U.S. patent application number 14/813397 was filed with the patent office on 2015-12-24 for compounds and methods for modulating fxr.
This patent application is currently assigned to NOVARTIS AG. The applicant listed for this patent is Phillip Alper, Donatella CHIANELLI, Daniel Mutnick, Vincent Paul Rucker, David C. Tully. Invention is credited to Phillip Alper, Donatella CHIANELLI, Daniel Mutnick, Vincent Paul Rucker, David C. Tully.
Application Number | 20150366856 14/813397 |
Document ID | / |
Family ID | 45349296 |
Filed Date | 2015-12-24 |
United States Patent
Application |
20150366856 |
Kind Code |
A1 |
Tully; David C. ; et
al. |
December 24, 2015 |
COMPOUNDS AND METHODS FOR MODULATING FXR
Abstract
The present invention relates to compounds of Formula (I),
##STR00001## a stereoisomer, enantiomer, a pharmaceutically
acceptable salt or an amino acid conjugate thereof; wherein
variables are as defined herein; and their pharmaceutical
compositions, which are useful as modulators of the activity of
Farnesiod X receptors (FXR).
Inventors: |
Tully; David C.; (Danville,
CA) ; Rucker; Vincent Paul; (Carlsbad, CA) ;
Alper; Phillip; (San Diego, CA) ; Mutnick;
Daniel; (Concord, CA) ; CHIANELLI; Donatella;
(San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Tully; David C.
Rucker; Vincent Paul
Alper; Phillip
Mutnick; Daniel
CHIANELLI; Donatella |
Danville
Carlsbad
San Diego
Concord
San Diego |
CA
CA
CA
CA
CA |
US
US
US
US
US |
|
|
Assignee: |
NOVARTIS AG
Basel
CH
|
Family ID: |
45349296 |
Appl. No.: |
14/813397 |
Filed: |
July 30, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13993138 |
Jun 11, 2013 |
9150568 |
|
|
PCT/US2011/062724 |
Nov 30, 2011 |
|
|
|
14813397 |
|
|
|
|
61554297 |
Nov 1, 2011 |
|
|
|
61425189 |
Dec 20, 2010 |
|
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Current U.S.
Class: |
514/255.05 ;
514/275; 514/278; 514/304 |
Current CPC
Class: |
C07D 451/06 20130101;
A61P 15/10 20180101; A61K 31/4709 20130101; A61K 31/46 20130101;
A61P 17/02 20180101; A61P 25/00 20180101; C07H 17/00 20130101; C07D
471/04 20130101; A61P 1/16 20180101; A61P 9/10 20180101; A61P 43/00
20180101; A61P 1/04 20180101; A61P 9/12 20180101; A61P 27/02
20180101; A61K 31/497 20130101; A61K 45/06 20130101; A61K 31/501
20130101; A61P 25/28 20180101; A61P 3/04 20180101; A61P 3/00
20180101; A61P 31/04 20180101; A61P 13/12 20180101; A61P 9/00
20180101; A61P 35/00 20180101; A61K 31/506 20130101; A61P 3/06
20180101; A61P 33/02 20180101; A61K 31/5025 20130101; A61K 31/706
20130101; C07D 487/04 20130101; A61P 3/10 20180101; A61P 13/08
20180101; A61P 1/00 20180101; C07D 519/00 20130101 |
International
Class: |
A61K 31/46 20060101
A61K031/46; A61K 31/497 20060101 A61K031/497; A61K 31/506 20060101
A61K031/506 |
Claims
1. A method for treating a condition mediated by FXR in a subject
suffering therefrom, comprising administering to a subject a
therapeutically effective amount of a compound of Formula (I-A),
(I-D), (I-E) or (I-H): ##STR00357## or a pharmaceutically
acceptable salt thereof; wherein R.sup.1 is phenyl substituted with
1-3 R.sup.1a; R.sup.3 is X--CO.sub.2R.sup.4; X is a bond; R.sup.4
is hydrogen or C.sub.1-6 alkyl; R.sup.1a and R.sup.6 are
independently halogen, C.sub.1-6 alkyl, haloC.sub.1-6 alkyl,
C.sub.1-6 alkoxy, haloC.sub.1-6 alkoxy; and m is 0-1.
2. The method of claim 1, wherein R.sup.6 is methyl, methoxy,
fluoro or trifluoromethoxy.
3. The method of claim 1, wherein said condition is cholestasis,
intrahepatic cholestasis, estrogen-induced cholestasis,
drug-induced cholestasis, cholestasis of pregnancy, parenteral
nutrition-associated cholestasis, primary biliary cirrhosis (PBC),
primary sclerosing cholangitis (PSC), progressive familiar
cholestasis (PFIC), non-alcoholic fatty liver disease (NAFLD),
non-alcoholic steatohepatitis (NASH), drug-induced bile duct
injury, gallstones, liver cirrhosis, alcohol-induced cirrhosis,
cystic fibrosis, bile duct obstruction, cholelithiasis, liver
fibrosis, dyslipidemia, atherosclerosis, diabetes, diabetic
nephropathy, colitis, newborn jaundice, kernicterus, veno-occlusive
disease, portal hypertension, metabolic syndrome,
hypercholesterolemia, intestinal bacterial overgrowth, or erectile
dysfunction.
4. The method of claim 3, wherein said condition is primary biliary
cirrhosis (PBC).
5. The method of claim 1, wherein said compound is administered in
combination with a second therapeutic agent.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent Ser. No.
13/993,138, which is a 371 U.S. national phase application of
international application number PCT/US2011/062724 filed 30 Nov.
2011, and claims the benefit of U.S. provisional patent application
No. 61/554,297 filed 1 Nov. 2011; and of U.S. provisional Ser. No.
61/425,189 filed 20 Dec. 2010; each of which is incorporated herein
by reference in its entirety.
TECHNICAL FIELD
[0002] The present invention relates to compositions and methods
for modulating the activity of farnesoid X receptors (FXRs).
BACKGROUND
[0003] The farnesoid X receptor (FXR) is a member of the nuclear
hormone receptor superfamily and is primarily expressed in the
liver, kidney and intestine (see, e.g., Seol et al. (1995) Mol.
Endocrinol. 9:72-85 and Forman et al. (1995) Cell 81:687-693). It
functions as a heterodimer with the retinoid X receptor (RXR) and
binds to response elements in the promoters of target genes to
regulate gene transcription. The FXR-RXR heterodimer binds with
highest affinity to an inverted repeat-1 (IR-1) response element,
in which consensus receptor-binding hexamers are separated by one
nucleotide. FXR is part of an interrelated process, in that FXR is
activated by bile acids (the end product of cholesterol metabolism)
(see, e.g., Makishima et al. (1999) Science 284: 1362-1365, Parks
et al. (1999) Science 284:1365-1368, Wang et al. (1999) MoI. Cell.
3:543-553), which serve to inhibit cholesterol catabolism. See
also, Urizar et al. (2000) J. Biol. Chem. 275:39313-39317.
[0004] FXR is a key regulator of cholesterol homeostasis,
triglyceride synthesis and lipogenesis. (Crawley, Expert Opinion
Ther. Patents (2010), 20(8): 1047-1057). In addition to the
treatment of dyslipidemia, multiple indications for FXR have been
described, including treatment of liver disease, diabetes, vitamin
D-related diseases, drug-induced side effects and hepatitis.
(Crawley, supra). While advances have been made in the development
of novel FXR agonists, significant room for improvement remains. It
is the object of the present invention to provide novel compounds
that are agonists or partial agonists of FXR exhibiting
physicochemical, in vitro and/or in vivo ADME (adsorption,
distribution, metabolism and excretion) properties superior to
known agonists of FXR and/or superior pharmacokinetics in vivo.
DISCLOSURE OF THE INVENTION
[0005] The present invention relates to compositions and methods
for modulating the activity of farnesoid X receptors (FXRs). In one
aspect, the present invention relates to compounds which act as
agonists or partial agonists of FXR.
[0006] In a first embodiment, the compounds of the invention are
defined by Formula (I):
##STR00002##
[0007] or a stereoisomer, enantiomer, a pharmaceutically acceptable
salt or an amino acid conjugate thereof;
[0008] Z is phenylene, C.sub.5-7 cycloalkylene or 5-10 membered
monocyclic or bicyclic heteroaryl containing 1-2 heteroatoms
selected from N, O and S; each of which is optionally substituted
with 1-2 R.sup.6 radicals selected from halogen, C.sub.1-6 alkyl,
haloC.sub.1-6 alkyl, C.sub.1-6 alkoxy, haloC.sub.1-6 alkoxy, or
cyclopropyl;
[0009] R.sup.1 is phenyl, pyridyl, bicyclo[3.1.0]hexanyl,
spiro[2.3]hexanyl, bicyclo[3.1.1]heptanyl, spiro[2.5]octanyl,
bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexan-6-yl,
spiro[2.3]hexan-5-yl, bicyclo[3.1.1]heptan-3-yl,
spiro[2.5]octan-4-yl, bicyclo[4.1.0]heptan-3-yl, cyclohexyl or
cyclopentyl, each of which is optionally substituted with 1-3
R.sup.1a; or R.sup.1 is cyclopropyl optionally substituted with 1-2
R.sup.1a or phenyl;
[0010] R.sup.1a is halogen, C.sub.1-6 alkyl, haloC.sub.1-6 alkyl,
C.sub.1-6 alkoxy, haloC.sub.1-6 alkoxy or cyclopropyl;
[0011] R.sup.2 is C.sub.1-3 alkyl, haloC.sub.1-3 alkyl or
cyclopropyl optionally substituted with C.sub.1-3 alkyl or
haloC.sub.1-3 alkyl;
[0012] R.sup.3 is --X--CO.sub.2R.sup.4, hydroxyC.sub.1-6 alkyl,
CONR.sup.4R.sup.5, CONR(CR.sub.2).sub.1-4CO.sub.2R.sup.4,
CONR(CR.sub.2).sub.1-4SO.sub.3R.sup.5 or tetrazolyl; wherein X is a
bond, C.sub.1-2 alkylene or cyclopropyl; and
[0013] R, R.sup.4 and R.sup.5 are independently hydrogen or
C.sub.1-6 alkyl.
[0014] In a second embodiment, the compounds of the invention are
defined by Formula (I) wherein R.sup.2 is cyclopropyl.
[0015] In a third embodiment, the compounds of the invention are
defined by Formula (I) in any of the first or second embodiments,
wherein Z is phenylene, pyridylene, pyrimidinylene, pyrazinylene,
pyridazinylene, thiazolylene, benzothiazolyl, benzo[d]isothiazolyl,
imidazo[1,2-a]pyridinyl, quinolinyl, 1H-indolyl,
pyrrolo[1,2-b]pyridazinyl, benzofuranyl, benzo[b]thiophenyl,
1H-indazolyl, benzo[d]isoxazolyl, quinazolinyl,
1H-pyrrolo[3,2-c]pyridinyl, pyrazolo[1,5-a]pyrimidinyl,
imidazo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl; each of which
is optionally substituted with 1-2 R.sup.6 radicals selected from
halogen, C.sub.1-6 alkyl, haloC.sub.1-6 alkyl, C.sub.1-6 alkoxy,
haloC.sub.1-6 alkoxy, or cyclopropyl.
[0016] In a fourth embodiment, the compounds of the invention are
selected from the group consisting of:
##STR00003##
[0017] or a stereoisomer, enantiomer, a pharmaceutically acceptable
salt or an amino acid conjugate thereof; m is 0-1; and R.sup.1,
R.sup.3 and R.sup.6 are as defined in Formula (I).
[0018] In a fifth embodiment, the compounds of the invention are
selected from the group consisting of:
##STR00004## ##STR00005##
[0019] or a stereoisomer, enantiomer, a pharmaceutically acceptable
salt or an amino acid conjugate thereof; m is 0-1; and R.sup.1,
R.sup.3 and R.sup.6 are as defined in Formula (I).
[0020] In a sixth embodiment, the compounds of the invention are
selected from the group consisting of:
##STR00006## ##STR00007##
[0021] or a stereoisomer, enantiomer, a pharmaceutically acceptable
salt or an amino acid conjugate thereof, wherein:
[0022] X.sup.1 and X.sup.2 are independently N, CH or CR.sup.6;
[0023] X.sup.3 is O or S;
[0024] R.sup.6 may be attached to any position in the ring;
[0025] m is 0-1; and R.sup.1, R.sup.3 and R.sup.6 are as defined in
Formula (I).
[0026] In a seventh embodiment, the compounds of the invention are
defined by Formula (I) and (IA)-(IY) in any of the above
embodiments, wherein R.sup.1 is phenyl substituted with 1-3
R.sup.1a; and R.sup.1a is halogen, C.sub.1-6 alkyl, haloC.sub.1-6
alkyl, C.sub.1-6 alkoxy, haloC.sub.1-6 alkoxy.
[0027] In an eighth embodiment, the compounds of the invention are
defined by Formula (I) and (IA)-(IY) in any of the above
embodiments, wherein R.sup.3 is X--CO.sub.2R.sup.4; X is a bond and
R.sup.4 is hydrogen or C.sub.1-6 alkyl.
[0028] In a ninth embodiment, the compounds of the invention are
defined by Formula (I) and (IA)-(IY) in any of the above
embodiments, wherein R.sup.6 is methyl, methoxy, fluoro or
trifluoromethoxy.
[0029] Specific compounds of the invention are selected from the
group consisting of: [0030] methyl
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylat-
e; [0031] methyl
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-
-carboxylate; [0032]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic
acid; [0033]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-
-carboxylic acid; [0034] methyl
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate-
; [0035] methyl
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6--
carboxylate; [0036]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic
acid; [0037]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6--
carboxylic acid; [0038] Methyl
2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)
isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-4-methoxybenzo[d]th-
iazole-6-carboxylate; [0039]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxyli-
c acid; [0040]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole--
6-carboxylic acid; [0041] methyl
2-(3-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy)--
8-azabicyclo[3.2.1]octan-8-yl)-4-methoxybenzo[d]thiazole-6-carboxylate;
[0042]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl-
}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-car-
boxylic acid; [0043]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-
-carboxylic acid; [0044] ethyl
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylate;
[0045] ethyl
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-ca-
rboxylate; [0046]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylic
acid; [0047]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-
-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-c-
arboxylic acid; [0048]
2-{2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}me-
thoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazol-6-yl}propan-2-ol;
[0049]
2-{2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]--
1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazol-6-
-yl}propan-2-ol; [0050]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxamid-
e; [0051]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1-
,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzot-
hiazole-6-carboxamide; [0052]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxamide; [0053]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxamide;
[0054]
2-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl-
}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxamide;
[0055]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-c-
arboxamide; [0056] ethyl
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylate;
[0057] ethyl
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-o-
xazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-car-
boxylate; [0058]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylic
acid; [0059]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-ca-
rboxylic acid; [0060] ethyl
2-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylate;
[0061] ethyl
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-o-
xazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-car-
boxylate; [0062]
2-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylic
acid; [0063]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-ca-
rboxylic acid; [0064] methyl
2-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate-
; [0065] methyl
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6--
carboxylate; [0066]
2-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic
acid; [0067]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6--
carboxylic acid; [0068]
2-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylic
acid; [0069]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-
-carboxylic acid; [0070] ethyl
2-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylate; [0071]
ethyl
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylate;
[0072]
2-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylic
acid; [0073]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol--
4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxyli-
c acid; [0074] methyl
2-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylate;
[0075] methyl
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carbox-
ylate; [0076]
2-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylic
acid; [0077]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol--
4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-
-carboxylic acid; [0078] methyl
2-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate;
[0079] methyl
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxy-
late; [0080]
2-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic
acid; [0081]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol--
4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6--
carboxylic acid; [0082] Ethyl
2-(3-((5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclohexyl)isoxazol-4--
yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxylate;
[0083]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)cyclohexyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxyli-
c acid; [0084]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[(1S,2S)-2-(trifluoromethyl)cyclohexyl]-
-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-
-6-carboxylic acid; [0085]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)cyclohexyl]-1,2-oxazol-4-yl}me-
thoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxy-
lic acid; [0086]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[(1S,2S)-2-(trifluoromethyl)cyclohexyl]-
-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benz-
othiazole-6-carboxylic acid; [0087]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)cyclohexyl]-1,2-oxazol-4-yl}me-
thoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carbox-
ylic acid; [0088]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[(1S,2S)-2-(trifluoromethyl)cyclohexyl]-
-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-ben-
zothiazole-6-carboxylic acid; [0089]
2-[3-{[5-cyclopropyl-3-(4,4-dimethylcyclohexyl)-1,2-oxazol-4-yl]methoxy}--
8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylic acid;
[0090]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(4,4-dimethylcyclohexyl)-1,2-oxazol-4-y-
l]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylic
acid; [0091]
2-[3-{[5-cyclopropyl-3-(4,4-dimethylcyclohexyl)-1,2-oxazol-4-yl]methoxy}--
8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic
acid; [0092]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(4,4-dimethylcyclohexyl)-1,2-oxazol-4-y-
l]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-car-
boxylic acid; [0093] methyl
5-(3-((5-cyclopropyl-3-(2-(trifluoromethyl)cyclohexyl)isoxazol-4-yl)metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl)pyrazine-2-carboxylate; [0094]
methyl
5-[(1R,3r,5S)-(3-((5-cyclopropyl-3-((1S,2S)-2-(trifluoromethyl)cyclohexyl-
)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)]pyrazine-2-carboxyl-
ate; [0095]
5-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)cyclohexyl]-1,2-oxazol-4-yl}me-
thoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylic acid;
[0096]
5-[(1R,3r,5S)-3-({5-cyclopropyl-3-[(1S,2S)-2-(trifluoromethyl)cyclohexyl]-
-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxy-
lic acid; [0097] methyl
2-(3-((5-cyclopropyl-3-(2-(trifluoromethyl)cyclohexyl)isoxazol-4-yl)metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl)-4-methylpyrimidine-5-carboxylate;
[0098] methyl
2-[(1R,3r,5S)-(3-((5-cyclopropyl-3-((1S,2S)-2-(trifluoromethyl)cyclohexyl-
)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)]-4-methylpyrimidine-
-5-carboxylate; [0099]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)cyclohexyl]-1,2-oxazol-4-yl}me-
thoxy)-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic
acid; [0100]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[(1S,2S)-2-(trifluoromethyl)cyclohexyl]-
-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidin-
e-4-carboxylic acid; [0101] methyl
2-(3-((3-cyclohexyl-5-cyclopropylisoxazol-4-yl)methoxy)-8-azabicyclo[3.2.-
1]octan-8-yl)-6-methylpyrimidine-4-carboxylate; [0102]
2-(3-((3-cyclohexyl-5-cyclopropylisoxazol-4-yl)methoxy)-8-azabicyclo[3.2.-
1]octan-8-yl)-6-methylpyrimidine-4-carboxylic acid; [0103]
2-[3-[(3-cyclohexyl-5-cyclopropyl-1,2-oxazol-4-yl)methoxy]-8-azabicyclo[3-
.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid;
[0104]
2-[(1R,3r,5S)-3-[(3-cyclohexyl-5-cyclopropyl-1,2-oxazol-4-yl)methoxy]-8-a-
zabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic
acid; [0105]
2-[3-[(3-cyclohexyl-5-cyclopropyl-1,2-oxazol-4-yl)methoxy]-8-azabi-
cyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylic
acid [0106]
2-[(1R,3r,5S)-3-[(3-cyclohexyl-5-cyclopropyl-1,2-oxazol-4-yl)metho-
xy]-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxyli-
c acid [0107] Ethyl
2-(3-((5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazol-4-yl)methoxy)-8-azab-
icyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxylate; [0108]
2-[3-({5-cyclopropyl-3-[2-phenylcyclopropyl]-1,2-oxazol-4-yl}methoxy)-8-a-
zabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylic acid;
[0109]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[(1S,2S)-2-phenylcyclopropyl]-1,2-oxazo-
l-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxy-
lic acid; [0110]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)cyclopropyl]-1,2-oxazol-4-yl}m-
ethoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carbox-
ylic acid; [0111]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[(1S,2S)-2-(trifluoromethyl)cyclopropyl-
]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-ben-
zothiazole-6-carboxylic acid; [0112]
2-[3-({5-cyclopropyl-3-[2-methylcyclopropyl]-1,2-oxazol-4-yl}methoxy)-8-a-
zabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic
acid; [0113]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[(1S,2S)-2-methylcyclopropyl]-1,-
2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzoth-
iazole-6-carboxylic acid; [0114]
2-[3-[(3,5-dicyclopropyl-1,2-oxazol-4-yl)methoxy]-8-azabicyclo[3.2.1]octa-
n-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid; [0115]
2-[(1R,3r,5S)-3-[(3,5-dicyclopropyl-1,2-oxazol-4-yl)methoxy]-8-azabicyclo-
[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid;
[0116]
2-[3-[(3,5-dicyclopropyl-1,2-oxazol-4-yl)methoxy]-8-azabicyclo[3.2.1]octa-
n-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylic acid; [0117]
2-[(1R,3r,5S)-3-[(3,5-dicyclopropyl-1,2-oxazol-4-yl)methoxy]-8-azabicyclo-
[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylic acid;
[0118] Ethyl
2-(3-((5-cyclopropyl-3-(spiro[2.5]octan-6-yl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxylate;
[0119]
2-[3-[(5-cyclopropyl-3-{spiro[2.5]octan-6-yl}-1,2-oxazol-4-yl)methoxy]-8--
azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylic acid;
[0120]
2-[(1R,3r,5S)-3-[(5-cyclopropyl-3-{spiro[2.5]octan-6-yl}-1,2-oxazol-4-yl)-
methoxy]-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylic
acid; [0121] Methyl
2-(3-((5-cyclopropyl-3-(spiro[2.5]octan-6-yl)isoxazol-4-yl)methoxy)-8-aza-
bicyclo[3.2.1]octan-8-yl)-4-fluorobenzo[d]thiazole-6-carboxylate;
[0122]
2-[3-[(5-cyclopropyl-3-{spiro[2.5]octan-6-yl]-1,2-oxazol-4-yl)methoxy}-8--
azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic
acid; [0123]
2-[(1R,3r,5S)-3-[(5-cyclopropyl-3-{spiro[2.5]octan-6-yl]-1,2-oxazo-
l-4-yl)methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole--
6-carboxylic acid;
Methyl
2-(3-((5-cyclopropyl-3-(spiro[2.5]octan-6-yl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)-4-methoxybenzo[d]thiazole-6-carboxylate;
[0125]
2-[3-[(5-cyclopropyl-3-{spiro[2.5]octan-6-yl]-1,2-oxazol-4-yl)meth-
oxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxyl-
ic acid; [0126]
2-[(1R,3r,5S)-3-[(5-cyclopropyl-3-{spiro[2.5]octan-6-yl]-1,2-oxazol-4-yl)-
methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carb-
oxylic acid; [0127]
2-[3-[(5-cyclopropyl-3-{spiro[2.5]octan-6-yl]-1,2-oxazol-4-yl)methoxy}-8--
azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic acid;
[0128]
2-[(1R,3r,5S)-3-[(5-cyclopropyl-3-{spiro[2.5]octan-6-yl]-1,2-oxazol-4-yl)-
methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic
acid; [0129]
2-({2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}m-
ethoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazol-6-yl}formamido)ace-
tic acid; [0130]
2-({2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-ox-
azol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazol-6-yl}fo-
rmamido)acetic acid; [0131]
2-({2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}m-
ethoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazol-6-yl}form-
amido)acetic acid; [0132]
2-({2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-ox-
azol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazo-
l-6-yl}formamido)acetic acid; [0133]
2-({6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}m-
ethoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridin-3-yl}formamido)acetic
acid; [0134]
2-({6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-
-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridin-3-yl}forma-
mido)acetic acid; [0135]
2-({2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}me-
thoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazol-6-yl}forma-
mido)acetic acid; [0136]
2-({2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxa-
zol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazol-
-6-yl}formamido)acetic acid; [0137]
2-({2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}m-
ethoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazol-6-yl}formamido)eth-
ane-1-sulfonic acid; [0138]
2-({2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-ox-
azol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazol-6-yl}fo-
rmamido)ethane-1-sulfonic acid; [0139]
2-({2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}m-
ethoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazol-6-yl}form-
amido)ethane-1-sulfonic acid; [0140]
2-({2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-ox-
azol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazo-
l-6-yl}formamido)ethane-1-sulfonic acid; [0141]
2-({2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}me-
thoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazol-6-yl}forma-
mido)ethane-1-sulfonic acid; [0142]
2-({2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxa-
zol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazol-
-6-yl}formamido)ethane-1-sulfonic acid; [0143]
2-({6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}m-
ethoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridin-3-yl}formamido)ethane-1-sulf-
onic acid; [0144]
2-({6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-ox-
azol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridin-3-yl}formamido)et-
hane-1-sulfonic acid; [0145] methyl
5-bromo-6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4--
yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylate;
[0146] methyl
5-bromo-6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phe-
nyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-car-
boxylate; [0147] Methyl
5-cyclopropyl-6-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-
-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)nicotinate; [0148]
Methyl
5-cyclopropyl-6-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phen-
yl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)nicotinate;
[0149]
5-cyclopropyl-6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxa-
zol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic
acid; [0150]
5-cyclopropyl-6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phen-
yl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carb-
oxylic acid; [0151] methyl
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylate; [0152]
methyl
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylate;
[0153]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-y-
l}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic
acid; [0154]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-
-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic
acid; [0155] methyl
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-5-carboxylate; [0156]
methyl
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-5-carboxylate;
[0157]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-y-
l}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-5-carboxylic
acid; [0158]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-
-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-5-carboxyli-
c acid; [0159] methyl
5-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylate; [0160]
methyl
5-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylate;
[0161]
5-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-y-
l}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylic
acid; [0162]
5-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-
-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylic
acid; [0163] methyl
6-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylate; [0164]
methyl
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylate;
[0165]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid; [0166]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic
acid; [0167] methyl
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylate;
[0168] methyl
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxy-
late; [0169]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic
acid; [0170]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-
-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4--
carboxylic acid; [0171] methyl
2-(3-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy)--
8-azabicyclo[3.2.1]octan-8-yl)-6-methylpyrimidine-4-carboxylate;
[0172]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic
acid; [0173]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-c-
arboxylic acid; [0174] methyl
2-{6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}me-
thoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridin-3-yl}acetate; [0175]
methyl
2-{6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxa-
zol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridin-3-yl}acetate;
[0176]
2-{6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridin-3-yl}acetic
acid; [0177]
2-{6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]--
1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridin-3-yl}acetic
acid; [0178] methyl
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)pyrimidine-5-carboxy-
late; [0179] methyl
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)pyrimidin-
e-5-carboxylate; [0180]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)pyrimidine-5-carboxy-
lic acid; [0181]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)pyrimidin-
e-5-carboxylic acid; [0182] methyl
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)pyridine-3-carboxyla-
te; [0183] methyl
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)pyridine--
3-carboxylate; [0184]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)pyridine-3-carboxyli-
c acid; [0185]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)pyridine--
3-carboxylic acid; [0186] methyl
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methylpyridine-3-carboxylate;
[0187] methyl
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-
-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methylpyridine-3-ca-
rboxylate; [0188]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methylpyridine-3-carboxylic
acid; [0189]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-
-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methylpyridine-3-ca-
rboxylic acid; [0190] methyl
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-5-methylpyridine-3-carboxylate;
[0191] methyl
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-
-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-5-methylpyridine-3-ca-
rboxylate; [0192]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-5-methylpyridine-3-carboxylic
acid; [0193]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-
-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-5-methylpyridine-3-ca-
rboxylic acid; [0194] methyl
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylate; [0195]
methyl
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylate;
[0196]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-y-
l}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylic
acid; [0197]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-
-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylic
acid; [0198] methyl
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-carboxylate; [0199]
methyl
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-carboxylate;
[0200]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-y-
l}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-carboxylic
acid; [0201]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-
-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-carboxyli-
c acid; [0202] methyl
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-2-carboxylate; [0203]
methyl
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-2-carboxylate;
[0204]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-y-
l}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-2-carboxylic
acid; [0205]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-
-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-2-carboxylic
acid; [0206] methyl
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-4-carboxylate; [0207]
methyl
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-4-carboxylate;
[0208]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-4-carboxylic acid; [0209]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-4-carboxylic
acid; [0210] methyl
6-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-2-methylpyridine-4-carboxylate;
[0211] methyl
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-2-methylpyridine-4-car-
boxylate; [0212]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyridine-4-carboxylic
acid; [0213]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyridine-4-car-
boxylic acid; [0214] methyl
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-5-carboxylate; [0215]
methyl
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-5-carboxylate;
[0216]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl-
}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-5-carboxylic
acid; [0217]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-5-carboxylic
acid; [0218] methyl
5-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylate;
[0219] methyl
5-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylate;
[0220]
5-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylic acid; [0221]
5-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylic
acid; [0222] methyl
6-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)pyridine-3-carboxylat-
e; [0223] methyl
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)pyridine-3-
-carboxylate; [0224]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)pyridine-3-carboxylic
acid; [0225]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)pyridine-3-
-carboxylic acid; [0226] methyl
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-carboxylate; [0227]
methyl
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-carboxylate;
[0228]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl-
}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-carboxylic
acid; [0229]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-carboxylic
acid; [0230] methyl
6-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-2-carboxylate; [0231]
methyl
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-2-carboxylate;
[0232]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-2-carboxylic acid; [0233]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-2-carboxylic
acid; [0234] methyl
6-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)pyridine-3-carboxylat-
e; [0235] methyl
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)pyridine-3-
-carboxylate; [0236]
6-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)pyridine-3-carboxylic
acid; [0237]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)pyridine-3-
-carboxylic acid; [0238] methyl
2-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-carboxylate; [0239]
methyl
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-carboxylate;
[0240]
2-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl-
}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-carboxylic
acid; [0241]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-carboxylic
acid; [0242] methyl
6-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-2-carboxylate; [0243]
methyl
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-2-carboxylate;
[0244] methyl
6-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl-
}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methylpyridine-3-carboxylate;
[0245] methyl
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methylpyridine-3-carboxylat-
e; [0246]
6-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4--
yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methylpyridine-3-carboxylic
acid; [0247]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methylpyridine-3-carboxylic
acid; [0248] methyl
2-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylate;
[0249] methyl
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-c-
arboxylate; [0250] methyl
4-chloro-6-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4--
yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylate;
[0251] methyl
4-chloro-6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phe-
nyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-car-
boxylate; [0252]
4-chloro-6-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4--
yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic
acid; [0253]
4-chloro-6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phe-
nyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-car-
boxylic acid; [0254] methyl
6-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-5-methylpyridine-3-carboxylate;
[0255] methyl
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-5-methylpyridine-3-car-
boxylate; [0256]
6-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-5-methylpyridine-3-carboxylic
acid; [0257]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-5-methylpyridine-3-car-
boxylic acid; [0258]
2-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic
acid; [0259]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-c-
arboxylic acid; [0260] methyl
6-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]pyridazine-3-carboxylate; [0261]
methyl
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridazine-3-carboxylate;
[0262]
6-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl-
}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridazine-3-carboxylic
acid; [0263]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridazine-3-carboxylic
acid; [0264] methyl
2-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-5-carboxylate; [0265]
methyl
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-5-carboxylate;
[0266]
2-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl-
}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-5-carboxylic
acid; [0267]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-5-carboxylic
acid; [0268] methyl
5-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylate; [0269]
methyl
5-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylate;
[0270]
5-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylic acid; [0271]
5-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylic
acid; [0272]
6-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl-
}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid;
[0273]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic
acid; [0274] methyl
6-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylate; [0275] methyl
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylate; [0276]
6-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid; [0277]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid;
[0278] methyl
2-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-5-carboxylate; [0279]
methyl
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-5-carboxylate;
[0280]
2-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]pyrimidine-5-carboxylic acid; [0281]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-5-carboxylic acid;
[0282] methyl
5-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylate; [0283]
methyl
5-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylate; [0284]
5-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylic acid; [0285]
5-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]pyrazine-2-carboxylic acid;
[0286] methyl
6-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)pyridine-3-carboxylat-
e; [0287] methyl
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)pyridine-3-carbox-
ylate; [0288]
6-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)pyridine-3-carboxylic
acid; [0289]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol--
4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)pyridine-3-
-carboxylic acid; [0290] methyl
5-cyclopropyl-6-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl-
]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylate;
[0291] methyl
5-cyclopropyl-6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluoropheny-
l)-1,2-oxazol-4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carbo-
xylate; [0292]
5-cyclopropyl-6-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl-
]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid;
[0293]
5-cyclopropyl-6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2--
oxazol-4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic
acid; [0294] methyl
2-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylate; [0295]
methyl
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylate;
[0296]
2-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic
acid; [0297]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol--
4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxyl-
ic acid; [0298] methyl
2-chloro-6-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]meth-
oxy}-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-carboxylate; [0299]
methyl
2-chloro-6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazo-
l-4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-carboxylate;
[0300] methyl
6-chloro-2-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]meth-
oxy}-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-carboxylate; [0301]
methyl
6-chloro-2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazo-
l-4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-carboxylate;
[0302] methyl
5-bromo-6-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]metho-
xy}-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylate; [0303]
methyl
5-bromo-6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-
-4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylate;
[0304] methyl
4-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-3-fluorobenzoate; [0305] methyl
4-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-3-fluorobenzoate;
[0306]
4-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-3-fluorobenzoic acid; [0307]
4-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-3-fluorobenzoic acid;
[0308] methyl
4-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-y-
l}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-3,5-difluorobenzoate;
[0309] methyl
4-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-
-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-3,5-difluorobenzoate;
[0310]
4-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-y-
l}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-3,5-difluorobenzoic acid;
[0311]
4-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-3,5-difluorobenzoic
acid; [0312] methyl
4-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-3,5-difluorobenzoate; [0313]
methyl
4-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-3,5-difluorobenzoate;
[0314]
4-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-3,5-difluorobenzoic acid; [0315]
4-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-3,5-difluorobenzoic
acid; [0316] methyl
4-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-3,5-difluorobenzoate; [0317]
methyl
4-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-3,5-difluorobenzoate;
[0318]
4-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl-
}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-3,5-difluorobenzoic acid;
[0319]
4-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-3,5-difluorobenzoic
acid; [0320] methyl
4-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-3-fluorobenzoate; [0321] methyl
4-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]-3-fluorobenzoate; [0322]
4-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-3-fluorobenzoic acid; [0323]
4-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]-3-fluorobenzoic acid; [0324]
methyl
4-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-3,5-difluorobenzoate; [0325] methyl
4-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]-3,5-difluorobenzoate; [0326]
4-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-3,5-difluorobenzoic acid; [0327]
4-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]-3,5-difluorobenzoic acid;
[0328] methyl
4-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl-
}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-3-fluorobenzoate; [0329]
methyl
4-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-3-fluorobenzoate;
[0330]
4-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-3-fluorobenzoic acid; [0331]
4-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-3-fluorobenzoic acid;
[0332] methyl
4-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl-
}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-3-fluorobenzoate; [0333]
methyl
4-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-3-fluorobenzoate;
[0334]
4-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-3-fluorobenzoic acid; [0335]
4-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-3-fluorobenzoic acid;
[0336]
4-(3-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)--
8-azabicyclo[3.2.1]octan-8-yl)-3-fluorobenzonitrile; [0337]
3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)--
8-[2-fluoro-4-(5H-1,2,3,4-tetrazol-5-yl)phenyl]-8-azabicyclo[3.2.1]octane;
[0338]
(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxa-
zol-4-yl}methoxy)-8-[2-fluoro-4-(5H-1,2,3,4-tetrazol-5-yl)phenyl]-8-azabic-
yclo[3.2.1]octane; [0339]
4-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-3-fluorobenzamide; [0340]
4-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-3-fluorobenzamide;
[0341] methyl
6-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)m-
ethoxy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]isothiazole-3-carboxylate;
[0342]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-y-
l}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,2-benzothiazole-3-carboxylic
acid; [0343]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,2-benzothiazole-3-carboxyl-
ic acid; [0344]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-1,2-benzothiazole-3-carboxylic
acid; [0345]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-
-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,2-benzothiazole-3-c-
arboxylic acid; [0346]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]imidazo[1,2-a]pyridine-3-carboxylic
acid; [0347]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]imidazo[1,2-a]pyridine-3-carb-
oxylic acid; [0348]
7-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]quinoline-3-carboxylic acid;
[0349]
7-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]quinoline-3-carboxylic
acid; [0350]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-y-
l}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1-methyl-1H-indole-2-carboxylic
acid; [0351]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1-methyl-1H-indole-2-carboxy-
lic acid; [0352]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]pyrrolo[1,2-b]pyridazine-6-carboxylic
acid; [0353]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrrolo[1,2-b]pyridazine-6-ca-
rboxylic acid; [0354]
4-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]benzoic acid; [0355]
4-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]benzoic acid; [0356]
1-{4-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}me-
thoxy)-8-azabicyclo[3.2.1]octan-8-yl]phenyl}cyclopropane-1-carboxylic
acid; [0357]
1-{4-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxa-
zol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]phenyl}cyclopropane-1-carb-
oxylic acid; [0358]
5-[3-{[5-cyclopropyl-3-(2-cyclopropylphenyl)-1,2-oxazol-4-yl]methoxy}-8-a-
zabicyclo[3.2.1]octan-8-yl]-4-methyl-1-benzofuran-2-carboxylic
acid; [0359]
5-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-cyclopropylphenyl)-1,2-oxazol-
-4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1-benzofuran-2-carb-
oxylic acid; [0360]
5-[3-{[3-(2-chlorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy}-8-azabic-
yclo[3.2.1]octan-8-yl]-4-methyl-1-benzofuran-2-carboxylic acid;
[0361]
5-[(1R,3r,5S)-3-{[3-(2-chlorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1-benzofuran-2-carboxylic
acid; [0362]
5-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1-benzofuran-2-carboxylic
acid; [0363]
5-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol--
4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1-benzofuran-2-carbo-
xylic acid; [0364]
5-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1-benzofuran-2-carboxylic
acid; [0365]
5-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1-benzofuran-2-carb-
oxylic acid; [0366]
5-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1-benzofuran-2-carboxylic
acid; [0367]
5-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1-benzofuran--
2-carboxylic acid; [0368]
5-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-1-benzothiophene-2-carboxylic
acid; [0369]
5-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-
-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1-benzothiophene-2-ca-
rboxylic acid; [0370]
5-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-1-benzofuran-2-carboxylic acid;
[0371]
5-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1-benzofuran-2-carboxylic
acid; [0372]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-1-benzofuran-2-carboxylic acid;
[0373]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1-benzofuran-2-carboxylic
acid; [0374]
5-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-1-methyl-1H-indazole-3-carboxylic
acid; [0375]
5-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-
-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1-methyl-1H-indazole--
3-carboxylic acid; [0376]
8-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]quinoline-3-carboxylic acid;
[0377]
8-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]quinoline-3-carboxylic
acid; [0378]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-y-
l}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,2-benzoxazole-3-carboxylic
acid; [0379]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,2-benzoxazole-3-carboxylic
acid; [0380]
5-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-1-methyl-1H-indole-2-carboxylic
acid; [0381]
5-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-
-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1-methyl-1H-indole-2--
carboxylic acid; [0382]
5-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-1-benzofuran-2-carboxylic acid;
[0383]
5-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1-benzofuran-2-carboxylic
acid; [0384]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-1,2-benzothiazole-3-carboxylic
acid; [0385]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,2-benzothiazole-3-ca-
rboxylic acid; [0386]
6-[3-{[5-cyclopropyl-3-(2-cyclopropylphenyl)-1,2-oxazol-4-yl]methoxy}-8-a-
zabicyclo[3.2.1]octan-8-yl]-1,2-benzothiazole-3-carboxylic acid;
[0387]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-cyclopropylphenyl)-1,2-oxazol-4-yl]m-
ethoxy}-8-azabicyclo[3.2.1]octan-8-yl]-1,2-benzothiazole-3-carboxylic
acid; [0388]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-5-fluoro-1,2-benzothiazole-3-carboxylic
acid; [0389]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-5-fluoro-1,2-benzothiazole-3-
-carboxylic acid; [0390]
7-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]imidazo[1,2-a]pyridine-2-carboxylic
acid; [0391]
7-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]imidazo[1,2-a]pyridine-2-carb-
oxylic acid; [0392]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-1-methyl-1H-indazole-3-carboxylic
acid; [0393]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-
-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1-methyl-1H-indazole--
3-carboxylic acid; [0394]
2-[3-({3-[bicyclo[3.1.0]hexan-6-yl]-5-cyclopropyl-1,2-oxazol-4-yl}methoxy-
)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic
acid; [0395]
2-[(1R,3r,5S)-3-({3-[(1R,5S)-bicyclo[3.1.0]hexan-6-yl]-5-cyclopropyl-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothia-
zole-6-carboxylic acid; [0396]
2-[3-({5-cyclopropyl-3-[1-methylbicyclo[3.1.0]hexan-6-yl]-1,2-oxazol-4-yl-
}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carb-
oxylic acid; [0397]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[(1R,5R,6S)-1-methylbicyclo[3.1.0]hexan-
-6-yl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,-
3-benzothiazole-6-carboxylic acid; [0398]
2-[3-[(3-cyclopentyl-5-cyclopropyl-1,2-oxazol-4-yl)methoxy]-8-azabicyclo[-
3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid;
[0399]
2-[(1R,3r,5S)-3-[(3-cyclopentyl-5-cyclopropyl-1,2-oxazol-4-yl)methoxy]-8--
azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic
acid; [0400]
2-[3-[(5-cyclopropyl-3-{spiro[2.3]hexan-5-yl}-1,2-oxazol-4-yl)meth-
oxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxyli-
c acid; [0401]
2-[(1R,3r,5S)-3-[(5-cyclopropyl-3-{spiro[2.3]hexan-5-yl}-1,2-oxazol-4-yl)-
methoxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carbo-
xylic acid; [0402]
2-[3-({5-cyclopropyl-3-[2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl]-1,2-oxa-
zol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazol-
e-6-carboxylic acid; [0403]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3-
.1.1]heptan-3-yl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]--
4-fluoro-1,3-benzothiazole-6-carboxylic acid; [0404]
2-[3-[(5-cyclopropyl-3-{spiro[2.5]octan-4-yl}-1,2-oxazol-4-yl)methoxy]-8--
azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic
acid; [0405]
2-[(1R,3r,5S)-3-[(5-cyclopropyl-3-{spiro[2.5]octan-4-yl}-1,2-oxazo-
l-4-yl)methoxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole--
6-carboxylic acid; [0406]
2-[3-({3-[bicyclo[4.1.0]heptan-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic
acid; [0407]
2-[(1R,3r,5S)-3-({3-[(1S,3S,6S)-bicyclo[4.1.0]heptan-3-yl]-5-cyclopropyl--
1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzo-
thiazole-6-carboxylic acid; [0408]
2-[3-{[5-cyclopropyl-3-(2-methylphenyl)-1,2-oxazol-4-yl]methoxy}-8-azabic-
yclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic
acid; [0409]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-methylphenyl)-1,2-oxazol-4-yl-
]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carb-
oxylic acid; [0410]
6-[3-{[5-cyclopropyl-3-(2-methylphenyl)-1,2-oxazol-4-yl]methoxy}-8-azabic-
yclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid; [0411]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-methylphenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid; [0412]
2-[3-{[5-cyclopropyl-3-(2-methylphenyl)-1,2-oxazol-4-yl]methoxy}-8-azabic-
yclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic acid; [0413]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-methylphenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic
acid; [0414]
2-[3-{[5-cyclopropyl-3-(2-methylphenyl)-1,2-oxazol-4-yl]methoxy}-8-
-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylic acid;
[0415]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-methylphenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylic
acid;
[0416]
2-[3-{[5-cyclopropyl-3-(2-methylphenyl)-1,2-oxazol-4-yl]methoxy}-8-
-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylic
acid; [0417]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-methylphenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylic
acid; [0418]
2-[3-{[5-cyclopropyl-3-(4-fluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-azabic-
yclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylic acid; [0419]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(4-fluorophenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylic
acid; [0420]
2-[3-{[5-cyclopropyl-3-(4-fluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-
-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylic
acid; [0421]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(4-fluorophenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylic
acid; [0422]
2-[3-{[5-cyclopropyl-3-(3-fluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-azabic-
yclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylic
acid; [0423]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(3-fluorophenyl)-1,2-oxazol-4-yl-
]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-car-
boxylic acid; [0424]
6-[3-{[5-cyclopropyl-3-(3-fluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-azabic-
yclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid; [0425]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(3-fluorophenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid; [0426]
2-[3-{[5-cyclopropyl-3-(3-fluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-azabic-
yclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic acid; [0427]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(3-fluorophenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic
acid; [0428]
2-[3-{[5-cyclopropyl-3-(2-fluoro-6-methylphenyl)-1,2-oxazol-4-yl]m-
ethoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carbo-
xylic acid; [0429]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-fluoro-6-methylphenyl)-1,2-oxazol-4--
yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-c-
arboxylic acid; [0430]
6-[3-{[5-cyclopropyl-3-(2-fluoro-6-methylphenyl)-1,2-oxazol-4-yl]methoxy}-
-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid; [0431]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-fluoro-6-methylphenyl)-1,2-oxazol-4--
yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic
acid; [0432]
2-[3-{[5-cyclopropyl-3-(2-fluoro-6-methylphenyl)-1,2-oxazol-4-yl]m-
ethoxy}-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic
acid; [0433]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-fluoro-6-methylphenyl)-1,2-oxazol-4--
yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic
acid; [0434]
2-[3-{[5-cyclopropyl-3-(2,6-dimethylphenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylic
acid; [0435]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-dimethylphenyl)-1,2-oxazol--
4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-
-carboxylic acid; [0436]
6-[3-{[5-cyclopropyl-3-(2,6-dimethylphenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid; [0437]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-dimethylphenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid;
[0438]
2-[3-{[5-cyclopropyl-3-(2,6-dimethylphenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic acid;
[0439]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-dimethylphenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic
acid; [0440]
2-[3-{[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy}-
-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylic
acid; [0441]
2-[(1R,3r,5S)-3-{[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4--
yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-c-
arboxylic acid; [0442]
6-[3-{[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy}-
-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid; [0443]
6-[(1R,3r,5S)-3-{[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4--
yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic
acid; [0444]
2-[3-{[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]m-
ethoxy}-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic
acid; [0445]
2-[(1R,3r,5S)-3-{[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4--
yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic
acid; [0446]
2-[3-{[3-(2-chlorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy}-8-azabic-
yclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylic
acid; [0447]
2-[(1R,3r,5S)-3-{[3-(2-chlorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl-
]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-car-
boxylic acid; [0448]
6-[3-{[3-(2-chlorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy}-8-azabic-
yclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid; [0449]
6-[(1R,3r,5S)-3-{[3-(2-chlorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid; [0450]
2-[3-{[3-(2-chlorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy}-8-azabic-
yclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic acid; [0451]
2-[(1R,3r,5S)-3-{[3-(2-chlorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic
acid; [0452]
2-[3-{[5-cyclopropyl-3-(2-cyclopropylphenyl)-1,2-oxazol-4-yl]metho-
xy}-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic
acid; [0453]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-cyclopropylphenyl)-1,2-oxazol-4-yl]m-
ethoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carbox-
ylic acid; [0454]
6-[3-{[5-cyclopropyl-3-(2-cyclopropylphenyl)-1,2-oxazol-4-yl]methoxy}-8-a-
zabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid; [0455]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-cyclopropylphenyl)-1,2-oxazol-4-yl]m-
ethoxy}-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid;
[0456]
6-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-5-methylpyridine-3-carboxylic acid;
[0457]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]-5-methylpyridine-3-carboxylic
acid; [0458]
6-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-4-methylpyridine-3-carboxylic
acid; [0459]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol--
4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methylpyridine-3-carboxylic
acid; [0460]
6-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-2-carboxylic acid; [0461]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-2-carboxylic
acid; [0462] methyl
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6-carboxylat-
e; [0463] methyl
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6-
-carboxylate; [0464]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6-carboxylic
acid; [0465]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6-
-carboxylic acid; [0466] methyl
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6-carboxylate-
; [0467] methyl
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6--
carboxylate; [0468]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6-carboxylic
acid; [0469]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6--
carboxylic acid; [0470] methyl
2-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6-carboxylate;
[0471] methyl
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6-carboxy-
late; [0472]
2-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6-carboxylic
acid; [0473]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol--
4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6--
carboxylic acid; [0474]
2-[3-{[5-cyclopropyl-3-(2-fluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-azabic-
yclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6-carboxylic
acid; [0475]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-fluorophenyl)-1,2-oxazol-4-yl-
]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6-carb-
oxylic acid; [0476]
2-[3-{[5-cyclopropyl-3-(4-fluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-azabic-
yclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6-carboxylic
acid; [0477]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(4-fluorophenyl)-1,2-oxazol-4-yl-
]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6-carb-
oxylic acid; [0478]
2-[3-{[5-cyclopropyl-3-(2-methylphenyl)-1,2-oxazol-4-yl]methoxy}-8-azabic-
yclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6-carboxylic
acid; [0479]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-methylphenyl)-1,2-oxazol-4-yl-
]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6-carb-
oxylic acid; [0480] methyl
2-[3-{[5-cyclopropyl-3-(2-methylphenyl)-1,2-oxazol-4-yl]methoxy}-8-azabic-
yclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6-carboxylate;
[0481] methyl
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-methylphenyl)-1,2-oxazol-4-yl-
]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6-carb-
oxylate; [0482]
2-[3-{[5-cyclopropyl-3-(2,4-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6-carboxylic
acid; [0483]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,4-difluorophenyl)-1,2-oxazol--
4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6--
carboxylic acid; [0484] methyl
4-bromo-2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4--
yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylate-
; [0485] methyl
4-bromo-2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,-
2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6--
carboxylate; [0486]
4-bromo-2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4--
yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylic
acid; [0487]
4-bromo-2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,-
2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6--
carboxylic acid; [0488]
6-cyclopropyl-2-[3-({5-cyclopropyl-3-[2-(difluoromethoxy)phenyl]-1,2-oxaz-
ol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-carboxylic
acid; [0489]
6-cyclopropyl-2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(difluoromethoxy)pheny-
l]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-car-
boxylic acid; [0490]
6-cyclopropyl-2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxa-
zol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-carboxylic
acid; [0491]
6-cyclopropyl-2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phen-
yl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-ca-
rboxylic acid; [0492]
6-cyclopropyl-2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxaz-
ol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-carboxylic
acid; [0493]
6-cyclopropyl-2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)pheny-
l]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-4-car-
boxylic acid; [0494]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-2-methylpyridine-3-carboxylic
acid; [0495]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-
-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-2-methylpyridine-3-ca-
rboxylic acid; [0496]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-2-methylpyridine-3-carboxylic
acid; [0497]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-2-methylpyridine-3-car-
boxylic acid; [0498]
6-[3-{[5-cyclopropyl-3-(2-methylphenyl)-1,2-oxazol-4-yl]methoxy}-8-azabic-
yclo[3.2.1]octan-8-yl]-2-methylpyridine-3-carboxylic acid; [0499]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-methylphenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-2-methylpyridine-3-carboxylic
acid; [0500]
6-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-2-methylpyridine-3-carboxylic
acid; [0501]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol--
4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-2-methylpyridine-3-carboxylic
acid; [0502]
6-[3-{[5-cyclopropyl-3-(2-fluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-azabic-
yclo[3.2.1]octan-8-yl]-2-methylpyridine-3-carboxylic acid; [0503]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-fluorophenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-2-methylpyridine-3-carboxylic
acid; [0504]
6-[3-{[5-cyclopropyl-3-(2,6-dimethylphenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-2-methylpyridine-3-carboxylic
acid; [0505]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-dimethylphenyl)-1,2-oxazol--
4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-2-methylpyridine-3-carboxylic
acid; [0506]
6-[3-{[5-cyclopropyl-3-(3-fluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-azabic-
yclo[3.2.1]octan-8-yl]-2-methylpyridine-3-carboxylic acid; [0507]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(3-fluorophenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-2-methylpyridine-3-carboxylic
acid; [0508]
6-[3-{[5-cyclopropyl-3-(2-fluoro-6-methylphenyl)-1,2-oxazol-4-yl]m-
ethoxy}-8-azabicyclo[3.2.1]octan-8-yl]-2-methylpyridine-3-carboxylic
acid; [0509]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-fluoro-6-methylphenyl)-1,2-ox-
azol-4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-2-methylpyridine-3-carbo-
xylic acid; [0510] 6-[3-1
[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy}-8-aza-
bicyclo[3.2.1]octan-8-yl]-2-methylpyridine-3-carboxylic acid;
[0511] 6-[(1R,3r,5S)-3-1
[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy}-8-aza-
bicyclo[3.2.1]octan-8-yl]-2-methylpyridine-3-carboxylic acid;
[0512]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]quinoline-6-carboxylic acid;
[0513]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]quinoline-6-carboxylic
acid;
[0514]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl-
}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]quinoline-6-carboxylic
acid; [0515]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]quinoline-6-carboxylic
acid; [0516]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]quinoline-5-carboxylic acid;
[0517]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]quinoline-5-carboxylic
acid; [0518]
4-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-y-
l}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]quinazoline-7-carboxylic
acid; [0519]
4-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-
-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]quinazoline-7-carboxyl-
ic acid; [0520]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-4-methylpyridine-2-carboxylic
acid; [0521]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2--
oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methylpyridine-2-car-
boxylic acid; [0522]
4-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-ca-
rboxylic acid; [0523]
4-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1-methyl-1H-pyrrolo[3,2-c]py-
ridine-7-carboxylic acid; [0524]
5-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid; [0525]
5-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazolo[1,5-a]pyrimidine-3-c-
arboxylic acid; [0526]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]imidazo[1,2-b]pyridazine-3-carboxylic
acid; [0527]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]imidazo[1,2-b]pyridazine-3-ca-
rboxylic acid; [0528]
2-[3-{[5-cyclopropyl-3-(2,4-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylic acid;
[0529]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,4-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylic
acid; [0530]
2-[3-{[5-cyclopropyl-3-(2,4-difluorophenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylic
acid; [0531]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,4-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carbox-
ylic acid; [0532]
6-[3-{[5-cyclopropyl-3-(2,4-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid; [0533]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,4-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid;
[0534]
2-[3-{[5-cyclopropyl-3-(2,3-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylic
acid; [0535]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,3-difluorophenyl)-1,2-oxazol--
4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-
-carboxylic acid; [0536]
6-[3-{[5-cyclopropyl-3-(2,3-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid; [0537]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,3-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid;
[0538]
2-[3-{[5-cyclopropyl-3-(2,3-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic acid;
[0539]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,3-difluorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic
acid; [0540]
2-[3-{[5-cyclopropyl-3-(2-fluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-azabic-
yclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylic
acid; [0541]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-fluorophenyl)-1,2-oxazol-4-yl-
]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-car-
boxylic acid; [0542]
2-[3-{[5-cyclopropyl-3-(2-fluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-azabic-
yclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic acid; [0543]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-fluorophenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-6-methylpyrimidine-4-carboxylic
acid; [0544]
6-[3-{[5-cyclopropyl-3-(2-fluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-
-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid; [0545]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-fluorophenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid; [0546]
2-[3-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylic acid;
[0547]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylic
acid; [0548]
2-[3-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methox-
y}-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylic
acid; [0549]
2-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carbox-
ylic acid; [0550]
6-[3-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid; [0551]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]me-
thoxy}-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid;
[0552]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}-
methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid;
[0553]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)pyridin-3-yl]-1,2-o-
xazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic
acid; [0554]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-thiazole-4-carboxylic acid;
[0555]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-thiazole-4-carboxylic
acid; [0556]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-thiazole-5-carboxylic acid;
[0557]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-thiazole-5-carboxylic
acid; [0558]
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-thiazole-5-carboxylic acid;
[0559]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-1,3-thiazole-5-carboxylic
acid; [0560]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]imidazo[1,2-b]pyridazine-2-carboxylic
acid; [0561]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]imidazo[1,2-b]pyridazine-2-ca-
rboxylic acid; [0562]
6-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]imidazo[1,2-b]pyridazine-2-carboxylic
acid; [0563]
6-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]imidazo[1,2-b]pyridazine-2-car-
boxylic acid; [0564]
5-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazolo[1,5-a]pyrimidine-2-carboxylic
acid; [0565]
5-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazolo[1,5-a]pyrimidine-2-c-
arboxylic acid; [0566]
5-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]pyrazolo[1,5-a]pyrimidine-2-carboxylic
acid; [0567]
5-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol--
4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazolo[1,5-a]pyrimidine-2-ca-
rboxylic acid; [0568]
6-[3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]methoxy}-8-az-
abicyclo[3.2.1]octan-8-yl]imidazo[1,2-b]pyridazine-2-carboxylic
acid; [0569]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol--
4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]imidazo[1,2-b]pyridazine-2-car-
boxylic acid; [0570]
6-[3-{[5-cyclopropyl-3-(2-fluoro-6-methylphenyl)-1,2-oxazol-4-yl]methoxy}-
-8-azabicyclo[3.2.1]octan-8-yl]imidazo[1,2-b]pyridazine-2-carboxylic
acid; [0571]
6-[(1R,3r,5S)-3-{[5-cyclopropyl-3-(2-fluoro-6-methylphenyl)-1,2-ox-
azol-4-yl]methoxy}-8-azabicyclo[3.2.1]octan-8-yl]imidazo[1,2-b]pyridazine--
2-carboxylic acid; [0572]
7-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]imidazo[1,2-a]pyridine-3-carboxylic
acid; [0573]
7-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]imidazo[1,2-a]pyridine-3-carb-
oxylic acid; [0574]
5-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazolo[1,5-a]pyridine-3-carboxylic
acid; [0575]
5-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-
-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyrazolo[1,5-a]pyridine-3-car-
boxylic acid; [0576]
6-((2-(3-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl)-4-fluorobenzo[d]thiazole-6-carbonyl)oxy-
)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; [0577]
(2S,3S,4S,5R,6S)-6-((2-41R,3S,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethyl-
)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-4-fluorobenz-
o[d]thiazole-6-carbonyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxy-
lic acid; [0578]
6-((2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)meth-
oxy)-8-azabicyclo[3.2.1]octan-8-yl)-4-fluorobenzo[d]thiazole-6-carbonyl)ox-
y)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; [0579]
(2S,3S,4S,5R,6S)-6-((2-41R,3S,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethox-
y)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-4-fluoroben-
zo[d]thiazole-6-carbonyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carbox-
ylic acid; [0580]
6-((6-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)meth-
oxy)-8-azabicyclo[3.2.1]octan-8-yl)nicotinoyl)oxy)-3,4,5-trihydroxytetrahy-
dro-2H-pyran-2-carboxylic acid; and [0581]
(2S,3S,4S,5R,6S)-6-((6-41R,3S,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethox-
y)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)nicotinoyl)o-
xy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; or
[0582] a stereoisomer, enantiomer, a pharmaceutically acceptable
salt or an amino acid conjugate thereof.
[0583] In one embodiment, the invention provides a glycine
conjugate of a compound of the invention. In another embodiment,
the invention provides a taurine conjugate of a compound of the
invention. In yet another embodiment, the invention provides an
acylglucuronide conjugate of a compound of the invention.
[0584] The present invention also provides a compound having
Formula (III)
##STR00008##
wherein R.sup.1 and R.sup.2 are as defined in Formula (I); or a
pharmaceutically acceptable salt thereof. In one embodiment,
R.sup.2 in Formula (III) is cyclopropyl.
[0585] Furthermore, the present invention provides a process for
preparing a compound of Formula (I), comprising reacting a compound
of Formula (III) with a compound of Y--Z--R.sup.3;
[0586] wherein Y is a leaving group (such as chloro or bromo);
and
[0587] R.sup.1, R.sup.2, R.sup.3 and Z are as defined in Formula
(I);
[0588] and optionally, converting a compound of Formula (I),
wherein the substituents have the meaning as defined in Formula
(I), into another compound of Formula (I) as defined in Formula
(I); and
[0589] recovering the resulting compound of Formula (I) in free
form or as a salt; and optionally converting the compound of
Formula (I) obtained in free form into a desired salt, or an
obtained salt into the free form.
DEFINITIONS
[0590] For purposes of interpreting this specification, the
following definitions will apply and whenever appropriate, terms
used in the singular will also include the plural and vice
versa.
[0591] As used herein, "C.sub.1-6alkyl" denotes a an alkyl radical
having from 1 up to 6, particularly up to 4 carbon atoms, the
radicals being either linear or branched with single or multiple
branching; for example, butyl, such as n-butyl, sec-butyl,
isobutyl, tert-butyl; propyl, such as n-propyl or isopropyl; ethyl
or methyl; more particularly, methyl, propyl or tert-butyl.
"C.sub.1-3 alkyl" refers to an alkyl radical as defined herein,
containing one to three carbon atoms.
[0592] As used herein, the term "alkylene" refers to divalent alkyl
group as defined herein above having a specified number of carbon
atoms. Representative examples of alkylene include, but are not
limited to, methylene, ethylene, n-propylene, iso-propylene,
n-butylene, sec-butylene, iso-butylene, tert-butylene, and the
like.
[0593] As used herein, "C.sub.3-8 cycloalkyl" refers to saturated
or unsaturated monocyclic or bicyclic hydrocarbon groups of 3-8
carbon atoms (including spirocyclic rings). Furthermore, the term
"C.sub.3-8 cycloalkyl" as used herein may encompass monovalent and
divalent cycloalkyls, which will be apparent to those skilled in
the art. Exemplary monocyclic hydrocarbon groups include, but are
not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclopentenyl, cyclohexyl, cyclohexenyl and the like, and
monovalent or divalent forms thereof. Exemplary bicyclic
hydrocarbon groups include but are not limited to
bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,
6,6-dimethylbicyclo[3.1.1]heptyl,
2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl,
bicyclo[3.1.0]hexanyl, bicyclo[3.1.0]hexan-6-yl, spiro[2.3]hexanyl,
spiro[2.3]hexan-5-yl, spiro[2.5]octanyl, bicyclo[3.1.1]heptanyl,
bicyclo[3.1.1]heptan-3-yl, bicyclo[4.1.0]heptanyl,
bicyclo[4.1.0]heptan-3-yl and the like, and monocyclic or divalent
forms thereof. Exemplary spirocyclic rings include but are not
limited to spiro[2.5]octan-6-yl and the like, and monocyclic or
divalent forms thereof.
[0594] As used herein, "aryl" refers to an aromatic hydrocarbon
group having 6-20 carbon atoms in the ring portion. Typically, aryl
is monocyclic, bicyclic or tricyclic aryl having 6-20 carbon atoms.
Furthermore, the term "aryl" as used herein, refers to an aromatic
substituent which can be a single aromatic ring, or multiple
aromatic rings that are fused together; and may encompass
monovalent and divalent aryls, which will be apparent to those
skilled in the art. Non-limiting examples include phenyl,
phenylene, naphthyl, naphthylene, tetrahydronaphthyl or
tetrahydronaphthylene.
[0595] As used herein, "heteroaryl" refers to a 5-14 membered
monocyclic- or bicyclic- or tricyclic-aromatic ring system having 1
to 8 heteroatoms. Typically, the heteroaryl is a 5-10 membered ring
system (e.g., 5-7 membered monocycle or an 8-10 membered bicycle)
or a 5-7 membered ring system. Furthermore, the term "heteroaryl"
as used herein may encompass monovalent or divalent heteroaryls,
which will be apparent to those skilled in the art. Typical
monocyclic heteroaryl groups include 2- or 3-thienyl, 2- or
3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or
5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-,
4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or
5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or
4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl,
2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, and monovalent or divalent
forms thereof. Typical bicyclic heteroaryl groups include
benzofuranyl, benzo[d]isothiazolyl, benzo[d]isoxazolyl,
benzothiazolyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridinyl,
imidazo[1,2-b]pyridazinyl, 1H-indolyl, 1H-indazolyl,
pyrazolo[1,5-a]pyridinyl, pyrrolo[1,2-b]pyridazinyl,
1H-pyrrolo[3,2-c]pyridinyl, pyrazolo[1,5-a]pyrimidinyl,
quinazolinyl and the like, and monovalent or divalent forms
thereof.
[0596] As used herein, "C.sub.1-6 alkoxy" refers to C.sub.1-6
alkyl-O--, and is particularly methoxy, ethoxy, isopropyloxy, or
tert-butoxy.
[0597] As used herein, "hydroxyC.sub.1-6 alkyl" refers to C.sub.1-6
alkyl-OH, wherein C.sub.1-6 alkyl is as defined above. The hydroxy
group may be attached to the alkyl radical on any carbon within the
alkyl radical, and is particularly hydroxymethyl, 2-hydroxyethyl or
2-hydroxy-2-propyl.
[0598] As used herein, "halogen" or "halo" refers to fluoro,
chloro, bromo, and iodo; and more particularly, fluoro or
chloro.
[0599] As used herein, "haloC.sub.1-6 alkyl" refers to an alkyl
radical, as defined above, that is substituted by one or more halo
radicals, as defined above, and is particularly fluoroC.sub.1-6
alkyl, more particularly trifluoromethyl.
[0600] As used herein, "haloC.sub.1-6alkoxy" refers to an alkoxy
radical, as defined above, that is substituted by one or more halo
radicals, as defined above, and is particularly fluoroC.sub.1-6
alkoxy, more particularly, trifluoromethoxy or difluoromethoxy.
[0601] As used herein, a "stereoisomer" refers to a compound made
up of the same atoms bonded by the same bonds but having different
three-dimensional structures, which are not interchangeable. The
present invention contemplates various stereoisomers and mixtures
thereof and includes "enantiomers", which refers to two
stereoisomers whose molecules are nonsuperimposeable mirror images
of one another.
[0602] As used herein, the term "amino acid conjugate" refers to
conjugates of the compound of Formula I, (I-A) to (I-Y), (I'), II,
and (II-A)-(II-K) with any suitable amino acid. Preferably, such
suitable amino acid conjugates of the compound of Formula I, (I-A)
to (I-Y), (I'), II, and (II-A)-(II-K) will have the added advantage
of enhanced integrity in bile or intestinal fluids. Suitable amino
acids include but are not limited to glycine, taurine and
acylglucuronide. Thus, the present invention encompasses the
glycine, taurine and acylglucuronide conjugates of the compound of
Formula I, (I-A) to (I-Y), (I'), II, and (II-A)-(II-K).
[0603] As used herein, the term "pharmaceutically acceptable
carrier" includes any and all solvents, dispersion media, coatings,
surfactants, antioxidants, preservatives (e.g., antibacterial
agents, antifungal agents), isotonic agents, absorption delaying
agents, salts, preservatives, drugs, drug stabilizers, binders,
excipients, disintegration agents, lubricants, sweetening agents,
flavoring agents, dyes, and the like and combinations thereof, as
would be known to those skilled in the art (see, for example,
Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing
Company, 1990, pp. 1289-1329). Except insofar as any conventional
carrier is incompatible with the active ingredient, its use in the
therapeutic or pharmaceutical compositions is contemplated.
[0604] As used herein, the term "therapeutically effective amount"
refers to an amount of the compound of Formula I, (I-A) to (I-Y),
(I'), II, and (II-A)-(II-K) which is sufficient to achieve the
stated effect. Accordingly, a therapeutical effective amount of a
compound of Formula I, (I-A) to (I-Y), (I'), II, and (II-A)-(II-K)
used in for the treatment of a condition mediated by FXR will be an
amount sufficient for the treatment of the condition mediated by
FXR.
[0605] As used herein, the term "subject" refers to an animal.
Typically the animal is a mammal. A subject also refers to for
example, primates (e.g., humans, male or female), cows, sheep,
goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the
like. In certain embodiments, the subject is a primate. In yet
other embodiments, the subject is a human.
[0606] As used herein, the term "treat", "treating" or "treatment"
of any disease or disorder refers in one embodiment, to
ameliorating the disease or disorder (i.e., slowing or arresting or
reducing the development of the disease or at least one of the
clinical symptoms thereof). In another embodiment "treat",
"treating" or "treatment" refers to alleviating or ameliorating at
least one physical parameter including those which may not be
discernible by the patient. In yet another embodiment, "treat",
"treating" or "treatment" refers to modulating the disease or
disorder, either physically, (e.g., stabilization of a discernible
symptom), physiologically, (e.g., stabilization of a physical
parameter), or both. In yet another embodiment, "treat", "treating"
or "treatment" refers to preventing or delaying the onset or
development or progression of the disease or disorder.
[0607] As used herein, a subject is "in need of" a treatment if
such subject would benefit biologically, medically or in quality of
life from such treatment.
[0608] As used herein, the term "dyslipidemia" refers to an
abonormality in, or abrnomal amounts of lipids and lipoproteins in
the blood and the disease states resulting, caused by, exacerbated
by, or adjunct to such abnormality (see, Dorland's Illustrated
Medical Dictionary, 29th edition, W.B. Saunders Publishing Company,
New York, N.Y.). Disease states encompassed within the definition
of dyslipidemia as used herein include hyperlipidemia,
hypertriglyceremia, low plasma HDL, high plasma LDL, high plasma
VLDL, liver cholestasis, and hypercholesterolemia.
[0609] As used herein, the phrase "diseases related to
dyslipidemia" as used herein refers to diseases including but not
limited to atherosclerosis, thrombosis, coronary artery disease,
stroke, and hypertension. Diseases related to dyslipidemia also
include metabolic diseases such as obesity, diabetes, insulin
resistance, and complications thereof.
[0610] As used herein, the term "cholestasis" refers to any
condition in which the flow of bile from the liver is blocked, and
may be intrahepatic (i.e., occurring inside the liver) or
extrahepatic (i.e., occurring outside the liver).
[0611] As used herein, "liver fibrosis" includes liver fibrosis due
to any cause, including but not limited to virally-induced liver
fibrosis such as that due to hepatitis B and C; exposure to alcohol
(alcoholic liver disease), pharmaceutical compounds, oxidative
stress, cancer radiation therapy or industrial chemicals; and
diseases such as primary biliary cirrhosis, fatty liver, obesity,
non-alcoholic steatohepatitis, cystic fibrosis, hemochromatosis,
and auto-immune hepatitis.
[0612] "FXR agonist" as used herein refers to an agent that
directly binds to and upregulates the activity of FXR.
[0613] As used herein, the term "a," "an," "the" and similar terms
used in the context of the present invention (especially in the
context of the claims) are to be construed to cover both the
singular and plural unless otherwise indicated herein or clearly
contradicted by the context.
[0614] The chemical naming protocol and structure diagrams used
herein employ and rely on the chemical naming features as utilized
by the ChemDraw program (available from CambridgeSoft Corp.,
Cambridge, Mass.). In particular, compound structures and names
were derived using Chemdraw Ultra (Version 10.0) and/or ChemAxon
Name Generator (J Chem Version 5.3.1.0).
MODES OF CARRYING OUT THE INVENTION
[0615] The present invention relates to compositions and methods
for FXR. Various embodiments of the invention are described herein.
It will be recognized that features specified in each embodiment
may be combined with other specified features to provide further
embodiments.
[0616] In one aspect, compounds of the invention are defined by
Formula (I):
##STR00009##
[0617] or a stereoisomer, enantiomer, a pharmaceutically acceptable
salt or an amino acid conjugate thereof;
[0618] Z is phenylene, C.sub.5-7 cycloalkylene or 5-10 membered
monocyclic or bicyclic heteroaryl containing 1-2 heteroatoms
selected from N, O and S; each of which is optionally substituted
with 1-2 R.sup.6 radicals selected from halogen, C.sub.1-6 alkyl,
haloC.sub.1-6 alkyl, C.sub.1-6 alkoxy, haloC.sub.1-6 alkoxy, or
cyclopropyl;
[0619] R.sup.1 is phenyl, pyridyl, bicyclo[3.1.0]hexanyl,
spiro[2.3]hexanyl, bicyclo[3.1.1]heptanyl, spiro[2.5]octanyl,
bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexan-6-yl,
spiro[2.3]hexan-5-yl, bicyclo[3.1.1]heptan-3-yl,
spiro[2.5]octan-4-yl, bicyclo[4.1.0]heptan-3-yl, cyclohexyl or
cyclopentyl, each of which is optionally substituted with 1-3
R.sup.1a; or R.sup.1 is cyclopropyl optionally substituted with 1-2
R.sup.1a or phenyl;
[0620] R.sup.1a is halogen, C.sub.1-6 alkyl, haloC.sub.1-6 alkyl,
C.sub.1-6 alkoxy, haloC.sub.1-6 alkoxy or cyclopropyl;
[0621] R.sup.2 is C.sub.1-3 alkyl, haloC.sub.1-3 alkyl or
cyclopropyl optionally substituted with C.sub.1-3 alkyl or
haloC.sub.1-3 alkyl;
[0622] R.sup.3 is --X--CO.sub.2R.sup.4, hydroxyC.sub.1-6 alkyl,
CONR.sup.4R.sup.5, CONR(CR.sub.2).sub.1-4CO.sub.2R.sup.4,
CONR(CR.sub.2).sub.1-4SO.sub.3R.sup.5 or tetrazolyl; wherein X is a
bond, C.sub.1-2 alkylene or cyclopropyl; and
[0623] R, R.sup.4 and R.sup.5 are independently hydrogen or
C.sub.1-6 alkyl.
[0624] In one embodiment, the compounds of the invention are
selected from the group consisting of:
##STR00010##
[0625] or a stereoisomer, enantiomer, a pharmaceutically acceptable
salt or an amino acid conjugate thereof; m is 0-1; and R.sup.1,
R.sup.3 and R.sup.6 are as defined in Formula (I).
[0626] In another embodiment, the compounds of the invention are
selected from the group consisting of:
##STR00011## ##STR00012##
[0627] or a stereoisomer, enantiomer, a pharmaceutically acceptable
salt or an amino acid conjugate thereof; m is 0-1; and R.sup.1,
R.sup.3 and R.sup.6 are as defined in Formula (I).
[0628] In yet another embodiment, the compounds of the invention
are selected from the group consisting of:
##STR00013## ##STR00014##
[0629] or a stereoisomer, enantiomer, a pharmaceutically acceptable
salt or an amino acid conjugate thereof, wherein:
[0630] X.sup.1 and X.sup.2 are independently N, CH or CR.sup.6;
[0631] X.sup.3 is O or S;
[0632] R.sup.6 may be attached to any position in the ring;
[0633] m is 0-1; and R.sup.1, R.sup.3 and R.sup.6 are as defined in
Formula (I).
[0634] In another aspect, the compounds of the invention are
defined by Formula (I'):
##STR00015##
[0635] wherein L is a bond, C.sub.1-4 alkylene or
C.sub.1-4alkylene-O--;
[0636] Z is phenyl, C.sub.5-7 cycloalkyl or 5-10 membered
monocyclic or bicyclic heteroaryl containing 1-2 heteroatoms
selected from N, O and S; each of which is optionally substituted
with 1-2 R.sup.6 radicals selected from halogen, C.sub.1-6 alkyl,
haloC.sub.1-6 alkyl, C.sub.1-6 alkoxy, haloC.sub.1-6 alkoxy,
cyclopropyl or NR.sup.4R.sup.5;
[0637] R.sup.1 is phenyl substituted with 1-3 R.sup.1a; or R.sup.1
is C.sub.3-8 cycloalkyl optionally substituted with 1-3 R.sup.1a or
phenyl;
[0638] R.sup.1a is halogen, C.sub.1-6 alkyl, haloC.sub.1-6 alkyl,
C.sub.1-6 alkoxy or haloC.sub.1-6 alkoxy;
[0639] R.sup.2 is C.sub.1-3 alkyl, haloC.sub.1-3 alkyl or
cyclopropyl optionally substituted with C.sub.1-3 alkyl or
haloC.sub.1-3 alkyl;
[0640] R.sup.3 is --X--CO.sub.2R.sup.4, hydroxyC.sub.1-6 alkyl,
CONR.sup.4R.sup.5, CONR(CR.sub.2).sub.1-4CO.sub.2R.sup.4,
CONR(CR.sub.2).sub.1-4SO.sub.3R.sup.5, cyano, tetrazolyl or
SO.sub.2NR.sup.4R.sup.5; wherein X is a bond or C.sub.1-2 alkylene;
and
[0641] R.sup.4 and R.sup.5 are independently hydrogen or C.sub.1-6
alkyl; or
[0642] a stereoisomer, enantiomer, a pharmaceutically acceptable
salt or an amino acid conjugate thereof.
[0643] In one embodiment, the compounds of the invention are
defined by Formula (I'), wherein L is a bond, --CH.sub.2-- or
--CH.sub.2--O--; and more particularly, wherein L is a bond.
[0644] In another embodiment, the compounds of the invention are
defined by Formula II:
##STR00016##
[0645] wherein Z is phenyl, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, benzothiazolyl or benzo[d]isothiazolyl; each of which
is optionally substituted with 1-2 R.sup.6 radicals selected from
halogen, C.sub.1-6 alkyl, haloC.sub.1-6 alkyl, C.sub.1-6 alkoxy,
haloC.sub.1-6 alkoxy, cyclopropyl or NR.sup.4R.sup.5;
[0646] R.sup.1 is phenyl substituted with 1-3 R.sup.1a; or R.sup.1
is C.sub.3-8 cycloalkyl optionally substituted with 1-3 R.sup.1a or
phenyl;
[0647] R.sup.1a is halogen, C.sub.1-6 alkyl, haloC.sub.1-6 alkyl,
C.sub.1-6 alkoxy or haloC.sub.1-6 alkoxy;
[0648] R.sup.2 is C.sub.1-3 alkyl, haloC.sub.1-3 alkyl or
cyclopropyl optionally substituted with C.sub.1-3 alkyl or
haloC.sub.1-3 alkyl;
[0649] R.sup.3 is CO.sub.2R.sup.4, hydroxyC.sub.1-6 alkyl,
CONR.sup.4R.sup.5, CONR(CR.sub.2).sub.1-4CO.sub.2R.sup.4,
CONR(CR.sub.2).sub.1-4SO.sub.3R.sup.5 or tetrazolyl; and
[0650] R.sup.4 and R.sup.5 are independently hydrogen or C.sub.1-6
alkyl; or
[0651] a stereoisomer, enantiomer, a pharmaceutically acceptable
salt or an amino acid conjugate thereof.
[0652] In yet another embodiment, the compounds of the invention
are selected from the group consisting of:
##STR00017## ##STR00018##
[0653] wherein R.sup.1 is phenyl substituted with 1-3 R.sup.1a; or
R.sup.1 is C.sub.3-8 cycloalkyl optionally substituted with 1-3
R.sup.1a or phenyl;
[0654] R.sup.1a is halogen, C.sub.1-6 alkyl, haloC.sub.1-6 alkyl,
C.sub.1-6alkoxy or haloC.sub.1-6alkoxy;
[0655] R.sup.3 is CO.sub.2R.sup.4, hydroxyC.sub.1-6 alkyl,
CONR.sup.4R.sup.5, CONR(CR.sub.2).sub.1-4CO.sub.2R.sup.4,
CONR(CR.sub.2).sub.1-4SO.sub.3R.sup.5 or tetrazolyl;
[0656] R.sup.4 and R.sup.5 are independently hydrogen or C.sub.1-6
alkyl;
[0657] R.sup.6 is halogen, C.sub.1-6 alkyl, haloC.sub.1-6 alkyl,
C.sub.1-6 alkoxy or haloC.sub.1-6 alkoxy;
[0658] m is 0-1; or
[0659] a stereoisomer, enantiomer, a pharmaceutically acceptable
salt or an amino acid conjugate thereof.
[0660] In other embodiments, the invention provides a compound of
Formula I, I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-I, I-J, I-K,
I-L, I-M, I-N, I-O, I-P, I-Q, I-R, I-S, I-T, I-U, I-V, I-W, I-X,
I-Y, (I'), II, II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H,
II-I, II-J or II-K (collectively, Formula I, (I-A) to (I-Y), (I'),
II, and (II-A)-(II-K)), wherein a substituent is defined,
collectively or in any combination or sub-combination, as
follows:
[0661] a) Z is phenyl, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, benzothiazolyl or benzo[d]-isothiazolyl; each of which
is optionally substituted with 1-2 R.sup.6 radicals; and more
particularly, Z is pyridyl, pyrimidinyl, pyrazinyl or
benzothiazolyl, each of which is optionally substituted with 1-2
R.sup.6 radicals;
[0662] b) R.sup.1 is phenyl substituted with 1-3 R.sup.1a; or
R.sup.1 is C.sub.3-8 cycloalkyl optionally substituted with 1-3
R.sup.1a or phenyl; particularly, R.sup.1 is phenyl,
spiro[2.5]octan-6-yl, bicyclo[3.1.0]hexan-6-yl,
spiro[2.3]hexan-5-yl, bicyclo[3.1.1]heptan-3-yl,
bicyclo[4.1.0]heptan-3-yl, cyclohexyl, cyclopentyl or norbonyl,
each of which is optionally substituted with 1-3 R.sup.1a; or
R.sup.1 is cyclopropyl optionally substituted with 1-2 R.sup.1a or
phenyl; and more particularly, R.sup.1 is phenyl or
spiro[2.5]octan-6-yl, each of which is optionally substituted with
1-2 R.sup.1a;
[0663] c) R.sup.1a is halogen, C.sub.1-6 alkyl, haloC.sub.1-6
alkyl, C.sub.1-6 alkoxy or haloC.sub.1-6 alkoxy; particularly
R.sup.1a is fluoro, methyl, trifluoromethyl, trifluoromethoxy,
difluoromethoxy or methoxy;
[0664] d) R.sup.2 is C.sub.1-3 alkyl, haloC.sub.1-3 alkyl or
cyclopropyl optionally substituted with C.sub.1-3 alkyl or
haloC.sub.1-3 alkyl; and more particularly, R.sup.2 is
cyclopropyl;
[0665] e) R.sup.3 is --X--CO.sub.2R.sup.4, hydroxyC.sub.1-6 alkyl,
CONR.sup.4R.sup.5, CONR(CR.sub.2).sub.1-4CO.sub.2R.sup.4,
CONR(CR.sub.2).sub.1-4SO.sub.3R.sup.5, cyano, tetrazolyl or
SO.sub.2NR.sup.4R.sup.5; particularly, R.sup.3 is
X--CO.sub.2R.sup.4, CONR(CR.sub.2)CO.sub.2R.sup.4,
CONR(CR.sub.2).sub.2SO.sub.3R.sup.5; and more particularly, R.sup.3
is X--CO.sub.2R.sup.4; X is a bond and each R.sup.4 and R.sup.5 are
independently hydrogen or C.sub.1-6 alkyl;
[0666] f) R.sup.6 is selected halogen, C.sub.1-6 alkyl,
haloC.sub.1-6 alkyl, C.sub.1-6 alkoxy, haloC.sub.1-6 alkoxy,
cyclopropyl or NR.sup.4R.sup.5 wherein R.sup.4 and R.sup.5 are
independently hydrogen or C.sub.1-6 alkyl; particularly, R.sup.6 is
selected from halo (particularly fluoro, chloro, bromo), C.sub.1-6
alkyl (particularly methyl), haloC.sub.1-6 alkyl (particularly
trifluoromethyl), C.sub.1-6 alkoxy (particularly methoxy) or
haloC.sub.1-6 alkoxy (particularly trifluoromethoxy); and more
particularly, R.sup.6 is methyl, methoxy, fluoro or
trifluoromethoxy; and [0667] g) m is 0-2; and more particularly, m
is 0-1.
[0668] In another aspect, the present invention provides
pharmaceutical compositions comprising a compound having Formula I,
(I-A) to (I-Y), (I'), II, and (II-A)-(II-K), and a pharmaceutically
acceptable carrier. The present invention also provides a
pharmaceutical composition comprising a compound of Formula I,
(I-A) to (I-Y), (I'), II, and (II-A)-(II-K) for use in the
treatment of a condition mediated by FXR.
[0669] The compounds of Formula I, (I-A) to (I-Y), (I'), II, and
(II-A)-(II-K), and their pharmaceutically acceptable salts exhibit
valuable pharmacological properties when tested in vitro in
cell-free kinase assays and in cellular assays, and are therefore
useful as pharmaceuticals. In particular, the compounds of the
invention are agonists of Farnesoid X receptors (FXRs), and are
useful as pharmaceuticals to treat FXR-mediated conditions such as
cholestasis, intrahepatic cholestasis, estrogen-induced
cholestasis, drug-induced cholestasis, cholestasis of pregnancy,
parenteral nutrition-associated cholestasis, primary biliary
cirrhosis (PBC), primary sclerosing cholangitis (PSC), progressive
familiar cholestasis (PFIC), non-alcoholic fatty liver disease
(NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced bile
duct injury, gallstones, liver cirrhosis, alcohol-induced
cirrhosis, cystic fibrosis, bile duct obstruction, cholelithiasis,
liver fibrosis, dyslipidemia, atherosclerosis, diabetes, diabetic
nephropathy, colitis, newborn jaundice, prevention of kernicterus,
veno-occlusive disease, portal hypertension, metabolic syndrome,
hypercholesterolemia, intestinal bacterial overgrowth, erectile
dysfunction, progressive fibrosis of the liver caused by any of the
diseases above or by infectious hepatitis, or other FXR-mediated
conditions leading to extrahepatic cholestasis. The compounds of
the invention are also useful for lowering total cholesterol,
lowering LDL cholesterol, lowering VLDL cholesterol, raising HDL
levels, and/or lowering triglyceride levels.
[0670] In one aspect, the invention provides methods for modulating
FXR in a cell, comprising contacting the cell with an effective
amount of a compound of Formula I, (I-A) to (I-Y), (I'), II, and
(II-A)-(II-K), or a pharmaceutical composition thereof.
[0671] In another aspect, the invention provides methods to treat,
ameliorate or prevent a FXR-mediated disorder in a subject
suffering there from, comprising administering to the subject a
therapeutically effective amount of a compound of Formula I, (I-A)
to (I-Y), (I'), II, and (II-A)-(II-K), or a pharmaceutical
composition thereof, and optionally in combination with a second
therapeutic agent. The present invention also provides for the use
of a compound of Formula I, (I-A) to (I-Y), (I'), II, and
(II-A)-(II-K), and optionally in combination with a second
therapeutic agent, in the manufacture of a medicament for treating
a FXR-mediated disorder such as cholestasis, intrahepatic
cholestasis, estrogen-induced cholestasis, drug-induced
cholestasis, cholestasis of pregnancy, parenteral
nutrition-associated cholestasis, primary biliary cirrhosis (PBC),
primary sclerosing cholangitis (PSC), progressive familiar
cholestasis (PFIC), non-alcoholic fatty liver disease (NAFLD),
non-alcoholic steatohepatitis (NASH), drug-induced bile duct
injury, gallstones, liver cirrhosis, alcohol-induced cirrhosis,
cystic fibrosis, bile duct obstruction, cholelithiasis, liver
fibrosis, dyslipidemia, atherosclerosis, diabetes, diabetic
nephropathy, colitis, newborn jaundice, prevention of kernicterus,
veno-occlusive disease, portal hypertension, metabolic syndrome,
hypercholesterolemia, intestinal bacterial overgrowth, or erectile
dysfunction.
[0672] In yet another aspect, the present invention provides a
combination comprising a therapeutically effective amount of a
compound of Formula I, (I-A) to (I-Y), (I'), II, and (II-A)-(II-K),
and a second therapeutic agent being useful in the treatment of
cholestasis, intrahepatic cholestasis, estrogen-induced
cholestasis, drug-induced cholestasis, cholestasis of pregnancy,
parenteral nutrition-associated cholestasis, primary biliary
cirrhosis (PBC), primary sclerosing cholangitis (PSC), progressive
familiar cholestasis (PFIC), non-alcoholic fatty liver disease
(NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced bile
duct injury, gallstones, liver cirrhosis, alcohol-induced
cirrhosis, cystic fibrosis, bile duct obstruction, cholelithiasis,
liver fibrosis, dyslipidemia, atherosclerosis, diabetes, diabetic
nephropathy, colitis, newborn jaundice, prevention of kernicterus,
veno-occlusive disease, portal hypertension, metabolic syndrome,
hypercholesterolemia, intestinal bacterial overgrowth, or erectile
dysfunction.
[0673] Unless specified otherwise, the term "compounds of the
present invention" refers to compounds of Formula I, (I-A) to
(I-Y), (I'), II, and (II-A)-(II-K), prodrugs thereof, salts of the
compound and/or prodrugs, hydrates or solvates of the compounds,
salts and/or prodrugs, as well as all stereoisomers (including
diastereoisomers and enantiomers), tautomers and isotopically
labeled compounds (including deuterium substitutions), as well as
inherently formed moieties (e.g., polymorphs, solvates and/or
hydrates).
[0674] Certain of the compounds described herein contain one or
more asymmetric centers or axes and may thus give rise to
enantiomers, diastereomers, and other stereoisomeric forms that may
be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
The present invention is meant to include all possible isomers,
including racemic mixtures, optically pure forms and intermediate
mixtures. Optically active (R)- and (S)-isomers may be prepared
using chiral synthons or chiral reagents, or resolved using
conventional techniques. If the compound contains a double bond,
the substituent may be E or Z configuration. If the compound
contains a disubstituted cycloalkyl, the cycloalkyl substituent may
have a cis- or trans-configuration. All tautomeric forms are also
intended to be included.
[0675] Any formula given herein is also intended to represent
unlabeled forms as well as isotopically labeled forms of the
compounds. Isotopically labeled compounds have structures depicted
by the formulas given herein except that one or more atoms are
replaced by an atom having a selected atomic mass or mass number.
Examples of isotopes that can be incorporated into compounds of the
invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorous, fluorine, and chlorine, such as .sup.2H, .sup.3H,
.sup.11C, .sup.13C, .sup.14C, .sup.15N, .sup.18F, .sup.31P,
.sup.32P, .sup.35S, .sup.36Cl and .sup.125I respectively. The
invention includes various isotopically labeled compounds as
defined herein, for example those into which radioactive isotopes,
such as .sup.3H, .sup.13C, and .sup.14C, are present. Such
isotopically labelled compounds are useful in metabolic studies
(with .sup.14C), reaction kinetic studies (with, for example
.sup.2H or .sup.3H), detection or imaging techniques, such as
positron emission tomography (PET) or single-photon emission
computed tomography (SPECT) including drug or substrate tissue
distribution assays, or in radioactive treatment of patients. In
particular, an .sup.18F or labeled compound may be particularly
desirable for PET or SPECT studies. Isotopically labeled compounds
of this invention and prodrugs thereof can generally be prepared by
carrying out the procedures disclosed in the schemes or in the
examples and preparations described below by substituting a readily
available isotopically labeled reagent for a non-isotopically
labeled reagent.
[0676] Further, substitution with heavier isotopes, particularly
deuterium (i.e., .sup.2H or D) may afford certain therapeutic
advantages resulting from greater metabolic stability, for example
increased in vivo half-life or reduced dosage requirements or an
improvement in therapeutic index. It is understood that deuterium
in this context is regarded as a substituent of a compound of
Formula I, (I-A) to (I-Y), (I'), II, and (II-A)-(II-K). The
concentration of such a heavier isotope, specifically deuterium,
may be defined by the isotopic enrichment factor. The term
"isotopic enrichment factor" as used herein means the ratio between
the isotopic abundance and the natural abundance of a specified
isotope. If a substituent in a compound of this invention is
denoted deuterium, such compound has an isotopic enrichment factor
for each designated deuterium atom of at least 3500 (52.5%
deuterium incorporation at each designated deuterium atom), at
least 4000 (60% deuterium incorporation), at least 4500 (67.5%
deuterium incorporation), at least 5000 (75% deuterium
incorporation), at least 5500 (82.5% deuterium incorporation), at
least 6000 (90% deuterium incorporation), at least 6333.3 (95%
deuterium incorporation), at least 6466.7 (97% deuterium
incorporation), at least 6600 (99% deuterium incorporation), or at
least 6633.3 (99.5% deuterium incorporation).
[0677] Isotopically-labeled compounds of Formula I, (I-A) to (I-Y),
(I'), II, and (II-A)-(II-K) can generally be prepared by
conventional techniques known to those skilled in the art or by
processes analogous to those described in the accompanying Examples
and Processes using an appropriate isotopically-labeled reagents in
place of the non-labeled reagent previously employed.
[0678] Pharmaceutically acceptable solvates in accordance with the
invention include those wherein the solvent of crystallization may
be isotopically substituted, e.g. D.sub.2O, d.sup.6-acetone,
d.sup.6-DMSO.
[0679] Compounds of the invention, i.e. compounds of Formula I,
(I-A) to (I-Y), (I'), II, and (II-A)-(II-K) that contain groups
capable of acting as donors and/or acceptors for hydrogen bonds may
be capable of forming co-crystals with suitable co-crystal formers.
These co-crystals may be prepared from compounds of Formula I,
(I-A) to (I-Y), (I'), II, and (II-A)-(II-K) by known co-crystal
forming procedures. Such procedures include grinding, heating,
co-subliming, co-melting, or contacting in solution compounds of
Formula I, (I-A) to (I-Y), (I'), II, and (II-A)-(II-K) with the
co-crystal former under crystallization conditions and isolating
co-crystals thereby formed. Suitable co-crystal formers include
those described in WO 2004/078163. Hence the invention further
provides co-crystals comprising a compound of Formula I, (I-A) to
(I-Y), (I'), II, and (II-A)-(II-K).
[0680] Any asymmetric atom (e.g., carbon or the like) of the
compound(s) of the present invention can be present in racemic or
enantiomerically enriched, for example the (R)-, (S)- or
(R,S)-configuration. In certain embodiments, each asymmetric atom
has at least 50% enantiomeric excess, at least 60% enantiomeric
excess, at least 70% enantiomeric excess, at least 80% enantiomeric
excess, at least 90% enantiomeric excess, at least 95% enantiomeric
excess, or at least 99% enantiomeric excess in the (R)- or
(S)-configuration. Substituents at atoms with unsaturated bonds
may, if possible, be present in cis-(Z)- or trans-(E)-form.
[0681] Accordingly, as used herein a compound of the present
invention can be in the form of one of the possible isomers,
rotamers, atropisomers, tautomers or mixtures thereof, for example,
as substantially pure geometric (cis or trans) isomers,
diastereomers, optical isomers (antipodes), racemates or mixtures
thereof. Any resulting mixtures of isomers can be separated on the
basis of the physicochemical differences of the constituents, into
the pure or substantially pure geometric or optical isomers,
diastereomers, racemates, for example, by chromatography and/or
fractional crystallization. Any resulting racemates of final
products or intermediates can be resolved into the optical
antipodes by known methods, e.g., by separation of the
diastereomeric salts thereof, obtained with an optically active
acid or base, and liberating the optically active acidic or basic
compound. In particular, a basic moiety may thus be employed to
resolve the compounds of the present invention into their optical
antipodes, e.g., by fractional crystallization of a salt formed
with an optically active acid, e.g., tartaric acid, dibenzoyl
tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl tartaric
acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
Racemic products can also be resolved by chiral chromatography,
e.g., high pressure liquid chromatography (HPLC) using a chiral
adsorbent.
[0682] Pharmacology and Utility
[0683] The compounds of Formula I, (I-A) to (I-Y), (I'), II, and
(II-A)-(II-K) in free form or in salt form, exhibit valuable
pharmacological properties, e.g. FXR modulating properties, e.g. as
indicated in in vitro and/or in vivo tests as provided in the next
sections, and are therefore indicated for therapy in treating a
disorder which may be treated by modulating FXR, such as those
described below.
[0684] FXR regulates a complex pattern of response genes in the
liver that have impact on diverse physiological processes. FXR
represses the induction of Cyp7A1 via the upregulation of mRNA
encoding SHP, a further nuclear receptor that is dominant
repressive over LRH-1. Parallel to the repression of bile acid
synthesis via SHP, FXR induces a range of so-called ABC (for
ATP-binding cassette) transporters that are responsible for the
export of toxic bile acids from the hepatocyte cytosol into the
canaliculi, the small bile duct ramifications where the bile
originates. This hepatoprotective function of FXR became first
apparent with the analysis of FXR knockout mice where under- or
overexpression of several ABC-transporters in the liver was shown
(Sinai et al., Cell 2000, 102(6), 731-744). Further detailed
analysis revealed that the major bile salt excretory pump BSEP or
ABCB 11, as well as the key enzyme which mediates lipid transfer
from lipoproteins to phospholipids, PLTP, and the two key
canalicular membrane transporters for phospholipids, MRP-2 (ABCC4)
and MDR-3 (ABCB4), are direct targets for ligand-directed
transcriptional activation by FXR. The fact that FXR seems to be
the major metabolite sensor and regulator for the synthesis, export
and re-circulation of bile acids suggested the use of FXR ligands
to induce bile flow and change bile acid composition towards a more
hydrophilic composition.
[0685] With the development of the first synthetic FXR ligand
GW4064 as a tool compound (Maloney et al., J. Med. Chem. 2000,
43(16), 2971-2974; Willson et al., Med. Res. Rev. 2001, 21(6)
513-22), and the development of the semisynthetic artificial bile
acid ligand 6-alpha-ethyl-CDCA, the effects of superstimulation of
FXR by potent agonists could be analyzed. It was shown that both
ligands induce bile flow in bile duct ligated animals. In addition
to choleretic effects, hepatoprotective effects could also be
demonstrated (Pellicciari et al., J. Med. Chem. 2002, 45(17),
3569-3572; Liu et al., J. Clin. Invest. 2003, 112(11), 1678-1687).
This hepatoprotective effect was further narrowed down to an
anti-fibrotic effect that results from the repression of Tissue
Inhibitors of Matrix-Metalloproteinases, TIMP-1 and 2, the
induction of collagen-deposit resolving Matrix-Metalloproteinase 2
(MMP-2) in hepatic stellate cells and the subsequent reduction of
alpha-collagen mRNA and Transforming growth factor beta (TGF-beta)
mRNA which are both pro-fibrotic factors by FXR agonists (Fiorucci
et al., Gastroenterology 2004, 127(5), 1497-1512; Fiorucci et al.,
Pharmacol. Exp. Ther. 2005, 314(2), 584-595).
[0686] The anti-fibrotic activity of FXR is at least partially
mediated by the induction of PPARy, a further nuclear receptor,
with which anti-fibrotic activity is associated (Fiorucci et al.,
J. Pharmacol. Exp. Ther. 2005, 315(1), 58-68; GaIIi et al.,
Gastroenterology 2002, 122(7), 1924-1940; Pineda Torra et al., MoI.
Endocrinol. 2003, 17(2), 259-272). Furthermore, anti-cholestatic
activity was demonstrated in bile-duct ligated animal models as
well as in animal models of estrogen-induced cholestasis (Fiorucci
et al., J. Pharmacol. Exp. Ther. 2005, 313(2), 604-612).
[0687] Genetic studies demonstrate that in hereditary forms of
cholestasis (Progressive Familiar Intrahepatic Cholestasis=PFIC,
Type I-IV), either nuclear localization of FXR itself is reduced as
a consequence of a mutation in the FIC1 gene (in PFIC Type I, also
called Byler's Disease) (Chen et al., Gastroenterology. 2004,
126(3), 756-64; Alvarez et al., Hum. MoI. Genet. 2004; 13(20),
2451-60) or levels of the FXR target gene encoding MDR-3
phospholipid export pump are reduced (in PFIC Type III). Taken
together, there is a growing body of evidence that FXR binding
compounds will demonstrate substantial clinical utility in the
therapeutic regimen of chronic cholestatic conditions such as
Primary Biliary Cirrhosis (PBC) or Primary Sclerosing Cholangitis
(PSC) (reviewed in: Rizzo et al., Curr. Drug Targets Immune Endocr.
Metabol. Disord. 2005, 5(3), 289-303; Zollner, MoI. Pharm. 2006,
3(3), 231-51, Cai et al., Expert Opin. Ther. Targets 2006, 10(3),
409-421).
[0688] Furthermore, FXR seems to be involved in the regulation of
many diverse physiological processes which are relevant in the
etiology and for the treatment of diseases as diverse as
cholesterol gallstones, metabolic disorders such as Type Il
Diabetes, dyslipidemias or obesity, chronic inflammatory diseases
such as Inflammatory Bowel Diseases or chronic intrahepatic forms
of cholestasis and many others diseases (Claudel et al.,
Arterioscler. Thromb. Vase. Biol. 2005, 25(10), 2020-2030; Westin
et al., Mini Rev. Med. Chem. 2005, 5(8), 719-727).
[0689] Cholesterol gallstones form due to low solubility of
cholesterol that is actively pumped out of the liver cell into the
lumen of the canaliculi. The relative percentage of the three major
components, bile acids, phospholipids and free cholesterol,
determines the formation of mixed micelles and hence apparent
solubility of free cholesterol in the bile. FXR polymorphisms map
as quantitative trait loci as one factor contributing to gallstone
disease (Wittenburg, Gastroenterology 2003, 125(3), 868-881). Using
the synthetic FXR tool compound GW4064, it could be demonstrated
that activation of FXR leads to an improvement of the Cholesterol
Saturation Index (CSI) and directly to an abolishment of gallstone
formation in C57L gallstone susceptible mice, whereas drug
treatment in FXR knockout mice shows no effect on gallstone
formation (Moschetta et al., Nature Medicine 2004, 10(12),
1352-1358). These results qualify FXR as a good target for the
development of small molecule agonists that can be used to prevent
cholesterol gallstone formation or to prevent reformation of
gallstones after surgical removal or Shockwave lithotripsy
(discussed in: S. Doggrell "New targets in and potential treatments
for cholesterol gallstone disease" Curr. Opin. Investig. Drugs
2006, 7(4), 344-348).
[0690] FXR has also been shown to be a key regulator of serum
triglycerides (Maloney et al., J. Med. Chem. 2000, 43(16),
2971-2974; Willson et al., Med. Res. Rev. 2001, 21(6), 513-22).
Recent reports indicate that activation of FXR by synthetic
agonists leads to significant reduction of serum triglycerides,
mainly in the form of reduced VLDL, but also to reduced total serum
cholesterol (Kast et al., MoI. Endocrinol. 2001, 15(10), 1720-1728;
Urizar et al., Science 2002, 296(5573), 1703-1706; Lambert et al.,
J. Biol. Chem. 2003, 278, 2563-2570; Watanabe et al., J. Clin.
Invest. 2004, 113(10), 1408-1418; Figge et al., J. Biol. Chem.
2004, 279(4), 2790-2799; Bilz et al., Am. J. Physiol. Endocrinol.
Metab. 2006, 290(4), E716-22).
[0691] However, the lowering of serum triglycerides is not a stand
alone effect. Treatment of db/db or ob/ob mice with synthetic FXR
agonist GW4064 resulted in marked and combined reduction of serum
triglycerides, total cholesterol, free fatty acids, ketone bodies
such as 3-OH Butyrate. Moreover, FXR activation engages with the
intracellular insulin signaling pathway in hepatocytes, resulting
in reduced output of glucose from liver gluconeogenesis but
concomitant increase in liver glycogen. Insulin sensitivity as well
as glucose tolerance were positively impacted by FXR treatment
(Stayrook et al., Endocrinology 2005, 146(3), 984-91; Zhang et al.,
Proc. Natl. Acad. Sci. USA 2006, 103(4), 1006-1011; Cariou et al.,
J. Biol. Chem. 2006, 281, 11039-11049; Ma et al., J. Clin. Invest.
2006, 116(4), 1102-1109; Duran-Sandoval et al., Biochimie 2005,
87(1), 93-98).
[0692] An effect on reduction of body weight was also recently
observed in mice overfed with a high lipid diet (Lihong et al.,
American Diabetes Association (ADA) 66th annual scientific
sessions, June 2006, Abstract Number 856-P). This weight loss
effect might result from FXR's induction of FGF-19, a fibroblast
growth factor that is known to lead to weight loss and athletic
phenotype (Holt et al., Genes Dev. 2003, 17(13), 1581-1591;
Tomlinson et al., Endocrinology 2002, 143(5), 1741-1747). Taken
together, FXR binding compounds are thought to be good candidates
for the treatment of Type II Diabetes because of their insulin
sensitization, glycogenogenic, and lipid lowering effects.
[0693] In one embodiment, said compounds and pharmaceutical
compositions are used for the preparation of a medicament for the
treatment of chronic intrahepatic and some forms of extrahepatic
cholestatic conditions, such as primary biliary cirrhosis (PBC),
primary sclerosing cholangitis (PSC), progressive familiar
cholestasis (PFIC), alcohol-induced cirrhosis and associated
cholestasis, or liver fibrosis resulting from chronic cholestatic
conditions or acute intraheptic cholestatic conditions such as
estrogen or drug induced cholestasis.
[0694] In another embodiment, the compounds according to the
invention and pharmaceutical compositions comprising said compounds
are used in the treatment of Type Il Diabetes which can be overcome
by FXR-mediated upregulation of systemic insulin sensitivity and
intracellular insulin signalling in liver, increased peripheral
glucose uptake and metabolisation, increased glycogen storage in
liver, decreased output of glucose into serum from liver-borne
gluconeogenesis.
[0695] The invention also relates to a compound of Formula I, (I-A)
to (I-Y), (I'), II, and (II-A)-(II-K), or to a pharmaceutical
composition comprising said compound, for the treatment of
gastrointestinal conditions with a reduced uptake of dietary fat
and fat-soluble dietary vitamins which can be overcome by increased
intestinal levels of bile acids and phospholipids.
[0696] In another embodiment, the compounds according to the
invention are useful for beneficially altering lipid profiles,
including but not limited to lowering total cholesterol levels,
lowering LDL cholesterol levels, lowering VLDL cholesterol levels,
raising HDL cholesterol levels, and/or lowering triglyceride
levels. Thus, the present invention provides a method for treating
FXR mediated conditions such as dyslipidemia and diseases related
to dyslipidemia comprising administering a therapeutically
effective amount of a compound of the present invention to a
subject in need thereof.
[0697] In a further embodiment, said compound or pharmaceutical
composition is used for treating a disease selected from the group
consisting of lipid and lipoprotein disorders such as
hypercholesterolemia, hypertriglyceridemia, and atherosclerosis as
a clinically manifest condition which can be ameliorated by FXR's
beneficial effect on raising HDL cholesterol, lowering serum
triglycerides, increasing conversion of liver cholesterol into bile
acids and increased clearance and metabolic conversion of VLDL and
other lipoproteins in the liver.
[0698] In one further embodiment, said compound and pharmaceutical
composition are used for the preparation of a medicament where the
combined lipid lowering, anti-cholestatic and anti-fibrotic effects
of FXR-targeted medicaments can be exploited for the treatment of
liver steatosis and associated syndromes such as non-alcoholic
steatohepatitis ("NASH"), or for the treatment of cholestatic and
fibrotic effects that are associated with alcohol-induced
cirrhosis, or with viral-borne forms of hepatitis.
[0699] In conjunction with the hypolipidemic effects, it was also
shown that loss of functional FXR leads to increased
atherosclerosis in ApoE knockout mice (Hanniman et al., J. Lipid
Res. 2005, 46(12), 2595-2604). Therefore, FXR agonists might have
clinical utility as anti-atherosclerotic and cardioprotective
drugs. The downregulation of Endothelin-1 in Vascular Smooth Muscle
Cells might also contribute to such beneficial therapeutic effects
(He et al., Circ. Res. 2006, 98(2), 192-9).
[0700] The invention also relates to a compound according to
Formula I, (I-A) to (I-Y), (I'), II, and (II-A)-(II-K), or a
pharmaceutical composition comprising said compound, for preventive
and posttraumatic treatment of cardiovascular disorders such as
acute myocardial infarction, acute stroke, or thrombosis which
occur as an endpoint of chronic obstructive atherosclerosis. In a
few selected publications, the effects of FXR and FXR agonists on
proliferation of cancer and non-malignant cells and apoptosis have
been assessed. From these preliminary results it seems as if FXR
agonists might also influence apoptosis in cancer cell lines
(Niesor et al., Curr. Pharm. Des. 2001, 7(4), 231-59) and in
Vascular Smooth Muscle Cells (VSMCs) (Bishop-Bailey et al., Proc.
Natl. Acad. Sci. USA. 2004, 101(10), 3668-3673).
[0701] Furthermore, FXR seems to be expressed in metastasizing
breast cancer cells and in colon cancer (Silva, J. Lipid Res. 2006,
47(4), 724-733; De Gottardi et al., Dig. Dis. Sci. 2004, 49(6),
982-989). Other publications that focus primarily on FXR's effect
on metabolism draw a line to intracellular signaling from FXR via
the Forkhead/Wingless (FOXO) family of transcriptional modulators
to the Phosphatidylinositol-trisphosphat (PI3)-Kinase/Akt signal
transduction pathway (Duran-Sandoval et al., J. Biol. Chem. 2005,
280(33), 29971-29979; Zhang et al., Proc. Natl. Acad. Sci. USA.
2006, 103(4), 1006-1011) that is similarly employed by insulin
intracellular signaling as well as neoplastically transformed
cells. Thus, FXR may also be a potential target for the treatment
of proliferative diseases, especially metastasizing cancer forms
that overexpress FXR or those where the FOXO/PI3-Kinase/Akt Pathway
is responsible for driving proliferation. Therefore, the compounds
according to Formula I, (I-A) to (I-Y), (I'), II, and
(II-A)-(II-K), or pharmaceutical composition comprising said
compounds are suitable for treating non-malignant
hyperproliferative disorders such as increased neointima formation
after balloon vessel dilatation and stent application due to
increased proliferation of vascular smooth muscle cells (VSMCs) or
Bening Prostate Hyperplasia (BPH), a pre-neoplastic form of
hyperproliferation, other forms of scar tissue formation and
fibrotisation which can be overcome by e.g. FXR-mediated
intervention into the PI-3Kinase/AKT/mTOR intracellular signalling
pathway, reduction in Matrix-Metalloproteinase activity and
alpha-Collagen deposition.
[0702] In a further embodiment, said compounds and pharmaceutical
compositions are used for the treatment of malignant
hyperproliferative disorders such as cancer (e.g. certain forms of
breast or prostate cancer) where interference with
PI-3-Kinase/AKT/mTOR signalling and/or induction of p27kip and/or
induction of apoptosis will have a beneficial impact.
[0703] FXR seems also to be involved in the control of
antibacterial defense in the intestine (Inagaki et al., Proc. Natl.
Acad. Sci. USA. 2006, 103(10), 3920-3905) although an exact
mechanism is not provided. From these published data, however, one
can conclude that treatment with FXR agonists might have a
beneficial impact in the therapy of Inflammatory Bowel Disorders
(IBD), in particular those forms where the upper (ileal) part of
the intestine is affected (e.g. ileal Crohn's disease) because this
seems to be the site of action of FXR's control on bacterial
growth. In IBD, the desensitization of the adaptive immune response
is somehow impaired in the intestinal immune system. Bacterial
overgrowth might then be the causative trigger towards
establishment of a chronic inflammatory response. Hence, dampening
of bacterial growth by FXR-borne mechanisms might be a key
mechanism to prevent acute inflammatory episodes. Thus, the
invention also relates to a compound according to formula (I) or a
pharmaceutical composition comprising said compound for treating a
disease related to Inflammatory Bowel Diseases such as Crohn's
disease or Colitis ulcerosa. FXR-mediated restoration of intestinal
barrier function and reduction in non-commensal bacterial load is
believed to be helpful in reducing the exposure of bacterial
antigens to the intestinal immune system and can therefore reduce
inflammatory responses.
[0704] The invention further relates to a compound or
pharmaceutical composition for the treatment of obesity and
associated disorders such as metabolic syndrome (combined
conditions of dyslipidemias, diabetes and abnormally high body-mass
index) which can be overcome by FXR-mediated lowering of serum
triglycerides, blood glucose and increased insulin sensitivity and
FXR-mediated weight loss.
[0705] In one embodiment, said compound or pharmaceutical
composition is for treating persistent infections by intracellular
bacteria or parasitic protozoae such as Mycobacterium spec.
(Treatment of Tuberculosis or Lepra), Listeria monocytogenes
(Treatment of Listeriosis), Leishmania spec. (Leishmaniosis),
Trypanosoma spec. (Chagas Disease; Trypanosomiasis; Sleeping
Sickness).
[0706] In a further embodiment, the compounds or pharmaceutical
composition of the present invention are useful in the preparation
of a medicament for treating clinical complications of Type I and
Type II Diabetes. Examples of such complications include Diabetic
Nephropathy, Diabetic Retinopathy, Diabetic Neuropathies,
Peripheral Arterial Occlusive Disease (PAOD). Other clinical
complications of Diabetes are also encompassed by the present
invention.
[0707] Furthermore, conditions and diseases which result from
chronic fatty and fibrotic degeneration of organs due to enforced
lipid and specifically triglyceride accumulation and subsequent
activation of profibrotic pathways may also be treated by applying
the compounds or pharmaceutical composition of the present
invention. Such conditions and diseases encompass Non-Alcoholic
Steatohepatitis (NASH) and chronic cholestatic conditions in the
liver, Glomerulosclerosis and Diabetic Nephropathy in the kidney,
Macula Degeneration and Diabetic Retinopathy in the eye and
Neurodegenerative diseases such as Alzheimer's Disease in the brain
or Diabetic Neuropathies in the peripheral nervous system.
[0708] Administration and Pharmaceutical Compositions
[0709] In another aspect, the present invention provides a
pharmaceutical composition comprising a compound of the present
invention and a pharmaceutically acceptable carrier. The
pharmaceutical composition can be formulated for particular routes
of administration such as oral administration, parenteral
administration, and rectal administration, etc. In addition, the
pharmaceutical compositions of the present invention can be made up
in a solid form (including without limitation capsules, tablets,
pills, granules, powders or suppositories), or in a liquid form
(including without limitation solutions, suspensions or emulsions).
The pharmaceutical compositions can be subjected to conventional
pharmaceutical operations such as sterilization and/or can contain
conventional inert diluents, lubricating agents, or buffering
agents, as well as adjuvants, such as preservatives, stabilizers,
wetting agents, emulsifers and buffers, etc.
[0710] Typically, the pharmaceutical compositions are tablets or
gelatin capsules comprising the active ingredient together with
[0711] a) diluents, e.g., lactose, dextrose, sucrose, mannitol,
sorbitol, cellulose and/or glycine;
[0712] b) lubricants, e.g., silica, talcum, stearic acid, its
magnesium or calcium salt and/or polyethyleneglycol; for tablets
also
[0713] c) binders, e.g., magnesium aluminum silicate, starch paste,
gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose
and/or polyvinylpyrrolidone; if desired
[0714] d) disintegrants, e.g., starches, agar, alginic acid or its
sodium salt, or effervescent mixtures; and/or
[0715] e) absorbents, colorants, flavors and sweeteners.
[0716] Tablets may be either film coated or enteric coated
according to methods known in the art.
[0717] Suitable compositions for oral administration include an
effective amount of a compound of the invention in the form of
tablets, lozenges, aqueous or oily suspensions, dispersible powders
or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use are prepared according to any
method known in the art for the manufacture of pharmaceutical
compositions and such compositions can contain one or more agents
selected from the group consisting of sweetening agents, flavoring
agents, coloring agents and preserving agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets may
contain the active ingredient in admixture with nontoxic
pharmaceutically acceptable excipients which are suitable for the
manufacture of tablets. These excipients are, for example, inert
diluents, such as calcium carbonate, sodium carbonate, lactose,
calcium phosphate or sodium phosphate; granulating and
disintegrating agents, for example, corn starch, or alginic acid;
binding agents, for example, starch, gelatin or acacia; and
lubricating agents, for example magnesium stearate, stearic acid or
talc. The tablets are uncoated or coated by known techniques to
delay disintegration and absorption in the gastrointestinal tract
and thereby provide a sustained action over a longer period. For
example, a time delay material such as glyceryl monostearate or
glyceryl distearate can be employed. Formulations for oral use can
be presented as hard gelatin capsules wherein the active ingredient
is mixed with an inert solid diluent, for example, calcium
carbonate, calcium phosphate or kaolin, or as soft gelatin capsules
wherein the active ingredient is mixed with water or an oil medium,
for example, peanut oil, liquid paraffin or olive oil.
[0718] Certain injectable compositions are aqueous isotonic
solutions or suspensions, and suppositories are advantageously
prepared from fatty emulsions or suspensions. Said compositions may
be sterilized and/or contain adjuvants, such as preserving,
stabilizing, wetting or emulsifying agents, solution promoters,
salts for regulating the osmotic pressure and/or buffers. In
addition, they may also contain other therapeutically valuable
substances. Said compositions are prepared according to
conventional mixing, granulating or coating methods, respectively,
and contain about 0.1-75%, or contain about 1-50%, of the active
ingredient.
[0719] Suitable compositions for transdermal application include an
effective amount of a compound of the invention with a suitable
carrier. Carriers suitable for transdermal delivery include
absorbable pharmacologically acceptable solvents to assist passage
through the skin of the host. For example, transdermal devices are
in the form of a bandage comprising a backing member, a reservoir
containing the compound optionally with carriers, optionally a rate
controlling barrier to deliver the compound of the skin of the host
at a controlled and predetermined rate over a prolonged period of
time, and means to secure the device to the skin.
[0720] Suitable compositions for topical application, e.g., to the
skin and eyes, include aqueous solutions, suspensions, ointments,
creams, gels or sprayable formulations, e.g., for delivery by
aerosol or the like. Such topical delivery systems will in
particular be appropriate for dermal application, e.g., for the
treatment of skin cancer, e.g., for prophylactic use in sun creams,
lotions, sprays and the like. They are thus particularly suited for
use in topical, including cosmetic, formulations well-known in the
art. Such may contain solubilizers, stabilizers, tonicity enhancing
agents, buffers and preservatives.
[0721] As used herein, a topical application may also pertain to an
inhalation or to an intranasal application. They may be
conveniently delivered in the form of a dry powder (either alone,
as a mixture, for example a dry blend with lactose, or a mixed
component particle, for example with phospholipids) from a dry
powder inhaler or an aerosol spray presentation from a pressurised
container, pump, spray, atomizer or nebuliser, with or without the
use of a suitable propellant.
[0722] Dosage forms for the topical or transdermal administration
of a compound of this invention include powders, sprays, ointments,
pastes, creams, lotions, gels, solutions, patches and inhalants.
The active compound may be mixed under sterile conditions with a
pharmaceutically acceptable carrier, and with any preservatives,
buffers, or propellants that may be desirable.
[0723] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, excipients, such
as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures
thereof.
[0724] Powders and sprays can contain, in addition to a compound of
this invention, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays can additionally contain
customary propellants, such as chlorofluorohydrocarbons and
volatile unsubstituted hydrocarbons, such as butane and
propane.
[0725] Transdermal patches have the added advantage of providing
controlled delivery of a compound of the present invention to the
body. Such dosage forms can be made by dissolving or dispersing the
compound in the proper medium. Absorption enhancers can also be
used to increase the flux of the compound across the skin. The rate
of such flux can be controlled by either providing a rate
controlling membrane or dispersing the active compound in a polymer
matrix or gel.
[0726] Ophthalmic formulations, eye ointments, powders, solutions
and the like, are also contemplated as being within the scope of
this invention.
[0727] The present invention further provides anhydrous
pharmaceutical compositions and dosage forms comprising the
compounds of the present invention as active ingredients, since
water may facilitate the degradation of certain compounds.
Anhydrous pharmaceutical compositions and dosage forms of the
invention can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
An anhydrous pharmaceutical composition may be prepared and stored
such that its anhydrous nature is maintained. Accordingly,
anhydrous compositions are packaged using materials known to
prevent exposure to water such that they can be included in
suitable formulary kits. Examples of suitable packaging include,
but are not limited to, hermetically sealed foils, plastics, unit
dose containers (e.g., vials), blister packs, and strip packs.
[0728] The invention further provides pharmaceutical compositions
and dosage forms that comprise one or more agents that reduce the
rate by which the compound of the present invention as an active
ingredient will decompose. Such agents, which are referred to
herein as "stabilizers," include, but are not limited to,
antioxidants such as ascorbic acid, pH buffers, or salt buffers,
etc.
[0729] The pharmaceutical composition or combination of the present
invention can be in unit dosage of about 1-1000 mg of active
ingredient(s) for a subject of about 50-70 kg, or about 1-500 mg or
about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about 1-50
mg of active ingredients. The therapeutically effective dosage of a
compound, the pharmaceutical composition, or the combinations
thereof, is dependent on the species of the subject, the body
weight, age and individual condition, the disorder or disease or
the severity thereof being treated. A physician, clinician or
veterinarian of ordinary skill can readily determine the effective
amount of each of the active ingredients necessary to prevent,
treat or inhibit the progress of the disorder or disease.
[0730] The above-cited dosage properties are demonstrable in vitro
and in vivo tests using advantageously mammals, e.g., mice, rats,
dogs, monkeys or isolated organs, tissues and preparations thereof.
The compounds of the present invention can be applied in vitro in
the form of solutions, e.g., aqueous solutions, and in vivo either
enterally, parenterally, advantageously intravenously, e.g., as a
suspension or in aqueous solution. The dosage in vitro may range
between about 10-3 molar and 10-9 molar concentrations. A
therapeutically effective amount in vivo may range depending on the
route of administration, between about 0.1-500 mg/kg, or between
about 1-100 mg/kg.
[0731] The compound of the present invention may be administered
either simultaneously with, or before or after, one or more other
therapeutic agent. The compound of the present invention may be
administered separately, by the same or different route of
administration, or together in the same pharmaceutical composition
as the other agents.
[0732] In one embodiment, the invention provides a product
comprising a compound of Formula I, (I-A) to (I-Y), (I'), II, and
(II-A)-(II-K) and at least one other therapeutic agent as a
combined preparation for simultaneous, separate or sequential use
in therapy. In one embodiment, the therapy is the treatment of a
disease or condition mediated by FXR. Products provided as a
combined preparation include a composition comprising a compound of
Formula I, (I-A) to (I-Y), (I'), II, and (II-A)-(II-K), and the
other therapeutic agent(s) together in the same pharmaceutical
composition, or the compound of Formula I, (I-A) to (I-Y), (I'),
II, and (II-A)-(II-K) and the other therapeutic agent(s) in
separate form, e.g. in the form of a kit.
[0733] In one embodiment, the invention provides a pharmaceutical
composition comprising a compound of Formula I, (I-A) to (I-Y),
(I'), II, and (II-A)-(II-K), and another therapeutic agent(s). It
is contemplated that the invention provides a pharmaceutical
composition comprising a compound of Formula I, (I-A) to (I-Y),
(I'), II, and (II-A)-(II-K) in combination with a naturally
occurring non-toxic bile acid, such as ursodeoxycholic acid, as an
aid in preventing possible depletion of fat-soluble vitamins
secondary to treatment with an FXR agonist. Accordingly, the
compounds of the invention may be administered concurrently with
the naturally occurring non-toxic bile acid, either as separate
entities or as a single formulation comprising a compound of
Formula I, (I-A) to (I-Y), (I'), II, and (II-A)-(II-K) and
naturally occurring bile acid.
[0734] Optionally, the pharmaceutical composition may comprise a
pharmaceutically acceptable excipient, as described above.
[0735] In one embodiment, the invention provides a kit comprising
two or more separate pharmaceutical compositions, at least one of
which contains a compound of Formula I, (I-A) to (I-Y), (I'), II,
and (II-A)-(II-K). In one embodiment, the kit comprises means for
separately retaining said compositions, such as a container,
divided bottle, or divided foil packet. An example of such a kit is
a blister pack, as typically used for the packaging of tablets,
capsules and the like.
[0736] The kit of the invention may be used for administering
different dosage forms, for example, oral and parenteral, for
administering the separate compositions at different dosage
intervals, or for titrating the separate compositions against one
another. To assist compliance, the kit of the invention typically
comprises directions for administration.
[0737] In the combination therapies of the invention, the compound
of the invention and the other therapeutic agent may be
manufactured and/or formulated by the same or different
manufacturers. Moreover, the compound of the invention and the
other therapeutic may be brought together into a combination
therapy: (i) prior to release of the combination product to
physicians (e.g. in the case of a kit comprising the compound of
the invention and the other therapeutic agent); (ii) by the
physician themselves (or under the guidance of the physician)
shortly before administration; (iii) in the patient themselves,
e.g. during sequential administration of the compound of the
invention and the other therapeutic agent.
[0738] Accordingly, the invention provides the use of a compound of
Formula I, (I-A) to (I-Y), (I'), II, and (II-A)-(II-K) for treating
a disease or condition mediated by FXR, wherein the medicament is
prepared for administration with another therapeutic agent. The
invention also provides the use of another therapeutic agent for
treating a disease or condition mediated by FXR, wherein the
medicament is administered with a compound of Formula I, (I-A) to
(I-Y), (I'), II, and (II-A)-(II-K).
[0739] The invention also provides a compound of Formula I, (I-A)
to (I-Y), (I'), II, and (II-A)-(II-K) for use in a method of
treating a disease or condition mediated by FXR, wherein the
compound of Formula I, (I-A) to (I-Y), (I'), II, and (II-A)-(II-K)
is prepared for administration with another therapeutic agent. The
invention also provides another therapeutic agent for use in a
method of treating a disease or condition mediated by FXR, wherein
the other therapeutic agent is prepared for administration with a
compound of Formula I, (I-A) to (I-Y), (I'), II, and (II-A)-(II-K).
The invention also provides a compound of Formula I, (I-A) to
(I-Y), (I'), II, and (II-A)-(II-K) for use in a method of treating
a disease or condition mediated by FXR, wherein the compound of
Formula I, (I-A) to (I-Y), (I'), II, and (II-A)-(II-K) is
administered with another therapeutic agent. The invention also
provides another therapeutic agent for use in a method of treating
a disease or condition mediated by FXR, wherein the other
therapeutic agent is administered with a compound of Formula I,
(I-A) to (I-Y), (I'), II, and (II-A)-(II-K).
[0740] The invention also provides the use of a Formula I, (I-A) to
(I-Y), (I'), II, and (II-A)-(II-K) for treating a disease or
condition mediated by FXR, wherein the patient has previously (e.g.
within 24 hours) been treated with another therapeutic agent. The
invention also provides the use of another therapeutic agent for
treating a disease or condition mediated by FXR, wherein the
patient has previously (e.g. within 24 hours) been treated with a
compound of Formula I, (I-A) to (I-Y), (I'), II, and
(II-A)-(II-K).
[0741] In one embodiment, the other therapeutic agent is useful in
the treatment of dyslipidemia, cholestasis, estrogen-induced
cholestasis, drug-induced cholestasis, primary biliary cirrhosis
(PBC), primary sclerosing cholangitis (PSC), progressive familiar
cholestasis (PFIC), alcohol-induced cirrhosis, cystic fibrosis,
cholelithiasis, liver fibrosis, atherosclerosis or diabetes,
particularly type II diabetes.
[0742] Processes for Making Compounds of the Invention
[0743] Typically, the compounds of Formula I, (I-A) to (I-Y), and
(II-A)-(II-K) can be prepared according to any one of Schemes I, II
and III, provided infra.
[0744] The present invention also provides a process for the
production of a compound of Formula I, comprising reacting a
compound of Formula III:
##STR00019##
[0745] with a compound of Formula Y--Z--R.sup.3;
[0746] wherein Y is a leaving group;
[0747] R.sup.1, R.sup.2 and Z are as defined in Formula I;
[0748] R.sup.3 is --X--CO.sub.2R.sup.4 wherein X is a bond or
methylene;
[0749] R.sup.4 is C.sub.1-6 alkyl; and R.sup.7 is H or a protecting
group; and
[0750] optionally, converting a compound of Formula I, wherein the
substituents have the meaning as defined, into another compound of
Formula I as defined; and
[0751] recovering the resulting compound of Formula I in free form
or as a salt; and optionally converting the compound of Formula I
obtained in free form into a desired salt, or an obtained salt into
the free form.
[0752] Each reaction step can be carried out in a manner known to
those skilled in the art. For example, a reaction can be carried in
the presence of a suitable solvent or diluent or of mixture
thereof. A reaction can also be carried, if needed, in the presence
of an acid or a base, with cooling or heating, for example in a
temperature range from approximately -30.degree. C. to
approximately 150.degree. C. In particular examples, a reaction is
carried in a temperature range from approximately 0.degree. C. to
100.degree. C., and more particularly, in a temperature range from
room temperature to approximately 80.degree. C., in an open or
closed reaction vessel and/or in the atmosphere of an inert gas,
for example nitrogen.
[0753] In one embodiment, the compounds of Formula I, (I-A) to
(I-Y), and (II-A)-(II-K) can be prepared following the procedures
in Scheme 1:
##STR00020##
[0754] wherein R.sup.1, R.sup.2 and Z are as defined in Formula I;
R is C.sub.1-6 alkyl; and Y is a leaving group.
[0755] In another embodiment, the compounds of Formula I, (I-A) to
(I-Y), and (II-A)-(II-K) can be prepared following the procedures
in Scheme 2:
##STR00021##
[0756] wherein R.sup.1, R.sup.2 and Z are as defined in Formula I;
R is C.sub.1-6 alkyl; and Y is a leaving group.
[0757] In yet another embodiment, the compounds of Formula I, (I-A)
to (I-Y), II, and (II-A)-(II-K) can be prepared following the
procedures in Scheme 3:
##STR00022##
[0758] wherein R.sup.1, R.sup.2 and Z are as defined in Formula I;
R is C.sub.1-6 alkyl; and Y is a leaving group.
[0759] The invention also relates to those forms of the process in
which a compound obtainable as an intermediate at any stage of the
process is used as starting material and the remaining process
steps are carried out, or in which a starting material is formed
under the reaction conditions or is used in the form of a
derivative, for example in a protected form or in the form of a
salt, or a compound obtainable by the process according to the
invention is produced under the process conditions and processed
further in situ. Compounds of the invention and intermediates can
also be converted into each other according to methods generally
known to those skilled in the art. Intermediates and final products
can be worked up and/or purified according to standard methods,
e.g. using chromatographic methods, distribution methods, (re-)
crystallization, and the like.
[0760] Within the scope of this text, only a readily removable
group that is not a constituent of the particular desired end
product of the compounds of the present invention is designated a
"protecting group", unless the context indicates otherwise. The
protection of functional groups by such protecting groups, the
protecting groups themselves, and their cleavage reactions are
described for example in standard reference works, such as J. F. W.
McOmie, "Protective Groups in Organic Chemistry", Plenum Press,
London and New York 1973, in T. W. Greene and P. G. M. Wuts,
"Protective Groups in Organic Synthesis", Third edition, Wiley, New
York 1999, in "The Peptides"; Volume 3 (editors: E. Gross and J.
Meienhofer), Academic Press, London and New York 1981, in "Methoden
der organischen Chemie" (Methods of Organic Chemistry), Houben
Weyl, 4th edition, Volume 15/I, Georg Thieme Verlag, Stuttgart
1974, in H.-D. Jakubke and H. Jeschkeit, "Aminosauren, Peptide,
Proteine" (Amino acids, Peptides, Proteins), Verlag Chemie,
Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann,
"Chemie der Kohlenhydrate: Monosaccharide and Derivate" (Chemistry
of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme
Verlag, Stuttgart 1974. A characteristic of protecting groups is
that they can be removed readily (i.e. without the occurrence of
undesired secondary reactions) for example by solvolysis,
reduction, photolysis or alternatively under physiological
conditions (e.g. by enzymatic cleavage).
[0761] All the above-mentioned process steps mentioned herein
before and hereinafter can be carried out under reaction conditions
that are known to those skilled in the art, including those
mentioned specifically, in the absence or, customarily, in the
presence of solvents or diluents, including, for example, solvents
or diluents that are inert towards the reagents used and dissolve
them, in the absence or presence of catalysts, condensation or
neutralizing agents, for example ion exchangers, such as cation
exchangers, e.g. in the H+ form, depending on the nature of the
reaction and/or of the reactants at reduced, normal or elevated
temperature, for example in a temperature range of from about
-100.degree. C. to about 190.degree. C., including, for example,
from approximately -80.degree. C. to approximately 150.degree. C.,
for example at from -80 to -60.degree. C., at room temperature, at
from -20 to 40.degree. C. or at reflux temperature, under
atmospheric pressure or in a closed vessel, where appropriate under
pressure, and/or in an inert atmosphere, for example under an argon
or nitrogen atmosphere.
[0762] At all stages of the reactions, mixtures of isomers that are
formed can be separated into the individual isomers, for example
diastereoisomers or enantiomers, or into any desired mixtures of
isomers, for example racemates or mixtures of diastereoisomers.
Mixtures of isomers obtainable according to the invention can be
separated in a manner known to those skilled in the art into the
individual isomers; diastereoisomers can be separated, for example,
by partitioning between polyphasic solvent mixtures,
recrystallisation and/or chromatographic separation, for example
over silica gel or by e.g. medium pressure liquid chromatography
over a reversed phase column, and racemates can be separated, for
example, by the formation of salts with optically pure salt-forming
reagents and separation of the mixture of diastereoisomers so
obtainable, for example by means of fractional crystallisation, or
by chromatography over optically active column materials.
[0763] The solvents from which those solvents that are suitable for
any particular reaction may be selected include those mentioned
specifically or, for example, water, esters, such as lower
alkyl-lower alkanoates, for example ethyl acetate, ethers, such as
aliphatic ethers, for example diethyl ether, or cyclic ethers, for
example tetrahydrofuran or dioxane, liquid aromatic hydrocarbons,
such as benzene or toluene, alcohols, such as methanol, ethanol or
1- or 2-propanol, nitriles, such as acetonitrile, halogenated
hydrocarbons, such as methylene chloride or chloroform, acid
amides, such as dimethylformamide or dimethyl acetamide, bases,
such as heterocyclic nitrogen bases, for example pyridine or
N-methylpyrrolidin-2-one, carboxylic acid anhydrides, such as lower
alkanoic acid anhydrides, for example acetic anhydride, cyclic,
linear or branched hydrocarbons, such as cyclohexane, hexane or
isopentane, methycyclohexane, or mixtures of those solvents, for
example aqueous solutions, unless otherwise indicated in the
description of the processes. Such solvent mixtures may also be
used in working up, for example by chromatography or
partitioning.
[0764] The compounds of the present invention are either obtained
in the free form, as a salt thereof, or as prodrug derivatives
thereof. When both a basic group and an acid group are present in
the same molecule, the compounds of the present invention may also
form internal salts, e.g., zwitterionic molecules. In many cases,
the compounds of the present invention are capable of forming acid
and/or base salts by virtue of the presence of amino and/or
carboxyl groups or groups similar thereto. As used herein, the
terms "salt" or "salts" refers to an acid addition or base addition
salt of a compound of the invention. "Salts" include in particular
"pharmaceutical acceptable salts". The term "pharmaceutically
acceptable salts" refers to salts that retain the biological
effectiveness and properties of the compounds of this invention
and, which typically are not biologically or otherwise
undesirable.
[0765] Salts of compounds of the present invention having at least
one salt-forming group may be prepared in a manner known to those
skilled in the art. For example, salts of compounds of the present
invention having acid groups may be formed, for example, by
treating the compounds with metal compounds, such as alkali metal
salts of suitable organic carboxylic acids, e.g. the sodium salt of
2-ethylhexanoic acid, with organic alkali metal or alkaline earth
metal compounds, such as the corresponding hydroxides, carbonates
or hydrogen carbonates, such as sodium or potassium hydroxide,
carbonate or hydrogen carbonate, with corresponding calcium
compounds or with ammonia or a suitable organic amine,
stoichiometric amounts or only a small excess of the salt-forming
agent preferably being used. Acid addition salts of compounds of
the present invention are obtained in customary manner, e.g. by
treating the compounds with an acid or a suitable anion exchange
reagent. Internal salts of compounds of the present invention
containing acid and basic salt-forming groups, e.g. a free carboxy
group and a free amino group, may be formed, e.g. by the
neutralisation of salts, such as acid addition salts, to the
isoelectric point, e.g. with weak bases, or by treatment with ion
exchangers. Salts can be converted into the free compounds in
accordance with methods known to those skilled in the art. Metal
and ammonium salts can be converted, for example, by treatment with
suitable acids, and acid addition salts, for example, by treatment
with a suitable basic agent.
[0766] Pharmaceutically acceptable acid addition salts can be
formed with inorganic acids and organic acids, e.g., acetate,
aspartate, benzoate, besylate, bromide/hydrobromide,
bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate,
chloride/hydrochloride, chlorotheophyllonate, citrate,
ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate,
hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate,
laurylsulfate, malate, maleate, malonate, mandelate, mesylate,
methylsulphate, naphthoate, napsylate, nicotinate, nitrate,
octadecanoate, oleate, oxalate, palmitate, pamoate,
phosphate/hydrogen phosphate/dihydrogen phosphate,
polygalacturonate, propionate, stearate, succinate,
sulfosalicylate, tartrate, tosylate, trifluoroacetate and
tris(hydroxymethyl)aminomethane salts.
[0767] Inorganic acids from which salts can be derived include, for
example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, and the like.
[0768] Organic acids from which salts can be derived include, for
example, acetic acid, propionic acid, glycolic acid, oxalic acid,
maleic acid, malonic acid, succinic acid, fumaric acid, tartaric
acid, citric acid, benzoic acid, mandelic acid, methanesulfonic
acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic
acid, and the like. Pharmaceutically acceptable base addition salts
can be formed with inorganic and organic bases.
[0769] Inorganic bases from which salts can be derived include, for
example, ammonium salts and metals from columns I to XII of the
periodic table. In certain embodiments, the salts are derived from
sodium, potassium, ammonium, calcium, magnesium, iron, silver,
zinc, and copper; particularly suitable salts include ammonium,
potassium, sodium, calcium and magnesium salts.
[0770] Organic bases from which salts can be derived include, for
example, primary, secondary, and tertiary amines, substituted
amines including naturally occurring substituted amines, cyclic
amines, basic ion exchange resins, and the like. Certain organic
amines include isopropylamine, benzathine, cholinate,
diethanolamine, diethylamine, lysine, meglumine, piperazine and
tromethamine.
[0771] The pharmaceutically acceptable salts of the present
invention can be synthesized from a parent compound, a basic or
acidic moiety, by conventional chemical methods. Generally, such
salts can be prepared by reacting free acid forms of these
compounds with a stoichiometric amount of the appropriate base
(such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the
like), or by reacting free base forms of these compounds with a
stoichiometric amount of the appropriate acid. Such reactions are
typically carried out in water or in an organic solvent, or in a
mixture of the two. Generally, use of non-aqueous media like ether,
ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable,
where practicable. Lists of additional suitable salts can be found,
e.g., in "Remington's Pharmaceutical Sciences", 20th ed., Mack
Publishing Company, Easton, Pa., (1985); and in "Handbook of
Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and
Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
[0772] The present invention also provides pro-drugs of the
compounds of the present invention that converts in vivo to the
compounds of the present invention. A pro-drug is an active or
inactive compound that is modified chemically through in vivo
physiological action, such as hydrolysis, metabolism and the like,
into a compound of this invention following administration of the
prodrug to a subject. The suitability and techniques involved in
making and using pro-drugs are well known by those skilled in the
art. Prodrugs can be conceptually divided into two non-exclusive
categories, bioprecursor prodrugs and carrier prodrugs. See The
Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic
Press, San Diego, Calif., 2001). Generally, bioprecursor prodrugs
are compounds, which are inactive or have low activity compared to
the corresponding active drug compound, that contain one or more
protective groups and are converted to an active form by metabolism
or solvolysis. Both the active drug form and any released metabolic
products should have acceptably low toxicity.
[0773] Carrier prodrugs are drug compounds that contain a transport
moiety, e.g., that improve uptake and/or localized delivery to a
site(s) of action. Desirably for such a carrier prodrug, the
linkage between the drug moiety and the transport moiety is a
covalent bond, the prodrug is inactive or less active than the drug
compound, and any released transport moiety is acceptably
non-toxic. For prodrugs where the transport moiety is intended to
enhance uptake, typically the release of the transport moiety
should be rapid. In other cases, it is desirable to utilize a
moiety that provides slow release, e.g., certain polymers or other
moieties, such as cyclodextrins. Carrier prodrugs can, for example,
be used to improve one or more of the following properties:
increased lipophilicity, increased duration of pharmacological
effects, increased site-specificity, decreased toxicity and adverse
reactions, and/or improvement in drug formulation (e.g., stability,
water solubility, suppression of an undesirable organoleptic or
physiochemical property). For example, lipophilicity can be
increased by esterification of (a) hydroxyl groups with lipophilic
carboxylic acids (e.g., a carboxylic acid having at least one
lipophilic moiety), or (b) carboxylic acid groups with lipophilic
alcohols (e.g., an alcohol having at least one lipophilic moiety,
for example aliphatic alcohols).
[0774] Exemplary prodrugs are, e.g., esters of free carboxylic
acids and S-acyl derivatives of thiols and O-acyl derivatives of
alcohols or phenols, wherein acyl has a meaning as defined herein.
Suitable prodrugs are often pharmaceutically acceptable ester
derivatives convertible by solvolysis under physiological
conditions to the parent carboxylic acid, e.g., lower alkyl esters,
cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or
di-substituted lower alkyl esters, such as the .omega.-(amino,
mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower
alkyl esters, the .alpha.-(lower alkanoyloxy, lower alkoxycarbonyl
or di-lower alkylaminocarbonyl)-lower alkyl esters, such as the
pivaloyloxymethyl ester and the like conventionally used in the
art. In addition, amines have been masked as arylcarbonyloxymethyl
substituted derivatives which are cleaved by esterases in vivo
releasing the free drug and formaldehyde (Bundgaard, J. Med. Chem.
2503 (1989)). Moreover, drugs containing an acidic NH group, such
as imidazole, imide, indole and the like, have been masked with
N-acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier
(1985)). Hydroxy groups have been masked as esters and ethers. EP
039,051 (Sloan and Little) discloses Mannich-base hydroxamic acid
prodrugs, their preparation and use.
[0775] Furthermore, the compounds of the present invention,
including their salts, may also be obtained in the form of
hydrates, or their crystals may, for example, include the solvent
used for crystallization. Different crystalline forms may be
present. The compounds of the present invention may inherently or
by design form solvates with pharmaceutically acceptable solvents
(including water); therefore, it is intended that the invention
embrace both solvated and unsolvated forms. The term "solvate"
refers to a molecular complex of a compound of the present
invention (including pharmaceutically acceptable salts thereof)
with one or more solvent molecules. Such solvent molecules are
those commonly used in the pharmaceutical art, which are known to
be innocuous to the recipient, e.g., water, ethanol, and the like.
The term "hydrate" refers to the complex where the solvent molecule
is water. The compounds of the present invention, including salts,
hydrates and solvates thereof, may inherently or by design form
polymorphs.
[0776] Compounds of the invention in unoxidized form may be
prepared from N-oxides of compounds of the invention by treating
with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl
phosphine, lithium borohydride, sodium borohydride, phosphorus
trichloride, tribromide, or the like) in a suitable inert organic
solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like)
at 0 to 80.degree. C.
[0777] All starting materials, building blocks, reagents, acids,
bases, dehydrating agents, solvents and catalysts utilized to
synthesize the compounds of the present invention are either
commercially available or can be produced by organic synthesis
methods known to one of ordinary skill in the art (Houben-Weyl 4th
Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). All
methods described herein can be performed in any suitable order
unless otherwise indicated herein or otherwise clearly contradicted
by context. The use of any and all examples, or exemplary language
(e.g. "such as") provided herein is intended merely to better
illuminate the invention and does not pose a limitation on the
scope of the invention otherwise claimed.
Preparation of Intermediates
Intermediate 1
##STR00023## ##STR00024##
[0778] 2-(Trifluoromethoxy)Benzaldehyde oxime (I-1B)
[0779] To a solution of sodium hydroxide (7 g, 175.00 mmol, 1.19
equiv) in water (120 mL) was added a stirred solution of
NH.sub.2OH.HCl (11.8 g, 169.78 mmol, 1.15 equiv) in water (120 mL)
at 0.degree. C. The resulting solution was stirred for 10 min at
0.degree. C. Then a solution of 2-(trifluoromethoxy)benzaldehyde
(28 g, 147.29 mmol, 1.00 equiv) in ethanol (120 mL) was added. The
resulting solution was allowed to stir for an additional 1 h at
room temperature. The resulting solution was diluted with 500 ml of
H.sub.2O, extracted with 2.times.700 mL of ethyl acetate and the
organic layers were combined, washed with 2.times.300 mL of brine,
dried over anhydrous sodium sulfate and concentrated under vacuum
to give (E)-2-(trifluoromethoxy)benzaldehyde oxime as an off-white
crystalline solid.
N-hydroxy-2-(trifluoromethoxy)benzimidoyl chloride (I-1C)
[0780] NCS (22 g, 166.04 mmol, 1.12 equiv) was slowly added to a
stirred solution of (E)-2-(trifluoromethoxy)benzaldehyde oxime (30
g, 146.27 mmol, 1.00 equiv) in N,N-dimethylformamide (300 mL)
keeping the internal temperature below 25.degree. C. The reaction
mixture was stirred for 1 h at room temperature. The resulting
solution was diluted with water (300 mL) and extracted with ethyl
acetate (2.times.500 mL). The organic layers were combined, washed
with brine (5.times.300 mL), dried over anhydrous sodium sulfate,
and concentrated under vacuum to give
(Z)-2-(trifluoromethoxy)benzoyl chloride oxime as a light yellow
crystalline solid.
Methyl
5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-carboxylate
(I-1D)
[0781] Potassium carbonate (11 g, 79.7 mmol, 1.09 equiv) was
suspended in THF (100 mL) and the mixture was stirred. A solution
of methyl 3-cyclopropyl-3-oxopropanoate (11 g, 77.5 mmol, 1.06
equiv) in 50 ml THF was added to the above stirred mixture and
stirred for 30 min at -10.degree. C. To this reaction mixture was
added a solution of (Z)-2-(trifluoromethoxy)benzoyl chloride oxime
(17.6 g, 73.3 mmol, 1.00 equiv) in THF (50 mL) at -5.degree. C. and
then allowed to stir for 6 h at 35.degree. C. The reaction mixture
was diluted with 200 mL of H.sub.2O, extracted with ethyl acetate
(2.times.300 mL). The organic layer was washed with brine
(2.times.200 mL), dried over anhydrous sodium sulfate, concentrated
under vacuum, and then purified by silica gel column chromatography
using ethyl acetate/petroleum ether (1:100-1:20) eluent to afford
methyl
5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-carboxylate
as a white solid.
(5-Cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)-methanol
(I-1E)
[0782] A 250-mL round-bottom flask was purged with nitrogen and a
suspension of LiAlH.sub.4 (2.5 g, 65.8 mmol, 2.87 equiv) in
tetrahydrofuran (50 mL) was added. This was followed by the
addition of a solution of methyl
5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-carboxylate
(7.5 g, 22.9 mmol, 1.00 equiv) in tetrahydrofuran (50 mL) dropwise
at -10.degree. C. The resulting reaction mixture was stirred for 30
min at -10.degree. C. When the reaction was complete, it was
quenched by the addition of 3 mL of ethyl acetate, followed by 3 mL
of water and 10 mL of 15% aqueous NaOH, all whilst maintaining a
vigorous stirring. The resulting white precipitate was filtered
through CELITE.RTM., and the filter cake was washed with 200 mL of
ethyl acetate. The filtrate was washed with brine (2.times.100 mL),
dried over anhydrous sodium sulfate, and concentrated under vacuum.
This resulted in 7 g of
(5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methanol
as yellow oil. (1H-NMR 300 MHz, CDCl.sub.3) .delta. 7.56 (m, 2H),
7.41 (m, 2H), 4.50 (s, 2H), 2.20 (m, 1H), 1.72 (s, 1H, --OH)
1.11-1.28 (m, 4H).
4-(Bromomethyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)-phenyl)isoxazole
(I-1F)
[0783] Into a 100 mL round bottom flask was placed
(5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)-methanol
(4 g, 13.3 mmol), triphenylphosphine (5.6 g, 20 mmol, 1.5 equiv)
and dichloromethane (40 mL). The mixture was stirred until
completely dissolved, and then slowly cannulated dropwise into a
stirring solution of carbon tetrabromide (6.6 g, 20 mmol, 1.5 eq)
in dichloromethane (20 ml). The mixture was stirred for one hour
and the solvent was then evaporated in vacuo. The crude residue was
purified by silica gel chromatography using a 0-50% gradient of
ethyl acetate/hexane. The desired product was obtained as a
colorless oil. MS m/z 361.9/363.9 (M+1, Br.sub.79/Br.sub.81 isotope
pattern).
tert-Butyl
3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)m-
ethoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (I-1G)
[0784] A 250-mL flask was purged with nitrogen and then charged
with N-Boc-nortropine (2.9 g, 12.8 mmol), 18-Crown-6 (3.4 g, 12.8
mmol), and anhydrous tetrahydrofuran (80 mL). Potassium
tert-butoxide (2.9 g, 25.6 mmol) was added in small portions, and
the mixture was stirred vigorously under nitrogen for 1 h.
4-(bromomethyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)-phenyl)isoxazole
(4.18 g, 11.6 mmol) was dissolved in anhydrous tetrahydrofuran (20
mL) and added dropwise, and the reaction mixture was stirred
overnight under a positive nitrogen pressure. The solvent was
removed in vacuo and the mixture diluted with water (100 mL) and
ethyl acetate (100 mL). The organic layer was separated, dried with
anhydrous MgSO.sub.4, and evaporated in vacuo. The crude residue
was purified by silica gel chromatography using a gradient of
0-100% ethyl acetate/hexanes to yield the desired product as yellow
oil. MS m/z 509.2 (M+1).
4-8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluorome-
thoxy)phenyl)isoxazole (I-1H)
[0785]
tert-butyl-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-
-4-yl)methoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate was
dissolved in 30 mL of a 20% solution of trifluoroacetic acid in
dichloromethane. The solution was stirred for 1 h at room
temperature and the solvent was evaporated. The residue was
dissolved in ethyl acetate (125 mL), washed with a saturated
solution of sodium bicarbonate (100 mL), the organic layer was
dried with anhydrous MgSO.sub.4 and evaporated in vacuo. The crude
residue was purified by silica gel chromatography using a gradient
of 0-20% ethanol/dichloromethane to afford the desired product as a
colorless oil. MS m/z 409.2 (M+1) .sup.1H NMR (DMSOd.sub.6, 400
MHz); .delta. 8.51 (br s, 1H, NH), 7.72-7.68 (m, 1H), 7.64 (dd,
J=7.6, 1.8 Hz, 1H), 7.58-7.52 (m, 2H), 4.33 (s, 2H), 3.81 (bs, 2H),
3.55 (t, J=4.5 Hz, 1H), 2.36-2.33 (m, 1H), 1.98 (app dt, J=14.8,
4.0 Hz, 2H), 1.91-1.76 (m, 6H), 1.14-1.07 (m, 4H).
[0786]
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(tr-
ifluoromethyl)phenyl)isoxazole (I-1I) was prepared following the
same procedures. MS m/z 393.2 (M+1); .sup.1H NMR (DMSOd.sub.6, 400
MHz); .delta. 8.51 (br s, 1H, NH), 7.92 (d, J=8.0, 1.8 Hz, 1H),
7.81 (app t, J=7.1 Hz, 1H), 7.78 (app t, J=7.1 Hz, 1H), 7.58 (d,
J=7.3 Hz, 1H), 4.24 (s, 2H), 3.81 (bs, 2H), 3.52 (t, J=3.7 Hz, 1H),
2.36-2.33 (m, 1H), 1.92 (app dt, J=14.8, 4.0 Hz, 2H), 1.81-1.69 (m,
6H), 1.14-1.09 (m, 4H).
[0787]
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(di-
fluoromethoxy)phenyl)isoxazole (I-1J) was prepared following the
same procedures. MS m/z 391.3 (M+1); .sup.1H NMR (CDCl.sub.3, 400
MHz); .delta. 9.10 (br s, 1H, NH), 7.32 (app t, J=8.4 Hz, 2H), 7.26
(app d, J=8.4 Hz, 2H), 6.44 (t, J=74 Hz, 1H, CHF.sub.2), 4.32 (s,
2H), 3.82 (bs, 2H), 3.56 (t, J=4.0 Hz, 1H), 2.32 (app dt, J=15.2,
4.6 Hz, 2H), 2.08-2.04 (m, 1H), 1.98-1.89 (m, 4H), 1.78 (app br d,
J=15.9 Hz, 2H), 1.26-1.20 (m, 2H), 1.14-1.09 (m, 2H).
[0788]
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2,6-d-
ifluorophenyl)isoxazole (I-1K) was prepared following the same
procedures. MS m/z 361.2 (M+1); .sup.1H NMR (CDCl.sub.3, 400 MHz);
.delta. 9.18 (br s, 1H, NH), 7.48-7.40 (m, 1H), 7.06-6.99 (m, 2H),
4.31 (s, 2H), 3.82 (bs, 2H), 3.59 (t, J=4.7 Hz, 1H), 2.16 (app dt,
J=15.9, 4.0 Hz, 2H), 2.09-2.02 (m, 1H), 1.98-1.92 (m, 4H), 1.76
(app br d, J=15.2 Hz, 2H), 1.26-1.19 (m, 2H), 1.15-1.09 (m,
2H).
Intermediate 2
Methyl 2-chloro-4-methoxybenzothiazole-6-carboxylate (I-2)
##STR00025##
[0789] Methyl 2-amino-4-methoxybenzo[d]thiazole-6-carboxylate
(I-2A)
[0790] A solution of NaSCN (27 g, 333.33 mmol, 4.00 equiv) in AcOH
(50 mL) was prepared in a three-necked, round-bottomed 100-mL
flask. A solution of methyl 4-amino-3-methoxybenzoate (15 g, 82.87
mmol, 1.00 equiv) in AcOH (50 mL) was added dropwise at 0.degree.
C., followed by the addition of a solution of Br.sub.2 (12 g, 75.00
mmol, 1.10 equiv) in AcOH (20 mL) dropwise at 0.degree. C. The
resulting solution was stirred for 4 h at room temperature, after
which point it was then diluted with 200 mL of water. The pH of the
solution was adjusted to pH=8 with sodium carbonate. The solids
were collected by filtration and dried in a warm oven under reduced
pressure to give methyl
2-amino-4-methoxybenzo[d]thiazole-6-carboxylate as a yellow
solid.
Methyl 2-chloro-4-methoxybenzo[d]thiazole-6-carboxylate (I-2)
[0791] A 1000-mL 3-necked round-bottom flask was charged with a
solution of methyl 2-amino-4-methoxybenzo[d]thiazole-6-carboxylate
(5 g, 21.01 mmol, 1.00 equiv) and H.sub.3PO.sub.4 (40 mL). To this
is added of a solution of NaNO.sub.2 (4.5 g, 65.22 mmol, 3.00
equiv) in water (10 mL) dropwise at 0.degree. C. The resulting
solution was stirred for 1 h at 0.degree. C. A solution of
CuSO.sub.4 (10 g, 62.50 mmol, 5.00 equiv) in water (10 mL) was then
added dropwise at 0.degree. C., followed by a solution of NaCl
(18.5 g, 318.97 mmol, 15.00 equiv) in water (10 mL) dropwise at
0.degree. C. The resulting solution was stirred for 1 h at room
temperature, and then diluted with 100 mL of water. The aqueous
solution was extracted with dichloromethane (2.times.50 mL) and the
combined organic layer was concentrated under vacuum. The residue
was purified by silica gel chromatography eluting with ethyl
acetate/petroleum ether (3:1) to give methyl
2-chloro-4-methoxybenzo[d]thiazole-6-carboxylate as a white solid.
(ES, m/z): Calc'd for C.sub.10H.sub.8ClNO.sub.3S [M+1].sup.+=258.
found 258. .sup.1H-NMR (CDCl.sub.3, ppm): 3.98 (s, 1H), 4.10 (s,
1H), 7.28 (s, 1H), 7.60 (d, 1H, J=1.2), 8.12 (d, 1H, J=1.2).
Intermediate 3
Methyl 2-bromo-4-fluorobenzothiazole-6-carboxylate (I-3)
##STR00026##
[0792] Methyl 3-fluoro-4-nitrobenzoate (I-3A)
[0793] Into a 2-L round-bottom flask was placed a solution of
3-fluoro-4-nitrobenzoic acid (100 g, 540.54 mmol, 1.00 equiv) and
HCl (50 mL) in methanol (800 mL). The resulting solution was
refluxed for 16 h. The resulting solution was diluted with 1000 mL
of EtOAc. The pH of the solution was adjusted to neutral with
saturated potassium bicarbonate solution. The resulting mixture was
washed with brine (2.times.500 mL), dried over anhydrous sodium
sulfate and concentrated under vacuum to give methyl
3-fluoro-4-nitrobenzoate as a pale yellow solid.
Methyl 4-amino-3-fluorobenzoate (I-3B)
[0794] Into a 2000-mL round-bottom flask maintained with a nitrogen
atmosphere, was placed a solution of methyl
3-fluoro-4-nitrobenzoate (98 g, 492.46 mmol, 1.00 equiv) in ethyl
acetate:methanol=1:1 (1000 mL). Then Pd/C (10 g, 10 wt %, Degussa
type) was added. The flask was fitted with a balloon of hydrogen,
and the heterogeneous reaction mixture was stirred for 16 h under a
hydrogen atmosphere at 30.degree. C. The catalyst solids were
filtered off and the filtrate was concentrated under vacuum to give
the desired product methyl 4-amino-3-fluorobenzoate.
Methyl 2-amino-4-fluorobenzo[d]thiazole-6-carboxylate (I-3C)
[0795] Into a 1000-mL round-bottom flask, was placed a solution of
methyl 4-amino-3-fluorobenzoate (45 g, 266.27 mmol, 1.00 equiv) and
NaSCN (86 g, 1.06 mol, 3.99 equiv) in AcOH (350 mL). This was
followed by the addition of a solution of Br.sub.2 (42 g, 262.50
mmol, 0.99 equiv) in AcOH (150 mL) dropwise at 0.degree. C. for 1
h. The resulting solution was stirred for 48 h at 30.degree. C.,
after which point the solids were filtered. The resulting solution
was diluted with H.sub.2O and the pH was adjusted to pH=8-9 with
ammonium hydroxide. The resulting precipitate was collected by
filtration to give the desired product methyl
2-amino-4-fluorobenzo[d]thiazole-6-carboxylate as a yellow
solid.
Methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate (I-3)
[0796] Into a 2000-mL 3-necked round-bottom flask, was placed a
suspension of CuBr.sub.2 (61 g, 272.32 mmol, 1.54 equiv) in
acetonitrile (800 mL). This was followed by the addition of t-BuONO
(48 mL) at 0.degree. C. dropwise over the course of 10 min To this
solution was added methyl
2-amino-4-fluorobenzo[d]thiazole-6-carboxylate (40 g, 176.99 mmol,
1.00 equiv), and the reaction mixture was stirred at 30.degree. C.
for 48 h. The reaction mixture was then diluted with EtOAc (1 L),
and the organic layer was washed with water (3.times.400 mL) and
brine (3.times.400 mL), dried over anhydrous sodium sulfate, and
concentrated under vacuum. The crude residue was applied onto a
silica gel column eluting with ethyl acetate/petroleum ether
(1:100-1:5) to give methyl
2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate as a white solid.
LCMS (m/z): Calc'd for C.sub.9H.sub.5BrFNO.sub.2S [M+1].sup.+=290.
found 290. .sup.1H-NMR: (CDCl.sub.3, ppm): 8.22 (d, 1H, J=0.9 Hz),
7.86 (dd, 1H, J=1.2, 9.6 Hz), 3.99 (s, 3H).
Intermediate 4
##STR00027##
[0797] (trans)-methyl 2-(trifluoromethyl)cyclohexanecarboxylate
(rac-I-4B)
[0798] A solution of 2-(trifluoromethyl)cyclohexanecarboxylic acid
(I-4A, JP 63051354 A 19880304, 42 g, 214 mmol) acid in methanol
(150 mL) was treated with trimethyl orthoformate (39 mL, 358 mmol)
followed by p-TsOH (3.7 g, 21.4 mmol) and refluxed for 48 hours.
The reaction was then cooled to rt, concentrated, diluted with
EtOAc and washed with saturated NaHCO.sub.3 and brine. Organics
were dried (MgSO.sub.4), filtered, concentrated, and distilled
(50-52.degree. C., 0.1 Torr) to give the title trans compound as a
clear oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.67 (s, 3H),
2.89 (dd, J=4.7, 4.7 Hz, 1H), 2.38 (m, 1H), 2.06 (m, 1H), 1.95 (m,
1H), 1.81 (m, 2H), 1.71 (m, 1H), 1.59 (m, 1H), 1.47 (m, 1H), 1.34
(m, 1H), MS m/z 211.1 (M+1).
(trans)-2-(trifluoromethyl)cyclohexyl)methanol (rac-I-4C)
[0799] A cold (0.degree. C.) solution of rac-1-4B (35 g, 166 mmol)
in THF (250 mL) was stirred with the slow addition of lithium
aluminum hydride in THF (1M solution, 250 mL), and then stirred for
1 hour. The reaction was cooled to 0.degree. C., stirred, and
treated with the dropwise addition of 1N HCl (25 mL). An additional
volume of 1N HCl (500 mL) was added until the salts of the reaction
had dissolved. The reaction was then extracted with Et.sub.2O and
the organic phase collected, dried (MgSO.sub.4), filtered,
concentrated, and distilled (73-76.degree. C., 0.1 mm Hg) to give
the desired alcohol. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.78
(m, 1H), 3.67 (m, 1H), 2.34 (m, 1H), 2.13 (m, 1H), 1.90 (m, 1H),
1.75 (m, 1H), 1.63 (m, 3H), 1.50 (m, 2H), 1.39 (m, 2H), MS m/z
165.1 (M-H.sub.2O).
Methyl
5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclohexyl)-isoxazole-4-
-carboxylate (rac-I-4D)
[0800] A cold (0.degree. C.) solution of rac-4-C (28.3 g, 155 mmol)
and trichloroisocyanuric acid (37.9 g, 163 mmol) in
CH.sub.2Cl.sub.2 (310 mL) was treated with TEMPO (242 mg, 1.55
mmol) and the reaction stirred for 2 h. The reaction was then
washed with a solution of saturated Na.sub.2CO.sub.3 (100 mL)
followed by 1 M HCl (50 mL), dried over MgSO.sub.4, filtered,
evaporated and redissolved in ethanol (15 mL). This solution was
then cooled to 0.degree. C. and treated with 50% (aq) hydroxylamine
(11.4 mL) and allowed to warm to room temperature and stir
overnight. The volatiles were removed in vacuo and extracted with
EtOAc. Organics were collected, dried (MgSO.sub.4), filtered, and
concentrated. The crude oxime (27.5 g, 141 mmol) was dissolved in
DMF (200 mL) and treated with the portionwise addition of
N-chlorosuccinimide (21.1 g, 157 mmol). The reaction slowly warmed
to rt and stirred for 1 hour. The reaction was treated with
saturated NaCl (aq.) and extracted with Et.sub.2O. Organics were
collected, dried (MgSO.sub.4), filtered, concentrated and
chromatographed (SiO.sub.2, linear gradient, 0-80% EtOAc in Hex) to
afford the chloro-oxime which was dissolved in methanol (5 mL).
[0801] In another flask, a cold (0.degree. C.) solution of methyl
3-cyclopropyl-3-oxopropanoate (23.7 g, 170 mmol) in methanol (35
mL) was treated with sodium methoxide (25% wt. solution in
methanol, 30 mL). After stirring for 20 minutes, the reaction was
treated with the dropwise addition of the chloro-oxime already in
methanol. The reaction warmed to rt and stirred for 30 min. The
reaction was concentrated in vacuo and diluted with EtOAc. The
organics were washed with saturated NaCl (aq) and saturated
NaHCO.sub.3 (aq.). Organics were collected, dried (MgSO.sub.4),
filtered, concentrated, and chromatographed (SiO.sub.2, linear
gradient, 0-80%, EtOAc in Hexanes) to give the desired ester as an
oil.
(5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclohexyl)isoxazol-4-yl)meth-
anol (I-4E)
[0802] A cold (0.degree. C.) solution of the rac-4-D (5.1 g, 20.5
mmol) in THF (70 mL) was treated with the dropwise addition of
lithium aluminum hydride (26.6 mL, 1M solution in THF). After 2 hr
of stirring, the reaction was cooled to 0.degree. C. and treated
with the dropwise addition of 1N HCl (aq.) until a solution
persisted. The reaction was then extracted with EtOAc. The organic
phase was dried (MgSO.sub.4), filtered, concentrated, and
chromatographed (SiO.sub.2, linear gradient, 0-80%, EtOAc in
hexanes) to give a racemic mixture of the title compound which was
resolved using a 4.6.times.100 mm ChiralPak AD-H column eluting at
30.degree. C. with a 85% CO.sub.2/15% MeOH solvent system. The peak
eluting at 1.82 minutes was collected. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 4.52 (m, 2H), 3.52 (m, 1H), 2.45 (m, 1H), 2.17
(m, 1H), 2.02 (m, 1H), 1.97-1.66 (m, 5H), 1.52 (m, 1H), 1.42 (m,
1H), 1.35 (m, 1H), 1.14 (m, 2H), 1.05 (m, 2H), MS m/z 290.1
(M+1).
4-(chloromethyl)-5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclohexyl)is-
oxazole (I-4)
[0803] A cold (0.degree. C.) solution of
(5-cyclopropyl-3-((1S,2S)-2-(trifluoromethyl)cyclohexyl)
isoxazol-4-yl)methanol (1.8 g, 6.2 mmol) dichloromethane was
treated with Hunig's base (953 .mu.L, 6.8 mmol) followed by methane
sulfonyl chloride (508 .mu.L, 6.5 mmol). After 6 hr of stirring,
the reaction was treated with H.sub.2O and phases separated. The
organic phase was collected, dried (MgSO.sub.4), filtered,
concentrated, and chromatographed (SiO.sub.2, linear gradient,
0-80% EtOAc in Hex) to give the title compound. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 4.48 (dd, J=36.5, 12.6 Hz, 2H), 3.48 (m,
1H), 2.44 (m, 1H), 2.15 (ddd, J=25.5, 12.8, 3.6 Hz, 1H), 2.04-1.87
(m, 4H), 1.82-1.68 (m, 2H), 1.55 (m, 1H), 1.35 (m, 1H), 1.14 (m,
2H), 1.09 (m, 2H), MS m/z 308.1 (M+1).
Intermediate 5
4-(chloromethyl)-5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclopropyl)i-
soxazole (rac-5)
##STR00028##
[0804] Methyl
5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclopropyl)isoxazole-4-carbo-
xylate (rac-I-5A)
[0805] A cold (0.degree. C.) solution of
(1S,2S)-2-(trifluoromethyl)-cyclopropanecarbaldehyde (J. Chem.
Soc., Perkin Trans. 2, 1984, 1907-1915; 2.0 g, 14.5 mmol) in
ethanol (5 mL) was treated with 50% (aq) hydroxylamine (1.3 mL) and
allowed to warm to rt and stir overnight. The volatiles were
removed in vacuo and extracted with EtOAc. Organics were collected,
dried (MgSO.sub.4), filtered, and concentrated. The crude oxime
(1.0 g, 6.5 mmol) was dissolved in DMF (11.3 mL) and treated with
the portionwise addition of N-chlorosuccinimide (980 mg, 7.3 mmol).
The reaction slowly warmed to rt and stirred for 1 hour. The
reaction was treated with saturated NaCl (aq.) and extracted with
Et.sub.2O. Organics were collected, dried (MgSO.sub.4), filtered
and concentrated to afford the crude chloro-oxime which was
dissolved in methanol (5 mL).
[0806] In another flask, a cold (0.degree. C.) solution of methyl
3-cyclopropyl-3-oxopropanoate (930 mg, 6.5 mmol) in methanol (15
mL) was treated with sodium methoxide (25% wt. solution in
methanol, 1.55 mL). After stirring for 15 minutes, the reaction was
treated with the dropwise addition of the chloro-oxime already in
methanol. The reaction warmed to rt and stirred for an additional
30 min. The reaction was concentrated in vacuo and diluted with
EtOAc. The organics were washed with saturated NaCl (aq) and
saturated NaHCO.sub.3 (aq.). Organics were collected, dried
(MgSO.sub.4), filtered, concentrated, and chromatographed
(SiO.sub.2, linear gradient, 0-80%, EtOAc in Hexanes) to give the
desired ester as an oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
3.89 (s, 3H), 2.79 (m, 2H), 2.11 (m, 1H), 1.42 (m, 2H), 1.22 (m,
4H), MS m/z 276.1 (M+1).
(5-cyclopropyl-3-((trans)-2-(trifluoromethyl)-cyclopropyl)
isoxazol-4-yl)methanol (rac-I-5B)
[0807] A cold (0.degree. C.) solution of methyl
5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclopropyl)isoxazole-4-carbo-
xylate (193 mg, 0.7 mmol) in THF (2.3 mL) was treated with the
dropwise addition of lithium aluminum hydride (1.4 mL, 1M solution
in THF). After 2 hr of stirring, the reaction was cooled to
0.degree. C. and treated with the dropwise addition of 1N HCl (aq.)
until a solution persisted. The reaction was then extracted with
EtOAc. The organic phase was dried (MgSO.sub.4), filtered,
concentrated, and chromatographed (SiO.sub.2, linear gradient,
0-80%, EtOAc in hexanes) to give the title compound. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 4.63 (d, J=4.5 Hz, 2H), 2.31 (m, 1H),
2.14 (m, 1H), 2.01 (m, 1H), 1.67 (dd, J=5.1, 4.9 Hz, 1H), 1.42 (m,
2H), 1.10 (m, 2H), 1.05 (m, 2H), MS m/z 248.1 (M+1).
4-(chloromethyl)-5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclopropyl)i-
soxazole (rac-I-5)
[0808] A solution of
(5-cyclopropyl-3-((trans)-2-(trifluoromethyl)-cyclopropyl)
isoxazol-4-yl)methanol (136 mg, 0.55 mmol) in dichloromethane (2
mL) was treated with triethylamine (230 .mu.L) followed by methane
sulfonyl chloride (45 .mu.L, 0.58 mmol). After 2 hr of stirring,
the r.times.n was treated with H.sub.2O and phases separated. The
organic phase was collected, dried (MgSO.sub.4), filtered,
concentrated, and chromatographed (SiO.sub.2, linear gradient,
0-80% EtOAc in Hex) to afford the title compound. MS m/z 266.1
(M+1).
Intermediate 6
4-(chloromethyl)-5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazole
(rac-I-6)
##STR00029##
[0810] trans-2-phenylcyclopropyl)methanol (rac-I-6A). To a solution
of commercially available trans-ethyl phenylcyclopropanecarboxylic
acid (3.0 g, 18.5 mmol) in anhydrous THF (27 mL) and cooled to
0.degree. C., lithium aluminum hydride (24 mL, of a 1 M solution in
THF) was added dropwise. After stirring for 14 h at rt, the
reaction mixture was cooled to 0.degree. C. and then quenched by
the dropwise addition of H.sub.2O (1.6 mL), 15% NaOH (1.6 mL),
H.sub.2O (2.4 mL) followed by Na.sub.2SO.sub.4 and filtered under
vacuum to afford trans-2-phenylcyclopropyl)methanol which was used
without purification. .sup.1H NMR (400 MHz, DMSO) .delta. 7.22-720
(m, 2H), 7.12-7.08 (1H), 7.06-7.04 (m, 2H), 4.61 (t, J=8.0 Hz, 1H),
3.48-3.42 (m, 1H), 3.37-3.31 (m, 1H), 2.11 (m, 1H), 1.79-1.74 (m,
1H), 1.29-1.21 (m, 1H), 0.88-0.79 (m, 2H). MS m/z 149.2 (M+1).
trans-2-Phenylcyclopropanecarbaldehyde (rac-I-6B)
[0811] To a solution of trans-2-phenylcyclopropyl)methanol rac-I-6A
(1.5 g, 10.1 mmol) in 1,4-dioxane (20 mL) MnO.sub.4 (4.4 g, 50.1
mmol) was added. The dark mixture was heated at 150.degree. C. for
0.5 h under microwave irradiation. The reaction mixture was
filtered through CELITE.RTM. and washed with EtOAc. The filtrate
was collected, washed with water and brine, dried over sodium
sulfate, filtered and concentrated to afford
trans-2-Phenylcyclopropanecarbaldehyde as brown oil (0.89 g) which
was used without further purification in the next step. .sup.1H NMR
(400 MHz, DMSO) .delta. 9.09 (d, J=5.6 Hz, 1H), 7.31-7.27 (m, 2H),
7.21-7.18 (m, 3H), 2.27-2.65 (m, 1H), 2.14-2.08 (m, 1H), 1.73-1.68
(m, 1H), 1.60-1.55 (m, 1H). MS m/z 147.2 (M+1).
trans-2-Phenylcyclopropanecarbaldehyde oxime (rac-I-6C)
[0812] A solution of trans-2-phenylcyclopropanecarbaldehyde
rac-I-6B (0.89 g, 6.1 mmol) in EtOH (12 mL) and cooled to 0.degree.
C. was treated with hydroxylamine hydrochloride (0.43 g, 6.1 mmol)
and Na.sub.2CO.sub.3. The reaction mixture was allowed to warm to
rt and stir for 12 h. The volatiles were removed in vacuo and
extracted with EtOAc. The organics were collected, dried over
Na.sub.2SO.sub.4 filtered, and concentrated to afford
trans-2-Phenylcyclopropanecarbaldehyde oxime which was used without
further purification.
trans-N-hydroxy-2-phenylcyclopropanecarbimidoyl chloride
(rac-I-6D)
[0813] To a solution of the crude
trans-2-phenylcyclopropanecarbaldehyde oxime rac-I-6C (04 g, 2.51
mmol) in DMF (5 mL) and cooled at 0.degree. C. N-chlorosuccinimide
(0.37 g, 2.7 mmol) was added portionwise. The reaction mixture was
slowly warmed to rt and stirred for 14 h. The reaction was quenched
with saturated NaCl (aq.) and extracted with Et.sub.2O. The
organics were collected, washed with water, brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. The
crude was purified by column chromatography on silica gel with
hexane-EtOAc (5 to 20% gradient as eluant) to yield
trans-N-hydroxy-2-phenylcyclopropanecarbimidoyl chloride.
5-cyclopropyl-3-(2phenylcyclopropyl)isoxazole-4-carboxylic acid
(rac-I-6E)
[0814] A solution of methyl 3-cyclopropyl-3-oxopropanoate (0.36 mL,
2.9 mmol) in methanol (8 mL) was cooled to 0.degree. C. and treated
with sodium methoxide (0.76 mL of a 25% wt. solution in MeOH).
After stirring for 20 minutes,
trans-N-hydroxy-2-phenylcyclopropanecarbimidoyl chloride rac-I-6D
(0.57 g, 2.9 mmol) in methanol (0.5 mL) was added dropwise. The
reaction mixture was warmed to rt and stirred for 1 h. The reaction
was concentrated in vacuo, diluted with water and extracted with
dichloromethane. The aqueous was acidified with 6N HCl to pH=5 and
extracted again with dichloromethane. The organics were washed with
brine dried over Na.sub.2SO.sub.4, filtered, concentrated to yield
5-cyclopropyl-3-(2phenylcyclopropyl)isoxazole-4-carboxylic acid as
clear oil which was directly used in the next step without further
purification. MS m/z 270.1 (M+1).
(5-cyclopropyl-3-2phenylcyclopropyl)isoxazol-4-yl)methanol
(rac-I-6F)
[0815] To a solution of
5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazole-4-carboxylic acid
rac-I-6E (0.49 g, 1.82 mmol) in THF and cooled to 0.degree. C.
lithium aluminum hydride (4.5 mL, of a 1M solution in THF) was
added dropwise. After stirring for 12 h at rt, the reaction mixture
was cooled back to 0.degree. C. and quenched by dropwise addition
of H.sub.2O (0.5 mL), 15% NaOH (0.5 mL), H.sub.2O (1 mL) followed
by Na.sub.2SO.sub.4 and filtered through CELITE.RTM. under vacuum.
The crude was purified by column chromatography on silica gel with
DCM-EtOAc 0 to 5% gradient as eluent to give
(5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazol-4-yl)methanol.
.sup.1H NMR (400 MHz, DMSO) .delta. 7.31-727 (m, 2H), 7.21-7.17 (m,
3H), 5.00 (t, J=5.2 Hz, 1H), 4.42-4.33 (m, 2H), 2.39-2.35 (m, 1H),
2.23-2.13 (m, 2H), 1.57-1.52 (m, 1H), 1.46-1.42 (m, 1H), 1.05-1.04
(m, 2H), 0.95-0.91 (M, 2H). MS m/z 256.1 (M+1).
4-(chloromethyl)-5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazole
(rac-I-6)
[0816] To a solution of rac-I-6F (0.16 g, 0.63 mmol) in
dichloromethane (6 mL) and triethylamine (0.12 mL, 0.81 mmol) and
cooled to 0.degree. C. methane sulfonyl chloride (0.06 mL, 0.81
mmol) was added. After stirring for 6 h the reaction was diluted
with water and the organic were extracted with DCM. The organic
layer was washed with water, brine, dried over Na.sub.2SO.sub.4,
filtered, concentrated to yield
4-(chloromethyl)-5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazole as
clear oil. .sup.1H NMR (400 MHz, DMSO) .delta. 7.32-718 (m, 5H),
4.82 (s, 1H), 2.41-2.36 (m, 1H), 2.31-2.23 (m, 2H), 1.58-1.53 (m,
1H), 1.51-1.46 (m, 1H), 1.21-1.07 (m, 2H), 1.01-0.97 (m, 2H). MS
m/z 273.1 (M+1).
Intermediate 7
4-(chloromethyl)-5-cyclopropyl-3-(spiro[2.5]octan-6-yl)isoxazole
(I-7
##STR00030##
[0817] Ethyl spiro[2.5]octane-6-carboxylate (I-7A)
[0818] To a solution of diethyl zinc (35 mL, of a 1M solution in
hexane) in DCM (30 mL) cooled to 0.degree. C., a solution of TFA
(2.7 mL, 35.0 mmol) in DCM (12 mL) was added dropwise. After
stirring the reaction mixture at 0.degree. C. for 1 h,
CH.sub.2I.sub.2 (2.8 mL, 35.0 mmol) in DCM (12 mL) was slowly added
and the mixture was stirred for an additional 40 min. After this
time, ethyl 4-methylenecyclohexanecarboxylate (2.36 g, 14.0 mmol)
in DCM (5 mL) was dropwise added to the flask and the reaction
mixture was stirred for an additional 2 h. The reaction mixture was
then diluted with DCM and washed with saturated aqueous NH.sub.4Cl.
The organic layer was collected, washed with brine, dried over
Na.sub.2SO.sub.4, filtered, concentrated to yield an oil residue
that was passed through a short silica gel column to afford ethyl
spiro[2.5]octane-6-carboxylate. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 4.13 (q, J=7.2 Hz, 2H), 2.31 (m, 1H), 1.90-1.86 (m, 2H),
1.67-1.61 (m, 4H), 1.24 (t, H=7.2 Hz, 3H), 0.95-0.95 (m, 2H),
0.29-0.18 (m, 4H). MS m/z 183 (M+1).
spiro[2.5]octan-6-ylmethanol (I-7B)
[0819] Spiro[2.5]octan-6-ylmethanol was prepared using the
analogous protocol as previously described for the preparation of
the alcohol I-6A. .sup.1H NMR (400 MHz, DMSO) .delta. 4.38 (t,
J=5.2 Hz, 1H), 3.23 (dd, J=6.4 and 5.2 Hz, 2H), 1.69-1.59 (m, 4H),
1.35-1.32 (m, 1H), 1.06-1.05 (m, 2H), 0.87-0.84 (m, 2H), 0.25-0.22
(m, 2H), 0.13-0.11 (m, 2H). MS m/z 141 (M+1).
spiro[2.5]octane-6-carbaldehyde (I-7C)
[0820] To a solution of spiro[2.5]octan-6-ylmethanol (1.83 g, 13
mmo) in dichloromethane (60 mL) was added NaHCO.sub.3 (30 mL of a
0.5 M aqueous solution) and K.sub.2CO.sub.3 (30 mL of a 0.05M
aqueous solution) and tehn cooled to 0.degree. C. TEMPO (0.203 g,
1.3 mmol), TBACl (0.361 g, 1.3 mmol), and NCS (0.36 g, 1.3 mmol)
were added successively, and the reaction mixture was stirred at rt
for 4 h. Using a separation funnel the organic layer was collected
and then washed with brine, dried over Na.sub.2SO.sub.4. The
organics were concentrated in vacuo and the crude residue was
purified by column chromatography on silica gel with a gradient of
20 to 60% hexane-DCM as eluant to afford the desired product
spiro[2.5]octane-6-carbaldehyde. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.66 (d, J=0.8 Hz, 1H), 2.30 (m, 1H), 1.91-1.88 (m, 2H),
1.67-1.48 (m, 4H), 1.09-104 (m, 2H), 0.31-0.29 (m, 2H), 0.22-0.20
(m, 2H). MS m/z 139.0 (M+1).
[0821] Spiro[2.5]octane-6-carbaldehyde oxime (I-7D),
N-hydroxyspiro[2.5]octane-6-carbimidoyl chloride (I-7E),
(5-cyclopropyl-3-(spiro[2.5]octan-6-yl)isoxazol-4-yl)methanol
(I-7F) were prepared following similar protocols described
previously for the preparation of I-6C, I-6D and I-6E,
respectively, and used in the next step without purification.
4-(Chloromethyl)-5-cyclopropyl-3-(spiro[2.5]octan-6-yl)isoxazole
was prepared by according to the analogous procedure as previously
described for the preparation of Intermediate 6. .sup.1H NMR (400
MHz, DMDO) .delta. 4.79 (s, 2H), 2.81-2.74 (m, 1H), 2.32-2.25 (m,
1H), 1.91-1.87 (m, 2H), 1.83-1.77 (m, H), 1.64-1.55 (m, 2H),
1.10-1.06 (m, 2H), 1.00-0.95 (m, 4H), 0.32-0.2 (m, 4H).
Intermediate 8
##STR00031##
[0823] Intermediates I-8A [MS m/z 375.2 (M-.sup.tBu+1)]; I-8B [MS
m/z 361.2 (M-.sup.tBu+1)]; I-8C and I-8D were prepared from
corresponding cyclopentanecarbaldehyde or yclohexanecarbaldehyde
using the analogous procedures as were described for the
preparation of Intermediate 1.
Intermediate 9
4-(chloromethyl)-5-cyclopropyl-3-(4,4-dimethylcyclohexyl)isoxazole
##STR00032## ##STR00033##
[0824] 4-(Methoxymethylene)-1,1-dimethylcyclohexane (I-9A)
[0825] An oven-dried 500 mL one-necked round bottomed flask was
charged with (methoxymethyl)triphenylphosphonium bromide (22.4 g,
65.4 mmol) and dry THF (40 mL) and then cooled to -78.degree. C. To
this solution was added n-BuLi (2.8 M in hexane, 23.3 mL, 65.4
mmol) over 10 min by syringe. The resultant red ylide solution was
then warmed to rt, stirred for 3 hours, and cooled to -78.degree.
C. To this ylide solution was added 4-dimethyl-cyclohexanone (5.5
g, 43.6 mmol) in dry THF (5 mL) via syringe over 10 min After being
stirred for 1 hour at -78.degree. C., the reaction mixture was
warmed to rt slowly and stirred for 10 hours. After that the
reaction mixture was cooled to 0.degree. C., quenched with aq.
NaHCO.sub.3 (60 mL), and extracted with ether (3.times.60 mL). The
organic layer was washed with brine (60 mL) and dried over sodium
sulfate, filtered, and concentrated. The residue was purified by
silica chromatography using hexane-Et.sub.2O isocratic 20% as
eluant to give the title compound as clear oil. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 5.75 (bs, 1H), 3.75 (s, 3H), 2.18 (ddd,
J=12.8, 6.4, 1.2 Hz, 2H), 1.95 (ddd, J=12.8, 6.4, 1.2 Hz, 2H), 1.27
(ddd, J=12.8, 6.8, 2.0 Hz, 4H), 0.91 (s, 6H). No ionization by
LCMS.
4,4-Dimethylcyclohexanecarbaldehyde (I-9B)
[0826] A solution of flask
4-(methoxymethylene)-1,1-dimethylcyclohexane (2.3 g, 14.9 mmol) in
a 4:1 THF/2N HCl mixture (100 mL) was refluxed for 1 hour. The
volatile was removed in vacuo and the residue was cooled to
0.degree. C. and neutralized with 1N NaOH and extracted with
Et.sub.2O (3.times.60 mL). The organic layer was washed with water
(50 mL), brine (60 mL) and dried over sodium sulfate, filtered, and
concentrated. The residue was purified by chromatography with
hexane-DCM 10% linear gradient as eluant to give the title compound
as clear oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.64 (d,
J=1.6 Hz, 1H), 2.19-2.12 (m, 1H), 1.79-1.72 (m, 2H), 1.59-1.40 (m,
5H), 1.25-1.18 (m, 1H), 0.92 (s, 3H), 0.87 (s, 3H). No ionization
by LCMS.
[0827] 4,4-Dimethylcyclohexanecarbaldehyde oxime (I-9C) was
prepared by reaction of 4,4-dimethylcyclohexanecarbaldehyde and
hydroxylamine hydrochloride by following the same protocol as
described for I-6C. MS m/z 156.1 (M+1).
[0828] N-Hydroxy-4,4-dimethylcyclohexanecarbimidoyl chloride (I-9D)
was prepared by reaction of 4,4-dimethylcyclohexanecarbaldehyde
oxime and N-chloro succinimide following the same protocol as
described for I-6B. MS m/z 190.1 (M+1).
[0829]
5-cyclopropyl-3-(4,4-dimethylcyclohexyl)isoxazole-4-carboxylic acid
(I-9E) Was prepared by reaction of
N-hydroxy-4,4-dimethylcyclohexanecarbimidoyl chloride and methyl
3-cyclopropyl-3-oxopropanoate following the same protocol as
described for I-6E. MS m/z 264.1 (M+1).
[0830]
(5-cyclopropyl-3-(4,4-dimethylcyclohexyl)isoxazol-4-yl)methanol
(I-9F) was prepared by reaction of methyl
5-cyclopropyl-3-(4,4-dimethylcyclohexyl)isoxazole-4-carboxylate and
LiAlH.sub.4 following the same protocol as described for I-6F.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.56 (s, 3H), 2.65 (m,
1H), 2.05-1.99 (m, 1H), 1.81-1.75 (m, 4H), 1.52-1.48 (m, 2H),
1.33-1.28 (m, 2H), 1.14-1.10 (m, 2H), 1.04-1.01 (m, 2H), 0.95 (s,
3H), 0.94 (s, 3H). MS m/z 250.1 (M+1).
[0831]
4-(chloromethyl)-5-cyclopropyl-3-(4,4-dimethylcyclohexyl)isoxazole
(I-9G) was prepared by following the analogous procedure as
previously described for intermediate 1-6. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 4.50 (s, 2H), 2.62-2.54 (m, 1H), 2.02-1.95 (m,
1H), 1.83-1.72 (m, 4H), 1.52-1.49 (m, 2H), 1.31 (ddd, J=25.2, 17.6,
5.6 Hz, 2H), 1.16-1.04 (m, 2H), 1.03-1.04 (m, 1H), 0.96 (s, 3H),
0.95 (s, 3H). MS m/z 268.1 (M+1).
[0832] tert-Butyl
3-((5-cyclopropyl-3-(4,4-dimethylcyclohexyl)isoxazol-4-yl)methoxy)-8-azab-
icyclo[3.2.1]octane-8-carboxylate (I-9H) was prepared by following
the analogous procedure as previously described for example 13. MS
m/z 403.2 (M-56+1).
[0833]
4-((8-Azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(4,4-d-
imethylcyclohexyl)isoxazole (I-91) was prepared by following the
analogous procedure as previously described for Example 13. MS m/z
359.2 (M+1).
Intermediate 10
##STR00034##
[0834] Ethyl bicyclo[3.1.0]hexane-6-carboxylate (I-10A)
[0835] A solution of cyclopentene (5.0 g, 0.073 mol) and
Rh.sub.2(OAc).sub.2 (23.8 mg, 0.073 mmol) in dichloromethane (23
mL) was treated with the dropwise addition of ethyl diazoacetate
(7.6 mL, 0.073 mol) in dichloromethane (23 mL) over 5 hours via
syringe pump. Reaction stirred for 30 min and was then passed
through a basic Alumina plug (dichloromethane as the elutant) to
remove any catalyst. Reaction was concentrated in vacuo and
chromatographed (SiO.sub.2, linear gradient, 0-60% EtOAc in Hexanes
to give the desired compound as a mixture of diastereomers. MS m/z
155.3 (M+1).
Bicyclo[3.1.0]hexane-6-carbaldehyde oxime (I-10B)
[0836] A cold (0.degree. C.) solution of the I-10A (5.2 g, 0.034
mol) in THF (113 mL) was treated with the dropwise addition of
lithium aluminum hydride (44 mL, 1M solution in Et.sub.2O). After 1
hr the reaction was recooled to 0.degree. C. and treated with the
dropwise addition of 1N HCl (aq.) until a solution persisted. The
reaction was then extracted with EtOAc. The organic phase was
collected, dried (MgSO.sub.4), filtered, and concentrated. The
crude liquid was distilled (62-67.degree. C. at 0.1 mmHg) to give
the desired material as a mixture of diastereomers.
[0837] A cold (-78.degree. C.) solution of oxalyl chloride (2.6 mL,
0.031 mol) in dichloromethane (70 mL) was treated with the dropwise
addition of DMSO (3.4 mL, 0.047 mol) in dichloromethane (15 mL).
After 2 minutes, the alcohol from above (3.1 g, 0.028 mol) in 30 mL
of dichloromethane was introduced. After 15 minutes, triethylamine
(19.3 mL) was introduced dropwise. The reaction was then warmed to
room temperature and diluted with dichloromethane and water. The
organic phase was collected, washed with 1N HCl (aq.), water,
saturated Na.sub.2CO.sub.3 (aq.), water, and brine. The organic
phase was then dried (MgSO.sub.4), filtered, concentrated, and
diluted with ethanol (10 mL). The ethanolic solution was cooled to
0.degree. C. and treated with 50% hydroxylamine (aq.) (2.2 mL). The
reaction warmed to room temperature and stirred overnight. The
reaction was concentrated in vacuo, diluted with EtOAc, and then
washed with water, dried (MgSO.sub.4), filtered, and concentrated.
MS m/z 126.2 (M+1).
N-hydroxybicyclo[3.1.0]hexane-6-carbimidoyl chloride (I-10C)
[0838] A cold (0.degree. C.) solution of I-10B (2.9 g, 0.022 mol)
in DMF (25 mL) was treated with the portionwise addition of NCS
(3.4 g, 0.026 mmol). The reaction slowly warmed to room temperature
and stirred for an additional hour. The reaction was treated with
sat'd NaCl (aq.) and extracted with Et.sub.2O. The organics were
dried (MgSO.sub.4), filtered, and concentrated. Crude material was
taken forward without further purification. MS m/z 160.1 (M+1).
Methyl
3-(bicyclo[3.1.0]hexan-6-yl)-5-cyclopropylisoxazole-4-carboxylate
(I-10D)
[0839] A cold (0.degree. C.) solution of methyl
3-cyclopropyl-3-oxopropanoate (4.2 g, 0.030 mol) in methanol (100
mL) was treated with the dropwise addition of sodium methoxide in
methanol (6.2 mL, 25 wt %). After 10 min, Intermediate I-10C (3.7
g, 0.023 mol) was introduced. The reaction stirred for 1 hour and
was then concentrated in vacuo, diluted with water and extracted
with EtOAc. The organic phase was washed with sat'd NaHCO.sub.3
(aq) and then dried (MgSO.sub.4), filtered, and concentrated. The
crude residue was purified and isomers separated by column
chromatography (SiO.sub.2, linear gradient, 0-15% EtOAc in Hexanes)
to afford the desired products. First eluting peak (400 MHz,
CDCl.sub.3): .delta. 3.87 (s, 3H), 2.75 (m, 1H), 2.16 (dd, J=3.4,
3.2 Hz, 1H), 1.91 (m, 2H), 1.84 (m, 2H), 1.77 (m, 2H), 1.64 (m,
1H), 1.26 (m, 1H), 1.20 (m, 2H), 1.13 (m, 2H); second eluting peak
(400 MHz, CDCl.sub.3): 3.85 (s, 3H), 2.78 (m, 1H), 1.84-1.72 (m,
7H), 1.42 (m, 1H), 1.22 (m, 2H), 1.14 (m, 2H), 0.37 (m, 1H); MS m/z
248.1 (M+1).
[0840] tert-butyl
3-((3-(bicyclo[3.1.0]hexan-6-yl)-5-cyclopropylisoxazol-4-yl)methoxy)-8-az-
abicyclo[3.2.1]octane-8-carboxylate (I-10E) was prepared following
analogous procedures in Intermediate 9. MS m/z 373.2
(M-.sup.tBu+1)).
[0841] tert-butyl
3-((5-cyclopropyl-3-(1-methylbicyclo[3.1.0]hexan-6-yl)isoxazol-4-yl)metho-
xy)-8-azabicyclo[3.2.1]octane-8-carboxylate (I-10F) was prepared
following analogous procedures in Intermediate 9. MS m/z 387.3
(M-.sup.tBu+1)).
Intermediate 11
4-(chloromethyl)-5-cyclopropyl-3-(spiro[2.5]octan-4-yl)isoxazole
##STR00035## ##STR00036##
[0842] Methyl 1,4-dioxaspiro[4.5]decane-6-carboxylate (I-11A)
[0843] To a solution of 2-oxocyclohexanecarboxylate (10.7 g, 68.5
mmol) in anhydrous toluene (80 mL) was added ethylene glycol (38.2
mL, 685 mmol) and pTSA (3.5 g, 20.55 mmol) and the reaction mixture
was heated to 120.degree. C. for 18 hours. The mixture was then
cooled to 0.degree. C. and carefully quenched with aq. sodium
carbonate. The volatile was separated and he aqueous was extracted
with ether (3.times.50 mL). The combined organic layer was washed
with sodium carbonate (2.times.50 mL), brine (60 mL), dried over
sodium sulfate, filtered, and concentrated. The residue was
purified by chromatography with hexane-EtOAc 10% linear gradient as
eluant to give the title compound as clear oil. MS m/z 201.1
(M+1).
1,4-dioxaspiro[4.5]decan-6-ylmethanol (I-11B)
[0844] To a solution of methyl
1,4-dioxaspiro[4.5]decane-6-carboxylate (3.87 g, 19.3 mmol) in THF
(40 mL) and cooled to 0.degree. C. LiAlH.sub.4 was added dropwise
and stirred for 5 hours. The reaction was quenched by subsequent
dropwise addition of water (1.3 mL) 15% NaOH (1.3 mL) and water
(2.6 mL) and filtered thru a CELITE.RTM. pad. Concentration of the
filtrate afforded the title compound as clear oil that was carried
to the next step without further purification. MS m/z 173.1
(M+1).
6-((Benzyloxy)methyl)-1,4-dioxaspiro[4.5]decane (I-11C)
[0845] A solution of 1,4-dioxaspiro[4.5]decan-6-ylmethanol (2.3 g,
13.3 mmol) in THF (20 mL) and cooled in an ice bath, was treated
with a NaH (0.48 g, 20.0 mmol). The reaction mixture was stirred
for 1 hour and then benzyl bromide (2.4 mL, 20 mmol) in THF (5 mL)
was added dropwise. The reaction was stirred at rt for 5 hours and
then diluted with ethyl acetate (100 mL). The organic layer was
washed with water, brine and dried over sodium sulfate and
concentrated. Purification by silica chromatography using
hexane-Et.sub.2O 20% linear gradient afforded the title compound as
pale yellow solid. MS m/z 263.2 (M+1).
2-((Benzyloxy)methyl)cyclohexanone (I-11D)
[0846] A solution of
6-((Benzyloxy)methyl)-1,4-dioxaspiro[4.5]decane (2.4 g 9.1 mmol) in
acetone (40 mL) was treated with 1.5N HCl (18 mL) and stirred at rt
for 5 hours. The reaction mixture was neutralized with aqueous
sodium carbonate and the volatile removed in vacuo. The residue was
extracted with Et.sub.2O (3.times.50 mL) and the combined organic
layer were washed with water (30 mL), brine (30 mL) and dried over
sodium sulfate and concentrated to yield the desired product as
pale yellow oil that was used in the next step without further
purification. MS m/z 219.1 (M+1).
(((2-Methylenecyclohexyl)methoxy)methyl)benzene (I-11E)
[0847] An oven-dried 250 mL one-necked round bottomed flask was
charged with methyltriphenylphosphonium bromide (4.3 g, 12.3 mmol)
and dry THF (20 mL) and then cooled to -78.degree. C. To this
solution was added n-BuLi (2.8 M in hexane, 4.3 mL, 12.3 mmol) over
10 min by syringe. The resultant red ylide solution was then warmed
to rt, stirred for 3 hours, and cooled to -78.degree. C. To this
ylide solution was added 2-((benzyloxy)methyl)cyclohexanone (1.8 g,
8.6 mmol) in dry THF (5 mL) via syringe over 10 min After being
stirred for 1 hour at -78.degree. C., the reaction mixture was
warmed to rt slowly and stirred for 10 hours. After that the
reaction mixture was cooled to 0.degree. C., quenched with aq.
NaHCO.sub.3 (60 mL), and extracted with ether (3.times.60 mL). The
organic layer was washed with brine (60 mL) and dried over sodium
sulfate, filtered, and concentrated. The residue was
chromatographed with hexane-Et.sub.2O isocratic 10% as eluant to
give the title compound as clear oil. MS m/z 217.1 (M+1).
4-((Benzyloxy)methyl)spiro[2.5]octane (I-11F)
[0848] This intermediate was prepared from
(((2-methylenecyclohexyl)methoxy)methyl)benzene by using the same
protocol as described for ethyl spiro[2.5]octane-6-carboxylate
(I-7A). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.35-7.31 (m,
4H), 7.29 (m, 1H) 4.49 (q, J=12.4 Hz, 2H), 3.52 (t, J=9.2 Hz, 1H),
3.41 (dd, J=9.2, 5.2 Hz, 1H), 1.72-1.67 (m, 1H), 1.49-1.43 (m, 4H),
1.33-1.26 (m, 1H), 0.88-0.85 (m, 1H), 0.37-0.31 (m, 2H), 0.19-0.14
(m, 2H). MS m/z 231.1 (M+1).
Spiro[2.5]octan-4-ylmethanol (I-11G)
[0849] To a solution of 4-((benzyloxy)methyl)spiro[2.5]-octane
(0.42 g, 1.8 mmol) in a 5:1 MeOH-EtOAc (12 mL) Pd/C (0.05 g, 5 wt
%, 50% wet Degussa type) was added. The flask was fitted with a
balloon of hydrogen, and the heterogeneous reaction mixture was
stirred for 2 hours under a hydrogen atmosphere at rt. The catalyst
solids were filtered off and the filtrate was concentrated under
vacuum to give the desired product spyri[2.5]octan-4-ylmethanol as
clear oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.74-3.62 (m,
2H), 3.48 (d, J=5.2 Hz, 2H), 1.65-1.59 (m, 2H), 1.51-1.43 (m, 3H),
1.27-1.24 (m, 1H), 1.12-1.11 (m, 1H), 0.96-0.95 (m, 1H), 0.41-0.37
(m, 1H), 0.29-0.17 (m, 3H). MS m/z 123.1 (M-17+1).
[0850] Spiro[2.5]octane-4-carbaldehyde (I-11H) was prepared by
following the same protocol as described for I-7B. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 9.80 (s, 1H), 2.08-2.04 (m, 1H), 1.67-2.56
(m, 4H), 1.48-1.34 (m, 4H), 0.95-0.92 (m, 1H), 0.62-0.57 (m, 1H),
0.51-0.46 (m, 1), 0.35-0.32 (m, 2H). MS m/z 139.1 (M+1).
[0851] Spiro[2.5]octane-4-carbaldehyde oxime (I-11I) was prepared
by reaction of spiro[2.5]octane-4-carbaldehyde and hydroxylamine
following the same procol as described for I-6c. MS m/z 154.1
(M+1).
[0852] N-hydroxyspiro[2.5]octane-4-carbimidoyl chloride (I-11J) was
prepared by reaction of spiro[2.5]octane-4-carbaldehyde oxime and
N-chloro-succinimide following the same protocol as described for
I-6B. MS m/z 188.0 (M+1).
[0853] 5-Cyclopropyl-3-(spiro[2.5]octan-4-yl)isoxazole-4-carboxylic
acid (I-11K) was prepared from
N-hydroxyspiro[2.5]octane-4-carbimidoyl chloride and methyl
3-cyclopropyl-3-oxopropanoate following the same protocol as
described for I-6E. MS m/z 262.1 (M+1).
[0854]
(5-Cyclopropyl-3-(spiro[2.5]octan-4-yl)isoxazol-4-yl)methanol
(I-11L) was prepared by reaction of
5-cyclopropyl-3-(spiro[2.5]octan-4-yl)isoxazole-4-carboxylic acid
and LiAlH.sub.4 following the same protocol as described for I-6F.
MS m/z 248.1 (M+1).
[0855]
4-(Chloromethyl)-5-cyclopropyl-3-(spiro[2.5]octan-4-yl)isoxazole
(I-11M) was prepared by reaction of
5-cyclopropyl-3-(spiro[2.5]octan-4-yl)isoxazol-4-yl)methanol and
methansulphonyl chloride following the same protocol as described
for I-6G. MS m/z 266.1 (M+1).
Intermediate 12
3-(bicyclo[4.1.0]heptan-3-yl)-4-(chloromethyl)-5-cyclopropylisoxazole
##STR00037##
[0856] Bicyclo[4.1.0]heptane-3-carboxylic acid (I-12A)
[0857] A solution of cyclohex-3-enecarboxylic acid (1.8 g, 26 mmol)
in dichloro methane (20 mL) was added to a 1.1 M solution of Et,Zn
in toluene (26 mL, 28.5 mmol) at 0.degree. C. and the resulting
suspension was stirred for 15 min. Diiodomethane (2.9 mL, 25.6
mmol) in dichloromethane (3 mL) was then added dropwise and the
pale yellow suspension was stirred at rt overnight as a white
precipitate appeared. The reaction mixture was poured into 1N HCl
and extracted with diethyl ether (3.times.60 mL). The organic phase
was extracted with 1N KOH. The aqueous phase was then acidified
with 1N HCl and extracted with dichloromethane. Evaporation of the
solvent gave the title compound as a white solid; only one
diastereomer was detectable by .sup.1H NMR. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 2.34-2.26 (m, 1H), 2.21-2.13 (m, 1H), 1.98-1.94
(m, 1H), 1.84-1.78 (m, 1H), 1.76-1.70 (m, 1H), 1.59-1.52 (m, 1H),
1.75-1.07 (m, 1H), 0.93-0.88 (m, 2H), 0.62-0.57 (m, 1H). MS m/z
141.2 (M+1).
[0858] Bicyclo[4.1.0]heptan-3-ylmethanol) (I-12B) was prepared by
reaction of bicyclo[4.1.0]heptane-3-carboxylic acid and LiAlH.sub.4
following the same protocol as described for I-6A. MS m/z 248.1
(M+1).
[0859] Bicyclo[4.1.0]heptane-3-carbaldehyde (I-12C) was prepared
from bicyclo[4.1.0]heptan-3-ylmethanol follwing the same protocol
as described for I-7B. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
9.57 (d, J=1.6 Hz, 1H), 2.27-2.19 (m, 1H), 2.15 (2.07 (m, 1H),
2.01-1.96 (m 2H), 1.85-1.76 (m, 1H), 1.74-1.68 (m, 1H), 1.53-2.46
(m, 1H), 1.04-0.90 (m, 3H), 0.63 (ddd, J=18.0, 8.8, 4.8 Hz, 1H),
-0.015 (q, J=5.2 Hz, 1H). MS m/z 125.1 (M+1).
[0860] Bicyclo[4.1.0]heptane-3-carbaldehyde oxime (I-12D) was
prepared by reaction of bicyclo[4.1.0]heptane-3-carbaldehyde and
hydroxylamine following the same procol as described for I-6c. MS
m/z 140.1 (M+1).
[0861] N-Hydroxybicyclo[4.1.0]heptane-3-carbimidoyl chloride
(I-12E) was prepared by reaction of
bicyclo[4.1.0]heptane-3-carbaldehyde oxime and N-chloro-succinimide
following the same protocol as described for I-6B. MS m/z 174.0
(M+1).
[0862]
3-(Bicyclo[4.1.0]heptan-3-yl)-5-cyclopropylisoxazole-4-carboxylic
acid (I-12F) was prepared from
N-hydroxybicyclo[4.1.0]heptane-3-carbimidoyl chloride and methyl
3-cyclopropyl-3-oxopropanoate following the same protocol as
described for I-6E. MS m/z 248.1 (M+1).
[0863]
(3-(Bicyclo[4.1.0]heptan-3-yl)-5-cyclopropylisoxazol-4-yl)methanol
(I-12G) was prepared by reaction of
3-(bicyclo[4.1.0]heptan-3-yl)-5-cyclopropylisoxazole-4-carboxylic
acid LiAlH.sub.4 following the same protocol as described for I-6G.
MS m/z 234.1 (M+1).
[0864]
4-(Chloromethyl)-5-cyclopropyl-3-(spiro[2.5]octan-4-yl)isoxazole
(I-12H) was prepared by reaction of
3-(bicyclo[4.1.0]heptan-3-yl)-5-cyclopropylisoxazol-4-yl)methanol
and methansulphonyl chloride following the same protocol as
described for I-6G. MS m/z 252.1 (M+1).
Intermediate 13
##STR00038##
[0865] Methyl 3-methylenecyclobutanecarboxylate (I-13A)
[0866] A cold (0.degree. C.) solution of
3-methylenecyclobutanecarboxylic acid (WO2007/063391, 6.07 g, 54.1
mmol) in dichloromethane (180 mL) and methanol (18 mL) was treated
with the dropwise addition of (trimethylsilyl)diazomethane (28.4
mL, 2.0 M in Hexanes). After 30 min, 1 mL of conc. HOAc was added
and the reaction concentrated in vacuo. (400 MHz, CDCl.sub.3)
.delta. 4.78 (m, 2H), 3.67 (s, 3H), 3.10 (m, 1H), 2.98 (m, 2H),
2.88 (m, 2H); MS m/z 127.1 (M+1).
Methyl spiro[2.3]hexane-5-carboxylate (I-13B)
[0867] A cold (0.degree. C.) solution of diethyl zinc (79.3 mL, 1.0
M in Hexanes) in dichloromethane (66 mL) was treated with the
dropwise addition of TFA (6.11 mL, 79.3 mL) in dichloromethane (27
mL). After 1 hour of stirring, diiodomethane (6.39 mL, 79.3 mmol)
in dichloromethane (27 mL) was then introduced. After 40 min, I-13A
(4.00 g, 31.7 mmol) dichloromethane (10 mL) was added dropwise. The
reaction was left to stir for 2 hours and then quenched with sat'd
NH.sub.4Cl (aq.). Phases were separated and the organic phase
collected, dried (MgSO.sub.4), filtered, concentrated, and
distilled (42-44.degree. C., 0.1 mmHg) to afford the desired
spirocycle. (400 MHz, CDCl.sub.3) .delta. 3.69 (s, 3H), 3.28 (m,
1H), 2.49 (m, 2H), 2.22 (m, 2H), 0.43 (m, 4H); MS m/z 141.1
(M+1).
Spiro[2.3]hexan-5-ylmethanol (I-13C)
[0868] A cold (0.degree. C.) solution of I-13B (2.00 g, 14.3 mmol)
in THF (48 mL) was treated with the dropwise addition of lithium
aluminum hydride (18.6 mL, 1.0 M solution in THF). After 2 hr of
stirring, the reaction was cooled to 0.degree. C. and treated with
the dropwise addition of 1N HCl (aq.) until a solution persisted.
The reaction was then extracted with EtOAc. The organic phase was
dried (MgSO.sub.4), filtered, concentrated, and distilled
(51-52.degree. C., 0.1 mm Hg) to give the desired material. (400
MHz, CDCl.sub.3) .delta. 3.69 (d, J=7.1 Hz, 2H), 2.58 (m, 1H), 2.15
(m, 2H), 1.83 (m, 2H), 1.73 (s, 1H), 0.38 (m, 4H); MS m/z 113.2
(M+1).
[0869] N-hydroxyspiro[2.3]hexane-5-carbimidoyl chloride (I-13D). A
cold (-78.degree. C.) solution of oxalyl chloride (0.58 mL, 6.7
mmol) in dichloromethane (13 mL) was treated with the dropwise
addition of DMSO (0.74 mL) in dichloromethane (4 mL). After 2
minutes, I-13C (684 mg, 6.10 mmol) in dichloromethane (8 mL) was
introduced. After 15 minutes, triethylamine (4.25 mL) was
introduced dropwise. The reaction was then warmed to room
temperature and diluted with dichloromethane and water. The organic
phase was collected and washed with 1N HCl (aq.), water, saturated
Na.sub.2CO.sub.3 (aq.), water, and brine. The organic phase was
dried (MgSO.sub.4), filtered, and concentrated. The crude material
was taken upon in ethanol (10 mL) and treated with 50%
hydroxylamine (0.56 mL). After overnight stirring, the reaction was
concentrated in vacuo. This residue was diluted with DMF (3.5 mL)
and cooled to 0.degree. C. NCS (0.91 g, 6.8 mmol) was introduced
and the reaction slowly warmed to room temperature and stirred for
2 hours. The reaction was treated with saturated NaCl (aq.) and
extracted with Et.sub.2O. Organics were washed with brine and then
dried (MgSO.sub.4), filtered, and concentrated. MS m/z 160.1
(M+1).
[0870] Methyl
5-cyclopropyl-3-(spiro[2.3]hexan-5-yl)isoxazole-4-carboxylate
(I-13E): A cold (0.degree. C.) solution of methyl
3-cyclopropyl-3-oxopropanoate (1.13 g, 7.93 mmol) in methanol (26
mL) was treated with the dropwise addition of sodium methoxide in
methanol (1.65 mL, 25% wt). After 10 min, I-13D (0.97 g, 6.1 mmol)
was introduced. The reaction stirred for 1 hour and was
concentrated in vacuo. The residue was diluted with water and
extracted with EtOAc. The organic phase was washed with sat'd
NaHCO.sub.3 (aq) and then dried (MgSO.sub.4), filtered, and
concentrated. The crude residue was purified by column
chromatography (SiO.sub.2, linear gradient, 0-10% EtOAc in hexanes)
to afford the desired spirocycle. (400 MHz, CDCl.sub.3) .delta.
3.96 (m, 1H), 3.84 (s, 3H), 2.80 (m, 1H), 2.57 (m, 2H), 2.38 (m,
2H), 1.26 (m, 2H), 1.16 (m, 2H), 0.51 (m, 2H), 0.39 (m, 2H); MS m/z
248.2 (M+1).
[0871] tert-butyl
3-((5-cyclopropyl-3-(spiro[2.3]hexan-5-yl)isoxazol-4-yl)methoxy)-8-azabic-
yclo[3.2.1]octane-8-carboxylate (I-13F) was prepared following the
same procedures in Intermediate 1. MS m/z 373.3 (M-.sup.tBu+1).
Intermediate 14
tert-butyl
3-((5-cyclopropyl-3-(2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)i-
soxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
##STR00039##
[0873] tert-butyl
3-((5-cyclopropyl-3-(2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)isoxazol-4--
yl)methoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate was prepared
from the commercially available
2,6,6-trimethylbicyclo[3.1.1]heptane-3-carboxylic acid following
analogous procedures in Intermediate 13. MS m/z 429.3
(M-.sup.tBu+1).
Intermediate 15
##STR00040## ##STR00041##
[0874] (E)-2-methylbenzaldehyde oxime (I-15B)
[0875] A solution of sodium hydroxide (2.00 g, 50.0 mmol, 1.19
equiv) in water (25 mL) was added to a stirred solution of
hydroxylamine hydrochloride (3.30 g, 47.8 mmol, 1.15 equiv) in
water (25 mL) at 0.degree. C. The resulting solution was stirred
for 10 min at 0.degree. C. Then a solution of 2-methylbenzaldehyde
(5.00 g, 41.6 mmol, 1.00 equiv) in ethanol (25 mL) was added slowly
over 5.0 min. The resulting solution was allowed to stir for an
additional 1 h at RT. The solution was diluted with H.sub.2O (100
mL), extracted with ethyl acetate (120 mL) and the organic layers
were combined, washed with brine (100 mL), dried over magnesium
sulfate and concentrated under vacuum to give
(E)-2-methylbenzaldehyde oxime as an off-white crystalline solid.
MS m/z 136.0 (M+1).
(Z)--N-hydroxy-2-methylbenzimidoyl chloride (I-15C)
[0876] N-Chlorosuccinimide (6.22 g, 46.59 mmol, 1.12 equiv) was
added portion wise to a stirred solution of
(E)-2-(trifluoromethoxy)benzaldehyde oxime (5.62 g, 41.6 mmol, 1.00
equiv) in N,N-dimethylformamide (25 mL) keeping the internal
temperature below 25.degree. C. The reaction mixture was stirred
for 1 h at RT. The resulting solution was diluted with water (100
mL) and extracted with ethyl acetate (2.times.75 mL). The organic
layers were combined, washed with brine (5.times.100 mL), dried
over magnesium sulfate, and concentrated under vacuum to give
(Z)--N-hydroxy-2-methylbenzimidoyl chloride as a light yellow
crystalline solid. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta.
12.32 (s, 1H), 7.46-7.28 (m, 5H), 2.36 (s, 3H), MS m/z 169.9, 171.9
(M+1, Cl.sub.35/Cl.sub.37 isotope pattern).
Methyl 5-cyclopropyl-3-(o-tolyl)isoxazole-4-carboxylate (I-15D)
[0877] Methyl 3-cyclopropropyl-3-oxopropanoate (5.23 g, 36.8 mmol)
and (Z)-5-cyclopropyl-N-hydroxy-3-(o-tolyl)isoxazole-4-carbimidoyl
chloride (6.23 g, 36.8 mmol) were combined in anhydrous methanol
(50 mL) and cooled to 0.degree. C. under a nitrogen atmosphere.
Sodium methoxide (25% in methanol, 11.0 mL, 44.2 mmol, 1.2 eq) was
added dropwise and the mixture was allowed to warm to RT over 1
hour. The mixture was diluted with ethyl acetate (120 mL) and water
(100 mL). The organic layer was separated and washed with brine (75
mL) then dried over magnesium sulfate and concentrated under
vacuum. The oil was purified by column chromatography (SiO.sub.2,
linear gradient, 0-100% ethyl acetate in hexanes) to afford the
desired product. MS m/z 258.0 (M+1).
(5-Cyclopropyl-3-(o-tolyl)isoxazol-4-yl)methanol (I-15-E)
[0878] Lithium aluminum hydride (1M in tetrahydrofuran, 29 mL, 29
mmol, 2.5 eq) was added to a dry three-necked flask filled with
nitrogen and cooled to 0.degree. C. Methyl
5-cyclopropyl-3-(o-tolyl)isoxazole-4-carboxylate (3.02 g, 11.7
mmol) was dissolved in tetrahydrofuran (40 mL) and added dropwise
to the flask, ensuring that the internal temperature remained below
-10.degree. C. The mixture was stirred for an hour, then ethyl
acetate (1.3 mL) was added dropwise, keeping the temperature below
0.degree. C. followed by water (1.3 mL), taking care that the
mixture was vigorously stirring at all times. Sodium hydroxide
solution (3.9 mL, 15% solution by weight) was added dropwise and
the mixture stirred vigorously for a further 30 minutes, warming up
to RT. The mixture was filtered through a CELITE.RTM. pad, which
was washed with ethyl acetate (120 mL). The organics were washed
with water (100 mL) and brine (75 mL) then dried over magnesium
sulfate and concentrated under vacuum and purified by column
chromatography (SiO.sub.2, linear gradient, 0-100% ethyl acetate in
hexanes) to afford the desired product. .sup.1H-NMR (MeOH-d.sub.4,
400 MHz) 8.7.41-7.26 (m, 4H), 4.36 (s, 2H), 2.34-2.27 (m, 1H), 2.26
(s, 3H), 1.19-1.15 (m, 4H), MS m/z 230.0 (M+1).
4-(Bromomethyl)-5-cyclopropyl-3-(o-tolyl)isoxazole (I-15F)
[0879] Into a 100 mL round bottom flask was placed
(5-cyclopropyl-3-(o-tolyl)isoxazol-4-yl)methanol (1.86 g, 8.11
mmol), triphenylphosphine (3.50 g, 12.2 mmol, 1.5 equiv) and
dichloromethane (50 mL). The mixture was stirred until completely
dissolved, and then slowly cannulated dropwise into a stirring
solution of carbon tetrabromide (4.00 g, 12.2 mmol, 1.5 eq) in
dichloromethane (20 mL). The solution was stirred for one hour and
the solvent was then evaporated in vacuo. The crude residue was
purified by silica gel chromatography using a 0-50% gradient of
ethyl acetate/hexanes. The desired product was obtained as a yellow
oil. MS m/z 292.0/294.0 (M+1, Br.sub.79/Br.sub.81 isotope
pattern).
tert-Butyl
3-((5-cyclopropyl-3-(o-tolyl)isoxazol-4-yl)methoxy)-8-azabicycl-
o[3.2.1]octane-8-carboxylate (I-15G)
[0880] A flask was purged with nitrogen and then charged with
N-Boc-nortropine (1.64 g, 7.20 mmol), 18-crown-6 (1.59 g, 6.00
mmol), and anhydrous tetrahydrofuran (60 mL). Potassium
tert-butoxide (1.34 g, 12.0 mmol) was added portion-wise, and the
mixture was stirred vigorously under nitrogen for 1 hour.
4-(Bromomethyl)-5-cyclopropyl-3-(o-tolyl)isoxazole (1.75 g, 6.00
mmol) in tetrahydrofuran (20 mL, anhydrous) was added dropwise, and
the reaction mixture was stirred for 1 hour under nitrogen. The
solvent was reduced in vacuo and the mixture diluted with water
(100 mL) and ethyl acetate (100 mL). The organic layer was
separated, dried over magnesium sulfate, and evaporated in vacuo.
The crude residue was purified by silica gel chromatography using a
gradient of 0-100% ethyl acetate/hexanes to yield the desired
product as a yellow oil. MS m/z 439.2 (M+1).
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(o-tolyl)isox-
azole (I-15H)
[0881] The previous amine, tert-Butyl
3-((5-cyclopropyl-3-(o-tolyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]oc-
tane-8-carboxylate (1.60 g, 3.65 mmol) was dissolved in
trifluoroacetic acid in dichloromethane (30 mL, 20% solution) at
RT. The solution was stirred for 1 hour at RT and the solvent was
evaporated. The residue was dissolved in ethyl acetate (125 mL),
washed with a saturated solution of sodium bicarbonate (100 mL),
the organic layer was dried with magnesium sulfate and evaporated
in vacuo. The crude residue was purified by silica gel
chromatography using a gradient of 0-20% ethanol/dichloromethane to
afford the desired product as a colorless oil. .sup.1H-NMR
(DMSO-d.sub.6, 400 MHz) .delta. 8.44 (bs, 1H), 7.43-7.34 (m, 2H),
7.32-7.28 (m, 2H), 4.21 (s, 2H), 3.83 (bs, 2H), 3.55 (t, J=4.0 Hz,
1H), 2.35-2.28 (m, 1H), 2.20 (s, 3H), 1.96-1.70 (m, 8H), 1.16-1.06
(m, 4H). MS m/z 339.2 (M+1).
##STR00042## ##STR00043##
[0882]
4-((8-Azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(3,4-d-
ifluorophenyl)isoxazole (I-15I) was prepared from
3,4-difluorobenzaldehyde according to the same procedures as
described for (I-15H). MS m/z 343.1 (M+1).
[0883]
4-((8-Azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(3-flu-
orophenyl)isoxazole (I-15J) was prepared from 3-fluorobenzaldehyde
according to the same procedures as described for (I-15H). MS m/z
343.1 (M+1).
[0884]
4-((8-Azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-flu-
oro-6-methylphenyl)isoxazole (I-15K) was prepared from
2-fluoro-6-methyl-benzaldehyde according to the same procedures as
described for (I-15H). NMR (DMSO-d.sub.6, 400 MHz) .delta. 8.54
(bs, 1H), 7.49-7.43 (m, 1H), 7.24-7.16 (m, 2H), 4.20 (s, 2H), 3.81
(bs, 2H), 3.52 (t, J=4.0 Hz, 1H), 2.37-2.30 (m, 1H), 2.14 (s, 3H),
1.95-1.66 (m, 8H), 1.20-1.06 (m, 4H). MS m/z 357.2 (M+1).
[0885]
4-((8-Azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2,6-d-
imethylphenyl)isoxazole (I-15L) was prepared from
2,6-dimethylbenzaldehyde according to the same procedures as
described for (I-15H). MS m/z 353.2 (M+1).
[0886]
4-((8-Azabicyclo[3.2.1]octan-3-yloxy)methyl)-3-(2-chloro-6-fluoroph-
enyl)-5-cyclopropylisoxazole (I-15M) was prepared from
2-chloro-6-fluorobenzaldehyde according to the same procedures as
described for (I-15H). MS m/z 377.1, 379.1 (M+1,
Cl.sub.35/Cl.sub.37 isotope pattern).
[0887]
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-3-(2-chlorophenyl)-5-c-
yclopropylisoxazole (I-15N) was prepared from
2-cyclopropylbenzaldehyde according to the same procedures as
described for (I-15H). MS m/z 359.1 (M+1).
[0888]
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-cyc-
lopropylphenyl)isoxazole (I-15O) was prepared from
2-chlorobenzaldehyde according to the same procedures as described
for (I-15H). MS m/z 365.2 (M+1).
[0889]
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2,4-d-
ifluorophenyl)isoxazole (I-15P) was prepared from
2,4-difluorobenzaldehyde according to the same procedures as
described for (I-15H). MS m/z 361.2 (M+1).
[0890]
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2,3-d-
ifluorophenyl)isoxazole (I-15Q) was prepared from
2,3-difluorobenzaldehyde according to the same procedures as
described for (I-15H). MS m/z 361.2 (M+1).
[0891]
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-flu-
orophenyl)isoxazole (I-15R) was prepared from 2-fluorobenzaldehyde
according to the same procedures as described for (I-15H). MS m/z
343.2 (M+1).
Intermediate 16
Methyl 2-bromo-4-methyl-benzothiazole-6-carboxylate (I-16B)
##STR00044##
[0892] Methyl 2-amino-4-methyl-benzothiazole-6-carboxylate
(I-16A)
[0893] Into a 500-mL round-bottom flask was placed a solution of
methyl 4-amino-3-methylbenzoate (4.00 g, 24.2 mmol, 1.00 equiv) and
NaSCN (7.00 g, 86.4 mol, 3.57 equiv) in AcOH (90 mL) that was
cooled to 0.degree. C. This was followed by the addition of a
solution of Br.sub.2 (3.9 g, 25 mmol, 1.0 equiv) in AcOH (25 mL)
dropwise, maintaining at 0.degree. C. over 20 min. The resulting
solution was allowed to warm to RT on its own accord (over
approximately 10 min) and stirred for 48 hrs at RT. At this time,
the solids of the reaction were filtered out. The resulting
solution was diluted with 100 mL H.sub.2O. The pH value of the
solution was adjusted to 8-9 with ammonia (using Whatman PH strip
paper to monitor PH adjustment) which furnished an immediate
precipitation. The solids were collected by filtration and washed
once with ice cold MeOH (50 mL) to afford as a yellow solid. MS m/z
223.0 (M+1). .sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta. 8.17 (app
d, J=1.0 Hz, 1H), 8.03 (br s, 2H, NH.sub.2), 7.68 (s, 1H), 3.82 (s,
3H), 2.42 (s, 3H).
Methyl 2-bromo-4-methyl-benzo[d]thiazole-6-carboxylate (I-16B)
[0894] Into a 40 mL reaction vessel equipped with a septum, stir
bar, and and nitrogen line, was placed solid copper (I) bromide-DMS
complex (824 mgs, 4.00 mmol) that was diluted with dry acetonitrile
(8 mL). The resulting dark suspension was cooled to 0.degree. C.
with an ice bath. Next was added 90% commercial stock solution of
tBuONO (tertbutyl nitrite, 1.0 mL, at 90% weight by weight
furnishes a calculated material delivery of 7.6 mmoles) in a
dropwise fashion over 5 min Next was added a slurry of methyl
2-amino-4-methyl-benzothiazole-6-carboxylate (627 mg, 2.81 mmol) in
acetonitrile (3 mL) via pipet, over 2 min to prevent any possible
exothermic event. The bath was pulled and the reaction was allowed
to warm to RT. After 3 hrs the reaction was heated to 45.degree. C.
for 45 min No starting material could be seen at this time as
monitored by LCMS analysis against a standard solution. Next the
reaction was cooled to RT, filtered to remove undesired solids, and
the resulting mother liquor was then added to water (20 mL) as a
rapidly stirred solution. The resulting solid was collected. MS m/z
285.9/287.9 (M+1, Br.sub.79/Br.sub.81 isotope pattern). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 8.62 (app d, J=1.0 Hz, 1H), 7.93
(app dd, J=1.5, 1.0 Hz, 1H), 3.94 (s, 3H), 2.80 (s, 3H).
Intermediate 17
7-bromo-imidazo[1,2-a]pyridine-3-carboxylic acid (I-17B)
##STR00045##
[0895] Ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate
(I-17A)
[0896] A solution of ethyl 2-chloro-3-oxopropanoate (245 g, 1.64
mol) and added 4-bromopyridin-2-amine (94 g, 546 mmol) in ethanol
(2 L) was heated to 80.degree. C. for 5 h, and then concentrated
under vacuum. The residue was applied to silica gel column (EA/PE,
1/2) for purification to give ethyl
7-bromoimidazo[1,2-a]pyridine-3-carboxylate as white solid.
[0897] 7-bromo-imidazo[1,2-a]pyridine-3-carboxylic acid (I-17B). To
a solution of ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate (67
g, 250 mmol) in methanol (500 mL), sodium hydroxide (2N, 249 ml,
500 mmol) was added. The resulting solution was stirred overnight
at room temperature. The pH of the solution was adjusted to pH=6
with HCl (2N). The solids were collected by filtration to afford
7-bromo-imidazo[1,2-a]pyridine-3-carboxylic acid as white solid. MS
[M+H]+ 241/243. .sup.1H-NMR: (DMSO-d6, 300 MHz): 13.3 (br, 1H),
9.19 (dd, J=7.5, 0.9 Hz, 1H), 8.25 (s, 1H), 8.15 (d, J=1.5 Hz, 1H),
7.39 (dd, J=7.5, 1.8 Hz, 1H).
Intermediate 18
Ethyl 6-bromoH-imidazo[1,2-a]pyridine-3-carboxylate (I-18B)
##STR00046##
[0898] Ethyl 2-chloro-3-oxopropanoate (I-18A)
[0899] A mixture of ethyl formate (385 g, 5.20 mol) and ethyl
chloroacetate (640 g, 5.20 mol) was added to a suspension of
potassium t-butoxide (583 g, 5.2 mol) in diisopropyl ether (5 L) at
0.degree. C., and the resulting mixture was stirred for 24 h at
room temperature. Then the pH of the solution was adjusted to pH=6
with concentrated sulfuric acid. The solid was filtered and the
filtrate was concentrated under reduced pressure to afford ethyl
2-chloro-3-oxopropanoate (18-A) as oil.
Ethyl 6-bromoH-imidazo[1,2-a]pyridine-3-carboxylate (I-18B)
[0900] A solution of ethyl 2-chloro-3-oxopropanoate (261 g, 1.74
mol) 5-bromopyridin-2-amine (100 g, 581 mmol) in ethanol (2 L) was
heated to 80.degree. C. for 5 h and concentrated under vacuum. The
residue was applied to silica gel column (EA/PE, 1/2) for
purification to afford ethyl
6-bromoH-imidazo[1,2-a]pyridine-3-carboxylate as white solid.
Intermediate 19
Methyl 2,4-dibromo-benzothiazole-6-carboxylate (I-19B)
##STR00047##
[0901] Methyl 2-amino-4-bromo-benzothiazole-6-carboxylate
(1-19A)
[0902] Into a 50-mL round-bottom flask, was placed a solution of
methyl 4-amino-3-bromobenzoate (500 mg, 2.17 mmol, 1.00 equiv) and
AcOH (9 mL) that was cooled to 0.degree. C. This was followed by
the addition of a solution of Br.sub.2 (500 mg, 3.12 mmol, 1.44
equiv) in AcOH (2 mL) dropwise at 0.degree. C. over 20 min. The
resulting solution was allowed to warm to RT on its own accord
(over 10 min) once the addition event was complete. Next, the RT
reaction was warmed gently to 45.degree. C. for 35 min until near
complete formation of the in situ intermediate di-bromo species
(M+H with a double Br mass spectrum pattern, m/z 308/310/312; ratio
1:2:1). To the reaction was next added NaSCN (500 mg, 6.17 mol,
2.84 equiv) in AcOH (9 mL). The reaction after 4 hrs was heated to
60.degree. C. for 24 hrs. At this time, an additional portion of
NaSCN (500 mg, 6.17 mol, 2.84 equiv) in AcOH (9 mL) was added and
the reaction was maintained at 60.degree. C. for 12 hrs longer. At
this time, the reaction was cooled to RT and filteration of all
undesired solids was done, with a MeOH wash (10 mL) of the filter
pad to ensure all liquor was extracted. The resulting liquor was
then diluted was then concentrated under vacuum and reduced to a
final volume of 20 mL which was subjected to reverse phase C-18
chromatography (30 to 100% acetonitrile:water, 0.05% TFA modified).
Concentration of chromatographic fractions was followed by removal
of any possible residual TFA using an SPE polymer supported acid
capture cartridge (PLHCO3 MP, part no PL3540-C603-Varian) with MeOH
(6 mL) as mobilizing agent. Upon concentration of the final eluent,
product was obtained as a light brown solid. MS m/z 286.9/288.9
(M+1, Br.sub.79/Br.sub.81 isotope pattern). .sup.1H-NMR (400 MHz,
MeOH-d.sub.4): .delta. 8.38 (br s, 2H, NH.sub.2), 7.96 (app d,
J=0.90 Hz, 1H), 7.92 (app d, J=0.90 Hz, 1H), 3.84 (s, 3H).
Methyl 2,4-dibromo-benzothiazole-6-carboxylate (I-19B)
[0903] Into a 40 mL reaction vessel equipped with a septum, stir
bar, and and nitrogen line, was placed solid copper (I) bromide-DMS
complex (70.0 mg, 0.341 mmol) that was diluted with dry
acetonitrile (2 mL). The resulting dark suspension was cooled to
0.degree. C. with an ice bath. Next was added 90% commercial stock
solution of t-BuONO (tert-butyl nitrite, 0.070 mL, at 90% weight by
weight furnishes a calculated material delivery of 0.53 mmoles) in
a dropwise fashion over 5 min Next was added a slurry of methyl
2-amino-4-bromo-benzothiazole-6-carboxylate (50 mg, 0.175 mmol) in
acetonitrile (1 mL) via pipet, over 2 min to prevent any possible
exothermic event. The bath was pulled and the reaction was allowed
to warm to RT. After 3 hrs, no starting material could be observed
as monitored by LCMS analysis against a standard solution. Next the
reaction was diluted with water (4 mL) and extracted with ethyl
acetate (20 mL). The organic extract was further washed with brine
(1 mL) and then dried over sodium sulfate to furnish a solid that
was used without further purification. MS m/z major observable:
249.9/251.9/253.9 (M+1, Br.sub.79/Br.sub.81 isotope pattern for
compound bearing two Br atoms.
Intermediate 20
Methyl 6-cyclopropyl-2-(methylsulfonyl)pyrimidine-4-carboxylate
(I-20B)
##STR00048##
[0904] 6-cyclopropyl-2-(methylsulfonyl)pyrimidine-4-carboxylic acid
(I-20A)
[0905] Into a 40 mL vessel was added
6-cyclopropyl-2-(methylthio)pyrimidine-4-carboxylic acid
(commercially available, Enamine Ltd, catalog number EN300-422464,
250 mg, 1.19 mmol) and acetonitrile (12.5 mL). This resulting
solution was then added dropwise at RT over 5 min to a separate 40
mL reaction vessel that was charged with a rapidly stirred
suspension of Oxone Aldrich supplied Oxone which is a
multicomponent triple salt mixture containing potassium
monopersulfate, 2KHSO.sub.5.KHSO.sub.4.K.sub.2SO.sub.4, 2.50 g,
4.10 mmol) and water (15 mL). Upon complete addition of the methyl
thiopyrimidine, the resulting suspension was heated to 65.degree.
C. for 20 min and subsequently cooled to RT. The resulting yellow
suspension was extracted with ethyl acetate (4.times.100 mL) and
the organic extracts were dried over magnesium sulfate, filtered
and concentrated to furnish the methyl sulfonyl pyrimidine as a
residue that was used directly in the next step without isolation.
MS m/z 243.1 (M+1).
Methyl 6-cyclopropyl-2-(methylsulfonyl)pyrimidine-4-carboxylate
(I-20B)
[0906] A suspension of
6-cyclopropyl-2-(methylsulfonyl)pyrimidine-4-carboxylic acid (200
mg, 0.82 mmol) in dichloromethane (2 mL) and methanol (0.5 mL) was
cooled to 0.degree. C. Trimethylsilyl diazomethane (2.0 M in
diethyl ether, 1.0 mL, 2.0 mmol) was added dropwise as not to
increase the internal temperature of the reaction. Upon complete
addition the suspension became a yellow colored solution that was
allowed to warm to RT and maintained for 1 h at that temperature.
At this time, acetic acid was added dropwise until the mixture was
colorless (c.a. 2 drops, 12 M) and the resulting solution was
concentrated under vacuum to a residue. The resulting oily yellow
solid was dissolved in sparing ice cold acetonitrile (0.5 mL) and
allowed to precipitate to furnish an off white waxy solid. MS m/z
257.1 (M+1). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.22 (s,
1H), 3.81 (s, 3H), 3.28 (s, 3H), 2.40-2.36 (m, 1H), 1.20-1.15 (m,
2H), 1.12-1.06 (m, 2H).
Intermediate 21
##STR00049##
[0908] Methyl-6-fluoro-2-methylnicotinate (I-21) was prepared from
commercially available 6-fluoro-2-methylnicotinic acid using the
analogous procedure previously described for the preparation of
Intermediate I-20b.
Intermediate 22
##STR00050##
[0909] Trimethyl
2-methoxypyrrolo[1,2-b]pyridazine-5,6,7-tricarboxylate (I-22B)
[0910] Commercially available 3-methoxypyridazine (3.00 g, 27.3
mmol) was dissolved in methanol (60 mL) and cooled to 0.degree. C.
Dimethylacetylene dicarboxylate (4.00 mL, 32.8 mmol, 1.2 eq) was
added dropwise while the reaction was rapidly stirred. The mixture
was maintained at -20.degree. C. for two days. A pale yellow solid
formed during this time that was recovered by filtration and washed
with cold methanol (2 mL) to furnish an off white solid. MS m/z
323.1 (M+1).
2-Methoxypyrrolo[1,2-b]pyridazine-6-carboxylic acid (I-22D)
[0911] Trimethyl
2-methoxypyrrolo[1,2-b]pyridazine-5,6,7-tricarboxylate (1.84 g,
5.72 mmol) was suspended in a solution of potassium hydroxide (1.60
g, 28.6 mmol, 5 eq) in water (5 mL) and the mixture was heated to
60.degree. C. for 1 h during which time all solids dissolved into a
yellow solution. The solution was acidified with concentrated HCl
(12 N, 5 mL) until pH=1 was achieved, and the mixture was heated to
90.degree. C. overnight. The mixture was then cooled to RT and a
dark solid was recovered by filtration. MS m/z 193.1 (M+1).
2-Hydroxypyrrolo[1,2-b]pyridazine-6-carboxylic acid (I-22E)
[0912] 2-Methoxypyrrolo[1,2-b]pyridazine-6-carboxylic acid (1.06 g,
5.50 mmol) was suspended in HBr (10 mL, 33% solution in acetic
acid) and heated to 50.degree. C. for 2 hrs. The solvent was
evaporated in vacuo and used directly (500 mgs). An analytical
standard was prepared using reverse phase HPLC with a gradient of
acetonitrile/water and 0.05% TFA as modifier. MS m/z 179.1 (M+1).
.sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 12.29 (bs, 1H), 11.60
(bs, 1H), 7.89-7.86 (m, 2H), 6.76 (d, J=2.0 Hz, 1H), 6.36 (d, J=9.6
Hz, 1H).
Methyl 2-hydroxypyrrolo[1,2-b]pyridazine-6-carboxylate (I-22F)
[0913] The semi-crude material from above,
2-Hydroxypyrrolo[1,2-b]pyridazine-6-carboxylic acid (100 mg, 0.56
mmol) was dissolved in methanol (5 mL) and concentrated sulfuric
acid (2 drops). The solution was heated to 80.degree. C. for 4
hours, and then the solvent evaporated in vacuo. The crude material
was used directly in the next step. MS m/z 193.1 (M+1).
Methyl
2-(((trifluoromethyl)sulfonyl)oxy)pyrrolo[1,2-b]pyridazine-6-carbox-
ylate (I-22G)
[0914] Methyl 2-hydroxypyrrolo[1,2-b]pyridazine-6-carboxylate (50
mg, 0.26 mmol) and diisopropylethylamine (0.13 mL, 0.78 mmol, 3 eq)
were combined in dichloromethane (5 mL) and cooled to 0.degree. C.
Triflic anhydride (0.09 mL, 0.52 mmol, 2 eq) was added and the
mixture stirred for 30 minutes then diluted with dichloromethane
(10 mL) and sodium bicarbonate solution (5 mL). The organics were
separated and dried, then evaporated in vacuo. The product was
purified by flash chromatography (0-100% ethyl acetate/hexanes) to
yield a pale brown solid. MS m/z 325.0 (M+1).
Intermediate 23
##STR00051##
[0916] Methyl 1-(4-bromophenyl)cyclopropanecarboxylate (1-23) was
prepared from commercially available
1-(4-bromophenyl)cyclopropanecarboxylic acid using the analogous
esterification protocol previously described for the preparation of
Intermediate I-20b. MS m/z 255.1/257.1 (M+1, Br.sub.79/Br.sub.81
isotope pattern). .sup.1H-NMR (MeOH-d.sub.4, 400 MHz) .delta. 7.42
(d, J=9.4 Hz, 2H), 7.33 (d, J=9.4 Hz, 2H), 3.62 (s, 3H), 1.58-1.52
(m, 2H), 1.21-1.17 (m, 2H).
Intermediate 24
##STR00052##
[0917] 5-(methoxycarbonyl)quinoline 1-oxide (I-24A)
[0918] Into a 50-mL round-bottom flask, was placed a solution of
methyl quinoline-5-carboxylate (94 mg, 0.50 mmol) and methylene
chloride (2 mL) that was cooled to 0.degree. C. This was followed
by the addition of a solid m-CPBA (commercial 65%, using 200 mg
gives calculated effective reagent at 0.70 mmol) in a portion-wise
fashion. The resulting suspension was allowed to warm to RT on its
own accord and maintained for 20 min. At this time the reaction was
diluted with MeOH (2 mL), filtered to remove undesired solids, and
then purified directly by reverse phase chromatography using 30%
acetonitrile/water eluent system to furnish the desired as a white
solid. MS m/z 204.0 (M+1). .sup.1H NMR (400 MHz, MeOH-d.sub.4):
.delta. 9.20 (d, J=8.8 Hz, 1H), 8.89 (d, J=8.8 Hz, 1H), 8.63 (d,
J=6.4 Hz, 1H), 8.40 (d, J=6.4 Hz, 1H), 7.92 (app t, J=8.6 Hz, 1H).
7.60 (dd, J=8.8, 7.5 Hz, 1H), 4.12 (s, 3H).
Methyl 2,4-dibromo-benzothiazole-6-carboxylate (I-24B)
[0919] Into a 2 mL reaction vessel equipped with a septum, stir
bar, and and nitrogen line, was placed 5-(methoxycarbonyl)
quinoline 1-oxide (70.0 mg, 0.345 mmol) and POCl.sub.3. The
resulting reddish solution was heated to 80.degree. C. for 10 min,
allowed to cool to RT, and was directly concentrated to a solid
residue in vacuo (1 mm Hg) at 50.degree. C. The resulting solid was
rinsed with ice cold acetonitrile (0.5 mL) to furnish an off white
soli. MS m/z 222.0/224.0 (M+1, Cl.sub.35/Cl.sub.37 isotope
pattern). .sup.1H NMR (400 MHz, MeOH-d.sub.4): .delta. 9.24 (dd,
J=8.8, 0.9 Hz, 1H), 8.22 (dd, J=7.2, 1.2 Hz, 1H), 8.11 (d, J=8.4
Hz, 1H), 7.71 (dd, J=8.4, 7.6 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 3.96
(s, 3H).
##STR00053##
[0920] Methyl 2-chloroquinoline-6-carboxylate (I-24D) was prepared
from methyl quinoline-6-carboxylate according to the analogous
procedure described above for the preparation of Intermediate
I-24B.
Intermediate 25
##STR00054##
[0921] 6-bromo-5-fluorobenzo[b]thiophene-2,3-dione (I-25A)
[0922] A solution of commercially available
3-bromo-4-fluorobenzenethiol (1 g, 4.8 mmol) in dry dichloromethane
(3 mL) was added dropwise to neat oxalyl chloride (2.1 mL, 24.1
mmol) at room temperature. Once the addition was complete, the
yellow reaction mixture was heated at reflux for 14 hours. The
volatiles were removed in vacuo to afford a yellow semi-solid
residue that was suspended in dry carbon disulfide (2 mL) and added
very slowly to a suspension of aluminum chloride (2.1 g, 21.6 mmol)
in dry carbon disulfide (2 mL) at room temperature. Once the
addition was complete, the reaction mixture was heated to
45.degree. C. for 3 hours. After this time, the reaction was cooled
back to room temperature and very slowly poured into ice water (10
mL), the solid that precipitated was filtered and dried in vacuo to
yield 6-bromo-5-fluorobenzo[b]thiophene-2,3-dione as red-orange
solid. MS m/z 260.8 and 262.9 (M+1; Br.sub.79/Br.sub.81 isotope
pattern.
6-bromo-5-fluorobenzo[d]isothiazole-3-carboxamide (I-25B)
[0923] To a solution of 6-bromo-5-fluorobenzo[b]thiophene-2,3-dione
(I-25A) (0.3 g, 1.1 mmol) in methanol (2 mL) cooled to 10.degree.
C. ammonium hydroxide (3 mL, 26.4 mmol, of a 28% aqueous solution)
was added dropwise and the reaction mixture stirred for 14 hours at
room temperature. After this time, the reaction flask was cooled
back to 10.degree. C. and hydrogen peroxide (0.3 mL of a 30%
aqueous solution) was added dropwise and the resulting suspension
was stirred for 1 hour. The solid was removed by filtration, washed
with water and dried in vacuo to afford
6-bromo-5-fluorobenzo[d]isothiazole-3-carboxamide (I-25B) and
4-bromo-5-fluorobenzo[d]isothiazole-3-carboxamide (I-25C) in a 1:1
mixture which was carried to the next step without further
purification. MS 274.9 and 276.9 (M+1; Br.sub.79/Br.sub.81 isotope
pattern).
6-Bromo-5-fluorobenzo[d]isothiazole-3-carboxylic acid (I-25D)
[0924] A suspension of
6-bromo-5-fluorobenzo[d]isothiazole-3-carboxamide (I-25B) and
4-bromo-5-fluorobenzo[d]isothiazole-3-carboxamide (I-25C) (93 mg,
0.34 mmol) in ethanol (1.5 ml) and 6N sodium hydroxide (0.22 mL,
1.35 mmol) was refluxed for 3 hours. The reaction mixture was
cooled to room temperature, diluted with water (2 mL) and acidified
with 2N HCl. The solid was removed by filtration, washed with water
and dried in vacuo to afford
6-bromo-5-fluorobenzo[d]isothiazole-3-carboxylic (I-25D).
.sup.1H-NMR (400 MHz, DMSO) .delta. 8.69 (d, J=6.4 Hz, 1H), 8.49
(d, J=9.6 Hz, 1H). MS 275.9 and 277.9 (M+1; Br.sub.79/Br.sub.81
isotope pattern).
Methyl 6-bromo-5-fluorobenzo[d]isothiazole-3-carboxylate
(I-25E)
[0925] 6-Bromo-5-fluorobenzo[d]isothiazole-3-carboxylic acid
(I-25D) (57 mg, 0.21 mmol) was suspended in dry methanol (5 mL) and
H.sub.2SO.sub.4 (0.2 mL) and refluxed for 3 hours. After this time
the reaction was cooled to room temperature and diluted with water
(3 mL) and neutralized with 5% aquesou Na.sub.2CO.sub.3 and
extracted with ethyl acetate. The organic layer was washed with
brine, dried over sodium sulfate and concentrated in vacuo to yield
methyl 6-bromo-5-fluorobenzo[d]isothiazole-3-carboxylate (I-25E).
MS 289.9 and 291.9 (M+1; Br.sub.79/Br.sub.81 isotope pattern).
Intermediate 26
##STR00055##
[0926] Ethyl 6-bromo-1-methyl-1H-indazole-3-carboxylate (I-26)
[0927] A solution of potassium tert-butoxide (0.46 g, 4.1 mmol) in
dry tetrahydrofuran (5 mL) was added dropwise to a solution of
ethyl 6-chloro-1-methyl-1H-indazole-3-carboxylate (0.9 g, 3.3 mmol)
in tetrahydrofuran (15 mL) and cooled to 0.degree. C. The reaction
mixture was stirred for 15 min and then a solution of iodomethane
(10 mL, 4.45 mmol) in tetrahydrofuran (8 mL) was added dropwise.
The reaction was stirred for 2 hr at room temperature, and then
diluted with water (100 mL) and extracted with ethyl acetate
(3.times.50 mL). The combined organic layers were washed with
water, brine, and dried over sodium sulfate. The removal of the
volatile in vacuo furnished a yellow solid that by trituration with
diethyl ether afforded ethyl
6-chloro-1-methyl-1H-indazole-3-carboxylate (I-26) as an off white
solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.06 (d, J=8.4 Hz,
1H), 7.65 (m, 1H), 7.41 (dd, J=8.8 and 1.6 Hz, 1H), 4.51 (q, J=7.2
Hz, 2H), 4.14 (s, 3H), 1.48 (t, J=7.2 Hz, 3H). MS m/z 283.0 and
285.0 ((M+1; Br.sub.79/Br.sub.81 isotope pattern).
Intermediate 27
##STR00056##
[0928] Ethyl
6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylate
(I-27)
[0929] To a suspension of ethyl
6-chloro-1-methyl-1H-indazole-3-carboxylate (0.43 g, 1.6 mmol) in
dry dichloromethane (10 mL) was added p-toluenesulfonic acid (27
mg, 0.16 mmol) followed by neat 2,3 dihydropyranyl (0.28 mL, 3.2
mmol) dropwise. The reaction mixture was stirred for 30 min, and
then diluted with dichloromethane (30 mL). The organic layer was
washed with 5% Na.sub.2CO.sub.3, water, brine, and then dried over
sodium sulfate. Removal of the solvent in vacuo afforded a yellow
residue which was triturated with a 9:1 hexane-ethyl acetate
mixture to furnish ethyl
6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylate
(I-27) as an off-white powder. .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.09 (dd, J=8.4 and 0.4 Hz, 1H), 7.92 (dd, J=1.6 and 0.8
Hz, 1H), 7.44 (dd, J=8.8 and 1.6 Hz, 1H), 5.81 (dd, J=9.6 and 2.8
Hz, 1H), 4.54 (q, J=7.2 Hz, 2H), 4-10-4.14 (m, 1H), 3.80-3.74 (m,
1H), 2.51-2.48 (m, 1H), 2.17-2.10 (m, 2H), 1.81-1.68 (m, 3H), 1.49
(t, J=7.2 Hz, 3H). MS m/z 353.0 and 355.1 (M+1; Br.sub.79/Br.sub.81
isotope pattern.
Intermediate 28
##STR00057##
[0930] 4-Iodo-5-methylpyridin-2-amine (I-28A)
[0931] In a 500 mL sealed tube 2-fluoro-4-iodo-5-methylpyridine
(4.0 g, 16.81 mmol) in 12N ammonium hydroxide (300 mL) was heated
to 110.degree. C. for 72 hours. Upon cooling to room temperature a
white solid separated. The solid was collected, washed with water
and dried in vacuo to afford 4-iodo-5-methylpyridin-2-amine (I-28A)
as an off-white solid which was carried on to the next step without
purification. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.82 (s,
1H), 7.04 (s, 1H), 4.27 (bs, 2H), 2.24 (s, 3H). MS m/z 235.0
(M+1).
Ethyl 7-iodo-6-methylimidazo[1,2-a]pyridine-3-carboxylate
(I-28B)
[0932] To a suspension of 4-iodo-5-methylpyridin-2-amine (I-28A)
(1.55 g. 6.6 mmol), sodium bicarbonate (0.67 g, 7.9 mmol) in dry
dimethoxyethane (10 mL) at room temperature, ethyl
2-chloro-3-oxopropanoate (1 g, 6.41 mmol) in dimethoxyethane (1 mL)
was added dropwise. The reaction mixture was heated to 100.degree.
C. for 1 h and then cooled to room temperature and diluted with
dichloromethane (50 mL). The organic layer was washed with water,
brine, dried over sodium sulfate and concentrated in vacuo. The
brown crude oil was purified by silica gel chromatography with a
gradient of 0-15% ethyl acetate/hexanes to yield ethyl
7-iodo-6-methylimidazo[1,2-a]pyridine-3-carboxylate (I-28B) as
light tan solid. .sup.1H-NMR (400 MHz, DMSO) .delta. 9.11 (s, 1H),
8.41 (s, 1H), 8.22 (s, 1H), 4.36 (q, J=7.2 Hz, 2H), 2.42 (s, 3H),
1.37 (t, J=7.2 Hz, 3H). MS m/z 331.0 (M+1).
Intermediate 29
##STR00058##
[0933] (2-(Trifluoromethyl)pyridin-3-yl)methanol (I-29A)
[0934] A solution of 2-(trifluoromethyl)nicotinic acid (5 g, 26.2
mml) in dry tetrahydrofuran (50 mL) was cooled to -10.degree. C.
and then treated with LiAlH.sub.4 (39 mL, of a 1M solution in THF)
by very slow addition. The reaction mixture was stirred at room
temperature for 14 hours. The reaction was then cooled to
-10.degree. C. and quenched with a very slow dropwise addition of
water (2 mL) and 6N HCl (1.2 mL). The reaction mixture was further
diluted with water and extracted with diethyl ether (3.times.100
mL). The organics were combined and washed with brine, dried over
sodium sulfate and concentrated in vacuo. The crude oily residue
was purified by silica gel chromatography with a gradient of 0-10%
ethyl acetate-dichloromethane to yield
(2-(trifluoromethyl)pyridin-3-yl)methanol (I-29A) as pale yellow
oil. .sup.1H-NMR (400 MHz, CDCl3) .delta. 8.61 (d, J=4.8 Hz, 1H),
8.15 (dd, J=8.0, and 0.8 Hz, 1H), 7.55 (dd, J=8.0 and 4.4 Hz, 1H),
4.95 (d, J=6.0 Hz, 2H), 2.02 (t, J=6.0 Hz, 1H). MS m/z 178.0
(M+1).
2-(Trifluoromethyl)nicotinaldehyde (I-29B)
[0935] MnO.sub.2 (6.10 g, 70.6 mmol) was added portionwise to a
solution of the above (2-(trifluoromethyl)pyridin-3-yl)methanol
(I-29A) (2.5 g, 14.1 mmol) in dry dichloromethane (300 mL), and the
resulting suspension was heated to 50.degree. C. for 72 hours.
After this time the mixture was filtered through CELITE.RTM. and
the filtrate concentrate in vacuo to afford a brown oil. This crude
oil was purified by silica gel chromatography using a gradient of
0-30% ethyl acetate-hexane to furnish
2-(trifluoromethyl)nicotinaldehyde (I-29B) as clear oil.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 10.4 (m, 1H), 8.89 (dd,
J=4.8 and 1.2 Hz, 1H), 8.45 (dd, J=8.0, and 1.6 Hz, 1H), 7.70 (dd,
J=8.0 and 4.8 Hz, 1H). MS m/z 176.0 (M+1).
Intermediate 1-30
##STR00059##
[0937]
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(tr-
ifluoromethyl)pyridin-3-yl)isoxazole (I-30) was prepared from
Intermediate 1-29 according to the procedures described previously
for the preparation of Intermediates 1-15.
Example 1
##STR00060##
[0938] Methyl
2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)-4-fluorobenzo[d]thiazole-6-carboxylate
(1-1A)
[0939] Into a 25-mL round-bottom flask equipped with a stir bar was
added sequentially
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethoxy)phenyl)isoxazole (I-1H) (0.525 g, 1.29 mmol), 3.6 mL of
N,N-dimethylacetamide, cesium carbonate (1.08 g, 3.31 mmol), and
methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate (1.12 g, 3.87
mmoles). After stirring the resulting slurry at room temperature
for 10 minutes, the mixture was then warmed to 60.degree. C. and
stirred for 1 h. The reaction slurry was allowed to cool to RT, and
was diluted with 200 mL of ethyl acetate and washed with water
(3.times.30 mL). The organic extracts were concentrated under
vacuum and directly purified using normal phase silica gel
chromatography (40 g silica column) with a 15 min gradient of 10%
to 60% ethyl acetate/hexanes. Desired fractions were concentrated
in vacuo, and the resulting residue crystallized upon standing to
give the desired product as a white crystalline solid.
2-[3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl}-1,2-oxazol-4-yl]methox-
y)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic
acid (1-1B)
[0940] To a 25-mL round-bottom flask equipped with a stir bar was
added sequentially methyl
2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)-4-fluorobenzo[d]thiazole-6-carboxylate
(0.55 g, 0.89 mmol), 4.0 mL of THF, 2.0 mL of MeOH, and 3 N aqueous
KOH solution (1 mL, 3 mmol). The resulting homogenous solution was
stirred for 1 hour at 70.degree. C., cooled to RT, and then
quenched with AcOH (roughly 0.2 mL of glacial acetic, 3 mmoles)
until pH=6 was achieved (Whatman class pH strip paper). At this
time the reaction was diluted with ethyl acetate (40 mL) and washed
with water (3.times.5 mL). The ethyl acetate fraction was
concentrated under vacuum to give to an oily residue. To the
resulting oil was then added 6 mL of MeOH. The oil quickly
dissolved, then immediately began to crystallize. Upon standing for
2.5 hrs the mother liquor was withdrawn and crystals washed
(3.times.2 mL of ice cold MeOH). The crystals were dried via vacuum
(10 mm Hg pressure at 45.degree. C. overnight) and then
recrystallized from acetonitrile, filtered, and dried under vacuum
to give the desired product
2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)-
methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-4-fluorobenzo[d]thiazole-6-carboxy-
lic acid.
2-[3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methoxy-
)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic
acid (1-2B)
[0941] Examples 1-2A and the corresponding acid 1-2B can be
prepared following the same procedures, from the reaction of
intermediate
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethyl)phenyl)isoxazole.
TABLE-US-00001 Physical Data Ex MS (m/z), .sup.1H NMR 1-1A
##STR00061## MS m/z 618.2 (M + 1); .sup.1H NMR (DMSO D.sub.6, 400
MHz) .delta. 8.13 (d, J = 1.6 Hz, 1H), 7.67-7.59 (m, 3H), 7.54-
7.50 (m, 2H), 4.41 (s, 2H), 4.31 (bs, 2H), 3.90 (s, 3H), 3.60 (t, J
= 4.8 Hz, 1H), 2.31-2.25 (m, 1H), 2.10 (app dt, J = 14.8, 4 Hz,
2H), 2.02-1.91 (m, 4H), 1.83 (app d, J = 14.8 Hz, 2H), 1.19- 1.15
(m, 4H). 1-1B ##STR00062## Elemental Analysis
(C.sub.30H.sub.29F.sub.4N.sub.3O.sub.6S): C 56.69, H 4.60, N 6.61;
Found: C 56.79, H 4.61, N 6.65. MS m/z 604.2 (M + 1); .sup.1H NMR
(MeOD, 400 MHz) .delta. 8.03 (d, J = 1.6 Hz, 1H), 7.57-7.53 (m,
2H), 7.49 (dd, J = 8.1, 1.8 Hz, 2H), 7.41 (app t, J = 7.6, 1H),
4.31 (s, 2H), 4.22 (broad s, 2H), 3.50 (t, J = 4.4 Hz, 1H),
2.22-2.15 (m, 1H), 2.00 (app dt, J = 14.8, 4.0 Hz, 2H), 1.91-1.81
(m, 4H), 1.75 (d, J = 14.4, 2H), 1.10-1.05 (m, 4H). 1-2A
##STR00063## MS m/z 602.3 (M + 1); .sup.1H NMR (DMSOd.sub.6, 400
MHz) .delta. 8.26 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 8 Hz, 1H),
7.84-7.74 (m, 2H), 7.63-7.60 (m, 2H), 4.26 (bs, 4H), 3.84 (s, 3H),
3.52 (t, J = 4 Hz, 1H), 2.39-2.31 (m, 1H), 2.01- 1.94 (m, 2H),
1.85-1.74 (m, 6H), 1.18- 1.06 (m, 4H). 1-2B ##STR00064## MS m/z
588.1 (M + 1); .sup.1H NMR (DMSOd.sub.6, 400 MHz) .delta. 8.21 (d,
J = 1.6 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.84-7.74 (m, 2H),
7.62-7.56 (m, 2H), 4.26 (bs, 4H), 3.52 (t, J = 4 Hz, 1H), 2.39-2.31
(m, 1H), 2.00-1.96 (m, 2H), 1.85-1.73 (m, 6H), 1.19-1.07 (m,
4H).
Example 2
##STR00065##
[0942] Methyl
2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)-4-methoxybenzo[d]thiazole-6-carboxylate
(2-1A)
[0943] The ester, methyl
2-chloro-4-methoxybenzo[d]thiazole-6-carboxylate (124 mg, 0.48
mmol) and
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethoxy)phenyl)isoxazole (200 mg, 0.48 mmol) and
diisopropylethylamine (0.1 mL, 0.7 mmol) were sequentially
dissolved in dimethylacetamide (1 mL) and heated to 120.degree. C.
overnight. The reaction mixture was allowed to cool to room
temperature and then diluted with ethyl acetate and aqueous
saturated sodium bicarbonate solution. The organics were separated,
the aqueous layer was subjected to a further wash with ethyl
acetate, and the organics were combined and dried (MgSO.sub.4) then
evaporated in vacuo. The product was purified by silica gel
chromatography with a gradient of 0-100% ethyl acetate/hexanes to
furnish 161 mg of a clear oil that was used directly in the
following transformation without further manipulation.
2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)--
8-azabicyclo[3.2.1]octan-8-yl)-4-methoxybenzo[d]thiazole-6-carboxylic
acid (2-2B)
[0944] The ester, methyl
2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)-4-methoxybenzo[d]thiazole-6-carboxylate
(161 mg, 0.26 mmol) was dissolved in tetrahydrofuran (1 mL) and
ethanol (1 mL) and subjected to an aqueous solution of potassium
hydroxide (100 mg, 2.5 mmol in 2 mL water). The mixture was heated
to 60.degree. C. for 2 hr and then the solvent was removed in
vacuo. The mixture was diluted with 5% aqueous citric acid and
extracted with ethyl acetate (2.times.100 mL). The organics were
dried (MgSO.sub.4) then evaporated in vacuo. The product was
purified by flash silica chromatography with a gradient of 0-100%
ethyl acetate/hexanes to give
2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)-4-methoxybenzo[d]thiazole-6-carboxylic
acid.
[0945] Examples 2-2A and the corresponding acid 2-2B can be
prepared following the same procedures, from the reaction of
intermediate
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethyl)phenyl)isoxazole, which was prepared following the
procedures for the preparation of Intermediate 1.
TABLE-US-00002 Physical Data Ex MS (m/z), .sup.1H NMR 2-1A
##STR00066## MS m/z 630.1 (M + 1) 2-1B ##STR00067## MS m/z 616.1 (M
+ 1); .sup.1H NMR (MeOD, 400 MHz) .delta. 8.77 (s, 2H), 7.66- 7.58
(m, 2H), 7.51 (app t, J = 8.0 Hz, 2H), 4.63 (bs, 2H), 4.40 (s, 2H),
3.55 (t, J = 4.4 Hz, 1H), 2.31-2.24 (m, 1H), 1.99-1.88 (m, 4H),
1.86-1.81 (m, 2H), 1.76 (d, J = 14.0 Hz, 2H), 1.19-1.15 (m, 4H).
2-2B ##STR00068## MS m/z 600.1 (M + 1); .sup.1H NMR (DMSOd.sub.6,
400 MHz) .delta. 7.90 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 7.6 Hz,
1H), 7.73 (dt, J = 24, 7.6 Hz, 2H), 7.54 (d, J = 7.2 Hz, 1H), 7.30
(d, J = 1.6 Hz, 1H), 4.18 (s, 2H), 4.11 (bs, 2H), 3.81 (s, 3H),
3.43 (t, J = 4.4 Hz, 1H), 2.30-2.23 (m, 1H), 1.92-1.87 (m, 2H),
1.76-1.72 (m, 3H), 1.67 (t, J = 13.6 Hz, 3H), 1.10-0.99 (m,
4H).
Example 3
[0946] The following compounds were prepared from
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethoxy)phenyl)isoxazole (I-1) and commercially available ethyl
2-chlorobenzo[d]thiazole-6-carboxylate according to the procedures
described for the preparation of Example 1 or 2.
TABLE-US-00003 Physical Data Ex MS (m/z), .sup.1H NMR 3A
##STR00069## MS m/z 614.2 (M + 1); .sup.1H NMR (DMSOd.sub.6, 400
MHz) .delta. 8.37 (d, J = 1.6 Hz, 1H), 7.85 (dd, J = 8.8, 2 Hz,
1H), 7.71-7.63 (m, 2H), 7.59-7.53 (m, 2H), 7.47 (d, J = 8.4 Hz,
1H), 4.34 (s, 2H), 4.29 (app q J = 7.2 Hz, 2H), 4.22 (s, 2H), 3.56
(t, J = 4.4 Hz, 1H), 2.39-2.32 (m, 1H), 1.98 (dt, J = 14.8, 4 Hz,
2H), 1.85-1.80 (m, 4H), 1.74 (d, J = 14.4 Hz, 2H), 1.32 (t, J = 7.2
Hz, 3H), 1.17-1.06 (m, 4H). 3B ##STR00070## MS m/z 586.2 (M + 1);
.sup.1H NMR (DMSOd.sub.6, 400 MHz); .delta. 8.30 (d, J = 1.6 Hz,
1H), 7.81 (dd, J = 8.4, 1.8 Hz, 1H), 7.71-7.62 (m, 2H), 7.60-7.53
(m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 4.33 (s, 2H), 4.19 (bs, 2H),
3.54 (t, J = 4.4 Hz, 1H), 2.39-2.31 (m, 1H), 1.98 (dt, J = 14.8, 4
Hz, 2H), 1.86-1.77 (m, 4H), 1.73 (app d, J = 16.4 Hz, 2H),
1.17-1.04 (m, 4H).
Example 4
2-(2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methox-
y)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazol-6-yl)propan-2-ol
##STR00071##
[0948] The ethyl ester Example 3-A, ethyl
2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxylate (20
mg, 0.033 mmol) was dissolved in THF (1.0 mL), and at RT was
charged with a solution of methyl magnesium chloride (0.4 mL, 3.0 M
THF, 1.2 mmol) in a dropwise fashion over a few minutes slowly
enough so as not to allow the internal temperature of the reaction
to exceed 30.degree. C. After 1 hr the reaction was cooled to
0.degree. C. and treated with MeOH (3 mL) in a dropwise fashion
(rapid evolution of gas, internal temperature did not exceed
10.degree. C.). The reaction was allowed to warm on its own accord
to RT and diluted with ethyl acetate (9 mL) and the cloudy
suspension was washed with 2.times.1 mL of 1 N HCl. The organic
extracts were dried in vacuo and the resulting residue was purified
using mass-directed reverse phase HPLC using gradient of 30 to 90%
acetonitrile/water with 0.05% TFA as modifier. The resulting
product was cold vacuum concentrated and free based using an SPE
polymer support cartridge and MeOH (2 mL) mobilizing solvent
(product SPE PLHCO3 MP part no PL3540-C603). All resulting methanol
effluent was concentrated to furnish the title compound as a white
powder.
TABLE-US-00004 Physical Data Ex MS (m/z), .sup.1H NMR 4
##STR00072## MS m/z 600.2 (M + 1); .sup.1H NMR (D.sub.4- MeOH, 400
MHz) .delta. 7.98 (dd, J = 8.8, 2.0 Hz, 1H), 7.88 (d, J = 1.6 Hz,
1H), 7.64- 7.58 (m, 2H), 7.52 (app t, J = 8.4 Hz, 1H), 7.41-7.36
(m, 2H), 4.52 (s, 2H), 4.31 (br s, 2H), 3.62 (t, J = 4.4 Hz, 1H),
2.39-2.32 (m, 1H), 2.09 (t, J = 4.4 Hz, 1H), 2.06 (t, J = 4.4 Hz,
1H), 2.02-1.96 (m, 4H), 1.82 (d, J = 14.4 Hz, 2H), 1.60 (br s, 6H),
1.21-1.15 (m, 4H).
Example 5
[0949] The previously described Example 1-1B,
2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)-4-fluorobenzo[d]thiazole-6-carboxylic
acid (20 mg, 0.033 mmol), was suspended in methylene chloride (0.6
mL), cooled to 0.degree. C. and treated with
N,N-diisopropylethylamine (aprox. 10 uL, 0.07 mmol) and oxalyl
chloride (10 uL, 0.10 mmol). After 20 minutes the reaction was
concentrated in vacuo to a reddish colored residue, suspended in
THF (0.5 mL) and then treated with 10 N ammonium hydroxide. After 1
hr of stirring, the reaction was diluted with ethyl acetate (1 mL),
and water washed (2.times.0.5 mL). The resulting organic extract
were concentrated to dryness, re-diluted with MeOH (2 mL), and
directly purified using mass-directed reverse phase HPLC, using
gradient of 30 to 90% acetonitrile/water, and 0.05% TFA as
modifier. All product fractions were cold vacuum concentrated and
free-based using an SPE polymer support cartridge and MeOH (2 mL)
mobilizing solvent (product SPE PLHCO3 MP part no PL3540-C603). All
resulting methanol effluent was concentrated to furnish the title
compound as a white powder, 14 mg (70%). MS m/z 603.1 (M+1).
[0950] Examples 5-2 and 5-3 were prepared following analogous
procedures.
TABLE-US-00005 Physical Data Ex MS (m/z), .sup.1H NMR 5-1
##STR00073## MS m/z 603.1 (M + 1); .sup.1H NMR (DMSO-D.sub.6, 400 M
Hz) .delta. 8.04 (app d, J = 11.2 Hz, 1H), 7.92( d, J = 1.6 Hz,
1H), 7.84 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.70-7.65
(m, 2H), 7.03 (br s, 1H), 6.96 (br s, 1H), 3.95 (br s, 2H), 3.80
(s, 2H), 3.00 (t, J = 4.4 Hz, 1H), 2.80-2.55 (m, 9H), 1.50-1.33 (m,
4H). 5-2 ##STR00074## MS m/z 529.2 (M + 1); .sup.1H NMR (MeOH-
d.sub.4, 400 M Hz) .delta. 8.38 (d, J = 2.0 Hz, 1H), 8.27 (dd, J =
9.6, 1.9 Hz, 1H), 7.74 (app dt, J = 8.0, 2.0 Hz, 1H), 7.61 (app d,
J = 8.0 Hz, 1H), 7.57-7.52 (m, 2H), 7.21 (dd, J = 8.4, 2.0 Hz, 1H),
4.49 (br s, 2H), 439 (s, 2H), 3.61 (app t, J = 4.4 Hz, 1H),
2.17-2.12 (m, 1H), 2.06-1.93 (m, 8H), 1.18-1.12 (m, 4H). NH.sub.2
of the amide is detectable by NMR in DMSO-d.sub.6, appearing
between 7.50 and 7.20 ppm, depending on residual water content. 5-3
##STR00075## MS m/z 526.2 (M + 1)
Example 6
[0951] Intermediates
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethyl)phenyl)isoxazole,
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(difluoro-
methoxy)phenyl)isoxazole or
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2,6-difluor-
ophenyl)isoxazole were prepared as described previously for the
preparation of Intermediate 1. The following compounds were then
prepared from the corresponding amine intermediates and
corresponding benzothiazoles according to the procedures described
previously for the preparation of Examples 1 or 2.
TABLE-US-00006 Physical Data Ex MS (m/z), .sup.1H NMR 6-1A
##STR00076## MS m/z 598.2 (M + 1) 6-1B ##STR00077## MS m/z 570.1 (M
+ 1); .sup.1H NMR (DMSOd.sub.6, 400 M Hz) .delta. 8.23 (d, J = 1.2
Hz, 1H), 7.85 (app d, J = 7.6 Hz, 1H), 7.77-7.74 (m, 2H), 7.68 (app
t, J = 7.2 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.35 (d, J = 8.4 Hz,
1H), 4.18 (s, 2H), 4.12 (bs, 2H), 3.44 (t, J = 4.4 Hz, 1H),
2.30-2.24 (m, 1H), 1.91 (dt, J = 14.8, 3.6 Hz, 2H), 1.80-1.63 (m,
6H), 1.01- 0.99 (m, 4H). 6-2A ##STR00078## MS m/z 596.2 (M + 1)
6-2B ##STR00079## MS m/z 568.2 (M + 1); .sup.1H NMR (DMSOd.sub.6,
400 M Hz) .delta. 8.22 (d, J = 2 Hz, 1H), 7.74 (dd, J = 8.4, 1.6
Hz, 1H), 7.56-7.52 (m, 1H), 7.44 (dd, J = 7.8, 1.8 Hz, 1H), 7.30
(d, J = 8 Hz, 2H), 7.35 (dd, J = 11.5, 3.4 Hz, 1H), 7.18 (t, J = 73
Hz, 1H), 4.26 (s, 2H), 4.11 (bs, 2H), 3.46 (t, J = 4.4 Hz, 1H),
2.30-2.23 (m, 1H), 1.90 (dt, J = 15.2, 4 Hz, 2H), 1.77-1.74 (m,
4H), 1.64 (d, J = 14.4 Hz, 2H), 1.08-0.98 (m, 4H). 6-3A
##STR00080## MS m/z 600.2 (M + 1), 6-3B ##STR00081## MS m/z 586.1
(M + 1). 6-4 ##STR00082## MS m/z 598.1 (M + 1); .sup.1H NMR
(DMSOd.sub.6, 400 M Hz) .delta. 7.98 (d, J = 1.6 Hz, 1H), 7.61 (td,
J = 6.6, 1.6 Hz, 1H),7.51 (dd, J = 8, 1.6 Hz, 1H), 7.40-7.36 (m,
3H), 7.25 (t, J = 73 Hz, 1H), 4.33 (s, 2H), 4.18 (bs, 2H), 3.89 (s,
3H), 3.52 (t, J = 4.4 Hz, 1H), 2.37- 2.30 (m, 1H), 2.00-1.95 (m,
2H), 1.81-1.77 (m, 4H), 1.71 (d, J = 14.4, 2H), 1.15-1.05 (m, 4H).
6-5A ##STR00083## MS m/z 566.2 (M + 1) 6-5B ##STR00084## MS m/z
538.1 (M + 1) 6-6A ##STR00085## MS m/z 582.2 (M + 1) 6-6B
##STR00086## MS m/z 568.1 (M + 1); .sup.1H NMR (MeOD, 400 M Hz)
.delta. 7.91 (d, J = 1.6 Hz, 1H), 7.64-7.56 (m, 1H), 7.31- 7.22 (m,
3H), 4.26 (s, 2H), 4.11 (bs, 2H), 3.82 (s, 3H), 3.46 (t, J = 4 Hz,
1H), 2.33-2.25 (m, 1H), 1.93-1.88 (m, 2H), 1.76-1.66 (m, 4H), 1.60
(d, J = 14.4 Hz, 2H), 1.10-1.00 (m, 4H). 6-7A ##STR00087## MS m/z
570.2 (M + 1) 6-7B ##STR00088## MS m/z 556.1 (M + 1)
Example 7
##STR00089##
[0952] tert-butyl
3-((5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclohexyl)isoxazol-4-yl)-
methoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (7-I)
[0953] A solution of N-Boc-nortropine (579 mg, 2.55 mmol) and
18-crown-6 (808 mg, 3.06 mmol) in THF (8.5 mL) was treated with
potassium tert-butoxide (343 mg, 3.06 mmol) and stirred for 10
minutes. A solution of
4-(chloromethyl)-5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclohexy-
l)isoxazole (784 mg, 2.55 mmol) in THF was added. The resulting
mixture was stirred at rt for 2 hours and then poured into water
and extracted with EtOAc. Organics were collected, dried
(MgSO.sub.4), filtered, concentrated and chromatographed
(SiO.sub.2, linear gradient, 0-60% EtOAc in Hexanes) to give the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.28 (m,
2H), 4.19 (m, 1H), 4.11 (m, 1H), 3.66 (dd, J=4.8, 4.7 Hz, 1H), 3.47
(dd, J=7.6, 3.7 Hz, 1H), 2.42 (m, 1H), 2.19 (ddd, J=25.2, 12.5, 3.4
Hz, 1H), 2.00-1.77 (m, 13H), 1.69 (m, 1H), 1.52 (m, 1H), 1.46 (s,
9H), 1.35 (m, 1H), 1.12 (m, 2H), 1.03 (m, 2H) 4; MS m/z 443.2
(M-.sup.tBu+1).
Ethyl
2-(3-((5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclohexyl)isoxaz-
ol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxyl-
ate (7A)
[0954] A solution of tert-butyl
3-((5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclohexyl)isoxazol-4-yl)-
methoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (67 mg, 0.13 mmol)
in dichloromethane (1 mL) was treated with TFA (500 .mu.L) and
stirred for 1 hr at rt. The reaction was concentrated in vacuo and
then diluted with NMP (1 mL) and then treated with Hunig's base
(110 .mu.L, 0.67 mmol) followed by ethyl
2-chlorobenzo[d]thiazole-6-carboxylate (33 mg, 0.13 mmol). After
heating overnight at 120.degree. C., the reaction was poured into
water and extracted with EtOAc. The organic phase was collected,
dried (MgSO.sub.4), filtered, and concentrated. The crude residue
was purified by chromatography (SiO.sub.2, linear gradient, 0-60%,
EtOAc in Hexanes) to give the title compound.
2-(3-((5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclohexyl)isoxazol-4-y-
l)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxylic
acid (7B)
[0955] A solution of ethyl
2-(3-((5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclohexyl)isoxazol-4--
yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxylate
(16 mg, 0.03 mmol) in ethanol (1 mL) was treated with potassium
hydroxide (4.5 mg, 0.08 mmol) and heated to 60.degree. C. for 2
hours. The reaction cooled RT, was concentrated in vacuo and then
treated with 10% citric acid (aq.) and extracted with EtOAc.
Organics were collected and concentrated. The crude material was
purified via mass-directed reverse phase HPLC.
TABLE-US-00007 Physical Data Ex MS (m/z), .sup.1H NMR 7A
##STR00090## MS m/z 604.2 (M + 1). 7B ##STR00091## MS rn/z 576.3 (M
+ 1); .sup.1H NMR (MeOD, 400 M Hz) .delta. 8.32 (d, J = 1.6 Hz,
1H), 7.96 (dd, J = 8.5, 1.7 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 4.41
(dd, J = 33.5, 12.0 Hz, 2H), 4.40 (m, 2H), 3.74 (m, 1H), 3.55 (m,
1H), 2.64 (m, 1H) 2.30-2.12 (m, 6H), 2.09- 2.03 (m, 4H), 1.91-1.74
(m, 5H), 1.52 (m, 1H), 1.45 (m, 1H), 1.07 (m, 4H).
Example 8
[0956] The following compounds were prepared from tert-butyl
3-((5-cyclopropyl-3-(2-(trifluoromethyl)cyclohexyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octane-8-carboxylate, tert-butyl
3-((5-cyclopropyl-3-(4,4-dimethylcyclohexyl)isoxazol-4-yl)methoxy)-8-azab-
icyclo[3.2.1]octane-8-carboxylate or tert-butyl
3-((3-cyclohexyl-5-cyclopropylisoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]o-
ctane-8-carboxylate and the corresponding benzothiazole, pyrimidyl
and pyrazine derivatives following the analogous procedures
described for the preparation of Example 7.
TABLE-US-00008 Physical Data Ex MS (m/z), .sup.1H NMR 8-1
##STR00092## MS m/z 594.3 (M + 1); .sup.1H NMR (CDCl.sub.3, 400 M
Hz) .delta. 8.13 (d, J = 1.5 Hz, 1H), 7.75 (dd, J = 11.2, 1.5 Hz,
1H), 4.38-4.30 (m, 4H), 3.88 (m, 1H), 3.67 (m, 1H), 3.48 (m, 1H),
2.44 (m, 1H), 2.22 (m, 5H), 2.09 (m, 2H), 2.02-1.91 (m, 4H), 1.81
(m, 2H), 1.70 (m, 1H), 1.53 (m, 1H), 1.36 (m, 1H), 1.13 (m, 2H),
1.05 (m, 2H). 8-2 ##STR00093## MS m/z 606.3 (M + 1); .sup.1H NMR
(MeOD, 400 M Hz) .delta. 7.98 (d, J = 1.4 Hz, 1H), 7.52 (d, J = 1.4
Hz, 1H), 4.41 (m, 4H), 4.00 (s, 3H), 3.73 (m, 1H), 3.55 (m, 1H),
2.63 (m, 1H), 2.29-2.12 (m, 7H), 2.11-2.01 (m, 5H), 1.91-1.75 (m,
5H), 1.55-1.43 (m, 2H), 1.09 (m, 4H). 8-3 ##STR00094## MS m/z 536.3
(M + 1); .sup.1H NMR (400 M Hz, DMSO) .delta. 12.7 (s, 1H), 8.35
(d, J = 2.0 Hz, 1H), 7.83 (dd, J = 8.4, 2.0 Hz, 1H), 7.46 (d, J =
8.4 Hz, 1H), 4.36 (m, 4H), 3.71 (m, 1H), 2.64 (m, 1H), 2.23-2.16
(m, 1H), 2.13-2.09 (m, 5H), 2.02-1.95 (m, 5H), 1.76- 1.72 (m, 2H),
1.68-1.58 (m, 2H), 1.46-1.42 (m, 2H), 1.26 (ddd, J = 26.0, 13.2,
4.0 Hz, 2H), 1.04-1.00 (m, 2H), 0.94-0.92 (m, 8H). MS m/z 536.1 (M
+ 1). 8-4 ##STR00095## MS m/z 554.3 (M + 1); 8-5A ##STR00096## MS
m/z 535.3 (M + 1) 8-5B ##STR00097## MS m/z 521.3 (M + 1);
.sup.1H-NMR (400 M Hz, d.sub.4-MeOD) .delta. 8.72 (s, 1H), 8.09 (s,
1H), 4.66 (s, 2H), 4.39 (dd, J = 33.5, 12.0 Hz, 2H), 3.67 (m, 1H),
3.55 (m, 1H), 2.64 (m, 1H), 2.27 (m, 2H), 2.16 (m, 2H), 2.02 (m,
6H), 1.83 (m, 5H), 1.50 (m, 2H), 1.07 (m, 4H); MS m/z 521.3 (M + 1)
8-6A ##STR00098## MS m/z 549.3 (M + 1) 8-6B ##STR00099## MS m/z
535.3 (M + 1); .sup.1H-NMR (400 M Hz, d.sub.4-MeOD) .delta. 6.95
(s, 1H), 4.78 (s, 1H), 4.38 (dd, J = 35.5, 12.0 Hz, 2H), 3.66 (m,
1H), 3.56 (m, 1H), 2.64 (m, 1H), 2.37 (s, 3H), 2.16 (m, 4H), 2.06
(m, 2H), 1.96- 1.75 (m, 9H), 1.55-1.43 (m, 2H), 1.06 (m, 4H); MS
m/z 535.3 (M + 1) 8-7A ##STR00100## MS m/z 481.3 (M + 1) 8-7B
##STR00101## MS m/z 538.3 (M + 1); 1H-NMR (400 M Hz, d.sub.4-MeOD)
.delta. 6.99 (s, 1H), 4.79 (s, 2H), 4.40 (s, 2H), 3.70 (m, 1H),
2.76 (tt, J = 11.7, 3.2 Hz, 1H), 2.39 (s, 3H), 2.20 (m, 2H), 2.15
(m, 1H), 2.09 (m, 2H), 1.98 (m, 6H), 1.86 (m, 2H), 1.77 (m, 1H),
1.59-1.29 (m, 5H), 1.10-1.02 (m, 4H); MS rn/z 467.3 (M + l
Example 9
[0957] The following examples may be prepared from Intermediate 8
tert-butyl
3-((3-cyclohexyl-5-cyclopropylisoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]o-
ctane-8-carboxylate and the corresponding benzothiazole following
the analogous procedures described for the preparation of Example
7.
TABLE-US-00009 Physical Data Ex MS (m/z), .sup.1H NMR 9-1
##STR00102## MS m/z 526.3 (M + 1) 9-2 ##STR00103## MS m/z 538.3 (M
+ 1)
Example 10
##STR00104##
[0958] tert-butyl
3-((5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazol-4-yl)methoxy)-8-azabicy-
clo[3.2.1]octane-8-carboxylate
[0959] A solution of N-Boc-nortropine (80 mg, 0.35 mmol) and
18-crown-6 (125 mg, 0.5 mmol) in THF (2.5 mL) was cooled to
0.degree. C., treated with potassium tert-butoxide (59 mg, 0.53
mmol) and stirred for 10 min. A solution of
4-(chloromethyl)-5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazole (80
mg, 0.29 mmol) in THF (0.5 mL) was added and the resulting mixture
stirred at rt for 2 h and then poured into water and extracted with
EtOAc. The organic layer was collected, washed with brine, dried
over Na.sub.2SO.sub.4, filtered, concentrated to yield tert-butyl
3-((5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazol-4-yl)methoxy)-8-azabicy-
clo[3.2.1]octane-8-carboxylate. MS m/z 409.1 (M -56+1).
[0960] Ethyl
2-(3-((5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazol-4-yl)methoxy)-8-azab-
icyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxylate (10A) was
prepared from tert-butyl
3-((5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazol-4-yl)methoxy)-8-azabicy-
clo[3.2.1]octane-8-carboxylate and ethyl
2-chlorobenzothiazole-6-carboxylate following the procedure
described in the preparation of Example 7. The crude product was
purified by silica gel column chromatography with hexane-EtOAc 20%
isocratic as eluant to yield the title compound.
2-(3-((5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazol-4-yl)methoxy)-8-azabi-
cyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxylic acid (10B)
[0961] A suspension of ethyl
2-(3-((5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazol-4-yl)methoxy)-8-azab-
icyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxylate (0.03 g,
0.05 mmol) in THF:MeOH:H.sub.2O=3:2:1 solution (0.6 mL) was treated
with 6N LiOH (0.05 mL) at rt for 14 h. The volatiles were removed
in vacuo, the residue diluted with water (1 mL), and 6N HCl was
added to adjust pH to 2. The solids were collected by filtration
and dried under vacuum to afford
2-(3-((5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxylic acid
as hydrochloride salt.
TABLE-US-00010 Physical Data Ex MS (m/z), .sup.1H NMR 10A
##STR00105## MS m/z 571.1 (M + 1). 10B ##STR00106## MS m/z 542.0 (M
+1). .sup.1H NMR (400 M Hz, D.sub.4MeOH) .delta. 8.35 (d, J = 1.6
Hz, 1H), 8.84 (dd, J = 8.4 and 1.6 Hz, 1H), 7.46 (d, J = 8.4 Hz,
1H), 7.29 (m, 2H), 7.20-7.16 (m, 3H), 4.19 (bs, 2H), 2.35-2.30 (m,
2H), 2.23-2.17 (m, 3H), 2.01-1.93 (m, 6H), 1.86- 1.78 (bm, 6H),
1.63-1.59 (m, 1H), 1.49- 1.48 (m, 1H), 1.06-1.03 (m, 3H), 0.97-0.93
(m, 2H).
Example 11
[0962] The following compound was prepared from
4-(chloromethyl)-5-cyclopropyl-3-(2-(trifluoromethyl)cyclopropyl)isoxazol-
e (rac-9) and the corresponding benzothiazole following the
analogous procedures described for the preparation of Example
7.
TABLE-US-00011 Physical Data Ex MS (m/z), .sup.1H NMR 11
##STR00107## MS m/z 552.2 (M + 1); .sup.1H NMR (MeOD, 400 M Hz)
.delta. 8.13 (s, 1H), 7.66 (dd, J = 11.6, 0.9 Hz, 1H), 4.51 (s,
2H), 4.44 (m, 1H), 3.78 (m, 1H), 2.40 (m, 1H), 2.32-2.21 (m, 5H),
2.20-2.13 (m, 1H), 2.12-2.07 (m, 5H), 1.42 (m, 2H), 1.10 (m, 2H),
1.04 (m, 2H).
Example 12
[0963] The following compounds may be prepared from
4-(chloromethyl)-5-cyclopropyl-3-(2-methylcyclopropyl)isoxazole or
4-(chloromethyl)-5-cyclopropyl-3-(cyclopropyl)isoxazole and the
corresponding benzothiazole following the analogous procedures
described for the preparation of Example 7.
TABLE-US-00012 Physical Data Ex MS (m/z), 1H NMR 12-1 ##STR00108##
MS m/z 498.2 (M + 1) 12-2 ##STR00109## MS m/z 484.2 (M + 1) 12-3
##STR00110## MS m/z 496.2 (M + 1)
Example 13
##STR00111##
[0965] tert-Butyl
3-((5-cyclopropyl-3-(spiro[2.5]octan-6-yl)isoxazol-4-yl)methoxy)-8-azabic-
yclo[3.2.1]octane-8-carboxylate (1-10) was prepared following the
same procedure as described for 7-I (Example 7) and was used
without purification in the next step. MS m/z 401.0 (M-56+1).
[0966] Ethyl
2-(3-((5-cyclopropyl-3-(spiro[2.5]octan-6-yl)isoxazol-4-yl)methoxy)-8-aza-
bicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxylate (13-1A) was
prepared using the same procedure as described for 7A in Example 7.
The crude was purified by column chromatography on silica gel with
hexane-EtOAc 20% isocratic as eluant.
[0967] Ethyl
2-(3-((5-cyclopropyl-3-(spiro[2.5]octan-6-yl)isoxazol-4-yl)methoxy)-8-aza-
bicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxylate (13-1B) was
hydrolyzed using the same protocol as described for Example 7. The
crude residue was diluted with water (1 mL) and 6N HCl was added
until pH=6. The solid formed was collected by filtration to afford
a white powder.
[0968] Examples 13-2A and 13-3A and their corresponding acids 13-2B
and 13-3B were prepared following the same procedures, from the
reaction of tert-Butyl
3-((5-cyclopropyl-3-(spiro[2.5]octan-6-yl)isoxazol-4-yl)methoxy)-8-azabic-
yclo[3.2.1]octane-8-carboxylate (I-10) and the corresponding
benzothiazole.
TABLE-US-00013 Physical Data Ex MS (m/z), .sup.1H NMR 13-1A
##STR00112## MS m/z 562.0 (M + 1). 13-1B ##STR00113## MS m/z 534.1
(M + 1). .sup.1H NMR (400 M Hz, DMSO) .delta. 8.33 (d, J = 1.2 Hz,
1H), 7.84 (dd, J = 8.4 and 1.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H),
4.37 (m, 3H), 3.72 (m, 1H), 2.22-2.19 (m, 2H), 2.14- 2.10 (m, 4H),
2.00-1.96 (m, 4H), 1.90- 1.86 (m, 2H) 1.78-1.74 (m, 2H), 1.66- 1.60
(m, 2H), 1.04-0.93 (m, 8H), 0.3-0.2 (m, 4H). 13-2A ##STR00114##
.sup.1H NMR (400 M Hz, DMSO) .delta. 8.28 (d, J = 1.2 Hz, 1H), 7.64
(dd, J = 11.2 and 1.6 Hz, 1H),4.38 (bs, 3H), 3.84 (s, 3H), 3.73 (m,
1H), 2.76-2.71 (m, 1H), 2.23-2.21 (m, 1H), 2.15-2.10 (m, 4H),
2.03-1.99 (m, 4H), 1.90-1.86 (m, 2H), 1.81-1.74 (m, 2H),
1.67-1.58(m, 2H), 1.04-0.93 (m, 7H), 0.32-0.20 (m, 4H). MS m/z
566.0 (M + 1). 13-2B ##STR00115## .sup.1H NMR (400 M Hz, DMSO)
.delta. 8.22 (s, 1H), 7.58 (d, J = 11.2 Hz, 1H),4.38 (bs, 3H), 3.84
3.73 (bs, 1H), 2.77-2.71 (m, 1H), 2.23-2.19 (m, 1H), 2.15-2.10 (m,
5H), 2.02-1.93 (m, 4H), 1.89-1.86 (m, 2H), 1.77-1.74 (m, 2H),
1.66-1.60 (m, 2H), 1.04-0.95 (m, 6H), 0.30-0.21 (m, 4H). MS m/z
552.2 (M + 1). 13-3A ##STR00116## MS m/z 578.0 (M + 1) 13-3B
##STR00117## .sup.1H NMR (400 M Hz, DMSO) .delta. 7.94 (s, 1H),
7.39 (d, J = 1.2 Hz, 1H), 4.37 (s, 2H), 4.29, s, 1H), 3.83 (s, 3H),
3.73 (appt. J = 4.4 Hz, 1H), 2.77-2.71 (m, 1H), 2.24-2.17 (m, 1H),
2.13-2.10 (m, 5H), 2.01-1.95 (m, 4H), 1.90-1.86 (m, 2H), 1.78 (dt,
J = 12.4 and 2.4 Hz, 2H), 1.63 (ddd, J = 25.2, 12.4, and 3.2 Hz,
2H), 1.04-1.02 (m, 2H), 0.95-0.94 (m, 5H), 0.32-0.29 (m, 2H),
0.21-0.20 (m, 2H). MS m/z 564.2 (M + 1).
Example 14
[0969] The following examples were prepared from tert-Butyl
3-((5-cyclopropyl-3-(spiro[2.5]octan-6-yl)isoxazol-4-yl)methoxy)-8-azabic-
yclo[3.2.1]octane-8-carboxylate (I-15) and the corresponding
benzothiazole, pyridyl or pyrimidyl derivatives following the
analogous procedures described for the preparation of Example
13.
TABLE-US-00014 Physical Data MS (m/z), .sup.1H NMR 14 ##STR00118##
.sup.1H NMR (400 M Hz, CDCl3) .delta. 7.12 (s, 1H), 4.76- 4.64 (bs,
2H), 4.34 (d, J = 2.4 Hz, 2H), 3.65 (bs 1H), 2.44 (s, 3H),
2.35-2.33 (m, 1H), 2.08-2.04 (m, 1H), 2.22-2.19 (m, 2H), 2.01-1.93
(m, 9H), 1.85- 1.79 (m, 2H), 1.25-1.24 (m, 3H), 1.12-1.10 (m, 2H),
1.04-1.00 (m, 4H), 0.34-0.23 (m, 2H). MS m/z 493.2 (M+ 1).
Example 15
##STR00119##
[0970] Methyl
2-(2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxamido)acetate
(15-1A)
[0971]
2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)me-
thoxy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxylic
acid (34 mg, 0.06 mmol) was combined with glycine methyl ester
hydrochloride (8 mg, 0.06 mmol),
0-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (25 mg, 0.065 mmol), diisopropylethylacetate
(0.05 ml) and dichloromethane (2 mL). The mixture was stirred for 1
hour, then the solvent was removed in vacuo. The residue was
suspended in ethyl acetate (15 mL) and washed with sodium
bicarbonate solution (5 mL). The organics were combined and dried
(MgSO.sub.4) then evaporated in vacuo. The product was purified by
flash silica chromatography with 0-100% ethyl acetate in hexanes
and used directly in the next procedure.
2-(2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methox-
y)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxamido)
acetic acid (15-1B)
[0972] Methyl
2-(2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)metho-
xy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxamido)acetate
was subjected to a solution of 4N LiOH in water (2 mL) and dioxane
(2 ml) and stirred for 2 hours. The solvent was reduced in vacuo
and the mixture diluted with 5% citric acid (10 ml) and extracted
with ethyl acetate (2.times.8 mL). The organics were combined and
dried (MgSO.sub.4) then evaporated in vacuo. The product was
purified with flash silica chromatography with
methanol/dichloromethane with a 0-40% gradient to give the title
compound as a white solid.
TABLE-US-00015 Physical Data Ex MS (m/z), 1H NMR 15-1B ##STR00120##
MS m/z 643.2 (M + 1); .sup.1H NMR (MeOD, 400 M Hz) .delta. 8.07 (d,
J = 1.6 Hz, 1H), 7.71 (dd, J = 8.4, 1.6 Hz, 1H), 7.57-7.48 (m, 2H),
7.41 (app t, J = 7.6 Hz, 2H), 7.35 (d, J = 8.4 Hz, 1H), 4.31 (s,
2H), 4.16 (bs, 2H), 3.95 (s, 2H), 3.50 (t, J = 4.4 Hz, 1H),
2.21-2.15 (m, 1H), 2.00 (dt, J = 14.8, 4 Hz, 2H), 1.91- 1.81 (m,
4H), 1.72 (d, J = 14.8 Hz, 2H), 1.09-1.05 (m, 4H). 15-2
##STR00121## MS m/z 661.2 (M + 1) 15-3 ##STR00122## MS m/z 587.2 (M
+ 1); .sup.1H NMR (MeOH-d.sub.4, 400 M Hz) .delta. 8.35 (d, J = 2.0
Hz, 1H), 8.29 (dd, J = 9.6, 3.0 Hz, 1H), 7.64 (app dt, J = 7.6, 2.0
Hz, 1H), 7.59 (app dd, J = 8.4, 2.0 Hz, 1H), 7.54-7.48 (m, 2H),
7.28 (d, J = 9.6 Hz, 1H), 4.56 (br s, 2H), 4.44 (s, 2H), 4.18 (s,
2H), 3.61 (app t, J = 4.4 Hz, 1H), 2.29-2.27 (m, 1H), 2.06-1.89 (m,
8H), 1.19-1.15 (m, 4H). 15-4 ##STR00123## MS m/z 645.1 (M + 1);
Example 16
##STR00124##
[0973]
2-(2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl-
)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxamido)eth-
anesulfonic acid (16-1)
[0974] Charged to a resealable and pressure tolerable vessel were
added the following in sequential order: the acid,
2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxylic acid
(58.3 mg, 0.1 mmol), tetrahydrofuran (1.0 mL), N-methyl morpholine
(approximately 0.1 mL, 0.7 mmol). The suspension was stirred at RT
for a few minutes until complete dissolution of the starting acid.
Next was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (27 mg, 0.15
mmol) and the resulting solution was stirred at 50.degree. C. for
20 minutes until a fine white precipitate formed. This precipitate
was physically agitated to ensure that all materials were
thoroughly mixed. Next the taurine (50 mg, 0.40 mmol) was added as
a dimethyl acetamide (4 mL) suspension. The resulting suspension
was sealed in the vessel and heated to 80.degree. C. for 2 hours.
The mixture was then cooled to RT. The mixture was diluted with
ethyl acetate 20 mL and water washed (2.times.3 mL). The organics
were dried under vacuum to a residue, the resulting residue was
diluted with 3 mL of MeOH, and the liquid was directly purified
using mass-directed reverse phase HPLC using gradient of 20 to 70%
acetonitrile/water with ammonium acetate (0.05%) as modifier. The
resulting product was cold vacuum concentrated to give the title
compound as a white powder.
[0975] Examples 16-2 and 16-3 were prepared following the same
procedures.
TABLE-US-00016 Physical Data Ex MS (m/z), .sup.1H NMR 16-1
##STR00125## MS m/z 693.2 (M + 1); .sup.1H NMR (MeOD, 400 M Hz)
.delta. 8.27 (d, J = 1.6 Hz, 1H), 8.00 (dd, J = 8.4, 1.9 Hz, 1H),
7.65- 7.53 (m, 2H), 7.42 (app t, J = 7.8 Hz, 2H), 7.35 (d, J = 8.4
Hz, 1H), 4.42 (br s, 4H), 3.81 (t, J = 6.4 Hz, 2H), 3.11 (t, J =
6.4 Hz, 2H), 2.18-1.93 (m, 8H), 1.72 (d, J = 14.8 Hz, 2H),
1.29-1.15 (m, 4H). 16-2 ##STR00126## MS m/z 711.2 (M + 1); 16-3
##STR00127## MS m/z 695.3 (M + 1); 16-4 ##STR00128## MS m/z, 637.2
(M + 1); .sup.1H NMR (MeOH-d.sub.4, 400 M Hz) .delta. 8.30 (d, J =
2.0 Hz, 1H), 8.26 (d, J = 9.6 Hz, 1H), 7.66 (app dt, J = 7.6, 2.0
Hz, 1H), 7.61 (app dd, J = 8.4, 2.0 Hz, 1H), 7.54-7.49 (m, 2H),
7.25 (dd, J = 9.4, 1.8 Hz, 1H), 4.55 (br s, 2H), 4.49 (s, 2H), 3.78
(t, J = 8.4 Hz, 2H), 3.60 (app t, J = 4.4 Hz, 1H), 3.07 (t, J = 8.4
Hz, 2H), 2.27-2.21 (m, 1H), 2.08- 1.93 (m, 8H), 1.21-1.16 (m,
4H).
Example 17
##STR00129##
[0976] Methyl
2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)-4-methylpyridine-6-carboxylate
(17A)
[0977] The amine,
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethoxy)phenyl)-isoxazole (125 mg, 0.31 mmol), dimethylacetamide
(1.5 mL), methyl 6-chloro-4-methylnicotinate (157 mg, 0.93 mmol),
and cesium carbonate (303 mg, 0.93 mmol) were combined sequentially
and heated to 60.degree. C. for 2 hours. The mixture was diluted
with water and extracted with ethyl acetate (2.times.10 mL). The
organics were dried (MgSO.sub.4) then evaporated in vacuo. The
product was purified by flash silica chromatography with a gradient
of 0-100% ethyl acetate/hexanes to furnish the desired compound as
a clear oil.
2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)--
8-azabicyclo[3.2.1]octan-8-yl)-4-methylpyridine-6-carboxylic acid
(17B)
[0978] The preceding ester, methyl
2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)-4-fluorobenzo[d]thiazole-6-carboxylate
was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL) and
subjected to an aqueous solution of potassium hydroxide (1N aqueous
solution, 2 mL, 2.0 mmoles). The mixture was heated to 60.degree.
C. for 2 hours then the solvent reduced in vacuo. The mixture was
diluted with 5% citric acid in water (8 mL) and extracted with
ethyl acetate (2.times.8 mL). The organics were dried (MgSO.sub.4)
then evaporated in vacuo. The product was purified using silica
flash chromatography with a gradient of 0-100% ethyl
acetate/hexanes to give the title compound as a white solid.
TABLE-US-00017 Physical Data Ex MS (m/z), .sup.1H NMR 17A
##STR00130## MS m/z 558.2 (M + 1); .delta. .sup.1H NMR (DMSO
D.sub.6, 400 M Hz) 8.55 (s, 1H), 7.70- 7.61 (m, 2H), 7.75-7.52 (m,
2H), 6.54 (s, 1H), 4.41 (bs, 2H), 4.32 (s, 2H), 3.73 (s, 3H), 3.46
(t, J = 4.0 Hz, 1H), 2.42 (s, 3H), 2.36-2.30 (m, 1H), 1.83-1.71 (m,
6H), 1.60 (d, J = 14.4 Hz, 2H), 1.19-1.03 (m, 4H). 17B ##STR00131##
MS m/z 544.1 (M + 1). .delta. .sup.1H NMR (DMSO D.sub.6, 400 M Hz)
12.24 (s, 1H), 8.56 (s, 1H), 7.70-7.63 (m, 2H), 7.57-7.52 (m, 2H),
6.52 (s, 1H), 4.41 (bs, 2H), 4.32 (s, 2H), 3.47 (t, J = 4.4 Hz,
1H), 2.43 (s, 3H), 2.37-2.30 (m, 1H), 1.83-1.71 (m, 6H), 1.60 (d, J
= 14.4 Hz, 2H), 1.15-1.06 (m, 4H).
Example 18
##STR00132##
[0979] Methyl
5-bromo-6-((1S,3R)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxaz-
ol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)nicotinate
(18-1)
[0980] The amine,
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethoxy)phenyl)isoxazole (83 mg, 0.20 mmol), N,N-dimethylacetamide
(0.6 mL), methyl 5-bromo-6-chloronicotinate (75 mg, 0.3 mmol), and
cesium carbonate (108 mg, 0.33 mmol) were combined sequentially and
heated to 60.degree. C. for about 3 hours. The mixture was diluted
with ethyl acetate 20 mL and water washed (2.times.3 mL). The
organics were dried under vacuum to a residue and submitted to
flash silica with a gradient of 0-100% ethyl acetate/hexanes to
give the title compound as a clear dense oil. MS m/z 622.2/624
(M+1, Br.sub.79/Br.sub.81 isotope pattern).
Methyl
5-cyclopropyl-6-(((1S,3R)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)-
phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)nicotinate
(18-2A)
[0981] The ester above, methyl
5-bromo-6-((1S,3R)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxaz-
ol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)nicotinate (80 mg,
0.13 mmoles) was charged to a 8 mL microwave vessel and dissolved
in anhydrous tetrahydrofuran (0.5 mL) under a positive pressure of
Ar, and treated with Pd(PPh.sub.3).sub.4, (45 mg, 0.039 mmol, Strem
Cat. No 46-2150. Lot code A2890118). The resulting slurry was then
treated with a solution of cyclopropyl zinc bromide (THF, 0.5 M, 4
mL, 2 mmoles, Rieke Organozinc Reagents of Lincoln Nebr., Cat no
2259 lot JEB10-17). The resulting slurry was degassed with Ar
(approx. flow rate 1 cc, at 1 min purge time). The reaction was
then subjected to microwave conditions (35 minutes in a CEM
Discover Instrument system, 10 W energy maximum, with stirring).
After the microwave event was complete and the reaction cooled, the
reaction was concentrated to dryness and re-suspended in ethyl
acetate (4 mL) and loaded on normal phase silica chromatography
using 10-100% ethyl acetate/hexanes to give the title compound as a
clear viscous oil.
5-cyclopropyl-6-((1S,3R)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)i-
soxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)nicotinic acid
(18-2B)
[0982] The ester above, methyl
5-cyclopropyl-6-((1S,3R)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)-
isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)nicotinate (60
mg, 0.103 mmoles) was dissolved in tetrahydrofuran (0.5 mL) and
methanol (0.5 mL) and subjected to an aqueous solution of potassium
hydroxide (6 N aqueous solution, 0.5 mL, 3.0 mmoles). The mixture
was heated to 70.degree. C. for 2 hours and then cooled to RT. The
pH of the solution was adjusted to pH=6 using aqueous AcOH (0.5 mL
of 6M). The mixture was diluted with ethyl acetate (20 mL),
extracted and water washed (3.times.1 mL). The organics were dried
(MgSO.sub.4) then evaporated in vacuo. The product crystallized
upon concentration of the ethyl acetate mother liquor, was washed
with sparing ice cold ethyl acetate/hexanes (1:1) (0.5 mL) and the
white solid dried to give the title compound.
[0983]
6-[(1R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxa-
zol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic
acid (18-3B) and
6-[(1R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-y-
l}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]pyridine-3-carboxylic acid
(18-6B) were prepared from Examples 18-3A and 18-6B, from the
reaction of
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethoxy)phenyl)isoxazole (I-1) or
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethyl)phenyl)isoxazole and the corresponding pyridyl
derivative.
[0984] Examples 18-4A and 18-5A and their corresponding acids 18-4B
and 18-6B were prepared from the following the same procedures,
from the reaction of
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethoxy)phenyl)isoxazole (I-1) and the corresponding pyrimidinyl
or pyrazinyl derivatives.
##STR00133##
[0985] Examples 18-7A and 18-8A and their corresponding acids 18-7B
and 18-8B were prepared following the same procedures, from the
reaction of
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethoxy)phenyl)isoxazole (I-1) or
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethyl)phenyl)isoxazole and the corresponding pyrimidinyl
derivatives.
TABLE-US-00018 Physical Data Ex MS (m/z), .sup.1H NMR 18-1
##STR00134## MS m/z 622.2/624 (M + 1, Br.sub.79/Br.sub.81 isotope
pattern) 18-2A ##STR00135## MS m/z 584.2 (M + 1). 18-2B
##STR00136## MS m/z 570.2 (M + 1); .sup.1H NMR (D.sub.4- MeOH, 400
M Hz) .delta. 8.34 (d, J = 1.9 Hz, 1H), 8.03 (s, 1H), 7.68-7.58 (m,
2H), 7.51 (app dt, J = 8.2, 0.9 Hz, 2H), 4.81 (br s, 2H, partly
obscured by water resonance in D.sub.4-MeOH ), 4.40 (s, 2H), 3.60
(app t, J = 4.9 Hz, 1H), 2.34-2.27 (m, 1H), 2.10 (app t, J = 4.0
Hz, 1H), 2.07 (app t, J = 4.8 Hz, 1H), 2.08-1.80 (m, 7H), 1.21-1.14
(m, 4H), 1.07 (app q, J = 6.5, 2H), 0.78 (app q, J = 6.2, 2H).
18-3A ##STR00137## MS m/z 544.2 (M + 1) 18-3B ##STR00138## MS m/z
530.2 (M + 1); .sup.1H NMR (MeOD, 400 M Hz) .delta. 8.64 (d, J = 2
Hz, 1H),7.98 (dd, J = 8.8, 2.4 Hz, 1H), 7.66- 7.58 (m, 2H),
7.52-7.48 (m, 2H), 6.64 (d, J = 9.2 Hz, 1H), 4.43 (bs, 2H), 4.38
(s, 2H), 3.52 (t, J = 4.4 Hz, 1H), 2.31-2.24 (m, 1H), 1.97-1.82 (m,
6H), 1.71 (d, J = 14.4 Hz, 2H), 1.18-1.14 (m, 4H). 18-4A
##STR00139## MS m/z 545.2 (M + 1), 18-4B ##STR00140## MS m/z 531.1
(M + 1), 18-5A ##STR00141## MS m/z 545.2 (M + 1), 18-5B
##STR00142## MS m/z 531.2 (M + 1); .sup.1H NMR (DMSOd.sub.6, 400 M
Hz) .delta. 8.51 (s, 1H), 8.01 (s, 1H), 7.64-7.56 (m, 2H), 7.51-
7.46 (m, 2H), 4.41 (bs, 2H), 4.26 (s, 2H), 3.40 (t, J = 4 Hz, 1H),
2.31-2.24 (m, 1H), 1.75-1.67 (m, 6H), 1.57 (d, J = 14.8 Hz, 2H),
1.09-0.97 (m, 4H). 18-6A ##STR00143## MS m/z 528.2 (M + 1) 18-6B
##STR00144## MS m/z 514.2 (M + 1); .sup.1H NMR (MeOD, 400 M Hz)
.delta. 8.54 (d, J = 2 Hz, 1H), 7.88 (dd, J = 8.8, 2.4 Hz, 1H),
7.79- 7.76 (m, 1H), 7.67-7.59 (m, 2H), 7.44 (d, J = 7.2 Hz, 1H),
6.55 (d, J = 8.8 Hz, 1H), 4.34 (bs, 2H), 4.17 (s, 2H), 3.39- 3.37
(m, 1H), 2.21-2.12 (m, 1H), 1.90- 1.74 (m, 6H), 1.63 (d, J = 14.8
Hz, 2H), 1.08-1.04 (m,4H). 18-7A ##STR00145## MS m/z 559.2 (M + 1),
18-7B ##STR00146## MS m/z 545.2 (M + 1); .sup.1H NMR (MeOD, 400 M
Hz) .delta. 7.65-7.59 (m, 2H), 7.52-7.48(m, 2H), 6.91 (s, 1H), 4.66
(bs, 2H), 4.37 (s, 2H), 3.52 (t, J = 4.8 Hz, 1H), 2.35 (s, 3H),
2.32-2.24 (m, 1H), 1.96-1.87 (m, 4H), 1.84-1.77 (m, 2H), 1.69 (d, J
= 14.4 Hz, 2H), 1.18-1.14 (m, 4H). 18-8A ##STR00147## MS m/z 515.3
(M + 1); 18-8B ##STR00148## MS m/z 529.3 (M + 1); .sup.1H NMR (DMSO
D.sub.6, 400 M Hz) .delta. 7.92 (d, J = 7.6 Hz, 1H), 7.83-7.73 (m,
2H), 7.60 (d, J = 7.6 Hz, 1H), 6.94 (s, 1H), 4.50 (bs, 2H), 4.23
(bs, 2H), 3.47-3.40(m, 1H), 2.38-2.29 (m, 4H), 1.81-1.61 (m, 8H),
1.16-1.04 (m, 4H).
Example 19
[0986] The following examples are prepared from
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethoxy)phenyl)isoxazole (I-1) and the corresponding pyridyl,
pyrimidinyl or pyrazinyl derivatives according to the procedure
described for the preparation of Example 18.
TABLE-US-00019 Physical Data Ex MS (m/z), .sup.1H NMR 19-1A
##STR00149## MS m/z 558.2 (M + 1) 19-1B ##STR00150## MS m/z 544.2
(M + 1) 19-2A ##STR00151## MS m/z 613.2 (M + 1), 19-2B ##STR00152##
MS m/z 599.2 (M + 1); .sup.1H NMR (MeOD, 400 M Hz) .delta. 8.70 (s,
1H), 7.64-7.56 (m, 2H), 7.51-7.46 (m, 2H), 4.44 (bs, 2H), 4.26 (s,
2H), 3.44 (t, J = 4 Hz, 1H), 2.31-2.24 (m, 1H), 1.78- 1.62 (m, 8H),
1.09-0.99 (m, 4H). 19-3A ##STR00153## MS m/z 612.2 (M + 1), 19-3B
##STR00154## MS m/z 598.2 (M + 1); .sup.1H NMR (DMSOd.sub.6, 400 M
Hz) .delta. 8.66 (s, 1H), 7.69-7.62 (m, 2H), 7.57-7.51 (m, 2H),
6.92 (s, 1H), 4.53 (bs, 2H), 4.32 (s, 2H), 3.50-3.47 (m, 1H),
2.37-2.27 (m, 1H), 1.84-1.70 (m, 6H), 1.65 (d, J = 14.4 Hz, 2H),
1.15-1.05 (m, 4H). 19-4A ##STR00155## MS m/z 558.2 (M + 1), 1H NMR
(MeOD, 400 M Hz) .delta. 8.55 (s, 1H), 7.70-7.61 (m, 2H), 7.75-7.52
(m, 2H), 6.54 (s, 1H), 4.41 (bs, 2H), 4.32 (s, 2H), 3.73 (s, 3H),
3.46(t, J = 4 Hz, 1H), 2.42 (s, 3H), 2.36-2.30 (m, 1H), 1.83- 1.71
(m, 6H), 1.60 (d, J = 14.4 Hz, 2H), 1.19-1.03 (m, 4H). 19-4B
##STR00156## MS m/z 544.3 (M + 1), 19-5A ##STR00157## MS m/z 545.3
(M + 1), 19-5B ##STR00158## MS m/z 531.2 (M + 1), 19-6A
##STR00159## MS m/z 545.2 (M + 1), 19-6B ##STR00160## MS m/z 531.2
(M + 1), 19-7A ##STR00161## MS m/z 544.2 (M + 1); .sup.1H NMR
(DMSOd.sub.6, 400 M Hz) .delta. 7.70-7.52 (m, 5H), 7.21 (d, J = 7.2
Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.37 (bs, 2H), 4.32 (s, 2H),
3.81 (s, 3H), 3.45 (t, J = 8.4 Hz, 1H), 2.37-2.30 (m, 1H),
1.82-1.65 (m, 6H), 1.58 (d, 14.4 Hz, 2H), 1.17-1.04 (m, 4H). 19-7B
##STR00162## MS m/z 530.2 (M + 1); .sup.1H NMR (MeOD, 400 M Hz)
.delta. 7.56-7.58 (m, 3H), 7.50 (app t, J = 8 Hz, 2H), 7.28 (d, J =
8.4 Hz, 1H), 6.86 (d, J = 6.8 Hz, 1H), 4.49 (bs, 2H), 4.38 (s, 2H),
3.50 (t, J = 4.4 Hz, 1H), 2.30-2.24 (m, 1H), 2.00- 1.89 (m, 4H),
1.89-1.81 (m, 2H), 1.70 (d, J = 14.4 Hz, 2H), 1.18-1.14 (m,
4H).
Example 20
##STR00163##
[0987] Methyl
2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)isonicotinate (20A)
[0988] The amine,
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethyl)phenyl)isoxazole (40 mg, 0.102 mmol) was added to 10 mL
re-sealable pressure capable vessel and charged with 0.6 mL of dry
THF and the oil was allowed to fully dissolve with gentle heating
(40.degree. C., 5 minutes). After the solution cooled to RT, the
solution was treated with 75 mg of 60% w/w NaH-min oil (effective
amount 45 mg, 1.9 mmol). A color change to yellow was observed and
the solution bubbled dramatically. After 1 min, an additional 0.4
mL of anhydrous THF was added. The solution was heated to
50.degree. C. for 3 minutes at which time methyl
2-chloroisonicotinate (60 mg, 0.35 mmoles) and CsF (51 mg, 0.33
mmol) were added sequentially. The reaction was maintained vented
for 4 minutes until most bubbling stopped. Reaction was sealed and
heated to 80.degree. C. with rapid stirring of resulting dense
slurry. After 3 hrs reaction was allowed to cool to RT and vented.
The resulting slurry was diluted with 3 mL of MeOH and liquid was
purified using reverse phase chromatography C-18 supported, using
an instrument equipped with a mass trigger collection device and a
gradient of 30 to 90% acetonitrile/water that was TFA modified
(0.05%). The resulting product was cold vacuum concentrated and
free based using an SPE polymer support cartridge and MeOH (5 mL)
mobilizing solvent (product SPE PLHCO3 MP part no PL3540-C603). All
resulting methanol effluent was concentrated to furnish the free
based intermediate ester as a viscous oil.
2-(3-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy)-8-
-azabicyclo[3.2.1]octan-8-yl)isonicotinic acid (20B)
[0989] The ester above, methyl
2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)isonicotinate (10.5 mg, 0.02 mmol),
was dissolved in anhydrous pyridine (2 mL), and treated with LiI
(65 mg, 0.5 mmoles). The suspension was stirred for 10 min at RT
and was heated to 115.degree. C. for 14 hours. The reaction was
cooled and treated with 0.3 mL of AcOH, diluted with water (1 mL),
and ethyl acetate extracted (3.times.10 mL). The resulting organic
extracts were concentrated to dryness, re-diluted with MeOH (2 mL),
and directly purified using mass-directed reverse phase
chromatography under a gradient of 30 to 90% acetonitrile/water
that was ammonium acetate modified (0.05%). All product fractions
were cold vacuum concentrated to furnish the desired carboxylic
acid product as a white solid.
TABLE-US-00020 Physical Data Ex MS (m/z), 'H NMR 20A ##STR00164##
MS m/z 528.2 (M + 1); .sup.1H NMR (D.sub.4-MeOH, 400 MHz) .delta.
8.26 (br dd, J = 6.0. 0.8 Hz, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.76
(app dq, J = 16.0, 7.2 Hz, 2H), 7.54 (d, J = 7.2, 0.9 Hz, 1H), 6.92
(dd, J = 6.4, 1.8 Hz, 1H), 6.83 (brs, 1H), 4.62 (br s, 1H), 4.25
(app q.sub.ab, J = 12.0 Hz, 2H), 3.92 (s, 3H), 3.83 (s, 1H), 3.63
(appt, J = 4.1 Hz, 1H), 2.31-2.20 (m, 1H), 1.98- 1.74 (m, 6H), 1.63
(br app d, J = 14.7 Hz, 2H), 1.15-1.09 (m, 4H). 20B ##STR00165## MS
m/z 514.1 (M + 1); .sup.1H NMR (D.sub.4-MeOH, 400 MHz) .delta. 7.82
(dd, J = 8.3, 0.9 Hz, 1H), 7.69 (app dq, J = 9.2, 4.5 Hz, 2H), 7.50
(d, J = 5.1 Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H), 6.55 (app dd, J =
2.5, 1.0 Hz, 1H), 6.35 (dd, J = 8.2, 1.7 Hz, 1H) 4.51 (s, 1H), 4.24
(app dd, J = 15.5, 11.2 Hz, 2H), 3.89 (br s, 1H), 3.59 (app t, J =
4.4 Hz, 1H), 2.28-2.16 (m, 1H), 2.15-1.67 (m, 8H), 1.15-1.09 (m,
4H).
Example 21
[0990] The following examples were prepared from
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethyl)phenyl)isoxazole and the corresponding pyridyl, pyrimidinyl
or pyrazinyl derivatives according to the procedure described for
the preparation of Example 18.
TABLE-US-00021 Ex Physical Data MS (m/z), .sup.1H NMR 21-1A
##STR00166## MS m/z 542.2 (M + 1) 21-1B ##STR00167## MS m/z 528.2
(M + 1) 21-2A ##STR00168## MS m/z 529.3 (M + 1) 21-2B ##STR00169##
MS m/z 515.2 (M + 1); .sup.1H NMR (MeOD, 400 MHz) .delta. 8.68 (s,
2H), 7.78 (d, J = 7.6 Hz, 1H), 7.68-7.58 (m, 2H), 7.45 (d, J= 7.2
Hz, 1H), 4.54 (bs, 2H), 4.18 (s, 2H), 3.42 (t, J = 4.4 Hz, 1H),
2.21-2.14 (m, 1H), 1.90-1.67 (m, 8H), 1.09-1.05 (m, 4H). 21-3A
##STR00170## MS m/z 529.2 (M + 1) 21-3B ##STR00171## MS m/z 515.2
(M + 1); .sup.1H NMR (MeOD, 400 MHz) .delta. 8.57 (d, J = 0.8 Hz,
1H), 7.91 (s, 1H), 7.77 (app d, J = 7.6 Hz, 1H), 7.67- 7.59 (m,
2H), 7.44 (d, J = 7.2 Hz, 1H), 4.42 (bs, 2H), 4.17 (s, 2H),
3.40-3.38 (m, 1H), 2.20-2.13 (m, 1H), 1.92-1.85 (m, 2H), 1.85-1.73
(m, 4H), 1.67 (d, J = 14.8 Hz, 2H), 1.08-1.05 (m, 4H). 21-4A
##STR00172## MS m/z 596.2 (M + 1) 21-4B ##STR00173## MS m/z 582.2
(M + 1) 21-5A ##STR00174## MS m/z 529.2 (M + 1) 21-5B ##STR00175##
MS m/z 515.3 (M + 1); .sup.1H NMR (MeOD, 400 MHz) .delta. 8.42 (d,
J = 4.8 Hz, 1H), 7.87 (app d, J = 7.6 Hz, 1H), 7.79-7.67 (m, 2H),
7.54 (d, J = 7.2 Hz, 1H), 7.04 (d, J = 5.2 Hz, 1H), 4.64 (bs, 2H),
4.26 (s, 2H), 3.50-3.48 (m, 1H), 2.30-2.23 (m, 1H), 1.97-1.81 (m,
6H), 1.73 (d, J = 14.8 Hz, 2H), 1.19-1.15 (m, 4H). 21-6A
##STR00176## MS m/z 528.2 (M + 1) 21-6B ##STR00177## MS m/z 514.2
(M + 1)
Example 22
[0991] The following examples are prepared from
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(difluoro-
methoxy)phenyl)isoxazole or
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2,6-difluor-
ophenyl) and the corresponding pyridyl, pyrimidinyl or pyrazinyl
derivatives according to the procedure described for the
preparation of Example 18.
TABLE-US-00022 Physical Data Ex MS (m/z), .sup.1H NMR 22-1A
##STR00178## MS m/z 594.3 (M + 1) 22-1B ##STR00179## MS m/z 580.1
(M + 1), 22-2A ##STR00180## MS m/z 527.2 (M + 1), 22-2B
##STR00181## MS m/z 513.2 (M + 1); .sup.1H NMR (MeOD, 400 MHz)
.delta. 8.38 (d, J = 4.8 Hz, 1H), 7.60-7.51 (m, 2H), 7.39- 7.34 (m,
2H), 7.01 (d, J = 1.2 Hz, 1H), 6.83 (t, J = 74, 1H), 4.63 (bs, 2H),
4.40 (s, 2H), 3.52 (t, J = 4.8 Hz, 1H), 2.31- 2.24 (m, 1H),
1.94-1.90 (m, 4H), 1.82- 1.77 (m, 2H), 1.71 (d, J = 14.4 Hz, 2H),
1.18-1.14 (m, 4H). 22-3 ##STR00182## MS m/z 526.2 (M + 1); .sup.1H
NMR (DMSOd.sub.6, 400 MHz) .delta. 7.64-7.57 (m, 2H), 7.52-7.48 (m,
1H), 7.43-7.05 (m, 4H), 6.89 (d, J = 8.4 Hz, 1H), 4.36 (bs, 2H),
4.31 (s, 2H), 3.81 (s, 3H), 3.43 (t, J = 4.4 Hz, 1H), 2.36-2.28 (m,
1H), 1.81-1.54 (m, 8H), 1.15-1.04 (m, 4H). 22-4A ##STR00183## MS
m/z 540.2 (M + 1) 22-4B ##STR00184## MS m/z 526.2 (M + 1); .sup.1H
NMR (D.sub.4- MeOH, 400 MHz) .delta. 8.60 (s, 1H), 7.56 (dt, J =
7.4, 1.8 Hz, 1H), 7.51 (dd, J = 10.5, 1.5 Hz, 1H), 7.38-7.33 (m,
2H), 6.82 (t, J = 76.5 Hz, 1H), 6.44 (s, 1H), 4.41 (br s, 2H), 4.39
(bs, 2H), 3.51 (t, J = 4.0 Hz, 1H), 2.30 (s, 3H), 2.29-2.22 (m,
1H), 1.97-1.77 (m, 6H), 1.72 (app br d, J = 14.5 Hz, 2H), 1.18-1.11
(m, 4H). 22-5 ##STR00185## MS m/z 541.2 (M + 1) 22-6A ##STR00186##
MS m/z 560.2/562.2 (M + 1, Cl.sub.35/Cl.sub.37 isotope pattern)
22-6B ##STR00187## MS m/z 547.1/549.1 (M + 1, Cl.sub.35/Cl.sub.37
isotope pattern) 22-7A ##STR00188## MS m/z 540.2 (M + 1) 22-7B
##STR00189## MS m/z 526.2 (M + 1); .sup.1H NMR (D.sub.4- MeOH, 400
MHz) .delta. 8.53 (d, J = 2.2 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H),
7.57 (dt, J = 7.8, 2.1 Hz, 1H), 7.51(dd, J = 8.0, 1.6 Hz, 1H);
7.40-7.34 (m, 2H), 6.68 (t, J = 72.0 Hz, 1H), 4.45 (s, 2H), 4.38
(bs, 2H), 3.64 (t, J = 4.6 Hz, 1H), 2.39-2.34 (m, 1H), 2.38 (s,
3H), 2.08-1.98 (m, 2H), 1.89-1.84 (m, 2H), 1.80-1.73 (m, 4H),
1.18-1.13 (m, 4H). 22-8 ##STR00190## MS m/z 527.2 (M + 1) 22-9A
##STR00191## MS m/z 527.2 (M + 1), 22-9B ##STR00192## MS m/z 513.2
(M + 1), 22-10A ##STR00193## MS m/z 527.2 (M + 1), 22-10B
##STR00194## MS mh 513.2 (M + 1), 22-11A ##STR00195## MS m/z 527.2
(M + 1), 22-11B ##STR00196## MS m/z 513.2 (M + 1), 22-12
##STR00197## MS m/z 512.2 (M + 1), 22-13A ##STR00198## MS m/z 496.2
(M + 1), 22-13B ##STR00199## MS m/z 482.2 (M + 1); 1H NMR (MeOD,
400 MHz) .delta. 8.64 (d, J = 2.4 Hz, 1H), 7.98 (dd, J = 9.2, 2.4
Hz, 1H), 7.62-7.55 (m, 1H), 7.19-7.13 (m, 2H), 6.65 (d, J = 9.2 Hz,
1H, 4.43 (bs, 2H), 4.37 (s, 2H), 3.50 (t, J = 4.8 Hz, 1H),
2.30-2.24 (m, 1H), 1.96-1.81 (m, 6H), 1.70 (d, J = 14.4 Hz, 2H),
1.19- 1.15 (m, 4H). 22-14A ##STR00200## MS m/z 497.2 (M + 1),
22-14B ##STR00201## MS m/z 483.2 (M + 1); 1H NMR (MeOD, 400 MHz)
.delta. 8.77 (s, 2H), 7.63-7.55 (m, 1H), 7.19-7.14 (m, 2H), 4.60
(bs, 2H), 4.37 (s, 2H), 3.53 (t, J = 4.4 Hz, 1H), 2.31-2.24 (m,
1H), 1.94- 1.78 (m, 6H), 1.73 (d, J = 14.4 Hz, 2H), 1.19-1.16 (m,
4H). 22-15A ##STR00202## MS m/z 497.2 (M + 1), 22-15B ##STR00203##
MS m/z 483.2 (M + 1); 1H NMR (MeOD, 400 MHz) .delta. 8.38 (d, J =
0.8 Hz, 1H), 8.01 (s, 1H), 7.63-7.55 (m, 1H), 7.19-7.13 (m, 2H),
4.51 (bs, 2H), 4.37 (s, 2H), 3.51 (t, J = 4.4 Hz, 1H), 2.31-2.24
(m, 1H), 1.99-1.81 (m, 6H), 1.73 (d, J = 14.4 Hz, 2H), 1.19- 1.14
(m, 4H). 22-16A ##STR00204## MS m/z 564.2 (M + 1), 22-16B
##STR00205## MS m/z 550.2 (M + 1), 22-17A ##STR00206## MS m/z 536.2
(M + 1); .sup.1H NMR (D.sub.4- MeOH, 400 MHz) .delta. 8.42 (d, J =
1.9 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.61 (app dt, J = 7.4, 6.2
Hz, 1H), 7.11-7.02 (m, 2H), 4.72 (br s, 2H), 4.40 (s, 2H), 3.85 (s,
3H), 3.40 (app t, J = 4.9 Hz, 1H), 2.27-2.18 (m, 1H), 2.07 (app t,
J = 3.5 Hz, 1H), 2.04 (app t, J = 3.9 Hz, 1H), 1.96-1.74 (m, 7H),
1.23-1.20 (m, 4H), 1.07-1.02 (m, 2H), 0.74-0.71 (m, 2H). 22-17B
##STR00207## MS m/z 522.2 (M + 1); .sup.1H NMR (D.sub.4- MeOH, 400
MHz) 8 8.56 (d, J = 1.9 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.63(app
dt, J = 7.2, 6.5 Hz, 1H), 7.21-7.05 (m, 2H), 4.68 (br s, 2H), 4.38
(s, 2H), 3.63 (app t, J = 4.9 Hz, 1H), 2.37-2.28 (m, 1H), 2.09 (app
t, J = 3.5 Hz, 1H), 2.06 (app t, J = 3.9 Hz, 1H), 1.96-1.74 (m,
7H), 1.25-1.20 (m, 4H), 1.06-1.00 (m, 2H), 0.74-0.71 (m, 2H).
22-18A ##STR00208## MS m/z 511.2 (M + 1) 22-18B ##STR00209## MS m/z
497.2 (M + 1) 22-19 ##STR00210## MS m/z 531.2/533.2 (M + 1,
Cl.sub.35/Cl.sub.37 isotope pattern) 22-20 ##STR00211## MS m/z
531.2/533.2 (M + 1, Cl.sub.35/Cl.sub.37 isotope pattern) 22-21
##STR00212## MS m/z 574.2/576.2 (M + 1, Br.sub.79/Br.sub.81 isotope
pattern)
Example 23
##STR00213##
[0992] Methyl
4-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorobenzoate (23A)
[0993] The amine,
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethoxy)phenyl)isoxazole (41.5 mg, 0.102 mmol), dimethylacetamide
(0.6 mL), methyl 3,4 difluorobenzoate (510 mg, 3.0 mmol), and
cesium carbonate (108 mg, 0.33 mmol) were combined sequentially and
heated to 100.degree. C. for about 20 minutes and then 120.degree.
C. for approximately 1 hour. The mixture was diluted with ethyl
acetate 20 mL and water washed (2.times.3 mL). The organics were
dried under vacuum to a residue, the resulting residue was diluted
with 3 mL of MeOH, and the liquid was directly purified using mass
directed reverse phase HPLC under a gradient of 30 to 90%
acetonitrile/water that was TFA modified (0.05%). The resulting
product was cold vacuum concentrated and free based using an SPE
polymer support cartridge and MeOH (5 mL) mobilizing solvent
(product SPE PLHCO3 MP part no PL3540-C603). All resulting methanol
effluent was concentrated to give the free based intermediate ester
as a dense oil.
4-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)--
8-azabicyclo[3.2.1]octan-8-yl)-3-fluorobenzoic acid (23B)
[0994] The ester above, methyl
4-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorobenzoate (24 mg, 0.043
mmoles) was dissolved in tetrahydrofuran (0.5 mL) and methanol (0.5
mL) and subjected to an aqueous solution of potassium hydroxide (6
N aqueous solution, 0.5 mL, 3.0 mmoles). The mixture was heated to
70.degree. C. for 2 hours and then cooled to RT. The pH of the
solution was adjusted to 6 using aqueous HCl (0.5 mL of 6N). The
mixture was diluted with ethyl acetate (20 mL), extracted and water
washed (3.times.1 mL). The organics were dried (MgSO.sub.4) then
evaporated in vacuo. The product crystallized upon concentration of
the ethyl acetate mother liquor, was washed with sparing ice cold
ethyl acetate (0.5 mL), and the white solid dried to give the title
compound.
TABLE-US-00023 Physical Data Ex MS (m/z), .sup.1H NMR 23A
##STR00214## MS m/z 561.2 (M + 1)); .sup.1H NMR (D.sub.4- MeOH, 400
MHz) .delta. 7.69-7.46 (m, 6H), 6.91 (t, J = 9.0 Hz, 1H), 4.38 (br
s, 2H), 4.28 (s, 2H), 3.84 (s, 3H), 3.51 (app t, J = 4.6 Hz, 1H),
2.33-2.21 (m, 1H), 2.00-1.76 (m, 6H), 1.68 (br app d, J = 13.9 Hz,
2H), 1.19-1.14 (m, 4H). 23B ##STR00215## MS m/z 547.2 (M + 1).
.sup.1H NMR (D.sub.4- MeOH, 400 MHz) .delta. 7.60-7.56 (m, 2H),
7.51 (d, J = 12.0 Hz, 1H), 7.47 (t, J = 7.1 Hz, 1H), 7.34 (app t, J
= 7.8 Hz, 2H), 6.67 (t, J = 7.8 Hz, 1H), 4.27 (s, 2H), 4.18 (br s,
2H), 3.42 (app t, J = 3.6 Hz, 1H), 2.07-2.00 (m, 1H), 1.94-1.72 (m,
6H), 1.56 (br app d, J = 15.1 Hz, 2H), 1.21-1.14 (m, 4H).
Example 24
[0995] The following examples are prepared from
4-((8-azabicyclo[3.2.1]octan-3-yloxylmethyl)-5-cyclopropyl-3-(2-(trifluor-
omethoxy)phenyl)isoxazole (I-1) and the corresponding fluorinated
methylbenzoate according to the procedure described for the
preparation of example 23.
TABLE-US-00024 Physical Data Ex MS (m/z), .sup.1H NMR 24-1A
##STR00216## MS m/z 579.2 (M + 1) 24-1B ##STR00217## MS m/z 565.3
(M + 1); .sup.1H NMR (D.sub.4- MeOH, 400 MHz) .delta. 7.70-7.60 (m,
2H), 7.51 (app dt, J = 7.6, 0.9 Hz, 2H), 7.39 (app br d, J = 10.0
Hz, 2H), 4.39 (s, 2H), 4.12 (br s, 2H), 3.58 (app t, J = 5.1 Hz,
1H), 2.31-2.24 (m, 1H), 2.06 (app t, J = 4.8 Hz, 1H), 2.00 (app t,
J = 4.8 Hz, 1H), 1.92-1.68 (m, 6H), 1.20-1.13 (m, 4H).
Example 25
[0996] The following examples are prepared from
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(difluoro-
methoxy)phenyl)isoxazole,
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethyl)phenyl)isoxazole, and
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2,6-difluor-
ophenyl)isoxazole, and the corresponding fluorinated methylbenzoate
according to the procedure described for the preparation of Example
23.
TABLE-US-00025 Physical Data Ex MS (m/z), .sup.1H NMR 25-1A
##STR00218## MS m/z 561.2 (M + 1), 25-1B ##STR00219## MS m/z 547.2
(M + 1) 25-2A ##STR00220## MS m/z 563.2 (M + 1) 25-2B ##STR00221##
MS m/z 549.2 (M + 1); .sup.1H NMR (D.sub.4- MeOH, 400 MHz) .delta.
7. 87(dd, J = 8.2, 0.9 Hz, 1H), 7.74 (app dq, J = 12.0, 7.5 Hz,
2H), 7.53 (d, J = 7.1 Hz, 1H), 7.47- 7.36 (m, 2H), 4.25 (s, 2H),
4.15 (br s, 2H), 3.54 (app t, J = 4.8 Hz, 1H), 2.30- 2.22 (m, 1H),
2.03 (app t, J = 4.3 Hz, 1H), 1.99 (app t, J = 4.5 Hz, 1H), 1.93-
1.72 (m, 6H), 1.19-1.13 (m, 4H). 25-3A ##STR00222## MS m/z 513.2 (M
+ 1), 25-3B ##STR00223## MS m/z 499.2 (M + 1), 25-4A ##STR00224##
MS m/z 531.2 (M + 1), 25-4B ##STR00225## MS m/z 517.2 (M + 1),
25-5A ##STR00226## MS m/z 545.2 (M + 1); .sup.1H NMR (D.sub.4-
MeOH, 400 MHz) .delta. 7.89 (br d, J = 7.5 Hz, 1H), 7.74 (app dq, J
= 11.3, 7.2 Hz, 2H), 7.66 (d, J = 7.0, 1.9 Hz, 1H), 7.58- 7.51 (m,
2H), 6.90 (t, J = 8.9, 1H), 4.29 (br s, 2H), 4.25 (s, 2H), 3.83 (s,
3H), 3.47 (app t, J = 4.1 Hz, 1H), 2.31-2.20 (m, 1H), 1.98-1.77 (m,
6H), 1.67 (br app d, J = 14.7 Hz, 2H), 1.21-1.15 (m, 4H). 25-5B
##STR00227## MS m/z 531.2 (M + 1) 25-6A ##STR00228## MS m/z 543.2
(M + 1) 25-6B ##STR00229## MS m/z 529.2 (M + 1)
Example 26
##STR00230##
[0998]
4-(3-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)met-
hoxy)-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorobenzonitrile (26-A)
was prepared from
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(difluoro-
methoxy)phenyl)isoxazole and 3,4-difluorobenzonitrile according to
the procedure described for the preparation of example 23.
5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)-4-(((8-(2-fluoro-4-(2H-tetrazo-
l-5-yl)phenyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)methyl)isoxazole
(26-B)
[0999]
4-(3-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)met-
hoxy)-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorobenzonitrile (70 mg,
0.14 mmol) was dissolved in N,N-dimethylacetamide (2 ml), sodium
azide (91 mg, 10 eq, 1.40 mmol) and ammonium chloride (75 mg, 10
eq, 1.40 mmol) were added, and the mixture was stirred at
120.degree. C. overnight. Upon cooling to room temperature, the
reaction mixture was diluted with ethyl acetate (30 mL) and washed
with brine (2.times.20 mL). The combined organics were separated,
dried (MgSO.sub.4), and evaporated in vacuo. The product was
purified by mass directed reverse phase HPLC to give a white
solid.
TABLE-US-00026 Physical Data Ex MS (m/z), .sup.1H NMR 26A
##STR00231## MS m/z 510.2 (M + 1) 26B ##STR00232## MS m/z 553.2 (M
+ 1)
Example 27
[1000] Example 27 was prepared from example 25-6B according to the
procedure previously described for the preparation of example
5.
TABLE-US-00027 Physical Data Ex MS (m/z), .sup.1H NMR 27
##STR00233## MS m/z 528.2 (M + 1)
Example 28
##STR00234##
[1001] Methyl
6-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]isothiazole-3-carboxylate
(28-1A)
[1002] A microwave vial was charged with methyl
6-bromobenzo[d]isothiazole-3-carboxylate (WO07056582, 85 mg, 0.31
mmol), cesium carbonate (220 mg, 0.68 mmol),
tris(dibenzylideneacetone)dipalladium(0) (13 mg, 0.014 mmol),
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos) (14
mg, 0.028 mmol), and degassed xylene (1.5 mL). The mixture was
degassed for 10 minutes and then
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethoxy)phenyl)isoxazole (I-1H) (115 mg, 0.28 mmol) in xylene (1
mL) was added. The reaction flask was evacuated and backfilled with
argon three times and then heated at 120.degree. C. for 12 hours.
The reaction mixture was cooled to rt, diluted with ethyl acetate
and filtered through a CELITE.RTM. pad, the filtrate concentrated,
and chromatographed on silica using linear gradient, 20-80%, EtOAc
in Hexanes) to give the desired ester as a yellow solid. MS m/z
600.2 (M+1), 622.2. (M+23).
6-(3-((5-Cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)--
8-azabicyclo[3.2.1]octan-8-yl)benzo[d]isothiazole-3-carboxylic acid
(28-1B)
[1003] Methyl
6-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]isothiazole-3-carboxylate
(37 mg, 0.062 mg) in a 3:2:1 THF-MeOH--H.sub.2O solution (1 mL) was
treated with a 6N LiOH solution (85 .rho.L, 0.49 mmol) at rt for 12
hours. After this time the organic was removed in vacuo and the
residue was diluted with water (1 mL.) and cooled in ice. 3N NaOH
was added dropwise until pH 7. The solid that separated was
collected by filtration, washed with additional water and dried in
vacuo to afford the
6-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]isothiazole-3-carboxylic
acid as off white solid. .sup.1H NMR (400 MHz, DMSO) .delta. 8.31
(d, J=8.0 Hz, 1H), 7.68-7.62 (m, 2H), 7.57-7.52 (m, 2H), 7.18 (bs,
1H), 6.90 (d, J=9.2 Hz, 1H), 4.31 (s, 2H), 4.18 (bs, 2H), 3.42 (m,
1H), 1.88-1.84 (m, 2H), 1.80 (1.78 (m, 4H), 1.53-1.49 (m, 2H),
1.15-1.03 (m, 5H). MS m/z 586.2 (M+1).
[1004] Examples 28-2 through Examples 28-26 were prepared from the
corresponding nortropine intermediates according to the procedures
described for Example 28-1.
TABLE-US-00028 Physical Data MS (m/z), .sup.1H NMR 28-1B
##STR00235## .sup.1H NMR (400 MHz, DMSO) .delta. 8.31 (d, J = 8.0
Hz, 1H), 7.68-7.62 (m, 2H), 7.57-7.52 (m, 2H), 7.18 (bs, 1H), 6.90
(d, J = 9.2 Hz, 1H), 4.31 (s, 2H), 4.18 (bs, 2H), 3.42 (m, 1H),
1.88-1.84 (m, 2H), 1.80 (1.78 (m, 4H), 1.53-1.49 (m, 2H), 1.15-1.03
(m, 5H). MS m/z 586.2 (M + 1). 28-2 ##STR00236## MS m/z 569.2 (M +
1) 28-3 ##STR00237## MS m/z 580.2 (M + 1) 28-4 ##STR00238## MS m/z
582.2 (M + 1); .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 12.41(s,
1H), 7.71-7.62 (m, 2H), 7.60-7.51 (m, 2H), 7.42 (d, J = 8.8 Hz,
1H), 7.05 (s, 1H), 6.72 (dd, J = 8.8, 2.0 Hz, 1H), 6.65 (s, 1H),
4.31 (s, 2H), 4.18 (bs, 2H), 3.90 (s, 3H), 3.41 (t, J = 4.4 Hz,
1H), 2.38-2.30 (m, 1H), 1.94-1.91 (m, 2H), 1.82-1.75 (m, 4H), 1.49
(d, J = 14.4 Hz, 2H), 1.16-1.06 (m, 4H). 28-5 ##STR00239## MS m/z
582.2 (M + 1) 28-6 ##STR00240## MS m/z 529.2 (M + 1). .sup.1H NMR
(MeOH-d.sub.4, 400 MHz) .delta. 7.82 (d, J = 9.2 Hz, 2H), 7.66-7.57
(m, 2H), 7.52-7.48 (m, 2H), 6.74 (d, J = 9.2 Hz, 2H), 4.36 (s, 2H),
4.18 (bs, 2H), 3.46 (t, J = 4.4 Hz, 1H), 2.29-2.23 (m, 1H), 1.98-
1.80 (m, 6H), 1.62 (d, J = 14.4 Hz, 2H), 1.17-1.13 (m, 4H). 28-7
##STR00241## MS m/z 569.2 (M + 1); .sup.1H NMR (MeOH-d.sub.4, 400
MHz) .delta. 7.68 (app dt, J = 7.9, 2.0 Hz, 1H), 7.61 (app dt, J =
8.0, 2.0 Hz, 1H), 7.48 (app t, J = 8.0 Hz, 2H), 7.19 (app d, J =
9.0 Hz, 2H), 6.78 (app d, J = 9.0 Hz, 2H), 4.40 (s, 2H), 4.04 (br
s, 2H), 3.38 (app t, J = 4.4 Hz, 1H), 2.27-2.21 (m, 1H), 2.04 (app
dt, J = 11.6, 1.3 Hz, 2H), 1.98-1.84 (m, 4H), 1.55-1.48 (m, 4H),
1.10-1.04 (m, 6H). 28-8 ##STR00242## MS m/z 539.2 (M + 1) 28-9
##STR00243## MS m/z 533.2/535.2 (M + 1, Cl.sub.35/Cl.sub.37 isotope
pattern) 28-10 ##STR00244## MS m/z 535.2 (M + 1) 28-11 ##STR00245##
Elemental Analysis (C.sub.31H.sub.29F.sub.3N.sub.2O.sub.6): C
63.91, H 5.02, N 4.81; Found: C 63.51, H 5.07, N 4.92. MS m/z 583.2
(M + 1); .sup.1H NMR (MeOH-d.sub.4, 400 MHz) .delta. 7.62 (app dt,
J = 8.0, 2.0 Hz, 1H), 7.60 (app dt, J = 8.0, 2.0 Hz, 1H), 7.54 (d,
J = 1.6 Hz, 1H), 7.49 (app t, J = 8.0 Hz, 2H), 7.24 (d, J = 9.2 Hz,
1H), 7.04 (d, J = 9.2 Hz, 1H), 4.40 (s, 2H), 3.67-3.62 (m, 3H),
2.59 (s, 3H), 2.31-2.27 (m, 1H), 2.08 (app dt, J = 14.6, 1.8 Hz,
2H), 2.00-1.74 (m, 6H), 1.15-1.08 (m, 4H). 28-12 ##STR00246## MS
m/z 567.2 (M + 1); .sup.1H NMR (MeOH-d.sub.4, 400 MHz) .delta. 7.92
(dd, J = 8.4, 1.2 Hz, 1H), 7.80 (d, J = 1.2 Hz, 1H), 7.72 (app dt,
J = 7.6, 1.0 Hz, 1H), 7.72 (app t, J = 7.6 Hz, 1H), 7.64-7.52 (m,
3H), 4.42 (bs, 4H), 3.78 (t, J = 4.7 Hz, 1H), 2.78 (s, 3H), 2.48
(app d, J = 15.6 Hz, 2H), 2.33-2.29 (m, 1H), 2.29- 2.20 (m, 4H),
2.08 (app dd, J = 10.4, 5.1 Hz, 2H), 1.22-1.16 (m, 4H). 28-13
##STR00247## MS m/z 585.2 (M + 1); .sup.1H NMR (MeOH-d.sub.4, 400
MHz) .delta. 8.00 (d, J = 1.2 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H),
7.64 (s, 1H), 7.60-7.52 (m, 2H), 7.45 (app t, J = 8.5 Hz, 2H), 7.38
(dd, J = 8.8, 1.2 Hz, 1H), 4.42 (s, 2H), 4.38 (br s, 2H), 3.58 (t,
J = 4.4 Hz, 1H), 2.35-2.30 (m, 1H), 2.08 (app dt, J = 14.6, 1.8 Hz,
2H), 2.10-1.85 (m, 6H), 1.18-1.12 (m, 4H). 28-14 ##STR00248## MS
m/z 569.2 (M + 1); .sup.1H NMR (MeOH-d.sub.4, 400 MHz) .delta. 7.82
(br s, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.62-7.43 (m, 6H), 4.43-4.38
(br s, 4H), 3.68 (t, J = 4.4 Hz, 1H), 2.38-2.29 (m, 3H), 2.21- 2.10
(m, 2H), 2.08 (app d, J = 13.6 Hz, 2H), 2.00 (app dd, J = 10.2, 4.9
Hz, 2H), 1.19-1.14 (m, 4H). 28-15 ##STR00249## MS m/z 569.2 (M + 1)
28-16 ##STR00250## MS m/z 583.2 (M + 1) 28-17 ##STR00251## MS m/z
580.2 (M + 1) 28-18 ##STR00252## MS m/z 570.2 (M + 1); .sup.1H NMR
(MeOH-d.sub.4, 400 MHz) .delta. 7.92 (d, J = 9.0 Hz, 1H), 7.67-7.61
(m, 2H), 7.54 (app t, J = 8.0 Hz, 2H), 6.92 (d, J = 8.2 Hz, 1H),
6.78 (app d, J = 1.2 Hz, 1H), 4.40 (s, 2H), 4.28 (br s, 2H), 3.44
(t, J = 4.0 Hz, 1H), 2.38-2.33 (m, 1H), 2.18-1.92 (m, 6H), 1.70
(app d, J = 14.0 Hz, 2H), 1.20-1.13 (m, 4H). 28-19 ##STR00253## MS
m/z 582.2 (M + 1) 28-20 ##STR00254## MS m/z 553.2 (M + 1); .sup.1H
NMR (MeOH-d.sub.4, 400 MHz) .delta. 7.88-7.83 (m, 2H), 7.70-7.63
(m, 3H), 7.58 (s, 1H), 7.48 (app d, J = 7.8 Hz, 1H), 7.42 (app d, J
= 7.8 Hz, 1H), 4.52 (bs, 2H), 4.38 (s, 2H), 3.62 (t, J = 4.4 Hz,
1H), 2.38- 2.30 (m, 3H), 2.18-2.10 (m, 4H), 1.97 (app dd, J = 10.0,
5.1 Hz, 2H), 1.18-1.10 (m, 4H). 28-21 ##STR00255## .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.59 (d, J = 8.8 Hz, 1H), 7.80-7.78 (m,
1H), 7.63- 7.57 (m, 2H), 7.45-7.43 (m, 1H), 6.94- 6.92 (m, 2H),
4.17 (s, 3H), 3.37 (bs, 1H), 2.12-2.05 (m, 1H), 1.99-1.93 (m, 4H),
1.63 (bs, 1H), 1.60 (bs, 1H), 1.30- 1.08 (m, 4H), 1.13-1.08 (m,
2H), 0.88- 0.83 (m, 2H). MS m/z 570.2 (M + 1). 28-22 ##STR00256##
.sup.1H NMR (400 MHz, DMSO) .delta. 8.32 (d, J = 8.8 Hz, 1H), 7.38
(dt, J = 6.8 and 2.4 Hz, 1H), 7.28-7.23 (m, 3H), 7.01 (bs, 1H),
6.95 (d, J = 8.0 Hz, 1H), 4.25 (s, 2H), 4.22 (bs, 2H), 3.40-3.37
(m, 2H), 1.86-1.76 (m, 7H), 1.57 (bs, 1H), 1.53 (bs, 1H), 1.14-1.06
(m, 5H), 0.88-0.84 (m, 2H), 068-0.64 (m, 2H). MS m/z 542.2 (M + 1).
28-23 ##STR00257## .sup.1H NMR (400 MHz, DMSO) .delta. 8.11 (d,
J.sub.H-F = 14.8 Hz, 1H), 7.70 (d, J.sub.H-F = 8.4 Hz, 1H),
7.68-7.66 (m, 1H), 7.65- 7.62 (m, 1H), 7.57-7.52 (m, 2H), 4.32 (s,
2H), 4.20 (bs, 2H), 3.49 (m, 1H), 2.34-2.32 (m, 1H), 1.94-1.90 (m,
2H), 1.79-1.77 (m, 5H), 1.66 (bs, 1H), 1.62 (bs, 1H), 1.14-1.11 (m,
2H), 1.08-1.07 (m, 2H). MS m/z 604.2 (M + 1). 28-24 ##STR00258## MS
m/z 569.2 (M + 1) 28-25 ##STR00259## .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.91 (d, J = 9.2 Hz, 1H), 7.49-7.43 (m, 2H),
7.33- 7.30 (m, 2H), 6.82 (d, J = 9.2 Hz, 1H), 6.36 (bs, 1H), 4.24
(bs, 2H), 4.10 (bs, 2H), 3.95 (s, 3H), 3.36 (m, 1H), 2.08- 2.03 (m,
1H), 1.96-1.82 (m, 6H), 1.52- 1.48 (m, 2H), 1.18-1.14 (m, 2H),
1.06- 1.01 (m, 2H). MS m/z 583.2 (M + 1). 28-26 ##STR00260##
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.98 (d, J = 8.8 Hz, 1H),
7.81 (d, J = 7.2 Hz, 1H), 7.64-7.59 (m, 2H), 7.45 (d, J = 7.2 Hz,
1H), 6.86 (d, J = 8.8 Hz, 1H), 6.41 (s, 1H), 4.17 (bs, 4H), 4.01
(s, 3H), 3.98 (m, 1H), 2.12-2.07 (m, 1H), 2.03-1.94 (m, 6H),
1.62-1.59 (m, 2H), 1.26-1.23 (m, 2H), 1.12-1.01 (m, 2H). MS m/z
567.2 (M + 1).
Example 29
[1005] The following examples were prepared from the corresponding
azabicyclo[3.2.1]octane intermediates and the corresponding
benzothiazole derivatives following the analogous procedures
described in Example 1.
TABLE-US-00029 Physical Data Ex MS (m/z), .sup.1H NMR 29-1
##STR00261## MS m/z 524.3 (M + 1); 1H-NMR (400 MHz, CDCl.sub.3)
.delta. 8.14 (d, J = 1.5 Hz, 1H), 7.76 (dd, J = 11.1, 1.5 Hz, 1H),
4.44 (s, 1H), 4.38 (2H), 3.70 (m, 1H), 2.25 (m, 4H), 2.09 (m, 2H),
2.01 (m, 2H), 1.96-1.77 (m, 7H), 1.68 (m, 1H), 1.56 (m, 1H), 1.22
(m, 2H), 1.08 (m, 2H), 1.00 (m, 2H); MS m/z 524.3 (M + 1) 29-2
##STR00262## MS m/z 538.3 (M + 1); 1H-NMR 29-3 ##STR00263## MS m/z
512.3 (M + 1); 1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.13 (d, J =
1.2 Hz, 1H), 7.76 (dd, J = 11.2, 1.3 Hz, 1H), 4.43 (s, 1H), 4.35
(s, 2H), 3.69 (m, 1H), 3.08 (m, 1H), 2.24 (m, 4H), 2.10-1.93 (m,
7H), 1.87-1.78 (m, 4H), 1.66 (m, 2H), 1.25 (m, 1H), 1.11 (m, 2H),
1.02 (m, 2H); MS m/z 512.3 (M + 1) 29-4 ##STR00264## MS m/z 524.2
(M + 1); 1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.14 (d, J = 1.4 Hz,
1H), 7.76 (dd, J = 11.2, 1.4 Hz, 1H), 4.43 (s, 1H), 4.31 (s, 2H),
3.69 (m, 3H), 2.63 (m, 2H), 2.37 (m, 2H), 2.23 (m, 4H), 2.08 (m,
2H), 2.01 (m, 1H), 1.97 (m, 2H), 1.12 (m, 2H), 1.03 (m, 2H), 0.54
(m, 2H), 0.44 (m, 2H); MS m/z 524.2 (M + 1) 29-5 ##STR00265## MS
m/z 580.3 (M + 1); 1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.13 (s,
1H), 7.75 (m, J = 11.1 Hz, 1H), 4.43 (s, 1H), 4.42 (s, 2H), 3.69
(m, 1H), 3.18 (m, 1H), 2.68 (m, 1H), 2.40 (m, 2H), 2.24 (m, 4H),
2.08 (m, 2H), 2.02-1.90 (m, 7H), 1.26 (s, 3H), 1.17 (m, 1H), 1.13
(m, 5H), 1.04 (m, 5H); MS m/z 580.2 (M + 1) 29-6 ##STR00266##
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.12 (d, J = 1.2 Hz, 1H)
7.76 (dd, J = 9.2, 1.2 Hz, 1H), 4.44 (bs 1H), 434-4.26 (m, 2H),
3.68 (t, J = 4.4 Hz, 1H), 2.76 (m, 1H), 2.26-2.21 (m, 2H),
2.10-2.08 (m, 2H) 2.04-1.91 (m, 2H), 2.04-1.91 (m, 4H), 1.88-1.76
(m, 2H), 1.62- 1.59 (m, 2H), 1.50-1.42 (m, 4H), 1.13-1.09 (m, 3H),
1.03-1.00 (m, 3), 0.49-0.47 (m, 1H), 0.28-0.12 (m, 2H). MS m/z
552.2 (M + 1) 29-7 ##STR00267## MS m/z 538.2 (M + 1); .sup.1H NMR
(400 MHz, DMSO) .delta. 8.17 (s, 1H), 7.58 (dd, J = 11.6, 1.2 Hz,
1H), 4.38-4.35 (m, 4H), 3.72 (bs, 1H), 2.33-1.86 (m, 14H),
1.65-1.61 (m, 1H), 1.54-1.48 (m, 1H,) 1.26-1.18 (m, 1H), 1.04-1.00
(m, 6H), 0.63-0.57 (m, 1H), 0.11- 0.07 (m, 1H). MS m/z 538.2 (M +
1).
Example 30
[1006] The following compounds were prepared from the corresponding
nortropine intermediates according to the procedures described
previously for the preparation of Example 1, Example 2 or Example
18.
TABLE-US-00030 Physical Data Ex MS (m/z), .sup.1H NMR 30-1
##STR00268## MS m/z 534.2 (M + 1); .sup.1H NMR (DMSO-d.sub.6, 400
MHz) .delta. 8.21 (d, J = 1.6 Hz, 1H), 7.58 (dd, J = 11.6, 1.6 Hz,
1H), 7.43-7.29 (m, 4H), 4.37- 4.23 (m, 4H), 3.56 (t, J = 4.2 Hz,
1H), 2.40-2.29 (m, 1H), 2.22 (s, 3H), 2.05-1.79 (m, 8H), 1.20-1.06
(m, 4H). 30-2 ##STR00269## MS m/z 460.3 (M + 1); .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. 12.45 (bs, 1H), 8.60 (d, J = 2.4
Hz, 1H), 7.87 (dd, J = 8.8, 2.4 Hz, 1H), 7.42-7.28 (m, 4H), 6.68
(d, J = 8.8 Hz, 1H), 4.45 (bs, 2H), 4.21 (s, 2H), 3.47 (t, J = 4.0
Hz, 1H), 2.38-2.28 (m, 1H), 2.21 (s, 3H), 1.92-1.78 (m, 6H), 1.66
(d, J = 14.8 Hz, 2H), 1.21-1.04 (m, 4H). 30-3 ##STR00270## MS m/z
475.3 (M + 1); 30-4 ##STR00271## MS m/z 516.1 (M + 1) 30-5
##STR00272## MS m/z 546.1 (M + 1); .sup.1H NMR (DMSO-d.sub.6, 400
MHz) .delta. 7.42-7.28 (m, 5H), 6.96 (s, 1H), 4.54 (bs, 2H), 4.21
(s, 2H), 3.49 (t, J = 4.0 Hz, 1H), 2.38-2.28 (m, 4H), 2.22 (s, 3H),
1.88-1.68 (m, 8H), 1.24-1.05 (m, 4H). 30-6 ##STR00273## MS m/z
520.1 (M + 1); .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 12.71
(s, 1H), 8.36 (d, J = 1.6 Hz, 1H), 7.86- 7.78 (m, 3H), 7.47 (d, J =
8.4 Hz, 1H), 7.42-7.36 (m, 2H), 4.46 (s, 2H), 4.31 (bs, 2H), 3.73
(t, J = 4.0 Hz, 1H), 2.38-2.32 (m, 1H), 2.14- 1.91 (m, 8H),
1.16-1.03 (m, 4H). 30-7 ##STR00274## MS m/z 550.1 (M + 1) 30-8
##STR00275## MS m/z 550.1 (M + 1) 30-9 ##STR00276## MS m/z 464.2 (M
+ 1); .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 12.46 (s, 1H),
8.62 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 8.8, 2.4 Hz, 1H), 7.63-7.56
(m, 3H), 7.43-7.37 (m, 1H), 6.72 (d, J = 8.8 Hz, 1H), 4.53 (bs,
2H), 4.47 (s, 2H), 3.68-3.64 (m, 1H), 2.40- 2.30 (m, 1H), 2.08-1.82
(m, 8H), 1.14-1.04 (m, 4H). 30-10 ##STR00277## MS m/z 479.1 (M + 1)
30-11 ##STR00278## MS m/z 564.1 (M + 1); .sup.1H NMR (DMSO-d.sub.6,
400 MHz) .delta. 12.76 (s, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.49-
7.43 (m, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.24-7.17 (m, 2H), 4.22 (s,
2H), 4.18 (bs, 2H), 3.89 (s, 3H), 3.50 (t, J = 4.0 Hz, 1H),
2.38-2.31 (m, 1H), 2.16 (s, 3H), 1.99-1.91 (m, 2H), 1.84-1.75 (m,
4H), 1.71 (d, J = 14.4 Hz, 2H), 1.19-1.07 (m, 4H). 30-12
##STR00279## MS m/z 478.1 (M + 1) 30-13 ##STR00280## MS m/z 493.1
(M + 1) 30-14 ##STR00281## MS m/z 560.2 (M + 1); .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. 12.70 (s, 1H), 7.96 (d, J = 1.6 Hz,
1H), 7.35 (d, 1.6 Hz, 1H), 7.29-7.25 (m, 1H), 7.14 (d, J = 8.0 Hz,
2H), 4.18 (bs, 2H), 4.10 (s, 2H), 3.87 (s, 3H), 3.47 (t, J = 4.4
Hz, 1H), 2.36-2.29 (m, 1H), 2.03 (s, 6H), 2.00-1.91 (m, 2H),
1.89-1.80 (m, 4H), 1.74 (d, J = 14.4 Hz, 2H), 1.15-1.06 (m, 4H).
30-15 ##STR00282## MS m/z 474.2 (M + 1) 30-16 ##STR00283## MS m/z
489.2 (M + 1); .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.27 (t,
J = 8.0 Hz, 1H), 7.14 (d, J = 7.6 Hz, 2H), 6.95 (s, 1H), 4.52 (bs,
2H), 4.09 (s, 2H), 3.42 (t, J = 4.0 Hz, 1H), 2.36-2.29 (m, 4H),
2.04 (s, 6H), 1.83-1.65 (m, 8H), 1.16-1.06 (m, 4H). 30-17
##STR00284## MS m/z 584.1, 586.1 (M + 1, Cl.sub.35/ Cl.sub.37
isotope pattern) 30-18 ##STR00285## MS m/z 498.1, 500.1 (M + 1,
Cl.sub.35/ Cl.sub.37 isotope pattern); .sup.1H NMR (DMSO-d.sub.6,
400 MHz) .delta. 12.41 (s, 1H), 8.58 (d, J = 1.6 Hz, 1H), 7.89-
7.85 (m, 1H), 7.64-7.60 (m, 1H), 7.52 (d, J = 5.2 Hz, 1H), 7.42 (t,
J = 6.0 Hz, 1H), 6.66 (d, J = 6.0 Hz, 1H), 4.42 (bs, 2H), 4.28 (s,
2H), 3.47-3.42 (m, 1H), 2.39-2.31 (m, 1H), 1.77-1.67 (m, 6H), 1.58
(d, J = 9.6 Hz, 2H), 1.20-1.07 (m, 4H). 30-19 ##STR00286## MS m/z
513.2, 515.2 (M + 1, Cl.sub.35/ Cl.sub.37 isotope pattern) 30-20
##STR00287## MS m/z 566.2, 568.1 (M + 1, Cl.sub.35/ Cl.sub.37
isotope pattern) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 12.68
(s, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.65- 7.64 (m, 1H), 7.59-7.54
(m, 1H), 7.51-7.47 (m, 2H), 7.37 (d, J = 1.6 Hz, 1H), 4.32 (s, 2H),
4.18 (bs, 2H), 3.89 (s, 3H), 3.52 (t, J = 4.4 Hz, 1H), 2.38-2.31
(m, 1H), 2.00-1.78 (m, 6H), 1.70 (d, J = 14.8 Hz, 2H), 1.17-1.06
(m, 4H). 30-21 ##STR00288## MS m/z 480.1, 482.1 (M + 1, Cl.sub.35/
Cl.sub.37 isotope pattern) 30-22 ##STR00289## MS m/z 495.1, 497.1
(M + 1, Cl.sub.35/ Cl.sub.37 isotope pattern) 30-23 ##STR00290## MS
m/z 560.2 (M + 1) 30-24 ##STR00291## MS m/z 486.2 (M + 1); .sup.1H
NMR (DMSO-d.sub.6, 400 MHz) .delta. 12.44 (s, 1H), 8.59 (d, J = 2.0
Hz, 1H), 7.87 (dd, J = 8.8, 2.4 Hz, 1H), 7.42-7.37 (m, 1H),
7.29-7.22 (m, 2H), 6.96 (d, J = 7.6 Hz, 1H), 6.67 (d, J = 8.8 Hz,
1H), 4.43 (bs, 2H), 4.27 (s, 2H), 3.46 (t, J = 4.4 Hz, 1H),
2.36-2.28 (m, 1H), 1.86-1.74 (m, 7H), 1.63 (d, J = 14.4 Hz, 2H),
1.16-1.06 (m, 4H), 0.90-0.83 (m, 2H), 0.69-0.65 (m, 2H). 30-25
##STR00292## MS m/z 496.2 (M + 1) 30-26 ##STR00293## MS m/z 496.3
(M + 1) 30-27 ##STR00294## MS m/z 512.2 (M + 1) 30-28 ##STR00295##
MS m/z 614.2 (M + 1); .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.
8.21 (d, J = 1.6 Hz, 1H), 7.70-7.60 (m, 3H), 7.56-7.52 (m, 2H),
4.38 (s, 2H), 4.26 (bs, 2H), 3.82 (s, 3H), 3.59 (t, J = 4.2 Hz,
1H), 2.42 (s, 3H), 2.36- 2.32 (m, 1H), 2.04 (app dt, J = 14.0, 4.1
Hz, 2H), 1.87-1.81 (m, 4H), 1.77 (app d, J = 14.2 Hz, 2H),
1.18-1.12 (m, 4H). 30-29 ##STR00296## MS m/z 600.2 (M + 1); .sup.1H
NMR (DMSO-d.sub.6, 400 MHz) .delta. 8.08 (d, J = 1.5 Hz, 1H),
7.64-7.58 (m, 3H), 7.46-7.42 (m, 2H), 4.31 (s, 2H), 4.18 (broad s,
2H), 3.44 (t, J = 4.2 Hz, 1H), 2.39 (s, 3H), 2.32-2.25 (m, 1H),
1.95 (app dt, J = 13.8, 4.0 Hz, 2H), 1.78-1.72 (m, 4H), 1.63 (d, J
= 14.2, 2H), 1.09-1.04 (m, 4H). 30-30 ##STR00297## MS m/z 598.1 (M
+ 1) 30-31 ##STR00298## MS m/z 584.2 (M + 1) 30-32 ##STR00299## MS
m/z 566.1 (M + 1); .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 8.21
(d, J = 1.1 Hz, 1H),7.68 (d, J = 1.1 Hz, 1H), 7.65 (app q, J = 1.2
Hz, 1H), 7.37-7.30 (m, 2H), 4.36 (s, 2H), 4.24 (br s, 2H), 3.83 (s,
3H), 3.54 (t, J = 4.0 Hz, 1H), 2.44 (s, 3H), 2.38- 2.36 (m, 1H),
1.97 (app dt, J = 14.2, 4.0 Hz, 2H), 1.83-1.74 (m, 4H), 1.72 (app
d, J = 14.6, 2H), 1.08-1.05 (m, 4H). 30-33 ##STR00300## MS m/z
552.2 (M + 1); .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 12.50
(br s, 1H, OH), 8.19 (d, J = 1.1 Hz, 1H), 7.74-7.69 (m, 2H),
7.33-7.28 (m, 2H), 4.32 (s, 2H), 4.22 (br s, 2H), 3.48 (t, J = 4.0
Hz, 1H), 2.43 (s, 3H), 2.35-2.33 (m, 1H), 1.99 (app dt, J = 142,
4.0 Hz, 2H), 1.88-1.77 (m, 4H), 1.74 (app d, J = 14.6 Hz, 2H),
1.18-1.09 (m, 4H). 30-34 ##STR00301## MS m/z 534.2 (M + 1) 30-35
##STR00302## MS m/z 534.2 (M + 1); .sup.1H NMR (MeOH-d.sub.4, 400
MHz) .delta. 7.81-7.74 (m, 4H), 7.22 (app t, J = 8.2 Hz, 2H), 4.46
(br s, 2H), 4.37 (s, 2H), 3.75 (t, J = 4.0 Hz, 1H), 2.50 (s, 3H),
2.29-1.98 (m, 7H), 1.95 (app d, J = 14.4 Hz, 2H), 1.16-1.12 (m,
4H). 30-36 ##STR00303## MS m/z 530.2 (M + 1); .sup.1H NMR
(MeOH-d.sub.4, 400 MHz) .delta. 8.08 (d, J = 1.6 Hz, 1H), 7.78 (d,
J =1.7 Hz, 1H), 7.38-7.24 (m, 4H), 4.28 (br s, 2H), 4.26 (s, 2H),
3.58 (t, J = 3.8 Hz, 1H), 2.58 (s, 3H), 2.29-2.21 (m, 1H), 2.24 (s,
3H), 2.01 (app dt, J = 14.2, 4.0 Hz, 2H), 2.06-1.87 (m, 4H), 1.82
(app d, J = 14.2 Hz, 2H), 1.09-1.07 (m, 4H). 30-37 ##STR00304## MS
m/z 544.2 (M + 1) 30-38 ##STR00305## MS m/z 552.2 (M + 1) 30-39
##STR00306## MS m/z 678.1/680.1 (M + 1, Br.sub.79/ Br.sub.81
isotope pattern). 30-40 ##STR00307## MS m/z 664.1/666.1 (M + 1,
Br.sub.79/ Br.sub.81 isotope pattern).; .sup.1H NMR (MeOH-d.sub.4,
400 MHz) .delta. 8.23 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 1.6 Hz,
1H), 7.68-7.59 (m, 2H), 7.56-7.46 (m, 2H), 4.38 (s, 2H), 4.19
(broad s, 2H), 3.54 (t, J = 4.4 Hz, 1H), 2.38- 2.32 (m, 1H), 1.99
(app dt, J = 14.0, 4.0 Hz, 2H), 1.90-1.84 (m, 4H), 1.73 (d, J =
14.0 Hz, 2H), 1.18-1.07 (m, 4H). 30-41 ##STR00308## MS m/z 553.2 (M
+ 1) 30-42 ##STR00309## MS m/z 571.2 (M + 1); .sup.1H NMR
(MeOH-d.sub.4, 400 MHz) .delta. 7.62 (dt, J = 8.0, 1.6 Hz, 1H),
7.59 (dd, J = 8.0, 1.6 Hz, 1H), 7.49 (app t, J = 7.2 Hz, 2H), 6.91
(br s, 1H), 4.48 (bs, 2H), 4.37 (s, 2H), 3.54 (t, J = 4.2 Hz, 1H),
2.28-2.26 (m, 1H), 1.94-1.72 (m, 6H), 1.69 (d, J = 14.0 Hz, 2H),
1.07- 1.00 (m, 4H). 30-43 ##STR00310## MS m/z 555.2 (M + 1) 30-44
##STR00311## MS m/z 544.2 (M + 1); 1H NMR (MeOH-d.sub.4, 400 MHz)
.delta. 8.00 (d, J = 9.1 Hz, 1H), 7.63 (app dt, J = 8.0, 1.6 Hz,
1H), 7.58 (dd, J = 8.0, 1.6 Hz, 1H), 7.50 (app t, J = 8.0 Hz, 2H),
6.42 (d, J = 9.1 Hz, 1H), 4.45 (bs, 2H), 4.37 (s, 2H), 3.50 (t, J =
4.4 Hz, 1H), 2.61 (s, 3H), 2.28- 2.23 (m, 1H), 1.97-1.88 (m, 4H),
1.81 (app dd, J = 8.8, 4.8 Hz, 2H), 1.70 (d, J = 14.4 Hz, 2H),
1.18-1.13 (m, 4H). 30-45 ##STR00312## MS m/z 528.2 (M + 1); .sup.1H
NMR (MeOH-d.sub.4, 400 MHz) .delta. 7.98 (d, J = 9.1 Hz, 1H), 7.86
(app dd, J = 7.2, 1.2 Hz, 1H), 7.75 (app t, J = 7.2 Hz, 1H), 7.72
(app t, J = 7.2 Hz, 1H), 7.52 (d, J = 12 Hz, 1H), 6.49 (d, J = 9.2
Hz, 1H), 4.46 (bs, 2H), 4.26 (s, 2H), 3.46 (t, J = 4.8 Hz, 1H),
2.61 (s, 3H), 2.27-2.23 (m, 1H), 1.98-1.88 (m, 4H), 1.82 (app dd, J
= 8.8, 4.8 Hz, 2H), 1.70 (d, J = 14.4 Hz, 2H), 1.18-1.14 (m, 4H).
30-46 ##STR00313## MS m/z 474.2 (M + 1) 30-47 ##STR00314## MS m/z
496.2 (M + 1) 30-48 ##STR00315## MS m/z 478.2 (M + 1); .sup.1H NMR
(MeOH-d.sub.4, 400 MHz) .delta. 8.00 (d, J = 9.2 Hz, 1H), 7.59-7.53
(m, 2H), 7.33 (app dt, J = 7.6, 1.2 Hz, 1H), 7.29 (app dt, J = 8.2,
1.2 Hz, 1H), 6.48 (d, J = 9.2 Hz, 1H), 4.47 (bs, 2H), 4.42 (s, 2H),
3.54 (t, J = 4.8 Hz, 1H), 2.62 (s, 3H), 2.31-2.24 (m, 1H),
1.94-1.90 (m, 4H), 1.81 (app dd, J = 8.8, 5.2 Hz, 2H), 1.72 (d, J =
14.4 Hz, 2H), 1.18-1.10 (m, 4H). 30-49 ##STR00316## MS m/z 488.2 (M
+ 1) 30-50 ##STR00317## MS m/z 478.2 (M + 1) 30-51 ##STR00318## MS
m/z 492.2 (M + 1); .sup.1H NMR (MeOH-d.sub.4, 400 MHz) .delta. 7.94
(d, J = 8.8 Hz, 1H), 7.30 (ddd, J = 14.4, 6.8, 6.0 Hz, 1H), 7.58
(d, J = 7.6 Hz, 1H), 6.97 (app t, J = 8.8 Hz, 1H), 6.37 (d, J = 8.8
Hz, 1H), 4.36 (bs, 2H), 4.16 (s, 2H), 3.36 (t, J = 4.4 Hz, 1H),
2.53 (s, 3H), 2.20-2.13 (m, 1H), 2.22 (s, 3H), 1.87-1.71 (m, 6H),
1.61 (d, J = 14.4 Hz, 2H), 1.09- 1.04 (m, 4H). 30-52 ##STR00319##
MS m/z 512.2/514.2 (M + 1, Cl.sub.35/Cl.sub.37 isotope pattern)
30-53 ##STR00320## MS m/z 580.2 (M + 1); .sup.1H NMR (MeOH-d.sub.4,
400 MHz) .delta. 8.42 (d, J = 1.2 Hz, 1H), 8.28 (d, J = 9.0 Hz,
1H), 8.22 (dd, J = 8.0, 1.2 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H),
7.59-7.52 (m, 2H), 7.41 (app t, J = 12 Hz, 2H), 7.28 (d, J = 9.0
Hz, 1H), 4.78 (bs, 2H), 4.42 (s, 2H), 3.62 (app t, J = 4.0 Hz, 1H),
2.26-2.21 (m, 1H), 2.16-1.93 (m, 8H), 1.16-1.11 (m, 4H). 30-54
##STR00321## MS m/z 564.2 (M + 1); .sup.1H NMR (MeOH-d.sub.4, 400
MHz) .delta. 8.52 (d, J = 1.2 Hz, 1H), 8.37 (d, J = 9.0 Hz, 1H),
8.32 (dd, J = 8.0, 1.2 Hz, 1H), 7.83 (app t, J = 7.2 Hz, 2H), 7.74-
7.63 (m, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 9.0 Hz, 1H),
4.78 (bs, 2H), 4.34 (s, 2H), 3.59 (app t, J = 4.0 Hz, 1H),
2.29-2.23 (m, 1H), 2.19-1.94 (m, 8H), 1.18-1.12 (m, 4H). 30-55
##STR00322## MS m/z 580.2 (M + 1) 30-56 ##STR00323## MS m/z 581.2
(M + 1); .sup.1H NMR (MeOH-d.sub.4, 400 MHz) .delta. 8.50 (s, 1H),
8.20-8.14 (m, 3H), 7.58-7.50 (m, 2H), 7.42 (app t, J = 6.4 Hz, 2H),
4.72 (s, 2H, partially obscured by water in MeOH-d.sub.4), 4.31 (s,
2H), 3.61 (app t, J = 4.0 Hz, 1H), 2.30- 1.90 (m, 7H), 1.79-1.71
(m, 2H), 1.10-1.04 (m, 4H). 30-57 ##STR00324## MS m/z 528.2 (M +
1); .sup.1H NMR (MeOH-d.sub.4, 400 MHz) .delta. 7.88 (d, J = 9.0
Hz, 1H), 7.75 (app t, J = 7.6 Hz, 1H), 7.72 (app t, J = 7.6 Hz,
1H), 7.53 (app d, J = 9.0 Hz, 1H), 7.32 (s, 1H), 7.15 (s, 1H), 4.60
(br s, 2H), 4.38 (s, 2H), 3.58 (app t, J = 4.4 Hz, 1H), 2.40 (s,
3H), 2.28- 2.22 (m, 1H), 2.08 (app d, J = 10.6 Hz, 2H), 2.02-1.95
(m, 4H), 1.84 (app d, J = 14.2 Hz, 2H), 1.18-1.13 (m, 4H). 30-58
##STR00325## MS m/z 583.2 (M + 1); .sup.1H NMR (MeOH-d.sub.4, 400
MHz) .delta. 7.64 (app dt, J = 7.6, 1.5 Hz, 1H), 7.60 (dd, J = 7.8,
1.5 Hz, 1H), 7.56 (app d, J = 9.0 Hz, 1H), 7.52 (app t, J = 6.6 Hz,
2H), 7.34 (d, J = 6.5 Hz, 1H), 6.93 (d, J = 6.5 Hz, 1H), 4.78 (br
s, 2H), 4.42 (s, 2H), 4.00 (s, 3H), 3.62 (app t, J = 4.0 Hz, 1H),
2.38-2.30 (m, 1H),
2.18-1.96 (m, 6H), 1.92 (app d, J = 14.2 Hz, 2H), 1.18-1.14 (m,
4H). 30-59 ##STR00326## MS m/z 570.2 (M + 1); .sup.1H NMR
(MeOH-d.sub.4, 400 MHz) .delta. 8.10 (br s, 1H), 7.81 (d, J = 8.6
Hz, 1H), 7.62- 7.56 (m, 2H), 7.52 (app t, J = 7.6 Hz, 2H), 7.18 (d,
J = 8.6 Hz, 1H), 4.42 (br s, 2H), 4.37 (s, 2H), 3.51 (app t, J =
4.4 Hz, 1H), 2.34-2.28 (m, 1H), 2.08 (app d, J = 10.4 Hz, 2H),
2.06-1.94 (m, 4H), 1.78 (app d, J = 14.2 Hz, 2H), 1.22-1.16 (m,
4H). 30-60 ##STR00327## MS m/z 570.2 (M + 1) 30-61 ##STR00328##
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.32 (d, J = 1.6Hz, 1H),
8.02 (dd, J = 8.8 and 2.0 Hz, 1H), 7.56-7.51 (m, 2H), 7.02-6.92 (m,
2H), 4.36 (d, J = 1.2 2H), 4.30 (bs, 1H), 3.59-3.57 (m, 1H),
2.17-2.06 (m, 3H), 2.02-1.98 (m, 4H), 1.85 (bs, 1H), 1.79 (bs, 1H),
1.25 (bs, 1H), 1.22-1.20 (m, 2H), 1.13-1.09 (m, 2H). MS m/z 538.1
(M + 1) 30-62 ##STR00329## .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.00 (bs, 1H), 7.54-7.50 (m, 2H), 7.01- 6.92 (m, 2H), 4.36
(bs, 2H), 4.02 (s, 3H), 3.57 (m, 1H), 2.17-2.15 (m, 3H), 1.98-1.96
(m, 4H), 1.82 (bs, 1H), 1.78 (bs, 1H), 1.25 (m, 1H), 1.21-1.20 (m,
2H), 1.12-1.09 (m, 2H). MS m/z 538.1 (M + 1). 30-63 ##STR00330## MS
m/z 482.2 (M + 1). 30-64 ##STR00331## .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.01 (d, J = 1.6Hz, 1H), 7.52 (d, J = 1.2Hz,
1H), 7.32-7.28 (m, 2H), 7.21-7.15 (m, 1H), 4.38 (bs, 3H), 4.02 (s,
3H), 3.58 (m, 1H), 2.17- 2.06 (m, 3H), 1.98-1.92 (m, 4H), 1.81 (bs,
1H), 1.78 (bs, 1H), 1.24- 1.20 (m, 2H), 1.14-1.09 (m, 2H). MS m/z
568.2 (M + 1). 30-65 ##STR00332## MS m/z 482.2 (M + 1). 30-66
##STR00333## .sup.1H NMR (400 MHz, DMSO) .delta. 7.67-7.60 (m, 1H),
7.43-7.34 (m, 2H), 6.75 (s, 1H), 4.41 (bs, 2H), 4.37 (bs, 2H), 3.51
(bs, 1H), 2.37- 2.30 (m, 4H), 1.83-1.80 (m, 1H), 1.75-1.70 (m, 6H),
1.63 (bs, 1H), 1.59 (bs, 1H), 1.16-1.11 (m, 2H), 1.09-1.05 (m, 2H).
MS m/z 497.2 (M + 1). 30-67 ##STR00334## .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.00 (d, J = 1.2Hz, 1H), 7.55-7.50 (m, 2H),
7.49-7.43 (m, 1H), 7.24-7.16 (m, 2H), 4.37 (bs, 2H), 4.34 (bs, 1H),
4.02 (s, 3H), 3.58 (m, 1H), 2.14-2.08 (m, 3H), 1.98-1.90 (m, 5H),
1.80 (bs, 1H), 1.77 (bs, 1H), 1.24-1.20 (m, 2H), 1.13-1.08 (m, 2H).
MS m/z 550.2 (M + 1). 30-68 ##STR00335## MS m/z 479.2 (M + 1).
30-69 ##STR00336## .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.82
(d, J = 2.4 Hz, 1H), 7.98 (dd, J = 9.2 and 2.4 Hz, 1H), 7.53 (dt, J
= 7.6 and 2.0 Hz, 1H), 7.48-7.42 (m, 1H), 7.23 (dd, J = 7.6 and 1.2
Hz, 1H), 7.20- 7.16 (m, 1H), 6.43 (d, J = 8.8 Hz, 1H), 4.36 (bs,
3H), 3.51 (m, 1H), 2.15-2.08 (m, 1H), 2.05-1.98 (m, 2H), 1.94-1.87
(m, 5H), 1.75 (bs, 1H), 1.71 (bs, 1H), 1.24-1.20 (m, 2H), 1.12-
1.07 (m, 2H). MS m/z 464.2 (M + 1). 30-70 ##STR00337## .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.32 (bs, 1H), 8.03-8.01 (m, 1H),
7.52- 7.50 (m, 1H), 7.43-7.41 (m, 2H), 7.36-7.34 (m, 1H), 4.27 (bs,
4H), 3.52 (m, 1H), 2.11-2.09 (m, 3H), 1.99-1.94 (m, 5H), 1.80 (bs,
1H), 1.76 (bs, 1H), 1.27-1.24 (m, 2H), 1.14-1.11 (m, 2H). MS m/z
570.1 and 572.1 (M + 1). 30-71 ##STR00338## .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.00 (d, J = 1.6 Hz, 1H), 7.51 (d, J = 1.6Hz,
1H), 7.43 (d, J = 1.6 Hz, 1H), 7.40 (bs, 1H), 7.36-7.32 (m, 1H),
4.33 (bs, 1H), 4.26 (s, 2H), 4.02 (s, 3H), 3.52 (m, 1H), 2.13- 2.04
(m, 3H), 1.96-1.89 (m, 5H), 1.78 (bs, 1H), 1.75 (bs, 1H), 1.27-
1.24 (m, 2H), 1.15-1.10 (m, 2H). MS m/z 600.1 and 602.1 (M + 1).
30-72 ##STR00339## .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.82
(d, J = 2.4 Hz, 1H), 7.98 (dd, J = 8.8 and 2.4 Hz, 1H), 7.42 (d, J
= 1.6 Hz, 1H), 7.40 (bs, 1H), 7.35-7.31 (m, 1H), 6.42 (d, J = 9.2
Hz, 1H), 4.25 (bs, 3H), 3.48 (m, 1H), 2.15-2.08 (m, 1H), 1.94-1.92
(m, 2H), 1.90- 1.86 (m, 5H), 1.73 (bs, 1H), 1.69 (bs, 1H),
1.27-1.24 (m, 2H), 1.14- 1.09 (m, 2H). MS m/z 514.2 and 5.16 (M +
1). 30-73 ##STR00340## MS m/z 515.2 (M + 1) 30-74 ##STR00341## MS
m/z 536.2 (M + 1) 30-75 ##STR00342## .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.75 (s, 1H), 7.53-7.46 (m, 2H), 7.38- 7.34 (m,
2H), 4.27 (s, 2H), 4.03 9bs, 1H), 3.44 (bs, 1H), 2.11-2.05 (m, 1H),
1.96-1.80 (m, 8H), 1.63 (bs, 1H), 1.60 (bs, 1H), 1.24-1.18 (m, 2H),
1.11 91.06 (m, 2H). MS m/z 536.1 (M + 1) 30-76 ##STR00343## MS m/z
520.1 (M + 1)
Example 31
##STR00344##
[1007] Ethyl
6-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)imidazo[1,2-b]pyridazine-2-carboxylate
(31-1.sup.a)
[1008] To a suspension of commercially available ethyl
6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (Il Farmaco, 1997,
52, 4, 213) (66 mg, 0.255 mmol) in NMP (2.5 mL) was added
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethoxy)phenyl)isoxazole (I-1) (120 mg, 0.29 mmol) and potassium
fluoride (51 mg, 0.88 mmol). The mixture was heated at 200.degree.
C. for 30 minutes under microwave irradiation. The mixture was
poured into water and extracted with ethyl acetate twice. The
combined organic layers were washed with brine, dried over sodium
sulfate, filtered and concentrated. The crude product was purified
using mass-triggered reverse phase HPLC using gradient of 40 to 60%
acetonitrile/water with 0.05% TFA as modifier to yield ethyl
6-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)imidazo[1,2-b]pyridazine-2-carboxylate
as TFA salt. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.17 (s,
1H), 7.67 (d, J=10.0 Hz, 1H), 7.54 (dd, J=7.6 and 2.0 Hz, 1H), 7.51
(dd, J=7.6 and 0.8 Hz, 1H), 7.40-7.37 (m, 2H), 6.72 (d, J=10.0 Hz,
1H), 4.43 (q, J=7.2 Hz, 4H), 4.32 (bs, 2H), 4.28 (bs, 2H), 3.48 (m,
1H), 2.14-2.07 (m, 1H), 2.05-1.86 (m, 6H), 1.69 (bs, 1H), 1.65 (bs,
1H), 1.42 (t, J=7.2 Hz, 3H), 1.25-1.20 (m, 2H), 1.13-1.08 (m, 2H).
MS m/z 598.2 (M+1).
[1009]
6-(3-((5-Cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)me-
thoxy)-8-azabicyclo[3.2.1]octan-8-yl)imidazo[1,2-b]pyridazine-2-carboxylic
acid (31-1B) was prepared from ethyl
6-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)imidazo[1,2-b]pyridazine-2-carboxylate
(31-A) using the analogous procedure as described for Example 1B.
MS m/z 570.1 (M+1).
[1010] Examples 31-2 through 31-6 were prepared from the
corresponding nortropine intermediates according to the procedures
described for Example 31-1.
TABLE-US-00031 Physical Data Ex MS (m/z), .sup.1H NMR 31-1
##STR00345## MS m/z 570.1 (M + 1). 31-2 ##STR00346## .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.19 (s, 1H), 7.81-7.79 (m, 2H),
7.63-7.59 (m, 2H), 7.54-7.44 (m, 1H), 6.80 (d, J = 10.0 Hz, 1H),
4.31 (bs, 2H), 4.19 (bs, 2H), 3.45 (m, 1H), 2.13-2.05 (m, 1H),
1.99-1.89 (m, 6H), 1.72 (bs, 1H), 1.69 (bs, 1H), 1.26-1.22 (m, 2H),
1.14-1.09 (m, 2H). MS m/z 554.2 (M + 1). 31-3 ##STR00347## MS m/z
570.2 (M + 1) 31-4 ##STR00348## MS m/z 554.2 (M + 1) 31-5
##STR00349## MS m/z 522.2 (M + 1) .sup.1H NMR (DMSO- d.sub.6, 400
MHz) .delta. 8.25 (s, 1H), 7.80 (d, J = 10.0 Hz, 1H), 7.69-7.62 (m,
1H), 7.34-7.28 (m, 2H), 7.11 (d, J = 10.0 Hz, 1H), 4.30 (app bs,
4H), 3.46 (t, J = 4.4 Hz, 1H), 2.38- 2.28 (m, 1H), 1.92-1.85 (m,
2H), 1.75-1.71 (m, 4H), 1.56 (d, J = 14.4 Hz, 2H), 1.15- 1.05 (m,
4H). 31-6 ##STR00350## MS m/z 518.2 (M + 1)
Example 32
##STR00351##
[1011] Ethyl
7-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-
-8-azabicyclo[3.2.1]octan-8-yl)imidazo[1,2-a]pyridine-3-carboxylate
(32-1A)
[1012] A sealable vessel was charged with ethyl
7-bromoimidazo[1,2-a]pyridine-3-carboxylate (67 mg, 0.25 mmol),
4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluor-
omethoxy)phenyl)isoxazole (I-1H) cesium carbonate (122 mg, 0.38
mmol), 1,4-dioxane (2 mL). The mixture was degassed (argon bubble,
10 min) and then tris(dibenzylideneacetone)dipalladium(0) (11 mg,
0.012 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (14
mg, 0.025 mmol) were added. The reaction flask was evacuated and
backfilled with Ar three successive times, and then heated to
120.degree. C. for 12 hours. The reaction mixture was cooled to RT,
diluted with ethyl acetate (8 mL) and filtered through a
CELITE.RTM. pad, the filtrate was washed with water (7 mL), dried
over magnesium sulfate, concentrated, and chromatographed on silica
using linear gradient, 0-100%, EtOAc in Hexanes) to give the
desired product as a waxy solid.
7-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)--
8-azabicyclo[3.2.1]octan-8-yl)imidazo[1,2-a]pyridine-3-carboxylic
acid (32-1)
[1013] The ethyl ester, (32-A) was dissolved in THF (1 mL), EtOH (1
mL) and treated with KOH solution (1 N, 0.6 mL, 0.6 mmoles) and
heated to 65.degree. C. for 1 hour followed by cooling to RT and
adjustment of the PH with HCl (1 N, 0.6 mL, 0.6 mmol) until PH 5.
At this time the reaction mixture was extracted with ethyl acetate
(3.times.5 mL) and the organic extracts were dried with magnesium
sulfate, concentrated in vacuo, and the residue purified by reverse
phase chromatography using acetonitrile and water that was TFA
modified (0.5%) to give the desired solid as its TFA-salt.
[1014] Example 32-2 was prepared from the corresponding nortropine
intermediate according to the procedures described for the
32-1.
TABLE-US-00032 Physical Data Ex MS (m/z), .sup.1H NMR 32-1
##STR00352## MS m/z 569.2 (M + 1); .sup.1H NMR (DMSO-d.sub.6, 400
MHz) .delta. 9.00 (d, J = 7.6 Hz, 1H), 8.44 (s, 1H), 7.72-7.62 (m,
2H), 7.58-7.52 (m, 2H), 7.17 (d, J = 8.0 Hz, 1H), 6.74 (s, 1H),
4.35 (app s, 4H), 3.54-3.39 (m, 1H), 2.39-2.31 (m, 1H), 1.85-1.82
(m, 6H), 1.68 (d, J = 14.4 Hz, 2H), 1.19-1.04 (m, 4H). 32-2
##STR00353## MS m/z 569.2 (M + 1)) .sup.1H NMR (DMSOd.sub.6, 400
MHz) .delta. 11.89 (s, 1H), 8.49 (d, J = 7.6 Hz, 1H), 8.09 (s, 1H),
7.60-7.52 (m, 4H), 6.89 (d, J = 2.4 Hz, 1H), 6.76 (dd, J = 7.6, 2.4
Hz, 1H), 4.32 (s, 2H), 4.18 (bs, 2H), 3.46 (t, J = 4.4 Hz, 1H),
2.37-2.29 (m, 1H), 1.91-1.80 (m, 6H), 1.62-1.58 (d, J = 14.4 Hz,
2H), 1.16-1.05 (m, 4H).
Example 33
[1015] The following examples were prepared according to the
procedures described in Kittelmann, M. et al., Adv. Synth. Catal.
2003, 345, 825-829.
TABLE-US-00033 Physical Data Ex MS (m/z), .sup.1H NMR 33-1
##STR00354## MS m/z 764.3 (M + 1); MS m/z 764.3 (M + 1); .sup.1H
NMR (DMSO d.sub.6, 600 MHz); .delta. 12.87 (br s, 1H), 8.31 (d, J =
1.2 Hz, 1H), 7.91 (app t, J = 8.0 Hz, 1H), 7.76 (app t, J = 8.0 Hz,
1H), 7.71 (d, J = 9.3 Hz, 1H), 7.61(d, J = 8.0 Hz, 1H), 5.58 (d, J
= 7.3 Hz, 1H), 4.25 (s, 4H), 3.83 (d, J = 8.7 Hz, 1H), 3.52 (app t,
J = 4.0 Hz, 1H), 3.43-3.31 (m, 4H), 2.36-2.32 (m, 1H), 1.96 (dt, J
= 14.0, 4.0 Hz, 2H), 1.85-1.73 (m, 6H), 1.18-1.04 (m, 4H). 33-2
##STR00355## MS m/z 780.2 (M + 1); 33-3 ##STR00356## MS m/z 706.3
(M + 1);
[1016] Assay Description
[1017] Human GST-FXR LBD Co-Activator Interaction Assay.
[1018] The FXR HTRF assay is a biochemical assay measuring the
interaction between FXR and a coactivator protein (SRC1). The
ligand-induced interaction with a coactivator protein is a critical
step in transcriptional activation by FXR. Thus, this is an assay
designed to measure FXR agonist activity of compounds.
[1019] Recombinant human Farnesoid X Receptor (FXR) ligand binding
domain (amino acids 193-472) fused to glutathione S-transferase
(GST) purified protein (GST-FXR LBD) was purchased (Invitrogen).
The ligand-dependent interaction between GST-FXR LBD and a peptide
derived from Steroid Receptor Coactivator-1 (SRC-1) was monitored
by Fluorescence Resonance Energy Transfer (FRET). GST-FXR LBD was
mixed with a biotin-labeled SRC-1 peptide
(Biotin-CPSSHSSLTERHKILHRLLQEG-SPS-CONH2 (SEQ ID NO: 1), American
Peptide) in assay buffer (50 mM Tris HCl, pH 7.4, 50 mM NaCl, 1 mM
TCEP and 0.2% bovine serum albumen) and plated in 384 black Proxi
plates (Greiner Bio-One). Test compounds (in DMSO solution) and
detection reagents (anti-GST-Cryptate labeled antibody and
Streptavidin-XL665 conjugate; CisBio) were added in assay buffer
containing 50 mM KF. Plates are incubated at room temperature in
the dark for 2.5 hours before reading on an Envision (PerkinElmer)
at 665 nm and 590 nm. The HTRF assay results were calculated from
the 665 nm/590 nm ratio (ratio=(A665 nm/A590 nm).times.10.sup.4)
and expressed in Delta F
%=(Ratiosample-Rationegative)/Rationegative.times.100.
[1020] A negative control (without Streptavidin-XL665) was run with
each assay and represented the background fluorescence. A reference
FXR agonist, GW4064, was included in each experiment as positive
control. The efficacy of each test compound was compared to that of
GW4064. At each concentration, the relative activity of the test
compound was expressed as Response
%=(R.sub.sample-R.sub.DMSO)/(R.sub.positive-R.sub.DMSO), where
R.sub.sample is the HTRF response (expressed in Delta F %) for the
test compound, R.sub.positive is the maximal response for GW4064 at
saturating concentrations, and R.sub.DMSO is the response for DMSO
control. The EC.sub.50 values were calculated using GraphPad Prism
(GraphPad Software) using non-linear regression curve fit
(log(agonist) vs. response variable slope (four parameters)).
[1021] Table 1 summarizes EC.sub.50 values for the compounds of the
invention in human GST-FXR LBD co-activator interaction assay.
TABLE-US-00034 FXR Co-activator Example interaction assay
(EC.sub.50, uM) 1-1A 0.014 1-1B 0.00019 1-2A 0.028 1-2B 0.00025
2-1B 0.00017 2-2B 0.003 3A 0.020 3B 0.00074 4 0.022 5-1 0.0076 5-2
0.0038 5-3 0.020 6-1A 0.063 6-1B 0.00067 6-2A 0.051 6-2B 0.00036
6-3A 0.012 6-3B 0.00027 6-4 0.00018 6-5A 0.0038 6-5B 0.0056 6-6A
0.014 6-6B 0.0003 6-7A 0.014 6-7B 0.00058 7B 0.016 8-1 0.004 8-2
0.0024 8-3 0.018 8-4 0.0089 8-5B 0.11 8-6B 0.10 8-7B 0.13 9-1 0.005
9-2 0.011 10B 0.098 11 0.030 12-1 0.025 12-2 0.040 12-3 0.04 13-1B
0.0013 13-2B 0.00053 13-3B 0.00067 14 0.035 15-1B 0.0006 15-2
0.0005 15-3 0.017 15-4 0.0008 16-1 0.0006 16-2 0.0004 16-3 0.0012
16-4 0.009 17A 0.032 17B 0.005 18-1 0.009 18-2B 0.007 18-3A 0.008
18-3B 0.004 18-4A 0.02 18-4B 0.01 18-5A 0.02 18-5B 0.003 18-6A 0.05
18-6B 0.005 18-7A 0.018 18-7B 0.002 18-8B 0.009 19-1A 0.18 19-1B
0.04 19-2A 0.08 19-2B 0.02 19-3A 0.09 19-3B 0.01 19-4A 0.07 19-4B
0.005 19-5A 0.20 19-5B 0.009 19-6A 0.05 19-6B 0.007 19-7A 0.01
19-7B 0.003 20A 0.17 20B 0.33 21-1A 0.30 21-1B 0.26 21-2A 0.12
21-2B 0.01 21-3A 0.18 21-3B 0.009 21-4A 0.25 21-4B 0.02 21-5A 0.11
21-5B 0.01 21-6A 0.06 21-6B 0.016 22-1A 0.53 22-1B 0.02 22-2A 0.06
22-2B 0.009 22-3 0.01 22-4A 0.02 22-4B 0.009 22-5 0.027 22-6A 0.056
22-6B 0.16 22-7A 0.01 22-7B 0.005 22-8 0.005 22-9A 1.03 22-9B 0.017
22-10A 0.36 22-10B 0.008 22-11A 0.11 22-11B 0.01 22-12 0.004 22-13A
0.08 22-13B 0.009 22-14A 0.07 22-14B 0.013 22-15A 0.13 22-15B 0.028
22-16A 0.16 22-16B 0.01 22-17A 0.065 22-17B 0.003 22-18A 0.043
22-18B 0.018 22-19 0.057 22-20 0.025 22-21 0.029 23A 0.006 23B
0.004 24-1A 0.04 24-1B 0.008 25-1A 0.028 25-1B 0.003 25-2A 0.42
25-2B 0.005 25-3A 0.08 25-3B 0.0009 25-4A 0.04 25-4B 0.002 25-5A
0.28 25-5B 0.001 25-6A 0.009 25-6B 0.003 26B 0.0003 27 0.002 28-1B
0.0006 28-2 0.016 28-3 0.0008 28-4 0.002 28-5 0.006 28-6 0.0017
28-7 0.021 28-8 0.0104 28-9 0.0003 28-10 0.0009 28-11 0.0013 28-12
0.0028 28-13 0.0074 28-14 0.0046 28-15 0.0034 28-16 0.063 28-17
0.0098 28-18 0.0082 28-19 0.0015 28-20 0.0012 28-21 0.0022 28-22
0.0002 28-23 0.0005 28-24 0.024 28-25 0.0011 28-26 0.0012 29-1
0.014 29-2 0.008 29-3 0.011 29-4 0.011 29-5 0.006 29-6 0.002 29-7
0.005 30-1 0.0003 30-2 0.010 30-3 0.015 30-4 0.0007 30-5 0.0004
30-6 0.042 30-7 0.018 30-8 0.021 30-9 0.34 30-10 0.48 30-11 0.0003
30-12 0.005 30-13 0.006 30-14 0.0012 30-15 0.009 30-16 0.024 30-17
0.0007 30-18 0.006 30-19 0.023 30-20 0.00074 30-21 0.003 30-22
0.019 30-23 0.0004 30-24 0.004 30-25 0.003 30-26 0.007 30-27 0.007
30-28 0.012 30-29 0.0005 30-30 0.120 30-31 0.007 30-32 0.149 30-33
0.0007 30-34 0.0018 30-35 0.046 30-36 0.0011 30-37 0.14 30-38
0.0018 30-39 0.036 30-40 0.0007 30-41 0.004 30-42 0.003 30-43
0.0046 30-44 0.008 30-45 0.018 30-46 0.22 30-47 0.12 30-48 0.034
30-49 0.14 30-50 0.70 30-51 0.052 30-52 0.026 30-53 0.001 30-54
0.016 30-55 0.001 30-56 0.0057 30-57 0.032 30-58 0.21 30-59 0.092
30-60 0.094 30-61 0.002 30-62 0.0006 30-63 0.057 30-64 0.007
30-65 0.086 30-66 0.22 30-67 0.0005 30-68 0.013 30-69 0.021 30-70
0.0002 30-71 0.0003 30-72 0.0014 30-73 0.074 30-74 0.003 30-75
0.017 30-76 0.016 31-1 0.012 31-2 0.013 31-3 0.002 31-4 0.004 31-5
0.010 31-6 0.009 32-1 0.003 32-2 0.004
[1022] It is understood that the examples and embodiments described
herein are for illustrative purposes only and that various
modifications or changes in light thereof will be suggested to
persons skilled in the art and are to be included within the spirit
and purview of this application and scope of the appended claims.
All publications, patents, and patent applications cited herein are
hereby incorporated by reference for all purposes.
Sequence CWU 1
1
1125PRTArtificial Sequencepeptide derived from Steroid Receptor
Coactivator-1 1Cys Pro Ser Ser His Ser Ser Leu Thr Glu Arg His Lys
Ile Leu His 1 5 10 15 Arg Leu Leu Gln Glu Gly Ser Pro Ser 20 25
* * * * *