U.S. patent application number 12/539232 was filed with the patent office on 2010-02-04 for 11-beta hsd1 inhibitors.
Invention is credited to Eva Binnun, Lihren Chen, Manus Ipek, Jinbo Lee, Katherine Lee, Huan-Qiu Li, Jianchang Li, Wei Li, Tarek Suhayl Mansour, John C. McKew, Eddine Saiah, Vipin Suri, Steve Y. Tam, Richard Vargas, Zhao-Kui Wan, Douglas P. Wilson, Yuchuan Wu, Jason Shaoyun Xiang.
Application Number | 20100029648 12/539232 |
Document ID | / |
Family ID | 38236242 |
Filed Date | 2010-02-04 |
United States Patent
Application |
20100029648 |
Kind Code |
A1 |
Xiang; Jason Shaoyun ; et
al. |
February 4, 2010 |
11-Beta HSD1 Inhibitors
Abstract
This invention relates to inhibiting 11.beta.HSD1.
Inventors: |
Xiang; Jason Shaoyun;
(Winchester, MA) ; Saiah; Eddine; (Brookline,
MA) ; Tam; Steve Y.; (Wellesley, MA) ; McKew;
John C.; (Arlington, MA) ; Chen; Lihren;
(Bedford, MA) ; Ipek; Manus; (Watertown, MA)
; Lee; Katherine; (West Newton, MA) ; Li;
Huan-Qiu; (Brighton, MA) ; Li; Jianchang;
(Carlisle, MA) ; Li; Wei; (Acton, MA) ;
Mansour; Tarek Suhayl; (New City, NY) ; Suri;
Vipin; (Waltham, MA) ; Vargas; Richard;
(Lexington, MA) ; Wu; Yuchuan; (Acton, MA)
; Wan; Zhao-Kui; (Arlington, MA) ; Lee; Jinbo;
(Andover, MA) ; Binnun; Eva; (Boston, MA) ;
Wilson; Douglas P.; (Ayer, MA) |
Correspondence
Address: |
WYETH LLC;PATENT LAW GROUP
5 GIRALDA FARMS
MADISON
NJ
07940
US
|
Family ID: |
38236242 |
Appl. No.: |
12/539232 |
Filed: |
August 11, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11703522 |
Feb 7, 2007 |
7632838 |
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12539232 |
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60771262 |
Feb 7, 2006 |
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Current U.S.
Class: |
514/235.8 ;
514/253.01; 514/255.02; 514/318 |
Current CPC
Class: |
A61P 25/28 20180101;
C07D 211/96 20130101; C07D 295/26 20130101; C07D 401/04 20130101;
A61P 3/10 20180101; A61P 17/02 20180101; A61P 3/00 20180101; C07D
413/02 20130101; C07D 403/02 20130101; A61P 3/04 20180101; C07D
409/02 20130101; A61P 9/10 20180101; A61P 3/06 20180101; A61P 43/00
20180101 |
Class at
Publication: |
514/235.8 ;
514/253.01; 514/255.02; 514/318 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/497 20060101 A61K031/497; A61K 31/4965
20060101 A61K031/4965; A61K 31/4545 20060101 A61K031/4545 |
Claims
1-93. (canceled)
94. A method for treating a disease or condition mediated by excess
or uncontrolled amounts of cortisol and/or other corticosteroids,
the method comprising administering to a subject in need thereof an
effective amount of a compound of formula I: ##STR00065## wherein:
R.sup.1 is: i) C.sub.6-C.sub.18 aryl or heteroaryl including 5-20
atoms, each of which is optionally substituted with from 1-10
R.sup.a; or (ii) C.sub.7-C.sub.20 aralkyl; heteroaralkyl including
6-20 atoms; arylheterocyclyl including 8-20 atoms; arylcycloalkenyl
including 8-20 atoms; or arylheterocycloalkenyl including 8-20
atoms; each of which is optionally substituted with from 1-10
R.sup.b; R.sup.2 is C.sub.6-C.sub.18 aryl or heteroaryl including
5-20 atoms, each of which is optionally substituted with from 1-10
R.sup.c; X is S(O).sub.n or S(O).sub.nNR.sup.6, wherein n is 1 or 2
and R.sup.6 is hydrogen, C.sub.1-C.sub.12 alkyl, or C.sub.3-16
cycloalkyl; each of V and Y is, independently, CR.sup.7 or N,
wherein R.sup.7 is hydrogen or C.sub.1-C.sub.12 alkyl, provided
that Y and V cannot both be CR.sup.7; one, two, three, or four of
W.sup.1, Z.sup.1, W.sup.2, and Z.sup.2 are each, independently: (i)
C.sub.1-C.sub.12 alkyl; or (ii) oxo; or (iii) C.sub.6-C.sub.18 aryl
or heteroaryl including 5-20 atoms, each of which is optionally
substituted with from 1-10 R.sup.a; or (iv) C.sub.7-C.sub.20
aralkyl; C.sub.3-C.sub.16 cycloalkyl; heteroaralkyl including 6-20
atoms; C.sub.3-C.sub.16 cycloalkenyl; heterocyclyl including 3-16
atoms; or heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; and the others are
hydrogen; R.sup.a at each occurrence is, independently: (i) halo;
NR.sup.dR.sup.e; nitro; azido; hydroxy; C.sub.1-C.sub.12 alkoxy or
C.sub.1-C.sub.12 thioalkoxy, each of which is optionally
substituted with 1-5 R.sup.f; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy,
heteroaryloxy including 5-20 atoms, or thioaryloxy including 5-20
atoms, each of which is optionally substituted with 1-5 R.sup.a';
C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy; C.sub.3-6
cycloalkyloxy, C.sub.3-C.sub.16 cycloalkenyloxy, heterocyclyloxy
including 3-16 atoms, heterocycloalkenyloxy including 3-16 atoms,
C.sub.7-C.sub.20 aralkoxy, or heteroaralkoxy including 6-20 atoms,
each of which is optionally substituted with 1-5 R.sup.b; mercapto;
cyano; --C(O)R.sup.g, --C(O)OR.sup.g; --OC(O)R.sup.g;
--C(O)SR.sup.g; --SC(O)R.sup.g; --C(S)SR.sup.g; --SC(S)R.sup.g;
--C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; or 2 R.sup.a together form C.sub.1-C.sub.3
alkylenedioxy; (ii) C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12
haloalkyl; each of which is optionally substituted with from 1-5
R.sup.j; or (iii) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16
cycloalkyl; heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or (iv)
C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20 alkynyl; or (v)
C.sub.6-C.sub.16 aryl or heteroaryl including 5-16 atoms, each of
which is optionally substituted with from 1-10 R.sup.a; R.sup.a' at
each occurrence is, independently, C.sub.1-C.sub.12 alkyl,
C.sub.1-C.sub.12 haloalkyl, C.sub.2-C.sub.12 alkenyl;
C.sub.1-C.sub.12 alkynyl; C.sub.3-C.sub.16 cycloalkyl;
C.sub.3-C.sub.16 cycloalkenyl, heterocyclyl including 3-16 atoms,
heterocycloalkenyl including 3-16 atoms; C.sub.7-C.sub.20 aralkyl;
C.sub.6-C.sub.16 aryl; heteroaryl including 5-16 atoms; halo;
NR.sup.dR.sup.e; nitro; azido, hydroxy; C.sub.1-C.sub.12 alkoxy;
C.sub.1-C.sub.12 thioalkoxy; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy;
heteroaryloxy including 5-20 atoms; thioaryloxy including 5-20
atoms; C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy; C.sub.3-C.sub.16 cycloalkenyloxy;
heterocyclyloxy including 3-16 atoms; heterocycloalkenyloxy
including 3-16 atoms; C.sub.7-C.sub.20 aralkoxy; heteroaralkoxy
including 6-20 atoms; mercapto; cyano; --C(O)R.sup.g,
--C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g;
--C(S)SR.sup.g; --SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e;
--NR.sup.hC(O)R.sup.i; --OC(O)NR.sup.dR.sup.e; or 2 R.sup.a'
together form C.sub.1-C.sub.3 alkylenedioxy; or 2 R.sup.a' together
form C.sub.1-C.sub.3 alkylenedioxy; R.sup.b at each occurrence is,
independently: (i) halo; NR.sup.dR.sup.e; nitro; azido; hydroxy;
oxo, thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12 alkoxy or
C.sub.1-C.sub.12 thioalkoxy, each of which is optionally
substituted with 1-5 R.sup.f; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy,
heteroaryloxy including 5-20 atoms, or thioaryloxy including 5-20
atoms, each of which is optionally substituted with 1-5 R.sup.a;
C.sub.2-C.sub.12 alkenyloxy; C.sub.1-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy, C.sub.3-C.sub.16 cycloalkenyloxy,
heterocyclyloxy including 3-16 atoms, heterocycloalkenyloxy
including 3-16 atoms, C.sub.7-C.sub.20 aralkoxy, or heteroaralkoxy
including 6-20 atoms, each of which is optionally substituted with
1-5 R.sup.b'; mercapto; cyano; --C(O)R.sup.g, --C(O)OR.sup.g,
--OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g; --C(S)SR.sup.g;
--SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; or 2 R.sup.b together form C.sub.1-C.sub.3
alkylenedioxy, or (ii) C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12
haloalkyl; each of which is optionally substituted with from 1-5
R.sup.j; or (iii) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16
cycloalkyl; heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b'; or (iv)
C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20 alkynyl; or (v)
C.sub.6-C.sub.16 aryl or heteroaryl including 5-16 atoms, each of
which is optionally substituted with from 1-10 R.sup.a; R.sup.b' at
each occurrence is, independently, C.sub.1-C.sub.12 alkyl or
C.sub.1-C.sub.12 haloalkyl, each of which is optionally substituted
with 1-5 R.sup.j; C.sub.2-C.sub.12 alkenyl; C.sub.2-C.sub.12
alkynyl; C.sub.3-C.sub.16 cycloalkyl; C.sub.1-C.sub.16
cycloalkenyl, heterocyclyl including 3-16 atoms, heterocycloalkenyl
including 3-16 atoms; C.sub.7-C.sub.20 aralkyl; C.sub.6-C.sub.16
aryl; heteroaryl including 5-16 atoms; halo; NR.sup.dR.sup.e;
nitro; azido, hydroxy; oxo, thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12
alkoxy; C.sub.1-C.sub.12 thioalkoxy; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy;
heteroaryloxy including 5-20 atoms; thioaryloxy including 5-20
atoms; C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy; C.sub.3-C.sub.16 cycloalkenyloxy;
heterocyclyloxy including 3-16 atoms; heterocycloalkenyloxy
including 3-16 atoms; C.sub.7-C.sub.20 aralkoxy; heteroaralkoxy
including 6-20 atoms; mercapto; cyano; --C(O)R.sup.g,
--C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g;
--C(S)SR.sup.g; --SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e;
--NR.sup.hC(O)R.sup.i; or --OC(O)NR.sup.dR.sup.e; or 2 R.sup.b'
together form C.sub.1-C.sub.3 alkylenedioxy; R.sup.c at each
occurrence is, independently: (i) halo; nitro; hydroxy;
C.sub.1-C.sub.12 alkoxy optionally substituted with 1-5 R.sup.f;
C.sub.1-C.sub.12 haloalkoxy; cyano; SO.sub.2R.sup.m; or 2 R.sup.c
together form C.sub.1-C.sub.3 alkylenedioxy; or (ii)
C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl; each of which
is optionally substituted with from 1-5 R.sup.j; or (iii)
C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16 cycloalkyl;
heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16 cycloalkenyl;
heterocyclyl including 3-16 atoms; or heterocycloalkenyl including
3-16 atoms; each of which is optionally substituted with from 1-10
R.sup.b; or (iv) C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20
alkynyl; or (v) C.sub.6-C.sub.16 aryl or heteroaryl including 5-16
atoms, each of which is optionally substituted with from 1-10
R.sup.a; each of R.sup.d, R.sup.e, R.sup.g, R.sup.h, and R.sup.k,
at each occurrence is, independently: (i) hydrogen; or (ii)
C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl; each of which
is optionally substituted with from 1-5 R.sup.j; or (iii)
C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16 cycloalkyl;
heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16 cycloalkenyl;
heterocyclyl including 3-16 atoms; or heterocycloalkenyl including
3-16 atoms; each of which is optionally substituted with from 1-10
R.sup.b; or (iv) C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20
alkynyl; or (v) C.sub.6-C.sub.16 aryl or heteroaryl including 5-16
atoms, each of which is optionally substituted with from 1-10
R.sup.a; R.sup.f is NR.sup.dR.sup.e; nitro; azido; hydroxy; oxo,
thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12 alkoxy or C.sub.1-C.sub.12
thioalkoxy, each of which is optionally substituted with 1-5
R.sup.f; C.sub.1-C.sub.12 haloalkoxy; C.sub.6-C.sub.16 aryloxy,
C.sub.6-C.sub.16 thioaryloxy, heteroaryloxy including 5-20 atoms,
or thioaryloxy including 5-20 atoms, each of which is optionally
substituted with 1-5 R.sup.a'; C.sub.2-C.sub.12 alkenyloxy;
C.sub.2-C.sub.12 alkynyloxy; C.sub.3-C.sub.16 cycloalkyloxy,
C.sub.3-C.sub.16 cycloalkenyloxy, heterocyclyloxy including 3-16
atoms, heterocycloalkenyloxy including 3-16 atoms, C.sub.7-C.sub.20
aralkoxy, or heteroaralkoxy including 6-20 atoms, each of which is
optionally substituted with 1-5 R.sup.b; mercapto; cyano;
--C(O)R.sup.g, --OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g;
--C(S)SR.sup.g; --SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e;
--NR.sup.hC(O)R.sup.i; --OC(O)NR.sup.dR.sup.e; R.sup.i is R.sup.g;
OR.sup.g; or NR.sup.dR.sup.e; R.sup.j is NR.sup.dR.sup.e; nitro;
azido; hydroxy; oxo; thioxo; .dbd.NR.sup.k; C.sub.1-C.sub.12 alkoxy
or C.sub.1-C.sub.12 thioalkoxy, each of which is optionally
substituted with 1-5 R.sup.f; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy,
heteroaryloxy including 5-20 atoms, or thioaryloxy including 5-20
atoms, each of which is optionally substituted with 1-5 R.sup.a';
C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy, heterocyclyloxy including 3-16
atoms, heterocycloalkenyloxy including 3-16 atoms, C.sub.7-C.sub.20
aralkoxy, or heteroaralkoxy including 6-20 atoms, each of which is
optionally substituted with 1-5 R.sup.b; mercapto; cyano;
C.sub.1-C.sub.3 alkylenedioxy; --C(O)R.sup.g, --C(O)OR.sup.g,
--OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g; --C(S)SR.sup.g;
--SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; R.sup.m is (i) C.sub.1-C.sub.12 alkyl or
C.sub.1-C.sub.12 haloalkyl; each of which is optionally substituted
with from 1-5 R.sup.j; or (ii) C.sub.7-C.sub.20 aralkyl;
C.sub.3-C.sub.16 cycloalkyl; heteroaralkyl including 6-20 atoms;
C.sub.3-C.sub.16 cycloalkenyl; heterocyclyl including 3-16 atoms;
or heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or (iii)
C.sub.6-C.sub.16 aryl or heteroaryl including 5-16 atoms, each of
which is optionally substituted with from 1-10 R.sup.a; and
provided: (a) when V and Y are both N, and R.sup.2 is substituted
pyridyl or pyrimidinyl, then R.sup.c cannot be C.sub.1-C.sub.12
alkoxy optionally substituted with 1-5 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; or SO.sub.2R.sup.m; and (b) when V and Y are both N, X
is SO.sub.2, one of Z.sup.1 and W.sup.2 is CH.sub.3, and R.sup.2 is
phenyl substituted with from 1-5 R.sup.c, then 1 R.sup.c must be
halo; C.sub.1-C.sub.12 haloalkoxy; cyano; or C.sub.1-C.sub.12
haloalkyl, optionally substituted with from 1-5 R.sup.j; or a
pharmaceutically acceptable salt and/or N-oxide thereof.
95-102. (canceled)
103. A method for treating a disease or condition selected from
type 2 diabetes, Syndrome X, obesity, dyslipidemia, hyperlipidemia,
hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL,
atherosclerosis, and a cognitive disorder, the method comprising
administering to a subject in need thereof an effective amount of a
compound of formula I: ##STR00066## wherein: R.sup.1 is: (i)
C.sub.6-C.sub.18 aryl or heteroaryl including 5-20 atoms, each of
which is optionally substituted with from 1-10 R.sup.a; or (ii)
C.sub.7-C.sub.20 aralkyl; heteroaralkyl including 6-20 atoms;
arylheterocyclyl including 8-20 atoms; arylcycloalkenyl including
8-20 atoms; or arylheterocycloalkenyl including 8-20 atoms; each of
which is optionally substituted with from 1-10 R.sup.b; R.sup.2 is
C.sub.6-C.sub.18 aryl or heteroaryl including 5-20 atoms, each of
which is optionally substituted with from 1-10 R.sup.c; X is
S(O).sub.n or S(O).sub.nNR.sup.6, wherein n is 1 or 2, and R.sup.6
is hydrogen, C.sub.1-C.sub.12 alkyl, or C.sub.3-C.sub.16
cycloalkyl; each of V and Y is, independently, CR.sup.7 or N,
wherein R.sup.7 is hydrogen or C.sub.1-C.sub.12 alkyl, provided
that Y and V cannot both be CR.sup.7; one, two, three, or four of
W.sup.1, Z.sup.1, W.sup.2, and Z.sup.2 are each, independently: (i)
C.sub.1-C.sub.12 alkyl; or (ii) oxo; or (iii) C.sub.6-C.sub.18 aryl
or heteroaryl including 5-20 atoms, each of which is optionally
substituted with from 1-10 R.sup.a; or (iv) C.sub.7-C.sub.20
aralkyl; C.sub.3-C.sub.16 cycloalkyl; heteroaralkyl including 6-20
atoms; C.sub.3-C.sub.16 cycloalkenyl; heterocyclyl including 3-16
atoms; or heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; and the others are
hydrogen; R.sup.a at each occurrence is, independently: (i) halo;
NR.sup.dR.sup.e; nitro; azido; hydroxy; C.sub.1-C.sub.12 alkoxy or
C.sub.1-C.sub.12 thioalkoxy, each of which is optionally
substituted with 1-5 R.sup.f, C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy,
heteroaryloxy including 5-20 atoms, or thioaryloxy including 5-20
atoms, each of which is optionally substituted with 1-5 R.sup.a';
C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy, C.sub.3-C.sub.16 cycloalkenyloxy,
heterocyclyloxy including 3-16 atoms, heterocycloalkenyloxy
including 3-16 atoms, C.sub.7-C.sub.20 aralkoxy, or heteroaralkoxy
including 6-20 atoms, each of which is optionally substituted with
1-5 R.sup.b; mercapto; cyano; --C(O)R.sup.g, --C(O)OR.sup.g;
--OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g; --C(S)SR.sup.g;
--SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; or 2 R.sup.a together form C.sub.1-C.sub.3
alkylenedioxy; (ii) C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12
haloalkyl; each of which is optionally substituted with from 1-5
R.sup.j; or (iii) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16
cycloalkyl; heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or (iv)
C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20 alkynyl; or (v)
C.sub.6-C.sub.16 aryl or heteroaryl including 5-16 atoms, each of
which is optionally substituted with from 1-10 R.sup.a'; R.sup.a'
at each occurrence is, independently, C.sub.1-C.sub.12 alkyl,
C.sub.1-C.sub.12 haloalkyl, C.sub.2-C.sub.12 alkenyl;
C.sub.2-C.sub.12 alkynyl; C.sub.3-C.sub.16 cycloalkyl;
C.sub.3-C.sub.16 cycloalkenyl, heterocyclyl including 3-16 atoms,
heterocycloalkenyl including 3-16 atoms; C.sub.7-C.sub.20 aralkyl;
C.sub.6-C.sub.16 aryl; heteroaryl including 5-16 atoms; halo;
NR.sup.dR.sup.e; nitro; azido, hydroxy; C.sub.1-C.sub.12 alkoxy;
C.sub.1-C.sub.12 thioalkoxy; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy;
heteroaryloxy including 5-20 atoms; thioaryloxy including 5-20
atoms; C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy; C.sub.3-C.sub.16 cycloalkenyloxy;
heterocyclyloxy including 3-16 atoms; heterocycloalkenyloxy
including 3-16 atoms; C.sub.7-C.sub.20 aralkoxy; heteroaralkoxy
including 6-20 atoms; mercapto; cyano; --C(O)R.sup.g,
--C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g;
--C(S)SR.sup.g; --SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e;
--NR.sup.hC(O)R.sup.i; --OC(O)NR.sup.dR.sup.e; or 2 R.sup.a'
together form C.sub.1-C.sub.3 alkylenedioxy; or 2 R.sup.a' together
form C.sub.1-C.sub.3 alkylenedioxy; R.sup.b at each occurrence is,
independently: (i) halo; NR.sup.dR.sup.e; nitro; azido; hydroxy;
oxo, thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12 alkoxy or
C.sub.1-C.sub.12 thioalkoxy, each of which is optionally
substituted with 1-5 R.sup.f; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy,
heteroaryloxy including 5-20 atoms, or thioaryloxy including 5-20
atoms, each of which is optionally substituted with 1-5 R.sup.a;
C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy, C.sub.3-C.sub.16 cycloalkenyloxy,
heterocyclyloxy including 3-16 atoms, heterocycloalkenyloxy
including 3-16 atoms, C.sub.7-C.sub.20 aralkoxy, or heteroaralkoxy
including 6-20 atoms, each of which is optionally substituted with
1-5 R.sup.b'; mercapto; cyano; --C(O)R.sup.g, --C(O)OR.sup.g;
--OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g; --C(S)SR.sup.g;
--SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; or 2 R.sup.b together form C.sub.1-C.sub.3
alkylenedioxy; or (ii) C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12
haloalkyl; each of which is optionally substituted with from 1-5
R.sup.j; or (iii) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16
cycloalkyl; heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b'; or (iv)
C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20 alkynyl; or (v)
C.sub.6-C.sub.16 aryl or heteroaryl including 5-16 atoms, each of
which is optionally substituted with from 1-10 R.sup.a; R.sup.b' at
each occurrence is, independently, C.sub.1-C.sub.12 alkyl or
C.sub.1-C.sub.12 haloalkyl, each of which is optionally substituted
with 1-5 R.sup.j; C.sub.2-C.sub.12 alkenyl; C.sub.2-C.sub.12
alkynyl; C.sub.3-C.sub.16 cycloalkyl; C.sub.3-C.sub.16
cycloalkenyl, heterocyclyl including 3-16 atoms, heterocycloalkenyl
including 3-16 atoms; C.sub.7-C.sub.20 aralkyl; C.sub.6-C.sub.16
aryl; heteroaryl including 5-16 atoms; halo; NR.sup.dR.sup.e;
nitro; azido, hydroxy; ox, thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12
alkoxy; C.sub.1-C.sub.12 thioalkoxy; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy;
heteroaryloxy including 5-20 atoms; thioaryloxy including 5-20
atoms; C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy; C.sub.3-C.sub.16 cycloalkenyloxy;
heterocyclyloxy including 3-16 atoms; heterocycloalkenyloxy
including 3-16 atoms; C.sub.7-C.sub.20 aralkoxy; heteroaralkoxy
including 6-20 atoms; mercapto; cyano; --C(O)R.sup.g,
--C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g;
--C(S)SR.sup.g; --SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e;
--NR.sup.hC(O)R.sup.i; or --OC(O)NR.sup.dR.sup.e; or 2 R.sup.b'
together form C.sub.1-C.sub.3 alkylenedioxy; R.sup.c at each
occurrence is, independently: (i) halo; nitro; hydroxy;
C.sub.1-C.sub.12 alkoxy optionally substituted with 1-5 R.sup.f;
C.sub.1-C.sub.12 haloalkoxy; cyano; SO.sub.2R.sup.m; or 2 R.sup.c
together form C.sub.1-C.sub.3 alkylenedioxy; or (ii)
C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl; each of which
is optionally substituted with from 1-5 R.sup.j; or (iii)
C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16 cycloalkyl;
heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16 cycloalkenyl;
heterocyclyl including 3-16 atoms; or heterocycloalkenyl including
3-16 atoms; each of which is optionally substituted with from 1-10
R.sup.b; or (iv) C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20
alkynyl; or (v) C.sub.6-C.sub.16 aryl or heteroaryl including 5-16
atoms, each of which is optionally substituted with from 1-10
R.sup.a; each of R.sup.d, R.sup.e, R.sup.g, R.sup.h, and R.sup.k,
at each occurrence is, independently: (i) hydrogen; or (ii)
C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl; each of which
is optionally substituted with from 1-5 R.sup.j; or (iii)
C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16 cycloalkyl;
heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16 cycloalkenyl;
heterocyclyl including 3-16 atoms; or heterocycloalkenyl including
3-16 atoms; each of which is optionally substituted with from 1-10
R.sup.b; or (iv) C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20
alkynyl; or (v) C.sub.6-C.sub.16 aryl or heteroaryl including 5-16
atoms, each of which is optionally substituted with from 1-10
R.sup.a; R.sup.f is NR.sup.dR.sup.e; nitro; azido; hydroxy; oxo,
thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12 alkoxy or C.sub.1-C.sub.12
thioalkoxy, each of which is optionally substituted with 1-5
R.sup.f; C.sub.1-C.sub.12 haloalkoxy; C.sub.6-C.sub.16 aryloxy,
C.sub.6-C.sub.16 thioaryloxy, heteroaryloxy including 5-20 atoms,
or thioaryloxy including 5-20 atoms, each of which is optionally
substituted with 1-5 R.sup.a'; C.sub.2-C.sub.12 alkenyloxy;
C.sub.2-C.sub.12 alkynyloxy; C.sub.3-C.sub.16 cycloalkyloxy,
C.sub.3-C.sub.16 cycloalkenyloxy, heterocyclyloxy including 3-16
atoms, heterocycloalkenyloxy including 3-16 atoms, C.sub.7-C.sub.20
aralkoxy, or heteroaralkoxy including 6-20 atoms, each of which is
optionally substituted with 1-5 R.sup.b; mercapto; cyano;
--C(O)R.sup.g, --OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g;
--C(S)SR.sup.g; --SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e;
--NR.sup.hC(O)R.sup.i; --OC(O)NR.sup.dR.sup.e; R.sup.i is R.sup.g;
OR.sup.g; or NR.sup.dR.sup.e; R.sup.j is NR.sup.dR.sup.e; nitro;
azido; hydroxy; oxo; thioxo; .dbd.NR.sup.k; C.sub.1-C.sub.12 alkoxy
or C.sub.1-C.sub.12 thioalkoxy, each of which is optionally
substituted with 1-5 R.sup.f; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy,
heteroaryloxy including 5-20 atoms, or thioaryloxy including 5-20
atoms, each of which is optionally substituted with 1-5 R.sup.a';
C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy, C.sub.3-C.sub.16 cycloalkenyloxy,
heterocyclyloxy including 3-16 atoms, heterocycloalkenyloxy
including 3-16 atoms, C.sub.7-C.sub.20 aralkoxy, or heteroaralkoxy
including 6-20 atoms, each of which is optionally substituted with
1-5 R.sup.b; mercapto; cyano; C.sub.1-C.sub.3 alkylenedioxy;
--C(O)R.sup.g, --C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g;
--SC(O)R.sup.g; --C(S)SR.sup.g; --SC(S)R.sup.g;
--C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; R.sup.m is (i) C.sub.1-C.sub.12 alkyl or
C.sub.1-C.sub.12 haloalkyl; each of which is optionally substituted
with from 1-5 R.sup.j; or (ii) C.sub.7-C.sub.20 aralkyl;
C.sub.3-C.sub.16 cycloalkyl; heteroaralkyl including 6-20 atoms;
C.sub.3-C.sub.16 cycloalkenyl; heterocyclyl including 3-16 atoms;
or heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or (iii)
C.sub.6-C.sub.16 aryl or heteroaryl including 5-16 atoms, each of
which is optionally substituted with from 1-10 R.sup.a; and
provided: (a) when V and Y are both N, and R.sup.2 is substituted
pyridyl or pyrimidinyl, then R.sup.c cannot be C.sub.1-C.sub.12
alkoxy optionally substituted with 1-5 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; or SO.sub.2R.sup.m; and (b) when V and Y are both N, X
is SO.sub.2, one of Z.sup.1 and W.sup.2 is CH.sub.3, and R.sup.2 is
phenyl substituted with from 1-5 R.sup.c, then 1 R.sup.c must be
halo; C.sub.1-C.sub.12 haloalkoxy; cyano; or C.sub.1-C.sub.12
haloalkyl, optionally substituted with from 1-5 R.sup.j; or a
pharmaceutically acceptable salt and/or N-oxide thereof.
104. The method of claim 103, wherein the disease or condition is
type 2 diabetes.
105. The method of claim 103, wherein the disease or condition is
Syndrome X.
106. The method of claim 103, wherein the disease or condition is
obesity.
107. The method of claim 103, wherein the disease or condition is
selected from dyslipidemia, hyperlipidemia, hypertriglyceridemia,
hypercholesterolemia, low HDL and high LDL.
108. The method of claim 103, wherein the disease or condition is
atherosclerosis.
109. The method of claim 103, wherein the disease or condition is a
cognitive disorder.
110. The method of claim 109, wherein the cognitive disorder is
Alzheimer's disease.
111. A method for promoting wound healing, the method comprising
administering to a subject in need thereof an effective amount of a
compound of formula I: ##STR00067## wherein: R.sup.1 is: (i)
C.sub.6-C.sub.18 aryl or heteroaryl including 5-20 atoms, each of
which is optionally substituted with from 1-10 R.sup.a; or (ii)
C.sub.7-C.sub.20 aralkyl; heteroaralkyl including 6-20 atoms;
arylheterocyclyl including 8-20 atoms; arylcycloalkenyl including
8-20 atoms; or arylheterocycloalkenyl including 8-20 atoms; each of
which is optionally substituted with from 1-10 R.sup.b; R.sup.2 is
C.sub.6-C.sub.18 aryl or heteroaryl including 5-20 atoms, each of
which is optionally substituted with from 1-10 R.sup.c; X is
S(O).sub.n or S(O).sub.nNR.sup.6, wherein n is 1 or 2, and R.sup.6
is hydrogen, C.sub.1-C.sub.12 alkyl, or C.sub.3-C.sub.16
cycloalkyl; each of V and Y is, independently, CR.sup.7 or N,
wherein R.sup.7 is hydrogen or C.sub.1-C.sub.12 alkyl, provided
that Y and V cannot both be CR.sup.7; one, two, three, or four of
W.sup.1, Z.sup.1, W.sup.2, and Z.sup.2 are each, independently: (i)
C.sub.1-C.sub.12 alkyl; or (ii) oxo; or (iii) C.sub.6-C.sub.18 aryl
or heteroaryl including 5-20 atoms, each of which is optionally
substituted with from 1-10 R.sup.a; or (iv) C.sub.7-C.sub.20
aralkyl; C.sub.3-C.sub.16 cycloalkyl; heteroaralkyl including 6-20
atoms; C.sub.3-C.sub.16 cycloalkenyl; heterocyclyl including 3-16
atoms; or heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; and the others are
hydrogen; R.sup.a at each occurrence is, independently: (i) halo;
NR.sup.dR.sup.e; nitro; azido; hydroxy; C.sub.1-C.sub.12 alkoxy or
C.sub.1-C.sub.12 thioalkoxy, each of which is optionally
substituted with 1-5 R.sup.f; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy,
heteroaryloxy including 5-20 atoms, or thioaryloxy including 5-20
atoms, each of which is optionally substituted with 1-5 R.sup.a';
C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy, C.sub.3-C.sub.16 cycloalkenyloxy,
heterocyclyloxy including 3-16 atoms, heterocycloalkenyloxy
including 3-16 atoms, C.sub.7-C.sub.20 aralkoxy, or heteroaralkoxy
including 6-20 atoms, each of which is optionally substituted with
1-5 R.sup.b; mercapto; cyano; --C(O)R.sup.g, --C(O)OR.sup.g;
--OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g; --C(S)SR.sup.g;
--SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; or 2 R.sup.a together form C.sub.1-C.sub.3
alkylenedioxy; (ii) C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12
haloalkyl; each of which is optionally substituted with from 1-5
R.sup.j; or (iii) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16
cycloalkyl; heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or (iv)
C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20 alkynyl; or (v)
C.sub.6-C.sub.16 aryl or heteroaryl including 5-16 atoms, each of
which is optionally substituted with from 1-10 R.sup.a'; R.sup.a'
at each occurrence is, independently, C.sub.1-C.sub.12 alkyl,
C.sub.1-C.sub.12 haloalkyl, C.sub.2-C.sub.12 alkenyl;
C.sub.2-C.sub.12 alkynyl; C.sub.3-C.sub.16 cycloalkyl;
C.sub.3-C.sub.16 cycloalkenyl, heterocyclyl including 3-16 atoms,
heterocycloalkenyl including 3-16 atoms; C.sub.7-C.sub.20 aralkyl;
C.sub.6-C.sub.16 aryl; heteroaryl including 5-16 atoms; halo;
NR.sup.dR.sup.e; nitro; azido, hydroxy; C.sub.1-C.sub.12 alkoxy;
C.sub.1-C.sub.12 thioalkoxy; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy;
heteroaryloxy including 5-20 atoms; thioaryloxy including 5-20
atoms; C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy; C.sub.3-C.sub.16 cycloalkenyloxy;
heterocyclyloxy including 3-16 atoms; heterocycloalkenyloxy
including 3-16 atoms; C.sub.7-C.sub.20 aralkoxy; heteroaralkoxy
including 6-20 atoms; mercapto; cyano; --C(O)R.sup.g,
--C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g;
--C(S)SR.sup.g; --SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e;
--NR.sup.hC(O)R.sup.i; --OC(O)NR.sup.dR.sup.e; or 2 R.sup.a'
together form C.sub.1-C.sub.3 alkylenedioxy; or 2 R.sup.a' together
form C.sub.1-C.sub.3 alkylenedioxy; R.sup.b at each occurrence is,
independently: (i) halo; NR.sup.dR.sup.e; nitro; azido; hydroxy;
oxo, thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12 alkoxy or
C.sub.1-C.sub.12 thioalkoxy, each of which is optionally
substituted with 1-5 R.sup.f; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy,
heteroaryloxy including 5-20 atoms, or thioaryloxy including 5-20
atoms, each of which is optionally substituted with 1-5 R.sup.a;
C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy, C.sub.3-C.sub.16 cycloalkenyloxy,
heterocyclyloxy including 3-16 atoms, heterocycloalkenyloxy
including 3-16 atoms, C.sub.7-C.sub.20 aralkoxy, or heteroaralkoxy
including 6-20 atoms, each of which is optionally substituted with
1-5 R.sup.b'; mercapto; cyano; --C(O)R.sup.g, --C(O)OR.sup.g;
--OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g; --C(S)SR.sup.g;
--SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; or 2 R.sup.b together form C.sub.1-C.sub.3
alkylenedioxy; or (ii) C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12
haloalkyl; each of which is optionally substituted with from 1-5
R.sup.j; or (iii) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16
cycloalkyl; heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b'; or (iv)
C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20 alkynyl; or (v)
C.sub.6-C.sub.16 aryl or heteroaryl including 5-16 atoms, each of
which is optionally substituted with from 1-10 R.sup.a; R.sup.b' at
each occurrence is, independently, C.sub.1-C.sub.12 alkyl or
C.sub.1-C.sub.12 haloalkyl, each of which is optionally substituted
with 1-5 R.sup.j; C.sub.2-C.sub.12 alkenyl; C.sub.2-C.sub.12
alkynyl; C.sub.3-C.sub.16 cycloalkyl; C.sub.3-C.sub.16
cycloalkenyl, heterocyclyl including 3-16 atoms, heterocycloalkenyl
including 3-16 atoms; C.sub.7-C.sub.20 aralkyl; C.sub.6-C.sub.16
aryl; heteroaryl including 5-16 atoms; halo; NR.sup.dR.sup.e;
nitro; azido, hydroxy; oxo, thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12
alkoxy; C.sub.1-C.sub.12 thioalkoxy; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy;
heteroaryloxy including 5-20 atoms; thioaryloxy including 5-20
atoms; C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy; C.sub.3-C.sub.16 cycloalkenyloxy;
heterocyclyloxy including 3-16 atoms; heterocycloalkenyloxy
including 3-16 atoms; C.sub.7-C.sub.20 aralkoxy; heteroaralkoxy
including 6-20 atoms; mercapto; cyano; --C(O)R.sup.g,
--C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g;
--C(S)SR.sup.g; --SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e;
--NR.sup.hC(O)R.sup.i; or --OC(O)NR.sup.dR.sup.e; or 2 R.sup.b'
together form C.sub.1-C.sub.3 alkylenedioxy; R.sup.c at each
occurrence is, independently: (i) halo; nitro; hydroxy;
C.sub.1-C.sub.12 alkoxy optionally substituted with 1-5 R.sup.f;
C.sub.1-C.sub.12 haloalkoxy; cyano; SO.sub.2R.sup.m; or 2 R.sup.c
together form C.sub.1-C.sub.3 alkylenedioxy; or (ii)
C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl; each of which
is optionally substituted with from 1-5 R.sup.j; or (iii)
C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16 cycloalkyl;
heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16 cycloalkenyl;
heterocyclyl including 3-16 atoms; or heterocycloalkenyl including
3-16 atoms; each of which is optionally substituted with from 1-10
R.sup.b; or (iv) C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20
alkynyl; or (v) C.sub.6-C.sub.16 aryl or heteroaryl including 5-16
atoms, each of which is optionally substituted with from 1-10
R.sup.a; each of R.sup.d, R.sup.e, R.sup.g, R.sup.h, and R.sup.k,
at each occurrence is, independently: (i) hydrogen; or (ii)
C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl; each of which
is optionally substituted with from 1-5 R.sup.j; or (iii)
C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16 cycloalkyl;
heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16 cycloalkenyl;
heterocyclyl including 3-16 atoms; or heterocycloalkenyl including
3-16 atoms; each of which is optionally substituted with from 1-10
R.sup.b; or (iv) C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20
alkynyl; or (v) C.sub.6-C.sub.16 aryl or heteroaryl including 5-16
atoms, each of which is optionally substituted with from 1-10
R.sup.a; R.sup.f is NR.sup.dR.sup.e; nitro; azido; hydroxy; oxo,
thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12 alkoxy or C.sub.1-C.sub.12
thioalkoxy, each of which is optionally substituted with 1-5
R.sup.f; C.sub.1-C.sub.12 haloalkoxy; C.sub.6-C.sub.16 aryloxy,
C.sub.6-C.sub.16 thioaryloxy, heteroaryloxy including 5-20 atoms,
or thioaryloxy including 5-20 atoms, each of which is optionally
substituted with 1-5 R.sup.a'; C.sub.2-C.sub.12 alkenyloxy;
C.sub.2-C.sub.12 alkynyloxy; C.sub.3-C.sub.16 cycloalkyloxy,
C.sub.3-C.sub.16 cycloalkenyloxy, heterocyclyloxy including 3-16
atoms, heterocycloalkenyloxy including 3-16 atoms, C.sub.7-C.sub.20
aralkoxy, or heteroaralkoxy including 6-20 atoms, each of which is
optionally substituted with 1-5 R.sup.b; mercapto; cyano;
--C(O)R.sup.g, --OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g;
--C(S)SR.sup.g; --SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e;
--NR.sup.hC(O)R.sup.i; --OC(O)NR.sup.dR.sup.e; R.sup.i is R.sup.g;
OR.sup.g; or NR.sup.dR.sup.e; R.sup.j is NR.sup.dR.sup.e; nitro;
azido; hydroxy; oxo; thioxo; .dbd.NR.sup.k; C.sub.1-C.sub.12 alkoxy
or C.sub.1-C.sub.12 thioalkoxy, each of which is optionally
substituted with 1-5 R.sup.f; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy,
heteroaryloxy including 5-20 atoms, or thioaryloxy including 5-20
atoms, each of which is optionally substituted with 1-5 R.sup.a';
C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy, C.sub.3-C.sub.16 cycloalkenyloxy,
heterocyclyloxy including 3-16 atoms, heterocycloalkenyloxy
including 3-16 atoms, C.sub.7-C.sub.20 aralkoxy, or heteroaralkoxy
including 6-20 atoms, each of which is optionally substituted with
1-5 R.sup.b; mercapto; cyano; C.sub.1-C.sub.3 alkylenedioxy;
--C(O)R.sup.g, --C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g;
--SC(O)R.sup.g; --C(S)SR.sup.g; --SC(S)R.sup.g;
--C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; R.sup.m is (i) C.sub.1-C.sub.12 alkyl or
C.sub.1-C.sub.12 haloalkyl; each of which is optionally substituted
with from 1-5 R.sup.j; or (ii) C.sub.7-C.sub.20 aralkyl;
C.sub.3-C.sub.16 cycloalkyl; heteroaralkyl including 6-20 atoms;
C.sub.3-C.sub.16 cycloalkenyl; heterocyclyl including 3-16 atoms;
or heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or (iii)
C.sub.6-C.sub.16 aryl or heteroaryl including 5-16 atoms, each of
which is optionally substituted with from 1-10 R.sup.a; and
provided: (a) when V and Y are both N, and R.sup.2 is substituted
pyridyl or pyrimidinyl, then R.sup.c cannot be C.sub.1-C.sub.12
alkoxy optionally substituted with 1-5 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; or SO.sub.2R.sup.m; and (b) when V and Y are both N, X
is SO.sub.2, one of Z.sup.1 and W.sup.2 is CH.sub.3, and R.sup.2 is
phenyl substituted with from 1-5 R.sup.c, then 1 R.sup.c must be
halo; C.sub.1-C.sub.12 haloalkoxy; cyano; or C.sub.1-C.sub.12
haloalkyl, optionally substituted with from 1-5 R.sup.j; or a
pharmaceutically acceptable salt and/or N-oxide thereof.
112. A method for treating a disease or condition mediated by
excess or uncontrolled amounts of cortisol and/or other
corticosteroids, the method comprising administering to a subject
in need thereof an effective amount of a compound of formula (I):
##STR00068## wherein: R.sup.1 is: (i) C.sub.6-C.sub.18 aryl or
heteroaryl including 5-20 atoms, each of which is optionally
substituted with from 1-10 R.sup.a; or (ii) C.sub.7-C.sub.20
aralkyl or heteroaralkyl including 6-20 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; R.sup.2 is: (i)
C.sub.6-C.sub.18 aryl substituted with from 1-10 R.sup.c; or
heteroaryl including 5-20 atoms, optionally substituted with from
1-10 R.sup.c; or (iii) OR.sup.1; SR.sup.1; or NR.sup.3R.sup.4,
wherein R.sup.3 and R.sup.4 are each, independently, hydrogen or
R.sup.1; X is S(O).sub.n or S(O).sub.nNR.sup.6, wherein n is 1 or
2, and R.sup.6 is hydrogen, C.sub.1-C.sub.12 alkyl, or
C.sub.3-C.sub.16 cycloalkyl; each of V and Y is, independently,
CR.sup.7 or N, wherein R.sup.7 is hydrogen or C.sub.1-C.sub.12
alkyl, provided that Y and V cannot both be CR.sup.7; each of
W.sup.1, Z.sup.1, W.sup.2, and Z.sup.2 is hydrogen; R.sup.a at each
occurrence is, independently: (i) halo; NR.sup.dR.sup.e; nitro;
azido; hydroxy; C.sub.1-C.sub.12 alkoxy or C.sub.1-C.sub.12
thioalkoxy, each of which is optionally substituted with 1-5
R.sup.f; C.sub.1-C.sub.12 haloalkoxy; C.sub.6-C.sub.16 aryloxy,
C.sub.6-C.sub.16 thioaryloxy, heteroaryloxy including 5-20 atoms,
or thioaryloxy including 5-20 atoms, each of which is optionally
substituted with 1-5 R.sup.a'; C.sub.2-C.sub.12 alkenyloxy;
C.sub.2-C.sub.12 alkynyloxy; C.sub.3-C.sub.16 cycloalkyloxy,
C.sub.3-C.sub.16 cycloalkenyloxy, heterocyclyloxy including 3-16
atoms, heterocycloalkenyloxy including 3-16 atoms, C.sub.7-C.sub.20
aralkoxy, or heteroaralkoxy including 6-20 atoms, each of which is
optionally substituted with 1-5 R.sup.b; mercapto; cyano;
--C(O)R.sup.g, --C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g;
--SC(O)R.sup.g; --C(S)SR.sup.g; --SC(S)R.sup.g;
--C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; or 2 R.sup.a together form C.sub.1-C.sub.3
alkylenedioxy; (ii) C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12
haloalkyl; each of which is optionally substituted with from 1-5
R.sup.j; or (iii) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16
cycloalkyl; heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or (iv)
C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20 alkynyl; or (v)
C.sub.6-C.sub.16 aryl or heteroaryl including 5-16 atoms, each of
which is optionally substituted with from 1-10 R.sup.a'; R.sup.a'
at each occurrence is, independently, C.sub.1-C.sub.12 alkyl,
C.sub.1-C.sub.12 haloalkyl, C.sub.2-C.sub.12 alkenyl;
C.sub.2-C.sub.12 alkynyl; C.sub.3-C.sub.16 cycloalkyl;
C.sub.3-C.sub.16 cycloalkenyl, heterocyclyl including 3-16 atoms,
heterocycloalkenyl including 3-16 atoms; C.sub.7-C.sub.20 aralkyl;
C.sub.6-C.sub.16 aryl; heteroaryl including 5-16 atoms; halo;
NR.sup.dR.sup.e; nitro; azido, hydroxy; C.sub.1-C.sub.12 alkoxy;
C.sub.1-C.sub.12 thioalkoxy; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy;
heteroaryloxy including 5-20 atoms; thioaryloxy including 5-20
atoms; C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy; C.sub.3-C.sub.16 cycloalkenyloxy;
heterocyclyloxy including 3-16 atoms; heterocycloalkenyloxy
including 3-16 atoms; C.sub.7-C.sub.20 aralkoxy; heteroaralkoxy
including 6-20 atoms; mercapto; cyano; --C(O)R.sup.g,
--C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g;
--C(S)SR.sup.g; --SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e;
--NR.sup.hC(O)R.sup.i; --OC(O)NR.sup.dR.sup.e; or 2 R.sup.a'
together form C.sub.1-C.sub.3 alkylenedioxy; or 2 R.sup.a' together
form C.sub.1-C.sub.3 alkylenedioxy; R.sup.b at each occurrence is,
independently: (i) halo; NR.sup.dR.sup.e; nitro; azido; hydroxy;
oxo, thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12 alkoxy or
C.sub.1-C.sub.12 thioalkoxy, each of which is optionally
substituted with 1-5 R.sup.f; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy,
heteroaryloxy including 5-20 atoms, or thioaryloxy including 5-20
atoms, each of which is optionally substituted with 1-5 R.sup.a;
C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy, C.sub.3-C.sub.16 cycloalkenyloxy,
heterocyclyloxy including 3-16 atoms, heterocycloalkenyloxy
including 3-16 atoms, C.sub.7-C.sub.20 aralkoxy, or heteroaralkoxy
including 6-20 atoms, each of which is optionally substituted with
1-5 R.sup.b'; mercapto; cyano; --C(O)R.sup.g, --C(O)OR.sup.g;
--OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g; --C(S)SR.sup.g;
--SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; or 2 R.sup.b together form C.sub.1-C.sub.3
alkylenedioxy; or (ii) C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12
haloalkyl; each of which is optionally substituted with from 1-5
R.sup.j; or (iii) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16
cycloalkyl; heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b'; or (iv)
C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20 alkynyl; or (v)
C.sub.6-C.sub.16 aryl or heteroaryl including 5-16 atoms, each of
which is optionally substituted with from 1-10 R.sup.a; R.sup.b' at
each occurrence is, independently, C.sub.1-C.sub.12 alkyl or
C.sub.1-C.sub.12 haloalkyl, each of which is optionally substituted
with 1-5 R.sup.j; C.sub.2-C.sub.12 alkenyl; C.sub.2-C.sub.12
alkynyl; C.sub.3-C.sub.16 cycloalkyl; C.sub.3-C.sub.16
cycloalkenyl, heterocyclyl including 3-16 atoms, heterocycloalkenyl
including 3-16 atoms; C.sub.7-C.sub.20 aralkyl; C.sub.6-C.sub.16
aryl; heteroaryl including 5-16 atoms; halo; NR.sup.dR.sup.e;
nitro; azido, hydroxy; oxo, thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12
alkoxy; C.sub.1-C.sub.12 thioalkoxy; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy;
heteroaryloxy including 5-20 atoms; thioaryloxy including 5-20
atoms; C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy; C.sub.3-C.sub.16 cycloalkenyloxy;
heterocyclyloxy including 3-16 atoms; heterocycloalkenyloxy
including 3-16 atoms; C.sub.7-C.sub.20 aralkoxy; heteroaralkoxy
including 6-20 atoms; mercapto; cyano; --C(O)R.sup.g,
--C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g;
--C(S)SR.sup.g; --SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e;
--NR.sup.hC(O)R.sup.i; or --OC(O)NR.sup.dR.sup.e; or 2 R.sup.b'
together form C.sub.1-C.sub.3 alkylenedioxy; R.sup.c at each
occurrence is, independently: (i) halo; nitro; hydroxy;
C.sub.1-C.sub.12 alkoxy optionally substituted with 1-5 R.sup.f;
C.sub.1-C.sub.12 haloalkoxy; cyano; SO.sub.2R.sup.m; or 2 R.sup.c
together form C.sub.1-C.sub.3 alkylenedioxy; or (ii)
C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl; each of which
is optionally substituted with from 1-5 R.sup.j; or (iii)
C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16 cycloalkyl;
heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16 cycloalkenyl;
heterocyclyl including 3-16 atoms; or heterocycloalkenyl including
3-16 atoms; each of which is optionally substituted with from 1-10
R.sup.b; or (iv) C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20
alkynyl; or (v) C.sub.6-C.sub.16 aryl or heteroaryl including 5-16
atoms, each of which is optionally substituted with from 1-10
R.sup.a; each of R.sup.d, R.sup.e, R.sup.f, R.sup.g, R.sup.h, and
R.sup.k, at each occurrence is, independently: (i) hydrogen; or
(ii) C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl; each of
which is optionally substituted with from 1-5 R.sup.j; or (iii)
C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16 cycloalkyl;
heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16 cycloalkenyl;
heterocyclyl including 3-16 atoms; or heterocycloalkenyl including
3-16 atoms; each of which is optionally substituted with from 1-10
R.sup.b; or (iv) C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20
alkynyl; or (v) C.sub.6-C.sub.16 aryl or heteroaryl including 5-16
atoms, each of which is optionally substituted with from 1-10
R.sup.a; R.sup.f is NR.sup.dR.sup.e; nitro; azido; hydroxy; oxo,
thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12 alkoxy or C.sub.1-C.sub.12
thioalkoxy, each of which is optionally substituted with 1-5
R.sup.f; C.sub.1-C.sub.12 haloalkoxy; C.sub.6-C.sub.16 aryloxy,
C.sub.6-C.sub.16 thioaryloxy, heteroaryloxy including 5-20 atoms,
or thioaryloxy including 5-20 atoms, each of which is optionally
substituted with 1-5 R.sup.a'; C.sub.2-C.sub.12 alkenyloxy;
C.sub.2-C.sub.12 alkynyloxy; C.sub.3-C.sub.16 cycloalkyloxy,
C.sub.3-C.sub.16 cycloalkenyloxy, heterocyclyloxy including 3-16
atoms, heterocycloalkenyloxy including 3-16 atoms, C.sub.7-C.sub.20
aralkoxy, or heteroaralkoxy including 6-20 atoms, each of which is
optionally substituted with 1-5 R.sup.b; mercapto; cyano;
--C(O)R.sup.g, --OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g;
--C(S)SR.sup.g; --SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e;
--NR.sup.hC(O)R.sup.i; --OC(O)NR.sup.dR.sup.e; R.sup.i is R.sup.g;
OR.sup.g; or NR.sup.dR.sup.e; R.sup.j is NR.sup.dR.sup.e; nitro;
azido; hydroxy; oxo, thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12 alkoxy
or C.sub.1-C.sub.12 thioalkoxy, each of which is optionally
substituted with 1-5 R.sup.f; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy,
heteroaryloxy including 5-20 atoms, or thioaryloxy including 5-20
atoms, each of which is optionally substituted with 1-5 R.sup.a';
C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy, C.sub.3-C.sub.16 cycloalkenyloxy,
heterocyclyloxy including 3-16 atoms, heterocycloalkenyloxy
including 3-16 atoms, C.sub.7-C.sub.20 aralkoxy, or heteroaralkoxy
including 6-20 atoms, each of which is optionally substituted with
1-5 R.sup.b; mercapto; cyano; C.sub.1-C.sub.3 alkylenedioxy;
--C(O)R.sup.g, --C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g;
--SC(O)R.sup.g; --C(S)SR.sup.g; --SC(S)R.sup.g;
--C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; R.sup.m is (i) C.sub.1-C.sub.12 alkyl or
C.sub.1-C.sub.12 haloalkyl; each of which is optionally substituted
with from 1-5 R.sup.j; or (ii) C.sub.7-C.sub.20 aralkyl;
C.sub.3-C.sub.16 cycloalkyl; heteroaralkyl including 6-20 atoms;
C.sub.3-C.sub.16 cycloalkenyl; heterocyclyl including 3-16 atoms;
or heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or (iii)
C.sub.6-C.sub.16 aryl or heteroaryl including 5-16 atoms, each of
which is optionally substituted with from 1-10 R.sup.a; and
provided: (a) when V and Y are both N, and R.sup.2 is substituted
pyridyl or pyrimidinyl, then R.sup.c cannot be C.sub.1-C.sub.12
alkoxy optionally substituted with 1-5 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; or SO.sub.2R.sup.m; and (b) when V and Y are both N and
X is SO.sub.2, then R.sup.1 cannot be 4-chlorophenyl; and (c) when
V and Y are both N and X is SO.sub.2, then R.sup.1 cannot be
1-chlorophenyl when R.sup.2 is: phenyl monosubstituted with
hydroxyl, C.sub.1-C.sub.6 alkoxy, chloro, or nitro; unsubstituted
pyridyl; pyridyl monosubstituted with hydroxyl, chloro, or nitro;
unsubstituted thiazolyl; thiazolyl monosubstituted with nitro or
hydroxymethyl; unsubstituted indolyl; or unsubstituted indazolyl;
and (d) when V and Y are both N and X is SO.sub.2, then R.sup.1
cannot be naphthyl when R.sup.2 is: unsubstituted pyridyl;
unsubstituted pyrimidinyl; phenyl monosubstituted with hydroxyl or
C.sub.1-C.sub.6 alkoxy; unsubstituted thiazolyl; or
5-chloro-2-methylphenyl; and (e) when Y is N and V is CH and X is
SO.sub.2, then R.sup.1 cannot be 1-chlorophenyl when R.sup.2 is:
phenyl monosubstituted with C.sub.1-C.sub.6 alkoxy or
C.sub.1-C.sub.6 alkyl; or substituted benzo[d]isoxazole; and (f)
when Y is N and V is CH and X is SO.sub.2, then R.sup.1 cannot be
naphthyl when R.sup.2 is phenyl monosubstituted with hydroxymethyl;
or a pharmaceutically acceptable salt and/or N-oxide thereof.
113. A method for treating a disease or condition mediated by
excess or uncontrolled amounts of cortisol and/or other
corticosteroids, the method comprising administering to a subject
in need thereof an effective amount of a compound of formula (I):
##STR00069## wherein: R.sup.1 is C.sub.7-C.sub.20 aralkyl,
C.sub.3-C.sub.16 cycloalkyl, or (C.sub.1-C.sub.12
alkyl)-(C.sub.3-C.sub.16 cycloalkyl), each of which is optionally
substituted with from 1-10 R.sup.b; R.sup.2 is: (i)
C.sub.6-C.sub.18 aryl or heteroaryl including 5-20 atoms, each of
which is optionally substituted with from 1-10 R.sup.c; or (ii)
OR.sup.1; SR.sup.1; or NR.sup.3R.sup.4, wherein R.sup.3 and R.sup.4
are each, independently, hydrogen or R.sup.1; X is CO; each of V
and Y is, independently, CR.sup.7 or N, wherein R.sup.7 is hydrogen
or C.sub.1-C.sub.12 alkyl, provided that Y and V cannot both be
CR.sup.7; each of W.sup.1, Z.sup.1, W.sup.2, and Z.sup.2 is,
independently: (i) hydrogen; or (ii) oxo; or (iii) C.sub.1-C.sub.12
alkyl; or (iv) C.sub.6-C.sub.18 aryl or heteroaryl including 5-20
atoms, each of which is optionally substituted with from 1-10
R.sup.a; or (v) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16
cycloalkyl; heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; R.sup.a at each
occurrence is, independently: (i) halo; NR.sup.dR.sup.e; nitro;
azido; hydroxy; C.sub.1-C.sub.12 alkoxy or C.sub.1-C.sub.12
thioalkoxy, each of which is optionally substituted with 1-5
R.sup.f; C.sub.1-C.sub.12 haloalkoxy; C.sub.6-C.sub.16 aryloxy,
C.sub.6-C.sub.16 thioaryloxy, heteroaryloxy including 5-20 atoms,
or thioaryloxy including 5-20 atoms, each of which is optionally
substituted with 1-5 R.sup.a'; C.sub.2-C.sub.12 alkenyloxy;
C.sub.2-C.sub.12 alkynyloxy; C.sub.3-C.sub.16 cycloalkyloxy,
C.sub.3-C.sub.16 cycloalkenyloxy, heterocyclyloxy including 3-16
atoms, heterocycloalkenyloxy including 3-16 atoms, C.sub.7-C.sub.20
aralkoxy, or heteroaralkoxy including 6-20 atoms, each of which is
optionally substituted with 1-5 R.sup.b; mercapto; cyano;
--C(O)R.sup.g, --C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g;
--SC(O)R.sup.g; --C(S)SR.sup.g; --SC(S)R.sup.g;
--C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; or 2 R.sup.a together form C.sub.1-C.sub.3
alkylenedioxy; (ii) C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12
haloalkyl; each of which is optionally substituted with from 1-5
R.sup.j; or (iii) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16
cycloalkyl; heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or (iv)
C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20 alkynyl; or (v)
C.sub.6-C.sub.16 aryl or heteroaryl including 5-16 atoms, each of
which is optionally substituted with from 1-10 R.sup.a'; R.sup.a'
at each occurrence is, independently, C.sub.1-C.sub.12 alkyl,
C.sub.1-C.sub.12 haloalkyl, C.sub.2-C.sub.12 alkenyl;
C.sub.2-C.sub.12 alkynyl; C.sub.3-C.sub.16 cycloalkyl;
C.sub.3-C.sub.16 cycloalkenyl, heterocyclyl including 3-16 atoms,
heterocycloalkenyl including 3-16 atoms; C.sub.7-C.sub.20 aralkyl;
C.sub.6-C.sub.16 aryl; heteroaryl including 5-16 atoms; halo;
NR.sup.dR.sup.e; nitro; azido, hydroxy; C.sub.1-C.sub.12 alkoxy;
C.sub.1-C.sub.12 thioalkoxy; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy;
heteroaryloxy including 5-20 atoms; thioaryloxy including 5-20
atoms; C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy; C.sub.3-C.sub.16 cycloalkenyloxy;
heterocyclyloxy including 3-16 atoms; heterocycloalkenyloxy
including 3-16 atoms; C.sub.7-C.sub.20 aralkoxy; heteroaralkoxy
including 6-20 atoms; mercapto; cyano; --C(O)R.sup.g,
--C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g;
--C(S)SR.sup.g; --SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e;
--NR.sup.hC(O)R.sup.i; --OC(O)NR.sup.dR.sup.e; or 2 R.sup.a'
together form C.sub.1-C.sub.3 alkylenedioxy; or 2 R.sup.a' together
form C.sub.1-C.sub.3 alkylenedioxy; R.sup.b at each occurrence is,
independently: (i) halo; NR.sup.dR.sup.e; nitro; azido; hydroxy;
oxo, thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12 alkoxy or
C.sub.1-C.sub.12 thioalkoxy, each of which is optionally
substituted with 1-5 R.sup.f; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy,
heteroaryloxy including 5-20 atoms, or thioaryloxy including 5-20
atoms, each of which is optionally substituted with 1-5 R.sup.a;
C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy, C.sub.3-C.sub.16 cycloalkenyloxy,
heterocyclyloxy including 3-16 atoms, heterocycloalkenyloxy
including 3-16 atoms, C.sub.7-C.sub.20 aralkoxy, or heteroaralkoxy
including 6-20 atoms, each of which is optionally substituted with
1-5 R.sup.b; mercapto; cyano; --C(O)R.sup.g, --C(O)OR.sup.g;
--OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g; --C(S)SR.sup.g;
--SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; or 2 R.sup.b together form C.sub.1-C.sub.3
alkylenedioxy; or (ii) C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12
haloalkyl; each of which is optionally substituted with from 1-5
R.sup.j; or (iii) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16
cycloalkyl; heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b'; or (iv)
C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20 alkynyl; or (v)
C.sub.6-C.sub.16 aryl or heteroaryl including 5-16 atoms, each of
which is optionally substituted with from 1-10 R.sup.a; R.sup.b' at
each occurrence is, independently, C.sub.1-C.sub.12 alkyl or
C.sub.1-C.sub.12 haloalkyl, each of which is optionally substituted
with 1-5 R.sup.j; C.sub.2-C.sub.12 alkenyl; C.sub.2-C.sub.12
alkynyl; C.sub.3-C.sub.16 cycloalkyl; C.sub.3-C.sub.16
cycloalkenyl, heterocyclyl including 3-16 atoms, heterocycloalkenyl
including 3-16 atoms; C.sub.7-C.sub.20 aralkyl; C.sub.6-C.sub.16
aryl; heteroaryl including 5-16 atoms; halo; NR.sup.dR.sup.e;
nitro; azido, hydroxy; oxo, thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12
alkoxy; C.sub.1-C.sub.12 thioalkoxy; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy;
heteroaryloxy including 5-20 atoms; thioaryloxy including 5-20
atoms; C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy; C.sub.3-C.sub.16 cycloalkenyloxy;
heterocyclyloxy including 3-16 atoms; heterocycloalkenyloxy
including 3-16 atoms; C.sub.7-C.sub.20 aralkoxy; heteroaralkoxy
including 6-20 atoms; mercapto; cyano; --C(O)R.sup.g,
--C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g;
--C(S)SR.sup.g; --SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e;
--NR.sup.hC(O)R.sup.i; or --OC(O)NR.sup.dR.sup.e; or 2 R.sup.b'
together form C.sub.1-C.sub.3 alkylenedioxy; R.sup.c at each
occurrence is, independently: (i) halo; nitro; hydroxy;
C.sub.1-C.sub.12 alkoxy optionally substituted with 1-5 R.sup.f;
C.sub.1-C.sub.12 haloalkoxy; cyano; SO.sub.2R.sup.m; or 2 R.sup.c
together form C.sub.1-C.sub.3 alkylenedioxy; or (ii)
C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl; each of which
is optionally substituted with from 1-5 R.sup.j; or (iii)
C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16 cycloalkyl;
heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16 cycloalkenyl;
heterocyclyl including 3-16 atoms; or heterocycloalkenyl including
3-16 atoms; each of which is optionally substituted with from 1-10
R.sup.b; or (iv) C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20
alkynyl; or (v) C.sub.6-C.sub.16 aryl or heteroaryl including 5-16
atoms, each of which is optionally substituted with from 1-10
R.sup.a; each of R.sup.d, R.sup.e, R.sup.g, R.sup.h, and R.sup.k,
at each occurrence is, independently: (i) hydrogen; or (ii)
C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl; each of which
is optionally substituted with from 1-5 R.sup.j; or (iii)
C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16 cycloalkyl;
heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16 cycloalkenyl;
heterocyclyl including 3-16 atoms; or heterocycloalkenyl including
3-16 atoms; each of which is optionally substituted with from 1-10
R.sup.b; or (iv) C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20
alkynyl; or (v) C.sub.6-C.sub.16 aryl or heteroaryl including 5-16
atoms, each of which is optionally substituted with from 1-10
R.sup.a; R.sup.f is NR.sup.dR.sup.e; nitro; azido; hydroxy; oxo,
thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12 alkoxy or C.sub.1-C.sub.12
thioalkoxy, each of which is optionally substituted with 1-5
R.sup.f; C.sub.1-C.sub.12 haloalkoxy; C.sub.6-C.sub.16 aryloxy,
C.sub.6-C.sub.16 thioaryloxy, heteroaryloxy including 5-20 atoms,
or thioaryloxy including 5-20 atoms, each of which is optionally
substituted with 1-5 R.sup.a'; C.sub.2-C.sub.12 alkenyloxy;
C.sub.2-C.sub.12 alkynyloxy; C.sub.3-C.sub.16 cycloalkyloxy,
C.sub.3-C.sub.16 cycloalkenyloxy, heterocyclyloxy including 3-16
atoms, heterocycloalkenyloxy including 3-16 atoms, C.sub.7-C.sub.20
aralkoxy, or heteroaralkoxy including 6-20 atoms, each of which is
optionally substituted with 1-5 R.sup.b; mercapto; cyano;
--C(O)R.sup.g, --OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g;
--C(S)SR.sup.g; --SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e;
--NR.sup.hC(O)R.sup.i; --OC(O)NR.sup.dR.sup.e; R.sup.i is R.sup.g;
OR.sup.g; or NR.sup.dR.sup.e; R.sup.j is NR.sup.dR.sup.e; nitro;
azido; hydroxy; oxo, thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12 alkoxy
or C.sub.1-C.sub.12 thioalkoxy, each of which is optionally
substituted with 1-5 R.sup.f; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy,
heteroaryloxy including 5-20 atoms, or thioaryloxy including 5-20
atoms, each of which is optionally substituted with 1-5 R.sup.a';
C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy, C.sub.3-C.sub.16 cycloalkenyloxy,
heterocyclyloxy including 3-16 atoms, heterocycloalkenyloxy
including 3-16 atoms, C.sub.7-C.sub.20 aralkoxy, or heteroaralkoxy
including 6-20 atoms, each of which is optionally substituted with
1-5 R.sup.b; mercapto; cyano; C.sub.1-C.sub.3 alkylenedioxy;
--C(O)R.sup.g, --C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g;
--SC(O)R.sup.g; --C(S)SR.sup.g; --SC(S)R.sup.g;
--C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; and R.sup.m is (i) C.sub.1-C.sub.12 alkyl
or C.sub.1-C.sub.12 haloalkyl; each of which is optionally
substituted with from 1-5 R.sup.j; or (ii) C.sub.7-C.sub.20
aralkyl; C.sub.3-C.sub.16 cycloalkyl; heteroaralkyl including 6-20
atoms; C.sub.3-C.sub.16 cycloalkenyl; heterocyclyl including 3-16
atoms; or heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or (iii)
C.sub.6-C.sub.16 aryl or heteroaryl including 5-16 atoms, each of
which is optionally substituted with from 1-10 R.sup.a; or a
pharmaceutically acceptable salt and/or N-oxide thereof.
114. A method for treating a disease or condition mediated by
excess or uncontrolled amounts of cortisol and/or other
corticosteroids, the method comprising administering to a subject
in need thereof an effective amount of a compound of formula (I):
##STR00070## wherein: R.sup.1 is C.sub.6-C.sub.18 aryl or
heteroaryl including 5-20 atoms, each of which is optionally
substituted with from 1-10 R.sup.a; R.sup.2 is C.sub.6-C.sub.16
cycloalkyl; C.sub.6-C.sub.16 cycloalkenyl; heterocyclyl including
3-16 atoms; or heterocycloalkenyl including 3-16 atoms; each of
which is optionally substituted with from 1-10 R.sup.b; X is
S(O).sub.n or S(O).sub.nNR.sup.6, wherein n is 1 or 2, and R.sup.6
is hydrogen, C.sub.1-C.sub.12 alkyl, or C.sub.3-C.sub.16
cycloalkyl; each of V and Y is, independently, CR.sup.7 or N,
wherein R.sup.7 is hydrogen or C.sub.1-C.sub.12 alkyl, provided
that Y and V cannot both be CR.sup.7; each of W.sup.1, Z.sup.1,
W.sup.2, and Z.sup.2 is, independently: (i) hydrogen; or (ii) oxo;
or (iii) C.sub.1-C.sub.12 alkyl; or (iv) C.sub.6-C.sub.18 aryl or
heteroaryl including 5-20 atoms, each of which is optionally
substituted with from 1-10 R.sup.a; or (v) C.sub.7-C.sub.20
aralkyl; C.sub.3-C.sub.16 cycloalkyl; heteroaralkyl including 6-20
atoms; C.sub.3-C.sub.16 cycloalkenyl; heterocyclyl including 3-16
atoms; or heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; R.sup.a at each
occurrence is, independently: (i) halo; NR.sup.dR.sup.e; nitro;
azido; hydroxy; C.sub.1-C.sub.12 alkoxy or C.sub.1-C.sub.12
thioalkoxy, each of which is optionally substituted with 1-5
R.sup.f; C.sub.1-C.sub.12 haloalkoxy; C.sub.6-C.sub.16 aryloxy,
C.sub.6-C.sub.16 thioaryloxy, heteroaryloxy including 5-20 atoms,
or thioaryloxy including 5-20 atoms, each of which is optionally
substituted with 1-5 R.sup.a'; C.sub.2-C.sub.12 alkenyloxy;
C.sub.2-C.sub.12 alkynyloxy; C.sub.3-C.sub.16 cycloalkyloxy,
C.sub.3-C.sub.16 cycloalkenyloxy, heterocyclyloxy including 3-16
atoms, heterocycloalkenyloxy including 3-16 atoms, C.sub.7-C.sub.20
aralkoxy, or heteroaralkoxy including 6-20 atoms, each of which is
optionally substituted with 1-5 R.sup.b; mercapto; cyano;
--C(O)R.sup.g, --C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g;
--SC(O)R.sup.g; --C(S)SR.sup.g; --SC(S)R.sup.g;
--C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; or 2 R.sup.a together form C.sub.1-C.sub.3
alkylenedioxy; (ii) C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12
haloalkyl; each of which is optionally substituted with from 1-5
R.sup.j; or (iii) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16
cycloalkyl; heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or (iv)
C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20 alkynyl; or (v)
C.sub.6-C.sub.16 aryl or heteroaryl including 5-16 atoms, each of
which is optionally substituted with from 1-10 R.sup.a'; R.sup.a'
at each occurrence is, independently, C.sub.1-C.sub.12 alkyl,
C.sub.1-C.sub.12 haloalkyl, C.sub.2-C.sub.12 alkenyl;
C.sub.2-C.sub.12 alkynyl; C.sub.3-C.sub.16 cycloalkyl;
C.sub.3-C.sub.16 cycloalkenyl, heterocyclyl including 3-16 atoms,
heterocycloalkenyl including 3-16 atoms; C.sub.7-C.sub.20 aralkyl;
C.sub.6-C.sub.16 aryl; heteroaryl including 5-16 atoms; halo;
NR.sup.dR.sup.e; nitro; azido, hydroxy; C.sub.1-C.sub.12 alkoxy;
C.sub.1-C.sub.12 thioalkoxy; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy;
heteroaryloxy including 5-20 atoms; thioaryloxy including 5-20
atoms; C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy; C.sub.3-C.sub.16 cycloalkenyloxy;
heterocyclyloxy including 3-16 atoms; heterocycloalkenyloxy
including 3-16 atoms; C.sub.7-C.sub.20 aralkoxy; heteroaralkoxy
including 6-20 atoms; mercapto; cyano; --C(O)R.sup.g,
--C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g;
--C(S)SR.sup.g; --SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e;
--NR.sup.hC(O)R.sup.i; --OC(O)NR.sup.dR.sup.e; or 2 R.sup.a'
together form C.sub.1-C.sub.3 alkylenedioxy; or 2 R.sup.a' together
form C.sub.1-C.sub.3 alkylenedioxy; R.sup.b at each occurrence is,
independently: (i) halo; NR.sup.dR.sup.e; nitro; azido; hydroxy;
oxo, thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12 alkoxy or
C.sub.1-C.sub.12 thioalkoxy, each of which is optionally
substituted with 1-5 R.sup.f; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy,
heteroaryloxy including 5-20 atoms, or thioaryloxy including 5-20
atoms, each of which is optionally substituted with 1-5 R.sup.a;
C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy, C.sub.3-C.sub.16 cycloalkenyloxy,
heterocyclyloxy including 3-16 atoms, heterocycloalkenyloxy
including 3-16 atoms, C.sub.7-C.sub.20 aralkoxy, or heteroaralkoxy
including 6-20 atoms, each of which is optionally substituted with
1-5 R.sup.b'; mercapto; cyano; --C(O)R.sup.g, --C(O)OR.sup.g;
--OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g; --C(S)SR.sup.g;
--SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; or 2 R.sup.b together form C.sub.1-C.sub.3
alkylenedioxy; or (ii) C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12
haloalkyl; each of which is optionally substituted with from 1-5
R.sup.j; or (iii) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16
cycloalkyl; heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b'; or (iv)
C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20 alkynyl; or (v)
C.sub.6-C.sub.16 aryl or heteroaryl including 5-16 atoms, each of
which is optionally substituted with from 1-10 R.sup.a; R.sup.b' at
each occurrence is, independently, C.sub.1-C.sub.12 alkyl or
C.sub.1-C.sub.12 haloalkyl, each of which is optionally substituted
with 1-5 R.sup.j; C.sub.2-C.sub.12 alkenyl; C.sub.2-C.sub.12
alkynyl; C.sub.3-C.sub.16 cycloalkyl; C.sub.3-C.sub.16
cycloalkenyl, heterocyclyl including 3-16 atoms, heterocycloalkenyl
including 3-16 atoms; C.sub.7-C.sub.20 aralkyl; C.sub.6-C.sub.16
aryl; heteroaryl including 5-16 atoms; halo; NR.sup.dR.sup.e;
nitro; azido, hydroxy; oxo, thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12
alkoxy; C.sub.1-C.sub.12 thioalkoxy; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy;
heteroaryloxy including 5-20 atoms; thioaryloxy including 5-20
atoms; C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy; C.sub.3-C.sub.16 cycloalkenyloxy;
heterocyclyloxy including 3-16 atoms; heterocycloalkenyloxy
including 3-16 atoms; C.sub.7-C.sub.20 aralkoxy; heteroaralkoxy
including 6-20 atoms; mercapto; cyano; --C(O)R.sup.g,
--C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g;
--C(S)SR.sup.g; --SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e;
--NR.sup.hC(O)R.sup.i; or --OC(O)NR.sup.dR.sup.e; or 2 R.sup.b'
together form C.sub.1-C.sub.3 alkylenedioxy; each of R.sup.d,
R.sup.e, R.sup.g, R.sup.h, and R.sup.k, at each occurrence is,
independently: (i) hydrogen; or (ii) C.sub.1-C.sub.12 alkyl or
C.sub.1-C.sub.12 haloalkyl; each of which is optionally substituted
with from 1-5 R.sup.j; or (iii) C.sub.7-C.sub.20 aralkyl;
C.sub.3-C.sub.16 cycloalkyl; heteroaralkyl including 6-20 atoms;
C.sub.3-C.sub.16 cycloalkenyl; heterocyclyl including 3-16 atoms;
or heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or (iv)
C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20 alkynyl; or (v)
C.sub.6-C.sub.16 aryl or heteroaryl including 5-16 atoms, each of
which is optionally substituted with from 1-10 R.sup.a; R.sup.f is
NR.sup.dR.sup.e; nitro; azido; hydroxy; oxo, thioxo, .dbd.NR.sup.k,
C.sub.1-C.sub.12 alkoxy or C.sub.1-C.sub.12 thioalkoxy, each of
which is optionally substituted with 1-5 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy,
heteroaryloxy including 5-20 atoms, or thioaryloxy including 5-20
atoms, each of which is optionally substituted with 1-5 R.sup.a';
C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy, C.sub.3-C.sub.16 cycloalkenyloxy,
heterocyclyloxy including 3-16 atoms, heterocycloalkenyloxy
including 3-16 atoms, C.sub.7-C.sub.20 aralkoxy, or heteroaralkoxy
including 6-20 atoms, each of which is optionally substituted with
1-5 R.sup.b; mercapto; cyano; --C(O)R.sup.g, --OC(O)R.sup.g;
--C(O)SR.sup.g; --SC(O)R.sup.g; --C(S)SR.sup.g; --SC(S)R.sup.g;
--C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; R.sup.i is R.sup.g; OR.sup.g; or
NR.sup.dR.sup.e; R.sup.j is NR.sup.dR.sup.e; nitro; azido; hydroxy;
oxo, thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12 alkoxy or
C.sub.1-C.sub.12 thioalkoxy, each of which is optionally
substituted with 1-5 R.sup.f; C.sub.1-C.sub.12 haloalkoxy;
C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy,
heteroaryloxy including 5-20 atoms, or thioaryloxy including 5-20
atoms, each of which is optionally substituted with 1-5 R.sup.a;
C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy, C.sub.3-C.sub.16 cycloalkenyloxy,
heterocyclyloxy including 3-16 atoms, heterocycloalkenyloxy
including 3-16 atoms, C.sub.7-C.sub.20 aralkoxy, or heteroaralkoxy
including 6-20 atoms, each of which is optionally substituted with
1-5 R.sup.b; mercapto; cyano; C.sub.1-C.sub.3 alkylenedioxy;
--C(O)R.sup.g, --C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g;
--SC(O)R.sup.g; --C(S)SR.sup.g; --SC(S)R.sup.g;
--C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; and R.sup.m is (i) C.sub.1-C.sub.12 alkyl
or C.sub.1-C.sub.12 haloalkyl; each of which is optionally
substituted with from 1-5 R.sup.j; or (ii) C.sub.7-C.sub.20
aralkyl; C.sub.3-C.sub.16 cycloalkyl; heteroaralkyl including 6-20
atoms; C.sub.3-C.sub.16 cycloalkenyl; heterocyclyl including 3-16
atoms; or heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or (iii)
C.sub.6-C.sub.16 aryl or heteroaryl including 5-16 atoms, each of
which is optionally substituted with from 1-10 R.sup.a; and
provided: (a) when V and Y are both N and X is SO.sub.2, then
R.sup.1 cannot be 1-chlorophenyl when R.sup.2 is unsubstituted
adamantyl or substituted or unsubstituted cyclohexyl; and (b) when
Y is N, V is CH, and X is SO.sub.2, then R.sup.1 cannot be
1-chlorophenyl when R.sup.2 is unsubstituted piperidyl, piperidyl
substituted with oxo, unsubstituted morpholinyl, or unsubstituted
pyrrolidinyl; or a pharmaceutically acceptable salt thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/771,262, filed on Feb. 7, 2006, which is
incorporated herein by reference in its entirety.
TECHNICAL FIELD
[0002] This invention relates to inhibiting 11.beta.HSD1.
BACKGROUND
[0003] Diabetes is generally characterized by relatively high
levels of plasma glucose (hyperglycemia) in the fasting state.
Patients having type 2 diabetes (non-insulin dependent diabetes
mellitus (NIDDM)) produce insulin (and even exhibit
hyperinsulinemia), whilst demonstrating hyperglycemia.
[0004] Type 2 diabetics can often develop insulin resistance, in
which the effect of insulin in stimulating glucose and lipid
metabolism is diminished. Further, patients having insulin
resistance, but have not developed type 2 diabetes, are also at
risk of developing Syndrome X (metabolic syndrome). Syndrome X is
characterized by insulin resistance, along with obesity (e.g.,
abdominal obesity), hyperinsulinemia, high blood pressure,
relatively low HDL and relatively high VLDL.
[0005] Glucocorticoids (e.g., cortisol in humans, corticosterone in
rodents) are counter regulatory hormones that oppose the action of
insulin. It is established that glucocorticoid activity is
controlled at the tissue level by intracellular interconversion of
active cortisol and inactive cortisone by the 11-beta
hydroxysteroid dehydrogenases, 11.beta.HSD1, which activates
cortisone and 11.beta.HSD2, which inactivates cortisol. Excess
levels of glucocorticoids (e.g., cortisol) can cause metabolic
complications. For example, excess cortisol is associated with
disorders including NIDDM, obesity, dyslipidemia, insulin
resistance, and hypertension.
[0006] It is believed that inhibition of 11.beta.HSD1 can reduce
the effects of excessive amounts of 11.beta.-hydroxysteroids, e.g.,
cortisol, and therefore can be useful for the treatment and control
of diseases mediated by abnormally high levels of cortisol and
other 11.beta.-hydroxysteroids, e.g., NIDDM, obesity, dyslipidemia,
and hypertension.
SUMMARY
[0007] In one aspect, this invention relates to a compound of
formula (I):
##STR00001##
[0008] in which:
[0009] R.sup.1 is:
[0010] (i) C.sub.6-C.sub.18 aryl or heteroaryl including 5-20
atoms, each of which is optionally substituted with from 1-10
R.sup.a; or
[0011] (ii) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16 cycloalkyl;
(C.sub.1-C.sub.12 alkyl)-(C.sub.3-C.sub.16 cycloalkyl);
heteroaralkyl including 6-20 atoms; arylheterocyclyl including 8-20
atoms; arylcycloalkenyl including 8-20 atoms;
arylheterocycloalkenyl including 8-20 atoms (e.g., arylheterocyclyl
including 8-20 atoms or arylheterocycloalkenyl including 8-20
atoms); C.sub.3-C.sub.16 cycloalkenyl; heterocyclyl including 3-16
atoms; or heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b;
[0012] R.sup.2 is:
[0013] (i) C.sub.6-C.sub.18 aryl or heteroaryl including 5-20
atoms, each of which is optionally substituted with from 1-10
R.sup.c; or
[0014] (ii) C.sub.3-C.sub.16 cycloalkyl; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or
[0015] (iii) OR.sup.1; SR.sup.1; or NR.sup.3R.sup.4, wherein
R.sup.3 and R.sup.4 are each, independently, hydrogen or R.sup.1;
or
[0016] (iv) C(O)R.sup.5, wherein R.sup.5 is C.sub.1-C.sub.20 alkyl
or C.sub.7-C.sub.20 aralkoxy;
[0017] X is CO, S(O).sub.n, or S(O).sub.nNR.sup.6 wherein n is 1 or
2, and R.sup.6 is hydrogen, C.sub.1-C.sub.12 alkyl, or
C.sub.3-C.sub.16 cycloalkyl;
[0018] each of V and Y is, independently, CR.sup.7 or N, wherein
R.sup.7 is hydrogen or C.sub.1-C.sub.12 alkyl, provided that Y and
V cannot both be CR.sup.7;
[0019] each of W.sup.1, Z.sup.1, W.sup.2, and Z.sup.2 is,
independently:
[0020] (i) hydrogen; or
[0021] (ii) oxo; or
[0022] (iii) C.sub.1-C.sub.12 alkyl; or
[0023] (iv) C.sub.6-C.sub.18 aryl or heteroaryl including 5-20
atoms, each of which is optionally substituted with from 1-10
R.sup.a; or
[0024] (ii) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16 cycloalkyl;
heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16 cycloalkenyl;
heterocyclyl including 3-16 atoms; or heterocycloalkenyl including
3-16 atoms; each of which is optionally substituted with from 1-10
R.sup.b;
[0025] R.sup.a at each occurrence is, independently:
[0026] (i) halo; NR.sup.dR.sup.e; nitro; azido; hydroxy;
C.sub.1-C.sub.12 alkoxy or C.sub.1-C.sub.12 thioalkoxy, each of
which is optionally substituted with 1-5 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; C.sub.6-C.sub.16 aryloxy, C.sub.6-C.sub.16 thioaryloxy,
heteroaryloxy including 5-20 atoms, or thioaryloxy including 5-20
atoms, each of which is optionally substituted with 1-5 R.sup.a';
C.sub.2-C.sub.12 alkenyloxy; C.sub.2-C.sub.12 alkynyloxy;
C.sub.3-C.sub.16 cycloalkyloxy, C.sub.3-C.sub.16 cycloalkenyloxy,
heterocyclyloxy including 3-16 atoms, heterocycloalkenyloxy
including 3-16 atoms, C.sub.7-C.sub.20 aralkoxy, or heteroaralkoxy
including 6-20 atoms, each of which is optionally substituted with
1-5 R.sup.b; mercapto; cyano; C.sub.1-C.sub.3 alkylenedioxy;
--C(O)R.sup.g, --C(O)OR.sup.g; --OC(O)R.sup.g; --C(O)SR.sup.g;
--SC(O)R.sup.g; --C(S)SR.sup.g; --SC(S)R.sup.g;
--C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; or
[0027] (ii) C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl;
each of which is optionally substituted with from 1-5 R.sup.j;
or
[0028] (iii) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16 cycloalkyl;
heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16 cycloalkenyl;
heterocyclyl including 3-16 atoms; or heterocycloalkenyl including
3-16 atoms; each of which is optionally substituted with from 1-10
R.sup.b; or
[0029] (iv) C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20 alkynyl;
or
[0030] (v) C.sub.6-C.sub.16 aryl or heteroaryl including 5-16
atoms, each of which is optionally substituted with from 1-10
R.sup.a';
[0031] R.sup.a' at each occurrence is, independently,
C.sub.1-C.sub.12 alkyl, C.sub.1-C.sub.12 haloalkyl,
C.sub.2-C.sub.12 alkenyl; C.sub.2-C.sub.12 alkynyl;
C.sub.3-C.sub.16 cycloalkyl; C.sub.3-C.sub.16 cycloalkenyl,
heterocyclyl including 3-16 atoms, heterocycloalkenyl including
3-16 atoms; C.sub.7-C.sub.20 aralkyl; C.sub.6-C.sub.16 aryl;
heteroaryl including 5-16 atoms; halo; NR.sup.dR.sup.e; nitro;
azido, hydroxy; C.sub.1-C.sub.12 alkoxy; C.sub.1-C.sub.12
thioalkoxy; C.sub.1-C.sub.12 haloalkoxy; C.sub.6-C.sub.16 aryloxy,
C.sub.6-C.sub.16 thioaryloxy; heteroaryloxy including 5-20 atoms;
thioaryloxy including 5-20 atoms; C.sub.2-C.sub.12 alkenyloxy;
C.sub.2-C.sub.12 alkynyloxy; C.sub.3-C.sub.16 cycloalkyloxy;
C.sub.3-C.sub.16 cycloalkenyloxy; heterocyclyloxy including 3-16
atoms; heterocycloalkenyloxy including 3-16 atoms; C.sub.7-C.sub.20
aralkoxy; heteroaralkoxy including 6-20 atoms; mercapto; cyano;
C.sub.1-C.sub.3 alkylenedioxy; --C(O)R.sup.g, --C(O)OR.sup.g;
--OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g; --C(S)SR.sup.g;
--SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i; or
--OC(O)NR.sup.dR.sup.e;
[0032] R.sup.b at each occurrence is, independently:
[0033] (i) halo; NR.sup.dR.sup.e; nitro; azido; hydroxy; oxo,
thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12 alkoxy or C.sub.1-C.sub.12
thioalkoxy, each of which is optionally substituted with 1-5
R.sup.f; C.sub.1-C.sub.12 haloalkoxy; C.sub.6-C.sub.16 aryloxy,
C.sub.6-C.sub.16 thioaryloxy, heteroaryloxy including 5-20 atoms,
or thioaryloxy including 5-20 atoms, each of which is optionally
substituted with 1-5 R.sup.a; C.sub.2-C.sub.12 alkenyloxy;
C.sub.2-C.sub.12 alkynyloxy; C.sub.3-C.sub.16 cycloalkyloxy,
C.sub.3-C.sub.16 cycloalkenyloxy, heterocyclyloxy including 3-16
atoms, heterocycloalkenyloxy including 3-16 atoms, C.sub.7-C.sub.20
aralkoxy, or heteroaralkoxy including 6-20 atoms, each of which is
optionally substituted with 1-5 R.sup.b; mercapto; cyano;
C.sub.1-C.sub.3 alkylenedioxy; --C(O)R.sup.g, --C(O)OR.sup.g;
--OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g; --C(S)SR.sup.g;
--SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; or
[0034] (ii) C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl;
each of which is optionally substituted with from 1-5 R.sup.j;
or
[0035] (iii) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16 cycloalkyl;
heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16 cycloalkenyl;
heterocyclyl including 3-16 atoms; or heterocycloalkenyl including
3-16 atoms; each of which is optionally substituted with from 1-10
R.sup.b; or
[0036] (iv) C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20 alkynyl;
or
[0037] (v) C.sub.6-C.sub.16 aryl or heteroaryl including 5-16
atoms, each of which is optionally substituted with from 1-10
R.sup.a;
[0038] R.sup.c at each occurrence is, independently:
[0039] (i) halo; nitro; hydroxy; C.sub.1-C.sub.12 alkoxy optionally
substituted with 1-5 R.sup.f; C.sub.1-C.sub.12 haloalkoxy; cyano;
C.sub.1-C.sub.3 alkylenedioxy; or SO.sub.2R.sup.m; or
[0040] (ii) C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl;
each of which is optionally substituted with from 1-5 R.sup.j;
or
[0041] (iii) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16 cycloalkyl;
heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16 cycloalkenyl;
heterocyclyl including 3-16 atoms; or heterocycloalkenyl including
3-16 atoms; each of which is optionally substituted with from 1-10
R.sup.b; or
[0042] (iv) C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20 alkynyl;
or
[0043] (v) C.sub.6-C.sub.16 aryl or heteroaryl including 5-16
atoms, each of which is optionally substituted with from 1-10
R.sup.a;
[0044] each of R.sup.d, R.sup.e, R.sup.g, R.sup.h, and R.sup.k, at
each occurrence is, independently:
[0045] (i) hydrogen; or
[0046] (ii) C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl;
each of which is optionally substituted with from 1-5 R.sup.j;
or
[0047] (iii) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16 cycloalkyl;
heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16 cycloalkenyl;
heterocyclyl including 3-16 atoms; or heterocycloalkenyl including
3-16 atoms; each of which is optionally substituted with from 1-10
R.sup.b; or
[0048] (iv) C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20 alkynyl;
or
[0049] (v) C.sub.6-C.sub.16 aryl or heteroaryl including 5-16
atoms, each of which is optionally substituted with from 1-10
R.sup.a;
[0050] R.sup.f is NR.sup.dR.sup.e; nitro; azido; hydroxy; oxo,
thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12 alkoxy or C.sub.1-C.sub.12
thioalkoxy, each of which is optionally substituted with 1-5
R.sup.f; C.sub.1-C.sub.12 haloalkoxy; C.sub.6-C.sub.16 aryloxy,
C.sub.6-C.sub.16 thioaryloxy, heteroaryloxy including 5-20 atoms,
or thioaryloxy including 5-20 atoms, each of which is optionally
substituted with 1-5 R.sup.a'; C.sub.2-C.sub.12 alkenyloxy;
C.sub.2-C.sub.12 alkynyloxy; C.sub.3-C.sub.16 cycloalkyloxy,
C.sub.3-C.sub.16 cycloalkenyloxy, heterocyclyloxy including 3-16
atoms, heterocycloalkenyloxy including 3-16 atoms, C.sub.7-C.sub.20
aralkoxy, or heteroaralkoxy including 6-20 atoms, each of which is
optionally substituted with 1-5 R.sup.b; mercapto; cyano;
C.sub.1-C.sub.3 alkylenedioxy; --C(O)R.sup.g, --OC(O)R.sup.g;
--C(O)SR.sup.g; --SC(O)R.sup.g; --C(S)SR.sup.g; --SC(S)R.sup.g;
--C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e;
[0051] R.sup.i is R.sup.g; OR.sup.g; NR.sup.dR.sup.e; or
heterocyclyl including 3-16 atoms; or heterocycloalkenyl including
3-16 atoms; each of which is optionally substituted with from 1-10
R.sup.b;
[0052] R.sup.j is NR.sup.dR.sup.e; nitro; azido; hydroxy; oxo,
thioxo, .dbd.NR.sup.k, C.sub.1-C.sub.12 alkoxy or C.sub.1-C.sub.12
thioalkoxy, each of which is optionally substituted with 1-5
R.sup.f; C.sub.1-C.sub.12 haloalkoxy; C.sub.6-C.sub.16 aryloxy,
C.sub.6-C.sub.16 thioaryloxy, heteroaryloxy including 5-20 atoms,
or thioaryloxy including 5-20 atoms, each of which is optionally
substituted with 1-5 R.sup.a'; C.sub.2-C.sub.12 alkenyloxy;
C.sub.2-C.sub.12 alkynyloxy; C.sub.3-C.sub.16 cycloalkyloxy,
C.sub.3-C.sub.16 cycloalkenyloxy, heterocyclyloxy including 3-16
atoms, heterocycloalkenyloxy including 3-16 atoms, C.sub.7-C.sub.20
aralkoxy, or heteroaralkoxy including 6-20 atoms, each of which is
optionally substituted with 1-5 R.sup.b; mercapto; cyano;
C.sub.1-C.sub.3 alkylenedioxy; --C(O)R.sup.g, --C(O)OR.sup.g;
--OC(O)R.sup.g; --C(O)SR.sup.g; --SC(O)R.sup.g; --C(S)SR.sup.g;
--SC(S)R.sup.g; --C(O)NR.sup.dR.sup.e; --NR.sup.hC(O)R.sup.i;
--OC(O)NR.sup.dR.sup.e; and
[0053] R.sup.m is
[0054] (i) C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl;
each of which is optionally substituted with from 1-5 R.sup.j;
or
[0055] (ii) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16 cycloalkyl;
heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16 cycloalkenyl;
heterocyclyl including 3-16 atoms; or heterocycloalkenyl including
3-16 atoms; each of which is optionally substituted with from 1-10
R.sup.b; or
[0056] (iii) C.sub.6-C.sub.16 aryl or heteroaryl including 5-16
atoms, each of which is optionally substituted with from 1-10
R.sup.a.
[0057] In some embodiments, one, two, three, or four of the
following conditions apply:
[0058] (a) when V and Y are both N, and R.sup.2 is substituted
pyridyl or pyrimidinyl, then R.sup.c cannot be C.sub.1-C.sub.12
alkoxy optionally substituted with 1-5 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; or SO.sub.2R.sup.m;
[0059] (b) when V and Y are both N, X is SO.sub.2, and R.sup.2 is
C.sub.3-C.sub.16 cycloalkyl, then R.sup.1 cannot be a
monosubstituted phenyl ring that is substituted at the
para-position with either substituted C.sub.1-C.sub.12 alkyl or
substituted C.sub.1-C.sub.12 haloalkyl;
[0060] (c) when V and Y are both N, X is CO, then R.sup.1 cannot be
unsubstituted or mono, di, or trisubstituted
pyrazolo[1,5-a]pyrimidin-2-yl;
[0061] (d) when V is N and Y is CH, and X is CO, then R.sup.2
cannot be C(O)R.sup.5.
[0062] In certain embodiments, conditions (a), (b), (c), and (d)
apply. In certain embodiments, conditions (b), (c), and (d) apply.
In certain embodiments, (a), (b), and (d) apply. In certain
embodiments, (b) and (d) apply.
[0063] In another aspect, this invention relates to a compound of
formula (I), in which:
[0064] R.sup.2 is:
[0065] (i) C.sub.6-C.sub.18 aryl, optionally substituted with from
1-10 R.sup.c; or heteroaryl including 5-20 atoms, optionally
substituted with from 1-10 R.sup.n;
[0066] (ii) C.sub.3-C.sub.16 cycloalkyl; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or
[0067] (iii) OR.sup.1; SR.sup.1; or NR.sup.3R.sup.4, wherein
R.sup.3 and R.sup.4 are each, independently, hydrogen or R.sup.1
or
[0068] (iv) C(O)R.sup.5, wherein R.sup.5 is C.sub.1-C.sub.20 alkyl
or C.sub.7-C.sub.20 aralkoxy;
[0069] R.sup.n at each occurrence is, independently:
[0070] (i) halo; nitro; hydroxy; cyano; or C.sub.1-C.sub.3
alkylenedioxy (e.g., halo; nitro; hydroxy; cyano); or
[0071] (ii) C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl;
each of which is optionally substituted with from 1-5 R.sup.j;
or
[0072] (iii) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16 cycloalkyl;
heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16 cycloalkenyl;
heterocyclyl including 3-16 atoms; or heterocycloalkenyl including
3-16 atoms; each of which is optionally substituted with from 1-10
R.sup.b; or
[0073] (iv) C.sub.2-C.sub.20 alkenyl or C.sub.2-C.sub.20 alkynyl;
or
[0074] (v) C.sub.6-C.sub.16 aryl or heteroaryl including 5-16
atoms, each of which is optionally substituted with from 1-10
R.sup.a;
[0075] provided:
[0076] (b) when V and Y are both N, X is SO.sub.2, and R.sup.2 is
C.sub.3-C.sub.16 cycloalkyl, then R.sup.1 cannot be a
monosubstituted phenyl ring that is substituted at the
para-position with either substituted C.sub.1-C.sub.12 alkyl or
substituted C.sub.1-C.sub.12 haloalkyl; and
[0077] (c) when V and Y are both N, X is CO, then R.sup.1 cannot be
unsubstituted or mono, di, or trisubstituted
pyrazolo[1,5-a]pyrimidin-2-yl; and
[0078] (d) when V is N and Y is CH, and X is CO, then R.sup.2
cannot be C(O)R.sup.5; and
[0079] R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, X, V,
Y, W.sup.1, Z.sup.1, W.sup.2, Z.sup.2, R.sup.a, R.sup.a', R.sup.b,
R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g, R.sup.h, R.sup.i,
R.sup.j, R.sup.k, and R.sup.m can be as defined anywhere
herein.
[0080] In a further aspect, this invention relates to a compound of
formula (I), in which:
[0081] R.sup.2 is:
[0082] (i) C.sub.6-C.sub.18 aryl or heteroaryl including 5-20
atoms, each of which is optionally substituted with from 1-10
R.sup.c; or
[0083] (ii) C.sub.6-C.sub.16 cycloalkyl; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or
[0084] (iii) OR.sup.1; SR.sup.1; or NR.sup.3R.sup.4, wherein
R.sup.3 and R.sup.4 are each, independently, hydrogen or R.sup.1;
or
[0085] (iv) C(O)R.sup.5, wherein R.sup.5 is C.sub.1-C.sub.20 alkyl
or C.sub.7-C.sub.20 aralkoxy;
[0086] provided:
[0087] (a) when V and Y are both N, and R.sup.2 is substituted
pyridyl or pyrimidinyl, then R.sup.c cannot be C.sub.1-C.sub.12
alkoxy optionally substituted with 1-5 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; or SO.sub.2R.sup.m; and
[0088] (c) when V and Y are both N, X is CO, then R.sup.1 cannot be
unsubstituted or mono, di, or trisubstituted
pyrazolo[1,5-a]pyrimidin-2-yl; and
[0089] (d) when V is N and Y is CH, and X is CO, then R.sup.2
cannot be C(O)R.sup.5; and
[0090] R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, X, V,
Y, W.sup.1, Z.sup.1, W.sup.2, Z.sup.2, R.sup.a, R.sup.a', R.sup.b,
R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g, R.sup.h, R.sup.i,
R.sup.j, R.sup.k, and R.sup.m can be as defined anywhere
herein.
[0091] In another aspect, this invention relates to a compound of
formula (I), in which:
[0092] R.sup.2 is:
[0093] (i) C.sub.6-C.sub.18 aryl or heteroaryl including 5-20
atoms, each of which is optionally substituted with from 1-10
R.sup.c; or
[0094] (ii) C.sub.3-C.sub.16 cycloalkyl; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or
[0095] (iii) OR.sup.1; SR.sup.1; or NR.sup.3R.sup.4, wherein
R.sup.3 and R.sup.4 are each, independently, hydrogen or
R.sup.1;
[0096] provided:
[0097] (a) when V and Y are both N, and R.sup.2 is substituted
pyridyl or pyrimidinyl, then R.sup.c cannot be C.sub.1-C.sub.12
alkoxy optionally substituted with 1-5 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; or SO.sub.2R.sup.m; and
[0098] (b) when V and Y are both N, X is SO.sub.2, and R.sup.2 is
C.sub.3-C.sub.16 cycloalkyl, then R.sup.1 cannot be a
monosubstituted phenyl ring that is substituted at the
para-position with either substituted C.sub.1-C.sub.12 alkyl or
substituted C.sub.1-C.sub.12 haloalkyl; and
[0099] (c) when V and Y are both N, X is CO, then R.sup.1 cannot be
unsubstituted or mono, di, or trisubstituted
pyrazolo[1,5-a]pyrimidin-2-yl; and
[0100] R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, X, V,
Y, W.sup.1, Z.sup.1, W.sup.2, Z.sup.2, R.sup.a, R.sup.a', R.sup.b,
R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g, R.sup.h, R.sup.i,
R.sup.j, R.sup.k, and R.sup.m can be as defined anywhere
herein.
[0101] In a further aspect, this invention relates to a compound of
formula (I), in which:
[0102] R.sup.2 is:
[0103] (i) C.sub.6-C.sub.18 aryl, optionally substituted with from
1-10 R.sup.c; or heteroaryl including 5-20 atoms, optionally
substituted with from 1-10 R.sup.n;
[0104] (ii) C.sub.6-C.sub.16 cycloalkyl; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or
[0105] (iii) OR.sup.1; SR.sup.1; or NR.sup.3R.sup.4, wherein
R.sup.3 and R.sup.4 are each, independently, hydrogen or R.sup.1;
or
[0106] (iv) C(O)R.sup.5, wherein R.sup.5 is C.sub.1-C.sub.20 alkyl
or C.sub.7-C.sub.20 aralkoxy;
[0107] provided:
[0108] (c) when V and Y are both N, X is CO, then R.sup.1 cannot be
unsubstituted or mono, di, or trisubstituted
pyrazolo[1,5-a]pyrimidin-2-yl; and
[0109] (d) when V is N and Y is CH, and X is CO, then R.sup.2
cannot be C(O)R.sup.5; and
[0110] R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, X, V,
Y, W.sup.1, Z.sup.1, W.sup.2, Z.sup.2, R.sup.a, R.sup.a', R.sup.b,
R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g, R.sup.h, R.sup.i,
R.sup.j, R.sup.k, R.sup.m, and R.sup.n can be as defined anywhere
herein.
[0111] In a further aspect, this invention relates to a compound of
formula (I), in which:
[0112] R.sup.2 is:
[0113] (i) C.sub.6-C.sub.18 aryl, optionally substituted with from
1-10 R.sup.c; or heteroaryl including 5-20 atoms, optionally
substituted with from 1-10 R.sup.n;
[0114] (ii) C.sub.3-C.sub.16 cycloalkyl; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or
[0115] (iii) OR.sup.1; SR.sup.1; or NR.sup.3R.sup.4, wherein
R.sup.3 and R.sup.4 are each, independently, hydrogen or
provided:
[0116] (b) when V and Y are both N, X is SO.sub.2, and R.sup.2 is
C.sub.3-C.sub.16 cycloalkyl, then R.sup.1 cannot be a
monosubstituted phenyl ring that is substituted at the
para-position with either substituted C.sub.1-C.sub.12 alkyl or
substituted C.sub.1-C.sub.12 haloalkyl; and
[0117] (c) when V and Y are both N, X is CO, then R.sup.1 cannot be
unsubstituted or mono, di, or trisubstituted
pyrazolo[1,5-a]pyrimidin-2-yl; and
[0118] R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, X, V,
Y, W.sup.1, Z.sup.1, W.sup.2, Z.sup.2, R.sup.a, R.sup.a', R.sup.b,
R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g, R.sup.h, R.sup.i,
R.sup.j, R.sup.k, and R.sup.m can be as defined anywhere
herein.
[0119] In a further aspect, this invention relates to a compound of
formula (I), in which:
[0120] R.sup.2 is:
[0121] (i) C.sub.6-C.sub.18 aryl or heteroaryl including 5-20
atoms, each of which is optionally substituted with from 1-10
R.sup.c; or
[0122] (ii) C.sub.6-C.sub.16 cycloalkyl; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or
[0123] (iii) OR.sup.1; SR.sup.1; or NR.sup.3R.sup.4, wherein
R.sup.3 and R.sup.4 are each, independently, hydrogen or
R.sup.1;
[0124] provided
[0125] (a) when V and Y are both N, and R.sup.2 is substituted
pyridyl or pyrimidinyl, then R.sup.c cannot be C.sub.1-C.sub.12
alkoxy optionally substituted with 1-5 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; or SO.sub.2R.sup.m; and
[0126] (c) when V and Y are both N, X is CO, then R.sup.1 cannot be
unsubstituted or mono, di, or trisubstituted
pyrazolo[1,5-a]pyrimidin-2-yl; and
[0127] R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, X, V,
Y, W.sup.1, Z.sup.1, W.sup.2, Z.sup.7, R.sup.a, R.sup.a', R.sup.b,
R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g, R.sup.h, R.sup.i,
R.sup.j, R.sup.k, and R.sup.m can be as defined anywhere
herein.
[0128] In a further aspect, this invention relates to a compound of
formula (I), in which:
[0129] R.sup.2 is:
[0130] (i) C.sub.6-C.sub.18 aryl, optionally substituted with from
1-10 R.sup.c; or heteroaryl including 5-20 atoms, optionally
substituted with from 1-10 R.sup.n;
[0131] (ii) C.sub.6-C.sub.16 cycloalkyl; C.sub.3-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b; or
[0132] (iii) OR.sup.1; SR.sup.1; or NR.sup.3R.sup.4, wherein
R.sup.3 and R.sup.4 are each, independently, hydrogen or
R.sup.1;
[0133] provided:
[0134] (c) when V and Y are both N, X is CO, then R.sup.1 cannot be
unsubstituted or mono, di, or trisubstituted
pyrazolo[1,5-a]pyrimidin-2-yl; and
[0135] R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, X, V,
Y, W.sup.1, Z.sup.1, W.sup.2, Z.sup.2, R.sup.a, R.sup.a', R.sup.b,
R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g, R.sup.h, R.sup.i,
R.sup.j, R.sup.k, and R.sup.m can be as defined anywhere
herein.
[0136] In a further aspect, this invention relates to a compound of
formula (I), in which:
[0137] R.sup.2 is:
[0138] (i) C.sub.6-C.sub.18 aryl or heteroaryl including 5-20
atoms, each of which is optionally substituted with from 1-10
R.sup.c; or
[0139] (iii) OR.sup.1; SR.sup.1; or NR.sup.3R.sup.4, wherein
R.sup.3 and R.sup.4 are each, independently, hydrogen or R.sup.1;
or
[0140] (iv) C(O)R.sup.5, wherein R.sup.5 is C.sub.1-C.sub.20 alkyl
or C.sub.7-C.sub.20 aralkoxy;
[0141] provided:
[0142] (a) when V and Y are both N, and R.sup.2 is substituted
pyridyl or pyrimidinyl, then R.sup.c cannot be C.sub.1-C.sub.12
alkoxy optionally substituted with 1-5 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; or SO.sub.2R.sup.m; and
[0143] (c) when V and Y are both N, X is CO, then R.sup.1 cannot be
unsubstituted or mono, di, or trisubstituted
pyrazolo[1,5-a]pyrimidin-2-yl; and
[0144] (d) when V is N and Y is CH, and X is CO, then R.sup.2
cannot be C(O)R.sup.5; and
[0145] R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, X, V,
Y, W.sup.1, Z.sup.1, W.sup.2, Z.sup.2, R.sup.a, R.sup.a', R.sup.b,
R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g, R.sup.h, R.sup.i,
R.sup.j, R.sup.k, and R.sup.m can be as defined anywhere
herein.
[0146] In a further aspect, this invention relates to a compound of
formula (I), in which:
[0147] R.sup.2 is:
[0148] (i) C.sub.6-C.sub.18 aryl, optionally substituted with from
1-10 R.sup.c; or heteroaryl including 5-20 atoms, optionally
substituted with from 1-10 R.sup.n;
[0149] (iii) OR.sup.1; SR.sup.1; or NR.sup.3R.sup.4, wherein
R.sup.3 and R.sup.4 are each, independently, hydrogen or R.sup.1;
or
[0150] (iv) C(O)R.sup.5, wherein R.sup.5 is C.sub.1-C.sub.20 alkyl
or C.sub.7-C.sub.20 aralkoxy;
[0151] provided:
[0152] (c) when V and Y are both N, X is CO, then R.sup.1 cannot be
unsubstituted or mono, di, or trisubstituted
pyrazolo[1,5-a]pyrimidin-2-yl; and
[0153] (d) when V is N and Y is CH, and X is CO, then R.sup.2
cannot be C(O)R.sup.5; and
[0154] R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, X, V,
Y, W.sup.1, Z.sup.1, W.sup.2, Z.sup.2, R.sup.a, R.sup.a', R.sup.b,
R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g, R.sup.h, R.sup.i,
R.sup.j, R.sup.k, R.sup.m, and R.sup.1 can be as defined anywhere
herein.
[0155] In a further aspect, this invention relates to a compound of
formula (I), in which:
[0156] R.sup.2 is:
[0157] (i) C.sub.6-C.sub.18 aryl or heteroaryl including 5-20
atoms, each of which is optionally substituted with from 1-10
R.sup.c; or
[0158] (iii) OR.sup.1; SR.sup.1; or NR.sup.3R.sup.4, wherein
R.sup.3 and R.sup.4 are each, independently, hydrogen or
R.sup.1;
[0159] provided
[0160] (a) when V and Y are both N, and R.sup.2 is substituted
pyridinyl or pyrimidinyl, then R.sup.c cannot be C.sub.1-C.sub.12
alkoxy optionally substituted with 1-5 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; or SO.sub.2R.sup.m; and
[0161] (c) when V and Y are both N, X is CO, then R.sup.1 cannot be
unsubstituted or mono, di, or trisubstituted
pyrazolo[1,5-a]pyrimidin-2-yl; and
[0162] R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, X, V,
Y, W.sup.1, Z.sup.1, W.sup.2, Z.sup.2, R.sup.a, R.sup.a', R.sup.b,
R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g, R.sup.h, R.sup.i,
R.sup.j, R.sup.k, and R.sup.m can be as defined anywhere
herein.
[0163] In a further aspect, this invention relates to a compound of
formula (I), in which:
[0164] R.sup.2 is:
[0165] (i) C.sub.6-C.sub.18 aryl, optionally substituted with from
1-10 R.sup.c; or heteroaryl including 5-20 atoms, optionally
substituted with from 1-10 R.sup.n;
[0166] (iii) OR.sup.1; SR.sup.1; or NR.sup.3R.sup.4, wherein
R.sup.3 and R.sup.4 are each, independently, hydrogen or
R.sup.1;
[0167] provided:
[0168] (c) when V and Y are both N, X is CO, then R.sup.1 cannot be
unsubstituted or mono, di, or trisubstituted
pyrazolo[1,5-a]pyrimidin-2-yl; and
[0169] R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, X, V,
Y, W.sup.1, Z.sup.1, W.sup.2, Z.sup.2, R.sup.a, R.sup.a', R.sup.b,
R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g, R.sup.h, R.sup.i,
R.sup.j, R.sup.k, and R.sup.m can be as defined anywhere
herein.
[0170] In one aspect, this invention relates to a compound of
formula (I), in which:
[0171] R.sup.1 is:
[0172] (i) C.sub.6-C.sub.18 aryl or heteroaryl including 5-20
atoms, each of which is optionally substituted with from 1-10
R.sup.a; or
[0173] (ii) C.sub.7-C.sub.20 aralkyl; heteroaralkyl including 6-20
atoms; arylheterocyclyl including 8-20 atoms; arylcycloalkenyl
including 8-20 atoms; or arylheterocycloalkenyl including 8-20
atoms; each of which is optionally substituted with from 1-10
R.sup.b;
[0174] R.sup.2 is C.sub.6-C.sub.18 aryl or heteroaryl including
5-20 atoms, each of which is optionally substituted with from 1-10
R.sup.c;
[0175] X is S(O).sub.n or S(O).sub.nNR.sup.6, wherein n is 1 or 2,
and R.sup.6 is hydrogen, C.sub.1-C.sub.12 alkyl, or
C.sub.3-C.sub.16 cycloalkyl;
[0176] one, two, three, or four of W.sup.1, Z.sup.1, W.sup.2, and
Z.sup.2 are each, independently:
[0177] (i) C.sub.1-C.sub.12 alkyl; or
[0178] (ii) oxo; or
[0179] (iii) C.sub.6-C.sub.18 aryl or heteroaryl including 5-20
atoms, each of which is optionally substituted with from 1-10
R.sup.a; or
[0180] (iv) C.sub.7-C.sub.20 aralkyl; C.sub.3-C.sub.16 cycloalkyl;
heteroaralkyl including 6-20 atoms; C.sub.3-C.sub.16 cycloalkenyl;
heterocyclyl including 3-16 atoms; or heterocycloalkenyl including
3-16 atoms; each of which is optionally substituted with from 1-10
R.sup.b; and the others are hydrogen; and
[0181] R.sup.6, R.sup.7, V, Y, R.sup.a, R.sup.a', R.sup.b, R.sup.c,
R.sup.d, R.sup.e, R.sup.f, R.sup.g, R.sup.h, R.sup.i, R.sup.j,
R.sup.k, and R.sup.m can be as defined anywhere herein.
[0182] In some embodiments, one or more of the following conditions
apply:
[0183] (a) when V and Y are both N, and R.sup.2 is substituted
pyridyl or pyrimidinyl, then R.sup.c cannot be C.sub.1-C.sub.12
alkoxy optionally substituted with 1-5 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; or SO.sub.2R.sup.m;
[0184] (e) when V and Y are both N, X is SO.sub.2, one of Z.sup.1
and W.sup.2 is C.sub.1-C.sub.4 alkyl (e.g., CH.sub.3), and R.sup.2
is phenyl substituted with from 1-5 R.sup.c, then 1 R.sup.c must be
halo; C.sub.1-C.sub.12 haloalkoxy; cyano; or C.sub.1-C.sub.12
haloalkyl, optionally substituted with from 1-5 R.sup.j (i.e., if 1
R.sup.c is present, then that R.sup.c substituent must be halo;
C.sub.1-C.sub.12 haloalkoxy; cyano; or C.sub.1-C.sub.12 haloalkyl,
optionally substituted with from 1-5 R.sup.j; if more than 1
R.sup.c is present, then one of the R.sup.c substituents must be
one of the four aforementioned substituents);
[0185] (f) when V and Y are both N, X is SO.sub.2, and R.sup.2 is
phenyl substituted with from 1-5 R.sup.1, then 1 R.sup.c must be
halo; C.sub.1-C.sub.12 haloalkoxy; cyano; or C.sub.1-C.sub.12
haloalkyl, optionally substituted with from 1-5 R.sup.j;
[0186] (g) when V and Y are both N, X is SO.sub.2, and one of
Z.sup.1 and W.sup.2 is C.sub.1-C.sub.4 alkyl (e.g., CH.sub.3), then
R.sup.1 cannot be 4-chlorophenyl;
[0187] (h) when V and Y are both N and X is SO.sub.2, then R.sup.1
cannot be 4-chlorophenyl;
[0188] (i) when V and Y are both N, X is SO.sub.2, and one of
Z.sup.1 and W.sup.2 is C.sub.1-C.sub.4 alkyl (e.g., CH.sub.3), then
R.sup.2 cannot be phenyl monosubstituted with C.sub.1-C.sub.4 alkyl
(CH.sub.3) or C.sub.1-C.sub.4 alkoxy (OCH.sub.3);
[0189] (j) when V and Y are both N and X is SO.sub.2, then R.sup.2
cannot be phenyl monosubstituted with C.sub.1-C.sub.4 alkyl
(CH.sub.3) or C.sub.1-C.sub.4 alkoxy (OCH.sub.3).
[0190] In certain embodiments, (a) applies. In certain embodiments,
(a) and any one of (e)-(j) apply. In certain embodiments, any one
of (e)-(j) applies. In certain embodiments, any two or three of
(e)-(j) applies, optionally in combination with (a). For example,
(e) or (f) and (g) or (h) and/or (i) and (j), optionally in
combination with (a).
[0191] In one aspect, this invention relates to a compound of
formula (I), in which:
[0192] R.sup.1 is:
[0193] (i) C.sub.6-C.sub.18 aryl or heteroaryl including 5-20
atoms, each of which is optionally substituted with from 1-10
R.sup.a; or
[0194] (ii) C.sub.7-C.sub.20 aralkyl or heteroaralkyl including
6-20 atoms; each of which is optionally substituted with from 1-10
R.sup.b
[0195] R.sup.2 is:
[0196] (i) C.sub.6-C.sub.18 aryl substituted with from 1-10
R.sup.c; or heteroaryl including 5-20 atoms, optionally substituted
with from 1-10 R.sup.c; or
[0197] (iii) OR.sup.1; SR.sup.1; or NR.sup.3R.sup.4, wherein
R.sup.3 and R.sup.4 are each, independently, hydrogen or
[0198] R.sup.1;
[0199] X is S(O).sub.n or S(O).sub.nNR.sup.6, wherein n is 1 or 2,
and R.sup.6 is hydrogen, C.sub.1-C.sub.12 alkyl, or
C.sub.3-C.sub.16 cycloalkyl;
[0200] each of W.sup.1, Z.sup.1, W.sup.2, and Z.sup.2 is hydrogen;
and
[0201] R.sup.3, R.sup.4, R.sup.6, R.sup.7, V, Y, R.sup.a, R.sup.a',
R.sup.b, R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g, R.sup.h,
R.sup.i, R.sup.j, R.sup.k and R.sup.m can be as defined anywhere
herein.
[0202] In some embodiments, one or more of the following conditions
apply:
[0203] (a) when V and Y are both N, and R.sup.2 is substituted
pyridyl or pyrimidinyl, then R.sup.c cannot be C.sub.1-C.sub.12
alkoxy optionally substituted with 1-5 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; or SO.sub.2R.sup.m;
[0204] (k) when V and Y are both N and X is SO.sub.2, then R.sup.1
cannot be 4-chlorophenyl;
[0205] (l) when V and Y are both N and X is SO.sub.2, then R.sup.1
cannot be 1-chlorophenyl when R.sup.2 is: phenyl monosubstituted
with hydroxyl, C.sub.1-C.sub.6 alkoxy, chloro, or nitro;
unsubstituted pyridyl; pyridyl monosubstituted with hydroxyl,
chloro, or nitro; unsubstituted thiazolyl; thiazolyl
monosubstituted with nitro or hydroxymethyl; unsubstituted indolyl;
or unsubstituted indazolyl;
[0206] (m) when V and Y are both N and X is SO.sub.2, then R.sup.1
cannot be naphthyl when R.sup.2 is: unsubstituted pyridyl;
unsubstituted pyrimidinyl; phenyl monosubstituted with hydroxyl or
C.sub.1-C.sub.6 alkoxy; unsubstituted thiazolyl; or
5-chloro-2-methylphenyl;
[0207] (n) when Y is N and V is CH and X is SO.sub.2, then R.sup.1
cannot be 1-chlorophenyl when R.sup.2 is: phenyl monosubstituted
with C.sub.1-C.sub.6 alkoxy or C.sub.1-C.sub.6 alkyl; or
substituted benzo[d]isoxazole;
[0208] (o) when Y is N and V is CH and X is SO.sub.2, then R.sup.1
cannot be naphthyl when R.sup.2 is phenyl monosubstituted with
hydroxymethyl.
[0209] In certain embodiments, (a) applies. In certain embodiments,
(a) and/or (k) applies. In certain embodiments, (a), (k) and any
one, two, three, or four of (l)-(o) apply.
[0210] In one aspect, this invention relates to a compound of
formula (I), in which:
[0211] R.sup.1 is C.sub.7-C.sub.20 aralkyl, C.sub.3-C.sub.16
cycloalkyl, or (C.sub.1-C.sub.12 alkyl)-(C.sub.3-C.sub.16
cycloalkyl), each of which is optionally substituted with from 1-10
R.sup.b;
[0212] R.sup.2 is:
[0213] (i) C.sub.6-C.sub.18 aryl or heteroaryl including 5-20
atoms, each of which is optionally substituted with from 1-10
R.sup.c; or
[0214] (ii) OR.sup.1; SR.sup.1; or NR.sup.3R.sup.4, wherein R.sup.3
and R.sup.4 are each, independently, hydrogen or R.sup.1;
[0215] X is CO; and
[0216] R.sup.3, R.sup.4, R.sup.6, R.sup.7, V, Y, W.sup.1, Z.sup.1,
W.sup.2, Z.sup.2, R.sup.a, R.sup.a', R.sup.b, R.sup.c, R.sup.d,
R.sup.e, R.sup.f, R.sup.g, R.sup.h, R.sup.i, R.sup.j, R.sup.k, and
R.sup.m can be as defined anywhere herein.
[0217] In one aspect, this invention relates to a compound of
formula (I), in which:
[0218] R.sup.1 is C.sub.6-C.sub.18 aryl or heteroaryl including
5-20 atoms, each of which is optionally substituted with from 1-10
R.sup.a;
[0219] R.sup.2 is C.sub.6-C.sub.16 cycloalkyl; C.sub.6-C.sub.16
cycloalkenyl; heterocyclyl including 3-16 atoms; or
heterocycloalkenyl including 3-16 atoms; each of which is
optionally substituted with from 1-10 R.sup.b;
[0220] X is S(O).sub.n or S(O).sub.nNR.sup.6, wherein n is 1 or 2,
and R.sup.6 is hydrogen, C.sub.1-C.sub.12 alkyl, or
C.sub.3-C.sub.16 cycloalkyl; and
[0221] R.sup.6, R.sup.1, V, Y, W.sup.1, Z.sup.1, W.sup.2, Z.sup.2,
R.sup.a, R.sup.a', R.sup.b, R.sup.c, R.sup.d, R.sup.e, R.sup.f,
R.sup.g, R.sup.h, R.sup.i, R.sup.j, R.sup.k, and R.sup.m can be as
defined anywhere herein.
[0222] In some embodiments, (p) and/or (q) apply:
[0223] (p) when V and Y are both N and X is SO.sub.2, then R.sup.1
cannot be 1-chlorophenyl when R.sup.2 is unsubstituted adamantyl or
substituted or unsubstituted cyclohexyl; and
[0224] (q) when Y is N, V is CH, and X is SO.sub.2, then R.sup.1
cannot be 1-chlorophenyl when R.sup.2 is unsubstituted piperidyl,
piperidyl substituted with oxo, unsubstituted morpholinyl, or
unsubstituted pyrrolidinyl; or a pharmaceutically acceptable salt
thereof.
[0225] In one aspect, this invention relates to a compound of
formula (VI-A):
##STR00002##
[0226] in which:
[0227] one or two of R.sup.a2, R.sup.a3, R.sup.a4, and R.sup.a6 are
each, independently, halo; NR.sup.dR.sup.e; hydroxyl;
C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl, each of which
is optionally substituted with from 1-2 R.sup.j; C.sub.1-C.sub.12
alkoxy, optionally substituted with 1-2 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; cyano; nitro; C.sub.6-C.sub.10 aryl or heteroaryl
including 5-12 atoms, each of which is optionally substituted with
from 1-2 R.sup.a'; C.sub.6-C.sub.10 aryloxy or heteroaryloxy
including 5-12 atoms, each of which is optionally substituted with
from 1-2 R.sup.a'; heterocyclyl including 3-10 atoms,
C.sub.3-C.sub.10 cycloalkyl, C.sub.7-C.sub.12 aralkoxy or
heteroaralkoxy including 6-12 atoms, each of which is optionally
substituted with 1-3 R.sup.b; --C(O)OR.sup.g;
--C(O)NR.sup.dR.sup.e; or --NR.sup.hC(O)R.sup.i; and the others are
hydrogen;
[0228] W.sup.1 is C.sub.1-C.sub.4 alkyl; and
[0229] one or two of R.sup.c22, R.sup.c23, R.sup.c24, R.sup.c25,
and R.sup.c26 are each, independently, halo; C.sub.1-C.sub.12 alkyl
or C.sub.1-C.sub.12 haloalkyl, each of which is optionally
substituted with from 1-3 R.sup.j; C.sub.1-C.sub.12 alkoxy;
C.sub.1-C.sub.12 haloalkoxy; cyano; nitro; or C.sub.6-C.sub.10 aryl
or heteroaryl including 5-12 atoms, each of which is optionally
substituted with from 1-2 R.sup.a; and the others are hydrogen.
[0230] In certain embodiments, one or more of the conditions
delineated in the Summary can apply. For example, (a) can apply. In
certain embodiments, (a) and any one of (e)-(j) apply. In certain
embodiments, any one of (e)-(j) applies. In certain embodiments,
any two or three of (e)-(j) applies, optionally in combination with
(a). For example, (e) or (f) and (g) or (h) and/or (i) and (j),
optionally in combination with (a).
[0231] In certain embodiments, (a) applies. In certain embodiments,
(a) and/or (k) applies. In certain embodiments, (a), (k) and any
one, two, three, or four of (l)-(o) apply.
[0232] Embodiments can include one or more of the following
features.
[0233] The compounds can be in the form of a pharmaceutically
acceptable salt. The compounds can be an N-oxide thereof and can
also be in the form of a pharmaceutically acceptable salt.
[0234] Each of V and Y can both be N. V can be CR.sup.7 (e.g., CH),
and Y can be N. Y can be CR.sup.7 (e.g., CH), and V can be N.
[0235] X can be SO.sub.2, SO.sub.2NH, or C(O).
[0236] One or two of W.sup.1, Z.sup.1, W.sup.2, and Z.sup.2 (e.g.,
W.sup.1 and Z.sup.2, e.g., W.sup.1) can each be, independently,
other than hydrogen (e.g., C.sub.1-C.sub.4 alkyl or oxo), and the
others can be hydrogen. One or two of W.sup.1, Z.sup.1, W.sup.2,
and Z.sup.2 (e.g., W.sup.1 and Z.sup.2, e.g., W.sup.1) can each be,
independently, C.sub.1-C.sub.4 alkyl, and the others can be
hydrogen. Each of Z.sup.1 and W.sup.2 can be hydrogen. One or both
of W.sup.1 and Z.sup.2 (e.g., W.sup.1) can each be, independently,
C.sub.1-C.sub.4 alkyl; and each of Z.sup.1 and W.sup.2 can be
hydrogen. W.sup.1 can be C.sub.1-C.sub.4 alkyl (e.g., CH.sub.3).
Each of W.sup.1, Z.sup.1, W.sup.2, and Z.sup.2 can be hydrogen.
[0237] R.sup.1 can be C.sub.6-C.sub.10 aryl, optionally substituted
with 1-4 R.sup.a. In some embodiments, R.sup.1 is other than
substituted or unsubstituted naphthyl.
[0238] R.sup.a at each occurrence can be, independently, halo;
C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl, each of which
is optionally substituted with from 1-2 R.sup.j; C.sub.1-C.sub.12
alkoxy, optionally substituted with 1-2 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; cyano; nitro; C.sub.6-C.sub.10 aryl or heteroaryl
including 5-12 atoms, each of which is optionally substituted with
from 1-2 R.sup.a'; C.sub.6-C.sub.10 aryloxy or heteroaryloxy
including 5-12 atoms, each of which is optionally substituted with
from 1-2 R.sup.a'; C.sub.3-C.sub.10 heterocyclyl, C.sub.3-C.sub.10
cycloalkyl, C.sub.7-C.sub.12 aralkoxy or heteroaralkoxy including
6-12 atoms, each of which is optionally substituted with 1-2
R.sup.b; or --NR.sup.hC(O)R.sup.i. In some embodiments, R.sup.a is
other than halo (e.g., chloro).
[0239] R.sup.a at each occurrence is, independently, halo;
NR.sup.dR.sup.e; hydroxyl; C.sub.1-C.sub.12 alkyl or
C.sub.1-C.sub.12 haloalkyl, each of which is optionally substituted
with from 1-2 R.sup.j; C.sub.1-C.sub.12 alkoxy, optionally
substituted with from 1-2 R.sup.f; C.sub.1-C.sub.12 haloalkoxy;
cyano; nitro; C.sub.6-C.sub.10 aryl or heteroaryl including 5-12
atoms, each of which is optionally substituted with from 1-2
R.sup.a; C.sub.6-C.sub.10 aryloxy or heteroaryloxy including 5-12
atoms, each of which is optionally substituted with from 1-2
R.sup.a'; heterocyclyl including 3-10 atoms, C.sub.3-C.sub.10
cycloalkyl, C.sub.7-C.sub.12 aralkoxy or heteroaralkoxy including
6-12 atoms, each of which is optionally substituted with 1-2
R.sup.b; --C(O)OR.sup.g; --C(O)NR.sup.dR.sup.e; or
--NR.sup.hC(O)R.sup.i. In some embodiments, R.sup.a is other than
halo (e.g., chloro).
[0240] R.sup.1 can be 1-naphthyl, 2-naphthyl, or phenyl (i.e.,
unsubstituted).
[0241] R.sup.1 can have formula (II):
##STR00003##
[0242] In certain embodiments, one of R.sup.a2, R.sup.a3, and
R.sup.a4 is halo; C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12
haloalkyl, each of which is optionally substituted with 1-2
R.sup.j; C.sub.1-C.sub.12 alkoxy, optionally substituted with 1-2
R.sup.f; C.sub.1-C.sub.12 haloalkoxy; cyano; nitro;
C.sub.6-C.sub.10 aryl or heteroaryl including 5-12 atoms, each of
which is optionally substituted with from 1-2 R.sup.a';
C.sub.6-C.sub.10 aryloxy, optionally substituted with from 1-2
R.sup.a'; C.sub.3-C.sub.10 heterocyclyl, C.sub.3-C.sub.10
cycloalkyl, or C.sub.7-C.sub.12 aralkoxy, each of which is
optionally substituted with 1-2 R.sup.b; or --NR.sup.hC(O)R.sup.i;
and the others are hydrogen.
[0243] In other embodiments, one of R.sup.a2, R.sup.a3, and
R.sup.a4 is halo; NR.sup.dR.sup.e; hydroxyl; C.sub.1-C.sub.12 alkyl
or C.sub.1-C.sub.12 haloalkyl, each of which is optionally
substituted with from 1-2 R.sup.j; C.sub.1-C.sub.12 alkoxy,
optionally substituted with 1-2 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; cyano; nitro; C.sub.6-C.sub.10 aryl or heteroaryl
including 5-12 atoms, each of which is optionally substituted with
from 1-2 R.sup.a'; C.sub.6-C.sub.10 aryloxy or heteroaryloxy
including 5-12 atoms, each of which is optionally substituted with
from 1-2 R.sup.a'; heterocyclyl including 3-10 atoms,
C.sub.3-C.sub.10 cycloalkyl, C.sub.7-C.sub.12 aralkoxy or
heteroaralkoxy including 6-12 atoms, each of which is optionally
substituted with 1-3 R.sup.b; --C(O)OR.sup.g;
--C(O)NR.sup.dR.sup.e; or --NR.sup.hC(O)R.sup.i; and the others are
hydrogen.
[0244] R.sup.a2, R.sup.a3, or R.sup.a4 (e.g., R.sup.a3 or R.sup.a4,
e.g., R.sup.a3) can be C.sub.1-C.sub.12 haloalkyl (e.g.,
C.sub.1-C.sub.4 haloalkyl), optionally substituted with 1-2 (e.g.,
1) R.sup.j. For example, R.sup.a3 or R.sup.a4 can be
1,1,1-trifluoro-2-hydroxy-2-propyl, in which the stereogenic carbon
(i.e., the carbon attached to the hydroxyl group) can have the R or
S configuration or some combination thereof (e.g., about 50% R and
about 50% S or any other non-racemic combination of
configurations). In some embodiments, R.sup.a3 or R.sup.a4 (e.g.,
R.sup.a3) can be:
##STR00004##
In these embodiments, each of the remaining substituents can be
hydrogen.
[0245] R.sup.a2, R.sup.a3, or R.sup.a4 can be C.sub.1-C.sub.12
alkyl, optionally substituted with 1 R.sup.j. For example, R.sup.a4
can be CH.sub.3 or a C.sub.3-C.sub.12 branched alkyl, such as
tert-butyl. As another example, R.sup.a3 or R.sup.a4 can be
C.sub.1-C.sub.12 alkyl, optionally substituted with 1 R.sup.j
(e.g., 2-hydroxy-2-propyl).
[0246] R.sup.a3 or R.sup.a4 (e.g., R.sup.a3) can be heterocyclyl
including 3-8 atoms, optionally substituted with from 1-3 (e.g., 1)
R.sup.b. In embodiments, R.sup.a3 or R.sup.a4 (e.g., R.sup.a3) can
be piperazinyl, piperidyl, morpholinyl, or pyrrolidinyl, each of
which is optionally substituted with 1-3 (e.g., 1) R.sup.b. For
example, R.sup.a3 or R.sup.a4 (e.g., R.sup.a3) can be
3-hydroxypyrrolidin-1-yl or 3-carboxypyrrolidin-1-yl.
[0247] In embodiments, R.sup.b at each occurrence can be,
independently, halo; NR.sup.dR.sup.e; hydroxyl; oxo;
C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl, each of which
is optionally substituted with from 1-3 R.sup.j; C.sub.1-C.sub.12
alkoxy, optionally substituted with 1-2 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; heterocyclyl including 3-10 atoms or C.sub.3-C.sub.10
cycloalkyl, each of which is optionally substituted with 1-3
R.sup.b; --C(O)R.sup.g; --C(O)OR.sup.g; --C(O)NR.sup.dR.sup.e;
--OC(O)R.sup.g; or --NR.sup.hC(O)R.sup.i.
[0248] R.sup.a3 or R.sup.4 (e.g., R.sup.a3) can be heteroaryl
including 5 or 6 atoms, optionally substituted with from 1-2
R.sup.a' (e.g., 1H-1,2,4-triazolyl).
[0249] R.sup.a2, R.sup.a3, or R.sup.a4 can be halo (e.g., chloro).
R.sup.a3 or R.sup.a4 can be phenyl or phenoxy, each of which is
optionally substituted with from 1-2 halo. R.sup.a4 can be
C.sub.1-C.sub.4 alkoxy, optionally substituted with 1 R.sup.f.
R.sup.a4 can be --NHC(O)R.sup.i. In embodiments, R.sup.i can be
C.sub.1-C.sub.4 alkyl; or R.sup.i can be NR.sup.dR.sup.e, in which
R.sup.d and R.sup.e can each be, independently, hydrogen or
C.sub.1-C.sub.4 alkyl; or R.sup.i can be heterocyclyl including 3-8
atoms. R.sup.a2, R.sup.a3, or R.sup.a4 can be C.sub.3-C.sub.10
cycloalkyl, optionally substituted with 1 R.sup.b (e.g.,
1-hydroxycyclopropyl).
[0250] R.sup.1 can have formula (II-A):
##STR00005##
[0251] In certain embodiments, two of R.sup.a2, R.sup.a3, R.sup.a4,
and R.sup.a6 can each be, independently, halo; NR.sup.dR.sup.e;
hydroxyl; C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl,
each of which is optionally substituted with 1-2 R.sup.j;
C.sub.1-C.sub.12 alkoxy, optionally substituted with from 1-2
R.sup.f; C.sub.1-C.sub.12 haloalkoxy; heterocyclyl including 3-10
atoms, optionally substituted with from 1-3 R.sup.b; heteroaryl
including 5-12 atoms, optionally substituted with from 1-2
R.sup.a'; --C(O)OR.sup.g; --C(O)NR.sup.dR.sup.e; or
--NR.sup.hC(O)R.sup.i; and the others can be hydrogen.
[0252] In other embodiments, one or two of R.sup.a2, R.sup.a3,
R.sup.a4, and R.sup.a6 can each be, independently, halo;
NR.sup.dR.sup.e; hydroxyl; C.sub.1-C.sub.12 alkyl or
C.sub.1-C.sub.12 haloalkyl, each of which is optionally substituted
with from 1-2 R.sup.j; C.sub.1-C.sub.12 alkoxy, optionally
substituted with 1-2 R.sup.f; C.sub.1-C.sub.12 haloalkoxy; cyano;
nitro; C.sub.6-C.sub.10 aryl or heteroaryl including 5-12 atoms,
each of which is optionally substituted with from 1-2 R.sup.a';
C.sub.6-C.sub.10 aryloxy or heteroaryloxy including 5-12 atoms,
each of which is optionally substituted with from 1-2 R.sup.a';
heterocyclyl including 3-10 atoms, C.sub.3-C.sub.10 cycloalkyl,
C.sub.7-C.sub.12 aralkoxy or heteroaralkoxy including 6-12 atoms,
each of which is optionally substituted with 1-3 R.sup.b;
--C(O)OR.sup.g; --C(O)NR.sup.dR.sup.e; or --NR.sup.hC(O)R.sup.i;
and the others can be hydrogen.
[0253] R.sup.a2 can be halo (e.g., chloro), and R.sup.a4 can be a
substituent other than hydrogen, such as halo; NR.sup.dR.sup.e;
hydroxyl; C.sub.1-C.sub.12 alkoxy, optionally substituted with from
1-2 R.sup.f; C.sub.1-C.sub.12 haloalkoxy; heterocyclyl including
3-10 atoms, optionally substituted with from 1-3 R.sup.b;
heteroaryl including 5-12 atoms, optionally substituted with from
1-2 R.sup.a'; --C(O)OR.sup.g; --C(O)NR.sup.dR.sup.e; or
--NR.sup.hC(O)R.sup.i. For example, R.sup.a2 can be halo (e.g.,
chloro), and R.sup.a4 can be heterocyclyl including 5-8 atoms,
optionally substituted with from 1-3 R.sup.b.
[0254] R.sup.1 can be 3,4-dichlorophenyl, 3-fluoro-4-bromophenyl,
2,6-dichlorophenyl, 2,4-difluorophenyl, 3,4-dimethoxyphenyl,
2-bromo-4-(trifluoromethyl)phenyl, or
##STR00006##
[0255] R.sup.1 can be heteroaryl including 5-14 atoms, optionally
substituted with from 1-5 (e.g., 1-2) R.sup.a.
[0256] R.sup.1 can be a monocyclic heteroaryl including 5-6 atoms,
optionally substituted with from 1-2 R.sup.a. In embodiments,
R.sup.1 can be thienyl, isoxazolyl, or pyridinyl, each of which is
optionally substituted with from 1-2 R.sup.a, wherein R.sup.a at
each occurrence is, independently, halo, C.sub.1-C.sub.4 alkyl, or
heterocyclyl including 3-8 atoms.
[0257] In certain embodiments, R.sup.1 can have formula (II-B):
##STR00007##
[0258] In some embodiments, R.sup.a122 and R.sup.a123 can each be,
independently, hydrogen; halo; NR.sup.dR.sup.e; C.sub.1-C.sub.12
alkyl or C.sub.1-C.sub.12 haloalkyl, each of which is optionally
substituted with from 1-2 R.sup.j; C.sub.6-C.sub.10 aryl or
heteroaryl including 5-12 atoms, each of which is optionally
substituted with from 1-2 R.sup.a'; heterocyclyl including 3-10
atoms, C.sub.3-C.sub.10 cycloalkyl, C.sub.7-C.sub.12 aralkoxy or
heteroaralkoxy including 6-12 atoms, each of which is optionally
substituted with 1-3 R.sup.b; --C(O)R.sup.g; --C(O)OR.sup.g;
--C(O)NR.sup.dR.sup.e; or --NR.sup.hC(O)R.sup.i.
[0259] R.sup.a222 can be halo; NR.sup.dR.sup.e; C.sub.1-C.sub.12
alkyl or C.sub.1-C.sub.12 haloalkyl, each of which is optionally
substituted with from 1-2 R.sup.j; C.sub.6-C.sub.10 aryl or
heteroaryl including 5-12 atoms, each of which is optionally
substituted with from 1-2 R.sup.a'; heterocyclyl including 3-10
atoms, C.sub.3-C.sub.10 cycloalkyl, C.sub.7-C.sub.12 aralkoxy or
heteroaralkoxy including 6-12 atoms, each of which is optionally
substituted with 1-3 R.sup.b; --C(O)R.sup.g; --C(O)OR.sup.g;
--C(O)NR.sup.dR.sup.e; or --NR.sup.hC(O)R.sup.i; and R.sup.a223 can
be hydrogen. For example, R.sup.a222 can be heterocyclyl including
3-8 atoms, optionally substituted with from 1-3 R.sup.b (e.g.,
piperazinyl, piperidyl, morpholinyl, or pyrrolidinyl, each of which
is optionally substituted with 1-3 R.sup.b).
[0260] R.sup.1 can be a bicyclic or tricyclic heteroaryl including
8-12 atoms, each of which is optionally substituted with from 1-2
R.sup.a. For example, R.sup.1 can be quinolyl, benzothienyl,
dibenzothienyl, benzofuryl, dibenzofuryl, or benzothiazolyl, each
of which is optionally substituted with from 1-2 R.sup.a, wherein
R.sup.a at each occurrence is, independently, halo, C.sub.1-C.sub.4
alkyl, or heterocyclyl including 3-8 atoms.
[0261] R.sup.1 can be C.sub.3-C.sub.12 cycloalkyl, optionally
substituted with from 1-5 R.sup.b. For example, R.sup.1 can be
cyclopropyl, cyclopentyl, cyclohexyl, or adamantyl, each of which
is optionally substituted with from 1-5 R.sup.b, wherein R.sup.b at
each occurrence is, independently, halo or C.sub.1-C.sub.4
alkyl.
[0262] R.sup.1 can be (C.sub.1-C.sub.6 alkyl)-(C.sub.3-C.sub.12
cycloalkyl), wherein the cycloalkyl ring is optionally substituted
with from 1-3 R.sup.b. For example, R.sup.1 can be
--CH.sub.2-(cyclopentyl), --CH.sub.2--(cyclohexyl), or
--CH.sub.2-(bicycloheptyl), wherein the cycloalkyl ring is
optionally substituted with from 1-3 C.sub.1-C.sub.4 alkyl.
[0263] R.sup.1 can be C.sub.7-C.sub.12 aralkyl, optionally
substituted with from 1-2 R.sup.b (e.g., benzyl, optionally
substituted with from 1-2 halo). R.sup.1 can be arylheterocyclyl
including 9-12 atoms.
[0264] R.sup.2 can be C.sub.6-C.sub.10 aryl, optionally substituted
with from 1-3 R.sup.c.
[0265] R.sup.2 can have formula (IV):
##STR00008##
[0266] In some embodiments, one of R.sup.c22, R.sup.c23, and
R.sup.c24 is halo; hydroxyl; C.sub.1-C.sub.12 alkyl;
C.sub.1-C.sub.12 haloalkyl; C.sub.1-C.sub.12 alkoxy;
C.sub.1-C.sub.12 haloalkoxy; cyano; nitro; or C.sub.6-C.sub.10
aryl, optionally substituted with from 1-2 R.sup.a; and the others
are hydrogen.
[0267] R.sup.c22 or R.sup.c23 (e.g., R.sup.c22) can be
C.sub.1-C.sub.4 haloalkyl (e.g., CF.sub.3). R.sup.c22 can be
C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkoxy. R.sup.c22,
R.sup.c23, or R.sup.c24 (e.g., R.sup.c23 or R.sup.c24, e.g.,
R.sup.c24) can be halo (e.g., fluoro). R.sup.c24 can be phenyl
substituted with 1 R.sup.a.
[0268] R.sup.2 can have formula (IV-A):
##STR00009##
[0269] In certain embodiments, two of R.sup.c22, R.sup.c23,
R.sup.c24, R.sup.c25, and R.sup.c26 can each be, independently,
halo; C.sub.1-C.sub.12 alkyl; C.sub.1-C.sub.12 haloalkyl; cyano,
C.sub.1-C.sub.12 alkoxy; heterocyclyl including 3-10 atoms,
optionally substituted with from 1-2 R.sup.b; heteroaryl including
from 5-10 atoms, optionally substituted with from 1-2 R.sup.a; or
SO.sub.2R.sup.m; and the others are hydrogen.
[0270] In other embodiments, one or two of R.sup.c22, R.sup.c23,
R.sup.c24, R.sup.c25, and R.sup.e26 can each be, independently,
halo; C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl, each of
which is optionally substituted with from 1-3 R.sup.j;
C.sub.1-C.sub.12 alkoxy; C.sub.1-C.sub.12 haloalkoxy; cyano; nitro;
or C.sub.6-C.sub.10 aryl or heteroaryl including 5-12 atoms, each
of which is optionally substituted with from 1-2 R.sup.a; and the
others are hydrogen.
[0271] Two of R.sup.c22, R.sup.c23, R.sup.c24, R.sup.c25 and
R.sup.c26 can each be, independently, halo; C.sub.1-C.sub.4
haloalkyl, optionally substituted with from 1-3 R.sup.j; cyano; or
heteroaryl including 5-6 atoms, optionally substituted with from
1-2 R.sup.a.
[0272] R.sup.c22 can be C.sub.1-C.sub.4 haloalkyl (e.g., CF.sub.3),
halo (e.g., chloro), C.sub.1-C.sub.6 alkoxy (e.g., OCH3), cyano, or
C.sub.1-C.sub.6 alkyl (e.g., CH.sub.3); and one of R.sup.c23,
R.sup.c24, and R.sup.c25 can be: heterocyclyl including 3-8 atoms,
optionally substituted with 1 R.sup.b; heteroaryl including 5 or 6
atoms, optionally substituted with 1 R.sup.a; or halo. In
embodiments, R.sup.c22 can be CF.sub.3, chloro, OCH.sub.3, cyano,
or CH.sub.3; and one of R.sup.c23, R.sup.c24 and R.sup.c25 can be:
heterocyclyl including 3-8 atoms, optionally substituted with 1
R.sup.b; heteroaryl including 5 or 6 atoms, optionally substituted
with 1 R.sup.a; or halo. In these embodiments, one of R.sup.c23,
R.sup.c24, and R.sup.c25 can be piperazinyl, optionally substituted
with 1 R.sup.b; morpholinyl, optionally substituted with 1 R.sup.b;
1H-1,2,4-triazolyl; or fluoro.
[0273] Two of R.sup.c22, R.sup.c23 R.sup.c24, R.sup.c25 and
R.sup.c26 can each be, independently, halo (e.g., fluoro) or
C.sub.1-C.sub.4 haloalkyl (e.g., CF.sub.3).
[0274] R.sup.c22 can be C.sub.1-C.sub.4 haloalkyl (e.g., CF.sub.3),
optionally substituted with from 1-3 R.sup.j; and R.sup.c24 can be
halo; C.sub.1-C.sub.4 haloalkyl, optionally substituted with from
1-3 R.sup.j; cyano; or heteroaryl including 5-6 atoms, optionally
substituted with from 1-2 R.sup.a. For example, R.sup.c22 can be
CF.sub.3. R.sup.c22 can be CF.sub.3, and R.sup.c24 can be halo (and
the others can be hydrogen).
[0275] R.sup.c22 and R.sup.c24 can each be, independently, fluoro
or chloro. For example, R.sup.c22 can be chloro, and R.sup.c24 can
be fluoro.
[0276] R.sup.2 can be 4-fluoro-2-(sulfonylmethyl)phenyl;
4-fluoro-2-(trifluoromethyl)phenyl; 2,3-dichlorophenyl;
2,4-difluorophenyl; 2,4-dimethylphenyl; 2,6-dichlorophenyl;
2,6-dimethylphenyl; 3,4-dichlorophenyl; or
3-fluoro-2-(trifluoromethyl)phenyl.
[0277] R.sup.2 can be heteroaryl including 5-12 atoms, optionally
substituted with from 1-3 (e.g., 1-2) R.sup.c.
[0278] R.sup.2 can have formula (III):
##STR00010##
[0279] In some embodiments, one or two of R.sup.c3, R.sup.c4,
R.sup.c5, and R.sup.c6 can each be, independently, halo;
C.sub.1-C.sub.12 alkyl; C.sub.1-C.sub.12 haloalkyl, optionally
substituted with 1-2 R.sup.j; cyano; or nitro; and the others are
hydrogen.
[0280] One of R.sup.c3, R.sup.c4, or R.sup.c5 (e.g., R.sup.c3) can
be C.sub.1-C.sub.4 haloalkyl (e.g., CF.sub.3). R.sup.c3 or R.sup.c5
can be chloro or fluoro. R.sup.c3 can be C.sub.1-C.sub.4 alkyl.
R.sup.c3 can be CF.sub.3, chloro, fluoro, cyano, CH.sub.3, or
nitro.
[0281] Two of R.sup.c3, R.sup.c4, R.sup.c5, and R.sup.c6 are each,
independently, halo or C.sub.1-C.sub.4 haloalkyl. For example, two
of R.sup.c3, R.sup.c4, R.sup.c5, and R.sup.c6 are each,
independently, fluoro or CF.sub.3.
[0282] R.sup.2 can be 1-quinolyl, 2-quinolyl, 1-isoquinolyl, or
3,5-dichloro-4-pyridyl.
[0283] R.sup.2 can be OR.sup.1, wherein R.sup.1 is C.sub.6-C.sub.10
aryl, or heteroaryl including 5-10 atoms, each of which is
optionally substituted with from 1-3 R.sup.a; or C.sub.7-C.sub.12
aralkyl, optionally substituted with from 1-3 R.sup.b.
[0284] R.sup.2 can have formula (V):
##STR00011##
[0285] In some embodiments, one of R.sup.c32, R.sup.c33, and
R.sup.c34 can be halo; C.sub.1-C.sub.12 alkyl; C.sub.1-C.sub.12
haloalkyl; C.sub.1-C.sub.12 alkoxy; C.sub.1-C.sub.12 haloalkoxy;
cyano; or nitro; and the others can be hydrogen. R.sup.c32 can be
C.sub.1-C.sub.4 haloalkyl (e.g., CF.sub.3) or C.sub.1-C.sub.4
alkyl. R.sup.c32 or R.sup.c34 can be C.sub.1-C.sub.4 alkoxy.
R.sup.c32 can be halo. For example, R.sup.2 can be
2,6-dichlorophenoxy.
[0286] R.sup.2 can be NR.sup.3R.sup.4, in which one of R.sup.3 and
R.sup.4 is hydrogen, and the other can be C.sub.6-C.sub.10 aryl,
optionally substituted with from 1-3 R.sup.a. For example, R.sup.2
can be 2-chlorophenylamino.
[0287] R.sup.2 is C.sub.3-C.sub.12 cycloalkyl, optionally
substituted with from 1-5 R.sup.b (e.g., C.sub.6-C.sub.12
cycloalkyl, optionally substituted with from 1-5 R.sup.b). For
example, R.sup.2 can be cyclohexyl, bicycloheptyl, cycloheptyl, or
adamantyl, each of which is optionally substituted with from 1-2
R.sup.b, in which R.sup.b at each occurrence can be, independently,
halo or C.sub.1-C.sub.4 alkyl.
[0288] Each of V and Y is N, and X is SO.sub.2, and embodiments can
include one or more of the features described anywhere herein.
[0289] The compound of formula (I) can be
(2R)-1,1,1-trifluoro-2-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-
-methylpiperazin-1-yl}sulfonyl)phenyl]propan-2-ol.
[0290] In one aspect, this invention features a pharmaceutical
composition, which includes a compound of formula (I) or a salt
(e.g., a pharmaceutically acceptable salt) or a prodrug thereof
(e.g., an effective amount thereof) and a pharmaceutically
acceptable adjuvant, carrier or diluent. In some embodiments, the
composition can further include an additional therapeutic
agent.
[0291] In one aspect, this invention relates to a method for
treating a disease or condition mediated by excess or uncontrolled
amounts of cortisol and/or other corticosteroids, which includes
administering to a subject in need thereof an effective amount of a
compound of formula (I) or a salt (e.g., a pharmaceutically
acceptable salt) or prodrug thereof.
[0292] In one aspect of the invention, this invention relates to
methods for treating diabetes (e.g., type I diabetes, type 2
diabetes), which includes administering to a subject in need
thereof an effective amount of a compound of formula I or a
pharmaceutically acceptable salt thereof.
[0293] In another aspect of the invention, this invention relates
to methods for treating Syndrome X, which includes administering to
a subject in need thereof an effective amount of a compound of
formula I or a pharmaceutically acceptable salt thereof.
[0294] In a further aspect of the invention, this invention relates
to methods for treating hyperglycemia, diabetes or insulin
resistance, which includes administering to a subject in need
thereof an effective amount of a compound of formula I or a
pharmaceutically acceptable salt thereof.
[0295] In one aspect of the invention, this invention relates to
methods for treating obesity, which includes administering to a
subject in need thereof an effective amount of a compound of
formula I or a pharmaceutically acceptable salt thereof.
[0296] In another aspect of the invention, this invention relates
to methods for treating a lipid disorder selected from the group
consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia,
hypercholesterolemia, low HDL and high LDL, which includes
administering to a subject in need thereof an effective amount of a
compound of formula I or a pharmaceutically acceptable salt
thereof.
[0297] In a further aspect of the invention, this invention relates
to methods for treating atherosclerosis, which include
administering to a subject in need thereof an effective amount of a
compound of formula I or a pharmaceutically acceptable salt
thereof.
[0298] In one aspect of the invention, this invention relates to
methods for treating a cognitive disorder (e.g., Alzheimer's
disease), which includes administering to a subject in need thereof
an effective amount of a compound of formula I or a
pharmaceutically acceptable salt thereof.
[0299] In another aspect of the invention, this invention relates
to methods for promoting wound healing, which includes
administering to a subject in need thereof an effective amount of a
compound of formula I or a pharmaceutically acceptable salt
thereof.
[0300] In a further aspect of the invention, this invention relates
to methods for treating, controlling, ameliorating, preventing,
delaying the onset of, or reducing the risk of developing one or
more of diabetes (e.g., type 1 or type 2 diabetes), Syndrome X,
hyperglycemia, low glucose tolerance, insulin resistance, obesity,
lipid disorders, dyslipidemia, hyperlipidemia,
hypertriglyceridemia, hypercholesterolemia, low HDL levels, high
LDL levels, atherosclerosis and its sequelae, vascular restenosis,
pancreatitis, abdominal obesity, neurodegenerative disease,
retinopathy, nephropathy, neuropathy, hypertension, coronary heart
disease, stroke, peripheral vascular disease, Cushing's syndrome,
glaucoma, osteoporosis, hyperinsulinemia, tuberculosis, psoriasis,
cognitive disorders and dementia (e.g., impairment associated with
aging and of neuronal dysfunction, e.g., Alzheimer's disease),
depression, viral diseases, inflammatory disorders, immune
disorders); or promoting wound healing, which includes
administering to a subject in need thereof an effective amount of a
compound of formula I or a pharmaceutically acceptable salt
thereof.
[0301] The invention also relates generally to inhibiting 11-beta
HSD1 with a compound having formula (I). In some embodiments, the
methods can include, e.g., contacting an 11.beta.HSD1 in a sample
(e.g., a tissue) with a compound having formula (I). In other
embodiments, the methods can include administering a compound
having formula (I) to a subject (e.g., a mammal, e.g., a mammal
subject to or at risk for diseases mediated by abnormally high
levels of cortisol and other 11.beta.-hydroxysteroids, e.g., NIDDM,
obesity, dyslipidemia, syndrome X, and hypertension). Accordingly,
in yet another aspect, this invention includes methods of screening
for compounds that inhibit 11.beta.HSD1.
[0302] In some embodiments, the subject can be a subject in need
thereof (e.g., a subject identified as being in need of such
treatment). Identifying a subject in need of such treatment can be
in the judgment of a subject or a health care professional and can
be subjective (e.g. opinion) or objective (e.g. measurable by a
test or diagnostic method). In some embodiments, the subject can be
a mammal. In certain embodiments, the subject is a human.
[0303] In a further aspect, this invention also relates to methods
of making compounds described herein. Alternatively, the method
includes taking any one of the intermediate compounds described
herein and reacting it with one or more chemical reagents in one or
more steps to produce a compound described herein.
[0304] In one aspect, this invention relates to any of the
compounds described herein.
[0305] In one aspect, this invention relates to a packaged product.
The packaged product includes a container, one of the
aforementioned compounds in the container, and a legend (e.g., a
label or an insert) associated with the container and indicating
administration of the compound for treatment and control of
diseases mediated by abnormally high levels of cortisol and other
11.beta.-hydroxysteroids, e.g., NIDDM and Syndrome X.
[0306] The term "mammal" includes organisms, which include mice,
rats, cows, sheep, pigs, rabbits, goats, and horses, monkeys, dogs,
cats, and preferably humans.
[0307] "An effective amount" refers to an amount of a compound that
confers a therapeutic effect (e.g., treats, controls, ameliorates,
prevents, delays the onset of, or reduces the risk of developing a
disease, disorder, or condition or symptoms thereof) on the treated
subject. The therapeutic effect may be objective (i.e., measurable
by some test or marker) or subjective (i.e., subject gives an
indication of or feels an effect). An effective amount of the
compound described above may range from about 0.01 mg/Kg to about
1000 mg/Kg, (e.g., from about 0.1 to about 100 mg/Kg, from about 1
to about 100 mg/Kg). Effective doses will also vary depending on
route of administration, as well as the possibility of co-usage
with other agents.
[0308] The term "halo" or "halogen" refers to any radical of
fluorine, chlorine, bromine or iodine. The term "carboxy" refers to
the --COOH radical.
[0309] In general, and unless otherwise indicated, substituent
(radical) prefix names are derived from the parent hydride by
either (i) replacing the "ane" in the parent hydride with the
suffixes "yl," "diyl," "triyl," "tetrayl," etc.; or (ii) replacing
the "e" in the parent hydride with the suffixes "yl," "diyl,"
"triyl," "tetrayl," etc. (here the atom(s) with the free valence,
when specified, is (are) given numbers as low as is consistent with
any established numbering of the parent hydride). Accepted
contracted names, e.g., adamantyl, naphthyl, anthryl, phenanthryl,
furyl, pyridyl, isoquinolyl, quinolyl, and piperidyl, and trivial
names, e.g., vinyl, allyl, phenyl, and thienyl are also used herein
throughout. Conventional numbering/lettering systems are also
adhered to for substituent numbering and the nomenclature of fused,
bicyclic, tricyclic, polycyclic rings.
[0310] The term "alkyl" refers to a saturated hydrocarbon chain
that may be a straight chain or branched chain, containing the
indicated number of carbon atoms. For example, C.sub.1-C.sub.20
alkyl indicates that the group may have from 1 to 20 (inclusive)
carbon atoms in it. Any atom can be substituted. Examples of alkyl
groups include without limitation methyl, ethyl, and
tert-butyl.
[0311] The term "cycloalkyl" refers to saturated monocyclic,
bicyclic, tricyclic, or other polycyclic hydrocarbon groups. Any
atom can be substituted, e.g., by one or more substituents. A ring
carbon serves as the point of attachment of a cycloalkyl group to
another moiety. Cycloalkyl groups can contain fused rings. Fused
rings are rings that share a common carbon atom. Cycloalkyl
moieties can include, e.g., cyclopropyl, cyclohexyl,
methylcyclohexyl (provided that the methylcyclohexyl group is
attached to another moiety via a cyclohexyl ring carbon and not the
methyl group), adamantyl, and norbornyl (bicycle[2.2.1]heptyl).
[0312] The term "haloalkyl" refers to an alkyl group, in which at
least one hydrogen atom is replaced by halo. In some embodiments,
more than one hydrogen atom (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, etc.
hydrogen atoms) on a alkyl group can be replaced by more than one
halogen (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23, 24, 25, 26, etc. halogen atoms). In
these embodiments, the hydrogen atoms can each be replaced by the
same halogen (e.g., fluoro) or the hydrogen atoms can be replaced
by a combination of different halogens (e.g., fluoro and chloro).
The term "haloalkyl" also includes alkyl moieties in which all
hydrogens have been replaced by halo (e.g., sometimes referred to
as perhaloalkyl moieties, such as trifluoromethyl).
[0313] The term "aralkyl" refers to an alkyl moiety in which an
alkyl hydrogen atom is replaced by an aryl group. One of the
carbons of the alkyl moiety serves as the point of attachment of
the aralkyl group to another moiety. Aralkyl includes groups in
which more than one hydrogen atom on an alkyl moiety has been
replaced by an aryl group. Any ring or chain atom can be
substituted e.g., by one or more substituents. Examples of
"aralkyl" include without limitation benzyl, 2-phenylethyl,
3-phenylpropyl, benzhydryl (diphenylmethyl), and trityl
(triphenylmethyl) groups.
[0314] The term "heteroaralkyl" refers to an alkyl moiety in which
an alkyl hydrogen atom is replaced by a heteroaryl group. One of
the carbons of the alkyl moiety serves as the point of attachment
of the aralkyl group to another moiety. Heteroaralkyl includes
groups in which more than one hydrogen atom on an alkyl moiety has
been replaced by a heteroaryl group. Any ring or chain atom can be
substituted e.g., by one or more substituents. Heteroaralkyl can
include, for example, 2-pyridylethyl.
[0315] The term "(alkyl)-(cycloalkyl)" refers to an alkyl moiety in
which an alkyl hydrogen atom is replaced by a cycloalkyl group. One
of the carbons of the alkyl moiety serves as the point of
attachment of the (alkyl)-(cycloalkyl) to another moiety. Any ring
or chain atom can be substituted e.g., by one or more substituents.
(alkyl)-(cycloalkyl) can include, for example:
##STR00012##
[0316] The term "alkenyl" refers to a straight or branched
hydrocarbon chain containing 2-20 carbon atoms and having one or
more double bonds. Any atom can be substituted, e.g., by one or
more substituents. Alkenyl groups can include, e.g., allyl,
1-butenyl, 2-hexenyl and 3-octenyl groups. One of the double bond
carbons can optionally be the point of attachment of the alkenyl
substituent. The term "alkynyl" refers to a straight or branched
hydrocarbon chain containing 2-20 carbon atoms and having one or
more triple bonds. Any atom can be substituted, e.g., by one or
more substituents. Alkynyl groups can include, e.g., ethynyl,
propargyl, and 3-hexynyl. One of the triple bond carbons can
optionally be the point of attachment of the alkynyl
substituent.
[0317] The term "alkoxy" refers to an --O-alkyl radical. The term
"mercapto" refers to an SH radical. The term "thioalkoxy" refers to
an --S-alkyl radical. The terms "aryloxy" and "heteroaryloxy" refer
to an --O-aryl radical and --O-heteroaryl radical, respectively.
The term "thioaryloxy" refers to an --S-aryl radical. The terms
"aralkoxy" and "heteroaralkoxy" refer to an --O-aralkyl radical and
--O-heteroaralkyl radical, respectively. The term "cycloalkoxy"
refers to an --O-cycloalkyl radical. The terms "cycloalkenyloxy"
and "heterocycloalkenyloxy" refer to an --O-cycloalkenyl radical
and --O-heterocycloalkenyl radical, respectively. The term
"heterocyclyloxy" refers to an --O-heterocyclyl radical. The terms
"alkenyloxy" and "alkynyloxy" refer to --O-alkenyl and --O-alkynyl
radicals, respectively.
[0318] The term "heterocyclyl" refers to a saturated monocyclic,
bicyclic, tricyclic or other polycyclic ring system having 1-4
heteroatoms if monocyclic, 1-8 heteroatoms if bicyclic, or 1-10
heteroatoms if tricyclic, said heteroatoms selected from O, N, or S
(e.g., carbon atoms and 1-4, 1-8, or 1-10 heteroatoms of N, O, or S
if monocyclic, bicyclic, or tricyclic, respectively). The
heteroatom or ring carbon is the point of attachment of the
heterocyclyl substituent to another moiety. Any atom can be
substituted, e.g., by one or more substituents. The heterocyclyl
groups can contain fused rings. Fused rings are rings that share a
common carbon atom. Heterocyclyl groups can include, e.g.,
tetrahydrofuryl, tetrahydropyranyl, piperidyl (piperidino),
piperazinyl, morpholinyl (morpholino), pyrrolinyl, and
pyrrolidinyl.
[0319] The term "cycloalkenyl" refers to partially unsaturated
monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon
groups. A ring carbon (e.g., saturated or unsaturated) is the point
of attachment of the cycloalkenyl substituent. Any atom can be
substituted e.g., by one or more substituents. The cycloalkenyl
groups can contain fused rings. Fused rings are rings that share a
common carbon atom. Cycloalkenyl moieties can include, e.g.,
cyclohexenyl, cyclohexadienyl, or norbornenyl.
[0320] The term "heterocycloalkenyl" refers to partially
unsaturated monocyclic, bicyclic, tricyclic, or other polycyclic
hydrocarbon groups having 1-4 heteroatoms if monocyclic, 1-8
heteroatoms if bicyclic, or 1-10 heteroatoms if tricyclic, said
heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-4,
1-8, or 1-10 heteroatoms of N, O, or S if monocyclic, bicyclic, or
tricyclic, respectively). A ring carbon (e.g., saturated or
unsaturated) or heteroatom is the point of attachment of the
heterocycloalkenyl substituent. Any atom can be substituted, e.g.,
by one or more substituents. The heterocycloalkenyl groups can
contain fused rings. Fused rings are rings that share a common
carbon atom. Heterocycloalkenyl groups can include, e.g.,
tetrahydropyridyl, and dihydropyranyl.
[0321] The term "aryl" refers to an aromatic monocyclic, bicyclic,
or tricyclic hydrocarbon ring system, wherein any ring atom can be
substituted, e.g., by one or more substituents. Aryl groups can
contain fused rings. Fused rings are rings that share a common
carbon atom. Aryl moieties can include, e.g., phenyl, naphthyl,
anthracenyl, and pyrenyl.
[0322] The term "heteroaryl" refers to an aromatic monocyclic,
bicyclic, tricyclic, or other polycyclic hydrocarbon groups having
1-4 heteroatoms if monocyclic, 1-8 heteroatoms if bicyclic, or 1-10
heteroatoms if tricyclic, said heteroatoms selected from O, N, or S
(e.g., carbon atoms and 1-4, 1-8, or 1-10 heteroatoms of N, O, or S
if monocyclic, bicyclic, or tricyclic, respectively). Any atom can
be substituted, e.g., by one or more substituents. Heteroaryl
groups can contain fused rings. Fused rings are rings that share a
common carbon atom. Heteroaryl groups include pyridyl, thienyl,
furyl (furanyl), imidazolyl, isoquinolyl, quinolyl and
pyrrolyl.
[0323] The terms "arylcycloalkenyl," "arylheterocyclyl," and
"arylheterocycloalkenyl" refer to bicyclic, tricyclic, or other
polycyclic ring systems that include an aryl ring fused to a
cycloalkenyl, heterocyclyl, and heterocycloalkenyl, respectively.
Any atom can be substituted, e.g., by one or more substituents. For
example, arylcycloalkenyl can include indenyl; arylheterocyclyl can
include 2,3-dihydrobenzofuryl, 1,2,3,4-tetrahydroisoquinolyl, and
2,2-dimethylchromanyl; and arylheterocycloalkenyl can include
1,4-dihydro-1,4-epoxynaphthyl.
[0324] The term "oxo" refers to an oxygen atom, which forms a
carbonyl (C.dbd.O) when attached to carbon or which forms part of a
sulfinyl or sulfonyl group when attached to a sulfur atom. The term
"thioxo" refers to an oxygen atom, which forms a thiocarbonyl
(C.dbd.S) when attached to carbon.
[0325] The term "substituent" refers to a group "substituted" on,
e.g., an alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl,
heteroaralkyl, heterocyclyl, heterocycloalkenyl, cycloalkenyl,
aryl, heteroaryl, arylcycloalkenyl, arylheterocyclyl, or
arylheterocycloalkenyl group at any atom of that group. In one
aspect, the substituent(s) (e.g., R.sup.a) on a group are
independently any one single, or any combination of two or more of
the permissible atoms or groups of atoms delineated for that
substituent. In another aspect, a substituent may itself be
substituted with any one of the above substituents (e.g.,
substituent R.sup.a can be substituted with R.sup.a').
[0326] In general, when a definition for a particular variable
includes both hydrogen and non-hydrogen (halo, alkyl, aryl, etc.)
possibilities, the term "substituent(s) other than hydrogen" and
the like refers collectively to the non-hydrogen possibilities for
that particular variable.
[0327] The details of one or more embodiments of the invention are
set forth in the description below. Other features and advantages
of the invention are in the claims.
DETAILED DESCRIPTION
[0328] This invention relates to 11-beta HSD1 inhibitor compounds,
pharmaceutical compositions and related methods.
[0329] The 11-beta HSD1 inhibitor compounds have the general
formula (I) below:
##STR00013##
in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, X, V, Y, W.sup.1, Z.sup.1, W.sup.2, Z.sup.2, R.sup.a,
R.sup.a', R.sup.b, R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g,
R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.m, and R.sup.n can be as
defined anywhere herein.
[0330] For ease of exposition, it is understood that where in this
specification (including the claims), a group is defined by "as
defined anywhere herein" (or the like), the definitions for that
particular group include the first occurring and broadest generic
definition as well as any subgeneric and specific definitions
delineated anywhere in this specification.
[0331] For ease of exposition, it is understood that any recitation
of ranges (e.g., C.sub.1-C.sub.20, 1-3) or subranges of a
particular range (e.g., C.sub.1-C.sub.4, C.sub.2-C.sub.6, 1-2) for
any of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, X, V, Y, W.sup.1, Z.sup.1, W.sup.2, Z.sup.2, R.sup.a,
R.sup.a', R.sup.b, R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g,
R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.m, and R.sup.n expressly
includes each of the individual values that fall within the recited
range, including the upper and lower limits of the recited range.
For example, the range C.sub.1-C.sub.4 alkyl is understood to mean
C.sub.1, C.sub.2, C.sub.3, or C.sub.4 alkyl or the range 1-3
R.sup.a is understood to mean 1, 2, or 3 R.sup.a.
[0332] In some embodiments, R.sup.1 can be:
[0333] (A) C.sub.6-C.sub.18 (e.g., C.sub.6-C.sub.14,
C.sub.6-C.sub.10, or phenyl) aryl or heteroaryl including 5-20
(e.g., 5-16, 5-12, or 5-6) atoms, each of which is optionally
substituted with from 1-10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1)
R.sup.a; or
[0334] (B) C.sub.3-C.sub.16 (e.g., C.sub.3-C.sub.14 or
C.sub.3-C.sub.10) cycloalkyl, optionally substituted with from 1-10
(e.g., 1-5, 1-4, 1-3, 1-2, or 1) R.sup.b; or
[0335] (C) (C.sub.1-C.sub.12 alkyl)-(C.sub.3-C.sub.16 cycloalkyl)
(e.g., (C.sub.1-C.sub.6 alkyl)-(C.sub.3-C.sub.12 cycloalkyl) or
(CH.sub.2)--(C.sub.3-C.sub.12 cycloalkyl), optionally substituted
with from 1-10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1) R.sup.b; or
[0336] (D) C.sub.7-C.sub.20 (e.g., C.sub.7-C.sub.16,
C.sub.7-C.sub.12, C.sub.7-C.sub.10) aralkyl, optionally substituted
with from 1-10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1) R.sup.b; or
[0337] (E) arylheterocyclyl including 8-20 (e.g., 8-16 or 9-12)
atoms, optionally substituted with from 1-10 (e.g., 1-5, 1-4, 1-3,
1-2, or 1) R.sup.b.
[0338] In some embodiments, R.sup.1 can be C.sub.6-C.sub.10 aryl,
optionally substituted with from 1-3 (e.g., 1-2 or 1) R.sup.a.
[0339] In certain embodiments, R.sup.1 can be unsubstituted phenyl
or unsubstituted napthyl (e.g., 1-naphthyl or 2-naphthyl).
[0340] In certain embodiments, R.sup.1 can be a monosubstituted (1
R.sup.a), disubstituted (2 R.sup.a), trisubstituted (3 R.sup.a),
tetrasubstituted (4 R.sup.a), or pentasubstituted (5 R.sup.a)
phenyl group of the general formula P-1:
##STR00014##
[0341] For purposes of clarification, each of the terms "ortho (o)
(or 2- or 6-); meta (m) (or 3- or 5-); or para (p) (or 4-)," when
used in conjunction with any substituted phenyl group, indicates
the location of the substituent(s) relative to the ring carbon that
is attached to the remainder of the molecule (i.e., C.sup.1 in
formula P-1 above). For example, a monosubstituted phenyl group
that is para substituted (or 4-substituted) is one having a
substituent attached to C.sup.4 in formula P-1 above. As another
example, a 2,6- (or ortho, ortho-) disubstituted phenyl group is
one having a substituent attached to C.sup.2 and to C.sup.6,
respectively, in formula P-1. As a further example, a 3,5- (or
meta, meta) disubstituted phenyl group is one having a substituent
attached to C.sup.3 and to C.sup.5, respectively, in formula
P-1.
[0342] In certain embodiments, R.sup.a at each occurrence can be,
independently, halo; C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12
haloalkyl, each of which is optionally substituted with from 1-2
R.sup.j; C.sub.1-C.sub.12 alkoxy, optionally substituted with 1-2
R.sup.f; C.sub.1-C.sub.12 haloalkoxy; cyano; nitro;
C.sub.6-C.sub.10 aryl or heteroaryl including 5-12 atoms, each of
which is optionally substituted with from 1-2 R.sup.a';
C.sub.6-C.sub.10 aryloxy or heteroaryloxy including 5-12 atoms,
each of which is optionally substituted with from 1-2 R.sup.a';
C.sub.3-C.sub.10 heterocyclyl, C.sub.3-C.sub.10 cycloalkyl,
C.sub.7-C.sub.12 aralkoxy or heteroaralkoxy including 6-12 atoms,
each of which is optionally substituted with 1-2 R.sup.b; or
--NR.sup.hC(O)R.sup.i. In some embodiments, R.sup.a is other than
halo (e.g., chloro).
[0343] R.sup.a at each occurrence is, independently, halo;
NR.sup.dR.sup.e; hydroxyl; C.sub.1-C.sub.12 alkyl or
C.sub.1-C.sub.12 haloalkyl, each of which is optionally substituted
with from 1-2 R.sup.j; C.sub.1-C.sub.12 alkoxy, optionally
substituted with from 1-2 R.sup.f; C.sub.1-C.sub.12 haloalkoxy;
cyano; nitro; C.sub.6-C.sub.10 aryl or heteroaryl including 5-12
atoms, each of which is optionally substituted with from 1-2
R.sup.a'; C.sub.6-C.sub.10 aryloxy or heteroaryloxy including 5-12
atoms, each of which is optionally substituted with from 1-2
R.sup.a'; heterocyclyl including 3-10 atoms, C.sub.3-C.sub.10
cycloalkyl, C.sub.7-C.sub.12 aralkoxy or heteroaralkoxy including
6-12 atoms, each of which is optionally substituted with 1-2
R.sup.b; --C(O)OR.sup.g; --C(O)NR.sup.dR.sup.e; or
--NR.sup.hC(O)R.sup.i. In some embodiments, R.sup.a is other than
halo (e.g., chloro).
[0344] For example, R.sup.a at each occurrence can be,
independently, chloro, fluoro, bromo, methyl, tert-butyl,
trifluoromethyl, trifluoromethoxy, methoxy, cyano, nitro, phenyl,
4-bromophenyl, 4-fluorophenyl, phenoxy, acetamido, (e.g., R or S)
1,1,1-trifluoro-2-hydroxypropan-2-yl, 2-hydroxypropan-2-yl,
1-hydroxycyclopropan-1-yl, 4-fluorophenoxy, pyrrolidin-1-yl,
3-hydroxypyrrolidin-1-yl, 3-carboxypyrrolidin-1-yl, morpholin-4-yl,
1-piperidyl, 4-piperidyl, 2-cyanopropoxy, piperazin-1-yl,
4-methylpiperazin-1-yl, 1H-1,2,4-triazolyl, or --NHC(O)R.sup.i in
which R.sup.i is morpholin-4-yl, N,N-dimethylamino, methylamino,
1-piperidyl, pyrrolidin-1-yl, or azapan-1-yl.
[0345] In certain embodiments, R.sup.1 can be a monosubstituted
phenyl group having formula (II):
##STR00015##
in which one of R.sup.a2, R.sup.a3, and R.sup.a4 can be halo;
C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl, each of which
is optionally substituted with 1-2 R.sup.j; C.sub.1-C.sub.12
alkoxy, optionally substituted with 1-2 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; cyano; nitro; C.sub.6-C.sub.10 aryl or heteroaryl
including 5-12 atoms, each of which is optionally substituted with
from 1-2 R.sup.a'; C.sub.6-C.sub.10 aryloxy, optionally substituted
with from 1-2 R.sup.a'; C.sub.3-C.sub.10 heterocyclyl,
C.sub.3-C.sub.10 cycloalkyl, or C.sub.7-C.sub.12 aralkoxy, each of
which is optionally substituted with 1-2 R.sup.b; or
--NR.sup.hC(O)R.sup.i; and the others are hydrogen.
[0346] In other embodiments, one of R.sup.a2, R.sup.a3, and
R.sup.a4 is halo; NR.sup.dR.sup.e; hydroxyl; C.sub.1-C.sub.12 alkyl
or C.sub.1-C.sub.12 haloalkyl, each of which is optionally
substituted with from 1-2 R.sup.j; C.sub.1-C.sub.12 alkoxy,
optionally substituted with 1-2 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; cyano; nitro; C.sub.6-C.sub.10 aryl or heteroaryl
including 5-12 atoms, each of which is optionally substituted with
from 1-2 R.sup.a'; C.sub.6-C.sub.10 aryloxy or heteroaryloxy
including 5-12 atoms, each of which is optionally substituted with
from 1-2 R.sup.a'; heterocyclyl including 3-10 atoms,
C.sub.3-C.sub.10 cycloalkyl, C.sub.7-C.sub.12 aralkoxy or
heteroaralkoxy including 6-12 atoms, each of which is optionally
substituted with 1-3 R.sup.b; --C(O)OR.sup.g;
--C(O)NR.sup.dR.sup.e; or --NR.sup.hC(O)R.sup.i; and the others are
hydrogen. For example, R.sup.1 can be a meta or para
monosubstituted phenyl ring.
[0347] R.sup.a2, R.sup.a3, or R.sup.a4 can be halo (e.g., chloro,
bromo, or fluoro, preferably chloro).
[0348] R.sup.a2, R.sup.a3, or R.sup.a4 (e.g., R.sup.a3 or R.sup.a4)
can be C.sub.1-C.sub.12 alkyl, optionally substituted with 1
R.sup.j (e.g., hydroxyl). For example, R.sup.a2, R.sup.a3, or
R.sup.a4 (e.g., R.sup.a3 or R.sup.a4, e.g., R.sup.a4) can be
CH.sub.3 or C.sub.3-C.sub.12 branched alkyl (e.g., tert-butyl). As
another example, R.sup.a2, R.sup.a3, or R.sup.a4 (e.g., R.sup.a3 or
R.sup.a4) can be 2-hydroxypropan-2-yl, i.e.,
(CH.sub.3C(OH)(CH.sub.3).
[0349] R.sup.a2, R.sup.a3, or R.sup.a4 can be C.sub.1-C.sub.4
haloalkyl, optionally substituted with 1 R.sup.j (e.g., hydroxyl).
For example, R.sup.a2, R.sup.a3, or R.sup.a4 (e.g., R.sup.a3 or
R.sup.a4, e.g., R.sup.a4) can be CF.sub.3. As another example,
R.sup.a2, R.sup.a3, or R.sup.a4 (e.g., R.sup.a3 or R.sup.a4) can be
(e.g., R or S) 1,1,1-trifluoro-2-hydroxypropan-2-yl, i.e.,
CF.sub.3C(OH)(CH.sub.3).
[0350] R.sup.a2, R.sup.a3, or R.sup.a4 can be C.sub.3-C.sub.10
cycloalkyl, optionally substituted with 1 R.sup.b (e.g., hydroxyl).
For example, R.sup.a2, R.sup.a3, or R.sup.a4 (e.g., R.sup.a3 or
R.sup.a4, e.g., R.sup.a4) can be 1-hydroxycyclopropan-1-yl.
[0351] R.sup.a3 or R.sup.a4 can be heterocyclyl including 3-8
atoms, optionally substituted with 1-3 (e.g., 1) R.sup.b (e.g.,
C.sub.1-C.sub.4 alkyl (e.g., CH.sub.3), OH, C.sub.3-C.sub.10
cycloalkyl, or COOR.sup.g (e.g., COOH)). For example, R.sup.a3 or
R.sup.a4 can be optionally substituted pyrrolidinyl (e.g.,
pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, or
3-carboxypyrrolidin-1-yl), morpholinyl (e.g., morpholin-4-yl),
piperidyl (e.g., 1-piperidyl or 4-piperidyl) or piperazinyl (e.g.,
piperazin-1-yl, 4-methylpiperazin-1-yl). For example, R.sup.a3 is
optionally substituted pyrrolidin-1-yl (e.g.,
3-hydroxypyrrolidin-1-yl).
[0352] In these embodiments, R.sup.b at each occurrence can be,
independently, halo; NR.sup.dR.sup.e; hydroxyl; oxo;
C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl, each of which
is optionally substituted with from 1-3 R.sup.j; C.sub.1-C.sub.12
alkoxy, optionally substituted with 1-2 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; heterocyclyl including 3-10 atoms or C.sub.3-C.sub.10
cycloalkyl, each of which is optionally substituted with 1-3
R.sup.b; --C(O)R.sup.g; --C(O)OR.sup.g; --C(O)NR.sup.dR.sup.e;
--OC(O)R.sup.g; or --NR.sup.hC(O)R.sup.i.
[0353] R.sup.a3 or R.sup.a4 can be heteroaryl including 5 or 6
atoms (e.g., 1H-1,2,4-triazolyl).
[0354] R.sup.a3 or R.sup.a4 can be phenyl or phenoxy, each of which
can be optionally substituted with from 1-2 halo (e.g., bromo or
fluoro). For example, R.sup.a3 or R.sup.a4 can be phenyl, phenoxy,
4-bromophenyl, 4-fluorophenyl, or 4-fluorophenoxy.
[0355] R.sup.a4 can be C.sub.1-C.sub.4 alkoxy, optionally
substituted with 1 R.sup.f (e.g., cyano). For example, R.sup.a4 can
be OCH.sub.3 or 2-cyanopropoxy.
[0356] R.sup.a4 can be --NHC(O)R.sup.i. R.sup.i can be
C.sub.1-C.sub.4 alkyl (e.g., CH.sub.3). R.sup.i can be
NR.sup.dR.sup.e, in which R.sup.d and R.sup.e can each be,
independently, hydrogen or C.sub.1-C.sub.4 alkyl (e.g., CH.sub.3).
For example, R.sup.i can be --N(CH.sub.3).sub.2 or --NHCH.sub.3.
R.sup.i can be heterocyclyl including 3-8 atoms (e.g.,
morpholin-4-yl, 1-piperidyl, pyrrolidin-1-yl, or azapan-1-yl).
[0357] R.sup.a4 can be C.sub.1-C.sub.4 haloalkoxy (e.g.,
OCF.sub.3).
[0358] R.sup.a2 can be nitro or cyano.
[0359] R.sup.a4 can be C.sub.7-C.sub.12 aralkoxy, optionally
substituted with 1-2 R.sup.b (e.g., chloro). For example, R.sup.a4
can be benzyloxy or 4-chlorobenzyloxy.
[0360] In certain embodiments, R.sup.1 can be a disubstituted
phenyl group having formula (II-A):
##STR00016##
[0361] In certain embodiments, two of R.sup.a2, R.sup.a3, R.sup.a4,
and R.sup.a6 can be, independently, halo; C.sub.1-C.sub.12
haloalkyl, optionally substituted with 1-2 R.sup.j;
C.sub.1-C.sub.12 alkoxy, optionally substituted with 1-2 R.sup.f;
or --NR.sup.hC(O)R.sup.i; and the others are hydrogen.
[0362] In certain embodiments, two of R.sup.a2, R.sup.a3, R.sup.a4,
and R.sup.a6 can each be, independently, halo; NR.sup.dR.sup.e;
hydroxyl; C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl,
each of which is optionally substituted with 1-2 R.sup.j;
C.sub.1-C.sub.12 alkoxy, optionally substituted with from 1-2
R.sup.f; C.sub.1-C.sub.12 haloalkoxy; heterocyclyl including 3-10
atoms, optionally substituted with from 1-3 R.sup.b heteroaryl
including 5-12 atoms, optionally substituted with from 1-2
R.sup.a'; --C(O)OR.sup.g; --C(O)NR.sup.dR.sup.e; or
--NR.sup.hC(O)R.sup.i; and the others can be hydrogen.
[0363] In other embodiments, two of R.sup.a2, R.sup.a3, R.sup.a4,
and R.sup.a6 can each be, independently, halo; NR.sup.dR.sup.e;
hydroxyl; C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl,
each of which is optionally substituted with from 1-2 R.sup.j;
C.sub.1-C.sub.12 alkoxy, optionally substituted with 1-2 R.sup.f;
C.sub.1-C.sub.12 haloalkoxy; cyano; nitro; C.sub.6-C.sub.10 aryl or
heteroaryl including 5-12 atoms, each of which is optionally
substituted with from 1-2 R.sup.a'; C.sub.6-C.sub.10 aryloxy or
heteroaryloxy including 5-12 atoms, each of which is optionally
substituted with from 1-2 R.sup.a'; heterocyclyl including 3-10
atoms, C.sub.3-C.sub.10 cycloalkyl, C.sub.7-C.sub.12 aralkoxy or
heteroaralkoxy including 6-12 atoms, each of which is optionally
substituted with 1-3 R.sup.b; --C(O)OR.sup.g;
--C(O)NR.sup.dR.sup.e; or --NR.sup.hC(O)R.sup.i; and the others can
be hydrogen.
[0364] R.sup.a3 and R.sup.a4 can each be, independently, halo
(e.g., chloro, bromo or phenyl) or C.sub.1-C.sub.4 alkoxy (e.g.,
OCH.sub.3).
[0365] R.sup.a2 and R.sup.a4 can each be, independently, halo
(e.g., fluoro or bromo), C.sub.1-C.sub.4 haloalkyl (e.g.,
CF.sub.3), or --NR.sup.hC(O)R.sup.i, in which R.sup.i can be
heterocyclyl including 3-8 atoms.
[0366] R.sup.a2 and R.sup.a6 can each be, independently, halo
(e.g., chloro).
[0367] For example, R.sup.1 can be 3,4-dichlorophenyl,
3-fluoro-4-bromophenyl, 2,6-dichlorophenyl, 2,4-difluorophenyl,
3,4-dimethoxyphenyl, 2-bromo-4-(trifluoromethyl)phenyl, or
##STR00017##
[0368] In other embodiments, R.sup.a2 can be halo (e.g., chloro),
and R.sup.a4 can be a substituent other than hydrogen, such as
halo; NR.sup.dR.sup.e; hydroxyl; C.sub.1-C.sub.12 alkoxy,
optionally substituted with from 1-2 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; heterocyclyl including 3-10 atoms, optionally
substituted with from 1-3 R.sup.b; heteroaryl including 5-12 atoms,
optionally substituted with from 1-2 R.sup.a'; --C(O)OR.sup.g;
--C(O)NR.sup.dR.sup.e; or --NR.sup.hC(O)R.sup.i. For example,
R.sup.a2 can be halo (e.g., chloro), and R.sup.a4 can be
heterocyclyl including 5-8 atoms, optionally substituted with from
1-3 R.sup.b.
[0369] In certain embodiments, R.sup.1 can be napthyl substituted
with from 1-2 R.sup.a (e.g., chloro). For example, R.sup.1 can be
5-chloronaphth-2-yl or 8-chloro-2-naphth-2-yl.
[0370] In some embodiments, R.sup.1 can be heteroaryl including
5-14 atoms, optionally substituted with from 1-3 (e.g., 1-2 or 1)
R.sup.a.
[0371] R.sup.1 can be a monocyclic heteroaryl including 5-6 atoms,
optionally substituted with from 1-2 R.sup.a (e.g., thienyl,
isoxazolyl, or pyridyl, each of which is optionally substituted
with from 1-2 R.sup.a, in which R.sup.a at each occurrence is,
independently, halo, C.sub.1-C.sub.4 alkyl, or heterocyclyl
including 3-8 atoms). For example, R.sup.1 can be 2-thienyl,
5-chlorothien-2-yl, 3,5-dimethylisoxazol-4-yl, or
2-morpholinopyridin-5-yl. As another example, R.sup.1 can have
formula (II-B) as described in the Summary.
[0372] R.sup.1 can be a bicyclic or tricyclic heteroaryl including
8-12 atoms, each of which is optionally substituted with from 1-2
R.sup.a (e.g., quinolyl, benzothienyl, dibenzothienyl, benzofuryl,
dibenzofuryl, or benzothiazolyl, each of which is optionally
substituted with from 1-2 R.sup.a, in which R.sup.a at each
occurrence is, independently, halo, C.sub.1-C.sub.4 alkyl, or
heterocyclyl including 3-8 atoms). For example, R.sup.1 can be
2-quinolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,
5-chloro-3-methylbenzo[b]thien-2-yl, dibenzo[b,d]fur-2-yl,
dibenzo[b,d]thien-2-yl, dibenzo[b,d]thien-3-yl,
dibenzo[b,d]fur-3-yl, 4-chloro-3-methylbenzo[b]thien-2-yl,
1,3-benzothiazol-2-yl, 5-morpholino-3-methylbenzo[b]thien-2-yl, or
5-(piperazin-1-yl)-3-methylbenzo[b]thien-2-yl.
[0373] In certain embodiments (e.g., when V and Y are both N, and X
is CO), when R.sup.1 is a bicyclic heteroaryl, then 1 heteroatom
can be present in the bicyclic heteroaryl (e.g., 1 oxygen, 1
nitrogen, or 1 sulfur, e.g., 1 oxygen or 1 sulfur); or 2
heteroatoms can be present (e.g., 2 oxygens, or 2 sulfurs, or 2
nitrogens, or 1 oxygen and 1 sulfur, or 1 oxygen and 1 nitrogen, or
1 sulfur and 1 nitrogen); or 3 heteroatoms can be present (e.g., 1
oxygen and 2 nitrogens; or 1 sulfur and 2 nitrogens; or 3
nitrogens, provided that the bicyclic heterocycle is other than
pyrazolo[1,5-a]pyrimidinyl:
##STR00018##
(e.g., other than unsubstituted or mono-, di-, or tri-substituted
pyrazolo[1,5-a]pyrimidinyl, e.g., other than unsubstituted or
mono-, di-, or tri-substituted pyrazolo[1,5-a]pyrimidin-2-yl); or 4
heteroatoms can be present (e.g., 1 oxygen and 3 nitrogens, or 1
sulfur and 3 nitrogens, or 4 nitrogens). In other embodiments, when
R.sup.1 is a nitrogenous, bicyclic heteroaryl (including those
nitrogenous bicyclic heteroaryls in which one or more oxygens
and/or sulfur(s) are also present), then R.sup.1 has other than 3
nitrogen atoms (e.g., 1 or 2 nitrogen atoms, e.g., more than three
nitrogen atoms, e.g., 4-8 nitrogen atoms).
[0374] In some embodiments, R.sup.1 can be C.sub.3-C.sub.12 (e.g.,
C.sub.3-C.sub.10) cycloalkyl, optionally substituted with from 1-5
(e.g., 1-4, 1-3, 1-2, or 1) R.sup.b (e.g., halo or C.sub.1-C.sub.4
alkyl). R.sup.1 can be monocyclic (e.g., optionally substituted
cyclopropyl, cyclopentyl, or cyclohexyl), bicyclic (e.g.,
optionally substituted bicycloheptyl), or polycyclic (e.g.,
optionally substituted adamantyl). For example, R.sup.1 can be
adamant-1-yl, cyclohexyl, 2-methylcyclohexan-1-yl,
3-methylcyclohexan-1-yl, 2,2,3,3-tetramethylcyclopropan-1-yl,
2,2-dichloro-1-methylcyclopropan-1-yl, or
1-methyl-3-isopropyl-cyclopentan-1-yl.
[0375] In some embodiments, R.sup.1 can be (C.sub.1-C.sub.6
alkyl)-(C.sub.3-C.sub.12 cycloalkyl), in which the cycloalkyl ring
is optionally substituted with from 1-3 R.sup.b. R.sup.1 can be
--(CH.sub.2).sub.1-6--(C.sub.3-C.sub.10 cycloalkyl), in which the
cycloalkyl ring is optionally substituted with from 1-3
C.sub.1-C.sub.4 alkyl (e.g., CH.sub.3). For example, R.sup.1 can be
--CH.sub.2-(cyclopentyl), --CH.sub.2-(cyclohexyl),
--CH.sub.2-(4-methylcyclohexyl), or --CH.sub.2-(bicycloheptyl).
[0376] In some embodiments, R.sup.1 can be C.sub.7-C.sub.12
aralkyl, optionally substituted with from 1-2 R.sup.b (e.g., halo).
R.sup.1 can be --(CH.sub.2).sub.1-6--(C.sub.6-C.sub.10 aryl), in
which the aryl ring is optionally substituted with from 1-2 halo
(e.g., chloro). For example, R.sup.1 can be benzyl, 4-chlorobenzyl;
or --(CH.sub.2)-(naphthyl), in which the CH.sub.2 group is attached
to the 1 or 2 position of the naphthalene ring.
[0377] In some embodiments, R.sup.1 can be arylheterocyclyl
including 9-12 atoms, optionally substituted with from 1-5 (e.g.,
1-4, 1-3, 1-2, or 1) R.sup.b (e.g., oxo, halo or C.sub.1-C.sub.4
alkyl), in which the heterocyclyl portion can include 1 or 2
heteroatoms (e.g., nitrogen or oxygen). For example, R.sup.1 can be
2,2-dimethylchromanyl.
[0378] In some embodiments, R.sup.2 can be:
[0379] (A) heteroaryl including 5-20 (e.g., 5-16, 5-12, or 5-6)
atoms, optionally substituted with from 1-10 (e.g., 1-5, 1-4, 1-3,
1-2, or 1) R.sup.c or R.sup.n; or C.sub.6-C.sub.18 (e.g.,
C.sub.6-C.sub.14, C.sub.6-C.sub.10, or phenyl) aryl optionally
substituted with from 1-10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1)
R.sup.c; or
[0380] (B) C.sub.3-C.sub.16 (e.g., C.sub.3-C.sub.14,
C.sub.3-C.sub.10, C.sub.6-C.sub.16, C.sub.6-C.sub.14,
C.sub.6-C.sub.10, C.sub.7-C.sub.16, C.sub.8-C.sub.16,
C.sub.9-C.sub.16, C.sub.10-C.sub.16, C.sub.7-C.sub.14,
C.sub.8-C.sub.14, C.sub.9-C.sub.14, C.sub.10-C.sub.14,
C.sub.7-C.sub.10, C.sub.8-C.sub.10, or C.sub.9-C.sub.10)
cycloalkyl, optionally substituted with from 1-10 (e.g., 1-5, 1-4,
1-3, 1-2, or 1) R.sup.b; or
[0381] (C)OR.sup.1; or NR.sup.3R.sup.4, in which R.sup.3 and
R.sup.4 can each be, independently, hydrogen or R.sup.1 (e.g.,
R.sup.1 can be C.sub.6-C.sub.18 (e.g., C.sub.6-C.sub.14,
C.sub.6-C.sub.10, or phenyl) aryl or heteroaryl including 5-20
(e.g., 5-16, 5-12, or 5-6) atoms; each of which is optionally
substituted with from 1-10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1)
R.sup.a); or
[0382] (D) heterocyclyl including 3-16 (e.g., 3-12, 3-10, 5-12, or
5-6) atoms, optionally substituted with from 1-10 (e.g., 1-5, 1-4,
1-3, 1-2, or 1) R.sup.b; or
[0383] (E) C(O)R.sup.5, in which R.sup.5 is C.sub.1-C.sub.20 (e.g.,
C.sub.1-C.sub.12, C.sub.1-C.sub.6, or C.sub.1-C.sub.4) alkyl or
C.sub.7-C.sub.20 (e.g., C.sub.7-C.sub.12 aralkoxy).
[0384] In certain embodiments, R.sup.2 can be (A), (B), (C), and/or
(D); or (A), (C), (D), and/or (E); or (A), (C), and/or (D); or (A)
and/or (C).
[0385] In certain embodiments, when R.sup.2 is (A), R.sup.2 is
optionally substituted heteroaryl including 5-20 (e.g., 5-16, 5-12,
or 5-6) atoms. In other embodiments, when R.sup.2 is (A), R.sup.2
is optionally substituted C.sub.6-C.sub.18 (e.g., C.sub.6-C.sub.14,
C.sub.6-C.sub.10, or phenyl) aryl.
[0386] In some embodiments, R.sup.2 can be heteroaryl including
5-12 atoms, optionally substituted with from 1-3 (e.g., 1-2 or 1)
R.sup.c or R.sup.n.
[0387] In certain embodiments, R.sup.2 can be a monosubstituted
pyridyl ring having formula (III):
##STR00019##
in which one or two of R.sup.c3, R.sup.c4, R.sup.c5, and R.sup.c6
can each be, independently, halo; C.sub.1-C.sub.12 alkyl;
C.sub.1-C.sub.12 haloalkyl, optionally substituted with 1-2
R.sup.j; cyano; or nitro; and the others are hydrogen.
[0388] One of R.sup.c3, R.sup.c4, or R.sup.c5 can be
C.sub.1-C.sub.4 haloalkyl (e.g., CF.sub.3). For example, R.sup.2
can be:
##STR00020##
[0389] One of R.sup.c3, R.sup.c4, R.sup.c5, and R.sup.c6 can be
halo (e.g., R.sup.c3 or R.sup.c5 can be chloro or fluoro).
[0390] One of R.sup.c3, R.sup.c4, R.sup.c5, and R.sup.c6 can be
C.sub.1-C.sub.4 alkyl (e.g., R.sup.c3 can be C.sub.1-C.sub.4 alkyl,
e.g., CH.sub.3).
[0391] One of R.sup.c3, R.sup.c4, R.sup.c5, and R.sup.c6 can be
cyano or nitro (e.g., R.sup.c3 or R.sup.c5 can be nitro or R.sup.c3
can be cyano).
[0392] Two of R.sup.c3, R.sup.c4, R.sup.c5, and R.sup.c6 can each
be, independently, halo or C.sub.1-C.sub.4 haloalkyl. For example,
two of R.sup.c3, R.sup.c4, R.sup.c5, and R.sup.c6 can each be,
independently, fluoro or CF.sub.3.
[0393] In certain embodiments, R.sup.2 can be a disubstituted (2
R.sup.c or 2 R.sup.n), trisubstituted (3 R.sup.c or 3 R.sup.n),
tetrasubstituted (4 R.sup.c or 4 R.sup.n) pyridyl ring. For
example, R.sup.2 can be 3,5-dichloro-4-pyridyl.
[0394] In certain embodiments, R.sup.2 can be 1-quinolyl,
2-quinolyl, 1-isoquinolyl, or pyrazinyl (e.g.,
2-cyanopyrazin-2-yl).
[0395] In some embodiments, R.sup.2 can be C.sub.6-C.sub.10 aryl,
optionally substituted with from 1-3 (e.g., 1-2 or 1) R.sup.c.
[0396] In certain embodiments, R.sup.2 can be a monosubstituted (1
R.sup.c), disubstituted (2 R.sup.c), trisubstituted (3 R.sup.c),
tetrasubstituted (4 R.sup.c), or pentasubstituted (5 R.sup.c)
phenyl group of the general formula P-1 described elsewhere.
[0397] In certain embodiments, R.sup.2 can be a monosubstituted
phenyl group having formula (IV):
##STR00021##
in which one of R.sup.c22, R.sup.c23, and R.sup.c24 can be halo;
hydroxyl; C.sub.1-C.sub.12 alkyl; C.sub.1-C.sub.12 haloalkyl;
C.sub.1-C.sub.12 alkoxy; C.sub.1-C.sub.12 haloalkoxy; cyano; nitro;
or C.sub.6-C.sub.10 aryl, optionally substituted with from 1-2
R.sup.a; and the others are hydrogen.
[0398] R.sup.c22 or R.sup.c23 can be C.sub.1-C.sub.4 haloalkyl
(e.g., CF.sub.3).
[0399] R.sup.c22 can be C.sub.1-C.sub.4 alkyl (e.g., CH.sub.3 or
CH.sub.2CH.sub.3); or nitro; or cyano; or hydroxyl; or
C.sub.1-C.sub.4 alkoxy (e.g., OCH.sub.3).
[0400] R.sup.c22, R.sup.c23, or R.sup.c24 can be halo (e.g.,
R.sup.c22, R.sup.c23, or R.sup.c24 can be fluoro; or R.sup.c22 can
be bromo; or R.sup.c24 can be chloro).
[0401] R.sup.c22 or R.sup.c24 can be phenyl optionally substituted
with 1 R.sup.a (e.g., C.sub.1-C.sub.4 alkoxy, e.g., OCH.sub.3). For
example, R.sup.c22 can be 2-methoxyphenyl.
[0402] In certain embodiments, R.sup.2 can be a disubstituted
phenyl group having formula (IV-A):
##STR00022##
[0403] In certain embodiments, two of R.sup.c22, R.sup.c23,
R.sup.c24, R.sup.c25, and R.sup.c26 can each be, independently,
halo; C.sub.1-C.sub.12 alkyl; C.sub.1-C.sub.12 haloalkyl; cyano,
C.sub.1-C.sub.12 alkoxy; heterocyclyl including 3-10 atoms,
optionally substituted with from 1-2 R.sup.b (e.g.,
C.sub.1-C.sub.12 alkyl (e.g., CH.sub.3)); heteroaryl including from
5-10 atoms, optionally substituted with from 1-2 R.sup.a; or
SO.sub.2R.sup.m; and the others are hydrogen.
[0404] In other embodiments, two of R.sup.c22, R.sup.c23,
R.sup.c24, R.sup.c25, and R.sup.c26 can each be, independently,
halo; C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl, each of
which is optionally substituted with from 1-3 R.sup.j;
C.sub.1-C.sub.12 alkoxy; C.sub.1-C.sub.12 haloalkoxy; cyano; nitro;
or C.sub.6-C.sub.10 aryl or heteroaryl including 5-12 atoms, each
of which is optionally substituted with from 1-2 R.sup.a; and the
others are hydrogen.
[0405] Two of R.sup.c22, R.sup.c23, R.sup.c24, R.sup.c25 and
R.sup.c26 can each be, independently, halo or C.sub.1-C.sub.4
haloalkyl (e.g., two of R.sup.c22, R.sup.c23, R.sup.c24, R.sup.c25
and R.sup.c26 can each be, independently, fluoro or CF.sub.3). For
example, R.sup.c22 can be C.sub.1-C.sub.4 haloalkyl (e.g.,
CF.sub.3) and R.sup.c23 or R.sup.c24 (e.g., R.sup.c24) can be halo
(e.g., fluoro).
[0406] R.sup.c22 can be C.sub.1-C.sub.4 haloalkyl (e.g., CF.sub.3),
halo (e.g., chloro), C.sub.1-C.sub.6 alkoxy (e.g., OCH.sub.3),
cyano, or C.sub.1-C.sub.6 alkyl (e.g., CH.sub.3); and one of
R.sup.c23, R.sup.c24, and R.sup.c25 can be heterocyclyl including
3-8 atoms, optionally substituted with 1 R.sup.b (e.g.,
C.sub.1-C.sub.12, e.g., C.sub.1-C.sub.6 alkyl, e.g., CH.sub.3);
heteroaryl including 5 or 6 atoms, optionally substituted with 1
R.sup.a; or halo (e.g., fluoro).
[0407] R.sup.c22 can be CF.sub.3, chloro, OCH.sub.3, cyano, or
CH.sub.3; and one of R.sup.c23, R.sup.c24, and R.sup.c25 can be
heterocyclyl including 3-8 atoms, optionally substituted with 1
R.sup.b; heteroaryl including 5 or 6 atoms, optionally substituted
with 1 R.sup.a; or halo.
[0408] In these embodiments, one of R.sup.c23, R.sup.c24, and
R.sup.c25 can be optionally substituted piperazinyl (e.g.,
piperazin-1-yl or 4-(C.sub.1-C.sub.6 alkyl)piperazin-1-yl);
optionally substituted morpholinyl (e.g., morpholin-4-yl);
1H-1,2,4-triazolyl; or fluoro.
[0409] R.sup.c22 and R.sup.c24 can each be, independently, halo
(e.g., chloro or fluoro); C.sub.1-C.sub.4 alkyl (e.g., CH.sub.3);
or SO.sub.2R.sup.m (e.g., SO.sub.2CH.sub.3).
[0410] R.sup.c22 and R.sup.c23; or R.sup.c22 and R.sup.c26; or
R.sup.c23 and R.sup.c24 can each be, independently, halo (e.g.,
chloro or fluoro) or C.sub.1-C.sub.4 alkyl (e.g., CH.sub.3).
[0411] R.sup.c22 can be C.sub.1-C.sub.4 haloalkyl (e.g., CF.sub.3),
optionally substituted with from 1-3 R.sup.j; and R.sup.c24 can be
halo; C.sub.1-C.sub.4 haloalkyl, optionally substituted with from
1-3 R.sup.j; cyano; or heteroaryl including 5-6 atoms, optionally
substituted with from 1-2 R.sup.a. For example, R.sup.c22 can be
CF.sub.3. R.sup.c22 can be CF.sub.3, and R.sup.c24 can be halo (and
the others can be hydrogen).
[0412] R.sup.c22 and R.sup.c24 can each be, independently, fluoro
or chloro. For example, R.sup.c22 can be chloro, and R.sup.c24 can
be fluoro.
[0413] For example, R.sup.2 can be
4-fluoro-2-(sulfonylmethyl)phenyl;
4-fluoro-2-(trifluoromethyl)phenyl; 2,3-dichlorophenyl;
2,4-difluorophenyl; 2,4-dimethylphenyl; 2,6-dichlorophenyl;
2,6-dimethylphenyl; 3,4-dichlorophenyl; or
3-fluoro-2-(trifluoromethyl)phenyl.
[0414] In some embodiments, R.sup.2 can be OR.sup.1, in which
R.sup.1 can be C.sub.6-C.sub.10 aryl, or heteroaryl including 5-10
atoms, each of which can be optionally substituted with from (e.g.,
1-2 or 1) R.sup.a; or R.sup.1 can be C.sub.7-C.sub.12 aralkyl,
optionally substituted with from 1-3 R.sup.b.
[0415] In certain embodiments, R.sup.2 can be unsubstituted
phenoxy.
[0416] In certain embodiments, R.sup.2 can be a monosubstituted
phenoxy group having formula (V):
##STR00023##
in which one of R.sup.c32, R.sup.c33, and R.sup.c34 can be halo;
C.sub.1-C.sub.12 alkyl; C.sub.1-C.sub.12 haloalkyl;
C.sub.1-C.sub.12 alkoxy; C.sub.1-C.sub.12 haloalkoxy; cyano; or
nitro; and the others are hydrogen.
[0417] R.sup.c32 can be C.sub.1-C.sub.4 haloalkyl (e.g.,
CF.sub.3).
[0418] R.sup.c32 can be C.sub.1-C.sub.4 alkyl (e.g., CH.sub.3,
CH.sub.2CH.sub.3, n-propyl, or iso-propyl).
[0419] R.sup.c32 or R.sup.c34 is C.sub.1-C.sub.4 alkoxy (e.g.,
OCH.sub.3).
[0420] R.sup.c32 can be halo (e.g., chloro or bromo); nitro or
cyano.
[0421] In certain embodiments, R.sup.2 can be a disubstituted
phenoxy group in which the phenyl ring is substituted, e.g., at the
2- and 6-positions with, e.g., C.sub.1-C.sub.4 alkyl (e.g.,
CH.sub.3) or halo (e.g., chloro). A preferred disubstituted phenoxy
group is 2,6-dichlorophenoxy:
##STR00024##
[0422] In certain embodiments, R.sup.2 can be an unsubstituted,
monosubstituted, or disubstituted pyridyloxy group. For example,
R.sup.2 can be:
##STR00025##
in which R.sup.a22 can be, e.g., hydrogen or halo (e.g.,
chloro).
[0423] In certain embodiments, R.sup.2 can be an unsubstituted,
monosubstituted, or disubstituted aralkoxy group. In certain
embodiments, R.sup.2 can be benzyloxy or monosubstituted benzyloxy
(e.g., 2-methoxybenzyloxy).
[0424] In some embodiments, R.sup.2 can be NR.sup.3R.sup.4, in
which one of R.sup.3 and R.sup.4 can be hydrogen, and the other is
C.sub.6-C.sub.10 aryl, optionally substituted with from 1-3 (e.g.,
1-2 or 1) R.sup.a. In certain embodiments, one of R.sup.3 and
R.sup.4 can be hydrogen, and the other is phenyl or monosubstituted
phenyl (e.g., substituted with halo, e.g., chloro). For example,
R.sup.2 can be 2-chlorophenylamino:
##STR00026##
[0425] In some embodiments, R.sup.2 can be C.sub.3-C.sub.12 (e.g.,
C.sub.3-C.sub.10) cycloalkyl, optionally substituted with from 1-5
(e.g., 1-4, 1-3, 1-2, or 1) R.sup.b (e.g., halo or C.sub.1-C.sub.4
alkyl).
[0426] In some embodiments, R.sup.2 can be C.sub.6-C.sub.12 (e.g.,
C.sub.6-C.sub.10, C.sub.7-C.sub.12, C.sub.8-C.sub.12,
C.sub.9-C.sub.12, C.sub.10-C.sub.12) cycloalkyl, optionally
substituted with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) R.sup.b
(e.g., halo or C.sub.1-C.sub.4 alkyl).
[0427] In certain embodiments, R.sup.2 can be monocyclic (e.g.,
optionally substituted cyclohexyl or cycloheptyl), bicyclic (e.g.,
optionally substituted bicycloheptyl), or polycyclic (e.g.,
optionally substituted adamantyl). For example, R.sup.1 can be
1-adamantyl, 3-methylcyclohexyl, cycloheptyl, or bicycloheptyl.
[0428] In some embodiments, R.sup.2 can be heterocyclyl including
3-8 atoms, optionally substituted with 1 R.sup.b (e.g.,
C.sub.1-C.sub.4 alkyl (e.g., CH.sub.3)). For example, R.sup.2 can
be morpholino or tetrahydropyranyl.
[0429] In some embodiments, R.sup.2 can be C(O)R.sup.5, in which
R.sup.5 is C.sub.1-C.sub.20 alkyl or C.sub.7-C.sub.20 aralkoxy. In
certain embodiments, R.sup.5 can be C.sub.1-C.sub.12 alkyl (e.g.,
C.sub.3-C.sub.12 branched alkyl, e.g., tert-butyl). In certain
embodiments, R.sup.5 can be an unsubstituted or monosubstituted
aralkoxy group (e.g., benzyloxy).
[0430] In some embodiments, X can be S(O).sub.n, (e.g.,
SO.sub.2).
[0431] In some embodiments, X can be CO.
[0432] In some embodiments, X can be S(O).sub.nNR.sub.6, in which n
can be 2, and R.sup.6 can be hydrogen, C.sub.1-C.sub.4 alkyl, or
C.sub.3-C.sub.8 cycloalkyl. In certain embodiments, X can be
S(O).sub.2NH.
[0433] In some embodiments, each of W.sup.1, Z.sup.1, W.sup.2, and
Z.sup.2 can be hydrogen.
[0434] In some embodiments, one or two of W.sup.1, Z.sup.1,
W.sup.2, and Z.sup.2 can each be, independently, C.sub.1-C.sub.4
alkyl (e.g., CH.sub.3) or oxo, and the others are hydrogen. For
example, W.sup.1 can be C.sub.1-C.sub.4 alkyl (e.g., CH.sub.3) or
oxo; or W.sup.2 can be oxo; or W.sup.1 and W.sup.2 or W.sup.1 and
Z.sup.2 can both be C.sub.1-C.sub.4 alkyl (e.g., CH.sub.3). Each of
the carbons bearing W.sup.1, Z.sup.1, W.sup.2, and Z.sup.2 can
have, independently, the R or the S stereochemical configuration
when W.sup.1, Z.sup.1, W.sup.2, or Z.sup.2 is other than hydrogen.
In certain embodiments, W.sup.1 can be C.sub.1-C.sub.4 alkyl (e.g.,
CH.sub.3), and the carbon bearing W.sup.1 can have the R
configuration.
[0435] One or two of W.sup.1, Z.sup.1, W.sup.2, and Z.sup.2 (e.g.,
W.sup.1 and Z.sup.2, e.g., W.sup.1) can each be, independently,
other than hydrogen (e.g., C.sub.1-C.sub.4 alkyl or oxo), and the
others can be hydrogen. One or two of W.sup.1, Z.sup.1, W.sup.2,
and Z.sup.2 (e.g., W.sup.1 and Z.sup.2, e.g., W.sup.1) can each be,
independently, C.sub.1-C.sub.4 alkyl, and the others can be
hydrogen. Each of Z.sup.1 and W.sup.2 can be hydrogen. One or both
of W.sup.1 and Z.sup.2 (e.g., W.sup.1) can each be, independently,
C.sub.1-C.sub.4 alkyl; and each of Z.sup.1 and W.sup.2 can be
hydrogen. W.sup.1 can be C.sub.1-C.sub.4 alkyl (e.g.,
CH.sub.3).
[0436] In some embodiments, Y and V can both be nitrogen, and the
11-beta HSD1 inhibitor compounds can have formula (VI):
##STR00027##
in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, X, W.sup.1, Z.sup.1, W.sup.2, Z.sup.2, R.sup.a, R.sup.a',
R.sup.b, R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g, R.sup.h,
R.sup.i, R.sup.j, R.sup.k, R.sup.m, and R.sup.n can be as defined
anywhere herein.
[0437] In some embodiments, X can be SO.sub.2, and the 11-beta HSD1
inhibitor compounds can include one or more of the following
features.
[0438] R.sup.1 can be:
[0439] (A) C.sub.6-C.sub.18 (e.g., C.sub.6-C.sub.14,
C.sub.6-C.sub.10, or phenyl) aryl or heteroaryl including 5-20
(e.g., 5-16, 5-12, or 5-6) atoms, each of which is optionally
substituted with from 1-10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1)
R.sup.a; for example, R.sup.1 can be C.sub.6-C.sub.10 aryl,
optionally substituted with from 1-3 (e.g., 1-2 or 1) R.sup.a or
heteroaryl including 5-14 atoms, optionally substituted with from
1-3 (e.g., 1-2 or 1) R.sup.a as described herein; and/or
[0440] (D) C.sub.7-C.sub.20 (e.g., C.sub.7-C.sub.16,
C.sub.7-C.sub.12, C.sub.7-C.sub.10) aralkyl, optionally substituted
with from 1-10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1) R.sup.b; for
example, R.sup.1 can be C.sub.7-C.sub.12 aralkyl, optionally
substituted with from 1-2 R.sup.b (e.g., halo) as described herein;
and/or (E) arylheterocyclyl including 8-20 (e.g., 8-16 or 9-12)
atoms, optionally substituted with from 1-10 (e.g., 1-5, 1-4, 1-3,
1-2, or 1) R.sup.b; for example, R.sup.1 can be arylheterocyclyl
including 9-12 atoms, optionally substituted with from 1-5 (e.g.,
1-4, 1-3, 1-2, or 1) R.sup.b (e.g., oxo, halo or C.sub.1-C.sub.4
alkyl), in which the heterocyclyl portion can include 1 or 2
heteroatoms (e.g., nitrogen or oxygen) as described herein.
[0441] R.sup.2 can be:
[0442] (A) heteroaryl including 5-20 (e.g., 5-16, 5-12, or 5-6)
atoms, optionally substituted with from 1-10 (e.g., 1-5, 1-4, 1-3,
1-2, or 1) R.sup.c or R.sup.n; or C.sub.6-C.sub.18 (e.g.,
C.sub.6-C.sub.14, C.sub.6-C.sub.10, or phenyl) aryl, optionally
substituted with from 1-10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1)
R.sup.c; for example, R.sup.2 can be heteroaryl including 5-12
atoms, optionally substituted with from 1-3 (e.g., 1-2 or 1)
R.sup.c or R.sup.n; or R.sup.2 can be C.sub.6-C.sub.10 aryl,
optionally substituted with from 1-3 (e.g., 1-2 or 1) R.sup.c as
described herein; and/or
[0443] (B) C.sub.3-C.sub.16 (e.g., C.sub.3-C.sub.14,
C.sub.3-C.sub.10, C.sub.6-C.sub.16, C.sub.6-C.sub.14, or
C.sub.6-C.sub.10) cycloalkyl, optionally substituted with from 1-10
(e.g., 1-5, 1-4, 1-3, 1-2, or 1) R.sup.b; for example, R.sup.2 can
be C.sub.3-C.sub.12 (e.g., C.sub.3-C.sub.10) cycloalkyl, optionally
substituted with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) R.sup.b
(e.g., halo or C.sub.1-C.sub.4 alkyl) or C.sub.6-C.sub.12 (e.g.,
C.sub.6-C.sub.10) cycloalkyl, optionally substituted with from 1-5
(e.g., 1-4, 1-3, 1-2, or 1) R.sup.b (e.g., halo or C.sub.1-C.sub.4
alkyl); as described herein; and/or
[0444] (D) heterocyclyl including 3-16 (e.g., 3-12, 3-10, 5-12, or
5-6) atoms, optionally substituted with from 1-10 (e.g., 1-5, 1-4,
1-3, 1-2, or 1) R.sup.b; for example, R.sup.2 can be heterocyclyl
including 3-8 atoms, optionally substituted with 1 R.sup.b (e.g.,
C.sub.1-C.sub.4 alkyl (e.g., CH.sub.3)) as described herein;
and/or
[0445] (E) C(O)R.sup.5, in which R.sup.5 is C.sub.1-C.sub.20 (e.g.,
C.sub.1-C.sub.12, C.sub.1-C.sub.6, or C.sub.1-C.sub.4) alkyl or
C.sub.7-C.sub.20 (e.g., C.sub.7-C.sub.12 aralkoxy) as described
herein.
[0446] In certain embodiments, R.sup.2 can be (A), (B), (C), and/or
(D); or (A), (C), (D), and/or (E); or (A), (C), and/or (D); or (A)
and/or (C).
[0447] In certain embodiments, when R.sup.2 is substituted pyridyl
or pyrimidinyl (e.g., 2-, 3-, or 4-pyridyl; or 2- or
3-pyrimidinyl), then R.sup.c cannot be C.sub.1-C.sub.12 alkoxy
optionally substituted with 1-5 R.sup.f; C.sub.1-C.sub.12
haloalkoxy; or SO.sub.2R.sup.m.
[0448] In certain embodiments, when R.sup.2 is a substituted
heteroaryl including 5-14 atoms (e.g., 5-12 atoms, 5-8 atoms, 5-6
atoms, or 6 atoms), then R.sup.2 is substituted with R.sup.n.
[0449] In certain embodiments, when R.sup.2 is C.sub.3-C.sub.16
cycloalkyl (e.g., C.sub.3-C.sub.5 cycloalkyl, e.g., C.sub.5
cycloalkyl, e.g., substituted C.sub.5 cycloalkyl, e.g., C.sub.5
cycloalkyl substituted with hydroxyl or imidazolyl) then R.sup.1
cannot be a monosubstituted phenyl ring that is substituted at the
para-position with either substituted C.sub.1-C.sub.12 alkyl or
substituted C.sub.1-C.sub.12 haloalkyl (e.g., a phenyl ring
substituted at the para-position with --CR.sup.21R.sup.22R.sup.23,
in which R.sup.21, R.sup.22 and R.sup.23 are each independently
hydrogen, halo, hydroxyl, cyano, nitro, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, alkoxy,
haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, heteroaryl
or aryl and at least one of R.sup.21, R.sup.22 and R.sup.23 is
other than hydrogen, e.g., a phenyl ring substituted at the
para-position with 2-hydroxy-1,1,1-trifluoro-2-propyl, i.e.,
CF.sub.3C(OH)(CH.sub.3)).
[0450] In certain embodiments, one or more of the other conditions
delineated in the Summary can apply. For example, (a) can apply. In
certain embodiments, (a) and any one of (e)-(j) apply. In certain
embodiments, any one of (e)-(j) applies. In certain embodiments,
any two or three of (e)-(j) applies, optionally in combination with
(a). For example, (e) or (f) and (g) or (h) and/or (i) and (j),
optionally in combination with (a).
[0451] In certain embodiments, (a) applies. In certain embodiments,
(a) and/or (k) applies. In certain embodiments, (a), (k) and any
one, two, three, or four of (l)-(o) apply.
[0452] In certain embodiments, R.sup.2 can be C.sub.6-C.sub.16
(e.g., C.sub.6-C.sub.14, C.sub.6-C.sub.10, C.sub.7-C.sub.16,
C.sub.8-C.sub.16, C.sub.9-C.sub.16, C.sub.10-C.sub.16,
C.sub.7-C.sub.14, C.sub.8-C.sub.14, C.sub.9-C.sub.14,
C.sub.10-C.sub.14, C.sub.7-C.sub.10, C.sub.8-C.sub.10, or
C.sub.9-C.sub.10) cycloalkyl, optionally substituted with from 1-5
(e.g., 1-4, 1-3, 1-2, or 1) R.sup.b (e.g., halo or C.sub.1-C.sub.4
alkyl).
[0453] A subset of compounds includes those having formula
(VI-A):
##STR00028##
[0454] in which:
[0455] one or two of R.sup.a2, R.sup.a3, R.sup.a4, and R.sup.a6 can
each be, independently, halo; C.sub.1-C.sub.12 alkyl or
C.sub.1-C.sub.12 haloalkyl, each of which is optionally substituted
with from 1-2 R.sup.j; C.sub.1-C.sub.12 alkoxy, optionally
substituted with 1-2 R.sup.f; C.sub.1-C.sub.12 haloalkoxy; cyano;
nitro; C.sub.6-C.sub.10 aryl or heteroaryl including 5-12 atoms,
each of which is optionally substituted with from 1-2 R.sup.a';
C.sub.6-C.sub.10 aryloxy, optionally substituted with from 1-2
R.sup.a'; C.sub.3-C.sub.10 heterocyclyl, C.sub.3-C.sub.10
cycloalkyl, or C.sub.7-C.sub.12 aralkoxy, each of which is
optionally substituted with 1-2 R.sup.b; or --NR.sup.hC(O)R.sup.i;
and the others are hydrogen;
[0456] W.sup.1 can be hydrogen or C.sub.1-C.sub.4 alkyl (e.g.,
CH.sub.3); and
[0457] one or two of R.sup.c22, R.sup.c23, R.sup.c24, R.sup.c25,
and R.sup.c26 can each be, independently, halo; hydroxyl;
C.sub.1-C.sub.12 alkyl; C.sub.1-C.sub.12 haloalkyl;
C.sub.1-C.sub.12 alkoxy; C.sub.1-C.sub.12 haloalkoxy; cyano; nitro;
C.sub.6-C.sub.10 aryl, optionally substituted with from 1-2
R.sup.a'; heterocyclyl including 3-10 atoms, optionally substituted
with from 1-2 R.sup.b (e.g., C.sub.1-C.sub.12 alkyl (e.g.,
CH.sub.3)); heteroaryl including from 5-10 atoms, optionally
substituted with from 1-2 R.sup.a'; or SO.sub.2R.sup.m; and the
others are hydrogen. The variables delineated in formula (VI) above
can also be as defined in the Summary and the conditions delineated
therein can apply.
[0458] In some embodiments, R.sup.a2, R.sup.a3, or R.sup.a4 can be
C.sub.1-C.sub.4 haloalkyl, optionally substituted with 1 R.sup.j
(e.g., hydroxyl). For example, R.sup.a2, R.sup.a3, or R.sup.a4
(e.g., R.sup.a3 or R.sup.a4) can be (e.g., R or S)
1,1,1-trifluoro-2-hydroxypropan-2-yl, i.e.,
CF.sub.3C(OH)(CH.sub.3), in which the stereogenic carbon (i.e., the
carbon attached to the hydroxyl group) can have the R or S
configuration or some combination thereof (e.g., about 50% R and
about 50% S or any other non-racemic combination of
configurations). In some embodiments, R.sup.a3 or R.sup.a4 (e.g.,
R.sup.a3) can be:
##STR00029##
In these embodiments, each of the remaining substituents can be
hydrogen.
[0459] In some embodiments, R.sup.a2, R.sup.a3, or R.sup.a4 (e.g.,
R.sup.a3 or R.sup.a4) can be C.sub.1-C.sub.12 alkyl, optionally
substituted with 1 R.sup.j (e.g., hydroxyl). For example, R.sup.a2,
R.sup.a3, or R.sup.a4 (e.g., R.sup.a3 or R.sup.a4) can be
2-hydroxy-2-propan-2-yl, i.e., CH.sub.3C(OH)(CH.sub.3).
[0460] In some embodiments, R.sup.a2, R.sup.a3, or R.sup.a4 can be
C.sub.3-C.sub.10 cycloalkyl, optionally substituted with 1 R.sup.b
(e.g., hydroxyl). For example, R.sup.a2, R.sup.a3, or R.sup.a4
(e.g., R.sup.a3 or R.sup.a4, e.g., R.sup.a4) can be
1-hydroxycyclopropan-1-yl.
[0461] In some embodiments, R.sup.a3 or R.sup.a4 can be
heterocyclyl including 3-8 atoms, optionally substituted with 1
R.sup.b (e.g., C.sub.1-C.sub.4 alkyl (e.g., CH.sub.3), OH,
C.sub.3-C.sub.10 cycloalkyl, or COOR.sup.g (e.g., COOH)). For
example, R.sup.a3 or R.sup.a4 can be optionally substituted
pyrrolidinyl (e.g., pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, or
3-carboxypyrrolidin-1-yl), morpholinyl (e.g., morpholin-4-yl),
piperidyl (e.g., 1-piperidyl or 4-piperidyl) or piperazinyl (e.g.,
piperazin-1-yl, 4-methylpiperazin-1-yl). In a preferred embodiment,
R.sup.a3 is optionally substituted pyrrolidin-1-yl (e.g.,
3-hydroxypyrrolidin-1-yl).
[0462] In some embodiments, R.sup.a3 or R.sup.a4 can be heteroaryl
including 5 or 6 atoms (e.g., 1H-1,2,4-triazolyl).
[0463] In some embodiments, W.sup.1 can be C.sub.1-C.sub.4 alkyl
(e.g., CH.sub.3).
[0464] In some embodiments, two of R.sup.c22, R.sup.c23, R.sup.c24,
R.sup.c25, and R.sup.c26 can each be, independently, halo or
C.sub.1-C.sub.4 haloalkyl (e.g., two of R.sup.c22, R.sup.c23,
R.sup.c24, R.sup.c25, and R.sup.c26 can each be, independently,
fluoro or CF.sub.3). For example, R.sup.c22 can be C.sub.1-C.sub.4
haloalkyl (e.g., CF.sub.3) and R.sup.c23 or R.sup.c24 (e.g.,
R.sup.c24) can be halo (e.g., fluoro).
[0465] In some embodiments, R.sup.c22 can be C.sub.1-C.sub.4
haloalkyl (e.g., CF.sub.3), halo (e.g., chloro), C.sub.1-C.sub.6
alkoxy (e.g., OCH.sub.3), cyano, or C.sub.1-C.sub.6 alkyl (e.g.,
CH.sub.3); and one of R.sup.c23, R.sup.c24, and R.sup.c25 can be
heterocyclyl including 3-8 atoms, optionally substituted with 1
R.sup.b (e.g., C.sub.1-C.sub.12, e.g., C.sub.1-C.sub.6 alkyl, e.g.,
CH.sub.3); heteroaryl including 5 or 6 atoms, optionally
substituted with 1 R.sup.a'; or halo (e.g., fluoro). For example,
one of R.sup.c23, R.sup.c24, and R.sup.c25 can be optionally
substituted piperazinyl (e.g., piperazin-1-yl or 4-(C.sub.1-C.sub.6
alkyl)piperazin-1-yl); optionally substituted morpholinyl (e.g.,
morpholin-4-yl); 1H-1,2,4-triazolyl; or fluoro.
[0466] In certain embodiments, R.sup.a4 can be
1,1,1-trifluoro-2-hydroxypropan-2-yl; W.sup.1 can be CH.sub.3;
R.sup.c22 can be C.sub.1-C.sub.4 haloalkyl (e.g., CF.sub.3), halo
(e.g., chloro), C.sub.1-C.sub.6 alkoxy (e.g., OCH.sub.3), cyano, or
C.sub.1-C.sub.6 alkyl (e.g., CH.sub.3); and R.sup.c23, R.sup.c24,
or R.sup.c25 can be optionally substituted piperazinyl (e.g.,
piperazin-1-yl or piperazin-1-yl substituted with C.sub.1-C.sub.6
alkyl, e.g., 4-(C.sub.1-C.sub.6 alkyl)piperazin-1-yl).
[0467] In certain embodiments, R.sup.a4 can be
1,1,1-trifluoro-2-hydroxypropan-2-yl; W.sup.1 can be CH.sub.3;
R.sup.c22 can be C.sub.1-C.sub.4 haloalkyl (e.g., CF.sub.3), halo
(e.g., chloro), C.sub.1-C.sub.6 alkoxy (e.g., OCH.sub.3), cyano, or
C.sub.1-C.sub.6 alkyl (e.g., CH.sub.3), and R.sup.c23, R.sup.c24,
or R.sup.c25 can be optionally substituted morpholinyl (e.g.,
morpholin-4-yl or morpholin-4-yl substituted with C.sub.1-C.sub.6
alkyl).
[0468] In certain embodiments, R.sup.a4 can be
1,1,1-trifluoro-2-hydroxypropan-2-yl; W.sup.1 can be CH.sub.3;
R.sup.c22 can be C.sub.1-C.sub.4 haloalkyl (e.g., CF.sub.3), halo
(e.g., chloro), C.sub.1-C.sub.6 alkoxy (e.g., OCH.sub.3), cyano, or
C.sub.1-C.sub.6 alkyl (e g, CH.sub.3), and R.sup.c23, R.sup.c24, or
R.sup.c25 can be optionally substituted 1H-1,2,4-triazolyl.
[0469] In certain embodiments, R.sup.a3 can be
1,1,1-trifluoro-2-hydroxypropan-2-yl; W.sup.1 can be CH.sub.3;
R.sup.c22 can be C.sub.1-C.sub.4 haloalkyl (e.g., CF.sub.3), halo
(e.g., chloro), C.sub.1-C.sub.6 alkoxy (e.g., OCH.sub.3), cyano, or
C.sub.1-C.sub.6 alkyl (e.g., CH.sub.3), and R.sup.c23, R.sup.c24,
or R.sup.c25 can be fluoro.
[0470] In certain embodiments, R.sup.a3 can be
2-hydroxypropan-2-yl; W.sup.1 can be CH.sub.3; R.sup.c22 can be
C.sub.1-C.sub.4 haloalkyl (e.g., CF.sub.3), halo (e.g., chloro),
C.sub.1-C.sub.6 alkoxy (e.g., OCH.sub.3), cyano, or C.sub.1-C.sub.6
alkyl (e.g., CH.sub.3), and R.sup.c23, R.sup.c24 or R.sup.c25 can
be fluoro.
[0471] In certain embodiments, R.sup.a4 can be
2-hydroxypropan-2-yl; W.sup.1 can be CH.sub.3; R.sup.c22 can be
C.sub.1-C.sub.4 haloalkyl (e.g., CF.sub.3), halo (e.g., chloro),
C.sub.1-C.sub.6 alkoxy (e.g., OCH.sub.3), cyano, or C.sub.1-C.sub.6
alkyl (e.g., CH.sub.3), and R.sup.c23, R.sup.c24 or R.sup.c25 can
be fluoro.
[0472] In certain embodiments, R.sup.a4 can be
1-hydroxycyclopropan-1-yl; W.sup.1 can be CH.sub.3; R.sup.c22 can
be C.sub.1-C.sub.4 haloalkyl (e.g., CF.sub.3), halo (e.g., chloro),
C.sub.1-C.sub.6 alkoxy (e.g., OCH.sub.3), cyano, or C.sub.1-C.sub.6
alkyl (e.g., CH.sub.3), and R.sup.c23, R.sup.c24, or R.sup.c25 can
be fluoro.
[0473] In certain embodiments, R.sup.a3 can be piperazin-1-yl,
4-(C.sub.1-C.sub.4 alkyl)piperazin-1-yl, or 4-(C.sub.3-C.sub.10
cycloalkyl)piperazin-1-yl; W.sup.1 can be CH.sub.3; R.sup.c22 can
be C.sub.1-C.sub.4 haloalkyl (e.g., CF.sub.3), halo (e.g., chloro),
C.sub.1-C.sub.6 alkoxy (e.g., OCH.sub.3), cyano, or C.sub.1-C.sub.6
alkyl (e.g., CH.sub.3), and R.sup.c23, R.sup.c24, or R.sup.c25 can
be fluoro.
[0474] In certain embodiments, R.sup.a3 can be 4-piperidyl,
1-(C.sub.1-C.sub.4 alkyl)-4-piperidyl, or 1-(C.sub.3-C.sub.10
cycloalkyl)piperidyl; W.sup.1 can be CH.sub.3; R.sup.c22 can be
C.sub.1-C.sub.4 haloalkyl (e.g., CF.sub.3), halo (e.g., chloro),
C.sub.1-C.sub.6 alkoxy (e.g., OCH.sub.3), cyano, or C.sub.1-C.sub.6
alkyl (e.g., CH.sub.3), and R.sup.c23, R.sup.c24, or R.sup.c25 can
be fluoro.
[0475] In certain embodiments, R.sup.a3 can be 1H-1,2,4-triazolyl;
W.sup.1 can be CH.sub.3; R.sup.c22 can be C.sub.1-C.sub.4 haloalkyl
(e.g., CF.sub.3), halo (e.g., chloro), C.sub.1-C.sub.6 alkoxy
(e.g., OCH.sub.3), cyano, or C.sub.1-C.sub.6 alkyl (e.g.,
CH.sub.3), and R.sup.c23, R.sup.c24, or R.sup.c25 can be
fluoro.
[0476] In certain embodiments, R.sup.a3 can be
3-hydroxypyrrolidin-1-yl; W.sup.1 can be CH.sub.3; R.sup.c22 can be
CF.sub.3; and R.sup.c23, R.sup.c24, or R.sup.c25 can be fluoro.
[0477] In certain embodiments, R.sup.a3 can be
3-carboxypyrrolidin-1-yl; W.sup.1 can be CH.sub.3; R.sup.c22 can be
CF.sub.3; and R.sup.c23, R.sup.c24, or R.sup.c25 can be fluoro.
[0478] In some embodiments, X can be CO, and the 111-beta HSD1
inhibitor compounds can include one or more of the following
features.
[0479] R.sup.1 can be:
[0480] (B) C.sub.3-C.sub.16 (e.g., C.sub.3-C.sub.14 or
C.sub.3-C.sub.10) cycloalkyl, optionally substituted with from 1-10
(e.g., 1-5, 1-4, 1-3, 1-2, or 1); R.sup.b as described herein;
and/or
[0481] (C) (C.sub.1-C.sub.12 alkyl)-(C.sub.3-C.sub.16 cycloalkyl)
(e.g., (C.sub.1-C.sub.6 alkyl)-(C.sub.3-C.sub.12 cycloalkyl) or
(CH.sub.2)--(C.sub.3-C.sub.12 cycloalkyl), optionally substituted
with from 1-10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1) R.sup.b as
described herein.
[0482] R.sup.2 can be heteroaryl including 5-20 (e.g., 5-16, 5-12,
or 5-6) atoms, optionally substituted with from 1-10 (e.g., 1-5,
1-4, 1-3, 1-2, or 1) R.sup.c or R.sup.n; or C.sub.6-C.sub.18 (e.g.,
C.sub.6-C.sub.14, C.sub.6-C.sub.10, or phenyl) aryl, optionally
substituted with from 1-10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1)
R.sup.c; for example, R.sup.2 can be heteroaryl including 5-12
atoms, optionally substituted with from 1-3 (e.g., 1-2 or 1)
R.sup.c or R.sup.n or C.sub.6-C.sub.10 aryl, optionally substituted
with from 1-3 (e.g., 1-2 or 1) R.sup.c as described herein. In
certain embodiments, R.sup.2 can be heteroaryl including 5-12
atoms, optionally substituted with from 1-3 (e.g., 1-2 or 1)
R.sup.c or R.sup.n.
[0483] In some embodiments, Y can be CR.sup.7 (e.g., CH) and V can
be nitrogen, and the 11-beta HSD1 inhibitor compounds can have
formula (VII):
##STR00030##
in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, X, W.sup.1, Z.sup.1, W.sup.2, Z.sup.2, R.sup.a, R.sup.a',
R.sup.b, R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g, R.sup.h,
R.sup.i, R.sup.j, R.sup.k, R.sup.m, and R.sup.n can be as
defined.
[0484] In certain embodiments, X can be SO.sub.2 or SO.sub.2NH, and
the 11-beta HSD1 inhibitor compounds can include one or more of the
following features.
[0485] R.sup.1 can be C.sub.6-C.sub.18 (e.g., C.sub.6-C.sub.14,
C.sub.6-C.sub.10, or phenyl) aryl or heteroaryl including 5-20
(e.g., 5-16, 5-12, or 5-6) atoms, each of which is optionally
substituted with from 1-10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1)
R.sup.a; for example, R.sup.1 can be C.sub.6-C.sub.10 aryl,
optionally substituted with from 1-3 (e.g., 1-2 or 1) R.sup.a or
heteroaryl including 5-14 atoms, optionally substituted with from
1-3 (e.g., 1-2 or 1) R.sup.a as described herein.
[0486] R.sup.2 can be heteroaryl including 5-20 (e.g., 5-16, 5-12,
or 5-6) atoms, optionally substituted with from 1-10 (e.g., 1-5,
1-4, 1-3, 1-2, or 1) R.sup.c or R.sup.n; or C.sub.6-C.sub.18 (e.g.,
C.sub.6-C.sub.14, C.sub.6-C.sub.10, or phenyl) aryl, optionally
substituted with from 1-10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1)
R.sup.c; for example, R.sup.2 can be heteroaryl including 5-12
atoms, optionally substituted with from 1-3 (e.g., 1-2 or 1)
R.sup.c or R.sup.n or C.sub.6-C.sub.10 aryl, optionally substituted
with from 1-3 (e.g., 1-2 or 1) R.sup.c as described herein. In
certain embodiments, R.sup.2 can be heteroaryl including 5-12
atoms, optionally substituted with from 1-3 (e.g., 1-2 or 1)
R.sup.c or R.sup.n as described herein.
[0487] In some embodiments, Y can be nitrogen and V can be CR.sup.7
(e.g., CH), and the 11-beta HSD1 inhibitor compounds can have
formula (VIII):
##STR00031##
in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, X, W.sup.1, Z.sup.1, W.sup.2, Z.sup.2, R.sup.a, R.sup.a',
R.sup.b, R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g, R.sup.h,
R.sup.i, R.sup.j, R.sup.k, R.sup.m, and R.sup.n can be as
defined.
[0488] In certain embodiments, X can be SO.sub.2, and the 11-beta
HSD1 inhibitor compounds can include one or more of the following
features.
[0489] R.sup.1 can be C.sub.6-C.sub.18 (e.g., C.sub.6-C.sub.14,
C.sub.6-C.sub.10, or phenyl) aryl or heteroaryl including 5-20
(e.g., 5-16, 5-12, or 5-6) atoms, each of which is optionally
substituted with from 1-10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1)
R.sup.a; for example, R.sup.1 can be C.sub.6-C.sub.10 aryl,
optionally substituted with from 1-3 (e.g., 1-2 or 1) R.sup.a or
heteroaryl including 5-14 atoms, optionally substituted with from
1-3 (e.g., 1-2 or 1) R.sup.a as described herein.
[0490] R.sup.2 can be:
[0491] (A) heteroaryl including 5-20 (e.g., 5-16, 5-12, or 5-6)
atoms, optionally substituted with from 1-10 (e.g., 1-5, 1-4, 1-3,
1-2, or 1) R.sup.c or R.sup.n; or C.sub.6-C.sub.18 (e.g.,
C.sub.6-C.sub.14, C.sub.6-C.sub.10, or phenyl) aryl, optionally
substituted with from 1-10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1)
R.sup.c; for example, R.sup.2 can be heteroaryl including 5-12
atoms, optionally substituted with from 1-3 (e.g., 1-2 or 1)
R.sup.c or R.sup.n; or R.sup.2 can be C.sub.6-C.sub.10 aryl,
optionally substituted with from 1-3 (e.g., 1-2 or 1) R.sup.c as
described herein; and/or
[0492] (C)OR.sup.1; or NR.sup.3R.sup.4, in which R.sup.3 and
R.sup.4 are each, independently, hydrogen or R.sup.1 (e.g.,
C.sub.6-C.sub.18 (e.g., C.sub.6-C.sub.14, C.sub.6-C.sub.10, or
phenyl) aryl or heteroaryl including 5-20 (e.g., 5-16, 5-12, or
5-6) atoms; each of which is optionally substituted with from 1-10
(e.g., 1-5, 1-4, 1-3, 1-2, or 1) R.sup.a); for example, R.sup.2 can
be OR.sup.1, in which R.sup.1 can be C.sub.6-C.sub.10 aryl, or
heteroaryl including 5-10 atoms, each of which can be optionally
substituted with from (e.g., 1-2 or 1) R.sup.a or R.sup.1 can be
C.sub.7-C.sub.12 aralkyl, optionally substituted with from 1-3
R.sup.b; or R.sup.2 can be NR.sup.3R.sup.4, in which one of R.sup.3
and R.sup.4 can be hydrogen, and the other is C.sub.6-C.sub.10
aryl, optionally substituted with from 1-3 (e.g., 1-2 or 1) R.sup.a
as described herein; and/or
[0493] (D) heterocyclyl including 3-16 (e.g., 3-12, 3-10, 5-12, or
5-6) atoms, optionally substituted with from 1-10 (e.g., 1-5, 1-4,
1-3, 1-2, or 1) R.sup.b; for example, R.sup.2 can be heterocyclyl
including 3-8 atoms, optionally substituted with 1 R.sup.b (e.g.,
C.sub.1-C.sub.4 alkyl (e.g., CH.sub.3)) as described herein.
[0494] In certain embodiments, when R.sup.2 is (A), R.sup.2 is
optionally substituted heteroaryl including 5-20 (e.g., 5-16, 5-12,
or 5-6) atoms. In other embodiments, when R.sup.2 is (A), R.sup.2
is optionally substituted C.sub.6-C.sub.18 (e.g., C.sub.6-C.sub.14,
C.sub.6-C.sub.10, or phenyl) aryl.
[0495] In certain embodiments, X can be CO, and the 11-beta HSD1
inhibitor compounds can include one or more of the following
features.
[0496] R.sup.1 can be:
[0497] (B) C.sub.3-C.sub.16 (e.g., C.sub.3-C.sub.14 or
C.sub.3-C.sub.10) cycloalkyl, optionally substituted with from 1-10
(e.g., 1-5, 1-4, 1-3, 1-2, or 1); R.sup.b as described herein;
and/or
[0498] (D) C.sub.7-C.sub.20 (e.g., C.sub.7-C.sub.16,
C.sub.7-C.sub.12, C.sub.7-C.sub.10) aralkyl, optionally substituted
with from 1-10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1) R.sup.b; for
example, R.sup.1 can be C.sub.7-C.sub.12 aralkyl, optionally
substituted with from 1-2 R.sup.b(e.g., halo) as described
herein.
[0499] R.sup.2 can be OR.sup.1; or NR.sup.3R.sup.4, in which
R.sup.3 and R.sup.4 are each, independently, hydrogen or R.sup.1
(e.g., C.sub.6-C.sub.18 (e.g., C.sub.6-C.sub.14, C.sub.6-C.sub.10,
or phenyl) aryl or heteroaryl including 5-20 (e.g., 5-16, 5-12, or
5-6) atoms; each of which is optionally substituted with from 1-10
(e.g., 1-5, 1-4, 1-3, 1-2, or 1) R.sup.a); for example, R.sup.2 can
be OR.sup.1, in which R.sup.1 can be C.sub.6-C.sub.10 aryl, or
heteroaryl including 5-10 atoms, each of which can be optionally
substituted with from (e.g., 1-2 or 1) R.sup.a; or R.sup.1 can be
C.sub.7-C.sub.12 aralkyl, optionally substituted with from 1-3
R.sup.b; or R.sup.2 can be NR.sup.3R.sup.4, in which one of R.sup.3
and R.sup.4 can be hydrogen, and the other is C.sub.6-C.sub.10
aryl, optionally substituted with from 1-3 (e.g., 1-2 or 1) R.sup.a
as described herein. In certain embodiments, R.sup.2 can be
OR.sup.1, in which R.sup.1 can be C.sub.6-C.sub.10 aryl, or
heteroaryl including 5-10 atoms, each of which can be optionally
substituted with from (e.g., 1-2 or 1) R.sup.a; or R.sup.1 can be
C.sub.7-C.sub.12 aralkyl, optionally substituted with from 1-3
R.sup.b.
[0500] It is understood that the actual electronic structure of
some chemical entities cannot be adequately represented by only one
canonical form (i.e. Lewis structure). While not wishing to be
bound by theory, the actual structure can instead be some hybrid or
weighted average of two or more canonical forms, known collectively
as resonance forms or structures. Resonance structures are not
discrete chemical entities and exist only on paper. They differ
from one another only in the placement or "localization" of the
bonding and nonbonding electrons for a particular chemical entity.
It can be possible for one resonance structure to contribute to a
greater extent to the hybrid than the others. Thus, the written and
graphical descriptions of the embodiments of the present invention
are made in terms of what the art recognizes as the predominant
resonance form for a particular species.
[0501] The compounds described herein can be synthesized according
to methods described herein and/or conventional, organic chemical
synthesis methods from commercially available starting materials
and reagents. The compounds described herein can be separated from
a reaction mixture and further purified by a method such as column
chromatography, high-pressure liquid chromatography, or
recrystallization. As can be appreciated by the skilled artisan,
further methods of synthesizing the compounds of the formulae
herein will be evident to those of ordinary skill in the art.
Additionally, the various synthetic steps may be performed in an
alternate sequence or order to give the desired compounds.
Synthetic chemistry transformations and protecting group
methodologies (protection and deprotection) useful in synthesizing
the compounds described herein are known in the art and include,
for example, those such as described in R. Larock, Comprehensive
Organic Transformations, VCH Publishers (1989); T. W. Greene and P.
G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John
Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's
Reagents for Organic Synthesis, John Wiley and Sons (1994); and L.
Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John
Wiley and Sons (1995), and subsequent editions thereof.
[0502] In some embodiments, the compounds described herein can be
prepared according to the general schemes below:
##STR00032## ##STR00033## ##STR00034## ##STR00035## ##STR00036##
##STR00037## ##STR00038## ##STR00039##
[0503] The compounds of this invention may contain one or more
asymmetric centers and thus occur as racemates and racemic
mixtures, single enantiomers, individual diastereomers and
diastereomeric mixtures. All such isomeric forms of these compounds
are expressly included in the present invention. The compounds of
this invention may also contain linkages (e.g., carbon-carbon
bonds, carbon-nitrogen bonds such as amide bonds) wherein bond
rotation is restricted about that particular linkage, e.g.
restriction resulting from the presence of a ring or double bond.
Accordingly, all cis/trans and E/Z isomers and rotational isomers
are expressly included in the present invention. The compounds of
this invention may also be represented in multiple tautomeric
forms, in such instances, the invention expressly includes all
tautomeric forms of the compounds described herein, even though
only a single tautomeric form may be represented (e.g., alkylation
of a ring system may result in alkylation at multiple sites, the
invention expressly includes all such reaction products). All such
isomeric forms of such compounds are expressly included in the
present invention. All crystal forms of the compounds described
herein are expressly included in the present invention.
[0504] The compounds of this invention include the compounds
themselves, as well as their salts and their prodrugs, if
applicable. A salt, for example, can be formed between an anion and
a positively charged substituent (e.g., amino) on a compound
described herein. Suitable anions include chloride, bromide,
iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate,
trifluoroacetate, and acetate. Likewise, a salt can also be formed
between a cation and a negatively charged substituent (e.g.,
carboxylate) on a compound described herein. Suitable cations
include sodium ion, potassium ion, magnesium ion, calcium ion, and
an ammonium cation such as tetramethylammonium ion. Examples of
prodrugs include esters and other pharmaceutically acceptable
derivatives, which, upon administration to a subject, are capable
of providing active compounds.
[0505] Pharmaceutically acceptable salts of the compounds of this
invention include those derived from pharmaceutically acceptable
inorganic and organic acids and bases. Examples of suitable acid
salts include acetate, adipate, alginate, aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, citrate, camphorate,
camphorsulfonate, digluconate, dodecylsulfate, ethanesulfonate,
formate, fumarate, glucoheptanoate, glycolate, hemisulfate,
heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxyethanesulfonate, lactate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate,
picrate, pivalate, propionate, salicylate, succinate, sulfate,
tartrate, thiocyanate, tosylate and undecanoate. Other acids, such
as oxalic, while not in themselves pharmaceutically acceptable, may
be employed in the preparation of salts useful as intermediates in
obtaining the compounds of the invention and their pharmaceutically
acceptable acid addition salts. Salts derived from appropriate
bases include alkali metal (e.g., sodium), alkaline earth metal
(e.g., magnesium), ammonium and N-(alkyl).sub.4.sup.+ salts. This
invention also envisions the quaternization of any basic
nitrogen-containing groups of the compounds disclosed herein. Water
or oil-soluble or dispersible products may be obtained by such
quaternization. Salt forms of the compounds of any of the formulae
herein can be amino acid salts of carboxy groups (e.g. L-arginine,
-lysine, -histidine salts).
[0506] The term "pharmaceutically acceptable carrier or adjuvant"
refers to a carrier or adjuvant that may be administered to a
subject (e.g., a patient), together with a compound of this
invention, and which does not destroy the pharmacological activity
thereof and is nontoxic when administered in doses sufficient to
deliver a therapeutic amount of the compound.
[0507] Pharmaceutically acceptable carriers, adjuvants and vehicles
that may be used in the compositions of this invention include, but
are not limited to, ion exchangers, alumina, aluminum stearate,
lecithin, self-emulsifying drug delivery systems (SEDDS) such as
d-.alpha.-tocopherol polyethyleneglycol 1000 succinate, surfactants
used in pharmaceutical dosage forms such as Tweens or other similar
polymeric delivery matrices, serum proteins, such as human serum
albumin, buffer substances such as phosphates, glycine, sorbic
acid, potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, salts or electrolytes, such as
protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates,
waxes, polyethylene-polyoxypropylene-block polymers, polyethylene
glycol and wool fat. Cyclodextrins such as .alpha.-, .beta.-, and
.gamma.-cyclodextrin, or chemically modified derivatives such as
hydroxyalkylcyclodextrins, including 2- and
3-hydroxypropyl-.beta.-cyclodextrins, or other solubilized
derivatives may also be advantageously used to enhance delivery of
compounds of the formulae described herein.
[0508] In general, the compounds described herein can be used for
treating, controlling, ameliorating, preventing, delaying the onset
of, or reducing the risk of developing one or more diseases,
disorders, conditions or symptoms mediated by excess or
uncontrolled amounts of cortisol and/or other corticosteroids.
While not wishing to be bound by any theory, it is believed that
the compounds described herein can reduce the levels of cortisol
and other corticosteroids (e.g., 11.beta.-hydroxysteroids) by
inhibiting the reductase activity of 11.beta.-HSD1. The diseases,
disorders, conditions or symptoms mediated by excess or
uncontrolled amounts of cortisol and/or other corticosteroids can
include diabetes (e.g., type 1 or type 2 diabetes), Syndrome X,
hyperglycemia, low glucose tolerance, insulin resistance, obesity,
lipid disorders, dyslipidemia, hyperlipidemia,
hypertriglyceridemia, hypercholesterolemia, low HDL levels, high
LDL levels, atherosclerosis and its sequelae, vascular restenosis,
pancreatitis, abdominal obesity, neurodegenerative disease,
retinopathy, nephropathy, neuropathy, hypertension, coronary heart
disease, stroke, peripheral vascular disease, Cushing's syndrome,
glaucoma, osteoporosis, hyperinsulinemia, tuberculosis, psoriasis,
cognitive disorders and dementia (e.g., impairment associated with
aging and of neuronal dysfunction, e.g., Alzheimer's disease),
depression, viral diseases, inflammatory disorders, immune
disorders. In some embodiments, the diseases, disorders conditions
or symptoms can further include those where insulin resistance is a
component. In other embodiments, the compounds described herein can
be used for promoting wound healing.
[0509] The compounds described herein generally have an inhibition
constant IC.sub.50 of less than about 10 .mu.M. Examples of such
compounds include those described herein in Examples 1A through 1Z;
1AA through 1AZ; 2A, 2B, 2D, 2E, 2F, 2G, 2H, 2I, 2J; 3A through 3D;
5, 6; 7A through 7Z; 7AA through 7AZ; 7BB through 7BD; 9F; 10A
through 10X; 11A through 11U; 12A through 12F; 13A; 13A-1 through
13A-7; 13B; 13B-1 through 13B-6; 13C; 14A through 14G; 18A through
18F; 29A through 29AD; 29AF through 29BI; 29BK though 29HN; and
29HP through 29IT. Generally, the IC.sub.50 ratio for 11-beta-HSD2
to 11-beta-HSD1 of a compound is at least about 100 or greater.
[0510] In some embodiments, the compounds described herein can be
coadministered with one or more other therapeutic agents. In
certain embodiments, the additional agents may be administered
separately, as part of a multiple dose regimen, from the compounds
of this invention (e.g., sequentially, e.g., on different
overlapping schedules with the administration of one or more
compounds of formula (I)). Alternatively, these agents may be part
of a single dosage form, mixed together with the compounds of this
invention in a single composition. In still another embodiment,
these agents can be given as a separate dose that is administered
at about the same time that one or more compounds of formula (I)
are administered (e.g., simultaneously with the administration of
one or more compounds of formula (I)). When the compositions of
this invention comprise a combination of a compound of the formulae
described herein and one or more additional therapeutic or
prophylactic agents, both the compound and the additional agent
should be present at dosage levels of between about 1 to 100%, and
more preferably between about 5 to 95% of the dosage normally
administered in a monotherapy regimen.
[0511] Other therapeutic agents can include DP-IV inhibitors;
insulin sensitizers (e.g., (i) PPAR agonists and (ii) biguanides);
insulin and insulin analogues and mimetics; sulfonylureas and other
insulin secretagogues; prandial glucose regulators,
alpha.-glucosidase inhibitors; glucagon receptor antagonists;
GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists; GIP,GIP
mimetics, and GIP receptor agonists; PACAP, PACAP mimetics, and
PACAP receptor 3 agonists; cholesterol lowering agents (e.g., (i)
HMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinyl
alcohol, nicotinic acid and salts thereof, (iv) PPAR.alpha.
agonists, (v) PPAR.alpha./.gamma. dual agonists, (vi) inhibitors of
cholesterol absorption, (vii) acyl CoA:cholesterol acyltransferase
inhibitors, and (viii) anti-oxidants; PPAR.delta. agonists);
antiobesity compounds (e.g., sibutramine and orlisat); an ileal
bile acid transporter inhibitor; anti-inflammatory agents excluding
glucocorticoids (e.g., aspirin); protein tyrosine phosphatase-1B
(PTP-1B) inhibitors; agents that suppress hepatic glucose output
(e.g., metformin); agents designed to reduce the absorption of
glucose from the intestine (e.g., acarbose); agents designed to
treat the complications of prolonged hyperglycemia (e.g., aldose
reductase inhibitors); antidiabetic agents (e.g., glucose
phosphatase inhibitors, glucose-6-phosphatase inhibitors, glucagon
receptor antagonists, glucose kinase activators, glycogen
phosphorylase inhibitors, fructose 1,6 bisphosphatase inhibitors,
glutamine:fructose-6-phosphate amidotransferase inhibitors);
antihypertensive agents (e.g., .beta. blockers (e.g., atenolol,
inderal), ACE inhibitors (e.g., lisinopril), calcium agonists
(e.g., nifedipine), angiotensin receptor antagonists (e.g.,
candesartan), a agonists and diuretic agents (e.g., furosemide,
benzthiazide)); and haemostasis modulators (e.g., antithrombotics,
activators of fibrinolysis and antiplatelet agents (e.g.,
clopidogrel, aspirin), thrombin antogonists, factor Xa inhibitors,
factor VIIa inhibitors, anticoagulants (e.g., heparin and low
molecular weight analogues, hirudin), warfarin).
[0512] The compounds and compositions described herein can, for
example, be administered orally, parenterally (e.g.,
subcutaneously, intracutaneously, intravenously, intramuscularly,
intraarticularly, intraarterially, intrasynovially, intrasternally,
intrathecally, intralesionally and by intracranial injection or
infusion techniques), by inhalation spray, topically, rectally,
nasally, buccally, vaginally, via an implanted reservoir, by
injection, subdermally, intraperitoneally, transmucosally, or in an
ophthalmic preparation, with a dosage ranging from about 0.01 mg/Kg
to about 1000 mg/Kg, (e.g., from about 0.01 to about 100 mg/kg,
from about 0.1 to about 100 mg/Kg, from about 1 to about 100 mg/Kg,
from about 1 to about 10 mg/kg) every 4 to 120 hours, or according
to the requirements of the particular drug. The interrelationship
of dosages for animals and humans (based on milligrams per meter
squared of body surface) is described by Freireich et al., Cancer
Chemother. Rep. 50, 219 (1966). Body surface area may be
approximately determined from height and weight of the patient.
See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y.,
537 (1970). In certain embodiments, the compositions are
administered by oral administration or administration by injection.
The methods herein contemplate administration of an effective
amount of compound or compound composition to achieve the desired
or stated effect. Typically, the pharmaceutical compositions of
this invention will be administered from about 1 to about 6 times
per day or alternatively, as a continuous infusion. Such
administration can be used as a chronic or acute therapy. The
amount of active ingredient that may be combined with the carrier
materials to produce a single dosage form will vary depending upon
the host treated and the particular mode of administration. A
typical preparation will contain from about 5% to about 95% active
compound (w/w). Alternatively, such preparations contain from about
20% to about 80% active compound.
[0513] Lower or higher doses than those recited above may be
required. Specific dosage and treatment regimens for any particular
patient will depend upon a variety of factors, including the
activity of the specific compound employed, the age, body weight,
general health status, sex, diet, time of administration, rate of
excretion, drug combination, the severity and course of the
disease, condition or symptoms, the patient's disposition to the
disease, condition or symptoms, and the judgment of the treating
physician.
[0514] Upon improvement of a patient's condition, a maintenance
dose of a compound, composition or combination of this invention
may be administered, if necessary. Subsequently, the dosage or
frequency of administration, or both, may be reduced, as a function
of the symptoms, to a level at which the improved condition is
retained when the symptoms have been alleviated to the desired
level. Patients may, however, require intermittent treatment on a
long-term basis upon any recurrence of disease symptoms.
[0515] The compositions of this invention may contain any
conventional non-toxic pharmaceutically-acceptable carriers,
adjuvants or vehicles. In some cases, the pH of the formulation may
be adjusted with pharmaceutically acceptable acids, bases or
buffers to enhance the stability of the formulated compound or its
delivery form.
[0516] The compositions may be in the form of a sterile injectable
preparation, for example, as a sterile injectable aqueous or
oleaginous suspension. This suspension may be formulated according
to techniques known in the art using suitable dispersing or wetting
agents (such as, for example, Tween 80) and suspending agents. The
sterile injectable preparation may also be a sterile injectable
solution or suspension in a non-toxic parenterally acceptable
diluent or solvent, for example, as a solution in 1,3-butanediol.
Among the acceptable vehicles and solvents that may be employed are
mannitol, water, Ringer's solution and isotonic sodium chloride
solution. In addition, sterile, fixed oils are conventionally
employed as a solvent or suspending medium. For this purpose, any
bland fixed oil may be employed including synthetic mono- or
diglycerides. Fatty acids, such as oleic acid and its glyceride
derivatives are useful in the preparation of injectables, as are
natural pharmaceutically-acceptable oils, such as olive oil or
castor oil, especially in their polyoxyethylated versions. These
oil solutions or suspensions may also contain a long-chain alcohol
diluent or dispersant, or carboxymethyl cellulose or similar
dispersing agents which are commonly used in the formulation of
pharmaceutically acceptable dosage forms such as emulsions and or
suspensions. Other commonly used surfactants such as Tweens or
Spans and/or other similar emulsifying agents or bioavailability
enhancers which are commonly used in the manufacture of
pharmaceutically acceptable solid, liquid, or other dosage forms
may also be used for the purposes of formulation.
[0517] The compositions of this invention may be orally
administered in any orally acceptable dosage form including, but
not limited to, capsules, tablets, emulsions and aqueous
suspensions, dispersions and solutions. In the case of tablets for
oral use, carriers which are commonly used include lactose and corn
starch. Lubricating agents, such as magnesium stearate, are also
typically added. For oral administration in a capsule form, useful
diluents include lactose and dried corn starch. When aqueous
suspensions and/or emulsions are administered orally, the active
ingredient may be suspended or dissolved in an oily phase is
combined with emulsifying and/or suspending agents. If desired,
certain sweetening and/or flavoring and/or coloring agents may be
added.
[0518] The compositions of this invention may also be administered
in the form of suppositories for rectal administration. These
compositions can be prepared by mixing a compound of this invention
with a suitable non-irritating excipient which is solid at room
temperature but liquid at the rectal temperature and therefore will
melt in the rectum to release the active components. Such materials
include, but are not limited to, cocoa butter, beeswax and
polyethylene glycols.
[0519] Topical administration of the compositions of this invention
is useful when the desired treatment involves areas or organs
readily accessible by topical application. For application
topically to the skin, the composition should be formulated with a
suitable ointment containing the active components suspended or
dissolved in a carrier. Carriers for topical administration of the
compounds of this invention include, but are not limited to,
mineral oil, liquid petroleum, white petroleum, propylene glycol,
polyoxyethylene polyoxypropylene compound, emulsifying wax and
water. Alternatively, the composition can be formulated with a
suitable lotion or cream containing the active compound suspended
or dissolved in a carrier with suitable emulsifying agents.
Suitable carriers include, but are not limited to, mineral oil,
sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl
alcohol, 2-octyldodecanol, benzyl alcohol and water. The
compositions of this invention may also be topically applied to the
lower intestinal tract by rectal suppository formulation or in a
suitable enema formulation.
[0520] Topically-transdermal patches are also included in this
invention. Also within the invention is a patch to deliver active
chemotherapeutic combinations herein. A patch includes a material
layer (e.g., polymeric, cloth, gauze, bandage) and the compound of
the formulae herein as delineated herein. One side of the material
layer can have a protective layer adhered to it to resist passage
of the compounds or compositions. The patch can additionally
include an adhesive to hold the patch in place on a subject. An
adhesive is a composition, including those of either natural or
synthetic origin, that when contacted with the skin of a subject,
temporarily adheres to the skin. It can be water resistant. The
adhesive can be placed on the patch to hold it in contact with the
skin of the subject for an extended period of time. The adhesive
can be made of a tackiness, or adhesive strength, such that it
holds the device in place subject to incidental contact, however,
upon an affirmative act (e.g., ripping, peeling, or other
intentional removal) the adhesive gives way to the external
pressure placed on the device or the adhesive itself, and allows
for breaking of the adhesion contact. The adhesive can be pressure
sensitive, that is, it can allow for positioning of the adhesive
(and the device to be adhered to the skin) against the skin by the
application of pressure (e.g., pushing, rubbing), on the adhesive
or device.
[0521] The compositions of this invention may be administered by
nasal aerosol or inhalation. Such compositions are prepared
according to techniques well-known in the art of pharmaceutical
formulation and may be prepared as solutions in saline, employing
benzyl alcohol or other suitable preservatives, absorption
promoters to enhance bioavailability, fluorocarbons, and/or other
solubilizing or dispersing agents known in the art.
[0522] A composition having the compound of the formulae herein and
an additional agent (e.g., a therapeutic agent) can be administered
using any of the routes of administration described herein. In some
embodiments, a composition having the compound of the formulae
herein and an additional agent (e.g., a therapeutic agent) can be
administered using an implantable device. Implantable devices and
related technology are known in the art and are useful as delivery
systems where a continuous, or timed-release delivery of compounds
or compositions delineated herein is desired. Additionally, the
implantable device delivery system is useful for targeting specific
points of compound or composition delivery (e.g., localized sites,
organs). Negrin et al., Biomaterials, 22 (6):563 (2001).
Timed-release technology involving alternate delivery methods can
also be used in this invention. For example, timed-release
formulations based on polymer technologies, sustained-release
techniques and encapsulation techniques (e.g., polymeric,
liposomal) can also be used for delivery of the compounds and
compositions delineated herein.
[0523] The invention will be further described in the following
examples. It should be understood that these examples are for
illustrative purposes only and are not to be construed as limiting
this invention in any manner.
EXAMPLES
Example 1
##STR00040##
[0525] Representative sulfonation (Step 1A): To a stirred solution
of 1-(3-(trifluoromethyl)phenyl)piperazine (300 mg, 1.3 mmol) and
4-methylbenzene-1-sulfonyl chloride (248 mg, 1.3 mmol) in anhydrous
dichloromethane (3 mL) was added diisopropylethylamine (0.27 mL,
1.6 mmol). The mixture was stirred overnight. Reaction was complete
as determined by TLC. The reaction mixture was purified with flash
column chromatography to yield
1-(4-methylphenylsulfonyl)-4-[3-(trifluoromethyl)phenyl]piperazine
in 81% yield (405 mg) as white solid.
[0526] .sup.1H NMR (400 MHz, DMSO-D.sub.6) .delta. ppm 2.41 (s, 3H)
2.85-3.06 (m, 4H) 3.27-3.33 (m, 4H) 7.09 (d, J=7.58 Hz, 1H)
7.13-7.22 (m, 2H) 7.41 (t, J=7.96 Hz, 1H) 7.48 (d, J=8.08 Hz, 2H)
7.62-7.70 (m, 2H); HRMS: calcd for
C.sub.18H.sub.19F.sub.3N.sub.2O.sub.2S+H+, 385.11921; found
(ESI-FTMS, [M+H].sup.1+), 385.1198; HPLC Method 1: room
temperature, 6.642 min, 97.94%. HPLC Method 2: room temperature,
7.178 min, 97.99%.
Example 1A
1-[(3,4-dichlorophenyl)sulfonyl]-4-(2-fluorophenyl)piperazine
[0527] Step 1A: Sulfonylation of 1-(2-fluorophenyl)piperazine.HCl
(325 mg, 1.5 mmol) with 3,4-dichlorobenzene-1-sulfonyl chloride
(368.3 mg, 1.5 mmol) was carried out according to a similar
procedure described for step 1A using anhydrous dichloromethane (3
mL) as solvent and diisopropylethylamine (0.575 mL, 3.3 mmol) as
base. 1-[(3,4-dichlorophenyl)sulfonyl]-4-(2-fluorophenyl)piperazine
was obtained in 85.8% yield (501 mg) as white solid.
[0528] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 3.02-3.16 (m, 8H)
6.94-7.19 (m, 4H) 7.76 (dd, J=8.46, 2.15 Hz, 1H) 7.96 (d, J=8.34
Hz, 1H) 7.99 (d, J=2.02 Hz, 1H); HRMS: calcd for
C.sub.16H.sub.15C.sub.12FN.sub.2O.sub.2S+H+, 389.02881; found
(ESI-FTMS, [M+H]1+), 389.029. HPLC Method 1: room temperature,
6.830 min, 98.81%. HPLC Method 2: room temperature, 7.491 min,
98.91%.
Example 1B
1-[(2-chlorophenyl)sulfonyl]-4-(2-fluorophenyl)piperazine
[0529] Step 1A: Sulfonylation of 1-(2-fluorophenyl)piperazine.HCl
(325 mg, 1.5 mmol) with 2-chlorobenzene-1-sulfonyl chloride (316.6
mg, 1.5 mmol) was carried out according to a similar procedure
described for step 1A using anhydrous dichloromethane (3 mL) as
solvent and diisopropylethylamine (0.575 mL, 3.3 mmol) as base.
1-[(2-chlorophenyl)sulfonyl]-4-(2-fluorophenyl)piperazine was
obtained in 75.5% yield (402 mg) as white solid.
[0530] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 2.99-3.09 (m, 4H)
3.29-3.37 (m, 4H) 6.95-7.19 (m, 4H) 7.56-7.64 (m, 1H) 7.66-7.78 (m,
2H) 8.02 (dd, J=7.96, 1.64 Hz, 1H); HRS: calcd for
C.sub.16H.sub.16ClFN.sub.2O.sub.2S+H+, 355.06778; found (ESI-FTMS,
[M+H]1+), 355.0686. HPLC Method 1: room temperature, 6.281 min,
99.76%. HPLC Method 2: room temperature, 6.916 min, 99.80%.
Example 1C
1-(2,6-dimethylphenyl)-4-(2-naphthylsulfonyl)piperazine
[0531] Sulfonylation was carried out according to a similar
procedure described for step 1A.
1-(2,6-dimethylphenyl)-4-(2-naphthylsulfonyl)piperazine was
obtained in 85% yield as white solid.
[0532] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.19 (s, 6H)
2.80-3.68 (m, 8H) 6.74-7.06 (m, 3H) 7.52-7.72 (m, 2H) 7.80 (d,
J=7.07 Hz, 1H) 7.87-8.24 (m, 3H) 8.39 (s, 1H). HRMS: calcd for
C.sub.22H.sub.24N.sub.2O.sub.2S+H+, 381.16312; found (ESI-FTMS,
[M+H].sup.1+), 381.1619.
Example 1D
1-[(2-chlorophenyl)sulfonyl]-4-(2,3-dichlorophenyl)piperazine
[0533] Sulfonylation was carried out according to a similar
procedure described for step 1A.
1-[(2-chlorophenyl)sulfonyl]-4-(2,3-dichlorophenyl)piperazine was
obtained in 95% yield as white solid.
[0534] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.96-3.18 (m, 4H)
3.33-3.64 (m, 4H) 6.93 (d, J=7.83 Hz, 1H) 7.07-7.22 (m, 3H) 7.43
(t, J=7.45 Hz, 1H) 7.48-7.68 (m, 2H) 8.08 (d, J=8.08 Hz, 1H). HRMS:
calcd for C.sub.16H.sub.15Cl.sub.3N.sub.2O.sub.2S+H+, 404.99925;
found (ESI-FTMS, [M+H].sup.1+), 404.9995; HPLC Method 1, room
temperature, 6.90 min, 98.56%; HPLC Method 2, room temperature,
7.45 min, 98.84%.
Example 1E
1-(2,3-dichlorophenyl)-4-(2-nalphthylsulfonyl)piperazine
[0535] Sulfonylation was carried out according to a similar
procedure described for step 1A.
1-(2,3-dichlorophenyl)-4-(2-naphthylsulfonyl)piperazine was
obtained in 90% yield as white solid.
[0536] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.12 (t, J=4.67
Hz, 4H) 3.28 (s, 4H) 6.93 (d, J=6.32 Hz, 1H) 7.07-7.23 (m, 2H)
7.53-7.74 (m, 2H) 7.74-7.89 (m, 1H) 7.91-8.00 (m, 1H) 8.02 (dd,
J=8.21, 4.17 Hz, 2H) 8.38 (s, 1H). HRMS: calcd for
C.sub.20H.sub.18Cl.sub.2N.sub.2O.sub.2S+H+, 421.05388; found
(ESI-FTMS, [M+H].sup.1+), 421.054; HPLC Method 1, room temperature,
6.98 min, 98.97%; HPLC Method 2, room temperature, 7.58 min,
95.34%.
Example 1F
1-(phenylsulfonyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine
[0537] Step 1Q: A solution of
1-[3-(trifluoromethyl)-2-pyridyl]piperazine (60 mg, 0.26 mmol), and
Benzene sulfonyl chloride (0.043 mL, 0.31 mmol) in DCM (4 mL) and
saturated sodium bicarbonate (2 mL) was stirred at room temperature
for 12 hours. The mixture was diluted with DCM (5 mL) and water (5
mL). The organic layer was collected and washed two times with
water, dried with magnesium sulfate, and concentrated. The product
was purified using column chromatography (20% Ethyl Acetate in
Hexanes) to produce
1-(phenylsulfonyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine
(81.1 mg, 84%).
[0538] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.18 (t, 4H) 3.35
(t, 4H) 7.03 (t, 1H) 7.57 (t, J=7.33 Hz, 2H) 7.64 (t, J=7.33 Hz,
1H) 7.80 (d, J=8.59 Hz, 2H) 7.85 (d, J=6.06 Hz, 1H) 8.42 (d, J=4.55
Hz, 1H); HRMS: calcd for C.sub.16H.sub.16F.sub.3N.sub.3O.sub.2S+H+,
372.09881; found (ESI-FTMS, [M+H].sup.1+), 372.0996.
Example 1G
1-[(2-chlorophenyl)sulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine
[0539] In an analogous manner to Example 1F, step 1Q
1-[(2-chlorophenyl)sulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-
e was prepared from 2-chlorosulfonyl chloride (44% yield).
[0540] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.27-3.35 (m, 4
m) 3.42-3.52 (m, 4H) 7.02-7.10 (m, 1H) 7.42 (t, J=7.58 Hz, 1H)
7.48-7.59 (m, 2H) 7.88 (d, J=9.09 Hz, 1H) 8.09 (d, J=9.09 Hz, 1H)
8.44 (d, J=3.79 Hz, 1H); HRMS: calcd for
C.sub.16H.sub.15ClF.sub.3N.sub.3O.sub.2S+H+, 406.05983; found
(ESI-FTMS, [M+H].sup.1+), 406.0611.
Example 1H
1-[(3-chlorophenyl)sulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine
[0541] In an analogous manner to Example 1F, step 1Q
1-[(3-chlorophenyl)sulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-
e was prepared from 3-chlorosulfonyl chloride (37% yield).
[0542] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.16-3.27 (m, 4H)
3.33-3.42 (m, 4H) 7.01-7.10 (m, 1H) 7.52 (t, J=7.83 Hz, 1H) 7.61
(d, J=8.08 Hz, 1H) 7.68 (d, J=7.58 Hz, 1H) 7.79 (s, 1H) 7.87 (d,
J=7.83 Hz, 1H) 8.44 (d, J=4.80 Hz, 1H); HRMS: calcd for
C.sub.16H.sub.15ClF.sub.3N.sub.3O.sub.2S+H+, 406.05983; found
(ESI-FTMS, [M+H].sup.1+), 406.0609.
Example 1I
1-(benzylsulfonyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine
[0543] In an analogous manner to Example 1F, step 1Q
1-(benzylsulfonyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine
was prepared from .alpha.-toluenesulfonyl chloride (45% yield).
[0544] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.19-3.24 (m, 4H)
3.24-3.30 (m, 4H) 4.24-4.31 (m, 2H) 7.05 (dd, J=7.71, 4.93 Hz, 1H)
7.35-7.47 (m, 5H) 7.88 (d, 1H) 8.44 (d, J=4.55 Hz, 1H); HRMS: calcd
for C.sub.17H.sub.18F.sub.3N.sub.3O.sub.2S+H+, 386.11446; found
(ESI-FTMS, [M+H].sup.1+), 386.1153.
Example 1J
1-[3-chlorobenzyl)sulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine
[0545] In an analogous manner to Example 1F, step 1Q
1-[(3-chlorobenzyl)sulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-
e was prepared from 3-chlorophenylmethane sulfonyl chloride (26%
yield).
[0546] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.25 (t, 4H) 3.32
(t, 4H) 4.20 (s, 2H) 7.00-7.15 (m, 1H) 7.30-7.42 (m, 3H) 7.45 (s,
1H) 7.89 (d, J=9.60 Hz, 1H) 8.45 (d, J=3.28 Hz, 1H); HRMS: calcd
for C.sub.17H.sub.17ClF.sub.3N.sub.3O.sub.2S+H+, 420.07548; found
(ESI-FTMS, [M+H].sup.1+), 420.0769.
Example 1K
1-[(3,4-dichlorobenzyl)sulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]pipera-
zine
[0547] In an analogous manner to Example 1F, step 1Q
1-[(3,4-dichlorobenzyl)sulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piper-
azine was prepared from 3,4-dichlorophenylmethane sulfonyl chloride
(29% yield).
[0548] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.27 (t, 4H) 3.35
(t, 4H) 4.16 (s, 2H) 7.07 (none, 1H) 7.08 (dd, J=5.43 Hz, 1H) 7.29
(d, J=2.27 Hz, 1H) 7.48 (d, J=8.08 Hz, 1H) 7.54 (d, J=2.02 Hz, 1H)
7.90 (d, J=7.83 Hz, 1H) 8.46 (d, J=3.54 Hz, 1H); HRMS: calcd for
C.sub.17H.sub.16Cl.sub.2F.sub.3N.sub.3O.sub.2S+H+, 454.03651; found
(ESI-FTMS, [M+H].sup.1+), 454.0381.
Example 1L
1-[(2-chlorophenyl)sulfonvyl]-4-(3,5-dichloropyridin-4-yl)piperazine
[0549] In an analogous manner to Example 1F, step 1Q
1-[(2-chlorophenyl)sulfonyl]-4-(3,5-dichloropyridin-4-yl)piperazine
was prepared from 1-(3,5-dichloro-4-pyridyl)piperazine (0.1 g, 0.43
mmol) and 2-chlorobenzene sulfonyl chloride (59% yield).
[0550] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.35-3.43 (m, 4H)
3.45-3.50 (m, 4H) 7.39-7.46 (m, 1H) 7.49-7.60 (m, 2H) 8.09 (d,
J=7.83 Hz, 1H) 8.36 (s, 2H); HRMS: calcd for
C.sub.15H.sub.14Cl.sub.3N.sub.3O.sub.2S+H+, 405.99450; found
(ESI-FTMS, [M+H].sup.1+), 405.9951.
Example 1M
1-[(3-chlorophenyl)sulfonyl]-4-(3,5-dichloropyridin-4-yl)piperazine
[0551] In an analogous manner to Example 1F, step 1Q
1-[(3-chlorophenyl)sulfonyl]-4-(3,5-dichloropyridin-4-yl)piperazine
was prepared from 1-(3,5-dichloro-4-pyridyl)piperazine (0.1 g, 0.43
mmol) and 3-chlorobenzene sulfonyl chloride (66% yield).
[0552] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.19-3.27 (m, 4H)
3.41-3.51 (m, 4H) 7.26 (s, 1H) 7.53 (t, J=7.83 Hz, 1H) 7.59-7.72
(m, 2H) 7.79 (s, 1H) 8.37 (s, 2H); HRMS: calcd for
C.sub.15H.sub.14Cl.sub.3N.sub.3O.sub.2S+H+, 405.99450; found
(ESI-FTMS, [M+H].sup.1+), 405.9956.
Example 1N
1-[(3,4-dichlorobenzyl)sulfonyl]-4-(3,5-dichloropyridin-4-yl)piperazine
[0553] In an analogous manner to Example 1F, step 1Q
1-[(3,4-dichlorobenzyl)sulfonyl]-4-(3,5-dichloropyridin-4-yl)piperazine
was prepared from 1-(3,5-dichloro-4-pyridyl)piperazine (0.1 g, 0.43
mmol) and 3,4-dichlorophenylmethyl sulfonyl chloride (61%
yield).
[0554] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.18-3.29 (m, 4H)
3.40-3.48 (m, 4H) 7.26 (s, 1H) 7.59-7.70 (m, 2H) 7.89 (d, J=1.77
Hz, 1H) 8.36 (s, 2H); HRMS: calcd for
C.sub.16H.sub.15Cl.sub.4N.sub.3O.sub.2S+H+, 453.97118; found
(ESI-FTMS, [M+H].sup.1+), 453.9733.
Example 1O
1-[(3-chlorophenyl)sulfonyl]-4-[2-(trifluoromethyl)phenyl]piperazine
[0555] In an analogous manner to Example 1E, step 1P
1-[(3-chlorophenyl)sulfonyl]-4-[2-(trifluoromethyl)phenyl]piperazine
was prepared from 1-(2-trifluoromethylphenyl)piperazine (0.1 g,
0.43 mmol) and 3-chlorobenzyl sulfonyl chloride (71% yield).
[0556] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.01 (t, J=4.80
Hz, 4H) 3.20 (s, 4H) 7.54 (d, J=8.08 Hz, 1H) 7.55-7.60 (m, 1H)
7.59-7.64 (m, 1H) 7.68 (d, J=6.57 Hz, 1H) 7.73 (d, J=6.82 Hz, 1H)
7.79 (t, J=1.89 Hz, 1H) 7.95 (d, J=8.08 Hz, 1H) 8.04 (t, J=1.89 Hz,
1H); HRMS: calcd for C.sub.17H.sub.16ClF.sub.3N.sub.2O.sub.2S+H+,
405.06458; found (ESI-FTMS, [M+H].sup.1+), 405.0649.
Example 1P
1-[(4-chlorophenyl)sulfonyl]-4-[2-(trifluoromethyl)phenyl]piperazine
[0557] In an analogous manner to Example 1E, step 1P
1-[(4-chlorophenyl)sulfonyl]-4-[2-(trifluoromethyl)phenyl]piperazine
was prepared from 1-(2-trifluoromethylphenyl)piperazine (0.1 g,
0.43 mmol) and 4-chlorobenzyl sulfonyl chloride (69% yield).
[0558] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.01 (t, J=4.80
Hz, 4H) 3.18 (s, 4H) 7.35 (d, J=8.08 Hz, 2H) 7.50-7.65 (m, 3H) 7.73
(d, J=8.59 Hz, 2H) 7.99 (d, J=8.59 Hz, 1H); HRMS: calcd for
C.sub.17H.sub.16ClF.sub.3N.sub.2O.sub.2S+H+, 405.06458; found
(ESI-FTMS, [M+H].sup.1+), 405.0649.
Example 1Q
1-[(3,4-dichlorophenyl)sulfonyl]-4-[2-(trifluoromethyl)phenyl]piperazine
[0559] In an analogous manner to Example 1E, step 1P
1-[(3,4-dichlorophenyl)sulfonyl]-4-[2-(trifluoromethyl)phenyl]piperazine
was prepared from 1-(2-trifluoromethylphenyl)piperazine (0.1 g,
0.43 mmol) and 3,4-dichlorobenzene sulfonyl chloride (82%
yield).
[0560] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.02 (t, J=4.80
Hz, 4H) 3.20 (s, 4H) 7.35 (d, J=8.08 Hz, 1H) 7.59-7.64 (m, 3H)
7.65-7.69 (m, 1H) 7.72 (d, J=8.59 Hz, 1H) 8.14 (d, J=2.27 Hz, 1H);
HRMS: calcd for C.sub.17H.sub.15Cl.sub.2F.sub.3N.sub.2O.sub.2S+H+,
439.02561; found (ESI-FTMS, [M+H].sup.1+), 439.0251.
Example 1R
1-[(3,4-dichlorobenzyl)sulfonyl]-4-[2-(trifluoromethyl)phenyl]piperazine
[0561] In an analogous manner to Example 1E, step 1P
1-[(3,4-dichlorobenzyl)sulfonyl]-4-[2-(trifluoromethyl)phenyl]piperazine
was prepared from 1-(2-trifluoromethylphenyl)piperazine (0.1 g,
0.43 mmol) and 3,4-dichlorophenylmethyl sulfonyl chloride (93%
yield).
[0562] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.60 (s, 2H)
2.92-2.96 (m, 4H) 3.31-3.38 (m, 4H) 7.25-7.35 (m, 4H) 7.48-7.58 (m,
2H) 7.64 (d, J=6.32 Hz, 1H); HRMS: calcd for
C.sub.18H.sub.17Cl.sub.2F.sub.3N.sub.2O.sub.2S+H+, 453.04126; found
(ESI-FTMS, [M+H].sup.1+), 453.0396.
Example 1S
3-{4-[(4-chlorophenyl)sulfonyl]piperazin-1-yl}pyrazine-2-carbonitrile
[0563] In an analogous manner to Example 1E, step 1P
3-{4-[(4-chlorophenyl)sulfonyl]piperazin-1-yl}pyrazine-2-carbonitrile
was prepared from (3-piperazine-1-yl)pyperazine-2-carbonitrile (0.1
g, 0.53 mmol) and 4-chlorobenzene sulfonyl chloride (40%
yield).
[0564] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.17-3.23 (m, 4H)
3.82-3.90 (m, 4H) 7.54 (d, J=8.84 Hz, 2H) 7.72 (d, J=8.59 Hz, 2H)
8.08 (d, J=2.27 Hz, 1H) 8.26 (d, J=2.27 Hz, 1H); HRMS: calcd for
C.sub.15H.sub.14ClN.sub.5O.sub.2S+H+, 364.06295; found (ESI-FTMS,
[M+H].sup.1+), 364.0636.
Example 1T
3-{4-[(3,4-dichlorophenyl)sulfonyl]piperazin-1-yl}pyrazine-2-carbonitrile
[0565] In an analogous manner to Example 1E, step 1P
3-{4-[(3,4-dichlorophenyl)sulfonyl]piperazin-1-yl}pyrazine-2-carbonitrile
was prepared from (3-piperazine-1-yl)pyperazine-2-carbonitrile (0.1
g, 0.53 mmol) and 3,4-dichlorobenzene sulfonyl chloride (75%
yield).
[0566] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.21-3.26 (m, 4H)
3.87 (t, 4H) 7.73 (s, 1H) 7.87 (t, J=2.15 Hz, 1H) 8.10 (d, J=2.27
Hz, 1H) 8.14 (d, J=2.27 Hz, 1H) 8.27 (d, J=2.27 Hz, 1H); HRMS:
calcd for C.sub.15H.sub.13Cl.sub.2N.sub.5O.sub.2S+H+, 398.02397;
found (ESI-FTMS, [M+H].sup.1+), 398.0223.
Example 1U
1-[(3,4-dichlorophenyl)sulfonyl]-4-(3'-methoxybiphenyl-2-yl)piperazine
[0567] In an analogous manner to Example 1E, step 1P,
1-[(3,4-dichlorophenyl)sulfonyl]-4-(3'-methoxybiphenyl-2-yl)piperazine
was prepared from (3-piperazine-1-yl)pyperazine-2-carbonitrile (0.1
g, 0.53 mmol) and 3,4-dichlorphenyl methyl sulfonyl chloride (18%
yield).
[0568] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.92 (s, 8H) 4.60
(d, J=5.56 Hz, 3H) 7.00 (d, J=8.08 Hz, 1H) 7.11 (t, J=6.95 Hz, 1H)
7.22-7.34 (m, 4H) 7.42 (d, J=7.33 Hz, 1H) 7.55 (d, J=8.34 Hz, 2H)
7.65 (d, J=8.59 Hz, 1H) 7.81 (s, 1H); HRMS: calcd for
C.sub.23H.sub.22Cl.sub.2N.sub.2O.sub.3S+H+, 477.08009; found
(ESI-FTMS, [M+H].sup.1+), 477.0784.
Example 1V
N-[4-({4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}sulfonyl)phenyl]a-
cetamide
[0569] The desired product was obtained in 98% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.13-2.33 (m, 3H)
3.07-3.23 (m, 4H) 3.26-3.45 (m, 4H) 6.99-7.08 (m, 1H) 7.46 (s, 1H)
7.66-7.80 (m, 4H) 7.85 (dd, J=7.71, 1.89 Hz, 1H) 8.42 (dd, J=4.80,
1.26 Hz, 1H). HRMS: calcd for
C.sub.18H.sub.19F.sub.3N.sub.4O.sub.3S+H+, 429.12027; found
(ESI-FTMS, [M+H].sup.1+), 429.1207.
Example 1W
1-[(3,4-dimethoxyphenyl)sulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piper-
azine
[0570] The desired product was obtained in 83% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.09-3.24 (m, 4H)
3.26-3.42 (m, 4H) 3.85-4.09 (m, 6H) 6.99 (d, J=8.59 Hz, 1H) 7.03
(dd, J=7.83, 4.80 Hz, 1H) 7.24 (d, J=2.02 Hz, 1H) 7.41 (dd, J=8.46,
2.15 Hz, 1H). HRMS: calcd for
C.sub.18H.sub.20F.sub.3N.sub.3O.sub.4S+H+, 432.11994; found
(ESI-FTMS, [M+H].sup.1+), 432.1212.
Example 1X
1-[(2,4-difluorophenyl)sulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]pipera-
zine
[0571] The desired product was obtained in 100% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.31-3.39 (m, 4H)
3.39-3.47 (m, 4H) 7.01-7.12 (m, 3H) 7.50-7.60 (m, 1H) 7.88 (dd,
J=7.83, 2.02 Hz, 1H) 8.45 (dd, J=4.80, 1.26 Hz, 1H). HRMS: calcd
for C.sub.16H.sub.14F.sub.5N.sub.3O.sub.2S+H+, 408.07996; found
(ESI-FTMS, [M+H].sup.1+), 408.0811.
Example 1Y
1-(2-naphthylsulfonyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine
[0572] The desired product was obtained in 92% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.16-3.31 (m, 4H)
3.32-3.50 (m, 4H) 6.97-7.10 (m, 1H) 7.58-7.73 (m, 2H) 7.76-7.87 (m,
2H) 7.95 (d, 1H) 8.01 (d, 2H) 8.35-8.46 (m, 2H). HRMS: calcd for
C.sub.20H.sub.18F.sub.3N.sub.3O.sub.2S+H+, 422.11446; found
(ESI-FTMS, [M+H].sup.1+), 422.1145.
Example 1Z
1-(1-benzothien-2-ylsulfonyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-
e
[0573] The desired product was obtained in 100% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.23-3.49 (m, 8H)
6.97-7.10 (m, 1H) 7.40-7.59 (m, 2H) 7.75-7.99 (m, 4H) 8.43 (dd,
J=4.80, 1.77 Hz, 1H). HRMS: calcd for
C.sub.18H.sub.16F.sub.3N.sub.3O.sub.2S.sub.2+H+, 428.07088; found
(ESI-FTMS, [M+H].sup.1+), 428.0716.
Example 1AA
1-(1-benzothien-3-ylsulfonyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-
e
[0574] The desired product was obtained in 80% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.21-3.41 (m, 8H)
7.02 (dd, J=7.45, 5.18 Hz, 1H) 7.43-7.59 (m, 2H) 7.84 (dd, J=7.58,
1.77 Hz, 1H) 7.92 (dd, J=7.07, 1.01 Hz, 1H) 8.21 (s, 1H) 8.29 (dd,
1H) 8.41 (dd, J=4.80, 1.26 Hz, 1H). HRMS: calcd for
C.sub.18H.sub.16F.sub.3N.sub.3O.sub.2S.sub.2+H+, 428.07088; found
(ESI-FTMS, [M+H].sup.1+), 428.072.
Example 1AB
1-(dibenzo[b,d]furan-3-ylsulfonyl)-4-[3-(trifluoromethyl)pyridin-2-yl]pipe-
razine
[0575] The desired product was obtained in 61% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.16-3.30 (m, 4H)
3.29-3.46 (m, 4H) 7.01 (dd, J=7.33, 4.29 Hz, 1H) 7.43 (t, 1H) 7.58
(t, 1H) 7.65 (d, 1H) 7.75-7.88 (m, 2H) 8.01-8.07 (m, 2H) 8.12 (d,
J=8.08 Hz, 1H) 8.41 (dd, J=4.80, 1.26 Hz, 1H). HRMS: calcd for
C.sub.22H.sub.18F.sub.3N.sub.3O.sub.3S+H+, 462.10937; found
(ESI-FTMS, [M+H].sup.1+), 462.1102.
Example 1AC
1-[(2,4-difluorophenyl)sulfonyl]-4-(3-methylpyridin-2-yl)piperazine
[0576] The desired product was obtained in 100% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.23 (s, 3H)
3.11-3.30 (m, 4H) 3.37-3.57 (m, 4H) 6.88 (dd, J=7.45, 4.93 Hz, 1H)
7.06 (t, J=8.46 Hz, 2H) 7.41 (dd, J=7.45, 1.14 Hz, 1H) 7.48-7.61
(m, 1H) 8.14 (dd, J=4.80, 1.26 Hz, 1H). HRMS: calcd for
C.sub.16H.sub.17F.sub.2N.sub.3O.sub.2S+H+, 354.10823; found
(ESI-FTMS, [M+H].sup.1+), 354.1084.
Example 1AD
1-[(3,4-dichlorobenzyl)sulfonyl]-4-(3-methylpyridin-2-yl)piperazine
[0577] The desired product was obtained in 70% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.25 (s, 3H)
3.07-3.29 (m, 4H) 3.24-3.45 (m, 4H) 6.86-6.94 (m, J=7.33, 4.80 Hz,
1H) 7.27-7.30 (m, J=8.21, 2.15 Hz, 1H) 7.42 (dd, J=7.33, 1.01 Hz,
1H) 7.47 (d, J=8.34 Hz, 1H) 7.54 (d, J=2.27 Hz, 1H) 8.16 (dd,
J=4.93, 1.39 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.19Cl.sub.2N.sub.3O.sub.2S+H+, 400.06478; found
(ESI-FTMS, [M+H].sup.1+), 400.0653.
Example 1AE
1-(3-methylpyridin-2-yl)-4-(2-naphthylsulfonyl)piperazine
[0578] The desired product was obtained in 100% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.10-2.19 (m, 3H)
3.16-3.41 (m, 8H) 6.85 (dd, J=7.33, 4.80 Hz, 1H) 7.36 (dd, J=7.33,
1.01 Hz, 1H) 7.59-7.73 (m, 2H) 7.81 (dd, J=8.72, 1.89 Hz, 1H) 7.95
(d, J=7.83 Hz, 1H) 8.01 (d, J=9.09 Hz, 2H) 8.11 (dd, J=4.80, 1.26
Hz, 1H) 8.39 (d, J=1.01 Hz, 1H). HRMS: calcd for
C.sub.20H.sub.21N.sub.3O.sub.2S+H+, 368.14272; found (ESI-FTMS,
[M+H].sup.1+), 368.1436.
Example 1AF
1-(1-benzothien-2-ylsulfonyl)-4-(3-methylpyridin-2-yl)piperazine
[0579] The desired product was obtained in 100% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.13-2.26 (m, 3H)
3.29 (d, 8H) 6.87 (dd, J=7.33, 4.80 Hz, 1H) 7.38 (dd, J=7.33, 1.01
Hz, 1H) 7.45-7.57 (m, 2H) 7.85 (s, 1H) 7.87-7.96 (m, 2H) 8.13 (dd,
J=5.18, 1.64 Hz, 1H). HRMS: calcd for
C.sub.18H.sub.19N.sub.3O.sub.2S.sub.2+H+, 374.09914; found
(ESI-FTMS, [M+H].sup.1+), 374.0998.
Example 1AG
1-(1-benzothien-3-ylsulfonyl)-4-(3-methylpyridin-2-yl)piperazine
[0580] The desired product was obtained in 100% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.11-2.23 (m, 3H)
3.11-3.29 (m, 4H) 3.26-3.44 (m, 4H) 6.86 (t, J=7.33, 4.80 Hz, 1H)
7.37 (dd, J=7.33, 1.26 Hz, 1H) 7.44-7.59 (m, 2H) 7.92 (dd, J=7.07,
1.01 Hz, 1H) 8.22 (s, 1H) 8.31 (dd, 1H). HRMS: calcd for
C.sub.18H.sub.19N.sub.3O.sub.2S.sub.2+H+, 374.09914; found
(ESI-FTMS, [M+H].sup.1+), 374.1004.
Example 1AH
1-[(2-chlorophenyl)sulfonyl]-4-(3-methylpyridin-2-yl)piperazine
[0581] The desired product was obtained in 73% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.24 (s, 1H)
3.07-3.26 (m, 4H) 3.38-3.56 (m, 4H) 6.88 (dd, J=7.45, 4.93 Hz, 1H)
7.38-7.45 (m, 2H) 7.46-7.61 (m, 2H) 8.09 (dd, J=7.83, 1.77 Hz, 1H)
8.14 (dd, J=4.80, 1.26 Hz, 1H). HRMS: calcd for
C.sub.16H.sub.18ClN.sub.3O.sub.2S+H+, 352.08810; found (ESI-FTMS,
[M+H].sup.1+), 352.0883.
Example 1AI
1-(dibenzo[b,d]furan-3-ylsulfonyl)-4-(3-methylpyridin-2-yl)piperazine
[0582] The desired product was obtained in 78% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.07-2.19 (m, 3H)
3.17-3.34 (m, 8H) 6.85 (dd, J=7.33, 5.05 Hz, 1H) 7.35 (dd, J=7.33,
1.26 Hz, 1H) 7.44 (t, 1H) 7.58 (t, 1H) 7.65 (dd, 1H) 7.81 (dd,
J=8.08, 1.52 Hz, 1H) 8.01-8.06 (m, 2H) 8.08-8.16 (m, 2H). HRMS:
calcd for C.sub.22H.sub.21N.sub.3O.sub.3S+H+, 408.13764; found
(ESI-FTMS, [M+H].sup.1+), 408.1388.
Example 1AJ
1-[(3,4-dichlorophenyl)sulfonyl]-4-(3-methylpyridin-2-yl)piperazine
[0583] The desired product was obtained in 94% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.11-2.26 (m, 3H)
3.08-3.35 (m, 8H) 6.75-6.95 (m, J=7.33, 4.80 Hz, 1H) 7.40 (dd,
J=7.45, 1.14 Hz, 1H) 7.59-7.68 (m, 2H) 7.89 (d, J=1.77 Hz, 1H) 8.14
(dd, J=4.67, 1.64 Hz, 1H), HRMS: calcd for
C.sub.16H.sub.17Cl.sub.2N.sub.3O.sub.2S+H+, 386.04913; found
(ESI-FTMS, [M+H].sup.1+), 386.0484.
Example 1AK
1-(3-methylpyridin-2-yl)-4-{[2-(trifluoromethyl)phenyl]sulfonyl}piperazine
[0584] The desired product was obtained in 68% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.23 (s, 3H)
3.13-3.26 (m, 4H) 3.35-3.49 (m, 4H) 6.85-6.93 (m, J=7.20, 4.67 Hz,
1H) 7.40 (dd, J=7.33, 1.01 Hz, 1H) 7.66-7.76 (m, 2H) 7.92 (dd, 1H)
8.11-8.20 (m, 2H). HRMS: calcd for
C.sub.17H.sub.18F.sub.3N.sub.3O.sub.2S+H+, 386.11446; found
(ESI-FTMS, [M+H].sup.1+), 386.115.
Example 1AL
1-[(4-chlorophenyl)sulfonyl]-4-(3-methylpyridin-2-yl)piperazine
[0585] The desired product was obtained in 63% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.18 (s, 3H)
3.11-3.30 (m, 8H) 6.83-6.92 (m, J=7.20, 4.93 Hz, 1H) 7.40 (d,
J=1.01 Hz, 1H) 7.51-7.59 (m, 2H) 7.71-7.78 (m, 2H) 8.13 (dd,
J=4.80, 1.26 Hz, 1H). HRMS: calcd for
C.sub.16H.sub.18ClN.sub.3O.sub.2S+H+, 352.08810; found (ESI-FTMS,
[M+H].sup.1+), 352.0879.
Example 1AM
1-(dibenzo[b,d]thien-3-ylsulfonyl)-4-[3-(trifluoromethyl)pyridin-2-yl]pipe-
razine
[0586] The desired product was obtained in 90% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.16-3.29 (m, 4H)
3.30-3.42 (m, 4H) 6.97-7.05 (m, J=7.83, 4.80 Hz, 1H) 7.49-7.62 (m,
2H) 7.79-7.88 (m, 2H) 7.92 (dd, J=6.57, 1.26 Hz, 1H) 8.25 (dd, 1H)
8.28-8.35 (m, 2H) 8.41 (dd, J=4.80, 1.26 Hz, 1H). HRMS: calcd for
C.sub.22H.sub.18F.sub.3N.sub.3O.sub.2S.sub.2+H+, 478.08653; found
(ESI-FTMS, [M+H].sup.1+), 478.0881.
Example 1AN
1-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl-
]piperazine
[0587] The desired product was obtained in 65% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.43-2.46 (m, 3H)
2.65-2.70 (m, 3H) 3.24-3.31 (m, 4H) 3.31-3.38 (m, 4H) 7.05-7.13 (m,
J=7.83, 4.80 Hz, 1H) 7.90 (dd, J=7.83, 2.02 Hz, 1H) 8.46 (dd,
J=4.55, 1.52 Hz, 1H). HRMS: calcd for
C.sub.15H.sub.17F.sub.3N.sub.4O.sub.3S+H+, 391.10462; found
(ESI-FTMS, [M+H].sup.1+), 391.1061.
Example 1AO
1-(dibenzo[b,d]furan-2-ylsulfonyl)-4-[3-(trifluoromethyl)pyridin-2-yl]pipe-
razine
[0588] The desired product was obtained in 90% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.17-3.30 (m, 4H)
3.31-3.43 (m, 4H) 6.98-7.08 (m, 1H) 7.44 (t, 1H) 7.56 (t, 1H) 7.64
(d, 1H) 7.74 (d, J=9.35 Hz, 1H) 7.84 (dd, J=7.83, 1.77 Hz, 1H) 7.91
(dd, J=8.72, 1.89 Hz, 1H) 8.04 (d, J=7.83 Hz, 1H) 8.41 (d, J=4.80,
1.26 Hz, 1H) 8.43 (d, J=1.26 Hz, 1H). HRMS: calcd for
C.sub.22H.sub.18F.sub.3N.sub.3O.sub.3S+H+, 462.10937; found
(ESI-FTMS, [M+H].sup.1+), 462.1081.
Example AP
1-(biphenyl-4-ylsulfonyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine
[0589] The desired product was obtained in 92% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.16-3.34 (m, 4H)
3.32-3.47 (m, 4H) 7.01-7.09 (m, J=7.71, 4.93 Hz, 1H) 7.41-7.48 (m,
1H) 7.48-7.56 (m, 1H) 7.66 (d, 2H) 7.79 (d, 2H) 7.88 (d, 3H) 8.45
(dd, J=4.55, 1.52 Hz, 1H). HRMS: calcd for
C.sub.22H.sub.20F.sub.3N.sub.3O.sub.2S+H+, 448.13011; found
(ESI-FTMS, [M+H].sup.1+), 448.1279.
Example 1AQ
1-[(2-chlorobenzyl)sulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine
[0590] The desired product was obtained in 58% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.20-3.28 (m, 4H)
3.28-3.36 (m, 4H) 4.44-4.49 (m, 2H) 6.98-7.09 (m, 1H) 7.28-7.34 (m,
2H) 7.39-7.45 (m, 1H) 7.57-7.63 (m, 1H) 7.87 (dd, J=7.71, 1.89 Hz,
1H) 8.42 (dd, J=4.80, 1.26 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.17ClF.sub.3N.sub.3O.sub.2S+H+, 420.07548; found
(ESI-FTMS, [M+H].sup.1+), 420.0742.
Example 1AR
1-[(4'-fluorobiphenyl-4-yl)sulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]pi-
perazine
[0591] The desired product was obtained in 94% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.15-3.29 (m, 4H)
3.32-3.45 (m, 4H) 7.04 (dd, J=7.71, 4.93 Hz, 1H) 7.13-7.22 (m, 2H)
7.55-7.64 (m, 2H) 7.67-7.76 (m, 2H) 7.82-7.91 (m, 3H) 8.43 (dd,
J=4.93, 1.39 Hz, 1H). HRMS: calcd for
C.sub.22H.sub.19F.sub.4N.sub.3O.sub.2S+H+, 466.12068; found
(ESI-FTMS, [M+H].sup.1+), 466.119.
Example 1AS
1-(dibenzo[b,d]thien-2-ylsulfonyl)-4-[3-(trifluoromethyl)pyridin-2-yl]pipe-
razine
[0592] The desired product was obtained in 95% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.19-3.29 (m, 4H)
3.37-3.45 (m, 4H) 6.98-7.06 (m, J=6.95, 4.93 Hz, 1H) 7.50-7.61 (m,
2H) 7.80-7.88 (m, 2H) 7.88-7.94 (m, 1H) 8.03 (d, J=9.09 Hz, 1H)
8.41 (dd, J=5.05, 1.26 Hz, 1H) 8.57 (d, J=1.26 Hz, 1H). HRMS: calcd
for C.sub.22H.sub.18F.sub.3N.sub.3O.sub.2S.sub.2+H+, 478.08653;
found (ESI-FTMS, [M+H].sup.1+), 478.0862.
Example 1AT
1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-4-[3-(trifluoromethyl)py-
ridin-2-yl]piperazine
[0593] The desired product was obtained in 98% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.71 (s, 3H) 3.37
(s, 8H) 7.05 (t, 1H) 7.47 (dd, J=8.59, 2.02 Hz, 1H) 7.77 (d, J=8.34
Hz, 1H) 7.81-7.90 (m, 2H) 8.43 (dd, J=4.80, 1.26 Hz, 1H). HRMS:
calcd for C.sub.19H.sub.17ClF.sub.3N.sub.3O.sub.2S.sub.2+H+,
476.04755; found (ESI-FTMS, [M+H].sup.1+), 476.0475.
Example 1AU
1-[(2-chlorophenyl)sulfonyl]-4-[2-(trifluoromethyl)phenyl]piperazine
[0594] In an analogous manner to Example 1E, step 1P
1-[(2-chlorophenyl)sulfonyl]-4-[2-(trifluoromethyl)phenyl]piperazine
was prepared from 1-(2-trifluoromethylphenyl)piperazine (0.1 g,
0.43 mmol) and 2-chlorobenzyl sulfonyl chloride (73% yield).
[0595] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.94-3.01 (m, 4H)
3.45 (d, J=4.29 Hz, 4H) 7.22-7.30 (m, 1H) 7.35 (d, J=7.83 Hz, 1H)
7.42 (t, J=8.08 Hz, 1H) 7.47-7.59 (m, 3H) 7.63 (d, J=8.08 Hz, 1H)
8.08 (d, J=7.83 Hz, 1H); HRMS: calcd for
C.sub.17H.sub.16ClF.sub.3N.sub.2O.sub.2S+H+, 405.06458; found
(ESI-FTMS, [M+H].sup.1+), 405.0648.
Example 1AV
2-({4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}sulfonyl)-1,3-benzot-
hiazole
[0596] The desired product was obtained in 30% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.23-3.39 (m, 4H)
3.44-3.62 (m, 4H) 6.94-7.01 (m, J=7.83, 4.80 Hz, 1H) 7.44-7.60 (m,
2H) 8.15 (d, J=7.33 Hz, 1H) 8.36 (dd, J=4.80, 1.26 Hz, 1H). HRMS:
calcd for C.sub.17H.sub.15F.sub.3N.sub.4O.sub.2S.sub.2+H+,
429.06613; found (ESI-FTMS, [M+H].sup.1+), 429.0661.
Example 1AW
1-(dibenzo[b,d]furan-2-ylsulfonyl)-4-(3-methylpyridin-2-yl)piperazine
[0597] The desired product was obtained in 91% yield as white
solid. HRMS: calcd for C.sub.22H.sub.21N.sub.3O.sub.3S+H+,
408.13764; found (ESI-FTMS, [M+H].sup.1+), 408.137. 1H NMR (400
MHz, CHLOROFORM-D) .delta. ppm 2.07-2.20 (m, 3H) 3.14-3.34 (m, 8H)
6.80-6.89 (m, J=7.33, 4.80 Hz, 3H) 7.35 (dd, J=7.33, 1.26 Hz, 1H)
7.44 (t, 1H) 7.56 (t, 1H) 7.64 (d, 1H) 7.73 (d, J=8.34 Hz, 1H) 7.92
(dd, J=8.72, 1.89 Hz, 1H) 8.03 (d, J=7.07 Hz, 1H) 8.11 (dd, J=4.93,
1.39 Hz, 1H) 8.44 (d, J=1.52 Hz, 1H).
Example 1AX
1-(dibenzo[b,d]thien-2-ylsulfonyl)-4-(3-methylpyridin-2-yl)piperazine
[0598] The desired product was obtained in 94% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.07-2.19 (m, 3H)
3.15-3.31 (m, 8H) 6.84 (dd, J=7.33, 4.80 Hz, 1H) 7.35 (dd, J=7.33,
1.01 Hz, 1H) 7.50-7.61 (m, 2H) 7.86 (dd, J=8.59, 1.77 Hz, 1H)
7.89-7.95 (m, 1H) 8.03 (d, J=8.34 Hz, 1H) 8.11 (dd, J=4.93, 1.39
Hz, 1H) 8.24-8.32 (m, 1H) 8.59 (d, J=1.26 Hz, 1H). HRMS: calcd for
C.sub.22H.sub.21N.sub.3O.sub.2S.sub.2+H+, 424.11479; found
(ESI-FTMS, [M+H].sup.1+), 424.1152.
Example 1AY
1-(dibenzo[b,d]thien-3-ylsulfonyl)-4-(3-methylpyridin-2-yl)piperazine
[0599] The desired product was obtained in 91% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.10-2.17 (m, 8H)
6.82-6.89 (m, J=7.33, 5.05 Hz, 1H) 7.35 (dd, J=7.33, 1.26 Hz, 1H)
7.50-7.63 (m, 2H) 7.87 (dd, J=8.34, 1.52 Hz, 1H) 7.92 (dd, J=7.20,
1.89 Hz, 1H) 8.12 (dd, J=4.55, 1.52 Hz, 1H) 8.22-8.28 (m, 1H)
8.29-8.38 (m, 2H). HRMS: calcd for
C.sub.22H.sub.21N.sub.3O.sub.2S.sub.2+H+, 424.11479; found
(ESI-FTMS, [M+H].sup.1+), 424.1137.
Example 1AZ
1-(biphenyl-4-ylsulfonyl)-4-(3-methylpyridin-2-yl)piperazine
[0600] The desired product was obtained in 95% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.09-2.23 (m, 3H)
3.16-3.34 (m, 8H) 6.86 (dd, J=7.33, 5.05 Hz, 1H) 7.38 (dd, J=6.95,
1.64 Hz, 1H) 7.39-7.45 (m, 1H) 7.45-7.54 (m, 2H) 7.58-7.67 (m, 2H)
7.72-7.80 (m, 2H) 7.81-7.91 (m, 2H) 8.13 (dd, J=4.93, 1.89 Hz, 1H).
HRMS: calcd for C.sub.22H.sub.23N.sub.3O.sub.2S+H+, 394.15837;
found (ESI-FTMS, [M+H].sup.1+), 394.1594.
Example 2
##STR00041##
[0601] Example 2A
1-[(4-tert-butylphenyl)sulfonyl]-4-(3-chloropyridin-2-yl)piperazine
[0602] Step 2A: tert-butyl piperazine-1-carboxylate (1.0 g, 5.37
mmol) and 2,3-dichloropyridine (795 mg, 5.37 mmol) charged to a
microwave vial was added with diisopropylethylamine (2.34 mL, 13.42
mmol) and DMF (1.0 mL). The reaction mixture was subject to
microwave irradiation at 165.degree. C. for 30 minutes. The
reaction was repeated six times in order to scale up. Combined
reaction mixture was partitioned between EtOAc and water, organic
layer washed with brine and dried over MgSO.sub.4. The crude
product obtained by solvent evaporation was purified via flash
column chromatography. tert-butyl
4-(3-chloropyridin-2-yl)piperazine-1-carboxylate was obtained in
20% yield (1.9 g) as yellow oil.
[0603] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.49 (s, 9H)
3.26-3.34 (m, 4H) 3.53-3.64 (m, 4H) 6.86 (dd, J=7.71, 4.67 Hz, 1H)
7.60 (dd, J=7.83, 1.77 Hz, 1H) 8.18 (dd, J=4.80, 1.77 Hz, 1H). HRS:
calcd for C.sub.14H.sub.20ClN.sub.3O.sub.2+H+, 298.13168; found
(ESI-FTMS, [M+H].sup.1+), 298.1319. HPLC Method 1: room
temperature, 6.051 min, 97.69%, HPLC Method 2: room temperature,
7.085 min, 98.91%.
[0604] Step 2B: To a clear solution of tert-butyl
4-(3-chloropyridin-2-yl)piperazine-1-carboxylate in anhydrous
dichloromethane (25 mL) was added TFA (25 mL) dropwise. The yellow
solution was stirred at room temperature for 2.5 hour. Reaction was
complete as determined by TLC. TFA was azeotropped with
dichloroethane to give 1-(3-chloropyridin-2-yl)piperazine in
quantitative yield (1.265 g).
[0605] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 3.19-3.32 (m, 4H)
3.39-3.51 (m, 4H) 7.10 (dd, J=7.83, 4.55 Hz, 2H) 7.87 (dd, J=7.83,
1.52 Hz, 2H) 8.27 (dd, J=4.80, 1.52 Hz, 2H) 8.87 (s, 1H).
[0606] Step 2C: To a stirred solution of
1-(3-chloropyridin-2-yl)piperazine (316 mg, 1.6 mmol) in anhydrous
dichloromethane (5 mL) was added diisopropylethylamine (0.975 mL,
5.6 mmol) then 4-tert-butylbenzene-1-sulfonyl chloride (372.4 mg,
1.6 mmol). The mixture was stirred at room temperature for 1.5
hour. Reaction was complete as determined by TLC. The reaction
mixture was purified with flash column chromatography to yield
1-[(4-tert-butylphenyl)sulfonyl]-4-(3-chloropyridin-2-yl)piperazine
in 59.3% yield (374 mg) as white solid.
[0607] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.36 (s, 9H)
3.17-3.25 (m, 4H) 3.39-3.47 (m, 4H) 6.86 (dd, J=7.71, 4.67 Hz, 1H)
7.52-7.60 (m, 3H) 7.68-7.75 (m, 2H) 8.16 (dd, J=4.80, 1.52 Hz, 1H).
HRMS: calcd for C19H24ClN3O2S+H+, 394.13505; found (ESI-FTMS,
[M+H]1+), 394.1358. HPLC Method 1: room temperature, 6.924 min,
99.05%, HPLC Method 2: room temperature, 7.499 min, 99.48%.
Example 2B
1-(3-chloropyridin-2-yl)-4-(2-naphthylsulfonyl)piperazine
[0608] Step 2C: Sulfonylation of 1-(3-chloropyridin-2-yl)piperazine
(632 mg, 3.2 mmol) with naphthalene-2-sulfonyl chloride (725 mg,
3.2 mmol) was carried out according to a similar procedure
described for example 2A (except that the sulfonyl chloride was
added before the diisopropylethylamine) using anhydrous
dichloromethane (10 mL) as solvent and diisopropylethylamine (1.4
mL, 8.0 mmol) as base.
1-(3-chloropyridin-2-yl)-4-(2-naphthylsulfonyl)piperazine was
obtained in 17.0% yield (210.2 mg) as white solid.
[0609] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.21-3.32 (m, 4H)
3.41-3.50 (m, 4H) 6.87 (dd, J=7.83, 4.80 Hz, 1H) 7.51-7.72 (m, 3H)
7.79 (dd, J=8.72, 1.89 Hz, 1H) 7.91-7.98 (m, 1H) 8.01 (d, J=8.34
Hz, 2H) 8.17 (dd, J=4.80, 1.77 Hz, 1H) 8.38 (d, J=1.77 Hz, 1H).
HRMS: calcd for C.sub.19H.sub.18ClN.sub.3O.sub.2S+H+, 388.08810;
found (ESI-FTMS, [M+H]1+), 388.0885. HPLC Method 1: room
temperature, 6.432 min, 99.82%, HPLC Method 2: room temperature,
7.178 min, 99.6%.
Example 2C
1-(3-chloropyridin-2-yl)-4-(1-naphthylsulfonyl)piperazine
[0610] Step 2C: Sulfonylation of 1-(3-chloropyridin-2-yl)piperazine
(316 mg, 1.6 mmol) with naphthalene-1-sulfonyl chloride (362.7 mg,
1.6 mmol) was carried out according to a similar procedure
described for example 2A (Except sulfonyl chloride was added before
diisopropylethylamine) using anhydrous dichloromethane (3 mL) as
solvent and diisopropylethylamine (1.4 mL, 8.0 mmol) as base.
1-(3-chloropyridin-2-yl)-4-(1-naphthylsulfonyl)piperazine was
obtained in 70.0% yield (434.0 mg) as white solid.
[0611] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 3.25 (s, 8H) 7.00 (dd,
J=7.71, 4.67 Hz, 1H) 7.63-7.82 (m, 4H) 8.08-8.22 (m, 3H) 8.33 (d,
J=8.34 Hz, 1H) 8.73 (d, J=7.83 Hz, 1H). HRMS: calcd for
C.sub.19H.sub.18ClN.sub.3O.sub.2S+H+, 388.08810; found (ESI-FTMS,
[M+H]1+), 388.0886. HPLC Method 1: room temperature, 6.476 min,
100%, HPLC Method 2: room temperature, 7.149 min, 100.0%.
Example 2D
1-[(2-chlorophenyl)sulfonyl]-4-(3-chloropyridin-2-yl)piperazine
[0612] Preparation of
1-[(2-chlorophenyl)sulfonyl]-4-(3-chloropyridin-2-yl)piperazine was
carried out according to a similar procedure described for example
2A. Yield 75%.
[0613] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.36-3.44 (m, 4H)
3.44-3.55 (m, 4H) 6.78-6.93 (m, J=7.83, 4.80 Hz, 1H) 7.38-7.46 (m,
1H) 7.47-7.52 (m, 1H) 7.52-7.56 (m, 1H) 7.59 (dd, J=7.71, 1.64 Hz,
1H) 8.09 (d, J=7.83 Hz, 1H) 8.17 (d, J=4.80 Hz, 1H). HRMS: calcd
for C.sub.15H.sub.15Cl.sub.2N.sub.3O.sub.2S+H+, 372.03348; found
(ESI-FTMS, [M+H].sup.1+), 372.0355.
Example 2E
1-[(4-chlorophenyl)sulfonyl]-4-(3-chloropyridin-2-yl)piperazine
[0614] Preparation of
1-[(4-chlorophenyl)sulfonyl]-4-(3-chloropyridin-2-yl)piperazine was
carried out according to a similar procedure described for example
2A. Yield 78%.
[0615] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.20 (br s, 4H)
3.43 (br s, 4H) 6.58-7.04 (m, 1H) 7.10-7.40 (m, 1H) 7.41-7.96 (m,
4H) 8.17 (s, 1H). HRMS: calcd for
C.sub.15H.sub.15Cl.sub.2N.sub.3O.sub.2S+H+, 372.03348; found
(ESI-FTMS, [M+H].sup.1+), 372.0345. HPLC Method 1, room
temperature, 6.00 min, 97.89%; HPLC Method 2, room temperature,
6.99 min, 97.48%.
Example 2F
1-(3-chloropyridin-2-yl)-4-[(4-methylphenyl)sulfonyl]piperazine
[0616] Preparation of
1-(3-chloropyridin-2-yl)-4-[(4-methylphenyl)sulfonyl]piperazine was
carried out according to a similar procedure described for example
2A. Yield 78%.
[0617] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 2.42 (s, 3H) 2.88-3.18
(m, 4H) 3.20-3.45 (m, 4H) 6.74-7.21 (m, J=7.58 Hz, 1H) 7.49 (d,
J=8.08 Hz, 2H) 7.67 (d, J=8.08 Hz, 2H) 7.79 (d, J=7.58 Hz, 1H) 8.20
(d, J=4.55 Hz, 1H). HRMS: calcd for
C.sub.16H.sub.18ClN.sub.3O.sub.2S+H+, 352.08810; found (ESI-FTMS,
[M+H].sup.1+), 352.0897.
Example 2G
1-(3-chloropyridin-2-yl)-4-[(4-methoxyphenyl)sulfonyl]piperazine
[0618] Preparation of
1-(3-chloropyridin-2-yl)-4-[(4-methoxyphenyl)sulfonyl]piperazine
was carried out according to a similar procedure described for
example 2A. Yield 75%.
[0619] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.99-3.28 (m, 4H)
3.36-3.51 (m, 4H) 3.89 (s, 3H) 6.87 (d, J=4.80 Hz, 1H) 6.98-7.07
(m, 2H) 7.56 (d, J=1.77 Hz, 1H) 7.67-7.84 (m, 2H) 8.16 (dd, J=4.67,
1.64 Hz, 1H). HRMS: calcd for C.sub.16H.sub.18ClN.sub.3O.sub.3S+H+,
368.08301; found (ESI-FTMS, [M+H].sup.1+), 368.0839.
Example 2H
1-(biphenyl-4-ylsulfonyl)-4-(3-chloropyridin-2-yl)piperazine
[0620] Preparation of
1-(biphenyl-4-ylsulfonyl)-4-(3-chloropyridin-2-yl)piperazine was
carried out according to a similar procedure described for example
2A. Yield 75%.
[0621] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.25 (d, J=8.84
Hz, 4H) 3.38-3.59 (m, J=8.84 Hz, 4H) 6.74-6.97 (m, 1H) 7.33-7.54
(m, 3H) 7.57 (d, J=7.83 Hz, 1H) 7.59-7.68 (m, J=8.08 Hz, 2H)
7.71-7.81 (m, 2H) 7.82-7.99 (m, 2H) 8.16 (d, J=4.80 Hz, 1H). HRMS:
calcd for C.sub.21H.sub.20ClN.sub.3O.sub.2S+H+, 414.10375; found
(ESI-FTMS, [M+H].sup.1+), 414.1042.
Example 2I
1-(benzylsulfonyl)-4-(3-chloropyridin-2-yl)piperazine
[0622] Preparation of
1-(benzylsulfonyl)-4-(3-chloropyridin-2-yl)piperazine was carried
out according to a similar procedure described for example 2A.
Yield 75%.
[0623] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.11-3.56 (m, 8H)
4.26 (s, 2H) 6.91 (dd, J=7.83, 4.80 Hz, 1H) 7.32-7.55 (m, 5H) 7.64
(d, J=7.83 Hz, 1H) 8.20 (d, J=4.80 Hz, 1H). HRMS: calcd for
C.sub.16H.sub.18ClN.sub.3O.sub.2S+H+, 352.08810; found (ESI-FTMS,
[M+H].sup.1+), 352.0881.
Example 2J
1-{[2-bromo-4-(trifluoromethyl)phenyl]sulfonyl}-4-(3-chloropyridin-2-yl)pi-
perazine
[0624] Preparation of
1-{[2-bromo-4-(trifluoromethyl)phenyl]sulfonyl}-4-(3-chloropyridin-2-yl)p-
iperazine was carried out according to a similar procedure
described for example 2A. Yield 75%.
[0625] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.38-3.46 (m,
J=4.80 Hz, 4H) 3.48-3.58 (m, J=4.80 Hz, 4H) 6.73-7.04 (m, 1H) 7.60
(d, J=7.58 Hz, 1H) 7.73 (d, J=8.08 Hz, 1H) 8.02 (s, 1H) 8.18 (d,
J=4.80 Hz, 1H) 8.25 (d, J=8.08 Hz, 1H). HRMS: calcd for
C.sub.16H.sub.14BrClF.sub.3N.sub.3O.sub.2S+H+, 483.97035; found
(ESI-FTMS, [M+H].sup.1+), 483.9716.
Example 2K
1-{[4-(benzyloxy)phenyl]sulfonyl}-4-[3-(trifluoromethyl)pyridin-2-yl]piper-
azine
[0626] Step 2A: tert-butyl piperazine-1-carboxylate (3.0 g, 16.11
mmol) and 2-chloro-3-trifluoromethylpyridine (2.93 g, 16.11 mmol)
charged to a microwave vial was added with diisopropylethylamine
(7.05 mL, 40.28 mmol) and DMF (1.0 mL). The reaction mixture was
subject to microwave irradiation at 160.degree. C. for 30 minutes.
The reaction mixture was partitioned between EtOAc and water,
organic layer washed with brine and dried over Na.sub.2SO.sub.4.
The crude product obtained by solvent evaporation was purified via
flash column chromatography.
4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid
tert-butyl ester was obtained in 33.9% yield (1.81 g) as light
yellow oil.
[0627] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.48 (s, 9H)
3.18-3.27 (m, 4H) 3.53-3.61 (m, 4H) 7.00-7.06 (m, 1H) 7.88 (dd,
J=7.83, 1.77 Hz, 1H) 8.44 (dd, J=4.80, 1.26 Hz, 1H).
[0628] Step 2B: To a clear solution of
4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid
tert-butyl ester in anhydrous dichloromethane (15 mL) was added TFA
(8 mL) dropwise. The yellow solution was stirred at room
temperature for 2.5 hour. Reaction was complete as determined by
TLC. TFA was removed under reduced pressure. The residue was
redissolved in dichloromethane (50 mL), and washed with sat.
K.sub.2CO.sub.3 solution first, then washed with brine and dried
over Na.sub.2SO.sub.4, filtered and concentrated down to give
1-(3-trifluoromethyl-pyridin-2-yl)-piperazine as a light yellow oil
(1.19 g, 96.0% yield).
[0629] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.60 (s, 1H)
2.93-3.08 (m, 4H) 3.17-3.36 (m, 4H) 6.97 (dd, J=7.20, 4.67 Hz, 1H)
7.85 (dd, J=7.83, 1.77 Hz, 1H) 8.37-8.52 (m, 1H).
[0630] Step 2C: To a stirred solution of
1-(3-trifluoromethyl-pyridin-2-yl)-piperazine (100 mg, 0.39 mmol)
in anhydrous dichloromethane (2 mL) was added
4-benzyloxy-benzenesulfonyl chloride (110.27 mg, 0.39 mmol) then
diisopropylethylamine (0.17 mL, 0.98 mmol). The mixture was stirred
at room temperature for 4 hour. Reaction was complete as determined
by TLC. The reaction mixture was purified with flash column
chromatography to yield
1-{[4-(benzyloxy)phenyl]sulfonyl}-4-[3-(trifluoromethyl)pyridin-2-yl]pipe-
razine in 78.9% yield (147 mg) as white solid.
[0631] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.12-3.20 (m, 4H)
3.32-3.39 (m, 4H) 5.14 (s, 2H) 7.00-7.06 (m, 1H) 7.07-7.13 (m, 2H)
7.34-7.47 (m, 5H) 7.70-7.77 (m, 2H) 7.85 (dd, J=7.83, 1.77 Hz, 1H)
8.43 (dd, J=4.80, 1.26 Hz, 1H). HRMS: calcd for
C.sub.23H.sub.22F.sub.3N.sub.3O.sub.3S+H+, 478.14067; found
(ESI-FTMS, [M+H].sup.1+), 478.1398. HPLC Method 1: room
temperature, 6.793 min, 99.02%; HPLC Method 2: room temperature,
7.419 min, 99.60%.
Example 2L
N-[4-({4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}sulfonyl)phenyl]m-
orpholine-4-carboxamide
[0632] The title compound was prepared according to a similar
procedure for Example 2A, step 2C. Yield 78.9%.
[0633] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.12-3.19 (m, 4H)
3.31-3.37 (m, 4H) 3.48-3.56 (m, 4H) 3.72-3.81 (m, 4H) 6.55-6.60 (m,
1H) 7.03 (dd, J=7.71, 4.93 Hz, 1H) 7.52-7.59 (m, 2H) 7.68-7.75 (m,
2H) 7.85 (dd, J=7.83, 2.02 Hz, 1H) 8.42 (dd, J=4.80, 1.77 Hz, 1H).
HRMS: calcd for C.sub.21H.sub.24F.sub.3N.sub.5O.sub.4S+H+,
500.15738; found (ESI-FTMS, [M+H].sup.1+), 500.1567. HPLC Method 1:
room temperature, 5.217 min, 99.80%, HPLC Method 2: room
temperature, 6.178 min, 99.84%.
Example 2M
1-{[4-(4-fluorophenoxy)phenyl]sulfonyl}-4-[3-(trifluoromethyl)pyridin-2-yl-
]piperazine
[0634] The title compound was prepared according to a similar
procedure for Example 2A, step 2C. Yield 89%.
[0635] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.14-3.20 (m, 4H)
3.32-3.38 (m, 4H) 7.00-7.16 (m, 7H) 7.70-7.77 (m, 2H) 7.86 (dd,
J=7.83, 1.77 Hz, 1H) 8.44 (dd, J=4.80, 1.77 Hz, 1H). HRMS: calcd
for C.sub.22H.sub.19F.sub.4N.sub.3O.sub.3S+H+, 482.11560; found
(ESI-FTMS, [M+H].sup.1+), 482.1148. HPLC Method 1: room
temperature, 6.823 min, 99.77%, HPLC Method 2: room temperature,
7.414 min, 97.29%.
Example 2N
3-[4-({4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}sulfonyl)phenoxy]-
propanenitrile
[0636] The title compound was prepared according to a similar
procedure for Example 2A, step 2C. Yield 55.7%.
[0637] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.90 (t, J=6.32
Hz, 2H) 3.12-3.20 (m, 4H) 3.30-3.38 (m, 4H) 4.28 (t, J=6.32 Hz, 2H)
7.00-7.08 (m, 3H) 7.72-7.80 (m, 2H) 7.85 (dd, J=7.71, 1.89 Hz, 1H)
8.43 (dd, J=4.80, 1.26 Hz, 1H). HRMS: calcd for
C.sub.19H.sub.19F.sub.3N.sub.4O.sub.3S+H+, 441.12027; found
(ESI-FTMS, [M+H].sup.1+), 441.1197. HPLC Method 1: room
temperature, 5.657 min, 99.00%, HPLC Method 2: room temperature,
6.226 min, 99.30%.
Example 2O
1-[(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)sulfonyl]-4-[3-(trifluorometh-
yl)pyridin-2-yl]piperazine
[0638] The title compound was prepared according to a similar
procedure for Example 2A, step 2C. Yield 81.7%.
[0639] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.37 (s, 6H) 1.86
(t, J=6.69 Hz, 2H) 2.84 (t, J=6.69 Hz, 2H) 3.13-3.19 (m, 4H)
3.32-3.39 (m, 4H) 6.88 (d, J=8.59 Hz, 1H) 7.02 (dd, J=7.83, 4.80
Hz, 1H) 7.47-7.54 (m, 2H) 7.85 (dd, J=7.71, 1.89 Hz, 1H) 8.43 (dd,
J=4.42, 1.64 Hz, 1H). HRMS: calcd for
C.sub.21H.sub.24F.sub.3N.sub.3O.sub.3S+H+, 456.15632; found
(ESI-FTMS, [M+H].sup.1+), 456.156. HPLC Method 1: room temperature,
6.762 min, 95.21%, HPLC Method 2: room temperature, 7.372 min,
95.92%.
Example 2P
N,N-dimethyl-N'-[4-({4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}sul-
fonyl)phenyl]urea
[0640] The title compound was prepared according to a similar
procedure for Example 2A, step 2C. Yield 63.1%.
[0641] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.06 (s, 6H)
3.11-3.19 (m, 4H) 3.30-3.38 (m, 4H) 6.55 (s, 1H) 6.98-7.05 (m, 1H)
7.54-7.62 (m, 2H) 7.67-7.73 (m, 2H) 7.84 (dd, J=7.83, 1.77 Hz, 1H)
8.39-8.44 (m, 1H). HRMS: calcd for
C.sub.19H.sub.22F.sub.3N.sub.5O.sub.3S+H+, 458.14682; found
(ESI-FTMS, [M+H].sup.1+), 458.1464. HPLC Method 1: room
temperature, 5.264 min, 99.31%, HPLC Method 2: room temperature,
6.137 min, 99.80%.
Example 2Q
N-methyl-N'-[4-({4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}sulfony-
l)phenyl]urea
[0642] The title compound was prepared according to a similar
procedure for Example 2A, step 2C. Yield 85%.
[0643] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.90 (d, J=4.80
Hz, 3H) 3.12-3.19 (m, 4H) 3.30-3.38 (m, 4H) 4.64 (s, 1H), 6.51 (s,
1H) 6.98-7.06 (m, 1H) 7.51-7.57 (m, 2H) 7.70 (d, J=8.59 Hz, 2H)
7.81-7.87 (m, 1H) 8.40-8.45 (m, 1H). HRMS: calcd for
C.sub.18H.sub.20F.sub.3N.sub.5O.sub.3S+H+, 444.13117; found
(ESI-FTMS, [M+H].sup.1+), 444.1306. HPLC Method 1: room
temperature, 5.042 min, 99.00%, HPLC Method 2: room temperature,
6.003 min, 99.53%.
Example 2R
N-[4-({4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}sulfonyl)phenyl]p-
iperidine-1-carboxamide
[0644] The title compound was prepared according to a similar
procedure for Example 2A, step 2C. Yield 88.8%.
[0645] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.63-1.71 (m, 6H)
3.11-3.18 (m, 4H) 3.30-3.37 (m, 4H) 3.43-3.53 (m, 4H) 6.58 (s, 1H)
7.02 (dd, J=7.83, 4.80 Hz, 1H) 7.52-7.59 (m, 2H) 7.67-7.73 (m, 2H)
7.84 (dd, J=7.96, 1.64 Hz, 1H) 8.42 (dd, J=4.93, 1.64 Hz, 1H).
HRMS: calcd for C.sub.22H.sub.26F.sub.3N.sub.5O.sub.3S+H+,
498.17812; found (ESI-FTMS, [M+H].sup.1+), 498.1786. HPLC Method 1:
room temperature, 5.883 min, 100%, HPLC Method 2: room temperature,
6.748 min, 100%.
Example 3
##STR00042##
[0646] Example 3A
1-(2,4-difluorophenyl)-4-(2-naphthylsulfonyl)piperazine
[0647] Step 3A: To a stirred solution of naphthalene-2-sulfonyl
chloride (350 mg, 1.54 mmol) and 1-(2,4-difluorophenyl)piperazine
(305.0 mg, 1.54 mmol) in anhydrous dichloromethane (5 mL) was added
diisopropylethylamine (0.670 mL, 3.85 mmol). The mixture was
stirred for 30 minutes. Reaction was complete as determined by TLC.
The reaction mixture was purified via flash column chromatography
to afford 1-(2,4-difluorophenyl)-4-(2-naphthylsulfonyl)piperazine
in 55% yield (327 mg) as white solid.
[0648] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 3.00-3.07 (m, 4H)
3.07-3.15 (m, 4H) 6.94-7.02 (m, 1H) 7.03-7.12 (m, 1H) 7.12-7.21 (m,
1H) 7.67-7.84 (m, 3H) 8.11 (d, J=8.08 Hz, 1 H) 8.21 (d, J=8.59 Hz,
1H) 8.25 (d, J=8.08 Hz, 1H) 8.49 (d, J=1.77 Hz, 1H). HRMS: calcd
for C.sub.20H.sub.18F.sub.2N.sub.2O.sub.2S+H+, 389.11298; found
(ESI-FTMS, [M+H]1+), 389.113. HPLC Method 1: room temperature,
6.658 min, 96.32%, HPLC Method 2: room temperature, 7.312 min,
99.29%.
Example 3B
1-(2,4-dimethylphenyl)-4-(2-naphthylsulfonyl)piperazine
[0649] Step 3A: Sulfonylation of 1-(2,4-dimethylphenyl)piperazine
(293 mg, 1.54 mmol) with naphthalene-2-sulfonyl chloride (350 mg,
1.54 mmol) was carried out according to a similar procedure
described for example 3A using anhydrous dichloromethane (5 mL) as
solvent and diisopropylethylamine (0.670 mL, 3.85 mmol) as base.
1-(2,4-dimethylphenyl)-4-(2-naphthylsulfonyl)piperazine was
obtained in 92% yield (539 mg) as white solid.
[0650] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 2.03 (s, 3H) 2.18 (s,
3H) 2.86 (t, J=4.80 Hz, 4H) 3.11 (s, 4H) 6.92 (s, 3H) 7.67-7.85 (m,
3H) 8.11 (d, J=8.08 Hz, 1H) 8.22 (d, J=8.84 Hz, 1H) 8.25 (d, J=8.08
Hz, 1H) 8.49 (d, J=1.52 Hz, 1H); HRMS: calcd for
C.sub.22H.sub.24N.sub.2O.sub.2S+H+, 381.16312; found (ESI-FTMS,
[M+H]1+), 381.163. HPLC Method 1: room temperature, 7.258 min,
99.49%, HPLC Method 2: room temperature, 7.817 min, 99.52%.
Example 3C
1-(2-ethylphenyl)-4-(2-naphthylsulfonyl)piperazine
[0651] Step 3A: Sulfonylation of 1-(2-ethylphenyl)piperazine (293
mg, 1.54 mmol) with naphthalene-2-sulfonyl chloride (350 mg, 1.54
mmol) was carried out according to a similar procedure described
for example 3A using anhydrous dichloromethane (5 mL) as solvent
and diisopropylethylamine (0.670 mL, 3.85 mmol) as base.
1-(2-ethylphenyl)-4-(2-naphthylsulfonyl)piperazine was obtained in
99% yield (579 mg) as white solid.
[0652] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 1.02 (t, J=7.45 Hz,
3H) 2.46 (d, J=7.33 Hz, 2H) 2.89 (t, J=4.67 Hz, 4H) 3.12 (s, 4H)
6.90-7.20 (m, 4H) 7.61-7.80 (m, 2H) 7.82 (d, J=8.59 Hz, 1H) 8.12
(d, J=7.83 Hz, 1H) 8.17-8.31 (m, 2H) 8.50 (d, J=1.77 Hz, 1H); HRMS:
calcd for C.sub.22H.sub.24N.sub.2O.sub.2S+H+, 381.16312; found
(ESI-FTMS, [M+H]1+), 381.1631. HPLC Method 1: room temperature,
7.204 min, 99.62%, HPLC Method 2: room temperature, 7.759 min,
99.62%.
Example 3D
1-[4-fluoro-2-(methylsulfonyl)phenyl]-4-(2-naphthylsulfonyl)piperazine
[0653] Step 3A: Sulfonylation of
1-(4-fluoro-2-(methylsulfonyl)phenyl)piperazine (316.6 mg, 1.23
mmol) with naphthalene-2-sulfonyl chloride (278 mg, 1.54 mmol) was
carried out according to a similar procedure described for example
3A using anhydrous dichloromethane (5 mL) as solvent and
diisopropylethylamine (0.256 mL, 1.47 mmol) as base.
1-[4-fluoro-2-(methylsulfonyl)phenyl]-4-(2-naphthylsulfonyl)piperazine
was obtained in 61.8% yield (340 mg) as white solid.
[0654] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 3.05 (s, 4H) 3.14 (s,
4H) 3.33 (s, 3H) 7.51-7.67 (m, 2H) 7.67-7.88 (m, 4H) 8.12 (d,
J=8.08 Hz, 1H) 8.17-8.31 (m, 2H) 8.51 (d, J=1.52 Hz, 1H). HRMS:
calcd for C.sub.21H.sub.21FN.sub.2O.sub.4S.sub.2+H+, 449.09995;
found (ESI-FTMS, [M+H]1+), 449.1003. HPLC Method 1: room
temperature, 5.864 min, 97.14%, HPLC Method 2: room temperature,
6.426 min, 97.56%.
Example 3E
1-(2-naphthylsulfonyl)-4-[2-(trifluoromethyl)phenyl]piperazine
[0655] Preparation of
1-(2-naphthylsulfonyl)-4-[2-(trifluoromethyl)phenyl]piperazine was
carried out according to a similar procedure described for example
3A. Yield 85%.
[0656] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.84-3.09 (m,
J=9.60 Hz, 4H) 3.12-3.46 (m, 4H) 7.15-7.30 (m, 1H) 7.35 (d, J=8.08
Hz, 1H) 7.44-7.58 (m, 1H) 7.58 (d, J=7.83 Hz, 1H) 7.62-7.74 (m, 2H)
7.79 (d, J=10.36 Hz, 1H) 7.96 (d, J=7.83 Hz, 1H) 7.99-8.17 (m, 2H)
8.38 (s, 1H). HRMS: calcd for
C.sub.21H.sub.19F.sub.3N.sub.2O.sub.2S+H+, 421.11921; found
(ESI-FTMS, [M+H].sup.1+), 421.1192; HPLC Method 1, room
temperature, 6.78 min, 99.04%; HPLC Method 2, room temperature,
7.43 min, 99.17%.
Example 3F
1-(2-bromophenyl)-4-(2-naphthylsulfonyl)piperazine
[0657] Preparation of
1-(2-bromophenyl)-4-(2-naphthylsulfonyl)piperazine was carried out
according to a similar procedure described for example 3A. Yield
85%.
[0658] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.95-3.19 (m, 4H)
3.19-3.44 (m, 4H) 6.83-6.99 (m, 1H) 6.98-7.12 (m, 1H) 7.19-7.35 (m,
1H) 7.51 (d, J=9.60 Hz, 1H) 7.58-7.74 (m, 2H) 7.80 (d, J=10.61 Hz,
1H) 7.95 (d, J=8.08 Hz, 1H) 8.02 (d, J=8.59 Hz, 2H) 8.38 (s, 1H).
HRMS: calcd for C.sub.20H.sub.19BrN.sub.2O.sub.2S+H+, 431.04233;
found (ESI-FTMS, [M+H].sup.1+), 431.0424. HPLC Method 1, room
temperature, 6.85 min, 100%; HPLC Method 2, room temperature, 7.49
min, 99.60%.
Example 4
1-(3-chloropyridin-2-yl)-4-[(3,4-dichlorophenyl)sulfonyl]-trans-2,5-dimeth-
ylpiperazine
[0659] Step 4A: To a stirred solution of
3,4-dichlorobenzene-1-sulfonyl chloride (840 mg, 3.42 mmol) and
2,5-dimethylpiperazine (1.171 g, 10.26 mmol) in anhydrous
dichloromethane (5 mL) was added diisopropylethylamine (1.2 mL,
6.84 mmol). The mixture was stirred overnight at room temperature.
Reaction was complete as determined by TLC. The reaction mixture
was diluted with dichloromethane, washed with water and dried over
MgSO.sub.4. After solvent evaporation crude product was treated
with ethyl acetate/hexanes. Solid impurity was filtered of and the
filtrate was concentrated to afford
1-(3,4-dichlorophenylsulfonyl)-2,5-dimethylpiperazine in
quantitative yield. It was carried to the next step without further
purification.
[0660] Step 4B:
1-(3,4-dichlorophenylsulfonyl)-2,5-dimethylpiperazine (1.04 g, 3.22
mmol), 2,3-dichloropyridine (476.5 mg. 3.22 mmol),
diisopropylethylamine (1.4 mL, 8.05 mmol) and DMF (1.2 mL) were
charged to a microwave vial and the mixture was irradiated at
200.degree. C. for 1 hour. Reaction was complete as determined by
TLC. The reaction mixture was diluted with ethyl acetate and washed
with water. After solvent evaporation crude product was purified
with flash column chromatography to yield
1-(3-chloropyridin-2-yl)-4-[(3,4-dichlorophenyl)sulfonyl]-2,5-di-
methylpiperazine in 2% yield (27.1 mg) as yellow solid.
[0661] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.08 (d, J=6.57
Hz, 3H) 1.12 (d, J=6.57 Hz, 3H) 3.26 (d, J=13.39 Hz, 1H) 3.44-3.52
(m, 1H) 3.54-3.66 (m, 2H) 4.14-4.37 (m, 2H) 6.84 (dd, J=7.58, 4.80
Hz, 1H) 7.50-7.70 (m, 3H) 7.93 (d, J=2.02 Hz, 1H) 8.15 (dd, J=4.80,
1.77 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.18Cl.sub.3N.sub.3O.sub.2S+H+, 434.02580; found
(ESI-FTMS, [M+H]1+), 434.028. HPLC Method 1: room temperature,
7.140 min, 99.62%, HPLC Method 2: room temperature, 7.684 min,
99.56%.
Example 5
Benzyl
(3S,5S)-4-[(4-tert-butylphenyl)sulfonyl]-3,5-dimethylpiperazine-1-c-
arboxylate
[0662] Step 5A: (S)-tert-butyl 1-oxopropan-2-ylcarbamate
(Boc-L-Alaninal) (3.0 g, 17.32 mmol) and (R)-1-aminopropan-2-ol
(1.95 g, 25.98 mmol) in anhydrous methanol (120 mL) was
hydrogenated at 1 atmosphere overnight using palladium, 10% wt. on
activated carbon (900 mg) as catalyst. Reaction was complete as
determined by TLC using CAN spray to visualize. The reaction
mixture was then filtered through a celite bed. After solvent
evaporation crude product was diluted with ethyl acetate, washed
with saturated NAHCO.sub.3 (aq.) and dried over MgSO.sub.4. Solvent
evaporation afforded tert-butyl
(S)-1-[(R)-2-hydroxypropylamino]propan-2-ylcarbamate] in 98.5%
yield (3.95 g). It was carried to the next step without further
purification.
[0663] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.14 (d, J=6.57
Hz, 3H) 1.15 (d, J=6.32 Hz, 3H) 1.45 (s, 9H) 2.39 (dd, J=12.13,
9.35 Hz, 1H) 2.53-2.78 (m, 3H) 3.14 (s, 1H) 3.70-3.81 (m, 2H) 4.52
(s, 1H)
[0664] Step 5B: To a stirred solution of tert-butyl
(S)-1-[(R)-2-hydroxypropylamino]propan-2-ylcarbamate (3.0 g, 12.93
mmol) and diisopropylethylamine (3.38 mL, 19.4 mmol) in anhydrous
dichloromethane (100 mL) at 0.degree. C. was added benzyl
chloroformate (2.65 g, 15.5 mmol). After stirring at 0.degree. C.
for 1 hour, the cooling bath was removed and the reaction mixture
was allowed to stir at room temperature for an additional 45
minutes. Reaction was complete as determined by TLC. The reaction
mixture was added with 1N HCl and extracted with dichloromethane.
Organic layer was washed with water then brine and it was dried
over MgSO.sub.4. Solvent evaporation afforded benzyl
{(2S)-2-[(tert-butoxycarbonyl)amino]propyl}[(2R)-2-hydroxypropyl]c-
arbamate in 84.5% yield (3.95 g) as colorless gummy oil.
[0665] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 0.90-1.04 (m, 6H) 1.35
(s, 9H) 1.99 (s, 1H) 3.10-3.22 (m, 2H) 3.28 (d, J=5.56 Hz, 1H) 3.80
(d, J=5.56 Hz, 2H) 4.69 (dd, J=17.18, 4.80 Hz, 1H) 5.00-5.10 (m,
2H) 6.59-6.71 (m, 1H) 7.29-7.42 (m, 5H). HRMS: calcd for
C.sub.19H.sub.30N.sub.2O.sub.5+H+, 367.22275; found (ESI-FTMS,
[M+H].sup.1+), 367.2235.
[0666] Step 5C: To a stirred solution of benzyl
{(2S)-2-[(tert-butoxycarbonyl)amino]propyl}[(2R)-2-hydroxypropyl]carbamat-
e (1.95 g, 5.32 mmol) and diisopropylethylamine (1.85 mL, 10.64
mmol) in anhydrous dichloromethane (110 mL) was added
dimethylaminopyridine (135 mg) and methane sulfonyl chloride (0.535
mL, 6.92 mmol). The mixture was stirred at room temperature for 1
hour. Reaction was complete as determined by TLC. The reaction
mixture was concentrated and purified using flash column
chromatography.
(1R)-2-([(benzyloxy)carbonyl]{(2S)-2-[(tert-butoxycarbonyl)amino]propyl}a-
mino)-1-methylethyl methanesulfonate was obtained in 97.0% yield
(2.29 g) as light yellow oil.
[0667] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 0.91-1.02 (m, 3H)
1.21-1.32 (m, 3H) 1.35 (s, 9H) 3.05 (d, 3H) 3.22 (d, J=8.59 Hz, 2H)
3.34-3.54 (m, 2H) 3.66-3.88 (m, 1H) 4.76-4.94 (m, 1H) 4.98-5.16 (m,
2H) 6.60-6.76 (m, 1H) 7.23-7.44 (m, 5H).
[0668] Step 5D: To a stirred solution of
(1R)-2-([(benzyloxy)carbonyl]{(2S)-2-[(tert-butoxycarbonyl)amino]propyl}a-
mino)-1-methylethyl methanesulfonate (2.29 g, 5.15 mmol) in
anhydrous dichloromethane (38 mL) was added TFA (38 mL) dropwise at
0.degree. C. The reaction mixture was stirred at room temperature
for 1 hour. Reaction was complete as determined by TLC. Most of TFA
was azeotropped with dichloroethane. The residue was then diluted
with dichloromethane and washed with 2N Na.sub.2CO.sub.3 (aq.),
organic layer was dried over MgSO.sub.4. Solvent evaporation
afforded
(R)-1-(((S)-2-aminopropyl)(benzyloxycarbonyl)amino)propan-2-yl
methanesulfonate in quantitative yield (1.8 g) as oil. It was
carried to the next step immediately.
[0669] Step 5E:
(R)-1-(((S)-2-aminopropyl)(benzyloxycarbonyl)amino)propan-2-yl
methanesulfonate (1.8 g, 5.15 mmol) dissolved in anhydrous MeOH
(120 mL) was heated up to 60.degree. C. for 4 hours. Reaction was
complete as determined by TLC. After overnight stirring at room
temperature solvent was evaporated to afford (3R,5R)-benzyl
3,5-dimethylpiperazine-1-carboxylate [L31285-103-1] in quantitative
yield (1.28 g) as gummy off white solid.
[0670] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.31-1.44 (m, 6H)
3.38-3.64 (m, 4H) 3.73-3.96 (m, 2H) 7.29-7.43 (m, 5H) 8.96 (s,
1H).
[0671] Step 5F: To a stirred solution of (3R,5R)-benzyl
3,5-dimethylpiperazine-1-carboxylate (500 mg, 2.02 mmol) in
anhydrous dichloromethane (8 mL) was added diisopropylethylamine
(1.4 mL, (8.08 mmol) followed by 4-tert-butylbenzene-1-sulfonyl
chloride (940 mg, 4.04 mmol). The reaction mixture was stirred for
68 hours. Reaction was complete as determined by TLC. After solvent
evaporation the crude product was purified by flash column
chromatography to afford benzyl
(3S,5S)-4-[(4-tert-butylphenyl)sulfonyl]-3,5-dimethylpiperazine-1-carboxy-
late in 42% yield (377 mg) as light yellow oil.
[0672] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 1.12 (d, J=6.57 Hz,
6H) 1.30 (s, 9H) 3.25 (s, 1H) 3.35 (s, 1H) 3.45-3.59 (m, 2H) 4.00
(s, 2H) 5.00-5.15 (m, 2H) 7.21-7.42 (m, 5H) 7.59 (d, J=8.84 Hz, 2H)
7.75 (d, J=8.59 Hz, 2H). HRMS: calcd for
C.sub.24H.sub.32N.sub.2O.sub.4S+H+, 445.21555; found (ESI-FTMS,
[M+H].sup.1+), 445.2169. HPLC Method 1: room temperature, 6.990
min, 98.43%, HPLC Method 2: room temperature, 7.534 min,
99.66%.
Example 6
(2S,6S)-1-[(4-tert-butylphenyl)sulfonyl]-4-(3-chloropyridin-2-yl)-2,6-dime-
thylpiperazine
[0673] Step 6A: A solution of benzyl
(3S,5S)-4-[(4-tert-butylphenyl)sulfonyl]-3,5-dimethylpiperazine-1-carboxy-
late (340 mg, 0.77 mmol) in anhydrous MeOH was hydrogenated at 1
atmosphere for 2 days using palladium, 10% wt. on activated carbon
(144 mg) as catalyst. Reaction was complete as determined by TLC.
The reaction mixture was then filtered through a celite bed. After
solvent evaporation crude product was purified via flash column
chromatography to afford
(2S,6S)-1-[(4-tert-butylphenyl)sulfonyl]-2,6-dimethylpiperazine in
53.9% yield (128 mg) as pale yellow oil.
[0674] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.23 (s, 3H) 1.24
(s, 3H) 1.33 (s, 9H) 2.63-2.67 (m, 1H) 2.68 (d, J=6.32 Hz, 1H) 2.94
(d, J=3.28 Hz, 1H) 2.97 (d, J=3.54 Hz, 1H) 3.92-4.00 (m, 2H) 7.47
(d, J=8.84 Hz, 2H) 7.75 (d, J=8.84 Hz, 2H). HRMS: calcd for
C.sub.16H.sub.26N.sub.2O.sub.2S+H+, 311.17877; found (ESI-FTMS,
[M+H].sup.1+), 311.179. HPLC Method 1: room temperature, 5.557 min,
99.41%, HPLC Method 2: room temperature, 4.760 min, 100.0%.
[0675] Step 6B: To a solution of
(2S,6S)-1-[(4-tert-butylphenyl)sulfonyl]-2,6-dimethylpiperazine
(120 mg, 0.39 mmol) and 2,3-Dichloropyridine (115 mg, 0.78 mmol) in
anhydrous 1,4-Dioxane (0.2 mL) was added diisopropylethylamine
(0.201 mL, 1.16 mmol). The mixture was subject to microwave
irradiation at 200.degree. C. for 1 hour. Reaction was half
complete as determined by TLC. The reaction mixture was diluted
with ethyl acetate and washed with saturated NH.sub.4Cl (aq.), 10%
HCl (aq.), water and brine. Organic layer was dried over
MgSO.sub.4. Solvent evaporation followed by flash column
chromatography afforded
(2S,6S)-1-[(4-tert-butylphenyl)sulfonyl]-4-(3-chloropyridin-2-yl)-2,6-dim-
ethylpiperazine in 27.7% yield (45 mg) as off white solid.
[0676] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.33 (s, 9H) 1.36
(s, 3H) 1.38 (s, 3H) 3.22 (d, J=6.32 Hz, 1H) 3.25 (d, J=6.32 Hz,
1H) 3.41 (d, J=3.03 Hz, 1H) 3.44 (d, J=3.28 Hz, 1H) 4.19-4.29 (m,
2H) 6.86 (dd, J=7.71, 4.67 Hz, 1H) 7.47 (d, J=8.84 Hz, 2H) 7.59
(dd, J=7.83, 1.52 Hz, 1H) 7.78 (d, J=8.84 Hz, 2H) 8.07-8.22 (m,
1H). HRMS: calcd for C.sub.21H.sub.28ClN.sub.3O.sub.2S+H+,
422.16635; found (ESI-FTMS, [M+H]1+), 422.1665. HPLC Method 1: room
temperature, 7.378 min, 96.04%, HPLC Method 2: room temperature,
7.756 min, 95.34%.
Example 7
##STR00043##
[0677] Example 7A
2-{4-[(3,4-dichlorophenyl)sulfonyl]piperidin-1-yl}-3-(trifluoromethyl)pyri-
dine
[0678] Step 7A: tert-butyl
4-[(methylsulfonyl)oxy]piperidine-1-carboxylate. The mesylate was
prepared from tert-butyl-4-hydroxy-1-piperidinecarboxylate using
the procedure from WO 0053362 Cheng S., et al. To a 0.degree. C.
solution of tert-butyl-4-hydroxy-1-piperidinecarboxylate (9.80 g,
49 mmol), Et.sub.3N (9.92 g, 13.7 mL, 98 mmol), and
CH.sub.2Cl.sub.2 (90 mL) was added MsCl (6.17 g, 4.20 mL, 53 mmol).
After 15 min, the ice bath was removed and the mixture was stirred
overnight at room temperature, poured into 1M HCl (90 mL) and
extracted with CH.sub.2Cl.sub.2 (2.times.60 mL). The organic phase
was washed with H.sub.2O and brine, dried (MgSO.sub.4), and
concentrated to afford the mesylate (12.9 g), an off-white solid,
in 95% yield.
[0679] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.71-1.91 (m, 2H),
1.90-2.15 (m, 2H), 3.04 (s, 3H), 3.18-3.50 (m, 2H), 3.49-3.96 (m,
2H), 4.68-5.04 (m, 1H).
[0680] Step 7B: tert-butyl
4-[(3,4-dichlorophenyl)thio]piperidine-1-carboxylate. A suspension
of the mesylate from Step 2 (3.8 g, 7.1 mmol),
3,4-dichlorothiophenol (2.9 g, 2.1 m-L), and K.sub.2CO.sub.3 (3.0
g, 11.4 mmol) in CH.sub.3CN (30 mL) was heated in a 90.degree. C.
bath for 16 h. The resulting mixture was diluted with H.sub.2O (100
mL) and EtOAc (100 mL). The aqueous phase was extracted with EtOAc
(50 mL). The combined organic phases were washed with H.sub.2O and
brine, dried (MgSO.sub.4) and concentrated to afford a yellow oil
which was purified by SiO.sub.2 chromatography (elution with 5 to
10% EtOAc-hex) to afford the thioether (3.97 g), a pale yellow oil,
in 80% yield.
[0681] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.35-1.59 (m,
11H), 1.92 (d, J=13.1 Hz, 2H), 2.93 (t, J=11.7 Hz, 2H), 3.13-3.32
(m, 1H), 3.96 (s, 2H), 7.23 (d, J=8.3 Hz, 1H), 7.37 (d, J=8.3 Hz, 1
H), 7.49 (s, 1H).
[0682] Step 7C: tert-butyl
4-[(3,4-dichlorophenyl)sulfonyl]piperidine-1-carboxylate. To a
0.degree. C. solution to the thioether from Step 2 (2.65 g, 7.3
mmol) in CH.sub.2Cl.sub.2 (150 mL) was added MCPBA (77%, 3.60 g, 16
mmol). After 2 h, sat. NaHCO.sub.3 solution (150 mL) was added and
the resulting suspension was stirred at room temperature for 15
min. The organic phase was separated and washed with 1N NaOH (50
mL), H.sub.2O (50 mL), and brine (50 mL), dried (MgSO.sub.4), and
concentrated partially. The crude product was adhered to SiO.sub.2
and purified by SiO.sub.2 chromatography (elution with 20 to 30%
EtOAc-hex) to afford the sulfone (2.79 g), a white solid, in 97%
yield.
[0683] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.44 (s, 9H),
1.54-1.71 (m, 2H), 1.98 (d, J=11.9 Hz, 2H), 2.67 (br s, 2H),
2.95-3.13 (m, 1H), 4.26 (br s, 2H), 7.67-7.70 (m, 2H), 7.96 (d,
J=1.3 Hz, 1H).
[0684] Step 7D: 4-[(3,4-dichlorophenyl)sulfonyl]piperidine. A
mixture of the sulfone from Step 7C (3.09 g, 7.8 mmol), MeOH (21
mL), and 5N HCl (4.5 mL) was heated to reflux for 1.5 h. The
mixture was cooled to room temperature and sat. Na.sub.2CO.sub.3
solution (80 mL) was added. The mixture was extracted with
CH.sub.2Cl.sub.2 (2.times.100 mL). The organic phase was washed
with H.sub.2O and brine, dried (MgSO.sub.4) and concentrated to
afford the amine (1.82 g), a white foam, in 79% yield.
[0685] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.39-1.70 (m, 3H),
2.00 (d, J=12.4 Hz, 2H), 2.57 (t, J=12.4 Hz, 2H), 3.04 (t, J=12.3
Hz, 1H), 3.20 (d, J=12.6 Hz, 2H), 7.68 (q, J=8.3 Hz, 2H), 7.96 (s,
1H).
[0686] Step 7E:
2-{4-[(3,4-dichlorophenyl)sulfonyl]piperidin-1-yl}-3-(trifluoromethyl)pyr-
idine. A mixture of the amine from Step 7D (200 mg, 0.68 mmol),
2-chloro-3-(trifluoromethyl)pyridine (200 mg, 1.36 mmol), DIEA
(0.36 mL, 2.04 mmol), and 1,4-dioxane (0.10 m-L) was heated in the
Emrys Creator microwave to 200.degree. C. for 1 h. The mixture was
diluted with sat. NH.sub.4Cl (20 mL) and EtOAc (50 mL). The organic
phase was washed with 10% HCl (25 mL), H.sub.2O (3.times.25 mL),
and brine (25 mL), dried (MgSO.sub.4), and concentrated. The
resulting yellow oil was purified by SiO.sub.2 chromatography
(elution with 10 to 30% EtOAc-hexanes), and lyophilized to afford
the title compound (0.19 g), a white solid, 64%.
[0687] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.80-2.01 (m, 2H),
2.02-2.16 (m, 2H), 2.75-2.95 (m, 2H), 3.02-3.24 (m, 1H), 3.69 (dd,
J=10.5, 2.7 Hz, 2H), 6.91-7.13 (m, 1H), 7.69 (d, J=8.3 Hz, 1H),
7.74 (dd, J=8.3, 2.2 Hz, 1H), 7.87 (dd, J=7.8, 1.5 Hz, 1H), 8.00
(d, J=2.0 Hz, 1H), 8.42 (dd, J=4.8, 1.3 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.15Cl.sub.2F.sub.3N.sub.2O.sub.2S+H+, 439.02561; found
(ESI-FTMS, [M+H].sup.1+), 439.0261; HPLC Method 1: room
temperature, 6.56 min, 97.0%. HPLC Method 2: room temperature, 7.24
min, 96.9%.
Example 7B
3-chloro-2-{4-[(3,4-dichlorophenyl)sulfonyl]piperidin-1-yl}pyridine
[0688] Step 7E: Using the procedure from Example 7A, Step 7E,
4-[(3,4-dichlorophenyl)sulfonyl]piperidine (200 mg, 0.68 mmol) was
reacted with 2,3-dichloropyridine (201 mg, 1.36 mmol) to afford the
title compound (90 mg), a white solid, in 33% yield.
[0689] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.83-2.02 (m, 2H),
2.04-2.21 (m, 2H), 2.70-2.89 (m, 2H), 3.02-3.28 (m, 1H), 3.81-4.05
(m, 2H), 6.86 (dd, J=7.8, 4.8 Hz, 1H), 7.59 (dd, J=7.7, 1.6 Hz,
1H), 7.68 (d, J=8.3 Hz, 1H), 7.74 (dd, J=8.4, 2.1 Hz, 1H), 8.00 (d,
J=2.0 Hz, 1H), 8.16 (dd, J=4.8, 1.8 Hz, 1H). HRMS: calcd for
C.sub.16H.sub.15Cl.sub.3N.sub.2O.sub.2S+H+, 404.99925; found
(ESI-FTMS, [M+H].sup.1+), 405.0012; HPLC Method 1: room
temperature, 6.44 min, 97.4%. HPLC Method 2: room temperature, 7.24
min, 97.9%.
Example 7C
2-{4-[(3,4-dichlorophenyl)sulfonyl]piperidin-1-yl}-5-(trifluoromethyl)pyri-
dine
[0690] Step 7E: Using the procedure from Example 7A, Step 7E,
4-[(3,4-dichlorophenyl)sulfonyl]piperidine (200 mg, 0.68 mmol) was
reacted with 2-chloro-5-(trifluoromethyl)pyridine (172 mg, 0.96
mmol) to afford the title compound (110 mg), a white solid, in 37%
yield.
[0691] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.66-1.88 (m, 2H),
2.10 (d, J=12.4 Hz, 2H), 2.89 (t, J=12.8 Hz, 2H), 3.07-3.35 (m,
1H), 4.57 (d, J=13.4 Hz, 2H), 6.65 (d, J=8.8 Hz, 1H), 7.57-7.82 (m,
3H), 7.97 (s, 1H), 8.38 (s, 1H). HRMS: calcd for
C.sub.17H.sub.15Cl.sub.2F.sub.3N.sub.2O.sub.2S+H+, 439.02561; found
(ESI-FTMS, [M+H].sup.1+), 439.0273. HPLC Method 1: room
temperature, 6.70 min, 98.8%. HPLC Method 2: room temperature, 7.32
min, 99.8%.
Example 7D
2-{4-[(3,4-dichlorophenyl)sulfonyl]piperidin-1-yl}-3-nitropyridine
[0692] Step 7E: Using the procedure from Example 7A, Step 7E,
4-[(3,4-dichlorophenyl)sulfonyl]piperidine (150 mg, 0.51 mmol) was
reacted with 2-chloro-3-nitropyridine (97 mg, 0.61 mmol) to afford
the title compound (212 mg), a yellow solid, in 74% yield.
[0693] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.80-1.95 (m, 2H),
2.03-2.13 (m, 2H), 2.95-3.08 (m, 2H), 3.12-3.26 (m, 1H), 3.90-4.01
(m, 2H), 6.81 (dd, J=8.1, 4.5 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.72
(dd, J=8.4, 1.9 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H), 8.15 (dd, J=8.0,
1.6 Hz, 1H), 8.34 (dd, J=4.5, 1.8 Hz, 1H). HRMS: calcd for
C.sub.16H.sub.15Cl.sub.2N.sub.3O.sub.4S+H+, 416.02331; found
(ESI-FTMS, [M+H].sup.1+), 416.0227.
Example 7E
1-{4-[(3,4-dichlorophenyl)sulfonyl]piperidin-1-yl}isoquinoline
[0694] Step 7E: Using the procedure from Example 7A, Step 7E,
4-[(3,4-dichlorophenyl)sulfonyl]piperidine (Example 1, Step 4, 150
mg, 0.51 mmol) was reacted with 1-chloroisoquinoline (100 mg, 0.61
mmol) to afford the title compound (215 mg), a white solid, in 51%
yield.
[0695] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.97-2.29 (m, 4H),
2.80-3.05 (m, 2H), 3.08-3.28 (m, 1H), 3.93 (d, J=13.1 Hz, 2H),
7.19-7.36 (m, 2H), 7.53 (t, J=7.7 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H),
7.70 (d, J=8.3 Hz, 1H), 7.77 (t, J=8.1 Hz, 2H), 7.95-8.07 (m, 2H),
8.12 (d, J=5.6 Hz, 1H). HRMS: calcd for
C.sub.20H.sub.18Cl.sub.2N.sub.2O.sub.2S+H+, 421.05388; found
(ESI-FTMS, [M+H].sup.1+), 421.0558. HPLC Method 1: room
temperature, 4.83 min, 98.8%. HPLC Method 2: room temperature, 6.63
min, 99.8%.
Example 7F
2-{4-[(3,4-dichlorophenyl)sulfonyl]piperidin-1-yl}nicotinonitrile
[0696] Step 7E: Using the procedure from Example 7A, Step 7E,
4-[(3,4-dichlorophenyl)sulfonyl]piperidine (150 mg, 0.51 mmol) was
reacted with 2-chloro-3-cyanopyridine (85 mg, 0.61 mmol) to afford
the title compound (202 mg), a white solid, in 77% yield.
[0697] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.78-1.96 (m, 2H),
2.11 (d, J=11.9 Hz, 2H), 2.99 (t, J=12.6 Hz, 2H), 3.10-3.27 (m,
1H), 4.50 (d, J=13.6 Hz, 2H), 6.80 (dd, J=7.6, 4.8 Hz, 1H),
7.61-7.75 (m, 2H), 7.78 (d, J=7.6 Hz, 1H), 7.99 (s, 1H), 8.34 (d,
J=4.8 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.15Cl.sub.2N.sub.3O.sub.2S+H+, 396.03348; found
(ESI-FTMS, [M+H].sup.1+), 396.0337. HPLC Method 1: room
temperature, 6.01 min, 99.1%. HPLC Method 2: room temperature, 6.74
min, 99.4%.
Example 7G
3,5-dichloro-4-{4-[(3,4-dichlorophenyl)sulfonyl]piperidin-1-yl}pyridine
[0698] Step 7E: Using the procedure from Example 7A, Step 7E,
4-[(3,4-dichlorophenyl)sulfonyl]piperidine (150 mg, 0.51 mmol) was
reacted with 3,4,5-trichloropyridine (224 mg, 1.22 mmol) to afford
the title compound (66 mg), a white solid, in 55% yield.
[0699] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.85-2.12 (m, 4H),
2.98-3.17 (m, 1H), 3.19-3.33 (m, 2H), 3.35-3.53 (m, 2H), 7.69 d,
J=8.3 Hz, 1H), 7.74 (dd, J=8.3, 2.0 Hz, 1H), 8.00 (d, J=2.0 Hz,
1H), 8.35 (s, 2H). HRMS: calcd for
C.sub.16H.sub.14Cl.sub.4N.sub.2O.sub.2S+H+, 438.96028; found
(ESI-FTMS, [M+H].sup.1+), 438.9612.
Example 7H
2-{4-[(3,4-dichlorophenyl)sulfonyl]piperidin-1-yl}quinoline
[0700] Step 7E: Using the procedure from Example 7A, Step 7E,
4-[(3,4-dichlorophenyl)sulfonyl]piperidine (150 mg, 0.51 mmol) was
reacted with 2-chloroquinoline (328 mg, 2.0 mmol) to afford the
title compound (39 mg), a white solid, in 18% yield.
[0701] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.65-1.92 (m, 2H),
1.95-2.32 (m, 2H), 2.80-3.01 (m, 2H), 2.99-3.35 (m, 1H), 4.63-4.77
(m, 2H), 6.96 (d, J=9.1 Hz, 1H), 7.19-7.28 (m, 1H), 7.50-7.58 (m,
1H), 7.60 (dd, J=8.0, 1.4 Hz, 1H), 7.63-7.74 (m, 3H), 7.90 (d,
J=8.8 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H). HRMS: calcd for
C.sub.20H.sub.18Cl.sub.2N.sub.2O.sub.2S+H+, 421.05388; found
(ESI-FTMS, [M+H].sup.1+), 421.0543. HPLC Method 1: room
temperature, 4.52 min, 99.1%. HPLC Method 2: room temperature, 5.38
min, 99.4%.
Example 7I
2-[4-(2-naphthylsulfonyl)piperidin-1-yl]-3-(trifluoromethyl)pyridine
[0702] Step 7E: The corresponding naphthyl amine from Step 7D (175
mg, 0.63 mmol) was reacted with
2-chloro-3-(trifluoromethyl)pyridine (231 mg, 1.3 mmol) as in
Example 7A, Step 7E to afford the title compound (196 mg), a white
powder, in 73% yield.
[0703] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.87-2.19 (m, 4H),
2.87 (t, J=12.3 Hz, 2H), 3.16 (t, J=11.9 Hz, 1H), 3.68 (d, J=12.4
Hz, 2H), 6.92-7.07 (m, 1H), 7.57-7.74 (m, 2H), 7.87 (dd, J=16.3,
8.2 Hz, 2H), 7.96 (d, J=7.8 Hz, 1H), 8.03 (d, J=8.6 Hz, 2H), 8.40
(d, J=4.5 Hz, 1H), 8.50 (s, 1H). HRMS: calcd for
C.sub.21H.sub.19F.sub.3N.sub.2O.sub.2S+H+, 421.11921; found
(ESI-FTMS, [M+H].sup.1+), 421.1208. HPLC Method 1: room
temperature, 6.37 min, 98.4%. HPLC Method 2: room temperature, 7.07
min, 98.7%.
Example 7J
3-chloro-2-[4-(2-naphthylsulfonyl)piperidin-1-yl]pyridine
[0704] Step 7E: Using the procedure from Example 7A, Step 7E,
4-(2-naphthylsulfonyl)piperidine (Example 1I, Step 3, 175 mg, 0.63
mmol) was reacted with 2,3-dichloropyridine (188 mg, 1.3 mmol) to
afford the title compound (119 mg), a white solid, in 48%
yield.
[0705] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.86-2.08 (m, 2H),
2.07-2.17 (m, 2H), 2.67-2.93 (m, 2H), 2.98-3.30 (m, 1H), 3.94 (dd,
J=10.9, 2.3 Hz, 2H), 6.83 (dd, J=7.6, 4.8 Hz, 1H), 7.56 (dd, J=7.8,
1.8 Hz, 1H), 7.60-7.74 (m, 2H), 7.89 (dd, J=8.6, 1.8 Hz, 1H), 7.96
(d, J=8.3 Hz, 1H), 8.00-8.09 (m, 2H), 8.14 (dd, J=4.7, 1.6 Hz, 1H),
8.50 (d, J=1.8 Hz, 1H). HRMS: calcd for
C.sub.20H.sub.19ClN.sub.2O.sub.2S+H+, 387.09285; found (ESI-FTMS,
[M+H].sup.1+), 387.0942. HPLC Method 1: room temperature, 6.25 min,
100%. HPLC Method 2: room temperature, 7.01 min, 100%.
Example 7K
2-[4-(2-naphthylsulfonyl)piperidin-1-yl]-5-(trifluoromethyl)pyridine
[0706] Step 7E: Using the procedure from Example 7A, Step 7E,
4-(2-naphthylsulfonyl)piperidine (130 mg, 0.51 mmol) was reacted
with 2-chloro-5-(trifluoromethyl)pyridine (181 mg, 1.0 mmol) to
afford the title compound (180 mg), a white solid, in 84%
yield.
[0707] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.70-1.88 (m, 2H),
2.02-2.37 (m, 2H), 2.80-2.98 (m, 2H), 3.15-3.40 (m, 1H), 4.54 (d,
J=13.6 Hz, 2H), 6.62 (d, J=8.8 Hz, 1H), 7.53-7.77 (m, 3H), 7.85
(dd, J=8.6, 1.8 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.98-8.08 (m, 2H),
8.29-8.39 (m, 1H), 8.46 (s, 1H). HRMS: calcd for
C.sub.21H.sub.19F.sub.3N.sub.2O.sub.2S+H+, 421.11921; found
(ESI-FTMS, [M+H].sup.1+), 421.1207. HPLC Method 1: room
temperature, 6.49 min, 99.6%. HPLC Method 2: room temperature, 7.11
min, 99.6%.
Example 7L
3,5-dichloro-4-[4-(2-naphthylsulfonyl)piperidin-1-yl]pyridine
[0708] Step 7L: Using the procedure from Example 7A, Step 7E,
4-(2-naphthylsulfonyl)piperidine (130 mg, 0.51 mmol) was reacted
with 3,4,5-trichloropyridine (182 mg, 1.0 mmol) to afford the title
compound (26 mg), a white solid, in 12% yield.
[0709] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.91-2.18 (m, 4H),
3.09-3.32 (m, 3H), 3.42 (d, J=12.9 Hz, 2H), 7.59-7.76 (m, 2H), 7.89
(dd, J=8.6, 1.8 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.99-8.10 (m, 2H),
8.32 (s, 2H), 8.50 (s, 1H). HRMS: calcd for
C.sub.20H.sub.18Cl.sub.2N.sub.2O.sub.2S+H+, 421.05388; found
(ESI-FTMS, [M+H].sup.1+), 421.0544. HPLC Method 1: room
temperature, 6.43 min, 99.6%. HPLC Method 2: room temperature, 7.21
min, 100%.
Example 7M
2-[4-(2-naphthylsulfonyl)piperidin-1-yl]-3-nitropyridine
[0710] Step 7E: Using the procedure from Example 7A, Step 7E,
4-(2-naphthylsulfonyl)piperidine (130 mg, 0.51 mmol) was reacted
with 2-chloro-3-nitropyridine (158 mg, 1.0 mmol) to afford the
title compound (148 mg), a yellow solid, in 73% yield.
[0711] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.80-1.99 (m, 2H),
2.11 (dd, J=12.5, 2.1 Hz, 2H), 2.86-3.12 (m, 2H), 3.16-3.34 (m,
1H), 3.94 (d, J=13.4 Hz, 2H), 6.77 (dd, J=8.1, 4.5 Hz, 1H),
7.59-7.77 (m, 1H), 7.86 (dd, J=8.6, 1.8 Hz, 1H), 7.95 (d, J=8.1 Hz,
1H), 7.98-8.08 (m, 2H), 8.12 (dd, J=8.1, 1.8 Hz, 1H), 8.31 (dd,
J=4.5, 1.8 Hz, 1H), 8.47 (s, 1H). HRMS: calcd for
C.sub.20H.sub.19N.sub.3O.sub.4S+H+, 398.11690; found (ESI-FTMS,
[M+H].sup.1+), 398.1162. HPLC Method 1: room temperature, 5.94 min,
99.1%. HPLC Method 2: room temperature, 6.64 min, 99.4%.
Example 7N
2-[4-(2-naphthylsulfonyl)piperidin-1-yl]-5-nitropyridine
[0712] Step 7E: Using the procedure from Example 7A, Step 7E,
4-(2-naphthylsulfonyl)piperidine (Example 1I, Step 3, 130 mg, 0.51
mmol) was reacted with 2-chloro-5-nitropyridine (158 mg, 1.0 mmol)
to afford the title compound (63 mg), a yellow solid, in 31%
yield.
[0713] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.71-1.93 (m, 2H),
2.18 (d, J=10.1 Hz, 2H), 2.88-3.10 (m, 2H), 3.16-3.42 (m, 1H), 4.65
(d, J=13.9 Hz, 2H), 6.56 (d, J=9.3 Hz, 1H), 7.62-7.79 (m, 2H), 7.85
(dd, J=8.6, 1.8 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.99-8.09 (m, 2H),
8.19 (dd, J=9.6, 2.8 Hz, 1H), 8.46 (d, J=1.8 Hz, 1H), 8.99 (d,
J=2.3 Hz, 1H). HRMS: calcd for C.sub.20H.sub.19N.sub.3O.sub.4S+H+,
398.11690; found (ESI-FTMS, [M+H].sup.1+), 398.1161. HPLC Method 1:
room temperature, 5.94 min, 97.6%. HPLC Method 2: room temperature,
6.63 min, 98.1%.
Example 7O
1-[4-(2-naphthylsulfonyl)piperidin-1-yl]isoquinoline
[0714] Step 7E: Using the procedure from Example 7A, Step 7E,
4-(2-naphthylsulfonyl)piperidine (130 mg, 0.51 mmol) was reacted
with 1-chloroisoquinoline (164 mg, 1.0 mmol) to afford the title
compound (151 mg), a white solid, in 31% yield.
[0715] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.07-2.28 (m, 4H),
2.77-2.98 (m, 2H), 3.15-3.33 (m, 1H), 3.91 (d, J=13.1 Hz, 2H),
7.23-7.31 (m, 1H), 7.46-7.55 (m, 1H), 7.57-7.63 (m, 1H), 7.64-7.77
(m, 3H), 7.93 (dd, J=8.7, 1.9 Hz, 1H), 7.99 (t, J=9.0 Hz, 2H),
8.02-8.09 (m, 2H), 8.10 (d, J=5.8 Hz, 1H), 8.54 (d, J=1.5 Hz, 1H).
HRMS: calcd for C.sub.24H.sub.22N.sub.2O.sub.2S+H+, 403.14747;
found (ESI-FTMS, [M+H].sup.1+), 403.1477. HPLC Method 1: room
temperature, 4.80 min, 99.2%. HPLC Method 2: room temperature, 6.61
min, 99.3%.
Example 7P
2-[4-(2-naphthylsulfonyl)piperidin-1-yl]nicotinonitrile
[0716] Step 7E: Using the procedure from Example 7A, Step 7E,
4-(2-naphthylsulfonyl)piperidine (Example 1I, Step 3, 130 mg, 0.51
mmol) was reacted with 2-chloro-3-cyanopyridine (139 mg, 1.0 mmol)
to afford the title compound (151 mg), a white solid, in 78%
yield.
[0717] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.84-2.04 (m, 2H),
2.15 (dd, J=12.6, 1.8 Hz, 2H), 2.79-3.09 (m, 2H), 3.15-3.37 (m,
1H), 4.31-4.69 (m, 2H), 6.77 (dd, J=7.6, 4.8 Hz, 1H), 7.60-7.81 (m,
3H), 7.87 (dd, J=8.6, 1.8 Hz, 1H), 7.96 (d, J=8.1 Hz, 1H),
7.99-8.10 (m, 2H), 8.32 (dd, J=4.8, 2.0 Hz, 1H), 8.48 (d, J=1.5 Hz,
1H). HRMS: calcd for C.sub.21H.sub.19N.sub.3O.sub.2S+H+, 378.12707;
found (ESI-FTMS, [M+H].sup.1+), 378.1275. HPLC Method 1: room
temperature, 5.77 min, 99.5%. HPLC Method 2: room temperature, 6.46
min, 99.4%.
Example 7Q
4-(2-naphthylsulfonyl)-1-[2-(trifluoromethyl)phenyl]piperidine
[0718] Step 7E: A 5 mL microwave reaction vial was charged with
4-(2-naphthylsulfonyl)piperidine (82 mg, 0.30 mmol),
2-bromobenzotrifluoride (67 mg, 0.30 mmol), NaOt-Bu (40 mg, 0.42
mmol), Pd.sub.2(dba).sub.3 (26 mg, 0.025 mmol), racemic BINAP (31
mg, 0.05 mmol), and dioxane (1.5 mL). The mixture was degassed with
N.sub.2, capped, and heated in a 90.degree. C. oil bath for 16 h.
The mixture was diluted with CH.sub.2Cl.sub.2 (10 mL) and filtered
through a plug of SiO.sub.2. The organic phase was concentrated and
purified by SiO.sub.2 chromatography (15 to 30% EtOAc-hex) to
afford the title compound (63 mg), a yellow oil, in 50% yield.
[0719] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.94-2.19 (m, 4H),
2.60-2.77 (m, 2H), 2.92-3.31 (m, 3H), 7.09-7.32 (m, 2H), 7.44-7.52
(m, 1H), 7.56-7.77 (m, 3H), 7.89 (dd, J=8.6, 1.8 Hz, 1H), 7.96 (d,
J=8.3 Hz, 1H), 7.99-8.11 (m, 2H), 8.50 (d, J=1.5 Hz, 1H). HRMS:
calcd for C.sub.22H.sub.20F.sub.3NO.sub.2S+H+, 420.12396; found
(ESI-FTMS, [M+H].sup.1+), 420.1245. HPLC Method 1: room
temperature, 6.82 min, 98.5%. HPLC Method 2: room temperature, 7.36
min, 98.4%.
Example 7R
3-methyl-2-[4-(2-naphthylsulfonyl)piperidin-1-yl]pyridine
[0720] Step 7E: Using the procedure from Example 7A,
4-(2-naphthylsulfonyl)piperidine (82 mg, 0.30 mmol) was reacted
with 2-bromo-6-methylpyridine (51 mg, 0.30 mmol) to afford the
title compound (40 mg), a yellow solid, in 54% yield.
[0721] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.88-2.06 (m, 2H),
2.13 (dd, J=12.4, 1.5 Hz, 2H), 2.66-2.82 (m, 2H), 3.07-3.33 (m,
1H), 3.53 (dd, J=10.5, 2.1 Hz, 2H), 6.85 (dd, J=7.3, 5.1 Hz, 1H),
7.38 (dd, J=7.3, 1.3 Hz, 1H), 7.61-7.76 (m, 2H), 7.90 (dd, J=8.6,
1.8 Hz, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.99-8.07 (m, 2H), 8.11 (dd,
J=5.3, 1.5 Hz, 1H), 8.50 (d, J=1.8 Hz, 1H). HRMS: calcd for
C.sub.21H.sub.22N.sub.2O.sub.2S+H+, 367.14747; found (ESI-FTMS,
[M+H].sup.1+), 367.148; HPLC Method 1: room temperature, 4.60 min,
94.7%. HPLC Method 2: room temperature, 5.65 min, 91.7%.
Example 7S
2-{4-[(3,4-dichlorophenyl)sulfonyl]piperidin-1-yl}-3-methylpyridine
[0722] Step 7E: Using the procedure from Example 7A, Step 7E,
4-[(3,4-dichlorophenyl)sulfonyl]piperidine (88 mg, 0.30 mmol) was
reacted with 2-bromo-6-methylpyridine (62 mg, 0.040 mL, 0.36 mmol)
to afford the title compound (37 mg), a pale yellow solid, in 32%
yield.
[0723] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.84-2.01 (m, 2H),
2.08 (d, J=12.4 Hz, 2H), 2.24 (s, 3H), 2.68-2.85 (m, 2H), 2.96-3.18
(m, 1H), 3.55 (d, J=10.6 Hz, 2H), 6.87 (dd, J=7.3, 5.1 Hz, 1H),
7.41 (dd, J=7.3, 1.3 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.74 (dd,
J=8.3, 2.1 Hz, 1H), 8.01 (d, J=2.0 Hz, 1H), 8.13 (dd, J=5.2, 1.6
Hz, 1H). HRMS: calcd for
C.sub.17H.sub.18Cl.sub.2N.sub.2O.sub.2S+H+, 385.05388; found
(ESI-FTMS, [M+H].sup.1+), 385.0545.
Example 7T
2-({-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}sulfonyl)quinoline
[0724] Step 7E: The corresponding quinoline amine from Step 7D (140
mg, 0.51 mmol) was reacted with
2-chloro-3-(trifluoromethyl)pyridine (182 mg, 1.0 mmol) as in
Example 7A, Step 7E to afford the title compound (101 mg), a white
powder, in 47% yield.
[0725] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.03-2.25 (m, 4H),
2.88-3.01 (m, 2H), 3.70 (d, J=13.1 Hz, 2H), 3.83-4.02 (m, 1H), 7.02
(dd, J=7.8, 4.8 Hz, 1H), 7.66-7.78 (m, 1H), 7.81-7.92 (m, 2H),
7.92-8.03 (m, 1H), 8.17 (d, J=8.6 Hz, 1H), 8.28 (dd, J=8.6, 1.0 Hz,
1H), 8.42 (dd, J=4.8, 1.3 Hz, 1H), 8.45 (d, J=8.6 Hz, 1H). HRMS:
calcd for C.sub.20H.sub.18F.sub.3N.sub.3O.sub.2S+H+, 422.11446;
found (ESI-FTMS, [M+H].sup.1+), 422.1148. HPLC Method 1: room
temperature, 6.05 min, 91.1%. HPLC Method 2: room temperature, 6.74
min, 90.7%.
Example 7U
2-{[1-(3,5-dichloropyridin-4-yl)piperidin-4-yl]sulfonyl}quinoline
[0726] Step 7E: Using the procedure from Example 7A, Step 7E,
2-(piperidin-4-ylsulfonyl)quinoline (150 mg, 0.51 mmol) was reacted
with 3,4,5-trichloropyridine (182 mg, 1.0 mmol) to afford the title
compound (34 mg), an off-white solid, in 16% yield.
[0727] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.06-2.24 (m, 4H),
3.25-3.40 (m, 2H), 3.40-3.52 (m, 2H), 3.84-4.01 (m, 1H), 7.69-7.79
(m, 1H), 7.83-7.92 (m, 1H), 7.97 (d, J=8.1 Hz, 1H), 8.18 (d, J=8.6
Hz, 1H), 8.28 (d, J=8.6 Hz, 1H), 8.34 (s, 2H), 8.47 (d, J=7.8 Hz,
1H). HRMS: calcd for C.sub.19H.sub.17Cl.sub.2N.sub.3O.sub.2S+H+,
422.04913; found (ESI-FTMS, [M+H].sup.1+), 422.0496. HPLC Method 1:
room temperature, 6.11 min, 97.5%. HPLC Method 2: room temperature,
6.91 min, 98.7%.
Example 7V
2-[4-(quinolin-2-ylsulfonyl)piperidin-1-yl]nicotinonitrile
[0728] Step 7E: Using the procedure from Example 7A, Step 7E,
2-(piperidin-4-ylsulfonyl)quinoline (Example 1T, Step 3, 150 mg,
0.51 mmol) was reacted with 2-chloro-3-cyanopyridine (139 mg, 1.0
mmol) to afford the title compound (166 mg), an off-white solid, in
86% yield.
[0729] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.06-2.26 (m, 4H),
2.95-3.28 (m, 2H), 3.90-4.11 (m, 1H), 4.41-4.62 (m, 2H), 6.77 (dd,
J=7.8, 4.8 Hz, 1H), 7.67-7.82 (m, 2H), 7.83-7.93 (m, 1H), 7.94-8.02
(m, 1H), 8.16 (d, J=8.3 Hz, 1H), 8.27 (dd, J=8.6, 1.0 Hz, 1H), 8.33
(dd, J=4.8, 2.0 Hz, 1H), 8.46 (d, J=7.8 Hz, 1H). HRMS: calcd for
C.sub.19H.sub.17Cl.sub.2N.sub.3O.sub.2S+H+, 422.04913; found
(ESI-FTMS, [M+H].sup.1+), 422.0496; HPLC purity H.sub.2O/CH.sub.3CN
97.5%, H.sub.2O/MeOH 98.7%. HRMS: calcd for
C.sub.20H.sub.18N.sub.4O.sub.2S+H+, 379.12232; found (ESI-FTMS,
[M+H].sup.1+), 379.1227. HPLC Method 1: room temperature, 5.38 min,
100%. HPLC Method 2: room temperature, 6.02 min, 100%.
Example 7W
2-[4-(phenylsulfonyl)piperidin-1-yl]-3-(trifluoromethyl)pyridine
[0730] Step 7E: To a microwave vial were charged
4-(phenylsulfonyl)piperidine (300 mg, 1.33 mmol),
2-chloro-3-(trifluoromethyl)pyridine, (484 mg, 2.66 mmol),
diisopropylethylamine (0.695 mL, 3.99 mmol) and 1,4-Dioxane (0.2
mL). The reaction mixture thus prepared was irradiated at
200.degree. C. for 1 hour. The reaction was complete as determined
by TLC. The residue was added with saturated NH.sub.4Cl (aq.) and
extracted with ethylacetate, washed with 10% HCl (aq.), water then
brine. Organic layer was dried over MgSO.sub.4. Solvent evaporation
afforded
2-[4-(phenylsulfonyl)piperidin-1-yl]-3-(trifluoromethyl)pyridine in
55% yield (270 mg) as white solid.
[0731] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.93 (dd,
J=12.63, 3.79 Hz, 2H) 2.01-2.13 (m, 2H) 2.78-2.94 (m, 2H) 3.08 (s,
1H) 3.68 (dd, J=10.61, 2.27 Hz, 2H) 7.02 (dd, J=7.83, 4.80 Hz, 1H)
7.60 (t, J=7.58 Hz, 2H) 7.65-7.74 (m, 1H) 7.86 (dd, J=7.83, 1.77
Hz, 1H) 7.88-7.97 (m, 2H) 8.41 (dd, J=4.80, 1.77 Hz, 1H). HRMS:
calcd for C.sub.17H.sub.17F.sub.3N.sub.2O.sub.2S+H+, 371.10356;
found (ESI-FTMS, [M+H].sup.1+), 371.1048. HPLC Method 1: room
temperature, 5.733 min, 99.40%, HPLC Method 2: room temperature,
6.463 min, 99.24%.
Example 7X
2-{4-[(2-chlorophenyl)sulfonyl]piperidin-1-yl}-3-(trifluoromethyl)pyridine
[0732] The title compound was prepared according to a similar
procedure described for Example 7A. Yield 74%.
[0733] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.90-2.00 (m,
2H), 2.01-2.14 (m, 2H), 2.86-2.99 (m, 2H), 3.64-3.76 (m, 3H),
7.00-7.06 (m, 1H), 7.46-7.52 (m, 1H), 7.56-7.62 (m, 2H), 7.87 (dd,
J=7.7, 1.9 Hz, 1H), 8.10-8.17 (m, 1H), 8.43 (dd, J=4.8, 2.0 Hz,
1H). HRMS: calcd for C.sub.17H.sub.16ClF.sub.3N.sub.2O.sub.2S+H+,
405.06458; found (ESI-FTMS, [M+H].sup.1+), 405.0661.
Example 7Y
3-chloro-2-{4-[(2-chlorophenyl)sulfonyl]piperidin-1-yl}pyridine
[0734] Using the procedure from Example 7A,
4-[(2-chlorophenyl)sulfonyl]piperidine (150 mg, 0.58 mmol) was
reacted with 2,3-dichloropyridine (173 mg, 1.16 mmol) to afford the
title compound (110 mg), a white solid, in 51% yield.
[0735] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.93-2.02 (m,
2H), 2.03-2.16 (m, 2H), 2.78-2.88 (m, 2H), 3.66-3.77 (m, 1H),
3.91-4.01 (m, J=110.5, 2.7 Hz, 2H), 6.85 (dd, J=7.8, 4.8 Hz, 1H),
7.46-7.52 (m, 1H), 7.56-7.61 (m, 3H), 8.11-8.15 (m, 1H), 8.16 (dd,
J=4.8, 1.8 Hz, 1H). HRMS: calcd for
C.sub.16H.sub.16Cl.sub.2N.sub.2O.sub.2S+H+, 371.03823; found
(ESI-FTMS, [M+H].sup.1+), 371.0384.
Example 7Z
3,5-dichloro-4-{4-[(2-chlorophenyl)sulfonyl]piperidin-1-yl}pyridine
[0736] Using the procedure from Example 7A,
4-[(2-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was
reacted with 2-chloro-5-(trifluoromethyl)pyridine (142 mg, 0.76
mmol) to afford the title compound (22 mg), a white solid, in 14%
yield.
[0737] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.89-2.00 (m,
2H), 2.03-2.17 (m, 2H), 3.24-3.36 (m, 2H), 3.40-3.49 (m, 2H),
3.65-3.77 (m, 1H), 7.44-7.54 (m, 1H), 7.57-7.63 (m, 2H), 8.06-8.19
(m, 1H), 8.35 (s, 2H). HRMS: calcd for
C.sub.16H.sub.15Cl.sub.3N.sub.2O.sub.2S+H+, 404.99925; found
(ESI-FTMS, [M+H].sup.1+), 404.9996.
Example 7AA
2-{4-[(3-chlorophenyl)sulfonyl]piperidin-1-yl}-3-(trifluoromethyl)pyridine
[0738] The title compound (161 mg, 69% yield) was prepared
according to a similar procedure described for example 7A.
[0739] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.86-2.01 (m,
2H), 2.01-2.13 (m, 2H), 2.88 (t, J=12.3 Hz, 2H), 3.03-3.14 (m, 1H),
3.69 (d, J=12.1 Hz, 2H), 7.03 (dd, J=7.2, 5.2 Hz, 1H), 7.55 (t,
J=7.8 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.86
(d, J=7.8 Hz, 1H), 7.91 (s, 1H), 8.42 (d, J=4.3 Hz, 1H). HRMS:
calcd for C.sub.17H.sub.16ClF.sub.3N.sub.2O.sub.2S+H+, 405.06458;
found (ESI-FTMS, [M+H].sup.1+), 405.0662.
Example 7AB
2-{4-[(3-chlorophenyl)sulfonyl]piperidin-1-yl}-5-(trifluoromethyl)pyridine
[0740] Step 7E: Using the procedure from Example 7A, Step 7E,
4-[(3-chlorophenyl)sulfonyl]piperidine (150 mg, 0.58 mmol) was
reacted with 2-chloro-5-(trifluoromethyl)pyridine (211 mg, 1.16
mmol), DIEA (0.3 ml, 1.74) and 1,4-dioxane (0.2 ml) to afford the
title compound (151 mg), a white solid, in 64% yield.
[0741] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.66-1.83 (m,
2H), 2.03-2.13 (m, 2H), 2.81-2.95 (m, 2H), 3.11-3.30 (m, 1H),
4.43-4.63 (m, 2H), 6.64 (d, J=9.1 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H),
7.59-7.70 (m, 2H), 7.78 (dd, J=7.8, 2.8 Hz, 1H), 7.88 (s, 1H), 8.38
(s, 1H). HRMS: calcd for
C.sub.17H.sub.16ClF.sub.3N.sub.2O.sub.2S+H+, 405.06458; found
(ESI-FTMS, [M+H].sup.1+), 405.0655.
Example 7AC
3-chloro-2-{4-[(3-chlorophenyl)sulfonyl]piperidin-1-yl}pyridine
[0742] Step 1: Using the procedure from Example 7A,
4-[(3-chlorophenyl)sulfonyl]piperidine (150 mg, 0.58 mmol) was
reacted with 2,3-dichloropyridine (173 mg, 1.16 mmol), DIEA (0.3
ml, 1.74) and 1,4-dioxane (0.2 ml) to afford the title compound (74
mg), a beige solid, in 34% yield.
[0743] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.90-2.01 (m,
2H), 2.05-2.13 (m, J=12.3, 2.1 Hz, 2H), 2.74-2.84 (m, 2H),
3.06-3.17 (m, 1H), 3.92-3.99 (m, 2H), 6.85 (dd, J=7.8, 4.8 Hz, 1H),
7.55 (t, J=8.1 Hz, 1H), 7.58 (dd, J=7.8, 1.8 Hz, 1H), 7.64-7.69 (m,
1H), 7.81 (dd, J=8.1, 1.3 Hz, 1H), 7.91 (s, 1H), 8.15 (dd, J=4.7,
1.6 Hz, 1H). HRMS: calcd for
C.sub.16H.sub.16Cl.sub.2N.sub.2O.sub.2S+H+, 371.03823; found
(ESI-FTMS, [M+H].sup.1+), 371.0399.
Example 7AD
3,5-dichloro-4-{4-[(3-chlorophenyl)sulfonyl]piperidin-1-yl}pyridine
[0744] Step 1: Using the procedure from Example 7A,
4-[(3-chlorophenyl)sulfonyl]piperidine (150 mg, 0.58 mmol) was
reacted with 3,4,5-trichloropyridine (216 mg, 1.16 mmol), DIEA (0.3
ml, 1.74) and 1,4-dioxane (0.2 ml) to afford the title compound (35
mg), a white solid, in 15% yield.
[0745] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.86-2.11 (m,
4H), 3.04-3.16 (m, 1H), 3.27 (t, J=12.3 Hz, 2H), 3.43 (d, J=13.4
Hz, 2H), 7.55 (t, J=7.8 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.81 (d,
J=7.8 Hz, 1H), 7.91 (s, 1H), 8.35 (s, 2H). HRMS: calcd for
C.sub.16H.sub.15Cl.sub.3N.sub.2O.sub.2S+H+, 404.99925; found
(ESI-FTMS, [M+H].sup.1+), 405.001.
Example 7AE
2-{4-[(3-chlorophenyl)sulfonyl]piperidin-1-yl}-3-nitropyridine
[0746] Step 1: Using the procedure from Example 7A,
4-[(3-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was
reacted with 2-chloro-3-nitropyridine (122 mg, 0.76 mmol), DIEA
(0.2 ml, 1.14) and 1,4-dioxane (0.3 ml) to afford the title
compound (118 mg), a yellow solid, in 81% yield.
[0747] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.79-1.96 (m,
2H), 2.02-2.12 (m, J=12.3, 2.7 Hz, 2H), 2.94-3.05 (m, 2H),
3.12-3.24 (m, 1H), 3.86-3.99 (m, 2H), 6.81 (dd, J=8.1, 4.5 Hz, 1H),
7.54 (t, J=7.7 Hz, 1H), 7.63-7.69 (m, 1H), 7.76-7.81 (m, 1H), 7.89
(s, 1H), 8.14 (dd, J=8.1, 1.8 Hz, 1H), 8.33 (dd, J=4.5, 1.8 Hz,
1H). HRMS: calcd for C.sub.16H.sub.16ClN.sub.3O.sub.4S+H+,
382.06228; found (ESI-FTMS, [M+H].sup.1+), 382.0624.
Example 7AF
2-{4-[(3-chlorophenyl)sulfonyl]piperidin-1-yl}-5-nitropyridine
[0748] Step 1: Using the procedure from Example 7A,
4-[(3-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was
reacted with 2-chloro-5-nitropyridine (122 mg, 0.76 mmol), DIEA
(0.2 ml, 1.14) and 1,4-dioxane (0.3 ml) to afford the title
compound (40 mg), a yellow solid, in 28% yield.
[0749] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.64-1.89 (m,
2H), 2.13 (dd, J=14.3, 1.9 Hz, 2H), 2.91-3.04 (m, 2H), 3.16-3.33
(m, 1H), 4.67 (d, J=13.6 Hz, 2H), 6.59 (d, J=11.0 Hz, 1H), 7.55 (t,
J=8.0 Hz, 1H), 7.61-7.72 (m, 1H), 7.74-7.81 (m, 1H), 7.88 (s, 1H),
8.22 (dd, J=9.5, 2.9 Hz, 1H), 9.02 (d, J=2.3 Hz, 1H). HRMS: calcd
for C.sub.16H.sub.16ClN.sub.3O.sub.4S+H+, 382.06228; found
(ESI-FTMS, [M+H].sup.1+), 382.0622.
Example 7AG
1-{4-[(3-chlorophenyl)sulfonyl]piperidin-1-yl}isoquinoline
[0750] Step 1: Using the procedure from Example 7A,
4-[(3-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was
reacted with 1-chloroisoquinoline (131 mg, 0.76 mmol), DIEA (0.2
ml, 1.14) and 1,4-dioxane (0.3 ml) to afford the title compound (4
mg), a beige solid, in 3% yield.
[0751] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.05-2.25 (broad,
m, 4H), 2.87-2.99 (m, 2H), 3.07-3.25 (m, 1H), 3.84-3.98 (m, J=12.6
Hz, 2H), 7.24-7.33 (m, 2H), 7.48-7.70 (m, 3H), 7.76 (d, J=8.3 Hz,
1H), 7.85 (d, J=7.8 Hz, 1H), 7.95 (s, 1H), 8.01 (d, J=8.6 Hz, 1H),
8.12 (d, J=5.6 Hz, 1H). HRMS: calcd for
C.sub.20H.sub.19ClN.sub.2O.sub.2S+H+, 387.09285; found (ESI-FTMS,
[M+H].sup.1+), 387.0933.
Example 7AH
2-{4-[(3-chlorophenyl)sulfonyl]piperidin-1-yl}nicotinonitrile
[0752] Step 1: Using the procedure from Example 7A,
4-[(3-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was
reacted with 2-chloro-3-cyanopyridine (108 mg, 0.76 mmol), DIEA
(0.2 ml, 1.14) and 1,4-dioxane (0.3 ml) to afford the title
compound (91 mg), a yellow solid, in 62% yield.
[0753] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.84-1.96 (m,
2H), 2.06-2.14 (m, 2H), 2.93-3.04 (m, 2H), 3.11-3.23 (m, 1H),
4.45-4.54 (m, 2H), 6.80 (dd, J=7.6, 4.8 Hz, 1H), 7.55 (t, J=8.0 Hz,
1H), 7.59-7.67 (m, 1H), 7.72-7.83 (m, 2H), 7.89 (s, 1H), 8.34 (dd,
J=4.8, 2.0 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.16ClN.sub.3O.sub.2S+H+, 362.07245; found (ESI-FTMS,
[M+H].sup.1+), 362.0737.
Example 7AI
2-{4-[(3-chlorophenyl)sulfonyl]piperidin-1-yl}-3-fluoropyridine
[0754] Step 1: Using the procedure from Example 7A,
4-[(3-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was
reacted with 2-chloro-3-fluoropyridine (100 mg, 0.76 mmol), DIEA
(0.2 ml, 1.14) and 1,4-dioxane (0.3 ml) to afford the title
compound (9 mg), a yellow solid, in 7% yield.
[0755] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.80-1.94 (m,
2H), 2.02-2.14 (m, 2H), 2.78-2.88 (m, 2H), 3.09-3.22 (m, 1H),
4.08-4.25 (m, 2H), 6.74-6.81 (m, 1H), 7.17-7.26 (m, 1H), 7.54 (t,
J=8.1 Hz, 1H), 7.61-7.70 (m, 1H), 7.75-7.84 (m, 1H), 7.90 (s, 1H),
7.94-8.04 (m, 1H). HRMS: calcd for
C.sub.16H.sub.16ClFN.sub.2O.sub.2S+H+, 355.06778; found (ESI-FTMS,
[M+H].sup.1+), 355.0693.
Example 7AJ
2-{4-[(4-chlorophenyl)sulfonyl]piperidin-1-yl
}-3-(trifluoromethylpyridine
[0756] Step 7E: The title compound (109 mg, 71% yield), a white
solid, was prepared according to a similar procedure described for
Example 7A.
[0757] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.85-1.98 (m,
2H), 1.99-2.13 (m, 2H), 2.87 (t, J=12.3 Hz, 2H), 2.95-3.15 (m, 1H),
3.67 (d, J=12.6 Hz, 2H), 6.95-7.09 (broad, m, 1H), 7.57 (d, J=8.3
Hz, 2H), 7.85 (d, J=5.1 Hz, 3H), 8.41 (broad, s, 1H). HRMS: calcd
for C.sub.17H.sub.16ClF.sub.3N.sub.2O.sub.2S+H+, 405.06458; found
(ESI-FTMS, [M+H].sup.1+), 405.0649.
Example 7AK
2-{4-[(4-chlorophenyl)sulfonyl]piperidin-1-yl}-5-(trifluoromethyl)pyridine
[0758] Step 1: Using the procedure from Example 7A,
4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was
reacted with 2-chloro-5-(trifluoromethyl)pyridine (138 mg, 0.76
mmol), DIEA (0.27 ml, 1.52 mmol) and 1,4-dioxane (0.3 ml) at
190.degree. C. to afford the title compound (112 mg), a white
solid, in 73% yield.
[0759] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.65-1.84 (m,
2H), 2.09 (d, J=13.4 Hz, 2H), 2.88 (t, J=12.9 Hz, 2H), 3.11-3.25
(m, 1H), 4.55 (d, J=14.9 Hz, 2H), 6.63 (d, J=8.3 Hz, 1H), 7.57 (d,
J=6.8 Hz, 2H), 7.62 (d, J=8.8 Hz, 1H), 7.82 (d, J=8.8 Hz, 2H), 8.37
(s, 1H). HRMS: calcd for
C.sub.17H.sub.16ClF.sub.3N.sub.2O.sub.2S+H+, 405.06458; found
(ESI-FTMS, [M+H].sup.1+), 405.0663.
Example 7AL
3-chloro-2-{4-[(4-chlorophenyl)sulfonyl]piperidin-1-yl}pyridine
[0760] Step 7E: Using the procedure from Example 7A,
4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was
reacted with 2,3-dichloropyridine (114 mg, 0.76 mmol), DIEA (0.27
ml, 1.52) and 1,4-dioxane (0.3 ml) at 190.degree. C. to afford the
title compound (56 mg), a white solid, in 40% yield.
[0761] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.79-1.97 (m,
2H), 2.02-2.22 (m, 2H), 2.77 (t, J=12.6 Hz, 2H), 2.97-3.19 (m, 1H),
3.94 (d, J=11.6 Hz, 2H), 6.71-6.95 (m, 1H), 7.58 (d, J=7.6 Hz, 3H),
7.85 (d, J=8.3 Hz, 2H), 8.15 (s, 1H). HRMS: calcd for
C.sub.16H.sub.16Cl.sub.2N.sub.2O.sub.2S+H+, 371.03823; found
(ESI-FTMS, [M+H].sup.1+), 371.0385.
Example 7AM
3,5-dichloro-4-{4-[(4-chlorophenyl)sulfonyl]piperidin-1-yl}pyridine
[0762] Step 1: Using the procedure from Example 7A,
4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was
reacted with 3,4,5-trichloropyridine (141 mg, 0.76 mmol), DIEA
(0.27 ml, 1.52) and 1,4-dioxane (0.3 ml) at 190.degree. C. to
afford the title compound (51 mg), a white solid, in 33% yield.
[0763] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.86-2.00 (m,
2H), 2.01-2.13 (m, 2H), 2.97-3.13 (m, 1H), 3.25 (t, J=12.3 Hz, 2H),
3.42 (d, J=12.4 Hz, 2H), 7.58 (d, 2H), 7.76-7.91 (m, 2H), 8.34 (s,
2H). HRMS: calcd for C.sub.16H.sub.15Cl.sub.3N.sub.2O.sub.2S+H+,
404.99925; found (ESI-FTMS, [M+H].sup.1+), 405.0012.
Example 7AN
1-{4-[(4-chlorophenyl)sulfonyl]piperidin-1-yl}isoquinoline
[0764] Step 1: Using the procedure from Example 7A,
4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was
reacted with 1-chloroisoquinoline (131 mg, 0.76 mmol), DIEA (0.27
ml, 1.52) and 1,4-dioxane (0.3 ml) at 190.degree. C. to afford the
title compound (15 mg), an off-white solid, in 10% yield.
[0765] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.00-2.19 (m,
4H), 2.81-2.99 (m, 2H), 3.05-3.28 (m, 1H), 3.92 (d, J=13.1 Hz, 2H),
7.27 (d, J=6.1 Hz, 1H), 7.43-7.54 (m, 1H), 7.56-7.64 (m, 3H), 7.75
(d, J=8.1 Hz, 1H), 7.81-7.94 (m, 2H), 8.00 (d, J=9.1 Hz, 1H), 8.12
(d, J=5.8 Hz, 1H). HRMS: calcd for
C.sub.20H.sub.19ClN.sub.2O.sub.2S+H+, 387.09285; found (ESI-FTMS,
[M+H].sup.1+), 387.0935.
Example 7AO
2-{4-[(4-chlorophenyl)sulfonyl]piperidin-1-yl}quinoline
[0766] Step 1: Using the procedure from Example 1A,
4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was
reacted with 2-chloroquinoline (124 mg, 0.76 mmol), DIEA (0.27 ml,
1.52) and 1,4-dioxane (0.3 ml) at 190.degree. C. to afford the
title compound (11 mg), a white solid, in 8% yield.
[0767] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.69-1.85 (m,
2H), 2.13 (d, J=13.1 Hz, 2H), 2.91 (t, J=13.3 Hz, 2H), 3.08-3.27
(m, 1H), 4.71 (d, J=13.9 Hz, 2H), 6.96 (d, J=7.8 Hz, 1H), 7.20-7.30
(m, 1H), 7.46-7.62 (m, 4H), 7.68 (d, J=8.6 Hz, 1H), 7.83 (d, J=8.3
Hz, 2H), 7.89 (d, J=9.3 Hz, 1H). HRMS: calcd for
C.sub.20H.sub.19ClN.sub.2O.sub.2S+H+, 387.09285; found (ESI-FTMS,
[M+H].sup.1+), 387.0947.
Example 7AP
2-{4-[(4-chlorophenyl)sulfonyl]piperidin-1-yl}-3-fluoropyridine
[0768] Step 1: Using the procedure from Example 7A,
4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was
reacted with 2-chloro-3-fluoropyridine (78 .mu.l, 0.76 mmol), DIEA
(0.27 ml, 1.52) and 1,4-dioxane (0.3 ml) at 190.degree. C. to
afford the title compound (18 mg), a white solid, in 13% yield.
[0769] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.75-1.92 (m,
2H), 2.01-2.13 (m, 2H), 2.67-2.88 (m, 2H), 3.04-3.18 (m, 1H),
4.14-4.23 (m, 2H), 6.71-6.81 (m, 1H), 7.17-7.26 (m, 1H), 7.51-7.61
(m, 2H), 7.79-7.87 (m, 2H), 7.93-8.02 (m, 1H). HRMS: calcd for
C.sub.16H.sub.16ClFN.sub.2O.sub.2S+H+, 355.06778; found (ESI-FTMS,
[M+H].sup.1+), 355.0691.
Example 7AQ
2-{4-[(4-chlorophenyl)sulfonyl]piperidin-1-yl}-4-(trifluoromethyl)pyridine
[0770] Step 1: Using the procedure from Example 1A,
4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was
reacted with 2-chloro-4-(trifluoromethyl)pyridine (99 .mu.l, 0.76
mmol), DIEA (0.27 ml, 1.52) and 1,4-dioxane (0.3 ml) at 190.degree.
C. to afford the title compound (49 mg), an off-white solid, in 32%
yield.
[0771] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.66-1.82 (m,
2H), 2.10 (dd, J=13.9, 3.3 Hz, 2H), 2.75-2.93 (m, 2H), 3.08-3.24
(m, 1H), 4.50 (d, J=13.6 Hz, 2H), 6.73-6.83 (m, 2H), 7.50-7.62 (m,
2H), 7.76-7.87 (m, 2H), 8.28 (d, J=5.1 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.16ClF.sub.3N.sub.2O.sub.2S+H+, 405.06458; found
(ESI-FTMS, [M+H].sup.1+), 405.0665.
Example 7AR
2-{4-[(4-tert-butylphenyl)sulfonyl]piperidin-1-yl}-3-(trifluoromethyl)pyri-
dine
[0772] The title compound (75 mg, 49% yield), a white solid, was
obtained according to a similar procedure described for Example
7A.
[0773] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.37 (s, 9H),
1.85-2.01 (m, 2H), 2.01-2.17 (m, 2H), 2.69-2.89 (m, 2H), 2.94-3.16
(m, 1H), 3.69 (d, J=13.1 Hz, 2H), 7.01 (dd, J=7.8, 4.8 Hz, 1H),
7.48-7.65 (m, 2H), 7.75-7.94 (m, 3H), 8.41 (d, J=4.8 Hz, 1H). HRMS:
calcd for C.sub.21H.sub.25F.sub.3N.sub.2O.sub.2S+H+, 427.16616;
found (ESI-FTMS, [M+H].sup.1+), 427.1666.
Example 7AS
2-{4-[(4-tert-butylphenyl)sulfonyl]piperidin-1-yl}-5-(trifluoromethyl)pyri-
dine
[0774] The title compound (119 mg), an off-white solid, was
obtained in 77% yield according to a similar procedure described
for example 7A.
[0775] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.36 (s, 9H),
1.67-1.81 (m, 2H), 2.05-2.17 (m, 2H), 2.83-2.93 (m, 2H), 3.11-3.24
(m, 1H), 4.54 (d, J=13.6 Hz, 2H), 6.63 (d, J=9.1 Hz, 1H), 7.54-7.59
(m, 2H), 7.60-7.66 (m, 1H), 7.71-7.85 (m, 2H), 8.36 (s, 1H). HRMS:
calcd for C.sub.21H.sub.25F.sub.3N.sub.2O.sub.2S+H+, 427.16616;
found (ESI-FTMS, [M+H].sup.1+), 427.1675.
Example 7AT
2-{4-[(4-tert-butylphenyl)sulfonyl]piperidin-1-yl}-3-chloropyridine
[0776] Step 1: Using the procedure from Example 7A,
4-[(4-tert-butylphenyl)sulfonyl]piperidine (100 mg, 0.36 mmol) was
reacted with 2,3-dichloropyridine (108 mg, 0.72 mmol), DIEA (0.25
ml, 1.44) and 1,4-dioxane (0.3 ml) at 185.degree. C. to afford the
title compound (40 mg), a white solid, in 28% yield.
[0777] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.37 (s, 9H),
1.88-2.02 (m, 2H), 2.10 (dd, J=12.1, 2.0 Hz, 2H), 2.68-2.85 (m,
2H), 3.00-3.20 (m, 1H), 3.94 (d, J=13.1 Hz, 2H), 6.84 (dd, J=7.8,
4.8 Hz, 1H), 7.49-7.63 (m, 3H), 7.83 (d, J=8.6 Hz, 2H), 8.15 (dd,
J=4.8, 1.5 Hz, 1H). HRMS: calcd for
C.sub.20H.sub.25ClN.sub.2O.sub.2S+H+, 393.13980; found (ESI-FTMS,
[M+H].sup.1+), 393.141.
Example 7AU
4-{4-[(4-tert-butylphenyl)sulfonyl]piperidin-1-yl}-3,5-dichloropyridine
[0778] Step 1: Using the procedure from Example 7A,
4-[(4-tert-butylphenyl)sulfonyl]piperidine (100 mg, 0.36 mmol) was
reacted with 3,4,5-trichloropyridine (134 mg, 0.72 mmol), DIEA
(0.25 ml, 1.44) and 1,4-dioxane (0.3 ml) at 185.degree. C. to
afford the title compound (16 mg), a white solid, in 10% yield.
[0779] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.37 (s, 9H),
1.90-2.03 (m, 2H), 2.03-2.11 (m, 2H), 3.02-3.12 (m, 1H), 3.18-3.31
(m, 2H), 3.37-3.48 (m, 2H), 7.60 (d, J=8.8 Hz, 2H), 7.83 (d, J=8.6
Hz, 2H), 8.33 (s, 2H). HRMS: calcd for
C.sub.20H.sub.24Cl.sub.2N.sub.2O.sub.2S+H+, 427.10083; found
(ESI-FTMS, [M+H].sup.1+), 427.1028.
Example 7AV
1-{4-[(4-tert-butylphenyl)sulfonyl]piperidin-1-yl}isoquinoline
[0780] Step 1: Using the procedure from Example 7A,
4-[(4-tert-butylphenyl)sulfonyl]piperidine (150 mg, 0.53 mmol) was
reacted with 1-chloroisoquinoline (183 mg, 1.06 mmol), DIEA (0.37
ml, 2.12) and 1,4-dioxane (0.2 ml) at 185.degree. C. to afford the
title compound (40 mg), a white solid, in 18% yield.
[0781] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.38 (s, 9H),
2.08-2.21 (m, 4H), 2.84-2.97 (m, 2H), 3.04-3.21 (m, 1H), 3.92 (d,
J=12.9 Hz, 2H), 7.23-7.28 (m, 1H), 7.48-7.54 (m, 1H), 7.58-7.66 (m,
3H), 7.75 (d, J=8.1 Hz, 1H), 7.87 (d, J=8.3 Hz, 2H), 8.01 (d, J=8.3
Hz, 1H), 8.11 (d, J=-5.8 Hz, 1H). HRMS: calcd for
C.sub.24H.sub.29N.sub.2O.sub.2S+H+, 409.19442; found (ESI-FTMS,
[M+H].sup.1+), 409.1959.
Example 7AX
2-{4-[(4-tert-butylphenyl)sulfonyl]piperidin-1-yl}quinoline
[0782] Step 1: Using the procedure from Example 7A,
4-[(4-tert-butylphenyl)sulfonyl]piperidine (150 mg, 0.53 mmol) was
reacted with 2-chloroquinoline (175 mg, 1.06 mmol), DIEA (0.37 ml,
2.12) and 1,4-dioxane (0.2 ml) at 185.degree. C. to afford the
title compound (39 mg), a white solid, in 18% yield.
[0783] .sup.1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.35 (s,
9H), 1.70-1.86 (m, 2H), 2.15 (d, J=12.9 Hz, 2H), 2.83-2.96 (m, 2H),
3.13-3.23 (m, 1H), 4.69 (d, J=13.6 Hz, 2H), 6.95 (d, J=9.1 Hz, 1H),
7.20-7.28 (m, 1H), 7.50-7.61 (m, 4H), 7.67 (d, J=8.3 Hz, 1H), 7.80
(d, J=8.3 Hz, 2H), 7.88 (d, J=9.3 Hz, 1H). HRMS: calcd for
C.sub.24H.sub.28N.sub.2O.sub.2S+H+, 409.19442; found (ESI-FTMS,
[M+H].sup.1+), 409.1952.
Example 7AY
2-{4-[(4-tert-butylphenyl)sulfonyl]piperidin-1-yl}-3-fluoropyridine
[0784] Step 1: Using the procedure from Example 7A,
4-[(4-tert-butylphenyl)sulfonyl]piperidine (100 mg, 0.36 mmol) was
reacted with 2-chloro-3-fluoropyridine (74 .mu.l, 0.72 mmol), DIEA
(0.25 ml, 1.44) and 1,4-dioxane (0.3 ml) at 185.degree. C. to
afford the title compound (13 mg), a white solid, in 10% yield.
[0785] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.36 (s, 9H),
1.79-1.92 (m, 2H), 2.10 (d, J=12.9 Hz, 2H), 2.78-2.87 (m, 2H),
3.05-3.17 (m, 1H), 4.18 (d, J=13.1 Hz, 2H), 6.72-6.78 (m, 1H),
7.17-7.25 (m, 1H), 7.58 (d, J=8.6 Hz, 2H), 7.81 (d, J=8.3 Hz, 2H),
7.95-7.99 (m, 1H). HRMS: calcd for
C.sub.20H.sub.25FN.sub.2O.sub.2S+H+, 377.16935; found (ESI-FTMS,
[M+H].sup.1+), 377.1705.
Example 7AZ
2-{4-[(4-tert-butylphenyl)sulfonyl]piperidin-1-yl}-4-(trifluoromethyl)pyri-
dine
[0786] Step 1: Using the procedure from Example 7A,
4-[(4-tert-butylphenyl)sulfonyl]piperidine (100 mg, 0.36 mmol) was
reacted with 2-chloro-4-(trifluoromethyl)pyridine (94 .mu.l, 0.72
mmol), DIEA (0.25 ml, 1.44) and 1,4-dioxane (0.3 ml) at 185.degree.
C. to afford the title compound (60 mg), an off-white solid, in 39%
yield.
[0787] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.36 (s, 9H),
1.68-1.82 (m, 2H), 2.12 (d, J=11.4 Hz, 2H), 2.82-2.92 (m, 2H),
3.11-3.22 (m, 1H), 4.49 (d, J=13.1 Hz, 2H), 6.75-6.79 (m, J=3.5 Hz,
2H), 7.58 (d, J=8.6 Hz, 2H), 7.80 (d, J=8.3 Hz, 2H), 8.27 (d, J=5.6
Hz, 1H). HRMS: calcd for C.sub.21H.sub.25F.sub.3N.sub.2O.sub.2S+H+,
427.16616; found (ESI-FTMS, [M+H].sup.1+), 427.1681.
Example 7BB
2-{4-[(4-tert-butylphenyl)sulfonyl]piperidin-1-yl}-3-methylpyridine
[0788] The title compound (90 mg), a white solid, was obtained in
67% yield according to a similar procedure described for example
7A.
[0789] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.37 (s, 9H),
1.87-2.02 (m, 2H), 2.05-2.14 (m, 2H), 2.24 (s, 3H), 2.69-2.80 (m,
2H), 3.01-3.12 (m, 1H), 3.53 (dd, J=10.6, 2.0 Hz, 2H), 6.86 (dd,
J=7.3, 4.8 Hz, 1H), 7.35-7.42 (m, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.83
(d, J=8.6 Hz, 2H), 8.12 (dd, J=5.2, 1.6 Hz, 1H). HRMS: calcd for
C.sub.21H.sub.28N.sub.2O.sub.2S+H+, 373.19442; found (ESI-FTMS,
[M+H].sup.1+), 373.1941.
Example 7BC
4-[(4-tert-butylphenyl)sulfonyl]-1-(2-methylphenyl)piperidine
[0790] Step 1: Using the procedure from Example 7A,
4-[(4-tert-butylphenyl)sulfonyl]piperidine (100 mg, 0.36 mmol) was
reacted with 2-bromotoluene (53 .mu.l, 0.43 mmol) to afford the
title compound (59 mg), a yellow solid, in 44% yield.
[0791] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.37 (s, 9H),
1.90-2.01 (m, 2H), 2.04-2.12 (m, 2H), 2.26 (s, 3H), 2.53-2.66 (m,
2H), 2.94-3.08 (m, 1H), 3.22 (d, J=1.9 Hz, 2H), 6.90-7.02 (m, 2H),
7.10-7.18 (m, 2H), 7.59 (d, J=8.6 Hz, 2H), 7.83 (d, J=8.8 Hz, 2H).
HRMS: calcd for C.sub.22H.sub.29NO.sub.2S+H+, 372.19917; found
(ESI-FTMS, [M+H].sup.1+), 372.1988.
Example 7BD
4-[(4-tert-butylphenyl)sulfonyl]-1-[2-(trifluoromethyl)phenyl]piperidine
[0792] Step 7E: Using the procedure from Example 7A,
4-[(4-tert-butylphenyl)sulfonyl]piperidine (100 mg, 0.36 mmol) was
reacted with 2-bromobenzotrifluoride (59 .mu.l, 0.43 mmol) to
afford the title compound (26 mg), a white solid, in 17% yield.
[0793] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.37 (s, 9H),
1.90-2.02 (m, 2H), 2.02-2.10 (m, 2H), 2.63-2.74 (m, 2H), 2.95-3.05
(m, 1H), 3.17 (d, J=11.6 Hz, 2H), 7.22 (t, J=7.7 Hz, 1H), 7.24-7.29
(m, 1H), 7.49 (t, J=7.1 Hz, 1H), 7.56-7.63 (m, 3H), 7.83 (d, J=8.8
Hz, 2H). HRMS: calcd for C.sub.22H.sub.26F.sub.3NO.sub.2S+H+,
426.17091; found (ESI-FTMS, [M+H].sup.1+), 426.1706.
Example 8
4-(3-chloropyridin-2-yl)-1-[(3,4-dichlorophenyl)sulfonyl]-cis-2,6-dimethyl-
piperazine
[0794] Step 8A: 2,6-dimethylpiperazine (291 mg, 2.55 mmol) and
2,3-dichloropyridine (377.4 mg, 2.55 mmol) were charged to a
microwave vial, dissolved in DMF (0.25 mL) and added with
diisopropylethylamine (1.1 mL, 6.38 mmol). The reaction mixture was
irradiated at 165.degree. C. for 30 minutes. The reaction was
complete as determined by TLC. After solvent removal the crud
product was purified via flush column chromatography to afford
1-(3-chloropyridin-2-yl)-3,5-dimethylpiperazine in 64.4% yield (370
mg).
[0795] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.18 (d, J=6.32
Hz, 6H) 2.40-2.63 (m, 2H) 3.02-3.24 (m, 2H) 3.66-3.82 (m, 2H) 6.83
(dd, J=7.58, 4.80 Hz, 1H) 7.58 (dd, J=7.71, 1.64 Hz, 1H) 8.18 (dd,
J=4.80, 1.77 Hz, 1H).
[0796] Step 8B: 1-(3-chloropyridin-2-yl)-3,5-dimethylpiperazine
(370 mg, 1.644 mmol) was dissolved in anhydrous dichloromethane (6
mL) added with 3,4-dichlorobenzene sulfonyl chloride (509 mg, 1.97
mmol) and diisopropylethylamine (0.72 mL, 4.11 mmol). The reaction
mixture thus prepared was stirred overnight at room temperature.
The reaction was complete as determined by TLC. It was purified via
flush column chromatography to afford
4-(3-chloropyridin-2-yl)-1-[(3,4-dichlorophenyl)sulfonyl]-2,6-dimethylpip-
erazin in 13% yield (110 mg) as a sticky solid.
[0797] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.60 (d, J=6.82
Hz, 6H) 2.69 (dd, J=12.38, 4.29 Hz, 2H) 3.56 (d, J=12.38 Hz, 2H)
4.01-4.36 (m, 2H) 6.90 (dd, J=7.83, 4.80 Hz, 1H) 7.56 (d, J=8.34
Hz, 1H) 7.61 (d, J=6.06 Hz, 1H) 7.66 (d, J=8.34 Hz, 1H) 7.94 (s,
1H) 8.15 (d, J=6.57 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.18Cl.sub.3N.sub.3O.sub.2S+H+, 434.02580; found
(ESI-FTMS, [M+H].sup.1+), 434.0272.
Example 9
##STR00044##
[0798] Example 9A
1-[3,4-dichlorophenyl)sulfonyl]-4-[4-fluoro-2-trifluoromethyl)phenyl]piper-
azine
[0799] Step 9A: A mixture of tert-butyl piperazine-1-carboxylate
1.04 g, (5.6 mmol), 2-bromo-5-fluoro benzotrifluoride (1.21 g, 5.0
mmol), tris(dibenzylidineacetone)dipalladium (0) (45.8 mg, 0.05
mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (93.4 mg,
0.15 mmol) and sodium tert-butoxide (600 mg, 6.25 mmol) were
charged to a microwave vial. Toluene (10.0 mL) was introduced under
nitrogen atmosphere and the reaction mixture was irradiated at
110.degree. C. for 30 minutes. Reaction was complete as determined
by TLC. The reaction was repeated four times. Reaction mixtures
were combined, diluted with ethylacetate, washed with water,
saturated brine then dried over MgSO.sub.4 and concentrated. The
crude product was purified via flash column chromatography to yield
tert-butyl-4-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate
in quantitative yield (6.8 g) as yellow oil.
[0800] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.49 (s, 9H) 2.82
(t, J=4.80 Hz, 4H) 3.55 (s, 4H) 7.15-7.26 (m, 1H) 7.27-7.39 (m,
2H). HPLC Method 1: room temperature, 7.000 min, 96.34%. HPLC
Method 2: room temperature, 7.609 min, 97.90%.
[0801] Step 9B: To a stirred solution of
tert-butyl-4-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate
(6.8 g, 19.5 mmol) in anhydrous dichloromethane (90 mL) was added
TFA (45 mL) dropwise at 0.degree. C. The reaction mixture was
stirred at 0.degree. C. for 15 minutes then the cooling bath was
removed and it was allowed to stir at room temperature for 2 hours.
Reaction was complete as determined by TLC. Most of TFA was
azeotropped with dichloroethane. The residue was then diluted with
dichloromethane and washed with saturated Na.sub.2CO.sub.3 (aq.).
Organic layer was dried over MgSO.sub.4. Solvent evaporation
afforded 1-(4-fluoro-2-trifluoromethyl)phenyl)piperazine in 79.9%
yield (3.86 g) as light brown oil. 1H NMR (400 MHz, CHLOROFORM-D)
.delta. ppm 2.78-2.90 (m, 4H) 2.96-3.04 (m, 4H) 7.18-7.25 (m, 1H)
7.29-7.42 (m, 2H).
[0802] Step 9C: To a stirred solution of
1-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine (386 mg, 1.555
mmol) and 3,4-dichlorobenzene-1-sulfonyl chloride (381.8 mg, 1.555
mmol) in anhydrous dichloromethane (3 mL) was added
diisopropylethylamine (1.35 mL, 7.775 mmol). The mixture was
stirred at room temperature for 30 minutes. Reaction was complete
as determined by TLC. The reaction mixture was diluted with
dichloromethane, washed with saturated Na.sub.2CO.sub.3 (aq.),
water then brine. Organic layer was dried over MgSO.sub.4. The
reaction mixture was purified via flash column chromatography to
yield
1-[(3,4-dichlorophenyl)sulfonyl]-4-[4-fluoro-2-trifluoromethyl)phenyl]pip-
erazine in 75.7% yield (538 mg) as white solid.
[0803] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 2.93 (t, J=4.67 Hz,
4H) 3.08 (s, 4H) 7.47-7.61 (m, 2H) 7.68-7.82 (m, 2H) 7.94-8.04 (m,
2H). HRMS: calcd for
C.sub.17H.sub.14Cl.sub.2F.sub.4N.sub.2O.sub.2S+H+, 457.01619; found
(ESI-FTMS, [M+H].sup.1+), 457.0168. HPLC Method 1: room
temperature, 7.212 min, 99.42%. HPLC Method 2: room temperature,
7.768 min, 99.76%.
Example 9B
1-[(2-chlorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]piperaz-
ine
[0804] Step 9C: Sulfonylation of
1-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine (386 mg, 1.55
mmol) with 2-chlorobenzene-1-sulfonyl chloride (382.2 mg, 1.555
mmol) was carried out according to a similar to the representative
sulfonation procedure described in Example 1 using anhydrous
dichloromethane (3 mL) as solvent and diisopropylethylamine (1.35
mL, 7.775 mmol) as base.
1-[(2-chlorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]pipera-
zine was obtained in 73.3% yield (481.8 mg) as white solid.
[0805] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 2.90 (t, J=4.67 Hz,
4H) 3.27 (s, 4H) 7.50-7.57 (m, 2H) 7.57-7.65 (m, 1H) 7.66-7.79 (m,
3H) 8.01 (dd, J=7.83, 1.52 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.15ClF.sub.4N.sub.2O.sub.2S+H+, 423.05516; found
(ESI-FTMS, [M+H].sup.1+), 423.0558. HPLC Method 1: room
temperature, 6.787 min, 98.54%. HPLC Method 2: room temperature,
7.371 min, 99.64%.
Example 9C
1-[(4-chlorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]piperaz-
ine
[0806] Step 9C: Sulfonylation of
1-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine (386 mg, 1.55
mmol) with 4-chlorobenzene-1-sulfonyl chloride (328.2 mg, 1.555
mmol) was carried out according to the representative sulfonation
procedure described in Example 1 using anhydrous dichloromethane (3
mL) as solvent and diisopropylethylamine (1.35 mL, 7.775 mmol) as
base.
1-[(4-chlorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]pipera-
zine was obtained in 69.2% yield (455 mg) as white solid.
[0807] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 2.93 (t, J=4.29 Hz,
4H) 3.02 (s, 4H) 7.48-7.60 (m, 2H) 7.73 (dd, J=8.72, 5.18 Hz, 1H)
7.75-7.85 (m, 4H). HRMS: calcd for
C.sub.17H.sub.15ClF.sub.4N.sub.2O.sub.2S+H+, 423.05516; found
(ESI-FTMS, [M+H].sup.1+), 423.0557. HPLC Method 1: room
temperature, 6.908 min, 95.67%. HPLC Method 2: room temperature,
7.474 min, 99.78%.
Example 9D
1-[(5-chloro-2-naphthyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]pi-
perazine
[0808] Step 1C: Sulfonylation of
1-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine (193 mg, 3.888
mmol) with 5-chloronaphthalene-2-sulfonyl chloride (202.1 mg, 0.777
mmol) was carried out according to the representative sulfonation
procedure described in Example 1 using anhydrous dichloromethane (3
mL) as solvent and diisopropylethylamine (0.7 mL, 3.887 mmol) as
base.
1-[(5-chloro-2-naphthyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]p-
iperazine was obtained in 69% yield (256 mg) as white solid.
[0809] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 2.94 (t, J=4.55 Hz,
4H) 3.09 (s, 4H) 7.41-7.59 (m, 2H) 7.64-7.79 (m, 2H) 7.97 (dd,
J=6.95, 5.94 Hz, 2H) 8.29 (d, J=8.34 Hz, 1H) 8.45 (d, J=8.84 Hz,
1H) 8.61 (d, J=1.77 Hz, 1H). HRMS: calcd for
C.sub.21H.sub.17ClF.sub.4N.sub.2O.sub.2S+H+, 473.07081; found
(ESI-FTMS, [M+H].sup.1+), 473.0715. HPLC Method 1: room
temperature, 7.443 min, 99.05%. HPLC Method 2: room temperature,
7.909 min, 99.73%.
Example 9E
1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-4-[5-fluoro-2-(trifluoro-
methyl)phenyl]piperazine
[0810]
1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-4-[5-fluoro-2-(tr-
ifluoromethyl)phenyl]piperazine was prepared in a similar fashion
as described in step 9C for example 9A.
[0811] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.71 (s, 3H)
2.96-3.08 (m, 4H) 3.38 (d, 4H) 6.95 (dd, J=16.17, 2.27 Hz, 1H) 7.02
(dd, J=9.73, 2.40 Hz, 1H) 7.49 (dd, J=8.59, 2.02 Hz, 1H) 7.61 (dd,
J=8.84, 6.06 Hz, 1H) 7.79 (d, J=8.59 Hz, 1H) 7.84 (d, J=2.02 Hz,
1H). HRMS: calcd for
C.sub.20H.sub.17ClF.sub.4N.sub.2O.sub.2S.sub.2+H+, 493.04288; found
(ESI-FTMS, [M+H].sup.1+), 493.0433.
Example 9F
1-[4-fluoro-2-(trifluoromethyl)phenyl]-4-(2-naphthylsulfonyl)piperazine
[0812]
1-[4-fluoro-2-(trifluoromethyl)phenyl]-4-(2-naphthylsulfonyl)pipera-
zine was prepared in a similar fashion as described in step 9C for
example 9A. Yield 25%.
[0813] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 2.93 (t, J=4.67 Hz,
4H) 3.07 (s, 4H) 7.46-7.59 (m, 2H) 7.66-7.84 (m, 4H) 8.12 (d,
J=8.08 Hz, 1H) 8.23 (t, J=9.22 Hz, 2H) 8.49 (s, 1H). HRMS: calcd
for C.sub.21H.sub.18F.sub.4N.sub.2O.sub.2S+H+, 439.10979; found
(ESI-FTMS, [M+H].sup.1+), 439.1092; HPLC Method 1, room
temperature, 6.97 min, 92.19%; HPLC method 2, room temperature,
7.54 min, 96.62%.
Example 10
##STR00045##
[0815] Step 10A. A solution of tert-butyl
4-hydroxypiperidine-1-carboxylate (3.7 g, 23 mmol) and triphenyl
phosphine (12.23 g, 46 mmol) in 50 ml THF was mixed in an
ice-H.sub.2O bath. A solution of diethyl azodicarboxylate (8.37 g,
46 mmol) in 50 ml THF was added drop-wise, followed by
2,6-dichlorophenol (3.87 g, 23 mmol). The mixture was warmed up to
room temperature and stirred for 22 hr. Solvent was removed under
vacuum and crude product was purified with column chromatography.
tert-Butyl 4-(2,6-dichlorophenoxy)piperidine-1-carboxylate was
obtained in 75% yield.
[0816] Step 10B. tert-Butyl
4-(2,6-dichlorophenoxy)piperidine-1-carboxylate (5.54 g) was mixed
with 50 ml of mixture of TFA and CH.sub.2Cl.sub.2 (1:1). The
mixture was stirred at room temperature for 4 hours. The solvents
were removed under vacuum residue was Freeze-dried using
CH.sub.3CN/water system. The desired
4-(2,6-dichlorophenoxy)piperidine was obtained as TFA salt (white
solid) in 100% yield.
[0817] Step 10C: piperazine or piperidine (0.5 mmol) was mixed with
2 ml of CH.sub.2Cl.sub.2 and diisopropylethyl amine (1 mmol), aryl
sulfonyl chloride (0.5 mmol) was added in one portion. The reaction
mixture was stirred at room temperature, and progress of the
reaction was monitored by TLC. When the reaction was completed, the
reaction mixture was loaded onto silica gel column the product was
isolated and purified by column chromatography. The following
compounds were prepared using this general procedure.
Example 10A
N-(4-{[4-(2,6-dichlorophenoxy)piperidin-1-yl]sulfonyl}phenyl)acetamide
[0818] The desired product was obtained in 34% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.85-2.15 (m, 4H)
2.18-2.29 (m, 3H) 2.91-3.08 (m, 2H) 3.33-3.51 (m, 2H) 4.21-4.40 (m,
1H) 6.96 (t, 1H) 7.27 (d, 2H) 7.42 (s, 1H) 7.64-7.78 (m, 4H). HRMS:
calcd for C.sub.19H.sub.20Cl.sub.2N.sub.2O.sub.4S+H+, 443.05936;
found (ESI-FTMS, [M+H].sup.1+), 443.0592.
Example 10B
4-(2,6-dichlorophenoxy)-1-[(3,4-dimethoxyphenyl)sulfonyl]piperidine
[0819] The desired product was obtained in 42% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.88-2.22 (m, 4H)
2.91-3.08 (m, 2H) 3.28-3.55 (m, 2H) 3.94 (d, J=7.58 Hz, 6H)
4.26-4.45 (m, 1H) 6.93-7.02 (m, 2H) 7.21-7.31 (m, 3H) 7.40 (dd,
J=8.34, 2.02 Hz, 1H). HRMS: calcd for
C.sub.19H.sub.21Cl.sub.2NO.sub.5S+H+, 446.05902; found (ESI-FTMS,
[M+H].sup.1+), 446.0585.
Example 10C
4-(2,6-dichlorophenoxy)-1-[(3,4-dichlorophenyl)sulfonyl]piperidine
[0820] The desired product was obtained in 48% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.89-2.23 (m, 4H)
2.98-3.18 (m, 2H) 3.34-3.50 (m, 2H) 4.29-4.46 (m, 1H) 6.97 (t, 1H)
7.24-7.27 (m, 2H) 7.59-7.64 (m, 2H) 7.88 (d, J=1.77 Hz, 1H). HRMS:
calcd for C.sub.17H.sub.15Cl.sub.4NO.sub.3S+H+, 453.95995; found
(ESI-FTMS, [M+H].sup.1+), 453.959.
Example 10D
4-(2,6-dichlorophenoxy)-1-[(2,4-difluorophenyl)sulfonyl]piperidine
[0821] The desired product was obtained in 36% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.83-2.18 (m, 4H)
3.18-3.40 (m, 2H) 3.55-3.72 (m, 2H) 4.32-4.50 (m, 1H) 6.89-7.12 (m,
3H) 7.27 (d, J=3.28 Hz, 2H) 7.46-7.59 (m, 1H). HRMS: calcd for
C.sub.17H.sub.15Cl.sub.2F.sub.2NO.sub.3S+H+, 422.01905; found
(ESI-FTMS, [M+H].sup.1+), 422.0187.
Example 10E
1-[(3,4-dichlorobenzyl)sulfonyl]-4-(2,6-dichlorophenoxy)piperidine
[0822] The desired product was obtained in 58% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.82-2.10 (m, 4H)
3.11-3.32 (m, 2H) 3.37-3.66 (m, 2H) 4.34-4.52 (m, 1H) 6.99 (t, 1H)
7.25-7.27 (m, 1H) 7.27-7.30 (m, 2H) 7.47 (d, J=8.34 Hz, 1H) 7.53
(d, J=2.02 Hz, 1H). HRMS: calcd for
C.sub.18H.sub.17Cl.sub.4NO.sub.3S+H+, 467.97560; found (ESI-FTMS,
[M+H].sup.1+), 467.9742.
Example 10F
4-(2,6-dichlorophenoxy)-1-(2-naphthylsulfonyl)piperidine
[0823] The desired product was obtained in 36% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.89-2.29 (m, 4H)
2.97-3.18 (m, 2H) 3.43-3.63 (m, 2H) 4.21-4.37 (m, 1H) 6.93 (t, 1H)
7.24 (t, 2H) 7.56-7.72 (m, 2H) 7.78 (dd, J=8.59, 1.77 Hz, 1H) 7.93
(d, J=7.58 Hz, 1H) 7.99 (d, J=8.84 Hz, 2H) 8.36 (d, J=1.26 Hz, 1H).
HRMS: calcd for C.sub.21H.sub.19Cl.sub.2NO.sub.3S+H+, 436.05354;
found (ESI-FTMS, [M+H].sup.1+), 436.0529.
Example 10G
1-(1-benzothien-2-ylsulfonyl)-4-(2,6-dichlorophenoxy)piperidine
[0824] The desired product was obtained in 56% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.94-2.21 (m, 4H)
3.01-3.26 (m, 2H) 3.49-3.70 (m, 2H) 4.27-4.43 (m, 1H) 6.95 (t, 1H)
7.26 (s, 2H) 7.43-7.55 (m, 2H) 7.82 (s, 1H) 7.89 (t, 2H). HRMS:
calcd for C.sub.19H.sub.17Cl.sub.2NO.sub.3S.sub.2+H+, 442.00996;
found (ESI-FTMS, [M+H].sup.1+), 442.0091.
Example 10H
1-(1-benzothien-3-ylsulfonyl)-4-(2,6-dichlorophenoxy)piperidine
[0825] The desired product was obtained in 49% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.87-2.14 (m, 4H)
2.96-3.27 (m, 2H) 3.50-3.69 (m, 2H) 4.18-4.40 (m, 1H) 6.94 (t, 1H)
7.23 (d, J=8.08 Hz, 2H) 7.37-7.55 (m, 2H) 7.90 (dd, 1H) 8.19 (s,
1H) 8.28 (dd, J=6.95, 1.14 Hz, 1H). HRMS: calcd for
C.sub.19H.sub.17Cl.sub.2NO.sub.3S.sub.2+H+, 442.00996; found
(ESI-FTMS, [M+H].sup.1+), 442.0093.
Example 10I
1-[(2-chlorophenyl)sulfonyl]-4-(2,6-dichlorophenoxy)piperidine
[0826] The desired product was obtained in 64% yield as colorless
semi-solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.91-2.13
(m, 4H) 3.19-3.35 (m, 2H) 3.64-3.78 (m, 2H) 4.33-4.51 (m, 1H) 6.98
(t, 1H) 7.27 (d, 2H) 7.37-7.44 (m, 1H) 7.45-7.59 (m, 2H) 8.08 (dd,
J=7.83, 1.77 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.16Cl.sub.3NO.sub.3S+H+, 419.99892; found (ESI-FTMS,
[M+H].sup.1+), 419.9985.
Example 10J
1-[(2-bromophenyl)sulfonyl]-4-(2,6-dichlorophenoxy)piperidine
[0827] The desired product was obtained in 80% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.90-2.16 (m, 4H)
3.24-3.35 (m, 2H) 3.67-3.81 (m, 2H) 4.30-4.49 (m, 1H) 6.98 (t, 1H)
7.29 (d, J=8.08 Hz, 2H) 7.36-7.50 (m, 2H) 7.76 (dd, J=7.96, 1.39
Hz, 1H) 8.12 (dd, J=7.71, 1.89 Hz, 1H); HRMS: calcd for
C.sub.17H.sub.16BrCl.sub.2NO.sub.3S+H+, 463.94840; found (ESI-FTMS,
[M+H].sup.1+), 463.9478.
Example 10K
1-[(2-chlorophenyl)sulfonyl]-4-(2,6-dichlorophenoxy piperidine
[0828] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.90-2.18 (m, 4H)
3.24-3.35 (m, 2H) 3.66-3.77 (m, 2H) 4.34-4.51 (m, 1H) 6.98 (t, 1H)
7.28 (s, 1H) 7.29-7.31 (m, 1H) 7.40 (t, 1H) 7.45-7.58 (m, 2H) 8.08
(dd, J=7.83, 1.26 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.16Cl.sub.3NO.sub.3S+H+, 419.99892; found (ESI-FTMS,
[M+H].sup.1+), 419.9985.
Example 10L
2-{[4-(2,6-dichlorophenoxy)piperidin-1-yl]sulfonyl}benzonitrile
[0829] The desired product was obtained in 70% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.89-2.15 (m, 4H)
3.23-3.41 (m, 2H) 3.56-3.70 (m, 2H) 4.35-4.45 (m, 1H) 6.97 (t, 1H)
7.29 (s, 1H) 7.68-7.80 (m, 2H) 7.90 (dd, J=7.33, 1.77 Hz, 1H) 8.08
(dd, J=7.58, 1.26 Hz, 1H); HRMS: calcd for
C.sub.18H.sub.16Cl.sub.2N.sub.2O.sub.3S+H+, 411.03314; found
(ESI-FTMS, [M+H].sup.1+), 411.0323.
Example 10M
4-(2,6-dichlorophenoxy)-1-[(2-nitrophenyl)sulfonyl]piperidine
[0830] The desired product was obtained in 82% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.92-2.19 (m, 4H)
3.20-3.45 (m, 2H) 3.62-3.78 (m, 2H) 4.31-4.51 (m, 1H) 6.99 (t, 1H)
7.29 (d, J=8.08 Hz, 2H) 7.61-7.65 (m, 1H) 7.68-7.75 (m, 2H)
8.00-8.05 (m, 1H); HRMS: calcd for
C.sub.17H.sub.16Cl.sub.2N.sub.2O.sub.5S+H+, 431.02297; found
(ESI-FTMS, [M+H].sup.1+), 431.0216.
Example 10N
4-(2,6-dichlorophenoxy)-1-[(4-phenoxyphenyl)sulfonyl]piperidine
[0831] The desired product was obtained in 50% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.92-2.21 (m, 4H)
2.90-3.10 (m, 2H) 3.32-3.52 (m, 2H) 4.27-4.45 (m, 1H) 6.97 (t, 1H)
7.03-7.12 (m, 4H) 7.23 (t, 1H) 7.26 (s, 1H) 7.28 (s, 1H) 7.36-7.45
(m, 2H) 7.71-7.76 (m, 2H). HRMS: calcd for
C.sub.23H.sub.21Cl.sub.2NO.sub.4S+H+, 478.06411; found (ESI-FTMS,
[M+H].sup.1+), 478.063.
Example 10O
4-(2,6-dichlorophenoxy)-1-{[2-(trifluoromethyl)phenyl]sulfonyl}piperidine
[0832] The desired product was obtained in 72% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.91-2.13 (m, 4H)
3.19-3.37 (m, 2H) 3.59-3.73 (m, 2H) 4.35-4.49 (m, 1H) 6.98 (t, 1H)
7.29 (d, J=8.08 Hz, 2H) 7.68-7.77 (m, 2H) 7.89-7.93 (m, 1H)
8.13-8.18 (m, 1H). HRMS: calcd for
C.sub.18H.sub.16Cl.sub.2F.sub.3NO.sub.3S+H+, 454.02528; found
(ESI-FTMS, [M+H].sup.1+), 454.0244.
Example 10P
1-[(4-chlorophenyl)sulfonyl]-4-(2,6-dichlorophenoxy)piperidine
[0833] The desired product was obtained in 74% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.88-2.16 (m, 4H)
2.97-3.13 (m, 2H) 3.31-3.51 (m, 2H) 4.26-4.41 (m, 1H) 6.97 (t, 1H)
7.26 (d, 2H) 7.48-7.56 (m, 2H) 7.70-7.76 (m, 2H). HRMS: calcd for
C.sub.17H.sub.16Cl.sub.3NO.sub.3S+H+, 419.99892; found (ESI-FTMS,
[M+H].sup.1+), 419.9982.
Example 10Q
4-(2,6-dichlorophenoxy)-1-(2-thienylsulfonyl)piperidine
[0834] The desired product was obtained in 74% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.92-2.21 (m, 4H)
3.03-3.15 (m, 2H) 3.38-3.55 (m, 2H) 4.31-4.48 (m, 1H) 6.97 (t, 1H)
7.15 (t, J=5.05, 3.79 Hz, 1H) 7.26 (s, 1H) 7.28 (s, 1H) 7.56 (dd,
J=3.66, 1.39 Hz, 1H) 7.62 (dd, J=4.93, 1.39 Hz, 1H). HRMS: calcd
for C.sub.15H.sub.15Cl.sub.2NO.sub.3S.sub.2+H+, 391.99431; found
(ESI-FTMS, [M+H].sup.1+), 391.9934.
Example 10R
1-(biphenyl-3-ylsulfonyl)-4-(2,6-dichlorophenoxy)piperidine
[0835] The desired product was obtained in 87% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.93-2.17 (m, 4H)
2.95-3.10 (m, 2H) 3.42-3.55 (m, 2H) 4.23-4.43 (m, 1H) 6.94 (t, 1H)
7.26 (d, J=2.53 Hz, 2H) 7.37-7.45 (m, 1H) 7.45-7.52 (m, 2H)
7.57-7.66 (m, 3H) 7.73-7.79 (m, 1H) 7.79-7.85 (m, 1H) 7.99 (t,
J=1.77 Hz, 1H). HRMS: calcd for
C.sub.23H.sub.21Cl.sub.2NO.sub.3S+H+, 462.06919; found (ESI-FTMS,
[M+H].sup.1+), 462.0675.
Example 10S
1-[(4'-bromobiphenyl-4-yl)sulfonyl]-4-(2,6-dichlorophenoxy)piperidine
[0836] The desired product was obtained in 90% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.87-2.19 (m, 4H)
3.00-3.16 (m, 2H) 3.38-3.52 (m, 2H) 4.28-4.43 (m, 1H) 6.95 (t,
J=8.08 Hz, 1H) 7.25 (d, J=7.83 Hz, 2H) 7.47 (d, J=8.34 Hz, 2H) 7.61
(d, J=8.34 Hz, 2H) 7.70 (d, J=8.34 Hz, 2H) 7.85 (d, J=8.34 Hz,
2H).
Example 10T
1-(dibenzo[b,d]furan-2-ylsulfonyl)-4-(2,6-dichlorophenoxy)piperidine
[0837] The desired product was obtained in 95% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.93-2.18 (m, 4H)
2.93-3.14 (m, 2H) 3.40-3.59 (m, 2H) 4.21-4.37 (m, 1H) 6.93 (t, 1H)
7.22 (d, J=7.83 Hz, 2H) 7.42 (t, 1H) 7.55 (t, 1H) 7.63 (d, 1H) 7.70
(d, J=9.35 Hz, 1H) 7.90 (dd, J=8.59, 2.02 Hz, 1H) 8.01 (d, J=7.83
Hz, 1H) 8.42 (d, J=1.26 Hz, 1H). HRMS: calcd for
C.sub.23H.sub.19Cl.sub.2NO.sub.4S+H+, 476.04846; found (ESI-FTMS,
[M+H].sup.1+), 476.0474.
Example 10U
1-(dibenzo[b,d]thien-2-ylsulfonyl)-4-(2,6-dichlorophenoxy)piperidine
[0838] The desired product was obtained in 97% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.93-2.20 (m, 4H)
2.97-3.13 (m, 2H) 3.47-3.61 (m, 2H) 4.22-4.34 (m, 1H) 6.92 (t, 1H)
7.22 (d, J=8.08 Hz, 2H) 7.51-7.58 (m, 2H) 7.83 (dd, J=8.34, 1.77
Hz, 1H) 7.86-7.94 (m, 1H) 8.00 (d, J=8.59 Hz, 1H) 8.21-8.28 (m, 1H)
8.56 (d, J=1.77 Hz, 1H). HRMS: calcd for
C.sub.23H.sub.19Cl.sub.2NO.sub.3S.sub.2+H+, 492.02561; found
(ESI-FTMS, [M+H].sup.1+), 492.0271.
Example 10V
1-(dibenzo[b,d]thien-3-ylsulfonyl)-4-(2,6-dichlorophenoxy)piperidine
[0839] The desired product was obtained in 93% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.92-2.16 (m, 4H)
3.00-3.14 (m, 2H) 3.45-3.61 (m, 2H) 4.21-4.36 (m, 1H) 6.93 (t, 1H)
7.23 (d, J=8.08 Hz, 2H) 7.48-7.60 (m, 2H) 7.85 (dd, J=8.34, 1.77
Hz, 1H) 7.91 (dd, J=6.57, 1.26 Hz, 1H) 8.20-8.26 (m, 1H) 8.27-8.34
(m, 2H). HRMS: calcd for
C.sub.23H.sub.19Cl.sub.2NO.sub.3S.sub.2+H+, 492.02561; found
(ESI-FTMS, [M+H].sup.1+), 492.0247.
Example 10W
4-(2,6-dichlorophenoxy)-1-[(4'-fluorobiphenyl-4-yl)sulfonyl]piperidine
[0840] The desired product was obtained in 93% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.89-2.17 (m, 4H)
2.98-3.13 (m, 2H) 3.36-3.55 (m, 2H) 4.28-4.40 (m, 1H) 6.95 (t, 1H)
7.17 (t, 2H) 7.26 (d, 2H) 7.54-7.62 (m, 2H) 7.70 (d, 2H) 7.84 (d,
2H). HRMS: calcd for C.sub.23H.sub.20Cl.sub.2FNO.sub.3S+H+,
480.05977; found (ESI-FTMS, [M+H].sup.1+), 480.06.
Example 10X
1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-4-(2,6-dichlorophenoxy)p-
iperidine
[0841] The desired product was obtained in 97% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.95-2.18 (m, 4H)
2.65-2.74 (m, 3H) 3.17-3.31 (m, 2H) 3.55-3.77 (m, 2H) 4.29-4.45 (m,
1H) 6.96 (t, 1H) 7.27 (d, 2H) 7.46 (dd, J=8.59, 2.02 Hz, 1H) 7.76
(d, J=8.59 Hz, 1H) 7.81 (d, J=2.02 Hz, 1H). HRMS: calcd for
C.sub.20H.sub.18Cl.sub.3NO.sub.3S.sub.2+H+, 489.98664; found
(ESI-FTMS, [M+H].sup.1+), 489.9852.
Example 11
##STR00046##
[0843] Step 11A: To a stirred solution of p-toluenesulfonyl
chloride (39.28 mmol) in dichloromethane (160 mL) was added
4-hydroxypiperidine (40.07 mmol) dropwise, followed by 13.7 ml
i-Pr2NEt. The mixture was stirred at room temperature for 3 h.
Solvent was removed under vacuum and crude product was purified
with flash column chromatography to yield 4-hydroxypiperidin
sulfonamide (I).
[0844] Step 11B: A solution of aryl alcohol (1.17 mmol) and
triphenyl phosphine (0.349 g, 1.33 mmol) in 2 ml THF was mixed in
an ice-H.sub.2O bath. A solution of diethyl azodicarboxylate (0.232
g, 1.33 mmol) in 2 ml THF was added drop-wise, followed by
4-hydroxypiperidin sulfonamide (I) (0.78 mmol). The mixture was
warmed up to room temperature and stirred for 22 hr. Solvent was
removed under vacuum and crude product was purified with column
chromatography. The following compounds were prepared using this
procedure.
Example 11A
4-(2,4-dichlorophenoxy)-1-[(4-methylphenyl)sulfonyl]piperidine
[0845] The desired product was obtained in 33% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.87-2.05 (m, 4H)
2.44 (s, 3H) 2.95-3.11 (m, 2H) 3.20-3.35 (m, 2H) 4.34-4.52 (m, 1H)
6.80 (d, J=8.84 Hz, 1H) 7.12 (dd, J=8.84, 2.53 Hz, 2H) 7.22-7.38
(m, 3H) 7.65 (d, J=8.08 Hz, 2H).
Example 11B
1-[(4-methylphenyl)sulfonyl]-4-phenoxypiperidine
[0846] The desired product was obtained in 80% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.83-2.17 (m, 4H)
2.45 (s, 3H) 2.98-3.28 (m, 4H) 4.23-4.45 (m, 1H) 6.80 (d, J=7.58
Hz, 2H) 6.93 (t, J=7.45 Hz, 3H) 7.24 (t, 3H) 7.34 (d, J=8.08 Hz,
2H) 7.66 (d, J=8.34 Hz, 2H).
Example 11C
4-(2-chlorophenoxy)-1-[(4-methylphenyl)sulfonyl]piperidine
[0847] The desired product was obtained in 72% yield as white
solid. 1H NMR (400 MHz, Acetone) .delta. ppm 1.82-1.97 (m, 2H)
1.96-2.05 (m, J=10.11 Hz, 2H) 2.47 (s, 3H) 3.06-3.24 (m, 4H)
4.55-4.75 (m, J=3.28 Hz, 1H) 6.89-6.99 (m, 1H) 7.16 (dd, 1H) 7.25
(t, 1H) 7.35 (dd, 1H) 7.48 (d, J=8.59 Hz, 2H) 7.70 (d, 2H).
Example 11D
4-(2-methoxyphenoxy)-1-[(4-methylphenyl)sulfonyl]piperidine
[0848] The desired product was obtained in 25% yield as oil-like
liquid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.85-2.08 (m,
4H) 2.44 (s, 3H) 2.97-3.16 (m, 2H) 3.18-3.35 (m, 2H) 3.70 (s, 3H)
4.17-4.38 (m, 1H) 6.80-6.89 (m, 3H) 6.90-7.00 (m, 1H) 7.33 (d,
J=8.08 Hz, 2H) 7.67 (d, J=8.08 Hz, 2H).
Example 11D
3-({1-[(4-methylphenyl)sulfonyl]piperidin-4-yl}oxy)pyridine
[0849] The desired product was obtained in 44% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.84-1.99 (m, 2H)
1.98-2.11 (m, 2H) 2.46 (s, 3H) 3.16 (t, J=5.56 Hz, 4H) 4.26-4.53
(m, 1H) 7.07-7.15 (m, 1H) 7.14-7.22 (m, 1H) 7.35 (d, J=8.08 Hz, 2H)
7.67 (d, J=8.34 Hz, 2H) 8.20 (d, J=3.03 Hz, 2H).
Example 11E
4-(2-fluorophenoxy)-1-[(4-methylphenyl)sulfonyl]piperidine
[0850] The desired product was obtained in 40% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.82-2.11 (m, 4H)
2.39-2.52 (m, 3H) 2.95-3.29 (m, 4H) 4.24-4.44 (m, 1H) 6.85-6.97 (m,
2H) 6.96-7.11 (m, 2H) 7.34 (d, J=8.34 Hz, 2H) 7.66 (d, J=8.34 Hz,
2H).
Example 11F
4-(biphenyl-4-yloxy)-1-[(4-methylphenyl)sulfonyl]piperidine
[0851] The desired product was obtained in 30% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.84-2.12 (m, 4H)
2.41-2.53 (m, 3H) 3.03-3.25 (m, 4H) 4.36-4.49 (m, 1H) 6.87 (dd, 2H)
7.30 (t, 1H) 7.35 (d, J=7.83 Hz, 2H) 7.37-7.43 (m, 2H) 7.44-7.54
(m, 4H) 7.67 (d, 2H).
Example 11G
4-(4-methoxyphenoxy)-1-[(4-methylphenyl)sulfonyl]piperidine
[0852] The desired product was obtained in 30% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.82-2.08 (m, 4H)
2.37-2.52 (m, 3H) 3.02-3.27 (m, 4H) 3.71-3.80 (m, 3H) 4.16-4.27 (m,
1H) 6.69-6.81 (m, 4H) 7.34 (d, J=8.08 Hz, 2H) 7.66 (d, J=8.08 Hz,
2H).
Example 11H
1-[(4-methylphenyl)sulfonyl]-4-[2-(trifluoromethyl)phenoxy]piperidine
[0853] The desired product was obtained in 44% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.90-2.11 (m, 4H)
2.45 (s, 3H) 2.80-2.99 (m, 2H) 3.28-3.49 (m, 2H) 4.54-4.72 (m, 1H)
6.89 (d, 1H) 6.96 (t, 1H) 7.33 (d, 2H) 7.42 (t, 1H) 7.51 (t, 1H)
7.64 (d, 2H).
Example 11I
4-(2,6-dichlorophenoxy)-1-[(4-methylphenyl)sulfonyl]piperidine
[0854] The desired product was obtained in 40% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.87-2.19 (m, 4H)
2.44 (s, 3H) 2.88-3.05 (m, 2H) 3.29-3.54 (m, 2H) 4.17-4.43 (m, 1H)
6.96 (t, 1H) 7.26 (d, 2H) 7.33 (d, J=8.08 Hz, 2H) 7.67 (d, 2H),
HRMS: calcd for C.sub.18H.sub.19Cl.sub.2NO.sub.3S+H+, 400.05354;
found (ESI-FTMS, [M+H].sup.1+), 400.0534.
Example 11J
4-(2-methylphenoxy)-1-[(4-methylphenyl)sulfonyl]piperidine
[0855] The desired product was obtained in 35% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.88-2.07 (m, 7H)
2.45 (s, 3H) 2.98-3.11 (m, 2H) 3.12-3.25 (m, 2H) 4.35-4.47 (m, 1H)
6.72 (d, 1H) 6.84 (t, 1H) 7.03-7.15 (m, 2H) 7.34 (d, 2H) 7.66 (d,
2H)
Example 11K
2-({1-[(4-methylphenyl)sulfonyl]piperidin-4-yl}oxy)benzonitrile
[0856] The desired product was obtained in 27% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.93-2.16 (m, 4H)
2.44 (s, 3H) 3.04-3.20 (m, 2H) 3.25-3.41 (m, 2H) 4.47-4.62 (m, 1H)
6.90 (d, J=8.34 Hz, 1H) 6.99 (t, 3H) 7.34 (d, J=7.83 Hz, 2H)
7.43-7.56 (m, 2H) 7.66 (d, J=8.34 Hz, 2H).
Example 11L
1-[(4-methylphenyl)sulfonyl]-4-(2-nitrophenoxy)piperidine
[0857] The desired product was obtained in 43% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.90-2.10 (m, 4H)
2.46 (s, 3H) 2.88-3.07 (m, 2H) 3.26-3.50 (m, 2H) 4.57-4.74 (m, 1H)
7.01 (t, 3H) 7.35 (d, 2H) 7.47 (t, 1H) 7.64 (d, 2H) 7.76 (dd,
1H).
Example 11M
4-[(2-methoxybenzyl)oxy]-1-[(4-methylphenyl)sulfonyl]piperidine
[0858] The desired product was obtained in 65% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.72-1.86 (m, 2H)
1.86-1.97 (m, 2H) 2.43 (s, 3H) 2.88-3.01 (m, 2H) 3.14-3.28 (m, 2H)
3.45-3.52 (m, 1H) 3.76 (s, 3H) 4.48 (s, 2H) 6.83 (d, J=8.34 Hz, 1H)
6.89 (t, 1H) 7.15-7.35 (m, 4H) 7.64 (d, J=8.34 Hz, 2H).
Example 11N
4-(2-bromophenoxy)-1-[(4-methylphenyl)sulfonyl]piperidine
[0859] The desired product was obtained in % yield as white solid.
1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.92-2.05 (m, 4H) 2.45
(s, 3H) 2.95-3.10 (m, 2H) 3.25-3.41 (m, 2H) 4.44-4.62 (m, J=3.79,
3.79 Hz, 1H) 6.82 (q, 2H) 7.19 (t, 1H) 7.35 (d, 2H) 7.45 (dd, 1H)
7.66 (d, 2H), HRMS: calcd for C.sub.18H.sub.20BrNO.sub.3S+H+,
410.04200; found (ESI-FTMS, [M+H].sup.1+), 410.0411.
Example 11O
4-(2,6-dimethylphenoxy)-1-[(4-methylphenyl)sulfonyl]piperidine
[0860] The desired product was obtained in 41% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.79-2.04 (m, 4H)
2.16-2.23 (m, 6H) 2.43 (s, 3H) 2.53-2.68 (m, 2H) 3.54-3.67 (m,
J=1.87 Hz, 2H) 3.69-3.87 (m, 1H) 6.82-6.93 (m, 1H) 6.97 (dd, 2H)
7.32 (d, 2H) 7.65 (d, 2H), HRMS: calcd for
C.sub.20H.sub.25NO.sub.3S+H+, 360.16279; found (ESI-FTMS,
[M+H].sup.1+), 360.1617.
Example 11P
4-(2-ethylphenoxy)-1-[(4-methylphenyl)sulfonyl]piperidine
[0861] The desired product was obtained in 14% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 0.94 (t, J=7.58
Hz, 3H) 1.85-2.10 (m, 4H) 2.36 (q, J=7.58 Hz, 2H) 2.44 (s, 3H)
2.89-3.06 (m, 2H) 3.18-3.41 (m, 2H) 4.37-4.58 (m, 1H) 6.73 (dd, 1H)
6.85 (t, 1H) 7.03-7.15 (m, 2H) 7.33 (d, J=7.83 Hz, 2H) 7.66 (d,
2H), HRMS: calcd for C.sub.20H.sub.25NO.sub.3S+H+, 360.16279; found
(ESI-FTMS, [M+H].sup.1+), 360.1617.
Example 11Q
1-[(4-methylphenyl)sulfonyl]-4-(2-propylphenoxy)piperidine
[0862] The desired product was obtained in 19% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 0.73 (t, J=7.33
Hz, 3H) 1.26-1.45 (m, 2H) 1.81-2.06 (m, 4H) 2.19-2.36 (m, 2H) 2.44
(s, 3H) 2.81-3.04 (m, 2H) 3.23-3.40 (m, 2H) 4.47 (t, J=4.04 Hz, 1H)
6.70 (d, 1H) 6.83 (t, 1H) 7.01-7.15 (m, 2H) 7.34 (d, 2H) 7.64 (d,
2H); HRMS: calcd for C.sub.21H.sub.27NO.sub.3S+H+, 374.17844; found
(ESI-FTMS, [M+H].sup.1+), 374.1785.
Example 11R
4-(2-isopropylphenoxy)-1-[(4-methylphenyl)sulfonyl]piperidine
[0863] The desired product was obtained in 36% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.00 (d, J=7.07
Hz, 6H) 1.91-2.07 (m, 4H) 2.44 (s, 3H) 2.85-3.10 (m, 3H) 3.14-3.38
(m, 2H) 4.30-4.56 (m, 1H) 6.72 (d, J=7.83 Hz, 1H) 6.89 (t, 1H) 7.08
(t, 1H) 7.15 (dd, J=7.45, 1.64 Hz, 1H) 7.33 (d, J=8.08 Hz, 2H) 7.65
(d, 2H); HRMS: calcd for C.sub.21H.sub.27NO.sub.3S+H+, 374.17844;
found (ESI-FTMS, [M+H].sup.1+), 374.1789.
Example 11S
4-(2-chloro-6-methylphenoxy)-1-[(4-methylphenyl)sulfonyl]piperidine
[0864] The desired product was obtained in 35% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta..delta. ppm 1.89-2.10
(m, 4H) 2.21 (s, 3H) 2.43 (s, 3H) 2.67-2.81 (m, 2H) 3.45-3.66 (m,
2H) 3.99-4.22 (m, 1H) 6.91 (t, J=7.71 Hz, 1H) 7.04 (d, J=7.58 Hz,
1H) 7.16 (dd, J=7.71, 1.39 Hz, 1H) 7.33 (d, J=7.83 Hz, 2H) 7.66 (d,
J=8.34 Hz, 2H); HRMS: calcd for C.sub.19H.sub.22ClNO.sub.3S+H+,
380.10817; found (ESI-FTMS, [M+H].sup.1+), 380.1085.
Example 11T
2-chloro-3-({1-[(4-methylphenyl)sulfonyl]piperidin-4-yl}oxy)pyridine
[0865] The desired product was obtained in 30% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.96-2.02 (m, 4H)
2.45 (s, 3H) 2.93-3.07 (m, 2H) 3.29-3.40 (m, 2H) 4.48-4.58 (m, 1H)
7.16 (d, J=3.03 Hz, 2H) 7.35 (d, J=8.08 Hz, 2H) 7.66 (d, 2H) 7.99
(t, J=3.16 Hz, 1H); HRMS: calcd for
C.sub.17H.sub.19ClN.sub.2O.sub.3S+H+, 367.08777; found (ESI-FTMS,
[M+H].sup.1+), 367.0884.
Example 11U
4-(2-bromophenoxy)-1-[(3,4-dimethoxyphenyl)sulfonyl]piperidine
[0866] The desired product was obtained in 49% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.88-2.06 (m, 4H)
2.94-3.15 (m, 2H) 3.26-3.43 (m, 2H) 3.95 (d, J=8.59 Hz, 6H)
4.48-4.62 (m, J=3.54, 3.54 Hz, 1H) 6.79-6.89 (m, 4H) 6.97 (d,
J=8.34 Hz, 1H) 7.18-7.25 (m, 2H) 7.40 (dd, J=8.46, 2.15 Hz, 1H)
7.47 (dd, J=7.96, 1.64 Hz, 1H). HRMS: calcd for
C.sub.19H.sub.22BrNO.sub.5S+H+, 456.04748; found (ESI-FTMS,
[M+H].sup.1+), 456.0472.
Example 12
##STR00047##
[0868] Step 12A. To a solution of
N-(tert-butoxycarbonyl)-4-piperidone (8.01 g, 39.4 mmol),
2-chloroaniline (5.74 g, 44.1 mmol) and acetic acid (2.80 g, 46.6
mmol) in 200 ml ethylene chloride ethane was added sodium
triacetoxyborohydride (8.37 g, 78.8 mmol). The mixture was stirred
at room temp for 2.5 days. Added 2N NaOH solution to adjust pH to
10. The organic phase was separated and washed with water, then
dried over Na.sub.2SO.sub.4. Solvent was removed under vacuum and
crude product was purified with flash column chromatography to
yield tert-butyl-4-(2-chlorophenylamino)piperidine-1-carboxylate in
8.2% yield (1.6 g) as white solid.
[0869] Step 12B.
tert-butyl-4-(2-chlorophenylamino)piperidine-1-carboxylate (1.54 g,
4.95 mmol) in 20 ml DME was mixed with 20 ml TFA at room temp for 3
hr. Solvent was removed under vacuum to give the desired product
(2.2 g).
[0870] Step 12C: The product obtained step 12B can then be coupled
to the appropriate sulfonyl chloride (e.g., ArSO.sub.2Cl) as
described elsewhere herein.
Example 12A
1-(1-benzothien-2-ylsulfonyl)-N-(2-chlorophenyl)piperidin-4-amine
[0871] The desired product was obtained in 99% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.59-1.75 (m, 2H)
2.09-2.24 (m, 2H) 2.72-2.85 (m, 2H) 3.23-3.45 (m, 1H) 3.75-3.88 (m,
2H) 4.12-4.22 (m, J=7.33, 4.55 Hz, 1H) 6.49-6.68 (m, 2H) 7.07 (t,
1H) 7.26 (t, 1H) 7.44-7.58 (m, 2H) 7.81-7.85 (m, 1H) 7.90 (t, 2H).
HRMS: calcd for C.sub.19H.sub.19ClN.sub.2O.sub.2S.sub.2+H+,
407.06492; found (ESI-FTMS, [M+H].sup.1+), 407.0645.
Example 12B
N-(2-chlorophenyl)-1-(dibenzo[b,d]furan-3-ylsulfonyl)piperidin-4-amine
[0872] The desired product was obtained in 90% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.61-1.71 (m, 2H)
2.07-2.20 (m, 2H) 2.56-2.72 (m, 2H) 3.22-3.33 (m, 1H) 3.73-3.86 (m,
2H) 4.08-4.19 (m, J=7.07, 7.07, 7.07 Hz, 1H) 6.52 (d, 1H) 6.61 (t,
1H) 7.05 (t, 1H) 7.21 (dd, 1H) 7.45 (t, 1H) 7.59 (t, 1H) 7.67 (d,
1H) 7.79 (dd, 1H) 8.11 (d, 1H). HRMS: calcd for
C.sub.23H.sub.21ClN.sub.2O.sub.3S+H+, 441.10342; found (ESI-FTMS,
[M+H].sup.1+), 441.1031.
Example 12C
N-(2-chlorophenyl)-1-[(2-chlorophenyl)sulfonyl]piperidin-4-amine
[0873] The desired product was obtained in 63% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.51-1.68 (m, 2H)
2.04-2.21 (m, 2H) 2.95-3.09 (m, 2H) 3.35-3.52 (m, 1H) 3.70-3.92 (m,
2H) 4.10-4.26 (m, J=7.58 Hz, 1H) 6.63 (t, 3H) 7.10 (t, 1H)
7.23-7.26 (m, 1H) 7.36-7.44 (m, 1H) 7.47-7.57 (m, 2H) 8.08 (dd,
J=7.71, 1.39 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.18Cl.sub.2N.sub.2O.sub.2S+H+, 385.05388; found
(ESI-FTMS, [M+H].sup.1+), 385.0536.
Example 12D
N-(2-chlorophenyl)-1-[(3-chlorophenyl)sulfonyl]piperidin-4-amine
[0874] The desired product was obtained in 63% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.57-1.71 (m, 2H)
2.09-2.20 (m, 2H) 2.63 (t, 2H) 3.26-3.40 (m, J=3.79 Hz, 1H)
3.63-3.79 (m, 2H) 4.10-4.20 (m, J=8.08 Hz, 1H) 6.53-6.68 (m, 2H)
7.08 (t, 1H) 7.24 (dd, 1H) 7.51 (t, 1H) 7.57-7.64 (m, 1H) 7.64-7.70
(m, 1H) 7.75-7.81 (m, 1H). HRMS: calcd for
C.sub.17H.sub.18Cl.sub.2N.sub.2O.sub.2S+H+, 385.05388; found
(ESI-FTMS, [M+H].sup.1+), 385.0537.
Example 12E
N-(2-chlorophenyl)-1-[(4-phenoxyphenyl)sulfonyl]piperidin-4-amine
[0875] The desired product was obtained in 64% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.57-1.71 (m, 2H)
2.13 (dd, J=13.01, 3.66 Hz, 2H) 2.55-2.72 (m, 2H) 3.23-3.39 (m,
J=8.08 Hz, 1H) 3.60-3.71 (m, 2H) 4.10-4.18 (m, J=7.83 Hz, 1H)
6.54-6.72 (m, 2H) 7.03-7.13 (m, 5H) 7.21-7.26 (m, 2H) 7.39-7.46 (m,
2H) 7.70-7.76 (m, 2H). HRMS: calcd for
C.sub.23H.sub.23ClN.sub.2O.sub.3S+H+, 443.11907; found (ESI-FTMS,
[M+H].sup.1+), 443.1198.
Example 12F
1-(biphenyl-4-ylsulfonyl)-N-(2-chlorophenyl)piperidin-4-amine
[0876] The desired product was obtained in 60% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.57-1.73 (m, 2H)
2.08-2.22 (m, 2H) 2.58-2.72 (m, 2H) 3.26-3.43 (m, 1H) 3.68-3.81 (m,
2H) 4.07-4.20 (m, J=7.83 Hz, 1H) 6.53-6.65 (m, 2H) 7.06 (t, 1H)
7.23 (dd, 1H) 7.40-7.47 (m, 1H) 7.47-7.55 (m, 2H) 7.60-7.66 (m, 2H)
7.73-7.79 (m, 2H) 7.82-7.87 (m, 2H). HRMS: calcd for
C.sub.23H.sub.23ClN.sub.2O.sub.2S+H+, 427.12415; found (ESI-FTMS,
[M+H].sup.1+), 427.1247.
Example 13
##STR00048##
[0877] Example 13A
1-[(3,4-dichlorophenyl)sulfonyl]-4-(3-fluoropyridin-2-yl)piperazine
[0878] The desired product was obtained in 90% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.07-3.31 (m, 4H)
3.51-3.72 (m, 4H) 6.74-6.84 (m, 1H) 7.22 (t, 1H) 7.58-7.67 (m, 2H)
7.87 (d, J=1.52 Hz, 1H) 7.98 (d, 1H).
Example 13B
2-{4-[(3,4-dichlorophenyl)sulfonyl]piperazin-1-yl}nicotinonitrile
[0879] The desired product was obtained in 70% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.09-3.31 (m, 4H)
3.63-3.88 (m, 4H) 6.84 (dd, J=7.58, 4.80 Hz, 1H) 7.55-7.70 (m, 2H)
7.79 (dd, J=7.58, 2.02 Hz, 1H) 7.87 (d, J=1.77 Hz, 1H) 8.35 (dd,
J=4.93, 1.90 Hz, 1H).
Example 13C
1-[(3,4-dichlorophenyl)sulfonyl]-4-(3-nitropyridin-2-yl)piperazine
[0880] The desired product was obtained in 45% yield as white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.11-3.27 (m, 4H)
3.48-3.66 (m, 4H) 6.85 (dd, J=7.96, 4.67 Hz, 1H) 7.54-7.71 (m, 2H)
7.86 (t, J=2.02 Hz, 1H) 8.15 (dd, J=8.08, 1.77 Hz, 1H) 8.34 (dd,
J=4.55, 1.77 Hz, 1H).
##STR00049##
Example 13A-1
2-{1-[(2-chlorophenyl)sulfonyl]piperidin-4-yl}-3-methylpyridine
[0881] Step 13AA:
1'-Benzyl-3-methyl-2',3',5',6'-tetrahydro-1'H-[2,4']bipyridinyl-4'-ol.
Following the procedure of N. I. Carruthers et al. (J. Med. Chem.
2005, 48, 1857-1872), to a -78.degree. C. solution of
2-bromo-3-methylpyridine (10.0 g, 7.1 mL, 57.1 mmol) in THF (150
mL) was added drop wise a solution of n-BuLi (2.5 M in hexanes,
25.1 mL, 62.8 mmol) over 10 min. After 1.5 h a solution of
N-benzyl-4-piperidone (10.8 g, 57.1 mmol) in THF (20 mL) was added
drop wise over 15 min and the mixture was allowed to slowly warm to
room temperature overnight. After 18 h sat. NH.sub.4Cl solution (40
mL) was added and the mixture was concentrated. The resulting
residue was diluted with 1N NaHCO.sub.3 (100 ml) and extracted with
EtOAc. The combined organic phase was washed with brine, dried
(MgSO.sub.4), and concentrated. Flash chromatography afforded the
alcohol (8.1 g), an orange viscous oil, in 50% yield.
[0882] Step 13AB:
1'-Benzyl-3-methyl-1',2',3',6'-tetrahydro-[2,4']bipyridinyl.
Thionyl chloride (10 mL) was added slowly drop wise to the alcohol
from Step 13AA (6.34 g, 22.45 mmol). After 20 h, the mixture was
concentrated, diluted with CH.sub.2Cl.sub.2 (100 mL) and cooled to
0.degree. C. Sat. NaHCO.sub.3 (300 mL) was slowly added to the
mixture. The aqueous phase was separated and extracted with
CH.sub.2Cl.sub.2 (2.times.150 mL). The combined organic extracts
were washed with H.sub.2O (2.times.150 mL) and brine (150 mL),
dried (MgSO.sub.4), and concentrated to afford the olefin (3.54 g),
a brown viscous oil, in 60% yield.
[0883] 1H NMR (400 MHz, MeOD) .delta. ppm 2.59 (s, 3H), 2.69-2.76
(m, 2H), 3.04 (t, J=5.7 Hz, 2H), 3.44 (q, J=2.8 Hz, 2H), 3.95 (s,
2H), 5.94-5.99 (m, 1H), 7.42 (dd, J=7.7, 4.9 Hz, 1H), 7.49-7.54 (m,
1H), 7.55-7.61 (m, 2H), 7.61-7.66 (m, 2H), 7.88 (d, J=8.6 Hz, 1H),
8.51 (dd, J=4.8, 1.0 Hz, 1H).
[0884] Step 13AC:
3-Methyl-1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl. The olefin
from Step 13AB (2.97 g, 11.23 mmol) was dissolved in EtOH (100 mL)
and transferred to a Parr shaker bottle. 20% Pd(OH).sub.2 (1.48 g)
was added, and the mixture was hydrogenated at 60 psi for 20 h. The
mixture was filtered and concentrated. The residue was re-dissolved
in MeOH (176 ml). 20% Pd(OH).sub.2 (2.0 g) and Acetyl Chloride
(1.44 g, 1.3 ml, 18.32 mmol) was added, and the mixture was
hydrogenated at 60 psi for 2 d. The mixture was filtered and
concentrated and adhered to silica. Purification by flash
chromatography (elution with 0 to 20% MeOH--CH.sub.2Cl.sub.2) to
afford the amine (1.51 g), an off-white 76% yield.
[0885] 1H NMR (400 MHz, MeOD) .delta. ppm 2.36-2.61 (m, 4H), 2.87
(s, 3H), 3.47-3.58 (m, 3H), 3.77-3.87 (m, 2H), 3.89-4.03 (m, 1H),
8.12 (dd, J=8.1, 5.8 Hz, 1H), 8.69 (d, J=7.1 Hz, 1H), 8.86 (d,
J=4.5 Hz, 1H).
[0886] Step 13AD:
2-{1-[(2-chlorophenyl)sulfonyl]piperidin-4-yl}-3-methylpyridine. To
a solution of the amine from Step 13AC (100 mg, 0.57 mmol) in
CH.sub.2Cl.sub.2 (2.9 mL) was added 2-chlorobenzenesulfonyl
chloride (150 mg, 0.097 mL, 0.69 mmol) and sat. NaHCO.sub.3 (1.4
mL). The biphasic mixture was stirred at room temperature
overnight. The reaction mixture was diluted with CH.sub.2Cl.sub.2
(3 mL) and poured into a Phase Separator cartridge. The organic
phase was concentrated and purified by flash chromatography
(elution with 0-30% EtOAc-hex). Lyophilization then afforded the
title compound (26 mg), a white solid, in 13% yield.
[0887] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.79 (d, J=14.1
Hz, 2H), 1.97-2.11 (m, 2H), 2.31 (s, 3H), 2.87-2.96 (m, 3H), 3.99
(dd, J=12.1 Hz, 2H), 7.03 (dd, J=7.6, 4.8 Hz, 1H), 7.36-7.42 (m,
2H), 7.46-7.56 (m, 2H), 8.10 (dd, J=8.0, 1.6 Hz, 1H), 8.39 (d,
J=4.8 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.19ClN.sub.2O.sub.2S+H+, 351.09285; found (ESI-FTMS,
[M+H].sup.1+), 351.0934.
Example 13A-2
2-{1-[(4-chlorophenyl)sulfonyl]piperidin-4-yl}-3-methylpyridine
[0888] Using the procedure from Example 13A-1, the title compound
was prepared and isolated as a white solid in 33% yield.
[0889] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.80 (d, J=14.4
Hz, 2H), 2.03-2.16 (m, 2H), 2.26 (s, 3H), 2.38-2.49 (m, 2H),
2.73-2.81 (m, 1H), 3.93 (d, J=11.4 Hz, 2H), 7.03 (dd, J=7.6, 4.8
Hz, 1H), 7.39 (d, J=6.6 Hz, 1H), 7.53 (d, J=8.6 Hz, 2H), 7.75 (d,
J=8.8 Hz, 2H), 8.38 (d, J=4.8 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.19ClN.sub.2O.sub.2S+H+, 351.09285; found (ESI-FTMS,
[M+H].sup.1+), 351.0935.
Example 13A-3
2-{1-[(2,6-dichlorophenyl)sulfonyl]piperidin-4-yl}-3-methylpyridine
[0890] Using the procedure from Example 13A-1, the title compound
was isolated as a white solid (82 mg) in 31% yield.
[0891] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.81 (d, J=14.7
Hz, 2H), 1.94-2.11 (m, 2H), 2.32 (s, 3H), 2.90-2.99 (m, 1H),
2.99-3.09 (m, 2H), 4.07 (d, J=12.4 Hz, 2H), 7.03 (dd, J=7.6, 4.8
Hz, 1H), 7.29-7.35 (m, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.44-7.50 (m,
2H), 8.38 (d, J=6.3 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.18Cl.sub.2N.sub.2O.sub.2S+H+, 385.05388; found
(ESI-FTMS, [M+H].sup.1+), 385.0543.
Example 13A-4
2-{1-[(3,4-dichlorophenyl)sulfonyl]piperidin-4-yl}-3-methylpyridine
[0892] Using the procedure from Example 13A-1, the title compound
(35 mg) was isolated as a white solid in 13% yield.
[0893] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.76-1.86 (m,
J=16.2, 1.3 Hz, 2H), 2.04-2.18 (m, 2H), 2.27 (s, 3H), 2.43-2.55 (m,
2H), 2.74-2.84 (m, 1H), 3.94 (d, J=11.4 Hz, 2H), 7.03 (dd, J=7.7,
4.7 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.64 (d, J=1.3 Hz, 2H), 7.90
(s, 1H), 8.39 (d, J=6.3 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.18Cl.sub.2N.sub.2O.sub.2S+H+, 385.05388; found
(ESI-FTMS, [M+H].sup.1+), 385.0545.
Example 13A-5
2-{1-[(4-tert-butylphenyl)sulfonyl]piperidin-4-yl}-3-methylpyridine
[0894] Using the procedure from Example 13A-1, the title compound
(105 mg) was isolated as a white solid in 41% yield.
[0895] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.37 (s, 9H),
1.79 (d, J=14.9 Hz, 2H), 2.02-2.17 (m, 2H), 2.26 (s, 3H), 2.40-2.51
(m, 2H), 2.71-2.84 (m, 1H), 3.95 (d, J=11.4 Hz, 2H), 7.02 (dd,
J=7.6, 4.8 Hz, 1H), 7.38 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H),
7.73 (d, J=8.8 Hz, 2H), 8.38 (d, J=6.3 Hz, 1H). HRMS: calcd for
C.sub.21H.sub.28N.sub.2O.sub.2S+H+, 373.19442; found (ESI-FTMS,
[M+H].sup.1+), 373.1946.
Example 13A-6
2-{1-[(4-bromophenyl)sulfonyl]piperidin-4-yl}-3-methylpyridine
[0896] Using the procedure from Example 13A-1, the title compound
(51 mg) was isolated as a white solid in 27% yield.
[0897] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.80 (d, J=13.4
Hz, 2H), 2.04-2.16 (m, 2H), 2.26 (s, 3H), 2.39-2.48 (m, 2H),
2.70-2.83 (m, 1H), 3.93 (d, J=11.6 Hz, 2H), 7.03 (dd, J=7.6, 4.8
Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.64-7.73 (m, 4H), 8.39 (d, J=6.1
Hz, 1H). HRMS: calcd for C.sub.17H.sub.19BrN.sub.2O.sub.2S+H+,
395.04233; found (ESI-FTMS, [M+H].sup.1+), 395.0432.
Example 13A-7
3-methyl-2-[1-(2-naphthylsulfonyl)piperidin-4-yl]pyridine
[0898] Using the procedure from Example 13A-1, the title compound
(92 mg) was isolated as a white solid in 36% yield.
[0899] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.79 (d, J=15.9
Hz, 2H), 2.05-2.18 (m, 2H), 2.21 (s, 3H), 2.42-2.51 (m, 2H),
2.68-2.77 (m, 1H), 4.02 (d, J=11.4 Hz, 2H), 7.01 (dd, J=7.6, 4.8
Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.60-7.71 (m, 2H), 7.82 (dd,
J=8.6, 1.8 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 8.00 (d, J=8.1 Hz, 2H),
8.35-8.40 (m, 2H). HRMS: calcd for
C.sub.21H.sub.22N.sub.2O.sub.2S+H+, 367.14747; found (ESI-FTMS,
[M+H].sup.1+), 367.1479.
##STR00050##
Example 13B-1
2-{1-[(2-chlorophenyl)sulfonyl]piperidin-4-yl}-3-(trifluoromethyl)pyridine
[0900] Step 13BA:
4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1 carboxylic
acid tert-butyl ester. The vinyl triflate was prepared from
tert-butyl-4-oxopiperidine-1-carboxylate using the procedure from
WO 2004/036649. To a -78.degree. C. solution of diisopropylamine
(6.0 mL, 42.1 mmol) in THF (59 mL) was added drop wise a solution
of n-BuLi (2.5 M in hexanes, 16.8 mL, 42.1 mmol) over 15 min. After
2 h a solution of the piperidone (7.13 g, 35.1 mmol) in THF (59 mL)
was added drop wise over 30 min. After 40 min at -78.degree. C. a
solution of N-phenyltrifluoromethanesulfonimide (15.2 g, 42.1 mmol)
in THF (59 ml) was added over 25 min. After 2.5 hr at -78.degree.
C. the mixture was allowed to slowly warm to room temperature.
After 16 h the mixture was diluted with a 1:1 solution of THF and
H.sub.2O (140 ml). The aqueous phase was extracted with EtOAc. The
combined organic phase was washed with brine, dried (MgSO.sub.4),
and concentrated to give 29.6 g of a brown solid. The crude product
was adhered to silica and eluted with 15% EtOAc/Hex to give 18.3 g
of a yellow oil. Purification by flash chromatography (elution with
0 to 15% EtOAc-Hex) afforded 13.26 g of a yellow viscous oil, a
mixture of the vinyl triflate and phenyl amine. The oil was
dissolved in EtOAc washed with 5% Citric acid, 1N NaOH and brine
dried (MgSO.sub.4), and concentrated to afford the vinyl triflate
(6.06 g), a yellow oil, in 52% yield. 1H NMR (400 MHz,
CHLOROFORM-D) .delta. ppm 1.48 (s, 9H), 2.40-2.52 (m, J=2.9, 1.4
Hz, 2H), 3.63 (t, J=5.6 Hz, 2H), 4.05 (d, J=2.8 Hz, 2H), 5.77 (s,
1H).
[0901] Step 13BB:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine--
1-carboxylic acid tert-butyl ester. A mixture of the vinyl triflate
from Step 13BA (3.0 g, 9.05 mmol), bis(pinacolato)diboron (2.53 g,
9.96 mmol), Dichloro[1-1'-bis(diphenylphosphino)ferrocene]palladium
(II) dichloromethane adduct (0.020 g, 0.27 mmol),
bis(diphenylphosphino)ferrocene (0.15 g, 0.27 mmol) and potassium
acetate (2.66 g, 27.15 mmol) in 1,4-dioxane (53 ml) was degassed
with N.sub.2 and heated to 80.degree. C. After 17 h, the mixture
was cooled to room temperature, filtered through celite eluting
with EtOAc. The filtrate was concentrated, adhered to silica and
chromatographed (elution with 5 to 20% EtOAc-Hex) to afford the
boronate (1.91 g), a white solid, in 68% yield. 1H NMR (400 MHz,
CHLOROFORM-D) .delta. ppm 1.26 (s, 12H), 1.46 (s, 9H), 2.22 (s,
2H), 3.44 (t, J=5.3 Hz, 2H), 3.95 (d, J=2.3 Hz, 2H), 6.46 (s,
1H).
[0902] Step 13BC:
3-Trifluoromethyl-3',6'-dihydro-2'H-[2,4']bipyridinyl-1'-carboxylic
acid tert-butyl ester. A mixture of the boronate from Step 13BB
(1.49 g, 4.82 mmol),
Dichloro[1-1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (703 mg, 0.96 mmol),
2-Bromo-3-(trifluoromethyl)pyridine (1.33 g, 5.78 mmol) and sodium
carbonate (2.04 g, 19.28 mmol) in a 7:3:2 solution of
dimethoxyethane/H.sub.2O/EtOH (30 ml) was degassed with N.sub.2 and
heated at 80.degree. C. After 20 h the mixture was cooled to room
temperature and diluted with equal portions of EtOAc and H.sub.2O,
the aqueous phase was then extracted with EtOAc. The combined
organic phase was washed with brine, dried (MgSO.sub.4) and
concentrated. Purification by flash chromatography (elution with 0
to 30% EtOAc-Hex) afforded the desired product (1.24 g), an orange
oil, in 78% yield. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.50
(s, 9H), 2.51 (s, 2H), 3.67 (s, 2H), 4.07 (s, 2H), 5.76 (s, 1H),
7.34 (dd, J=8.1, 4.8 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 8.75 (d,
J=4.8 Hz, 1H).
[0903] Step 13BD:
3-Trifluoromethyl-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-carboxy-
lic acid tert-butyl ester. The olefin from Step 13BC (1.23 g, 3.75
mmol) was dissolved in EtOH (100 mL) and transferred to a Parr
shaker bottle. 10% Pd/C (1.0 g) was added, and the mixture was
hydrogenated at 60 psi for 16 h. The mixture was filtered, fresh
Pd/C (3.0 g) was added, and the mixture was hydrogenated at 60 psi
for 2 d. The mixture was filtered and concentrated to afford the
piperidine (1.22 g), brown viscous oil, in 98% yield. 1H NMR (400
MHz, CHLOROFORM-D) .delta. ppm 1.48 (s, 9H), 1.71 (d, J=12.9 Hz,
2H), 1.86-2.08 (m, 2H), 2.83 (broad, s, 2H), 3.05-3.24 (m, 1H),
4.25 (broad, s, 2H), 7.24 (dd, J=8.1, 4.8 Hz, 1H), 7.91 (d, J=8.1
Hz, 1H), 8.73 (d, J=4.3 Hz, 1H).
[0904] Step 13BE:
3-Trifluoromethyl-1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl. A
mixture of the piperidine from Step 13BD (1.22 g, 3.69 mmol), MeOH
(15 mL), and 6N HCl (2.2 mL) was heated to reflux for 3 h. The
mixture was cooled to room temperature and diluted with sat.
Na.sub.2CO.sub.3 solution (30 mL). The mixture was extracted with
CH.sub.2Cl.sub.2 (2.times.50 mL). The organic phase was washed with
H.sub.2O and brine, dried (MgSO.sub.4) and concentrated to afford
the amine (608 mg), an off-white solid, 72% yield. 1H NMR (400 MHz,
CHLOROFORM-D) .delta. ppm 1.75 (d, J=13.4 Hz, 2H), 1.90-2.05 (m,
2H), 2.38 (s, 1H), 2.75-2.85 (m, 2H), 3.19 (t, J=12.1 Hz, 1H),
3.22-3.29 (m, 2H), 7.23 (dd, J=7.8, 4.8 Hz, 1H), 7.90 (d, J=6.8 Hz,
1H), 8.74 (d, J=3.8 Hz, 1H).
[0905] Step 13BF:
2-{1-[(2-chlorophenyl)sulfonyl]piperidin-4-yl}-3-(trifluoromethyl)pyridin-
e. To a solution of the amine from Step 13BE (100 mg, 0.43 mmol) in
CH.sub.2Cl.sub.2 (2.9 mL) was added 2-chlorobenzenesulfonyl
chloride (113 mg, 73 .mu.l, 0.52 mmol) and sat. NaHCO.sub.3 (1.4
mL). The biphasic mixture was stirred at room temperature
overnight. The reaction mixture was diluted with CH.sub.2Cl.sub.2
(3 mL) and poured into a Phase Separator cartridge. The organic
phase was concentrated and purified by flash chromatography
(elution with 0-20% EtOAc-hex). Lyophilization then afforded the
title compound (121 mg), a white solid, in 70% yield. 1H NMR (400
MHz, CHLOROFORM-D) .delta. ppm 1.79 (d, J=13.6 Hz, 2H), 2.09-2.23
(m, 2H), 2.82-2.92 (m, 2H), 3.08 (t, J=1.9 Hz, 1H), 4.02 (d, J=12.4
Hz, 2H), 7.21-7.27 (m, 1H), 7.37-7.44 (m, 1H), 7.46-7.52 (m, 1H),
7.53-7.59 (m, 1H), 7.89 (dd, J=8.0, 1.6 Hz, 1H), 8.09 (d, J=6.3 Hz,
1H), 8.73 (d, J=3.5 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.16ClF.sub.3N.sub.2O.sub.2S+H+, 405.06458; found
(ESI-FTMS, [M+H].sup.1+), 405.0652.
Example 13B-2
2-{1-[(4-chlorophenyl)sulfonyl]piperidin-4-yl}-3-(trifluoromethyl)pyridine
[0906] Using the procedure from Example 13B-1, the title compound
(168 mg) was prepared and isolated as a white solid in 97%
yield.
[0907] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.80 (d, J=12.6
Hz, 2H), 2.13-2.27 (m, 2H), 2.34-2.45 (m, 2H), 2.94 (t, J=11.4 Hz,
1H), 3.95 (d, J=11.6 Hz, 2H), 7.21-7.28 (m, 1H), 7.54 (d, J=8.3 Hz,
2H), 7.74 (d, J=8.6 Hz, 2H), 7.89 (d, J=7.8 Hz, 1H), 8.73 (d, J=4.8
Hz, 1H). HRMS: calcd for
C.sub.17H.sub.16ClF.sub.3N.sub.2O.sub.2S+H+, 405.06458; found
(ESI-FTMS, [M+H].sup.1+), 405.065.
Example 13B-3
2-{1-[(3,4-dichlorophenyl)sulfonyl]piperidin-4-yl}-3-(trifluoromethyl)pyri-
dine
[0908] Using the procedure from Example 13B-1, the title compound
(178 mg) was prepared and isolated as a white solid in 94%
yield.
[0909] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.82 (d, J=14.1
Hz, 2H), 2.13-2.28 (m, 2H), 2.39-2.50 (m, 2H), 2.89-3.02 (m, 1H),
3.96 (d, J=11.6 Hz, 2H), 7.22-7.29 (m, 1H), 7.59-7.68 (m, 2H),
7.86-7.93 (m, 2H), 8.73 (d, J=4.8 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.15Cl.sub.2F.sub.3N.sub.2O.sub.2S+H+, 439.02561; found
(ESI-FTMS, [M+H].sup.1+), 439.0256.
Example 13B-4
2-{1-[(4-tert-butylphenyl)sulfonyl]piperidin-4-yl}-3-(trifluoromethyl)pyri-
dine
[0910] Using the procedure from Example 13AA, the title compound
(172 mg) was prepared and isolated as a white solid in 94%
yield.
[0911] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.38 (s, 9H),
1.79 (d, J=12.9 Hz, 2H), 2.13-2.30 (m, 2H), 2.35-2.45 (m, 2H), 2.94
(t, J=11.6 Hz, 1H), 3.96 (d, J=9.6 Hz, 2H), 7.24 (dd, J=8.1, 4.8
Hz, 1H), 7.56 (d, J=8.6 Hz, 2H), 7.67-7.76 (m, 2H), 7.88 (d, J=8.1
Hz, 1H), 8.73 (d, J=3.5 Hz, 1H). HRMS: calcd for
C.sub.21H.sub.25F.sub.3N.sub.2O.sub.2S+H+, 427.16616; found
(ESI-FTMS, [M+H].sup.1+), 427.1662.
Example 13B-5
2-[1-(2-naphthylsulfonyl)piperidin-4-yl]-3-(trifluoromethyl)pyridine
[0912] Using the procedure from Example 13AA, the title compound
(168 mg) was isolated as a white solid in 93% yield.
[0913] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.79 (d, J=13.1
Hz, 2H), 2.16-2.29 (m, 2H), 2.38-2.48 (m, 2H), 2.89 (t, J=11.2 Hz,
1H), 4.04 (d, J=11.4 Hz, 2H), 7.23 (dd, J=8.0, 4.7 Hz, 1H),
7.59-7.70 (m, 2H), 7.80 (dd, J=8.6, 1.8 Hz, 1H), 7.86 (d, J=8.1 Hz,
1H), 7.95 (d, J=7.8 Hz, 1H), 7.98-8.04 (m, 2H), 8.38 (s, 1H), 8.72
(d, J=4.8 Hz, 1H). HRMS: calcd for
C.sub.21H.sub.19F.sub.3N.sub.2O.sub.2S+H+, 421.11921; found
(ESI-FTMS, [M+H].sup.1+), 421.1189.
Example 13B-6
2-{1-[(2,6-dichlorophenyl)sulfonyl]piperidin-4-yl}-3-(trifluoromethyl)pyri-
dine
[0914] Using the procedure from Example 13AA, the title compound
(126 mg) was isolated as a white solid in 67% yield.
[0915] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.81 (d, J=13.1
Hz, 2H), 2.08-2.22 (m, 2H), 2.92-3.05 (m, 2H), 3.13 (t, J=11.9 Hz,
1H), 4.11 (d, J=12.4 Hz, 2H), 7.20-7.28 (m, 1H), 7.29-7.36 (m, 1H),
7.44-7.52 (m, 2H), 7.90 (d, J=7.8 Hz, 1H), 8.72 (d, J=4.5 Hz, 1H).
HRMS: calcd for C.sub.17H.sub.15Cl.sub.2F.sub.3N.sub.2O.sub.2S+H+,
439.02561; found (ESI-FTMS, [M+H].sup.1+), 439.0255.
Example 14
##STR00051##
[0916] Example 14A
1-[(3-chlorophenyl)sulfonyl]-4-[2-(trifluoromethyl)phenyl]piperidine
[0917] Step 14A:
1-Benzyl-4-[2-(trifluoromethyl)phenyl]piperidin-4-ol. Following the
procedure of N. I. Carruthers et al. (J. Med. Chem. 2005, 48,
1857-1872), to a -78.degree. C. solution of 2-bromobenzotrifluoride
(12.9 g, 7.8 mL, 57 mmol) in THF (225 mL) was added dropwise a
solution of n-BuLi (2.5 M in hexanes, 26 mL, 65 mmol) over 10 min.
After 1 h, the reaction mixture was stirred at 0.degree. C. for 10
min, recooled to -78.degree. C., and a solution of
N-benzyl-4-piperidone (10.7 g, 57 mmol) in THF (40 mL) was added
dropwise via addition funnel over 10 min. After 2 h at -78.degree.
C., sat. NH.sub.4Cl solution (200 mL) was added and the mixture was
warmed to room temperature. The aqueous phase was extracted with
EtOAc (2.times.200 mL). The organic phase was washed with H2O (200
mL) and brine (150 mL), dried (MgSO.sub.4), and concentrated. Flash
chromatography afforded the alcohol (2.7 g), a yellow oil, slightly
contaminated with piperidone starting material, in .about.15%
yield.
[0918] Step 14B:
1-Benzyl-4-[2-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine.
Thionyl chloride (10 mL) was added slowly dropwise to the alcohol
from Step 14A (4.9 g, 14.6 mmol). After 2 h, the mixture was
concentrated, diluted with CH.sub.2Cl.sub.2 (50 mL), and added
slowly to a stirred solution of sat. NaHCO.sub.3 (200 mL). The
aqueous phase was separated and extracted with CH.sub.2Cl.sub.2
(2.times.150 mL). The combined organic extracts were washed with
H.sub.2O (2.times.150 mL) and brine (150 mL), dried (MgSO.sub.4),
and concentrated. Flash chromatography (elution with 10-30%
EtOAc-hexanes) afforded the olefin (2.75 g), a yellow oil, in 59%
yield. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.38 (dd, J=4.5,
2.8 Hz, 2H), 2.70 (t, J=5.7 Hz, 2H), 3.14 (q, J=2.9 Hz, 2H), 3.66
(s, 2H), 5.57 (s, 1H), 7.22-7.30 (m, 2H), 7.31-7.42 (m, 5H), 7.47
(t, J=7.6 Hz, 1H), 7.63 (d, J=7.1 Hz, 1H).
[0919] Step 14C: Following the procedure of N. I. Carruthers et al.
(J. Med. Chem. 2005, 48, 1857-1872), the olefin from Step 14B (2.99
g, 9.4 mmol) was dissolved in EtOH (50 mL) and transferred to a
Parr shaker bottle. 10% Pd/C (wet Degussa, 3.0 g) was added, and
the mixture was hydrogenated at 50 psi for 16 h. The mixture was
filtered, fresh Pd/C (3.0 g) was added, and the mixture was
hydrogenated at 50 psi for 2 d. The mixture was filtered and
concentrated to afford a beige solid that was purified by flash
chromatography (elution with 10% MeOH--CH.sub.2Cl.sub.2 to 0.1%
E.sub.t3N-10% MeOH--CH.sub.2Cl.sub.2) to afford the amine (1.24 g),
a yellow oil, contaminated with Et.sub.3N, in .about.57% yield.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.62-1.87 (m, 4H),
2.70-2.84 (m, 2H), 2.97-3.10 (m, 1H), 3.19 (d, J=11.6 Hz, 2H),
7.18-7.35 (m, 1H), 7.44-7.56 (m, 2H), 7.61 (d, J=7.8 Hz, 1H).
[0920] Step 14D: To a solution of the amine from Step 14C (150 mg,
0.65 mmol) in CH.sub.2Cl.sub.2 (4 mL) was added
3-chlorobenzenesulfonyl chloride (165 mg, 0.11 mL, 0.78 mmol) and
saturated NaHCO.sub.3 (2 mL). The biphasic mixture was stirred for
6 h. The reaction mixture was diluted with CH.sub.2Cl.sub.2 (3 mL)
and poured into a Phase Separator cartridge. The organic phase was
concentrated and purified by flash chromatography (elution with
2-10% EtOAc-hex). Lyophilization then afforded the title compound
(176 mg), a white solid, in 67% yield.
[0921] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.80-2.01 (m, 4H),
2.26-2.49 (m, 2H), 2.69-2.94 (m, 1H), 3.98 (d, J=11.9 Hz, 2H), 7.31
(t, J=7.7 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.48-7.58 (m, 2H),
7.58-7.65 (m, 2H), 7.66-7.72 (m, 1H), 7.79 (t, J=1.9 Hz, 1H). HRMS:
calcd for C.sub.18H.sub.17ClF.sub.3NO.sub.2S+H+, 404.06934; found
(ESI-FTMS, [M+H].sup.1+), 404.0692. HPLC Method 1: room
temperature, 6.99 min, 99.2%. HPLC Method 2: room temperature, 7.54
min, 97.7%.
Example 14B
1-[(4-chlorophenyl)sulfonyl]-4-[2-(trifluoromethyl)phenyl]piperidine
[0922] Using the procedure from Example 14A, Step 14D,
1-benzyl-4-[2-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine
(Example 14A, Step 14C, 150 mg, 0.65 mmol) was reacted with
4-chlorobenzenesulfonyl chloride (165 mg, 0.78 mmol) to afford the
title compound (219 mg), a white solid, in 84% yield.
[0923] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.74-1.98 (m, 4H),
2.26-2.43 (m, 2H), 2.68-2.95 (m, 1H), 3.96 (d, J=11.9 Hz, 2H), 7.31
(t, J=7.6 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.48-7.57 (m, 3H), 7.61
(d, J=7.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H). HRMS: calcd for
C.sub.18H.sub.17ClF.sub.3NO.sub.2S+H+, 404.06934; found (ESI-FTMS,
[M+H].sup.1+), 404.0696. HPLC Method 1: room temperature, 6.99 min,
99.6%. HPLC Method 2: room temperature, 7.53 min, 99.4%.
Example 14C
1-[(3,4-dichlorophenyl)sulfonyl]-4-[2-(trifluoromethyl)phenyl]piperidine
[0924] Using the procedure from Example 14A,
1-benzyl-4-[2-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine
(Example 14A, Step 14C, 150 mg, 0.65 mmol) was reacted with
3,4-dichlorobenzenesulfonyl chloride (191 mg, 0.12 mL, 0.78 mmol)
to afford the title compound (211 mg), a white solid, in 74%
yield.
[0925] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.77-1.96 (m, 4H),
2.29-2.58 (m, 2H), 2.72-3.00 (m, 1H), 3.97 (d, J=12.1 Hz, 2H), 7.32
(t, J=7.7 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H),
7.58-7.69 (m, 3H), 7.88 (d, J=1.8 Hz, 1H). HRMS: calcd for
C.sub.18H.sub.16Cl.sub.2F.sub.3NO.sub.2S+H+, 438.03036; found
(ESI-FTMS, [M+H].sup.1+), 438.0303. HPLC Method 1: room
temperature, 7.31 min, 99.3%. HPLC Method 2: room temperature, 7.84
min, 99.4%.
Example 14D
1-[(4-tert-butylphenyl)sulfonyl]-4-[2-(trifluoromethyl)phenyl]piperidine
[0926] Using the procedure from Example 14A, Step 14D,
1-benzyl-4-[2-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine
(Example 14A, Step 14C, 150 mg, 0.65 mmol) was reacted with
4-tert-butylbenzenesulfonyl chloride (182 mg, 0.78 mmol) to afford
the title compound (135 mg), a white solid, in 49% yield.
[0927] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.71-1.97 (m, 4H),
2.24-2.53 (m, 2H), 2.69-2.99 (m, 1H), 3.97 (d, J=11.9 Hz, 2H), 7.30
(t, J=7.7 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.48-7.63 (m, 4H), 7.72
(d, J=8.6 Hz, 2H). HRMS: calcd for
C.sub.22H.sub.26F.sub.3NO.sub.2S+H+, 426.17091; found (ESI-FTMS,
[M+H].sup.1+), 426.1714. HPLC Method 1: room temperature, 7.52 min,
99.5%. HPLC Method 2: room temperature, 7.85 min, 99.3%.
Example 14E
1-(2-naphthylsulfonyl)-4-[2-(trifluoromethyl)phenyl]piperidine
[0928] Using the procedure from Example 14A, the title compound
(235 mg) was isolated as a white solid, in 86% yield.
[0929] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.68-2.09 (m, 4H),
2.26-2.62 (m, 2H), 2.52-3.04 (m, 1H), 4.05 (d, J=11.6 Hz, 2H), 7.29
(t, J=7.6 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H),
7.58 (d, J=8.1 Hz, 1H), 7.61-7.74 (m, 2H), 7.80 (dd, J=8.6, 1.8 Hz,
1H), 7.96 (d, J=8.1 Hz, 1H), 7.98-8.12 (m, 2H), 8.37 (d, J=1.5 Hz,
1H). HRMS: calcd for C.sub.22H.sub.20F.sub.3NO.sub.2S+H+,
420.12396; found (ESI-FTMS, [M+H].sup.1+), 420.1244. HPLC Method 1:
room temperature, 7.12 min, 99.4%. HPLC Method 2: room temperature,
7.66 min, 99.3%.
Example 14F
1-[(2,6-dichlorophenyl)sulfonyl]-4-[2-(trifluoromethyl)phenyl]piperidine
[0930] Using the procedure from Example 14A, the title compound
(236 mg) was isolated as a white solid, in 83% yield.
[0931] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.79-1.96 (m, 4H),
2.86-3.01 (m, 2H), 3.02-3.13 (m, 1H), 4.12 (d, J=12.9 Hz, 2H),
7.28-7.38 (m, 2H), 7.42 (d, J=7.8 Hz, 1H), 7.46-7.57 (m, 3H), 7.62
(d, J=8.1 Hz, 1H). HRMS: calcd for
C.sub.18H.sub.16Cl.sub.2F.sub.3NO.sub.2S+H+, 438.03036; found
(ESI-FTMS, [M+H].sup.1+), 438.0307. HPLC Method 1: room
temperature, 7.03 min, 99.2%. HPLC Method 2: room temperature, 7.53
min, 99.1%.
Example 14G
1-[(4-bromophenyl)sulfonyl]-4-[2-(trifluoromethyl)phenyl]piperidine
[0932] Using the procedure from Example 14A, the title compound
(209 mg) was isolated as a white solid, in 72% yield.
[0933] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.78-1.97 (m, 4H),
2.28-2.41 (m, 2H), 2.75-2.92 (m, 1H), 3.96 (d, J=12.1 Hz, 2H), 7.31
(t, J=7.7 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H),
7.61 (d, J=7.8 Hz, 1H), 7.66 (d, J=8.7 Hz, 2H), 7.72 (d, J=8.7 Hz,
2H). HRMS: calcd for C.sub.18H.sub.17BrF.sub.3NO.sub.2S+H+,
448.01882; found (ESI-FTMS, [M+H].sup.1+), 448.0192. HPLC Method 1:
room temperature, 7.06 min, 99.7%. HPLC Method 2: room temperature,
7.58 min, 99.4%.
Example 14H
1-[(2-fluorophenyl)sulfonyl]-4-[2-(trifluoromethyl)phenyl]piperidine
[0934] Using the procedure from Example 14A, the title compound (25
mg) was isolated as a white solid, in 15% yield.
[0935] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.80-1.96 (m, 4H),
2.54-2.71 (m, 2H), 2.87-3.03 (m, 1H), 4.04 (d, J=12.1 Hz, 2H),
7.18-7.37 (m, 3H), 7.42 (d, J=8.1 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H),
7.57-7.66 (m, 2H), 7.82-7.96 (m, 1H). HRMS: calcd for
C.sub.18H.sub.17F.sub.4NO.sub.2S+H+, 388.09889; found (ESI-FTMS,
[M+H].sup.1+), 388.0991. HPLC Method 1: room temperature, 6.64 min,
98.1%. HPLC Method 2: room temperature, 7.22 min, 97.0%.
Example 14I
1-[(3-fluorophenyl)sulfonyl]-4-[2-(trifluoromethyl)phenyl]piperidine
[0936] Using the procedure from Example 14A, the title compound (93
mg) was isolated as a white solid, in 55% yield.
[0937] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.73-2.02 (m, 4H),
2.28-2.55 (m, 2H), 2.75-3.07 (m, 1H), 3.98 (d, J=111.9 Hz, 2H),
7.28-7.39 (m, 2H), 7.41 (d, J=8.1 Hz, 1H), 7.46-7.65 (m, 5H). HRMS:
calcd for C.sub.18H.sub.17F.sub.4NO.sub.2S+H+, 388.09889; found
(ESI-FTMS, [M+H].sup.1+), 388.0991. HPLC Method 1: room
temperature, 6.71 min, 98.7%. HPLC Method 2: room temperature, 7.32
min, 100%.
Example 14J
4-[2-(trifluoromethyl)phenyl]-1-{[2-(trifluoromethyl)phenyl]sulfonyl}piper-
idine
[0938] Using the procedure from Example 14A, the title compound
(110 mg) was isolated as a white solid, in 57% yield.
[0939] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.75-2.00 (m, 4H),
2.60-2.90 (m, 2H), 2.94-3.14 (m, 1H), 4.00 (d, J=12.9 Hz, 2H), 7.31
(t, J=7.7 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.53 (t, J=7.5 Hz, 1H),
7.62 (d, J=7.8 Hz, 1H), 7.66-7.81 (m, 2H), 7.86-8.00 (m, 1H),
8.07-8.24 (m, 1H). HRMS: calcd for
C.sub.19H.sub.17F.sub.6NO.sub.2S+H+, 438.09569; found (ESI-FTMS,
[M+H].sup.1+), 438.0958. HPLC Method 1: room temperature, 6.89 min,
99.1%. HPLC Method 2: room temperature, 7.37 min, 100%.
Example 14K
4-[2-(trifluoromethyl)phenyl]-1-{[3-(trifluoromethyl)phenyl]sulfonyl}piper-
idine
[0940] Using the procedure from Example 14A, the title compound (92
mg) was isolated as a white solid, in 48% yield.
[0941] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.78-2.13 (m, 4H),
2.26-2.50 (m, 2H), 2.78-3.11 (m, 1H), 4.01 (d, J=12.1 Hz, 2H), 7.32
(t, J=7.7 Hz, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.54 (t, J=7.6 Hz, 1H),
7.61 (d, J=7.8 Hz, 1H), 7.74 (t, J=7.8 Hz, 1H), 7.91 (d, J=7.8 Hz,
1H), 7.99 (d, J=7.8 Hz, 1H), 8.06 (s, 1H). HRMS: calcd for
C.sub.19H.sub.17F.sub.6NO.sub.2S+H+, 438.09569; found (ESI-FTMS,
[M+H].sup.1+), 438.0959. HPLC Method 1: room temperature, 6.98 min,
98.4%. HPLC Method 2: room temperature, 7.52 min, 98.9%.
Example 14L
4-[2-(trifluoromethyl)phenyl]-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piper-
idine
[0942] Using the procedure from Example 14A, the title compound (90
mg) was isolated as a white solid, in 47% yield.
[0943] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.74-2.00 (m, 4H),
2.21-2.53 (m, 2H), 2.67-3.27 (m, 1H), 4.00 (d, J=11.4 Hz, 2H), 7.32
(t, J=7.7 Hz, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.53 (t, J=7.6 Hz, 1H),
7.61 (d, J=7.8 Hz, 1H), 7.85 (d, J=8.3 Hz, 2H), 7.93 (d, J=8.3 Hz,
2H). HRMS: calcd for C.sub.19H.sub.17F.sub.6NO.sub.2S+H+,
438.09569; found (ESI-FTMS, [M+H].sup.1+), 438.0959. HPLC Method 1:
room temperature, 7.03 min, 99.3%. HPLC Method 2: room temperature,
7.53 min, 99.0%.
Example 14M
1-[(4-methoxyphenyl)sulfonyl]-4-[2-(trifluoromethyl)phenyl]piperidine
[0944] Using the procedure from Example 14A, the title compound
(117 mg) was isolated as a white solid, in 67% yield.
[0945] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.66-2.04 (m, 4H),
2.19-2.46 (m, 2H), 2.51-3.09 (m, 1H), 3.90 (s, 3H), 3.94 (d, J=11.4
Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 7.30 (t, J=7.7 Hz, 1H), 7.42 (d,
J=8.1 Hz, 1H), 7.53 (t, J=7.6 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.73
(d, J=9.1 Hz, 2H). HRMS: calcd for
C.sub.19H.sub.20F.sub.3NO.sub.3S+H+, 400.11887; found (ESI-FTMS,
[M+H].sup.1+), 400.1192. HPLC Method 1: room temperature, 6.63 min,
99.0%. HPLC Method 2: room temperature, 7.27 min, 98.5%.
Example 14N
1-{[4-(trifluoromethoxy)phenyl]sulfonyl}-4-[2-(trifluoromethyl)phenyl]pipe-
ridine
[0946] Using the procedure from Example 14A, the title compound
(126 mg) was isolated as a white solid, in 64% yield.
[0947] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.72-2.02 (m, 4H),
2.26-2.55 (m, 2H), 2.75-3.01 (m, 1H), 3.98 (t, J=11.9 Hz, 2H), 7.31
(t, J=7.6 Hz, 1H), 7.40 (appar d, J=8.1 Hz, 3H), 7.53 (t, J=7.7 Hz,
1H), 7.61 (d, J=7.8 Hz, 1H), 7.85 (d, J=8.8 Hz, 2H). HRMS: calcd
for C.sub.19H.sub.17F.sub.6NO.sub.3S+H+, 454.09061; found
(ESI-FTMS, [M+H].sup.1+), 454.0909. HPLC Method 1: room
temperature, 7.09 min, 89.7%. HPLC Method 2: room temperature, 7.57
min, 89.9%.
Example 14O
1-[(4-bromo-3-fluorophenyl)sulfonyl]-4-[2-(trifluoromethyl)phenyl]piperidi-
ne
[0948] Using the procedure from Example 14A, the title compound
(115 mg) was isolated as a white solid, in 57% yield.
[0949] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.70-2.06 (m, 4H),
2.28-2.51 (m, 2H), 2.74-3.07 (m, 1H), 3.96 (d, J=11.1 Hz, 2H), 7.32
(t, J=7.6 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.46 (dd, J=8.3, 1.3 Hz,
1H), 7.50-7.57 (m, 2H), 7.61 (d, J=7.8 Hz, 1H), 7.78 (dd, J=8.3,
6.6 Hz, 1H). HRMS: calcd for C.sub.18H.sub.16BrF.sub.4NO.sub.2S+H+,
466.00940; found (ESI-FTMS, [M+H].sup.1+), 466.0097. HPLC Method 1:
room temperature, 7.11 min, 98.7%. HPLC Method 2: room temperature,
7.68 min, 98.2%.
Example 15
##STR00052##
[0950] Example 15A
4-(naphthalene-2-sulfonyl)-1-(3-trifluoromethyl-pyridin-2-yl)-piperazin-2--
one
[0951] Step 15A: To a stirred solution of piperazine-2-one (353.3
mg, 3.5 mmol) and naphthalene-2-sulfonyl chloride (800 mg, 3.5
mmol) in anhydrous dichloromethane (15 mL) was added
diisopropylethylamine (1.54 mL, 8.8 mmol). The mixture was stirred
for 30 min. Reaction was complete as determined by TLC. The
reaction mixture was filtered, washed with hexane to give a first
batch. The mother liquor was washed with saturated ammonium
chloride, then washed with saturated brine, separated, dried over
sodium sulphate. Then hexane was added, lots of precipitate formed.
The was filtered, washed with hexane to give a second batch. The
two batches were combined to yield
4-(naphthalene-2-sulfonyl)-piperazin-2-one in 92.5% yield (947 mg)
as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm
3.35-3.40 (m, 2H) 3.42-3.48 (m, 2H) 3.79 (s, 2H) 6.11 (s, 1H)
7.63-7.73 (m, 2H) 7.77 (dd, J=8.72, 1.89 Hz, 1H) 7.94 (d, J=7.83
Hz, 1H) 7.98-8.05 (m, 2H) 8.38 (s, 1H).
[0952] Step 15B: An oven-dried microwave vial was charged with of
4-(naphthalene-2-sulfonyl)-piperazin-2-one (100 mg, 0.34 mmol),
2-bromo-3-trifluoromethylpyridine (115.3 mg, 0.51 mmol), powdered
anhydrous potassium carbonate (94 mg, 0.68 mmol), and CuI (6.5 mg,
0.034 mmol). The vial was purged and back-filled with N.sub.2.
Anhydrous 1,4-dioxane (1.2 mL) was added, followed by 3.7 .mu.L
(0.034 mmol) of N,N'-dimethyl-1,2-ethylenediamine. The blue
suspension was heated in a 110.degree. C. oil bath for 48 hr. After
cooling to room temperature, the brown suspension was diluted with
H.sub.2O and EtOAc. The layers were separated, and the aqueous
layer was washed with EtOAc (2.times.). The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered, and concentrated under
reduced pressure. The residue was purified by prep HPLC to provide
4.8 mg (3.2%) of
4-(Naphthalene-2-sulfonyl)-1-(3-trifluoromethyl-pyridin-2-yl)-piperazin-2-
-one as a light yellow solid.
[0953] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.38-3.46 (m, 1H)
3.57-3.66 (m, 1H) 3.68-3.79 (m, 1H) 3.82-3.91 (m, 1H) 3.98-4.09 (m,
2H) 7.46 (dd, J=7.83, 4.80 Hz, 1H) 7.64-7.74 (m, 2H) 7.81 (dd,
J=8.59, 1.77 Hz, 1H) 7.94-8.09 (m, 4H) 8.42 (d, J=1.77 Hz, 1H) 8.71
(dd, J=5.05, 1.77 Hz, 1H). HRMS: calcd for
C.sub.20H.sub.16F.sub.3N.sub.3O.sub.3S+H+, 436.09372; found
(ESI-FTMS, [M+H].sup.1+), 436.0936.
Example 15B
4-(3,4-dichloro-benzenesulfonyl)-1-(3-trifluoromethyl-pyridin-2-yl)-pipera-
zin-2-one
[0954] Step 15A: Sulfonylation of piperazine-2-one (326.2 mg, 3.3
mmol) with 3,4-dichlorobenzene-sulfonyl chloride (800 mg, 3.3 mmol)
was carried out according to a similar procedure described for
example 15A using anhydrous dichloromethane (8 mL) as solvent and
diisopropylethylamine (1.42 mL, 8.2 mmol) as base.
4-(3,4-dichloro-benzenesulfonyl)-piperazin-2-one was obtained in
90.3% yield (912 mg) as white solid. 1H NMR (400 MHz, DMSO-D6)
.delta. ppm 3.17-3.24 (m, 2H) 3.25-3.30 (m, 2H) 3.59 (s, 2H) 7.79
(dd, J=8.46, 2.15 Hz, 1H) 7.94 (d, J=8.34 Hz, 1H) 8.06 (d, J=2.02
Hz, 1H) 8.08 (s, 1H).
[0955] Step 15B: Amidation of
4-(3,4-dichloro-benzenesulfonyl)-piperazin-2-one (150 mg, 0.49
mmol) with 2-bromo-3-trifluoromethylpyridine (164.5 mg, 0.73 mmol)
was carried out according to a similar procedure described for
example 15A using powdered anhydrous potassium carbonate (134.1 mg,
0.97 mmol) as base, CuI (9.2 mg, 0.049 mmol) as catalyst,
N,N'-dimethyl-1,2-ethylenediamine (5.2 .mu.L, 0.049 mmol) as
ligand, and anhydrous 1,4-dioxane (1.8 mL) as solvent.
4-(3,4-dichloro-benzenesulfonyl)-1-(3-trifluoromethyl-pyridin-2-yl)-piper-
azin-2-one was obtained in 10% yield (21 mg) as an off-white
solid.
[0956] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.38-3.47 (m, 1H)
3.57-3.65 (m, 1H) 3.68-3.76 (m, 1H) 3.82-3.89 (m, 1H) 3.98-4.08 (m,
2H) 7.46-7.53 (m, 1H) 7.64-7.72 (m, 2H) 7.93 (d, J=1.77 Hz, 1H)
8.09 (dd, J=7.96, 1.39 Hz, 1H) 8.75 (dd, J=4.80, 1.26 Hz, 1H);
HRMS: calcd for C.sub.16H.sub.12Cl.sub.2F.sub.3N.sub.3O.sub.3S+H+,
454.00013; found (ESI-FTMS, [M+H].sup.1+), 454; HPLC Method 1: room
temperature, 5.484 min, 100%, HPLC Method 2: room temperature,
6.418 min, 97.52%.
Example 16
Example 16A
1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[2-(trifluoromethyl)phenyl]piperazi-
n-1-yl}sulfonyl)phenyl]propan-2-ol
[0957] Step 16A: A mixture of (R)-2-methyl-piperazine (300 mg, 2.99
mmol), 2-bromo benzotrifluoride (612 mg, 2.72 mmol),
tris(dibenzylidineacetone)dipalladium (0) (24.72 mg, 0.027 mmol),
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (51.06 mg, 0.082
mmol) and sodium tert-butoxide (326.77 mg, 3.4 mmol) were charged
to a microwave vial. Toluene (3.0 mL) was introduced under nitrogen
atmosphere and the reaction mixture was irradiated at 110.degree.
C. for 30 minutes. Reaction was complete as determined by TLC. The
reaction was repeated at (R)-2-methyl-piperazine (1.0 g, 9.98
mmol). Reaction mixtures were combined, diluted with
dichloromethane, washed with water, saturated brine then dried over
Na.sub.2SO.sub.4 and concentrated. The crude product was purified
via flash column chromatography to yield
(R)-3-methyl-1-(2-trifluoromethyl-phenyl)-piperazine as yellow oil
(1.23 g, 39.6% yield). 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm
1.07 (d, J=6.32 Hz, 3H) 2.41-2.51 (m, 1H) 2.74-2.84 (m, 1H)
2.90-2.98 (m, 2H) 3.00-3.13 (m, 3H) 7.18-7.25 (m, 1H) 7.35 (d,
J=8.08 Hz, 1H) 7.47-7.55 (m, 1H) 7.62 (d, J=7.83 Hz, 1H).
[0958] Step 16B: To a stirred solution of
(R)-3-methyl-1-(2-trifluoromethyl-phenyl)-piperazine (500 mg, 2.05
mmol) and 4-acetylbenzenesulfonyl chloride (448.23 mg, 2.05 mmol)
in anhydrous dichloromethane (6 mL) was added diisopropylethylamine
(0.71 mL, 4.1 mmol). The mixture was stirred at room temperature
for over night. Reaction was complete as determined by TLC. The
reaction mixture was purified via flash column chromatography to
yield
(R)-1-{4-[2-methyl-4-(2-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-ph-
enyl}-ethanone in 74.0% yield (646.7 mg) as a light yellow solid.
1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.20 (d, J=6.57 Hz, 3H)
2.67 (s, 3H) 2.75-2.83 (m, 2H) 2.98 (d, J=10.11 Hz, 1H) 3.06 (d,
J=10.11 Hz, 1H) 3.33-3.43 (m, 1H) 3.76 (d, J=10.61 Hz, 1H) 4.26 (d,
J=6.82 Hz, 1H) 7.23-7.30 (m, 2H) 7.52 (t, J=7.71 Hz, 1H) 7.62 (d,
J=8.08 Hz, 1H) 7.89-7.99 (m, 2H) 8.07-8.14 (m, 2H).
[0959] Step 16C: To a 50 mL flask containing
(R)-1-{4-[2-methyl-4-(2-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-ph-
enyl}-ethanone (200 mg, 0.47 mmol) and 2.34 mL of 0.5 M
TMS-CF.sub.3 was added 0.47 mL of 1.0 M tetrabutylammonium fluoride
in THF at 0.degree. C. After stirring for 4 h, the solution was
diluted with saturated NaHCO.sub.3, extracted
(2.times.CH.sub.2Cl.sub.2), washed with brine and dried over
Na.sub.2SO.sub.4, and concentrated under reduced pressure.
Purification by flash column chromatography to yield
1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[2-(trifluoromethyl)phenyl]piperaz-
in-1-yl}sulfonyl)phenyl]propan-2-ol in 31.8% yield (74.1 mg) as a
colorless oil.
[0960] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.19-1.29 (m, 3H)
1.84 (s, 3H) 2.56 (s, 1H) 2.72-2.82 (m, 2H) 2.92-2.98 (m, 1H) 3.03
(dd, J=11.12, 3.54 Hz, 1H) 3.32-3.45 (m, 1H) 3.74 (d, J=13.14 Hz,
1H) 4.26 (dd, J=6.44, 3.41 Hz, 1H) 7.21-7.30 (m, 2H) 7.48-7.55 (m,
1H) 7.59-7.65 (m, 1H) 7.77 (d, J=8.34 Hz, 2H) 7.85-7.92 (m, 2H).
HPLC Method 1: room temperature, 6.486 min, 99.56%, HPLC Method 2:
room temperature, 7.222 min, 98.64%.
Example 16B
(2R)-1-[(2-chlorophenyl)sulfonyl]-2-methyl-4-[2-(trifluoromethyl)phenyl]pi-
perazine
[0961] The title compound was prepared according to a similar
procedure for Example 16A, step 16B. Yield 86%.
[0962] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.35 (d, J=6.82
Hz, 3H) 2.75-2.84 (m, 2H) 2.96 (dd, J=11.24, 2.91 Hz, 1H) 3.12 (dd,
J=11.12, 3.54 Hz, 1H) 3.53-3.63 (m, 1H) 3.73 (d, J=13.14 Hz, 1H)
4.11-4.20 (m, 1H) 7.22-7.28 (m, 1H) 7.32 (d, J=7.83 Hz, 1H)
7.38-7.43 (m, 1H) 7.47-7.57 (m, 3H) 7.64 (dd, J=7.83, 1.26 Hz, 1H)
8.15 (dd, J=7.96, 1.64 Hz, 1H). HPLC Method 1: room temperature,
6.950 min, 99.45%, HPLC Method 2: room temperature, 7.436 min,
99.80%.
Example 16C
(2R)-1-[(3,4-dichlorophenyl)sulfonyl]-2-methyl-4-[2-(trifluoromethyl)pheny-
l]piperazine
[0963] The title compound was prepared according to a similar
procedure for Example 16A, step 16B. Yield 92.3%.
[0964] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.20-1.29 (m, 3H)
2.74-2.86 (m, 2H) 2.93-3.12 (m, 2H) 3.32-3.43 (m, 1H) 3.71 (d,
J=12.63 Hz, 1H) 4.18-4.27 (m, 1H) 7.23-7.32 (m, 3H) 7.53 (t, J=7.83
Hz, 1H) 7.59-7.70 (m, 3H) 7.94 (d, J=2.02 Hz, 1H). HPLC Method 1:
room temperature, 7.363 min, 96.36%, HPLC Method 2: room
temperature, 7.845 min, 96.64%.
Example 16D
(2R)-1-[(4-chlorophenyl)sulfonyl]-2-methyl-4-[2-(trifluoromethyl)phenyl]pi-
perazine
[0965] The title compound was prepared according to a similar
procedure for Example 16A, step 16B. Yield 90.5%.
[0966] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.21 (d, J=6.57
Hz, 3H) 2.74-2.83 (m, 2H) 2.97 (d, J=10.86 Hz, 1H) 3.06 (dd,
J=11.12, 3.54 Hz, 1H) 3.31-3.41 (m, 1H) 3.71 (d, J=12.63 Hz, 1H)
4.17-4.27 (m, 1H) 7.22-7.31 (m, 2H) 7.46-7.56 (m, 3H) 7.63 (d,
J=7.83 Hz, 1H) 7.75-7.83 (m, 2H). HPLC Method 1: room temperature,
7.044 min, 97.87%, HPLC Method 2: room temperature, 7.541 min,
98.11%.
Example 16E
(2R)-1-[(5-chloro-2-thienyl)sulfonyl]-2-methyl-4-[2-(trifluoromethyl)pheny-
l]piperazine
[0967] The title compound was prepared according to a similar
procedure for Example 16A, step 16B. Yield 70.7%.
[0968] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.30 (d, J=6.82
Hz, 3H) 2.76-2.87 (m, 2H) 2.96-3.03 (m, 1H) 3.09 (dd, J=11.12, 3.54
Hz, 1H) 3.35-3.48 (m, 1H) 3.70 (d, J=12.63 Hz, 1H) 4.24 (d, J=6.82
Hz, 1H) 6.95 (d, J=4.04 Hz, 1H) 7.24-7.34 (m, 2H) 7.38 (d, J=4.04
Hz, 1H) 7.54 (t, J=7.71 Hz, 1H) 7.61-7.68 (m, 1H). HPLC Method 1:
room temperature, 7.162 min, 99.59%, HPLC Method 2: room
temperature, 7.621 min, 99.80%.
Example 16F
(2R)-1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-2-methyl-4-[2-(trif-
luoromethyl)phenyl]piperazine
[0969] The title compound was prepared according to a similar
procedure for Example 16A, step 16B. Yield 86.1%.
[0970] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.33 (d, J=6.82
Hz, 3H) 2.69 (s, 3H) 2.78-2.89 (m, 2H) 2.94-3.04 (m, 1H) 3.12 (d,
J=10.86 Hz, 1H) 3.45-3.57 (m, 1H) 3.82 (d, J=12.88 Hz, 1H) 4.31 (d,
J=6.82 Hz, 1H) 7.22-7.31 (m, 2H) 7.46 (dd, J=8.59, 2.02 Hz, 1H)
7.49-7.54 (m, 1H) 7.62-7.66 (m, 1H) 7.77 (d, J=8.59 Hz, 1H) 7.80
(d, J=2.02 Hz, 1H). HPLC Method 1: room temperature, 7.710 min,
99.78%, HPLC Method 2: room temperature, 8.038 min, 99.77%.
Example 16G
(2R)-1-[(5-chloro-2-naphthyl)sulfonyl]-2-methyl-4-[2-(trifluoromethyl)phen-
yl]piperazine
[0971] The title compound was prepared according to a similar
procedure for Example 16A, step 16B. Yield 88.8%.
[0972] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.22 (d, J=6.82
Hz, 3H) 2.76-2.84 (m, 2H) 2.98 (d, J=12.63 Hz, 1H) 3.05-3.11 (m,
1H) 3.38-3.47 (m, 1H) 3.78-3.84 (m, 1H) 4.30 (s, 1H) 7.21-7.30 (m,
2H) 7.47-7.57 (m, 2H) 7.62 (dd, J=7.83, 1.26 Hz, 1H) 7.74 (dd,
J=7.58, 1.01 Hz, 1H) 7.88-7.96 (m, 2H) 8.41-8.46 (m, 2H). HPLC
Method 1: room temperature, 7.566 min, 99.33%, HPLC Method 2: room
temperature, 7.951 min, 99.11%.
Example 17
##STR00053##
[0973] Example 17A
2-chloro-N-{1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}benzenesulfo-
namide
[0974] Step 17A: tert-Butyl
{1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}carbamate. A
mixture of 4-(tertbutoxycarbonylamino)piperidine (1.0 g, 5.0 mmol),
2-chloro-4-trifluoromethylpiperidine (3.6 g, 20.0 mmol), DIEA (6.0
mL, 30.0 mmol), and dioxane (2.0 mL) was heated in a microwave
reactor at 150.degree. C. for 2 h. the mixture was cooled, diluted
with CH.sub.2Cl.sub.2 (50 mL), and poured in 1N HCl (100 mL). The
aqueous phase was extracted with CH.sub.2Cl.sub.2 (2.times.100 mL).
The combined organic extracts were washed with H.sub.2O and brine,
dried (MgSO.sub.4), and concentrated. Purification by SiO.sub.2
chromatography afforded the tert-butyl carbamate (1.39 g), a pale
yellow oil, in 80% yield.
[0975] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.46 (s, 9H),
1.48-1.68 (m, 2H), 2.04 (d, J=12.4 Hz, 2H), 2.80-3.10 (m, 2H), 3.54
(d, J=13.1 Hz, 2H), 3.65 (br s, 1H), 4.52 (br s, 1H), 6.98 (dd,
J=7.7, 4.7 Hz, 1H), 7.85 (dd, J=7.7, 1.9 Hz, 1H), 8.42 (dd, J=4.8,
2.0 Hz, 1H).
[0976] Step 17B:
1-[3-(Trifluoromethyl)pyridin-2-yl]piperidin-4-amine. A solution of
TFA (10 mL) and CH.sub.2Cl.sub.2 (10 mL) was added to a flask
containing the tert-butyl carbamate from Step 17A (1.39 g, 4.0
mmol). After 1 h, the mixture was concentrated, diluted with
CH.sub.2Cl.sub.2 (100 mL), washed with 1N NaOH (100 mL), H.sub.2O
(100 mL) and brine (100 mL), dried (MgSO.sub.4), and concentrated
to afford the amine (0.57 g, 57%), a pale yellow oil. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 1.38-1.70 (m, 2H), 1.75-2.08 (m, 2H),
2.44 (br s, 2H), 2.71-3.21 (m, 3H), 3.59 (d, J=13.4 Hz, 2H),
6.76-7.13 (m, 1H), 7.85 (dd, J=7.7, 1.9 Hz, 1H), 8.41 (dd, J=4.8,
1.3 Hz, 1H).
[0977] Step 17C:
1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-amine (100 mg, 0.42
mmol) was reacted with 2-chlorobenzenesulfonyl chloride (106 mg,
0.50 mmol) to afford the title compound (73 mg), a white solid, in
41% yield.
[0978] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.46-1.72 (m, 2H),
1.76-1.93 (m, 2H), 2.70-3.07 (m, 2H), 3.27-3.39 (m, 1H), 3.40-3.61
(m, 2H), 5.04 (d, J=7.6 Hz, 1H), 6.99 (dd, J=7.5, 4.4 Hz, 1H),
7.37-7.49 (m, 1H), 7.49-7.64 (m, 2H), 7.84 (dd, J=7.7, 1.9 Hz, 1H),
8.14 (dd, J=7.6, 1.3 Hz, 1H), 8.40 (dd, J=4.8, 1.5 Hz, 1H). HRMS:
calcd for C.sub.17H.sub.17ClF.sub.3N.sub.3O.sub.2S+H+, 420.07548;
found (ESI-FTMS, [M+H].sup.1+), 420.0756. HPLC Method 1: room
temperature, 6.69 min, 97.0%. HPLC Method 2: room temperature, 6.18
min, 97.0%.
Example 17B
3-chloro-N-{1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}benzenesulfo-
namide
[0979] Step 17C: Using the procedure from Example 17A, Step 17C,
1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-amine (100 mg, 0.42
mmol) was reacted with 3-chlorobenzenesulfonyl chloride (106 mg,
0.50 mmol) to afford the title compound (71 mg), a white solid, in
40% yield.
[0980] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.51-1.70 (m, 2H),
1.79-1.97 (m, 2H), 2.81-2.99 (m, 2H), 3.21-3.56 (m, 3H), 4.64 (d,
J=7.8 Hz, 1H), 7.00 (dd, J=8.2, 5.2 Hz, 1H), 7.48 (t, J=8.1 Hz,
1H), 7.54-7.62 (m, 1H), 7.73-7.82 (m, 1H), 7.85 (dd, J=8.0, 1.6 Hz,
1H), 7.91 (t, J=1.8 Hz, 1H), 8.41 (dd, J=4.8, 1.3 Hz, 1H). HRMS:
calcd for C.sub.17H.sub.17ClF.sub.3N.sub.3O.sub.2S+H+, 420.07548;
found (ESI-FTMS, [M+H].sup.1+), 420.0759. HPLC Method 1: room
temperature, 6.18 min, 95.9%. HPLC Method 2: room temperature, 6.94
min, 96.2%.
Example 17C
4-chloro-N-{1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}benzenesulfo-
namide
[0981] Using the procedure from Example 17A, the title compound
(142 mg) was isolated as a white solid, in 81% yield.
[0982] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.51-1.70 (m, 2H),
1.75-1.95 (m, 2H), 2.86-3.02 (m, 2H), 3.28-3.41 (m, 1H), 3.41-3.57
(m, 2H), 4.61 (d, J=7.8 Hz, 1H), 6.86-7.07 (m, 1H), 7.50 (d, J=8.8
Hz, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.78 (d, J=8.8 Hz, 1H), 7.81-7.93
(m, 2H), 8.41 (dd, J=4.7, 1.4 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.17ClF.sub.3N.sub.3O.sub.2S+H+, 420.07548; found
(ESI-FTMS, [M+H].sup.1+), 420.0761. HPLC Method 1: room
temperature, 6.26 min, 98.5%. HPLC Method 2: room temperature, 6.95
min, 98.5%.
Example 17D
4-bromo-N-{1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}benzenesulfon-
amide
[0983] Step 17C: Using the procedure from Example 17A, the title
compound (47 mg) was isolated as a white solid, in 24% yield.
[0984] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.45-1.73 (m, 2H),
1.77-1.96 (m, 2H), 2.64-3.09 (m, 2H), 3.21-3.73 (m, 3H), 4.57 (d,
J=7.8 Hz, 1H), 7.00 (dd, J=6.8, 4.8 Hz, 1H), 7.67 (d, J=8.8 Hz,
2H), 7.78 (d, J=8.8 Hz, 2H), 7.85 (dd, J=8.0, 1.9 Hz, 1H), 8.41
(dd, J=4.8, 1.3 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.17BrF.sub.3N.sub.3O.sub.2S+H+, 464.02497; found
(ESI-FTMS, [M+H].sup.1+), 464.0258. HPLC Method 1: room
temperature, 6.26 min, 95.4%. HPLC Method 2: room temperature, 7.02
min, 95.1%.
Example 17E
3-fluoro-N-{1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}benzenesulfo-
namide
[0985] Step 17C: Using the procedure from Example 17A, the title
compound (73 mg) was isolated as a white solid, in 43% yield.
[0986] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.48-1.71 (m, 2H),
1.82-1.99 (m, 2H), 2.69-3.09 (m, 2H), 3.20-3.59 (m, 3H), 4.63 (d,
J=7.8 Hz, 1H), 7.00 (dd, J=7.8, 4.8 Hz, 1H), 7.27-7.39 (m, 1H),
7.42-7.59 (m, 1H), 7.57-7.67 (m, 1H), 7.67-7.79 (m, 1H), 7.85 (dd,
J=7.8, 1.8 Hz, 1H), 8.41 (dd, J=4.8, 1.3 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.17F.sub.4N.sub.3O.sub.2S+H+, 404.10503; found
(ESI-FTMS, [M+H].sup.1+), 404.1056. HPLC Method 1: room
temperature, 5.90 min, 97.8%. HPLC Method 2: room temperature, 6.67
min, 97.7%.
Example 17F
4-bromo-3-fluoro-N-{1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}benz-
enesulfonamide
[0987] Step 17C: Using the procedure from Example 17A, the title
compound (137 mg) was isolated as a white solid, in 68% yield.
[0988] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.49-1.70 (m, 2H),
1.90 (dd, J=12.5, 3.9 Hz, 2H), 2.82-3.05 (m, 2H), 3.18-3.56 (m,
3H), 4.57 (d, J=8.1 Hz, 1H), 7.01 (dd, J=7.3, 5.1 Hz, 1H), 7.58
(dd, J=8.3, 1.5 Hz, 1H), 7.66 (dd, J=7.8, 2.0 Hz, 1H), 7.74 (dd,
J=8.3, 6.6 Hz, 1H), 7.85 (dd, J=7.8, 1.8 Hz, 1H), 8.41 (dd, J=4.7,
1.4 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.16BrF.sub.4N.sub.3O.sub.2S+H+, 482.01555; found
(ESI-FTMS, [M+H].sup.1+), 482.0164. HPLC Method 1: room
temperature, 6.35 min, 98.0%. HPLC Method 2: room temperature, 7.14
min, 97.6%.
Example 17G
3,4-dichloro-N-{1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}benzenes-
ulfonamide
[0989] Step 17C: Using the procedure from Example 17A, the title
compound (95 mg) was isolated as a white solid, in 50% yield.
[0990] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.50-1.70 (m, 2H),
1.82-1.99 (m, 2H), 2.82-3.10 (m, 2H), 3.19-3.57 (m, 3H), 4.65 (d,
J=7.8 Hz, 1H), 7.01 (dd, J=7.1, 4.8 Hz, 1H), 7.61 (d, J=8.3 Hz,
1H), 7.73 (dd, J=8.3, 2.0 Hz, 1H), 7.85 (dd, J=7.8, 1.8 Hz, 1H),
8.00 (d, J=2.3 Hz, 1H), 8.41 (dd, J=4.8, 1.8 Hz, 1H). HRMS: calcd
for C.sub.17H.sub.16Cl.sub.2F.sub.3N.sub.3O.sub.2S+H+, 454.03651;
found (ESI-FTMS, [M+H].sup.1+), 454.0372. HPLC Method 1: room
temperature, 6.55 min, 96.6%. HPLC Method 2: room temperature, 7.32
min, 96.8%.
Example 17H
N-{1-[3-(trifluoromethylpyridin-2-yl]piperidin-4-yl}naphthalene-2-sulfonam-
ide
[0991] Step 17C: Using the procedure from Example 17A, the title
compound (114 mg) was isolated as a white solid, in 62% yield.
[0992] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.59 (dd, 3H),
1.79-1.96 (m, 2H), 2.76-2.99 (m, 2H), 3.26-3.62 (m, 3H), 4.58 (d,
J=8.1 Hz, 1H), 6.98 (dd, J=8.1, 5.1 Hz, 1H), 7.59-7.71 (m, 2H),
7.82 (dd, J=7.8, 2.0 Hz, 1H), 7.87 (dd, J=8.7, 1.9 Hz, 1H),
7.90-7.96 (m, 1H), 7.99 (d, J=8.8 Hz, 2H), 8.38 (dd, J=4.8, 1.8 Hz,
1H), 8.49 (d, J=1.3 Hz, 1H). HRMS: calcd for
C.sub.21H.sub.20F.sub.3N.sub.3O.sub.2S+H+, 436.13011; found
(ESI-FTMS, [M+H].sup.1+), 436.1303. HPLC Method 1: room
temperature, 6.30 min, 95.0%. HPLC Method 2: room temperature, 7.04
min, 95.5%.
Example 17I
4-tert-butyl-N-{1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}benzenes-
ulfonamide
[0993] Step 17C: Using the procedure from Example 17A, the title
compound (107 mg) was isolated as a white solid, in 58% yield.
[0994] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.35 (s, 9H),
1.55-1.67 (m, 2H), 1.89 (dd, J=12.5, 4.2 Hz, 2H), 2.82-2.97 (m,
2H), 3.26-3.41 (m, 1H), 3.41-3.57 (m, 2H), 4.41 (d, J=7.6 Hz, 1H),
6.91-7.03 (m, 1H), 7.52 (d, J=8.8 Hz, 2H), 7.73-7.90 (m, 3H), 8.40
(dd, J=4.8, 1.3 Hz, 1H). HRMS: calcd for
C.sub.21H.sub.26F.sub.3N.sub.3O.sub.2S+H+, 442.17706; found
(ESI-FTMS, [M+H].sup.1+), 442.1773. HPLC Method 1: room
temperature, 6.74 min, 88.8%. HPLC Method 2: room temperature, 7.34
min, 92.4%.
Example 18
##STR00054##
[0996] The piperazine or piperidine derivative (1.0 mmol) was mixed
with 5 ml of CH.sub.2Cl.sub.2 and diisopropylethyl amine (2.4
mmol), aryl or alkyl acid chloride (1.2 mmol) or alkyl or aryl
chloroformate (1.2 mmol) was added in one portion. The reaction
mixture was stirred at room temperature and monitored by TLC (2-24
hrs). When the reaction was completed, the reaction mixture was
loaded onto a silica gel column to remove high polar impurities.
The product was isolated and purified by column chromatography. The
following compounds were prepared using this general procedure.
Example 18A
1-(1-adamantylcarbonyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine
[0997] The desired product was obtained in 90% yield as a oil. 1H
NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.59-1.88 (m, 6H) 2.01-2.13
(m, 9H) 3.24-3.32 (m, 4H) 3.78-3.93 (m, 4H) 7.02-7.11 (m, 1H) 7.92
(dd, J=7.71, 1.89 Hz, 1H) 8.46 (dd, J=4.93, 1.89 Hz, 1H). HRMS:
calcd for C.sub.21H.sub.26F.sub.3N.sub.3O+H+, 394.21007; found
(ESI-FTMS, [M+H].sup.1+), 394.2097.
Example 18B
1-(cyclohexylcarbonyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine
[0998] The desired product was obtained in 75% yield as a colorless
oil. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.19-1.40 (m, 3H)
1.48-1.65 (m, J=11.87, 2.78 Hz, 2H) 1.64-1.94 (m, 5H) 2.46-2.57 (m,
1H) 3.19-3.37 (m, 4H) 3.60-3.83 (m, 4H) 7.02-7.12 (m, J=7.83, 4.80
Hz, 1H) 7.92 (dd, J=7.71, 1.89 Hz, 1H) 8.47 (dd, J=4.80, 1.26 Hz,
1H). HRMS: calcd for C.sub.17H.sub.22F.sub.3N.sub.3O+H+, 342.17877;
found (ESI-FTMS, [M+H].sup.1+), 342.1784.
Example 18C
1-[(4-chlorophenyl)acetyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine
[0999] The desired product was obtained in 68% yield as a colorless
oil. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.11-3.18 (m, 2H)
3.19-3.27 (m, 2H) 3.55-3.65 (m, 2H) 3.73 (s, 2H) 3.76-3.82 (m, 2H)
7.00-7.09 (m, J=7.83, 4.80 Hz, 1H) 7.17-7.23 (m, 2H) 7.28-7.33 (m,
2H) 7.85-7.93 (m, J=7.58, 1.77 Hz, 1H) 8.44 (dd, J=4.93, 1.39 Hz,
1H). HRMS: calcd for C.sub.18H.sub.17ClF.sub.3N.sub.3O+H+,
384.10850; found (ESI-FTMS, [M+H].sup.1+), 384.108.
Example 18D
Adamantan-1-yl-[4-(2,6-dichloro-phenoxy)-piperidin-1-yl]-methanone
[1000] The desired product was obtained in 85% yield as a colorless
oil. mp 191-199, 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm
1.68-1.82 (m, 9H) 1.83-1.98 (m, 6H) 1.97-2.13 (m, 4H) 3.29-3.49 (m,
2H) 4.09-4.28 (m, 2H) 4.43-4.54 (m, 1H) 6.99 (t, 1H) 7.29-7.31 (m,
1H) 7.31-7.33 (m, 1H).
Example 18E
1-[(4-chlorophenyl)acetyl]-4-(2,6-dichlorophenoxy)piperidine
[1001] The desired product was obtained in 70% yield as a oil. 1H
NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.68-1.83 (m, 2H) 1.86-2.00
(m, 2H) 3.22-3.39 (m, 1H) 3.42-3.56 (m, 1H) 3.73 (s, 2H) 3.77-3.91
(m, 1H) 4.01-4.14 (m, 1H) 4.36-4.49 (m, 1H) 6.98 (t, 1H) 7.18-7.23
(m, 2H) 7.27-7.34 (m, 4H). HRMS: calcd for
C.sub.19H.sub.18Cl.sub.3NO.sub.2+H+, 398.04759; found (ESI-FTMS,
[M+H].sup.1+), 398.0492.
Example 18F
1-(cyclohexylcarbonyl)-4-(2,6-dichlorophenoxy)piperidine
[1002] The desired product was obtained in 85% yield as a colorless
oil. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.16-1.40 (m, 3H)
1.42-1.64 (m, 2H) 1.62-1.87 (m, 5H) 1.87-2.09 (m, J=14.15, 14.15
Hz, 4H) 2.43-2.58 (m, 1H) 3.25-3.41 (m, 2H) 3.79-3.98 (m, J=13.39
Hz, 1H) 4.06-4.21 (m, 1H) 4.40-4.55 (m, 1H) 6.99 (t, 1H) 7.29-7.31
(m, 1H) 7.30-7.33 (m, 1H). HRMS: calcd for
C.sub.18H.sub.23Cl.sub.2NO.sub.2+H+, 356.11786; found (ESI-FTMS,
[M+H].sup.1+), 356.1197.
Example 18G
tert-butyl
4-[(3,4-dichlorophenyl)sulfonyl]piperazine-1-carboxylate
[1003] The desired product was obtained in 80% yield as a white
solid. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.33-1.52 (m, 9H)
2.91-3.09 (m, 4H) 3.45-3.64 (m, 4H) 7.57 (dd, 1H) 7.63 (d, 1H) 7.84
(d, J=2.02 Hz, 1H).
Example 19
##STR00055##
[1004] Example 19A
1-[(3-isopropyl-1-methylcyclopentyl)carbonyl]-4-[3-(trifluoromethyl)pyridi-
n-2-yl]piperazine
[1005] Step 19A: To a stirred solution of
3-isopropyl-1-methylcyclopentanecarboxylic acid (89 mg, 0.52 mmol)
and 1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (242 mg, 1.04
mmol) in N,N-dimethylformamide (1 mL) was added
benzotriazole-1yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate (700 mg, 1.56 mmol). The reaction was heated in
a microwave at 150.degree. C. for 5 minutes. The reaction mixture
was purified with HPLC to yield
1-[(3-isopropyl-1-methylcyclopentyl)carbonyl]-4-[3-(trifluoromethyl)pyrid-
in-2-yl]piperazine in 42% yield (83.3 mg) as off-white solid.
[1006] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.90 (t, J=6.57
Hz, 6H) 1.12-1.45 (m, 5H) 1.47-1.69 (m, 3H) 1.76-1.90 (m, 2H)
2.20-2.43 (m, 1H) 3.12-3.35 (m, 4H) 3.59-3.87 (m, 4H) 7.06 (dd,
J=7.83, 4.80 Hz, 1H) 7.90 (dd, J=7.83, 1.77 Hz, 1H) 8.46 (dd,
J=4.67, 1.39 Hz, 1H). HRMS: calcd for
C.sub.20H.sub.28F.sub.3N.sub.3O+H+, 384.22572; found (ESI-FTMS,
[M+H].sup.1+), 384.2253. HPLC Method 1: room temperature, 7.177
min, 97.88%. HPLC Method 2: room temperature, 7.801 min,
99.06%.
Example 19B
1-[(2,2-dichloro-1-methylcyclopropyl)carbonyl]-4-[3-(trifluoromethyl)pyrid-
in-2-yl]piperazine
[1007] Step 19A: Coupling of
1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol)
with 2,2-dichloro-1-methylcyclopropanecarboxylic acid (100 mg, 0.59
mmol) was carried out according to a similar procedure described
for example 19A using N,N-dimethylformamide (1 mL) as solvent and
benzotriazole-1yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent.
1-[(2,2-dichloro-1-methylcyclopropyl)carbonyl]-4-[3-(trifluoromethyl)pyri-
din-2-yl]piperazine was obtained in 56% yield (127 mg) as colorless
oil.
[1008] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.42 (d, J=7.58
Hz, 1H) 1.57 (s, 3H) 2.11 (d, J=7.58 Hz, 1H) 3.13-3.34 (m, 2H)
3.35-3.47 (m, 2H) 3.63-3.81 (m, 3H) 3.81-4.20 (m, 1H) 6.94-7.21 (m,
1H) 7.93 (dd, J=7.83, 1.77 Hz, 1H) 8.48 (dd, J=4.80, 1.26 Hz, 1H).
HRMS: calcd for C.sub.15H.sub.16Cl.sub.2F.sub.3N.sub.3O+H+,
382.06953; found (ESI-FTMS, [M+H].sup.1+), 382.069. HPLC Method 1:
room temperature, 6.036 min, 100.00%. HPLC Method 2: room
temperature, 7.073 min, 99.71%.
Example 19C
1-(cyclohexylacetyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine
[1009] Step 19A: Coupling of
1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol)
with 2-cyclohexylacetic acid (100 mg, 0.70 mmol) was carried out
according to a similar procedure described for example 19A using
N,N-dimethylformamide (1 mL) as solvent and
benzotriazole-1yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent.
1-(cyclohexylacetyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine
was obtained in 56% yield (140 mg) as colorless oil.
[1010] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.90-1.37 (m, 5H)
1.59-1.89 (m, 6H) 2.27 (d, J=6.82 Hz, 2H) 3.15-3.36 (m, 4H)
3.56-3.71 (m, 2H) 3.70-3.86 (m, 2H) 7.07 (dd, J=7.33, 5.05 Hz, 1H)
7.90 (dd, J=7.71, 1.89 Hz, 1H) 8.46 (dd, J=4.80, 1.26 Hz, 1H).
HRMS: calcd for C.sub.18H.sub.24F.sub.3N.sub.3O+H+, 356.19442;
found (ESI-FTMS, [M+H].sup.1+), 356.1942. HPLC Method 1: room
temperature, 6.253 min, 98.75%. HPLC Method 2: room temperature,
7.279 min, 97.47%.
Example 19D
1-(cyclopentylacetyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine
[1011] Step 19A: Coupling of
1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol)
with 2-cyclopentylacetic acid (100 mg, 0.78 mmol) was carried out
according to a similar procedure described for example 19A using
N,N-dimethylformamide (1 mL) as solvent and
benzotriazole-1yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent.
1-(cyclopentylacetyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine
was obtained in 43% yield (114 mg) as colorless oil.
[1012] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.03-1.36 (m, 2H)
1.41-1.79 (m, 4H) 1.72-1.97 (m, 2H) 2.10-2.32 (m, 1H) 2.42 (d,
J=7.33 Hz, 2H) 3.06-3.37 (m, 4H) 3.48-3.77 (m, 2H) 3.71-4.06 (m,
2H) 7.07 (dd, J=7.33, 4.80 Hz, 1H) 7.91 (dd, J=7.83, 1.77 Hz, 1H)
8.46 (dd, J=4.67, 1.39 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.22F.sub.3N.sub.3O+H+, 342.17877; found (ESI-FTMS,
[M+H].sup.1+), 342.1784. HPLC Method 1: room temperature, 6.082
min, 100.00%. HPLC Method 2: room temperature, 7.121 min,
99.55%.
Example 19E
1-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-4-[3-(trifluoromethyl)pyridin-
-2-yl]piperazine
[1013] Step 19A: Coupling of
1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol)
with 2,2,3,3-tetramethylcyclopropanecarboxylic acid (100 mg, 0.70
mmol) was carried out according to a similar procedure described
for example 1A using N,N-dimethylformamide (1 mL) as solvent and
benzotriazole-1yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent.
1-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-4-[3-(trifluoromethyl)pyridi-
n-2-yl]piperazine was obtained in 67% yield (166 mg) as colorless
oil.
[1014] HRMS: calcd for C.sub.18H.sub.24F.sub.3N.sub.3O+H+,
356.19442; found (ESI-FTMS, [M+H].sup.1+), 356.1942. HPLC Method 1:
room temperature, 6.399 min, 99.04%. HPLC Method 2: room
temperature, 7.328 min, 98.59%.
Example 19F
1-[(4-methylcyclohexyl)acetyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazi-
ne
[1015] Step 19A: Coupling of
1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol)
with 2-(4-methylcyclohexyl)acetic acid (100 mg, 0.64 mmol) was
carried out according to a similar procedure described for example
19A using N,N-dimethylformamide (1 mL) as solvent and
benzotriazole-1yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent.
1-[(4-methylcyclohexyl)acetyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperaz-
ine was obtained in 43% yield (102 mg) as colorless oil.
[1016] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.08 (s, 1H) 1.19
(d, J=2.27 Hz, 12H) 2.79-3.52 (m, 4H) 3.50-3.99 (m, 4H) 7.06 (dd,
J=7.45, 5.18 Hz, 1H) 7.90 (dd, J=7.83, 1.77 Hz, 1H) 8.46 (dd,
J=4.80, 1.52 Hz, 1H). HRMS: calcd for
C.sub.19H.sub.26F.sub.3N.sub.3O+H+, 370.21007; found (ESI-FTMS,
[M+H].sup.1+), 370.2097. HPLC Method 1: room temperature, 6.761
min, 100.00%. HPLC Method 2: room temperature, 7.578 min,
100.00%.
Example 19G
1-(bicyclo[2.2.1]hept-2-ylacetyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piper-
azine
[1017] Step 19A: Coupling of
1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol)
with 2-(bicyclo[2.2.1]heptan-2-yl)acetic acid (100 mg, 0.65 mmol)
was carried out according to a similar procedure described for
example 19A using N,N-dimethylformamide (1 mL) as solvent and
benzotriazole-1yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent.
1-(bicyclo[2.2.1]hept-2-ylacetyl)-4-[3-(trifluoromethyl)pyridin-2-yl]pipe-
razine was obtained in 82% yield (195 mg) as colorless oil.
[1018] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.56-0.83 (m, 1H)
0.98-1.67 (m, 6H) 1.75-1.98 (m, 1H) 2.07-2.61 (m, 5H) 3.10-3.38 (m,
4H) 3.56-3.69 (m, 2H) 3.70-3.84 (m, 2H) 7.06 (dd, J=7.83, 4.80 Hz,
1H) 7.90 (dd, J=7.71, 1.89 Hz, 1H) 8.46 (dd, J=4.80, 1.52 Hz, 1H).
HRMS: calcd for C.sub.19H.sub.24F.sub.3N.sub.3O+H+, 368.19442;
found (ESI-FTMS, [M+H].sup.1+), 368.1941. HPLC Method 1: room
temperature, 6.489 min, 99.72%. HPLC Method 2: room temperature,
7.421 min, 99.63%.
Example 19H
1-[(3-methylcyclohexyl)carbonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]pipera-
zine
[1019] Step 19A: Coupling of
1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol)
with 3-methylcyclohexanecarboxylic acid (100 mg, 0.70 mmol) was
carried out according to a similar procedure described for example
19A using N,N-dimethylformamide (1 mL) as solvent and
benzotriazole-1yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent.
1-[(3-methylcyclohexyl)carbonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piper-
azine was obtained in 45% yield (112 mg) as colorless oil.
[1020] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.87-1.06 (m, 3H)
1.12-1.92 (m, 7H) 1.93-2.13 (m, 1H) 2.46-2.64 (m, 1H) 2.70-2.90 (m,
1H) 3.10-3.39 (m, 4H) 3.55-3.84 (m, 4H) 7.06 (dd, J=7.07, 4.80 Hz,
1H) 7.90 (dd, J=7.83, 1.77 Hz, 1H) 8.46 (dd, J=4.80, 1.26 Hz, 1H).
HRMS: calcd for C.sub.18H.sub.24F.sub.3N.sub.3O+H+, 356.19442;
found (ESI-FTMS, [M+H].sup.1+), 356.1942. HPLC Method 1: room
temperature, 6.420 min, 98.80%. HPLC Method 2: room temperature,
7.354 min, 98.10%.
Example 19I
1-[(2-methylcyclohexyl)carbonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]pipera-
zine
[1021] Step 19A: Coupling of
1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol)
with 2-methylcyclohexanecarboxylic acid (100 mg, 0.70 mmol) was
carried out according to a similar procedure described for example
19A using N,N-dimethylformamide (1 mL) as solvent and
benzotriazole-1yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent.
1-[(2-methylcyclohexyl)carbonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piper-
azine was obtained in 45% yield (112 mg) as colorless oil.
[1022] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.95 (d, J=7.07
Hz, 3H) 1.13-2.17 (m, 9H) 2.65-2.83 (m, 1H) 3.06-3.41 (m, 4H)
3.51-3.74 (m, 3H) 3.80-3.98 (m, 1H) 7.06 (dd, J=7.83, 4.80 Hz, 1H)
7.90 (dd, J=7.58, 1.77 Hz, 1H) 8.46 (dd, J=4.80, 1.26 Hz, 1H).
HRMS: calcd for C.sub.18H.sub.24F.sub.3N.sub.3O+H+, 356.19442;
found (ESI-FTMS, [M+H].sup.1+), 356.1942. HPLC Method 1: room
temperature, 6.388 min, 99.03%. HPLC Method 2: room temperature,
7.333 min, 99.27%.
Example 20
##STR00056##
[1023] Example 20A
1-[(2-chlorophenyl)sulfonyl]-4-(2,6-dichlorophenyl)piperazine
[1024] Step 20A: 2,6-dichlorobromobenzene (2.26 g, 10 mmole),
N-Boc-piperazine (2.05 g, 11 mmole), Pd.sub.2(dba).sub.3 (92 mg, 1
mol %), BINAP (187 mg, 3 mol %), and sodium tert-butoxide (1.15 g,
12 mmole) were charged in a microwave vessel. The vessel was
capped, purged with nitrogen, and 20 mL toluene added. The reaction
mixture was heated to 110.degree. C. for 30 minutes in the
microwave and then the mixture was filtered through celite, rinsing
with EtOAc. The filtrate was evaporated and then filtered through a
pad of silica gel, eluting with dichloromethane. Evaporation gave
crude 4-(2,6-Dichloro-phenyl)-piperazine-1-carboxylic acid
tert-butyl ester as an orange oil that was taken on to the next
step without further purification.
[1025] Step 20B: 4-(2,6-Dichloro-phenyl)-piperazine-1-carboxylic
acid tert-butyl ester (crude material from Step 20A) was dissolved
in 50 mL dichloromethane and TFA (25 mL) was added and the mixture
stirred at room temperature for 1 hour. The solvent was evaporated,
then co-evaporated 3 times with dichloromethane. Obtain
1-(2,6-Dichloro-phenyl)-piperazine, trifluoroacetic acid salt, as a
yellow crystalline solid. ESI-MS: m/e=231 [M+H].sup.+.
[1026] Step 20C: 1-(2,6-Dichloro-phenyl)-piperazine,
trifluoroacetic acid salt (207 mg, 0.6 mmole) and DIPEA (0.32 mL,
1.8 mmole) were dissolved in 2.5 mL dichloromethane and
2-chlorophenylsulfonyl chloride (152 mg, 0.72 mmole) was added and
stirred at room temperature for 1 hour. The reaction mixture was
partitioned between water and dichloromethane and the organic layer
dried over Na.sub.2SO.sub.4 and evaporated. The crude product was
purified by flash chromatography using a gradient of 2% EtOAc/Hex
to 10% EtOAc/Hex. Obtain the title compound in 37% yield as a white
crystalline solid.
[1027] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.23-3.29 (m, 4H)
3.41-3.48 (m, 4H) 7.00 (t, J=8.08 Hz, 1H) 7.23-7.28 (m, 1H)
7.38-7.45 (m, 2H) 7.48-7.59 (m, 2H) 8.09 (dd, J=7.96, 1.64 Hz, 1H).
HRMS: calcd for C.sub.16H.sub.15Cl.sub.3N.sub.2O.sub.2S+H+,
404.99925; found (ESI-FTMS, [M+H]1+), 404.9992. HPLC Method 1: room
temperature, 7.013 min, 98.61%, HPLC Method 2: room temperature,
7.531 min, 98.77%.
Example 20B
1-[(4-chlorophenyl)sulfonyl]-4-(2,6-dichlorophenyl)piperazine
[1028] The title compound was obtained in 42% yield as a white
crystalline solid according to a similar procedure described for
example 20A.
[1029] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.15-3.21 (m, 4H)
3.28-3.33 (m, 4H) 6.97-7.03 (m, 1H) 7.23-7.28 (m, 4H) 7.53-7.57 (m,
1H) 7.72-7.77 (m, 1H). HRMS: calcd for
C.sub.16H.sub.15Cl.sub.3N.sub.2O.sub.2S+H+, 404.99925; found
(ESI-FTMS, [M+H]1+), 404.9991. HPLC Method 1: room temperature,
7.104 min, 100.00%, HPLC Method 2: room temperature, 7.624 min,
100.00%.
Example 20C
1-(2,6-dichlorophenyl)-4-[(3,4-dichlorophenyl)sulfonyl]piperazine
[1030] The title compound was obtained in 40% yield as a white
crystalline solid according to a similar procedure described for
example 20A.
[1031] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.17-3.22 (m, 4H)
3.28-3.33 (m, 4H) 7.01 (t, J=7.96 Hz, 1H) 7.22-7.28 (m, 2H)
7.60-7.67 (m, 2H) 7.89 (d, J=1.77 Hz, 1H). HRMS: calcd for
C.sub.16H.sub.14Cl.sub.4N.sub.2O.sub.2S+H+, 438.96028; found
(ESI-FTMS, [M+H]1+), 438.96. HPLC Method 1: room temperature, 7.440
min, 100.00%, HPLC Method 2: room temperature, 7.935 min,
100.00%.
Example 21
##STR00057##
[1032] Example 21A
1-[(2-chlorophenyl)sulfonyl]-4-[3-fluoro-2-(trifluoromethyl)phenyl]piperaz-
ine
[1033] Step 21A: 3-fluoro-2-trifluoromethylbromobenzene (2.43 g, 10
mmole), N-Boc-piperazine (2.05 g, 11 mmole), Pd.sub.2(dba).sub.3
(92 mg, 1 mol %), BINAP (187 mg, 3 mol %), and sodium tert-butoxide
(1.15 g, 12 mmole) were charged in a microwave vessel. The vessel
was capped, purged with nitrogen, and 20 mL toluene added. The
reaction mixture was heated to 110.degree. C. for 30 minutes in the
microwave and then the mixture was filtered through celite, rinsing
with EtOAc. The filtrate was evaporated and then filtered through a
pad of silica gel, eluting with dichloromethane. Evaporation gave
crude 4-(3-fluoro-2-trifluoromethyl)-piperazine-1-carboxylic acid
tert-butyl ester as a red oil that was taken on to the next step
without further purification. ESI-MS: m/e=293 [M-tBu].sup.+.
[1034] Step 21B:
4-(3-fluoro-2-trifluoromethyl)-piperazine-1-carboxylic acid
tert-butyl ester (crude material from Step 21A) was dissolved in 50
mL dichloromethane and TFA (25 mL) was added and the mixture
stirred at room temperature for 1 hour. The solvent was evaporated,
then co-evaporated 3 times with dichloromethane. Obtain
1-(3-Fluoro-2-trifluoromethyl-phenyl)-piperazine, trifluoroacetic
acid salt, as a low-melting red solid. ESI-MS: m/e=249
[M+H].sup.+.
[1035] Step 21C: 1-(3-Fluoro-2-trifluoromethyl-phenyl)-piperazine,
trifluoroacetic acid salt (217 mg, 0.6 mmole) and DIPEA (0.32 mL,
1.8 mmole) were dissolved in 2.5 mL dichloromethane and
2-chlorophenylsulfonyl chloride (152 mg, 0.72 mmole) was added and
stirred at room temperature overnight. The reaction mixture was
partitioned between water and dichloromethane and the organic layer
dried over Na.sub.2SO.sub.4 and evaporated. The crude product was
purified by flash chromatography using a gradient of 5% EtOAc/Hex
to 25% EtOAc/Hex. The title compound was obtained in 54% yield as a
white solid.
[1036] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.01 (t, J=4.80
Hz, 4H) 3.46 (br.s, 4H) 6.90-7.03 (m, 2H) 7.25-7.27 (m, 1H)
7.40-7.59 (m, 3H) 8.07 (dd, J=7.83, 1.77 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.15ClF.sub.4N.sub.2O.sub.2S+H+, 423.05516; found
(ESI-FTMS, [M+H]1+), 423.0555. HPLC Method 1: room temperature,
6.625 min, 100.00%, HPLC Method 2: room temperature, 7.202 min,
100.00%.
Example 21B
1-[(4-chlorophenyl)sulfonyl]-4-[3-fluoro-2-(trifluoromethyl)phenyl]piperaz-
ine
[1037] The title compound was obtained in 56% yield as a white
solid according to a similar procedure described for example
21A.
[1038] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.04 (t, J=4.42
Hz, 4H) 3.17 (br.s, 4H) 6.90-7.04 (m, 2H) 7.41-7.50 (m, 1H)
7.52-7.59 (m, 2H) 7.69-7.76 (m, 2H). HRMS: calcd for
C.sub.17H.sub.15ClF.sub.4N.sub.2O.sub.2S+H+, 423.05516; found
(ESI-FTMS, [M+H]1+), 423.0555. HPLC Method 1: room temperature,
6.786 min, 86.35%, HPLC Method 2: room temperature, 7.317 min,
82.80%.
Example 21C
1-[(3,4-dichlorophenyl)sulfonyl]-4-[3-fluoro-2-(trifluoromethyl)phenyl]pip-
erazine
[1039] The title compound was obtained in 52% yield as a white
solid according to a similar procedure described for example
21A.
[1040] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.05 (t, J=4.55
Hz, 4H) 3.20 br. (s, 4H) 6.92-7.03 (m, 1H) 7.25-7.27 (m, 1H)
7.42-7.50 (m, 1H) 7.58-7.63 (m, 1H) 7.64-7.68 (m, 1H) 7.88 (d,
J=2.02 Hz, 1H). HRMS: calcd for
C.sub.17H.sub.14Cl.sub.2F.sub.4N.sub.2O.sub.2S+H+, 457.01619; found
(ESI-FTMS, [M+H]1+), 457.0166. HPLC Method 1: room temperature,
7.105 min, 100.00%, HPLC Method 2: room temperature, 7.635 min,
99.39%.
Example 21D
1-[(4-tert-butylphenyl)sulfonyl]-4-[3-fluoro-2-(trifluoromethyl)phenyl]pip-
erazine
[1041] The title compound was obtained in 30% yield as a white
solid according to a similar procedure described for example
21A.
[1042] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 1.38 (s, 9H) 3.03
(t, J=4.55 Hz, 4H) 3.20 (br.s, 4H) 6.93 (dd, J=10.86, 8.34 Hz, 1H)
6.98-7.03 (m, 1H) 7.41-7.49 (m, 1H) 7.55-7.60 (m, 2H) 7.68-7.73 (m,
2H). HRMS: calcd for C.sub.21H.sub.24F.sub.4N.sub.2O.sub.2S+H+,
445.15674; found (ESI-FTMS, [M+H]1+), 445.1571. HPLC Method 1: room
temperature, 7.28 min, 99.04%, HPLC Method 2: room temperature,
7.66 min, 99.34%.
Example 21E
1-[3-fluoro-2-(trifluoromethyl)phenyl]-4-(2-naphthylsulfonyl)piperazine
[1043] The title compound was obtained in 62% yield as a white
solid according to a similar procedure described for example
21A.
[1044] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.04 (t, J=4.42
Hz, 4H) 3.23 (br.s, 4H) 6.88-6.96 (m, 1H) 7.00 (d, J=8.34 Hz, 1H)
7.39-7.49 (m, 1H) 7.60-7.73 (m, 2H) 7.75-7.81 (m, 1H) 7.92-8.06 (m,
3H) 8.37 (s, 1H). HRMS: calcd for
C.sub.21H.sub.18F.sub.4N.sub.2O.sub.2S+H+, 439.10979; found
(ESI-FTMS, [M+H]1+), 439.11. HPLC Method 1: room temperature, 6.896
min, 97.58%, HPLC Method 2: room temperature, 7.44 min, 96.54%.
Example 22
##STR00058##
[1045] Representative Procedure
[1046] Step 22A: 4-Oxo-piperidine-1-carboxylic acid tert-butyl
ester (2.99 g, 15 mmole), morpholine (1.4 mL, 15.8 mmole), acetic
acid (1.0 mL, 18 mmole) were dissolved in 30 mL dichloroethane and
sodium triacetoxyborohydride (6.36 g, 30 mmole) was added and the
reaction mixture was stirred at room temperature for 2 hours. The
mixture was diluted with dichloromethane and then washed with 2N
NaOH, water, and dried (MgSO.sub.4). Filtration and evaporation
gave 3.84 g (95%) 4-morpholin-4-yl-piperidine-1-carboxylic acid
tert-butyl ester as a colorless oil that solidified on
standing.
[1047] Step 22B: 4-morpholin-4-yl-piperidine-1-carboxylic acid
tert-butyl ester (3.85 g, 14.2) was dissolved in 25 mL
dichloromethane and 20 mL trifluoroacetic acid was added and
stirred at room temperature for 90 minutes. The reaction mixture
was then evaporated then co-evaporated twice with dichloromethane.
The semisolid residue was triturated with 75 mL ether, stirred at
room temperature 1 hour, then filtered to give 5.03 g of
4-piperidin-4-yl-morpholine, bis-trifluoroacetic acid salt (89%) as
a white solid.
[1048] Step 22C: 4-piperidin-4-yl-morpholine, bis-trifluoroacetic
acid salt (299 mg, 0.75 mmole) and DIPEA (0.54 mL, 3 mmole) were
dissolved in 2 mL dichloromethane and 2-chlorophenylsulfonyl
chloride (189 mg, 0.9 mmole) was added and the reaction mixture
stirred at room temperature overnight. The reaction was diluted
with dichloromethane, washed with water and dried over
Na.sub.2SO.sub.4. The organic layer was evaporated then dissolved
in 5 mL EtOAc then 2-3 mL 1M HCl/EtOAc was added and stirred at
room temperature. The resulting solid was filtered to give 225 mg
(75%) of 4-{1-[(2-chlorophenyl)sulfonyl]piperidin-4-yl}morpholine,
hydrochloric acid salt as a white solid.
[1049] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 1.61-1.75 (m, 2H) 2.19
(d, J=11.87 Hz, 2H) 2.69-2.82 (m, 2H) 2.97-3.10 (m, 2H) 3.26-3.43
(m, 3H) 3.77-3.89 (m, 4H) 3.92-3.99 (m, 2H) 7.55-7.61 (m, 1H)
7.67-7.75 (m, 2H) 7.99 (dd, J=7.96, 1.39 Hz, 1H). HPLC Method 1:
room temperature, 3.297 min, 100.00%, HPLC Method 2: room
temperature, 2.869 min, 100.00%.
Example 22A
4-{1-[(3,4-dichlorophenyl)sulfonyl]piperidin-4-yl}morpholine
[1050] The title compound was obtained in 53% yield as a white
solid according to a similar procedure described for example
22A.
[1051] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 1.66-1.80 (m, 2H) 2.16
(d, J=12.63 Hz, 2H) 2.29-2.39 (m, 2H) 2.96-3.08 (m, 2H) 3.15-3.24
(m, 1H) 3.29-3.39 (m, 2H) 3.73-3.85 (m, 4H) 3.96 (d, J=13.89 Hz,
2H) 7.74 (dd, J=8.34, 2.02 Hz, 1H) 7.95 (d, J=8.34 Hz, 1H) 8.00 (d,
J=2.02 Hz, 1H). HPLC Method 1: room temperature, 4.046 min,
100.00%, HPLC Method 2: room temperature, 3.978 min, 100.00%.
Example 23
[1052] The following compounds can be prepared according to the
following scheme.
##STR00059##
Example 23A
1-bicyclo[2.2.1]hept-2-yl-4-[(3,4-dichlorophenyl)sulfonyl]piperazine
[1053] ESI-MS, [M+H].sup.1+: 389.02.
Example 23B
1-bicyclo[2.2.1]hept-2-yl-4-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl-
]piperazine
[1054] ESI-MS, [M+H].sup.1+: 425.02.
Example 23C
1-(3,4-dichlorophenylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)piperazine
[1055] ESI-MS, [M+H].sup.1+: 378.97.
Example 24
[1056] The following compounds can be prepared according to the
following scheme.
##STR00060##
Example 24A
4-[5-({4-[4-fluoro-2-(trifluoromethyl)phenyl]piperazin-1-yl}sulfonyl)pyrid-
in-2-yl]morpholine
[1057] Yield 41.5%. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm
2.94-3.02 (m, 4H) 3.07-3.23 (m, 4H) 3.67-3.74 (m, 4H) 3.80-3.89 (m,
4H) 6.66 (d, J=9.09 Hz, 1H) 7.18-7.43 (m, 3H) 7.77 (dd, J=9.09,
2.53 Hz, 1H) 8.54 (d, J=2.53 Hz, 1H). HPLC Method 1: room
temperature, 6.215 min, 99.73%, HPLC Method 2: room temperature,
7.042 min, 100%.
Example 24B
N-[4-({4-[4-fluoro-2-(trifluoromethyl)phenyl]piperazin-1-yl}sulfonyl)pheny-
l]pyrrolidine-1-carboxamide
[1058] Yield 81.02%. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm
1.93-2.12 (m, 4H) 2.95 (t, J=4.67 Hz, 4H) 3.14 (s, 4H) 3.51 (t,
J=6.69 Hz, 4H) 6.44 (s, 1H) 7.17-7.42 (m, 3H) 7.60-7.75 (m, 4H).
HPLC Method 1: room temperature, 6.059 min, 100%, HPLC Method 2:
room temperature, 6.941 min, 100%.
Example 24C
N-[3-chloro-4-({4-[4-fluoro-2-(trifluoromethyl)phenyl]piperazin-1-yl}sulfo-
nyl)phenyl]azepane-1-carboxamide
[1059] Yield 90.72%. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm
1.61-1.67 (m, 4H) 1.81 (s, 4H) 2.91 (t, J=4.67 Hz, 4H) 3.39 (s, 4H)
3.48-3.57 (m, 4H) 6.55 (s, 1H) 7.19-7.40 (m, 4H) 7.80 (d, J=2.27
Hz, 1H) 7.94 (d, J=8.84 Hz, 1H). HPLC Method 1: room temperature,
6.963 min, 99.43%, HPLC Method 2: room temperature, 7.575 min,
99.58%.
Example 24D
4-(5-{[4-(4-fluorophenyl)piperazin-1-yl]sulfonyl}pyridin-2-yl)morpholine
[1060] Yield 39.3%. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.17
(s, 8H) 3.63-3.74 (m, 4H) 3.75-3.90 (m, 4H) 6.63 (d, J=9.09 Hz, 1H)
6.78-6.90 (m, 2H) 6.88-7.03 (m, 2H) 7.78 (dd, J=9.09, 2.53 Hz, 1H)
8.54 (d, J=1.77 Hz, 1H). HPLC Method 1: room temperature, 5.506
min, 100%, HPLC Method 2: room temperature, 6.343 min, 100%.
Example 24E
N-(4-{[4-(4-fluorophenyl)piperazin-1-yl]sulfonyl}phenyl)pyrrolidine-1-carb-
oxamide
[1061] Yield 73.1%. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm
1.97-2.06 (m, 4H) 3.15 (s, 8H) 3.49 (t, J=6.57 Hz, 4H) 6.41 (s, 1H)
6.79-6.87 (m, 2H) 6.95 (dd, J=9.09, 8.08 Hz, 2H) 7.59-7.65 (m, 2H)
7.66-7.73 (m, 2H). HPLC Method 1: room temperature, 5.469 min,
100%, HPLC Method 2: room temperature, 6.325 min, 100%.
Example 24F
N-(3-chloro-4-{[4-(4-fluorophenyl)piperazin-1-yl]sulfonyl}phenyl)azepane-1-
-carboxamide
[1062] Yield 60.8%. 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm
1.59-1.67 (m, 4H) 1.74-1.84 (m, 4H) 3.07-3.16 (m, 4H) 3.37-3.45 (m,
4H) 3.47-3.56 (m, 4H) 6.56 (s, 1H) 6.81-6.89 (m, 2H) 6.91-7.02 (m,
2H) 7.38 (dd, J=8.72, 2.15 Hz, 1H) 7.76 (d, J=2.27 Hz, 1H) 7.94 (d,
J=8.59 Hz, 1H). HPLC Method 1: room temperature, 6.382 min, 98.96%,
HPLC Method 2: room temperature, 7.144 min, 99.00%.
Example 25
[1063] The following compounds can be prepared according to the
following scheme.
##STR00061##
Example 25A
1-[4-fluoro-2-(trifluoromethyl)phenyl]-4-[(3-piperidin-1-ylphenyl)sulfonyl-
]piperazine
[1064] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 1.50-1.69 (m, 6H) 2.91
(d, J=4.29 Hz, 4H) 2.99 (s, 4H) 3.20-3.29 (m, 4H) 7.07 (d, J=8.08
Hz, 1H) 7.14 (s, 1H) 7.29 (d, J=8.34 Hz, 1H) 7.40-7.61 (m, 3H)
7.65-7.77 (m, 1H). HRMS: calcd for
C.sub.22H.sub.25F.sub.4N.sub.3O.sub.2S+H+, 472.16763; found
(ESI-FTMS, [M+H].sup.1+), 472.1681. HPLC Method 1: room
temperature, 7.301 min, 98.52%. HPLC Method 2: room temperature,
7.746 min, 98.54%.
Example 25B
4-[3-({4-[4-fluoro-2-(trifluoromethyl)phenyl]piperazin-1-yl}sulfonyl)pheny-
l]morpholine
[1065] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 2.91 (t, J=4.29 Hz,
4H) 3.00 (s, 4H) 3.16-3.26 (m, 4H) 3.70-3.81 (m, 4H) 7.10-7.21 (m,
2H) 7.26-7.36 (m, 1H) 7.44-7.61 (m, 3H) 7.73 (d, J=5.05 Hz, 1H).
HRMS: calcd for C.sub.21H.sub.23F.sub.4N.sub.3O.sub.3S+H+,
474.14690; found (ESI-FTMS, [M+H].sup.1+), 474.1464. HPLC Method 1:
room temperature, 7.157 min, 98.07%. HPLC Method 2: room
temperature, 6.452 min, 97.21%.
Example 25C
1-[4-fluoro-2-(trifluoromethyl)phenyl]-4-[(3-pyrrolidin-1
ylphenyl)sulfonyl]piperazine
[1066] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.03-2.09 (m, 4H)
2.95 (t, J=4.80 Hz, 4H) 3.19 (s, 4H) 3.29-3.39 (m, 4H) 6.75 (dd,
J=8.08, 2.27 Hz, 1H) 6.84-6.90 (m, 1H) 7.00 (d, J=8.59 Hz, 1H)
7.19-7.26 (m, 1H) 7.27-7.39 (m, 3H). HRMS: calcd for
C.sub.21H.sub.23F.sub.4N.sub.3O.sub.2S+H+, 458.15198; found
(ESI-FTMS, [M+H].sup.1+), 458.1525. HPLC Method 1: room
temperature, 7.221 min, 97.78%. HPLC Method 2: room temperature,
7.718 min, 97.61%.
Example 26
[1067] The following compounds can be prepared according to the
following scheme.
##STR00062##
Example 26A
1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-4-(3-fluorophenyl)pipera-
zine
[1068] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.71 (s, 3H)
3.24-3.31 (m, 4H) 3.37 (d, J=4.29 Hz, 4H) 6.48-6.67 (m, 3H)
7.12-7.23 (m, 1H) 7.47 (dd, J=8.59, 2.02 Hz, 1H) 7.76 (dd, J=8.59,
0.51 Hz, 1H) 7.82 (dd, J=2.02, 0.51 Hz, 1H). HRMS: calcd for
C.sub.19H.sub.18ClFN.sub.2O.sub.2S.sub.2+H+, 425.05550; found
(ESI-FTMS, [M+H].sup.1+), 425.0557. HPLC Method 1: room
temperature, 7.123 min, 99.58%. HPLC Method 2: room temperature,
7.698 min, 99.75%.
Example 26B
1-[(5-chloro-2-naphthyl)sulfonyl]-4-(3-fluorophenyl)piperazine
[1069] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.25 (d, J=3.54
Hz, 8H) 6.45-6.66 (m, 3H) 7.07-7.22 (m, 1H) 7.49-7.60 (m, 1H) 7.76
(dd, J=7.45, 1.14 Hz, 1H) 7.82-7.98 (m, 2H) 8.38 (d, J=2.02 Hz, 1H)
8.44 (d, J=8.84 Hz, 1H). HRMS: calcd for
C.sub.20H.sub.18ClFN.sub.2O.sub.2S+H+, 405.08343; found (ESI-FTMS,
[M+H].sup.1+), 405.0838. HPLC Method 1: room temperature, 7.571
min, 99.44%. HPLC Method 2: room temperature, 6.963 min,
99.64%.
Example 27
[1070] The following compounds can be prepared according to the
following scheme.
##STR00063##
Example 27A
1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-4-[3-(trifluoromethyl)py-
ridin-2-yl]piperazin-2-one
[1071] Step 27A): To a solution of piperazin-2-one (1.0 g, 10.0
mmol) in DMF (1.0 mL) was added 2-chloro-3-trifluoromethylpyridine
(2.0 g, 11.0 mmol) and DIPEA (2.0 mL, 12.0 mmol). The reaction
mixture was heated to 150.degree. C. under microwave conditions for
one hour, after which maximum attainable conversion to desired
product was judged complete by LCMS. The crude reaction mixture was
quenched with H.sub.2O (5 mL), resulting in precipitation of the
desired product, in >75% purity. The crude solid was then
dissolved in ethyl acetate (25 mL) and washed with brine
(2.times.10 mL). The organic layer was dried over Na.sub.2SO.sub.4,
decanted, and concentrated in vacuo, and the resultant crude oil
was purified via normal phase SiO.sub.2 column chromatography using
a 50%-100% ethyl acetate/hexanes solvent gradient. The desired
product was isolated in >99% purity, 30% yield (720 mg).
[1072] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 3.21-3.28 (m, 2H)
3.39-3.46 (m, 2H) 3.76 (s, 2H) 7.23 (dd, J=7.58, 5.05 Hz, 1H) 7.96
(s, 1H) 8.11 (dd, J=7.83, 1.77 Hz, 1H) 8.54 (dd, J=4.80, 1.52 Hz,
1H); LCMS: calcd for C.sub.10H.sub.10F.sub.3N.sub.3O+H+, 246.08;
found ([M+H].sup.1+), 246.19; HPLC Method 1: room temperature, 4.16
min, 89.3%. HPLC Method 2: room temperature, 4.1214 min,
95.92%.
[1073] Step 27B: A solution of
4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-2-one (150 mg, 0.61
mmol) in anhydrous THF (2.0 mL) was cooled to -78.degree. C.,
followed by drop-wise addition of LHMDS (0.92 mL, 0.92 mmol (1.0 M
in THF)). The reaction was allowed to stir five minutes after which
a solution of 5-chloro-3-methyl-2-benzothiophene sulfonyl chloride
in anhydrous THF (221 mg, 0.79 mmol in 1 mL) was added drop-wise.
The reaction mixture was allowed to stir at -78.degree. C. for
approximately two hours, after which it was judged complete by TLC.
The reaction was quenched with excess H.sub.2O (10 mL), extracted
into ethyl acetate (3.times.10 mL), and finally washed with aqueous
NaHCO.sub.3 (2.times.10 mL). The organic layers were combined and
dried over Na.sub.2SO.sub.4, decanted, and concentrated in vacuo.
The resultant crude oil was purified via normal phase SiO.sub.2
column chromatography using a 5%-20% EA/Hex solvent gradient. The
desired product, was isolated in >95% purity, 3.5% yield (10
mg).
[1074] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 2.77 (s, 3H)
3.62-3.68 (m, 2H) 3.99 (s, 2H) 4.02-4.08 (m, 2H) 7.12 (dd, J=7.96,
4.93 Hz, 1H) 7.49 (d, J=8.72, 1.89 Hz, 1H) 7.85 (d, J=1.77 Hz, 1H)
7.94 (dd, J=7.96, 1.64 Hz, 1H) 8.33 (dd, J=4.80, 1.26 Hz, 1H);
LCMS: calcd for C.sub.198H.sub.15ClF.sub.3N.sub.3O.sub.3S.sub.2+H+,
490.02; found ([M+H].sup.1+), 490.05; HPLC Method 1: room
temperature, 6.771 min, 97.56%. HPLC Method 2: room temperature,
3.375 min, 97.92%.
Example 27B
3-(2-(naphthalen-2-yl)ethylsulfonyl)-1-(3-(trifluoromethyl)pyridin-2-yl)im-
idazolidin-4-one
[1075] Step 27A: Prepared according to the procedure for example
27A, affording 50 mg of the desired sulfonamide in >95% purity
(21% yield).
[1076] 1H NMR (400 MHz, CHLOROFORM-D) .delta. ppm 3.49-3.54 (m, 2H)
3.57-3.64 (m, 2H) 3.73-3.78 (m, 2H) 3.99 (s, 2H) 4.04-4.09 (m, 2H)
7.10 (dd, J=7.83, 4.80 Hz, 1H) 7.39-7.44 (m, 2H) 7.49-7.55 (m, 1H)
7.55-7.62 (m, 1H) 7.79 (dd, J=6.82, 2.78 Hz, 1H) 7.88 (dd, J=8.08,
0.76 Hz, 1H) 7.94 (dd, J=7.71, 1.89 Hz, 1H) 8.04 (d, J=8.59 Hz, 1H)
8.37 (dd, J=4.80, 1.77 Hz, 1H); LCMS: calcd for
C.sub.21H.sub.18F.sub.3N.sub.32O.sub.3S+H+, 450.10; found
([M+H].sup.1+), 450.23; HPLC Method 1: room temperature, 6.448 min,
98.49%. HPLC Method 2: room temperature, 7.151 min, 99.25%.
Example 28
[1077] The following compounds can be prepared according to the
following scheme.
##STR00064##
Example 28A
4-{3-Methyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-b-
enzo[b]thiophen-5-yl}-morpholine
[1078] Step 28A:
1-(5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-4-(3-trifluoromethyl-p-
yridin-2-yl)-piperazine (142.5 mg, 0.3 mmol), Pd.sub.2(dba).sub.3
(13.7 mg, 0.015 mmol), t-BuONa (82.7 mg, 0.84 mmol) and the ligand
(9 mg, 0.03 mmol) were mixed in a sealed tube which was flushed
with N.sub.2. To this was added toluene (2 mL) and then morpholine
(21 .mu.L, 0.24 mmol). The resultant mixture was heated at
80.degree. C. for 4 hours. The solvent was removed under vacuum and
the crude product was purified with flash column chromatography to
yield
4-{3-Methyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]--
benzo[b]thiophen-5-yl}-morpholine in 52% yield (82 mg) as white
solid. HRMS: calcd for
C.sub.23H.sub.25F.sub.3N.sub.4O.sub.3S.sub.2+H+, 527.13929; found
(ESI-FTMS, [M+H].sup.1+), 527.1392.
Example 28B
1-(3-Methyl-5-piperazin-1-yl-benzo[b]thiophene-2-sulfonyl)-4-(3-trifluorom-
ethyl-pyridin-2-yl)-piperazine
[1079] Step 28A:
1-(5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-4-(3-trifluoromethyl-p-
yridin-2-yl)-piperazine (142.5 mg, 0.3 mmol), Pd.sub.2(dba).sub.3
(13.7 mg, 0.015 mmol), t-BuONa (82.7 mg, 0.84 mmol) and the ligand
(9 mg, 0.03 mmol) were mixed in a sealed tube which was flushed
with N.sub.2. To this was added toluene (2 mL) and then
1-BOC-piperazine (67.1 mg, 0.36 mmol). The resultant mixture was
heated at 80.degree. C. for 3 hours. The solvent was removed under
vacuum and the crude product was purified with flash column
chromatography to yield
4-{3-methyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]--
benzo[b]thiophen-5-yl}-piperazine-1-carboxylic acid tert-butyl
ester 68% yield (128 mg) as white solid.
[1080] Step 28B: To a solution of
4-{3-methyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]--
benzo[b]thiophen-5-yl}-piperazine-1-carboxylic acid tert-butyl
ester (95 mg, 0.18 mmol) in DCM (4 mL) was added TFA (1 mL). The
resultant mixture was stirred at ambient temperature for 3 hours.
The solvent was removed under vacuum. The crude product was
triturated with ether then water to give
1-(3-Methyl-5-piperazin-1-yl-benzo[b]thiophene-2-sulfonyl)-4-(3-trif-
luoromethyl-pyridin-2-yl)-piperazine as a light yellow solid (51
mg, 66%).
Example 28C
1-(4-Piperidin-1-yl-benzenesulfonyl)-4-(3-trifluoromethyl-pyridin-2-yl)-pi-
perazine
[1081] Step 28A:
4-bromobenzenesulfonyl)-4-(3-trifluoromethyl-pyridin-2-yl)-piperazine
(135.5 mg, 0.3 mmol), Pd.sub.2(dba).sub.3 (13.7 mg, 0.015 mmol),
t-BuONa (82.7 mg, 0.84 mmol) and the ligand (9 mg, 0.03 mmol) were
mixed in a sealed tube which was flushed with N.sub.2. To this was
added toluene (2 mL) and then piperidine (35 .mu.L, 0.36 mmol). The
resultant mixture was heated at 80.degree. C. for 2 hours. The
solvent was removed under vacuum and the crude product was purified
with flash column chromatography to yield
1-(4-Piperidin-1-yl-benzenesulfonyl)-4-(3-trifluoromethyl-pyridin-2-
-yl)-piperazine in 85% yield (116 mg) as white solid.
Example 28D
4-{4-[4-(3-Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-phenyl}-mo-
rpholine
[1082] Step 28A:
4-bromobenzenesulfonyl)-4-(3-trifluoromethyl-pyridin-2-yl)-piperazine
(135.5 mg, 0.3 mmol), Pd.sub.2(dba).sub.3 (13.7 mg, 0.015 mmol),
t-BuONa (82.7 mg, 0.84 mmol) and the ligand (9 mg, 0.03 mmol) were
mixed in a sealed tube which was flushed with N.sub.2. To this was
added toluene (2 mL) and then morpholine (31.5 .mu.L, 0.36 mmol).
The resultant mixture was heated at 80.degree. C. for 2 hours. The
solvent was removed under vacuum and the crude product was purified
with flash column chromatography to yield
4-{4-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-phenyl}-m-
orpholine in 78% yield (106 mg) as a white solid.
Example 28E
1-Methyl-{4-{4-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]--
phenyl}}-piperazine
[1083] Step 28A:
4-bromobenzenesulfonyl)-4-(3-trifluoromethyl-pyridin-2-yl)-piperazine
(135.5 mg, 0.3 mmol), Pd.sub.2(dba).sub.3 (13.7 mg, 0.015 mmol),
t-BuONa (82.7 mg, 0.84 mmol) and the ligand (9 mg, 0.03 mmol) were
mixed in a sealed tube which was flushed with N.sub.2. To this was
added toluene (2 mL) and then morpholine (31.5 .mu.L, 0.36 mmol).
The resultant mixture was heated at 80.degree. C. for 2 hours. The
solvent was removed under vacuum and the crude product was purified
with flash column chromatography to yield
1-Methyl-{4-{4-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-
-phenyl}}-piperazine in 67% yield (93 mg) as a yellow solid.
Example 29
Example 29A
[1084] Step 1: (R)-2-methyl-piperazine (3.5 g, 34.9 mmol),
2-bromo-5-fluoro benzotrifluoride (7.74 g, 31.7 mmol), BINAP (0.59
g, 0.95 mmol), tBuONa (4.58 g, 47.65 mmol) and Pd.sub.2(dba).sub.3
(0.29 g, 0.32 mmol) were mixed in the flask and purged with
N.sub.2. Anhydrous toluene (50 mL) was added and purged with
N.sub.2 again. The resulting mixture was heated in an oil bath at
100.degree. C. under N.sub.2 for 3 hours. The mixture was cooled to
room temperature, diluted with dichloromethane (150 mL), washed
with H.sub.2O (30 mL) first, then washed with saturated brine (30
mL). The combined organic layer was dried over Na.sub.2SO.sub.4,
concentrated down under reduced pressure to give a brown color
liquid as crude. The crude product was purified on silica gel
column eluted with 5-10% MeOH in DCM to give
(3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-3-methylpiperazine as a
light yellow oil (6.85 g, 82%).
[1085] Step 2: To a solution of
(3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-3-methylpiperazine (2.5
g, 9.53 mmol) in DCM (50 mL) at 0.degree. C. was added 3-acetyl
benzenesulfonyl chloride (2.08 g, 9.53 mmol) and DIPEA (3.32 mL,
19.06 mmol). The resultant mixture was stirred at room temperature
overnight, then washed with H.sub.2O first, the aqueous layer was
extracted with DCM (2.times.50 mL). The combined organic layer was
dried over Na.sub.2SO.sub.4. The crude product was purified on SiO2
gel column eluted with 30-40% EtOAc in hexanes to give
1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl-
}sulfonyl)phenyl]ethanone as an off white solid (3.7 g, 90%). Step
3: To
1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl-
}sulfonyl)phenyl]ethanone (3.7 g, 8.33 mmol) was added TMS-CF.sub.3
(50 mL, 25 mmol, 0.5 M in THF) at room temperature. This was cooled
down to 0.degree. C. in an ice bath, then TBAF (8.33 mL, 8.33 mmol,
1.0 M in THF) was added slowly. The resultant mixture was stirred
at 0.degree. C. for 30 min, then stirred at room temperature for 5
hours. The resultant mixture was diluted with saturated NaHCO.sub.3
(40 mL), washed with DCM (100 mL). This was separated, the organic
layer was washed with saturated brine, dried over Na.sub.2SO.sub.4.
The crude product was purified on SiO.sub.2 gel column eluted with
30-50% EtOAc in Hexanes first, then purified again on SiO.sub.2 gel
column eluted with 2.5% MeOH in DCM to give
1,1,1-trifluoro-2-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-
-methylpiperazin-1-yl}sulfonyl)phenyl]propan-2-ol as a white solid
(2.76 g, 64%).
[1086] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.15-1.23 (m, 3H)
1.85 (s, 3H) 2.55 (s, 1H) 2.66-2.76 (m, 2H) 2.87 (d, J=9.85 Hz, 1H)
2.92-3.00 (m, 1H) 3.32-3.41 (m, 1H) 3.75 (d, J=13.14 Hz, 1H)
4.22-4.24 (m, 1H) 7.18-7.23 (m, 2H) 7.32 (dd, J=8.59, 2.02 Hz, 1H)
7.58 (t, J=7.83 Hz, 1H) 7.79-7.89 (m, 2H) 8.10 (d, J=5.56 Hz, 1H).
HRMS: calcd for C.sub.21H.sub.21F.sub.7N.sub.2O.sub.3S+H+,
515.12339; found (ESI-FTMS, [M+H].sup.1+), 515.123. HPLC Method 1:
room temperature, 6.882 min, 99.13%, HPLC Method 2: room
temperature, 7.550 min, 100%.
[1087] Step 4: The product of step 3 (2.97 g 5.78 mmol) was
separated by chiral column. The diastereomers were separated using
prep SFC (15% IPA/85% CO.sub.2, chiralpak AS-H) to provide:
[1088]
(2R)-1,1,1-trifluoro-2-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phe-
nyl]-2-methylpiperazin-1-yl}sulfonyl)phenyl]propan-2-ol as a white
solid (1.32 g). 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.21
(dd, J=6.44, 5.18 Hz, 3H) 1.84 (s, 3H) 2.63 (s, 1H) 2.67-2.75 (m,
2H) 2.84-2.90 (m, 1H) 2.95 (dd, J=10.99, 3.41 Hz, 1H) 3.31-3.41 (m,
1H) 3.75 (d, J=12.88 Hz, 1H) 4.18-4.27 (m, 1H) 7.19-7.23 (m, 2H)
7.32 (dd, J=8.59, 2.02 Hz, 1H) 7.58 (t, J=7.83 Hz, 1H) 7.81 (d,
J=7.83 Hz, 1H) 7.85-7.88 (m, 1H) 8.11 (s, 1H); HRMS: calcd for
C.sub.21H.sub.21F.sub.7N.sub.2O.sub.3S+H+, 515.12339; found
(ESI-FTMS, [M+H].sup.1+), 515.12488; and
[1089]
(2S)-1,1,1-trifluoro-2-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phe-
nyl]-2-methylpiperazin-1-yl}sulfonyl)phenyl]propan-2-ol as a white
solid (1.26 g). 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
1.17-1.23 (m, 3H) 1.85 (d, J=1.01 Hz, 3H) 2.54 (s, 1H) 2.66-2.73
(m, 2H) 2.87 (d, J=8.34 Hz, 1H) 2.97 (dd, J=11.24, 3.41 Hz, 1H)
3.32-3.41 (m, 1H) 3.75 (d, J=12.88 Hz, 1H) 4.24 (s, 1H) 7.18-7.24
(m, 2H) 7.29-7.35 (m, 1H) 7.58 (t, J=8.08 Hz, 1H) 7.80-7.88 (m, 2H)
8.10 (s, 1H); HRMS: calcd for
C.sub.21H.sub.21F.sub.7N.sub.2O.sub.3S+H+, 515.12339; found
(ESI-FTMS, [M+H].sup.1+), 515.12492.
Example 29B
[1090]
1-(3-bromo-benzenesulfonyl)-4-(4-fluoro-2-trifluoromethyl-phenyl)-2-
-methyl-piperazine was prepared from the corresponding sulfonyl
chloride and piperazine according to the sulfonation methods
described above (diisopropylethylamine/CH.sub.2Cl.sub.2). A dry
sample
1-(3-bromo-benzenesulfonyl)-4-(4-fluoro-2-trifluoromethyl-phenyl)-2-methy-
l-piperazine (Compound B, 3.43 g, 7.14 mmol) was dissolved in 50 mL
dry THF at 25.degree. C. under nitrogen. The solution was cooled to
-78.degree. C. n-BuLi (2.59 M in hexane, 2.89 mL, 7.49 mmol) was
added in 20 seconds. The resulting yellow solution was stirred at
-78.degree. C. for 30 seconds, and 1,1,1-trifluoro-propan-2-one
(0.70 mL, 7.49 mmol) was added in less than 5 seconds. After the
reaction mixture was stirred at -78.degree. C. for 30 min, water
(0.5 mL) was added. The cooling bath was removed. The reaction
mixture was warmed to 25.degree. C. and concentrated to yield a
yellow oily residue, which was dissolved in 10 mL toluene.
Combiflash of the toluene solution (40 g silica gel column, ethyl
acetate:hexane=5:95 to 30:70 in 50 min) afforded
1,1,1-trifluoro-2-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-meth-
ylpiperazin-1-yl}sulfonyl)phenyl]propan-2-ol (3.05 g, 82%) as a
white solid.
[1091] The following compounds were prepared using a procedures
similar to those described in Example 29A.
Example 29C
1,1,1-trifluoro-2-[4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methy-
lpiperazin-1-yl}sulfonyl)phenyl]propan-2-ol
[1092] The title compound was obtained in 51.4% yield (166.6 mg) as
a light yellow solid. HRMS: calcd for
C.sub.21H.sub.21F.sub.7N.sub.2O.sub.3S+H+, 515.12339; found
(ESI-FTMS, [M+H].sup.1+), 515.1227. HPLC Method 1: room
temperature, 6.580 min, 99.41%, HPLC Method 2: room temperature,
7.307 min, 98.12%.
Example 29D
1,1,1-trifluoro-2-[4-({(2R)-4-[3-fluoro-2-(trifluoromethyl)phenyl]-2-methy-
lpiperazin-1-yl}sulfonyl)phenyl]propan-2-ol
[1093] Yield 85.1%. HRMS: calcd for
C.sub.21H.sub.21F.sub.7N.sub.2O.sub.3S+H+, 515.12339; found
(ESI-FTMS, [M+H].sup.1+), 515.1247. HPLC Method 1: room
temperature, 6.679 min, 99.48%, HPLC Method 2: room temperature,
7.333 min, 99.0%.
Example 29E
3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sul-
fonyl)benzoic acid
[1094] Yield 12.1%. HRMS: calcd for
C.sub.19H.sub.18F.sub.4N.sub.2O.sub.4S+H+, 447.09962; found
(ESI-FTMS, [M+H].sup.1+), 447.1008. HPLC Method 1: room
temperature, 6.210 min, 90.00%, HPLC Method 2: room temperature,
7.226 min, 95.84%.
Example 29F
(2R)-1-[(5-bromo-2-methoxyphenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)-
phenyl]-2-methylpiperazine
[1095] Yield 72.9%. HRMS: calcd for
C.sub.19H.sub.19BrF.sub.4N.sub.2O.sub.3S+H+, 511.03086; found
(ESI-FTMS, [M+H].sup.1+), 511.0293.
Example 29G
1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[3-(trifluoromethyl)pyridin-4-yl]pi-
perazin-1-yl}sulfonyl)phenyl]propan-2-ol
[1096] Yield 87.5%. HRMS: calcd for
C.sub.20H.sub.21F.sub.6N.sub.3O.sub.3S+H+, 498.12806; found
(ESI-FTMS, [M+H].sup.1+), 498.1289.
Example 29H
1,1,1-trifluoro-2-(4-{[(2R)-4-(4-fluoro-2-methylphenyl)-2-methylpiperazin--
1-yl]sulfonyl}phenyl)propan-2-ol
[1097] Yield 42.9%. HRMS: calcd for
C.sub.21H.sub.24F.sub.4N.sub.2O.sub.3S+H+, 461.15165; found
(ESI-FTMS, [M+H].sup.1+), 461.1519.
Example 29I
2-(4-{[(2R)-4-(2-chloro-4-fluorophenyl)-2-methylpiperazin-1-yl]sulfonyl}ph-
enyl)-1,1,1-trifluoropropan-2-ol
[1098] Yield 63.6%. HRMS: calcd for
C.sub.20H.sub.21ClF.sub.4N.sub.2O.sub.3S+H+, 481.09703; found
(ESI-FTMS, [M+H].sup.1+), 481.0975.
Example 29J
5-fluoro-2-((3R)-3-methyl-4-{[4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)p-
henyl]sulfonyl}piperazin-1-yl)benzonitrile
[1099] Yield 83.8%. HRMS: calcd for
C.sub.21H.sub.21F.sub.4N.sub.3O.sub.3S+H+, 472.13125; found
(ESI-FTMS, [M+H].sup.1+), 472.1316.
Example 29K
2-(3-{[(2R)-4-(2-chloro-4-fluorophenyl)-2-methylpiperazin-1-yl]sulfonyl}ph-
enyl)-1,1,1-trifluoropropan-2-ol
[1100] Yield 63.6%. HRMS: calcd for
C.sub.20H.sub.21ClF.sub.4N.sub.2O.sub.3S+H+, 481.09703; found
(ESI-FTMS, [M+H].sup.1+), 481.09623.
Example 29L
1,1,1-trifluoro-2-(4-{[(2R)-4-(4-fluoro-2-methoxyphenyl)-2-methylpiperazin-
-1-yl]sulfonyl}phenyl)propan-2-ol
[1101] Yield 76.6%. HRMS: calcd for
C.sub.21H.sub.24F.sub.4N.sub.2O.sub.4S+H+, 477.14657; found
(ESI-FTMS, [M+H].sup.1+), 477.14454.
Example 29M
1,1,1-trifluoro-2-(3-{[(2R)-4-(4-fluoro-2-methylphenyl)-2-methylpiperazin--
1-yl]sulfonyl}phenyl)propan-2-ol
[1102] Yield 82.2%. HRMS: calcd for
C.sub.21H.sub.24F.sub.4N.sub.2O.sub.3S+H+, 461.15165; found
(ESI-FTMS, [M+H].sup.1+), 461.15059.
Example 29N
2-(3-{[(2R)-4-(2-chloro-4-fluorophenyl)-2-methylpiperazin-1-yl]sulfonyl}ph-
enyl)propan-2-ol
[1103] Yield 88%. HRMS: calcd for
C.sub.21H.sub.21ClF.sub.6N.sub.2O.sub.3S+H+, 531.09383; found
(ESI-FTMS, [M+H].sup.1+), 531.09359.
Example 29O
1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[2-(trifluoromethoxy)phenyl]piperaz-
in-1-yl}sulfonyl)phenyl]propan-2-ol
[1104] Yield 88%. HRMS: calcd for
C.sub.21H.sub.22F.sub.6N.sub.2O.sub.4S+H+, 513.12772; found
(ESI-FTMS, [M+H].sup.1+), 513.12786.
Example 29P
4-((3R)-3-methyl-4-{[4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl]sul-
fonyl}piperazin-1-yl)-3-(trifluoromethyl)benzonitrile
[1105] Yield 46.7%. HRMS: calcd for
C.sub.22H.sub.21F.sub.6N.sub.3O.sub.3S+H+, 522.12806; found
(ESI-FTMS, [M+H].sup.1+), 522.12846.
Example 29Q
2-(4-{[(2R)-4-(2,4-dichlorophenyl)-2-methylpiperazin-1-yl]sulfonyl}phenyl)-
-1,1,1-trifluoropropan-2-ol
[1106] Yield 82.6%. HRMS: calcd for
C.sub.20H.sub.2)Cl.sub.2F.sub.3N.sub.2O.sub.3S+H+, 497.06748; found
(ESI-FTMS, [M+H].sup.1+), 497.06732.
Example 29R
2-(4-{[(2R)-4-(2-chloro-4-methylphenyl)-2-methylpiperazin-1-yl]sulfonyl}ph-
enyl)-1,1,1-trifluoropropan-2-ol
[1107] Yield 86.9%. HRMS: calcd for
C.sub.21H.sub.24ClF.sub.3N.sub.2O.sub.3S+H+, 477.12210; found
(ESI-FTMS, [M+H].sup.1+), 477.12206.
Example 29S
2-[3-({(2R)-4-[4-chloro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)phenyl]-1,1,1-trifluoropropan-2-ol
[1108] Yield 86.2%. HRMS: calcd for
C.sub.21H.sub.21ClF.sub.6N.sub.2O.sub.3S+H+, 531.09383; found
(ESI-FTMS, [M+H].sup.1+), 531.09365.
Example 29T
1,1,1-trifluoro-2-[3-({(2R)-2-methyl-4-[2-(trifluoromethoxy)phenyl]piperaz-
in-1-yl}sulfonyl)phenyl]propan-2-ol
[1109] Yield 89.9%. HRMS: calcd for
C.sub.21H.sub.22F.sub.6N.sub.2O.sub.4S+H+, 513.12772; found
(ESI-FTMS, [M+H].sup.1+), 513.12744.
Example 29U
4-((3R)-3-methyl-4-{[3-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl]sul-
fonyl}piperazin-1-yl)-3-(trifluoromethyl)benzonitrile
[1110] Yield 43.9%. HRMS: calcd for
C.sub.22H.sub.21F.sub.6N.sub.3O.sub.3S+H+, 522.12806; found
(ESI-FTMS, [M+H].sup.1+), 522.12844.
Example 29T'
2-(3-{[(2R)-4-(2,4-dichlorophenyl)-2-methylpiperazin-1-yl]sulfonyl}phenyl)-
-1,1,1-trifluoropropan-2-ol
[1111] Yield 84.5%. HRMS: calcd for
C.sub.20H.sub.21Cl.sub.2F.sub.3N.sub.2O.sub.3S+H+, 497.06748; found
(ESI-FTMS, [M+H].sup.1+), 497.0673.
Example 29U'
2-(3-{[(2R)-4-(2-chloro-4-methylphenyl)-2-methylpiperazin-1-yl]sulfonyl}ph-
enyl)-1,1,1-trifluoropropan-2-ol
[1112] Yield 86.9%. HRMS: calcd for
C.sub.21H.sub.24ClF.sub.3N.sub.2O.sub.3S+H+, 477.12210; found
(ESI-FTMS, [M+H].sup.1+), 477.12238.
Example 29V
2-(3-{[(2R)-4-{6-[1-amino-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]pyridin-
-3-yl}-2-methylpiperazin-1-yl]sulfonyl}phenyl)-1,1,1-trifluoropropan-2-ol
[1113] Step A: A mixture of (R)-2-methyl-piperazine (1.0 g, 9.98
mmol), 5-bromo 2-cyanopyridine (1.66 g, 9.08 mmol),
tris(dibenzylidineacetone)dipalladium (0) (83.15 mg, 0.0908 mmol),
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (169.37 mg, 0.272
mmol) and sodium tert-butoxide (1.09 g, 11.35 mmol) were charged to
a microwave vial. Toluene (10.0 mL) was introduced under nitrogen
atmosphere and the reaction mixture was irradiated at 110.degree.
C. for 35 minutes. Reaction was complete as determined by TLC.
Reaction mixtures was diluted with dichloromethane, washed with
water, saturated brine then dried over Na.sub.2SO.sub.4 and
concentrated. The crude product was purified via flash column
chromatography to yield
5-[(3R)-3-methylpiperazin-1-yl]pyridine-2-carbonitrile as brown
color oil (1.15 g, 39.1% yield).
[1114] Step B: To a stirred solution of
5-[(3R)-3-methylpiperazin-1-yl]pyridine-2-carbonitrile (250 mg,
1.24 mmol) and 3-acetylbenzenesulfonyl chloride (270.3 mg, 1.24
mmol) in anhydrous dichloromethane (4 mL) was added
diisopropylethylamine (0.43 mL, 2.48 mmol). The mixture was stirred
at room temperature for over night. Reaction was complete as
determined by TLC. The reaction mixture was purified via flash
column chromatography to yield
5-{(3R)-4-[(3-acetylphenyl)sulfonyl]-3-methylpiperazin-1-yl}pyridine-2-ca-
rbonitrile in 80.3% yield (383 mg) as a light yellow solid.
[1115] Step C: To a 50 mL flask containing
5-{(3R)-4-[(3-acetylphenyl)sulfonyl]-3-methylpiperazin-1-yl}pyridine-2-ca-
rbonitrile (383 mg, 0.996 mmol) and 6.0 mL of 0.5 M TMS-CF.sub.3,
was added 0.996 mL of 1.0 M tetrabutylammonium fluoride in THF at
0.degree. C. After stirring for 2 h, the solution was diluted with
saturated NaHCO.sub.3, extracted (2.times.CH.sub.2Cl.sub.2), washed
with brine and dried over Na.sub.2SO.sub.4, and concentrated under
reduced pressure. Purification by flash column chromatography to
yield
2-(3-{[(2R)-4-{6-[1-amino-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]pyridi-
n-3-yl}-2-methylpiperazin-1-yl]sulfonyl}phenyl)-1,1,1-trifluoropropan-2-ol
as a light yellow solid. HRMS: calcd for
C.sub.22H.sub.23F.sub.9N.sub.4O.sub.3S+H+, 595.14199; found
(ESI-FTMS, [M+H].sup.1+), 595.14231.
Example 29W
2-(3-{[(2R)-4-(2,4-difluorophenyl)-2-methylpiperazin-1-yl]sulfonyl}phenyl)-
-1,1,1-trifluoropropan-2-ol
[1116] Yield 67.8%. HRMS: calcd for
C.sub.20H.sub.21F.sub.5N.sub.2O.sub.3S+H+, 465.12658; found
(ESI-FTMS, [M+H].sup.1+), 465.12772.
Example 29X
1,1,1-trifluoro-2-[3-({(2R)-2-methyl-4-[4-(1H-tetrazol-5-yl)-2-(trifluorom-
ethyl)phenyl]piperazin-1-yl}sulfonyl)phenyl]propan-2-ol
[1117] The compound of Example 29U,
4-((3R)-3-methyl-4-{[3-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl]su-
lfonyl}piperazin-1-yl)-3-(trifluoromethyl)benzonitrile, was used as
starting material to make the title compound. A mixture of
4-((3R)-3-methyl-4-{[3-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl]su-
lfonyl}piperazin-1-yl)-3-(trifluoromethyl)benzonitrile (300 mg,
0.58 mmol), NaN.sub.3 (112.5 mg, 1.73 mmol), Et.sub.3NHCl (238.1
mg, 1.73 mmol) were charged to a microwave vial. Toluene (3 mL) was
introduced under nitrogen atmosphere and the reaction mixture was
heated at 100.degree. C. over night in an oil bath. Reaction was
complete as determined by TLC. Reaction mixtures was diluted with
EtoAc, washed with 10% HCl until pH=6-7. The organic layer was
dried over Na.sub.2SO.sub.4 and concentrated. The crude product was
purified via prep HPLC under acidic condition to yield
1,1,1-trifluoro-2-[3-({(2R)-2-methyl-4-[4-(1H-tetrazol-5-yl)-2-(trifluoro-
methyl)phenyl]piperazin-1-yl}sulfonyl)phenyl]propan-2-ol as a white
solid (111.2 mg, 34.3 yield %). HRMS: calcd for
C.sub.22H.sub.22F.sub.6N.sub.6O.sub.3S+H+, 565.14510; found
(ESI-FTMS, [M+H].sup.1+), 565.14524.
Example 29Y
1,1,1,3,3,3-hexafluoro-2-[4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]--
2-methylpiperazin-1-yl}sulfonyl)phenyl]propan-2-amine
[1118] The title compound was prepared in a manner similar to that
described in Example 29V. In step B, 4-cyanobenzenesulfonyl
chloride was used as starting material to make intermediate. Yield
5.3%. HRMS: calcd for C.sub.21H.sub.19F.sub.10N.sub.3O.sub.2S+H+,
568.11110; found (ESI-FTMS, [M+H].sup.1+), 568.11129.
Example 29Z
4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sul-
fonyl)benzamide
[1119] Yield 31.9%. HRMS: calcd for
C.sub.19H.sub.19F.sub.4N.sub.3O.sub.3S+H+, 446.11560; found
(ESI-FTMS, [M+H].sup.1+), 446.11559.
Example 29AA
1,1,1,3,3,3-hexafluoro-2-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]--
2-methylpiperazin-1-yl}sulfonyl)phenyl]propan-2-amine
[1120] The title compound was prepared in a manner similar to that
described in Example 29V. In step B, 3-cyanobenzenesulfonyl
chloride was used as starting material to make intermediate. Yield
24.1%. HRMS: calcd for C.sub.21H.sub.19F.sub.10N.sub.3O.sub.2S+H+,
568.11110; found (ESI-FTMS, [M+H].sup.1+), 568.11142.
Example 29AB
3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sul-
fonyl)benzamide
[1121] Yield 18.8%. HRMS: calcd for
C.sub.19H.sub.19F.sub.4N.sub.3O.sub.3S+H+, 446.11560; found
(ESI-FTMS, [M+H].sup.1+), 446.11556.
Example 29AC
5-[(3R)-3-methyl-4-{[3-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl]sul-
fonyl}piperazin-1-yl]pyridine-2-carbonitrile
[1122] Yield 82.2%. HRMS: calcd for
C.sub.20H.sub.21F.sub.3N.sub.4O.sub.3S+H+, 455.13592; found
(ESI-FTMS, [M+H].sup.1+), 455.13594.
Example 29AD
2-[4-({(2R)-4-[4-[1-amino-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-2-(tri-
fluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)phenyl]-1,1,1-trifluo-
ropropan-2-ol
[1123] The title compound was prepared in a manner similar to that
described in Example 29V. HRMS: calcd for
C.sub.24H.sub.23F.sub.12N.sub.3O.sub.3S+H+, 662.13412; found
(ESI-FTMS, [M+H].sup.1+), 662.13495.
Example 29AD'
2-(3-{[(2R)-4-{4-[1-amino-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-2-(tri-
fluoromethyl)phenyl}-2-methylpiperazin-1-yl]sulfonyl}phenyl)-1,1,1-trifluo-
ropropan-2-ol
[1124] The title compound was prepared in a manner similar to that
described in Example 29V. HRMS: calcd for
C.sub.24H.sub.23F.sub.12N.sub.3O.sub.3S+H+, 662.13412; found
(ESI-FTMS, [M+H].sup.1+), 662.13513.
Example 29AE
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-({5-[5-(trifluorome-
thyl)isoxazol-3-yl]-2-thienyl}sulfonyl)piperazine
[1125] Yield 70-80%. HRMS: calcd for
C.sub.20H.sub.16F.sub.7N.sub.3O.sub.3S.sub.2+H+, 544.05940; found
(ESI-FTMS, [M+H].sup.1+), 544.05847.
Example 29AF
4-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)pyridin-2-yl]morpholine
[1126] Yield 54.8%. HRMS: calcd for
C.sub.21H.sub.24F.sub.4N.sub.4O.sub.3S+H+, 489.15780; found
(ESI-FTMS, [M+H].sup.1+), 489.15913.
Example 29AG
N-[3-chloro-4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpipera-
zin-1-yl}sulfonyl)phenyl]morpholine-4-carboxamide
[1127] Yield 85.0%. HRMS: calcd for
C.sub.23H.sub.25ClF.sub.4N.sub.4O.sub.4S+H+, 565.12939; found
(ESI-FTMS, [M+H].sup.1+), 565.1304.
Example 29AH
4-[(3R)-4-{[3-(1-hydroxy-1-methylethyl)phenyl]sulfonyl}-3-methylpiperazin--
1-yl]-3-(trifluoromethyl)benzonitrile
[1128] Yield 65%. HRMS: calcd for
C.sub.22H.sub.24F.sub.3N.sub.3O.sub.3S+H+, 468.15632; found
(ESI-FTMS, [M+H].sup.1+), 468.15712.
Example 29AI
1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[2-(trifluoromethyl)phenyl]piperazi-
n-1-yl}sulfonyl)phenyl]propan-2-ol
[1129] HRMS: calcd for C.sub.21H.sub.22F.sub.6N.sub.2O.sub.3S+H+,
497.13281; found (ESI-FTMS, [M+H].sup.1+), 497.1322;
Example 29AJ
(S)-1,1,1-trifluoro-2-(4-((R)-2-methyl-4-(2-(trifluoromethyl)phenyl)pipera-
zin 1-ylsulfonyl)phenyl)propan-2-ol
[1130] The title compound was prepared by resolving the
enantiomeric mixture of Example 29AI,
(1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[2-(trifluoromethyl)phenyl]pipera-
zin-1-yl}sulfonyl)phenyl]propan-2-ol), using preparative SPC.
Solvent evaporation afforded
(S)-1,1,1-trifluoro-2-(4-((R)-2-methyl-4-(2-(trifluoromethyl)phenyl)piper-
azin-1-ylsulfonyl)phenyl)propan-2-ol as a white solid (80.4
mg).
Example 29AK
(R)-1,1,1-trifluoro-2-(4-((R)-2-methyl-4-(2-(trifluoromethyl)phenyl)pipera-
zin-1-ylsulfonyl)phenyl)propan-2-ol
[1131] The title compound was prepared by resolving the
enantiomeric mixture of Example 29AI,
(1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[2-(trifluoromethyl)phenyl]pipera-
zin-1-yl}sulfonyl)phenyl]propan-2-ol), using preparative SPC.
Solvent evaporation afforded
(R)-1,1,1-trifluoro-2-(4-((R)-2-methyl-4-(2-(trifluoromethyl)phenyl)piper-
azin-1-ylsulfonyl)phenyl)propan-2-ol as a white solid (70.2
mg).
Example 29AL
(2R)-1-[(3-bromophenyl)sulfonyl]-4-(2-chloro-4-fluorophenyl)-2-methylpiper-
azine
[1132] HRMS: calcd for C.sub.17H.sub.17BrClFN.sub.2O.sub.2S+H+,
446.99394; found (ESI-FTMS, [M+H].sup.1+), 446.99325;
Example 29AM
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(4-piperazin-1-yl--
1-naphthyl)sulfonyl]piperazine
[1133] Step 2A and 2B: The intermediate
(2R)-1-[(4-bromo-1-naphthyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phen-
yl]-2-methylpiperazine was prepared according to a similar
procedure for Example II-1A, step 1A and step 1B.
[1134] Step 2C: A mixture of
(2R)-1-[(4-bromo-1-naphthyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phen-
yl]-2-methylpiperazine (250 mg, 0.47 mmol),
4-methyl-piperazine-1-carboxylic acid tert-butyl ester (175.1 mg,
0.94 mmol), tris(dibenzylidineacetone)dipalladium (0) (4.3 mg,
0.0047 mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (8.78
mg, 0.014 mmol) and sodium tert-butoxide (56.5 mg, 0.59 mmol) were
charged to a microwave vial. Toluene (3.0 mL) was introduced under
nitrogen atmosphere and the reaction mixture was irradiated at
110.degree. C. for 35 minutes. Reaction was complete as determined
by TLC. Reaction mixtures was diluted with dichloromethane, washed
with water, saturated brine then dried over Na.sub.2SO.sub.4 and
concentrated. The crude product was purified via flash column
chromatography to yield tert-butyl
4-[4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl-
}sulfonyl)-1-naphthyl]piperazine-1-carboxylate as yellow gum (200.1
mg, 66.9% yield).
[1135] Step 2D: To a 50 mL flask containing tert-butyl
4-[4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl-
}sulfonyl)-1-naphthyl]piperazine-1-carboxylate (185.2 mg) and 5 mL
of CH.sub.2Cl.sub.2 was added 3 mL of TFA. This was stirred at room
temperature for 4.5 hr. Reaction was complete as determined by TLC.
Solvent and TFA was removed under vacuum. The resulting residue was
dissolved in CH.sub.2Cl.sub.2, washed with sat. K.sub.2CO.sub.3
until pH=8, then washed with saturated brine, dried over
Na.sub.2SO.sub.4 and concentrated down to yield
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(4-piperazin-1-yl-
-1-naphthyl)sulfonyl]piperazine as a yellow solid (136.3 mg, 87.3%
yield). HRMS: calcd for C.sub.26H.sub.28F.sub.4N.sub.4O.sub.2S+H+,
537.19418; found (ESI-FTMS, [M+H].sup.1+), 537.1968. HPLC Method 1:
room temperature, 5.003 min, 94.44%, HPLC Method 2: room
temperature, 6.254 min, 93.74%.
Example 29AN
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-{[4-(4-methylpipera-
zin-1-yl)-1-naphthyl]sulfonyl}piperazine
[1136] The title compound was prepared according to a similar
procedure for Example II-4A Yield 71.3%. HRMS: calcd for
C.sub.27H.sub.30F.sub.4N.sub.4O.sub.2S+H+, 551.20983; found
(ESI-FTMS, [M+H].sup.+), 551.2119. HPLC Method 1: room temperature,
5.058 min, 92.54%, HPLC Method 2: room temperature, 6.187 min,
92.23%.
Example 29AO
2-[4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)phenyl]propan-2-ol
[1137] 41.5% yield. HRMS: calcd for
C.sub.21H.sub.24F.sub.4N.sub.2O.sub.3S+H+, 461.15165; found
(ESI-FTMS, [M+H].sup.1+), 461.1517.
Example 29AP
2-(4-{[(2R)-4-(2-chloro-4-fluorophenyl)-2-methylpiperazin-1-yl]sulfonyl}ph-
enyl)propan-2-ol
[1138] Yield 72.5%. HRMS: calcd for
C.sub.20H.sub.24ClFN.sub.2O.sub.3S+H+, 427.12529; found (ESI-FTMS,
[M+H].sup.1+), 427.12476.
Example 29AQ
2-(3-{[(2R)-4-(2-chloro-4-fluorophenyl)-2-methylpiperazin-1-yl]sulfonyl}ph-
enyl)propan-2-ol
[1139] Yield 81.5%. HRMS: calcd for
C.sub.20H.sub.24ClFN.sub.2O.sub.3S+H+, 427.12529; found (ESI-FTMS,
[M+H].sup.1+), 427.12517.
Example 29AR
4-((3R)-3-methyl-4-{[3-(4-methylpiperazin-1-yl)phenyl]sulfonyl}piperazin-1-
-yl)-3-(trifluoromethyl)benzonitrile
[1140] Yield 59.8%. HRMS: calcd for
C.sub.24H.sub.28F.sub.3N.sub.5O.sub.2S+H+, 508.19885; found
(ESI-FTMS, [M+H].sup.1+), 508.20129.
Example 29AS
4-{(3R)-4-[(3-bromophenyl)sulfonyl]-3-methylpiperazin-1-yl}-3-(trifluorome-
thyl)benzonitrile
[1141] Yield 85.2%. HRMS: calcd for
C.sub.19H.sub.17BrF.sub.3N.sub.3O.sub.2S+H+, 488.02497; found
(ESI-FTMS, [M+H].sup.1+), 488.02487.
Example 29AT
(2R)-1-[(3-bromophenyl)sulfonyl]-4-(2,4-dichlorophenyl)-2-methylpiperazine
[1142] Yield 98.6%. HRMS: calcd for
C.sub.17H.sub.17BrCl.sub.2N.sub.2O.sub.2S+H+, 462.96439; found
(ESI-FTMS, [M+H].sup.1+), 462.9633.
Example 29AU
(2R)-4-(2,4-dichlorophenyl)-2-methyl-1-{[3-(4-methylpiperazin-1-yl)phenyl]-
sulfonyl}piperazine
[1143] Yield 78%. HRMS: calcd for
C.sub.22H.sub.28Cl.sub.2N.sub.4O.sub.2S+H+, 483.13828; found
(ESI-FTMS, [M+H].sup.1+), 483.13912.
Example 29AV
(2R)-1-[(3-bromophenyl)sulfonyl]-2-methyl-4-(2,4,5-trifluorophenyl)piperaz-
ine
[1144] Yield 95.6%. HRMS: calcd for
C.sub.17H.sub.16BrF.sub.3N.sub.2O.sub.2S+H+, 449.01407; found
(ESI-FTMS, [M+H].sup.1+), 449.0139.
Example 29AW
(2R)-2-methyl-1-{[3-(4-methylpiperazin-1-yl)phenyl]sulfonyl}-4-(2,4,5-trif-
luorophenyl)piperazine
[1145] Yield 80%. HRMS: calcd for
C.sub.22H.sub.27F.sub.3N.sub.4O.sub.2S+H+, 469.18796; found
(ESI-FTMS, [M+H].sup.1+), 469.1891.
Example 29AX
3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sul-
fonyl)phenol
[1146] Step A: (R)-2-methyl-piperazine (3.88 g, 38.70 mmol),
2-bromo, 5-fluoro benzotrifluoride (8.55 g, 35.18 mmol),
tris(dibenzylidineacetone)dipalladium (0) (32.0 mg g, 0.35 mmol),
rac-2,2'-bis(diphenylphosphino)-1,1-binaphthyl (657.0 mg, 1.06
mmol) and sodium tert-butoxide (5.07 g, 52.77 mmol) were charged to
a reaction flask. Toluene (40 mL) was introduced under nitrogen
atmosphere and the reaction mixture was heated up at 110.degree. C.
for 5.0 hours. Reaction was complete as determined by TLC. The
reaction mixture was diluted with dichloromethane, washed with
water, saturated brine then dried over MgSO.sub.4 and concentrated.
The crude product was purified via flash column chromatography to
yield (R)-1-(4-fluoro-2-(trifluoromethyl)phenyl)-3-methylpiperazine
as a light brown oil (3.1 g, 33.6% yield).
[1147] Step B: To a stirred solution of
(R)-1-(4-fluoro-2-(trifluoromethyl)phenyl)-3-methylpiperazine (5.34
g, 21.86 mmol) in anhydrous dichloromethane (20 mL) was added
diisopropylethylamine (10.3 mL, 59.1 mmol) at 0.degree. C. The
reaction mixture was stirred at room temperature for 15 minutes
then 3-Methoxy benzene sulfonyl chloride (2.44 g, 11.82 mmol)
dissolved in dichloromethane (10 mL) was introduced dropwise. The
cooling bath was removed and the mixture was stirred at room
temperature for 0.5 hour. Reaction was complete as determined by
TLC. The reaction mixture was diluted with dichloromethane washed
with saturated NaHCO.sub.3 (aqueous), dried over MgSO.sub.4 and
concentrated. The crude product was purified via flash column
chromatography to yield
(R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-1-(3-methoxyphenylsulfonyl)-2--
methylpiperazine in quantitative yield (5.10 g) as a white
solid.
[1148] Step C: A stirred solution of
(R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-1-(3-methoxyphenylsulfonyl)-2--
methylpiperazine (2.22 g, 5.13 mmol) in anhydrous dichloromethane
(60 mL) was cooled down to -50.degree. C. (acetone+dry ice bath).
BBr.sub.3 (1M in CH.sub.2Cl.sub.2) was added dropwise via addition
funnel while keeping the temperature between -50.degree. C. and
-55.degree. C. Then the reaction mixture was stirred at -50.degree.
C. to -20.degree. C. for 3 hours. Reaction was complete as
determined by TLC. The reaction mixture was quenched with water and
diluted with dichloromethane. pH was adjusted to 7 using saturated
NaHCO.sub.3 (aqueous) and it was allowed to stir for 20 minutes.
The layers were separated; the organic layer was dried over
MgSO.sub.4 and concentrated. The reaction was repeated in 2.85 g
scale. The combined crud products were purified via flash column
chromatography to yield
3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazi-
n-1-yl}sulfonyl)phenol in 96% yield (4.07 g) as a white solid.
HRMS: calcd for C.sub.18H.sub.18F.sub.4N.sub.2O.sub.3S+H+,
419.10470; found (ESI-FTMS, [M+H].sup.1+), 419.104; HPLC Method 1:
room temperature, 6.318 min, 100%, HPLC Method 2: room temperature,
7.220 min, 99.48%.
Example 29AY
2-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)phenoxy]-N,N-dimethylethanamine
[1149] Yield 98.75%. HRMS: calcd for
C.sub.22H.sub.27F.sub.4N.sub.3O.sub.3S+H+, 490.17820; found
(ESI-FTMS, [M+H].sup.1+), 490.17796; HPLC Method 1: room
temperature, 5.899 min, 98.23%, HPLC Method 2: room temperature,
4.828 min, 98.75%.
Example 29AZ
3-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)phenoxy]-N,N-dimethylpropan-1-amine
[1150] Yield 57.2%. HRMS: calcd for
C.sub.23H.sub.29F.sub.4N.sub.3O.sub.3S+H+, 504.19385; found
(ESI-FTMS, [M+H].sup.1+), 504.19386; HPLC Method 1: room
temperature, 5.970 min, 97.87%, HPLC Method 2: room temperature,
4.881 min, 98.31%.
Example 29BA
4-{(3R)-4-[(3-hydroxyphenyl)sulfonyl]-3-methylpiperazin-1-yl}-3-(trifluoro-
methyl)benzonitrile
[1151] A light yellow solid (615 mg, 96.4 yield %). HRMS: calcd for
C.sub.19H.sub.18F.sub.3N.sub.3O.sub.3S+H+, 426.10937; found
(ESI-FTMS, [M+H].sup.1+), 426.10931.
Example 29BB
4-{(3R)-4-[(3-methoxyphenyl)sulfonyl]-3-methylpiperazin-1-yl}-3-(trifluoro-
methyl)benzonitrile
[1152] Yield 92.7%. HRMS: calcd for
C.sub.20H.sub.20F.sub.3N.sub.3O.sub.3S+H+, 440.12502; found
(ESI-FTMS, [M+H].sup.1+), 440.12536.
Example 29BC
4-((3R)-3-methyl-4-{[3-(1H-1,2,4-triazol-1-yl)phenyl]sulfonyl}piperazin-1--
yl)-3-(trifluoromethyl)benzonitrile
[1153] Step 8A:
4-[(3R)-3-methylpiperazin-1-yl]-3-(trifluoromethyl)benzonitrile was
prepared according to procedures similar to those described
above.
[1154] Step 8B:
4-{(3R)-4-[(3-fluorophenyl)sulfonyl]-3-methylpiperazin-1-yl}-3-(trifluoro-
methyl)benzonitrile was prepared according to procedures similar to
those described above.
[1155] Step 8C: A mixture of
4-{(3R)-4-[(3-fluorophenyl)sulfonyl]-3-methylpiperazin-1-yl}-3-(trifluoro-
methyl)benzonitrile (349 mg, 0.82 mmol), 1,2,4-triazole (112.6 mg,
1.64 mmol), K.sub.2CO.sub.3 (226.7 mg, 1.64 mmol), and CuI (15.6
mg, 0.082 mmol) were charged to a microwave vial. NMP (3 mL) was
introduced under nitrogen atmosphere and the reaction mixture was
heated at 166.degree. C. for 3 hr in an oil bath. Reaction was
complete as determined by TLC. Reaction mixtures was diluted with
dichloromethane, washed with water, saturated brine then dried over
Na.sub.2SO.sub.4 and concentrated. The crude product was purified
via prep HPLC under neutral condition to yield
4-((3R)-3-methyl-4-{[3-(1H-1,2,4-triazol-1-yl)phenyl]sulfonyl}piperazin-1-
-yl)-3-(trifluoromethyl)benzonitrile as a light tan color solid
(176.8 mg, 45.3% yield). HRMS: calcd for
C.sub.21H.sub.19F.sub.3N.sub.6O.sub.2S+H+, 477.13150; found
(ESI-FTMS, [M+H].sup.1+), 477.13303.
Example 29BD
4-{(3R)-4-[(3-fluorophenyl)sulfonyl]-3-methylpiperazin-1-yl}-3-(trifluorom-
ethyl)benzonitrile
[1156] Yield 92.1%. HRMS: calcd for
C.sub.19H.sub.17F.sub.4N.sub.3O.sub.2S+H+, 428.10503; found
(ESI-FTMS, [M+H].sup.1+), 428.1049.
Example 29BE
4-((3R)-3-methyl-4-{[3-(4H-1,2,4-triazol-4-yl)phenyl]sulfonyl}piperazin-1--
yl)-3-(trifluoromethyl)benzonitrile
[1157] HRMS: calcd for C.sub.21H.sub.19F.sub.3N.sub.6O.sub.2S+H+,
477.13150; found (ESI-FTMS, [M+H].sup.1+), 477.13273.
Example 29BF
(2R)-4-(2,4-dichlorophenyl)-2-methyl-1-{[3-(1H-1,2,4-triazol-1-yl)phenyl]s-
ulfonyl}piperazine
[1158] Yield 48.5%. HRMS: calcd for
C.sub.19H.sub.19Cl.sub.2N.sub.5O.sub.2S+H+, 452.07092; found
(ESI-FTMS, [M+H].sup.1+), 452.07066.
Example 29BG
(2R)-2-methyl-1-{[3-(1H-1,2,4-triazol-1-yl)phenyl]sulfonyl}-4-(2,4,5-trifl-
uorophenyl)piperazine
[1159] Yield 11.3%. HRMS: calcd for
C.sub.19H.sub.18F.sub.3N.sub.5O.sub.2S+H+, 438.12060; found
(ESI-FTMS, [M+H].sup.1+), 438.12062.
Example 29BH
(2R)-1-[(3-bromophenyl)sulfonyl]-4-[2,5-difluoro-4-(1H-1,2,4-triazol-1-yl)-
phenyl]-2-methylpiperazine
[1160] HRMS: calcd for Cl.sub.9H.sub.18BrF.sub.2N.sub.5O.sub.2S+H+,
498.04054; found (ESI-FTMS, [M+H].sup.1+), 498.04153.
Example 29BI
4-[(3R)-3-methyl-4-{[3-(1H-1,2,4-triazol-1-yl)phenyl]sulfonyl}piperazin-1--
yl]benzonitrile
[1161] Yield 40.7%. HRMS: calcd for
C.sub.20H.sub.20N.sub.6O.sub.2S+H+, 409.14412; found (ESI-FTMS,
[M+H].sup.1+), 409.14386.
Example 29BJ
5-[(3R)-3-methyl-4-{[3-(1H-1,2,4-triazol-1-yl)phenyl]sulfonyl}piperazin-1--
yl]pyridine-2-carbonitrile
[1162] Yield 59.0%. HRMS: calcd for
C.sub.19H.sub.19N.sub.7O.sub.2S+H+, 410.13937; found (ESI-FTMS,
[M+H].sup.1+), 410.13914.
Example 29BK
2-[3-({(2R)-4-[4-(aminomethyl)-2-(trifluoromethyl)phenyl]-2-methylpiperazi-
n-1-yl}sulfonyl)phenyl]-1,1,1-trifluoropropan-2-ol
[1163] Step 9A: To a flask containing
4-((3R)-3-methyl-4-{[3-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl]su-
lfonyl}piperazin-1-yl)-3-(trifluoromethyl)benzonitrile (50 mg, 0.10
mmol) and 2 mL of THF was added CoCl.sub.2 (32.5 mg, 0.25 mmol) at
0.degree. C., then NaBH.sub.4 (28.4 mg, 0.75 mmol) was added,
followed by adding 1 mL of MeOH. The reaction mixture was stirred
at 0.degree. C. for 0.5 hr. Reaction was complete as determined by
TLC. The reaction mixture was filtered, washed with EtoAc. The
filtrate was washed with H.sub.2O, then washed with sat. brine and
dried over Na.sub.2SO.sub.4, and concentrated under reduced
pressure. Purification by flash column chromatography to yield
2-[3-({(2R)-4-[4-(aminomethyl)-2-(trifluoromethyl)phenyl]-2-methylp-
iperazin-1-yl}sulfonyl)phenyl]-1,1,1-trifluoropropan-2-ol as a
white solid. Yield 29%. HRMS: calcd for
C.sub.22H.sub.25F.sub.6N.sub.3O.sub.3S+H+, 526.15936; found
(ESI-FTMS, [M+H].sup.1+), 526.15985.
Example 29BL
2-[3-({(2R)-4-[4-(aminomethyl)-2-(trifluoromethyl)phenyl]-2-methylpiperazi-
n-1-yl}sulfonyl)phenyl]propan-2-ol
[1164] The title compound was prepared according to a similar
procedure for Example II-9A. Yield 41.0% HRMS: calcd for
C.sub.22H.sub.28F.sub.3N.sub.3O.sub.3S+H+, 472.18762; found
(ESI-FTMS, [M+H].sup.1+), 472.18899.
Example 29BM
4-chloro-2-fluoro-5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-
piperazin-1-yl}sulfonyl)benzamide
[1165] Step A: The intermediate
(3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-3-methylpiperazine was
prepared according to procedures similar to those described
herein.
[1166] Step B: To a stirred solution of
4-chloro-5-chlorosulfonyl-2-fluoro-benzoic acid (306.4 mg, 1.20
mmol) in anhydrous dichloromethane (5 mL) was added TMSCl (0.43 mL,
3.42 mmol). This was stirred at room temperature for 30 min. Then
added a solution of
(3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-3-methylpiperazine (300
mg, 1.14 mmol) in anhydrous dichloromethane (3 mL), followed by
adding diisopropylethylamine (1.19 mL, 6.84 mmol) slowly. The
mixture was stirred at room temperature for 3 hr. Reaction was
complete as determined by TLC. The reaction mixture was diluted
with H.sub.2O, extracted (2.times.CH.sub.2Cl.sub.2), washed with
brine and dried over Na.sub.2SO.sub.4, and concentrated under
reduced pressure. Purification by flash column chromatography to
yield
4-chloro-2-fluoro-5-[4-(4-fluoro-2-trifluoromethyl-phenyl)-2-methyl-piper-
azine-1-sulfonyl]-benzoic acid as a dark yellow solid.
[1167] Step C: To a flask containing
4-chloro-2-fluoro-5-[4-(4-fluoro-2-trifluoromethyl-phenyl)-2-methyl-piper-
azine-1-sulfonyl]-benzoic acid (645 mg, 1.29 mmol) and 10 mL of
anhydrous THF was added CDI (628.97 mg, 3.88 mmol). The reaction
mixture was refluxed under N.sub.2 for 2.5 hr. The reaction mixture
was cooled down to room temperature, then 15 mL of NH.sub.3H.sub.2O
was added, this was stirred at room temperature for 2 hr. Acidified
the reaction mixture with 6N HCl until pH=4-5, extracted
(2.times.EtoAc), washed with brine and dried over Na.sub.2SO.sub.4,
and concentrated under reduced pressure. Purification by prep HPLC
under neutral condition to yield
4-chloro-2-fluoro-5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methy-
lpiperazin-1-yl}sulfonyl)benzamide as an off-white solid (6.0 mg,
0.9% yield). HRMS: calcd for
C.sub.19H.sub.17ClF.sub.5N.sub.3O.sub.3S+H+, 498.06720; found
(ESI-FTMS, [M+H].sup.1+), 498.06793.
Example 29BN
2-chloro-4-fluoro-5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-
piperazin-1-yl}sulfonyl)benzoic acid
[1168] Yield 19.3%. HRMS: calcd for
C.sub.19H.sub.16ClF.sub.5N.sub.2O.sub.4S+H+, 499.05122; found
(ESI-FTMS, [M+H].sup.1+), 499.05277.
Example 29BO
3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sul-
fonyl)-4-methoxybenzamide
[1169] Yield 75.6%. HRMS: calcd for
C.sub.20H.sub.21F.sub.4N.sub.3O.sub.4S+H+, 476.12617; found
(ESI-FTMS, [M+H].sup.1+), 476.12811.
Example 29BP
4-chloro-3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-
-1-yl}sulfonyl)benzamide
[1170] Yield 32.5%. HRMS: calcd for
C.sub.19H.sub.18ClF.sub.4N.sub.3O.sub.3S+H+, 480.07663; found
(ESI-FTMS, [M+H].sup.1+), 480.07798.
Example 29BQ
1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[1-oxido-3-(trifluoromethyl)pyridin-
-4-yl]piperazin-1-yl}sulfonyl)phenyl]propan-2-ol
[1171] To a flask containing
1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[3-(trifluoromethyl)pyridin-4-yl]p-
iperazin-1-yl}sulfonyl)phenyl]propan-2-ol (60 mg, 0.12 mmol) and
1.5 mL of DCM/MeOH (9/1, v/v) was added MMPP (74.6 mg, 0.15 mmol).
The resulting slurry was stirred at room temperature over night.
Reaction was complete as determined by TLC. This was filtered,
washed with DCM. The filtrate was concentrated under reduced
pressure. Purification by flash column chromatography to yield
1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[1-oxido-3-(trifluoromethyl)pyridi-
n-4-yl]piperazin-1-yl}sulfonyl)phenyl]propan-2-ol as a white solid
(13.5 mg, 21.9 yield). HRMS: calcd for
C.sub.20H.sub.21F.sub.6N.sub.3O.sub.4S+H+, 514.12297; found
(ESI-FTMS, [M+H].sup.1+), 514.12174.
Example 29BR
1,1,1-trifluoro-2-[3-({4-[4-fluoro-2-(trifluoromethyl)phenyl]piperidin-1-y-
l}sulfonyl)phenyl]propan-2-ol
[1172] Prepared according to scheme II-12. HRMS: calcd for
C.sub.21H.sub.20F.sub.7NO.sub.3S+H+, 500.11249; found (ESI-FTMS,
[M+H].sup.1+), 500.11256.
Example 29BR
N-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)phenyl]-N,1-dimethylpyrrolidin-3-amine
[1173] Step A:
(R)-1-(4-fluoro-2-(trifluoromethyl)phenyl)-3-methylpiperazine was
prepared according to procedures similar to those described above
using 2-bromo, 5-fluorobenzotrifluoride was used as starting
material. Yield 57.4%.
[1174] Step B:
(R)-1-(3-bromophenylsulfonyl)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-me-
thylpiperazine was prepared according to procedures similar to
those described above using 2-Bromobenzene sulfonyl chloride as
starting material. Yield 93.6%.
[1175] Step 5C:
N-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl-
}sulfonyl)phenyl]-N,1-dimethylpyrrolidin-3-amine was prepared
according to procedures similar to those described above except
instead of conventional heating, microwave irradiation was used at
110.degree. C., for 30 minutes and N,N'-dimethyl-3-aminopyrrolidine
was used as starting material. Yield 36.8%. HRMS: calcd for
C.sub.24H.sub.30F.sub.4N.sub.4O.sub.2S+H+, 515.20983; found
(ESI-FTMS, [M+H].sup.1+), 515.2104; HPLC Method 1: room
temperature, 4.854 min, 99.40%, HPLC Method 2: room temperature,
5.969 min, 99.20%.
Example 29BS
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-{[3-(4-methylpipera-
zin-1-yl)phenyl]sulfonyl}piperazine
[1176] Yield 27.9%. HRMS: calcd for
C.sub.23H.sub.27F.sub.4N.sub.3O.sub.2S+H+, 486.18328; found
(ESI-FTMS, [M+H].sup.1+), 486.18327;
Example 29BT
N-{1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1--
yl}sulfonyl)phenyl]pyrrolidin-3-yl}-N-methylacetamide
[1177] Yield 25.3%. HRMS: calcd for
C.sub.25H.sub.30F.sub.4N.sub.4O.sub.3S+H+, 543.20475; found
(ESI-FTMS, [M+H].sup.1+), 543.20336; HPLC Method 1: room
temperature, 6.629 min, 96.40%, HPLC Method 2: room temperature,
7.462 min, 96.06%.
Example 29BU
{(2S)-1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-
-1-yl}sulfonyl)phenyl]pyrrolidin-2-yl}methanol
[1178] Yield 54.4%. HRMS: calcd for
C.sub.23H.sub.27F.sub.4N.sub.3O.sub.3S+H+, 502.17820; found
(ESI-FTMS, [M+H].sup.1+), 502.17748;
Example 29BV
(3R)-1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin--
1-yl}sulfonyl)phenyl]pyrrolidin-3-ol
[1179] Yield 76.6%. HRMS: calcd for
C.sub.22H.sub.25F.sub.4N.sub.3O.sub.3S+H+, 488.16255; found
(ESI-FTMS, [M+H].sup.1+), 488.16359;
Example 29BW
{(2R)-1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-
-1-yl}sulfonyl)phenyl]pyrrolidin-2-yl}methyl acetate
[1180] Yield 54.0%. HRMS: calcd for
C.sub.25H.sub.29F.sub.4N.sub.3O.sub.4S+H+, 544.18877; found
(ESI-FTMS, [M+H].sup.1+), 544.18921.
Example 29BX
(methyl
1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperaz-
in-1-yl}sulfonyl)phenyl]pyrrolidine-3-carboxylate
[1181] HRMS: calcd for C.sub.24H.sub.27F.sub.4N.sub.3O.sub.4S+H+,
530.17312; found (ESI-FTMS, [M+H].sup.1+), 530.17135
Example 29BY
1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)phenyl]pyrrolidine-3-carboxylic acid
[1182] The title compound was obtained by hydrolyzing
(1-(3-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yls-
ulfonyl)phenyl)pyrrolidin-2-yl)methyl acetate using 1N NaOH. Yield
90%. HRMS: calcd for C.sub.23H.sub.25F.sub.4N.sub.3O.sub.4S+H+,
516.15747; found (ESI-FTMS, [M+H].sup.1+), 516.15646.
Example 29BZ
{(2R)-1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-
-1-yl}sulfonyl)phenyl]pyrrolidin-2-yl}methanol
[1183] Yield 29.0%. HRMS: calcd for
C.sub.23H.sub.27F.sub.4N.sub.3O.sub.3S+H+, 502.17820; found
(ESI-FTMS, [M+H].sup.1+), 502.17972.
Example 29CA
1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)phenyl]pyrrolidin-3-ol
[1184] HRMS: calcd for C.sub.22H.sub.25F.sub.4N.sub.3O.sub.3S+H+,
488.16255; found (ESI-FTMS, [M+H].sup.1+), 488.1636.
Example 29CB
1-(3-{[(2R)-4-(2-chloro-4-fluorophenyl)-2-methylpiperazin-1-yl]sulfonyl}ph-
enyl)pyrrolidin-3-ol
[1185] HRMS: calcd for C.sub.21H.sub.25ClFN.sub.3O.sub.3S+H+,
454.13619; found (ESI-FTMS, [M+H].sup.1+), 454.13559.
Example 29CC
(2R)-4-(2-chloro-4-fluorophenyl)-2-methyl-1-({3-[4-(2-oxo-2-pyrrolidin-1
ylethyl)piperazin-1-yl]phenyl}sulfonyl)piperazine
[1186] HRMS: calcd for C.sub.27H.sub.35ClFN.sub.5O.sub.3S+H+,
564.22059; found (ESI-FTMS, [M+H].sup.1+), 564.22189.
Example 29CD
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-1-({3-[(2S)-2-(methoxymethyl)p-
yrrolidin-1-yl]phenyl}sulfonyl)-2-methylpiperazine
[1187] HRMS: calcd for C.sub.24H.sub.29F.sub.4N.sub.3O.sub.3S+H+,
516.19385; found (ESI-FTMS, [M+H].sup.1+), 516.19562.
Example 29CE
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-{[3-(4-pyrrolidin-1-
-ylpiperidin-1-yl)phenyl]sulfonyl}piperazine
[1188] HRMS: calcd for C.sub.27H.sub.34F.sub.4N.sub.4O.sub.2S+H+,
555.24113; found (ESI-FTMS, [M+H].sup.1+), 555.24346.
Example 29CF
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-({3-[4-(2-oxo-2-pyr-
rolidin-1-ylethyl)piperazin-1-yl]phenyl}sulfonyl)piperazine
[1189] HRMS: calcd for C.sub.28H.sub.35F.sub.4N.sub.5O.sub.3S+H+,
598.24695; found (ESI-FTMS, [M+H].sup.1+), 598.2501.
Example 29CG
(3S)-1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin--
1-yl}sulfonyl)phenyl]pyrrolidin-3-ol
[1190] HRMS: calcd for C.sub.22H.sub.25F.sub.4N.sub.3O.sub.3S+H+,
488.16255; found (ESI-FTMS, [M+H].sup.1+), 488.16074.
Example 29CH
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(3-pyrrolidin-1-yl-
phenyl)sulfonyl]piperazine
[1191] HRMS: calcd for C.sub.22H.sub.25F.sub.4N.sub.3O.sub.2S+H+,
472.16763; found (ESI-FTMS, [M+H].sup.1+), 472.16822.
Example 29CI
1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)phenyl]pyrrolidin-3-amine
[1192] HRMS: calcd for C.sub.22H.sub.26F.sub.4N.sub.4O.sub.2S+H+,
487.17853; found (ESI-FTMS, [M+H].sup.1+), 487.18047.
Example 29CJ
4-({1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-
-yl}sulfonyl)phenyl]pyrrolidin-3-yl}carbonyl)morpholine
[1193] Yield 31.6%. HRMS: calcd for
C.sub.27H.sub.32F.sub.4N.sub.4O.sub.4S+H+, 585.21531; found
(ESI-FTMS, [M+H].sup.1+), 585.21414; HPLC Method 1: room
temperature, 6.641 min, 97.09%, HPLC Method 2: room temperature,
7.428 min, 95.08%.
Example 29CK
N-cyclohexyl-1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpi-
perazin-1-yl}sulfonyl)phenyl]pyrrolidine-3-carboxamide
[1194] Yield 16.8%. HRMS: calcd for
C.sub.29H.sub.36F.sub.4N.sub.4O.sub.3S+H+, 597.25170; found
(ESI-FTMS, [M+H].sup.1+), 597.25049; HPLC Method 1: room
temperature, 7.319 min, 96.16%, HPLC Method 2: room temperature,
7.893 min, 98.77%.
Example 29CL
N,N-diethyl-1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpip-
erazin-1-yl}sulfonyl)phenyl]pyrrolidine-3-carboxamide
[1195] Yield 39.4%. HRMS: calcd for
C.sub.27H.sub.34F.sub.4N.sub.4O.sub.3S+H+, 571.23605; found
(ESI-FTMS, [M+H].sup.1+), 571.23575; HPLC Method 1: room
temperature, 7.171 min, 100%, HPLC Method 2: room temperature,
7.710 min, 100%.
Example 29CM
1-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsul-
fonyl)thiophen-2-yl)pyrrolidine-2-carboxamide
[1196] Step 15C: tert-butyl
1-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsu-
lfonyl)thiophen-2-yl)pyrrolidine-2-carboxylate was prepared
according to for a procedure similar to the Buchwald couplings
described herein. Yield 19%
[1197] Step 15D: tert-butyl
1-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsu-
lfonyl)thiophen-2-yl)pyrrolidine-2-carboxylate (316.0 mg, 0.547
mmol), CeCl.sub.3.7H.sub.2O (815.0 mg, 2.19 mmol) and KI (363.0 mg,
2.19 mmol) charged to a microwave vial were added with CH.sub.3CN
(12 mL) and water (0.2 mL). The reaction mixture was subjected to
microwave irradiation at 110.degree. C. for 1 hour. This reaction
was repeated twice. Both reaction mixtures were then combined and
the supernatant clear solution was transferred into a flask, added
with CH.sub.2Cl.sub.2 and stirred at room temperature. Solid was
filtered off, filtrate concentrated, dried under high vacuum to
yield crude
1-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsu-
lfonyl)thiophen-2-yl)pyrrolidine-2-carboxylic acid which will be
used as it is for the next step.
[1198] Step 15E: Crude
1-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsu-
lfonyl)thiophen-2-yl)pyrrolidine-2-carboxylic acid (570 mg, 1.094
mmol) charged to a reaction flask was dissolved in THF (23 mL). To
it was added CDI (649 mg, 4.38 mmol) and the reaction mixture was
heated to reflux for 1 hour. After cooling down to room temperature
excess NH.sub.4OH (28% NH.sub.3) (23 ml) was added dropwise via
addition funnel. The reaction mixture was left to stir at room
temperature for 10 minutes, then it was diluted with ethyl acetate,
acidified (pH acidic) using 10% HCl (aqueous) and stirred for 5
minutes. The layers were separated, and the organic layer was
washed with saturated brine, dried over MgSO.sub.4, concentrated.
Crude product containing a significant amount of starting acid by
TLC was subjected to the same reaction and work up conditions.
After reaction completion crude was purified via flash column
chromatography to yield
1-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsu-
lfonyl)thiophen-2-yl)pyrrolidine-2-carboxamide as white solid (180
mg, 31% yield). HRMS: calcd for
C.sub.21H.sub.24F.sub.4N.sub.4O.sub.3S.sub.2+H+, 521.12987; found
(ESI-FTMS, [M+H].sup.1+), 521.13026.
Example 29CN
(R)-2-chloro-3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-
-ylsulfonyl)benzamide
[1199] The title compound was prepared in a manner similar to that
described in Example 29CM. Yield 24.8%. HRMS: calcd for
C.sub.23H.sub.25ClF.sub.4N.sub.4O.sub.3S+H+, 549.13448; found
(ESI-FTMS, [M+H].sup.1+), 549.13507.
Example 29CO
1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)phenyl]pyrrolidine-3-carboxamide
[1200] HRMS: calcd for C.sub.23H.sub.26F.sub.4N.sub.4O.sub.3S+H+,
515.17345; found (ESI-FTMS, [M+H].sup.1+), 515.17243;
Example 29CP
1-[2-chloro-3-({(2R)-4-[4-cyano-2-(trifluoromethyl)phenyl]-2-methylpiperaz-
in-1-yl}sulfonyl)phenyl]prolinamide
[1201] Yield 52.0%. HRMS: calcd for
C.sub.24H.sub.25ClF.sub.3N.sub.5O.sub.3S+H+, 556.13915; found
(ESI-FTMS, [M+H].sup.1+), 556.13923.
Example 29CQ
1-[3-({(2R)-4-[4-cyano-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}s-
ulfonyl)phenyl]prolinamide
[1202] HRMS: calcd for C.sub.24H.sub.26F.sub.3N.sub.5O.sub.3S+H+,
522.17812; found (ESI-FTMS, [M+H].sup.1+), 522.17711.
Example 29CR
1-(3-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsul-
fonyl)phenyl)pyrrolidine-2-carboxamide
[1203] HRMS: calcd for C.sub.23H.sub.26F.sub.4N.sub.4O.sub.3S+H+,
515.17345; found (ESI-FTMS, [M+H].sup.1+), 515.17506.
Example 29CS
1-(3-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsul-
fonyl)phenyl)pyrrolidine-2-carboxylic acid
[1204] HRMS: calcd for C.sub.23H.sub.25F.sub.4N.sub.3O.sub.4S+H+,
516.15747; found (ESI-FTMS, [M+H].sup.1+), 516.15865.
Example 29CT
2-fluoro-5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-
-1-yl}sulfonyl)benzamide
[1205] Step 16A and 16B: The intermediate
2-fluoro-5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazi-
n-1-yl}sulfonyl)benzonitrile was prepared according to procedures
similar to those described in Example 29A.
[1206] Step 16C: To a flask containing
2-fluoro-5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazi-
n-1-yl}sulfonyl)benzonitrile (399 mg, 0.90 mmol) was added a
mixture of TFA/H.sub.2SO.sub.4 (4 mL, 2/2 v/v). The reaction
mixture was stirred at room temperature for 5 days. Reaction was
complete as determined by TLC. Slowly poured the reaction mixture
to the ice, then neutralized the reaction mixture with 3N NaOH
until pH=7-8, extracted with EtOAc (2.times.150 mL). The combined
organic layer was washed with sat. brine and dried over
Na.sub.2SO.sub.4, and concentrated under reduced pressure.
Purification by prep HPLC under neutral condition to yield
2-fluoro-5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazi-
n-1-yl}sulfonyl)benzamide as a white solid (243.7 mg, 58.4%). HRMS:
calcd for C.sub.19H.sub.18F.sub.5N.sub.3O.sub.3S+H+, 464.10618;
found (ESI-FTMS, [M+H].sup.1+), 464.10639.
Example 29CU
1,1,1-trifluoro-2-(3-((2R,6S)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2,6-d-
imethylpiperazin-1-ylsulfonyl)phenyl)propan-2-ol
[1207] A white solid (2.76 g, 66%). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.49 (d, 6H) 1.78-1.89 (m, 3H) 2.43-2.78
(m, 5H) 4.08-4.26 (m, 2H) 7.07-7.15 (m, 1H) 7.16-7.22 (m, 1H)
7.29-7.37 (m, 1H) 7.51-7.63 (m, 1H) 7.77-7.84 (m, 1H) 7.88-7.95 (m,
1H) 8.08-8.15 (m, 1H). HPLC Method 1: room temperature, 6.955 min,
99.23%, HPLC Method 2: room temperature, 7.574 min, 97.80%.
Example 29CV
4-{(3R)-3-methyl-4-[(5-piperazin-1-yl-2-thienyl)sulfonyl]piperazin-1-yl}be-
nzonitrile
[1208] Yield 59.9%. HRMS: calcd for
C.sub.20H.sub.25N.sub.5O.sub.2S.sub.2+H+, 432.15224; found
(ESI-FTMS, [M+H].sup.1+), 432.15278.
Example 29CW
(2R)-1-[(3-bromophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2--
methylpiperazine
[1209] Step 1A: A mixture of 1 (7.92 g, 79.07 mmol), 2 (18.3 g,
75.3 mmol), BINAP (2.81 g, 4.52 mmol), tBuONa (10.86 g, 112.95
mmol) and Pd.sub.2(dba).sub.3 (2.07 g, 2.259 mmol) was mixed and
purged with N.sub.2. Anhydrous toluene (200 mL) was added and
purged with N.sub.2 again. The resultant mixture was heated in an
oil bath at 100.degree. C. under N.sub.2 for 5 hours. After
cooling, diluted with EtOAc (200 mL), filtered through a pad of
Celite and washed with EtOAc (200 mL). The combined organic layer
was washed with aq. NaHCO.sub.3. The aqueous layer was back
extracted with EtOAc (2.times.100 mL). The combined organic layer
was dried over Na.sub.2SO.sub.4. The crude product was purified on
SiO.sub.2 gel column eluted with 0-25% MeOH in EtOAc to give 3 as a
light yellow oil (14.5 g, 73%).
[1210] Step 1B: To a solution of
(R)-1-(4-fluoro-2-(trifluoromethyl)phenyl)-3-methylpiperazine (5 g,
19 mmol) in DCM (50 mL) at 0.degree. C. was added DIPEA (6.62 mL,
38 mmol) 3-bromophenylsulfonyl chloride (3.29 mL, 22.8 mmol). The
resultant mixture was stirred at room temperature overnight, then
washed with aq. NaHCO.sub.3. The aqueous layer was extracted with
DCM (2.times.50 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4. The crude product was purified on SiO2 gel column
eluted with 5-15% EtOAc in hexanes to give 4 as a white solid (7.9
g, 86%). HRMS: calcd for
C.sub.18H.sub.17BrF.sub.4N.sub.2O.sub.2S+H+, 481.02030; found
(ESI-FTMS, [M+H].sup.1+), 481.0208.
Example 29CX
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-{[3-(4-methylpipera-
zin-1-yl)phenyl]sulfonyl}piperazine
[1211] Step 1C: A mixture of
(2R)-1-[(3-bromophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-
-methylpiperazine (8 g, 16.667 mmol), N-Me-piperazine (2.22 mL, 20
mmol), bis-t-Bu-biphenylphosphine (298.2 mg, 1.0 mmol), tBuONa (2.4
g, 25 mmol) and Pd.sub.2(dba).sub.3 (305.2 mg, 0.333 mmol) was
mixed and purged with N.sub.2. Anhydrous toluene (80 mL) was added
and purged with N.sub.2 again. The resultant mixture was heated in
an oil bath at 110.degree. C. under N.sub.2 for 5 hours. After
cooling, diluted with EtOAc (100 mL), filtered through a pad of
Celite and washed with EtOAc (100 mL). The combined organic layer
was washed with aq. NaHCO.sub.3. The aqueous layer was back
extracted with EtOAc (2.times.50 mL). The combined organic layer
was dried over Na.sub.2SO.sub.4. The crude product was purified on
SiO.sub.2 gel column eluted with 0-25% MeOH in EtOAc to give the
desired product as a light yellow solid (6.5 g, 78%). HRMS: calcd
for C.sub.23H.sub.28F.sub.4N.sub.4O.sub.2S+H+, 501.19418; found
(ESI-FTMS, [M+H].sup.1+), 501.1944.
Example 29CY
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(3-piperazin-1-ylp-
henyl)sulfonyl]piperazine
[1212] Step 1D: To a solution of (R)-tert-butyl
4-(3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfon-
yl)phenyl)piperazine-1-carboxylate (970 mg, 1.655 mmol) in DCM (15
mL) was added TFA (5 mL) at room temperature. The resultant mixture
was stirred for 4 h then bascified with 5% aq. NH3. The precipitate
was collected and washed with water to give the desired product as
a light yellow solid (795 mg, 99%). HRMS: calcd for
C.sub.22H.sub.26F.sub.4N.sub.4O.sub.2S+H+, 487.17853; found
(ESI-FTMS, [M+H].sup.1+), 487.17747.
Example 29CZ
(2R)-1-{[3-(4-ethylpiperazin-1-yl)phenyl]sulfonyl}-4-[4-fluoro-2-(trifluor-
omethyl)phenyl]-2-methylpiperazine
[1213] Step 1E: To a solution of
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(3-piperazin-1-yl-
phenyl)sulfonyl]piperazine (120 mg, 0.247 mmol) in MeOH (2 mL) was
added CH.sub.3CHO (12 mg, 0.27 mmol), HOAc (17.7 .mu.L, 0.3 mmol)
and NaBH.sub.3CN (8 mg, 0.125 mmol) at room temperature. The
resultant mixture was stirred till disappearance of starting
material as monitored by LCMS. The solvent was removed. The crude
product was purified by SiO2 column eluted with DCM/MeOH to give
the desired product as a light yellow solid (116 mg, 100%). HRMS:
calcd for C.sub.24H.sub.30F.sub.4N.sub.4O.sub.2S+H+, 515.20983;
found (ESI-FTMS, [M+H].sup.1+), 515.20891.
[1214] The following examples (Examples 29DA to 29EK) were prepared
using procedures similar to those described in Examples
29CW-29CZ.
Example 29DA
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-1-{[3-(4-isopropylpiperazin-1--
yl)phenyl]sulfonyl}-2-methylpiperazine
[1215] Yield 100%. HRMS: calcd for
C.sub.25H.sub.32F.sub.4N.sub.4O.sub.2S+H+, 529.22548; found
(ESI-FTMS, [M+H].sup.1+), 529.22456.
Example 29DB
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-1-{[3-(4-isobutylpiperazin-1-y-
l)phenyl]sulfonyl}-2-methylpiperazine
[1216] Yield 65%. HRMS: calcd for
C.sub.26H.sub.34F.sub.4N.sub.4O.sub.2S+H+, 543.24113; found
(ESI-FTMS, [M+H].sup.1+), 543.2412.
Example 29DC
(2R)-1-{[3-(4-cyclohexylpiperazin-1-yl)phenyl]sulfonyl}-4-[4-fluoro-2-(tri-
fluoromethyl)phenyl]-2-methylpiperazine
[1217] Yield 56%. HRMS: calcd for
C.sub.29H.sub.36F.sub.4N.sub.4O.sub.2S+H+, 569.25678; found
(ESI-FTMS, [M+H].sup.1+), 569.25578.
Example 29DD
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-({3-[4-(tetrahydro--
2H-pyran-4-yl)piperazin-1-yl]phenyl}sulfonyl)piperazine
[1218] Yield 63%. HRMS: calcd for
C.sub.27H.sub.34F.sub.4N.sub.4O.sub.3S+H+, 571.23605; found
(ESI-FTMS, [M+H].sup.1+), 571.23507.
Example 29DE
(2R)-1-{[3-(4-acetylpiperazin-1-yl)phenyl]sulfonyl}-4-[4-fluoro-2-(trifluo-
romethyl)phenyl]-2-methylpiperazine
[1219] Yield 58%. HRMS: calcd for
C.sub.24H.sub.28F.sub.4N.sub.4O.sub.3S+H+, 529.18910; found
(ESI-FTMS, [M+H].sup.1+), 529.1879.
Example 29DF
Methyl
4-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazi-
n-1-yl}sulfonyl)phenyl]piperazine-1-carboxylate
[1220] Yield 97%. HRMS: calcd for
C.sub.24H.sub.28F.sub.4N.sub.4O.sub.4S+H+, 545.18401; found
(ESI-FTMS, [M+H].sup.1+), 545.1827.
Example 29DG
N-ethyl-4-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperaz-
in-1-yl}sulfonyl)phenyl]piperazine-1-carboxamide
[1221] Yield 71%. HRMS: calcd for
C.sub.24H.sub.28F.sub.4N.sub.4O.sub.4S+H+, 545.18401; found
(ESI-FTMS, [M+H].sup.1+), 545.1827.
Example 29DH
(2R)-1-[(5-bromo-2-thienyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl-
]-2-methylpiperazine
[1222] Yield 95%. HRMS: calcd for
C.sub.16H.sub.15BrF.sub.4N.sub.2O.sub.2S.sub.2+H+, 486.97672; found
(ESI-FTMS, [M+H].sup.1+), 486.9753
Example 29DI
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(5-pyridin-2-yl-2--
thienyl)sulfonyl]piperazine
[1223] Yield 77%. HRMS: calcd for
C.sub.21H.sub.19F.sub.4N.sub.3O.sub.2S.sub.2+H+, 486.09276; found
(ESI-FTMS, [M+H].sup.1+), 486.09151.
Example 29DJ
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-{[5-(1,3-oxazol-5-y-
l)-2-thienyl]sulfonyl}piperazine
[1224] Yield 58%. HRMS: calcd for
C.sub.19H.sub.17F.sub.4N.sub.3O.sub.3S.sub.2+H+, 476.07202; found
(ESI-FTMS, [M+H].sup.1+), 476.07045.
Example 29DK
(2R)-1-[(4-bromo-5-chloro-2-thienyl)sulfonyl]-4-[4-fluoro-2-(trifluorometh-
yl)phenyl]-2-methylpiperazine
[1225] HRMS: calcd for
C.sub.16H.sub.14BrClF.sub.4N.sub.2O.sub.2S.sub.2+H+, 520.93774;
found (ESI-FTMS, [M+H].sup.1+), 520.93796;
Example 29DM
(2R)-1-[(5-chloro-2-thienyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)pheny-
l]-2-methylpiperazine
[1226] HRMS: calcd for
C.sub.16H.sub.15ClF.sub.4N.sub.2O.sub.2S.sub.2+H+, 443.02723; found
(ESI-FTMS, [M+H].sup.1+), 443.02752.
Example 29DN
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-{[3-(5-methyl-2-fur-
yl)phenyl]sulfonyl}piperazine
[1227] HRMS: calcd for C.sub.23H.sub.22F.sub.4N.sub.2O.sub.3S+H+,
483.13600; found (ESI-FTMS, [M+H].sup.1+), 483.13551.
Example 29DO
4-[(3R)-4-{[3-(2,4-dimethyl-1,3-thiazol-5-yl)phenyl]sulfonyl}-3-methylpipe-
razin-1-yl]-3-(trifluoromethyl)benzonitrile
[1228] HRMS: calcd for
C.sub.24H.sub.23F.sub.3N.sub.4O.sub.2S.sub.2+H+, 521.12873; found
(ESI-FTMS, [M+H].sup.1+), 521.12984.
Example 29DP
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-{[3-(trifluorometho-
xy)phenyl]sulfonyl}piperazine
[1229] Yield 84%. HRMS: calcd for
C.sub.19H.sub.17F.sub.7N.sub.2O.sub.3S+H+, 487.09208; found
(ESI-FTMS, [M+H].sup.1+), 487.09309.
Example 29DQ
(2R)-1-{[3-(difluoromethoxy)phenyl]sulfonyl}-4-[4-fluoro-2-(trifluoromethy-
l)phenyl]-2-methylpiperazine
[1230] Yield 84%. HRMS: calcd for
C.sub.19H.sub.18F.sub.6N.sub.2O.sub.3S+H+, 469.10151; found
(ESI-FTMS, [M+H].sup.1+), 469.10142.
Example 29DR
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-{[5-(4-methylpipera-
zin-1-yl)-2-thienyl]sulfonyl}piperazine
[1231] Yield 54%. MS (LC-ESIMS) m/z 507.2.
Example 29DS
4-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)-2-thienyl]morpholine
[1232] Yield 59%. MS (LC-ESIMS) m/z 494.0
Example 29DT
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(5-piperidin-1-yl--
2-thienyl)sulfonyl]piperazine
[1233] Yield 50%. MS (LC-ESIMS) m/z 492.1.
Example 29DT
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(5-piperidin-1-yl--
2-thienyl)sulfonyl]piperazine
[1234] Yield 81%. HRMS: calcd for
C.sub.20H.sub.24F.sub.4N.sub.4O.sub.2S.sub.2+H+, 493.13495; found
(ESI-FTMS, [M+H].sup.1+), 493.13585.
Example 29DU
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-({5-[(3R)-3-methylp-
iperazin-1-yl]-2-thienyl}sulfonyl)piperazine
[1235] Yield 82%. HRMS: calcd for
C.sub.21H.sub.26F.sub.4N.sub.4O.sub.2S.sub.2+H+, 507.15060; found
(ESI-FTMS, [M+H].sup.1+), 507.15115.
Example 29DV
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-({5-[(3S)-3-methylp-
iperazin-1-yl]-2-thienyl}sulfonyl)piperazine
[1236] Yield 59%. HRMS: calcd for
C.sub.21H.sub.26F.sub.4N.sub.4O.sub.2S.sub.2+H+, 507.15060; found
(ESI-FTMS, [M+H].sup.1+), 507.1505.
Example 29DW
1-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)-2-thienyl]-N,N-dimethylpiperidin-4-amine
[1237] Yield 70%. MS (LC-ESIMS) m/z 535.1.
Example 29DX
4-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)-2-thienyl]-2,6-cis-dimethylmorpholine
[1238] Yield 67%. HRMS: calcd for
C.sub.22H.sub.27F.sub.4N.sub.3O.sub.3S.sub.2+H+, 522.15027; found
(ESI-FTMS, [M+H].sup.1+), 522.14978.
Example 29DY
4-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)-2-thienyl]piperazin-2-one
[1239] Yield 77%. MS (LC-ESI-MS) m/z 507.3.
Example 29DZ
1-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)-2-thienyl]piperidine-4-carboxamide
[1240] Yield 37%. HRMS: calcd for
C.sub.22H.sub.26F.sub.4N.sub.4O.sub.3S.sub.2+H+, 535.14552; found
(ESI-FTMS, [M+H].sup.1+), 535.14646.
Example 29EA
(2R)-1-({5-[3,5-cis-dimethylpiperazin-1-yl]-2-thienyl}sulfonyl)-4-[4-fluor-
o-2-(trifluoromethyl)phenyl]-2-methylpiperazine
[1241] Yield 52.2%. HRMS: calcd for
C.sub.22H.sub.28F.sub.4N.sub.4O.sub.2S.sub.2+H+, 521.16625; found
(ESI-FTMS, [M+H].sup.1+), 521.16822.
Example 29EA
1-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)-2-thienyl]piperidine-4-carboxylic acid
[1242] HRMS: calcd for
C.sub.22H.sub.25F.sub.4N.sub.3O.sub.4S.sub.2+H+, 536.12954; found
(ESI-FTMS, [M+H].sup.1+), 536.13032.
Example 29EB
(2R)-1-{[5-(4-acetylpiperazin-1-yl)-2-thienyl]sulfonyl}-4-[4-fluoro-2-(tri-
fluoromethyl)phenyl]-2-methylpiperazine
[1243] Yield 85%. HRMS: calcd for
C.sub.22H.sub.26F.sub.4N.sub.4O.sub.3S.sub.2+H+, 535.14552; found
(ESI-FTMS, [M+H].sup.1+), 535.14534.
Example 29EC
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-1-{[5-(4-isobutyrylpiperazin-1-
-yl)-2-thienyl]sulfonyl}-2-methylpiperazine
[1244] Yield 56%. HRMS: calcd for
C.sub.24H.sub.30F.sub.4N.sub.4O.sub.3S.sub.2+H+, 563.17682; found
(ESI-FTMS, [M+H].sup.1+), 563.17644.
Example 29ED
Methyl
4-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazi-
n-1-yl}sulfonyl)-2-thienyl]piperazine-1-carboxylate
[1245] Yield 78%. HRMS: calcd for
C.sub.22H.sub.26F.sub.4N.sub.4O.sub.4S.sub.2+H+, 551.14043; found
(ESI-FTMS, [M+H].sup.1+), 551.14026.
Example 29EE
Isopropyl
4-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiper-
azin-1-yl}sulfonyl)-2-thienyl]piperazine-1-carboxylate
[1246] Yield 84%. HRMS: calcd for
C.sub.24H.sub.30F.sub.4N.sub.4O.sub.4S.sub.2+H+, 579.17173; found
(ESI-FTMS, [M+H].sup.1+), 579.17159.
Example 29EF
4-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)-2-thienyl]-N-isopropylpiperazine-1-carboxamide
[1247] Yield 91%. HRMS: calcd for
C.sub.24H.sub.31F.sub.4N.sub.5O.sub.3S.sub.2+H+, 578.18772; found
(ESI-FTMS, [M+H].sup.1+), 578.18767.
Example 29EG
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-1-{[5-(4-isopropylpiperazin-1--
yl)-2-thienyl]sulfonyl}-2-methylpiperazine
[1248] Yield 73%. HRMS: calcd for
C.sub.23H.sub.30F.sub.4N.sub.4O.sub.2S.sub.2+H+, 535.18190; found
(ESI-FTMS, [M+H].sup.1+), 535.18259.
Example 29EH
(2R)-1-{[5-(4-cyclohexylpiperazin-1-yl)-2-thienyl]sulfonyl}-4-[4-fluoro-2--
(trifluoromethyl)phenyl]-2-methylpiperazine
[1249] Yield 77%. HRMS: calcd for
C.sub.26H.sub.34F.sub.4N.sub.4O.sub.2S.sub.2+H+, 575.21320; found
(ESI-FTMS, [M+H].sup.1+), 575.21408.
Example 29EI
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-({5-[4-(tetrahydro--
2H-pyran-4-yl)piperazin-1-yl]-2-thienyl}sulfonyl)piperazine
[1250] Yield 69%. HRMS: calcd for
C.sub.25H.sub.32F.sub.4N.sub.4O.sub.3S.sub.2+H+, 577.19247; found
(ESI-FTMS, [M+H].sup.1+), 577.19308.
Example 29EJ
2-{4-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1--
yl}sulfonyl)-2-thienyl]piperazin-1-yl}ethanol
[1251] Yield 69%. HRMS: calcd for
C.sub.22H.sub.28F.sub.4N.sub.4O.sub.3S.sub.2+H+, 537.16117; found
(ESI-FTMS, [M+H].sup.1+), 537.16153.
Example 29EK
1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)phenyl]piperidin-4-ol
[1252] Yield 36%. HRMS: calcd for
C.sub.23H.sub.27F.sub.4N.sub.3O.sub.3S+H+, 502.17820; found
(ESI-FTMS, [M+H].sup.1+), 502.17957.
Example 29EL
1,1,1,3,3,3-hexafluoro-2-[4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]--
2-methylpiperazin-1-yl}sulfonyl)phenyl]propan-2-ol
[1253] Step 2A: To a solution of
(R)-1-(4-bromophenylsulfonyl)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-me-
thylpiperazine (265 mg, 0.55 mmol) in dry THF (2.5 mL) was added
tBuLi (0.65 mL, 1.7 M in pentane, 1.1 mmol) at -78.degree. C. The
resultant mixture was stirred for 5 min then CF.sub.3COCF.sub.3 was
bubbled into the solution and stirred another 30 min before
quenched by addition of aq. NH4Cl. The aq. layer was extracted with
DCM and combined organic layer was dried over MgSO4. The crude
product was purified on SiO2 gel column eluted with hexanes/EtOAc
to give the desired product as a white solid (125 mg, 40%). HRMS:
calcd for C.sub.21H.sub.18F.sub.10N.sub.2O.sub.3S+H+, 569.09512;
found (ESI-FTMS, [M+H].sup.1+), 569.0967.
[1254] The following examples (29EM to 29EU) were prepared using
procedures similar to those in Scheme III-2.
Example 29EM
4-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)phenyl]-1-methylpiperidin-4-ol
[1255] Yield 34%. HRMS: calcd for
C.sub.24H.sub.29F.sub.4N.sub.3O.sub.3S+H+, 516.19385; found
(ESI-FTMS, [M+H].sup.1+), 516.19400.
Example 29EN
4-[4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)phenyl]-1-methylpiperidin-4-ol
[1256] Yield 26%. HRMS: calcd for
C.sub.24H.sub.29F.sub.4N.sub.3O.sub.3S+H+, 516.19385; found
(ESI-FTMS, [M+H].sup.1+), 516.1939.
Example 29EO
2,2,2-trifluoro-1-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methy-
lpiperazin-1-yl}sulfonyl)-2-thienyl]ethanone
Example 29EP
2-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)-2-thienyl]propan-2-ol
[1257] Yield 70%. HRMS: calcd for
C.sub.19H.sub.22F.sub.4N.sub.2O.sub.3S.sub.2+H+, 467.10807; found
(ESI-FTMS, [M+H].sup.1+), 467.10824.
Example 29EQ
1,1,1-trifluoro-2-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methy-
lpiperazin-1-yl}sulfonyl)-2-thienyl]propan-2-ol
[1258] Yield 86%. HRMS: calcd for
C.sub.19H.sub.19F.sub.7N.sub.2O.sub.3S.sub.2+H+, 521.07980; found
(ESI-FTMS, [M+H].sup.1+), 521.07991.
Example 29ER
5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sul-
fonyl)thiophene-2-carboxylic acid
[1259] Yield 86%. HRMS: calcd for
C.sub.17H.sub.16F.sub.4N.sub.2O.sub.4S.sub.2+H+, 453.05604; found
(ESI-FTMS, [M+H].sup.1+), 453.05652.
Example 29ES
3,3,3-trifluoro-2-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methy-
lpiperazin-1-yl}sulfonyl)-2-thienyl]-2-hydroxypropanoic acid
[1260] HRMS: calcd for
C.sub.17H.sub.16F.sub.4N.sub.2O.sub.4S.sub.2+H+, 453.05604; found
(ESI-FTMS, [M+H].sup.1+), 453.05652.
Example 29ET
(2S)-1,1,1-trifluoro-2-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2--
methylpiperazin-1-yl}sulfonyl)-2-thienyl]propan-2-ol
[1261] Prepared by chiral HPLC separation of Example 29EQ. MS
(LC-ESIMS) m/z 521.1. MS (LC-ESIMS) m/z 519.2.
Example 29EU
(2R)-1,1,1-trifluoro-2-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2--
methylpiperazin-1-yl}sulfonyl)-2-thienyl]propan-2-ol
[1262] Prepared by chiral HPLC separation of Example 29EQ. MS
(LC-ESIMS) m/z 520.7. MS (LC-ESIMS) m/z 519.0.
Example 29EV
5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sul-
fonyl)-N,N-dimethylthiophene-2-carboxamide
[1263] Step 3A: To a solution of
5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}su-
lfonyl)thiophene-2-carboxylic acid (260 mg, 0.575 mmol) in DCM (5
mL) was added (COCl).sub.2 (150.5 .mu.L, 1.726 mmol) and DMF (1
small drop). The resultant mixture was stirred for 3 h. The solvent
was evaporated and the crude residue was redissolved in dioxane (5
mL). To this was added 2N NH3 in EtOH (2 mL). The reaction mixture
was stirred for 6 h then concentrated. The crude product was
purified on SiO2 column eluted with hexanes/EtOAc to give the
titled compound (less polar fraction, a side product) as a light
yellow solid (48 mg, 17%). HRMS: calcd for
C.sub.19H.sub.21F.sub.4N.sub.3O.sub.3S.sub.2+H+, 480.10332; found
(ESI-FTMS, [M+H].sup.1+), 480.1042.
Example 29EW
5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sul-
fonyl)thiophene-2-carboxamide
[1264] Method 1: Prepared according to Step 3A in Example 29EV as
the major product, as a white solid (180 mg, 69%).
[1265] Method 2: To a solution of
5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}su-
lfonyl)thiophene-2-carboxylic acid (1.15 g, 2.54 mmol) in THF (10
mL) was added Im.sub.2CO (825.1 mg, 5.08 mmol). The resultant
mixture was stirred for 4 h. To this was added 2N NH.sub.3 in EtOH
(6.3 mL). The reaction mixture was stirred overnight then
concentrated. The crude product was purified by HPLC to give the
titled compound as a white solid (789 mg, 69%). HRMS: calcd for
C.sub.17H.sub.17F.sub.4N.sub.3O.sub.3S.sub.2+H+, 452.07202; found
(ESI-FTMS, [M+H].sup.1+), 452.07369.
Example 29EX
tert-butyl
4-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpipe-
razin-1-yl}sulfonyl)phenyl]piperidine-1-carboxylate
[1266] Step 4A: A reaction mixture of
(R)-1-(3-bromophenylsulfonyl)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-me-
thylpiperazine (1.008 g, 2.1 mmol), boronate ester (620 mg, 2
mmol), PdCl.sub.2(dppf) (43.9 mg, 0.06 mmol), dppf (33.3 mg, 0.06
mmol) and KOAc (589 mg, 6 mmol) in dioxane (8 mL) was degassed and
sealed. The reaction mixture was heated to 80.degree. C. for 3 h
then 100.degree. C. for 2 h. It was diluted with DCM after cooling
and washed with brine. The crude product was purified on SiO2 gel
column eluted with hexanes/EtOAc to give (R)-tert-butyl
4-(3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfon-
yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate as a light yellow
solid (628 mg, 54%).
[1267] Step 4B: To a solution of (R)-tert-butyl
4-(3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfon-
yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (620 mg, 1.06
mmol) in MeOH (50 mL) was added Pd/C (.about.100 mg). The mixture
was purged with nitrogen and then stirred under H2 balloon at room
temperature for 2 h. The reaction mixture was filtered through
Celite and concentrated. The crude product was purified by SiO2 gel
column eluted with hexanes/EtOAc to give the titled compound as a
light yellow solid (569 mg, 92%). HRMS: calcd for
C.sub.28H.sub.35F.sub.4N.sub.3O.sub.4S+H+, 586.23572; found
(ESI-FTMS, [M+H].sup.1+), 586.23585.
Example 29EY
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(3-piperidin-4-ylp-
henyl)sulfonyl]piperazine
[1268] Step 4C: To a solution of tert-butyl
4-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl-
}sulfonyl)phenyl]piperidine-1-carboxylate (540 mg, 0.923 mmol) in
DCM (15 mL) was added TFA (5 mL). The reaction mixture was stirred
at room temperature for 2 h and washed with aq. Na.sub.2CO.sub.3.
The organic layer was dried over Na2SO4, concentrated and
redissolved in Et2O and acidified with 1N HCl in Et2O to give the
titled compound as a white solid (427 mg, 89%). HRMS: calcd for
C.sub.23H.sub.27F.sub.4N.sub.3O.sub.2S+H+, 486.18328; found
(ESI-FTMS, [M+H].sup.1+), 486.18382.
Example 29EZ
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-{[3-(1-methylpiperi-
din-4-yl)phenyl]sulfonyl}piperazine
[1269] Step 4D: To a solution of
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(3-piperidin-4-yl-
phenyl)sulfonyl]piperazine (81 mg, 0.155 mmol) in MeOH (2 mL) was
added (CHO)n 27 mg, 0.93 mmol), HOAc (13.7 .mu.L, 0.23 mmol) and
NaBH.sub.3CN (6 mg, 0.093 mmol). The reaction mixture was stirred
at room temperature overnight then 50.degree. C. till disappearance
of starting material. The reaction was diluted with DCM and
quenched with aq. NaHCO3. The organic layer was separated and dried
over Na2SO4 and purified on SiO2 gel column eluted with
hexanes/EtOAc to give the desired product as a sticky oil (65 mg,
84%). It was redissolved in Et2O and acidified with 1N HCl in Et2O
and triturated with hexanes/Et2O to give the titled compound as a
white solid. HRMS: calcd for
C.sub.24H.sub.29F.sub.4N.sub.3O.sub.2S+H+, 500.19893; found
(ESI-FTMS, [M+H].sup.1+), 500.19765.
Example 29FA
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-1-{[3-(1-isopropylpiperidin-4--
yl)phenyl]sulfonyl}-2-methylpiperazine
[1270] Prepared according to the synthesis of Example 29EZ in Step
4D from
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(3-piperidin-4-yl-
phenyl)sulfonyl]piperazine (81 mg, 0.155 mmol) and acetone (23
.mu.L, 0.31 mmol) as a sticky oil (75 mg, 92%). It was redissolved
in Et.sub.2O and acidified with 1N HCl in Et2O and triturated with
hexanes/Et.sub.2O to give the titled compound as a white solid.
HRMS: calcd for C.sub.26H.sub.33F.sub.4N.sub.3O.sub.2S+H+,
528.23023; found (ESI-FTMS, [M+H].sup.1+), 528.22834.
Example 29FB
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(5-piperidin-4-yl--
2-thienyl)sulfonyl]piperazine
[1271] Prepared according to the synthesis of Example 29EY in Step
4C from (R)-tert-butyl
4-(5-(4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfon-
yl)thiophen-2-yl)piperidine-1-carboxylate (150 mg, 0.253 mmol) in
DCM (3 mL) and TFA (1 mL), purified by SiO2 column eluted with
EtOAc/MeOH to give the titled compound as a white solid (75 mg,
60%). HRMS: calcd for
C.sub.21H.sub.25F.sub.4N.sub.3O.sub.2S.sub.2+H+, 492.13970; found
(ESI-FTMS, [M+H].sup.1+), 492.14043.
Example 29FC
2-(4-{[(2R)-4-(2,4-difluorophenyl)-2-methylpiperazin-1-yl]sulfonyl}phenyl)-
-1,1,1-trifluoropropan-2-ol
[1272] Step 5A: To a solution of
(R)-1-(4-(4-(2,4-difluorophenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)et-
hanone (360 mg, 0.87 mmol, prepared according to procedures similar
to those described in Example 29A) was added TMSCF.sub.3 (5.2 mL,
0.5 M in THF, 2.6 mmol) and TBAF (0.87 mL, 1 M in THF, 1.0 mmol) at
0.degree. C. The resultant mixture was stirred for 6 h then rt
overnight. It was washed with aq. NH4Cl and aq. layer was extracted
with DCM. The organic layer was dried over Na2SO4. The crude
product was purified on SiO2 column eluted with hexanes/EtOAc to
give the desired product as a white solid (329 mg, 81%). HRMS:
calcd for C.sub.20H.sub.21F.sub.5N.sub.2O.sub.3S+H+, 465.12658;
found (ESI-FTMS, [M+H].sup.1+), 465.12565.
Example 29FD
2-(4-{[(2R)-4-(2,4-difluorophenyl)-2-methylpiperazin-1-yl]sulfonyl}phenyl)-
propan-2-ol
[1273] Step 5B: To a solution of
(R)-1-(4-(4-(2,4-difluorophenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)et-
hanone (220 mg, 0.558 mmol, prepared according to procedures
similar to those described in Example 29A in THF (3 mL) was added
MeLi (0.42 mL, 1.6 M in THF, 0.67 mmol) at -78.degree. C. The
resultant mixture was stirred for 6 h then quenched with aq. NH4Cl
and aq. layer. It was extracted with DCM. The organic layer was
dried over Na2SO4. The crude product was purified on SiO2 column
eluted with hexanes/EtOAc to give the desired product as a white
solid (167 mg, 73%). HRMS: calcd for
C.sub.20H.sub.24F.sub.2N.sub.2O.sub.3S+H+, 411.15484; found
(ESI-FTMS, [M+H].sup.1+), 411.15477.
Example 29FE
1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[4-(4-methylpiperazin-1-yl)-2-(trif-
luoromethyl)phenyl]piperazin-1-yl}sulfonyl)phenyl]propan-2-ol
[1274] Prepared according to procedures similar those described in
Example 29FC from
(R)-1-(4-(2-methyl-4-(4-(4-methylpiperazin-1-yl)-2-(trifluorome-
thyl)phenyl)piperazin-1-ylsulfonyl)phenyl)ethanone (180 mg, 0.344
mmol), as a white solid (87.6 mg, 43%). HRMS: calcd for
C.sub.26H.sub.32F.sub.6N.sub.4O.sub.3S+H+, 595.21721; found
(ESI-FTMS, [M+H].sup.1+), 595.21453.
Example 29FF
(R)-2-(3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsul-
fonyl)phenyl)propan-2-ol
[1275] Prepared according to procedures similar those described in
Example 29FD from
(R)-1-(3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpipera-
zin-1-ylsulfonyl)phenyl)ethanone, as a white solid. HRMS: calcd for
C.sub.21H.sub.24F.sub.4N.sub.2O.sub.3S+H+, 461.15165; found
(ESI-FTMS, [M+H].sup.1+), 461.1523.
Example 29FG
1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[3-(1H-1,2,4-triazol-1-yl)-2-(trifl-
uoromethyl)phenyl]piperazin-1-yl}sulfonyl)phenyl]propan-2-ol
[1276] Prepared according to procedures similar those described in
Example 29FC from
(R)-1-(4-(4-(3-(1H-1,2,4-triazol-1-yl)-2-(trifluoromethyl)pheny-
l)-2-methylpiperazin-1-ylsulfonyl)phenyl)ethanone, as a white
solid. HRMS: calcd for C.sub.23H.sub.23F.sub.6N.sub.5O.sub.3S+H+,
564.14985; found (ESI-FTMS, [M+H].sup.1+), 564.14965.
Example 29FH
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-{[3-(1H-imidazol-1--
yl)phenyl]sulfonyl}piperazine
[1277] Step 6A: A suspension of
(R)-1-(3-bromophenylsulfonyl)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-me-
thylpiperazine (168 mg, 0.35 mmol),
1,2-trans-diaminomethylcyclohexane (2.9 mg, 0.015 mmol), K3PO4 (8.5
mmg, 0.06 mmol) and Imidazole (41 mg, 0.6 mmol) in dioxane (0.6 mL)
was degassed and heated to 120.degree. C. in a sealed tube till
disappearance of starting material as monitored by LCMS. The crude
reaction mixture was filtered through a pad of Celite and washed
with EtOAc. The crude product was purified on SiO2 column eluted
with hexanes/EtOAc to give the desired product as a white solid
(123 mg, 75%). HRMS: calcd for
C.sub.21H.sub.20F.sub.4N.sub.4O.sub.2S+H+, 469.13158; found
(ESI-FTMS, [M+H].sup.1+), 469.13336.
Example 29FI
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-{[3-(1H-pyrazol-1-y-
l)phenyl]sulfonyl}piperazine
[1278] Prepared according to procedures similar to those described
in Example 29FH from
(R)-1-(3-bromophenylsulfonyl)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-me-
thylpiperazine (168 mg, 0.35 mmol), and Imidazole (41 mg, 0.6 mmol)
as a white solid (152.3 mg, 93%). HRMS: calcd for
C.sub.21H.sub.20F.sub.4N.sub.4O.sub.2S+H+, 469.13158; found
(ESI-FTMS, [M+H].sup.1+), 469.13318.
Example 29FJ
(2R)-2-methyl-1-{[3-(1H-1,2,4-triazol-1-yl)phenyl]sulfonyl}-4-[4-(1H-1,2,4-
-triazol-1-yl)-2-(trifluoromethyl)phenyl]piperazine
[1279] Prepared according to procedures similar to those described
in Example 29FH from
(R)-1-(3-bromophenylsulfonyl)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-me-
thylpiperazine (96 mg, 0.2 mmol), salicylaldoxime (2.8 mg, 0.02
mmol), K3PO4 (8.5 mmg, 0.06 mmol) and triazole (27.6 mg, 0.4 mmol)
in DMF (0.4 mL) as a white solid (major product, 89.4 mg, 86%).
HRMS: calcd for C.sub.22H.sub.21F.sub.3N.sub.8O.sub.2S+H+,
519.15330; found (ESI-FTMS, [M+H].sup.1+), 519.15377.
Example 29FK
1-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)-2-thienyl]piperazin-2-one
[1280] Prepared by acid treatment (1N HCl in EtOAc) of tert-butyl
4-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsu-
lfonyl)thiophen-2-yl)-3-oxopiperidine-1-carboxylate, as a white
solid [tert-butyl
4-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsu-
lfonyl)thiophen-2-yl)-3-oxopiperidine-1-carboxylate was prepared
according to procedures similar to those described in Example 29FH
from
(R)-1-(5-bromothiophen-2-ylsulfonyl)-4-(4-fluoro-2-(trifluoromethyl)pheny-
l)-2-methylpiperazine (292 mg, 0.6 mmol), and tert-butyl
3-oxopiperazine-1-carboxylate (181 mg, 0.9 mmol) as a white solid
(major product, 89.4 mg, 86%)]. HRMS: calcd for
C.sub.20H.sub.22F.sub.4N.sub.4O.sub.3S.sub.2+H+, 507.11422; found
(ESI-FTMS, [M+H].sup.1+), 507.11461.
Example 29FL
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-{[3-(1H-1,2,4-triaz-
ol-1-yl)phenyl]sulfonyl}piperazine
[1281] Prepared according to procedures similar to those described
in Example 29FH from
(R)-1-(3-bromophenylsulfonyl)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-me-
thylpiperazine, without using ligand, as a white solid. HRMS: calcd
for C.sub.20H.sub.19F.sub.4N.sub.5O.sub.2S+H+, 470.12683; found
(ESI-FTMS, [M+H].sup.1+), 470.1276.
Example 29FM
(2R)-1-{[2-chloro-4-(1H-1,2,4-triazol-1-yl)phenyl]sulfonyl}-4-[4-fluoro-2--
(trifluoromethyl)phenyl]-2-methylpiperazine
[1282] Prepared according to procedures similar to those described
in Example 29FH from
(R)-1-(2-chloro-4-fluorophenylsulfonyl)-4-(4-fluoro-2-(trifluoromethyl)ph-
enyl)-2-methylpiperazine, without using ligand, as a white solid.
HRMS: calcd for C.sub.20H.sub.18ClF.sub.4N.sub.5O.sub.2S+H+,
504.08786; found (ESI-FTMS, [M+H].sup.1+), 504.08778.
Example 29FN
(2R)-1-{[3-chloro-4-(1H-1,2,4-triazol-1-yl)phenyl]sulfonyl}-4-[4-fluoro-2--
(trifluoromethyl)phenyl]-2-methylpiperazine
[1283] Prepared according to procedures similar to those described
in Example 29FH from
(R)-(3-chloro-4-fluorophenylsulfonyl)-4-(4-fluoro-2-(trifluoromethyl)phen-
yl)-2-methylpiperazine, without using ligand, as a white solid.
HRMS: calcd for C.sub.20H.sub.18ClF.sub.4N.sub.5O.sub.2S+H+,
504.08786; found (ESI-FTMS, [M+H].sup.1+), 504.08934.
Example 29FO
3-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)-2-thienyl]-2-methylpropanoic acid
[1284] Step 7A: To a solution of
(R)-1-(5-bromothiophen-2-ylsulfonyl)-4-(4-fluoro-2-(trifluoromethyl)pheny-
l)-2-methylpiperazine (389 mg, 0.8 mmol), Pd2(dba).sub.3 (22 mg,
0.024 mmol), ZnF2 (41.6 mg, 0.4 mmol) and P(tBu.sub.3)HBF.sub.4
(13.9 mg, 0.048 mmol) in DMF (1 mL) was added ketene acetal (0.256
mL, 1.2 mmol) under nitrogen. The resultant mixture was stirred at
100.degree. C. for 3 h. After cooling, it was diluted with EtOAc
and washed with brine. Dried over MgSO4. The crude product was
purified on SiO2 gel column eluted with hexanes/EtOAc to give
3-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl-
}sulfonyl)-2-thienyl]-2-methylpropanoic acid methyl ester as a
light yellow sticky oil (285 mg, 70%).
[1285] Step 7B: To a solution of
3-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl-
}sulfonyl)-2-thienyl]-2-methylpropanoic acid methyl ester (115 mg,
0.2 mmol) in THF (3 mL) was added LiOH (excess) and water (3 mL).
The reaction mixture was stirred at rt overnight and acidified with
1N aq. HCl, then extracted with EtOAc. The organic layer was dried
over Na2SO4. The crude product was purified on SiO2 column eluted
with hexanes/EtOAc to give the titled compounds as a light yellow
solid (94 mg, 95%). HRMS: calcd for
C.sub.20H.sub.22F.sub.4N.sub.2O.sub.4S.sub.2+H+, 495.10299; found
(ESI-FTMS, [M+H].sup.1+), 495.10293.
Example 29FP
2-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)phenyl]-2-methylpropanoic acid
[1286] Prepared according to procedures similar to those described
in Example 29FO. Yield 87%. HRMS: calcd for
C.sub.22H.sub.24F.sub.4N.sub.2O.sub.4S+H+, 489.14657; found
(ESI-FTMS, [M+H].sup.1+), 489.14748.
Example 29FQ
2-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)phenyl]-2-methylpropanamide
[1287] Prepared according to the procedures similar to those
described in Example 29FO. Yield 73%. HRMS: calcd for
C.sub.22H.sub.25F.sub.4N.sub.3O.sub.3S+H+, 488.16255; found
(ESI-FTMS, [M+H].sup.1+), 488.164.
Example 29FR
3-chloro-4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-
-1-yl}sulfonyl)benzamide
[1288] Step 9A: A mixture of
(R)-3-chloro-4-(4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin--
1-ylsulfonyl)benzonitrile (290 mg, 0.626 mmol) in H.sub.2SO.sub.4
(3 mL) and TFA (6 mL) was stirred at rt overnight. To this was
added ice-water. The precipitate was collected by filtration and
washed with water to give the desired product as a white solid
(267.5 mg, 89%). HRMS: calcd for
C.sub.19H.sub.18ClF.sub.4N.sub.3O.sub.3S+H+, 480.07663; found
(ESI-FTMS, [M+H].sup.1+), 480.07642.
Example 29FS
(2S)-3,3,3-trifluoro-2-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2--
methylpiperazin-1-yl}sulfonyl)phenyl]propane-1,2-diol
[1289] Step A:
(2R)-1-[(3-bromophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-
-methylpiperazine (960 mg, 2.0 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (559
mg, 2.2 mmol), PdCl.sub.2(dppf).sub.2 (82 mg, 0.1 mmol) and KOAc
(588 mg, 6 mmol) in DMSO (5 mL) was degassed and heated in a sealed
tube in an oil bath at 60.degree. C. for 12 hours. After cooling,
diluted with Et.sub.2O and washed with brine and extracted with
Et.sub.2O. The combined organic layer was dried over
Na.sub.2SO.sub.4. The crude product was purified on SiO.sub.2 gel
column eluted with hexanes/EtOAc to give the desired product
(R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-1-(3-(4,4,5,5-
-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylsulfonyl)piperazine (916
mg, 87%).
[1290] Step B: A solution of
(R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-1-(3-(4,4,5,5-tetrame-
thyl-1,3,2-dioxaborolan-2-yl)phenylsulfonyl)piperazine (106 mg, 0.2
mmol) and Pd(PPh.sub.3 (12 mg, 0.01 mmol) in THF (2 mL) was
degassed and then added Na.sub.2CO.sub.3 (0.6 mL, 1.0 M in water,
0.6 mmol) and 2-bromo-3,3,3-trifluoroprop-1-ene (105 mg, 0.6 mmol)
under N.sub.2. The resultant mixture was heated in a sealed tube in
an oil bath at 60.degree. C. overnight. After cooling, diluted with
Et.sub.2O (10 mL), washed with brine and extracted with Et.sub.2O.
The combined organic layer was dried over Na.sub.2SO.sub.4. The
crude product was purified on SiO.sub.2 gel column eluted with
hexanes/EtOAc to give
(R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-1-(3-(3,3,3-trifluoro-
prop-1-en-2-yl)phenylsulfonyl)piperazine as a colorless oil (83 mg,
85%).
[1291] Step C: A slurry of
(R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-1-(3-(3,3,3-trifluoro-
prop-1-en-2-yl)phenylsulfonyl)piperazine was dissolved in aqueous
tBuOH (1:1 vol) with slight heating via heat gun, under continuous
stirring until 75% of the solid was in solution. The solution was
allowed to cool slightly, (T=40-50.degree. C. max), and then slowly
added to a flask containing 5 mol % (DHQ)Phal ligand, and 1.0 eq.
MeSO.sub.2NH.sub.2 at 0.degree. C. Immediately following, AD mix
.alpha. (1.5 g/mmol of substrate) was added to the solution, and it
was allowed to stir at 0.degree. C., never exceeding 2-3.degree. C.
for 48 hours, after which it can be judged complete by TLC
(EtOAc/Hexanes 1/5 vol). Workup: Add excess saturated aqueous
Na.sub.2S.sub.2O.sub.3 and allow the reaction to stir for 20-30
minutes, warming to room temperature, and extract into DCM. The
organic layer was dried over Na.sub.2SO.sub.4 and washed with
brine. The crude product was purified on SiO.sub.2 gel column
eluted with hexanes/EtOAc to give the desired product as a white
solid. HRMS: calcd for C.sub.21H.sub.21F.sub.7N.sub.2O.sub.4S+H+,
531.11830; found (ESI-FTMS, [M+H].sup.1+), 531.11699.
Example 29FT
(2S)-3,3,3-trifluoro-2-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2--
methylpiperazin-1-yl}sulfonyl)phenyl]propane-1,2-diol
[1292] The title compound was according to the procedure described
in Example 29FS except that AD mix cc was replaced with AD mix P.
HRMS: calcd for C.sub.21H.sub.21F.sub.7N.sub.2O.sub.4S+H+,
531.11830; found (ESI-FTMS, [M+H].sup.1+), 531.11675.
Example 29FU
(2S,4S)-1-[(3-bromophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]-
-2-methylpiperidine
[1293] Step 11A: A reaction mixture of
4-fluoro-2-(trifluoromethyl)benzoyl fluoride (1.36 mL, 10 mmol),
dimethyl 2-oxopropylphosphonate (1.366 mL, 10 mmol) and
K.sub.2CO.sub.3 (1.65 g, 12 mmol) in MeCN (20 mL) was stirred at
room temperature for 26 h. It was then diluted with EtOAc and
washed with brine. The organic layer was dried over
Na.sub.2SO.sub.4 and crude product was purified on SiO.sub.2 gel
column eluted with hexanes/EtOAc to give the desired product
(E)-4-(4-fluoro-2-(trifluoromethyl)phenyl)but-3-en-2-one (2.3 g,
99%).
[1294] Step B: A solution of
(E)-4-(4-fluoro-2-(trifluoromethyl)phenyl)but-3-en-2-one (696 mg,
3.0 mmol), and Jacobsen [(s,s)-(salen)]2Al (69.2 mg, 0.045 mmol)
and ethyl cyanoacetate (383.8 mL, 3.6 mmol) in cyclohexane (13 mL)
was stirred at room temperature for 24 h. The solvent was removed,
and the crude product was purified on SiO.sub.2 gel column eluted
with hexanes/EtOAc to give the desired product (2R,3R)-ethyl
2-cyano-3-(4-fluoro-2-(trifluoromethyl)phenyl)-5-oxohexanoate (750
mg, 72%).
[1295] Step C: A solution of (2R,3R)-ethyl
2-cyano-3-(4-fluoro-2-(trifluoromethyl)phenyl)-5-oxohexanoate (750
mg, 2.17 mmol) in DMSO (20 mL) and water (10 mL) was heated to
130.degree. C. in microwave oven for 1.5 h. It was diluted with
water (80 mL) and extracted with Et.sub.2O (3.times.80 mL). The
organic layer was dried over MgSO.sub.4. The crude product was
purified on SiO.sub.2 gel column eluted with hexanes/EtOAc to give
the desired product
(S)-3-(4-fluoro-2-(trifluoromethyl)phenyl)-5-oxohexanenitrile (500
mg, 84%).
[1296] Step D: To a solution of
(S)-3-(4-fluoro-2-(trifluoromethyl)phenyl)-5-oxohexanenitrile (482
mg, 1.76 mmol) was added NaBH.sub.4 in MeOH (10 mL) at 0.degree. C.
The reaction was stirred for 20 minutes and quenched with aq. NH4Cl
and then extracted with DCM. The organic layer was dried over
MgSO.sub.4 and the crude product mixture was purified on SiO.sub.2
gel column eluted with hexanes/EtOAC to give the desired product
(3S)-3-(4-fluoro-2-(trifluoromethyl)phenyl)-5-hydroxyhexanenitrile
(390 mg, 81%, 3.5:1 mixture).
[1297] Step E: To a solution of
(3S)-3-(4-fluoro-2-(trifluoromethyl)phenyl)-5-hydroxyhexanenitrile
(340 mg, 1.23 mmol) in DCE (6 mL) was added TEA (516 mL, 3.9 mmol)
and then MsCl (124.4 mL, 1.61 mmol) at 0.degree. C. It was stirred
at room temperature overnight and washed with brine. The crude
reaction product was purified on SiO.sub.2 gel column eluted with
hexanes/EtOAc to give the desired mesylate (420 mg, 97%).
[1298] Step F: To a solution of mesylate, obtained from Step E, in
MeOH was added Pd/C (.about.60 mg). The reaction mixture was
stirred under H.sub.2 at 50 psi for 4 days. It was then filtered
through a pad of Celite. The resultanted methanol solution was
concentrated (.about.5 mL). To this was added DIPEA (436 ml-L, 2.5
mmol). The reaction mixture was then heated in microwave oven at
100.degree. C. for 30 minutes. The solvent was removed under
vacuum. The crude product was purified on SiO.sub.2 column eluted
with EtOAc/MeOH to give the desired product
(2S,4S)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperidine
as single diastereomer (150 mg, 51%).
[1299] Step G: Prepared from
(2S,4S)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperidine
(120 mg, 0.46 mmol) and 3-bromophenylsulfonyl chloride (99.4 mL,
0.69 mmol) according to scheme III-11 in 97% yield. HRMS: calcd for
C.sub.19H.sub.18BrF.sub.4NO.sub.2S+H+, 480.02505; found (ESI-FTMS,
[M+H].sup.1+), 480.02396.
Example 29FV
1-[3-({(2S,4S)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperidin-1--
yl}sulfonyl)phenyl]-4-methylpiperazine
[1300] The title compound was prepared in a manner similar to that
described in Example 29FU. Yield 24%. HRMS: calcd for
C.sub.24H.sub.29F.sub.4N.sub.3O.sub.2S+H+, 500.19893; found
(ESI-FTMS, [M+H].sup.1+), 500.19814.
Example 29FW
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-1-[(4-methoxyphenyl)sulfonyl]--
2-methylpiperazine
[1301] Step 1. A 1 L round bottom flask was charged with a stirbar,
(R)-2-Methylpiperazine (20.0 g, 200.0 mmol), Sodium tert-butoxide
(28.0 g, 300 mmol), BINAP (12.4 g, 20 mmol), and
Pd.sub.2(dba).sub.3. The flask was sealed and vacuum-purged with
N.sub.2 three times. Toluene (500.0 mL) was then added under
N.sub.2, followed by 2-Bromo-5-Fluorobenzotrifluoride (31.4 mL,
220.0 mmol). The reaction mixture was heated to 105.degree. C.
under thermal conditions for three hours, upon which the reaction
cooled to room temperature, and diluted with diethyl ether (2.0 L)
and filtered through celite, to remove inorganics and excess BINAP.
The filtrate was collected and the product was extracted into 10%
HCl (2.times.500 mL). The organic layers were then discarded and
the aqueous layer was basified to pH 10 using 3MNaOH (.about.300
mL). Product was then extracted into ether (3.times.500 mL). The
organic layers were combined and dried over Na.sub.2SO.sub.4,
decanted, and concentrated in vacuo, and the resultant crude oil
(>95% purity by .sup.1H-NMR) was taken on to the next step
without further purification. 90% yield (51 g).
[1302] Step 2: To solution of
1-(4-Fluoro-2-trifluoromethyl-phenyl)-3-methyl-piperazine (200 mg,
0.76 mmol) and DIPEA (0.33 mL, 1.90 mmol) in DCM (8.0 mL) was added
4-Methoxybenzenesulfonyl chloride. The reaction was allowed to stir
over a 12-16 hr period, after which it was judged complete by TLC.
The reaction mixture was concentrated in-vacuo, and the resultant
crude oil was purified via normal phase SiO.sub.2 column
chromatography using a 2%-10% EtOAc/Hex solvent gradient. The
desired product, was isolated in >95% purity. HRMS: calcd for
C.sub.19H.sub.20F.sub.4N.sub.2O.sub.3S+H+, 433.12035; found
([M+H].sup.+), 433.12037.
Example 29FX
4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sul-
fonyl)benzonitrile
[1303] Step 2: Prepared according to the procedure for Example
29FW, step 2, with the exception of a slightly more polar solvent
system for purification (2%-20% EtOAc/Hex) affording 230 mg of the
desired sulfonamide in >95% purity (65% yield). HRMS: calcd for
C.sub.19H.sub.17F.sub.4N.sub.3O.sub.2S+H+, 428.10503; found
([M+H].sup.+), 428.1057; HPLC Method 1: room temperature, 6.822
min, 92.14%. HPLC Method 2: room temperature, 7.395 min,
90.74%.
Example 29FY
(2R)-1-[(4-bromo-2-chlorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)p-
henyl]-2-methylpiperazine
[1304] Step 2: Prepared according to the procedure for Example
29FW, step 2, affording 850 mg of the desired sulfonamide in
>95% purity (72% yield). HRMS: calcd for
C.sub.18H.sub.16BrClF.sub.4N.sub.2O.sub.2S+H+, 514.98132; found
([M+H].sup.+), 514.98153; HPLC Method 1: room temperature, 7.704
min, 99.20%. HPLC Method 2: room temperature, 8.125 min,
98.12%.
Example 29FZ
(2R)-1-[(4,5-dichloro-2-thienyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)p-
henyl]-2-methylpiperazine
[1305] Step 2: Prepared according to the procedure for Example
29FW, step 2, affording 900 mg of the desired sulfonamide in
>95% purity (83% yield). HRMS: calcd for
C.sub.16H.sub.14Cl.sub.2F.sub.4N.sub.2O.sub.2S.sub.2+H+, 476.98826;
found ([M+H].sup.+), 476.9865; HPLC Method 1: room temperature,
7.771 min, 96.52%. HPLC Method 2: room temperature, 8.194 min,
97.28%.
Example 29GA
(2R)-1-[(3-chloro-2-methylphenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)-
phenyl]-2-methylpiperazine
[1306] Step 2: Prepared according to the procedure for Example
29FW, step 2, affording 876 mg of the desired sulfonamide in
>95% purity (80% yield). HRMS: calcd for
C.sub.19H.sub.19ClF.sub.4N.sub.2O.sub.2S+H+, 451.08646; found
([M+H].sup.+), 451.0849; HPLC Method 1: room temperature, 7.623
min, 96.58%. HPLC Method 2: room temperature, 8.050 min,
96.36%.
Example 29GB
(2R)-1-[(2,3-dichlorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)pheny-
l]-2-methylpiperazine
[1307] Step 2: Prepared according to the procedure for Example
29FW, step 2, affording 876 mg of the desired sulfonamide in
>95% purity (83% yield). HRMS: calcd for
C.sub.18H.sub.16Cl.sub.2F.sub.4N.sub.2O.sub.2S+H+, 471.03184; found
([M+H].sup.+), 471.0303; HPLC Method 1: room temperature, 7.529
min, 100%. HPLC Method 2: room temperature, 7.972 min, 99.21%.
Example 29GC
(2R)-1-[(3-fluorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-
-methylpiperazine
[1308] Step 2: Prepared according to the procedure for Example
29FW, step 2, affording 1.1 g of the desired sulfonamide in >95%
purity (87% yield). HRMS: calcd for
C.sub.18H.sub.17F.sub.5N.sub.2O.sub.2S+H+, 421.10036; found
([M+H].sup.+), 421.0991.
Example 29GD
3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sul-
fonyl)aniline
[1309] Step 2: Prepared according to the procedure for Example
29FW, step 2, affording 330 mg of
4-(4-Fluoro-2-trifluoromethyl-phenyl)-2-methyl-1-(3-nitro-benzenesulfonyl-
)-piperazine in >95% purity (47% yield).
[1310] Step 3: A solution of
4-(4-Fluoro-2-trifluoromethyl-phenyl)-2-methyl-1-(3-nitro-benzenesulfonyl-
)-piperazine (330 mg, 0.8 mmol) and a catalytic amount of 10% Pd/C
in EtOAc (25 mL) was stirred under H.sub.2 (1 atm) at ambient
temperature for two hours, after which the reduction was judged
complete by TLC. The H.sub.2 removed under vacuum, and the reaction
mixture was filtered through celite, and rinsed with EtOAc
(3.times.25 mL), and the filtrate was concentrated in vacuo,
affording 180 mg of the desired sulfonamide in >95% purity (62%
yield). HRMS: calcd for C.sub.18H.sub.19F.sub.4N.sub.3O.sub.2S+H+,
418.12068; found ([M+H].sup.+), 418.12119.
Example 29GE
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-(2-thienylsulfonyl)-
piperazine
[1311] Step 2: Prepared according to the procedure for Example
29FW, step 2, affording 330 mg of the desired sulfonamide in
>95% purity (98% yield). HRMS: calcd for
C.sub.16H.sub.16F.sub.4N.sub.2O.sub.2S.sub.2+H+, 409.06621; found
([M+H].sup.+), 409.06656; HPLC Method 1: room temperature, 7.382
min, 88.19%. HPLC Method 2: room temperature, 6.871 min,
78.28%.
Example 29GF
4-{(3R)-4-[(4-bromo-2-chlorophenyl)sulfonyl]-3-methylpiperazin-1-yl}-3-(tr-
ifluoromethyl)benzonitrile
[1312] Step 2: Prepared according to the procedure for Example
29FW, step 2, with the exception of a slightly more polar solvent
system for purification (2%-30% EtOAc/Hex) affording 150 mg of the
desired sulfonamide in >95% purity (33% yield). HRMS: calcd for
C.sub.19H.sub.16BrClF.sub.3N.sub.3O.sub.2S+H+, 521.98600; found
([M+H].sup.+), 521.98688.
Example 29GG
4-{(3R)-4-[(4-bromo-2-fluorophenyl)sulfonyl]-3-methylpiperazin-1-yl}-3-(tr-
ifluoromethyl)benzonitrile
[1313] Step 2: Prepared according to the procedure for Example
29FW, step 2, with the exception of a slightly more polar solvent
system for purification (2%-30% EtOAc/Hex) affording 200 mg of the
desired sulfonamide in >95% purity (45% yield). HRMS: calcd for
C.sub.19H.sub.16BrF.sub.4N.sub.3O.sub.2S+H+, 506.01555; found
([M+H].sup.+), 506.01605.
Example 29GH
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-{[4-(trifluorometho-
xy)phenyl]sulfonyl}piperazine
[1314] Step 2: Prepared according to the procedure for Example
29FW, step 2, affording the desired sulfonamide in >95% purity.
HRMS: calcd for C.sub.19H.sub.17F.sub.7N.sub.2O.sub.3S+H+,
487.09208; found ([M+H].sup.+), 487.09215; HPLC Method 1: room
temperature, 7.660 min, 92.30%. HPLC Method 2: room temperature,
7.797 min, 83.08%.
Example 29GI
4-[3-chloro-4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpipera-
zin-1-yl}sulfonyl)phenyl]morpholine
[1315] A 5-mL microwave vial was charged with a stirbar,
(2R)-1-[(4-bromo-2-chlorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)-
phenyl]-2-methylpiperazine (250 mg, 0.49 mmol), Sodium
tert-butoxide (77 mg, 0.74 mmol), BINAP (31 mg, 0.05 mmol), and
Pd.sub.2(dba).sub.3 (25 mg, 0.03 mmol). The vial was sealed and
vacuum-purged with N.sub.2 three times. Toluene (2.0 mL) was then
added under N.sub.2, followed by morpholine (0.05 mL, 0.53 mmol).
The reaction mixture was heated to 75.degree. C. under thermal
conditions for 30 minutes, upon which the reaction was judged
complete by LCMS. The reaction mixture was diluted with EtOAc (100
mL), and filtered through celite to remove inorganics. The filtrate
was concentrated in vacuo and the crude product was directly loaded
onto a SiO.sub.2 column and purified via normal phase
chromatography (5%-50% EtOAc/Hexanes gradient), affording the
desired compound in >95% purity. HRMS: calcd for
C.sub.22H.sub.24ClF.sub.4N.sub.3O.sub.3S+H+, 522.12358; found
([M+H].sup.+), 522.12358; HPLC Method 1: room temperature, 7.125
min, 100%. HPLC Method 2: room temperature, 7.664 min, 100%.
Example 29GJ
(2R)-1-[(2-chloro-4-piperidin-1-ylphenyl)sulfonyl]-4-[4-fluoro-2-(trifluor-
omethyl)phenyl]-2-methylpiperazine
[1316] Prepared according to the procedure for Example 29GI,
affording the desired compound in >95% purity. HRMS: calcd for
C.sub.23H.sub.26ClF.sub.4N.sub.3O.sub.2S+H+, 520.14431; found
([M+H].sup.+), 520.1445; HPLC Method 1: room temperature, 7.914
min, 79.25%. HPLC Method 2: room temperature, 8.209 min,
78.92%.
Example 29GK
(2R)-1-{[2-chloro-4-(4-methylpiperazin-1-yl)phenyl]sulfonyl}-4-[4-fluoro-2-
-(trifluoromethyl)phenyl]-2-methylpiperazine
[1317] Prepared according to the procedure for Example 29GI, with
the exception of purification which was done on reversed phase
HPLC, under acidic conditions, (10%-90% ACN/H.sub.2O gradient),
affording the desired compound in >95% purity. HRMS: calcd for
C.sub.23H.sub.27ClF.sub.4N.sub.4O.sub.2S+H+, 535.15521; found
([M+H].sup.+), 535.1576; HPLC Method 1: room temperature, 4.647
min, 89.88%. HPLC Method 2: room temperature, 5.774 min,
93.13%.
Example 29GL
(2R)-1-[(4-tert-butoxy-2-chlorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluorome-
thyl)phenyl]-2-methylpiperazine
[1318] Buchwald Reaction Prepared according to the procedure for
Example 29GI, without an amine, (excess NaOtBu as nucleophile),
affording the desired compound in >95% purity. HPLC Method 1:
room temperature, 8.041 min, 97.87%. HPLC Method 2: room
temperature, 8.296 min, 98.22%.
Example 29GM
(2R)-1-[(4-tert-butoxy-2-fluorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluorome-
thyl)phenyl]-2-methylpiperazine
[1319] Buchwald Reaction Prepared according to the procedure for
Example 29GI, affording the desired compound in >95% purity.
HRMS: calcd for C.sub.23H.sub.27F.sub.5N.sub.4O.sub.2S+H+,
493.15788; found ([M+H].sup.+), 493.15802.
Example 29GN
3-chloro-4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-
-1-yl}sulfonyl)-N,N-dimethylaniline
[1320] Buchwald Amination Prepared according to the procedure for
Example 29GI, affording the desired compound in >95% purity.
HRMS: calcd for C.sub.20H.sub.22ClF.sub.4N.sub.3O.sub.2S+H+,
480.11301; found ([M+H].sup.+), 480.1129; HPLC Method 1: room
temperature, 7.390 min, 82.15%. HPLC Method 2: room temperature,
7.824 min, 76.87%.
Example 29GO
(2R)-1-[(2-chloro-4-pyrrolidin-1-ylphenyl)sulfonyl]-4-[4-fluoro-2-(trifluo-
romethyl)phenyl]-2-methylpiperazine
[1321] Buchwald Amination Prepared according to the procedure for
Example 29GI, affording the desired compound in >95% purity.
HRMS: calcd for C.sub.22H.sub.24ClF.sub.4N.sub.3O.sub.2S+H+,
506.12866; found ([M+H].sup.+), 506.12849; HPLC Method 1: room
temperature, 7.786 min, 87.96%. HPLC Method 2: room temperature,
8.019 min, 86.35%.
Example 29GP
N-tert-butyl-3-chloro-4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-me-
thylpiperazin-1-yl}sulfonyl)aniline
[1322] Buchwald Amination: Prepared according to the procedure for
Example 29GI, affording the desired compound in >95% purity.
HRMS: calcd for C.sub.22H.sub.26ClF.sub.4N.sub.3O.sub.2S+H+,
508.14431; found ([M+H].sup.+), 508.14549; HPLC Method 1: room
temperature, 7.622 min, 95.55%. HPLC Method 2: room temperature,
7.963 min, 72.56%.
Example 29GQ
3-chloro-4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-
-1-yl}sulfonyl)-N-isobutylaniline
[1323] Buchwald Amination Prepared according to the procedure for
Example 29GI, affording the desired compound in >95% purity.
HRMS: calcd for C.sub.22H.sub.26ClF.sub.4N.sub.3O.sub.2S+H+,
508.14431; found ([M+H].sup.+), 508.1442; HPLC Method 1: room
temperature, 7.692 min, 88.44%. HPLC Method 2: room temperature,
8.035 min, 81.22%.
Example 29GR
1-[3-chloro-4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpipera-
zin-1-yl}sulfonyl)phenyl]piperidin-4-ol
[1324] Buchwald Amination Prepared according to the procedure for
Example 29GI, with the exception of the use of a more polar solvent
system for purification (20%-100% EtOAc/Hexanes) affording the
desired compound in >95% purity. HPLC Method 1: room
temperature, 6.637 min, 84.22%. HPLC Method 2: room temperature,
7.517 min, 83.74%.
Example 29GS
(2R)-1-({2-chloro-4-[(3S)-3-methylpiperazin-1-yl]phenyl}sulfonyl)-4-[4-flu-
oro-2-(trifluoromethyl)phenyl]-2-methylpiperazine
[1325] Buchwald Amination Prepared according to the procedure for
Example 29GI, with the exception of purification protocol; product
precipitated out of the organic layer as it was being concentrated
in vacuo, and upon filtration, it was afforded in >95% purity.
HRMS: calcd for C.sub.23H.sub.27ClF.sub.4N.sub.4O.sub.2S+H+,
535.15521; found ([M+H].sup.+), 535.15532; HPLC Method 1: room
temperature, 5.139 min, 92.40%. HPLC Method 2: room temperature,
6.299 min, 100%.
Example 29GT
1-[3-chloro-4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpipera-
zin-1-yl}sulfonyl)phenyl]-N,N-dimethylpiperidin-4-amine
[1326] Buchwald Amination: Prepared according to the procedure for
Example 29GI, with the exception of purification using a more polar
solvent system (0%-10% MeOH/EtOAc) affording the desired compound
in >95% purity. HRMS: calcd for
C.sub.25H.sub.31ClF.sub.4N.sub.4O.sub.2S+H+, 563.18651; found
([M+H].sup.+), 563.18857; HPLC Method 1: room temperature, 5.258
min, 85.99%. HPLC Method 2: room temperature, 6.356 min, 100%.
Example 29GU
4-[3-chloro-4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpipera-
zin-1-yl}sulfonyl)phenyl]thiomorpholine 1,1-dioxide
[1327] Prepared according to the procedure for Example 29GI, with
the exception of purification using a more polar solvent system
(5%-40% EtOAc/Hexanes) affording the desired compound in >95%
purity. HRMS: calcd for
C.sub.22H.sub.24ClF.sub.4N.sub.3O.sub.4S.sub.2+H+, 570.09056; found
([M+H].sup.+), 570.09181; HPLC Method 1: room temperature, 6.908
min, 89.31%. HPLC Method 2: room temperature, 7.186 min,
60.60%.
Example 29GV
4-[3-fluoro-4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpipera-
zin-1-yl}sulfonyl)phenyl]morpholine
[1328] Prepared according to the procedure for Example 29GI,
affording 100 mg of the desired compound in >95% purity (49%
yield). HRMS: calcd for C.sub.22H.sub.24F.sub.5N.sub.3O.sub.3S+H+,
506.15313; found ([M+H].sup.+), 506.15321.
Example 29GW
4-[3-chloro-4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpipera-
zin-1-yl}sulfonyl)phenyl]-2,6-cis-dimethylmorpholine
[1329] Prepared according to the procedure for Example 29GI,
affording the desired compound in >95% purity. HRMS: calcd for
C.sub.24H.sub.28ClF.sub.4N.sub.3O.sub.3S+H+, 550.15488; found
([M+H].sup.+), 550.15497; HPLC Method 1: room temperature, 7.454
min, 98.89%. HPLC Method 2: room temperature, 6.334 min,
87.84%.
Example 29GX
1-[3-chloro-4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpipera-
zin-1-yl}sulfonyl)phenyl]piperidine-4-carboxylic acid
[1330] Prepared according to the procedure for Example 29GI, with
the ethyl ester of the amine, affording the ethyl ester of the
desired compound in >95% purity. Removal of the ester group was
achieved under basic conditions (KOH.sub.(aq)/THF), yielding the
desired acid compound. HRMS: calcd for
C.sub.24H.sub.26ClF.sub.4N.sub.3O.sub.4S+H+, 564.13414; found
([M+H].sup.+), 564.13421; HPLC Method 1: room temperature, 7.942
min, 92.23%. HPLC Method 2: room temperature, 7.591 min,
92.35%.
Example 29GY
4-[3-chloro-4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpipera-
zin-1-yl}sulfonyl)phenyl]piperazin-2-one
[1331] Prepared according to the procedure for Example 29GI, with
the exception of purification protocol; the crude solid afforded
after workup was triturated with EtOAc, yielding the desired
compound in >95% purity. HRMS: calcd for
C.sub.22H.sub.23ClF.sub.4N.sub.4O.sub.3S+H+, 535.11883; found
([M+H].sup.+), 535.11947.
Example 29GZ
1-[3-chloro-4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpipera-
zin-1-yl}sulfonyl)phenyl]piperidine-4-carboxamide
[1332] Prepared according to the procedure for Example 29GI,
affording the desired compound in >95% purity. HRMS: calcd for
C.sub.24H.sub.27ClF.sub.4N.sub.4O.sub.3S+H+, 563.15013; found
([M+H].sup.+), 563.15087. HPLC Method 1: room temperature, 7.358
min, 87.78%. HPLC Method 2: room temperature, 6.165 min,
86.98%.
Example 29HA
(2R)-1-({2-chloro-4-[(3R)-3-methylpiperazin-1-yl]phenyl}sulfonyl)-4-[4-flu-
oro-2-(trifluoromethyl)phenyl]-2-methylpiperazine
[1333] Buchwald Amination Prepared according to the procedure for
Example 29GI, affording the desired compound in >95% purity.
HRMS: calcd for C.sub.23H.sub.27ClF.sub.4N.sub.4O.sub.2S+H+,
535.15521; found ([M+H].sup.+), 535.15631; HPLC Method 1: room
temperature, 5.209 min, 85.44%. HPLC Method 2: room temperature,
6.358 min, 84.83%.
Example 29HB
1-[3-chloro-4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpipera-
zin-1-yl}sulfonyl)phenyl]piperazin-2-one
[1334] Buchwald Amination: Prepared according to the procedure for
Example 29GI, with the 4-Boc-protected amine, affording the
Boc-protected analog of the desired compound in >95% purity.
Removal of the Boc group was achieved under acidic conditions
(TFA/DCM), yielding the desired free amine. HRMS: calcd for
C.sub.22H.sub.23ClF.sub.4N.sub.4O.sub.3S+H+, 535.11883; found
([M+H].sup.+), 535.11947.
Example 29HC
(2R)-1-{[2-chloro-4-(4-fluoropiperidin-1-yl)phenyl]sulfonyl}-4-[4-fluoro-2-
-(trifluoromethyl)phenyl]-2-methylpiperazine
[1335] Prepared according to the procedure for Example 29GI,
affording the desired compound in >95% purity. HRMS: calcd for
C.sub.21H.sub.24F.sub.5N.sub.3O.sub.2S.sub.2+H+, 510.13028; found
([M+H].sup.+), 510.12968.
Example 29HD
(2R)-1-{[3-(4,4-difluoropiperidin-1-yl)phenyl]sulfonyl}-4-[4-fluoro-2-(tri-
fluoromethyl)phenyl]-2-methylpiperazine
[1336] Prepared according to the procedure for Example 29GI,
affording the desired compound in >95% purity. HRMS: calcd for
C.sub.21H.sub.23F.sub.6N.sub.3O.sub.2S.sub.2+H+, 522.16444; found
([M+H].sup.+), 522.16468.
Example 29HE
4-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)-4-methoxyphenyl]morpholine
[1337] Prepared from
1-(5-Bromo-2-methoxy-benzenesulfonyl)-4-(4-fluoro-2-trifluoromethyl-pheny-
l)-2-methyl-piperazine and morpholine using sodium tert-butoxide,
BINAP, Pd.sub.2 dba.sub.3 and toluene, affording the desired
compound in >95% purity. HRMS: calcd for
C.sub.23H.sub.27F.sub.4N.sub.3O.sub.4S+H+, 518.17312; found
([M+H].sup.+), 518.1716.
Example 29HF
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-1-[(2-methoxy-5-piperidin-1-yl-
phenyl)sulfonyl]-2-methylpiperazine
[1338] Prepared according to Example 29HE, affording the desired
compound in >95% purity. HRMS: calcd for
C.sub.24H.sub.29F.sub.4N.sub.3O.sub.3S+H+, 516.19385; found
([M+H].sup.+), 516.1943; HPLC Method 1: room temperature, 6.597
min, 84.34%. HPLC Method 2: room temperature, 7.739 min,
88.94%.
Example 29HG
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-1-{[2-methoxy-5-(4-methylpiper-
azin-1-yl)phenyl]sulfonyl}-2-methylpiperazine
[1339] Prepared according to Example 29HE, with the exception of
purification by reversed phase HPLC under acidic conditions
(10%-90% ACN/H.sub.2O), affording the desired compound in >95%
purity. HRMS: calcd for C.sub.24H.sub.30F.sub.4N.sub.4O.sub.3S+H+,
531.20475; found ([M+H].sup.+), 531.2064; HPLC Method 1: room
temperature, 4.514 min, 87.19%. HPLC Method 2: room temperature,
5.435 min, 89.27%.
Example 29HH
4-[2-chloro-3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpipera-
zin-1-yl}sulfonyl)phenyl]morpholine
[1340] HRMS: calcd for C.sub.22H.sub.24ClF.sub.4N.sub.3O.sub.3S+H+,
522.12358; found ([M+H].sup.+), 522.1237.
Example 29HI
(2R)-1-[(2-chloro-3-piperidin-1-ylphenyl)sulfonyl]-4-[4-fluoro-2-(trifluor-
omethyl)phenyl]-2-methylpiperazine
[1341] HRMS: calcd for C.sub.23H.sub.26ClF.sub.4N.sub.3O.sub.2S+H+,
520.14431; found ([M+H].sup.+), 520.14552.
Example 29HJ
4-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-ylp-
henyl}sulfonyl)-2-methylphenyl]morpholine
[1342] HRMS: calcd for C.sub.23H.sub.27F.sub.4N.sub.3O.sub.3S+H+,
502.17820; found ([M+H].sup.+), 502.1787.
Example 29HK
4-[3-chloro-5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpipera-
zin-1-ylphenyl}sulfonyl)-2-thienyl]morpholine
[1343] HRMS: calcd for
C.sub.20H.sub.22ClF.sub.4N.sub.3O.sub.3S.sub.2+H+, 528.08000; found
([M+H].sup.+), 528.0800.
Example 29HL
(2R)-1-{[3-(4-fluoropiperidin-1-yl)phenyl]sulfonyl}-4-[4-fluoro-2-(trifluo-
romethyl)phenyl]-2-methylpiperazine
[1344] HRMS: calcd for C.sub.23H.sub.26F.sub.5N.sub.3O.sub.2S+H+,
504.17386; found ([M+H].sup.+), 504.17263.
Example 29HM
(2R)-1-{[3-(4,4-difluoropiperidin-1-yl)phenyl]sulfonyl}-4-[4-fluoro-2-(tri-
fluoromethyl)phenyl]-2-methylpiperazine
[1345] HRMS: calcd for C.sub.23H.sub.25F.sub.6N.sub.3O.sub.2S+H+,
522.16444; found ([M+H].sup.+), 522.16468.
Example 29HN
4-[4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)phenyl]morpholine
[1346] HPLC Method 1: room temperature, 6.8951 min, 75.92%. HPLC
Method 2: room temperature, 7.523 min, 78.91%.
Example 29HO
ethyl
1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-
-1-yl}sulfonyl)phenyl]piperidine-4-carboxylate
[1347] HRMS: calcd for C.sub.20H.sub.19F.sub.4N.sub.5O.sub.2S+H+,
470.12683; found ([M+H].sup.+), 470.12538.
Example 29HP
4-{(3R)-4-[(4-tert-butoxy-2-chlorophenyl)sulfonyl]-3-methylpiperazin-1-yl}-
-3-(trifluoromethyl)benzonitrile
[1348] HRMS: calcd for C.sub.23H.sub.25ClF.sub.3N.sub.3O.sub.3S+H+,
516.13300; found ([M+H].sup.+), 516.13467.
Example 29HQ
4-{(3R)-4-[(4-tert-butoxy-2-fluorophenyl)sulfonyl]-3-methylpiperazin-1-yl}-
-3-(trifluoromethyl)benzonitrile
Example 29HR
1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)phenyl]-N,N-dimethylpiperidine-4-carboxamide
[1349] Step 1: To a solution of ethyl
1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl-
}sulfonyl)phenyl]piperidine-4-carboxylate (100 mg, 0.18 mmol) in
THF (5.0 mL) was added 2.0M KOH (0.5 mL, 1.0 mmol). The reaction
was allowed to stir at ambient temperature over a 16 hour period,
after which it was judged complete by LCMS. THF was removed in
vacuo, and the remaining aqueous solution was acidified to pH 4 via
addition of 10% HCl solution drop-wise. The resultant precipitate
was filtered and rinsed with cold H.sub.2O (3.times.25 mL),
yielding the desired carboxy acid compound in >95% purity. HRMS:
calcd for C.sub.24H.sub.27F.sub.4N.sub.3O.sub.4S+H+, 530.17312;
found ([M+H].sup.+), 530.17463.
[1350] Step 2: To a solution of
1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl-
}sulfonyl)phenyl]piperidine-4-carboxylic acid (200 mg, 0.38 mmol)
in DMF (4.0 mL) was added BOP (202 mg, 0.46 mmol), DIPEA (0.33 mL,
1.9 mmol), and finally N'N-dimethylamine (0.6 mL, 1.1 mmol). The
reaction was allowed to stir at ambient temperature over a 16 hour
period, after which it was judged complete by LCMS. The reaction
mixture was diluted with EtOAc (50 mL), and washed with saturated
NaHCO.sub.3(aq) (3.times.25 mL). The organic layer was dried over
Na.sub.2SO.sub.4, decanted, and concentrated in vacuo. The
resultant crude oil was purified on a normal phase SiO.sub.2 column
(20%-80% EtOAc/Hexanes) affording the desired amide in >95%
purity. HRMS: calcd for C.sub.26H.sub.32F.sub.4N.sub.4O.sub.3S+H+,
557.22040; found ([M+H].sup.+), 557.22195.
Example 29HS
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-({3-[4-(pyrrolidin--
1-ylcarbonyl)piperidin-1-yl]phenyl}sulfonyl)piperazine
[1351] Prepared according to the procedures of Example 29HR,
affording the desired amide in >95% purity. HRMS: calcd for
C.sub.28H.sub.34F.sub.4N.sub.4O.sub.3S+H+, 583.23605; found
([M+H].sup.+), 583.23752.
Example 29HT
4-({1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-
-yl}sulfonyl)phenyl]piperidin-4-yl}carbonyl)morpholine
[1352] Prepared according to the procedures of Example 29HR,
affording the desired amide in >95% purity. HRMS: calcd for
C.sub.28H.sub.34F.sub.4N.sub.4O.sub.4S+H+, 599.23096; found
([M+H].sup.+), 599.23172.
Example 29HU
N-tert-butyl-1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpi-
perazin-1-yl}sulfonyl)phenyl]piperidine-4-carboxamide
[1353] Prepared according to the procedure of Example 29HR,
affording the desired amide in >95% purity. HRMS: calcd for
C.sub.28H.sub.36F.sub.4N.sub.4O.sub.3S+H+, 585.25170; found
([M+H].sup.+), 585.25309.
Example 29HV
1-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)phenyl]-N-isobutylpiperidine-4-carboxamide
[1354] Prepared according to the procedure of Example 29HR,
affording the desired amide in >95% purity. HRMS: calcd for
C.sub.28H.sub.36F.sub.4N.sub.4O.sub.3S+H+, 585.25170; found
([M+H].sup.+), 585.25262.
Example 29HW
(2R)-1-(biphenyl-3-ylsulfonyl)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-me-
thylpiperazine
[1355] A 5 mL microwave vial was charged with a stir bar,
1-(3-Bromo-benzenesulfonyl)-4-(4-fluoro-2-trifluoromethyl-phenyl)-2-methy-
l-piperazine (230 mg, 0.48 mmol), phenylboronic acid (65 mg, 0.53
mmol), potassium fluoride (111 mg, 1.92 mmol), and palladium
tetrakis (28 mg, 0.024 mmol). The vial was sealed and vacuum-purged
with N.sub.2, after which aqueous THF (4 mL 3:1 vol) was added. The
reaction was heated to 120.degree. C. under microwave conditions
for 10 minutes, after which it was judged complete by LCMS. The
aqueous layer was removed using a simple pasteur pipet, and the
organic phase was diluted with EtOAc (25 mL), and filtered through
celite to remove inorganics. The filtrate was concentrated in vacuo
and the resultant crude oil was purified using anormal phase
SiO.sub.2 column chromatography (5%-35% EtOAc/Hexanes), affording
the desired biphenyl compound in >95% purity. HRMS: calcd for
C.sub.24H.sub.22F.sub.4N.sub.2O.sub.2S+H+, 479.14109; found
([M+H].sup.+), 479.1394.
Example 29HX
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(3-pyridin-4-ylphe-
nyl)sulfonyl]piperazine
[1356] Prepared according to the procedure for Example 29HW, with
the exception of a more polar solvent system during purification
(50%-100% EtOAc/Hexanes), affording the desired compound in >95%
purity. HRMS: calcd for C.sub.23H.sub.21F.sub.4N.sub.3O.sub.2S+H+,
480.13633; found ([M+H].sup.+), 480.1355.
Example 29HY
3'-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}su-
lfonyl)biphenyl-4-carboxylic acid
[1357] Suzuki Coupling: Prepared according to the procedure for
Example 29HW, with the exception of a more polar solvent system
during purification (50%-100% EtOAc/Hexanes), followed by
trituration of the chromatographed material using 100% EtOAc,
affording the desired compound in >95% purity. HRMS: calcd for
C.sub.25H.sub.22F.sub.4N.sub.2O.sub.4S+H+, 523.13092; found
([M+H].sup.+), 523.129.
Example 29HZ
3-fluoro-4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-
-1-yl}sulfonyl)phenol
[1358] Step 1: A solution of
(2R)-1-[(4-tert-butoxy-2-fluorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluorom-
ethyl)phenyl]-2-methylpiperazine (375 mg, 0.76 mmol) in DCM (25 mL)
was added TFA (5 mL). The reaction was allowed to stir for 1 hour,
after which it was judged complete by LCMS. The reaction was
concentrated in vacuo to remove excess TFA, and the crude oil was
dissolved in DCM (20 mL) and washed with saturated NaHCO.sub.3(aq)
(3.times.25 mL). The organic phase was dried over Na.sub.2SO.sub.4,
and decanted, then concentrated in vacuo affording the desired
phenol in >95% purity, which was used in subsequent synthetic
steps without purification. HRMS: calcd for
C.sub.18H.sub.17F.sub.5N.sub.2O.sub.3S+H+, 437.09528; found
([M+H].sup.+), 437.09527.
Example 29IA
2-chloro-4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-
-1-yl}sulfonyl)phenol
[1359] Step 1: Prepared from
(2R)-1-[(4-tert-butoxy-2-chlorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluorom-
ethyl)phenyl]-2-methylpiperazine according to the procedure for
example IV-7A, affording the desired phenol in >95% purity.
HRMS: calcd for C.sub.18H.sub.17ClF.sub.4N.sub.2O.sub.3S+H+,
453.06573; found ([M+H].sup.+), 453.06635.
Example 29IB
(2R)-1-{[2-chloro-4-(2-methoxyethoxy)phenyl]sulfonyl}-4-[4-fluoro-2-(trifl-
uoromethyl)phenyl]-2-methylpiperazine
[1360] Prepared according to Example 29HZ. HRMS: calcd for
C.sub.21H.sub.23ClF.sub.4N.sub.2O.sub.4S+H+, 511.10759; found
([M+H].sup.+), 511.10791.
Example 29IC
(2R)-1-[(2-chloro-4-ethoxyphenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)-
phenyl]-2-methylpiperazine
[1361] Prepared according to the procedure in Example 29HZ,
affording the desired aryl ether in >95% purity. HRMS: calcd for
C.sub.20H.sub.21ClF.sub.4N.sub.2O.sub.3S+H+, 481.09703; found
([M+H].sup.+), 481.09732.
Example 29ID
2-[3-chloro-4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpipera-
zin-1-yl}sulfonyl)phenoxy]-N,N-dimethylethanamine
[1362] Prepared according to the procedure in Example 29HZ,
affording the desired aryl ether in >95% purity. HRMS: calcd for
C.sub.22H.sub.26ClF.sub.4N.sub.3O.sub.3S+H+, 524.13923; found
([M+H].sup.+), 524.14061.
Example 29IE
(2R)-1-{[2-chloro-4-(difluoromethoxy)phenyl]sulfonyl}-4-[4-fluoro-2-(trifl-
uoromethyl)phenyl]-2-methylpiperazine
[1363] Purification (5%-50% EtOAc/Hexanes) afforded the desired
aryl ether in >95% purity. HRMS: calcd for
C.sub.19H.sub.17ClF.sub.6N.sub.2O.sub.3S+H+, 503.06253; found
(ESI-FTMS, [M+H].sup.1+), 503.06351.
Example 29IF
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-{[3-(4H-1,2,4-triaz-
ol-4-yl)phenyl]sulfonyl}piperazine
[1364] Cyclization. A solution of the aniline (400 mg, 0.96 mmol),
N'N-dimethyl-formyl-hydrazine (140 mg, 1.15 mmol), and a catalytic
amount of pTSA in toluene (20 mL) was heated at reflux (130.degree.
C.) under N.sub.2 over a 12-16 hour period, after which the
reaction was judged complete by LCMS. The reaction was then cooled
to ambient temperature and the solvent was concentrated in vacuo,
affording a crude oil which was purified by reversed phase HPLC
under neutral conditions (30%-90% ACN/H.sub.2O), affording the
desired 1,3,4-triazole compound in >95% purity. HRMS: calcd for
C.sub.20H.sub.19F.sub.4N.sub.5O.sub.2S+H+, 470.12683; found
([M+H].sup.+), 470.12538.
Example 29IG
(2R)-4-(2,4-dichlorophenyl)-2-methyl-1-{[3-(4H-1,2,4-triazol-4-yl)phenyl]s-
ulfonyl}piperazine
[1365] Cyclization: Prepared according to the procedure in Example
29IF, affording the desired 1,3,4-triazole compound in >95%
purity. HRMS: calcd for C.sub.19H.sub.19Cl.sub.2N.sub.5O.sub.2S+H+,
452.07092; found ([M+H].sup.+), 452.07148.
Example 29IH
1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[3-(1H-1,2,4-triazol-1-yl)-2-(trifl-
uoromethyl)phenyl]piperazin-1-yl}sulfonyl)phenyl]propan-2-ol
[1366] Step 1: A solution of the methyl ketone intermediate (550
mg, 1.25 mmol) and CuI (25 mg, 0.125 mmol) in NMP (10 mL), was
heated to 170.degree. C. under thermal conditions over a 12-16 hour
period, after which the reaction was judged complete by LCMS. The
reaction was then cooled to ambient temperature and clear reaction
mixture was directly purified by reversed phase HPLC under neutral
conditions (40%-95% ACN/H.sub.2O), affording the 1,2,4-triazole
methyl ketone intermediate in >95% purity.
[1367] Step 2. A solution of the 1,2,4-triazole methyl ketone
intermediate (200 mg, 0.4 mmol) in 0.5M TMSCF.sub.3 in THF (2.4 mL)
under N.sub.2 was cooled to 0.degree. C. A solution of 1.0M
TBAF/THF (0.4 mL) was then added drop-wise and the reaction was
allowed to stir, while warming to room temperature. The reaction
was judged complete by LCMS after 1 hour, and was diluted with
EtOAc (25 mL), and washed with saturated NaHCO.sub.3(aq) and dried
over Na.sub.2SO.sub.4. The crude product was then purified by
normal phase SiO.sub.2 chromatography (10%-60% EtOAc/Hexanes)
affording the desired compound in >95% purity. HRMS: calcd for
C.sub.23H.sub.23F.sub.6N.sub.5O.sub.3S+H+, 564.14985; found
([M+H].sup.+), 564.14965.
Example 29II
1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[4-(1H-1,2,4-triazol-1-yl)-2-(trifl-
uoromethyl)phenyl]piperazin-1-yl}sulfonyl)phenyl]propan-2-ol
[1368] Step 1: Prepared according to the method described above,
affording the 1,2,4-triazole methyl ketone intermediate in >95%
purity.
[1369] Step 2: Prepared according to the method described above,
affording the desired compound in >95% purity. HRMS: calcd for
C.sub.23H.sub.23F.sub.6N.sub.5O.sub.3S+H+, 564.14985; found
([M+H].sup.+), 564.1506.
Example 29IJ
1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[5-(1H-1,2,4-triazol-1-yl)-2-(trifl-
uoromethyl)phenyl]piperazin-1-yl}sulfonyl)phenyl]propan-2-ol
[1370] Step 1: Prepared according to the method described above.
HRMS: calcd for C.sub.23H.sub.23F.sub.6N.sub.5O.sub.3S+H+,
564.14985; found ([M+H].sup.+), 564.14905.
Example 29IK
4-[3-chloro-4-({(2R)-2-methyl-4-[4-(1H-1,2,4-triazol-1-yl)-2-(trifluoromet-
hyl)phenyl]piperazin-1-yl}sulfonyl)phenyl]morpholine
[1371] Step 1. Prepared according to the method described above,
affording the 1,2,4-triazole morpholino compound in >95%
purity.
Example 29IL
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-{[4-(1H-tetrazol-5--
yl)phenyl]sulfonyl}piperazine
[1372] Step 1: To a solution of the nitrile compound described
herein (150 mg, 0.35 mmol) in toluene (3.5 mL) was added
Et.sub.3N*HCl (139 mg, 1.05 mmol) and NaN.sub.3 (66 mg, 1.05 mmol).
The reaction was heated to 100.degree. C. under thermal conditions
over a 12-16 hour period, after which the reaction was judged
complete by LCMS. The reaction was diluted with EtOAc, and washed
3.times. with 10% HCl. The organic phase was concentrated and the
resultant crude solid was triturated with Et.sub.2O, affording the
desired tetrazole in >95% purity. HRMS: calcd for
C.sub.19H.sub.18F.sub.4N.sub.6O.sub.2S+H+, 471.12208; found
([M+H].sup.+), 471.1225.
Example 29IM
1,1,1-trifluoro-2-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methy-
lpiperazin-1-yl}sulfonyl)-4-methoxyphenyl]propan-2-ol
[1373] Step i: To a solution of
1-(5-Bromo-2-methoxy-benzenesulfonyl)-4-(4-fluoro-2-trifluoromethyl-pheny-
l)-2-methyl-piperazine (100 mg, 0.196 mmol) in anhydrous THF (2.0
mL) at -78.degree. C. was added n-BuLi (0.07 mL, 0.205 mmol)
drop-wise. The reaction was allowed to stir at -78.degree. C. for
several minutes, after which, the CF.sub.3-Weinreb-amide reagent
(0.024 mL, 0.205 mmol) was added drop-wise. The reaction was
stirred and allowed to warm to room temperature over a 4-5 hour
period, after which the reaction was judged complete by LCMS. The
reaction concentrated in vacuo and the resultant crude oil was
purified via normal phase SiO.sub.2 chromatography (5%-35%
EtOAc/Hexanes), affording the trifluoroacetylated intermediate in
>95% purity.
[1374] Step ii: A solution of the trifluoroacetylated intermediate
in anhydrous THF was cooled to -78.degree. C. Drop-wise,
methyl-lithium was added, and the reaction was allowed to stir at
-78.degree. C. for 2-3 hours, after which the reaction was judged
complete by TLC. The reaction was allowed to warm to ambient
temperature, and directly purified by reversed phase HPLC under
acidic conditions, affording the desired trifluoropropanol compound
in >95% purity. HRMS: calcd for
C.sub.22H.sub.23F.sub.7N.sub.2O.sub.4S+H+, 545.13395; found
([M+H].sup.+), 545.1341.
Example 29IN
1-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)-2-thienyl]piperidin-4-ol
[1375] HRMS: calcd for
C.sub.21H.sub.25F.sub.4N.sub.3O.sub.3S.sub.2+H+, 508.13462; found
(ESI-FTMS, [M+H].sup.1+), 508.13469.
Example 29IO
(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-1-{[5-(4-methoxypiperidin-1-yl-
)-2-thienyl]sulfonyl}-2-methylpiperazine
[1376] HRMS: calcd for
C.sub.22H.sub.27F.sub.4N.sub.3O.sub.3S.sub.2+H+, 522.15027; found
([M+H].sup.+), 522.15046.
Example 29IP
(2R)-4-(2,4-dichlorophenyl)-2-methyl-1-[(5-piperazin-1-yl-2-thienyl)sulfon-
yl]piperazine
[1377] HRMS: calcd for
C.sub.19H.sub.24Cl.sub.2N.sub.4O.sub.2S.sub.2+H+, 475.07905; found
([M+H].sup.+), 475.08118.
Example 29IQ
(2R)-1-{[5-(4-fluoropiperidin-1-yl)-2-thienyl]sulfonyl}-4-[4-fluoro-2-(tri-
fluoromethyl)phenyl]-2-methylpiperazine
[1378] HRMS: calcd for
C.sub.21H.sub.24F.sub.5N.sub.3O.sub.2S.sub.2+H+, 510.13028; found
(ESI-FTMS, [M+H].sup.1+), 510.12968.
Example 29IR
(2R)-1-{[5-(4,4-difluoropiperidin-1-yl)-2-thienyl]sulfonyl}-4-[4-fluoro-2--
(trifluoromethyl)phenyl]-2-methylpiperazine
[1379] MS (LC-ESIMS) m/z 527.83.
Example 29IS
4-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)-2-thienyl]benzoic acid
[1380] HRMS: calcd for
C.sub.23H.sub.20F.sub.4N.sub.2O.sub.4S.sub.2+H+, 529.08734; found
([M+H].sup.+), 529.08803.
Example 29IT
4-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}-
sulfonyl)-2-thienyl]benzamide
[1381] HRMS: calcd for
C.sub.23H.sub.21F.sub.4N.sub.3O.sub.3S.sub.2+H+, 528.10332; found
([M+H].sup.+), 528.10464.
Example 30
[1382] Compounds described herein can be tested in a cell-based
assay using a stable CHO cell line expressing human 11b-HSD1. Cells
are plated at 20,000 cells/well in 96 well plates and incubated
overnight (12-16 hrs) at 37.degree. C./5% CO.sub.2. Cells are
treated with different concentration of compound in 90 microliter
serum-free media and incubated for 30 minutes at 37.degree. C./5%
CO.sub.2. 10 ul of 5 micromolar cortisone (final concentration 500
nM) is then added to the cells and the plate is incubated at
37.degree. C./5% CO.sub.2 for 120 minutes. 15 microliter of media
is withdrawn and amount of cortisol in the media is measured using
the DiscoverX HitHunter Cortisol Assay (DiscoverX corp, CA).
[1383] All references cited herein, whether in print, electronic,
computer readable storage media or other form, are expressly
incorporated by reference in their entirety, including but not
limited to, abstracts, articles, journals, publications, texts,
treatises, internet web sites, databases, patents, and patent
publications.
[1384] A number of embodiments of the invention have been
described. Nevertheless, it will be understood that various
modifications may be made without departing from the spirit and
scope of the invention. Accordingly, other embodiments are within
claims.
* * * * *