U.S. patent application number 10/356158 was filed with the patent office on 2004-04-15 for cycloalkyl inhibitors of potassium channel function.
Invention is credited to Beaudoin, Serge, Finlay, Heather, Gross, Michael F., Jeon, Yoon T., Lloyd, John, Yan, Lin.
Application Number | 20040072880 10/356158 |
Document ID | / |
Family ID | 27663264 |
Filed Date | 2004-04-15 |
United States Patent
Application |
20040072880 |
Kind Code |
A1 |
Lloyd, John ; et
al. |
April 15, 2004 |
Cycloalkyl inhibitors of potassium channel function
Abstract
Novel cycloalkyl compounds useful as inhibitors of potassium
channel function (especially inhibitors of the K.sub.v1 subfamily
of voltage gated K.sup.+ channels, especially inhibitors K.sub.v1.5
which has been linked to the ultra-rapidly activating delayed
rectifier K.sup.+ current I.sub.Kur), methods of using such
compounds in the prevention and treatment of arrhythmia and
I.sub.Kur-associated conditions, and pharmaceutical compositions
containing such compounds.
Inventors: |
Lloyd, John; (Yardley,
PA) ; Jeon, Yoon T.; (Belle Meade, NJ) ;
Finlay, Heather; (Skillman, NJ) ; Yan, Lin;
(East Brunswick, NJ) ; Gross, Michael F.; (Durham,
NC) ; Beaudoin, Serge; (Morrisville, NC) |
Correspondence
Address: |
STEPHEN B. DAVIS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
27663264 |
Appl. No.: |
10/356158 |
Filed: |
January 31, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60353884 |
Feb 1, 2002 |
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Current U.S.
Class: |
514/362 ;
514/364; 514/401; 514/484; 514/512; 514/517; 514/588; 514/593;
514/601; 548/125; 548/134; 558/260; 558/47; 560/115; 564/39;
564/40; 564/80 |
Current CPC
Class: |
C07C 235/60 20130101;
C07C 2601/02 20170501; C07D 295/13 20130101; A61P 5/42 20180101;
A61P 11/00 20180101; C07D 233/64 20130101; A61P 17/02 20180101;
A61P 25/08 20180101; C07C 233/59 20130101; C07D 217/22 20130101;
C07C 2601/14 20170501; C07D 241/06 20130101; A61P 1/00 20180101;
A61P 37/06 20180101; C07C 2602/08 20170501; A61P 17/06 20180101;
A61P 25/28 20180101; A61P 27/02 20180101; A61P 1/04 20180101; A61P
21/00 20180101; A61P 35/00 20180101; C07D 239/94 20130101; C07C
233/60 20130101; C07C 279/16 20130101; C07C 311/16 20130101; C07C
323/62 20130101; C07C 233/65 20130101; C07D 261/14 20130101; C07D
333/28 20130101; A61P 9/00 20180101; C07D 233/56 20130101; C07D
333/38 20130101; A61P 9/12 20180101; C07D 233/48 20130101; C07D
251/46 20130101; C07D 239/42 20130101; C07D 309/04 20130101; C07C
279/24 20130101; C07C 235/34 20130101; C07D 231/12 20130101; C07D
261/08 20130101; C07D 309/08 20130101; A61P 11/08 20180101; A61P
25/00 20180101; C07D 333/58 20130101; A61P 3/10 20180101; A61P
29/00 20180101; C07C 2601/10 20170501; C07D 295/26 20130101; C07D
213/69 20130101; C07D 235/14 20130101; C07D 249/04 20130101; C07D
271/06 20130101; C07D 295/215 20130101; A61P 1/16 20180101; C07C
235/46 20130101; C07C 307/04 20130101; C07D 213/40 20130101; C07D
487/04 20130101; C07C 307/10 20130101; C07C 307/02 20130101; C07D
307/68 20130101; C07C 235/06 20130101; C07D 249/08 20130101; A61K
45/06 20130101; A61P 9/06 20180101; C07C 2603/66 20170501; C07D
295/185 20130101; A61P 19/02 20180101; A61P 37/02 20180101; C07D
239/95 20130101; C07C 233/58 20130101; C07D 233/76 20130101; C07C
311/59 20130101; C07D 333/62 20130101; C07D 471/04 20130101; C07C
311/55 20130101; C07C 311/64 20130101; C07C 307/08 20130101; C07D
251/44 20130101; C07D 409/12 20130101; C07D 413/12 20130101; A61P
43/00 20180101; A61P 11/06 20180101; A61P 37/00 20180101; C07C
279/28 20130101; C07C 311/29 20130101; A61P 7/02 20180101; C07C
2601/04 20170501; C07D 213/82 20130101; C07D 333/20 20130101 |
Class at
Publication: |
514/362 ;
514/364; 514/517; 514/484; 514/512; 514/601; 514/588; 514/593;
548/134; 548/125; 558/047; 558/260; 560/115; 564/039; 564/040;
564/080; 514/401 |
International
Class: |
A61K 031/433; A61K
031/4245; A61K 031/325; A61K 031/4172; A61K 031/255; A61K
031/17 |
Claims
We claim:
1. A compound of Formula I 797enantiomers, diastereomers, solvates
or salts thereof wherein the dashed line represents an optional
double bond, provided that R.sup.1a is absent when a double bond is
present; m and p are independently 0, 1, 2 or 3; R.sup.1 is
798--N(R.sup.8)R.sup.14, --N(R.sup.8)C(O)R.sup.14,
--C(.dbd.NR.sup.8b)R.sup.8c, --SO.sub.2R.sup.8c, --CO.sub.2H,
--OC(O)CCl.sub.3, --C(O)R.sup.8c, --CO.sub.2R.sup.8c,
--C(.dbd.S)R.sup.8c, --NR.sup.6R.sup.7, --OC(O)NR.sup.6R.sup.7,
--N.sub.3, optionally substituted aryl, optionally substituted
heteroaryl, optionally substituted heterocyclo, halo,
perfluoroalkyl, cyano, nitro, hydroxy, optionally substituted
alkoxy, optionally substituted aryloxy, optionally substituted
heteroaryloxy, optionally substituted alkyl, optionally subsituted
alkenyl, or optionally subsituted alkynyl; R.sup.1a is H, or a
group listed in the definition of R.sup.X; or R.sup.1 and R.sup.1a
together form oxo; or R.sup.1 and R.sup.1a together with the carbon
atom to which they are attached combine to form an optionally
substituted spiro-fused heterocyclo group; or R.sup.1 and R.sup.1a
together combine to form a group 799R.sup.2 is heteroaryl,
(heteroaryl)alkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyclo)alkyl, alkyl, alkenyl or cycloalkyl, any of which may
be optionally independently substituted with one or more groups
T.sup.1, T.sup.2 or T.sup.3; J is a bond, C.sub.1-4 alkylene
optionally independently substituted with one or more groups
T.sup.1a, T.sup.2a or T.sup.3a, or C.sub.1-4 alkenylene optionally
independently substituted with one or more groups T.sup.1a,
T.sup.2a or T.sup.3a; R.sup.3 is 800R.sup.4 is alkyl, haloalkyl,
alkenyl, cycloalkyl, heterocyclo, aryl, or heteroaryl any of which
may be optionally independently substituted with one or more groups
T.sup.1b, T.sup.2b or T.sup.3b; R.sup.4a is R.sup.4 or OR.sup.4;
R.sup.5 is --NR.sup.6aR.sup.7a, or heteroaryl, (heteroaryl)alkyl,
aryl, (aryl)alkyl, alkyl, cycloalkyl, (cycloalkyl)alkyl,
heterocyclo, (heterocyclo)alkyl, alkyl, alkenyl or alkynyl any of
which may be optionally independently substituted with one or more
groups T.sup.1c, T.sup.2c or T.sup.3c; R.sup.6, R.sup.6a, R.sup.7,
R.sup.7a, R.sup.8, R.sup.8a, R.sup.8a1, R.sup.8a2, R.sup.8a3,
R.sup.8a4, R.sup.8a5 and R.sup.9 are independently H, alkyl,
hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy,
(hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl,
(heterocyclooxy)alkyl, (heteroaryloxy)alkyl, (cyano)alkyl,
(alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl,
aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo,
(heterocyclo)alkyl, --C(O)R.sup.12, --CO.sub.2R.sup.12,
--C(O)--NR.sup.12R.sup.13, or --NR.sup.12R.sup.13 any of which may
be optionally independently substituted with one or more groups
T.sup.1d, T.sup.2d or T.sup.3d; or R.sup.6 and R.sup.7, or R.sup.6a
and R.sup.7a together with the nitrogen atom to which they are
attached may combine to form a saturated or unsaturated 4 to 8
membered ring optionally independently substituted with one or more
groups T.sup.1d, T.sup.2d or T.sup.3d; or one of R.sup.6 or
R.sup.7, may combine with one of R.sup.8, R.sup.8a or R.sup.9 to
form a saturated or unsaturated 5 to 8 membered ring optionally
independently substituted with one or more groups T.sup.1d,
T.sup.2d or T.sup.3d. or one of R.sup.6a or R.sup.7a, may combine
with R.sup.8a1 to form a saturated or unsaturated 5 to 8 membered
ring optionally independently substituted with one or more groups
T.sup.1d, T.sup.2d or T.sup.3d R.sup.8b is independently H, alkyl,
aryl, cyano, nitro, acyl or --SO.sub.2(alkyl); R.sup.8c is
independently H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,
arylalkyl, cycloheteroalkyl, heteroaryl, amino or alkoxy; R.sup.8d
is R.sup.4, COR.sup.4, CO.sub.2R.sup.4, SO.sub.2R.sup.4,
CONR.sup.6R.sup.7, or SO.sub.2--NR.sup.6R.sup.7; R.sup.10
R.sup.10a, R.sup.11 and R.sup.11a are independently H, alkyl, aryl,
(aryl)alkyl, alkoxy, (alkoxy)alkyl, halo, hydroxy, (hydroxy)alkyl,
amino, amido, heteroaryl, (heteroaryl)alkyl, heterocyclo,
(heterocyclo)alkyl, sulfonamido, cycloalkyl, (cycloalkyl)alkyl, or
cyano any of which may be optionally independently substituted on
available atoms with one or more groups T.sup.1e, T.sup.2e or
T.sup.3e; or R.sup.10a and R.sup.10a, or R.sup.11 and R.sup.11a may
combine to form oxo; or R.sup.10a may combine with R.sup.11a to
form a bond; or R.sup.10 may combine with R.sup.9 to form a
saturated or unsaturated ring; R.sup.12 and R.sup.13 are
independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy,
heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl,
(heterocylooxy)alkyl, (heteroaryloxy)alkyl, cycloalkyl,
(cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl,
(heteroaryl)alkyl, heterocyclo, or (heterocyclo)alkyl any of which
may be optionally independently substituted with one or more groups
T.sup.1f, T.sup.2f or T.sup.3f or R.sup.12 and R.sup.13 together
with the nitrogen atom to which they are attached may combine to
form a saturated or unsaturated ring which may be optionally
independently substituted with one or more groups T.sup.1f,
T.sup.2f or T.sup.3f; W is .dbd.NR.sup.8a2,
.dbd.N--CO.sub.2R.sup.8a2, .dbd.N--COR.sup.8a2, .dbd.N--CN, or
.dbd.N--SO.sub.2R.sup.8a2; X is 801Z, Z.sup.1 and Z.sup.2 are
independently .dbd.O, .dbd.S, .dbd.NR.sup.8a4 or .dbd.N--CN;
R.sup.14 is independently 802where q is 1, 2 or 3; R.sup.Y is an
optional oxo substituent attached to any available ring carbon
atom; X.sup.1 is O, S, NR.sup.8a5 or CH.sub.2; and X.sup.2 is
NR.sup.8a5 or CH.sub.2; R.sup.X is one or more optional
substituents, attached to any available ring carbon atom,
independently selected from T.sup.1g, T.sup.2g or T.sup.3g;
T.sup.1-1g, T.sup.2-2g and T.sup.3-3g are are each independently
(1) hydrogen or T.sup.6, where T.sup.6 is (i) alkyl,
(hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,
(aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or
(heteroaryl)alkyl; (ii) a group (i) which is itself substituted by
one or more of the same or different groups (i); or (iii) a group
(i) or (ii) which is independently substituted by one or more
(preferably 1 to 3) of the following groups (2) to (13) of the
definition of T.sup.1-1g, T.sup.2-2g and T.sup.3-3g, (2) --OH or
--OT.sup.6, (3) --SH or --ST.sup.6, (4) --C(O).sub.tH,
--C(O).sub.tT.sup.6, or --O--C(O)T.sup.6, where t is 1 or 2; (5)
--SO.sub.3H, --S(O).sub.tT.sup.6, or S(O).sub.tN(T.sup.9)T.sup.6,
(6) halo, (7) cyano, (8) nitro, (9) -T.sup.4-NT.sup.7T.sup.8, (10)
-T.sup.4-N(T.sup.9)-T.sup.5-NT.sup.7T.sup.8, (11)
-T.sup.4-N(T.sup.10)-T.- sup.5-T.sup.6, (12)
-T.sup.4-N(T.sup.10)-T.sup.5-H, (13) oxo, T.sup.4 and T.sup.5 are
each independently (1) a single bond, (2)
-T.sup.11-S(O).sub.t-T.sup.12-, (3) -T.sup.11-C(O)-T.sup.12-, (4)
-T.sup.11-C(S)-T.sup.12-, (5) -T.sup.11-O-T.sup.12-, (6)
-T.sup.11-S-T.sup.12-, (7) -T.sup.11-O--C(O)-T.sup.12-, (8)
-T.sup.11-C(O)--O-T.sup.12-, (9)
-T.sup.11-C(.dbd.NT.sup.9a)-T.sup.12, or (10)
-T.sup.11-C(O)--C(O)-T.sup.12- T.sup.7, T.sup.8, T.sup.9, T.sup.9a
and T.sup.10 (1) are each independently hydrogen or a group
provided in the definition of T.sup.6, or (2) T.sup.7 and T.sup.8
may together be alkylene or alkenylene, completing a 3- to
8-membered saturated or unsaturated ring together with the atoms to
which they are attached, which ring is unsubstituted or substituted
with one or more groups listed in the definition of T.sup.1-1g,
T.sup.2-2g and T.sup.3-3g, or (3) T.sup.7 or T.sup.8, together with
T.sup.9, may be alkylene or alkenylene completing a 3- to
8-membered saturated or unsaturated ring together with the nitrogen
atoms to which they are attached, which ring is unsubstituted or
substituted with one or more groups listed in the definition of
T.sup.1-1g, T.sup.2-2g and T.sup.3-3g, or (4) T.sup.7 and T.sup.8
or T.sup.9 and T.sup.10 together with the nitrogen atom to which
they are attached may combine to form a group
--N.dbd.CT.sup.13T.sup.14 where T.sup.13 and T.sup.14 are each
independently H or a group provided in the definition of T.sup.6;
T.sup.11 and T.sup.12 are each independently (1) a single bond, (2)
alkylene, (3) alkenylene, or (4) alkynylene; provided that (i)
R.sup.2 is other than 803when conditions (a) and (b) are both met
(a) -J-R.sup.3 is 804and (b) R.sup.1 is H, halo, hydroxy, cyano,
nitro, aryl, alkoxy, aryloxy, heteroaryloxy, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, --OC(.dbd.O)CCl.sub.3, --SO.sub.2(alkyl),
--SO.sub.2(aryl), --SO.sub.2(arylalkyl), --CO.sub.2H,
--C(.dbd.O)(alkyl), --CO.sub.2(alkyl),
--C(.dbd.O)NR.sup.6*R.sup.7*, --NR.sup.6*R.sup.7*,
--OC(.dbd.O)NR.sup.6*R.sup.7*, --N.sub.3,
--N(R.sup.8)C(O)NR.sup.6*R.sup.- 7*, --OC(.dbd.O)OR.sup.4
--OC(.dbd.O)R.sup.4, or --N(H)S(O.sub.2)R.sup.4, or R.sup.1 and
R.sup.1a combine to form oxo; or R.sup.1 and R.sup.1a together with
the carbon atom to which they are attached combine to form a spiro
fused heterocylo group, or R.sup.1 and R.sup.1a together combine to
form a group 805where R.sup.6* and R.sup.7* are each independently
H, aryl, --C(O)aryl, --CO.sub.2aryl, alkyl, --C(O)alkyl,
--CO.sub.2alkyl, --S(O).sub.ualkyl, --C(O)S(O).sub.ualkyl,
--S(O).sub.uaryl, --C(O)S(O).sub.uaryl, or heterocyclo; R.sup.5a is
806R.sup.8a H, or alkyl; and u is 0, 1, 2 or 3; (ii) R.sup.2 is
other than thienyl when conditions (c) and (d) are both met (c)
-J-R.sup.3 is --NR.sup.6bR.sup.7b where R.sup.6b and R.sup.7b are
independently H, alkyl, cycloalkyl, or R.sup.6b and R.sup.7b
combine to form an N-containing cyclic group containing at least
one double bond; and (d) R.sup.1 is alkyl, cycoalkyl, alkenyl,
alkynyl, alkoxy, amino or cyano (iii) said compound is other than a
compound of the formula 807where R.sup.1c is --OC(O)NHR.sup.7c or
--OC(O)R.sup.4b; R.sup.2a is alkyl or phenyl; R.sup.3a is
808R.sup.4b is alkyl; R.sup.5b is --NHR.sup.7d or benzyl
substituted with one to three groups independently selected from
halo, alkyl or alkoxy R.sup.7c is H, alkyl, phenyl or benyl;
R.sup.7d is phenyl substituted with one to three groups
independently selected from halo, alkyl or alkoxy; R.sup.Xa is
hydroxy, --OC(o)NHR.sup.7c or --OC(O)R.sup.4b; R.sup.Xb and
R.sup.Xc are independently H or alkyl; n* is 1 to 4; n** is 0 to 3;
(iv) R.sup.2 is other than phenyl when conditions (e) and (f) are
both met (e) R.sup.1 is alkyl, alkoxy, or phenyl; and (f)
-J-R.sup.3 is an N-aryl substituted piperazinyl group; (v) R.sup.1
is other than hydroxy, alkoxy, aryloxy, alkyl or aryl when
conditions (g) and (h) are both met, or R.sup.1 and R.sup.1a do not
form .dbd.CH.sub.2 when conditions (g) and (h) are both met (g)
R.sup.2 is alkyl, aryl or arylalkyl; and (h) -J-R.sup.3 is
--NR.sup.6eR.sup.7e or --(CHR.sup.20)--R.sup.5c where R.sup.5c is
optionally substituted phenyl; R.sup.6e is hydrogen, hydroxy or
alkoxy; R.sup.7e is optionally substituted phenyl; and R.sup.20 is
hydrogen, hydroxy or alkoxy; (vi) R.sup.2 is other than optionally
substituted phenyl or pyridyl when conditions (j) and (k) are both
met (j) R.sup.1a is H, hydroxy, alkyl or (hydroxy)alkyl, and
R.sup.1 is H, hydroxy, --(CH.sub.2).sub.n*--NR.sup.6fR.sup.7f,
--(CH.sub.2).sub.n*--CO.sub.2R.su- p.8e, cycloalkyl, heterocylco,
or heteroaryl; or R.sup.1a and R.sup.1 combine to form oxo,
--O(CH.sub.2).sub.m*O--, or .dbd.CHCO.sub.2R.sup.8e where n* is 0
to 2; m* is 1 or 2; R.sup.6f and R.sup.7f are independently H,
alkyl, alkenyl, (hydroxy)alkyl, cycloalkyl, (cycloalkyl)alkyl,
aryl, (aryl)alkyl, heterocylco, (heterocyclo)alkyl, heteroaryl,
(heteroaryl)alkyl, CHO, --C(O)-alkyl, --C(O)-cycloalkyl,
--C(O)-(cycloalkyl)alkyl, --C(O)-aryl, --C(O)-(aryl)alkyl,
--C(O)-heterocylco, --C(O)-(heterocyclo)alkyl,
--C(O)-alkyl-NR.sup.8eR.su- p.8f, --C(O)--NR.sup.8eR.sup.8f,
--CO.sub.2-alkyl, -alkyl-CO.sub.2-alkyl, --CO.sub.2-cycloalkyl,
--CO.sub.2-(cycloalkyl)alkyl, --CO.sub.2-aryl,
--CO.sub.2-(aryl)alkyl, --CO.sub.2-heterocylco,
--CO.sub.2-(heterocylo)al- kyl, --CO.sub.2-NR.sup.8eR.sup.8f,
--CO.sub.2-alkyl-NR.sup.8eCOR.sup.8f, -alkyl-NR.sup.8eCOR.sup.8f,
--NR.sup.8eCO.sub.2R.sup.8f, -alkyl-NR.sup.8eCO.sub.2R.sup.8f,
--C(O)N(R.sup.8e)(aryl), -alkyl-C(O)N(R.sup.8e)(aryl),
--C(O)N(R.sup.8e)(heterocycle),
-alkyl-C(O)N(R.sup.8e)(heterocycle); or R.sup.6f and R.sup.7f
together with the nitrogen atome to which they are attached combine
to form an optionally substituted heterocyclo ring selected from
809R.sup.8e and R.sup.8f are independently H, alkyl, cycloalkyl,
(fluoro)alkyl, or --CH.sub.2CO.sub.2-alkyl; R.sup.8g is H, alkyl,
cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl, CHO,
--C(O)-alkyl, --C(O)-cycloalkyl, --C(O)-(cycloalkyl)alkyl,
--C(O)-aryl, --C(O)-(aryl)alkyl, --C(O)-heterocylco,
--C(O)-(heterocyclo)alkyl, --CO.sub.2-alkyl, --CO.sub.2-cycloalkyl,
--CO.sub.2-(cycloalkyl)alkyl, --CO.sub.2-aryl,
--CO.sub.2-(aryl)alkyl, --CO.sub.2-hetercyclo,
--CO.sub.2-(heterocyclo)al- kyl, --CO.sub.2--NR.sup.6fR.sup.7f, or
--CO.sub.2-(alkyl)-NR.sup.6fR.sup.7- f; (k) -J-R.sup.3 is a group
--C(O)--NR.sup.8a1--(CR.sup.15R.sup.16)--R.su- p.5*,
--(CR.sup.15R.sup.16)--NR.sup.8a1--C(O)--R.sup.5*,
--(CR.sup.15R.sup.16)--NR.sup.8a1--(CR.sup.17R.sup.18)--R.sup.5*,
--C(O)O--(CR.sup.15R.sup.16)--R.sup.5*,
--(CR.sup.15R.sup.16)--OC(O)--R.s- up.5*,
--(CR.sup.15R.sup.16)--O--(CR.sup.17R.sup.18)--R.sup.5*,
--C(R.sup.15).dbd.C(R.sup.16)--R.sup.5*,
--(CR.sup.15R.sup.16)--C(R.sup.1- 7).dbd.C(R.sup.18)--R.sup.5*,
--(CR.sup.15R.sup.16)--C(R.sup.17R.sup.18)---
(CR.sup.19R.sup.20)--R.sup.5*,
--C(O)--(CR.sup.15R.sup.16)--(CR.sup.17R.su- p.18)--R.sup.5*,
--(CR.sup.15R.sup.16)--C(O)--(CR.sup.17R.sup.18)--R.sup.5- *,
--(CR.sup.15R.sup.16)--(CR.sup.17R.sup.18)--C(O)--R.sup.5*,
--N(R.sup.8a1)--C(O)--(CR.sup.15R.sup.16)--R.sup.5*,
--N(R.sup.8a1)--(CR.sup.15R.sup.16)--(CR.sup.17R.sup.18)--R.sup.5*,
--N(R.sup.8a1)--C(O)--C(O)--R.sup.5*,
--OC(O)--(CR.sup.15R.sup.16)--R.sup- .5*, or
--O--(CR.sup.15R.sup.16)--(CR.sup.17R.sup.18)--R.sup.5*, where
R.sup.5* is 810where T.sup.1c* is hydroxy, alkyl, fluoroalkyl,
alkenyl, cycloalklyl, (cycloalkyl)alkyl, alkoxy, fluoroalkoxy,
(alkoxy)alkyl, (alkoxy)alkoxy, (fluoroalkoxy)alkyl, alkenyloxy,
cycloalkyloxy, (cycloalkyl)alkoxy, phenoxy, cyano, halo,
--NT.sup.7T.sup.8 where T.sup.7 and T.sup.8 are as defined above,
--SH, --ST.sup.6 where T is as defined above, --S(O).sub.tT.sup.6
where t is as defined above, --C(O).sub.tH, --C(O).sub.tT.sup.6 or
--C(O)--NT.sup.7T.sup.8; T.sup.2c* is H, halogen, alkyl or alkoxy;
or when T.sup.1c* is adjacent to T.sup.2c* they may combine to form
a 5 or 6-membered heterocylo or heteroaryl ring optionally
substituted with alkyl, fluroalkyl, .dbd.O or .dbd.S T.sup.3c* is
H, halogen, alkyl, fluroalkyl, alkoxy, fluoralkoxy, cycloalkyl,
(cycloalkyl)alkyl, cyano, heteroaryl, --NT.sup.7T.sup.8, --SH,
--ST.sup.6, --S(O).sub.tT.sup.6, --C(O).sub.tH, --C(O).sub.tT.sup.6
or --C(O)--NT.sup.7T.sup.8, or alkyl subsituted with cyano,
CO.sub.2H, CO.sub.2T.sup.6, or --C(O)--NT.sup.7T.sup.8; and
R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19 and R.sup.20 are
independently H, hydroxy, alkyl, alkenyl, (hydroxy)alkyl,
(alkoxy)alkyl, --(CH.sub.2).sub.n*--NR.su- p.6fR.sup.7f, --CHO,
--C(O)alkyl, or --CO.sub.2alkyl; or R.sup.15 and R.sup.16 together
form --CH.sub.2CH.sub.2--; or R.sup.17 and R.sup.18 together form
--CH.sub.2CH.sub.2--; or R.sup.19 and R.sup.20 together form
--CH.sub.2CH.sub.2--.
2. A compound of claim 1 wherein R.sup.1 is
811--C(.dbd.NR.sup.8b)R.sup.8- c, --C(.dbd.S)R.sup.8c,
--NR.sup.6R.sup.7a1, or --OC(O)NR.sup.6R.sup.7a1; where R.sup.7a1
is heteroaryl.
3. A compound of claim 1 wherein -J-R.sup.3 is other than 812
4. A compound of claim 3 wherein -J-R.sup.3 is other than
813814
5. A compound of claim 1 wherein R.sup.2 is other than 815where A
is phenyl or pyridyl.
6. A compound of claim 2 wherein -J-R.sup.3 is other than 816
7. A compound of claim 6 wherein -J-R.sup.3 is other than
817818
8. A compound of claim 2 wherein R.sup.2 is other than 819where A
is phenyl or pyridyl.
9. A compound of claim 7 wherein R.sup.2 is other than 820where A
is phenyl or pyridyl.
10. A compound of claim 1 wherein J is a bond or alkylene; R.sup.1
is 821or hydroxy; R.sup.2 is alkyl, alkenyl, benzyl, phenyl,
thienyl or benzothienyl any of which may be optionally substituted
with one or more groups T.sup.1, T.sup.2 or T.sup.3; 822R.sup.5 is
optionally substituted alkyl, optionally substituted cycloalkyl,
optionally substituted aryl, optionally substituted heteroaryl or
--NR.sup.6aR.sup.7a.
11. A compound of claim 1 wherein R.sup.1 is (a)
--N(R.sup.8)--SO.sub.2--N- R.sup.6R.sup.7, or
--N(R.sup.8)--C(W)--NR.sup.6R.sup.7 where R.sup.6 and R.sup.7 are
independently (i) H, or (ii) alkyl, cycloalkyl, alkenyl, alkynyl,
aryl, heteroaryl, heterocyclo, alkoxy, (aryl)alkyl,
(cycloalkyl)alkyl, (heteroaryl)alkyl, (heterocyclo)alkyl,
(alkoxy)alkyl, or NR.sup.12R.sup.13 any of which may be optionally
independently substituted with one or more OH, SH, OT.sup.6,
ST.sup.6, C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano, halo, oxo,
alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl,
(SH)alkyl, (OT.sup.6)alkyl, (ST.sup.6)alkyl,
(C(O).sub.tT.sup.6)alkyl, (NT.sup.7T.sup.8)alkyl, (cyano)alkyl,
(aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl, or R.sup.6
and R.sup.7 combine to form a heterocylo ring optionally
substituted with one or more OH, SH, OT.sup.6, ST.sup.6,
C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano, halo, oxo, alkyl,
haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl,
(OT.sup.6)alkyl, (ST.sup.6)alkyl, (C(O).sub.tT.sup.6)alkyl,
(NT.sup.7T.sup.8)alkyl, (cyano)alkyl, (aryl)alkyl,
(heteroaryl)alkyl or (heterocyclo)alkyl; and R.sup.8 is (i) H; or
(ii) alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo,
(cycloalkyl)alky, (aryl)alkyl, (heteroaryl)alkyl or
(heterocyclo)alkyl any of which may be optionally independently
substituted with one or more OH, SH, OT.sup.6, ST.sup.6,
C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano, halo, oxo, alkyl,
haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl,
(OT.sup.6)alkyl, (ST.sup.6)alkyl, (C(O).sub.tT.sup.6)alkyl,
(NT.sup.7T.sup.8)alkyl, (cyano)alkyl, (aryl)alkyl,
(heteroaryl)alkyl or (heterocyclo)alkyl, (b)
--N(R.sup.8)--C(Z)--N(R.sup.8a)--SO.sub.2--R.sup.4 or
--N(R.sup.8)C(Z)--N(R.sup.8a)SO.sub.2--OH where R.sup.4 is (i) H,
or (ii) alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,
heterocyclo, alkoxy, (aryl)alkyl, (cycloalkyl)alkyl,
(heteroaryl)alkyl, (heterocyclo)alkyl, (alkoxy)alkyl, or
NR.sup.12R.sup.13 any of which may be optionally independently
substituted with one or more OH, SH, OT.sup.6, ST.sup.6,
C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano, halo, oxo, alkyl,
haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl,
(OT.sup.6)alkyl, (ST.sup.6)alkyl, (C(O).sub.tT.sup.6)alkyl,
(NT.sup.7T.sup.8)alkyl, (cyano)alkyl, (aryl)alkyl,
(heteroaryl)alkyl or (heterocyclo)alkyl; and R.sup.8 and R.sup.8a
are independently (i) H; or (ii) alkyl, cycloalkyl, aryl,
heteroaryl, heterocyclo, (cycloalkyl)alky, (aryl)alkyl,
(heteroaryl)alkyl or (heterocyclo)alkyl any of which may be
optionally independently substituted with one or more OH, SH,
OT.sup.6, ST.sup.6, C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano,
halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo,
(OH)alkyl, (SH)alkyl, (OT.sup.6)alkyl, (ST.sup.6)alkyl,
(C(O).sub.tT.sup.6)alkyl, (NT.sup.7T.sup.8)alkyl, (cyano)alkyl,
(aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; or (c) or a
group 823R.sup.1a is H,; R.sup.2 is phenyl, (phenyl)alkyl, napthyl,
thienyl benzothienyl, alkyl or alkenyl any of which may be
optionally independently substituted with one or more OH, SH,
OT.sup.6, ST.sup.6, C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano,
halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo,
(OH)alkyl, (SH)alkyl, (OT.sup.6)alkyl, (ST.sup.6)alkyl,
(C(O).sub.tT.sup.6)alkyl, (NT.sup.7T.sup.8)alkyl, (cyano)alkyl,
(aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; J is a bond,
methylene or ethylene; R.sup.3 is (a) --R.sup.5 or where R.sup.5 is
heteroaryl, heterocyclo or --NR.sup.6R.sup.7a any of which may be
optionally independently substituted with one or more OH, SH,
OT.sup.6, ST.sup.6, C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano,
halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo,
(OH)alkyl, (SH)alkyl, (OT.sup.6)alkyl, (ST.sup.6)alkyl,
(C(O).sub.tT.sup.6)alkyl, (NT.sup.7T.sup.8)alkyl, (cyano)alkyl,
(aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; (b)
--C(Z.sup.1)--R.sup.5, or --O--C(Z.sup.1)--R.sup.5, where R.sup.5
is aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl) or
--NR.sup.6aR.sup.7a; and R.sup.6a and R.sup.7a are independently
(i) H; or (ii) alkyl, cylcoalkyl, aryl, (aryl)alkyl, heteroaryl
(heteroaryl)alkyl, heterocyclo or (heterocyclo)alkyl any of which
may be optionally independently substituted with one or more OH,
SH, OT.sup.6, ST.sup.6, C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano,
halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo,
(OH)alkyl, (SH)alkyl, (OT.sup.6)alkyl, (ST.sup.6)alkyl,
(C(O).sub.tT.sup.6)alkyl, (NT.sup.7T.sup.8)alkyl, (cyano)alkyl,
(aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; or (c)
--N(R.sup.8a1)--C(Z.sup.1)--R.sup.5, or
--N(R.sup.8a)--SO.sub.2--R.su- p.5 where R.sup.5 is aryl,
(aryl)alkyl, hetreoaryl, (heteroaryl)alkyl, heterocyclo,
(heterocyclo)alkyl, alkyl, alkenyl, alkynyl, cycloalkyl,
(alkoxy)alkyl, or (cycloalkoxy)alkyl any of which may be optionally
independently substituted with one or more OH, SH, OT.sup.6,
ST.sup.6, C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano, halo, oxo,
alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl,
(SH)alkyl, (OT.sup.6)alkyl, (ST.sup.6)alkyl,
(C(O).sub.tT.sup.6)alkyl, (NT.sup.7T.sup.8)alkyl, (cyano)alkyl,
(aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; and R.sup.8a1
is (i) H; or (ii) alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo,
(cycloalkyl)alky, (aryl)alkyl, (heteroaryl)alkyl or
(heterocyclo)alkyl any of which may be optionally independently
substituted with one or more OH, SH, OT.sup.6, ST.sup.6,
C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano, halo, oxo, alkyl,
haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl,
(OT.sup.6)alkyl, (ST.sup.6)alkyl, (C(O).sub.tT.sup.6)alkyl,
(NT.sup.7T.sup.8)alkyl, (cyano)alkyl, (aryl)alkyl,
(heteroaryl)alkyl or (heterocyclo)alkyl, R.sup.5 is optionally
substituted alkyl, optionally substituted cycloalkyl, optionally
substituted heteroayl, optionally substituted aryl or
--NR.sup.6aR.sup.7a; R.sup.6, R.sup.6a, R.sup.7 and R.sup.7a are
independently H, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted cycloalkyl,
optionally substituted heterocyclo, optionally substituted
(aryl)alkyl, optionally substituted (heteroaryl)alkyl, optionally
substituted (heterocylco)alkyl, optionally substituted alkyl, or
COR.sup.12; or R.sup.6 and R.sup.7, or R.sup.6a and R.sup.7a
together with the nitrogen to which thery are attached combine to
form an optionally substituted saturated or unsaturated 5 to 8
membered ring.
12. A compound of claim 1 wherein R.sup.1 is (a) hydrogen, or
hydroxy; (b) --O--C(O)--NR.sup.6R.sup.7,
--N(R.sup.8)--SO.sub.2--NR.sup.6R.sup.7, or
--N(R.sup.8)--C(W)--NR.sup.6R.sup.7 where R.sup.6 and R.sup.7 are
independently (i) H, or (ii) alkyl, cycloalkyl, alkenyl, alkynyl,
aryl, heteroaryl, heterocyclo, alkoxy, (aryl)alkyl,
(cycloalkyl)alkyl, (heteroaryl)alkyl, (heterocyclo)alkyl,
(alkoxy)alkyl, or NR.sup.12R.sup.13 any of which may be optionally
independently substituted with one or more OH, SH, OT.sup.6,
ST.sup.6, C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano, halo, oxo,
alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl,
(SH)alkyl, (OT.sup.6)alkyl, (ST.sup.6)alkyl,
(C(O).sub.tT.sup.6)alkyl, (NT.sup.7T.sup.8)alkyl, (cyano)alkyl,
(aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl, or R.sup.6
and R.sup.7 combine to form a heterocylo ring optionally
substituted with one or more OH, SH, OT.sup.6, ST.sup.6,
C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano, halo, oxo, alkyl,
haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl,
(OT.sup.6)alkyl, (ST.sup.6)alkyl, (C(O).sub.tT.sup.6)alkyl,
(NT.sup.7T.sup.8)alkyl, (cyano)alkyl, (aryl)alkyl,
(heteroaryl)alkyl or (heterocyclo)alkyl; and R.sup.8 is (i) H; or
(ii) alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo,
(cycloalkyl)alky, (aryl)alkyl, (heteroaryl)alkyl or
(heterocyclo)alkyl any of which may be optionally independently
substituted with one or more OH, SH, OT.sup.6, ST.sup.6,
C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano, halo, oxo, alkyl,
haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl,
(OT.sup.6)alkyl, (ST.sup.6)alkyl, (C(O).sub.tT.sup.6)alkyl,
(NT.sup.7T.sup.8)alkyl, (cyano)alkyl, (aryl)alkyl,
(heteroaryl)alkyl or (heterocyclo)alkyl, (c) --O--C(O)--R.sup.4,
--N(R.sup.8)--C(Z)--N(R.sup.8a)--SO.sub.2--R.sub.4 or
--N(R.sup.8)--C(Z)--N(R.sup.8a)--SO.sub.2--OH where R.sup.4 is (i)
H, or (ii) alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,
heterocyclo, alkoxy, (aryl)alkyl, (cycloalkyl)alkyl,
(heteroaryl)alkyl, (heterocyclo)alkyl, (alkoxy)alkyl, or
NR.sup.12R.sup.13 any of which may be optionally independently
substituted with one or more OH, SH, OT.sup.6, ST.sup.6,
C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano, halo, oxo, alkyl,
haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl,
(OT.sup.6)alkyl, (ST.sup.6)alkyl, (C(O).sub.tT.sup.6)alkyl,
(NT.sup.7T.sup.8)alkyl, (cyano)alkyl, (aryl)alkyl,
(heteroaryl)alkyl or (heterocyclo)alkyl; and R.sup.8 and R.sup.8a
are independently (i) H; or (ii) alkyl, cycloalkyl, aryl,
heteroaryl, heterocyclo, (cycloalkyl)alky, (aryl)alkyl,
(heteroaryl)alkyl or (heterocyclo)alkyl any of which may be
optionally independently substituted with one or more OH, SH,
OT.sup.6, ST.sup.6, C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano,
halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo,
(OH)alkyl, (SH)alkyl, (OT.sup.6)alkyl, (ST.sup.6)alkyl,
(C(O).sub.tT.sup.6)alkyl, (NT.sup.7T.sup.8)alkyl, (cyano)alkyl,
(aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; or (d) or a
group 824R.sup.1a is H,; R.sup.2 is phenyl, (phenyl)alkyl, napthyl,
thienyl benzothienyl, alkyl or alkenyl any of which may be
optionally independently substituted with one or more OH, SH,
OT.sup.6, ST.sup.6, C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano,
halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo,
(OH)alkyl, (SH)alkyl, (OT.sup.6)alkyl, (ST.sup.6)alkyl,
(C(O).sub.tT.sup.6)alkyl, (NT.sup.7T.sup.8)alkyl, (cyano)alkyl,
(aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; J is a bond,
methylene or ethylene; R.sup.3 is (a) --R.sup.5 or where R.sup.5 is
heteroaryl, heterocyclo either of which may be optionally
independently substituted with one or more OH, SH, OT.sup.6,
ST.sup.6, C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano, halo, oxo,
alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl,
(SH)alkyl, (OT.sup.6)alkyl, (ST.sup.6)alkyl,
(C(O).sub.tT.sup.6)alkyl, (NT.sup.7T.sup.8)alkyl, (cyano)alkyl,
(aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; (b)
--C(Z.sup.1)--R.sup.5, or --O--C(Z.sup.1)--R.sup.- 5, where Z is
.dbd.NR.sup.8a4 or .dbd.N--CN; R.sup.5 is aryl, (aryl)alkyl,
heteroaryl, (heteroaryl)alkyl) or --NR.sup.6aR.sup.7a; and R.sup.6a
and R.sup.7a are independently (i) H; or (ii) alkyl, cylcoalkyl,
aryl, (aryl)alkyl, heteroaryl (heteroaryl)alkyl, heterocyclo or
(heterocyclo)alkyl any of which may be optionally independently
substituted with one or more OH, SH, OT.sup.6, ST.sup.6,
C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano, halo, oxo, alkyl,
haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl,
(OT.sup.6)alkyl, (ST.sup.6)alkyl, (C(O).sub.tT.sup.6)alkyl,
(NT.sup.7T.sup.8)alkyl, (cyano)alkyl, (aryl)alkyl,
(heteroaryl)alkyl or (heterocyclo)alkyl; or (c)
--N(R.sup.8a1)--C(Z.sup.1)--R.sup.5, or
--N(R.sup.8a1)--SO.sub.2--R.s- up.5 where Z.sup.1 is
.dbd.NR.sup.8a4 or .dbd.N--CN; R.sup.5 is aryl, (aryl)alkyl,
hetreoaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl,
alkyl, alkenyl, alkynyl, cycloalkyl, (alkoxy)alkyl, or
(cycloalkoxy)alkyl any of which may be optionally independently
substituted with one or more OH, SH, OT.sup.6, ST.sup.6,
C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano, halo, oxo, alkyl,
haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl,
(OT.sup.6)alkyl, (ST.sup.6)alkyl, (C(O).sub.tT.sup.6)alkyl,
(NT.sup.7T.sup.8)alkyl, (cyano)alkyl, (aryl)alkyl,
(heteroaryl)alkyl or (heterocyclo)alkyl; and R.sup.8a1 is (i) H; or
(ii) alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo,
(cycloalkyl)alky, (aryl)alkyl, (heteroaryl)alkyl or
(heterocyclo)alkyl any of which may be optionally independently
substituted with one or more OH, SH, OT.sup.6, ST.sup.6,
C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano, halo, oxo, alkyl,
haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl,
(OT.sup.6)alkyl, (ST.sup.6)alkyl, (C(O).sub.tT.sup.6)alkyl,
(NT.sup.7T.sup.8)alkyl, (cyano)alkyl, (aryl)alkyl,
(heteroaryl)alkyl or (heterocyclo)alkyl, R.sup.5 is optionally
substituted alkyl, optionally substituted cycloalkyl, optionally
substituted heteroayl, optionally substituted aryl or
--NR.sup.6aR.sup.7a; R.sup.6, R.sup.6a, R.sup.7 and R.sup.7a are
independently H, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted cycloalkyl,
optionally substituted heterocyclo, optionally substituted
(aryl)alkyl, optionally substituted (heteroaryl)alkyl, optionally
substituted (heterocylco)alkyl, optionally substituted alkyl, or
COR.sup.12; or R.sup.6 and R.sup.7, or R.sup.6a and R.sup.7a
together with the nitrogen to which thery are attached combine to
form an optionally substituted saturated or unsaturated 5 to 8
membered ring.
13. A pharmaceutical composition comprising at least one compound
of claim 1 together with a suitable vehicle or carrier
therefor.
14. A pharmaceutical composition of claim 13 further comprising at
least one additional therapeutic agent selected from
anti-arrhythmic agents, calcium channel blockers, anti-platelet
agents, anti-hypertensive agents, anti-thrombotic/anti-thrombolytic
agents, anti-coagulants, HMG-CoA reductase inhibitors,
anti-diabetic agents, thyroid mimetics, mineralocorticoid receptor
antagonists, or cardiac glycosides.
15. The pharmaceutical composition of claim 14 wherein (a) the
additional anti-arrhythmic agent is selected from sotalol,
dofetilide, diltiazem and verapamil; (b) the anti-platelet agent is
selected from clopidogrel, ifetroban and aspirin; (c) the
anti-hypertensive agent is selected from beta adrenergic blockers,
ACE inhibitors, A II antagonists, ET antagonists, Dual ET/A II
antagonists, and vasopepsidase inhibitors; (d) the
anti-thrombotic/anti-thrombolytic agent is selected from tPA,
recombinant tPA, TNK, nPA, factor VIIa inhibitors, factor Xa
inhibitors and thrombin inhibitors; (e) the anti-coagulant is
selected from warfarin and heparins; (f) the HMG-CoA reductase
inhibitor is selected from pravastatin, lovastatin, atorvastatin,
simvastatin, NK-104 and ZD-4522; (g) the anti-diabetic agent is
selected from biguanides and biguanide/glyburide combinations; (h)
the mineralocorticoid receptor antagonist is selected from
spironolactone and eplerinone; and (i) the cardiac glycoside is
selected from digitalis and ouabain.
16. The pharmaceutical composition of claim 15 wherein (a) the ACE
inhibitors are selected from captopril, zofenopril, fosinopril,
enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril,
ramipril, and lisinopril; and (b) the vasopepsidase inhibitors are
selected from omapatrilat and gemopatrilat.
17. A method treating I.sub.Kur-associated disorders comprising the
step of administering to a patient in need thereof an effective
amount of at least one compound of the following formula I
825enantiomers, diastereomers, solvates or salts thereof wherein
the dashed line represents an optional double bond, provided that
R.sup.1a is absent when a double bond is present; m and p are
independently 1, 2 or 3; R.sup.1 is 826--N(R.sup.8)R.sup.14,
--N(R.sup.8)C(O)R.sup.14, --C(.dbd.NR.sup.8b)R.sup.8c,
--SO.sub.2R.sup.8c, --CO.sub.2H, --OC(O)CCl.sub.3, --C(O)R.sup.8c,
--CO.sub.2R.sup.8c, --C(.dbd.S)R.sup.8c, --NR.sup.6R.sup.7,
--OC(O)NR.sup.6R.sup.7, --N.sub.3, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted
heterocyclo, halo, perfluoroalkyl, cyano, nitro, hydroxy,
optionally substituted alkoxy, optionally substituted aryloxy,
optionally substituted heteroaryloxy, optionally substituted alkyl,
optionally subsituted alkenyl, or optionally subsituted alkynyl;
R.sup.1a is H or a group listed in the definition of R.sup.X; or
R.sup.1 and R.sup.1a together form oxo; or R.sup.1 and R.sup.1a
together with the carbon atom to which they are attached combine to
form an optionally substituted spiro-fused heterocyclo group; or
R.sup.1 and R.sup.1a together combine to form a group 827R.sup.2 is
heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, heterocylco,
(heterocyclo)alkyl, alkyl, alkenyl or cycloalkyl, any of which may
be optionally independently substituted with one or more groups
T.sup.1, T.sup.2 or T.sup.3; J is a bond, C.sub.1-4 alkylene
optionally independently substituted with one or more groups
T.sup.1a, T.sup.2a or T.sup.3a, or C.sub.1-4 alkenylene optionally
independently substituted with one or more groups T.sup.1a,
T.sup.2a or T.sup.3a; R.sup.3 is 828R.sup.4 is alkyl, haloalkyl,
alkenyl, cycloalkyl, hetercyclo, aryl, or heteroaryl any of which
may be optionally independently substituted with one or more groups
T.sup.1b, T.sup.2b or T.sup.3b; R.sup.4a is R.sup.4 or OR.sup.4;
R.sup.5 is --NR.sup.6aR.sup.7a, or heteroaryl, (heteroaryl)alkyl,
aryl, (aryl)alkyl, alkyl, cycloalkyl, (cycloalkyl)alkyl,
hetercyclo, (heterocyclo)alkyl, alkyl, alkenyl or alkynyl any of
which may be optionally independently substituted with one or more
groups T.sup.1c, T.sup.2c or T.sup.3c; R.sup.6, R.sup.6a, R.sup.7,
R.sup.7a, R.sup.8, R.sup.8a1, R .sup.8a2, R.sup.8a3 R.sup.8a4,
R.sup.8a5, and R.sup.9 are independently H, alkyl, hydroxy, alkoxy,
aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl,
(alkoxy)alkyl, (aryloxy)alkyl, (heterocylooxy)alkyl,
(heteroaryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl,
cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl,
(heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, --C(O)R.sup.12,
--CO.sub.2R.sup.12, --C(O)--NR.sup.12R.sup.13, or
--NR.sup.12R.sup.13 any of which may be optionally independently
substituted with one or more groups T.sup.1d, T.sup.2d or T.sup.3d;
or R.sup.6 and R.sup.7, or R.sup.6a and R.sup.7a together with the
nitrogen atom to which they are attached may combine to form a
saturated or unsaturated 4 to 8 membered ring optionally
independently substituted with one or more groups T.sup.1d,
T.sup.2d or T.sup.3d; or one of R.sup.6a or R.sup.7a, may combine
with one of R.sup.8, R.sup.8a or R.sup.9 to form a saturated or
unsaturated 5 to 8 membered ring optionally independently
substituted with one or more groups T.sup.1d, T.sup.2d or T.sup.3d;
or one of R.sup.6a or R.sup.7a, may combine with R.sup.8a1 to form
a saturated or unsaturated 5 to 8 membered ring optionally
independently substituted with one or more groups T.sup.1d,
T.sup.2d or T.sup.3d R.sup.8b is independently H, alkyl, aryl,
cyano, nitro, acyl or --SO.sub.2(alkyl); R.sup.8c is independently
H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl,
cycloheteroalkyl, heteroaryl, amino or alkoxy; R.sup.8d is R.sup.4,
COR.sup.4, CO.sub.2R.sup.4, SO.sub.2R.sup.4, CONR.sup.6R.sup.7, or
SO.sub.2--NR.sup.6R.sup.7; R.sup.10 R.sup.10a, R.sup.11 and
R.sup.11a are independently H, alkyl, aryl, (aryl)alkyl, alkoxy,
(alkoxy)alkyl, halo, hydroxy, (hydroxy)alkyl, amino, amido,
heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl,
sulfonamido, cycloalkyl, (cycloalkyl)alkyl, or cyano any of which
may be optionally independently substituted on available atoms with
one or more groups T.sup.1e, T.sup.2e or T.sup.3e; or R.sup.10a and
R.sup.10a, or R.sup.11 and R.sup.11a may combine to form oxo; or
R.sup.10a may combine with R.sup.11a to form a bond; or R.sup.10
may combine with R.sup.9 to form a saturated or unsaturated ring;
R.sup.12 and R.sup.13 are independently H, alkyl, hydroxy, alkoxy,
aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl,
(alkoxy)alkyl, (aryloxy)alkyl, (heterocylooxy)alkyl,
(heteroaryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,
(aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, or
(heterocyclo)alkyl any of which may be optionally independently
substituted with one or more groups T.sup.1f, T.sup.2f or T.sup.3f
or R.sup.12 and R.sup.13 together with the nitrogen atom to which
they are attached may combine to form a saturated or unsaturated
ring which may be optionally independently substituted with one or
more groups T.sup.1f, T.sup.2f or T.sup.3f; W is .dbd.NR.sup.8a2,
.dbd.N--CO.sub.2R.sup.8a2, .dbd.N--COR.sup.8a2, .dbd.N--CN, or
.dbd.N--SO.sub.2R.sup.8a2; X is 829Z, Z.sup.1 and Z.sup.2 are
independently .dbd.O, .dbd.S, .dbd.NR.sup.8a4 or .dbd.N--CN;
R.sup.14 is independently 830where q is 1, 2 or 3; R.sup.Y is an
optional oxo substituent attached to any available ring carbon
atom; X.sup.1 is O, S, NR.sup.8a5 or CH.sub.2; and X.sup.2 is
NR.sup.8a5 or CH.sub.2; R.sup.X is one or more optional
substituents, attached to any available ring carbon atom,
independently selected from T.sup.1g, T.sup.2g or T.sup.3g;
T.sup.1-1g, T.sup.2-2g, and T.sup.3-3g are are each independently
(1) hydrogen or T.sup.6, where T.sup.6 is (i) alkyl,
(hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,
(aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or
(heteroaryl)alkyl; (ii) a group (i) which is itself substituted by
one or more of the same or different groups (i); or (iii) a group
(i) or (ii) which is independently substituted by one or more
(preferably 1 to 3) of the following groups (2) to (13) of the
definition of T.sup.1-1g, T.sup.2-2g and T.sup.3-3g, (2) --OH or
--OT.sup.6, (3) --SH or --ST.sup.6, (4) --C(O).sub.tH,
--C(O).sub.tT.sup.6, or --O--C(O)T.sup.6, where t is 1 or 2; (5)
--SO.sub.3H, --S(O).sub.tT.sup.6, or S(O).sub.tN(T.sup.9)T.sup.6,
(6) halo, (7) cyano, (8) nitro, (9) -T.sup.4-NT.sup.7T.sup.8, (10)
-T.sup.4-N(T.sup.9)-T.sup.5-NT.sup.7T.sup.8, (11)
-T.sup.4-N(T.sup.10)-T.- sup.5-T.sup.6, (12)
-T.sup.4-N(T.sup.10)-T.sup.5-H, (13) oxo, T.sup.4 and T.sup.5 are
each independently (1) a single bond, (2)
-T.sup.11-S(O).sub.tT.sup.12-, (3) -T.sup.11-C(O)-T.sup.2-, (4)
-T.sup.11-C(S)-T.sup.12-, (5) -T.sup.11-O-T.sup.12-, (6)
-T.sup.11-S-T.sup.12-, (7) -T.sup.11-O--C(O)-T.sup.12-, (8)
-T.sup.11-C(O)--O-T.sup.12-, (9)
-T.sup.11-C(.dbd.NT.sup.9a)-T.sup.12-, or (10)
-T.sup.11-C(O)--C(O)-T.sup.12- T.sup.7, T.sup.8, T.sup.9, T.sup.9a
and T.sup.10 (1) are each independently hydrogen or a group
provided in the definition of T.sup.6, or (2) T.sup.7 and T.sup.8
may together be alkylene or alkenylene, completing a 3- to
8-membered saturated or unsaturated ring together with the atoms to
which they are attached, which ring is unsubstituted or substituted
with one or more groups listed in the definition of T.sup.1-1g,
T.sup.2-2g and T.sup.3-3g, or (3) T.sup.7 or T.sup.8, together with
T.sup.9, may be alkylene or alkenylene completing a 3- to
8-membered saturated or unsaturated ring together with the nitrogen
atoms to which they are attached, which ring is unsubstituted or
substituted with one or more groups listed in the definition of
T.sup.1-1g, T.sup.2-2g and T.sup.3-3g, or (4) T.sup.7 and T.sup.8
or T.sup.9 and T.sup.10 together with the nitrogen atom to which
they are attached may combine to form a group
--N.dbd.CT.sup.13T.sup.14 where T.sup.13 and T.sup.14 are each
independently H or a group provided in the definition of T.sup.6;
T.sup.11 and T.sup.12 are each independently (1) a single bond, (2)
alkylene, (3) alkenylene, or (4) alkynylene; provided that R.sup.2
is other than 831when conditions (a) and (b) are both met 832and
(a) -J-R.sup.3 is ; and (b) R.sup.1 is H, halo, hydroxy, cyano,
nitro, aryl, alkoxy, aryloxy, heteroaryloxy, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, --OC(.dbd.O)CCl.sub.3, --SO.sub.2(alkyl),
--SO.sub.2(aryl), --SO.sub.2(arylalkyl), --CO.sub.2H,
--C(.dbd.O)(alkyl), --CO.sub.2(alkyl),
--C(.dbd.O)NR.sup.6*R.sup.7*, --NR.sup.6*R.sup.7*,
--OC(.dbd.O)NR.sup.6*R.sup.7*, --N.sub.3,
--N(R.sup.8)C(O)NR.sup.6*R.sup.- 7*,
--OC(.dbd.O)OR.sup.4--OC(.dbd.O)R.sup.4, or
--N(H)S(O.sub.2)R.sup.4, or R.sup.1 and R.sup.1a combine to form
oxo; or R.sup.1 and R.sup.1a together with the carbon atom to which
they are attached combine to form a spiro fused heterocylo group,
or R.sup.1 and R.sup.1a together combine to form a group 833where
R.sup.6* and R.sup.7* are each independently H, aryl, --C(O)aryl,
--CO.sub.2aryl, alkyl, --C(O)alkyl, --CO.sub.2alkyl,
--S(O).sub.ualkyl, --C(O)S(O).sub.ualkyl, --S(O).sub.uaryl,
--C(O)S(O).sub.uaryl, or heterocyclo; R.sup.5a is 834R.sup.8a H, or
alkyl; and u is 0, 1, 2 or 3.
18. The method of claim 17 wherein the I.sub.Kur-associated
condition is arrhythmia.
19. The method of claim 18 wherein the arrhythmia is a
supraventricular arrhythmia.
20. The method of claim 19 wherein the supraventricular arrhythmia
is atrial fibrillation.
21. The method of claim 19 wherein the supraventricular arrhythmia
is atrial flutter.
22. The method of claim 17 wherein the I.sub.Kur-associated
condition is a gastrointensinal disorder.
23. The method of claim 22 wherein the gastrointestinal disorder is
reflux esauphagitis.
24. The method of claim 22 wherein the gastrointestinal disorder is
a motility disorder.
25. The method of claim 17 wherein the I.sub.Kur-associated
condition is an inflammatory or immunological disease.
26. The method of claim 25 wherein the inflammatory disease is
chronic obstructive pulmonary disease.
27. A method of treating diabetes, cognitive disorders, or epilepsy
comprising administering to a patient in need thereof an effective
amount of at least one compound of the following formula I
835enantiomers, diastereomers, solvates or salts thereof wherein
the dashed line represents an optional double bond, provided that
R.sup.1a is absent when a double bond is present; m and p are
independently 1, 2 or 3; R.sup.1 is 836--N(R.sup.8)R.sup.14,
--N(R.sup.8)C(O)R.sup.14, --C(.dbd.NR.sup.8b)R.sup.8c,
--SO.sub.2R.sup.8c, --CO.sub.2H, --OC(O)CCl.sub.3, --C(O)R.sup.8c,
--CO.sub.2R.sup.8c, --C(.dbd.S)R.sup.8c, --NR.sup.6R.sup.7,
--OC(O)NR.sup.6R.sup.7, --N.sub.3, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted
heterocyclo, halo, perfluoroalkyl, cyano, nitro, hydroxy,
optionally substituted alkoxy, optionally substituted aryloxy,
optionally substituted heteroaryloxy, optionally substituted alkyl,
optionally subsituted alkenyl, or optionally subsituted alkynyl;
R.sup.1a is H or a group listed in the definition of R.sup.X; or
R.sup.1 and R.sup.1a together form oxo; or R.sup.1 and R.sup.10
together with the carbon atom to which they are attached combine to
form an optionally substituted spiro-fused heterocyclo group; or
R.sup.1 and R.sup.1a together combine to form a group 837R.sup.2 is
heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, heterocylco,
(heterocyclo)alkyl, alkyl, alkenyl or cycloalkyl, any of which may
be optionally independently substituted with one or more groups
T.sup.1, T.sup.2 or T.sup.3; J is a bond, C.sub.1-4 alkylene
optionally independently substituted with one or more groups
T.sup.1a, T.sup.2a or T.sup.3a, or C.sub.1-4 alkenylene optionally
independently substituted with one or more groups T.sup.1a,
T.sup.2a or T.sup.3a; R.sup.3 is 838R.sup.4 is alkyl, haloalkyl,
alkenyl, cycloalkyl, hetercyclo, aryl, or heteroaryl any of which
may be optionally independently substituted with one or more groups
T.sup.1b, T.sup.2b or T.sup.3b; R.sup.4a is R.sup.4or OR.sup.4;
R.sup.5 is --NR.sup.6aR.sup.7a, or heteroaryl, (heteroaryl)alkyl,
aryl, (aryl)alkyl, alkyl, cycloalkyl, (cycloalkyl)alkyl,
hetercyclo, (heterocyclo)alkyl, alkyl, alkenyl or alkynyl any of
which may be optionally independently substituted with one or more
groups T.sup.1c, T.sup.2c or T.sup.3c; R.sup.6, R.sup.6a, R.sup.7,
R.sup.7a, R.sup.8, R.sup.8a, R.sup.8a1, R.sup.8a2, R.sup.8a3,
R.sup.8a4, R.sup.8a5 and R.sup.9 are independently H, alkyl,
hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy,
(hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl,
(heterocylooxy)alkyl, (heteroaryloxy)alkyl, (cyano)alkyl,
(alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl,
aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo,
(heterocyclo)alkyl, --C(O)R.sup.12, --CO.sub.2R.sup.12,
--C(O)--NR.sup.12R.sup.13, or --NR.sup.12R.sup.13 any of which may
be optionally independently substituted with one or more groups
T.sup.1d, T.sup.2d or T.sup.3d; or R.sup.6 and R.sup.7, or R.sup.6a
and R.sup.7a together with the nitrogen atom to which they are
attached may combine to form a saturated or unsaturated 4 to 8
membered ring optionally independently substituted with one or more
groups T.sup.1d, T.sup.2d or T.sup.3d; or one of R.sup.6 or
R.sup.7, may combine with one of R.sup.8, R.sup.8a or R.sup.9 to
form a saturated or unsaturated 5 to 8 membered ring optionally
independently substituted with one or more groups T.sup.1d,
T.sup.2d or T.sup.3d. or one of R.sup.6a or R.sup.7a, may combine
with R.sup.8a1 to form a saturated or unsaturated 5 to 8 membered
ring optionally independently substituted with one or more groups
T.sup.1d, T.sup.2d or T.sup.3d R.sup.8b is independently H, alkyl,
aryl, cyano, nitro, acyl or --SO.sub.2(alkyl); R.sup.8c is
independently H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,
arylalkyl, cycloheteroalkyl, heteroaryl, amino or alkoxy; R.sup.8d
is R.sup.4, COR.sup.4, CO.sub.2R.sup.4, SO.sub.2R.sup.4,
CONR.sup.6R.sup.7, or SO.sub.2--NR.sup.6R.sup.7; R.sup.10
R.sup.10a, R.sup.11 and R.sup.11a are independently H, alkyl, aryl,
(aryl)alkyl, alkoxy, (alkoxy)alkyl, halo, hydroxy, (hydroxy)alkyl,
amino, amido, heteroaryl, (heteroaryl)alkyl, heterocyclo,
(heterocyclo)alkyl, sulfonamido, cycloalkyl, (cycloalkyl)alkyl, or
cyano any of which may be optionally independently substituted on
available atoms with one or more groups T.sup.1e, T.sup.2e or
T.sup.3e; or R.sup.10a and R.sup.10a, or R.sup.11 and R.sup.11a may
combine to form oxo; or R.sup.10a may combine with R.sup.11a to
form a bond; or R.sup.10 may combine with R.sup.9 to form a
saturated or unsaturated ring; R.sup.12 and R.sup.13 are
independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy,
heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl,
(heterocylooxy)alkyl, (heteroaryloxy)alkyl, cycloalkyl,
(cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl,
(heteroaryl)alkyl, heterocyclo, or (heterocyclo)alkyl any of which
may be optionally independently substituted with one or more groups
T.sup.1f, T.sup.2f or T.sup.3f or R.sup.12 and R.sup.13 together
with the nitrogen atom to which they are attached may combine to
form a saturated or unsaturated ring which may be optionally
independently substituted with one or more groups T.sup.1f,
T.sup.2f or T.sup.3f; W is .dbd.NR.sup.8a2,
.dbd.N--CO.sub.2R.sup.8a2, .dbd.N--COR.sup.8a2, .dbd.N--CN, or
.dbd.N--SO.sub.2R.sup.8a2; X is 839Z, Z.sup.1 and Z.sup.2 are
independently .dbd.O, .dbd.S, .dbd.NR.sup.8a4 or .dbd.N--CN;
R.sup.14 is independently 840where q is 1, 2 or 3; R.sup.Y is an
optional oxo substituent attached to any available ring carbon
atom; X.sup.1 is O, S, NR.sup.8a5 or CH.sub.2; and X.sup.2is
NR.sup.8a5 or CH.sub.2; R.sup.X is one or more optional
substituents, attached to any available ring carbon atom,
independently selected from T.sup.1g, T.sup.2g or T.sup.3g;
T.sup.1-1g, T.sup.2-2g, and T.sup.3-3g are are each independently
(1) hydrogen or T.sup.6, where T.sup.6 is (i) alkyl,
(hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,
(aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or
(heteroaryl)alkyl; (ii) a group (i) which is itself substituted by
one or more of the same or different groups (i); or (iii) a group
(i) or (ii) which is independently substituted by one or more
(preferably 1 to 3) of the following groups (2) to (13) of the
definition of T.sup.1-1g, T.sup.2-2g and T.sup.3-3g, (2) --OH or
--OT.sup.6, (3) --SH or --ST.sup.6, (4) --C(O).sub.tH,
--C(O).sub.tT.sup.6, or --O--C(O)T.sup.6, where t is 1 or 2; (5)
--SO.sub.3H, --S(O).sub.tT.sup.6, or S(O).sub.tN(T.sup.9)T.sup.6,
(6) halo, (7) cyano, (8) nitro, (9) -T.sup.4-NT.sup.7T.sup.8, (10)
-T.sup.4-N(T.sup.9)-T.sup.5-NT.sup.7T.sup.8, (11)
-T.sup.4-N(T.sup.10)T.s- up.5-T.sup.6, (12)
-T.sup.4-N(T.sup.10)-T.sup.5-H, (13) oxo, T.sup.4 and T.sup.5 are
each independently (1) a single bond, (2)
-T.sup.11-S(O).sub.t-T.sup.12-, (3) -T.sup.11-C(O)-T.sup.12-, (4)
-T.sup.11-C(S)-T.sup.12-, (5) -T.sup.11-O-T.sup.12-, (6)
-T.sup.11-S-T.sup.12-, (7) -T.sup.11-O--C(O)-T.sup.12-, (8)
-T.sup.11-C(O)--O-T.sup.12-, (9)
-T.sup.11-C(.dbd.NT.sup.9a)-T.sup.12-, or (10)
-T.sup.11-C(O)--C(O)-T.sup.12-, T.sup.7, T.sup.8, T.sup.9, T.sup.9a
and T.sup.10 (1) are each independently hydrogen or a group
provided in the definition of T.sup.6, or (2) T.sup.7 and T.sup.8
may together be alkylene or alkenylene, completing a 3- to
8-membered saturated or unsaturated ring together with the atoms to
which they are attached, which ring is unsubstituted or substituted
with one or more groups listed in the definition of T.sup.1-1g,
T.sup.2-2g and T.sup.3-3g, or (3) T.sup.7 or T.sup.8, together with
T.sup.9, may be alkylene or alkenylene completing a 3- to
8-membered saturated or unsaturated ring together with the nitrogen
atoms to which they are attached, which ring is unsubstituted or
substituted with one or more groups listed in the definition of
T.sup.1-1g, T.sup.2-2g and T.sup.3-3g, or (4) T.sup.7 and T.sup.8
or T.sup.9 and T.sup.10 together with the nitrogen atom to which
they are attached may combine to form a group
--N.dbd.CT.sup.13T.sup.14 where T.sup.13 and T14 are each
independently H or a group provided in the definition of T.sup.6;
T.sup.11 and T.sup.12 are each independently (1) a single bond, (2)
alkylene, (3) alkenylene, or (4) alkynylene; provided that R.sup.2
is other than 841when conditions (a) and (b) are both met (a)
-J-R.sup.3 is 842and (b) R.sup.1 is H, halo, hydroxy, cyano, nitro,
aryl, alkoxy, aryloxy, heteroaryloxy, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
--OC(.dbd.O)CCl.sub.3, --SO.sub.2(alkyl), --SO.sub.2(aryl),
--SO.sub.2(arylalkyl), --CO.sub.2H, --C(.dbd.O)(alkyl),
--CO.sub.2(alkyl), --C(.dbd.O)NR.sup.6*R.sup.7*,
--NR.sup.6*R.sup.7*, --OC(.dbd.O)NR.sup.6*R.sup.7*, --N.sub.3,
--N(R.sup.8)C(O)NR.sup.6*R.sup.- 7*,
--OC(.dbd.O)OR.sup.4--OC(.dbd.O)R.sup.4, or
--N(H)S(O.sub.2)R.sup.4, or R.sup.1 and R.sup.1a combine to form
oxo; or R.sup.1 and R.sup.1a together with the carbon atom to which
they are attached combine to form a spiro fused heterocylo group,
or R.sup.1 and R.sup.1a together combine to form a group 843where
R.sup.6* and R.sup.7* are each independently H, aryl, --C(O)aryl,
--CO.sub.2aryl, alkyl, --C(O)alkyl, --CO.sub.2alkyl,
--S(O).sub.ualkyl, --C(O)S(O).sub.ualkyl, --S(O).sub.uaryl,
--C(O)S(O).sub.uaryl, or heterocyclo; R.sup.5a is 844R.sup.8a H, or
alkyl; and u is 0, 1, 2 or 3.
28. A compound of Formula I 845enantiomers, diastereomers or salts
thereof wherein the dashed line represents an optional double bond,
provided that R.sup.1a is absent when a double bond is present; m
and p are independently 0, 1, 2 or 3; R.sup.1 is
846N(R.sup.8)R.sup.14, --N(R.sup.8)C(O)R.sup.14,
--C(.dbd.NR.sup.8b)R.sup.8c, --SO.sub.2R.sup.8c, --CO.sub.2H,
--OC(O)CCl.sub.3, --C(O)R.sup.8c, --CO.sub.2R.sup.8c,
--C(.dbd.S)R.sup.8c, --NR.sup.6R.sup.7, --OC(O)NR.sup.6R.sup.7,
--N.sub.3, optionally substituted aryl, optionally substituted
heteroaryl, optionally substituted heterocyclo, halo,
perfluoroalkyl, cyano, nitro, hydroxy, optionally substituted
alkoxy, optionally substituted aryloxy, optionally substituted
heteroaryloxy, optionally substituted alkyl, optionally subsituted
alkenyl, or optionally subsituted alkynyl; R.sup.1a is H, or a
group listed in the definition of R.sup.X; or R.sup.1 and R.sup.1a
together form oxo; or R.sup.1 and R.sup.1a together with the carbon
atom to which they are attached combine to form an optionally
substituted spiro-fused heterocyclo group; or R.sup.1 and R.sup.1a
together combine to form a group R.sup.9 847R.sup.2 is heteroaryl,
(heteroaryl)alkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyclo)alkyl, alkyl or cycloalkyl, any of which may be
optionally independently substituted with one or more groups
T.sup.1, T.sup.2 or T.sup.3; J is a bond, C.sub.1-4 alkylene
optionally independently substituted with one or more groups
T.sup.1a, T.sup.2a or T.sup.3a, or C.sub.1-4 alkenylene optionally
independently substituted with one or more groups T.sup.1a,
T.sup.2a or T.sup.3a; R.sup.3 is 848R.sup.4 is alkyl, haloalkyl,
alkenyl, cycloalkyl, heterocyclo, aryl, or heteroaryl any of which
may be optionally independently substituted with one or more groups
T.sup.1b, T.sup.2b or T.sup.3b; R.sup.4a is R.sup.4 or OR.sup.4;
R.sup.5 is --NR.sup.6aR.sup.7a, or heteroaryl, (heteroaryl)alkyl,
aryl, (aryl)alkyl, alkyl, cycloalkyl, (cycloalkyl)alkyl,
heterocyclo, (heterocyclo)alkyl, or alkyl any of which may be
optionally independently substituted with one or more groups
T.sup.1c, T.sup.2c or T.sup.3c; R.sup.6, R.sup.6a, R.sup.7,
R.sup.8, R.sup.8a, R.sup.8a1, R.sup.8a2, R.sup.8a3, R.sup.8a4,
R.sup.8a5 and R.sup.9 are independently H, alkyl, hydroxy, alkoxy,
aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl,
(alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl,
(heteroaryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl,
cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl,
(heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, --C(O)R.sup.12,
--CO.sub.2R.sup.12, --C(O)--NR.sup.12R.sup.13, or
--NR.sup.12R.sup.13 any of which may be optionally independently
substituted with one or more groups T.sup.1d, T.sup.2d or T.sup.3d;
or R.sup.6 and R.sup.7, or R.sup.6a and R.sup.7a together with the
nitrogen atom to which they are attached may combine to form a
saturated or unsaturated 4 to 8 membered ring optionally
independently substituted with one or more groups T.sup.1d,
T.sup.2d or T.sup.3d; or one of R.sup.6 or R.sup.7, may combine
with one of R.sup.8, R.sup.8a or R.sup.9 to form a saturated or
unsaturated 5 to 8 membered ring optionally independently
substituted with one or more groups T.sup.1d, T.sup.2d or T.sup.3d.
or one of R.sup.6a or R.sup.7a, may combine with R.sup.8a1 to form
a saturated or unsaturated 5 to 8 membered ring optionally
independently substituted with one or more groups T.sup.1d,
T.sup.2d or T.sup.3d R.sup.8b is independently H, alkyl, aryl,
cyano, nitro, acyl or --SO.sub.2(alkyl); R.sup.8c is independently
H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl,
cycloheteroalkyl, heteroaryl, amino or alkoxy; R.sup.8d is R.sup.4,
COR.sup.4, CO.sub.2R.sup.4, SO.sub.2R.sup.4, CONR.sup.6R.sup.7, or
SO.sub.2--NR.sup.6R.sup.7; R.sup.10 R.sup.10a, R.sup.11 and
R.sup.11a are independently H, alkyl, aryl, (aryl)alkyl, alkoxy,
(alkoxy)alkyl, halo, hydroxy, (hydroxy)alkyl, amino, amido,
heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl,
sulfonamido, cycloalkyl, (cycloalkyl)alkyl, cyano or oxo any of
which may be optionally independently substituted on available
atoms with one or more groups T.sup.1e, T.sup.2e or T.sup.3e; or
R.sup.10a may combine with R.sup.11a to form a bond; or R.sup.10
may combine with R.sup.9 to form a saturated or unsaturated ring;
R.sup.12 and R.sup.13 are independently H, alkyl, hydroxy, alkoxy,
aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl,
(alkoxy)alkyl, (aryloxy)alkyl, (heterocylooxy)alkyl,
(heteroaryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,
(aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, or
(heterocyclo)alkyl any of which may be optionally independently
substituted with one or more groups T.sup.1f, T.sup.2f or T.sup.3f
or R.sup.12 and R.sup.13 together with the nitrogen atom to which
they are attached may combine to form a saturated or unsaturated
ring which may be optionally independently substituted with one or
more groups T.sup.1f, T.sup.2f or T.sup.3f; +P2 W is
.dbd.NR.sup.8a2, .dbd.NCO.sub.2R.sup.8a2, .dbd.N--COR.sup.8a2,
.dbd.N--CN, or .dbd.N--SO.sub.2R.sup.8a2; X is 849Z, Z.sup.1 and
Z.sup.2 are independently .dbd.O, .dbd.S, .dbd.NR.sup.8a4 or
.dbd.N--CN; R.sup.14 is independently 850where q is 1, 2 or 3;
R.sup.Y is an optional oxo substituent attached to any available
ring carbon atom; X.sup.1 is O, S, NR.sup.8a5 or CH.sub.2; and
X.sup.2 is NR.sup.8a5 or CH.sub.2; R.sup.X is one or more optional
substituents, attached to any available ring carbon atom,
independently selected from T.sup.1g, T.sup.2g or T.sup.3g;
T.sup.1-1g, T.sup.2-2g, and T.sup.3-3g are are each independently
(1) hydrogen or T.sup.6, where T.sup.6 is (i) alkyl,
(hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,
(aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or
(heteroaryl)alkyl; (ii) a group (i) which is itself substituted by
one or more of the same or different groups (i); or (iii) a group
(i) or (ii) which is independently substituted by one or more
(preferably 1 to 3) of the following groups (2) to (13) of the
definition of T.sup.1-1g, T.sup.2-2g and T.sup.3-3g, (2) --OH or
--OT.sup.6, (3) --SH or --ST.sup.6, (4) --C(O).sub.tH,
--C(O).sub.tT.sup.6, or --O--C(O)T.sup.6, where t is 1 or 2; (5)
--SO.sub.3H, --S(O).sub.tT.sup.6, or S(O).sub.tN(T.sup.9)T.sup.6,
(6) halo, (7) cyano, (8) nitro, (9) -T.sup.4-NT.sup.7T.sup.8, (10)
-T.sup.4-N(T.sup.9)-T.sup.5-NT.sup.7T.sup.8, (11)
-T.sup.4-N(T.sup.10)-T.- sup.5-T.sup.6, (12)
-T.sup.4-N(T.sup.10)-T.sup.5-H, (13) oxo, T.sup.4 and T.sup.5 are
each independently (1) a single bond, (2)
-T.sup.11-S(O).sub.t-T.sup.12-, (3) -T.sup.11-C(O)-T.sup.12-, (4)
-T.sup.11-C(S)-T.sup.12-, (5) -T.sup.11-O-T.sup.12-, (6)
-T.sup.11-S-T.sup.12-, (7) -T.sup.11-O--C(O)-T.sup.12-, (8)
-T.sup.11-C(O)--O-T.sup.12-, (9)
-T.sup.11-C(.dbd.NT.sup.9a)-T.sup.12-, or (10)
-T.sup.11-C(O)--C(O)-T.sup.12- T.sup.7, T.sup.8, T.sup.9, T.sup.9a
and T.sup.10 (1) are each independently hydrogen or a group
provided in the definition of T.sup.6, or (2) T.sup.7 and T.sup.8
may together be alkylene or alkenylene, completing a 3- to
8-membered saturated or unsaturated ring together with the atoms to
which they are attached, which ring is unsubstituted or substituted
with one or more groups listed in the definition of T.sup.1-1g,
T.sup.2-2g and T.sup.3-3g, or (3) T.sup.7 or T.sup.8, together with
T.sup.9, may be alkylene or alkenylene completing a 3- to
8-membered saturated or unsaturated ring together with the nitrogen
atoms to which they are attached, which ring is unsubstituted or
substituted with one or more groups listed in the definition of
T.sup.1-1g, T.sup.2-2g and T.sup.3-3, or (4) T.sup.7 and T.sup.8 or
T.sup.9 and T.sup.10 together with the nitrogen atom to which they
are attached may combine to form a group --N.dbd.CT.sup.13T.sup.14
where T.sup.13 and T.sup.14 are each independently H or a group
provided in the definition of T.sup.6; T.sup.11 and T.sup.12 are
each independently (1) a single bond, (2) alkylene, (3) alkenylene,
or (4) alkynylene; provided that (i) R.sup.2 is other than 851when
conditions (a) and (b) are both met (a) -J-R.sup.3 is 852and (b)
R.sup.1 is H, halo, hydroxy, cyano, nitro, aryl, alkoxy, aryloxy,
heteroaryloxy, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, --OC(.dbd.O)CCl.sub.3,
--SO.sub.2(alkyl), --SO.sub.2(aryl), --SO.sub.2(arylalkyl),
--CO.sub.2H, --C(.dbd.O)(alkyl), --CO.sub.2(alkyl),
--C(.dbd.O)NR.sup.6*R.sup.7*, --NR.sup.6*R.sup.7*,
--OC(.dbd.O)NR.sup.6*R.sup.7*, --N.sub.3,
--N(R.sup.8)C(O)NR.sup.6*R.sup.- 7, --OC(.dbd.O)OR.sup.4
--OC(.dbd.O)R.sup.4, or --N(H)S(O.sub.2)R.sup.4, or R.sup.1 and
R.sup.1a combine to form oxo; or R.sup.1 and R.sup.1a together with
the carbon atom to which they are attached combine to form a spiro
fused heterocylo group, or R.sup.1 and R.sup.1a together combine to
form a group 853where R.sup.6* and R.sup.7* are each independently
H, aryl, --C(O)aryl, --CO.sub.2aryl, alkyl, --C(O)alkyl,
--CO.sub.2alkyl, --S(O).sub.ualkyl, --C(O)S(O).sub.ualkyl,
--S(O).sub.uaryl, --C(O)S(O).sub.uaryl, or heterocyclo; R.sup.5a is
854R.sup.8a H, or alkyl; and u is 0, 1, 2 or 3; (ii) R.sup.2 is
other than thienyl when conditions (c) and (d) are both met (c)
-J-R.sup.3 is --NR.sup.6bR.sup.7b where R.sup.6b and R.sup.7b are
independently H, alkyl, cycloalkyl, or R.sup.6b and R.sup.7b
combine to form an N-containing cyclic group containing at least
one double bond; and (d) R.sup.1 is alkyl, cycoalkyl, alkenyl,
alkynyl, alkoxy, amino or cyano (iii) said compound is other than a
compound of the formula 855where R.sup.1c is --OC(O)NHR.sup.7c or
--OC(O)R.sup.4b; R.sup.2a is alkyl or phenyl; R.sup.3a is
856R.sup.4b is alkyl; R.sup.5b is --NHR.sup.7d or benzyl
substituted with one to three groups independently selected from
halo, alkyl or alkoxy R.sup.7c is H, alkyl, phenyl or benyl;
R.sup.7d is phenyl substituted with one to three groups
independently selected from halo, alkyl or alkoxy; R.sup.Xa is
hydroxy, --OC(O)NHR.sup.7c or --OC(O)R.sup.4b; R.sup.Xb and
R.sup.Xc are independently H or alkyl; n* is 1 to 4; n** is 0 to 3;
(iv) R.sup.2 is other than phenyl when conditions (e) and (f) are
both met (e) R.sup.1 is alkyl, alkoxy, or phenyl; and (f)
-J-R.sup.3 is an N-aryl substituted piperazinyl group; (v) R.sup.1
is other than hydroxy, alkoxy, aryloxy, alkyl or aryl when
conditions (g) and (h) are both met, or R.sup.1 and R.sup.1a do not
form .dbd.CH.sub.2 when conditions (g) and (h) are both met (g)
R.sup.2 is alkyl, aryl or arylalkyl; and (h) -J-R.sup.3 is
--NR.sup.6eR.sup.7e or --(CHR.sup.2O)--R.sup.5c where R.sup.5c is
optionally substituted phenyl; R.sup.6e is hydrogen, hydroxy or
alkoxy; R.sup.7e is optionally substituted phenyl; and R.sup.20 is
hydrogen, hydroxy or alkoxy; (vi) R.sup.2 is other than optionally
substituted phenyl or pyridyl when conditions (j) and (k) are both
met (j) R.sup.1a is H, hydroxy, alkyl or (hydroxy)alkyl, and
R.sup.1 is H, hydroxy, --(CH.sub.2).sub.n*--NR.sup.6fR.sup.7f,
--(CH.sub.2).sub.n*--CO.sub.2R.su- p.8e, cycloalkyl, heterocylco,
or heteroaryl; or R.sup.1a and R.sup.1 combine to form oxo,
--O(CH.sub.2).sub.m*O--, or .dbd.CHCO.sub.2R.sup.8e where n* is 0
to 2; m* is 1 or 2; R.sup.6f and R.sup.7f are independently H,
alkyl, alkenyl, (hydroxy)alkyl, cycloalkyl, (cycloalkyl)alkyl,
aryl, (aryl)alkyl, heterocylco, (heterocyclo)alkyl, heteroaryl,
(heteroaryl)alkyl, CHO, --C(O)-alkyl, --C(O)-cycloalkyl,
--C(O)-(cycloalkyl)alkyl, --C(O)-aryl, --C(O)-(aryl)alkyl,
--C(O)-heterocylco, --C(O)-(heterocyclo)alkyl,
--C(O)alkyl-NR.sup.8eR.sup- .8f, --CO.sub.2-alkyl,
-alkyl-CO.sub.2-alkyl, --CO.sub.2-cycloalkyl,
--CO.sub.2-(cycloalkyl)alkyl, --CO.sub.2-aryl,
--CO.sub.2-(aryl)alkyl, --CO.sub.2-heterocylco,
--CO.sub.2-(heterocylo)alkyl, --CO.sub.2--NR.sup.8eR.sup.8f,
--CO.sub.2-alkyl-NR.sup.8eR.sup.8f, --NR.sup.8eCOR.sup.8f,
-alkyl-NR.sup.8eCOR.sup.8f, --NR.sup.8eCO.sub.2R.sup.8f,
alkyl-NR.sup.8eCO.sub.2R.sup.8f--C(O)N(R.sup- .8e)(aryl),
-alkyl-C(O)N(R.sup.8e)(aryl), --C(O)N(R.sup.8e)(heterocycle),
-alkyl-C(O)N(R.sup.8e)(heterocycle); or R.sup.6f and R.sup.7f
together with the nitrogen atome to which they are attached combine
to form an optionally substituted heterocyclo ring selected from
857R.sup.8e and R.sup.8f are independently H, alkyl, cycloalkyl,
(fluoro)alkyl, or --CH.sub.2CO.sub.2-alkyl; R.sup.8g is H, alkyl,
cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl, CHO,
--C(O)-alkyl, --C(O)-cycloalkyl, --C(O)-(cycloalkyl)alkyl,
--C(O)-aryl, --C(O)-(aryl)alkyl, --C(O)-heterocylco,
--C(O)-(heterocyclo)alkyl, --CO.sub.2-alkyl, --CO.sub.2-cycloalkyl,
--CO.sub.2-(cycloalkyl)alkyl, --CO.sub.2-aryl, --CO.sub.2-(aryl
)alkyl, --CO.sub.2-hetercyclo, --CO.sub.2-(heterocyclo)a- lkyl,
--CO.sub.2--NR.sup.6fR.sup.7f, or
--CO.sub.2-(alkyl)-NR.sup.6fR.sup.- 7f; (k) -J-R.sup.3 is a group
--C(O)--NR.sup.8a1--(CR.sup.15R.sup.16)--R.s- up.5*,
--(CR.sup.15R.sup.16)--NR.sup.8a1--C(O)--R.sup.5*,
--(CR.sup.15R.sup.16)--NR.sup.8a1--(CR.sup.17R.sup.18)--R.sup.5*,
--C(O)O--(CR.sup.15R.sup.16)--R.sup.5*,
--(CR.sup.15R.sup.16)--OC(O)--R.s- up.5*,
--(CR.sup.15R.sup.16)--O--(CR.sup.17R.sup.18)--R.sup.5*,
--C(R.sup.15).dbd.C(R.sup.16)--R.sup.5*,
--(CR.sup.15R.sup.16)--C(R.sup.1- 7).dbd.C(R.sup.18)--R.sup.5*,
--(CR.sup.15R.sup.16)--C(R.sup.17R.sup.18)---
(CR.sup.19R.sup.20)--R.sup.5*,
--C(O)--(CR.sup.15R.sup.16)--(CR.sup.17R.su- p.18)--R.sup.5*,
--(CR.sup.15R.sup.16)--C(O)--(CR.sup.17R.sup.18)--R.sup.5- *,
--(CR.sup.15R.sup.16)--(CR.sup.17R.sup.18)--C(O)--R.sup.5*,
--N(R.sup.8a1)--C(O)--(CR.sup.15R.sup.16)--R.sup.5*,
--N(R.sup.8a1)--(CR.sup.15R.sup.16)--(CR.sup.17R.sup.18)--R.sup.5*,
--N(R.sup.8a1)--C(O)--C(O)--R.sup.5*,
--OC(O)--(CR.sup.15R.sup.16)--R.sup- .5*, or
--O--(CR.sup.15R.sup.16)--(CR.sup.17R.sup.18)--R.sup.5*, where
R.sup.5* is 858where T.sup.1c* is hydroxy, alkyl, fluoroalkyl,
alkenyl, cycloalklyl, (cycloalkyl)alkyl, alkoxy, fluoroalkoxy,
(alkoxy)alkyl, (alkoxy)alkoxy, (fluoroalkoxy)alkyl, alkenyloxy,
cycloalkyloxy, (cycloalkyl)alkoxy, phenoxy, cyano, halo,
--NT.sup.7T.sup.8 where T.sup.7 and T.sup.8 are as defined above,
--SH, --ST.sup.6 where T.sup.6 is as defined above,
--S(O).sub.tT.sup.6 where t is as defined above, --C(O).sub.tH,
--C(O).sub.tT.sup.6 or --C(O)--NT.sup.7T.sup.8; T.sup.2c* is H,
halogen, alkyl or alkoxy; or when T.sup.1c* is adjacent to
T.sup.2c* they may combine to form a 5 or 6-membered heterocylo or
heteroaryl ring optionally substituted with alkyl, fluroalkyl,
.dbd.O or .dbd.S T.sup.3c* is H, halogen, alkyl, fluroalkyl,
alkoxy, fluoralkoxy, cycloalkyl, (cycloalkyl)alkyl, cyano,
heteroaryl, --NT.sup.7T.sup.8, --SH, --ST.sup.6,
--S(O).sub.tT.sup.6, --C(O).sub.tH, --C(O).sub.tT.sup.6 or
--C(O)--NT.sup.7T.sup.8, or alkyl subsituted with cyano, CO.sub.2H,
CO.sub.2T.sup.6, or --C(O)--NT.sup.7T.sup.8; and R.sup.15,
R.sup.16, R.sup.17, R.sup.18, R.sup.19 and R.sup.20 are
independently H, hydroxy, alkyl, alkenyl, (hydroxy)alkyl,
(alkoxy)alkyl, --(CH.sub.2).sub.n*--NR.su- p.6fR.sup.7f, --CHO,
--C(O)alkyl, or --CO.sub.2alkyl; or R.sup.15 and R.sup.16 together
form --CH.sub.2CH.sub.2--; or R.sup.17 and R.sup.18 together form
--CH.sub.2CH.sub.2--; or R.sup.19 and R.sup.20 together form
--CH.sub.2CH.sub.2--.
Description
[0001] This application claims priority to U.S. Provisional
Application Serial No. 60/353,884 filed Feb. 1, 2002 the entirety
of which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention provides for cycloalkyl compounds
useful as inhibitors of potassium channel function (especially
inhibitors of the K.sub.v1 subfamily of voltage gated K.sup.+
channels, more especially inhibitors K.sub.v1.5 which has been
linked to the ultra-rapidly activating delayed rectifier K.sup.+
current I.sub.Kur) and to pharmaceutical compositions containing
such compounds. The present invention further provides for methods
of using such compounds in the treatment of arrhythmia,
I.sub.Kur-associated disorders, and other disorders mediated by ion
channel function.
BACKGROUND OF THE INVENTION
[0003] The importance of potassium channels was first recognized
approximately fifty years ago when Hodgkin and Huxley discovered
that potassium ions contributed to the current that excited the
squid giant axon. Research in the area, however, was hampered by
the lack of selective, high affinity ligands for potassium
channels. But the advent of recombinant DNA techniques and single
cell and whole cell voltage clamp techniques has changed the slow
pace of the field. Indeed, potassium channels that exhibit
functional, pharmacological and tissue distribution characteristics
have been cloned. These cloned potassim channels are useful targets
in assays for identifying candidate compounds for the treatment of
various disease states. Potassium channels have turned out to be
the most diverse family of ion channels discovered to date. They
modulate a number of cellular events such as muscle contraction,
neuro-endocrine secretion, frequency and duration of action
potentials, electrolyte homeostatis, and resting membrane
potential.
[0004] Potassium channels are expressed in eukaryotic and
procaryotic cells and are elements in the control of electrical and
non-electrical cellular functions. Potassium channels have been
classified according to their biophysical and pharmacological
characteristics. Subclasses of these channels have been named based
on amino acid sequence and functional properties. Salient among
these are the voltage dependent potassium channels, for example
voltage gated potassium channels (e.g., K.sub.v1, K.sub.v2,
K.sub.v3, K.sub.v4). Subtypes within these subclasses have been
characterized as to their putative function, pharmacology and
distribution in cells and tissues (Chandy and Gutman,
"Voltage-gated potassium channel genes" in Handbook of Receptors
and Channels--Ligand and Voltage-gated Ion Channels, ed. R. A.
North, 1995; Doupnik et al., Curr. Opin. Neurobiol. 5:268, 1995).
For example, the K.sub.v1 class of potassium channels is further
subdivided depending on the molecular sequence of the channel, for
example K.sub.v1.1, K.sub.v1.2, K.sub.v1.3, K.sub.v1.4, K.sub.v1.5,
K.sub.v1.6, and K.sub.v1.7. Functional voltage-gated K.sup.+
channels can exist as multimeric structures formed by the
association of either identical or dissimilar subunits. This
phenomena is thought to account for the wide diversity of K.sup.+
channels. However, subunit compositions of native K.sup.+ channels
and the physiologic role that particular channels play are, in most
cases, still unclear.
[0005] Membrane depolarization by K.sub.v1.3 inhibition has been
shown to be an effective method to prevent T-cell proliferation and
therefore has applications in many autoimmune conditions.
Inhibition of K.sup.+ channels in the plasma membrane of human
T-lymphocytes has been postulated to play a role in eliciting
immunosuppressive responses by regulating intracellular Ca.sup.++
homeostasis, which has been found to be important in T-cell
activation.
[0006] The K.sub.v1.3 voltage-gated potassium channel is found in
neurons, blood cells, osteoclasts and T-lymphocytes. The Chandy and
Cahalan laboratories proposed a hypothesis that blocking the
K.sub.v1.3 channel would elicit an immunosuppressant response.
(Chandy et al., J. Exp. Med. 160, 369, 1984; Decoursey et al.,
Nature, 307, 465, 1984). However, the K.sup.+ channel blockers
employed in their studies were non-selective. Until research with
the peptide margatoxin, a peptide found in scorpion venom, no
specific inhibitor of the K.sub.v1.3 channel existed to test this
hypothesis. Although a laboratory (Price et al., Proc. Natl, Acad,
Sci. USA, 86, 10171, 1989) showed that charybdotoxin would block
K.sub.v1.3 in human T-cells, charybdotoxin was subsequently shown
to inhibit four different K.sup.+ channels (K.sub.v1.3 and three
distinct small conductance Ca.sup.++ activated K.sup.+ channels) in
human T-lymphocytes, limiting the use of this toxin as a probe for
the physiological role of K.sub.v1.3 (Leonard et al., Proc. Natl,
Acad. Sci, USA, 89, 10094, 1992). Margatoxin, on the other hand,
blocks only Kv1.3 in T-cells, and has immunosuppressant activity on
both in in vitro and in vivo models. (Lin et al., J. exp. Med, 177,
637, 1993). The therapeutic utility of this compound, however, is
limited by its potent toxicity. Recently, a class of compounds has
been reported that may be an attractive alternative to the above
mentioned drugs, see for example U.S. Pat. Nos. 5,670,504;
5,631,282; 5,696,156; 5,679,705; and 5,696,156. While addressing
some of the activity/toxicity problems of previous drugs, these
compounds tend to be of large molecular weight and are generally
produced by synthetic manipulation of a natural product, isolation
of which is cumbersome and labor intensive.
[0007] Immunoregulatory abnormalities have been shown to exist in a
wide variety of autoimmune and chronic inflammatory diseases,
including systemic lupus erythematosis, chronic rheumatoid
arthritis, type I and II diabetes mellitus, inflammatory bowel
disease, biliary cirrhosis, uveitis, multiple sclerosis and other
disorders such as Crohn's disease, ulcerative colitis, bullous
pemphigoid, sarcoidosis, psoriasis, ichthyosis, Graves
ophthalmopathy and asthma.
[0008] Although the underlying pathogenesis of each of these
conditions may be quite different, they have in common the
appearance of a variety of auto-antibodies and self-reactive
lymphocytes. Such self-reactivity may be due, in part, to a loss of
the homeostatic controls under which the normal immune system
operates. Similarly, following a bone-marrow or an organ
transplantation, the host lymphocytes recognize the foreign tissue
antigens and begin to produce antibodies which lead to graft
rejection.
[0009] One end result of an autoimmune or a rejection process is
tissue destruction caused by inflammatory cells and the mediators
they release. Anti-inflammatory agents such as NSAID's act
principally by blocking the effect or secretion of these mediators
but do nothing to modify the immunologic basis of the disease. On
the other hand, cytotoxic agents, such as cyclophosphamide, act in
such a nonspecific fashion that both the normal and autoimmune
responses are shut off. Indeed, patients treated with such
nonspecific immunosuppressive agents are as likely to succumb from
infection as they are from their autoimmune disease.
[0010] Cyclosporin A (CsA), which was approved by the US FDA in
1983 is currently the leading drug used to prevent rejection of
transplanted organs. In 1993, FK-506 (Prograf) was approved by the
US FDA for the prevention of rejection in liver transplantation.
CsA and FK-506 act by inhibiting the body's immune system from
mobilizing its vast arsenal of natural protecting agents to reject
the transplant's foreign protein. In 1994, CsA was approved by the
US FDA for the treatment of severe psoriasis and has been approved
by European regulatory agencies for the treatment of atopic
dermatitis. Though they are effective in fighting transplant
rejection, CsA and FK-506 are known to cause several undesirable
side effects including nephrotoxicity, neurotoxicity, and
gastrointestinal discomfort. Therefore, a selective
immunosuppressant without these side effects still remains to be
developed. Potassium channel inhibitors promise to be the solution
to this problem.
[0011] Atrial fibrillation (AF) and atrial flutter are the most
common cardiac arrhythmias in clinical practice and are likely to
increase in prevalence with the aging of the population. Currently,
AF affects more than 1 million Americans annually, represents over
5% of all admissions for cardiovascular diseases and causes more
than 80,000 strokes each year in the United States. While AF is
rarely a lethal arrhythmia, it is responsible for substantial
morbidity and can lead to complications such as the development of
congestive heart failure or thromboembolism. Currently available
Class I and Class III antiarrhythmic drugs reduce the rate of
recurrence of AF, but are of limited use because of a variety of
potentially adverse effects including ventricular proarrhythmia.
Because current therapy is inadequate and fraught with side
effects, there is a clear need to develop new therapeutic
approaches.
[0012] Antiarrhythmic agents of Class III are drugs that cause a
selective prolongation of the duration of the action potential
without significant cardiac depression. Available drugs in this
class are limited in number. Examples such as sotalol and
amiodarone have been shown to possess interesting Class III
properties (Singh B. N., Vaughan Williams E. M. "A Third Class of
Anti-Arrhythmic Action: Effects On Atrial And Ventricular
Intracellular Potentials And Other Pharmacological Actions On
Cardiac Muscle, of MJ 1999 and AH 3747" Br. J. Pharmacol 1970;
39:675-689. and Singh B. N., Vaughan Williams E. M, "The Effect of
Amiodarone, A New Anti-Anginal Drug, On Cardiac Muscle", Br J.
Pharmacol 1970; 39:657-667), but these are not selective Class III
agents. Sotalol also possesses Class II effects which may cause
cardiac depression and is contraindicated in certain susceptible
patients. Amiodarone, also is not a selective Class III
antiarrhythmic agent because it possesses multiple
electrophysiological actions and is severely limited by side
effects (Nademanee, K. "The Amiodarone Odessey". J. Am. Coll.
Cardiol. 1992;20:1063-1065.) Drugs of this class are expected to be
effective in preventing ventricular fibrillation. Selective class
III agents, by definition, are not considered to cause myocardial
depression or an induction of arrhythmias due to inhibition of
conduction of the action potential as seen with Class I
antiarrhythmic agents.
[0013] Class III agents increase myocardial refractoriness via a
prolongation of cardiac action potential duration. Theoretically,
prolongation of the cardiac action potential can be achieved by
enhancing inward currents (i.e. Na.sup.+ or Ca.sup.2+ currents;
hereinafter I.sub.Na and I.sub.Ca, respectively) or by reducing
outward repolarizing potassium (K.sup.+) currents. The delayed
rectifier (I.sub.K) K.sup.+ current is the main outward current
involved in the overall repolarization process during the action
potential plateau, whereas the transient outward (I.sub.to) and
inward rectifier (I.sub.KI) K.sup.+ currents are responsible for
the rapid initial and terminal phases of repolarization,
respectively. Cellular electrophysiologic studies have demonstrated
that I.sub.K consists of two pharmacologically and kinetically
distinct K.sup.+ current subtypes, I.sub.Kr (rapidly activating and
deactivating) and I.sub.Ks (slowly activating and deactivating)
(Sanguinetti and Jurkiewicz, Two Components Of Cardiac Delayed
Rectifier K.sup.+ Current: Differential Sensitivity To Block By
Class III Antiarrhythmic Agents, J Gen Physiol 1990, 96:195-215).
Class III antiarrhythmic agents currently in development, including
d-sotalol, dofetilide (UK-68,798), almokalant (H234/09), E-4031 and
methanesulfonamide-N-[1'-6-cyano-1,2,3,4-tetrahydro-2-naphthalenyl)-3,4-d-
ihydro-4-hydroxyspiro[2H-1-benzopyran-2,4'-piperidin]-6yl]monochloride,
predominantly, if not exclusively, block I.sub.Kr. Although,
amiodarone is a blocker of I.sub.Ks (Balser J. R. Bennett, P. B.,
Hondeghem, L. M. and Roden, D. M. "Suppression Of Time-Dependent
Outward Current In Guinea Pig Ventricular Myocytes: Actions Of
Quinidine And Amiodarone. Circ. Res. 1991, 69:519-529), it also
blocks I.sub.Na and I.sub.Ca, effects thyroid function, is as a
nonspecific adrenergic blocker, and acts as an inhibitor of the
enzyme phospholipase (Nademanee, K. "The Amiodarone Odessey" .J.Am.
Coll. Cardiol.1992;20:1063-1065). Therefore its method of treating
arrhythmia is uncertain. Most Class III agents that are known to be
in development predominantly block I.sub.Kr.
[0014] Reentrant excitation (reentry) has been shown to be a
prominent mechanism underlying supraventricular arrhythmias in man.
Reentrant excitation requires a critical balance between slow
conduction velocity and sufficiently brief refractory periods to
allow for the initiation and maintenance of multiple reentry
circuits to coexist simultaneously and sustain AF. Increasing
myocardial refractoriness by prolonging action potential duration
(APD), prevents and/or terminates reentrant arrhythmias. Most
selective Class III antiarrhythmic agents currently in development,
such as d-sotalol and dofetilide predominantly, if not exclusively,
block I.sub.kr, the rapidly activating component of I.sub.K found
both in the human atrium and ventricle.
[0015] Since these I.sub.kr blockers increase APD and
refractoriness both in atria and ventricle without affecting
conduction per se, theoretically they represent potential useful
agents for the treatment of arrhythmias like AF. These agents have
a liability in that they have an enhanced risk of proarrhythmia at
slow heart rates. For example, torsades de points has been observed
when these compounds are utilized (Roden, D. M. "Current Status of
Class III Antiarrhythmic Drug Therapy", Am J. Cardiol, 1993;
72:44B-49B). This exaggerated effect at slow heart rates has been
termed "reverse frequency-dependence", and is in contrast to
frequency-independent or frequency-dependent actions (Hondeghem, L.
M. "Development of Class III Antiarrhythmic Agents".
J.Cadiovasc.Cardiol. 20 (Suppl.2):S17-S22).
[0016] The slowly activating component of the delayed rectifier
(I.sub.ks) potentially overcomes some of the limitations of
I.sub.kr blockers associated with ventricular arrhythmias. Because
of its slow activation kinetics however, the role of I.sub.ks in
atrial repolarization may be limited due to the relatively short
APD of the atrium. Consequently, although I.sub.ks blockers may
provide distinct advantage in the case of ventricular arrhythmias,
their ability to affect SVT is considered to be minimal.
[0017] The ultra-rapidly activating delayed rectifier K.sup.+
current (I.sub.kur) is believed to represent the native counterpart
to a cloned potassium channel designated Kv1.5 and, while present
in human atrium, it appears to be absent in human ventricle.
Furthermore, because of its rapidity of activation and limited slow
inactivation, I.sub.kur is believed to contribute significantly to
repolarization in human atrium. Consequently, a specific blocker of
I.sub.kur, that is a compound which blocks Kv1.5, would overcome
the short coming of other compounds by prolonging refractoriness by
retarding repolarization in the human atrium without causing the
delays in ventricular reporlarization that underlie arrhythmogenic
after depolarizations and acquired long QT syndrome observed during
treatment with current Class III drugs.
[0018] In intact human atrial myocytes an ultra-rapidly activating
delayed rectifier K.sup.+ current I.sub.kur which is also known as
the sustained outward current, I.sub.sus or I.sub.so, has been
identified and this current has properties and kinetics identical
to those expressed by the human K.sup.+ channel clone (hKv1.5, HK2)
when isolated from human heart and stably expressed in human
(HEK-293) cell lines (Wang et al., 1993, Circ Res 73:1061-1076;
Fedida et al., 1993, Circ Res 73:210-216; Snyders et al., 1993, J
Gen Physiol 101:513-543) and originally cloned from rat brain
(Swanson et al., 10, Neuron 4:929-939). Although various
antiarrythmic agents are now available on the market, those having
both satisfactory efficacy and a high margin of safety have not
been obtained. For example, antiarrythmic agents of Class I
according to the classification scheme of Vaughan-Williams
("Classification Of Antiarrhythmic Drugs: In: Cardiac Arrhythmias,
edited by: E. Sandoe, E. Flensted-Jensen, K. Olesen; Sweden, Astra,
Sodertalje, pp449-472, 1981) which cause a selective inhibition of
the maximum velocity of the upstroke of the action potential
(.sub.max) are inadequate for preventing ventricular fibrillation.
In addition, they have problems regarding safety, namely, they
cause a depression of myocardial contractility and have a tendency
to induce arrhythmias due to an inhibition of impulse conduction.
Beta-adrenoceptor blockers and calcium antagonists which belong to
Class II and IV, respectively, have a defect in that their effects
are either limited to a certain type of arrhythmia or are
contraindicated because of their cardiac depressant properties in
certain patients with cardiovascular disease. Their safety,
however, is higher than that of the antiarrhythmic agents of Class
I.
SUMMARY OF THE INVENTION
[0019] The present invention provides cycloalkyl compounds of the
following formula I, including enantiomers, diastereomers, and
salts thereof, useful as inhibitors of potassium channel function
(especially inhibitors of the K.sub.v1 subfamily of voltage gated
K.sup.+ channels, more especially inhibitors of K.sub.v1.5 which
has been linked to the ultra-rapidly activating delayed rectifier
K.sup.+ current, I.sub.Kur) for the treatment of disorders such as
arrhythmia and I.sub.Kur-associated disorders: 1
[0020] including enantiomers, diastereomers and salts thereof
wherein
[0021] the dashed line represents an optional double bond, provided
that R.sup.1a is absent when a double bond is present;
[0022] m and p are independently 0, 1, 2 or 3;
[0023] R.sup.1 is 2
[0024] --N(R.sup.8)R.sup.14, --N(R.sup.8)C(O)R.sup.14,
--C(.dbd.NR.sup.8b)R.sup.8c, --SO.sub.2R.sup.8c, --CO.sub.2H,
--OC(O)CCl.sub.3, --C(O)R.sup.8c, --CO.sub.2R.sup.8c,
--C(.dbd.S)R.sup.8c, --NR.sup.6R.sup.7, --OC(O)NR.sup.6R.sup.7,
--N.sub.3, optionally substituted aryl, optionally substituted
heteroaryl, optionally substituted heterocyclo, halo,
perfluoroalkyl, cyano, nitro, hydroxy, optionally substituted
alkoxy, optionally substituted aryloxy, optionally substituted
heteroaryloxy, optionally substituted alkyl, optionally subsituted
alkenyl, or optionally subsituted alkynyl;
[0025] R.sup.1a is H or R.sup.X;
[0026] or R.sup.1 and R.sup.1a together form oxo;
[0027] or R.sup.1 and R.sup.1a together with the carbon atom to
which they are attached combine to form an optionally substituted
spiro-fused heterocyclo group;
[0028] or R.sup.1 and R.sup.1a together combine to form a group
3
[0029] R.sup.2 is heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl,
heterocyclo, (heterocyclo)alkyl, alkyl, alkenyl or cycloalkyl, any
of which may be optionally independently substituted with one or
more groups T.sup.1, T.sup.2or T.sup.3;
[0030] J is a bond, C.sub.1-4 alkylene optionally independently
substituted with one or more groups T.sup.1a, T.sup.2a or T.sup.3a,
or C.sub.1-4 alkenylene optionally independently substituted with
one or more groups T.sup.1a, T.sup.2a or T.sup.3a;
[0031] R.sup.3 is 4
[0032] R.sup.4 is alkyl, haloalkyl, alkenyl, cycloalkyl,
heterocyclo, aryl, or heteroaryl any of which may be optionally
independently substituted with one or more groups T.sup.1b,
T.sup.2b or T.sup.3b;
[0033] R.sup.4a is R.sup.4 or OR.sup.4;
[0034] R.sup.5 is --NR.sup.6aR.sup.7a, or heteroaryl,
(heteroaryl)alkyl, aryl, (aryl)alkyl, alkyl, cycloalkyl,
(cycloalkyl)alkyl, heterocyclo, (heterocyclo)alkyl, alkyl, alkenyl
or alkynyl any of which may be optionally independently substituted
with one or more groups T.sup.1c, T.sup.2c or T.sup.3c;
[0035] R.sup.6, R.sup.6a, R.sup.7, R.sup.8, R.sup.8a, R.sup.8a1,
R.sup.8a2, R.sup.8a3, R.sup.8a4, R.sup.8a5 and R.sup.9 are
independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy,
heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl,
(heterocyclooxy)alkyl, (heteroaryloxy)alkyl, (cyano)alkyl,
(alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl,
aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo,
(heterocyclo)alkyl, --C(O)R, --CO.sub.2R ,
--C(O)--NR.sup.12R.sup.13, or --NR.sup.12R.sup.13 any of which may
be optionally independently substituted with one or more groups
T.sup.1d, T.sup.2d or T.sup.3d;
[0036] or R.sup.6 and R.sup.7, or R.sup.6a and R.sup.7a together
with the nitrogen atom to which they are attached may combine to
form a saturated or unsaturated 4 to 8 membered ring (either
cycloalkyl or heterocylco) optionally independently substituted
with one or more groups T.sup.1d, T.sup.2d or T.sup.3d;
[0037] or one of R.sup.6 or R.sup.7, may combine with one of
R.sup.8, R.sup.8a or R.sup.9 to form a saturated or unsaturated 5
to 8 membered ring (either cycloalkyl or heterocylco) optionally
independently substituted with one or more groups T.sup.1d,
T.sup.2d or T.sup.3d.
[0038] or one of R.sup.6a or R.sup.7a, may combine with R.sup.8a1
to form a saturated or unsaturated 5 to 8 membered ring (either
cycloalkyl or heterocylco) optionally independently substituted
with one or more groups T.sup.1d, T.sup.2d or T.sup.3d
[0039] R.sup.8b is independently H, alkyl, aryl, cyano, nitro, acyl
or --SO.sub.2(alkyl);
[0040] R.sup.8c is independently H, alkyl, cycloalkyl, alkenyl,
alkynyl, aryl, arylalkyl, cycloheteroalkyl, heteroaryl, amino or
alkoxy;
[0041] R.sup.8d is R.sup.4, COR.sup.4, CO.sub.2R.sup.4,
SO.sub.2R.sup.4, CONR.sup.6R.sup.7, or
SO.sub.2--NR.sup.6R.sup.7;
[0042] R.sup.10 R.sup.10a, R.sup.11 and R.sup.11a are independently
H, alkyl, aryl, (aryl)alkyl, alkoxy, (alkoxy)alkyl, halo, hydroxy,
(hydroxy)alkyl, amino, amido, heteroaryl, (heteroaryl)alkyl,
heterocyclo, (heterocyclo)alkyl, sulfonamido, cycloalkyl,
(cycloalkyl)alkyl, or cyano any of which may be optionally
independently substituted on available atoms (as allowed by
valence) with one or more groups T.sup.1e, T.sup.2e or
T.sup.3e;
[0043] or R.sup.10 and R.sup.10a, or R.sup.11 and R.sup.11a may
combine to form oxo;
[0044] or R.sup.10a may combine with R.sup.11a to form a bond;
[0045] or R.sup.10 may combine with R.sup.9 to form a saturated or
unsaturated ring;
[0046] R.sup.12 and R.sup.13 are independently H, alkyl, hydroxy,
alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl,
(alkoxy)alkyl, (aryloxy)alkyl, (heterocylooxy)alkyl,
(heteroaryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,
(aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, or
(heterocyclo)alkyl any of which may be optionally independently
substituted with one or more groups T.sup.1f, T.sup.2f or
T.sup.3f
[0047] or R.sup.12 and R.sup.13 together with the nitrogen atom to
which they are attached may combine to form a saturated or
unsaturated ring (either cycloalkyl or heterocylco) which may be
optionally independently substituted with one or more groups
T.sup.1f, T.sup.2f or T.sup.3f;
[0048] W is .dbd.NR.sup.8a2, .dbd.N--CO.sub.2R.sup.8a2,
.dbd.N--COR.sup.8a2, .dbd.N--CN, or .dbd.N--SO.sub.2R.sup.8a2;
[0049] X is 5
[0050] Z, Z.sup.1 and Z.sup.2 are independently .dbd.O, .dbd.S,
.dbd.NR.sup.8a4 or .dbd.N--CN;
[0051] R.sup.14 is independently 6
[0052] where q is 1, 2 or 3;
[0053] R.sup.Y is an optional oxo substituent attached to any
available ring carbon atom;
[0054] X.sup.1 is O, S, NR.sup.8a5 or CH.sub.2; and
[0055] X.sup.2 is NR.sup.8a5 or CH.sub.2;
[0056] R.sup.X is one or more optional substituents, attached to
any available ring carbon atom, independently selected from
T.sup.1g, T.sup.2g or T.sup.3g;
[0057] T.sup.1-1g, T.sup.2-2g, and T.sup.3-3g are are each
independently
[0058] (1) hydrogen or T.sup.6, where T.sup.6 is
[0059] (i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,
cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl,
aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or
(heteroaryl)alkyl;
[0060] (ii) (ii) a group (i) which is itself substituted by one or
more of the same or different groups (i); or
[0061] (iii) (iii) a group (i) or (ii) which is independently
substituted by one or more (preferably 1 to 3) of the following
groups (2) to (13) of the definition of T.sup.1-1g, T.sup.2-2g and
T.sup.3-3g,
[0062] (2) --OH or --OT.sup.6,
[0063] (3) --SH or --ST.sup.6,
[0064] (4) --C(O).sub.tH, --C(O).sub.tT.sup.6, or --O--C(O)T.sup.6,
where t is 1 or 2;
[0065] (5) --SO.sub.3H, --S(O).sub.tT.sup.6, or
S(O).sub.tN(T.sup.9)T.sup.- 6,
[0066] (6) halo,
[0067] (7) cyano,
[0068] (8) nitro,
[0069] (9) -T.sup.4-NT.sup.7T.sup.8,
[0070] (10) -T.sup.4-N(T.sup.9)-T.sup.5-NT.sup.7T.sup.8,
[0071] (11) -T-N(T.sup.10)-T.sup.5-T.sup.6,
[0072] (12) -T.sup.4-N(T.sup.10)-T.sup.5-H,
[0073] (13) oxo,
[0074] T.sup.4 and T.sup.5 are each independently
[0075] (1) a single bond,
[0076] (2) -T.sup.11-S(O).sub.t-T.sup.12-,
[0077] (3) -T.sup.11-C(O)-T.sup.12-,
[0078] (4) -T.sup.11-C(S)-T.sup.12-,
[0079] (5) -T.sup.11-O-T.sup.12-,
[0080] (6) -T.sup.11-S-T.sup.12-,
[0081] (7) -T.sup.11-O--C(O)-T.sup.12-,
[0082] (8) -T.sup.11-C(O)--O-T.sup.12-,
[0083] (9) -T.sup.11-C(.dbd.NT.sup.9a)-T.sup.12-, or
[0084] (10) -T.sup.11-C(O)--C(O)-T.sup.12-
[0085] T.sup.7, T.sup.8, T.sup.9, T.sup.9a and T.sup.10
[0086] (1) are each independently hydrogen or a group provided in
the definition of T.sup.6, or
[0087] (2) T.sup.7 and T.sup.8 may together be alkylene or
alkenylene, completing a 3- to 8-membered saturated or unsaturated
ring together with the atoms to which they are attached, which ring
is unsubstituted or substituted with one or more groups listed in
the description of T.sup.1-1g, T.sup.2-2g and T.sup.3-3g, or
[0088] (3) T.sup.7 or T.sup.8, together with T.sup.9, may be
alkylene or alkenylene completing a 3- to 8-membered saturated or
unsaturated ring together with the nitrogen atoms to which they are
attached, which ring is unsubstituted or substituted with one or
more groups listed in the description of T.sup.1-1g, T.sup.2-2g and
T.sup.3-3g, or
[0089] (4) T.sup.7 and T.sup.8 or T.sup.9 and T.sup.10 together
with the nitrogen atom to which they are attached may combine to
form a group --N.dbd.CT.sup.13T.sup.14 where T.sup.13 and T.sup.14
are each independently H or a group provided in the definition of
T.sup.6; and
[0090] T.sup.11 and T.sup.13 are each independently
[0091] (1) a single bond,
[0092] (2) alkylene,
[0093] (3) alkenylene, or
[0094] (4) alkynylene.
[0095] The present invention provides novel methods for the
prevention and treatment of arrhythmia and I.sub.Kur-associated
disorders employing one or more compounds of the formula I,
enantiomers, diastereomers or pharmaceutically acceptable salts
thereof. In particular the present invention provides a novel
method for the selective prevention and treatment of
supraventricular arrhythmias.
[0096] Preferred compounds within the scope of formula I include
compounds of formula I.sub.a, I.sub.b and I.sub.c: 7
[0097] Preferred compounds within the scope of formula I include
compounds and salts thereof wherein one or more, and especially all
of R.sup.1, R.sup.1a, R.sup.2, J and R.sup.3 are selected from the
following definitions:
[0098] R.sup.1 is hydrogen, hydroxy, --NR.sup.6R.sup.7,
--O--C(O)--NR.sup.6R.sup.7, --O--C(O)--R.sup.4,
--N(R.sup.8)--SO.sub.2--N- R.sup.6R.sup.7,
--N(R.sup.8)--C(Z)-N(R.sup.8a)--SO.sub.2--R.sup.4,
--N(R.sup.8)--C(Z)-N(R.sup.8a)--SO.sub.2--OH, --SO.sub.2--R.sup.8c,
--N(R.sup.8)--C(W)--NR.sup.6R.sup.7, or a group 8
[0099] R.sup.1a is H, or R.sup.1a and R.sup.1 combine from oxo or
an optionally substituted spiro-fused heterocyclo group;
[0100] R.sup.2 is optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted aryl (especially phenyl
or napthyl), optionally substituted (aryl)alkyl (especially
benzyl), or optionally substituted heteroaryl (especially thienyl,
benzothienyl, pyridinyl or isoxazolyl);
[0101] J is a bond, optionally substituted C.sub.1-4 alkylene
(especially methylene) or optionally substituted C.sub.1-4
alkenylene (especially ethenylene);
[0102] R.sup.3 is --R, --OR.sup.5, --C(Z.sup.1)-R.sup.5,
--C(Z)-O--R.sup.5, --O--C(Z.sup.1)-R.sup.5,
--N(R.sup.8a1)--C(Z.sup.1)-R.- sup.5,
--N(R.sup.8a1)--C(Z.sup.1)-O--R.sup.5, or
--N(R.sup.8a1)--SO.sub.2-- -R.sup.5;
[0103] R.sup.5 is optionally substituted aryl, optionally
substituted (aryl)alkyl, optionally substituted heteroaryl,
optionally substituted (heteroaryl)alkyl, optionally substituted
heterocylco, optionally substituted (heterocylco)alkyl, optionally
subsituted cycloalkyl, optionally substituted (cycloalkyl)alkyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, --NR.sup.6aR.sup.7a or a group,
9
[0104] R.sup.6, R.sup.6a, R.sup.7 and R.sup.7a are independently H,
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, optionally substituted
heterocyclo, optionally substituted (aryl)alkyl, optionally
substituted (heteroaryl)alkyl, optionally substituted
(heterocylco)alkyl, optionally substituted alkyl, or
COR.sup.12;
[0105] or R.sup.6 and R.sup.7, or R.sup.6a and R.sup.7a together
with the nitrogen to which thery are attached combine to form an
optionally substituted saturated or unsaturated 5 to 8 membered
ring; and
[0106] R.sup.4, R.sup.8, R.sup.8a1, R.sup.8c, R.sup.9, R.sup.10,
R.sup.10a, R.sup.11, R.sup.11a, X, X.sup.1, Z.sup.1 and W are as
defined above.
[0107] More preferred compounds within the scope of formula I
include compounds and salts thereof wherein one or more, and
especially all of R.sup.1, R.sup.1a, R.sup.2a, J and R.sup.3 are
selected from the following definitions:
[0108] R.sup.1 is hydrogen, hydroxy, --O--C(O)--NR.sup.6R.sup.7,
--O--C(O)--R.sup.4, --N(R.sup.8)--SO.sub.2--NR.sup.6R.sup.7,
--SO.sub.2R.sup.8c, --N(R.sup.8)--C(W)--NR.sup.6R.sup.7,
--N(R.sup.8)--C(Z)-N(R.sup.8a)--SO.sub.2--R.sup.4,
--N(R.sup.8)--C(Z)-N(R.sup.8a)--SO.sub.2--OH, or a group 10
[0109] R.sup.1a is H,;
[0110] R.sup.2 is phenyl, napthyl, thienyl benzothienyl, alkyl or
alkenyl any of which may be optionally substituted as described
above;
[0111] J is a bond, methylene or ethylene;
[0112] R.sup.3 is --R.sup.5, --C(Z.sup.1)-R.sup.5,
--O--C(Z.sup.1)-R.sup.5- , or
--N(R.sup.8a1)--C(Z.sup.1)-R.sup.5;
[0113] R.sup.5 is optionally substituted alkyl, optionally
substituted cycloalkyl, optionally substituted heteroayl,
optionally substituted aryl or --NR.sup.6aR.sup.7a;
[0114] R.sup.6, R.sup.6a, R.sup.7 and R.sup.7a are independently H,
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, optionally substituted
heterocyclo, optionally substituted (aryl)alkyl, optionally
substituted (heteroaryl)alkyl, optionally substituted
(heterocylco)alkyl, optionally substituted alkyl, or
COR.sup.12;
[0115] or R.sup.6 and R.sup.7, or R.sup.6a and R.sup.7a together
with the nitrogen to which thery are attached combine to form an
optionally substituted saturated or unsaturated 5 to 8 membered
ring; and
[0116] R.sup.4, R.sup.8, R.sup.8a1, R.sup.8c, R.sup.9, R.sup.10,
R.sup.10a, R.sup.11, R.sup.11a, X, Z.sup.1 and W are as defined
above.
[0117] Most preferred compounds within the scope of formula I
include compounds and salts thereof wherein one or more, and
especially all of R.sup.1, R.sup.1a, R.sup.2, J and R.sup.3 are
selected from the following definitions:
[0118] R.sup.1 is
[0119] (a) hydrogen, or hydroxy;
[0120] (b) --O--C(O)--NR.sup.6R.sup.7,
--N(R.sup.8)--SO.sub.2--NR.sup.6R.s- up.7, or
--N(R.sup.8)--C(W)--NR.sup.6R.sup.7
[0121] where
[0122] R.sup.6 and R.sup.7 are independently
[0123] (i) H, or
[0124] (ii) alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,
heterocyclo, alkoxy, (aryl)alkyl, (cycloalkyl)alkyl,
(heteroaryl)alkyl, (heterocyclo)alkyl, (alkoxy)alkyl, or NR.sup.12
R.sup.13 any of which may be optionally independently substituted
with one or more OH, SH, OT.sup.6, ST.sup.6, C(O).sub.tT.sup.6,
NT.sup.7T.sup.8, cyano, halo, oxo, alkyl, haloalkyl, aryl,
heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT.sup.6)alkyl,
(ST.sup.6 )alkyl, (C(O).sub.tT.sup.6)alkyl, (NT.sup.7T.sup.8)alkyl,
(cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or
(heterocyclo)alkyl,
[0125] or R.sup.6 and R.sup.7 combine to form a heterocylo ring
optionally substituted with one or more OH, SH, OT.sup.6, ST.sup.6,
C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano, halo, oxo, alkyl,
haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl,
(OT.sup.6)alkyl, (ST.sup.6)alkyl, (C(O).sub.tT.sup.6)alkyl,
(NT.sup.7T.sup.8)alkyl, (cyano)alkyl, (aryl)alkyl,
(heteroaryl)alkyl or (heterocyclo)alkyl; and
[0126] R.sup.8 is
[0127] (i) H; or
[0128] (ii) alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo,
(cycloalkyl)alky, (aryl)alkyl, (heteroaryl)alkyl or
(heterocyclo)alkyl any of which may be optionally independently
substituted with one or more OH, SH, OT.sup.6, ST.sup.6,
C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano, halo, oxo, alkyl,
haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl,
(OT.sup.6)alkyl, (ST.sup.6)alkyl, (C(O).sub.tT.sup.6)alkyl,
(NT.sup.7T.sup.8)alkyl, (cyano)alkyl, (aryl)alkyl,
(heteroaryl)alkyl or (heterocyclo)alkyl,
[0129] (c) --O--C(O)--R.sup.4,
--N(R.sup.8)--C(Z)-N(R.sup.8a)--SO.sub.2--R- .sup.4 or
--N(R.sup.8)--C(Z)-N(R.sup.8a)--SO.sub.2--OH
[0130] where
[0131] R.sup.4 is
[0132] (i) H, or
[0133] (ii) alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,
heterocyclo, alkoxy, (aryl)alkyl, (cycloalkyl)alkyl,
(heteroaryl)alkyl, (heterocyclo)alkyl, (alkoxy)alkyl, or NR.sup.12
R.sup.13 any of which may be optionally independently substituted
with one or more OH, SH, OT.sup.6, ST.sup.6, C(O).sub.tT.sup.6,
NT.sup.7T.sup.8, cyano, halo, oxo, alkyl, haloalkyl, aryl,
heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT.sup.6)alkyl,
(ST.sup.6)alkyl, (C(O).sub.tT.sup.6)alkyl, (NT.sup.7T.sup.8)alkyl,
(cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl;
and
[0134] R.sup.8 and R.sup.8a are independently
[0135] (i) H; or
[0136] (ii) alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo,
(cycloalkyl)alky, (aryl)alkyl, (heteroaryl)alkyl or
(heterocyclo)alkyl any of which may be optionally independently
substituted with one or more OH, SH, OT.sup.6, ST.sup.6,
C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano, halo, oxo, alkyl,
haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl,
(OT.sup.6)alkyl, (ST.sup.6)alkyl, (C(O).sub.tT.sup.6)alkyl,
(NT.sup.7T.sup.8)alkyl, (cyano)alkyl, (aryl)alkyl,
(heteroaryl)alkyl or (heterocyclo)alkyl; or
[0137] (d) or a group 11
[0138] R.sup.1a is H,;
[0139] R.sup.2 is phenyl, (phenyl)alkyl, napthyl, thienyl
benzothienyl, alkyl or alkenyl any of which may be optionally
independently substituted with one or more OH, SH, OT.sup.6,
ST.sup.6, C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano, halo, oxo,
alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl,
(SH)alkyl, (OT.sup.6)alkyl, (ST.sup.6)alkyl,
(C(O).sub.tT.sup.6)alkyl, (NT.sup.7T.sup.8)alkyl, (cyano)alkyl,
(aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl;
[0140] J is a bond, methylene or ethylene;
[0141] R.sup.3 is
[0142] (a) --R.sup.5 or where R.sup.5 is heteroaryl, heterocyclo or
--NR.sup.6aR.sup.7a any of which may be optionally independently
substituted with one or more OH, SH, OT.sup.6, ST.sup.6,
C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano, halo, oxo, alkyl,
haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl,
(OT.sup.6)alkyl, (ST.sup.6)alkyl, (C(O).sub.tT.sup.6)alkyl,
(NT.sup.7T.sup.8)alkyl, (cyano)alkyl, (aryl)alkyl,
(heteroaryl)alkyl or (heterocyclo)alkyl;
[0143] (b) --C(Z.sup.1)-R.sup.5, or --O--C(Z.sup.1)-R.sup.5,
[0144] where
[0145] R is aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl) or
--NR.sup.6aR.sup.7a; and
[0146] R.sup.6a and R.sup.7a are independently
[0147] (i) H; or
[0148] (ii) alkyl, cylcoalkyl, aryl, (aryl)alkyl, heteroaryl
(heteroaryl)alkyl, heterocyclo or (heterocyclo)alkyl any of which
may be optionally independently substituted with one or more OH,
SH, OT.sup.6, ST.sup.6, C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano,
halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo,
(OH)alkyl, (SH)alkyl, (OT.sup.6)alkyl, (ST.sup.6)alkyl,
(C(O).sub.tT.sup.6)alkyl, (NT.sup.7T.sup.8)alkyl, (cyano)alkyl,
(aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; or
[0149] (c) --N(R.sup.8a1)--C(Z.sup.1)-R.sup.5, or
--N(R.sup.8a1)--SO.sub.2- --R.sup.5
[0150] where
[0151] R.sup.5 is aryl, (aryl)alkyl, hetreoaryl, (heteroaryl)alkyl,
heterocyclo, (heterocyclo)alkyl, alkyl, alkenyl, alkynyl,
cycloalkyl, (alkoxy)alkyl, or (cycloalkoxy)alkyl any of which may
be optionally independently substituted with one or more OH, SH,
OT.sup.6, ST.sup.6, C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano,
halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo,
(OH)alkyl, (SH)alkyl, (OT.sup.6)alkyl, (ST.sup.6)alkyl,
(C(O).sub.tT.sup.6)alkyl, (NT.sup.7T.sup.8)alkyl, (cyano)alkyl,
(aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; and
[0152] R.sup.8a1 is
[0153] (i) H; or
[0154] (ii) alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo,
(cycloalkyl)alky, (aryl)alkyl, (heteroaryl)alkyl or
(heterocyclo)alkyl any of which may be optionally independently
substituted with one or more OH, SH, OT.sup.6 ST.sup.6,
C(O).sub.tT.sup.6, NT.sup.7T.sup.8, cyano, halo, oxo, alkyl,
haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl,
(OT.sup.6)alkyl, (ST.sup.6)alkyl, (C(O).sub.tT.sup.6)alkyl,
(NT.sup.7T.sup.8)alkyl, (cyano)alkyl, (aryl)alkyl,
(heteroaryl)alkyl or (heterocyclo)alkyl,
[0155] R.sup.5 is optionally substituted alkyl, optionally
substituted cycloalkyl, optionally substituted heteroayl,
optionally substituted aryl or --NR.sup.6aR.sup.7a;
[0156] R.sup.6, R.sup.6a, R.sup.7 and R.sup.7a are independently H,
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, optionally substituted
heterocyclo, optionally substituted (aryl)alkyl, optionally
substituted (heteroaryl)alkyl, optionally substituted
(heterocylco)alkyl, optionally substituted alkyl, or
COR.sup.12;
[0157] or R.sup.6 and R.sup.7, or R.sup.6a and R.sup.7a together
with the nitrogen to which thery are attached combine to form an
optionally substituted saturated or unsaturated 5 to 8 membered
ring; and
[0158] R.sup.4, R.sup.8, R.sup.8a1, R.sup.8c, R.sup.9, R.sup.10,
R.sup.10a, R.sup.11, R.sup.11a, X, Z.sup.1 and W are as defined
above.
DETAILED DESCRIPTION OF THE INVENTION
[0159] The following are definitions of terms used in this
specification. The initial definition provided for a group or term
herein applies to that group or term throughout the present
specification, individually or as part of another group, unless
otherwise indicated.
[0160] The terms "alk" or "alkyl" refer to straight or branched
chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1
to 8 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, etc. Lower
alkyl groups, that is, alkyl groups of 1 to 6 carbon atoms, are
generally most preferred. The term "substituted alkyl" refers to
alkyl groups substituted with one or more groups listed in the
definition of T.sup.1-1g, T.sup.2-2g and T.sup.3-3g, preferably
selected from cyano, halo, oxo, hydroxy, --OT.sup.6,
--C(O).sub.tT.sup.6, --OC(O)T.sup.6, -T.sup.4-NT.sup.7T.sup.8- ,
-T.sup.4-N(T.sup.9)-T.sup.5-T.sup.6, --S(O).sub.tT.sup.6 or
--S(O).sub.tN(T.sup.9)T.sup.6.
[0161] The term "alkenyl" refers to straight or branched chain
hydrocarbon groups having 2 to 12 carbon atoms, preferably 2 to 4
carbon atoms, and at least one double carbon to carbon bond (either
cis or trans), such as ethenyl. The term "substituted alkenyl"
refers to alkenyl groups substituted with one or more groups listed
in the definition of T.sup.1-1g, T.sup.2-2g and T.sup.3-3g,
preferably selected from cyano, halo, oxo, hydroxy, --OT.sup.6,
--C(O).sub.tT.sup.6, --OC(O)T.sup.6, -T.sup.4-NT.sup.7T.sup.8,
-T.sup.4-N(T.sup.9)-T.sup.5-T.sup.6, --S(O).sub.tT.sup.6 or
--S(O).sub.tN(T.sup.9)T.sup.6.
[0162] The term "alkynyl" refers to straight or branched chain
hydrocarbon groups having 2 to 12 carbon atoms, preferably 2 to 4
carbon atoms, and at least one triple carbon to carbon bond, such
as ethynyl. The term "substituted alkynyl" refers to alkynyl groups
substituted with one or more groups listed in the definition of
T.sup.1-1g, T.sup.2-2g and T.sup.3-3g, preferably selected from
cyano, halo, oxo, hydroxy, --OT.sup.6, --C(O).sub.tT.sup.6,
--OC(O)T.sup.6, -T.sup.4-NT.sup.7T.sup.8- ,
-T.sup.4-N(T.sup.9)-T.sup.5-T.sup.6, --S(O).sub.tT or
--S(O).sub.tN(T.sup.9)T.sup.6.
[0163] The term "alkylene" refers to a straight chain bridge of 1
to 4 carbon atoms connected by single bonds (e.g.,
--(CH.sub.2).sub.x-- wherein x is 1 to 5), which may be substituted
with one or more groups listed in the definition of T.sup.1-1g,
T.sup.2-2g and T.sup.3-3g, preferably selected from cyano, halo,
oxo, hydroxy, --OT.sup.6, --C(O).sub.t.sup.6, --OC(O)T.sup.6,
-T.sup.4-NT.sup.7T.sup.8, -T.sup.4-N(T.sup.9)-T.sup.5-T.sup.6,
--S(O).sub.tT.sup.6 or --S(O).sub.tN(T.sup.9)T.sup.6.
[0164] The term "alkenylene" refers to a straight chain bridge of 2
to 5 carbon atoms having one or two double bonds that is connected
by single bonds and may be substituted with one or more groups
listed in the definition of T.sup.1-1g, T.sup.2-2g and T.sup.3-3g,
preferably selected from cyano, halo, oxo, hydroxy, --OT.sup.6,
--C(O).sub.tT.sup.6, --OC(O)T.sup.6, -T.sup.4-NT.sup.7T.sup.8,
-T.sup.4-N(T.sup.9)-T.sup.5-T.s- up.6, --S(O).sub.tT.sup.6 or
--S(O).sub.tN(T.sup.9)T.sup.6. Exemplary alkenylene groups are
--CH.dbd.CH--CH.dbd.CH--, --CH.sub.2--CH.dbd.CH--,
--CH.sub.2--CH.dbd.CH--CH.sub.2--, --C(CH.sub.3).sub.2CH.dbd.CH--
and --CH(C.sub.2H.sub.5)--CH.dbd.CH--.
[0165] The term "alkynylene" refers to a straight chain bridge of 2
to 5 carbon atoms that has a triple bond therein, is connected by
single bonds, and may be substituted with one or more groups listed
in the definition of T.sup.1-1g, T.sup.2-2g and T.sup.3-3g,
preferably selected from cyano, halo, oxo, hydroxy, --OT.sup.6,
--C(O).sub.tT.sup.6, --OC(O)T.sup.6, --T.sup.4-NT.sup.7T.sup.8,
-T.sup.4-N(T.sup.9)-T.sup.5-T.- sup.6, --S(O).sub.tT.sup.6 or
--S(O).sub.tN(T.sup.9)T.sup.6. Exemplary alkynylene groups are
--C.ident.C--, --CH.sub.2--C.ident.C--, --CH(CH.sub.3)--C.ident.C--
and --C.ident.C--CH(C.sub.2H.sub.5)CH.sub.2--- .
[0166] The terms "ar" or "aryl" refer to aromatic homocyclic (i.e.,
hydrocarbon) mono-, bi- or tricyclic ring-containing groups
preferably having 6 to 14 members such as phenyl, naphthyl and
biphenyl, as well as such rings fused to a cycloalkyl,
cycloalkenyl, heterocyclo, or heteroaryl ring. Examples include:
12
[0167] and the like. The term "substituted aryl" refers to aryl
groups substituted with one or more groups listed in the definition
of T.sup.1-1g, T.sup.2-2g and T.sup.3-3g, preferably selected
cyano, halo, oxo, hydroxy, --OT.sup.6, C(O).sub.tT.sup.6,
--OC(O)T.sup.6, -T.sup.4-NT.sup.7T.sup.8,
-T.sup.4-N(T.sup.9)-T.sup.5T.sup.6, --S(O).sub.tT.sup.6 or
--S(O).sub.tN(T.sup.9)T.sup.6.
[0168] The term "cycloalkyl" refers to saturated and partially
unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon
groups containing 1 to 3 rings, including monocyclicalkyl,
bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20
carbons forming the rings, preferably 3 to 7 carbons, forming the
ring and which may be fused to 1 or 2 aromatic or heterocyclo
rings, which include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl,
cyclohexenyl, 13
[0169] and the like. The terms "substituted cycloalkyl" refers to
cycloalkyl groups substituted with one or more groups listed in the
definition of T.sup.1-1g, T.sup.2-2g and T.sup.3-3g preferably
selected from cyano, halo, oxo, hydroxy, --OT.sup.6,
--C(O).sub.tT.sup.6, --OC(O)T.sup.6, -T.sup.4-NT.sup.7T.sup.8,
-T.sup.4-N(T.sup.9)-T.sup.5-T.s- up.6, --S(O).sub.tT.sup.6 or
--S(O).sub.tN(T.sup.9)T.sup.6.
[0170] The terms "halogen" and "halo" refer to fluorine, chlorine,
bromine and iodine.
[0171] The terms "heterocycle", "heterocyclic", "heterocyclic
group" or "heterocyclo" refer to fully saturated or partially or
unsaturated cyclic groups (for example, 3 to 13 member monocyclic,
7 to 17 member bicyclic, or 10 to 20 member tricyclic ring systems,
preferably containing a total of 3 to 10 ring atoms) which have at
least one heteroatom in at least one carbon atom-containing ring.
Each ring of the heterocyclic group containing a heteroatom may
have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen
atoms and/or sulfur atoms, where the nitrogen and sulfur
heteroatoms may optionally be oxidized and the nitrogen heteroatoms
may optionally be substituted or quaternized. The heterocyclic
group may be attached at any heteroatom or carbon atom of the ring
or ring system. The rings of multi-ring heterocycles may be either
fused, bridged and/or joined through one or more spiro unions.
Exemplary heterocyclic groups include 14
[0172] and the like.
[0173] The terms "substituted heterocycle", "substituted
heterocyclic", "substituted heterocyclic group" and "substituted
heterocycle" refer to heterocycle, heterocyclic and heterocyclo
groups substituted with one or more groups listed in the definition
of T.sup.1-1g, T.sup.2-2g and T.sup.3-3g, preferably selected from
cyano, halo, oxo, hydroxy, --OT.sup.6, --C(O).sub.tT.sup.6,
--OC(O)T.sup.6, -T.sup.4-NT.sup.7T.sup.8- ,
-T.sup.4-N(T.sup.9)-T.sup.5-T.sup.6, --S(O).sub.tT.sup.6 or
--S(O).sub.tN(T.sup.9)T.sup.6.
[0174] The term "heteroaryl" as used herein alone or as part of
another group refers to a 5-6- or 7-membered aromatic rings
containing from 1 to 4 nitrogen atoms and/or 1 or 2 oxygen or
sulfur atoms provided that the ring contains at least 1 carbon atom
and no more than 4 heteroatoms. The heteroaryl ring is linked
through an available carbon or nitrogen atom. Also included within
the definition of heteroaryl are such rings fused to a cycloalkyl,
aryl, cycloheteroalkyl, or another heteroaryl ring. One, two, or
three available carbon or nitrogen atoms in the heteroaryl ring can
be optionally substituted with substituents listed in the
description of T.sup.1, T.sub.2 and T.sub.3. Also an available
nitrogen or sulfur atom in the heteroaryl ring can be oxidized.
Examples of heteroaryl rings include 1516
[0175] Throughout the specification, groups and substituents
thereof may be chosen to provide stable moieties and compounds.
[0176] The compounds of formula I form salts which are also within
the scope of this invention. Reference to a compound of the formula
I herein is understood to include reference to salts thereof,
unless otherwise indicated. The term "salt(s)", as employed herein,
denotes acidic and/or basic salts formed with inorganic and/or
organic acids and bases. In addition, when a compound of formula I
contains both a basic moiety and an acidic moiety, zwitterions
("inner salts") may be formed and are included within the term
"salt(s)" as used herein. Pharmaceutically acceptable (i.e.,
non-toxic, physiologically acceptable) salts are preferred,
although other salts are also useful, e.g., in isolation or
purification steps which may be employed during preparation. Salts
of the compounds of the formula I may be formed, for example, by
reacting a compound I with an amount of acid or base, such as an
equivalent amount, in a medium such as one in which the salt
precipitates or in an aqueous medium followed by
lyophilization.
[0177] The compounds of formula I which contain a basic moiety may
form salts with a variety of organic and inorganic acids. Exemplary
acid addition salts include acetates (such as those formed with
acetic acid or trihaloacetic acid, for example, trifluoroacetic
acid), adipates, alginates, ascorbates, aspartates, benzoates,
benzenesulfonates, bisulfates, borates, butyrates, citrates,
camphorates, camphorsulfonates, cyclopentanepropionates,
digluconates, dodecylsulfates, ethanesulfonates, fumarates,
glucoheptanoates, glycerophosphates, hemisulfates, heptanoates,
hexanoates, hydrochlorides (formed with hydrochloric acid),
hydrobromides (formed with hydrogen bromide), hydroiodides,
2-hydroxyethanesulfonates, lactates, maleates (formed with maleic
acid), methanesulfonates (formed with methanesulfonic acid),
2-naphthalenesulfonates, nicotinates, nitrates, oxalates,
pectinates, persulfates, 3-phenylpropionates, phosphates, picrates,
pivalates, propionates, salicylates, succinates, sulfates (such as
those formed with sulfuric acid), sulfonates (such as those
mentioned herein), tartrates, thiocyanates, toluenesulfonates such
as tosylates, undecanoates, and the like.
[0178] The compounds of formula I which contain an acidic moiety
may form salts with a variety of organic and inorganic bases.
Exemplary basic salts include ammonium salts, alkali metal salts
such as sodium, lithium, and potassium salts, alkaline earth metal
salts such as calcium and magnesium salts, salts with organic bases
(for example, organic amines) such as benzathines,
dicyclohexylamines, hydrabamines (formed with
N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,
N-methyl-D-glucamides, t-butyl amines, and salts with amino acids
such as arginine, lysine and the like.
[0179] Basic nitrogen-containing groups may be quaternized with
agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and
butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain
halides (e.g. decyl, lauryl, myristyl and stearyl chlorides,
bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl
bromides), and others.
[0180] Prodrugs and solvates of the compounds of the invention are
also contemplated herein. The term "prodrug", as employed herein,
denotes a compound which, upon administration to a subject,
undergoes chemical conversion by metabolic or chemical processes to
yield a compound of the formula I, or a salt and/or solvate
thereof. Solvates of the compounds of formula I are preferably
hydrates.
[0181] To the extent that compounds of the formula I, and salts
thereof, may exist in their tautomeric form, all such tautomeric
forms are contemplated herein as part of the present invention.
[0182] All stereoisomers of the present compounds, such as those
which may exist due to asymmetric carbons on the various R and Z
substituents, including enantiomeric forms (which may exist even in
the absence of asymmetric carbons) and diastereomeric forms, are
contemplated within the scope of this invention. Individual
stereoisomers of the compounds of the invention may, for example,
be substantially free of other isomers, or may be admixed, for
example, as racemates or with all other, or other selected,
stereoisomers. The chiral centers of the present invention can have
the S or R configuration as defined by the IUPAC 1974
Recommendations.
[0183] The terms "including", "such as", "for example" and the like
are intended to refer to exemplary embodiments and not to limit the
scope of the present invention.
[0184] Schemes
[0185] Compounds of the formula I may be prepared using the
sequence of steps outlined below. Specifically, compounds of the
formula I where R1 is --O--CO--NR.sup.6R.sup.7, R.sup.2 is aryl,
substituted aryl or heteroaryl and -J-R.sup.3 is
--CH.sub.2--NH--CO--R.sup.5 may be prepared using Scheme 1. 17
[0186] Bis Michael addition to acetonitrile 2 and subsequent
Dieckmann condensation yields the intermediate cyclohexyl
.beta.-keto ester 4. Krapcho decarboxylation to the ketone followed
by ketone protection and reduction of the nitrile 6 generates the
primary amine 7. The amine is subsequently acylated, deprotected
and the resulting ketone 9 reduced. The cis and trans alcohols may
be separated and taken on to final product esters and
carbamates.
[0187] Compounds of the formula I where R.sup.1 is
--NR.sup.8--C(NCN)--NR.- sup.6R.sup.7, R.sup.2 is aryl, substituted
aryl or heteroaryl and -J-R.sup.3 is --CH.sub.2--NH--CO--R.sup.5
may be prepared using Scheme 2. 18
[0188] Protection of the ketone moiety of commercially available
compound 1, followed by reduction of nitrile with LAH provides the
amine 3. The amine is acylated and the ketal moiety deprotected to
provide the ketone 4. Reductive amination produces the amine 5.
Compounds of formula 6 may be prepared by displacement of phenoxy
group from diphenyl cyanourea. Warming 6 and an amine at
60-75.degree. C. in alcoholic solvents provides the compound 7.
[0189] Alternatively, compounds of the formula I where R.sup.1 is
--NR.sup.8--C(NCN)--NR.sup.6R.sup.7, R is aryl, substituted aryl or
heteroaryl and -J-R3 is --CH.sub.2--NH--CO--R.sup.5 may be prepared
using Scheme 3. 19
[0190] Compound 1 used in this preparation is readily prepared from
commercially available reagents by the methods well known to those
skilled in the art. Assembly of substituted cyclohexyl
cyanoguanidines such as compound 3 can be done using methodology
described in Scheme 2. Hydrolysis of the TFA protecting group and
acylation of the amine 4 may provide the compounds of formula
5.
[0191] Compounds of the formula I where R.sup.1 is
--NH--SO.sub.2--NR.sup.- 6R.sup.7, R.sup.2 is aryl, substituted
aryl or heteroaryl and -J-R.sup.3 is --CH.sub.2--NH--CO--R.sup.5
may be prepared using Scheme 4. 20
[0192] The amine 1 may be converted to the corresponding sulfonyl
oxazolidine in a way described in the literature (Dewynter, G., et
als. Tetrahedron, 1996, 52, 14217-14224). Compounds of formula 3
may be prepared by displacement reaction of oxazolidine 2 with
amines at temperature of 65-75.degree. C. in alcholic solvents such
as ethanol and isopropanol.
[0193] Compounds of the formula I where R.sup.1 is
--NH--C(.dbd.NCO.sub.2R- .sup.8)--NR.sup.6R.sup.7, R.sup.2 is aryl,
substituted aryl or heteroaryl and -J-R.sup.3 is
--CH.sub.2--NH--CO--R.sup.5 may be prepared using Scheme 5. 21
[0194] Treatment of the amine 1 with isothiocyanoformate may
provide the thiourea 2, which would provide the compounds of
formula 3 by the coupling with the amine in the presence of
EDCI.
[0195] Compounds of the formula I where R.sup.1 is a hydantoin
heterocycle, R.sup.2 is aryl, substituted aryl or heteroaryl and
-J-R.sup.3 is --CH.sub.2--NH--CO--R.sup.5 may be prepared using
Scheme 6. 22
[0196] The isocyanate 2 could be obtained upon treating the amine 1
with phosgene. Treatment of the isocyanate 2 with substituted
aminoester at 65-75.degree. C. in alcoholic solvents such as
ethanol or isopropanol can provide the compounds of formula 3.
[0197] Alternatively, compounds of formula 3 could be obtained by
treating the amine 1 with substituted isocyanoactate in proper
solvents such as dichloromethane or THF, followed by ring closure
under acidic conditions according to Scheme 7. 23
[0198] Compounds of the formula I where R.sup.1 is an
imidazolidine-2-one heterocycle, R.sup.2 is aryl, substituted aryl
or heteroaryl and -J-R.sup.3 is --CH.sub.2--NH--CO--R.sup.5 may be
prepared using Scheme 8. 24
[0199] Reductive amination of the ketone 1 with the substituted
ethylenediamine 2 may provide cyclohexylamine 3. The amine 3 can be
converted to the corresponding cyclic ureas of formula 5 upon
treatment with carbonyl diimidazole 4 in a solvent such as THF or
dichloromethane.
[0200] Compounds of the formula I where R.sup.1 is an
imidazolidine-2-ylidine cyanamide heterocycle, R.sup.2 is aryl,
substituted aryl or heteroaryl and -J-R.sup.3 is
--CH.sub.2--NH--CO--R.su- p.5 may be prepared using Scheme 9.
25
[0201] The same intermediate 1 from Scheme 7 may produce the
compounds of formula 3 upon treating it with diphenyl
cyanocarbonidate 2 at temperature of 65-75.degree. C. in alcholic
solvents such as ethanol or isopropanol.
[0202] Compounds of the formula I where -J-R.sup.3 is
--CH.sub.2--NH--R.sup.6 where R6 is aryl or heteroaryl may be
prepared using Scheme 10. 26
[0203] The intermediate 1 may react with a substituted aryl or
heteroaryl compound where X is Cl, Br, I, OTf or similar leaving
group in the presence of a palladium catalyst such as
Pd.sub.2(dba).sub.3 to produce compound 2.
[0204] Compounds of the formula I where -J-R.sup.3 is
--CONR.sup.6R.sup.7 may be prepared using Scheme 11 27
[0205] The carboxylic acid 1 may be made to react with amine
HNR.sup.6R.sup.7 using a variety of standard coupling procedures
known in the literature to give amide compounds of formula 2.
Activation of the carboxylic acid by conversion to the carboxylic
acid chloride or carboxylic acid fluoride in a solvent such as
methylene chloride or acetonitrile followed by reaction with an
amine in the presence of a base such as triethylamine or pyridine
is a particularly useful coupling procedure.
[0206] Compounds of the formula I where R.sup.1 is
--O--CO--NR.sup.6R.sup.- 7, and -J-R.sup.3 is a heterocycle, for
example oxadiazole, can be prepared using Scheme 12. 28
[0207] Nitrile 1 may be made to react with hydoxylamine in an
organic solvent such as n-propanol to give carboxamidine 2.
Carboxamidine 2 may be acylated with a variety of carboxylic acids,
carboxylic acid chlorides or carboxylic acid fluorides using
standard coupling procedures and the resulting intermediates may be
made to undergo cyclization upon heating to give 1,2,4-oxadiazole
3. Deprotection of the ketal group of the 1,2,4-oxadiazole 3
followed by reduction of the ketone using a reducing agent such
sodium borohydride in an organic solvent such as tetrahydrofuran
gives hydroxy compound 4. The hydroxy compound 4 may be converted
to the carbamate 5 by first reacting the hydroxy derivative with
4-nitrophenyl chloroformate to obtain the carbonate intermediate
which is then reacted with an amine to form the carbamate.
[0208] Compounds of the formula I where R1 is
--O--CO--NR.sup.6R.sup.7, and -J-R3 is a heterocycle, for example
tetrazole, can be prepared using Scheme 13. 29
[0209] Nitrile 1 may be made to react with sodium azide in a
organic solvent such as N,N-dimethylformamide at elevated
temperatures to form the tetrazole 2. The tetrazole 2 may be
alkylated by treatment with an alkyl halide in the presence of a
base such as potassium carbonate in an organic solvent such as
aceteonitrile. Deprotection of the ketal group of the alkylated
tetrazole 3 followed by reduction of the ketone using a reducing
agent such sodium borohydride in an organic solvent such as
tetrahydrofuran gives the hydroxy compound 4. The hydroxy compound
4 may be converted to the carbamate 5 by first reacting the hydroxy
derivative with 4-nitrophenyl chloroformate to obtain the carbonate
intermediate which is then reacted with an amine to form the
carbamate.
[0210] Compounds of the formula I where -J-R.sup.3 is a
heterocycle, for example 3H-quinazolin-4-one, can be prepared using
Scheme 14. 30
[0211] The carboxylic acid 1 may react with an anthranilic acid
using a variety of standard coupling procedures known in the
literature to give amide compound 2. Cyclization of compound 2
under basic conditions in an organic solvent such as ethanol at
elevated temperatures would give compounds of formula 3.
[0212] Compounds of the formula I where -J-R.sup.3 is a
heterocycle, for example benzoxazole, can be prepared using Scheme
15. 31
[0213] The carboxylic acid 1 may be made to react with a
2-aminophenol derivative using a variety of standard coupling
procedures known in the literature to give amide compound 2.
Cyclization of compound 2 under acidic conditions in an organic
solvent such as p-xylene at elevated temperatures would give
compounds of formula 3
[0214] Compounds of the formula I where -J-R.sup.3 is a
heterocycle, for example benzimidazole, can be prepared using
Scheme 16. 32
[0215] The carboxylic acid 1 may be made to react with an
o-phenylenediamine derivative using a variety of standard coupling
procedures known in the literature to give amide compound 2.
Cyclization of compound 2 under acidic conditions in a solvent such
as acetic acid at elevated temperatures would give compounds of
formula 3.
[0216] Compounds of the formula I where -J-R.sup.3is
--CO--NR.sup.6aR.sup.7a and R.sup.1 is --O--CO--NR.sup.6R.sup.7 can
be prepared using Scheme 17. 33
[0217] The nitrile 1 may be converted to the carboxylic acid 2 by
treatment with a base such as sodium hydroxide in a solvent such as
ethylene glycol at elevated temperatures. The carboxylic acid 2 may
be made to react with an amine HNR.sup.6aR.sup.7a using a variety
of standard coupling procedures known in the literature to give
amide compounds 3. Deprotection of the ketal group of the amide 3
followed by reduction of the ketone using a reducing agent such as
sodium borohydride in an organic solvent such as tetrahydrofuran
gives the hydroxy compound 4. The hydroxy compound 4 may be
converted to the carbamate of formula 5 by first reacting the
hydroxy derivative 4 with 4-nitrophenyl chloroformate to obtain the
carbonate intermediate which is then reacted with HNR.sup.6R.sup.7
to form the carbamate.
[0218] Compounds of the formula I where -J-R.sup.3 is
--CO--NR.sup.6aR.sup.7a and R.sup.1 is --NR.sup.8--CO--R.sup.4 can
be prepared using Scheme 18. 34
[0219] The carboxylic acid 1 may be made to react with an amine
HNR.sup.6aR.sup.7a using a variety of standard coupling procedures
known in the literature to give amide compounds 2. Deprotection of
the ketal group of the amide 2 followed by reductive amination of
the ketone by first treating the ketone with amine H.sub.2NR.sup.8
to form the imine intermediate followed by reduction of the imine
with a reducing agent such as and sodium cyanoborohydride in an
organic solvent such as methanol gives the amino compound 3. The
amino compound 3 may be made to react with a carboxylic acid
R.sup.4CO.sub.2H using a variety of standard coupling procedures to
give compound 4.
[0220] Compounds of the formula I where -J-R.sup.3 is
--CONR.sup.6aR.sup.7a and R.sup.1 is
--NR.sup.8--C(NCN)--NR.sup.6R.sup.7 can be prepared using Scheme
19. 35
[0221] Amine 1 may react with diphenylcyanocarbonimidate in a
solvent such as acetonitrile at elevated temperature to give an
intermediate 2 which can further react with amine HNR.sup.6R.sup.7
to give compound 3.
[0222] Compounds of formula I wherein -J-R.sup.3 is an
(amino)methyl group may be prepared using methodology such as that
described in Example 323 or the following schemes 20 and 21. 36
[0223] Additional compounds within the scope of the present
invention can be prepared from the compounds obtained by the above
described methods through conversion of the substituent groups to
other functionality by the usual methods of chemical synthesis, as
illustrated in the following examples.
[0224] Compounds of formula I that contain chiral centers may be
obtained in non-racemic form by non-racemic synthesis or resolution
by methods well known to those skilled in the art. Compounds that
are non-racemic are designated as "chiral" in the examples.
[0225] In the examples described below it may be necessary to
protect reactive functionality such as hydroxy, amino, thio or
carboxy groups, where these are desired in the final product, to
avoid their unwanted participation in reactions. The introduction
and removal of protecting groups are well known to those skilled in
the art, for example see (Green, T. W. in "Protective Groups in
Organic Synthesis", John Wiley and Sons, 1991).
[0226] Utility
[0227] Compounds within the scope of the present invention inhibit
the K.sub.v1 subfamily of voltage-gated K.sup.+ channels, and as
such are useful in the treatment and/or prevention of various
disorders: cardiac arrhythmias, including supraventricular
arrhythmias, atrial arrhythmias, atrial flutter, atrial
fibrillation, complications of cardiac ischemia, and use as heart
rate control agents; angina pectoris including relief of
Prinzmetal's symptoms, vasospastic symptoms and variant symptoms;
gastrointestinal disorders including reflux esauphagitis,
functional dispepsia, motility disorders (including constipation
and diarrhea), and irritable bowel syndrome; disorders of vascular
and visceral smooth muscle including asthma, chronic obstructive
pulmonary disease, adult respiratory distress syndrome, peripheral
vascular disease (including intermittent claudication), venous
insufficiency, impotence, cerebral and coronary spasm and Raynaud's
disease; inflammatory and immunological disease including
inflammatory bowel disease, rheumatoid arthritis, graft rejection,
asthma, chronic obstructive pulmonary disease, cystic fibrosis and
atherosclerosis; cell poliferative disorders including restenosis
and cancer (including leukemia); disorders of the auditory system;
disorders of the visual system including macular degeneration and
cataracts; diabetes including diabetic retinopathy, diabetic
nephropathy and diabetic neuropathy; muscle disease including
myotonia and wasting; peripheral neuropathy; cognitive disorders;
migraine; memory loss including Alzheimer's and dementia; CNS
mediated motor dysfunction including Parkinson's disease, and
ataxia; epilepsy; and other ion channel mediated disorders.
[0228] As inhibitors of the K.sub.v1 subfamily of voltage-gated
K.sup.+ channels compounds of the present invention are useful to
treat a variety of disorders including resistance by
transplantation of organs or tissue, graft-versus-host diseases
brought about by medulla ossium transplantation, rheumatoid
arthritis, systemic lupus erythematosus, hashimoto's thyroiditis,
multiple sclerosis, myasthenia gravis, type I diabetes uveitis,
juvenile-onset or recent-onset diabetes mellitus, posterior
uveitis, allergic encephalomyelitis, glomerulonephritis, infectious
diseases caused by pathogenicmicroorganisms, inflammatory and
hyperproliferative skin diseases, psoriasis, atopical dermatitis,
contact dermatitis, eczematous dermatitises, seborrhoeis
dermatitis, lichen planus, pemphigus, bullous pemphigoid,
epidermolysis bullosa, urticaria, angioedemas, vasculitides,
erythemas, cutaneous eosinophilias, Lupus erythematosus, acne,
alopecia areata, keratoconjunctivitis, vernal conjunctivitis,
uveitis associated with Behcet's disease, keratitis, herpetic
keratitis, conical cornea, dystrophia epithelialis corneae, corneal
leukoma, ocular pemphigus, Mooren's ulcer scleritis, Graves'
opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen
allergies, reversible obstructive airway disease, bronchial asthma,
allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma,
chronic or inveterate asthma, late asthma and airway
hyper-responsiveness, bronchitis, gastric ulcers, vascular damage
caused by ischemic diseases and thrombosis, ischemic bowel
diseases, inflammatory bowel diseases, necrotizing enterocolitis,
intestinal lesions associated with thermal burns and leukotriene
B.sub.4-mediated diseases, Coeliaz diseases, proctitis,
eosinophilic gastroenteritis, mastocytosis, Crohn's disease,
ulcerative colitis, migraine, rhinitis, eczema, interstitial
nephritis, Good-pasture's syndrome, hemolytic-uremic syndrome,
diabetic nephropathy, multiple myositis, Guillain-Barre syndrome,
Meniere's disease, polyneuritis, multiple neuritis, mononeuritis,
radiculopathy, hyperthroidism, Basedow's disease, pure red cell
aplasia, aplastic anemia, hypoplastic anemia, idiopathic
thrombocytopenic purpura, autoimmune hemolytic anemia,
agranulocytosis, pernicious anemia, megaloblastic anemia,
anerythroplasia; osteoporosis, sarcoidosis, fibroid lung, idopathic
interstitial pneumonia, dermatomyositis, leukoderma vulgaris,
ichthyosis vulgaris, photoallergic sensitivity, cutaneous T cell
lymphoma, arteriosclerosis, atherosclerosis, aortitis syndrome,
polyarteritis nodosa, myocardosis, scleroderma, Wegener's
granuloma, Sjogren's syndrome, adiposis, eosinophilic fascitis,
lesions of gingiva, periodontium, alveolar bone, substantia osses
dentis, glomerulonephritis, male pattern alopecia or alopecia
senilis by preventing epilation or providing hair germination
and/or promoting hair generation and hair growth, muscular
dystrophy; Pyoderma and Sezary's syndrome, Addison's disease,
ischemia-reperfusion injury of organs which occurs upon
preservation, transplantation or ischemic disease, endotoxin-shock,
pseudomembranous colitis, colitis caused by drug or radiation,
ischemic acute renal insufficiency, chronic renal insufficiency,
toxinosis caused by lung-oxygen or drugs, lung cancer, pulmonary
emphysema, cataracta, siderosis, retinitis, pigentosa, senile
macular degeneration, vitreal scarring, corneal alkali burn,
dermatitis erythema multiforme, linear IgA ballous dermatitis and
cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis,
diseases caused by environmental pollution, aging, carcinogenis,
metastatis of carcinoma and hypobaropathy, disease caused by
histamine or leukotriene-C.sub.4 release, Behcet's disease,
autoimmune hepatitis, primary biliary cirrhosis sclerosing
cholangitis, partial liver resection, acute liver necrosis,
necrosis caused by toxin, viral hepatitis, shock, or anoxia,
B-virus hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholic
cirrhosis, hepatic failure, fulminant hepatic failure, late-onset
hepatic failure, "acute-on-chronic" liver failure, augention of
chemotherapeutic effect, cytomegalovirus infection, HCMV infection,
AIDS, cancer, senile dementia, trauma, and chronic bacterial
infection.
[0229] The compounds of the present invention are antiarrhythmic
agents which are useful in the prevention and treatment (including
partial alleviation or cure) of arrhythmias. As inhibitors of
K.sub.v1.5 compounds within the scope of the present invention are
particularly useful in the selective prevention and treatment of
supraventricular arrhythmias such as atrial fibrillation, and
atrial flutter. By "selective prevention and treatment of
supraventricular arrhythmias" is meant the prevention or treatment
of supraventricular arrhythmias wherein the ratio of the
prolongation of the atrial effective refractory period to the
prolongation of the ventricular effective refractory period is
greater than 1:1. This ratio is preferably greater than 4:1, more
preferably greater than 10:1, and most preferably such that
prolongation of the atrial effective refractory response period is
achieved without significantly detectable prolongation of the
ventricular effective refractory period.
[0230] In addition, the compounds within the scope of the present
invention block I.sub.Kur, and thus may be useful in the prevention
and treatment of all I.sub.Kur-associated conditions. An
"I.sub.Kur-associated condition" is a disorder which may be
prevented, partially alleviated or cured by the administration of
an I.sub.Kur blocker. The Kv1.5 gene is known to be expressed in
stomach tissue, intestinal/colon tissue, the pulmonary artery, and
pancreatic beta cells. Thus, administration of an I.sub.Kur blocker
could provide useful treatment for disorders such as: reflux
esauphagitis, functional dispepsia, constipation, asthma, and
diabetes. Additionally, Kv1.5 is known to be expressed in the
anterior pituitary. Thus, administration of an I.sub.Kur blocker
could stimulate growth hormone secretion. I.sub.Kur inhibitors can
additionally be useful in cell poliferative disorders such as
leukemia, and autoimmune diseases such as rheumatoid arthritis and
transplant rejection.
[0231] The present invention thus provides methods for the
prevention or treatment of one or more of the aforementioned
disorders, comprising the step of administering to a subject in
need thereof an effective amount of at least one compound of the
formula I. Other therapeutic agents such as those described below
may be employed with the inventive compounds in the present
methods. In the methods of the present invention, such other
therapeutic agent(s) may be administered prior to, simultaneously
with or following the administration of the compound(s) of the
present invention.
[0232] The present invention also provides pharmaceutical
compositions comprising at least one of the compounds of the
formula I or salts thereof capable of preventing or treating one or
more of the aforementioned disorders in an amount effective
therefor, and a pharmaceutically acceptable vehicle or diluent. The
compositions of the present invention may contain other therapeutic
agents as described below, and may be formulated, for example, by
employing conventional solid or liquid vehicles or diluents, as
well as pharmaceutical additives of a type appropriate to the mode
of desired administration (for example, excipients, binders,
preservatives, stabilizers, flavors, etc.) according to techniques
such as those well known in the art of pharmaceutical
formulation.
[0233] The compounds of the formula I may be administered by any
suitable means, for example, orally, such as in the form of
tablets, capsules, granules or powders; sublingually; bucally;
parenterally, such as by subcutaneous, intravenous, intramuscular,
or intrasternal injection or infusion techniques (e.g., as sterile
injectable aqueous or non-aqueous solutions or suspensions);
nasally such as by inhalation spray; topically, such as in the form
of a cream or ointment; or rectally such as in the form of
suppositories; in dosage unit formulations containing non-toxic,
pharmaceutically acceptable vehicles or diluents. The present
compounds may, for example, be administered in a form suitable for
immediate release or extended release. Immediate release or
extended release may be achieved by the use of suitable
pharmaceutical compositions comprising the present compounds, or,
particularly in the case of extended release, by the use of devices
such as subcutaneous implants or osmotic pumps. In the case where
the compounds of formula I are being administered to prevent or
treat arrhythmias, the compounds may be administered to achieve
chemical conversion to normal sinus rhythm, or may optionally be
used in conjunction with electrical cardioconversion.
[0234] Exemplary compositions for oral administration include
suspensions which may contain, for example, microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweeteners or flavoring agents such as those known in the art; and
immediate release tablets which may contain, for example,
microcrystalline cellulose, dicalcium phosphate, starch, magnesium
stearate and/or lactose and/or other excipients, binders,
extenders, disintegrants, diluents and lubricants such as those
known in the art. The compounds of formula I may also be delivered
through the oral cavity by sublingual and/or buccal administration.
Molded tablets, compressed tablets or freeze-dried tablets are
exemplary forms which may be used. Exemplary compositions include
those formulating the present compound(s) with fast dissolving
diluents such as mannitol, lactose, sucrose and/or cyclodextrins.
Also included in such formulations may be high molecular weight
excipients such as celluloses (avicel) or polyethylene glycols
(PEG). Such formulations may also include an excipient to aid
mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy
propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose
(SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to
control release such as polyacrylic copolymer (e.g., Carbopol 934).
Lubricants, glidants, flavors, coloring agents and stabilizers may
also be added for ease of fabrication and use.
[0235] Exemplary compositions for nasal aerosol or inhalation
administration include solutions in saline which may contain, for
example, benzyl alcohol or other suitable preservatives, absorption
promoters to enhance bioavailability, and/or other solubilizing or
dispersing agents such as those known in the art.
[0236] Exemplary compositions for parenteral administration include
injectable solutions or suspensions which may contain, for example,
suitable non-toxic, parenterally acceptable diluents or solvents,
such as mannitol, 1,3-butanediol, water, Ringer's solution, an
isotonic sodium chloride solution, or other suitable dispersing or
wetting and suspending agents, including synthetic mono- or
diglycerides, and fatty acids, including oleic acid.
[0237] Exemplary compositions for rectal administration include
suppositories which may contain, for example, a suitable
non-irritating excipient, such as cocoa butter, synthetic glyceride
esters or polyethylene glycols, which are solid at ordinary
temperatures, but liquify and/or dissolve in the rectal cavity to
release the drug.
[0238] Exemplary compositions for topical administration include a
topical carrier such as Plastibase (mineral oil gelled with
polyethylene).
[0239] The effective amount of a compound of the present invention
may be determined by one of ordinary skill in the art, and includes
exemplary dosage amounts for an adult human of from about 0.001 to
100 mg/kg of body weight of active compound per day, which may be
administered in a single dose or in the form of individual divided
doses, such as from 1 to 4 times per day. It will be understood
that the specific dose level and frequency of dosage for any
particular subject may be varied and will depend upon a variety of
factors including the activity of the specific compound employed,
the metabolic stability and length of action of that compound, the
species, age, body weight, general health, sex and diet of the
subject, the mode and time of administration, rate of excretion,
drug combination, and severity of the particular condition.
Preferred subjects for treatment include animals, most preferably
mammalian species such as humans, and domestic animals such as
dogs, cats and the like, subject to the aforementioned
disorders.
[0240] The compounds of the present invention may be employed alone
or in combination with each other and/or other suitable therapeutic
agents useful in the treatment of the aforementioned disorders or
other disorders, including: other antiarrhythmic agents such as
Class I agents (e.g., propafenone), Class II agents (e.g.,
carvadiol and propranolol), Class III agents (e.g., sotalol,
dofetilide, amiodarone, azimilide and ibutilide), Class IV agents
(e.g., diltiazem and verapamil), 5HT antagonists (e.g., sulamserod,
serraline and tropsetron), and dronedarone; calcium channel
blockers (both L-type and T-type) such as diltiazem, verapamil,
nifedipine, amlodipine and mybefradil; Cyclooxygenase inibitors
(i.e., COX-1 and/or COX-2 inhibitors) such as aspirin,
indomethacin, ibuprofen, piroxicam, naproxen, celebrex, vioxx and
NSAIDs; anti-platelet agents such as GPIIb/EIIIa blockers (e.g.,
abciximab, eptifibatide and tirofiban), P2Y.sub.12 antagonists
(e.g., clopidogrel, ticlopidine and CS-747), thromboxane receptor
antagonists (e.g., ifetroban), aspirin, and PDE-III inhibitors
(e.g., dipyridamole) with or without aspirin; diruetics such as
chlorothiazide, hydrochlorothiazide, flumethiazide,
hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,
trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid
tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide,
triamtrenene, amiloride, and spironolactone; anti-hypertensive
agents such as alpha adrenergic blockers, beta adrenergic blockers,
calcium channel blockers, diuretics, renin inhibitors, ACE
inhibitors, (e.g., captropril, zofenopril, fosinopril, enalapril,
ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril,
lisinopril), A II antagonists (e.g., losartan, irbesartan,
valsartan), ET antagonists (e.g. sitaxsentan, atrsentan and
compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265),
Dual ET/AII antagonist (e.g., compounds disclosed in WO 00/01389),
neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors
(dual NEP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat),
nitrates, and combinations of such anti-hypertensive agents;
antithrombotic/thrombolyti- c agents such as tissue plasminogen
activator (tPA), recombinant tPA, tenecteplase (TNK), lanoteplase
(nPA), factor VIIa inhibitors, factor Xa inhibitors, thromin
inibitors (e.g., hirudin and argatroban), PAI-1 inhibitors (i.e.,
inactivators of tissue plasminogen activator inhibitors),
a2-antiplasmin inhibitors, streptokinase, urokinase, prourokinase,
anisoylated plasminogen streptokinase activator complex, and animal
or salivary gland plasminogen activators; anticoagulants such as
warfarin and heparins (including unfractionated and low molecular
weight heparins such as enoxaparin and dalteparin); HMG-CoA
reductase inhibitors such as pravastatin lovastatin, atorvastatin,
simvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or
nisbastatin) and ZD-4522 (a.k.a. rosuvastatin, or atavastatin or
visastatin); other cholesterol/lipid lowering agents such as
squalene synthetase inhibitors, fibrates, and bile acid
sequestrants (e.g., questran); antipoliferative agents such as
cyclosporin A, taxol, FK 506, and adriamycin; antitumor agents such
as taxol, adriamycin, epothilones, cisplatin and carboplatin;
anti-diabetic agents such as biguanides (e.g. metformin),
glucosidase inhibitors (e.g. acarbose), insulins, meglitinides
(e.g. repaglinide), sulfonylureas (e.g. glimepiride, glyburide and
glipizide), biguanide/glyburide combinations (i.e,. glucovance),
thiozolidinediones (e.g. troglitazone, rosiglitazone and
pioglitazone), PPAR-gamma agonists, aP2 inhibitors, and DP4
inhibitors; thyroid mimetics (including thyroid receptor
antagonists) (e.g., thyrotropin, polythyroid, KB-130015, and
dronedarone); Mineralocorticoid receptor antagonists such as
spironolactone and eplerinone; growth hormone secretagogues;
anti-osteoporosis agents (e.g., alendronate and raloxifene);
hormone replacement therapy agents such as estrogen (including
conjugated estrogens in premarin), and estradiol; antidepressants
such as nefazodone and sertraline; antianxiety agents such as
diazepam, lorazepam, buspirone, and hydroxyzine pamoate; oral
contraceptives; anti-ulcer and gastroesophageal reflux disease
agents such as famotidine, ranitidine, and omeprazole; anti-obesity
agents such as orlistat; cardiac glycosides including digitalis and
ouabain; phosphodiesterase inibitors including PDE III inhibitors
(e.g. cilostazol), and PDE V inhibitors (e.g., sildenafil); protein
tyrosine kinase inhibitors; steroidal anti-inflammatory agents such
as prednisone, and dexamethasone; and other anti-inflammatory
agents such as enbrel.
[0241] The above other therapeutic agents, when employed in
combination with the compounds of the present invention, may be
used, for example, in those amounts indicated in the Physicians'
Desk Reference (PDR) or as otherwise determined by one of ordinary
skill in the art.
[0242] Assays to determine the degree of activity of a compound as
an I.sub.Kur inhibitor are well known in the art and are described
in references such as J. Gen. Physiol. April;101(4):513-43, and Br.
J. Pharnacol. May 1995;115(2):267-74.
[0243] Assays to determine the degree of activity of a compound as
an inhibitor of other members of the K.sub.v1 subfamily are also
well known in the art. For example, inhibition of K.sub.v1.1,
K.sub.v1.2 and K.sub.v1.3 can be measured using procedures
described by Grissmer S, et al., Mol Pharmacol June
1994;45(6):1227-34. Inhibition of Kv1.4 can be measured using
procedures described by Petersen K R, and Nerbonne J M, Pflugers
Arch February 1999;437(3):381-92. Inhibition of Kv1.6 can be
measured using procedures described by Bowlby M R, and Levitan I B,
J Neurophysiol June 1995;73(6):2221-9. And inhibition of Kv1.7 can
be measured using procedures described by Kalman K, et al., J Biol
Chem Mar. 6, 1998;273(10):5851-7.
[0244] Compounds within the scope of the present invention
demonstrate activity in K.sub.v1 assays such as the ones described
above.
[0245] All documents cited in the present specification are
incorporated herein by reference in their entirety.
[0246] The following examples and preparations describe the manner
and process of making and using the invention and are illustrative
rather than limiting. It is to be understood that there may be
other embodiments which fall within the spirit and scope of the
invention as defined by the claims appended hereto.
EXAMPLE 1
[0247] 37
[0248] Cis and
Trans-N-(4-Hydroxy-1-thiophen-2-yl-cyclohexylmethyl)-2-meth-
oxy-benzamide
[0249] Synthesis: 3839
[0250] Compound 2: Triton B (0.19 mL, 40% by weight solution in
methanol, 0.42 mmol) was added to a solution of 2-thiophene
acetonitrile (500 mg, 4.06 mmol) in acetonitrile (27 mL) at room
temperature. The reaction mixture was heated under nitrogen to
95.degree. C. and methylacrylate (3.6 mL, 40 mmol) was added slowly
(vigorous exotherm). After 5 h, the reaction mixture was allowed to
cool and diluted with 50 mL of ether. The solution was transferred
to a separation funnel and washed successively with HCl (1N,
2.times.20 mL) and saturated NaCl (1.times.20 mL). The organic
portion was dried over anhydrous Na.sub.2SO.sub.4, decanted and
concentrated yielding 1.10 g (92% crude yield) of 2 as a dark brown
oil .sup.1H NMR (CDCl.sub.3) 2.2 ppm, 2H, multiplet; 2.3 ppm, 2H,
multiplet; 2.4 ppm, 2H, multiplet; 3.65 ppm, 6H, singlet; 6.97 ppm,
1H, dd, J=3.6 and 6.2 Hz; 7.13 ppm, 1H, dd, J=1.2 and 3.6 Hz; 7.32
ppm, 1H, dd, J=1.2 and 5.1 Hz.
[0251] Compound 3: Compound 2 (1.10 g, 3.72 mmol) was dissolved in
anhydrous dimethylethylene glycol (20 mL). Sodium hydride (60%
dispersion in mineral oil, 360 mg, 11.2 mmol) was added slowly to
the solution and the resulting brown slurry was heated under
nitrogen to 95.degree. C. for 4.5 h then allowed to cool overnight
(12 h). The slurry was poured carefully into 15 mL of water and
diluted with 100 mL ether. The organic portion was washed with HCl
(3.7N, 2.times.20 mL), dried over anhydrous Na.sub.2SO.sub.4,
decanted and concentrated yielding a brown oil. The crude oil was
purified by silica gel flash chromatography elution with 3:1
hexane:ethylacetate yielding 298 mg (31% isolated yield) of 3 as a
pale brown oil. HPLC Rt 3.10 min, Purity 100%, YMC S5 column
4.6.times.50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2%
H.sub.3PO.sub.4) UV detection at 220 nm. LCMS Rt 1.61 min, [M+Na]
286.10 YMC S5 column 4.6.times.30 mm, 2 min gradient 0 to 100% MeOH
(90% in water, 0.1% TFA) UV detection at 220 nm. .sup.1H NMR
(CDCl.sub.3) 2.2 ppm, 2H, multiplet; 2.4 ppm, 2H, multiplet; 2.7
ppm, 2H, multiplet; 2.75 ppm, 1H, d, J=13.6 Hz; 3.15ppm, 1H, d,
J=15.0 Hz; 7.00 ppm, 1H, dd, J=3.6 and 5.1 Hz; 7.18 ppm, 1H, dd,
J=1.2 and 3.6 Hz; 7.29 ppm, 1H, dd, J=1.2 and 5.2 Hz; 12.2 ppm, 1H,
singlet.
[0252] Compound 4: To a solution of .beta.-keto ester 3 (298 mg,
1.13 mmol) in DMSO (8 mL containing 0.5 mL water) was added NaCl
(420 mg, 7.24 mmol). The reaction mixture was heated to 150.degree.
C. for 5 h then allowed to cool to ambient temperature. The
solution was diluted with 1:1 ether:ethylacetate (50 mL),
transferred to a separation funnel and washed with 10% LiCl
(3.times.20 mL). The organic portion was dried over anhydrous
Na.sub.2SO.sub.4, decanted and concentrated yielding 4 as a pale
brown powder sufficiently pure to be used in the next step, (184
mg, 80% yield). HPLC Rt 2.36 min, Purity 97%, YMC S5 column
4.6.times.50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2%
H.sub.3PO.sub.4) UV detection at 220 nm. .sup.1H NMR (CDCl.sub.3)
2.3 ppm, 2H, multiplet; 2.6 ppm, 4H, multiplet; 2.9 ppm, 2H,
multiplet; 7.00 ppm, 1 H, dd, J=3.6 and 6.2 Hz; 7.20 ppm, 1H, dd,
J=1.2 and 3.6 Hz; 7.32 ppm, 1H, dd, J=1.2 and 5.1 Hz.
[0253] Compound 5: was dissolved in toluene (2 mL) and ethylene
glycol (0.54 mL, 9.6 mmol) and toluene sulfonic acid (9 mg, 0.05
mmol) added. The solution was heated to reflux with Dean-Stark
azeotropic removal of water for 14 h. The cooled reaction mixture
was diluted with ether (100 mL) and washed with water (3.times.20
mL). The organic portion was dried over anhydrous Na.sub.2SO.sub.4,
decanted and concentrated yielding 5 as a pale brown oil, (323 mg,
crude quantative yield). HPLC Rt 2.90 min, Purity 83.0%, YMC S5
column 4.6.times.50 mm, 4 min gradient 0 to 100% MeOH (90% in
water, 0.2% H.sub.3PO.sub.4) UV detection at 220 nm. .sup.1H NMR
(CDCl.sub.3) 1.9 ppm, 2H, multiplet; 2.0 ppm, 2H, multiplet; 2.1
ppm, 2H, multiplet; 2.2 ppm, 2H, multiplet; 4.00 ppm, 4H,
multiplet; 6.98 ppm, 1H, dd, J=1.2 and 3.6 Hz; 7.14 ppm, 1H, dd,
J=1.2 and 5.1 Hz; 7.27 ppm, 1H, dd, J=1.2 and 5.1 Hz.
[0254] Compound 6: At ambient temperature a solution of LiAlH.sub.4
(1.0M in THF, 1.35 mL, 1.35 mmol) was added to a solution of 5 in
THF (5 mL). The resulting slurry was heated to reflux under
nitrogen for 3 h then cooled to 0.degree. C. 1N NaOH (0.3 mL) was
added dropwise and after 10 min of vigorous stirring, anhydrous
Na.sub.2SO.sub.4 was added. The slurry was filtered through a glass
frit and the filter washed with THF, then the filtrate concentrated
to yield 151 mg (66% yield) of 6 as a colorless oil. HPLC Rt 1.47
min, Purity 98%, YMC S5 column 4.6.times.50 mm, 4 min gradient 0 to
100% MeOH (90% in water, 0.2% H.sub.3PO.sub.4) UV detection at 220
nm. .sup.1H NMR (CDCl.sub.3) 1.7 ppm, 4H, multiplet; 1.8 ppm, 2H,
multiplet; 2.1 ppm, 2H, multiplet; 2.7 ppm, 2H, multiplet; 3.92,
4H, multiplet; 6.86, 1H, dd, J=0.9 and 3.5 Hz; 6.97, 1H, dd, J=3.5
and 5.0 Hz; 7.21, 1H, dd, J=0.9 and 5.0 Hz.
[0255] Compound 7 At ambient temperature ortho-anisoyl chloride
(107 mg, 0.597 mmol) was added to a solution of amine 6 in
dichloromethane (2 mL) and TEA (63 mg, 0.63 mmol). The resulting
pale yellow solution was stirred for 1 h then loaded directly onto
a silica gel chromatography column. The column was eluted with 1:1
hexane:ethylacetate to provide 195 mg (85% yield) of the amide 7 as
a colorless oil. HPLC Rt 3.34 min, Purity 97%, YMC S5 column
4.6.times.50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2%
H.sub.3PO.sub.4) UV detection at 220 nm. LCMS Rt 1.73 min, [M+1]
388.13 YMC S5 column 4.6.times.30 mm, 2 min gradient 0 to 100% MeOH
(90% in water, 0.1% TFA) UV detection at 220 nm. .sup.1H NMR
(CDCl.sub.3) 1.7 ppm, 4H, multiplet; 2.0 ppm, 2H, multiplet; 2.2
ppm, 2H, multiplet; 3.68 ppm, 2H, d, J=6.0 Hz; 3.73, 3H, s; 4.1
ppm, 4H, multiplet; 6.89 ppm, 1H, d, J=8.3 Hz; 6.95 ppm, 1H, dd,
J=0.9 and 3.5 Hz; 7.01 ppm, 1H, dd, J=3.5 and 5.1 Hz; 7.06 ppm, 1H,
dd, J=7.4 and 8.0 Hz; 7.27 ppm, 1H, dd, J=0.8 and 4.9 Hz; 7.40 ppm,
1H, dd, J=1.1 and 1.7 Hz; 7.8 ppm, 1H, br s; 8.19 ppm, 1H, dd,
J=1.8 and 7.8 Hz.
[0256] Compound 8: (195 mg, 0.504 mmol) was dissolved in THF (4 mL)
and 2N HCl was added (1 mL). The resulting solution was heated to
40.degree. C. for 3 h, allowed to cool, diluted with ether (50 mL)
and washed with sat. NaHCO.sub.3 (3.times.20 mL). The organic
portion was dried over anhydrous Na.sub.2SO.sub.4, decanted and
concentrated yielding 200 mg (crude quantative yield) of 9 as a
colorless oil. HPLC Rt 3.00 min, Purity 92%, YMC S5 column
4.6.times.50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2%
H.sub.3PO.sub.4) UV detection at 220 nm. LCMS Rt 1.55 min, [M+1]
333.08 YMC S5 column 4.6.times.30 mm, 2 min gradient 0 to 100% MeOH
(90% in water, 0.1% TFA) UV detection at 220 nm. .sup.1H NMR
(CDCl.sub.3) 2.2 ppm, 2H, multiplet; 2.5 ppm, 6H, multiplet; 3.75,
3H, s; 3.79 ppm, 1H, d, J=6.2 Hz; 6.92 ppm, 1H, d, J=8.3 Hz; 7.03
ppm, 1H, dd, J=0.9 and 3.5 Hz; 7.08 ppm, 2H, multiplet; 7.35 ppm,
1H, dd, J=0.8 and 5.1 Hz; 7.43 ppm, 1H, ddd, J=1.8, 7.5 and 8.5 Hz;
7.9 ppm, 1H, br t; 8.20 ppm, 1H, dd, J=1.8 and 7.8 Hz.
[0257] Compounds 9 and 10: To a solution of crude ketone 8 (200 mg
crude, 0.504 mmol) in THF (4mL) was added NaBH.sub.4 (44 mg, 1.5
mmol). The reaction mixture was stirred at ambient temperature
under nitrogen for 14 h then the slurry diluted with
dichloromethane (100 mL). The slurry was transferred to a
separatory funnel and the organic portion washed with 1N HCl
(2.times.20 mL), dried over anhydrous Na.sub.2SO.sub.4, decanted
and concentrated yielding a mixture of 9 and 10 as a colorless oil.
The isomers were separated by preparative thin layer chromatography
(25.times.25 cm, 1 mm plate with UV indicator at 254 nm) using 2:1
dichloromethane:MTBE as eluent. Compound 9 (43 mg) was isolated as
the less polar constituent: HPLC Rt 3.16 min, Purity 95%, YMC S5
column 4.6.times.50 mm, 4 min gradient 0 to 100% MeOH (90% in
water, 0.2% H.sub.3PO.sub.4) UV detection at 220 nm. LCMS Rt 1.64
min, [M+1] 346.10 YMC S5 column 4.6.times.30 mm, 2 min gradient 0
to 100% MeOH (90% in water, 0.1% TFA) UV detection at 220 nm.
.sup.1H NMR (MeOD) 1.3 ppm, 2H, multiplet; 1.5 ppm, 2H, multiplet;
2.1 ppm, 2H, brd; 3.37 ppm, 2H, s; 3.5 ppm, 1H, multiplet; 3.64
ppm, 3H, s; 6.8 ppm, 4H, multiplet; 7.22 ppm, 1H, dd, J=0.7 and 5.4
Hz; 7.32 ppm, 1H, dd, J=1.8 and 8.7 Hz; 7.78 ppm, 1H, dd, J=1.7 and
7.8 Hz; 8.0 ppm, 1H, br s. Compound 10 (47 mg) was isolated as the
more polar constituent: HPLC Rt 2.95 min, Purity 94%, YMC S5 column
4.6.times.50 mm, 4min gradient 0 to 100% MeOH (90% in water, 0.2%
H.sub.3PO.sub.4) UV detection at 220 nm. LCMS Rt 1.52 min, [M+1]
346.13 YMC S5 column 4.6.times.30 mm, 2 min gradient 0 to 100% MeOH
(90% in water, 0.1% TFA) UV detection at 220 nm. .sup.1H NMR (MeOD)
1.6 ppm, 4H, multiplet; 1.8 ppm, 2H, multiplet; 2.0 ppm, 2H,
multiplet; 3.62 ppm, 1H, d, J=5.9 Hz; 3.63, 1H, br multiplet; 3.64
ppm, 3H, s; 6.9 ppm, 4H, multiplet; 7.26 ppm, 1H, dd, J=0.6 and 4.6
Hz; 7.36 ppm, 1H, dd, J=1.8 and 8.7 Hz; 7.87 ppm, 1H, dd, J=1.8 and
7.8 Hz; 8.0 ppm, 1H, br t.
EXAMPLES 2-12
[0258] Examples 2 to 12 were prepared using methodology described
in Example 1.
1 Ex. Structure Name [M + 1] 2 40 N-(4-Hydroxy-1- thiophen-3-yl-
cyclohexylmethyl)-2- methoxy-benzamide 346 3 41 N-(4-Hydroxy-1-
thiophen-3-yl- cyclohexylmethyl)-2- methoxy-benzamide 346 4 42
N-[1-(3-Ethyl-5- methyl-isoxazol-4- yl)-4-hydroxy-
cyclohexylmethyl]-2- methoxy-benzamide 373 5 43 N-(1-
Benzo[b]thiophen-3- yl-4-hydroxy- cyclohexylmethyl)-2-
methoxy-benzamide 396 6 44 N-(1- Benzo[b]thiophen-3- yl-4-hydroxy-
cyclohexylmethyl)-2- methoxy-benzamide 396 7 45 2,5-Dimethyl-furan-
3-carboxylic acid (1- benzo[b]thiophen-3- yl-4-hydroxy-
cyclohexylmethyl)- amide 384 8 46 2,5-Dimethyl-furan- 3-carboxylic
acid (1- benzo[b]thiophen-3- yl-4-hydroxy- cyclohexylmethyl)- amide
384 9 47 5-Chloro-4-methoxy- thiophene-3- carboxylic acid (1-
benzo[b]thiophen-3- yl-4-hydroxy- cyclohexylmethyl)- amide 437 10
48 5-Chloro-4-methoxy- thiophene-3- carboxylic acid (1-
benzo[b]thiophen-3- yl-4-hydroxy- cyclohexylmethyl)- amide 437 11
49 Pyridine-2- carboxylic acid (1- benzo[b]thiophen-3-
yl-4-hydroxy- cyclohexylmethyl)- amide 367 12 50 Pyridine-2-
carboxylic acid (1- benzo[b]thiophen-3- yl-4-hydroxy-
cyclohexylmethyl)- amide 367
EXAMPLE 13
[0259] 51
[0260] Trans-Ethyl-carbamic acid
4-[(2-methoxy-benzoylamino)-methyl]-4-thi- ophen-2-yl-cyclohexyl
ester
[0261] Synthesis: 52
[0262] Compound 1 The synthesis of 1 is described in Example 1.
[0263] Compound 2: At ambient temperature
4-nitrophenylchloroformate (45 mg, 0.22 mmol) was added to a
solution of alcohol 1 (43 mg, 0.12 mmol) in dichloromethane (10 mL)
containing triethylamine (ca. 38 mg). The resulting yellow solution
was stirred for 72 h then purified directly by silica gel
chromatography elution with 2:1 hexane:ethylacetate yielding 32 mg
(52% yield) of 2 as a colorless oil. HPLC Rt 3.91 min, Purity 84%,
YMC S5 column 4.6.times.50 mm, 4 min gradient 0 to 100% MeOH (90%
in water, 0.2% H.sub.3PO.sub.4) UV detection at 220 nm. .sup.1H NMR
(CDCl.sub.3) 1.8 ppm, 4H, multiplet; 2.1 ppm, 2H, multiplet; 2.3
ppm, 2H, multiplet; 3.69 ppm, 1H, d, J=6.0 Hz; 3.75 ppm, 3H, s; 4.8
ppm, 1H, multiplet; 6.9 ppm, 3H, multiplet; 7.05 ppm, 2H,
multiplet; 7.32 ppm, 1H, d, J=8.0 Hz; 7.45 ppm, 1H, dd, J=1.8 and
8.7 Hz; 7.9 ppm, 1H, br t; 8.15 ppm, 1H, d, J=8.0 Hz; 8.20 ppm, 1H,
dd, J=1.8 and 7.8 Hz.
[0264] Compound 3: A solution of ethylamine (0.8 mL, 2.0M in THF)
was added to a solution of 2 (32 mg, 0.062 mmol) in dichloromethane
(3 mL) at ambient temperature. After 1 h the yellow solution was
loaded directly onto a preparative thin layer chrmoatography plate
(25.times.25 cm, 1 mm with UV indicator at 254 nm). The plate was
eluted using 1:1 hexane:ethylacetate to provide 11 mg (43% yield)
of 3 as a colorless glass. HPLC Rt 3.37 min, Purity 96%, YMC S5
column 4.6.times.50 mm, 4 min gradient 0 to 100% MeOH (90% in
water, 0.2% H.sub.3PO.sub.4) UV detection at 220 nm. LCMS Rt 1.71
min, [M+1] 417.14 YMC S5 column 4.6.times.30 mm, 2 min gradient 0
to 100% MeOH (90% in water, 0.1% TFA) UV detection at 220 nm.
.sup.1H NMR (CDCl.sub.3) 1.09 ppm, 3H, t, J=7.1 Hz; 1.6 ppm, 2H,
multiplet; 1.8 ppm, 2H, multiplet; 2.0 ppm, 2H, multiplet; 2.2 ppm,
2H, multiplet; 3.18 ppm, 2H, multiplet; 3.65 ppm, 2H, d, J=6.0 Hz;
3.74 ppm, 3H, s; 4.72 ppm, 1H, br s; 4.48 ppm, 1H, br s; 6.90 ppm,
1H, d, J=8.2 Hz; 6.95 ppm, 1H, d, J=3.0 Hz; 7.15 ppm, 2H,
multiplet; 7.28 ppm, 1H, d, J=5.0 Hz; 7.45 ppm, 1H, dd, J=1.8 and
8.8 Hz; 7.8 ppm, 1H, br s; 8.20 ppm, 1H, d, J=2.2 and 7.7 Hz.
EXAMPLES 14-27
[0265] Examples 14 to 27 were prepared using methodology described
in Example 13.
2 Ex. Structure Name [M + 1] 14 53 Ethyl-carbamic acid 4-
[(2-methoxy- benzoylamino)- methyl]-4-thiophen-2- yl-cyclohexyl
ester 417 15 54 Ethyl-carbamic acid 4- [(2-methoxy- benzoylamino)-
methyl]-4-thiophen-2- yl-cyclohexyl ester 417 16 55 Ethyl-carbamic
acid 4- [(2-methoxy- benzoylamino)- methyl]-4-thiophen-3-
yl-cyclohexyl ester 417 17 56 Ethyl-carbamic acid 4- [(2-methoxy-
benzoylamino)- methyl]-4-thiophen-3- yl-cyclohexyl ester 417 18 57
Ethyl-carbamic acid 4- (3-ethyl-5-methyl- isoxazol-4-yl)-4-[(2-
methoxy- benzoylamino)- methyl]-cyclohexyl ester 444 19 58
Ethyl-carbamic acid 4- (3-ethyl-5-methyl- isoxazol-4-yl)-4-[(2-
methoxy- benzoylamino)- methyl]-cyclohexyl ester 444 20 59
Ethyl-carbamic acid 4- benzo[b]thiophen-3- yl-4-[(2-methoxy-
benzoylamino)- methyl]-cyclohexyl ester 467 21 60 Ethyl-carbamic
acid 4- benzo[b]thiophen-3- yl-4-[(2-methoxy- benzoylamino)-
methyl]-cyclohexyl ester 467 22 61 Ethyl-carbamic acid 4-
[(2-methoxy- benzoylamino)- methyl]-4-pyridin-2- yl-cyclohexyl
ester 412 23 62 Ethyl-carbamic acid 4- [(2-methoxy- benzoylamino)-
methyl]-4-pyridin-2- yl-cyclohexyl ester 455 24 63 Ethyl-carbamic
acid 4- benzo[b]thiophen-3- yl-4-{[(2,5-dimethyl-
furan-3-carbonyl)- amino]-methyl}- cyclohexyl ester 455 25 64
Ethyl-carbamic acid 4- benzo[b]thiophen-3- yl-4-{[(2,5-dimethyl-
furan-3-carbonyl)- amino]-methyl}- cyclohexyl ester 507 26 65
Ethyl-carbamic acid 4- benzo[b]thiophen-3- yl-4-{[(5-chloro-4-
methoxy-thiophene-3- carbonyl)-amino]- methyl}-cyclohexyl ester 507
27 66 Ethyl-carbamic acid 4- benzo[b]thiophen-3-
yl-4-{[(5-chloro-4- methoxy-thiophene-3- carbonyl)-amino]-
methyl}-cyclohexyl ester 418
EXAMPLE 28
[0266] 67
[0267] Acetic Acid
4[(2-methoxy-benzoylamino)-methyl]-4-thiophen-3-yl-cycl- ohexyl
ester
[0268] Synthesis: 68
[0269] Compound 1: The synthesis of 1 is described in Example
1.
[0270] Compound 2: At ambient temperature acetyl chloride (6 mg,
0.08 mmol) was added to a solution of alcohol 1 (14 mg, 0.040 mmol)
in dichloromethane (10 mL) containing TEA (ca. 8 mg). The resulting
yellow solution was stirred for 16 h then purified directly by
preparative HPLC YMC ODS S5 20.times.100 mm column 30-100% MeOH
(90% in water, 0.1% TFA) gradient over 8 min with flow rate 20
mL/min and UV detection at 220 nm. The ester 2 eluted at a
retention time of 8.6 min. and was isolated as a colorless oil (6.6
mg, yield 43%). HPLC Rt 3.42 min, Purity 100%, YMC S5 column
4.6.times.50 mm, 4 min gradient 0 to 100% MeOH (90% in water, 0.2%
H.sub.3PO.sub.4) UV detection at 220 nm. LCMS Rt 1.78 min, [M+1]
388.13 YMC S5 column 4.6.times.30 mm, 2 min gradient 0 to 100% MeOH
(90% in water, 0.1% TFA) UV detection at 220 nm. .sup.1H NMR
(CDCl.sub.3) 1.7 ppm, 2H, multiplet; 1.8 ppm, 2H, multiplet; 1.9
ppm, 4H, multiplet; 2.06 ppm, 3H, s; 3.71 ppm, 3H, s; 3.71 ppm, 2H,
d, J=8.0 Hz; 5.3 ppm, 1H, septet; 6.90 ppm, 1H, d, J=8.3 Hz; 7.06
ppm, 1H, t; 7.1 ppm, 2H, multiplet; 7.4 ppm, 2H, multiplet; 7.74
ppm, 1H, br t; 8.19 ppm, 1H, dd, J=1.8 Hz and 7.8 Hz.
EXAMPLES 29-30
[0271] Examples 29 to 30 were synthesized using methodology
described in Example 28.
3 Ex. Structure Name [M + 1] 29 69 Butyric acid 4-[(2- methoxy-
benzoylamino)- methyl]-4- thiophen-3- yl-cyclohexyl ester 416 30 70
Butyric acid 4-[(2- methoxy- benzoylamino)- methyl]-4- thiophen-3-
yl-cyclohexyl ester 416
EXAMPLE 31
[0272] 71
[0273]
cis-2-Methoxy-N-[4-(N-methyl-N'-cyanoguanidino)-1-phenyl-cyclohexyl-
methyl]-benzamide.
[0274] Synthesis: 7273
[0275] Compound 1: Compound 1 is commercially available.
[0276] Compound 2: To a solution of
4-phenyl-4-cyano-cyclohexane-1-one 1 (10 g, 50 mmol) in 200 ml of
toluene was added p-toluenesulfonic acid monohydrate (2.5 g, 13.1
mmol) and ethylene glycol (20 ml, 360 mmol) in a portion,
respectively. The resulting solution was stirred at reflux for 5 h.
The reaction mixture was concentrated in vacuo to yield oily
residue. It was then diluted with EtOAc (200 ml) and washed with
aq. NaHCO.sub.3 (50 ml.times.2) and brine (50 ml.times.1). The
organic layer was dried over MgSO.sub.4 and concentrated in vacuo
to provide an oil (12.9 g, >95%), which was subjected to the
following reaction without any further purification.
[0277] Compound 3: Into a solution of the nitrile 2 (12.9 g) in 100
ml of THF was added 60 ml of 1M LAH/THF dropwide and the resulting
solution was stirred at reflux for 2 h. The reaction mixture was
cooled to 0.degree. C. and quenched carefully with water. The
reaction mixture was diluted with EtOAc (500 ml) and washed with
aq. LiOH--NaCl (50 ml.times.3). The organic layer was dried over
MgSO.sub.4 and concentrated in vacuo to provide an oil (13.6 g,
>95%), which was subjected to the following reaction without
further purification.
[0278] Compound 4: To a solution of amine 3 (5.9 g, 24 mmol) and
Et.sub.3N (6.0 ml, 43 mmol) in 100 ml of CH.sub.2Cl.sub.2 was added
anisoyl chloride (4.5 ml, 30.4 mmol) dropwise at 0.degree. C. and
the resulting solution was stirred for 2 h. The reaction mixture
was concentrated in vacuo, yielding a white solid residue which was
partitioned between EtOAc (200 ml) and aq. NaHCO.sub.3 (50 ml). The
organic layer was dried over MgSO.sub.4 and concentrated in vacuo
to provide an oil, which was diluted in 50 ml of THF and 50 ml of
2N aq. HCl. The resulting solution was stirred for 12 h at
25.degree. C. The reaction mixture was diluted with EtOAc (200 ml).
The organic layer was separated, washed with brine (50 ml.times.2),
and dried over MgSO.sub.4. Concentration of the organic layer
produced an oily residue, which was purified on column
chromatography (50% EtOAc/Hex) to yield 6.8 g (20.2 mmol, 84% for
two steps) of the desired product.
[0279] Compound 5: To a solution of the ketone 4 (13 g, 38.6 mmol)
in 100 ml of MeOH was added NH.sub.4OAc (23.2 g, 300 mmol) and
NaBH(OAc).sub.3 (12.2 g, 57.8 mmol) and the resulting mixture was
stirred for 12 h at 25.degree. C. The reaction mixture was
concentrated in vacuo to produce a solid residue, which was
partitioned between EtOAc (200 ml) and 1N aq. NaOH (30 ml.times.2).
The organic layer was dried over MgSO.sub.4. Concentration of the
organic solution provided oily residue, which was subjected to
column chromatography (10% NH.sub.3--MeOH/CH.sub.2Cl.sub.2) to
obtain 10.8 g of the desired product as 1:1 mixture of two
diastereoisomers.
[0280] Compounds 6 and 7: The amine 5 (3.6 g, 10.7 mmol) was
dissolved in CH.sub.3CN (100 ml). A solution of
di-tert-butyldicarbonate (3.5 g, 16 mmol) dissolved in 30 ml of
CH.sub.3CN was added dropwise. The mixture was stirred for 2 h at
25.degree. C. Reaction mixture was concentrated in vacuo to provide
an oily residue, which was subjected to column chromatography (50%
Hex/EtOAc) to yeild 2.1 g of trans-isomer (retention time: 2.43
min) and 1.9 g of the cis-isomer (retention time: 2.67 min)of the
boc-protected amine. Each of the amines were dissolved in 40 ml of
25% TFA/CH.sub.2Cl.sub.2 and stirred at 25.degree. C. for 2 h. They
were concentrated in vacuo to provide oily residues, which were
dissolved in EtOAc (150 ml, respectively) and washed with 1N aq.
NaOH (100 ml.times.2). The organic layers were dried over
MgSO.sub.4 and concentrated in vacuo to provide an oil, which
corresponds to the amine of a single diastereoisomer.
[0281] Compound 9: To a solution of the cis-isomer of the amine 6
(700 mg, 2.07 mmol) in 40 ml of 2-propanol was added diphenyl
cyanocarbonimidate (0.48 g, 2.07 mmol) and the reaction mixture was
stirred at reflux for 4 h. It was concentrated in vacuo to provide
an oil, which was used in a following reactions without any further
purification.
[0282] Compound 10: To a solution of 9 (100 mg, 0.21 mmol) in 2 ml
of 2-propanol was added 2 ml of MeNH.sub.2 (2N in THF). The mixture
was stirred for 2 h at 75.degree. C. in a sealed tube. The reaction
mixture was cooled to room temperature and concentrated in vacuo to
provide oily residue, which was purified by preparative HPLC (YMC
S5 ODS 30.times.250 mm reverse phase column; 30 min gradient from
70:30 A:B to 100% B, where solvent A=90:10:0.1 H.sub.2O: MeOH:TFA
and solvent B=90:10:0.1 MeOH:H.sub.2O:TFA) to provide 53.4 mg (0.13
mmol, 62%) of the desired product as a white solid after
lyophilization (MeOH/H.sub.2O ). [M+H]=420.
EXAMPLES 32-52
[0283] Examples 32 to 52 were synthesized using methodology
described in Example 31.
4 Ex. Structure Name (M + H) 32 74 cis-2-Methoxy-N-
[4-(N-benzyl-N'- cyano-guanidino)-1- phenyl- cyclohexylmethyl]-
benzamide 496 33 75 cis-2-Methoxy-N- [4-(N,N-diethyl-
cyano-guanidino)-1- phenyl- cyclohexylmethyl]- benzamide 462 34 76
cis-2-Methoxy-N- [4-(N,N-dipropyl- N'-cyano- guanidino)-1- phenyl-
cyclohexylmethyl]- benzamide 490 35 77 cis-2-Methoxy-N-
[4-(N-propyl-N'- cyano-guanidino)-1- phenyl- cyclohexylmethyl]-
benzamide 448 36 78 cis-2-Methoxy-N- [4-(N-ethyl-N'-
cyano-guanidino)-1- phenyl- cyclohexylmethyl]- benzamide 434 37 79
cis-2-Methoxy-N- [4-(N-hexyl-N'- cyano-guanidino)-1- phenyl-
cyclohexylmethyl]- benzamide 490 38 80 cis-2-Methoxy-N-
[4-(N-methyl-N- benzyl-N'-cyano- guanidino)-1- phenyl-cyclohexyl-
methyl]-benzamide 510 39 81 cis-2-Methoxy-N- [4-(N-tert-butyl-N'-
cyano-guanidino)-1- phenyl- cyclohexylmethyl]- benzamide 462 40 82
cis-2-Methoxy-N- [4-(N- cyanoguanidino)-1- phenyl-cyclohexyl-
methyl]-benzamide 406 41 83 cis-2-Methoxy-N- [4-(N-acetonitrilo-
N'-cyano- guanidino)-1- phenyl-cyclohexyl- methyl]-benzamide 445 42
84 cis-2-Methoxy-N- [4-(azetidinyl-N- cyano-guanidino)-1- phenyl-
cyclohexylmethyl]- benzamide 446 43 85 cis-2-Methoxy-N-
[4-(N-cyclopropyl- N'-cyano- guanidino)-1- phenyl-cyclohexyl-
methyl]-benzamide 446 44 86 cis-2-Methoxy-N- [4-(N-(2-
hydroxyethyl)-N'- cyano-guanidino)-1- phenyl-cyclohexyl-
methyl]-benzamide 450 45 87 cis-2-Methoxy-N- [4-(N-allylic-N'-
cyano-guanidino)-1- phenyl- cyclohexylmethyl]- benzamide 446 46 88
cis-N-{4-[N'- hydroxy-1-methyl- ethyl)-N"- cyanoguanidino]-1-
phenyl-cyclohexyl- methyl}-2-methoxy- benzamide 464 47 89
cis-2-Methoxy-N- [4-(N-prop-2-ylnyl- N'-cyano- guanidino)-1-
phenyl-cyclohexyl- methyl]-benzamide 444 48 90 cis-2-Methoxy-N-
[4-(N- cyclopropylmethyl- N'-cyano- guanidino)-1-
phenyl-cyclohexyl- methyl]-benzamide 460 49 91 cis-2-Methoxy-N-
[4-(pyrrolidinyl-N- cyano-guanidino)-1- phenyl-cyclohexyl-
methyl]-benzamide 460 50 92 cis-2-Methoxy-N- [4-(N-methoxy-N'-
cyano-guanidino)-1- phenyl- cyclohexylmethyl]- benzamide 436 51 93
cis-2-Methoxy-N- [4-(N-methylamino- N'-cyano- guanidino)-1-
phenyl-cyclohexyl- methyl]-benzamide 435 52 94 cis-2-Methoxy-N-
[4-(N,N-dimethyl- N'-cyano- guanidino)-1- phenyl-
cyclohexylmethyl]- benzamide 434
EXAMPLE 53
[0284] 95
[0285]
trans-2-Methoxy-N-[4-(N-methyl-N'-cyanoguanidino)-1-phenyl-cyclohex-
ylmethyl]-benzamide
[0286] Synthesis: 96
[0287] Compound 1: compound 1 was synthesized as described in
Example 31.
[0288] Compound 2: To a solution of the trans-amine 1 (300 mg, 1.26
mmol) in 20 ml of 2-propanol was added diphenyl cyanocarbonidate
(0.24 g, 1.26 mmol) and the resulting mixture was stirred at reflux
for 4 h. The reaction mixture was concentrated in vacuo to provide
an oil, which was used in a following reaction without any further
purification.
[0289] Compound 3: To solution of intermediate 2 (100 mg, 0.21
mmol) in 2 ml of 2-propanol was added 2 ml of methylamine (2N in
THF). The mixture was stirred for 2 h at 75 .degree. C. in a sealed
tube. The reaction mixture was cooled down and concentrated in
vacuo to provide oily residue, which was purified by preparative
HPLC (described in Example 1) to provide 49.3 mg (0.12 mmol, 57%)
of the desired product as a white solid after lyophilization
(MeOH/H2O). [M+H]=420.
EXAMPLES 54-61
[0290] Examples 54 to 61 were synthesized using methodology
described in Example 53.
5 Ex. Structure Name (M + H) 54 97 trans-2-Methoxy-N-[4-
(N-benzyl-N'- cyanoguanidino)-1- phenyl-cyclohexyl-
methyl]-benzamide 434 55 98 trans-2-Methoxy-N-[4- (N,N-diethyl-N'-
cyanoguanidino)-1- phenyl-cyclohexyl- methyl]-benzamide 490 56 99
trans-2-Methoxy-N-[4- (N,N-dipropyl-N'- cyanoguanidino)-1-
phenyl-cyclohexyl- methyl]-benzamide 510 57 100
trans-2-Methoxy-N-[4- (N-propyl-N'- cyanoguanidino)-1-
phenyl-cyclohexyl- methyl]-benzamide 462 58 101
trans-2-Methoxy-N-[4- (N-ethyl-N'- cyanoguanidino)-1-
phenyl-cyclohexyl- methyl]-benzamide 434 59 102
trans-2-Methoxy-N-[4- (N-n-hexyl-N'- cyanoguanidino)-1-
phenyl-cyclohexyl- methyl]-benzamide 490 60 103
trans-2-Methoxy-N-[4- (N-methyl-N-benzyl- N'-cyanoguanidino)-1-
phenyl-cyclohexyl- methyl]-benzamide 10 61 104
trans-2-Methoxy-N-[4- (N-tert-butyl-N'- cyanoguanidino)-1-
phenyl-cyclohexyl- methyl]-benzamide 462
EXAMPLE 62 and 63:
[0291] 105
[0292] trans and
cis-N-[4-(N,N'-Diethyl-cyanoguanidino)-1-phenyl-1cyclohex-
ylmethyl]-2-methoxy-benzamide. 106
[0293] Compound 1: The synthesis of 1 is described in example
31.
[0294] Compound 2: To a solution of the ketone 1 (0.34 g, 1 mmol)
in 35 ml of dichloromethane was addded EtNH.sub.2 (1 ml of 2M
solution in THF, 2 mmol), NaBH(OAc).sub.3 (0.42 g, 2 mmol) and
drops of AcOH (cat. amount). The resulting solution was stirred at
25.degree. C. for 3 h. Reaction mixture was concentrated in vacuo
yielding oily residue, which was diluted in 250 ml of AcOH and
washed with 1N aq. NaOH (20 ml.times.2). The organic layer was
dried over Na.sub.2SO.sub.4 and concentrated in vacuo to provide 2
as an oil (0.35 g, >95%), which was subjected to the following
reaction without further purification.
[0295] Compound 3: A solution of diphenyl cyanocarbonidate (2.4 g,
10 mmol) and EtNH.sub.2 (5 ml of 2M solution in MeOH, 10 mmol) in
10 ml of 2-propanol was stirred for 4 h at 70.degree. C. in a
sealed tube. The reaction mixture was concentrated in vacuo
yielding a white solid, which was purified on column chromatography
(30% EtOAc/Hex) to yield 1.6 g (85%) of the desired product 3 as a
white solid.
[0296] Compound 4: A solution of compound 2 (110 mg, 0.3 mmol) and
compound 3 (74 mg, 0.39 mmol) in 5 ml of 2-propanol was stirred for
12 h at 70.degree. C. The reaction mixture was concentrated and
purified on preparative-HPLC (described in a synthesis of Example
31) to provide the cis and trans diastereoisomers. Trans compound
(retention time: 3.19 min) (23 mg) and cis compound (retention
time: 3036 min) (14 mg) were obtained as colorless oils. Mass Spec
[M+H].sup.+ 462.
EXAMPLE 64:
[0297] 107
[0298]
trans-2-Methoxy-N-[4-(N-ethyl-N'-sulfenylureido)-1-phenyl-cyclohexy-
lmethyl]-benzamide
[0299] Synthesis: 108
[0300] Compound 1:: The synthesis of 1 was described in Example
31.
[0301] Compound 2: Chlorosulfonyl isocyanate (0.37 ml, 4.1 mmmol)
was dissolved in 40 ml of dichloromethane and cooled to 0.degree.
C. Chloroethanol (0.27 ml, 4.1 mmol) was added slowly and the
reaction mixture was stirred for additional 1.5 h at 0.degree. C. A
solution of the amine 1 (1.4 g, 4.1 mmol) and Et.sub.3N (1.3 ml,
12.4 mmol) in 50 ml of dichloromethane was added slowly into the
reaction mixture so that reaction temperature did not exceed
5.degree. C. The reaction mixture was allowed to warm to 25.degree.
C. and stirred overnight. The reaction was quenched by dropwise
addition of 2N HCl and saturated with NaCl. The organic layer was
separated and the aqueous layer was extracted with dichloromethane
(100 ml.times.3). The combined organic layer was dried over
MgSO.sub.4 and concentrated in vacuo to provide 2 as a white solid
(2.0 g), which was subjected to the following reactions without
further purification.
[0302] Compound 3: A solution of 2 (90 mg, 0.18 mmol), EtNH.sub.2
(0.4 mmol, 0.2 ml of 2M solution in MeOH) and Et.sub.3N (0.1 ml) in
2 ml of CH.sub.3CN was stirred for 2 h at 65.degree. C. The
reaction mixture was purified in preparative HPLC (described in the
synthesis of Example 31) to yield 12.1 mg of 3 as a colorless oil.
Mass Spec [M+H].sup.+=446.
EXAMPLES 65-72
[0303] Examples 65 to 72 were synthesized using methodology
described in Example 64.
6 Ex. Structure Name (M + H) 65 109 trans-2-Methoxy-N-
[4-(N-methyl-N-benzyl- N'-sulfenylureido)- 1-phenyl-cyclohexyl-
methyl]-benzamide 522 66 110 trans-2-Methoxy-N-
[4-(N-tert-butyl-N'- sulfenylureido)-1- phenyl-cyclohexyl-
methyl]-benzamide 474 67 111 trans-2-Methoxy-N- [4-(N-phenyl-N'-
sulfenylureido)-1- phenyl-cyclohexyl- methyl]-benzamide 494 68 112
trans-2-Methoxy-N- [4-(N,N-diethyl-N'- sulfenylureido)-1-
phenyl-cyclohexyl- methyl]-benzamide 474 69 113 trans-2-Methoxy-N-
[4-(N-benzyl-N'- sulfenylureido)-1- phenyl-cyclohexyl-
methyl]-benzamide 508 70 114 trans-2-Methoxy-N- [4-(N-propyl-N'-
sulfenylureido)-1- phenyl-cyclohexyl- methyl]-benzamide 500 71 115
trans-2-Methoxy-N- [4-(N,N-dipropyl- N'-sulfenylureido)-
1-phenyl-cyclohexyl- methyl]-benzamide 502 72 116
trans-2-Methoxy-N- [4-(N-(4-N- methylpiperazinyl)-N'-
sulfenylureido)-1-phenyl- cyclohexyl-methyl]-benzamide 501
EXAMPLE 73:
[0304] 117
[0305]
cis-2-Methoxy-N-{4-[N-(4-anisoyl)-N'-sulfenylureido]-1-phenyl-cyclo-
hexylmethyl}-benzamide
[0306] Synthesis: 118
[0307] Compound 1: The synthesis of 1 was described in Example
31.
[0308] Compound 2: Chlorosulfonyl isocyanate (0.22 ml, 2.5 mmol)
was dissolved in 2 ml of dichloromethane and cooled to 0.degree. C.
Chloroethanol (0.16 ml, 0.25 mmol) was added slowly and the
reaction mixture was stirred for additional 1.5 h at 0.degree. C. A
solution of the cis-amine 1 (0.85 g, 2.5 mmol) and Et.sub.3N (0.8
ml, 7.6 mmol) in 30 ml of dichloromethane was added slowly into the
reaction mixture. The solution was allowed to warm to 25.degree. C.
and stirred overnight. The reaction was quenched by dropwise
addition of 2N HCl and saturated with NaCl. The organic layer was
separated and the aqueous layer was extracted with dichloromethane
(60 ml.times.3). The combined organic layer was dried over
MgSO.sub.4 and concentrated in vacuo, yielding a white solid, which
was purified by column chromatograophy (50% Hex/EtOAc) to provide
1.1 g (2.2 mmol, 87%) of 2 as a white solid.
[0309] Compound 3: A solution of 2 (17 mg, 0.035 mmol), and
p-anisidine (10 mg, 0.08 mmol) in 1 ml of CH.sub.3CN was stirred
for 2 h at 65.degree. C. The reaction mixture was purified by
preparative HPLC (described in a synthesis of Example 31) to yield
3.2 mg of the 3 as a colorless oil. Mass Spec [M+H].sup.+524.
EXAMPLES 74-147
Examples 74 to 147 were synthesized using methodology described in
Example 73.
[0310]
7 Ex. Structure Name (M + H) 74 119 cis-2-Methoxy-N-[4-(N-
methyl-N-benzyl-N'- sulfenylureido)-1-phenyl- cyclohexyl-methyl]-
benzamide 522 75 120 cis-2-Methoxy-N-[4-(N- tert-butyl-N'-
sulfenylurido)-1-phenyl- cyclohexyl-methyl]- benzamide 474 76 121
cis-2-Methoxy-N-[4-(N- phenyl-N'- sulfenylurido)-1-phenyl-
cyclohexyl-methyl]- benzamide 494 77 122 cis-2-Methoxy-N-[4-
(N,N-diethyl-N'- sulfenylurido)-1-phenyl- cyclohexyl-methyl]-
benzamide 474 78 123 cis-2-Methoxy-N-[4-(N- benzyl-N'-
sulfenylurido)-1-phenyl- cyclohexyl-methyl]- benzamide 508 79 124
cis-2-Methoxy-N-[4-(N- ethyl-N'-sulfenylurido)-
1-phenyl-cyclohexyl- methyl]-benzamide 446 80 125
cis-2-Methoxy-N-[4- (N,N-dipropyl-N'- sulfenylurido)-1-phenyl-
cyclohexyl-methyl]- benzamide 502 81 126 cis-2-Methoxy-N-[4-(N-
propyl-N'-sulfenylurido- )- 1-phenyl-cyclohexyl- methyl]-benzamide
460 82 127 cis-2-Methoxy-N-[4-(2- oxo-oxazolidine-3-
sulfonylamino)-1- phenyl-cyclohexyl- methyl]-benzamide 488 83 128
cis-2-Methoxy-N-[4-(N- methyl-N'- sulfenylurido)-1-phenyl-
cyclohexyl-methyl[- benzamide 432 84 129 cis-N-[4-(4-Phenyl-
piperidine-1- sulfonylamino)-1- phenyl-cyclohexyl-
methyl]-2-methoxy- benzamide 563 85 130 cis-N-[4-(4-Cyano-4-
phenyl-piperidine-1- sulfonylamino)-1- phenyl-cyclohexyl-
methyl]-2-methoxy- benzamide 587 86 131 cis-N-[4-(4-Methyl-
piperidine-1- sulfonylamino)-1- phenyl-cyclohexyl-
methyl]-2-methoxy- benzamide 501 87 132 cis-2-Methoxy-N-[4-(N-
Allyl-N'-sulfenylurido)- 1-phenyl-cyclohexyl- methyl]-benzamide 458
88 133 cis-2-Methoxy-N-{4-[N- (3-isoxazol)-N'-
sulfenylurido]-1-phenyl- cyclohexyl-methyl}- benzamide 485 89 134
cis-2-Methoxy-N-{4-[N- (3-cyano-phenyl)-N'-
sulfenylurido]-1-phenyl- cyclohexyl-methyl}- benzamide 519 90 135
cis-2-Methoxy-N-{4-[N- (4-methylbenzyl)-N'-
sulfenylurido]-1-phenyl- cyclohexyl-methyl}- benzamide 522 91 136
cis-2-Methoxy-N-{4-[N- (5-methyl-1H-3-pyrazol)-
N'-sulfenylurido]-1- phenyl-cyclohexyl- methyl}-benzamide 498 92
137 cis-2-Methoxy-N-{4-[N- 1-(3-N,N-diethyl- propyl)-N'-
sulfenylurido]-1-phenyl- cyclohexyl-methyl}]- benzamide 531 93 138
cis-2-Methoxy-N-{4-[N- 1-(3-N,N-dimethyl-2,2- dimethyl-propyl)-N'-
sulfenyluridol]-1-phenyl- cyclohexyl-methyl}]- benzamide 531 94 139
cis-2-Methoxy-N-[4-(N- methyl-N-2- hydroxyethyl-N'-
sulfenylurido)-1-phenyl- cyclohexyl-methyl]- benzamide 476 95 140
2-Methoxy-N-[4- (morpholine-4- sulfonylamino)-1- phenyl-cyclohexyl-
methyl]-benzamide 488 96 141 cis-N-[4-(4-Methyl- piperidine-1-
sulfonylamino)-1- phenyl-cyclohexyl- methyl]-2-methoxy- benzamide
515 97 142 cis-2-Methoxy-N-{4-[N- (ethoxy2-ethyl)-N'-
sulfenylurido]-1-phenyl- cyclohexyl-methyl}- benzamide 490 98 143
cis-2-Methoxy-N-[4-(N- indan-1-yl-N'- sulfenylurido)-1-phenyl-
cyclohexyl-methyl]- benzamide 534 99 144 cis-2-Methoxy-N-{4-[N-
(2,4-difluoro-benzyl)-N'- sulfenylurido]-1-phenyl-
cyclohexyl-methyl}- benzamide 544 100 145 cis-2-Methoxy-N-{4-
[N,N-di(2-hydroxy- ethyl)-N'-sulfenyl- undo]-1-phenyl-
cyclohexyl-methyl]- benzamide 506 101 146 cis-2-Methoxy-N-{4-[N-
methyl-N-(pyridin-2-yl- ethyl)-N'-sulfenyl- urido]-1-phenyl-
cyclohexyl-methyl}- benzamide 537 102 147 cis-2-Methoxy-N-{4-[N-
(pyridin-2-yl-methyl)-N'- sulfenyl-urido]-1-phenyl-
cyclohexyl-methyl}- benzamide 509 103 148 cis-2-Methoxy-N-{4-[N-
(4-methyl-pyridin-2-yl)- N'-sulfenylurido]-1- phenyl-cyclohexyl-
methyl}-benzamide 509 104 149 cis-2-Methoxy-N-{4-[N-
(3-fluoro-phenyl)-N'- sulfenylurido]-1-phenyl- cyclohexyl-methyl}-
benzamide 512 105 150 cis-2-Methoxy-N-{4-[N- (4-anisoyl)-N'-
sulfenylurido]-1-phenyl- cyclohexyl-methyl}- benzamide 524 106 151
cis-2-Methoxy-N-{4-[N- (3-fluoro-4-methyl- phenyl)-N'-
sulfenylurido]-1-phenyl- cyclohexyl-methyl}- benzamide 526 107 152
cis-2-Methoxy-N-{4-[N- (tetrazol-5-yl)-N'-
sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}- benzamide 486 108 153
cis-2-Methoxy-N-{4-[N- (1H-pyrazol-3-yl)-N'-
sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}- benzamide 484 109 154
cis-2-Methoxy-N-{4-[N- (4-fluoro-.quadrature.-methyl-
benzyl)-N'-sulfenyl- urido]-1-phenyl- cyclohexyl-methyl}- benzamide
540 110 155 N-[4-(4-Acetyl- [1,4]diazepane-1- sulfonylamino)-1-
phenyl-cyclohexyl- methyl]-2-methoxy- benzamide 543 111 156
cis-2-Methoxy-N-[4-(N- methyl-N-propyl-N'- sulfenylurido)-1-phenyl-
cyclohexyl-methyl]- benzamide 474 112 157 cis-2-Methoxy-N-{4-[N-
(2-methoxyethyl)-N'- sulfenylurido]-1-phenyl- cyclohexyl-methyl}-
benzamide 476 113 158 cis-2-Methoxy-N-{4-[N-
(2,2,2-trifluoroethyl)-N'- sulfenylurido]-1-phenyl- -
cyclohexyl-methyl}- benzamide 500 114 159 cis-2-Methoxy-N-{4-[N-
(4-fluoro-benzyl)-N'- sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}-
benzamide 526 115 160 cis-2-Methoxy-N-{4-[N- (2-methyl-2-propen-1-
yl)-N'-sulfenyl-urido]-1- phenyl-cyclohexyl- methyl}-benzamide
methyl}-benzamide 472 116 161 cis-2-Methoxy-N-{4-[N-
(2-methyl-1-propan-1- yl)-N'-sulfenyl-urido]-1- phenyl-cyclohexyl-
methyl}-benzamide 474 117 162 cis-2-Methoxy-N-{4-[N-
(imidazol-4-ylethyl)-N'- sulfenyl-urido]-1-phenyl-
cyclohexyl-methyl}- benzamide 512 118 163 N-{4-[4-(4-Fluoro-
phenyl)-piperazine-1- sulfonylamino]-1- phenyl-cyclohexyl-
methyl}-2-methoxy- benzamide 581 119 164 2-Methoxy-N-[1-phenyl-
4-(piperazine-1- sulfonylamino)- cyclohexylmethyl]- benzamide 457
120 165 cis-2-Methoxy-N-{4-[N- methyl-N-1-(2-N,N-
dimethyl-ethyl)-N'- sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}-
benzamide 503 121 166 cis-2-Methoxy-N-[4-(N- cyclohexyl-methyl-N'-
sulfenyl-urido)-1-phenyl- cyclohexyl-methyl]- benzamide 514 122 167
cis-2-Methoxy-N-{4-[N- (pyridin-2-yl)-N'- sulfenyl-urido]-1-phenyl-
cyclohexyl-methyl}- benzamide 495 123 168 cis-2-Methoxy-N-{4-[N-
1-(2-hydroxymethyl- propyl)-N'-sulfenyl- undo]-1-phenyl-
cyclohexyl-methyl}- benzamide 490 124 169 cis-2-Methoxy-N-{4-[N-
(bis-hydroxymethyl- methyl)-N'-sulfenyl- urido]-1-phenyl-
cyclohexyl-methyl}- benzamide 492 125 170 cis-2-Methoxy-N-{4-[N-
1-(2-hydroxymethyl-3- methyl-propyl)-N'- sulfenyl-urido]-1-phenyl-
cyclohexyl-methyl}- benzamide 504 126 171 cis-2-Methoxy-N-{4-[N-
1-(1-hydroxymethyl- ethyl)-N'-sulfenyl- urido]-1-phenyl-
cyclohexyl-methyl}- benzamide 476 127 172 N-[4-((R)3-Hydroxy-
pyrrolidine-1- sulfonylamino)-1- phenyl- cyclohexylmethyl]-2-
methoxy-benzamide 488 128 173 cis-2-Methoxy-N-{4-[N-
1-(2-hydroxy-propyl)-N'- sulfenyl-urido]-1-phenyl-
cyclohexyl-methyl}- benzamide 476 129 174 N-[4-((S)-3-Hydroxy-
pyrrolidine-1- sulfonylamino)-1- phenyl- cyclohexylmethyl]-2-
methoxy-benzamide 488 130 175 cis-2-Methoxy-N-{4-[N-
methyl-N-1-(2-methoxy- ethyl)-N'-sulfenyl- urido]-1-phenyl-
cyclohexyl-methyl}- benzamide 490 131 176 cis-2-Methoxy-N-{4-[N-
1-((S)-2,3-dihydroxy-propyl)-N'-sulfenyl- urido]-1-phenyl-
cyclohexyl-methyl}- benzamide 492 132 177 N-[4-(3-Hydroxy-
piperidine-1- sulfonylamino)-1- phenyl- cyclohexylmethyl]-2-
methoxy-benzamide 502 133 178 N-[4-((R)-2- Hydroxymethyl-
pyrrolidine-1- sulfonylamino)-1- phenyl- cyclohexylmethyl]-2-
methoxy-benzamide 502 134 179 N-[4-((s)-2- Hydroxymethyl-
pyrrolidine-1- sulfonylamino)-1- phenyl- cyclohexylmethyl]-2-
methoxy-benzamide 502 135 180 cis-2-Methoxy-N-{4-[N-
((R)-tetrahydrofuran-2- yl-methyl)-N'-sulfenyl- urido]-1-phenyl-
cyclohexyl-methyl}- benzamide 502 136 181 cis-2-Methoxy-N-{4-[N-
((S)-tetrahydrofuran-2- yl-methyl)-N'-sulfenyl- urido]-1-phenyl-
cyclohexyl-methyl}- benzamide 502 137 182 cis-2-Methoxy-N-{4-[N-
1-(1-methoxymethyl- propyl)-N'-sulfenyl- urido]-1-phenyl-
cyclohexyl-methyl}- benzamide 504 138 183 cis-2-Methoxy-N-{4-[N-
C-(3,4-dihydro-2H- pyran-2- yl)methylamino]-N'-
sulfenyl-urido]-1-phenyl- cyclohexyl-methyl}- benzamide 514 139 184
N-[4-(2,6-Dimethyl- morpholine-4- sulfonylamino)-1- phenyl-
cyclohexylmethyl]-2- methoxy-benzamide 516 140 185
cis-2-Methoxy-N-[4-(N- .alpha.-(R)-hydroxymethyl-
benzyl-N'-sulfenyl- urido)-1-phenyl- cyclohexyl-methyl]- benzamide
538 141 186 cis-2-Methoxy-N-[4-(N- .alpha.-(S)-hydroxymethyl-
benzyl-N'-sulfenyl- urido)-1-phenyl- cyclohexyl-methyl]- benzamide
538 142 187 cis-2-Methoxy-N-{4-[N- 1-((R)-2,3-dihydroxy-
propyl)-N'-sulfenyl- urido]-1-phenyl- cyclohexyl-methyl}- benzamide
492 143 188 cis-2-Methoxy-{N-[4- (N-4-ethylacetylphenyl-
N'-sulfenyl-urido]-1- phenyl-cyclohexyl- methyl}-benzamide 580 144
189 cis-2-Methoxy-{N-[4- (N-4-(2- hydroxyethyl)phenyl)-
N'-sulfenyl-urido]-1- phenyl-cyclohexyl- methyl}-benzamide 538 145
190 cis-2-Methoxy-{N-[4- (N-4-(1- hydroxyethyl)phenyl)-
N'-sulfenyl-urido]-1- phenyl-cyclohexyl- methyl}-benzamide 538 146
191 cis-2-Methoxy-{N-[4- (N-4- hydroxymethylphenyl)-
N'-sulfenyl-urido-1- phenyl]-cyclohexyl- methyl}-benzamide 524 147
192 cis-2-Methoxy-{N-[4- (N-2-hydroxy-indan-1-
yl)-N'-sulfenyl-urido-1- phenyl]-cyclohexyl- methyl}-benzamide
550
EXAMPLE 148:
[0311] 193
[0312]
cis-N-[4-(N'-Ethyl-guanidino)-1-phenyl-cyclohexylmethyl]-2-methoxy--
benzamide
[0313] Synthesis: 194
[0314] Compound 1: The synthesis of compound 1 was described in
Example 31.
[0315] Compound 2: To a solution of the amine 1 (0.35 g, 1.0 mmol)
in 10 ml of dichloromethane and 5 ml of aq. NaHCO.sub.3 was added
thiophosgene (0.3 ml, 4.0 mmol) in one portion. The reaction
mixture stirred for 2 h at 25.degree. C. The organic layer was then
separated and concentrated in vacuo to provide an oil (0.34 g,
89%). The oil was dissolved in 10 ml of 7N NH.sub.3/MeOH and
stirred for 12 h at 25.degree. C. The reaction mixture was
concentrated in vacuo to provide 2 as an oil which was used in the
following reaction without further purification.
[0316] Compound 3: To a solution of 2 in 10 ml of CH.sub.3CN was
added MeI (0.5 ml) and the resulting solution was stirred for 12 h
at 25.degree. C. The reaction mixture was concentrated in vacuo to
provide a white solid which was partitioned between EtOAc (50 ml)
and brine (20 ml). The organic layer was dried over MgSO.sub.4 and
concentrated in vacuo to yield 350 mg (>95%) of 3 as an oil
which was subjected to the following reaction without further
purification.
[0317] Compound 4: To a solution of 3 (0.17 g, 0.45 mmol) in 10 ml
of dichloromethane was added triethylamine (0.2 ml) and acetyl
chloride (0.2 ml, 2.8 mmol) and the resulting solution was stirred
for 1 h at 0.degree. C. The reaction mixture was diluted with EtOAc
(50 ml) and washed with brine (10 ml.times.2). The organic layer
was dried over MgSO.sub.4 and concentrated in vacuo to yield 4 as a
dark oil which was subjected to the following reaction without
further purification.
[0318] Compound 5: A solution of 4 (35 mg, 0.077 mmol) and
ethylamine (1 mmol, 0.5 ml of 2M NH.sub.3 in THF) in 1 ml of
2-propanol was stirred for 12 h at 70.degree. C. in a sealed tube.
The reaction mixture was then subjected to prearative HPLC
purification (described in a synthesis of Example 31) to yield 17.9
mg (40%) of the desired product 5 as a colorless oil. Mass Spec
[M+H].sup.+=409.
EXAMPLES 149-152
[0319] Examples 149 to 152 were synthesized using methodology
described in Example 148.
8 Ex. Structure Name (M + H) 149 195 cis-N-[4-(N',N'-
dimethyl-guanidino)-1- phenyl-cyclohexyl-
methyl]-2-methoxy-benzamide 409 150 196 cis-N-[4-(N'-benzyl-
guanidino)-1-phenyl- cyclohexyl-methyl]-2- methoxy-benzamide 471
151 197 cis-N-[4-(N'-methyl- guanidino)-1-phenyl-
cyclohexyl-methyl]-2- methoxy-benzamide 395 152 198
cis-N-[4-(N'-allyl- guanidino)-1-phenyl- cyclohexyl-methyl]-2-
methoxy-benzamide 421
EXAMPLE 153
[0320] 199
[0321]
cis-2,4-Dimethoxy-N-[4-(N-methyl-N'-cyanoguanidino)-1-phenyl-cycloh-
exylmethyl]-benzamide
[0322] Synthesis: 200201
[0323] Compound 1 The synthesis of 1 was described in Example
31.
[0324] Compound 2: To a solution of the amine 1 (1.0 g, 4.0 mmol)
and triethylamine (0.67 ml, 4.8 mmol) in 10 ml of dichloromethane
was added trifluoroacetic anhydride (1.0 ml, 4.8 mmol) dropwise and
the resulting solution was stirred at -78.degree. C. for 2 h. The
reaction mixture was concentrated in vacuo to provide an oily
residue which was partitioned between EtOAc (100 ml) and brine (20
ml.times.2). The organic layer was dried over MgSO.sub.4 and
concentrated in vacuo to provide the desired product 2 (1.3 g, 0.38
mmol, >95%) as a colorless oil. It was subjected to the
following reaction without further purification.
[0325] Compound 3: The intermediate 2 (1.3 g) was dissolved in THF
(50 ml). Into the solution was added 30 ml of 2N HCl and the
resulting solution was stirred for 12 h at 25.degree. C. The HPLC
analysis showed the complete disappearance of the starting material
and formation of a new product. The reaction mixture was diluted
with EtOAc (100 ml) and washed with aq. NaHCO.sub.3 (30
ml.times.2). The organic layer was dried over MgSO.sub.4 and
concentrated in vacuo to provide 1.2 g (>95%) of 3 as an
oil.
[0326] Compound 4: To the solution of the ketone 3 (1.2 g, 4 mmol)
in MeOH (60 ml) was added NH.sub.4OAc (2.5 g, 31 mmol) followed by
addition of NaBH(OAc).sub.3 (1.4 g, 5.2 mmol) in one portion. The
resulting solution was stirred for 3 h at 25.degree. C. The
reaction mixture was concentrated and the resulting solid was
redissolved in EtOAc (100 ml) and washed with aq. NaOH (1M, 30
ml.times.2). The organic layer was dried over MgSO.sub.4 and
concentrated in vacuo to provide an oil which is a 1:1 mixture of
the cis and trans diastereomers of the desired amine 4.
[0327] Compound 5: To a solution of the amine 4 (0.30 g, 1 mmol) in
2-propanol (2 ml) was added diphenyl cyanocarbonidate (240 mg, 1
mmol) and the resulting solution was stirred for 3 h at 70.degree.
C. HPLC analysis indicated completion of the reaction. The reaction
mixture was cooled to 25.degree. C. and transferred into a sealed
tube. To the sealed tube was added 2 ml of 2M MeNH.sub.2 (4 mmol).
The resulting solution was stirred for another 5 h at 70.degree. C.
The reaction mixture was concentrated to 2 ml of solution and
purified on preparative HPLC (described in a synthesis of Example
31) to provide cis-isomer (retention time: 2.90 min) (70 mg) and
trans-isomer (retention time: 2.65 min) (60 mg) of compound 5.
[0328] Compound 6: The cis isomer of intermediate 5 (1.1 g, 2.9
mmol) was dissolved in 40 ml of 1:1 mixture of MeOH--H.sub.2O with
7% aq. K.sub.2CO.sub.3 and the resulting solution was stirred for 3
h at 25.degree. C. HPLC analysis indicated completion of the
reaction. The reaction mixture was concentrated in vacuo to provide
a white solid, which was partitioned between EtOAc (100 ml) and
brine (20 ml.times.2). The aqueous layer was extracted with EtOAc
(50 ml). The organic layer was dried over MgSO.sub.4 and
concentrated in vacuo to provide 0.81 g (>95%) of 6 as an oil
which was subjected to the following reaction without any further
purification.
[0329] Compound 7: To a solution of the amine 6 (40 mg, 0.014 mmol)
in 2 ml of dichloromethane was added 2,4-dimethoxybenzoic acid (38
mg, 0.021 mmol), EDCI (60 mg, 0.031 mmol) and diisopropylethylamine
(57 .mu.L, 0.031 mmol) sequentially. The mixture as allowed to
stirred for 30 h at 35.degree. C. The reaction mixture was purified
on preparative HPLC (described in a synthesis of Example 31) to
provide 6.7 mg of the desired product 7 as a colorless oil. Mass
Spec [M+H].sup.+=450.
EXAMPLES 154-170
[0330] Examples 154 to 170 were synthesized using methodology
described in Example 153.
9 Ex. Structure Name (M + H) 154 202 cis-2,4-Dimethoxy-
N-[4-(N-methyl-N'- cyanoguanidino)-1- phenyl- cyclohexylmethyl]-
benzamide 450 155 203 cis-2,4,5- Trimethoxy-N-[4-(N- methyl-N'-
cyanoguanidino)-1- phenyl- cyclohexylmethyl]- benzamide 480 156 204
cis-2,3-Dimethoxy- N-[4-(N-methyl-N'- cyanoguanidino)-1- phenyl-
cyclohexylmethyl]- benzamide 450 157 205 cis-2-Phenoxy-N-[4-
(N-methyl-N'- cyanoguanidino)-1- phenyl- cyclohexylmethyl]-
benzamide 482 158 206 cis-(2,4-Dimethoxy- pyridin-3-yl)-N-[4-
(N-methyl-N'- cyanoguanidino)-1- phenyl- cyclohexylmethyl]-
benzamide 451 159 207 cis-(2-Phenoxy- pyridin-3-yl)-N-[4-
(N-methyl-N'- cyanoguanidino)-1- phenyl- cyclohexylmethyl]-
benzamide 483 160 208 cis-2,3-Diethoxy-N- [4-(N-methyl-N'-
cyanoguanidino)-1- phenyl- cyclohexylmethyl]- benzamide 478 161 209
cis-2-Methoxy-4- thiomethoxy-N-[4- (N-methyl-N'- cyanoguanidino)-1-
phenyl- cyclohexylmethyl]- benzamide 466 162 210 cis-2-Methoxy-3-
methyl-N-[4-(N- methyl-N'- cyanoguanidino)-1- phenyl-
cyclohexylmethyl]- benzamide 434 163 211 cis-2-Isopropoxy-N-
[4-(N-methyl-N'- cyanoguanidino)-1- phenyl- cyclohexylmethyl]-
benzamide 448 164 212 cis-2,6-Dimethoxy-3- chloro-N-[4-(N-
methyl-N'- cyanoguanidino)-1- phenyl- cyclohexylmethyl]- benzamide
485 165 213 2-Methoxy- naphthalene-1- carboxylic acid [4-
(N'-methyl- cyanoguanidino)-1- phenyl- cyclohexylmethyl]- amide 470
166 214 cis-2,3,4-Triethoxy- N-[4-(N-methyl-N'- cyanoguanidino)-1-
phenyl- cyclohexylmethyl]- benzamide 480 167 215 cis-(2-Methoxy-
pyridin-3-yl)-N-[4- (N-methyl-N'- cyanoguanidino)-1- phenyl-
cyclohexylmethyl]- benzamide 421 168 216 N-[4-(N'-Methyl-
cyanoguanidino)-1- phenyl- cyclohexylmethyl]-2- trifluoromethoxy-
benzamide 474 169 217 2-Ethoxy- naphthalene-1- carboxylic acid [4-
(N'-methyl- cyanoguanidino)-1- phenyl- cyclohexylmethyl]- amide 484
170 218 2-Benzyloxy-N-[4- (N'-methyl- cyanoguanidino)-1- phenyl-
cyclohexylmethyl]- benzamide 496
EXAMPLE 171:
[0331] 219
[0332]
2-Methoxy-N-[4-(N-ethyl-N'-ethoxycarbonyl-guanidino)-1-phenyl-cyclo-
hexylmethyl]-benzamide.
[0333] Synthesis: 220
[0334] Compound 1: The synthesis of 1 was described in Example
31.
[0335] Compound 2: To a solution of the amine 1 (mixture of cis and
trans isomers, 0.34 g, 1.0 mmol) in 15 ml of dichloromethane was
added 0.12 ml of ethyl isothiocyanatoformate (0.12 ml, 1.0 mmol) at
0.degree. C. The mixture was stirred for 0.5 h at 0.degree. C. and
3 h at 25.degree. C. The reaction mixture was diluted with 100 ml
of dichloromethane and washed with 1N HCl (20 ml) and brine (20
ml). The organic solution was dried over MgSO.sub.4 and
concentrated in vacuo to provide 0.43 g (95%) of the desired
product 2 as a colorless oil which was subjected to the following
reaction without further purification.
[0336] Compound 3: To a solution of the intermediate 2 (50 mg, 0.11
mmol) in 5 ml of dichloromethane was added ethylamine (0.1 ml of 2N
in THF, 0.2 mmol), EDCI (42 mg, 0.22 mmol) and
diisopropylethylamine (0.02 ml, 0.11 mmol) sequentially. The
reaction mixture was stirred for 12 h at 25.degree. C. The reaction
mixture was purified by preparative HPLC (described in a synthesis
of Example 31) to yield 22.2 mg (42%) of the desired product 3 (1:1
mixture of cis- and trans-isomers) as a colorless oil. Mass Spec
[M+H].sup.+=481.
EXAMPLES 172-178
[0337] Examples 172 to 178 were synthesized using methodology
described in Example 171.
10 Ex. Structure Name (M + H) 172 221 2-Methoxy-N-[4-(N- ethyl-N'-
ethoxycarbonyl- guanidino)-1-phenyl- cyclohexylmethyl]- benzamide
495 173 222 2-Methoxy-N-[4-(N- tert-butyl-N'- ethoxycarbonyl-
guanidino)-1-phenyl- cyclohexylmethyl]- benzamide 509 174 223
2-Methoxy-N-[4-(N-n- hexyl-N'- ethoxycarbonyl- guanidino)-1-phenyl-
cyclohexylmethyl]- benzamide 537 175 224 2-Methoxy-N-[4-(N,N-
dipropyl-N'- ethoxycarbonyl- guanidino)-1-phenyl-
cyclohexylmethyl]- benzamide 537 176 225 2-Methoxy-N-[4-(N-
benzyl-N'- ethoxycarbonyl- guanidino)-1-phenyl- cyclohexylmethyl]-
benzamide 543 177 226 2-Methoxy-N-[4-(N- methyl-N-benzyl-N'-
ethoxycarbonyl- guanidino)-1-phenyl- cyclohexylmethyl]- benzamide
557 178 227 2-Methoxy-N-[4-(N- ethoxycarbonyl- guanidino)-1-phenyl-
cyclohexylmethyl]- benzamide 453
EXAMPLE 179:
[0338] 228
[0339]
cis-N-[4-(2,5-Dioxo-imidazolin-1-yl)-1-phenyl-cyclohexylmethyl]-2-m-
ethoxy-benzamide
[0340] Synthesis: 229
[0341] Compound 1: The synthesis of compound 1 was described in
Example 31.
[0342] Compound 2: To a solution of the cis-amine (50 mg, 0.15
mmol) in 5 ml of dichloromethane was added ethyl isocyanatoacetate
(30 mg, 0:16 mmol) in one portion and the reaction mixture was
stirred for 5 h at 25.degree. C. The reaction mixture was then
concentrated in vacuo yielding an oily residue, which was dissolved
in 1 ml of EtOH--3N aq.HCl (1:1 mixture). The mixture was stirred
for 12 h at 45.degree. C. The reaction mixture was purified on
preparative HPLC to yield 23.4 mg (37%) of the desired product 2 as
a white solid. Mass Spec [M+H].sup.+=422.
EXAMPLE 180:
[0343] 230
[0344]
cis-N-[4-(2,5-Dioxo-4-(s)-isopropyl-imidazolin-1-yl)-1-phenyl-cyclo-
hexylmethyl]-2-methoxy-benzamide.
[0345] Synthesis: 231
[0346] Compound 1; The synthesis of 1 was described in Example
31.
[0347] Compound 2: The reaction was carried out in a same procedure
as described in Example 179 starting with the cis-amine 1 (50 mg,
0.15 mmol) and methyl (S)-(-)-2-isocyanato-3-methylbutyrate (35 mg,
0.23 mmol) to provide 16.7 mg (0.036 mmol, 24%) of the desired
product as a white solid. Mass Spec [M+H].sup.+=464.
Example 181:
[0348] 232
[0349]
trans-N-[4-(2,5-Dioxo-imidazolin-1-yl)-1-phenyl-cyclohexylmethyl]-2-
-methoxy-benzamide.
[0350] Synthesis: 233
[0351] Compound 1: The synthesis of 1 was described in Example
31.
[0352] Compound 2: The reaction was carried out in a same procedure
as described in Example 179 starting with the trans-amine (50 mg,
0.15 mmol) ethyl isocyanatoacetate (30 mg, 0.16 mmol) to provide
6.4 mg (0.015 mmol, 10%) of the desired product as a white solid.
Mass Spec [M+H].sup.+=422.
EXAMPLE 182:
[0353] 234
[0354]
trans-N-[4-(2,5-Dioxo-4-(s)-isopropyl-imidazolin-1-yl)-1-phenyl-cyc-
lohexylmethyl]-2-methoxy-benzamide
[0355] Synthesis: 235
[0356] Compound 1: The synthesis of 1 was described in Example
31.
[0357] Compound 2: The reaction was carried out in a same procedure
as described in Example 180 starting with the trans-amine (50 mg,
0.15 mmol) and methyl (S)-(-)-2-isocyanato-3-methylbutyrate (35 mg,
0.23 mmol) to provide 23.4 mg (0.051 mmol, 33%) of the desired
product as a white solid. Mass Spec [M+H].sup.+=464.
EXAMPLE 183:
[0358] 236
[0359]
cis-N-[4-(2,5-Dioxo-4-(s)-tetrahydro-pyrrolo[1,2-C]imidazol-2-yl)-1-
-phenyl-cyclohexylmethyl]-2-methoxy-benzamide.
[0360] Synthesis: 237
[0361] Compound 1: The synthesis of 1 was described in Example
31.
[0362] Compound 2: To a solution of the cis-amine 1 (200 mg, 0.59
mmol) in 10 ml of dichloromethane was added 10 ml of aq.
NaHCO.sub.3. To the heterogeneous solution was added 1 ml of
phosgene (20% in toluene) dropwise and the resulting mixture was
stirred for 5 h at 25.degree. C. The organic layer was separated.
The aqueous layer was extracted with dichloromethane (20 ml). The
combined organic layer was dried over MgSO.sub.4 and concentrated
in vacuo to provide an oil, which was identified as the desired
product 2 and subjected to the following reaction without further
purification.
[0363] Compound 3: To a solution of the isocyanate 2 ({fraction
(1/10)} of 2 produced in the previous step) in 1 ml of 2-propanol
was added 0.1 ml of triethylamine and L-proline methyl ester.HCl
(100 mg, 0.61 mmol) and the resulting solution was stirred for 12 h
at 25.degree. C. The reaction mixture was mixed with 1 ml of 3N aq.
HCl and the resulting solution was stirred for 12 h at 70.degree.
C. It was cooled to 25.degree. C. and purified by preparative HPLC
(described in a synthesis of Example 31) to provide 14.6 mg (53%)
of the desired product 3 as a colorless oil. Mass Spec
[M+H].sup.+=462.
EXAMPLES 184-192
[0364] Examples 184 to 192 were synthesized using methodology
described in Example 183.
11 Ex. Structure Name (M + H) 184 238 cis-N-[4-(2,5-Dioxo-4-
(s)-benzyl-imidazolin-1- yl)-1-phenyl- cyclohexylmethyl]-2-
methoxy-benzamide 512 185 239 cis-N-[4-(2,5-Dioxo-4-
(s)-isobutyl-imidazolin- 1-yl)-1-phenyl- cyclohexylmethyl]-2-
methoxy-benzamide 478 186 240 cis-N-[4-(2,5-Dioxo-4-
(s)-ethyl-imidazolin-1- yl)-1-phenyl- cyclohexylmethyl]-2-
methoxy-benzamide 450 187 241 cis-N-[4-(2,5-Dioxo-4-
(s)-hydroxymethyl- imidazolin-1-yl)-1- phenyl- cyclohexylmethyl]-2-
methoxy-benzamide 451 188 242 cis-N-{4-[2,5-Dioxo-4-
(s)-(imidazo-4- yl)methyl-imidazolin-1- yl]-1-phenyl-
cyclohexylmethyl}-2- methoxy-benzamide 502 189 243
cis-N-[4-(5,7-Dioxo- 4,6-diaza-spiro- [2.4]hept-6-yl)--1-
phenyl-cyclohexyl- methyl]-2-methoxy- benzamide 448 190 244
cis-N-[4-(1,3-Dioxo-4- (s)-tetrahydro- imidazo[1,5-a]-pyridin-
2-yl)-1-phenyl- cyclohexyl-methyl]-2- methoxy-benzamide 76 191 245
cis-N-[4-(3-Benzyl-2,5- dioxo-imidazolidin-1- yl)-1-phenyl-
cyclohexyl-methyl]-2- methoxy-benzamide 512 192 246
cis-N-[4-(3-Methyl-2,5- dioxo-imidazolidin-1- yl)-1-phenyl-
cyclohexyl-methyl]-2- methoxy-benzamide 436
EXAMPLE 193:
[0365] 247
[0366] cis- and
trans-N-(2,4-Dioxo-1-phenyl-1,3-diaza-spiro[4,5]dec-8-ylme-
thyl)-2-methoxy-benzamide
[0367] Synthesis 248
[0368] Compound 1 The synthesis of 1 was described in Example
31.
[0369] Compounds 2 and 3: To a solution of the ketone (0.48 g, 1.42
mmol) in 20 ml of 50% aq. EtOH was added KCN (0.11 g, 1.70 mmol)
and (NH.sub.4).sub.2CO.sub.3 (0.68 g, 7.10 mmol) in one portion,
respectively and the resulting solution was stirred for 12 h at
55.degree. C. The mixture was concentrated in vacuo yielding an
aqueous solution, which was extracted with EtOAc (100 ml.times.3).
The organic layer was dried over MgSO.sub.4 and concentrated in
vacuo yielding a colorless oil. Upon dissolving the oil in
dichloromethane a white solid precipitated out. The white solid
(230 mg) was comprised of two diastereoisomers in a 1:1 ratio. The
mother liquor was concentrated in vacuo to provide an oil, which
was purified on prep-HPLC (described in a synthesis of Example 31)
to yield 16.1 mg of one isomer (retention time: 2.82 min). The
white solid was dissolved in 30 ml of hot EtOH and stored for 5
days at 25.degree. C. to provide 55.7 mg a white solid precipitate
of the other isomer. Mass Spec for both compounds
[M+H].sup.+=408.
EXAMPLE 194
[0370] 249
[0371]
cis-2-Methoxy-N-[4-(2-oxo-imidazolidin-1-yl)-1-phenyl-cyclohexylmet-
hyl]-benzamide
[0372] Synthesis: 250
[0373] Compound 1: The synthesis of compound 1 was described in
Example 31.
[0374] Compounds 2 and 3: To a solution of the ketone 1 (0.5 g, 1.5
mmol) in 10 ml of dichloroethane was added N-acetylethylenediamine
(0.34 ml, 3.0 mmol) and NaBH(OAc).sub.3 (0.64 g, 3.0 mmol) in a
portion, respectively and the resulting solution was stirred for 12
h at 25.degree. C. It was diluted with dichloromethane (50 ml) and
washed with 1N aq. NaOH. Organic layer was separated and
concentrated in vacuo to provide oily residue. The residue was
dissolved in 20 ml of dichloromethane and stirred with 1.0 g (4.5
mmol) of di-tert-butyl dicarbonate for 1 h at 25.degree. C. The
reaction mixture was concentrated in vacuo yielding an oily residue
which was purified on preparative HPLC (described in the synthesis
of Example 31) to provide both cis-2 (retention time: 2.42 min) and
trans-3 (retention time: 2.57 min) isomers.
[0375] Compound 4: Compound 2 was dissolved in 20 ml of 3N aq. HCl
and stirred for 12 h at 25.degree. C. The reaction was cooled to
0.degree. C., basified with 20% aq. NaOH and extracted with
dichloromethane (50 ml.times.3). The organic layer was dried over
MgSO.sub.4 and concentrated in vacuo to provide 157 mg of 4.
[0376] Compound 5: The cis-amine 4 (100 mg, 0.26 mmol) was
dissolved in 5 ml of dichloromethane and stirred with
carbonyldiimidazole (100 mg, 0.61 mmol) for 12 h at 25.degree. C.
The reaction mixture was concentrated and subjected to preparative
HPLC (described in the synthesis of Example 31) to yield 14.6 mg of
the desired product as a white solid. Mass Spec
[M+H].sup.+=408.
EXAMPLE 195
[0377] 251
[0378]
trans-2-Methoxy-N-[4-(2-oxo-imidazolidin-1-yl)-1-phenyl-cyclohexylm-
ethyl]-benzamide
[0379] Synthesis: 252
[0380] Compound 1: The synthesis of compound 1 was described in
Example 31.
[0381] Compounds 2 and 3: The synthesis of compounds 2 and 3 is
described in Example 194.
[0382] Compound 4: Compound 3 was dissolved in 20 ml of 3N aq. HCl
and stirred for 12 h at 25.degree. C. The reaction was cooled to
0.degree. C, basified with 20% aq. NaOH and extracted with
dichloromethane (50 ml.times.3). The organic layer was dried over
MgSO.sub.4 and concentrated in vacuo to provide 135 mg of 4.
[0383] Compound 5: The trans-amine 4 (100 mg, 0.26 mmol) was
dissolved in 5 ml of dichloromethane and stirred with
carbonyldiimidazole (100 mg, 0.61 mmol) for 12 h at 25.degree. C.
The reaction mixture was concentrated and subjected to preparative
HPLC (described in the synthesis of Example 31) to yield 15.8 mg of
the desired product as a white solid. Mass Spec
[M+H].sup.+=408.
EXAMPLE 196
[0384] 253
[0385]
cis-N-[4-(2-Cyanoimino-imidazolin-1-yl)-1-phenyl-cyclohexylmethyl]--
2-methoxy-benzamide
[0386] Synthesis: 254
[0387] Compound 1: The synthesis of 1 was described in Example
194.
[0388] Compound 2; A solution of the cis-amine (75 mg, 0.20 mmol)
and diphenyl cyanocarbonidate (75 mg, 0.32 mmol) in 3 ml of
2-propanol was stirred for 4 h at 70.degree. C. The reaction
mixture was purified on preparative HPLC (described in Example 31)
to provide 32.0 mg (37%) of the desired product 2 as a colorless
oil. Mass Spec [M+H].sup.+=432.
EXAMPLE 197
[0389] 255
[0390]
trans-N-[4-(2-Cyanoimino-imidazolin-1-yl)-1-phenyl-cyclohexylmethyl-
]-2-methoxy-benzamide
[0391] Synthesis: 256
[0392] Compound 1: The synthesis of 1 was described in Example
194.
[0393] Compound 2 The reaction was carried out in a same procedure
described in Example 196, starting with 75 mg (0.20 mmol) of the
trans-amine and diphenyl cyanocarbonidate (75 mg, 0.32 mmol) to
provide 47.6 mg (0.11 mmol, 55%) of the desired product 2 as a
white solid. Mass Spec [M+H].sup.+=432.
EXAMPLE 198
[0394] 257
[0395] 1-Phenyl-cyclohexanecarboxylic acid benzylamide
[0396] Synthesis: 258
[0397] Compound 1: Compound 1 is commercially available.
[0398] Compound 2 A suspension of 1-phenyl-cyclohexanecarboxylic
acid 1 (0.010 g; 0.049 mmol) in methylene chloride (1 mL) was
cooled to 0.degree. C. and treated with triethylamine (0.010 mL;
0.072 mmol) followed by tetramethylfluoroformamidinium
hexafluorophosphate (0.014 g; 0.053 mmol). After warming to room
temperature (approximately 1 h), the solvent was removed and the
residue was used in the subsequent reaction.
[0399] Compound 3: Compound 2 was dissolved in acetonitrile (1 mL).
PS-DIEA (polystyrene-diisopropylethylamine resin; 0.2 g) was added
and the resulting suspension was treated with benzyl amine (0.006
mg; 0.056 mmol) and shaken at room temperature. After 12 h, PS-TsCl
(polystyrene-tosyl chloride, high loading resin; 0.2 g) was added
and the reaction mixture is allowed to shake an additional 12 h.
The reaction mixture was filtered and concentrated to give 0.011 g
(79%) of compound 3. LCMS m/z=294.4 (M+H).sup.+
EXAMPLES 199-289
[0400] Examples 199 to 289 were synthesized using methodology
described in Example 198. In some cases, further purification was
accomplished using reverse phase HPLC.
12 Ex. Structure Name M + H 199 259 1-Phenyl- cyclohexanecarboxylic
acid 3,4-difluoro- benzylamide 330.4 200 260 1-Phenyl-
cyclohexanecarboxylic acid 4-chloro- benzylamide 328.9 201 261
1-Phenyl- cyclohexanecarboxylic acid [2-(4-methoxy-
phenyl)-ethyl]-amide 338.5 202 262 1-Phenyl- cyclohexanecarboxylic
acid 2,4-dimethoxy- benzylamide 354.5 203 263 1-Phenyl-
cyclohexanecarboxylic acid (1-phenyl-ethyl)- amide 308.4 204 264
1-Phenyl- cyclohexanecarboxylic acid (3-phenyl- propyl)-amide 322.5
205 265 1-Phenyl- cyclohexanecarboxylic acid 2-methoxy- benzylamide
324.4 206 266 1-Phenyl- cyclohexanecarboxylic acid 2-chloro-
benzylamide 328.9 207 267 (1-Phenyl- cyclohexyl)-
(4-phenyl-piperazin-1- yl)-methanone 349.5 208 268 1-Phenyl-
cyclohexanecarboxylic acid (biphenyl-3- ylmethyl)-amide 370.5 209
269 1-Phenyl- cyclohexanecarboxylic acid 3-fluoro-5-
trifluoromethyl- benzylamide 380.4 210 270 1-Phenyl-
cyclohexanecarboxylic acid (1-phenyl-ethyl)- amide 308.4 211 271
1-Phenyl- cyclohexanecarboxylic acid (1-phenyl-ethyl)- amide 308.4
212 272 1-Phenyl- cyclohexanecarboxylic acid (3,3-diphenyl-
propyl)-amide 398.6 213 273 1-Phenyl- cyclohexanecarboxylic acid
4-trifluoromethyl- benzylamide 362.4 214 274 (4-Benzo[1,3]dioxol-
5-ylmethyl- piperazin-1-yl)-(1- phenyl-cyclohexyl)- methanone 407.5
215 275 1-Phenyl- cyclohexanecarboxylic acid 3-methyl- benzylamide
308.4 216 276 1-Phenyl- cyclohexanecarboxylic acid 3,4-dichloro-
benzylamide 363.3 217 277 1-Phenyl- cyclohexanecarboxylic acid
4-methyl- benzylamide 308.4 218 278 1-Phenyl- cyclohexanecarboxylic
acid (biphenyl-2- ylmethyl)-amide 370.5 219 279 1-Phenyl-
cyclohexanecarboxylic acid (4-phenyl-butyl)- amide 336.5 220 280
1-Phenyl- cyclohexanecarboxylic acid [2-(4-chloro-
phenyl)-ethyl]-amide 342.9 221 281 1-Phenyl- cyclohexanecarboxylic
acid [2-(3- trifluoromethyl- phenyl)-ethyl]- amide 376.4 222 282
1-Phenyl- cyclohexanecarboxylic acid [2-(2-fluoro-
phenyl)-ethyl]-amide 326.4 223 283 1-Phenyl- cyclohexanecarboxylic
acid 3-trifluoromethyl- benzylamide 362.4 224 284 1-Phenyl-
cyclohexanecarboxylic acid 4-fluoro- benzylamide 312.4 225 285
1-Phenyl- cyclohexanecarboxylic acid (2-phenoxy- ethyl)-amide 324.4
226 286 1-(4-Chloro-phenyl)- cyclohexanecarboxylic acid
(4-phenyl-butyl)- amide 370.9 227 287 1-(4-Chloro-phenyl)-
cyclohexanecarboxylic acid [2-(4-chloro- phenyl)-ethyl]-amide 377.3
228 288 1-(4-Chloro-phenyl)- cyclohexanecarboxylic acid [2-(3-
trifluoromethyl- phenyl)-ethyl]-amide 410.9 229 289
1-(4-Chloro-phenyl)- cyclohexanecarboxylic acid [2-(2-fluoro-
phenyl)-ethyl]-amide 360.9 230 290 1-(4-Chloro-phenyl)-
cyclohexanecarboxylic acid 4-chloro- benzylamide 363.3 231 291
1-(4-Chloro-phenyl)- cyclohexanecarboxylic acid 3-trifluoromethyl-
benzylamide 396.9 232 292 1-(4-Chloro-phenyl)-
cyclohexanecarboxylic acid 4-fluoro- benzylamide 346.8 233 293
1-(4-Chloro-phenyl)- cyclohexanecarboxylic acid (biphenyl-2-
ylmethyl)-amide 405.0 234 294 1-(4-Chloro-phenyl)-
cyclohexanecarboxylic acid 4-trifluoromethyl- benzylamide 396.9 235
295 1-(4-Chloro-phenyl)- cyclohexanecarboxylic acid (2-phenoxy-
ethyl)-amide 358.9 236 296 1-(4-Fluoro-phenyl)-
cyclohexanecarboxylic acid (4-phenyl-butyl)- amide 354.5 237 297
1-(4-Fluoro-phenyl)- cyclohexanecarboxylic acid [2-(4-chloro-
phenyl)-ethyl]-amide 360.9 238 298 1-(4-Fluoro-phenyl)-
cyclohexanecarboxylic acid [2-(3- trifluoromethyl-
phenyl)-ethyl]-amide 394.4 239 299 1-(4-Fluoro-phenyl)-
cyclohexanecarboxylic acid [2-(2-fluoro- phenyl)-ethyl]-amide 344.4
240 300 1-(4-Fluoro-phenyl)- cyclohexanecarboxylic acid 4-chloro-
benzylamide 346.8 241 301 1-(4-Fluoro-phenyl)-
cyclohexanecarboxylic acid 3-trifluoromethyl- benzylamide 380.4 242
302 1-(4-Fluoro-phenyl)- cyclohexanecarboxylic acid 4-fluoro-
benzylamide 330.4 243 303 1-(4-Fluoro-phenyl)-
cyclohexanecarboxylic acid (biphenyl-2- ylmethyl)-amide 387.5 244
304 1-(4-Fluoro-phenyl)- cyclohexanecarboxylic acid
4-trifluoromethyl- benzylamide 380.4 245 305 1-(4-Fluoro-phenyl)-
cyclohexanecarboxylic acid (2-phenoxy- ethyl)-amide 342.4 246 306
1-(3-Fluoro-phenyl)- cyclohexanecarboxylic acid (4-phenyl-butyl)-
amide 354.5 247 307 1-(3-Fluoro-phenyl)- cyclohexanecarboxylic acid
[2-(4-chloro- phenyl)-ethyl]-amide 360.9 248 308
1-(3-Fluoro-phenyl)- cyclohexanecarboxylic acid [2-(3-
trifluoromethyl- phenyl)-ethyl]-amide 394.4 249 309
1-(3-Fluoro-phenyl)- cyclohexanecarboxylic acid [2-(2-fluoro-
phenyl)-ethyl]-amide 344.4 250 310 1-(3-Fluoro-phenyl)-
cyclohexanecarboxylic acid 4-chloro- benzylamide 346.8 251 311
1-(3-Fluoro-phenyl)- cyclohexanecarboxylic acid 3-trifluoromethyl-
benzylamide 380.4 252 312 1-(3-Fluoro-phenyl)-
cyclohexanecarboxylic acid 4-fluoro-benzylamide 330.4 253 313
1-(3-Fluoro-phenyl)- cyclohexanecarboxylic acid (biphenyl-2-
ylmethyl)-amide 388.5 254 314 1-(3-Fluoro-phenyl)-
cyclohexanecarboxylic acid 4-trifluoromethyl- benzylamide 380.4 255
315 1-(3-Fluoro-phenyl)- cyclohexanecarboxylic acid
(2-phenoxy-ethyl)- amide 341.4 256 316 1-(2-Fluoro-phenyl)-
cyclohexanecarboxylic acid (4-phenyl-butyl)- amide 354.5 257 317
1-(2-Fluoro-phenyl)- cyclohexanecarboxylic acid [2-(4-chloro-
phenyl)-ethyl]-amide 360.9 258 318 1-(2-Fluoro-phenyl)-
cyclohexanecarboxylic acid [2-(3- trifluoromethyl-
phenyl)-ethyl]-amide 384.4 259 319 1-(2-Fluoro-phenyl)-
cyclohexanecarboxylic acid [2-(2-fluoro- phenyl)-ethyl]-amide 344.4
260 320 1-(2-Fluoro-phenyl)- cyclohexanecarboxylic acid 4-chloro-
benzylamide 346.8 261 321 1-(2-Fluoro-phenyl)-
cyclohexanecarboxylic acid 3-trifluoromethyl- benzylamide 380.4 262
322 1-(2-Fluoro-phenyl)- cyclohexanecarboxylic acid 4-fluoro-
benzylamide 330.4 263 323 1-(2-Fluoro-phenyl)-
cyclohexanecarboxylic acid (biphenyl-2-ylmethyl)- amide 387.5 264
324 1-(2-Fluoro-phenyl)- cyclohexanecarboxylic acid
4-trifluoromethyl- benzylamide 380.4 265 325 1-(2-Fluoro-phenyl)-
cyclohexanecarboxylic acid (2-phenoxy- ethyl)-amide 342.4 266 326
1-p-Tolyl- cyclohexanecarboxylic acid [2-(3,4-dimethyl-
phenyl)-ethyl]- amide 350.5 267 327 1-p-Tolyl-
cyclohexanecarboxylic acid (2-m-tolyl-ethyl)- amide 336.5 268 328
1-p-Tolyl- cyclohexanecarboxylic acid [2-(4-bromo-
phenyl)-ethyl]-amide 401.4 269 329 1-p-Tolyl- cyclohexanecarboxylic
acid (2-p-tolyl-ethyl)- amide 336.5 270 330 1-p-Tolyl-
cyclohexanecarboxylic acid (3-phenyl- propyl)-amide 336.5 271 331
1-p-Tolyl- cyclohexanecarboxylic acid [2-(2-chloro-
phenyl)-ethyl]-amide 356.9 272 332 1-p-Tolyl- cyclohexanecarboxylic
acid [2-(4-chloro- phenyl)-ethyl]-amide 356.9 273 333 1-p-Tolyl-
cyclohexanecarboxylic acid [2-(2,4-dichloro- phenyl)-ethyl]-amide
391.4 274 334 1-p-Tolyl- cyclohexanecarboxylic acid [2-(3-chloro-
phenyl)-ethyl]-amide 356.9 275 335 1-p-Tolyl- cyclohexanecarboxylic
acid 4-fluoro- benzylamide 326.4 276 336 1-p-Tolyl-
cyclohexanecarboxylic acid [2-(3,4-dichloro- phenyl)-ethyl]-amide
391.4 277 337 1-p-Tolyl- cyclohexanecarboxylic acid 3-methyl-
benzylamide 322.5 278 338 1-p-Tolyl- cyclohexanecarboxylic acid
(4-phenyl-butyl)- amide 350.5 279 339 1-p-Tolyl-
cyclohexanecarboxylic acid [2-(2-methoxy- phenyl)-ethyl]-amide
352.5 280 340 1-p-Tolyl- cyclohexanecarboxylic acid (2-phenoxy-
ethyl)-amide 338.5 281 341 1-p-Tolyl- cyclohexanecarboxylic acid
(biphenyl-2- ylmethyl)-amide 384.5 282 342 1-p-Tolyl-
cyclohexanecarboxylic acid (2-thiophen-2-yl- ethyl)-amide 328.5 283
343 1-p-Tolyl- cyclohexanecarboxylic acid 4-methoxy- benzylamide
338.5 284 344 1-p-Tolyl- cyclohexanecarboxylic acid [2-(4-ethyl-
phenyl)-ethyl]-amide 350.5 285 345 1-p-Tolyl- cyclohexanecarboxylic
acid [2-(2-fluoro- phenyl)-ethyl]-amide 340.5 286 346 1-p-Tolyl-
cyclohexanecarboxylic acid 4-methyl- benzylamide 322.5 287 347
1-p-Tolyl- cyclohexanecarboxylic acid 3-methoxy- benzylamide 338.5
288 348 1-p-Tolyl- cyclohexanecarboxylic acid 2-methoxy-
benzylamide 338.5 289 349 1-p-Tolyl- cyclohexanecarboxylic acid
(1-phenyl-ethyl)- amide 322.5
EXAMPLE 290
[0401] 350
[0402] 1-(4-fluoro-phenyl)-cyclohexanecarboxylic acid
[2-(4-chloro-phenyl)-ethyl]-(1-methyl-1H-imidazol-2-ylmethyl)-amide
[0403] Synthesis: 351
[0404] Compound 1: Compound 1 is commercially available.
[0405] Compound 2: A suspension 2-(4-chlorophenyl)ethylamine (2.25
mL; 16.1 mmol) and sodium sulfate (10.0 g; 70.4 mmol) in methanol
(20 mL) was treated with 1-methyl-1H-imidazole-2-carbaldehyde (1.80
g; 16.3 mmol) and heated to 40.degree. C. After 24 h, the reaction
mixture was cooled to 0.degree. C., treated with sodium borohydride
(0.73 g; 19.3 mmol) and allowed to slowly warm to room temperature.
After 3 h, the solvent was removed and the crude residue was
partitioned between ethyl acetate and saturated aqueous sodium
bicarbonate. The organic layer was separated, washed with saturated
aqueous sodium chloride, dried (magnesium sulfate) and
concentrated. The oily residue was dissolved in tetrahydrofuran and
treated with a solution of 1N HCl in diethyl ether (35 mL). A white
precipitate formed immediately and was collected to give 5 g (96%)
of
[2-(4-chloro-phenyl)-ethyl]-(1-methyl-1H-imidazol-2-ylmethyl)-amine.2HCl.
LCMS m/z=250.7 (M+H).sup.+
[0406] Compound 3: A suspension of
1-(4-fluoro-phenyl)-cyclohexanecarboxyl- ic acid (0.106 mg; 0.48
mmol) in methylene chloride (10 mL) was treated with oxalyl
chloride (0.042 mL; 0.48 mmol) and 1 drop of N,N-dimethylformamide.
The reaction mixture was allowed to stir at room temperature for 15
min at which time triethylamine (0.28 mL; 2.0 mmol) and
[2-(4-Chloro-phenyl)-ethyl]-(1-methyl-1H-imidazol-2-ylmethyl)-amine.2-
HCl (0.16 g; 0.50 mmol) was added. After an addition 30 min of
stirring the solvent was removed and the residue was purified using
reverse phase HPLC to give 0.114 g (52%) of 3 as a white solid.
LCMS m/z=455.0 (M+H).sup.+.
EXAMPLE 291
[0407] 352
[0408] 1-(4-Chloro-phenyl)-cyclohexanecarboxylic acid
[2-(4-chloro-phenyl)ethyl]-(1-methyl-1H-imidazol-2-ylmethyl)-amide.
[0409] Synthesis:
[0410] The titled compound was prepared using methodology described
in Example 290. LCMS m/z=471.5 (M+H).sup.+.
EXAMPLE 292
[0411] 353
[0412] 1-(4-fluoro-phenyl)-cyclohexanecarboxylic acid
benzyl-(1-methyl-1H-imidazol-2-ylmethyl)-amide.
[0413] The titled compound was prepared using methodology described
in Example 290. LCMS m/z=406.5 (M+H).sup.+
EXAMPLE 293
[0414] 354
[0415] Ethyl-carbamic acid
4-[5-(3-methoxy-benzyl)-[1,2,4]oxadiazol-3-yl]--
4-phenyl-cyclohexyl ester.
[0416] Synthesis: 355356
[0417] Compound 1: the synthesis of Compound 1 is described in
Example 31.
[0418] Compound 2: A solution of compound 1 (5.8 g; 23.8 mmol),
hydroxylamine hydrochloride (4.21 g; 60.6 mmol) and sodium
methoxide (3.27 g; 60.6 mmol) in n-propanol (100 mL) was heated at
98.degree. C. overnight. The reaction mixture was concentrated
under reduced pressure, diluted with EtOAc (100 mL), washed with
H.sub.2O and dried over anhydrous sodium sulfate. Purification by
flash chromatography (1:1; Hexanes:ethyl acetate) gave 2 (4.6 g;
71%) as a white solid. LCMS m/z=277.1 (M+H).sup.+
[0419] Compound 3: To a solution of Compound 2 (0.100 g, 0.36 mmol)
in 2-methoxyethyl ether (5 mL) was added potassium carbonate (0.72
mmol) followed by 3-methoxyphenyl acetyl chloride (0.067 g, 0.36
mmol). The reaction mixture was stirred at room temperature for 30
min. then heated at 120.degree. C. for 3 h. After cooling to room
temperature, the reaction mixture was diluted with water, extracted
with ethyl acetate and dried over anhydrous sodium sulfate.
Purification by column chromatography on silica gel (7:3
hexanes:ethyl acetate) gave 3 (0.085 g; 58%) as an oil. .sup.1H NMR
(CDCl.sub.3, 300 MHz): .delta. (ppm) 1.65-1.80 (4 H, m), 2.25-2.40
(2 H, m), 2.60-2.70 (2 H, m), 3.74 (3 H, s), 3.94 (4 H, s), 4.14 (2
H, s), 6.75-6.90 (3 H, m), 7.15-7.45 (6 H, m); LCMS m/z=407.2
(M+H).sup.+.
[0420] Compound 4: A solution of Compound 3 (80 mg, 0.20 mmol) in
tetrahydrofuran (1.25 mL) was treated with 2 N HCl (0.4 mL) and
heated at 40.degree. C. for 6 h. Saturated aqueous sodium
bicarbonate was added. The aqueous phase was extracted with ethyl
acetate and the organic phase dried over anhydrous sodium sulfate.
Purification by column chromatography on silica gel (7:3
hexanes:ethyl acetate) gave 4 (40 mg; 60%) as an oil. LCMS
m/z=363.2 (M+H).sup.+.
[0421] Compound 5: A solution of 4 (1.2 g, 3.31 mmol) in
tetrahydrofuran (20 mL) at 0.degree. C. was treated with sodium
borohydride (250 mg, 6.62 mmol). After stirring from 0.degree. C.
to room temperature overnight, the reaction mixture was quenched
with saturated aqueous sodium carbonate and extracted with ethyl
acetate. The organic layer was washed with saturated aqueous sodium
chloride and dried over anhydrous sodium sulfate. Purification by
column chromatography on silica gel (7:3 hexanes:ethyl acetate)
gave 5 (1.12 g, 93%). LCMS m/z=365.5 (M+H).sup.+.
[0422] Compound 6: .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. (ppm)
1.11 (3 H, t, J=7.1 Hz), 1.50-1.70 (2 H, m), 1.90-2.18 (4 H, bd,
J=9.7 Hz), 2.88 (2 H, bd, J=13.6 Hz), 3.10-3.25 (2 H, m), 3.74 (3
H, s), 4.14 (2 H, s), 4.60-4.80 (2 H, m), 6.70-6.90 (3 H, m),
7.08-7.40 (6 H, m). LCMS m/z=436.2 (M+H).sup.+.
EXAMPLES 294-322
[0423] Examples 294 to 322 were synthesized using methodology
described in Example 293. In some cases, further purification was
accomplished using reverse phase HPLC.
13 Ex. Structure Name M + H 295 357 4-Phenyl-4-(5- phenyl-
[1,2,4]oxadiazol-3- yl)-cyclohexanone 319.4 296 358
4-[5-(2-Methoxy- phenyl)- [1,2,4]oxadiazol-3- yl]-4-phenyl-
cyclohexanone 349.4 297 359 Ethyl-carbamic acid 4-phenyl-4-(5-
phenyl- [1,2,4]oxadiazol-3- yl)-cyclohexyl ester 392.5 298 360
Ethyl-carbamic acid 4-[5-(2-methoxy- phenyl)- [1,2,4]oxadiazol-3-
yl]-4-phenyl- cyclohexyl ester 422.5 299 361 Ethyl-carbamic acid
4-[5-(3-chloro- phenyl)- [1,2,4]oxadiazol-3- yl]-4-phenyl-
cyclohexyl ester 426.9 300 362 Ethyl-carbamic acid 4-[5-(4-chloro-
phenyl)- [1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 426.9
301 363 Ethyl-carbamic acid 4-phenyl-4-(5-p-tolyl-
[1,2,4]oxadiazol-3- yl)-cyclohexyl ester 406.5 302 364
[2-(1-Methyl- pyrrolidin-2-yl)- ethyl]-carbamic acid
4-[5-(3-methoxy- benzyl)- [1,2,4]oxadiazol-3- yl]-4-phenyl-
cyclohexyl ester 519.7 303 365 Thiophen-2-ylmethyl- carbamic acid
4-[5- (3-methoxy-benzyl)- [1,2,4]oxadiazol-3- yl]-4-phenyl-
cyclohexyl ester 504.6 304 366 4-Phenyl-butyl)- carbamic acid 4-[5-
(3-methoxy-benzyl)- [1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl
ester 540.7 305 367 Cyclopropylmethyl- carbamic acid 4-[5-
(3-methoxy-benzyl)- [1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl
ester 462.6 306 368 (2-Pyridin-4-yl- ethyl)-carbamic acid
4-[5-(3-methoxy- benzyl)- [1,2,4]oxadiazol-3- yl]-4-phenyl-
cyclohexyl ester 513.6 307 369 (Tetrahydro-furan-2-
ylmethyl)-carbamic acid 4-[5-(3- methoxy-benzyl)-
[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 492.6 308 370
2-Thiophen-2-yl- ethyl)-carbamic acid 4-[5-(3-methoxy- benzyl)-
[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 518.6 309 371
(2-Pyridin-2-yl- ethyl)-carbamic acid 4-[5-(3-methoxy- benzyl)-
[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 513.6 310 372
Isobutyl-carbamic acid 4-[5-(3- methoxy-benzyl)-
[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 464.6 311 373
Phenethyl-carbamic acid 4-[5-(3- methoxy-benzyl)-
[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 512.6 312 374
Butyl-carbamic acid 4-[5-(3-methoxy- benzyl)- [1,2,4]oxadiazol-3-
yl]-4-phenyl- cyclohexyl ester 464.6 313 375 Allyl-carbamic acid
4-[5-(3-methoxy- benzyl)- [1,2,4]oxadiazol-3- yl]-4-phenyl-
cyclohexyl ester 448.5 314 376 Cyclohexyl-carbamic acid 4-[5-(3-
methoxy-benzyl)- [1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester
490.6 315 377 Pyridin-4-ylmethyl- carbamic acid 4-[5-
(3-methoxy-benzyl)- [1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl
ester 499.6 316 378 Propyl-carbamic acid 4-[5-(3-methoxy- benzyl)-
[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 450.5 317 379
Cyclopentyl-carbamic acid 4-[5-(3- methoxy-benzyl)-
[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 476.6 318 380
(2-Methoxy-ethyl)- methyl-carbamic acid 4-[5-(3-methoxy- benzyl)-
[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 480.6 319 381
Cyclohexylmethyl- carbamic acid 4-[5- (3-methoxy-benzyl)-
[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 504.6 320 382
(2-Pyridin-3-yl- ethyl)-carbamic acid 4-[5-(3-methoxy- benzyl)-
[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 513.6 321 383
(2,4-Dichloro- benzyl)-carbamic acid 4-[5-(3- methoxy-benzyl)-
[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 567.5 322 384
Benzyl-methyl- carbamic acid 4-[5- (3-methoxy-benzyl)-
[1,2,4]oxadiazol-3- yl]-4-phenyl- cyclohexyl ester 512.6
EXAMPLE 323
[0424] 385
[0425] Ethyl-carbamic acid
4-(isoquinolin-1-ylaminomethyl)-4-phenyl-cycloh- exyl ester
[0426] Synthesis: 386
[0427] Compound 1: Synthesis of compound 1 is described in Example
31
[0428] Compound 2: is commercially available
[0429] Compound 3: A mixture of compound 1 (2.0 g, 8.09 mmol), 2
(1.1 g, 6.75 mmol), sodium-t-butoxide (908 mg, 9.75 mmol),
palladium acetate (75.7 mg, 0.34 mmol) and
2-(di-t-butylphosphino)biphenyl (100.7 mg, 0.3374 mmol) in toluene
(20 mL) was heated at 110.degree. C. for 20 h. The insolubles were
filtered off through CELITE, the solvent was removed under reduced
pressure and the residue was purified by flash chromatography
through silica eluting with 40% ethyl acetate-hexane providing the
title compound (1.5 g, 50% yield) as a yellow oil.
[0430] Compound 4: Dioxolane 3 (1.5 g) was dissolved in THF,
diluted with 2N HCl and stirred overnight. The solution was added
to a mixture of ethyl acetate and saturated sodium bicarbonate. The
organic solution was washed with an additional two portions of
bicarbonate solution followed by brine. The solution was dried over
sodium sulfate and the solvent removed under reduced pressure
providing 1.25 g (94%) of Compound 4 as an orange syrup which was
used without further purification.
[0431] Compounds 5 and 6: Sodium borohydride (215 mg, 5.82 mmol)
was added to a solution of ketone 4 (1.25 g, 3.79 mmol) in THF (10
mL) and the mixture was stirred overnight. The reaction was
partitioned between ethyl acetate and dilute HCl. The aqueous layer
was basified with saturated sodium bicarbonate. The product was
extracted into ethyl acetate which was dried over sodium sulfate
and the solvent removed under reduced pressure. Flash
chromatography through silica with ethyl acetate as eluent provided
5 (isomer A, 469 mg) and 6 (isomer B, 170 mg).
[0432] Compound 7: Camphorsulphonic acid (160.1 mg, 0.689 mmol) was
added to a stirred solution of 5 (114 mg, 0.344 mmol) in
dichloromethane (10 mL). After 5 min. ethyl isocyanate (32.7 .mu.L,
0.414 mmol) was added and stirring continued for 2 h. The reaction
was quenched with a methanolic solution of ammonia, the solvent was
removed under reduced pressure and the residue was flash
chromatographed through silica eluting with 60% ethyl
acetate-hexane, then 5% methanol-dichloromethane affording 10.2 mg
of the title compound, [M+H]=404.
EXAMPLE 324
[0433] 387
[0434] Ethyl-carbamic acid
4-(isoquinolin-1-ylaminomethyl)-4-phenyl-cycloh- exyl ester
[0435] Synthesis: 388
[0436] Compound 1: Synthesis of compound 1 is described in Example
323.
[0437] Compound 2: In a reaction similar to that described in
example 323, Compound 1 (76.3 mg, 0.230 mmol), camphorsulfonic acid
(106.8 mg, 0.460 mmol) and ethyl isocyanate (21.8 .mu.L, 0.276
mmol) in dichloromethane (10 mL) produced 16.3 mg of Compound 2,
[M+H]=403.
EXAMPLE 325
[0438] 389
[0439] Isoquinolin-1-yl-(1-phenyl-cyclohexylmethyl)-amine
[0440] Synthesis: 390
[0441] Compound 1: Compound 1 is commercially available
[0442] Compound 2: A suspension of 1-phenyl-1-cyclohexane
carboxylic acid (0.484 g; 2.37 mmol) in methylene chloride (30 ml)
was treated with oxalyl chloride (0.23 mL; 2.64 mmol) and 1 drop of
N,N-dimethylformamide. The reaction mixture was allowed to stir at
room temperature for 30 minutes at which time triethylamine (1 mL;
7.2 mmol) and 1-aminoisoquinoline (0.36 g; 2.50 mmol). After an
additional 15 minutes of stirring the reaction mixture was washed
with water and saturated aqueous sodium chloride, dried (magnesium
sulfate) and concentrated. The crude residue was purified by column
chromatography on silicia gel using 3:1:1 hexane:ethyl
acetate:dichloromethane as the eluent to give 0.605 g of
1-phenyl-cyclohexanecarboxylic acid isoquinolin-1-ylamide as a
white foam. LCMS m/z=331.2 (M+H).sup.+
[0443] Compound 3: A solution of 1-phenyl-cyclohexanecarboxylic
acid isoquinolin-1-ylamide (0.117 g; 0.35 mmol) in tetrahydrofuran
(10 mL) was cooled to 0.degree. C. and treated with lithium
aluminum hydride (0.040 g; 1.05 mmol). The reaction mixture was
allowed to slowly warm to room temperature. After 18 h at room
temperature additional lithium aluminum hydride was added (0.04 g;
1.05 mmol) and the reaction mixture was heated at 40.degree. C. for
2 h. The reaction mixture was cooled back to 0.degree. C. and
carefully quenched by the dropwise addition of water. The
tetrahydrofuran was removed by evaporation and the crude residue
was diluted with ethyl acetate and saturated aqueous sodium
bicarbonate. The organic layer was separated, washed with saturated
aqueous sodium chloride, dried (magnesium sulfate), filtered and
concentrated. Column chromatography on silicia gel using 7:3
hexane:ethyl acetate as the eluent gave 0.042 g of
isoquinolin-1-yl-(1-phenyl-cyclohexylmethyl)-amine as a light
yellow oil. LCMS m/z=317.2 (M+H).sup.+; .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta. (ppm) 7.96 (1H, d, J=6.0 Hz), 7.54-7.26 (9 H, m),
6.61 (1 H, d, J=6.0 Hz), 4.80 (1 H, broad S), 3.76 (2 H, d, J=5.4
Hz), 2.26-2.20 (2 H, m), 1.84-1.77 (2 H, m), 1.66-1.61 (2 H, m),
1.55-1.43 (4 H, m); .sup.13C NMR (CDCl.sub.3, 75 MHz) 155.4, 144.9,
141.4, 137.1, 129.5, 128.9 (two carbons), 127.1, 127.0 (two
carbons), 126.4, 125.8, 121.0, 118.1, 110.5, 52.2, 42.6, 34.3 (two
carbons), 26.6, 22.2 (two carbons).
EXAMPLES 326-329
[0444] Examples 326 to 329 were synthesized using methodology
described in Example 325.
14 Example Structure Name M + H 326 391 1-Phenyl-
cyclohexanecarboxylic acid[1,7]naphthyridin-8-ylamide 332.2 327 392
[1,7]Naphthyridin-8-yl- (1-phenyl- cyclohexylmethyl)-amine 318.2
328 393 1-Phenyl- cyclopropanecarboxylic acid isoquinolin-1-ylamide
289.1 329 394 Isoquinolin-1-yl-(1- phenyl- cyclopropylmethyl)-amine
275.2
EXAMPLE 330
[0445] 395
[0446] (1-phenyl-cyclohexylmethyl)-quinazolin-4-yl-amine
[0447] Synthesis: 396
[0448] Compound 1: Compound 1 is commercially available.
[0449] Compound 2: A solution of 1-phenyl-cyclohexanecarbonitrile
(11.0 g; 59 mmol) in tetrahydrofuran (100 mL) was cooled to
0.degree. C. and treated with lithium aluminum hydride (11 g, 289
mmol) in several portions over the course of 0.5 h. When the
addition of lithium aluminum hydride was complete the cooling bath
was removed and the reaction mixture was allowed to stir at room
temperature for 12 h. The reaction mixture was cooled back to
0.degree. C. and carefully quenched by dropwise addition of 2 N
NaOH (approximately 20 mL), diluted with ethyl ether, filtered
through a celite plug and dried (magnesium sulfate).
C-(1-Phenyl-cyclohexyl)-methylamine was obtained as a colorless oil
which was used without further purification. LCMS m/z=190.2
(M+H).sup.+
[0450] Compound 3: A solution of
C-(1-phenyl-cyclohexyl)-methylamine (0.28 g; 1.48 mmol) in
tetrahydrofuran (10 mL) at room temperature was treated with
triethylamine (0.3 mL; 2.2 mmol) and 2,4-dichloro-quinazoline (0.32
g; 1.62 mmol). The reaction was stirred at room temperature 12 h at
which time the solvent was removed by rotary evaporation. The crude
residue was portioned between ethyl acetate and 10% aqueous HCl.
The organic layer was separated, washed with saturated aqueous
sodium chloride, dried (magnesium sulfate), filtered and
concentrated. The product was recrystallized from methylene
chloride to give (2-chloro-quinazolin-4-yl)-
-(1-phenyl-cyclohexylmethyl)-amine as a white solid. LCMS m/z=352.2
(M+H).sup.+
[0451] Compound 4: A solution of
(2-chloro-quinazolin-4-yl)-(1-phenyl-cycl- ohexylmethyl)-amine
(0.065 g; 0.18 mmol) in anhydrous methanol (2 mL) was treated with
10% palladium on carbon (200 mg) and placed under an atmosphere of
hydrogen (45 psi). The reaction mixture was shaken at room
temperature for 3 h. The reaction mixture was filtered through
celite and evaporated. The crude residue was purified by column
chromatography on silicia gel using 9:1 ethyl acetate:hexane as the
eluent to give 0.052 g
(1-phenyl-cyclohexylmethyl)-quinazolin-4-yl-amine as a white foam.
LCMS m/z=318.2 (M+H).sup.+
EXAMPLE 331
[0452] 397
[0453]
N.sup.2-ethyl-N.sup.4-(1-phenyl-cyclohexylmethyl)-quinazoline-2,4-d-
iamine
[0454] Synthesis: 398
[0455] Compound 1: Compound 1 is prepared as described above.
[0456] Compound 2:
(2-chloro-quinazolin-4-yl)-(1-phenyl-cyclohexylmethyl)-- amine
(0.052 g; 0.15 mmol) was treated with 1 mL of a 2 M solution of
ethylamine in tetrahydrofuran. The reaction vessel was tightly
sealed and the reaction mixture was heated at 60.degree. C. for 24
h. The volatile components were removed under vacuum and the crude
residue was purified directly be preparative HPLC to give 0.020 g
of N.sup.2-ethyl-N.sup.4-(1--
phenyl-cyclohexylmethyl)-quinazoline-2,4-diamine as a white solid.
LCMS m/z=361.2 (M+H).sup.+
EXAMPLE 332
[0457] 399
[0458] Synthesis: 400
[0459] Compound 1: Compound 1 is commercially available.
[0460] Compound 2: To a refluxing solution of
2-flourophenylacetonitrile (5 ml, 41 mmol) in 100 ml of
acetonitrile was added dropwise methyl acrylate (36 ml, 400 mmol)
in 100 ml of acetonitrile for 3 h period. The resulting solution
was stirred for additional 6 h at reflux. Reaction mixture was
concentrated in vacuo, yielding oily residue, which was purified on
column chromatography (40% EtOAc/Hexane) to produce compound 2
(11.2 g, 89%) as a colorless oil.
[0461] Compound 3: To a solution of compound 2 in 200 ml of DCM was
added NaH (2.5 g, 108 mmol) in a portion and the resulting solution
was stirred at reflux for 12 h. Reaction mixture was cooled to
-78.degree. C. and quenched by adding ice. The mixture was diluted
with EtOAc (150 ml) and organic layer was filtered out. The
concentration of organic layer provided an oil (8.8 g, 89%), which
corresponds to the desired product in NMR analysis and was
subjected to the following reaction without further
purification.
[0462] Compound 4: Compound 3 was dissolved in 80 ml of DMSO and 4
ml of H.sub.2O. The mixture was stirred at 140.degree. C. for 15 h.
The reaction mixture was cooled down, diluted with EtOAc (400 ml)
and washed with 10% aqueous LiCl (30 ml.times.3). The aqueous layer
was extracted with EtOAc (50 ml.times.2). The combined organic
layer was dried over MgSO.sub.4 and concentrated in vacuo to
provide oily residue, which was purified on column chromatography
(25-50% EtOAc/hexane) to provide the desired product (5.5 g,
65%).
[0463] Compound 5: Synthesis of compound 5 was carried out in an
exactly same reaction sequence as in a synthesis of Example 31,
where the compound 1 in example 31 was substituted compound 4 in
this example. [M+H]=438.
EXAMPLES 333-334
Examples 333 to 334 were synthesized using methodology described in
Example 332.
[0464]
15 Example Structure [M + H] 333 401 452 334 402 478
EXAMPLE 335
[0465] 403
[0466] Synthesis: 404
[0467] Compound 1: Compound 1 is commercially available.
[0468] Compound 2: Compound 2 is prepared in an exact same
procedure as described in synthesis of Example 333 where
3-fluorophenylacetonitrile replaced 2-fluorophenylacetonitrile in
synthesis of Example 335.
[0469] Compound 3: Compound 3 was prepared in a sequence described
in synthesis of Example 31, where
4-(3-fluorophenyl)-4-cyanocyclohexanone 2 was used instead of
compound 1 in example 31. [M+H]=438.
[0470] Examples 336 to 341 were synthesized using methodology
described in Example 335.
16 Example Structure [M + H] 336 405 438 337 406 452 338 407 452
339 408 464 340 409 478 341 410 478
EXAMPLE 342
[0471] 411
[0472] Synthesis: 412
[0473] Compound 1: Compound 1 is commercially available.
[0474] Compound 2: Compound 2 is prepared in an exact same
procedure as described in synthesis of Example 332 where
4-fluorophenylacetonitrile replaced the
2-fluorophenylacetonitrile.
[0475] Compound 3: Compound 3 was prepared in a sequence described
in synthesis of Example 31, where compound 2 was used instead of
compound 1 in example 31. [M+H]=438.
EXAMPLES 343-348
[0476] Examples 343 to 348 were synthesized using methodology
described in Example 342.
17 Example Structure [M + H] 343 413 438 344 414 452 345 415 452
346 416 478 347 417 478 348 418 464
EXAMPLE 349
[0477] 419
[0478] Synthesis: 420
[0479] Compound 1: The synthesis of 1 was described in Example
31.
[0480] Compound 2: The synthesis of 2 was described in Example
73.
[0481] Compound 3: A solution of 2 (20 mg, 0.041 mmol),
4-(aminomethyl)pyridine (10 mg, 0.10 mmol) in 1 ml of CH.sub.3CN
was stirred for 2 h at 65.degree. C. The reaction mixture was
purified by preparative HPLC (described in a synthesis of Example
31) to yield 11.2 mg of the 3 as a colorless oil. Mass Spec
[M+H]=509.
EXAMPLES 350-396
[0482] Examples 350 to 396 were synthesized using methodology
described in Example 349.
18 Exam- [M + ple Structure H] 350 421 567 351 422 567 352 423 567
353 424 620 354 425 509 355 426 548 356 427 524 357 428 566 358 429
496 359 430 537 360 431 537 361 432 485 362 433 523 363 434 527 364
435 529 365 436 537 366 437 495 367 438 529 368 439 515 369 440 539
370 441 595 371 442 531 372 443 581 373 444 523 374 445 523 375 446
418 376 447 539 377 448 567 378 449 538 379 450 632 380 451 607 381
452 646 382 453 600 383 454 647 384 455 588 385 456 588 386 457 588
387 458 608 388 459 608 389 460 574 390 461 574 391 462 609 392 463
653 393 464 618 394 465 628 395 466 590 396 467 579
EXAMPLE 397
[0483] 468
[0484] Compound 1: Compound 1 is commercially available.
[0485] Compound 2: Compound 2 is prepared in an exact same
procedure as described in synthesis of Example 332 where
2-methoxyphenylacetonitrile replaced the 2-fluorophenylacetonitrile
in synthesis of Example 332.
[0486] Compound 3: Compound 3 was prepared in a sequence described
in synthesis of Example 31, where
4-(2-methoxyphenyl)-4-cyanocyclohexanone 2 was used instead of
compound 1 in example 31. [M+H]=450.
EXAMPLES 398-404
[0487] Examples 398 to 404 were synthesized using methodology
described in Example 397.
19 Example Structure [M + H] 398 469 476 399 470 476 400 471 490
401 472 490 402 473 464 403 474 450 404 475 464
EXAMPLE 405
[0488] 476
[0489] Synthesis: 477
[0490] Compound 1: The synthesis of 1 was described in Example
388.
[0491] Compound 2: The synthesis of 2 was proceeded in a same
procedure described in Example 73.
[0492] Compound 3: A solution of 2 (40 mg, 0.083 mmol),
4-(aminomethyl)pyridine (20 mg, 0.20 mmol) in 1 ml of CH.sub.3CN
was stirred for 2 h at 65.degree. C. The reaction mixture was
purified by preparative HPLC (described in a synthesis of Example
31) to yield 8.9 mg of the 3 as a colorless oil. Mass Spec
[M+H]=539.
EXAMPLES 406-410
[0493] Examples 406 to 410 were synthesized using methodology
described in Example 405.
20 Exam- [M + ple Structure H] 406 478 596 407 479 596 408 480 538
409 481 538 410 482 539
EXAMPLES 411 and 412
[0494] 483
[0495] Synthesis: 484
[0496] Compound 1: Synthesis of compound 1 is described in Example
31.
[0497] Compound 2: To a specially designed vial for microwave
reactor was added compound 1 (0.57 g, 2.3 mmol),
Pd.sub.2(dba).sub.3 (42 mg, 0.046 mmol), BINAP (79 mg, 0.13 mmol)
and t-BuONa (0.38 g, 2.3 mmol) in a portion. The reaction vial was
placed under vacuum to remove air. Toward the mixture was, then,
added 22 ml of degassed THF and the reaction vial was capped. The
reaction mixture was placed in microwave reactor and heated for 20
min at 180.degree. C. The reaction mixture was cooled down and
placed on column chromatography (20-50% EtOAc/Hexane) to yield 0.62
g (72%) of the desired product as oily solid.
[0498] Compound 3: Compound 2 (3.0 g, 8.0 mmol) was dissolved in
THF (60 ml) and aq. HCl (10 ml), and the resulting solution was
stirred for 4 h at 35.degree. C. THF was evaporated from the
reaction mixture and the remaining aqueous solution was extracted
with EtOAc (100 ml.times.2). The organic layer was dried over MgSO4
and concentrated in vacuo to provide an oil (2.4 g,>95%), which
was identified as the desired product (1:1 mixture of two isomers)
and subjected to the following reaction without any further
purification (>95% pure).
[0499] Compound 4: To a solution of compound 3 (1.2 g, 3.6 mmol) in
50 ml of MeOH was added NH.sub.4OAc (2.2 g, 27 mmol) and
NaBH(OAc).sub.3 (0.98 g, 4.6 mmol) in a portion and the resulting
solution was stirred at room temperature for 12 h. The reaction
mixture was concentrated in vacuo, yielding oily residue, which was
partitioned between EtOAc (200 ml) and brine (50 ml). The aqueous
layer was further extracted with EtOAc (50 ml.times.2). The
combined organic solution was dried over MgSO4 and concentrated in
vacuo to yield an oil (1.2 g,>95%), which was identified as the
desired product and subjected to following reactions without
further purification (>90% pure).
[0500] Compounds 5 and 6: Synthesis of compound 4 was carried out
in an exact same procedure as in synthesis of Example 31 using
compound 4 (0.13 g, 0.39 mmol), diphenyl cyanocarbonimidate (94 mg,
0.39 mmol) and 5 ml of 2 N MeNH.sub.2 in MeOH to produce 20.9 mg of
compound 5 and 12.3 mg of compound 6.
EXAMPLES 413-418
[0501] Examples 413 to 418 were synthesized using methodology
described in Example 411.
21 Example Structure [M + H] 413 485 427 414 486 427 415 487 453
416 488 453 417 489 439 418 490 439
EXAMPLE 419
[0502] 491
[0503] Synthesis: 492
[0504] Compound 1: Synthesis of compound 1 is described in Example
153.
[0505] Compound 2: Compound 2 was prepared as a part of the library
synthesis. The general procedure is following:
[0506] To a solution of the compound 1 (8.3 mg, 0.03 mmol) in 1 ml
of 1,2-dichloroethane was added 3-(trifluoromethyl)benzoyl chloride
(20 .mu.L, 0.14 mmol) and 20 mg polymer-bound amine (PL-MPH resin,
Polymer Laboratories) in a portion and the resulting mixture was
swirled for 12 h. Toward the reaction mixture was added
polymer-bound resin PL-EDA (50 mg, Polymer Laboratories) and the
resulting mixture was swirled for additional 5 h. The reaction
mixture was then filtered and concentrated in speed-vac to yield
8.0 mg (0.020 mmol, 67%) of the desired product as a colorless oil.
[M+H]=458.
EXAMPLES 420-449
[0507] Examples 420 to 449 were synthesized using methodology
described in Example 419.
22 Exam- [M + ple Structure H] 420 493 396 421 494 426 422 495 434
423 496 446 424 497 447 425 498 451 426 499 459 427 500 482 428 501
493 429 502 494 430 503 498 431 504 518 432 505 368 433 506 380 434
507 400 435 508 404 436 509 408 437 510 409 438 511 415 439 512 420
440 513 420 441 514 434 442 515 434 443 516 450 444 517 450 445 518
460 446 519 471 447 520 500 448 521 506 449 522 483
EXAMPLE 450
[0508] 523
[0509] Synthesis: 524
[0510] Compound 1: Synthesis of compound 1 is described in Example
153.
[0511] Compound 2: Compound 2 was prepared as a part of the library
synthesis. The general procedure is following:
[0512] To a solution of the acid (10 mg, 0.06 mmol) in 1 ml of DCM
and 0.3 ml of DMF was added EDCI (11.5 mg, 0.06 mmol), and HOAt
(8.2 mg, 0.06 mmol). Toward the solution was added the compound 1
(11 mg, 0.04 mmol) in 1.2 ml of DCE-DMF (2:1). The reaction mixture
was allowed to stir for 12 h at 25.degree. C. The reaction mixture
was purified on prep-HPLC (see Example 31) and concentrated in
speed-vac to yield 10.8 mg (0.021 mmol, 41%) of the desired product
as a colorless oil.
EXAMPLES 451-562
[0513] Examples 451 to 562 were synthesized using methodology
described in Example 450.
23 Exam- [M + ple Structure H] 451 525 440 452 526 422 453 527 429
454 528 420 455 529 424 456 530 422 457 531 429 458 532 422 459 533
433 460 534 432 461 535 419 462 536 436 463 537 436 464 538 426 465
539 457 466 540 424 467 541 450 468 542 441 469 543 450 470 544 435
471 545 440 472 546 423 473 547 455 474 548 430 475 549 456 476 550
441 477 551 419 478 552 440 479 553 447 480 554 440 481 555 455 482
556 419 483 557 446 484 558 448 485 559 448 486 560 455 487 561 422
488 562 423 489 563 450 490 564 382 491 565 385 492 566 391 493 567
384 494 568 386 495 569 368 496 570 381 497 571 410 498 572 406 499
573 405 500 574 406 501 575 407 502 576 366 503 577 371 504 578 397
505 579 408 506 580 398 507 581 408 508 582 358 509 583 414 510 584
392 511 585 407 512 586 410 513 587 372 514 588 385 515 589 405 516
590 398 517 591 413 518 592 417 519 593 417 520 594 371 521 595 406
522 596 407 523 597 394 524 598 412 525 599 408 526 600 398 527 601
380 528 602 406 529 603 404 530 604 406 531 605 408 532 606 381 533
607 397 534 608 371 535 609 411 536 610 369 537 611 406 538 612 406
539 613 399 540 614 408 541 615 407 542 616 407 543 617 406 544 618
368 545 619 407 546 620 398 547 621 356 548 622 396 549 623 384 550
624 380 551 625 384 552 626 397 553 627 380 554 628 379 555 629 407
556 630 385 557 631 410 558 632 410 559 633 406 560 634 393 561 635
397 562 636 396
EXAMPLE 563
[0514] 637
[0515] Synthesis: 638639
[0516] Compound 1: Synthesis of compound 1 is described in Example
31.
[0517] Compound 2: To a solution of 6-methoxysalicyclic acid (4.2
g, 25 mmol) in DCM (15 ml) and DMF (5 ml) was added EDCI (3.8 g,
1.3 25 mmol) and HOAt (33.4 g, 25 mmol) in a portion, respectively
and the resulting solution was stirred for 0.5 h. The mixture was
added dropwise into a solution of compound 1 (4.7 g, 19 mmol) in 15
ml of DCM. The resulting solution was stirred for 12 h at
25.degree. C. The reaction mixture was evaporated in vacuo to yield
oily residue, which was purified on column chromatography (20-50%
EtOAc/Hexane) to provide the compound 2 (5.8 g, 77%) as a colorless
oil.
[0518] Compound 3: Compound 2 (5.8 g, 14.6 mmol) was dissolved in
THF (80 ml) and 2N HCl-MeOH (40 ml). The mixture was allowed to
stir for 5 h at 50.degree. C. The reaction mixture was then poured
into EtOAc (300 ml) and the organic layer was separated. The
aqueous layer was extracted with EtOAc (50 ml.times.2). The
combined organic layer was washed with aq. NaHCO.sub.3, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo to provide the desired
product (4.0 g, 80%), which was pure (>95%) and subjected to
following reactions without any further purification.
[0519] Compound 4: The compound 3 (4.0 g, 11.3 mmol) was dissolved
in MeOH (100 ml) and stirred with NaBH.sub.4 (0.50 g, 13 mmol) for
3 h at -78.degree. C. HPLC analysis showed the reaction was
completed. The mixture was concentrated in vacuo to produce a white
solid mixture, which was partitioned between EtOAc (200 ml) and
brine (50 ml). The organic layer was dried over Na.sub.2SO.sub.4
and concentrated in vacuo to provide the alcohol (4.0 g,>95%) as
an oil. The alcohol was dissolved in 30 ml of DCM and added
pyridine (10 ml) and methanesulfonyl chloride (1.1 ml, 13.6 mmol)
at 0.degree. C. The resulting solution was stirred for 12 h at
25.degree. C. The reaction was quenched by adding water. Aqueous
layer was further extracted with DCM (20 mL.times.2). The combined
organic solution was washed with 1N aq. HCl (30 ml.times.2) and
dried over Na.sub.2SO.sub.4. Concentration of the organic solution
provided the desired product (5.2 g, 85% pure) as an oil, which was
subjected to following reaction without any further
purification.
[0520] Compound 5: The compound 4 from above was dissolved in 20 ml
of DMF and was added NaN.sub.3 (1.2 g, 15 mmol). The mixture was
allowed to stir at 80.degree. C. for 12 h. The reaction mixture was
concentrated in vacuo to remove DMF and partitioned between EtOAc
(100 ml) and brine (30 ml). The aqueous layer was extracted with
EtOAc (50 ml.times.2). The combined organic solution was purified
on CombiFlash (0 to 20% EtOAc/hexane) to yield the desired product
(2.0 g, 5.3 mmol, 53% for two steps) as a mixture of cis- and
trans-isomers (4:1) ratio.
[0521] Compound 6: The compound 5 was dissolved in 30 ml of MeOH
and was added catalytic amount of 10% Pd/C. The mixture was placed
under H.sub.2 and stirred for 2 h at 25.degree. C. The reaction
mixture was filtered through celite assisted funnel. The filtrate
was concentrated in vacuo to provide the desired product (1.4 g,
75%) as a colorless oil.
[0522] Compound 7: To a solution of the compound 6 (0.36 g, 1 mmol)
in 10 ml of isopropanol was added diphenyl cyanocarbonimidate (0.24
g, 1 mmol) and the resulting solution was stirred for 5 h at
60.degree. C. The reaction mixture was then concentrated in vacuo
to provide oily residue, which was dissolved in 10 ml of
MeNH2--MeOH solution and stirred for 5 h at 80.degree. C. in a
sealed tube. The reaction mixture was concentrated and purified on
CombiFlash (20-100% EtOAc/Hexane) to yield the desired product
(0.34 g, 78%). [M+H]=436.
EXAMPLES 564-571
[0523] Examples 564 to 571 were synthesized using methodology
described in Example 563.
24 Example Structure [M + H] 564 640 422 565 641 422 566 642 450
567 643 450 568 644 476 569 645 476 570 646 462 571 647 462
EXAMPLE 572 AND EXAMPLE 573
[0524] 648
[0525] Synthesis: 649
[0526] Compound 1: Synthesis of compound 1 is described in Example
554.
[0527] Compound 2: To a solution of chloro sulfonylisocyanate (22
.mu.l, 0.25 mmol) in 1 ml of DCM was added chloroethanol (17 .mu.l,
0.25 mmol) at 0.degree. C. The reaction was then allowed to stir
for additional 4 h 25.degree. C. The reaction mixture was cooled
down to 0.degree. C. again and added 90 mg (0.25 mmol) of compound
1 in 2 ml of DCM. The reaction mixture was stirred for additional
12 h at 25.degree. C. The reaction mixture was then diluted with 10
ml of DCM and washed with 1N aq. HCl. Organic solution was dried
over Na.sub.2SO.sub.4 and concentrated in vacuo to provide 130 mg
of the desired product, which was subjected to the following
reaction without any further purification.
[0528] Compound 3 and 4: Compound 2 (30 mg, 0.07 mmol) and
4-(aminomethyl)pyridine (16 mL, 0.14 mmol) was diluted in 1 ml of
CH.sub.3CN and stirred for 12 h at 60.degree. C. The reaction
mixture was purified on preparative HPLC (see Example 31) to
provide 12.7 mg of Example 572 and 3.3 mg of Example 573.
EXAMPLES 574-579
[0529] Examples 574 to 579 were synthesized using methodology
described in Example 572.
25 Example Structure [M + H] 574 650 525 575 651 525 576 652 540
577 653 540 578 654 506 579 655 506
EXAMPLE 580
[0530] 656
[0531] Synthesis: 657
[0532] Compound 1: Synthesis of compound 1 is described in Example
31.
[0533] Compound 2: To a solution of compound 1 (0.20 g, 0.60 mmol)
and Et.sub.3N (0.5 ml) in 5 ml of DCM was added triphosgene (0.20
g, 0.67 mmol) in a portion and the resulting solution was stirred
for I h at 25.degree. C. The reaction mixture was concentrated in
vacuo to provide oily residue, which was purified on column
chromatography (50% EtOAc/Hexane) to yield 213 mg (0.58 g, >95%)
of the desired product as an oil.
[0534] Compound 3: To a solution of the compound 2 (20 mg, 0.055
mmol) and benzenesulfonamide (20 mg, 0.13 mmol) in 2 ml of acetone
was added 0.2 ml of 1N aq. NaOH in a portion and the resulting
solution was stirred for 1 h at 25.degree. C. The solution was
neutralized by adding 0.2 ml of aq. HCl and subjected to
preparative HPLC see Example 31) to provide 10.1 mg (0.019 mmol,
30%) of the desired product as a white solid after concentration in
speed-vac. [M+H]=522.
EXAMPLES 581-590
[0535] Examples 581 to 590 were synthesized using methodology
described in Example 580.
26 Ex- am- [M + ple Structure H] 581 658 587 582 659 615 583 660
460 584 661 462 585 662 618 586 663 563 587 664 661 588 665 514 589
666 601 590 667 461
EXAMPLE 591
[0536] 668
[0537] Synthesis: 669
[0538] Compound 1: Synthesis of compound 1 is described in Example
31.
[0539] Compound 2: To a solution of compound 1 (338 mg, 1.0 mmol)
in 10 ml of ethanol was added dimethyl N-cyanodithioiminocarbonate
(147 mg, 1.0 mmol) in a portion and the resulting solution was
stirred for 2 h at 70.degree. C. HPLC and LC-MS analysis showed a
completion of the reaction. Reaction mixture was concentrated in
vacuo to provide an oil, which was subjected to the following
reaction without any further purification.
[0540] Compound 3: Compound 2 (40 mg, 0.09 mmol), NaOH (3.7 .mu.g,
0.09 mmol) and 4-chlorobenzenesulfonamide (34 mg, 0. 1 8 mmol) were
dissolved in 1 ml of dioxane. The resulting solution was stirred
for 15 min at 230.degree. C. in microwave reactor. The reaction
mixture was then cooled down and purified in preparative HPLC (see
Example 31) to yield 6.2 mg, (0.011 mmol, 11%) of the deised
product as a light gray solid upon concentration of the elute.
[M+H]=581.
EXAMPLES 592 AND 593
[0541] Examples 592 and 593 were synthesized using methodology
described in Example 591.
27 Example Structure [M + H] 592 670 546 593 671 484
EXAMPLE 594
[0542] 672
[0543] Synthesis: 673674
[0544] Compound 1: Compound 1 is commercially available.
[0545] Compound 2: To a solution of compound 1 (4.6 ml, 40 mmol) in
100 ml of dry THF was added MeLi (2N in THF, 40 mmol) dropwise and
the resulting solution was stirred for 1 h at -78.degree. C. Toward
the solution was added bromoepihydrin (3.4 ml, 40 mmol) in 50 ml of
THF dropwise for 30 min period and the reaction mixture was stirred
for another 1 h at -78.degree. C. MeMgBr (3M in THF, 40 mmol) was
added into the reaction mixture. The reaction mixture was stirred
for additional 12 h at ambient temperature. Reaction mixture was,
then, diluted with EtOAc (250 mL) and washed with brine (50
ml.times.3). Organic layer was dried over MgSO4 and concentrated in
vacuo to provide oily residue, which was purified on CombiFlash (0
to 100% EtOAc/Hexane) to provide 5.6 g, (29 mmol, 73%) of the
desired product as a mixture of cis and trans isomers (4:1).
[0546] Compound 3: Toward solution of compound 2 (1.6 g, 9.0 mmol)
in 30 ml of THF was added LAH (1.0 M in THF, 10 mmol) and the
resulting solution was stirred for 4 h at 70.degree. C. The
reaction was quenched by adding pieces of ice and mixture was
filtered through celite. Concentration of filterate provided an oil
(1.5 g, >95%), which was subjected to following reaction without
any further purification.
[0547] Compound 4: To a solution of the compound 3 (1.5 g, 9.0
mmol) in 50 ml of THF and Et.sub.3N (2.0 ml) was added anisoyl
chloride (1.3 ml, 9.0 mmol) dropwise and the resulting solution was
stirred for 1 h at 25.degree. C. Reaction mixture was then diluted
with EtOAc (100 ml) and washed with brine. Organic solution was
dried over MgSO.sub.4 and concentrated in vacuo to provide an oil,
which was identified as bis-acylated product. The product was
dissolved in 30% aq. THF (20 ml) and LiOH (300 mg) was added into
it. The resulting mixture was stirred for 12 h at 70.degree. C. The
mixture was diluted with EtOAc (50 ml) and washed with brine (30
ml). Concentration of the organic layer after drying over
MgSO.sub.4 provided oily residue, which was purified on CombiFlash
to provide 1.5 g, (4.5 mmol, 50% for two steps) of the desired
product as a colorless oil.
[0548] Compound 5: Compound 4 was dissolved in 10 ml of DCM and 2
ml of pyridine. Toward the solution was added methanesulfonyl
chloride (1 ml, 13 mmol) and the resulting solution was stirred for
2 h at 25.degree. C. The reaction mixture was diluted with EtOAc
(200 ml) and washed with brine (30 ml.times.2). The organic layer
was dried over MgSO.sub.4 and concentrated in vacuo to provide an
oil, which was subjected to following reaction without any further
purification.
[0549] Compound 6: Compound 5 and NaN.sub.3 (1.3 g, 8.9 mmol) were
dissolved in 10 ml of DMF and the mixture was stirred for 5 h at
120.degree. C. The reaction mixture was diluted with EtOAc (100 ml)
and washed with brine (20 ml.times.3). The organic solution was
dried over Na.sub.2SO.sub.4 and concentrated in vacuo to provide an
oil, which was purified CombiFlash (0-30% EtOAc/hexane) to provide
1.1 g of the azide. The azide was dissolved in 20 ml of MeOH and
catalytic amount of 10% Pd--C was added into the solution. The
reaction mixture was stirred under H.sub.2 for 2 h. Reaction
mixture was filtered through funnel (Whatman, 0.45 .mu.m NYL) and
concentrated in vacuo to provide the desired product (1.1 g, 79%
from compound 4) as a colorless oil.
[0550] Compound 7: To a solution of compound 6 (180 mg, 0.58 mmol)
in 5 ml of isopropanol was added diphenyl cyanocarbonimidate (150
mg, 0.64 mmol) and the resulting solution was stirred for 2 h at
80.degree. C. The reaction mixture was then concentrated in vacuo
to provide oily residue It was redissolved in 5 ml of 2N MeNH.sub.2
in methanol and stirred for 5 h at 80.degree. C. in a sealed tube.
Progress of the reaction was monitored by HPLC. The reaction
mixture was concentrated in vacuo to yield oily residue, which was
purified on CombiFlash (0-100% EtOAc/hexane) to provide 0.12 g
(0.29 mmol, 50%) of the desired product as a mixture of cis and
trans isomers. [M+H]=410.
EXAMPLES 595-597
[0551] Examples 595 to 597 were synthesized using methodology
described in Example 594.
28 Example Structure [M + H] 595 675 424 596 676 424 597 677 396
598 678 436
EXAMPLE 599
[0552] 679
[0553]
cis-N-{4-[N'-Cyano-N"-ethyl-N-(2-methoxy-ethyl)-guanidino]-1-phenyl-
-cyclohexylmethyl}-2-methoxy-benzamide
[0554] Synthesis: 680
[0555] Compound 1: The synthesis of 1 has been previously
described.
[0556] Compounds 2 and 3: To a solution of 1 (185 mg, 0.55 mmol) in
1,2-dichloroethane (2 mL) was added 2-methoxyethylamine (0.048 mL,
0.55 mmol) followed by sodium triacetoxyborohydride (163 mg, 0.77
mmol) and acetic acid (0.031 mL, 0.55 mmol), then the reaction
stirred for 1.5 hours. The reaction was quenched by addition of 1N
NaOH (2 mL) then extracted with Et.sub.2O (3.times.4 mL). The
combined organic extracts were washed with brine (2 mL), dried
(MgSO.sub.4) filtered and concentrated in vacuo. The residue was
chromatographed on silica, gradiently eluted using 1:1:98 to 1:5:94
NH.sub.4OH/MeOH/CHCl.sub.3, to give 2 (80 mg, 37% yield, HPLC Rt
1.50 min using Phenomenex 30.times.4.6 5 u column over 2 min
gradient using flow rate of 5 mL/min. 0 to 100% Solvent B. Solvent
A=10/90/0.1% MeOH/H2O/TFA. Solvent B=90/10/0.1%. M+H=397.3) and 3
(66 mg, 30% yield, HPLC Rt 1.43 min using Phenomenex 30.times.4.6 5
u column over 2 min gradient using flow rate of 5 mL/min. 0 to 100%
Solvent B. Solvent A=10/90/0.1% MeOH/H2O/TFA. Solvent B=90/10/0.1%.
M+H=397.3) as white solids.
[0557] Compound 4: To a solution of the cis-isomer of the amine 2
(15 mg, 0.038 mmol) in 2-propanol (1 mL) was added
1-cyano-3-ethyl-2-phenyl-isour- ea (36 mg, 0.19 mmol) then the
reaction mixture was heated in a 75.degree. C. oil-bath for 5 days.
The solvent was removed under a stream of nitrogen then the residue
purified by prep TLC eluted with 5:20:75 MeOH/EtOAc/hexanes to give
4 (9.5 mg, 51% yield, HPLC Rt 1.88 min using Phenomenex
30.times.4.6 5u column over 2 min gradient using flow rate of 5
mL/min. 0 to 100% Solvent B. Solvent A=10/90/0.1% MeOH/H2O/TFA.
Solvent B=90/10/0.1%. M+H=492.3) as a white solid.
EXAMPLES 600-604
[0558] Examples 600 to 604 were prepared using methodology
described in Example 599.
29 Ex. Structure Name [M + 1] 600 681 Cis-N-[4-(N'-Cyano-N"-
ethyl-N-methyl-guanidino)- 1-phenyl-cyclohexylmethyl]-
2-methoxy-benzamide 448 601 682 Cis-N-[4-(N-Benzyl-N'-
cyano-N"-ethyl-guanidino)- 1-phenyl-cyclohexylmethyl]-
2-methoxy-benzamide 524 602 683 Cis-N-[4-(N'-Cyano-N"-
ethyl-N-pyridin-2-ylmethyl- guanidino)-1-phenyl-
cyclohexylmethyl]-2-methoxy- benzamide 525 603 684
Cis-N-[4-(N'-Cyano-N"- ethyl-N-pyridin-3-ylmethyl-
guanidino)-1-phenyl- cyclohexylmethyl]-2-methoxy- benzamide 525 604
685 Cis-N-[4-(N'-Cyano-N"- ethyl-N-furan-2-ylmethyl-
guanidino)-1-phenyl- cyclohexylmethyl]-2- methoxy-benzamide 514
EXAMPLE 605
[0559] 686
[0560]
trans-N-{4-[N'-Cyano-N"-ethyl-N-(2-methoxy-ethyl)-guanidino]-1-phen-
yl-cyclohexylmethyl}-2-methoxy-benzamide
[0561] Synthesis: 687
[0562] Compound 3: The synthesis of compound 3 is described in
Example 599.
[0563] Compound 5: To a solution of the trans-isomer of the amine 3
(15 mg, 0.038 mmol) in 2-propanol (1 mL) was added
1-cyano-3-ethyl-2-phenyl-i- sourea (36 mg, 0.19 mmol) then the
reaction mixture was heated in a 75.degree. C. oil-bath for 5 days.
The solvent was removed under a stream of nitrogen then the residue
purified by prep TLC eluted with 5:20:75 MeOH/EtOAc/hexanes to give
5 (10.8 mg, 58% yield, HPLC Rt 1.77 min using Phenomenex
30.times.4.6 5 u column over 2 min gradient using flow rate of 5
mL/min. 0 to 100% Solvent B. Solvent A=10/90/0.1% MeOH/H2O/TFA.
Solvent B=90/10/0.1%. M+H=492.3) as a white solid.
EXAMPLES 606-609
[0564] Examples 606 to 609 were prepared using methodology
described in Example 605.
30 Ex. Structure Name [M + 1] 606 688 Trans-N-[4-(N'-Cyano-N"-
ethyl-N-methyl- guanidino)-1-phenyl- cyclohexylmethyl]-2-
methoxy-benzamide 448 607 689 Trans-N-[4-(N'-Cyano-N"-
ethyl-N-pyridin-2- ylmethyl-guanidino)-1- phenyl-cyclohexylmethyl]-
2-methoxy-benzamide 525 608 690 Trans-N-[4-(N'-Cyano-N"-
ethyl-N-pyridin-3- ylmethyl-guanidino)-1- phenyl-cyclohexylmethyl]-
2-methoxy-benzamide 525 609 691 Trans-N-[4-(N'-Cyano-N"-
ethyl-N-furan-2-ylmethyl- guanidino)-1-phenyl- cyclohexylmethyl]-2-
methoxy-benzamide 514
EXAMPLE 610
[0565] 692
[0566]
cis-2-Methoxy-N-{4-[(2-methoxy-ethyl)-(morpholine-4-sulfonyl)-amino-
]-1-phenyl-cyclohexylmethyl}-benzamide
[0567] Synthesis: 693
[0568] Compound 2: The synthesis of compound 2 is described in
Example 599.
[0569] Compound 6: To a solution of the cis-isomer of the amine 2
(15 mg, 0.038 mmol) in dimethylformamide (0.5 mL) was added
triethylamine (0.007 mL, 0.05 mmol) followed by
morpholine-4-sulfonyl chloride (8.4 mg, 0.045 mmol) and a catalytic
amount of DMAP. The reaction was stirred for 5 days then diluted
with 50% EtOAc/hexanes (4 mL) and washed w/ 0.1N HCl (2 mL) and
brine (2 mL). The organic phase was dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. The residue was purified by
prep TLC eluted with 3:25:72 MeOH/hexanes /EtOAc to give 6 (7.8 mg,
38% yield, HPLC Rt 2.30 min using Phenomenex 30.times.4.6 5 u
column over 2 min gradient with I min hold time using flow rate of
5 mL/min. 0 to 100% Solvent B. Solvent A=10/90/0.1% MeOH/H2O/TFA.
Solvent B=90/10/0.1%. M+H=546.1) as a white solid.
EXAMPLES 611-615
[0570] Examples 611 to 615 were prepared using methodology
described in Example 610.
31 Ex. Structure Name [M + 1] 611 694 Cis-2-Methoxy-N-{4-
[methyl-(morpholine-4- sulfonyl)-amino]-1-phenyl-
cyclohexylmethyl}- benzamide 502 612 695 Cis-N-{4-[Benzyl-
(morpholine-4-sulfonyl)- amino]-1-phenyl- cyclohexylmethyl}-2-
methoxy-benzamide 578 613 696 Cis-2-Methoxy-N-{4-
[(morpholine-4-sulfonyl)- pyridin-2-ylmethyl- amino]-1-phenyl-
cyclohexylmethyl}- benzamide 579 614 697 Cis-2-Methoxy-N-{4-
[(morpholine-4-sulfonyl)- pyridin-3-ylmethyl- amino]-1-phenyl-
cyclohexylmethyl}- benzamide 579 615 698 Cis-N-{4-[Furan-2-
ylmethyl-(morpholine-4- sulfonyl)-amino]-1-phenyl-
cyclohexylmethyl}-2- methoxy-benzamide 568
EXAMPLE 616
[0571] 699
[0572]
trans-2-Methoxy-N-{4-[(2-methoxy-ethyl)-(morpholine-4-sulfonyl)-ami-
no]-1-phenyl-cyclohexylmethyl}-benzamide 700
[0573] Compound 3: The synthesis of compound 3 is described in
Example 599.
[0574] Compound 7: To a solution of the trans-isomer of the amine 3
(15,mg, 0.038 mmol) in dimethylformamide (0.5 mL) was added
triethylamine (0.007 mL, 0.05 mmol) followed by
morpholine-4-sulfonyl chloride (8.4 mg, 0.045 mmol) and a catalytic
amount of DMAP. The reaction was stirred for 5 days then diluted
with 50% EtOAc/hexanes (4 mL) and washed w/ 0.1N HCl (2 mL) and
brine (2 mL). The organic phase was dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. The residue was purified by
prep TLC eluted with 3:25:72 MeOH/hexanes/EtOAc to give 7 (3.8 mg,
18% yield, HPLC Rt 2.20 min using Phenomenex 30.times.4.6 5 u
column over 2 min gradient with 1 min hold time using flow rate of
5 mL/min. 0 to 100% Solvent B. Solvent A=10/90/0.1% MeOH/H2O/TFA.
Solvent B=90/10/0.1%. M+H=546.1) as a white solid.
EXAMPLES 617-621
[0575] Examples 617 to 621 were prepared using methodology
described in Example 616.
32 Ex. Structure Name [M + 1] 617 701 Trans-2-Methoxy-N-{4-
[methyl-(morpholine-4- sulfonyl)-amino]-1- phenyl-
cyclohexylmethyl}- benzamide 502 618 702 Trans-N-{4-[Benzyl-
(morpholine-4- sulfonyl)-amino]-1- phenyl- cyclohexylmethyl}-2-
methoxy-benzamide 578 619 703 Trans-2-Methoxy-N-{4- [(morpholine-4-
sulfonyl)-pyridin-2- ylmethyl-amino]-1- phenyl- cyclohexylmethyl}-
benzamide 579 620 704 Trans-2-Methoxy-N-{4- [(morpholine-4-
sulfonyl)-pyridin-3- ylmethyl-amino]-1- phenyl- cyclohexylmethyl}-
benzamide 579 621 705 Trans-N-{4-[Furan-2- ylmethyl-(morpholine-4-
sulfonyl)-amino]-1- phenyl- cyclohexylmethyl}-2- methoxy-benzamide
568
EXAMPLE 622
[0576] 706
[0577] N-(1-Benzyl-cyclohexylmethyl)-2-methoxy-benzamide
[0578] Synthesis: 707
[0579] Compound 1: Compound 1 is commercially available.
[0580] Compound 2: A solution of cyclohexanecarbonitrile (6.14 g;
56.2 mmol) in tetrahydrofuran (40 mL) was cooled to -78.degree. C.
under argon and treated with a 2M solution of lithium
diisopropylamide in THF/n-heptane (36 mL; 72 mmol). The cooling
bath was removed and the reaction mixture was allowed to stir at
room temperature for 10 minutes. The reaction mixture was cooled
back to -78.degree. C., treated with a solution of benzyl bromide
(9.8 g; 57.3 mmol) in tetrahydrofuran (10 mL) and allowed to slowly
warm to room temperature overnight. The reaction mixture was
concentrated and the residue was portioned between ethyl ether and
a 10% aqueous hydrochloric acid solution. The organic layer was
separated, washed with saturated aqueous sodium chloride, dried
(anhydrous sodium sulfate), filtered and concentrated. Column
chromatography on silica gel using 9:1 hexane:ethyl acetate as the
eluent gave 11 g of compound 2 as a clear oil. Mass Spec
[M+H].sup.+=200.
[0581] Compound 3: A solution of compound 2 (3.8 g; 19.1 mmol) in
tetrahydrofuran (40 mL) was cooled to 0.degree. C. and treated with
lithium aluminum hydride (3.8 g; 100.1 mmol) in portions. The
reaction mixture was allowed to slowly warm to room temperature
overnight. The reaction mixture was carefully quenched with 2N
sodium hydroxide (approximately 2 mL), filtered through a plug of
celite using ethyl acetate as the eluent, dried (anhydrous sodium
sulfate), filtered and concentrated to give 3.8 g of compound 3 as
a clear oil which was used in the next step with no additional
purification. Mass Spec [M+H].sup.+=204.
[0582] Title Compound: A solution of compound 3 (0.38 g; 1.8 mmol)
in tetrahydrofuran (20 mL) was treated with triethylamine (0.2 mL;
1.4 mmol) followed by o-anisoyl chloride (0.34 g; 2.0 mmol) at room
temperature. The reaction was allowed to stir 48 h at which time
the solvent was removed under reduced pressure. The residue was
portioned between ethyl acetate and a 10% aqueous hydrochloric acid
solution. The organic layer was separated, washed with saturated
aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered
and concentrated. Column chromatography on silica gel using 8:1
hexane:ethyl acetate as the eluent gave 0.46 g of
N-(1-benzyl-cyclohexylmethyl)-2-methoxy-benzamide as a clear oil.
Mass Spec [M+H].sup.+=338.
EXAMPLES 623-647
[0583] Examples 623-647 may be prepared using methodology described
in Example 622.
33 Ex. Structure Name [M + H].sup.+ 623 708 N-(1-Benzyl-
cyclohexylmethyl)-2- trifluoromethyl-benzamide 376 624 709
N-(1-Benzyl- cyclohexylmethyl)-3- methoxy-benzamide 338 625 710
N-(1-Benzyl- cyclohexylmethyl)-3-cyano- benzamide 333 626 711
N-(1-Benzyl- cyclohexylmethyl)-2-fluoro- 6-trifluoromethyl-
benzamide 394 627 712 N-(1-Benzyl- cyclohexylmethyl)-4-fluoro-
2-trifluoromethyl- benzamide 394 628 713 N-(1-Benzyl-
cyclohexylmethyl)-2,4- difluoro- benzenesulfonamide 380 629 714
N-(1-Benzyl- cyclohexylmethyl)-2,5- dimethoxy- benzenesulfonamide
404 630 715 N-(1-Benzyl- cyclohexylmethyl)-2,3- difluoro-benzamide
344 631 716 N-(1-Benzyl- cyclohexylmethyl)-4- methyl-benzamide 322
632 717 N-(1-Benzyl- cyclohexylmethyl)-2,4- difluoro-benzamide 344
633 718 N-(1-Benzyl- cyclohexylmethyl)-2,6- difluoro-benzamide 344
634 719 N-(1-Benzyl- cyclohexylmethyl)-2-chloro- nicotinamide 343
635 720 N-(1-Benzyl- cyclohexylmethyl)-2- methoxy-acetamide 276 636
721 N-(1-Benzyl- cyclohexylmethyl)-3,4- difluoro-benzamide 344 637
722 N-(1-Benzyl- cyclohexylmethyl)-2,4,5- trifluoro-benzamide 362
638 723 N-(1-Benzyl- cyclohexylmethyl)-5-fluoro- 2-methyl-benzamide
340 639 724 N-(1-Benzyl- cyclohexylmethyl)-3-chloro- benzamide 342
640 725 N-(1-Benzyl- cyclohexylmethyl)- benzamide 308 641 726
N-(1-Benzyl- cyclohexylmethyl)-3,5- dimethoxy-benzamide 368 642 727
N-(1-Benzyl- cyclohexylmethyl)-2- trifluoromethoxy-
benzenesulfonamide 428 643 728 N-(1-Benzyl- cyclohexylmethyl)-2-
phenyl-acetamide 322 644 729 N-(1-Benzyl- cyclohexylmethyl)-2-(4-
fluoro-phenyl)-acetamide 340 645 730 N-(1-Benzyl-
cyclohexylmethyl)-2-(4- methoxy-phenyl)-acetamide 352 646 731
2-Phenyl- cyclopropanecarboxylic acid (1-benzyl-
cyclohexylmethyl)-amide 348 647 732 N-(1-Benzyl-
cyclohexylmethyl)-3- phenyl-propionamide 336
EXAMPLE 648
[0584] 733
[0585] 2-Methoxy-N-(1-phenyl-cyclohexylmethyl)-nicotinamide
[0586] Synthesis: 734
[0587] Compound 1: Compound 1 was prepared as described in Example
330.
[0588] Title Compound: A suspension of 2-methoxynicotinic acid
(0.23 g; 1.5 mmol) in methylene chloride (15 ml) was treated with
oxalyl chloride (0.14 mL; 1.6 mmol) and 2 drops of
N,N-dimethylformamide. The reaction mixture was allowed to stir at
room temperature for 30 minutes at which time triethylamine (0.3
mL; 2.2 mmol) and compound 1 (0.315 g; 1.66 mmol). After an
additional 15 minutes of stirring the reaction mixture was washed
with water and saturated aqueous sodium chloride, dried (magnesium
sulfate) and concentrated. The crude residue was purified by column
chromatography on silicia gel using 7:3 hexane:ethyl acetate as the
eluent to give 0.37 g of
2-Methoxy-N-(1-phenyl-cyclohexylmethyl)-nico- tinamide as a white
solid. Mass Spec [M+H].sup.+=325.
EXAMPLE 649
[0589] 735
[0590] Synthesis: 736
[0591] Compound 1: Compound 1 was prepared as described in Example
330.
[0592] Compound 2: A solution of compound 1 (1.2 g; 6.3 mmol) in
anhydrous acetonitrile (30 mL) was treated with diphenyl
N-cyanocarbonimidate (2.2 g; 9.2 mmol) and heated at 80.degree. C.
for 4 h. The reaction mixture was allowed to stand at room
temperature overnight. The white precipitate that formed was
collected by filtration and washed with hexane to provide 1.0 g of
compound 2 as a white solid. Mass Spec [M+H].sup.+=334.
[0593] Title Compound: Compound 2 (0.027 g; 0.08 mmol) was treated
with a 2 M solution of ethylamine in THF (0.5 mL; 1 mmol) and
heated at 60.degree. C. in a screw cap vial overnight. The solvent
and excess ethylamine was removed by evaporation and the crude
product was purified by preparative reverse-phase liquid
chromatography to give 0.008 g of the title compound as a white
solid. Mass Spec. [M+H].sup.+=285.
EXAMPLES 650-660
[0594] Examples 650-660 were prepared using methodology described
in Example 649.
34 [M + Ex. Structure H].sup.+ 650 737 348 651 738 408 652 739 326
653 740 312 654 741 349 655 742 349 656 743 378 657 744 362 658 745
328 659 746 374 660 747 312
EXAMPLE 661
[0595] 748
[0596]
5-Benzyl-3-(1-phenyl-cyclohexylmethyl)-imidazolidine-2,4-dione
[0597] Synthesis: 749
[0598] Compound 1: Compound 1 was prepared as described in Example
330.
[0599] Title Compound: A solution of compound 1 (0.255 g; 1.35
mmol) in anhydrous dichloromethane (8 mL) was treated with ethyl
2-isocyanato-3-phenylpropionate (0.325 g; 0.38 mmol) and stirred at
room temperature overnight. The solvent was removed by evaporation,
the residue was dissolved in ethanol (1 mL), 6N hydrochloric acid
(0.5 mL) and water (0.5 mL) and the reaction mixture was heated to
50.degree. C. After 3 h at 50.degree. C., additional 6N
hydrochloric acid (1 mL) was added and the reaction mixture was
heated at 65.degree. C. overnight. The reaction mixture was
concentrated and the crude product was purified directly by column
chromatography on silica gel using 1:1 ethyl acetate:hexane as the
the eluent to give 0.053 g of
5-Benzyl-3-(1-phenyl-cyclohexylmethyl)-imidazolidine-2,4-dione as a
white solid. Mass Spec [M+H].sup.+=363.
EXAMPLE 662
[0600] 750
[0601] 1-Isopropenyl-cyclohexanecarboxylic acid
(3-phenyl-propyl)-amide
[0602] Synthesis: 751
[0603] Compound 1: Compound 1 is commercially available.
[0604] Compound 2: To a solution of diisopropylamine (4.2 mL) in
THF (30 mL) at 0.degree. C. was added n-BuLi in hexanes (1.6 M, 19
mL). After stirring for 30 min., the reaction mixture was cooled to
-78.degree. C. and cyclohexanecarbonitrile (1.09 g, 10 mmol) in THF
(10 mL) was added drop wise. After 2 h, acetone (1.16 g, 20 mmol)
was added. The reaction mixture was stirred from -78.degree. C. to
rt overnight, diluted with Et.sub.2O (100 mL), washed with 1N HCl,
H.sub.2O, brine and dried over anhydrous sodium sulfate.
Purification by flash chromatography (1:1, hexanes-Et.sub.2O) gave
1-(1-hydroxy-1-methyl-ethyl)-cyclohexanecarbonitr- ile (1.27 g,
76%) as a colorless oil. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
(ppm) 0.86-1.91 (8 H, m), 1.35 (6 H, s), 2.01 (2 H, d, J=12.8 Hz),
3.65 (1 H, t, J=6.4 Hz). Mass Spec [M+H].sup.+=168.1.
[0605] Compound 3: Compound 2 (530 mg, 3.17 mmol) and phosphorus
oxychloride (11.7 g, 76.1 mmol) in CHCl.sub.3 (12 mL) was heated at
reflux for 18 h then cooled to rt. Water (75 mL) was slowly added.
The aqueous layer was extracted with CH.sub.2Cl.sub.2 (2.times.)
and the combined extracts were dried over anhydrous sodium sulfate.
Purification by flash chromatography (2:1,
hexanes-CH.sub.2Cl.sub.2) gave
1-isopropenyl-cyclohexanecarbonitrile (1.27 g, 76%) as a colorless
oil. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 1.16-2.17 (13
H, m), 4.96 (1 H, s), 5.11 (1 H, s). Mass Spec
[M+H].sup.+=150.1.
[0606] Compound 4: Compound 3 (280 mg, 1.87 mmol) and KOH (460 mg,
8.20 mmol) in ethylene glycol (3.7 mL) was heated at 185.degree. C.
for 18 h then cooled to rt. The reaction mixture was diluted with
H.sub.2O then extracted with Et.sub.2O (2.times.). The aqueous
phase was acidified with 6N HCl then extracted with
CH.sub.2Cl.sub.2 (3.times.) and dried over anhydrous sodium sulfate
to give 1-isopropenyl-cyclohexanecarboxylic acid (234 mg, 74%) as a
waxy white solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm)
1.16-1.65 (9 H, m), 1.79 (3 H, s), 2.16-2.20 (2 H, m), 4.99 (2 H,
s). Mass Spec [M+H].sup.+=169.1.
[0607] Title Compound: Compound 4 was made to react with
3-phenylpropylamine using methodology described in Example 74 to
give 1-isopropenyl-cyclohexanecarboxylic acid
(3-phenyl-propyl)-amide. Mass Spec [M+H].sup.+=286.1.
EXAMPLES 663-665
[0608] Examples 663-665 were prepared using methodology described
in Example 662.
35 Ex Structure Name [M + H].sup.+ 663 752 1-Isopropenyl-
cyclohexanecarboxylic acid(3,3-diphenyl- propyl)-amide 362 664 753
1-Isopropenyl- cyclohexanecarboxylic acid(biphenyl-3-
ylmethyl)-amide 334 665 754 1-Isopropenyl- cyclohexanecarboxylic
acid isoquinolin-1- ylamide 295
EXAMPLE 666
[0609] 755
[0610] 1-Isopropyl-cyclohexanecarboxylic acid
(3-phenyl-propyl)-amide
[0611] Synthesis: 756
[0612] Compound 1: Compound 1 may be prepared as described in
Example 662.
[0613] Title Compound: Compound 1 (33 mg, 0.12 mmol) and 10% Pd on
carbon (30 mg), in EtOH (1 mL) was stirred under hydrogen for 18 h.
The reaction mixture was filtered over celite and concentrated to
give 1-isopropyl-cyclohexanecarboxylic acid (3-phenyl-propyl)-amide
(33 mg, 100%) as a colorless oil. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. (ppin) 0.86 (6 H, d, J=6.8 Hz), 1.00-1.40 (5 H, m),
1.50-1.65 (4 H, m), 1.80-1.90 (4 H, m), 2.67 (2 H, t, J=7.5 Hz),
3.33-3.48 (2 H, m), 5.59 (1 H, ),7.17-7.31 (5 H, m). Mass Spec
[M+H].sup.+=288.
EXAMPLES 667-668
[0614] Examples 667-668 were prepared using methodology described
in Example 666.
36 Ex Structure Name [M + H].sup.+ 667 757 1-Isopropyl-
cyclohexanecarboxylic acid (3,3-diphenyl-propyl)- amide 364 668 758
1-Isopropyl- cyclohexanecarboxylic acid (biphenyl-3-ylmethyl)-
amide 336
EXAMPLE 669
[0615] 759
[0616] N-(1-Isopropenyl-cyclohexylmethyl)-2-methoxy-benzamide
[0617] Synthesis: 760
[0618] Compound 1: Compound I may be prepared as described in
Example 662.
[0619] Compound 2: To Compound 1 (100 mg, 0.67 mmol) in THF (3 mL)
cooled to 0.degree. C. was added LAH (102 mg, 2.68 mmol). The
reaction mixture was stirred from 0.degree. C. to rt overnight then
quenched with H.sub.2O (0.1 mL), 15% NaOH (0.1 mL), H.sub.2O (0.3
mL), filtered then dried over anhydrous sodium sulfate to give
(1-isopropenyl-cyclohexyl)-methylamine (63 mg, 61% as a colorless
oil. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 1.05-1.80 (15
H, m), 2.46 (2 H, s), 4.76 (1 H, s), 5.07 (1 H, s). Mass Spec
[M+H].sup.+=154.
[0620] Title Compound: Compound 2 was made to react with o-anisoyl
chloride using methodology described in Example 1 to provide
N-(1-isopropenyl-cyclohexylmethyl)-2-methoxy-benzamide. Mass Spec
[M+H].sup.+=288.
EXAMPLE 670
[0621] Example 670 was prepared using methodology described in
Example 669:
37 [M + Ex Structure Name H].sup.+ 670 761 N- Bicyclohexyl-
1'-en-1- ylmethyl-2- methoxy- benzamide 328
EXAMPLE 671
[0622] 762
[0623] N-(1-Isopropyl-cyclohexylmethyl)-2-methoxy-benzamide
[0624] Synthesis: 763
[0625] Compound 1: Compound 1 was prepared as described in Example
669.
[0626] Title Compound: The title compound was prepared using
methodology described in Example 669. Mass Spec
[M+H].sup.+=290.
EXAMPLE 672
[0627] 764
[0628]
2-Methyl-3-(1-phenyl-cyclohexylmethyl)-3H-imidazo[4,5-b]pyridine
[0629] Synthesis: 765
[0630] Compound 1: Compound 1 may be prepared as described in
Example 330.
[0631] Compound 2: A solution of compound 1 (1.21 g; 6.39 mmol) in
anhydrous tetrahydrofuran (30 mL) was treated with
N,N-diisopropylethylamine (1 mL; 5.73 mmol) and
2-bromo-3-nitro-pyridine (1.18 g; 5.81 mmol). The reaction mixture
was heated at 60.degree. C. for 21 h. The solvent was removed under
reduced pressure and the residue was treated with ethyl acetate and
10% aqueous hydrochloric acid. The organic layer was separated,
washed with saturated aqueous sodium chloride, dried (anhydrous
sodium sulfate), filtered and concentrated. The product was
purified by recrystalization from a minimum amount of ethyl acetate
to provide 1.3 g of
(3-nitro-pyridin-2-yl)-(1-phenyl-cyclohexylmethyl)-amine as light
tan solid. Mass Spec [M+H].sup.+=312.
[0632] Compound 3: A solution of compound 2 (0.96 g; 3.1 mmol) in
tetrahydrofuran (25 mL) and methanol (10 mL) was cooled to
0.degree. C. under argon. Sodium borohydride (0.62 g; 16.4 mmol)
and nickel(II) chloride (0.06 g; 0.46 mmol) were added and the
cooling bath was removed. The reaction mixture was stirred at room
temperature for 1 h at which TLC analysis indicated no starting
material remained. The reaction was quenched with 2N NaOH (5 mL)
and the volatile components were removed under reduced pressure.
The residue was treated with ethyl acetate and 1N NaOH. The organic
layer was separated, washed with saturated aqueous sodium chloride,
dried (anhydrous sodium sulfate), filtered and concentrated. The
product was purified by recrystalization from a minimum amount of
ethyl acetate and several drops of methanol to provide 0.47 g of
(N2-(1-phenyl-cyclohexylmethyl)-pyridine-2,3-diamine as a white
solid. Mass Spec [M+H].sup.+=282.
[0633] Title Compound: Compound 3 (0.087 g; 0.31 mmol), acetic acid
(1 mL) and EEDQ (0.094 g; 0.38 mmol) were combined and heated to
120.degree. C. under argon for 4 h. The reaction mixture was cooled
to room temperature, diluted with acetonitrile and water, and
purified by preparative reverse-phase liquid chromatography to
provide 0.01 g of
2-methyl-3-(1-phenyl-cyclohexylmethyl)-3H-imidazo[4,5-b]pyridine as
a white solid. Mass Spec [M+H].sup.+=306.
EXAMPLE 673
[0634] 766
[0635]
3-(1-Phenyl-cyclohexylmethyl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-o-
ne
[0636] Synthesis: 767
[0637] Compound 1: Compound 1 was prepared as described in Example
672.
[0638] Title Compound: A solution of compound 1 (0.095 g; 0.34
mmol) in dichloromethane (2 mL) was treated with triethylamine
(0.05 mL; 0.36 mmol) and diphosgene (0.041 mL; 0.34 mmol) and
allowed to stir at room temperature for 2 h. Additional
dichloromethane and 5% aqueous hydrochloric acid was added to the
reaction mixture. The organic layer was separated, washed with
saturated aqueous sodium chloride and concentrated. The residue was
dissolved in an acetonitrile/water mixture and lyophilized to
provide 0.04 g of 3-(1-phenyl-cyclohexylmethyl)-1,3-di-
hydro-imidazo[4,5-b]pyridin-2-one as a white solid. Mass Spec
[M+H].sup.+=308.
EXAMPLE 674
[0639] 768
[0640]
{2-[(1-Phenyl-cyclohexylmethyl)-amino]-pyridin-3-yl}-methanol
[0641] Synthesis: 769
[0642] Compound 1: Compound 1 may be prepared as described in
Example 330.
[0643] Compound 2: Compound 2 may be prepared using methodology
described in Example 672 using ethyl 2-chloronicotinate instead of
2-bromo-3-nitro-pyridine. The product was isolated as a colorless
oil by column chromatography on silica gel using 8:2 hexane:ethyl
acetate as the eluent. Mass Spec [M+H].sup.+=339.
[0644] Title Compound: A solution of compound 2 (0.15 g; 0.43 mmol)
in tetrahydrofuran (6 mL) was cooled to 0.degree. C. under argon.
Lithium aluminum hydride (0.073 g; 19.2 mmol) was added in 10 mg
portions. After the addition was complete the cooling bath was
removed and the reaction mixture was allowed to stir at room
temperature for 0.5 h. The reaction was quenched with water (1 mL)
and the reaction mixture was concentrated under reduced pressure.
The residue was treated with ethyl acetate and saturated aqueous
sodium bicarbonate. The organic layer was separated, washed with
saturated aqueous sodium chloride, dried (anhydrous sodium
sulfate), filtered and concentrated. Column chromatography on
silica gel using 1:1 hexane:ethyl acetate as the eluent gave 0.06 g
of {2-[(1-phenyl-cyclohexylmethyl)-amino]-pyridin-3-yl}-methanol as
a white foam. Mass Spec [M+H].sup.+=297.
EXAMPLE 675
[0645] 770
[0646]
N-(4-Methyl-pyridin-2-yl)-3-phenyl-N-(1-phenyl-cyclohexylmethyl)-pr-
opionamide
[0647] Synthesis: 771
[0648] Compound 1: Compound 1 is commercially available.
[0649] Compound 2: Compound 2 may be prepared using methodology
described in Example 325 using 4-methyl-pyridin-2-ylamine instead
of isoquinolin-1-ylamine. The product was purified by
recyrstalization from a minimum amount of ethyl acetate, several
drops of methanol and several drops of hexane to give compound 2 as
a brown powder. Mass Spec [M+H].sup.+=295.
[0650] Compound 3: Compound 3 may be prepared using methodology
described in Example 325. The product was isolated as a colorless
oil. Mass Spec [M+H].sup.+=281.
[0651] Title compound: A solution of compound 3 (0.035 g; 0.13
mmol) in acetonitrile (2 mL) was treated with
polystyrene-diisopropylethylamine (PS-DIEA) (200 mg) and
hydrocinnamoyl chloride (0.05 g; 0.3 mmol). The reaction was
allowed to shake for 6 h. The reaction mixture was purified
directly by preparative reverse phase liquid chromatography to
provide 0.02 g of
N-(4-methyl-pyridin-2-yl)-3-phenyl-N-(1-phenyl-cyclohexylmethyl-
)-propionamide as a white solid. Mass Spec [M+H].sup.+=413.
EXAMPLES 676-680
[0652] Examples 675-680 were prepared using methodology described
in Example 675.
38 Ex Structure Name [M + H].sup.+ 676 772 N-(4-Methyl-pyridin-2-
yl)-3-phenyl-N-(1-phenyl- cyclohexylmethyl)- acrylamide 411 677 773
2-Methoxy-N-(4-methyl- pyridin-2-yl)-N-(1-phenyl-
cyclohexylmethyl)- benzamide 415 678 774 N-(4-Methyl-pyridin-2-
yl)-2-phenyl-N-(1-phenyl- cyclohexylmethyl)- acetamide 399 679 775
N-(4-Methyl-pyridin-2- yl)-N-(1-phenyl- cyclohexylmethyl)-
benzamide 385 680 776 N-(4-Methyl-pyridin-2- yl)-N-(1-phenyl-
cyclohexylmethyl)- acetamide 323
EXAMPLE 681
[0653] 777
[0654]
3-Phenyl-N-(1-phenyl-cyclohexylmethyl)-N-pyrimidin-2-yl-propionamid-
e
[0655] Synthesis: 778
[0656] Compound 1: Compound 1 may be prepared as described in
Example 330.
[0657] Compound 2: Compound 2 may be prepared using methodology
described in Example 672. Mass Spec [M+H].sup.+=268.
[0658] Compound 3: A solution of compound 2 (0.1 g; 0.37 mmol) in
tetrahydrofuran (2 mL) was treated with triethylamine (0.1 mL; 0.72
mmol) and hydrocinnamoyl chloride (0.08 g; 0.47 mmol). The reaction
mixture was allowed to stir at room temperature for 48 h. The
solvent was removed by evaporation and the residue purified
directly by preparative reverse phase liquid chromatography to
provide 0.018 g of 3-phenyl-N-(1-phenyl-cy-
clohexylmethyl)-N-pyrimidin-2-yl-propionamide as a white solid.
Mass Spec [M+H].sup.+=400.
EXAMPLE 682
[0659] 779
[0660] 2-Methoxy-N-[2-(1-phenyl-cyclohexyl)-ethyl]-benzamide
[0661] Synthesis: 780
[0662] Compound 1: Compound 1 is commercially available.
[0663] Compound 2: To a suspension of LAH (3.8 g, 0.1 mol) cooled
to 0.degree. C. was slowly added 1-phenyl-cyclohexanecarboxylic
acid (10.2 g, 50.0 mmol). After stirring from 0.degree. C. to rt
overnight, the reaction mixture was quenched with H.sub.2O (3.8
mL), 15% NaOH (3.8 mL), H.sub.2O (11.4 mL) and filtered. The salt
was washed with Et.sub.2O and the combined organic phase dried over
anhydrous sodium sulfate to give (1-phenyl-cyclohexyl)-methanol
(8.48 g, 89%) as a white solid. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. (ppm) 1.30-1.70 (9 H, m), 2.15-2.36 (2 H, m), 3.51 (2 H,
s), 7.20-7.27 (1 H, m), 7.34-7.41 (4 H, m). Mass Spec
[M+H].sup.+=191.1.
[0664] Compound 3: To compound 2 (5.0 g, 26.3 mmol) in
CH.sub.2Cl.sub.2 (50 mL) was added 13.4 g (31.6 mmol) of
Dess-Martin periodinane. After 2 h, sodium thiosulfate (58 g)
followed by sat. NaHCO.sub.3 (200 mL) was added. After stirring for
1 h, the reaction mixture was diluted with EtOAc then washed with
H.sub.2O, brine and dried over anhydrous sodium sulfate.
Purification by flash chromatography (3:1, hexane-EtOAc) gave
1-phenyl-cyclohexanecarbaldehyde (4.47 g, 90%) as a colorless oil.
Mass Spec [M+H].sup.+=189.1.
[0665] Compound 4: To compound 3 (4.47 g, 23.7 mmol) in PhCH.sub.3
(130 mL) at 0.degree. C. was added 36 mL of diethylaluminium
cyanide (1.0 M/PhCH.sub.3). After stirring for 3 h at 0.degree. C.
the reaction mixture was quenched with sat. Rochelle's salt and
stirred at rt for 2 h. The aqueous layer was extracted with
CH.sub.2Cl.sub.2 (2.times.) and the combined extracts dried over
anhydrous sodium sulfate.
Hydroxy-(1-phenyl-cyclohexyl)-acetonitrile was used without
purification. Mass Spec [M+H].sup.+=216.1.
[0666] Compound 5: To compound 4 (23.7 mmol) in CH.sub.2Cl.sub.2
(80 mL) was added 5.07 g (28.4 mmol) of
1,1'-thiocarbonyldiimidazole followed by DMAP (0.579 g, 4.74 mmol).
After stirring overnight the reaction mixture was washed with H2O
and dried over anhydrous sodium sulfate. Purification by flash
chromatography (3:1, hexane-EtOAc) gave imidazole-1-carbothioic
acid O-[cyano-(1-phenyl-cyclohexyl)-methyl]ester (6.27 g, 81%) as a
yellow syrup. Mass Spec [M+H].sup.+=326.1.
[0667] Compound 6: Compound 5 (6.27 g, 19.3 mmol), Bu.sub.3SnH
(16.8 g, 57.8 mmol) and AIBN (0.63 g, 3.85 mmol) in PhCH.sub.3 (100
mL) was heated at reflux for 1 h then concentrated. Purification by
flash chromatography (hexane then 4:1, hexane-EtOAc) gave
(1-phenyl-cyclohexyl)-acetonitrile (3.84 g, 100%) as a colorless
oil. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. (ppm) 1.20-1.80 (8
H, m), 2.25-2.49 (2 H, m), 2.49 (2 H, s), 7.35-7.46 (5 H, m). Mass
Spec [M+H].sup.+=210.1.
[0668] Compound 7: To compound 6 (500 mg, 2.51 mmol) in THF (10 mL)
cooled at 0.degree. C. was slowly added 382 mg (10.04 mmol) of LAH.
After stirring from 0.degree. C. to rt overnight, the reaction
mixture was cooled to 0.degree. C. then quenched with H.sub.2O
(0.38 mL), 15% NaOH (0.38 mL), H.sub.2O (1.14 mL) and filtered. The
salt was washed with Et.sub.2O and the combined organic phase dried
over anhydrous sodium sulfate to give
2-(1-phenyl-cyclohexyl)-ethylamine (510 mg, 100%) as a colorless
oil. Mass Spec [M+H].sup.+=204.2
[0669] Title Compound:
2-Methoxy-N-[2-(1-phenyl-cyclohexyl)-ethyl]-benzami- de may be
prepared using methodology described in Example 1. Mass Spec
[M+H].sup.+=338.
EXAMPLE 683
[0670] Example 683 was prepared using methodology described in
Example 682
39 [M + Ex structure Name H].sup.+ 683 781 2-Hydroxy-6-
methoxy-N-[2- (1-phenyl- cyclohexyl)- ethyl]- benzamide 354
EXAMPLE 684
[0671] 782
[0672] N-(2-Methoxy-phenyl)-2-(1-phenyl-cyclohexyl)-acetamide
[0673] Synthesis: 783
[0674] Compound 1: Compound 1 was prepared as described in Example
682.
[0675] Compound 2: Compound 1 (3.58 g, 17.96 mmol) and KOH (4.42 g,
78.77 mmol) in ethylene glycol (35 mL) was heated at 170.degree. C.
for 48 h then cooled to rt. The reaction mixture was diluted with
H.sub.2O then extracted with Et.sub.2O (2.times.). The aqueous
phase was acidified with 6N HCl then extracted with Et.sub.2O
(3.times.) and dried over anhydrous sodium sulfate to give
(1-phenyl-cyclohexyl)-acetic acid (3.43 mg, 88%) as a tan solid.
Mass Spec [M+H].sup.+=219.1.
[0676] Title Compound: To compound 2 (50 mg, 0.23 mmol) in
CH.sub.2Cl.sub.2 (1 mL) was added 24 .mu.L (0.27 mmol) of oxalyl
chloride followed by one drop of DMF. After 1 h, o-anisidine (28
mg, 0.23 mmol) followed by Et.sub.3N (97 .mu.L, 0.27 mmol) was
added. After stirring for 3 h, the reaction mixture was diluted
with EtOAc, washed with 1 N HCl, 1 N NaOH, H.sub.2O, brine and
dried over anhydrous sodium sulfate. Purification by flash
chromatography (9:1, hexane-EtOAc) gave
N-(2-methoxy-phenyl)-2-(1-phenyl-cyclohexyl)-acetamide (37 mg, 50%)
as a white solid. Mass Spec [M+H].sup.+=324.
EXAMPLE 685
[0677] 784
[0678] 2-(1-Phenyl-cyclohexylmethyl)-1H-benzoimidazole
[0679] Synthesis: 785
[0680] Compound 1: Compound 1 was prepared as described in Example
684.
[0681] Compound 2: To compound 1 (100 mg, 0.046 mmol) in
CH.sub.2Cl.sub.2 (2 mL) was added 48 .mu.L (0.54 mmol) of oxalyl
chloride followed by one drop of DMF. After 1.5 h, the resulting
acid chloride was added to a solution of 1,2-phenylenediamine (28
mg, 0.23 mmol) Et.sub.3N (190 .mu.L, 0.1.38 mmol) was added. After
stirring for 1 h, the reaction mixture was diluted with EtOAc,
washed with 1 N HCl, 1 N NaOH, H.sub.2O, brine and dried over
anhydrous sodium sulfate. N-(2-Amino-phenyl)-2-(1-phenyl-cyclo-
hexyl)-acetamide was used in next step without purification.
[0682] Title Compound: Compound 2 (0.46 mmol) in glacial AcOH (2
mL) was heated at 100.degree. C. for 2 h then cooled to rt. The
reaction mixture was concentrated and the residue purified by flash
chromatography (1:1, hexane-EtOAc) to give
2-(1-phenyl-cyclohexylmethyl)-1H-benzoimidazole (73 mg, 54%) as a
white solid. Mass Spec [M+H].sup.+=291.
EXAMPLE 686-687
[0683] Examples 686-687 were prepared using methodology described
in Example 685.
40 [M + Ex structure Name H].sup.+ 686 786 1-Methyl-2-(1- phenyl-
cyclohexylmethyl)- 1H-benzoimidazole 305 687 787 7-Methoxy-2-(1-
phenyl- cyclohexylmethyl)- 1H-benzoimidazole 321
EXAMPLE 688
[0684] 788
[0685] 2-(1-Phenyl-cyclohexylmethyl )-3H-quinazolin-4-one
[0686] Synthesis: 789
[0687] Compound 1: Compound 1 was prepared as described in Example
684.
[0688] Compound 2: To compound 2 (75 mg, 0.0.34 mmol) in
CH.sub.2Cl.sub.2 (1 mL) was added 36 .mu.L (0.0.41 mmol) of oxalyl
chloride followed by one drop of DMF. After 1 h, anthranilamide (46
mg, 0.0.34 mmol) followed by Et.sub.3N (150 .mu.L, 1.02 mmol) was
added. After stirring overnight, the reaction mixture was diluted
with EtOAc, washed with 1 N HCl, 1 N NaOH, H.sub.2O, brine and
dried over anhydrous sodium sulfate. Purification by flash
chromatography (1:1, hexane-EtOAc) gave
2-[2-(1-phenyl-cyclohexyl)-acetylamino]-benzamide (78 mg, 68%) as a
white solid. Mass Spec [M+H].sup.+=337.2.
[0689] Title Compound: The amide (73 mg, 0.217 mmol) in EtOH (1 mL)
and 2N NaOH (1 mL) was heated at 80.degree. C. for 1 h. The
reaction mixture was concentrated, extracted with CH.sub.2Cl.sub.2
(3.times.) then dried over anhydrous sodium sulfate. Purification
by flash chromatography (1:1, hexane-EtOAc) gave
2-(1-phenyl-cyclohexylmethyl)-3H-quinazolin-4-one (66 mg, 96%) as a
white solid. Mass Spec [M+H].sup.+=319.2.
EXAMPLE 689
[0690] 790
[0691] 1-(1-Phenyl-cyclohexylmethoxy)-isoquinoline
[0692] Synthesis: 791
[0693] Compound 1: Compound 1 was prepared using methodology
described in Example 682.
[0694] Title Compound: A solution of compound 1 (0.23 g; 1.23 mmol)
in tetrahydrofuran (10 mL) was cooled to 0.degree. C. under argon.
Sodium hydride (0.080 g; 3.3 mmol) was slowly added in 5-10 mg
portions. After the addition was complete the reaction mixture was
allowed to stir at 0.degree. C. for 0.25 h and 1-chloroisoquinoline
(0.32 g; 2.0 mmol) was added. The reaction mixture was allowed to
slowly warm to room temperature overnight. Additional sodium
hydride (0.080 g; 3.3 mmol) was added and the reaction mixture was
heated at 60.degree. C. for 7 h. The solvent was removed by
evaporation and the residue was purified by column chromatography
on silica gel using 8:2 hexane:ethyl acetate as the eluent to
provide 0.02 g of 1-(1-phenyl-cyclohexylmethoxy)-isoquinoline. Mass
Spec [M+H].sup.+=318.
EXAMPLES 690-694
[0695] Examples 690-694 were prepared using methodology described
in Example 325.
41 Ex structure Name [M + H].sup.+ 690 792 (1-Isopropenyl-
cyclohexylmethyl)- isoquinolin-1-yl-amine 281 691 793
1-(3-Fluoro-phenyl)- cyclohexanecarboxylic acid isoquinolin-1-
ylamide 349 692 794 1-(2-Fluoro-phenyl)- cyclohexanecarboxylic acid
isoquinolin-1- ylamide 349 693 795 [1-(3-Fluoro-phenyl)-
cyclohexylmethyl]- isoquinolin-1-yl-amine 335 694 796
[1-(2-Fluoro-phenyl)- cyclohexylmethyl]- isoquinolin-1-yl-amine
335
* * * * *