U.S. patent application number 17/242016 was filed with the patent office on 2021-08-26 for glucosylceramide synthase inhibitors.
This patent application is currently assigned to GENZYME CORPORATION. The applicant listed for this patent is GENZYME CORPORATION. Invention is credited to Elyse BOURQUE, Mario CABRERA-SALAZAR, Cassandra CELATKA, Seng CHENG, Mary A. CROMWELL, Andrew GOOD, Bradford HIRTH, Katherine JANCSICS, John P. LEONARD, Lingyun LI, James LILLIE, Hanlan LIU, Elina MAKINO, John MARSHALL, Paul MASON, Markus METZ, Fazeela MORSHED, Thomas O'SHEA, Ronald SCHEULE, Renato SKERLJ, Bing WANG, Yibin XIANG, Zhong ZHAO.
Application Number | 20210261557 17/242016 |
Document ID | / |
Family ID | 1000005567600 |
Filed Date | 2021-08-26 |
United States Patent
Application |
20210261557 |
Kind Code |
A1 |
BOURQUE; Elyse ; et
al. |
August 26, 2021 |
GLUCOSYLCERAMIDE SYNTHASE INHIBITORS
Abstract
The invention relates to inhibitors of glucosylceramide synthase
(GCS) useful for the treatment of metabolic diseases, such as
lysosomal storage diseases, either alone or in combination with
enzyme replacement therapy, and for the treatment of cancer.
Inventors: |
BOURQUE; Elyse; (Blaine,
WA) ; CABRERA-SALAZAR; Mario; (Framingham, MA)
; CELATKA; Cassandra; (Hull, MA) ; CHENG;
Seng; (Natick, MA) ; CROMWELL; Mary A.;
(Groton, MA) ; GOOD; Andrew; (Wallingford, CT)
; HIRTH; Bradford; (Framingham, MA) ; JANCSICS;
Katherine; (Wilmington, MA) ; LEONARD; John P.;
(Manchester, NH) ; LI; Lingyun; (Waltham, MA)
; LILLIE; James; (Wellesley, MA) ; LIU;
Hanlan; (Lexington, MA) ; MAKINO; Elina;
(Winchester, MA) ; MARSHALL; John; (Hopedale,
MA) ; MASON; Paul; (Natick, MA) ; METZ;
Markus; (Waltham, MA) ; MORSHED; Fazeela;
(Waltham, MA) ; O'SHEA; Thomas; (Wellesley,
MA) ; SCHEULE; Ronald; (Hopkinton, MA) ;
SKERLJ; Renato; (West Newton, MA) ; WANG; Bing;
(Newton, MA) ; XIANG; Yibin; (Dracut, MA) ;
ZHAO; Zhong; (Wayland, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GENZYME CORPORATION |
Cambridge |
MA |
US |
|
|
Assignee: |
GENZYME CORPORATION
Cambridge
MA
|
Family ID: |
1000005567600 |
Appl. No.: |
17/242016 |
Filed: |
April 27, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16542166 |
Aug 15, 2019 |
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17242016 |
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14835402 |
Aug 25, 2015 |
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16542166 |
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14471958 |
Aug 28, 2014 |
9126993 |
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14835402 |
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14030725 |
Sep 18, 2013 |
9139580 |
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14471958 |
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PCT/US2012/029417 |
Mar 16, 2012 |
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14030725 |
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61590711 |
Jan 25, 2012 |
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61454034 |
Mar 18, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/46 20130101;
C07D 455/02 20130101; C07D 453/02 20130101; C07D 453/00 20130101;
A61K 38/47 20130101; A61K 31/454 20130101; C12Y 302/01022 20130101;
A61K 31/439 20130101; C07D 487/08 20130101; A61K 31/506 20130101;
A61K 31/551 20130101 |
International
Class: |
C07D 487/08 20060101
C07D487/08; A61K 31/439 20060101 A61K031/439; A61K 31/454 20060101
A61K031/454; A61K 38/47 20060101 A61K038/47; C07D 453/02 20060101
C07D453/02; C07D 453/00 20060101 C07D453/00; A61K 31/46 20060101
A61K031/46; A61K 31/506 20060101 A61K031/506; A61K 31/551 20060101
A61K031/551; C07D 455/02 20060101 C07D455/02 |
Claims
1. A compound represented by the following structural formula,
##STR00014## or a pharmaceutically acceptable salt or prodrug
thereof, wherein: n is 1, 2 or 3; m is 0 or 1; p is 0 or 1; t is 0,
1 or 2; y is 1 or 2; z is 0, 1 or 2; E is S, O, NH, NOH, NNO.sub.2,
NCN, NR, NOR or NSO.sub.2R; X.sup.1 is CR.sup.1 when m is 1 or N
when m is 0; X.sup.2 is O, --NH, --CH.sub.2--, SO.sub.2,
NH--SO.sub.2; CH(C.sub.1-C.sub.6) alkyl or --NR.sup.2; X.sup.3 is
O, --NH, --CH.sub.2--, CO, --CH(C.sub.1-C.sub.6) alkyl, SO.sub.2NH,
--CO--NH-- or --NR.sup.3; X.sup.4 is CR.sup.4R.sup.5, CH.sub.2
CR.sup.4R.sup.5 or CH.sub.2--(C.sub.1-C.sub.6)
alkyl-CR.sup.4R.sup.5; X.sup.5 is a direct bond, O, S, SO.sub.2,
CR.sup.4R.sup.5; (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy,
(C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkenyloxy, R is
(C.sub.6-C.sub.12)aryl, (C.sub.2-C.sub.9)heteroaryl,
(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkyl; R.sup.1 is H,
CN, (C.sub.1-C.sub.6)alkylcarbonyl, or (C.sub.1-C.sub.6)alkyl;
R.sup.2 and R.sup.3 are each independently --H,
(C.sub.1-C.sub.6)alkyl optionally substituted by one or more
substituents selected from the group consisting of halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.6-C.sub.12)aryl,
(C.sub.2-C.sub.9)heteroaryl,
(C.sub.1-C.sub.6)alkyl(C.sub.6-C.sub.12)aryl,
halo(C.sub.6-C.sub.12)aryl, and halo(C.sub.2-C.sub.9)heteroaryl, or
optionally when X.sup.2 is --NR.sup.2 and X.sup.3 is --NR.sup.3,
R.sup.2 and R.sup.3 may be taken together with the nitrogen atoms
to which they are attached form a non-aromatic heterocyclic ring
optionally substituted by with one or more substituents selected
from halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.6-C.sub.12)aryl,
(C.sub.2-C.sub.9)heteroaryl,
(C.sub.1-C.sub.6)alkyl(C.sub.6-C.sub.12)aryl,
halo(C.sub.6-C.sub.12)aryl, and halo(C.sub.2-C.sub.9)heteroaryl;
R.sup.4 and R.sup.5 are independently selected from H,
(C.sub.1-C.sub.6)alkyl, or taken together with the carbon to which
they are attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring
or spiro (C.sub.3-C.sub.10)cycloalkoxy ring: R.sup.6 is --H,
halogen, --CN, (C.sub.6-C.sub.12)aryl, (C.sub.6-C.sub.12)aryloxy,
(C.sub.1-C.sub.6)alkyloxy; (C.sub.1-C.sub.6)alkyl optionally
substituted by one to four halo or (C.sub.1-C.sub.6)alkyl; A.sup.1
is (C.sub.2-C.sub.6)alkynyl; (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.6-C.sub.12)aryl, (C.sub.2-C.sub.9)heteroaryl,
(C.sub.2-C.sub.9)heterocycloalkyl or
benzo(C.sub.2-C.sub.9)heterocycloalkyl optionally substituted with
one or more substituents selected from the group consisting of
halo, (C.sub.1-C.sub.6)alkyl optionally substituted by one to three
halo; (C.sub.1-C.sub.6)alkenyl, amino, (C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)dialkylamino, (C.sub.1-C.sub.6)alkoxy, nitro, CN,
--OH, (C.sub.1-C.sub.6)alkyloxy optionally substituted by one to
three halo; (C.sub.1-C.sub.6)alkoxycarbonyl, and (C.sub.1-C.sub.6)
alkylcarbonyl; A.sup.2 is H, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.6-C.sub.12)aryl, (C.sub.2-C.sub.9)heteroaryl,
(C.sub.2-C.sub.9)heterocycloalkyl or
benzo(C.sub.2-C.sub.9)heterocycloalkyl optionally substituted with
one or more substituents selected from the group consisting of
halo, (C.sub.1-C.sub.6)alkyl optionally substituted by one to three
halo; (C.sub.1-C.sub.6)alkylenyl, amino, (C.sub.1-C.sub.6)
alkylamino, (C.sub.1-C.sub.6)dialkylamino, (C.sub.1-C.sub.6)alkoxy,
O(C.sub.3-C.sub.6 cycloalkyl), (C.sub.3-C.sub.6) cycloalkoxy,
nitro, CN, OH, (C.sub.1-C.sub.6)alkyloxy optionally substituted by
one to three halo; (C.sub.3-C.sub.6) cycloalkyl, (C.sub.1-C.sub.6)
alkoxycarbonyl, (C.sub.1-C.sub.6) alkylcarbonyl, (C.sub.1-C.sub.6)
haloalkyl; with the proviso that the sum of n+t+y+z is not greater
than 6; with the proviso that when p is 0; X.sup.2 is NH--SO.sub.2
and X.sup.3 is NH; with the proviso that when n is 1; t is 0; y is
1; z is 1; X.sup.2 is NH; E is O; X.sup.3 is NH; A.sup.2 is H and
X.sup.5 is a direct bond; A.sup.1 is not unsubstituted phenyl,
halophenyl or isopropenyl phenyl; with the proviso that when n is
1; t is 0; y is 1; z is 1; X.sup.2 is O; E is O; X.sup.3 is NH;
A.sup.1 is (C.sub.6-C.sub.12)aryl and X.sup.5 is a direct bond;
A.sup.2 is H and R.sup.4 is H then R.sup.5 is not cyclohexyl; and
with the proviso that when n is 1; t is 0: y is 1; z is 1; X.sup.2
is NH: E is O; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are both
hydrogen; A.sup.2 is H and X.sup.5 is a direct bond; then A.sup.1
is not unsubstituted phenyl.
2. A compound according to claim 1, wherein n is 1; t is 0: y is 1
and z is 1.
3. A compound according to claim 1, wherein n is 1; t is 1; y is 1
and z is 1.
4. A compound according to claim 1, wherein n is 2; t is 0; y is 1
and z is 1.
5. A compound according to claim 1, wherein n is 2; t is 1; y is 1
and z is 1.
6. A compound according to claim 1, wherein n is 3; t is 0; y is 1
and z is 1.
7. A compound according to claim 1, wherein n is 1; t is 2; y is 1
and z is 1.
8. A compound according to claim 1, wherein n is 1; t is 0; y is 1
and z is 0.
9. A compound according to claim 1, wherein n is 1; t is 1; y is 1
and z is 0.
10. A compound according to claim 1, wherein n is 2; t is 0; y is 1
and z is 0.
11. A compound according to claim 1, wherein n is 2; t is 1; y is 1
and z is 0.
12. A compound according to claim 1, wherein n is 3; t is 0; y is 1
and z is 0.
13. A compound according to claim 1, wherein n is 1; t is 2; y is 1
and z is 0.
14. A compound according to claim 1, wherein n is 1; t is 1; y is 2
and z is 0.
15. A compound according to claim 1, wherein n is 2; t is 0; y is 2
and z is 0.
16. A compound according to claim 1, wherein m is 1 and X.sup.1 is
CR.sup.1.
17. A compound according to claim 1, wherein m is 0 and X.sup.1 is
N.
18. A compound according to claim 1, wherein m is 1; E is O;
X.sup.2 is O and X.sup.3 is NH.
19. A compound according to claim 1, wherein m is 1; E is O;
X.sup.2 is NH and X.sup.3 is NH.
20. A compound according to claim 1, wherein m is 1; E is O;
X.sup.2 is CH.sup.2 and X.sup.3 is NH.
21. A compound according to claim 1, wherein m is 1; E is O;
X.sup.2 is NH and X.sup.3 is CH.sup.2.
22. A compound according to claim 1, wherein m is 1; E is S;
X.sup.2 is NH and X.sup.3 is NH.
23. A compound according to claim 1, wherein m is 0; E is O;
X.sup.1 is NH and X.sup.3 is NH.
24. A compound according to claim 1, wherein m is 1; E is O;
X.sup.2 is NH and X.sup.3 is CO--NH.
25. A compound according to claim 1, wherein m is 1; p is 0;
X.sup.2 is NH--SO.sub.2 and X.sup.3 is NH.
26. A compound according to claim 1, wherein R.sup.4 and R.sup.5
are each (C.sub.1-C.sub.6)alkyl or taken together with the carbon
to which they are attached to form a spiro
(C.sub.3-C.sub.10)cyclo-alkyl ring or a spiro
(C.sub.3-C.sub.10)cycloalkoxy ring.
27. A compound according to claim 26, wherein R.sup.4 and R.sup.5
are each methyl.
28. A compound according to claim 26, wherein R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring.
29. A compound according to claim 28, wherein R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro cyclopropyl ring.
30. A compound according to claim 26, wherein R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkoxy ring.
31. A compound according to claim 1, wherein A.sup.1 is
(C.sub.2-C.sub.6)alkynyl or (C.sub.6-C.sub.12)aryl.
32. A compound according to claim 1, wherein A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl.
33. A compound according to claim 32, wherein A.sup.1 is thiophene,
thiazole, isothiazole, furane, oxazole, isoxazole, pyrrole,
imidazole, pyrazole, triazole, pyridine, pymiridine, pyridazine,
indole, benzotiazole, benzoisoxazole, benzopyrazole,
benzoimidazole, benzofuran, benzooxazole or benzoisoxazole.
34. A compound according to claim 1, wherein A.sup.1 is
(C.sub.2-C.sub.9)heterocycloalkyl.
35. A compound according to claim 34, wherein A.sup.1 is
pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl,
pyranyl, thiopyranyl, aziridinyl, azetidinyl, oxiranyl,
methylenedioxyl, chromenyl, barbituryl, isoxazolidinyl,
1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl,
1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl,
thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,
1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,
1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,
tetrahydroazepinyl, piperazinyl, piperizin-2-onyl,
piperizin-3-onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl,
imidazolidinyl, 2-imidazolidinyl, 1,4-dioxanyl,
8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl,
3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl,
2,5-diazabicyclo[2.2.2]octanyl,
octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[4.1.0]heptanyl,
3-azabicyclo[3.1.0]hexanyl 2-azaspiro[4.4]nonanyl,
7-oxa-1-aza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl or
octahydro-1H-indolyl.
36. A compound according to claim 1, wherein A.sup.1 is
benzo(C.sub.2-C.sub.9)heterocycloalkyl.
37. A compound according to claim 36, wherein A.sup.1 is
2,3-dihydrobenzo[b][1,4]dioxine or
2,2-difluorobenzo[d][1,3]dioxole.
38. A compound according to claim 1, wherein R.sup.6 is H.
39. A compound according to claim 1, X.sup.5 is a direct bond.
40. A compound according to claim 1, X.sup.5 is a
CR.sup.4R.sup.5.
41. A compound according to claim 40, wherein R.sup.4 and R.sup.5
are each methyl.
42. A compound according to claim 40, wherein R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring.
43. A compound according to claim 42, wherein R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro cyclopropyl ring.
44. A compound according to claim 40, wherein R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkoxy ring.
45. A compound according to claim 1, wherein A.sup.2 is
(C.sub.6-C.sub.12)aryl.
46. A compound according to claim 1, wherein A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
47. A compound according to claim 46, wherein A.sup.2 is
pyridine.
48. A compound according to claim 1, wherein A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
49. A compound according to claim 48, wherein A.sup.2 is
pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl,
pyranyl, thiopyranyl, aziridinyl, azetidinyl, oxiranyl,
methylenedioxyl, chromenyl, barbituryl, isoxazolidinyl,
1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl,
1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl,
thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,
1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,
1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,
tetrahydroazepinyl, piperazinyl, piperizin-2-onyl,
piperizin-3-onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl,
imidazolidinyl, 2-imidazolidinyl, 1,4-dioxanyl,
8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl,
3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl,
2,5-diazabicyclo[2.2.2]octanyl,
octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[4.1.0]heptanyl,
3-azabicyclo[3.1.0]hexanyl 2-azaspiro[4.4]nonanyl,
7-oxa-1-aza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl or
octahydro-1H-indolyl.
50. A compound according to claim 1, wherein A.sup.2 is
benzo(C.sub.2-C.sub.9)heterocycloalkyl.
51. A compound according to claim 50, wherein A.sup.2 is
2,3-dihydrobenzo[b][1,4]dioxine or
2,2-difluorobenzo[d][1,3]dioxole.
52. A compound according to claim 1, where R.sup.1 is hydrogen or
methyl.
53. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are taken together with the carbon to which
they are attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring
or spiro (C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen
or methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
54. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are each independently methyl; R.sup.6 is a
hydrogen or methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
55. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are taken together with the carbon to which
they are attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring
or spiro (C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen
or methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
56. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are each independently methyl; R.sup.6 is a
hydrogen or methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
57. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are taken together with the carbon to which
they are attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring
or spiro (C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen
or methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
58. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are each independently methyl; R.sup.6 is a
hydrogen or methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5
is a direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
59. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
60. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
61. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.3 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
62. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
63. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or C.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
64. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
65. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
66. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
67. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
68. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
69. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
70. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
71. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
72. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
73. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
74. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
75. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or C.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
76. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
77. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.3 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
78. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
79. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
80. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
81. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.3 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
82. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
83. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2: X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
84. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
85. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
86. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
87. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
88. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
89. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.1 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
90. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
91. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
92. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
93. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
94. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
95. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
96. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
97. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
98. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
99. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
100. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
101. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are taken together with the carbon to which
they are attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring
or spiro (C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen
or methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
102. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are each independently methyl; R.sup.6 is a
hydrogen or methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
103. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are taken together with the carbon to which
they are attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring
or spiro (C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen
or methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is
a direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
104. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are each independently methyl; R.sup.6 is a
hydrogen or methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl;
X.sup.5 is a direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
105. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
taken together with the carbon to which they are attached to form a
spiro (C3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
106. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.3 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
107. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
108. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
109. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
110. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
111. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
112. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
113. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
114. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
115. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
116. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
117. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
l; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.3 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
118. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.3 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
119. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
120. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
121. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
122. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
123. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
124. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
125. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
126. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
127. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
128. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
129. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
130. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
131. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
132. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
133. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are taken together with the carbon to which
they are attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring
or spiro (C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen
or methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
134. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are each independently methyl; R.sup.6 is a
hydrogen or methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5
is a direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
135. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are taken together with the carbon to which
they are attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring
or spiro (C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen
or methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is
a direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
136. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are each independently methyl; R.sup.6 is a
hydrogen or methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl;
X.sup.5 is a direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
137. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
138. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
139. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
140. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
141. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
142. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
143. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
144. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
145. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
146. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
147. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
148. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
149. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH: R.sup.4 and R.sup.5 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
150. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
151. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
152. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
153. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X3 is NH; R.sup.4 and R.sup.5 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
154. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
155. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
156. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
157. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
158. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
159. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
160. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
161. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
162. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
163. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
164. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
165. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are taken together with the carbon to which
they are attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring
or spiro (C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen
or methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
166. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are each independently methyl; R.sup.6 is a
hydrogen or methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5
is a direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
167. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.3 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
168. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
169. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or C.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
170. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
171. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
172. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
173. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or C.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
174. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
175. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
176. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
177. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
178. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
179. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
180. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
181. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are taken together with the carbon to which
they are attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring
or spiro (C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen
or methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
182. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are each independently methyl; R.sup.6 is a
hydrogen or methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
183. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are taken together with the carbon to which
they are attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring
or spiro (C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen
or methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
184. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are each independently methyl; R.sup.6 is a
hydrogen or methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl;
X.sup.5 is a direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
185. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.3 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
186. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.6-C.sub.12)aryl; X.sup.1 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
187. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
188. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
189. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
190. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
191. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
192. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond,
O or CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
193. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
194. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
195. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
196. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond,
O or CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
197. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.3 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
198. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
199. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
200. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
201. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
202. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
203. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
204. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond,
O or CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
205. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
206. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
207. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
208. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
209. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
210. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
211. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
212. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond,
O or CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
213. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are taken together with the carbon to which
they are attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring
or spiro (C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen
or methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
214. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are each independently methyl; R.sup.6 is a
hydrogen or methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5
is a direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
215. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are taken together with the carbon to which
they are attached to form a Spiro (C.sub.3-C.sub.10)cycloalkyl ring
or spiro (C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen
or methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
216. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; p is 1; E is O; X.sup.2 is O; X.sup.3 is NH; R.sup.1 is H;
R.sup.4 and R.sup.5 are each independently methyl; R.sup.6 is a
hydrogen or methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl;
X.sup.5 is a direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
217. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
218. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
219. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
220. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.3 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
221. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
222. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
223. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
224. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond,
O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
225. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
226. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
227. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
228. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond,
O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
229. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
230. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
231. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.3 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
232. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is S; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.3 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
233. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
234. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X.sup.3 is NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
235. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X3 is NH; R.sup.4 and R.sup.5 are
taken together with the carbon to which they are attached to form a
spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
236. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is SO.sub.2; X.sup.2 is NH; X3 is NH; R.sup.4 and R.sup.5 are
each independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1
is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
237. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
238. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
239. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
240. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is N; m is 0; E is
O; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
241. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sub.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
242. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O
or CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
243. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are taken together with the carbon to which they are attached to
form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
244. A compound according to claim 1, wherein n is 1; 2 or 3; t is
0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X.sup.1 is CR.sup.1; m is
1; E is O; X.sup.2 is NH; X.sup.3 is CO--NH; R.sup.4 and R.sup.5
are each independently methyl; R.sup.6 is a hydrogen or methyl;
A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond,
O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
245. A compound according to claim 1, wherein A.sup.1 is
(C.sub.3-C.sub.10)cycloalkyl.
246. A compound according to claim 1, wherein A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
247. A compound according to claim 1, or a pharmaceutically
acceptable salt or prodrug thereof, selected from the group
consisting of: 1-azabicyclo[2.2.2]oct-3-yl
[2-(2,4'-difluorobiphenyl-4-yl)propan-2-yl]carbamate;
1-azabicyclo[2.2.2]oct-3-yl
{2-[4-(1,3-benzothiazol-6-yl)phenyl]propan-2-yl}carbamate;
1-azabicyclo[3.2.2]non-4-yl
{1-[5-(4-fluorophenyl)pyridin-2-yl]cyclopropyl}carbamate;
1-azabicyclo[2.2.2]oct-3-yl
{1-[3-(4-fluorophenoxy)phenyl]cyclopropyl}carbamate;
1-azabicyclo[2.2.2]oct-3-yl
{1-[4-(1,3-benzothiazol-5-yl)phenyl]cyclopropyl}carbamate;
1-azabicyclo[2.2.2]oct-3-yl
[1-(4'-fluoro-3'-methoxybiphenyl-4yl)cyclopropyl]carbamate;
1-azabicyclo[2.2.2]oct-3-yl
[3-(4'-fluorobiphenyl-4-yl)oxetan-3-yl]carbamate;
1-azabicyclo[2.2.2]oct-3-yl
{1-[6-(4-fluorophenoxy)pyridin-2-yl]cyclopropyl}carbamate;
1-azabicyclo[2.2.2]oct-3-yl
[3-(4'-fluorobiphenyl-4-yl)pentan-3-yl]carbamate;
1-azabicyclo[2.2.2]oct-3-yl
{2-[2-(4-fluorophenyl)-2H-indazol-6-yl]propan-2 yl}carbamate;
1-azabicyclo[2.2.2]oct-3-yl
{2-[2-(1H-pyrrol-1-yl)pyridin-4-yl]propan-2-yl}carbamate;
1-(3-ethyl-1-azabicyclo[2.2.2]oct-3-yl)-3-[1-(4'-fluorobiphenyl-4-yl)cycl-
opropyl]urea;
N-(1-azabicyclo[2.2.2]oct-3-yl)-N'-[1-(4'-fluorobiphenyl-4yl)cyclopropyl]-
ethanediamide; 1-azabicyclo[2.2.2]oct-3-yl
(1-{4[(4,4difluorocyclohexyl)oxy]phenyl}cyclopropyl) carbamate;
1-(4-methyl-1-azabicyclo[3.2.2]non-4-yl)-3-[1-(5-phenylpyridin-2-yl)cyclo-
propyl]urea;
1-[1-(4'-fluorobiphenyl-4-yl)cyclopropyl]-1-methyl-3-(3-methyl-1-azabicyc-
lo[2.2.2]oct-3-yl)urea;
1-[1-(4'-fluorobiphenyl-4-yl)cyclopropyl]-1-methyl-3-(3-methyl-1-azabicyc-
lo[2.2.2]oct-3-yl)urea;
1-{2-[4'-(2-methoxyethoxy)biphenyl-4-yl]propan-2-yl}-3-(3-methyl-1-azabic-
yclo[2.2.2]oct-3-yl)urea;
2-(1-azabicyclo[3.2.2]non-4-yl)-N-[1-(5-phenylpyridin-2-yl)cyclopropyl]ac-
etamide;
3-(4'-fluorobiphenyl-4-yl)-3-methyl-N-(4-methyl-1-azabicyclo[3.2.-
2]non-4-yl)butanamide;
N-[2-(biphenyl-4-yl)propan-2-yl]-N'-(3-methyl-1-azabicyclo[2.2.2]oct-3-yl-
)sulfuric diamide;
N-[2-(4'-fluorobiphenyl-4-yl)propan-2-yl]-N'-(3-methyl-1-azabicyclo[2.2.2-
]oct-3-yl)sulfuric diamide;
1-(3-butyl-1-azabicyclo[2.2.2]oct-3-yl)-3-{2-[1-(4-fluorophenyl)-1H-pyraz-
ol-4-yl]propan-2-yl}urea; 1-azabicyclo[2.2.2]oct-3-yl
[4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl]carbamate;
1-(3-butyl-1-azabicyclo[2.2.2]oct-3-yl)-3-[4-(4-fluorophenyl)-2-methylbut-
-3-yn-2-yl]urea;
N-[1-(4'-fluorobiphenyl-4-yl)cyclopropyl]-1,4-diazabicyclo[3.2.2]nonane-4-
-carboxamide;
1-(2-(4'-fluoro-[1,1'-biphenyl]-4-yl)propan-2-yl)-3-(3-methyl-1-azabicycl-
o[3.2.2]nonan-3-yl)urea;
1-(2-(4'-fluoro-[1,1'-biphenyl]-4-yl)propan-2-yl)-3-(4-methyl-1-azabicycl-
o[4.2.2]decan-4-yl)urea;
1-(2-(4'-fluoro-[1,1'-biphenyl]-4-yl)propan-2-yl)-3-(3-methyl-1-azabicycl-
o[4.2.2]decan-3-yl)urea; and
1-(2-(4'-fluoro-[1,1'-biphenyl]-4-yl)propan-2-yl)-3-(5-methyl-1-azabicycl-
o[4.2.2]decan-5-yl)urea.
248. A pharmaceutical composition for treating a disease or
disorder mediated by glucosylceramide synthase (GCS) or a disease
or disorder in which GCS is implicated in a subject in need of such
treatment comprising administering to the subject an effective
amount of a compound according to claim 1.
249. A method for treating a disease or disorder mediated by
glucosylceramide synthase (GCS) or a disease or disorder in which
GCS is implicated in a subject in need of such treatment comprising
administering to the subject an effective amount of a compound
according to claim 1.
250. The method of claim 249, wherein the disease or disorder is
cancer.
251. The method of claim 249, wherein the disease or disorder is a
metabolic disorder.
252. The method of claim 249, wherein the disease or disorder is a
neuropathic disease.
253. The method of claim 252, wherein the neuropathic disease is
Alzheimers disease.
254. The method of claim 252, wherein the neuropathic disease is
Parkinsons disease.
255. The method for inducing decreased glucosylceramide synthase
catalytic activity in a cell, in vitro, comprising contacting the
cell with an effect amount of a compound according to claim 1.
256. A compound according to claim 1, represented by the following
structural formula, ##STR00015## or a pharmaceutically acceptable
salt or prodrug thereof.
257. A compound according to claim 1, represented by the following
structural formula, ##STR00016## or a pharmaceutically acceptable
salt or prodrug thereof.
258. A method of treating a subject diagnosed as having a lysosomal
storage disease, comprising administering to the subject an
effective amount of the compound according to claim 1.
259. The method of claim 258, wherein the lysosomal storage disease
results from a defect in the glycosphingolipid pathway.
260. The method of claim 259, wherein the lysosomal storage disease
is selected from the group consisting of Gaucher, Fabry,
G.sub.M1-gangliosidosis, G.sub.M2 Activator deficiency, Tay-Sachs
and Sandhoff.
261. The method of claim 260, wherein the lysosomal storage disease
is Fabry.
262. The method of claim 258, further comprising the step of
administering to the subject a therapeutically effective amount of
a lysosomal enzyme.
263. The method of claim 262, wherein the lysosomal enzyme is
selected from the group consisting of glucocerebrosidase,
alpha-galactosidase A, Hexosaminidase A, Hexosaminidase B and
G.sub.M1-ganglioside-.beta.-galactosidase.
264. The method of claim 262, wherein the lysosomal enzyme is
alpha-galactosidase A.
265. The method of claim 262, wherein prior to treatment the
subject has elevated levels of a lysosomal substrate.
266. The method of claim 265, wherein the subject undergoing
treatment has lower combined amounts of the lysosomal substrate in
the urine and plasma than a subject treated with either the
lysosomal enzyme or compound alone.
267. The method of claim 266, wherein the substrate is selected
from the group consisting of globotriaosylceramide and
lyso-globotriaosylceramide, and combinations thereof.
268. The method of claim 258, wherein the compound is represented
by the following structural formula, ##STR00017## or a
pharmaceutically acceptable salt or prodrug thereof.
269. The method of claim 258, wherein the compound is represented
by the following structural formula, ##STR00018## or a
pharmaceutically acceptable salt or prodrug thereof.
270. A method of reducing glucosylceramide synthase (GCS) activity
in a subject diagnosed as having a lysosomal storage disease,
comprising administering to the patient an effective amount of the
compound according to claim 1, either alone or as a combination
therapy with an enzyme replacement therapy.
Description
BACKGROUND OF THE INVENTION
Field of the Invention
[0001] The present invention relates generally to the field of
therapeutics for cancer and metabolic diseases. More specifically,
the invention relates to inhibitors of glucosylceramide synthase
(GCS) useful for the treatment of metabolic diseases, such as
lysosomal storage diseases, either alone or in combination with
enzyme replacement therapy, and for the treatment of cancer.
Summary of the Related Art
[0002] Glucosylceramide synthase (GCS) is a pivotal enzyme which
catalyzes the initial glycosylation step in the biosynthesis of
glucosylceramide-base glycosphingolipids (GSLs) namely via the
pivotal transfer of glucose from UDP-glucose (UDP-Glc) to ceramide
to form glucosylceramide (See FIG. 1). GCS is a transmembrane, type
III integral protein localized in the cis/medial Golgi.
Glycosphingolipids (GSLs) are believed to be integral for the
dynamics of many cell membrane events, including cellular
interactions, signaling and trafficking. Synthesis of GSL
structures has been shown (see, Yamashita et al., Proc. Natl. Acad.
Sci. USA 1999, 96(16), 9142-9147) to be essential for embryonic
development and for the differentiation of some tissues. Ceramide
plays a central role in sphingolipid metabolism and downregulation
of GCS activity has been shown to have marked effects on the
sphingolipid pattern with diminished expression of
glycosphingolipids. Sphingolipids (SLs) have a biomodulatory role
in physiological as well as pathological cardiovascular conditions.
In particular, sphingolipids and their regulating enzymes appear to
play a role in adaptive responses to chronic hypoxia in the
neonatal rat heart (see, El Alwanit et al., Prostaglandins &
Other Lipid Mediators 2005, 78(1-4), 249-263).
[0003] GCS inhibitors have been proposed for the treatment of a
variety of diseases (see for example, WO2005068426). Such
treatments include treatment of glycolipid storage diseases (e.g.,
Tay Sachs, Sandhoffs, GM2 Activator deficiency, GM1 gangliosidosis
and Fabry diseases), diseases associated with glycolipid
accumulation (e.g., Gaucher disease; Miglustat (Zavesca), a GCS
inhibitor, has been approved for therapy in type 1 Gaucher disease
patients, see, Treiber et al., Xenobiotica 2007, 37(3), 298-314),
diseases that cause renal hypertrophy or hyperplasia such as
diabetic nephropathy; diseases that cause hyperglycemia or
hyperinsulemia; cancers in which glycolipid synthesis is abnormal,
infectious diseases caused by organisms which use cell surface
glycolipids as receptors, infectious diseases in which synthesis of
glucosylceramide is essential or important, diseases in which
synthesis of glucosylceramide is essential or important, diseases
in which excessive glycolipid synthesis occurs (e.g.,
atherosclerosis, polycystic kidney disease, and renal hypertrophy),
neuronal disorders, neuronal injury, inflammatory diseases or
disorders associated with macrophage recruitment and activation
(e.g., rheumatoid arthritis, Crohn's disease, asthma and sepsis)
and diabetes mellitus and obesity (see, WO 2006053043).
[0004] In particular, it has been shown that overexpression of GCS
is implicated in multi-drug resistance and disrupts
ceramide-induced apoptosis. For example, Turzanski et al.,
(Experimental Hematology 2005, 33 (1), 62-72 have shown that
ceramide induces apoptosis in acute myeloid leukemia (AML) cells
and that P-glycoprotein (p-gp) confers resistance to
ceramide-induced apoptosis, with modulation of the
ceramide-glucosylceramide pathway making a marked contribution to
this resistance in TF-1 cells. Thus, GCS inhibitors can be useful
for treatment of proliferative disorders by inducing apoptosis in
diseased cells.
SUMMARY OF THE INVENTION
[0005] The present invention refers to a compound represented by
the following structural formula,
##STR00001##
[0006] or a pharmaceutically acceptable salt or prodrug thereof,
wherein:
[0007] n is 1, 2 or 3;
[0008] m is 0 or 1;
[0009] p is 0 or 1;
[0010] t is 0, 1 or 2;
[0011] y is 1 or 2;
[0012] z is 0, 1 or 2;
[0013] E is S, O, NH, NOH, NNO.sub.2, NCN, NR, NOR or
NSO.sub.2R;
[0014] X.sup.1 is CR.sup.1 when m is 1 or N when m is 0;
[0015] X.sup.2 is O, --NH, --CH.sub.2--, SO.sub.2, NH--SO.sub.2;
CH(C.sub.1-C.sub.6) alkyl or --NR.sup.2;
[0016] X.sup.3 is O, --NH, --CH.sub.2--, CO, --CH(C.sub.1-C.sub.6)
alkyl, SO.sub.2NH, --CO--NH-- or --NR.sup.3;
[0017] X.sup.4 is CR.sup.4R.sup.5, CH.sub.2 CR.sup.4R.sup.5 or
CH.sub.2 (C.sub.1-C.sub.6) alkyl-CR.sup.4R.sup.5;
[0018] X.sup.5 is a direct bond, O, S, SO.sub.2, CR.sup.4R.sup.5;
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy,
(C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkenyloxy;
[0019] R is (C.sub.6-C.sub.12)aryl, (C.sub.2-C.sub.9)heteroaryl,
(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkyl;
[0020] R.sup.1 is H, CN, (C.sub.1-C.sub.6)alkylcarbonyl, or
(C.sub.1-C.sub.6)alkyl;
[0021] R.sup.2 and R.sup.3 are each independently --H,
(C.sub.1-C.sub.6)alkyl optionally substituted by one or more
substituents selected from the group consisting of halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.6-C.sub.12)aryl,
(C.sub.2-C.sub.9)heteroaryl,
(C.sub.1-C.sub.6)alkyl(C.sub.6-C.sub.12)aryl,
halo(C.sub.6-C.sub.12)aryl, and halo(C.sub.2-C.sub.9)heteroaryl, or
optionally when X.sup.2 is NR.sup.2 and X.sup.3 is NR.sup.3,
R.sup.2 and R.sup.3 may be taken together with the nitrogen atoms
to which they are attached form a non-aromatic heterocyclic ring
optionally substituted by with one or more substituents selected
from halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.6-C.sub.12)aryl,
(C.sub.2-C.sub.9)heteroaryl,
(C.sub.1-C.sub.6)alkyl(C.sub.6-C.sub.12)aryl,
halo(C.sub.6-C.sub.12)aryl, and
halo(C.sub.2-C.sub.9)heteroaryl;
[0022] R.sup.4 and R.sup.5 are independently selected from H,
(C.sub.1-C.sub.6)alkyl, or taken together with the carbon to which
they are attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring
or spiro (C.sub.3-C.sub.10)cycloalkoxy ring;
[0023] R.sup.6 is --H, halogen, --CN, (C.sub.6-C.sub.12)aryl,
(C.sub.6-C.sub.12)aryloxy, (C.sub.1-C.sub.6)alkyloxy;
(C.sub.1-C.sub.6)alkyl optionally substituted by one to four halo
or (C.sub.1-C.sub.6)alkyl;
[0024] A.sup.1 is (C.sub.2-C.sub.6)alkynyl; (C.sub.6-C.sub.12)aryl,
(C.sub.2-C.sub.9)heteroaryl, (C.sub.2-C.sub.9)heterocycloalkyl or
benzo(C.sub.2-C.sub.9)heterocycloalkyl optionally substituted with
one or more substituents selected from the group consisting of
halo, (C.sub.1-C.sub.6)alkyl optionally substituted by one to three
halo; (C.sub.1-C.sub.6)alkenyl, amino, (C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6) dialkylamino, (C.sub.1-C.sub.6)alkoxy, nitro, CN,
--OH, (C.sub.1-C.sub.6)alkyloxy optionally substituted by one to
three halo; (C.sub.1-C.sub.6)alkoxycarbonyl, and (C.sub.1-C.sub.6)
alkylcarbonyl;
[0025] A.sup.2 is H, (C.sub.6-C.sub.12)aryl,
(C.sub.2-C.sub.9)heteroaryl, (C.sub.2-C.sub.9)heterocycloalkyl or
benzo(C.sub.2-C.sub.9)heterocycloalkyl optionally substituted with
one or more substituents selected from the group consisting of
halo, (C.sub.1-C.sub.6)alkyl optionally substituted by one to three
halo; (C.sub.1-C.sub.6)alkylenyl, amino, (C.sub.1-C.sub.6)
alkylamino, (C.sub.1-C.sub.6)dialkylamino, (C.sub.1-C.sub.6)alkoxy,
O(C3-C6 cycloalkyl), (C.sub.3-C.sub.6) cycloalkoxy, nitro, CN, OH,
(C.sub.1-C.sub.6)alkyloxy optionally substituted by one to three
halo; (C.sub.3-C.sub.6) cycloalkyl, (C.sub.1-C.sub.6)
alkoxycarbonyl, (C.sub.1-C.sub.6) alkylcarbonyl, (C.sub.1-C.sub.6)
haloalkyl;
[0026] with the proviso that the sum of n+t+y+z is not greater than
6;
[0027] with the proviso that when p is 0; X.sup.2 is NH--SO.sub.2
and X.sup.3 is NH;
[0028] with the proviso that when n is 1; t is 0; y is 1; z is 1;
X.sup.2 is NH; E is O; X.sup.3 is NH; A.sup.2 is H and X.sup.5 is a
direct bond; A.sup.1 is not unsubstituted phenyl, halophenyl or
isopropenyl phenyl;
[0029] with the proviso that when n is 1; t is 0; y is 1; z is 1;
X.sup.2 is O; E is O; X.sup.3 is NH; A.sup.1 is
(C.sub.6-C.sub.12)aryl and X.sup.5 is a direct bond; A.sup.2 is H
and R.sup.4 is H then R.sup.5 is not cyclohexyl; and
[0030] with the proviso that when n is 1; t is 0; y is 1; z is 1;
X.sup.2 is NH; E is O; X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are
both hydrogen; A.sup.2 is H and X.sup.5 is a direct bond; then
A.sup.1 is not unsubstituted phenyl. Certain aspects of the
invention include administering the foregoing compound to a patient
as part of combination therapy that includes an enzyme replacement
therapy (ERT) and small molecule therapy (SMT) to reduce the amount
of and/or inhibit substrate accumulation in a patient diagnosed
with a lysosomal storage disease.
[0031] The present invention further relates to the compound of
Formula I, wherein n is 1; t is 0; y is 1 and z is 1.
[0032] The present invention further relates to the compound of
Formula I, wherein n is 1; t is 1; y is 1 and z is 1.
[0033] The present invention further relates to the compound of
Formula I, wherein n is 2; t is 0; y is 1 and z is 1.
[0034] The present invention further relates to the compound of
Formula I, wherein n is 2; t is 1; y is 1 and z is 1.
[0035] The present invention further relates to the compound of
Formula I, wherein n is 3; t is 0; y is 1 and z is 1.
[0036] The present invention further relates to the compound of
Formula I, wherein n is 1; t is 2; y is 1 and z is 1.
[0037] The present invention further relates to the compound of
Formula I, wherein n is 1; t is 0; y is 1 and z is 0.
[0038] The present invention further relates to the compound of
Formula I, wherein n is 1; t is 1; y is 1 and z is 0.
[0039] The present invention further relates to the compound of
Formula I, wherein n is 2; t is 0; y is 1 and z is 0.
[0040] The present invention further relates to the compound of
Formula I, wherein n is 2; t is 1; y is 1 and z is 0.
[0041] The present invention further relates to the compound of
Formula I, wherein n is 3; t is 0; y is 1 and z is 0.
[0042] The present invention further relates to the compound of
Formula I, wherein n is 1; t is 2; y is 1 and z is 0.
[0043] The present invention further relates to the compound of
Formula I, wherein n is 1; t is 1; y is 2 and z is 0.
[0044] The present invention further relates to the compound of
Formula I, wherein n is 2; t is 0; y is 2 and z is 0.
[0045] The present invention further relates to the compound of
Formula I, wherein m is 1 and X.sup.1 is CR.sup.1.
[0046] The present invention further relates to the compound of
Formula I, wherein m is 0 and X.sup.1 is N.
[0047] The present invention further relates to the compound of
Formula I, wherein m is 1; E is O; X.sup.2 is O and X.sup.3 is
NH.
[0048] The present invention further relates to the compound of
Formula I, wherein m is 1; E is O; X.sup.2 is NH and X.sup.3 is
NH.
[0049] The present invention further relates to the compound of
Formula I, wherein m is 1; E is O; X.sup.2 is CH.sup.2 and X.sup.3
is NH.
[0050] The present invention further relates to the compound of
Formula I, wherein m is 1; E is O; X.sup.2 is NH and X.sup.3 is
CH.sup.2.
[0051] The present invention further relates to the compound of
Formula I, wherein m is 1; E is S; X.sup.2 is NH and X.sup.3 is
NH.
[0052] The present invention further relates to the compound of
Formula I, wherein m is 0; E is O; X.sup.1 is NH and X.sup.3 is
NH.
[0053] The present invention further relates to the compound of
Formula I, wherein m is 1; E is O; X.sup.2 is NH and X.sup.3 is
CO--NH.
[0054] The present invention further relates to the compound of
Formula I, wherein m is 1; p is 0; X.sup.2 is NH--SO.sub.2 and
X.sup.3 is NH.
[0055] The present invention further relates to the compound of
Formula I, wherein R.sup.4 and R.sup.5 are each
(C.sub.1-C.sub.6)alkyl or taken together with the carbon to which
they are attached to form a spiro (C.sub.3-C.sub.10)cyclo-alkyl
ring or a spiro (C.sub.3-C.sub.10)cycloalkoxy ring.
[0056] The present invention further relates to the compound of
Formula I, wherein R.sup.4 and R.sup.5 are each methyl.
[0057] The present invention further relates to the compound of
Formula I, wherein R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring.
[0058] The present invention further relates to the compound of
Formula I, wherein R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro cyclopropyl
ring.
[0059] The present invention further relates to the compound of
Formula I, wherein R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkoxy ring.
[0060] The present invention further relates to the compound of
Formula I, wherein A.sup.1 is (C.sub.2-C.sub.6)alkynyl or
(C.sub.6-C.sub.12)aryl.
[0061] The present invention further relates to the compound of
Formula I, wherein A.sup.1 is (C.sub.2-C.sub.9)heteroaryl.
[0062] The present invention further relates to the compound of
Formula I, wherein A.sup.1 is thiophene, thiazole, isothiazole,
furane, oxazole, isoxazole, pyrrole, imidazole, pyrazole, triazole,
pyridine, pymiridine, pyridazine, indole, benzotiazole,
benzoisoxazole, benzopyrazole, benzoimidazole, benzofuran,
benzooxazole or benzoisoxazole.
[0063] The present invention further relates to the compound of
Formula I, wherein A.sup.1 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0064] The present invention further relates to the compound of
Formula I, wherein A.sup.1 is pyrrolidinyl, tetrahydrofuranyl,
dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl,
aziridinyl, azetidinyl, oxiranyl, methylenedioxyl, chromenyl,
barbituryl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,
1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,
piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,
1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,
1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,
tetrahydroazepinyl, piperazinyl, piperizin-2-onyl,
piperizin-3-onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl,
imidazolidinyl, 2-imidazolidinyl, 1,4-dioxanyl,
8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl,
3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl,
2,5-diazabicyclo[2.2.2]octanyl,
octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[4.1.0]heptanyl,
3-azabicyclo[3.1.0]hexanyl 2-azaspiro[4.4]nonanyl,
7-oxa-1-aza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl or
octahydro-1H-indolyl.
[0065] The present invention further relates to the compound of
Formula I, wherein A.sup.1 is
benzo(C.sub.2-C.sub.9)heterocycloalkyl.
[0066] The present invention further relates to the compound of
Formula I, wherein A.sup.1 is 2,3-dihydrobenzo[b][1,4] dioxine or
2,2-difluorobenzo[d][1,3]dioxole.
[0067] The present invention further relates to the compound of
Formula I, wherein R.sup.6 is H.
[0068] The present invention further relates to the compound of
Formula I, X.sup.5 is a direct bond.
[0069] The present invention further relates to the compound of
Formula I, X.sup.5 is a CR.sup.4R.sup.5.
[0070] The present invention further relates to the compound of
Formula I, wherein R.sup.4 and R.sup.5 are each methyl.
[0071] The present invention further relates to the compound of
Formula I, wherein R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring.
[0072] The present invention further relates to the compound of
Formula I, wherein R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro cyclopropyl
ring.
[0073] The present invention further relates to the compound of
Formula I, wherein R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkoxy ring.
[0074] The present invention further relates to the compound of
Formula I, wherein A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0075] The present invention further relates to the compound of
Formula I, wherein A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0076] The present invention further relates to the compound of
Formula I, wherein A.sup.2 is pyridine.
[0077] The present invention further relates to the compound of
Formula I, wherein A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0078] The present invention further relates to the compound of
Formula I, wherein A.sup.2 is pyrrolidinyl, tetrahydrofuranyl,
dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl,
aziridinyl, azetidinyl, oxiranyl, methylenedioxyl, chromenyl,
barbituryl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,
1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,
piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,
1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,
1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,
tetrahydroazepinyl, piperazinyl, piperizin-2-onyl,
piperizin-3-onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl,
imidazolidinyl, 2-imidazolidinyl, 1,4-dioxanyl,
8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl,
3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl,
2,5-diazabicyclo[2.2.2]octanyl,
octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[4.1.0]heptanyl,
3-azabicyclo[3.1.0]hexanyl 2-azaspiro[4.4]nonanyl,
7-oxa-1-aza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl or
octahydro-1H-indolyl.
[0079] The present invention further relates to the compound of
Formula I, wherein A.sup.2 is
benzo(C.sub.2-C.sub.9)heterocycloalkyl.
[0080] The present invention further relates to the compound of
Formula I, where R.sup.1 is hydrogen or methyl.
[0081] The present further relates to the compound of Formula I,
wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or
2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2 is O;
X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are taken together
with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0082] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are each
independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0083] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are taken
together with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0084] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are each
independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0085] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are taken
together with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0086] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are each
independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0087] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0088] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl;
X.sup.5 is a direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0089] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0090] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; in is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl;
X.sup.5 is a direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0091] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; in is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0092] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0093] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0094] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0095] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0096] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0097] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0098] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0099] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together
with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0100] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0101] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together
with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0102] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0103] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together
with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0104] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0105] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0106] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl;
X.sup.5 is a direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0107] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0108] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl;
X.sup.5 is a direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0109] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0110] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0111] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0112] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0113] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0114] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0115] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0116] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0117] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are taken together with the carbon to which they are
attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0118] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are each independently methyl; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0119] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; in is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are taken together with the carbon to which they are
attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0120] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are each independently methyl; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0121] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are taken together with the carbon to which they are
attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0122] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are each independently methyl; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0123] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0124] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0125] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0126] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0127] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.3 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0128] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0129] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; tis 0, 1 or 2; y is 0 or 1; z is
0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2 is
O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are taken
together with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0130] The present invention further relates to the compound of
Formula I, wherein 11 is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are each
independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0131] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are taken
together with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0132] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are each
independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0133] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0134] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl;
X.sup.5 is a direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0135] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0136] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0137] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0138] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0139] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0140] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0141] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together
with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0142] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0143] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together
with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0144] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0145] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0146] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl;
X.sup.5 is a direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0147] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0148] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0149] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0150] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0151] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0152] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0153] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are taken together with the carbon to which they are
attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0154] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are each independently methyl; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0155] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are taken together with the carbon to which they are
attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0156] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are each independently methyl; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0157] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0158] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0159] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0160] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0161] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are taken
together with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0162] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are each
independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0163] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are taken
together with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0164] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are each
independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0165] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0166] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0167] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0168] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0169] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0170] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0171] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0172] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0173] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together
with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0174] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0175] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together
with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0176] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0177] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0178] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0179] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0180] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0181] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0182] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0183] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0184] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0185] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are taken together with the carbon to which they are
attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0186] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or t is 0, 1 or 2; y is 0 or 1; z is
0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4 and
R.sup.5 are each independently methyl; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0187] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are taken together with the carbon to which they are
attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0188] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are each independently methyl; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0189] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0190] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heterocycloalkyl.
[0191] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0192] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heterocycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0193] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are taken
together with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0194] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are each
independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0195] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0196] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0197] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0198] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0199] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together
with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0200] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0201] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0202] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0203] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0204] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0205] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are taken together with the carbon to which they are
attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0206] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are each independently methyl; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0207] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0208] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0209] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.3 are taken
together with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
[0210] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is R.sup.4 and R.sup.5 are each
independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
[0211] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; in is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are taken
together with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0212] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are each
independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0213] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
[0214] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl;
X.sup.5 is a direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
[0215] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0216] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0217] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
[0218] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
[0219] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0220] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0221] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together
with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
[0222] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
[0223] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together
with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0224] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0225] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
[0226] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl;
X.sup.5 is a direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
[0227] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0228] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0229] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
[0230] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
[0231] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0232] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0233] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are taken together with the carbon to which they are
attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
[0234] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; in is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are each independently methyl; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
[0235] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; in is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are taken together with the carbon to which they are
attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0236] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are each independently methyl; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0237] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.6-C.sub.12)aryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
[0238] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.6-C.sub.12)aryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
[0239] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.6-C.sub.12)aryl.
[0240] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.6-C.sub.12)aryl.
[0241] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are taken
together with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
[0242] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are each
independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
[0243] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are taken
together with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0244] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; p is 1; E is O; X.sup.2
is O; X.sup.3 is NH; R.sup.1 is H; R.sup.4 and R.sup.5 are each
independently methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0245] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NET; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
[0246] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
[0247] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0248] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0249] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
[0250] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
[0251] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0252] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CH.sub.2; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0253] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together
with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
[0254] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
[0255] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together
with the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0256] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is
CH.sub.2; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0257] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
[0258] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
[0259] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0260] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is S; X.sup.2 is NH;
X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently methyl;
R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0261] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
[0262] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
[0263] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are taken together with
the carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0264] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is SO.sub.2; X.sup.2
is NH; X.sup.3 is NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0265] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are taken together with the carbon to which they are
attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
[0266] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are each independently methyl; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
[0267] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are taken together with the carbon to which they are
attached to form a spiro (C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0268] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is N; m is 0; E is O; X.sup.3 is NH; R.sup.4
and R.sup.5 are each independently methyl; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0269] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct
bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.3-C.sub.10)cycloalkyl.
[0270] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.2-C.sub.9)heteroaryl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
[0271] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.3 is CO--NH; R.sup.4 and R.sup.5 are taken together with the
carbon to which they are attached to form a spiro
(C.sub.3-C.sub.10)cycloalkyl ring or spiro
(C.sub.3-C.sub.10)cycloalkoxy ring; R.sup.6 is a hydrogen or
methyl; A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a
direct bond, O or CR.sup.4R.sup.5 and A.sup.2 is
(C.sub.2-C.sub.9)heteroaryl.
[0272] The present invention further relates to the compound of
Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z
is 0, 1 or 2; X.sup.1 is CR.sup.1; m is 1; E is O; X.sup.2 is NH;
X.sup.1 is CO--NH; R.sup.4 and R.sup.5 are each independently
methyl; R.sup.6 is a hydrogen or methyl; A.sup.1 is
(C.sub.3-C.sub.10)cycloalkyl; X.sup.5 is a direct bond, O or
CR.sup.4R.sup.5 and A.sup.2 is (C.sub.2-C.sub.9)heteroaryl.
[0273] The present invention further relates to the compound of
Formula I, wherein A.sup.1 is (C.sub.3-C.sub.10)cycloalkyl.
[0274] The present invention further relates to the compound of
Formula I, wherein A.sup.2 is (C.sub.3-C.sub.10)cycloalkyl.
[0275] The present invention further relates to the compound of
Formula I, or a pharmaceutically acceptable salt or prodrug
thereof, selected from the group consisting of: [0276]
1-azabicyclo[2.2.2]oct-3-yl
[2-(2,4'-difluorobiphenyl-4-yl)propan-2-yl]carbamate; [0277]
1-azabicyclo[2.2.2]oct-3-yl
{2-[4-(1,3-benzothiazol-6-yl)phenyl]propan-2-yl}carbamate; [0278]
1-azabicyclo[3.2.2]non-4-yl
{1-[5-(4-fluorophenyl)pyridin-2-yl]cyclopropyl}carbamate; [0279]
1-azabicyclo[2.2.2]oct-3-yl
{1-[3-(4-fluorophenoxy)phenyl]cyclopropyl}carbamate; [0280]
1-azabicyclo[2.2.2]oct-3-yl
{1-[4-(1,3-benzothiazol-5-yl)phenyl]cyclopropyl}carbamate; [0281]
1-azabicyclo[2.2.2]oct-3-yl
[1-(4'-fluoro-3'-methoxybiphenyl-4yl)cyclopropyl]carbamate; [0282]
1-azabicyclo[2.2.2]oct-3-yl
[3-(4'-fluorobiphenyl-4-yl)oxetan-3-yl]carbamate; [0283]
1-azabicyclo[2.2.2]oct-3-yl
{1-[6-(4-fluorophenoxy)pyridin-2-yl]cyclopropyl}carbamate; [0284]
1-azabicyclo[2.2.2]oct-3-yl
[3-(4'-fluorobiphenyl-4-yl)pentan-3-yl]carbamate; [0285]
1-azabicyclo[2.2.2]oct-3-yl
{2-[2-(4-fluorophenyl)-2H-indazol-6-yl]propan-2 yl}carbamate;
[0286] 1-azabicyclo[2.2.2]oct-3-yl
{2-[2-(1H-pyrrol-1-yl)pyridin-4-yl]propan-2-yl}carbamate; [0287]
1-(3-ethyl-1-azabicyclo[2.2.2]oct-3-yl)-3-[1-(4'-fluorobiphenyl-4-yl)cycl-
opropyl]urea; [0288]
N-(1-azabicyclo[2.2.2]oct-3-yl)-N'-[1-(4'-fluorobiphenyl-4yl)cyclopropyl]-
ethanediamide; [0289] 1-azabicyclo[2.2.2]oct-3-yl
(1-{4[(4,4difluorocyclohexyl)oxy]phenyl}cyclopropyl) carbamate;
[0290]
1-(4-methyl-1-azabicyclo[3.2.2]non-4-yl)-3-[1-(5-phenylpyridin-2-yl)cyclo-
propyl]urea; [0291]
1-[1-(4'-fluorobiphenyl-4-yl)cyclopropyl]-1-methyl-3-(3-methyl-1-azabicyc-
lo[2.2.2]oct-3-yl)urea; [0292]
1-[1-(4'-fluorobiphenyl-4-yl)cyclopropyl]-1-methyl-3-(3-methyl-1-azabicyc-
lo[2.2.2]oct-3-yl)urea; [0293]
1-{2-[4'-(2-methoxyethoxy)biphenyl-4-yl]propan-2-yl}-3-(3-methyl-1-azabic-
yclo[2.2.2]oct-3-yl)urea; [0294]
2-(1-azabicyclo[3.2.2]non-4-yl)-N-[1-(5-phenylpyridin-2-yl)cyclopropyl]ac-
etamide; [0295]
3-(4'-fluorobiphenyl-4-yl)-3-methyl-N-(4-methyl-1-azabicyclo[3.2.2]non-4--
yl)butanamide; [0296]
N-[2-(biphenyl-4-yl)propan-2-yl]-N'-(3-methyl-1-azabicyclo[2.2.2]oct-3-yl-
)sulfuric diamide; [0297]
N-[2-(4'-fluorobiphenyl-4-yl)propan-2-yl]-N'-(3-methyl-1-azabicyclo[2.2.2-
]oct-3-yl)sulfuric diamide; [0298]
1-(3-butyl-1-azabicyclo[2.2.2]oct-3-yl)-3-{2-[1-(4-fluorophenyl)-1H-pyraz-
ol-4-yl]propan-2-yl}urea; [0299] 1-azabicyclo[2.2.2]oct-3-yl
[4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl]carbamate; [0300]
1-(3-butyl-1-azabicyclo[2.2.2]oct-3-yl)-3-[4-(4-fluorophenyl)-2-methylbut-
-3-yn-2-yl]urea; [0301]
N-[1-(4'-fluorobiphenyl-4-yl)cyclopropyl]-1,4-diazabicyclo[3.2.2]nonane-4-
-carboxamide; [0302]
1-(2-(4'-fluoro-[1,1'-biphenyl]-4-yl)propan-2-yl)-3-(3-methyl-1-azabicycl-
o[3.2.2]nonan-3-yl)urea; [0303]
1-(2-(4'-fluoro-[1,1'-biphenyl]-4-yl)propan-2-yl)-3-(4-methyl-1-azabicycl-
o[4.2.2]decan-4-yl)urea; [0304]
1-(2-(4'-fluoro-[1,1'-biphenyl]-4-yl)propan-2-yl)-3-(3-methyl-1-azabicycl-
o[4.2.2]decan-3-yl)urea; and [0305]
1-(2-(4'-fluoro-[1,1'-biphenyl]-4-yl)propan-2-yl)-3-(5-methyl-1-azabicycl-
o[4.2.2]decan-5-yl)urea.
[0306] The present invention further relates to a pharmaceutical
composition for treating a disease or disorder mediated by
glucosylceramide synthase (GCS) or a disease or disorder in which
GCS is implicated in a subject in need of such treatment comprising
administering to the subject an effective amount of the compound of
Formula I.
[0307] The present invention further relates to a method for
treating a disease or disorder mediated by glucosylceramide
synthase (GCS) or a disease or disorder in which GCS is implicated
in a subject in need of such treatment comprising administering to
the subject an effective amount of the compound of Formula I.
[0308] The present invention further relates to a method for
treating a disease or disorder such as cancer.
[0309] The present invention further relates to a method for
treating a disease or disorder such as a metabolic disorder.
[0310] The present invention further relates to a method for
treating a disease or disorder such as a neuropathic disease.
[0311] The present invention further relates to a method wherein
the neuropathic disease is Alzheimers disease.
[0312] The present invention further relates to a method wherein
the neuropathic disease is Parkinsons disease.
[0313] The present invention further relates to the method for
inducing decreased glucosylceramide synthase catalytic activity in
a cell, in vitro, comprising contacting the cell with an effect
amount of the compound of Formula I.
[0314] The present invention further relates to the compound of
formula I, represented by the following structural formula,
##STR00002##
or a pharmaceutically acceptable salt or prodrug thereof.
[0315] The present invention further relates to the compound of
formula I, represented by the following structural formula,
##STR00003##
or a pharmaceutically acceptable salt or prodrug thereof.
[0316] The present invention further relates to a method of
treating a subject diagnosed as having a lysosomal storage disease,
the method including administering to the subject an effective
amount of the compound of formula I, and in certain embodiments the
compound is represented by following structural formulas,
##STR00004##
or a pharmaceutically acceptable salt or prodrug thereof, or
##STR00005##
or a pharmaceutically acceptable salt or prodrug thereof.
[0317] In certain embodiments of the invention, the lysosomal
storage disease results from a defect in the glycosphingolipid
pathway.
[0318] In certain embodiments of the invention, the lysosomal
storage disease is Gaucher, Fabry, G.sub.M1-gangliosidosis,
G.sub.M2 Activator deficiency, Tay-Sachs or Sandhoff.
[0319] The present invention further relates to a method of
treating a subject diagnosed as having a lysosomal storage disease,
the method including administering to the subject an effective
amount of the compound of formula I and administering to the
subject a therapeutically effective amount of a lysosomal
enzyme.
[0320] In certain embodiments of the invention, the lysosomal
enzyme is glucocerebrosidase, alpha-galactosidase A, Hexosaminidase
A, Hexosaminidase B or
G.sub.M1-ganglioside-.beta.-galactosidase.
[0321] In certain embodiments of the invention, the subject has
elevated levels of a lysosomal substrate prior to treatment and
once undergoing treatment the subject has lower combined amounts of
the lysosomal substrate in the urine and plasma than a subject
treated with either the lysosomal enzyme or compound alone.
[0322] In certain embodiments of the invention, the substrate is
globotriaosylceramide or lyso-globotriaosylceramide, and
combinations thereof.
[0323] The present invention further relates to a method of
reducing glucosylceramide synthase (GCS) activity in a subject
diagnosed as having a lysosomal storage disease, including
administering to the patient an effective amount of the compound of
formula I, either alone or as a combination therapy with an enzyme
replacement therapy.
[0324] The present invention further relates to a method of
reducing accumulation of a GCS-derived material in a subject
diagnosed as having a lysosomal storage disease, including
administering to the patient an effective amount of the compound of
formula I, either alone or as a combination therapy with an enzyme
replacement therapy.
[0325] This invention provides a method of combination therapy for
treatment of a subject diagnosed as having a lysosomal storage
disease comprising alternating between administration of an enzyme
replacement therapy and a small molecule therapy.
[0326] This invention provides a method of combination therapy for
treatment of a subject diagnosed as having a lysosomal storage
disease comprising simultaneously administering an enzyme
replacement therapy and a small molecule therapy.
[0327] In the various combination therapies of the invention, it
will be understood that administering small molecule therapy may
occur prior to, concurrently with, or after, administration of
enzyme replacement therapy. Similarly, administering enzyme
replacement therapy may occur prior to, concurrently with, or
after, administration of small molecule therapy.
Definitions
[0328] As used herein, the term "pharmaceutically acceptable salt"
means either a pharmaceutically acceptable acid addition salt or a
pharmaceutically acceptable base addition salt of a currently
disclosed compound that may be administered without any resultant
substantial undesirable biological effect(s) or any resultant
deleterious interaction(s) with any other component of a
pharmaceutical composition in which it may be contained.
[0329] As used herein, the term "prodrug" means a pharmacological
derivative of a parent drug molecule that requires
biotransformation, either spontaneous or enzymatic, within the
organism to release the active drug. For example, prodrugs are
variations or derivatives of the compounds of Formula I that have
groups cleavable under certain metabolic conditions, which when
cleaved, become the compounds of Formula I. Such prodrugs then are
pharmaceutically active in vivo, when they undergo solvolysis under
physiological conditions or undergo enzymatic degradation. Prodrug
compounds herein may be called single, double, triple, etc.,
depending on the number of biotransformation steps required to
release the active drug within the organism, and the number of
functionalities present in a precursor-type form. Prodrug forms
often offer advantages of solubility, tissue compatibility, or
delayed release in the mammalian organism (See, Bundgard, Design of
Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985 and
Silverman,
[0330] The Organic Chemistry of Drug Design and Drug Action, pp.
352-401, Academic Press, San Diego, Calif., 1992). Prodrugs
commonly known in the art include well-known acid derivatives, such
as, for example, esters prepared by reaction of the parent acids
with a suitable alcohol, amides prepared by reaction of the parent
acid compound with an amine, basic groups reacted to form an
acylated base derivative, etc. Of course, other prodrug derivatives
may be combined with other features disclosed herein to enhance
bioavailability. As such, those of skill in the art will appreciate
that certain of the presently disclosed compounds having free
amino, amido, hydroxy or carboxylic groups can be converted into
prodrugs. Prodrugs include compounds having an amino acid residue,
or a polypeptide chain of two or more (e.g., two, three or four)
amino acid residues which are covalently joined through peptide
bonds to free amino, hydroxy or carboxylic acid groups of the
presently disclosed compounds. The amino acid residues include the
20 naturally occurring amino acids commonly designated by three
letter symbols and also include 4-hydroxyproline, hydroxylysine,
demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine,
gamma-aminobutyric acid, citrulline homocysteine, homoserine,
ornithine and methionine sulfone. Prodrugs also include compounds
having a carbonate, carbamate, amide or alkyl ester moiety
covalently bonded to any of the above substituents disclosed
herein.
[0331] As used herein, the term "(C.sub.1-C.sub.6)alkyl" means a
saturated linear or branched free radical consisting essentially of
1 to 6 carbon atoms and a corresponding number of hydrogen atoms.
Exemplary (C.sub.1-C.sub.6)alkyl groups include methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, etc. Of course, other
(C.sub.1-C.sub.6)alkyl groups will be readily apparent to those of
skill in the art given the benefit of the present disclosure.
[0332] As used herein, the term "(C.sub.3-C.sub.10)cycloalkyl"
means a nonaromatic saturated free radical forming at least one
ring consisting essentially of 3 to 10 carbon atoms and a
corresponding number of hydrogen atoms. As such,
(C.sub.3-C.sub.10)cycloalkyl groups can be monocyclic or
multicyclic. Individual rings of such multicyclic cycloalkyl groups
can have different connectivities, e.g., fused, bridged, spiro,
etc. in addition to covalent bond substitution. Exemplary
(C.sub.3-C.sub.10)cycloalkyl groups include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, norbornanyl,
bicyclo[3.2.1]octanyl, octahydro-pentalenyl, spiro[4.5]decanyl,
cyclopropyl substituted with cyclobutyl, cyclobutyl substituted
with cyclopentyl, cyclohexyl substituted with cyclopropyl, etc. Of
course, other (C.sub.3-C.sub.10)cycloalkyl groups will be readily
apparent to those of skill in the art given the benefit of the
present disclosure.
[0333] As used herein, the term "(C.sub.2-C.sub.9)heterocycloalkyl"
means a nonaromatic free radical having 3 to 10 atoms (i.e., ring
atoms) that form at least one ring, wherein 2 to 9 of the ring
atoms are carbon and the remaining ring atom(s) (i.e., hetero ring
atom(s)) is selected from the group consisting of nitrogen, sulfur,
and oxygen. As such, (C.sub.2-C.sub.9)heterocycloalkyl groups can
be monocyclic or multicyclic. Individual rings of such multicyclic
heterocycloalkyl groups can have different connectivities, e.g.,
fused, bridged, spiro, etc. in addition to covalent bond
substitution. Exemplary (C.sub.2-C.sub.9)heterocycloalkyl groups
include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,
tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, azetidinyl,
oxiranyl, methylenedioxyl, chromenyl, barbituryl, isoxazolidinyl,
1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl,
1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl,
thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,
1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,
1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,
tetrahydroazepinyl, piperazinyl, piperizin-2-onyl,
piperizin-3-onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl,
imidazolidinyl, 2-imidazolidinyl, 1,4-dioxanyl,
8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl,
3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl,
2,5-diazabicyclo[2.2.2]octanyl,
octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[4.1.0]heptanyl,
3-azabicyclo[3.1.0]hexanyl 2-azaspiro[4.4]nonanyl,
7-oxa-1-aza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl,
octahydro-1H-indolyl, etc. In general, the
(C.sub.2-C.sub.9)heterocycloalkyl group typically is attached to
the main structure via a carbon atom or a nitrogen atom. Of course,
other (C.sub.2-C.sub.9)heterocycloalkyl groups will be readily
apparent to those of skill in the art given the benefit of the
present disclosure.
[0334] As used herein, the term "(C.sub.2-C.sub.9)heteroaryl" means
an aromatic free radical having 5 to 10 atoms (i.e., ring atoms)
that form at least one ring, wherein 2 to 9 of the ring atoms are
carbon and the remaining ring atom(s) (i.e., hetero ring atom(s))
is selected from the group consisting of nitrogen, sulfur, and
oxygen. As such, (C.sub.2-C.sub.9)heteroaryl groups can be
monocyclic or multicyclic. Individual rings of such multicyclic
heteroaryl groups can have different connectivities, e.g., fused,
etc. in addition to covalent bond substitution. Exemplary
(C.sub.2-C.sub.9)heteroaryl groups include furyl, thienyl,
thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl,
triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl,
pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl,
1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl,
purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl,
5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,
benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,
isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl,
indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl,
phthalazinyl, quinoxalinyl, quinazolinyl and benzoxazinyl, etc. In
general, the (C.sub.2-C.sub.9)heteroaryl group typically is
attached to the main structure via a carbon atom, however, those of
skill in the art will realize when certain other atoms, e.g.,
hetero ring atoms, can be attached to the main structure. Of
course, other (C.sub.2-C.sub.9)heteroaryl groups will be readily
apparent to those of skill in the art given the benefit of the
present disclosure.
[0335] As used herein, the term "(C.sub.6-C.sub.10)aryl" means
phenyl or naphthyl.
[0336] As used herein, the term "halo" means fluorine, chlorine,
bromine, or iodine.
[0337] As used herein, the term "amino" means a free radical having
a nitrogen atom and 1 to 2 hydrogen atoms. As such, the term amino
generally refers to primary and secondary amines. In that regard,
as used herein and in the appended claims, a tertiary amine is
represented by the general formula RR'N--, wherein R and R' are
carbon radicals that may or may not be identical. Nevertheless, the
term "amino" generally may be used herein to describe a primary,
secondary, or tertiary amine, and those of skill in the art will
readily be able to ascertain the identification of which in view of
the context in which this term is used in the present
disclosure.
[0338] As used herein, the term "combination therapy" means
treating a patient with two or more therapeutic platforms (e.g.,
enzyme replacement therapy and small molecule therapy) in rotating,
alternating and/or simultaneous treatment schedules. Examples of
treatment schedules may include, but are not limited to: (1) enzyme
replacement therapy, then small molecule therapy; (2) small
molecule therapy, then enzyme replacement therapy; (3) enzyme
replacement therapy concurrent with small molecule therapy, and (4)
and any combination of the foregoing. Combination therapy may
provide a temporal overlap of therapeutic platforms, as needed,
depending on the clinical course of a given storage disease in a
given subject.
[0339] As used herein, the term "enzyme replacement therapy", or
"ERT" means administering an exogenously-produced natural or
recombinant enzyme to a patient who is in need thereof. In the case
of a lyosomal storage disease, for example, the patient accumulates
harmful levels of a substrate (i.e., material stored) in lysosomes
due to a deficiency or defect in an enzyme responsible for
metabolizing the substrate, or due to a deficiency in an enzymatic
activator required for proper enzymatic function. Enzyme
replacement therapy is provided to the patient to reduce the levels
of (i.e., debulk) accumulated substrate in affected tissues. Table
1 provides a list of lysosomal storage diseases and identifies the
corresponding enzyme deficiency and accumulated substrate for each
disease. Enzyme replacement therapies for treating lysosomal
storage diseases are known in the art. In accordance with a
combination therapy of the invention, the lysosomal enzymes
identified in Table 1 can be used for enzyme replacement therapy to
reduce the levels of corresponding substrate in a patient diagnosed
with the respective lysosomal storage disease.
[0340] As used herein, "effective amount" of an enzyme or small
molecule, when delivered to a subject in a combination therapy of
the invention, is an amount sufficient to improve the clinical
course of a lysosomal storage disease, where clinical improvement
is measured by any of the variety of defined parameters well known
to the skilled artisan.
ABBREVIATIONS
[0341] ACN refers to acetonitrile. DMF refers to
N,N-dimethylformamide. DMSO refers to dimethylsulfoxide. EtOAc
refers to ethyl acetate. EtOH refers to ethanol. Hunig's Base
refers to diisopropylethyl amine ("DIPEA"). MeOH refers to
methanol. NaOH refers to sodium hydroxide. THF refers to
tetrahydrofuran. TFA refers to trifluoroacetic acid.
[0342] Additional features and advantages of compounds disclosed
herein will be apparent from the following detailed description of
certain embodiments.
BRIEF DESCRIPTION OF THE DRAWINGS
[0343] FIG. 1 Presents the metabolic pathway for the potential
synthesis of Gb3 and lyso-Gb3. Documented synthetic pathways are
shown with black arrows and undocumented (potential) pathways are
shown with grey arrows.
[0344] FIG. 2A Chemical structure of (S)-Quinuclidin-3-yl
(2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate
[0345] FIG. 2B Chemical structure of Quinuclidin-3-yl
(2-(4'-fluoro-[1,1'-biphenyl]-3-yl)propan-2-yl)carbamate
[0346] FIG. 3 Gb3 concentration in kidney (A) and heart (B) from 12
month old Fabry mice treated with 300 mg/kg/day (1R,2R)-Octanoic
acid[2-(2',3'-dihydro-benzo [1,4]
dioxin-6'-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide-L-tartaric
acid salt ("GZ 638") or 60 mg/kg/day (S)-Quinuclidin-3-yl
(2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate
(S)-2-hydroxysuccinate salt ("GZ 452").
[0347] FIG. 4A Study timeline showing Fabry mice starting treatment
with 60 mg/kg/day GZ 452 starting at 3, 8 and 12 months of age.
Periodic blood-draws, urine collection, hot-plate and activity
chamber assays were performed as indicated.
[0348] FIG. 4B Gb3 concentration in urine (A) and plasma (B) from
Fabry mice starting treatment with 60 mg/kg/day GZ 452 at either 3
or 8 months of age. Drug treatment (Rx) was for either 2 or 4
months.
[0349] FIG. 5 Gb3 (A) and lyso-Gb3 (B) concentration in kidney
tissue from 12 month old Fabry mice that were either untreated
(UNT) or treated with 60 mg/kg/day GZ 452 for 4 months (SRT).
[0350] FIG. 6A Study timeline showing Fabry mice being treated with
alpha-galactosidase A (1 mg/kg every 2 months) or with 60 mg/kg/day
GZ 452 or a combination of the 2 treatments starting at 3 months of
age. Periodic blood-draws, urine collection and hot-plate assays
were performed as indicated.
[0351] FIG. 6B Plasma (A&C) and urine (B&D) Gb3 (A&C)
and lyso-Gb3 (C&D) concentrations from 5 month old Fabry mice
treated with alpha-galactosidase A alone (ERT), GZ 452 alone (SRT)
or a combination of the two (E+S) for 2 months.
[0352] FIG. 7 N-linked acyl chain isoform analysis of Gb3 isolated
from Fabry mouse plasma, urine and kidney.
[0353] FIG. 8 Latency (time to respond) to a heat stimulus
(55.degree. C. hotplate) of 10 month old Fabry mice following 7
months treatment with alpha-galactosidase A (ERT), GZ 452 (SRT) or
a combination of the two (E+S) relative to untreated mice (UNT) and
wild-type mice (WT).
[0354] FIG. 9 Glucosyl ceramide (GluCer) and Glucosyl sphingosine
(GluSph) are significantly elevated in the brains of neonatal K14
mice. Mass spectrometry analysis of glucosyl- and
galactosylceramides shows that (A) GluCer was elevated 10-fold in
K14 mice (an animal model of Neonatal Gaucher disease, also known
as Gaucher disease Type 2) compared to WT mice through the first 2
weeks of life, (B) GalCer levels were similar over time for both
K14 and WT mice, (C) GluSph levels were .gtoreq.10-fold higher in
K14 mice than age-matched WT mice over the first 2 weeks of life;
GluSph levels in WT animals were below the level of detection
(<0.3 ng/mg). (D) There were no significant differences in brain
weights between K14 and WT mice over the first 2 weeks of life.
Data points represent mean values and error bars SEM for N=4.
[0355] FIG. 10 Systemic administration of Quinuclidin-3-yl
(2-(4'-fluoro-[1,1'-biphenyl]-3-yl)propan-2-yl)carbamate ("GZ 161")
reduces GluCer and GluSph levels in the K14 mouse brain. K14 and WT
mice were treated daily (IP) beginning at P4 with vehicle or 5
mg/kg GZ 161, and brains analyzed for GluCer and GluSph at P10. GZ
161-treated animals were asymptomatic at this time. Treatment with
GZ 161 reduced K14 (A) GluCer levels by 70% and (B) GluSph levels
by 60%. Post-treatment levels of both glycosphingolipids remained
significantly elevated compared to their WT littermates and
genotypes were confirmed by post-mortem DNA analysis. *p<0.05.
N=4/group.
[0356] FIG. 11 Systemic administration of GZ 161 reduces CD68
staining throughout the brain of K14 mice. (Upper panels)
Representative immunohistochemical CD 68 staining at P10 in the
hippocampus, thalamus, brainstem and cerebellum of K14 mice treated
daily (CP) beginning at postnatal day 4 (P4) with vehicle or GZ 161
and WT mice. (Lower panels) Quantitation of staining in the groups
shown above, showing that systemic treatment with GZ 161 results in
significant reductions the CD68+ cells in all brain regions.
Similar reductions were observed in other structures such as the
olfactory bulb and frontal cortex (data not shown). **p<0.01.
N=4/group
[0357] FIG. 12 Systemic administration of GZ 161 reduces F4/80
staining in some brain regions of K14 mice. (Upper panels)
Representative immunohistochemical F4/80 staining at P10 in the
hippocampus, thalamus, brainstem and cerebellum of K14 mice treated
daily (IP) beginning at P4 with vehicle or GZ 161, and WT mice.
(Lower panels) Quantitation of staining in the groups shown above,
showing that systemic treatment with GZ 161 results in significant
reductions the F4/80+ cells in the thalamus and brainstem. Similar
reductions were observed in other structures such as the olfactory
bulb and frontal cortex; statistical differences were observed in
both structures (data not shown). *p<0.05. N=4/group
[0358] FIG. 13 Systemic administration of GZ 161 decreases gliosis
in K14 mice. (Upper panels) Representative immunohistochemical GFAP
staining at P10 in the hippocampus, thalamus, brainstem and
cerebellum of K14 mice treated daily (IP) beginning at P4 with
vehicle or GZ 161, and WT mice. (Lower panels) Quantitation of
staining in the groups shown above, showing that systemic treatment
with GZ 161 results in significant reductions the GFAP+ cells in
the hippocampus and cerebellum; statistical differences were
observed in both structures (data not shown).
[0359] FIG. 14 Systemic administration of GZ 161 increases the
median lifespan of K14 mice. K14 mice were injected (IP) daily
beginning at P4 with vehicle or GZ 161 or given a combined
treatment of three intracerebroventricular (ICV) injections of rhGC
at P1, 2, 3 together with daily (IP) injections of GZ 161 beginning
at P4. Vehicle treated mice had a 15 day median lifespan (N=25); GZ
161 treated mice had an 18 day median lifespan (N=12; p<0.0001
compared to vehicle-treated); mice coadministered GZ 161 and rhGC
had a 26 day median lifespan (N=13)
[0360] FIG. 15 GZ 161 appears to cross the blood/placental barrier.
Systemic administration (20 mg/kg/day in food) of GZ 161 to
pregnant WT mice reduces the GluCer load in whole brain homogenates
of mice at birth (P0). N=7; p<0.0001)
[0361] FIG. 16 Treating K14 mice with GZ 161 in utero has a minimal
effect on survival. K14 mice treated daily (IP) beginning at P4
with vehicle had a median lifespan of 14 days (N=13). Systemic
administration (20 mg/kg/day in food) of GZ 161 to pregnant K14
mice and then daily systemic (IP) administration of GZ 161 (5
mg/kg) to the pups beginning at P0 extended lifespan to 19 days
(N=13), a result similar to treating pups daily systemically (IP)
with GZ 161 at 5 mg/kg beginning at P4 (N=12).
[0362] FIG. 17 Gb3 levels in kidney tissue from 12 month old male
and female Fabry mice treated with GZ 452, GZ 161 and GZ 638. Mice
began treatment at 8 months old and were treated for 4 months with:
60 mg/kg/day GZ 452, 120 mg/kg/day GZ 452, 20 mg/kg/day GZ 161, 300
mg/kg/day GZ 638, plus WT and UNT controls.
DETAILED DESCRIPTION
[0363] Although specific embodiments of the present disclosure will
now be described with reference to the preparations and schemes, it
should be understood that such embodiments are by way of example
only and merely illustrative of but a small number of the many
possible specific embodiments which can represent applications of
the principles of the present disclosure. Various changes and
modifications will be obvious to those of skill in the art given
the benefit of the present disclosure and are deemed to be within
the spirit and scope of the present disclosure as further defined
in the appended claims.
[0364] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one
having ordinary skill in the art to which this disclosure belongs.
Although other compounds or methods can be used in practice or
testing, certain preferred methods are now described in the context
of the following preparations and schemes.
##STR00006##
##STR00007##
##STR00008##
##STR00009##
##STR00010##
##STR00011##
##STR00012##
##STR00013##
[0365] In reaction 1 of Preparation A, the compound of formula A-7
is converted to the corresponding compound of formula A-1, wherein
X is OH, by reducing A-7 with a reducing agent, preferably lithium
aluminum hydride in aprotic solvent such tetrahydrofuran. The
reaction is stirred at a temperature between 0.degree. C. and room
temperature for a time period between about 15 minutes to about 2
hours, preferably about 30 minutes. Alternatively, the compound of
formula A-7 is converted to the corresponding compound of formula
A-1, wherein X is OH, by reducing A-7 under approximately 1
atmosphere of hydrogen in presence of a catalyst, preferably
platinum oxide, and a polar solvent such methanol or ethanol for a
period of 2 hours to 6 hours, preferably 4 hours. Alternatively,
the compound of formula A-7 is converted to the corresponding
compound of formula A-1, wherein X is NH, by reacting A-7 with
hydroxylamine hydrochloride and sodium acetate in a polar solvent
such ethanol, methanol, isopropanol, preferably isopropanol. The
reaction mixture is stirred at a temperature between 50-80.degree.
C. for a period of 2 hours to 7 hours, preferably 3 hours.
Subsequently, the compound so formed above is converted to compound
of formula A-1 with a reducing agent, preferably sodium metallic in
a polar protic solvent such ethanol, methanol, propanol, preferably
n-propanol. The reaction is stirred overnight at 50-80.degree. C.,
preferably solvent reflux temperature.
[0366] In reaction 2 of Preparation A, the compound of formula A-7
is converted to the corresponding compound of formula A-5, wherein
R1, n and z are as defined above, by adding a solution of
R1-magnesium bromide in ether to a solution of A-7 in a aprotic
solvent, such as ether, at a temperature between about -60.degree.
C. to about -90.degree. C., preferably about -78.degree. C. for a
time period between about 1 hour to about 4 hours, preferably about
2 hours. Alternatively, the compound of formula A-7 can be reacted
with R1-lithium to afford the compound of formula A-5.
[0367] In reaction 3 of Preparation A, the compound of formula A-5
is converted to the corresponding compound of formula A-4, wherein
R1, n and z are as defined above, by treating A-5 with a strong
acid, preferably sulfuric acid, in the presence of acetonitrile.
The reaction is stirred overnight at room temperature.
[0368] In reaction 4 of Preparation A, the compound of formula A-4
is converted to the corresponding compound of formula A-3, wherein
R1, n and z are as defined above, by treating A-4 with an acid,
preferably hydrochloric acid. The reaction is stirred at reflux for
a period of 18 hours to 72 hours, preferably 24 hours and basified
to pH=8 by treatment with an inorganic base in aqueous solution,
such as sodium hydroxide.
[0369] In reaction 5 of Preparation A, the compound of formula A-7
is converted to the corresponding compound of formula A-6, wherein
R1, n and z are as defined above, by reacting A-7 with a triphenyl
phosphonium ylide to give the corresponding alkene compound of
formula A-6. The reaction is stirred at room temperature for
overnight.
[0370] In reaction 6 of Preparation A, the compound of formula A-6
is converted to the corresponding compound of formula A-3, wherein
R1, n and z are as defined above, by reducing A-6 under
approximately 1 atmosphere of hydrogen in the presence of a
catalyst, preferably palladium on carbon, and a polar solvent, such
as methanol, ethanol or ethyl acetate. The reaction is stirred at
room temperature for a time period between about 2 hours to about
24 hour, preferably about 18 hours. Subsequently, the compound so
formed is treated with a base, preferably lithium hydroxide, in a
mixture of solvent such tetrahydrofuran, methanol and water to
afford the compound of A-3. The reaction is stirred overnight at
room temperature.
[0371] In reaction 1 of Preparation B, the compound of formula B-2
is converted to the corresponding compound of formula B-1, by
reducing B-2 with a reducing agent, preferably lithium aluminum
hydride in aprotic solvent such tetrahydrofuran. The reaction is
stirred at a temperature between 0.degree. C. and room temperature
for a time period between about 15 minutes to about 2 hours,
preferably about 30 minutes.
[0372] In reaction 1 of Preparation C, the compound of C-4 is
converted to the corresponding compound of formula C-3, wherein X
is bromine or chloride, by reacting C-4 with boronic acid in the
presence of a catalyst, preferably
1,1'-bis(diphenylphosphino)ferrocene-palladium(II)-dichloride, and
potassium carbonate. The reaction is microwaved in a mixture of
dimethoxyethane and water at a temperature between about
130.degree. C. to about 170.degree. C., preferably about
150.degree. C., for a time period between about 15 min to about 1
hour, preferably about 30 min. Alternatively, the reaction can be
performed using solvent such dioxane and stirred overnight at
100.degree. C. under conventional heating.
[0373] In reaction 2 of Preparation C, the compound of C-3 is
converted to the corresponding compound of formula C-1, wherein f
is 1 to 8 and A1, X5 and A2 are as defined above, by adding ethyl
magnesium bromide dropwise to a mixture of C-3 and titanium
isopropoxide in ether. The reaction is stirred at a temperature
between about -50.degree. C. to about -90.degree. C., preferably
about -70.degree. C. The resulting reaction mixture is allowed to
warm to about 20.degree. C. to about 30.degree. C., preferably
about 25.degree. C., and allowed to stir for an additional time
period between about 30 minutes to about 2 hours, preferably about
1 hour. Boron trifluoride diethyl etherate is then added to the
mixture dropwise at a temperature between about 20.degree. C. to
about 30.degree. C., preferably about 25.degree. C.
[0374] In reaction 3 of Preparation C, the compound of C-3 is
converted to the corresponding compound of formula C-2, wherein A1,
X5 and A2 are as defined above, by first stirring a suspension of
cerium (III) chloride in an aprotic solvent, such as
tetrahydrofuran, at room temperature for time period between about
30 minutes to about 2 hours, preferably about 1 hour. The resulting
suspension is cooled to a temperature between about -60.degree. C.
to about -90.degree. C., preferably about -78.degree. C. and an
organolithium agent is added, preferably methyl lithium in an ether
solution. The resulting organocerium complex is allowed to form for
a time period between about 30 minutes to about 2 hours, preferably
about 1 hour, followed by the addition of C-3 in an aprotic
solvent, such as tetrahydrofuran. The resulting reaction mixture is
then warmed to room temperature and allowed to stir for time period
between about 16 hours to about 20 hours, preferably about 18
hours.
[0375] In reaction 1 of Preparation D, the compound of D-5, wherein
R is CO2Et or CN and X is bromine or chloride, is converted to the
corresponding compound of formula D-3, by reacting D-5 with an
alkyl dihalide such 1,2-dibromoethane. Subsequently, the compound
so formed is treated with an inorganic base such lithium hydroxide
or potassium hydroxide, in a mixture of solvent such
tetrahydrofuran, methanol, glycol and water to afford the compound
of D-3, wherein f is 1 to 8. The reaction is stirred overnight at a
temperature between 25.degree. C. and 130.degree. C. Alternatively,
to form the corresponding compound of formula D-3, wherein X is
X5-A2, D-5 must first be reacted according to the procedure
discussed above in reaction 1 of Preparation C.
[0376] In reaction 2 of Preparation D, the compound of D-3 is
converted to the corresponding compound of formula D-1 by reacting
D-3 with a base such triethylamine and diphenylphosphoryl azide in
aprotic solvent such toluene. The reaction was heated to a
temperature range between 80.degree. C.-110.degree. C., preferably
at 110.degree. C. for 15 min to 1 hour, preferably 30 minutes. The
so formed intermediate is then treated with tert-butyl alcohol for
overnight period at 60-110.degree. C., preferably 90.degree. C.
Subsequently, the so formed carbamate is converted to the
corresponding compound of formula D-1, wherein f is 1 to 8, by a
treatment under acidic media using preferably trifluoroacetic acid
in dichloromethane at room temperature for a period of 30 min to 5
hours, preferably 2 hours.
[0377] In reaction 3 of Preparation D, the compound of D-5, wherein
R is CO2Et or CN and X is bromine or chloride, is converted to the
corresponding compound of formula D-4, by reacting D-5 with an
alkyl halide such Mel. Subsequently, the compound so formed is
treated with an inorganic base such lithium hydroxide or potassium
hydroxide, in a mixture of solvent such tetrahydrofuran, methanol,
glycol and water to afford the compound of D-4. The reaction is
stirred overnight at a temperature between 25.degree. C. and
130.degree. C. Alternatively, to form the corresponding compound of
formula D-4, wherein X is X5-A2, D-5 must first be reacted
according to the procedure discussed above in reaction 1 of
Preparation C.
[0378] In reaction 4 of Preparation D, the compound of D-4 is
converted to the corresponding compound of formula D-2, by reacting
D-4 with a base such triethylamine and diphenylphosphoryl azide in
aprotic solvent such toluene. The reaction was heated to a
temperature range between 80.degree. C.-110.degree. C., preferably
at 110.degree. C. for 15 min to 1 hour, preferably 30 minutes. The
so formed intermediate is then treated with tert-butyl alcohol for
overnight period at 60-110.degree. C., preferably 90.degree. C.
Subsequently, the so formed carbamate is converted to the
corresponding compound of formula D-1 by a treatment under acidic
media using preferably trifluoroacetic acid in dichloromethane at
room temperature for a period of 30 min to 5 hours, preferably 2
hours.
[0379] In reaction 1 of Preparation E, the compound of formula E-2,
wherein X is bromide or chloride, is converted to the corresponding
compound of formula E-1, by reacting E-2 with methyl magnesium
bromide in ether, at a temperature between about -60.degree. C. to
about -90.degree. C., preferably about -78.degree. C. for a time
period between about 30 min to about 3 hours, preferably about 2
hours. Alternatively, to form the corresponding compound of formula
E-1, wherein X is X5-A2, E-2 must first be reacted according to the
procedure discussed above in reaction 1 of Preparation C.
[0380] In reaction 2 of Preparation E, the compound of formula E-1
is converted to the corresponding compound of D-2 by treating E-1
with a strong acid, preferably sulfuric acid, in the presence of
chloroacetonitrile. The reaction is stirred overnight at room
temperature. Subsequently, the so formed compound is treated with
thiourea in a polar protic solvent such ethanol for an overnight
period at 80.degree. C. to form the corresponding compound of
formula D-2. Alternatively, E-1 is treated with sodium azide and
trifluoroacetic acid in an aprotic solvent such dichloromethane at
a temperature range of -10.degree. C. to room temperature,
preferably 0.degree. C. The so formed compound is reduced in
presence of triphenylphosphine in a solution of tetrahydrofuran and
water to form corresponding compound of formula D-2. The reaction
is stirred at a temperature range 25-80.degree. C., preferably at
room temperature for a period of 2 hours to 24 hours, preferably 18
hours.
[0381] In reaction 1 of Scheme 1, the compounds of formula A-1 or
A-2 are converted to the corresponding compounds of Formula II,
wherein f is 1 to 8, or III, respectively, by adding triphosgene to
a suspension of C-1 or C-2 and triethylamine in a aprotic solvent,
such as tetrahydrofuran. The reaction is stirred at room
temperature for a time period between about 5 minutes to about 20
minutes, preferably about 15 minutes, and a small amount of ether
was added. The triethylammonium salt generated is filtered off.
Separately, sodium hydride is added to a suspension of A-1 or A-2,
wherein X is OH or NH, in an aprotic solvent, such as
tetrahydrofuran, at 0.degree. C. or room temperature. The reaction
is stirred at room temperature for a time period between about 5
minutes to about 20 minutes, preferably about 15 minutes, and the
isocyanate tetrahydrofuran/ether solution so formed above is added
dropwise. Alternatively, the compounds of Formula II and III may be
formed by reacting the compounds of D3 or D4 with A-1 and A-2 in
presence of a base such triethylamine and diphenylphosphoryl azide
in aprotic solvent such toluene as described in procedure discussed
above in reaction 4 of Preparation D.
[0382] In reaction 1 of Scheme 2, the compounds of formula A-1, A-2
or B-1 are converted to the corresponding compounds of Formula IV,
V, VI and VII, wherein f is 1 to 8, respectively, by adding
triphosgene to a suspension of C-1, C-2, D-1 or D-2 and
triethylamine in a aprotic solvent, such as tetrahydrofuran or
toluene. The reaction is stirred at room temperature for a time
period between about 5 minutes to about 20 minutes, preferably
about 15 minutes, and a small amount of ether was added.
Subsequently, A-1 or A-2, wherein X is NH, is added to the
isocyanate solution so formed above and the reaction is stirred at
a temperature range of 25-100.degree. C., preferably at room
temperature for a period of about 2 hours to 24 hours, preferably
18 hours.
[0383] In reaction 1 of Scheme 3, the compound of formula A-3 is
converted to the corresponding compounds of Formula VIII, wherein f
is 1 to 8, and IX, respectively by reacting A3 with C1, C-2, D-1 or
D-2 via peptidic coupling using carbodiimide coupling agent such
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and
1-hydroxy-benzotriazole or
2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium
hexafluorophosphate in solvent such tetrahydrofuran or
dimethylformamide. The reaction is stirred at room temperature for
overnight.
[0384] Although specific embodiments of the present disclosure will
now be described with reference to the preparations and schemes, it
should be understood that such embodiments are by way of example
only and merely illustrative of but a small number of the many
possible specific embodiments which can represent applications of
the principles of the present disclosure. Various changes and
modifications will be obvious to those of skill in the art given
the benefit of the present disclosure and are deemed to be within
the spirit and scope of the present disclosure as further defined
in the appended claims.
[0385] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one
having ordinary skill in the art to which this disclosure belongs.
Although other compounds or methods can be used in practice or
testing, certain preferred methods are now described in the context
of the following preparations and schemes.
[0386] All pharmaceutically acceptable salts, prodrugs, tautomers,
hydrates and solvates of the compounds presently disclosed are also
within the scope of the present disclosure.
[0387] Presently disclosed compounds that are basic in nature are
generally capable of forming a wide variety of different salts with
various inorganic and/or organic acids.
[0388] Although such salts are generally pharmaceutically
acceptable for administration to animals and humans, it is often
desirable in practice to initially isolate a compound from the
reaction mixture as a pharmaceutically unacceptable salt and then
simply convert the latter back to the free base compound by
treatment with an alkaline reagent, and subsequently convert the
free base to a pharmaceutically acceptable acid addition salt. The
acid addition salts of the base compounds can be readily prepared
using conventional techniques, e.g., by treating the base compound
with a substantially equivalent amount of the chosen mineral or
organic acid in an aqueous solvent medium or in a suitable organic
solvent such as, for example, methanol or ethanol. Upon careful
evaporation of the solvent, the desired solid salt is obtained.
[0389] Acids which can be used to prepare the pharmaceutically
acceptable acid addition salts of the base compounds are those
which can form non-toxic acid addition salts, i.e., salts
containing pharmacologically acceptable anions, such as chloride,
bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid
phosphate, acetate, lactate, citrate or acid citrate, tartrate or
bitartrate, succinate, maleate, fumarate, gluconate, saccharate,
benzoate, methanesulfonate and pamoate [i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
[0390] Presently disclosed compounds that are acidic in nature,
e.g., contain a COOH or tetrazole moiety, are generally capable of
forming a wide variety of different salts with various inorganic
and/or organic bases. Although such salts are generally
pharmaceutically acceptable for administration to animals and
humans, it is often desirable in practice to initially isolate a
compound from the reaction mixture as a pharmaceutically
unacceptable salt and then simply convert the latter back to the
free acid compound by treatment with an acidic reagent, and
subsequently convert the free acid to a pharmaceutically acceptable
base addition salt. These base addition salts can be readily
prepared using conventional techniques, e.g., by treating the
corresponding acidic compounds with an aqueous solution containing
the desired pharmacologically acceptable cations, and then
evaporating the resulting solution to dryness, preferably under
reduced pressure. Alternatively, they also can be prepared by
mixing lower alkanolic solutions of the acidic compounds and the
desired alkali metal alkoxide together, and then evaporating the
resulting solution to dryness in the same manner as before. In
either case, stoichiometric quantities of reagents are preferably
employed in order to ensure completeness of reaction and maximum
product yields of the desired solid salt.
[0391] Bases which can be used to prepare the pharmaceutically
acceptable base addition salts of the base compounds are those
which can form non-toxic base addition salts, i.e., salts
containing pharmacologically acceptable cations, such as, alkali
metal cations (e.g., potassium and sodium), alkaline earth metal
cations (e.g., calcium and magnesium), ammonium or other
water-soluble amine addition salts such as
N-methylglucamine-(meglumine), lower alkanolammonium and other such
bases of organic amines.
[0392] Isotopically-labeled compounds are also within the scope of
the present disclosure. As used herein, an "isotopically-labeled
compound" refers to a presently disclosed compound including
pharmaceutical salts and prodrugs thereof, each as described
herein, in which one or more atoms are replaced by an atom having
an atomic mass or mass number different from the atomic mass or
mass number usually found in nature. Examples of isotopes that can
be incorporated into compounds presently disclosed include isotopes
of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and
chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, and
.sup.36Cl, respectively.
[0393] By isotopically-labeling the presently disclosed compounds,
the compounds may be useful in drug and/or substrate tissue
distribution assays. Tritiated (.sup.3H) and carbon-14 (.sup.14C)
labeled compounds are particularly preferred for their ease of
preparation and detectability. Further, substitution with heavier
isotopes such as deuterium (.sup.2H) can afford certain therapeutic
advantages resulting from greater metabolic stability, for example
increased in vivo half-life or reduced dosage requirements and,
hence, may be preferred in some circumstances. Isotopically labeled
compounds presently disclosed, including pharmaceutical salts and
prodrugs thereof, can be prepared by any means known in the
art.
[0394] Stereoisomers (e.g., cis and trans isomers) and all optical
isomers of a presently disclosed compound (e.g., R and S
enantiomers), as well as racemic, diastereomeric and other mixtures
of such isomers are within the scope of the present disclosure.
[0395] The compounds, salts, prodrugs, hydrates, and solvates
presently disclosed can exist in several tautomeric forms,
including the enol and imine form, and the keto and enamine form
and geometric isomers and mixtures thereof. Tautomers exist as
mixtures of a tautomeric set in solution. In solid form, usually
one tautomer predominates. Even though one tautomer may be
described, all tautomers are within the scope of the present
disclosure.
[0396] Atropisomers are also within the scope of the present
disclosure. Atropisomers refer to compounds that can be separated
into rotationally restricted isomers.
[0397] The present disclosure also provides pharmaceutical
compositions comprising at least one presently disclosed compound
and at least one pharmaceutically acceptable carrier. The
pharmaceutically acceptable carrier can be any such carrier known
in the art including those described in, for example, Remington's
Pharmaceutical Sciences, Mack Publishing Co., (A. R. Gennaro edit.
1985). Pharmaceutical compositions of the compounds presently
disclosed may be prepared by conventional means known in the art
including, for example, mixing at least one presently disclosed
compound with a pharmaceutically acceptable carrier.
[0398] Presently disclosed pharmaceutical compositions can be used
in an animal or human. Thus, a presently disclosed compound can be
formulated as a pharmaceutical composition for oral, buccal,
parenteral (e.g., intravenous, intramuscular or subcutaneous),
topical, rectal or intranasal administration or in a form suitable
for administration by inhalation or insufflation.
[0399] The compounds presently disclosed may also be formulated for
sustained delivery according to methods well known to those of
ordinary skill in the art. Examples of such formulations can be
found in U.S. Pat. Nos. 3,119,742, 3,492,397, 3,538,214, 4,060,598,
and 4,173,626.
[0400] For oral administration, the pharmaceutical composition may
take the form of, for example, a tablet or capsule prepared by
conventional means with a pharmaceutically acceptable excipient(s)
such as a binding agent (e.g., pregelatinized maize starch,
polyvinylpyrrolidone or hydroxypropyl methylcellulose); filler
(e.g., lactose, microcrystalline cellulose or calcium phosphate);
lubricant (e.g., magnesium stearate, talc or silica); disintegrant
(e.g., potato starch or sodium starch glycolate); and/or wetting
agent (e.g., sodium lauryl sulphate). The tablets may be coated by
methods well known in the art. Liquid preparations for oral
administration may take the form of a, for example, solution, syrup
or suspension, or they may be presented as a dry product for
constitution with water or other suitable vehicle before use. Such
liquid preparations may be prepared by conventional means with a
pharmaceutically acceptable additive(s) such as a suspending agent
(e.g., sorbitol syrup, methyl cellulose or hydrogenated edible
fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous
vehicle (e.g., almond oil, oily esters or ethyl alcohol); and/or
preservative (e.g., methyl or propyl p-hydroxybenzoates or sorbic
acid).
[0401] For buccal administration, the composition may take the form
of tablets or lozenges formulated in a conventional manner.
[0402] Presently disclosed compounds may be formulated for
parenteral administration by injection, including using
conventional catheterization techniques or infusion. Formulations
for injection may be presented in unit dosage form, e.g., in
ampules or in multi-dose containers, with an added preservative.
The compositions may take such forms as suspensions, solutions or
emulsions in oily or aqueous vehicles, and may contain a
formulating agent such as a suspending, stabilizing and/or
dispersing agent recognized by those of skill in the art.
Alternatively, the active ingredient may be in powder form for
reconstitution with a suitable vehicle, e.g., sterile pyrogen-free
water, before use.
[0403] For topical administration, a presently disclosed compound
may be formulated as an ointment or cream.
[0404] Presently disclosed compounds may also be formulated in
rectal compositions such as suppositories or retention enemas,
e.g., containing conventional suppository bases such as cocoa
butter or other glycerides.
[0405] For intranasal administration or administration by
inhalation, presently disclosed compounds may be conveniently
delivered in the form of a solution or suspension from a pump spray
container that is squeezed or pumped by the patient or as an
aerosol spray presentation from a pressurized container or a
nebulizer, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol, the dosage unit may be
determined by providing a valve to deliver a metered amount. The
pressurized container or nebulizer may contain a solution or
suspension of the presently disclosed compound. Capsules and
cartridges (made, for example, from gelatin) for use in an inhaler
or insufflator may be formulated containing a powder mix of a
presently disclosed compound and a suitable powder base such as
lactose or starch.
[0406] A proposed dose of a presently disclosed compound for oral,
parenteral or buccal administration to the average adult human for
the treatment or prevention of a TPO-related disease state is about
0.1 mg to about 2000 mg. In certain embodiments, the proposed dose
is from about 0.1 mg to about 200 mg of the active ingredient per
unit dose. Irrespective of the amount of the proposed dose,
administration of the compound can occur, for example, 1 to 4 times
per day.
[0407] Aerosol formulations for the treatment or prevention of the
conditions referred to above in the average adult human are
preferably arranged so that each metered dose or "puff" of aerosol
contains about 20 mg to about 10,000 mg, preferably, about 20 mg to
about 1000 mg of a presently disclosed compound. The overall daily
dose with an aerosol will be within the range from about 100 mg to
about 100 mg. In certain embodiments, the overall daily dose with
an aerosol generally will be within the range from about 100 mg to
about 10 mg. Administration may be several times daily, for example
2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each
time.
[0408] Aerosol combination formulations for the treatment or
prevention of the conditions referred to above in the average adult
human are preferably arranged so that each metered dose or "puff"
of aerosol contains from about 0.01 mg to about 1000 mg of a
combination comprising a presently disclosed compound. In certain
embodiments, each metered dose or "puff" of aerosol contains about
0.01 mg to about 100 mg of a combination comprising a presently
disclosed compound. In certain embodiments, each metered dose or
"puff" of aerosol contains about 1 mg to about 10 mg of a
combination comprising a presently disclosed compound.
Administration may be several times daily, for example 2, 3, 4 or 8
times, giving for example, 1, 2 or 3 doses each time.
[0409] Pharmaceutical compositions and methods of treatment or
prevention comprising administering prodrugs of at least one
presently disclosed compound are also within the scope of the
present disclosure.
Glucosylceramide Synthase Assay
[0410] An enzyme assay using microsomes as a source of
glucosylceramide synthase activity. Fluorescent ceramide substrate
is delivered to membrane-bound enzyme as a complex with albumin.
After reaction, ceramide and glucosylceramide are separated and
quantitated by reverse-phase HPLC with fluorescence detection.
Procedure
Preparation of Microsomes from A375 Human Melanoma Cells
[0411] Cell suspension was sonicated on ice to complete cell lysis
followed by centrifugation at spin down at 10,000 g for 10 min. at
4.degree. C.
[0412] Supernatant was cleared by centrifugation again at 100,000 g
for 1 hour at 4.degree. C. in the Pellet was resuspended in lysis
buffer, aliquoted and stored at -80.degree. C.
Glucosylceramide Synthase Assay
[0413] Substrate and microsome were combined 1:1, mix well on a
plate shaker seal the plate and incubate 1 hour at room temperature
in the dark
[0414] The was stop with stop solution into the reaction plate and
transferred analysis plate;
RP-HPLC Analysis
[0415] column: MercuryMS.TM. (Phenomenex) replaceable cartridge
(Luna C.sub.8, 3 .quadrature.m, 20.times.4 mm) [0416] system:
Agilent 1100 with Agilent 1200 series fluorescence detector [0417]
mobile phase: 1% formic acid in 81% methanol, 19% water, flow rate
0.5 mL/min, isocratic run, 4 min [0418] sample diluent: 0.1 mM
C.sub.8 ceramide (adsorption blocker) in 50% isopropanol, 50% water
(v/v) [0419] fluorescence detection: .quadrature..sub.ex=470 nm,
.quadrature..sub.cm=530 nm [0420] under these conditions, NBD
C.sub.6 GluCer had a retention time of about 1.7 min and NBD
C.sub.6 Cer ran at about 2.1 min; the peaks were clearly separate
to the baseline and were integrated automatically by the HPLC
software [0421] % conversion of substrate to product was used as
the readout for inhibitor testing to avoid variability due to
dilution error or sample evaporation
[0422] All of the exemplified compounds had an IC.sub.50 value of
less than 5 .mu.M in the Reporter Assay.
EXPERIMENTAL
General Procedure A: Carbamate/Urea Formation with Triphosgene
[0423] To a suspension of amine hydrochloride (1 equivalent) and
triethylamine (3-4 equivalents) in a THF (concentration
.about.0.2M) at room temperature was added triphosgene (0.35
equivalent). The reaction mixture was stirred for 10 min and small
amount of ether (1-2 mL) was added. The triethylammonium salt was
filtered off to afford a clear solution of isocyanate in
THF/ether.
[0424] To a solution of alcohol (1.5 equivalents) in THF
(concentration .about.0.2M) at room temperature was added NaH [60%,
oil] (1.5 equivalents). The reaction mixture was stirred for 15 min
and the above solution (isocyanate in THF/ether) was added
dropwise.
[0425] In a standard workup, the reaction was quenched with brine.
The solution was extracted with EtOAc and the organic layer was
dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude
material was purified on combiflash (SiO.sub.2 cartridge,
CHCl.sub.3 and 2N NH.sub.3 in MeOH) to afford the corresponding
carbamate.
[0426] Alternatively: To a suspension of amine hydrochloride A (1
equivalent) and triethylamine (3-4 equivalents) in a THF
(concentration .about.0.2M) at room temperature was added
triphosgene (0.35 equivalent). The reaction mixture was stirred for
10 min and small amount of ether (1-2 mL) was added. The
triethylammonium salt was filtered off to afford a clear solution
of isocyanate in THF/ether.
[0427] To a solution of amine B (1 equivalent) in THF
(concentration .about.1.0M) at room temperature was added the above
solution (isocyanate in THF/ether) dropwise. The reaction was
stirred for a period of 18 h and concentrated. The crude material
was purified on combiflash (SiO.sub.2 cartridge, CHCl.sub.3 and 2N
NH.sub.3 in MeOH) to afford the corresponding urea.
General Procedure B: Alkylation with Organocerium
[0428] A suspension of CeCl.sub.3 (4 equivalents) in THF
(concentration .about.0.2M) was stirred at room temperature for 1
h. The suspension was cooled to -78.degree. C. and MeLi/Ether
[1.6M] (4 equivalents) was added dropwise. The organocerium complex
was allowed to form for a period of 1 h and a solution of nitrile
(1 equivalent) in THF (concentration 2.0M) was added dropwise. The
reaction mixture was warmed up to room temperature and stirred for
18 h. The solution was cooled to 0.degree. C. and quenched with
water (.about.1 mL) followed by addition of 50% aqueous solution of
ammonium hydroxide (.about.3 mL) until precipitated formed and
settled to the bottom of the flask. The mixture was filtered
through a pad of celite and concentrated. The crude material was
treated with a solution of HCl/dioxane [4.0M]. The intermediate
arylpropan-2-amine hydrochloride was triturated in ether and used
as is for the next step. Alternatively, the crude free base amine
was purified on combiflash (SiO.sub.2 cartridge, CHCl.sub.3 and 2N
NH.sub.3 in MeOH) to afford the corresponding arylpropylamine.
General Procedure C: Urea Formation with Carbonyl Diimidazole
(CDI)
[0429] A solution of amine A (1 equivalent) and CDI (1.3
equivalent) in THF (concentration .about.0.15M) was stirred at
reflux for 1 h. A solution of amine B (1.3 equivalent) in THF was
added and the reaction mixture was stirred for an additional 1.5 h.
The reaction was cooled to room temperature and diluted with ether.
The desired compound precipitated and was filtered off. The crude
material was purified on combiflash (basic Al.sub.2O.sub.3
cartridge, CHCl.sub.3 and MeOH) or (SiO.sub.2 cartridge, CHCl.sub.3
and 2N NH.sub.3 in MeOH) to afford the corresponding urea.
General Procedure D: Urea Formation with Triphosgene
[0430] To a suspension of amine A (1 equivalent) and triethylamine
(4 equivalents) in a THF (concentration .about.0.15M) at room
temperature was added triphosgene (0.35 equivalent). The reaction
mixture was stirred for 15 min and amine B (1.1 equivalent) was
added. The reaction mixture was stirred at room temperature for 18
h and then diluted with EtOAc. The organic layer was washed with
aqueous NaOH [1.0 M], dried over Na.sub.2SO.sub.4, filtered and
concentrated. The crude material was purified on combiflash
(SiO.sub.2 cartridge, CHCl.sub.3 and 2N NH.sub.3 in MeOH) to afford
the corresponding urea.
General Procedure E: Suzuki Coupling
[0431] To a solution of aryl halide (1 equivalent) in a mixture of
DME/water [4:1] (concentration .about.0.2M) was added boronic acid
(2 equivalents), palladium catalyst (0.1-0.25 equivalent) and
sodium carbonate (2 equivalents). The reaction mixture was
microwaved 25 min at 150.degree. C. After filtering through a
celite plug and concentrating, the crude product was purified on
combiflash (SiO.sub.2 cartridge, CHCl.sub.3 and 2N NH.sub.3 in
MeOH) to afford the corresponding coupling adduct.
[0432] Alternatively: To a solution of aryl halide (1 equivalent)
in a mixture of toluene/water [20:1] (concentration .about.0.2 M)
was added boronic acid (1.3-2.5 equivalents), palladium catalyst
(0.05-0.15 equivalent), tricyclohexylphosphine (0.15-0.45
equivalent) and potassium phosphate (5 equivalents). The reaction
mixture was microwaved 25 min at 150.degree. C. After filtering
through a celite plug and concentrating, the crude product was
purified on combiflash (SiO.sub.2 cartridge, CHCl.sub.3 and 2N
NH.sub.3 in MeOH) to afford the corresponding coupling adduct.
General Procedure F: Hydrogenation
[0433] To a solution of substrate in methanol, ethanol or EtOAc
(concentration .about.0.2M) was added palladium catalyst (20% w/w
of substrate). The reaction mixture was stirred at room temperature
under 1 atm of H.sub.2 until completion. The reaction was filtered
through a celite plug followed by two rinses with chloroform. The
crude product was concentrated and purified on combiflash
(SiO.sub.2 cartridge, CHCl.sub.3 and 2N NH.sub.3 in MeOH) to afford
the hydrogenated product. Alternatively, the final material was
purified by precipitation or recristallization.
General Procedure G: Cyclopropanation
[0434] To a mixture of arylnitrile (1 equivalent) and
Ti(Oi-Pr).sub.4 (1.7 equivalents) stirring at -70.degree. C., was
added dropwise EtMgBr [3.0 M in ether] (1.1 equivalents). The
reaction mixture was allowed to warm to 25.degree. C. and stirred
for 1 h. To the above mixture was added BF.sub.3.Et.sub.2O (3
equivalents) dropwise at 25.degree. C. After the addition, the
mixture was stirred for another 2 h, and then quenched with aqueous
HCl [2M]. The resulting solution was then basified by adding
aqueous NaOH [2M]. The organic material was extracted with ethyl
ether. The organic layers were combined, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude material was
purified by silica gel column chromatography (eluting with
petroleum ether/EtOAc: 10/1 to 1/1) to give the corresponding
1-aryl-cyclopropanamine.
General Procedure H: Coupling Via In-Situ Curtius Rearrangement
[0435] A mixture of acid (1 equivalent), triethylamine (2.5
equivalents), DPPA (1.0 equivalent) in toluene (concentration
.about.0.3M) was refluxed for 30 min. The mixture was cooled to
room temperature and alcohol (1 equivalent) was added. After
addition, the mixture was heated at 90.degree. C. for 18 h. The
reaction was cool down to room temperature, diluted with EtOAc and
washed with saturated aqueous sodium dicarbonate. The organic phase
was dried over Na.sub.2SO.sub.4, concentrated and purified by
prep-TLC (EtOAc/MeOH 5:1, containing 1% of TEA) to afford the
corresponding carbamate.
General Procedure I: Amide Formation Using EDCI
[0436] To a solution of amine (1 equivalent) in DMF or THF
(concentration .about.0.3M) was added EDCI (1.2-2.5 equivalents),
HOBT (1.2-2.5 equivalents), DIPEA (1.2-2.5 equivalents) and
triethylamine (few drops). The reaction mixture was stirred and the
acid (1.2 equivalents) was added. The reaction was stirred at room
temperature for 18 h and then concentrated. The residue was
dissolved in EtOAc and washed with brine. The organic layer was
dried over Na.sub.2SO.sub.4 and concentrated. The crude material
was purified by prep-HPLCMS or by combiflash (SiO.sub.2 cartridge,
CHCl.sub.3 and 2N NH.sub.3 in MeOH).
Preparation A
Intermediate 1
2-(3-bromophenyl)propan-2-amine hydrochloride
[0437] To a solution of methyl 3-bromobenzoate (15.0 g, 69.8 mmol)
in THF (140 mL) at -78.degree. C. was added dropwise a solution of
MeMgBr/diethyl ether [3.0M] (58 mL). The reaction mixture was
warmed up to room temperature and stirred for 2 h. The solution was
poured to an aqueous saturated solution of ammonium chloride and
the organic material was extracted with EtOAc. The organic layer
was dried over Na.sub.2SO.sub.4, filtered and concentrated to
afford the corresponding alcohol (14.9 g) which was used without
further purification.
[0438] To a solution of 2-(3-bromophenyl)propan-2-ol (17.2 g, 79.8
mmol) in chloroacetonitrile (160 mL) was added acetic acid (14 mL).
The reaction mixture was cooled to 0.degree. C. and H.sub.2SO.sub.4
(14 mL) was added dropwise. The reaction mixture was warmed to room
temperature and stirred for 18 h. The reaction was then poured into
ice and extracted with EtOAc. The organic layer was washed with
aqueous NaOH [1.0M] solution and brine, dried over Na.sub.2SO.sub.4
and concentrated to afford the corresponding chloroacetamide (21.4
g) which was used without further purification.
[0439] To a solution of
N-(2-(3-bromophenyl)propan-2-yl)-2-chloroacetamide (20.3 g) in
ethanol (120 mL) was added acetic acid (20 mL). The reaction
mixture was stirred at reflux for 18 h. The solution was cooled to
room temperature and the precipitate was filtered off on a celite
pad. The filtrate was concentrated and the residue was dissolved in
EtOAc. The organic layer was treated with aqueous NaOH [1.0M]
solution, dried over Na.sub.2SO.sub.4 and concentrated. The crude
material was treated with a solution of HCl/dioxane [4M]. The
intermediate 2-(3-bromophenyl)propan-2-amine hydrochloride was
triturated in ether and used as is for the next step (7.50 g, 43%).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.69 (q, J=1.8 Hz, 1H),
7.55 (ddd, J=1.0, 1.8, 7.9 Hz, 1H), 7.49 (ddd, J=1.0, 2.0, 8.0 Hz,
1H), 7.38 (t, J=8.0 Hz, 1H), 1.71 (s, 6H) ppm.
Preparation B
Intermediate 2
2-(5-bromo-2-fluorophenyl)propan-2-amine hydrochloride
[0440] To a solution of 5-bromo-2-fluorobenzoic acid (4.85 g, 22.8
mmol) in methanol (45 mL) was added H.sub.2SO.sub.4 (4.5 mL). The
reaction mixture was stirred at room temperature for 18 h and the
solution was concentrated. The residue was treated with an aqueous
NaOH [10% w/v] solution and the organic material was extracted with
CHCl.sub.3. The organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated to afford the corresponding ester (4.69
g, 91%) which was used without further purification.
[0441] The ester intermediate (4.69 g, 20.1 mmol) was converted to
intermediate 2 using the same procedure reported in example
intermediate 1 to afford the corresponding ammonium salt (3.94 g,
67% overall yield) as a white solid. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.67-7.57 (m, 2H), 7.21 (dd, J=8.7, 12.3 Hz,
1H), 1.77 (s, 6H) ppm.
Intermediate 3
2-(3-bromo-4-fluorophenyl)propan-2-amine hydrochloride
[0442] 5-Bromo-2-fluorobenzoic acid was transformed to intermediate
3 using the same procedure reported in example intermediate 2 to
afford the corresponding ammonium salt (2.79 g, 49% overall yield)
as a white solid.
Intermediate 4
2-(3-bromo-2-fluorophenyl)propan-2-amine
[0443] 3-Bromo-2-fluorobenzoic acid was transformed to intermediate
4 using the same procedure reported in example intermediate 2 to
afford the corresponding amine as pale yellow oil.
Intermediate 5
2-(4-bromophenyl)propan-2-amine hydrochloride
[0444] Using general procedure B, bromobenzonitrile (2.00 g, 11.0
mmol) was converted to the corresponding
2-(4-bromophenyl)propan-2-amine, which was afforded as a brown oil
(1.20 g, 51%).
Preparation C
Intermediate 6
1,4-Diazabicyclo[3.2.2]nonane
[0445] To a stirred solution of 1,4-diazabicyclo[3.2.2]nonan-3-one
(1.0 g, 7.2 mmol) in 1,4-dioxane (7.2 mL) at room temperature was
added lithium aluminum hydride [2.0M/THF] (4.1 mL, 8.2 mmol). The
reaction mixture was then heated at reflux for 6 hours before
cooling to room temperature. The reaction was quenched by the
stepwise addition of 200 .quadrature.L of H.sub.2O, 200
.quadrature.L of 15% aqueous NaOH, and 600 .quadrature.L of
H.sub.2O. The mixture was filtered through Celite which was
subsequently washed with EtOAc. The combined filtrate was
concentrated in vacuo to afford the product (0.82 g, 90%) which was
used without further purification. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 3.28-3.25 (m, 1H), 2.99-2.95 (m, 8H), 1.86-1.80
(m, 3H), 1.69-1.64 (m, 2H) ppm.
Preparation D
Intermediate 7
2-Methylquinuclidin-3-ol
[0446] A solution of potassium carbonate (11.4 g, 82.8 mmol) and
quinuclidine hydrate (5.00 g, 20.4 mmol) was dissolved in H.sub.2O
(15.6 mL). When completely dissolved, dichloromethane (20.4 mL) was
added and the reaction was stirred at room temperature overnight.
The organic phase was separated and the aqueous phase extracted
with chloroform (3.times.50 mL). The combined organic layers were
dried over MgSO.sub.4, filtered and concentrated in vacuo. The
product was used without further purification. .sup.1H NMR (400
MHz, CDCl.sub.3) 2.79 (s, 1H), 5.19 (s, 1H), 3.14-3.06 (m, 2H),
2.99-2.91 (m, 2H), 2.57-2.55 (m, 1H), 1.98-1.93 (m, 4H) ppm.
[0447] The 2-methylenequinuclidin-3-one (3.50 g) in ethanol (30 mL)
was reduced over 10% Pd/C (50 wt %) under a H.sub.2 atmosphere.
When judged complete by TLC (.about.3 days), the catalyst was
filtered off and the filter cake washed with ethyl acetate. The
solvent was removed in vacuo to afford the desired product (2.80 g,
80%) was obtained and used without further purification. H NMR (400
MHz, CDCl.sub.3) 3.37-3.31 (m, 1H), 3.21-3.13 (m, 2H), 3.09-3.00
(m, 1H), 2.97-2.89 (m, 1H), 2.46-2.43 (m, 1H), 2.05-1.91 (m, 4H),
1.34 (d, J=7.6 Hz, 3H) ppm.
[0448] To 2-methylquinuclidin-3-one (0.50 g, 3.60 mmol) in
1,4-dioxane (18 mL) at room temperature was added lithium aluminum
hydride [1.0M/THF] (4.1, 4.1 mmol). The reaction mixture was
stirred at room temperature for 15 minutes. The reaction was
quenched by the stepwise addition of 116 .quadrature.L of H.sub.2O,
116 .quadrature.L of 15% aqueous NaOH, and 348 .quadrature.L of
H.sub.2O. The mixture was filtered through Celite which was
subsequently washed with EtOAc. The solvent was removed in vacuo to
afford the product (0.48 g, 95%) which was used without further
purification as a 2:1 mixture of diastereomers.
Preparation E
Intermediate 8
1-azabicyclo[3.2.2]nonan-4-ol
[0449] To 1-azabicyclo[3.2.2]nonan-4-one (0.20 g, 1.4 mmol) in
1,4-dioxane (2.8 mL) at 0.degree. C. was added lithium aluminum
hydride [1.0M/THF] (1.7 mL, 1.7 mmol). The reaction mixture was
maintained at 0.degree. C. for 15 minutes. The reaction was
quenched by the stepwise addition of 46 .quadrature.L of H.sub.2O,
46 .quadrature.L of 15% aqueous NaOH, and 138 .quadrature.L of
H.sub.2O. The mixture was filtered through Celite which was
subsequently washed with EtOAc. The solvent was removed in vacuo to
afford the product (0.19 g, 96%) which was used without further
purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.90-3.86
(m, 1H), 3.09-3.03 (m, 1H), 2.96-2.91 (dd, J=9.2, 6.8 Hz, 1H),
2.86-2.75 (m, 3H), 2.71-2.64 (m, 1H), 2.34-2.27 (bs s, 1H),
1.98-1.86 (m, 3H), 1.71-1.59 (m, 3H), 1.51-1.35 (m, 1H) ppm.
Preparation F
Intermediate 9
1-Azabicyclo[2.2.1]heptan-3-ol
[0450] To a mixture of sodium methoxide (2.00 g, 37.9 mmol) in
methanol (9 mL) at 0.degree. C. was added glycine methyl ester
hydrochloride (4.76 g, 37.9 mmol) and dimethyl itaconate (5.00 g,
31.6 mmol.) The reaction was heated at reflux for 16 hours before
cooling to room temperature. The solid was filtered off and washed
with dichloromethane. The filtrate was concentrated and the residue
diluted with 5N HCl (50 mL). The aqueous layer was extracted with
dichloromethane (4.times.50 mL), dried over MgSO.sub.4, filtered
and concentrated in vacuo. The product was used without further
purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.04 (dd,
J=82.0, 17.6 Hz), 3.74-3.64 (m, 8H), 3.32-3.24 (m, 1H), 2.77-2.63
(m, 2H) ppm.
[0451] To methyl
1-(2-methoxy-2-oxoethyl)-5-oxopyrrolidine-3-carboxylate (3.40 g,
16.0 mmol) in THF (20 mL) at 0.degree. C. was added borane-THF
[1.0M/THF] (32.0 mL, 32.0 mmol). The reaction was stirred at reflux
for 1 hour and then cooled to room temperature where it was allowed
to stir an additional 12 hours. The reaction was quenched by the
addition of a saturated solution of potassium carbonate (5.52 g in
20 mL H.sub.2O) and heated at reflux for an additional 1 hour
before cooling to room temperature. The solvent was removed in
vacuo and the residue made acidic by the addition of 5N HCl (25
mL). The aqueous layer was extracted with dichloromethane
(2.times.30 mL). The pH of the aqueous layer was then made basic by
the addition of solid potassium carbonate. The aqueous layer was
further extracted with dichloromethane (5.times.30 mL). The
combined organic layers were dried over MgSO.sub.4, filtered and
concentrated in vacuo. The product was used without further
purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.66 (s,
3H), 3.63 (s, 3H), 3.29 (ABq, 2H, J=24.0, 16.8 Hz), 3.06-3.02 (m,
2H), 2.87-2.81 (m, 1H), 2.71-2.65 (m, 1H), 2.56-2.50 (m, 1H),
2.09-2.04 (in, 2H) ppm.
[0452] To a refluxing solution of potassium tert-butoxide (2.46 g,
22.0 mmol) in toluene (32 mL) was added dropwise a solution of
methyl 1-(2-methoxy-2-oxoethyl)pyrrolidine-3-carboxylate (2.00 g,
10.0 mmol) in toluene (10 mL) over 1 hour. The reaction was allowed
to stir and additional 3 hours at reflux before first cooling to
room temperature then cooling to -10.degree. C. Acetic acid (1.3
mL) was then added with stirring. The toluene layer was extracted
with 5N HCl (4.times.50 mL). The combined aqueous layers were
heated at 110.degree. C. for 8 hours. The reaction was then cooled
to room temperature and the volume reduced by half in vacuo. The pH
of the reaction mixture was made basic by the addition of solid
potassium carbonate. The aqueous layer was extracted with
dichloromethane (5.times.50 mL) and the combined organic layers
were concentrated in vacuo. To the crude product was added ethyl
ether. The solid filtered off to afford the desired product (0.30
g, 27%) which was used without further purification. .sup.1H NMR
(400 MHz, CDCl.sub.3) 3.05-2.96 (m, 3H), 2.76 (s, 2H), 2.72-2.66
(m, 2H), 2.09-2.01 (m, 1H), 1.78-1.71 (m, 1H) ppm.
[0453] The 1-azabicyclo[2.2.1]heptan-3-one (0.30 g, 2.7 mmol) in
ethanol (2-3 mL) was reduced over PtO.sub.2 (50 wt %) under a
H.sub.2 atmosphere. After stirring 4 hours, the catalyst was
filtered off and the filtercake washed with ethanol. The ethanol
was removed in vacuo to afford the desired product (0.29 g, 95%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.36-4.35 (m, 1H),
3.10-3.05 (m, 1H), 2.95-2.88 (m, 1H), 2.72-2.66 (m, 1H), 2.63-2.57
(m, 2H), 2.48-2.44 (dd, J=10.0, 3.2 Hz, 1H), 2.11-2.05 (m, 2H),
1.51-1.44 (m, 1H) ppm.
Preparation. G
Intermediate 10
(R)-3-methylquinuclidin-3-amine and
(S)-3-methylquinuclidin-3-amine
[0454] To a well-stirred solution of MeLi [3.0M/diethyl ether]
(67.0 mL, 201 mmol) in anhydrous diethyl ether (150 mL) at
-78.degree. C. was added, dropwise, a solution of quinuclidin-3-one
(12.5 g, 100 mmol) in diethyl ether (100 mL). The resulting
solution was maintained at -78.degree. C. for 1 hour, then at room
temperature for 18 hours. Water (60 mL) was added dropwise at
0.degree. C. and the mixture was concentrated in vacuo to give a
residue, which was purified by neutral aluminum oxide column
chromatography (0-20% MeOH in CHCl.sub.3) to give
3-methylquinuclidin-3-ol (10.0 g, 71%) as a light yellow solid. To
stirred acetonitrile (250 mL) at 0.degree. C. was slowly added
concentrated sulfuric acid (100 mL). The resulting solution was
added dropwise to a mixture of 3-methylquinuclidin-3-ol (9.10 g,
64.5 mmol) in acetonitrile (250 mL) at 0.degree. C. The reaction
mixture was stirred at room temperature for 60 hours, then cooled
with an ice bath and basified with aqueous sodium hydroxide
solution to pH 10. The mixture was extracted with 5:1 (v/v)
CHCl.sub.3/i-PrOH. The organic layer was concentrated to afford a
residue which was diluted with 2N aq. HCl and washed with 5:1 (v/v)
CHCl.sub.3/i-PrOH. The remaining aqueous layer was then basified
with 2N NaOH and extracted with 5:1 (v/v) CHCl.sub.3/i-PrOH. The
combined organic layers were washed with water, dried
(Na.sub.2SO.sub.4) and concentrated to give 9.5 g (82%) of the
desired compound as a light yellow oil. The 2 enantiomers of the
above intermediate are separated from each other by using chiral
column on supercritical fluid chromatography (SFC) system.
[0455] A solution of the above chiral acetamide intermediate (9.50
g, 52.0 mmol) in conc. HCL (100 mL) was refluxed for 3 days, cooled
with an ice bath and neutralised with aqueous sodium hydroxide
solution to pH 1. The mixture was washed with 5:1 (v/v)
CHCl.sub.3/i-PrOH. The aqueous layer was then basified with 2N NaOH
and extracted with 5:1 (v/v) CHCl.sub.3/i-PrOH). The combined
extracts were washed with water, dried (Na.sub.2SO.sub.4) and
concentrated to give 5.00 g (69%) of the desired chiral compound as
a light yellow semi-solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 2.72-2.39 (m, 6H), 2.01-1.96 (m, 1H), 1.67-1.61 (m, 1H),
1.43-1.36 (m, 2H), 1.23-1.17 (m, 1H), 1.09 (s, 3H) ppm. .sup.13C
NMR (125 MHz, DMSO-d.sub.6) .delta. 65.3, 48.3, 46.6, 46.4, 34.2,
30.0, 24.8, 22.8 ppm. Purity: >99% (GC-MS); retention time 6.63
min; (M) 140.1.
Preparation H
Intermediate 11
2-(3-(4-fluorophenyl)isothiazol-5-yl)propan-2-amine
[0456] To a stirred suspension of 4-fluorobenzamide (70.00 g, 503.1
mmol) in toluene (900 mL) was added chlorocarbonyl sulfenyl
chloride (83.0 mL, 1.00 mol). The mixture was heated overnight at
60.degree. C. and concentrated. The resulting tan solid was
triturated with methylene chloride (200 mL), collected by suction
filtration and rinsed with additional methylene chloride
(4.times.70 mL). The crude product was impregnated onto silica (100
g) and chromatographed in a large filter funnel dry loaded with
silica using a hexane/ethyl acetate gradient. The product
5-(4-fluorophenyl)-1,3,4-oxathiazol-2-one was afforded as an
off-white solid (55.98 g, 56%).
[0457] To a stirred solution of
5-(4-fluorophenyl)-1,3,4-oxathiazol-2-one (42.80 g, 217.1 mmol) in
o-dichlorobenzene (600 mL) was added ethyl propiolate (66.0 mL, 651
mmol). The mixture was heated overnight at 135.degree. C. and
concentrated. The residual oil was purified by flash chromatography
using a hexane/ethyl acetate gradient to afford ethyl
3-(4-fluorophenyl)isothiazole-5-carboxylate as a pale golden solid
(17.35 g, 32%). The more polar, ethyl
3-(4-fluorophenyl)isothiazole-4-carboxylate isomer (generated in
.about.57/43 ratio versus the desired product) was discarded.
[0458] To a stirred and cooled (0.degree. C.) solution of ethyl
3-(4-fluorophenyl)isothiazole-5-carboxylate (38.50 g, 153.2 mmol)
in THF (400 mL) was added a solution of methylmagnesium bromide in
diethyl ether (3.0 M, 128 mL, 384 mmol), dropwise over 20 minutes.
After another 1.5 hours at 0.degree. C., the reaction was quenched
by the slow addition of ethyl acetate (20 mL) and concentrated. The
residue was taken up in aqueous NH.sub.4Cl (400 mL) and extracted
with ethyl acetate (2.times.150 mL). The combined extracts were
dried (Na.sub.2SO.sub.4) and concentrated. The resulting amber
syrup was purified by flash chromatography using a hexane/ethyl
acetate gradient to afford
2-(3-(4-fluorophenyl)isothiazol-5-yl)propan-2-ol as soft, golden
solid (29.02 g, 80%).
[0459] 2-(3-(4-Fluorophenyl)isothiazol-5-yl)propan-2-ol (29.00 g,
122.2 mmol) was taken up in thionyl chloride (75 mL). The mixture
was cooled (ice bath) briefly and stirred. After 4 hours the
reaction was concentrated and the residue was partitioned between
ethyl acetate (200 mL) and aqueous NaHCO.sub.3 (300 mL). The
organic layer was combined with a back extract of the aqueous layer
(ethyl acetate, 1.times.100 mL), dried (Na.sub.2SO.sub.4) and
concentrated to afford a mixture of
5-(2-chloropropan-2-yl)-3-(4-fluorophenyl)isothiazole product and
3-(4-fluorophenyl)-5-(prop-1-en-2-yl)isothiazole elimination
byproduct (.about.63/39 ratio) as a dark amber oil (29.37 g). This
material was used without purification in the next reaction.
[0460] To a stirred solution of the product of the previous step in
DMSO (80 mL) was added sodium azide (14.89 g, 229.0 mmol). The
mixture was heated at 50.degree. C. overnight, diluted with ethyl
acetate (250 mL) and washed with water (6.times.400 mL). The
organic layer was dried (Na.sub.2SO.sub.4) and concentrated to
afford a mixture of
5-(2-azidopropan-2-yl)-3-(4-fluorophenyl)isothiazole and
3-(4-fluorophenyl)-5-(prop-1-en-2-yl)isothiazole (.about.56/44
ratio) as a dark amber oil (29.10 g). This material was used
without purification in the next reaction.
[0461] The product of the previous step was combined with 10%
palladium on carbon (50% water; 7.50 g) and taken up in methanol
(350 mL). The stirred suspension was cycled between vacuum and a
nitrogen purge three times. After an additional evacuation, the
reaction was backfilled with hydrogen gas (balloon reservoir) and
stirred overnight. The reaction was filtered through Celite. The
filtrate was combined with methanol rinsings of the Celite and
concentrated. The resulting dark amber oil purified by flash
chromatography using a methylene chloride/methanol gradient to
afford 2-(3-(4-fluorophenyl)isothiazol-5-yl)propan-2-amine as
viscous, amber oil (14.23 g, 49% over 3 steps).
[0462] Several approaches are being used or pursued for the
treatment of LSDs, most of which focus on enzyme replacement
therapy for use alone in disease management. Numerous approved
enzyme replacement therapies are commercially available for
treating LSDs (e.g., Myozyme.RTM. for Pompe disease,
Aldurazyme.RTM. for Mucopolysaccharidosis I, Cerezyme.RTM. for
Gaucher disease and Fabrazyme.RTM. for Fabry disease).
Additionally, the inventors have identified a number of small
molecules for use alone in the management of LSDs. The therapeutic
methods of the invention described herein provide treatment options
for the practitioner faced with management of various lysosomal
storage diseases, as described in detail below.
[0463] In certain aspects of the invention, the compounds of the
present invention may be used to treat a metabolic disease, such as
a lysosomal storage disease (LSD), either alone or as a combination
therapy with an enzyme replacement therapy. In other aspects of the
invention, the compounds of the present invention may be used to
inhibit or reduce GCS activity in a subject diagnosed with a
metabolic disease, such as an LSD, either alone or as a combination
therapy with an enzyme replacement therapy. In other aspects of the
invention, the compounds of the present invention may be used to
reduce and/or inhibit the accumulation of a stored material (e.g.,
lysosomal substrate) in a subject diagnosed with a metabolic
disease, such as an LSD. In certain embodiments of the foregoing
aspects, the LSD is Gaucher (type 1, type 2 or type 3), Fabry,
G.sub.M1-gangliosidosis or G.sub.M2-gangliosidoses (e.g., GM2
Activator Deficiency, Tay-Sachs and Sandhoff). Table 1 lists
numerous LSDs and identifies the corresponding deficient enzyme
that may be used as an ERT in the foregoing aspects of the
invention.
[0464] In other scenarios it may be necessary to provide SMT to a
patient whose condition requires the reduction of substrates in the
brain and thus is not treatable by systemic administration of ERT.
While direct intracerebroventricular or intathecal administration
can reduce substrate levels in the brain, systemic administration
of ERT is not amenable for LSD's with Central Nervous System (CNS)
involvement due to its incapacity to cross the Blood Brain Barrier
(BBB) and SMT may prove beneficial in patients having residual
enzymatic activities in the CNS.
[0465] In accordance with the present invention, SMT is provided to
a patient to treat a cancer and/or metabolic disease, such as, a
lysosomal storage disease. The SMT may include one or more small
molecules. The SMT includes administering to the patient compounds
of the present invention. In particular embodiments, the compound
is (5)-Quinuclidin-3-yl
(2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate or
Quinuclidin-3-yl
(2-(4'-fluoro-[1,1'-biphenyl]-3-yl)propan-2-yl)carbamate, or
combinations thereof.
[0466] In certain embodiments, compounds of the invention, such as,
for example, (S)-Quinuclidin-3-yl
(2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate and
Quinuclidin-3-yl
(2-(4'-fluoro-[1,1'-biphenyl]-3-yl)propan-2-yl)carbamate may be
used for treatment of virtually any storage disease resulting from
a defect in the glycosphingolipid pathway (e.g. Gaucher (i.e., type
1, type 2 type 3), Fabry, G.sub.M1-gangliosidosis,
G.sub.M2-gangliosidoses (e.g., GM2 Activator Deficiency, Tay-Sachs
and Sandhoff)). In a particularly preferred embodiment,
(S)-Quinuclidin-3-yl
(2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate or a
pharmaceutically acceptable salt or prodrug thereof is used to
inhibit and/or reduce the accumulation of Gb3 and/or lyso-Gb3 in a
patient with Fabry disease, either alone or as a combination
therapy with enzyme replacement therapy (see Examples). In a
preferred embodiment, the enzyme replacement therapy includes
administering alpha-galactosidase A to the Fabry patient. Indeed,
the Examples below demonstrate that a GCS inhibitor of the
invention effectively reduces Gb3 and lyso-Gb3 storage in a mouse
model of Fabry disease, thus supporting its use as a viable
approach for the treatment of Fabry disease. Furthermore, in vivo
combination therapy data provided in the Examples strongly suggest
that a combined therapeutic approach could be both additive and
complementary.
[0467] In certain embodiments, compounds of the invention, such as,
for example, (S)-Quinuclidin-3-yl
(2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate and
Quinuclidin-3-yl
(2-(4'-fluoro-[1,1'-biphenyl]-3-yl)propan-2-yl)carbamate may be
used for reducing the level of GluCer and GluSph in the brain of a
subject diagnosed with neuropathic Gaucher disease, either alone or
in combination with ERT (e.g., glucocerebrosidase
administration).
[0468] Dosage regimens for a small molecule therapy component of a
combination therapy of the invention are generally determined by
the skilled clinician and are expected to vary significantly
depending on the particular storage disease being treated and the
clinical status of the particular affected individual. The general
principles for determining a dosage regimen for a given SMT of the
invention for the treatment of any storage disease are well known
to the skilled artisan. Guidance for dosage regimens can be
obtained from any of the many well known references in the art on
this topic. Further guidance is available, inter alia, from a
review of the specific references cited herein. In certain
embodiments, such dosages may range from about 0.5 mg/kg to about
300 mg/kg, preferably from about 5 mg/kg to about 60 mg/kg (e.g., 5
mg/kg, 10 mg/kg, 15, mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg,
40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg and 60 mg/kg) by
intraperitoneal, oral or equivalent administration from one to five
times daily. Such dosages may range from about 5 mg/kg to about 5
g/kg, preferably from about 10 mg/kg to about 1 g/kg by oral,
intraperitoneal or equivalent administration from one to five times
daily. In one embodiment, doses range from about about 10 mg/day to
about 500 mg/day (e.g., 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day,
50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day,
110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160
mg/day, 170 mg/day, 180 mg/day, 190 mg/day, 200 mg/day, 210 mg/day,
220 mg/day, 230 mg/day, 240 mg/day, 250 mg/day, 260 mg/day, 270
mg/day, 280 mg/day, 290 mg/day, 300 mg/day). A particularly
preferred oral dose range is from about 50 mg to about 100 mg,
wherein the dose is administered twice daily. A particular oral
dose range for a compound of the present invention is from about 5
mg/kg/day to about 600 mg/kg/day. In a particular oral dose range
for a compound of the present invention is from about 1 mg/kg/day
to about 120 mg/kg/day, e.g., 1 mg/kg/day, 5 mg/kg/day, 10
mg/kg/day, 15 mg/kg/day, 20 mg/kg/day, 25 mg/kg/day, 30 mg/kg/day,
35 mg/kg/day, 40 mg/kg/day, 45 mg/kg/day, 50 mg/kg/day, 55
mg/kg/day or 60 mg/kg/day, 65 mg/kg/day, 70 mg/kg/day, 75
mg/kg/day, 80 mg/kg/day, 85 mg/kg/day, 90 mg/kg/day, 95 mg/kg/day,
100 mg/kg/day, 105 mg/kg/day, 110 mg/kg/day, 115 mg/kg/day or 120
mg/kg/day.
[0469] In certain embodiments, the invention relates to combination
therapies of SMT using compounds of the invention and ERT therapy
for the treatment of lysosomal storage diseases. A partial list of
known lysosomal storage diseases that can be treated in accordance
with the invention is set forth in Table 1, including common
disease name, material stored, and corresponding enzyme deficiency
(adapted from Table 38-4 of Kolodny et al., 1998, Id.).
TABLE-US-00001 TABLE 1 Lysosomal Storage Diseases Disease Material
Stored Enzyme Deficiency Sphingolipidoses Gaucher Glucocerebroside,
Glucocerebrosidase glucosylsphingosine Niemann-Pick Sphingomyelin
Sphingomyelinase Niemann-Pick B Sphingomyelin Sphingomyelinase
Farber Ceramide Ceramidase G.sub.M1-gangliosidosis
G.sub.M1-ganglioside, G.sub.M1-ganglioside-.beta.- glycoprotein
galactosidase G.sub.M2-gangliosidosis G.sub.M2-ganglioside,
Hexosaminidase A and B (Sandhoff) globoside Tay-Sachs
G.sub.M2-ganglioside Hexosaminidase A Krabbe Galactosylceramide
.beta.-Galactocerebrosidase Mucopolysaccharidoses Hurler-Scheie
(MPS I) Dermatan sulfate, heparin .alpha.-L-iduronidase Sulfate
Hunter (MPS II) Dermatan sulfate, heparin Iduronate sulfatase
sulfate Sanfilippo (MPS III) Type A Heparan sulfate
Heparan-N-sulfatase Type B Heparan sulfate
N-acetyl-.alpha.-glucosaminidase Type C Heparan sulfate Acetyl CoA:
.alpha.-glucosaminide acetyl-transferase Type D Heparan sulfate
N-acetyl-.alpha.-glucosamine-6- sulfatase Marquio (MPS IV) Type A
Keratan sulfate Galactosamine-6-sulfatase Type B Keratan sulfate
.beta.-galactosidase Maroteaux-Lamy Dermatan sulfate
Galactosamine-4-sulfatase (MPS VI) (arylsulfatase B) Sly (MPS VII)
Dermatan sulfate, heparan .beta.-glucuronidase Sulfate
Mucosulfatidosis Sulfatides, Arylsulfatase A, B and C,
mucopolysaccharides other sulfatases Mucolipidoses Sialidoses
Sialyloligosaccharides, .alpha.-neuraminidase glycoproteins
Mucolipidosis II Sialyloligosaccharides, High serum, low fibroblast
glycoproteins, enzymes; N-acetyl- glycolipids
glucosamine-1-phosphate transferase Mucolipidosis III
Glycoproteins, glycolipids Same as above Mucolipidosis IV
Glycolipids, glycoproteins Mcoln1 transm protein Other Diseases of
Complex_Carbohydrate Metabolism Fabry Globotriaosylceramide(Gb3),
.alpha.-galactosidase A lyso-Gb3 Schindler O-linked glycopeptides
.alpha.-N-acetylgalactosaminidase Pompe Glycogen
.alpha.-glucosidase Sialic acid storage Free sialic acid Unknown
disease Fucosidosis Fucoglycolipids, .alpha.-fucosidase
fucosyloligosaccharides Mannosidosis Mannosyloligosaccharides
.alpha.-mannosidase Aspartylglucosaminuria Aspartylglucosamine
Aspartylglucosamine amidase Wolman Cholesteryl esters, Acid lipase
Triglycerides Neuronal Ceroid Lipofuscinoses (NCLs)* Infantile NCL
Granular osmophilic deposits, Palmitoyl-protein Saposins A and D
thioesterase thioesterase (PPT1) Late Infantile Curvilinear
profiles, Tripeptidyl protease 1 ATP synthase subunit c (TPP1)
Finnish variant Fingerprint/Rectilinear profiles, CLN5 ATP synthase
subunit c Variant Fingerprint/Rectilinear profiles, CLN6 ATP
synthase subunit c Juvenile Fingerprint profile, CLN3 ATP synthase
subunit c Adult Variable Unknown Northern Epilepsy Rectilinear
profile, CLN8 ATP synthase subunit c Turkish variant
Fingerprint/Rectilinear Unknown profiles - constituents unknown
Lysosomal diseases of cholesterol transport and metabolism
Niemann-Pick type C Unesterified cholesterol NPC1 or NPC2 *Davidson
et al., The Neuronal Ceroid Lipofuscinosis, Clinical Features and
Molecular Basis of Disease. In Barranger J A and Cabrera-Salazar M
A (Eds) Lysosomal Storage Disorders. 2007. pp. 371-388. Springer,
New York, U.S.A.
[0470] Any method known to the skilled artisan may be used to
monitor disease status and the effectiveness of a combination
therapy of the invention. Clinical monitors of disease status may
include but are not limited to organ volume (e.g. liver, spleen),
hemoglobin, erythrocyte count, hematocrit, thrombocytopenia,
cachexia (wasting), and plasma chitinase levels (e.g.
chitotriosidase). Chitotriosidase, an enzyme of the chitinase
family, is known to be produced by macrophages in high levels in
subjects with lysosomal storage diseases (see Guo et al., 1995, J.
Inherit. Metab. Dis. 18, 717-722; den Tandt et al., 1996, J.
Inherit. Metab. Dis. 19, 344-350; Dodelson de Kremer et al., 1997,
Medicina (Buenos Aires) 57, 677-684; Czartoryska et al., 2000,
Clin. Biochem. 33, 147-149; Czartoryska et al., 1998, Clin.
Biochem. 31, 417-420; Mistry et al., 1997, Baillieres Clin.
Haematol. 10, 817-838; Young et al., 1997, J. Inherit. Metab. Dis.
20, 595-602; Hollak et al., 1994, J. Clin. Invest. 93, 1288-1292).
Chitotriosidase is preferably measured in conjunction with
angiotensin converting enzyme and non tartrate resistant acid
phosphatase to monitor response to treatment of Gaucher
patients.
[0471] Methods and formulations for administering the combination
therapies of the invention include all methods and formulations
well known in the art (see, e.g., Remington's Pharmaceutical
Sciences, 1980 and subsequent years, 16th ed. and subsequent
editions, A. Oslo editor, Easton Pa.; Controlled Drug Delivery,
1987, 2nd rev., Joseph R. Robinson & Vincent H. L. Lee, eds.,
Marcel Dekker, ISBN: 0824775880; Encyclopedia of Controlled Drug
Delivery, 1999, Edith Mathiowitz, John Wiley & Sons, ISBN:
0471148288; U.S. Pat. No. 6,066,626 and references cited therein;
see also, references cited in sections below).
[0472] According to the invention, the following general approaches
are provided for combination therapy in the treatment of lysosomal
storage diseases. Each general approach involves combining enzyme
replacement therapy with small molecule therapy in a manner
consistent with optimizing clinical benefit while minimizing
disadvantages associated with using each therapy alone.
[0473] In one embodiment of the invention, enzyme replacement
therapy (alone or in combination with small molecule therapy) is
administered to initiate treatment (i.e., to de-bulk the subject),
and small molecule therapy is administered after the de-bulking
phase to achieve and maintain a stable, long-term therapeutic
effect without the need for frequent intravenous ERT injections.
For example, enzyme replacement therapy may be administered
intravenously (e.g. over a one to two hour period) once, on a
weekly basis, once every two weeks, or once every two months, for
several weeks or months, or longer (e.g., until an involved
indicator organ such as spleen or liver shows a decrease in size).
Moreover, the ERT phase of initial de-bulking treatment can be
performed alone or in combination with a small molecule therapy. A
small molecule therapeutic component is particularly preferred
where the small molecule is compatible with oral administration,
thus providing further relief from frequent intravenous
intervention.
[0474] Alternating among ERT and SMT, or supplementing SMT with ERT
as needed, provides a strategy for simultaneously taking advantage
of the strengths and addressing the weaknesses associated with each
therapy when used alone. An advantage of ERT, whether used for
de-bulking and/or for more long-term care, is the much broader
clinical experience available to inform the practitioner's
decisions. Moreover, a subject can be effectively titrated with ERT
during the de-bulking phase by, for example, monitoring biochemical
metabolites in urine or other body samples, or by measuring
affected organ volume. A disadvantage of ERT, however, is the
frequency of the administration required, typically involving
intravenous injection on a weekly or bi-weekly basis due to the
constant re-accumulation of the substrate. The use of small
molecule therapy to reduce the amount of or inhibit substrate
accumulation in a patient can in turn reduce the administration
frequency of ERT. For example, a bi-weekly enzyme replacement
therapy dosing regimen can be offered an "ERT holiday" (e.g., using
a SMT) so that frequent enzyme injections are not required therapy.
Furthermore, treating a lysosomal storage disease with combination
therapy can provide complementary therapeutic approaches. Indeed,
as demonstrated in the Examples below, a combination therapy of SMT
and ERT can provide significant improvements over either
therapeutic platform alone. These data suggest that combination
therapy using SMT and ERT can be both additive and complementary.
In one embodiment, ERT may be used as a de-bulking strategy (i.e.,
to initiate treatment), followed by or simultaneously supplemented
with SMT using a compound of the present invention. In another
embodiment, a patient is first treated with SMT using a compound of
the present invention, followed by or simultaneously supplemented
with ERT. In other embodiments, a SMT is used to inhibit or reduce
further accumulation of substrate (or re-accumulation of substrate
if used after debulking with ERT) in a patient with a lysosomal
storage disease, and optionally provided ERT as needed to reduce
any further substrate accumulation. In one embodiment, this
invention provides a method of combination therapy for treatment of
a subject diagnosed as having a lysosomal storage disease
comprising alternating between administration of an enzyme
replacement therapy and a small molecule therapy. In another
embodiment, this invention provides a method of combination therapy
for treatment of a subject diagnosed as having a lysosomal storage
disease comprising simultaneously administering an enzyme
replacement therapy and a small molecule therapy. In the various
combination therapies of the invention, it will be understood that
administering small molecule therapy may occur prior to,
concurrently with, or after, administration of enzyme replacement
therapy. Similarly, administering enzyme replacement therapy may
occur prior to, concurrently with, or after, administration of
small molecule therapy.
[0475] In any of the embodiments of the invention, the lysosomal
storage disease is selected from the group consisting of Gaucher
(types 1, 2 and 3), Niemann-Pick, Farber, G.sub.M1-gangliosidosis,
G.sub.M2-gangliosidoses (e.g., GM2 Activator Deficiency, Tay-Sachs
and Sandhoff), Krabbe, Hurler-Scheie (MPS I), Hunter (MPS II),
Sanfilippo (MPS III) Type A, Sanfilippo (MPS III) Type B,
Sanfilippo (MPS III) Type C, Sanfilippo (MPS III) Type D, Marquio
(MPS IV) Type A, Marquio (MPS IV) Type B, Maroteaux-Lamy (MPS VI),
Sly (MPS VII), mucosulfatidosis, sialidoses, mucolipidosis II,
mucolipidosis III, mucolipidosis IV, Fabry, Schindler, Pompe,
sialic acid storage disease, fucosidosis, mannosidosis,
aspartylglucosaminuria, Wolman, and neuronal ceroid
lipofucsinoses.
[0476] Further, the ERT provides an effective amount of at least
one of the following enzymes; glucocerebrosidase, sphingomyelinase,
ceramidase, G.sub.M1-ganglioside-beta-galactosidase, hexosaminidase
A, hexosaminidase B, beta-galactocerebrosidase,
alpha-L-iduronidase, iduronate sulfatase, heparan-N-sulfatase,
N-acetyl-alpha-glucosaminidase, acetyl CoA:alpha-glucosaminide
acetyl-transferase, N-acetyl-alpha-glucosamine-6-sulfatase,
galactosamine-6-sulfatase, beta-galactosidase,
galactosamine-4-sulfatase (arylsulfatase B), beta-glucuronidase,
arylsulfatase A, arylsulfatase C, alpha-neuraminidase,
N-acetyl-glucosamine-1-phosphate transferase, alpha-galactosidase
A, alpha-N-acetylgalactosaminidase, alpha-glucosidase,
alpha-fucosidase, alpha-mannosidase, aspartylglucosamine amidase,
acid lipase, palmitoyl-protein thioesterase (CLN-1), FPT1, TPP1,
CLN3, CLN5, CLN6, CLN8, NPC1 or NPC2.
[0477] In accordance with the invention, the SMT and/or ERT produce
a diminution in at least one of the following stored materials;
glucocerebroside, sphingomyelin, ceramide, G.sub.M1-ganglioside,
G.sub.M2-ganglioside, globoside, galactosylceramide, dermatan
sulfate, heparan sulfate, keratan sulfate, sulfatides,
mucopolysaccharides, sialyloligosaccharides, glycoproteins,
sialyloligosaccharides, glycolipids, globotriaosylceramide,
O-linked glycopeptides, glycogen, free sialic acid,
fucoglycolipids, fucosyloligosaccharides, mannosyloligosaccharides,
aspartylglucosamine, cholesteryl esters, triglycerides, granular
osmophilic deposits--Saposins A and D, ATP synthase subunit c, NPC1
or NPC2.
[0478] In certain embodiments of the invention, the small molecule
therapy comprises administering to the subject an effective amount
of (S)-Quinuclidin-3-yl
(2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate (see FIG.
2A). In other embodiments, the small molecule therapy comprises
administering to the subject an effective amount of
Quinuclidin-3-yl
(2-(4'-fluoro-[1,1'-biphenyl]-3-yl)propan-2-yl)carbamate (see FIG.
2B). The small molecule therapy may include administering to a
subject one or more compounds. In certain embodiments, at least one
of the compounds is a compound of the present invention, such as
those shown in FIGS. 2A and/or 2B.
[0479] Enzyme replacement therapy can provoke unwanted immune
responses. Accordingly, immunosuppressant agents may be used
together with an enzyme replacement therapy component of a
combination therapy of the invention. Such agents may also be used
with a small molecule therapy component, but the need for
intervention here is generally less likely. Any immunosuppressant
agent known to the skilled artisan may be employed together with a
combination therapy of the invention. Such immunosuppressant agents
include but are not limited to cyclosporine, FK506, rapamycin,
CTLA4-Ig, and anti-TNF agents such as etanercept (see e.g. Moder,
2000, Ann. Allergy Asthma Immunol. 84, 280-284; Nevins, 2000, Curr.
Opin. Pediatr. 12, 146-150; Kurlberg et al., 2000, Scand. J.
Immunol. 51, 224-230; Ideguchi et al., 2000, Neuroscience 95,
217-226; Potter et al., 1999, Ann. N.Y. Acad. Sci. 875, 159-174;
Slavik et al., 1999, Immunol. Res. 19, 1-24; Gaziev et al., 1999,
Bone Marrow Transplant. 25, 689-696; Henry, 1999, Clin. Transplant.
13, 209-220; Gummert et al., 1999, J. Am. Soc. Nephrol. 10,
1366-1380; Qi et al., 2000, Transplantation 69, 1275-1283). The
anti-IL2 receptor (.alpha.-subunit) antibody daclizumab (e.g.
Zenapax.TM.), which has been demonstrated effective in transplant
patients, can also be used as an immunosuppressant agent (see e.g.
Wiseman et al., 1999, Drugs 58, 1029-1042; Beniaminovitz et al.,
2000, N. Engl J. Med. 342, 613-619; Ponticelli et al., 1999, Drugs
R. D. 1, 55-60; Berard et al., 1999, Pharmacotherapy 19, 1127-1137;
Eckhoff et al., 2000, Transplantation 69, 1867-1872; Ekberg et al.,
2000, Transpl. Int. 13, 151-159). Additional immunosuppressant
agents include but are not limited to anti-CD2 (Branco et al.,
1999, Transplantation 68, 1588-1596; Przepiorka et al., 1998, Blood
92, 4066-4071), anti-CD4 (Marinova-Mutafchieva et al., 2000,
Arthritis Rheum. 43, 638-644; Fishwild et al., 1999, Clin. Immunol.
92, 138-152), and anti-CD40 ligand (Hong et al., 2000, Semin.
Nephrol. 20, 108-125; Chirmule et al., 2000, J. Virol. 74,
3345-3352; Ito et al.; 2000, J. Immunol. 164, 1230-1235).
[0480] Any combination of immunosuppressant agents known to the
skilled artisan can be used together with a combination therapy of
the invention. One immunosuppressant agent combination of
particular utility is tacrolimus (FK506) plus sirolimus (rapamycin)
plus daclizumab (anti-IL2 receptor .alpha.-subunit antibody). This
combination is proven effective as an alternative to steroids and
cyclosporine, and when specifically targeting the liver. Moreover,
this combination has recently been shown to permit successful
pancreatic islet cell transplants. See Denise Grady, The New York
Times, Saturday, May 27, 2000, pages A1 and A11. See also A. M.
Shapiro et al., Jul. 27, 2000, "Islet Transplantation In Seven
Patients With Type 1 Diabetes Mellitus Using A Glucocorticoid-Free
Immunosuppressive Regimen", N. Engl. J. Med. 343, 230-238; Ryan et
al., 2001, Diabetes 50, 710-719. Plasmaphoresis by any method known
in the art may also be used to remove or deplete antibodies that
may develop against various components of a combination
therapy.
[0481] Immune status indicators of use with the invention include
but are not limited to antibodies and any of the cytokines known to
the skilled artisan, e.g., the interleukins, CSFs and interferons
(see generally, Leonard et al., 2000, J. Allergy Clin. Immunol.
105, 877-888; Oberholzer et al., 2000, Crit. Care Med. 28 (4
Suppl.), N3-N12; Rubinstein et al., 1998, Cytokine Growth Factor
Rev. 9, 175-181). For example, antibodies specifically
immunoreactive with the replacement enzyme can be monitored to
determine immune status of the subject. Among the two dozen or so
interleukins known, particularly preferred immune status indicators
are IL-1.alpha., IL-2, IL-4, IL-8 and IL-10. Among the colony
stimulating factors (CSFs), particularly preferred immune status
indicators are G-CSF, GM-CSF and M-CSF. Among the interferons, one
or more alpha, beta or gamma interferons are preferred as immune
status indicators.
[0482] In the sections which follow, various components that may be
used for eight specific lysosomal storage diseases are provided
(i.e., Gaucher (including types 1, 2 and 3), Fabry, Niemann-Pick B,
Hunter, Morquio, Maroteaux-Lamy, Pompe, and Hurler-Scheie). In
subsequent sections, further enabling disclosure for enzyme
replacement therapy and small molecule therapy components of a
combination therapy of the invention are provided.
Gaucher
[0483] As noted above, Gaucher's disease is caused by the
deficiency of the enzyme glucocerebrosidase
(beta-D-glucosyl-N-acylsphingosine glucohydrolase, EC 3.2.1.45) and
accumulation of glucocerebroside (glucosylceramide). For an enzyme
replacement therapy component of a combination therapy of the
invention for the treatment of Gaucher's disease, a number of
references are available which set forth satisfactory dosage
regimens and other useful information relating to treatment (see
Morales, 1996, Gaucher's Disease: A Review, The Annals of
Pharmacotherapy 30, 381-388; Rosenthal et al., 1995, Enzyme
Replacement Therapy for Gaucher Disease: Skeletal Responses to
Macrophage-targeted Glucocerebrosidase, Pediatrics 96, 629-637;
Barton et al., 1991, Replacement Therapy for Inherited Enzyme
Deficiency--Macrophage-targeted Glucocerebrosidase for Gaucher's
Disease, New England Journal of Medicine 324, 1464-1470; Grabowski
et al., 1995, Enzyme Therapy in Type 1 Gaucher Disease: Comparative
Efficacy of Mannose-terminated Glucocerebrosidase from Natural and
Recombinant Sources, Annals of Internal Medicine 122, 33-39;
Pastores et al., 1993, Enzyme Therapy in Gaucher Disease Type 1:
Dosage Efficacy and Adverse Effects in 33 Patients treated for 6 to
24 Months, Blood 82, 408-416); and Weinreb et al., Am. J. Med.;
113(2):112-9 (2002).
[0484] In one embodiment, an ERT dosage regimen of from 2.5 units
per kilogram (U/kg) three times a week to 60 U/kg once every two
weeks is provided, where the enzyme is administered by intravenous
infusion over 1-2 hours. A unit of glucocerebrosidase is defined as
the amount of enzyme that catalyzes the hydrolysis of one micromole
of the synthetic substrate para-nitrophenyl-p-D-glucopyranoside per
minute at 37.degree. C. In another embodiment, a dosage regimen of
from 1 U/kg three times a week to 120 U/kg once every two weeks is
provided. In yet another embodiment, a dosage regimen of from 0.25
U/kg daily or three times a week to 600 U/kg once every two to six
weeks is provided.
[0485] Since 1991, alglucerase (Ceredase.RTM.) has been available
from Genzyme Corporation. Alglucerase is a placentally-derived
modified form of glucocerebrosidase. In 1994, imiglucerase
(Cerezyme.RTM.) also became available from Genzyme Corporation.
Imiglucerase is a modified form of glucocerebrosidase derived from
expression of recombinant DNA in a mammalian cell culture system
(Chinese hamster ovary cells). Imiglucerase is a monomeric
glycoprotein of 497 amino acids containing four N-linked
glycosylation sites. Imiglucerase has the advantages of a
theoretically unlimited supply and a reduced chance of biological
contaminants relative to placentally-derived aglucerase. These
enzymes are modified at their glycosylation sites to expose mannose
residues, a maneuver which improves lysosomal targeting via the
mannose-6-phosphate receptor. Imiglucerase differs from placental
glucocerebrosidase by one amino acid at position 495 where
histidine is substituted for arginine. Several dosage regimens of
these products are known to be effective (see Morales, 1996, Id.;
Rosenthal et al., 1995, Id.; Barton et al., 1991, Id.; Grabowski et
al., 1995, Id.; Pastores et al., 1993, Id.). For example, a dosage
regimen of 60 U/kg once every two weeks is of clinical benefit in
subjects with moderate to severe disease. The references cited
above and the package inserts for these products should be
consulted by the skilled practitioner for additional dosage regimen
and administration information. See also U.S. Pat. Nos. 5,236,838
and 5,549,892 assigned to Genzyme Corporation.
[0486] As noted above, Gaucher Disease results from a deficiency of
the lysosomal enzyme glucocerebrosidase (GC). In the most common
phenotype of Gaucher disease (type 1), pathology is limited to the
reticuloendothelial and skeletal systems and there are no
neuropathic symptoms. See Barranger, Glucosylceramide lipidosis:
Gaucher disease. In: Scriver C R B A, Sly W S, Valle D, editor. The
Metabolic Basis of Inherited Disease. New York: McGraw-Hill. pp.
3635-3668 (2001). In neuropathic Gaucher disease (nGD), subdivided
into type 2 and type 3 Gaucher disease, the deficiency of
glucocerebrosidase (GC) causes glucosylceramide (GluCer; GL-1) and
glucosylsphingosine (GluSph) to accumulate in the brain, leading to
neurologic impairment. Type 2 Gaucher disease is characterized by
early onset, rapid progression, extensive pathology in the viscera
and central nervous system, and death usually by 2 years of age.
Type 3 Gaucher disease, also known as subacute nGD, is an
intermediate phenotype with varying age of onset and different
degrees of severity and rates of progression. Goker-Alpan et al.,
The Journal of Pediatrics 143: 273-276 (2003). A recent development
has produced the K14 InI/InI mouse model of type 2 Gaucher disease
(hereinafter, the "K14 mouse"); this mouse model closely
recapitulates the human disease showing ataxia, seizures,
spasticity and a reduced median lifespan of only 14 days. Enquist
et al., PNAS 104: 17483-17488 (2007).
[0487] As in patients with nGD, several mouse models of the disease
have increased levels of GluCer and GluSph in the brain due to the
deficiency in GC activity. Liu et al., PNAS 95: 2503-2508 (1998)
and Nilsson, J. Neurochem 39: 709-718 (1982). The "K14" mice
display a neuropathic phenotype that shares many pathologic
features with type 2 Gaucher disease, such as neurodegeneration,
astrogliosis, microglial proliferation, and increased levels of
GluCer and GluSph in specific brain regions. Enquist et al.
(2007).
[0488] Clinical management of patients affected by nGD poses a
challenge for treating physicians both because of the severity of
type 2 disease and the inability of the current therapies to cross
the blood brain barrier (BBB). Current treatment of non-nGD relies
on the intravenous delivery of recombinant human glucocerebrosidase
(Imiglucerase; Cerezyme.TM.) to replace the missing enzyme or the
administration of glucosylceramide synthase inhibitors to attenuate
substrate (GL-1) production. However, these drugs do not cross the
blood brain barrier, and thus are not expected to provide
therapeutic benefit for nGD patients. Current small molecule
glucosylceramide synthase inhibitors in the clinic are not likely
to address the neuropathic phenotypes of nGD. An evaluation of a
compound of the present invention, Quinuclidin-3-yl
(2-(4'-fluoro-[1,1'-biphenyl]-3-yl)propan-2-yl)carbamate
(hereinafter, "Gz161"), in the K14 mouse model of type 2 Gaucher
disease demonstrated that it could indeed reduce brain GluCer and
GluSph (see Examples 122-125). It also reduced brain neuropathology
and extended the lifespan of this model. Moreover, a combined
approach using both enzyme replacement and small molecule substrate
reduction may represent a superior therapy for type 2 Gaucher
disease.
Fabry
[0489] As noted previously, Fabry's disease is caused by the
deficiency of the lysosomal enzyme alpha-galactosidase A. The
enzymatic defect leads to systemic deposition of glycosphingolipids
having terminal alpha-galactosyl moieties, predominantly
globotriaosylceramide (GL3 or Gb3) and, to a lesser extent,
galabiosylceramide and blood group B glycosphingolipids.
[0490] Several assays are available to monitor disease progression
and to determine when to switch from one treatment modality to
another. In one embodiment, an assay to determine the specific
activity of alpha-galactosidase A in a tissue sample may be used.
In another embodiment, an assay to determine the accumulation of
Gb3 may be used. In another embodiment, the practitioner may assay
for deposition of glycosphingolipid substrates in body fluids and
in lysosomes of vascular endothelial, perithelial and smooth muscle
cells of blood vessels. Other clinical manifestations which may be
useful indicators of disease management include proteinuria, or
other signs of renal impairment such as red cells or lipid globules
in the urine, and elevated erythrocyte sedimentation rate. One can
also monitor anemia, decreased serum iron concentration, high
concentration of beta-thromboglobulin, and elevated reticulocyte
counts or platelet aggregation. Indeed, any approach for monitoring
disease progression which is known to the skilled artisan may be
used (See generally Desnick R J et al., 1995, .alpha.-Galactosidase
A Deficiency: Fabry Disease, In: The Metabolic and Molecular Bases
of Inherited Disease, Scriver et al., eds., McGraw-Hill, N.Y.,
7.sup.th ed., pages 2741-2784). A preferred surrogate marker is
pain for monitoring Fabry disease management. Other preferred
methods include the measurement of total clearance of the enzyme
and/or substrate from a bodily fluid or biopsy specimen. A
preferred dosage regimen for enzyme replacement therapy in Fabry
disease is 1-10 mg/kg i.v. every other day. A dosage regimen from
0.1 to 100 mg/kg i.v. at a frequency of from every other day to
once weekly or every two weeks can be used.
Niemann-Pick B
[0491] As previously noted, Niemann-Pick B disease is caused by
reduced activity of the lysosomal enzyme acid sphingomyelinase and
accumulation of membrane lipid, primarily sphingomyelin. An
effective dosage of replacement acid sphingomyelinase to be
delivered may range from about 0.01 mg/kg to about 10 mg/kg body
weight at a frequency of from every other day to weekly, once every
two weeks, or once every two months. In other embodiments an
effective dosage may range from about 0.03 mg/kg to about 1 mg/kg;
from about 0.03 mg/kg to about 0.1 mg/kg; and/or from about 0.3
mg/kg to about 0.6 mg/kg. In a particular embodiment, a patient is
administering acid sphingomyelinase in an escalating dose regimen
at the following sequential doses: 0.1 mg/kg; 0.3 mg/kg; 0.6 mg/kg;
and 1.0 mg/kg, wherein each dose of acid sphingomyelinase is
administered at least twice, and each dose is administered at two
week intervals, and wherein the patient is monitored for toxic side
effects before elevating the dose to the next level (See U.S.
Patent Application Publication No. 2011/0052559.
Hurler-Scheie (MPS I)
[0492] Hurler, Scheie, and Hurler-Scheie disease, also known as MPS
I, are caused by inactivation of alpha-iduronidase and accumulation
of dermatan sulfate and heparan sulfate. Several assays are
available to monitor MPS I disease progression. For example,
alpha-iduronidase enzyme activity can be monitored in tissue biopsy
specimens or cultured cells obtained from peripheral blood. In
addition, a convenient measure of disease progression in MPS I and
other mucopolysaccharidoses is the urinary excretion of the
glycosaminoglycans dermatan sulfate and heparan sulfate (see
Neufeld et al., 1995, Id.). In a particular embodiment,
alpha-iduronidase enzyme is administered once weekly as an
intravenous infusion at a dosage of 0.58 mg/kg of body weight.
Hunter (MPS II)
[0493] Hunter's disease (a.k.a. MPS II) is caused by inactivation
of iduronate sulfatase and accumulation of dermatan sulfate and
heparan sulfate. Hunter's disease presents clinically in severe and
mild forms. A dosage regimen of therapeutic enzyme from 1.5 mg/kg
every two weeks to 50 mg/kg every week is preferred.
Morquio (MPS IV)
[0494] Morquio's syndrome (a.k.a. MPS IV) results from accumulation
of keratan sulfate due to inactivation of either of two enzymes. In
MPS IVA the inactivated enzyme is galactosamine-6-sulfatase and in
MPS WB the inactivated enzyme is beta-galactosidase. A dosage
regimen of therapeutic enzyme from 1.5 mg/kg every two weeks to 50
mg/kg every week is preferred.
Maroteaux-Lamy (MPS VI)
[0495] Maroteaux-Lamy syndrome (a.k.a. MPS VI) is caused by
inactivation of alactosamine-4-sulfatase (arylsulfatase B) and
accumulation of dermatan sulfate. A dosage regimen of from 1.5
mg/kg every two weeks to 50 mg/kg every week is a preferred range
of effective therapeutic enzyme provided by ERT. Optimally, the
osage employed is less than or equal to 10 mg/kg per week. A
preferred surrogate marker for MPS VI disease progression is
roteoglycan levels.
Pompe
[0496] Pompe's disease is caused by inactivation of the acid
alpha-glucosidase enzyme and accumulation of glycogen. The acid
alpha-glucosidase gene resides on human chromosome 17 and is
designated GAA. H. G. Hers first proposed the concept of inborn
lysosomal disease based on his studies of this disease, which he
referred to as type II glycogen storage disease (GSD II) and which
is now also termed acid maltase deficiency (AMD) (see Hers, 1965,
Gastroenterology 48, 625). In a particular embodiment, GAA is
administered every 2 weeks as an intravenous infusion at a dosage
of 20 mg/kg body weight.
[0497] Several assays are available to monitor Pompe disease
progression. Any assay known to the skilled artisan may be used.
For example, one can assay for intra-lysosomal accumulation of
glycogen granules, particularly in myocardium, liver and skeletal
muscle fibers obtained from biopsy. Alpha-glucosidase enzyme
activity can also be monitored in biopsy specimens or cultured
cells obtained from peripheral blood. Serum elevation of creatine
kinase (CK) can be monitored as an indication of disease
progression. Serum CK can be elevated up to ten-fold in
infantile-onset patients and is usually elevated to a lesser degree
in adult-onset patients. See Hirschhorn R, 1995, Glycogen Storage
Disease Type II: Acid alpha-Glucosidase (Acid Maltase) Deficiency,
In: The Metabolic and Molecular Bases of Inherited Disease, Scriver
et al., eds., McGraw-Hill, N.Y., 7.sup.th ed., pages 2443-2464.
Enzyme Replacement Therapy
[0498] The following sections set forth specific disclosure and
alternative embodiments available for the enzyme replacement
therapy component of a combination therapy of the invention.
Generally, dosage regimens for an enzyme replacement therapy
component of a combination therapy of the invention are generally
determined by the skilled clinician. Several examples of dosage
regimens for the treatment of Gaucher's disease with
glucocerebrosidase are provided above. The general principles for
determining a dosage regimen for any given ERT component of a
combination therapy of the invention for the treatment of any LSD
will be apparent to the skilled artisan from publically available
information, such as, for example, a review of the specific
references cited in the sections for each specific LSD. An ERT may
be administered to a patient by intravenous infusion.
Intracerebroventricular and/or intrathecal infusion may be used
(e.g., in addition to intravenous infusion) to administer ERT to a
patient diagnosed with a lysosomal storage disease having CNS
manifestations.
[0499] Any method known in the art may be used for the manufacture
of the enzymes to be used in an enzyme replacement therapy
component of a combination therapy of the invention. Many such
methods are known and include but are not limited to the Gene
Activation technology developed by Shire plc (see U.S. Pat. Nos.
5,968,502 and 5,272,071).
Small Molecule Therapy
[0500] The following section also sets forth specific disclosures
and alternative embodiments available for the small molecule
therapy component of a combination therapy of the invention. Dosage
regimens for a small molecule therapy component of a combination
therapy of the invention are generally determined by the skilled
clinician and are expected to vary significantly depending on the
particular storage disease being treated and the clinical status of
the particular affected individual. The general principles for
determining a dosage regimen for a given SMT component of any
combination therapy of the invention for the treatment of any
storage disease are well known to the skilled artisan. Guidance for
dosage regimens can be obtained from any of the many well known
references in the art on this topic. Further guidance is available,
inter alia, from a review of the specific references cited
herein.
[0501] Generally, compounds of the present invention, such as, for
example, (S)-Quinuclidin-3-yl
(2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate and
Quinuclidin-3-yl
(2-(4'-fluoro-[1,1'-biphenyl]-3-yl)propan-2-yl)carbamate may be
used in the combination therapies of the invention for treatment of
virtually any storage disease resulting from a lesion in the
glycosphingolipid pathway (e.g. Gaucher, Fabry,
G.sub.M1-gangliosidosis and G.sub.M2-gangliosidoses (e.g., GM2
Activator Deficiency, Tay-Sachs and Sandhoff)). Likewise,
aminoglycosides (e.g. gentamicin, G418) may be used in the
combination therapies of the invention for any storage disease
individual having a premature stop-codon mutation (i.e., nonsense
mutation). Such mutations are particularly prevalent in Hurler
syndrome. A small molecule therapy component of a combination
therapy of the invention is particularly preferred where there is a
central nervous system manifestation to the storage disease being
treated (e.g., Sandhoff, Tay-Sachs, Niemann-Pick Type A, and
Gaucher types 2 and 3), since small molecules can generally cross
the blood-brain barrier with ease when compared to other
therapies.
[0502] Preferred dosages of substrate inhibitors used in a
combination therapy of the invention are easily determined by the
skilled artisan. In certain embodiments, such dosages may range
from about 0.5 mg/kg to about 300 mg/kg, preferably from about 5
mg/kg to about 60 mg/kg (e.g., 5 mg/kg, 10 mg/kg, 15, mg/kg, 20
mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg,
55 mg/kg and 60 mg/kg) by intraperitoneal, oral or equivalent
administration from one to five times daily. Such dosages may range
from about 5 mg/kg to about 5 g/kg, preferably from about 10 mg/kg
to about 1 g/kg by oral, intraperitoneal or equivalent
administration from one to five times daily. In one embodiment,
doses range from about about 10 mg/day to about 500 mg/day (e.g.,
10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day,
70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120
mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day,
180 mg/day, 190 mg/day, 200 mg/day, 210 mg/day, 220 mg/day, 230
mg/day, 240 mg/day, 250 mg/day, 260 mg/day, 270 mg/day, 280 mg/day,
290 mg/day, 300 mg/day). A particularly preferred oral dose range
is from about 50 mg to about 100 mg, wherein the dose is
administered twice daily. A particular oral dose range for a
compound of the present invention is from about 5 mg/kg/day to
about 600 mg/kg/day. In a particular oral dose range for a compound
of the present invention is from about 1 mg/kg/day to about 100
mg/kg/day, e.g., 1 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 15
mg/kg/day, 20 mg/kg/day, 25 mg/kg/day, 30 mg/kg/day, 35 mg/kg/day,
40 mg/kg/day, 45 mg/kg/day, 50 mg/kg/day, 55 mg/kg/day or 60
mg/kg/day, 65 mg/kg/day, 70 mg/kg/day, 75 mg/kg/day, 80 mg/kg/day,
85 mg/kg/day, 90 mg/kg/day, 95 mg/kg/day or 100 mg/kg/day.
[0503] A rotating combination of therapeutic platforms (i.e.,
enzyme replacement and small molecule therapy) is preferred.
However, subjects may also be treated by overlapping both
approaches as needed, as determined by the skilled clinician.
Examples of treatment schedules may include but are not limited to:
(1) SMT followed by ERT; (2) ERT followed by SMT; and (3) ERT and
SMT provided at about the same time. As noted previously, temporal
overlap of therapeutic platforms may also be performed, as needed,
depending on the clinical course of a given storage disease in a
given subject.
[0504] Treatment intervals for various combination therapies can
vary widely and may generally be different among different storage
diseases and different individuals depending on how aggressively
storage products are accumulated. For example, Fabry storage
product accumulation may be slow compared to rapid storage product
accumulation in Pompe. Titration of a particular storage disease in
a particular individual is carried out by the skilled artisan by
monitoring the clinical signs of disease progression and treatment
success.
[0505] The various macromolecules that accumulate in lysosomal
storage diseases are not uniformly distributed, but instead are
deposited in certain preferred anatomic sites for each disease.
However, an exogenously supplied enzyme is generally taken up by
cells of the reticuloendothelial system and sorted to the lysosomal
compartment where it acts to hydrolyze the accumulated substrate.
Moreover, cellular uptake of therapeutic enzyme can be augmented by
certain maneuvers to increase lysosomal targeting (see e.g. U.S.
Pat. No. 5,549,892 by Friedman et al., assigned to Genzyme
Corporation, which describes recombinant glucocerebrosidase having
improved pharmacokinetics by virtue of remodeled oligosaccharide
side chains recognized by cell surface mannose receptors which are
endocytosed and transported to lysosomes).
[0506] Some treatment modalities target some affected organs better
than others. In Fabry, for example, if ERT does not reach the
kidney well enough for a satisfactory clinical outcome, SMT can be
used to reduce the substrate levels in the kidney. As demonstrated
in Example 112 and FIG. 6B, SMT effectively reduced Gb3 levels
(i.e., the substrate accumulated in Fabry patients) in the urine of
a Fabry mouse model to a greater extent than ERT. The kidneys are
believed to be the major source of urine Gb3. In contrast, FIG. 6B
shows ERT effectively reduced the Gb3 levels in the plasma to a
greater extent than SMT. These results demonstrate that a
combination therapy of ERT and SMT provides a complementary
therapeutic strategy that takes advantage of the strengths and
addresses the weaknesses associated with each therapy employed
alone. SMT is able to cross the BBB, providing a powerful approach,
when combined with ERT, for treating LSDs having CNS
manifestations, such as Niemarm Pick Type A and Neuropathic Gaucher
disease (nGD). Moreover, substrate reduction by SMT combined with
enzyme replacement address the storage problem at separate and
distinct intervention points which may enhance clinical
outcome.
[0507] It will be understood that reference to simultaneous or
concurrent administration of two or more therapies does not require
that they be administered at the same time, just that they be
acting in the subject at the same time.
Example 1
quinuclidin-3-yl 1-phenylcyclobutylcarbamate
[0508] Using general procedure A, 1-phenylcyclobutanamine
hydrochloride (100 mg, 0.540 mmol) and quinuclidin-3-ol (103 mg,
0.810 mmol) gave quinuclidin-3-yl 1-phenylcyclobutylcarbamate (76
mg, 47%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.43 (d, J=7.9 Hz, 2H), 7.34 (t, J=7.7 Hz, 2H), 7.23 (t,
J=7.3 Hz, 1H), 5.75-5.25 (m, 1H), 4.60 (br s, 1H), 3.25-2.22 (m,
9H), 2.16-2.03 (m, 1H), 2.02-0.94 (m, 6H), 0.88 (t, J=6.8 Hz, 1H)
ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 158.1, 128.5,
126.9, 125.6, 71.4, 59.4, 55.7, 47.5, 46.6, 34.0, 31.8, 29.9, 25.5,
24.7, 22.9, 19.7, 15.3, 14.4 ppm. Purity: >99.9% UPLCMS (210
nm); retention time 0.62 min; (M+1) 331.
Example 2
quinuclidin-3-yl
2-(benzo[d][1,3]dioxol-5-yl)propan-2-ylcarbamate
[0509] Using general procedure B,
benzo[d][1,3]dioxole-5-carbonitrile (1.00 g, 6.81 mmol) was
converted to 2-(benzo[d][1,3]dioxol-5-yl)propan-2-amine
hydrochloride (692 mg, 47%).
[0510] Using general procedure A, the above ammonium chloride
intermediate (150 mg, 0.695 mmol) and quinuclidin-3-ol gave
quinuclidin-3-yl 2-(benzo[d][1,3]dioxol-5-yl)propan-2 ylcarbamate
(125 mg, 54%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
6.91 (dd, J=1.9 Hz, 1H), 6.87 (dd, J=1.9, 8.2 Hz, 1H), 6.75 (d,
J=8.2 Hz, 1H), 5.93 (s, 2H), 5.12 (s, 1H), 4.69-4.66 (m, 1H),
3.26-2.11 (m, 7H), 2.03-1.07 (m, 4H), 1.63 (s, 6H) ppm. .sup.13C
NMR (100 MHz, CDCl.sub.3) .delta. 156.7, 147.9, 118.0, 108.1,
106.1, 101.2, 71.2, 55.9, 55.3, 47.6, 46.7, 29.9, 29.7, 25.6, 24.8,
19.8 ppm. Purity: 97.5% UPLCMS (210 nm); retention time 0.65 min;
(M+1) 333.
Example 3
quinuclidin-3-yl 2-(naphthalen-1-yl)propan-2-ylcarbamate
[0511] Using general procedure A, 2-(naphthalen-1-yl)propan-2-amine
hydrochloride (100 mg, 0.450 mmol) and quinuclidin-3-ol gave
quinuclidin-3-yl 2-(naphthalen-1-yl)propan-2-ylcarbamate (115 mg,
59%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.79-8.46
(m, 1H), 7.99-7.72 (m, 2H), 7.69-7.36 (m, 4H), 5.86-5.37 (m, 1H),
4.72-4.34 (m, 1H), 3.25-2.20 (m, 6H), 2.16-0.41 (m, 5H), 1.93 (s,
6H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 154.6, 135.2,
130.7, 129.7, 128.8, 125.9, 125.3, 123.9, 72.2, 71.1, 56.5, 55.7,
47.6, 46.6, 31.8, 31.2, 25.5, 24.8, 22.9, 19.7, 14.4 ppm. Purity:
100% UPLCMS (210 nm); retention time 0.80 min; (M+1) 339.
Preparation
Example 4
(R)-quinuclidin-3-yl
2-(3-(prop-1-en-2-yl)phenyl)propan-2-ylcarbamate
[0512] To a solution of (R)-quinuclidin-3-ol (194 mg, 1.52 mmol) in
THF (5 mL) at room temperature was added NaH [60%, oil] (64 mg, 1.6
mmol). The reaction mixture was stirred for 15 min and
1-(2-isocyanatopropan-2-yl)-3-(prop-1-en-2-yl)benzene (302 uL, 1.53
mmol) was added dropwise. The reaction was stirred for a period of
30 min and quenched with brine. The solution was extracted with
EtOAc and the organic layer was dried over Na.sub.2SO.sub.4 and
concentrated. The crude material was purified on a combiflash
(SiO.sub.2 cartridge, CHCl.sub.3 and 2N NH.sub.3 in MeOH) to afford
the corresponding carbamate (475 mg, 95%) as a clear oil. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.49 (s, 1H), 7.31 (br s, 3H),
5.33 (s, 1H), 5.17 (s, 1H), 5.08 (s, 1H), 4.77-4.61 (m, 1H),
3.33-2.27 (m, 5H), 2.14 (s, 3H), 2.25-0.75 (m, 6H), 1.68 (br s, 6H)
ppm. .sup.13C NMR. (100 MHz, CDCl.sub.3) .delta. 154.7, 147.2,
143.7, 141.6, 128.5, 124.2, 122.1, 112.8, 70.9, 55.7, 55.5, 47.5,
46.6, 32.2, 31.5, 29.9, 29.6, 25.5, 24.6, 22.9, 22.2, 19.6 ppm.
Purity: 100% UPLCMS (210 nm); retention time 0.84 min; (M+1) 329.2.
Anal. Calcd. for C.sub.20H.sub.28N.sub.2O.sub.2.0.06 (CHCl.sub.3):
C, 71.59; H, 8.40; N, 8.58. Found: C, 71.51; H, 9.05; N, 8.60.
Preparation J
Example 5
quinuclidin-3-yl 2-(3-isopropoxyphenyl)propan-2-ylcarbamate
[0513] A solution of 3-cyanophenol (1.00 g, 8.39 mmol),
2-iodopropane (839 uL, 8.39 mmol) and cesium carbonate (2.73 g,
8.39 mmol) in 1:1 CH.sub.2Cl.sub.2/CH.sub.3CN (16 mL) was stirred
at reflux for 18 h. The reaction mixture was cooled to room
temperature and filtered through Celite. The filtrate was
concentrated and the crude material purified on a combiflash
(SiO.sub.2 cartridge, CH.sub.2Cl.sub.2) to afford the corresponding
ether (763 mg, 57%) as a white solid.
[0514] Using general procedure B, 3-isopropoxybenzonitrile (763 mg,
4.24 mmol) was converted to the corresponding
2-(3-isopropoxyphenyl)propan-2-amine (362 mg, 45%) as a clear
oil.
[0515] Using general procedure A, the above amine (100 mg, 0.520
mmol) and quinuclidin-3-ol gave quinuclidin-3-yl
2-(3-isopropoxyphenyl)propan-2-ylcarbamate (110 mg, 61%) as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.17 (t, J=7.9 Hz,
1H), 6.92 (d, J=7.8 Hz, 1H), 6.89 (t, 0.1=2.1 Hz, 1H), 6.70 (d,
0.1=8.1 Hz, 1H), 5.38-5.13 (m, 1H), 4.58 (br s, 1H), 4.49 (hept,
J=6.1 Hz, 1H), 3.31-2.04 (m, 6H), 2.00-0.79 (m, 5H) 1.60 (br s,
6H), 1.28 (d, J=6.1 Hz, 6H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3)
.delta. 158.1, 129.5, 117.2, 113.6, 71.1, 69.9, 55.8, 55.4, 47.6,
46.6, 29.4, 25.6, 24.8, 22.3, 19.7 ppm. Purity: >99.9% UPLCMS
(210 nm); retention time 0.83 min; (M+1) 347.
Example 6
quinuclidin-3-yl 2-(3-bromo-2-fluorophenyl)propan-2-ylcarbamate
[0516] Using general procedure A,
2-(3-bromo-2-fluorophenyl)propan-2-amine (1.0 g, 4.3 mmol) and
quinuclidin-3-ol gave quinuclidin-3-yl
2-(3-bromo-2-fluorophenyl)propan-2-ylcarbamate (957 mg, 58%) as a
white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.45 (ddd,
J=1.6, 6.3, 7.9 Hz, 1H), 7.31 (td, J=1.6, 7.7 Hz, 1H), 6.99 (td,
J=1.0, 8.0 Hz, 1H), 5.31-5.15 (br s, 1H), 4.59 (br s, 1H),
3.25-2.19 (m, 6H), 2.06-0.81 (m, 5H), 1.73 (s, 3H), 1.71 (s, 3H)
ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 158.1, 155.6,
132.5, 127.1, 127.0, 124.8, 124.8, 110.6, 110.4, 71.5, 55.7, 54.2,
47.5, 46.7, 29.9, 28.4, 25.5, 24.8, 19.7 ppm. Purity: >99.9%
UPLCMS (210 nm); retention time 0.79 min; (M+1) 385.
Example 7
(+/-) quinuclidin-3-yl (1R,2S)-2-phenylcyclopropylcarbamate
[0517] Using general procedure A,
(+/-)((1S,2R)-2-isocyanatocyclopropyl)benzene (117 uL, 0.780 mmol)
and quinuclidin-3-ol gave (+/-) quinuclidin-3-yl
(1R,2S)-2-phenylcyclopropylcarbamate (63 mg, 28%) as a white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.30-7.05 (m, 5H), 5.43
(br s, 1H), 4.77 (br s, 1H), 3.23 (dd, J=9.0, 14.0 Hz, 1H),
2.97-2.65 (m, 6H), 2.15-1.12 (m, 8H) ppm. .sup.13C NMR (100 MHz,
CDCl.sub.3) .delta. 157.1, 140.7, 140.2, 128.5, 126.8, 126.3, 71.5,
55.7, 47.5, 46.6, 32.7, 25.6, 25.2, 24.5, 19.5, 16.2 ppm. Purity:
>99.9% UPLCMS (210 nm); retention time 0.67 min; (M+1) 287.
Example 8
quinuclidin-3-yl 1-phenylcyclohexylcarbamate
[0518] Using general procedure A, 1-phenylcyclohexanamine (36 mg,
0.21 mmol) and quinuclidin-3-ol gave quinuclidin-3-yl
1-phenylcyclohexylcarbamate (40 mg, 58%) as a white solid. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.41 (d, J=7.4 Hz, 2H), 7.32 (t,
J=7.7 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 5.19-4.98 (br s, 1H),
4.70-4.56 (s, 1H), 3.34-0.83 (in, 21H) ppm. .sup.13C NMR (100 MHz,
CDCl.sub.3) .delta. 158.4, 128.3, 126.5, 124.9, 57.2, 46.3, 36.1,
25.4, 24.2, 22.0, 19.2, 15.2 ppm. Purity: >99.9% UPLCMS (210
mu); retention time 0.84 min; (M+1) 329.
Preparation K
Example 9
(R)-1-(2-(3-(prop-1-en-2-yl)phenyl)propan-2-yl)-3-(quinuclidin-3-yl)urea
[0519] To a solution of (R)-quinuclidin-3-amine dihydrochloride
(120 mg, 0.603 mmol) and
1-(2-isocyanatopropan-2-yl)-3-(prop-1-en-2-yl)benzene (119 mg,
0.597 mmol) in THF (3 mL) was added triethylamine (168 uL, 1.21
mmol). The reaction mixture was stirred at room temperature for 18
h and then quenched with brine. The mixture was extracted with
CHCl.sub.3 and the organic layer was dried (Na.sub.2SO.sub.4) and
concentrated. The crude material was purified on a combiflash
(SiO.sub.2 cartridge, CHCl.sub.3 and 2N NH.sub.3 in MeOH) to afford
the corresponding urea (163 mg, 50%) as a white solid. NMR (400
MHz, CDCl.sub.3) .delta. 7.62 (t, J=1.6 Hz, 1H), 7.44 (dt, J=1.9,
7.0 Hz, 1H), 7.41-7.33 (m, 2H), 5.35 (br s, 1H), 5.11 (p, J=1.4 Hz,
1H), 4.84 (s, 1H), 4.21 (d, J=7.5 Hz, 1H), 3.70-3.61 (m, 1H), 3.13
(ddd, J=2.3, 9.3, 14.2 Hz, 1H), 2.71-2.54 (m, 3H), 2.30-2.22 (m,
1H), 2.15 (dd, J=0.8, 1.4, 3H), 2.05-1.96 (m, 1H), 1.65 (s, 3H),
1.64 (s, 3H), 1.65-1.60 (m, 1H) 1.54-1.45 (m, 2H), 1.22-1.12 (m,
1H), 0.95-0.80 (m, 1H) ppm. .sup.13C NMR (400 MHz, CDCl.sub.3)
.delta. 157.4, 148.5, 143.8, 141.3, 128.4, 124.4, 123.8, 122.2,
112.6, 55.2, 53.4, 46.2, 46.1, 44.5, 30.5, 30.4, 25.0, 22.2, 17.7,
8.9 ppm. Purity: 97.5% UPLCMS (210 nm); retention time 0.83 min;
(M+1) 328.
Example 10
1-(2-(naphthalen-2-yl)propan-2-yl)-3-(quinuclidin-3-yl)urea
[0520] Using general procedure B, naphthalene-2-carbonitrile (1.00
g, 6.53 mmol) was converted to the corresponding
2-(naphthalen-2-yl)propan-2-amine (294 mg, 25%) as a clear oil.
[0521] Using general procedure C, quinuclidin-3-amine (102 mg,
0.808 mmol), CDT (131 mg, 0.808 mmol) and
2-(naphthalen-2-yl)propan-2-amine (150 mg, 0.819 mmol) gave
1-(2-(naphthalen-2-yl)propan-2-yl)-3-(quinuclidin-3-yl)urea (132
mg, 49%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.94-7.78 (m, 4H), 7.69 (dd, J=2.0, 8.7 Hz, 1H), 7.53-7.46
(m, 2H), 4.84 (s, 1H), 4.23 (d, J=8.0 Hz, 1H), 3.68-3.54 (m, 1H),
3.07 (ddd, J=2.3, 9.3, 14.1 Hz, 1H), 2.61-2.51 (m, 2H), 2.42-2.32
(m, 1H), 1.95-1.83 (m, 2H), 1.75 (s, 3H), 1.74 (s, 3H), 1.58-1.54
(m, 1H), 1.46-1.40 (m, 2H), 1.03-0.91 (m, 1H), 0.72-0.60 (m, 1H)
ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 157.5, 143.7,
133.4, 132.8, 129.3, 128.1, 127.8, 126.9, 126.7, 124.4, 124.0,
57.0, 55.0, 47.1, 47.1, 46.6, 30.5, 30.3, 26.0, 25.9, 20.0 ppm.
Purity: >99.9% UPLCMS (210 nm); retention time 0.71 min; (M+1)
338.
Example 11
1-(2-methyl-2-(m-tolyl)propyl)-3-(3-methylquinuclidin-3-yl)urea
[0522] Using general procedure D,
2-methyl-2-(m-tolyl)propan-1-amine hydrochloride (100 mg, 0.501
mmol), triethylamine (279 uL, 2.00 mmol), triphosgene (47 mg, 0.18
mmol) and 3-methylquinuclidin-3-amine 2,2,2-trifluoroacetate (140
mg, 0.550 mmol) gave
1-(2-methyl-2-(m-tolyl)propyl)-3-(3-methylquinuclidin-3-yl)urea (41
mg, 25%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.23 (t, J=7.7 Hz, 1H), 7.18-7.12 (m, 2H), 7.04 (d, J=7.5
Hz, 1H), 4.12 (s, 1H), 4.08 (t, J=6.0 Hz, 1H), 3.39-3.22 (m, 2H),
2.81-2.62 (m, 6H), 2.34 (s, 3H), 1.98-1.89 (m, 1H), 1.80-1.63 (m,
2H), 1.51-1.23 (m, J=26.9 Hz, 2H), 1.37 (s, 3H), 1.30 (s, 6H) ppm.
.sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 157.9, 147.1, 138.2,
128.6, 127.1, 127.1, 123.3, 64.0, 52.2, 52.1, 46.9, 46.7, 39.2,
31.2, 27.1, 26.8, 25.4, 23.5, 22.7, 21.9. Purity: >99.9% UPLCMS
(210 nm); retention time 0.79 min; (M+1) 330.
Example 12
1-(2-(3-methoxyphenyl)propan-2-yl)-3-(quinuclidin-3-yl)urea
[0523] Using general procedure C, quinuclidin-3-amine (380 mg, 3.01
mmol), CDI (489 mg, 3.01 mmol) and
2-(3-methoxyphenyl)propan-2-amine (506 mg, 3.07 mmol) gave
1-(2-(3-methoxyphenyl)propan-2-yl)-3-(quinuclidin-3-yl)urea (560
mg, 59%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.35-7.29 (m, 1H), 7.14-7.07 (m, 2H), 6.87-6.81 (ddd, 1H),
4.76 (s, 1H), 4.19 (d, 1H), 3.81 (s, 3H), 3.70-3.62 (m, 1H),
3.19-3.10 (m, 1H), 2.74-2.59 (m, 3H), 2.37-2.26 (m, 1H), 2.07-1.98
(dd, 1H), 1.80 (br s, 1H), 1.69-1.63 (m, 1H), 1.63 (s, 3H), 1.62
(s, 3H), 1.58-1.44 (m, 2H), 1.28-1.14 (m, 1H), 1.02-0.90 (m, 1H)
ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 160.0, 157.5,
148.4, 129.9, 117.7, 112.0, 111.9, 56.7, 55.3, 54.6, 47.2, 46.8,
46.4, 30.1, 25.8, 20.0 ppm. Purity: >99.4% UPLCMS (210 nm);
retention time 1.73 min; (M+1) 318.
Example 13
quinuclidin-3-yl 2-(3-methoxyphenyl)propan-2-ylcarbamate
[0524] Using general procedure A, 1-(3-methoxyphenyl)propan-2-amine
(327 mg, 1.98 mmol) and quinuclidin-3-ol gave quinuclidin-3-yl
2-(3-methoxyphenyl)propan-2-ylcarbamate (370 mg, 59%) as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.30-7.20 (m, 1H),
7.03-6.97 (m, 1H), 6.97-6.93 (m, 1H), 6.80-6.74 (dd, 1H), 5.18-5.00
(br s, 1H), 4.67-4.57 (m, 1H), 3.80 (s, 3H), 3.30-2.12 (br m, 7H),
2.02-1.00 (m, 10H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.
159.7, 154.5, 149.0, 129.3, 117.2, 111.4, 111.0, 70.9, 55.7, 55.1,
47.4, 46.5, 29.4, 25.4, 24.6, 19.6 ppm. Purity: >99.9% UPLCMS
(210 nm); retention time 1.85 min; (M+1) 319.
Example 14
quinuclidin-3-yl 2-(3-methoxyphenyl)propan-2-ylcarbamate
[0525] Using general procedure A, 1-(4-methoxyphenyl)propan-2-amine
hydrochloride (316 mg, 1.57 mmol) and quinuclidin-3-ol gave
quinuclidin-3-yl 2-(3-methoxyphenyl)propan-2-ylcarbamate (370 mg,
59%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.33 (d, 2H), 6.86 (d, 2H), 5.15-5.01 (br s, 1H), 4.66-4.57 (m,
1H), 3.79 (s, 3H), 3.33-2.12 (m, 7H), 2.10-0.96 (m, 10H) ppm.
.sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 158.1, 154.5, 139.2,
125.8, 113.5, 70.7, 55.7, 55.2, 54.6, 47.2, 46.3, 31.2, 29.4, 25.3,
24.5, 19.4 ppm. Purity: >94.1% UPLCMS (210 nm); retention time
1.81 min; (M+1) 319.
Example 15
quinuclidin-3-yl 2-(4-tert-butylphenyl)propan-2-ylcarbamate
[0526] Using general procedure A,
1-(4-tert-butylphenyl)propan-2-amine (348 mg, 1.82 mmol) and
quinuclidin-3-ol gave quinuclidin-3-yl
2-(4-tert-butylphenyl)propan-2-ylcarbamate
[0527] (427 mg, 68%) as a white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.34 (s, 4H), 5.09 (br s, 1H), 4.69-4.52 (m,
1H), 3.47-2.05 (m, 711), 3.33-2.12 (m, 7H), 2.00-0.80 (m, 20H) ppm.
.sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 156.2, 149.4, 144.5,
125.3, 124.5, 70.9, 55.8, 55.1, 47.5, 46.6, 34.4, 31.4, 29.8, 29.3,
25.5, 24.6, 19.6 ppm. Purity: >98.2% UPLCMS (210 nm); retention
time 2.29 min; (M+1) 345.
Example 16
quinuclidin-3-yl 2-(4-isopropylphenyl)propan-2-ylcarbamate
[0528] Using general procedure A,
1-(4-isopropylphenyl)propan-2-amine (158 mg, 0.891 mmol) and
quinuclidin-3-ol gave quinuclidin-3-yl
2-(4-isopropylphenyl)propan-2-ylcarbamate (205 mg, 70%) as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.33 (d, J=7.3 Hz,
2H), 7.19 (s, 1H), 7.17 (s, 1H), 5.09 (s, 1H) 4.69-4.51 (br s, 1H)
3.30-1.30 (m, 17H), 1.24 (s, 3H), 1.22 (s, 3H), 1.06-0.77 (m, 1H)
ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 156.2, 147.1,
144.4, 126.4, 124.7, 70.9, 55.7, 55.0, 47.4, 46.5, 33.6, 29.8,
29.4, 25.4, 24.6, 24.0, 19.5 ppm. Purity: >98.3% UPLCMS (210
nm); retention time 2.19 min; (M+1) 331.
Example 17
quinuclidin-3-yl 2-(4-ethylphenyl)propan-2-ylcarbamate
[0529] Using general procedure A, 1-(4-ethylphenyl)propan-2-amine
(230 mg, 1.41 mmol) and quinuclidin-3-ol gave quinuclidin-3-yl
2-(4-ethylphenyl)propan-2-ylcarbamate (248 mg, 56%) as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.33 (d, J=7.3 Hz,
2H), 7.19 (s, 1H), 7.17 (s, 1H), 5.09 (s, 1H) 4.69-4.51 (br s, 1H)
3.34-0.73 (m, 22H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.
154.5, 144.3, 142.4, 127.8, 124.7, 71.0, 55.6, 55.1, 47.4, 46.5,
29.6, 28.3, 25.4, 24.6, 19.5, 15.8, 15.4 ppm. Purity: >99.5%
UPLCMS (210 nm); retention time 2.07 min; (M+1) 317.
Example 18
quinuclidin-3-yl 2-o-tolylpropan-2-ylcarbamate
[0530] Using general procedure A, 2-o-tolylpropan-2-amine (230 mg,
1.52 mmol) and quinuclidin-3-ol gave quinuclidin-3-yl
2-o-tolylpropan-2-ylcarbamate (200 mg, 44%) as a white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) (rotamers) .delta. 7.33 (s, br,
1H), 7.15-7.10 (m, 3H), 5.35-5.20 (m, 1H), 4.60 (br s, 1H),
3.20-2.60 (m, 5H), 2.5 (s, 3H), 2.15 (br s, 1H), 1.80-1.30 (m,
10H). .sup.13C NMR (100 MHz, CDCl.sub.3) (rotamers) .delta. 154.2,
144.5, 140.2, 133.0, 127.1, 126.2, 126.1, 72.2, 71, 56.0, 46.6,
46.7, 31.0, 29.0, 26.0, 24.7, 22.3, 19.7. Purity: >95% UPLCMS
(210 nm); (M+1) 303.
Example 19
quinuclidin-3-yl 2-(2-methoxyphenyl)propan-2-ylcarbamate
[0531] Using general procedure A, 2-(2-methoxyphenyl)propan-2-amine
(150 mg, 0.908 mmol) and quinuclidin-3-ol gave quinuclidin-3-yl
2-(2-methoxyphenyl)propan-2-ylcarbamate (60 mg, 21%) as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) (rotamers) .delta. 7.3 (m,
1H), 7.2 (m, 1H), 6.9 (m, 2H), 5.4 (s, br, 1H), 4.6 (m, 1H), 3.8
(s, 1H), 3.1 (m, 1H), 2.4-2.8 (m, 5H), 1.9 (s, 1H), 1.3-1.7 (m,
10H). .sup.13C NMR (100 MHz, CDCl.sub.3) (rotamers) .delta. 157,
155, 140, 134, 129, 127, 121, 111, 70, 56, 55, 48, 47, 29, 26, 25,
20. Purity: >99% UPLCMS (210 nm); (M+1) 319.
Preparation L
Example 20
1-(3-cyanoquinuclidin-3-yl)-3-(2-(3-(prop-1-en-2-yl)phenyl)propan-2-yl)ure-
a
[0532] 3-Amino-3-cyanoquinuclidine was prepared as described in the
literature (Fernandez, M. A.; Gonzalez, G.; Martinez, M.; Galvez,
E. Anales de la Real Academia de Farmacia 1988, 54, 502).
[0533] To a solution of 3-amino-3-cyanoquinuclidine (100 mg, 0.661
mmol) in CH.sub.2Cl.sub.2 (5 mL) was added, dropwise,
3-isoprenyl-0,0-dimethylbenzyl isocyanate (0.13 mL, 0.66 mmol). The
reaction mixture was stirred at room temperature for 18 hours,
concentrated and subjected to flash chromatography over silica gel
(19:1 CH.sub.2Cl.sub.2/7M NH.sub.3(CH.sub.3OH)). The title product
was obtained as a white solid (155 mg, 67%). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.52 (s, 1H), 7.35-7.25 (m, 3H), 5.34 (s, 1H),
5.05 (s, 1H), 2.60-3.41 (m, 6H), 2.25-2.32 (m, 1H), 2.13 (s, 3H),
1.42-2.10 (m, 4H), 1.64 (s, 6H) ppm. .sup.13C NMR (100 MHz,
CD.sub.3OD) .delta. 157.0, 147.9, 144.0, 141.4, 128.1, 124.0,
123.4, 121.9, 121.7, 111.5, 61.0, 55.1, 50.4, 30.9, 23.3, 22.5,
21.0 19.0 ppm. Purity: >99.9% UPLCMS (210 nm); retention time
0.82 min; (M+1) 353.
Preparation M
Example 21
1-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-3-{2-[3-(prop-1-en-2-yl)phenyl]propan-
-2-yl}urea
[0534] To a suspension of (S)-(-)-3-aminoquinculidine
dihydrochloride (120 mg, 0.603 mmol) and triethylamine (168 uL,
1.21 mmol) in THF (2 mL) at room temperature was added
3-isopropenyl-.quadrature.,.quadrature.-dimethylbenzyl-isocyanate
(121 mg, 0.601 mmol). The reaction mixture was stirred for 18 hr
and then washed with saturated aqueous NaHCO.sub.3. The organic
phase was dried over Na.sub.2SO.sub.4 and concentrated. The crude
material was purified on a combiflash (SiO.sub.2 cartridge,
CHCl.sub.3 and 2N NH.sub.3 in MeOH) to afford the title compound
(29 mg, 47%) as an off-white solid. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.51 (dt, J=2.5, 1.2 Hz, 1H), 7.41-7.14 (m,
3H), 5.32 (dd, J=1.6, 0.8 Hz, 1H), 5.06 (s, 1H), 3.74-3.60 (m, 1H),
3.31-3.29 (m, 2H), 3.19 (ddd, J=13.7, 9.5, 1.6 Hz, 1H), 2.88-2.50
(m, 4H), 2.37 (ddd, J=14.0, 4.9, 2.2 Hz, 1H), 2.14 (ddd, J=2.3,
1.8, 1.0 Hz, 3H), 1.81-1.63 (m, 4H), 1.62 (d, J=6.2 Hz, 6H),
1.55-1.38 (in, 1H) ppm. .sup.13C NMR (100 MHz, CD.sub.3OD) .delta.
158.4, 148.4, 144.0, 141.3, 128.0, 124.1, 123.3, 121.9, 111.4,
55.7, 54.7, 46.7, 46.4, 46.0, 29.6, 29.4, 28.4, 26.1, 25.1, 21.0,
19.4 ppm. Purity: >96% UPLCMS (210 nm); retention time 0.81 min;
(M+1) 329.5.
Preparation N
Example 22
1-(1-azabicyclo[2.2.2]oct-3-yl)-3-{2-[3-(propan-2-yl)phenyl]propan-2-yl}ur-
ea
[0535] To a solution of 3-aminoquinuclidine (150 mg, 1.19 mmol) in
THF (5 mL) was added
3-isopropenyl-.quadrature.,.quadrature.-dimethylbenzylisocyanate.
The solution was stirred at room temperature for 30 min, then
concentrated onto silica gel and purified on a combiflash
(SiO.sub.2 cartridge, CHCl.sub.3 and 2N NH.sub.3 in MeOH) to afford
an off-white solid (299 mg, 77%).
[0536] Using general procedure F, the above isoprenyl urea (150 mg,
1.19 mmol) and palladium hydroxide (30 mg, 20 wt. % on carbon) gave
1-(1-azabicyclo[2.2.2]oct-3-yl)-3-{2-[3-(propan-2-yl)phenyl]propan-2-yl}u-
rea (116 mg, 77%) as an off-white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.38-7.28 (m, 3H), 7.16 (dt, J=6.9, 1.6 Hz,
1H), 4.93 (s, 1H), 4.26 (d, J=7.5 Hz, 1H), 3.70-3.58 (m, 1H), 3.11
(ddd, J=14.1, 9.4, 2.3 Hz, 1H), 2.90 (hept, J=6.9 Hz, 1H),
2.71-2.52 (m, 4H), 2.31-2.19 (m, 1H), 1.98 (dd, J=14.2, 2.9 Hz,
1H), 1.61 (d, J=2.0 Hz, 6H), 1.52-1.43 (m, 2H), 1.23 (d, J=6.9 Hz,
6H), 1.19-1.09 (m, 1H), 0.92-0.79 (m, 1H) ppm. .sup.13C NMR (100
MHz, CDCl.sub.3) .delta. 157.6, 150.1, 146.1, 129.2, 125.8, 124.1,
123.3, 57.1, 54.9, 47.4, 47.0, 46.6, 34.5, 30.7, 30.5, 26.1, 26.0,
24.3, 24.2, 20.3 ppm. Purity: 94% UPLCMS (210 nm); retention time
0.87 min; (M+1) 329.3.
Example 23
1-(1-azabicyclo[2.2.2]oct-3-yl)-3-[1-(naphthalen-1-yl)ethyl]urea
[0537] 3-Aminoquinculidene dihydrochloride (150 mg, 0.753 mmol) was
mixed with THF (3 mL) and triethylamine (152 mg, 1.50 mmol) before
adding 1-(1-naphthyl)ethylisocyanate (149 mg, 0.752 mmol). The
mixture was stirred 48 h at room temperature. The reaction solution
was concentrated and purified on a combiflash (SiO.sub.2 cartridge,
CHCl.sub.3 and 2N NH.sub.3 in MeOH) to afford the title compound as
an off-white solid (46 mg, 19%). .sup.1H NM R (400 MHz, CDCl.sub.3)
.delta. 8.20-8.05 (m, 1H), 7.85 (dd, J=7.9, 1.5 Hz, 1H), 7.75 (d,
J=8.1 Hz, 1H), 7.59-7.34 (m, 4H), 5.55 (hept, 1H), 5.35-5.19 (m,
1H), 4.84 (dd, 1H), 3.70-3.53 (m, 1H), 3.09 (ddd, 1H), 2.74-2.28
(m, 4H), 2.17 (ddd, J=1.8, 4.5, 14.1 Hz, 1H), 1.75-1.62 (m, 1H),
1.55 (dd, J=1.8, 6.8 Hz, 3H), 1.52-1.06 (m, 4H) ppm. .sup.13C NMR
(100 MHz, CDCl.sub.3) .delta. 157.7, 140.0, 134.1, 130.9, 129.2,
128.3, 126.8, 126.7, 126.7, 126.0, 125.6, 123.2, 123.1, 122.8,
122.7, 56.9, 56.7, 47.4, 47.3, 46.7, 46.4, 26.1, 25.9, 22.7, 22.6,
20.1, 20.0 ppm. Purity: 97% UPLCMS (210 nm); retention time 0.68
min; (M+1) 324.2
Example 24
1-(1-azabicyclo[2.2.2]oct-3-yl)-3-[2-(3-bromophenyl)propan-2-yl]urea
[0538] Using general procedure C, quinuclidin-3-amine (100 mg,
0.792 mmol), CDI (128 mg, 0.789 mmol) and
2-(3-bromophenyl)propan-2-amine (170 mg, 0.791 mmol) gave the title
compound as a white solid (166 mg, 75%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.50 (s, 1H), 7.30 (t, J=7.2 Hz, 2H), 7.15 (t,
J=7.9 Hz, 1H), 5.54 (d, J=22.7 Hz, 1H), 5.16 (d, J=29.7 Hz, 1H),
3.60 (s, 1H), 3.14 (ddd, J=13.3, 9.4, 1.6 Hz, 1H), 2.61 (d, J=52.6
Hz, 4H), 2.18 (dd, J=14.1, 2.8 Hz, 1H), 1.66 (d, J=3.0 Hz, 2H),
1.51 (d, J=7.6 Hz, 6H), 1.28 (s, 3H) ppm. .sup.13C NMR (100 MHz,
CDCl.sub.3) .delta. 157.1, 150.4, 130.3, 130.0, 128.6, 124.0,
123.0, 57.0, 54.6, 47.6, 47.2, 46.8, 30.5, 30.3, 26.3, 26.2, 20.2
ppm. Purity: 100% UPLCMS (210 nm); retention time 0.66 min; (M+1)
367.8.
Example 25
1-(1-azabicyclo[2.2.2]oct-3-yl)-3-[2-(biphenyl-3-yl)propan-2-yl]urea
[0539] Using general procedure E,
1-(1-azabicyclo[2.2.2]oct-3-yl)-3-[2-(3-bromophenyl)propan-2-yl]urea
(111 mg, 0.301 mmol), phenylboronic acid (78.8 mg, 0.606 mmol) and
tetrakis(triphenylphosphine)palladium(0) gave the title compound as
an off-white solid (21 mg, 11%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.74 (s, 1H), 7.52-7.40 (m, 8H), 4.89 (s, 1H), 4.28 (d,
J=7.3 Hz, 1H), 3.75-3.59 (m, 1H), 3.15 (ddd, J=1.9, 9.3, 13.9 Hz,
1H), 2.46 (m, 4H), 2.05 (dd, J=3.5, 14.0 Hz, 1H), 1.68 (d, J=4.7
Hz, 6H), 1.66-0.76 (m, 5H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3)
.delta. 157.4, 146.9, 142.5, 141.1, 129.7, 129.1, 127.8, 127.4,
126.7, 124.8, 124.7, 57.1, 55.1, 30.7, 30.1, 26.1, 26.0, 20.2 ppm.
Purity: 100% UPLCMS (210 nm); retention time 0.78 min; (M+1)
364.0.
Example 26
1-azabicyclo[2.2.2]oct-3-yl
{2-[3-(propan-2-yl)phenyl]propan-2-yl}carbamate
[0540] Using general procedure F, 1-azabicyclo[2.2.2]oct-3-yl
{2-[3-(prop-1-en-2-yl)phenyl]propan-2-yl}carbamate (48.8 mg, 0.146
mmol) and palladium hydroxide (30 mg, 20 wt. % on carbon) gave the
title compound as an off-white solid (16 mg, 33%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.24 (d, J=5.1 Hz, 3H), 7.10 (d, 1H), 5.12
(s, 1H), 4.63 (s, 1H), 3.54-2.96 (m, 1H), 2.89 (s, 1H), 2.68 (s,
5H), 2.17-1.75 (m, 2H), 1.67 (s, 6H), 1.62-1.30 (m, 2H), 1.24 (d,
J=6.9 Hz, 6H), 1.15-0.85 (m, 1H) ppm. .sup.13C NMR (100 MHz,
CDCl.sub.3) .delta. 149.1, 128.5, 124.9, 123.1, 122.5, 55.8, 55.6,
46.6, 34.5, 25.6, 24.6, 24.3, 19.7 ppm. Purity: 94% UPLCMS (210
nm); retention time 0.89 min; (M+1) 331.1.
Example 27
1-azabicyclo[2.2.2]oct-3-yl
[2-(3-bromophenyl)propan-2-yl]carbamate
[0541] Using general procedure A, 2-(3-bromophenyl)propan-2-amine
hydrochloride (2.00 g, 7.89 mmol) and quinuclidin-3-ol gave the
title compound as a white solid (2.23 g, 76%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.54 (s, 1H), 7.41-7.30 (m, 2H), 7.19 (t,
J=7.9 Hz, 1H), 5.11 (s, 1H), 4.68-4.54 (m, 1H), 3.51-2.11 (m, 6H),
2.04-1.68 (m, 2H), 1.63 (d, J=10.2 Hz, 6H), 1.51-0.67 (m, 3H) ppm.
.sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 156.0, 154.7, 150.6,
149.7, 130.2, 130.0, 128.4, 123.7, 72.5, 71.6, 71.5, 55.8, 55.1,
47.6, 46.7, 31.2, 29.9, 29.8, 29.5, 25.6, 24.8, 19.7 ppm. Purity:
100% UPLCMS (210 nm); retention time 0.69 min; (M+1) 368.8.
Example 28
1-azabicyclo[2.2.2]oct-3-yl
[2-(3-cyclopropylphenyl)propan-2-yl]carbamate
[0542] Using general procedure E, 11-azabicyclo[2.2.2]oct-3-yl
[2-(3-bromophenyl)propan-2-yl]carbamate (44.3 mg, 0.121 mmol),
cyclopropyl boronic acid (14 mg, 0.16 mmol) and palladium (II)
acetate gave the title compound as an off-white solid (21 mg, 11%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.54 (s, 1H), 7.41-7.30
(m, 2H), 7.19 (t, J=7.9 Hz, 1H), 5.11 (s, 1H), 4.68-4.54 (m, 1H),
3.51-2.11 (m, 6H), 2.04-1.68 (m, 2H), 1.63 (d, J=10.2 Hz, 6H), 1.36
(d, J=9.5 Hz, 3H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.
147.2, 144.2, 128.6, 128.4, 125.0, 123.7, 122.8, 122.1, 110.0,
72.2, 71.4, 55.9, 55.4, 47.7, 47.3, 46.7, 33.1, 31.6, 30.0, 29.6,
25.6, 24.8, 19.8, 19.3, 15.8, 9.5 ppm. Purity: 91% UPLCMS (210 nm);
retention time 0.75 min; (M+1) 329.0.
Example 29
1-azabicyclo[2.2.2]oct-3-yl
[2-(biphenyl-3-yl)propan-2-yl]carbamate
[0543] Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl
[2-(3-bromophenyl)propan-2-yl]carbamate (600 mg, 1.63 mmol),
phenylboronic acid (398 mg, 3.27 mmol) and palladium (II) acetate
gave the title compound as a white solid (379 mg, 64%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.61 (s, 1H), 7.56 (d, J=7.4 Hz, 2H),
7.50-7.38 (m, 4H), 7.34 (m, 2H), 5.16 (s, 1H), 4.63 (s, 1H),
3.39-2.09 (m, 6H), 1.72 (s, 6H), 2.02-0.73 (m, 5H) ppm. .sup.13C
NMR (100 MHz, CDCl.sub.3) .delta. 154.8, 147.8, 141.6, 129.0,
129.0, 128.6, 127.5, 125.8, 125.0, 124.0, 71.6, 71.3, 55.9, 55.5,
47.6, 46.8, 31.5, 30.2, 30.0, 29.5, 25.6, 24.8, 19.8 ppm. Purity:
99% UPLCMS (210 nm); retention time 0.84 min; (M+1) 365.0. Anal.
Calcd. for C.sub.23H.sub.28N.sub.2O.sub.2.0.29 (CHCl.sub.3): C,
70.02; H, 7.14; N, 7.01. Found: C, 70.02; H, 7.37; N, 6.84.
Example 30
1-azabicyclo[2.2.2]oct-3-yl
{2-[3-(2-methylpropyl)phenyl]propan-2-yl}carbamate
[0544] Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl
[2-(3-bromophenyl)propan-2-yl]carbamate (75 mg, 0.20 mmol),
2-methylpropyl boronic acid (28.1 mg, 0.276 mmol) and palladium
(II) acetate gave the title compound as a white solid (50 mg, 71%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.21 (d, J=4.9 Hz, 2H),
7.16 (s, 1H), 7.00 (s, 1H), 5.17 (s, 1H), 4.60 (s, 1H), 3.35-2.10
(m, 6H), 2.45 (d, J=7.1 Hz, 2H), 1.82 (dt, J=6.8, 13.5 Hz, 1H),
2.03-0.94 (m, 5H), 1.65 (s, 6H), 0.89 (d, J=6.6 Hz, 6H) ppm.
.sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 172.6, 172.1, 170.8,
170.2, 160.1, 160.0, 157.8, 157.7, 140.4, 139.8, 130.5, 130.4,
130.0, 129.8, 129.5, 129.3, 127.9, 127.7, 120.8, 120.7, 120.3,
113.9, 113.6, 113.2, 113.0, 110.5, 110.4, 66.6, 66.5, 56.8, 56.3,
55.4, 55.4, 54.0, 53.7, 51.1, 46.6, 43.8, 43.7, 42.0, 38.4, 37.8,
37.7, 33.8, 33.2, 27.4, 27.0, 25.7, 25.5, 20.9, 20.9 ppm. Purity:
90% UPLCMS (210 nm); retention time 0.89 min; (M+1) 345.
Example 31
1-azabicyclo[2.2.2]oct-3-yl
[2-(5-bromo-2-fluorophenyl)propan-2-yl]carbamate
[0545] Using general procedure A,
2-(5-bromo-2-fluorophenyl)propan-2-amine hydrochloride (100 mg,
0.372 mmol) and quinuclidin-3-ol gave the title compound as a white
solid (90.3 mg, 98%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.45 (dd, J=2.3, 7.3 Hz, 1H), 7.31 (ddd, J=2.5, 4.2, 8.6 Hz, 1H),
6.88 (dd, J=8.6, 11.9 Hz, 1H), 5.38 (s, 1H), 4.82-4.33 (m, 1H),
3.28-2.28 (m, 6H), 1.68 (d, J=9.0 Hz, 6H), 1.98-1.27 (m, 5H) ppm.
.sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 161.1, 158.6, 131.7,
131.6, 131.0, 131.0, 118.6, 118.3, 116.8, 55.8, 54.0, 47.6, 46.7,
28.5, 25.6, 24.8, 19.7 ppm. Purity: 100% UPLCMS (210 nm); retention
time 0.81 min; (M+1) 386.7. Anal. Calcd. for
C.sub.17H.sub.22BrEN.sub.2O.sub.2.0.37 (CHCl.sub.3): C, 52.20; H,
5.66; N, 7.14. Found: C, 52.21; H, 5.57; N, 7.13.
Example 32
1-azabicyclo[2.2.2]oct-3-yl
[2-(4'-fluorobiphenyl-3-yl)propan-2-yl]carbamate
[0546] Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl
[2-(3-bromophenyl)propan-2-yl]carbamate (600 mg, 1.63 mmol),
4-fluorophenyl boronic acid (457 mg, 3.27 mmol) and palladium (II)
acetate gave the title compound as a white solid (373 mg, 60%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.56 (s, 1H), 7.52 (dd,
J=5.4, 8.4 Hz, 2H), 7.42-7.38 (m, 3H), 7.12 (m, 2H), 5.18 (s, 1H),
4.62 (s, 1H), 2.66 (m, 6H), 1.72 (s, 6H), 2.01-0.83 (m, 5H) ppm.
.sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 125.0, 124.0, 123.8,
116.0, 116.0, 71.3, 55.9, 55.5, 47.6, 46.7, 29.6, 25.6, 24.8, 19.8
ppm. Purity: 98.0% UPLCMS (210 nm); retention time 0.95 min; (M+1)
382.9. Anal. Calcd. for C.sub.23H.sub.27FN.sub.2O.sub.2.0.37
(CHCl.sub.3): C, 65.86; H, 6.47; N, 6.57. Found: C, 65.85; H, 6.69;
N, 6.49.
Example 33
1-azabicyclo[2.2.2]oct-3-yl
[2-(4-fluorobiphenyl-3-yl)propan-2-yl]carbamate
[0547] Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl
[2-(5-bromo-2-fluorophenyl)propan-2-yl]carbamate (990 mg, 2.57
mmol), phenylboronic acid (209 mg, 1.71 mmol) and palladium (11)
acetate gave the title compound as a white solid (257 mg, 26%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.58-7.49 (m, 3H),
7.44-7.38 (m, 3H), 7.35-7.29 (m, 1H), 7.08 (dd, J=8.4, 12.1 Hz,
1H), 5.30 (s, 1H), 4.75-4.42 (m, 1H), 2.89 (d, J=10.2 Hz, 6H),
1.81-1.66 (m, 6H), 2.04-1.18 (m, 5H) ppm. .sup.13C NMR (100 MHz,
CDCl.sub.3) .delta. 161.7, 159.3, 140.7, 137.3, 137.3, 131.7,
131.7, 131.0, 129.0, 127.5, 127.3, 126.7, 117.1, 116.9, 71.4, 55.8,
54.3, 47.6, 46.7, 28.6, 25.6, 24.8, 19.8 ppm. Purity: 92.0% UPLCMS
(210 nm); retention time 0.95 min; (M+1) 382.9. Anal. Calcd. for
C.sub.23H.sub.27FN.sub.2O.sub.2.0.4 (CHCl.sub.3): C, 65.39; H,
6.43; N, 6.52. Found: C, 65.39; H, 6.51; N, 6.42.
Example 34
1-azabicyclo[2.2.2]oct-3-yl
{2-[2-fluoro-5-(2-methylpropyl)phenyl]propan-2-yl}carbamate
[0548] Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl
[2-(5-bromo-2-fluorophenyl)propan-2-yl]carbamate (120 mg, 0.312
mmol), 2-methylpropylboronic acid (79.4 mg, 0.779 mmol) and
palladium (II) acetate gave the title as a white solid compound (37
mg, 33%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.08 (dd,
J=2.0, 8.2 Hz, 1H), 6.95 (d, J=4.9 Hz, 1H), 6.93-6.85 (m, 1H), 5.23
(s, 1H), 4.72-4.52 (m, 1H), 3.20-2.47 (m, 6H), 2.41 (d, J=7.1 Hz,
2H), 1.89-1.76 (m, 1H), 2.02-1.26 (m, 5H), 1.70 (d, J=7.6 Hz, 6H),
0.88 (d, J=6.6 Hz, 6H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3)
.delta. 160.4, 158.0, 137.1, 137.1, 129.2, 129.1, 128.1, 116.2,
116.0, 71.2, 55.8, 54.2, 47.6, 46.7, 45.1, 30.5, 29.9, 28.6, 27.0,
25.6, 24.8, 22.5, 19.8, 19.5 ppm. Purity: 95.0% UPLCMS (210 nm);
retention time 1.02 min; (M+1) 363.
Example 35
1-azabicyclo[2.2.2]oct-3-yl
[2-(5-cyclopropyl-2-fluorophenyl)propan-2-yl]carbamate
[0549] Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl
[2-(5-bromo-2-fluorophenyl)propan-2-yl]carbamate (750 mg, 0.649
mmol), cyclopropylboronic acid (139 mg, 1.62 mmol) and palladium
(H) acetate gave the title compound as a white solid (727 mg, 86%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.08 (d, J=6.4 Hz, 1H),
6.97-6.78 (m, 2H), 5.19 (s, 1H), 4.65-4.57 (m, 1H), 2.66 (s, 6H),
1.85 (tt, J=5.1, 8.4 Hz, 1H), 2.00-1.17 (m, 5H), 1.71 (d, J=8.7 Hz,
6H), 0.92 (ddd, J=4.6, 6.3, 8.4 Hz, 2H), 0.62 (dt, J=4.7, 6.4 Hz,
2H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 160.2, 157.8,
139.2, 139.2, 125.6, 125.5, 125.4, 116.5, 116.3, 71.3, 55.8, 54.2,
47.6, 46.7, 29.9, 29.6, 28.6, 25.6, 24.8, 19.6, 15.2, 9.1 ppm.
Purity: 100% UPLCMS (210 nm); retention time 0.87 min; (M+1) 347.2.
Anal. Calcd. for C.sub.20H.sub.27FN.sub.2O.sub.2.0.07 (CHCl.sub.3):
C, 68.00; H., 7.70; N, 7.90. Found: C, 67.99; H, 7.86; N, 7.81.
Example 36
1-azabicyclo[2.2.2]oct-3-yl
[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate
[0550] Using general procedure A,
2-(3-bromo-4-fluorophenyl)propan-2-amine hydrochloride (1.00 g,
3.72 mmol) and quinuclidin-3-ol gave the title compound as a white
solid (434 mg, 30%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.57
(s, 1H), 7.38-7.25 (m, 1H), 7.06 (t, J=8.5 Hz, 1H), 5.62 (s, 1H),
4.86-4.32 (m, 1H), 3.33-2.12 (m, 6H), 1.73 (t, J=7.2 Hz, 5H), 1.61
(d, J=9.6 Hz, 6H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.
159.1, 156.7, 154.6, 130.4, 125.8, 125.7, 116.4, 116.2, 109.1,
108.9, 71.3, 55.7, 54.7, 47.4, 46.5, 29.9, 29.6, 25.5, 24.6, 22.9,
19.6 ppm. Purity: 100% UPLCMS (210 nm); retention time 0.79 min;
(M+1) 387.8. Anal. Calcd. for
C.sub.17H.sub.22BrFN.sub.2O.sub.2.0.27 (CHCl.sub.3): C, 49.68; H,
5.38; N, 6.71. Found: C, 49.67; H, 5.39; N, 6.74.
Example 37
1-azabicyclo[2.2.2]oct-3-yl
[2-(6-fluorobiphenyl-3-yl)propan-2-yl]carbamate
[0551] Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl
[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate (750 mg, 1.95
mmol), phenyl boronic acid (418 mg, 4.87 mmol) and palladium (II)
acetate gave the title compound as a white solid (195 mg, 29%). NMR
(400 MHz, CDCl.sub.3) .delta. 7.49 (s, 2H), 7.46-7.38 (m, 3H), 7.35
(dd, J=4.3, 11.7 Hz, 2H), 7.08 (dd, J=8.6, 10.1 Hz, 1H), 5.10 (s,
1H), 4.60 (s, 1H), 3.33-2.10 (m, 6H), 1.67 (d, J=7.9 Hz, 6H), 1.67
(m, 5H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 159.9,
157.4, 136.2, 129.3, 129.0, 128.7, 127.9, 127.6, 125.7, 125.6,
71.0, 66.1, 55.7, 55.1, 47.5, 46.6, 29.9, 29.6, 25.5, 24.5, 19.5,
15.5 ppm. Purity: 98% UPLCMS (210 nm); retention time 0.95 min;
(M+1) 382.9. Anal. Calcd. for C.sub.23H.sub.27FN.sub.2O.sub.2.0.29
(CHCl.sub.3): C, 67.08; H, 6.60; N, 6.72. Found: C, 67.09; H, 6.95;
N, 6.37.
Example 38
1-azabicyclo[2.2.2]oct-3-yl{2-[4-fluoro-3-(2-methylpropyl)phenyl]propan-2--
yl}carbamate
[0552] Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl
[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate (125 mg, 0.324
mmol), 2-methylpropylboronic acid (66 mg, 0.65 mmol) and palladium
(II) acetate gave the title compound as a white solid (27 mg, 23%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.23-7.11 (m, 2H),
7.04-6.82 (m, 1H), 5.11 (s, 1H), 4.59 (s, 1H), 3.32-2.12 (m, 6H),
2.48 (d, J=7.2 Hz, 2H), 1.86 (d, J=6.7, Hz, 1H), 2.05-0.96 (m, 5H),
1.62 (d, J=5.8 Hz, 6H), 0.90 (d, J=6.6 Hz, 6H) ppm. .sup.13C NMR
(100 MHz, CDCl.sub.3) .delta. 161.4, 159.0, 154.7, 142.5, 128.3,
124.0, 115.1, 114.9, 71.2, 66.1, 55.8, 55.0, 47.6, 46.7, 38.7,
29.9, 29.6, 25.6, 24.8, 22.6, 19.7, ppm. Purity: 85% UPLCMS (210
nm); retention time 1.0 min; (M+1) 362.9.
Example 39
1-azabicyclo[2.2.2]oct-3-yl
[2-(4',6-difluorobiphenyl-3-yl)propan-2-yl]carbamate
[0553] Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl
[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate (125 mg, 0.324
mmol), 4-fluoroboronic acid (64 mg, 0.46 mmol) and palladium (II)
acetate gave the title compound as a white solid (76 mg, 56%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.48 (t, 2H), 7.44-7.29
(m, 2H), 7.21-7.00 (m, 3H), 5.27 (s, 1H), 4.68-4.55 (m, 1H),
3.29-2.10 (m, 6H), 1.67 (d, J=9.4 Hz, 6H), 2.01-0.69 (m, 5H) ppm.
.sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 163.9, 161.4, 159.8,
157.3, 154.8, 143.5, 132.2, 130.9, 127.9, 127.8, 127.4, 125.9,
125.8, 116.2, 116.0, 115.7, 115.5, 71.4, 66.1, 55.9, 47.6, 46.7,
30.0, 39.7, 25.6, 24.8, 19.8 ppm. Purity: 98% UPLCMS (210 nm);
retention time 0.96 min; (M+1) 400.9.
Example 40
1-azabicyclo[2.2.2]oct-3-yl
{2-[4-fluoro-3-(pyrimidin-5-yl)phenyl]propan-2-yl}carbamate
[0554] Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl
[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate (150 mg, 0.389
mmol), pyrimidine-5-boronic acid (75.9 mg, 0.613 mmol) and
tris(dibenzylideneacetone)dipalladium(0) gave the title compound as
a white solid (49 mg, 31%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.22 (s, 1H), 8.92 (s, 2H), 7.55-7.41 (m, 2H), 7.19 (dd,
J=8.7, 9.9 Hz, 1H), 5.37 (s, 1H), 4.72-4.49 (m, 1H), 3.34-2.04 (m,
6H), 2.04-0.98 (m, 5H), 1.66 (t, J=10.9 Hz, 6H) ppm. .sup.13C NMR
(100 MHz, CDCl.sub.3) .delta. 159.9, 157.9, 157.4, 156.6, 154.7,
130.2, 127.85, 127.77, 126.9, 122.0, 121.8, 116.7, 116.5, 116.2,
71.6, 55.9, 54.9, 47.6, 46.7, 30.3, 29.6, 25.6, 24.8, 19.8 ppm.
Purity: 93% UPLCMS (210 nm); retention time 0.63 min; (M+1)
384.9
Example 41
1-azabicyclo[2.2.2]oct-3-yl
{2-[4-fluoro-3-(pyridin-3-yl)phenyl]propan-2-yl}carbamate
[0555] Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl
[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate (110 mg, 0.286
mmol), pyridine-3-boronic acid (53 mg, 0.43 mmol) and
tris(dibenzylideneacetone)dipalladium(0) gave the title compound as
a white solid (42 mg, 39%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.78 (s, 1H), 8.62 (d, J=3.5 Hz, 1H), 7.86 (s, 1H), 7.46
(d, J=7.2 Hz, 2H), 7.38 (dd, J=4.9, 7.9 Hz, 1H), 7.15 (dd, J=8.7,
9.9 Hz, 1H), 5.32 (s, 1H), 4.69-4.57 (m, 1H), 2.68 (s, 6H), 1.70
(d, J=11.3 Hz, 6H), 2.08-0.94 (m, 5H) ppm. .sup.13C NMR (100 MHz,
CDCl.sub.3) .delta. 160.0, 157.5, 149.9, 149.0, 136.6, 132.1,
127.3, 126.8, 126.7, 125.5, 125.3, 123.5, 116.4, 116.2, 71.5, 55.9,
55.0, 47.6, 46.7, 30.1, 29.66, 25.6, 24.8, 19.7 ppm. Purity: 100%
UPLCMS (210 nm); retention time 0.54 min; (M+1) 367.8.
Example 42
1-azabicyclo[2.2.2]oct-3-yl
{2-[4-fluoro-3-(furan-3-yl)phenyl]propan-2-yl}carbamate
[0556] Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl
[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate (110 mg, 0.296
mmol), furan-3-boronic acid (47.9 mg, 0.428 mmol) and
tris(dibenzylideneacetone)dipalladium(0) gave the title compound as
a white solid (47 mg, 44%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.88 (ddd, J=0.9, 1.5, 2.5 Hz, 1H), 7.53 (dd, J=2.5, 7.1
Hz, 1H), 7.50 (t, J=1.7 Hz, 1H), 7.31-7.23 (m, 1H), 7.08 (dd,
J=8.6, 10.6 Hz, 1H), 6.76 (dt, J=0.8, 1.7 Hz, 1H), 5.22 (s, 1H),
4.62 (s, 1H), 3.40-2.11 (m, 6H), 2.02-0.87 (m, 5H), 1.59 (dd,
J=11.6, 70.3 Hz, 6H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3)
.delta. 160.0, 157.5, 150.2, 143.9, 127.44, 127.36, 127.0, 126.1,
123.8, 116.6, 116.4, 71.5, 55.9, 55.0, 47.6, 46.7, 30.1, 29.9,
25.6, 24.8, 19.8 ppm. Purity: 96% UPLCMS (210 nm); retention time
0.85 min; (M+1) 372.9.
Example 43
1-azabicyclo[2.2.2]oct-3-yl
{2-[4-fluoro-3-(pyridin-4-yl)phenyl]propan-2-yl}carbamate
[0557] Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl
[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate (130 mg, 0.291
mmol), pyridine-4-boronic acid (54 mg, 0.43 mmol) and
tris(dibenzylideneacetone)dipalladium(0) gave the title compound as
a white solid (46 mg, 41%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.68 (dd, J=1.6, 4.5 Hz, 2H), 7.61-7.39 (m, 4H), 7.15 (dd,
J=8.6, 10.2 Hz, 1H), 5.31 (s, 1H), 4.69-4.57 (m, 1H), 3.40-2.07 (m,
6H), 1.69 (d, J=10.8 Hz, 6H), 2.06-0.74 (m, 5H) ppm. .sup.13C NMR
(100 MHz, CDCl.sub.3) .delta. 160.0, 157.6, 143.3, 141.6, 141.5,
126.7, 126.6, 124.9, 124.8, 120.1, 119.9, 116.1, 115.9, 115.4,
115.1, 109.2, 71.4, 55.9, 55.0, 47.6, 46.7, 29.9, 25.6, 24.8, 19.8
ppm. Purity: 97% UPLCMS (210 nm); retention time 0.82 min; (M+1)
384.6.
Example 44
1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(2-phenylpropan-2-yl)urea
[0558] Using general procedure C, quinuclidin-3-amine (102 mg, 0.6
mmol), CDI (1.31 mg, 0.789 mmol) and cumylamine (95 mg, 0.70 mmol)
gave the title compound as a white solid (21 mg, 10%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.61-7.47 (m, 2H), 7.44-7.37 (m, 2H),
7.34-7.28 (m, 1H), 4.86 (s, 1H), 4.20 (d, J=7.3 Hz, 1H), 3.71-3.60
(m, 1H), 3.14 (ddd, J=2.3, 9.4, 14.2 Hz, 1H), 2.79-1.89 (m, 6H),
1.64 (d, J=3.3 Hz, 6H), 1.58-1.10 (m, 5H) ppm. .sup.13C NMR (100
MHz, CDCl.sub.3) .delta. 157.4, 146.2, 129.3, 127.8, 125.8, 57.1,
54.9, 47.7, 47.1, 46.7, 30.6, 30.5, 26.0, 20.3 ppm. Purity: 79%
UPLCMS (210 nm); retention time 0.61 min; (M+1) 288.2.
Preparation O
Example 45
3-cyano-1-azabicyclo[2.2.2]oct-3-yl
{2-[3-(prop-1-en-2-yl)phenyl]propan-2-yl}carbamate
[0559] To a solution of 3-hydroxyquinuclidine-3-carbonitrile (38
mg, 0.25 mmol) in acetonitrile/dioxane (3 mL) at room temperature
was added triethylamine (7.0 uL, 0.05 mmol). The reaction mixture
was stirred for 15 min and
1-(2-isocyanatopropan-2-yl)-3-(prop-1-en-2-yl)benzene (49.0 uL,
0.248 mmol) was added dropwise. The reaction was stirred for a
period of 18 h at 65.degree. C. and concentrated. The crude
material was purified on a combiflash (SiO.sub.2 cartridge,
CHCl.sub.3 and 2N NH.sub.3 in MeOH) to afford the corresponding
carbamate as a clear oil (57 mg, 65%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.42-7.20 (s, 5H), 6.61 (s, 1H), 5.11 (s, 1H),
3.29 (d, 0.1=12.0 Hz, 1H), 3.09 (d, 0.1=12.0 Hz, 1H), 2.93 (d,
J=4.0 Hz, 2H), 2.79-2.68 (m, 2H), 2.13 (s, 6H) 2.05-2.00 (m, 2H),
1.91 (s, 3H), 1.87 (s, 2H), 1.50-1.37 (m, 2H) ppm. .sup.13C NMR
(100 MHz, CDCl.sub.3) .delta. 135.4, 128.7, 125.2, 124.5, 124.0,
122.0, 112.9, 61.2, 47.0, 46.2, 32.4, 31.8, 29.9, 29.4, 29.2, 26.6,
25.7, 23.7, 22.8, 22.2, 19.2 ppm. Purity: >99% UPLCMS (210 nm);
retention time 0.81 min; (M+1) 354.
Preparation P
Example 46
N-(2-(3-(prop-1-en-2-yl)phenyl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane--
4-carboxamide
[0560] To a solution of 1,4-diazabicyclo[3.2.2]nonane (350 mg, 2.77
mmol) and 1-(2-isocyanatopropan-2-yl)-3-(prop-1-en-2-yl)benzene
(1.09 mL, 5.55 mmol) in chloroform (2 mL) was added 3-4 pieces of
molecular sieves. The reaction mixture was stirred at room
temperature for 18 h and then concentrated. The crude material was
purified on a combiflash (SiO.sub.2 cartridge, CHCl.sub.3 and 2N
NH.sub.3 in MeOH) to afford the corresponding urea as an off-white
solid (650 mg, 36%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.48
(s, 1H), 7.31-7.26 (m, 3H), 5.34 (s, 1H), 5.07 (s, 1H), 4.73 (br s,
1H), 4.03 (BR s, 1H), 3.64 (m, 2H), 3.14-3.03 (m, 6H), 2.15 (s, 3H)
2.06 (m, 2H), 1.72 (m, 8H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3)
.delta. 155.7, 148.3, 143.8, 141.3, 128.5, 124.1, 123.9, 122.0,
112.5, 57.8, 55.8, 48.1, 46.4 (2.times.), 41.2, 30.2 (2.times.),
27.3 (2.times.), 22.1 ppm. Purity: >98% UPLCMS (210 nm);
retention time 0.71 min; (M+1) 328
Example 47
biphenyl-2-yl 1,4-diazabicyclo[3.2.2]nonane-4-carboxylate
[0561] Biphenyl-2-yl carbonochloridate (83.0 mg, 0.358 mmol) was
treated with 1,4-diazabicyclo[3.2.2] nonane (113 mg, 0.896 mmol)
using the same procedure reported in example 46 to afford the title
compound as an off-white solid (17 mg, 15%). Purity: >99% UPLCMS
(210 nm); retention time 0.75 min; (M+1) 323.
Example 48
N-{2-[3-(propan-2-yl)phenyl]propan-2-yl}-1,4-diazabicyclo[3.2.2]nonane-4-c-
arboxamide
[0562] Using general procedure F,
N-(2-(3-(prop-1-en-2-yl)phenyl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane-
-4-carboxamide (100 mg, 0.305 mmol) and palladium, (20 mg, 20 wt. %
on carbon) gave the title compound as an off-white solid (60 mg,
57%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.28-7.21 (m, 3H),
7.11 (d, J=8.0 Hz, 1H), 4.71 (s, 1H), 4.02 (s, 1H), 3.66 (t, J=8.0
Hz, 2H) 3.15 (m, 7H), 2.06 (br s, 2H), 1.77 (s, 7H) 1.26 (d, J=4.0
Hz, 6H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 155.8,
148.9, 148.5, 128.5.1, 124.7, 123.1, 122.4, 57.8, 56.0, 48.1, 46.4,
41.2, 34.5, 32.2, 30.4, 30.0, 29.9, 27.3, 24.3, 22.9 ppm. Purity:
>91% UPLCMS (210 nm); retention time 0.74 min; (M+1) 330.
Preparation Q
Example 49
(+/-)-(3S,4S)-1-azabicyclo[2.2.1]heptan-3-yl-2-(3-(prop-1-en-2-yl)phenyl)p-
ropan-2-ylcarbamate
[0563] To a solution of
(+/-)-(3S,4S)-1-azabicyclo[2.2.1]heptan-3-ol (294 mg, 2.6 mmol) in
THF (5 mL) at room temperature was added NaH [60%, oil] (107 mg,
2.67 mmol). The reaction mixture was stirred for 15 min and
1-(2-isocyanatopropan-2-yl)-3-(prop-1-en-2-yl)benzene (344 uL, 1.73
mmol) was added dropwise. The reaction was stirred for a period of
30 min and quenched with brine. The solution was extracted with
EtOAc and the organic layer was dried over Na.sub.2SO.sub.4 and
concentrated. The crude material was purified on a combiflash
(SiO.sub.2 cartridge, CHCl.sub.3 and 2N NH.sub.3 in MeOH) to afford
the corresponding carbamate as a clear oil (140 mg, 26%). .sup.1H
NMR (400 MHz, CDCl.sub.3) 7.26-7.20 (m, 3H), 7.11 (m, 1H), 5.18 (s,
1H), 5.19 (br s, 1H), 5.01 (s, 1H), 4.81 (br s, 1H), 2.99 (br s,
1H), 2.82 (br s, 1H), 2.70 (br s, 1H), 2.53 (br s, 2H), 2.33 (br s,
1H), 2.02 (s, 3H), 1.76 (br s, 1H) 1.61 (br s, 6H), 1.52 (br s,
1H), 1.37 (br s, 1H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3)
.delta. 147.1, 143.7, 141.5, 128.5, 124.1, 122.1, 112.7, 75.6,
60.6, 59.4, 55.4, 54.3, 53.9, 41.5, 29.9, 29.8, 29.4, 22.2, 21.6
ppm. Purity: >98% UPLCMS (210 nm); retention time 0.83 min;
(M+1) 315
Example 50
(+/-)-(3S,4S)-1-azabicyclo[2.2.1]hept-3-yl{2-[3-(propan-2-yl)phenyl]propan-
-2-yl}carbamate
[0564] Using general procedure F,
(+/-)-(3S,4S)-1-azabicyclo[2.2.1]heptan-3-yl
2-(3-(prop-1-en-2-yl)phenyl)propan-2-ylcarbamate (110 mg, 0.350
mmol) and palladium (20 mg, 20 wt. % on carbon) gave the title
compound as an off-white solid (36 mg, 46%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.25-7.19 (m, 3H), 7.11 (d, J=8.0 Hz, 1H), 5.19
(s, 1H), 4.91 (s, 1H), 3.44 (t, J=4.0 Hz, 2H) 3.19 (br s, 1H), 3.02
(br s, 1H), 2.89 (m, 2H), 2.69 (br s, 1H), 2.39 (br s, 1H), 1.91
(br s, 1H), 1.66 (br s, 7H) 1.26 (d, J=4.0 Hz, 6H) ppm. .sup.13C
NMR (100 MHz, CDCl.sub.3) .delta. 128.5 (2.times.), 124.8, 123.1
(2.times.), 122.4 (2.times.), 77.4, 60.6, 59.4, 55.5, 41.5, 34.5,
29.9, 29.9, 29.5, 24.3 (2.times.), 21.6 ppm. Purity: >95% UPLCMS
(210 nm); retention time 0.88 min; (M+1) 317.
Example 51
N-[2-(3-bromo-4-fluorophenyl)propan-2-yl]-1,4-diazabicyclo[3.2.2]nonane-4--
carboxamide
[0565] Using general procedure A,
2-(3-bromo-4-fluorophenyl)propan-2-amine hydrochloride (1.00 g,
3.72 mmol) and 1,4-diazabicyclo[3.2.2]nonane gave the title
compound as a white solid (265 mg, 18%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.54-7.52 (m, 1H), 7.31-7.25 (m, 1H), 7.04 (t,
J=8.0 Hz, 1H), 4.71 (s, 1H), 3.99 (br s, 1H), 3.59 (t, J=8.0 Hz,
2H), 3.13-2.95 (m, 6H), 2.04-1.97 (m, 2H) 1.77-1.67 (m, 2H), 1.65
(s, 6H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 158.9,
156.4, 155.4, 145.9, 130.2, 125.6, 116.2, 57.8, 54.9, 48.3, 46.6,
46.6, 41.6, 30.5, 30.5, 27.6, 27.6 ppm. Purity: >99% UPLCMS (210
nm); retention time 0.73 min; (M+1) 384.
Example 52
N-[2-(6-fluorobiphenyl-3-yl)propan-2-yl]-1,4-diazabicyclo[3.2.2]nonane-4-c-
arboxamide
[0566] Using general procedure E,
N-[2-(3-bromo-4-fluorophenyl)propan-2-yl]-1,4-diazabicyclo[3.2.2]nonane-4-
-carboxamide (100 mg, 0.261 mmol), phenylboronic acid (79 mg, 0.65
mmol) and palladium (II) acetate gave the title compound as an
off-white solid (66 mg, 66%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.54 (m, 2H), 7.44-7.40 (m, 5H), 7.08 (m, 1H), 4.78 (br s,
1H), 4.00 (br s, 1H), 3.60 (m, 2H), 3.11-2.92 (m, 6H), 2.00 (m, 2H)
1.67 (m, 7H), 1.26 (s, 1H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3)
.delta. 159.6, 155.6, 144.6, 136.5, 129.3, 128.6, 128.5, 127.8,
127.5, 125.7, 125.6, 116.1, 115.9, 57.9, 55.3, 48.2, 46.4, 46.4,
41.6, 30.6, 30.5, 29.9, 27.6 ppm. Purity: >99% UPLCMS (210 nm);
retention time 0.88 min; (M+1) 382.
Example 53
N-[2-(4',6-difluorobiphenyl-3-yl)propan-2-yl]-1,4-diazabicyclo[3.2.2]nonan-
e-4-carboxamide
[0567] Using general procedure E,
N-[2-(3-bromo-4-fluorophenyl)propan-2-yl]-1,4-diazabicyclo[3.2.2]nonane-4-
-carboxamide (100 mg, 0.261 mmol), 4-fluorophenyl boronic acid (91
mg, 0.65 mmol) and palladium (11) acetate gave the title compound
as an off-white solid (64 mg, 62%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.48 (m, 2H), 7.37-7.30 (m, 2H), 7.10-7.03 (m,
3H), 4.77 (s, 1H), 3.99 (br s, 1H), 3.58 (m, 2H), 3.10-2.90 (m,
6H), 1.98 (m, 2H) 1.71 (m, 8H) ppm. .sup.13C NMR (100 MHz,
CDCl.sub.3) .delta. 163.7, 161.3, 159.5, 157.1, 155.6, 144.6,
131.0, 130.9, 127.4, 127.2, 125.7, 116.1, 115.6, 57.9, 55.2, 48.2,
46.4, 46.4, 41.5, 30.6, 30.6, 27.6, 27.6 ppm. Purity: >99%
UPLCMS (210 nm); retention time 0.90 min; (M+1) 400.
Example 54
N-[2-(naphthalen-1-yl)propan-2-yl]-1,4-diazabicyclo[3.2.2]nonane-4-carboxa-
mide
[0568] Using general procedure A, 2-(naphthalen-1-yl)propan-2-amine
hydrochloride (227 mg, 1.23 mmol) and 1,4-diazabicyclo[3.2.2]nonane
gave the title compound as a white solid (206 mg, 50%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.63-8.60 (m, 1H), 7.90-7.87 (m, 1H),
7.78 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.47-7.42 (m, 3H),
4.86 (s, 1H), 3.94 (br s, 1H), 3.61 (m, 2H), 3.11-2.88 (m, 7H),
2.01-1.91 (m, 7H), 1.68-1.62 (m, 2H) ppm. .sup.13C NMR (100 MHz,
CDCl.sub.3) .delta. 176.2, 155.5, 142.6, 135.3, 130.6, 129.9,
128.8, 126.3, 125.4, 125.2, 123.9, 57.3, 57.1, 47.7, 45.8, 45.8,
40.7, 29.4, 29.4, 26.9, 26.9 ppm. Purity: >99% UPLCMS (210 nm);
retention time 0.72 min; (M+1) 338.
Example 55
N-(2-(5-bromo-2-fluorophenyl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane-4--
carboxamide
[0569] Using general procedure A,
2-(5-bromo-2-fluorophenyl)propan-2-amine hydrochloride (100 mg,
0.372 mmol) and 1,4-diazabicyclo[3.2.2]nonane gave the title
compound as a white solid (70 mg, 49%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.48 (m, 1H), 7.28 (m, 1H), 6.86 (m, 1H), 4.85
(s, 1H), 3.98 (br s, 1H), 3.56 (m, 2H), 3.14-2.91 (m, 7H), 1.99 (m,
2H) 1.71 (m, 7H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.
161.1, 158.6, 155.7, 131.3, 113.1, 118.3, 118.0 57.8, 54.0, 48.1,
46.4, 46.4, 41.5, 29.1, 29.1, 27.5, 27.5 ppm. Purity: >99%
UPLCMS (210 nm); retention time 0.73 min; (M+1) 384.
Example 56
N-[2-(4-fluorobiphenyl-3-yl)propan-2-yl]-1,4-diazabicyclo[3.2.2]nonane-4-c-
arboxamide
[0570] Using general procedure E,
N-(2-(5-bromo-2-fluorophenyl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane-4-
-carboxamide (100 mg, 0.261 mmol), phenyl boronic acid (30 mg, 0.25
mmol) and palladium (II) acetate gave the title compound as an
off-white solid (27 mg, 39%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.56-7.51 (m, 3H), 7.41-7.37 (m, 3H), 7.32-7.30 (m, 1H),
7.03 (m, 1H), 4.90 (s, 1H), 4.00 (br s, 1H), 3.59 (m, 2H),
3.11-2.92 (m, 6H), 2.04-1.98 (m, 2H) 1.78 (s, 6H), 1.73-1.67 (m,
2H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 161.8, 159.4,
155.9, 140.9, 137.2, 134.6, 128.9, 127.4, 127.3, 127.2, 127.1,
127.0, 116.9, 57.9, 54.4, 48.1, 46.5, 46.5, 41.4, 29.9, 29.3, 27.5,
27.5 ppm. Purity: >99% UPLCMS (210 nm); retention time 0.90 min;
(M+1) 400.
Example 57
N-(2-(3-isopropoxyphenyl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane-4-carb-
oxamide
[0571] Using general procedure A,
2-(3-isopropoxyphenyl)propan-2-amine hydrochloride (60 mg, 0.31
mmol) and 1,4-diazabicyclo[3.2.2]nonane gave the title compound as
a white solid (70 mg, 57%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.17 (t, J=8.0 Hz, 1H), 6.92-6.87 (m, 2H), 6.69 (d, J=8.0
Hz, 1H) 4.66 (br s, 1H), 4.48 (m, 1H), 3.94 (br s, 1H) 3.56 (m,
2H), 3.08-2.90 (m, 514), 1.96 (m, 2H) 1.69-1.60 (m, 7H), 1.27 (d,
J=8.0 Hz, 6H), 1.17 (br s, 2H) ppm. .sup.13C NMR (100 MHz,
CDCl.sub.3) .delta. 158.0, 155.7, 150.3, 129.4, 117.1, 113.4,
113.1, 77.5, 69.8, 55.7, 48.2, 46.4, 46.4, 46.3, 41.5, 30.3, 30.0,
29.9, 27.6, 22.3 ppm. Purity: >99% UPLCMS (210 nm); retention
time 0.75 min; (M+1) 346.
Example 58
N-(biphenyl-3-yl)-1,4-diazabicyclo[3.2.2]nonane-4-carboxamide
[0572] Using general procedure A, biphenyl-3-amine (100 mg, 0.592
mmol) and 1,4-diazabicyclo[3.2.2]nonane gave the title compound as
an off white solid (93 mg, 49%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.60 (m, 1H), 7.56-53 (m, 2H), 7.39-7.21 (m, 6H), 6.67 (br
s, 1H), 4.85 (s, 1H), 4.16 (br s, 1H), 3.66-3.61 (m, 2H), 3.07-2.86
(m, 6H), 1.97 (m, 2H) 1.68 (m, 2H) ppm. .sup.13C NMR (100 MHz,
CDCl.sub.3) .delta. 154.7, 142.0, 141.1, 139.9, 129.3, 128.8,
128.8, 127.5, 127.3, 127.3, 122.0, 119.4, 119.2, 57.5, 48.4, 46.3,
46.3, 42.1, 27.5, 27.5 ppm. Purity: >96% UPLCMS (210 nm);
retention time 0.75 min; (M+1) 333.
Example 59
N-{2-[2-fluoro-5-(2-methylpropyl)phenyl]propan-2-yl}-1,4-diazabicyclo[3.2.-
2]nonane-4-carboxamide
[0573] Using general procedure E,
N-(2-(5-bromo-2-fluorophenyl)propan-2-yl)-1,4-diazabicyclo
[0574] [3.2.2]nonane-4-carboxamide (100 mg, 0.261 mmol), with
isopropyl boronic acid (66 mg, 0.65 mmol) and palladium (ID acetate
gave the title compound as an off-white solid (27 mg, 39%). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.08 (d, J=8.0 Hz, 1H), 6.93-6.81
(m, 2H), 4.85 (s, 1H), 3.96 (br s, 1H), 3.65 (q, J=8.0 Hz, 1H),
3.55 (t, J=8.0 Hz, 2H), 3.09-2.90 (m, 5H), 2.40 (d, J=4.0 Hz, 1H),
2.01-1.92 (m, 2H) 1.81-1.61 (m, 8H), 1.22-1.17 (m, 2H), 0.87 (d,
J=8.0 Hz, 6H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.
160.5, 158.0, 155.9, 137.0, 133.6, 128.8, 116.0, 57.9, 54.3, 48.1,
46.4 (2.times.), 45.2, 41.4, 30.5, 29.9, 29.2, 29.2, 27.5, 22.6,
22.6 ppm. Purity: >99% UPLCMS (210 nm); retention time 0.94 min;
(M+1) 362.
Example 60
N-(biphenyl-2-yl)-1,4-diazabicyclo[3.2.2]nonane-4-carboxamide
[0575] Using general procedure A, 1-isocyanatobiphenyl (50 mg, 0.26
mmol) and 1,4-diazabicyclo[3.2.2]nonane gave the title compound as
a white solid (55 mg, 65%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.15 (d, J=8.0 Hz, 1H), 7.45-7.31 (m, 6H), 7.16 (d, J=8.0
Hz, 1H), 7.04 (t, J=8.0 Hz, 1H), 6.47 (br s, 1H), 3.63 (br s, 1H),
3.57 (t, J=8.0 Hz, 2H), 3.00-2.80 (m, 6H), 1.68 (m, 2H) 1.43 (m,
2H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 154.2, 138.9,
136.6, 131.7, 129.7, 129.5, 129.5, 129.3, 129.3, 128.7, 128.1,
122.6, 120.5, 57.6, 48.5, 46.2, 46.2, 41.6, 29.9, 27.3 ppm. Purity:
>99% UPLCMS (210 nm); retention time 0.64 min; (M+1) 322.
Example 61
N-(naphthalen-1-yl)-1,4-diazabicyclo[3.2.2]nonane-4-carboxamide
[0576] Using general procedure A, 1-isocyanatonaphthalene (208 mg,
1.23 mmol) and 1,4-diazabicyclo[3.2.2]nonane gave the title
compound as a white solid (150 mg, 48%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.80-7.72 (m, 2H), 7.64 (d, J=8.0 Hz, 1H), 7.56
(d, J=8.0 Hz, 1H), 7.44-7.35 (m, 3H), 6.65 (br s, 1H), 4.18 (br s,
1H), 3.64 (t, J=8.0 Hz, 2H), 3.09-2.91 (m, 6H), 2.08-1.93 (m, 2H)
1.74-1.66 (m, 2H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.
155.3, 134.4, 134.3, 128.9, 128.2, 126.2, 126.1, 126.0, 125.1,
121.2, 121.0, 57.6, 48.7, 46.4, 46.4, 42.2, 27.6, 27.6 ppm. Purity:
>99% UPLCMS (210 nm); retention time 0.53 min; (M+1) 296.
Example 62
(S)-quinuclidin-3-yl 2-(biphenyl-4-yl)propan-2-ylcarbamate
[0577] Using general procedure B, bromobenzonitrile (2.00 g, 11.0
mmol) was converted to the corresponding
2-(4-bromophenyl)propan-2-amine (1.20 g, 51%) as a brown oil.
[0578] Using general procedure A, 2-(4-bromophenyl)propan-2-amine
(1.0 g, 4.7 mmol) and (S)-quinuclidin-3-ol gave
(S)-quinuclidin-3-yl 2-(4-bromophenyl)propan-2-ylcarbamate (1.0 g,
58%) as a brown oil.
[0579] Using general procedure E, the above bromide (200 mg, 0.540
mmol), phenylboronic acid (133 mg, 1.10 mmol) and
[PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 gave the title compound as a
white solid (70 mg, 35%). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
7.60-7.53 (m, 4H), 7.47 (d, J=8.5 Hz, 2H), 7.42 (t, J=7.5 Hz, 2H),
7.33 (t, J=7.5 Hz, 1H), 5.26 (br s, 1H), 4.64 (m, 1H), 3.33-3.15
(m, 1H), 3.10-2.45 (m, 5H), 2.40-1.80 (m, 2H), 1.78-1.58 (m, 7H),
1.55-1.33 (m, 2H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3) .delta.
154.5, 146.1, 140.8, 139.5, 128.7, 127.2, 127.1, 127.1, 125.2,
70.9, 55.5, 55.1, 47.4, 46.4, 31.1, 29.5, 25.3, 24.5, 19.5 ppm.
Purity: 100% LCMS (214 nm & 254 nm); retention time 1.56 min;
(M+1) 365.
Example 63
quinuclidin-3-yl
2-(4-(pyrimidin-5-yl)phenyl)propan-2-ylcarbamate
[0580] Using general procedure E, quinuclidin-3-yl
2-(4-bromophenyl)propan-2-ylcarbamate (200 mg, 0.540 mmol),
pyrimidin-5-ylboronic acid (136 mg, 1.12 mmol) and
[PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 gave the title compound as a
white solid (80 mg, 40%). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
9.17 (s, 1H), 8.92 (s, 2H), 7.58-7.51 (m, 4H), 5.34 (s, 1H), 4.61
(m, 1H), 3.20-3.10 (m, 1H), 2.92-2.41 (m, 5H), 2.00-1.76 (m, 2H),
1.72-1.53 (m, 7H), 1.52-1.32 (m, 2H) ppm. .sup.13C NMR (125 MHz,
CDCl.sub.3) .delta. 157.4, 154.8, 154.5, 148.2, 134.0, 132.5,
127.0, 126.0, 71.2, 55.6, 55.0, 47.4, 46.3, 29.7, 29.4, 25.4, 24.5,
19.5 ppm. Purity: >96% LCMS (214 nm & 254 nm); retention
time 1.34 min; (M+1) 366.
Example 64
quinuclidin-3-yl 1-(biphenyl-4-yl)cyclopropylcarbamate
[0581] Using general procedure G, bromobenzonitrile (3.00 g, 16.5
mmol) was converted to the corresponding
1-(4-bromophenyl)cyclopropanamine (1.80 g, 51%) as a yellow
solid.
[0582] Using general procedure A, 1-(4-bromophenyl)cyclopropanamine
(1.0 g, 4.7 mmol) and quinuclidin-3-ol gave quinuclidin-3-yl
1-(4-bromophenyl)cyclopropyl-carbamate (1.3 g, 75%) as a white
semi-solid.
[0583] Using general procedure E, the above carbamate (400 mg, 1.12
mmol), phenylboronic acid (267 mg, 2.22 mmol) and
[PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 the title compound as a viscous
oil (100 mg, 25%). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.47
(d, J=7.5 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.33 (t, J=7.5 Hz, 2H),
7.26-7.15 (m, 3H), 5.93 (br s, 0.6H), 5.89 (br s, 0.4H), 4.67 (m,
1H), 3.20-3.06 (m, 1H), 2.88-2.42 (m, 5H), 1.98-1.08 (m, 9H) ppm.
.sup.13C NMR (125 MHz, CDCl.sub.3) .delta. 155.0, 141.0, 139.7,
138.2, 127.7, 126.1, 126.0, 124.8, 124.1, 70.0, 54.5, 46.3, 45.4,
34.1, 24.3, 23.2, 18.3, 17.0 ppm. Purity: 100% LCMC (214 nm &
254 nm); retention time 1.52 min; (M+1) 363.
Preparation R
Example 65
quinuclidin-3-yl 1-(4-(pyridin-2-yl)phenyl)cyclopropylcarbamate
[0584] To a solution of quinuclidin-3-yl
1-(4-bromophenyl)cyclopropylcarbamate (870 mg, 2.43 mmol) in 30 mL
1,4-dioxane, was added bis(pinacolato)diboron (1.81 g, 7.22 mmol),
CH.sub.3COOK (2.10 g, 21.4 mmol), and
[PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 (97 mg, 0.12 mmol). The mixture
was stirred at 80.degree. C. for 18 h. The solvent was evaporated
and the residue was extracted with EtOAc. The extracts were
concentrated and purified by silica gel column chromatography
(eluting with EtOAc/methanol from 20/1 to 10/1, containing 1% of
TEA) to give quinuclidin-3-yl
1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropylcarba-
mate (260 mg, 33%) as a brown semi-solid.
[0585] Using general procedure E, the above boronate (260 mg, 0.632
mmol), 2-bromopyridine (149 mg, 0.941 mmol) and Pd.sub.2(dba).sub.3
(32.0 mg, 0.036 mmol) gave the title as a white semi-solid compound
(70 mg, 31%). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.58 (d,
J=4.5 Hz, 1H), 7.82 (d, J=7.0 Hz, 2H), 7.66-7.57 (m, 2H), 7.23-7.15
(m, 2H), 7.11 (t, J=5.0 Hz, 1H), 6.16 (br s, 0.6H), 5.97 (br s,
0.4H), 4.63 (m, 1H), 3.17-3.02 (m, 1H), 2.90-2.38 (m, 5H),
1.90-1.10 (m, 9H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3) .delta.
156.1, 155.2, 148.6, 143.0, 136.3, 135.7, 125.9, 124.5, 120.9,
119.4, 70.3, 54.6, 46.3, 45.4, 34.1, 24.4, 23.5, 18.5, 17.3 ppm.
Purity: 100% LCMS (214 nm & 254 nm); retention time 1.18 (M+H)
364.
Example 66
quinuclidin-3-yl
1-(4-(pyrimidin-5-yl)phenyl)cyclopropylcarbamate
[0586] Using general procedure E, the above quinuclidin-3-yl
1-(4-bromophenyl)cyclopropyl-carbamate (400 mg, 1.10 mmol),
pyrimidin-5-ylboronic acid (204 mg, 1.64 mmol) and
[PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 gave the title compound as a
viscous oil (110 mg, 28%). .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. (s, 1H), .quadrature..quadrature..quadrature. (s, 2H), 7.44
(d, J=8.5 Hz, 2H), 7.33-7.25 (m, 2H), 6.02 (br s, 0.7H), 6.02 (br
s, 0.3H), 4.65 (m, 1H), 3.20-3.05 (m, 1H), 2.86-2.40 (m, 5H),
1.98-1.12 (m, 9H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3) 156.3,
155.1, 153.7, 143.3, 132.9, 131.1, 126.0, 125.3, 70.5, 54.7, 46.4,
45.4, 34.1, 24.4, 23.5, 18.5, 17.5 ppm. Purity: 100% LCMS (214 nm
& 254 nm); retention time 1.29 min; (M+1) 365.
Example 67
(S)-quinuclidin-3-yl
1-(4'-fluorobiphenyl-4-yl)cyclopropylcarbamate
[0587] Using general procedure E, (S)-quinuclidin-3-yl
1-(4-bromophenyl)cyclopropyl carbamate, 4-F-phenylboronic acid and
[PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 gave the title compound as a
white solid (45%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.06-7.83 (d, 1H), 7.69-7.66 (m, 2H), 7.59-7.55 (m, 2H), 7.29-7.22
(m, 4H), 4.56-4.54 (m, 1H), 3.13-2.32 (m, 6H), 1.91-1.19 (m, 9H)
ppm. .sup.13C NMR (125 MHz, DMSO-d.sub.6) .delta. 163.2, 161.2,
156.4, 143.7, 136.9, 128.9, 128.8, 126.8, 125.6, 116.2, 116.0,
70.7, 55.8, 47.4, 46.4, 34.8, 25.7, 24.6, 19.6, 18.7, 18.6 ppm.
Purity: >97% LCMS (214 nm & 254 nm); retention time 1.96
min; (M+1) 381.2.
Example 68
1-azabicyclo[3.2.2] nonan-4-yl 1-(4'-fluorobiphenyl-4-yl)
cyclopropylcarbamate
[0588] Using general procedure E, 1-azabicyclo[3.2.2]nonan-4-yl
1-(4-bromophenyl)-cyclopropyl carbamate, 4-F-phenylboronic acid and
[PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 gave the title compound as a
white solid (27%). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
7.52-7.48 (m, 4H), 7.33-7.28 (m, 2H), 7.14-7.11 (t, J=8.5 Hz, 2H),
5.47-5.33 (d, 1H), 4.93-4.89 (m, 1H), 3.15-2.75 (m, 6H), 2.10-0.88
(m, 11H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3) .delta. 163.4,
161.4, 155.7, 142.1, 138.3, 136.9, 128.5, 128.5, 127.0, 125.9,
125.4, 115.7, 115.5, 78.8, 51.7, 48.3, 44.9, 35.2, 33.7, 30.6,
29.7, 24.8, 22.2, 18.1 ppm. Purity: >99% LCMS (214 nm & 254
nm); retention time 1.56 min; (M+1) 395.2.
Example 69
(S)-quinuclidin-3-yl
1-(4-(5-fluoropyridin-2-yl)phenyl)cyclopropylcarbamate
[0589] Using general procedure E, (S)-quinuclidin-3-yl
(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)phenyl)cyclopropyl)ca-
rbamate, 2-bromo-5-fluoropyridine and
[PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 gave the title compound as a
white solid (34%). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
8.51-8.52 (d, J=3.5 Hz, 1H), 7.87-7.85 (d, J=10.5 Hz, 2H),
7.69-7.67 (m, 1H), 7.47-7.42 (m, 1H), 7.32-7.27 (m, 2H), 5.79-5.66
(d, 1H), 4.73-4.71 (t, J=5.0 Hz, 1H), 3.22-3.19 (m, 1H), 2.87-2.61
(m, 5H), 2.01-1.22 (m, 9H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3)
.delta. 160.8, 157.4, 156.1, 153.5, 144.4, 137.8, 136.3, 126.7,
125.7, 124.9, 123.6, 121.1, 71.6, 55.7, 47.4, 46.5, 35.3, 29.7,
25.4, 24.8, 19.4, 18.2 ppm. Purity: >99% LCMS (214 nm & 254
nm); retention time 1.41 min; (M+1) 382.2.
Preparation S
Example 70
(S)-1-(1-(4'-fluorobiphenyl-4-yl)cyclopropyl)-3-(3-methylquinuclidin-3-yl)-
urea
[0590] In a three-necked round-bottomed flask fitted with two
pressure-equalizing addition funnels and a rubber tube connected
with a gas flowmeter, a suspension of
1-(4'-fluoro-[1,1'-biphenyl]-4-yl)cyclopropanamine (1.50 g, 7.07
mmol) in a mixture of 20 mL of water and 1 mL of conc. HCl was
stirred for 10 min. Toluene (10 mL) was added and the solution was
maintained under vigorous stirring and cooled down to 0.degree. C.
A solution of triphosgene (3.10 g, 10.6 mmol) in 20 mL of toluene
and 40 mL of saturated aqueous NaHCO.sub.3 was added dropwise over
1 h period. The reactional mixture was stirred for an additional 30
min. The stirring was stopped and the upper toluene layer was then
separated out, dried (Na.sub.2SO.sub.4) and concentrated to afford
the corresponding isocyanate which is used in the next step without
further purification.
[0591] To a solution of the above isocyanate (134 mg, 0.571 mmol)
in 15 mL of toluene was added (S)-3-methylquinuclidin-3-amine (80
mg, 0.57 mmol). The resulting mixture was heated at reflux
overnight, cooled to ambient temperature and concentrated in vacuo
to give a residue, which was purified by reverse phase
chromatography on a combiflash (0-20% MeCN in water) to afford the
title compound as a white solid (73 mg, 33%). .sup.1H NMR (500 MHz
CDCl.sub.3) .delta. 7.52-7.48 (m, 4H), 7.27-7.25 (d, J=10.0 Hz,
2H), 7.13-7.09 (m, 2H), 5.39 (s, 1H), 4.78 (s, 1H), 2.95-2.71 (m,
5H), 2.65-2.64 (m, 1H), 1.94-1.93 (m, 1H), 1.69-1.68 (m, 1H),
1.46-1.38 (m, 5H), 1.36-1.33 (m, 4H), 1.26-1.23 (m, 1H) ppm.
.sup.13C NMR (125 MHz CDCl.sub.3) .delta. 163.5, 161.5, 157.5,
141.5, 138.5, 136.6, 136.6, 128.5, 128.4, 127.2, 124.7, 115.8,
115.6, 63.8, 52.3, 46.6, 46.3, 34.9, 31.0, 25.0, 23.2, 22.5, 20.2,
20.0 ppm. Purity: >99% LCMS (214 nm & 254 nm); retention
time 1.51 min; (M+H.sup.+) 394.2.
Example 71
(S)-1-azabicyclo[2.2.2]oct-3-yl
[1-(2',4'-difluorobiphenyl-4-yl)cyclopropyl]carbamate
[0592] Using general procedure E, (S)-quinuclidin-3-yl
1-(4-bromophenyl)cyclopropylcarbamate (0.446 g, 1.22 mmol),
2,4-difluorophenyl boronic acid (0.386 g, 2.44 mmol) and
Pd(OAc).sub.2 (0.015 g, 0.067 mmol) gave the title compound as a
tan solid (0.111 g, 23%). .sup.1H NMR (CDCl.sub.3) .delta. 7.43
(dd, J=8.4, 1.6 Hz, 2H), 7.40-7.33 (m, 1H), 7.31 (d, J=7.7 Hz, 2H),
6.99-6.81 (m, 2H), 5.54 (d, J=48.0 Hz, 1H), 4.82-4.65 (m, 1H),
3.30-3.07 (m, 1H), 2.98-2.44 (m, 5H), 1.97 (d, J=32.7 Hz, 1H), 1.83
(d, J=10.3 Hz, 1H), 1.64 (s, 1H), 1.52 (s, 1H), 1.39 (s, 1H), 1.31
(d, J=6.8 Hz, 4H) ppm. .sup.13C NMR major rotomer (CDCl.sub.3)
.delta. 162.2 (dd, J=12.8, 249.1 Hz), 159.8 (dd, J=11.8, 251.0 Hz),
156.9, 156.0, 142.6, 133.1, 131.3 (m), 128.9, 125.6, 124.9, 111.5
(dd, J=3.9, 21.2 Hz) 104.4 (dd, J=25.2, 29.4 Hz), 72.1, 71.6, 55.7,
47.4, 46.5, 35.7, 35.3, 25.5, 24.6, 24.4, 19.5, 18.1 ppm. Purity:
LCMS >99.3% (214 nm & 254 nm); retention time 0.90 min;
(M+1) 399.0
Example 72
1-azabicyclo[2.2.2]oct-3-yl
[1-(4'-methoxybiphenyl-4-yl)cyclopropyl]carbamate
[0593] Using general procedure E, quinuclidin-3-yl
1-(4-bromophenyl)cyclopropylcarbamate (0.485 g, 1.33 mmol),
4-methoxyphenyl boronic acid (0.404 g, 2.66 mmol) and Pd(OAc).sub.2
(0.016 g, 0.071 mmol) gave the title compound as a grey solid
(0.337 mg, 65%). .sup.1H. NMR (CDCl.sub.3) .delta. 7.48 (dd, J=8.6,
5.5 Hz, 4H), 7.29 (d, J=7.6 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 5.58
(d, J=48.7 Hz, 1H), 4.83-4.63 (m, 1H), 3.84 (s, 3H), 3.20 (dd,
J=24.0, 15.5 Hz, 1H), 2.97-2.42 (m, 5H), 1.97 (d, J=30.9 Hz, 1H),
1.81 (s, 1H), 1.75-1.33 (m, 3H), 1.28 (d, J=6.8 Hz, 4H) ppm.
.sup.13C NMR major rotomer (CDCl.sub.3) .delta. 159.1, 156.0,
141.4, 139.0, 133.4, 128.0, 126.7, 125.9, 114.2, 71.5, 55.7, 55.3,
47.4, 46.5, 35.3, 25.5, 24.6, 19.6, 17.8 ppm. Purity: LCMS
>97.1% (214 nm & 254 nm); retention time 0.88 min; (M+1)
393.4.
Preparation T
Example 73
quinuclidin-3-yl
2-(5-(4-fluorophenyl)thiophen-3-yl)propan-2-ylcarbamate
[0594] To a stirred and cooled (0.degree. C.) solution of ethyl
5-bromothiophene-3-carboxylate (13.30 g, 56.57 mmol) in THF (100
mL) was added a solution of methylmagnesium bromide in diethyl
ether [3.0 M] (55.0 mL, 165 mmol), dropwise over 20 minutes. After
2 hours, the reaction solution was concentrated. The residue was
taken up in aqueous NH.sub.4Cl (200 mL) and extracted with ethyl
acetate (2.times.100 mL). The combined extracts were dried
(Na.sub.2SO.sub.4) and concentrated. The resulting amber oil was
purified by flash chromatography using a hexane/ethyl acetate
gradient to afford 2-(5-bromothiophen-3-yl)propan-2-ol as a pale
amber oil (8.05 g, 64%).
[0595] To a stirred solution of 2-(5-bromothiophen-3-yl)propan-2-ol
(8.03 g, 36.3 mmol) in methylene chloride (80 mL) was added sodium
azide (7.08 g, 109 mmol) followed by trifluoroacetic acid (8.0 mL;
dropwise over 5-6 minutes). The thickening suspension was stirred
for 1.5 hour before diluting with water (350 mL) and extracting
with ethyl acetate (1.times.200 mL). The organic layer was washed
with aqueous NaHCO.sub.3 (1.times.250 mL), dried (Na.sub.2SO.sub.4)
and concentrated to afford the crude azide product. To a stirred
solution of this material in THF (160 mL) was added water (11 mL)
followed by triphenylphosphine (23.8 g, 90.7 mmol). The reaction
was stirred for 2 days before concentrating. The resulting residue
was dissolved in ethyl acetate (250 mL) and extracted with 1 N
aqueous HCl (4.times.75 mL). The combined extracts were basified
with concentrated NH.sub.4OH and extracted with ethyl acetate
(2.times.100 mL). These extracts were, in turn, dried
(Na.sub.2SO.sub.4) and concentrated. The resulting amber oil was
purified by flash chromatography using a methylene
chloride/methanol/ammonia gradient to afford a mixture of
2-(5-bromothiophen-3-yl)propan-2-amine and triphenylphosphine oxide
(.about.70/30 ratio) as a viscous amber oil (1.32 g, 17%).
[0596] To a stirred solution of 3-quinuclidinol (3.00 g, 23.6 mmol)
in THF (100 mL) was added 4-nitrophenyl chloroformate (5.94 g,
29.5). After stirring for 4 hours, the precipitate was filtered
off, rinsed with THF and air dried on the frit under house vacuum.
The filtercake was dissolved in ethyl acetate (150 mL) and washed
with aqueous NaHCO.sub.3 (1.times.150 mL) and water (2.times.150
mL). The organic layer was dried (Na.sub.2SO.sub.4) and
concentrated to afford crude 4-nitrophenyl quinuclidin-3-yl
carbonate product, which was used in the next step without
purification.
[0597] To a stirred solution of
2-(5-bromothiophen-3-yl)propan-2-amine (0.366 g, 1.66 mmol) in THF
(10 mL) was added 4-nitrophenyl quinuclidin-3-yl carbonate (0.571
g, 1.95 mmol) and a few granules of 4-(dimethylamino)pyridine. The
mixture was refluxed overnight, concentrated and partitioned
between ethyl acetate (50 mL) and aqueous NaHCO.sub.3 (50 mL). The
organic layer was washed again with aqueous NaHCO.sub.3 (1.times.50
mL), dried (Na.sub.2SO.sub.4) and concentrated. The resulting dirty
yellow gum was purified by flash chromatography using a
chloloform/methanol/ammonia gradient to afford quinuclidin-3-yl
(1-(5-bromothiophen-3-yl)cyclopropyl)carbamate as an off-white
solid (0.305 g, 49%).
[0598] Using general procedure E, quinuclidin-3-yl
(1-(5-bromothiophen-3-yl)cyclopropyl)carbamate (0.227 g, 0.742
mmol), 4-fluorophenyl boronic acid (0.208 g, 1.49 mmol),
tricyclohexylphosphine (0.021 g, 0.075 mmol), potassium phosphate
(0.866, 4.08 mmol) and palladium acetate (8.0 mg, 36
.quadrature.mol) gave the title compound as a gray solid (0.142 g,
49%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.60-7.45 (m, 2H),
7.24-7.19 (m, 1H), 7.10-6.97 (m, 3H), 5.23 (br s, 1H), 4.72-4.61
(m, 1H), 3.30-3.04 (m, 1H), 3.03-2.25 (m, 5H), 2.09-1.02 (m, 11H)
ppm. .sup.13C NMR (400 MHz, CDCl.sub.3) .delta. 162.3 (d, J=247.1
Hz), 154.5, 149.8, 143.6, 130.7, 127.4 (d, J=8.1 Hz), 121.8, 118.9,
115.8 (d, J=21.6 Hz), 70.8, 55.5, 53.4, 47.3, 46.4, 29.0, 25.4,
24.4, 19.4 ppm. Purity: 95.8% UPLCMS (210 nm & 254 nm);
retention time 0.90 min; (M+1) 389.
Preparation U
Example 74
(S)-quinuclidin-3-yl
2-(3-(4-fluorophenyl)isothiazol-5-yl)propan-2-ylcarbamate
[0599] To stirred solution of
2-(3-(4-fluorophenyl)isothiazol-5-yl)propan-2-amine (1.21 g, 5.12
mmol) in toluene was added a solution of phosgene in toluene
[.about.1.9 M] (10.8 mL, 20.5 mmol). The reaction was heated at
reflux for two hours and then concentrated. The residue was
coevaporated with toluene (2.times.15 mL) to afford the crude
isocyanate intermediate as golden oil. This material was taken up
in toluene (10 mL) and treated with (S)-3-quinuclidinol (0.749 g,
5.89 mmol). The reaction was heated at reflux overnight and
concentrated. The residue was purified by flash chromatography
using a chloloform/methanol/ammonia gradient to afford the title
compound as a white solid (0.971 g, 49%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.09-8.00 (m, 2H), 7.87 (br s, 1H), 7.75 (s,
1H), 7.35-7.25 (m, 2H), 4.54-4.45 (m, 1H), 3.14-2.92 (m, 1H),
2.87-2.17 (m, 5H), 1.98-0.98 (m, 11H) ppm. .sup.13C NMR (400 MHz,
DMSO-d.sub.6) .delta. 180.1, 165.6, 162.6 (d, J=246.4 Hz), 154.7,
131.2 (d, J=3.0 Hz), 128.7 (d, J=8.4 Hz), 118.2, 115.7 (d, J=21.8
Hz), 70.6, 55.3, 52.8, 46.9, 45.9, 29.9, 25.2, 24.2, 19.2 ppm.
Purity: 100% UPLCMS (210 nm & 254 nm); retention time 0.82 min;
(M+1) 390.
Preparation V
Example 75
(S)-quinuclidin-3-yl
2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-ylcarbamate
[0600] To a stirred solution of 4-fluorothiobenzamide (8.94 g, 57.6
mmol) in ethanol (70 mL) was added ethyl 4-chloroacetoacetate (7.8
mL, 58 mmol). The reaction was heated at reflux for 4 hours,
treated with an addition aliquot of ethyl 4-chloroacetoacetate (1.0
mL, 7.4 mmol) and refluxed for an additional 3.5 hours. The
reaction was then concentrated and the residue was partitioned
between ethyl acetate (200 mL) and aqueous NaHCO.sub.3 (200 mL).
The organic layer was combined with a back extract of the aqueous
layer (ethyl acetate, 1.times.75 mL), dried (Na.sub.2SO.sub.4) and
concentrated. The resulting amber oil was purified by flash
chromatography using a hexane/ethyl acetate gradient to afford
ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)acetate as a low melting,
nearly colorless solid (13.58 g, 89%).
[0601] To a stirred solution of ethyl
2-(2-(4-fluorophenyl)thiazol-4-yl)acetate (6.28 g, 23.7 mmol) in
DMF (50 mL) was added sodium hydride [60% dispersion in mineral
oil] (2.84 g, 71.0 mmol). The frothy mixture was stirred for 15
minutes before cooling in an ice bath and adding iodomethane (4.4
mL, 71 mmol). The reaction was stirred overnight, allowing the
cooling bath to slowly warm to room temperature. The mixture was
then concentrated and the residue partitioned between ethyl acetate
(80 mL) and water (200 mL). The organic layer was washed with a
second portion of water (1.times.200 mL), dried (Na.sub.2SO.sub.4)
and concentrated. The resulting amber oil was purified by flash
chromatography using a hexane/ethyl acetate gradient to afford
ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoate as a
colorless oil (4.57 g, 66%).
[0602] To a stirred solution of ethyl
2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoate (4.56 g, 15.5
mmol) in 1:1:1 THF/ethanol/water (45 mL) was added lithium
hydroxide monohydrate (2.93 g, 69.8 mmol). The reaction was stirred
overnight, concentrated and redissolved in water (175 mL). The
solution was washed with ether (1.times.100 mL), acidified by the
addition of 1.0N HCl (80 mL) and extracted with ethyl acetate
(2.times.70 mL). The combined extracts were dried
(Na.sub.2SO.sub.4) and concentrated to afford
2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoic acid as a
white solid (4.04 g, 98%). This material was used in the next step
without purification.
[0603] To a stirred and cooled (0.degree. C.) solution of
2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoic acid (4.02 g,
15.2 mmol) in THF (100 mL) was added triethylamine (4.2 mL, 30
mmol) followed by isobutyl chloroformate (3.0 mL, 23 mmol). The
reaction was stirred cold for another 1 hour before adding a
solution of sodium azide (1.98 g, 30.5 mmol) in water (20 mL). The
reaction was stirred overnight, allowing the cooling bath to slowly
warm to room temperature. The mixture was then diluted with water
(100 mL) and extracted with ethyl acetate (2.times.60 mL). The
combined extracts were washed with aqueous NaHCO.sub.3 (1.times.150
mL) and brine (1.times.100 mL), dried (Na.sub.2SO.sub.4) and
concentrated. After coevaporating with toluene (2.times.50 mL), the
resulting white solid was taken up in toluene (100 mL) and refluxed
for 4 hours. (S)-3-quinuclidinol (3.87 g, 30.4 mmol) was then added
and reflux was continued overnight. The reaction was concentrated
and the residue partitioned between ethyl acetate (100 mL) and
aqueous NaHCO.sub.3 (150 mL). The organic layer was washed with
water (1.times.150 mL), dried (Na.sub.2SO.sub.4) and concentrated.
The resulting off-white solid was purified by flash chromatography
using a chloloform/methanol/ammonia gradient to afford the title
compound as a white solid (4.34 g, 73%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.96-7.88 (m, 2H), 7.16-7.04 (m, 3H), 5.55 (br
s, 1H), 4.69-4.62 (m, 1H), 3.24-3.11 (m, 1H), 3.00-2.50 (m, 5H),
2.01-1.26 (m, 11H) ppm. .sup.13C NMR (400 MHz, CDCl.sub.3) .delta.
166.4, 165.1, 163.8 (d, J=250.3 Hz), 162.9, 155.0, 130.1 (d, J=3.3
Hz), 128.4 (d, J=8.5 Hz), 115.9 (d, J=22.3 Hz), 112.5, 71.2, 55.7,
54.2, 47.5, 46.5, 28.0, 25.5, 24.7, 19.6 ppm. Purity: 100% UPLCMS
(210 nm & 254 nm); retention time 0.83 min; (M+1) 390.
Preparation W
Example 76
(S)-quinuclidin-3-yl
2-(4-(4-fluorophenyl)thiazol-2-yl)propan-2-ylcarbamate
[0604] To a stirred solution of ethyl 3-amino-3-thioxopropanoate
(20.00 g, 135.9 mmol) in ethanol (120 mL) was added
2-bromo-4'-fluoroacetophenone (29.49 g, 135.9 mmol). The mixture
was refluxed for 1 hour, concentrated and partitioned between ethyl
acetate (300 mL) and aqueous NaHCO.sub.3 (400 mL). The organic
layer was combined with a back extract of the aqueous layer (ethyl
acetate, 1.times.100 mL), dried (Na.sub.2SO.sub.4) and
concentrated. The resulting light brown solid was purified by flash
chromatography using a hexane/ethyl acetate gradient to afford
ethyl 2-(4-(4-fluorophenyl)thiazol-2-yl)acetate as an off-white
solid (29.92 g, 83%).
[0605] To a stirred and cooled (-78.degree. C.) solution of ethyl
2-(4-(4-fluorophenyl)thiazol-2-yl)acetate (10.00 g, 37.69 mmol) in
THF (250 mL) was added a solution of potassium t-butoxide in THF
[1.0 M] (136 mL, 136 mmol), dropwise over 15 minutes, followed by
18-crown-6 (1.6 mL, 7.5 mmol). After an additional 30 minutes at
-78.degree. C., iodomethane (8.5 mL) was added, dropwise over 5
minutes. The reaction was stirred cold for another 2 hours before
pouring into water (450 mL) and extracting with ethyl acetate
(2.times.150 mL). The combined extracts were washed with brine
(1.times.200 mL), dried (Na.sub.2SO.sub.4) and concentrated. The
resulting brown oil was purified by flash chromatography using a
hexane/ethyl acetate gradient to afford ethyl
2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropanoate as a pale
amber oil (8.64 g, 78%).
[0606] To a stirred solution of ethyl
2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropanoate (0.900 g,
3.07 mmol) in 1:1:1 THF/ethanol/water (15 mL) was added lithium
hydroxide monohydrate (0.451 g, 10.7 mmol). After overnight
stirring, the reaction was concentrated and redissolved in water
(80 mL). The solution was washed with ether (1.times.50 mL),
acidified with the addition of 1 N HCl (15 mL) and extracted with
ethyl acetate (2.times.50 mL). The combined extracts were dried
(Na.sub.2SO.sub.4) and concentrated to afford
2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropanoic acid as a pale
golden solid (0.808 g, 99%).
[0607] To stirred and cooled (0.degree. C.) solution of
2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropanoic acid (0.784 g,
2.96 mmol) in THF (25 mL) was added triethylamine (0.82 mL, 5.9
mmol) followed by isobutyl chloroformate (0.58 mL, 4.4 mmol). The
reaction was stirred cold for another 1 hour before adding a
solution of sodium azide (0.385 g, 5.92 mmol) in water (7 mL). The
reaction was stirred overnight, allowing the cooling bath to slowly
warm to room temperature. The mixture was then diluted with water
(100 mL) and extracted with ethyl acetate (2.times.60 mL). The
combined extracts were washed with aqueous NaHCO.sub.3 (1.times.150
mL) and brine (1.times.100 mL), dried (Na.sub.2SO.sub.4) and
concentrated. After coevaporating with toluene (2.times.30 mL), the
resulting off-white solid was taken up in toluene (25 mL) and
refluxed for 4 hours. (S)-3-quinuclidinol (0.753 g, 5.92 mmol) was
then added and reflux was continued for 3 hours. The reaction was
concentrated and the residue was purified by flash chromatography
using a chloloform/methanol/ammonia gradient to afford the title
compound as a white solid (0.793 g, 69%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.90-7.81 (m, 2H), 7.32 (s, 1H), 7.14-7.05 (m,
2H), 5.76 (br s, 1H), 4.72-4.65 (m, 1H), 3.26-3.10 (m, 1H),
3.03-2.37 (m, 5H), 2.05-1.23 (m, 11H) ppm. .sup.13C NMR (400 MHz,
CDCl.sub.3) .delta. 177.6, 162.6 (d, J=248.4 Hz), 154.8, 153.6,
130.8 (d, J=3.2 Hz), 128.1 (d, J=8.1 Hz), 115.9 (d, J=21.7 Hz),
112.2, 71.6, 55.7, 47.4, 46.5, 29.1, 25.4, 24.7, 19.6 ppm. Purity:
100% UPLCMS (210 nm & 254 nm); retention time 0.82 min; (M+1)
390.
Example 77
quinuclidin-3-yl 1-(4-(benzyloxy)phenyl)cyclopropylcarbamate
[0608] A mixture of 4-cyanophenol (5.0 g, 42 mmol), benzylbromide
(8.6 g, 50 mmol), potassium carbonate (11.6 g, 84.0 mmol) in DMF
(40 mL) was stirred at 100.degree. C. for 3 h. The precipitate was
filtered off and the filtrate was diluted with EtOAc and washed
with water. The organic layer was dried (Na.sub.2SO.sub.4) and
concentrated. The resulting crude product was purified by silica
gel column chromatography (eluting with petroleum ether/EtOAc from
20/1 to 5/1) to give 4-(benzyloxy)benzonitrile as a white solid
(8.1 g, 92%).
[0609] Using general procedure G, 4-(benzyloxy)benzonitrile (6.00
g, 28.7 mmol) was converted to the corresponding
1-(4-(benzyloxy)phenyl)cyclopropanamine as a yellow solid (1.8 g,
26%).
[0610] Using general procedure A,
1-(4-(benzyloxy)phenyl)cyclopropanamine (600 mg, 2.51 mmol) and
quinuclidin-3-ol gave the title compound as a viscous oil (170 mg,
17%). 1H NMR (500 MHz, CDCl.sub.3) .delta. 7.34 (d, J=7.0 Hz, 2H),
7.30 (t, J=7.0 Hz, 2H), 7.25 (t, J=7.0 Hz, 1H), 7.16 (d, J=8.5 Hz,
1H), 7.07 (d, J=7.0 Hz, 1H), 6.83 (d, J=8.0 Hz, 2H), 5.50 (br s,
0.6H), 5.40 (br s, 0.4H), 4.96 (s, 2H), 4.64 (m, 1H), 3.20-3.15 (m,
1H), 2.88-2.50 (m, 5H), 1.95-1.05 (m, 9H) ppm. .sup.13C NMR (125
MHz, CDCl.sub.3) .delta. 156.6, 154.8, 136.0, 134.2, 127.6, 126.9,
126.4, 125.4, 113.7, 70.0, 69.0, 54.5, 46.3, 45.4, 34.2, 24.3,
23.3, 18.3, 15.8 ppm. Purity: >90% LCMS (214 nm & 254 nm);
retention time 1.57 min; (M+1) 393.
Example 78
quinuclidin-3-yl biphenyl-3-ylmethylcarbamate
[0611] To a stirred and cooled (0.degree. C.) solution of
triphosgene (0.80 g, 2.7 mmol) in THF (20 mL) was added, dropwise,
a mixture of (3-bromophenyl)methanamine (1.0 g, 5.4 mmol) and
triethylamine (1.08 g, 10.7 mmol) in THF (30 mL) over 2 h. After
the addition was complete, the mixture was refluxed for 1 h and
then cooled to room temperature. Quinuclidin-3-ol (1.40 g, 10.7
mmol) was added, and the mixture was refluxed for 18 h. The solvent
was removed in vacuo, and the residue was dissolved in EtOAc,
washed with water, dried over Na.sub.2SO.sub.4, and concentrated.
The crude residue was purified by silica gel column chromatography
(eluting with EtOAc/methanol=10/1) to give quinuclidin-3-yl
3-bromobenzylcarbamate as a colourless liquid (0.68 g, 37%).
[0612] Using general procedure E, quinuclidin-3-yl
3-bromobenzylcarbamate (237 mg, 0.700 mmol), phenylboronic acid
(171 mg, 1.4 mmol) and [PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 gave the
title compound as a viscous semi-solid (110 mg, 47%). .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 7.57 (d, J=7.5 Hz, 2H), 7.50 (m, 2H),
7.62-7.38 (m, 3H), 7.35 (t, J=7.5 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H),
5.32-5.17 (m, 1H), 7.78 (m, 1H), 4.42 (d, J=6.0 Hz, 2H), 3.26 (m,
1H), 2.95-2.65 (m, 5H), 2.05 (m, 1H), 1.84 (m, 1H), 1.70 (m, 1H),
1.58 (m, 1H), 1.42 (m, 1H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3)
.delta. 155.2, 140.7, 139.8, 138.0, 128.1, 127.8, 126.4, 126.1,
125.5, 125.4, 125.3, 70.1, 54.4, 46.2, 45.3, 44.1, 24.3, 23.1, 18.2
ppm. Purity: >98% LCMS (214 nm & 254 nm); retention time
1.44 min; (M+1) 337.
Example 79
quinuclidin-3-yl 3-(pyrimidin-5-yl)benzylcarbamate
[0613] Using general procedure E, quinuclidin-3-yl
3-bromobenzylcarbamate (203 mg, 0.600 mmol), pyrimidin-5-ylboronic
acid (149 mg, 1.2 mmol) and [PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 gave
the title compound as a viscous semi-solid (110 mg, 54%). .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. 9.20 (s, 1H), 8.94 (s, 2H), 7.51
(m, 3H), 7.40 (m, 1H), 5.62 (m, 1H), 4.81 (m, 1H), 4.50-4.40 (m,
2H), 3.30 (m, 1H), 2.97-2.65 (m, 5H), 2.12 (m, 1H), 1.92-1.82 (m,
1H), 1.79-1.69 (m, 1H), 1.65-1.56 (m, 1H), 1.50-1.42 (m, 1H) ppm.
.sup.13C NMR (125 MHz, CDCl.sub.3) .delta. 157.6, 156.2, 154.9,
140.1, 134.7, 134.1, 129.8, 128.2, 126.2, 70.9, 55.2, 47.2, 46.2,
44.8, 25.2, 23.8, 19.0 ppm. Purity: >95 LCMS (214 nm & 254
nm); retention time 1.22 min; (M+1) 339.
Example 80
quinuclidin-3-yl 3-(benzyloxy)benzylcarbamate
[0614] A mixture of 2-(3-hydroxyphenyl)acetic acid (0.6 g, 3.95
mmol), benzyl bromide (0.710 g, 4.14 mmol), potassium hydroxide
(0.550 g, 9.87 mmol), KI (13 mg, 0.079 mmol) in THF (20 mL) was
refluxed for 18 h. The solvent was removed and the residue was
dissolved in 50 mL of water and extracted with ether. The aqueous
layer was acidified with aqueous 1N HCl and the white precipitate
that formed was filtered off to afford
2-(3-(benzyloxy)phenyl)acetic acid as a gray solid (0.87 g,
91%).
[0615] Using general procedure H, 2-(3-(benzyloxy)phenyl)acetic
acid (242 mg, 1.00 mmol) and quinuclidin-3-ol gave the title
compound as a viscous semi-solid (200 mg, 55%). .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 7.42 (d, J=7.5 Hz, 2H), 7.38 (t, J=7.5 Hz,
2H), 7.32 (t, J=7.0 Hz, 1H), 7.24 (d, J=7.5 Hz, 1H), 6.92 (s, 1H),
6.88 (d, J=7.0 Hz, 2H), 5.30 (m, 1H), 5.05 (s, 2H), 4.75 (m, 1H),
4.32 (d, J=6.0 Hz, 2H), 3.23 (m, 1H), 2.93-2.60 (m, 5H), 2.08-1.96
(m, 1H), 1.88-1.75 (m, 1H), 1.72-1.62 (m, 1H), 1.60-1.50 (m, 1H),
1.42-1.34 (m, 1H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3) .delta.
159.1, 156.3, 140.2, 136.8, 129.7, 128.6, 128.0, 127.5, 120.0,
114.1, 113.6, 71.3, 70.0, 55.5, 47.3, 46.4, 45.0, 25.4, 24.3, 19.3
ppm. Purity: >95% LCMS (214 nm & 254 nm); retention time
1.51 min; (M+1) 367
Example 81
quinuclidin-3-yl 4-phenoxybenzylcarbamate
[0616] Using general procedure H, 2-(3-phenoxyphenyl)acetic acid
(228 mg, 1.00 mmol), and quinuclidin-3-ol gave the title compound
as a viscous semi-solid (70 mg, 20%). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.29-7.18 (m, 3H), 7.03 (t, J=7.5 Hz, 1H),
6.96-6.90 (m, 3H), 6.86 (s, 1H), 6.82 (d, J=8.5 Hz, 1H), 5.40-5.15
(m, 1H), 4.70 (m, 1H), 4.25 (d, J=6.0 Hz, 2H), 3.18 (m, 1H),
2.90-2.60 (m, 5H), 2.03-1.92 (m, 1H), 1.82-1.74 (m, 1H), 1.68-1.60
(m, 1H), 1.57-1.45 (m, 1H), 1.40-1.32 (m, 1H) ppm. .sup.13C NMR
(125 MHz, CDCl.sub.3) .delta. 156.6, 155.9, 155.1, 139.6, 129.0,
128.8, 122.4, 121.1, 118.0, 116.7, 69.7, 54.1, 46.1, 45.2, 43.7,
24.2, 22.7, 18.0 ppm. Purity: 100% LCMS (214 nm & 254 nm);
retention time 1.50 min; (M+1) 353.
Example 82
quinuclidin-3-yl 3-isopropoxybenzylcarbamate
[0617] A mixture containing 2-(3-hydroxyphenyl)acetic acid (0.800
g, 5.26 mmol), 2-bromopropane (0.971 g, 7.89 mmol), potassium
hydroxide (0.740 g, 13.2 mmol), K1 (18 mg, 0.11 mmol) in 20 mL EtOH
was refluxed for 18 h. The solvent was removed and the residue was
dissolved in 50 mL of water and extracted with ether. The aqueous
layer was acidified with aqueous 1N HCl and extracted with EtOAc.
The organic layers were dried (Na.sub.2SO.sub.4) and concentrated
to afford a residue which was purified by silica gel chromatography
(petroleum ether/EtOAc 4:1) to get 2-(3-(benzyloxy)phenyl)acetic
acid as a white solid (0.45 g, 44%).
[0618] Using general procedure H, 2-(3-isopropoxyphenyl)acetic acid
(291 mg, 1.50 mmol), and quinuclidin-3-ol gave the title compound
as a viscous semi-solid (120 mg, 25%). .sup.1H-NMR (500 MHz,
CDCl.sub.3) .delta. 7.23 (t, J=7.5 Hz, 1H), 6.86-6.77 (m, 3H),
5.16-5.00 (m, 1H), 4.78 (m, 1H), 4.55 (m, 1H), 4.32 (d, J=5.0 Hz,
2H), 3.26 (m, 1H), 2.95-2.70 (m, 5H), 2.10-2.05 (m, 1H), 1.90-1.80
(m, 1H), 1.75-1.65 (m, 1H), 1.63-1.53 (m, 1H), 1.47-1.37 (m, 1H),
1.33 (d, J=5.5 Hz, 6H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3)
.delta. 158.1, 156.2, 140.1, 129.7, 119.6, 115.2, 114.6, 71.0,
69.8, 55.3, 47.2, 46.3, 45.0, 25.3, 24.1, 22.0, 19.2 ppm. Purity:
>90% LCMS (214 nm & 254 nm); retention time 1.42 min; (M+1)
319.
Example 83
quinuclidin-3-yl 3-isobutoxybenzylcarbamate
[0619] A mixture containing 2-(3-hydroxyphenyl)acetic acid (1.0 g,
6.6 mmol), 1-bromo-2-methylpropane (1.08 g, 7.91 mmol), potassium
hydroxide (0.920 g, 16.4 mmol), KI (22 mg, 0.13 mmol) in EtOH (20
mL) was refluxed for 18 h. The solvent was removed and the residue
was dissolved in 50 mL of water and extracted with ether. The
aqueous layer was acidified with aqueous 1N HCl and extracted with
EtOAc. The organic layers were dried (Na.sub.2SO.sub.4) and
concentrated to afford a residue which was purified by silica gel
chromatography (petroleum ether/EtOAc 4:1) to get
2-(3-(benzyloxy)phenyl)acetic acid as a white solid (0.42 g,
31%).
[0620] Using general procedure H, 2-(3-isobutoxyphenyl)acetic acid
(208 mg, 1.00 mmol) and quinuclidin-3-ol gave the title compound as
a viscous semi-solid (130 mg, 39%). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.23 (t, J=7.5 Hz, 1H), 6.86-6.76 (m, 3H),
5.35-5.10 (m, 1H), 4.77 (m, 1H), 4.31 (d, J=5.5 Hz, 2H), 3.69 (d,
J=6.5 Hz, 2H), 3.26 (m, 1H), 2.95-2.70 (m, 5H), 2.10-2.00 (m, 2H),
1.88-1.80 (m, 1H), 1.75-1.63 (m, 1H), 1.62-1.52 (m, 1H), 1.45-1.36
(m, 1H), 1.01 (d, J=6.5 Hz, 6H) ppm. .sup.13C NMR (125 MHz,
CDCl.sub.3) .delta. 159.6, 156.1, 139.9, 129.7, 119.6, 113.9,
113.4, 74.4, 70.9, 55.3, 47.2, 46.3, 45.1, 28.3, 25.3, 23.9, 19.3,
19.1 ppm. Purity: >95% LCMS (214 nm & 254 nm); retention
time 1.50 min; (M+1) 333.
Example 84
quinuclidin-3-yl 3-(cyclopropylmethoxy)benzylcarbamate
[0621] A mixture containing 2-(3-hydroxyphenyl)acetic acid (1.0 g,
6.6 mmol), (bromomethyl) cyclopropane (0.97 g, 7.2 mmol), potassium
hydroxide (0.920 g, 16.4 mmol), KI (22 mg, 0.13 mmol) in EtOH (20
mL) was refluxed for 18 h. The solvent was removed in vacuo, and
the residue was dissolved in 50 mL of water and extracted with
ether. The aqueous layer was acidified with aqueous 1N HCl and
extracted with EtOAc. The organic layers were dried
(Na.sub.2SO.sub.4) and concentrated to afford a residue which was
purified by silica gel chromatography (petroleum ether/EtOAc 4:1)
to get 2-(3-(cyclopropylmethoxy)phenyl)acetic acid as a white solid
(0.80 g, 59%).
[0622] Using general procedure H,
2-(3-(cyclopropylmethoxy)phenyl)acetic acid (300 mg, 1.50 mmol) and
quinuclidin-3-ol gave the title compound as a viscous oil (90 mg,
19%). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.24 (t, J=7.5 Hz,
1H), 6.88-6.78 (m, 3H), 5.13-4.95 (m, 1H), 4.74 (m, 1H), 4.33 (d,
J=6.0 Hz, 2H), 3.79 (d, J=7.0 Hz, 2H), 3.23 (m, 1H), 2.93-2.63 (m,
5H), 2.04-1.98 (m, 1H), 1.85-1.76 (m, 1H), 1.72-1.60 (m, 1H),
1.58-1.50 (m, 1H), 1.41-1.22 (m, 2H), 0.68-0.62 (m, 2H), 0.37-0.32
(m, 2H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3) .delta. 158.2,
155.5, 139.3, 128.6, 118.6, 112.8, 112.3, 71.7, 70.4, 54.5, 46.2,
45.3, 43.9, 24.4, 23.5, 18.5, 9.3, 2.2 ppm. Purity: >95% LCMS
(214 nm & 254 nm); retention time 1.44 min; (M+1) 331.
Preparation X
Example 85
N-(2-(biphenyl-4-yl)propan-2-yl)-2-(quinuclidin-3-yl)acetamide
[0623] To a solution of 2-(quinuclidin-3-yl)acetic acid
hydrochloride (0.97 g, 4.7 mmol) in DMF (30 mL) was added HATU
(1.79 g, 4.72 mmol), 2-(4-bromophenyl)propan-2-amine (1.0 g, 4.7
mmol), and triethylamine (3.9 mL, 28 mmol). The resulting mixture
was stirred at 60.degree. C. for 16 h. The mixture was concentrated
in vacuo, diluted with EtOAc and washed with brine. The organic
layer was dried over Na.sub.2SO.sub.4 and evaporated to afford
crude product, which was purified by silica gel column
chromatography (EtOAc/methanol 50/1 to 3/1) to obtain
N-(2-(4-bromophenyl)propan-2-yl)-2-(quinuclidin-3-yl)acetamide as a
yellow solid (1.3 g, 76%).
[0624] Using general procedure E,
N-(2-(4-bromophenyl)propan-2-yl)-2-(quinuclidin-3-yl)acetamide (200
mg, 0.550 mmol), phenylboronic acid (134 mg, 1.00 mmol) and
[PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 gave the title compound as a
viscous brown oil (58 mg, 32%). .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.58-7.50 (m, 4H), 7.44-7.37 (m, 4H), 7.31 (t, J=7.0 Hz,
1H), 6.50 (s, 1H), 3.16 (m, 1H), 3.02 (m, 1H), 2.92-2.78 (m, 3H),
2.60 (m, 1H), 2.40-2.20 (m, 3H), 1.47-1.90 (m, 11H) ppm. .sup.13C
NMR (125 MHz, CDCl.sub.3) .delta. 170.5, 146.1, 140.7, 139.2,
128.8, 127.2, 127.0 125.2, 55.6, 53.1, 46.8, 46.2, 40.3, 31.7,
29.3, 29.2, 26.0, 24.4, 19.7 ppm. Purity: 100% LCMS (214 nm &
254 nm); retention time 1.55 min; (M+1) 363.
Example 86
quinuclidin-3-yl biphenyl-3-ylcarbamate
[0625] To a solution of quinuclidin-3-ol (635 mg, 5.00 mmol) in THF
(15 mL) was added NaH [60% dispersion in mineral oil] (260 mg, 6.50
mmol) at room temperature. The mixture was stirred for 15 min and
3-bromophenyl isocyanate (990 mg, 5.00 mmol) was added under
stirring. The resulting mixture was stirred at room temperature for
18 h, quenched with brine and extracted with EtOAc. The organic
layers were combined, dried over Na.sub.2SO.sub.4 and concentrated.
The crude product was purified by silica gel column chromatography
(eluting with EtOAc/methanol 3:1) to give quinuclidin-3-yl
3-bromophenylcarbamate as a white solid (0.70 g, 43%).
[0626] Using general procedure E, above carbamate intermediate (130
mg, 0.402 mmol), phenylboronic acid (72 mg, 0.6 mmol) and
[PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 gave the title compound as a
white solid (75 mg, 58%). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
7.67 (br s, 1H), 7.59 (d, J=7.5 Hz, 2H), 7.43 (t, J=7.5 Hz, 2H),
7.41-7.28 (m, 4H), 6.77 (br s, 1H), 4.85 (m, 1H), 3.30 (m, 1H),
2.98-2.75 (m, 5H), 2.12 (m, 1H), 1.93-1.68 (m, 2H), 1.64-1.55 (m,
1H), 1.47-1.40 (m, 1H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3)
.delta. 153.3, 142.3, 140.7, 138.3, 129.5, 128.8, 127.5, 127.2,
122.3, 117.4, 72.1, 55.4, 47.4, 46.5, 30.9, 25.4, 24.5, 19.5 ppm.
Purity: 100% LCMS (214 nm & 254 nm); retention time 1.53 min;
(M+1) 323.
Example 87
quinuclidin-3-yl 2'-methoxybiphenyl-3-ylcarbamate
[0627] Using general procedure E, quinuclidin-3-yl
3-bromophenylcarbamate, 2-methoxy-phenylboronic acid and
[PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 gave the title compound as a
white solid (75 mg, 58%). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
7.49 (br s, 1H), 7.41 (br s, 1H), 7.37-7.28 (m, 3H), 7.23 (d, J=7.5
Hz, 1H), 7.04-6.94 (m, 3H), 4.83 (m, 1H), 3.80 (s, 3H), 3.29 (m,
1H), 2.97-2.70 (m, 5H), 2.10 (m, 1H), 1.91-1.82 (m, 1H), 1.74-1.65
(m, 1H), 1.62-1.53 (m, 1H), 1.46-1.37 (m, 1H) ppm. .sup.13C NMR
(125 MHz, CDCl.sub.3) .delta. 156.4, 153.4, 139.4, 137.6, 130.9,
130.2, 128.8, 128.6, 124.8, 120.8, 119.9, 117.3, 111.2, 72.0, 55.6,
55.4, 47.4, 46.5, 25.4, 24.5, 19.5 ppm. Purity: >95% LCMS (214
nm & 254 nm); retention time 1.52 min; (M+1) 353.
Example 88
quinuclidin-3-yl 2'-ethylbiphenyl-3-ylcarbamate
[0628] Using general procedure E, quinuclidin-3-yl
3-bromophenylcarbamate, 2-ethylphenylboronic acid and
[PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 gave the title compound as a
white solid (110 mg, 78%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.42-7.28 (m, 5H), 7.25-7.16 (m, 2H), 7.03-7.00 (m, 1H),
6.88 (br s, 1H), 4.83 (m, 1H), 3.27 (m, 1H), 2.98-2.70 (m, 5H),
2.61 (q, J=7.6 Hz, 2H), 2.08 (m, 1H), 1.92-1.80 (m, 1H), 1.75-1.65
(m, 1H), 1.63-1.55 (m, 1H), 1.46-1.37 (m, 1H), 1.10 (t, J=7.6 Hz,
3H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 152.1, 141.7,
140.4, 139.9, 136.4, 128.6, 127.5, 127.4, 126.4, 124.3, 123.2,
118.4, 115.9, 71.0, 54.3, 46.2, 45.3, 25.0, 24.2, 23.4, 18.3, 14.5
ppm. Purity: 100% LCMS (214 nm & 254 nm); retention time 1.61
min; (M+1) 351.
Example 89
quinuclidin-3-yl 3'-methoxybiphenyl-3-ylcarbamate
[0629] Using general procedure E, quinuclidin-3-yl
3-bromophenylcarbamate, 3-methoxyphenylboronic acid and
[PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 gave the title compound as a
white solid (100 mg, 71%). .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.63 (br s, 1H), 7.40-7.27 (m, 4H), 7.17 (d, J=8.0 Hz, 1H),
7.11 (m, 1H), 7.07 (br s, 1H), 6.89 (dd, J=8.0, 2.0 Hz, 1H), 4.85
(m, 1H), 3.85 (s, 3H), 3.30 (m, 1H), 2.99-2.70 (m, 5H), 2.12 (m,
1H), 1.92-1.84 (m, 1H), 1.75-1.68 (m, 1H), 1.62-1.55 (m, 1H),
1.48-1.40 (m, 1H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3) .delta.
159.9, 153.4, 142.3, 142.1, 138.4, 129.8, 129.4, 122.3, 119.7,
117.7, 112.9, 112.8, 72.0, 55.4, 55.3, 47.4, 46.5, 25.4, 24.5, 19.5
ppm. Purity: >97% LCMS (214 nm & 254 nm); retention time
1.52 min; (M+1) 353
Example 90
quinuclidin-3-yl 3'-ethylbiphenyl-3-ylcarbamate
[0630] To a solution of 1-bromo-3-ethylbenzene (370 mg, 2.00 mmol)
in 5 mL 1,4-dioxane, was added bis(pinacolato)diboron (609 mg, 2.40
mmol), CH.sub.3COOK (589 mg, 6.02 mmol), and
[PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 (75 mg, 0.09 mmol). The mixture
was stirred at 80.degree. C. for 5 h. The mixture was cooled,
diluted with water, and extracted with EtOAc. The combined extracts
were dried (Na.sub.2SO.sub.4) and concentrated to afford the crude
boronate (410 mg, >100%), which was used without purification in
the next step.
[0631] Using general procedure E, quinuclidin-3-yl
3-bromophenylcarbamate, 3-ethylphenylboronic acid and
[PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 gave the title compound as a
white solid (78 mg, 56%). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
7.64 (br s, 1H), 7.43-7.27 (m, 6H), 7.24 (br s, 1H), 7.18 (d, J=8.0
Hz, 1H), 4.85 (m, 1H), 3.30 (m, 1H), 2.99-2.73 (m, 5H), 2.70 (q,
J=7.5 Hz, 2H), 2.12 (m, 1H), 1.92-1.84 (m, 1H), 1.75-1.67 (m, 1H),
1.62-1.55 (m, 1H), 1.48-1.38 (m, 1H), 1.27 (t, J=7.5 Hz, 3H) ppm.
.sup.13C NMR (125 MHz, CDCl.sub.3) .delta. 153.5, 144.8, 142.4,
140.8, 138.4, 129.4, 128.8, 127.1, 126.8, 124.6, 122.3, 117.4,
72.1, 55.4, 47.4, 46.5, 29.0, 25.4, 24.5, 19.5, 15.7 ppm. Purity:
>98% LCMS (214 nm & 254 nm); retention time 1.66 min; (M+1)
351.
Example 91
quinuclidin-3-yl biphenyl-2-ylcarbamate
[0632] To a solution of quinuclidin-3-ol (382 mg, 3.00 mmol) in THF
(15 mL) was added NaH [60% dispersion in mineral oil] (156 mg, 3.90
mmol) at room temperature. The mixture was stirred for 15 min and
2-bromophenyl isocyanate (594 mg, 3.00 mmol) was added under
stirring. The resulting mixture was stirred at room temperature for
18 h, quenched with brine and extracted with EtOAc. The organic
layers were combined, dried over Na.sub.2SO.sub.4 and concentrated.
The resulting crude product was purified by silica gel column
chromatography (EtOAc/methanol 3:1) to give the product
quinuclidin-3-yl 2-bromophenylcarbamate as viscous oil (0.80 g,
82%).
[0633] Using general procedure E, quinuclidin-3-yl
2-bromophenylcarbamate (130 mg, 0.400 mmol), phenylboronic acid (96
mg, 0.8 mmol) and [PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 gave the title
compound as a white solid (112 mg, 87%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.07 (br s, 1H), 7.55-7.33 (m, 6H), 7.25-7.21
(dd, J=7.6 & 1.6 Hz, 1H), 7.43 (td, J=8.0, 1.2 Hz, 1H), 6.65
(br s, 1H), 4.78 (m, 1H), 3.24 (m, 1H), 2.90-2.68 (m, 5H), 2.04 (m,
1H), 1.80-1.62 (m, 2H), 1.61-1.50 (m, 1H), 1.41-1.30 (m, 1H) ppm.
.sup.13C NMR (100 MHz, CDCl.sub.3) 151.2, 135.9, 132.5, 129.5,
128.0, 127.0, 126.9, 126.2, 125.7, 121.4, 117.9, 69.9, 53.1, 45.1,
44.3, 23.1, 22.3, 17.2 ppm. Purity: 100% LCMS (214 nm & 254
nm); retention time 1.47 min; (M+1) 323.
Example 92
quinuclidin-3-yl 2'-methoxybiphenyl-2-ylcarbamate
[0634] Using general procedure E, quinuclidin-3-yl
2-bromophenylcarbamate, 2-methoxyphenylboronic acid and
[PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 gave the title compound as a
white solid (102 mg, 72%). .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.95 (br s, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.37 (t, J=7.5 Hz,
1H), 7.25 (d, J=7.5 Hz, 1H), 7.15 (t, J=7.5 Hz, 1H), 7.09 (t, J=7.5
Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.72 (br s, 1H), 4.76 (m, 1H),
3.82 (s, 3H), 3.23 (m, 1H), 2.90-2.64 (m, 5H), 1.98-2.08 (m, 1H),
1.81-1.63 (m, 2H), 1.60-1.50 (m, 1H), 1.42-1.30 (m, 1H) ppm.
.sup.13C NMR (125 MHz, CDCl.sub.3) .delta. 156.2, 153.8, 135.6,
132.1, 130.9, 129.7, 128.3, 127.1, 123.8, 121.5, 111.3, 71.8, 55.7,
55.5, 47.3, 46.5, 25.3, 24.5, 19.4 ppm. Purity: 100% LCMS (214 nm
& 254 nm); retention time 1.48 min; (M+1) 353.
Example 93
quinuclidin-3-yl 2'-ethylbiphenyl-2-ylcarbamate
[0635] Using general procedure E, quinuclidin-3-yl
2-bromophenylcarbamate, 2-ethylphenylboronic and
[PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 gave the title compound as a
white solid (71 mg, 51%). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
8.11 (br s, 1H), 7.43-7.34 (m, 3H), 7.33-7.28 (m, 1H), 7.18-7.08
(m, 3H), 6.24 (br s, 1H), 4.75 (m, 1H), 3.23 (m, 1H), 2.85-2.65 (m,
5H), 2.40 (m, 2H), 2.02 (m, 1H), 1.73-1.62 (m, 2H), 1.61-1.50 (m,
1H), 1.40-1.30 (m, 1H), 1.05 (m, 3H) ppm. .sup.13C NMR (125 MHz,
CDCl.sub.3) .delta. 153.3, 142.9, 136.4, 135.3, 130.6, 130.3,
130.1, 129.0, 128.7, 128.4, 126.4, 123.0, 119.1, 72.1, 55.2, 47.3,
46.4, 26.0, 25.3, 24.5, 19.3, 15.2 ppm. Purity: >98% LCMS (214
nm & 254 nm); retention time 1.55 min; (M+1) 351.
Example 94
quinuclidin-3-yl 3'-methoxybiphenyl-2-ylcarbamate
[0636] Using general procedure E, quinuclidin-3-yl
2-bromophenylcarbamate, 3-methoxyphenylboronic acid and
[PdCl.sub.2(Pddf)]CH.sub.2Cl.sub.2 gave the title compound as a
white solid (120 mg, 85%). .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 8.08 (br s, 1H), 7.40 (t, J=7.5 Hz, 1H), 7.36 (t, J=7.5 Hz,
1H), 7.23 (dd, J=7.5, 1.5 Hz, 1H), 7.13 (td, J=7.5, 1.5 Hz, 1H),
6.96 (dd, J=8.0, 2.0 Hz, 2H), 6.91 (t, J=1.5 Hz, 1H), 6.73 (br s,
1H), 4.79 (m, 1H), 3.84 (s, 3H), 3.24 (m, 1H), 2.90-2.70 (m, 5H),
2.05 (m, 1H), 1.80-1.70 (m, 2H), 1.62-1.52 (m, 1H), 1.41-1.32 (m,
1H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3) .delta. 160.1, 153.4,
139.5, 134.7, 131.5, 130.1, 130.1, 128.5, 123.5, 121.4, 119.9,
114.7, 113.6, 72.1, 55.3, 55.3, 47.3, 46.5, 25.3, 24.5, 19.4 ppm.
Purity: >98% LCMS (214 nm & 254 nm); retention time 1.48
min; (M+1) 353
Example 95
quinuclidin-3-yl 3'-ethylbiphenyl-2-ylcarbamate
[0637] Using general procedure E, quinuclidin-3-yl
2-bromophenylcarbamate, 3-ethylphenylboronic acid and
[PdCl.sub.2(pddf)]CH.sub.2Cl.sub.2 gave the title compound as a
white solid (120 mg, 86%). .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 8.09 (br s, 1H), 7.41 (t, J=7.5 Hz, 1H), 7.36 (t, J=7.5 Hz,
1H), 7.26-7.18 (m, 4H), 7.14 (t, J=7.5 Hz, 1H), 6.71 (br s, 1H),
4.79 (m, 1H), 3.25 (m, 1H), 2.90-2.65 (m, 7H), 2.05 (m, 1H),
1.80-1.64 (m, 2H), 1.62-1.52 (m, 1H), 1.40-1.32 (m, 1H), 1.28 (t,
J=7.5 Hz, 3H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3) .delta.
153.4, 145.2, 138.1, 134.7, 131.8, 130.2, 129.1, 128.8, 128.4,
127.5, 126.6, 123.5, 120.1, 72.0, 55.3, 47.3, 46.4, 28.9, 25.3,
24.5, 19.4, 15.7 ppm. Purity: >95% LCMS (214 nm & 254 nm);
retention time 1.55 min; (M+1) 351.
Preparation Y
Example 96
quinuclidin-3-yl 2-isopropoxyphenylcarbamate
[0638] To a mixture of 3-aminophenol (1.50 g, 13.8 mmol),
isopropanol (3.3 g, 55 mmol), and triphenylphosphine (14.4 g, 54.9
mmol) in THF (15 mL), was added dropwise diethylazodicarboxylate
(9.60 g, 55.0 mmol) over a 30 min period. The mixture was stirred
at room temperature for 3 h and concentrated. The residue was
diluted with water, acidified with aqueous 2N HCl and extracted
with ether. The aqueous phase was basified with aqueous 2N NaOH and
extracted with EtOAc. The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated. The resulting crude product
was purified by silica gel column chromatograph (petroleum
ether/EtOAc 10:1 to 5:1) to afford 3-isopropoxybenzenamine as
yellow oil (1.3 g, 64%).
[0639] Using general procedure A, 3-isopropoxybenzenamine (300 mg,
2.00 mmol) and quinuclidin-3-ol gave the title compound as a
viscous oil (130 mg, 22%). .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.20 (br s, 1H), 7.09 (t, J=8.5 Hz, 1H), 7.05 (br s, 1H),
6.77 (d, J=8.0 Hz, 1H), 6.51 (d, J=8.5 Hz, 1H), 4.75 (m, 1H), 4.46
(m, 1H), 3.26-3.18 (m, 1H), 2.92-2.65 (m, 5H), 2.04 (m, 1H), 1.80
(m, 1H), 1.63 (m, 1H), 1.52 (m, 1H), 1.35 (m, 1H), 1.28 (d, J=5.5
Hz, 6H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3) .delta. 157.5,
152.2, 138.2, 128.7, 110.1, 109.6, 105.1, 70.7, 68.9, 54.3, 46.3,
45.4, 28.7, 24.3, 23.3, 21.0, 18.3 ppm. Purity: >90% LCMS (214
nm & 254 nm); retention time 1.43 min; (M+1) 305.
Example 97
quinuclidin-3-yl 2-isobutoxyphenylcarbamate
[0640] To a mixture of 3-aminophenol (500 mg, 4.60 mmol),
2-methylpropan-1-ol (1.40 g, 18.9 mmol) and triphenylphosphine
(4.80 g, 16.2 mmol) in THF (10 mL) was added dropwise
diethylazodicarboxylate (3.20 g, 18.3 mmol) over a 30 min period.
The mixture was stirred at room temperature for 3 h. The solvent
was evaporated and the residue was diluted with water, acidified
with aqueous 2N HCl and extracted with ether. The aqueous phase was
basified with aqueous 2N NaOH and extracted with EtOAc. The
combined organic layers were dried (Na.sub.2SO.sub.4) and
concentrated. The resulting crude product was purified by silica
gel column chromatograph (petroleum ether/EtOAc 15:1) to afford
3-isobutoxybenzenamine as yellow oil (330 mg, 45%).
[0641] Using general procedure A, 3-isobutoxybenzenamine (330 mg,
2.00 mmol) and quinuclidin-3-ol gave the title compound as a
viscous oil (140 mg, 22%). .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.17 (t, J=8.0 Hz, 1H), 7.15 (br s, 1H), 6.81 (d, J=8.5 Hz,
1H), 6.80 (br s, 1H), 6.61 (d, J=8.5 Hz, 1H), 4.83 (m, 1H), 3.71
(d, J=6.5 Hz, 2H), 3.34-3.21 (m, 1H), 2.97-2.72 (m, 5H), 2.12-2.04
(m, 2H), 1.90-1.84 (m, 1H), 1.75-1.67 (m, 1H), 1.55-1.63 (m, 1H),
1.46-1.38 (m, 1H), 1.01 (d, J=6.5 Hz, 611) ppm. .sup.13C NMR (100
MHz, CDCl.sub.3) .delta. 159.9, 153.4, 139.3, 129.6, 110.6, 109.7,
105.0, 74.4, 72.0, 55.4, 47.3, 46.5, 28.3, 25.4, 24.5, 19.5, 19.3
ppm. Purity: 100% LCMS (214 nm & 254 nm); retention time 1.56
min; (M+1) 319.
Example 98
quinuclidin-3-yl 2-(cyclopropylmethoxy)phenylcarbamate
[0642] To a mixture of 3-aminophenol (300 mg, 2.70 mmol),
cyclopropylmethanol (793 mg, 11.0 mmol) and triphenylphosphine
(2.90 g, 11.0 mmol) in THF (6 mL) was added dropwise
diethylazodicarboxylate (1.90 g, 11.0 mmol) over a 30 min period.
The mixture was stirred at room temperature for 3 h. The solvent
was evaporated and the residue was diluted with water, acidified
with aqueous 2N HCl and extracted with ether. The aqueous phase was
basified with aqueous 2N NaOH and extracted with EtOAc. The
combined organic layers were dried (Na.sub.2SO.sub.4) and
concentrated. The resulting crude product was purified by silica
gel column chromatograph (petroleum ether/EtOAc 15:1) to afford
3-(cyclopropylmethoxy)benzenamine as a brown oil (260 mg, 58%).
[0643] Using general procedure A, 3-(cyclopropylmethoxy)benzenamine
(260 mg, 1.60 mmol) and quinuclidin-3-ol gave the title compound as
a viscous oil (80 mg, 16%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.72 (br s, 1H), 7.14 (br s, 1H), 7.13 (t, J=8.0 Hz, 1H),
6.85 (d, J=8.0 Hz, 1H), 6.57 (dd, J=8.0, 2.0 Hz, 1H), 4.85 (m, 1H),
3.75 (d, J=6.8 Hz, 2H), 3.35-3.26 (m, 1H), 3.05-2.78 (m, 5H),
2.18-2.12 (m, 1H), 1.97-1.86 (m, 1H), 1.80-1.67 (m, 1H), 1.66-1.55
(m, 1H), 1.52-1.42 (m, 1H), 1.26-1.15 (m, 1H), 0.61-0.55 (m, 2H),
0.31-0.26 (in, 2H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.
158.6, 152.1, 138.3, 128.6, 109.9, 108.9, 104.0, 71.7, 69.7, 53.8,
46.0, 45.2, 28.7, 24.1, 22.4, 17.8, 9.2, 2.2 ppm. Purity: 100% LCMS
(214 nm & 254 nm); retention time 1.46 min; (M+1) 317.
Example 99
1-benzyl-3-(quinuclidin-3-yl)imidazolidin-2-one
[0644] To a stirred solution of quinuclidin-3-amine hydrochloride
(324 mg, 0.199 mmol) in DMF (30 ml) was added triethylamine (3
drops) followed by (isocyanatomethyl)benzene (275 mg, 2.10 mmol)
carefully. The resultant mixture was stirred at 25.degree. C. for
18 h. After HPLC separation, 1-benzyl-3-(quinuclidin-3-yl)urea (283
mg, 55%) was obtained.
[0645] To a solution of 1-benzyl-3-(quinuclidin-3-yl)urea (260 mg,
1.00 mmol) in DMF (30 ml) was added NaH [60% dispersion in mineral
oil] (96 mg, 2.4 mmol) with ice bath cooling. The resultant mixture
was stirred for 2 h before BrCH.sub.2CH.sub.2Br (0.75 g, 4.0 mmol)
was added carefully. The reaction was stirred for an additional 18
h at about 25.degree. C. After HPLC separation, the aqueous layer
was lyophilized and purified by prep-TLC (CHCl.sub.3 to 5% MeOH in
CHCl.sub.3 to 5% 2N NH.sub.3(MeOH) in CHCl.sub.3) to give the title
compound (81 mg, 28%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.19-7.22 (m, 4H), 7.11-7.14 (m, 1H), 6.09 (dd, J=15.2, 8.4 Hz,
1H), 5.45 (dd, J=15.6, 4.0 Hz, 1H), 5.30 (dd, J=8.0, 3.6 Hz, 1H),
4.17-4.29 (m, 4H), 3.66-3.75 (m, 2H), 3.47 (d, J=12.4 Hz, 1H),
3.19-3.27 (m, 3H), 2.34 (br s, 1H), 2.22 (d, J=2.4 Hz, 1H), 1.92
(br s, 2H), 1.75 (br s, 1H) ppm. .sup.13C NMR (400 MHz, CDCl.sub.3)
.delta. 158.9, 141.1, 140.4, 128.7, 127.4, 127.3, 113.6, 63.6,
57.1, 56.0, 45.6, 43.9, 25.2, 23.0, 18.8 ppm. Purity: 93.8% HPLCMS
(210 nm); retention time 1.84 min; (M+1) 286.
Example 100
N-(1aza-bicyclo[2.2.2]oct-3-yl)-4-p-tolyl-butyramide
[0646] Using general procedure I, 1-aza-bicyclo[2.2.2]oct-3-ylamine
(200 mg, 1.00 mmol) and -p-tolyl-butyric acid (220 mg, 1.2 mmol)
gave N-(1-aza-bicyclo[2.2.2]oct-3-yl)-4-p-tolyl-butyramide (114 mg,
40%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.06 (s, 4H), 4.19 (m, 1H), 3.66-3.73 (t, J=8.4 Hz, 1H), 3.29-3.33
(m, 4H), 2.91 (dd, J=8.0, J=3.6 Hz, 1H), 2.59 (t, J=7.6 Hz, 2H),
2.28 (s, 3H), 2.24 (t, J=7.6 Hz, 2H), 2.15-2.16 (m, 1H), 2.02-2.14
(m, 1H), 1.92-2.01 (m, 2H), 1.81-1.91 (m, 3H) ppm. .sup.13C NMR
(400 MHz, CDCl.sub.3) .delta. 175.1, 138.6, 135.1, 128.8, 128.2,
52.7, 47.4, 47.3, 44.5, 34.8, 27.3, 24.3, 21.6, 19.8, 17.1 ppm.
Purity: 99.7% HPLCMS (210 nm); retention time 1.76 min; (M+1)
287.
Example 101
N-(1-aza-bicyclo[2.2.2]oct-3-yl)-4-(4-methoxy-phenyl)-butyramide
[0647] Using general procedure I, 1-aza-bicyclo[2.2.2]oct-3-ylamine
(200 mg, 1.00 mmol) and 4-(4-methoxy-phenyl)-butyric acid gave the
title compound as a white solid (85 mg, 28%). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.08 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.4 Hz, 2H),
4.18 (br s, 1H), 3.74 (s, 3H), 3.68 (d, J=11.6 Hz, 1H), 3.24-3.33
(m, 4H), 2.98-3.03 (m, 1H), 2.57 (t, J=7.6 Hz, 2H), 2.24 (t, J=7.6
Hz, 2H), 2.03-2.16 (m, 2H), 2.02 (br s, 2H), 1.85-1.91 (m, 3H) ppm.
.sup.13C NMR (400 MHz, CD.sub.3OD) .delta. 175.2, 158.3, 133.6,
129.2, 113.6, 54.5, 52.6, 47.2, 46.4, 44.5, 34.9, 34.2, 27.5, 24.4,
21.5, 17.1 ppm. Purity: 96.4% HPLCMS (210 nm); retention time 1.76
min; (M+1) 303.
Example 102
Biphenyl-3-carboxylic acid (1-aza-bicyclo[2.2.2]oct-3-yl)-amide
[0648] Using general procedure I, 1-aza-bicyclo[2.2.2]oct-3-ylamine
(200 mg, 1.00 mmol) and biphenyl-3-carboxylic acid gave the title
compound as a white solid (211 mg, 68%). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.86 (s, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.53 (d,
J=8.0 Hz, 1H), 7.40 (d, J=7.6 Hz, 2H), 7.28 (t, J=7.6 Hz, 1H), 7.19
(t, J=7.6 Hz, 2H), 7.11 (t, J=7.6 Hz, 1H), 4.21 (br s, 1H), 3.56
(t, J=11.6 Hz, 1H), 3.11-3.22 (m, 1H), 3.05-3.10 (m, 4H), 2.10 (q,
J=3.2 Hz, 1H), 1.95 (br s, 1H), 1.79-1.83 (m, 2H), 1.59-1.20 (m,
1H) ppm. .sup.13C NMR (400 MHz, CD.sub.3OD) .delta. 169.6, 141.6,
140.2, 134.5, 130.3, 129.0, 127.7, 126.9, 126.3, 125.9, 51.9, 46.4,
46.0, 45.6, 24.6, 21.6, 17.3 ppm. Purity: 99.8% HPLCMS (210 nm);
retention time 1.60 min; (M+1) 307.
Example 103
N-(1-aza-bicyclo[2.2.2]oct-3-yl)-2-biphenyl-4-yl-acetamide
[0649] Using general procedure I, 1-aza-bicyclo[2.2.2]oct-3-ylamine
(200 mg, 1.00 mmol) and biphenyl-4-yl-acetic acid gave the title
compound as a white solid (140 mg, 44%). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.56 (t, J=8.0 Hz, 4H), 7.29-7.41 (m, 5H), 4.19
(br s, 1H), 3.70 (t, J=7.2 Hz, 1H), 3.58 (s, 2H), 3.24-3.31 (m,
5H), 3.12-3.19 (m, 1H), 2.16-2.17 (m, 2H), 1.95-1.98 (m, 2H), 1.82
(br s, 1H) ppm. .sup.13C NMR (400 MHz, CD.sub.3OD) .delta. 173.1,
140.8, 140.0, 134.7, 129.4, 128.7, 126.9, 52.3, 46.4, 45.9, 44.3,
41.9, 24.4, 21.5, 17.1 ppm. Purity: 93.9% HPLCMS (210 nm);
retention time 2.87 min; (M+1) 321.
Preparation Z
Example 104
2-(quinuclidin-3-yl)-N-(1-p-tolylcyclopropyl)acetamide
[0650] To a solution of methyl 2-(dimethoxyphosphoryl)acetate (2.70
g, 14.8 mmol) in THF (200 ml) at 0.degree. C. was added NaH [60%
dispersion in mineral oil] (600 mg, 15.0 mmol). After 1 h of
stirring, quinuclidin-3-one (2.00 g, 12.4 mmol) was added and the
resultant mixture was stirred at room temperature for 18 h. The
reaction was quenched with 50 ml water at 0.degree. C. and the
mixture was extracted with EtOAc. The organic layers were combined
and concentrated under reduced pressure to afford crude methyl
2-(quinuclidin-3-ylidene)acetate, which was used in next step
without purification (1.2 g, 70%).
[0651] A mixture of methyl 2-(quinuclidin-3-ylidene)acetate (70 mg,
0.38 mmol) and Pd/C (100 mg, 20% w/w) in EtOH (10 mL) was stirred
under H.sub.2 (20 psi) at room temperature for 18 h. The reaction
solution was filtered through Celite and the filtrate was
concentrated under reduced pressure to afford crude methyl
2-(quinuclidin-3-yl)acetate (60 mg, 85%), which was used with
purification in the next step.
[0652] A mixture of methyl 2-(quinuclidin-3-yl) acetate (1.1 g, 6.0
mmol) and 50 mL of conc. HCl [12M] was stirred at 70.degree. C. for
18 h. The reaction mixture was concentrated under reduced pressure
to afford crude 2-(quinuclidin-3-yl)acetic acid, which was used
without purification in the next step (900 mg, 86%).
[0653] Using general procedure I, 2-(quinuclidin-3-yl)acetic acid
(169 mg, 1.00 mmol) and 1-p-tolylcyclopropanamine (149 mg, 1.10
mmol) gave the title compound as a white solid (60 mg, 18%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.86 (s, 1H), 6.96-7.07
(m, 4H), 3.22-3.37 (m, 2H), 2.85-3.05 (m, 4H), 2.39-2.45 (m, 2H),
2.21 (s, 3H), 1.45-1.92 (m, 5H), 1.07-1.23 (m, 5H) ppm. .sup.13C
NMR (400 MHz, CDCl.sub.3) .delta. 171.6, 139.8, 136.1, 129.2,
125.6, 52.1, 50.9, 46.5, 46.0, 39.2, 34.9, 30.8, 24.5, 21.1, 18.7,
17.6 ppm. Purity: 96.2% HPLCMS (210 nm); retention time 1.21 min;
(M+1) 299.
Example 105
N-(2-(3-methoxyphenyl)propan-2-yl)-2-(quinuclidin-3-yl)acetamide
[0654] Using general procedure I, 2-(quinuclidin-3-yl)acetic acid
(169 mg, 1.00 mmol) and 2-(3-methoxyphenyl)propan-2-amine (182 mg,
1.10 mmol) gave the title compound as a white solid (126 mg, 40%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.39 (s, 1H), 7.20 (t,
J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 6.71
(dd, J=8.0, 2.0 Hz, 1H), 3.75 (s, 3H), 3.31-3.42 (m, 2H), 3.00-3.19
(m, 4H), 2.47-2.60 (m, 2H), 2.27 (dd, J=14.0, 6.0 Hz, 1H),
1.83-2.06 (m, 4H), 1.64-1.74 (m, 1H), 1.61 (d, J=12.4 Hz, 6H) ppm.
.sup.13C NMR (400 MHz, CDCl.sub.3) .delta. 170.0, 159.7, 149.3,
129.5, 117.5, 111.8, 111.0, 55.9, 55.4, 52.0, 50.6, 46.6, 46.0,
39.7, 30.9, 29.7, 29.1, 24.3, 18.8 ppm. Purity: 93.7% HPLCMS (210
nm); retention time 0.76 min; (M+1) 317.
Example 106
2-(1-aza-bicyclo[2.2.2]oct-3-yl)-N-[1-(3-isopropyl-phenyl)-1-methyl-ethyl]-
-acetamide
[0655] To a solution of
1-(1-isocyanato-1-methyl-ethyl)-3-isopropenyl-benzene (10 g, 50
mmol) in t-BuOH (1000 mL) was added KOH (40.0 g, 71.6 mmol). The
mixture was stirred at reflux for 3 h. The resultant mixture was
cooled down to room temperature, concentrated and dissolved in
CH.sub.2Cl.sub.2. Solid residue was filtered off and the organic
layer was adjusted to pH<7 using conc. HCl. The ammonium salt
was extracted with water. The aqueous layer was made basic using an
aqueous NaOH solution [5% w/w, 200 ml] and free based amine was
then extracted with CH.sub.2Cl.sub.2. The organic layers were
combined, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to give
1-(3-isopropenyl-phenyl)-1-methyl-ethylamine (3.3 g, 63%).
[0656] A solution of the above compound (8.5 g, 48 mmol) and
PtO.sub.2 (1.8 g, 8.0 mmol) in EtOH (600 mL) was stirred at room
temperature under 1 atm of H.sub.2 for 18 h. The reaction was
filtered through Celite and concentrated under reduced pressure to
give 1-(3-isopropyl-phenyl)-1-methyl-ethylamine (5.0 g, 58%).
[0657] Using general procedure I,
(1-aza-bicyclo[2.2.2]oct-3-yl)-acetic acid (200 mg, 1.20 mmol) and
1-(3-isopropyl-phenyl)-1-methyl-ethylamine gave the title compound
as a white solid (42 mg, 10%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.15-1.20 (m, 3H), 7.05 (d, J=8.4 Hz, 1H), 3.41-3.45 (m,
1H), 3.26 (s, 2H), 3.15-3.22 (m, 2H), 2.71-2.82 (m, 2H), 2.41-2.47
(m, 3H), 2.05-2.12 (m, 1H), 1.79-1.90 (m, 4H), 1.61 (d, J=8.0 Hz,
6H), 1.21 (d, J=6.4 Hz, 6H) ppm. .sup.13C NMR (400 MHz,
DMSO-d.sub.6) .delta. 171.1, 148.7, 147.3, 128.1, 123.9, 122.8,
122.2, 55.6, 52.1, 46.5, 45.9, 38.8, 34.5, 30.7, 28.9, 28.5, 23.8,
23.4, 18.0 ppm. Purity: 96.8% HPLCMS (210 nm); retention time 1.93
min; (M+1) 329.
Example 107
2-(1-aza-bicyclo[2.2.2]oct-3-yl)-N-[2-(2-methoxy-phenyl)-ethyl]-acetamide
[0658] Using general procedure I,
(1-aza-bicyclo[2.2.2]oct-3-yl)-acetic acid (200 mg, 1.20 mmol) and
2-(2-methoxy-phenyl)-ethylamine gave the title compound as a white
solid (60 mg, 15%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.17
(t, J=7.2 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H),
6.84 (t, J=7.6 Hz, 1H), 3.89 (s, 3H), 3.35-3.45 (m, 3H), 3.21-3.31
(m, 3H), 2.76-2.83 (in, 31-1), 2.29-2.45 (m, 3H), 1.82-2.01 (m,
3H), 1.72-1.81 (m, 2H) ppm. .sup.13C NMR (400 MHz, CD.sub.3OD)
.delta. 172.0, 158.0, 130.4, 127.8, 127.2, 120.2, 110.4, 54.6,
52.0, 46.4, 45.9, 39.1, 38.3, 30.7, 30.2, 23.8, 17.9 ppm. Purity:
92.4% HPLCMS (210 nm); retention time 1.59 min; (M+1) 303.
Example 108
1-(1-aza-bicyclo[2.2.2]oct-3-yl)-3-[1-(3-isopropyl-phenyl)-cyclopropyl]-ur-
ea
[0659] A mixture of 3-isopropyl-benzoic acid (5.00 g, 30.4 mmol) in
SOCl.sub.2 (50 ml) was stirred at 100.degree. C. for 2 h. The
reaction mixture was concentrated to give 3-isopropyl-benzoyl
chloride (5.00 g, 91%).
[0660] Into a solution of the above acid chloride (5.00 g, 27.0
mmol) in CH.sub.2Cl.sub.2 (20 ml) at -70.degree. C. was added,
dropwise, a solution of NH.sub.3/CH.sub.2Cl.sub.2 (200 mL). The
mixture was stirred at room temperature for 18 h and then
concentrated to give 3-isopropyl-benzamide (4.2 g, 93%).
[0661] A solution of the above amide (4.20 g, 25.7 mmol) in
POCl.sub.3 (36.0 g, 236 mmol) was stirred at 80.degree. C. for 18
h. The solution was concentrated and the residue was poured into
water (100 mL). The mixture was exacted with EtOAc. The organic
layers were combined, washed by brine, dried over Na.sub.2SO.sub.4
and concentrated to give 3-isopropyl-benzonitrile (3.00 g,
80%).
[0662] Using general procedure G, 3-isopropyl-benzonitrile (3.00 g,
20.6 mmol) was converted to the corresponding
1-(3-isopropyl-phenyl)-cyclopropylamine (0.80 g, 22%).
[0663] Using general procedure C, the above amine (300 mg, 1.71
mmol), quinuclidin-3-amine (215 mg, 1.71 mmol) and CDI (290 mg,
2.05 mmol) gave the title compound as a white solid (88 mg, 46%).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.18 (t, J=8.0 Hz, 1H),
7.12 (s, 1H), 7.01 (dd, J=19.2, 7.6 Hz, 2H), 3.74-3.77 (m, 1H),
3.18-3.24 (m, 1H), 2.71-2.87 (m, 5H), 2.42-2.47 (m, 1H), 1.63-1.82
(m, 4H), 1.45 (br s, 1H), 1.21-1.26 (m, 10H) ppm. .sup.13C NMR (400
MHz, CD.sub.3OD) .delta. 193.0, 168.7, 160.1, 128.2, 122.7, 121.9,
55.3, 46.8, 46.1, 34.1, 25.9, 25.0, 23.5, 19.6, 18.2 ppm. Purity:
92.4% HPLCMS (210 nm); retention time 2.53 min; (M+1) 328.
Example 109
2-(1-aza-bicyclo[2.2.2]oct-3-yl)-N-[1-(3-isopropyl-phenyl)-cyclopropyl]-ac-
etamide
[0664] Using general procedure I,
1-(3-isopropyl-phenyl)-cyclopropylamine (278 mg, 1.58 mmol) and
(1-aza-bicyclo[2.2.2]oct-3-yl)-acetic acid (267 mg, 1.58 mmol) gave
the title compound as a white solid (70 mg, 14%). .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 7.16 (t, J=8.0 Hz, 1H), 7.07 (s, 1H), 6.97
(dd, J=19.2, 7.6 Hz, 2H), 3.16-3.23 (m, 1H), 2.79-2.97 (m, 5H),
2.51-2.58 (m, 1H), 2.23-2.41 (m, 3H), 1.83-1.92 (m, 1H), 1.68-1.81
(m, 3H), 1.54-1.62 (m, 1H), 1.15-1.25 (m, 10H) ppm. .sup.13C NMR
(400 MHz, CD.sub.3OD) .delta. 173.6, 148.5, 142.4, 127.8, 123.6,
123.1, 122.0, 73.0, 53.1, 46.6, 45.9, 39.3, 34.1, 32.3, 28.1, 26.4,
24.4, 19.7, 16.8 ppm. Purity: 96.9% HPLCMS (210 nm); retention time
2.55 min; (M+1) 327.
Example 110
[1-(3-isopropyl-phenyl)-cyclopropyl]-carbamic acid
1-aza-bicyclo[2.2.2]oct-3-yl ester
[0665] Using general procedure A,
1-(3-isopropyl-phenyl)-cyclopropylamine (278 mg, 1.58 mmol) and
quinuclidin-3-ol gave the title compound as a white solid (75 mg,
22%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.17 (m, 1H), 7.09
(s, 1H), 6.97-7.08 (m, 2H), 4.72-4.79 (in, 1H), 3.36-3.42 (m, 1H),
2.79-3.08 (m, 5H), 1.93-2.17 (m, 2H), 1.81-1.90 (m, 1H), 1.67-1.78
(m, 2H), 1.31-1.54 (m, 1H), 1.13-1.28 (m, 10H) ppm. .sup.13C NMR
(400 MHz, CD.sub.3OD) .delta. 157.1, 148.4, 143.1, 128.1, 123.9,
123.0, 122.4, 69.2, 54.4, 46.7, 45.7, 34.7, 34.3, 24.9, 23.3, 22.0,
18.0, 17.3 ppm. Purity: 99.2% HPLCMS (210 nm); retention time 1.83
min; (M+1) 329.
Example 111
In Vivo Efficacy Studies of Small Molecule Therapy Using
(S)-Quinuclidin-3-yl
(2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate
(S)-2-hydroxysuccinate Salt on Fabry Mouse Model
[0666] Here, in vivo experiments are described using a GCS
inhibitor in a Fabry mouse model and demonstrate that substrate
reduction therapy (SRT) is equally effective at reducing the levels
of both Gb3 and lyso-Gb3 in the plasma, kidney and urine of Fabry
mice. The study was designed to evaluate whether substrate
inhibition (i.e. "substrate reduction therapy") using a compounds
of the invention types could reduce the accumulation of the storage
material globotriaosylceramide (Gb3) and lysoglobotriaosylceramide
(lyso-Gb3). Recently it has been proposed that urinary lyso-Gb3 may
represent a reliable biomarker of clinical relevance for Fabry
disease (Aerts et al., PNAS USA 105:2812-2817 (2008); and
Auray-Blais et al., Clin Chim Acta 411:1906-1914 (2010)). The
metabolic origin of the lyso-Gb3 is not known and can conceivably
be derived through either deacylation of Gb3 or through anabolic
synthesis from glucosylsphingosine.
[0667] In FIG. 2, black arrows indicate demonstrated pathways, gray
arrows are undocumented pathways. ERT using a-Galactosidase A is
known to degrade both Gb3 and lyso-Gb3. Accordingly, SRT using a
GCS inhibitor would be most effective at limiting lyso-Gb3
accumulation if the lyso-Gb3 is generated primarily through
deacylation of Gb3, a GCS dependent pathway. These experiements
demonstrate that SRT using GCS inhibitors in a mouse model of Fabry
disease reduced both Gb3 and lyso-Gb3, thus supporting the use of
compounds of the invention as viable therapeutic options for Fabry
patients.
[0668] In the following experiments, mice dosed with GCS inhibitors
at either 60 mg/kg/day of (S)-Quinuclidin-3-yl
(2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate
(S)-2-hydroxysuccinate salt (hereinafter "GZ 452") or 300 mg/kg/day
of (1R,2R)-Octanoic acid[2-(2',3'-dihydro-benzo [1,4]
dioxin-6'-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide-L-tartaric
acid salt (hereinafter "GZ 638") as a component of the pelleted
food diet provided ad libitum. Lipid analysis was by ESI/MS as
described in Marshall et al., PLoS ONE 5:e15033 (2010). As
discussed in further detail below, treatment started when the mice
were 3, 8 or 12 months of age to test the efficacy at different
disease severities. Blood and urine was collected monthly and
periodic tissue harvests provided materials to evaluate efficacy of
the therapy (Gb3 and lyso-Gb3 levels). Previous studies
demonstrated that earlier generation glucosylceramide synthase
inhibitors (of the P4-like class) could delay the rate of Gb3
accumulation, however, as discussed below, treatment with Genz-452
could not only prevent or delay further accumulation but effected
reductions of the absolute levels of both Gb3 and lyso-Gb3 in the
tissues tested (liver, heart, urine, plasma). As further discussed
below, the efficacy of SMT was affected by the age of the mice at
the start of treatment. Generally, the older the mouse, the higher
the levels of Gb3 stored and thus a longer period of treatment was
required in order to affect similar therapeutic benefit (see FIG.
4). The experiments and results are described further below.
GCS Inhibitor Reduces Gb3 Levels in Fabry Mouse Visceral Tissue
[0669] In this experiment, Fabry mice were treated with GCS
inhibitors in their diet for 4 months starting at 8 months old. We
have previously reported that eliglustat tartrate (GZ 638) at 300
mg/kg/day (SRT GZ 638) is effective at inhibiting further
accumulation of tissue Gb3 (as shown here by the non-significant
changes in Gb3 relative to the starting levels UNT (start)). As
shown in FIG. 3, a more potent GCS inhibitor, GZ 452, was also
evaluated (at 60 mg/kg/day) (SRT-Gz452) and found not only to
prevent further accumulation but also to significantly reduce
stored Gb3 relative to the starting levels (UNT (start)).
Age-matched wild-type levels (WT) are also shown. These results
demonstrate that GZ 638 is a potent GCS inhibitor and effectively
reduces Gb3 levels in visceral tissues of the Fabry mouse.
SRT Reduces Urine and Plasma Gb3 in Both Younger and Older Fabry
Mice
[0670] In this experiment, Fabry mice were treated with GZ 452 in
their diet (Rx:) for 2 or 4 months starting at either 3 or 8 months
of age (Age:) as indicated in FIGS. 4A and 4B. The urine Gb3 levels
of younger and older mice were equally responsive to SRT treatment,
achieving .about.90% reduction with 2 months of treatment. Plasma
levels of Gb3 were slower to respond to treatment, with older mice
requiring twice the treatment time of younger mice (4 vs. 2 months)
to achieve .about.50% reduction. These results demonstrate that GZ
638 effectively reduces Gb3 levels in urine and plasma in younger
and older Fabry mice.
SRT Reduces Both Gb3 and Lyso-Gb3 in Fabry Mouse Kidney
[0671] In this experiment, Fabry mice were treated with Genz-452 in
their diet for 4 months starting at 8 months of age. As shown in
FIG. 5, kidney tissue was analyzed for (A) Gb3 and (B) lyso-Gb3
from age-matched untreated Fabry mice (UNT), GZ 452-treated Fabry
mice (SRT) and wild-type control mice (WT). SRT resulted in similar
significant relative reductions in levels (60-70%) for both Gb3 and
lyso-Gb3. These results demonstrate that GZ 638 effectively reduces
both Gb3 and Lyso-Gb3 levels in kidney tissues of Fabry mice.
Example 112
In Vivo Efficacy Studies of Combination Therapy on Fabry Mouse
Model Using GZ 452 and Alpha-Galactosidase A
[0672] Fabry mice were used to test the in vivo efficacy of
combining enzyme replacement therapy with small molecule therapy in
a concurrent treatment format. The study was designed to evaluate
whether substrate inhibition (i.e. "substrate reduction therapy")
using the GZ 452 compound could reduce re-accumulation of the
storage material Gb3 and lyso-Gb3. The study protocol called for
three distinct treatment groups of 3 month old male Fabry mice
(FIG. 6A). The first group received intravenous injections of
alpha-galactosidase A enzyme (ERT) at 1 mg/kg to reduce Gb3 levels
and was repeated every 2 months. The second group received the same
enzyme injections as group 1, but also were dosed with GZ 452 at 60
mg/kg/day as a component of the pelleted diet. The third group
received only the daily dosing of GZ 452 in their diet. A fourth
group received no treatment to serve as vehicle controls and a
fifth group of wild-type animals provided `normal` Gb3 and lyso-Gb3
values. Monthly urine and blood collections and three monthly
tissue harvests provide materials to evaluate relative efficacy of
the therapies (FIG. 6A).
[0673] After 2 months (mice were 5 months old), plasma (FIG. 6B,
panels A and C) and urine (FIG. 6B, panels B & D) were analyzed
for Gb3 (FIG. 6B, panels A and B) and lyso-Gb3 (FIG. 6B, panels C
and D). In plasma, ERT and SRT reduced both Gb3 (panel A) and
lyso-Gb3 (panel C) levels, and combining ERT and SRT resulted in
significant improvements over either therapeutic alone. Urine Gb3
levels were unaffected by ERT, but significantly reduced by SRT
(panel B). Urine lyso-Gb3 was similarly reduced by all treatments
(panel D), suggesting that urine Gb3 and lyso-Gb3 may originate
from distinct sources. The results from these studies show that the
SMT was effective at reducing Gb3 in the kidney and urine. ERT was
more effective than SMT at reducing Gb3 in the plasma, however the
most effective therapy was derived from combining the two
therapies. SMT therapy alone or in combination with ERT was also
capable of affecting (reducing accumulation) of lyso-Gb3.
Example 113
[0674] Gb3 Acyl Chain isoform Profile The relative abundance of the
different carbon chain length amido-linked acyl groups was
determined for Gb3 from plasma, urine and kidney of Fabry mice. As
shown in FIG. 7, major plasma isoforms were C16:0 and C24:1. Urine
and kidney isoform profiles were nearly identical, with C24:0 and
C22:0 being the predominant chain lengths. These data are
consistent with urine Gb3 coming predominantly from the
kidney--probably through epidermal exosomal shedding. Correlating
these results with those in FIG. 6, in which ERT reduced plasma and
urine lyso-Gb3 but not urine Gb3, suggests that the lyso-Gb3 in
urine is derived from plasma filtrate. This differentiation of
source for urine Gb3 and lyso-Gb3, if also true for patients, may
explain why lyso-Gb3 is thought to be a more accurate predictor of
disease severity and treatment efficacy than urine Gb3.
Example 114
SRT but not ERT Significantly Delays Loss of Thermal Nociceptive
Response
[0675] Three month old Fabry mice were treated with GZ 452 in their
diet (SRT), .alpha.gal once every 2 months (ERT), or a combination
of the 2 treatments (E+S), as described above. After 6 months of
combination therapy, the thermal nociceptive response time
(latency) was evaluated by placing the mice on a 55.degree. C.
hotplate and recording the time to respond (i.e., a distinctive
hind-paw flick). As shown in FIG. 8, after 7 months of treatment
(10 month old mice) the ERT-only treated group was not
significantly different to the untreated group (UNT). The SRT and
combination treated groups had significantly shorter response times
to the heat stimulus. These results demonstrate that SRT (but not
ERT) delayed the loss of a thermal nociceptive response, a
surrogate for the peripheral neuropathy often seen in Fabry
patients.
Example 115
nGD Mouse Model for In Vivo Studies of SMT Using Gz161
[0676] K14 InI/InI (abbreviated as K14) mice were obtained from
Lund University (Enquist et al. (2007)) and bred under a protocol
approved by the Institutional Animal Care and Use Committee. Pups
obtained from heterozygote matings were tail clipped and genotyped
within one day of birth (by P1). The DNA was extracted using a
lysis buffer of 5 mM EDTA, 0.2% SIDS, 200 mM NaCl, 100 mM. Tris pH
8.0 supplemented with 0.25 mg/ml Proteinase K (Invitrogen,
Carlsbad, Calif.), precipitated with 100% isopropanol and
redissolved in 1.times. Tris EDTA buffer. The DNA was then used for
polymerase chain reaction (PCR) to determine the presence of the GC
gene under the K14 keratin promoter (CRE) (Enquist et al. (2007)).
To determine the Neomycin resistance site disruption of the murine
glucocerebrosidase gene (NEO) we used a three primer approach: GC
WT Fwd 5'-TGTTCCCCAACACAATGCTCTTT-3'; Rev
5'-TCTGTGACTCTGATGCCACCTTG-3' and Neo Rev 5'-AAGACAGAATAAAACGCACGG
GTG-3' as previously described in Cabrera-Salazar et al.,
Experimental Neurology 225: 436-444 (2010).
[0677] Newborn mice received daily 5 mg/kg intraperitoneal
injections of Quinuclidin-3-yl
(2-(4'-fluoro-[1,1'-biphenyl]-3-yl)propan-2-yl)carbamate
(hereinafter "GZ 161") in a volume of 10 .mu.l/gram of body weight
starting at postnatal day 4. K14 mice and wild type littermates
were humanely sacrificed at postnatal day 10 (pre-symptomatic) and
at day 14 (humane endpoint) to evaluate glycosphingolipid (GSL)
levels. Mice received a 150 mg/kg dose of pentobarbital (Euthasol,
Virbac Inc, Fort Worth, Tex.) and were transcardially perfused with
cold 0.9% NaCl solution. Brains were dissected and divided; one
hemisphere was used for GSL analysis and the other was fixed in 4%
paraformaldehyde for 96 hours and processed for histology.
[0678] To determine if further benefits could be achieved by
prenatal exposure to GZ 161, a subset of pregnant K14 females
received GZ 161 in food using a formulation calculated to provide
20 mg/kg/day during the final 5-7 days of gestation. Females
receiving GZ 161 were switched to standard diet after delivery and
the pups received daily IP injections of GZ 161 at a dose of 5
mg/kg (10 .mu.l per gram of body weight) starting at P1. A set of
WT pups born to females receiving the drug or standard formula was
sacrificed immediately after birth to determine whether in utero
exposure to GZ 161 could reduce brain GSL levels.
Example 116
Glycosphingolipid Quantitation
[0679] Quantitative sphingolipid analysis was performed by liquid
chromatography and tandem mass spectrometry (LC/MS/MS) as
previously described in Merrill et al., Methods 36: 207-224 (2005).
Briefly, 10 .mu.l of brain tissue homogenate (tissue weight/water:
100 mg/ml) was extracted with 1.00 ml of an organic solvent mixture
(97% acetonitrile, 2% methanol, and 1% acetic acid, v/v) and
vortexed vigorously for 10 min. Extracted sphingolipids (GluCer and
GluSph) were directly separated by hydrophilic liquid
chromatography (Atlantis HILIC column, Waters Corp.) and analyzed
by triple quadrupole tandem mass spectrometry (API 4000, Applied
Biosystems/MDS SCIEX) and compared with sphingolipid standards
(Matreya, LLC; Pleasant Gap, Pa.)
Example 117
Reformulation of Recombinant Human Glucocerebrosidase
[0680] Recombinant human glucocerebrosidase (rhGC) was reformulated
as previously described in Cabrera-Salazar et al. (2010). Briefly,
rhGC was bound using a cation-exchange (CM Sepharose) and human
serum albumin (HSA) was added to the eluate as a stabilizer. The
formulation for ICV administration was 2 mg/ml rhGC in a 10 mM
sodium phosphate buffer at pH 7.2 containing 135 mM sodium
chloride, 5 mg/ml HSA and 0.01% polysorbate 80.
Example 118
Intracerebroventricular Injections
[0681] An animal model of neuropathic Gaucher disease (nGD)
identified as K14 were cryoanesthesized and received 2 .mu.l
bilateral intracerebroventricular (ICV) injections of either rhGC
at 2 mg/ml or vehicle as previously described. (Cabrera-Salazar et
al. (2010)) The injected pups were monitored for recovery and
returned to the mother following the procedure.
Example 119
Histopathology
[0682] After genotype confirmation, animals were humanely
sacrificed at 10 days of age, At this age K14 mice are
asymptomatic. Mice received an intraperitoneal injection of 150
mg/kg sodium pentobarbital ((Euthasol, Virbac Inc, Fort Worth,
Tex.) and were perfused by an intracardial infusion of chilled 0.9%
sodium chloride. Brains were removed and post fixed in 4%
paraformaldehyde for 72 hours. Tissue was transferred to PBS and
paraffin embedded. Sagital sections 5 .mu.m thick were cut and
stained as described below. Gliosis and the presence of cells of
the macrophage lineage were evaluated by means of glial fibrillary
acidic protein staining and expression of CD68 and F4/80
pan-macrophage markers using the Leica Bond Max Immunostainer
system (Leica Microsystems, Wetzlar, Germany).
[0683] GFAP staining: Paraffin sections were placed on mounting
slides and processed using the Bond Polymer Refine IHC system
(Leica Microsystems, Wetlzar, Germany) blocked for 10 minutes in
serum-free protein block (Dako systems, Glostrup, Denmark),
incubated for 30 minutes in a 1:1500 dilution of primary anti-GFAP
antibody in Dako antibody diluent (Dako, Glostrup, Denmark), and
stained using the Bond Polymer Refine detection kit (Leica
Microsystems, Wetzlar, Germany).
[0684] F4/80 staining: Paraffin sections were placed on mounting
slides and processed using the Bond Polymer Refine IHC system
(Leica Microsystems, Wetlzar, Germany), incubated for 30 minutes in
a 1:2500 dilution of rat anti-mouse F4/80 antibody (eBioscience,
San Diego, Calif.) or Rat IgG2a (eBioscience, San Diego, Calif.) as
an isotype control. Slides were then incubated with a 1:250
dilution of rabbit anti-rat secondary antibody (Vector
laboratories, Burlingame, Calif.) and stained using the Bond
Polymer Refine detection kit (Leica Microsystems, Wetzlar,
Germany).
[0685] CD 68 staining: Paraffin sections were placed on mounting
slides and processed using the Bond Polymer Refine IHC system
(Leica Microsystems, Wetlzar, Germany), incubated for 30 minutes in
a 1:2500 dilution of rat anti-mouse CD68 clone FA-11 antibody (AbD
Serotec, Oxford, UK) or Rat IgG2a isotype control (AbD Serotec,
Oxford, UK). Slides were then incubated with a 1:250 dilution of
rabbit anti-rat secondary antibody (Vector laboratories,
Burlingame, Calif.) and stained using the Bond Polymer Refine
detection kit (Leica Microsystems, Wetzlar, Germany).
[0686] For each staining technique exposure-matched digital images
were obtained from similar brain regions of each experimental group
using the Aperio ScanScope XT system (Aperio Technologies, Vista,
Calif.). Stained slides were digitalized in high resolution and six
areas of interest were highlighted in each slide and analyzed
independently by histomorphometry. Positively stained area and
nuclei were determined and quantitative data were analyzed by a
one-way analysis of variance followed by Tukey's multiple
comparison test using the Graph Pad Prism V 4.0 (GraphPad Software,
San Diego, Calif.). Differences between group means with p<0.05
were considered significant.
Example 119
Survival
[0687] K14 mice received daily intraperitoneal injections of GZ 161
at a dose of 5 mg/kg of body weight as described above. A separate
cohort of animals also received ICV injections of GC at postnatal
days 1, 2 and 3 followed by daily IP injections of GZ 161. Animals
that reached weaning age received GZ 161 in a special chow designed
to provide a dose of 60 mg/kg/day. All animals were monitored daily
for the development of neurological complications. Mice were
sacrificed when they reached a humane endpoint (inability to right
within 10 seconds after being placed in lateral recumbence) by an
injection of 150 mg/kg sodium pentobarbital (Euthasol, Virbac Inc,
Fort Worth, Tex.). This time point was recorded as end of life and
analyzed using Kaplan-Meier plots.
Example 120
Statistical Analysis
[0688] Values shown correspond to means and error bars represent
standard error of the mean. Comparisons between groups were
analyzed by a one-way analysis of variance followed by Tukey's
multiple comparison test. Comparison of substrate reduction in
utero was analyzed by the unpaired t test with Welch's correction.
Kaplan-Meier survival curves were analyzed using the log-rank test
equivalent to the Mantel-Haenszel test. All statistical analyses
were performed using GraphPad Prism v4.0 (GraphPad Software, San
Diego, Calif.). Differences between group means with p<0.05 were
considered significant.
Example 121
Substrate Accumulation in K14 Mouse Brain
[0689] Before evaluating drug effects on brain lipids, we compared
the time dependent changes in GluCer, GalCer and GluSph levels in
the K14 mouse brain to those of a wild type (WT) mouse control.
FIG. 9, panels A and B show that in WT mouse brain, the predominant
GL-1 isomer in the first few days of life was GluCer; by postnatal
day 14 (P14) the predominant isomer was GalCer. These results are
consistent with those of a study in rat brain, which found that
GluCer is synthesized at a higher rate during the first week of
life and is followed by an increased synthesis of GalCer starting
at P8 (Brenkert et al., Brain Research 36: 183-193 (1972)). FIG. 9,
panel A also shows that in K14 mice GluCer was elevated 10-fold
relative to WT mice and that this increase was sustained through
the first 2 weeks of life until the mice died around P14.
[0690] In agreement with previous mouse models of neuropathic
Gaucher disease (Liu et al., PNAS 95: 2503-2508 (1998)), FIG. 9,
panel C shows that at birth the lysoglycosphingolipid GluSph was
elevated >20-fold in the brains of the K14 mouse model relative
to WT mice. This increase was sustained through the first 2 weeks
of life and was even higher in animals sacrificed at end stage
(FIG. 9, panel C). In WT littermates of the K14 mice, GluSph levels
were below the threshold of detection (0.3 ng/mg of tissue). FIG.
9, panel D shows that these elevated glycosphingolipids and
lysoglycosphingolipids in the K14 mouse did not appear to have an
impact on brain weight (relative to that of WT mice). Given the
known toxicity of GluSph, therapeutic strategies geared towards
reducing the accumulation of these substrates in the K14 mouse
brain might be expected to have an impact on the pathologic
features of the disease and the lifespan of the animals.
Example 122
Intraperitoneal Administration of GZ 161 Reduces GluCer and GluSph
Levels in the Brains of K14 Mice
[0691] FIG. 10 shows that compared to vehicle-treated K14 mice at
the humane endpoint (14-15 days of age), daily intraperitoneal (IP)
administration of GZ 161 reduced brain levels of both GluCer and
GluSph by >60%. K14 mice treated with GZ 161 were asymptomatic
at this time point. Even though GZ 161 administration significantly
reduced the levels of these glycosphingolipids, FIG. 10 shows that
they nonetheless remained elevated several-fold over those of
age-matched wild-type mice; GluSph was not detected in samples
analyzed from WT or heterozygote littermates. The reduction of
brain glycosphingolipids as a consequence of systemic drug
administration strongly suggests that GZ 161 is both capable of
crossing the blood brain barrier and inhibiting its target enzyme,
GCS.
Example 123
Intraperitoneal Administration of Gz 161 Reduces
Microglial/Macrophage Staining Throughout the Brain of K14 Mice
[0692] Cells of the myeloid lineage can be detected in the murine
brain using antibodies to antigens such as F4/80 and CD68. F4/80 is
a transmembrane glycoprotein found on ramified (quiescent)
microglia and macrophages, while CD68 is a lysosomal protein
expressed at relatively high levels in macrophages and activated
(reactive) microglia, and at lower levels in ramified microglia.
Increased F4/80 and CD68 staining in the brain may occur through
recruitment of monocytes or microglial proliferation, and is a
normal response to injury and inflammation. FIG. 11 shows
qualitatively and quantitatively that compared to wild type mice at
10 days of age (P10), the K14 mouse brain has increased numbers of
CD68+ cells in multiple locations (hippocampus, thalamus,
brainstem, cerebellum). The greatest concentration of CD68+ cells
was seen in the thalamus and brainstem, two sites that also show
pathology in type 2 Gaucher patients. (Conradi et al., Acta
Neuropathologica 65: 99-109 (1984); Conradi et al., Acta
Neuropathologica 82: 152-157 (1991); and Wong et al., Molecular
Genetics and Metabolism 82: 192-207 (2004)). FIG. 11 also shows
that systemic administration of GZ 161 reduces the numbers of CD68+
cells in all of these locations; treatment also reduced CD68+ cells
in the olfactory bulb and frontal cortex (data not shown).
Consistent with the CD68 histopathology, FIG. 12 shows increased
F4/80 staining relative to WT animals in vehicle treated K14 mice
at P10. Daily IP injections of GZ 161 reduced the numbers of F4/80+
cells in the thalamus and brainstem, but had marginal effects in
other brain regions. Taken together with the CD68 data, these
results suggest that systemic treatment of the K14 mouse with GZ
161 results in decreased numbers of macrophages/microglia in
multiple brain regions.
Example 124
Intraperitoneal Administration of GZ 161 Reduces Gliosis in Several
Brain Regions of K14 Mice
[0693] Astrocytes can undergo hypertrophy or proliferate in
response to inflammation and neuronal damage or death, a process
known as astrogliosis. Glial fibrillary acidic protein (GFAP) is an
intermediate filament protein that is heavily expressed in
activated (reactive) astrocytes, and can therefore be used to
monitor astrogliosis. FIG. 13 shows that at P10 GFAP staining was
increased compared to WT levels in several brain regions
(hippocampus, thalamus, brainstem, cerebellum) of the K14 mouse,
indicating the presence of reactive astrocytes. FIG. 13 also shows
that systemic treatment of K14 mice with GZ 161 led to decreased
GFAP staining in the hippocampus and cerebellum at P10; staining
was also decreased in the olfactory bulb and frontal cortex (data
not shown). Thus, these GFAP results are consistent with the above
macrophage/microglial data demonstrating that the K14 mouse likely
has an ongoing inflammatory process that can be attenuated to some
degree by systemic administration of GZ 161.
Example 125
Intraperitoneal Administration of GZ 161 Increases Survival of K14
Mice
[0694] Given the positive effects of GZ 161 treatment on brain
glycosphingolipids and histopathology, we asked whether these
effects translated into increased survival of the K14 mouse. FIG.
14 demonstrates that vehicle treated K14 mice have a median
lifespan of 15 days, consistent with our previous findings in this
mouse model (Cabrera-Salazar et al. (2010)). Systemic (IP)
treatment of K14 mice with GZ 161 resulted in an extension in
median lifespan to 18 days (p<0.0001), consistent with a benefit
of the molecular and cellular effects of the drug in the brain
shown above.
[0695] In previous experiments, it was shown in the K14 mouse that
neonatal (P1-P3) intracerebroventricular injections of GC could
extend median survival even further, viz., to 23 days
(Cabrera-Salazar et al. (2010)). Because GC and GZ 161 both have
the potential to decrease levels of the same glycosphingolipid,
namely GluCer (GC by degrading GluCer; GZ 161 by inhibiting its
synthesis) we also asked whether the combination of Gz161 and
intracerebroventricular (ICV) administration of GC would provide
survival benefit superior to that resulting from either individual
agent. FIG. 14 demonstrates that the combination of ICV GC (at
P1,2,3) and daily IP Gz161 led to a median survival of 26 days,
significantly greater than GZ 161 alone or ICV GC (p=0.0007). Thus,
systemic administration of GZ 161 appears to be additive to ICV GC,
and provides additional survival benefit.
Example 126
Prenatal Administration of GZ 161 Fails to Increase Survival of K14
Mice
[0696] Because the GluSph levels in the K14 mouse brain were found
to be elevated at least 10-fold over normal at P1, and it has been
documented that GluSph is elevated in the brains of mice and humans
affected by nGD even prenatally (Orvisky et al., Pediatric Research
48: 233-237 (2000)), it was investigated whether a survival
advantage could be gained by treating K14 mice with GZ 161 in
utero. FIG. 15 shows that treating WT mouse dams with GZ 161 led to
an 5-fold decrease in GluCer levels in the newborn mouse brain
(P0), suggesting that GZ 161 could cross the blood/placental
barrier. However, giving K14 dams GZ 161 and then treating the
resulting pups IP with GZ 161 failed to extend survival beyond that
of mice given systemic GZ 161 postnatally alone (18 days) (FIGS. 14
and 16). These data are thus consistent with the results described
in FIG. 14, and imply that although GZ 161 can effect reductions in
glycosphingolipids and neuropathology, the current treatment regime
is insufficient to rescue the CNS. These results are consistent
with our previous results in this model using
intracerebroventricular injections of recombinant human
glucocerebrosidase (Cabrera-Salazar et al. (2010)), and together
suggest that more robust and continuous depletion of
glycosphingolipids such as GluCer will be necessary to improve
survival further.
[0697] These data show both qualitatively and quantitatively that
systemic (IP) administration of GZ 161 to neonatal K14 mice
significantly reduces substrate load, ameliorates the pathological
features of the disease and increases median lifespan. When
combined with ICV-delivered rhGC, systemic administration of GZ 161
resulted in additive increases in lifespan, implying that such a
combination might be more efficacious than either monotherapy alone
in nGD patients. Given the implications of these studies that GZ
161 can apparently cross the BBB and inhibit its target enzyme,
glucosylceramide synthase, it is reasonable to assume that this
molecule could also be used to treat other LSDs resulting from a
buildup of substrates downstream from GluCer.
[0698] It is important to note that in the current studies, GZ 161
was administered to K14 mice in a time frame in which GluCer and
GluSph were being produced in the developing mouse brain at
relatively high levels compared to WT mice (FIG. 9); Brenkert et
al., 1972). Daily IP treatment with GZ 161 successfully reduced,
but did not normalize GluCer and GluSph levels in the K14 brain
(FIG. 10). There are several lines of evidence suggesting that
GluSph and other lysosphingolipids such as galactosyl sphingosine
may contribute to CNS pathology by initiating the production of
inflammatory mediators Giri et al., Journal of lipid research 47:
1478-1492 (2006) and Graler et al., Molecular and Cell Biology of
Lipids 1582: 168-174 (2002). The ability of GZ 161 to decrease
GluSph levels and concurrently result in decreased
macrophage/microglial and astrocyte staining (FIGS. 11-13) is
consistent with this hypothesis. Because GluSph also has known
neurotoxic properties (Schueler et al., Neurobiology of Disease 14:
595-601 (2003); Orvisky et al., Molecular Genetics and Metabolism
76: 262-270 (2002); Sun et al., Hum Mol Genet 19: 1088-1097 (2010);
and Pelled et al., Journal of Inherited Metabolic Disease 23:
175-184 (2000)), the inability of GZ 161 treatment to normalize
GluSph levels is consistent with GluSph as a potential contributor
to the early death seen in this model.
[0699] Taken together, the preclinical results in the K14 mouse
model shown here suggest that administration of GZ 161 may mitigate
disease progression and neurologic symptoms in type 2 and type 3
Gaucher disease patients. However, it is difficult to predict the
potential benefits of such a therapeutic approach in symptomatic
type 2 patients since it is known that their brains contain very
high levels of GluSph that date back to prenatal life. Goker-Alpan
et al., The Journal of Pediatrics 143: 273-276 (2003). Type 3
Gaucher disease may be more amenable to treatment since the brain
levels of GluSph are lower (Nilsson, J Neurochem 39: 709-718
(1982), the progression of the disease is slower despite being part
of a phenotypic continuum (Goker-Alpan et al. (2003)), and in some
cases the patients can be identified by mutational analysis before
the onset of the neuropathic phenotype (Ida et al., Human Genetics
105: 120-126 (1999)). Based on the current results, it would appear
that an early, aggressive approach will be needed to treat these
patients. Small molecule inhibitors of glucosylceramide synthase
may represent one arm of a comprehensive approach.
Example 127
SMT of Male and Female Fabry Mice Treated with GZ 452, GZ 161 and
GZ 638
[0700] Fabry mice began treatment at .about.8 months old and were
treated for 4 months with: 60 mg/kg/day GZ 452 (Fab 452@ 60 mkd),
120 mg/kg/day GZ 452 (Fab 452 @120 mkd), 20 mg/kg/day GZ 161 (Fab
161 @20 mkd), 300 mg/kg/day GZ 638 (Fab 638 @300 mkd). Kidney
tissue from 12 month old male and female Fabry mice were tested for
Gb3 levels. As shown in FIG. 17, GZ 161 and GZ 452 significantly
reduced the amount of Gb3 present in kidney tissue relative to
untreated controls (Fab UNT 12 mo).
Sequence CWU 1
1
3123DNAArtificial Sequenceoligonucleotide primer 1tgttccccaa
cacaatgctc ttt 23223DNAArtificial Sequenceoligonucleotide primer
2tctgtgactc tgatgccacc ttg 23324DNAArtificial
Sequenceoligonucleotide primer 3aagacagaat aaaacgcacg ggtg 24
* * * * *