to 6-membered ring, or [0123] B-A-Z.sup.1
form a 3- to 6-membered ring, or [0124] B-A-Z.sup.1, together with
any one or two of Z.sup.2 and Z.sup.3, or any one or two of Z.sup.4
and Z.sup.5, form a 4- to 6-membered ring, wherein the ring and
ring G form a fused or bridged ring structure;
[0125] R.sup.11 and R.sup.12 are each independently H, halogen, or
C.sub.1-C.sub.6 alkyl, or R.sup.11 and R.sup.12, together with the
carbon atom to which R.sup.11 and R.sup.12 are bonded, form a 3- to
6-membered ring, provided that when CR.sup.11R.sup.12--NR.sup.13 or
NR.sup.13--CR.sup.11R.sup.12 forms a 3- to 6-membered ring, one of
R.sup.11 and R.sup.12 is absent;
[0126] R.sup.13 is H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.3-C.sub.6 heterocycle, C.sub.6-C.sub.10 aryl,
heteroaryl comprising one or two 5- or 6-membered rings and one to
four heteroatoms selected from N, O, and S, C(O)--C.sub.1-C.sub.6
alkyl, C(O)-phenyl, C(O)O--C.sub.1-C.sub.6 alkyl,
C(O)NR.sup.17R.sup.18, S(O).sub.2--C.sub.1-C.sub.6 alkyl, or
S(O).sub.2NR.sup.17R.sup.18, provided that when CR.sup.11R.sup.12
NR.sup.13 or NR.sup.13--CR.sup.11R.sup.12 forms a 3- to 6-membered
ring, R.sup.13 is absent;
[0127] R.sup.17 and R.sup.18 are each independently H,
C.sub.1-C.sub.6 alkyl, or C.sub.6-C.sub.10 aryl;
[0128] Z.sup.1 is a carbon atom;
[0129] R.sup.5 is H, halogen, OH, C.sub.1-C.sub.6 alkyl,
O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F,
NR.sup.17R.sup.18, NR.sup.17C(O)--C.sub.1-C.sub.6 alkyl,
C(O)NR.sup.17R.sup.18, S--C.sub.1-C.sub.6 alkyl,
S(O)--C.sub.1-C.sub.6 alkyl, S(O).sub.2--C.sub.1-C.sub.6 alkyl,
S(O).sub.2NR.sup.17R.sup.18, NR.sup.17S(O).sub.2--C.sub.1-C.sub.6
alkyl, C.sub.6-C.sub.10 aryl, phenyl, benzyl, heteroaryl comprising
one 5- or 6-membered ring and one to four heteroatoms selected from
N, O, and S, C.sub.3-C.sub.6 cycloalkyl, or heterocyclyl comprising
one 4- to 6-membered ring and one to four heteroatoms selected from
N, O, and S, or when B-A-Z.sup.1 form a 3- to 6-membered ring,
absent, or [0130] A-Z.sup.1--R.sup.5 form a 3- to 6-membered ring,
or [0131] Z.sup.1--R.sup.5, together with R.sup.2 and the carbon
atom to which the R.sup.2 is bonded, form a 4- to 6-membered ring,
wherein the ring and ring G form a fused or bridged ring structure,
provided that when A-B is NR.sup.13--C(O),
NR.sup.13--CR.sup.11R.sup.12, O--CR.sup.11R.sup.12, or O--C(O),
then R.sup.5 is not OH, O--C.sub.1-C.sub.6 alkyl,
S--C.sub.1-C.sub.6 alkyl, NR.sup.17R.sup.18,
NR.sup.17C(O)--C.sub.1-C.sub.6 alkyl, or
NR.sup.17S(O).sub.2--C.sub.1-C.sub.6 alkyl;
[0132] Z.sup.2 is C(R.sup.2).sub.p or C(O);
[0133] Z.sup.3 is C(R.sup.2).sub.p; or [0134] any one or two of
Z.sup.2 and Z.sup.3, together with A-Z.sup.1 or B-A-Z.sup.1, form a
3- to 6-membered ring, wherein the ring and ring G form a fused or
bridged ring structure, or [0135] when X is CR.sup.14R.sup.15 or
NR.sup.16, Z.sup.3--N--(Z.sup.7).sub.t--X form a 4- to 6-membered
ring;
[0136] Z.sup.4 is C(R.sup.2).sub.p;
[0137] Z.sup.5 is C(R.sup.2).sub.p or C(O); or [0138] any one or
two of Z.sup.4 and Z.sup.5, together with A-Z.sup.1 or B-A-Z.sup.1,
form a 3- to 6-membered ring, wherein the ring and ring G form a
fused or bridged ring structure, or [0139] when X is
CR.sup.14R.sup.15 or NR.sup.16, Z.sup.4--N--(Z.sup.7).sub.t--X form
a 4- to 6-membered ring;
[0140] p is 1 or 2;
[0141] each R.sup.2 is independently H, halogen, OH,
C.sub.1-C.sub.6 alkyl, CF.sub.3, O--C.sub.1-C.sub.6 alkyl,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 heterocycle, C.sub.6-C.sub.10 aryl,
O--C.sub.6-C.sub.10 aryl, C(O)--C.sub.1-C.sub.6 alkyl,
C(O)NR.sup.17R.sup.18, NR.sup.17R.sup.18,
NR.sup.17C(O)--C.sub.1-C.sub.6 alkyl, S(O).sub.2NR.sup.17R.sup.18,
or NR.sup.17S(O).sub.2--C.sub.1-C.sub.6 alkyl, or [0142] any two
R.sup.2 bonded to different carbon atoms, together with the carbon
atoms to which the two R.sup.2 are bonded, form a 4- to 7-membered
ring, or [0143] any two R.sup.2 bonded to the same carbon atom,
together with the carbon atom to which the two R.sup.2 are bonded,
form a 3- to 6-membered ring, or [0144] R.sup.2, together with the
carbon atom to which the R.sup.2 is bonded, and Z.sup.1--R.sup.5,
form a 4- to 6-membered ring, wherein the ring and ring G form a
fused or bridged ring structure, provided that when R.sup.2 is
bonded to a carbon atom adjacent to the nitrogen atom in ring G,
then R.sup.2 is H, halogen, C.sub.1-C.sub.6 alkyl, CF.sub.3,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 heterocycloalkyl,
C.sub.6-C.sub.10 aryl, C(O)--C.sub.1-C.sub.6 alkyl,
C(O)NR.sup.17R.sup.18, or S(O).sub.2NR.sup.17R.sup.18;
[0145] Z.sup.6 is a carbon atom;
[0146] R.sup.1 is H or C.sub.1-C.sub.6 alkyl, or when A-B--Z.sup.6
form a 3- to 6-membered ring, absent, or B--Z.sup.6--R.sup.1 form a
3- to 6-membered ring;
[0147] Cy.sup.1 and Cy.sup.2 are each independently H,
C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 aryl, heteroaryl comprising
one or two 5- or 6-membered rings and one to four heteroatoms
selected from N, O, and S, C.sub.3-C.sub.10 cycloalkyl,
C.sub.5-C.sub.13 bicyclic group, or heterocyclyl comprising one or
two 3- to 6-membered rings and one to four heteroatoms selected
from N, O, and S, wherein the aryl, heteroaryl, cycloalkyl,
bicyclic group, and heterocycyl are each independently optionally
substituted with one or more substituents independently selected
from: [0148] halogen, CH.sub.2F, CHF.sub.2, CF.sub.3,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, OH,
O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F,
C.sub.6-C.sub.10 aryl, heteroaryl comprising one 5- or 6-membered
ring and one to four heteroatoms selected from N, O, and S, and
NR.sup.17R.sup.18, or
[0149] A-B--Z.sup.6-Cy.sup.1 or A-B--Z.sup.6-Cy.sup.2 form a 4- to
8-membered ring, or
[0150] B--Z.sup.6-Cy.sup.1 or B--Z.sup.6-Cy.sup.2 form a 3- to
6-membered ring;
[0151] Z.sup.7 is C(R.sup.3).sub.w, or [0152] when X is
CR.sup.14R.sup.15 or NR.sup.16, Z.sup.3--N--(Z.sup.7).sub.t--X or
Z.sup.4--N--(Z.sup.7).sub.t--X form a 4- to 6-membered ring, or
[0153] when X is CR.sup.14R.sup.15, Z.sup.7--X, together with
R.sup.14 or R.sup.15, form a 3- to 6-membered ring, or [0154] when
X is NR.sup.16, Z.sup.7--X, together with R.sup.16, form a 3- to
6-membered ring, or [0155] Z.sup.7--X--Z.sup.8 form a 3- to
6-membered ring, or [0156] Z.sup.7--X--Z.sup.8-Cy.sup.3 form a 4-
to 6-membered ring;
[0157] each w is independently 1 or 2;
[0158] t is 1, 2, 3, or 4, provided that when X is O, S, S(O),
S(O).sub.2, or NR.sup.16, then t is not 1;
[0159] each R.sup.3 is independently H, halogen, C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 heterocycle, OH,
O--C.sub.1-C.sub.6 alkyl, S--C.sub.1-C.sub.6 alkyl,
NR.sup.17R.sup.18, C(O)NR.sup.17R.sup.18,
NR.sup.17C(O)--C.sub.1-C.sub.6 alkyl,
NR.sup.17S(O).sub.2--C.sub.1-C.sub.6 alkyl, or
S(O).sub.2NR.sup.17R.sup.18, or [0160] any two R.sup.3 bonded to
the same carbon atom, together with the carbon atom to which the
two R.sup.3 are bonded, form C.dbd.O, provided that the C.dbd.O is
not directly bonded to the nitrogen atom in ring G, or [0161] any
two R.sup.3 bonded to the same carbon atom or different carbon
atoms, together with the one or two carbon atoms to which the two
R.sup.3 are bonded, form a 3- to 6-membered ring, provided that
when X is O, S, or NR.sup.16, then the R.sup.3 in the
C(R.sup.3).sub.w directly bonded to X is not OH, O--C.sub.1-C.sub.6
alkyl, S--C.sub.1-C.sub.6 alkyl, NR.sup.17R.sup.18,
NR.sup.17C(O)--C.sup.1-C.sub.6 alkyl,
NR.sup.17S(O).sub.2--C.sub.1-C.sub.6 alkyl, or
S(O).sub.2NR.sup.17R.sup.18;
[0162] X is a bond, O, CR.sup.14R.sup.15, S, S(O), S(O).sub.2,
C.dbd.O, or NR.sup.16, or [0163] when X is CR.sup.14R.sup.15 or
NR.sup.16, Z.sup.3--N--Z.sup.7--X or Z.sup.4--N--Z.sup.7--X form a
4- to 6-membered ring, or [0164] when X is CR.sup.14R.sup.15,
Z.sup.7--X or Z.sup.8--X, together with R.sup.14 or R.sup.15, form
a 3- to 6-membered ring, or [0165] when X is NR.sup.16, Z.sup.7--X
or Z.sup.8--X, together with R.sup.16, form a 3- to 6-membered
ring, or [0166] Z.sup.7--X--Z.sup.8 form a 3- to 6-membered ring,
or [0167] Z.sup.7--X--Z.sup.8-Cy.sup.3 form a 4- to 6-membered
ring, or [0168] X--Z.sup.8-Cy.sup.3 form a 3- to 6-membered ring;
provided that when X is O, S, S(O), S(O).sub.2, or NR.sup.16, then
t is 2, 3, or 4;
[0169] R.sup.14 and R.sup.15 are each independently, H, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, phenyl, or
heteroaryl comprising one 5- or 6-membered ring and one to four
heteroatoms selected from N, O, and S, or R.sup.14 and R.sup.15,
together with the carbon atom to which R.sup.14 and R.sup.15 are
bonded, form C.sub.3-C.sub.6 cycloalkyl, C.sub.5-C.sub.13 bicyclic
group, or heterocyclyl comprising one or two 3- to 6-membered rings
and one to four heteroatoms selected from N, O, and S, or when
Z.sup.3--N--Z.sup.7--X or Z.sup.4--N--Z.sup.7--X form a 4- to
6-membered ring, absent, or [0170] R.sup.14 or R.sup.15, together
with Z.sup.7--X or Z.sup.8--X, form a 3- to 6-membered ring;
[0171] R.sup.16 is, H, C.sub.1-C.sub.6 alkyl, phenyl, heteroaryl
comprising one 5- or 6-membered ring and one to four heteroatoms
selected from N, O, and S, C(O)--C.sub.1-C.sub.6 alkyl,
C(O)-phenyl, C(O)O--C.sub.1-C.sub.6 alkyl, C(O)NR.sup.17R.sup.18,
S(O).sub.2--C.sub.1-C.sub.6 alkyl, or S(O).sub.2NR.sup.17R.sup.18,
or when Z.sup.3--N--Z.sup.7--X or Z.sup.4--N--Z.sup.7--X form a 4-
to 6-membered ring, absent, or [0172] R.sup.16, together with
Z.sup.7--X or Z.sup.8--X, form a 3- to 6-membered ring;
[0173] Z.sup.8 is C(R.sup.4).sub.n, or [0174] when X is
CR.sup.14R.sup.15, Z.sup.8--X, together with R.sup.14 or R.sup.15,
form a 3- to 6-membered ring, or [0175] when X is NR.sup.16,
Z.sup.8--X, together with R.sup.16, form a 3- to 6-membered ring,
or [0176] Z7--X--Z.sup.8 form a 3- to 6-membered ring, or [0177]
Z.sup.7--X--Z.sup.8-Cy.sup.3 form a 4- to 6-membered ring, or
[0178] X--Z.sup.8-Cy.sup.3 form a 3- to 6-membered ring, or [0179]
Z.sup.8, together with R.sup.4 and Cy.sup.3, form a 3- to
6-membered ring;
[0180] each u is independently 1 or 2;
[0181] n is 0, 1, or 2;
[0182] each R.sup.4 is independently H, halogen, C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 heterocycle,OH,
O--C.sub.1-C.sub.6 alkyl, S--C.sub.1-C.sub.6 alkyl,
NR.sup.17R.sup.18, C(O)NR.sup.17R.sup.18,
NR.sup.17C(O)--C.sub.1-C.sub.6 alkyl,
NR.sup.17S(O).sub.2--C.sub.1-C.sub.6 alkyl, or
S(O).sub.2NR.sup.17R.sup.18, or [0183] any two R.sup.4 bonded to
the same carbon atom, together with the carbon atom to which the
two R.sup.4 are bonded, form C.dbd.O, or [0184] any two R.sup.4
bonded to the same carbon atom or on different carbon atoms,
together with the one or two carbon atoms to which the two R.sup.4
are bonded, form a 3- to 6-membered ring, or [0185] R.sup.4,
together with Z.sup.8-Cy.sup.3, form a 3- to 6-membered ring,
provided that when X is O, S, or NR.sup.16, then the R.sup.4 in the
C(R.sup.4).sub.n directly bonded to X is not OH, O--C.sub.1-C.sub.6
alkyl, S--C.sub.1-C.sub.6 alkyl, or NR.sup.17R.sup.18; and
[0186] Cy.sup.3 is H, C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 aryl,
heteroaryl comprising one or two 5- or 6-membered rings and one to
four heteroatoms selected from N, O, and S, C.sub.3-C.sub.10
cycloalkyl, C.sub.5-C.sub.13 bicyclic group, or heterocyclyl
comprising one or two 3- to 6-membered rings and one to four
heteroatoms selected from N, O, and S, wherein the aryl,
heteroaryl, cycloalkyl, bicyclic group, and heterocycyl are each
independently optionally substituted with one or more substituents
independently selected from: [0187] halogen, CH.sub.2F, CHF.sub.2,
CF.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, OH,
O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F,
C.sub.6-C.sub.10 aryl, heteroaryl comprising one 5- or 6-membered
ring and one to four heteroatoms selected from N, O, and S, and
NR.sup.17R.sup.18, or [0188] Z.sup.7--X--Z.sup.8-Cy.sup.3 form a 4-
to 6-membered ring, or [0189] X--Z.sup.8-Cy.sup.3 form a 3- to
6-membered ring, or [0190] Z.sup.8-Cy.sup.3, together with R.sup.4,
form a 3- to 6-membered ring, provided that when
Z.sup.7--X--Z.sup.8 is (CH.sub.2).sub.1-6, then Cy.sup.3 is not
phenyl, which is optionally substituted, methylenedioxyphenyl,
isoindoline-1,3,-dione, or dihydrobenzofuranyl.
[0191] The language "A.sup.1-A.sup.2 forms a ring," wherein each of
A.sup.1 and A.sup.2 is a moiety described herein, refers to taken
together A.sup.1 and A.sup.2 forming a ring. The language
"A.sup.1-A.sup.2-A.sup.3 forms a ring," wherein each of A.sup.1,
A.sup.2, and A.sup.3 is a moiety described herein, refers to taken
together, with the intervening A.sup.2, A.sup.1 and A.sup.3 forming
a ring. The language "A.sup.1-A.sup.2-A.sup.3-A.sup.4 forms a
ring," wherein each of A.sup.1, A.sup.2, A.sup.3, and A.sup.4 is a
moiety described herein, refers to taken together, with the
intervening A.sup.2 and A.sup.3, A.sup.1 and A.sup.4 forming a
ring.
[0192] In some embodiments, Cy.sup.1, Cy.sup.2 and Cy.sup.3 are
each different. In further embodiments, Cy.sup.1 and Cy.sup.2 are
different.
[0193] In certain embodiments, none of Cy.sup.1 and Cy.sup.2 is H.
In certain embodiments, Cy.sup.3 is not H. In certain embodiments,
each of Cy.sup.1, Cy.sup.2, and Cy.sup.3 is not H. In certain
embodiments, each of Cy.sup.1 and Cy.sup.2 is not H or
C.sub.1-C.sub.6 alkyl. In certain embodiments, Cy.sup.3 is not H or
C.sub.1-C.sub.6 alkyl. In certain embodiments, each of Cy.sup.1,
Cy.sup.2, and Cy.sup.3 is not H or C.sub.1-C.sub.6 alkyl.
[0194] In some embodiments, Cy.sup.1, Cy.sup.2 or Cy.sup.3 is
independently C.sub.6-C.sub.10 aryl, heteroaryl comprising one or
two 5- or 6-membered rings and one to four heteroatoms selected
from N, O, and S, C.sub.3-C.sub.10 cycloalkyl, or C.sub.5-C.sub.13
bicyclic group, wherein the aryl, heteroaryl, cycloalkyl, and
bicyclic group are each independently optionally substituted with
one or more substituents independently selected from halogen,
CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, OH,
O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and
NR.sup.17R.sup.18. In further embodiments, Cy.sup.1, Cy.sup.2 or
Cy.sup.3 is independently phenyl, dihydroindenyl, pyridyl,
pyridinonyl, quinolinyl, benzodihydrodioxinyl, quinolinonyl,
benzofuranyl, benzoxazolyl, benzothiazolyl, or
methylenedioxyphenyl, each of which is independently optionally
substituted with one or more substituents independently selected
from Cl, F, CF.sub.3, methyl, OH, OCH.sub.3, and OCF.sub.3.
[0195] In other embodiments, Cy.sup.1, Cy.sup.2 or Cy.sup.3 is
independently C.sub.3-C.sub.10 cycloalkyl (e.g., cyclohexyl) or
C.sub.5-C.sub.13 bicyclic group, wherein the cycloalkyl and
bicyclic group are each independently optionally substituted with
one or more substituents independently selected from halogen,
CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, OH,
O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and
NR.sup.17R.sup.18.
[0196] In other embodiments, Cy.sup.1, Cy.sup.2 or Cy.sup.3 is
independently heterocyclyl comprising one or two 3- to 6-membered
rings and one to four heteroatoms selected from N, O, and S,
wherein the heterocycyl is optionally substituted with one or more
substituents independently selected from halogen, CH.sub.2F,
CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6-alkyl, OH,
O--C.sub.1-C.sub.6-alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and
NR.sup.17R.sup.18.
[0197] In other embodiments, Cy.sup.1, Cy.sup.2 or Cy.sup.3 is
independently C.sub.5-C.sub.13 bicyclic group, wherein the bicyclic
group includes spirocyclic rings or fused rings, and the bicyclic
group includes aromatic, partially saturated, and/or saturated
rings. In further embodiments, Cy.sup.1, Cy.sup.2 or Cy.sup.3 is
independently
##STR00003##
[0198] In certain embodiments, each of Cy.sup.1 and Cy.sup.2 is
phenyl, wherein the phenyl groups are independently optionally
substituted with one or more substituents as described herein.
[0199] In certain embodiments, Cy.sup.1 is phenyl, and Cy.sup.2 is
heteroaryl comprising one 5- or 6-membered ring and one to four
heteroatoms selected from N, O, and S, wherein the phenyl and the
heteroaryl are independently optionally substituted with one or
more substituents as described herein. In certain embodiments,
Cy.sup.1 is phenyl, and Cy.sup.2 is pyridyl, wherein the phenyl and
the pyridyl are independently optionally substituted with one or
more substituents as described herein. In certain embodiments,
Cy.sup.1 is phenyl, and Cy.sup.2 is 2-pyridyl, wherein the phenyl
and the 2-pyridyl are independently optionally substituted with one
or more substituents as described herein. In certain embodiments,
Cy.sup.1 is phenyl, and Cy.sup.2 is 3-pyridyl or 4-pyridyl, wherein
the phenyl, the 3-pyridyl, and the 4-pyridyl are independently
optionally substituted with one or more substituents as described
herein.
[0200] In certain embodiments, Cy.sup.1 is phenyl, and Cy.sup.2 is
oxazolyl (e.g., 4-oxazolyl), wherein the phenyl and the oxazolyl
(e.g., 4-oxazolyl) are independently optionally substituted with
one or more substituents as described herein.
[0201] In certain embodiments, Cy.sup.1 is phenyl, and Cy.sup.2 is
heteroaryl comprising one 5- or 6-membered rings that are fused to
each other and one to four heteroatoms selected from N, O, and S,
wherein the phenyl and the heteroaryl are independently optionally
substituted with one or more substituents as described herein. In
certain embodiments, Cy.sup.1 is phenyl, and Cy.sup.2 is quinolinyl
(e.g., 2-quinolinyl), wherein the phenyl and the quinolinyl (e.g.,
2-quinolinyl) are independently optionally substituted with one or
more substituents as described herein.
[0202] In certain embodiments, each of Cy.sup.1 and Cy.sup.2 is
heteroaryl comprising one 5- or 6-membered ring and one to four
heteroatoms selected from N, O, and S, wherein the phenyl and the
heteroaryl are independently optionally substituted with one or
more substituents as described herein. In certain embodiments, each
of Cy.sup.1 and Cy.sup.2 is pyridyl, wherein the pyridyl groups are
independently optionally substituted with one or more substituents
as described herein. In certain embodiments, Cy.sup.1 is pyridyl,
and Cy.sup.2 is 2-pyridyl, wherein the pyridyl and the 2-pyridyl
are independently optionally substituted with one or more
substituents as described herein. In certain embodiments, Cy.sup.1
is pyridyl, and Cy.sup.2 is 3-pyridyl or 4-pyridyl, wherein the
pyridyl, the 3-pyridyl, and the 4-pyridyl are independently
optionally substituted with one or more substituents as described
herein.
[0203] In certain embodiments, Cy.sup.1 is a C.sub.5-C.sub.13
bicyclic group (e.g., phenyl fused with monocylic, 5- to 6-membered
heterocyclyl, wherein 1 or 2 atoms in the heterocyclyl ring system
are independently N, O, or S), and Cy.sup.2 is heteroaryl
comprising one 5- or 6-membered ring and one to four heteroatoms
selected from N, O, and S, wherein the C.sub.5-C.sub.13 bicyclic
group and the heteroaryl are independently optionally substituted
with one or more substituents as described herein. In certain
embodiments, Cy.sup.1 is a C.sub.5-C.sub.13 bicyclic group (e.g.,
phenyl fused with monocylic, 5- to 6-membered heterocyclyl, wherein
1 or 2 atoms in the heterocyclyl ring system are independently N,
O, or S), and Cy.sup.2 is pyridyl (e.g., 2-pyridyl), wherein the
C.sub.5-C.sub.13 bicyclic group and the pyridyl (e.g., 2-pyridyl)
are independently optionally substituted with one or more
substituents as described herein.
[0204] In certain embodiments, Cy.sup.1 is C.sub.3-C.sub.10
cycloalkyl (e.g., cyclohexyl), and Cy.sup.2 is heteroaryl
comprising one 5- or 6-membered ring and one to four heteroatoms
selected from N, O, and S, wherein the C.sub.3-C.sub.10 cycloalkyl
(e.g., cyclohexyl) and the heteroaryl are independently optionally
substituted with one or more substituents as described herein. In
certain embodiments, Cy.sup.1 is C.sub.3-C.sub.10 cycloalkyl (e.g.,
cyclohexyl), and Cy.sup.2 is pyridyl (e.g., 2-pyridyl), wherein the
C.sub.3-C.sub.10 cycloalkyl (e.g., cyclohexyl) and the pyridyl
(e.g., 2-pyridyl) are independently optionally substituted with one
or more substituents as described herein.
[0205] In certain embodiments, Cy.sup.3 is C.sub.1-C.sub.6 alkyl
(e.g., Me).
[0206] In certain embodiments, Cy.sup.3 is unsubstituted
phenyl.
[0207] In certain embodiments, Cy.sup.3 is phenyl substituted with
one or more substituents as described herein.
[0208] In certain embodiments, Cy.sup.3 is heterocyclyl comprising
one 3- to 6-membered ring and one to four heteroatoms selected from
N, O, and S, wherein the heterocycyl is optionally substituted with
one or more substituents as described herein. In certain
embodiments, Cy.sup.3 is heterocyclyl comprising one 6-membered
ring and one to four heteroatoms selected from N, O, and S, wherein
the heterocycyl is optionally substituted with one or more
substituents as described herein. In certain embodiments, Cy.sup.3
is heterocyclyl comprising one 3- to 6-membered ring and one
heteroatom selected from N, wherein the heterocycyl is optionally
substituted with one or more substituents as described herein.
[0209] In certain embodiments, Cy.sup.3 is heteroaryl comprising
one 5- or 6-membered ring and one to four heteroatoms selected from
N, O, and S, wherein the heteroaryl is optionally substituted with
one or more substituents as described herein. In certain
embodiments, Cy.sup.3 is pyridyl (e.g., 2-pyridyl, 3-pyridyl, or
4-pyridyl), wherein the pyridyl (e.g., 2-pyridyl, 3-pyridyl, or
4-pyridyl) is optionally substituted with one or more substituents
as described herein.
[0210] In certain embodiments, Cy.sup.3 is heteroaryl comprising
two 6-membered rings that are fused to each other and one to four
heteroatoms selected from N, O, and S, wherein the heteroaryl is
optionally substituted with one or more substituents as described
herein. In certain embodiments, Cy.sup.3 is quinolinyl (e.g.,
7-quinolinyl), wherein the quinolinyl (e.g., 7-quinolinyl) is
optionally substituted with one or more substituents as described
herein.
[0211] In certain embodiments, Cy.sup.3 is heteroaryl comprising
one 5-membered ring and one 6-membered ring and one to four
heteroatoms selected from N, O, and S, wherein the 5-membered ring
and the 6-membered ring are fused to each other, and wherein the
heteroaryl is optionally substituted with one or more substituents
as described herein. In certain embodiments, Cy.sup.3 is
benzothiazolyl (e.g., 6-benzothiazolyl), wherein the benzothiazolyl
(e.g., 6-benzothiazolyl) is optionally substituted with one or more
substituents as described herein. In certain embodiments, Cy.sup.3
is benzofuranyl (e.g., 2-benzofuranyl), wherein the benzofuranyl
(e.g., 2-benzofuranyl) is optionally substituted with one or more
substituents as described herein. In certain embodiments, Cy.sup.3
is benzoxazolyl (e.g., 2-benzoxazolyl), wherein the benzoxazolyl
(e.g., 2-benzoxazolyl) is optionally substituted with one or more
substituents as described herein.
[0212] In certain embodiments, Cy.sup.3 is C.sub.3-C.sub.10
cycloalkyl (e.g., cyclohexyl), wherein the C.sub.3-C.sub.10
cycloalkyl (e.g., cyclohexyl) is optionally substituted with one or
more substituents as described herein.
[0213] In certain embodiments, Cy.sup.3 is a C.sub.5-C.sub.13
bicyclic group (e.g., phenyl fused with C.sub.3-C.sub.7
carbocycle), wherein the C.sub.5-C.sub.13 bicyclic group is
optionally substituted with one or more substituents as described
herein.
[0214] In some embodiments, R.sup.1 is H. In other embodiments,
R.sup.1 is C.sub.1-C.sub.6 alkyl.
[0215] In some embodiments, A-B is C(O)--NR.sup.13,
CR.sup.11R.sup.12--NR.sup.13, NR.sup.13--C(O), C(O), or
CR.sup.11R.sup.12--O. In further embodiments, A-B is
C(O)--NR.sup.13 or CR.sup.11R.sup.12--NR.sup.13.
[0216] In some embodiments, A-B is C(O)--NR.sup.13. In further
embodiments, A-B is C(O)--NH. In other embodiments, A-B is
C(O)--N--C.sub.1-C.sub.6 alkyl. In further embodiments, A-B is
C(O)--NCH.sub.3.
[0217] In other embodiments, A-B is CR.sup.11R.sup.12--NR.sup.13.
In further embodiments, A-B is CH.sub.2--NH. In other embodiments,
A-B is CH.sub.2--N--C.sub.1-C.sub.6 alkyl. In further embodiments,
A-B is CH.sub.2--NCH.sub.3. In other embodiments, A-B is
CHCH.sub.3--NCH.sub.3.
[0218] In other embodiments, A-B is NR.sup.13--C(O). In further
embodiments, A-B is NH--C(O).
[0219] In other embodiments, A-B is or CR.sup.11R.sup.12--O. In
further embodiments, A-B is CH.sub.2--O.
[0220] In other embodiments, A-B is C(O)--CR.sup.11R.sup.12 or
C(O)--O.
[0221] In other embodiments, A-B is CR.sup.11R.sup.12 C(O),
NR.sup.13--CR.sup.11R.sup.12, O--CR.sup.11R.sup.12, or O--C(O).
[0222] In some embodiments, R.sup.11 and R.sup.12 are each
independently H, halogen, or C.sub.1-C.sub.6 alkyl. In further
embodiments, R.sup.11 and R.sup.12 are each independently H or
methyl. In further embodiments, R.sup.11 and R.sup.12 are each H.
In other embodiments, one of R.sup.11 and R.sup.12 is H, and the
other is methyl.
[0223] In other embodiments, R.sup.11 and R.sup.12, together with
the carbon atom to which R.sup.11 and R.sup.12 are attached, form a
3- to 6-membered ring optionally comprising one to three
heteroatoms selected from N, O, and S.
[0224] In certain embodiments, R.sup.13 is H, C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 heterocycle,
C.sub.6-C.sub.10 aryl, heteroaryl comprising one or two 5- or
6-membered rings and one to four heteroatoms selected from N, O,
and S, C(O)--C.sub.1-C.sub.6 alkyl, C(O)-phenyl,
C(O)O--C.sub.1-C.sub.6 alkyl, C(O)NR.sup.17R.sup.18,
S(O).sub.2--C.sub.1-C.sub.6 alkyl, or S(O).sub.2NR.sup.17R.sup.19,
provided that when CR.sup.11R.sup.12--N.sup.13 or
NR.sup.13--CR.sup.11R.sup.12 forms a 3- to 6-membered ring,
R.sup.13 is absent.
[0225] In some embodiments, R.sup.13 is H or straight-chain
C.sub.1-C.sub.6 or branched C.sub.3-C.sub.6 alkyl. In further
embodiments, R.sup.13 is H, methyl, ethyl, CH.sub.2CF.sub.3, or
i-propyl. In further embodiments, R.sup.13 is H. In other
embodiments, R.sup.13 is methyl. In certain embodiments, R.sup.13
is C.sub.1-C.sub.6 haloalkyl (e.g., C.sub.1-C.sub.6 fluoroalkyl).
In certain embodiments, R.sup.13 is --CH.sub.2CF.sub.3.
[0226] In other embodiments, R.sup.13 is C(O)--C.sub.1-C.sub.6
alkyl. In further embodiments, R.sup.13 is C(O)CH.sub.3.
[0227] In some embodiments, A-Z.sup.1--R.sup.5 form a 3- to
6-membered ring optionally comprising one to three heteroatoms
selected from N, O, and S.
[0228] In some embodiments, B-A-Z.sup.1 form a 3- to 6-membered
ring optionally comprising one to three heteroatoms selected from
N, O, and S. In further embodiments, B-A-Z.sup.1 form a 4- to
6-membered ring optionally comprising one to three heteroatoms
selected from N, O, and S. In further embodiments, B-A-Z.sup.1 form
a 4- to 6-membered ring optionally comprising one N. In further
embodiments, the N is bonded to Z.sup.6.
[0229] In some embodiments, A-Z.sup.1 or B-A-Z.sup.1, together with
any one or two of Z.sup.2 and Z.sup.3, or any one or two of Z.sup.4
and Z.sup.5, form a 4- to 6-membered ring optionally comprising one
to three heteroatoms selected from N, O, and S, wherein the ring
and ring G form a bridged or fused ring structure. In further
embodiments, B-A-Z.sup.1, together with Z.sup.2 or Z.sup.5, form a
4- to 6-membered ring optionally comprising one to three
heteroatoms selected from N, O, and S, wherein the ring and ring G
form a fused ring structure. In further embodiments, B-A-Z.sup.1,
together with Z.sup.2 or Z.sup.5, form a 5- to 6-membered ring
optionally comprising one to three heteroatoms selected from N, O,
and S, wherein the ring and ring G form a fused ring structure. In
further embodiments, B-A-Z.sup.1, together with Z.sup.2 or Z.sup.5,
form a 5- to 6-membered ring optionally comprising one N, wherein
the ring and ring G form a fused ring structure. In further
embodiments, the N is bonded to Z.sup.6.
[0230] In some embodiments, R.sup.5 is H, methyl, benzyl or F. In
further embodiments, R.sup.5 is H or methyl. In further
embodiments, R.sup.5 is H. In further embodiments, R.sup.5 is
methyl.
[0231] In some embodiments, each R.sup.2 is independently H, F,
CH.sub.3, or CF.sub.3. In further embodiments, each R.sup.2 is
H.
[0232] In some embodiments, any two R.sup.2 bonded to different
carbon atoms, together with the carbon atoms to which the two
R.sup.2 are bonded, form a 4- to 7-membered ring, which can be
saturated, partially saturated, unsaturated, or aromatic, and can
comprise 0-4 heteroatoms selected from N, O, and S. In further
embodiments, any two R.sup.2 bonded to different carbon atoms,
together with the carbon atoms to which the two R.sup.2 are bonded,
form a phenyl ring.
[0233] In some embodiments, X is O. In other embodiments, X is a
bond. In other embodiments, X is S, S(O), or S(O).sub.2. In yet
other embodiments, X is NR.sup.16.
[0234] In some embodiments, R.sup.3 and R.sup.4 are each
independently H or C.sub.1-C.sub.6 alkyl. In further embodiments,
R.sup.3 and R.sup.4 are each independently H or methyl. In further
embodiments, R.sup.3 and R.sup.4 are each H. In some embodiments,
at least one of R.sup.3 and R.sup.4 is not H.
[0235] In some embodiments, R.sup.14 and R.sup.15 are each
independently H, halogen, C.sub.1-C.sub.6 alkyl, phenyl, or
heteroaryl comprising one 5- or 6-membered ring and one to four
heteroatoms selected from N, O, and S. In further embodiments,
R.sup.14 and R.sup.15 are each independently H, halogen, or phenyl.
In further embodiments, R.sup.14 and R.sup.15 are each H.
[0236] In some embodiments, R.sup.16 is H, C.sub.1-C.sub.6 alkyl,
or C(O)--C.sub.1-C.sub.6 alkyl. In further embodiments, R.sup.16 is
H. In other embodiments, R.sup.16 is phenyl or heteroaryl
comprising one 5- or 6-membered ring and one to four heteroatoms
selected from N, O, and S. In further embodiments, R.sup.16 is
phenyl or pyridyl.
[0237] In some embodiments, R.sup.17 and R.sup.18 are each
independently H, methyl, or ethyl.
[0238] In some embodiments, n is 0 or 1. In further embodiments, n
is 0. In other embodiments, n is 1 or 2.
[0239] In some embodiments, t is 1, 2, or 3. In further
embodiments, t is 2 or 3. In some embodiments, t is 1. In other
embodiments, t is 2. In other embodiments, t is 3. In other
embodiments, t is 4.
[0240] Any of the embodiments described above or herein below can
be combined with one another.
[0241] In some embodiments, n is 0 and X is O. In other
embodiments, n is 0 and X is a bond.
[0242] In some embodiments, t is 2 or 3 and X is O. In further
embodiments, t is 2 and X is O. In other embodiments, t is 1 or 2
and X is a bond.
[0243] In certain embodiments,
--(Z.sup.8).sub.n--X--(Z.sup.7).sub.t-- is
--O--(C(R.sup.3).sub.2).sub.t--. In certain embodiments,
--(Z.sup.8).sub.n--X--(Z.sup.7).sub.t-- is --O--(CH.sub.2).sub.t--.
In certain embodiments, --(Z.sup.8).sub.n--X--(Z.sup.7).sub.t-- is
--O--(CH.sub.2).sub.2--. In certain embodiments,
--(Z.sup.8).sub.n--X--(Z.sup.7).sub.t-- is --O--(CH.sub.2).sub.3--
or --O--(CH.sub.2).sub.4--. In certain embodiments,
--(Z.sup.8).sub.n--X--(Z.sup.7).sub.t-- is
--O--(C(R.sup.3).sub.2).sub.2-- (e.g., --O--CH.sub.2--CHMe- or
--O--CH.sub.2--C(Me).sub.2-).
[0244] In certain embodiments,
--(Z.sup.8).sub.n--X--(Z.sup.7).sub.t-- is
--(C(R.sup.3).sub.2).sub.t--. In certain embodiments,
--(Z.sup.8).sub.n--X--(Z.sup.7).sub.t-- is --(CH.sub.2).sub.t--
(e.g., --CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, or
--(CH.sub.2).sub.4--).
[0245] In some embodiments, A-B is C(O)--NR.sup.13 or
CH.sub.2--NR.sup.13, each R.sup.3 is independently H or
C.sub.1-C.sub.6 alkyl, and t is 2 or 3. In further embodiments,
each R.sup.3 is H. In further embodiments, A-B is C(O)--NH or
CH.sub.2--NH, and t is 2 or 3. In further embodiments, t is 2. In
further embodiments, n is 0. In further embodiments, R.sup.5 is H
or methyl.
[0246] In some embodiments, A-B is C(O)--NR.sup.13, and X is O. In
further embodiments, A-B is C(O)--NH, X is O, and each R.sup.3 is
H. In further embodiments, A-B is C(O)--NH, X is O, each R.sup.3 is
H, and n is 0. In further embodiments, A-B is C(O)--NH, X is O,
each R.sup.3 is H, n is O, and t is 2.
[0247] In some embodiments, A-B is C(O)--NR.sup.13, X is O, and
Cy.sup.1, Cy.sup.2 or Cy.sup.3 is independently phenyl, pyridyl, or
methylenedioxyphenyl, each of which is optionally substituted. In
further embodiments, Cy.sup.1, Cy.sup.2 or Cy.sup.3 is
independently phenyl, pyridyl, or methylenedioxyphenyl, each of
which is optionally substituted with one or more substituents
independently selected from Cl, F, CF.sub.3, methyl, OH, OCH.sub.3,
and OCF.sub.3. In further embodiments, A-B is C(O)--NH, X is O,
each R.sup.3 is H, Cy.sup.1, Cy.sup.2 or Cy.sup.3 is independently
phenyl, pyridyl, or methylenedioxyphenyl, each of which is
optionally substituted, and n is 0. In further embodiments, A-B is
C(O)--NH, X is O, each R.sup.3 is H, Cy.sup.1, Cy.sup.2 or Cy.sup.3
is independently phenyl, pyridyl, or methylenedioxyphenyl, each of
which is optionally substituted, n is 0, and t is 2.
[0248] In other embodiments, A-B is CH.sub.2--NR.sup.13, and X is
O. In further embodiments, A-B is CH.sub.2--NH, X is O, and each
R.sup.3 is H. In further embodiments, A-B is CH.sub.2--NH, X is O,
each R.sup.3 is H, and n is 0. In further embodiments, A-B is
CH.sub.2--NH, X is O, each R.sup.3 is H, n is 0, and t is 2.
[0249] In some embodiments, A-B is CH.sub.2--NH, X is O, and
Cy.sup.1, Cy.sup.2 or Cy.sup.3 is independently phenyl, pyridyl, or
methylenedioxyphenyl, each of which is optionally substituted. In
further embodiments, Cy.sup.1, Cy.sup.2 or Cy.sup.3 is
independently phenyl, pyridyl, or methylenedioxyphenyl, each of
which is optionally substituted with one or more substituents
independently selected from Cl, F, CF.sub.3, methyl, OH, OCH.sub.3,
and OCF.sub.3. In further embodiments, A-B is CH.sub.2--NH, X is O,
each R.sup.3 is H, Cy.sup.1, Cy.sup.2 or Cy.sup.3 is independently
phenyl, pyridyl, or methylenedioxyphenyl, each of which is
optionally substituted, and n is 0. In further embodiments, A-B is
CH.sub.2--NH, X is O, each R.sup.3 is H, Cy.sup.1, Cy.sup.2 or
Cy.sup.3 is independently phenyl, pyridyl, or methylenedioxyphenyl,
each of which is optionally substituted, n is 0, and t is 2.
[0250] In certain embodiments, a phenyl group described herein is
substituted at the 2-position with one substituent as described
herein. In certain embodiments, a phenyl group described herein is
substituted at the 3-position with one substituent as described
herein. In certain embodiments, a phenyl group described herein is
substituted at the 4-position with one substituent as described
herein. In certain embodiments, a phenyl group described herein is
substituted at the 2- and 3-positions, or at the 2- and
4-positions, or at the 2- and 5-positions, or at the 2- and
6-positions, or at the 3- and 4-positions, or at the 3- and
5-positions, with two substituents as described herein.
[0251] In certain embodiments, each of Z.sup.2, Z.sup.3, Z.sup.4,
and Z.sup.5 is C(R.sup.2).sub.2. In certain embodiments, each of
Z.sup.2, Z.sup.3, Z.sup.4, and Z.sup.5 is CH.sub.2.
[0252] In certain embodiments, Z.sup.6 is of the R configuration.
In certain embodiments, Z.sup.6 is of the S configuration.
[0253] In one embodiment, the present invention provides a compound
having Formula II:
##STR00004##
wherein z is 1, 2, 3, 4, 5, 6, 7, or 8, and each of the other
variables are as defined for Formula I, and can be any substituent
as illustrated herein.
[0254] In one embodiment, the present invention provides a compound
having Formula IV:
##STR00005##
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof,
wherein:
[0255] Cy.sup.1, Cy.sup.2, and Cy.sup.3 are each independently H,
C.sub.1-C.sub.3 alkyl, phenyl, heteroaryl comprising one or two 5-
or 6-membered rings and one to four heteroatoms selected from N, O,
and S, C.sub.5-C.sub.6 cycloalkyl, C.sub.5-C.sub.13 bicyclic group,
or heterocyclyl comprising one or two 3- to 6-membered rings and
one to four heteroatoms selected from N, O, and S, wherein
Cy.sup.1, Cy.sup.2, and Cy.sup.3 are each independently optionally
substituted with one or more substituents independently selected
from halogen, CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6
alkyl, OH, O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, and NR.sup.17R.sup.18;
[0256] each R.sup.3 is the same and is selected from H and
C.sub.1-C.sub.3 alkyl;
[0257] R.sup.5 is H or C.sub.1-C.sub.3 alkyl;
[0258] R.sup.13 is H or C.sub.1-C.sub.3 alkyl;
[0259] R.sup.17 and R.sup.18 are each independently H or
C.sub.1-C.sub.3 alkyl; and
[0260] v is 1, 2, or 3.
[0261] In certain embodiments, a compound of Formula IV is of the
formula:
##STR00006##
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof.
[0262] In certain embodiments, a compound of Formula IV is of the
formula:
##STR00007##
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof.
[0263] In certain embodiments, a compound of Formula IV is of the
formula:
##STR00008##
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof,
wherein:
[0264] each instance of R.sup.20 is independently selected from
halogen, CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, OH,
O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and
NR.sup.17R.sup.18; and
[0265] r is 0, 1, 2, 3, 4, or 5.
[0266] In certain embodiments, a compound of Formula IV is of the
formula:
##STR00009##
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof,
wherein:
[0267] each instance of R.sup.20 is independently selected from
halogen, CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, OH,
O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and
NR.sup.17R.sup.18;
[0268] s is 0, 1, 2, 3, or 4; and
[0269] r is 0, 1, 2, 3, 4, or 5.
[0270] In certain embodiments, a compound of Formula IV is of the
formula:
##STR00010##
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof,
wherein:
[0271] each instance of R.sup.20 is independently selected from
halogen, CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, OH,
O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and
NR.sup.17R.sup.18;
[0272] s is 0, 1, 2, 3, or 4; and
[0273] each instance of r is independently 0, 1, 2, 3, 4, or 5.
[0274] In certain embodiments, a compound of Formula IV is of the
formula:
##STR00011##
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof.
[0275] In certain embodiments, a compound of Formula IV is of the
formula:
##STR00012##
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof,
wherein:
[0276] each instance of R.sup.20 is independently selected from
halogen, CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, OH,
O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and
NR.sup.17R.sup.18; and
[0277] r is 0, 1, 2, 3, 4, or 5.
[0278] In certain embodiments, a compound of Formula IV is of the
formula:
##STR00013##
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof,
wherein:
[0279] each instance of R.sup.20 is independently selected from
halogen, CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, OH,
O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and
NR.sup.17R.sup.18;
[0280] s is 0, 1, 2, 3, or 4; and
[0281] r is 0, 1, 2, 3, 4, or 5.
[0282] In certain embodiments, a compound of Formula IV is of the
formula:
##STR00014##
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof,
wherein:
[0283] each instance of R.sup.20 is independently selected from
halogen, CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, OH,
O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and
NR.sup.17R.sup.18;
[0284] s is 0, 1, 2, 3, or 4; and
[0285] each instance of r is independently 0, 1, 2, 3, 4, or 5.
[0286] In some embodiments, Cy.sup.1, Cy.sup.2, or Cy.sup.3 is
independently phenyl, heteroaryl comprising one or two 5- or
6-membered rings and one to four heteroatoms selected from N, O,
and S, C.sub.5-C.sub.6 cycloalkyl, or C.sub.5-C.sub.13 bicyclic
group, each independently optionally substituted with one or more
substituents independently selected from halogen, CH.sub.2F,
CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, OH, O--C.sub.1-C.sub.6
alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and NR.sup.17R.sup.18. In
further embodiments, Cy.sup.1, Cy.sup.2, or Cy.sup.3 is
independently phenyl, methylenedioxyphenyl, dihydroindenyl,
pyridyl, pyridinonyl, quinolinyl, benzodihydrodioxinyl,
quinolinonyl, benzofuranyl, benzoxazolyl, or benzothiazolyl, each
independently optionally substituted with one or more substituents
independently selected from halogen, CH.sub.2F, CHF.sub.2,
CF.sub.3, C.sub.1-C.sub.6 alkyl, OH, O--C.sub.1-C.sub.6 alkyl,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and NR.sup.17R.sup.18. In
further embodiments, Cy.sup.1, Cy.sup.2, or Cy.sup.3 is
independently phenyl, methylenedioxyphenyl, dihydroindenyl,
pyridyl, pyridinonyl, quinolinyl, benzodihydrodioxinyl,
quinolinonyl, benzofuranyl, benzoxazolyl, or benzothiazolyl, each
independently optionally substituted with one or more substituents
independently selected from halogen, CH.sub.2F, CHF.sub.2,
CF.sub.3, O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2, and
OCH.sub.2F, preferably from Cl, F, CH.sub.3, CF.sub.3, OCH.sub.3,
and OCF.sub.3.
[0287] In further embodiments, one of Cy.sup.1 and Cy.sup.2 is
phenyl or methylenedioxyphenyl, the other is heteroaryl comprising
one or two 5- or 6-membered rings and one to four heteroatoms
selected from N, O, and S, preferably pyridyl or quinolinyl, more
preferably pyridyl, and Cy.sup.3 is C.sub.1-C.sub.3 alkyl, phenyl,
heteroaryl comprising one or two 5- or 6-membered rings and one to
four heteroatoms selected from N, O, and S, C.sub.5-C.sub.6
cycloalkyl, or C.sub.5-C.sub.13 bicyclic group, preferably phenyl
or heteroaryl comprising one or two 5- or 6-membered rings and one
to four heteroatoms selected from N, O, and S, more preferably
phenyl, dihydroindenyl, pyridyl, pyridinonyl, quinolinyl,
benzodihydrodioxinyl, quinolinonyl, benzofuranyl, benzoxazolyl, or
benzothiazolyl, more preferably phenyl or pyridyl, wherein
Cy.sup.1, Cy.sup.2 and Cy.sup.3 are each independently optionally
substituted with one or more substituents independently selected
from Cl, F, CH.sub.3, CF.sub.3, OCH.sub.3, and OCF.sub.3.
[0288] In other embodiments, Cy.sup.1 and Cy.sup.2 are each
heteroaryl comprising one or two 5- or 6-membered rings and one to
four heteroatoms selected from N, O, and S, preferably pyridyl, and
Cy.sup.3 is phenyl, wherein Cy.sup.1, Cy.sup.2 and Cy.sup.3 are
each independently optionally substituted with one or more
substituents independently selected from Cl, F, CH.sub.3, CF.sub.3,
OCH.sub.3, and OCF.sub.3.
[0289] In other embodiments, Cy.sup.1, Cy.sup.2 and Cy.sup.3 are
each phenyl, optionally substituted with one or more substituents
independently selected from Cl, F, CH.sub.3, CF.sub.3, OCH.sub.3,
and OCF.sub.3.
[0290] In some embodiments, Cy.sup.3 is phenyl, one of Cy.sup.1 and
Cy.sup.2 is heteroaryl comprising one or two 5- or 6-membered rings
and one to four heteroatoms selected from N, O, and S, preferably
pyridyl or quinolinyl, more preferably pyridyl, and the other is H,
straight-chain C.sub.1-C.sub.6 or branched C.sub.3-C.sub.6 alkyl,
or C.sub.5-C.sub.6 cycloalkyl, wherein the phenyl and heteroaryl
are each independently optionally substituted with one or more
substituents independently selected from halogen, CH.sub.2F,
CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, OH, O--C.sub.1-C.sub.6
alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and NR.sup.17R.sup.18,
preferably halogen, CH.sub.2F, CHF.sub.2, CF.sub.3,
O--C.sub.1-C.sub.6 alkyl, OCHF.sub.2, OCH.sub.2F, and OCF.sub.3,
more preferably Cl, F, CH.sub.3, CF.sub.3, OCH.sub.3, and
OCF.sub.3.
[0291] In some embodiments, each R.sup.3 is H or methyl. In further
embodiments, each R.sup.3 is H.
[0292] In some embodiments, R.sup.5 is H. In other embodiments,
R.sup.5 is CH.sub.3.
[0293] In some embodiments, R.sup.13 is H or methyl. In further
embodiments, R.sup.13 is H.
[0294] In some embodiments, R.sup.17 and R.sup.18 are each
independently H. In some embodiments, R.sup.17 and R.sup.18 are
each independently methyl. In some embodiments, one of R.sup.17 and
R.sup.18 is H, and the other is methyl.
[0295] In some embodiments, v is 1.
[0296] Any of the embodiments described above or herein below can
be combined with one another.
[0297] In one embodiment, the present invention provides a compound
having Formula V:
##STR00015##
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof,
wherein:
[0298] Cy.sup.1, Cy.sup.2 and Cy.sup.3 are each independently
phenyl, heteroaryl comprising one or two 5- or 6-membered rings and
one to four heteroatoms selected from N, O, and S, or
C.sub.5-C.sub.13 bicyclic group, wherein Cy.sup.1, Cy.sup.2, and
Cy.sup.3 are each independently optionally substituted with one or
more substituents independently selected from halogen, CH.sub.2F,
CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, OH, O--C.sub.1-C.sub.6
alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and
NR.sup.17R.sup.18;
[0299] R.sup.5 is H or C.sub.1-C.sub.3 alkyl;
[0300] R.sup.11 and R.sup.12 are each independently H or
C.sub.1-C.sub.3 alkyl;
[0301] R.sup.13 is H, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3
haloalkyl, or C(O)--C.sub.1-C.sub.3 alkyl; and
[0302] R.sup.17 and R.sup.18 are each independently H or
C.sub.1-C.sub.3 alkyl. In certain embodiments, a compound of the
invention is of Formula V, or a stereoisomer, racemate, tautomer,
polymorph, hydrate, or solvate thereof, or a pharmaceutically
acceptable salt thereof, wherein:
[0303] Cy.sup.1, Cy.sup.2 and Cy.sup.3 are each independently
phenyl, heteroaryl comprising one or two 5- or 6-membered rings and
one to four heteroatoms selected from N, O, and S, or
C.sub.5-C.sub.13 bicyclic group, wherein Cy.sup.1, Cy.sup.2, and
Cy.sup.3 are each independently optionally substituted with one or
more substituents independently selected from halogen, CH.sub.2F,
CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, OH, O--C.sub.1-C.sub.6
alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and
NR.sup.17R.sup.18;
[0304] R.sup.5 is H or C.sub.1-C.sub.3 alkyl;
[0305] R.sup.11 and R.sup.12 are each independently H or
C.sub.1-C.sub.3 alkyl;
[0306] R.sup.13 is H, C.sub.1-C.sub.3 alkyl, CH.sub.2CF.sub.3, or
C(O)--C.sub.1-C.sub.3 alkyl; and
[0307] R.sup.17 and R.sup.18 are each independently H or
C.sub.1-C.sub.3 alkyl.
[0308] In certain embodiments, a compound of Formula V is of the
formula:
##STR00016##
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof,
wherein:
[0309] each instance of R.sup.20 is independently selected from
halogen, CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, OH,
O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and
NR.sup.17R.sup.18; and
[0310] r is 0, 1, 2, 3, 4, or 5.
[0311] In certain embodiments, a compound of Formula V is of the
formula:
##STR00017##
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof,
wherein:
[0312] each instance of R.sup.20 is independently selected from
halogen, CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, OH,
O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and
NR.sup.17R.sup.18;
[0313] s is 0, 1, 2, 3, or 4; and
[0314] r is 0, 1, 2, 3, 4, or 5.
[0315] In certain embodiments, a compound of Formula V is of the
formula:
##STR00018##
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof,
wherein:
[0316] each instance of R.sup.20 is independently selected from
halogen, CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, OH,
O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and
NR.sup.17R.sup.18;
[0317] s is 0, 1, 2, 3, or 4; and
[0318] each instance of r is independently 0, 1, 2, 3, 4, or 5.
[0319] In some embodiments, Cy.sup.1, Cy.sup.2, or Cy.sup.3 is
independently phenyl or heteroaryl comprising one or two 5- or
6-membered rings and one to four heteroatoms selected from N, O,
and S, each independently optionally substituted with one or more
substituents independently selected from halogen, CH.sub.2F,
CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, OH, O--C.sub.1-C.sub.6
alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and NR.sup.17R.sup.18. In
further embodiments, Cy.sup.1, Cy.sup.2, or Cy.sup.3 is
independently phenyl or pyridyl, each independently optionally
substituted with one or more substituents independently selected
from halogen, CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6
alkyl, OH, O---C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, and NR.sup.17R.sup.18. In further embodiments,
Cy.sup.1, Cy.sup.2, or Cy.sup.3 is independently phenyl or pyridyl,
each independently optionally substituted with one or more
substituents independently selected from halogen, CH.sub.2F,
CHF.sub.2, CF.sub.3, O--C.sub.1-C.sub.6 alkyl, OCF.sub.3,
OCHF.sub.2, and OCH.sub.2F, preferably from Cl, F, CH.sub.3,
CF.sub.3, OCH.sub.3, and OCF.sub.3.
[0320] In further embodiments, one of Cy.sup.1 and Cy.sup.2 is
phenyl, the other is heteroaryl comprising one or two 5- or
6-membered rings and one to four heteroatoms selected from N, O,
and S, preferably pyridyl, and Cy.sup.3 is phenyl, wherein
Cy.sup.1, Cy.sup.2 and Cy.sup.3 are each independently optionally
substituted with one or more substituents independently selected
from Cl, F, CH.sub.3, CF.sub.3, OCH.sub.3, and OCF.sub.3.
[0321] In other embodiments, Cy.sup.1, Cy.sup.2 and Cy.sup.3 are
each phenyl, optionally substituted with one or more substituents
independently selected from Cl, F, CH.sub.3, CF.sub.3, OCH.sub.3,
and OCF.sub.3.
[0322] In other embodiments, one of Cy.sup.1 and Cy.sup.2 is
C.sub.5-C.sub.13 bicyclic group, the other is heteroaryl comprising
one or two 5- or 6-membered rings and one to four heteroatoms
selected from N, O, and S, and Cy.sup.3 is phenyl, wherein
Cy.sup.1, Cy.sup.2 and Cy.sup.3 are each independently optionally
substituted with one or more substituents independently selected
from Cl, F, CH.sub.3, CF.sub.3, OCH.sub.3, and OCF.sub.3.
[0323] In some embodiments, R.sup.5 is H or methyl. In further
embodiments, R.sup.5 is H.
[0324] In some embodiments, R.sup.11 and R.sup.12 are each
independently H or methyl. In further embodiments, R.sup.11 and
R.sup.12 are each H. In other embodiments, one of R.sup.11 and
R.sup.12 is H, and the other is methyl.
[0325] In certain embodiments, R.sup.13 is H, C.sub.1-C.sub.3
alkyl, or C(O)--C.sub.1-C.sub.3 alkyl. In some embodiments,
R.sup.13 is H, methyl, isopropyl, CH.sub.2CF.sub.3, or
C(O)CH.sub.3. In further embodiments, R.sup.13 is H or methyl. In
some embodiments, R.sup.13 is H. In some embodiments, R.sup.13 is
methyl or isopropyl. In certain embodiments, R.sup.13 is
C.sub.1-C.sub.3 haloalkyl (e.g., C.sub.1-C.sub.3 fluoroalkyl). In
certain embodiments, R.sup.13 is --CH.sub.2CF.sub.3.
[0326] In some embodiments, R.sup.17 and R.sup.18 are each
independently H. In some embodiments, R.sup.17 and R.sup.18 are
each independently methyl. In some embodiments, one of R.sup.17 and
R.sup.18 is H, and the other is methyl.
[0327] In one embodiment, the present invention provides a compound
having Formula VI:
##STR00019##
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof,
wherein:
[0328] Cy.sup.1, Cy.sup.2 and Cy.sup.3 are each independently
phenyl or heteroaryl comprising one or two 5- or 6-membered rings
and one to four heteroatoms selected from N, O, and S, wherein
Cy.sup.1, Cy.sup.2, and Cy.sup.3 are each independently optionally
substituted with one or more substituents independently selected
from halogen, CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6
alkyl, OH, O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, and NR.sup.17R.sup.18;
[0329] m1 and m2 are each independently is 0, 1, or 2, provided
that m1 and m2 are not both 0; and
[0330] R.sup.17 and R.sup.18 are each independently H or
C.sub.1-C.sub.3 alkyl.
[0331] In some embodiments, Cy.sup.1, Cy.sup.2, or Cy.sup.3 is
independently phenyl or heteroaryl comprising one or two 5- or
6-membered rings and one to four heteroatoms selected from N, O,
and S, each independently optionally substituted with one or more
substituents independently selected from Cl, F, CH.sub.3, CF.sub.3,
OCH.sub.3, and OCF.sub.3.
[0332] In further embodiments, Cy.sup.1, Cy.sup.2, or Cy.sup.3 is
independently phenyl or pyridyl, each independently optionally
substituted with one or more substituents independently selected
from Cl, F, CH.sub.3, CF.sub.3, OCH.sub.3, and OCF.sub.3.
[0333] In further embodiments, one of Cy.sup.1 and Cy.sup.2 is
phenyl, the other is heteroaryl comprising one or two 5- or
6-membered rings and one to four heteroatoms selected from N, O,
and S, preferably pyridyl, and Cy.sup.3 is phenyl, wherein
Cy.sup.1, Cy.sup.2 and Cy.sup.3 are each independently optionally
substituted with one or more substituents independently selected
from Cl, F, CH.sub.3, CF.sub.3, OCH.sub.3, and OCF.sub.3,
preferably Cl or CF.sub.3.
[0334] In some embodiments, m1 is 1. In some embodiments, m2 is 1.
In some embodiments, one of m1 and m2 is 1, and the other of m1 and
m2 is 2.
[0335] In some embodiments, R.sup.17 and R.sup.18 are each
independently H. In some embodiments, R.sup.17 and R.sup.18 are
each independently methyl. In some embodiments, one of R.sup.17 and
R.sup.18 is H, and the other is methyl.
[0336] In one embodiment, the present invention provides a compound
having Formula VII:
##STR00020##
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof,
wherein:
[0337] Cy.sup.1, Cy.sup.2 and Cy.sup.3 are each independently
phenyl, heteroaryl comprising one or two 5- or 6-membered rings and
one to four heteroatoms selected from N, O, and S, or
C.sub.5-C.sub.13 bicyclic group, wherein Cy.sup.1, Cy.sup.2, and
Cy.sup.3 are each independently optionally substituted with one or
more substituents independently selected from halogen, CH.sub.2F,
CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, OH, O--C.sub.1-C.sub.6
alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and
NR.sup.17R.sup.18;
[0338] R.sup.17 and R.sup.18 are each independently H or
C.sub.1-C.sub.3 alkyl; and
[0339] o is 1, 2, or 3.
[0340] In certain embodiments, a compound of Formula VII is of the
formula:
##STR00021##
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof,
wherein:
[0341] each instance of R.sup.20 is independently selected from
halogen, CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, OH,
O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and
NR.sup.17R.sup.18;
[0342] s is 0, 1, 2, 3, or 4; and
[0343] r is 0, 1, 2, 3, 4, or 5.
[0344] In some embodiments, Cy.sup.1, Cy.sup.2, or Cy.sup.3 is
independently phenyl, pyridyl, pyridinonyl, benzofuranyl,
benzoxazolyl, dihydroindenyl, or benzodihydrodioxinyl, each
independently optionally substituted with one or more substituents
independently selected from halogen, CH.sub.2F, CHF.sub.2,
CF.sub.3, C.sub.1-C.sub.6 alkyl, OH, O--C.sub.1-C.sub.6 alkyl,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, or NR.sup.17R.sup.18, preferably
halogen, more preferably F.
[0345] In further embodiments, one of Cy.sup.1 and Cy.sup.2 is
phenyl, the other is heteroaryl comprising one or two 5- or
6-membered rings and one to four heteroatoms selected from N, O,
and S, preferably pyridyl, and Cy.sup.3 is heteroaryl comprising
one or two 5- or 6-membered rings and one to four heteroatoms
selected from N, O, and S or bicyclic group, preferably
pyridinonyl, benzofuranyl, benzoxazolyl, dihydroindenyl, or
benzodihydrodioxinyl, wherein Cy.sup.1, Cy.sup.2, and Cy.sup.3 are
each independently optionally substituted with one or more
substituents independently selected from halogen, CH.sub.2F,
CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6 alkyl, OH, O--C.sub.1-C.sub.6
alkyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, and NR.sup.17R.sup.18,
preferably halogen, more preferably F.
[0346] In some embodiments, R.sup.17 and R.sup.18 are each
independently H. In some embodiments, R.sup.17 and R.sup.18 are
each independently methyl. In some embodiments, one of R.sup.17 and
R.sup.18 is H, and the other is methyl.
[0347] In some embodiments, o is 1. In some embodiments, o is 2. In
some embodiments, o is 3.
[0348] In certain embodiments, a compound of the invention is not
of the formula:
##STR00022##
or a salt thereof.
[0349] In certain embodiments, at least one of Cy.sup.1, Cy.sup.2,
and Cy.sup.3 is not substituted or unsubstituted phenyl.
[0350] In yet another embodiment, the present invention provides a
compound having Formula VIII:
##STR00023##
or a stereoisomer, racemate, tautomer, polymorph, hydrate, or
solvate thereof, or a pharmaceutically acceptable salt thereof,
wherein:
[0351] Cy.sup.1, Cy.sup.2 and Cy.sup.3 are each independently
phenyl or heteroaryl comprising one or two 5- or 6-membered rings
and one to four heteroatoms selected from N, O, and S, wherein
Cy.sup.1, Cy.sup.2, and Cy.sup.3 are each independently optionally
substituted with one or more substituents independently selected
from halogen, CH.sub.2F, CHF.sub.2, CF.sub.3, C.sub.1-C.sub.6
alkyl, OH, O--C.sub.1-C.sub.6 alkyl, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, and NR.sup.17R.sup.18; and
[0352] R.sup.17 and R.sup.18 are each independently H or
C.sub.1-C.sub.3 alkyl.
[0353] In some embodiments, Cy.sup.1, Cy.sup.2, or Cy.sup.3 is
independently phenyl or heteroaryl comprising one or two 5- or
6-membered rings and one to four heteroatoms selected from N, O,
and S, each independently optionally substituted with one or more
substituents independently selected from Cl, F, CH.sub.3, CF.sub.3,
OCH.sub.3, and OCF.sub.3.
[0354] In further embodiments, Cy.sup.1, Cy.sup.2, or Cy.sup.3 is
independently phenyl or pyridyl, each independently optionally
substituted with one or more substituents independently selected
from Cl, F, CH.sub.3, CF.sub.3, OCH.sub.3, and OCF.sub.3.
[0355] In further embodiments, one of Cy.sup.1 and Cy.sup.2 is
phenyl, the other is heteroaryl comprising one or two 5- or
6-membered rings and one to four heteroatoms selected from N, O,
and S, preferably pyridyl, and Cy.sup.3 is phenyl, wherein
Cy.sup.1, Cy.sup.2 and Cy.sup.3 are each independently optionally
substituted with one or more substituents independently selected
from Cl, F, CH.sub.3, CF.sub.3, OCH.sub.3, and OCF.sub.3,
preferably Cl or CF.sub.3.
[0356] In some embodiments, R.sup.17 and R.sup.18 are each
independently H. In some embodiments, R.sup.17 and R.sup.18 are
each independently methyl. In some embodiments, one of R.sup.17 and
R.sup.18 is H, and the other is methyl.
[0357] In certain embodiments, at least one instance of R.sup.20 is
halogen. In certain embodiments, at least one instance of R.sup.20
is F. In certain embodiments, at least one instance of R.sup.20 is
Cl. In certain embodiments, at least one instance of R.sup.20 is Br
or I. In certain embodiments, at least one instance of R.sup.20 is
C.sub.1-C.sub.6 alkyl (e.g., Me). In certain embodiments, at least
one instance of R.sup.20 is O--C.sub.1-C.sub.6 alkyl. In certain
embodiments, at least one instance of R.sup.20 is --OMe. In certain
embodiments, all instances of R.sup.20 are the same.
[0358] In certain embodiments, at least one instance of r is 0. In
certain embodiments, each instance of r is 0. In certain
embodiments, at least one instance of r is 1. In certain
embodiments, at least one instance of r is 2, 3, or 4. In certain
embodiments, at least one instance of r is 5. In certain
embodiments, two instances of r are the same.
[0359] In certain embodiments, s is 0. In certain embodiments, s is
1. In certain embodiments, s is 2 or 3. In certain embodiments, s
is 4.
[0360] In certain embodiments, a compound of the invention is a
compound shown in Table 1, or a stereoisomer, racemate, tautomer,
polymorph, hydrate, or solvate thereof, or a pharmaceutically
acceptable salt thereof.
TABLE-US-00001 TABLE 1 Compound # Compound Name 1
(R)-1-(2-(3-chlorophenoxy)ethyl)-N-((4-chlorophenyl)(pyridin-2-
yl)methyl)piperidine-4-carboxamide
(S)-1-(2-(3-chlorophenoxy)ethyl)-N-((4-chlorophenyl)(pyridin-2-
yl)methyl)piperidine-4-carboxamide 2
(R)-1-(2-(4-chlorophenoxy)ethyl)-N-((4-chlorophenyl)(pyridine-2-yl)methy-
l) piperidine-4-carboxamide
(S)-1-(2-(4-chlorophenoxy)ethyl)-N-((4-chlorophenyl)(pyridine-2-yl)methyl-
) piperidine-4-carboxamide 3
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-
fluorophenoxy)ethyl)piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-
fluorophenoxy)ethyl)piperidine-4-carboxamide 4
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(3-
fluorophenoxy)ethyl)piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(3-
fluorophenoxy)ethyl)piperidine-4-carboxamide 5
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-
fluorophenoxy)ethyl)piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-
fluorophenoxy)ethyl)piperidine-4-carboxamide 6
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-
(trifluoromethyl)phenoxy)ethyl) piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-
(trifluoromethyl)phenoxy)ethyl) piperidine-4-carboxamide 7
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(3-
(trifluoromethyl)phenoxy)ethyl) piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(3-
(trifluoromethyl)phenoxy)ethyl) piperidine-4-carboxamide 8
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-
(trifluoromethyl)phenoxy)ethyl) piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-
(trifluoromethyl)phenoxy)ethyl) piperidine-4-carboxamide 9
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-oxopyridin-1(2H)-
yl)ethyl) piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-oxopyridin-1(2H)-
yl)ethyl) piperidine-4-carboxamide 10
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(pyridin-3-
yloxy)ethyl)piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(pyridin-3-
yloxy)ethyl)piperidine-4-carboxamide 11
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-oxopyridin-1(4H)-
yl)ethyl) piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-oxopyridin-1(4H)-
yl)ethyl) piperidine-4-carboxamide 12 (R)-N-((4-chlorophenyl)
(pyridin-2-yl) methyl)-1-(2-(3-methoxyphenoxy) ethyl)
piperidine-4-carboxamide (S)-N-((4-chlorophenyl) (pyridin-2-yl)
methyl)-1-(2-(3-methoxyphenoxy) ethyl) piperidine-4-carboxamide 13
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-methoxyphenoxy)eth-
yl) piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-methoxyphenoxy)ethyl-
) piperidine-4-carboxamide 14
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2,5-
difluorophenoxy)ethyl) piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2,5-difluorophenoxy)et-
hyl) piperidine-4-carboxamide 15
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-((2-oxo-1,2,3,4-
tetrahydroquinolin-7-yl)oxy)ethyl)piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-((2-oxo-1,2,3,4-
tetrahydroquinolin-7-yl)oxy)ethyl)piperidine-4-carboxamide 16
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(quinolin-7-yloxy)eth-
yl) piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(quinolin-7-yloxy)ethyl-
) piperidine-4-carboxamide 17 (R)-N-((4-chlorophenyl)
(pyridin-2-yl) methyl)-1-(2-(cyclohexyloxy) ethyl)
piperidine-4-carboxamide (S)-N-((4-chlorophenyl) (pyridin-2-yl)
methyl)-1-(2-(cyclohexyloxy) ethyl) piperidine-4-carboxamide 18
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(3-phenylpropyl)piperidi-
ne-4- carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(3-phenylpropyl)piperidine-
-4- carboxamide 19 (R)-1-(2-(Benzo[d] thiazol-6-yloxy)
ethyl)-N-((4-chlorophenyl)(pyridin-2-yl) methyl)
piperidine-4-carboxamide (S)-1-(2-(Benzo[d] thiazol-6-yloxy)
ethyl)-N-((4-chlorophenyl)(pyridin-2-yl) methyl)
piperidine-4-carboxamide 20
(R)-N-((3-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-(2-
(trifluoromethyl)phenoxy) ethyl) piperidine-4-carboxamide
(S)-N-((3-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-(2-
(trifluoromethyl)phenoxy) ethyl) piperidine-4-carboxamide 21
(R)-1-(2-(2-chlorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-yl)meth-
yl) piperidine-4-carboxamide
(S)-1-(2-(2-chlorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-yl)methyl-
) piperidine-4-carboxamide 22
(R)-1-(2-(2-fluorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-yl)meth-
yl) piperidine-4-carboxamide
(S)-1-(2-(2-fluorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-yl)methyl-
) piperidine-4-carboxamide 23
(R)-N-((3-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidi-
ne-4- carboxamide
(S)-N-((3-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-
-4- carboxamide 24
(R)-N-((2-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidi-
ne-4- carboxamide
(S)-N-((2-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-
-4- carboxamide 25
(R)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidi-
ne-4- carboxamide
(S)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-
-4- carboxamide 26
(R)-N-((3-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidi-
ne-4- carboxamide
(S)-N-((3-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-
-4- carboxamide 27
(R)-N-((3-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidi-
ne-4- carboxamide
(S)-N-((3-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-
-4- carboxamide 28
(R)-N-((2-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidi-
ne-4- carboxamide
(S)-N-((2-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-
-4- carboxamide 29
(R)-1-(2-phenoxyethyl)-N-(pyridin-2-yl(pyridin-3-yl)methyl)piperidine-4-
- carboxamide
(S)-1-(2-phenoxyethyl)-N-(pyridin-2-yl(pyridin-3-yl)methyl)piperidine-4-
carboxamide 30
N-(di(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4-carboxamide
31
(R)-1-(2-phenoxyethyl)-N-(pyridin-2-yl(4-(trifluoromethyl)phenyl)methyl-
) piperidine-4-carboxamide
(S)-1-(2-phenoxyethyl)-N-(pyridin-2-yl(4-(trifluoromethyl)phenyl)methyl)
piperidine-4-carboxamide 32
(R)-1-(2-phenoxyethyl)-N-(pyridin-2-yl(3-(trifluoromethyl)phenyl)methyl-
) piperidine-4-carboxamide
(S)-1-(2-phenoxyethyl)-N-(pyridin-2-yl(3-(trifluoromethyl)phenyl)methyl)
piperidine-4-carboxamide 33
(R)-1-(2-phenoxyethyl)-N-(pyridin-2-yl(2-(trifluoromethyl)phenyl)methyl-
) piperidine-4-carboxamide
(S)-1-(2-phenoxyethyl)-N-(pyridin-2-yl(2-(trifluoromethyl)phenyl)methyl)
piperidine-4-carboxamide 34
(R)-N-((4-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperid-
ine- 4-carboxamide
(S)-N-((4-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidin-
e- 4-carboxamide 35
(R)-N-((3-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperid-
ine- 4-carboxamide
(S)-N-((3-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidin-
e- 4-carboxamide 36
(R)-N-((2-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide
(S)-N-((2-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide 37
(R)-N-(cyclohexyl(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4-
carboxamide
(S)-N-(cyclohexyl(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4-
carboxamide 38
(R)-N-(2-methyl-1-(pyridin-2-yl(propyl)-1-(2-phenoxyethyl)piperidine-4-
carboxamide
(S)-N-(2-methyl-1-(pyridin-2-yl)propyl)-1-(2-phenoxyethyl)piperidine-4-
carboxamide 39
(R)-N-((4-chlorophenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-
carboxamide
(S)-N-((4-chlorophenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-
carboxamide 40
(R)-N-((4-chlorophenyl)(2-fluorophenyl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(2-fluorophenyl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide 41
(R)-N-((4-chlorophenyl)(3-fluorophenyl)methyl)-1-(2-
phenoxyethyl)piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(3-fluorophenyl)methyl)-1-(2-
phenoxyethyl)piperidine-4-carboxamide 42
(R)-N-((4-chlorophenyl)(4-fluorophenyl)methyl)-1-(2-
phenoxyethyl)piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(4-fluorophenyl)methyl)-1-(2-
phenoxyethyl)piperidine-4-carboxamide 43
(R)-N-((4-chlorophenyl)(2-methoxyphenyl)methyl)-1-(2-
phenoxyethyl)piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(2-methoxyphenyl)methyl)-1-(2-
phenoxyethyl)piperidine-4-carboxamide 44
(R)-N-((4-chlorophenyl)(4-methoxyphenyl)methyl)-1-(2-
phenoxyethyl)piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(4-methoxyphenyl)methyl)-1-(2-
phenoxyethyl)piperidine-4-carboxamide 45
(R)-N-((4-fluorophenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-
carboxamide
(S)-N-((4-fluorophenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-
carboxamide 46
(R)-N-((3-methoxyphenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-
carboxamide
(S)-N-((3-methoxyphenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-
carboxamide 47
N-(bis(4-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-carboxamid-
e 48
N-(bis(2-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-carboxamid-
e 49 (R)-N-((2-fluorophenyl)(4-fluorophenyl)methyl)-1-(2-
phenoxyethyl)piperidine-4-carboxamide
(S)-N-((2-fluorophenyl)(4-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperidi-
ne- 4-carboxamide 50
(R)-N-((2-fluorophenyl)(3-methoxyphenyl)methyl)-1-(2-
phenoxyethyl)piperidine-4-carboxamide
(S)-N-((2-fluorophenyl)(3-methoxyphenyl)methyl)-1-(2-
phenoxyethyl)piperidine-4-carboxamide 51
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-methyl-1-(2-phenoxyethyl-
) piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-methyl-1-(2-phenoxyethyl)
piperidine-4-carboxamide 52
(R)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-
(trifluoromethyl)phenoxy)ethyl) piperidine-4-carboxamide
(S)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-
(trifluoromethyl)phenoxy)ethyl) piperidine-4-carboxamide 53
(R)-1-(2-(2-chlorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methy-
l) piperidine-4-carboxamide
(S)-1-(2-(2-chlorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)
piperidine-4-carboxamide 54
(R)-1-(2-(2-fluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methy-
l) piperidine-4-carboxamide
(S)-1-(2-(2-fluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)
piperidine-4-carboxamide 55
(R)-1-(2-(benzo[d]thiazol-6-yloxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-
yl)methyl)piperidine-4-carboxamide
(S)-1-(2-(benzo[d]thiazol-6-yloxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-
yl)methyl)piperidine-4-carboxamide 56
(R)-1-(2-(2,6-difluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)m-
ethyl) piperidine-4-carboxamide
(S)-1-(2-(2,6-difluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)met-
hyl) piperidine-4-carboxamide 57
(R)-1-(2-(2,5-difluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)m-
ethyl) piperidine-4-carboxamide
(S)-1-(2-(2,5-difluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)met-
hyl) piperidine-4-carboxamide 58
(R)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-methyl-1-phenoxypropa-
n- 2-yl)piperidine-4-carboxamide
(S)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-methyl-1-phenoxypropan--
2- yl)piperidine-4-carboxamide 59
(R)-1-(benzofuran-2-ylmethyl)-N-((4-fluorophenyl)(pyridin-2-
yl)methyl)piperidine-4-carboxamide
(S)-1-(benzofuran-2-ylmethyl)-N-((4-fluorophenyl)(pyridin-2-
yl)methyl)piperidine-4-carboxamide 60
(R)-1-(benzo[d]oxazol-2-ylmethyl)-N-((4-fluorophenyl)(pyridin-2-
yl)methyl)piperidine-4-carboxamide
(S)-1-(benzo[d]oxazol-2-ylmethyl)-N-((4-fluorophenyl)(pyridin-2-
yl)methyl)piperidine-4-carboxamide 61
(R)-1-((2,3-dihydro-1H-inden-2-yl)methyl)-N-((4-fluorophenyl)(pyridin-2-
- yl)methyl) piperidine-4-carboxamide
(S)-1-((2,3-dihydro-1H-inden-2-yl)methyl)-N-((4-fluorophenyl)(pyridin-2-
yl)methyl) piperidine-4-carboxamide 62
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(3-phenoxypropyl)piperid-
ine- 4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(3-phenoxypropyl)piperidin-
e- 4-carboxamide 63
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidi-
ne-4- carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-
-4- carboxamide 64
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-methylpiperidine-4-
carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-methylpiperidine-4-
carboxamide 65
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-methoxyethyl)piperidi-
ne-4- carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-methoxyethyl)piperidine-
-4- carboxamide 66
(R)-1-(2-(2-chlorophenoxy)ethyl)-N-((4-chlorophenyl)(pyridin-2-yl)methy-
l) piperidine-4-carboxamide
(S)-1-(2-(2-chlorophenoxy)ethyl)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)
piperidine-4-carboxamide 67
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2,6-
difluorophenoxy)ethyl) piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2,6-difluorophenoxy)et-
hyl) piperidine-4-carboxamide 68
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-
(trifluoromethoxy)phenoxy) ethyl) piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-
(trifluoromethoxy)phenoxy) ethyl) piperidine-4-carboxamide 69
(R)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-
phenoxyethyl)piperidine-4-carboxamide
(S)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-
phenoxyethyl)piperidine-4-carboxamide 70
(R)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-(2-
(trifluoromethyl) phenoxy)ethyl) piperidine-4-carboxamide
(S)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-(2-
(trifluoromethyl) phenoxy)ethyl) piperidine-4-carboxamide 71
(R)-1-(2-(2-fluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methy-
l)-4- methylpiperidine-4-carboxamide
(S)-1-(2-(2-fluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)-
-4- methylpiperidine-4-carboxamide 72
(R)-1-(4-chlorophenyl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-
yl)methyl)-N-methyl-1-(pyridin-2-yl)methanamine
(S)-1-(4-chlorophenyl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-
yl)methyl)-N-methyl-1-(pyridin-2-yl)methanamine 73
(R)-1-(4-chlorophenyl)-N-methyl-1-(pyridin-2-yl)-N-((1-(2-(2-
(trifluoromethyl) phenoxy)ethyl)piperidin-4-yl)methyl)methanamine
(S)-1-(4-chlorophenyl)-N-methyl-1-(pyridin-2-yl)-N-((1-(2-(2-
(trifluoromethyl) phenoxy)ethyl)piperidin-4-yl)methyl)methanamine
74
(R)-1-(4-fluorophenyl)-N-methyl-N-((1-(2-phenoxyethyl)piperidin-4-
yl)methyl)-1-(pyridin-2-yl)methanamine
(S)-1-(4-fluorophenyl)-N-methyl-N-((1-(2-phenoxyethyl)piperidin-4-
yl)methyl)-1-(pyridin-2-yl)methanamine 75
(R)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-1-(4-
fluorophenyl)-N-methyl-1-(pyridin-2-yl)methanamine
(S)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-1-(4-
fluorophenyl)-N-methyl-1-(pyridin-2-yl)methanamine 76
(R)-1-(3-methoxyphenyl)-N-methyl-N-((1-(2-phenoxyethyl)piperidin-4-
yl)methyl)-1-(pyridin-2-yl)methanamine
(S)-1-(3-methoxyphenyl)-N-methyl-N-((1-(2-phenoxyethyl)piperidin-4-
yl)methyl)-1-(pyridin-2-yl)methanamine 77
(R)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-1-(3-
methoxyphenyl)-N-methyl-1-(pyridin-2-yl)methanamine
(S)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-1-(3-
methoxyphenyl)-N-methyl-1-(pyridin-2-yl)methanamine 78
(R)-1-(4-fluorophenyl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1-
(pyridin-2-yl) methanamine
(S)-1-(4-fluorophenyl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1-
(pyridin-2-yl) methanamine 79
(R)-1-(4-chlorophenyl)-N-methyl-N-((1-(2-phenoxyethyl)piperidin-4-
yl)methyl)-1-(pyridin-2-yl)methanamine
(S)-1-(4-chlorophenyl)-N-methyl-N-((1-(2-phenoxyethyl)piperidin-4-
yl)methyl)-1-(pyridin-2-yl)methanamine 80
(R)-1-(3-methoxyphenyl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1-
(pyridin-2-yl)methanamine
(S)-1-(3-methoxyphenyl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1-
(pyridin-2-yl)methanamine 81
(R)-1-(4-chlorophenyl)-1-(2-fluorophenyl)-N-((1-(2-phenoxyethyl)piperid-
ine- 4-yl) methyl)methanamine
(S)-1-(4-chlorophenyl)-1-(2-fluorophenyl)-N-((1-(2-phenoxyethyl)piperidin-
e- 4-yl) methyl)methanamine 82
(R)-1-(2-(benzo[d]thiazol-6-yloxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-
- yl)methyl) piperidine-4-carboxamide
(S)-1-(2-(benzo[d]thiazol-6-yloxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-
yl)methyl) piperidine-4-carboxamide 83
N-(bis(4-fluorophenyl)methyl)-1-(2-(2-chlorophenoxy)ethyl)piperidine-4-
carboxamide 84
N-(bis(2-fluorophenyl)methyl)-1-(2-(2-chlorophenoxy)ethyl)piperidine-4-
carboxamide 85
(R)-1-(2-(2-chlorophenoxy)ethyl)-N-((2-fluorophenyl)(4-fluorophenyl)met-
hyl) piperidine-4-carboxamide
(S)-1-(2-(2-chlorophenoxy)ethyl)-N-((2-fluorophenyl)(4-fluorophenyl)methy-
l) piperidine-4-carboxamide 86
(R)-1-(2-(2-chlorophenoxy)ethyl)-N-((2-fluorophenyl)(3-methoxyphenyl)
methyl) piperidine-4-carboxamide
(S)-1-(2-(2-chlorophenoxy)ethyl)-N-((2-fluorophenyl)(3-methoxyphenyl)
methyl) piperidine-4-carboxamide 87
(R)-1-(4-chlorophenyl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-
yl)methyl)-1-(2-fluorophenyl)methanamine
(S)-1-(4-chlorophenyl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-
yl)methyl)-1-(2-fluorophenyl)methanamine 88
(R)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-1-(3-
methoxyphenyl)-1-(pyridin-2-yl)methanamine
(S)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-1-(3-
methoxyphenyl)-1-(pyridin-2-yl)methanamine 89
(R)-1-(4-chlorophenyl)-N-((1-(2-(2,5-difluorophenoxy)ethyl)piperidin-4-
yl)methyl)-1-(pyridin-2-yl)methanamine
(S)-1-(4-chlorophenyl)-N-((1-(2-(2,5-difluorophenoxy)ethyl)piperidin-4-
yl)methyl)-1-(pyridin-2-yl)methanamine 90
(R)-1-(2-(2,5-difluorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-
yl)methyl) piperidine-4-carboxamide
(S)-1-(2-(2,5-difluorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-
yl)methyl) piperidine-4-carboxamide 91
(R)-N-((4-chlorophenyl)(3-fluoropyridin-4-yl)methyl)-1-(2-(2-
fluorophenoxy)ethyl) piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(3-fluoropyridin-4-yl)methyl)-1-(2-(2-
fluorophenoxy)ethyl) piperidine-4-carboxamide 92
(R)-N-((4-chlorophenyl)(5-fluoropyridin-2-yl)methyl)-1-(2-(2-
fluorophenoxy)ethyl) piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(5-fluoropyridin-2-yl)methyl)-1-(2-(2-
fluorophenoxy)ethyl) piperidine-4-carboxamide 93
(R)-1-(2-(2-fluorophenoxy)ethyl)-N-(pyridin-2-yl(3-(trifluoromethoxy)ph-
enyl) methyl)piperidine-4-carboxamide
(S)-1-(2-(2-fluorophenoxy)ethyl)-N-(pyridin-2-yl(3-(trifluoromethoxy)phen-
yl) methyl)piperidine-4-carboxamide 94
(R)-N-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methyl)-1-(2-
-(2- fluoro phenoxy)ethyl)piperidine-4-carboxamide
(S)-N-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methyl)-1-(2-(-
2- fluoro phenoxy)ethyl)piperidine-4-carboxamide 95
(R)-N-(benzo[d][1,3]dioxol-5-yl(pyridin-2-yl)methyl)-1-(2-(2-fluorophen-
oxy) ethyl) piperidine-4-carboxamide
(R)-N-(benzo[d][1,3]dioxol-5-yl(pyridin-2-yl)methyl)-1-(2-(2-fluorophenox-
y) ethyl) piperidine-4-carboxamide 96
(R)-N-((4-chlorophenyl)(2-fluorophenyl)methyl)-1-(2-(2-fluorophenoxy)et-
hyl) piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(2-fluorophenyl)methyl)-1-(2-(2-fluorophenoxy)ethy-
l) piperidine-4-carboxamide 97
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-methyl-1-(1-(2-phenoxy
ethyl) piperidin-4-yl)ethan-1-amine 98
2-((4-chlorophenyl)(pyridin-2-yl)methyl)-5-(2-phenoxyethyl)octahydro-1H-
- pyrrolo[3,4-c]pyridine 99
(R)-2-((4-chlorophenyl)((1-(2-phenoxyethyl)piperidin-4-yl)methoxy)
methyl) pyridine
(S)-2-((4-chlorophenyl)((1-(2-phenoxyethyl)piperidin-4-yl)methoxy)
methyl) pyridine 100
(R)-2-((4-chlorophenyl)(pyridin-2-yl)methyl)-5-(2-(2-
(trifluoromethyl)phenoxy) ethyl)octahydro-1H-pyrrolo[3,4-c]pyridine
(S)-2-((4-chlorophenyl)(pyridin-2-yl)methyl)-5-(2-(2-
(trifluoromethyl)phenoxy) ethyl)octahydro-1H-pyrrolo[3,4-c]pyridine
101
(R)-1-(4-fluorophenyl)-N-((4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)e-
thyl) piperidin-4-yl)methyl)-1-(pyridin-2-yl)methanamine
(S)-1-(4-fluorophenyl)-N-((4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethy-
l) piperidin-4-yl)methyl)-1-(pyridin-2-yl)methanamine 102
(R)-1-(benzo[d][1,3]dioxol-5-yl)-N-((1-(2-phenoxyethyl)piperidin-4-
yl)methyl)-1-(pyridin-2-yl)methanamine
(S)-1-(benzo[d][1,3]dioxol-5-yl)-N-((1-(2-phenoxyethyl)piperidin-4-
yl)methyl)-1-(pyridin-2-yl)methanamine 103
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-
phenoxyethyl)piperidin-4-yl) methyl) propan-2-amine
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-
phenoxyethyl)piperidin-4-yl) methyl) propan-2-amine 104
(R)-2-((4-chlorophenyl)(pyridin-2-yl)methyl)-7-(2-phenoxyethyl)-2,7-di-
aza spiro[3.5]nonane
(S)-2-((4-chlorophenyl)(pyridin-2-yl)methyl)-7-(2-phenoxyethyl)-2,7-diaza
spiro[3.5]nonane 105
(R)-2-((4-chlorophenyl)(pyridin-2-yl)methyl)-8-(2-phenoxyethyl)-2,8-
diazaspiro[4.5] decane
(S)-2-((4-chlorophenyl)(pyridin-2-yl)methyl)-8-(2-phenoxyethyl)-2,8-
diazaspiro[4.5] decane 106
(R)-2-((4-chlorophenyl)(pyridin-2-yl)methyl)-8-(2-(2-
(trifluoromethyl)phenoxy) ethyl)-2,8-diazaspiro[4.5]decane
(S)-2-((4-chlorophenyl)(pyridin-2-yl)methyl)-8-(2-(2-
(trifluoromethyl)phenoxy) ethyl)-2,8-diazaspiro[4.5]decane 107
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-
phenoxyethyl)piperidin-4-yl) methyl) acetamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-
phenoxyethyl)piperidin-4-yl) methyl) acetamide 108
N-(isoquinolin-1-ylmethyl)-1-(2-(2-methoxyphenoxy)ethyl)piperidine-4-
carboxamide 109
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-methoxyphenoxy)
ethyl)piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-methoxyphenoxy)
ethyl)piperidine-4-carboxamide 110
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(4-henoxybutyl)piperidi-
ne-4- carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(4-henoxybutyl)piperidine--
4- carboxamide 111
(R)-N-((4-chlorophenyl)(pyridin-3-yl)methyl)-1-(2-phenoxyethyl)
piperidine- 4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-3-yl)methyl)-1-(2-phenoxyethyl)
piperidine-4- carboxamide 112
(R)-N-((4-chlorophenyl)(pyridin-4-yl)methyl)-1-(2-phenoxyethyl)
piperidine- 4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-4-yl)methyl)-1-(2-phenoxyethyl)
piperidine-4- carboxamide 113
(R)-1-(2-phenoxyethyl)-N-(phenyl(pyridin-2-yl)methyl)piperidine-4-
carboxamide
(S)-1-(2-phenoxyethyl)-N-(phenyl(pyridin-2-yl)methyl)piperidine-4-
carboxamide 114
(R)-1-(4-chlorophenyl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1-
(pyridin-2-yl)methanamine
(S)-1-(4-chlorophenyl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1-
(pyridin-2-yl)methanamine 115
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2,4-difluorophenoxy-
) ethyl)piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2,4-difluorophenoxy)
ethyl)piperidine-4-carboxamide 116
(R)-N-((4-chlorophenyl)(5-fluoropyridin-2-yl)methyl)-1-(2-phenoxyethyl-
) piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(5-fluoropyridin-2-yl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide 117
(R)-N-((4-chlorophenyl)(3-fluoropyridin-4-yl)methyl)-1-(2-
phenoxyethyl)piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(3-fluoropyridin-4-yl)methyl)-1-(2-
phenoxyethyl)piperidine-4-carboxamide 118
(R)-1-(2-phenoxyethyl)-N-(pyridin-2-yl(3-(trifluoromethoxy)phenyl)
methyl)piperidine-4-carboxamide
(S)-1-(2-phenoxyethyl)-N-(pyridin-2-yl(3-(trifluoromethoxy)phenyl)
methyl)piperidine-4-carboxamide 119
(R)-N-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methyl)-1-(-
2- phenoxyethyl)piperidine-4-carboxamide
(S)-N-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methyl)-1-(2-
phenoxyethyl)piperidine-4-carboxamide 120
(R)-1-(4-chlorophenyl)-1-(pyridin-2-yl)-N-((1-(2-(2-(trifluoromethyl)
phenoxy)ethyl)piperidin-4-yl)methyl)methanamine
(S)-1-(4-chlorophenyl)-1-(pyridin-2-yl)-N-((1-(2-(2-(trifluoromethyl)
phenoxy)ethyl)piperidin-4-yl)methyl)methanamine 121
(R)-1-(4-chlorophenyl)-N-((1-(2-(2-fluorophenoxy) ethyl)
piperidin-4-yl) methyl)-1-(pyridin-2-yl) methanamine
(S)-1-(4-chlorophenyl)-N-((1-(2-(2-fluorophenoxy) ethyl)
piperidin-4-yl) methyl)-1-(pyridin-2-yl) methanamine 122
(R)-N-((1-(2-(2-fluorophenoxy) ethyl) piperidin-4-yl) methyl)-1-(4-
fluorophenyl)-1-(pyridin-2-yl) methanamine
(S)-N-((1-(2-(2-fluorophenoxy) ethyl) piperidin-4-yl) methyl)-1-(4-
fluorophenyl)-1-(pyridin-2-yl) methanamine 123
(R)-N-((4-chlorophenyl)(2-fluorophenyl)methyl)-1-(2-(2,5-difluoropheno-
xy) ethyl) piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(2-fluorophenyl)methyl)-1-(2-(2,5-difluorophenoxy)
ethyl) piperidine-4-carboxamide 125
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-2,2,2-trifluoro-N-((1-(2-
phenoxyethyl)piperidin-4-yl)methyl)ethanamine
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-2,2,2-trifluoro-N-((1-(2-
phenoxyethyl)piperidin-4-yl)methyl)ethanamine 126
(R)-2-(4-chlorophenyl)-N-(1-(2-phenoxyethyl)piperidin-4-yl)-2-(pyridin-
-2- yl)acetamide
(S)-2-(4-chlorophenyl)-N-(1-(2-phenoxyethyl)piperidin-4-yl)-2-(pyridin-2-
yl)acetamide 127
(R)-2-((4-chlorophenyl)((1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperi-
din-4- yl)methoxy)methyl)pyridine
(S)-2-((4-chlorophenyl)((1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-
-4- yl)methoxy)methyl)pyridine 129
(R)-N-((3-methoxyphenyl)(oxazol-4-yl)methyl)-1-(2-phenoxyethyl)piperid-
ine- 4-carboxamide
(S)-N-((3-methoxyphenyl)(oxazol-4-yl)methyl)-1-(2-phenoxyethyl)piperidine-
- 4-carboxamide 130
(R)-N-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methyl)-1-(-
2-(2,4- difluorophenoxy)ethyl)piperidine-4-carboxamide
(S)-N-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methyl)-1-(2-(-
2,4- difluorophenoxy)ethyl)piperidine-4-carboxamide 131
(R)-1-(4-chlorophenyl)-N-methyl-N-((4-methyl-1-(2-phenoxyethyl)piperid-
in- 4-yl)methyl)-1-(pyridin-2-yl)methanamine
(S)-1-(4-chlorophenyl)-N-methyl-N-((4-methyl-1-(2-phenoxyethyl)piperidin-
4-yl)methyl)-1-(pyridin-2-yl)methanamine 132
(R)-1-(4-chlorophenyl)-N-((1-(2-(4-fluorophenoxy)ethyl)piperidin-4-
yl)methyl)-1-(pyridin-2-yl)methanamine
(S)-1-(4-chlorophenyl)-N-((1-(2-(4-fluorophenoxy)ethyl)piperidin-4-
yl)methyl)-1-(pyridin-2-yl)methanamine 133
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-(2-
fluorophenoxy)ethyl)piperidin-4-yl)methyl)propan-2-amine
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-(2-
fluorophenoxy)ethyl)piperidin-4-yl)methyl)propan-2-amine 134
(R)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-N-((3-
methoxyphenyl)(pyridin-2-yl)methyl)propan-2-amine
(S)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-N-((3-
methoxyphenyl)(pyridin-2-yl)methyl)propan-2-amine 135
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-(4-
fluorophenoxy)ethyl)piperidin-4-yl)methyl)propan-2-amine
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-(4-
fluorophenoxy)ethyl)piperidin-4-yl)methyl)propan-2-amine 136
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-2,2,2-trifluoro-N-((1-(2--
(2- fluorophenoxy)ethyl)piperidin-4-yl)methyl)ethan-1-amine
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-2,2,2-trifluoro-N-((1-(2-(2-
fluorophenoxy)ethyl)piperidin-4-yl)methyl)ethan-1-amine 137
(R)-1-(4-chlorophenyl)-N-methyl-1-(pyridin-2-yl)-N-((1-(2-(4-
(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)methyl)methanamine
(S)-1-(4-chlorophenyl)-N-methyl-1-(pyridin-2-yl)-N-((1-(2-(4-
(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)methyl)methanamine
138
(R)-1-(benzo[d][1,3]dioxol-5-yl)-N-((1-(2-(2-fluorophenoxy)ethyl)piper-
idin-4- yl)methyl)-N-methyl-1-(pyridin-2-yl)methanamine
(S)-1-(benzo[d][1,3]dioxol-5-yl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidi-
n-4- yl)methyl)-N-methyl-1-(pyridin-2-yl)methanamine 139
(R)-1-(benzo[d][1,3]dioxol-5-yl)-N-((1-(2-(2-fluorophenoxy)ethyl)piper-
idin-4- yl)methyl)-1-(pyridin-2-yl)methanamine
(S)-1-(benzo[d][1,3]dioxol-5-yl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidi-
n-4- yl)methyl)-1-(pyridin-2-yl)methanamine 140
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-((2,3-dihydrobenzo[b][1,4]d-
ioxin- 2-yl)methyl)piperidine-4-carboxamide 141
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(pyridin-2-
yloxy)ethyl)piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(pyridin-2-
yloxy)ethyl)piperidine-4-carboxamide 142
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(pyridin-4-
yloxy)ethyl)piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(pyridin-4-
yloxy)ethyl)piperidine-4-carboxamide 143
(R)-N-((3-methoxyphenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-
phenoxyethyl)piperidine-4-carboxamide
(S)-N-((3-methoxyphenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-
phenoxyethyl)piperidine-4-carboxamide 144
(R)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-
phenoxyethyl)piperidine-4-carboxamide
(S)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-
phenoxyethyl)piperidine-4-carboxamide 145
(R)-1-(2-(2,4-difluorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-
yl)methyl)piperidine-4-carboxamide
(S)-1-(2-(2,4-difluorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-
yl)methyl)piperidine-4-carboxamide 146
(R)-N-((3-methoxyphenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-
- carboxamide
(S)-N-((3-methoxyphenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-
carboxamide
[0361] In certain embodiments, a compound of the present invention
is a compound shown in Table 1, or a stereoisomer, racemate, or
tautomer thereof, or a pharmaceutically acceptable salt thereof. In
certain embodiments, a compound of the present invention is a
compound shown in Table 1, or a pharmaceutically acceptable salt
thereof.
[0362] The present invention relates to novel compounds that
modulate dopamine D2 receptors. For example, compounds of the
present invention have an EC.sub.50<0.1 .mu.M in the assay for
.beta.-arrestin antagonist activity. For example, compounds of the
present invention have an EC.sub.50 of 0.1-1.0 .mu.M in the assay
for .beta.-arrestin antagonist activity. For example, compounds of
the present invention have an EC.sub.50 of 1.0-10.0 .mu.M in the
assay for .beta.-arrestin antagonist activity. For example,
compounds of the present invention have an EC.sub.50 of 10.0-30.0
.mu.M in the assay for .beta.-arrestin antagonist activity.
Accordingly, compounds of the present invention are useful in
treating or preventing a disease or disorder in which modulation of
D2 receptors plays a role.
[0363] For example, compounds of the present invention are
selective antagonists of D2 receptors. For example, compounds of
the present invention are selective .beta.-arrestin antagonists,
but not cAMP antagonists. For example, compounds of the present
invention display at least 1.5-fold, 2-fold, 3-fold, 4-fold,
5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold,
30-fold, 40-fold, 50-fold, or 100-fold stronger .beta.-arrestin
antagonist activity than cAMP antagonist activity. For example,
compounds of the present invention display at least 1.5-fold,
2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold,
10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or 100-fold
decrease in EC.sub.50 for .beta.-arrestin antagonist activity than
cAMP antagonist activity. Accordingly, compounds of the present
invention are useful in treating or preventing a disease or
disorder in which modulation of D2 receptors plays a role, while at
the same time, can reduce the undesirable side effects associated
with D2 receptor activity (e.g., side effects arising from
antagonizing the cAMP pathway).
[0364] For example, compounds of the present invention have an
EC.sub.50<0.1 .mu.M in the assay for .beta.-arrestin antagonist
activity and an EC.sub.50>0.1 .mu.M in the assay for cAMP
antagonist activity. For example, compounds of the present
invention have an EC.sub.50<0.1 .mu.M in the assay for
.beta.-arrestin antagonist activity and an EC.sub.50 of 0.1-1.0
.mu.M in the assay for cAMP antagonist activity. For example,
compounds of the present invention have an EC.sub.50<0.1 .mu.M
in the assay for .beta.-arrestin antagonist activity and an
EC.sub.50 of 1.0-10.0 .mu.M in the assay for cAMP antagonist
activity. For example, compounds of the present invention have an
EC.sub.50<0.1 .mu.M in the assay for .beta.-arrestin antagonist
activity and an EC.sub.50 of 10.0-30.0 .mu.M in the assay for cAMP
antagonist activity. For example, compounds of the present
invention have an EC.sub.50<0.1 .mu.M in the assay for
.beta.-arrestin antagonist activity and an EC.sub.50.gtoreq.30.0
.mu.M in the assay for cAMP antagonist activity. Accordingly,
compounds of the present invention are useful in treating or
preventing a disease or disorder in which modulation of D2
receptors plays a role, while at the same time, can reduce the
undesirable side effects associated with D2 receptor activity
(e.g., side effects arising from antagonizing the cAMP
pathway).
[0365] For example, compounds of the present invention have an
EC.sub.50 of 0.1-1.0 .mu.M in the assay for .beta.-arrestin
antagonist activity and an EC.sub.50>1.0 .mu.M in the assay for
cAMP antagonist activity. For example, compounds of the present
invention have an EC.sub.50 of 0.1-1.0 .mu.M in the assay for
.beta.-arrestin antagonist activity and an EC.sub.50 of 1.0-10.0
.mu.M in the assay for cAMP antagonist activity. For example,
compounds of the present invention have an EC.sub.50 of 0.1-1.0
.mu.M in the assay for .beta.-arrestin antagonist activity and an
EC.sub.50 of 10.0-30.0 .mu.M in the assay for cAMP antagonist
activity. For example, compounds of the present invention have an
EC.sub.50 of 0.1-1.0 .mu.M in the assay for .beta.-arrestin
antagonist activity and an EC.sub.50.gtoreq.30.0 .mu.M in the assay
for cAMP antagonist activity. Accordingly, compounds of the present
invention are useful in treating or preventing a disease or
disorder in which modulation of D2 receptors plays a role, while at
the same time, can reduce the undesirable side effects associated
with D2 receptor activity (e.g., side effects arising from
antagonizing the cAMP pathway).
[0366] For example, compounds of the present invention have an
EC.sub.50 of 1.0-10.0 .mu.M in the assay for .beta.-arrestin
antagonist activity and an EC.sub.50>10.0 .mu.M in the assay for
cAMP antagonist activity. For example, compounds of the present
invention have an EC.sub.50 of of 1.0-10.0 .mu.M in the assay for
.beta.-arrestin antagonist activity and an EC.sub.50 of 10.0-30.0
.mu.M in the assay for cAMP antagonist activity. For example,
compounds of the present invention have an EC.sub.50 of of 1.0-10.0
.mu.M in the assay for .beta.-arrestin antagonist activity and an
EC.sub.50.gtoreq.30.0 .mu.M in the assay for cAMP antagonist
activity. Accordingly, compounds of the present invention are
useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role, while at the same time,
can reduce the undesirable side effects associated with D2 receptor
activity (e.g., side effects arising from antagonizing the cAMP
pathway).
[0367] For example, compounds of the present invention have an
EC.sub.50 of of 10.0-30.0 .mu.M in the assay for .beta.-arrestin
antagonist activity and an EC.sub.50>30.0 .mu.M in the assay for
cAMP antagonist activity. Accordingly, compounds of the present
invention are useful in treating or preventing a disease or
disorder in which modulation of D2 receptors plays a role, while at
the same time, can reduce the undesirable side effects associated
with D2 receptor activity (e.g., side effects arising from
antagonizing the cAMP pathway).
[0368] For example, compounds of the present invention are
selective .beta.-arrestin antagonists and cAMP agonists. For
example, compounds of the present invention have an
EC.sub.50<0.1 .mu.M in the assay for .beta.-arrestin antagonist
activity and an EC.sub.50<0.1 .mu.M in the assay for cAMP
agonist activity. For example, compounds of the present invention
have an EC.sub.50<0.1 .mu.M in the assay for .beta.-arrestin
antagonist activity and an EC.sub.50 of 0.1-1.0 .mu.M in the assay
for cAMP agonist activity. For example, compounds of the present
invention have an EC.sub.50<0.1 .mu.M in the assay for
.beta.-arrestin antagonist activity and an EC.sub.50 of 1.0-10.0
.mu.M in the assay for cAMP agonist activity. For example,
compounds of the present invention have an EC.sub.50<0.1 .mu.M
in the assay for .beta.-arrestin antagonist activity and an
EC.sub.50 of 10.0-30.0 .mu.M in the assay for cAMP agonist
activity. Accordingly, compounds of the present invention are
useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role, while at the same time,
can reduce the undesirable side effects associated with D2 receptor
activity (e.g., side effects arising from antagonizing the cAMP
pathway).
[0369] For example, compounds of the present invention have an
EC.sub.50 of 0.1-1.0 82 M in the assay for .beta.-arrestin
antagonist activity and an EC.sub.50<0.1 .mu.M in the assay for
cAMP agonist activity. For example, compounds of the present
invention have an EC.sub.50 of 0.1-1.0 .mu.M in the assay for
.beta.-arrestin antagonist activity and an EC.sub.50 of 0.1-1.0
.mu.M in the assay for cAMP agonist activity. For example,
compounds of the present invention have an EC.sub.50 of 0.1-1.0
.mu.M in the assay for .beta.-arrestin antagonist activity and an
EC.sub.50 of 1.0-10.0 .mu.M in the assay for cAMP agonist activity.
For example, compounds of the present invention have an EC.sub.50
of 0.1-1.0 .mu.M in the assay for .beta.-arrestin antagonist
activity and an EC.sub.50 of 10.0-30.0 .mu.M in the assay for cAMP
agonist activity. Accordingly, compounds of the present invention
are useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role, while at the same time,
can reduce the undesirable side effects associated with D2 receptor
activity (e.g., side effects arising from antagonizing the cAMP
pathway).
[0370] For example, compounds of the present invention have an
EC.sub.50 of 1.0-10.0 .mu.M in the assay for .beta.-arrestin
antagonist activity and an EC.sub.50<0.1 .mu.M in the assay for
cAMP agonist activity. For example, compounds of the present
invention have an EC.sub.50 of 1.0-10.0 .mu.M in the assay for
.beta.-arrestin antagonist activity and an EC.sub.50 of 0.1-1.0
.mu.M in the assay for cAMP agonist activity. For example,
compounds of the present invention have an EC.sub.50 of 1.0-10.0
.mu.M in the assay for .beta.-arrestin antagonist activity and an
EC.sub.50 of 1.0-10.0 .mu.M in the assay for cAMP agonist activity.
For example, compounds of the present invention have an EC.sub.50
of 1.0-10.0 .mu.M in the assay for .beta.-arrestin antagonist
activity and an EC.sub.50 of 10.0-30.0 .mu.M in the assay for cAMP
agonist activity. Accordingly, compounds of the present invention
are useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role, while at the same time,
can reduce the undesirable side effects associated with D2 receptor
activity (e.g., side effects arising from antagonizing the cAMP
pathway).
[0371] For example, compounds of the present invention have an
EC.sub.50 of 10.0-30.0 .mu.M in the assay for .beta.-arrestin
antagonist activity and an EC.sub.50<0.1 .mu.M in the assay for
cAMP agonist activity. For example, compounds of the present
invention have an EC.sub.50 of 10.0-30.0 .mu.M in the assay for
.beta.-arrestin antagonist activity and an EC.sub.50 of 0.1-1.0
.mu.M in the assay for cAMP agonist activity. For example,
compounds of the present invention have an EC.sub.50 of 10.0-30.0
.mu.M in the assay for .beta.-arrestin antagonist activity and an
EC.sub.50 of 1.0-10.0 .mu.M in the assay for cAMP agonist activity.
For example, compounds of the present invention have an EC.sub.50
of 10.0-30.0 .mu.M in the assay for .beta.-arrestin antagonist
activity and an EC.sub.50 of 10.0-30.0 .mu.M in the assay for cAMP
agonist activity. Accordingly, compounds of the present invention
are useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role, while at the same time,
can reduce the undesirable side effects associated with D2 receptor
activity (e.g., side effects arising from antagonizing the cAMP
pathway).
[0372] For example, compounds of the present invention are
selective .beta.-arrestin antagonists and agonists of cAMP and
.beta.-arrestin. Accordingly, compounds of the present invention
are useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role, while at the same time,
can reduce the undesirable side effects associated with D2 receptor
activity (e.g., side effects arising from antagonizing the cAMP
pathway).
[0373] For example, compounds of the present invention are
.beta.-arrestin antagonists and cAMP antagonists. For example,
compounds of the present invention have an EC.sub.50<0.1 .mu.M
in the assay for .beta.-arrestin antagonist activity and an
EC.sub.50<0.1 .mu.M in the assay for cAMP antagonist activity.
For example, compounds of the present invention have an
EC.sub.50<0.1 .mu.M in the assay for .beta.-arrestin antagonist
activity and an EC.sub.50 of 0.1-1.0 .mu.M in the assay for cAMP
antagonist activity. For example, compounds of the present
invention have an EC.sub.50 of 0.1-1.0 .mu.M in the assay for
.beta.-arrestin antagonist activity and an EC.sub.50 of 0.1-1.0
.mu.M in the assay for cAMP antagonist activity. For example,
compounds of the present invention have an EC.sub.50 of 0.1-1.0
.mu.M in the assay for .beta.-arrestin antagonist activity and an
EC.sub.50 of 1.0-10.0 .mu.M in the assay for cAMP antagonist
activity. For example, compounds of the present invention have an
EC.sub.50 of 1.0-10.0 .mu.M in the assay for .beta.-arrestin
antagonist activity and an EC.sub.50 of 1.0-10.0 .mu.M in the assay
for cAMP antagonist activity. For example, compounds of the present
invention have an EC.sub.50 of of 1.0-10.0 .mu.M in the assay for
.beta.-arrestin antagonist activity and an EC.sub.50 of 10.0-30.0
.mu.M in the assay for cAMP antagonist activity. For example,
compounds of the present invention have an EC.sub.50 of 10.0-30.0
.mu.M in the assay for .beta.-arrestin antagonist activity and an
EC.sub.50 of 10.0-30.0 .mu.M in the assay for cAMP antagonist
activity. Accordingly, compounds of the present invention are
useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role.
[0374] The present invention relates to novel compounds that
modulate dopamine D2 receptors. For example, compounds of the
present invention have an EC.sub.50<0.1 .mu.M in the assay for
.beta.-arrestin agonist activity. For example, compounds of the
present invention have an EC.sub.50 of 0.1-1.0 .mu.M in the assay
for .beta.-arrestin agonist activity. For example, compounds of the
present invention have an EC.sub.50 of 1.0-10.0 .mu.M in the assay
for .beta.-arrestin agonist activity. For example, compounds of the
present invention have an EC.sub.50 of 10.0-30.0 .mu.M in the assay
for .beta.-arrestin agonist activity. Accordingly, compounds of the
present invention are useful in treating or preventing a disease or
disorder in which modulation of D2 receptors plays a role.
[0375] For example, compounds of the present invention are
selective agonists of D2 receptors. For example, compounds of the
present invention are selective .beta.-arrestin agonists, but not
cAMP agonists. For example, compounds of the present invention
display at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold,
7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 30-fold,
40-fold, 50-fold, or 100-fold stronger .beta.-arrestin agonist
activity than cAMP agonist activity. For example, compounds of the
present invention display at least 1.5-fold, 2-fold, 3-fold,
4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold,
20-fold, 30-fold, 40-fold, 50-fold, or 100-fold decrease in
EC.sub.50 for .beta.-arrestin agonist activity than cAMP agonist
activity. Accordingly, compounds of the present invention are
useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role.
[0376] For example, compounds of the present invention have an
EC.sub.50<0.1 .mu.M in the assay for .beta.-arrestin agonist
activity and an EC.sub.50.gtoreq.0.1 .mu.M in the assay for cAMP
agonist activity. For example, compounds of the present invention
have an EC.sub.50<0.1 .mu.M in the assay for .beta.-arrestin
agonist activity and an EC.sub.50 of 0.1-1.0 .mu.M in the assay for
cAMP agonist activity. For example, compounds of the present
invention have an EC.sub.50<0.1 .mu.M in the assay for
.beta.-arrestin agonist activity and an EC.sub.50 of 1.0-10.0 .mu.M
in the assay for cAMP agonist activity. For example, compounds of
the present invention have an EC.sub.50<0.1 .mu.M in the assay
for .beta.-arrestin agonist activity and an EC.sub.50 of 10.0-30.0
.mu.M in the assay for cAMP agonist activity. For example,
compounds of the present invention have an EC.sub.50<0.1 .mu.M
in the assay for .beta.-arrestin agonist activity and an
EC.sub.50.gtoreq.30.0 .mu.M in the assay for cAMP agonist activity.
Accordingly, compounds of the present invention are useful in
treating or preventing a disease or disorder in which modulation of
D2 receptors plays a role.
[0377] For example, compounds of the present invention have an
EC.sub.50 of 0.1-1.0 .mu.M in the assay for .beta.-arrestin agonist
activity and an EC.sub.50>1.0 .mu.M in the assay for cAMP
agonist activity. For example, compounds of the present invention
have an EC.sub.50 of 0.1-1.0 .mu.M in the assay for .beta.-arrestin
agonist activity and an EC.sub.50 of 1.0-10.0 .mu.M in the assay
for cAMP agonist activity. For example, compounds of the present
invention have an EC.sub.50 of 0.1-1.0 .mu.M in the assay for
.beta.-arrestin agonist activity and an EC.sub.50 of 10.0-30.0
.mu.M in the assay for cAMP agonist activity. For example,
compounds of the present invention have an EC.sub.50 of 0.1-1.0
.mu.M in the assay for .beta.-arrestin agonist activity and an
EC.sub.50.gtoreq.30.0 .mu.M in the assay for cAMP agonist activity.
Accordingly, compounds of the present invention are useful in
treating or preventing a disease or disorder in which modulation of
D2 receptors plays a role.
[0378] For example, compounds of the present invention have an
EC.sub.50 of 1.0-10.0 .mu.M in the assay for .beta.-arrestin
agonist activity and an EC.sub.50>10.0 .mu.M in the assay for
cAMP agonist activity. For example, compounds of the present
invention have an EC.sub.50 of of 1.0-10.0 .mu.M in the assay for
.beta.-arrestin agonist activity and an EC.sub.50 of 10.0-30.0
.mu.M in the assay for cAMP agonist activity. For example,
compounds of the present invention have an EC.sub.50 of of 1.0-10.0
.mu.M in the assay for .beta.-arrestin agonist activity and an
EC.sub.50.gtoreq.30.0 .mu.M in the assay for cAMP agonist activity.
Accordingly, compounds of the present invention are useful in
treating or preventing a disease or disorder in which modulation of
D2 receptors plays a role.
[0379] For example, compounds of the present invention have an
EC.sub.50 of of 10.0-30.0 .mu.M in the assay for .beta.-arrestin
agonist activity and an EC.sub.50>30.0 .mu.M in the assay for
cAMP agonist activity. Accordingly, compounds of the present
invention are useful in treating or preventing a disease or
disorder in which modulation of D2 receptors plays a role.
[0380] For example, compounds of the present invention are
selective .beta.-arrestin agonists and cAMP antagonists. For
example, compounds of the present invention have an
EC.sub.50<0.1 .mu.M in the assay for .beta.-arrestin agonist
activity and an EC.sub.50<0.1 .mu.M in the assay for cAMP
antagonist activity. For example, compounds of the present
invention have an EC.sub.50<0.1 .mu.M in the assay for
.beta.-arrestin agonist activity and an EC.sub.50 of 0.1-1.0 .mu.M
in the assay for cAMP antagonist activity. For example, compounds
of the present invention have an EC.sub.50<0.1 .mu.M in the
assay for .beta.-arrestin agonist activity and an EC.sub.50 of
1.0-10.0 .mu.M in the assay for cAMP antagonist activity. For
example, compounds of the present invention have an
EC.sub.50<0.1 .mu.M in the assay for .beta.-arrestin agonist
activity and an EC.sub.50 of 10.0-30.0 .mu.M in the assay for cAMP
antagonist activity. Accordingly, compounds of the present
invention are useful in treating or preventing a disease or
disorder in which modulation of D2 receptors plays a role.
[0381] For example, compounds of the present invention have an
EC.sub.50 of 0.1-1.0 .mu.M in the assay for .beta.-arrestin agonist
activity and an EC.sub.50<0.1 .mu.M in the assay for cAMP
antagonist activity. For example, compounds of the present
invention have an EC.sub.50 of 0.1-1.0 .mu.M in the assay for
.beta.-arrestin agonist activity and an EC.sub.50 of 0.1-1.0 .mu.M
in the assay for cAMP antagonist activity. For example, compounds
of the present invention have an EC.sub.50 of 0.1-1.0 .mu.M in the
assay for .beta.-arrestin agonist activity and an EC.sub.50 of
1.0-10.0 .mu.M in the assay for cAMP antagonist activity. For
example, compounds of the present invention have an EC.sub.50 of
0.1-1.0 .mu.M in the assay for .beta.-arrestin agonist activity and
an EC.sub.50 of 10.0-30.0 .mu.M in the assay for cAMP antagonist
activity. Accordingly, compounds of the present invention are
useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role.
[0382] For example, compounds of the present invention have an
EC.sub.50 of 1.0-10.0 .mu.M in the assay for .beta.-arrestin
agonist activity and an EC.sub.50<0.1 .mu.M in the assay for
cAMP antagonist activity. For example, compounds of the present
invention have an EC.sub.50 of 1.0-10.0 .mu.M in the assay for
.beta.-arrestin agonist activity and an EC.sub.50 of 0.1-1.0 .mu.M
in the assay for cAMP antagonist activity. For example, compounds
of the present invention have an EC.sub.50 of 1.0-10.0 .mu.M in the
assay for .beta.-arrestin agonist activity and an EC.sub.50 of
1.0-10.0 .mu.M in the assay for cAMP antagonist activity. For
example, compounds of the present invention have an EC.sub.50 of
1.0-10.0 .mu.M in the assay for .beta.-arrestin agonist activity
and an EC.sub.50 of 10.0-30.0 .mu.M in the assay for cAMP
antagonist activity. Accordingly, compounds of the present
invention are useful in treating or preventing a disease or
disorder in which modulation of D2 receptors plays a role.
[0383] For example, compounds of the present invention have an
EC.sub.50 of 10.0-30.0 .mu.M in the assay for .beta.-arrestin
agonist activity and an EC.sub.50<0.1 .mu.M in the assay for
cAMP antagonist activity. For example, compounds of the present
invention have an EC.sub.50 of 10.0-30.0 .mu.M in the assay for
.beta.-arrestin agonist activity and an EC.sub.50 of 0.1-1.0 .mu.M
in the assay for cAMP antagonist activity. For example, compounds
of the present invention have an EC.sub.50 of 10.0-30.0 .mu.M in
the assay for .beta.-arrestin agonist activity and an EC.sub.50 of
1.0-10.0 .mu.M in the assay for cAMP antagonist activity. For
example, compounds of the present invention have an EC.sub.50 of
10.0-30.0 .mu.M in the assay for .beta.-arrestin agonist activity
and an EC.sub.50 of 10.0-30.0 .mu.M in the assay for cAMP
antagonist activity. Accordingly, compounds of the present
invention are useful in treating or preventing a disease or
disorder in which modulation of D2 receptors plays a role.
[0384] For example, compounds of the present invention are
selective .beta.-arrestin agonists and antagonists of cAMP and
.beta.-arrestin. Accordingly, compounds of the present invention
are useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role.
[0385] For example, compounds of the present invention are
.beta.-arrestin agonists and cAMP agonists. For example, compounds
of the present invention have an EC.sub.50<0.1 .mu.M in the
assay for .beta.-arrestin agonist activity and an EC.sub.50<0.1
.mu.M in the assay for cAMP agonist activity. For example,
compounds of the present invention have an EC.sub.50<0.1 .mu.M
in the assay for .beta.-arrestin agonist activity and an EC.sub.50
of 0.1-1.0 .mu.M in the assay for cAMP agonist activity. For
example, compounds of the present invention have an EC.sub.50 of
0.1-1.0 .mu.M in the assay for .beta.-arrestin agonist activity and
an EC.sub.50 of 0.1-1.0 .mu.M in the assay for cAMP agonist
activity. For example, compounds of the present invention have an
EC.sub.50 of 0.1-1.0 .mu.M in the assay for .beta.-arrestin agonist
activity and an EC.sub.50 of 1.0-10.0 .mu.M in the assay for cAMP
agonist activity. For example, compounds of the present invention
have an EC.sub.50 of 1.0-10.0 .mu.M in the assay for
.beta.-arrestin agonist activity and an EC.sub.50 of 1.0-10.0 .mu.M
in the assay for cAMP agonist activity. For example, compounds of
the present invention have an EC.sub.50 of of 1.0-10.0 .mu.M in the
assay for .beta.-arrestin agonist activity and an EC.sub.50 of
10.0-30.0 .mu.M in the assay for cAMP agonist activity. For
example, compounds of the present invention have an EC.sub.50 of
10.0-30.0 .mu.M in the assay for .beta.-arrestin agonist activity
and an EC.sub.50 of 10.0-30.0 .mu.M in the assay for cAMP agonist
activity. Accordingly, compounds of the present invention are
useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role, while at the same time,
can reduce the undesirable side effects associated with D2 receptor
activity (e.g., side effects arising from antagonizing the cAMP
pathway). The present invention relates to novel compounds that
modulate dopamine D2 receptors. For example, compounds of the
present invention have an EC.sub.50<0.1 .mu.M in the assay for
cAMP antagonist activity. For example, compounds of the present
invention have an EC.sub.50 of 0.1-1.0 .mu.M in the assay for cAMP
antagonist activity. For example, compounds of the present
invention have an EC.sub.50 of 1.0-10.0 .mu.M in the assay for cAMP
antagonist activity. For example, compounds of the present
invention have an EC.sub.50 of 10.0-30.0 .mu.M in the assay for
cAMP antagonist activity. Accordingly, compounds of the present
invention are useful in treating or preventing a disease or
disorder in which modulation of D2 receptors plays a role.
[0386] For example, compounds of the present invention are
selective antagonists of D2 receptors. For example, compounds of
the present invention are selective cAMP antagonists, but not
.beta.-arrestin antagonists. For example, compounds of the present
invention display at least 1.5-fold, 2-fold, 3-fold, 4-fold,
5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold,
30-fold, 40-fold, 50-fold, or 100-fold stronger cAMP antagonist
activity than .beta.-arrestin antagonist activity. For example,
compounds of the present invention display at least 1.5-fold,
2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold,
10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or 100-fold
decrease in EC.sub.50 for cAMP antagonist activity than
.beta.-arrestin antagonist activity. Accordingly, compounds of the
present invention are useful in treating or preventing a disease or
disorder in which modulation of D2 receptors plays a role.
[0387] For example, compounds of the present invention have an
EC.sub.50<0.1 .mu.M in the assay for cAMP antagonist activity
and an EC.sub.50.gtoreq.0.1 .mu.M in the assay for .beta.-arrestin
antagonist activity. For example, compounds of the present
invention have an EC.sub.50<0.1 .mu.M in the assay for cAMP
antagonist activity and an EC.sub.50 of 0.1-1.0 .mu.M in the assay
for .beta.-arrestin antagonist activity. For example, compounds of
the present invention have an EC.sub.50<0.1 .mu.M in the assay
for cAMP antagonist activity and an EC.sub.50 of 1.0-10.0 .mu.M in
the assay for .beta.-arrestin antagonist activity. For example,
compounds of the present invention have an EC.sub.50<0.1 .mu.M
in the assay for cAMP antagonist activity and an EC.sub.50 of
10.0-30.0 .mu.M in the assay for .beta.-arrestin antagonist
activity. For example, compounds of the present invention have an
EC.sub.50<0.1 .mu.M in the assay for cAMP antagonist activity
and an EC.sub.50.gtoreq.30.0 .mu.M in the assay for .beta.-arrestin
antagonist activity. Accordingly, compounds of the present
invention are useful in treating or preventing a disease or
disorder in which modulation of D2 receptors plays a role.
[0388] For example, compounds of the present invention have an
EC.sub.50 of 0.1-1.0 .mu.M in the assay for cAMP antagonist
activity and an EC.sub.50>1.0 .mu.M in the assay for
.beta.-arrestin antagonist activity. For example, compounds of the
present invention have an EC.sub.50 of 0.1-1.0 .mu.M in the assay
for cAMP antagonist activity and an EC.sub.50 of 1.0-10.0 .mu.M in
the assay for .beta.-arrestin antagonist activity. For example,
compounds of the present invention have an EC.sub.50 of 0.1-1.0
.mu.M in the assay for cAMP antagonist activity and an EC.sub.50 of
10.0-30.0 .mu.M in the assay for .beta.-arrestin antagonist
activity. For example, compounds of the present invention have an
EC.sub.50 of 0.1-1.0 .mu.M in the assay for cAMP antagonist
activity and an EC.sub.50.gtoreq.30.0 .mu.M in the assay for
.beta.-arrestin antagonist activity. Accordingly, compounds of the
present invention are useful in treating or preventing a disease or
disorder in which modulation of D2 receptors plays a role.
[0389] For example, compounds of the present invention have an
EC.sub.50 of 1.0-10.0 .mu.M in the assay for cAMP antagonist
activity and an EC.sub.50>10.0 .mu.M in the assay for
.beta.-arrestin antagonist activity. For example, compounds of the
present invention have an EC.sub.50 of of 1.0-10.0 .mu.M in the
assay for cAMP antagonist activity and an EC.sub.50 of 10.0-30.0
.mu.M in the assay for .beta.-arrestin antagonist activity. For
example, compounds of the present invention have an EC.sub.50 of of
1.0-10.0 .mu.M in the assay for cAMP antagonist activity and an
EC.sub.50>30.0 .mu.M in the assay for .beta.-arrestin antagonist
activity. Accordingly, compounds of the present invention are
useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role.
[0390] For example, compounds of the present invention have an
EC.sub.50 of of 10.0-30.0 .mu.M in the assay for cAMP antagonist
activity and an EC.sub.50>30.0 .mu.M in the assay for
.beta.-arrestin antagonist activity. Accordingly, compounds of the
present invention are useful in treating or preventing a disease or
disorder in which modulation of D2 receptors plays a role.
[0391] For example, compounds of the present invention are
selective cAMP antagonists and .beta.-arrestin agonists. For
example, compounds of the present invention have an
EC.sub.50<0.1 .mu.M in the assay for cAMP antagonist activity
and an EC.sub.50<0.1 .mu.M in the assay for .beta.-arrestin
agonist activity. For example, compounds of the present invention
have an EC.sub.50<0.1 .mu.M in the assay for cAMP antagonist
activity and an EC.sub.50 of 0.1-1.0 .mu.M in the assay for
.beta.-arrestin agonist activity. For example, compounds of the
present invention have an EC.sub.50<0.1 .mu.M in the assay for
cAMP antagonist activity and an EC.sub.50 of 1.0-10.0 .mu.M in the
assay for .beta.-arrestin agonist activity. For example, compounds
of the present invention have an EC.sub.50<0.1 .mu.M in the
assay for cAMP antagonist activity and an EC.sub.50 of 10.0-30.0
.mu.M in the assay for .beta.-arrestin agonist activity.
Accordingly, compounds of the present invention are useful in
treating or preventing a disease or disorder in which modulation of
D2 receptors plays a role.
[0392] For example, compounds of the present invention have an
EC.sub.50 of 0.1-1.0 .mu.M in the assay for cAMP antagonist
activity and an EC.sub.50<0.1 .mu.M in the assay for
.beta.-arrestin agonist activity. For example, compounds of the
present invention have an EC.sub.50 of 0.1-1.0 .mu.M in the assay
for cAMP antagonist activity and an EC.sub.50 of 0.1-1.0 .mu.M in
the assay for .beta.-arrestin agonist activity. For example,
compounds of the present invention have an EC.sub.50 of 0.1-1.0
.mu.M in the assay for cAMP antagonist activity and an EC.sub.50 of
1.0-10.0 .mu.M in the assay for .beta.-arrestin agonist activity.
For example, compounds of the present invention have an EC.sub.50
of 0.1-1.0 .mu.M in the assay for cAMP antagonist activity and an
EC.sub.50 of 10.0-30.0 .mu.M in the assay for .beta.-arrestin
agonist activity. Accordingly, compounds of the present invention
are useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role.
[0393] For example, compounds of the present invention have an
EC.sub.50 of 1.0-10.0 .mu.M in the assay for cAMP antagonist
activity and an EC.sub.50<0.1 .mu.M in the assay for
.beta.-arrestin agonist activity. For example, compounds of the
present invention have an EC.sub.50 of 1.0-10.0 .mu.M in the assay
for cAMP antagonist activity and an EC.sub.50 of 0.1-1.0 .mu.M in
the assay for .beta.-arrestin agonist activity. For example,
compounds of the present invention have an EC.sub.50 of 1.0-10.0
.mu.M in the assay for cAMP antagonist activity and an EC.sub.50 of
1.0-10.0 .mu.M in the assay for .beta.-arrestin agonist activity.
For example, compounds of the present invention have an EC.sub.50
of 1.0-10.0 .mu.M in the assay for cAMP antagonist activity and an
EC.sub.50 of 10.0-30.0 .mu.M in the assay for .beta.-arrestin
agonist activity. Accordingly, compounds of the present invention
are useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role.
[0394] For example, compounds of the present invention have an
EC.sub.50 of 10.0-30.0 .mu.M in the assay for cAMP antagonist
activity and an EC.sub.50<0.1 .mu.M in the assay for
.beta.-arrestin agonist activity. For example, compounds of the
present invention have an EC.sub.50 of 10.0-30.0 .mu.M in the assay
for cAMP antagonist activity and an EC.sub.50 of 0.1-1.0 .mu.M in
the assay for .beta.-arrestin agonist activity. For example,
compounds of the present invention have an EC.sub.50 of 10.0-30.0
.mu.M in the assay for cAMP antagonist activity and an EC.sub.50 of
1.0-10.0 .mu.M in the assay for .beta.-arrestin agonist activity.
For example, compounds of the present invention have an EC.sub.50
of 10.0-30.0 .mu.M in the assay for cAMP antagonist activity and an
EC.sub.50 of 10.0-30.0 .mu.M in the assay for .beta.-arrestin
agonist activity. Accordingly, compounds of the present invention
are useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role.
[0395] For example, compounds of the present invention are
selective cAMP antagonists and agonists of cAMP and
.beta.-arrestin. Accordingly, compounds of the present invention
are useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role.
[0396] For example, compounds of the present invention are cAMP
antagonists and .beta.-arrestin antagonists. For example, compounds
of the present invention have an EC.sub.50<0.1 .mu.M in the
assay for cAMP antagonist activity and an EC.sub.50<0.1 .mu.M in
the assay for .beta.-arrestin antagonist activity. For example,
compounds of the present invention have an EC.sub.50<0.1 .mu.M
in the assay for cAMP antagonist activity and an EC.sub.50 of
0.1-1.0 .mu.M in the assay for .beta.-arrestin antagonist activity.
For example, compounds of the present invention have an EC.sub.50
of 0.1-1.0 .mu.M in the assay for cAMP antagonist activity and an
EC.sub.50 of 0.1-1.0 .mu.M in the assay for .beta.-arrestin
antagonist activity. For example, compounds of the present
invention have an EC.sub.50 of 0.1-1.0 .mu.M in the assay for cAMP
antagonist activity and an EC.sub.50 of 1.0-10.0 .mu.M in the assay
for .beta.-arrestin antagonist activity. For example, compounds of
the present invention have an EC.sub.50 of 1.0-10.0 .mu.M in the
assay for cAMP antagonist activity and an EC.sub.50 of 1.0-10.0
.mu.M in the assay for .beta.-arrestin antagonist activity. For
example, compounds of the present invention have an EC.sub.50 of of
1.0-10.0 .mu.M in the assay for cAMP antagonist activity and an
EC.sub.50 of 10.0-30.0 .mu.M in the assay for .beta.-arrestin
antagonist activity. For example, compounds of the present
invention have an EC.sub.50 of 10.0-30.0 .mu.M in the assay for
cAMP antagonist activity and an EC.sub.50 of 10.0-30.0 .mu.M in the
assay for .beta.-arrestin antagonist activity. Accordingly,
compounds of the present invention are useful in treating or
preventing a disease or disorder in which modulation of D2
receptors plays a role.
[0397] The present invention relates to novel compounds that
modulate dopamine D2 receptors. For example, compounds of the
present invention have an EC.sub.50<0.1 .mu.M in the assay for
cAMP agonist activity. For example, compounds of the present
invention have an EC.sub.50 of 0.1-1.0 .mu.M in the assay for cAMP
agonist activity. For example, compounds of the present invention
have an EC.sub.50 of 1.0-10.0 .mu.M in the assay for cAMP agonist
activity. For example, compounds of the present invention have an
EC.sub.50 of 10.0-30.0 .mu.M in the assay for cAMP agonist
activity. Accordingly, compounds of the present invention are
useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role.
[0398] For example, compounds of the present invention are
selective agonists of D2 receptors. For example, compounds of the
present invention are selective cAMP agonists, but not
.beta.-arrestin agonists. For example, compounds of the present
invention display at least 1.5-fold, 2-fold, 3-fold, 4-fold,
5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold,
30-fold, 40-fold, 50-fold, or 100-fold stronger cAMP agonist
activity than .beta.-arrestin agonist activity. For example,
compounds of the present invention display at least 1.5-fold,
2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold,
10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or 100-fold
decrease in EC.sub.50 for cAMP agonist activity than
.beta.-arrestin agonist activity.
[0399] For example, compounds of the present invention have an
EC.sub.50<0.1 .mu.M in the assay for cAMP agonist activity and
an EC.sub.50.gtoreq.0.1 .mu.M in the assay for .beta.-arrestin
agonist activity. For example, compounds of the present invention
have an EC.sub.50<0.1 .mu.M in the assay for cAMP agonist
activity and an EC.sub.50 of 0.1-1.0 .mu.M in the assay for
.beta.-arrestin agonist activity. For example, compounds of the
present invention have an EC.sub.50<0.1 .mu.M in the assay for
cAMP agonist activity and an EC.sub.50 of 1.0-10.0 .mu.M in the
assay for .beta.-arrestin agonist activity. For example, compounds
of the present invention have an EC.sub.50<0.1 .mu.M in the
assay for cAMP agonist activity and an EC.sub.50 of 10.0-30.0 .mu.M
in the assay for .beta.-arrestin agonist activity. For example,
compounds of the present invention have an EC.sub.50<0.1 .mu.M
in the assay for cAMP agonist activity and an EC.sub.50.gtoreq.30.0
.mu.M in the assay for .beta.-arrestin agonist activity.
Accordingly, compounds of the present invention are useful in
treating or preventing a disease or disorder in which modulation of
D2 receptors plays a role.
[0400] For example, compounds of the present invention have an
EC.sub.50 of 0.1-1.0 .mu.M in the assay for cAMP agonist activity
and an EC.sub.50>1.0 .mu.M in the assay for .beta.-arrestin
agonist activity. For example, compounds of the present invention
have an EC.sub.50 of 0.1-1.0 .mu.M in the assay for cAMP agonist
activity and an EC.sub.50 of 1.0-10.0 .mu.M in the assay for
.beta.-arrestin agonist activity. For example, compounds of the
present invention have an EC.sub.50 of 0.1-1.0 .mu.M in the assay
for cAMP agonist activity and an EC.sub.50 of 10.0-30.0 .mu.M in
the assay for .beta.-arrestin agonist activity. For example,
compounds of the present invention have an EC.sub.50 of 0.1-1.0
.mu.M in the assay for cAMP agonist activity and an
EC.sub.50.gtoreq.30.0 .mu.M in the assay for .beta.-arrestin
agonist activity. Accordingly, compounds of the present invention
are useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role.
[0401] For example, compounds of the present invention have an
EC.sub.50 of 1.0-10.0 .mu.M in the assay for cAMP agonist activity
and an EC.sub.50>10.0 .mu.M in the assay for .beta.-arrestin
agonist activity. For example, compounds of the present invention
have an EC.sub.50 of of 1.0-10.0 .mu.M in the assay for cAMP
agonist activity and an EC.sub.50 of 10.0-30.0 .mu.M in the assay
for .beta.-arrestin agonist activity. For example, compounds of the
present invention have an EC.sub.50 of of 1.0-10.0 .mu.M in the
assay for cAMP agonist activity and an EC.sub.50.gtoreq.30.0 .mu.M
in the assay for .beta.-arrestin agonist activity. Accordingly,
compounds of the present invention are useful in treating or
preventing a disease or disorder in which modulation of D2
receptors plays a role.
[0402] For example, compounds of the present invention have an
EC.sub.50 of of 10.0-30.0 .mu.M in the assay for cAMP agonist
activity and an EC.sub.50>30.0 .mu.M in the assay for
.beta.-arrestin agonist activity. Accordingly, compounds of the
present invention are useful in treating or preventing a disease or
disorder in which modulation of D2 receptors plays a role.
[0403] For example, compounds of the present invention are
selective cAMP agonists and .beta.-arrestin antagonists. For
example, compounds of the present invention have an
EC.sub.50<0.1 .mu.M in the assay for cAMP agonist activity and
an EC.sub.50<0.1 .mu.M in the assay for .beta.-arrestin
antagonist activity. For example, compounds of the present
invention have an EC.sub.50<0.1 .mu.M in the assay for cAMP
agonist activity and an EC.sub.50 of 0.1-1.0 .mu.M in the assay for
.beta.-arrestin antagonist activity. For example, compounds of the
present invention have an EC.sub.50<0.1 .mu.M in the assay for
cAMP agonist activity and an EC.sub.50 of 1.0-10.0 .mu.M in the
assay for .beta.-arrestin antagonist activity. For example,
compounds of the present invention have an EC.sub.50<0.1 .mu.M
in the assay for cAMP agonist activity and an EC.sub.50 of
10.0-30.0 .mu.M in the assay for .beta.-arrestin antagonist
activity. Accordingly, compounds of the present invention are
useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role, while at the same time,
can reduce the undesirable side effects associated with D2 receptor
activity (e.g., side effects arising from antagonizing the cAMP
pathway).
[0404] For example, compounds of the present invention have an
EC.sub.50 of 0.1-1.0 .mu.M in the assay for cAMP agonist activity
and an EC.sub.50<0.1 .mu.M in the assay for .beta.-arrestin
antagonist activity. For example, compounds of the present
invention have an EC.sub.50 of 0.1-1.0 .mu.M in the assay for cAMP
agonist activity and an EC.sub.50 of 0.1-1.0 .mu.M in the assay for
.beta.-arrestin antagonist activity. For example, compounds of the
present invention have an EC.sub.50 of 0.1-1.0 .mu.M in the assay
for cAMP agonist activity and an EC.sub.50 of 1.0-10.0 .mu.M in the
assay for .beta.-arrestin antagonist activity. For example,
compounds of the present invention have an EC.sub.50 of 0.1-1.0
.mu.M in the assay for cAMP agonist activity and an EC.sub.50 of
10.0-30.0 .mu.M in the assay for .beta.-arrestin antagonist
activity. Accordingly, compounds of the present invention are
useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role, while at the same time,
can reduce the undesirable side effects associated with D2 receptor
activity (e.g., side effects arising from antagonizing the cAMP
pathway).
[0405] For example, compounds of the present invention have an
EC.sub.50 of 1.0-10.0 .mu.M in the assay for cAMP agonist activity
and an EC.sub.50<0.1 .mu.M in the assay for .beta.-arrestin
antagonist activity. For example, compounds of the present
invention have an EC.sub.50 of 1.0-10.0 .mu.M in the assay for cAMP
agonist activity and an EC.sub.50 of 0.1-1.0 .mu.M in the assay for
.beta.-arrestin antagonist activity. For example, compounds of the
present invention have an EC.sub.50 of 1.0-10.0 .mu.M in the assay
for cAMP agonist activity and an EC.sub.50 of 1.0-10.0 .mu.M in the
assay for .beta.-arrestin antagonist activity. For example,
compounds of the present invention have an EC.sub.50 of 1.0-10.0
.mu.M in the assay for cAMP agonist activity and an EC.sub.50 of
10.0-30.0 .mu.M in the assay for .beta.-arrestin antagonist
activity. Accordingly, compounds of the present invention are
useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role, while at the same time,
can reduce the undesirable side effects associated with D2 receptor
activity (e.g., side effects arising from antagonizing the cAMP
pathway).
[0406] For example, compounds of the present invention have an
EC.sub.50 of 10.0-30.0 .mu.M in the assay for cAMP agonist activity
and an EC.sub.50<0.1 .mu.M in the assay for .beta.-arrestin
antagonist activity. For example, compounds of the present
invention have an EC.sub.50 of 10.0-30.0 .mu.M in the assay for
cAMP agonist activity and an EC.sub.50 of 0.1-1.0 .mu.M in the
assay for .beta.-arrestin antagonist activity. For example,
compounds of the present invention have an EC.sub.50 of 10.0-30.0
.mu.M in the assay for cAMP agonist activity and an EC.sub.50 of
1.0-10.0 .mu.M in the assay for .beta.-arrestin antagonist
activity. For example, compounds of the present invention have an
EC.sub.50 of 10.0-30.0 .mu.M in the assay for cAMP agonist activity
and an EC.sub.50 of 10.0-30.0 .mu.M in the assay for
.beta.-arrestin antagonist activity. Accordingly, compounds of the
present invention are useful in treating or preventing a disease or
disorder in which modulation of D2 receptors plays a role, while at
the same time, can reduce the undesirable side effects associated
with D2 receptor activity (e.g., side effects arising from
antagonizing the cAMP pathway).
[0407] For example, compounds of the present invention are
selective cAMP agonists and antagonists of cAMP and
.beta.-arrestin. Accordingly, compounds of the present invention
are useful in treating or preventing a disease or disorder in which
modulation of D2 receptors plays a role.
[0408] For example, compounds of the present invention are cAMP
agonists and .beta.-arrestin agonists. For example, compounds of
the present invention have an EC.sub.50<0.1 .mu.M in the assay
for cAMP agonist activity and an EC.sub.50<0.1 .mu.M in the
assay for .beta.-arrestin agonist activity. For example, compounds
of the present invention have an EC.sub.50<0.1 .mu.M in the
assay for cAMP agonist activity and an EC.sub.50 of 0.1-1.0 .mu.M
in the assay for .beta.-arrestin agonist activity. For example,
compounds of the present invention have an EC.sub.50 of 0.1-1.0
.mu.M in the assay for cAMP agonist activity and an EC.sub.50 of
0.1-1.0 .mu.M in the assay for .beta.-arrestin agonist activity.
For example, compounds of the present invention have an EC.sub.50
of 0.1-1.0 .mu.M in the assay for cAMP agonist activity and an
EC.sub.50 of 1.0-10.0 .mu.M in the assay for .beta.-arrestin
agonist activity. For example, compounds of the present invention
have an EC.sub.50 of 1.0-10.0 .mu.M in the assay for cAMP agonist
activity and an EC.sub.50 of 1.0-10.0 .mu.M in the assay for
.beta.-arrestin agonist activity. For example, compounds of the
present invention have an EC.sub.50 of of 1.0-10.0 .mu.M in the
assay for cAMP agonist activity and an EC.sub.50 of 10.0-30.0 .mu.M
in the assay for .beta.-arrestin agonist activity. For example,
compounds of the present invention have an EC.sub.50 of 10.0-30.0
.mu.M in the assay for cAMP agonist activity and an EC.sub.50 of
10.0-30.0 .mu.M in the assay for .beta.-arrestin agonist activity.
Accordingly, compounds of the present invention are useful in
treating or preventing a disease or disorder in which modulation of
D2 receptors plays a role.
TABLE-US-00002 TABLE 2 Abbreviations TFA: trifluoroacetic acid
HATU:
1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-h]pyridinium
3-oxid hexafluorophosphate,
N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-
ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide LAH:
lithium aluminium hydride DMP: Dess Martin periodinane [O]:
oxidation using suitable oxidants such as Dess Martin periodinane,
pyridinium chlorochromate, pyridinium dichromate, or oxidation
reagents used in Swern oxidation, Parikh-Doering oxidation,
Corey-Kim oxidation or Pfitzner-Moffatt oxidation Boc:
tert-butyloxycarbonyl Fmoc: 9-fluorenylmethoxycarbonyl
[0409] The terms "compounds of the invention", "compound of the
invention", "compounds of the present invention"and "compounds of
the present invention", and the like, unless the context indicates
otherwise, refer collectively to the novel compounds of any
formulae or specific compounds described herein, and their salts,
solvates, stereoisomers, tautomers, racemates, polymorphs and
hydrates.
[0410] When a range of values is listed, it is intended to
encompass each value and sub-range within the range. For example
"Cl-6 alkyl" is intended to encompass, C1, C2, C3, C4, C5, C6,
C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5,
C3-4, C4-6, C4-5, and C5-6 alkyl. For example "1-6" is intended to
encompass, 1, 2, 3, 4, 5, 6, 1-6, 1-5, 1-4, 1-3, 1-2, 2-6, 2-5,
2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, and 5-6.
[0411] As used herein, the term "halogen" refers to fluorine,
chlorine, bromine or iodine.
[0412] As used herein, the term "alkyl" refers to a radical of a
straight-chain or branched saturated hydrocarbon group having from
1 to 20 carbon atoms ("C1-20 alkyl"). In some embodiments, an alkyl
group has 1 to 10 carbon atoms ("C1-10 alkyl"). In some
embodiments, an alkyl group has 1 to 9 carbon atoms ("C1-9 alkyl").
In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-8
alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon
atoms ("C1-7 alkyl"). In some embodiments, an alkyl group has 1 to
6 carbon atoms ("C1-6 alkyl"). In some embodiments, an alkyl group
has 1 to 5 carbon atoms ("C1-5 alkyl"). In some embodiments, an
alkyl group has 1 to 4 carbon atoms ("C1-4 alkyl"). In some
embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-3 alkyl").
In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-2
alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C1
alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon
atoms ("C2-6 alkyl"). Examples of C1-6 alkyl groups include methyl
(C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4),
tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5),
3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl
(C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of
alkyl groups include n-heptyl (C7), n-octyl (C8) and the like.
Unless otherwise specified, each instance of an alkyl group is
independently optionally substituted, e.g., unsubstituted (an
"unsubstituted alkyl") or substituted (a "substituted alkyl") with
one or more substituents.
[0413] The term "substituted alkyl" refers to alkyl moieties having
substituents replacing one or more hydrogen atoms on one or more
carbons of the hydrocarbon backbone. Such substituents can include,
for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,
phosphonato, phosphinato, amino (including alkylamino,
dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino
(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and
ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,
thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,
sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,
alkylaryl, or an aromatic or heteroaromatic moiety. Cycloalkyls can
be further substituted, e.g., with the substituents described
above. An "alkylaryl" or an "aralkyl" moiety is an alkyl
substituted with an aryl (e.g., phenylmethyl (benzyl)).
[0414] The term "haloalkyl" is a substituted alkyl group, wherein
one or more of the hydrogen atoms are independently replaced by a
halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments,
the haloalkyl moiety has 1 to 8 carbon atoms ("C.sub.1-C.sub.8
haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 6
carbon atoms ("C.sub.1-C.sub.6haloalkyl"). In some embodiments, the
haloalkyl moiety has 1 to 4 carbon atoms ("C.sub.1-C.sub.4
haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 3
carbon atoms ("C.sub.1-C.sub.3 haloalkyl"). In some embodiments,
the haloalkyl moiety has 1 to 2 carbon atoms ("C.sub.1-C.sub.2
haloalkyl"). Examples of haloalkyl groups include --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3, --CF.sub.2CF.sub.3,
--CF.sub.2CF.sub.2CF.sub.3, --CCl.sub.3, --CFCl.sub.2,
--CF.sub.2Cl, and the like.
[0415] As used herein, the term "cyclic ring" or "cyclic group"
refers to a saturated or unsaturated carbocyclic ring, i.e., a ring
composed exclusively of carbon atoms, or to a saturated or
unsaturated heterocyclic ring, i.e., a carbocyclic ring wherein one
or more ring atoms are replaced with an heteroatom independently
selected from oxygen, nitrogen, and sulfur. Cyclic rings may
involve 3-10 atoms that form the ring. In some embodiments, the
cyclic rings involve 3-5 ring atoms, in other embodiments, the
cyclic rings involve 4-6 ring atoms, in yet other embodiments,
cyclic rings involve 5-7 ring atoms. The cyclic rings can be
monocyclic rings or fused systems that may include bicyclic rings,
for example, 5-5, 5-6, 6-5, 6-6 as well as spirocyclic systems such
as 4-4, 4-5, 4-6, 5-6 and 6-6. The cyclic ring may be further
substituted with substituents such as C1-C6 alkyl (linear,
branched, cyclic or heterocyclic): In some embodiments, cyclic
groups may include pseudo-cyclic groups comprising straight- or
branched substituted or subsubstituted alkyl groups, for example
C.sub.3-C.sub.10 alkyl groups.
[0416] As used herein, the term "cycloalkyl" refers to a saturated
or unsaturated cyclic monovalent hydrocarbon, containing one or two
rings and comprising 3-10 ring atoms, preferably 4-8 ring atoms,
and more preferably 5-6 ring carbon atoms. Examples of a cycloalkyl
useful in the context of the present invention are cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl,
preferably cyclopentyl and cyclohexyl, more preferably cyclohexyl.
Cycloalkyl also includes hydrocarbon spirocyclique groups.
[0417] As used herein, the term "heterocyclyl" refers to a
saturated or unsaturated cycloalkyl wherein one or more ring atoms
are replaced with an heteroatom independently selected from oxygen,
nitrogen, and sulfur. The term heterocyclyl also encompasses
partially hydrogenated and oxo derivatives of heteroaryl compounds.
Examples of a heterocyclyl useful in the context of the present
invention are pyrrolidinyl, tetrahydrofuranyl,
tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl,
tetrahydrothiopyranyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl,
isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, and
dithiolanyl.
[0418] As used herein, the term "bicyclic group" refers to a group
containing two cyclic groups, with 5-12 or 6-12 ring atoms,
optionally containing 1-3 heteroatoms independently selected from
nitrogen, oxygen or sulfur, said two cyclic groups being fused or
bridged or forming a spirocycle. Preferably, the two cyclic groups
are fused and one of the two cyclic groups is a phenyl while the
other is a cycloalkyl or heterocycloalkyl, wherein the phenyl,
cycloalkyl and heterocycloalkyl are optionally substituted.
Examples of a bicyclic group useful in the context of the present
invention are oxo-tetrahydroquinolinyl, benzodioxolyl,
difluorobenzodioxolyl and dihydroindenyl. Each cycle in the
bicyclic group can be independently aromatic, unsaturated,
partially saturated, or saturated.
[0419] As used herein, the term "spirocycle" refers to a bicyclic
compound wherein the two cyclic groups connect only through one
atom.
[0420] Further examples of bicyclic groups include bridged ring
systems such as bicycloalkanes and azabicycloalkanes although such
bridged ring systems are generally less preferred. By "bridged ring
systems" is meant ring systems in which two rings share more than
two atoms, see for example Advanced Organic Chemistry, by Jerry
March, 4th. Edition, Wiley Interscience, pages 131-133, 1992.
Examples of bridged ring systems include bicyclo[2.2.1]heptane,
aza-bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,
aza-bicyclo[2.2.2]octane, bicyclo[3.2.1]octane and
aza-bicyclo[3.2.1]octane. A particular example of a bridged ring
system is the 1-aza-bicyclo[2.2.2]octan-3-yl group.
[0421] As used herein, the term "aryl" refers to a polyunsaturated
aromatic carbocyclic group comprising one ring (i.e., phenyl) or
several fused rings (for example naphthyl) or several rings linked
via a covalent bond (for example biphenyl), which typically contain
5 to 12 and preferentially 6 to 10 carbon atoms, and wherein at
least one ring is aromatic. An aryl group described herein may be
monocyclic, bicyclic, or tricyclic. Examples of an aryl useful in
the context of the present invention are phenyl, naphtyl and
biphenyl, preferably phenyl.
[0422] As used herein, the term "heteroaryl" refers to an aryl
containing 1-4 ring heteroatoms independently selected from
nitrogen, oxygen, and sulphur. The nitrogen heteroatom may be
substituted or unsubstituted with substituents, for example with an
alkyl group and/or the nitrogen heteroatom may be derivatised to
form a salt or amine oxide. A heteroaryl group described herein may
be monocyclic, bicyclic, or tricyclic. Examples of a heteroaryl
useful in the context of the present invention are furyl, thienyl,
pyrrolyl, pyranyl, thiopyranyl, imidazolyl, pyrazolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, pyridyl, quinolinyl,
isoquinolinyl, indolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,
benzothiazolyl, benzisothiazolyl, benzoimidazolyl and
benzopyrazole, preferably pyridyl, quinolinyl, benzofuranyl,
benzoxazolyl and benzothiazolyl.
[0423] The terms "aryl" and "heteroaryl" include multicyclic aryl
and heteroaryl groups, e.g., tricyclic, bicyclic, e.g.,
naphthalene, benzoxazole, benzodioxazole, benzothiazole,
benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline,
isoquinoline, naphthridine, indole, benzofuran, purine, benzofuran,
deazapurine, and indolizine. In the case of multicyclic aromatic
rings, only one of the rings needs to be aromatic (e.g.,
2,3-dihydroindole), although all of the rings may be aromatic
(e.g., quinoline). The second ring can also be fused or
bridged.
[0424] The aryl or heteroaryl aromatic ring can be substituted at
one or more ring positions with such substituents as described
above, for example, alkyl, alkenyl, akynyl, halogen, hydroxyl,
alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl,
aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl,
arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl,
aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato,
phosphinato, amino (including alkylamino, dialkylamino, arylamino,
diarylamino and alkylarylamino), acylamino (including
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),
amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,
trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an
aromatic or heteroaromatic moiety. Aryl groups can also be fused or
bridged with alicyclic or heterocyclic rings, which are not
aromatic so as to form a multicyclic system (e.g., tetralin,
methylenedioxyphenyl).
[0425] As used herein, "carbocycle" or "carbocyclic ring" is
intended to include any stable monocyclic, bicyclic, or tricyclic
ring having the specified number of carbons, any of which may be
saturated, unsaturated, or aromatic. For example, a
C.sub.3-C.sub.14 carbocycle is intended to include a monocyclic,
bicyclic or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13 or 14 carbon atoms. Examples of carbocycles include, but are not
limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,
cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl,
cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl,
cyclooctadienyl, fluorenyl, phenyl, naphthyl, indanyl, adamantyl
and tetrahydronaphthyl. Bridged rings are also included in the
definition of carbocycle, including, for example,
[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane
and [2.2.2]bicyclooctane. A bridged ring occurs when one or more
carbon atoms link two non-adjacent carbon atoms. In one embodiment,
bridge rings are one or two carbon atoms. It is noted that a bridge
always converts a monocyclic ring into a tricyclic ring. When a
ring is bridged, the substituents recited for the ring may also be
present on the bridge. Fused (e.g., naphthyl, tetrahydronaphthyl)
and spiro rings are also included.
[0426] As used herein, "heterocycle" includes any ring structure
(saturated or partially unsaturated) which contains at least one
ring heteroatom (e.g., N, O or S). A heterocycle group described
herein may be monocyclic, bicyclic, or tricyclic. A heterocycle
group described herein may comprise only carbon and nitrogen atoms
in the heterocyclic ring system. A heterocycle group described
herein may comprise only carbon and oxygen atoms in the
heterocyclic ring system. Examples of heterocycles include, but are
not limited to, morpholine, pyrrolidine, tetrahydrothiophene,
piperidine, piperazine and tetrahydrofuran. Examples of
heterocyclic groups include, but are not limited to, acridinyl,
azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,
benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,
benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,
benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl,
chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran,
furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl,
3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl,
isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,
methylenedioxyphenyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
1,2,4-oxadiazol5(4H)-one, oxazolidinyl, oxazolyl, oxindolyl,
pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,
phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,
piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,
pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,
pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,
pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,
pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,
quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,
tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,
tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,
thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,
thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and
xanthenyl.
[0427] The term "x- to y-membered ring" (wherein x is an integer
selected from 3, 4, 5, 6, 7, and 8, preferably from 3, 4, and 5,
and more preferably from 3 and 4; and y is an integer selected from
4, 5, 6, 7, 8, 9, 10, 11, and 12, preferably from 5, 6, 7, 8, and
9, and 10) includes cyclic ring, cyclic group, carbocycle,
heterocycle, aryl, and heteroaryl, each having x- to y-number of
ring atoms, as defined herein.
[0428] The term "alkoxy" or "alkoxyl" includes substituted and
unsubstituted alkyl, alkenyl and alkynyl groups covalently linked
to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals
include, but are not limited to, methoxy, ethoxy, isopropyloxy,
propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy
groups include halogenated alkoxy groups. The alkoxy groups can be
substituted with groups such as alkenyl, alkynyl, halogen,
hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,
phosphonato, phosphinato, amino (including alkylamino,
dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties.
Examples of halogen substituted alkoxy groups include, but are not
limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
chloromethoxy, dichloromethoxy and trichloromethoxy.
[0429] The term "substituted", as used herein, means that any one
or more hydrogen atoms on the designated atom is replaced with a
selection from the indicated groups, provided that the designated
atom's normal valency is not exceeded, and that the substitution
results in a stable compound. When a substituent is keto (i.e.,
.dbd.O), then 2 hydrogen atoms on the atom are replaced. Keto
substituents are not present on aromatic moieties. Ring double
bonds, as used herein, are double bonds that are formed between two
adjacent ring atoms (e.g., C.dbd.C, C.dbd.N or N.dbd.N). "Stable
compound" and "stable structure" are meant to indicate a compound
that is sufficiently robust to survive isolation to a useful degree
of purity from a reaction mixture, and formulation into an
efficacious therapeutic agent.
[0430] When a bond to a substituent is shown to cross a bond
connecting two atoms in a ring, then such substituent may be bonded
to any atom in the ring. When a substituent is listed without
indicating the atom via which such substituent is bonded to the
rest of the compound of a given formula, then such substituent may
be bonded via any atom in such formula. Combinations of
substituents and/or variables are permissible, but only if such
combinations result in stable compounds.
[0431] When any variable (e.g., R.sub.1) occurs more than one time
in any constituent or formula for a compound, its definition at
each occurrence is independent of its definition at every other
occurrence. Thus, for example, if a group is shown to be
substituted with 0-2 R.sub.1 moieties, then the group may
optionally be substituted with up to two R.sub.1 moieties and
R.sub.1 at each occurrence is selected independently from the
definition of R.sub.1. Also, combinations of substituents and/or
variables are permissible, but only if such combinations result in
stable compounds.
[0432] Except as described herein, any of the above defined alkyl,
cycloalkyl, aryl, heteroaryl, carbocycle, heterocycle, and alkoxy,
may be unsubstituted or independently substituted with up to six,
preferably one, two or three substituents, selected from the group
consisting of: halo (such as F, Cl or Br); hydroxy; lower alkyl
(such as C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.3 alkyl), wherein the
lower alkyl may be substituted with any of the substituents defined
herein; lower alkanoyl; lower alkoxy (such as methoxy); aryl (such
as phenyl or naphthyl); substituted aryl (such as fluoro phenyl or
methoxy phenyl); aryl lower alkyl such as benzyl; amino; mono or
di-lower alkyl amino (such as dimethylamino); lower alkanoyl amino
acetylamino; amino lower alkoxy (such as ethoxyamine); nitro;
cyano; cyano lower alkyl; carboxy; lower carbalkoxy (such as
methoxy carbonyl; n-propoxy carbonyl or iso-propoxy carbonyl);
lower aryloyl, such as benzoyl; carbamoyl; N-mono- or N,N di-lower
alkyl carbamoyl; lower alkyl carbamic acid ester; amidino;
guanidine; ureido; mercapto; sulfo; lower alkylthio; sulfoamino;
sulfonamide; benzosulfonamide; sulfonate; sulfanyl lower alkyl
(such as methyl sulfanyl); sulfoamino; aryl sulfonamide; halogen
substituted or unsubstituted aryl sulfonate (such as chloro-phenyl
sulfonate); lower alkylsulfinyl; arylsulfinyl; aryl-lower
alkylsulfinyl; lower alkylarylsulfinyl; lower alkanesulfonyl;
arylsulfonyl; aryl-lower alkylsulfonyl; lower aryl alkyl; lower
alkylarylsulfonyl; halogen-lower alkylmercapto; halogen-lower
alkylsulfonyl; such as trifluoromethane sulfonyl;
phosphono(--P(.dbd.O)(OH).sub.2); hydroxy-lower alkoxy phosphoryl
or di-lower alkoxyphosphoryl; urea and substituted urea; and alkyl
carbamic acid ester or carbamates (such as
ethyl-N-phenyl-carbamate).
[0433] The compounds of the present invention are capable of
further forming salts. All of these forms are also contemplated
within the scope of the claimed invention.
[0434] As used herein, a salt of the compound of the invention
refers to derivatives of the compounds of the present invention
wherein the parent compound is modified by making acid or base
salts thereof. Examples of salts include, but are not limited to,
mineral or organic acid salts of basic residues such as amines,
alkali or organic salts of acidic residues such as carboxylic
acids, and the like. The salts include the conventional non-toxic
salts or the quaternary ammonium salts of the parent compound
formed, for example, from non-toxic inorganic or organic acids. For
example, such conventional non-toxic salts include, but are not
limited to, those derived from inorganic and organic acids selected
from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic,
benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic,
ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic,
gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic,
hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic,
hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic,
maleic, malic, mandelic, methane sulfonic, napsylic, nitric,
oxalic, pamoic, pantothenic, phenylacetic, phosphoric,
polygalacturonic, propionic, salicyclic, stearic, subacetic,
succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene
sulfonic, and the commonly occurring amine acids, e.g., glycine,
alanine, phenylalanine, arginine, etc.
[0435] Other examples of salts of the compounds of the invention
include salts with the following acid: hexanoic acid, cyclopentane
propionic acid, pyruvic acid, malonic acid,
3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid,
3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, muconic acid, and the like. The present invention also
encompasses salts formed when an acidic proton present in the
parent compound either is replaced by a metal ion, e.g., an alkali
metal ion, an alkaline earth ion, or an aluminum ion; or
coordinates with an organic base such as ethanolamine,
diethanolamine, triethanolamine, tromethamine, N-methylglucamine,
and the like.
[0436] The free base of the compounds of the present invention can
be protonated at the N atom(s) of an amine and/or N containing
heterocycle moiety to form a salt. The term "free base" refers to
the amine compounds in non-salt form. The free form of the specific
salt compounds described may be isolated using techniques known in
the art. For example, the free form may be regenerated by treating
the salt with a suitable dilute aqueous base solution such as
dilute aqueous sodium hydroxide, potassium carbonate, ammonia and
sodium bicarbonate. The free forms may differ from their respective
salt forms somewhat in certain physical properties, such as
solubility in polar solvents, but the acid and base salts are
otherwise pharmaceutically equivalent to their respective free
forms for purposes of the invention.
[0437] The salts can be synthesized from the compounds of the
invention which contain basic moieties by conventional chemical
methods. Generally, the salts of the basic compounds are prepared
either by ion exchange chromatography or by reacting the free base
with stoichiometric amounts or with an excess of the desired
salt-forming inorganic or organic acid in a suitable solvent or
various combinations of solvents.
[0438] The salts of the instant invention can be prepared from
compounds of the invention by reacting with an inorganic, organic
acid or polymeric acid. For example, conventional non-toxic salts
include those derived from acids such as hydrochloric acid,
toluenesulfonic acid, sulfuric acid, benzenesulfonic acid, fumaric
acid or succinic acid, especially toluenesulfonic acid, pamoic acid
(see for example, WO2005/016261; U.S. Pat. No. 6,987,111; US
20050032836; US 20060040922).
[0439] Compounds of the present invention that contain nitrogens
can be converted to N-oxides by treatment with an oxidizing agent
(e.g., 3-chloroperoxybenzoic acid (m-CPBA) and/or hydrogen
peroxides) to afford other compounds of the present invention.
Thus, all shown and claimed nitrogen-containing compounds are
considered, when allowed by valency and structure, to include both
the compound as shown and its N-oxide derivative (which can be
designated as N.fwdarw.O or N.sup.+-O.sup.-). Furthermore, in other
instances, the nitrogens in the compounds of the present invention
can be converted to N-hydroxy or N-alkoxy compounds. For example,
N-hydroxy compounds can be prepared by oxidation of the parent
amine by an oxidizing agent such as m-CPBA. All shown and claimed
nitrogen-containing compounds are also considered, when allowed by
valency and structure, to cover both the compound as shown and its
N-hydroxy (i.e., N--OH) and N-alkoxy (i.e., N--OR, wherein R is
substituted or unsubstituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkenyl, C.sub.1-C.sub.6 alkynyl, 3-14-membered carbocycle or
3-14-membered heterocycle) derivatives.
[0440] In the present specification, the structural formula of the
compound represents a certain isomer for convenience in some cases,
but the present invention includes all isomers, such as geometrical
isomers, optical isomers based on an asymmetrical carbon,
stereoisomers, tautomers, and the like. In addition, a crystal
polymorphism may be present for the compounds represented by the
formula. It is noted that any crystal form, crystal form mixture,
or anhydride or hydrate thereof is included in the scope of the
present invention. Furthermore, so-called metabolite which is
produced by degradation of the present compound in vivo is included
in the scope of the present invention.
[0441] "Isomerism" means compounds that have identical molecular
formulae but differ in the sequence of bonding of their atoms or in
the arrangement of their atoms in space. Isomers that differ in the
arrangement of their atoms in space are termed "stereoisomers".
Stereoisomers that are not mirror images of one another are termed
"diastereoisomers", and stereoisomers that are non-superimposable
mirror images of each other are termed "enantiomers" or sometimes
optical isomers. A mixture containing equal amounts of individual
enantiomeric forms of opposite chirality is termed a "racemic
mixture".
[0442] A carbon atom bonded to four nonidentical substituents is
termed a "chiral center".
[0443] "Chiral isomer" means a compound with at least one chiral
center. Compounds with more than one chiral center may exist either
as an individual diastereomer or as a mixture of diastereomers,
termed "diastereomeric mixture". When one chiral center is present,
a stereoisomer may be characterized by the absolute configuration
(R or S) of that chiral center. Absolute configuration refers to
the arrangement in space of the substituents attached to the chiral
center. The substituents attached to the chiral center under
consideration are ranked in accordance with the Sequence Rule of
Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.
1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413;
Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al.,
Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).
[0444] "Geometric isomer" means the diastereomers that owe their
existence to hindered rotation about double bonds. These
configurations are differentiated in their names by the prefixes
cis and trans, or Z and E, which indicate that the groups are on
the same or opposite side of the double bond in the molecule
according to the Cahn-Ingold-Prelog rules.
[0445] Furthermore, the structures and other compounds discussed in
this invention include all atropic isomers thereof. "Atropic
isomers" are a type of stereoisomer in which the atoms of two
isomers are arranged differently in space. Atropic isomers owe
their existence to a restricted rotation caused by hindrance of
rotation of large groups about a central bond. Such atropic isomers
typically exist as a mixture, however as a result of recent
advances in chromatography techniques; it has been possible to
separate mixtures of two atropic isomers in select cases.
[0446] "Tautomer" is one of two or more structural isomers that
exist in equilibrium and is readily converted from one isomeric
form to another. This conversion results in the formal migration of
a hydrogen atom accompanied by a switch of adjacent conjugated
double bonds. Tautomers exist as a mixture of a tautomeric set in
solution. In solid form, usually one tautomer predominates. In
solutions where tautomerization is possible, a chemical equilibrium
of the tautomers will be reached. The exact ratio of the tautomers
depends on several factors, including temperature, solvent and pH.
The concept of tautomers that are interconvertable by
tautomerizations is called tautomerism.
[0447] Of the various types of tautomerism that are possible, two
are commonly observed. In keto-enol tautomerism a simultaneous
shift of electrons and a hydrogen atom occurs. Ring-chain
tautomerism arises as a result of the aldehyde group (--CHO) in a
sugar chain molecule reacting with one of the hydroxy groups (--OH)
in the same molecule to give it a cyclic (ring-shaped) form as
exhibited by glucose. Common tautomeric pairs are: ketone-enol,
amide-nitrile, lactam-lactim, amide-imidic acid tautomerism in
heterocyclic rings (e.g., in nucleobases such as guanine, thymine
and cytosine), amine-enamine and enamine-enamine.
[0448] It is to be understood that the compounds of the present
invention may be depicted as different tautomers. It should also be
understood that when compounds have tautomeric forms, all
tautomeric forms are intended to be included in the scope of the
present invention, and the naming of the compounds does not exclude
any tautomer form.
[0449] The term "crystal polymorphs", "polymorphs" or "crystal
forms" means crystal structures in which a compound (or a salt or
solvate thereof) can crystallize in different crystal packing
arrangements, all of which have the same elemental composition.
Different crystal forms usually have different X-ray diffraction
patterns, infrared spectral, melting points, density hardness,
crystal shape, optical and electrical properties, stability and
solubility. Recrystallization solvent, rate of crystallization,
storage temperature, and other factors may cause one crystal form
to dominate. Crystal polymorphs of the compounds can be prepared by
crystallization under different conditions.
[0450] Additionally, the compounds of the present invention, for
example, the salts of the compounds, can exist in either hydrated
or unhydrated (the anhydrous) form or as solvates with other
solvent molecules. Nonlimiting examples of hydrates include
monohydrates, dihydrates, etc. Nonlimiting examples of solvates
include ethanol solvates, acetone solvates, etc.
[0451] "Solvate" means solvent addition forms that contain either
stoichiometric or non stoichiometric amounts of solvent. Some
compounds have a tendency to trap a fixed molar ratio of solvent
molecules in the crystalline solid state, thus forming a solvate.
If the solvent is water the solvate formed is a hydrate; and if the
solvent is alcohol, the solvate formed is an alcoholate. Hydrates
are formed by the combination of one or more molecules of water
with one molecule of the substance in which the water retains its
molecular state as H.sub.2O.
[0452] The present invention is intended to include all isotopes of
atoms occurring in the present compounds. Isotopes include those
atoms having the same atomic number but different mass numbers. By
way of general example and without limitation, isotopes of hydrogen
include tritium and deuterium, and isotopes of carbon include C-13
and C-14.
[0453] A prodrug may be a pharmacologically inactive derivative of
a biologically active substance (the "parent drug" or "parent
molecule") that requires transformation within the body in order to
release the active drug, and that has improved delivery properties
over the parent drug molecule. The transformation in vivo may be,
for example, as the result of some metabolic process, such as
chemical or enzymatic hydrolysis of a carboxylic, phosphoric or
sulphate ester, or reduction or oxidation of a susceptible
functionality.
[0454] The compounds of the present invention can also be prepared
as prodrugs, for example, pharmaceutically acceptable prodrugs. The
terms "pro-drug" and "prodrug" are used interchangeably herein and
refer to any compound which releases an active parent drug in vivo.
Since prodrugs are known to enhance numerous desirable qualities of
pharmaceuticals (e.g., solubility, bioavailability, manufacturing,
etc.), the compounds of the present invention can be delivered in
prodrug form. Thus, the present invention is intended to cover
prodrugs of the presently claimed compounds, methods of delivering
the same and compositions containing the same. "Prodrugs" are
intended to include any covalently bonded carriers that release an
active parent drug of the present invention in vivo when such
prodrug is administered to a subject. Prodrugs in the present
invention are prepared by modifying functional groups present in
the compound in such a way that the modifications are cleaved,
either in routine manipulation or in vivo, to the parent compound.
Prodrugs include compounds of the present invention wherein a
hydroxy, amino, sulfhydryl, carboxy or carbonyl group is bonded to
any group that may be cleaved in vivo to form a free hydroxyl, free
amino, free sulfhydryl, free carboxy or free carbonyl group,
respectively.
[0455] Examples of prodrugs include, but are not limited to, esters
(e.g., acetate, dialkylaminoacetates, formates, phosphates,
sulfates and benzoate derivatives) and carbamates (e.g.,
N,N-dimethylaminocarbonyl) of hydroxy functional groups, esters
(e.g., ethyl esters, morpholinoethanol esters) of carboxyl
functional groups, N-acyl derivatives (e.g., N-acetyl) N-Mannich
bases, Schiff bases and enaminones of amino functional groups,
oximes, acetals, ketals and enol esters of ketone and aldehyde
functional groups in compounds of the invention, and the like, See
Bundegaard, H., Design of Prodrugs, p1-92, Elesevier, New
York-Oxford (1985).
[0456] As used herein, the term "combination", as applied to two or
more compounds and/or agents (also referred to herein as the
components), is intended to define material in which the two or
more compounds/agents are associated. The terms "combined" and
"combining" in this context are to be interpreted accordingly.
[0457] As used herein, the term "in combination" may refer to
compounds/agents that are administered as part of the same overall
treatment regimen. As such, the posology of each of the two or more
compounds/agents may differ: each may be administered at the same
time or at different times. It will therefore be appreciated that
the compounds/agents of the combination may be administered
sequentially (e.g., before or after) or simultaneously, either in
the same pharmaceutical formulation (i.e., together), or in
different pharmaceutical formulations (i.e., separately).
Simultaneously in the same formulation is as a unitary formulation
whereas simultaneously in different pharmaceutical formulations is
non-unitary. The posologies of each of the two or more
compounds/agents in a combination therapy may also differ with
respect to the route of administration.
[0458] The term "drug" or "active substance" as used herein
includes the free base, or pharmaceutically acceptable salts,
solvates, stereoisomers, racemates, tautomers, polymorphs and
hydrates thereof, or mixtures thereof.
[0459] As used herein, the term "selective" when used to describe
.beta.-arrestin antagonist, .beta.-arrestin agonist, cAMP
antagonist, or cAMP agonist means "biased" .beta.-arrestin
antagonist, .beta.-arrestin agonist, cAMP antagonist, or cAMP
agonist, unless the specific circumstances dictate otherwise (i.e.,
"selective" and "biased" are used interchangeably). The term
"selective" or "biased" means that a compound preferentially binds
to or otherwise interacts with one of .beta.-arrestin and cAMP over
the other. For example, the compound binds to or otherwise
interacts with one of .beta.-arrestin and cAMP with an EC.sub.50
that is lower that the EC.sub.50 for the other, such as described
herein.
Synthesis of the Compounds of the Invention
[0460] The present invention provides methods for the synthesis of
the compounds of each of the formulae described herein. The present
invention also provides detailed methods for the synthesis of
various disclosed compounds of the present invention according to
the following schemes and examples.
[0461] Throughout the description, where compositions are described
as having, including, or comprising specific components, it is
contemplated that compositions also consist essentially of, or
consist of, the recited components. Similarly, where methods or
processes are described as having, including, or comprising
specific process steps, the processes also consist essentially of,
or consist of, the recited processing steps. Further, it should be
understood that the order of steps or order for performing certain
actions is immaterial so long as the invention remains operable.
Moreover, two or more steps or actions can be conducted
simultaneously.
[0462] The synthetic processes of the invention can tolerate a wide
variety of functional groups, therefore various substituted
starting materials can be used. The processes generally provide the
desired final compound at or near the end of the overall process,
although it may be desirable in certain instances to further
convert the compound to a pharmaceutically acceptable salt, ester
or prodrug thereof.
[0463] Compounds of the present invention can be prepared in a
variety of ways using commercially available starting materials,
compounds known in the literature, or from readily prepared
intermediates, by employing standard synthetic methods and
procedures either known to those skilled in the art, or which will
be apparent to the skilled artisan in light of the teachings
herein. Standard synthetic methods and procedures for the
preparation of organic molecules and functional group
transformations and manipulations can be obtained from the relevant
scientific literature or from standard textbooks in the field.
Although not limited to any one or several sources, classic texts
such as Smith, M. B., March, J., March's Advanced
[0464] Organic Chemistry: Reactions, Mechanisms, and Structure,
5.sup.th edition, John Wiley & Sons: New York, 2001; and
Greene, T. W., Wuts, P. G. M., Protective Groups in Organic
Synthesis, 3.sup.rd edition, John Wiley & Sons: New York, 1999,
incorporated by reference herein, are useful and recognized
reference textbooks of organic synthesis known to those in the art.
The following descriptions of synthetic methods are designed to
illustrate, but not to limit, general procedures for the
preparation of compounds of the present invention.
[0465] Compounds of the present invention can be conveniently
prepared by a variety of methods familiar to those skilled in the
art. The compounds each of the formulae described herein may be
prepared according to the following procedures from commercially
available starting materials or starting materials which can be
prepared using literature procedures. These procedures show the
preparation of representative compounds of the invention.
[0466] All the abbreviations used in this application are found in
"Protective Groups in Organic Synthesis" by John Wiley & Sons,
Inc, or the MERCK INDEX by MERCK & Co., Inc, or other chemistry
books or chemicals catalogs by chemicals vendor such as Aldrich, or
according to usage know in the art.
[0467] A general synthetic scheme is presented in Scheme 1
below.
##STR00024##
[0468] Scheme 1 illustrates a general synthetic route, using
piperidine-4-carboxylic acid as a starting material. The piperidine
nitrogen is first protected with labile protecting groups known in
the art, such as Boc or Fmoc (representative protecting groups and
deprotecting reagents can be found, for example, in Greene and
Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley
& Sons, New York, 1991, Encyclopedia of Reagents for Organic
Synthesis (Ed: L. Paquette) 2004, J. Wiley & Sons, New York).
Compounds of the present invention may be synthesized by coupling
of suitable amides at the 4-carboxylic acid moiety of the
piperidine ring (referred to herein as the northern end of the
piperidine ring), as well as extending the molecule by alkylation
at the piperidine nitrogen (referred to herein as the southern end
of the piperidine ring). The synthesis may involve coupling first
at the northern end of the piperidine ring, followed by alkylation
at the southern end of the piperdine ring (route BA), or alkylation
at the southern end of the piperidine ring first, followed by
coupling at the northern end of the piperidine ring (route AB), as
depicted in Scheme 1.
[0469] Examples of suitable building blocks or synthons A and B,
for use respectively, in alkylation at the southern end and
coupling at the northern end of the piperidine ring are also
depicted in Scheme 1. Depending on the specific substituents, one
skilled in the art would know that the Grignard reagent used in the
synthesis of synthon B may be prepared using either Cy.sup.1MgBr or
Cy.sup.2MgBr, to couple with the corresponding aldehyde or ketone,
to form the corresponding alcohol that contains both Cy.sup.1 and
Cy.sup.2. Methods of alkylation to form synthon A and Grignard
coupling, followed by oxidative amination to form synthon B are
well-known in the art of organic synthesis.
[0470] The amino compounds synthesized by route AB may be further
derivatised at the amino group, for example, with alkylating agents
to form the corresponding N-alkylated compound, as depicted in
Scheme 1.
[0471] An exemplary synthetic route for the synthesis of compounds
of the present invention is further illustrated in Scheme 1A.
##STR00025## ##STR00026##
Assays for Activities of the Compounds of the Invention
[0472] The present invention provides methods for assessing the in
vitro and in vivo biological activities (e.g., antagonistic or
agonistic activities) of the compounds of the invention. Biological
activities (e.g., antagonistic or agonistic activities) of the
compounds of the present invention can be tested in a variety of
ways using commercially available materials, reagents known in the
literature or readily prepared, by employing routine methods and
procedures either known to those skilled in the art, or which will
be apparent to the skilled artisan in light of the teachings
herein. Theses methods and procedures can be obtained from the
relevant scientific literature or from standard textbooks in the
field. The following descriptions of assays are designed to
illustrate, but not to limit, general procedures for evaluating the
activities of compounds of the present invention.
[0473] A general description of the assays is presented below.
Preparation of Cells for Biological Assays
[0474] Cells are prepared for assays by growing cultures for the
requisite period of time (e.g., up to 2 weeks). Frozen cells are
thawed, and then transferred into growth media. If necessary, the
cells can be gently centrifuged and then resuspended in growth
media. When the cells reached the necessary confluence (e.g.,
.about.95%), the cells are passaged and used for various biological
assays, such as those described herein below.
.beta.-Arrestin Agonist Assay
[0475] The assays can be performed using proper detection reagents
either prepared using routine methods known in the art or
commercially available (e.g., PathHunter.RTM. .beta.-Arrestin
Detecting Kit (DiscoveR.sub.X)). Cells are grown to the necessary
confluence and then detached. The cells are then centrifuged,
washed, resuspended, and seeded into a container (e.g., 384-well
plate). The cells are incubated (e.g., at 37.degree. C., 5%
CO.sub.2) for the appropriate period of time (e.g., 24 hours),
before various compounds (e.g., a compound of the invention or a
control compound) are added to the cells. After incubation of the
cells with the compounds, detection reagents (e.g., a buffer
containing Emerald II: Galactor-Star as provided DiscoveR.sub.X)
are added to the cells. The read-out (e.g., luminescence, or
fluorescence) is detected using standard equipment.
.beta.-Arrestin Antagonist Assay
[0476] The assays can be conducted in the same manner as the
.beta.-arrestin agonist assay, except that before addition of the
detection reagents, a D2 receptor agonist (e.g., Quinpirole) is
added to the cells. The detection reagents are then added, and the
read-out is detected.
Gi/cAMP Agonist Assay
[0477] The assays can be performed using proper detection reagents
either prepared using routine methods known in the art or
commercially available (e.g., PE Lance Ultra cAMP kit (TRF0263)).
Cells are grown to the necessary confluence and then detached. The
cells are then centrifuged, washed, resuspended, and seeded into a
container (e.g., 384-well plate). The cells are incubated (e.g., at
37.degree. C., 5% CO.sub.2) for the appropriate period of time
(e.g., 24 hours), before various compounds (e.g., a compound of the
invention or a control compound) are added to the cells.
Afterwards, cAMP inducing agents (e.g., Forskolin) are added to and
incubated with the cells before detection reagents (e.g., a cAMP
antibody, such as ULight-anti-cAMP solution) are added to the
cells. Read-out (e.g., luminescence, or fluorescence) is detected
using standard equipment.
Gi/cAMP Antagonist Assay
[0478] The assays can be conducted in the same manner as the
Gi/cAMP agonist assay, except that before addition of the detection
reagents, a D2 receptor agonist (e.g., Quinpirole) is added to the
cells. The detection reagents are then added, and the read-out is
detected.
Pharmacokinetic Studies on Mice Brains
[0479] Test animals are administered (e.g., intraperitoneally,
intravenously, orally) with a dose of test compounds (e.g.,
compounds of the invention). Blood samples are collected and plasma
is harvested from the blood. Brain tissues are also isolated and
homogenized. Concentrations of the test compounds administered in
the plasma and brain samples are determined using routine analytic
methods, such as LC-MS/MS.
Positron Emission Tomography Studies on Rodents
[0480] Non-radiolabeled test compounds (e.g., vehicle, compounds of
the invention, control compounds) are administered to the test
animal, followed by administration of a radiotracer (e.g., carbon
11-labeled raclopride ([.sup.11C]RAC), which can be synthesized
from the O-desmethyl RAC precursor and [11C] methyl iodide and
subsequently purified by high-performance liquid chromatography as
previously described (Farde L, et al. (1985) PNAS, USA
82(11):3863-3867)). Positron emission tomography (PET) and skeletal
computed tomography (CT) data are collected using standard
equipment, such as a GammaMedica Triumph trimodal PET/SPECT/CT
scanner (Quebec, Canada) or a Concorde Microsystems R4 microPET
scanner (Knoxville, Tenn., USA). Routine data processing is
employed, including substraction of random coincidences collected
in a delayed time window, and reconstruction of scatter-corrected
sinograms using a known algorithm (e.g., 3-dimensional iterative
maximum likelihood expectation maximization (3D-MLEM) algorithm).
Regions of Interest (ROIs) are drawn on reconstructed images
estimating peak [.sup.11C]RAC uptake in striata (averaged between
left and right hemispheres) and cerebellum as reference region for
non-displaceable (ND) tracer uptake. ROI dimensions, placement and
striatal D2/D3 binding potential (BP.sub.ND) are evaluated by
graphical analysis (e.g., using Logan distribution volume ratio
(DVR) linearization as previously described (BP.sub.ND.=DVR-1;
Alexoff D, et al. (2002) JNucMed 44(5): 815-822; Logan J, et al.
(1996) JCerebral Blood Flow and Metabolism 16(5):843-840)).
Amphetamine Induced Hyperactivity Studies
[0481] Amphetamine-induced hyperactivity (AIH) can be examined
using routine behavior methods, such as in open-field chambers.
Activity is detected by various methods, such as infrared beam.
Daily sessions are binned for statistical analysis. AIH can be run
over various time frames, according to the need of the study, such
as as follows:
[0482] Day 1: test animals are acclimated to the injection
procedure by injecting prior to being placed in the chambers. Test
animals are then placed into the open-field a certain time period
(e.g., 20 min) and then removed for a saline injection. Test
animals are placed back into the open-field for an additional
period of time (e.g., 30 min), at which point the test animals are
returned to their home cage.
[0483] Day 2: repeat Day 1, with the exception that the timing may
be different (e.g., the second day may last for one hour (20
minutes injection 40 minutes)).
[0484] Day 3: test animals are challenged by amphetamine. Test
animals are pre-treated with D2 antagonist compounds (e.g.,
compounds of the invention) prior to being placed in the open
field. After a certain period of time, test animals are removed and
challenged with amphetamine, following protocols known to one
skilled in the art, for example Jones C. A, et. al. Br J Pharmacol.
2011, 164(4):1162-1194; Pan J Q, et. al. Neuropsychopharmacology.
2011, 36(7):1397-1411.
Rotarod Performance
[0485] In the test, test animals are placed on a horizontally
oriented, rotating cylinder (rod) suspended above a cage floor. The
test animals naturally try to stay on the rotating cylinder, or
rotarod, and avoid falling to the ground. Test animals are
administered with various compounds (e.g., compounds of the
invention or control compounds). The length of time that a given
animal stays on this rotating rod is a measure of the animal's
balance, coordination, physical condition, and motor-planning. The
speed of the rotarod is mechanically driven, and can be held
constant.
Pharmaceutical Compositions
[0486] The present invention also provides a pharmaceutical
composition comprising a compound of any formulae or selected from
any compounds described herein, and at least one pharmaceutically
acceptable excipient or carrier.
[0487] The term "pharmaceutical composition" is defined herein as
comprising an effective amount of at least one active substance
(e.g., compounds of the present invention), and at least one
pharmaceutically acceptable carrier or excipient, in a form
suitable for administration to a subject. In one embodiment, the
pharmaceutical composition is in bulk or in unit dosage form. The
unit dosage form is any of a variety of forms, including, for
example, a capsule, an IV bag, a tablet, a single pump on an
aerosol inhaler or a vial. The quantity of active ingredient (e.g.,
a formulation of the disclosed compound or salt, hydrate, solvate
or isomer thereof) in a unit dose of composition is an effective
amount and is varied according to the particular treatment
involved. One skilled in the art will appreciate that it is
sometimes necessary to make routine variations to the dosage
depending on the age and condition of the patient. The dosage will
also depend on the route of administration. A variety of routes are
contemplated, including oral, parenteral, topical, intranasal,
ophthalmic, otic, rectal, transdermal, and transmucosal, and the
like. Dosage forms for the topical or transdermal administration of
a compound of the invention include powders, sprays, ointments,
pastes, creams, lotions, gels, solutions, patches and inhalants. In
one embodiment, the active compound is mixed under sterile
conditions with a pharmaceutically acceptable carrier, and with any
preservatives, buffers or propellants that are required.
[0488] The term "pharmaceutically acceptable" as used herein
pertains to compounds, materials, compositions, and/or dosage forms
which are, within the scope of sound medical judgment, suitable for
use in contact with the tissues of a subject (e.g., human) without
excessive toxicity, irritation, allergic response, or other problem
or complication, commensurate with a reasonable benefit/risk ratio.
Each carrier, excipient, etc. must also be "acceptable" in the
sense of being compatible with the other ingredients of the
formulation.
[0489] The term "pharmaceutically acceptable carrier or excipient"
refers to a carrier medium which does not interfere with the
effectiveness of the biological activity of the active compound(s)
and which is not excessively toxic to the host at the concentration
at which it is administered. The term includes solvents, dispersion
media, coatings, isotonic agents, adsorption delaying agents, and
the like. The use of such media and agents for pharmaceutically
active substances is well known in the art (see for example ", E.
W. Martin, 18.sup.th Ed., 1990, Mack Publishing Co. Easton, Pa.,
which is incorporated herein by reference in its entirety). In
certain embodiments, the pharmaceutically acceptable carrier or
excipient is a veterinary acceptable carrier or excipient.
[0490] The term "therapeutically effective amount" or "effective
amount", as used herein, refers to an amount of a pharmaceutical
agent to treat, ameliorate, or prevent an identified disease or
condition, or to exhibit a detectable therapeutic or inhibitory
effect. The effect can be detected by any assay method known in the
art. The precise effective amount for a subject will depend upon
the subject's body weight, size, and health; the nature and extent
of the condition; and the therapeutic or combination of
therapeutics selected for administration. Therapeutically effective
amounts for a given situation can be determined by routine
experimentation that is within the skill and judgment of the
clinician.
[0491] For any compound, the therapeutically effective amount can
be estimated initially either in cell culture assays, or in animal
models, usually rats, mice, rabbits, dogs, or pigs. The animal
model may also be used to determine the appropriate concentration
range and route of administration. Such information can then be
used to determine useful doses and routes for administration in
humans. Therapeutic/prophylactic efficacy and toxicity may be
determined by standard pharmaceutical procedures in cell cultures
or experimental animals, e.g., ED.sub.50 (the dose therapeutically
effective in 50% of the population) and LD.sub.50 (the dose lethal
to 50% of the population). The dose ratio between toxic and
therapeutic effects is the therapeutic index, and it can be
expressed as the ratio, LD.sub.50/ED.sub.50. Pharmaceutical
compositions that exhibit large therapeutic indices are preferred.
The dosage may vary within this range depending upon the dosage
form employed, sensitivity of the patient, and the route of
administration.
[0492] Dosage and administration are adjusted to provide sufficient
levels of the active agent(s) or to maintain the desired effect.
Factors which may be taken into account include the severity of the
disease state, general health of the subject, age, weight, and
gender of the subject, diet, time and frequency of administration,
drug combination(s), reaction sensitivities, and tolerance/response
to therapy. Long-acting pharmaceutical compositions may be
administered every 3 to 4 days, every week, or once every two weeks
depending on half-life and clearance rate of the particular
formulation.
[0493] The compounds may be in fine particulate form, freeze-dried
as a powder formulation (see for example, CA 2837693;
WO2009/017250; US 20100196486), in a low hygroscopic form (see for
example, U.S. Pat. Nos. 7,910,589, 8,017,615, 8,399,469, 8,580,796,
8,642,760; US 20040058935), or liquid or gel formulations (see for
example, US 20130209552; US 20130171237; WO2012/058091).
[0494] Any suitable pharmaceutically acceptable excipient can be
added to the compositions of the invention. Excipients may be added
for numerous reasons, for example to facilitate manufacture,
enhance stability, control release, enhance product
characteristics, enhance bioavailability, enhance patient
acceptability and combinations thereof. Examples of
pharmaceutically acceptable excipients include diluents, vehicles,
binders, disintegrants, glidants, compression aids, colouring
agents, organoleptic ingredients such as flavoring agents or
sweeteners, suspending agents, dispersing agents, film formers,
printing inks, lubricants, preservatives, fillers, buffers,
stabilisers, or other materials well known to those skilled in the
art. These excipients may be used in a conventional manner, and
alone or in any combination.
[0495] Exemplary binders, which may be used to help to hold the
dosage form together, include polyvinyl pyrrolidone, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, methylcellulose,
hydroxyethyl cellulose, sugars, and combinations thereof.
Disintegrants (such as croscarmellose sodium) expand when wet
causing a tablet to break apart. Lubricants typically aid in the
processing of powder materials. Exemplary lubricants include
calcium stearate, glycerol behenate, magnesium stearate, mineral
oil, polyethylene glycol, sodium stearylfumarate, stearic acid,
talc, vegetable oil, zinc stearate, and combinations thereof An
example of a glidant is silicon dioxide.
[0496] The formulations described herein may contain a filler, such
as a water insoluble or water soluble filler, or combinations
thereof. Typical water insoluble fillers include silicon dioxide,
titanium dioxide, talc, aluinina, starch, kaolin, polacrilin
potassiuin, powdered cellulose, microcrystalline cellulose, and
combinations thereof. Typical water-soluble fillers include water
soluble sugars and sugar alcohols, preferably lactose, glucose,
fructose, sucrose, mannose, dextrose, galactose, the corresponding
sugar alcohols and other sugar alcohols, such as mannitol,
sorbitol, xylitol, and combinations thereof.
[0497] The present invention further provides pharmaceutical
compositions, as defined above, and methods of making a
pharmaceutical composition comprising admixing such as blending,
filling, granulation and compressing, at least one active compound,
as defined above, together with one or more pharmaceutically
acceptable carriers or excipients, as described herein. The
compositions of the invention can be prepared for example by Direct
compression and wet granulation. These and other methods are
described and/or exemplified in more detail herein.
[0498] The pharmaceutical compositions can be in any form suitable
for administration via various routes, including but not limited
to, oral, parenteral, topical, intranasal, ophthalmic, otic,
rectal, transdermal, and transmucosal. Where the compositions are
intended for parenteral administration, they can be formulated for
intravenous, intramuscular, intraperitoneal, or subcutaneous
administration or for direct delivery into a target organ or tissue
by injection, infusion or other means of delivery. The delivery can
be by bolus injection, short term infusion or longer term infusion
and can be via passive delivery or through the utilisation of a
suitable infusion pump.
[0499] Pharmaceutical formulations adapted for parenteral
administration include aqueous and non-aqueous sterile solutions
which may contain a sterile diluent such as water, saline solution,
fixed oils, polyethylene glycols, glycerine, propylene glycol or
other synthetic solvents; anti-oxidants such as ascorbic acid or
sodium bisulfite; buffers such as acetates, citrates or phosphates;
bacteriostats such as benzyl alcohol or methyl parabens;
co-solvents; organic solvent mixtures; chelating agents such as
ethylenediaminetetraacetic acid; agents for the adjustment of
tonicity such as sodium chloride or dextrose; cyclodextrin
complexation agents; emulsifying agents (for forming and
stabilizing emulsion formulations); liposome components for forming
liposomes; gellable polymers for forming polymeric gels;
lyophilisation protectants; and combinations of agents for, inter
alia, stabilising the active ingredient in a soluble form and
rendering the formulation isotonic with the blood of the intended
recipient. Pharmaceutical formulations for parenteral
administration may also take the form of aqueous and non-aqueous
sterile suspensions which may include suspending agents and
thickening agents (R. G. Strickly, Solubilizing Excipients in oral
and injectable formulations, Pharmaceutical Research, Vol 21(2)
2004, p 201-230). Pharmaceutical formulations for parenteral
administration may also be provided in finely divided sterile
powder form for making up extemporaneously with sterile water for
injection.
[0500] A drug molecule that is ionizable can be solubilized to the
desired concentration by pH adjustment if the drug's pK.sub.a is
sufficiently away from the formulation pH value. The acceptable
range is pH 2-12 for intravenous and intramuscular administration,
but subcutaneously the range is pH 2.7-9.0. The solution pH is
controlled by either the salt form of the drug, strong acids/bases
such as hydrochloric acid or sodium hydroxide, or by solutions of
buffers which include but are not limited to buffering solutions
formed from glycine, citrate, acetate, maleate, succinate,
histidine, phosphate, tris(hydroxymethyl)-aminomethane (TRIS), or
carbonate.
[0501] The combination of an aqueous solution and a water-soluble
organic solvent/surfactant (i.e., a cosolvent) is often used in
injectable formulations. The water-soluble organic solvents and
surfactants used in injectable formulations include but are not
limited to propylene glycol, ethanol, polyethylene glycol 300,
polyethylene glycol 400, glycerin, dimethylacetamide (DMA),
N-methyl-2-pyrrolidone (NMP; Pharmasolve), dimethylsulphoxide
(DMSO), Solutol HS15, Cremophor EL, Cremophor RH 60, and
polysorbate 80. Such formulations can usually be, but are not
always, diluted prior to injection.
[0502] Propylene glycol, PEG 300, ethanol, Cremophor EL, Cremophor
RH 60, and polysorbate 80 are the entirely organic water-miscible
solvents and surfactants used in commercially available injectable
formulations and can be used in combinations with each other. The
resulting organic formulations are usually diluted at least 2-fold
prior to IV bolus or IV infusion.
[0503] Alternatively increased water solubility can be achieved
through molecular complexation with cyclodextrins.
[0504] Liposomes are closed spherical vesicles composed of outer
lipid bilayer membranes and an inner aqueous core and with an
overall diameter of <100 .mu.m. Depending on the level of
hydrophobicity, moderately hydrophobic drugs can be solubilized by
liposomes if the drug becomes encapsulated or intercalated within
the liposome. Hydrophobic drugs can also be solubilized by
liposomes if the drug molecule becomes an integral part of the
lipid bilayer membrane, and in this case, the hydrophobic drug is
dissolved in the lipid portion of the lipid bilayer. A typical
liposome formulation contains water with phospholipid at 5-20
mg/ml, an isotonicifier, a pH 5-8 buffer, and optionally
cholesterol.
[0505] The formulations may be presented in unit-dose or multi-dose
containers, for example sealed ampoules, vials and disposable
syringes, and may be stored in a freeze-dried (lyophilised)
condition requiring only the addition of the sterile liquid
carrier, for example water for injections, immediately prior to
use.
[0506] The pharmaceutical formulation can be prepared by
lyophilising a compound of the invention or acid addition salt
thereof. Lyophilisation refers to the procedure of freeze-drying a
composition. Freeze-drying and lyophilisation are therefore used
herein as synonyms. A typical process is to solubilise the compound
and the resulting formulation is clarified, sterile filtered and
aseptically transferred to containers appropriate for
lyophilisation (e.g., vials). In the case of vials, they are
partially stoppered with lyo-stoppers. The formulation can be
cooled to freezing and subjected to lyophilisation under standard
conditions and then hermetically capped forming a stable, dry
lyophile formulation. The composition will typically have a low
residual water content, e.g., less than 5%, e.g., less than 1% by
weight based on weight of the lyophile.
[0507] The lyophilisation formulation may contain other excipients
for example, thickening agents, dispersing agents, buffers,
antioxidants, preservatives, and tonicity adjusters. Typical
buffers include phosphate, acetate, citrate and glycine. Examples
of antioxidants include ascorbic acid, sodium bisulphite, sodium
metabisulphite, monothioglycerol, thiourea, butylated
hydroxytoluene, butylated hydroxyl anisole, and
ethylenediaminetetraacetic acid salts. Preservatives may include
benzoic acid and its salts, sorbic acid and its salts, alkyl esters
of para-hydroxybenzoic acid, phenol, chlorobutanol, benzyl alcohol,
thimerosal, benzalkonium chloride and cetylpyridinium chloride. The
buffers mentioned previously, as well as dextrose and sodium
chloride, can be used for tonicity adjustment if necessary. Bulking
agents are generally used in lyophilisation technology for
facilitating the process and/or providing bulk and/or mechanical
integrity to the lyophilized cake. Bulking agent means a freely
water soluble, solid particulate diluent that when co-lyophilised
with the compound or salt thereof, provides a physically stable
lyophilized cake, a more optimal freeze-drying process and rapid
and complete reconstitution. The bulking agent may also be utilised
to make the solution isotonic.
[0508] The water-soluble bulking agent can be any of the
pharmaceutically acceptable inert solid materials typically used
for lyophilisation. Such bulking agents include, for example,
sugars such as glucose, maltose, sucrose, and lactose; polyalcohols
such as sorbitol or mannitol; amino acids such as glycine; polymers
such as polyvinylpyrrolidine; and polysaccharides such as
dextran.
[0509] The ratio of the weight of the bulking agent to the weight
of active compound is typically within the range from about 1 to
about 5, for example of about 1 to about 3, e.g., in the range of
about 1 to 2.
[0510] Alternatively they can be provided in a solution form which
may be concentrated and sealed in a suitable vial. Sterilisation of
dosage forms may be via filtration or by autoclaving of the vials
and their contents at appropriate stages of the formulation
process. The supplied formulation may require further dilution or
preparation before delivery for example dilution into suitable
sterile infusion packs.
[0511] Extemporaneous injection solutions and suspensions may be
prepared from sterile powders, granules and tablets.
[0512] In one preferred embodiment of the invention, the
pharmaceutical composition is in a form suitable for intravenous
administration, for example by injection or infusion. In another
preferred embodiment, the pharmaceutical composition is in a form
suitable for subcutaneous (s.c.) administration.
[0513] The compounds may be in the form of a solid or solution, or
modified so as to be suitable for oral administration (see for
example, U.S. Pat. Nos. 7,655,798, 8,093,387, 8,529,949; US
20020193438, WO2006/097344). Suitable formulated may also include
wet granulation pharmaceutical compositions (see for example, US
20070154544; WO2007/081366), inclusion complexes, for example with
cyclodextrin (see for example, U.S. Pat. Nos. 7,115,587, 7,550,445;
WO2004/017897), formulated with microspheres (see for example, US
20090043898; WO2009/00169) or formulated as a patch for transdermal
delivery (see for example, US 20130171237; US 20130209552;
WO2012/058091). Compounds of the present invention may also be
formulated to have extended-release profiles, see for example, U.S.
Pat. Nos. 8,338,427, 8,338,428; WO2005/016262, WO2013/133448).
[0514] Pharmaceutical compositions containing a compound of the
invention can be formulated in accordance with known techniques,
e.g., by means of conventional mixing, dissolving, granulating,
dragee-making, levigating, emulsifying, encapsulating, entrapping,
or lyophilizing processes, see for example, Remington's
Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., USA.
Pharmaceutical compositions may be formulated in a conventional
manner using one or more pharmaceutically acceptable carriers
comprising excipients and/or auxiliaries that facilitate processing
of the active compounds into preparations that can be used
pharmaceutically. Of course, the appropriate formulation is
dependent upon the route of administration chosen.
[0515] Pharmaceutical dosage forms suitable for oral administration
include tablets, capsules, caplets, pills, lozenges, syrups,
solutions, powders, granules, elixirs and suspensions, sublingual
tablets, wafers or patches and buccal patches.
[0516] Tablet compositions can contain a unit dosage of active
compound together with an inert diluent or carrier such as a sugar
or sugar alcohol, e.g., lactose, sucrose, sorbitol or mannitol;
and/or a non-sugar derived diluent such as sodium carbonate,
calcium phosphate, calcium carbonate, or a cellulose or derivative
thereof such as methyl cellulose, ethyl cellulose, hydroxypropyl
methyl cellulose, and starches such as corn starch. Tablets may
also contain such standard ingredients as binding and granulating
agents such as polyvinylpyrrolidone, disintegrants (e.g., swellable
crosslinked polymers such as crosslinked carboxymethylcellulose),
lubricating agents (e.g., stearates), preservatives (e.g.,
parabens), antioxidants (e.g., BHT), buffering agents (for example
phosphate or citrate buffers), and effervescent agents such as
citrate/bicarbonate mixtures. Such excipients are well known and do
not need to be discussed in detail here.
[0517] Capsule formulations may be of the hard gelatin or soft
gelatin variety and can contain the active component in solid,
semi-solid, or liquid form. Gelatin capsules can be formed from
animal gelatin or synthetic or plant derived equivalents
thereof.
[0518] The solid dosage forms (tablets, capsules etc.) can be
coated or un-coated, but typically have a coating, for example a
protective film coating (e.g., a wax or varnish) or a release
controlling coating. The coating (e.g., a Eudragit.TM. type
polymer) can be designed to release the active component at a
desired location within the gastro-intestinal tract. Thus, the
coating can be selected so as to degrade under certain pH
conditions within the gastrointestinal tract, thereby selectively
release the compound in the stomach or in the ileum or duodenum.
Alternatively or additionally, the coating can be used as a taste
masking agent to mask unpleasant tastes such as bitter tasting
drugs. The coating may contain sugar or other agents that assist in
masking unpleasant tastes.
[0519] Instead of, or in addition to, a coating, the drug can be
presented in a solid matrix comprising a release controlling agent,
for example a release delaying agent which may be adapted to
selectively release the compound under conditions of varying
acidity or alkalinity in the gastrointestinal tract. Alternatively,
the matrix material or release retarding coating can take the form
of an erodible polymer (e.g., a maleic anhydride polymer) which is
substantially continuously eroded as the dosage form passes through
the gastrointestinal tract. As a further alternative, the active
compound can be formulated in a delivery system that provides
osmotic control of the release of the compound. Osmotic release and
other delayed release or sustained release formulations may be
prepared in accordance with methods well known to those skilled in
the art.
[0520] Compositions for topical use include ointments, creams,
sprays, patches, gels, liquid drops and inserts (for example
intraocular inserts). Such compositions can be formulated in
accordance with known methods.
[0521] Further examples of topical compositions include dressings
such as bandages and adhesive plasters impregnated with active
ingredients and optionally one or more excipients or diluents.
Carriers which may be used include e.g., polyhydric alcohols such
as polyethylene glycols, propylene glycol or glycerol. Suitable
excipients are those known in the art to be appropriate.
[0522] Examples of formulations for rectal or intra-vaginal
administration include pessaries and suppositories which may be,
for example, formed from a shaped mouldable or waxy material
containing the active compound. Thus, unit-dose suppositories or
pessaries may be prepared by admixture of the active ingredient
with one or more conventional solid carriers, for example coca
butter, and shaping the resulting mixture. Further examples of
mouldable waxy materials include polymers such as high molecular
weight polyalkylene glycols, e.g., high molecular weight
polyethylene glycols. Alternatively, in the case of vaginal
administration, the formulation may be presented as a tampon
impregnated with the active ingredients and optionally one or more
excipients or diluents. Other formulations suitable for rectal and
vaginal administration include creams, gels, foams, pastes and
sprays.
[0523] Compositions for administration by inhalation may take the
form of inhalable powder compositions or liquid or powder sprays,
and can be administrated in standard form using powder inhaler
devices or aerosol dispensing devices. Such devices are well known.
For administration by inhalation, the powdered formulations
typically comprise the active compound together with an inert solid
powdered diluent such as lactose. The compounds are delivered in
the form of an aerosol spray from pressured container or dispenser,
which contains a suitable propellant, e.g., a gas such as carbon
dioxide, or a nebulizer.
[0524] For transmucosal or transdermal administration, penetrants
appropriate to the barrier to be permeated are used in the
formulation. Such penetrants are generally known in the art, and
include, for example, for transmucosal administration, detergents,
bile salts, and fusidic acid derivatives. Transmucosal
administration can be accomplished through the use of nasal sprays
or suppositories. For transdermal administration, the active
compounds are formulated into ointments, salves, gels, or creams as
generally known in the art.
[0525] It is advantageous to formulate oral or parenteral
compositions in dosage unit form for ease of administration and
uniformity of dosage. Dosage unit form as used herein refers to
physically discrete units suited as unitary dosages for the subject
to be treated; each unit containing a predetermined quantity of
active compound calculated to produce the desired therapeutic
effect in association with the required pharmaceutical carrier. The
specification for the dosage unit forms of the invention are
dictated by and directly dependent on the unique characteristics of
the active compound and the particular therapeutic effect to be
achieved.
[0526] The pharmaceutical formulations can be included in a
container, pack, or dispenser together with instructions for
administration. The pharmaceutical formulations may be presented to
a patient in "patient packs" containing an entire course of
treatment in a single package, usually a blister pack. Patient
packs have an advantage over traditional prescriptions, where a
pharmacist divides a patient's supply of a pharmaceutical from a
bulk supply, in that the patient always has access to the package
insert contained in the patient pack, normally missing in patient
prescriptions. The inclusion of a package insert has been shown to
improve patient compliance with the physician's instructions.
[0527] The invention also provides a pharmaceutical composition
comprising one or more compounds of the present invention and a
pharmaceutically acceptable carrier or excipient, in combination
with another pharmaceutically active substance selected from a
lithium compound selected from lithium carbonate, lithium citrate,
lithium orotate, lithium bromide or lithium chloride; valproate; a
serotonin reuptake inhibitor selected from fluoxetine, venlafaxine,
citalopram, paroxetine, sertraline, indalpine, zimelidine,
dapoxetine, fluvoxamine, tianeptine, duloxetine or escitalopram;
chlorpromazine, droperidol, fluphenazine, haloperidol, loxapine,
molindone, perphenazine, pimozide, prochlorperazine, thiothixene,
thioridazine, trifluoperazine, levomepromazine, aripiprazole,
asenapine, clozapine, iloperidone, lurasidone, olanzapine,
paliperidone, quetiapine, risperidone, ziprasidone, amisulpride,
blonanserin, clotiapine, mosapramine, perospirone, sertindole,
sulpiride; caffeine, a caffeine derivative, nicotine, a nicotine
derivative, phencyclidine, quinpirole, salvinorin a, apomorphine,
bromocriptine, cabergoline, ciladopa, dihydrexidine, dinapsoline,
doxanthrine, epicriptine, lisuride, pergolide, piribedil,
pramipexole, propylnorapomorphine, quinagolide, ropinirole,
rotigotine, roxindole, sumanirole; other compounds with interact
with dopamine D2 receptor selected from amisulpride, nemomapride,
nemoxipride, eticlopride, reclopride, talipexole, roxindole,
bifeprunox, aplindore, mesoridazine, haloperidol, thixathene,
flupenthixol, butyrophenone, perclamol [(-) 3-PPP], saritozan,
olanzapine, dopanmine, quinpirole, bromocriptine; anti-depressants
selected from agomelatine, amitriptyline, amoxapine, clomipramine,
desipramine, dosulepine hydrochloride, doxepine, imipramine,
maprotiline, a mixture of nortriptyline and fluphenazine,
opipramol, quinupramine, trimipramine, a mixture of melitracene and
flupentixol, pranipexole.
[0528] The invention also provides a kit comprising (i) one or more
compounds of the present invention, (ii) an additional compound
selected from a lithium compound selected from lithium carbonate,
lithium citrate, lithium orotate, lithium bromide or lithium
chloride; valproate; a serotonin reuptake inhibitor selected from
fluoxetine, venlafaxine, citalopram, paroxetine, sertraline,
indalpine, zimelidine, dapoxetine, fluvoxamine, tianeptine,
duloxetine or escitalopram; Chlorpromazine, Droperidol,
Fluphenazine, Haloperidol, Loxapine, Molindone, Perphenazine,
Pimozide, Prochlorperazine, Thiothixene, Thioridazine,
Trifluoperazine, Levomepromazine, Aripiprazole, Asenapine,
Clozapine, Iloperidone, Lurasidone, Olanzapine, Paliperidone,
Quetiapine, Risperidone, Ziprasidone, Amisulpride, Blonanserin,
Clotiapine, Mosapramine, Perospirone, Sertindole, Sulpiride;
caffeine, a caffeine derivative, nicotine, a nicotine derivative,
Phencyclidine, Quinpirole, Salvinorin A, Apomorphine,
Bromocriptine, Cabergoline, Ciladopa, Dihydrexidine, Dinapsoline,
Doxanthrine, Epicriptine, Lisuride, Pergolide, Piribedil,
Pramipexole, Propylnorapomorphine, Quinagolide, Ropinirole,
Rotigotine, Roxindole, Sumanirole; other compounds with interact
with dopamine D2 receptor selected from Amisulpride, nemomapride,
nemoxipride, eticlopride, reclopride, talipexole, roxindole,
bifeprunox, aplindore, mesoridazine, haloperidol, thixathene,
flupenthixol, butyrophenone, perclamol [(-) 3-PPP], saritozan,
olanzapine, dopanmine, quinpirole, bromocriptine; other
anti-depressants selected from Agomelatine, amitriptyline,
amoxapine, clomipramine, desipramine, dosulepine hydrochloride,
doxepine, imipramine, maprotiline, a mixture of nortriptyline and
fluphenazine, opipramol, quinupramine, trimipramine, a mixture of
melitracene and flupentixol, pranipexole, and (iii) instructions
for administration of (i) and (ii). The association of the two or
more compounds/agents in a combination may be physical or
non-physical. Examples of physically associated combined
compounds/agents include: compositions (e.g., unitary formulations)
comprising the two or more compounds/agents in a mixture (for
example within the same unit dose); compositions comprising
material in which the two or more compounds/agents are
chemically/physicochemically linked (for example by crosslinking,
molecular agglomeration or binding to a common vehicle moiety);
compositions comprising material in which the two or more
compounds/agents are chemically/physicochemically co-packaged (for
example, disposed on or within lipid vesicles, particles (e.g.,
micro- or nanoparticles) or emulsion droplets); pharmaceutical
kits, pharmaceutical packs or patient packs in which the two or
more compounds/agents are co-packaged or co-presented (e.g., as
part of an array of unit doses);
[0529] Examples of non-physically associated combined
compounds/agents include: material (e.g., a non-unitary
formulation) comprising at least one of the two or more
compounds/agents together with instructions for the extemporaneous
association of the at least one compound to form a physical
association of the two or more compounds/agents; material (e.g., a
non-unitary formulation) comprising at least one of the two or more
compounds/agents together with instructions for combination therapy
with the two or more compounds/agents; material comprising at least
one of the two or more compounds/agents together with instructions
for administration to a patient population in which the other(s) of
the two or more compounds/agents have been (or are being)
administered; material comprising at least one of the two or more
compounds/agents in an amount or in a form which is specifically
adapted for use in combination with the other(s) of the two or more
compounds/agents.
[0530] As used herein, the term "pharmaceutical pack" defines an
array of one or more unit doses of a pharmaceutical composition,
optionally contained within common outer packaging. In
pharmaceutical packs comprising a combination of two or more
compounds/agents, the individual compounds/agents may be unitary or
non-unitary formulations. The unit dose(s) may be contained within
a blister pack. The pharmaceutical pack may optionally further
comprise instructions for use.
[0531] As used herein, the term "pharmaceutical kit" or "kit"
defines an array of one or more unit doses of a pharmaceutical
composition together with dosing means (e.g., measuring device)
and/or delivery means (e.g., inhaler or syringe), optionally all
contained within common outer packaging. In pharmaceutical kits
comprising a combination of two or more compounds/agents, the
individual compounds/agents may be unitary or non-unitary
formulations. The unit dose(s) may be contained within a blister
pack. The pharmaceutical kit may optionally further comprise
instructions for use.
[0532] As used herein, the term "patient pack" defines a package,
prescribed to a patient, which contains pharmaceutical compositions
for the whole course of treatment. Patient packs usually contain
one or more blister pack(s). Patient packs have an advantage over
traditional prescriptions, where a pharmacist divides a patient's
supply of a pharmaceutical from a bulk supply, in that the patient
always has access to the package insert contained in the patient
pack, normally missing in patient prescriptions. The inclusion of a
package insert has been shown to improve patient compliance with
the physician's instructions.
[0533] The term "stable" as used herein, refers to dosage form
which is physically, or polymorphically stable. The dosage form
according to present invention may remain physically stable, that
is there are no substantial changes with respect to physical
attributes like colour etc. The dosage form according to present
invention may remain polymorphically stable that is the polymorph
(crystalline or amorphous) in the dosage form does not rearranges
into another form upon storage.
Method of Use
[0534] The term "patient" refers to a warm-blood animal, preferably
a human being, i.e., a subject of both genders and at any stage
development (i.e., neonate, infant, juvenile, adolescent, adult).
The invention is particularly directed to adolescents and adults.
Some embodiments, in particular concerning regulation of
galactorrhea, are specifically directed to female.
[0535] As used herein, "treating" or "treat" describes the
management and care of a patient for the purpose of combating a
disease, condition, or disorder and includes the administration of
a compound of the present invention, or a pharmaceutically
acceptable salt, prodrug, metabolite, polymorph or solvate thereof,
to alleviate the symptoms or complications of a disease, condition
or disorder, or to eliminate the disease, condition or
disorder.
[0536] As used herein, "preventing" or "prevent" describes reducing
or eliminating the onset of the symptoms or complications of the
disease, condition or disorder.
[0537] As used herein, the term "alleviate" is meant to describe a
process by which the severity of a sign or symptom of a disorder is
decreased. Importantly, a sign or symptom can be alleviated without
being eliminated. In a preferred embodiment, the administration of
pharmaceutical compositions of the invention leads to the
elimination of a sign or symptom, however, elimination is not
required. Effective dosages are expected to decrease the severity
of a sign or symptom. For instance, a sign or symptom of a disorder
such as cancer, which can occur in multiple locations, is
alleviated if the severity of the cancer is decreased within at
least one of multiple locations.
[0538] As used herein, the term "modulation", as applied to the
activity of the dopamine activity at D2 receptors, is intended to
define a change in the level of biological activity of the
dopaminergic activity. Thus, modulation encompasses physiological
changes which effect an increase or decrease in the dopaminergic
activity. In the latter case, the modulation may be described as
"inhibition". The modulation may arise directly or indirectly, and
may be mediated by any mechanism and at any physiological level,
including for example at the level of gene expression (including
for example transcription, translation and/or post-translational
modification), at the level of expression of genes encoding
regulatory elements which act directly or indirectly on the levels
of dopaminergic activity. Thus, modulation may imply
elevated/suppressed expression or over- or under-expression of
dopaminergic activity, including gene amplification (i.e., multiple
gene copies) and/or increased or decreased expression by a
transcriptional effect, as well as hyper- (or hypo-) activity and
(de)activation of dopaminergic activity (including (de)activation)
by mutation(s). The terms "modulated", "modulating" and "modulate"
are to be interpreted accordingly.
[0539] The present invention provides a method of modulating D2
receptor activity by administering one or more compounds of the
present invention to a subject. The active compound will be
administered to a subject in need thereof (for example a human or
animal patient) in an amount sufficient to achieve the desired
therapeutic effect.
[0540] The present invention also provides use of one or more
compounds of the present invention as a .beta.-arrestin biased D2
receptor agonist or antagonist. The present invention also provides
use of one or more compounds of the present invention as a biased
cAMP agonist or antagonist.
[0541] The present invention provides a method of treating or
preventing a disease or disorder, comprising administering a
compound of the invention, wherein modulation of the D2 receptors
(e.g., .beta.-arrestin or Gi/cAMP) plays a role in the disease or
disorder (iniation, development, etc.). In one embodiment, the
disease or disorder is a nervous system disease or disorder in
which modulation of D2 receptors (e.g., .beta.-arrestin or Gi/cAMP)
plays a role. The nervous system disorder is selected from an
anxiety disorder (e.g., phobias, generalized anxiety disorder,
social anxiety disorder, panic disorder, agoraphobia,
obsessive-compulsive disorder, and post-traumatic stress disorder),
a dissociative disorder (e.g., dissociative amnesia, dissociative
fugue, dissociative identity (multiple personality) disorder, and
depersonalization disorder), a mood disorder (e.g., depression,
dysthymia, bipolar disorder, mania, hypomania, and Cyclothymic
Disorder), an eating disorder (e.g., anorexia nervosa, bulimia
nervosa, exercise bulimia, and binge eating disorder), a sleep
disorder (insomnia, hypersomnia, narcolepsy, nightmare disorder,
sleep terror disorder, and sleepwalking), a developmental disorder
(e.g., autism spectrum disorders, oppositional defiant disorder and
conduct disorder, and attention deficit hyperactivity disorder), a
somatoform disorder (e.g., body dysmorphic disorder, conversion
disorder, hypochondriasis disorder, pain disorder, and somatization
disorder), a personality disorder (e.g., antisocial personality
disorder, borderline personality disorder, narcissistic personality
disorder), a psychiatric syndrome (e.g., Capgras syndrome, De
Clerambault syndrome, Othello syndrome, Ganser syndrome, Cotard
delusion, and Ekbom syndrome, and additional disorders such as the
Couvade syndrome and Geschwind syndrome), a psychotic disorder
(e.g., brief psychotic disorder, delusional disorder,
Schizoaffective disorder, Schizophrenia, Schizophreniform, shared
psychotic disorder), substance abuse, Parkinson's disease,
Huntington's disease, Alzheimer's disease, dementia, Niemann-Pick
disorder, a pituitary disorder (e.g., pituitary adenoma, and a
pituitary tumor such as prolactinoma)), Tourette's syndrome,
Tourette-like disorders, and restless leg syndrome.
[0542] In one embodiment, the present invention provides a method
of treating or preventing a disease or disorder in which modulation
of D2 receptors (e.g., .beta.-arrestin or Gi/cAMP) plays a role,
selected from obsessive-compulsive disorder, post-traumatic stress
disorder, depression, bipolar disorder, mania, hypomania, autism
spectrum disorders, attention deficit hyperactivity disorder,
delusional disorder, Schizoaffective disorder, Schizophrenia,
Schizophreniform, substance abuse, Parkinson's disease,
Huntington's disease, Alzheimer's disease, dementia, Niemann-Pick
disorder, a pituitary disorder, Tourette's syndrome, Tourette-like
disorders, and restless leg syndrome.
[0543] In another embodiment, the disease or disorder is a
non-nervous system disease or disorder in which modulation of D2
receptors (e.g., .beta.-arrestin or Gi/cAMP) plays a role, such as
cardiovascular diseases or disorders (e.g., hypertension), renal
diseases or disorders (e.g., a disease or disorder associated with
diuresis and natriuresis), and endocrine diseases or disorders
(e.g., galactorrhea), and immunological diseases or disorders.
[0544] The present invention also provides a method of treating or
preventing a disease or disorder in which modulation of D2
receptors (e.g., .beta.-arrestin or Gi/cAMP) plays a role (e.g.,
the diseases and disorders described above), comprising
administering a compound of the invention and an additional
therapeutic agent. In one embodiment, the additional therapeutic
agent is lithium carbonate, lithium citrate, lithium orotate,
lithium bromide or lithium chloride. In another embodiment, the
additional therapeutic agent is valproate. In another embodiment,
the additional therapeutic agent is caffeine (e.g., as to
Parkinsons), a caffeine derivative (e.g., as to Parkinsons),
nicotine (e.g., as to Parkinsons), a nicotine derivative (e.g., as
to Parkinsons), Phencyclidine (a.k.a. PCP), Quinpirole, Salvinorin
A (chief active constituent of the herb salvia divinorum),
Apomorphine (Apokyn) (e.g., as to Parkinson's disease, restless leg
syndrome), Bromocriptine (Parlodel) (e.g., as to Parkinson's
disease, restless leg syndrome), Cabergoline (Dostinex) (e.g., as
to Parkinson's disease, restless leg syndrome), Ciladopa (e.g., as
to Parkinson's disease, restless leg syndrome), Dihydrexidine
(e.g., as to Parkinson's disease, restless leg syndrome),
Dinapsoline (e.g., as to Parkinson's disease, restless leg
syndrome), Doxanthrine (e.g., as to Parkinson's disease, restless
leg syndrome), Epicriptine (e.g., as to Parkinson's disease,
restless leg syndrome), Lisuride (e.g., as to Parkinson's disease,
restless leg syndrome), Pergolide (e.g., as to Parkinson's disease,
restless leg syndrome), Piribedil (e.g., as to Parkinson's disease,
restless leg syndrome), Pramipexole (e.g., as to Parkinson's
disease, restless leg syndrome) (Mirapex and Sifrol),
Propylnorapomorphine (e.g., as to Parkinson's disease, restless leg
syndrome), Quinagolide (Norprolac) (e.g., as to Parkinson's
disease, restless leg syndrome), Ropinirole (e.g., as to
Parkinson's disease, restless leg syndrome) (Requip), Rotigotine
(e.g., as to Parkinson's disease, restless leg syndrome) (Neupro),
Roxindole (e.g., as to Parkinson's disease, restless leg syndrome),
or Sumanirole (e.g., as to Parkinson's disease, restless leg
syndrome).
[0545] The present invention also provides a method of treating or
preventing a disease or disorder in which modulation of D2
receptors (e.g., .beta.-arrestin or Gi/cAMP) plays a role (e.g.,
the diseases and disorders described above), comprising
administering a compound of the invention and a serotonin reuptake
inhibitor such as fluoxetine, venlafaxine, citalopram, paroxetine,
sertraline, indalpine, zimelidine, dapoxetine, fluvoxamine,
tianeptine, duloxetine or escitalopram (see for example,
US20060154938).
[0546] The present invention also provides a method of treating or
preventing a disease or disorder in which modulation of D2
receptors (e.g., .beta.-arrestin or Gi/cAMP) plays a role (e.g.,
the diseases and disorders described above), comprising
administering a compound of the invention alone or in combination
with antipsychotics. Examples of typical (first generation)
antipsychotics include Chlorpromazine, Droperidol, Fluphenazine,
Haloperidol, Loxapine, Molindone, Perphenazine, Pimozide,
Prochlorperazine, Thiothixene, Thioridazine, Trifluoperazine,
Levomepromazine. Examples of atypical (second generation)
antipsychotics include Aripiprazole, Asenapine, Clozapine,
Iloperidone, Lurasidone, Olanzapine, Paliperidone, Quetiapine,
Risperidone, Ziprasidone, Amisulpride, Blonanserin, Clotiapine,
Mosapramine, Perospirone, Sertindole, Sulpiride. Other compounds
which can be used in combination with the compounds of the
invention are for example compounds that interact with dopamine D2
receptor selected from amisulpride, nemomapride, nemoxipride,
eticlopride, reclopride, talipexole, roxindole, bifeprunox,
aplindore, mesoridazine, haloperidol, thixathene, flupenthixol,
butyrophenone, perclamol [(-)3-PPP], saritozan, olanzapine,
dopanmine, quinpirole, bromocriptine; other anti-depressants
selected from Agomelatine, amitriptyline, amoxapine, clomipramine,
desipramine, dosulepine hydrochloride, doxepine, imipramine,
maprotiline, a mixture of nortriptyline and fluphenazine,
opipramol, quinupramine, trimipramine, a mixture of melitracene and
flupentixol, pranipexole.
[0547] The compounds are generally administered to a subject in
need of such administration, for example, a human or animal
patient, preferably a human.
[0548] The compounds will typically be administered in amounts that
are therapeutically or prophylactically useful and which generally
are non-toxic. However, in certain situations (for example in the
case of life threatening diseases), the benefits of administering a
compound of the Formula I may outweigh the disadvantages of any
toxic effects or side effects, in which case it may be considered
desirable to administer compounds in amounts that are associated
with a degree of toxicity. The quantity of compound administered
and the type of composition used will be commensurate with the
nature of the disease or physiological condition being treated and
will be at the discretion of the physician.
[0549] The compounds may be administered over a prolonged term to
maintain beneficial therapeutic effects or may be administered for
a short period only. Alternatively they may be administered in a
pulsatile or continuous manner.
[0550] The compounds as defined herein can be administered as the
sole therapeutic agent or they can be administered in combination
therapy with one of more other compounds for treatment of a
particular disease state, for example, a nervous system disorder.
The compounds of the invention may also be administered in
conjunction with other treatments such as radiotherapy,
photodynamic therapy, gene therapy, surgery and controlled
diets.
[0551] Where the compound is administered in combination with other
therapeutic agents, the compounds can be administered
simultaneously or sequentially. When administered sequentially,
they can be administered at closely spaced intervals (e.g., within
minutes) or at longer intervals (e.g., hours apart, or longer), the
precise dosage regimen being commensurate with the properties of
the therapeutic agent(s).
[0552] For use in combination therapy with another therapeutic
agent, the compound and other therapeutic agents can be, for
example, formulated together in a dosage form. In an alternative,
the individual therapeutic agents may be formulated separately and
presented together in the form of a kit, optionally with
instructions for their use.
[0553] Actual dosage levels of the active ingredients in the
pharmaceutical compositions of the invention may be varied so as to
obtain an amount of the active ingredient which is effective to
achieve the desired therapeutic response for a particular patient,
composition, and mode of administration, without being toxic to the
patient.
[0554] The selected dosage level will depend upon a variety of
factors including the activity of the particular compound of the
present invention employed, the route of administration, the time
of administration, the rate of excretion of the particular compound
being employed, the duration of the treatment, other drugs,
compounds and/or materials used in combination with the particular
compound employed, the age, sex, weight, condition, general health
and prior medical history of the patient being treated, and like
factors well known in the medical arts.
[0555] A person skilled in the art would know through his or her
common general knowledge the use of suitable dosing regimes and
combination therapies. The regimen of administration can affect
what constitutes an effective amount. The compound of the invention
can be administered to the subject either prior to or after the
onset of a dopaminergic disorder. Further, several divided dosages,
as well as staggered dosages, can be administered daily or
sequentially, or the dose can be continuously infused, or can be a
bolus injection. Further, the dosages of the compound(s) of the
invention can be proportionally increased or decreased as indicated
by the exigencies of the therapeutic or prophylactic situation.
[0556] A physician or veterinarian having ordinary skill in the art
can readily determine and prescribe the effective amount of the
pharmaceutical composition required. For example, the physician or
veterinarian could start doses of the compounds of the invention
employed in the pharmaceutical composition at levels lower than
that required in order to achieve the desired therapeutic effect
and gradually increase the dosage until the desired effect is
achieved.
[0557] While it is possible for a compound of the present invention
to be administered alone, it is preferable to administer the
compound as a pharmaceutical composition.
[0558] The present invention also relates to use of a compound of
the invention or a pharmaceutically acceptable salt, stereoisomer,
racemate, tautomer, polymorph, hydrate, or solvate thereof, or use
of a pharmaceutical composition of the invention, for treating
treating or preventing a disease or disorder in which modulation of
D2 receptors (e.g., .beta.-arrestin or Gi/cAMP) plays a role (e.g.,
diseases and disorders described herein). In one embodiment, the
disease or disorder is a nervous system disease or disorder
selected from obsessive-compulsive disorder, post-traumatic stress
disorder, depression, bipolar disorder, mania, hypomania, autism
spectrum disorders, attention deficit hyperactivity disorder,
delusional disorder, Schizoaffective disorder, Schizophrenia,
Schizophreniform, substance abuse, Parkinson's disease,
Huntington's disease, Alzheimer's disease, dementia, Niemann-Pick
disorder, a pituitary disorder, Tourette's syndrome, Tourette-like
disorders, and restless leg syndrome. In another embodiment, the
disease or disorder is a non-nervous system disease or disorder in
which modulation of D2 receptors (e.g., .beta.-arrestin or Gi/cAMP)
plays a role, such as cardiovascular diseases or disorders (e.g.,
hypertension), renal diseases or disorders (e.g., a disease or
disorder associated with diuresis and natriuresis), and endocrine
diseases or disorders (e.g., galactorrhea), and immunological
diseases or disorders.
[0559] The present invention also relates to use of a compound of
the invention, or a pharmaceutically acceptable salt, stereoisomer,
racemate, tautomer, polymorph, hydrate, or solvate thereof, or use
of a pharmaceutical composition of the invention, in the
manufacture of a medicament for the treatment or prevention of a
disease or disorder in which modulation of D2 receptors (e.g.,
.beta.-arrestin or Gi/cAMP) plays a role (e.g., diseases and
disorders described herein). In one embodiment, the disease or
disorder is a nervous system disease or disorder selected from
obsessive-compulsive disorder, post-traumatic stress disorder,
depression, bipolar disorder, mania, hypomania, autism spectrum
disorders, attention deficit hyperactivity disorder, delusional
disorder, Schizoaffective disorder, Schizophrenia,
Schizophreniform, substance abuse, Parkinson's disease,
Huntington's disease, Alzheimer's disease, dementia, Niemann-Pick
disorder, a pituitary disorder, Tourette's syndrome, Tourette-like
disorders, and restless leg syndrome. In another embodiment, the
disease or disorder is a non-nervous system disease or disorder
associated in which modulation of D2 receptors (e.g.,
.beta.-arrestin or Gi/cAMP) plays a role, such as cardiovascular
diseases or disorders (e.g., hypertension), renal diseases or
disorders (e.g., a disease or disorder associated with diuresis and
natriuresis), and endocrine diseases or disorders (e.g.,
galactorrhea), and immunological diseases or disorders.
[0560] All percentages and ratios used herein, unless otherwise
indicated, are by weight. Other features and advantages of the
present invention are apparent from the different examples. The
provided examples illustrate different components and methodology
useful in practicing the present invention. The examples do not
limit the claimed invention. Based on the present disclosure the
skilled artisan can identify and employ other components and
methodology useful for practicing the present invention.
EXAMPLES
Synthesis of Intermediate I
##STR00027##
[0561] Step 1: (4-Chlorophenyl)(pyridin-2-yl)methanol
##STR00028##
[0563] To a stirred suspension of magnesium (5.37 g, 223.75 mmol, 3
equiv) in dry THF (60 mL) under argon atmosphere was added iodine
(2 crystals), 1,2-dibromo ethane (2 drops). 1-bromo-4-chlorobenzene
(25.76 g, 134.39 mmol, 1.8 equiv) was then added dropwise for 1 h
at room temperature. The reaction mixture was stirred at room
temperature for 1 h. A solution of picolinaldehyde (8 g, 74.68
mmol) in dry THF (19 mL) was added drop wise at room temperature
and stirred for 2 h. After completion of reaction, the reaction
mixture was quenched with saturated ammonium chloride solution and
extracted with EtOAc. The combined organic extract was washed with
water, brine, dried over sodium sulfate, filtered and concentrated
under reduced pressure. Purification using silica gel column
chromatography (40% EtOAc/hexanes as eluent) afforded 12.26 g of
(4-chlorophenyl) (pyridin-2-yl) methanol (yield=75%). ESI+MS: m/z
220 ([M+H].sup.+).
Step 2: (4-Chlorophenyl)(pyridin-2-yl)methanone
##STR00029##
[0565] To a stirred solution of (4-chlorophenyl) (pyridin-2-yl)
methanol (5 g, 22.83 mmol) in CH.sub.2Cl.sub.2 (85 mL) under argon
atmosphere was added pyridinium chlorochromate (5.9 g, 27.37 mmol,
1.2 equiv) and celite (5 g) at 0.degree. C. The reaction mixture
was warmed to room temperature and stirred for 2 h. After
completion of the reaction, the reaction mixture was filtered
through celite, washed with CH.sub.2Cl.sub.2 and the filtrate was
concentrated under reduced pressure. Purification using silica gel
column chromatography (20% EtOAc/Hexanes as eluent) afforded 3.5 g
of (4-chlorophenyl) (pyridin-2-yl) methanone (Yield=71%). ESI+MS:
m/z 218 ([M+H].sup.+).
Step 3: (4-Chlorophenyl)(pyridin-2-yl)methanone oxime
##STR00030##
[0567] To a stirred solution of (4-chlorophenyl) (pyridin-2-yl)
methanone (3.5 g, 16.12 mmol) in MeOH (35 mL) under argon
atmosphere was added hydroxyl amine hydrochloride (3.36 g, 48.35
mmol, 3 equiv) at 0.degree. C. The reaction mixture was warmed to
room temperature and stirred for 12 h. After completion, the
volatiles were removed under reduced pressure and ethyl acetate was
added to the residue. The organic layer was washed with saturated
NaHCO.sub.3 solution, dried over sodium sulfate, filtered and the
concentrate under reduced pressure. The crude was triturated with
n-hexane to afford 3.1 g of (4-chlorophenyl) (pyridin-2-yl)
methanone oxime (Yield=83%). ESI+MS: m/z 233 ([M+H].sup.+).
Step 4: (4-Chlorophenyl)(pyridin-2-yl)methanamine
##STR00031##
[0569] To a stirred solution of (4-chlorophenyl) (pyridin-2-yl)
methanone oxime (3.1 g, 13.36 mmol) in trifluoro acetic acid (20
mL) under argon atmosphere was added Zn-dust (2.6 g, 40.00 mmol, 3
equiv) at 0.degree. C. The reaction mixture was warmed to room
temperature and stirred for 4 h. After completion, the volatiles
were removed under reduced pressure, the pH was adjusted to
.about.8 with 10% NaHCO.sub.3 solution and extracted with EtOAc.
The combined organic extract was dried over sodium sulfate,
filtered and concentrated under reduced pressure to afford 2.18 g
of (4-chlorophenyl) (pyridin-2-yl) methanamine (Yield=75%). Ion
trap: m/z 219.1 ([M+H].sup.+).
Step 5: tert-butyl
4-(((4-chlorophenyl)(pyridin-2-yl)methyl)carbamoyl)piperidine-1-carboxyla-
te
##STR00032##
[0571] To a stirred solution of (4-chlorophenyl) (pyridin-2-yl)
methanamine (2 g, 9.17 mmol) in DMF (10 mL) under argon atmosphere
were added 1-(tert-butoxycarbonyl) piperidine-4-carboxylic acid
(2.1 g, 9.16 mmol, 1 equiv), HATU (5.23 g, 13.75 mmol, 1.5 equiv)
and diisopropyl ethyl amine (3.23 mL, 18.34 mmol, 2 equiv) at
0.degree. C. The reaction mixture was warmed to room temperature
and stirred for 4 h. After completion, the reaction mixture was
quenched with ice cold water and extracted with EtOAc. The combined
organic extract was dried over sodium sulfate, filtered and
concentrated under reduced pressure. Purification using silica gel
column chromatography (40% EtOAc/Hexanes as eluent) afforded 2.5 g
of tert-butyl 4-(((4-chlorophenyl) (pyridin-2-yl) methyl)
carbamoyl) piperidine-1-carboxylate (Yield=64%). ESI+MS: m/z 430
([M+H].sup.+).
Step 6:
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(Intermediate-I)
##STR00033##
[0573] To a stirred solution of tert-butyl 4-(((4-chlorophenyl)
(pyridin-2-yl) methyl) carbamoyl) piperidine-1-carboxylate (2.5 g,
5.87 mmol) in CH.sub.2Cl.sub.2 (20 mL) under argon atmosphere was
added trifluoro acetic acid (2.23 mL, 29.13 mmol, 5 equiv) at
0.degree. C. The reaction mixture was warmed to room temperature
and stirred for 3 h. After completion of the reaction, the
volatiles were removed and the solvent was removed under reduced
pressure. The pH was adjusted to .about.7 with saturated
NaHCO.sub.3 solution and extracted with CH.sub.2Cl.sub.2. The
combined organic extract was dried over sodium sulfate, filtered
and concentrated under reduced pressure to afford 1.63 g of
N-((4-chlorophenyl) (pyridin-2-yl) methyl) piperidine-4-carboxamide
(Int-I) (Yield=85%). ESI+MS: m/z 330 ([M+H].sup.+).
Synthesis of Intermediate-1
##STR00034##
[0574] 1-(2-bromoethoxy)-3-chlorobenzene
[0575] To a stirred solution of 3-chlorophenol (5 g, 39.06 mmol) in
DMF (30 mL) under argon atmosphere were added 1,2-dibromo ethane
(6.7 mL, 77.71 mmol, 2 equiv) and potassium carbonate (5.4 g, 39.13
mmol, 1 equiv) at room temperature. The reaction mixture was heated
at 100.degree. C. and stirred for 16 h. After completion, the
reaction mixture was diluted with water and extracted with EtOAc.
The combined organic extract was washed with brine, dried over
sodium sulphate, filtered and concentrated under reduced pressure.
Purification using silica gel column chromatography (2%
EtOAc/Hexanes as eluent) afforded 3.1 g of
1-(2-bromoethoxy)-3-chlorobenzene (Yield=34%).
Synthesis of Intermediate-2
##STR00035##
[0576] 1-(2-Bromoethoxy)-2-fluorobenzene
[0577] To a stirred solution of 2-fluorophenol (0.5 g, 4.46 mmol)
in aqueous sodium hydroxide solution (0.78 g, 4.46 mmol, 1 equiv,
in 5 mL of water) was added 1,2-dibromo ethane (1.25 g, 6.69 mmol,
1.5 equiv) at room temperature. The reaction mixture was heated at
130.degree. C. and stirred for 16 h. After completion, the reaction
mixture was extracted with EtOAc. The combined organic extract was
washed with brine, dried over sodium sulphate, filtered and
concentrated under reduced pressure. Purification using silica gel
column chromatography (2% EtOAc/Hexanes as eluent) afforded 0.340 g
of 1-(2-bromoethoxy)-2-fluorobenzene (Yield=34.8%).
Synthesis of Intermediate-3
##STR00036##
[0578] 1-(2-Bromo ethoxy)-2-(trifluoromethyl)benzene
[0579] To a stirred solution of 2-(trifluoromethyl) phenol (1 g,
6.17 mmol) in acetone (20 mL) under argon atmosphere were added
potassium carbonate (0.851 g, 6.15 mmol, 1 equiv) and 1,2-dibromo
ethane (1.07 mL, 12.34 mmol, 2 equiv) at room temperature. The
reaction mixture was heated at 60.degree. C. and stirred for 16 h.
After completion, the reaction mixture was diluted with water and
extracted with EtOAc. The combined organic extract was dried over
sodium sulfate, filtered and concentrated under reduced pressure.
Purification using silica gel column chromatography (2%
EtOAc/Hexanes as eluent) afforded 0.40 g of
1-(2-bromoethoxy)-2-(trifluoromethyl) benzene (Yield=24%).
Synthesis of Intermediate-4
##STR00037##
[0580] 1-(2-bromoethyl)pyridin-2(1H)-one
[0581] To a stirred solution of pyridin-2-ol (5 g, 52.57 mmol) in
DMF (50 mL) under argon atmosphere were added cesium carbonate
(17.03 g, 52.56 mmol, 1.0 eqiuv) and 1-chloro-2-bromo ethane (15.06
g, 104.94 mmol, 2 equiv) at room temperature and stirred for 16 h.
After completion, the reaction mixture was diluted with water and
extracted with CH.sub.2Cl.sub.2. The combined organic extract was
dried over sodium sulfate, filtered and concentrated under reduced
pressure. Purification using silica gel column chromatography (1%
MeOH/CH.sub.2Cl.sub.2 as eluent) afforded 1.0 g of
1-(2-bromoethyl)pyridin-2(1H)-one (Yield=12%). ESI+MS: m/z 158.1
([M+H].sup.+).
Synthesis of Intermediate-5
##STR00038##
[0582] 7-(2-bromoethoxy)quinolin-2(1H)-one
[0583] To a stirred solution of 7-hydroxyquinolin-2(1H)-one (1 g,
6.21 mmol) in MeOH (20 mL) under argon atmosphere were added
1,2-dibromo ethane (1.74 g, 9.31 mmol, 1.5 equiv) and potassium
hydroxide (0.453 g, 8.07 mmol, 1.3 equiv) at room temperature. The
reaction mixture was heated at 65.degree. C. and stirred for 4 h.
After completion, the volatiles were removed under reduced
pressure. The residue was diluted with water and extracted with
EtOAc. The combined organic extract was dried over sodium sulfate,
filtered and concentrated under reduced pressure. Purification
using silica gel column chromatography (1% MeOH/CH.sub.2Cl.sub.2 as
eluent) afforded 7-(2-bromoethoxy)quinolin-2(1H)-one 0.27 g
(Yield=16.2%). ESI+MS: m/z 267.9 ([M+H].sup.+).
[0584] One skilled in the art will recognize that other compounds
described below were prepared in a similar manner to the procedures
described above.
[0585] One skilled in the art will recognize that other compounds
described below were prepared in a similar manner to the procedures
described above.
(2-Bromoethoxy)benzene
##STR00039##
[0587] Title compound was prepared from phenol (20 g, 213 mmol)
using the general methodology of Int-2 and afforded 26 g of
(2-bromoethoxy)benzene (Yield=61%).
2-(2-bromoethoxy)-2-chlorobenzene
##STR00040##
[0589] Title compound was prepared from 2-chlorophenol (1 g, 7.78
mmol) using general methodology of Intermediate-1 to obtain 0.348 g
of 1-(2-bromoethoxy)-2-chlorobenzene (Yield=19%).
1-(2-Bromoethoxy)-4-chlorobenzene
##STR00041##
[0591] Title compound was prepared from 4-chlorophenol (5 g, 39.06
mmol) using the general methodology of Intermediate-1 and afforded
3 g of 1-(2-Bromoethoxy)-4-chlorobenzene (Yield=33%).
1-(2-Bromoethoxy)-3 -fluorobenzene
##STR00042##
[0593] Title compound was prepared from 3-fluorophenol (4 g, 35.71
mmol) using the general methodology of Intermediate-2 and afforded
3 g of 1-(2-bromoethoxy)-3-fluorobenzene (Yield=38%).
1-(2-bromoethoxy)-4-fluorobenzene
##STR00043##
[0595] Title compound was prepared from 4-fluorophenol (4 g, 35.71
-mmol) using the general methodology of Intermediate-2 and afforded
2.8 g of 1-(2-bromoethoxy)-4-fluorobenzene (Yield=35%).
2-(2 -Bromoethoxy)-1,4-difluorobenzene
##STR00044##
[0597] Title compound was prepared from 2,6-difluorophenol (1 g,
7.69 mmol) using the general methodology of Intermediate-2 and
afforded 1.1 g of 2-(2-bromoethoxy)-1,4-difluorobenzene
(Yield=60%).
2-(2-bromoethoxy)-1,4-difluorobenzene
##STR00045##
[0599] Title compound was prepared from 2,5-difluorophenol (5 g,
38.4 mmol) using the general methodology of Int-2 and afforded 3.5
g of 2-(2-bromoethoxy)-1,4-difluorobenzene (Yield=39%).
1-(2-bromoethoxy)-2-(trifluoromethyl)benzene
##STR00046##
[0601] Title compound was prepared from 2-(trifluoromethyl)phenol
(1 g, 6.17 mmol) using the general methodology of Intermediate-3 to
obtain 0.398 g of 1-(2-bromoethoxy)-2-(trifluoromethyl)benzene
(Yield=24%).
1-(2-bromoethoxy)-3-(trifluoromethyl)benzene
##STR00047##
[0603] Title compound was prepared from 3-(trifluoromethyl) phenol
(2 g, 12.34 mmol) using general methodology of Intermediate-3 and
afforded 0.74 g of 1-(2-bromoethoxy)-3-(trifluoromethyl) benzene
(Yield=22%).
1-(2-bromoethoxy)-4-(trifluoromethyl)benzene
##STR00048##
[0605] Title compound was prepared from 4-(trifluoromethyl) phenol
(1 g, 6.17 mmol) using the general methodology of Intermediate-3
and afforded 0.3 g of 1-(2-bromoethoxy)-4-(trifluoromethyl) benzene
(Yield=19%).
3-(2-Bromoethoxy) pyridine
##STR00049##
[0607] Title compound was prepared from pyridin-3-ol (5 g, 52.57
mmol) using the general methodology of Intermediate-4 and afforded
0.6 g of 3-(2-bromoethoxy) pyridine (Yield=6%).
1-(2-bromoethyl)pyridin-4(1H)-one
##STR00050##
[0609] Title compound was prepared from pyridin-4-ol (5 g, 52.5
mmol) using the general methodology of Intermediate-4 and afforded
0.85 g of 1-(2-bromoethyl)pyridin-4(1H)-one (Yield=8%).
1-(2-bromoethoxy)-3-methoxybenzene
##STR00051##
[0611] Title compound was prepared from 3-methoxyphenol (5 g, 40.27
mmol) using the general methodology of Intermediate-2 and afforded
3.6 g of 1-(2-bromoethoxy)-3-methoxybenzene (Yield=39%).
1-(2-bromoethoxy)-4-methoxybenzene
##STR00052##
[0613] Title compound was prepared from 3-methoxyphenol (5 g, 40.27
mmol) using the general methodology of Int-2 and afforded 3.5 g of
1-(2-bromoethoxy)-4-methoxybenzene (Yield=38%).
7-(2-bromoethoxy) quinolone
##STR00053##
[0615] Title compound was prepared from quinolin-7-ol (1 g, 6.89
mmol) using the general methodology of Int-1 and afforded 0.21 g of
7-(2-bromoethoxy) quinolone (Yield=21%).
6-(2-Bromoethoxy) benzo[d]thiazole
##STR00054##
[0617] Title compound was prepared from benzo[d]thiazol-6-ol (1 g,
6.62 mmol) using the general methodology of Int-1 and afforded 0.39
g of 6-(2-bromoethoxy) benzo[d]thiazole (Yield=23%).
(3-bromopropoxy)benzene:
##STR00055##
[0619] Title compound was prepared from phenol (5 g, 53.1 mmol)
using the general methodology of Intermediate-2 and afforded 9 g of
(3-bromopropoxy)benzene (Yield=79%).
Synthesis of Intermediate-6:
(2-Chlorophenyl)(pyridin-2-yl)methanamine
##STR00056##
[0620] (2-Chlorophenyl)(pyridin-2-yl)methanone oxime
##STR00057##
[0622] Title compound was prepared from
(2-chlorophenyl)(pyridin-2-yl)methanone (0.250 g, 1.14 mmol) using
the conditions of step 3 in the general methodology of key
Intermediate-I to obtain 0.25 g of
(E)-(2-chlorophenyl)(pyridin-2-yl)methanone oxime (Yield=94%).
(2-Chlorophenyl)(pyridin-2-yl)methanamine
##STR00058##
[0624] Title compound was prepared from
(E)-(3-chlorophenyl)(pyridin-2-yl)methanone oxime (0.250 g, 1.07
mmol) using the conditions of step 4 in the general methodology of
key Intermediate-I and afforded 0.180 g of
(2-chlorophenyl)(pyridin-2-yl)methanamine (Yield=77%). ESI+MS: m/z:
219.2 ([M+H].sup.+).
[0625] One skilled in the art will recognize that other compounds
described below were prepared in a similar manner to the procedures
described above.
(4-fluorophenyl)(pyridin-2-yl)methanamine
##STR00059##
[0627] Title compound was prepared using the same chemistry as for
intermediate-6 and replacing
(2-chlorophenyl)(pyridin-2-yl)methanone with
(4-fluorophenyl)(pyridin-2-yl)methanone and afforded 0.160 g of
(4-fluorophenyl)(pyridin-2-yl)methanamine (Yield=71%).
[0628] ESI+MS: m/z: 203.1([M+H].sup.+).
(3-fluorophenyl)(pyridin-2-yl)methanamine
##STR00060##
[0630] Title compound was prepared using the same chemistry as for
intermediate-6 and replacing
(2-chlorophenyl)(pyridin-2-yl)methanone with
(3-fluorophenyl)(pyridin-2-yl)methanone and afforded 0.180 g of
(3-fluorophenyl)(pyridin-2-yl)methanamine (Yield=96%); ESI+MS: m/z:
203.2([M+H].sup.+).
(2-fluorophenyl)(pyridin-2-yl)methanamine
##STR00061##
[0632] Title compound was prepared using the same chemistry as for
intermediate-6 and replacing
(2-chlorophenyl)(pyridin-2-yl)methanone with
(2-fluorophenyl)(pyridin-2-yl)methanone and afforded 0.140 g of
(2-fluorophenyl)(pyridin-2-yl)methanamine (Yield=68%); ESI+MS: m/z:
202.8([M+H].sup.+).
(4-methoxyphenyl)(pyridin-2-yl)methanamine
##STR00062##
[0634] Title compound was prepared using the same chemistry as for
intermediate-6 and replacing
(2-chlorophenyl)(pyridin-2-yl)methanone with
(4-methoxyphenyl)(pyridin-2-yl)methanone and afforded 0.180 g of
(4-methoxyphenyl)(pyridin-2-yl)methanamine (Yield=96%).
(3 -Methoxyphenyl)(pyridin-2-yl)methanamine
##STR00063##
[0636] Title compound was prepared using the same chemistry as for
intermediate-6 and replacing
(2-chlorophenyl)(pyridin-2-yl)methanone with
(3-methoxyphenyl)(pyridin-2-yl)methanone and afforded 0.140 g of
(3-methoxyphenyl)(pyridin-2-yl)methanamine (Yield=60%).
(2 -Methoxyphenyl)(pyridin-2-yl)methanamine
##STR00064##
[0638] Title compound was prepared using the same chemistry as for
intermediate-6 and replacing
(2-chlorophenyl)(pyridin-2-yl)methanone with
(2-methoxyphenyl)(pyridin-2-yl)methanone and afforded 0.180 g of
(2-methoxyphenyl)(pyridin-2-yl)methanamine (Yield=96%).
Cyclohexyl(pyridin-2-yl)methanamine
##STR00065##
[0640] Title compound was prepared using the same chemistry as for
intermediate-6 and replacing
(2-chlorophenyl)(pyridin-2-yl)methanone with
cyclohexyl(pyridin-2-yl)methanone and afforded 0.180 g of
cyclohexyl(pyridin-2-yl)methanamine (Yield=74%).
2-Methyl-1-(pyridin-2-yl)propan-1-amine
##STR00066##
[0642] Title compound was prepared using the same chemistry as for
intermediate-6 and replacing
(2-chlorophenyl)(pyridin-2-yl)methanone with
2-methyl-1-(pyridin-2-yl)propan-1-one and afforded 0.1 g of
2-methyl-1-(pyridin-2-yl)propan-1-amine (Yield=44%).
(4-Chlorophenyl)(phenyl)methanamine
##STR00067##
[0644] Title compound was prepared using the same chemistry as for
intermediate-6 and replacing
(2-chlorophenyl)(pyridin-2-yl)methanone with
(4-chlorophenyl)(phenyl)methanone and afford 0.2 g of
(4-chlorophenyl)(phenyl)methanamine (Yield=93%).
(4-chlorophenyl)(2-fluorophenyl)methanamine
##STR00068##
[0646] Title compound was prepared using the same chemistry as for
intermediate-6 and replacing
(2-chlorophenyl)(pyridin-2-yl)methanone with
(4-chlorophenyl)(2-fluorophenyl)methanone and afford 0.060 g of
(4-chlorophenyl)(2-fluorophenyl)methanamine (Yield=32%).
(4-Chlorophenyl)(3-fluorophenyl)methanamine
##STR00069##
[0648] Title compound was prepared using the same chemistry as for
intermediate-6 and replacing
(2-chlorophenyl)(pyridin-2-yl)methanone with
(4-chlorophenyl)(3-fluorophenyl)methanone and afforded 0.140 g of
(4-chlorophenyl)(3-fluorophenyl)methanamine (Yield=82%).
(4-Chlorophenyl)(4-fluorophenyl)methanamine
##STR00070##
[0650] Title compound was prepared using the same chemistry as for
intermediate-6 and replacing
(2-chlorophenyl)(pyridin-2-yl)methanone with
(4-chlorophenyl)(4-fluorophenyl)methanone and afforded 0.120 g of
(4-chlorophenyl)(4-fluorophenyl)methanamine (Yield=69%).
(4-chlorophenyl)(2-methoxyphenyl)methanamine
##STR00071##
[0652] Title compound was prepared using the same chemistry as for
intermediate-6 and replacing
(2-chlorophenyl)(pyridin-2-yl)methanone with
(4-chlorophenyl)(2-methoxyphenyl)methanone and afforded 0.120 g of
(4-chlorophenyl)(2-methoxyphenyl)methanamine (Yield=70%).
(4-Chlorophenyl)(4-methoxyphenyl)methanamine
##STR00072##
[0654] Title compound was prepared using the same chemistry as for
intermediate-6 and replacing
(2-chlorophenyl)(pyridin-2-yl)methanone with
(4-chlorophenyl)(4-methoxyphenyl)methanone and afforded 0.1 g of
(4-chlorophenyl)(4-methoxyphenyl)methanamine (Yield=59%).
(4-Fluorophenyl)(phenyl)methanamine
##STR00073##
[0656] Title compound was prepared using the same chemistry as for
intermediate-6 and replacing
(2-chlorophenyl)(pyridin-2-yl)methanone with
(4-fluorophenyl)(phenyl)methanone and afforded 0.150 g of
(4-fluorophenyl)(phenyl)methanamine (Yield=64%).
(3-Methoxyphenyl)(phenyl)methanamine
##STR00074##
[0658] Title compound was prepared using the same chemistry as for
intermediate-6 and replacing
(2-chlorophenyl)(pyridin-2-yl)methanone with
(3-methoxyphenyl)(phenyl)methanone and afforded 0.150 g of
(3-methoxyphenyl)(phenyl)methanamine (Yield=80%).
Bis(4-fluorophenyl)methanamine
##STR00075##
[0660] Title compound was prepared using the same chemistry as for
intermediate-6 and replacing
(2-chlorophenyl)(pyridin-2-yl)methanone with
bis(4-fluorophenyl)methanone and afforded 0.650 g of
bis(4-fluorophenyl)methanamine (Yield=86%).
(2-Fluorophenyl)(3-methoxyphenyl)methanamine
##STR00076##
[0662] Title compound was prepared using the same chemistry as for
intermediate-6 and replacing
(2-chlorophenyl)(pyridin-2-yl)methanone with
(2-fluorophenyl)(3-methoxyphenyl)methanone and afforded 0.4 g of
(2-fluorophenyl)(3-methoxyphenyl)methanamine (Yield=80%).
(4-fluorophenyl)(pyridin-2-yl)methanamine
##STR00077##
[0664] Title compound was prepared using the same chemistry as for
intermediate-6 and replacing
(2-chlorophenyl)(pyridin-2-yl)methanone with
(4-fluorophenyl)(pyridin-2-yl)methanone and afforded 0.5 g of
(4-fluorophenyl)(pyridin-2-yl)methanamine (Yield=89%).
Synthesis of Intermediate-7:
Pyridin-2-yl(pyridin-4-yl)methanamine
##STR00078##
[0666] To a stirred solution of
(Z)-pyridin-2-yl(pyridin-4-yl)methanone oxime (0.225 g, 1.12 mmol)
in MeOH (3 mL) under argon was added 10% Pd/C (0.075 g) at room
temperature. The reaction mixture was stirred for 4 h under H.sub.2
balloon pressure. After completion of the reaction, the reaction
mixture was filtered through celite, washed with methanol and the
solvent was removed under reduced pressure to afford 0.180 g of
pyridin-2-yl(pyridin-4-yl)methanamine (Yield=86%).
[0667] One skilled in the art will recognize that other compounds
described below were prepared in a similar manner to the procedures
described above.
Pyridin-2-yl(pyridin-3 -yl)methanamine
##STR00079##
[0669] Title compound was prepared using the same chemistry as for
intermediate-7 and replacing
(Z)-pyridin-2-yl(pyridin-4-yl)methanone oxime with
(Z)-pyridin-2-yl(pyridin-3-yl)methanone oxime and afforded 0.175 g
of pyridin-2-yl(pyridin-3-yl)methanamine (Yield=84%); ESI+MS: m/z:
186.0 ([M+H].sup.+).
Di(pyridin-2-yl)methanamine
##STR00080##
[0671] Title compound was prepared was prepared using the same
chemistry as for intermediate-7 and replacing
(Z)-pyridin-2-yl(pyridin-4-yl)methanone oxime with
di(pyridin-2-yl)methanone oxime (0.150 g, 0.753 mmol) and afforded
0.1 g of di(pyridin-2-yl)methanamine (Yield=72%). ESI+MS: m/z:
186.0 ([M+H].sup.+).
Bis(2 -fluorophenyl)methanamine
##STR00081##
[0673] Title compound was prepared using the same chemistry as for
intermediate-7 and replacing
(Z)-pyridin-2-yl(pyridin-4-yl)methanone oxime with
bis(2-fluorophenyl)methanone oxime and afforded 0.6 g of
bis(2-fluorophenyl)methanamine (Yield=80%).
(2-fluorophenyl)(4-fluorophenyl)methanamine
##STR00082##
[0675] Title compound was prepared using the same chemistry as for
intermediate-7 and replacing
(Z)-pyridin-2-yl(pyridin-4-yl)methanone oxime with
2-fluorophenyl)(4-fluorophenyl)methanone oxime and afforded 0.6 g
of (2-fluorophenyl)(4-fluorophenyl)methanamine (Yield=80%).
(3-methoxyphenyl)(oxazol-4-yl)methanamine
##STR00083##
[0677] Title compound was prepared using the same chemistry as for
intermediate-7 and replacing
(Z)-pyridin-2-yl(pyridin-4-yl)methanone oxime with
(Z)-(3-methoxyphenyl)(oxazol-4-yl)methanone oxime and afforded 0.19
g of (3-methoxyphenyl)(oxazol-4-yl)methanamine
(Yield=quantitative).
Synthesis of Intermediate-8:
[0678] Pyridin-2-yl(4-(trifluoromethyl)phenyl)methanamine
##STR00084##
[0679] Title compound was prepared from
(Z)-pyridin-2-yl(4-(trifluoromethyl)phenyl)methanone oxime (0.150
g, 0.753 mmol) using the conditions in step 4 in the general
methodology of key Intermediate-I and afforded 0.140 g of
pyridin-2-yl(4-(trifluoromethyl)phenyl)methanamine (Yield=74%).
ESI+MS: m/z: 253.2 ([M+H].sup.+).
[0680] One skilled in the art will recognize that other compounds
described below were prepared in a similar manner to the procedures
described above.
Pyridin-2-yl(3-(trifluoromethyl)phenyl)methanamine
##STR00085##
[0682] Title compound was prepared using the same chemistry as for
intermediate-8 by replacing
(Z)-pyridin-2-yl(4-(trifluoromethyl)phenyl)methanone oxime with
(Z)-pyridin-2-yl(3-(trifluoromethyl)phenyl)methanone oxime and
afforded 0.2 g of
(Z)-pyridin-2-yl(3-(trifluoromethyl)phenyl)methanone oxime
(Yield=75%). ESI+MS: m/z: 267.1 ([M+H].sup.+).
Pyridin-2-yl(2-(trifluoromethyl)phenyl)methanamine
##STR00086##
[0684] Title compound was prepared using the same chemistry as for
intermediate-8 by replacing
(Z)-pyridin-2-yl(4-(trifluoromethyl)phenyl)methanone oxime with
(Z)-pyridin-2-yl(2-(trifluoromethyl)phenyl)methanone oxime and
afforded 0.1 g of
pyridin-2-yl(2-(trifluoromethyl)phenyl)methanamine (Yield=53%).
(4-chlorophenyl)(3-fluoropyridin-4-yl)methanamine
##STR00087##
[0686] Title compound was prepared in 4 steps using chemistry
described for key intermediate-I and replacing picolinaldehyde with
3-fluoroisonicotinaldehyde and afforded 0.7 g of
(4-chlorophenyl)(3-fluoropyridin-4-yl)methanamine (Yield=93%).
(4-chlorophenyl)(5-fluoropyridin-2-yl)methanamine
##STR00088##
[0688] Title compound was prepared in 4 steps using chemistry
described for key intermediate-I and replacing picolinaldehyde with
5-fluoropicolinaldehyde and afforded 0.4 g of
(4-chlorophenyl)(5-fluoropyridin-2-yl)methanamine (Yield=94%).
Pyridin-2-yl(3-(trifluoromethoxy)phenyl)methanamine
##STR00089##
[0690] Title compound was prepared in 4 steps using chemistry
described for key intermediate-I and replacing
1-bromo-4-chlorobenzene with 1-bromo-3-(trifluoromethoxy)benzene
and afforded 0.3 g of
pyridin-2-yl(3-(trifluoromethoxy)phenyl)methanamine (Yield=79%).
ESI+MS: m/z: 269.2 ([M+H].sup.+).
(2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methanamine
##STR00090##
[0692] Title compound was prepared in 4 steps using chemistry
described for key intermediate-I and replacing
1-bromo-4-chlorobenzene with
5-bromo-2,2-difluorobenzo[d][1,3]dioxole and afforded 0.45 g of
(2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methanamine
(Yield=86%). ESI+MS: m/z: 265.2 ([M+H].sup.+).
[0693] Benzo[d][1,3]dioxol-5-yl(pyridin-2-yl)methanamine
##STR00091##
[0694] Title compound was prepared in 4 steps using chemistry
described for key intermediate-I and replacing
1-bromo-4-chlorobenzene with 5-bromobenzo[d][1,3]dioxole and
afforded 0.6 g of benzo[d][1,3]dioxol-5-yl(pyridin-2-yl)methanamine
(Yield=71%). ESI+MS: m/z: 229.1 ([M+H].sup.+).
(4-chlorophenyl)(pyridin-3-yl)methanamine
##STR00092##
[0696] Title compound was prepared in 4 steps using chemistry
described for key intermediate-I and replacing
pyridine-2-carboxaldehyde with pyridine-3-carboxaldehyde and
afforded 0.6 g of (4-chlorophenyl)(pyridin-3-yl)methanamine
(Yield=64%). ESI+MS: m/z: 219.2 ([M+H].sup.+).
(4-chlorophenyl)(pyridin-4-yl)methanamine
##STR00093##
[0698] Title compound was prepared in 4 steps using chemistry
described for key intermediate-I and replacing
pyridine-2-carboxaldehyde with pyridine-4-carboxaldehyde and
afforded 0.15 g of (4-chlorophenyl)(pyridin-4-yl)methanamine
(Yield=80%). ESI+MS: m/z: 219.0 ([M+H].sup.+).
Phenyl(pyridin-2-yl)methanamine
##STR00094##
[0700] Title compound was prepared in 4 steps using chemistry
described for key intermediate-I and replacing
1-bromo-4-chlorobenzene with bromobenzene and afforded 0.41 g of
phenyl(pyridin-2-yl)methanamine (Yield=88%). ESI+MS: m/z: 185.2
([M+H].sup.+).
Example-1
1-(2-(3-chlorophenoxy)ethyl)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)piper-
idine-4-carboxamide (I)
##STR00095##
[0702] To a stirred solution of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(Int-I) (0.20 g, 0.60 mmol) in CH.sub.3CN (5 mL) were added
potassium carbonate (0.251 g, 1.81 mmol, 3 equiv) and
1-(2-bromoethoxy)-3-chlorobenzene (0.143 g, 0.60 mmol, 1 equiv) at
room temperature. The reaction mixture was heated at 80.degree. C.
and stirred for 6 h. After completion, the reaction mixture was
diluted with water and extracted with CH.sub.2Cl.sub.2. The
combined organic extract was dried over sodium sulfate, filtered
and concentrated under reduced pressure. Purification using silica
gel column chromatography (3% MeOH/CH.sub.2Cl.sub.2 as eluent)
afforded 0.05 g of 1-(2-(3-chlorophenoxy)
ethyl)-N-((4-chlorophenyl) (pyridin-2-yl) methyl)
piperidine-4-carboxamide (Yield=17%).
[0703] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.71(d, 1H,
J=6.4 Hz), 8.51(d, 1H, J=4.0 Hz), 7.78-7.76 (m, 1H), 7.44 (d, 1H,
J=8.0 Hz), 7.37-7.25 (m, 6H), 7.21-7.09 (m, 3H), 6.13 (d, 1H, J=8.4
Hz), 4.20-4.10 (m, 2H), 2.90-2.80 (m, 2H), 2.70-2.65 (m, 2H), 2.33
(t, 1H, J=2.4 Hz), 2.01 (bs, 2H), 1.66-1.58 (m, 4H); ESI+MS:
m/z:484.5 ([M+H].sup.+). Enantiomers of 1 were separated using
chiral HPLC (method D) and afforded pure enantiomers 1a and 1b.
Example-2
1-(2-(4-chlorophenoxy)ethyl)-N-((4-chlorophenyl)(pyridine-2-yl)methyl)
piperidine-4-carboxamide (2)
##STR00096##
[0705] Title compound was prepared from N-((4-chlorophenyl)
(pyridin-2-yl) methyl) piperidine-4-carboxamide (Int-I) (0.20 g,
0.60 mmol) using the general methodology of Example-1. The product
was washed with n-pentane and ether and afforded 0.1 g of
1-(2-(4-chlorophenoxy) ethyl)-N-((4-chlorophenyl) (pyridine-2-yl)
methyl) piperidine-4-carboxamide (Yield=34%).
[0706] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.70 (d, 1H,
J=8.0 Hz), 8.51 (d, 1H, J=4.0 Hz), 7.80-7.75 (m, 1H), 7.44 (d, 1H,
J=8.0 Hz), 7.37-7.35 (m, 7H), 6.96 (d, 2H, J=8.8 Hz), 6.13 (d, 1H,
J=8.4 Hz), 4.05 (bs, 2H), 2.92 (bs, 2H), 2.65 (bs, 2H), 2.33-2.32
(m, 1H), 2.01 (bs, 2H), 1.66-1.55 (m, 4H); ESI+MS: m/z: 484.5
([M+H].sup.+).
Example-3
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-fluorophenoxy)ethyl)pip-
eridine-4-carboxamide (3)
##STR00097##
[0708] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(Int-I) (0.20 g, 0.60 mmol) using the general methodology of
Example-1, and afforded 0.06 g of N((4-chlorophenyl)(pyridin-2-yl)
methyl)-1-(2-(2-fluorophenoxy)ethyl) piperidine-4-carboxamide
(Yield=21%).
[0709] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.71 (d, 1H,
J=6.4 Hz), 8.51 (d, 1H, J=4.0 Hz), 7.78-7.76 (m, 1H), 7.44 (d, 1H,
J=8.0 Hz), 7.37-7.25 (m, 5H), 7.21-7.09 (m, 3H), 6.92 (d, 1H, J=5.2
Hz), 6.13 (d, 1H, J=8.4 Hz), 4.20-4.10 (m, 2H), 2.90-2.80 (m, 2H),
2.70-2.65 (m, 2H), 2.33 (t, 1H, J=2.4 Hz), 2.04 (s, 2H), 1.66-1.58
(m, 4H); ESI+MS: m/z: 468 ([M+H].sup.+). Enantiomers of 3 were
separated using chiral HPLC (method D) and afforded pure
enantiomers 3a and 3b.
Example-4
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(3-fluorophenoxy)ethyl)pip-
eridine-4-carboxamide (4)
##STR00098##
[0711] Title compound was prepared from N-((4-chlorophenyl)
(pyridin-2-yl) methyl) piperidine-4-carboxamide (Int-I) (0.20 g,
0.60 mmol) using the general methodology of Example-1 and afforded
0.08 g of N-((4-chlorophenyl) (pyridin-2-yl)
methyl)-1-(2-(3-fluorophenoxy) ethyl) piperidine-4-carboxamide
(Yield=28%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.71 (d,
1H, J=7.6 Hz), 8.51 (d, 1H, J=3.6 Hz), 7.80-7.76 (m, 1H), 7.44 (d,
1H, J=7.6 Hz), 7.37-7.26 (m, 6H), 6.83-6.72 (m, 3H), 6.13 (d, 1H,
J=8.4 Hz), 4.20-4.07 (m, 2H), 2.99-2.93 (m, 2H), 2.70-2.60 (m, 2H),
2.40-2.33 (m, 1H), 2.10-1.95 (m, 2H), 1.66-1.55 (m, 4H); ESI+MS:
m/z: 468.5 ([M+H].sup.+). Enantiomers of 4 were separated using
chiral HPLC (method E) and afforded pure enantiomers 4a and 4b.
Example-5
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-fluorophenoxy)ethyl)pip-
eridine-4-carboxamide (5)
##STR00099##
[0713] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(Int-I) (0.20 g, 0.60 mmol) using the general methodology of
Example-1 and afforded 0.1 g of
N((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-fluoro phenoxy)
ethyl) piperidine-4-carboxamide (Yield=35%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 8.70 (d, 1H, J=8.0 Hz), 8.50 (d, 1H, J=4.0
Hz), 7.79-7.75 (m, 1H), 7.44 (d, 1H, J=8.0 Hz), 7.36-7.25 (m, 5H),
7.10-7.07 (m, 2H), 6.94-6.92 (m, 2H), 6.12 (d, 1H, J=8.5 Hz),
4.05-3.95 (m, 2H), 2.95-2.90 (m, 2H), 2.65-2.60 (m, 2H), 2.36-2.30
(m, 1H), 2.05-1.96 (m, 2H), 1.65-1.54 (m, 4H); ESI+MS: m/z 468
([M+H].sup.+).
Example-6
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-(trifluoromethyl)phenox-
y)ethyl) piperidine-4-carboxamide (6)
##STR00100##
[0715] Title compound was prepared from N-((4-chlorophenyl)
(pyridin-2-yl) methyl) piperidine-4-carboxamide (Int-I) (0.20 g,
0.60 mmol) using the general methodology of Example-1 and afforded
0.02 g of
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-(trifluoromethyl)
phenoxy) ethyl) piperidine -4-carboxamide (Yield=6%). .sup.1H NMR
(500 MHz, DMSO-d.sub.6): .delta. 8.71 (d, 1H, J=7.5 Hz), 8.51 (d,
1H, J=4.5 Hz), 7.78 (t, 1H, J=7.0 Hz), 7.62-7.59 (m, 2H), 7.44, (d,
1H, J=7.5 Hz), 7.37-7.26 (m, 6H), 7.08 (t, 1H, J=7.5 Hz), 6.13 (d,
1H, J=8.0 Hz), 4.22-4.18 (m, 2H), 2.97-2.90 (m, 2H), 2.75-2.68 (m,
2H), 2.38-2.30 (m, 1H), 2.10-2.00 (m, 2H), 1.68-1.52 (m, 4H);
ESI+MS: m/z: 518 ([M+H].sup.+). Enantiomers of 6 were separated
using chiral HPLC (method F) and afforded pure enantiomers 6a and
6b.
Example-7
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(3-(trifluoromethyl)phenoxy)-
ethyl) piperidine-4-carboxamide (7)
##STR00101##
[0717] Title compound was prepared from N-((4-chlorophenyl)
(pyridin-2-yl) methyl) piperidine-4-carboxamide (Int-I) (0.20 g,
0.60 mmol) using the general methodology of Example-1 and afforded
0.09 g of N-((4-chlorophenyl) (pyridin-2-yl)
methyl)-1-(2-(3-(trifluoromethyl) phenoxy) ethyl)
piperidine-4-carboxamide (Yield=29%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 8.71 (d, 1H, J=8.0 Hz), 8.51 (d, 1H, J=4.5
Hz), 7.78 (t, 1H, J=7.0 Hz), 7.55-7.42 (m, 2H), 7.40-7.23 (m, 8H),
6.13 (d, 1H, J=8.5 Hz), 4.17-4.12 (m, 2H), 2.97-2.93 (m, 2H),
2.69-2.67 (m, 2H), 2.37-2.31 (m, 1H), 2.04-1.99 (m, 2H), 1.69-1.51
(m, 4H); ESI+MS: m/z: 517.6 ([M+H].sup.+).
Example-8
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-(trifluoromethyl)phenoxy)-
ethyl) piperidine-4-carboxamide (8)
##STR00102##
[0719] Title compound was prepared from N-((4-chlorophenyl)
(pyridin-2-yl) methyl) piperidine-4-carboxamide (Int-I) (0.20 g,
0.61 mmol) using the general methodology of Example-1 and afforded
0.1 g of N-((4-chlorophenyl) (pyridin-2-yl)
methyl)-1-(2-(4-(trifluoromethyl) phenoxy)ethyl)
piperidine-4-carboxamide (Yield=32%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.71 (d, 1H, J=8.0 Hz), 8.51 (d, 1H, J=4.0
Hz), 7.80-7.76 (m, 1H), 7.63 (d, 2H, J=8.4 Hz), 7.45 (d, 1H, J=8.0
Hz), 7.37-7.27 (m, 4H), 7.27-7.26 (m, 1H), 7.12 (d, 2H, J=8.4 Hz),
6.13 (d, 1H, J=8.0 Hz), 4.20-4.15 (m, 2H), 2.99-2.95 (m, 2H),
2.71-2.63 (m, 2H), 2.40-2.30 (m, 1H), 2.10-1.95 (m, 2H), 1.74-1.55
(m, 4H); ESI+MS: m/z: 518.6 ([M+H].sup.+).
Example-9
N((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-oxopyridin-1(2H)-yl)ethyl)
piperidine-4-carboxamide (9)
##STR00103##
[0721] Title compound was prepared from N-((4-chlorophenyl)
(pyridin-2-yl) methyl) piperidine-4-carboxamide (Int-I) (0.20 g,
0.60 mmol) using the general methodology of Example-1 and afforded
0.09 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-oxopyridin-1(2H)-yl)ethy-
l)piperidine-4-carboxamide (Yield=33%). .sup.1H NMR (500 MHz,
CD.sub.3OD): .delta. 8.51 (d, 1H, J=4.5 Hz), 7.80-7.77 (m, 1H),
7.60 (d, 1H, J=6.5 Hz), 7.51-7.48 (m, 1H), 7.38 (d, 1H, J=7.5 Hz),
7.31-7.24 (m, 5H), 6.51 (d, 1H, J=9.0 Hz), 6.35 (t, 1H, J=6.5 Hz),
6.14 (s, 1H), 4.10 (t, 2H, J=7.0 Hz), 3.00 (d, 2H, J=11.5 Hz), 2.67
(t, 2H, J=7.0 Hz), 2.41-2.35 (m, 1H), 2.18-2.13 (m, 2H), 1.80-1.69
(m, 4H); ESI+MS: m/z 451 ([M+H].sup.+).
Example-10
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(pyridin-3-yloxy)ethyl)pip-
eridine-4-carboxamide (10)
##STR00104##
[0723] Title compound was prepared from N-((4-chlorophenyl)
(pyridin-2-yl) methyl) piperidine-4-carboxamide (Int-I) (0.20 g,
0.60 mmol) using the general methodology of Example-1 and afforded
0.09 g of N-((4-chlorophenyl) (pyridin-2-yl)
methyl)-1-(2-(pyridin-3-yloxy) ethyl) piperidine-4-carboxamide
(Yield=33%). .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 8.70 (d,
1H, J=8.5 Hz), 8.51 (d, 1H, J=4.0 Hz), 8.28 (d, 1H, J=3.0 Hz), 8.15
(d, 1H, J=4.0 Hz), 7.78-7.76 (m, 1H), 7.44 (d, 1H, J=7.5 Hz),
7.40-7.26 (m, 7H), 6.13 (d, 1H, J=8.0 Hz), 4.13 (t, 2H, J=5.5 Hz),
2.94 (d, 2H, J=10.5 Hz), 2.69-2.63 (m, 2H), 2.36-2.32 (m, 1H), 2.02
(t, 2H, J=11.5 Hz), 1.66-1.52 (m, 4H); ESI+MS: m/z:451
([M+H].sup.+).
Example-11
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-oxopyridin-1(4H)-yl)eth-
yl) piperidine-4-carboxamide (II)
##STR00105##
[0725] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(Int-I) (0.20 g, 0.60 mmol) using the general methodology of
Example-1. The crude was purified using preparative HPLC to afford
0.02 g of N-((4-chlorophenyl)(pyridin-2-yl)
methyl)-1-(2-(4-oxopyridin-1(4H)-yl)ethyl)piperidine-4-carboxamide
(Yield=7.3%).
[0726] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.72 (d, 1H,
J=8.4 Hz), 8.51 (d, 1H, J=4.0 Hz), 7.80-7.75 (m, 1H), 7.62 (d, 2H,
J=7.6 Hz), 7.44 (d, 1H J=8.0 Hz), 7.37-7.25 (m, 5H), 6.13-6.05 (m,
2H), 5.73 (d, 1H, J=11.6 Hz), 3.95-3.85 (m, 2H), 2.90-2.82(m, 2H),
2.65-2.55 (m, 2H), 2.40-2.35 (m, 1H), 2.00-1.92 (m, 2H), 1.70-1.60
(m, 2H), 1.58-1.45 (m, 2H); ESI+MS: m/z: 451 ([M+H].sup.+).
Enantiomers of 11 were separated using chiral HPLC (method G) and
afforded pure enantiomers 11a and 11b.
Example-12
N-((4-chlorophenyl) (pyridin-2-yl) methyl)-1-(2-(3-methoxyphenoxy)
ethyl) piperidine-4-carboxamide (12)
##STR00106##
[0728] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(Int-I) (0.20 g, 0.60 mmol) using the general methodology of
Example-1 and afforded 0.09 g of N-((4-chlorophenyl) (pyridin-2-yl)
methyl)-1-(2-(3-methoxyphenoxy) ethyl) piperidine-4-carboxamide
(Yield=30%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.72 (br
s, 1H), 8.51 (d, 1H, J=4.0 Hz), 7.80-7.76 (m, 1H), 7.44 (d, 1H,
J=8.0 Hz), 7.37-7.29 (m, 4H), 7.27-7.26 (m, 1H), 7.16 (t, 1H, J=8.0
Hz), 6.52-6.49 (m, 3H), 6.13 (d, 1H, J=8.4 Hz), 4.10-4.04 (m, 2H),
3.11 (s, 3H), 2.99-2.94 (m, 2H), 2.67-2.66 (m, 2H), 2.40-2.32 (m,
1H), 2.10-2.04 (m, 2H), 1.74-1.58 (m, 4H); ESI+MS: m/z: 480.5
([M+H].sup.+).
Example-13
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-methoxyphenoxy)ethyl)
piperidine-4-carboxamide (13)
##STR00107##
[0730] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(Int-I) (0.20 g, 0.60 mmol) using the general methodology of
Example-1 and afforded 0.11 g of N-((4-chlorophenyl) (pyridin-2-yl)
methyl)-1-(2-(4-methoxyphenoxy)ethyl) piperidine-4-carboxamide
(Yield=37%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.71 (d,
1H, J=6.4 Hz), 8.51 (d, 1H, J=4.0 Hz), 7.80-7.76 (m, 1H), 7.44 (d,
1H, J=7.6 Hz), 7.37-7.29 (m, 4H), 7.27-7.26 (m, 1H), 6.88-6.82 (m,
4H), 6.37 (d, 1H, J=8.4 Hz), 4.01-3.98 (m, 2H), 3.68 (s, 3H),
2.99-2.93 (m, 2H), 2.66-2.64 (m, 2H), 2.35-2.34 (m, 1H), 2.10-2.01
(m, 2H), 1.74-1.58 (m, 4H); ESI+MS: m/z:480.5 ([M+H].sup.+).
Example-14
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2,5-difluorophenoxy)ethyl-
) piperidine-4-carboxamide (14)
##STR00108##
[0732] Title compound was prepared from N-((4-chlorophenyl)
(pyridin-2-yl) methyl) piperidine-4-carboxamide (Int-I) (0.20 g,
0.60 mmol) using the general methodology of Example-1 and afforded
0.05 g of N-((4-chlorophenyl) (pyridin-2-yl)
methyl)-1-(2-(2,5-difluorophenoxy) ethyl) piperidine-4-carboxamide
(Yield=34%) as white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.711 (d, 1H, J=8.4 Hz), 8.51 (d, 1H, J=4.8 Hz), 7.80-7.76
(m, 1H), 7.45 (d, 1H, J=8.0 Hz), 7.37-7.33 (m, 4H), 7.31-7.19 (m,
2H), 7.16-7.11 (m, 1H), 6.76-6.72 (m, 1H), 6.13 (d, 1H, J=8.4 Hz),
4.14 (t, 2H, J=11.6 Hz), 2.94 (d, 2H, J=11.6 Hz), 2.69 (t, 2H,
J=11.2 Hz), 2.36-2.31 (m, 1H), 2.02 (t, 2H, J=11.6 Hz), 1.65-1.51
(m, 4H); ESI+MS: m/z 486 ([M+H].sup.+). Enantiomers of 14 were
separated using chiral HPLC (method G) and afforded pure
enantiomers 14a and 14b.
Example-15
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-((2-oxo-1,2-dihydroquinoli-
n-7-yl)oxy)ethyl)piperidine-4-carboxamide (15)
##STR00109##
[0734] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(Int-I) (0.154 g, 0.46 mmol) using the general methodology of
Example-1 and afforded 0.03 g of
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-((2-oxo-1,2-dihydroquinol-
in-7-yl)oxy)ethyl)piperidine-4-carboxamide (Yield=12%). .sup.1H NMR
(500 MHz, DMSO-d.sub.6): .delta. 11.54 (s, 1H), 8.71 (d, 1H, J=7.0
Hz), 8.51 (d, 1H, J=4.0 Hz), 7.80-7.76 (m, 2H), 7.54 (d, 1H, J=4.5
Hz), 7.44 (d, 1H, J=8.0 Hz), 7.37-7.33 (m, 4H), 7.27 (t, 1H, J=7.0
Hz), 6.79 (s, 2H), 6.28 (d, 1H, J=8.0 Hz), 6.13 (d, 1H, J=8.5 Hz),
4.10-4.05 (m, 2H), 2.99-2.94 (m, 2H), 2.69-2.63 (m, 2H), 2.36-2.35
(m, 1H), 2.08-2.03 (m, 2H), 1.67-1.66 (m, 2H), 1.58-1.56 (m, 2H);
ESI+MS: m/z: 517.3 ([M+H].sup.+).
Example-16
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(quinolin-7-yloxy)ethyl)
piperidine-4-carboxamide (16):
##STR00110##
[0736] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(Int-1) (0.20 g, 0.60 mmol) using the general methodology of
Example-1 and afforded 0.05 g of
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(quinolin-7-yloxy)ethyl)
piperidine-4-carboxamide (Yield=17%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 8.82-8.79 (m, 1H), 8.71 (br s, 1H), 8.50 (d,
1H, J=4.0 Hz), 8.25 (d, 1H, J=8.0 Hz), 7.86 (d, 1H, J=9.0 Hz), 7.77
(t, 1H, J=8.0 Hz), 7.44 (d, 1H, J=8.0 Hz), 7.40-7.31 (m, 6H),
7.32-7.22 (m, 2H), 6.13 (d, 1H, J=8.0 Hz), 4.25-4.20 (m, 2H),
3.00-2.90 (m, 2H), 2.78-2.70 (m, 2H), 2.30-2.28 (m, 1H), 2.10-2.02
(m, 2H), 1.70-1.55 (m, 4H); ESI+MS: m/z: 501 ([M+H].sup.+).
Enantiomers of 16 were separated using chiral HPLC (method H) and
afforded pure enantiomers 16a and 16b.
Example-17
N-((4-chlorophenyl) (pyridin-2-yl) methyl)-1-(2-(cyclohexyloxy)
ethyl) piperidine-4-carboxamide (17)
##STR00111##
[0738] To a stirred solution of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(Int-I) (0.20 g, 0.60 mmol) in CH.sub.3CN (5 mL) was added
(2-bromoethoxy)cyclohexane (0.15 g, 0.72 mmol, 1.2 equiv) and
potassium carbonate (0.251 g, 1.81 mmol, 3 equiv) at room
temperature. The reaction mixture was heated at 80.degree. C. and
stirred for 16 h in a sealed tube. After completion, the reaction
mixture was diluted with water and extracted with CH.sub.2Cl.sub.2.
The combined organic extract was dried over sodium sulfate,
filtered and the solvent was removed under reduced pressure.
Purification using silica gel column chromatography (5%
MeOH/CH.sub.2Cl.sub.2 as eluent) afforded 0.04 g of
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(cyclohexyloxy)ethyl)
piperidine-4-carboxamide (Yield=14%). .sup.1H NMR (500 MHz,
CD.sub.3OD): .delta. 8.54 (d, 1H, J=5.0 Hz), 7.82-7.81(m, 1H), 7.40
(d, 1H, J=8.0 Hz), 7.34-7.28 (m, 5H), 6.17 (s, 1H), 3.71-3.68 (m,
2H), 3.30-3.25 (m, 2H), 2.90-2.80 (m, 2H), 2.55 (d, 3H, J=10.5 Hz),
1.95-1.85 (m, 6H), 1.78-1.73 (m, 2H), 1.55-1.50 (m, 1H), 1.35-1.25
(m, 6H); ESI+MS: m/z 456 ([M+H].sup.+).
Example-18
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(3-phenylpropyl)piperidine-4-ca-
rboxamide (18)
##STR00112##
[0740] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(Int-1) (0.20 g, 0.60 mmol) using the general methodology of
Example-1. The crude was purified using preparative HPLC
purification to afford 0.08 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(3-phenylpropyl)piperidine-4-c-
arboxamide (Yield=29%).
[0741] .sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta. 8.70 (d, 1H,
J=8.4 Hz), 8.50 (d, 1H, J=3.6 Hz), 7.80-7.75 (m, 1H), 7.44 (d, 1H,
J=7.6 Hz), 7.37-7.31 (m, 4H), 7.28-7.24 (m, 3H), 7.19-7.13 (m, 3H),
6.13 (d, 1H, J=8.4 Hz), 2.90-2.85 (m, 2H), 2.56 (t, 2H, J=7.6 Hz),
2.33-2.30 (m, 1H), 2.24-2.23 (m, 2H), 1.90-1.83 (m, 2H), 1.72-1.54
(m, 6H); ESI+MS: m/z: 448.5 ([M+H].sup.+).
Example-19
1-(2-(Benzo[d]thiazol-6-yloxy)
ethyl)-N-((4-chlorophenyl)(pyridin-2-yl) methyl)
piperidine-4-carboxamide (19)
##STR00113##
[0743] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(Int-I) (0.15 g, 0.45 mmol) using the general methodology of
Example-1 and afforded 0.09 g of
1-(2-(benzo[d]thiazol-6-yloxy)ethyl)-N((4-chlorophenyl
(pyridin-2-yl) methyl)piperidine-4-carboxamide (Yield=39%). .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 9.17 (s, 1H), 8.71 (d, 1H,
J=8.0 Hz), 8.51 (d, 1H, J=4.0 Hz), 7.94 (d, 1H, J=9.2 Hz),
7.80-7.73 (m, 2H), 7.45 (d, 1H, J=8.0 Hz), 7.37-7.31(m, 4H),
7.28-7.25 (m, 1H), 7.12 (dd, 1H, J.sub.1,2=2.8 Hz, J.sub.1,3=9.2
Hz), 6.13 (d, 1H, J=8.4 Hz), 4.14 (t, 2H, J=5.6 Hz), 2.98-2.94 (m,
2H), 2.72-2.69 (m, 2H), 2.37-2.32 (m, 1H), 2.06-2.01 (m, 2H),
1.66-1.53 (m, 4H); ESI+MS: m/z: 507 ([M+H]).sup.+.
Synthesis of Intermediate II
##STR00114##
[0745] Key intermediate II was synthesized using a similar
synthetic sequence as key intermediate I but (4-chlorophenyl)
(pyridin-2-yl) methanone was replaced with (3-methoxyphenyl)
(pyridin-2-yl) methanone in step 3.
Example-20
N-((3-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-(2-(trifluoromethyl)phenoxy-
) ethyl) piperidine-4-carboxamide (20)
##STR00115##
[0747] Title compound was prepared from N-((3-methoxyphenyl)
(pyridin-2-yl) methyl) piperidine-4-carboxamide (Int-II) (0.13 g,
0.40 mmol) using the general methodology of Example-1 and afforded
0.05 g of N-((3-methoxyphenyl) (pyridin-2-yl)
methyl)-1-(2-(2-(trifluoromethyl) phenoxy) ethyl)
piperidine-4-carboxamide (Yield=24%). .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 8.51 (dd, 1H, J.sub.1,2=0.8, J.sub.1,3=1.6
Hz), 7.79 (dd, 1H, J.sub.1,2=9.6, J.sub.1,3=2.0 Hz), 7.57-7.53 (m,
2H), 7.39 (d, 1H, J=8.0 Hz), 7.31-7.28 (m, 1H), 7.23-7.16 (m, 2H),
7.05 (t, 1H, J=7.6 Hz), 6.84-6.80 (m, 3H), 6.13 (s, 1H), 4.24 (t,
2H, J=10.8 Hz), 3.75 (s, 3H), 3.13-3.09 (m, 2H), 2.86 (t, 2H, J=5.2
Hz), 2.45-2.38 (m, 1H), 2.31-2.24 (m, 2H), 1.90-1.75 (m, 4H);
ESI+MS: m/z 514 ([M+H].sup.+).
Example-21
1-(2-(2-chlorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-yl)methyl)
piperidine-4-carboxamide (21)
##STR00116##
[0749] Title compound was prepared from
N-((3-methoxyphenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(Int-II) (0.12 g, 0.36 mmol) using the general methodology of
Example-1. The crude was purified by preparative HPLC purification
and afforded 0.035 g of 1-(2-(2-chlorophenoxy)
ethyl)-N-((3-methoxyphenyl) (pyridin-2-yl) methyl)
piperidine-4-carboxamide (Yield=20%). .sup.1HNMR (400 MHz,
CD.sub.3OD): .delta. 8.51 (d, 1H, J=4.4 Hz), 7.78 (dt, 1H,
J.sub.1,2=1.6 Hz, J.sub.1,4=9.2 Hz), 7.39 (d, 1H, J=7.6 Hz), 7.34
(dd, 1H, J.sub.1,2=1.6 Hz, J.sub.1,3=8.0 Hz), 7.31-7.19 (m, 3H)
7.07-7.05 (m, 1H), 6.91 (dt, 1H, J.sub.1,2=1.2 Hz, J.sub.1,4=8.8
Hz), 6.84-6.80 (m, 3H), 6.13 (s, 1H), 4.19 (t, 2H, J=5.6 Hz), 3.75
(s, 3H) 3.15 (d, 2H, J=11.6 Hz), 2.87 (t, 2H, J=5.6 Hz), 2.46-2.38
(m, 1H), 2.34-2.27 (m, 2H), 1.90-1.77 (m, 4H); ESI+MS: m/z 480
([M+H].sup.+).
Example-22
1-(2-(2-fluorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-yl)methyl)
piperidine-4-carboxamide (22)
##STR00117##
[0751] Title compound was prepared from
N((3-methoxyphenyl)(pyridin-2-yl) methyl)piperidine-4-carboxamide
(Int-II) (0.15 g, 0.46 mmol) using the general methodology of
Example-1. The crude was purified by preparative HPLC and afforded
0.05 g of
1-(2-(2-fluorophenoxy)ethyl)-N-((4(3-methoxyphenyl)(pyridin-2-yl)methyl)p-
iperidine-4-carboxamide (Yield=23%). .sup.1HNMR (400 MHz,
CD.sub.3OD): .delta. 8.51-8.50 (m, 1H), 7.78 (dt, 1H, J.sub.1,2=1.6
Hz, J.sub.1,4=9.2 Hz), 7.39 (d, 1H, J=8.0 Hz), 7.31-7.28 (m, 1H),
7.23-7.19 (m, 1H), 7.11-7.04 (m, 3H), 6.93-6.88 (m, 1H), 6.84-6.79
(m, 3H), 6.13 (s, 1H), 4.18 (t, 2H, J=5.6 Hz), 3.74 (s, 3H), 3.10
(d, 2H, J=11.6 Hz), 2.85-2.81 (m, 2H), 2.45-2.37 (m, 1H), 2.29-2.22
(m, 2H), 1.85-1.76 (m, 4H); ESI+MS: m/z 464 ([M+H].sup.+).
Enantiomers of 22 were separated using chiral HPLC (method I) and
afforded pure enantiomers 22a and 22b.
Synthesis of Key Intermediate III
1-(2-phenoxyethyl) piperidine-4-carboxylic acid (Int-III)
##STR00118##
[0752] Step 1: Methyl
1-(2-phenoxyethyl)piperidine-4-carboxylate
##STR00119##
[0754] To a stirred solution of (2-bromoethoxy)benzene (1 g, 5
mmol) in CH.sub.3CN (50 mL) were added methyl
piperidine-4-carboxylate (0.715 g, 5 mmol, 1 equiv) and sodium
bicarbonate (1.26 g, 15 mmol, 3 equiv) at room temperature. The
reaction mixture was heated at100.degree. C. and stirred for 16 h.
After completion, the reaction mixture was diluted with water and
extracted with EtOAc. The combined organic extract was washed with
brine, filtered and dried over sodium sulphate. The solvent was
removed under reduced pressure. Purification using silica gel
column chromatography (20% EtOAc/Hexanes as eluent) afforded 1 g of
methyl 1-(2-phenoxyethyl) piperidine-4-carboxylate (Yield=76%).
ESI+MS: m/z: 264.1 ([M+H].sup.+).
Step 2: 1-(2-Phenoxyethyl) piperidine-4-carboxylic acid
(Int-III)
##STR00120##
[0756] To a stirred solution of methyl 1-(2-phenoxyethyl)
piperidine-4-carboxylate (1 g, 3.80 mmol) in THF/H.sub.2O/MeOH
(15:5:15) was added lithium hydroxide (0.479 g, 11.4 mmol, 3 equiv)
at 0.degree. C. and the reaction was stirred at room temperature
for 3 h. After completion, the reaction was diluted with water and
methanol and THF were removed under reduced pressure. The pH was
adjusted to 7 with 1N HCl (aq) and extracted with EtOAc. The
combined organic extract was washed with brine, filtered and dried
over sodium sulphate. The solvent was removed under reduced
pressure to afforded 0.8 g of 1-(2-Phenoxyethyl)
piperidine-4-carboxylic acid (Yield=84%). Ion trap: m/z: 250.2
([M+H].sup.+).
1-(2-(2-chlorophenoxy)ethyl)piperidine-4-carboxylic acid
##STR00121##
[0758] Title compound was prepared in 2 steps using the same
chemistry described for intermediate III by replacing
(2-bromoethoxy)benzene with (2-bromoethoxy)-2-chlorobenzene and
afforded 0.75 g of
1-(2-(2-chlorophenoxy)ethyl)piperidine-4-carboxylic acid
(Yield=79%); Ion trap: m/z: 284.2 ([M+H].sup.+).
1-(2-(2-fluorophenoxy)ethyl)piperidine-4-carboxylic acid
##STR00122##
[0760] Title compound was prepared in 2 steps using the same
chemistry described for intermediate III by replacing
(2-bromoethoxy)benzene with (2-bromoethoxy)-2-fluorobenzene and
afforded 1.2 g of
1-(2-(2-fluorophenoxy)ethyl)piperidine-4-carboxylic acid
(Yield=70%). ESI+MS: m/z: 268.2 ([M+H].sup.+).
1-(2-(2-methoxyphenoxy)ethyl)piperidine-4-carboxylic acid
##STR00123##
[0762] Title compound was prepared in 2 steps using the same
chemistry described for intermediate III by replacing
(2-bromoethoxy)benzene with (2-bromoethoxy)-2-methoxybenzene and
afforded 0.62 g of
1-(2-(2-methoxyphenoxy)ethyl)piperidine-4-carboxylic acid
(Yield=90%). ESI+MS: m/z: 280.6 ([M+H].sup.+).
Example-23
N-((4(3-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4--
carboxamide (23)
##STR00124##
[0764] Title compound was prepared from coupling of
(3-chlorophenyl) (pyridin-2-yl)methanamine (0.2 g, 0.915 mmol, 1
equiv) and 1-(2-phenoxyethyl) piperidine-4-carboxylic acid
(Int-III) (0.274 g, 1.09 mmol, 2 equiv) using the amide bond
coupling step conditions used in general methodology for key
Intermediate-I and afforded 0.04 g of N-((3-chlorophenyl)
(pyridin-2-yl) methyl)-1-(2-phenoxyethyl) piperidine-4-carboxamide
(Yield=10%). .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 8.75 (d,
1H, J=8.0 Hz), 8.52 (d, 1H, J=4.0 Hz), 7.80-7.77 (m, 1H), 7.47 (d,
1H, J=8.0 Hz), 7.39 (s, 1H), 7.35-7.25 (m, 6H), 6.93-6.90 (m, 3H),
6.15 (d, 1H, J=8.0 Hz), 4.10-4.05 (m, 2H), 2.99-2.95 (m, 2H),
2.69-2.64 (m, 2H), 2.39-2.35 (m, 1H), 2.05-2.03 (m, 2H), 1.68-1.57
(m, 4H); ESI+MS: m/z: 470.5 ([M+H].sup.+).
Example-24
N-((4(2-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4--
carboxamide (24)
##STR00125##
[0766] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.299 g, 1.2
mmol, 1.5 equiv) and (2-chlorophenyl)(pyridin-2-yl)methanamine
(0.175 g, 0.8 mmol, 1 equiv) using the conditions in step 5 in the
general methodology of key Intermediate-I. The crude compound was
purified by washing with pentane to afforded 0.06 g of
N-((2-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4-c-
arboxamide (Yield=16%). .sup.1H NMR (500 MHz, DMSO-d.sub.6):
.delta. 8.70 (d,1H, J=8.0 Hz), 8.49 (d, 1H, J=4.5 Hz), 7.79-7.75
(m, 1H), 7.41 (d, 1H, J=7.5 Hz), 7.36-7.24 (m, 7H), 6.92-6.88 (m,
3H), 6.45(d,1H, J=8.0 Hz), 4.04 (t, 2H, J=6.5 Hz), 2.91 (d, 2H,
J=10.5 Hz), 2.65 (t, 2H, J=6.0 Hz), 2.32-2.28 (m, 1H), 2.00(t, 2H,
J=10.5 Hz), 1.67-1.53 (m, 4H); ESI+MS: m/z: 450.2
([M+H].sup.+).
Example-25
N-((4(4-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4--
carboxamide (25)
##STR00126##
[0768] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid (Int-III) (0.296 g,
1.18 mmol, 1.5 equiv) and (4-fluorophenyl)(pyridin-2-yl)methanamine
(0.160 g, 0.791 mmol, 1 equiv) using the conditions in step 5 in
the general methodology of key Intermediate-I. The crude compound
was purified by washings with pentane to afford 0.18 g of
N-((4-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4-c-
arboxamide (Yield=53%).
[0769] .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 8.67 (d, 1H,
J=8.5 Hz), 8.49 (s, 1H), 7.76 (t, 1H, J=7.5 Hz), 7.43 (d, 1H, J=7.5
Hz,), 7.32 (t, 2H, J=6.5 Hz), 7.25 (d, 3H, J=7.0 Hz), 7.11 (t, 2H,
J=8.5 Hz), 6.91 (d, 2H, J=8.5 Hz), 6.12 (d, 1H, J=8.5 Hz), 4.03 (t,
2H, J=6.5 Hz), 2.93 (d, 2H, J=10.0 Hz), 2.69-2.61 (m, 2H),
2.39-2.35 (m, 1H), 2.00 (t, 2H, J=10.5 Hz), 1.69-1.61 (s, 2H), 1.56
(t, 2H, J=11.5 Hz); Ion Trap: m/z: 434.5 ([M+H].sup.+).
Example-26
N-((4(3-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4--
carboxamide (26)
##STR00127##
[0771] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid (Int-III) (0.266 g,
1.06 mmol, 1.2 equiv) and (3-fluorophenyl)(pyridin-2-yl)methanamine
(0.180 g, 0.890 mmol, 1 equiv) using the conditions in step 5 in
the general methodology of key Intermediate-I. The crude residue
was purified by column chromatography eluting with 2% MeOH in DCM
to afford 0.04 g of N-((3-dihydroindole), dihydroindole),
2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4-carboxamide
(Yield=10%). .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 8.73 (d,
1H, J=8.0 Hz), 8.51 (d, 1H, J=5.0 Hz), 7.78 (t, 1H, J=7.0 Hz), 7.47
(d, 1H, J=7.5 Hz), 7.36-7.22 (m, 4H), 7.17-7.14 (m, 2H), 7.07-7.03
(m, 1H), 6.94-6.90 (m, 3H), 6.16 (d, 1H, J=8.5 Hz), 4.14-4.07 (m,
2H), 2.98-2.95 (m, 2H), 2.69-2.64 (m, 2H), 2.38-2.35 (m, 1H),
2.07-2.03 (m, 2H), 1.70-1.58 (m, 4H). Ion Trap: m/z: 434.3
([M+H].sup.+).
Example-27
N-((4(3-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4--
carboxamide (27)
##STR00128##
[0773] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid (Int-III) (0.259 g,
1.03 mmol, 1.5 equiv) and (2-fluorophenyl)(pyridin-2-yl)methanamine
(0.140 g, 0.692 mmol, 1 equiv) using the conditions in step 5 in
the general methodology of key Intermediate-I. The crude compound
was purified by washing with pentane (4 times) to furnish 0.150 g
of
N-((3-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4-c-
arboxamide (Yield=50%). .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.71 (d, 1H, J=8.5 Hz), 8.48 (d, 1H, J=4.0 Hz), 7.77 (t,
1H, J=8.0 Hz), 7.36-7.24 (m, 6H), 7.16-7.11 (m, 2H), 6.92-6.88 (m,
3H), 6.37 (d, 1H J=8.0 Hz), 4.03 (t, 2H, J=6.0 Hz), 2.94-2.93 (m,
2H), 2.65 (t, 2H, J=11.5 Hz), 2.34-2.30 (m, 1H), 2.00 (t, 2H,
J=11.0 Hz), 1.66-1.60 (m, 2H), 1.58-1.54 (m, 2H). Ion Trap: m/z:
434.5 ([M+H].sup.+).
Example-28
N-((4(2-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4--
carboxamide (28)
##STR00129##
[0775] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid (Int-III) (0.202 g,
0.810 mmol, 1.5 equiv) and pyridin-2-yl(pyridin-4-yl)methanamine
(0.100 g, 0.540 mmol, 1 equiv) using the conditions in step 5 in
the general methodology of key Intermediate-I. The crude compound
was purified by washing with pentane (4 times) to furnish 0.025 g
of
N-((2-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4-c-
arboxamide as (Yield=11%). .sup.1H NMR (500 MHz, DMSO-d.sub.6):
.delta. 8.78 (d, 1H, J=8.5 Hz), 8.52-8.47 (m, 3H), 7.80 (t, 1H,
J=15.5 Hz), 7.49 (d, 1H, J=8.5 Hz), 7.31-7.25 (m, 5H), 6.93-6.89
(m, 3H), 6.15 (d, 1H, J=8.0 Hz), 4.04(t, 2H, J=11.5 Hz), 2.94 (bs,
2H), 2.67-2.63 (m, 2H), 2.36 (bs, 1H), 2.02 (bs, 2H), 1.72-1.64 (m,
2H), 1.60-1.53 (m, 2H); ESI+MS: m/z: 417.4 ([M+H].sup.+).
Example-29
1-(2-phenoxyethyl)-N-(pyridin-2-yl(pyridin-3-yl)methyl)piperidine-4-carbox-
amide (29)
##STR00130##
[0777] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid (Int-III) (0.202 g,
0.810 mmol, 1.5 equiv) and pyridin-2-yl(pyridin-3-yl)methanamine
(0.100 g, 0.540 mmol, 1 equiv) using the conditions in step 5 in
the general methodology of key Intermediate-I. The crude compound
was purified by washing with pentane (4 times) to furnish 0.080 g
of
1-(2-phenoxyethyl)-N-(pyridin-2-yl(pyridin-3-yl)methyl)piperidine-4-carbo-
xamide (Yield=36%). .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta.
8.78 (d, 1H, J=8.0 Hz), 8.536-8.51 (m, 2H), 8.43-8.42 (m, 1H), 7.79
(t, 1H, J=15.0 Hz), 7.69 (d, 1H, J=8.0 Hz), 7.48 (d, 1H, J=8.0 Hz),
7.34-7.25 (m, 4H), 6.91 (t, 3H, J=16.5 Hz), 6.18 (d, 1H, J=8.0 Hz),
4.04 (t, 2H, J=11.5 Hz), 2.94 (d, 2H, J=11.5 Hz), 2.66-2.63 (m,
2H), 2.35-2.31 (m, 2H), 2.02 (t, 2H, J=12.0 Hz), 1.67 (d, 2H,
J=12.5 Hz), 1.58-1.55 (m, 2H); ESI+MS: m/z: 417.4
([M+H].sup.+).
Example-30
N-(di(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4-carboxamide
(30)
##STR00131##
[0779] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid (Int-III) (0.202 g,
0.810 mmol, 1.5 equiv) and di(pyridin-2-yl)methanamine (0.100 g,
0.540 mmol, 1 equiv) using the conditions in step 5 in the general
methodology of key Intermediate-I. The crude compound was purified
by washing with pentane (4 times) to furnish 0.090 g of
N-(di(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4-carboxamide
(Yield=40%). .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 8.69 (d,
1H, J=7.6 Hz), 8.47-8.46 (m, 2H), 7.77-7.73 (m, 2H), 7.45 (d, 2H,
J=7.6 Hz), 7.29-7.23 (m, 4H), 6.92 (t, 3H, J=16.0 Hz), 6.17 (d, 1H,
J=8.0 Hz), 4.06 (s, 2H), 2.95 (s, 2H), 2.73-2.67 (m, 2H), 2.41 (s,
1H), 2.03 (s, 2H), 1.69 (s, 2H), 1.580 (d, 2H, J=10.8 Hz); ESI+MS:
m/z: 417.5 ([M+H].sup.+).
Example-31
1-(2-phenoxyethyl)-N-(pyridin-2-yl(4-(trifluoromethyl)phenyl)methyl)
piperidine-4-carboxamide (31)
##STR00132##
[0781] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.166 g, 0.66
mmol, 1.2 equiv) and pyridin-2-yl(4-(trifluoromethyl) phenyl)
methanamine (0.140 g, 0.55 mmol, 1 equiv) using the conditions in
step 5 in the general methodology of key Intermediate-I. The crude
compound was purified by HPLC to afford 0.030 g of
1-(2-phenoxyethyl)-N-(pyridin-2-yl(4-(trifluoromethyl)phenyl)methyl)piper-
idine-4-carboxamide (Yield=11%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 8.79 (d, 1H, J=8.0 Hz), 8.52 (d, 1H, J=4.0
Hz), 7.80 (t, 1H, J=7.5 Hz), 7.67 (d, 2H, J=8.0 Hz), 7.55-7.48 (m,
3H), 7.30-7.25 (m, 3H), 6.93-6.90 (m, 3H), 6.23 (d, 1H, J=7.5 Hz),
4.05 (t, 2H, J=6.0 Hz), 2.95 (d, 2H, J=10.0 Hz), 2.68-2.67 (m, 2H),
2.38-2.35 (m, 1H), 2.04-2.00 (m, 2H), 1.69-1.67 (m, 2H), 1.61-1.56
(m, 2H). ESI+MS: m/z: 484.3 ([M+H].sup.+).
Example-32
1-(2-phenoxyethyl)-N-(pyridin-2-yl(3-(trifluoromethyl)phenyl)methyl)
piperidine-4-carboxamide (32)
##STR00133##
[0783] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.178 g, 0.714
mmol, 1.2 equiv) and pyridin-2-yl(3-(trifluoromethyl) phenyl)
methanamine (0.150 g, 0.595 mmol, 1 equiv) using the conditions in
step 5 in the general methodology of key Intermediate-I. The crude
residue was purified by column chromatography (2% MeOH in DCM as
eluent) to afford 0.040 g of
1-(2-phenoxyethyl)-N-(pyridin-2-yl(3-(trifluoromethyl)phenyl)
methyl) piperidine-4-carboxamide (Yield=13%).
[0784] .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 8.81 (d, 1H,
J=3.5 Hz), 8.52 (d, 1H, J=4.5 Hz), 7.81-7.79 (m, 1H), 7.69 (s, 1H),
7.65-7.50 (m, 4H), 7.30-7.25 (m, 3H), 6.93-6.90 (m, 3H), 6.25 (d,
1H, J=8.0 Hz), 4.05 (t, 2H, J=6.0 Hz), 2.95 (d, 2H, J=10.0 Hz),
2.68-2.63 (m, 2H), 2.38-2.34 (m, 1H), 2.02 (t, 2H, J=11.5 Hz),
1.67-1.64 (m, 2H), 1.58-1.56 (m, 2H). Ion Trap: m/z: 484.5
([M+H].sup.+).
Example-33
1-(2-phenoxyethyl)-N-(pyridin-2-yl(2-(trifluoromethyl)phenyl)methyl)
piperidine-4-carboxamide (33)
##STR00134##
[0786] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.119 g, 0.476
mmol, 1.2 equiv) and pyridin-2-yl(2-(trifluoromethyl) phenyl)
methanamine (0.100 g, 0.396 mmol, 1 equiv) using the conditions in
step 5 in the general methodology of key Intermediate-I. The crude
compound was purified by prep HPLC and afforded 0.025 g of
1-(2-phenoxyethyl)-N-(pyridin-2-yl(2-(trifluoromethyl)phenyl)methyl)
piperidine-4-carboxamide (Yield=13%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 8.72 (d, 1H, J=5.0 Hz), 8.47 (d, 1H, J=4.5
Hz), 7.80-7.77 (m, 1H), 7.71 (d, 1H, J=7.5 Hz), 7.64 (t, 1H, J=7.5
Hz), 7.48 (d, 2H, J=6.5 Hz), 7.27 (t, 4H, J=8.5 Hz), 6.93-6.90 (m,
3H), 6.48 (d, 1H, J=7.5 Hz), 4.04 (t, 2H, J=6.0 Hz), 2.96-2.92 (m,
2H), 2.67-2.64 (m, 2H), 2.29-2.25 (m, 1H), 2.20-1.96 (m, 2H),
1.70-1.67 (m, 1H), 1.61-1.52 (m, 3H). ESI+MS: m/z: 484.3
([M+H].sup.+).
Example-34
N-((4(4-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4-
-carboxamide (34)
##STR00135##
[0788] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.251 g, 1.008
mmol, 1.2 equiv) and (4-methoxyphenyl)(pyridin-2-yl)methanamine
(0.180 g, 0.840 mmol, 1 equiv) using the conditions in step 5 in
the general methodology of key Intermediate-I. The crude residue
was purified by column chromatography (2% MeOH in DCM as elutant)
to afford 0.050 g of
N-((4(4-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide (Yield=13%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 8.59 (d, 1H, J=8.5 Hz), 8.47 (d, 1H, J=3.5
Hz), 7.76-7.71 (m, 1H), 7.39 (d, 1H, J=8.0 Hz), 7.27-7.18 (m, 5H),
6.91 (d, 3H, J=8.0 Hz), 6.83 (d, 2H, J=8.0 Hz), 6.04 (d, 1H, J=8.5
Hz), 4.06-4.03 (m, 2H), 3.69 (s, 3H), 2.97-2.93 (m, 2H), 2.68-2.59
(m, 1H), 2.00-1.97 (m, 4H), 1.64-1.56 (m, 4H); ESI+MS: m/z: 446.6
([M+H].sup.+).
Example-35
N-((4(3-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4-
-carboxamide (35)
##STR00136##
[0790] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.227 g, 0.910
mmol, 1.5 equiv) and (3-methoxyphenyl)(pyridin-2-yl)methanamine
(0.130 g, 0.607 mmol, 1 equiv) using the conditions in step 5 in
the general methodology of key Intermediate-I. The crude residue
was purified by washing with pentane to furnish 0.060 g of
N-((3-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4--
carboxamide (Yield=22%). .sup.1H NMR (500 MHz, DMSO-d.sub.6):
.delta. 8.64 (d, 1H, J=8.5 Hz), 8.49 (d, 1H, J=4.5 Hz), 7.75 (t,
1H, J=8.0 Hz), 7.43 (d, 1H, J=8.0 Hz), 7.27-7.17 (m, 4H), 6.91-6.85
(m, 5H), 6.77 (d, 1H, J=7.5 Hz), 6.08 (d, 1H, J=8.5 Hz), 4.04 (t,
2H, J=5.5 Hz), 3.69 (s, 3H), 2.94 (d, 2H, J=9.5 Hz), 2.65-2.62 (m,
2H), 2.34-2.31 (m, 1H), 2.02 (t, 2H, J=11 Hz), 1.68-1.59 (m, 2H),
1.59-1.54 (m, 2H); ESI+MS: m/z: 446.3 ([M+H].sup.+). Enantiomers of
35 were separated using chiral HPLC (method J) and afforded pure
enantiomers 35a and 35b. The absolute configuration of 35b was
confirmed to be (S) through crystallization of
(S)-(3-methoxyphenyl)(pyridin-2-yl)methanamine hydrochloride (see
ortep representation on FIG. 7).
Example-36
N((2-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide (36)
##STR00137##
[0792] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.251 g, 1.008
mmol, 1.2 equiv) and (2-methoxyphenyl)(pyridin-2-yl)methanamine
(0.180 g, 0.840 mmol, 1 equiv) using the conditions in step 5 in
the general methodology of key Intermediate-I. The crude residue
was purified by column chromatography (2% MeOH in DCM as eluent)
afforded 0.050 g
N-((2-methoxyphenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide (Yield=13%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 8.51 (d, 1H, J=8.0 Hz), 8.44 (d, 1H, J=5.0
Hz), 7.73-7.69 (m, 1H), 7.28-7.19 (m, 6H), 6.95-6.87 (m, 5H), 6.40
(d, 1H, J=8.0 Hz), 4.03-4.00 (m, 2H), 3.73 (s, 3H), 2.95-2.91 (m,
2H), 2.69-2.63 (m, 2H), 2.35-2.31 (m, 1H), 1.99-1.95 (m, 2H),
1.64-1.62 (m, 2H), 1.56-1.52 (m, 2H); ESI+MS: m/z: 446.5
([M+H].sup.+).
Example-37
N-(cyclohexyl(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4-carboxam-
ide (37):
##STR00138##
[0794] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.283 g, 1.13
mmol, 1.2 equiv) and cyclohexyl(pyridin-2-yl)methanamine (0.180 g,
0.946 mmol, 1 equiv) using the conditions in step 5 in the general
methodology of key Intermediate-I. The crude residue was purified
by column chromatography (2% MeOH in DCM as eluent) and afforded
0.030 g of
N-(cyclohexyl(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4-carboxa-
mide (Yield=7%). .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 8.51
(d, 1H, J=8.0 Hz), 8.44 (d, 1H, J=5.0 Hz), 7.73-7.69 (m, 1H),
7.28-7.19 (m, 4H), 6.95-6.87 (m, 3H), 4.69 (t, 1H, J=17.0 Hz), 4.04
(t, 2H, J=12.0 Hz), 2.96-2.90 (m, 2H), 2.67-2.50 (m, 2H), 2.30-2.22
(m, 1H), 2.04-1.97 (m, 2H), 1.78-1.76 (m, 1H), 1.66 (bs,3H),
1.60-1.48 (m, 4H), 1.23-1.09 (m, 2H), 1.09 (bs,3H), 1.00-0.89 (m,
2H); ESI+MS: m/z: 446.5 ([M+H].sup.+).
Example-38
N-(2-methyl-1-(pyridin-2-yl)propyl)-1-(2-phenoxyethyl)piperidine-4-carboxa-
mide (38)
##STR00139##
[0796] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.199 g, 0.799
mmol, 1.2 equiv) and 2-methyl-1-(pyridin-2-yl)propan-1-amine (0.100
g, 0.666 mmol, 1 equiv) using the conditions in step 5 in the
general methodology of key Intermediate-I. The crude compound was
purified by column chromatography (2% MeOH in DCM as elutant)
afforded 0.050 g of
N-(2-methyl-1-(pyridin-2-yl)propyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide (Yield=20%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 8.50 (d, 1H, J=4.0 Hz), 8.02 (d, 1H, J=9.0
Hz), 7.74-7.71 (m, 1H), 7.30-7.22 (m, 4H), 6.93-6.90 (m, 3H), 4.69
(t, 1H, J=8.0 Hz), 4.04 (t, 2H, J=6.0 Hz), 2.96 2.91 (m, 2H),
2.67-2.65 (m, 2H), 2.29-2.25 (m, 1H), 2.15-2.10 (m, 1H), 2.05-1.98
(m, 2H), 1.70-1.67 (m, 1H), 1.62-1.50 (m, 3H), 0.83 (d, 3H, J=6.0
Hz), 0.72 (d, 3H, J=7.0 Hz). Ion trap: m/z: 382.4
([M+H].sup.+).
Example-39
N-((4(4-chlorophenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-carbox-
amide (39)
##STR00140##
[0798] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.275 g, 1.10
mmol, 1.2 equiv) and (4-chlorophenyl)(phenyl)methanamine (0.200 g,
0.919 mmol, 1 equiv) using the conditions in step 5 in the general
methodology of key Intermediate-I. The crude residue was purified
by column chromatography (2% MeOH in DCM as eluent) furnished 0.060
g of
N-((4-chlorophenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-carboxa-
mide (Yield=14%). .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 8.67
(d, 1H, J=8.5 Hz), 7.37 (d, 2H, J=8.5 Hz), 7.33-7.22 (m, 9H),
6.92-6.89 (m, 3H), 6.09 (d, 1H, J=8.0 Hz), 4.10-4.04 (m, 2H),
2.96-2.95 (m, 2H), 2.67-2.63 (m, 2H), 2.28-2.26 (m, 1H), 2.04-2,01
(m, 2H), 1.66-1.58 (m, 4H); ESI+MS: m/z: 449.5 ([M+H].sup.+).
Example-40
N((4-chlorophenyl)(2-fluorophenyl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide (40)
##STR00141##
[0800] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.076 g, 0.305
mmol, 1.2 equiv) and (4-chlorophenyl)(2-fluorophenyl)methanamine
(0.060 g, 0.255 mmol, 1 equiv) using the conditions in step 5 in
the general methodology of key Intermediate-I. The crude residue
was purified by prep HPLC afforded 0.030 g of
N-((4-chlorophenyl)(2-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-
-carboxamide (Yield=24%). .sup.1H NMR (500 MHz, DMSO-d.sub.6):
.delta. 8.72 (d, 1H, J=8.5 Hz), 7.41-7.32 (m, 4H), 7.29-7.16 (m,
6H), 6.93-6.90 (m, 3H), 6.33 (d, 1H, J=8.0 Hz), 4.06 (t, 2H, J=5.5
Hz), 2.97-2.95 (m, 2H), 2.68-2.64 (m, 2H), 2.29-2.27 (m, 1H),
2.05-2.02 (m, 2H), 1.68-1.57 (m, 4H); ESI+MS: m/z: 467.5
([M+H].sup.+). Enantiomers of 40 were separated using chiral HPLC
(method K) and afforded pure enantiomers 40a and 40b.
Example-41
N-((4(4-chlorophenyl)(3-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperidine--
4-carboxamide (41)
##STR00142##
[0802] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.178 g, 0.713
mmol, 1.2 equiv) and (4-chlorophenyl)(3-fluorophenyl)methanamine
(0.140 g, 0.594 mmol, 1 equiv) using the conditions in step 5 in
the general methodology of key Intermediate-I. The crude residue
was purified by prep HPLC furnished 0.030 g of
N-((4-chlorophenyl)(3
-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-carboxamide
(Yield=11%). .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.35-7.33
(m, 3H), 7.29-7.21 (m, 4H), 7.05 (d, 1H, J=6.4 Hz), 7.02-6.93 (m,
5H), 6.17 (s, 1H), 4.19 (t, 2H, J=4.8 Hz), 3.31-3,34 (m, 2H),
3.083.05(m, 2H), 2.53-2.46 (m, 3H), 1.92-1.90 (m, 4H); ESI+MS: m/z:
467.3 ([M+H].sup.+).
Example-42
N-((4(4-chlorophenyl)(4-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperidine--
4-carboxamide (42)
##STR00143##
[0804] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.152 g, 0.611
mmol, 1.2 equiv) and (4-chlorophenyl)(4-fluorophenyl)methanamine
(0.120 g, 0.509 mmol, 1 equiv) using the conditions in step 5 in
the general methodology of key Intermediate-I. The crude residue
was purified by column chromatography eluting with 2% MeOH in DCM
as elutant affording 0.035 g N-((4-chlorophenyl)
(4-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-carboxamide
(Yield=15%). .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.36-7.32
(m, 2H), 7.28-7.21 (m, 6H), 7.09-7.05 (m, 2H), 6.94-6.90 (m, 3H),
6.16 (s, 1H), 4.13 (t, 2H, J=5.6 Hz), 3.12 (d, 2H, J=11.6 Hz), 2.83
(t, 2H, J=5.6 Hz), 2.38-2.36 (m, 1H), 2.28-2.21 (m, 2H), 1.92-1.82
(m, 4H). ESI+MS: m/z: 467.2 ([M+H].sup.+). Enantiomers of 42 were
separated using chiral HPLC (method K) and afforded pure
enantiomers 42a and 42b.
Example-43
N-((4(4-chlorophenyl)(2-methoxyphenyl)methyl)-1-(2-phenoxyethyl)piperidine-
-4-carboxamide (43)
##STR00144##
[0806] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.145 g, 0.581
mmol, 1.2 equiv) and (4-chlorophenyl)(2-methoxyphenyl) methanamine
(0.120 g, 0.484 mmol, 1 equiv) using the conditions in step 5 in
the general methodology of key Intermediate-I. The crude residue
was purified by column chromatography (2% MeOH in DCM as eluent)
furnished 0.080 g of
N-((4-chlorophenyl)(2-methoxyphenyl)methyl)-1-(2-phenoxyethyl)piperidine--
4-carboxamide (Yield=34%). .sup.1H NMR (500 MHz, CD.sub.3OD):
.delta. 7.33-7.29 (m, 5H), 7.18 (d, 3H, J=8.0 Hz), 7.01-6.93 (m,
5H), 6.43 (s, 1H), 4.32 (t, 2H, J=5.0 Hz), 3.78 (s, 3H), 3.62-3.58
(m, 2H), 3.46-3.44 (m, 2H), 3.02-3.00 (m, 2H), 2.68-2.64 (m, 1H),
2.03 (d, 4H, J=16.5 Hz). ESI+MS: m/z: 479.2 ([M+H].sup.+).
Example-44
N-((4(4-chlorophenyl)(4-methoxyphenyl)methyl)-1-(2-phenoxyethyl)piperidine-
-4-carboxamide (44)
##STR00145##
[0808] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.121 g, 0.484
mmol, 1.2 equiv) and (4-chlorophenyl)(4-methoxyphenyl)methanamine
(0.100 g, 0.404 mmol, 1 equiv) using the conditions in step 5 in
the general methodology of key Intermediate-I. The crude residue
was purified by column chromatography eluting with (2% MeOH in DCM
as eluent) afforded 0.056 g of
N-((4-chlorophenyl)(4-methoxyphenyl)methyl)-1-(2-phenoxyethyl)piperidine--
4-carboxamide (Yield=29%). .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 7.33-7.26 (m, 4H), 7.21 (d, 2H, J=8.4 Hz), 7.13 (d, 2H,
J=8.8 Hz), 6.96-6.93 (m, 3H), 6.88 (d, 2H, J=8.4 Hz), 6.09 (s, 1H),
4.21 (t, 2H, J=5.6 Hz), 3.80 (s, 3H), 3.35-3.34 (m, 2H), 3.12-3.11
(m, 2H), 2.60-2.59 (m, 2H), 2.50-2.46 (m, 1H), 1.93-1.91 (m, 4H);
ESI+MS: m/z: 479.3 ([M+H].sup.+).
Example-45
N-((4(4-fluorophenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-carbox-
amide (45)
##STR00146##
[0810] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.223 g, 0.894
mmol, 1.2 equiv) and (4-fluorophenyl)(phenyl)methanamine (0.150 g,
0.745 mmol, 1 equiv) using the conditions in step 5 in the general
methodology of key Intermediate-I. The crude compound was purified
by prep. HPLC column chromatography to furnish 0.060 g of
N-((4-fluorophenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-carboxa-
mide (Yield=19%). .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.
7.34-7.31 (m, 2H), 7.28-7.22 (m, 7H), 7.04 (t, 2H, J=10.0 Hz),
6.93-6.91 (m, 3H), 6.16 (s, 1H), 4.15 (t, 2H, J=5.6 Hz), 3.17 (d,
2H, J=11.6 Hz), 2.93-2.91 (m, 2H), 2.41-2.35 (m, 3H), 1.89-1.83 (m,
4H); ESI+MS: m/z: 433.2 ([M+H].sup.+). Enantiomers of 45 were
separated using chiral HPLC (method H) and afforded pure
enantiomers 45a and 45b.
Example-46
N-((4(3-methoxyphenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-carbo-
xamide (46)
##STR00147##
[0812] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.210 g, 0.844
mmol, 1.2 equiv) and (4-fluorophenyl)(phenyl)methanamine (0.150 g,
0.703 mmol, 1 equiv) using the conditions in step 5 in the general
methodology of key Intermediate-I. The crude residue was purified
by silica gel column chromatography (2% MeOH in DCM as elutant)
afforded 0.035 g of
N-((3-methoxyphenyl)(phenyl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide. (Yield=11%). .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 7.33-7.30 (m, 2H), 7.28-7.21 (m, 6H),
6.93-6.90 (m, 3H), 6.83-6.80 (m, 3H), 6,13 (s, 1H), 4.14 (t, 2H,
J=5.6 Hz), 3.74(s, 3H), 3.15 (d, 2H, J=12.0 Hz), 2.88 (t, 2H, J=5.2
Hz), 2.45-2.37 (m, 1H), 2.34-2.28 (m, 2H), 1.92-1.84 (m, 4H);
ESI+MS: m/z: 445.3 ([M+H].sup.+).
Example-47
N-(bis(4-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-carboxamide
(47)
##STR00148##
[0814] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.205 g, 0.821
mmol, 1.2 equiv) and bis(4-fluorophenyl)methanamine (0.150 g, 0.684
mmol, 1 equiv) using the conditions in step 5 in the general
methodology of key Intermediate-I. The crude compound was purified
by prep HPLC purification to furnish 0.010 g of
N-(bis(4-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-carboxamide
(Yield=4%). .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.30-7.24
(m, 6H), 7.10-7.06 (m, 4H), 6.95-6,92 (m, 3H), 6.19 (s, 1H), 4.14
(t, 2H, J=5.6 Hz), 3.13 (d, 2H, J=11.6 Hz), 2.85 (t, 2H, J=5.2 Hz),
2.41-2.35 (m, 1H), 2.25 (dt, 2H, J.sub.1,2=4.4 Hz, J.sub.1,4=14.8
Hz), 1.92-1.82 (m, 4H); Ion trap: m/z: 451.4 ([M+H].sup.+).
Example-48
N-(bis(2-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-carboxamide
(48)
##STR00149##
[0816] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.171 g, 0.684
mmol, 1.2 equiv) and bis(2-fluorophenyl)methanamine (0.125 g, 0.570
mmol, 1 equiv) using the conditions in step 5 in the general
methodology of key Intermediate-I. The crude residue was purified
by column chromatography (5% MeOH in DCM as eluent) furnished
N-(bis(2-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-carboxamide
0.025 g (Yield=9%). .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.
7.35-7.28 (m, 4H), 7.24-7.09 (m, 6H), 6.99-6.96 (m, 3H), 6.67 (s,
1H), 4.26 (t, 2H, J=5.2 Hz), 3.44 (d, 2H, J=12.0 Hz), 3.26-3.25 (m,
2H), 2.82-2.77 (m, 2H), 2.60-2.52 (m, 1H), 1.99-1,93 (m, 4H);
ESI+MS: m/z: m/z: 451.5 ([M+H].sup.+).
Example-49
N-((2-fluorophenyl)(4-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperidine-4--
carboxamide (49)
##STR00150##
[0818] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.205 g, 0.821
mmol, 1.2 equiv) and (2-fluorophenyl)(4-fluorophenyl)methanamine 4
(0.150 g, 0.684 mmol, 1 equiv) using the conditions in step 5 in
the general methodology of key Intermediate-I. The crude residue
was purified by column chromatography (2% MeOH in DCM as eluent)
afforded 0.040 g
N-((2-fluorophenyl)(4-fluorophenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-
-carboxamide (Yield=13%). .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 7.35-7.16 (m, 6H), 7.13-6.99 (m, 7H), 6.41 (s, 1H), 4.35
(t, 2H, J=4.8 Hz), 3.68-3.66 (m, 2H), 3,57 (t, 2H, J=4.8 Hz),
3.13-3.11 (m, 2H), 2.69-2.67 (m, 1H), 2.09-2,03 (m, 4H); ESI+MS:
m/z 451.5 ([M+H].sup.+).
Example-50
N-((4(2-fluorophenyl)(3-methoxyphenyl)methyl)-1-(2-phenoxyethyl)piperidine-
-4-carboxamide (50)
##STR00151##
[0820] Title compound was prepared from coupling of
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.194 g, 0.778
mmol, 1.2 equiv) and (2-fluorophenyl)(3-methoxyphenyl) methanamine
4 (0.150 g, 0.649 mmol, 1 equiv) using the conditions in step 5 in
the general methodology of key Intermediate-I. The crude compound
was purified by column chromatography (2% MeOH in DCM as eluent)
afforded 0.080 g of N-((2-fluorophenyl)(3-methoxy
phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-carboxamide
(Yield=26%). .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.34-7.21
(m, 5H), 7.17-7.06 (m, 2H), 6.92-6.89 (m, 3H), 6.84-6.81 (m, 1H),
6.81-6.77 (m, 2H), 6.40 (s, 1H), 4.11 (t, 2H, J=5.6 Hz), 3.74 (s,
3H), 3.13-3.07 (m, 2H), 2.81 (t, 2H, J=5.6 Hz), 2.42-2.34 (m, 1H),
2.26-2.19 (m, 2H), 1.90-1.78 (m, 4H); ESI+MS: m/z: 463.6
([M+H].sup.+).
Example-51
N((4-chlorophenyl)(pyridin-2-yl)methyl)-N-methyl-1-(2-phenoxyethyl)
piperidine-4-carboxamide (51)
##STR00152##
[0821] 1-(4-chlorophenyl)-N-methyl-1-(pyridin-2-yl)methanamine
##STR00153##
[0823] Title compound was prepared by reductive amination of
(4-chlorophenyl)(pyridin-2-yl)methanone (1 g, 4.59 mmol) using the
general methodology of Example-59 and afforded 0.5 g of
1-(4-chlorophenyl)-N-methyl-1-(pyridin-2-yl)methanamine
(Yield=47%).
tert-butyl-4-(((4-chlorophenyl)(pyridin-2-yl)methyl)(methyl)carbamoyl)pip-
eridine-1-carboxylate:
##STR00154##
[0824] Title compound was prepared from coupling of 1
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0.049 g, 0.215
mmol, 1 equiv) and
1-(4-chlorophenyl)-N-methyl-1-(pyridin-2-yl)methanamine (0.050 g,
0.215 mmol, 1 equiv) using the conditions in step 5 in the general
methodology of key Intermediate-I and afforded 0.060 g of
tert-butyl
4-(((4-chlorophenyl)(pyridin-2-yl)methyl)(methyl)carbamoyl)piperidine-1-c-
arboxylate. Crude material was used in the next step without
further purification.
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-methylpiperidine-4-carboxamide
##STR00155##
[0826] Title compound was prepared from deprotection of (tert-butyl
4-(((4-chlorophenyl)(pyridin-2-yl)methyl)(methyl)carbamoyl)piperidine-1-c-
arboxylate (0.180 g, 0.405 mmol) using the conditions described in
step 6 in the general methodology of key Intermediate-I and
afforded 0.1 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-methylpiperidine-4-carboxamide
(Yield=72%).
##STR00156##
[0827] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-methyl
piperidine-4-carboxamide (0.1 g, 0.29 mmol) using the general
methodology of Example-1. The crude residue was purified by prep
HPLC purification to afford 0.039 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-methyl-1-(2-phenoxyethyl)piper-
idine-4-carboxamide (Yield=21%). .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 8.57-8.56 (m, 1H), 7.81 (t, 1H, J=7.6 Hz), 7.40-7.33 (m,
3H), 7.29-7.23 (m, 3H), 7.14 (d, 2H, J=6.8 Hz), 7.06 (d, 1H, J=8.4
Hz), 6.97-6.89 (m, 4H), 4.13 (t, 2H, J=5.6 Hz), 3.14-3.12 (m, 2H),
2.97 (s, 3H), 2.67-2.63 (m, 2H), 2.13-2.07 (m, 2H), 1.72-1.57 (m,
4H); ESI+MS: m/z: 464.4 ([M+H].sup.+).
Synthesis of Intermediate IV
##STR00157##
[0828] tert-butyl
4-(((4-fluorophenyl)(pyridin-2-yl)methyl)carbamoyl)piperidine-1-carboxyla-
te
##STR00158##
[0830] Title compound was prepared from
(4-fluorophenyl)(pyridin-2-yl)methanamine (0.5 g, 2.47 mmol using
the conditions in step 5 in the general methodology of key
Intermediate-I and afforded 0.8 g of tert-butyl
4-(((4-fluorophenyl)(pyridin-2-yl)methyl)carbamoyl)piperidine-1-carboxyla-
te (Yield=78%).
N-((4-fluorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
##STR00159##
[0832] To a stirred solution of tert-butyl
4-(((4-fluorophenyl)(pyridin-2-yl)methyl)carbamoyl)
piperidine-1-carboxylate (0.8 g, 1.93 mmol) in MeOH (5 mL) was
added 2M HCl in ether (0.47 mL, 9.67 mmol, 5 equiv) at 0.degree. C.
The reaction mixture was warmed to room temperature and stirred for
3 h. After completion of the reaction, the volatiles were removed
under reduced pressure. The pH was adjusted to 7 with saturated
NaHCO.sub.3 solution and extracted with EtOAc (3.times.50 mL). The
combined organic extract was dried over sodium sulphate, filtered
and concentrated under reduced pressure to afford 0.5 g of
N-((4-fluorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(Yield=82%).
Example-52
N-((4(4-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-(trifluoromethyl)phenox-
y)ethyl) piperidine-4-carboxamide (52)
##STR00160##
[0834] Title compound was prepared from
N-((4-fluorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
key Intermediate-IV (0.150 g, 0.47 mmol) using the general
methodology of Example-1. Purification using preparative HPLC
afforded 0.005 g of
N-((4-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-(trifluoromethyl)phenoxy-
)ethyl)piperidine-4-carboxamide (Yield=2%). .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 8.52 (d, 1H, J=4.8 Hz), 7.81-7.71 (m, 1H),
7.55 (t, 2H, J=7.6 Hz), 7.37 (d, 1H, J=7.6 Hz), 7.31-7.27 (m, 3H),
7.16 (d, 1H, J=8.4 Hz), 7.06-7.01 (m, 3H), 6.16 (s, 1H), 4.23 (t,
2H, J=5.6 Hz), 3.01 (d, 2H, J=12.2 Hz), 2.85 (t, 2H, J=5.2 Hz),
2.44-2.36 (m, 1H), 2.30-2.23 (m, 2H), 1.83-1.74 (m, 4H). ESI+MS:
m/z: 502 ([M+H].sup.+). Enantiomers of 52 were separated using
chiral HPLC (method A) and afforded pure enantiomers 52a and
52b.
Example-53
1-(2-(2-chlorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)
piperidine-4-carboxamide (53)
##STR00161##
[0836] Title compound was prepared from
N-((4-fluorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
key Intermediate-IV (0.150 g, 0.47 mmol) using the general
methodology of Example-1. The product was purified by using silica
gel column chromatography (3% MeOH/DCM as eluent) afforded 0.040 g
of
1-(2-(2-chlorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)pipe-
ridine-4-carboxamide (Yield=17%). .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 8.52-8.51 (m, 1H), 7.79 (dt, 1H, J.sub.1,2=1.6
Hz, J.sub.1,4=9.6 Hz), 7.39 (d, 1H, J=8.0 Hz), 7.34 (dd, 1H,
J.sub.1,2=1.6 Hz, J.sub.1,3=7.6 Hz), 7.32-7.26 (m, 3H), 7.25-7.22
(m, 1H), 7.07-7.06 (m, 1H), 7.05-7.01 (m, 2H), 6.91 (dt, 1H,
J.sub.1,2=1.6 Hz, J.sub.1,4=9.2 Hz), 6.16 (s, 1H), 4.20 (t, 2H,
J=5.6 Hz), 3.17 (t, 2H, J=11.6 Hz), 2.90 (t, 2H, J=5.2 Hz),
2.46-2.38 (m, 1H), 2.37-2.30 (m, 2H), 1.85-1.80 (m, 4H); ESI+MS:
m/z: 468.2 ([M+H].sup.+). Enantiomers of 53 were separated using
chiral HPLC (method A) and afforded pure enantiomers 53a and
53b.
Example-54
1-(2-(2-fluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)
piperidine-4-carboxamide (54)
##STR00162##
[0838] Title compound was prepared from
N-((4-fluorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
key intermediate IV (0.150 g, 0.47 mmol) using the general
methodology of Example-1.The product was purified by using silica
gel column chromatography (3% MeOH/DCM as eluent) afforded 0.040 g
of
1-(2-(2-fluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)pipe-
ridine-4-carboxamide (Yield=19%). .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 8.52 (d, 1H, J=4.4 Hz), 7.79 (dt, 1H,
J.sub.1,2=1.6 Hz, J.sub.1,4=9.2 Hz), 7.39 (d, 1H, J=8.0 Hz),
7.32-7.27 (m, 3H), 7.11-7.01 (m, 5H), 6.94-6.88 (m, 1H), 6.16 (s,
1H), 4.19 (t, 2H, J=5.6 Hz), 3.11(d, 2H, J=7.2 Hz), 2.85 (t, 2H,
J=5.6 Hz), 2.45-2.37 (m, 1H), 2.30-2.24 (m, 2H), 1.85-1.79 (m, 4H);
ESI+MS: m/z:452.2 ([M+H].sup.+). Enantiomers of 54 were separated
using chiral HPLC (method B) and afforded pure enantiomers 54a and
54b.
Example-55
1-(2-(benzo[d]thiazol-6-yloxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)meth-
yl)piperidine-4-carboxamide (55)
##STR00163##
[0840] Title compound was prepared from
N-((4-fluorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
key Intermediate-IV (0.1 g, 0.31 mmol) using the general
methodology of Example-1. The crude residue was purified by column
chromatography and further purified by Prep HPLC to afford 0.013 g
of 1-(2-(benzo[d]thiazol-6-yloxy)ethyl)-N-((4-fluorophenyl)
(pyridin-2-yl)methyl)piperidine-4-carboxamide Yield (8%). .sup.1H
NMR (400 MHz, CD.sub.3OD): .delta. .delta. 9.03 (s, 1H), 8.52 (d,
1H, J=4.4 Hz), 7.92 (d, 1H, J=9.2 Hz), 7.78 (dt, 1H, J.sub.1,2=2.0
Hz, J.sub.1,4=9.6 Hz), 7.59 (d, 1H, J=2.0 Hz), 7.38 (d, 1H, J=8.0
Hz), 7.31-7.27 (m, 3H), 7.16 (dd, 1H, J.sub.1,2=2.4 Hz,
J.sub.1,3=9.2 Hz), 7.06-7.01 (m, 2H), 6.16 (s, 1H), 4.20 (t, 2H,
J=5.6 Hz), 3.09 (d, 2H, J=12.0 Hz), 2.84 (t, 2H, J=5.6 Hz),
2.45-2.37 (m, 1H), 2.26-2.19 (m, 2H), 1.85-1.80 (m, 4H); ESI+MS:
m/z:491.4 ([M+H].sup.+).
Example-56
1-(2-(2,6-difluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)
piperidine-4-carboxamide (56)
##STR00164##
[0842] Title compound was prepared from
N-((4-fluorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
key Intermediate-IV (0.120 g, 0.38 mmol) using the general
methodology of Example-1. The product was purified by using silica
gel column chromatography (3% MeOH/DCM as eluent) and further
purified by prep HPLC purification to afford 0.030 g
1-(2-(2,6-difluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)-
piperidine-4-carboxamide (Yield=17%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 8.68 (d, 1H, J=8.0 Hz), 8.51 (d, 1H, J=4.0
Hz), 7.78 (t, 1H, J=8.0 Hz), 7.44 (d, 1H, J=8.0 Hz), 7.35-7.28 (m,
2H), 7.28-7.26 (m, 1H), 7.15-7.09 (m, 5H), 6.13 (d, 1H, J=8.0 Hz),
4.17 (t, 2H, J=5.0 Hz), 2.89 (d, 2H, J=11.0 Hz), 2.65 (t, 2H, J=5.5
Hz), 2.33-2.29 (m, 1H), 2.00 (t, 2H, J=11.0 Hz), 1.65-1.63 (m, 2H),
1.52-1.45 (m, 2H); ESI+MS: m/z: 470.5 ([M+H].sup.+).
Example-57
1-(2-(2,5-difluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)
piperidine-4-carboxamide (57)
##STR00165##
[0844] Title compound was prepared from
N-((4-fluorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
key Intermediate-IV (0.1 g, 0.31 mmol) using the general
methodology of Example-1. The product was purified by silica gel
column chromatography (2% MeOH/DCM as eluent) to afford 0.060 g of
1-(2-(2,5-difluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)-
piperidine-4-carboxamide (Yield=40%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 8.69 (d, 1H, J=8.5 Hz), 8.51 (d, 1H, J=4.5
Hz), 7.85 (t, 1H, J=8.0 Hz), 7.45 (d, 1H, J=8.0 Hz), 7.35-7.22 (m,
4H), 7.16-7.13 (m, 3H), 6.76 (t, 1H, J=8.0 Hz), 6.14 (d, 1H, J=8.5
Hz), 4.15 (t, 2H, J=5.5 Hz), 2.96-2.94 (m, 2H), 2.69-2.67 (m, 2H),
2.36-2.31 (m, 1H), 2.05-2.01 (m, 2H), 1.67-1.65 (m, 2H), 1.66-1.54
(m, 2H); ESI+MS: m/z: 470.5 ([M+H].sup.+).
Example-58
N-((4(4-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-methyl-1-phenoxypropan-2-y-
l)piperidine-4-carboxamide (58)
##STR00166## ##STR00167##
[0845] Methyl
2-(4-(((4-fluorophenyl)(pyridin-2-yl)methyl)carbamoyl)piperidin-1-yl)-2-m-
ethyl propanoate
##STR00168##
[0847] To a solution of
N-((4-fluorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(0.3 g, 0.957 mmol) and methyl 2-bromo-2-methylpropanoate (0.173 g,
0.957 mmol, 1.0 equiv) in acetone was added potassium carbonate.
The reaction mixture was stirred at 70.degree. C. for 16 hrs. Then
it was quenched by addition of water and ethyl acetate and the
aqueous phase was reextracted twice with ethyl acetate. The
combined organic layers were then dried over Na.sub.2SO.sub.4,
filtered and concentrated. Column chromatography on silica gel
using 1% methanol in DCM afforded 0.22 g of
methyl-2-(4-(((4-fluorophenyl)(pyridin-2-yl)methyl)carbamoyl)piperidin-1--
yl)-2-methyl propanoate (Yield=56%); ESI+MS: m/z: 414.4
([M+H].sup.+).
N-((4(4-fluorophenyl)(pyridin-2-yl)methyl)-1-(1-hydroxy-2-methylpropan-2-y-
l)piperidine-4-carboxamide
##STR00169##
[0849] To a stirred solution of
(4-(((4-fluorophenyl)(pyridin-2-yl)methyl)carbamoyl)piperidin-1-yl)-2-met-
hylpropanoate (0.22 g, 0.53 mmol) in THF (3 mL) was added lithium
aluminium hydride (0.0303 g, 0.798 mmol, 1.5 equiv) at 0.degree. C.
The reaction was stirred at room temperature for 2 h. After
completion, the reaction mass was quenched with ethyl acetate, aq.
Na.sub.2SO.sub.4 and extracted with EtOAc. The combined organic
extract was washed with brine and dried under reduced pressure to
afforded 0.150 g of
N-((4-fluorophenyl)(pyridin-2-yl)methyl)-1-(1-hydroxy-2-methylpropan-2-yl-
)piperidine-4-carboxamide (Yield=73%); ESI+MS: m/z: 386.4
([M+H].sup.+).
2-(4-(((4-fluorophenyl)(pyridin-2-yl)methyl)carbamoyl)piperidin-1-yl)-2-me-
thylpropyl methanesulfonate
##STR00170##
[0851] To a stirred solution of
N-((4-fluorophenyl)(pyridin-2-yl)methyl)-1-(1-hydroxy-2-methyl
propan-2-yl)piperidine-4-carboxamide (0.150 g, 0.389 mmol) in DCM
(5 mL) were added triethylamine (0.079 g, 0.778 mmol, 2 equiv) and
methane sulfonyl chloride (0.049 g, 0.428 mmol, 1.2 equiv) at
0.degree. C. The reaction mixture was stirred at room temperature
for 1 h. After completion, the reaction mass was quenched with
water and extracted with EtOAc. The combined organic extracts were
washed with brine, filtered and dried over sodium sulphate. The
solvent was removed under reduced pressure to afford crude 0.150 g
of
2-(4-(((4-fluorophenyl)(pyridin-2-yl)methyl)carbamoyl)piperidin-1-yl)-2-m-
ethylpropyl methanesulfonate (Yield=83%).
N-((4(4-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-methyl-1-phenoxy
propan-2-yl)piperidine-4-carboxamide
##STR00171##
[0853] To a solution of
2-(4-(((4-fluorophenyl)(pyridin-2-yl)methyl)carbamoyl)piperidin-1-yl)-2-m-
ethylpropylmethanesulfonate (0.150 g, 0.32 mmol) and phenol (0.0457
g, 0.48 mmol, 1.5 equiv) in acetonitrile was added potassium
carbonate (134 mg, 0.97 mmol, 3.0 equiv.). The reaction mixture was
stirred at 80.degree. C. for 16 hrs. After completion of the
reaction (monitored by TLC), diluted with water and extracted with
ethyl acetate. The organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The crude
compound was purified by prep HPLC purification to afford 0.020 g
of
N-((4-fluorophenyl)(pyridin-2-yl)methyl)-1-(2-methyl-1-phenoxypropan-2-yl-
)piperidine-4-carboxamide (Yield=13%). .sup.1H NMR (400 MHz,
DMSO-D.sub.6): .delta. 8.68 (d, 1H, J=8.4 Hz), 8.51-8.50 (m, 1H),
7.77 (dt, 1H, J.sub.1,2=1.6 Hz, J.sub.1,4=9.2 Hz), 7.44 (d, 1H,
J=8.0 Hz), 7.35-7.31 (m, 2H), 7.28-7.24 (m, 3H), 7.14-7.09 (m, 2H),
7.05-7.01 (m, 1H), 6.96-6.94 (m, 2H), 6.13 (d, 1H, J=8.4 Hz), 2.96
(d, 2H, J=11.6 Hz), 2.50-2.49 (m, 2H), 2.30-2.27 (m, 1H), 2.17 (dt,
2H, J.sub.1,2=4.4 Hz, J.sub.1,4=14.8 Hz), 1.63-1.59 (m, 4H), 1.20
(s, 6H); ESI+MS: m/z: 462.6 ([M+H].sup.+).
Example-59
1-(benzofuran-2-ylmethyl)-N-((4(4-fluorophenyl)(pyridin-2-yl)methyl)piperi-
dine-4-carboxamide (59)
##STR00172##
[0855] To a stirred solution of
N-((4(4-fluorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(key Intermediate-IV) (0.150 g, 0.479 mmol) in DCE (3 mL) were
added benzofuran-2-carbaldehyde (0.07 g, 0.479 mmol, 1 equiv), and
acetic acid (0.0287 g, 0.479 mmol, 1 equiv) at 0.degree. C. and the
reaction was stirred at room temperature for 1 h. Then sodium
triacetoxy borohydride (0.281 g, 1.43 mmol, 3 equiv) was added.
After completion, the reaction mass was quenched with water and pH
was adjusted .about.7 with saturated NaHCO.sub.3 solution and
extracted with CH.sub.2Cl.sub.2. The combined organic extract was
dried over sodium sulphate, filtered and concentrated under reduced
pressure. The crude compound was purified by prep HPLC to afford
0.040 g of
1-(benzofuran-2-ylmethyl)-N-((4(4-fluorophenyl)(pyridin-2-yl)methyl)piper-
idine-4-carboxamide (Yield=19%). .sup.1H NMR (400 MHz,
DMSO-D.sub.6): .delta. 8.66 (d, 1H, J=8.4 Hz), 8.50-8.49 (m, 1H),
7.76 (dt, J.sub.1,2=2.0 Hz, 1H, J.sub.1,4=9.6 Hz), 7.58-7.51 (m,
2H), 7.43 (d, 1H, J=8.0 Hz), 7.34-7.30 (m, 2H), 7.27-7.18 (m, 3H),
7.13-7.09 (m, 2H), 6.74 (s, 1H), 6.12 (d, 1H, J=8.4 Hz), 3.64 (s,
2H), 2.89 (d, 2H, J=10.8 Hz), 2.35-2.29 (m, 1H), 2.07-2.00 (m, 2H),
1.69-1.53 (m, 4H); ESI+MS: m/z: 444.5 ([M+H].sup.+).
Example-60
1-(benzo[d]oxazol-2-ylmethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)pipe-
ridine-4-carboxamide (60)
##STR00173##
[0857] Title compound was prepared from
N-((4-fluorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
key Intermediate-IV (0.100 g, 0.319 mmol) using the general
methodology of Example-1. The product was purified by prep HPLC
purification to afford 0.040 g of
1-(2-(2,6-difluorophenoxy)ethyl)-N-((4(4-fluorophenyl)(pyridin-2-yl)methy-
l)piperidine-4-carboxamide (Yield=28%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.67 (d, 1H, J=8.4 Hz), 8.49 (dd, 1H,
J.sub.1,2=0.8 Hz, J.sub.1,3=4.8 Hz), 7.78-7.70 (m, 3H), 7.44-7.24
(m, 6H), 7.13-7.09 (m, 2H), 6.12 (d, 1H, J=8.0 Hz), 3.83 (s, 2H),
2.92 (d, 2H, J=11.2 Hz), 2.37-2.29 (m, 1H), 2.19-2.13 (m, 2H),
1.70-1.54 (m, 4H); ESI+MS: m/z:445.5 ([M+H].sup.+).
Example-61
1-((2,3-dihydro-1H-inden-2-yl)methyl)-N-((4-fluorophenyl)(pyridin-2-yl)met-
hyl) piperidine-4-carboxamide (61)
##STR00174##
[0859] Title compound was prepared from
N-((4-fluorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
key Intermediate-IV (0.100 g, 0.319 mmol) using the general
methodology of Example-1. The product was purified by Prep HPLC
purification to afford 0.030 g of
1-((2,3-dihydro-1H-inden-2-yl)methyl)-N-((4-fluorophenyl)(pyridin-2-yl)me-
thyl)piperidine-4-carboxamide (Yield=20%). .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 8.52 (d, 1H, J=7.6 Hz), 7.80 (dt, 1H,
J.sub.1,3=7.6 Hz, J.sub.1,4=6.0 Hz), 7.39 (d, 1H, J=8.0 Hz),
7.32-7.27 (m, 3H), 7.15-7.12 (m, 2H), 7.08-7.02 (m, 4H), 6.17 (s,
1H), 3.83 (s, 2H), 3.04-3.01 (m, 4H), 2.75-2.64 (m, 3H), 2.45-2.35
(m, 3H), 2.11-2.04 (m, 2H), 1.84-1.79 (m, 4H); ESI+MS: m/z:444.6
([M+H].sup.+).
Example-62
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(3-phenoxypropyl)piperidine-4-
-carboxamide (62):
##STR00175##
[0860] Methyl 1-(3 -phenoxypropyl)piperidine-4-carboxylate
##STR00176##
[0862] Title compound was prepared from (3-bromopropoxy)benzene
(1.5 g, 6.97 mmol) using the general methodology of step 1 in the
synthesis of key intermediate III and afforded 1 g of (3-methyl
1-(3-phenoxypropyl)piperidine-4-carboxylate (Yield=52%).
1-(3-phenoxypropyl)piperidine-4-carboxylic acid
##STR00177##
[0864] Title compound was prepared from methyl
1-(3-phenoxypropyl)piperidine-4-carboxylate (1 g, 3.61 mmol) using
the general methodology of step 2 in the synthesis of key
intermediate III and afforded 0.8 g of 1-(3-phenoxypropyl)
piperidine-4-carboxylic acid (Yield=84%).
N-((4-chlorophenyl)(pyridin-2
-yl)methyl)-1-(3-phenoxypropyl)piperidine-4-carboxamide
##STR00178##
[0866] Title compound was prepared from
1-(3-phenoxypropyl)piperidine-4-carboxylic acid (0.1 g, 0.457 mmol)
using the conditions in step 5 in the general methodology of key
Intermediate-I. The product was purified by preparative HPLC to
afford 0.04 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(3-phenoxypropyl)pip-
eridine-4-carboxamide (Yield=19%). .sup.1H NMR (400 MHz, DMSO-d6):
.delta. 8.70 (d, J=8.4 Hz,1H), 8.51(d, J=4.0 Hz,1H), 7.81 (dt, 1H,
J.sub.1,3=7.6 Hz, J.sub.1,2=1.6 Hz), 7.44 (d, J=7.6 Hz, 1H),
7.45-7.24 (m, 7H), 6.92-6.88 (m, 3H), 6.13(d, J=8.4 Hz, 1H), 3.97
(t, J=6.4 Hz, 2H), 2.88 (d, J=10.8 Hz, 2H), 2.41-2.30 (m, 3H),
1.90-1.82 (m, 4H), 1.65-1.53(m, 4H); ESI+MS: m/z 465
([M+H].sup.+).
Example-63
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidine-4--
carboxamide (63):
##STR00179##
[0868] Title compound was prepared from
1-(2-phenoxyethyl)piperidine-4-carboxylic acid III (0.150 g, 0.602
mmol) using the conditions in step 5 in the general methodology of
key Intermediate-I. The crude was purified by preparative HPLC to
afford 0.05 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperidin-
e-4-carboxamide (Yield=18%). .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.70 (d, 1H, J=8.4 Hz), 8.51 (d, 1H, J=4.0 Hz), 7.80-7.75
(m, 1H), 7.44 (d, 1H, J=7.6 Hz), 7.37-7.35(m, 4H), 7.33-7.24 (m,
3H), 6.93-6.89 (m, 3H), 6.13 (d, 1H, J=8.4 Hz), 4.04 (t, 2H, J=6.0
Hz), 2.94 (d, 2H, J=10.8 Hz), 2.67-2.64 (m, 2H), 2.36-2.32 (m, 1H),
2.31-2.30 (m, 2H), 2.04-1.93 (m, 2H), 1.65 (s, 2H), 1.61-1.513 (m,
2H); ESI+MS: m/z 450 ([M+H].sup.+). Enantiomers of 63 were
separated using chiral HPLC (method E) and afforded pure
enantiomers 63a and 63b.
Example-64
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-methylpiperidine-4-carboxamid-
e (64)
##STR00180##
[0870] To a solution of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(0.240 g, 0.728 mmol) in CH.sub.2Cl.sub.2 (3 mL) under argon
atmosphere were added paraformaldehyde (0.03 g, 1.09 mmol), sodium
triacetoxy borohydride (0.463 g, 2.18 mmol, 3 equiv) and acetic
acid (0.04 mL) at 0.degree. C. The reaction mixture was and stirred
at room temperature for 16 h. After completion, the reaction was
diluted with CH.sub.2Cl.sub.2 and washed with saturated NaHCO.sub.3
solution and brine. The combined organic extract was dried over
sodium sulfate, filtered and concentrated under reduced pressure.
Purification using silica gel column chromatography (4%
MeOH/CH.sub.2Cl.sub.2 as eluent) afforded 0.08 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-methylpiperidine-4-carboxamide
(Yield=31%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.70 (d,
1H, J=8.4 Hz), 8.50 (d, 1H, J=4.4 Hz), 7.80-7.76 (m, 1H), 7.44 (d,
1H, J=7.6 Hz), 7.37-7.25 (m, 5H), 6.12 (d, 1H, J=8.4 Hz), 2.75 (t,
2H, J=11.2 Hz), 2.32-2.25 (m, 1H), 2.12 (s, 3H), 1.80 (t, 2H,
J=11.6 Hz), 1.62-1.49 (m, 4H); ESI+MS: m/z 344 ([M+H].sup.+).
Example-65
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-methoxyethyl)piperidine-4--
carboxamide (65)
##STR00181##
[0872] To a solution of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(0.130 g, 0.394 mmol) in 5 mL of DMF under argon atmosphere were
added potassium carbonate (0.163 g, 1.18 mmol, 3 equiv),
1-chloro-2-methoxy ethane (0.056 g, 0.591 mmol, 1.5 eqiuv) at
0.degree. C. and the reaction was heated to 80.degree. C. and
stirred for 16 h. After completion, the volatiles were removed
under reduced pressure; water was added to the residue and
extracted with EtOAc. The combined organic extract was dried over
sodium sulfate, filtered and concentrated under reduced pressure.
Purification using preparative HPLC afforded 0.035 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-methoxyethyl)piperidine-4-c-
arboxamide (Yield=22%). .sup.1H NMR (400 MHz, DMSO-d6): .delta.
8.69 (d, 1H, J=8.4 Hz), 8.50 (t, 1H, J=4.8 Hz), 7.80-7.75 (m, 1H),
7.44 (d, 1H, J=7.6 Hz), 7.37-7.25 (m, 5H), 6.12 (d, 1H, J=8.0 Hz),
3.40 (t, 2H, J=11.6 Hz), 3.21 (s, 3H), 2.87 (d, 2H, J=12.8 Hz),
2.44-2.43 (m, 2H), 2.33-2.28 (m, 1H), 1.95-1.90 (m, 2H), 1.62-1.49
(m, 4H); ESI+MS: m/z: 387 ([M+H].sup.+).
Example-66
1-(2-(2-chlorophenoxy)ethyl)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)
piperidine-4-carboxamide (66)
##STR00182##
[0874] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(0.2 g, 0.606 mmol) using the general methodology of Example-1. The
crude compound was purified using silica gel column chromatography
(3% MeOH/CH.sub.2Cl.sub.2 as eluent) to afford 0.155 g of
1-(2-(2-chlorophenoxy)ethyl)-N-((4-chlorophenyl)(pyridin-2-yl)methyl)pipe-
ridine-4-carboxamide (Yield=51%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 8.70 (d, 1H, J=8.0 Hz), 8.50 (d, 1H, J=4.5
Hz), 7.79-7.75 (m, 1H), 7.44 (d, 2H, J=8.5 Hz), 7.40-7.25 (m, 6H),
7.15 (d, 1H, J=8.0 Hz), 6.93 (t, 1H, J=8.0 Hz), 6.12 (d, 1H, J=8.5
Hz), 4.19-4.10 (m, 2H), 2.97 (d, 2H, J=9.0 Hz), 2.75-2.70 (m, 2H),
2.34 (d, 1H, J=10.5 Hz), 2.10-2.04 (m, 2H), 1.65-1.54 (m, 4H);
ESI+MS: m/z: 484 ([M+H].sup.+).
Example-67
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2,6-difluorophenoxy)ethyl-
) piperidine-4-carboxamide (67)
##STR00183##
[0876] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(0.120 g, 0.364 mmol) using the general methodology of Example-1.
The crude was washed with pentane to afford 0.1 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2,6-difluorophenoxy)ethyl)-
piperidine-4-carboxamide (Yield=57%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.69(d, 1H, J=8.4 Hz), 8.50 (dd, 1H,
J.sub.1,2=0.8 Hz, J.sub.1,3=4.8 Hz), 7.80-7.75 (m, 1H), 7.44 (d,
1H, J=8.0 Hz), 7.37-7.25 (m, 5H), 7.12-7.07 (m, 3H), 6.12 (d, 1H,
J=8.4 Hz), 4.16 (t, 2H, J=5.6 Hz), 2.88 (d, 2H, J=11.2 Hz),
2.67-2.62 (m, 2H), 2.33-2.27 (m, 1H), 1.98 (t, 2H, J=9.6 Hz),
1.64-1.61 (m, 2H), 1.52-1.42 (m, 2H); ESI+MS: m/z 486
([M+H].sup.+).
Example-68
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-(trifluoromethoxy)phenoxy-
) ethyl) piperidine-4-carboxamide (68)
##STR00184##
[0878] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(0.120 g, 0.364 mmol) using the general methodology of Example-1.
The crude was purified by silica gel column chromatography (2%
MeOH/CH.sub.2Cl.sub.2 as eluent) to afford 0.1 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-(trifluoromethoxy)phenox-
y)ethyl) piperidine-4-carboxamide (52%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 8.71 (d, 1H, J=8.5 Hz), 8.52 (d, 1H, J=4.5
Hz), 7.79 (t, 1H, J=7.5 Hz,), 7.45 (d, 1H, J=8.0 Hz), 7.38-7.25 (m,
8H), 7.01 (t, 1H, J=7.5 Hz), 6.13 (t, 1H, J=8.0 Hz), 4.17-4.15 (m,
2H), 2.96 (d, 2H, J=9.5 Hz), 2.71-2.69 (m, 2H), 2.37-2.34 (m, 1H),
2.05 (t, 2H, J=11.0 Hz), 166-1.55 (m, 4H); ESI+MS: m/z 534
([M+H].sup.+).
Synthesis of Intermediate V
##STR00185##
[0879] Step 1:
tert-butyl-4-(((4-fluorophenyl)(pyridin-2-yl)methyl)carbamoyl)-4-methylpi-
peridine-1-carboxylate
##STR00186##
[0881] Title compound was prepared from
(4-fluorophenyl)(pyridin-2-yl)methanamine (0.3 g, 1.48 mmol) using
the conditions in step 5 in the general methodology of key
Intermediate-I. The crude compound was purified by silica gel
column chromatography to afford 0.5 g of tert-butyl
4-(((4-fluorophenyl)(pyridin-2-yl)methyl)carbamoyl)-4-methylpiperidine-1--
carboxylate (Yield=79%).
Step 2:
N-((4-fluorophenyl)(pyridin-2-yl)methyl)-4-methylpiperidine-4-carb-
oxamide hydrochloride
##STR00187##
[0883] To a stirred solution of tert-butyl
4-(((4-fluorophenyl)(pyridin-2-yl)methyl)carbamoyl)-4-methylpiperidine-1--
carboxylate (0.5 g, 1.17 mmol) in MeOH (2 mL) was added 4 N HCl in
1,4-dioxane (0.5 mL) at 0.degree. C. The reaction was stirred at
room temperature for 4 h. After completion, the volatiles were
removed under reduced pressure. The crude was washed with ether to
afford 0.2 g of
N-((4-fluorophenyl)(pyridin-2-yl)methyl)-4-methylpiperidine-4-carboxamide
hydrochloride (Yield=47%). ESI+MS: m/z 328.4 ([M+H].sup.+).
Example-69
N-((4(4-fluorophenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-phenoxyethyl)pipe-
ridine-4-carboxamide (69)
##STR00188##
[0885] Title compound was prepared from
N-((4-fluorophenyl)(pyridin-2-yl)methyl)-4-methyl
piperidine-4-carboxamide hydrochloride (0.1 g, 0.305 mmol) using
the general methodology of Example-1. The crude compound was
purified by preparative HPLC to afford 0.090 g of
N-((4-fluorophenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-phenoxyethyl)piper-
idine-4-carboxamide (Yield=64%). .sup.1H NMR (500 MHz, CD.sub.3OD):
.delta. 8.56 (d, 1H, J=5.0 Hz), 7.80 (dt, 1H, J.sub.1,2=2.0 Hz,
J.sub.1,4=9.0 Hz), 7.39 (d, 1H, J=8.5 Hz), 7.34-7.26 (m, 5H), 7.03
(t, 2H, J=8.0 Hz), 6.95-6.91 (m, 3H), 6.21 (s, 1H), 4.12 (t, 2H,
J=5.5 Hz), 2.84-2.82 (m, 4H), 2.50-2.46 (m, 2H), 2.21-2.19 (m, 2H),
1.66-1.61 (m, 2H), 1.23 (s, 3H); ESI+MS: m/z 448 ([M+H].sup.+).
Enantiomers of 69 were separated using chiral HPLC (method G) and
afforded pure enantiomers 69a and 69b.
Example-70
N-((4(4-fluorophenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-(2-(trifluorometh-
yl) phenoxy)ethyl) piperidine-4-carboxamide (70)
##STR00189##
[0887] Title compound was prepared from
N-((4-fluorophenyl)(pyridin-2-yl)methyl)-4-methyl
piperidine-4-carboxamide hydrochloride (0.1 g, 0.305 mmol) using
the general methodology of Example-1. The crude was purified by
preparative HPLC to afford 0.1 g of
N-((4-fluorophenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-(2-(trifluoromethy-
l)phenoxy)ethyl) piperidine-4-carboxamide (Yield=64%). .sup.1H NMR
(500 MHz, CD.sub.3OD): .delta. 8.55 (d, 1H, J=4.5 Hz), 7.79 (dt,
1H, J.sub.1,2=1.5 Hz, J.sub.1,4=8.5 Hz), 7.59-7.56 (m, 2H), 7.39
(d, 1H, J=8.0 Hz), 7.33-7.27 (m, 3H), 7.17 (d, 1H, J=8.5 Hz),
7.09-7.02 (m, 3H), 6.21 (s, 1H), 4.21 (t, 2H, J=5.5 Hz), 2.89-2.85
(m, 4H), 2.51-2.49 (m, 2H), 2.21-2.18 (m, 2H), 1.64-1.59 (m, 2H),
1.22 (s, 3H); ESI+MS: m/z 516 ([M+H].sup.+). Enantiomers of 70 were
separated using chiral HPLC (method B) and afforded pure
enantiomers 70a and 70b.
Example-71
1-(2-(2-fluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)-4-me-
thylpiperidine-4-carboxamide (71)
##STR00190##
[0889] Title compound was prepared from
N-((4-fluorophenyl)(pyridin-2-yl)methyl)-4-methyl
piperidine-4-carboxamide hydrochloride (0.3 g, 0.825 mmol) using
the general methodology of Example-1, and afforded 150 mg of
1-(2-(2-fluorophenoxy)ethyl)-N-((4-fluorophenyl)(pyridin-2-yl)methyl)-4-m-
ethylpiperidine-4-carboxamide (Yield=51%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.52 (d, 1H, J=4.0 Hz), 8.33 (d, 1H, J=6.8
Hz), 7.80-7.76 (m, 1H), 7.44 (d, 1H, J=8.0 Hz), 7.34-7.26 (m, 3H),
7.21-7.09 (m, 5H), 6.95-6.92 (m, 1H), 6.21 (d, 1H, J=7.6 Hz),
4.15-4.13 (m, 2H), 2.72-2.71 (m, 4H), 2.34-2.32 (m, 2H), 2.15-2.05
(m, 2H), 1.50-1.45 (m, 2H), 1.14 (s, 3H); ESI+MS: m/z: 466
([M+H].sup.+).
Synthesis of Intermediate VI
##STR00191##
[0890] tert-butyl
4-((((4-chlorophenyl)(pyridin-2-yl)methyl)(methyl)amino)methyl)piperidine-
-1-carboxylate
##STR00192##
[0892] Title compound was prepared from
2-(chloro(4-chlorophenyl)methyl)pyridine (0.3 g, 1.26 mmol) and
tert-butyl 4-((methylamino)methyl)piperidine-1-carboxylate (0.288
g, 1.26 mmol, 1 equiv) using the general methodology of Example-1.
Purification using silica gel column chromatography (40%
EtOAc/Hexanes as eluent) afforded 0.450 g of tert-butyl
4-((((4-chlorophenyl)(pyridin-2-yl)methyl)(methyl)amino)methyl)piperidine-
-1-carboxylate (Yield=83%).
1-(4-chlorophenyl)-N-methyl-N-(piperidin-4-ylmethyl)-1-(pyridin-2-yl)metha-
namine hydrochloride
##STR00193##
[0894] Title compound was prepared from tert-butyl
4-((((4-chlorophenyl)(pyridin-2-yl)methyl)(methyl)amino)methyl)piperidine-
-1-carboxylate (0.45 g, 1.04 mmol) using the general methodology of
step 2 of the synthesis of intermediate-V to afford 0.3 g of
1-(4-chlorophenyl)-N-methyl-N-(piperidin-4-ylmethyl)-1-(pyridin-2-yl)meth-
anamine hydrochloride (Yield=78%).
Example-72
1-(4-chlorophenyl)-N-((4(1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl-
)-N-methyl-1-(pyridin-2-yl)methanamine (72)
##STR00194##
[0896] Title compound was prepared from
1-(4-chlorophenyl)-N-methyl-N-(piperidin-4-ylmethyl)-1-(pyridin-2-yl)meth-
anamine hydrochloride (0.2 g, 0.546 mmol) using the general
methodology of Example-1. The crude compound was purified by
preparative HPLC to afford 0.050 g of
1-(4-chlorophenyl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-
-N-methyl-1-(pyridin-2-yl)methanamine (Yield=19%). .sup.1H NMR (500
MHz, DMSO-d.sub.6): .delta. 8.44 (d, 1H, J=4.0 Hz), 7.77-7.74 (m,
1H), 7.55 (d, 1H, J=7.5 Hz), 7.43 (d, 2H, J=8.0 Hz), 7.35 (d, 2H,
J=8.5 Hz), 7.23-7.11 (m, 4H), 6.93-6.91 (m, 1H), 4.50 (s, 1H), 4.11
(t, 2H, J=6.0 Hz), 2.88 (d, 2H, J=11.5 Hz), 2.68-2.64 (m, 2H),
2.13-1.98 (m, 7H), 1.72 (d, 2H, J=11.50 Hz), 1.55-1.48 (m, 1H),
0.99-0.89 (m, 2H); ESI+MS: m/z: 468 ([M+H].sup.+). Enantiomers of
72 were separated using chiral HPLC (method K) and afforded pure
enantiomers 72a and 72b.
Example-73
1-(4-chlorophenyl)-N-methyl-1-(pyridin-2-yl)-N-((4(1-(2-(2-(trifluoromethy-
l) phenoxy)ethyl)piperidin-4-yl)methyl)methanamine (73)
##STR00195##
[0898] Title compound was prepared from
1-(4-chlorophenyl)-N-methyl-N-(piperidin-4-ylmethyl)-1-(pyridin-2-yl)meth-
anamine hydrochloride (0.15 g, 0.45 mmol) using the general
methodology of Example-1 to afford 0.06 g (Yield=28%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 8.43 (d, 1H, J=5.2 Hz), 7.77-7.72
(m, 1H), 7.62-7.53 (m, 3H), 7.42 (d, 2H, J=8.4 Hz), 7.34-7.32 (m,
2H), 7.26-7.19 (m, 2H), 7.07 (t, 1H, J=7.6 Hz), 4.49 (s, 1H), 4.17
(t, 2H, J=6.0 Hz), 2.86 (d, 2H, J=11.2 Hz), 2.69-2.66 (m, 2H),
2.13-2.00 (m, 7H), 1.70 (d, 2H, J=12.0 Hz), 1.54-1.48 (m, 1H),
0.98-0.88 (m, 2H); ESI+MS: m/z: 518 ([M+H].sup.+).
Synthesis of Intermediate VII
##STR00196##
[0899] 1-(4-fluorophenyl)-N-methyl-N-(piperidin-4-ylmethyl)-1-(p
yridin-2-yl)methanamine hydrochloride (Int-VII)
[0900]
1-(4-fluorophenyl)-N-methyl-N-(piperidin-4-ylmethyl)-1-(pyridin-2-y-
l)methanamine hydrochloride was synthesized in 2 steps using the
same chemistry as described for key intermediate-VI by replacing
2-(chloro(4-chlorophenyl)methyl)pyridine by
2-(chloro(4-fluorophenyl)methyl)pyridine and afforded 450 mg of
1-(4-fluorophenyl)-N-methyl-N-(piperidin-4-ylmethyl)-1-(pyridin-2-yl)meth-
anamine hydrochloride (Yield=89%). ESI+MS: m/z 314.4
([M+H].sup.+).
Example-74
1-(4-fluorophenyl)-N-methyl-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1-
-(pyridin-2-yl)methanamine (74)
##STR00197##
[0902] Title compound was prepared from
1-(4-fluorophenyl)-N-methyl-N-(piperidin-4-ylmethyl)-1-(pyridin-2-yl)meth-
anamine hydrochloride (0.20 g, 0.57 mmol) using the general
methodology of Example-1 to afford 0.15 g (Yield=60%). .sup.1H NMR
(500 MHz, DMSO-d.sub.6): .delta. 8.44 (d, 1H, J=4.5 Hz), 7.73-7.70
(m, 1H), 7.56 (d, 1H, J=7.5 Hz), 7.43 (t, 2H, J=8.5 Hz), 7.29-7.20
(m, 3H), 7.11 (t, 2H, J=9.0 Hz), 6.92 (d, 3H, J=6.5 Hz), 4.49 (s,
1H), 4.10-4.03 (m, 2H), 2.87 (d, 2H, J=9.5 Hz), 2.65-2.63 (m, 2H),
2.14-2.11 (m, 1H), 2.06 (s, 3H), 2.03-1.99 (m, 3H), 1.73 (d, 2H,
J=12.0 Hz), 1.55-1.52 (m, 1H), 0.99-0.96 (m, 2H). ESI+MS: m/z 434
([M+H].sup.+). Enantiomers of 74 were separated using chiral HPLC
(method D) and afforded pure enantiomers 74a and 74b.
Example-75
N-((4(1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-1-(4-fluorophenyl-
)-N-methyl-1-(pyridin-2-yl)methanamine (75)
##STR00198##
[0904] Title compound was prepared from
1-(4-fluorophenyl)-N-methyl-N-(piperidin-4-ylmethyl)-1-(pyridin-2-yl)meth-
anamine hydrochloride (0.20 g, 0.54 mmol) using the general
methodology of Example-1. The crude was purified by preparative
HPLC to afford 0.05 g of
N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-1-(4-fluorophenyl)-
-N-methyl-1-(pyridin-2-yl)methanamine (Yield=19%). .sup.1H NMR (500
MHz, DMSO-d.sub.6): .delta. 8.44 (d, 1H, J=4.0 Hz), 7.76 (t, 1H,
J=6.5 Hz), 7.56 (d, 1H, J=7.5 Hz), 7.44 (d, 2H, J=8.0 Hz),
7.22-7.09 (m, 6H), 6.95-6.92 (m, 1H), 4.49 (s, 1H), 4.15-4.10 (m,
2H), 2.90-2.85 (m, 2H), 2.67-2.64 (m, 1H), 2.14-2.01 (m, 7H), 1.72
(d, 2H, J=11.0 Hz), 1.53-1.51 (m, 1H), 0.97-0.94 (m, 2H); ESI+MS:
m/z 452 ([M+H].sup.+).
Example-76
1-(3-methoxyphenyl)-N-methyl-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)--
1-(pyridin-2-yl)methanamine (76)
##STR00199##
[0905]
1-(3-methoxyphenyl)-N-methyl-N-(piperidin-4-ylmethyl)-1-(pyridin-2--
yl)methanamine hydrochloride
##STR00200##
[0907] Title compound was synthesized in 2 steps using the same
chemistry as described for key intermediate-VI by replacing
2-(chloro(4-chlorophenyl)methyl)pyridine with
2-(chloro(3-methoxyphenyl)methyl)pyridine and afforded 0.8 g of
1-(4-fluorophenyl)-N-methyl-N-(piperidin-4-ylmethyl)-1-(pyridin-2-yl)meth-
anamine hydrochloride (Yield=65%). ESI+MS: m/z 414.5
([M+H].sup.+).
1-(3-methoxyphenyl)-N-methyl-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)--
1-(pyridin-2-yl)methanamine
##STR00201##
[0909] Title compound was prepared from
1-(3-methoxyphenyl)-N-methyl-N-(piperidin-4-ylmethyl)-1-(pyridin-2-yl)met-
hanamine hydrochloride (0.150 g, 0.461 mmol) using the general
methodology of Example-1 to afford 0.1 g of
1-(3-methoxyphenyl)-N-methyl-N-((1-(2-phenoxyethyl)
piperidin-4-yl)methyl)-1-(pyridin-2-yl)methanamine (Yield=48%).
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.38 (d, 1H, J=4.8 Hz),
7.80-7.71 (m, 2H), 7.28-7.22 (m, 3H), 7.17 (m, 1H, J=8.0 Hz), 7.03
(t, 2H, J=8.0 Hz), 6.93-6.91 (m, 3H), 6.74 (dd, 1H, J.sub.1,2=2.4
Hz, J.sub.1,3=8.4 Hz), 4.38 (s, 1H), 4.13 (t, 2H, J=5.6 Hz), 3.75
(s, 3H), 3.07 (d, 2H, J=8.8 Hz), 2.85 (t, 2H, J=5.2 Hz), 2.31-2.22
(m, 3H), 2.20 (s, 3H), 2.12-2.07 (m, 1H), 1.95 (d, 1H, J=13.6 Hz),
1.86 (d, 1H, J=14.0 Hz), 1.72-1.68 (m, 1H), 1.20-1.15 (m, 2H);
ESI+MS: m/z 446 ([M+H].sup.+). Enantiomers of 76 were separated
using chiral HPLC (method D) and afforded pure enantiomers 76a and
76b.
Example-77
N-((4(1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-1-(3-methoxypheny-
l)-N-methyl-1-(pyridin-2-yl)methanamine (77)
##STR00202##
[0911] Title compound was prepared from
1-(3-methoxyphenyl)-N-methyl-N-(piperidin-4-ylmethyl)-1-(pyridin-2-yl)met-
hanamine hydrochloride (0.150 g, 0.414 mmol) using the general
methodology of Example-1. The crude compound was purified using
silica gel column chromatography (2% MeOH/CH.sub.2Cl.sub.2 as
eluent) to afford 0.120 g of
N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-1-(3-methoxyphenyl-
)-N-methyl-1-(pyridin-2-yl)methanamine (Yield=60%). .sup.1HNMR (400
MHz, DMSO-d.sub.6): .delta. 8.41 (d, 1H, J=4.0 Hz), 7.73 (dt, 1H,
J.sub.1,2=2.0 Hz, J.sub.1,4=9.6 Hz), 7.56 (d, 1H, J=8.0 Hz),
7.21-7.08 (m, 5H), 6.98-6.93 (m, 3H), 6.77-6.74 (m, 1H), 4.40 (s,
1H), 4.12-4.11 (m, 2H), 3.70 (s, 3H), 2.89-2.88 (m, 2H), 2.72-2.71
(m, 1H), 2.70-2.65 (m, 1H), 2.17-2.12 (m, 1H), 2.03-2.00 (m, 6H),
1.80-1.73 (m, 2H), 1.57-1.53 (m, 1H), 0 99-0.95 (m, 2H); ESI+MS:
m/z 463 ([M+H].sup.+). Enantiomers of 77 were separated using
chiral HPLC (method K) and afforded pure enantiomers 77a and
77b.
Example-78
1-(4-fluorophenyl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1-(pyridin-
-2-yl) methanamine (78)
##STR00203## ##STR00204##
[0912] Step 1: Methyl
1-(2-phenoxyethyl)piperidine-4-carboxylate
##STR00205##
[0914] Title compound was prepared from (2-bromoethoxy)benzene (1.5
g, 7.46 mmol) using the general methodology of step 1 in the
synthesis of key intermediate III and afforded 1 g of methyl
1-(2-phenoxyethyl)piperidine-4-carboxylate (Yield=51%).
Step 2: (1-(2-Phenoxyethyl)piperidin-4-yl)methanol
##STR00206##
[0916] To a solution of methyl 1-(2-phenoxyethyl)
piperidine-4-carboxylate (1 g, 3.80 mmol) in THF at 0.degree. C.
was added lithium aluminium hydride (0.216 g, 5.7 mmol, 1.5 equiv.)
portionwise over a period of 10 minutes and then the reaction was
maintained at RT for 2 h. After completion, the reaction mixture
was quenched with sat.Na.sub.2SO.sub.4 and extracted with ethyl
acetate. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentracted under reduced pressure
to afford 0.8 g of (1-(2-phenoxyethyl)piperidin-4-yl)methanol
(Yield=90%). ESI+MS: m/z: 236.2 ([M+H].sup.+).
Step 3: 1-(2-phenoxyethyl)piperidine-4-carbaldehyde
##STR00207##
[0918] To a stirred solution of
(1-(2-phenoxyethyl)piperidin-4-yl)methanol (0.6 g, 2.55 mmol) in
DCM (5 mL) were added Dess-Martin periodinane (1.62 g, 3.82 mmol,
1.5 equiv) and sodium hydrogen carbonate (0.428 g, 5.10 mmol, 2
equiv) at 0.degree. C. The reaction mixture was stirred at room
temperature for 16 h. After completion, the reaction mass was
quenched with sat. sodium thiosulphate and extracted with EtOAc.
The combined organic extract was washed with brine, filtered and
dried over sodium sulphate. The solvent was removed under reduced
pressure. The crude residue was purified by column chromatography
eluting with 10% EtOAc in hexane to afford 0.3 g of
1-(2-phenoxyethyl)piperidine-4-carbaldehyde (Yield=50%).
Step 4:
1-(4-fluorophenyl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1--
(pyridin-2-yl) methanamine
##STR00208##
[0920] Title compound was prepared from reductive amination of
1-(2-phenoxyethyl)piperidine-4-carbaldehyde (0.150 g, 0.643 mmol)
using the general methodology described in Example-59. The crude
residue was purified by Prep HPLC purification to afford 0.025 g of
1-(4-fluorophenyl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1-(pyridi-
n-2-yl)methanamine (Yield=12%). .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 8.49 (d, 1H, J=4.4 Hz), 7.76 (dt, 1H, J.sub.1,2=1.6 Hz,
J.sub.1,4=9.2 Hz), 7.48-7.42 (m, 3H), 7.28-7.23 (m, 3H), 7.01 (t,
2H, J=6.8 Hz), 6.93-6.90 (m, 3H), 4.91 (s, 1H), 4.13 (t, 2H, J=5.6
Hz), 3.08 (d, 2H, J=11.2 Hz), 2.85 (t, 2H, J=5.6 Hz), 2.47-2.38 (m,
2H), 2.23 (t, 2H, J=11.6 Hz), 1.84-1.80 (m, 2H), 1.61-1.55 (m, 1H),
1.34-1.24 (m, 2H); ESI+MS: m/z: 420.5 ([M+H].sup.+). Enantiomers of
78 were separated using chiral HPLC (method B) and afforded pure
enantiomers 78a and 78b.
Example-79
1-(4-chlorophenyl)-N-methyl-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1-
-(pyridin-2-yl)methanamine (79)
##STR00209##
[0921] 1-(4-chlorophenyl)-N-methyl-1-(pyridin-2-yl)methanamine
(SBF-MA1304-025)
##STR00210##
[0923] Title compound was prepared from reductive amination of
(4-chlorophenyl)(pyridin-2-yl)methanone (1 g, 4.59 mmol) using the
general methodology of Example-59. The crude compound was purified
by column chromatography eluting with 5% Methanol in DCM to
afforded 0.535 g of
1-(4-chlorophenyl)-N-methyl-1-(pyridin-2-yl)methanamine
(Yield=50%).
1-(4-chlorophenyl)-N-methyl-N-((1-(2-phenoxyethyl)piperidin-4-yl)
methyl)-1-(pyridin-2-yl)methanamine
[0924] Title compound was prepared from reductive amination of
1-(2-phenoxyethyl)piperidine-4-carbaldehyde (0.130 g, 0.559 mmol)
and 1-(4-chlorophenyl)-N-methyl-1-(pyridin-2-yl) methanamine (0.1
g, 0.430 mmol, 1 equiv) using the general methodology of
Example-59. The crude residue was purified by prep HPLC
purification to furnish 0.050 g of
1-(4-chlorophenyl)-N-methyl-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)--
1-(pyridin-2-yl)methanamine (Yield=26%). .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 8.39 (dd, 1H, J.sub.1,2=0.8 Hz, J.sub.1,3=4.8
Hz), 7.79 (dt, 1H, J.sub.1,2=1.6 Hz, J.sub.1,4=9.61 Hz), 7.70 (d,
1H, J=8.0 Hz), 7.45-7.43 (m, 2H), 7.30-7.23 (m, 5H), 6.93-6.90 (m,
3H), 4.44 (s, 1H), 4.12 (t, 2H, J=5.6 Hz), 3.05-3.02 (m, 2H), 2.82
(t, 2H, J=5.2 Hz), 2.25-2.09 (m, 7H), 1.92-1.84 (m, 2H), 1.70-1.64
(m, 1H), 1.19-1.01 (m, 2H); Ion trap: m/z: 450.8 ([M+H].sup.+).
Enantiomers of 79 were separated using chiral HPLC (method H) and
afforded pure enantiomers 79a and 79b.
Example-80
1-(3-methoxyphenyl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1-(pyridi-
n-2-yl)methanamine (80)
##STR00211##
[0926] Title compound was prepared from reductive amination of
1-(2-phenoxyethyl)piperidine-4-carbaldehyde (0.142 g, 0.607 mmol)
and (3-methoxyphenyl)(pyridin-2-yl)methanamine (0.1 g, 0.467 mmol,
1 equiv) using the general methodology of Example-59. The crude
material was purified by prep HPLC purification to afford 0.080 g
of
1-(3-methoxyphenyl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1-(pyrid-
in-2-yl)methanamine (Yield=40%).
[0927] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.49-8.47 (m,
1H), 7.75 (dt, 1H, J.sub.1,2=1.6 Hz, J.sub.1,4=9.6 Hz), 7.47 (d,
1H, J=8.0 Hz), 7.28-7.18 (m, 4H), 7.01-7.0 (m, 1H), 6.99-6.97 (m,
1H), 6.92-6.89 (m, 3H), 6.80-6.77 (m, 1H), 4.85 (s, 1H), 4.11 (t,
2H, J=5.6 Hz), 3.76 (s, 3H), 3.04 (d, 2H, J=11.6 Hz), 2.80 (t, 2H,
J=5.6 Hz), 2.48-2.38 (m, 2H), 2.17 (t, 2H, J=12.0 Hz), 1.82-1.79
(m, 2H), 1.61-1.53 (m, 1H), 1.34-1.31 (m, 1H), 1.29-1.23 (m, 1H);
ESI+MS: m/z: 432.6 ([M+H].sup.+).
Example-81
1-(4-chlorophenyl)-1-(2-fluorophenyl)-N-((1-(2-phenoxyethyl)piperidine-4-y-
l) methyl)methanamine (81)
##STR00212##
[0929] Title compound was prepared from reductive amination of
1-(2-phenoxyethyl)piperidine-4-carbaldehyde (0.129 g, 0.552 mmol)
and (4-chlorophenyl)(2-fluorophenyl)methanamine (0.1 g, 0.424 mmol,
1 equiv) using the general methodology of Example-59. The crude
residue was purified by prep HPLC purification to afford 0.1 g of
1-(4-chlorophenyl)-1-(2-fluorophenyl)-N-((1-(2-phenoxyethyl)piperidin-4-y-
l)methyl)methanamine (Yield=35%). .sup.1H NMR (500 MHz,
DMSO-D.sub.6): .delta. 7.59 (t, 1H, J=6.4 Hz), 7.39-7.34 (m, 4H)
7.28-7.24 (m, 3H), 7.20-7.09 (m, 2H), 6.93-6.90 (m, 3H), 5.02 (s,
1H), 4.04 (t, 2H, J=6.0 Hz), 2.89 (d, 2H, J=11.0 Hz), 2.65 (t, 2H,
J=5.5 Hz), 2.50-2.49 (m, 1H), 2.30-2.29 (m, 2H), 1.98 (t, 2H,
J=11.0 Hz), 1.70 (d, 2H, J=12.0 Hz), 1.41-1.34 (m, 1H), 1.14-1.10
(m, 2H); ESI+MS: m/z: 453.5 ([M+H].sup.+). Enantiomers of 81 were
separated using chiral HPLC (method C) and afforded pure
enantiomers 81a and 81b.
Example-82
1-(2-(benzo[d]thiazol-6-yloxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-yl)met-
hyl) piperidine-4-carboxamide (82)
##STR00213##
[0931] Title compound was prepared from
N-((3-methoxyphenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(100 mg, 0.307 mmol) using the general methodology of Example-1.
The crude residue was purified by prep HPLC to afford 0.060 g of
1-(2-(benzo[d]thiazol-6-yloxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-yl)me-
thyl)piperidine-4-carboxamide (Yield=38%). .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 9.04 (s, 1H), 8.52-8.50 (m, 1H), 7.93 (d, 1H,
J=8.8 Hz), 7.78 (dt, 1H, J.sub.1,2=2.0 Hz, J.sub.1,4=9.6 Hz), 7.60
(d, 1H, J=2.4 Hz), 7.39 (d, 1H, J=8.0 Hz), 7.31-7.28 (m, 1H),
7.23-7.16 (m, 2H), 6.84-6.79 (m, 3H), 6.13 (s, 1H), 4.22 (t, 2H,
J=5.6 Hz), 3.74 (s, 3H), 3.13-3.08 (m, 2H), 2.86 (t, 2H, J=5.2 Hz),
2.46-2.39 (m, 1H), 2.28-2.22 (m, 2H), 1.89-1.77 (m, 4H); Ion trap:
m/z:503.7 ([M+H].sup.+).
Example-83
N-(bis(4-fluorophenyl)methyl)-1-(2-(2-chlorophenoxy)ethyl)piperidine-4-car-
boxamide (83):
##STR00214##
[0933] Title compound was prepared from coupling of
1-(2-(2-chlorophenoxy)ethyl)piperidine-4-carboxylic acid (0.233 g,
0.821 mmol, 1.2 equiv) and bis(4-fluorophenyl)methanamine (0.150 g,
0.684 mmol, 1 equiv) using the conditions in step 5 in the general
methodology of key Intermediate-I. The crude compound was purified
by prep HPLC purification to furnish 0.012 g of
N-(bis(4-fluorophenyl)methyl)-1-(2-(2-chlorophenoxy)ethyl)piperidine-4-ca-
rboxamide (Yield=4%). .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.
7.34 (dd, 1H, J.sub.1,2=1.6 Hz, J.sub.1,3=8.0 Hz), 7.26-7.22 (m,
5H), 7.07-7.02 (m, 5H), 6.91 (dt, 1H, J.sub.1,2=1.2 Hz,
J.sub.1,4=8.8 Hz), 6.16 (s, 1H), 4.02 (t, 2H, J=5.6 Hz), 3.18 (d,
2H, J=12.0 Hz), 2.91 (t, 2H, J=5.6 Hz), 2.41-2.31 (m, 3H),
1.89-1.80 (m, 4H); Ion trap: m/z: 485.5 ([M+H].sup.+).
Example-84
N-(bis(2-fluorophenyl)methyl)-1-(2-(2-chlorophenoxy)ethyl)piperidine-4-car-
boxamide (84)
##STR00215##
[0935] Title compound was prepared from coupling of
1-(2-(2-chlorophenoxy)ethyl)piperidine-4-carboxylic acid (0.194 g,
0.684 mmol, 1.2 equiv) and bis(2-fluorophenyl)methanamine (0.125 g,
0.570 mmol, 1 equiv) using the conditions in step 5 in the general
methodology of key Intermediate-I. The crude compound was purified
by silica gel column chromatography (2% MeOH/DCM as eluent)
afforded 0.030 g of
N-(bis(2-fluorophenyl)methyl)-1-(2-(2-chlorophenoxy) ethyl)
piperidine-4-carboxamide (Yield=10%). .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 7.41 (dd, 1H, J.sub.1,2=1.6 Hz, J.sub.1,3=7.6
Hz), 7.36-7.29 (m, 3H), 7.22 (dt, 2H, J.sub.1,2=1.2 Hz,
J.sub.1,4=9.2 Hz), 7.18-7.09 (m, 5H), 7.02 (dt, 1H, J.sub.1,2=1.2
Hz, J.sub.1,4=8.8 Hz), 6.66 (m, 1H), 4.44 (t, 2H, J=4.8 Hz),
3.81-3.80 (m, 2H), 3.64 (t, 2H, J=4.8 Hz), 3.31-3.30 (m, 2H),
2.70-2.69 (m, 1H), 2.10-2.09 (m, 4H); ESI+MS: m/z: 485.4
([M+H].sup.+).
Example-85
1-(2-(2-chlorophenoxy)ethyl)-N-((2-fluorophenyl)(4-fluorophenyl)methyl)
piperidine-4-carboxamide (85)
##STR00216##
[0937] Title compound was prepared from coupling of
1-(2-(2-chlorophenoxy)ethyl)piperidine-4-carboxylic acid (0.233 g,
0.821 mmol, 1.2 equiv) and
(2-fluorophenyl)(4-fluorophenyl)methanamine (0.150 g, 0.684 mmol, 1
equiv) using the conditions in step 5 in the general methodology of
key Intermediate-I. The crude compound was purified by silica gel
column chromatography (2% MeOH/DCM as eluent) afforded 0.050 g of
1-(2-(2-chlorophenoxy)ethyl)-N-((2-fluorophenyl)(4-fluorophenyl)methyl-
)piperidine-4-carboxamide (Yield=15%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 8.69 (d, 1H, J=8.0 Hz), 7.40-7.12 (m, 12H),
6.92 (t, 1H, J=7.5 Hz), 6.31 (d, 1H, J=8.5 Hz), 4.13 (t, 2H, J=6.0
Hz), 2.97-2.96 (m, 2H), 2.71-2.69 (m, 2H), 2.27-2.23 (m, 1H),
2.07-2.03 (m, 2H), 1.63-1.51 (m, 4H); ESI+MS: m/z: 485.5
([M+H].sup.+).
Example-86
1-(2-(2-chlorophenoxy)ethyl)-N-((2-fluorophenyl)(3-methoxyphenyl)
methyl) piperidine-4-carboxamide (86)
##STR00217##
[0939] Title compound was prepared from coupling of
1-(2-(2-chlorophenoxy)ethyl)piperidine-4-carboxylic acid (0.147 g,
0.519 mmol, 1.2 equiv) and (2-fluorophenyl)(3-methoxyphenyl)
methanamine (0.100 g, 0.432 mmol, 1 equiv) using the conditions in
step 5 in the general methodology of key Intermediate-I. The crude
compound was purified by prep HPLC purification to furnish 0.040 g
of
1-(2-(2-chlorophenoxy)ethyl)-N-((2-fluorophenyl)(3-methoxyphenyl)
methyl)piperidine-4-carboxamide (Yield=18%). .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 7.35-7.32 (m, 2H), 7.30-7.21 (m, 3H),
7.17-7.11 (m, 1H), 7.08-7.05 (m, 2H), 6.91 (dt, 1H, J.sub.1,2=1.2
Hz, J.sub.1,4=8.8 Hz), 6.84-6.77 (m, 3H), 6.40 (s, 1H), 4.20 (t,
2H, J=5.2 Hz), 3.74 (s, 3H), 3.18-3.15 (m, 2H), 2.89 (t, 2H, J=5.2
Hz), 2.41-2.29 (m, 3H), 1.88-1.79 (m, 4H); ESI+MS: m/z: 497.6
([M+H].sup.+).
Example-87
1-(4-chlorophenyl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)--
1-(2-fluorophenyl)methanamine (87)
##STR00218##
[0940] (1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methanol
##STR00219##
[0942] Title compound was prepared from methyl
1-(2-(2-fluorophenoxy)ethyl)piperidine-4-carboxylate (1.2 g, 4.27
mmol) using the conditions of step 2 in Example-78 to obtain 0.850
g (1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methanol
(Yield=67%).
1-(2 -(2 -fluorophenoxy)ethyl)piperidine-4-carbaldehyde
##STR00220##
[0944] Title compound was prepared
(1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methanol (0.850 g, 3.36
mmol) using the conditions of step 3 in Example-78 to obtain 0.5 g
1-(2-(2-fluorophenoxy)ethyl)piperidine-4-carbaldehyde
(Yield=59%).
1-(4-chlorophenyl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)--
1-(2-fluorophenyl)methanamine
##STR00221##
[0946] Title compound was prepared from of 1-(2-(2-fluorophenoxy)
ethyl) piperidine-4-carbaldehyde (0.147 g, 0.583 mmol) using the
general methodology of Example-59. The crude residue was purified
by preparative HPLC purification to afford 0.040 g of
1-(4-chlorophenyl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-
-1-(2-fluorophenyl)methanamine (Yield=16%). .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 7.54 (dt, 1H, J.sub.1,2=2.0 Hz, J.sub.1,4=9.2
Hz), 7.39-7.37 (m, 2H), 7.30-7.21 (m, 3H), 7.17-7.13 (m, 1H),
7.10-7.00 (m, 4H), 6.94-6.90 (m, 1H), 5.11 (s, 1H), 4.20 (t, 2H,
J=5.6 Hz), 3.10 (d, 2H, J=11.6 Hz), 2.89 (t, 2H, J=5.2 Hz), 2.43
(d, 2H, J=6.8 Hz), 2.29-2.23 (m, 2H), 1.84-1.81 (m, 2H), 1.58-1.54
(m, 1H), 1.30-1.29 (m, 2H); ESI+MS: m/z: 471.5 ([M+H].sup.+).
Example-88
N-((4(1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-1-(3-methoxypheny-
l)-1-(pyridin-2-yl)methanamine (88)
##STR00222##
[0948] Title compound was prepared from reductive amination of
1-(2-phenoxyethyl)piperidine-4-carbaldehyde (0.117 g, 0.467 mmol)
and (3-methoxyphenyl)(pyridin-2-yl)methanamine (0.1 g, 0.467 mmol,
1 equiv) using the general methodology of Example-59. The crude
residue was purified by prep HPLC purification to afford 0.050 g of
N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-1-(3-methoxyphenyl-
)-1-(pyridin-2-yl)methanamine (Yield=26%). .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 8.48 (d, 1H, J=4.0 Hz), 7.75 (dt, 1H,
J.sub.1,2=1.6 Hz, J.sub.1,4=9.6 Hz), 7.46 (d, 1H, J=8.0 Hz),
7.27-7.19 (m, 2H), 7.11-7.05 (m, 3H), 7.01-6.97 (m, 2H), 6.94-6.89
(m, 1H), 6.79 (dd, 1H, J.sub.1,2=2.0 Hz, J.sub.1,3=8.4 Hz), 4.83
(s, 1H), 4.20 (t, 2H, J=5.6 Hz), 3.76 (s, 3H), 3.13-3.08 (m, 2H),
2.87 (t, 2H, J=5.6 Hz), 2.50-2.40 (m, 2H), 2.25 (t, 2H, J=11.6 Hz),
1.82 (d, 2H, J=12.4 Hz), 1.60-1.59 (m, 1H), 1.34-1.26 (m, 2H);
ESI+MS: m/z: 450.5 ([M+H].sup.+). Enantiomers of 88 were separated
using chiral HPLC (method B) and afforded pure enantiomers 88a and
88b.
Example-89
1-(4-chlorophenyl)-N-((1-(2-(2,5-difluorophenoxy)ethyl)piperidin-4-yl)meth-
yl)-1-(pyridin-2-yl)methanamine (89)
##STR00223##
[0950] Title compound was prepared from
1-(4-chlorophenyl)-N-(piperidin-4-ylmethyl)-1-(pyridin-2-yl)methanamine
dihydrochloride 1 (100 mg, 0.257 mmol) using the general
methodology of Example-1. The product was purified by using silica
gel column chromatography (2% MeOH/CH.sub.2Cl.sub.2 as eluent)
afforded 0.050 g of
1-(4-chlorophenyl)-N-((1-(2-(2,5-difluorophenoxy)
ethyl)piperidin-4-yl)methyl)-1-(pyridin-2-yl)methanamine
(Yield=41%).
[0951] .sup.1H NMR (400 MHz, DMSO-D.sub.6): .delta. 8.46 (d, 1H,
J=4.0 Hz), 7.73 (dt, 1H, J.sub.1,2=1.6 Hz, J.sub.1,4=9.2 Hz), 7.45
(s, 1H), 7.41 (d, 2H, J=8.4 Hz), 7.33 (d, 2H, J=8.4 Hz), 7.25-7.19
(m, 2H), 7.15-7.10 (m, 2H), 6.76-6.70 (m, 1H), 4.83 (s, 1H), 4.13
(t, 2H, J=7.6 Hz), 2.89 (d, 2H, J=10.4 Hz), 2.67-2.66 (m, 2H),
2.33-2.29 (m, 2H), 2.10-1.98 (m, 2H), 1.68 (d, 2H, J=11.2 Hz),
1.48-1.40 (m, 1H), 1.13-1.05 (m, 2H); ESI+MS: m/z:472.5
([M+H].sup.+). Enantiomers of 89 were separated using chiral HPLC
(method L) and afforded pure enantiomers 89a and 89b.
Example-90
1-(2-(2,5-difluorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-yl)methyl)
piperidine-4-carboxamide (90)
##STR00224##
[0953] Title compound was prepared from
N-((3-methoxyphenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(100 mg, 0.461 mmol) using the general methodology of Example-1.
The product was purified by using silica gel column chromatography
(2% MeOH/DCM as eluent) afforded 0.070 g of
1-(2-(2,5-difluorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-yl)methyl-
) piperidine-4-carboxamide (Yield=31%). .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 8.51 (d, 1H, J=4.4 Hz), 7.79 (dt, 1H,
J.sub.12=1.6 Hz, J.sub.1,4=9.2 Hz), 7.39 (d, 1H, J=8.0 Hz),
7.31-7.28 (m, 1H), 7.23-7.19 (m, 1H), 7.10-7.04 (m, 1H), 6.95-6.90
(m, 1H), 6.85-6.80 (m, 3H), 6.66-6.60 (m, 1H), 6.13 (s, 1H), 4.18
(t, 2H, J=5.6 Hz), 3.75 (s, 3H), 3.10 (d, 2H, J=12.0 Hz), 2.86 (t,
2H, J=5.2 Hz), 2.46-2.38 (m, 1H), 2.31-2.24 (m, 2H), 1.91-1.76 (m,
4H); ESI+MS: m/z 482.6 ([M+H].sup.+).
Example-91
N-((4(4-chlorophenyl)(3-fluoropyridin-4-yl)methyl)-1-(2-(2-fluorophenoxy)e-
thyl) piperidine-4-carboxamide (91)
##STR00225##
[0955] Title compound was prepared from coupling of
1-(2-(2-fluorophenoxy)ethyl)piperidine-4-carboxylic acid (0.271 g,
1.01 mmol, 1.2 equiv) and
(4-chlorophenyl)(3-fluoropyridin-4-yl)methanamine 5 (0.2 g, 0.845
mmol, 1 equiv) using the conditions in step 5 in the general
methodology of key Intermediate-I. The product was purified by
using silica gel column chromatography (2% MeOH/DCM as eluent) to
afford 0.1 g of
N-((4-chlorophenyl)(3-fluoropyridin-4-yl)methyl)-1-(2-(2-fluorop-
henoxy)ethyl)piperidine-4-carboxamide (Yield=24%). .sup.1H NMR (400
MHz, CD.sub.3OD): .delta. 8.42 (d, 1H, J=2.0 Hz), 8.40 (d, 1H,
J=5.2 Hz), 7.40-7.36 (m, 3H), 7.24 (d, 2H, J=8.4 Hz), 7.12-7.06 (m,
3H), 6.97-6.93 (m, 1H), 6.39 (s, 1H), 4.25 (t, 2H, J=5.2 Hz),
3.30-3.26 (m, 2H), 3.13-3.03 (m, 2H), 2.50-2.32 (m, 3H), 1.89-1.88
(m, 4H); ESI+MS: m/z: 486.4 ([M+H].sup.+). Enantiomers of 91 were
separated using chiral HPLC (method C) and afforded pure
enantiomers 91a and 91b.
Example-92
N-((4(4-chlorophenyl)(5-fluoropyridin-2-yl)methyl)-1-(2-(2-fluorophenoxy)e-
thyl) piperidine-4-carboxamide (92)
##STR00226##
[0957] Title compound was prepared from coupling of
1-(2-(2-fluorophenoxy)ethyl)piperidine-4-carboxylic acid (0.271 g,
1.01 mmol, 1.2 equiv) and
(4-chlorophenyl)(5-fluoropyridin-2-yl)methanamine (0.2 g, 0.845
mmol, 1 equiv) using the conditions in step 5 in the general
methodology of key Intermediate-I. The product was purified by
using silica gel column chromatography (2% MeOH/DCM as eluent) to
afford 0.2 g of
N-((4-chlorophenyl)(5-fluoropyridin-2-yl)methyl)-1-(2-(2-fluorop-
henoxy)ethyl)piperidine-4-carboxamide (Yield=47%). .sup.1H NMR (500
MHz, CD.sub.3OD): .delta. 8.45 (s, 1H), 7.61-7.58 (m, 1H),
7.44-7.29 (m, 1H), 7.29-7.10 (m, 4H), 7.14-7.08 (m, 3H), 6.95 (t,
1H, J=6.0 Hz), 6.19 (s, 1H), 4.25 (t, 2H, J=5.5 Hz), 3.23 (d, 2H,
J=11.0 Hz), 3.12-2.99 (m, 2H), 2.48-2.45 (m, 3H), 1.89-1.88 (m,
4H); ESI+MS: m/z: 486 ([M].sup.+). Enantiomers of 92 were separated
using chiral HPLC (method G) and afforded pure enantiomers 92a and
92b.
Example-93
1-(2-(2-fluorophenoxy)ethyl)-N-(pyridin-2-yl(3-(trifluoromethoxy)phenyl)
methyl)piperidine-4-carboxamide (93)
##STR00227##
[0959] Title compound was prepared from coupling of
1-(2-(2-fluorophenoxy)ethyl)piperidine-4-carboxylic acid 6 (0.179
g, 0.671 mmol, 1.2 equiv) and
pyridin-2-yl(3-(trifluoromethoxy)phenyl)methanamine 5 (0.15 g,
0.559 mmol, 1 equiv) using the conditions in step 5 in the general
methodology of key Intermediate-I. The product was purified by
using silica gel column chromatography (2% MeOH/DCM as eluent) to
afford 0.1 g of
1-(2-(2-fluorophenoxy)ethyl)-N-(pyridin-2-yl(3-(trifluoromethoxy)phenyl)m-
ethyl)piperidine-4-carboxamide (Yield=32%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.77(d, 1H, J=8.5 Hz), 8.52(d, 1H, J=4.5
Hz), 7.79 (t, 1H, J=7.0 Hz), 7.49 (d, 1H, J=7.5 Hz), 7.43 (t, 1H,
J=8.0 Hz),7 .30-7 .27 (m, 3H), 7.22-7.16 (m, 3H), 7.10 (t, 1H,
J=7.5 Hz), 6.94-6.90 (m, 1H), 6.20 (d, 1H, J=8.0 Hz), 4.12(t, 2H,
J=5.5 Hz), 2.95 (d, 2H, J=8.5 Hz), 2.69 (t, 2H, J=5.5
Hz),2.37-2.33(m, 1H), 2.03 (t, 2H, J=11.0 Hz), 1.69-1.52(m, 4H);
ESI+MS: m/z: 518.6 ([M+H].sup.+). Enantiomers of 93 were separated
using chiral HPLC (method M) and afforded pure enantiomers 93a and
93b.
Example-94
N-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methyl)-1-(2-(2-flu-
oro phenoxy)ethyl)piperidine-4-carboxamide (94)
##STR00228##
[0961] Title compound was prepared from coupling of
1-(2-(2-fluorophenoxy)ethyl)piperidine-4-carboxylic acid 6 (0.243
g, 0.908 mmol, 1.2 equiv) and
(2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methanamine 5
(0.2 g, 0.757 mmol, 1 equiv) using the conditions in step 5 in the
general methodology of key Intermediate-I. The product was purified
by using silica gel column chromatography (2% MeOH/DCM as eluent)
to afford 0.2 g of N-((2,2-difluoro
benzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methyl)-1-(2-(2-fluorophenoxy)ethy-
l)piperidine-4-carboxamide (Yield=50%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 8.70(d, 1H, J=8.5 Hz), 8.51 (d, 1H, J=4.5
Hz), 7.77 (t, 1H, J=8.0 Hz), 7.46 (d, 1H, J=7.5 Hz), 7.39 (s, 1H),
7.33-7.26 (m, 2H), 7.19-7.09 (m, 4H), 6.92-6.91 (m, 1H), 6.16 (d,
1H, J=8.0 Hz), 4.12 (t, 2H, J=5.5 Hz), 2.95 (d, 2H, J=11.0 Hz),
2.69 (t, 2H, J=5.5 Hz),2.33-2.31(m, 1H), 2.03 (t, 2H, J=11.5
Hz),1.68-1.54(m, 4H); ESI+MS: m/z: 514.6 ([M+H].sup.+). Enantiomers
of 94 were separated using chiral HPLC (method A) and afforded pure
enantiomers 94a and 94b.
Example-95
N-(benzo[d][1,3]dioxol-5-yl(pyridin-2-yl)methyl)-1-(2-(2-fluorophenoxy)
ethyl) piperidine-4-carboxamide (95)
##STR00229##
[0963] Title compound was prepared from coupling of
1-(2-(2-fluorophenoxy)ethyl)piperidine-4-carboxylic acid 6 (0.281
g, 1.05 mmol, 1.2 equiv) and
benzo[d][1,3]dioxol-5-yl(pyridin-2-yl)methanamine 5 (0.2 g, 0.876
mmol, 1 equiv) using the conditions in step 5 in the general
methodology of key Intermediate-I. The product was purified by
using silica gel column chromatography (2% MeOH/DCM as eluent) and
further purified by prep HPLC purification to furnish 0.1 g of
N-(benzo[d][1,3]dioxol-5-yl(pyridin-2-yl)methyl)-1-(2-(2-fluorophenoxy)
ethyl) piperidine-4-carboxamide (Yield=24%). .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 8.51(d, 1H, J=4.4 Hz), 7.80-7.76 (m, 1H), 7.37
(d, 1H, J=8.0 Hz), 7.31-7.28 (m, 1H), 7.15-7.08 (m, 3H), 6.98-6.93
(m, 1H), 6.77-6.74 (m, 3H), 6.07 (s, 1H), 5.90 (d, 2H, J=2.4 Hz),
4.29 (t, 2H, J=4.8 Hz), 3.38 (d, 2H, J=11.2 Hz), 3.20-3.17 (m, 2H),
2.71-2.51 (m, 3H), 2.03-1.85 (m, 4H); ESI+MS: m/z: 478.5
([M+H].sup.+). Enantiomers of 95 were separated using chiral HPLC
(method G) and afforded pure enantiomers 95a and 95b.
Example-96
N-((4-chlorophenyl)(2-fluorophenyl)methyl)-1-(2-(2-fluorophenoxy)ethyl)
piperidine-4-carboxamide (96)
##STR00230##
[0965] Title compound was prepared from coupling of
1-(2-(2-fluorophenoxy)ethyl)piperidine-4-carboxylic acid 2 (0.204
g, 0.764 mmol, 1.2 equiv) (4-chlorophenyl)(2-fluorophenyl)
methanamine 1 (0.150 g, 0.636 mmol, 1 equiv) using the conditions
in step 5 in the general methodology of key Intermediate-I. The
product was purified by prep HPLC purification to furnish 0.015 g
of
N-((4-chlorophenyl)(2-fluorophenyl)methyl)-1-(2-(2-fluorophenoxy)ethyl)
piperidine-4-carboxamide (Yield=5%). .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 7.36-7.30 (m, 3H), 7.26 (dt, 1H, J.sub.1,2=2.0
Hz, J.sub.1,4=9.211Z), 7.21-7.15 (m, 3H), 7.12-7.04 (m, 4H),
6.94-6.88 (m, 1H), 6.41 (s, 1H), 4.18 (t, 2H, J=5.6 Hz), 3.12-3.08
(m, 2H), 2.83 (t, 2H, J=5.6 Hz), 2.41-2.33 (m, 1H), 2.27-2.21 (m,
2H), 1.89-1.77 (m, 4H) ; ESI+MS: m/z: 485.6 ([M+H].sup.+).
Enantiomers of 96 were separated using chiral HPLC (method N) and
afforded pure enantiomers 96a and 96b.
Example-97
N((4-chlorophenyl)(pyridin-2-yl)methyl)-N-methyl-1-(1-(2-phenoxy
ethyl) piperidin-4-yl)ethan-1-amine (97)
##STR00231##
[0966] tert-butyl
4-(1-(methylamino)ethyl)piperidine-1-carboxylate
##STR00232##
[0968] To a stirred solution of tert-butyl
4-acetylpiperidine-1-carboxylate (1 g, 4.40 mmol) in MeOH (10 mL)
under argon atmosphere were added methanamine hydrochloride (0.594
g, 8.80 mmol, 2 equiv) and sodium cyanoborohydride (0.829 g, 13.20
mmol, 3 equiv) at 0.degree. C. The reaction mixture was warmed to
room temperature and stirred for 16 h. After completion of the
reaction, the volatiles were removed and the solvent was removed
under reduced pressure. The pH was adjusted to 7 with saturated
NaHCO.sub.3 solution and extracted with CH.sub.2Cl.sub.2. The
combined organic extract was dried over sodium sulfate, filtered
and concentrated under reduced pressure to afford crude residue
which was purified by column chromatography eluting with 50% ethyl
acetate in Hexane to afford 0.5 g of tert-butyl
4-(1-(methylamino)ethyl) piperidine-1-carboxylate (Yield=47%).
ESI+MS: m/z 243.3 ([M+H].sup.+).
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-fluorophenoxy)ethyl)piper-
idine-4-carboxamide
##STR00233##
[0970] Title compound was prepared from tert-butyl
4-(1-(methylamino)ethyl)piperidine-1-carboxylate (0.5 g, 2.06 mmol)
using the general methodology of Example-1. The crude residue was
purified by column chromatography eluting with (3% MeOH in DCM as
eluent) to afford 0.4 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-fluorophenoxy)e-
thyl)piperidine-4-carboxamide (Yield=44%).
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-methyl-1-(piperidin-4-yl)ethan--
1-amine hydrochloride
##STR00234##
[0972] Title compound was prepared from
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(4-fluorophenoxy)ethyl)pi-
peridine-4-carboxamide (0.4 g, 0.901 mmol) using the general
methodology of step 2 in the synthesis of intermediate-V. The crude
HCl salt 0.3 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-methyl-1-(piperidin-4-yl)ethan-
-1-amine hydrochloride was used in the next step as such
(Yield=88%).
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-methyl-1-(1-(2-phenoxyethyl)pip-
eridin-4-yl)ethan-1-amine
##STR00235##
[0974] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-methyl-1-(piperidin-4-yl)ethan-
-1-amine hydrochloride (0.3 g, 0.789 mmol) using the general
methodology of Example-1. The crude residue was purified by column
chromatography eluting with (3% MeOH in DCM as eluent) to afford
0.14 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-methyl-1-(1-(2-phenoxyethyl)pi-
peridin-4-yl)ethan-1-amine (Yield=38%).
[0975] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.41 (t, 1H,
J=4.8 Hz), 7.75-7.72 (m, 1H), 7.63-7.7.44 (m, 3H), 7.34-7.26 (m,
4H), 7.19-7.17 (m, 1H), 6.93 (d, 3H, J=7.6 Hz), 4.76 (d, 1H, J=13.6
Hz), 4.05 (bs, 2H), 3.05-2.85 (m, 2H), 2.65-2.63 (m, 1H), 2.32-2.16
(m, 2H), 2.01-1.94 (m, 5H), 1.56-1.54 (m, 1H), 1.25-1.20 (m, 4H),
1.17-1.14 (m, 1H), 0.85-0.80 (m, 2H); ESI+MS: m/z: 344.4
([M+H].sup.+). All stereoisomers of 97 were separated using chiral
HPLC (method H) and afforded 97a, 97b, 97c and 97d.
Example-98
2-((4-chlorophenyl)(pyridin-2-yl)methyl)-5-(2-phenoxyethyl)octahydro-1H-py-
rrolo[3,4-e]pyridine (98)
##STR00236##
[0976] tert-butyl
2-((4-chlorophenyl)(pyridin-2-yl)methyl)octahydro-5H-pyrrolo[3,4-c]pyridi-
ne-5-carboxylate
##STR00237##
[0978] Title compound was prepared from tert-butyl
4-(1-(methylamino)ethyl)piperidine-1-carboxylate (0.190 g, 0.840
mmol) using the general methodology of Example-1. The crude residue
was purified by column chromatography eluting with (50% EtOAc in
Hexane as eluent) to afford 0.3 g of tert-butyl
2-((4-chlorophenyl)(pyridin-2-yl)methyl)octahydro-5H-pyrrolo[3,4-c]pyridi-
ne-5-carboxylate (Yield=83%).
2
-((4-chlorophenyl)(pyridin-2-yl)methyl)octahydro-1H-pyrrolo[3,4-c]pyridi-
ne hydrochloride
##STR00238##
[0980] Title compound was prepared from
2-(2-phenoxyethyl)octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate
(0.3 g, 0.701 mmol) using the general methodology of step 2 in the
synthesis of intermediate-V. The crude HCl salt 0.220 g of
2-((4-chlorophenyl)(pyridin-2-yl)methyl)
octahydro-1H-pyrrolo[3,4-c]pyridine hydrochloride was used in the
next step as such (Yield=86%).
2-((4-chlorophenyl)(pyridin-2-yl)methyl)-5-(2-phenoxyethyl)octahydro-1H-py-
rrolo[3,4-c]pyridine
##STR00239##
[0982] Title compound was prepared from
2-((4-chlorophenyl)(pyridin-2-yl)methyl)octahydro-1H-pyrrolo[3,4-c]pyridi-
ne hydrochloride (0.220 g, 0.604 mmol) using the general
methodology of Example-1. The crude residue was purified by column
chromatography eluting with (4% MeOH in DCM as eluent) to afford
0.150 g diastereomeric mixture of
2-((4-chlorophenyl)(pyridin-2-yl)methyl)-5-(2-phenoxyethyl)octahydro-1H-p-
yrrolo[3,4-c]pyridine (Yield=54%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.40 (d, 1H, J=4.0 Hz), 7.74 (t, 1H, J=7.6
Hz), 7.56 (d, 1H, J=7.6 Hz), 7.47 (d, 2H, J=8.4 Hz), 7.32 (d, 2H,
J=8.0 Hz), 7.26 (t, 2H, J=15.6 Hz), 7.18 (t, 1H, J=12.0 Hz), 6.90
(t, 3H, J=7.2 Hz), 4.65 (s, 1H), 4.03 (t, 2H, J=6.0 Hz), 2.67-2.66
(m, 2H), 2.58-2.53 (m, 2H), 2.44-2.40 (m, 3H), 2.25-2.08 (m, 3H),
1.64-1.61 (m, 2H), 1.25-1.22 (m, 2H); ESI+MS: m/z: 448.5
([M+H].sup.+).
Example-99
2-((4-chlorophenyl)((1-(2-phenoxyethyl)piperidin-4-yl)methoxy)
methyl) pyridine (99)
##STR00240##
[0984] To a stirred solution of
(1-(2-phenoxyethyl)piperidin-4-yl)methanol (0.3 g, 1.27 mmol) in
THF (5 mL) was added sodium hydride (0.046 g, 1.9 mmol, 1.5 equiv)
and 10 minutes later, 2-(chloro(4-chlorophenyl)methyl)pyridine
(0.304 g, 1.27 mmol, 1.0 equiv) at room temperature. The reaction
mixture was heated at 80.degree. C. and stirred for 16 h. After
completion, water was added to the reaction mixture and extracted
with EtOAc. The combined organic extract was washed with brine,
dried over sodium sulphate, filtered and concentrated under reduced
pressure. Purification using prep HPLC purification to furnish
0.012 g of
2-((4-chlorophenyl)((1-(2-phenoxyethyl)piperidin-4-yl)methoxy)methyl)pyri-
dine (Yield=2%). .sup.1H NMR (400 MHz, CD.sub.3OD-d.sub.4): .delta.
8.45-8.43 (m, 1H), 7.86-7.82 (m, 1H), 7.62-7.60 (m, 1H), 7.39-7.36
(m, 2H), 7.32-7.23 (m, 5H), 6.93-6.89 (m, 3H), 5.42 (s, 1H), 4.12
(t, 2H, J=5.6 Hz), 3.36 (d, 2H, J=6.0 Hz), 3.07 (d, 2H, J=11.6 Hz),
2.82 (t, 2H, J=5.6 Hz), 2.22-2.16 (m, 2H), 1.89-1.69 (m, 3H),
1.46-1.36 (m, 2H); ESI+MS: m/z: 437 ([M+H].sup.+).
Example-100
2-((4-chlorophenyl)(pyridin-2-yl)methyl)-5-(2-(2-(trifluoromethyl)phenoxy)
ethyl)octahydro-1H-pyrrolo[3,4-c]pyridine (100)
##STR00241##
[0986] Title compound was prepared from
24(4-chlorophenyl)(pyridin-2-yl)methyl)octahydro-1H-pyrrolo[3,4-c]pyridin-
e hydrochloride (0.200 g, 0.529 mmol) using the general methodology
of Example-1. The crude residue was purified by prep HPLC
purification to furnish 0.130 g
2-((4-chlorophenyl)(pyridin-2-yl)methyl)-5-(2-(2-(trifluoromethyl)
phenoxy) ethyl) octahydro-1H-pyrrolo[3,4-c]pyridine (Yield=46%).
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.41 (d, 1H, J=5.2 Hz),
7.82-7.78 (m, 1H), 7.69 (d, 1H, J=7.6 Hz), 7.58-7.48 (m, 4H),
7.30-7.24 (m, 3H), 7.16 (d, 1H, J=8.0 Hz), 7.06 (t, 1H, J=7.6 Hz),
4.37 (s, 1H), 4.23 (t, 2H, J=5.6 Hz), 2.85 (t, 2H, J=5.6 Hz),
2.60-2.50 (m, 6H), 2.35 (s, 2H), 1.70-1.67 (m, 6H); ESI+MS: m/z:
530.6 ([M+H].sup.+).
Example-101
1-(4-fluorophenyl)-N-((4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)
piperidin-4-yl)methyl)-1-(pyridin-2-yl)methanamine (101)
##STR00242##
[0987] (4-fluorophenyl)(pyridin-2-yl)methanol
##STR00243##
[0989] To a stirred solution of
(4-fluorophenyl)(pyridin-2-yl)methanone (1) (0.5 g, 2.48 mmol) in
MeOH (5 mL) was added sodium borohydride (0.282 g, 7.46 mmol, 3
equiv) at 0.degree. C. The reaction mixture was warmed to room
temperature and stirred for 4 h. After completion, the reaction
mixture was filtered through celite, washed with CH.sub.2Cl.sub.2
and the filtrate was concentrated under reduced pressure to afford
0.450 g of (4-fluorophenyl)(pyridin-2-yl)methanol (Yield=89%).
2-(chloro(4-fluorophenyl)methyl)pyridine
##STR00244##
[0991] (4-fluorophenyl)(pyridin-2-yl)methanol (0.450 g, 2.21 mmol)
was diluted in DCM (5 mL) and thionyl chloride (0.395 g, 3.32 mmol)
was added at 0.degree. C. The reaction mixture was stirred at room
temperature for 6 hrs. The solvents were then evaporated and the
mixture was dissolved in DCM and washed with a saturated solution
of sodium bicarbonate. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated. Flash chromatography
on silica gel using 10% ethyl acetate in hexanes afforded 0.450 g
of 2-(chloro(4-fluorophenyl)methyl)pyridine (Yield=92%).
tert-butyl
4-((((4-fluorophenyl)(pyridin-2-yl)methyl)amino)methyl)-4-methy-
lpiperidine-1-carboxylate
##STR00245##
[0993] Title compound was prepared from
2-(chloro(4-fluorophenyl)methyl)pyridine (0.4 g, 1.80 mmol) using
the general methodology of Example-1. The crude residue was
purified by column chromatography eluting with (40% EtOAc in Hexane
as eluent) to afford 0.6 g of tert-butyl
4-((((4-fluorophenyl)(pyridin-2-yl)methyl)amino)methyl)-4-methylpiperidin-
e-1-carboxylate (Yield=80%).
1-(4-fluorophenyl)-N-((4-methylpiperidin-4-yl)methyl)-1-(pyridin-2-yl)meth-
anamine hydrochloride
##STR00246##
[0995] Title compound was prepared from tert-butyl
4-((((4-fluorophenyl)(pyridin-2-yl)methyl) amino)
methyl)-4-methylpiperidine-1-carboxylate (0.6 g, 1.45 mmol) using
conditions described in step 2 of the synthesis of key
intermediate-V. The crude HCl salt 0.450 g of
1-(4-fluorophenyl)-N-((4-methylpiperidin-4-yl)methyl)-1-(pyridin-2-yl)met-
hanamine hydrochloride was used in the next step as such
(Yield=80%).
1-(4-fluorophenyl)-N-((4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)
ethyl) piperidin-4-yl)methyl)-1-(pyridin-2-yl)methanamine
##STR00247##
[0997] Title compound was prepared from
1-(4-fluorophenyl)-N-((4-methylpiperidin-4-yl)methyl)-1-(pyridin-2-yl)met-
hanamine hydrochloride (0.450 g, 1.16 mmol) using the general
methodology of Example-1. The crude residue was purified by column
chromatography (3% MeOH in DCM) afforded 0.3 g
1-(4-fluorophenyl)-N-((4-methyl-1-(2-(2-(trifluoromethyl) phenoxy)
ethyl) piperidin-4-yl)methyl)-1-(pyridin-2-yl)methanamine
(Yield=51%). .sup.1H NMR (400 MHz, DSMO-d.sub.6): .delta. 8.47 (d,
1H, J=4.8 Hz), 7.74-7.70 (m, 1H), 7.63-7.58 (m, 2H), 7.44-7.40 (m,
3H), 7.27-7.19 (m, 2H), 7.10 (t, 3H, J=8.4 Hz), 4.82 (s, 1H),
4.18-4.17 (m, 2H), 2.67-2.66 (m, 2H), 2.56-2.54 (m, 1H), 2.46-2.45
(m, 2H), 2.35-2.32 (m, 2H), 2.26-2.25 (m, 2H), 1.46-1.45 (m, 2H),
1.36-1.23 (m, 2H), 0.91 (s, 3H); ESI+MS: m/z: 502.6 ([M+H].sup.+).
Enantiomers of 101 were separated using chiral HPLC (method P) and
afforded pure enantiomers 101a and 101b.
Example-102
1-(benzo[d][1,3]dioxol-5-yl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)--
1-(pyridin-2-yl)methanamine (102)
##STR00248##
[0999] Title compound was prepared from
benzo[d][1,3]dioxol-5-yl(pyridin-2-yl)methanamine (0.098 g, 0.429
mmol) and 1-(2-phenoxyethyl)piperidine-4-carbaldehyde (0.1 g, 0.429
mmol, 1 equiv) using the conditions described in Example 68 to
afford 0.015 g (Yield=8%). .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 8.46 (dd, 1H, J.sub.1,2=0.8 Hz, J.sub.1,3=4.8 Hz), 7.74
(dt, 1H, J.sub.1,2=2.0 Hz, J.sub.1,4=15.6 Hz), 7.45 (d, 1H, J=8.0
Hz), 7.27-7.22 (m, 3H), 6.92-8.87 (m, 5H), 6.73 (d, 1H, J=7.6 Hz),
5.87 (dd, 2H, J.sub.1,2=1.2 Hz, J.sub.1,3=5.2 Hz), 4.84-4.80 (m,
1H), 4.10 (t, 2H, J=5.6 Hz), 3.02 (d, 2H, J=11.2 Hz), 2.78 (t, 2H,
J=5.6 Hz), 2.46-2.36 (m, 2H), 2.17 (t, 2H, J=11.6 Hz), 1.79 (d, 2H,
J=11.6 Hz), 1.59-1.50 (m, 1H), 1.32-1.28 (m, 1H), 1.26-1.21 (m,
1H); ESI+MS: m/z 446 ([M+H].sup.+). Enantiomers of 102 were
separated using chiral HPLC (method D) and afforded pure
enantiomers 102a and 102b.
Example-103
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-phenoxyethyl)piperidin-4-
-yl) methyl) propan-2-amine (103)
##STR00249##
[1000] N-((4-chlorophenyl)(pyridin-2-yl)methyl)propan-2-amine
##STR00250##
[1002] To a solution of 2-(chloro(4-chlorophenyl)methyl)pyridine (1
g, 4.20 mmol) in CH.sub.3CN (25 mL) under argon atmosphere were
added isopropyl amine (5 mL, 61.1 mmol, 14.54 equiv) and potassium
carbonate (1.71 g, 12.64 mmol, 3 equiv) in a sealed tube and the
reaction was heated at 80.degree. C. for 16 h. After completion,
the reaction was diluted with water and extracted with EtOAc. The
combined organic extract was dried over sodium sulfate, filtered
and concentrated under reduced pressure. Purification using silica
gel column chromatography (40% EtOAc/Hexanes as eluent) afforded
0.360 g of N-((4-chlorophenyl)(pyridin-2-yl)methyl)propan-2-amine
(Yield=33%). ESI+MS: m/z 261.2 ([M+H].sup.+).
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-phenoxyethyl)piperidin-
-4-yl)methyl)propan-2-amine
##STR00251##
[1004] To a stirred solution of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)propan-2-amine (0.150 g,
0.575 mmol) in 00 mL of CH.sub.2Cl.sub.2 under argon atmosphere
were added 1-(2-phenoxyethyl)piperidine-4-carbaldehyde (0.134 g,
0.575 mmol, 1 equiv) at 0.degree. C. and stirred for 5 min. Then
sodium triacetoxy borohydride (0.366 g, 1.726 mmol, 3 equiv),
acetic acid (0.0345 g, 0.575 mmol, 1 equiv) was added and the
reaction mixture was stirred at room temperature for 72 h. After
completion, the pH was adjusted to 7 with saturated NaHCO.sub.3
solution and extracted with CH.sub.2Cl.sub.2. The combined organic
extract was dried over sodium sulfate, filtered and concentrated
under reduced pressure. The crude was purified by preparative HPLC
to afford 0.013 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-phenoxyethyl)piperidin--
4-yl)methyl)propan-2-amine (Yield=5%). .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 8.42 (dd, 1H, J.sub.1,2=1.2 Hz, J.sub.1,3=5.2
Hz), 7.82-7.77 (m, 1H), 7.66 (d, 1H, J=8.0 Hz), 7.38-7.36 (m, 2H),
7.29-7.23 (m, 5H), 6.92-6.89 (m, 3H), 5.03 (s, 1H), 4.08 (t, 2H,
J=5.6 Hz), 3.12-3.05 (m, 1H), 2.96 (d, 2H, J=11.6 Hz), 2.73 (t, 2H,
J=5.6 Hz), 2.47-2.36 (m, 2H), 1.94-1.87 (m, 2H), 1.70-1.63 (m, 2H),
1.12-1.00 (m, 2H), 0.97 (d, 3H, J=6.4 Hz), 0.89-0.86 (m, 4H);
ESI+MS: m/z 478 ([M+H].sup.+). Enantiomers of 103 were separated
using chiral HPLC (method C) and afforded pure enantiomers 103a and
103b.
Example-104
2((4-chlorophenyl)(pyridin-2-yl)methyl)-7-(2-phenoxyethyl)-2,7-diaza
spiro[3.5]nonane (104)
##STR00252##
[1005] tert-butyl
7-(2-phenoxyethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate
##STR00253##
[1007] Title compound was prepared from tert-butyl
2,7-diazaspiro[3.5]nonane-2-carboxylate (0.2 g, 0.884 mmol) using
the general methodology of Example-1 to afford 0.250 g (Yield=82%).
ESI+MS: m/z 347.4 ([M+H].sup.+).
7-(2-phenoxyethyl)-2,7-diazaspiro[3.5]nonane hydrochloride
##STR00254##
[1009] Title compound was prepared from tert-butyl
7-(2-phenoxyethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (0.250
g, 0.722 mmol) using the conditions described in step 2 for the
synthesis of key Intermediate-V to afford 0.170 g (Yield=83%).
ESI+MS: m/z 247.3 ([M+H].sup.+).
2-((4-chlorophenyl)(pyridin-2-yl)methyl)-7-(2-phenoxyethyl)-2,7-diazaspiro-
[3.5]nonane
##STR00255##
[1011] Title compound was prepared from
2-(chloro(4-chlorophenyl)methyl)pyridine (0.126 g, 0.530 mmol) and
7-(2-phenoxyethyl)-2,7-diazaspiro[3.5]nonane hydrochloride (0.150
g, 0.530 mmol, 1 equiv) using the general methodology of Example-1.
The crude was purified by preparative HPLC purification to afford
0.010 g 2-((4-chlorophenyl)(pyridin-2-yl)methyl)-7-(2-phenoxy
ethyl)-2,7-diazaspiro[3.5]nonane (Yield=4%). .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 8.43 (m, 1H), 7.80-7.76 (m, 1H), 7.58 (d, 1H,
J=8.0 Hz), 7.44-7.42 (m, 2H), 7.29-7.22 (m, 5H), 6.92-6.88 (m, 3H),
4.58 (s, 1H), 4.09 (t, 2H, J=5.6 Hz), 3.01-2.94 (m, 4H), 2.74 (t,
2H, J=5.6 Hz), 2.50 (br s, 4H), 1.84 (t, 4H, J=5.2 Hz); ESI+MS: m/z
448 ([M+H].sup.+).
Example-105
2-((4-chlorophenyl)(pyridin-2-yl)methyl)-8-(2-phenoxyethyl)-2,8-diazaspiro-
[4.5]decane (105)
##STR00256##
[1013]
2-((4-chlorophenyl)(pyridin-2-yl)methyl)-8-(2-phenoxyethyl)-2,8-dia-
zaspiro[4.5]decane was synthesized in 3 steps using the same
chemistry as Example-104 and replacing tert-butyl
2,7-diazaspiro[3.5]nonane-2-carboxylate with tert-butyl
2,8-diazaspiro[4.5]decane-8-carboxylate to afford 0.060 g of
2-((4-chlorophenyl)(pyridin-2-yl)methyl)-8-(2-phenoxyethyl)-2,8-diaza
spiro[4.5]decane (Yield=41%). .sup.1H NMR (500 MHz, DMSO-d.sub.6):
.delta. 8.42 (d, 1H, J=4.5 Hz), 7.77-7.74 (m, 1H), 7.58 (d, 1H,
J=8.0 Hz), 7.47 (d, 2H, J=8.5 Hz), 7.34 (d, 2H, J=8.5 Hz),
7.28-7.19 (m, 3H), 6.91-6.90 (m, 3H), 4.36 (s, 1H), 4.02 (t, 2H,
J=6.0 Hz), 3.10-2.90 (m, 2H), 2.63-2.60 (m, 3H), 2.41-2.36 (m, 5H),
2.25-2.21 (m, 2H), 1.56-1.51 (m, 4H); ESI+MS: m/z 462
([M+H].sup.+). Enantiomers of 105 were separated using chiral HPLC
(method B) and afforded pure enantiomers 105a and 105b.
Example-106
2-((4-chlorophenyl)(pyridin-2-yl)methyl)-8-(2-(2-(trifluoromethyl)phenoxy)
ethyl)-2,8-diazaspiro[4.5]decane (106)
##STR00257##
[1015] Title compound was synthesized in 3 steps using the same
chemistry as Example-104 and replacing tert-butyl
2,7-diazaspiro[3.5]nonane-2-carboxylate with tert-butyl 2,8-diaza
spiro[4.5]decane-8-carboxylate and (2-bromoethoxy)-benzene with
1-(2-bromoethoxy)-2-(trifluoromethyl)benzene to afford 0.130 g of
product (Yield=46%). .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.
8.41 (d, 1H, J=5.2 Hz), 7.82-7.78 (m, 1H), 7.69 (d, 1H, J=7.6 Hz),
7.58-7.48 (m, 4H), 7.30-7.24 (m, 3H), 7.16 (d, 1H, J=8.0 Hz), 7.06
(t, 1H, J=7.6 Hz), 4.37 (s, 1H), 4.23 (t, 2H, J=5.6 Hz), 2.85 (t,
2H, J=5.6 Hz), 2.60-2.50 (m, 6H), 2.35 (s, 2H), 1.70-1.67 (m, 6H);
ESI+MS: m/z: 530.6 ([M+H].sup.+).
Example-107
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-phenoxyethyl)piperidin-4-
-yl) methyl) acetamide (107)
##STR00258##
[1017] tert-butyl
4-((((4-chlorophenyl)(pyridin-2-yl)methyl)amino)methyl)piperidine-1-carbo-
xylate
##STR00259##
[1018] Title compound was prepared from
2-(chloro(4-chlorophenyl)methyl)pyridine (1 g, 4.20 mmol) and
tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.9 g, 4.20
mmol, 1 equiv) using the general methodology of Example-1 to afford
1 g of tert-butyl
4-((((4-chlorophenyl)(pyridin-2-yl)methyl)amino)methyl)piperidine-1-carbo-
xylate (Yield=57%).
tert-butyl
4-((((4-chlorophenyl)(pyridin-2-yl)methyl)acetamido)methyl)pipe-
ridine-1-carboxylate
##STR00260##
[1020] To a solution of tert-butyl
4-((((4-chlorophenyl)(pyridin-2-yl)methyl)amino)methyl)
piperidine-1-carboxylate (0.3 g, 0.721 mmol) in CH.sub.2Cl.sub.2 (5
mL) under argon atmosphere were added triethyl amine (0.3 mL, 2.16
mmol, 3 equiv) and acetyl chloride (0.07 mL, 1.082 mmol, 1.5 equiv)
at 0.degree. C. The reaction was stirred at room temperature for 16
h. After completion, the reaction was diluted with water and
extracted with CH.sub.2Cl.sub.2 (2.times.25 mL). The combined
organic extract was dried over sodium sulfate, filtered and
concentrated under reduced pressure. Purification using column
chromatography (30% EtOAc/Hexanes as eluent) afforded 0.250 g of
tert-butyl 4-((N-((4-chlorophenyl)(pyridin-2-yl)methyl)
acetamido)methyl)piperidine-1-carboxylate (Yield=76%). ESI+MS: m/z
458.5 ([M+H].sup.+).
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-(piperidin-4-ylmethyl)acetamide
hydrochloride
##STR00261##
[1022] Title compound was prepared from tert-butyl
4-((N-((4-chlorophenyl)(pyridin-2-yl)methyl)acetamido)methyl)piperidine-1-
-carboxylate (0.250 g, 0.546 mmol) using the conditions described
in step 2 for the synthesis of key intermediate-V and afforded 0.2
g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-(piperidin-4-ylmethyl)acetamid-
e hydrochloride (Yield=93%). ESI+MS: m/z 358.4 ([M+H].sup.+).
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-phenoxyethyl)piperidin-
-4-yl) methyl) acetamide
##STR00262##
[1024] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-(piperidin-4-ylmethyl)acetamid-
e hydrochloride (0.2 g, 0.507 mmol) and (2-bromoethoxy)benzene
(0.102 g, 0.507 mmol, 1 equiv) using general methodology of
Example-1. The crude was purified by preparative HPLC to afford
0.060 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-phenoxyethyl)piperidin--
4-yl) methyl) acetamide (Yield=24%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 8.55 (br s, 1H), 7.78 (brs, 1H), 7.40 (d,
2H, J=7.5 Hz), 7.31-7.21 (m, 5H), 6.93-6.89 (m, 3H), 6.43 (br s,
1H), 4.00 (t, 2H, J=6.0 Hz), 3.37-3.35 (m, 2H), 2.76 (br s, 2H),
2.64-2.57 (m, 2H), 2.08 (s,3H), 1.71-1.69 (m, 2H), 1.30-1.25 (m,
4H), 0.88-0.86 (m, 2H); ESI+MS: m/z 478 ([M+H].sup.+).
Example-108
N-(isoquinolin-b
1-ylmethyl)-1-(2-(2-methoxyphenoxy)ethyl)piperidine-4-carboxamide
(108)
##STR00263##
[1026] Title compound was prepared from coupling of
1-(2-(2-methoxyphenoxy)ethyl)piperidine-4-carboxylic acid (0.05 g,
0.179 mmol, 1.1 equiv) and isoquinolin-1-ylmethanamine (0.026 g,
0.163 mmol, 1 equiv) using the conditions in step 5 in the general
methodology of key Intermediate-I. The crude compound was purified
by column chromatography (2% MeOH in DCM as elutant) afforded 0.026
g of
N-(isoquinolin-1-ylmethyl)-1-(2-phenoxyethyl)piperidine-4-carboxamide
(Yield=38%). .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 8.69 (s,
1H), 8.39 (d, 1H, J=7.0 Hz), 8.26 (d, 1H, J=7.0 Hz), 7.98 (d, 1H,
J=7.0 Hz), 7.85-7.65 (m, 3H), 7.10-7.00 (m, 3H), 6.95-6.85 (m, 1H),
5.06 (s, 2H), 4.33 (s, 2H), 3.87 (s, 3H), 3.85-3.70 (m, 2H), 3.58
(bs, 2H), 3.25-3.05 (m, 2H), 2.80-2.60 (m, 2H), 2.25-2.00 (m, 4H).
ESI+MS: m/z 420.4 ([M+H].sup.+).
Example-109
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2-methoxyphenoxy)
ethyl)piperidine-4-carboxamide (109)
##STR00264##
[1028] To a stirred solution of (4-chlorophenyl) (pyridin-2-yl)
methanamine (0.1 g, 0.45 mmol, 1 equiv) in DMF (3 mL) under argon
atmosphere were added
1-(2-(2-methoxyphenoxy)ethyl)piperidine-4-carboxylic acid (0.19 g,
0.68 mmol, 1.5 equiv), HATU (0.34 g, 0.91 mmol, 2 equiv) and
diisopropyl ethyl amine (0.2 mL, 1.14 mmol, 2.5 equiv) at 0.degree.
C. The reaction mixture was warmed to room temperature and stirred
for 16 h. After completion, the reaction mixture was quenched with
cold water and extracted with EtOAc. The combined organic extract
was dried over sodium sulfate, filtered and concentrated under
reduced pressure. Purification using silica gel column
chromatography (6% MeOH/CH.sub.2Cl.sub.2 as eluent) afforded 0.08 g
of N-((4-chlorophenyl)
(pyridin-2-yl)methyl)-1-(2-(2-methoxyphenoxy)ethyl)piperidine-4-carboxami-
de (Yield=36%). .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 8.71
(d, J=8.4 Hz, 1H), 8.51 (d, J=4.0 Hz, 1H), 7.80-7.76 (m, 1H), 7.45
(d, J=8.0 Hz, 1H), 7.37-7.31 (m, 4H), 7.29-7.26 (m, 1H), 6.98-6.90
(m, 2H), 6.89-6.84 (m, 2H), 6.13 (d, J=8.4 Hz, 1H), 4.06-4.02 (m,
2H), 3.74 (s, 3H), 3.01-2.97 (m, 2H), 2.69-2.64 (m, 1H), 2.35-2.33
(m, 1H), 2.08-2.01 (m, 2H), 1.67-1.56 (m, 5H); ESI+MS: m/z 480
([M+H].sup.+).
Example-110
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(4-henoxybutyl)piperidine-4-c-
arboxamide (110)
##STR00265##
[1029] Methyl 1-(4-phenoxybutyl)piperidine-4-carboxylate
##STR00266##
[1031] To a stirred solution of methyl piperidine-4-carboxylate
(1.25 g, 8.73 mmol, 1 equiv) and (4-bromobutoxy)benzene (2 g, 8.73
mmol) in CH.sub.3CN (20 mL) under argon atmosphere was added sodium
bicarbonate (2.2 g, 26.2 mmol, 3 equiv) at room temperature. The
reaction mixture was heated at 70.degree. C. and stirred for 16 h.
After completion, the reaction mixture was diluted with water and
extracted with EtOAc. The combined organic extract was washed with
brine and dried over sodium sulphate. The solvent was removed under
reduced pressure. Purification using silica gel column
chromatography (40% EtOAc/Hexanes as eluent) to afford 1.2 g methyl
1-(4-phenoxybutyl)piperidine-4-carboxylate (Yield=47%). ESI+MS:
m/z: 292.3 ([M+H].sup.+).
1-(4-phenoxybutyl)piperidine-4-carboxylic acid
##STR00267##
[1033] To a stirred solution of methyl
1-(4-phenoxybutyl)piperidine-4-carboxylate (1.0 g, 3.43 mmol, 1
equiv) in 25 mL of 2:2:1 mixture of THF:MeOH:H.sub.2O was added
lithium hydroxide (0.43 g, 10.30 mmol, 3 equiv) at 0.degree. C. and
the reaction mixture was stirred at room temperature for 3 h. After
completion, volatiles were removed under reduced pressure; pH was
adjusted to 7 with 1N HCl (aq), the obtained solid was filtered and
dried under reduced pressure to afford 0.9 g of
1-(4-phenoxybutyl)piperidine-4-carboxylic acid (Yield=95%). ESI+MS:
m/z: 278.0 ([M+H].sup.+).
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(4-henoxybutyl)piperidine-4-c-
arboxamide
##STR00268##
[1035] Title compound was prepared from coupling of
(4-chlorophenyl) (pyridin-2-yl) methanamine (0.1 g, 0.45 mmol, 1
equiv) and 1-(4-phenoxybutyl)piperidine-4-carboxylic acid (0.19 g,
0.68 mmol, 1.5 equiv) using the conditions in step 5 in the general
methodology of key Intermediate-I. Purification using silica gel
column chromatography (4% MeOH/CH.sub.2Cl.sub.2 as eluent) afforded
0.07 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(4-benoxybutyl)piperidine-4-ca-
rboxamide (Yield=31%). .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta.
8.72 (br s,1H), 8.51 (d, J=3.6 Hz, 1H), 7.78 (dt, J=9.2, 1.6 Hz,
1H), 7.44 (d, J=8.0 Hz, 1H), 7.37-7.24 (m, 7H), 6.92-6.88 (m, 3H),
6.13 (d, J=8.4 Hz, 1H), 3.96 (t, J=6.4 Hz, 2H), 3.31-3.29 (m, 1H),
2.94-2.89 (m, 2H), 2.38-2.35 (m, 2H), 1.92-1.84 (m, 2H), 1.72-1.54
(m, 8H); ESI+MS: m/z 479 ([M+H].sup.+).
Example-111
N((4-chlorophenyl)(pyridin-3-yl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide (111)
##STR00269##
[1037] Title compound was prepared from
(4-chlorophenyl)(pyridin-3-yl)methanamine (0.1 g, 0.44 mmol, 1
equiv) and 1-(2-phenoxyethyl)piperidine-4-carboxylic acid (0.17 g,
0.68 mmol, 1.5 equiv) using the conditions in step 5 in the general
methodology of key Intermediate-I to afford 0.05 g of
N-((4-chlorophenyl)(pyridin-3-yl)methyl)-1-(2-phenoxyethyl)piperidine-4-c-
arboxamide (Yield=24%). .sup.1H NMR (DMSO-d.sub.6, 400 MHz):
.delta. 8.76 (d, J=8.4 Hz, 1H), 8.50 (s, 1H), 8.46 (d, J=6.0 Hz,
1H), 7.64 (d, J=8.0 Hz, 1H), 7.42-7.25 (m, 7H), 6.93-6.89 (m, 3H),
6.17 (d, J=8.4 Hz, 1H), 4.04 (t, J=6.0 Hz, 2H), 2.96-2.94 (m, 2H),
2.66 (t, J=5.6 Hz, 2H), 2.33-2.22 (m, 1H), 2.01 (t, J=10.8 Hz, 2H),
1.69-1.54 (m, 4H); ESI+MS: m/z 450.5 ([M+H].sup.+).
Example-112
N((4-chlorophenyl)(pyridin-4-yl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide (112):
##STR00270##
[1039] Title compound was prepared from
(4-chlorophenyl)(pyridin-4-yl)methanamine (0.1 g, 0.44 mmol, 1
equiv) and 1-(2-phenoxyethyl)piperidine-4-carboxylic acid (0.17 g,
0.68 mmol, 1.5 equiv) using the conditions in step 5 in the general
methodology of key Intermediate-I to afford 0.07 g of
N-((4-chlorophenyl)(pyridin-4-yl)methyl)-1-(2-phenoxyethyl)piperidine-4-c-
arboxamide (Yield=34%). .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta.
8.56 (d, J=6.0 Hz, 2H), 7.32 (d, J=8.8 Hz, 2H), 7.29-7.27 (m, 1H),
7.12-7.10 (m, 4H), 6.95 (t, J=7.2 Hz, 1H), 6.89 (d, J=7.6 Hz, 2H),
6.17 (d, J=7.6 Hz, 1H), 6.07-6.05 (m, 1H), 4.11 (t, J=5.6 Hz, 2H),
3.12-3.09 (m, 2H), 2.85 (t, J=5.6 Hz, 2H), 2.26-2.23 (m, 3H),
1.91-1.80 (m, 4H); Ion trap: m/z 450.5 ([M+H].sup.+).
Example-113
1-(2-phenoxyethyl)-N-(phenyl(pyridin-2-yl)methyl)piperidine-4-carboxamide
(113)
##STR00271##
[1041] Title compound was prepared from
phenyl(pyridin-2-yl)methanamine (0.1 g, 0.54 mmol, 1 equiv) and
1-(2-phenoxyethyl)piperidine-4-carboxylic acid (0.20 g, 0.81 mmol,
1.5 equiv) using the conditions in step 5 in the general
methodology of key Intermediate-I to afford 0.12 g of
1-(2-phenoxyethyl)-N-(phenyl(pyridin-2-yl)methyl)piperidine-4-carboxamide
(Yield=53%). .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 8.69 (d,
J=8.4 Hz, 1H), 8.50 (d, J=4.4 Hz, 1H), 7.76 (dt, J=9.2, 1.6 Hz,
1H), 7.44 (d, J=8.0 Hz, 1H), 7.30-7.19 (m, 8H), 6.94-6.90 (m, 3H),
6.13 (d, J=8.4 Hz, 1H), 4.06 (t, J=5.6 Hz, 2H), 2.99-2.97 (m, 2H),
2.74-2.69 (m, 2H), 2.40-2.33 (m, 1H), 2.09-2.04 (m, 2H), 1.67-1.57
(m, 4H); ESI+MS: m/z 416 ([M+H].sup.+).
Example-114
1-(4-chlorophenyl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1-(pyridin-
-2-yl)methanamine (114)
##STR00272##
[1043] Title compound was prepared from
1-(2-phenoxyethyl)piperidine-4-carbaldehyde (0.1 g, 0.42 mmol, 1
equiv) and (4-chlorophenyl)(pyridin-2-yl)methanamine (0.14 g, 0.64
mmol, 1.5 equiv) using the general methodology described in
Example-59. Purification using preparative HPLC afforded 0.03 g of
1-(4-chlorophenyl)-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)-1-(pyridi-
n-2-1)methanamine (Yield=16%). .sup.1H NMR (DMSO-d.sub.6, 400 MHz):
.delta. 8.46 (d, J=4.0 Hz, 1H), 7.72 (dt, J=9.6, 1.6 Hz, 1H),
7.44-7.40 (m, 3H), 7.33 (d, J=8.4 Hz, 2H), 7.28-7.19 (m, 4H),
6.92-6.89 (m, 4H), 4.03 (t, J=5.2 Hz, 2H), 2.90-2.88 (m, 2H),
2.67-2.63 (m, 2H), 2.30-2.29 (m, 2H), 1.99-1.95 (m, 2H), 1.70-1.67
(m, 2H), 1.33-1.28 (m, 1H); 1.12-1.09 (m, 2H); ESI+MS: m/z 436.4
([M+H].sup.+). Enantiomers of 114 were separated using chiral HPLC
(method H) and afforded pure enantiomers 114a and 114b.
Example-115
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2,4-difluorophenoxy)
ethyl)piperidine-4-carboxamide (115)
##STR00273##
[1045] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
(0.1 g, 0.30 mmol, 1 equiv) and
1-(2-bromoethoxy)-2,4-difluorobenzene (0.07 g, 0.3 mmol, 1 equiv)
using the general methodology of Example-1 to afford 0.098 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2,4-difluorophenoxy)ethyl)-
piperidine-4-carboxamide (Yield=78%). .sup.1H NMR (DMSO-d.sub.6,
400 MHz): .delta. 8.72 (d, J=8.0 Hz, 1H), 8.51 (d, J=4.0 Hz, 1H),
7.78 (dt, J=9.6, 2.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.37-7.31 (m,
4H), 7.28-7.01 (m, 3H), 6.98 (t, J=6.4 Hz, 1H), 6.13 (d, J=8.4 Hz,
1H), 4.14-4.12 (m, 2H), 3.01-2.94 (m, 2H), 2.75-2.71 (m, 2H),
2.36-2.32 (m, 1H), 2.08-2.07 (m, 2H), 1.67-1.56 (m, 4H); ESI+MS:
m/z 486.0 ([M+H].sup.+). Enantiomers of 115 were separated using
chiral HPLC (method E) and afforded pure enantiomers 115a and
115b.
Example-116
N((4-chlorophenyl)(5-fluoropyridin-2-yl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide (116)
##STR00274##
[1047] Title compound was prepared from
(4-chlorophenyl)(5-fluoropyridin-2-yl)methanamine (0.2 g, 0.84
mmol, 1 equiv) and 1-(2-phenoxyethyl)piperidine-4-carboxylic acid
(0.25 g, 1.01 mmol, 1.2 equiv) using the conditions in step 5 in
the general methodology of key Intermediate-I to afford 0.08 g of
N-((4-chlorophenyl)(5-fluoropyridin-2-yl)methyl)-1-(2-phenoxyethyl)piperi-
dine-4-carboxamide (Yield=20%). .sup.1H NMR (DMSO-d.sub.6, 500
MHz): .delta. 8.72 (d, J=8.0 Hz, 1H), 8.51(s, 1H), 7.73 (dt,
J=12.0, 3.0 Hz, 1H), 7.54-7.51 (m, 1H), 7.38-7.26 (m, 6H),
6.93-6.90 (m, 3H), 6.17 (d, J=8.5 Hz, 1H), 4.05 (t, J=6.0 Hz, 2H),
2.96-2.94 (m, 2H), 2.67-2.64 (m, 2H), 2.36-2.33 (m, 1H), 2.02 (t,
J=10.5 Hz, 2H), 1.69-1.65 (m, 2H), 1.60-1.56 (m, 2H); ESI+MS: m/z
468.4 ([M+H].sup.+).
Example-117
N-((4(4-chlorophenyl)(3-fluoropyridin-4-yl)methyl)-1-(2-phenoxyethyl)piper-
idine-4-carboxamide (117)
##STR00275##
[1049] Title compound was prepared from
(4-chlorophenyl)(3-fluoropyridin-4-yl)methanamine (0.2 g, 0.84
mmol, 1 equiv) and 1-(2-phenoxyethyl)piperidine-4-carboxylic acid
(0.25 g, 1.01 mmol, 1.2 equiv) using the conditions in step 5 in
the general methodology of key Intermediate-I to afford 0.06 g of
N-((4-chlorophenyl)(3-fluoropyridin-4-yl)methyl)-1-(2-phenoxyethyl)
piperidine-4-carboxamide (Yield=15%). .sup.1H NMR (DMSO-d.sub.6,
400 MHz): .delta. 8.81 (d, J=8.0 Hz, 1H), 8.51 (s, 1H), 8.44 (d,
J=4.8 Hz, 1H), 7.43-7.38 (m, 3H), 7.28-7.25 (m, 4H), 6.93-6.89 (m,
3H), 6.30 (d, J=8.0 Hz, 1H), 4.04 (t, J=6.0 Hz, 2H), 2.96-2.93 (m,
2H), 2.67-2.65 (m, 2H), 2.27-2.24 (m, 1H), 2.01 (t, J=12.0 Hz, 2H),
1.70-1.54 (m, 4H); Ion trap: m/z 468.7 ([M+H].sup.+).
Example-118
1-(2-phenoxyethyl)-N-(pyridin-2-yl(3-(trifluoromethoxy)phenyl)methyl)
piperidine-4-carboxamide (118)
##STR00276##
[1051] Title compound was prepared from
pyridin-2-yl(3-(trifluoromethoxy)phenyl)methanamine (0.1 g, 0.55
mmol, 1 equiv) and 1-(2-phenoxyethyl)piperidine-4-carboxylic acid
(0.16 g, 0.67 mmol, 1.2 equiv) using the conditions in step 5 in
the general methodology of key Intermediate-I. Purification using
preparative HPLC afforded 0.1 g of
1-(2-phenoxyethyl)-N-(pyridin-2-yl(3-(trifluoromethoxy)phenyl)
methyl)piperidine-4-carboxamide (Yield=36%)..sup.1H NMR
(DMSO-d.sub.6, 400 MHz): .delta. 8.78 (d, J=8.4 Hz, 1H), 8.52 (d,
J=4.0 Hz, 1H), 7.79 (dt, J=9.6, 2.0 Hz, 1H), 7.49-7.41 (m, 2H),
7.36-7.34 (m, 1H) 7.30-7.20 (m, 5H), 6.93-6.89 (m, 3H), 6.20 (d,
J=8.4 Hz, 1H), 4.05 (t, J=5.6 Hz, 2H), 2.96-2.94 (m, 2H), 2.68-2.64
(m, 2H), 2.39-2.32 (m, 1H), 2.02 (t, J=11.6 Hz, 2H), 1.70-1.52 (m,
4H); ESI+MS: m/z 500.6 ([M+H].sup.+). Enantiomers of 118 were
separated using chiral HPLC (method M) and afforded pure
enantiomers 118a and 118b.
Example-119
N-((4(2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methyl)-1-(2-phen-
oxy ethyl)piperidine-4-carboxamide (119)
##STR00277##
[1053] Title compound was prepared from
(2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methanamine
(0.2 g, 0.75 mmol, 1 equiv) and
1-(2-phenoxyethyl)piperidine-4-carboxylic acid (0.22 g, 0.90 mmol,
1.2 equiv) using the conditions in step 5 in the general
methodology of key Intermediate-I to afford 0.11 g of
N-((4(2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methyl)-1-(2-phe-
noxyethyl)piperidine-4-carboxamide (Yield=29%). .sup.1H NMR
(DMSO-d.sub.6, 400 MHz): .delta. 8.70 (d, J=8.4 Hz, 1H), 8.51 (d,
J=5.6 Hz, 1H), 7.77 (dt, J=9.6, 1.6 Hz, 1H), 7.46 (d, J=8.0 Hz,
1H), 7.39-7.37 (m, 1H), 7.33-7.31 (m, 1H), 7.28-7.24 (m, 3H), 7.18
(d, J=8.4 Hz, 1H), 6.93-6.89 (m, 3H), 6.15 (d, J=8.0 Hz, 1H), 4.04
(t, J=6.0 Hz, 2H), 2.96-2.93 (m, 2H), 2.67-2.64 (m, 2H), 2.36-2.29
(m, 1H), 2.01 (t, J=11.2 Hz, 2H), 1.68-1.52 (m, 4H); ESI+MS: m/z
496.5 ([M+H].sup.+. Enantiomers of 119 were separated using chiral
HPLC (method D) and afforded pure enantiomers 119a and 119b.
Example-120:
1-(4-chlorophenyl)-1-(pyridin-2-yl)-N-((1-(2-(2-(trifluoromethyl)
phenoxy)ethyl) piperidin-4-yl)methyl)methanamine (120)
##STR00278##
[1055] Title compound was prepared from
1-(4-chlorophenyl)-N-(piperidin-4-ylmethyl)-1-(pyridin-2-yl)methanamine
dihydrochloride (0.2 g, 0.514 mmol, 1 equiv) and
1-(2-bromoethoxy)-2-(trifluoromethyl)benzene (0.138 g, 0.514 mmol,
1 equiv) using the general methodology of Example-1 to afford 0.1 g
of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(2,4-difluorophenoxy)ethyl)-
piperidine-4-carboxamide (Yield=38%). .sup.1H NMR (DMSO-d.sub.6,
500 MHz): .delta. 8.47 (d, J=4.0 Hz, 1H), 7.73 (dt, J=8.5, 1.5 Hz,
1H), 7.62-7.59 (m, 2H), 7.45-7.33 (m, 5H), 7.27-7.20 (m, 2H), 7.07
(t, J=7.5 Hz, 1H), 4.83 (d, J=5.0 Hz, 1H), 4.18 (t, J=6.0 Hz, 2H),
2.90-2.88 (m, 2H), 2.69-2.64 (m, 2H), 2.29 (t, J=6.0 Hz, 2H), 2.01
(t, J=11.0 Hz, 2H), 1.69-1.66 (m, 2H), 1.41-1.39 (m, 1H), 1.12-1.07
(m, 2H). ESI+MS: m/z 504 ([M+H].sup.+).
Example 121
1-(4-chlorophenyl)-N-((1-(2-(2-fluorophenoxy) ethyl)
piperidin-4-yl) methyl)-1-(pyridin-2-yl) methanamine (121)
##STR00279##
[1057] To a stirred solution of (4-chlorophenyl)(pyridin-2-yl)
methanamine (0.10 g, 0.43 mmol) in CH.sub.2Cl.sub.2 (5 mL) under
argon atmosphere was added 1-(2-(2-fluorophenoxy) ethyl)
piperidine-4-carbaldehyde (0.108 g, 0.43 mmol, 1 equiv) at
0.degree. C. and stirred for 5 min. Then sodium triacetoxy
borohydride (0.27 g, 1.28 mmol, 3 equiv) and acetic acid (0.024 mL,
0.43 mmol, 1 equiv) were added. The reaction mixture was warmed to
room temperature and stirred for 16 h. After completion, the pH of
the reaction mixture was adjusted to .about.7 using saturated
NaHCO.sub.3 solution (5 mL) and extracted with CH.sub.2Cl.sub.2
(2.times.20 mL). The combined organic extract was dried over sodium
sulfate, filtered and concentrated under reduced pressure. The
crude was purified by preparative HPLC to afford 0.03 g of
1-(4-chlorophenyl)-N-((1-(2-(2-fluorophenoxy) ethyl)
piperidin-4-yl) methyl)-1-(pyridin-2-yl) methanamine
(Yield=15%).
[1058] .sup.1HNMR (400 MHz, CD.sub.3OD): .delta. 8.49-8.47 (m, 1H),
7.77 (dt, 1H, J.sub.1,2=2.0 Hz, J.sub.1,4=9.6 Hz), 7.48 (d, 1H,
J=8.0 Hz,), 7.42-7.40 (m, 2H), 7.31-7.24 (m, 3H), 7.09-7.04 (m,
3H), 6.94-6.90 (m, 1H), 4.91 (s, 1H), 4.19 (t, 2H, J=5.6 Hz), 3.06
(d, 2H, J=11.2 Hz), 2.84 (t, 2H, J=5.6 Hz), 2.46-2.37 (m, 2H), 2.21
(t, 2H, J=11.6 Hz), 1.80 (d, 2H, J=11.6 Hz), 1.59-1.53 (m, 1H),
1.32-1.26 (m, 1H), 1.25-1.22 (m, 1H); ESI+MS: m/z 454
([M+H].sup.+).
Example-122
N-((1-(2-(2-fluorophenoxy) ethyl) piperidin-4-yl)
methyl)-1-(4-fluorophenyl)-1-(pyridin-2-yl) methanamine (122)
##STR00280##
[1060] Title compound was prepared from
(4-fluorophenyl)(pyridin-2-yl) methanamine (0.10 g, 0.27 mmol)
using the methodology of Example-121 and afforded 0.03 g of
N-((1-(2-(2-fluorophenoxy) ethyl) piperidin-4-yl)
methyl)-1-(4-fluorophenyl)-1-(pyridin-2-yl) methanamine
(Yield=14%). .sup.1HNMR (400 MHz, CD.sub.3OD): .delta. 8.50 (d, 1H,
J=4.0 Hz), 7.77 (dt, 1H, J.sub.1,2=2.0 Hz, J.sub.1,4=9.6 Hz),
7.47-7.43 (m, 3H), 7.29-7.26 (m, 1H), 7.13-7.02 (m, 5H), 6.96-6.91
(m, 1H), 4.98 (s, 1H), 4.25 (t, 2H, J=5.2 Hz), 3.22 (d, 2H, J=11.6
Hz) 3.03 (t, 2H, J=5.2 Hz), 2.492.41 (m, 4H), 1.89-1.86 (m, 2H),
1.67-1.63 (m, 1H), 1.39-1.26 (m, 2H); ESI+MS: m/z 438
([M+H].sup.+).
Example-123
N-((4-chlorophenyl)(2-fluorophenyl)methyl)-1-(2-(2,5-difluorophenoxy)
ethyl) piperidine-4-carboxamide (123)
##STR00281##
[1062] Title compound was prepared from
(4-chlorophenyl)(2-fluorophenyl) methanamine (0.15 g, 0.63 mmol)
and 1-(2-(2,5-difluorophenoxy)ethyl)piperidine-4-carboxylic acid
(0.18 g, 0.63 mmol) using the conditions in step 5 in the general
methodology of key Intermediate-I and afforded 0.20 g of
N((4-chlorophenyl)(2-fluorophenyl)methyl)-1-(2-(2,5-difluorophenoxy)
ethyl) piperidine-4-carboxamide (Yield=62%). .sup.1HNMR (400 MHz,
CD.sub.3OD): .delta. 7.38-7.36 (m, 3H), 7.29-7.02 (m, 7H),
6.78-6.75 (m, 1H), 6.42(s, 1H), 4.43 (t, J=4.5 Hz, 2H), 3.70-3.46
(m, 4H), 3.18-3.12 (m, 2H), 2.69-2.67 (m, 1H), 2.10-2.07(m, 4H);
ESI+MS: m/z 503 ([M+H].sup.+).
Example-125
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-2,2,2-trifluoro-N-((1-(2-phenox-
yethyl)piperidin-4-yl)methyl)ethanamine (125)
##STR00282##
[1063]
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-2,2,2-trifluoroethanamin-
e
##STR00283##
[1065] Title compound was prepared from
(4-chlorophenyl)(pyridin-2-yl)methanone (1.2 g, 5.5 mmol) using the
methodology of Example-121 and afforded 0.5 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-2,2,2-trifluoroethanamine
(Yield=31%). ESI+MS: m/z 301.2 ([M+H].sup.+).
tert-butyl
4-((((4-chlorophenyl)(pyridin-2-yl)methyl)(2,2,2-trifluoroethyl-
)amino)methyl) piperidine-1-carboxylate
##STR00284##
[1067] To a stirred solution of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-2,2,2-trifluoroethanamine
(0.3 g, 1.0 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate
(0.21 g, 1.0 mmol) in DCM (5 ml) was added TFA (0.077 ml, 1.0 mmol)
followed by NaBH(OAc).sub.3 (0.63 g, 3.0 mmol) at 0.degree. C. The
reaction mixture was brought to RT and continued for 16 h. After
completion of the reaction (monitored by TLC), the mixture was
diluted with sat.NaHCO.sub.3 and extracted with DCM. The organic
layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated
under reduced pressure. The crude compound was purified by column
chromatography (20% ethyl acetate in hexane) to afford tert-butyl
4-((((4-chlorophenyl)(pyridin-2-yl)methyl)(2,2,2-trifluoroethyl)amino)met-
hyl)piperidine-1-carboxylate as thick syrup. ESI+MS: m/z 498.6
([M+H].sup.+).
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-2,2,2-trifluoro-N-(piperidin-4-yl-
methyl)ethanamine hydrochloride
##STR00285##
[1069] Title compound was prepared from tert-butyl
4-((((4-chlorophenyl)(pyridin-2-yl)methyl)(2,2,2-trifluoroethyl)amino)met-
hyl)piperidine-1-carboxylate (0.20 g, 0.40 mmol) using the
conditions described in step 2 for the synthesis of key
intermediate-V and afforded 0.15 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-2,2,2-trifluoro-N-(pip-
eridin-4-ylmethyl)ethanamine hydrochloride (Yield=86%). ESI+MS: m/z
398.4 ([M+H].sup.+).
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-2,2,2-trifluoro-N-((1
-(2-phenoxyethyl)piperidin-4-yl)methyl)ethanamine (125)
##STR00286##
[1071] Title compound was prepared from
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-2,2,2-trifluoro-N-(piperidin-4-
-ylmethyl)ethanamine hydrochloride (0.15 g, 0.35 mmol) using the
general methodology of Example-1. The crude compound was purified
by silica gel column chromatography to afford 0.10 g of
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-2,2,2-trifluoro-N-((1-(2-pheno-
xyethyl)piperidin-4-yl)methyl)ethanamine (Yield=56%). .sup.1H NMR
(400 MHz, CD.sub.3OD): .delta. 8.56-8.54 (m, 1H), 7.85-7.80 (m,
1H), 7.51-7.49 (m, 1H), 7.34-7.23 (m, 7H), 6.93-6.89 (m, 3H), 5.27
(s, 1H), 4.11 (t, J=5.6 Hz, 2H), 3.48-3.33 (m, 2H), 3.04-2.99 (m,
2H), 2.79 (t, J=5.6 Hz, 2H), 2.66-2.53 (m, 2H), 2.18-2.11 (m, 2H),
1.95-1.91 (m, 1H), 1.72-1.67 (m, 1H), 1.62-1.60 (m, 1H), 1.19-1.09
(m, 2H); ESI+MS: m/z: 518.6 ([M+H].sup.+).
[1072] Enantiomers of 125 were separated using chiral HPLC (method
R) and afforded pure enantiomers 125a and 125b.
Example-126
2-(4-chlorophenyl)-N-(1-(2-phenoxyethyl)piperidin-4-yl)-2-(pyridin-2-yl)ac-
etamide (126)
##STR00287##
[1073] tert-butyl
4-(2-(4-chlorophenyl)-2-(pyridin-2-yl)acetamido)piperidine-1-carboxylate
##STR00288##
[1075] To a solution of
2-(4-chlorophenyl)-2-(pyridin-2-yl)acetonitrile (0.5 g, 2.19 mmol)
in H.sub.2O (5 mL) was added NaOH (87 mg, 2.19 mmol) at RT. The
reaction mixture was stirred at 100.degree. C. for 12 h. After
completion of the reaction, aq. layer was lyophilized and afforded
the crude of sodium salt (750 mg) as a white solid with 93% LCMS
purity. This material was used in the next step without further
purification. To a stirred solution of the crude sodium salt (0.40
g) in DMF (10 mL) were added HATU (0.85 g, 2.23 mmol), DIPEA (0.38
g, 2.97 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (0.30
g, 1.48 mmol) at 0.degree. C. The reaction mixture was stirred at
RT for 12 h. After completion, the reaction mass was diluted with
ice-cold water. The obtained solid was filtered and dried under
vaccum. The crude solid was purified by triturating with
EtOAc/Pentane to afford pure compound as off white solid (0.23 g,
35% yield).
2-(4-chlorophenyl)-N-(piperidin-4-yl)-2-(pyridin-2-yl)acetamide
hydrochloride
##STR00289##
[1077] Title compound was prepared from tert-butyl
4-(2-(4-chlorophenyl)-2-(pyridin-2-yl)acetamido)piperidine-1-carboxylate
(0.20 g, 0.40 mmol) using the conditions described in step 2 for
the synthesis of key intermediate-V and afforded 0.15 g of
2-(4-chlorophenyl)-N-(piperidin-4-yl)-2-(pyridin-2-yl)acetamide
hydrochloride (Yield=86%). ESI+MS: m/z 398.4 ([M+H].sup.+).
2-(4-chlorophenyl)-N-(1-(2-phenoxyethyl)piperidin-4-yl)-2-(pyridin-2-yl)ac-
etamide (126)
##STR00290##
[1079] Title compound was prepared from
2-(4-chlorophenyl)-N-(piperidin-4-yl)-2-(pyridin-2-yl)acetamide
hydrochloride (0.19 g, 0.58 mmol) using the general methodology of
Example-1. The crude compound was purified by silica gel column
chromatography to afford 0.08 g of
2-(4-chlorophenyl)-N-(1-(2-phenoxyethyl)piperidin-4-yl)-2-(pyridin-2-yl)a-
cetamide (Yield=29%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
8.47 (d, J=7.2 Hz, 1H), 8.33 (d, J=7.6 Hz, 1H), 7.71 (dt, J=9.6,
2.0 Hz, 1H), 7.38-7.36 (m, 5H), 7.28-7.23 (m, 3H), 6.92 (d, J=7.6
Hz, 3H), 5.09 (s, 1H), 4.05-4.02 (m, 2H), 3.61-3.52 (m, 1H),
2.89-2.79 (m, 2H), 2.69-2.62 (m, 2H), 2.13-2.08 (m, 2H), 1.73-1.67
(m, 2H), 1.44-1.33 (m, 2H); ESI+MS: m/z: 450.5 ([M+H].sup.+).
Example-127:
2-((4-chlorophenyl)((1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-y-
l)methoxy)methyl)pyridine (127):
##STR00291##
[1081] The title compound was prepared from
2-((4-chlorophenyl)(piperidin-4-ylmethoxy)methyl)pyridine
hydrochloride (0.42 g, 1.19 mmol) using the general methodology of
Example-1. The crude compound was purified by silica gel column
chromatography to afford 0.15 g of
2-((4-chlorophenyl)((1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidi-
n-4-yl)methoxy)methyl)pyridine (Yield=25%). .sup.1H NMR (500 MHz,
CD.sub.3OD): .delta. 8.45 (d, 1H, J=4.5 Hz), 7.79 (t, 1H, J=7.0
Hz), 7.58 (d, 2H, J=8.0 Hz), 7.50 (d, 1H, J=8.0 Hz), 7.38-7.35 (m,
4H), 7.26-7.23 (m, 2H), 7.07 (t, 1H, J=7.0 Hz), 5.42 (s, 1H), 4.19
(bs, 2H), 3.30-3.26 (m, 2H), 2.91 (bs, 2H), 2.69 (bs, 2H), 2.04
(bs, 2H), 1.70-1.50 (m, 3H), 1.25-1.15 (m, 2H); ESI+MS: m/z: 505.5
([M+H].sup.+).
Example-129
N-((4(3-methoxyphenyl)(oxazol-4-yl)methyl)-1-(2-phenoxyethyl)piperidine-4--
carboxamide (129):
##STR00292##
[1083] Title compound was prepared from coupling of
(3-methoxyphenyl)(oxazol-4-yl)methanamine (0.2 g, 0.98 mmol, 1
equiv) and 1-(2-phenoxyethyl) piperidine-4-carboxylic acid
(Int-III) (0.366 g, 1.47 mmol, 1.5 equiv) using the amide bond
coupling step conditions used in general methodology for key
Intermediate-I and afforded 0.018 g of
N-((3-methoxyphenyl)(oxazol-4-yl)methyl)-1-(2-phenoxyethyl)piperidine-4-c-
arboxamide (Yield=4%). .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.
8.16 (s, 1H), 7.61 (t, J=1.0 Hz, 1H), 7.27-7.23 (m, 3H), 6.94-6.89
(m, 5H), 6.88-6.83 (m, 1H), 6.09 (s, 1H), 4.12 (t, J=5.6 Hz, 2H),
3.77 (s, 3H), 3.12-3.06 (m, 2H), 2.81 (t, J=5.6 Hz, 2H), 2.39-2.30
(m, 1H), 2.26-2.18 (m, 2H), 1.87-1.77 (m, 4H); ESI+MS: m/z: 436.2
([M+H].sup.+).
Example-130
N-((4(2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methyl)-1-(2-(2,4-
-difluorophenoxy)ethyl)piperidine-4-carboxamide (130)
##STR00293##
[1085] Title compound was prepared from
N-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methyl)piperidine--
4-carboxamide hydrochloride (0.2 g, 0.49 mmol) using the general
methodology of Example-1. The crude compound was purified by silica
gel column chromatography to afford 0.20 g of
N-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(pyridin-2-yl)methyl)-1-(2-(2,4--
difluorophenoxy)ethyl)piperidine-4-carboxamide (Yield=77%). .sup.1H
NMR (400 MHz, DMSO-d6): .delta. 8.70 (d, 1H, J=8.0 Hz), 8.52-8.50
(m, 1H), 7.78 (dt, 1H, J=9.6 Hz, 1.6 Hz), 7.46 (d, 1H, J=8.0 Hz),
7.39-7.38 (m, 1H), 7.28 (d, 1H, J=8.4 Hz), 7.30-7.17 (m, 4H),
7.01-6.97 (m, 1H), 6.15 (d, 1H, J=8.0 Hz), 4.11 (t, 2H, J=5.6 Hz),
2.93 (d, 2H, J=10.8 Hz), 2.68-2.65 (m, 2H), 2.35-2.30 (m, 1H), 2.02
(t, 2H, J=10.8 Hz), 1.68-1.52 (m, 4H); ESI+MS: m/z: 532.4
([M+H].sup.+). Enantiomers of 130 were separated using chiral HPLC
(method F) and afforded pure enantiomers 130a and 130b.
Example-131
1-(4-chlorophenyl)-N-methyl-N-((4(4-methyl-1-(2-phenoxyethyl)piperidin-4-y-
l)methyl)-1-(pyridin-2-yl)methanamine (131)
##STR00294##
[1087] Title compound was prepared from
1-(4-chlorophenyl)-N-methyl-N-((4-methylpiperidin-4-yl)methyl)-1-(pyridin-
-2-yl)methanamine hydrochloride (0.09 g, 0.24 mmol) using the
general methodology of Example-1. The crude compound was purified
by silica gel column chromatography to afford 0.012 g of
1-(4-chlorophenyl)-N-methyl-N-((4-methyl-1-(2-phenoxyethyl)piperidin-4-yl-
)methyl)-1-(pyridin-2-yl)methanamine (Yield=11%). .sup.1H NMR (400
MHz, DMSO-d6): .delta. 8.74 (d, J=4.4 Hz, 1H), 7.95-7.91 (m, 1H),
7.60 (d, J=8.4 Hz, 2H), 7.52-7.46 (m, 4H), 7.30 (t, J=8.4 Hz, 2H),
7.01-6.97 (m, 3H), 5.70 (s, 1H), 4.35 (bs, 2H), 3.58 (bs, 4H),
3.31-3.24 (m, 3H), 3.03-2.99 (m, 1H), 2.79 (s, 3H), 2.00-1.69 (m,
4H), 1.28 (s, 3H); ESI+MS: m/z: 464.5 ([M+H].sup.+).
Example-132
1-(4-chlorophenyl)-N-((1-(2-(4-fluorophenoxy)ethyl)piperidin-4-yl)methyl)--
1-(pyridin-2-yl)methanamine (132)
##STR00295##
[1089] Title compound was prepared from
1-(4-chlorophenyl)-N-(piperidin-4-ylmethyl)-1-(pyridin-2-yl)methanamine
hydrochloride (0.2 g, 0.57 mmol) using the general methodology of
Example-1. The crude compound was purified by silica gel column
chromatography to afford 0.12 g of
1-(4-chlorophenyl)-N-((1-(2-(4-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-
-1-(pyridin-2-yl)methanamine (Yield=47%). .sup.1H NMR (400 MHz,
DMSO-d6): .delta. 8.47-8.46 (m, 1H), 7.74-7.70 (m, 1H), 7.44-7.40
(m, 3H), 7.34-7.32 (m, 2H), 7.22-7.19 (m, 1H), 7.11-7.06 (m, 2H),
6.94-6.91 (m, 2H), 4.82 (s, 1H), 4.01 (t, J=6.0 Hz, 2H), 2.87 (d,
J=11.2 Hz, 2H), 2.64-2.61 (m, 2H), 2.33-2.28 (m, 2H), 1.96 (t,
J=9.6 Hz, 2H), 1.68 (d, J=11.2 Hz, 2H), 1.43-1.37 (m, 1H),
1.13-1.05 (m, 2H); ESI+MS: m/z: 454.5 ([M+H].sup.+).
Example-133
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-(2-fluorophenoxy)ethyl-
)piperidin-4-yl)methyl)propan-2-amine (133)
##STR00296##
[1091] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-(piperidin-4-ylmethyl)propan-2-
-amine hydrochloride (0.15 g, 0.38 mmol) using the general
methodology of Example-1. The crude compound was purified by silica
gel column chromatography to afford 0.07 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-(2-fluorophenoxy)ethyl)-
piperidin-4-yl)methyl)propan-2-amine (Yield=37%). .sup.1H NMR (400
MHz, DMSO-d6): .delta. 8.47 (d, J=4.0 Hz, 1H), 7.77-7.71 (m, 1H),
7.48 (d, J=7.6 Hz, 1H), 7.39-7.32 (m, 4H), 7.25-7.07 (m, 4H),
6.93-6.88 (m, 1H), 5.00 (s, 1H), 4.08 (t, J=6.0 Hz, 2H), 3.05-2.99
(m, 1H), 2.84-2.83 (m, 2H), 2.62-2.59 (m, 2H), 2.35-2.32 (m,
2H),1.81-1.79 (m, 2H), 1.60-1.52 (m, 2H), 0.92-0.84 (m, 6H), 0.73
(d, J=6.4 Hz, 3H); ESI+MS: m/z: 496.2 ([M+H].sup.+). Enantiomers of
133 were separated using chiral HPLC (method C) and afforded pure
enantiomers 133a and 133b.
Example-134
N-((4(1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-N-((3-methoxyphen-
yl)(pyridin-2-yl)methyl)propan-2-amine (134)
##STR00297##
[1093] Title compound was prepared from
N-((3-methoxyphenyl)(pyridin-2-yl)methyl)-N-(piperidin-4-ylmethyl)propan--
2-amine hydrochloride (0.2 g, 0.51 mmol) using the general
methodology of Example-1. The crude compound was purified by silica
gel column chromatography to afford 0.07 g of
N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-yl)methyl)-N-((3-methoxypheny-
l)(pyridin-2-yl)methyl)propan-2-amine (Yield=28%). .sup.1H NMR (400
MHz, DMSO-d6): .delta. 8.46 (d, J=3.6 Hz, 1H), 7.75-7.71 (m, 1H),
7.48 (d, J=8.0 Hz, 1H), 7.24-7.09 (m, 5H), 6.96-6.88 (m, 3H),
6.78-6.76 (m, 1H), 4.94 (s, 1H), 4.08 (t, J=5.6 Hz, 2H), 3.70 (s,
3H), 3.08-3.01 (m, 1H), 2.84-2.82 (m, 2H), 2.61-2.59 (m, 2H),
2.50-2.49 (m, 2H), 2.36-2.25 (m, 2H), 1.77-1.74 (m, 2H), 1.58-1.55
(m, 2H), 0.91-0.85 (m, 4H), 0.73 (d, J=6.4 Hz, 3H); ESI+MS: m/z:
492.3 ([M+H].sup.+).
Example-135
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-(4-fluorophenoxy)ethyl-
)piperidin-4-yl)methyl)propan-2-amine (135)
##STR00298##
[1095] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-(piperidin-4-ylmethyl)propan-2-
-amine hydrochloride (0.15 g, 0.38 mmol) using the general
methodology of Example-1. The crude compound was purified by silica
gel column chromatography to afford 0.025 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-N-((1-(2-(4-fluorophenoxy)ethyl)-
piperidin-4-yl)methyl)propan-2-amine (Yield=14%). .sup.1H NMR (400
MHz, CD.sub.3OD): .delta. 8.43-8.41 (m, 1H), 7.82-7.78 (m, 1H),
7.66 (d, J=8.0 Hz, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.30-7.27 (m, 3H),
7.01-6.88 (m, 4H), 5.03 (s, 1H), 4.05 (t, J=5.6 Hz, 2H), 3.13-3.05
(m, 1H), 2.98-2.95 (m, 2H), 2.73 (t, J=11.2 Hz, 2H), 2.45-2.37 (m,
2H), 1.92 (t, J=12.0 Hz, 2H), 1.74-1.65 (m, 2H), 1.16-1.1.04 (m,
2H), 0.98 (d, J=6.8 Hz, 3H), 0.87-0.86 (m, 1H), 0.85 (d, J=6.8 Hz,
3H); ESI+MS: m/z: 496.6 ([M+H].sup.+).
Example-136
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-2,2,2-trifluoro-N-((1-(2-(2-flu-
orophenoxy)ethyl)piperidin-4-yl)methyl)ethan-1-amine (136)
##STR00299##
[1097] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-2,2,2-trifluoro-N-(piperidin-4-y-
lmethyl)ethan-1-amine hydrochloride (0.2 g, 0.46 mmol) using the
general methodology of Example-1. The crude compound was purified
by silica gel column chromatography to afford 0.10 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-2,2,2-trifluoro-N-((1-(2-(2-fluo-
rophenoxy)ethyl)piperidin-4-yl)methyl)ethan-1-amine (Yield=41%).
.sup.1H NMR (400 MHz, DMSO-d6): .delta. 8.61-8.60 (m, 1H),
7.83-7.79 (m, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.39-7.35 (m, 2H),
7.34-7.31 (m, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.20-7.14 (m, 2H),
7.12-7.08 (m, 1H), 6.94-6.89 (m, 1H), 5.25 (s, 1H), 4.12 (t, J=6.0
Hz, 2H), 3.53-3.46 (m, 1H), 3.40-3.31 (m, 1H), 2.90-2.85 (m, 2H),
2.66 (t, J=5.6 Hz, 2H), 2.53-2.50 (m, 1H), 2.49-2.44 (m, 1H), 1.99
(t, J=11.6 Hz, 2H), 1.82-1.77 (m, 1H), 1.57-1.53 (m, 2H), 0.97-0.91
(m, 2H); ESI+MS: m/z: 536.6 ([M+H].sup.+). Enantiomers of 136 were
separated using chiral HPLC (method R) and afforded pure
enantiomers 136a and 136b.
Example-137
1-(4-chlorophenyl)-N-methyl-1-(pyridin-2-yl)-N-((1-(2-(4-(trifluoromethyl)-
phenoxy)ethyl)piperidin-4-yl)methyl)methanamine (137)
##STR00300##
[1099] Title compound was prepared from
1-(4-chlorophenyl)-N-methyl-N-(piperidin-4-ylmethyl)-1-(pyridin-2-yl)meth-
anamine hydrochloride (0.10 g, 0.27 mmol) using the general
methodology of Example-1. The crude compound was purified by silica
gel column chromatography to afford 0.05 g of
1-(4-chlorophenyl)-N-methyl-1-(pyridin-2-yl)-N-((1-(2-(4-(trifluoromethyl-
)phenoxy)ethyl)piperidin-4-yl)methyl)methanamine (Yield=35%).
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.41-8.39 (m, 1H),
7.81-7.77 (m, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H),
7.45-7.43 (m, 2H), 7.30-7.23 (m, 3H), 7.07 (d, J=8.8 Hz, 2H), 4.45
(s, 1H), 4.19 (t, J=5.6 Hz, 2H), 3.04-3.01 (m, 2H), 2.84 (t, J=5.2
Hz, 2H), 2.26-2.19 (m, 3H), 2.15 (s, 3H), 2.12-2.09 (m, 1H),
1.92-1.84 (m, 2H), 1.70-1.64 (m, 1H),1.20-1.09 (m, 2H); ESI+MS:
m/z: 518.6 ([M+H].sup.+).
Example-138
1-(benzo[d][1,3]dioxol-5-yl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-y-
l)methyl)-N-methyl-1-(pyridin-2-yl)methanamine (138)
##STR00301##
[1101] Title compound was prepared from
1-(benzo[d][1,3]dioxol-5-yl)-N-methyl-N-(piperidin-4-ylmethyl)-1-(pyridin-
-2-yl)methanamine hydrochloride (0.20 g, 0.53 mmol) using the
general methodology of Example-1. The crude compound was purified
by silica gel column chromatography to afford 0.08 g of
1-(benzo[d][1,3]dioxol-5-yl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4--
yl)methyl)-N-methyl-1-(pyridin-2-yl)methanamine (Yield=32%).
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.38-8.37 (m, 1H),
7.80-7.76 (m , 1H), 7.71-7.69 (m, 1H), 7.25-7.21 (m, 1H), 7.11-7.03
(m, 3H), 6.97 (s , 1H), 6.94-6.85 (m, 2H), 6.70 (d, J=8.0 Hz, 1H),
5.87 (dd, J=1.2 Hz, J=7.2 Hz, 2H), 4.32 (s, 1H), 4.18 (t, J=5.6 Hz,
2H), 3.02 (d, J=11.6 Hz, 2H), 2.82 (t, J=5.6 Hz, 2H), 2.28-2.16 (m,
3H), 2.14 (s, 3H) 2.10-2.05 (m, 1H), 1.91-1.82 (m, 2H), 1.68-1.61
(m, 1H), 1.19-1.08 (m, 2H); ESI+MS: m/z: 478.6 ([M+H].sup.+).
Enantiomers of 138 were separated using chiral HPLC (method F) and
afforded pure enantiomers 138a and 138b.
Example-139
1-(benzo[d][1,3]dioxol-5-yl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4-y-
l)methyl)-1-(pyridin-2-yl)methanamine (139)
##STR00302##
[1103] Title compound was prepared from
1-(benzo[d][1,3]dioxol-5-yl)-N-(piperidin-4-ylmethyl)-1-(pyridin-2-yl)met-
hanamine hydrochloride (0.125 g, 0.35 mmol) using the general
methodology of Example-1. The crude compound was purified by silica
gel column chromatography to afford 0.07 g of
1-(benzo[d][1,3]dioxol-5-yl)-N-((1-(2-(2-fluorophenoxy)ethyl)piperidin-4--
yl)methyl)-1-(pyridin-2-yl)methanamine (Yield=44%). .sup.1H NMR
(400 MHz, CD.sub.3OD): .delta. 8.49-8.48 (m, 1H), 7.77-7.73 (m,
1H), 7.44 (d, J=8 Hz, 1H), 7.27-7.24 (m, 1H), 7.10-7.05 (m, 3H),
6.94-6.88 (m, 3H), 6.74 (d, J=7.6 Hz, 1H), 5.89 (dd, J=1.2 Hz,
J=5.2 Hz, 2H), 4.90 (s, 1H), 4.20 (t, J=5.6 Hz, 2H), 3.09 (d,
J=11.6 Hz, 2H), 2.87 (t, J=5.6 Hz, 2H), 2.49-2.39 (m, 2H),
2.27-2.22 (m, 2H), 1.85-1.77 (m, 2H), 1.61-1.55 (m, 1H), 1.40-1.20
(m, 2H); ESI+MS: m/z: 464.5 ([M+H].sup.+). Enantiomers of 139 were
separated using chiral HPLC (method D) and afforded pure
enantiomers 139a and 139b.
Example-140
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-((2,3-dihydrobenzo[b][1,4]dioxi-
n-2-yl)methyl)piperidine-4-carboxamide (140)
##STR00303##
[1105] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
hydrochloride (0.2 g, 0.55 mmol) using the general methodology of
Example-1. The crude compound was purified by silica gel column
chromatography to afford 0.08 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-((2,3-dihydrobenzo[b][1,4]diox-
in-2-yl)methyl)piperidine-4-carboxamide (Yield=31%). .sup.1H NMR
(400 MHz, CD.sub.3OD): .delta. 8.53-8.51 (m, 1H), 7.81-7.77 (m,
1H), 7.39 (d, J=8.0 Hz, 1H), 7.32-7.25 (m, 5H), 6.84-6.77 (m, 4H),
6.16 (s, 1H), 4.33-4.25 (m, 2H), 3.95-3.90 (m, 1H), 3.12-3.09 (m,
1H), 3.02-2.98 (m, 1H), 2.68-2.57 (m, 2H), 2.43-2.35 (m, 1H),
2.27-2.15 (m, 2H), 1.85-1.78 (m, 4H); ESI+MS: m/z: 478.5
([M+H].sup.+).
Example-141
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(pyridin-2-yloxy)ethyl)pip-
eridine-4-carboxamide (141)
##STR00304##
[1106]
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-hydroxyethyl)piperidi-
ne-4-carboxamide
##STR00305##
[1108] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
hydrochloride (0.15 g, 0.41 mmol) using the general methodology of
Example-1. The crude compound was purified by silica gel column
chromatography to afford 0.13 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-hydroxyethyl)piperidine-4-c-
arboxamide (Yield=85%). ESI+MS: m/z: 374.4 ([M+H].sup.+).
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(pyridin-2-yloxy)ethyl)pip-
eridine-4-carboxamide
##STR00306##
[1110] To a solution of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-hydroxyethyl)piperidine-4-c-
arboxamide (0.13 g, 0.35 mmol) in DMF (2 mL) at 0.degree. C. under
nitrogen was added NaH (0.033 g, 1.39 mmol) and the reaction
mixture was stirred for 10 minutes. 2-bromopyridine (0.22 g, 1.39
mmol) was then added dropwise and the reaction mixture was stirred
at 100.degree. C. for 16 hours. The reaction mixture was then
diluted in water and extracted with DCM, dried over Na2SO4,
filtered and concentrated. Purification by flash chromatography on
silica gel afforded
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(pyridin-2-yloxy)ethyl)pipe-
ridine-4-carboxamide (0.01 g, Yield 7%) as a thick sirup. .sup.1H
NMR (400 MHz, CD.sub.3OD): .delta. 8.53-8.51 (m, 1H), 8.11-8.09 (m,
1H), 7.81-7.77 (m, 1H), 7.68-7.64 (m, 1H), 7.38 (d, J=8.0 Hz, 1H),
7.33-7.24 (m, 5H), 6.95-6.91 (m, 1H), 6.80-6.78 (m, 1H), 6.16 (s,
1H), 4.42 (t, J=5.6 Hz, 2H), 3.12-3.07 (m, 2H), 2.82 (t, J=6.0 Hz,
2H), 2.45-2.37 (m, 1H), 2.27-2.20 (m, 2H), 1.84-1.78 (m, 4H);
ESI+MS: m/z: 451.5 ([M+H].sup.+).
Example-142
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(pyridin-4-yloxy)ethyl)pip-
eridine-4-carboxamide (142)
##STR00307##
[1112] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
hydrochloride (0.3 g, 0.82 mmol) using the general methodology of
Example-1. The crude compound was purified by silica gel column
chromatography to afford 0.03 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-1-(2-(pyridin-4-yloxy)ethyl)pipe-
ridine-4-carboxamide (Yield=8%). .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 8.55-8.50 (m, 1H), 8.36-8.34 (m, 1H), 7.83-7.78 (m, 1H),
7.40 (d, J=8.0 Hz, 1H), 7.36-7.25 (m, 5H), 7.03-7.00 (m, 2H), 6.17
(s, 1H), 4.25 (t, J=5.6 Hz, 2H), 3.12-3.06 (m, 2H), 2.86 (t, J=5.2
Hz, 2H), 2.46-2.38 (m, 1H), 2.30-2.20 (m, 2H), 1.85-1.75 (m, 4H);
ESI+MS: m/z: 451.5 ([M+H].sup.+).
Example-143
N-((4(3-methoxyphenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-phenoxyethyl)pip-
eridine-4-carboxamide (143)
##STR00308##
[1114] Title compound was prepared from
N-((3-methoxyphenyl)(pyridin-2-yl)methyl)-4-methylpiperidine-4-carboxamid-
e hydrochloride (0.15 g, 0.40 mmol) using the general methodology
of Example-1. The crude compound was purified by silica gel column
chromatography to afford 0.06 g of
N-((3-methoxyphenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-phenoxyethyl)pipe-
ridine-4-carboxamide (Yield=33%). .sup.1H NMR (400 MHz, DMSO-d6):
.delta. 8.48-8.47 (m, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.75-7.70 (m,
1H), 7.30-7.20 (m, 5H), 7.16-7.14 (m, 1H), 6.98 (d, J=7.6 Hz, 1H),
6.92-6.85 (m, 4H), 6.44 (d, J=7.6 Hz, 1H), 4.02 (t, J=5.6 Hz, 2H),
3.77 (s, 3H), 2.65-2.50 (m, 4H), 2.30-2.20 (m, 2H), 2.08-2.02 (m,
2H), 1.44-1.35 (m, 2H), 1.11 (s, 3H); ESI+MS: m/z: 460.5
([M+H].sup.+).
Example-144
N-((4(4-chlorophenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-phenoxyethyl)pipe-
ridine-4-carboxamide (144)
##STR00309##
[1116] Title compound was prepared from
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-4-methylpiperidine-4-carboxamide
hydrochloride (0.2 g, 0.53 mmol) using the general methodology of
Example-1. The crude compound was purified by silica gel column
chromatography to afford 0.1 g of
N-((4-chlorophenyl)(pyridin-2-yl)methyl)-4-methyl-1-(2-phenoxyethyl)piper-
idine-4-carboxamide (Yield=41%). .sup.1H NMR (400 MHz, DMSO-d6):
.delta. 8.53-8.51 (m, 1H), 8.29 (d, J=8.0 Hz, 1H), 7.81-7.76 (m,
1H), 7.45 (d, J=8.0 Hz, 1H), 7.37-7.23 (m, 7H), 6.93-6.88 (m, 3H),
6.19 (d, J=8.0 Hz, 1H), 4.02 (t, J=5.6 Hz, 2H), 2.65-2.55 (m, 4H),
2.26-2.20 (m, 2H), 2.09-2.04 (m, 2H), 1.45-1.40 (m, 2H), 1.12 (s,
3H); ESI+MS: m/z: 464.7 ([M+H].sup.+). Enantiomers of 144 were
separated using chiral HPLC (method E) and afforded pure
enantiomers 144a and 144b.
Example-145
1-(2-(2,4-difluorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-yl)methyl)-
piperidine-4-carboxamide (145)
##STR00310##
[1118] Title compound was prepared from
N-((3-methoxyphenyl)(pyridin-2-yl)methyl)piperidine-4-carboxamide
hydrochloride (0.2 g, 0.55 mmol) using the general methodology of
Example-1. The crude compound was purified by silica gel column
chromatography to afford 0.12 g of
1-(2-(2,4-difluorophenoxy)ethyl)-N-((3-methoxyphenyl)(pyridin-2-yl)methyl-
)piperidine-4-carboxamide (Yield=45%). .sup.1H NMR (400 MHz,
DMSO-d6): .delta. 8.66 (d, J=8.0 Hz, 1H), 8.50 (d, J=4.0 Hz, 1H),
7.78-7.74 (m, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.28-7.15 (m, 4H),
7.01-6.97 (m, 1H), 6.89-6.85 (m, 2H), 6.80-6.75 (m, 1H), 6.09 (d,
J=8.4 Hz, 1H), 4.15-4.05 (m, 2H), 3.71 (s, 3H), 2.98-2.90 (m, 2H),
2.68-2.66 (m, 2H), 2.34-2.32 (m, 1H), 2.08-1.98 (m, 2H), 1.70-1.50
(m, 4H); ESI+MS: m/z: 482.5 ([M+H].sup.+). Enantiomers of 145 were
separated using chiral HPLC (method G) and afforded pure
enantiomers 145a and 145b.
Example-146
N-((4(3-methoxyphenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-carbo-
xamide (146)
##STR00311##
[1120] Title compound was prepared from coupling of
(3-methoxyphenyl)(phenyl)methanamine (0.15 g, 0.70 mmol, 1 equiv)
and 1-(2-phenoxyethyl) piperidine-4-carboxylic acid (Int-III) (0.21
g, 0.84 mmol, 1.2 equiv) using the amide bond coupling step
conditions used in general methodology for key Intermediate-I and
afforded 0.035 g of
N-((3-methoxyphenyl)(phenyl)methyl)-1-(2-phenoxyethyl)piperidine-4-carbox-
amide (Yield=11%). .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.
7.33-7.30 (m, 2H), 7.28-7.21 (m, 6H), 6.93-6.90 (m, 3H), 6.83-6.80
(m, 3H), 6.13 (s, 1H), 4.14 (t, J=5.6 Hz, 2H), 3.75 (s, 3H), 3.15
(d, J=12.0 Hz, 2H), 2.88 (t, J=5.2 Hz, 2H), 2.45-2.37 (m, 1H),
2.34-2.28 (m, 2H), 1.92-1.82 (m, 4H); ESI+MS: m/z: 445.3
([M+H].sup.+).
[1121] One of skill in the art would understand the present
invention to encompass subgenera that may be derived from the
foregoing genera, subgenera and list of exemplary compounds, as
herein disclosed or herein listed. Further, from the foregoing and
the disclosure herein, the skilled person can readily select
suitable moieties for any of the variable substituents identified
in the formulae herein described.
Example 147
Chiral Separation using HPLC
[1122] Mixtures of stereoisomers (e.g., enantiomers or
diastereomers) described herein were separated with any one of
Method A to Method R of chiral HPLC. The earlier-eluted
stereoisomer was designated with "a", and the later-eluted
stereoisomer was designated with "b". For example, enantiomers of 1
were separated using chiral HPLC, Method D, and afforded the pure
enantiomers 1a and 1b, wherein 1a was the earlier-eluted
stereoisomer, and 1b was the later-eluted stereoisomer.
Method A:
[1123] Column: Chiralpak ADH (250.times.4.6 mm, 5 .mu.m) [1124]
Eluent A: n-Hexanes [1125] Eluent B: Ethanol [1126] Elution using
A:B 75:25 at 1 ml/min
Method B:
[1126] [1127] Column: Chiralpak ADH (250.times.4.6 mm, 5 .mu.m)
[1128] Eluent A: 0.1% DEA in n-Hexanes [1129] Eluent B: Ethanol
[1130] Elution using A:B 80:20 at 1 ml/min
Method C:
[1130] [1131] Column: Chiralpak IA (250.times.4.6 mm, 5 .mu.m)
[1132] Eluent A: 0.1% DEA in n-Hexanes [1133] Eluent B:
DCM/Methanol 80:20 [1134] Elution using A:B 98:2 at 1 ml/min
Method D:
[1134] [1135] Column: Chiralpak ADH (250.times.4.6 mm, 5 .mu.m)
[1136] Eluent A: 0.1% DEA in n-Hexanes [1137] Eluent B:
Ethanol/Methanol 50:50 [1138] Elution using A:B 75:25 at 1
ml/min
Method E:
[1138] [1139] Column: Chiralpak IC (250.times.4.6 mm, 5 .mu.m)
[1140] Eluent A: 0.1% DEA in n-Hexanes [1141] Eluent B:
DCM/Methanol 50:50 [1142] Elution using A:B 90:10 at 1 ml/min
Method F:
[1142] [1143] Column: Chiralpak IC (250.times.4.6 mm, 5 .mu.m)
[1144] Eluent A: 0.1% DEA in n-Hexanes [1145] Eluent B: Ethanol
[1146] Elution using A:B 95:5 at 1 ml/min
Method G:
[1146] [1147] Column: Chiralpak IA (250.times.4.6 mm, 5 .mu.m)
[1148] Eluent A: 0.1% DEA in n-Hexanes [1149] Eluent B:
DCM/Methanol 50:50 [1150] Elution using A:B 90:10 at 1 ml/min
Method H:
[1150] [1151] Column: Chiralpak IB (250.times.4.6 mm, 5 .mu.m)
[1152] Eluent A: 0.1% DEA in n-Hexanes [1153] Eluent B:
DCM/Methanol 50:50 [1154] Elution using A:B 90:10 at 1 ml/min
Method I:
[1154] [1155] Column: Chiralpak IA (250.times.4.6 mm, 5 .mu.m)
[1156] Eluent A: n-Hexanes [1157] Eluent B: DCM/Methanol 50:50
[1158] Elution using A:B 80:20 at 1 ml/min
Method J:
[1158] [1159] Column: Chiralpak IA (250.times.4.6 mm, 5 .mu.m)
[1160] Eluent A: n-Hexanes [1161] Eluent B: Ethanol [1162] Elution
using A:B 70:30 at 1 ml/min
Method K:
[1162] [1163] Column: Chiralpak ADH (250.times.4.6 mm, 5 .mu.m)
[1164] Eluent A: 0.1% DEA in n-Hexanes [1165] Eluent B: Ethanol
[1166] Elution using A:B 85:15 at 1 ml/min
Method L:
[1166] [1167] Column: Chiralpak IA (250.times.4.6 mm, 5 .mu.m)
[1168] Eluent A: 0.1% DEA in n-Hexanes [1169] Eluent B: Isopropanol
[1170] Elution using A:B 90:10 at 1 ml/min
Method M:
[1170] [1171] Column: Chiralpak IA (250.times.4.6 mm, 5 .mu.m)
[1172] Eluent A: 0.1% DEA in n-Hexanes [1173] Eluent B: Ethanol
[1174] Elution using A:B 85:15 at 1 ml/min
Method N:
[1174] [1175] Column: Chiralcel ODH (250.times.4.6 mm, 5 .mu.m)
[1176] Eluent A: 0.1% TFA in n-Hexanes [1177] Eluent B:
Ethanol/Methanol 50:50 [1178] Elution using A:B 90:10 at 1
ml/min
Method P:
[1178] [1179] Column: Chiralpak ADH (250.times.4.6 mm, 5 .mu.m)
[1180] Eluent A: 0.1% DEA in n-Hexanes [1181] Eluent B: Isopropanol
[1182] Elution using A:B 90:10 at 1 ml/min
Method R:
[1182] [1183] Column: Chiralpak IB (250.times.4.6 mm, 5 .mu.m)
[1184] Eluent A: 0.1% DEA in n-Hexanes [1185] Eluent B: Isopropanol
[1186] Elution using A:B 95:5 at 1 ml/min
Example-148
Biological
[1187] Activity Suitable cell lines for use in the below assays,
e.g., Gi/cAMP and .beta.-arrestin assays include CHO-K1 cell
expressing human D2R/.beta.-arrestin (purchased from
DiscoveR.sub.X). The cell lines were grown or maintained in growth
media comprising Ham's F-12 (Cellgro 10-080-CV), 10% HI FBS (Gibco
16140), 1.times. Penn/Strep/Glutamine (Gibco #10378), 600 ug/ml
Geneticin (Gibco #10131) and 300 ug/ml Hygromycin (Invitrogen
10687-010).
[1188] Cells were prepared for assays by growing cultures for up to
2 weeks (from about 6-20 passages). A vial of frozen cells was
thawed in a water bath held at 37.degree. C. The cells were then
transferred into a 50 ml tube with 10 ml growth media. The vial was
rinsed with growth media and the contents transferred to the 50 ml
tube. The 50 ml tube was centrifuged at 1200 rpm for 5 minutes at
room temperature. The supernatant was decanted and the pellet of
cells were re-suspended in growth media and grown at 37.degree. C.,
95% humidity, 5% CO.sub.2 When the cells reached about 90%
confluence (approximately 3 days between passages), the cells were
passaged and used for either the agonist or antagonist assays as
described below.
.beta.-Arrestin Agonist Assay
[1189] The cells were prepared for .beta.-arrestin assays as
described above. The assays were performed using a PathHunter.RTM.
.beta.-Arrestin Detecting Kit (DiscoveR.sub.X). The cells were
grown on 225 mm dishes, then washed once with 1.times. PBS
(Cellgro), followed by digestion with 2.5 ml 1.times. Detachment
reagent (DRX 92-0009) for approximately 2 minutes. Plating 2
reagent ((DRX 93-0563R2B, 10 ml) was added to the plate, and the
cells were transferred into a 50 ml centrifuge tube and centrifuged
at room temperature using BD Dynac III at 1200 rpm for 5 minutes.
The supernatant was decanted and the pellet was re-suspended in
Plating 2 reagent at an optimized density of 2.5.times.10.sup.5
cells/ml. The cells were then plated onto white 384 well plates, to
a final cell density of 5000 cells/20 .mu.l/well. The plates were
then transferred to a humidified incubator maintained at 37.degree.
C., 5% CO.sub.2, and incubated for 24 hours prior to testing. The
compounds were then pin-transferred (100 nL) to the cells, and was
incubated for 90 minutes at 37.degree. C. The detection reagent
(9.6 .mu.L, Buffer: Emerald II: Galactor-Star in a 19:5:1 ratio,
i.e., 14.06 mL: 3.7 mL: 0.74 mL=18.5 mL) was then added to the
agonist plates. The plates were then incubated for 60 minutes at
room temperature in the dark, before reading the assay results
using the protocol Luminescence (Aperture luminescence 384-well) on
an EnVision.RTM. detection instrument (Perkin Elmer).
.beta.-Arrestin Antagonist Assay
[1190] The cells were prepared for .beta.-arrestin assays as
described above. The assays were performed using a PathHunter.RTM.
.beta.-Arrestin Detecting Kit (DiscoveR.sub.X). The cells were
grown on 225 mm dishes, then washed once with 1.times. PBS
(Cellgro), followed by digestion with 2.5 ml 1.times. Detachment
reagent (DRX 92-0009) for approximately 2 minutes. Plating 2
reagent ((DRX 93-0563R2B, 10 ml) was added to the plate, and the
cells were transferred into a 50 ml centrifuge tube and centrifuged
at room temperature using BD Dynac III at 1200 rpm for 5 minutes.
The supernatant was decanted and the pellet was re-suspended in
Plating 2 reagent at an optimized density of 2.5.times.10.sup.5
cells/ml. The cells were then plated onto white 384 well plates, to
an optimized final cell density of 5000 cells/200/ well. The plates
were then transferred to a humidified incubator maintained at
37.degree. C., 5% CO.sub.2, and incubated for 24 hours prior to
testing. The compounds were then pin-transferred (100 nL) to the
cells, and incubated for 10 minutes at 37.degree. C., before
addition of Quinpirole (5 uL of a 650 nM solution, 78.50 of
quinpirole (100 .mu.M in DMSO) into 12 mL Plating 2 reagent) to
each well, to final concentration of 130 nM. The plates were then
incubated for 90 minutes at 37.degree. C. before addition of the
detection reagents (12 .mu.L, Buffer: Emerald II:
Galactor-Star=19:5:1 ratio 14.06 mL: 3.7 mL: 0.74 mL=18.5 mL) to
the plates. The plates were then incubated for 60 minutes at room
temperature in the dark before reading the assay results using the
protocol Luminescence (Aperture luminescence 384-well) on an
EnVision.RTM. detection instrument (Perkin Elmer).
Gi/cAMP Agonist Assay
[1191] The cells were prepared for Gi/cAMP assays as described
above. The assays were performed using a PE Lance Ultra cAMP kit
(TRF0263). The cells were grown on 225 mm dishes, then washed once
with 1.times. PBS (Cellgro) before digestion with 2.5 ml 1.times.
Detachment reagent (DRX 92-0009) for about 2 minutes. PBS (20 ml)
was then added to the plate, and the cells were transferred to a 50
ml centrifuge tube, and centrifuged at room temperature using BD
Dynac III, at 1200 rpm for 5 minutes. The supernatant was decanted
and the pellet was re-suspended in stimulation buffer at an optimal
density of 6.67.times.10e5 cells/ml, before plating onto white 384
well plates (150/well) to a final concentration of 10,000
cells/ISO/well. Compounds were pin-transferred (100 nL) to the
cells, and incubated for 10 min. at 37.degree. C. Forskolin (50 of
a 10 .mu.M solution, 12 .mu.L Forskolin (10 mM in DMSO) into 12 mL
Stimulation buffer) was then added to each well to final
concentration to 2.504 Forskolin, and the plates were then
incubated at room temperature for 30 minutes. Eu-cAMP tracer
solution (100, PerkinElmer, 3600 of Tracer in 17.64 ml kit buffer)
and ULight-anti-cAMP solution (100, 120 .mu.L antibody in 17.88 ml
kit buffer) was then added to each well. The plates were then
incubated at room temperature for about 1 hr in the dark before
reading the assay results using protocol Lance (Excitation 320 nm,
Emission filter 665 nm, second emission filter 615 nm, Top mirror
Lance Delfia) on an EnVision.RTM. detection instrument (Perkin
Elmer).
Gi/cAMP Antagonist Assay
[1192] The cells were prepared for Gi/cAMP assays as described
above. The assays were performed using a PE Lance Ultra cAMP kit
(TRF0263). The cells were grown on 225 mm dishes, then washed once
with 1.times. PBS (Cellgro) before digestion with 2.5 ml 1.times.
Detachment reagent (DRX 92-0009) for about 2 minutes. PBS (20 ml)
was then added to the plate, and the cells were transferred to a 50
ml centrifuge tube, and centrifuged at room temperature using BD
Dynac III, at 1200 rpm for 5 minutes. The supernatant was decanted
and the pellet was re-suspended in stimulation buffer at an
optimized density of 6.67.times.10e5 cells/ml, before plating onto
white 384 well plates (150/well) to a final concentration of about
10,000 cells/ISO/well. Chemical plate was pin-transferred (100 nL)
to the cells, and incubated for 10 min. at 37.degree. C. A 5 .mu.l
mixture containing Forskolin (10 .mu.M, 12 .mu.L Forskolin (10 mM
in DMSO) into 12 mL stimulation buffer) and Quinpirole (10.8 nM,
131 .mu.L Quinpirole (1 .mu.M in DMSO) into 12 mL Forskolin buffer)
were added to each well to a final concentration of 2.504 Forskolin
and 2.7 nM Quinpirole. The plates were then incubated at room
temperature for about 30 minutes before addition of Eu-cAMP tracer
solution (100, PerkinElmer) and then ULight-anti-cAMP solution
(100) to each well. Following incubation at room temperature for 1
hr in the dark, the assay results were read using protocol Lance
(Excitation 320 nm, Emission filter 665 nm, second emission filter
615 nm, Top mirror Lance Delfia) on an EnVision.RTM. detection
instrument (Perkin Elmer).
Pharmacokinetic Studies on Mice Brains
[1193] Twelve male C57BL/6 mice were weighed and administered
intraperitoneally with a dose of test compound (of Example 35)
solution formulation. The dosing volume administered for the
intraperitoneal route was at 10 mL/kg. Blood samples (approximately
60 .mu.L) were collected from retro-orbital plexus of each mouse
under light isoflurane anesthesia at 0.08, 0.5, 1, 2, 4, and 8 hr.
Following the collection of blood, plasma was also harvested by
centrifugation and stored at -70.degree. C. until analysis. After
collection of plasma, the animals were euthanized and brain samples
were isolated at 0.08, 0.5, 1, 2, 4, and 8 hr. Tissue samples
(brain) were homogenized using ice-cold phosphate buffer saline (pH
7.4) and homogenates were stored below -70.degree. C. until
analysis. Total homogenate volume was three times the tissue
weight. Concentrations of test compound in mouse plasma and brain
samples were determined by LC-MS/MS method.
[1194] Identical extraction procedures were used for the
plasma/brain homogenate study samples and the spiked plasma
calibration standards: A 25 .mu.L sample of either study sample
(plasma/brain) or spiked calibration standard was added to
individual pre-labeled micro-centrifuge tubes. A volume of 100
.mu.L of IS (antipyrine, 500 ng/mL) prepared in acetonitrile was
then added to the micro-centrifuge tubes, except in a sample used
as a negative control where only acetonitrile was added and
vortexed for 5 minutes. Samples were centrifuged for 20 minutes at
the speed of 4000 rpm at 4.degree. C. Following centrifugation, 100
.mu.L of the supernatant was sampled from each centrifuge tube and
transferred into insert vials. These vials remained within the
auto-sampler for the LC/MS/MS analysis. Standards used for
calibration were prepared by spiking 10 .mu.L of the test compound
in 190 .mu.L of control (used as a negative control) mouse
plasma/brain homogenate.
[1195] The plasma and brain concentration-time data of test
compound was provided for data analysis. The plasma and brain
concentration-time data was then used for the pharmacokinetic
analysis. Non-Compartmental-Analysis module in Phoenix.RTM.
WinNonlin.RTM. (Version 6.3) was used to assess the pharmacokinetic
parameters. Peak plasma concentrations (C.sub.max) and time for the
peak plasma concentrations (T.sub.max) were the observed values.
The areas under the concentration time curve (AUC.sub.last and
AUC.sub.inf) were calculated by linear trapezoidal rule. The
terminal elimination rate constant, ke was determined by regression
analysis of the linear terminal portion of the log plasma
concentration-time curve.
[1196] Illustrative results are presented in FIG. 2, the
pharmacokinetic parameters are as follow:
TABLE-US-00003 T.sub.max C.sub.max AUC.sub.last AUC.sub.INF
T.sub.1/2 CL Vss Compound Matrix Route (hr) (.mu.g/L) (.mu.g/L*hr)
(.mu.g/L*hr) (hr) (L/hr/kg) (L/kg) Plasma i.p. 0.50 709.91 1470.78
1507.16 1.62 6.64 15.48 Brain i.p. 1.00 740.63 1335.28 1347.55 1.35
7.42 14.41 CL Vss Example T.sub.max C.sub.max AUC.sub.last
AUC.sub.INF T.sub.1/2 mg/(hr* mg/(.mu.mol/L)/ 35b (hr) (.mu.mol/L)
(hr*.mu.mol/L) (hr*.mu.mol/L) (hr) .mu.mol/L)/kg kg Plasma i.p.
0.50 1.59 3.31 3.39 1.62 2.96 6.89 Brain i.p. 1.00 1.66 3.00 3.03
1.35 3.30 6.41
Positron Emission Tomography Studies on Rodents
[1197] All animal procedures were performed in accordance with the
National Institutes of Health Guide for the Care and Use of
Laboratory Animals and were approved by the Massachusetts General
Hospital Institutional Animal Care and Use Facility. Male
Sprague-Dawley rats (8-14 weeks old, Charles River Labs) were used
for the study with animals pair-housed on a diurnal 12:12
light/dark cycle with free access to food and water. The rats were
stabilized under anesthesia (2% isoflurane in 1.5 L/min oxygen)
before an intravenous (i.v.) catheter was placed in the lateral
tail vein (BD Angiocath #381112, 24G) and non-radiolabeled test
compounds were administered 5-180 minutes prior to radiotracer
administration. All test compounds (vehicle, compound of Example
35, Clozapine) were solubilized in a solution of (10% DMSO, 10%
Tween-80, 80% saline) and injected at a volume .ltoreq.2 mL/kg.
Baseline control scans were obtained from pretreatment time-matched
control animals administered an equivalent volume of vehicle alone.
Respiration of each animal was monitored for the duration of the
procedure.
[1198] Carbon 11-labeled raclopride ([.sup.11C]RAC) was synthesized
from the O-desmethyl RAC precursor and [11C] methyl iodide and
subsequently purified by high-performance liquid chromatography as
previously described (Farde L, et al. (1985) PNAS, USA
82(11):3863-3867). For each scan, 1.0.+-.0.15 mCi [.sup.11C]RAC
radiotracer was administered via i.v. catheter in a volume
.ltoreq.1.5 mL in a vehicle containing (10% ethanol, 90% saline).
Positron emission tomography (PET) and skeletal computed tomography
(CT) data were collected using a GammaMedica Triumph trimodal
PET/SPECT/CT scanner (Quebec, Canada) or PET data alone using a
Concorde Microsystems R4 microPET scanner (Knoxville, Tenn., USA).
Each [.sup.11C]RAC scan included subtraction of random coincidences
collected in a delayed time window. Scatter-corrected sinograms
were reconstructed using a 3-dimensional iterative maximum
likelihood expectation maximization (3D-MLEM) algorithm with 16
iterations yielding an image resolution of .about.1.5 mm FWHM (Full
Width at Half Maximum). Pixel size in reconstructed images was 0.26
mm transaxially, 0.6 mm slice thickness. Regions of Interest (ROIs)
were drawn on reconstructed images estimating peak [.sup.11C]RAC
uptake in striata (averaged between left and right hemispheres) and
cerebellum as reference region for non-displaceable (ND) tracer
uptake. ROI dimensions, placement and striatal D2/D3 binding
potential (BP.sub.ND) were evaluated by graphical analysis using
Logan distribution volume ratio (DVR) linearization as previously
described (BP.sub.ND.=DVR-1; Alexoff D, et al. (2002) JNucMed
44(5): 815-822; Logan J, et al. (1996) JCerebral Blood Flow and
Metabolism 16(5):843-840).
[1199] Illustrative results are presented in FIG. 3.
Amphetamine Induced Hyperactivity Studies
[1200] Amphetamine-induced hyperactivity (AIH) was examined in
eight identical open-field chambers (16.5''.times.16''.times.12'';
AccuScan Instruments, Columbus, Ohio). Activity was detected by
infrared beam breaks and recorded automatically by VersaMax
software (AccuScan). Daily sessions were automatically binned in 5
minute intervals (VersaDat; AccuSacn) for statistical analysis. AIH
was run over three consecutive days as follows:
[1201] Day 1: Mice were acclimated to the injection procedure by
injecting 30 minutes prior to being placed in the chambers (to
match the timing of day 3 compound administration).Mice were then
placed into the open-field for 20 minutes and then removed for a
saline injection (to match the timing of amphetamine administration
on day 3). Mice were placed back into the open-field for an
additional 30 minutes, at which point the mice were returned to
their home cage.
[1202] Day 2 was run identically to Day 1, with the exception that
the second day lasted for one hour (20
minutes.fwdarw.injection.fwdarw.40 minutes).
[1203] Day 3 was the amphetamine challenge day. Mice were
pre-treated with D2 antagonist compounds (compound of Example 35)
30 minutes prior to being placed in the open field. After 20
minutes, mice were removed and challenged with amphetamine,
following protocols known to one skilled in the art, for example
Jones C. A, et. al. Br J Pharmacol. 2011, 164(4):1162-1194; Pan J
Q, et. al. Neuropsychopharmacology. 2011, 36(7):1397-1411.
[1204] Illustrative results are presented in FIG. 4.
Rotarod Performance
[1205] In the test, mice were placed on a horizontally oriented,
rotating cylinder (rod) suspended above a cage floor, which was low
enough not to injure the animal, but high enough to induce
avoidance of fall. The mice naturally try to stay on the rotating
cylinder, or rotarod, and avoid falling to the ground. Mice were
administered clozaril at 3 mg/kg (test group was 7); or the
compound of Example 35 (either 10 mg/kg (test group was 7) or 30
mg/kg (test group was 8) or vehicle (test group was 14). The mice
had an average weight of 20 grams (as do the mice in all examples
herein). The length of time that a given animal stays on this
rotating rod is a measure of the animal's balance, coordination,
physical condition, and motor-planning. The speed of the rotarod is
mechanically driven, and was held constant. The results are
illustrated in FIG. 5. The compound of Example 35 promotes far less
catalepsy than the known antipsychotic Clozapine at efficacious
doses.
Heatmap
[1206] The heatmap of FIG. 6 represents binding across various
relevant CNS biological targets including GPCRs, transporters, etc.
for clozapine, aripiprazole and amisulpride, alongside exemplary
compounds of the invention--compounds 35b, 79, 105, and 70b.
Results of Gi/cAMP and .beta.-Arrestin Antagonist and Agonist
Aassays using CHO -K1 Cell Line Expressing Human
D2R/.beta.-Arrestin
[1207] Herein exemplified compounds were analyzed by way of the
foregoing Gi/cAMP and .beta.-arrestin antagonist and agonist assays
using CHO-K1 cell line expressing human D2R/.beta.-arrestin and
thus both the Gi/cAMP and .beta.-arrestin pathways were monitored
in both agonist and antagonist (Quinpirole was used as agonist)
modes. FIG. 1 shows representative curves obtained for selected D2
ligands: Clozapine, Aripiprazole, and compounds of the invention
35b, 63, 79, 16a and 52. Compounds 35b, 63 and 79 are
representative .beta.-arrestin biased D2R antagonists. Compound 16
is a representative cAMP-biased agonist, and Compound 52 is a
representative dual antagonist. Table 3 tabulates the results as to
the various exemplified compounds, in dopamine P-arrestin and cAMP
assays in agonist and antagonist modes. In table 3, Emax is higher
than 20%.
MDR1-MDCKII Permeability Assay
[1208] This is a standard permeability assay that predicts brain
penetration. It was ran by the CRO Absorption Systems
(www.absorption.com/drug-discovery/permeability/cell-based/).
TABLE-US-00004 TABLE 3 Biological data from testing compounds in
the foregoing Gi/cAMP and .beta.-arrestin antagonist and agonist
assays using CHO-K1 cell line expressing human D2R/.beta.-arrestin.
Both the Gi/cAMP and .beta.-arrestin pathways were monitored in
both agonist and antagonist (quinpirole used as agonist) modes. The
D2 binding Ki values were determined using a radioligand binding
assay. EC.sub.50 or IC.sub.50 values were categorized as follows.
Emax values for a given pathway ranged from 10-100%. D2 binding
.beta.-arrestin cAMP .beta.-arrestin cAMP Compound # K.sub.i
Antagonist Antagonist Agonist Agonist Aripiprazole A A E A A
Clozapine B B B E E UNC9994 B E B A UNC9975 B B E A Quinpirole E E
A A Dopamine E E B A MLS1547 C E E A 63 B B E E B 63a C E E B 63b B
B E E 113 C E E A 24 C E E C 23 B B E E 33 D E E C 32 B B E D 31 C
E E B 30 D E E C 29 C E E B 28 C E E B 27 C E E B 26 C B E E 25 C C
D E D 25a C E E B 25b C C E E 78 C C E B 78a C C E B 78b C C E E
122 B B E C 74 B B E A 74a C E E C 74b B B E B 75 B B E A 36 D E E
E 35 C C E C 35a D D E D 35b C C C E C 118 C E E A 118a D E E D
118b C E E C 93 B E E A 93a C B E D 93b C E E B 34 C E E B 95 B B B
E B 95a B B E E 95b B B E C 119 B E E A 119a C C E E 119b C E B A
94 B E B A 94a B B A E E 94b B E E B A 46 C C E E 37 B C E E 38 C E
E C 39 B B E E 111 B E E B 112 C E E A 40 C B B E E 40a B B E E 40b
C E E C 96 B B E B 96a C E E C 96b B B E E 123 B E E A 41 C B E E
42 B B B E B 42a B B E B 42b C C E D 43 C E E C 44 C D E E 51 C E E
B 79 B B E E A 79a C C E E 79b B C E E B 114 B B A E E 114a B A A E
B 114b B E E B 107 B E E B 103 A E E A 103a B A E B 103b B E B A
105 A B E C B 105a B E B A 105b C E C B 104 D E E C 97 A A E E 97a
C B E B 97b B B E B 97c A A E E 97d B B E E 98 E E B A 121 B B E E
89 B B E E 89a B B E E 89b C D E B 120 A A E E 72 A A C E A 72a B B
E C B 72b A A E E 73 A A E E 80 C C E B 102 B B E B 102a C C E E
102b C C E C 88 B B E A 88a C B E E 88b C C E B 76 C D E A 76a C B
E B 76b C C E C 77 B C E A 77a B B B E B 77b C B E E 81 B B E E 81a
B B E E 81b C B E E 87 B B E E 62 C B E E 110 C B E E 65 D C E E 64
D C E E 18 C E E B 61 D D E E 109 A A E E 12 C B E D 13 C E E C 68
A A E E 66 B A A E D 1 B E E A 1a C B E E 1b C E C A 2 C E E B 3 B
E E A 3a B B E E 3b B E E A 4 B E E A 4a C E C B 4b C B E E 5 C C E
D 115 C E E B 115a C E E B 115b B B E E 14 B E E A 14a C E B A 14b
B C E E 67 B A E E 9 C C E E 10 D E E B 11 D E D E E 11a B C E E
11b E E E E 6 B A A E E 6a A A E E 6b A A E E 7 B B E B 8 D E E D
17 C B E E 19 C E E B 15 D E E E 16 D E E C A 16a E E C A 16b E E E
C 116 C E E B 92 B B B E B 92a B B E B 92b C C E D 117 C E E B 91 B
B E B 91a C E E B 91b B B E E 45 A A E E 45a B B E E 45b B B E B 54
B B E E 54a A A E E 54b C E E B 56 B B E E 57 B E E B 53 B A A E E
53a B B E E 53b B B E E 52 A A E E 52a B A E E 52b B B E E 70 B B E
B 70a A A E E 70b C E E A 69 B E B A 69a C E B B 69b B B E B A 55 C
C E E 59 E D E E 60 E E E E 47 C B E E 83 A A E E 49 B C E C 85 A A
E E 48 C E E C 84 B B E E 50 C E E B 86 A A E E 22 B B E E 22a B B
E D 22b B B E E 90 C C E C 21 B B E E 20 B A E E 82 D C E E 108 C E
E A 58 D D E E 71 B E A A 99 C E E B 101 B A E E 101a B B E E 101b
B B E E 106 B C E C 124 A A E E 125 B B B E B 125a C E E B 125b B C
E E 126 C E E A 127 A A E E 128 B B E A 128a D B E E 128b C B B E A
129 E E E C 130 C E B A 130a C B E E 130b C E B A 146 C C E E 131 C
E C A 132 C C E E 133 A A E A 133a A A E E 133b B E A A 134 B B E
A
135 C B E E 136 A A E C 136a B E B C 136b A A E E 137 C C E E 138 B
E E B 138a B E B A 138b B A E A 139 C B E C 139a B B E A 139b C B E
B 140 C C E C 141 C C E E 142 D D E E 143 C E C B 144 A E A A 144a
A A E A A 144b B E B A 145 C C E D 145a D C E E 145b C B E E (A =
<0.1 .mu.M, B = 0.1-1.0 .mu.M, C = 1.0-10.0 .mu.M, D = 10.0-30.0
.mu.M, E = >30 .mu.M)
[1209] UNC9994 is of the formula:
##STR00312##
UNC9975 is of the formula:
##STR00313##
Quinpirole is of the formula
##STR00314##
Dopamine is of the formula:
##STR00315##
MLS1547 is of the formula:
##STR00316##
TABLE-US-00005 TABLE 4 Additional exemplary results of the
biological assays of select compounds of the invention, and
exemplary analytical data of select compounds of the invention
Analytical (h: human; m: mouse; r: rat) MDR1- Plasma Microsomal
MDCKII Caco2 Solubility Protein Stability: Stability: Compound A-B/
A-B/ in PBS Binding % remaining % remaining Number B-A B-A (.mu.M)
% bound after 5 hours after 60 minutes 63 25.1/19.9 476 h96.3,
m97.4 h94.5, m93.4 h58, m37, r55 23 225 h97.7, m97.0, r96.7 h100,
m100, r96 h76, m41, r77 32 151 h97.0, m96.9, r97.7 h91, m74, r98
h61, m37, r46 31 27 h97.7, m97.4, r98.6 h94.2, m84.5, r100 h53,
m57, r55 28 434 h75.3, m72.2, r76.7 h100, m95, r99 h87, m52, r78 26
460 h93.8, m94.3, r95.4 h100, m92, r99 h84, m66, r96 25 33.7/50.5
452 h92, m95.3, r97 h100, m97, r94.5 h93, m76, r100 35 26.7/46.7
441 h91.4, m92.6, r95.8 h100, m98, r99.6 h83, m74, r80 35b
0.97/53.1 472 h91.9, m91.3, r93.3 h98, m100, r87 h75, m62, r96 118b
m35 93 m12 93b m19 95 m33 95b m12 119b m97.4 m100 m51 94a m2 94b
m26 146 h97.8, m96.0, r97.9 h98, m96, r88 h56, m36, r27 37 197
h95.3, m94.9, r97.6 h100, m98, r100 h71, m31, r28 39 3.3 h97.9,
m98.0, r95.4 h100, m93, r86 h49, m65, r55 111 496/217 h94.7, m97.3,
r97.8 h100, m100, r98 h60, m39, r51 112 19 h93.6, m95, r98 h100,
m95, r95 h52, m29, r53 40 4.4/1.9 0.4 h98.9, m99.0, r97.7 h100,
m100, r90 h45, m50, r57 96 m26 41 <0.1 h99.3, m99.4, r98.6 h100,
m100, r96 h45, m64, r78 42 <0.1 h99.3, m99.3, r98.6 h98, m100,
r93 h40, m59, r70 51 m0 79 6.17/22.1 m0 79b 8 m100 m100 m0 114
>500/159 h98.6, m97.7, r99.5 h100, m100, r100 h63, m6, r20 99 m7
103 m100 m97 m1 135 m2 125 m12 105 m18 105a m1 104 m45 97b m3 72a
1.4 m100 m100 m0 137 m1 88 461 m1 77a m1 18 352 h95.4, m94.4, r97.3
h94.9, m90.5, r93.2 h78, m43, r55 109 >500 h59, m40, r57 66
15.1/2.4 10.5 h99.3, m99.2, r99.4 h99.7, m100, r88.1 h46, m7, r35 3
43 h75.4, m98.5, r68.5 h92, m100, r86 h64, m22, r44 5 311 h80.5,
m97.9, r85.8 h91.2, m90.5, r95.2 h71, m42, r84 115 30.4/11.5 220
h99.2, m98.5, r99.5 h91.2, m86.2, r98.0 h63, m26, r77 14 36.1
h99.1, m98.5, r99.4 h96.7, m100, r78.2 h49, m11, r44 10 >500
h75, m44, r57 11 >500 h51.5, m60.9, r78.9 h98.2, m89.5, r100
h95, m100, r100 6 0.7 h99.3, m99.2, r100 h99, m98.8, r69.3 h52,
m22, r32 6a m31 6b m2 7 0.7 h100, m99.6, r100 h91.5, m100, r93.5
h87, m44, r76 8 1.1 h100, m100, r100 h100, m100, r98.1 h82, m53,
r100 15 4.1 h97.7, m97.4, r99.0 h96, m100, r91 h56, m44, r68 16 14
h99, m97.7, r97.9 h98, m94, r97 h34, m45, r75 92 m22 91b m1 45 6.5
h98.3, m98.5, r98.8 h95, m91, r85 h56, m62, r59 54 28.4/39.3
>500 h95.8, m96.1, r97.3 h96, m100, r78 h70, m29, r66 53
27.4/23.9 149 h79.0, m97.9, r91.4 h100, m96, r78 h42, m3, r16 52
12.5/9.0 27 h99.1, m99.1, r97.9 h84, m89, r55 h46, m7, r7 70b m0
144a m1 22b m12
[1210] The foregoing examples are presented for the purpose of
illustrating the invention and should not be construed as imposing
any limitation on the scope of the invention. It will be readily
apparent that numerous modifications and alterations may be made to
the specific embodiments of the invention described above and
illustrated in the examples without departing from the principles
underlying the invention. All such modifications and alterations
not departing from the spirit or scope of the present invention are
intended to be embraced by this application.
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