U.S. patent application number 15/012954 was filed with the patent office on 2016-08-04 for novel cyclopropabenzofuranyl pyridopyrazinediones.
The applicant listed for this patent is Pfizer Inc.. Invention is credited to Christopher William am Ende, Douglas Scott Johnson, Gregory Wayne Kauffman, Martin Youngjin Pettersson, Antonia Friederike Stepan, Patrick Robert Verhoest.
Application Number | 20160222007 15/012954 |
Document ID | / |
Family ID | 55299692 |
Filed Date | 2016-08-04 |
United States Patent
Application |
20160222007 |
Kind Code |
A1 |
Pettersson; Martin Youngjin ;
et al. |
August 4, 2016 |
Novel Cyclopropabenzofuranyl Pyridopyrazinediones
Abstract
Compounds and pharmaceutically acceptable salts of the compounds
are disclosed, wherein the compounds have the structure of Formula
I ##STR00001## wherein X, R.sup.1, R.sup.2a, R.sup.2b, R.sup.4a,
R.sup.4b, R.sup.5a, R.sup.5b, R.sup.6, R.sup.7, R.sup.10, R.sup.11,
and y are as defined in the specification. Corresponding
pharmaceutical compositions, methods of treatment, methods of
synthesis, and intermediates are also disclosed.
Inventors: |
Pettersson; Martin Youngjin;
(Littleton, MA) ; am Ende; Christopher William;
(Mystic, CT) ; Johnson; Douglas Scott; (Concord,
MA) ; Kauffman; Gregory Wayne; (East Greenwich,
RI) ; Stepan; Antonia Friederike; (Brookline, MA)
; Verhoest; Patrick Robert; (Newton, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Pfizer Inc. |
New York |
NY |
US |
|
|
Family ID: |
55299692 |
Appl. No.: |
15/012954 |
Filed: |
February 2, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62111222 |
Feb 3, 2015 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 471/04 20130101;
A61P 25/28 20180101; A61K 31/4985 20130101 |
International
Class: |
C07D 471/04 20060101
C07D471/04 |
Claims
1. A compound having the structure of Formula I: ##STR00039## or
pharmaceutically acceptable salts thereof, wherein: X is a (5- to
14-membered)heteroaryl containing 1-3 heteroatoms; R.sup.1, where
chemically permissible, is selected from the group consisting of
hydrogen, halogen, cyano, hydroxy, oxo, --SF.sub.5, nitro,
optionally substituted (C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.3-C.sub.8)cycloalkyl, --N(R.sup.4)(R.sup.5),
--N(R.sup.4)(C.dbd.(O)R.sup.5), --C(.dbd.O)N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4, and
--C(.dbd.O)--OR.sup.4; R.sup.2a and R.sup.2b, where chemically
permissible, at each occurrence, are independently selected from
the group consisting of hydrogen, halogen, cyano, hydroxy,
--SF.sub.5, nitro, optionally substituted (C.sub.1-C.sub.6)alkyl,
optionally substituted (C.sub.2-C.sub.6)alkenyl, optionally
substituted (C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.3-C.sub.8)cycloalkyl, optionally substituted
phenyl, --N(R.sup.4)(R.sup.5), --N(R.sup.4)(C.dbd.(O)R.sup.5),
--C(.dbd.O)N(R.sup.4)(R.sup.5), --O--C(.dbd.O)N(R.sup.4)(R.sup.5),
--C(.dbd.O)--R.sup.4, and --C(.dbd.O)--OR.sup.4; or R.sup.2a and
R.sup.2b together with the carbon atom(s) to which they are
attached form a (C.sub.3-C.sub.8)cycloalkyl or a (4- to
10-membered)heterocycloalkyl, wherein the
(C.sub.3-C.sub.8)cycloalkyl and the (4- to
10-membered)heterocycloalkyl are optionally substituted with one to
three R.sup.8; R.sup.4a and R.sup.4b, where chemically permissible,
are each independently selected from the group consisting of
hydrogen, halogen, cyano, hydroxy, oxo, --SF.sub.5, nitro,
optionally substituted (C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.3-C.sub.8)cycloalkyl, optionally substituted
phenyl, --N(R.sup.4)(R.sup.5), --N(R.sup.4)(C.dbd.(O)R.sup.5),
--C(.dbd.O)N(R.sup.4)(R.sup.5), --O--C(.dbd.O)N(R.sup.4)(R.sup.5),
--C(.dbd.O)--R.sup.4, and --C(.dbd.O)--OR.sup.4; or R.sup.4a and
R.sup.4b together with the carbon atom to which they are attached
form a (C.sub.3-C.sub.8)cycloalkyl, wherein the
(C.sub.3-C.sub.8)cycloalkyl is optionally substituted with one to
three R.sup.8; R.sup.5a and R.sup.5b, at each occurrence, are
independently selected from the group consisting of hydrogen,
halogen, cyano, hydroxy, oxo, --SF.sub.5, nitro, optionally
substituted (C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.3-C.sub.8)cycloalkyl, optionally substituted
phenyl, --N(R.sup.4)(R.sup.5), --N(R.sup.4)(C.dbd.(O)R.sup.5),
--C(.dbd.O)N(R.sup.4)(R.sup.5), --O--C(.dbd.O)N(R.sup.4)(R.sup.5),
--C(.dbd.O)--R.sup.4, and --C(.dbd.O)--OR.sup.4; or R.sup.5a and
R.sup.5b together with the carbon atom to which they are attached
form a (C.sub.3-C.sub.8)cycloalkyl, wherein said
(C.sub.3-C.sub.8)cycloalkyl is optionally substituted with one to
three R.sup.8; R.sup.6 and R.sup.7 are each independently selected
from the group consisting of hydrogen, halogen, cyano, --SF.sub.5,
nitro, optionally substituted (C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.3-C.sub.8)cycloalkyl, optionally substituted
phenyl, --N(R.sup.4)(R.sup.5), --N(R.sup.4)(C.dbd.(O)R.sup.5),
--C(.dbd.O)N(R.sup.4)(R.sup.5), --O--C(.dbd.O)N(R.sup.4)(R.sup.5),
--C(.dbd.O)--R.sup.4, --C(.dbd.O)--OR.sup.4, and --OR.sup.9;
provided that R.sup.6 and R.sup.7 cannot both be hydroxy; R.sup.8,
at each occurrence, is independently selected from the group
consisting of cyano, halogen, hydroxy, --SF.sub.5, nitro,
optionally substituted (C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.1-C.sub.6)alkoxy, and optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl; R.sup.9 is selected
from the group consisting of hydrogen and optionally substituted
(C.sub.1-C.sub.6)alkyl; y is an integer selected from 1, 2, 3 or 4;
ring B is optionally substituted with one to three R.sup.10,
wherein each R.sup.10 is independently selected from the group
consisting of halogen, cyano, hydroxy, --SF.sub.5, nitro,
optionally substituted (C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.3-C.sub.8)cycloalkyl, --N(R.sup.4)(R.sup.5),
--N(R.sup.4)(C.dbd.(O)R.sup.5), --C(.dbd.O)N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4, and
--C(.dbd.O)--OR.sup.4; or two R.sup.10 substituents taken together
with the carbon atom(s) to which they are attached form an
optionally substituted (C.sub.3-C.sub.8)cycloalkyl; ring D is
optionally substituted with one to four R.sup.11, wherein each
R.sup.11 is independently selected from the group consisting of
halogen, cyano, hydroxy, --SF.sub.5, nitro, optionally substituted
(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.3-C.sub.8)cycloalkyl, optionally substituted (4- to
6-membered)heterocycloalkyl; --N(R.sup.4)(R.sup.5),
--N(R.sup.4)(C.dbd.(O)R.sup.5), --C(.dbd.O)N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4,
--C(.dbd.O)--OR.sup.4; and R.sup.4 and R.sup.5, at each occurrence,
are each independently selected from hydrogen or optionally
substituted (C.sub.1-C.sub.6)alkyl; provided that the compound is
not
7-(4-methyl-1H-imidazol-1-yl)-2-{[5-(trifluoromethyl)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazin-
e-1,6-dione.
2. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein X is represented by: Xi) a (5- to
6-membered)heteroaryl containing 1-3 heteroatoms; Xii) a
(6-membered)heteroaryl containing 1-3 heteroatoms; or Xiii) a
(5-membered)heteroaryl containing 1-3 heteroatoms.
3. The compound according to claim 2, or a pharmaceutically
acceptable salt thereof, wherein X is a (5-membered)heteroaryl
selected from the group consisting of triazolyl, imidazolyl,
furanyl, thiophenyl, pyrazolyl, isothiazolyl, thiazolyl,
isoxazolyl, and oxazolyl.
4. The compound according to claim 3, or a pharmaceutically
acceptable salt thereof, wherein X is imidazolyl.
5. The compound according to claim 3, or a pharmaceutically
acceptable salt thereof, wherein X is triazolyl.
6. The compound according to claim 5, or a pharmaceutically
acceptable salt thereof, wherein: R.sup.1, where chemically
permissible, is selected from the group consisting of hydrogen,
halogen, cyano, hydroxy, oxo, --SF.sub.5, nitro, optionally
substituted (C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.3-C.sub.8)cycloalkyl, --N(R.sup.4)(R.sup.5),
--N(R.sup.4)(C.dbd.(O)R.sup.5), --C(.dbd.O)N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4, and
--C(.dbd.O)--OR.sup.4; R.sup.2a and R.sup.2b, where chemically
permissible, at each occurrence, are independently selected from
the group consisting of hydrogen, halogen, cyano, hydroxy,
--SF.sub.5, nitro, optionally substituted (C.sub.1-C.sub.6)alkyl,
optionally substituted (C.sub.2-C.sub.6)alkenyl, optionally
substituted (C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.3-C.sub.8)cycloalkyl, optionally substituted
phenyl, --N(R.sup.4)(R.sup.5), --N(R.sup.4)(C.dbd.(O)R.sup.5),
--C(.dbd.O)N(R.sup.4)(R.sup.5), --O--C(.dbd.O)N(R.sup.4)(R.sup.5),
--C(.dbd.O)--R.sup.4, and --C(.dbd.O)--OR.sup.4; or R.sup.2a and
R.sup.2b together with the carbon atom(s) to which they are
attached form a (C.sub.3-C.sub.8)cycloalkyl or a (4- to
10-membered)heterocycloalkyl, wherein the
(C.sub.3-C.sub.8)cycloalkyl and the (4- to
10-membered)heterocycloalkyl are optionally substituted with one to
three R.sup.8; R.sup.4a and R.sup.4b, where chemically permissible,
are each independently selected from the group consisting of
hydrogen, halogen, cyano, hydroxy, oxo, --SF.sub.5, nitro,
optionally substituted (C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.3-C.sub.8)cycloalkyl, optionally substituted
phenyl, --N(R.sup.4)(R.sup.5), --N(R.sup.4)(C.dbd.(O)R.sup.5),
--C(.dbd.O)N(R.sup.4)(R.sup.5), --O--C(.dbd.O)N(R.sup.4)(R.sup.5),
--C(.dbd.O)--R.sup.4, and --C(.dbd.O)--OR.sup.4; or R.sup.4a and
R.sup.4b together with the carbon atom to which they are attached
form a (C.sub.3-C.sub.8)cycloalkyl, wherein the
(C.sub.3-C.sub.8)cycloalkyl is optionally substituted with one to
three R.sup.8; R.sup.5a and R.sup.5b, at each occurrence, are
independently selected from the group consisting of hydrogen,
halogen, cyano, hydroxy, oxo, --SF.sub.5, nitro, optionally
substituted (C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.3-C.sub.8)cycloalkyl, optionally substituted
phenyl, --N(R.sup.4)(R.sup.5), --N(R.sup.4)(C.dbd.(O)R.sup.5),
--C(.dbd.O)N(R.sup.4)(R.sup.5), --O--C(.dbd.O)N(R.sup.4)(R.sup.5),
--C(.dbd.O)--R.sup.4, and --C(.dbd.O)--OR.sup.4; or R.sup.5a and
R.sup.5b together with the carbon atom to which they are attached
form a (C.sub.3-C.sub.8)cycloalkyl, wherein said
(C.sub.3-C.sub.8)cycloalkyl is optionally substituted with one to
three R.sup.8; R.sup.6 and R.sup.7 are each independently selected
from the group consisting of hydrogen, halogen, cyano, --SF.sub.5,
nitro, optionally substituted (C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.3-C.sub.8)cycloalkyl, optionally substituted
phenyl, --N(R.sup.4)(R.sup.5), --N(R.sup.4)(C.dbd.(O)R.sup.5),
--C(.dbd.O)N(R.sup.4)(R.sup.5), --O--C(.dbd.O)N(R.sup.4)(R.sup.5),
--C(.dbd.O)--R.sup.4, --C(.dbd.O)--OR.sup.4, and --OR.sup.9;
provided that R.sup.6 and R.sup.7 cannot both be hydroxy; R.sup.8,
at each occurrence, is independently selected from the group
consisting of cyano, halogen, hydroxy, --SF.sub.5, nitro,
optionally substituted (C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.1-C.sub.6)alkoxy, and optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl; R.sup.9 is selected
from the group consisting of hydrogen and optionally substituted
(C.sub.1-C.sub.6)alkyl; y is an integer selected from 1, 2, 3 or 4;
ring B is optionally substituted with one to three R.sup.10,
wherein each R.sup.10 is independently selected from the group
consisting of halogen, cyano, hydroxy, --SF.sub.5, nitro,
optionally substituted (C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.3-C.sub.8)cycloalkyl, --N(R.sup.4)(R.sup.5),
--N(R.sup.4)(C.dbd.(O)R.sup.5), --C(.dbd.O)N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4,
--C(.dbd.O)--OR.sup.4; or two R.sup.10 substituents taken together
with the carbon atom(s) to which they are attached form an
optionally substituted (C.sub.3-C.sub.8)cycloalkyl; ring D is
optionally substituted with one to four R.sup.11, wherein each
R.sup.11 is independently selected from the group consisting of
halogen, cyano, hydroxy, --SF.sub.5, nitro, optionally substituted
(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.3-C.sub.8)cycloalkyl, optionally substituted (4- to
6-membered)heterocycloalkyl; --N(R.sup.4)(R.sup.5),
--N(R.sup.4)(C.dbd.(O)R.sup.5), --C(.dbd.O)N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4,
--C(.dbd.O)--OR.sup.4; and R.sup.4 and R.sup.5, at each occurrence,
are each independently selected from hydrogen or optionally
substituted (C.sub.1-C.sub.6)alkyl.
7. The compound according to claim 3, or a pharmaceutically
acceptable salt thereof, wherein: R.sup.1 is selected from the
group consisting of hydrogen, halogen, cyano, hydroxy, optionally
substituted (C.sub.1-C.sub.6)alkyl, and optionally substituted
(C.sub.1-C.sub.6)alkoxy; wherein the (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)alkoxy are optionally substituted with one to
three substituents selected from halogen, oxo, cyano, hydroxy, or
--SF.sub.5; R.sup.2a and R.sup.2b are each independently selected
from hydrogen, halogen, cyano, hydroxy or optionally substituted
(C.sub.1-C.sub.6)alkyl; R.sup.4a, R.sup.4b, R.sup.5a and R.sup.5b
are each independently selected from the group consisting of
hydrogen, halogen, cyano, hydroxy, oxo, --SF.sub.5, optionally
substituted (C.sub.1-C.sub.6)alkyl, and optionally substituted
(C.sub.1-C.sub.6)alkoxy, wherein the (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)alkoxy are optionally substituted with one to
three substituents selected from halogen, oxo, cyano, hydroxy, or
--SF.sub.5; R.sup.6 and R.sup.7 are each independently selected
from the group consisting of hydrogen, cyano, halogen, --SF.sub.5,
optionally substituted (C.sub.1-C.sub.6)alkyl, and optionally
substituted (C.sub.1-C.sub.6)alkoxy, wherein the
(C.sub.1-C.sub.6)alkyl and (C.sub.1-C.sub.6)alkoxy are optionally
substituted with one to three substituents selected from halogen,
oxo, cyano, hydroxy, or --SF.sub.5; y is 1; ring B is optionally
substituted with one to two R.sup.10, wherein each R.sup.10 is
independently selected from halogen, cyano, hydroxy, --SF.sub.5,
optionally substituted (C.sub.1-C.sub.6)alkyl, and optionally
substituted (C.sub.1-C.sub.6)alkoxy, wherein the
(C.sub.1-C.sub.6)alkyl and (C.sub.1-C.sub.6)alkoxy are optionally
substituted with one to three substituents selected from halogen,
oxo, cyano, hydroxy, or --SF.sub.5; and ring D is optionally
substituted with one to three R.sup.11, wherein each R.sup.11 is
independently selected from the group consisting of halogen, cyano,
hydroxy, optionally substituted (C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.1-C.sub.6)alkoxy, --SF.sub.5,
--N(R.sup.4)(R.sup.5), nitro, and optionally substituted
(C.sub.3-C.sub.8)cycloalkyl, wherein the (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, and (C.sub.3-C.sub.8)cycloalkyl are
optionally substituted with one to three substituents independently
selected from halogen, cyano, hydroxy, --SF.sub.5, and optionally
substituted (C.sub.1-C.sub.6)alkyl, wherein R.sup.4 and R.sup.5 are
each independently selected from hydrogen or optionally substituted
(C.sub.1-C.sub.6)alkyl.
8. The compound according to claim 7, or a pharmaceutically
acceptable salt thereof, wherein: R.sup.1 is an optionally
substituted (C.sub.1-C.sub.6)alkyl, wherein the
(C.sub.1-C.sub.6)alkyl is substituted with one to three
substituents selected from halogen, oxo, cyano, hydroxy, or
--SF.sub.5; and R.sup.2a, R.sup.2b, R.sup.4a, R.sup.4b, R.sup.5a
and R.sup.5b are each independently i) hydrogen; or ii) optionally
substituted (C.sub.1-C.sub.6)alkyl, wherein the
(C.sub.1-C.sub.6)alkyl is substituted with one to three
substituents selected from halogen, oxo, cyano, hydroxy, or
--SF.sub.5.
9. The compound according to claim 8, or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is methyl; and R.sup.2a,
R.sup.2b, R.sup.4a, R.sup.4b, R.sup.5a and R.sup.5b are each
independently hydrogen.
10. The compound according to claim 8, or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is methyl; R.sup.2a,
R.sup.2b, R.sup.5a and R.sup.5b are each independently hydrogen;
and one of R.sup.4a and R.sup.4b is hydrogen and the other is
methyl.
11. The compound according to claim 8, or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is methyl; one of R.sup.2a
and R.sup.2b is hydrogen and the other is methyl; R.sup.4a,
R.sup.4b, R.sup.5a and R.sup.5b are each independently
hydrogen.
12. A compound having the structure of Formula II: ##STR00040## or
a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is
selected from the group consisting of hydrogen, halogen, cyano,
hydroxy, optionally substituted (C.sub.1-C.sub.6)alkyl, and
optionally substituted (C.sub.1-C.sub.6)alkoxy; wherein the
(C.sub.1-C.sub.6)alkyl and (C.sub.1-C.sub.6)alkoxy are optionally
substituted with one to three substituents selected from halogen,
oxo, cyano, hydroxy, or --SF.sub.5; R.sup.2a, R.sup.2b, R.sup.4a,
R.sup.4b, R.sup.5a and R.sup.5b are each independently selected
from hydrogen, halogen, cyano, hydroxy or optionally substituted
(C.sub.1-C.sub.6)alkyl; ring B is optionally substituted with one
to two R.sup.10, wherein each R.sup.10 is independently selected
from halogen or optionally substituted (C.sub.1-C.sub.6)alkyl; and
ring D is optionally substituted with one to three R.sup.11,
wherein each R.sup.11 is independently selected from halogen,
optionally substituted (C.sub.1-C.sub.6)alkyl, and optionally
substituted (C.sub.1-C.sub.6)alkoxy; provided that the compound is
not
7-(4-methyl-1H-imidazol-1-yl)-2-{[5-(trifluoromethyl)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazin-
e-1,6-dione.
13. The compound according to claim 12, wherein: R.sup.1 is
selected from the group consisting of hydrogen, halogen, cyano,
hydroxy, (C.sub.1-C.sub.6)alkyl, and (C.sub.1-C.sub.6)alkoxy;
wherein the (C.sub.1-C.sub.6)alkyl and (C.sub.1-C.sub.6)alkoxy are
optionally substituted with one to three fluoro atoms; R.sup.2a,
R.sup.2b, R.sup.4a, R.sup.4b, R.sup.5a and R.sup.5b are each
independently selected from hydrogen or (C.sub.1-C.sub.6)alkyl,
wherein the (C.sub.1-C.sub.6)alkyl is methyl; ring B is optionally
substituted with one to two R.sup.10, wherein each R.sup.10 is
selected from: i) halogen selected from fluoro or chloro, or ii)
(C.sub.1-C.sub.6)alkyl, wherein the (C.sub.1-C.sub.6)alkyl is
methyl; and ring D is optionally substituted with one to three
R.sup.11, wherein each R.sup.11 is selected from: i) halogen
selected from fluoro or chloro; ii) optionally substituted
(C.sub.1-C.sub.6)alkyl selected from the group consisting of
fluoromethyl, difluoromethyl, and trifluoromethyl; and iii)
optionally substituted (C.sub.1-C.sub.6)alkoxy, wherein the
optionally substituted (C.sub.1-C.sub.6)alkoxy is selected from the
group consisting of fluoromethoxy, difluoromethoxy,
trifluoromethoxy.
14. The compound according to claim 12, wherein R.sup.1 is a
(C.sub.1-C.sub.6)alkyl wherein the alkyl is methyl.
15. A compound having the structure of Formula III: ##STR00041## or
a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is
selected from the group consisting of hydrogen, halogen, cyano,
hydroxy, optionally substituted (C.sub.1-C.sub.6)alkyl, and
optionally substituted (C.sub.1-C.sub.6)alkoxy; wherein the
(C.sub.1-C.sub.6)alkyl and (C.sub.1-C.sub.6)alkoxy are optionally
substituted with one to three substituents selected from halogen,
oxo, cyano, hydroxy, or --SF.sub.5; R.sup.2a, R.sup.2b, R.sup.4a,
R.sup.4b, R.sup.5a and R.sup.5b are each independently selected
from hydrogen, halogen, cyano, hydroxy or optionally substituted
(C.sub.1-C.sub.6)alkyl; ring B is optionally substituted with one
to two R.sup.10, wherein each R.sup.10 is independently selected
from halogen or optionally substituted (C.sub.1-C.sub.6)alkyl; and
ring D is optionally substituted with one to three R.sup.11,
wherein each R.sup.11 is independently selected from halogen,
optionally substituted (C.sub.1-C.sub.6)alkyl, and optionally
substituted (C.sub.1-C.sub.6)alkoxy.
16. The compound according to claim 15, wherein: R.sup.1 is
selected from the group consisting of hydrogen, halogen, cyano,
hydroxy, (C.sub.1-C.sub.6)alkyl, and (C.sub.1-C.sub.6)alkoxy;
wherein the (C.sub.1-C.sub.6)alkyl and (C.sub.1-C.sub.6)alkoxy are
optionally substituted with one to three fluoro atoms; R.sup.2a,
R.sup.2b, R.sup.4a, R.sup.4b, R.sup.5a and R.sup.5b are each
independently selected from hydrogen or (C.sub.1-C.sub.6)alkyl,
wherein the (C.sub.1-C.sub.6)alkyl is methyl; ring B is optionally
substituted with one to two R.sup.10, wherein each R.sup.10 is
selected from: i) halogen selected from fluoro or chloro, or ii)
(C.sub.1-C.sub.6)alkyl, wherein the (C.sub.1-C.sub.6)alkyl is
methyl; and ring D is optionally substituted with one to three
R.sup.11, wherein each R.sup.11 is selected from: i) halogen
selected from fluoro or chloro; ii) optionally substituted
(C.sub.1-C.sub.6)alkyl selected from the group consisting of
fluoromethyl, difluoromethyl, and trifluoromethyl; and iii)
optionally substituted (C.sub.1-C.sub.6)alkoxy, wherein the
optionally substituted (C.sub.1-C.sub.6)alkoxy is selected from the
group consisting of fluoromethoxy, difluoromethoxy, and
trifluoromethoxy.
17. A compound selected from the group consisting of:
7-(4-methyl-1H-imidazol-1-yl)-2-{[1a-methyl-5-(trifluoromethoxy)-1,1a-dih-
ydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,-
2-a]pyrazine-1,6-dione;
7-(4-methyl-1H-imidazol-1-yl)-2-{[(1aS,6bS)-1a-methyl-5-(trifluoromethoxy-
)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-
-pyrido[1,2-a]pyrazine-1,6-dione;
7-(4-methyl-1H-imidazol-1-yl)-2-{[(1aR,6bR)-1a-methyl-5-(trifluoromethoxy-
)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-
-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[3-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b-
][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aS,6bS)-3-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aR,6bR)-3-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b-
][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aS,6bS)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aR,6bR)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b-
][1]benzofuran-6b-yl]methyl}-7-(3-methyl-1H-1,2,4-triazol-1-yl)-3,4-dihydr-
o-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aS,6bS)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(3-methyl-1H-1,2,4-triazol-1-yl)--
3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aR,6bR)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(3-methyl-1H-1,2,4-triazol-1-yl)--
3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aS,6bS)-4-chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aR,6bR)-4-chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aS,6bS)-5-(difluoromethoxy)-4-fluoro-1a-methyl-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aR,6bR)-5-(difluoromethoxy)-4-fluoro-1a-methyl-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aS,6bS)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-[4-(hydroxymethyl)-1H-imidazol-1--
yl]-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
7-(4-methyl-1H-imidazol-1-yl)-2-{[(1aS,6bS)-1a-methyl-5-(trifluoromethyl)-
-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,6-dione;
7-(4-methyl-1H-imidazol-1-yl)-2-{[(1aR,6bR)-1a-methyl-5-(trifluoromethyl)-
-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aS,6bS)-4-fluoro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aR,6bR)-4-fluoro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aS,6bS)-3-fluoro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aR,6bR)-3-fluoro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aS,6bS)-3-chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aR,6bR)-3-chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione; or the pharmaceutically
acceptable salts thereof.
18.
2-{[(1aS,6bS)-4-Fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6b-
H-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3-
,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a
pharmaceutically acceptable salt thereof.
19.
2-{[(1aR,6bR)-4-Fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6b-
H-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3-
,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a
pharmaceutically acceptable salt thereof.
20.
2-{[(1aS,6bS)-3-Fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6b-
H-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3-
,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a
pharmaceutically acceptable salt thereof.
21. 2-{[(1aR,6bR)-3-Fluoro-1a-methyl-5-(trifluoromethoxy)-1,
1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-im-
idazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a
pharmaceutically acceptable salt thereof.
22.
2-{[(1aS,6bS)-4-Chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-
-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,-
4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically
acceptable salt thereof.
23.
2-{[(1aR,6bR)-4-Chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-
-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,-
4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically
acceptable salt thereof.
24.
2-(((1aS,6bS)-4-fluoro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-
-cyclopropa[b]benzofuran-6b-yl)methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically
acceptable salt thereof.
25.
2-(((1aR,6bR)-4-fluoro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-
-cyclopropa[b]benzofuran-6b-yl)methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically
acceptable salt thereof.
26.
2-(((1aS,6bS)-3-fluoro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-
-cyclopropa[b]benzofuran-6b-yl)methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically
acceptable salt thereof.
27.
2-(((1aR,6bR)-3-fluoro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-
-cyclopropa[b]benzofuran-6b-yl)methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically
acceptable salt thereof.
28. A method for reducing the production of amyloid beta (A.beta.)
peptides, in a subject in need thereof, the method comprising
administering to said subject a therapeutically effective amount of
a compound according to claim 1, or a pharmaceutically acceptable
salt thereof.
29. A method for reducing the production of amyloid beta A.beta.42
peptide, in a subject in need thereof, the method comprising
administering to said subject a therapeutically effective amount of
a compound according to claim 1, or a pharmaceutically acceptable
salt thereof.
30. A method of modulating the gamma-secretase complex in a subject
in need thereof, the method comprising administering to said
subject a therapeutically effective amount of a compound according
to claim 1 or a pharmaceutically acceptable salt thereof.
31. A method for treating Alzheimer's disease in a subject in need
thereof, the method comprising administering to a subject a
therapeutically effective amount of a compound according to claim
1, or a pharmaceutically acceptable salt thereof.
32. A pharmaceutical composition comprising a compound of claim 1,
or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable excipient.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to novel
cyclopropabenzofuranyl pyridopyrazinedione compounds of Formula I
useful for the treatment of neurodegenerative and/or neurological
disorders, such as Alzheimer's disease, etc.
BACKGROUND OF THE INVENTION
[0002] Dementia results from a wide variety of distinctive
pathological processes. The most common pathological processes
causing dementia are Alzheimer's disease (AD), cerebral amyloid
angiopathy (CM) and prion-mediated diseases (see, e.g., Haan et
al., Clin. Neurol. Neurosurg. 1990, 92(4):305-310; Glenner et al.,
J. Neurol. Sci. 1989, 94:1-28). AD affects nearly half of all
people past the age of 85, the most rapidly growing portion of the
United States population. As such, the number of AD patients in the
United States is expected to increase from about 4 million to about
14 million by 2050.
[0003] The present invention relates to a group of
.gamma.-secretase modulators, useful for the treatment of
neurodegenerative and/or neurological disorders such as Alzheimer's
disease and Down's syndrome. (see Ann. Rep. Med. Chem. 2007, Olsen
et al., 42: 27-47).
SUMMARY OF THE INVENTION
[0004] The present invention is directed to .gamma.-secretase
modulators as described by Formula I:
##STR00002##
or pharmaceutically acceptable salts thereof, wherein:
[0005] X is a (5- to 14-membered)heteroaryl containing 1-3
heteroatoms;
[0006] R.sup.1, where chemically permissible, is selected from the
group consisting of hydrogen, halogen, cyano, hydroxy, oxo,
--SF.sub.5, nitro, optionally substituted (C.sub.1-C.sub.6)alkyl,
optionally substituted (C.sub.2-C.sub.6)alkenyl, optionally
substituted (C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.3-C.sub.8)cycloalkyl, --N(R.sup.4)(R.sup.5),
--N(R.sup.4)(C.dbd.(O)R.sup.5), --C(.dbd.O)N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4, and
--C(.dbd.O)--OR.sup.4;
[0007] R.sup.2a and R.sup.2b, where chemically permissible, at each
occurrence, are independently selected from the group consisting of
hydrogen, halogen, cyano, hydroxy, --SF.sub.5, nitro, optionally
substituted (C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.3-C.sub.8)cycloalkyl, optionally substituted
phenyl, --N(R.sup.4)(R.sup.5), --N(R.sup.4)(C.dbd.(O)R.sup.5),
--C(.dbd.O)N(R.sup.4)(R.sup.5), --O--C(.dbd.O)N(R.sup.4)(R.sup.5),
--C(.dbd.O)--R.sup.4, and --C(.dbd.O)--OR.sup.4; or R.sup.2a and
R.sup.2b together with the carbon atom(s) to which they are
attached form a (C.sub.3-C.sub.8)cycloalkyl or a (4- to
10-membered)heterocycloalkyl, wherein the
(C.sub.3-C.sub.8)cycloalkyl and the (4- to
10-membered)heterocycloalkyl are optionally substituted with one to
three R.sup.8;
[0008] R.sup.4a and R.sup.4b, where chemically permissible, are
each independently selected from the group consisting of hydrogen,
halogen, cyano, hydroxy, oxo, --SF.sub.5, nitro, optionally
substituted (C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.3-C.sub.8)cycloalkyl, optionally substituted
phenyl, --N(R.sup.4)(R.sup.5), --N(R.sup.4)(C.dbd.(O)R.sup.5),
--C(.dbd.O)N(R.sup.4)(R.sup.5), --O--C(.dbd.O)N(R.sup.4)(R.sup.5),
--C(.dbd.O)--R.sup.4, and --C(.dbd.O)--OR.sup.4; or R.sup.4a and
R.sup.4b together with the carbon atom to which they are attached
form a (C.sub.3-C.sub.8)cycloalkyl, wherein the
(C.sub.3-C.sub.8)cycloalkyl is optionally substituted with one to
three R.sup.8;
[0009] R.sup.5a and R.sup.5b, at each occurrence, are independently
selected from the group consisting of hydrogen, halogen, cyano,
hydroxy, oxo, --SF.sub.5, nitro, optionally substituted
(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.3-C.sub.8)cycloalkyl, optionally substituted
phenyl, --N(R.sup.4)(R.sup.5), --N(R.sup.4)(C.dbd.(O)R.sup.5),
--C(.dbd.O)N(R.sup.4)(R.sup.5), --O--C(.dbd.O)N(R.sup.4)(R.sup.5),
--C(.dbd.O)--R.sup.4, and --C(.dbd.O)--OR.sup.4; or R.sup.5a and
R.sup.5b together with the carbon atom to which they are attached
form a (C.sub.3-C.sub.8)cycloalkyl, wherein said
(C.sub.3-C.sub.8)cycloalkyl is optionally substituted with one to
three R.sup.8;
[0010] R.sup.6 and R.sup.7 are each independently selected from the
group consisting of hydrogen, halogen, cyano, --SF.sub.5, nitro,
optionally substituted (C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.3-C.sub.8)cycloalkyl, optionally substituted
phenyl, --N(R.sup.4)(R.sup.5), --N(R.sup.4)(C.dbd.(O)R.sup.5),
--C(.dbd.O)N(R.sup.4)(R.sup.5), --O--C(.dbd.O)N(R.sup.4)(R.sup.5),
--C(.dbd.O)--R.sup.4, --C(.dbd.O)--OR.sup.4, and --OR.sup.9;
provided that R.sup.6 and R.sup.7 cannot both be hydroxy;
[0011] R.sup.8, at each occurrence, is independently selected from
the group consisting of cyano, halogen, hydroxy, --SF.sub.5, nitro,
optionally substituted (C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.1-C.sub.6)alkoxy, and optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl;
[0012] R.sup.9 is selected from the group consisting of hydrogen
and optionally substituted (C.sub.1-C.sub.6)alkyl;
[0013] y is an integer selected from 1, 2, 3 or 4;
[0014] ring B is optionally substituted with one to three R.sup.10,
wherein each R.sup.10 is independently selected from the group
consisting of halogen, cyano, hydroxy, --SF.sub.5, nitro,
optionally substituted (C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.3-C.sub.8)cycloalkyl, --N(R.sup.4)(R.sup.5),
--N(R.sup.4)(C.dbd.(O)R.sup.5), --C(.dbd.O)N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4,
--C(.dbd.O)--OR.sup.4; or two R.sup.10 substituents taken together
with the carbon atom(s) to which they are attached form an
optionally substituted (C.sub.3-C.sub.8)cycloalkyl;
[0015] ring D is optionally substituted with one to four R.sup.11,
wherein each R.sup.11 is independently selected from the group
consisting of halogen, cyano, hydroxy, --SF.sub.5, nitro,
optionally substituted (C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.3-C.sub.8)cycloalkyl, optionally substituted (4- to
6-membered)heterocycloalkyl; --N(R.sup.4)(R.sup.5),
--N(R.sup.4)(C.dbd.(O)R.sup.5), --C(.dbd.O)N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4, and
--C(.dbd.O)--OR.sup.4; and
[0016] R.sup.4 and R.sup.5, at each occurrence, are each
independently selected from hydrogen or optionally substituted
(C.sub.1-C.sub.6)alkyl;
[0017] provided that the compound is not
7-(4-methyl-1H-imidazol-1-yl)-2-{[5-(trifluoromethyl)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazin-
e-1,6-dione.
[0018] Compounds of the invention include Examples 2-22, C22, C33,
C40 and C44 or a pharmaceutically acceptable salt thereof as
described herein.
[0019] Also provided herein are compositions comprising a
pharmaceutically effective amount of one or more of the compounds
described herein and a pharmaceutically acceptable vehicle, carrier
or excipient.
[0020] The compounds of Formula I are .gamma.-secretase modulators.
.gamma.-Secretase plays a role in the production of amyloid beta
protein (A.beta.) plaques associated with Alzheimer's disease.
Accordingly, the compounds of Formula I are believed to be useful
in treating a variety of neurodegenerative and/or neurological
disorders related to A.beta. production.
[0021] Other features and advantages of this invention will be
apparent from this specification and the appending claims which
describe the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0022] The headings within this document are only being utilized to
expedite its review by the reader. They should not be construed as
limiting the invention or claims in any manner.
DEFINITIONS AND EXEMPLIFICATIONS
[0023] As used throughout this application, including the claims,
the following terms have the meanings defined below, unless
specifically indicated otherwise. The plural and singular should be
treated as interchangeable, other than the indication of
number:
[0024] The term "(C.sub.1-C.sub.6)alkyl" refers to a linear or
branched-chain saturated hydrocarbyl substituent (i.e., a
substituent obtained from a hydrocarbon by removal of a hydrogen)
containing from 1 to 6 carbon atoms. Examples of such substituents
include methyl, ethyl, propyl (including n-propyl and isopropyl),
butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl),
pentyl, and hexyl.
[0025] The term "optionally substituted (C.sub.1-C.sub.6)alkyl", as
used herein, refers to a (C.sub.1-C.sub.6)alkyl as defined above,
in which one or more hydrogen atoms are replaced by a substituent
selected from the group consisting of halogen, oxo, cyano, hydroxy,
--SF.sub.5, nitro, --N(R.sup.4)(R.sup.5),
--N(R.sup.4)(C(.dbd.O)R.sup.5), --N(R.sup.4)C(.dbd.O)--OR.sup.5,
--C(.dbd.O)--N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4,
--C(.dbd.O)--OR.sup.4, and (C.sub.3-C.sub.8)cycloalkyl, in which
R.sup.4 and R.sup.5 are each independently hydrogen or optionally
substituted (C.sub.1-C.sub.6)alkyl. For example, a
(C.sub.1-C.sub.6)alkyl moiety can be substituted with one or more
halogen atoms to form a "halo(C.sub.1-C.sub.6)alkyl".
Representative examples of a halo(C.sub.1-C.sub.6)alkyl include,
but are not limited to, fluoromethyl, difluoromethyl,
trifluoromethyl, fluoroethyl, difluoroethyl, pentafluoroethyl, and
the like.
[0026] The term "(C.sub.1-C.sub.3)alkyl" refers to a linear or
branched-chain saturated hydrocarbyl substituent (i.e., a
substituent obtained from a hydrocarbon by removal of a hydrogen)
containing from 1 to 3 carbon atoms. Examples of such substituents
include methyl, ethyl, and propyl (including n-propyl and
isopropyl).
[0027] The term "(C.sub.2-C.sub.6)alkenyl" refers to an aliphatic
hydrocarbon having from 2 to 6 carbon atoms and having at least one
carbon-carbon double bond, including straight chain or
branched-chain groups having at least one carbon-carbon double
bond. Representative examples include, but are not limited to,
ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl,
2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. When the compounds
of the invention contain a (C.sub.2-C.sub.6)alkenyl group, the
compound may exist as the pure E (entgegen) form, the pure Z
(zusammen) form, or any mixture thereof.
[0028] The term "optionally substituted (C.sub.2-C.sub.6)alkenyl"
refers to a (C.sub.2-C.sub.6)alkenyl as defined above, in which one
or more hydrogen atoms are replaced by a substituent selected from
the group consisting of halogen, oxo, cyano, hydroxy, --SF.sub.5,
nitro, --N(R.sup.4)(R.sup.5), --N(R.sup.4)(C(.dbd.O)R.sup.5),
--N(R.sup.4)C(.dbd.O)--OR.sup.5, --C(.dbd.O)--N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4,
--C(.dbd.O)--OR.sup.4, and (C.sub.3-C.sub.8)cycloalkyl, in which
R.sup.4 and R.sup.5 are each independently hydrogen or optionally
substituted (C.sub.1-C.sub.6)alkyl.
[0029] The term "(C.sub.2-C.sub.6)alkynyl" refers to an aliphatic
hydrocarbon having from 2 to 6 carbon atoms and having at least one
carbon-carbon triple bond, including straight chain or branched
chain groups having at least one carbon-carbon triple bond.
Representative examples of an alkynyl include, but are not limited
to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and
1-butynyl.
[0030] The term "optionally substituted (C.sub.2-C.sub.6)alkynyl"
refers to a (C.sub.2-C.sub.6)alkynyl as defined above, in which one
or more hydrogen atoms are replaced by a substituent selected from
the group consisting of halogen, oxo, cyano, hydroxy, --SF.sub.5,
--N(R.sup.4)(R.sup.5), --N(R.sup.4)(C(.dbd.O)R.sup.5),
--N(R.sup.4)C(.dbd.O)--OR.sup.5, --C(.dbd.O)--N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4,
--C(.dbd.O)--OR.sup.4, and (C.sub.3-C.sub.8)cycloalkyl, in which
R.sup.4 and R.sup.5 are each independently hydrogen or optionally
substituted (C.sub.1-C.sub.6)alkyl.
[0031] The term "halogen" refers to fluorine (which may be depicted
as --F), chlorine (which may be depicted as --Cl), bromine (which
may be depicted as --Br), or iodine (which may be depicted as
--I).
[0032] The term "(C.sub.1-C.sub.6)alkoxy" as used herein, means a
(C.sub.1-C.sub.6)alkyl group, as defined above, attached to the
parent molecular moiety through an oxygen atom. Examples include,
but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy,
butoxy, tert-butoxy, pentyloxy, and hexyloxy.
[0033] The term "optionally substituted (C.sub.1-C.sub.6)alkoxy" as
used herein, refers to a (C.sub.1-C.sub.6)alkoxy group, as defined
above, in which one or more hydrogen atoms are replaced by a
substituent selected from the group consisting of halogen, oxo,
cyano, hydroxy, --SF.sub.5, nitro, --N(R.sup.4)(R.sup.5),
--N(R.sup.4)(C(.dbd.O)R.sup.5), --N(R.sup.4)C(.dbd.O)--OR.sup.5,
--C(.dbd.O)--N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4,
--C(.dbd.O)--OR.sup.4, and (C.sub.3-C.sub.8)cycloalkyl, in which
R.sup.4 and R.sup.5 are each independently hydrogen or optionally
substituted (C.sub.1-C.sub.6)alkyl. For example, a
(C.sub.1-C.sub.6)alkoxy can be substituted with one or more halogen
atoms to form a "halo(C.sub.1-C.sub.6)alkoxy". Representative
examples of a halo(C.sub.1-C.sub.6)alkoxy include, but are not
limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
fluoroethoxy, and pentafluoroethoxy, and the like.
[0034] The term "(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl" as
used herein, means a (C.sub.1-C.sub.6)alkoxy group, as defined
above, attached to the parent moiety through a
(C.sub.1-C.sub.6)alkyl group, as defined above. Examples include,
but are not limited to, methoxymethyl, methoxyethyl and the
like.
[0035] The term "optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl" as used herein,
means a (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl group, as
defined above, in which one or more hydrogen atoms are replaced by
a substituent selected from the group consisting of halogen, oxo,
cyano, hydroxy, --SF.sub.5, nitro, --N(R.sup.4)(R.sup.5),
--N(R.sup.4)(C(.dbd.O)R.sup.5), --N(R.sup.4)C(.dbd.O)--OR.sup.5,
--C(.dbd.O)--N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4,
--C(.dbd.O)--OR.sup.4, and (C.sub.3-C.sub.8)cycloalkyl, in which
R.sup.4 and R.sup.5 are each independently hydrogen or optionally
substituted (C.sub.1-C.sub.6)alkyl.
[0036] The term "thio(C.sub.1-C.sub.6)alkyl" as used herein, means
a (C.sub.1-C.sub.6)alkyl group, as defined above, appended to the
parent molecular moiety through a sulfur atom. Representative
examples of thio(C.sub.1-C.sub.6)alkylthio include, but are not
limited to, thiomethyl, thioethyl, thio(tert-butyl), and
thiohexyl.
[0037] The term "optionally substituted
thio(C.sub.1-C.sub.6)alkyl", as used herein, refers to a
thio(C.sub.1-C.sub.6)alkyl group, as defined above, in which one or
more hydrogen atoms are replaced by a substituent selected from the
group consisting of halogen, oxo, cyano, hydroxy, --SF.sub.5,
nitro, --N(R.sup.4)(R.sup.5), --N(R.sup.4)(C(.dbd.O)R.sup.5),
--N(R.sup.4)C(.dbd.O)--OR.sup.5, --C(.dbd.O)--N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4,
--C(.dbd.O)--OR.sup.4, and (C.sub.3-C.sub.8)cycloalkyl, in which
R.sup.4 and R.sup.5 are each independently hydrogen or optionally
substituted (C.sub.1-C.sub.6)alkyl.
[0038] The term "(C.sub.3-C.sub.8)cycloalkyl" refers to a
carbocyclic substituent obtained by removing a hydrogen from a
saturated carbocyclic molecule having from 3 to 8 carbon atoms. A
"(C.sub.3-C.sub.6)cycloalkyl" refers to a carbocyclic substituent
obtained by removing a hydrogen from a saturated carbocyclic
molecule having from 3 to 6 carbon atoms. A
"(C.sub.3-C.sub.8)cycloalkyl" may be a monocyclic ring, examples of
which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and cyclooctyl. Alternatively, a cycloalkyl may
contain more than one ring, such as a
(C.sub.4-C.sub.8)bicycloalkyl. The term
"(C.sub.4-C.sub.8)bicycloalkyl" refers to a bicyclic system
containing 4 to 8 carbon atoms. The bicycloalkyl may be fused, such
as bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane,
bicyclo[2.2.0]hexane, bicyclo[3.1.0]hexane, bicyclo[3.2.0]heptane
and bicyclo[3.3.0]octane. The term "bicycloalkyl" also includes
bridged bicycloalkyl systems such as, but not limited to,
bicyclo[2.2.1]heptane and bicyclo[1.1.1]pentane.
[0039] The term "optionally substituted
"(C.sub.3-C.sub.8)cycloalkyl" refers to a
(C.sub.3-C.sub.8)cycloalkyl, as defined above, in which one or more
hydrogen atoms are replaced by a substituent selected from the
group consisting of halogen, oxo, cyano, hydroxy, --SF.sub.5,
nitro, --N(R.sup.4)(R.sup.5), --N(R.sup.4)(C(.dbd.O)R.sup.5),
--N(R.sup.4)C(.dbd.O)--OR.sup.5, --C(.dbd.O)--N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4,
--C(.dbd.O)--OR.sup.4, and (C.sub.3-C.sub.8)cycloalkyl, in which
R.sup.4 and R.sup.5 are each independently hydrogen or optionally
substituted (C.sub.1-C.sub.6)alkyl.
[0040] The term "(C.sub.6-C.sub.10)aryl" refers to an aromatic
substituent containing from 6 to 10 carbon atoms, consisting of one
ring or two fused rings. Examples of such aryl substituents
include, but are not limited to, phenyl and naphthyl. The
(C.sub.6-C.sub.10)aryl may also include phenyl and naphthyl
substituents that are optionally fused to a
(C.sub.3-C.sub.6)cycloalkyl ring (e.g.,
bicyclo[4.2.0]octa-1,3,5-trienyl) or a (5- to
6-membered)heterocycloalkyl ring (e.g., dihydrobenzofuranyl,
benzodioxolyl, and oxoisoindolinyl) as defined herein, wherein a
group having such a fused aryl group as a substituent is attached
to a carbon atom of the aryl. When the aryl is phenyl, it is also
referred to herein as an "optionally substituted phenyl".
[0041] The term "optionally substituted (C.sub.6-C.sub.10)aryl"
refers to a (C.sub.6-C.sub.10)aryl, as defined above, in which one
or more hydrogen atoms are replaced by a substituent selected from
the group consisting of halogen, cyano, hydroxy, --SF.sub.5, nitro,
--N(R.sup.4)(R.sup.5), --N(R.sup.4)(C(.dbd.O)R.sup.5),
--N(R.sup.4)C(.dbd.O)--OR.sup.5, --C(.dbd.O)--N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4,
--C(.dbd.O)--OR.sup.4, and (C.sub.3-C.sub.8)cycloalkyl, in which
R.sup.4 and R.sup.5 are each independently hydrogen or optionally
substituted (C.sub.1-C.sub.6)alkyl.
[0042] The term "heterocycloalkyl," as used herein, refers to a
cycloalkyl as defined above, wherein at least one of the ring
carbon atoms is replaced with a heteroatom selected from nitrogen,
oxygen or sulfur. A "(4- to 10-membered)heterocycloalkyl" refers to
a heterocycloalkyl substituent as defined above containing a total
of 4 to 10 ring atoms, wherein at least one of the ring atoms is a
heteroatom selected from oxygen, nitrogen, or sulfur. A
heterocycloalkyl may be a single ring with up to 10 total members.
Alternatively, a heterocycloalkyl as defined above may comprise 2
or 3 rings fused together, wherein at least one such ring contains
a heteroatom as a ring atom (i.e., nitrogen, oxygen, or sulfur). In
a group that has a heterocycloalkyl substituent, the ring atom of
the heterocycloalkyl substituent that is attached to the group may
be the at least one heteroatom, when the heteroatom is a nitrogen
having the appropriate valence, or it may be a ring carbon atom,
where the ring carbon atom may be in the same ring as the at least
one heteroatom or where the ring carbon atom may be in a different
ring from the at least one heteroatom. Similarly, if the
heterocycloalkyl substituent is in turn substituted with a group or
substituent, the group or substituent may be bound to the at least
one heteroatom when the heteroatom is a nitrogen having the
appropriate valence, or it may be bound to a ring carbon atom,
where the ring carbon atom may be in the same ring as the at least
one heteroatom or where the ring carbon atom may be in a different
ring from the at least one heteroatom.
[0043] Also included in the definition of "heterocycloalkyl" are
heterocycloalkyls that are fused to a (C.sub.6-C.sub.10)aromatic
ring or a (5- to 10-membered)heteroaromatic ring. When such a fused
heterocycloalkyl group is substituted with one or more
substituents, the one or more substituents, unless otherwise
specified, are each bound to a heteroatom of the heterocycloalkyl
group when the heteroatom is nitrogen having the appropriate
valence or to a carbon atom of the heterocycloalkyl group. Examples
of heterocycloalkyl rings include, but are not limited to,
azetidinyl, dihydrofuranyl, dihydrothiophenyl,
tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydrotriazinyl,
tetrahydropyrazolyl, tetrahydrooxazinyl, tetrahydropyrimidinyl,
octahydrobenzofuranyl, octahydrobenzimidazolyl,
octahydrobenzothiazolyl, imidazolidinyl, pyrrolidinyl, piperidinyl,
piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl,
thiomorpholinyl, tetrahydropyranyl, tetrahydrothiazinyl,
tetrahydrothiadiazinyl, tetrahydrooxazolyl, morpholinyl, oxetanyl,
tetrahydrodiazinyl, oxazinyl, oxathiazinyl, quinuclidinyl,
chromanyl, isochromanyl, dihydrobenzoxazinyl, indolinyl,
isoindolinyl, dihydrobenzofuranyl, tetrahydroquinolyl, isochromyl,
dihydro-1H-isoindolyl, 2-azabicyclo[2.2.1]heptanonyl,
3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo [4.1.0]heptanyl and the
like. Further examples of heterocycloalkyl rings include
tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl,
imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl,
pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl,
piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl,
1,3-oxazolidin-3-yl, 1,4-oxazepan-4-yl, isothiazolidinyl,
1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl,
1,2-tetrahydrothiazin-2-yl, 1,3-thiazinan-3-yl,
1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,
1,4-oxazin-4-yl, oxazolidinonyl, 2-oxo-piperidinyl (e.g.,
2-oxo-piperidin-1-yl), and the like.
[0044] The term "optionally substituted heterocycloalkyl" [e.g.,
optionally substituted (4- to 6-membered)heterocycloalkyl] refers
to a heterocycloalkyl, as defined above, in which one or more
hydrogen atoms, where chemically permissible, are replaced by a
substituent selected from the group consisting of halogen, oxo,
cyano, hydroxy, --SF.sub.5, nitro, --N(R.sup.4)(R.sup.5),
--N(R.sup.4)(C(.dbd.O)R.sup.5), --N(R.sup.4)C(.dbd.O)--OR.sup.5,
--C(.dbd.O)--N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4,
--C(.dbd.O)--OR.sup.4, and (C.sub.3-C.sub.8)cycloalkyl, in which
R.sup.4 and R.sup.5 are each independently hydrogen or optionally
substituted (C.sub.1-C.sub.6)alkyl.
[0045] The term "(5- to 14-membered)heteroaryl" refers to a
heteroaryl ring having from 5 to 14 ring atoms in which at least
one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or
sulfur), with the remaining ring atoms being independently selected
from the group consisting of carbon, oxygen, nitrogen, and sulfur.
A "(5- to 6-membered)heteroaryl" refers to a heteroaryl ring having
from 5 to 6 ring atoms in which at least one of the ring atoms is a
heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining
ring atoms being independently selected from the group consisting
of carbon, oxygen, nitrogen, and sulfur. A "(6-membered)heteroaryl"
refers to a heteroaryl ring having 6 ring atoms. A
"(5-membered)heteroaryl" refers to a heteroaryl ring having 5 ring
atoms in which at least one of the ring atoms is a heteroatom. A
heteroaryl may consist of a single ring or 2 or 3 fused rings.
Examples of heteroaryls include, but are not limited to, 6-membered
ring substituents such as pyridinyl, pyrazinyl, pyrimidinyl and
pyridazinyl; 5-membered heteroaryls such as triazolyl, imidazolyl,
furanyl, isoxazolyl, isothiazolyl, 1,2,3-, 1,2,4, 1,2,5-, or
1,3,4-oxadiazolyl, oxazolyl, thiophenyl, thiazolyl, and pyrazolyl;
6/5-membered fused ring substituents such as indolyl, indazolyl,
benzofuranyl, benzimidazolyl, benzothienyl, benzoxadiazolyl,
benzothiazolyl, isobenzothiofuranyl, benzothiofuranyl,
benzisoxazolyl, benzoxazolyl, furanopyridinyl, purinyl,
imidazopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl,
thienopyridinyl, triazolopyrimidinyl, triazolopyridinyl (e.g.,
[1,2,4]triazolo[1,5-a]pyridin-2-yl), and anthranilyl; and
6/6-membered fused ring substituents such as quinolinyl,
isoquinolinyl, cinnolinyl, quinazolinyl, oxochromenyl, and
1,4-benzoxazinyl. In a group that has a heteroaryl substituent, the
ring atom of the heteroaryl substituent that is bound to the group
may be the at least one heteroatom when the heteroatom is nitrogen
having the appropriate valence, or it may be a ring carbon atom,
where the ring carbon atom may be in the same ring as the at least
one heteroatom or where the ring carbon atom may be in a different
ring from the at least one heteroatom. Similarly, if the heteroaryl
substituent is in turn substituted with a group or substituent, the
group or substituent may be bound to the at least one heteroatom
when the heteroatom is a nitrogen having the appropriate valence or
it may be bound to a ring carbon atom, where the ring carbon atom
may be in the same ring as the at least one heteroatom, or where
the ring carbon atom may be in a different ring from the at least
one heteroatom.
[0046] It is to be understood that the "(5- to
14-membered)heteroaryl" may be optionally fused to a
(C.sub.3-C.sub.8)cycloalkyl group, or to a (4- to
10-membered)heterocycloalkyl group, as defined herein. A group
having such a fused heteroaryl group as a substituent is attached
to an aromatic carbon of the heteroaryl group or to a heteroatom of
the heteroaryl group when the heteroatom is nitrogen having the
appropriate valence. Such a fused heteroaryl group may be
substituted with up to four substituents; the substituents, unless
otherwise specified, are each bound to an aromatic carbon of the
heteroaryl group or to a heteroatom of the heteroaryl group when
the heteroatom is nitrogen having the appropriate valence.
[0047] The terms "optionally substituted (5- to
14-membered)heteroaryl", "optionally substituted (5- to
6-membered)heteroaryl" and "optionally substituted (5- to
6-membered)nitrogen-containing heteroaryl" refer to a (5- to
14-membered)heteroaryl, a (5- to 6-membered)heteroaryl, and a (5-
to 6-membered)nitrogen-containing heteroaryl, as defined above, in
which one or more hydrogen atoms are replaced, where chemically
permissible, by a substituent selected from the group consisting of
halogen, oxo, cyano, hydroxy, --SF.sub.5, nitro,
--N(R.sup.4)(R.sup.5), --N(R.sup.4)(C(.dbd.O)R.sup.5),
--N(R.sup.4)C(.dbd.O)--OR.sup.5, --C(.dbd.O)--N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4,
--C(.dbd.O)--OR.sup.4, and (C.sub.3-C.sub.8)cycloalkyl, in which
R.sup.4 and R.sup.5 are each independently hydrogen or optionally
substituted (C.sub.1-C.sub.6)alkyl. The substituent can be attached
to the heteroaryl moiety at any available carbon atom or to a
heteroatom when the heteroatom is nitrogen having the appropriate
valence.
[0048] The term "hydrogen" refers to a hydrogen substituent, and
may be depicted as --H.
[0049] The term "hydroxy" or "hydroxyl" refers to --OH. When used
in combination with another term(s), the prefix "hydroxy" indicates
that the substituent to which the prefix is attached is substituted
with one or more hydroxy substituents. Compounds bearing a carbon
to which one or more hydroxy substituents are attached include, for
example, alcohols, enols and phenol.
[0050] The term "cyano" (also referred to as "nitrile") means --CN,
which also may be depicted:
##STR00003##
[0051] The term "oxo" means a .dbd.O group.
[0052] If a substituent is described as being "substituted," a
non-hydrogen substituent is in the place of a hydrogen substituent
on a carbon or nitrogen of the substituent. Thus, for example, a
substituted alkyl substituent is an alkyl substituent wherein at
least one non-hydrogen substituent is in the place of a hydrogen
substituent on the alkyl substituent. To illustrate,
monofluoroalkyl is alkyl substituted with a fluoro substituent, and
difluoroalkyl is alkyl substituted with two fluoro substituents. It
should be recognized that if there is more than one substitution on
a substituent, each non-hydrogen substituent may be identical or
different (unless otherwise stated).
[0053] If a substituent is described as being "optionally
substituted," the substituent may be either (1) not substituted, or
(2) substituted. If a carbon of a substituent is described as being
optionally substituted with one or more of a list of substituents,
one or more of the hydrogens on the carbon (to the extent there are
any) may separately and/or together be replaced with an
independently selected optional substituent. If a nitrogen of a
substituent is described as being optionally substituted with one
or more of a list of substituents, one or more of the hydrogens on
the nitrogen (to the extent there are any) may each be replaced
with an independently selected optional substituent. As a further
example, when there are optional substituents that can be present,
e.g., R.sup.10 or R.sup.11, those substituents are as specified in
the present specification, and when not present, the atom to which
the optional substituent could be attached (i.e., C or N) would
have the requisite number of hydrogens attached.
[0054] This specification uses the terms "substituent," "radical,"
and "group" interchangeably.
[0055] If a substituent is described as being optionally
substituted with up to a particular number of non-hydrogen
substituents, that substituent may be either (1) not substituted;
or (2) substituted by up to that particular number of non-hydrogen
substituents or by up to the maximum number of substitutable
positions on the substituent, whichever is less. Thus, for example,
if a substituent is described as a heteroaryl optionally
substituted with up to 3 non-hydrogen substituents, then any
heteroaryl with less than 3 substitutable positions would be
optionally substituted by up to only as many non-hydrogen
substituents as the heteroaryl has substitutable positions. To
illustrate, tetrazolyl (which has only one substitutable position)
would be optionally substituted with up to one non-hydrogen
substituent. To illustrate further, if an amino nitrogen is
described as being optionally substituted with up to 2 non-hydrogen
substituents, then the nitrogen will be optionally substituted with
up to 2 non-hydrogen substituents if the amino nitrogen is a
primary nitrogen, whereas the amino nitrogen will be optionally
substituted with up to only 1 non-hydrogen substituent if the amino
nitrogen is a secondary nitrogen.
[0056] If substituents are described as being "independently
selected" from a group, each substituent is selected independent of
the other(s). Each substituent therefore may be identical to or
different from the other substituent(s).
[0057] As used herein, unless specified, the point of attachment of
a substituent can be from any suitable position of the
substituent.
[0058] When a bond to a substituent is shown to cross a bond
connecting two atoms in a ring, then such substituent may be bonded
to any of the ring-forming atoms in that ring that are
substitutable.
[0059] "Patient" refers to warm-blooded animals such as, for
example, pigs, cows, chickens, horses, guinea pigs, mice, rats,
gerbils, cats, rabbits, dogs, monkeys, chimpanzees, and humans.
[0060] "Treating" or "treat", as used herein, unless otherwise
indicated, means reversing, alleviating, inhibiting the progress
of, or preventing the disorder or condition to which such term
applies, or one or more symptoms of such disorder or condition. The
term "treatment", as used herein, unless otherwise indicated,
refers to the act of treating as "treating" is defined immediately
above. The term "treating" also includes adjuvant and neo-adjuvant
treatment of a subject.
[0061] "Pharmaceutically acceptable" indicates that the substance
or composition must be compatible, chemically and/or
toxicologically, with the other ingredients comprising a
formulation, and/or the mammal being treated therewith.
[0062] "Isomer" means "stereoisomer" and "geometric isomer" as
defined below.
[0063] "Stereoisomer" refers to compounds that possess one or more
chiral centers, which may each exist in the R or S configuration.
Stereoisomers include all diastereomeric, enantiomeric and epimeric
forms as well as racemates and mixtures thereof.
[0064] "Geometric isomer" refers to compounds that may exist in
cis, trans, anti, entgegen (E), and zusammen (Z) forms as well as
mixtures thereof.
[0065] As used herein the terms "Formula I", "Formula II", and
"Formula III" may be hereinafter referred to as "compound(s) of the
invention." Such terms are also defined to include all forms of the
compounds of Formulas I through III including hydrates, solvates,
isomers, crystalline and non-crystalline forms, isomorphs,
polymorphs, and metabolites thereof. For example, the compounds of
Formulas I through III, or pharmaceutically acceptable salts
thereof, may exist in unsolvated and solvated forms with
pharmaceutically acceptable solvents such as water, ethanol and the
like. When the solvent or water is tightly bound, the complex will
have a well-defined stoichiometry independent of humidity. When,
however, the solvent or water is weakly bound, as in channel
solvates and hygroscopic compounds, the water/solvent content will
be dependent on humidity and drying conditions. In such cases,
non-stoichiometry will be the norm. In general, the solvated forms
are considered equivalent to the unsolvated forms for the purposes
of the present invention.
[0066] The compounds of the invention may exist as clathrates or
other complexes. Included within the scope of the invention are
complexes such as clathrates, drug-host inclusion complexes wherein
the drug and host are present in stoichiometric or
non-stoichiometric amounts. Also included are complexes of the
compounds of the present invention containing two or more organic
and/or inorganic components, which may be in stoichiometric or
non-stoichiometric amounts. The resulting complexes may be ionized,
partially ionized, or non-ionized. For a review of such complexes,
see J. Pharm. Sci., 64 (8), 1269-1288 by Haleblian (August
1975).
[0067] Compounds of the invention may exist as geometric isomers.
The compounds of the invention may possess one or more asymmetric
centers, thus existing as two, or more, stereoisomeric forms. The
present invention includes all the individual stereoisomers and
geometric isomers of the compounds of the invention and mixtures
thereof. Individual enantiomers can be obtained by resolution,
chiral chromatography, or other methods well-known to those skilled
in the art, or by using the relevant enantiomeric reactant or
reagent in the synthesis.
[0068] The carbon-carbon bonds of the compounds of the invention
may be depicted herein using a solid line (), a solid wedge (), or
a dotted wedge (). The use of a solid line to depict bonds to
asymmetric carbon atoms is meant to indicate that all possible
stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.)
at that carbon atom are included. The use of either a solid or
dotted wedge to depict bonds to asymmetric carbon atoms is meant to
indicate that the stereoisomer shown is present. When present in
racemic compounds, solid and dotted wedges are used to define
relative stereochemistry, rather than absolute stereochemistry.
Racemic compounds possessing such indicated relative
stereochemistry are marked with (+/-). For example, unless stated
otherwise, it is intended that the compounds of the invention can
exist as stereoisomers, which include cis and trans isomers,
optical isomers such as R and S enantiomers, diastereomers,
geometric isomers, rotational isomers, conformational isomers,
atropisomers, and mixtures thereof. The compounds of the invention
may exhibit more than one type of isomerism, and consist of
mixtures thereof (such as racemates and diastereomeric pairs). Also
included are acid addition or base addition salts wherein the
counterion is optically active, for example, D-lactate or L-lysine,
or racemic, for example, DL-tartrate or DL-arginine.
[0069] When any racemate crystallizes, crystals of two different
types are possible. The first type is the racemic compound (true
racemate) referred to above wherein one homogeneous form of crystal
is produced containing both enantiomers in equimolar amounts. The
second type is the racemic mixture or conglomerate wherein two
forms of crystal are produced in equimolar amounts each comprising
a single enantiomer.
[0070] The present invention also includes all pharmaceutically
acceptable isotopically labeled compounds, which are identical to
those recited in Formulas I through III except that one or more
atoms are replaced by an atom having the same atomic number, but an
atomic mass or mass number different from the atomic mass or mass
number which predominates in nature. Examples of isotopes suitable
for inclusion in the compounds of the present invention include,
but are not limited to, isotopes of hydrogen, such as .sup.2H,
.sup.3H; carbon, such as .sup.11C, .sup.13C, and .sup.14C;
chlorine, such as .sup.36Cl; fluorine, such as .sup.18F; iodine,
such as .sup.123I and .sup.125I; nitrogen, such as .sup.13N and
.sup.15N; oxygen, such as .sup.15O, .sup.17O, and .sup.18O;
phosphorus, such as .sup.32P; and sulfur, such as .sup.35S. Certain
isotopically labeled compounds of the present invention, for
example those incorporating a radioactive isotope, are useful in
drug and/or substrate tissue distribution studies (e.g., assays).
The radioactive isotopes tritium, i.e., .sup.3H, and carbon-14,
i.e., .sup.14C, are particularly useful for this purpose in view of
their ease of incorporation and ready means of detection.
Substitution with heavier isotopes such as deuterium, i.e.,
.sup.2H, may afford certain therapeutic advantages resulting from
greater metabolic stability, for example, increased in vivo
half-life or reduced dosage requirements and, hence, may be
preferred in some circumstances. Substitution with
positron-emitting isotopes, such as .sup.11C, .sup.18F, .sup.15O
and .sup.13N, can be useful in positron emission tomography (PET)
studies for examining substrate receptor occupancy. Isotopically
labeled compounds of the present invention can generally be
prepared by conventional techniques known to those skilled in the
art or by processes analogous to those described in the
accompanying Schemes and/or in the Examples and Preparations, by
using an appropriate isotopically labeled reagent in place of the
non-labeled reagent previously employed. Pharmaceutically
acceptable solvates in accordance with the invention include those
wherein the solvent of crystallization may be isotopically
substituted, e.g., D.sub.2O, acetone-d.sub.6, or DMSO-d.sub.6.
Compounds of the present invention, as well as the compounds
exemplified in Examples 1-22 described below, include isotopically
labeled versions of these compounds, such as, but not limited to,
the deuterated and tritiated isotopes and all other isotopes
discussed above.
[0071] The compounds of this invention may be used in the form of
salts derived from inorganic or organic acids. Depending on the
particular compound, a salt of the compound may be advantageous due
to one or more of the salt's physical properties, such as enhanced
pharmaceutical stability in differing temperatures and humidities,
or a desirable solubility in water or oil. In some instances, a
salt of a compound also may be used as an aid in the isolation,
purification, and/or resolution of the compound.
[0072] Where a salt is intended to be administered to a patient (as
opposed to, for example, being used in an in vitro context), the
salt preferably is pharmaceutically acceptable. The term
"pharmaceutically acceptable salt" refers to a salt prepared by
combining a compound of the invention with an acid whose anion, or
a base whose cation, is generally considered suitable for human
consumption. Pharmaceutically acceptable salts are particularly
useful as products of the methods of the present invention because
of their greater aqueous solubility relative to the parent
compound.
[0073] Suitable pharmaceutically acceptable acid addition salts of
the compounds of the present invention when possible include those
derived from inorganic acids, such as hydrochloric, hydrobromic,
hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric,
nitric, carbonic, sulfonic, and sulfuric acids, and organic acids
such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic,
fumaric, gluconic, glycolic, isothionic, lactic, lactobionic,
maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic,
toluenesulfonic, tartaric, and trifluoroacetic acids. Suitable
organic acids generally include but are not limited to aliphatic,
cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic,
and sulfonic classes of organic acids.
[0074] Specific examples of suitable organic acids include but are
not limited to acetate, trifluoroacetate, formate, propionate,
succinate, glycolate, gluconate, digluconate, lactate, malate,
tartrate, citrate, ascorbate, glucuronate, maleate, fumarate,
pyruvate, aspartate, glutamate, benzoate, anthranilate, stearate,
salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate
(pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate,
pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate,
sufanilate, cyclohexylaminosulfonate, .beta.-hydroxybutyrate,
galactarate, galacturonate, adipate, alginate, butyrate,
camphorate, camphorsulfonate, cyclopentanepropionate,
dodecylsulfate, glycoheptanoate, glycerophosphate, heptanoate,
hexanoate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,
pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate, and
undecanoate.
[0075] Furthermore, where the compounds of the invention carry an
acidic moiety, suitable pharmaceutically acceptable salts thereof
may include alkali metal salts, e.g., sodium or potassium salts;
alkaline earth metal salts, e.g., calcium or magnesium salts; and
salts formed with suitable organic ligands, e.g., quaternary
ammonium salts. In another embodiment, base salts are formed from
bases which form non-toxic salts, including aluminum, arginine,
benzathine, choline, diethylamine, diolamine, glycine, lysine,
meglumine (N-methylglucamine), olamine, tromethamine and zinc
salts.
[0076] Organic salts may be made from secondary, tertiary or
quaternary amine salts, such as tromethamine, diethylamine,
N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine, and procaine. Basic
nitrogen-containing groups may be quaternized with agents such as
lower alkyl (C.sub.1-C.sub.6) halides (e.g., methyl, ethyl, propyl,
and butyl chlorides, bromides, and iodides), dialkyl sulfates
(e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain
halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides,
bromides, and iodides), arylalkyl halides (e.g., benzyl and
phenethyl bromides), and others.
[0077] In one embodiment, hemisalts of acids and bases may also be
formed, for example, hemisulfate and hemicalcium salts.
[0078] Also within the scope of the present invention are so-called
"prodrugs" of the compound of the invention. Thus, certain
derivatives of the compound of the invention that may have little
or no pharmacological activity themselves can, when administered
into or onto the body, be converted into the compound of the
invention having the desired activity, for example, by hydrolytic
cleavage. Such derivatives are referred to as "prodrugs." Further
information on the use of prodrugs may be found in "Pro-drugs as
Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi
and V. Stella) and "Bioreversible Carriers in Drug Design,"
Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical
Association). Prodrugs in accordance with the invention can, for
example, be produced by replacing appropriate functionalities
present in the compounds of the present invention with certain
moieties known to those skilled in the art as "pro-moieties" as
described, for example, in "Design of Prodrugs" by H. Bundgaard
(Elsevier, 1985).
[0079] This invention also encompasses compounds of the invention
containing protective groups. One skilled in the art will
appreciate that compounds of the invention can also be prepared
with certain protecting groups that are useful for purification or
storage and can be removed before administration to a patient. The
protection and deprotection of functional groups is described in
"Protective Groups in Organic Chemistry", edited by J. F. W.
McOmie, Plenum Press (1973) and "Protective Groups in Organic
Synthesis", 3rd edition, T. W. Greene and P. G. M. Wuts,
Wiley-Interscience (1999).
[0080] Typically, a compound of the invention is administered in an
amount effective to treat a condition as described herein. The
compounds of the invention are administered by any suitable route
in the form of a pharmaceutical composition adapted to such a
route, and in a dose effective for the treatment intended.
Therapeutically effective doses of the compounds required to treat
the progress of the medical condition are readily ascertained by
one of ordinary skill in the art using preclinical and clinical
approaches familiar to the medicinal arts. The term
"therapeutically effective amount" as used herein refers to that
amount of the compound being administered which will relieve to
some extent one or more of the symptoms of the disorder being
treated.
Compounds
[0081] The compounds of Formula I, as depicted above, have a fused
bicyclic core represented by
3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione. On the left side of
the core, the pyridinone ring is substituted with R.sup.6, R.sup.7,
and a (5- to 14-membered)heteroaryl moiety represented by X,
wherein X is further substituted with R.sup.1; and on the right
side of the core the pyrazinone ring is substituted with R.sup.4a,
R.sup.4b, R.sup.5a, R.sup.5b and a pendant cyclopropabenzofuranyl
moiety represented by the following structure:
##STR00004##
[0082] In certain embodiments, in Formula I as depicted above,
R.sup.1, R.sup.2a, R.sup.2b, R.sup.4a, R.sup.4b, R.sup.5a,
R.sup.5b, R.sup.6, R.sup.7, R.sup.10, R.sup.11, and y are as
defined above; and X is represented by: [0083] Xi) a (5- to
6-membered)heteroaryl containing 1-3 heteroatoms; [0084] Xii) a
(6-membered)heteroaryl containing 1-3 heteroatoms; or [0085] Xiii)
a (5-membered)heteroaryl containing 1-3 heteroatoms.
[0086] In certain other embodiments, the (5- to
6-membered)heteroaryl is selected from the group consisting of
triazolyl, imidazolyl, furanyl, thiophenyl, pyrazolyl,
isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, pyridinyl,
pyrimidinyl, pyrazinyl, and pyridazinyl.
[0087] In certain embodiments, the (6-membered)heteroaryl is
selected from the group consisting of pyridinyl, pyrimidinyl,
pyrazinyl, and pyridazinyl.
[0088] In certain other embodiments, the (5-membered)heteroaryl is
selected from the group consisting of triazolyl, imidazolyl,
furanyl, thiophenyl, pyrazolyl, isothiazolyl, thiazolyl,
isoxazolyl, and oxazolyl.
[0089] In certain other embodiments, X is a (5-membered)heteroaryl,
wherein the heteroaryl is imidazolyl.
[0090] In certain other embodiments, X is a (5-membered)heteroaryl,
wherein the heteroaryl is triazolyl.
[0091] In certain other embodiments, in Formula I as depicted
above, X is represented by one of the embodiments as immediately
described above, wherein:
[0092] R.sup.1, where chemically permissible, is selected from the
group consisting of hydrogen, halogen, cyano, hydroxy, oxo,
--SF.sub.5, nitro, optionally substituted (C.sub.1-C.sub.6)alkyl,
optionally substituted (C.sub.2-C.sub.6)alkenyl, optionally
substituted (C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.3-C.sub.8)cycloalkyl, --N(R.sup.4)(R.sup.5),
--N(R.sup.4)(C.dbd.(O)R.sup.5), --C(.dbd.O)N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4, and
--C(.dbd.O)--OR.sup.4;
[0093] R.sup.2a and R.sup.2b, where chemically permissible, at each
occurrence, are independently selected from the group consisting of
hydrogen, halogen, cyano, hydroxy, --SF.sub.5, nitro, optionally
substituted (C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.3-C.sub.8)cycloalkyl, optionally substituted
phenyl, --N(R.sup.4)(R.sup.5), --N(R.sup.4)(C.dbd.(O)R.sup.5),
--C(.dbd.O)N(R.sup.4)(R.sup.5), --O--C(.dbd.O)N(R.sup.4)(R.sup.5),
--C(.dbd.O)--R.sup.4, and --C(.dbd.O)--OR.sup.4; or R.sup.2a and
R.sup.2b together with the carbon atom(s) to which they are
attached form a (C.sub.3-C.sub.8)cycloalkyl or a (4- to
10-membered)heterocycloalkyl, wherein the
(C.sub.3-C.sub.8)cycloalkyl and the (4- to
10-membered)heterocycloalkyl are optionally substituted with one to
three R.sup.8;
[0094] R.sup.4a and R.sup.4b, where chemically permissible, are
each independently selected from the group consisting of hydrogen,
halogen, cyano, hydroxy, oxo, --SF.sub.5, nitro, optionally
substituted (C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.3-C.sub.8)cycloalkyl, optionally substituted
phenyl, --N(R.sup.4)(R.sup.5), --N(R.sup.4)(C.dbd.(O)R.sup.5),
--C(.dbd.O)N(R.sup.4)(R.sup.5), --O--C(.dbd.O)N(R.sup.4)(R.sup.5),
--C(.dbd.O)--R.sup.4, and --C(.dbd.O)--OR.sup.4; or R.sup.4a and
R.sup.4b together with the carbon atom to which they are attached
form a (C.sub.3-C.sub.8)cycloalkyl, wherein the
(C.sub.3-C.sub.8)cycloalkyl is optionally substituted with one to
three R.sup.8;
[0095] R.sup.5a and R.sup.5b, at each occurrence, are independently
selected from the group consisting of hydrogen, halogen, cyano,
hydroxy, oxo, --SF.sub.5, nitro, optionally substituted
(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.3-C.sub.8)cycloalkyl, optionally substituted
phenyl, --N(R.sup.4)(R.sup.5), --N(R.sup.4)(C.dbd.(O)R.sup.5),
--C(.dbd.O)N(R.sup.4)(R.sup.5), --O--C(.dbd.O)N(R.sup.4)(R.sup.5),
--C(.dbd.O)--R.sup.4, and --C(.dbd.O)--OR.sup.4; or R.sup.5a and
R.sup.5b together with the carbon atom to which they are attached
form a (C.sub.3-C.sub.8)cycloalkyl, wherein said
(C.sub.3-C.sub.8)cycloalkyl is optionally substituted with one to
three R.sup.8;
[0096] R.sup.6 and R.sup.7 are each independently selected from the
group consisting of hydrogen, halogen, cyano, --SF.sub.5, nitro,
optionally substituted (C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.3-C.sub.8)cycloalkyl, optionally substituted
phenyl, --N(R.sup.4)(R.sup.5), --N(R.sup.4)(C.dbd.(O)R.sup.5),
--C(.dbd.O)N(R.sup.4)(R.sup.5), --O--C(.dbd.O)N(R.sup.4)(R.sup.5),
--C(.dbd.O)--R.sup.4, --C(.dbd.O)--OR.sup.4, and --OR.sup.9;
provided that R.sup.6 and R.sup.7 cannot both be hydroxy;
[0097] R.sup.8, at each occurrence, is independently selected from
the group consisting of cyano, halogen, hydroxy, --SF.sub.5, nitro,
optionally substituted (C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.1-C.sub.6)alkoxy, and optionally substituted
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl;
[0098] R.sup.9 is selected from the group consisting of hydrogen
and optionally substituted (C.sub.1-C.sub.6)alkyl;
[0099] y is an integer selected from 1, 2, 3 or 4;
[0100] ring B is optionally substituted with one to three R.sup.10,
wherein each R.sup.10 is independently selected from the group
consisting of halogen, cyano, hydroxy, --SF.sub.5, nitro,
optionally substituted (C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.3-C.sub.8)cycloalkyl, --N(R.sup.4)(R.sup.5),
--N(R.sup.4)(C.dbd.(O)R.sup.5), --C(.dbd.O)N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4,
--C(.dbd.O)--OR.sup.4; or two R.sup.10 substituents taken together
with the carbon atom(s) to which they are attached form an
optionally substituted (C.sub.3-C.sub.8)cycloalkyl;
[0101] ring D is optionally substituted with one to four R.sup.11,
wherein each R.sup.11 is independently selected from the group
consisting of halogen, cyano, hydroxy, --SF.sub.5, nitro,
optionally substituted (C.sub.1-C.sub.6)alkyl, optionally
substituted (C.sub.2-C.sub.6)alkenyl, optionally substituted
(C.sub.2-C.sub.6)alkynyl, optionally substituted
thio(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, optionally substituted
(C.sub.3-C.sub.8)cycloalkyl, optionally substituted (4- to
6-membered)heterocycloalkyl; --N(R.sup.4)(R.sup.5),
--N(R.sup.4)(C.dbd.(O)R.sup.5), --C(.dbd.O)N(R.sup.4)(R.sup.5),
--O--C(.dbd.O)N(R.sup.4)(R.sup.5), --C(.dbd.O)--R.sup.4,
--C(.dbd.O)--OR.sup.4; and
[0102] R.sup.4 and R.sup.5, at each occurrence, are each
independently selected from hydrogen or optionally substituted
(C.sub.1-C.sub.6)alkyl;
[0103] provided that the compound is not
7-(4-methyl-1H-imidazol-1-yl)-2-{[5-(trifluoromethyl)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazin-
e-1,6-dione.
[0104] In certain other embodiments, in Formula I as depicted
above, X is a (5-membered)heteroaryl selected from the group
consisting of triazolyl, imidazolyl, furanyl, thiophenyl,
pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, and oxazolyl,
wherein:
[0105] R.sup.1 is selected from the group consisting of hydrogen,
halogen, cyano, hydroxy, optionally substituted
(C.sub.1-C.sub.6)alkyl, and optionally substituted
(C.sub.1-C.sub.6)alkoxy; wherein the (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)alkoxy are optionally substituted with one to
three substituents selected from halogen, oxo, cyano, hydroxy, or
--SF.sub.5;
[0106] R.sup.2a and R.sup.2b are each independently selected from
hydrogen, halogen, cyano, hydroxy or optionally substituted
(C.sub.1-C.sub.6)alkyl;
[0107] R.sup.4a, R.sup.4b, R.sup.5a and R.sup.5b are each
independently selected from the group consisting of hydrogen,
halogen, cyano, hydroxy, oxo, --SF.sub.5, optionally substituted
(C.sub.1-C.sub.6)alkyl, and optionally substituted
(C.sub.1-C.sub.6)alkoxy, wherein the (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)alkoxy are optionally substituted with one to
three substituents selected from halogen, oxo, cyano, hydroxy, or
--SF.sub.5;
[0108] R.sup.6 and R.sup.7 are each independently selected from the
group consisting of hydrogen, cyano, halogen, --SF.sub.5,
optionally substituted (C.sub.1-C.sub.6)alkyl, and optionally
substituted (C.sub.1-C.sub.6)alkoxy, wherein the
(C.sub.1-C.sub.6)alkyl and (C.sub.1-C.sub.6)alkoxy are optionally
substituted with one to three substituents selected from halogen,
oxo, cyano, hydroxy, or --SF.sub.5;
[0109] y is 1;
[0110] ring B is optionally substituted with one to two R.sup.10,
wherein each R.sup.10 is independently selected from halogen,
cyano, hydroxy, --SF.sub.5, optionally substituted
(C.sub.1-C.sub.6)alkyl, and optionally substituted
(C.sub.1-C.sub.6)alkoxy, wherein the (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)alkoxy are optionally substituted with one to
three substituents selected from halogen, oxo, cyano, hydroxy, or
--SF.sub.5; and
[0111] ring D is optionally substituted with one to three R.sup.11,
wherein each R.sup.11 is independently selected from the group
consisting of halogen, cyano, hydroxy, optionally substituted
(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.1-C.sub.6)alkoxy, --SF.sub.5, --N(R.sup.4)(R.sup.5), nitro,
and optionally substituted (C.sub.3-C.sub.8)cycloalkyl, wherein the
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, and
(C.sub.3-C.sub.8)cycloalkyl are optionally substituted with one to
three substituents independently selected from halogen, cyano,
hydroxy, --SF.sub.5, and optionally substituted
(C.sub.1-C.sub.6)alkyl, wherein R.sup.4 and R.sup.5 are each
independently selected from hydrogen or optionally substituted
(C.sub.1-C.sub.6)alkyl;
[0112] provided that the compound is not
7-(4-methyl-1H-imidazol-1-yl)-2-{[5-(trifluoromethyl)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazin-
e-1,6-dione.
[0113] In certain embodiments, in Formula I as immediately
described above:
[0114] R.sup.1 is an optionally substituted (C.sub.1-C.sub.6)alkyl,
wherein the (C.sub.1-C.sub.6)alkyl is substituted with one to three
substituents selected from halogen, oxo, cyano, hydroxy, or
--SF.sub.5; and
[0115] R.sup.2a, R.sup.2b, R.sup.4a, R.sup.4b, R.sup.5a and
R.sup.5b are each independently [0116] i) hydrogen; or [0117] ii)
optionally substituted (C.sub.1-C.sub.6)alkyl, wherein the
(C.sub.1-C.sub.6)alkyl is substituted with one to three
substituents selected from halogen, oxo, cyano, hydroxy, or
--SF.sub.5.
[0118] In certain other embodiments, R.sup.1 is methyl; and
R.sup.2a, R.sup.2b, R.sup.4a, R.sup.4b, R.sup.5a and R.sup.5b are
each independently hydrogen.
[0119] In certain other embodiments, R.sup.1 is methyl; R.sup.2a,
R.sup.2b, R.sup.5a and R.sup.5b are each independently hydrogen;
and one of R.sup.4a and R.sup.4b is hydrogen and the other is
methyl.
[0120] In another embodiment, R.sup.1 is methyl; one of R.sup.2a
and R.sup.2b is hydrogen and the other is methyl; and R.sup.4a,
R.sup.4b, R.sup.5a and R.sup.5b are each independently
hydrogen.
[0121] To further elucidate the compounds of the present invention,
wherein X is a (5-membered)heteroaryl ring and the
(5-membered)heteroaryl ring is imidazolyl or triazolyl, the
following subgenuses are described below:
[0122] Formula II, as depicted below, is a subset of Formula I, as
depicted above, wherein X is a (5-membered)heteroaryl wherein the
heteroaryl is imidazolyl, R.sup.1 is a (C.sub.1-C.sub.6)alkyl
wherein the (C.sub.1-C.sub.6)alkyl is methyl, R.sup.6 and R.sup.7
are each hydrogen, y is 1, and the cyclopropabenzofuranyl moiety is
attached via the benzylic position of the cyclopropabenzofuranyl
moiety:
##STR00005##
[0123] In certain embodiments, in Formula II, as depicted above, or
a pharmaceutically acceptable salt thereof:
[0124] R.sup.1 is selected from the group consisting of hydrogen,
halogen, cyano, hydroxy, optionally substituted
(C.sub.1-C.sub.6)alkyl, and optionally substituted
(C.sub.1-C.sub.6)alkoxy; wherein the (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)alkoxy are optionally substituted with one to
three substituents selected from halogen, oxo, cyano, hydroxy, or
--SF.sub.5;
[0125] R.sup.2a, R.sup.2b, R.sup.4a, R.sup.4b, R.sup.5a and
R.sup.5b are each independently selected from hydrogen, halogen,
cyano, hydroxy or optionally substituted
(C.sub.1-C.sub.6)alkyl;
[0126] ring B is optionally substituted with one to two R.sup.10,
wherein each R.sup.10 is independently selected from halogen or
optionally substituted (C.sub.1-C.sub.6)alkyl; and
[0127] ring D is optionally substituted with one to three R.sup.11,
wherein each R.sup.11 is independently selected from halogen,
optionally substituted (C.sub.1-C.sub.6)alkyl, and optionally
substituted (C.sub.1-C.sub.6)alkoxy;
[0128] provided that the compound is not
7-(4-methyl-1H-imidazol-1-yl)-2-{[5-(trifluoromethyl)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazin-
e-1,6-dione.
[0129] In certain embodiments, Formula II is as immediately
described above:
[0130] R.sup.1 is selected from the group consisting of hydrogen,
halogen, cyano, hydroxy, (C.sub.1-C.sub.6)alkyl, and
(C.sub.1-C.sub.6)alkoxy; wherein the (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)alkoxy are optionally substituted with one to
three fluoro atoms;
[0131] R.sup.2a, R.sup.2b, R.sup.4a, R.sup.4b, R.sup.5a and
R.sup.5b are each independently selected from hydrogen or
(C.sub.1-C.sub.6)alkyl, wherein the (C.sub.1-C.sub.6)alkyl is
methyl;
[0132] ring B is optionally substituted with one to two R.sup.10,
wherein each R.sup.10 is selected from: [0133] i) halogen selected
from fluoro or chloro, or [0134] ii) (C.sub.1-C.sub.6)alkyl,
wherein the (C.sub.1-C.sub.6)alkyl is methyl; and
[0135] ring D is optionally substituted with one to three R.sup.11,
wherein each R.sup.11 is selected from: [0136] i) halogen selected
from fluoro or chloro; [0137] ii) optionally substituted
(C.sub.1-C.sub.6)alkyl, wherein the (C.sub.1-C.sub.6)alkyl is
methyl and the methyl is optionally substituted with one to three
fluoro (e.g., fluoromethyl, difluoromethyl, or trifluoromethyl);
and [0138] iii) optionally substituted (C.sub.1-C.sub.6)alkoxy,
wherein the (C.sub.1-C.sub.6)alkoxy is methoxy and the methoxy is
optionally substituted with one to three fluoro (e.g.,
fluoromethoxy, difluoromethoxy, or trifluoromethoxy).
[0139] In any of the above-mentioned embodiments for Formula II,
R.sup.1 is a (C.sub.1-C.sub.6)alkyl wherein the alkyl is methyl. In
certain embodiments, when R.sup.1 is methyl, the R.sup.1--X moiety
of Formula I is 4-methyl-1H-imidazol-1-yl.
[0140] Formula III, as depicted below, is a subset of Formula I as
depicted above, wherein X is a (5-membered)heteroaryl, wherein the
heteroaryl is triazolyl, R.sup.1 is a (C.sub.1-C.sub.6)alkyl,
wherein the (C.sub.1-C.sub.6)alkyl is methyl, R.sup.6 and R.sup.7
are each hydrogen, y is 1, and the cyclopropabenzofuranyl moiety is
attached via the benzylic position of the cyclopropabenzofuranyl
moiety:
##STR00006##
[0141] In certain embodiments, in Formula III, as depicted above,
or a pharmaceutically acceptable salt thereof:
[0142] R.sup.1 is selected from the group consisting of hydrogen,
halogen, cyano, hydroxy, optionally substituted
(C.sub.1-C.sub.6)alkyl, and optionally substituted
(C.sub.1-C.sub.6)alkoxy; wherein the (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)alkoxy are optionally substituted with one to
three substituents selected from halogen, oxo, cyano, hydroxy, or
--SF.sub.5;
[0143] R.sup.2a, R.sup.2b, R.sup.4a, R.sup.4b, R.sup.5a and
R.sup.5b are each independently selected from hydrogen, halogen,
cyano, hydroxy or optionally substituted
(C.sub.1-C.sub.6)alkyl;
[0144] ring B is optionally substituted with one to two R.sup.10,
wherein each R.sup.10 is independently selected from halogen or
optionally substituted (C.sub.1-C.sub.6)alkyl; and
[0145] ring D is optionally substituted with one to three R.sup.11,
wherein each R.sup.11 is independently selected from halogen,
optionally substituted (C.sub.1-C.sub.6)alkyl, and optionally
substituted (C.sub.1-C.sub.6)alkoxy;
[0146] In certain embodiments, Formula III is as immediately
described above:
[0147] R.sup.1 is selected from the group consisting of hydrogen,
halogen, cyano, hydroxy, (C.sub.1-C.sub.6)alkyl, and
(C.sub.1-C.sub.6)alkoxy; wherein the (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)alkoxy are optionally substituted with one to
three fluoro atoms;
[0148] R.sup.2a, R.sup.2b, R.sup.4a, R.sup.4b, R.sup.5a and
R.sup.5b are each independently selected from hydrogen or
(C.sub.1-C.sub.6)alkyl, wherein the (C.sub.1-C.sub.6)alkyl is
methyl;
[0149] ring B is optionally substituted with one to two R.sup.10,
wherein each R.sup.10 is selected from: [0150] i) halogen selected
from fluoro or chloro, or [0151] ii) (C.sub.1-C.sub.6)alkyl,
wherein the (C.sub.1-C.sub.6)alkyl is methyl; and
[0152] ring D is optionally substituted with one to three R.sup.11,
wherein each R.sup.11 is selected from: [0153] i) halogen selected
from fluoro or chloro; [0154] ii) optionally substituted
(C.sub.1-C.sub.6)alkyl, wherein the (C.sub.1-C.sub.6)alkyl is
methyl and the methyl is optionally substituted with one to three
fluoro (e.g., fluoromethyl, difluoromethyl, or trifluoromethyl);
and [0155] iii) optionally substituted (C.sub.1-C.sub.6)alkoxy,
wherein the (C.sub.1-C.sub.6)alkoxy is methoxy and the methoxy is
optionally substituted with one to three fluoro (e.g.,
fluoromethoxy, difluoromethoxy, or trifluoromethoxy).
[0156] In any of the above-mentioned embodiments for Formula III,
R.sup.1 is a (C.sub.1-C.sub.6)alkyl wherein the alkyl is methyl. In
certain embodiments, when R.sup.1 is methyl, the R.sup.1--X moiety
is 3-methyl-1H-1,2,4-triazol-1-yl.
[0157] In certain other embodiments, compounds of the present
invention are selected from the group consisting of: [0158]
7-(4-methyl-1H-imidazol-1-yl)-2-{[1a-methyl-5-(trifluoromethoxy)-1,1a-dih-
ydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,-
2-a]pyrazine-1,6-dione; [0159]
7-(4-methyl-1H-imidazol-1-yl)-2-{[(1aS,6bS)-1a-methyl-5-(trifluoromethoxy-
)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-
-pyrido[1,2-a]pyrazine-1,6-dione; [0160]
7-(4-methyl-1H-imidazol-1-yl)-2-{[(1aR,6bR)-1a-methyl-5-(trifluoromethoxy-
)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-
-pyrido[1,2-a]pyrazine-1,6-dione; [0161]
2-{[3-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b-
][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,6-dione; [0162]
2-{[(1aS,6bS)-3-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione; [0163]
2-{[(1aR,6bR)-3-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione; [0164]
2-{[4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b-
][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,6-dione; [0165]
2-{[(1aS,6bS)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione; [0166]
2-{[(1aR,6bR)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione; [0167]
2-{[4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b-
][1]benzofuran-6b-yl]methyl}-7-(3-methyl-1H-1,2,4-triazol-1-yl)-3,4-dihydr-
o-2H-pyrido[1,2-a]pyrazine-1,6-dione; [0168]
2-{[(1aS,6bS)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(3-methyl-1H-1,2,4-triazol-1-yl)--
3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione; [0169]
2-{[(1aR,6bR)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(3-methyl-1H-1,2,4-triazol-1-yl)--
3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione; [0170]
2-{[(1aS,6bS)-4-chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione; [0171]
2-{[(1aR,6bR)-4-chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione; [0172]
2-{[(1aS,6bS)-5-(difluoromethoxy)-4-fluoro-1a-methyl-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione; [0173]
2-{[(1aR,6bR)-5-(difluoromethoxy)-4-fluoro-1a-methyl-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione; [0174]
2-{[(1aS,6bS)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-[4-(hydroxymethyl)-1H-imidazol-1--
yl]-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione; [0175]
7-(4-methyl-1H-imidazol-1-yl)-2-{[(1aS,6bS)-1a-methyl-5-(trifluoromethyl)-
-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,6-dione; [0176]
7-(4-methyl-1H-imidazol-1-yl)-2-{[(1aR,6bR)-1a-methyl-5-(trifluoromethyl)-
-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,6-dione; [0177]
2-{[(1aS,6bS)-4-fluoro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione; [0178]
2-{[(1aR,6bR)-4-fluoro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione; [0179]
2-{[(1aS,6bS)-3-fluoro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione; [0180]
2-{[(1aR,6bR)-3-fluoro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione; [0181]
2-{[(1aS,6bS)-3-chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione; and [0182]
2-{[(1aR,6bR)-3-chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione; or
[0183] the pharmaceutically acceptable salts thereof.
[0184] In another embodiment, selected compounds of the present
invention, or pharmaceutically acceptable salts thereof, may be
useful for the treatment of neurodegeneration and psychiatric
disorders, including Alzheimer's disease or Niemann-Pick disease
type C.
[0185] In certain embodiments, selected compounds of the present
invention may be useful for use in reducing the production of
amyloid beta (A.beta.) proteins in a subject in need thereof.
[0186] In certain embodiments, selected compounds of the present
invention may be useful for treating Alzheimer's disease or
Niemann-Pick disease type C in a patient, the method comprising
administering a therapeutically effective amount of a compound of
the present invention or a pharmaceutically acceptable salt
thereof, to a patient in need thereof.
[0187] In certain embodiments, the present invention is directed to
a pharmaceutical composition comprising selected compounds of the
present invention, or a pharmaceutically acceptable salt thereof,
and a pharmaceutically acceptable excipient.
[0188] In certain embodiments, the present invention is directed to
a method for reducing the production of amyloid beta (A.beta.)
proteins in a subject in need thereof, the method comprising
administering to said subject a therapeutically effective amount of
a compound of Formula I, Formula II or Formula III, or a
pharmaceutically acceptable salt thereof.
[0189] In certain other embodiments, the present invention is
directed to a method of treating Alzheimer's disease in a subject
in need thereof, the method comprising administering to said
subject a therapeutically effective amount of a compound of Formula
I, Formula II or Formula III, or a pharmaceutically acceptable salt
thereof.
Pharmacology
[0190] Alzheimer's disease (AD) research indicates that the disease
is associated with the buildup of plaques in variable shapes and
sizes in the brain. The primary plaques associated with AD are
composed of amyloid beta peptides (A.beta.). A.beta. is produced
when the amyloid precursor protein (APP) undergoes successive
proteolysis by the aspartyl proteases .beta.- and .gamma.-secretase
(Haas et al., "Trafficking and proteolytic processing of APP." Cold
Spring Harbor Perspect. Med., 2011). .gamma.-Secretase is a large
complex consisting of at least four different integral proteins,
one of which is presenilin and has been identified as the catalytic
component that harbors the catalytic aspartates (De Strooper, Bart
et al., "Presenilins and .gamma.-Secretase: Structure, Function,
and Role in Alzheimer's Disease. "Cold Spring Harbor Perspect. Med.
2012; 2:a006304). Presenilin 1 and 2 were first discovered as sites
of missense mutations responsible for early-onset Alzheimer's
disease. The encoded multipass membrane proteins were subsequently
found to be the catalytic components of .gamma.-secretases,
membrane-embedded aspartyl protease complexes responsible for
generating the carboxyl terminus of the amyloid beta protein from
the amyloid protein precursor. (De Strooper, Bart et al.; 2012).
Accordingly, targeting the .gamma.-secretase complex for drug
discovery has become a main focus of Alzheimer's disease
research.
[0191] The compounds of the present invention are believed to be
.gamma.-secretase modulators, which modulate the .gamma.-secretase
complex such that longer pathogenic A.beta. peptides (i.e.,
A.beta.342) are reduced and shorter A.beta. species (i.e.,
A.beta.37 and/or A.beta.38) are increased. .gamma.-Secretase
modulators can be used for treating conditions or diseases of the
central nervous system involving the .gamma.-secretase complex,
such as Niemann-Pick disease type C; neurological disorders (such
as migraine; epilepsy; Alzheimer's disease; Parkinson's disease;
brain injury; stroke; cerebrovascular diseases (including cerebral
arteriosclerosis, cerebral amyloid angiopathy, hereditary cerebral
hemorrhage, and brain hypoxia-ischemia); cognitive disorders
(including amnesia, senile dementia, HIV-associated dementia,
Alzheimer's disease, Huntington's disease, Lewy body dementia,
vascular dementia, drug-related dementia, myoclonus, dystonia,
delirium, Pick's disease, Creutzfeldt-Jacob disease, HIV disease,
Gilles de la Tourette's syndrome, epilepsy, and mild cognitive
impairment); tardive dyskinesia; muscular spasms and disorders
associated with muscular spasticity or weakness including tremors;
mental deficiency (including spasticity, Down's syndrome and
fragile X syndrome); sleep disorders (including hypersomnia,
circadian rhythm sleep disorder, insomnia, parasomnia, and sleep
deprivation) and psychiatric disorders such as anxiety (including
acute stress disorder, generalized anxiety disorder, social anxiety
disorder, panic disorder, post-traumatic stress disorder,
agoraphobia, and obsessive-compulsive disorder); factitious
disorders (including acute hallucinatory mania); impulse control
disorders (including compulsive gambling and intermittent explosive
disorder); mood disorders (including bipolar I disorder, bipolar II
disorder, mania, mixed affective state, major depression, chronic
depression, seasonal depression, psychotic depression, premenstrual
syndrome (PMS), premenstrual dysphoric disorder (PDD), and
postpartum depression); psychomotor disorders; psychotic disorders
(including schizophrenia, schizoaffective disorder,
schizophreniform, and delusional disorder); drug dependence
(including narcotic dependence, alcoholism, amphetamine dependence,
cocaine addiction, nicotine dependence, and drug withdrawal
syndrome); eating disorders (including anorexia, bulimia, binge
eating disorder, hyperphagia, obesity, compulsive eating disorders
and pagophagia); sexual dysfunction disorders; urinary
incontinence; neuronal damage disorders (including ocular damage,
retinopathy or macular degeneration of the eye; tinnitus, hearing
impairment and loss; and brain edema) and pediatric psychiatric
disorders (including attention deficit disorder, attention
deficit/hyperactive disorder, conduct disorder, and autism) in a
mammal, preferably a human, comprising administering to said mammal
a therapeutically effective amount of a compound of the present
invention or a pharmaceutically acceptable salt thereof.
[0192] In certain embodiments, the compounds of the present
invention can be utilized for treating a neurological disorder
(such as migraine; epilepsy; Alzheimer's disease; Parkinson's
disease; Niemann Pick type C; brain injury; stroke; cerebrovascular
disease; cognitive disorder; sleep disorder) or a psychiatric
disorder (such as anxiety; factitious disorder; impulse control
disorder; mood disorder; psychomotor disorder; psychotic disorder;
drug dependence; eating disorder; and pediatric psychiatric
disorder) in a mammal, preferably a human, comprising administering
to said mammal a therapeutically effective amount of a compound of
the invention or pharmaceutically acceptable salt thereof.
[0193] Compounds of the present invention may also be useful for
improving memory (both short term and long term) and learning
ability.
[0194] The text revision of the fourth edition of the Diagnostic
and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000,
American Psychiatric Association, Washington D.C.) provides a
diagnostic tool for identifying many of the disorders described
herein. The skilled artisan will recognize that there are
alternative nomenclatures, nosologies, and classification systems
for disorders described herein, including those as described in the
DMS-IV and that terminology and classification systems evolve with
medical scientific progress.
Formulations
[0195] The compounds of the invention may be administered orally.
Oral administration may involve swallowing, so that the compound
enters the gastrointestinal tract, or buccal or sublingual
administration may be employed, by which the compound enters the
blood stream directly from the mouth.
[0196] In another embodiment, the compounds of the invention may
also be administered directly into the blood stream, into muscle,
or into an internal organ. Suitable means for parenteral
administration include intravenous, intraarterial, intraperitoneal,
intrathecal, intraventricular, intraurethral, intrasternal,
intracranial, intramuscular and subcutaneous. Suitable devices for
parenteral administration include needle (including microneedle)
injectors, needle-free injectors and infusion techniques.
[0197] In another embodiment, the compounds of the invention may
also be administered topically to the skin or mucosa, that is,
dermally or transdermally. In another embodiment, the compounds of
the invention can also be administered intranasally or by
inhalation. In another embodiment, the compounds of the invention
may be administered rectally or vaginally. In another embodiment,
the compounds of the invention may also be administered directly to
the eye or ear.
[0198] The dosage regimen for the compounds and/or compositions
containing the compounds is based on a variety of factors,
including the type, age, weight, sex and medical condition of the
patient; the severity of the condition; the route of
administration; and the activity of the particular compound
employed. Thus the dosage regimen may vary widely. Dosage levels of
the order from about 0.01 mg to about 100 mg per kilogram of body
weight per day are useful in the treatment of the above-indicated
conditions. In one embodiment, the total daily dose of a compound
of the invention (administered in single or divided doses) is
typically from about 0.01 to about 100 mg/kg. In another
embodiment, the total daily dose of the compound of the invention
is from about 0.1 to about 50 mg/kg, and in another embodiment,
from about 0.5 to about 30 mg/kg (i.e., mg compound of the
invention per kg body weight). In one embodiment, dosing is from
0.01 to 10 mg/kg/day. In another embodiment, dosing is from 0.1 to
1.0 mg/kg/day. Dosage unit compositions may contain such amounts or
submultiples thereof to make up the daily dose. In many instances,
the administration of the compound will be repeated a plurality of
times in a day (typically no greater than 4 times). Multiple doses
per day typically may be used to increase the total daily dose, if
desired.
[0199] For oral administration, the compositions may be provided in
the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0,
10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500
milligrams of the active ingredient for the symptomatic adjustment
of the dosage to the patient. A medicament typically contains from
about 0.01 mg to about 500 mg of the active ingredient, or in
another embodiment, from about 1 mg to about 100 mg of active
ingredient. Intravenously, doses may range from about 0.1 to about
10 mg/kg/minute during a constant rate infusion.
[0200] Suitable subjects according to the present invention include
mammalian subjects. Mammals according to the present invention
include, but are not limited to, canine, feline, bovine, caprine,
equine, ovine, porcine, rodents, lagomorphs, primates, and the
like, and encompass mammals in utero. In one embodiment, humans are
suitable subjects. Human subjects may be of either gender and at
any stage of development.
[0201] In another embodiment, the invention comprises the use of
one or more compounds of the invention for the preparation of a
medicament for the treatment of the conditions recited herein.
[0202] For the treatment of the conditions referred to above, the
compounds of the invention can be administered as compound per se.
Alternatively, pharmaceutically acceptable salts are suitable for
medical applications because of their greater aqueous solubility
relative to the parent compound.
[0203] In another embodiment, the present invention comprises
pharmaceutical compositions. Such pharmaceutical compositions
comprise a compound of the invention presented with a
pharmaceutically acceptable carrier. The carrier can be a solid, a
liquid, or both, and may be formulated with the compound as a
unit-dose composition, for example, a tablet, which can contain
from 0.05% to 95% by weight of the active compounds. A compound of
the invention may be coupled with suitable polymers as targetable
drug carriers. Other pharmacologically active substances can also
be present.
[0204] The compounds of the present invention may be administered
by any suitable route, preferably in the form of a pharmaceutical
composition adapted to such a route, and in a dose effective for
the treatment intended. The active compounds and compositions, for
example, may be administered orally, rectally, parenterally, or
topically.
[0205] Oral administration of a solid dose form may be, for
example, presented in discrete units, such as hard or soft
capsules, pills, cachets, lozenges, or tablets, each containing a
predetermined amount of at least one compound of the present
invention. In another embodiment, the oral administration may be in
a powder or granule form. In another embodiment, the oral dose form
is sub-lingual, such as, for example, a lozenge. In such solid
dosage forms, the compounds of the invention are ordinarily
combined with one or more adjuvants. Such capsules or tablets may
contain a controlled-release formulation. In the case of capsules,
tablets, and pills, the dosage forms also may comprise buffering
agents or may be prepared with enteric coatings.
[0206] In another embodiment, oral administration may be in a
liquid dose form. Liquid dosage forms for oral administration
include, for example, pharmaceutically acceptable emulsions,
solutions, suspensions, syrups, and elixirs containing inert
diluents commonly used in the art (i.e., water). Such compositions
also may comprise adjuvants, such as wetting, emulsifying,
suspending, flavoring (e.g., sweetening), and/or perfuming
agents.
[0207] In another embodiment, the present invention comprises a
parenteral dose form. "Parenteral administration" includes, for
example, subcutaneous injections, intravenous injections,
intraperitoneal injections, intramuscular injections, intrasternal
injections, and infusion. Injectable preparations (i.e., sterile
injectable aqueous or oleaginous suspensions) may be formulated
according to the known art using suitable dispersing, wetting,
and/or suspending agents.
[0208] In another embodiment, the present invention comprises a
topical dose form. "Topical administration" includes, for example,
transdermal administration, such as via transdermal patches or
iontophoresis devices, intraocular administration, or intranasal or
inhalation administration. Compositions for topical administration
also include, for example, topical gels, sprays, ointments, and
creams. A topical formulation may include a compound which enhances
absorption or penetration of the active ingredient through the skin
or other affected areas. When the compounds of this invention are
administered by a transdermal device, administration will be
accomplished using a patch either of the reservoir and porous
membrane type or of a solid matrix variety. Typical formulations
for this purpose include gels, hydrogels, lotions, solutions,
creams, ointments, dusting powders, dressings, foams, films, skin
patches, wafers, implants, sponges, fibers, bandages and
microemulsions. Liposomes may also be used. Typical carriers
include alcohol, water, mineral oil, liquid petrolatum, white
petrolatum, glycerin, polyethylene glycol and propylene glycol.
Penetration enhancers may be incorporated--see, for example, Finnin
and Morgan, J. Pharm. Sci., 88 (10), 955-958 (1999).
[0209] Formulations suitable for topical administration to the eye
include, for example, eye drops wherein the compound of this
invention is dissolved or suspended in a suitable carrier. A
typical formulation suitable for ocular or aural administration may
be in the form of drops of a micronized suspension or solution in
isotonic, pH-adjusted, sterile saline. Other formulations suitable
for ocular and aural administration include ointments,
biodegradable (e.g., absorbable gel sponges, collagen) and
non-biodegradable (e.g., silicone) implants, wafers, lenses and
particulate or vesicular systems, such as niosomes or liposomes. A
polymer such as crossed-linked polyacrylic acid, polyvinyl alcohol,
hyaluronic acid, a cellulosic polymer, for example,
hydroxypropylmethyl cellulose, hydroxyethyl cellulose, or methyl
cellulose, or a heteropolysaccharide polymer, for example, gelan
gum, may be incorporated together with a preservative, such as
benzalkonium chloride. Such formulations may also be delivered by
iontophoresis.
[0210] For intranasal administration or administration by
inhalation, the active compounds of the invention are conveniently
delivered in the form of a solution or suspension from a pump spray
container that is squeezed or pumped by the patient or as an
aerosol spray presentation from a pressurized container or a
nebulizer, with the use of a suitable propellant. Formulations
suitable for intranasal administration are typically administered
in the form of a dry powder (either alone; as a mixture, for
example, in a dry blend with lactose; or as a mixed component
particle, for example, mixed with phospholipids, such as
phosphatidylcholine) from a dry powder inhaler or as an aerosol
spray from a pressurized container, pump, spray, atomizer
(preferably an atomizer using electrohydrodynamics to produce a
fine mist), or nebulizer, with or without the use of a suitable
propellant, such as 1,1,1,2-tetrafluoroethane or
1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder
may comprise a bioadhesive agent, for example, chitosan or
cyclodextrin.
[0211] In another embodiment, the present invention comprises a
rectal dose form. Such rectal dose form may be in the form of, for
example, a suppository. Cocoa butter is a traditional suppository
base, but various alternatives may be used as appropriate.
[0212] Other carrier materials and modes of administration known in
the pharmaceutical art may also be used. Pharmaceutical
compositions of the invention may be prepared by any of the
well-known techniques of pharmacy, such as effective formulation
and administration procedures. The above considerations in regard
to effective formulations and administration procedures are well
known in the art and are described in standard textbooks.
Formulation of drugs is discussed in, for example, Hoover, John E.,
Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,
Pa., 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms,
Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds.,
Handbook of Pharmaceutical Excipients (3.sup.rd Ed.), American
Pharmaceutical Association, Washington, 1999.
[0213] The compounds of the present invention can be used, alone or
in combination with other therapeutic agents, in the treatment of
various conditions or disease states. The compound(s) of the
present invention and other therapeutic agent(s) may be
administered simultaneously (either in the same dosage form or in
separate dosage forms) or sequentially. An exemplary therapeutic
agent may be, for example, a metabotropic glutamate receptor
agonist.
[0214] The administration of two or more compounds "in combination"
means that the two compounds are administered closely enough in
time that the presence of one alters the biological effects of the
other. The two or more compounds may be administered
simultaneously, concurrently or sequentially. Additionally,
simultaneous administration may be carried out by mixing the
compounds prior to administration or by administering the compounds
at the same point in time but at different anatomic sites or using
different routes of administration.
[0215] The phrases "concurrent administration,"
"co-administration," "simultaneous administration," and
"administered simultaneously" mean that the compounds are
administered in combination.
[0216] The present invention includes the use of a combination of a
.gamma.-secretase modulator compound as provided by the compounds
of the invention and one or more additional pharmaceutically active
agent(s). If a combination of active agents is administered, then
they may be administered sequentially or simultaneously, in
separate dosage forms or combined in a single dosage form.
Accordingly, the present invention also includes pharmaceutical
compositions comprising an amount of: (a) a first agent comprising
a compound of the present invention or a pharmaceutically
acceptable salt of the compound; (b) a second pharmaceutically
active agent; and (c) a pharmaceutically acceptable carrier,
vehicle or diluent.
[0217] Various pharmaceutically active agents may be selected for
use in conjunction with the compounds of the present invention,
depending on the disease, disorder, or condition to be treated.
Pharmaceutically active agents that may be used in combination with
the compositions of the present invention include, without
limitation:
[0218] (i) acetylcholinesterase inhibitors, such as donepezil
hydrochloride (ARICEPT, MEMAC), physostigmine salicylate
(ANTILIRIUM), physostigmine sulfate (ESERINE), metrifonate,
neostigmine, ganstigmine, pyridostigmine (MESTINON), ambenonium
(MYTELASE), demarcarium, Debio 9902 (also known as ZT-1;
Debiopharm), rivastigmine (EXELON), ladostigil, NP-0361,
galantamine hydrobromide (RAZADYNE, RIMINYL, NIVALIN), tacrine
(COGNEX), tolserine, velnacrine maleate, memoquin, huperzine A
(HUP-A; NeuroHitech), phenserine, edrophonium (ENLON, TENSILON),
and INM-176;
[0219] (ii) amyloid-.beta. (or fragments thereof), such as
A.beta..sub.1-15 conjugated to pan HLA DR-binding epitope (PADRE),
ACC-001 (Elan/Wyeth), ACI-01, ACI-24, AN-1792, Affitope AD-01,
CAD106, and V-950;
[0220] (iii) antibodies to amyloid-.beta. (or fragments thereof),
such as ponezumab, solanezumab, bapineuzumab (also known as
AAB-001), AAB-002 (Wyeth/Elan), ACI-01-Ab7, BAN-2401, intravenous
Ig (GAMMAGARD), LY2062430 (humanized m266; Lilly), R1450 (Roche),
ACU-5A5, huC091, and those disclosed in International Patent
Publication Nos WO04/032868, WO05/025616, WO06/036291, WO06/069081,
WO06/118959, in US Patent Publication Nos US2003/0073655,
US2004/0192898, US2005/0048049, US2005/0019328, in European Patent
Publication Nos EP0994728 and 1257584, and in U.S. Pat. No.
5,750,349;
[0221] (iv) amyloid-lowering or -inhibiting agents (including those
that reduce amyloid production, accumulation and fibrillization)
such as dimebon, davunetide, eprodisate, leuprolide, SK-PC-B70M,
celecoxib, lovastatin, anapsos, oxiracetam, pramiracetam,
varenicline, nicergoline, colostrinin, bisnorcymserine (also known
as BNC), NIC5-15 (Humanetics), E-2012 (Eisai), pioglitazone,
clioquinol (also known as PBT1), PBT2 (Prana Biotechnology),
flurbiprofen (ANSAID, FROBEN) and its R-enantiomer tarenflurbil
(FLURIZAN), nitroflurbiprofen, fenoprofen (FENOPRON, NALFON),
ibuprofen (ADVIL, MOTRIN, NUROFEN), ibuprofen lysinate,
meclofenamic acid, meclofenamate sodium (MECLOMEN), indomethacin
(INDOCIN), diclofenac sodium (VOLTAREN), diclofenac potassium,
sulindac (CLINORIL), sulindac sulfide, diflunisal (DOLOBID),
naproxen (NAPROSYN), naproxen sodium (ANAPROX, ALEVE), ARC031
(Archer Pharmaceuticals), CAD-106 (Cytos), LY450139 (Lilly),
insulin-degrading enzyme (also known as insulysin), the gingko
biloba extract EGb-761 (ROKAN, TEBONIN), tramiprosate (CEREBRIL,
ALZHEMED), eprodisate (FIBRILLEX, KIACTA), compound W
(3,5-bis(4-nitrophenoxy)benzoic acid), NGX-96992, neprilysin (also
known as neutral endopeptidase (NEP)), scyllo-inositol (also known
as scyllitol), atorvastatin (LIPITOR), simvastatin (ZOCOR),
KLVFF-(EEX)3, SKF-74652, ibutamoren mesylate, BACE inhibitors such
as ASP-1702, SCH-745966, JNJ-715754, AMG-0683, AZ-12304146,
BMS-782450, GSK-188909, NB-533, E2609 and TTP-854; gamma secretase
modulators such as ELND-007; and RAGE (receptor for advanced
glycation end-products) inhibitors, such as TTP488 (Transtech) and
TTP4000 (Transtech), and those disclosed in U.S. Pat. No.
7,285,293, including PTI-777;
[0222] (v) alpha-adrenergic receptor agonists, such as guanfacine
(INTUNIV, TENEX), clonidine (CATAPRES), metaraminol (ARAMINE),
methyldopa (ALDOMET, DOPAMET, NOVOMEDOPA), tizanidine (ZANAFLEX),
phenylephrine (also known as neosynephrine), methoxamine,
cirazoline, guanfacine (INTUNIV), lofexidine, xylazine, modafinil
(PROVIGIL), adrafinil, and armodafinil (NUVIGIL);
[0223] (vi) beta-adrenergic receptor blocking agents (beta
blockers), such as carteolol, esmolol (BREVIBLOC), labetalol
(NORMODYNE, TRANDATE), oxprenolol (LARACOR, TRASACOR), pindolol
(VISKEN), propanolol (INDERAL), sotalol (BETAPACE, SOTALEX,
SOTACOR), timolol (BLOCADREN, TIMOPTIC), acebutolol (SECTRAL,
PRENT), nadolol (CORGARD), metoprolol tartrate (LOPRESSOR),
metoprolol succinate (TOPROL-XL), atenolol (TENORMIN), butoxamine,
and SR 59230A (Sanofi);
[0224] (vii) anticholinergics, such as amitriptyline (ELAVIL,
ENDEP), butriptyline, benztropine mesylate (COGENTIN),
trihexyphenidyl (ARTANE), diphenhydramine (BENADRYL), orphenadrine
(NORFLEX), hyoscyamine, atropine (ATROPEN), scopolamine
(TRANSDERM-SCOP), scopolamine methylbromide (PARMINE),
dicycloverine (BENTYL, BYCLOMINE, DIBENT, DILOMINE), tolterodine
(DETROL), oxybutynin (DITROPAN, LYRINEL XL, OXYTROL), penthienate
bromide, propantheline (PRO-BANTHINE), cyclizine, imipramine
hydrochloride (TOFRANIL), imipramine maleate (SURMONTIL),
lofepramine, desipramine (NORPRAMIN), doxepin (SINEQUAN, ZONALON),
trimipramine (SURMONTIL), and glycopyrrolate (ROBINUL);
[0225] (viii) anticonvulsants, such as carbamazepine (TEGRETOL,
CARBATROL), oxcarbazepine (TRILEPTAL), phenytoin sodium (PHENYTEK),
fosphenytoin (CEREBYX, PRODILANTIN), divalproex sodium (DEPAKOTE),
gabapentin (NEURONTIN), pregabalin (LYRICA), topirimate (TOPAMAX),
valproic acid (DEPAKENE), valproate sodium (DEPACON),
1-benzyl-5-bromouracil, progabide, beclamide, zonisamide (TRERIEF,
EXCEGRAN), CP-465022, retigabine, talampanel, and primidone
(MYSOLINE);
[0226] (ix) antipsychotics, such as lurasidone (LATUDA, also known
as SM-13496; Dainippon Sumitomo), aripiprazole (ABILIFY),
chlorpromazine (THORAZINE), haloperidol (HALDOL), iloperidone
(FANAPTA), flupentixol decanoate (DEPIXOL, FLUANXOL), reserpine
(SERPLAN), pimozide (ORAP), fluphenazine decanoate, fluphenazine
hydrochloride, prochlorperazine (COMPRO), asenapine (SAPHRIS),
loxapine (LOXITANE), molindone (MOBAN), perphenazine, thioridazine,
thiothixine, trifluoperazine (STELAZINE), ramelteon, clozapine
(CLOZARIL), norclozapine (ACP-104), risperidone (RISPERDAL),
paliperidone (INVEGA), melperone, olanzapine (ZYPREXA), quetiapine
(SEROQUEL), talnetant, amisulpride, ziprasidone (GEODON),
blonanserin (LONASEN), and ACP-103 (Acadia Pharmaceuticals);
[0227] (x) calcium channel blockers such as lomerizine, ziconotide,
nilvadipine (ESCOR, NIVADIL), diperdipine, amlodipine (NORVASC,
ISTIN, AMLODIN), felodipine (PLENDIL), nicardipine (CARDENE),
nifedipine (ADALAT, PROCARDIA), MEM 1003 and its parent compound
nimodipine (NIMOTOP), nisoldipine (SULAR), nitrendipine, lacidipine
(LACIPIL, MOTENS), lercanidipine (ZANIDIP), lifarizine, diltiazem
(CARDIZEM), verapamil (CALAN, VERELAN), AR-R 18565 (AstraZeneca),
and enecadin;
[0228] (xi) catechol O-methyltransferase (COMT) inhibitors, such as
nitecapone, tolcapone (TASMAR), entacapone (COMTAN), and
tropolone;
[0229] (xii) central nervous system stimulants, such as
atomoxetine, reboxetine, yohimbine, caffeine, phenmetrazine,
phendimetrazine, pemoline, fencamfamine (GLUCOENERGAN, REACTIVAN),
fenethylline (CAPTAGON), pipradol (MERETRAN), deanol (also known as
dimethylaminoethanol), methylphenidate (DAYTRANA), methylphenidate
hydrochloride (RITALIN), dexmethylphenidate (FOCALIN), amphetamine
(alone or in combination with other CNS stimulants, e.g. ADDERALL
(amphetamine aspartate, amphetamine sulfate, dextroamphetamine
saccharate, and dextroamphetamine sulfate)), dextroamphetamine
sulfate (DEXEDRINE, DEXTROSTAT), methamphetamine (DESOXYN),
lisdexamfetamine (VYVANSE), and benzphetamine (DIDREX);
[0230] (xiii) corticosteroids, such as prednisone (STERAPRED,
DELTASONE), prednisolone (PRELONE), prednisolone acetate (OMNIPRED,
PRED MILD, PRED FORTE), prednisolone sodium phosphate (ORAPRED
ODT), methylprednisolone (MEDROL); methylprednisolone acetate
(DEPO-MEDROL), and methylprednisolone sodium succinate
(A-METHAPRED, SOLU-MEDROL);
[0231] (xiv) dopamine receptor agonists, such as apomorphine
(APOKYN), bromocriptine (PARLODEL), cabergoline (DOSTINEX),
dihydrexidine, dihydroergocryptine, fenoldopam (CORLOPAM), lisuride
(DOPERGIN), terguride spergolide (PERMAX), piribedil (TRIVASTAL,
TRASTAL), pramipexole (MIRAPEX), quinpirole, ropinirole (REQUIP),
rotigotine (NEUPRO), SKF-82958 (GlaxoSmithKline), cariprazine,
pardoprunox and sarizotan;
[0232] (xv) dopamine receptor antagonists, such as chlorpromazine,
fluphenazine, haloperidol, loxapine, risperidone, thioridazine,
thiothixene, trifluoperazine, tetrabenazine (NITOMAN, XENAZINE),
7-hydroxyamoxapine, droperidol (INAPSINE, DRIDOL, DROPLETAN),
domperidone (MOTILIUM), L-741742, L-745870, raclopride, SB-277011A,
SCH-23390, ecopipam, SKF-83566, and metoclopramide (REGLAN);
[0233] (xvi) dopamine reuptake inhibitors such as bupropion,
safinamide, nomifensine maleate (MERITAL), vanoxerine (also known
as GBR-12909) and its decanoate ester DBL-583, and amineptine;
[0234] (xvii) gamma-aminobutyric acid (GABA) receptor agonists,
such as baclofen (LIORESAL, KEMSTRO), siclofen, pentobarbital
(NEMBUTAL), progabide (GABRENE), and clomethiazole;
[0235] (xviii) histamine 3 (H3) antagonists such as ciproxifan,
tiprolisant, S-38093, irdabisant, pitolisant, GSK-239512,
GSK-207040, JNJ-5207852, JNJ-17216498, HPP-404, SAR-110894,
trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclob-
utanecarboxamide (PF-3654746 and those disclosed in US Patent
Publication Nos US2005-0043354, US2005-0267095, US2005-0256135,
US2008-0096955, US2007-1079175, and US2008-0176925; International
Patent Publication Nos WO2006/136924, WO2007/063385, WO2007/069053,
WO2007/088450, WO2007/099423, WO2007/105053, WO2007/138431, and
WO2007/088462; and U.S. Pat. No. 7,115,600);
[0236] (xix) immunomodulators such as glatiramer acetate (also
known as copolymer-1; COPAXONE), MBP-8298 (synthetic myelin basic
protein peptide), dimethyl fumarate, fingolimod (also known as
FTY720), roquinimex (LINOMIDE), laquinimod (also known as
ABR-215062 and SAIK-MS), ABT-874 (human anti-lL-12 antibody;
Abbott), rituximab (RITUXAN), alemtuzumab (CAMPATH), daclizumab
(ZENAPAX), and natalizumab (TYSABRI);
[0237] (xx) immunosuppressants such as methotrexate (TREXALL,
RHEUMATREX), mitoxantrone (NOVANTRONE), mycophenolate mofetil
(CELLCEPT), mycophenolate sodium (MYFORTIC), azathioprine (AZASAN,
IMURAN), mercaptopurine (PURI-NETHOL), cyclophosphamide (NEOSAR,
CYTOXAN), chlorambucil (LEUKERAN), cladribine (LEUSTATIN, MYLINAX),
alpha-fetoprotein, etanercept (ENBREL), and
4-(benzyloxy)-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-1H,1'H-2,2'-bipyr-
role (also known as PNU-156804);
[0238] (xxi) interferons, including interferon beta-1a (AVONEX,
REBIF) and interferon beta-lb (BETASERON, BETAFERON);
[0239] (xxii) levodopa (or its methyl or ethyl ester), alone or in
combination with a DOPA decarboxylase inhibitor (e.g., carbidopa
(SINEMET, CARBILEV, PARCOPA), benserazide (MADOPAR),
.alpha.-methyldopa, monofluoromethyldopa, difluoromethyldopa,
brocresine, or m-hydroxybenzylhydrazine);
[0240] (xxiii) N-methyl-D-aspartate (NMDA) receptor antagonists,
such as memantine (NAMENDA, AXURA, EBIXA), amantadine (SYMMETREL),
acamprosate (CAMPRAL), besonprodil, ketamine (KETALAR), delucemine,
dexanabinol, dexefaroxan, dextromethorphan, dextrorphan,
traxoprodil, CP-283097, himantane, idantadol, ipenoxazone, L-701252
(Merck), lancicemine, levorphanol (DROMORAN), LY-233536 and
LY-235959 (both Lilly), methadone, (DOLOPHINE), neramexane,
perzinfotel, phencyclidine, tianeptine (STABLON), dizocilpine (also
known as MK-801), EAB-318 (Wyeth), ibogaine, voacangine,
tiletamine, riluzole (RILUTEK), aptiganel (CERESOTAT), gavestinel,
and remacimide;
[0241] (xxiv) monoamine oxidase (MAO) inhibitors, such as
selegiline (EMSAM), selegiline hydrochloride (L-deprenyl, ELDEPRYL,
ZELAPAR), desmethylselegiline, brofaromine, phenelzine (NARDIL),
tranylcypromine (PARNATE), moclobemide (AURORIX, MANERIX),
befloxatone, safinamide, isocarboxazid (MARPLAN), nialamide
(NIAMID), rasagiline (AZILECT), iproniazid (MARSILID, IPROZID,
IPRONID), CHF-3381 (Chiesi Farmaceutici), iproclozide, toloxatone
(HUMORYL, PERENUM), bifemelane, desoxypeganine, harmine (also known
as telepathine or banasterine), harmaline, linezolid (ZYVOX,
ZYVOXID), and pargyline (EUDATIN, SUPIRDYL);
[0242] (xxv) muscarinic receptor (particularly M1 subtype)
agonists, such as cevimeline, levetiracetam, bethanechol chloride
(DUVOID, URECHOLINE), itameline, pilocarpine (SALAGEN), NGX267,
arecoline, L-687306 (Merck), L-689660 (Merck), furtrethonium iodide
(FURAMON, FURANOL), furtrethonium benzensulfonate, furtrethonium
p-toluenesulfonate, McN-A-343, oxotremorine, sabcomeline, AC-90222
(Acadia Pharmaceuticals), and carbachol (CARBASTAT, MIOSTAT,
CARBOPTIC);
[0243] (xxvi) neuroprotective drugs such as bosutinib, condoliase,
airmoclomol, lamotrigine, perampanel, aniracetam, minaprime,
2,3,4,9-tetrahydro-1H-carbazol-3-one oxime, desmoteplase,
anatibant, astaxanthin, neuropeptide NAP (e.g., AL-108 and AL-208;
both Allon Therapeutics), neurostrol, perampenel, ispronicline,
bis(4-.beta.-D-glucopyranosyloxybenzyl)-2-.beta.-D-glucopyranosyl-2-isobu-
tyltartrate (also known as dactylorhin B or DHB), formobactin,
xaliproden (XAPRILA), lactacystin, dimeboline hydrochloride
(DIMEBON), disufenton (CEROVIVE), arundic acid (ONO-2506, PROGLIA,
CEREACT), citicoline (also known as cytidine 5'-diphosphocholine),
edaravone (RADICUT), AEOL-10113 and AEOL-10150 (both Aeolus
Pharmaceuticals), AGY-94806 (also known as SA-450 and Msc-1),
granulocyte-colony stimulating factor (also known as AX-200),
BAY-38-7271 (also known as KN-387271; Bayer AG), ancrod (VIPRINEX,
ARWIN), DP-b99 (D-Pharm Ltd), HF-0220
(17-.beta.-hydroxyepiandrosterone; Newron Pharmaceuticals), HF-0420
(also known as oligotropin), pyridoxal 5'-phosphate (also known as
MC-1), microplasmin, S-18986, piclozotan, NP031112, tacrolimus,
L-seryl-L-methionyl-L-alanyl-L-lysyl-L-glutamyl-glycyl-L-valine,
AC-184897 (Acadia Pharmaceuticals), ADNF-14 (National Institutes of
Health), stilbazulenyl nitrone, SUN-N8075 (Daiichi Suntory
Biomedical Research), and zonampanel;
[0244] (xxvii) nicotinic receptor agonists, such as epibatidine,
bupropion, CP-601927, varenicline, ABT-089 (Abbott), ABT-594,
AZD-0328 (AstraZeneca), EVP-6124, R3487 (also known as MEM3454;
Roche/Memory Pharmaceuticals), R4996 (also known as MEM63908;
Roche/Memory Pharmaceuticals), TC-4959 and TC-5619 (both
Targacept), and RJR-2403;
[0245] (xxviii) norepinephrine (noradrenaline) reuptake inhibitors,
such as atomoxetine (STRATTERA), doxepin (APONAL, ADAPIN,
SINEQUAN), nortriptyline (AVENTYL, PAMELOR, NORTRILEN), amoxapine
(ASENDIN, DEMOLOX, MOXIDIL), reboxetine (EDRONAX, VESTRA),
viloxazine (VIVALAN), maprotiline (DEPRILEPT, LUDIOMIL, PSYMION),
bupropion (WELLBUTRIN), and radaxafine;
[0246] (xxix) phosphodiesterase (PDE) inhibitors, including but not
limited to, (a) PDE1 inhibitors (e.g., vinpocetine (CAVINTON,
CERACTIN, INTELECTOL) and those disclosed in U.S. Pat. No.
6,235,742), (b) PDE2 inhibitors (e.g.,
erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), BAY 60-7550, and those
described in U.S. Pat. No. 6,174,884), (c) PDE3 inhibitors (e.g.,
anagrelide, cilostazol, milrinone, olprinone, parogrelil, and
pimobendan), (d) PDE4 inhibitors (e.g., apremilast, ibudilast,
roflumilast, rolipram, Ro 20-1724, ibudilast (KETAS), piclamilast
(also known as RP73401), CDP840, cilomilast (ARIFLO), roflumilast,
tofimilast, oglemilast (also known as GRC 3886), tetomilast (also
known as OPC-6535), lirimifast, theophylline (UNIPHYL, THEOLAIR),
arofylline (also known as LAS-31025), doxofylline, RPR-122818, or
mesembrine), and (e) PDE5 inhibitors (e.g., sildenafil (VIAGRA,
REVATIO), tadalafil (CIALIS), vardenafil (LEVITRA, VIVANZA),
udenafil, avanafil, dipyridamole (PERSANTINE), E-4010, E-4021,
E-8010, zaprinast, iodenafil, mirodenafil, DA-8159, and those
disclosed in International Patent Applications WO2002/020521,
WO2005/049616, WO2006/120552, WO2006/126081, WO2006/126082,
WO2006/126083, and WO2007/122466), (f) PDE7 inhibitors; (g) PDE8
inhibitors; (h) PDE9 inhibitors (e.g., BAY 73-6691 (Bayer AG) and
those disclosed in US Patent Publication Nos US2003/0195205,
US2004/0220186, US2006/0111372, US2006/0106035, and U.S. Ser. No.
12/118,062 (filed May 9, 2008)), (i) PDE10 inhibitors such as
2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxy}methyl)quinoline
(PF-2545920), and SCH-1518291, and (j) PDE11 inhibitors;
[0247] (xxx) quinolines, such as quinine (including its
hydrochloride, dihydrochloride, sulfate, bisulfate and gluconate
salts), chloroquine, sontoquine, hydroxychloroquine (PLAQUENIL),
mefloquine (LARIAM), and amodiaquine (CAMOQUIN, FLAVOQUINE);
[0248] (xxxi) .beta.-secretase inhibitors, such as ASP-1702,
SCH-745966, JNJ-715754, AMG-0683, AZ-12304146, BMS-782450,
GSK-188909, NB-533, LY-2886721, E-2609, HPP-854, (+)-phenserine
tartrate (POSIPHEN), LSN-2434074 (also known as LY-2434074),
KMI-574, SCH-745966, Ac-rER (N.sup.2-acetyl-D-arginyl-L-arginine),
loxistatin (also known as E64d), and CA074Me;
[0249] (xxxii) .gamma.-secretase inhibitors and modulators, such as
BMS-708163 (Avagacest), WO20060430064 (Merck), DSP8658 (Dainippon),
ITI-009, L-685458 (Merck), ELAN-G, ELAN-Z,
4-chloro-N-[2-ethyl-1(S)-(hydroxymethyl)butyl]benzenesulfonamide;
[0250] (xxxiii) serotonin (5-hydroxytryptamine) 1A (5-HT.sub.1A)
receptor antagonists, such as spiperone, levo-pindolol, BMY 7378,
NAD-299, S(-)-UH-301, NAN 190, lecozotan;
[0251] (xxxiv) serotonin (5-hydroxytryptamine) 2C (5-HT.sub.2c)
receptor agonists, such as vabicaserin, and zicronapine;
[0252] (xxxv) serotonin (5-hydroxytryptamine) 4 (5-HT.sub.4)
receptor agonists, such as PRX-03140 (Epix);
[0253] (xxxvi) serotonin (5-hydroxytryptamine) 6 (5-HT.sub.6)
receptor antagonists, such as A-964324, AVI-101, AVN-211, mianserin
(TORVOL, BOLVIDON, NORVAL), methiothepin (also known as
metitepine), ritanserin, ALX-1161, ALX-1175, MS-245, LY-483518
(also known as SGS518; Lilly), MS-245, Ro 04-6790, Ro 43-68544, Ro
63-0563, Ro 65-7199, Ro 65-7674, SB-399885, SB-214111, SB-258510,
SB-271046, SB-357134, SB-699929, SB-271046, SB-742457
(GlaxoSmithKline), Lu AE58054 (Lundbeck A/S), and PRX-07034
(Epix);
[0254] (xxxvii) serotonin (5-HT) reuptake inhibitors such as
alaproclate, citalopram (CELEXA, CIPRAMIL), escitalopram (LEXAPRO,
CIPRALEX), clomipramine (ANAFRANIL), duloxetine (CYMBALTA),
femoxetine (MALEXIL), fenfluramine (PONDIMIN), norfenfluramine,
fluoxetine (PROZAC), fluvoxamine (LUVOX), indalpine, milnacipran
(IXEL), paroxetine (PAXIL, SEROXAT), sertraline (ZOLOFT, LUSTRAL),
trazodone (DESYREL, MOLIPAXIN), venlafaxine (EFFEXOR), zimelidine
(NORMUD, ZELMID), bicifadine, desvenlafaxine (PRISTIQ),
brasofensine, vilazodone, cariprazine, neuralstem and
tesofensine;
[0255] (xxxviii) trophic factors, such as nerve growth factor
(NGF), basic fibroblast growth factor (bFGF; ERSOFERMIN),
neurotrophin-3 (NT-3), cardiotrophin-1, brain-derived neurotrophic
factor (BDNF), neublastin, meteorin, and glial-derived neurotrophic
factor (GDNF), and agents that stimulate production of trophic
factors, such as propentofylline, idebenone, PYM50028 (COGANE;
Phytopharm), and AIT-082 (NEOTROFIN);
[0256] (xxxix) Glycine transporter-1 inhibitors such as
paliflutine, ORG-25935, JNJ-17305600, and ORG-26041;
[0257] (xl) AMPA-type glutamate receptor modulators such as
perampanel, mibampator, selurampanel, GSK-729327, and
N-{(3S,4S)-4-[4-(5-cyanothiophen-2-yl)phenoxy]tetrahydrofuran-3-yl}propan-
e-2-sulfonamide;
and the like.
[0258] The present invention further comprises kits that are
suitable for use in performing the methods of treatment described
above. In one embodiment, the kit contains a first dosage form
comprising one or more of the compounds of the present invention
and a container for the dosage, in quantities sufficient to carry
out the methods of the present invention.
[0259] In another embodiment, the kit of the present invention
comprises one or more compounds of the invention.
[0260] The compounds of the present invention, or their
pharmaceutically acceptable salts, may be prepared by the methods
described below, together with synthetic methods known in the art
of organic chemistry, or modifications and derivatizations that are
familiar to those of ordinary skill in the art. The starting
materials used herein are commercially available or may be prepared
by routine methods known in the art [such as those methods
disclosed in standard reference books such as the Compendium of
Organic Synthetic Methods, Vol. I-XII (published by
Wiley-Interscience)]. Preferred methods include, but are not
limited to, those described below.
[0261] During any of the following synthetic sequences, it may be
necessary and/or desirable to protect sensitive or reactive groups
on any of the molecules concerned. This can be achieved by means of
conventional protecting groups, such as those described in T. W.
Greene, Protective Groups in Organic Chemistry, John Wiley &
Sons, 1981; T. W. Greene and P. G. M. Wuts, Protective Groups in
Organic Chemistry, John Wiley & Sons, 1991; and T. W. Greene
and P. G. M. Wuts, Protective Groups in Organic Chemistry, John
Wiley & Sons, 1999, which are hereby incorporated by
reference.
[0262] Compounds of the present invention, or their
pharmaceutically acceptable salts, can be prepared according to the
reaction Schemes discussed herein below. Unless otherwise
indicated, the substituents in the Schemes are defined as above.
Isolation and purification of the products is accomplished by
standard procedures, which are known to a chemist of ordinary
skill.
[0263] It will be understood by one skilled in the art that the
various symbols, superscripts and subscripts used in the schemes,
methods and examples are used for convenience of representation
and/or to reflect the order in which they are introduced in the
schemes, and are not intended to necessarily correspond to the
symbols, superscripts or subscripts in the appended claims. The
schemes are representative of methods useful in synthesizing the
compounds of the present invention. They are not to constrain the
scope of the invention in any way.
Schemes
[0264] When intermediates used to synthesize compounds of the
present invention incorporate a basic center, their suitable acid
addition salts may be employed in synthetic pathways. Such suitable
addition salts include but are not limited to those derived from
inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric,
hydroiodic, boric, fluoroboric, phosphoric, nitric, carbonic, and
sulfuric acids, and organic acids such as acetic, benzenesulfonic,
benzoic, ethanesulfonic, fumaric, lactic, maleic, methanesulfonic,
trifluoromethanesulfonic, succinic, toluenesulfonic, and
trifluoroacetic acids. Suitable organic acids generally include but
are not limited to aliphatic, cycloaliphatic, aromatic,
araliphatic, heterocyclic, carboxylic, and sulfonic classes of
organic acids.
[0265] Specific examples of suitable organic acids include but are
not limited to acetate, trifluoroacetate, formate, propionate,
succinate, lactate, maleate, fumarate, benzoate, p-hydroxybenzoate,
phenylacetate, mandelate, methanesulfonate, ethanesulfonate,
benzenesulfonate, toluenesulfonate, adipate, butyrate, camphorate,
cyclopentanepropionate, dodecylsulfate, heptanoate, hexanoate,
nicotinate, 2-naphthalenesulfonate, oxalate, 3-phenylpropionate,
pivalate, and undecanoate.
[0266] Furthermore, where intermediates used to prepare compounds
of the invention carry an acidic moiety, suitable salts thereof may
be employed for synthesis. Such salts include alkali metal salts,
e.g., lithium, sodium, or potassium salts; alkaline earth metal
salts, e.g., calcium or magnesium salts; and salts formed with
suitable organic ligands such as amines or quaternary ammonium
cations. Organic salts of such acidic intermediates may be made
from primary, secondary or tertiary amines such as methylamine,
diethylamine, ethylenediamine or trimethylamine. Quaternary amines
may be prepared by reaction of tertiary amines with agents such as
lower alkyl (C.sub.1-C.sub.6) halides (e.g., methyl, ethyl, propyl,
and butyl chlorides, bromides, and iodides), dialkyl sulfates
(e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), arylalkyl
halides (e.g., benzyl and phenethyl bromides), and others.
##STR00007##
[0267] Scheme 1 above illustrates one synthetic sequence for the
preparation of compounds depicted by Formula I. In the initial step
of the synthesis, as depicted, an appropriate ester of a compound
of Formula 1.1, wherein R.sup.1 is typically a
(C.sub.1-C.sub.6)alkyl such as methyl, ethyl, tert-butyl and the
like, is heated in the presence of an aqueous acid such as
hydrochloric acid to furnish the corresponding pyridinone acid of
Formula 1.2. During this initial step, the R.sup.1--X, R.sup.6 and
R.sup.7 substituents of Formula 1.1 should be represented by the
same moieties as are desired in the final product, or a protected
variation thereof. For example, the final product of Example 1 can
be prepared utilizing reaction Scheme 1, where R.sup.1 is
represented by methyl, X is represented by imidazolyl, and R.sup.6
and R.sup.7 of Formula 1.1 are each represented by hydrogen.
[0268] Next, the acid intermediate of Formula 1.2 is subjected to
an amide coupling and in situ cyclization reaction with an amino
alcohol of Formula 1.3 using an appropriate amide coupling reagent
such as HATU
[O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate]. The reaction is carried out in the presence
of a suitable base such as N,N-diisopropylethylamine, and in a
solvent such as dichloromethane or N,N-dimethylformamide. During
this step, y of Formula 1.3 should be represented by an integer as
desired in the final product, and the A, R.sup.2a, R.sup.2b,
R.sup.4a, R.sup.4b, R.sup.5a, R.sup.5b substituents should be
represented by the same moieties as are desired in the final
product, or a protected variation thereof. For example, the final
product of Example 1 can be prepared utilizing reaction Scheme 1,
where R.sup.2a, R.sup.2b, R.sup.4a, R.sup.4b, R.sup.5a, and
R.sup.5b are each hydrogen, y is 1, and A represents
5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl.
##STR00008##
[0269] Scheme 2 illustrates another synthetic sequence for the
preparation of compounds of Formula I. Reaction of a chloroaldehyde
of Formula 2.1 and an amine of Formula 2.2 using one of many
reductive amination protocols known to those skilled in the art
provides the chloroalkylamine of Formula 2.3. For example, this
reaction may be carried out by using a reducing agent such as
sodium triacetoxyborohydride in a suitable solvent such as
methanol. During this step, y of the amine of Formula 2.2 should be
represented by an integer as desired in the final product. The
R.sup.5a and R.sup.5b substituents of Formula 2.1 and the A,
R.sup.2a, and R.sup.2b substituents of the amine of Formula 2.2
should also be represented by the same moieties as are desired in
the final product, or a protected variation thereof.
[0270] Following purification, the resultant chloroalkylamine of
Formula 2.3 may be isolated and stored as its hydrochloride salt.
The final compound of Formula I may then be prepared by treating a
mixture of the chloroalkylamine of Formula 2.3, the acid of Formula
1.2 (Scheme 1), and a base such as N,N-diisopropylethylamine with a
suitable amide coupling reagent such as BOP-CI
[bis(2-oxo-3-oxazolidinyl)phosphonic chloride], T3P
[2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide]
or HATU (preferably HATU) in a solvent such as dichloromethane.
During this step the R.sup.1--X, R.sup.6 and R.sup.7 substituents
of Formula 1.2 should be represented by the same moieties as are
desired in the final product, or a protected variation thereof.
##STR00009##
[0271] Scheme 3 represents several synthetic sequences for the
preparation of the aminoalcohol of Formula 1.3, which can readily
be envisioned and developed by one skilled in the art. For example,
the aminoalcohol of Formula 1.3 may be prepared by carrying out a
reductive amination of a ketone of Formula 3.1 with an amine of
Formula 2.2 using one of many procedures well known to those
skilled in the art.
[0272] Another method involves reductive amination of an aldehyde
of Formula 3.2 with an amine of Formula 2.2, followed by removal of
the tert-butyl(dimethyl)silyl (TBS) protecting group by using a
suitable procedure including treatment with methanolic hydrogen
chloride or tetrabutylammonium fluoride.
[0273] Another method for the synthesis of an aminoalcohol of
Formula 1.3 involves alkylation of an amine of Formula 3.3 with a
halide or mesylate of Formula 3.4.
[0274] Yet another method involves alkylation of an amine of
Formula 2.2 with a bromoalcohol of Formula 3.5. Methods of
synthesis for various amines of Formula 2.2, as well as alternative
methods of preparation of aminoalcohols of Formula 1.3, are
exemplified in the Experimental Section.
[0275] A person skilled in the art, utilizing these disclosures in
combination with what is commonly known in the art, may further
generalize those syntheses to allow access to a wide variety of
amines of Formula 2.2 and aminoalcohols of Formula 1.3, including
but not limited to variations in which y is represented by an
integer as desired in the final product, and A, R.sup.2a, R.sup.2b,
R.sup.4a, R.sup.4b, R.sup.5a, and R.sup.5b substituents are
represented by the same moieties as are desired in the final
product, or a protected variation thereof.
##STR00010##
[0276] Scheme 4 illustrates one synthetic sequence for the
preparation of compounds of Formula 1.1 where
R.sup.1--X=4-methylimidazol-1-yl or 3-methyltriazol-1-yl. A
3-aminopyridine compound of Formula 4.1 is brominated using
N-bromosuccinimide (NBS) in a solvent such as a mixture of DMSO and
water. During this initial step the R.sup.6 and R.sup.7
substituents are represented by the same moieties as are desired in
the final product, or a protected variation thereof. The resulting
intermediate of Formula 4.2 is then heated with sodium methoxide in
a suitable solvent such as 1,4-dioxane to afford the methoxy
compound of Formula 4.3. The intermediate of Formula 4.3 is then
treated with a mixture of acetic anhydride and formic acid to
afford a formamide of Formula 4.4, which is alkylated with
chloroacetone in the presence of potassium iodide and a base such
as cesium carbonate in a suitable solvent such as
N,N-dimethylformamide. The resulting intermediate of Formula 4.5 is
then heated in the presence of NH.sub.4OAc in acetic acid to
furnish the imidazole derivative of Formula 4.6. Finally, the
compound of Formula 1.1 can be prepared by subjecting the
intermediate of Formula 4.6 to a carbonylation/esterification
reaction. This transformation may be carried out by heating a
solution of the bromo compound of Formula 4.6 and a base such as
triethylamine in an appropriate alcohol solvent ("ROH"), wherein R
is typically a (C.sub.1-C.sub.6)alkyl such as methyl or ethyl,
under an atmosphere of CO in the presence of a suitable palladium
catalyst such as Pd(dppf)Cl.sub.2.dichloromethane
{[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
dichloromethane complex} to provide the ester of Formula 1.1.
##STR00011##
[0277] Scheme 5 depicts alternative synthetic sequences for the
preparation of compounds of Formula 1.1. In a first step, a pyridyl
derivative of Formula 5.1 is oxidized with an oxidizing agent such
as mCPBA [3-chloroperoxybenzoic acid] in a suitable solvent such as
dichloroethane to afford the corresponding N-oxide of Formula 5.2.
During this initial step the R.sup.6 and R.sup.7 substituents of
Formula 5.1 are represented by the same moieties as are desired in
the final product, or a protected variation thereof. The N-oxide of
Formula 5.2 is then heated in the presence of TMSCN [trimethylsilyl
cyanide] and a base such as triethylamine in a solvent such as
acetonitrile to afford the nitrile intermediate of Formula 5.3. The
corresponding ester may then be prepared from Formula 5.3 in two
steps by subjecting Formula 5.3 to sodium methoxide in a solvent
such as THF, followed by treatment with an appropriate alcohol
solvent ("ROH"), wherein R is typically a (C.sub.1-C.sub.6)alkyl
such as methyl, ethyl and the like, and an acid such as
hydrochloric acid. The ester of Formula 5.5 is a versatile
intermediate that allows introduction of a variety of heterocycles
R.sup.1--X. For example, Formula 5.5 may be subjected to a Suzuki
coupling with a heteroarylboronic acid, using methods well known to
those skilled in the art [see Tetrahedron 2002, 58, 9633-9695].
Alternatively, the compound of Formula 5.5 may be coupled to a
heterocycle X using a direct arylation approach [see D. Lapointe et
al., J. Org. Chem. 2011, 76, 749-759, and references therein]. For
example, the compound of Formula 5.5 may be coupled to
2-methyl-1,3-oxazole [Formula 5.7 where R.sup.1=Me] by heating in
the presence of a suitable palladium catalyst such as
allylpalladium chloride dimer and a base such as potassium
carbonate in a solvent such as 1,4-dioxane, to afford the
intermediate of Formula 1.1 where
R.sup.1--X=2-methyl-1,3-oxazol-5-yl.
[0278] Alternatively, the compound of Formula 5.5 may be converted
to the corresponding boronate of Formula 5.6, using a
palladium-catalyzed cross coupling with a diboron reagent such as
5,5,5',5'-tetramethyl-2,2'-bi-1,3,2-dioxaborinane in the presence
of potassium acetate and a palladium catalyst such as
Pd(dppf)Cl.sub.2.dichloromethane in a solvent such as 1,4-dioxane.
The resulting boronate intermediate of Formula 5.6 can in turn be
subjected to a Suzuki coupling with a heteroaryl halide to afford
the final compound of Formula 1.1. Another method for the
introduction of a heterocycle X involves the use of a Chan-Lam
coupling [see Tetrahedron Lett. 2003, 44, 3863-3865, and Synthesis
2008, 5, 795-799]. For example, the boronate of Formula 5.6 may be
coupled to a substituted imidazole of Formula 5.8 or to a
substituted triazole of Formula 5.9. by heating with a suitable
copper source such as copper(I) oxide or copper(II) acetate in a
solvent such as methanol in the presence of air to afford the
intermediate of Formula 1.1 where X=imidazol-1-yl or
triazol-1-yl.
##STR00012##
[0279] Scheme 6 illustrates yet another set of synthetic sequences
for the preparation of compounds of Formula I. Heating an
intermediate of Formula 6.1 in an acid such as hydrochloric acid
affords the pyridinone acid intermediate of Formula 6.2. During
this initial step, the R.sup.6 and R.sup.7 substituents of Formula
6.1 are represented by the same moieties as are desired in the
final product, or a protected variation thereof. Next, the acid of
Formula 6.2 may be subjected to a coupling/cyclization reaction
with an aminoalcohol of Formula 1.3 (Scheme 1) to afford an
intermediate of Formula 6.3 using chemistry described in Scheme 1.
During this step, y of Formula 1.3 should be represented by an
integer as desired in the final product, and the R.sup.2a,
R.sup.2b, R.sup.4a, R.sup.4b, R.sup.5a, R.sup.5b, R.sup.10 and
R.sup.11 substituents should be represented by the same moieties as
are desired in the final product, or a protected variation
thereof.
[0280] An alternative synthesis of the intermediate of Formula 6.3
involves heating a mixture of the intermediate of Formula 6.2,
dibromoethane, and a base such as cesium carbonate in a solvent
such as N,N-dimethylformamide to afford a lactone of Formula 6.4.
During this initial step, the R.sup.6 and R.sup.7 substituents of
Formula 6.1 are represented by the same moieties as are desired in
the final product, or a protected variation thereof. The resultant
intermediate of Formula 6.3 may then be subjected to an amidation
reaction with an amine of Formula 2.2 (Scheme 2). This
transformation may be carried using a number of different
conditions. For example, the lactone of Formula 6.2 and the amine
of Formula 2.2 may be heated in the presence of a base such as
1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (TBD) in a
solvent such as N,N-dimethylformamide, followed by addition of
ethyl trifluoroacetate to afford the lactam of Formula 6.3 wherein
R.sup.4a=R.sup.4b=R.sup.5a=R.sup.5b=H. During the amidation step, y
of Formula 2.2 should be represented by an integer as desired in
the final product.
[0281] The final compound, Formula I, may then be formed directly
from Formula 6.3 or via the boronate of Formula 6.5, using the
strategies discussed in Scheme 5. Alternatively, compounds of
Formula I where heterocycle X is linked to the pyridinone ring via
a C--N bond may be formed by palladium-catalyzed cross coupling.
For example, the triazole of Formula 6.6 may be coupled to Formula
6.3 by heating in the presence of a palladium catalyst such as
tris(dibenzylideneacetone)dipalladium(0) and a suitable ligand such
as
di-tert-butyl[3,4,5,6-tetramethyl-2',4',6'-tri(propan-2-yl)biphenyl-2-yl]-
phosphane and base such as potassium phosphate in a solvent such as
toluene to afford the final compound of Formula I where
X=1,2,4-triazol-1-yl.
##STR00013##
[0282] Scheme 7 illustrates another synthetic sequence for the
preparation of compounds of Formula I, where
R.sup.4a=R.sup.4b=R.sup.5a=R.sup.5b=H. The method involves heating
a mixture of a compound of Formula 1.2 (Scheme 1), dibromoethane,
and a base such as cesium carbonate in a solvent such as
N,N-dimethylformamide to afford the lactone intermediate of Formula
7.1. During this initial step, the R.sup.1--X, R.sup.6 and R.sup.7
substituents of Formula 1.2 are represented by the same moieties as
are desired in the final product, or a protected variation thereof.
The lactone of Formula 7.1 may then be reacted with an amine of
Formula 2.2 (from Scheme 2) in the presence of a reagent such as
DIBAL (diisobutylaluminum hydride) or
bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct in a
solvent such as THF to afford the amide alcohol of Formula 7.2.
During this step, y of Formula 2.2 should be represented by an
integer as desired in the final product, and the R.sup.2a,
R.sup.2b, R.sup.10 and R.sup.11 substituents should be represented
by the same moieties as are desired in the final product, or a
protected variation thereof. The intermediate of Formula 7.2 may be
reacted with methanesulfonyl chloride in the presence of a base
such as triethylamine in a solvent such as THF, followed by
treatment with a base such as
1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (TBD) to afford
the compound of Formula I wherein
R.sup.4a=R.sup.4b=R.sup.5a=R.sup.5b=H. Alternatively, the ring
closure may be carried out in a stepwise fashion by first
converting the alcohol of Formula 7.2 into the corresponding
chloride by treatment with thionyl chloride, followed by
deprotonation of the amide NH with a suitable base such as lithium
bis(trimethylsilyl)amide to afford the final compound of Formula I.
Alternatively, a solution of lactam 7.1 and amine 2.2 in
N,N-dimethylformamide may be treated with
1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (TBD) in
N,N-dimethylformamide to form intermediate 7.2, which is then
directly converted to Formula I in the same pot via addition of
ethyl trifluoroacetate.
##STR00014##
[0283] Compounds of Formula I where X is imidazolyl and R.sup.1 is
hydroxymethyl may be prepared in one step from the corresponding
compound of Formula I where X is imidazolyl and R.sup.1 is methyl.
This transformation can be carried out via incubation with
microsomes from a suitable species such as monkey in the presence
of magnesium chloride and nicotinamide adenine dinucleotide
phosphate (NADPH) in a suitable buffer such as potassium phosphate
(pH 7.4).
##STR00015## ##STR00016##
[0284] A number of routes can be envisioned to access intermediates
of Formula 2.2, where R.sup.2a=R.sup.2b=H, R.sup.10=methyl, y=1,
R.sup.10 is connected to the quaternary carbon atom adjacent to the
benzofuran oxygen atom, and the aminomethyl substituent is
connected to the benzylic position. One approach commences with
bromination or iodination of a phenol of Formula 9.1 using a
suitable halogenating reagent such as N-bromosuccinamide (NBS) or
N-iodosuccinamide (NIS). During this step, the R.sup.11 substituent
should be represented by the same moiety as is desired in the final
product, or a protected variation thereof. The resultant phenol
intermediate of Formula 9.2 is then reacted with benzyl
chloromethyl ether in the presence of a suitable base such as
potassium carbonate and in a solvent such as acetonitrile to afford
an intermediate of Formula 9.3. This compound is then subjected to
a Sonogashira coupling with trimethyl(prop-2-yn-1-yl)silane using a
copper source such as copper(I) iodide and a palladium catalyst
such as dichlorobis(triphenylphosphine)palladium(II) in
triethylamine. The trimethylsilyl protecting group is subsequently
removed using a fluoride source such as tetra-N-butylammonium
fluoride (TBAF) in a solvent such as tetrahydrofuran to afford an
intermediate of Formula 9.5. This compound can then be heated in
the presence of a platinum catalyst such as
di-.mu.-chloro-dichlorobis(ethylene)diplatinum(III) in a solvent
such as toluene to afford benzofuran intermediate 9.6. The benzyl
protecting group is then removed via hydrogenolysis using palladium
hydroxide on carbon in cyclohexene. Cyclopropanation of the
benzofuran 2,3-double bond can be carried under a number of
conditions such as the Simmons-Smith reaction. For example, the
intermediate of Formula 9.7 is treated with diethylzinc and
diiodomethane in a suitable solvent such as dichloromethane to
afford the cyclopropyl benzofuran alcohol intermediate of Formula
9.8. The primary alcohol in the intermediate of Formula 9.8 may
then be converted to the corresponding primary amine using a number
of procedures well known to those skilled in the art. For example,
this functional group interconversion can be accomplished via a
Mitsunobu reaction with phthalimide followed by deprotection using
a reagent such as hydrazine monohydrate in a solvent such as
dichloromethane and methanol to afford the desired amine of Formula
2.2.
##STR00017##
[0285] Scheme 10 displays an alternative synthetic route to
intermediates of Formula 2.2 where R.sup.2a=R.sup.2b=H, y=1,
R.sup.10 is connected to the quaternary carbon atom adjacent to the
benzofuran oxygen atom, and the aminomethyl substituent is
connected to the benzylic position. In this approach, the phenol of
Formula 9.2 undergoes a 1,4-addition to an alkyne derivative of
Formula 10.1 in the presence of a base such as potassium carbonate
in a solvent such as acetonitrile. During this step, the R.sup.10
and R.sup.11 substituents should be represented by the same moiety
as is desired in the final product, or a protected variation
thereof. The resulting compound of Formula 10.2 is then subjected
to an intramolecular Heck reaction using a suitable palladium
catalyst such as bis(tri-tert-butylphosphine)palladium(0) in the
presence of a base such as triethylamine in a solvent such as
acetonitrile. The resultant benzofuran intermediate of Formula 10.3
is then subjected to cyclopropanation using trimethylsulfoxonium
iodide in dimethyl sulfoxide in the presence of a base such as
potassium tert-butoxide. The ester is immediately hydrolyzed to the
corresponding acid of Formula 10.4 using a suitable base such as
potassium hydroxide or potassium tert-butoxide. The final step in
the sequence involves conversion of the carboxylic acid of Formula
10.4 to the amine of Formula 2.2. This functional group
interconversion can be carried out under a number of different
conditions known to those skilled in the art. For example, amide
coupling of acid 10.4 with ammonium hydroxide and a coupling
reagent such as 1,1'-carbonyldiimidazole delivers the primary amide
of Formula 10.5, which is subsequently reduced using a suitable
reducing agent such as bis(2-methoxyethoxy)aluminum hydride in a
solvent such as toluene.
EXPERIMENTAL PROCEDURES AND WORKING EXAMPLES
[0286] The following illustrate the synthesis of various compounds
of the present invention. Additional compounds within the scope of
this invention may be prepared using the methods illustrated in
these Examples, either alone or in combination with techniques
generally known in the art.
[0287] Experiments were generally carried out under inert
atmosphere (nitrogen or argon), particularly in cases where oxygen-
or moisture-sensitive reagents or intermediates were employed.
Commercial solvents and reagents were generally used without
further purification. Anhydrous solvents were employed where
appropriate, generally AcroSeal.RTM. products from Acros Organics
or DriSolv.RTM. products from EMD Chemicals. In other cases,
commercial solvents were passed through columns packed with 4 .ANG.
molecular sieves, until the following QC standards for water were
attained: a) <100 ppm for dichloromethane, toluene,
N,N-dimethylformamide and tetrahydrofuran; b) <180 ppm for
methanol, ethanol, 1,4-dioxane and diisopropylamine. For very
sensitive reactions, solvents were further treated with metallic
sodium, calcium hydride or molecular sieves, and distilled just
prior to use. Products were generally dried under vacuum before
being carried on to further reactions or submitted for biological
testing. Mass spectrometry data is reported from either liquid
chromatography-mass spectrometry (LCMS), atmospheric pressure
chemical ionization (APCI) or gas chromatography-mass spectrometry
(GCMS) instrumentation. Chemical shifts for nuclear magnetic
resonance (NMR) data are expressed in parts per million (ppm, 8)
referenced to residual peaks from the deuterated solvents employed.
In some examples, chiral separations were carried out to separate
enantiomers of certain compounds of the invention (in some
examples, the separated enantiomers are designated as ENT-1 and
ENT-2, according to their order of elution). In some examples, the
optical rotation of an enantiomer was measured using a polarimeter.
According to its observed rotation data (or its specific rotation
data), an enantiomer with a clockwise rotation was designated as
the (+)-enantiomer and an enantiomer with a counter-clockwise
rotation was designated as the (-)-enantiomer. Racemic compounds
are indicated by the presence of (+/-) adjacent to the structure;
in these cases, indicated stereochemistry represents the relative
(rather than absolute) configuration of the compound's
substituents.
[0288] Reactions proceeding through detectable intermediates were
generally followed by LCMS, and allowed to proceed to full
conversion prior to addition of subsequent reagents. For syntheses
referencing procedures in other Examples or Methods, reaction
conditions (reaction time and temperature) may vary. In general,
reactions were followed by thin-layer chromatography or mass
spectrometry, and subjected to work-up when appropriate.
Purifications may vary between experiments: in general, solvents
and the solvent ratios used for eluents/gradients were chosen to
provide appropriate R.sub.fs or retention times.
Example 1
7-(4-Methyl-1H-imidazol-1-yl)-2-{[5-(trifluoromethyl)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-
-1,6-dione (1)
[0289] (The compound of Example 1 was previously disclosed in U.S.
Provisional Patent Application No. 61/973,436, filed on Apr. 1,
2014 as Example 19. While this compound is not encompassed by the
claims of the present application, it is being exemplified herein
to provide additional synthetic methodology).
##STR00018## ##STR00019##
Step 1. Synthesis of
4-{[2-iodo-4-(trifluoromethyl)phenoxy]methyl}-2,2-dimethyl-1,3-dioxolane
(C1)
[0290] Diisopropyl azodicarboxylate (8.2 mL, 42 mmol) was added
slowly, in a drop-wise manner, to a 0.degree. C. solution of
(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (5.5 g, 42 mmol) and
triphenylphosphine (10.9 g, 42 mmol) in tetrahydrofuran (80 mL).
2-Iodo-4-(trifluoromethyl)phenol (8.0 g, 28 mmol) was slowly added
to the 0.degree. C. reaction mixture, which was then allowed to
stir at room temperature for 6 hours. After removal of solvent in
vacuo, the residue was partitioned between water and ethyl acetate,
and the organic layer was washed with water, dried over sodium
sulfate, filtered, and concentrated under reduced pressure. Silica
gel chromatography (Eluent: 10% ethyl acetate in hexane) afforded
the product as a light yellow liquid. Yield: 6.5 g, 16 mmol, 57%.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.02 (br s, 1H), 7.58 (br
d, J=8.6 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 4.48-4.56 (m, 1H), 4.23
(dd, J=8.4, 6.2 Hz, 1H), 4.18 (dd, half of ABX pattern, J=9.5, 4.2
Hz, 1H), 4.04-4.11 (m, 2H), 1.49 (s, 3H), 1.42 (s, 3H).
Step 2. Synthesis of
3-[2-iodo-4-(trifluoromethyl)phenoxy]propane-1,2-diol (C2)
[0291] A solution of C1 (6.5 g, 16 mmol) in acetic acid (3.2 mL, 56
mmol) and water (0.29 mL, 16 mmol) was stirred at room temperature
for 18 hours, whereupon it was concentrated under reduced pressure.
The residue was washed with pentane, and the resulting solid was
taken into the following step without further purification. Yield:
5.25 g, 14.5 mmol, 91%. GCMS m/z 362 [M.sup.+]. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.01-8.04 (m, 1H), 7.60 (br d, J=8.6 Hz,
1H), 6.89 (d, J=8.6 Hz, 1H), 4.13-4.23 (m, 3H), 3.83-3.97 (m, 2H),
2.71 (d, J=4.5 Hz, 1H), 2.05 (dd, J=6.2, 6.0 Hz, 1H).
Step 3. Synthesis of
1-{[tert-butyl(dimethyl)silyl]oxy}-3-[2-iodo-4-(trifluoromethyl)phenoxy]p-
ropan-2-ol (C3)
[0292] To a solution of C2 (5.25 g, 14.5 mmol) in
N,N-dimethylformamide (50 mL) was added imidazole (1.1 g, 16 mmol),
followed by slow addition of tert-butyl(dimethyl)silyl chloride
(2.4 g, 16 mmol). After 6 hours at room temperature, the reaction
mixture was diluted with ice water and then extracted with ethyl
acetate. The combined organic layers were dried over sodium
sulfate, filtered, and concentrated in vacuo; silica gel
chromatography (Eluent: 5% ethyl acetate in hexanes) provided the
product as a light yellow liquid. Yield: 4.12 g, 8.65 mmol, 60%.
NMR (400 MHz, CDCl.sub.3) .delta. 8.01-8.03 (m, 1H), 7.58 (br d,
J=8.6 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 4.05-4.17 (m, 3H), 3.84-3.92
(m, 2H), 2.58 (d, J=5.8 Hz, 1H), 0.91 (s, 9H), 0.10 (s, 3H), 0.09
(s, 3H).
Step 4. Synthesis of
1-{[tert-butyl(dimethyl)silyl]oxy}-3-[2-iodo-4-(trifluoromethyl)phenoxy]p-
ropan-2-one (C4)
[0293] Dess-Martin periodinane
[1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one; 11.0
g, 25.9 mmol] was added to a 0.degree. C. solution of C3 (4.12 g,
8.65 mmol) in dichloromethane (40 mL), and the reaction mixture was
stirred for 14 hours. Excess oxidant was removed via filtration
through a pad of diatomaceous earth; the filtrate was diluted with
water and extracted with dichloromethane. The combined organic
layers were concentrated in vacuo, and the crude product was used
in the following step without additional purification. Yield: 3.7
g, 7.8 mmol, 90%. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.05-8.07 (m, 1H), 7.57 (br d, J=8.6 Hz, 1H), 6.70 (d, J=8.6 Hz,
1H), 4.94 (s, 2H), 4.59 (s, 2H), 0.96 (s, 9H), 0.15 (s, 6H).
Step 5. Synthesis of
3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-(trifluoromethyl)-2,3-dihydr-
o-1-benzofuran-3-ol (C5)
[0294] Methyllithium (1.6 M solution in diethyl ether, 9.2 mL, 15
mmol) was slowly added to a -78.degree. C. solution of C4 (3.5 g,
7.4 mmol) in tetrahydrofuran (30 mL), and the reaction mixture was
stirred at this temperature for 5 hours. Aqueous ammonium chloride
solution was then slowly added, and the resulting mixture was
extracted with ethyl acetate. The combined organic layers were
dried over sodium sulfate, filtered, and concentrated in vacuo to
provide the crude product (2.1 g), which was used directly in the
next step. .sup.1H NMR (400 MHz, CDCl.sub.3), product peaks only:
.delta. 7.62-7.65 (m, 1H), 7.51-7.55 (m, 1H), 6.91 (d, J=8.6 Hz,
1H), 4.49 (s, 2H), 3.84 (AB quartet, J.sub.AB=9.8 Hz,
.DELTA..nu..sub.AB=11.3 Hz, 2H), 0.94 (s, 9H), 0.12 (s, 3H), 0.10
(s, 3H).
Step 6. Synthesis of
[5-(trifluoromethyl)-1-benzofuran-3-yl]methanol (C6)
[0295] An aqueous solution of p-toluenesulfonic acid (10%, 11 mL)
was slowly added to a solution of C5 (from the previous step; 2.1
g, .ltoreq.6.0 mmol) in acetone (20 mL), and the reaction mixture
was allowed to stir at room temperature for 14 hours. Acetone was
removed via concentration in vacuo, and the aqueous residue was
extracted with ethyl acetate. The combined organic layers were
dried over sodium sulfate, filtered, and concentrated under reduced
pressure; silica gel chromatography (Eluent: 5% ethyl acetate in
hexane) afforded the product (435 mg) as a light yellow liquid.
Also isolated was the tert-butyl(dimethyl)silyl-protected
derivative of C6; this was subjected to p-toluenesulfonic acid in a
similar manner, providing an additional 150 mg of the product.
Total yield: 585 mg, 2.71 mmol, 37% over two steps. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.00 (br s, 1H), 7.73 (br s, 1H),
7.56-7.63 (m, 2H), 4.90 (br d, J=5.3 Hz, 2H), 1.68 (t, J=5.6 Hz,
1H).
Step 7. Synthesis of
[5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]me-
thanol (C7)
[0296] To a 0.degree. C. solution of C6 (100 mg, 0.46 mmol) in
dichloromethane (10 mL) was added diiodomethane (744 mg, 2.78
mmol), followed by slow addition of diethylzinc (1 M solution in
hexanes, 1.39 mL, 1.39 mmol) at the same temperature. The reaction
mixture was allowed to slowly warm to room temperature, whereupon
it was stirred for 3 hours. It was then quenched via addition of
saturated sodium thiosulfate solution, and extracted with
dichloromethane; the combined organic layers were washed with
saturated aqueous sodium chloride solution, dried over sodium
sulfate, filtered, and concentrated in vacuo. Silica gel
chromatography (Gradient: 0% to 30% ethyl acetate in hexanes)
provided the product as a yellow oil. Yield: 50 mg, 0.22 mmol, 48%.
GCMS m/z 230 [M.sup.+]. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
7.75-7.78 (m, 1H), 7.47 (br d, J=8.3 Hz, 1H), 7.00 (d, J=8.8 Hz,
1H), 4.98 (dd, J=5.9, 5.4 Hz, 1H), 4.93 (dd, J=5.5, 1.8 Hz, 1H),
3.93 (dd, half of ABX pattern, J=11.8, 5.9 Hz, 1H), 3.73 (dd, half
of ABX pattern, J=11.9, 5.3 Hz, 1H), 1.26 (dd, J=6.2, 5.8 Hz, 1H),
0.40 (dd, J=6.5, 1.8 Hz, 1H).
Step 8. Synthesis of
[5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]me-
thyl methanesulfonate (C8)
[0297] Triethylamine (0.27 mL, 1.9 mmol) and methanesulfonyl
chloride (61 .mu.L, 0.79 mmol) were added to a 0.degree. C.
solution of C7 (150 mg, 0.65 mmol) in dichloromethane (10 mL), and
the reaction mixture was allowed to slowly warm to room
temperature. After it had stirred for 6 hours, the reaction mixture
was quenched via addition of saturated aqueous sodium bicarbonate
solution, and extracted with dichloromethane. The combined organic
layers were washed with saturated aqueous sodium chloride solution,
dried over sodium sulfate, filtered, and concentrated in vacuo to
afford the product (120 mg). This material was used directly in the
following step.
Step 9. Synthesis of
1-[5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]-
methanamine (C9)
[0298] To a 0.degree. C. solution of C8 (from the previous step;
120 mg, .ltoreq.0.39 mmol) in methanol (1 mL) was added methanolic
ammonia (5 mL) and the reaction mixture was heated at 70.degree. C.
for 16 hours in a sealed tube. It was then evaporated to dryness;
the residue was mixed with water and extracted with ethyl acetate.
The combined organic layers were washed with saturated aqueous
sodium chloride solution, dried over sodium sulfate, filtered, and
concentrated in vacuo. Chromatography on silica gel (Eluent: 10%
methanol in dichloromethane) afforded the product as a light yellow
gum. Yield: 50 mg, 0.22 mmol, 34% over two steps.
Step 10. Synthesis of
1-(2-hydroxyethyl)-5-(4-methyl-1H-imidazol-1-yl)-6-oxo-N-{[5-(trifluorome-
thyl)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-1,6-dihydr-
opyridine-2-carboxamide (C11)
[0299] To a solution of C9 (115 mg, 0.502 mmol) in tetrahydrofuran
(1 L) was added
bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct (270
mg, 1.05 mmol). The reaction mixture was heated to 40.degree. C.
for 45 minutes, whereupon it was treated with
7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,6-di-
one (C10, which may be prepared via the method of C. W. amEnde et
al., PCT Int. Appl., WO 2012131539, Oct. 4, 2012) (120 mg, 0.49
mmol) and heated to 65.degree. C. for 5 hours. The reaction was
quenched via addition of 1 M aqueous sodium hydroxide solution, and
the resulting slurry was diluted with water and extracted with 5%
methanol in dichloromethane; the combined organic layers were
washed with saturated aqueous sodium chloride solution, dried over
sodium sulfate, filtered, and concentrated in vacuo. Trituration
with 10% ethyl acetate in hexanes afforded the product as an
off-white solid (100 mg), which was used in the next step without
additional purification. LCMS m/z 475.0 [M+H].sup.+.
Step 11. Synthesis of
1-(2-chloroethyl)-5-(4-methyl-1H-imidazol-1-yl)-6-oxo-N-{[5-(trifluoromet-
hyl)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-1,6-dihydro-
pyridine-2-carboxamide (C12)
[0300] To a -10.degree. C. solution of C11 (from the previous step;
100 mg, .ltoreq.0.21 mmol) in dichloromethane (10 mL) was added
triethylamine (90 .mu.L, 0.65 mmol), followed by drop-wise addition
of methanesulfonyl chloride (70 mg, 0.61 mmol). The reaction
mixture was then allowed to warm to room temperature and stir for 2
hours, whereupon it was diluted with dichloromethane, washed with
aqueous sodium bicarbonate solution and with saturated aqueous
sodium chloride solution, dried over sodium sulfate, filtered, and
evaporated in vacuo. The product was obtained as a sticky brown
solid (100 mg), which was used in the next step without additional
purification.
Step 12. Synthesis of
7-(4-methyl-1H-imidazol-1-yl)-2-{[5-(trifluoromethyl)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazin-
e-1,6-dione (1)
[0301] To a solution of C12 (from the previous step; 100 mg,
.ltoreq.0.20 mmol) in tetrahydrofuran (10 mL) was added
1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (99 mg, 0.71
mmol) and the reaction mixture was allowed to stir at room
temperature for 16 hours. Ice water was added, and the mixture was
evaporated to dryness under reduced pressure; the residue was
diluted with water and extracted with ethyl acetate. The combined
organic layers were washed with saturated aqueous sodium chloride
solution, dried over sodium sulfate, filtered, and concentrated in
vacuo. Reversed phase HPLC (Column: YMC-Actus Triart C18, 5 .mu.m;
Mobile phase A: 20 mM ammonium bicarbonate in water; Mobile phase
B: acetonitrile; Gradient: 10% to 55% B) afforded the product as an
off-white solid. Yield: 18 mg, 39 .mu.mol, 8% over three steps.
LCMS m/z 457.0 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.20 (s, 1H), 7.62-7.65 (m, 1H), 7.43 (d, J=7.6 Hz, 1H),
7.40-7.45 (m, 1H), 7.24-7.3 (m, 1H, assumed; partially obscured by
solvent peak), 7.09-7.13 (m, 1H), 6.91 (d, J=8.6 Hz, 1H), 4.90-4.94
(m, 1H), 4.86 (d, J=14.7 Hz, 1H), 4.26-4.35 (m, 1H), 4.11-4.20 (m,
1H), 3.54-3.64 (m, 2H), 3.43 (d, J=14.8 Hz, 1H), 2.28 (s, 3H), 1.25
(dd, J=6.7, 5.8 Hz, 1H), 0.62 (dd, J=7, 2 Hz, 1H).
Examples 2 and 3
7-(4-Methyl-1H-imidazol-1-yl)-2-{[(1aS,6bS)-1a-methyl-5-(trifluoromethoxy)-
-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,6-dione (2) and
7-(4-Methyl-1H-imidazol-1-yl)-2-{[(1aR,6bR)-1a-methyl-5-(trifluoromethoxy-
)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-
-pyrido[1,2-a]pyrazine-1,6-dione (3)
##STR00020## ##STR00021##
[0302] Step 1. Synthesis of 2-iodo-4-(trifluoromethoxy) phenol
(C13)
[0303] 4-(Trifluoromethoxy)phenol (4.0 mL, 31 mmol) was added to a
suspension of N-iodosuccinimide (95%, 6.95 g, 29.3 mmol) in acetic
acid (2.0 mL, 35 mmol), and the mixture was stirred for 5 minutes.
Sulfuric acid (98%, 0.5 mL, 9 mmol) was introduced, and stirring
was continued at room temperature for 48 hours, whereupon the
reaction mixture was poured into water (100 mL) and extracted with
diethyl ether. The combined organic layers were washed with water,
washed twice with 1 M aqueous sodium thiosulfate solution, treated
with decolorizing carbon, and dried over magnesium sulfate. After
the mixture had been filtered through a pad of diatomaceous earth
and silica gel, the filtrate was concentrated in vacuo to provide
the product as an oil (13.2 g). By .sup.1H NMR analysis, this
product contained a significant quantity of ethyl acetate. Yield,
corrected for ethyl acetate: 8.5 g, 28 mmol, 96%. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.54 (br d, J=2.6 Hz, 1H), 7.15 (br dd,
J=8.9, 2.6 Hz, 1H), 6.99 (d, J=8.9 Hz, 1H).
Step 2. Synthesis of
1-[(benzyloxy)methoxy]-2-iodo-4-(trifluoromethoxy)benzene (C14)
[0304] A solution of C13 (9.30 g, 30.6 mmol) in acetonitrile (100
mL) was treated with potassium carbonate (8.46 g, 61.2 mmol),
followed by benzyl chloromethyl ether (6.38 mL, 45.9 mmol). The
reaction mixture was allowed to stir at room temperature overnight,
whereupon it was partitioned between water and diethyl ether. The
combined organic layers were washed with water, dried over
magnesium sulfate, filtered, and concentrated in vacuo;
purification via silica gel chromatography (Gradient: 0% to 5%
ethyl acetate in heptane) provided the product as an oil. Yield:
10.8 g, 25.5 mmol, 83%. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.67 (br d, J=2.2 Hz, 1H), 7.30-7.40 (m, 5H), 7.19 (br dd, half of
ABX pattern, J=9, 2 Hz, 1H), 7.14 (d, half of AB quartet, J=9.0 Hz,
1H), 5.35 (s, 2H), 4.76 (s, 2H).
Step 3. Synthesis of (3-{2-[(benzyloxy)
methoxy]-5-(trifluoromethoxy)phenyl}prop-2-yn-1-yl)(trimethyl)silane
(C15)
[0305] A mixture of C14 (2.80 g, 6.60 mmol), copper(I) iodide (254
mg, 1.33 mmol), and dichlorobis(triphenylphosphine)palladium(II)
(99%, 468 mg, 0.660 mmol) in triethylamine (20 mL) was stirred for
5 minutes, whereupon trimethyl(prop-2-yn-1-yl)silane (80%, 1.85 mL,
9.9 mmol) was added and the reaction mixture was heated to
50.degree. C. After 5 hours, it was cooled to room temperature and
partitioned between diethyl ether and saturated aqueous ammonium
chloride solution. The organic layer was washed with 1 M aqueous
hydrochloric acid, dried over magnesium sulfate, filtered, and
concentrated in vacuo. The product was obtained as a thick oil,
which was used without additional purification. Yield: 2.69 g, 6.58
mmol, quantitative. GCMS m/z 408.2 [M.sup.+].
Step 4. Synthesis of
1-[(benzyloxy)methoxy]-2-(prop-1-yn-1-yl)-4-(trifluoromethoxy)benzene
(C16)
[0306] Tetrabutylammonium fluoride (1 M solution in
tetrahydrofuran; 10 mL, 10 mmol) was added to a solution of C15
(2.60 g, 6.36 mmol) in tetrahydrofuran (25 mL), and the reaction
mixture was stirred at room temperature. After 2 hours, it was
partitioned between water and diethyl ether; the organic layer was
washed with water, dried over magnesium sulfate, filtered, and
concentrated under reduced pressure. Silica gel chromatography
(Gradient: 0% to 5% ethyl acetate in heptane) afforded the product
as an oil. Yield: 1.99 g, 5.92 mmol, 93%. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.29-7.40 (m, 5H), 7.24-7.27 (m, 1H, assumed;
partially obscured by solvent peak), 7.17 (d, half of AB quartet,
J=9.0 Hz, 1H), 7.08 (br d, half of AB quartet, J=9 Hz, 1H), 5.36
(s, 2H), 4.78 (s, 2H), 2.12 (s, 3H).
Step 5. Synthesis of
3-[(benzyloxy)methyl]-2-methyl-5-(trifluoromethoxy)-1-benzofuran
(C17)
[0307] Compound C16 (1.99 g, 5.92 mmol) and
di-mu-chloro-dichlorobis(ethylene)diplatinum(II) (Zeise's dimer;
190 mg, 0.32 mmol) were combined in toluene (20 mL) and heated to
35.degree. C. for 3 hours. After the reaction mixture had cooled to
room temperature, silica gel chromatography (Gradient: 0% to 5%
ethyl acetate in heptane) provided the product as a solid. Yield:
1.50 g, 4.46 mmol, 75%. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.29-7.42 (m, 7H), 7.09 (br d, J=8.8 Hz, 1H), 4.61 (s, 2H), 4.57
(s, 2H), 2.44 (s, 3H).
Step 6. Synthesis of
[2-methyl-5-(trifluoromethoxy)-1-benzofuran-3-yl]methanol (C18)
[0308] A solution of C17 (1.80 g, 5.35 mmol) in ethanol (25 mL) was
treated with palladium hydroxide on carbon (20%, 1.0 g).
Cyclohexene (6 mL, 60 mmol) was added, and the reaction mixture was
heated at reflux for 5 hours, whereupon it was cooled and treated
with additional palladium hydroxide on carbon (1.0 g) and
cyclohexene (6 mL, 60 mmol). After being heated overnight at
reflux, the reaction mixture was filtered through diatomaceous
earth, and the filtrate was concentrated in vacuo. Silica gel
chromatography (Gradient: 0% to 50% ethyl acetate in heptane)
afforded the product as a white solid. Yield: 787 mg, 3.20 mmol,
60%. GCMS m/z 246.1 [M.sup.+]. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.47 (br s, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.10 (br d, J=8.8
Hz, 1H), 4.77 (s, 2H), 2.48 (s, 3H).
Step 7. Synthesis of
[1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofur-
an-6b-yl]methanol (C19)
[0309] Diethylzinc (1.0 M solution in hexane; 10.4 mL, 10.4 mmol)
was cooled in an ice bath, diluted with dichloromethane (10 mL),
and treated with a solution of diiodomethane (1.67 mL, 20.7 mmol)
in dichloromethane (2 mL). After 5 minutes, a solution of C18 (510
mg, 2.07 mmol) in dichloromethane (10 mL) was added, and stirring
was continued for 5 minutes at 0.degree. C. The reaction mixture
was then allowed to warm to room temperature and stir for 4 hours,
whereupon it was quenched with saturated aqueous ammonium chloride
solution. The mixture was extracted with diethyl ether, and the
combined organic layers were dried over magnesium sulfate,
filtered, concentrated in vacuo, and purified via silica gel
chromatography (Gradient: 5% to 30% ethyl acetate in heptane). The
product was obtained as a solid. Yield: 500 mg, 1.9 mmol, 92%. GCMS
m/z 260.1 [M.sup.+]. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.26-7.30 (m, 1H, assumed; largely obscured by solvent peak), 6.98
(br d, J=8.8 Hz, 1H), 6.79 (d, J=8.7 Hz, 1H), 4.14 (d, J=12.1 Hz,
1H), 3.87 (d, J=12.0 Hz, 1H), 1.76 (s, 3H), 1.07 (d, J=6.2 Hz, 1H),
0.62 (d, J=6.2 Hz, 1H).
Step 8. Synthesis of
2-{[1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]benzo-
furan-6b-yl]methyl}-1H-isoindole-1,3(2H)-dione (C20)
[0310] 1H-Isoindole-1,3(2H)-dione (1.64 g, 11.1 mmol) and
triphenylphosphine (2.89 g, 11.0 mmol) were added to a solution of
C19 (2.40 g, 9.22 mmol) in tetrahydrofuran (50 mL). Diisopropyl
azodicarboxylate (95%, 2.07 mL, 10.2 mmol) was added drop-wise, and
the reaction mixture was allowed to stir at room temperature for 2
hours. It was then partitioned between diethyl ether and saturated
aqueous sodium chloride solution, and the organic layer was dried
over magnesium sulfate, filtered, and concentrated in vacuo. Silica
gel chromatography (Gradient: 5% to 50% ethyl acetate in heptane)
afforded the product as a thick oil. Yield: 1.6 g, 4.1 mmol, 44%.
LCMS m/z 389.8 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.86-7.90 (m, 2H), 7.73-7.77 (m, 2H), 7.61-7.65 (m, 1H),
6.94 (br d, J=8.7 Hz, 1H), 6.75 (d, J=8.7 Hz, 1H), 4.24 (d, J=15.2
Hz, 1H), 3.98 (d, J=15.3 Hz, 1H), 1.92 (s, 3H), 1.12 (d, J=6.3 Hz,
1H), 0.52 (d, J=6.3 Hz, 1H).
Step 9. Synthesis of
1-[1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]benzof-
uran-6b-yl]methanamine (C21)
[0311] Hydrazine monohydrate (2.0 mL, 41 mmol) was added to a
solution of C20 (1.6 g, 4.1 mmol) in dichloromethane (10 mL) and
methanol (10 mL). The reaction mixture was stirred overnight at
room temperature, whereupon it was partitioned between 1 M aqueous
sodium hydroxide solution and diethyl ether. The aqueous layer was
extracted with diethyl ether, and the combined organic layers were
dried over sodium sulfate, filtered, and concentrated under reduced
pressure, providing the product as a thick oil. Yield: 1.0 g, 3.9
mmol, 95%. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.20-7.24 (m,
1H), 6.97 (br d, J=8.7 Hz, 1H), 6.78 (d, J=8.7 Hz, 1H), 3.39 (d,
J=14.2 Hz, 1H), 2.86 (d, J=14.0 Hz, 1H), 1.75 (s, 3H), 0.95 (d,
J=6.2 Hz, 1H), 0.55 (d, J=6.2 Hz, 1H).
Step 10. Synthesis of
7-(4-methyl-1H-imidazol-1-yl)-2-{[1a-methyl-5-(trifluoromethoxy)-1,1a-dih-
ydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,-
2-a]pyrazine-1,6-dione (C22)
[0312] 1,3,4,6,7,8-Hexahydro-2H-pyrimido[1,2-a]pyrimidine (97%, 830
mg, 5.78 mmol) was added to a solution of C21 (1.00 g, 3.86 mmol)
and C10 (1.26 g, 5.14 mmol) in N,N-dimethylformamide (4 mL). After
3 hours at room temperature, the reaction mixture was treated with
ethyl trifluoroacetate (1.1 mL, 9.2 mmol) and allowed to stir
overnight. Aqueous sodium hydroxide solution (1 M, 6 mL, 6 mmol)
was added, and the mixture was stirred for 15 minutes at room
temperature. The solid was collected via filtration, rinsed with
water and with diethyl ether, and azeotroped 3 times with toluene,
affording the product as an off-white solid. Yield: 1.68 g, 3.45
mmol, 89%. LCMS m/z 487.4 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3), characteristic peaks: .delta. 8.21 (s, 1H), 7.45 (d,
J=7.7 Hz, 1H), 7.11-7.14 (m, 1H), 6.98 (br d, J=9 Hz, 1H), 6.81 (d,
J=8.7 Hz, 1H), 5.05 (d, J=15.2 Hz, 1H), 4.23 (ddd, half of ABXY
pattern, J=14, 8, 4 Hz, 1H), 4.15 (ddd, half of ABXY pattern, J=14,
7, 4 Hz, 1H), 3.56 (ddd, half of ABXY pattern, J=13, 7, 4 Hz, 1H),
3.46 (ddd, half of ABXY pattern, J=13, 8, 4 Hz, 1H), 3.18 (d,
J=15.2 Hz, 1H), 2.29 (s, 3H), 1.84 (s, 3H), 1.00 (d, J=6.5 Hz, 1H),
0.68 (d, J=6.4 Hz, 1H).
Step 11. Isolation of
7-(4-methyl-1H-imidazol-1-yl)-2-{[(1aS,6bS)-1a-methyl-5-(trifluoromethoxy-
)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-
-pyrido[1,2-a]pyrazine-1,6-dione (2) and
7-(4-methyl-1H-imidazol-1-yl)-2-{[(1aR,6bR)-1a-methyl-5-(trifluoromethoxy-
)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-
-pyrido[1,2-a]pyrazine-1,6-dione (3)
[0313] Compound C22 (1.68 g, 3.45 mmol) was separated into its
component enantiomers via supercritical fluid chromatography
(Column: Chiral Technologies Chiralpak AD-H, 5 .mu.m; Mobile phase:
30% [0.2% ammonium hydroxide in methanol] in carbon dioxide). Each
enantiomer was then dissolved in ethyl acetate (10 mL), passed
through a syringe filter, and concentrated in vacuo. The
first-eluting enantiomer was triturated with diethyl ether to
afford 3 as a solid. The second-eluting enantiomer was
recrystallized from ethyl acetate/heptane to provide 2 as a
solid.
[0314] 3: Yield: 435 mg, 0.894 mmol, 26%. LCMS m/z 487.4
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.28 (br s,
1H), 7.77 (d, J=7.8 Hz, 1H), 7.28-7.32 (m, 2H), 7.28 (d, J=7.8 Hz,
1H), 6.96-7.01 (m, 1H), 6.83 (d, J=8.7 Hz, 1H), 4.93 (d, J=15.1 Hz,
1H), 4.13-4.25 (m, 2H), 3.72 (ddd, J=13, 6, 5 Hz, 1H), 3.50 (ddd,
J=13, 8, 5 Hz, 1H), 3.39 (d, J=15.2 Hz, 1H), 2.23 (d, J=0.9 Hz,
3H), 1.85 (s, 3H), 1.14 (d, J=6.4 Hz, 1H), 0.57 (d, J=6.5 Hz,
1H).
[0315] 2: Yield: 447 mg, 0.919 mmol, 27%. LCMS m/z 487.4
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.28 (br s,
1H), 7.77 (d, J=7.8 Hz, 1H), 7.28-7.32 (m, 2H), 7.28 (d, J=7.8 Hz,
1H), 6.96-7.01 (m, 1H), 6.83 (d, J=8.8 Hz, 1H), 4.93 (d, J=15.1 Hz,
1H), 4.13-4.25 (m, 2H), 3.72 (ddd, J=13, 6, 5 Hz, 1H), 3.50 (ddd,
J=13, 8, 5 Hz, 1H), 3.39 (d, J=15.2 Hz, 1H), 2.23 (d, J=0.8 Hz,
3H), 1.85 (s, 3H), 1.14 (d, J=6.4 Hz, 1H), 0.57 (d, J=6.4 Hz, 1H).
Compound 2 was subjected to X-ray structural analysis (see below),
which established its absolute stereochemistry. Compound 2 was more
potent than its enantiomer 3 (see Table 7); this potency difference
was observed for all of the separated enantiomers in these
Examples, and was used to assign the absolute stereochemistry in
all cases, in direct analogy with 2 and 3.
Single Crystal X-Ray Analysis of Compound 2
[0316] Data collection was performed on a Bruker APEX
diffractometer at room temperature. Data collection consisted of
omega and phi scans.
[0317] The structure was solved by direct methods using SHELX
software suite in the space group P1. The structure was
subsequently refined by the full-matrix least squares method. All
non-hydrogen atoms were found and refined using anisotropic
displacement parameters.
[0318] The conformations of the two molecules in the asymmetric
unit are slightly different from one other. Both molecules have the
same stereochemistry.
[0319] All hydrogen atoms were placed in calculated positions and
were allowed to ride on their carrier atoms. The final refinement
included isotropic displacement parameters for all hydrogen
atoms.
[0320] Analysis of the absolute structure using likelihood methods
(Hooft 2008) was performed using PLATON (Spek 2010). The results
indicate that the absolute structure has been correctly assigned.
The method calculates that the probability that the structure is
correct is 100.0%. The Hooft parameter is reported as 0.07 with an
esd of 0.06.
[0321] The final R-index was 5%. A final difference Fourier
revealed no missing or misplaced electron density.
[0322] Pertinent crystal, data collection, and refinement
information is summarized in Table 1. Atomic coordinates, bond
lengths, bond angles, and displacement parameters are listed in
Tables 2-5.
[0323] Software and References [0324] SHELXTL, Version 5.1, Bruker
AXS, 1997. [0325] PLATON, A. L. Spek, J. Appl. Cryst. 2003, 36,
7-13. [0326] MERCURY, C. F. Macrae, P. R. Edington, P. McCabe, E.
Pidcock, G. P. Shields, R. Taylor, M. Towler, and J. van de Streek,
J. Appl. Cryst. 2006, 39, 453-457. [0327] OLEX2, O. V. Dolomanov,
L. J. Bourhis, R. J. Gildea, J. A. K. Howard, and H. Puschmann, J.
Appl. Cryst. 2009, 42, 339-341. [0328] R. W. W. Hooft, L. H.
Straver, and A. L. Spek, J. Appl. Cryst. 2008, 41, 96-103. [0329]
H. D. Flack, Acta Cryst. 1983, A39, 867-881.
TABLE-US-00001 [0329] TABLE 1 Crystal data and structure refinement
for 2. Empirical formula
C.sub.24H.sub.21F.sub.3N.sub.4O.sub.4.cndot.H.sub.2O Formula weight
486.45.cndot.18.02 Temperature 296(2)K Wavelength 1.54178 .ANG.
Crystal system Triclinic Space group P1 Unit cell dimensions a =
6.6264(13) .ANG. .alpha. = 85.796(14).degree.. b = 7.8303(18) .ANG.
.beta. = 85.470(13).degree.. c = 22.676(5) .ANG. .gamma. =
69.694(12).degree.. Volume 1098.7(4) .ANG..sup.3 Z 2 Density
(calculated) 1.531 Mg/m.sup.3 Absorption coefficient 1.070
mm.sup.-1 F(000) 528 Crystal size 0.44 .times. 0.28 .times. 0.02
mm.sup.3 Theta range for data collection 3.92 to 75.44.degree.
Index ranges -7 <= h <= 8, -9 <= k <= 9, -28 <= l
<= 28 Reflections collected 47975 Independent reflections 8409
[R(int) = 0.0591] Completeness to theta = 67.42.degree. 94.9%
Absorption correction Empirical Max. and min. transmission 0.9789
and 0.6502 Refinement method Full-matrix least-squares on F.sup.2
Data/restraints/parameters 8409/3/653 Goodness-of-fit on F.sup.2
1.045 Final R indices [l > 2sigma(l)] R1 = 0.0498, wR2 = 0.1078
R indices (all data) R1 = 0.0776, wR2 = 0.1205 Absolute structure
parameter 0.010(15) Largest diff. peak and hole 0.350 and -0.205
e..ANG..sup.-3
TABLE-US-00002 TABLE 2 Atomic coordinates (.times.10.sup.4) and
equivalent isotropic displacement parameters (.ANG..sup.2 .times.
10.sup.3) for 2. U(eq) is defined as one third of the trace of the
orthogonalized U.sup.ij tensor. x y z U(eq) O(1) 6220(3) 3512(4)
5522(1) 66(1) O(2) -850(3) 3297(4) 7118(1) 65(1) O(3) 1088(4)
3538(3) 9359(1) 59(1) O(4) 8843(4) -1958(3) 9402(1) 58(1) O(5)
6668(3) -649(3) 4986(1) 58(1) O(6) 1207(3) 3621(3) 3150(1) 58(1)
O(7) 6354(4) 1725(3) 1207(1) 63(1) O(8) 9200(4) 7429(3) 1072(1)
58(1) F(1) 10879(5) -962(5) 8784(2) 130(1) F(2) 12248(4) -3031(4)
9426(1) 92(1) F(3) 10687(5) -347(4) 9649(2) 120(1) F(4) 11615(7)
6781(6) 1706(2) 148(2) F(5) 12563(5) 6046(5) 857(2) 153(2) F(6)
11462(5) 8765(4) 1046(1) 108(1) N(1) 4964(5) 6957(4) 4069(1) 58(1)
N(2) 3148(4) 6036(3) 4798(1) 41(1) N(3) 3684(4) 3491(3) 6227(1)
42(1) N(4) 2597(4) 2304(4) 7349(1) 51(1) N(5) 3814(6) -2090(6)
6465(2) 84(1) N(6) 2854(4) -310(3) 5672(1) 46(1) N(7) 4789(3)
1192(3) 4255(1) 37(1) N(8) 4782(4) 3031(3) 3150(1) 41(1) C(1)
5068(5) 6128(5) 4595(2) 56(1) C(2) 2881(5) 7380(4) 3921(1) 48(1)
C(3) 2170(7) 8349(5) 3344(2) 61(1) C(4) 1758(5) 6858(5) 4361(2)
51(1) C(5) 2625(5) 5349(4) 5345(1) 39(1) C(6) 563(5) 5826(5)
5557(1) 50(1) C(7) 27(5) 5093(5) 6095(1) 51(1) C(8) 1586(5) 3941(4)
6423(1) 42(1) C(9) 4321(5) 4075(4) 5686(1) 44(1) C(10) 5360(5)
2221(6) 6590(1) 60(1) C(11) 4713(5) 2404(6) 7219(2) 68(1) C(12)
1013(5) 3146(5) 6998(1) 48(1) C(13) 2187(6) 1483(5) 7921(1) 53(1)
C(14) 2422(5) 2490(4) 8417(1) 48(1) C(15) 1928(7) 4516(5) 8356(2)
66(1) C(16) 553(6) 3778(5) 8767(2) 57(1) C(17) -1751(7) 4174(6)
8698(2) 79(1) C(18) 3087(5) 2275(5) 9402(1) 50(1) C(19) 3966(5)
1538(4) 8876(1) 46(1) C(20) 5883(5) 134(5) 8867(2) 49(1) C(21)
6891(5) -464(4) 9392(2) 50(1) C(22) 6053(6) 289(5) 9904(2) 57(1)
C(23) 4109(6) 1687(5) 9917(2) 60(1) C(24) 10628(7) -1590(6) 9314(2)
68(1) C(25) 4461(7) -1528(6) 5965(2) 77(1) C(26) 1668(7) -1189(5)
6511(2) 62(1) C(27) 474(9) -1531(7) 7047(2) 97(2) C(28) 1075(6)
-119(6) 6033(2) 66(1) C(29) 2881(5) 586(4) 5113(1) 41(1) C(30)
1022(5) 1672(4) 4875(1) 48(1) C(31) 1049(5) 2496(4) 4318(1) 46(1)
C(32) 2914(4) 2229(4) 4007(1) 36(1) C(33) 4925(5) 299(4) 4804(1)
41(1) C(34) 6795(4) 878(4) 3901(1) 44(1) C(35) 6645(5) 2524(4)
3506(1) 45(1) C(36) 2898(5) 3023(4) 3398(1) 40(1) C(37) 4864(5)
4036(4) 2593(1) 50(1) C(38) 6253(5) 2897(4) 2125(1) 45(1) C(39)
7514(6) 886(5) 2208(2) 60(1) C(40) 5735(6) 1526(5) 1810(2) 55(1)
C(41) 3761(8) 1048(7) 1889(2) 87(1) C(42) 7224(5) 3046(4) 1140(1)
47(1) C(43) 7187(5) 3847(4) 1650(1) 44(1) C(44) 7845(5) 5304(4)
1639(1) 45(1) C(45) 8629(5) 5859(4) 1110(2) 48(1) C(46) 8725(6)
5031(5) 612(2) 58(1) C(47) 8045(7) 3581(5) 623(2) 66(1) C(48)
11161(7) 7242(6) 1163(2) 70(1) O(1W) 7768(5) 6991(4) 3086(1) 84(1)
O(2W) 6075(9) 7130(10) 7482(2) 189(2)
TABLE-US-00003 TABLE 3 Bond lengths [.ANG.] and angles [.degree.]
for 2. O(1)--C(9) 1.217(4) N(3)--C(9) 1.364(4) O(2)--C(12) 1.209(4)
N(3)--C(10) 1.469(4) O(3)--C(18) 1.356(4) N(4)--C(12) 1.321(4)
O(3)--C(16) 1.398(4) N(4)--C(11) 1.438(4) O(4)--C(24) 1.308(5)
N(4)--C(13) 1.454(4) O(4)--C(21) 1.412(4) N(5)--C(25) 1.282(5)
O(5)--C(33) 1.221(3) N(5)--C(26) 1.350(5) O(6)--C(36) 1.220(3)
N(6)--C(25) 1.342(5) O(7)--C(42) 1.343(4) N(6)--C(28) 1.351(4)
O(7)--C(40) 1.409(4) N(6)--C(29) 1.406(4) O(8)--C(48) 1.288(5)
N(7)--C(32) 1.365(3) O(8)--C(45) 1.402(4) N(7)--C(33) 1.375(4)
F(1)--C(24) 1.286(5) N(7)--C(34) 1.451(3) F(2)--C(24) 1.285(5)
N(8)--C(36) 1.330(4) F(3)--C(24) 1.290(5) N(8)--C(37) 1.446(4)
F(4)--C(48) 1.285(5) N(8)--C(35) 1.450(4) F(5)--C(48) 1.269(5)
C(2)--C(4) 1.322(5) F(6)--C(48) 1.282(5) C(2)--C(3) 1.488(5)
N(1)--C(1) 1.311(4) C(5)--C(6) 1.344(4) N(1)--C(2) 1.366(4)
C(5)--C(9) 1.449(4) N(2)--C(1) 1.341(4) C(6)--C(7) 1.384(4)
N(2)--C(4) 1.372(4) C(7)--C(8) 1.345(4) N(2)--C(5) 1.384(4)
C(8)--C(12) 1.482(4) N(3)--C(8) 1.356(4) C(10)--C(11) 1.461(5)
C(13)--C(14) 1.469(5) C(1)--N(1)--C(2) 105.5(3) C(14)--C(19)
1.486(4) C(1)--N(2)--C(4) 105.8(3) C(14)--C(15) 1.502(5)
C(1)--N(2)--C(5) 127.6(3) C(14)--C(16) 1.508(5) C(4)--N(2)--C(5)
126.5(3) C(15)--C(16) 1.478(5) C(8)--N(3)--C(9) 123.0(2)
C(16)--C(17) 1.468(5) C(8)--N(3)--C(10) 119.3(2) C(18)--C(19)
1.361(4) C(9)--N(3)--C(10) 117.6(2) C(18)--C(23) 1.365(5)
C(12)--N(4)--C(11) 121.0(3) C(19)--C(20) 1.361(5)
C(12)--N(4)--C(13) 121.0(3) C(20)--C(21) 1.382(5)
C(11)--N(4)--C(13) 117.4(3) C(21)--C(22) 1.332(5)
C(25)--N(5)--C(26) 105.2(3) C(22)--C(23) 1.371(5)
C(25)--N(6)--C(28) 104.4(3) C(26)--C(28) 1.318(5)
C(25)--N(6)--C(29) 130.4(3) C(26)--C(27) 1.457(5)
C(28)--N(6)--C(29) 125.2(3) C(29)--C(30) 1.357(4)
C(32)--N(7)--C(33) 125.0(2) C(29)--C(33) 1.427(4)
C(32)--N(7)--C(34) 118.2(2) C(30)--C(31) 1.379(4)
C(33)--N(7)--C(34) 116.6(2) C(31)--C(32) 1.331(4)
C(36)--N(8)--C(37) 120.1(3) C(32)--C(36) 1.471(4)
C(36)--N(8)--C(35) 119.8(2) C(34)--C(35) 1.494(4)
C(37)--N(8)--C(35) 117.5(2) C(37)--C(38) 1.479(4) N(1)--C(1)--N(2)
111.6(3) C(38)--C(40) 1.479(5) C(4)--C(2)--N(1) 109.8(3)
C(38)--C(43) 1.481(4) C(4)--C(2)--C(3) 129.7(3) C(38)--C(39)
1.510(5) N(1)--C(2)--C(3) 120.4(3) C(39)--C(40) 1.466(5)
C(2)--C(4)--N(2) 107.2(3) C(40)--C(41) 1.475(6) C(6)--C(5)--N(2)
120.6(3) C(42)--C(43) 1.350(4) C(6)--C(5)--C(9) 120.0(3)
C(42)--C(47) 1.352(4) N(2)--C(5)--C(9) 119.4(3) C(43)--C(44)
1.353(4) C(5)--C(6)--C(7) 120.8(3) C(44)--C(45) 1.372(4)
C(8)--C(7)--C(6) 120.0(3) C(45)--C(46) 1.328(5) C(7)--C(8)--N(3)
120.2(3) C(46)--C(47) 1.358(5) C(7)--C(8)--C(12) 120.0(3)
C(18)--O(3)--C(16) 109.2(3) N(3)--C(8)--C(12) 119.8(3)
C(24)--O(4)--C(21) 116.9(3) O(1)--C(9)--N(3) 119.3(3)
C(42)--O(7)--C(40) 108.9(2) O(1)--C(9)--C(5) 124.8(3)
C(48)--O(8)--C(45) 117.9(3) N(3)--C(9)--C(5) 115.9(3)
C(11)--C(10)--N(3) 110.8(3) F(3)--C(24)--O(4) 112.7(4)
N(4)--C(11)--C(10) 111.7(3) N(5)--C(25)--N(6) 112.9(4)
O(2)--C(12)--N(4) 124.0(3) C(28)--C(26)--N(5) 109.6(3)
O(2)--C(12)--C(8) 118.8(3) C(28)--C(26)--C(27) 132.6(4)
N(4)--C(12)--C(8) 117.2(3) N(5)--C(26)--C(27) 117.9(4)
N(4)--C(13)--C(14) 112.4(3) C(26)--C(28)--N(6) 108.0(3)
C(13)--C(14)--C(19) 119.8(3) C(30)--C(29)--N(6) 120.9(3)
C(13)--C(14)--C(15) 120.9(3) C(30)--C(29)--C(33) 121.5(3)
C(19)--C(14)--C(15) 114.4(3) N(6)--C(29)--C(33) 117.7(3)
C(13)--C(14)--C(16) 124.0(3) C(29)--C(30)--C(31) 120.7(3)
C(19)--C(14)--C(16) 103.4(3) C(32)--C(31)--C(30) 119.9(3)
C(15)--C(14)--C(16) 58.8(2) C(31)--C(32)--N(7) 119.3(3)
C(16)--C(15)--C(14) 60.8(2) C(31)--C(32)--C(36) 119.1(3)
O(3)--C(16)--C(17) 113.1(3) N(7)--C(32)--C(36) 121.6(2)
O(3)--C(16)--C(15) 115.4(3) O(5)--C(33)--N(7) 120.8(3)
C(17)--C(16)--C(15) 123.6(3) O(5)--C(33)--C(29) 125.6(3)
O(3)--C(16)--C(14) 107.1(3) N(7)--C(33)--C(29) 113.6(2)
C(17)--C(16)--C(14) 127.2(3) N(7)--C(34)--C(35) 109.6(2)
C(15)--C(16)--C(14) 60.4(2) N(8)--C(35)--C(34) 111.2(2)
O(3)--C(18)--C(19) 113.1(3) O(6)--C(36)--N(8) 123.9(3)
O(3)--C(18)--C(23) 125.0(3) O(6)--C(36)--C(32) 119.6(3)
C(19)--C(18)--C(23) 121.8(3) N(8)--C(36)--C(32) 116.5(2)
C(20)--C(19)--C(18) 119.0(3) N(8)--C(37)--C(38) 113.4(3)
C(20)--C(19)--C(14) 133.8(3) C(37)--C(38)--C(40) 125.6(3)
C(18)--C(19)--C(14) 107.2(3) C(37)--C(38)--C(43) 116.5(3)
C(19)--C(20)--C(21) 118.6(3) C(40)--C(38)--C(43) 103.8(3)
C(22)--C(21)--C(20) 122.3(3) C(37)--C(38)--C(39) 124.5(3)
C(22)--C(21)--O(4) 117.6(3) C(40)--C(38)--C(39) 58.7(2)
C(20)--C(21)--O(4) 120.1(3) C(43)--C(38)--C(39) 114.0(3)
C(21)--C(22)--C(23) 119.4(3) C(40)--C(39)--C(38) 59.5(2)
C(18)--C(23)--C(22) 118.9(3) O(7)--C(40)--C(39) 115.1(3)
F(2)--C(24)--F(1) 109.6(4) O(7)--C(40)--C(41) 112.0(3)
F(2)--C(24)--F(3) 107.4(4) C(39)--C(40)--C(41) 124.5(3)
F(1)--C(24)--F(3) 104.6(4) O(7)--C(40)--C(38) 107.0(3)
F(2)--C(24)--O(4) 109.7(3) C(39)--C(40)--C(38) 61.7(2)
F(1)--C(24)--O(4) 112.7(4) C(41)--C(40)--C(38) 127.5(3)
O(7)--C(42)--C(43) 113.0(3) C(44)--C(45)--O(8) 120.1(3)
O(7)--C(42)--C(47) 125.4(3) C(45)--C(46)--C(47) 119.5(3)
C(43)--C(42)--C(47) 121.6(3) C(42)--C(47)--C(46) 119.0(3)
C(42)--C(43)--C(44) 119.4(3) F(5)--C(48)--F(6) 107.9(4)
C(42)--C(43)--C(38) 107.3(3) F(5)--C(48)--O(8) 114.1(4)
C(44)--C(43)--C(38) 133.3(3) F(6)--C(48)--O(8) 109.6(4)
C(43)--C(44)--C(45) 118.3(3) F(5)--C(48)--F(4) 105.8(4)
C(46)--C(45)--C(44) 122.0(3) F(6)--C(48)--F(4) 106.5(4)
C(46)--C(45)--O(8) 117.7(3) O(8)--C(48)--F(4) 112.5(4)
TABLE-US-00004 TABLE 4 Anisotropic displacement parameters
(.ANG..sup.2 .times. 10.sup.3) for 2. The anisotropic displacement
factor exponent takes the form: -2.pi..sup.2[h.sup.2
a*.sup.2U.sup.11 + . . . + 2 h k a* b* U.sup.12]. U.sup.11 U.sup.22
U.sup.33 U.sup.23 U.sup.13 U.sup.12 O(1) 37(1) 89(2) 56(2) 6(1)
7(1) -7(1) O(2) 42(1) 104(2) 52(1) 19(1) -6(1) -32(1) O(3) 67(2)
62(2) 45(1) -2(1) 2(1) -19(1) O(4) 62(2) 54(1) 63(2) 9(1) -15(1)
-26(1) O(5) 40(1) 73(2) 51(1) 11(1) -7(1) -8(1) O(6) 34(1) 84(2)
48(1) 13(1) -11(1) -14(1) O(7) 92(2) 67(2) 43(1) -9(1) 2(1) -44(1)
O(8) 59(2) 52(1) 65(2) 8(1) -2(1) -21(1) F(1) 104(2) 158(3) 116(3)
61(2) 12(2) -46(2) F(2) 66(1) 85(2) 119(2) 0(2) -22(1) -15(1) F(3)
90(2) 105(2) 189(3) -55(2) -3(2) -55(2) F(4) 166(3) 185(4) 120(3)
63(3) -81(2) -92(3) F(5) 68(2) 142(3) 254(5) -83(3) 28(2) -37(2)
F(6) 110(2) 105(2) 138(3) 9(2) -10(2) -74(2) N(1) 53(2) 72(2) 49(2)
-3(2) 8(1) -24(2) N(2) 39(1) 46(2) 38(1) -3(1) 1(1) -15(1) N(3)
34(1) 54(2) 37(1) 3(1) -6(1) -13(1) N(4) 43(1) 76(2) 34(2) 7(1)
-9(1) -22(1) N(5) 89(3) 103(3) 49(2) 18(2) -8(2) -22(2) N(6) 49(2)
49(2) 35(2) -4(1) 1(1) -10(1) N(7) 28(1) 46(1) 36(1) 1(1) -2(1)
-11(1) N(8) 36(1) 49(2) 36(1) 1(1) 3(1) -15(1) C(1) 48(2) 77(2)
43(2) -7(2) 7(2) -25(2) C(2) 55(2) 48(2) 38(2) -7(2) 4(2) -17(2)
C(3) 73(2) 58(2) 46(2) -1(2) 6(2) -16(2) C(4) 46(2) 55(2) 49(2)
4(2) -2(2) -15(2) C(5) 38(2) 39(2) 40(2) -2(1) 2(1) -13(1) C(6)
37(2) 56(2) 51(2) 8(2) -5(1) -10(2) C(7) 31(2) 68(2) 51(2) 10(2)
-2(1) -14(2) C(8) 32(2) 54(2) 41(2) -2(1) -1(1) -17(1) C(9) 36(2)
54(2) 44(2) -4(2) -2(1) -16(2) C(10) 37(2) 89(3) 45(2) 10(2) -10(1)
-13(2) C(11) 44(2) 114(3) 44(2) 9(2) -12(2) -26(2) C(12) 41(2)
61(2) 43(2) 1(2) -3(1) -20(2) C(13) 62(2) 64(2) 39(2) 7(2) -12(2)
-27(2) C(14) 56(2) 54(2) 36(2) 6(1) -4(1) -23(2) C(15) 86(3) 61(2)
49(2) 8(2) -6(2) -25(2) C(16) 64(2) 60(2) 46(2) 8(2) -7(2) -22(2)
C(17) 70(3) 89(3) 70(3) 0(2) -5(2) -19(2) C(18) 56(2) 57(2) 43(2)
-3(2) 0(2) -26(2) C(19) 54(2) 54(2) 36(2) 2(1) -5(1) -27(2) C(20)
59(2) 56(2) 41(2) 1(2) -6(2) -30(2) C(21) 54(2) 44(2) 56(2) 3(2)
-10(2) -22(2) C(22) 73(2) 66(2) 39(2) 5(2) -14(2) -33(2) C(23)
77(3) 70(2) 39(2) -5(2) -7(2) -31(2) C(24) 65(3) 63(2) 78(3) 3(2)
-9(2) -26(2) C(25) 61(2) 103(3) 48(2) 16(2) -4(2) -8(2) C(26) 87(3)
59(2) 38(2) -2(2) 10(2) -25(2) C(27) 131(4) 87(3) 61(3) 14(2) 16(3)
-32(3) C(28) 63(2) 76(3) 48(2) 11(2) 14(2) -15(2) C(29) 46(2) 44(2)
33(2) -5(1) -1(1) -14(2) C(30) 36(2) 65(2) 41(2) -3(2) 6(1) -17(2)
C(31) 29(1) 63(2) 44(2) -2(2) -2(1) -12(2) C(32) 29(1) 41(2) 37(2)
0(1) -3(1) -10(1) C(33) 38(2) 41(2) 40(2) -2(1) -4(1) -10(1) C(34)
26(1) 53(2) 50(2) -1(2) 2(1) -10(1) C(35) 34(2) 56(2) 45(2) 0(2)
-2(1) -18(1) C(36) 36(2) 45(2) 37(2) -2(1) -1(1) -11(1) C(37) 46(2)
52(2) 46(2) 5(2) 4(1) -12(2) C(38) 49(2) 47(2) 40(2) -1(1) 3(1)
-19(2) C(39) 75(2) 48(2) 51(2) 1(2) 3(2) -14(2) C(40) 72(2) 59(2)
41(2) -2(2) 5(2) -34(2) C(41) 113(4) 95(3) 80(3) -8(2) 8(3) -70(3)
C(42) 63(2) 47(2) 36(2) -1(1) 0(1) -25(2) C(43) 46(2) 44(2) 38(2)
-2(1) 3(1) -14(2) C(44) 47(2) 47(2) 40(2) -1(1) 2(1) -15(2) C(45)
54(2) 41(2) 48(2) 4(2) 2(2) -18(2) C(46) 76(2) 61(2) 40(2) 3(2)
7(2) -29(2) C(47) 97(3) 74(3) 37(2) -8(2) 8(2) -41(2) C(48) 66(3)
68(3) 79(3) 5(2) -15(2) -26(2) O(1W) 78(2) 82(2) 83(2) 9(2) 15(2)
-24(2) O(2W) 152(4) 250(6) 138(4) 1(4) -35(3) -31(4)
TABLE-US-00005 TABLE 5 Hydrogen coordinates (.times.10.sup.4) and
isotropic displacement parameters (.ANG..sup.2 .times. 10.sup.3)
for 2. x y z U(eq) H(1) 6316 5661 4802 67 H(3A) 832 8225 3259 92
H(3B) 3243 7830 3036 92 H(3C) 1974 9617 3364 92 H(4) 298 7018 4372
61 H(6) -516 6658 5339 60 H(7) -1411 5396 6230 62 H(10A) 5614 981
6486 72 H(10B) 6694 2468 6509 72 H(11A) 5744 1442 7447 81 H(11B)
4729 3563 7339 81 H(13A) 3183 239 7955 64 H(13B) 737 1441 7944 64
H(15A) 2898 5004 8527 79 H(15B) 1323 5146 7992 79 H(17A) -2547 5397
8808 118 H(17B) -2238 3334 8948 118 H(17C) -1975 4048 8293 118
H(20) 6501 -411 8515 59 H(22) 6781 -130 10249 68 H(23) 3497 2226
10270 72 H(25) 5893 -1924 5821 92 H(27A) 1411 -2507 7284 146 H(27B)
-713 -1861 6942 146 H(27C) -63 -449 7269 146 H(28) -321 1634 5957
80 H(30) -284 1862 5091 58 H(31) -234 237 4159 55 H(34A) 7076 -171
3664 53 H(34B) 7977 627 4158 53 H(35A) 6544 3532 3744 54 H(35B)
7942 2275 3247 54 H(37A) 5395 5013 2657 60 H(37B) 3415 4586 2459 60
H(39A) 8972 438 2032 72 H(39B) 7287 272 2582 72 H(41A) 3899 62 1643
131 H(41B) 2544 2088 1779 131 H(41C) 3555 683 2296 131 H(44) 7767
5913 1982 54 H(46) 9253 5443 259 70 H(47) 8143 2964 281 80
Examples 4 and 5
2-{[(1aS,6bS)-3-Fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (4) and
2-{[(1aR,6bR)-3-Fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (5)
##STR00022## ##STR00023##
[0330] Step 1. Synthesis of
[2-fluoro-4-(trifluoromethoxy)phenyl]boronic acid (C23)
[0331] Tripropan-2-yl borate (43.6 g, 232 mmol) was added to a
solution of 4-bromo-3-fluorophenyl trifluoromethyl ether (50.0 g,
193 mmol) in toluene (400 mL) and tetrahydrofuran (100 mL), and the
mixture was cooled to -78.degree. C. n-Butyllithium (2.5 M
solution; 92.7 mL, 232 mmol) was then added drop-wise, at a rate
that maintained the reaction temperature below -60.degree. C., and
the reaction mixture was stirred at -70.degree. C. for 4 hours.
After the reaction mixture had been warmed to -20.degree. C., it
was quenched via addition of aqueous hydrochloric acid (2 M, 200
mL), and then stirred at room temperature (20.degree. C.) for 40
minutes. The aqueous layer was extracted with ethyl acetate
(3.times.50 mL), and the combined organic layers were washed with
saturated aqueous sodium chloride solution (100 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo to afford the
product (43 g) as a white solid, which was carried directly to the
next step.
Step 2. Synthesis of 2-fluoro-4-(trifluoromethoxy) phenol (C24)
[0332] To a 20.degree. C. solution of C23 (from the previous step;
43 g, .ltoreq.193 mmol) in dichloromethane (300 mL) was added
hydrogen peroxide (30% solution, 99 mL, 1.0 mol), and the reaction
mixture was stirred at 20.degree. C. for 2 hours. It was then
partitioned between water (200 mL) and dichloromethane (200 mL);
the aqueous layer was extracted with dichloromethane (2.times.100
mL), and the combined organic layers were washed with saturated
aqueous sodium chloride solution (200 mL), dried over sodium
sulfate, filtered, and concentrated under reduced pressure. Silica
gel chromatography (Eluent: 10% ethyl acetate in petroleum ether)
provided the product (30 g, which by .sup.1H NMR analysis consisted
of a 1:0.3 molar ratio of product and ethyl acetate) as a yellow
oil. Corrected yield: 26 g, 130 mol, 67% over 2 steps. LCMS m/z
195.0 [M-H.sup.+]. .sup.1H NMR (400 MHz, CDCl.sub.3), product peaks
only: .delta. 6.98-7.05 (m, 2H), 6.94 (br d, half of AB quartet,
J=9 Hz, 1H) 5.54 (br d, J=3.3 Hz, 1H).
Step 3. Synthesis of 2-fluoro-6-iodo-4-(trifluoromethoxy)phenol
(C25)
[0333] A mixture of C24 (9.5 g, 48 mmol) and N-iodosuccinimide (12
g, 53 mmol) in N,N-dimethylformamide (50 mL) was stirred at
25.degree. C. for 4 hours, whereupon it was diluted with water (300
mL) and extracted with tert-butyl methyl ether (3.times.100 mL).
The combined organic layers were washed sequentially with saturated
aqueous sodium hydrogen sulfite solution (50 mL) and saturated
aqueous sodium chloride solution (50 mL), dried over sodium
sulfate, filtered, and concentrated in vacuo. Chromatography on
silica gel (Gradient: 0% to 20% ethyl acetate in petroleum ether)
afforded the product as a yellow oil. Yield: 12.0 g, 37.3 mmol,
78%. LCMS m/z 320.9 [M-H.sup.+]. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.40 (br s, 1H), 7.06 (dd, J=10.2, 2.0 Hz, 1H), 5.78 (br s,
1H).
Step 4. Synthesis of
2-[(benzyloxy)methoxy]-1-fluoro-3-iodo-5-(trifluoromethoxy)benzene
(C26)
[0334] Benzyl chloromethyl ether (7.66 g, 48.9 mmol) was added to a
mixture of C25 (10.5 g, 32.6 mmol) and potassium carbonate (9.01 g,
65.2 mmol) in acetonitrile (100 mL), and the resulting suspension
was stirred at 25.degree. C. for 2 hours. The reaction mixture was
then diluted with water (400 mL) and extracted with dichloromethane
(3.times.200 mL); the combined organic layers were dried over
sodium sulfate, filtered, and concentrated in vacuo. Silica gel
chromatography (Gradient: 0% to 20% ethyl acetate in petroleum
ether) provided the product as a colorless oil. Yield: 12.3 g, 27.8
mmol, 85%. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.46-7.51 (m,
1H), 7.30-7.41 (m, 5H), 7.06 (ddq, J=10.9, 2.8, 0.7 Hz, 1H), 5.33
(s, 2H), 4.93 (s, 2H).
Step 5. Synthesis of
2-[(benzyloxy)methoxy]-1-fluoro-3-(prop-1-yn-1-yl)-5-(trifluoromethoxy)be-
nzene (C27)
[0335] A mixture of C26 (12.0 g, 27.1 mmol), but-2-ynoic acid (4.56
g, 54.2 mmol), and cesium carbonate (13.3 g, 40.8 mmol) in toluene
(200 mL) was treated with allylpalladium chloride dimer (497 mg,
1.36 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (785
mg, 1.36 mmol). The reaction mixture was degassed twice with
nitrogen, whereupon it was heated to 80.degree. C. for 16 hours,
then filtered through diatomaceous earth. The filtrate was
concentrated in vacuo and purified by silica gel chromatography
(Gradient: 0% to 30% ethyl acetate in petroleum ether), affording
the product as a yellow oil. Yield: 9.2 g, 26 mmol, 96%. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.30-7.40 (m, 5H), 7.05-7.09 (m,
1H), 6.96 (br dd, J=10.7, 2.6 Hz, 1H), 5.35 (s, 2H), 4.91 (s, 2H),
2.07 (s, 3H).
Step 6. Synthesis of
3-[(benzyloxy)methyl]-7-fluoro-2-methyl-5-(trifluoromethoxy)-1-benzofuran
(C28)
[0336] Di-mu-chloro-dichlorobis(ethylene)diplatinum(II) (840 mg,
1.43 mmol) was added to a solution of C27 (9.2 g, 26 mmol) in
toluene (200 mL); the reaction mixture was stirred at 35.degree. C.
for 16 hours, then allowed to stand at 25.degree. C. for 2 days.
The reaction mixture was concentrated in vacuo, and the residue was
purified via silica gel chromatography (Gradient: 0% to 20% ethyl
acetate in petroleum ether) to afford the product as a yellow oil.
Yield: 6.5 g, 18 mmol, 69%. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.30-7.41 (m, 5H), 7.19-7.23 (m, 1H), 6.91 (brd, J=10.5 Hz,
1H), 4.59 (s, 2H), 4.56 (s, 2H), 2.46 (s, 3H).
Step 7. Synthesis of
[7-fluoro-2-methyl-5-(trifluoromethoxy)-1-benzofuran-3-yl]methanol
(C29)
[0337] To a solution of C28 (3.0 g, 8.5 mmol) in ethanol (150 mL)
was added palladium hydroxide on carbon (300 mg), and the reaction
mixture was degassed three times with hydrogen. The resulting black
suspension was stirred at 60.degree. C. for 16 hours under 50 psi
of hydrogen, whereupon it was filtered through diatomaceous earth.
The filtrate was concentrated in vacuo; the residue was combined
with material from a second reaction (carried out on 3.0 g of C28,
8.5 mmol) and subjected to chromatography on silica gel (Gradient:
0% to 50% ethyl acetate in petroleum ether), affording the product
as a white solid. Yield: 3.60 g, 13.6 mmol, 80%. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.28-7.31 (m, 1H), 6.92 (br d, J=10.7 Hz,
1H), 4.77 (br s, 2H), 2.52 (s, 3H).
Step 8. Synthesis of
[3-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1-
]benzofuran-6b-yl]methanol (C30)
[0338] Diiodomethane (43.8 g, 164 mmol) and diethylzinc (1 M
solution in toluene, 81.8 mmol, 81.8 mL) were added to a solution
of C29 (2.70 g, 10.2 mmol) in toluene (200 mL), and the reaction
mixture was stirred at 30.degree. C. for 16 hours. It was then
added drop-wise to water (200 mL) at 0.degree. C.; the resulting
mixture was stirred for 10 minutes, whereupon it was filtered
through diatomaceous earth. The aqueous layer was extracted with
ethyl acetate (3.times.100 mL), and the combined organic layers
were washed with saturated aqueous sodium chloride solution (100
mL), dried over sodium sulfate, filtered, and concentrated under
reduced pressure. Chromatography on silica gel (Gradient: 0% to 30%
ethyl acetate in petroleum ether) provided the product as a yellow
oil. Yield: 2.0 g, 7.2 mmol, 71%. LCMS m/z 261.0 [M-OH].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.10-7.12 (m, 1H), 6.85
(br d, J=10.5 Hz, 1H), 4.12 (d, J=12.0 Hz, 1H), 3.87 (d, J=12.0 Hz,
1H), 1.80 (s, 3H), 1.14 (d, J=6.5 Hz, 1H), 0.70 (d, J=6.5 Hz,
1H).
Step 9. Synthesis of
2-{[3-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b-
][1]benzofuran-6b-yl]methyl}-1H-isoindole-1,3(2H)-dione (C31)
[0339] Diisopropyl azodicarboxylate (640 mg, 3.16 mmol) was added
drop-wise to a mixture of C30 (800 mg, 2.88 mmol),
1H-isoindole-1,3(2H)-dione (465 mg, 3.16 mmol), and
triphenylphosphine (830 mg, 3.16 mmol) in tetrahydrofuran (60 mL).
The reaction mixture was stirred at 25.degree. C. for 20 hours,
whereupon it was concentrated in vacuo. Silica gel chromatography
(Gradient: 0% to 20% ethyl acetate in petroleum ether) provided the
product as a colorless oil. Yield: 880 mg, 2.16 mmol, 75%. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.86-7.91 (m, 2H), 7.73-7.78 (m,
2H), 7.46-7.49 (m, 1H), 6.81 (br d, J=10.3 Hz, 1H), 4.24 (d, J=15.2
Hz, 1H), 3.97 (d, J=15.3 Hz, 1H), 1.96 (s, 3H), 1.19 (d, J=6.6 Hz,
1H), 0.61 (d, J=6.8 Hz, 1H).
Step 10. Synthesis of
1-[3-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b]-
[1]benzofuran-6b-yl]methanamine (C32)
[0340] To a solution of C31 (500 mg, 1.2 mmol) in methanol (30 mL)
was added hydrazine monohydrate (50% aqueous solution, 5 mL, 50
mmol), and the reaction mixture was stirred at 25.degree. C. for 16
hours. After solvent had been removed in vacuo, the residue was
diluted with dichloromethane (5 mL) and filtered; the filtrate was
concentrated under reduced pressure to afford the product as a
colorless oil. Yield: 300 mg, 1.1 mmol, 92%. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.39-7.43 (m, 1H), 7.21 (br d, J=10.9 Hz,
1H), 3.15 (d, J=13.8 Hz, 1H), 2.80 (d, J=13.9 Hz, 1H), 1.71 (s,
3H), 1.17 (d, J=6.3 Hz, 1H), 0.50 (d, J=6.3 Hz, 1H).
Step 11. Synthesis of
2-{[3-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b-
][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,6-dione (C33)
[0341] 1,3,4,6,7,8-Hexahydro-2H-pyrimido[1,2-a]pyrimidine (191 mg,
1.37 mmol) was added to a suspension of C10 (252 mg, 1.03 mmol) and
C32 (190 mg, 0.685 mmol) in N,N-dimethylformamide (5 mL), and the
reaction mixture was stirred at 25.degree. C. for 30 minutes. Ethyl
trifluoroacetate (386 mg, 2.72 mmol) was then added drop-wise over
5 minutes at 25.degree. C., whereupon the reaction mixture was
stirred at 60.degree. C. for 1 hour, cooled, and combined with
similar material derived from a second reaction (carried out on
42.2 mg of C32, 0.152 mmol). The mixture was diluted with aqueous
sodium hydroxide solution (1 M, 5 mL) and saturated aqueous sodium
chloride solution (5 mL), and extracted with dichloromethane
(3.times.5 mL). The combined organic layers were dried over sodium
sulfate, filtered, and concentrated in vacuo. Purification via
silica gel chromatography (Gradient: 0% to 10% methanol in
dichloromethane) provided the racemic product as a yellow gum.
Yield: 180 mg, 0.357 mmol, 43%. LCMS m/z 505.2 [M+H].sup.+. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.22 (br s, 1H), 7.45 (d, J=7.6
Hz, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.12 (br s, 1H), 7.04-7.08 (m,
1H), 6.85 (br d, J=10 Hz, 1H), 5.06 (d, J=15.2 Hz, 1H), 4.23 (dd,
J=5.9, 5.6 Hz, 2H), 3.57 (ddd, half of ABXY pattern, J=13, 6, 5 Hz,
1H), 3.48 (ddd, half of ABXY pattern, J=13, 6, 6 Hz, 1H), 3.16 (d,
J=15.2 Hz, 1H), 2.28 (d, J=1 Hz, 3H), 1.89 (s, 3H), 1.07 (d, J=6.8
Hz, 1H), 0.76 (d, J=6.6 Hz, 1H).
Step 12. Isolation of
2-{[(1aS,6bS)-3-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (4) and
2-{[(1aR,6bR)-3-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (5)
[0342] Racemate C33 (160 mg, 0.32 mmol) was separated into its
component enantiomers using supercritical fluid chromatography
[Column: Chiral Technologies Chiralpak AD, 10 .mu.m; Mobile phase:
30% (methanol containing 0.1% ammonium hydroxide) in carbon
dioxide]. The second-eluting enantiomer was 4, isolated as a white
solid. Yield: 71 mg, 0.14 .mu.mol, 44%. LCMS m/z 505.1 [M+H].sup.+.
Retention time: 7.68 minutes (Column: Chiral Technologies Chiralpak
AD-H, 4.6.times.250 mm, 5 .mu.m; Mobile phase A: carbon dioxide;
Mobile phase B: methanol containing 0.05% diethylamine; Gradient:
5% to 40% B; Flow rate: 2.5 mL/minute). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.22 (br s, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.29
(d, J=7.8 Hz, 1H), 7.12 (br s, 1H), 7.05-7.08 (m, 1H), 6.85 (br d,
J=10.2 Hz, 1H), 5.05 (d, J=15.2 Hz, 1H), 4.23 (dd, J=6.2, 5.5 Hz,
2H), 3.57 (ddd, half of ABXY pattern, J=13, 5.5, 5.5 Hz, 1H), 3.48
(ddd, half of ABXY pattern, J=13, 6, 6 Hz, 1H), 3.17 (d, J=15.3 Hz,
1H), 2.28 (br s, 3H), 1.89 (s, 3H), 1.07 (d, J=6.8 Hz, 1H), 0.76
(d, J=6.6 Hz, 1H).
[0343] The first-eluting enantiomer, 5, was also obtained as a
white solid. Yield: 73 mg, 0.14 .mu.mol, 44%. LCMS m/z 505.2
[M+H].sup.+. Retention time: 6.42 minutes, using the same
analytical conditions as those reported above for 4. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.21 (br s, 1H), 7.45 (d, J=7.8 Hz,
1H), 7.29 (d, J=7.8 Hz, 1H), 7.12 (br s, 1H), 7.04-7.08 (m, 1H),
6.85 (br d, J=10.4 Hz, 1H), 5.06 (d, J=15.3 Hz, 1H), 4.23 (dd,
J=6.0, 5.6 Hz, 2H), 3.57 (ddd, half of ABXY pattern, J=13, 5.5, 5.5
Hz, 1H), 3.48 (ddd, half of ABXY pattern, J=13, 6, 6 Hz, 1H), 3.16
(d, J=15.3 Hz, 1H), 2.28 (d, J=0.8 Hz, 3H), 1.89 (s, 3H), 1.07 (d,
J=6.8 Hz, 1H), 0.76 (d, J=6.8 Hz, 1H).
Examples 6 and 7
2-{[(1aS,6bS)-4-Fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (6) and
2-{[(1aR,6bR)-4-Fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (7)
##STR00024##
[0344] Step 1. Synthesis of
5-fluoro-2-iodo-4-(trifluoromethoxy)phenol (C34)
[0345] A mixture of 3-fluoro-4-(trifluoromethoxy)phenol (7.0 g, 36
mmol) and N-iodosuccinimide (95%, 8.45 g, 35.7 mmol) in acetic acid
(10 mL) was stirred at room temperature for 5 minutes and then
treated with concentrated sulfuric acid (18 M, 0.58 mL, 10.4 mmol).
After the reaction mixture had stirred overnight, it was
partitioned between water and diethyl ether. The organic layer was
washed with water and with 2 M aqueous sodium thiosulfate solution,
treated with activated carbon, and dried over magnesium sulfate.
The mixture was filtered through a pad of diatomaceous earth and
silica gel, and the filtrate was concentrated in vacuo, providing
the product as an oil (11.0 g), which by .sup.1H NMR analysis
contained two molar equivalents of acetic acid. Yield, corrected
for acetic acid: 8.0 g, 25 mmol, 70%. GCMS m/z 322.0 [M.sup.+].
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.60 (br d, J=8.1 Hz,
1H), 6.88 (d, J=10.9 Hz, 1H).
Step 2. Synthesis of ethyl
(2E)-3-[5-fluoro-2-iodo-4-(trifluoromethoxy)phenoxy]but-2-enoate
(C35)
[0346] A mixture of C34 [from the previous step; 11.0 g (corrected
for acetic acid: 8.0 g, 25 mmol)], ethyl but-2-ynoate (4.0 mL, 34
mmol), and potassium carbonate (18.0 g, 130 mmol) in acetonitrile
(100 mL) was heated at reflux for 6 hours, then allowed to stir at
room temperature overnight. After the reaction mixture had been
partitioned between water and diethyl ether, the organic layer was
washed with water and with saturated aqueous sodium chloride
solution, dried over magnesium sulfate, filtered, and concentrated
in vacuo. Chromatography on silica gel (Gradient: 0% to 5% ethyl
acetate in heptane) provided the product as an oil. Yield: 8.60 g,
19.8 mmol, 79%. GCMS m/z 434.1 [M.sup.+]. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.78 (br d, J=8.0 Hz, 1H), 6.98 (d, J=10.0 Hz,
1H), 4.78 (s, 1H), 4.13 (q, J=7.1 Hz, 2H), 2.53 (s, 3H), 1.25 (t,
J=7.1 Hz, 3H).
Step 3. Synthesis of ethyl
6-fluoro-2-methyl-5-(trifluoromethoxy)-1-benzofuran-3-carboxylate
(C36)
[0347] A stream of nitrogen was bubbled through a solution of C35
(250 mg, 0.576 mmol) in acetonitrile (5 mL) for 10 minutes,
whereupon triethylamine (0.40 mL, 2.9 mmol) was added to the
solution, followed by bis(tri-tert-butylphosphine)palladium(0)
(14.9 mg, 29.2 .mu.mol). The reaction mixture was heated to
90.degree. C. for 20 hours, cooled to room temperature, and
partitioned between diethyl ether and water. The organic layer was
washed with water, dried over magnesium sulfate, filtered, and
concentrated under reduced pressure; silica gel chromatography
(Gradient: 0% to 5% ethyl acetate in heptane) provided the product
as a white solid. Yield: 148 mg, 0.483 mmol, 84%. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.91 (dq, J=7.7, 1.1 Hz, 1H), 7.30 (d,
J=9.3 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 2.78 (s, 3H), 1.45 (t, J=7.1
Hz, 3H).
Step 4. Synthesis of
4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]-
benzofuran-6b-carboxylic acid (C37)
[0348] A suspension of trimethylsulfoxonium iodide (98%, 1.35 g,
6.01 mmol) in dimethyl sulfoxide (10 mL) was treated with potassium
tert-butoxide (645 mg, 5.75 mmol) and stirred at room temperature
for 30 minutes. A solution of C36 (1.60 g, 5.22 mmol) in dimethyl
sulfoxide (5 mL) and tetrahydrofuran (2 mL) was added; the reaction
mixture was stirred for 2 hours, whereupon it was treated with
additional trimethylsulfoxonium iodide (98%, 300 mg, 1.3 mmol) and
potassium tert-butoxide (130 mg, 1.16 mmol). After 30 minutes,
potassium hydroxide (85%, 700 mg, 11 mmol) was added, and stirring
was continued for 2 hours. Water (10 mL) was added to the reaction
mixture, which was then adjusted to a pH of 4-5 via addition of 1 M
aqueous hydrochloric acid. The mixture was extracted with ethyl
acetate (3.times.50 mL), and the combined organic layers were
washed with water and with saturated aqueous sodium chloride
solution, dried over sodium sulfate, filtered, and concentrated in
vacuo. The resulting thick oil was treated with heptane (100 mL),
concentrated under reduced pressure, dissolved in diethyl ether,
washed twice with water, dried over sodium sulfate, filtered, and
concentrated in vacuo. The product was obtained as a solid. Yield:
1.40 g, 4.79 mmol, 92%. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
7.57 (br d, J=7.9 Hz, 1H), 6.83 (d, J=10.4 Hz, 1H), 1.98 (d, J=6.2
Hz, 1H), 1.83 (s, 3H), 0.92 (d, J=6.3 Hz, 1H).
Step 5. Synthesis of
4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]-
benzofuran-6b-carboxamide (C38)
[0349] 1,1'-Carbonyldiimidazole (266 mg, 1.64 mmol) was added to a
solution of C37 (400 mg, 1.37 mmol) in tetrahydrofuran (10 mL), and
the reaction mixture was stirred at room temperature for 30
minutes. Concentrated ammonium hydroxide solution (0.7 mL) was
added, and stirring was continued for 1 hour, whereupon the
reaction mixture was partitioned between water and diethyl ether.
The organic layer was washed with water, dried over sodium sulfate,
filtered, and concentrated in vacuo, providing the product as a
pasty solid. Yield: 390 mg, 1.34 mmol, 98%. GCMS m/z 291.2
[M.sup.+]. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.50 (br d,
J=7.9 Hz, 1H), 7.41 (br s, 1H), 7.31 (br s, 1H), 7.15 (d, J=10.9
Hz, 1H), 1.96 (d, J=6.6 Hz, 1H), 1.65 (s, 3H), 0.75 (d, J=6.6 Hz,
1H).
Step 6. Synthesis of
1-[4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b]-
[1]benzofuran-6b-yl]methanamine (C39)
[0350] Sodium bis(2-methoxyethoxy)aluminum hydride (3.3 M solution
in toluene; 7.0 mL, 23 mmol) was added to a solution of C38 (1.70
g, 5.84 mmol) in toluene (30 mL). The reaction mixture was stirred
at room temperature for 2 hours, whereupon it was cooled in an ice
bath and quenched with aqueous sodium hydroxide solution (1 M, 30
mL). The resulting mixture was extracted with diethyl ether; the
combined organic layers were washed with saturated aqueous sodium
chloride solution, dried over sodium sulfate, filtered, and
concentrated in vacuo. Silica gel chromatography (Gradient: 0% to
5% methanol in dichloromethane) afforded the product as a thick
oil. Yield: 1.2 g, 4.3 mmol, 74%. GCMS m/z 260.2
[M-NH.sub.3].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.25-7.31 (m, 1H, assumed; partially obscured by solvent peak),
6.66 (d, J=10.2 Hz, 1H), 3.34 (d, J=14.0 Hz, 1H), 2.87 (d, J=14.0
Hz, 1H), 1.75 (s, 3H), 0.95 (d, J=6.3 Hz, 1H), 0.56 (d, J=6.3 Hz,
1H).
Step 7. Synthesis of
2-{[4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b-
][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H--
pyrido[1,2-a]pyrazine-1,6-dione (C40)
[0351] Conversion of C39 to the product was carried out using the
method described for synthesis of C22 from C21 in Examples 2 and 3.
The product was obtained as a white solid. Yield: 560 mg, 1.11
mmol, 97%. LCMS m/z 505.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.22 (d, J=1.2 Hz, 1H), 7.45 (d, J=7.7 Hz, 1H),
7.24-7.31 (m, 2H, assumed; partially obscured by solvent peak),
7.11-7.14 (m, 1H), 6.68 (d, J=10.0 Hz, 1H), 5.06 (d, J=15.1 Hz,
1H), 4.26 (ddd, half of ABXY pattern, J=14.2, 6.3, 4.7 Hz, 1H),
4.20 (ddd, half of ABXY pattern, J=14.3, 8.0, 4.4 Hz, 1H), 3.56
(ddd, half of ABXY pattern, J=13.2, 6.3, 4.5 Hz, 1H), 3.46 (ddd,
half of ABXY pattern, J=13.2, 7.9, 4.5 Hz, 1H), 3.12 (d, J=15.2 Hz,
1H), 2.29 (br s, 3H), 1.84 (s, 3H), 1.00 (d, J=6.6 Hz, 1H), 0.68
(d, J=6.6 Hz, 1H).
Step 8. Isolation of
2-{[(1aS,6bS)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (6) and
2-{[(1aR,6bR)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-d-
ihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (7)
[0352] Separation of C40 (560 mg, 1.1 mmol) into its component
enantiomers was carried out via supercritical fluid chromatography
[Column: Chiral Technologies Chiralpak AD-H, 5 .mu.m; Mobile phase:
30% (0.2% ammonium hydroxide in methanol) in carbon dioxide]. Each
enantiomer was then dissolved in ethyl acetate (15 mL), filtered,
and concentrated in vacuo; suspension in diethyl ether followed by
filtration provided the products, both as solids. Compound 6 was
the second-eluting enantiomer. Yield: 160 mg, 0.317 mg, 28%. LCMS
m/z 505.1 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.22 (s, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.26-7.31 (m, 2H, assumed;
partially obscured by solvent peak), 7.13 (br s, 1H), 6.68 (d,
J=10.0 Hz, 1H), 5.06 (d, J=15.2 Hz, 1H), 4.26 (ddd, half of ABXY
pattern, J=14, 6, 5 Hz, 1H), 4.20 (ddd, half of ABXY pattern, J=14,
8, 4 Hz, 1H), 3.56 (ddd, half of ABXY pattern, J=13, 6, 5 Hz, 1H),
3.46 (ddd, half of ABXY pattern, J=13, 8, 5 Hz, 1H), 3.12 (d,
J=15.2 Hz, 1H), 2.29 (s, 3H), 1.84 (s, 3H), 1.00 (d, J=6.6 Hz, 1H),
0.68 (d, J=6.6 Hz, 1H).
[0353] Compound 7 was the first-eluting enantiomer. Yield: 180 mg,
0.357 mmol, 31%. LCMS m/z 505.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.22 (s, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.26-7.31
(m, 2H, assumed; partially obscured by solvent peak), 7.13 (br s,
1H), 6.68 (d, J=10.0 Hz, 1H), 5.06 (d, J=15.2 Hz, 1H), 4.26 (ddd,
half of ABXY pattern, J=14.5, 6, 5 Hz, 1H), 4.20 (ddd, half of ABXY
pattern, J=14.3, 7.8, 4.3 Hz, 1H), 3.56 (ddd, half of ABXY pattern,
J=13, 6, 4.5 Hz, 1H), 3.46 (ddd, half of ABXY pattern, J=13, 8, 5
Hz, 1H), 3.12 (d, J=15.1 Hz, 1H), 2.29 (s, 3H), 1.84 (s, 3H), 1.00
(d, J=6.6 Hz, 1H), 0.68 (d, J=6.6 Hz, 1H).
Examples 8 and 9
2-{[(1aS,6bS)-4-Fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(3-methyl-1H-1,2,4-triazol-1-yl)-3-
,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (8) and
2-{[(1aR,6bR)-4-Fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(3-methyl-1H-1,2,4-triazol-1-yl)--
3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (9)
##STR00025## ##STR00026##
[0354] Step 1. Synthesis of
5-bromo-6-oxo-1,6-dihydropyridine-2-carboxylic acid (C41)
[0355] Bromine (115 g, 720 mmol) was added drop-wise to a
suspension of 6-oxo-1,6-dihydropyridine-2-carboxylic acid (25 g,
180 mmol) in acetic acid (400 mL). The reaction mixture was heated
to 80.degree. C. for 16 hours, whereupon it was concentrated to
dryness under reduced pressure. The residue was triturated with
tert-butyl methyl ether (200 mL) and filtered; the filter cake was
washed with tert-butyl methyl ether (3.times.100 mL) to provide the
product as a gray solid. Yield: 39.0 g, 179 mmol, 99%. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.03 (d, J=7.3 Hz, 1H), 6.83 (d,
J=7.3 Hz, 1H).
Step 2. Synthesis of 7-bromo-3,4-dihydropyrido[2,
1-c][1,4]oxazine-1,6-dione (C42)
[0356] This transformation was carried out in four identical
batches. 1,2-Dibromoethane (9.48 g, 50.5 mmol) was added to a
suspension of C41 (10.0 g, 45.9 mmol) and cesium carbonate (37.4 g,
115 mmol) in N,N-dimethylformamide (50 mL). The reaction mixture
was stirred at 95.degree. C. for 2 hours, whereupon it was cooled
to about 30.degree. C. and combined with the other three batches.
This material was poured into dichloromethane (600 mL) and stirred
at room temperature for 10 minutes, then filtered. The filter cake
was washed with dichloromethane (200 mL), and the combined
filtrates were concentrated to dryness under reduced pressure. The
residue was mixed with dichloromethane (100 mL), stirred at
25.degree. C. for 20 minutes, and then filtered. The collected
solid was dissolved in a mixture of dichloromethane (500 mL) and
methanol (30 mL), and filtered through silica gel (10 g). This
filtrate was concentrated in vacuo and triturated with a mixture of
dichloromethane (50 mL) and tert-butyl methyl ether (50 mL),
affording the product as a pale yellow solid. Yield: 13 g, 53 mmol,
29%. LCMS m/z 245.8 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.91 (d, J=7.5 Hz, 1H), 7.14 (d, J=7.5 Hz, 1H), 4.64 (dd,
J=5.3, 5.1 Hz, 2H), 4.36 (dd, J=5.3, 5.1 Hz, 2H).
Step 3. Synthesis of
7-bromo-2-{[4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cycl-
opropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine--
1,6-dione (C43)
[0357] 1,3,4,6,7,8-Hexahydro-2H-pyrimido[1,2-a]pyrimidine (97%, 932
mg, 6.49 mmol) was added to a mixture of C39 (1.20 g, 4.33 mmol)
and C42 (1.37 g, 5.61 mmol) in N,N-dimethylformamide (5 mL). The
reaction mixture was stirred at room temperature for 2 hours, then
treated with ethyl trifluoroacetate (1.3 mL, 10.9 mmol). After 1
hour, aqueous sodium hydroxide solution (1 M, 10 mL) was added, and
stirring was continued for 15 minutes. The mixture was then
extracted with ethyl acetate, and the combined organic layers were
washed with water, dried over sodium sulfate, filtered, and
concentrated in vacuo. Chromatography on silica gel (Gradient: 30%
to 100% ethyl acetate in heptane) provided the product as an oil.
Yield: 1.76 g, 3.50 mmol, 81%. LCMS m/z 503.3, 505.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.86 (d, J=7.6 Hz, 1H),
7.24-7.28 (m, 1H, assumed; partially obscured by solvent peak),
7.07 (d, J=7.6 Hz, 1H), 6.67 (d, J=9.9 Hz, 1H), 5.01 (d, J=15.2 Hz,
1H), 4.18 (dd, J=6.0, 5.8 Hz, 2H), 3.52 (ddd, half of ABXY pattern,
J=13, 5.5, 5.5 Hz, 1H), 3.42 (ddd, half of ABXY pattern, J=13, 6, 6
Hz, 1H), 3.11 (d, J=15.2 Hz, 1H), 1.82 (s, 3H), 0.98 (d, J=6.6 Hz,
1H), 0.67 (d, J=6.6 Hz, 1H).
Step 4. Synthesis of
2-{[4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b-
][1]benzofuran-6b-yl]methyl}-7-(3-methyl-1H-1,2,4-triazol-1-yl)-3,4-dihydr-
o-2H-pyrido[1,2-a]pyrazine-1,6-dione (C44)
[0358] A mixture of tris(dibenzylideneacetone)dipalladium(0) (98%,
94.7 mg, 0.101 mmol) and
di-tert-butyl[3,4,5,6-tetramethyl-2',4',6'-tri(propan-2-yl)biphenyl-2-yl]-
phosphane (95%, 103 mg, 0.203 mmol) in toluene (10 mL) was degassed
with nitrogen for 5 minutes, then heated at 125.degree. C. for 3
minutes. In a separate flask, a mixture of C43 (1.70 g, 3.38 mmol),
3-methyl-1H-1,2,4-triazole (561 mg, 6.75 mmol), and potassium
phosphate (1.48 g, 6.97 mmol) in toluene (10 mL) and 1,4-dioxane
(10 mL) was degassed with nitrogen for 10 minutes. The catalyst
solution was transferred to the reaction flask via syringe, and the
reaction mixture was heated at 125.degree. C. for 2 hours,
whereupon it was partitioned between water and ethyl acetate. The
organic layer was dried over sodium sulfate, filtered, and
concentrated in vacuo; silica gel chromatography (Gradient: 50% to
100% ethyl acetate in heptane) provided the product as an off-white
solid. Yield: 1.3 g, 2.6 mmol, 77%. LCMS m/z 506.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3), characteristic peaks: .delta.
9.52 (br s, 1H), 8.21 (d, J=7.9 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H),
7.25-7.31 (m, 1H, assumed; partially obscured by solvent peak),
6.68 (d, J=10.0 Hz, 1H), 5.05 (d, J=15.2 Hz, 1H), 4.20-4.32 (m,
2H), 3.53-3.62 (m, 1H), 3.14 (d, J=15.2 Hz, 1H), 2.49 (s, 3H), 1.84
(s, 3H), 1.00 (d, J=6.6 Hz, 1H), 0.69 (d, J=6.5 Hz, 1H).
Step 5. Isolation of
2-{[(1aS,6bS)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(3-methyl-1H-1,2,4-triazol-1-yl)--
3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (8) and
2-{[(1aR,6bR)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cy-
clopropa[b][1]benzofuran-6b-yl]methyl}-7-(3-methyl-1H-1,2,4-triazol-1-yl)--
3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (9)
[0359] Compound C44 (1.3 g, 2.6 mmol) was separated into its
component enantiomers via supercritical fluid chromatography
[Column: Phenomenex Lux Cellulose-4, 5 .mu.m; Mobile phase: 30%
(1:1 acetonitrile/methanol) in carbon dioxide]. The individual
enantiomers from the separation were dissolved in ethyl acetate (10
mL), passed through a syringe filter, concentrated in vacuo, and
then precipitated with diethyl ether; both enantiomers were
obtained as solids. Example 8 was the second-eluting enantiomer.
Yield: 415 mg, 0.821 mmol, 32%. LCMS m/z 506.4 [M+H].sup.+. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 9.53 (br s, 1H), 8.21 (d, J=7.9
Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.29 (dq, J=7.5, 1.0 Hz, 1H), 6.68
(d, J=10.0 Hz, 1H), 5.05 (d, J=15.2 Hz, 1H), 4.20-4.32 (m, 2H),
3.57 (ddd, half of ABXY pattern, J=13.2, 6.0, 4.9 Hz, 1H),
3.44-3.51 (m, 1H), 3.14 (d, J=15.2 Hz, 1H), 2.48 (s, 3H), 1.84 (s,
3H), 1.00 (d, J=6.6 Hz, 1H), 0.69 (d, J=6.6 Hz, 1H).
[0360] The first-eluting enantiomer was compound 9. Yield: 412 mg,
0.815 mmol, 31%. LCMS m/z 506.4 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 9.52 (br s, 1H), 8.21 (d, J=7.9 Hz, 1H), 7.38
(d, J=7.9 Hz, 1H), 7.28 (dq, J=7.6, 1.0 Hz, 1H), 6.68 (d, J=10.0
Hz, 1H), 5.05 (d, J=15.2 Hz, 1H), 4.20-4.32 (m, 2H), 3.57 (ddd,
half of ABXY pattern, J=13.2, 6.0, 4.9 Hz, 1H), 3.44-3.51 (m, 1H),
3.14 (d, J=15.2 Hz, 1H), 2.49 (s, 3H), 1.84 (s, 3H), 1.00 (d, J=6.6
Hz, 1H), 0.69 (d, J=6.7 Hz, 1H).
Examples 10 and 11
2-{[(1aS,6bS)-4-Chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cycl-
opropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dih-
ydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (10) and
2-{[(1aR,6bR)-4-Chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (11)
##STR00027##
[0361] Step 1. Synthesis of
5-chloro-2-iodo-4-(trifluoromethyl)phenol (C45)
[0362] A mixture of 3-chloro-4-(trifluoromethyl)phenol (3.00 g,
15.3 mmol) and N-iodosuccinimide (95%, 3.61 g, 15.2 mmol) in acetic
acid (10 mL) was stirred for 5 minutes, whereupon sulfuric acid (18
M, 0.25 mL, 4.5 mmol) was added. After the reaction mixture had
been stirred at room temperature for 2 days, it was partitioned
between diethyl ether and water. The organic layer was washed with
water and with 2 M aqueous sodium thiosulfate solution, then
treated with activated carbon and dried over magnesium sulfate. The
mixture was filtered through a pad of diatomaceous earth and silica
gel, and the filtrate was concentrated in vacuo to afford an oil
(4.9 g) containing product, acetic acid, and solvent. This material
was taken into the following step without additional purification.
GCMS m/z 322.0 [M.sup.+]. .sup.1H NMR (400 MHz, CDCl.sub.3),
product peaks only: .delta. 7.95 (s, 1H), 7.12 (s, 1H).
Step 2. Synthesis of ethyl
(2E)-3-[5-chloro-2-iodo-4-(trifluoromethyl)phenoxy]but-2-enoate
(C46)
[0363] A mixture of C45 (from the previous step; 4.9 g,
.ltoreq.15.3 mmol) and potassium carbonate (10.5 g, 76.0 mmol) in
acetonitrile (100 mL) was stirred for 10 minutes. Ethyl
but-2-ynoate (2.0 mL, 17 mmol) was added, and the reaction mixture
was heated at reflux overnight; GCMS analysis indicated partial
conversion to product. The reaction mixture was partitioned between
1 M aqueous hydrochloric acid and a 1:1 mixture of diethyl ether
and heptane. The organic layer was washed with water and with
saturated aqueous sodium chloride solution, then dried over sodium
sulfate, filtered, and concentrated in vacuo. Silica gel
chromatography (Gradient: 0% to 25% ethyl acetate in heptane)
afforded recovered C45 (2.84 g) and a mixture of product and the
des-iodo analogue (0.88 g). The recovered C45 was resubjected to
the reaction conditions and worked up in the same manner, affording
the product (1.2 g) as a thick oil that slowly solidified, and
recovered C45 (1.6 g). A portion of this C45 (1.2 g, 3.7 mmol) was
dissolved in toluene (10 mL) and treated with
1,4-diazabicyclo[2.2.2]octane (411 mg, 3.66 mmol), followed by
ethyl but-2-ynoate (1 mL, 9 mmol). The reaction mixture was heated
at 100.degree. C. for 18 hours, then cooled to room temperature and
combined with the 0.88 g of material isolated above. This mixture
was partitioned between diethyl ether and 1 M aqueous hydrochloric
acid; the organic layer was washed with 1 M aqueous hydrochloric
acid and with water, then dried over magnesium sulfate, filtered,
and concentrated under reduced pressure. Chromatography on silica
gel (Gradient: 0% to 5% ethyl acetate in heptane) afforded
additional product (2.0 g) as an oil. Combined yield: 3.2 g, 7.4
mmol, 48% over 2 steps. GCMS m/z 434.1 [M.sup.+]. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.14 (s, 1H), 7.20 (br s, 1H), 4.80-4.82
(m, 1H), 4.14 (q, J=7.1 Hz, 2H), 2.54 (d, J=0.6 Hz, 3H), 1.26 (t,
J=7.1 Hz, 3H).
Step 3. Synthesis of ethyl
6-chloro-2-methyl-5-(trifluoromethyl)-1-benzofuran-3-carboxylate
(C47)
[0364] A solution of C46 (3.10 g, 7.13 mmol) in acetonitrile (20
mL) was purged with nitrogen for 10 minutes, then treated with
triethylamine (5.0 mL, 36 mmol), followed by
bis(tri-tert-butylphosphine)palladium(0) (184 mg, 0.360 mmol). The
reaction mixture was heated at 90.degree. C. for 1 hour, whereupon
it was partitioned between diethyl ether and 1 M aqueous
hydrochloric acid. The organic layer was washed with water and with
saturated aqueous sodium chloride solution, dried over magnesium
sulfate, and treated with activated carbon. The mixture was
filtered through a pad of diatomaceous earth, and the filtrate was
concentrated in vacuo. Silica gel chromatography (Gradient: 0% to
5% ethyl acetate in heptane) afforded the product as an
off-white/tan solid. Yield: 1.00 g, 3.26 mmol, 46%. GCMS m/z 306.1
[M.sup.+]. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.33 (s, 1H),
7.60 (s, 1H), 4.44 (q, J=7.1 Hz, 2H), 2.80 (s, 3H), 1.46 (t, J=7.1
Hz, 3H).
Step 4. Synthesis of
4-chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]b-
enzofuran-6b-carboxylic acid (C48)
[0365] A suspension of trimethylsulfoxonium iodide (98%, 820 mg,
3.7 mmol) in dimethyl sulfoxide (5 mL) was treated with potassium
tert-butoxide (1 M solution in tetrahydrofuran; 3.59 mL, 3.59 mmol)
and allowed to stir at room temperature for 20 minutes. A solution
of C47 (1.00 g, 3.26 mmol) in dimethyl sulfoxide (5 mL) and
tetrahydrofuran (3 mL) was added, and stirring was continued for
1.5 hours. At this point, additional trimethylsulfoxonium iodide
(98%, 125 mg, 0.557 mmol) and potassium tert-butoxide (1 M solution
in tetrahydrofuran; 0.5 mL, 0.5 mmol) were introduced, and the
reaction was allowed to proceed for 1.5 hours. Crushed potassium
hydroxide pellets (85%, 540 mg, 8.2 mmol) were added, and the
reaction mixture was stirred for 2 hours; it was then adjusted to a
pH of 4-5 via addition of 1 M aqueous hydrochloric acid. The
mixture was extracted with ethyl acetate, and the combined organic
layers were washed with water and with saturated aqueous sodium
chloride solution, dried over sodium sulfate, filtered, and
concentrated in vacuo to afford the product as a pasty solid (1.16
g); this material was impure by .sup.1H NMR analysis, and was used
in the following step without further purification. .sup.1H NMR
(400 MHz, DMSO-d.sub.6), product peaks only: .delta. 13.2-13.4 (v
br s, 1H), 7.94 (s, 1H), 7.35 (s, 1H), 1.97 (d, J=6.4 Hz, 1H), 1.80
(s, 3H), 1.07 (d, J=6.4 Hz, 1H).
Step 5. Synthesis of
4-chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]b-
enzofuran-6b-carboxamide (C49)
[0366] Conversion of C48 (from the previous step; 1.10 g,
.ltoreq.3.1 mmol) to the product was carried out according to the
method described for synthesis of C38 from C37 in Examples 6 and 7.
The product was isolated as a thick oil (1.1 g), which was impure
by .sup.1H NMR analysis; this material was taken to the next step
without additional purification. GCMS m/z 291.1 [M.sup.+]. .sup.1H
NMR (400 MHz, DMSO-d.sub.6), product peaks only: .delta. 7.76 (s,
1H), 7.33 (s, 1H), 2.03 (d, J=6.6 Hz, 1H), 1.68 (s, 3H), 0.79 (d,
J=6.6 Hz, 1H).
Step 6. Synthesis of
1-[4-chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][-
1]benzofuran-6b-yl]methanamine (C50)
[0367] Sodium bis(2-methoxyethoxy)aluminum hydride (3.3 M solution
in toluene; 4.2 mL, 13.9 mmol) was added to a solution of C49 (from
the previous step; 1.0 g, .ltoreq.2.8 mmol) in toluene (25 mL) and
tetrahydrofuran (5 mL). After 2 hours at room temperature, the
reaction mixture was cooled in an ice bath, quenched with aqueous
sodium hydroxide solution (1 M, 25 mL, 25 mmol), and extracted with
diethyl ether. The organic layer was washed with saturated aqueous
sodium chloride solution, dried over sodium sulfate, filtered, and
concentrated in vacuo, affording the product as a thick gum (865
mg). By .sup.1H NMR analysis, this material was impure; it was used
in the following step without additional purification. .sup.1H NMR
(400 MHz, CDCl.sub.3), product peaks only: .delta. 7.66 (s, 1H),
6.94 (s, 1H), 3.39 (d, J=14.0 Hz, 1H), 2.89 (d, J=14.1 Hz, 1H),
1.77 (s, 3H), 1.01 (d, J=6.4 Hz, 1H), 0.54 (d, J=6.3 Hz, 1H).
Step 7. Synthesis of
2-{[(1aS,6bS)-4-chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (10) and
2-{[(1aR,6bR)-4-chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (11)
[0368] 1,3,4,6,7,8-Hexahydro-2H-pyrimido[1,2-a]pyrimidine (97%, 671
mg, 4.68 mmol) was added to a mixture of C50 (from the previous
step; 865 mg, .ltoreq.2.8 mmol) and C10 (993 mg, 4.05 mmol) in
N,N-dimethylformamide (5 mL). After 2 hours, ethyl trifluoroacetate
(0.93 mL, 7.8 mmol) was added to the reaction mixture, and stirring
was continued for 1 hour. Aqueous sodium hydroxide solution (1 M,
10 mL, 10 mmol) was added and the mixture was stirred for 15
minutes, whereupon it was partitioned between water and ethyl
acetate. The organic layer was washed with water, dried over sodium
sulfate, filtered, and concentrated in vacuo. After the residue had
been purified via chromatography on silica gel (Gradient: 0% to 10%
methanol in ethyl acetate), it was triturated with diethyl ether,
and the resulting solid (470 mg) was separated into its component
enantiomers via supercritical fluid chromatography [Column: Chiral
Technologies Chiralpak AD-H, 5 .mu.m; Mobile phase: 20% (1:1
acetonitrile/methanol) in carbon dioxide]. Each enantiomer was then
dissolved in ethyl acetate (10 mL) and passed through a syringe
filter. The eluents were concentrated in vacuo and triturated with
diethyl ether, to afford each product as a solid.
[0369] Compound 10 was the second-eluting enantiomer. Yield: 114
mg, 0.226 mmol, 8% over 4 steps. LCMS m/z 505.4, 507.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.31 (br s, 1H), 7.79 (s,
1H), 7.77 (d, J=7.8 Hz, 1H), 7.31 (br s, 1H), 7.27 (d, J=7.8 Hz,
1H), 7.04 (s, 1H), 4.85 (d, J=15.1 Hz, 1H), 4.33 (ddd, half of ABXY
pattern, J=14, 6, 4 Hz, 1H), 4.19 (ddd, half of ABXY pattern, J=14,
9, 4 Hz, 1H), 3.73 (ddd, half of ABXY pattern, J=13, 6, 4 Hz, 1H),
3.5-3.58 (m, 1H), 3.50 (d, J=15.3 Hz, 1H), 2.23 (br s, 3H), 1.87
(s, 3H), 1.23 (d, J=6.8 Hz, 1H), 0.63 (d, J=6.7 Hz, 1H).
[0370] The first-eluting enantiomer was 11. Yield: 122 mg, 0.242
mmol, 9% over 4 steps. LCMS m/z 505.4, 507.3 [M+H].sup.+. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.30 (br s, 1H), 7.79 (s, 1H),
7.77 (d, J=7.7 Hz, 1H), 7.30 (br s, 1H), 7.27 (d, J=7.7 Hz, 1H),
7.04 (s, 1H), 4.85 (d, J=15.2 Hz, 1H), 4.33 (ddd, half of ABXY
pattern, J=14, 6, 4 Hz, 1H), 4.19 (ddd, half of ABXY pattern, J=14,
9, 4 Hz, 1H), 3.73 (ddd, half of ABXY pattern, J=13, 6, 4 Hz, 1H),
3.54 (ddd, half of ABXY pattern, J=13, 9, 4 Hz, 1H), 3.50 (d,
J=15.3 Hz, 1H), 2.23 (d, J=0.8 Hz, 3H), 1.87 (s, 3H), 1.23 (d,
J=6.8 Hz, 1H), 0.63 (d, J=6.6 Hz, 1H).
Examples 12 and 13
2-{[(1aS,6bS)-5-(Difluoromethoxy)-4-fluoro-1a-methyl-1,1a-dihydro-6bH-cycl-
opropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dih-
ydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (12) and
2-{[(1aR,6bR)-5-(Difluoromethoxy)-4-fluoro-1a-methyl-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (13)
##STR00028## ##STR00029##
[0371] Step 1. Synthesis of
4-bromo-1-(difluoromethoxy)-2-fluorobenzene (C51)
[0372] 4-Bromo-2-fluorophenol (2.78 mL, 25.4 mmol) was added to a
mixture of cesium carbonate (97%, 12.8 g, 38.1 mmol),
N,N-dimethylformamide (100 mL), and water (10 mL) at 70.degree. C.
Sodium chloro(difluoro)acetate (9.69 g, 63.6 mmol) was then
introduced portion-wise, over 30 minutes. The reaction mixture was
allowed to stir at 70.degree. C. overnight, whereupon it was cooled
to room temperature and poured into water. The resulting mixture
was extracted three times with ethyl acetate; the combined organic
layers were washed sequentially with 1 M aqueous sodium hydroxide
solution, water, and saturated aqueous sodium chloride solution,
dried over magnesium sulfate, filtered, and concentrated in vacuo.
Silica gel chromatography (Gradient: 0% to 20% ethyl acetate in
heptane) afforded the product as a colorless oil. Yield: 1.50 g,
6.22 mmol, 24%. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.36 (dd,
J=9.7, 2.3 Hz, 1H), 7.28 (ddd, J=8.7, 2.2, 1.6 Hz, 1H), 7.14 (br
dd, J=8.6, 8.4 Hz, 1H), 6.54 (t, J.sub.HF=73.0 Hz, 1H).
Step 2. Synthesis of 4-(difluoromethoxy)-3-fluorophenol (C52)
[0373] A mixture of water (3 mL) and 1,4-dioxane (3 mL) was purged
with nitrogen for 15 minutes, whereupon potassium hydroxide (85%,
1.64 g, 24.8 mmol), tris(dibenzylideneacetone)dipalladium(0) (57
mg, 62 mmol), and
di-tert-butyl[3,4,5,6-tetramethyl-2',4',6'-tri(propan-2-yl)biphenyl-2-yl]-
phosphane (97%, 123 mg, 0.248 mmol) were added. After addition of
C51 (1.50 g, 6.22 mmol), the reaction mixture was heated at
100.degree. C. for 1 hour, then cooled to room temperature and
treated with aqueous sodium hydroxide solution (1 M, 100 mL). The
resulting mixture was washed with diethyl ether (50 mL), adjusted
to acidic pH via addition of concentrated hydrochloric acid, and
extracted with diethyl ether (2.times.150 mL). These extracts were
combined, treated with decolorizing carbon, dried over magnesium
sulfate, filtered, and concentrated in vacuo, affording the product
(1.36 g) as an oil. This material contained significant solvent by
.sup.1H NMR analysis, and was taken to the following step without
additional manipulation. .sup.1H NMR (400 MHz, CDCl.sub.3), product
peaks only: .delta. 7.08 (br dd, J=8.9, 8.9 Hz, 1H), 6.65 (dd,
J=11.6, 2.9 Hz, 1H), 6.56 (ddd, J=8.9, 2.9, 1.5 Hz, 1H), 6.45 (t,
J.sub.HF=73.9 Hz, 1H).
Step 3. Synthesis of 2-bromo-4-(difluoromethoxy)-5-fluorophenol
(C53)
[0374] A solution of C52 (from the previous step; 1.36 g,
.ltoreq.6.22 mmol; estimated to contain .about.4.6 mmol of C52 from
analysis of the .sup.1H NMR spectrum) in dichloromethane (23 mL)
was cooled in an ice bath and treated with bromine (0.24 mL, 4.6
mmol) in a drop-wise manner. The reaction mixture was allowed to
warm slowly to room temperature overnight, whereupon it was washed
with aqueous sodium thiosulfate solution, dried over magnesium
sulfate, filtered, and concentrated in vacuo. The product was
obtained as an oil (1.4 g), which contained solvent as judged by
.sup.1H NMR analysis; this material was used directly in the
following step. GCMS m/z 256.0 [M.sup.+]. .sup.1H NMR (400 MHz,
CDCl.sub.3), product peaks only: .delta. 7.40 (br d, J=7.9 Hz, 1H),
6.88 (d, J=11.0 Hz, 1H), 6.47 (t, J.sub.HF=73.2 Hz, 1H), 5.67-5.78
(br s, 1H).
Step 4. Synthesis of ethyl
(2E)-3-[2-bromo-4-(difluoromethoxy)-5-fluorophenoxy]but-2-enoate
(C54)
[0375] 1,4-Diazabicyclo[2.2.2]octane (589 mg, 5.25 mmol) was added
to a solution of C53 (from the previous step; 1.4 g, estimated to
contain .about.4.3 mmol of C53 from analysis of the .sup.1H NMR
spectrum) and ethyl but-2-ynoate (0.90 mL, 7.7 mmol) in toluene (13
mL). The reaction mixture was heated at 90.degree. C. for 6 hours,
whereupon it was cooled to room temperature and partitioned between
1 M aqueous hydrochloric acid and diethyl ether. The organic layer
was washed sequentially with 1 M aqueous hydrochloric acid, 1 M
aqueous sodium hydroxide solution, and with water. It was then
dried over magnesium sulfate, filtered, and concentrated in vacuo.
Chromatography on silica gel (Gradient: 0% to 5% ethyl acetate in
heptane) afforded the product as a thick oil. Yield: 1.23 g, 3.33
mmol, 54% over 3 steps. GCMS m/z 323, 325 [M-(OEt)].sup.+. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.55 (br d, J=7.9 Hz, 1H), 6.99
(d, J=10.0 Hz, 1H), 6.56 (t, J.sub.HF=72.5 Hz, 1H), 4.78 (s, 1H),
4.13 (q, J=7.1 Hz, 2H), 2.52 (s, 3H), 1.25 (t, J=7.1 Hz, 3H).
Step 5. Synthesis of ethyl
5-(difluoromethoxy)-6-fluoro-2-methyl-1-benzofuran-3-carboxylate
(C55)
[0376] A solution of C54 (1.23 g, 3.33 mmol) and triethylamine (2.0
mL, 14 mmol) in acetonitrile (10 mL) was purged with nitrogen for
15 minutes. Bis(tri-tert-butylphosphine)palladium(0) (170 mg, 0.33
mmol) was introduced, and the reaction mixture was heated at
90.degree. C. for 2 hours, whereupon it was cooled to room
temperature and partitioned between heptane and 1 M aqueous
hydrochloric acid. The organic layer was washed with 1 M aqueous
hydrochloric acid and with water, then dried over magnesium
sulfate, filtered, and concentrated in vacuo. The resulting solid
was dissolved in methanol (30 mL), treated with decolorizing
carbon, stirred for 10 minutes, and filtered through diatomaceous
earth. Removal of solvent under reduced pressure provided the
product as an off-white solid. Yield: 510 mg, 1.77 mmol, 53%. GCMS
m/z 288.1 [M.sup.+]. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.83
(d, J=7.8 Hz, 1H), 7.27 (d, J=9.6 Hz, 1H), 6.57 (t, J.sub.HF=73.8
Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 2.77 (s, 3H), 1.45 (t, J=7.1 Hz,
3H).
Step 6. Synthesis of 5-(difluoromethoxy)-4-fluoro-1a-methyl-1,
1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-carboxylic acid
(C56)
[0377] Potassium tert-butoxide (1.0 M solution, 2.1 mL, 2.1 mmol)
was added to a suspension of trimethylsulfoxonium iodide (98%,
0.477 g, 2.12 mmol) in dimethyl sulfoxide (4.5 mL), and the mixture
was allowed to stir at room temperature for 30 minutes. A solution
of C55 (510 mg, 1.77 mmol) in tetrahydrofuran (2.5 mL) was then
introduced in a drop-wise manner over 15 minutes, and the reaction
mixture was stirred at room temperature for 1 hour. Crushed
potassium hydroxide pellets (85%, 0.292 g, 4.42 mmol) were added,
and stirring was continued for 1 hour, whereupon the reaction
mixture was cooled in an ice bath, diluted with water (25 mL), and
washed with heptane (50 mL). The aqueous layer was cooled in an ice
bath and adjusted to a pH of 4-5 via addition of concentrated
hydrochloric acid. The mixture was extracted with diethyl ether,
and the combined organic layers were washed with water and with
saturated aqueous sodium chloride solution, dried over sodium
sulfate, filtered, and concentrated in vacuo. The product was
obtained as a thick oil, which solidified to a yellow-orange solid
upon standing. Yield: 214 mg, 0.780 mmol, 44%. LCMS m/z 273.4
[M-H.sup.+]. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.52 (d,
J=7.9 Hz, 1H), 6.68 (d, J=10 Hz, 1H), 6.48 (t, J.sub.HF=73.9 Hz,
1H), 2.04 (d, J=6.2 Hz, 1H), 1.88 (s, 3H), 0.99 (d, J=6.2 Hz,
1H).
Step 7. Synthesis of
5-(difluoromethoxy)-4-fluoro-1a-methyl-1,1a-dihydro-6bH-cyclopropa[b][1]b-
enzofuran-6b-carboxamide (C57)
[0378] Compound C56 (214 mg, 0.780 mmol) was converted to the
product using the method described for synthesis of C38 from C37 in
Examples 6 and 7. The product was obtained as a thick oil (200 mg)
that contained significant solvent via .sup.1H NMR analysis; this
material was taken directly to the following step. GCMS m/z 273.1
[M.sup.+]. .sup.1H NMR (400 MHz, CDCl.sub.3), product peaks only:
.delta. 7.33 (d, J=7.6 Hz, 1H), 6.73 (d, J=10.2 Hz, 1H), 6.49 (t,
J.sub.HF=73.5 Hz, 1H), 5.77-5.99 (br m, 2H), 2.11 (d, J=6.3 Hz,
1H), 1.74 (s, 3H), 0.77 (d, J=6.3 Hz, 1H).
Step 8. Synthesis of
1-[5-(difluoromethoxy)-4-fluoro-1a-methyl-1,1a-dihydro-6bH-cyclopropa[b][-
1]benzofuran-6b-yl]methanamine (C58)
[0379] A solution of C57 (from the previous step; 200 mg, <0.73
mmol) in toluene (2 mL) was cooled in an ice bath and slowly
treated with sodium bis(2-methoxyethoxy)aluminum hydride (3.3 M
solution in toluene, 0.56 mL, 1.8 mmol), while the internal
reaction temperature was kept below 15.degree. C. Upon completion
of the addition, the ice bath was removed and the reaction mixture
was allowed to warm to room temperature and stir overnight. Sodium
bis(2-methoxyethoxy)aluminum hydride (3.3 M solution in toluene,
2.2 mL, 7.3 mmol) was again added, and stirring was continued at
room temperature for 24 hours, whereupon additional sodium
bis(2-methoxyethoxy)aluminum hydride (3.3 M solution in toluene,
2.7 mL, 8.9 mmol) was introduced. After the reaction mixture had
stirred at room temperature for 24 hours, it was heated at
50.degree. C. for 24 hours. It was then allowed to cool to room
temperature, further cooled in an ice bath, and quenched via slow
addition of aqueous sodium hydroxide solution (1 M, 50 mL), while
the internal temperature was maintained below 30.degree. C. This
mixture was stirred for 15 minutes, whereupon it was extracted with
diethyl ether (3.times.20 mL); the combined organic layers were
dried over sodium sulfate, filtered, and concentrated in vacuo to
afford the product as a thick oil (105 mg), which was substantially
impure via .sup.1H NMR analysis. This material was used directly in
the following step. GCMS m/z 242.1 [M-NH.sub.3].sup.+.
Step 9. Synthesis of
2-{[(1aS,6bS)-5-(difluoromethoxy)-4-fluoro-1a-methyl-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (12) and
2-{[(1aR,6bR)-5-(difluoromethoxy)-4-fluoro-1a-methyl-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-di-
hydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (13)
[0380] 1,3,4,6,7,8-Hexahydro-2H-pyrimido[1,2-a]pyrimidine (97%,
94.7 mg, 0.660 mmol) was added to a mixture of C58 (from the
previous step; 105 mg, <0.40 mmol) and C10 (129 mg, 0.526 mmol)
in N,N-dimethylformamide (1 mL), and the reaction mixture was
stirred at room temperature for 2 hours. Ethyl trifluoroacetate
(0.12 mL, 1.01 mmol) was added, and after an additional hour of
stirring, the reaction mixture was treated with aqueous sodium
hydroxide solution (1 M, 1.5 mL) and allowed to stir for 30
minutes, whereupon it was extracted three times with ethyl acetate.
The combined organic layers were washed twice with saturated
aqueous sodium chloride solution, dried over magnesium sulfate,
filtered, and concentrated in vacuo. The residue was subjected to
chromatography on silica gel (Gradient: 0% to 3% methanol in
dichloromethane), followed by purification using supercritical
fluid chromatography [Column: Chiral Technologies Chiralpak AD-H, 5
.mu.m; Mobile phase: 30% (methanol containing 0.6% ammonium
hydroxide) in carbon dioxide].
[0381] Compound 12 was the second-eluting enantiomer. Yield: 4.4
mg, 9.0 .mu.mol, 1.2% over three steps. LCMS m/z 487.3 [M+H].sup.+.
Retention time: 3.86 minutes {Analysis via supercritical fluid
chromatography [Column: Chiral Technologies Chiralpak AD-H,
4.6.times.100 mm, 5 .mu.m; Mobile phase: 40% (methanol containing
0.6% ammonium hydroxide) in carbon dioxide; Flow rate: 1.5
mL/minute]}.
[0382] The first-eluting enantiomer was 13. Yield: 4.4 mg, 9.0
.mu.mol, 1.2% over three steps. LCMS m/z 487.3 [M+H].sup.+.
Retention time: 2.81 minutes using an analytical system identical
to that employed for 12.
Example 14
2-{[(1aS,6bS)-4-Fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyc-
lopropa[b][1]benzofuran-6b-yl]methyl}-7-[4-(hydroxymethyl)-1H-imidazol-1-y-
l]-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (14)
##STR00030##
[0384] Compound 6 (0.4 mg, 800 nmol) was incubated with liver
microsomes (from male monkeys; 1.5 mg/mL), magnesium chloride (3.3
mM), and NADPH (1.3 mM), in 0.1 M potassium phosphate buffer (pH
7.4; total volume of incubation solution, 40 mL). The reaction
mixture was shaken at 37.degree. C. in a water bath for 67 minutes,
whereupon acetonitrile (40 mL) was added and the mixture was spun
at 1700 g for 5 minutes. The supernatant was subjected to vacuum
centrifugation to a volume of approximately 15 mL, to which was
added formic acid (0.5 mL), acetonitrile (0.5 mL), and water
(sufficient to reach a total volume of 50 mL). This mixture was
spun at 40000 g for 30 minutes. The supernatant was purified via
reversed phase chromatography (Column: Agilent Polaris C18, 5
.mu.m; Mobile phase A: 0.1% aqueous formic acid; Mobile phase B:
acetonitrile; Gradient: 1% to 90% B) to afford the product. Yield:
17 .mu.g, 32 nmol, 4%. LCMS m/z 521.1 [M+H].sup.+. .sup.1H NMR (600
MHz, DMSO-d.sub.6), characteristic peaks: .delta. 8.25 (s, 1H),
7.84 (d, J=7.8 Hz, 1H), 7.52 (s, 1H), 7.49 (d, J=7.8 Hz, 1H),
7.07-7.12 (m, 2H), 4.58 (d, J=15.0 Hz, 1H), 4.39 (s, 2H), 4.16-4.22
(m, 1H), 4.13 (ddd, half of ABXY pattern, J=14, 8, 4 Hz, 1H),
3.68-3.74 (m, 1H), 3.54 (d, J=15.1 Hz, 1H), 3.50 (ddd, J=13, 8, 4
Hz, 1H), 1.80 (s, 3H), 0.59 (d, J=6.4 Hz, 1H).
TABLE-US-00006 TABLE 6 Method of Synthesis and Physicochemical Data
for Examples 15-22. Method of Preparation; Non- commercial Example
starting .sup.1H NMR (400 MHz, CDCl.sub.3), .delta.; LCMS, Number
materials Structure observed ion m/z [M + H].sup.+ 15 Examples 4
and 5.sup.1 ##STR00031## 8.19-8.25 (m, 1H), 7.56-7.59 (m, 1H), 7.45
(d, J = 7.6 Hz, 1H), 7.40 (br d, J = 8.4 Hz, 1H), 7.30 (d, J = 7.8
Hz, 1H), 7.09-7.15 (m, 1H), 6.90 (d, J = 8.3 Hz, 1H), 5.04 (d, J =
15.2 Hz, 1H), 4.25- 4.33 (m, 1H), 4.20 (ddd, half of ABXY pattern,
J = 14, 8, 4 Hz, 1H), 3.58 (ddd, half of ABXY pattern, J = 13, 6, 4
Hz, 1H), 3.46 (ddd, half of ABXY pattern, J = 13, 8, 4 Hz, 1H),
3.27 (d, J = 15.1 Hz, 1H), 2.28 (br s, 3H), 1.86 (s, 3H), 1.04 (d,
J = 6.5 Hz, 1H), 0.67 (d, J = 6.5 Hz, 1H); 471.0 16 Examples 4 and
5.sup.1 ##STR00032## 8.19-8.23 (m, 1H), 7.56-7.59 (m, 1H), 7.45 (d,
J = 7.8 Hz, 1H), 7.40 (br d, J = 8.3 Hz, 1H), 7.30 (d, J = 7.6 Hz,
1H), 7.10-7.14 (m, 1H), 6.90 (d, J = 8.3 Hz, 1H), 5.04 (d, J = 15.3
Hz, 1H), 4.25- 4.33 (m, 1H), 4.20 (ddd, half of ABXY pattern, J =
14, 8.5, 4 Hz, 1H), 3.54- 3.62 (m, 1H), 3.46 (ddd, half of ABXY
pattern, J = 13, 8.5, 4 Hz, 1H), 3.27 (d, J = 15.2 Hz, 1H), 2.28
(s, 3H), 1.86 (s, 3H), 1.04 (d, J = 6.6 Hz, 1H), 0.67 (d, J = 6.5
Hz, 1H); 471.0 17 Examples 2 and 3.sup.2,3 ##STR00033## .sup.1H NMR
(400 MHz, CD.sub.3OD), .delta. 8.42- 8.49 (br s, 1H), 7.81 (d, J =
7.7 Hz, 1H), 7.67 (br d, J = 7.4 Hz, 1H), 7.34- 7.39 (br s, 1H),
7.28 (d, J = 7.8 Hz, 1H), 6.79 (br d, J = 11 Hz, 1H), 4.81- 4.90
(m, 1H, assumed; partially obscured by water peak), 4.29-4.37 (m,
1H), 4.20 (ddd, half of ABXY pattern, J = 14, 9, 4 Hz, 1H),
3.69-3.78 (m, 1H), 3.50-3.59 (m, 1H), 3.50 (d, J = 15.2 Hz, 1H),
2.26 (s, 3H), 1.87 (s, 3H), 1.20 (d, J = 6.6 Hz, 1H), 0.62 (d, J =
6.6 Hz, 1H); 489.4 18 Examples 2 and 3.sup.2,3 ##STR00034## .sup.1H
NMR (400 MHz, CD.sub.3OD), .delta. 8.28 (br s, 1H), 7.77 (d, J =
7.8 Hz, 1H), 7.67 (br d, J = 7.3 Hz, 1H), 7.28-7.31 (br s, 1H),
7.27 (d, J = 7.7 Hz, 1H), 6.79 (br d, J = 11.2 Hz, 1H), 4.82-4.87
(m, 1H, assumed; partially obscured by water peak), 4.33 (ddd, half
of ABXY pattern, J = 14.2, 6.2, 4.3 Hz, 1H), 4.20 (ddd, half of
ABXY pattern, J = 14.2, 8.7, 4.2 Hz, 1H), 3.73 (ddd, J = 13.2, 6.2,
4.3 Hz, 1H), 3.54 (ddd, J = 13.3, 8.7, 4.2 Hz, 1H), 3.50 (d, J =
15.2 Hz, 1H), 2.23 (d, J = 0.8 Hz, 3H), 1.87 (s, 3H), 1.20 (d, J =
6.6 Hz, 1H), 0.62 (d, J = 6.7 Hz, 1H); 489.4 19 Examples 4 and
5.sup.4 ##STR00035## 8.20 (br s, 1H), 7.44 (d, J = 7.8 Hz, 1H),
7.40-7.42 (m, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.20 (br d, J = 10.3
Hz, 1H), 7.11 (br s, 1H), 5.03 (d, J = 15.2 Hz, 1H), 4.34 (ddd,
half of ABXY pattern, J = 14.3, 6.3, 4.3 Hz, 1H), 4.18 (ddd, half
of ABXY pattern, J = 14.3, 8.7, 4.3 Hz, 1H), 3.58 (ddd, half of
ABXY pattern, J = 13.0, 6.2, 4.3 Hz, 1H), 3.48 (ddd, half of ABXY
pattern, J = 13.1, 8.6, 4.1 Hz, 1H), 3.24 (d, J = 15.2 Hz, 1H),
2.27 (br s, 3H), 1.90 (s, 3H), 1.11 (d, J = 6.9 Hz, 1H), 0.75 (d, J
= 6.8 Hz, 1H); 489.2 20 Examples 4 and 5.sup.4 ##STR00036## 8.21
(br s, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.40-7.43 (m, 1H), 7.28 (d, J
= 8.0 Hz, 1H), 7.21 (br d, J = 10.4 Hz, 1H), 7.11 (br s, 1H), 5.04
(d, J = 15.2 Hz, 1H), 4.35 (ddd, half of ABXY pattern, J = 14, 6, 4
Hz, 1H), 4.19 (ddd, half of ABXY pattern, J = 14, 8.5, 4 Hz, 1H),
3.58 (ddd, half of ABXY pattern, J = 13, 6, 4 Hz, 1H), 3.48 (ddd,
half of ABXY pattern, J = 13, 8.5, 4 Hz, 1H), 3.25 (d, J = 15.3 Hz,
1H), 2.28 (s, 3H), 1.90 (s, 3H), 1.11 (d J = 6.9 Hz, 1H), 0.75 (d,
J = 6.9 Hz, 1H); 489.2 21 Examples 4 and 5.sup.5,6 ##STR00037##
8.20-8.23 (m, 1H), 7.50-7.53 (m, 1H), 7.44 (d, J = 7.6 Hz, 1H),
7.42-7.45 (m, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.10-7.13 (m, 1H),
5.07 (d, J = 15.2 Hz, 1H), 4.37 (ddd, half of ABXY pattern, J = 14,
6, 4 Hz, 1H), 4.18 (ddd, half of ABXY pattern, J = 14, 9, 4 Hz,
1H), 3.53-3.61 (m, 1H), 3.48 (ddd, half of ABXY pattern, J = 13, 9,
4 Hz, 1H), 3.22 (d, J = 15.3 Hz, 1H), 2.28 (br s, 3H), 1.92 (s,
3H), 1.11 (d, J = 6.8 Hz, 1H), 0.75 (br d, J = 6.7 Hz, 1H); 505.0
22 Examples 4 and 5.sup.5,6 ##STR00038## 8.21 (d, J = 1.1 Hz, 1H),
7.50-7.53 (m, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.42-7.44 (m, 1H),
7.28 (d, J = 7.9 Hz, 1H), 7.10- 7.13 (m, 1H), 5.07 (d, J = 15.2 Hz,
1H), 4.37 (ddd, half of ABXY pattern, J = 14.3, 6.0, 4.2 Hz, 1H),
4.18 (ddd, half of ABXY pattern, J = 14.4, 8.8, 4.2 Hz, 1H), 3.57
(ddd, half of ABXY pattern, J = 13.0, 6.2, 4.2 Hz, 1H), 3.48 (ddd,
half of ABXY pattern, J = 13.0, 8.7, 4.1 Hz, 1H), 3.22 (d, J = 15.2
Hz, 1H), 2.28 (d, J = 0.8 Hz, 3H), 1.92 (s, 3H), 1.11 (d, J = 6.8
Hz, 1H), 0.75 (d, J = 6.9 Hz, 1H); 505.0
[0385] 1. Examples 15 and 16 were isolated from the racemic mixture
via supercritical fluid chromatography (Column: Chiral Technologies
Chiralpak AD-3, 3 .mu.m; Mobile phase A: carbon dioxide; Mobile
phase B: methanol containing 0.05% diethylamine; Gradient: 5% to
40% B). Analytical supercritical fluid chromatography (Column:
Chiralpak AD-3, 150.times.4.6 mm, 3 .mu.m; Mobile phase A: carbon
dioxide; Mobile phase B: methanol containing 0.05% diethylamine;
Gradient: 5% to 40% B over 5.5 min, then 40% B for 2 minutes; Flow
rate: 2.5 mL/minute) yielded a retention time of 5.69 minutes for
Example 15, and a retention time of 5.42 minutes for Example
16.
[0386] 2. The requisite 5-fluoro-2-iodo-4-(trifluoromethyl)phenol
was synthesized via treatment of a solution of
3-fluoro-4-(trifluoromethyl)phenol in acetic acid with
N-iodosuccinimide and sulfuric acid.
[0387] 3. Examples 17 and 18 were isolated from the racemic mixture
via supercritical fluid chromatography [Column: Princeton PPU, 5
.mu.m; Mobile phase: 30% (0.2% ammonium hydroxide in ethanol) in
carbon dioxide]. Example 17 was the second-eluting enantiomer in
this system, with Example 18 eluting first.
[0388] 4. Examples 19 and 20 were isolated from the racemic mixture
via supercritical fluid chromatography [Column: Chiral Technologies
Chiralpak AD, 10 .mu.m; Mobile phase: 35% (methanol containing 0.1%
ammonium hydroxide) in carbon dioxide]. Example 19 was the
second-eluting enantiomer in this system, with Example 20 eluting
first.
[0389] 5. In this case, cleavage of the benzyl ether was not
carried out via hydrogenation; instead, treatment with
2,3-dichloro-5,6-dicyano-1,4-benzoquinone in dichloromethane
afforded the corresponding aldehyde, which was reduced using sodium
borohydride.
[0390] 6. Examples 21 and 22 were isolated from the racemic mixture
via supercritical fluid chromatography [Column: Chiral Technologies
Chiralpak AD, 5 .mu.m, Mobile phase: 40% (methanol containing 0.05%
diethylamine) in carbon dioxide]. Example 21 was the second-eluting
enantiomer in this system, with Example 22 eluting first.
Cell-Based .gamma.-Secretase Assay with ELISA Readout
[0391] The ability of compounds to modulate production of amyloid
beta protein A.beta.(1-42) was determined using human WT-APP
overexpressing CHO cells. Cells were plated at 22,000 cells/100
.mu.L well in 96 well tissue culture treated, clear plates (Falcon)
in DMEM/F12 based medium and incubated for 24 h at 37.degree. C.
Compounds for testing were diluted in 100% DMSO to achieve an
eleven point, half log, dose response for IC.sub.50 determinations.
Compounds were added in fresh medium to achieve 1% final DMSO.
Appropriate vehicle or inhibitor controls were added into control
wells individually to obtain minimum or maximum inhibition values,
respectively, for the assay signal window before the plates were
incubated for .about.24 h at 37.degree. C. This procedure produces
conditioned media in each well, which is tested for A.beta.(1-42)
levels in the ELISA detection step described next. The remaining
cell cultures in each well are also tested for cell toxicity as
described below.
[0392] Coating of ELISA assay plates was initiated by addition of
50 .mu.L/well of an in-house A.beta.(1-42) specific antibody (3
.mu.g/mL) in 0.1 M NaHCO.sub.3 (pH 9.0) into black 384-well
Maxisorp.RTM. plates (Nunc); incubation was carried out overnight
at 4.degree. C. The capture antibody was then aspirated from the
ELISA assay plates and plates were washed either 2.times.100 .mu.L
with a Matrical Squirt plate washer, or 3.times.90 .mu.L with a
Thermo Combi, using Wash Buffer (Dulbecco's PBS, 0.05% Tween 20).
90 .mu.L/well of Blocking Buffer (Dulbecco's PBS, 1.0% BSA (Sigma
A7030) was then added to plates. Ambient temperature incubation was
allowed to proceed for a minimum of 2 h. Blocking Buffer was then
removed and 20 .mu.L/well Assay Buffer (Dulbecco's PBS, 1.0% BSA
(Sigma A7030), 0.05% Tween 20) was then added. At this point, 35
.mu.L (40 .mu.L prior to August, 2012) (in duplicate) of
experimental conditioned media (described above) was transferred
into wells of the blocked ELISA plates containing the capture
antibody, followed by overnight incubation at 4.degree. C. Cell
toxicity was also measured in the corresponding remaining cells
after removal of the conditioned media for the A.beta.(1-42) assay
by a colorimetric cell proliferation assay (CellTiter
96.RTM.AQ.sub.ueous One Solution Cell Proliferation Assay, Promega)
according to the manufacturer's instructions.
[0393] After overnight incubation of the ELISA assay plates at
4.degree. C., unbound A.beta. peptides were removed via either
2.times.100 .mu.L washes with a Matrical Squirt plate washer, or
3.times.90 .mu.L washes with a Thermo Combi, using Wash Buffer.
Europium (Eu) labeled (custom labeled, PerkinElmer) A.beta.(1-16)
6e10 Monoclonal Antibody (Covance #SIG-39320) was added, (50
.mu.L/well Eu-6e10 @1:10,000, 20 uM EDTA) in Assay Buffer.
Incubation at ambient temperature for a minimum of 2 h was followed
by either 2.times.100 .mu.L washes with a Matrical Squirt plate
washer, or 3.times.90 .mu.L washes with a Thermo Combi, using Wash
Buffer, before 30 .mu.L/well of Delfia Enhancement Solution
(PerkinElmer) was added. Following 30 to 60 min ambient temperature
incubation, the plates were read on an EnVision plate reader
(PerkinElmer) using standard DELFIA TRF settings. Data analysis
including inhibitory IC.sub.50 determination was performed using
nonlinear regression fit analysis (in-house software) and the
appropriate plate mean values for the maximum and minimum
inhibition controls.
[0394] Biological data for the compounds of Examples 1-22 and C22,
C33, C40 and C44 are found in Table 7 below:
TABLE-US-00007 TABLE 7 A.beta. 42B IC.sub.50 (nM) Geometric mean of
2-4 determinations (unless Example otherwise Number indicated)
IUPAC Name 1 48.5
7-(4-methyl-1H-imidazol-1-yl)-2-{[5-(trifluoromethyl)-
1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-
3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione C22 19.5
7-(4-methyl-1H-imidazol-1-yl)-2-{[1a-methyl-5-
(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]
benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]
pyrazine-1,6-dione 2 6.5
7-(4-methyl-1H-imidazol-1-yl)-2-{[(1aS,6bS)-1a-methyl-5-
(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]
benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]
pyrazine-1,6-dione 3 59.2
7-(4-methyl-1H-imidazol-1-yl)-2-{[(1aR,6bR)-1a-methyl-
5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]
benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]
pyrazine-1,6-dione C33 9.3.sup.a
2-{[3-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-
6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-
1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione 4
4.9 2-{[(1aS,6bS)-3-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-
dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-
7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]
pyrazine-1,6-dione 5 59.2
2-{[(1aR,6bR)-3-fluoro-1a-methyl-5-(trifluoromethoxy)-
1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]
methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido
[1,2-a]pyrazine-1,6-dione C40 11.2
2-{[4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-
6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-
1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine- 1,6-dione 6
7.0 2-{[(1aS,6bS)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-
1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-
7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]
pyrazine-1,6-dione 7 38.0
2-{[(1aR,6bR)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-
dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-
7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]
pyrazine-1,6-dione C44 68.9
2-{[4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-
6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(3-methyl-
1H-1,2,4-triazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-
1,6-dione 8 36.6
2-{[(1aS,6bS)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-
1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]
methyl}-7-(3-methyl-1H-1,2,4-triazol-1-yl)-3,4-dihydro-
2H-pyrido[1,2-a]pyrazine-1,6-dione 9 519
2-{[(1aR,6bR)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-
1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]
methyl}-7-(3-methyl-1H-1,2,4-triazol-1-yl)-3,4-dihydro-
2H-pyrido[1,2-a]pyrazine-1,6-dione 10 3.0.sup.b
2-{[(1aS,6bS)-4-chloro-1a-methyl-5-(trifluoromethyl)-
1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-
7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]
pyrazine-1,6-dione 11 10.0
2-{[(1aR,6bR)-4-chloro-1a-methyl-5-(trifluoromethyl)-
1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-
7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-
a]pyrazine-1,6-dione 12 17.8
2-{[(1aS,6bS)-5-(difluoromethoxy)-4-fluoro-1a-methyl-1,1a-
dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-
7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]
pyrazine-1,6-dione 13 84.9
2-{[(1aR,6bR)-5-(difluoromethoxy)-4-fluoro-1a-methyl-1,1a-
dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-
7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]
pyrazine-1,6-dione 14 18.7
2-{[(1aS,6bS)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-
1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]
methyl}-7-[4-(hydroxymethyl)-1H-imidazol-1-yl]-
3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione 15 8.5.sup.b
7-(4-methyl-1H-imidazol-1-yl)-2-{[(1aS,6bS)-1a-methyl-
5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]
benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]
pyrazine-1,6-dione 16 47.3
7-(4-methyl-1H-imidazol-1-yl)-2-{[(1aR,6bR)-1a-methyl-
5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]
benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]
pyrazine-1,6-dione 17 4.4.sup.b
2-{[(1aS,6bS)-4-fluoro-1a-methyl-5-(trifluoromethyl)-
1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-
7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]
pyrazine-1,6-dione 18 20.2
2-{[(1aR,6bR)-4-fluoro-1a-methyl-5-(trifluoromethyl)-
1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-
7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]
pyrazine-1,6-dione 19 11.1
2-{[(1aS,6bS)-3-fluoro-1a-methyl-5-(trifluoromethyl)-
1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-
7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]
pyrazine-1,6-dione 20 50.1
2-{[(1aR,6bR)-3-fluoro-1a-methyl-5-(trifluoromethyl)-
1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-
7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]
pyrazine-1,6-dione 21 16.0
2-{[(1aS,6bS)-3-chloro-1a-methyl-5-(trifluoromethyl)-
1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-
7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]
pyrazine-1,6-dione 22 58.3
2-{[(1aR,6bR)-3-chloro-1a-methyl-5-(trifluoromethyl)-
1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-
7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]
pyrazine-1,6-dione .sup.aReported IC.sub.50 value is from a single
determination. .sup.bReported IC.sub.50 value is the geometric mean
of determinations.
* * * * *