U.S. patent application number 17/127966 was filed with the patent office on 2021-06-17 for cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis b.
The applicant listed for this patent is Janssen Sciences Ireland Unlimited Company. Invention is credited to Samuel Dominique DEMIN, Sandrine Celine GROSSE, Geerwin Yvonne Paul HACHE, Lili HU, Stefaan Julien LAST, Serge Maria Aloysius PIETERS, Pierre Jean-Marie Bernard RABOISSON, Geert ROMBOUTS, Koen VANDYCK, Sandrine Marie Helene VENDEVILLE, Wim Gaston VERSCHUEREN.
Application Number | 20210179635 17/127966 |
Document ID | / |
Family ID | 1000005419570 |
Filed Date | 2021-06-17 |
United States Patent
Application |
20210179635 |
Kind Code |
A1 |
VENDEVILLE; Sandrine Marie Helene ;
et al. |
June 17, 2021 |
CYCLIZED SULFAMOYLARYLAMIDE DERIVATIVES AND THE USE THEREOF AS
MEDICAMENTS FOR THE TREATMENT OF HEPATITIS B
Abstract
Inhibitors of HBV replication of Formula (I-A) ##STR00001##
including stereochemically isomeric forms, and salts, hydrates,
solvates thereof, wherein R.sup.a to R.sup.d, and R.sup.1 to
R.sup.8 have the meaning as defined herein. The present invention
also relates to processes for preparing said compounds,
pharmaceutical compositions containing them and their use, alone or
in combination with other HBV inhibitors, in HBV therapy.
Inventors: |
VENDEVILLE; Sandrine Marie
Helene; (Woluwe-Saint-Pierre, BE) ; LAST; Stefaan
Julien; (Lint, BE) ; DEMIN; Samuel Dominique;
(Antwerpen, BE) ; GROSSE; Sandrine Celine;
(Turnhout, BE) ; HACHE; Geerwin Yvonne Paul;
(Kapellan, BE) ; HU; Lili; (Mechelen, BE) ;
PIETERS; Serge Maria Aloysius; (Hulst, NL) ;
ROMBOUTS; Geert; (Barsbeek, BE) ; VANDYCK; Koen;
(Beringen-Paal, BE) ; VERSCHUEREN; Wim Gaston;
(Berchem, BE) ; RABOISSON; Pierre Jean-Marie Bernard;
(Wavre, BE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Janssen Sciences Ireland Unlimited Company |
Co Cork |
|
IE |
|
|
Family ID: |
1000005419570 |
Appl. No.: |
17/127966 |
Filed: |
December 18, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15195809 |
Jun 28, 2016 |
10875876 |
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17127966 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 31/407 20130101; A61K 31/542 20130101; C07D 515/20 20130101;
A61K 31/554 20130101; C07D 513/20 20130101; A61P 31/20 20180101;
C07D 513/04 20130101; C07D 515/10 20130101; C07D 291/08 20130101;
C07D 515/04 20130101 |
International
Class: |
C07D 513/04 20060101
C07D513/04; C07D 513/20 20060101 C07D513/20; C07D 515/04 20060101
C07D515/04; C07D 515/20 20060101 C07D515/20; C07D 291/08 20060101
C07D291/08; A61P 31/20 20060101 A61P031/20; A61K 31/407 20060101
A61K031/407; A61K 31/542 20060101 A61K031/542; A61K 31/554 20060101
A61K031/554; A61K 45/06 20060101 A61K045/06; C07D 515/10 20060101
C07D515/10 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 2, 2015 |
EP |
15175021.3 |
Oct 15, 2015 |
EP |
15189903.6 |
Dec 18, 2015 |
EP |
15201332.2 |
Feb 16, 2016 |
EP |
16157726.7 |
Claims
1. A compound of Formula (I-A) ##STR00285## or a stereoisomer or
tautomeric form thereof, wherein ##STR00286## represents a
monocyclic 5 membered aryl optionally containing one nitrogen or
sulfur, such aryl optionally being substituted with one or more
substituents each independently selected from the group consisting
of C.sub.1-C.sub.3alkyl, in particular methyl,
C.sub.3-C.sub.4cycloalkyl, --CN and halogen; ##STR00287##
represents a 6 membered aryl optionally containing one nitrogen
atom; X represents --CR.sup.2R.sup.3--; Y represents
C.sub.1-C.sub.7alkanediyl or C.sub.2-C.sub.7alkenediyl, each
optionally substituted with one or more substituents each
independently selected from the group consisting of
C.sub.1-C.sub.4alkyl, fluoro, and --OH; Z represents a heteroatom
or a single bond; R.sup.a, R.sup.b, R.sup.c and R.sup.d are each
independently selected from the group consisting of hydrogen,
halogen, --CHF.sub.2, --CF.sub.2-methyl, --CH.sub.2F, --CF.sub.3,
--OCF.sub.3, --CN, C.sub.3-C.sub.4cycloalkyl and
--C.sub.1-C.sub.4alkyl; R.sup.1 is hydrogen or
C.sub.1-C.sub.10alkyl optionally substituted with one or more
substituents each independently selected from the group consisting
of --OH, fluoro, and oxo; R.sup.2 is selected from the group
consisting of hydrogen; C.sub.1-C.sub.10alkyl optionally
substituted with one or more substituents each independently
selected from the group consisting of --OH, fluoro, methoxy, oxo,
and --C(.dbd.O)OC.sub.1-C.sub.4alkyl; C.sub.1-C.sub.3alkyl-R.sup.7;
C.sub.2-C.sub.4alkynyl; a 3-7 membered saturated ring optionally
containing one or more heteroatoms each independently selected from
the group consisting of O, S and N; and monocyclic aryl optionally
containing one or two heteroatoms; wherein the
C.sub.1-C.sub.3alkyl-R.sup.7, 3-7 membered saturated ring or the
monocyclic aryl are each optionally substituted with one or more
R.sup.8 substituents; R.sup.3 is hydrogen or C.sub.1-6alkyl
optionally substituted with --OH; or R.sup.2 and R.sup.3 taken
together with the carbon atom to which they are attached form a 3-7
membered saturated ring optionally containing one or more
heteroatoms each independently selected from the group consisting
of O, S and N, and optionally being substituted with one or more
substituents each independently selected from the group consisting
of --OH, fluoro, methoxy, oxo, --C(.dbd.O)OC.sub.1-C.sub.4alkyl,
benzyl, and C.sub.1-C.sub.4alkyl optionally substituted with one or
more substituents each independently selected from fluoro and/or
OH; R.sup.7 represents a monocyclic aryl optionally containing one
or two heteroatoms, and optionally being substituted with one or
two substituents each independently selected from the group
consisting of halo and C.sub.1-3alkyl; a 3-7 membered saturated
ring optionally containing one or more heteroatoms each
independently selected from the group consisting of O, S and N; or
--NR.sup.9R.sup.10; wherein R.sup.9 and R.sup.10 are each
independently selected from hydrogen and C.sub.1-C.sub.3alkyl
optionally substituted with one or more fluoro substituents; each
R.sup.8 is independently selected from the group consisting of
--OH, fluoro, methoxy, oxo, --C(.dbd.O)OC.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkyloxyC.sub.1-C.sub.4alkyloxy, and
C.sub.1-C.sub.4alkyl optionally substituted with one or more
substituents each independently selected from fluoro and/or OH; or
a pharmaceutically acceptable salt or a solvate thereof.
2. The compound according to claim 1, wherein ##STR00288##
represents a monocyclic 5 membered aryl optionally containing one
nitrogen or sulfur, such aryl optionally being substituted with one
or more substituents each independently selected from the group
consisting of C.sub.1-C.sub.3alkyl, in particular methyl,
C.sub.3-C.sub.4cycloalkyl, --CN and halogen; ##STR00289##
represents a 6 membered aryl optionally containing one nitrogen
atom; X represents --CR.sup.2R.sup.3--; Y represents
C.sub.1-C.sub.7alkanediyl or C.sub.2-C.sub.7alkenediyl each
optionally being substituted with one or more substituents each
independently selected from C.sub.1-C.sub.4alkyl and --OH; Z
represents a heteroatom, preferably oxygen, or a single bond;
R.sup.a, R.sup.b, R.sup.c and R.sup.d are each independently
selected from the group consisting of Hydrogen, halogen,
--CHF.sub.2, --CF.sub.2-methyl, --CF.sub.3, --OCF.sub.3, --CN,
C.sub.3-C.sub.4cycloalkyl and --C.sub.1-C.sub.4alkyl; R.sup.1 is
Hydrogen or C.sub.1-C.sub.6alkyl, such C.sub.1-C.sub.6alkyl
optionally being substituted with one or more substituents each
independently selected from the group consisting of --OH, Fluoro,
oxo, and C.sub.1-C.sub.4alkyl optionally substituted with one or
more Fluoro and/or --OH; R.sup.2 is selected from the group
consisting of hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.3alkyl-R.sup.7, a 3-7 membered saturated ring
optionally containing one or more heteroatoms each independently
selected from the group consisting of O, S and N, and monocyclic
aryl optionally containing one or two heteroatoms, such
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.3alkyl-R.sup.7, 3-7 membered
saturated ring or monocyclic aryl optionally being substituted with
one or more R.sup.8; R.sup.3 is hydrogen or C.sub.1-6alkyl; or
R.sup.2 and R.sup.3 taken together form together with the carbon
atom to which they are attached a 3-7 membered saturated ring
optionally containing one or more heteroatoms each independently
selected from the group consisting of O, S and N, such 3-7 membered
saturated ring optionally being substituted with one or more
R.sup.8; R.sup.7 represents a monocyclic aryl optionally containing
one or two heteroatoms; a 3-7 membered saturated ring optionally
containing one or more heteroatoms each independently selected from
the group consisting of O, S and N; or --NR.sup.9R.sup.10; wherein
R.sup.9 and R.sup.10 are each independently selected from Hydrogen
and C.sub.1-C.sub.3alkyl; each R.sup.8 independently is selected
from the group consisting of --OH, Fluoro, methoxy, oxo,
--C(.dbd.O)OC.sub.1-C.sub.4alkyl and C.sub.1-C.sub.4alkyl
optionally substituted with one or more substituents each
independently selected from Fluoro and/or OH.
3. The compound according to claim 1, wherein ##STR00290##
represents a monocyclic 5 membered aryl optionally containing one
nitrogen or sulfur, such aryl optionally being substituted with one
or more substituents each independently selected from the group
consisting of C.sub.1-C.sub.3alkyl, C.sub.3-C.sub.4cycloalkyl, --CN
and halogen; ##STR00291## represents a 6 membered aryl; X
represents --CR.sup.2R.sup.3--; Y represents
C.sub.1-C.sub.7alkanediyl or C.sub.2-C.sub.7alkenediyl each
optionally being substituted with one or more substituents each
independently selected from C.sub.1-C.sub.4alkyl and --OH; Z
represents a heteroatom, preferably oxygen, or a single bond;
R.sup.a, R.sup.b, R.sup.c and R.sup.d are each independently
selected from the group consisting of hydrogen, halogen,
--CHF.sub.2, --CF.sub.2-methyl, --CH.sub.2F, --CF.sub.3,
--OCF.sub.3, --CN, C.sub.3-C.sub.4cycloalkyl and
--C.sub.1-C.sub.4alkyl; R.sup.1 is Hydrogen or
C.sub.1-C.sub.6alkyl, such C.sub.1-C.sub.6alkyl optionally being
substituted with one or more substituents each independently
selected from the group consisting of --OH, Fluoro, oxo, and
C.sub.1-C.sub.4alkyl optionally substituted with one or more Fluoro
and/or --OH; R.sup.2 is selected from the group consisting of
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.3alkyl-R.sup.7, a 3-7
membered saturated ring optionally containing one or more
heteroatoms each independently selected from the group consisting
of O, S and N, and monocyclic aryl optionally containing one or two
heteroatoms, such C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.3alkyl-R.sup.7, 3-7 membered saturated ring or
monocyclic aryl optionally being substituted with one or more
R.sup.8; R.sup.3 is hydrogen; or R.sup.2 and R.sup.3 taken together
form together with the carbon atom to which they are attached a 3-7
membered saturated ring optionally containing one or more
heteroatoms each independently selected from the group consisting
of O, S and N, such 3-7 membered saturated ring optionally being
substituted with one or more R.sup.8; R.sup.7 represents a
monocyclic aryl optionally containing one or two heteroatoms; a 3-7
membered saturated ring optionally containing one or more
heteroatoms each independently selected from the group consisting
of O, S and N; or --NR.sup.9R.sup.10; wherein R.sup.9 and R.sup.10
are each independently selected from Hydrogen and
C.sub.1-C.sub.3alkyl; each R.sup.8 independently is selected from
the group consisting of --OH, Fluoro, methoxy, oxo,
--C(.dbd.O)OC.sub.1-C.sub.4alkyl and C.sub.1-C.sub.4alkyl
optionally substituted with one or more substituents each
independently selected from Fluoro and/or OH.
4. The compound according to claim 1, having Formula (A)
##STR00292## or a stereoisomer or tautomeric form thereof, wherein:
##STR00293## represents a monocyclic 5 membered aryl optionally
containing one nitrogen or sulfur, such aryl optionally substituted
with one or more methyl, --CN or halogen; ##STR00294## represents a
6 membered aryl optionally containing one nitrogen atom; X
represents --CR.sup.2R.sup.3--; Y represents a
C.sub.1-C.sub.7alkanediyl or C.sub.2-C.sub.7alkenediyl each
optionally substituted with one or more C1-C4alkyl or --OH; Z
represents a heteroatom, preferably oxygen, or a single bond;
R.sup.a, R.sup.b, R.sup.c and R.sup.d are independently selected
from the group consisting of Hydrogen, halogen, --CHF.sub.2,
--CF.sub.2-methyl, --CH.sub.2F, --CF.sub.3, --OCF.sub.3, --CN,
C.sub.3-C.sub.4cycloalkyl and --C.sub.1-C.sub.4alkyl; R.sup.1 is
hydrogen or C.sub.1-C.sub.6alkyl, such C.sub.1-C.sub.6alkyl
optionally being substituted with one or more substituents each
independently selected from the group consisting of --OH, Fluoro,
oxo, and C.sub.1-C.sub.4alkyl optionally substituted with one or
more Fluoro and/or --OH; R.sup.2 is selected from the group
consisting of hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.3alkyl-R.sup.7, a 3-7 membered saturated ring
optionally containing one or more heteroatoms each independently
selected from the group consisting of O, S and N, and monocyclic
aryl optionally containing one or two heteroatoms, such
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.3alkyl-R.sup.7, 3-7 membered
saturated ring or monocyclic aryl optionally being substituted with
one or more R.sup.8; R.sup.3 is hydrogen; or R.sup.2 and R.sup.3
taken together form together with the carbon atom to which they are
attached a 3-7 membered saturated ring optionally containing one or
more heteroatoms each independently selected from the group
consisting of O, S and N, such 3-7 membered saturated ring
optionally substituted with one or more R.sup.8; R.sup.7 represents
a monocyclic aryl optionally containing one or two heteroatoms;
each R.sup.8 independently is selected from the group consisting of
--OH, Fluoro, methoxy, oxo, --C(.dbd.O)OC.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl optionally substituted with one or more Fluoro
and/or OH; or a pharmaceutically acceptable salt or a solvate
thereof.
5. The compound according to claim 1, wherein ##STR00295##
represents ##STR00296## or, wherein R.sup.4 is hydrogen or methyl;
and R.sup.6 is selected from hydrogen.
6. The compound according to claim 1, wherein ##STR00297##
represents ##STR00298## wherein R.sup.5 is hydrogen or halogen; and
R.sup.6 is selected from hydrogen, methyl, --CN and halogen.
7. The compound according to claim 1, wherein ring C consists of 6
to 8 atoms.
8. The compound according to claim 1, wherein Y--Z is a
C.sub.2alkenediyl.
9. The compound according to claim 1 wherein Z is an oxygen.
10. The compound according to claim 1, wherein R.sup.2 is
C.sub.1-C.sub.6alkyl optionally substituted with one or more
substituents each independently selected from the group consisting
of OH, fluoro, and methoxy.
11. The compound according to claim 1, wherein ##STR00299##
represents phenyl, and R.sup.a is selected from hydrogen and
halogen; R.sup.b is hydrogen or a halogen; R.sup.c is selected from
halogen, CH.sub.3, CHF.sub.2, CF.sub.3, and --CN; and R.sup.d is
selected from hydrogen and halogen.
12. The compound according to claim 1, wherein R.sup.2 is
C.sub.1-C.sub.4alkyl optionally substituted with one or more
Fluoro.
13. The compound according to claim 1, wherein R.sup.2 is
C.sub.1-C.sub.6alkyl optionally substituted with one or more OH
substituents.
14. The compound according to claim 1, R.sup.1 is hydrogen.
15. (canceled)
16. (canceled)
17. A pharmaceutical composition comprising a compound of claim 1,
and a pharmaceutically acceptable carrier.
18. (canceled)
19. A method of treating a human, infected by HBV, or being at risk
of infection by HBV, said method comprising the administration of a
therapeutically effective amount of a compound of claim 1.
20. A process for the preparation of a compound of claim 1,
comprising the step of (a) reacting a compound of Formula (V) with
an amine of Formula (VI) in the presence of a base in a solvent to
form a compound of Formula (Ia) and optionally subjecting the
compound of Formula (Ia) to hydrogenation ##STR00300## or (b)
subjecting a compound of Formula (XXXIV) to Heck conditions to form
a compound of Formula (Ia) and optionally subjecting the compound
of Formula (Ia) to hydrogenation ##STR00301## or (c) reacting a
compound of Formula (XXXX) with an amine of Formula (VI) in the
presence of a suitable base in a suitable solvent ##STR00302##
wherein the amine of Formula (VI) is ##STR00303## Y* is
C.sub.2-C.sub.7alkenediyl, Y** is C.sub.1-C.sub.7alkanediyl, and
all other variables are as defined in any one of claims 1 to
14.
21-24. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention relates to inhibitors of HBV
replication. The invention also relates to processes for preparing
said compounds, pharmaceutical compositions containing them and
their use, alone or in combination with other HBV inhibitors, in
HBV therapy.
BACKGROUND OF THE INVENTION
[0002] The Hepatitis B virus (HBV) is an enveloped, partially
double-stranded DNA (dsDNA) virus of the Hepadnavirus family
(Hepadnaviridae). Its genome contains 4 overlapping reading frames:
the precore/core gene; the polymerase gene; the L, M, and S genes,
which encode for the 3 envelope proteins; and the X gene.
[0003] Upon infection, the partially double-stranded DNA genome
(the relaxed circular DNA; rcDNA) is converted to a covalently
closed circular DNA (cccDNA) in the nucleus of the host cell and
the viral mRNAs are transcribed. Once encapsidated, the pregenomic
RNA (pgRNA), which also codes for core protein and Pol, serves as
the template for reverse transcription, which regenerates the
partially dsDNA genome (rcDNA) in the nucleocapsid.
[0004] HBV has caused epidemics in parts of Asia and Africa, and it
is endemic in China. HBV has infected approximately 2 billion
people worldwide of which approximately 350 million people have
developed chronic infections. The virus causes the disease
hepatitis B and chronic infection is correlated with a strongly
increased risk for the development cirrhosis and hepatocellular
carcinoma. Additionally, HBV acts as a helper virus to hepatitis
delta virus (HDV), and it is estimated that more than 15 million
people may be HBV/HDV co-infected worldwide, with an increased risk
of rapid progression to cirrhosis and increased hepatic
decompensation, than patients suffering from HBV alone (Hughes, S.
A. et al. Lancet 2011, 378, 73-85).
[0005] Transmission of hepatitis B virus results from exposure to
infectious blood or body fluids, while viral DNA has been detected
in the saliva, tears, and urine of chronic carriers with high titer
DNA in serum.
[0006] An effective and well-tolerated vaccine exists, but direct
treatment options are currently limited to interferon and the
following antivirals; tenofovir, lamivudine, adefovir, entecavir
and telbivudine.
[0007] In addition, heteroaryldihydropyrimidines (HAPs) were
identified as a class of HBV inhibitors in tissue culture and
animal models (Weber et al., Antiviral Res. 54: 69-78).
[0008] WO2013/006394, published on Jan. 10, 2013, relates to a
subclass of sulfamoyl-arylamides active against HBV.
[0009] WO2013/096744, published on Jun. 26, 2013 relates to
compounds active against HBV.
[0010] Amongst the problems which HBV direct antivirals may
encounter are toxicity, mutagenicity, lack of selectivity, poor
efficacy, poor bioavailability, low solubility and difficulty of
synthesis.
[0011] There is a need for additional HBV inhibitors that may
overcome at least one of these disadvantages or that have
additional advantages such as increased potency or an increased
safety window.
SUMMARY OF THE INVENTION
[0012] The present invention relates to a compound of Formula
(I-A)
##STR00002##
or a stereoisomer or tautomeric form thereof, wherein
##STR00003## [0013] represents a monocyclic 5 or 6 membered aryl
optionally containing one or two heteroatoms, such aryl optionally
being substituted with one or more substituents each independently
selected from the group consisting of C.sub.1-C.sub.3alkyl, in
particular methyl, C.sub.3-C.sub.4cycloalkyl, --CN and halogen;
[0013] ##STR00004## [0014] represents a 6 membered aryl optionally
containing one nitrogen atom; [0015] X represents
--CR.sup.2R.sup.3--; [0016] Y represents C.sub.1-C.sub.7alkanediyl
or C.sub.2-C.sub.7alkenediyl, each optionally substituted with one
or more substituents each independently selected from the group
consisting of C.sub.1-C.sub.4alkyl, fluoro, and --OH; [0017] Z
represents a heteroatom, preferably NH or oxygen and more
preferably oxygen, or a single bond; [0018] R.sup.a, R.sup.b,
R.sup.c and R.sup.d are each independently selected from the group
consisting of hydrogen, halogen, --CHF.sub.2, --CF.sub.2-methyl,
--CH.sub.2F, --CF.sub.3, --OCF.sub.3, --CN,
C.sub.3-C.sub.4cycloalkyl and --C.sub.1-C.sub.4alkyl; [0019]
R.sup.1 is hydrogen or C.sub.1-C.sub.10alkyl optionally substituted
with one or more substituents each independently selected from the
group consisting of --OH, fluoro, and oxo; [0020] R.sup.2 is
selected from the group consisting of hydrogen;
C.sub.1-C.sub.10alkyl optionally substituted with one or more
substituents each independently selected from the group consisting
of --OH, fluoro, methoxy, oxo, and
--C(.dbd.O)OC.sub.1-C.sub.4alkyl; C.sub.1-C.sub.3alkyl-R.sup.7;
C.sub.2-C.sub.4alkynyl; a 3-7 membered saturated ring optionally
containing one or more heteroatoms each independently selected from
the group consisting of O, S and N; and monocyclic aryl optionally
containing one or two heteroatoms; wherein the
C.sub.1-C.sub.3alkyl-R.sup.7, 3-7 membered saturated ring or the
monocyclic aryl are each optionally substituted with one or more
R.sup.8 substituents; [0021] R.sup.3 is hydrogen or C.sub.1-6alkyl
optionally substituted with --OH; in particular, hydrogen or
methyl; [0022] or R.sup.2 and R.sup.3 taken together with the
carbon atom to which they are attached form a 3-7 membered
saturated ring optionally containing one or more heteroatoms each
independently selected from the group consisting of O, S and N, and
optionally being substituted with one or more substituents each
independently selected from the group consisting of --OH, fluoro,
methoxy, oxo, --C(.dbd.O)OC.sub.1-C.sub.4alkyl, benzyl, and
C.sub.1-C.sub.4alkyl optionally substituted with one or more
substituents each independently selected from fluoro and/or OH;
[0023] R.sup.7 represents a monocyclic aryl optionally containing
one or two heteroatoms, and optionally being substituted with one
or two substituents each independently selected from the group
consisting of halo and C.sub.1-3alkyl; a 3-7 membered saturated
ring optionally containing one or more heteroatoms each
independently selected from the group consisting of O, S and N; or
--NR.sup.9R.sup.10; [0024] wherein R.sup.9 and R.sup.10 are each
independently selected from hydrogen and C.sub.1-C.sub.3alkyl
optionally substituted with one or more fluoro substituents; [0025]
each R.sup.8 is independently selected from the group consisting of
--OH, fluoro, methoxy, oxo, --C(.dbd.O)OC.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkyloxyC.sub.1-C.sub.4alkyloxy, and
C.sub.1-C.sub.4alkyl optionally substituted with one or more
substituents each independently selected from fluoro and/or OH;
[0026] or a pharmaceutically acceptable salt or a solvate
thereof.
[0027] The invention further relates to a pharmaceutical
composition comprising a compound of Formula (I-A), and a
pharmaceutically acceptable carrier.
[0028] The invention also relates to the compounds of Formula (I-A)
for use as a medicament, preferably for use in the prevention or
treatment of an HBV infection in a mammal.
[0029] In a further aspect, the invention relates to a combination
of a compound of Formula (I-A), and another HBV inhibitor.
DETAILED DESCRIPTION OF THE INVENTION
[0030] The present invention relates to a compound of Formula (I-A)
as defined hereinbefore.
[0031] More in particular, the present invention relates to a
compound of Formula (I-A)
##STR00005##
or a stereoisomer or tautomeric form thereof, wherein
##STR00006## [0032] represents a monocyclic 5 or 6 membered aryl
optionally containing one or two heteroatoms, such aryl optionally
being substituted with one or more substituents each independently
selected from the group consisting of C.sub.1-C.sub.3alkyl, in
particular methyl, C.sub.3-C.sub.4cycloalkyl, --CN and halogen;
[0032] ##STR00007## [0033] represents a 6 membered aryl optionally
containing one nitrogen atom; [0034] X represents
--CR.sup.2R.sup.3--; [0035] Y represents C.sub.1-C.sub.7alkanediyl
or C.sub.2-C.sub.7alkenediyl each optionally being substituted with
one or more substituents each independently selected from
C.sub.1-C.sub.4alkyl and --OH; [0036] Z represents a heteroatom,
preferably oxygen, or a single bond; [0037] R.sup.a, R.sup.b,
R.sup.c and R.sup.d are each independently selected from the group
consisting of Hydrogen, halogen, --CHF.sub.2, --CF.sub.2-methyl,
--CH.sub.2F, --CF.sub.3, --OCF.sub.3, --CN,
C.sub.3-C.sub.4cycloalkyl and --C.sub.1-C.sub.4alkyl; [0038]
R.sup.1 is Hydrogen or C.sub.1-C.sub.6alkyl, such
C.sub.1-C.sub.6alkyl optionally being substituted with one or more
substituents each independently selected from the group consisting
of --OH, Fluoro, oxo, and C.sub.1-C.sub.4alkyl optionally
substituted with one or more Fluoro and/or --OH; [0039] R.sup.2 is
selected from the group consisting of hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.3alkyl-R.sup.7, a 3-7 membered
saturated ring optionally containing one or more heteroatoms each
independently selected from the group consisting of O, S and N, and
monocyclic aryl optionally containing one or two heteroatoms, such
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.3alkyl-R.sup.7, 3-7 membered
saturated ring or monocyclic aryl optionally being substituted with
one or more R.sup.8; [0040] R.sup.3 is hydrogen or C.sub.1-6alkyl;
in particular, hydrogen or methyl; [0041] or R.sup.2 and R.sup.3
taken together form together with the carbon atom to which they are
attached a 3-7 membered saturated ring optionally containing one or
more heteroatoms each independently selected from the group
consisting of O, S and N, such 3-7 membered saturated ring
optionally being substituted with one or more R.sup.8; [0042]
R.sup.7 represents a monocyclic aryl optionally containing one or
two heteroatoms; a 3-7 membered saturated ring optionally
containing one or more heteroatoms each independently selected from
the group consisting of O, S and N; or --NR.sup.9R.sup.10; [0043]
wherein R.sup.9 and R.sup.10 are each independently selected from
Hydrogen and C.sub.1-C.sub.3alkyl; [0044] each R.sup.8
independently is selected from the group consisting of --OH,
Fluoro, methoxy, oxo, --C(.dbd.O)OC.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl optionally substituted with one or more
substituents each independently selected from Fluoro and/or OH;
[0045] or a pharmaceutically acceptable salt or a solvate
thereof.
[0046] In a particular embodiment, the invention relates to a
compound of Formula (I-A)
##STR00008##
or a stereoisomer or tautomeric form thereof, wherein:
##STR00009## [0047] represents a monocyclic 5 or 6 membered aryl
optionally containing one or two heteroatoms, such aryl optionally
being substituted with one or more substituents each independently
selected from the group consisting of C.sub.1-C.sub.3alkyl, in
particular methyl, C.sub.3-C.sub.4cycloalkyl, --CN and halogen;
[0047] ##STR00010## [0048] represents a 6 membered aryl optionally
containing one nitrogen atom; [0049] X represents
--CR.sup.2R.sup.3--; [0050] Y represents C.sub.1-C.sub.7alkanediyl
or C.sub.2-C.sub.7alkenediyl each optionally being substituted with
one or more substituents each independently selected from
C.sub.1-C.sub.4alkyl and --OH; [0051] Z represents a heteroatom,
preferably oxygen, or a single bond; [0052] R.sup.a, R.sup.b,
R.sup.c and R.sup.d are each independently selected from the group
consisting of hydrogen, halogen, --CHF.sub.2, --CF.sub.2-methyl,
--CH.sub.2F, --CF.sub.3, --OCF.sub.3, --CN,
C.sub.3-C.sub.4cycloalkyl and --C.sub.1-C.sub.4alkyl; [0053]
R.sup.1 is hydrogen or C.sub.1-C.sub.6alkyl, such
C.sub.1-C.sub.6alkyl optionally being substituted with one or more
substituents each independently selected from the group consisting
of --OH, Fluoro, oxo, and C.sub.1-C.sub.4alkyl optionally
substituted with one or more Fluoro and/or --OH; [0054] R.sup.2 is
selected from the group consisting of hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.3alkyl-R.sup.7, a 3-7 membered
saturated ring optionally containing one or more heteroatoms each
independently selected from the group consisting of O, S and N, and
monocyclic aryl optionally containing one or two heteroatoms, such
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.3alkyl-R.sup.7, 3-7 membered
saturated ring or monocyclic aryl optionally being substituted with
one or more R.sup.8; [0055] R.sup.3 is hydrogen; [0056] or R.sup.2
and R.sup.3 taken together form together with the carbon atom to
which they are attached a 3-7 membered saturated ring optionally
containing one or more heteroatoms each independently selected from
the group consisting of O, S and N, such 3-7 membered saturated
ring optionally being substituted with one or more R.sup.8; [0057]
R.sup.7 represents a monocyclic aryl optionally containing one or
two heteroatoms; a 3-7 membered saturated ring optionally
containing one or more heteroatoms each independently selected from
the group consisting of O, S and N; or --NR.sup.9R.sup.10; [0058]
wherein R.sup.9 and R.sup.10 are each independently selected from
hydrogen and C.sub.1-C.sub.3alkyl; [0059] each R.sup.8
independently is selected from the group consisting of --OH,
Fluoro, methoxy, oxo, --C(.dbd.O)OC.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl optionally substituted with one or more
substituents each independently selected from Fluoro and/or OH;
[0060] or a pharmaceutically acceptable salt or a solvate
thereof.
[0061] In a further particular embodiment, the invention relates to
a compound of Formula (I-A) as defined herein, or a stereoisomer or
tautomeric form thereof, wherein:
##STR00011## [0062] represents a monocyclic 5 or 6 membered aryl
optionally containing one or two heteroatoms, such aryl optionally
being substituted with one or more substituents each independently
selected from the group consisting of C.sub.1-C.sub.3alkyl, in
particular methyl, C.sub.3-C.sub.4cycloalkyl, --CN and halogen;
[0062] ##STR00012## [0063] represents a 6 membered aryl optionally
containing one nitrogen atom; [0064] X represents
--CR.sup.2R.sup.3--; [0065] Y represents a
C.sub.1-C.sub.7alkanediyl or C.sub.2-C.sub.7alkenediyl each
optionally substituted with one or more C.sub.1-C.sub.4alkyl or
--OH; [0066] Z represents a heteroatom, preferably oxygen, or a
single bond; [0067] R.sup.a, R.sup.b, R.sup.c and R.sup.d are
independently selected from the group consisting of Hydrogen,
halogen, --CHF.sub.2, --CF.sub.2-methyl, --CH.sub.2F, --CF.sub.3,
--OCF.sub.3, --CN, C.sub.3-C.sub.4cycloalkyl and
--C.sub.1-C.sub.4alkyl; [0068] R.sup.1 is Hydrogen or
C.sub.1-C.sub.6alkyl, such C.sub.1-C.sub.6alkyl optionally being
substituted with one or more substituents each independently
selected from the group consisting of --OH, Fluoro, oxo, and
C.sub.1-C.sub.4alkyl optionally substituted with one or more Fluoro
and/or --OH; [0069] R.sup.2 is selected from the group consisting
of hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.3alkyl-R.sup.7, a
3-7 membered saturated ring optionally containing one or more
heteroatoms each independently selected from the group consisting
of O, S and N, and monocyclic aryl optionally containing one or two
heteroatoms, such C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.3alkyl-R.sup.7, 3-7 membered saturated ring or
monocyclic aryl optionally being substituted with one or more
R.sup.8; [0070] R.sup.3 is hydrogen; [0071] or R.sup.2 and R.sup.3
taken together form together with the carbon atom to which they are
attached a 3-7 membered saturated ring optionally containing one or
more heteroatoms each independently selected from the group
consisting of O, S and N, such 3-7 membered saturated ring
optionally substituted with one or more R.sup.8; [0072] R.sup.7
represents a monocyclic aryl optionally containing one or two
heteroatoms; [0073] each R.sup.8 independently is selected from the
group consisting of --OH, Fluoro, methoxy, oxo,
--C(.dbd.O)OC.sub.1-C.sub.4alkyl and C.sub.1-C.sub.4alkyl
optionally substituted with one or more Fluoro and/or OH; [0074] or
a pharmaceutically acceptable salt or a solvate thereof.
[0075] In a further embodiment, the invention relates to a compound
of Formula (I-A) as defined herein, or a stereoisomer or tautomeric
form thereof, wherein:
##STR00013##
represents
##STR00014##
wherein R.sup.4 is hydrogen, --C.sub.1-C.sub.3alkyl or
C.sub.3-C.sub.4cycloalkyl; in particular methyl; R.sup.5 is
hydrogen or halogen; in particular fluoro; and wherein R.sup.6 is
selected from hydrogen, methyl, --CN and halogen; in particular,
hydrogen or methyl; in particular, hydrogen or fluoro, in
particular hydrogen; and all other variables are as defined in
Formula (I-A); or a pharmaceutically acceptable salt or a solvate
thereof. The present invention further relates in particular to a
compound of Formula (A)
##STR00015## [0076] or a stereoisomer or tautomeric form thereof,
wherein:
[0076] ##STR00016## [0077] represents a monocyclic 5 or 6 membered
aryl optionally containing one or two heteroatoms, such aryl
optionally substituted with one or more methyl, --CN or
halogen;
[0077] ##STR00017## [0078] represents a 6 membered aryl optionally
containing one nitrogen atom; [0079] X represents
--CR.sup.2R.sup.3--; [0080] Y represents a
C.sub.1-C.sub.7alkanediyl or C.sub.2-C.sub.7alkenediyl each
optionally substituted with one or more C.sub.1-C.sub.4alkyl or
--OH; [0081] Z represents a heteroatom, preferably oxygen, or a
single bond; [0082] R.sup.aR.sup.b, R.sup.c and R.sup.d are
independently selected from the group consisting of Hydrogen,
halogen, --CHF.sub.2, --CF.sub.2-methyl, --CH.sub.2F, --CF.sub.3,
--OCF.sub.3, --CN, C.sub.3-C.sub.4cycloalkyl and
--C.sub.1-C.sub.4alkyl; [0083] R.sup.1 is Hydrogen or
C.sub.1-C.sub.6alkyl, such C.sub.1-C.sub.6alkyl optionally being
substituted with one or more substituents each independently
selected from the group consisting of --OH, Fluoro, oxo, and
C.sub.1-C.sub.4alkyl optionally substituted with one or more Fluoro
and/or --OH; [0084] R.sup.2 is selected from the group consisting
of hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.3alkyl-R.sup.7, a
3-7 membered saturated ring optionally containing one or more
heteroatoms each independently selected from the group consisting
of O, S and N, and monocyclic aryl optionally containing one or two
heteroatoms, such C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.3alkyl-R.sup.7, 3-7 membered saturated ring or
monocyclic aryl optionally being substituted with one or more
R.sup.8; [0085] R.sup.3 is hydrogen; [0086] or R.sup.2 and R.sup.3
taken together form together with the carbon atom to which they are
attached a 3-7 membered saturated ring optionally containing one or
more heteroatoms each independently selected from the group
consisting of O, S and N, such 3-7 membered saturated ring
optionally substituted with one or more R.sup.8; [0087] R.sup.7
represents a monocyclic aryl optionally containing one or two
heteroatoms; [0088] Each R.sup.8 independently is selected from the
group consisting of --OH, Fluoro, methoxy, oxo,
--C(.dbd.O)OC.sub.1-C.sub.4alkyl and C.sub.1-C.sub.4alkyl
optionally substituted with one or more Fluoro and/or OH; [0089] or
a pharmaceutically acceptable salt or a solvate thereof.
[0090] The invention further relates to a pharmaceutical
composition comprising a compound of Formula (A), and a
pharmaceutically acceptable carrier.
[0091] The invention also relates to the compounds of Formula (A)
for use as a medicament, preferably for use in the prevention or
treatment of an HBV infection in a mammal.
[0092] In a further aspect, the invention relates to a combination
of a compound of Formula (A), and another HBV inhibitor.
[0093] Whenever used hereinafter, the term "compounds of Formula
(I-A)" or "compounds of Formula (A)",
##STR00018##
or "the present compounds" or similar term is meant to include all
compounds of general Formula (I-A), (A), (A*), (B), or (C), salts,
stereoisomeric forms and racemic mixtures or any subgroups
thereof.
[0094] The present invention relates in particular to compounds of
Formula (A)
##STR00019## [0095] or a stereoisomer or tautomeric form thereof,
wherein:
[0095] ##STR00020## [0096] represents a monocyclic 5 or 6 membered
aryl optionally containing one or two heteroatoms, such aryl
optionally substituted with one or more methyl, --CN or
halogen;
[0096] ##STR00021## [0097] represents a 6 membered aryl optionally
containing one nitrogen atom; [0098] X represents
--CR.sup.2R.sup.3--; [0099] Y represents a
C.sub.1-C.sub.7alkanediyl or C.sub.2-C.sub.7alkenediyl each
optionally substituted with one or more C.sub.1-C.sub.4alkyl or
--OH; [0100] Z represents a heteroatom, preferably oxygen, or a
single bond; [0101] R.sup.aR.sup.b, R.sup.c and R.sup.d are
independently selected from the group consisting of Hydrogen,
halogen, --CHF.sub.2, --CF.sub.2-methyl, --CH.sub.2F, --CF.sub.3,
--OCF.sub.3, --CN, C.sub.3-C.sub.4cycloalkyl and
--C.sub.1-C.sub.4alkyl; [0102] R.sup.1 is Hydrogen or
C.sub.1-C.sub.6alkyl, such C.sub.1-C.sub.6alkyl optionally being
substituted with one or more substituents each independently
selected from the group consisting of --OH, Fluoro, oxo, and
C.sub.1-C.sub.4alkyl optionally substituted with one or more Fluoro
and/or --OH; [0103] R.sup.2 is selected from the group consisting
of hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.3alkyl-R.sup.7, a
3-7 membered saturated ring optionally containing one or more
heteroatoms each independently selected from the group consisting
of O, S and N, and monocyclic aryl optionally containing one or two
heteroatoms, such C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.3alkyl-R.sup.7, 3-7 membered saturated ring or
monocyclic aryl optionally being substituted with one or more
R.sup.8; [0104] R.sup.3 is hydrogen; [0105] or R.sup.2 and R.sup.3
taken together form together with the carbon atom to which they are
attached a 3-7 membered saturated ring optionally containing one or
more heteroatoms each independently selected from the group
consisting of O, S and N, such 3-7 membered saturated ring
optionally substituted with one or more R.sup.8; [0106] R.sup.7
represents a monocyclic aryl optionally containing one or two
heteroatoms; [0107] Each R.sup.8 independently is selected from the
group consisting of --OH, Fluoro, methoxy, oxo,
--C(.dbd.O)OC.sub.1-C.sub.4alkyl and C.sub.1-C.sub.4alkyl
optionally substituted with one or more Fluoro and/or OH; [0108] or
a pharmaceutically acceptable salt or a solvate thereof.
[0109] In one embodiment, the present invention relates to
compounds of Formula (A)
##STR00022## [0110] or a stereoisomer or tautomeric form thereof,
wherein:
[0110] ##STR00023## [0111] represents a monocyclic 5 or 6 membered
aryl optionally containing one or two heteroatoms, such aryl
optionally substituted with one or more methyl, --CN or
halogen;
[0111] ##STR00024## [0112] represents a 6 membered aryl optionally
containing one nitrogen atom; [0113] X represents
--CR.sup.2R.sup.3--; [0114] Y represents a
C.sub.1-C.sub.7alkanediyl or C.sub.2-C.sub.7alkenediyl each
optionally substituted with one or more C.sub.1-C.sub.4alkyl;
[0115] Z represents a heteroatom, preferably oxygen, or a single
bond; [0116] R.sup.a, R.sup.b, R.sup.c and R.sup.d are
independently selected from the group consisting of Hydrogen,
halogen, --CHF.sub.2, --CF.sub.2-methyl, --CH.sub.2F, --CF.sub.3,
--OCF.sub.3, --CN, C.sub.3-C.sub.4cycloalkyl and
--C.sub.1-C.sub.4alkyl; [0117] R.sup.1 is Hydrogen or
C.sub.1-C.sub.6alkyl, such C.sub.1-C.sub.6alkyl optionally being
substituted with one or more substituents each independently
selected from the group consisting of --OH, Fluoro, oxo, and
C.sub.1-C.sub.4alkyl optionally substituted with one or more Fluoro
and/or --OH; [0118] R.sup.2 is selected from the group consisting
of hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.3alkyl-R.sup.7 and
monocyclic aryl optionally containing one or two heteroatoms, such
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.3alkyl-R.sup.7 or monocyclic
aryl optionally being substituted with one or more R.sup.8; [0119]
R.sup.3 is hydrogen; [0120] or R.sup.2 and R.sup.3 taken together
form together with the carbon atom to which they are attached a 3-7
membered saturated ring optionally containing one or more
heteroatoms each independently selected from the group consisting
of O, S and N, such 3-7 membered saturated ring optionally
substituted with one or more Fluoro and/or OH, or
C.sub.1-C.sub.4alkyl optionally substituted with one or more Fluoro
and/or --OH; [0121] R.sup.7 represents a monocyclic aryl optionally
containing one or two heteroatoms; [0122] Each R.sup.8
independently is selected from the group consisting of --OH,
Fluoro, methoxy, oxo, and C.sub.1-C.sub.4alkyl optionally
substituted with one or more Fluoro and/or OH; [0123] or a
pharmaceutically acceptable salt or a solvate thereof.
[0124] In one embodiment, the invention relates to compounds of
Formula (B)
##STR00025## [0125] or Formula (C)
[0125] ##STR00026## [0126] wherein R.sup.a, R.sup.b, R.sup.c and
R.sup.d are independently selected from the group consisting of
Hydrogen, halogen, --CHF.sub.2, --CF.sub.2-methyl, --CH.sub.2F,
--CF.sub.3, --OCF.sub.3, --CN, C.sub.3-C.sub.4cycloalkyl and
--C.sub.1-C.sub.4alkyl; [0127] R.sup.1 is Hydrogen or
C.sub.1-C.sub.6alkyl, such C.sub.1-C.sub.6alkyl optionally being
substituted with one or more substituents each independently
selected from the group consisting of --OH, Fluoro, oxo, and
C.sub.1-C.sub.4alkyl optionally substituted with one or more Fluoro
and/or --OH; [0128] R.sup.2 is selected from the group consisting
of hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.3alkyl-R.sup.7 and
monocyclic aryl optionally containing one or two heteroatoms, such
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.3alkyl-R.sup.7 or monocyclic
aryl optionally being substituted with one or more R.sup.8; [0129]
R.sup.3 is hydrogen; [0130] or R.sup.2 and R.sup.3 taken together
form together with the carbon atom to which they are attached a 3-7
membered saturated ring optionally containing one or more
heteroatoms each independently selected from the group consisting
of O, S and N, such 3-7 membered saturated ring optionally
substituted with one or more Fluoro and/or OH, or
C.sub.1-C.sub.4alkyl optionally substituted with one or more Fluoro
and/or --OH; [0131] R.sup.4 is Hydrogen, --C.sub.1-C.sub.3alkyl or
C.sub.3-C.sub.4cycloalkyl, preferably methyl; [0132] R.sup.5 is
Hydrogen or Halogen, preferably Fluoro; [0133] R.sup.6 is selected
from hydrogen, methyl, --CN and halogen; [0134] R.sup.7 represents
a monocyclic aryl optionally containing one or two heteroatoms;
[0135] And each R.sup.8 independently is selected from the group
consisting of --OH, Fluoro, methoxy, oxo, and C.sub.1-C.sub.4alkyl
optionally substituted with one or more Fluoro and/or --OH; [0136]
or a pharmaceutically acceptable salt or a solvate thereof.
[0137] In an additional embodiment, the invention relates to
compounds of Formula (I-A), (A), (A*), (B) or (C) as described
herein, wherein R.sup.1 is Hydrogen or C.sub.1-C.sub.6alkyl
optionally substituted with one or more substituents, in particular
1-3 substituents, each independently selected from the group
consisting of --OH, and Fluoro.
[0138] An additional embodiment of the present invention relates to
compounds of Formula (I-A) having, in particular, Formula (I-AA1)
or Formula (I-AA2)
##STR00027##
wherein Ring B represents phenyl or 4-pyridyl; wherein in Formula
(I-AA2) represents a single or a double bond; R.sup.2 is selected
from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.3alkyl-R.sup.7, a 3-7 membered saturated ring
optionally containing one or more heteroatoms each independently
selected from the group consisting of O, S and N, and monocyclic
aryl optionally containing one or two heteroatoms, such
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.3alkyl-R.sup.7, 3-7 membered
saturated ring or monocyclic aryl optionally being substituted with
one or more R.sup.8; R.sup.3 is hydrogen or C.sub.1-C.sub.6alkyl,
in particular hydrogen or methyl; R.sup.4 is C.sub.1-C.sub.3alkyl,
in particular methyl; R.sup.6 is hydrogen or methyl; R.sup.7 is
selected from the group consisting of a monocyclic aryl optionally
containing one or two heteroatoms; a 3-7 membered saturated ring
optionally containing one or more heteroatoms each independently
selected from the group consisting of O, S and N; or
--NR.sup.9R.sup.10; wherein R.sup.9 and R.sup.10 are each
independently selected from hydrogen and C.sub.1-C.sub.3alkyl; each
R.sup.8 independently is selected from the group consisting of
--OH, fluoro, methoxy, oxo, --C(.dbd.O)OC.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl optionally substituted with one or more
substituents each independently selected from fluoro and/or OH;
R.sup.a is selected from hydrogen and halogen, in particular
hydrogen; R.sup.b is absent when ring B is pyridyl or is hydrogen
or a halogen, in particular a halogen, when ring B is phenyl;
R.sup.c is selected from halogen, CH.sub.3, CHF.sub.2, CF.sub.3,
and --CN; R.sup.d is selected from hydrogen and halogen, in
particular hydrogen;
[0139] or a pharmaceutically acceptable salt or a solvate
thereof.
[0140] A further embodiment the present invention relates to
compounds of Formula (I-A) having, in particular, Formula (I-A1) or
Formula (I-A2)
##STR00028##
wherein Ring B represents phenyl or 4-pyridyl; wherein in Formula
(I-A2) represents a single or a double bond; R.sup.2 is selected
from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.3alkyl-R.sup.7, a 3-7 membered saturated ring
optionally containing one or more heteroatoms each independently
selected from the group consisting of O, S and N, and monocyclic
aryl optionally containing one or two heteroatoms, such
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.3alkyl-R.sup.7, 3-7 membered
saturated ring or monocyclic aryl optionally being substituted with
one or more R.sup.8; R.sup.4 is C.sub.1-C.sub.3alkyl, in particular
methyl; R.sup.6 is hydrogen or methyl; R.sup.7 is selected from the
group consisting of a monocyclic aryl optionally containing one or
two heteroatoms; a 3-7 membered saturated ring optionally
containing one or more heteroatoms each independently selected from
the group consisting of O, S and N; or --NR.sup.9R.sup.10; wherein
R.sup.9 and R.sup.10 are each independently selected from hydrogen
and C.sub.1-C.sub.3alkyl; each R.sup.8 independently is selected
from the group consisting of --OH, fluoro, methoxy, oxo,
--C(.dbd.O)OC.sub.1-C.sub.4alkyl and C.sub.1-C.sub.4alkyl
optionally substituted with one or more substituents each
independently selected from fluoro and/or OH; R.sup.a is selected
from hydrogen and halogen, in particular hydrogen; R.sup.b is
absent when ring B is pyridyl or is hydrogen or a halogen, in
particular a halogen, when ring B is phenyl; R.sup.c is selected
from halogen, CH.sub.3, CHF.sub.2, CF.sub.3, and --CN; R.sup.d is
selected from hydrogen and halogen, in particular hydrogen; or a
pharmaceutically acceptable salt or a solvate thereof.
[0141] In a further embodiment the present invention relates to
compounds of Formula (I-A) having, in particular, Formula (I-A1')
or Formula (I-A2')
##STR00029##
wherein Ring B represents phenyl or 4-pyridyl; wherein in Formula
(I-A2) represents a single or a double bond; R.sup.2 is selected
from the group consisting of C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.3alkyl-R.sup.7, a 3-7 membered saturated ring
optionally containing one or more heteroatoms each independently
selected from the group consisting of O, S and N, and monocyclic
aryl optionally containing one or two heteroatoms, such
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.3alkyl-R.sup.7, 3-7 membered
saturated ring or monocyclic aryl optionally being substituted with
one or more R.sup.8; R.sup.4 is C.sub.1-C.sub.3alkyl, in particular
methyl; R.sup.6 is hydrogen or methyl; R.sup.7 is selected from the
group consisting of a monocyclic aryl optionally containing one or
two heteroatoms; a 3-7 membered saturated ring optionally
containing one or more heteroatoms each independently selected from
the group consisting of O, S and N; or --NR.sup.9R.sup.10; wherein
R.sup.9 and R.sup.19 are each independently selected from hydrogen
and C.sub.1-C.sub.3alkyl; each R.sup.8 independently is selected
from the group consisting of --OH, fluoro, methoxy, oxo,
--C(.dbd.O)OC.sub.1-C.sub.4alkyl and C.sub.1-C.sub.4alkyl
optionally substituted with one or more substituents each
independently selected from fluoro and/or OH; R.sup.a is selected
from hydrogen and halogen, in particular hydrogen; R.sup.b is
absent when ring B is pyridyl or is hydrogen or a halogen, in
particular a halogen, when ring B is phenyl; R.sup.c is selected
from halogen, CH.sub.3, CHF.sub.2, CF.sub.3, and --CN; R.sup.d is
selected from hydrogen and halogen, in particular hydrogen; or a
pharmaceutically acceptable salt or a solvate thereof.
[0142] In a further embodiment the present invention relates to
compounds of Formula (I-A) having, in particular, Formula (I-A1')
or Formula (I-A2'), as defined herein wherein R.sup.2 is
C.sub.1-C.sub.6alkyl optionally substituted with 1-4 substituents
each independently selected from the group consisting of --OH,
fluoro, and methoxy, in particular OH and fluoro; Ring B represents
phenyl; R.sup.a is selected from hydrogen and halogen;
R.sup.b is hydrogen or a halogen, in particular a halogen; and
R.sup.c is selected from halogen, CH.sub.3, CHF.sub.2, CF.sub.3,
and CN; and the rest of the variables are as defined herein.
[0143] Another embodiment of the present invention relates to those
compounds of Formula (I-A), Formula (I-AA1), Formula (I-AA2),
Formula (I-A1), Formula (I-A2), Formula (I-A1'), Formula (I-A2'),
Formula (A), Formula (B), or Formula (C) or any subgroup thereof as
mentioned in any of the other embodiments wherein one or more of
the following restrictions apply: [0144] (a) Ring C consists of 6
to 8 atoms, preferably 7 atoms. [0145] (b) Y represents linear
C.sub.1-C.sub.7alkanediyl or C.sub.2-C.sub.7alkenediyl, each
optionally substituted with 1-3 substituents each independently
selected from the group consisting of fluoro and OH. [0146] (c) Y
represents linear C.sub.1-C.sub.7alkanediyl or
C.sub.2-C.sub.7alkenediyl, each optionally substituted with --OH.
[0147] (d) R.sup.2 is C.sub.1-C.sub.6alkyl optionally substituted
with one or more Fluoro and/or OH substituents, each independently
selected. Preferably, R.sup.2 is a branched C.sub.1-C.sub.6alkyl
substituted with one or more Fluoro substituents. [0148] (e)
R.sup.2 is C.sub.1-C.sub.6alkyl optionally substituted with one or
more OH substituents. In particular, R.sup.2 is C.sub.1-6alkyl
substituted with one OH. [0149] (f) R.sup.2 is C.sub.1-C.sub.4alkyl
optionally substituted with one or more fluoro substituents. [0150]
(g) R.sup.2 is C.sub.3-C.sub.6alkyl optionally substituted with one
or more fluoro substituents. [0151] (h) R.sup.3 is
C.sub.1-C.sub.4alkyl, in particular methyl. [0152] (i) R.sup.3 is
C.sub.1-C.sub.4alkyl, in particular methyl; and R.sup.2 is selected
from the group consisting of C.sub.1-C.sub.6alkyl, and monocyclic
aryl optionally containing one or two heteroatoms, such
C.sub.1-C.sub.6alkyl or monocyclic aryl optionally being
substituted with one or more R.sup.8, wherein R.sup.8 is as defined
herein. [0153] (j) R.sup.4 is C.sub.1-C.sub.3alkyl, preferably
methyl. [0154] (k) R.sup.b is Hydrogen or Fluoro. [0155] (l)
R.sup.b and R.sup.c are independently selected from hydrogen,
fluoro and CN. [0156] (m) R.sup.b and R.sup.c are independently
selected from Hydrogen or Fluoro. [0157] (n) R.sup.b and R.sup.c
are independently selected from fluoro and CN. [0158] (o) R.sup.a
and/or R.sup.d is Hydrogen [0159] (p) R.sup.a and R.sup.d are both
Hydrogen. [0160] (q) R.sup.b and/or R.sup.c are Fluoro. [0161] (r)
R.sup.1 is hydrogen or C.sub.1-C.sub.6alkyl optionally substituted
with one or more substituents, in particular 1-4 substituents, each
independently selected from the group consisting of --OH and
fluoro. [0162] (s) R.sup.1 is hydrogen.
[0162] ##STR00030## represents phenyl.
##STR00031## represents phenyl substituted with one or more halogen
substituents.
##STR00032## represents phenyl substituted with at least one
Halogen, more preferably at least one Fluoro, even more preferably
2 Fluoro. [0163] (w) R.sup.7 is a 3-7 membered saturated ring, in
particular cyclopropyl. [0164] (x) R.sup.2 is selected from the
group consisting of methyl, ethyl, isopropyl,
[0164] ##STR00033## [0165] (y) R.sup.2 is selected from the group
consisting of methyl, ethyl, isopropyl,
##STR00034##
[0165] ##STR00035## represents phenyl, and R.sup.a, R.sup.b,
R.sup.c and R.sup.d are each independently selected from the group
consisting of hydrogen, halogen, --CHF.sub.2, --CF.sub.2-methyl,
--CF.sub.3, --OCF.sub.3, --CN, C.sub.3-C.sub.4cycloalkyl and
--C.sub.1-C.sub.4alkyl.
##STR00036## represents phenyl, and R.sup.a is selected from
hydrogen and halogen; R.sup.b is hydrogen or a halogen, in
particular a halogen; R.sup.c is selected from halogen, CH.sub.3,
CHF.sub.2, CF.sub.3, and --CN; and R.sup.d is selected from
hydrogen and halogen, in particular hydrogen.
##STR00037## represents phenyl, and R.sup.a is selected from
hydrogen and halogen; R.sup.b is hydrogen or a halogen, in
particular a halogen; R.sup.c is selected from halogen, CH.sub.3,
CF.sub.3, and --CN; and R.sup.d is selected from hydrogen and
halogen, in particular hydrogen.
[0166] Further combinations of any of the embodiments are also
envisioned to be in the scope of the present invention.
[0167] In an additional embodiment, the present invention relates
to a compound of Formula (I-A) as defined herein, or a stereoisomer
or tautomeric form thereof, wherein
##STR00038## represents a monocyclic 5 or 6 membered aryl or
heteroaryl selected from the group consisting of pyrrolyl,
thiophenyl, pyrazolyl, phenyl, and pyridyl, each optionally
substituted with one or two substituents each independently
selected from the group consisting of C.sub.1-C.sub.3alkyl, in
particular methyl, C.sub.3-C.sub.4cycloalkyl, --CN and halogen;
##STR00039## represents phenyl or pyridyl; [0168] X represents
--CR.sup.2R.sup.3--; [0169] Y represents linear
C.sub.1-C.sub.7alkanediyl or C.sub.2-C.sub.7alkenediyl, each
optionally substituted with one, two or three substituents each
independently selected from the group consisting of fluoro and
--OH; [0170] Z represents oxygen, or a single bond; [0171] R.sup.a,
R.sup.b, R.sup.c and R.sup.d are each independently selected from
the group consisting of hydrogen, halogen, --CHF.sub.2,
--CF.sub.2-methyl, --CH.sub.2F, --CF.sub.3, --OCF.sub.3, --CN,
C.sub.3-C.sub.4cycloalkyl and --C.sub.1-C.sub.4alkyl; [0172]
R.sup.1 is hydrogen or C.sub.1-C.sub.6alkyl optionally substituted
with one, two, three or four substituents each independently
selected from the group consisting of --OH and fluoro; [0173]
R.sup.2 is selected from the group consisting of hydrogen;
C.sub.1-C.sub.6alkyl optionally substituted with 1-4 substituents
each independently selected from the group consisting of --OH,
fluoro, methoxy, oxo, and --C(.dbd.O)OC.sub.1-C.sub.4alkyl;
C.sub.1-C.sub.3alkyl-R.sup.7; C.sub.2-C.sub.4alkynyl; a 3-7
membered saturated ring optionally containing one or two
heteroatoms each independently selected from the group consisting
of O, S and N; and monocyclic aryl optionally containing one or two
heteroatoms; wherein the C.sub.1-C.sub.3alkyl-R.sup.7, 3-7 membered
saturated ring or the monocyclic aryl are each optionally
substituted with one or more R.sup.8 substituents; [0174] R.sup.3
is hydrogen or C.sub.1-6alkyl optionally substituted with --OH; in
particular, hydrogen or methyl; [0175] or R.sup.2 and R.sup.3 taken
together with the carbon atom to which they are attached form a 3-7
membered saturated ring optionally containing one or more
heteroatoms each independently selected from the group consisting
of O, S and N, and optionally being substituted with one or more
substituents each independently selected from the group consisting
of --OH, fluoro, methoxy, oxo, benzyl, and C.sub.1-C.sub.4alkyl;
[0176] R.sup.7 represents a monocyclic aryl optionally containing
one or two heteroatoms, and optionally being substituted with one
or two substituents each independently selected from the group
consisting of halo and C.sub.1-3alkyl; a 3-7 membered saturated
ring optionally containing one or more heteroatoms each
independently selected from the group consisting of O, S and N; or
--NR.sup.9R.sup.10; [0177] wherein R.sup.9 and R.sup.10 are each
independently selected from hydrogen and C.sub.1-C.sub.3alkyl
optionally substituted with one or more fluoro substituents; [0178]
each R.sup.8 is independently selected from the group consisting of
--OH, fluoro, methoxy, oxo, --C(.dbd.O)OC.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkyloxyC.sub.1-C.sub.4alkyloxy, and
C.sub.1-C.sub.4alkyl optionally substituted with one or more
substituents each independently selected from fluoro and/or OH;
[0179] or a pharmaceutically acceptable salt or a solvate
thereof.
[0180] In an additional embodiment, the present invention relates
to a compound of Formula (I-A) as defined herein, or a stereoisomer
or tautomeric form thereof, wherein
##STR00040## [0181] represents a monocyclic 5 membered heteroaryl
selected from the group consisting of pyrrolyl, thiophenyl and
pyrazolyl, each optionally substituted with one or two substituents
each independently selected from the group consisting of
C.sub.1-C.sub.3alkyl, in particular methyl;
[0181] ##STR00041## [0182] represents phenyl or pyridyl; [0183] X
represents --CR.sup.2R.sup.3--; [0184] Y represents linear
C.sub.1-C.sub.7alkanediyl or C.sub.2-C.sub.7alkenediyl, each
optionally substituted with one or two substituents each
independently selected from the group consisting of fluoro and
--OH; [0185] Z represents oxygen, or a single bond; [0186] R.sup.a,
R.sup.b, R.sup.c and R.sup.d are each independently selected from
the group consisting of hydrogen, halogen, --CHF.sub.2,
--CF.sub.2-methyl, --CH.sub.2F, --CF.sub.3, --OCF.sub.3, --CN,
C.sub.3-C.sub.4cycloalkyl and --C.sub.1-C.sub.4alkyl; [0187]
R.sup.1 is hydrogen or C.sub.1-C.sub.3alkyl optionally substituted
with one, two or three substituents each independently selected
from the group consisting of --OH and fluoro; more in particular,
hydrogen; [0188] R.sup.2 is selected from the group consisting of
hydrogen; C.sub.1-C.sub.6alkyl optionally substituted with one,
two, three or four substituents each independently selected from
the group consisting of [0189] --OH, fluoro, and methoxy;
C.sub.1-C.sub.3alkyl-R.sup.7; C.sub.2-C.sub.4alkynyl; 3-7 membered
saturated ring optionally containing one or two heteroatoms each
independently selected from the group consisting of O, S and N
selected from the group consisting of cyclopropyl,
tetrahydropyranyl and piperidinyl; and monocyclic aryl optionally
containing one or two heteroatoms selected from the group
consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl,
imidazolyl, and oxazolyl; wherein the C.sub.1-C.sub.3alkyl-R.sup.7,
3-7 membered saturated ring or the monocyclic aryl are each
optionally substituted with one or more R.sup.8 substituents;
[0190] R.sup.3 is hydrogen or C.sub.1-3alkyl optionally substituted
with --OH; in particular, hydrogen or methyl; [0191] or R.sup.2 and
R.sup.3 taken together with the carbon atom to which they are
attached form a cyclopropyl, oxetanyl, tetrahydrofuranyl,
tetrahydropyranyl, pyrrolidinyl or piperidinyl ring, each
optionally being substituted with benzyl; [0192] R.sup.7 is
selected from the group consisting of phenyl, pyridyl, pyrazolyl,
imidazolyl, and oxazolyl, each optionally substituted with one or
two substituents each independently selected from the group
consisting of halo and C.sub.1-3alkyl; cyclopropyl; and
--NR.sup.9R.sup.10; [0193] wherein R.sup.9 and R.sup.10 are each
independently selected from hydrogen and C.sub.1-C.sub.3alkyl
optionally substituted with one or more fluoro substituents; each
R.sup.8 is independently selected from the group consisting of
--OH, fluoro, methoxy, oxo, --C(.dbd.O)OC.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkyloxyC.sub.1-C.sub.4alkyloxy, and
C.sub.1-C.sub.4alkyl optionally substituted with one or more
substituents each independently selected from fluoro and/or OH;
[0194] or a pharmaceutically acceptable salt or a solvate
thereof.
[0195] In a further embodiment, the invention relates to compounds
of Formula (I-A), (A) or (A*), as defined herein, wherein
##STR00042## [0196] is selected from the group consisting of
pyrrolyl, thienyl and pyrazolyl, each optionally substituted with
one or two substituents each independently selected from the group
consisting of C.sub.1-C.sub.3alkyl, in particular methyl, --CN and
halo.
[0197] In an additional embodiment, the invention relates to
compounds of the invention, as defined herein, wherein [0198]
R.sup.2 is selected from the group consisting of hydrogen,
C.sub.1-C.sub.6alkyl optionally substituted with 1-4 substituents
each independently selected from the group consisting of --OH,
fluoro and methoxy; C.sub.1-C.sub.3alkyl-R.sup.7 optionally
substituted with --OH; a heterocyclyl selected from piperidinyl and
tetrahydropyranyl, each optionally substituted with
C.sub.1-C.sub.4alkyl, which may be optionally substituted with 1-3
fluoro substituents; and aryl or heteroaryl selected from the group
consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, and
oxazolyl, each ptionally substituted with methyl; wherein R.sup.7
is selected from the group consisting of cyclopropyl, phenyl,
pyridyl, oxazolyl, pyrazolyl and imidazolyl, each optionally
substituted with 1-3 substituents each independently selected from
halo and methyl; and --NR.sup.9R.sup.10, wherein R.sup.9 and
R.sup.10 are each independently selected from hydrogen,
C.sub.1-C.sub.3alkyl and C.sub.1-C.sub.3alkyl substituted with 1-3
fluoro substituents; [0199] R.sup.3 is hydrogen or C.sub.1-6alkyl
optionally substituted with --OH; in particular, hydrogen or
methyl; [0200] or R.sup.2 and R.sup.3 taken together with the
carbon atom to which they are attached form a cyclopropyl, an
oxetanyl, a tetrahydrofuranyl or a pyrrolidinyl ring optionally
substituted with benzyl, in particular an oxetanyl or a
tetrahydrofuranyl ring.
[0201] In an additional embodiment, the invention relates to
compounds of the invention, as defined herein, wherein [0202]
R.sup.2 is selected from the group consisting of
C.sub.1-C.sub.6alkyl optionally substituted with 1-4 substituents
each independently selected from the group consisting of --OH and
fluoro; C.sub.1-C.sub.3alkyl-R.sup.7; optionally substituted with
--OH; [0203] piperidinyl or tetrahydropyranyl, each of which may be
optionally substituted with C.sub.1-C.sub.4alkyl, which may be
optionally substituted with 1-3 fluoro substituents; [0204] phenyl,
pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, each of which optionally
being substituted with methyl; [0205] wherein R.sup.7 is selected
from cyclopropyl, phenyl, pyridyl, oxazolyl, pyrazolyl and
imidazolyl, each of which optionally being substituted with 1-3
substituents each independently selected from halo and methyl; and
--NR.sup.9R.sup.10, wherein R.sup.9 and R.sup.10 are each
independently selected from hydrogen and C.sub.1-C.sub.3alkyl;
[0206] R.sup.3 is hydrogen or C.sub.1-6alkyl; in particular,
hydrogen or methyl; [0207] or R.sup.2 and R.sup.3 taken together
with the carbon atom to which they are attached form a cyclopropyl,
an oxetanyl or a tetrahydrofuranyl, in particular an oxetanyl or a
tetrahydrofuranyl ring.
[0208] Preferred compounds according to the invention are compound
or a stereoisomer or tautomeric form thereof with a Formula as
represented in the synthesis of compounds section and of which the
activity is displayed in Table 1.
Definitions
[0209] The term "aryl" means a monocyclic or polycyclic aromatic
ring comprising carbon atoms, and hydrogen atoms. If indicated,
such aromatic ring may include one or more heteroatoms (then also
referred to as heteroaryl), preferably, 1 to 3 heteroatoms,
independently selected from nitrogen, oxygen, and sulfur,
preferably nitrogen. As is well known to those skilled in the art,
heteroaryl rings have less aromatic character than their all-carbon
counter parts. Thus, for the purposes of the present invention, a
heteroaryl group need only have some degree of aromatic character.
Illustrative examples of aryl groups are optionally substituted
phenyl. Illustrative examples of heteroaryl groups according to the
invention include optionally substituted pyrrole, pyridine, and
imidazole. Thus, the term monocyclic aryl optionally containing one
or more heteroatoms, for example one or two heteroatoms, refers for
example, to a 5- or 6-membered aryl or heteroaryl group such as,
but not limited to, phenyl, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl and
oxazolyl.
[0210] The terms "C.sub.1-xalkyl" and C.sub.1-C.sub.xalkyl can be
used interchangeably.
[0211] The term "C.sub.1-10alkyl", "C.sub.1-6alkyl",
"C.sub.1-3alkyl" as a group or part of a group refers to a
hydrocarbyl radical of Formula C.sub.nH.sub.2n+1 wherein n is a
number ranging from 1 to 10, from 1 to 6, or from 1 to 3. For
example, in the case that C.sub.1-3alkyl is coupled to a further
radical, it refers to a Formula C.sub.nH.sub.2n. C.sub.1-3alkyl
groups comprise from 1 to 3 carbon atoms, more preferably 1 to 2
carbon atoms. C.sub.1-3alkyl includes all linear, or branched alkyl
groups with between 1 and 3 carbon atoms, and thus includes such as
for example methyl, ethyl, n-propyl, and i-propyl.
[0212] C.sub.1-4alkyl as a group or part of a group defines
straight or branched chain saturated hydrocarbon radical having
from 1 to 4 carbon atoms such as the group defined for
C.sub.1-3alkyl and butyl and the like.
[0213] C.sub.1-6alkyl and C.sub.2-6alkyl as a group or part of a
group defines straight or branched chain saturated hydrocarbon
radicals having from 1 to 6 carbon atoms, or from 2 to 6 carbon
atoms such as the groups defined for C.sub.1-4alkyl and pentyl,
hexyl, 2-methylbutyl and the like.
[0214] The term "C.sub.1-7alkanediyl" as a group or part of a group
defines bivalent straight or branched chained saturated hydrocarbon
radicals having from 1 to 7 carbon atoms such as, for example,
methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl,
hexanediyl and heptanediyl.
[0215] The term "C.sub.2-7alkenediyl" as a group or part of a group
defines straight or branched chain bivalent hydrocarbon radicals
having from 2 to 7 carbon atoms and having at least one double
bond, preferably one double bond, such as ethenediyl, propenediyl,
butenediyl, pentenediyl, hexenediyl and heptenediyl and the
like.
[0216] The term "C.sub.3-C.sub.4cycloalkyl" is generic to
cyclopropyl and cyclobutyl.
[0217] As used herein, the term "3-7 membered saturated ring" means
saturated cyclic hydrocarbon (cycloalkyl) with 3, 4, 5, 6 or 7
carbon atoms and is generic to cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and cycloheptyl.
[0218] Such saturated ring optionally contains one or more
heteroatoms (also referred to as heterocyclyl), such that at least
one carbon atom is replaced by a heteroatom selected from N, O and
S, in particular from N and O. Examples include oxetanyl,
tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl,
thiolane 1,1-dioxide and pyrrolidinyl. Preferred are saturated
cyclic hydrocarbons with 3 or 4 carbon atoms and 1 oxygen atom.
Examples include oxetanyl, and tetrahydrofuranyl.
[0219] It should be noted that different isomers of the various
heterocycles may exist within the definitions as used throughout
the specification. For example, pyrrolyl may be 1H-pyrrolyl or
2H-pyrrolyl.
[0220] The term halo and halogen are generic to Fluoro, Chloro,
Bromo or lodo. Preferred halogens are Bromo, Fluoro and Chloro.
[0221] The term "heteroatom" refers to an atom other than carbon or
hydrogen in a ring structure or a saturated backbone as defined
herein. Typical heteroatoms include N(H), O, S.
[0222] The term *R and *S depicted in a structural formula indicate
that a racemic mixture of the compound is separated into its 2
enantiomers. The first eluting enantiomer is indicated with *R and
the second eluting enantiomer is indicated with *S. Both *R and *S
therefore indicate a specific separated enantiomer, but the
sterocenter conformation is not established.
[0223] It should also be noted that the radical positions on any
molecular moiety used in the definitions may be anywhere on such
moiety as long as it is chemically stable. For instance pyridyl
includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes
1-pentyl, 2-pentyl and 3-pentyl.
[0224] The term
##STR00043##
or ring B represents a 6 membered aryl optionally containing one
nitrogen atom. Ring B can therefore be referred to as phenyl or
pyridyl.
##STR00044##
represents a monocyclic 5 or 6 membered aryl optionally containing
one or two heteroatoms, such aryl optionally being substituted with
one or more substituents each independently selected from the group
consisting of C.sub.1-C.sub.3alkyl, in particular methyl,
C.sub.3-C.sub.4cycloalkyl, --CN and halogen. Such monocyclic 5 or 6
membered aryl or heteroaryl groups, as defined herein, include, but
are not limited to phenyl, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl and oxazolyl.
Ring A can alternatively be depicted bearing the optional
substituents C.sub.1-C.sub.3alkyl, C.sub.3-C.sub.4cycloalkyl, --CN
and halogen at particular positions, as defined herein, by
referring to such substituents as R.sup.4, R.sup.5 and R.sup.6, as
applicable.
[0225] Lines drawn from substituents into ring systems indicate
that the bond may be attached to any of the suitable ring
atoms.
[0226] Positions indicated on ring B (e.g. ortho, meta and/or para)
are indicated relative to the bond connecting aryl B to the main
structure. An example with regard to the position of meta R.sup.a,
location is indicated relative to the nitrogen (*) connected to the
main structure as shown in Formula (A*).
##STR00045##
[0227] When any variable (e.g. halogen or C.sub.1-4alkyl) occurs
more than one time in any constituent, each definition is
independent.
[0228] The expression "one or more substituents" refers in
particular to 1, 2, 3, 4, or more substituents, in particular to 1,
2, 3, or 4 substituents, more in particular, to 1, 2, or 3
substituents.
[0229] Combinations of substituents and/or variables are
permissible only if such combinations result in chemically stable
compounds. "Stable compound" is meant to indicate a compound that
is sufficiently robust to survive isolation to a useful degree of
purity from a reaction mixture, and formulation into a therapeutic
agent.
[0230] For therapeutic use, the salts of the compounds of Formula
(I-A), (A), (B), (C), are those wherein the counter ion is
pharmaceutically or physiologically acceptable. However, salts
having a pharmaceutically unacceptable counter ion may also find
use, for example, in the preparation or purification of a
pharmaceutically acceptable compound of Formula (I-A), (A), (B),
(C). All salts, whether pharmaceutically acceptable or not are
included within the ambit of the present invention.
[0231] The pharmaceutically acceptable or physiologically tolerable
addition salt forms which the compounds of the present invention
are able to form can conveniently be prepared using the appropriate
acids, such as, for example, inorganic acids such as hydrohalic
acids, e.g. hydrochloric or hydrobromic acid, sulfuric,
hemisulphuric, nitric, phosphoric and the like acids; or organic
acids such as, for example, acetic, aspartic, dodecyl-sulphuric,
heptanoic, hexanoic, nicotinic, propanoic, hydroxyacetic, lactic,
pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic,
tartaric, citric, methane-sulfonic, ethanesulfonic,
benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,
p-aminosalicylic, pamoic and the like acids.
[0232] Conversely said acid addition salt forms can be converted by
treatment with an appropriate base into the free base form.
[0233] The term "solvate" comprises the solvent addition forms as
well as the salts thereof, which the compounds of the present
invention are able to form. Examples of such solvent addition forms
are, e.g. hydrates, alcoholates and the like.
[0234] The present compounds may also exist in their tautomeric
forms. For example, tautomeric forms of amide (--C(.dbd.O)--NH--)
groups are iminoalcohols (--C(OH).dbd.N--). Tautomeric forms,
although not explicitly indicated in the structural formulae
represented herein, are intended to be included within the scope of
the present invention.
[0235] The term stereochemically isomeric forms of compounds of the
present invention, as used hereinbefore, defines all possible
compounds made up of the same atoms bonded by the same sequence of
bonds but having different three-dimensional structures which are
not interchangeable, which the compounds of the present invention
may possess. Unless otherwise mentioned or indicated, the chemical
designation of a compound encompasses the mixture of all possible
stereochemically isomeric forms which said compound may possess.
Said mixture may contain all diastereomers and/or enantiomers of
the basic molecular structure of said compound. All
stereochemically isomeric forms of the compounds of the present
invention both in pure form or in a mixture with each other are
intended to be embraced within the scope of the present
invention.
[0236] Pure stereoisomeric forms of the compounds and intermediates
as mentioned herein are defined as isomers substantially free of
other enantiomeric or diastereomeric forms of the same basic
molecular structure of said compounds or intermediates. In
particular, the term `stereoisomerically pure` concerns compounds
or intermediates having a stereoisomeric excess of at least 80% (i.
e. minimum 90% of one isomer and maximum 10% of the other possible
isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one
isomer and none of the other), more in particular, compounds or
intermediates having a stereoisomeric excess of 90% up to 100%,
even more in particular having a stereoisomeric excess of 94% up to
100% and most in particular having a stereo-isomeric excess of 97%
up to 100%. The terms `enantiomerically pure` and
`diastereomerically pure` should be understood in a similar way,
but then having regard to the enantiomeric excess or the
diastereomeric excess, respectively, of the mixture in
question.
[0237] Pure stereoisomeric forms of the compounds and intermediates
of this invention may be obtained by the application of art-known
procedures. For instance, enantiomers may be separated from each
other by the selective crystallization of their diastereomeric
salts with optically active acids or bases. Examples thereof are
tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and
camphosulfonic acid. Alternatively, enantiomers may be separated by
chromatographic techniques using chiral stationary phases. Said
pure stereochemically isomeric forms may also be derived from the
corresponding pure stereochemically isomeric forms of the
appropriate starting materials, provided that the reaction occurs
stereospecifically. Preferably, if a specific stereoisomer is
desired, said compound will be synthesized by stereospecific
methods of preparation. These methods will advantageously employ
enantiomerically pure starting materials.
[0238] The stereomeric forms of compounds of Formula (I-A), (A),
(B), or (C), can be obtained separately by conventional methods.
Appropriate physical separation methods that may advantageously be
employed are, for example, selective crystallization and
chromatography, e.g. column chromatography.
[0239] The present invention is also intended to include all
isotopes of atoms occurring on the present compounds. Isotopes
include those atoms having the same atomic number but different
mass numbers. By way of general example and without limitation,
Hydrogen includes the tritium and deuterium isotopes. Carbon
includes the C-13 and C-14 isotopes.
[0240] In a further aspect, the present invention concerns a
pharmaceutical composition comprising a therapeutically or
prophylactically effective amount of a compound of Formula (I-A),
or of Formula (A), (B) or (C) as specified herein, and a
pharmaceutically acceptable carrier. A prophylactically effective
amount in this context is an amount sufficient to prevent HBV
infection in subjects being at risk of being infected. A
therapeutically effective amount in this context is an amount
sufficient to stabilize HBV infection, to reduce HBV infection, or
to eradicate HBV infection, in infected subjects. In still a
further aspect, this invention relates to a process of preparing a
pharmaceutical composition as specified herein, which comprises
intimately mixing a pharmaceutically acceptable carrier with a
therapeutically or prophylactically effective amount of a compound
of Formula (I-A), (A) (B) or (C), as specified herein.
[0241] Therefore, the compounds of the present invention or any
subgroup thereof may be formulated into various pharmaceutical
forms for administration purposes. As appropriate compositions
there may be cited all compositions usually employed for
systemically administering drugs. To prepare the pharmaceutical
compositions of this invention, an effective amount of the
particular compound, optionally in addition salt form or solvate
form, as the active ingredient is combined in intimate admixture
with a pharmaceutically acceptable carrier, which carrier may take
a wide variety of forms depending on the form of preparation
desired for administration. These pharmaceutical compositions are
desirable in unitary dosage form suitable, particularly, for
administration orally, rectally, percutaneously, or by parenteral
injection. For example, in preparing the compositions in oral
dosage form, any of the usual pharmaceutical media may be employed
such as, for example, water, glycols, oils, alcohols and the like
in the case of oral liquid preparations such as suspensions,
syrups, elixirs, emulsions and solutions; or solid carriers such as
starches, sugars, kaolin, lubricants, binders, disintegrating
agents and the like in the case of powders, pills, capsules, and
tablets. Because of their ease in administration, tablets and
capsules represent the most advantageous oral dosage unit forms, in
which case solid pharmaceutical carriers are employed. For
parenteral compositions, the carrier will usually comprise sterile
water, at least in large part, though other ingredients, for
example, to aid solubility, may be included. Injectable solutions,
for example, may be prepared in which the carrier comprises saline
solution, glucose solution or a mixture of saline and glucose
solution. Injectable suspensions may also be prepared in which case
appropriate liquid carriers, suspending agents and the like may be
employed. Also included are solid form preparations intended to be
converted, shortly before use, to liquid form preparations. In the
compositions suitable for percutaneous administration, the carrier
optionally comprises a penetration enhancing agent and/or a
suitable wetting agent, optionally combined with suitable additives
of any nature in minor proportions, which additives do not
introduce a significant deleterious effect on the skin. The
compounds of the present invention may also be administered via
oral inhalation or insufflation in the form of a solution, a
suspension or a dry powder using any art-known delivery system.
[0242] It is especially advantageous to formulate the
aforementioned pharmaceutical compositions in unit dosage form for
ease of administration and uniformity of dosage. Unit dosage form
as used herein refers to physically discrete units suitable as
unitary dosages, each unit containing a predetermined quantity of
active ingredient calculated to produce the desired therapeutic
effect in association with the required pharmaceutical carrier.
Examples of such unit dosage forms are tablets (including scored or
coated tablets), capsules, pills, suppositories, powder packets,
wafers, injectable solutions or suspensions and the like, and
segregated multiples thereof.
[0243] The compounds of Formula (I-A), (A), (B), or (C) are active
as inhibitors of the HBV replication cycle and can be used in the
treatment and prophylaxis of HBV infection or diseases associated
with HBV. The latter include progressive liver fibrosis,
inflammation and necrosis leading to cirrhosis, end-stage liver
disease, and hepatocellular carcinoma. HBV acts as a helper virus
to HDV, which infects only subjects suffering from HBV infection.
Therefore, in a particular embodiment, said compounds of Formula
(I-A), (A), (B), or (C) can be used in the treatment and/or
prophylaxis of HBV/HDV co-infection, or diseases associated with
HBV/HDV co-infection.
[0244] Due to their antiviral properties, particularly their
anti-HBV properties, the compounds of Formula (I-A), (A), (B), or
(C), or any subgroup thereof, are useful in the inhibition of the
HBV replication cycle, in particular in the treatment of
warm-blooded animals, in particular humans, infected with HBV, and
for the prophylaxis of HBV infections. The present invention
furthermore relates to a method of treating a warm-blooded animal,
in particular a human, infected by HBV, or being at risk of
infection by HBV, said method comprising the administration of a
therapeutically effective amount of a compound of Formula (I-A),
(A), (B), or (C). In a particular embodiment, the warm-blooded
animal, in particular the human, may be HBV/HDV co-infected, or be
at risk of HBV/HDV co-infection.
[0245] The compounds of Formula (I-A), (A), (B), or (C), as
specified herein, may therefore be used as a medicine, in
particular as medicine to treat or prevent HBV infection. Said use
as a medicine or method of treatment comprises the systemic
administration to HBV infected subjects or to subjects susceptible
to HBV infection of an amount effective to combat the conditions
associated with HBV infection or an amount effective to prevent HBV
infection. In a particular embodiment, said HBV infection is in
particular HBV/HDV co-infection.
[0246] The present invention also relates to the use of the present
compounds in the manufacture of a medicament. The present invention
also relates to the use of the present compounds in the manufacture
of a medicament for the treatment or the prevention of HBV
infection. In a particular embodiment, the invention relates to the
use of the present compounds in the manufacture of a medicament for
the treatment or the prevention of HBV/HDV co-infection.
[0247] In general it is contemplated that an antiviral effective
daily amount would be from about 0.01 to about 50 mg/kg, or about
0.01 to about 30 mg/kg body weight. It may be appropriate to
administer the required dose as two, three, four or more sub-doses
at appropriate intervals throughout the day. Said sub-doses may be
formulated as unit dosage forms, for example, containing about 1 to
about 500 mg, or about 1 to about 300 mg, or about 1 to about 100
mg, or about 2 to about 50 mg of active ingredient per unit dosage
form.
[0248] The present invention also concerns combinations of a
compound of Formula (I-A), (A), (B), or (C), or any subgroup
thereof, as specified herein with other anti-HBV agents. The term
"combination" may relate to a product or kit containing (a) a
compound of Formula (I-A), (A), (B), or (C), as specified above,
and (b) at least one other compound/agent capable of treating HBV
infection (herein designated as anti-HBV agent), as a combined
preparation for simultaneous, separate or sequential use in
treatment of HBV infections. In an embodiment, the invention
concerns a combination of a compound of Formula (I-A), (A), (B), or
(C), or any subgroup thereof with at least one anti-HBV agent. In a
particular embodiment, the invention concerns a combination of a
compound of Formula (I-A), (A), (B), or (C), or any subgroup
thereof with at least two anti-HBV agents. In a particular
embodiment, the invention concerns a combination of a compound of
Formula (I-A), (A), (B), or (C), or any subgroup thereof with at
least three anti-HBV agents. In a particular embodiment, the
invention concerns a combination of a compound of Formula (I-A),
(A), (B), or (C), or any subgroup thereof with at least four
anti-HBV agents.
[0249] The term anti-HBV agent also includes compounds that are
therapeutic nucleic acids, antibodies or proteins either in their
natural form or chemically modified and/or stabilized. The term
therapeutic nucleic acid includes but is not limited to nucleotides
and nucleosides, oligonucleotides, polynucleotides, of which non
limiting examples are antisense oligonucleotides, miRNA, siRNA,
shRNA, therapeutic vectors and DNA/RNA editing components.
[0250] The term anti-HBV agent also includes compounds capable of
treating HBV infection via immunomodulation. Examples of
immunomodulators are interferon-.alpha. (IFN-.alpha.), pegylated
interferon-.alpha. or stimulants of the innate immune system such
as Toll-like receptor 7 and/or 8 agonists and therapeutic or
prophylactic vaccines. One embodiment of the present invention
relates to combinations of a compound of Formula (I-A), (A), (B),
or (C), or any subgroup thereof, as specified herein, with an
immunomodulating compound, more specifically a Toll-like receptor 7
and/or 8 agonist.
[0251] The additional HBV antiviral(s) can be selected for example,
from therapeutic vaccines; RNA interference therapeutic/antisense
oligonucleotides (siRNA, ddRNA, shRNA); immunomodulators (TLR
agonists (TLR7, TLR8 or TLR9 agonists); STING agonists; RIG-I
modulators; NKT modulators; IL agonists; Interleukin or other
immune active proteins, therapeutic and prophylactic vaccines and
immune checkpoint modulators); HBV entry inhibitors; cccDNA
modulators; capsid assembly inhibitors/modulators; core or X
protein targeting agents; nucleotide analogues; nucleoside
analogues; interferons or modified interferons; HBV antivirals of
distinct or unknown mechanism; cyclophilin inhibitors; and sAg
release inhibitors.
[0252] In particular, the combination of previously known anti-HBV
agents, such as interferon-.alpha. (IFN-.alpha.), pegylated
interferon-.alpha., 3TC, tenofovir, lamivudine, entecavir,
telbivudine, and adefovir or a combination thereof, and, a compound
of Formula (I-A), (A), (B), or (C), or any subgroup thereof can be
used as a medicine in a combination therapy.
[0253] Particular examples of such HBV antiviral(s) include, but
are not limited to: [0254] RNA interference (RNAi) therapeutics:
TKM-HBV (also known as ARB-1467), ARB-1740, ARC-520, ARC-521,
BB-HB-331, REP-2139, ALN-HBV, ALN-PDL, LUNAR-HBV, GS3228836 and
GS3389404; [0255] HBV entry inhibitors: Myrcludex B, IVIG-Tonrol,
GC-1102; [0256] HBV capsid inhibitor/modulators, core or X
targeting agents, direct cccDNA inhibitors, cccDNA formation
inhibitors or cccDNA epigenetic modifiers: BAY 41-4109, NVR 3-778,
GLS-4, NZ-4 (also known as W28F), Y101, ARB-423, ARB-199, ARB-596,
JNJ-56136379, ASMB-101 (also known as AB-V102), ASMB-103, CHR-101,
CC-31326; AT-130 [0257] HBV polymerase inhibitors: entecavir
(Baraclude, Entavir), lamivudine (3TC, Zeffix, Heptovir, Epivir,
and Epivir-HBV), telbivudine (Tyzeka, Sebivo), clevudine,
besifovir, adefovir (hepsera), tenofovir (in particular tenofovir
disoproxil fumarate (Viread), tenofovir alafenamide fumarate
(TAF)), tenofovir disoproxil orotate (also known as DA-2802),
tenofovir disopropxil aspartate (also known as CKD-390), AGX-1009,
and CMX157); [0258] Zidovudine, Didanosine, Zalcitabine, Stavudine,
and Abacavir; [0259] cyclophilin inhibitors: OCB-030 (also known as
NVP-018), SCY-635, SCY-575, and CPI-431-32; [0260] dinucleotides:
SB9200; [0261] compounds of distinct or unknown mechanism, such as
but not limited to AT-61
((E)-N-(1-chloro-3-oxo-1-phenyl-3-(piperidin-1-yl)prop-1-en-2-yl)benzamid-
e),
((E)-N-(1-bromo-1-(2-methoxyphenyl)-3-oxo-3-(piperidin-1-yl)prop-1-3n--
2-yl)-4-nitrobenzamide), and similar analogs; REP-9AC (also known
as REP-2055), REP-9AC' (also known as REP-2139), REP-2165 and
HBV-0259; [0262] TLR agonists (TLR7, 8 and/or 9): RG7795 (also
known as RO-6864018), GS-9620, SM360320
(9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine) and AZD 8848
(methyl
[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-pyrin-9-yl)propyl][3-(4-mo-
rpholinyl)propyl]amino}methyl)phenyl]acetate); ARB-1598; [0263]
RIG-I modulators: SB-9200; [0264] SMAC inhibitor: Birinapant [0265]
Check Point inhibitors: BMS-936558 (Opdivo (nivolumab)),
KEYTRUDA.RTM. (pembrolizumab); [0266] therapeutic vaccines:
HBsAG-HBIG, HB-Vac, ABX203, NASVAC, GS-4774, GX-110 (also known as
HB-110E), CVI-HBV-002, RG7944 (also known as INO-1800), TG-1050,
FP-02 (Hepsyn-B), AIC649, VGX-6200, KW-2, TomegaVax-HBV, ISA-204,
NU-500, INX-102-00557 HBV MVA, PepTcell; [0267] IL agonists and
immune acting proteins: INO-9112; recombinant IL12; [0268]
interferons: interferon alpha (IFN-.alpha.), interferon alpha-2a,
recombinant interferon alpha-2a, peginterferon alpha-2a (Pegasys),
interferon alpha-2b (Intron A), recombinant interferon alpha-2b,
interferon alpha-2b XL, peginterferon alpha-2b, glycosylated
interferon alpha-2b, interferon alpha-2c, recombinant interferon
alpha-2c, interferon beta, interferon beta-1a, peginterferon
beta-1a, interferon delta, interferon lambda (IFN-.lamda.),
peginterferon lambda-1, interferon omega, interferon tau,
interferon gamma (IFN-.gamma.), interferon alfacon-1, interferon
alpha-nl, interferon alpha-n3, albinterferon alpha-2b, BLX-883,
DA-3021, P1101 (also known as AOP2014), PEG-infergen, Belerofon,
INTEFEN-IFN, albumin/interferon alpha 2a fusion protein, rHSA-IFN
alpha 2a, rHSA-IFN alpha 2b, PEG-IFN-SA, interferon alpha
biobetter; in particular, peginterferon alpha-2a, peginterferon
alpha-2b, glycosylated interferon alpha-2b, peginterferon beta-1a,
and peginterferon lambda-1; more in particular, peginterferon
alpha-2a; [0269] HDV targeting agent: Lonalarnib
[0270] In a further embodiment, the additional HBV antiviral
compound is selected from the compounds disclosed in WO2013102655,
WO2013174962, WO2014033167, WO2014033170, WO2014033176,
WO2014131847, WO2014161888, WO2014184350, WO2014184365,
WO2015011281, WO2015059212, WO2015118057, WO2013/096744,
WO2014/165128, WO2015/073774, WO2015/109130.
[0271] In a further embodiment, the additional HBV antiviral
compound is selected from the compounds based on the HAP scaffold,
in particular those disclosed in Roche US20160083383, in particular
compounds 19, 21, 22, 25, 27, 30, 34, 36; 38, 42, 43, 54, 55, 59,
62, 73, 76, 82B, 86B, 87B, 88B and 91B WO2014184328, WO2014037480,
US20150252057, WO2015132276(A1), WO 2013144129.
Medshine Discovery Inc
WO 2015180631
[0272] Sunshine lake pharma co
WO 2015144093
Generic Synthesis
[0273] The substituents represented by R.sup.a,b,c,d or R.sup.1 in
this general synthesis section are meant to include any substituent
or reactive species that is suitable for transformation into any
R.sup.a,b,c,d or R.sup.1 substituent according to the present
invention without undue burden for the person skilled in the
art.
[0274] A possible synthesis of compound of general formula (I) is
described in schemes 1, 2, 3 and 4.
[0275] Compound of general formula (II) can be reacted with an
amine of general formula (III), wherein X has the meaning as
defined in the claims, for example a C.sub.1-C.sub.6alkanediyl
optionally being substituted with one or more substituents each
independently selected from the group consisting of --OH, Fluoro,
and oxo, for example in an organic solvent like acetonitrile or DCM
possibly in the presence of an organic base like for example
triethylamine or DIPEA, or an inorganic base like for example
sodium bicarbonate. The formed compound of general formula (IV) can
be ring closed under Heck conditions with a ligand like
bis(tri-tert-butylphosphine)palladium(0) to a compound of general
formula (V). Compound of general formula (IV) can also be reacted
with potassium allyltrifluoroborate under Suzuki conditions with a
ligand like bis(tri-tert-butylphosphine)palladium(0) in the
presence of an inorganic base like Cs.sub.2CO.sub.3 to give a
mixture of compound of general formula (VII) and compound of
general formula (VIII). Compound of general formula (VII) or
compound of general formula (VIII) can be ring closed under
metathesis conditions with a catalyst like Grubbs catalyst 2.sup.nd
generation, resulting in the formation of a compound of general
formula (V). The compound of general formula (V) can be reacted
with an amine of general formula (VI) in the presence of a base
like for example lithium bis(trimethylsilyl)amide, in a solvent
like for example THF, resulting in the formation of a compound of
general formula (Ia), wherein Y* represents an alkenediyl and Z a
single bond. Hydrogenation of the double bond forms a compound of
general formula (Ib), wherein Y** represents an alkanediyl and Z a
single bond. Alternatively the amide can be formed via the
classical routes known by the person skilled in the art
like--without any limitations--via the acid and a coupling reagent
like HATU or via activation to the acid chloride and reaction with
an amine of general formula (VI). Compound of general formula (IV)
can also be reacted with an amine of general formula (VI) in the
presence of a base like for example lithium
bis(trimethylsilyl)amide, in a solvent like for example THF,
resulting in the formation of a compound of general formula
(XXXIV). The formed compound of general formula (XXXIV) can be ring
closed under Heck conditions with a ligand like
bis(tri-tert-butylphosphine)palladium(0) to a compound of general
formula (Ia), wherein Y* represents an alkenediyl and Z a single
bond.
[0276] Compound of general formula (II) can be reacted with an
aminoalcohol of general formula (XXXI), wherein X has the meaning
as defined in the claims, for example a C.sub.1-C.sub.6alkanediyl
optionally being substituted with one or more substituents each
independently selected from the group consisting of --OH, Fluoro,
and oxo, for example in an organic solvent like acetonitrile or DCM
possibly in the presence of an organic base like for example
triethylamine or DIPEA, or an inorganic base like for example
sodium bicarbonate. The formed compound of general formula (XXXII)
can be oxidized in a solvent like THF with an oxidant like
2-iodoxybenzoic acid resulting in a compound of general formula
(XXXIII). Compound of general formula (XXXIII) can be reacted under
Wittig conditions to a compound of general formula (IV).
##STR00046##
[0277] Alternatively, as described in Scheme 2, a compound of
formula (II) can be reacted with an amine of general formula (IX),
for example in an organic solvent like acetonitrile or DCM possibly
in the presence of an organic base like for example triethylamine
or DIPEA, or an inorganic base like for example sodium bicarbonate.
The formed compound of general formula (X) can be reacted with
potassium allyltrifluoroborate under Suzuki conditions with a
ligand like bis(tri-tert-butylphosphine)palladium(0) in the
presence of an inorganic base like Cs.sub.2CO.sub.3 to give a
mixture of compound of general formula (XI) and compound of general
formula (XII). A compound of general formula (XI) or a compound of
general formula (XII) can be reacted with an amine of general
formula (VI) in the presence of a base like for example lithium
bis(trimethylsilyl)amide, in a solvent like for example THF,
results in the formation of a compound of general formula (XIII) or
general formula (XV). A compound of general formula (XIII) or a
compound of general formula (XV) can be reacted under Mitsonobu
conditions with an alcohol of general formula (XVII), wherein X has
the meaning as defined in the claims, for example a
C.sub.1-C.sub.6alkanediyl optionally being substituted with one or
more substituents each independently selected from the group
consisting of --OH, Fluoro, and oxo, and results in a compound of
general formula (XIV) or a compound of general formula (XVI). A
compound of general formula (XIV) or a compound of general formula
(XVI) can be ring closed under metathesis conditions with a
catalyst like Grubbs catalyst 2.sup.nd generation, resulting in the
formation of a compound of general
[0278] Formula (Ia), wherein Y* represents an alkenediyl and Z a
single bond. Hydrogenation of the double bond forms a compound of
general formula (Ib), wherein Y** represents an alkanediyl and Z a
single bond.
##STR00047## ##STR00048## ##STR00049##
[0279] Alternatively, as described in Scheme 3, a compound of
formula (XVIII) can be reacted with an alcohol of general formula
(XIX), for example in an organic solvent like THF or DCM possibly
in the presence of an organic base like for example triethylamine
or DIPEA, or an inorganic base like for example sodium bicarbonate.
The formed compound of general formula (XX) can be coupled with an
amine of general formula (VI) in the presence of a base like for
example lithium bis(trimethylsilyl)amide, in a solvent like for
example THF. The formed compound of general formula (XXI) can be
ring closed in the presence of a base like CsF, resulting in a
compound of general formula (Ic) wherein Z is oxygen.
[0280] A compound of formula (XXII) can be reacted with an alcohol
of general formula (XIX), for example in a mixture of an organic
solvent like THF or DCM with water, possibly in the presence of an
organic base like for example triethylamine or DIPEA, or an
inorganic base like for example sodium carbonate. The formed
compound of general formula (XXIII) can be coupled with an amine of
general formula (VI) in the presence of an activating reagent like
for example HATU and an organic base like triethylamine or DIPEA,
resulting in a compound of general formula (XXI).
##STR00050##
[0281] Alternatively, as described in Scheme 4, a compound of
formula (II) can be treated with ammonia in a solvent like dioxane,
resulting in a compound of general formula (XXIV). The formed
compound (XXIV) can either be coupled with a 1-3-diketoalkane like
pentane-2,4-dione or heptane-3,5-dione resulting in a compound of
general formula (XXV) wherein Ry is a C.sub.1-C.sub.4alkyl or under
Stille conditions with a stannane like
(Z)-1-ethoxy-2-(tributylstarmypethene resulting in a compound of
general formula (XXIX). Compounds of general formula's (XXV) can be
ring closed under acidic conditions using an acid like TFA to a
compound of general formula (XXVI) wherein Rz is a
C.sub.1-C.sub.4alkyl. Compounds of general formula's (XXIX) can be
ring closed under acidic conditions using an acid like TFA to a
compound of general formula (XXVI) where Rz is hydrogen. The formed
compound of general formula (XXVI) can either be hydrogenated to
form a compound of general formula (XXVII) or coupled with and
amine of general formula (VI) in the presence of a base like for
example lithium bis(trimethylsilyl)amide, in a solvent like for
example THF, resulting in a compound of general formula (XXX). The
compound of general formula (XXVII) can be alkylated for example
with an alkylbromide, followed by a coupling with and amine of
general formula (VI) in the presence of a base like for example
lithium bis(trimethylsilyl)-amide, in a solvent like for example
THF, resulting in a compound of general formula (Ib), wherein Y**
represents an alkanediyl and Z a single bond. Compound of general
formula (XXX) can be hydrogenated to a compound of general formula
(Id), wherein Y** represents an alkanediyl and Z a single bond. A
compound of general formula (XXVII) can be coupled with an amine of
general formula (VI) in the presence of a base like for example
lithium bis(trimethylsilyl)amide, in a solvent like for example
THF, resulting in a compound of general formula (Id), wherein Y**
represents an alkanediyl and Z a single bond.
##STR00051##
[0282] Alternatively, as described in Scheme 5, a compound of
formula (XXXV) can be reacted with a compound of general formula
(XXXVI), wherein X has the meaning as defined in the claims, for
example a C.sub.1-C.sub.6alkanediyl optionally being substituted
with one or more substituents each independently selected from the
group consisting of --OH, Fluoro, and oxo, for example in a solvent
like DMF under Suzuki conditions with a ligand like
bis(tri-tert-butylphosphine)palladium(0) in the presence of an
organic base like Hunigs' base. The formed compound of general
formula (XXXVII) can be reduced under catalytic conditions using
palladium on carbon under a hydrogen gas atmosphere. The formed
compound of general formula (XXXVIII) can be deprotected with a
reagent like ethylenediamine in a solvent like n-butanol to form a
compound of general formula (XXXIX). A compound of general formula
(XXXIX) can be chlorosulfonated in the presence of chlorosulfonic
acid and thionyl chloride and then ring closed via quenching in a
saturated aqueous solution of an inorganic base like NaHCO.sub.3 or
Na.sub.2CO.sub.3 to a compound of general formula (XXXX) wherein
Y** represents an alkanediyl and Z a single bond. Compound of
general formula (XXXX) can be reacted with an amine of general
formula (VI) in the presence of a base like for example lithium
bis(trimethylsilyl)amide, in a solvent like for example THF,
resulting in the formation of a compound of general formula
(Ib).
##STR00052##
[0283] Alternatively, as described in Scheme 6, a compound of
formula (XXXXI) can be reacted with a compound of general formula
(XXXXII), wherein X has the meaning as defined in the claims, for
example a C.sub.1-C.sub.6alkanediyl optionally being substituted
with one or more substituents each independently selected from the
group consisting of --OH, Fluoro, and oxo, for example in a solvent
like ACN in the presence of an organic base like Hunigs' base. The
formed compound of general formula (XXXXIII) can be ring closed via
Mitsunobu conditions. After deprotection of the formed compound of
general formula (XXXXIV) and reaction with an amine of general
formula (VI) in the presence of a base like for example lithium
bis(trimethylsilyl)amide, in a solvent like for example THF, a
compound of general formula (Ic) can be formed.
##STR00053##
[0284] Alternatively, as described in Scheme 7, a compound of
formula (XXXXV) can be reacted with a compound of general formula
(XXXXVI), for example in a solvent like dioxane in the presence of
silver carbonate. The tert-butyl ester of the formed compound of
general formula (XXXXVII) can be cleaved using TFA in a solvent
like DCM. Consecutive esterification in a solvent like DMF with
methyliodide in the presence of an inorganic base like
Cs.sub.2CO.sub.3 can result in a compound of general formula
(XXXXVIII). A compound of general formula (XXXXVIII) can be
chlorosulfonated in the presence of chlorosulfonic acid and thionyl
chloride and then ring closed via quenching in a saturated aqueous
solution of an inorganic base like NaHCO.sub.3 or Na.sub.2CO.sub.3.
The resulting compound of formula (XXXXIX) can be reacted with a
Grignard reagent like methylmagnesium bromide in a solvent like THF
to form a compound of general formula (XXXXX). The formed compound
of general formula (XXXXX) can be reacted with an amine of general
formula (VI) in the presence of a base like for example lithium
bis(trimethylsilyl)amide, in a solvent like for example THF,
resulting in the formation of a compound of general formula
(XXXXXI)
##STR00054##
General Procedure LCMS Methods
[0285] The High Performance Liquid Chromatography (HPLC)
measurement was performed using a LC pump, a diode-array (DAD) or a
UV detector and a column as specified in the respective methods. If
necessary, additional detectors were included (see table of methods
below).
[0286] Flow from the column was brought to the Mass Spectrometer
(MS) which was configured with an atmospheric pressure ion source.
It is within the knowledge of the skilled person to set the tune
parameters (e.g. scanning range, dwell time . . . ) in order to
obtain ions allowing the identification of the compound's nominal
monoisotopic molecular weight (MW). Data acquisition was performed
with appropriate software. Compounds are described by their
experimental retention times (Rt) and ions. If not specified
differently in the table of data, the reported molecular ion
corresponds to the [M+H].sup.+ (protonated molecule) and/or
[M-H].sup.- (deprotonated molecule). In case the compound was not
directly ionizable the type of adduct is specified (i.e.
[M+NH.sub.4].sup.+, [M+HCOO].sup.-, etc. . . . ). All results were
obtained with experimental uncertainties that are commonly
associated with the method used.
[0287] Hereinafter, "SQD" means Single Quadrupole Detector, "MSD"
Mass Selective Detector, "RT" room temperature, "BEH" bridged
ethylsiloxane/silica hybrid, "DAD" Diode Array Detector, "HSS" High
Strength silica., "Q-Tof" Quadrupole Time-of-flight mass
spectrometers, "CLND", ChemiLuminescent Nitrogen Detector, "ELSD"
Evaporative Light Scanning Detector,
LCMS Methods
[0288] (Flow expressed in mL/min; column temperature (T) in
.degree. C.; Run time in minutes).
TABLE-US-00001 Method code Instrument Column Mobile phase Gradient
Flow Col T ##EQU00001## Run time A Waters: Acquity .RTM. UPLC .RTM.
- Waters: HSS T3 (1.8 .mu.m, A: 10 mM CH3COONH4 in 95% H2O + From
100% A to 5% A in 2.10 min, to 0% 0.8 55 ##EQU00002## 3.5 DAD and
2.1*100 5% CH3CN A in 0.90 min, SQD mm) B: CH3CN to 5% A in 0.5 min
B Waters: Acquity .RTM. UPLC .RTM. - Waters: BEH C18 A: 10 mM
CH3COONH4 in 95% H2O + From 95% A to 5% A in 1.3 min, held for 0.8
55 ##EQU00003## 2 DAD and (1.7 .mu.m, 5% CH3CN 0.7 min. SQD 2.1*50
B: CH3CN mm) C Waters: Acquity .RTM. UPLC .RTM. - Waters: HSS T3
(1.8 .mu.m, A: 10 mM CH3COONH4 in 95% H2O + From 95% A to 0% A in
2.5 min, to 5% 0.8 55 ##EQU00004## 3 DAD and 2.1*100 5% CH3CN A in
0.5 min SQD mm) B: CH3CN D Waters: Acquity .RTM. UPLC .RTM. -
Waters: HSS T3 (1.8 .mu.m, A: 10 mM CH3COONH4 in 95% H2O + From
100% A to 5% A in 2.10 min, to 0% 0.7 55 ##EQU00005## 3.5 DAD and
2.1*100 5% CH3CN A in 0.90 min, SQD mm) B: CH3CN to 5% A in 0.5 min
Z Waters: Alliance .RTM.- DAD - Atlantis T3 column A: 70% CH3OH,
30% H2O 100% B to 5% B in 9 min, hold 3.0 min to 1.5 45
##EQU00006## 13.5 ZMD (5 .mu.m, B: 0.1 formic 100% B in 1 and CLND
4.6 .times. acid min and hold 8060 Antek 100 mm) in H2O/ 0.5 min
CH3OH 95/5
General Procedure for SFC-MS Methods
[0289] The SFC measurement was performed using an Analytical
Supercritical fluid chromatography (SFC) system composed by a
binary pump for delivering carbon dioxide (CO.sub.2) and modifier,
an autosampler, a column oven, a diode array detector equipped with
a high-pressure flow cell standing up to 400 bars. If configured
with a Mass Spectrometer (MS) the flow from the column was brought
to the (MS). It is within the knowledge of the skilled person to
set the tune parameters (e.g. scanning range, dwell time . . . ) in
order to obtain ions allowing the identification of the compound's
nominal monoisotopic molecular weight (MW). Data acquisition was
performed with appropriate software.
[0290] Analytical SFC-MS Methods (Flow expressed in mL/min; column
temperature (T) in .degree. C.; Run time in minutes, Backpressure
(BPR) in bars).
TABLE-US-00002 Method code column mobile phase gradient Flow Col T
##EQU00007## Run time BPR ##EQU00008## E Daicel Chiralpak .RTM.
AD-H column (5.0 .mu.m, 250 .times. 4.6 mm) A: CO.sub.2 B: EtOH +
0.2% iPrNH.sub.2 25% B hold 4 min, to 50% in 1 min 5 40
##EQU00009## 7 110 ##EQU00010## hold 2 min F Daicel Chiralpak .RTM.
AD-H column (5.0 .mu.m, 250 .times. 4.6 mm) A: CO.sub.2 B: EtOH +
0.2% iPrNH.sub.2 30% B hold 4 min, to 50% in 1 min 5 40
##EQU00011## 7 110 ##EQU00012## hold 2 min G Whelk .RTM.-O-(R,R)
column (5.0 .mu.m, 250 .times. 4.6 mm) A: CO.sub.2 B: MeOH + 0.2%
iPrNH.sub.2 35% B hold 4 min, to 50% in 1 min 5 40 ##EQU00013## 7
110 ##EQU00014## hold 2 min H Daicel Chiralpak .RTM. AD-H column
(5.0 .mu.m, 250 .times. 4.6 mm) A: CO.sub.2 B: EtOH + 0.2%
iPrNH.sub.2 10% B hold 4 min, to 50% in 1 min 5 40 ##EQU00015## 7
110 ##EQU00016## hold 2 min I Daicel Chiralpak .RTM. AD-H column
(5.0 .mu.m, 250 .times. 4.6 mm) A: CO.sub.2 B: EtOH + 0.2%
iPrNH.sub.2 20% B hold 4 min, to 50% in 1 min 5 40 ##EQU00017## 7
110 ##EQU00018## hold 2 min J Daicel Chiralpak .RTM. AD-H column
(5.0 .mu.m, 250 .times. 4.6 mm) A: CO.sub.2 B: EtOH + 0.2%
iPrNH.sub.2 45% B hold 4 min, to 50% in 1 min 5 40 ##EQU00019## 7
110 ##EQU00020## hold 2 min K Daicel Chiralpak .RTM. AD-H column
(5.0 .mu.m, 250 .times. 4.6 mm) A: CO.sub.2 B: EtOH + 0.2%
iPrNH.sub.2 40% B hold 4 min, to 50% in 1 min 5 40 ##EQU00021## 7
110 ##EQU00022## hold 2 min L Whelk .RTM.-O-(R,R) column (5.0
.mu.m, 250 .times. 4.6 mm) A: CO.sub.2 B: EtOH + 0.2% iPrNH.sub.2
40% B hold 4 min, to 50% in 1 min 5 40 ##EQU00023## 7 110
##EQU00024## hold 2 min M Whelk .RTM.-O-(R,R) column (5.0 .mu.m,
250 .times. 4.6 mm) A: CO.sub.2 B: iPrOH + 0.2% iPrNH.sub.2 40% B
hold 4 min, to 50% in 1 min 5 40 ##EQU00025## 7 110 ##EQU00026##
hold 2 min N Daicel Chiralpak .RTM. AD-H column (5.0 .mu.m, 250
.times. 4.6 mm) A: CO.sub.2 B: EtOH + 0.2% iPrNH.sub.2 35% B hold 4
min, to 50% in 1 min 5 40 ##EQU00027## 7 110 ##EQU00028## hold 2
min O Daicel Chiralpak .RTM. ID-H column (5.0 .mu.m, 250 .times.
4.6 mm) A: CO.sub.2 B: EtOH + 0.2% iPrNH.sub.2 35% B hold 4 min, to
50% in 1 min 5 40 ##EQU00029## 7 110 ##EQU00030## hold 2 min P
Daicel Chiralpak .RTM. AD-H column (5.0 .mu.m, 250 .times. 4.6 mm)
A: CO.sub.2 B: EtOH - iPrOH + 35% B hold 4 min, to 50% in 1 min 5
40 ##EQU00031## 7 110 ##EQU00032## 0.2% iPrNH.sub.2 hold 2 min Q
Daicel Chiralpak .RTM. AD-H column (5.0 .mu.m, 250 .times. 4.6 mm)
A: CO.sub.2 B: EtOH + 0.2% iPrNH.sub.2 5% B hold 4 min, to 50% in 1
min 5 40 ##EQU00033## 7 110 ##EQU00034## hold 2 min R Daicel
Chiralpak .RTM. AD3 column (3.0 .mu.m, 150 .times. 4.6 mm) A:
CO.sub.2 B: EtOH + 0.2% iPrNH.sub.2 10%-50% B in 6 min, hold 3.5
min 2.5 40 ##EQU00035## 9.5 110 ##EQU00036## S Whelk .RTM.-O-(R,R)
column (5.0 .mu.m, 250 .times. 4.6 mm) A: CO.sub.2 B: EtOH - iPrOH
+ 35% B hold 4 min, to 50% in 1 min 5 40 ##EQU00037## 7 110
##EQU00038## 0.2% iPrNH.sub.2 hold 2 min T Daicel Chiralpak .RTM.
AS3 column (3.0 .mu.m, 150 .times. 4.6 mm) A: CO.sub.2 B: EtOH +
0.2% iPrNH.sub.2 + 10%-50% B in 6 min, hold 3.5 min 2.5 40
##EQU00039## 9.5 110 ##EQU00040## 3% H.sub.2O U Daicel Chiralpak
.RTM. ID-H column (3.0 .mu.m, 150 .times. 4.6 mm) A: CO.sub.2 B:
EtOH + 0.2% iPrNH.sub.2 + 10%-50% B in 6 min, hold 3.5 min 2.5 40
##EQU00041## 9.5 110 ##EQU00042## 3% H.sub.2O V Daicel Chiralpak
.RTM. AD-H column (3.0 .mu.m, 150 .times. 4.6 mm) A: CO.sub.2 B:
MeOH + 0.2% iPrNH.sub.2 + 10%-50% B in 6 min, hold 3.5 min 2.5 40
##EQU00043## 9.5 110 ##EQU00044## 3% H.sub.2O W Daicel Chiralpak
.RTM. AD-H column (3.0 .mu.m, 150 .times. 4.6 mm) A: CO.sub.2 B:
iPrOH + 0.2% iPrNH.sub.2 + 10%-50% B in 6 min, hold 3.5 min 2.5 40
##EQU00045## 9.5 110 ##EQU00046## 3% H.sub.2O X Whelk .RTM.-O-
(R,R) column (5.0 .mu.m, 250 .times. 4.6 mm) A: CO.sub.2 B: EtOH +
0.2% iPrNH.sub.2 10%-50% B in 6 min, hold 3.5 min 2.5 40
##EQU00047## 9.5 110 ##EQU00048## Y Daicel Chiralpak .RTM. OD-H
column (3.0 .mu.m, 150 .times. 4.6 mm) A: CO.sub.2 B: EtOH + 0.2%
iPrNH.sub.2 + 10%-50% B in 6 min, hold 3.5 min 2.5 40 ##EQU00049##
9.5 110 ##EQU00050## 3% H.sub.2O AA Daicel Chiralpak .RTM. IC-H
column (3.0 .mu.m, 150 .times. 4.6 mm) A: CO.sub.2 B: EtOH + 0.2%
iPrNH.sub.2 + 10%-50% B in 6 min, hold 3.5 min 2.5 40 ##EQU00051##
9.5 110 ##EQU00052## 3% H.sub.2O AB Daicel Chiralpak .RTM. AS3
column (3.0 .mu.m, 150 .times. 4.6 mm) A: CO.sub.2 B: MeOH + 0.2%
iPrNH.sub.2 10%-50% B in 6 min, hold 3.5 min 2.5 40 ##EQU00053##
9.5 110 ##EQU00054## AC Daicel Chiralpak .RTM. AS3 column (3.0
.mu.m, 150 .times. 4.6 mm) A: CO.sub.2 B: iPrOH + 0.2% iPrNH.sub.2
10%-50% B in 6 min, hold 3.5 min 2.5 40 ##EQU00055## 9.5 110
##EQU00056## AD Daicel Chiralpak .RTM. AD-H column (3.0 .mu.m, 150
.times. 4.6 mm) A: CO.sub.2 B: EtOH - iPrOH + 10%-50% B in 6 min,
hold 3.5 min 2.5 40 ##EQU00057## 9.5 110 ##EQU00058## 0.2%
iPrNH.sub.2
[0291] Melting points (MP) reported in .degree. C. are referring to
the peak observed in differential scanning calorimetry (DSC): From
30 to 300.degree. C. at 10.degree. C./min.
Synthesis of Compounds
Compound 1:
(9E)-N-(3,4-difluorophenyl)-4,14-dimethyl-2,2-dioxo-2.lamda..sup.6-thia-3-
,14-diazabicyclo[10.3.0]pentadeca-1(15),9,12-triene-13-carboxamide
##STR00055##
[0293] Methyl
3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (500 mg,
1.58 mmol), oct-7-en-2-amine (221 mg, 1.74 mmol) and Hunig's base
(0.82 mL, 0.75 g/mL, 4.74 mmol) were dissolved in THF (5 mL) and
stirred overnight at room temperature. The volatiles were removed
under reduced pressure and the residue was purified on silica using
a heptane to EtOAc gradient yielding methyl
3-bromo-1-methyl-4-(1-methylhept-6-enylsulfamoyl)pyrrole-2-carboxylate
(507 mg) as an oil which solidified on standing. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 1.09 (d, J=6.6 Hz, 3H), 1.22-1.36
(m, 4H), 1.37-1.50 (m, 2H), 1.89-2.06 (m, 2H), 3.11-3.38 (m, 1H),
3.91 (s, 3H), 3.92-3.95 (m, 3H), 4.53 (d, J=7.7 Hz, 1H), 4.89-5.01
(m, 2H), 5.76 (ddt, J-17.1, 10.3, 6.7, 6.7 Hz, 1H), 7.35 (s,
1H).
[0294] Methyl
3-bromo-1-methyl-4-(1-methylhept-6-enylsulfamoyl)pyrrole-2-carboxylate
(100 mg, 0.25 mmol), potassium allyltrifluoroborate (109 mg, 0.74
mmol), bis(tri-tert-butylphosphine)palladium(0) (12.6 mg, 0.025
mmol) and Cs.sub.2CO.sub.3 (240 mg, 0.74 mmol) were dissolved in a
mixture of DME (5 mL) and water (1 mL) and heated in the microwave
oven at 120.degree. C. for 30 minutes. The volatiles were removed
under reduced pressure and the residue was purified on silica using
a heptane to EtOAc gradient yielding methyl
3-allyl-1-methyl-4-(1-methylhept-6-enylsulfamoyl)pyrrole-2-carboxylate
(62 mg) as a clear oil.
[0295] Methyl
3-allyl-1-methyl-4-(1-methylhept-6-enylsulfamoyl)pyrrole-2-carboxylate
(62 mg, 0.17 mmol) was dissolved in DCE (50 mL) and heated to
80.degree. C. while bubbling N.sub.2 through the reaction mixture.
Grubbs catalyst 2nd generation (14.3 mg, 0.017 mmol) was added and
heating was continued for 2 hours. The volatiles were removed under
reduced pressure and the residue was purified on silica using a
heptane to EtOAc gradient yielding methyl
(9Z)-4,14-dimethyl-2,2-dioxo-2-thia-3,14-diazabicyclo-[10.3.0]pent-
adeca-1(15),9,12-triene-13-carboxylate (35 mg). Method B; Rt: 1.19
min. m/z: 341 (M+H).sup.+ Exact mass: 340.1.
[0296] Methyl
(9Z)-4,14-dimethyl-2,2-dioxo-2-thia-3,14-diazabicyclo[10.3.0]pentadeca-1(-
15),9,12-triene-13-carboxylate (35 mg, 0.1 mmol) and
3,4-difluoroaniline (12.4 .mu.L, 1.29 g/mL, 0.12 mmol) were
dissolved in THF (5 mL). Lithium bis(trimethylsilyl)-amide (0.31
mL, 1 M in THF, 0.31 mmol) was added and the reaction mixture was
stirred overnight at room temperature. The reaction mixture was
quenched with NH.sub.4Cl (aq., sat., 5 mL). The organic layer was
removed and the aqueous layer extracted with DCM (2.times.5 mL).
The combined organic layers were evaporated to dryness and the
residue purified on silica using a heptane to EtOAc gradient. The
obtained product was crystallized from a DCM:DIPE mixture yielding
compound 1 as an off-white powder. .sup.1H NMR (600 MHz,
CHLOROFORM-d) .delta. ppm 1.15-1.21 (m, 1H) 1.22 (d, J=6.5 Hz, 3H)
1.23-1.30 (m, 1H) 1.41-1.49 (m, 3H) 1.66-1.73 (m, 1H) 2.02-2.10 (m,
1H) 2.32 (br d, J=13.5 Hz, 1H) 3.27 (dt, J-12.3, 6.2 Hz, 1H) 3.64
(br d, J=18.5 Hz, 1H) 3.85 (br dd, 5.0 Hz, 1H) 3.91 (s, 3H) 4.24
(d, J=6.2 Hz, 1H) 5.28-5.36 (m, 1H) 5.93 (br d, J=15.6 Hz, 1H)
7.01-7.06 (m, 1H) 7.06-7.12 (m, 1H) 7.31 (s, 1H) 7.58 (ddd, J-12.0,
7.1, 2.6 Hz, 1H) 7.94 (br s, 1H). Method B; Rt: 1.17 min. m/z: 438
(M+H).sup.+ Exact mass: 437.2.
Compounds 2a and 2b:
8Z--N-(3,4-difluorophenyl)-4,13-dimethyl-2,2-dioxo-2.lamda..sup.6-thia-3,-
13-diazabicyclo[9.3.0]tetradeca-1(14),8,11-triene-12-carboxamide
and
8E-N-(3,4-difluorophenyl)-4,13-dimethyl-2,2-dioxo-2.lamda..sup.6-thia-3,1-
3-diazabicyclo[9.3.0]tetra-deca-1(14),8,11-triene-12-carboxamide
##STR00056##
[0298] Methyl
3-bromo-1-methyl-4-(1-methylhept-6-enylsulfamoyl)pyrrole-2-carboxylate
(420 mg, 1.03 mmol), potassium allyltrifluoroborate (458 mg, 3.09
mmol), bis(tri-tert-butylphosphine)palladium(0) (52.7 mg, 0.1 mmol)
and Cs.sub.2CO.sub.3 (1008 mg, 3.09 mmol) were dissolved in a
mixture of DME (5 mL) and water (1 mL) and heated in the microwave
oven at 120.degree. C. for 30 minutes. The volatiles were removed
under reduced pressure and the residue was purified on silica using
a heptane to EtOAc gradient yielding methyl
3-allyl-1-methyl-4-[[(E)-1-methylhept-5-enyl]sulfamoyl]pyrrole-2-carboxyl-
ate (258 mg) as a clear oil.
[0299] Methyl
3-allyl-1-methyl-4-[[(E)-1-methylhept-5-enyl]sulfamoyl]pyrrole-2-carboxyl-
ate (258 mg, 0.7 mmol) was dissolved in DCE (50 mL) and N.sub.2 was
bubbled through the reaction mixture. Grubbs catalyst 2.sup.nd
generation (38.7 mg, 0.046 mmol) was added and the reaction mixture
was heated for 5 hours. The volatiles were removed under reduced
pressure and the residue was purified on silica using a heptane to
EtOac gradient yielding methyl
(8Z)-4,13-dimethyl-2,2-dioxo-2-thia-3,13-diazabicyclo[9.3.0]tetradeca-1(1-
4),8,11-triene-12-carboxylate as an off-white powder.
[0300] Methyl
(8Z)-4,13-dimethyl-2,2-dioxo-2-thia-3,13-diazabicyclo[9.3.0]tetradeca-1(1-
4),-8,11-triene-12-carboxylate (22 mg, 0.067 mmol) and
3,4-difluoroaniline (8.2 .mu.L, 1.29 g/mL, 0.081 mmol) were
dissolved in THF (5 mL). Lithium bis(trimethylsilyl)-amide (1M in
THF) (202 .mu.L, 1 M in THF, 0.2 mmol) was added and the reaction
mixture was stirred overnight at room temperature. The reaction
mixture was quenched with NH4Cl (aq., sat., 5 mL). The organic
layer was removed and the aqueous layer extracted with DCM
(2.times.5 mL). The combined organic layers were evaporated to
dryness and the residue purified on silica using a heptane to EtOAc
gradient. The obtained product was purified via Prep HPLC
(Stationary phase: RP XBridge Prep C18 ODB-5 .mu.m, 30.times.250
mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3 solution in water, ACN)
yielding compound 2a (7.2 mg).sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 1.30 (d, J=6.4 Hz, 3H), 1.36-1.48 (m, 4H), 1.84 (br dd,
5.1 Hz, 1H), 1.93-2.10 (m, 1H), 3.30-3.41 (m, 1H), 3.56-3.68 (m,
1H), 3.77-3.84 (m, 1H), 3.85 (s, 3H), 4.02-4.26 (m, 1H), 5.54-5.74
(m, 2H), 7.09-7.19 (m, 2H), 7.26 (s, 1H), 7.65-7.72 (m, 1H), 8.11
(br s, 1H). Method D; Rt: 2.05 min. m/z: 424 (M+H).sup.+ Exact
mass: 423.1 and compound 2b (18.2 mg).sup.1H NMR (400 MHz,
CHLOROFORM-d) 6 ppm -0.05-0.05 (m, 1H), 1.25 (d, J=6.2 Hz, 3H),
1.36-1.45 (m, 1H), 1.47-1.65 (m, 3H), 2.00-2.27 (m, 2H), 3.05 (br
s, 1H), 3.48-3.69 (m, 2H), 3.75-3.90 (m, 3H), 4.34 (br s, 1H), 5.34
(dt, J-15.6, 7.5 Hz, 1H), 5.84 (dt, J-15.7, 4.1 Hz, 1H), 7.08-7.22
(m, 2H), 7.63-7.72 (m, 1H), 7.91 (br s, 1H). Method D; Rt: 2.09
min. m/z: 424 (M+H).sup.+ Exact mass: 423.1.
Compound 3:
(5Z)--N-(3,4-difluorophenyl)-8-methyl-1,1-dioxo-2-[(1R)-2,2,2-trifluoro-1-
-methyl-ethyl]-3,4-dihydropyrrolo[3,4-g]thiazocine-7-carboxamide
##STR00057##
[0302] Methyl
3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (5 g, 15.79
mmol), (R)-1,1,1-trifluoro-2-propylamine (2.68 g, 23.7 mmol),
NaHCO.sub.3(3.98 g, 47.4 mmol) and molecular sieves (10 g) were
dispensed in ACN (75 mL) in a 150 mL pressure vessel. This
suspension was stirred overnight at 80.degree. C. The reaction
mixture was filtered and the volatiles were removed under reduced
pressure. The residue was purified on silica using a heptane to
EtOAc gradient. The fractions containing the product were
evaporated to dryness yielding methyl
3-bromo-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrol-
e-2-carboxylate (4.89 g) as a white powder.
[0303] Methyl
3-bromo-1-methyl-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]pyrrol-
e-2-carboxylate (2 g, 5.09 mmol), potassium allyltrifluoroborate
(2.26 g, 15.3 mmol), bis(tri-tert-butylphosphine)palladium(0) (260
mg, 0.51 mmol) and Cs.sub.2CO.sub.3 (4.97 g, 15.3 mmol) were
dissolved in a mixture of DME (15 mL) and water (3 mL) and heated
in the microwave oven at 100.degree. C. for 30 minutes. The
volatiles were removed under reduced pressure and the residue was
purified on silica using a heptane to EtOAc gradient yielding
methyl
1-methyl-3-[(E)-prop-1-enyl]-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulf-
amoyl]pyrrole-2-carboxylate (1.18 g) as a light brown powder.
[0304] Methyl
1-methyl-3-[(E)-prop-1-enyl]-4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]-sul-
famoyl]pyrrole-2-carboxylate (1.18 g, 3.33 mmol) and
3,4-difluoroaniline (404 .mu.L, 1.29 g/mL, 4 mmol) were dissolved
in THF (25 mL). Lithium bis(trimethylsilyl)amide (10 mL, 1 M in
THF, 10 mmol) was added and the reaction mixture was stirred
overnight at room temperature. The reaction mixture was quenched
with NH.sub.4Cl (aq., sat., 10 mL). The organic layer was removed
and the aqueous layer extracted with DCM (2.times.5 mL). The
combined organic layers were evaporated to dryness and the residue
purified on silica using a heptane to EtOAc gradient yielding
N-(3,4-difluoro-phenyl)-1-methyl-3-[(E)-prop-1-enyl]-4-[[(1R)-2,2,2-trifl-
uoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide (1.08 g) as a
brown powder.
[0305] DIAD (0.12 mL, 1.04 g/mL, 0.6 mmol) was added to a solution
of
N-(3,4-difluoro-phenyl)-1-methyl-3-[(E)-prop-1-enyl]-4-[[(1R)-2,2,2-trifl-
uoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide (180 mg, 0.4
mmol), 3-buten-1-ol (31.6 mg, 0.44 mmol) and triphenylphosphine
(157 mg, 0.6 mmol) in THF (5 mL). The reaction mixture was stirred
overnight at room temperature. LCMS showed 60% conversion to the
desired product. 3-buten-1-ol (31.6 mg, 0.44 mmol),
triphenylphosphine (157 mg, 0.6 mmol) and DIAD (0.12 mL, 1.04 g/mL,
0.6 mmol) were added and the reaction mixture was stirred for 1
hour. The volatiles were removed under reduced pressure and the
residue was purified on silica using a heptane to EtOAc gradient
yielding
4-[but-3-enyl-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]-N-(3,4-difl-
uorophenyl)-1-methyl-3-[(E)-prop-1-enyl]pyrrole-2-carboxamide (120
mg) as a clear oil.
[0306] 4-[but-3-enyl-[(1R)-2,2,2-trifl
uoro-1-methyl-ethyl]sulfamoyl]-N-(3,4-difluorophenyl)-1-methyl-3-[(E)-pro-
p-1-enyl]pyrrole-2-carboxamide (120 mg, 0.24 mmol) was dissolved in
DCE (150 mL) and N.sub.2 was bubbled through the reaction mixture.
Grubbs catalyst 2.sup.nd generation (20.2 mg, 0.024 mmol) was added
and the reaction mixture was heated at 80.degree. C. overnight. The
volatiles were removed under reduced pressure and the residue was
purified on silica using a heptane to EtOAc gradient yielding
compound 3 (92 mg) as a white powder. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.37 (br d, J=7.0 Hz, 3H), 2.39 (br s,
2H), 3.49-3.61 (m, 2H), 3.99 (s, 3H), 4.71 (dt, 7.6 Hz, 1H), 6.24
(dt, J-10.6, 8.8 Hz, 1H), 6.75 (d, J=10.8 Hz, 1H), 7.07-7.17 (m,
2H), 7.30 (s, 1H), 7.60-7.70 (m, 2H); Method B; Rt: 1.13 min. m/z:
464 (M+H).sup.+ Exact mass: 463.1.
Compound 4:
N-(3,4-difluorophenyl)-8-methyl-1,1-dioxo-2-[(1R)-2,2,2-trifluoro-1-methy-
l-ethyl]-3,4,5,6-tetrahydropyrrolo[3,4-g]thiazocine-7-carboxamide
##STR00058##
[0308] Compound 3 (80 mg, 0.17 mmol) was dissolved in MeOH (20 mL),
Pd/C (10%) (18 mg, 0.017 mmol) was added and the reaction mixture
was stirred overnight under a hydrogen atmosphere. The volatiles
were removed under reduced pressure and the residue was purified on
silica using a heptane to EtOac gradient yielding compound 4 (63.1
mg) as a white powder after crystallisation from DCM:DIPE. .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.36 (d, J=7.0 Hz, 3H),
1.63-1.73 (m, 2H), 1.73-1.86 (m, 2H), 3.13-3.34 (m, 2H), 3.51-3.60
(m, 2H), 3.84 (s, 3H), 4.76 (dt, J-15.1, 7.5 Hz, 1H), 7.08-7.20 (m,
3H), 7.53 (s, 1H), 7.67 (ddd, J-12.0, 7.2, 2.4 Hz, 1H); Method B;
Rt: 1.18 min. m/z: 466 (M+H).sup.+ Exact mass: 465.1; MP:
137.3.degree. C.
Compound 5:
(4Z)--N-(3,4-difluorophenyl)-3,8-dimethyl-L1-dioxo-3,6-dihydro-2H-pyrrolo-
[3,4-g]thiazocine-7-carboxamide
##STR00059##
[0310] Methyl
3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (1000 mg,
3.16 mmol) and 3-buten-2-amine, hydrochloride (374 mg, 3.47 mmol)
were dissolved in THF (5 mL). Hunig's base (1.63 mL, 0.75 g/mL,
9.48 mmol) was added and the reaction mixture was stirred overnight
at room temperature. NH.sub.4Cl (sat., aq., 5 mL) was added and the
organic layer was removed. The aqueous layer was extracted with DCM
(2.times.5 mL) and the combined organic layers were evaporated to
dryness. The residue was purified on silica using a heptane to
EtOAc gradient yielding methyl
3-bromo-1-methyl-4-(1-methylallylsulfamoyl)pyrrole-2-carboxylate
(981 mg) as a white powder.
[0311] Methyl
3-bromo-1-methyl-4-(1-methylallylsulfamoyl)pyrrole-2-carboxylate
(200 mg, 0.57 mmol), potassium allyltrifluoroborate (253 mg, 1.71
mmol), bis(tri-tert-butyl-phosphine)palladium(0) (29 mg, 0.057
mmol) and Cs.sub.2CO.sub.3 (557 mg, 1.71 mmol) were dissolved in a
mixture of DME (5 mL) and water (1 mL) and heated in the microwave
oven at 80.degree. C. for 30 minutes. The volatiles were removed
under reduced pressure and the residue was purified on silica using
a heptane to EtOAc gradient yielding methyl
3-allyl-1-methyl-4-(1-methylallylsulfamoyl)pyrrole-2-carboxylate
(47 mg) and methyl
3,7-dimethyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]thiazepine-6-carboxylate
(79 mg).
[0312] Methyl
3-allyl-1-methyl-4-(1-methylallylsulfamoyl)pyrrole-2-carboxylate
(47 mg, 0.15 mmol) was dissolved in DCE (100 mL) and N.sub.2 was
bubbled through the reaction mixture. Grubbs catalyst 2.sup.nd
generation (26 mg, 0.03 mmol) was added and the reaction mixture
was heated at 80.degree. C. overnight. The volatiles were removed
under reduced pressure and the residue was purified on silica using
a heptane to EtOAc gradient yielding methyl
(4Z)-3,8-dimethyl-1,1-dioxo-3,6-dihydro-2H-pyrrolo[3,4-g]thiazocin-
e-7-carboxylate (31 mg).
[0313] Methyl
(4Z)-3,8-dimethyl-1,1-dioxo-3,6-dihydro-2H-pyrrolo[3,4-g]thiazocine-7-car-
boxylate (31 mg, 0.11 mmol) and 3,4-difluoroaniline (13.2 .mu.L,
1.29 g/mL, 0.13 mmol) were dissolved in THF (5 mL). Lithium
bis(trimethylsilyl)amide (0.33 mL, 1 M in THF, 0.33 mmol) was added
and the reaction mixture was stirred overnight at room temperature.
The reaction mixture was quenched with NH.sub.4Cl (aq., sat., 5
mL). The organic layer was removed and the aqueous layer extracted
with DCM (2.times.5 mL). The combined organic layers were
evaporated to dryness and the residue purified on silica using a
heptane to EtOAc gradient. The obtained product was purified via
prep. HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 .mu.m,
30.times.150 mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3 solution in
water, MeOH) yielding compound 5 (9.7 mg) as a white powder.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.23 (d, J=6.8 Hz,
3H), 3.16-3.29 (m, 1H), 3.58 (dd, J-13.5, 10.2 Hz, 1H), 3.68 (s,
3H), 4.37-4.48 (m, 1H), 5.30 (dd, J-10.0, 7.6 Hz, 1H), 5.69 (q,
J=9.1 Hz, 1H), 7.28 (br d, J=9.9 Hz, 1H), 7.39 (s, 1H), 7.40-7.46
(m, 2H), 7.81-7.90 (m, 1H), 10.56 (s, 1H); Method B; Rt: 0.97 min.
m/z: 382 (M+H).sup.+ Exact mass: 381.1.
Compound 6:
N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-2-[(1R)-2,2,2-trifluoro-1-methy-
l-ethyl]-3H-pyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00060##
[0315] DIAD (0.16 mL, 1.04 g/mL, 0.8 mmol) was added to a solution
of
N-(3,4-difluoro-phenyl)-1-methyl-3-[(E)-prop-1-enyl]-4-[[(1R)-2,2,2-trifl-
uoro-1-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide (180 mg, 0.4
mmol), 2-propen-1-ol (25.5 mg, 0.44 mmol) and triphenylphosphine
(209 mg, 0.8 mmol) in THF (5 mL). The reaction mixture was stirred
overnight at room temperature. The volatiles were removed under
reduced pressure and the residue was purified on silica using a
heptane to EtOAc gradient. The obtained residue was purified via
prep. HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 .mu.m,
30.times.150 mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3 solution in
water, MeOH) yielding
4-[allyl-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]-N-(3,4-difluoro--
phenyl)-1-methyl-3-[(E)-prop-1-enyl]pyrrole-2-carboxamide (81 mg).
4-[allyl-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]sulfamoyl]-N-(3,4-difluorop-
henyl)-1-methyl-3-[(E)-prop-1-enyl]pyrrole-2-carboxamide (81 mg,
0.16 mmol) was dissolved in DCE (100 mL) and N.sub.2 was bubbled
through the reaction mixture. Grubbs catalyst 2.sup.nd generation
(28 mg, 0.033 mmol) was added and the reaction mixture was heated
at 80.degree. C. overnight. The volatiles were removed under
reduced pressure and the residue was purified via prep. HPLC
(Stationary phase: RP XBridge Prep C18 OBD-10 .mu.m, 30.times.150
mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3 solution in water, MeOH)
yielding compound 6 (50.1 mg) as a white powder after
crystallization from DCM:DIPE. .sup.1H NMR (360 MHz, DMSO-d.sub.6)
.delta. ppm 1.17 (d, J=7.0 Hz, 3H), 3.74 (s, 3H), 4.10 (dd, J-21.2,
4.8 Hz, 1H), 4.28-4.37 (m, 1H), 4.37-4.45 (m, 1H), 5.68-5.75 (m,
1H), 6.57 (br d, J=12.8 Hz, 1H), 7.40-7.49 (m, 2H), 7.67 (s, 1H),
7.81-7.89 (m, 1H), 10.76 (s, 1H); Method B; Rt: 1.13 min. m/z: 450
(M+H).sup.+ Exact mass: 449.1.
Compound 7:
N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-2,3-dihydropyrrolo-[3,4-f]t-
hiazepine-6-carboxamide
##STR00061##
[0317] Methyl
3,7-dimethyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]thiazepine-6-carboxylate
(79 mg, 0.29 mmol) and 3,4-difluoroaniline (36 .mu.L, 1.29 g/mL,
0.35 mmol) were dissolved in THF (5 mL). Lithium
bis(trimethylsilyl)amide (0.88 mL, 1 M in THF, 0.88 mmol) was added
and the reaction mixture was stirred overnight at room temperature.
The reaction mixture was quenched with NH.sub.4Cl (aq., sat., 5
mL). The organic layer was removed and the aqueous layer extracted
with DCM (2.times.5 mL). The combined organic layers were
evaporated to dryness and the residue purified on silica using a
heptane to EtOAc gradient. The resulting product was purified via
prep. HPLC (Stationary phase: RP XBridge Prep C18 ODB-5 .mu.m,
30.times.250 mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3 solution in
water, ACN) yielding compound 7. .sup.1H NMR (360 MHz,
CHLOROFORM-d) .delta. ppm 1.41 (d, J=7.3 Hz, 3H), 3.71 (q, J=7.0
Hz, 1H), 3.76 (s, 3H), 4.40 (br s, 1H), 5.61 (dd, J-12.4, 2.6 Hz,
1H), 6.53 (dd, J-12.4, 2.2 Hz, 1H), 7.10-7.26 (m, 3H), 7.71 (ddd,
J-12.0, 7.2, 2.4 Hz, 1H), 8.20 (br s, 1H); Method D; Rt: 1.72 min.
m/z: 368 (M+H).sup.+ Exact mass: 367.1. This racemic mixture was
seperated in enantiomers 7a (19.5 mg) and 7b (13.4 mg) by
preparative SFC (Stationary phase: Chiralpak Diacel AD 20.times.250
mm, Mobile phase: CO.sub.2, EtOH with 0.4% iPrNH.sub.2). Method E;
Rt: 7a:1.80 min, 7b: 2.33 min.
Compound 8:
N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3-(trifluoromethyl)-2,3-dihydro-
pyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00062##
[0319] Methyl
3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (1000 mg,
3.16 mmol), 1,1,1-trifluorobut-3-en-2-ylamine (612 mg, 3.79 mmol),
NaHCO.sub.3 (1062 mg, 12.64 mmol) and molecular sieves (2 g) were
dispensed in ACN (30 mL) and the reaction mixture was stirred 4
days at 80.degree. C. The reaction mixture was filtered and the
filtrate was evaporated to dryness. The residue was purified on
silica using a heptane to EtOAc gradient yielding methyl
3-bromo-1-methyl-4-[1-(trifluoromethyl)-allylsulfamoyl]pyrrole-2-carboxyl-
ate (894 mg) as a white powder.
[0320] Methyl
3-bromo-1-methyl-4-[1-(trifluoromethyl)allylsulfamoyl]pyrrole-2-carboxyla-
te (837 mg, 2.07 mmol), bis(tri-tert-butylphosphine)palladium(0)
(211 mg, 0.41 mmol) and TEA (286 .mu.L, 0.73 g/mL, 2.07 mmol) were
dissolved in DMF (5 mL). The reaction mixture was heated in the
microwave oven for 30 minutes at 120.degree. C. The volatiles were
removed under reduced pressure and the residue was purified on
silica using a heptane to EtOac gradient yielding methyl
7-methyl-1,1-dioxo-3-(trifluoro-methyl)-2,3-dihydropyrrolo[3,4-f]thiazepi-
ne-6-carboxylate (470 mg).
[0321] Methyl
7-methyl-1,1-dioxo-3-(trifluoromethyl)-2,3-dihydropyrrolo[3,4-f]thiazepin-
e-6-carboxylate (470 mg, 1.45 mmol) and 3,4-difluoroaniline (176
.mu.L, 1.29 g/mL, 1.74 mmol) were dissolved in THF (5 mL). Lithium
bis(trimethylsilyl)amide (4.35 mL, 1 M in THF, 4.35 mmol) was added
and the reaction mixture was stirred overnight at room temperature.
The reaction mixture was quenched with NH.sub.4Cl (aq., sat., 5
mL). The organic layer was removed and the aqueous layer extracted
with DCM (2.times.5 mL). The combined organic layers were
evaporated to dryness and the residue purified via Prep HPLC
(Stationary phase: RP XBridge Prep C18 OBD-10 .mu.m, 30.times.150
mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3 solution in water, MeOH)
yielding compound 8 (28.1 mg) as a white powder. .sup.1H NMR (360
MHz, DMSO-d.sub.6) .delta. ppm 3.75 (s, 3H), 4.88 (br s, 1H), 5.80
(dd, J-12.2, 3.0 Hz, 1H), 6.77-6.83 (m, 1H), 7.41-7.49 (m, 2H),
7.73 (s, 1H), 7.81-7.89 (m, 1H), 8.64 (br d, J=10.1 Hz, 1H), 10.83
(s, 1H); Method D; Rt: 1.89 min. m/z: 420 (M-H).sup.- Exact mass:
421.1; MP: 245.6.degree. C.
Compound 9:
N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]-thiaz-
epine-6-carboxamide
##STR00063##
[0323] Methyl
3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (500 mg,
1.58 mmol) and allylamine (223 mg, 3.79 mmol) were dissolved in THF
(5 mL). Hunig's base (1.63 mL, 0.75 g/mL, 9.48 mmol) was added and
the reaction mixture was stirred overnight at room temperature.
NH.sub.4Cl (sat., aq., 5 mL) was added and the organic layer was
removed. The aqueous layer was extracted with DCM (2.times.5 mL)
and the combined organic layers were evaporated to dryness. The
residue was purified on silica using a heptane to EtOAc gradient
yielding methyl
4-(allylsulfamoyl)-3-bromo-1-methyl-pyrrole-2-carboxylate (488 mg)
as a white powder.
[0324] Methyl
4-(allylsulfamoyl)-3-bromo-1-methyl-pyrrole-2-carboxylate (430 mg,
1.28 mmol), bis(tri-tert-butylphosphine)palladium(0) (130 mg, 0.26
mmol) and TEA (177 .mu.L, 0.73 g/mL, 1.28 mmol) were dissolved in
DMF (5 mL) and heated in the microwave for 30 minutes at
140.degree. C. The reaction mixture was directly purified via Prep
HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 .mu.m,
30.times.150 mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3 solution in
water, ACN) yielding methyl
7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]thiazepine-6-carboxylate
(75 mg).
[0325] Methyl
7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]thiazepine-6-carboxylate
(75 mg, 0.29 mmol) and 3,4-difluoroaniline (36 .mu.L, 1.29 g/mL,
0.35 mmol) were dissolved in THF (5 mL). Lithium
bis(trimethylsilyl)amide (0.88 mL, 1 M in THF, 0.88 mmol) was added
and the reaction mixture was stirred overnight at room temperature.
The reaction mixture was quenched with NH.sub.4Cl (aq., sat., 5
mL). The organic layer was removed and the aqueous layer extracted
with DCM (2.times.5 mL). The combined organic layers were
evaporated to dryness and the residue purified on silica using a
heptane to EtOac gradient yielding compound 9 as a light brown
powder after crystallization from a DCM:DIPE mixture. .sup.1H NMR
(360 MHz, DMSO-d.sub.6) .delta. ppm 3.71 (s, 3H), 3.89 (ddd, J=6.4,
3.9, 1.8 Hz, 2H), 5.65 (dt, J-12.5, 4.0 Hz, 1H), 6.52 (dt, J-12.8,
1.7 Hz, 1H), 7.39-7.48 (m, 2H), 7.55 (s, 1H), 7.62 (t, J=6.5 Hz,
1H), 7.82-7.89 (m, 1H), 10.76 (s, 1H); Method B; Rt: 0.84 min. m/z:
352 (M-H).sup.- Exact mass: 353.1; MP: 221.9.degree. C.
Compound 10:
N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3-
,4-f]thiazepine-6-carboxamide
##STR00064##
[0327] Compound 7a (120 mg, 0.33 mmol) and Pd/C (10%) (35 mg, 0.033
mmol) were dispensed in MeOH (20 mL). The reaction mixture was set
under a hydrogen atmosphere and stirred for 2 hours. The reaction
mixture was filtered and evaporated to dryness yielding compound
10a (111 mg) as a white powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.13 (d, J=6.8 Hz, 3H), 1.23-1.40 (m, 1H), 1.84 (br dd,
6.5 Hz, 1H), 2.78-3.01 (m, 2H), 3.58-3.66 (m, 1H), 3.69 (s, 3H),
6.89-7.17 (m, 1H), 7.37-7.45 (m, 3H), 7.81-7.89 (m, 1H), 10.49 (br
s, 1H); Method B; Rt: 0.90 min. m/z: 368 (M-H).sup.- Exact mass:
369.1; MP: 231.6.degree. C.
[0328] Compound 10b (35.6 mg) was prepared similarly as described
for compound 10a, using compound 7b instead of compound 7a. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.13 (d, J=6.8 Hz, 3H),
1.29-1.40 (m, 1H), 1.84 (br dd, 6.5 Hz, 1H), 2.78-3.02 (m, 2H),
3.58-3.66 (m, 1H), 3.69 (s, 3H), 7.01 (br s, 1H), 7.36-7.44 (m,
3H), 7.81-7.88 (m, 1H), 10.48 (br s, 1H); Method B; Rt: 0.90 min.
m/z: 368 (M-H).sup.- Exact mass: 369.1; MP: 229.8.degree. C.
Compound 11:
N-(3,4-difluorophenyl)-3,6-dimethyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo-[3,4-
-e]thiazine-5-carboxamide
##STR00065##
[0330] Methyl
3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (2.2 g,
6.95 mmol) was dissolved in ammonia (60 mL, 0.5 M in dioxane, 30
mmol). The reaction mixture was stirred at 4 days at room
temperature. The volatiles were removed and the residue was
dissolved in 2-Me-THF and washed with water. The organic layer was
dried (MgSO.sub.4), filtered, and evaporated to dryness to afford
methyl 3-bromo-1-methyl-4-sulfamoyl-pyrrole-2-carboxylate (2 g) as
a white powder. Method B; Rt: 0.55 min. m/z: 295 (M-H).sup.- Exact
mass: 296.
[0331] A mixture of methyl
3-bromo-1-methyl-4-sulfamoyl-pyrrole-2-carboxylate (1.20 g, 3.92
mmol), pentane-2,4-dione (1.18 g, 11.8 mmol), copper(I) iodide
(74.6 mg, 0.39 mmol) and potassium phosphate tribasic (1.66 g, 7.83
mmol) in DMSO (18 mL) was stirred under a N.sub.2 atmosphere at
90.degree. C. overnight. The mixture was quenched with HCl (aq.,
1M, 20 mL), the solution was extracted with EtOAc (3.times.50 mL).
The organic layers were combined, dried over sodium sulfate and
evaporated to dryness. The brown residue was purified using silica
gel column chromatography (EtOAc in heptane from 0 to 100%) to
afford methyl
3-acetonyl-4-(acetylsulfamoyl)-1-methyl-pyrrole-2-carboxylate (1.22
g) as light brown powder. Method B; Rt: 0.41 min. m/z: 315
(M-H).sup.- Exact mass: 316.0.
[0332] Methyl
3-acetonyl-4-(acetylsulfamoyl)-1-methyl-pyrrole-2-carboxylate (1.22
g, 3.86 mmol) was dissolved in TFA and heated at reflux for 2
hours. The reaction mixture was concentrated. The residue was
dissolved in DCM (20 mL) and washed with NaHCO.sub.3(aq., sat.,
2.times.5 mL), dried (Na.sub.2SO.sub.4), filtered, the filtrate
concentrated in vacuo and the crude residue was purified using
silica gel column chromatography (EtOAc in heptane from 0 to 100%)
to afford methyl
3,6-dimethyl-1,1-dioxo-2H-pyrrolo[3,4-e]thiazine-5-carboxylate (203
mg). .sup.1H NMR (360 MHz, DMSO-d.sub.6) .delta. ppm 2.02 (d, J=1.1
Hz, 3H), 3.81 (s, 3H), 3.92 (s, 3H), 6.24 (br s, 1H), 7.86 (s, 1H),
10.52 (br s, 1H); Method B; Rt: 0.59 min. m/z: 255 (M-H).sup.-
Exact mass: 256.0. To a solution of methyl
3,6-dimethyl-1,1-dioxo-2H-pyrrolo[3,4-e]thiazine-5-carboxylate (203
mg, 0.79 mmol) and 3,4-difluoroaniline (123 mg, 0.95 mmol) in THF
(5 mL) was added lithium bis(trimethylsilyl)amide (3.17 mL, 1 M in
THF, 3.17 mmol). The reaction mixture was stirred at room
temperature for 40 minutes and quenched with NH.sub.4Cl (aq., sat.,
5 mL). The aqueous layer was extracted with DCM (3.times.50 mL).
The combined organic layers were dried (Na.sub.2SO.sub.4),
concentrated and the residue was purified on silica using a heptane
to EtOAc gradient yielding a brown powder which was triturated in
methanol. The precipitation was filtered and the solids were washed
with methanol to afford
N-(3,4-difluorophenyl)-3,6-dimethyl-1,1-dioxo-2H-pyrrolo-[3,4-e]thiazine--
5-carboxamide (33 mg) as a white powder. Method B; Rt: 0.80 min.
m/z: 354 (M+H).sup.+ Exact mass: 353.0.
[0333]
N-(3,4-difluorophenyl)-3,6-dimethyl-1,1-dioxo-2H-pyrrolo[3,4-e]thia-
zine-5-carboxamide (33 mg, 0.093 mmol) was dissolved in THF (40 mL)
and under a nitrogen atmosphere Pd/C (10%) (56 mg, 0.053 mmol) was
added. The reaction mixture was hydrogenated for 1 hour. The
reaction mixture was filtered over decalite. The filter was washed
with THF (3.times.50 mL). The filtrate was evaporated to dryness
and the residue was purified using silica gel column chromatography
(EtOAc in heptane from 0 to 100%) to afford compound 11 (18 mg) as
a white powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.26 (d, J=6.6 Hz, 3H), 2.51-2.58 (m, 1H), 2.83 (dd, 3.5 Hz, 1H),
3.55-3.70 (m, 1H), 3.77 (br s, 3H), 7.08 (br d, J=10.9 Hz, 1H),
7.37-7.46 (m, 2H), 7.61 (s, 1H), 7.77-7.85 (m, 1H), 10.15 (s, 1H);
Method B; Rt: 0.87 min. m/z: 354 (M-H).sup.- Exact mass: 355.0.
Compound 12:
N-(3,4-difluorophenyl)-7-fluoro-3-methyl-1,1-dioxo-3,4-dihydro-2H-5,1.lam-
da..sup.6,2-benzoxathiazepine-6-carboxamide
##STR00066##
[0335] Na.sub.2CO.sub.3 (2.06 g, 19.5 mmol) was dissolved in water
(30 mL). To this was added DL-alaninol (2.93 g, 39.0 mmol) at once
followed by THF (30 mL). The obtained solution was stirred and
cooled in an ice bath. 3-(chlorosulfonyl)-2,6-difluorobenzoic acid
(5.00 g, 19.5 mmol) was dissolved in THF (40 mL) and this was added
drop wise to the stirring solution. The resulting mixture was
stirred for 30 minutes while cooling was continued. Then the
mixture was stirred for 3 hours at room temperature. The mixture
was concentrated in vacuo until only water remained. Then 20 mL of
water was added and the mixture was acidified with exactly 20 mL
HCl (aq., 1M). This was extracted using 2-Me-THF (3.times.50 mL).
The combined organics were washed with brine (50 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo yielding
2,6-difluoro-3-[(2-hydroxy-1-methyl-ethyl)sulfamoyl]benzoic acid as
a yellow powder (4.9 g). Method D; Rt: 0.75 min. m/z: 294
(M-H).sup.- Exact mass: 295.0.
[0336] 2,6-difluoro-3-[(2-hydroxy-1-methyl-ethyl)sulfamoyl]benzoic
acid (1.00 g, 3.18 mmol), 3,4-difluoroaniline (623 mg, 4.78 mmol),
HATU (1.33 mg, 3.5 mmol) and DIPEA (1.65 mL, 0.75 g/mL, 9.55 mmol)
were dissolved in DMF (2 mL) and stirred at room temperature for 2
hours. This mixture was injected directly onto a silica plug and
purified using silica gel column chromatography (gradient elution:
EtOAc:heptane 0:100 to 100:0) yielding
N-(3,4-difluorophenyl)-2,6-difluoro-3-[(2-hydroxy-1-methyl-ethyl)sulfamoy-
l]benzamide (987 mg) as an oil.
[0337]
N-(3,4-difluorophenyl)-2,6-difluoro-3-[(2-hydroxy-1-methyl-ethyl)su-
lfamoyl]-benzamide (887 mg, 2.18 mmol) in DMF (8 mL) was treated
with NaH (437 mg, 60% dispersion in mineral oil, 10.9 mmol) at room
temperature and this was stirred for 2 minutes. Then it was heated
under microwave irradiation to 110.degree. C. for 40 minutes. The
reaction mixture was poured into ice water (100 mL) and this was
extracted using EtOAc (3.times.100 mL). The combined extracts were
washed with brine (100 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The crude was purified using silica gel
column chromatography (gradient elution: EtOAc:heptane 0:100 to
30:70) yielding an oil which was crystallised out of boiling
diisopropylether/acetonitrile yielding compound 12 (191 mg) as a
white powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.10
(d, J=7.04 Hz, 3H) 3.66 (dd, J-12.32, 9.68 Hz, 1H) 3.77-3.88 (m,
1H) 4.45 (dd, J-12.43, 2.31 Hz, 1H) 7.32 (t, J=8.69 Hz, 1H)
7.35-7.50 (m, 2H) 7.79-7.91 (m, 3H) 10.97 (s, 1H); Method B; Rt:
0.89 min. m/z: 387 (M+H).sup.+ Exact mass: 386.1.
Compound 13:
N-(3,4-difluorophenyl)-6-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo-[3,4-e]t-
hiazine-5-carboxamide
##STR00067##
[0339] To a solution of methyl
3-bromo-1-methyl-4-sulfamoyl-pyrrole-2-carboxylate (300 mg, 0.98
mmol) in DMF (10 mL) was added
(Z)-1-ethoxy-2-(tributylstannyl)ethene (490 .mu.L, 1.08 g/mL, 1.47
mmol). The reaction mixture was purged with nitrogen for 5 minutes
and bis(tri-tert-butylphosphine)palladium(0) (150 mg, 0.29 mmol)
was added. The reaction mixture was heated at 140.degree. C. for 20
minutes. The reaction mixture was poured into water and extracted
with EtOAc (3.times.30 mL). The combined organic layers were washed
with brine, dried (Na.sub.2SO.sub.4) and concentrated to give a
brown oil. This oil was dissolved in acetonitrile and washed with
heptane. The solution was concentrated to dryness to afford methyl
3-[(E)-2-ethoxyvinyl]-1-methyl-4-sulfamoyl-pyrrole-2-carboxylate
(707 mg) as a brown oil. Method B; Rt: 0.63 min. m/z: 289
(M+H).sup.+ Exact mass: 288.0.
[0340] Methyl
3-[(Z)-2-ethoxyvinyl]-1-methyl-4-sulfamoyl-pyrrole-2-carboxylate
(707 mg, 1.15 mmol) was dissolved TFA (5 mL) and stirred at room
temperature for 1 hour. The reaction mixture was concentrated and
dissolved in THF (50 mL) and concentrated to methyl
6-methyl-1,1-dioxo-2H-pyrrolo[3,4-e]thiazine-5-carboxylate (600 mg)
as a brown oil. Method D; Rt: 1.10 min. m/z: 243 (M+H).sup.+ Exact
mass: 242.0.
[0341] Methyl
6-methyl-1,1-dioxo-2H-pyrrolo[3,4-e]thiazine-5-carboxylate (70 mg,
0.29 mmol) was dissolved in THF (20 mL) and under a nitrogen
atmosphere Pd/C (10%) (26.4 mg, 0.025 mmol) was added. The reaction
mixture was hydrogenated for 18 hours. The reaction mixture was
filtered over decalite. The filter was washed with THF (3.times.20
mL). The combined filtrates were evaporated to dryness. The residue
was purified using silica gel column chromatography (EtOAc in
heptane from 0 to 100%) to afford methyl
6-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-e]thiazine-5-carboxylate
(73 mg) as a white powder. Method B; Rt: 0.62 min. m/z: 243
(M-H).sup.- Exact mass: 244.0.
[0342] To a solution of methyl
6-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-e]thiazine-5-carboxylate
(20 mg, 0.078 mmol) and 3,4-difluoroaniline (12.1 mg, 0.093 mmol)
in THF (2 mL) was added lithium bis(trimethylsilyl)amide (0.31 mL,
1 M in THF, 0.31 mmol). The reaction mixture was stirred at room
temperature for 30 minutes and quenched with NH.sub.4Cl (aq., sat.,
2 mL). The aqueous layer was extracted with DCM (3.times.5 mL) and
ethyl acetate (15 mL). The combined organic layers were
concentrated and the residue was purified twice on silica (EtOAc in
heptane from 0 to 100%) and via Prep HPLC (Stationary phase: RP
XBridge Prep C18 OBD-10 .mu.m, 30.times.150 mm, Mobile phase: 0.25%
NH.sub.4HCO.sub.3 solution in water, ACN) yielding compound 13 (15
mg) as a white powder. .sup.1H NMR (360 MHz, DMSO-d.sub.6) .delta.
ppm 2.72-2.79 (m, 2H), 3.42-3.50 (m, 2H), 3.78 (br s, 3H), 7.18 (br
s, 1H), 7.37-7.47 (m, 2H), 7.63 (s, 1H), 7.78-7.85 (m, 1H), 10.21
(br s, 1H); Method B; Rt: 0.82 min. m/z: 340 (M-H).sup.- Exact
mass: 341.0.
Compound 14:
N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo-[3,4-
-b][1,4,5]oxathiazepine-6-carboxamide
##STR00068##
[0344] Ethyl
4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (500 mg,
1.85 mmol), DL-alaninol (209 mg, 2.78 mmol) and Hunig's base (0.96
mL, 0.75 g/mL, 5.56 mmol) were dissolved in THF and stirred
overnight at room temperature. The formed precipitate was filtered
off and the filtrate was evaporated to dryness. The residue was
purified on silica using a heptane to EtOAc gradient yielding ethyl
3-fluoro-4-[(2-hydroxy-1-methyl-ethyl)sulfamoyl]-1-methyl-pyrrole-2-carbo-
xylate (513 mg) as a white powder.
[0345] Ethyl
3-fluoro-4-[(2-hydroxy-1-methyl-ethyl)sulfamoyl]-1-methyl-pyrrole-2-carbo-
xylate (240 mg, 0.78 mmol) and 3,4-difluoroaniline (0.094 mL, 1.29
g/mL, 0.93 mmol) were dissolved in THF (5 mL). Lithium
bis(trimethylsilyl)amide (2.34 mL, 1 M in THF, 2.34 mmol) was added
and the reaction mixture was stirred overnight at room temperature.
Lithium bis(trimethylsilyl)amide (0.5 mL, 1 M in THF, 0.5 mmol) was
added and the reaction mixture was stirred 1 hour. NH.sub.4Cl
(sat., aq., 5 mL) was added and the organic layer was removed. The
aqueous layer was extracted with DCM (2.times.5 mL) and the
combined organic layers were evaporated to dryness. The residue was
purified on silica using a heptane to EtOac gradient yielding
N-(3,4-difluoro-phenyl)-3-fluoro-4-[(2-hydroxy-1-methyl-ethyl)sulfamoyl]--
1-methyl-pyrrole-2-carboxamide (225 mg) as a white powder after
crystallization from a DCM:DIPE mixture.
[0346]
N-(3,4-difluorophenyl)-3-fluoro-4-[(2-hydroxy-1-methyl-ethyl)sulfam-
oyl]-1-methyl-pyrrole-2-carboxamide (183 mg, 0.47 mmol) and cesium
fluoride (15.5 mg, 0.94 mmol) were dispensed in DMF (3 mL). The
reaction mixture was heated in the microwave oven for 2 hours at
140.degree. C. The reaction mixture was purified via prep. HPLC
(Stationary phase: RP XBridge Prep C18 OBD-10 .mu.m, 30.times.150
mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3 solution in water, ACN)
yielding compound 14 (130 mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.10-1.20 (m, 3H), 3.78-3.86 (m, 5H), 4.51-4.59 (m,
1H), 7.36-7.48 (m, 3H), 7.61 (br s, 1H), 7.85 (ddd, J-13.1, 7.4,
2.3 Hz, 1H), 9.44 (s, 1H); Method D; Rt: 1.82 min. m/z: 372
(M+H).sup.+ Exact mass: 371.1. This racemic mixture was seperated
in enantiomers 14a (40.6 mg) and 14b (36.9 mg) by preparative SFC
(Stationary phase: Chiralpak Diacel AD 20.times.250 mm, Mobile
phase: CO.sub.2, EtOH with 0.4% iPrNH.sub.2). Method F; Rt:
14a:1.52 min, 14b: 2.14 min.
Compound 15:
(5Z)--N-(3,4-difluorophenyl)-3,8-dimethyl-1,1-dioxo-3,4-dihydro-2H-pyrrol-
o[3,4-g]thiazocine-7-carboxamide
##STR00069##
[0348] Methyl
3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (1000 mg,
3.16 mmol) and pent-4-en-2-ylamine hydrochloride (423 mg, 3.47
mmol) were dissolved in THF (5 mL). Hunig's base (1.63 mL, 0.75
g/mL, 9.48 mmol) was added and the reaction mixture was stirred
overnight at room temperature. NH.sub.4Cl (sat., aq., 5 mL) was
added and the organic layer was removed. The aqueous layer was
extracted with DCM (2.times.5 mL) and the combined organic layers
were evaporated to dryness. The residue was purified on silica
using a heptane to EtOAc gradient yielding methyl
3-bromo-1-methyl-4-(1-methylbut-3-enylsulfamoyl)pyrrole-2-carboxyl-
ate (965 mg) as a white powder.
[0349] Methyl
3-bromo-1-methyl-4-(1-methylbut-3-enylsulfamoyl)pyrrole-2-carboxylate
(97 mg, 0.28 mmol), bis(tri-tert-butylphosphine)palladium(0) (13.6
mg, 0.027 mmol) and TEA (36.8 .mu.L, 0.73 g/mL, 0.27 mmol) were
dissolved in DMF (5 mL) and heated in the microwave oven at
150.degree. C. for 30 minutes. The reaction mixture was purified
via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 .mu.m,
30.times.150 mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3 solution in
water, ACN) yielding methyl
(5Z)-3,8-dimethyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-g]thiazocine-7-car-
boxylate (41 mg).
[0350] Methyl
(5Z)-3,8-dimethyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-g]thiazocine-7-car-
boxylate (41 mg, 0.14 mmol) and 3,4-difluoroaniline (17.5 .mu.L,
1.29 g/mL, 0.17 mmol) were dissolved in THF (5 mL). Lithium
bis(trimethylsilyl)amide (433 .mu.L, 1 M in THF, 0.43 mmol) was
added and the reaction mixture was stirred overnight at room
temperature. The reaction mixture was quenched with NH.sub.4Cl
(aq., sat., 5 mL). The organic layer was removed and the aqueous
layer extracted with DCM (2.times.5 mL). The combined organic
layers were evaporated to dryness and the residue purified via Prep
HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 .mu.m,
30.times.150 mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3 solution in
water, MeOH) yielding compound 15. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.32 (d, J=7.0 Hz, 3H), 2.08-2.16 (m,
1H), 2.46 (ddd, J-13.6, 8.6, 1.8 Hz, 1H), 3.51 (quind, J=6.9, 6.9,
6.9, 6.9, 1.8 Hz, 1H), 3.92 (s, 3H), 6.08 (dt, J-11.0, 8.8 Hz, 1H),
6.77 (d, J-11.0 Hz, 1H), 7.31 (dt, J-10.4, 9.0 Hz, 1H), 7.38-7.44
(m, 2H), 7.89 (ddd, J-13.0, 7.4, 2.6 Hz, 1H); Method D; Rt: 1.78
min. m/z: 382 (M+H).sup.+ Exact mass: 381.1. This racemic mixture
was seperated in enantiomers 15a (4.7 mg) and 15b (4.2 mg) by
preparative SFC (Stationary phase: Kromasil (R,R) Whelk-O 1 10/100,
Mobile phase: CO.sub.2, MeOH+0.4 iPrNH.sub.2). Method G; Rt: 15a:
2.31 min, 15b: 2.75 min.
Compound 16:
N-(3,4-difluorophenyl)-2-isopropyl-6-methyl-1,1-dioxo-3,4-dihydropyrrolo[-
3,4-e]thiazine-5-carboxamide
##STR00070##
[0352] Methyl
6-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-e]thiazine-5-carboxylate
(40 mg, 0.11 mmol) was dissolved in DMF (1 mL) and 2-bromopropane
(17.2 .mu.L, 2.28 g/mL, 0.32 mmol) was added. The reaction mixture
was stirred at room temperature for 66 hours. The reaction mixture
was diluted with water and extracted with EtOAc (3.times.10 mL).
The combined organic layers were dried and concentrated to dryness.
The white solid was purified using silica gel column chromatography
(EtOAc in heptane from 0 to 100%) to afford methyl
2-isopropyl-6-methyl-1,1-dioxo-3,4-dihydropyrrolo[3,4-e]thiazine-5-carbox-
ylate (20 mg) as a white powder. Method B; Rt: 0.84 min. m/z: 287
(M+H).sup.+ Exact mass: 286.0.
[0353] To a solution of methyl
2-isopropyl-6-methyl-1,1-dioxo-3,4-dihydropyrrolo-[3,4-e]thiazine-5-carbo-
xylate (20 mg, 0.07 mmol) and 3,4-difluoroaniline (10.82 mg, 0.084
mmol) in THF (2 mL) was added lithium bis(trimethylsilyl)amide
(0.28 mL, 1 M in THF, 0.28 mmol) and the reaction mixture was
stirred 1 hour at room temperature. Lithium
bis(trimethylsilyl)amide (0.28 mL, 1 M in THF, 0.28 mmol) was added
and the reaction mixture was stirred 5 minutes at room temperature
and quenched with NH.sub.4Cl (aq., sat., 2 mL). The aqueous layer
was extracted with DCM (3.times.5 mL). The combined organic layers
were concentrated and the residue was purified on silica (EtOAc in
heptane from 0 to 100%) to afford a brown powder. This was
triturated in hot methanol. The white suspension was filtered to
afford compound 16 (18 mg) as an off white solid. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 1.16 (d, J=6.8 Hz, 6H), 2.83-2.90
(m, 2H), 3.58-3.65 (m, 2H), 3.78 (s, 3H), 4.09-4.21 (m, 1H),
7.36-7.46 (m, 2H), 7.63 (s, 1H), 7.77-7.83 (m, 1H), 10.08 (br s,
1H); Method B; Rt: 0.98 min. m/z: 384 (M+H).sup.+ Exact mass:
383.0.
Compound 17:
N-(3,4-difluorophenyl)-3-ethyl-6-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[-
3,4-e]thiazine-5-carboxamide
##STR00071##
[0355] Methyl
3-ethyl-6-methyl-1,1-dioxo-2H-pyrrolo[3,4-e]thiazine-5-carboxylate
was prepared similarly as described for methyl
3,6-dimethyl-1,1-dioxo-2H-pyrrolo[3,4-e]-thiazine-5-carboxylate,
using heptane-3,5-dione instead of pentane-2,4-dione. Methyl
3-ethyl-6-methyl-1,1-dioxo-2H-pyrrolo[3,4-e]thiazine-5-carboxylate
(128 mg, 0.18 mmol) was dissolved in MeOH (10 mL) and under a
nitrogen atmosphere Pd/C (10%) (20 mg, 0.018 mmol) was added. The
reaction mixture was hydrogenated for 18 hours. Pd/C (10%) (20 mg,
0.018 mmol) was added under nitrogen atmosphere. The reaction
mixture was hydrogenated for 18 hours at 50.degree. C. The reaction
mixture was filtered over decalite. The filter cake was washed with
MeOH (3.times.20 mL). The filtrate was evaporated to dryness and
the residue was purified using silica gel column chromatography
(EtOAc in heptane from 0 to 100%) to afford methyl
3-ethyl-6-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-e]thiazine-5-carbox-
ylate (20 mg). Method B; Rt: 0.74 min. m/z: 271 (M-H).sup.- Exact
mass: 272.0.
[0356] To a solution of methyl
3-ethyl-6-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo-[3,4-e]thiazine-5-carbo-
xylate (20 mg, 0.073 mmol) and 3,4-difluoroaniline (9.5 mg, 0.073
mmol) in THF (2 mL) was added lithium bis(trimethylsilyl)amide
(0.29 mL, 1 M in THF, 0.29 mmol). The reaction mixture was stirred
at room temperature for 30 minutes and quenched with NH.sub.4Cl
(aq., sat., 2 mL). The aqueous layer was extracted with DCM
(3.times.5 mL). The combined organic layers were concentrated and
the residue was purified via Prep HPLC (Stationary phase: RP
XBridge Prep C18 OBD-10 .mu.m, 30.times.150 mm, Mobile phase: 0.25%
NH.sub.4HCO.sub.3 solution in water, ACN) yielding compound 17 (4.5
mg) as an off white powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 0.96 (tt, J=7.3, 1.0 Hz, 3H), 1.54-1.63 (m, 2H),
2.45-2.55 (m, 1H), 2.80-2.92 (m, 1H), 3.16-3.44 (m, 1H), 3.77 (s,
3H), 6.92-7.05 (m, 1H), 7.37-7.46 (m, 2H), 7.60 (s, 1H), 7.77-7.84
(m, 1H), 10.09-10.19 (m, 1H); Method B; Rt: 0.91 min. m/z: 368
(M-H).sup.- Exact mass: 369.1.
Compound 18:
N-(3,4-difluorophenyl)-2,3,7-trimethyl-1,1-dioxo-3H-pyrrolo-[3,4-f]thiaze-
pine-6-carboxamide
##STR00072##
[0358] Trimethylsulfoxonium iodide (123 mg, 0.56 mmol) and
potassium tert-butoxide (58 mg, 0.52 mmol) were dissolved in DMSO
(5 mL) at 50.degree. C. Compound 7 (100 mg, 0.27 mmol) dissolved in
DMSO (5 mL) was added dropwise and the reaction mixture was stirred
overnight at 50.degree. C. Trimethylsulfoxonium iodide (123 mg,
0.56 mmol) and potassium tert-butoxide (58 mg, 0.52 mmol) were
dissolved in DMSO (5 mL) and this was added to the reaction mixture
which was stirred for another hour. The reaction mixture was
purified via prep HPLC (Stationary phase: RP XBridge Prep C18
OBD-10 .mu.m, 30.times.150 mm, Mobile phase: 0.25%
NH.sub.4HCO.sub.3 solution in water, MeOH) yielding compound 18
(23.7 mg). .sup.1H NMR (400 MHz, ACETONE-d.sub.6) .delta. ppm 1.41
(d, J=7.5 Hz, 3H), 2.53 (s, 3H), 3.86 (s, 3H), 4.88 (qt, J=7.5, 2.6
Hz, 1H), 5.40 (dd, 2.5 Hz, 1H), 6.67 (dd, J-12.5, 2.9 Hz, 1H), 7.34
(dt, J-10.4, 9.0 Hz, 1H), 7.44 (s, 1H), 7.47-7.56 (m, 1H), 7.94
(ddd, 7.5, 2.6 Hz, 1H), 9.84 (br s, 1H); Method B; Rt: 0.99 min.
m/z: 382 (M+H).sup.+ Exact mass: 381.1.
Compound 19:
N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-spiro[2,4-dihydropyrrolo-[3,4-b-
][1,4,5]oxathiazepine-3,1'-cyclopropane]-6-carboxamide
##STR00073##
[0360] Compound 19 (18.1 mg) was prepared similarly as described
for compound 14, using 1-amino-cyclopropanemethanol instead of
DL-alaninol. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.91-1.04 (m, 4H), 3.83 (s, 3H), 4.15 (s, 2H), 7.36-7.47 (m, 2H),
7.49 (s, 1H), 7.84 (ddd, 7.5, 2.2 Hz, 1H), 8.23 (s, 1H), 9.51 (s,
1H); Method B; Rt: 0.94 min. m/z: 384 (M+H).sup.+ Exact mass:
383.1.
Compound 20:
(3R)--N-(3,4-difluorophenyl)-3-ethyl-7-methyl-1,1-dioxo-3,4-dihydro-2H-py-
rrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00074##
[0362] Compound 20 (36.6 mg) was prepared similarly as described
for compound 14, using (R)-(-)-2-amino-1-butanol instead of
DL-alaninol. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.98
(t, J=7.4 Hz, 3H), 1.37-1.55 (m, 2H), 3.47-3.59 (m, 1H), 3.82 (s,
3H), 3.83-3.89 (m, 1H), 4.56-4.62 (m, 1H), 7.36-7.49 (m, 3H), 7.54
(br d, J=8.4 Hz, 1H), 7.85 (ddd, J-13.2, 7.5, 2.4 Hz, 1H), 9.43 (s,
1H); Method B; Rt: 0.99 min. m/z: 386 (M+H).sup.+ Exact mass:
385.1.
Compound 21:
N-(3,4-difluorophenyl)-3,8-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3-
,4-b][1,4,5]oxathiazocine-7-carboxamide
##STR00075##
[0364] Compound 21 (137.3 mg) was prepared similarly as described
for compound 14, using 3-aminobutan-1-ol instead of DL-alaninol.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.04 (d, J=5.9 Hz,
3H), 1.21 (d, J=6.6 Hz, 3H), 1.66-1.76 (m, 1H), 1.97-2.05 (m, 1H),
3.78-3.85 (m, 4H), 4.21 (ddd, J-11.8, 8.4, 3.2 Hz, 1H), 4.31-4.38
(m, 1H), 7.36-7.48 (m, 3H), 7.63 (d, J=9.2 Hz, 1H), 7.86 (ddd,
J-13.3, 7.4, 2.4 Hz, 1H), 9.54 (s, 1H); Method B; Rt: 0.96 min.
m/z: 386 (M+H).sup.+ Exact mass: 385.1.
Compound 22:
(3S)--N-(3,4-difluorophenyl)-3-isopropyl-7-methyl-1,1-dioxo-3,4-dihydro-2-
H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00076##
[0366] Compound 22 (46.5 mg) was prepared similarly as described
for compound 14, using (S)-(+)-2-amino-3-methyl-1-butanol instead
of DL-alaninol. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.94 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.6 Hz, 3H), 1.85 (dq, 6.8 Hz,
1H), 3.46 (br s, 1H), 3.83 (s, 3H), 3.94 (dd, J-12.7, 9.1 Hz, 1H),
4.70 (dd, J-12.5, 1.5 Hz, 1H), 7.36-7.55 (m, 4H), 7.86 (ddd,
J-13.1, 7.4, 2.5 Hz, 1H), 9.42 (s, 1H); Method B; Rt: 1.05 min.
m/z: 400 (M+H).sup.+ Exact mass: 399.1.
Compound 23: (3 S)--N-(3,4-difluorophenyl)-7-methyl-3-[(1
S)-1-methylpropyl]-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiaz-
epine-6-carboxamide
##STR00077##
[0368] Compound 23 (30.8 mg) was prepared similarly as described
for compound 14, using L-isoleucinol instead of DL-alaninol.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.87 (t, J=7.4 Hz,
3H), 0.94 (d, J=6.8 Hz, 3H), 1.22-1.33 (m, 1H), 1.46-1.56 (m, 1H),
1.56-1.65 (m, 1H), 3.53 (br s, 1H), 3.83 (s, 3H), 3.94 (dd, J-12.8,
9.0 Hz, 1H), 4.71 (d, J=11.0 Hz, 1H), 7.36-7.45 (m, 1H), 7.45-7.52
(m, 2H), 7.56 (br s, 1H), 7.86 (ddd, J-13.2, 7.4, 2.5 Hz, 1H), 9.42
(s, 1H); Method B; Rt: 1.10 min. m/z: 414 (M+H).sup.+ Exact mass:
413.1.
Compound 24:
N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-spiro[2,4-dihydropyrrolo-[3,4-b-
][1,4,5]oxathiazepine-3,3'-oxetane]-6-carboxamide
##STR00078##
[0370] Compound 24 (51.6 mg) was prepared similarly as described
for compound 14, using (3-aminooxetan-3-yl)methanol instead of
DL-alaninol. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 3.82
(s, 3H), 4.47 (d, J=6.8 Hz, 2H), 4.65 (d, J=6.8 Hz, 2H), 4.76 (s,
2H), 7.38-7.46 (m, 1H), 7.49 (s, 1H), 7.50-7.54 (m, 1H), 7.89 (ddd,
J-13.1, 7.4, 2.5 Hz, 1H), 8.47 (s, 1H), 9.46 (s, 1H); Method B; Rt:
0.88 min. m/z: 400 (M+H).sup.+ Exact mass: 399.1.
Compound 25:
(3R)--N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3-phenyl-3,4-dihydro-2H-p-
yrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00079##
[0372] Compound 25 (5 mg) was prepared similarly as described for
compound 14, using (D)-beta-aminophenethyl alcohol instead of
DL-alaninol. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 3.86
(br s, 3H), 4.15-4.26 (m, 1H), 4.74 (br d, J=11.7 Hz, 1H), 4.92 (br
d, J=9.2 Hz, 1H), 7.28-7.44 (m, 4H), 7.48 (br s, 3H), 7.58 (s, 1H),
7.85 (br s, 1H), 9.43 (br s, 1H); Method B; Rt: 1.07 min. m/z: 432
(M-H).sup.- Exact mass: 433.1.
Compound 26:
(3S)--N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3-phenyl-3,4-dihydro-2H-p-
yrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00080##
[0374] Compound 26 (8.8 mg) was prepared similarly as described for
compound 14, using (S)-(+)-2-phenylglycinol instead of DL-alaninol.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 3.86 (s, 3H), 4.20
(dd, J-12.8, 9.7 Hz, 1H), 4.74 (dd, 2.0 Hz, 1H), 4.92 (br d, J=8.1
Hz, 1H), 7.31-7.44 (m, 4H), 7.44-7.51 (m, 3H), 7.56 (s, 1H), 7.85
(ddd, 7.5, 2.4 Hz, 1H), 8.24 (br s, 1H), 9.43 (br s, 1H); Method B;
Rt: 1.07 min. m/z: 432 (M-H).sup.- Exact mass: 433.1.
Compound 27:
(3R)--N-(3,4-difluorophenyl)-3-isopropyl-7-methyl-1,1-dioxo-3,4-dihydro-2-
H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00081##
[0376] Compound 27 (22.7 mg) was prepared similarly as described
for compound 14, D-valinol instead of DL-alaninol. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 0.96 (dd, J-12.1, 6.8 Hz, 6H), 1.85
(dq, J-13.3, 6.7 Hz, 1H), 3.46 (br d, J=6.8 Hz, 1H), 3.83 (s, 3H),
3.94 (dd, J-12.8, 9.2 Hz, 1H), 4.69 (dd, 1.5 Hz, 1H), 7.36-7.54 (m,
4H), 7.86 (ddd, J-13.2, 7.4, 2.5 Hz, 1H), 9.42 (s, 1H); Method D;
Rt: 2.00 min. m/z: 400 (M+H).sup.+ Exact mass: 399.1.
Compound 28:
N-(3,4-difluorophenyl)-3,4,7-trimethyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3-
,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00082##
[0378] Compound 28 (18.1 mg) was prepared similarly as described
for compound 14, using 3-amino-2-butanol instead of DL-alaninol.
Method B; Rt: 0.94 min. m/z: 384 (M+H).sup.+ Exact mass: 383.1
Compound 29:
(*S)-3,7-dimethyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)-2,3-dihydropyrrolo[-
3,4-f]thiazepine-6-carboxamide
##STR00083##
[0380] 3-chloro-1-butene (88.1 g, 973 mmol) was added to an
overhead stirred suspension of potassium phthalimide (157 g, 848
mmol) and K.sub.2CO.sub.3 (23.5 g, 170 mmol) in DMF (1.3 L). The
reaction mixture was heated to 120.degree. C. for 5 hours. The
reaction mixture was allowed to cool to room temperature and
stirred overnight at room temperature. The reaction mixture was
quenched in ice cold water (6 L) and filtered. The filter cake was
washed with cold water (300 mL) and dried on the air for one hour
and then in the vacuum oven for 3 days yielding
2-(1-methylallyl)isoindoline-1,3-dione (148 g) as a white powder.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.51 (d, J=7.0 Hz,
3H), 4.79-4.87 (m, 1H), 5.10-5.20 (m, 2H), 6.11 (ddd, 10.5, 5.7 Hz,
1H), 7.82-7.89 (m, 4H). This racemic mixture was seperated in
enantiomers (*R)-2-(1-methylallyl)isoindoline-1,3-dione (43.6 g)
and (*S)-2-(1-methylallyl)isoindoline-1,3-dione (48 g) by
preparative Chiral HPLC (Stationary phase: Chiralpak Diacel AD
microhm 2000 gr, Mobile phase: Isocratic 100% MeOH), where *R means
first eluting enantiomer and *S means second eluting
enantiomer.
[0381] To a solution of (*S)-2-(1-methylallyl)isoindoline-1,3-dione
(5.03 g, 25 mmol) in EtOH (10 mL) was added ethanolamine (6.34 mL,
1.01 g/mL, 105 mmol). The mixture was heated at 45.degree. C. for
20 h and allowed to reach room temperature and then at 90.degree.
C. for hours. The flask was equipped with a short path distillation
apparatus and the ethanol and free amine was distilled as an
azeotrope at atmospheric pressure. The pot temperature was
120.degree. C. and the boiling point of the ethanol+amine
distillate was 80.degree. C. To the distillate (6.8 mol % in
ethanol) was added a solution of methyl
3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (5.00 g,
15.8 mmol) in DCM (100 mL) and Hunig's base (5.44 mL, 0.75 g/mL,
31.6 mmol). The reaction mixture was stirred at room temperature
for 18 h. The reaction mixture was concentrated to dryness and the
residue was dissolved in DCM (100 mL) and washed with saturated
aqueous ammonium chloride solution. The organic layer was separated
and dried (Na.sub.2SO.sub.4), filtered and concentrated to dryness.
The residue was purified using silica gel column chromatography
(EtOAc in heptane from 0 to 100%) to afford methyl
3-bromo-1-methyl-4-[[(1*S)-1-methylallyl]sulfamoyl]pyrrole-2-carboxylate
(4.08 g) as a white powder.
[0382] Compound 29 (139 mg) was prepared similarly as described for
compound 8, using methyl
3-bromo-1-methyl-4-[[(1*S)-1-methylallyl]sulfamoyl]pyrrole-2-carboxylate
instead of methyl
3-bromo-1-methyl-4-[1-(trifluoromethyl)allylsulfamoyl]pyrrole-2-carboxyla-
te and heating 5 minutes instead of 30 minutes, using
3,4,5-trifluoroaniline instead of 3,4-difluoroaniline. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.31 (d, J=7.3 Hz, 3H), 3.71
(s, 3H), 4.20-4.33 (m, 1H), 5.59 (dd, J-12.6, 2.4 Hz, 1H), 6.43
(dd, J-12.6, 2.6 Hz, 1H), 7.48-7.68 (m, 4H), 10.86 (s, 1H); Method
B; Rt: 0.97 min. m/z: 384 (M-H).sup.- Exact mass: 385.1.
Compound 30:
(*S)--N-[4-fluoro-3-(trifluoromethyl)phenyl]-3,7-dimethyl-1,1-dioxo-2,3-d-
ihydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00084##
[0384] Compound 30 (126 mg) was prepared similarly as described for
compound 29, using 4-fluoro-3-(trifluoromethyl)aniline instead of
3,4,5-trifluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.31 (d, J=7.3 Hz, 3H), 3.72 (s, 3H), 4.22-4.32 (m, 1H), 5.58
(dd, J-12.6, 2.4 Hz, 1H), 6.48 (dd, J-12.6, 2.6 Hz, 1H), 7.48-7.61
(m, 3H), 7.92-8.00 (m, 1H), 8.20 (dd, J=6.5, 2.7 Hz, 1H), 10.84 (br
s, 1H); Method B; Rt: 1.00 min. m/z: 416 (M-H).sup.- Exact mass:
417.1.
Compound 31:
(*S)--N-(4-fluoro-3-methyl-phenyl)-3,7-dimethyl-1,1-dioxo-2,3-dihydropyrr-
olo[3,4-f]thiazepine-6-carboxamide
##STR00085##
[0386] Compound 31 (106 mg) was prepared similarly as described for
compound 29, using 4-fluoro-3-methylaniline instead of
3,4,5-trifluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.31 (d, J=7.3 Hz, 3H), 2.19-2.26 (m, 3H), 3.70 (s, 3H),
4.22-4.31 (m, 1H), 5.55 (dd, J-12.5, 2.4 Hz, 1H), 6.43 (dd, J-12.6,
2.6 Hz, 1H), 7.11 (t, J=9.2 Hz, 1H), 7.37-7.79 (m, 4H), 10.50 (br
s, 1H); Method B; Rt: 0.92 min. m/z: 362 (M-H).sup.- Exact mass:
363.1.
Compound 32:
(*S)--N-(3-cyano-4-fluoro-phenyl)-3,7-dimethyl-1,1-dioxo-2,3-dihydropyrro-
lo[3,4-f]thiazepine-6-carboxamide
##STR00086##
[0388] Compound 32 (78 mg) was prepared similarly as described for
compound 29, using 5-amino-2-fluorobenzonitrile instead of
3,4,5-trifluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.31 (d, J=7.5 Hz, 3H), 3.72 (s, 3H), 4.23-4.32 (m, 1H), 5.58
(dd, J-12.6, 2.4 Hz, 1H), 6.47 (dd, J-12.6, 2.6 Hz, 1H), 7.51-7.60
(m, 3H), 7.97 (ddd, J=9.2, 4.9, 2.7 Hz, 1H), 8.19 (dd, J=5.8, 2.7
Hz, 1H), 10.86 (br s, 1H); Method B; Rt: 0.84 min. m/z: 373
(M-H).sup.- Exact mass: 374.1.
Compound 33:
(3R)--N-(3,4-difluorophenyl)-3-[(1R)-1-hydroxyethyl]-7-methyl-1,1-dioxo-3-
,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00087##
[0390] Compound 33 (44.1 mg) was prepared similarly as described
for compound 14, using L-threoninol instead of DL-alaninol. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.10 (d, J=6.4 Hz, 3H),
3.60-3.70 (m, 1H), 3.83 (s, 3H), 3.85-4.00 (m, 2H), 4.74 (d, J-11.4
Hz, 1H), 4.96 (d, J=4.6 Hz, 1H), 7.35-7.44 (m, 2H), 7.44-7.50 (m,
2H), 7.87 (ddd, 7.5, 2.4 Hz, 1H), 9.44 (s, 1H); Method B; Rt: 0.87
min. m/z: 402 (M+H).sup.+ Exact mass: 401.1.
Compound 34:
(3S)--N-(3,4-difluorophenyl)-3-[(1R)-1-hydroxyethyl]-7-methyl-1,1-dioxo-3-
,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00088##
[0392] Compound 34 (93.6 mg) was prepared similarly as described
for compound 14, using D-allo-threoninol instead of DL-alaninol.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.21 (d, J=6.2 Hz,
3H), 3.38-3.45 (m, 1H), 3.56-3.64 (m, 1H), 3.82 (s, 3H), 3.97 (dd,
J-12.5, 9.0 Hz, 1H), 4.89 (dd, J-12.8, 2.0 Hz, 1H), 5.05 (d, J=5.9
Hz, 1H), 7.36-7.44 (m, 1H), 7.44-7.49 (m, 2H), 7.61 (d, J=9.7 Hz,
1H), 7.87 (ddd, J-13.2, 7.5, 2.4 Hz, 1H), 9.42 (s, 1H); Method B;
Rt: 0.86 min. m/z: 402 (M+H).sup.+ Exact mass: 401.1.
Compound 35:
(3R)--N-(3,4-difluorophenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-3-
,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00089##
[0394] Compound 35 (68.5 mg) was prepared similarly as described
for compound 14, using L-allo-threoninol instead of DL-alaninol.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.21 (d, J=6.2 Hz,
3H), 3.35-3.44 (m, 1H), 3.60 (dt, J=8.1, 6.1 Hz, 1H), 3.82 (s, 3H),
3.97 (dd, J-12.8, 9.0 Hz, 1H), 4.89 (dd, J-12.7, 1.9 Hz, 1H), 5.04
(d, J=5.9 Hz, 1H), 7.36-7.44 (m, 1H), 7.44-7.49 (m, 2H), 7.61 (d,
J=9.7 Hz, 1H), 7.87 (ddd, 7.5, 2.4 Hz, 1H), 9.42 (s, 1H); Method B;
Rt: 0.86 min. m/z: 402 (M+H).sup.+ Exact mass: 401.1.
Compound 36:
(3R)--N-(3,4-difluorophenyl)-3-[(R)-hydroxy(phenyl)methyl]-7-methyl-1,1-d-
ioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00090##
[0396] Compound 36 (81.4 mg) was prepared similarly as described
for compound 14, using (1R,2R)-(-)-2-amino-1-phenyl-1,3-propanediol
instead of DL-alaninol. Method B; Rt: 1.00 min. m/z: 464
(M+H).sup.+ Exact mass: 463.1
Compound 37:
(3S)--N-(3,4-difluorophenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-3-
,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00091##
[0398] Compound 37 (105.5 mg) was prepared similarly as described
for compound 14, using D-threoninol instead of DL-alaninol. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.10 (d, J=6.4 Hz, 3H),
3.61-3.70 (m, 1H), 3.82 (s, 3H), 3.85-3.99 (m, 2H), 4.74 (d, J-11.4
Hz, 1H), 4.96 (d, J=4.6 Hz, 1H), 7.36-7.44 (m, 2H), 7.44-7.50 (m,
2H), 7.87 (ddd, 7.5, 2.6 Hz, 1H), 9.44 (s, 1H); Method B; Rt: 0.87
min. m/z: 402 (M+H).sup.+ Exact mass: 401.1.
Compound 38:
(3S)--N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3-(3-pyridylmethyl)-3,4-d-
ihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00092##
[0400] Compound 38 (7.1 mg) was prepared similarly as described for
compound 14, using (2S)-2-amino-3-(3-pyridyl)propan-1-ol instead of
DL-alaninol. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
2.86-3.10 (m, 2H), 3.94 (s, 3H), 4.13 (br s, 1H), 4.36 (dd, J-13.0,
9.0 Hz, 1H), 4.66 (dd, J-12.9, 3.0 Hz, 1H), 5.35 (br s, 1H), 7.03
(s, 1H), 7.06-7.16 (m, 2H), 7.27-7.34 (m, 1H), 7.61-7.70 (m, 2H),
8.45 (d, J=1.5 Hz, 1H), 8.51 (dd, J=4.8, 1.5 Hz, 1H), 8.66 (s, 1H);
Method B; Rt: 0.91 min. m/z: 449 (M+H).sup.+ Exact mass: 448.1.
Compound 39:
(3*S)-3,7-dimethyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)-2,3,4,5-tetrahydro-
pyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00093##
[0402] Compound 39 (41 mg) was prepared similarly as described for
compound 10, using compound 29 instead of compound 7. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.13 (d, J=6.8 Hz, 3H), 1.34
(q, J=12.2 Hz, 1H), 1.84 (br dd, J-14.0, 6.4 Hz, 1H), 2.78-2.99 (m,
1H), 3.57-3.66 (m, 1H), 3.69 (s, 3H), 7.03 (d, J=9.6 Hz, 1H), 7.44
(s, 1H), 7.54-7.66 (m, 1H), 10.59 (s, 1H); Method B; Rt: 0.91 min.
m/z: 386 (M-H).sup.- Exact mass: 387.1.
Compound 40:
(3*S)--N-[4-fluoro-3-(trifluoromethyl)phenyl]-3,7-dimethyl-1,1-dioxo-2,3,-
4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00094##
[0404] Compound 40 (49 mg) was prepared similarly as described for
compound 10, using compound 30 instead of compound 7. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.13 (d, J=6.8 Hz, 3H),
1.27-1.41 (m, 1H), 1.81-1.88 (m, 1H), 2.80-2.89 (m, 1H), 2.94-3.02
(m, 1H), 3.59-3.67 (m, 1H), 3.69 (s, 3H), 7.02 (d, J=9.6 Hz, 1H),
7.43 (s, 1H), 7.51 (t, J=9.8 Hz, 1H), 7.91-7.96 (m, 1H), 8.20 (dd,
J=6.6, 2.7 Hz, 1H), 10.58 (s, 1H); Method B; Rt: 1.01 min. m/z: 418
(M-H).sup.- Exact mass: 419.1.
Compound 41:
(3*S)--N-(4-fluoro-3-methyl-phenyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrah-
ydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00095##
[0406] Compound 41 (52 mg) was prepared similarly as described for
compound 10, using compound 31 instead of compound 7. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.13 (d, J=6.8 Hz, 3H), 1.35
(q, J=12.3 Hz, 1H), 1.84 (br dd, J=14.0, 6.4 Hz, 1H), 2.20-2.24 (m,
3H), 2.78-2.98 (m, 2H), 3.59-3.73 (m, 4H), 7.00 (d, J=9.5 Hz, 1H),
7.10 (t, J=9.2 Hz, 1H), 7.39 (s, 1H), 7.45-7.52 (m, 1H), 7.62 (dd,
J=7.1, 2.7 Hz, 1H), 10.23 (s, 1H); Method B; Rt: 0.92 min. m/z: 364
(M-H).sup.- Exact mass: 365.1.
Compound 42:
(3*S)-3,7-dimethyl-1,1-dioxo-N-[2-(trifluoromethyl)-4-pyridyl]-2,3-dihydr-
opyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00096##
[0408] Compound 42 (115 mg) was prepared similarly as described for
compound 29, using 4-amino-2-trifluoromethylpyridine instead of
3,4,5-trifluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.32 (d, J=7.3 Hz, 3H), 3.74 (s, 3H), 4.22-4.34 (m, 1H), 5.61
(dd, J=12.6, 2.4 Hz, 1H), 6.49 (dd, J=12.6, 2.6 Hz, 1H), 7.56-7.63
(m, 2H), 7.89 (dd, J=5.5, 2.0 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 8.67
(d, J=5.5 Hz, 1H), 11.21 (br s, 1H); Method B; Rt: 0.86 min. m/z:
401 (M+H).sup.+ Exact mass: 400.1.
Compound 43:
N-(3,4-difluorophenyl)-7-methyl-3-(1-methylpyrazol-4-yl)-1,1-dioxo-3,4-di-
hydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00097##
[0410] Compound 43 (53.6 mg) was prepared similarly as described
for compound 14, using 2-amino-2-(1-methyl-1
h-pyrazol-4-yl)ethan-1-ol instead of DL-alaninol. The ring closure
was obtained after heating overnight at 140.degree. C. in DMA and
compound 43 was purified using a heptane to EtOAc:EtOH 3:1
gradient. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 3.81 (s,
3H), 3.84 (s, 3H), 3.98-4.11 (m, 1H), 4.72 (dd, J=12.5, 2.2 Hz,
1H), 4.86 (td, J=9.6, 1.9 Hz, 1H), 7.36-7.44 (m, 1H), 7.44-7.51 (m,
2H), 7.53 (s, 1H), 7.72 (s, 1H), 7.82-7.89 (m, 1H), 8.02 (d, J=9.7
Hz, 1H), 9.46 (s, 1H); Method B; Rt: 0.90 min. m/z: 438 (M+H).sup.+
Exact mass: 437.1.
Compound 44:
(3S)--N-(3,4-difluorophenyl)-7-fluoro-3-isopropyl-1,1-dioxo-3,4-dihydro-2-
H-5,1.lamda..sup.6,2-benzoxathiazepine-6-carboxamide
##STR00098##
[0412] Compound 44 (11.5 mg) was prepared similarly as described
for compound 12, using L-valinol instead of DL-alaninol. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.94 (dd, J=6.71, 1.65 Hz,
6H) 1.80 (dq, J=13.70, 6.80 Hz, 1H) 3.43-3.56 (m, 1H) 3.80 (dd,
J=12.43, 10.01 Hz, 1H) 4.55 (dd, J=12.54, 2.20 Hz, 1H) 7.31 (t,
J=8.69 Hz, 1H) 7.35-7.51 (m, 2H) 7.70 (br d, J=8.58 Hz, 1H)
7.80-7.92 (m, 2H) 10.98 (s, 1H); Method B; Rt: 1.03 min. m/z: 413
(M-H).sup.- Exact mass: 414.1.
Compound 45:
(3S)--N-(3-cyano-4-fluoro-phenyl)-7-fluoro-3-isopropyl-1,1-dioxo-3,4-dihy-
dro-2H-5,1.lamda..sup.6,2-benzoxathiazepine-6-carboxamide
##STR00099##
[0414] Compound 45 (378.5 mg) was prepared similarly as described
for compound 44, using 5-amino-2-fluorobenzonitrile instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 0.94 (dd, J=6.82, 2.20 Hz, 6H) 1.80 (dq, J=13.78, 6.78 Hz, 1H)
3.48 (br s, 1H) 3.80 (dd, J=12.54, 10.12 Hz, 1H) 4.56 (dd, J=12.54,
2.20 Hz, 1H) 7.33 (t, J=8.69 Hz, 1H) 7.56 (t, J=9.13 Hz, 1H) 7.70
(br s, 1H) 7.85-7.98 (m, 2H) 8.20 (dd, J=5.72, 2.64 Hz, 1H) 11.14
(s, 1H); Method B; Rt: 0.98 min. m/z: 420 (M-H).sup.- Exact mass:
421.1.
Compound 46:
(3R)-7-fluoro-N-(3-fluoro-4-methyl-phenyl)-3-isopropyl-1,1-dioxo-3,4-dihy-
dro-2H-5,1.lamda..sup.6,2-benzoxathiazepine-6-carboxamide
##STR00100##
[0416] Compound 46 (155.1 mg) was prepared similarly as described
for compound 44, using 4-fluoro-3-methylaniline instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 0.94 (dd, J=6.82, 1.98 Hz, 6H) 1.80 (dq, J=13.78, 6.78 Hz, 1H)
2.24 (d, J=1.54 Hz, 3H) 3.41-3.60 (m, 1H) 3.80 (dd, J=12.32, 9.90
Hz, 1H) 4.53 (dd, J=12.54, 2.20 Hz, 1H) 7.13 (t, J=9.24 Hz, 1H)
7.29 (t, J=8.58 Hz, 1H) 7.40-7.52 (m, 1H) 7.63 (dd, J=6.93, 2.53
Hz, 1H) 7.68 (br d, J=7.48 Hz, 1H) 7.87 (dd, J=8.80, 6.38 Hz, 1H)
10.70 (s, 1H); Method B; Rt: 1.04 min. m/z: 409 (M-H).sup.- Exact
mass: 410.1.
Compound 47:
N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3-(trifluoromethyl)-2,3,4,5-tet-
rahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00101##
[0418] 1,1,1-trifluorobut-3-en-2-ylamine (306 mg, 1.90 mmol) was
dissolved in pyridine (5 mL). Methyl
3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (500 mg,
1.58 mmol) was added and the mixture stirred at room temperature
for 16 hours. The reaction mixture was filtered and the filtrate
was evaporated to dryness. The residue was purified by column
chromatography using a gradient from 0 till 50% EtOAc in heptane
over 15 column volumes. The product fractions were concentrated in
vacuum to yield methyl
3-bromo-1-methyl-4-[1-(trifluoromethyl)allylsulfamoyl]pyrrole-2-carboxyla-
te (385 mg) as a white powder. Method D; Rt: 1.74 min. m/z: 405
(M+H).sup.+ Exact mass: 404.0.
[0419] Methyl
3-bromo-1-methyl-4-[1-(trifluoromethyl)allylsulfamoyl]pyrrole-2-carboxyla-
te (385 mg), bis(tri-tert-butylphosphine)palladium(0) (211 mg, 0.41
mmol) and trimethylamine (286 .mu.L, 2.07 mmol) were dissolved in
DMF (5 mL). The reaction mixture was heated in the microwave oven
for 30 minutes at 120.degree. C. The volatiles were removed under
reduced pressure and the residue was purified by column
chromatography using a gradient from 0 till 50% EtOAc in heptane
over 15 column volumes. The product fractions were concentrated in
vacuo to yield methyl
7-methyl-1,1-dioxo-3-(trifluoromethyl)-2,3-dihydropyrrolo[3,4-f]thiazepin-
e-6-carboxylate (152 mg) as a white solid. Method D; Rt: 1.64 min.
m/z: 405 (M+H).sup.+ Exact mass: 404.0.
[0420] Methyl
7-methyl-1,1-dioxo-3-(trifluoromethyl)-2,3-dihydropyrrolo[3,4-f]thiazepin-
e-6-carboxylate (152 mg) and Pd/C (10%) (50 mg, 0.047 mmol) were
dispensed in MeOH (50 mL). The reaction mixture was set under a
hydrogen atmosphere and stirred for 2 hours. The reaction mixture
was filtered and the volatiles were removed under reduced pressure
yielding methyl
7-methyl-1,1-dioxo-3-(trifluoromethyl)-2,3,4,5-tetrahydropyrrolo[3,4-f]th-
iazepine-6-carboxylate (153 mg) as a white powder.
[0421] Methyl
7-methyl-1,1-dioxo-3-(trifluoromethyl)-2,3,4,5-tetrahydropyrrolo-[3,4-f]t-
hiazepine-6-carboxylate (153 mg) and 3,4-difluoroaniline (57 .mu.L,
0.56 mmol) were dissolved in THF (10 mL). Lithium
bis(trimethylsilyl)amide (1.41 mL, 1 M in THF, 1.41 mmol) was added
and the reaction mixture was stirred 4 hours at room temperature.
NH.sub.4Cl (sat., aq., 5 mL) was added and the organic layer was
removed. The aqueous layer was extracted with DCM (2.times.5 mL)
and the combined organic layers were evaporated to dryness. The
residue was purified via prep. HPLC (Stationary phase: RP XBridge
Prep C18 OBD-10 .mu.m, 30.times.150 mm, mobile phase: 0.25%
NH.sub.4HCO.sub.3 solution in water, MeOH) compound 47 (73 mg) as a
white powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.58-1.69 (m, 1H), 2.11 (br dd, J=13.8, 6.3 Hz, 1H), 2.84-2.95 (m,
1H), 3.12 (br dd, J=15.6, 6.2 Hz, 1H), 3.70 (s, 3H), 4.18-4.31 (m,
1H), 7.37-7.50 (m, 2H), 7.54 (s, 1H), 7.79-7.88 (m, 1H), 8.04 (d,
J=10.4 Hz, 1H), 10.54 (s, 1H); Method D; Rt: 1.82 min. m/z: 422
(M-H).sup.- Exact mass: 423.1.
Compound 48:
(3R)--N-(3,4-difluorophenyl)-7-fluoro-3-isopropyl-1,1-dioxo-3,4-dihydro-2-
H-5,1.lamda..sup.6,2-benzoxathiazepine-6-carboxamide
##STR00102##
[0423] Compound 48 (75.5 mg) was prepared similarly as described
for compound 12, using D-valinol instead of DL-alaninol. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.94 (dd, J=6.71, 1.87 Hz,
6H) 1.66-1.94 (m, 1H) 3.48 (br t, J=7.59 Hz, 1H) 3.80 (dd, J=12.43,
10.01 Hz, 1H) 4.55 (dd, J=12.54, 2.20 Hz, 1H) 7.23-7.35 (m, 1H)
7.36-7.51 (m, 2H) 7.70 (s, 1H) 7.79-7.94 (m, 2H) 10.97 (s, 1H);
Method B; Rt: 1.02 min. m/z: 413 (M-H).sup.- Exact mass: 414.1.
Compound 49:
(3R)--N-(3-cyano-4-fluoro-phenyl)-7-fluoro-3-isopropyl-1,1-dioxo-3,4-dihy-
dro-2H-5,1.lamda..sup.6,2-benzoxathiazepine-6-carboxamide
##STR00103##
[0425] Compound 49 (39.7 mg) was prepared similarly as described
for compound 48, using 5-amino-2-fluorobenzonitrile instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 0.94 (dd, J=6.82, 2.20 Hz, 6H) 1.80 (dq, J=13.64, 6.82 Hz, 1H)
3.43-3.54 (m, 1H) 3.81 (dd, J=12.43, 10.01 Hz, 1H) 4.56 (dd,
J=12.54, 2.20 Hz, 1H) 7.32 (t, J=8.58 Hz, 1H) 7.56 (t, J=9.13 Hz,
1H) 7.71 (br s, 1H) 7.84-8.04 (m, 2H) 8.20 (dd, J=5.61, 2.75 Hz,
1H) 11.15 (br s, 1H); Method B; Rt: 0.97 min. m/z: 420 (M-H).sup.-
Exact mass: 421.1.
Compound 50:
(3*S)--N-(2-bromo-4-pyridyl)-3,7-dimethyl-1,1-dioxo-2,3-dihydropyrrolo[3,-
4-f]thiazepine-6-carboxamide
##STR00104##
[0427] Compound 50 (42 mg) was prepared similarly as described for
compound 29, using 4-amino-2-bromopyridine instead of
3,4,5-trifluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.31 (d, J=7.5 Hz, 3H), 3.72 (s, 3H), 4.19-4.33 (m, 1H), 5.61
(dd, J=12.5, 2.4 Hz, 1H), 6.45 (dd, J=12.8, 2.6 Hz, 1H), 7.55-7.60
(m, 2H), 7.63 (dd, J=5.6, 1.9 Hz, 1H), 7.96 (d, J=1.8 Hz, 1H), 8.29
(d, J=5.6 Hz, 1H), 11.05 (s, 1H); Method D; Rt: 1.52 min. m/z: 411
(M+H).sup.+ Exact mass: 410.0.
Compound 51:
(3*S)--N-[3-(difluoromethyl)-4-fluoro-phenyl]-3,7-dimethyl-1,1-dioxo-2,3--
dihydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00105##
[0429] Compound 51 (46 mg) was prepared similarly as described for
compound 29, using 3-(difluoromethyl)-4-fluoro-aniline instead of
3,4,5-trifluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.31 (d, J=7.5 Hz, 3H), 3.71 (s, 3H), 4.20-4.33 (m, 1H), 5.57
(dd, J=12.5, 2.4 Hz, 1H), 6.46 (dd, J=12.6, 2.6 Hz, 1H), 7.23 (br
t, J=54.4 Hz, 1H), 7.38 (t, J=9.6 Hz, 1H), 7.51-7.58 (m, 2H),
7.77-7.87 (m, 1H), 8.06 (dd, J=6.3, 2.7 Hz, 1H), 10.75 (s, 1H);
Method B; Rt: 0.90 min. m/z: 398 (M-H).sup.- Exact mass: 399.1.
Compound 52:
(3*S)--N-(3-chloro-2,4-difluoro-phenyl)-3,7-dimethyl-1,1-dioxo-2,3-dihydr-
opyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00106##
[0431] Compound 52 (40 mg) was prepared similarly as described for
compound 29, using 3-chloro-2,4-difluoroaniline instead of
3,4,5-trifluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.31 (d, J=7.5 Hz, 3H), 3.73 (s, 3H), 4.20-4.33 (m, 1H), 5.60
(dd, J=12.5, 2.4 Hz, 1H), 6.58 (dd, J=12.7, 2.5 Hz, 1H), 7.36 (td,
J=9.0, 2.0 Hz, 1H), 7.55 (s, 1H), 7.57 (d, J=9.3 Hz, 1H), 7.64 (td,
J=8.7, 5.8 Hz, 1H), 10.45 (br s, 1H); Method B; Rt: 0.93 min. m/z:
400 (M-H).sup.- Exact mass: 401.0.
Compound 53:
(3*S)-3,7-dimethyl-1,1-dioxo-N-[2-(trifluoromethyl)-4-pyridyl]-2,3,4,5-te-
trahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00107##
[0433] To a solution of methyl
3-bromo-1-methyl-4-[[(1*S)-1-methylallyl]sulfamoyl]pyrrole-2-carboxylate
(3.5 g, 10 mmol) in DMA (200 mL), in a pressure tube, purged with
nitrogen, was added Hunig's base (1.89 mL, 0.75 g/mL, 11.0 mmol)
and bis(tri-tert-butylphosphine)palladium(0) (0.76 g, 1.49 mmol).
The reaction mixture was heated for 10 minutes at 140.degree. C.
The reaction mixture was poured into HCL (aq., 0.5 M, 150 mL). The
resulting suspension was extracted with ethyl acetate (3.times.100
mL). The combined organic layers were dried (Na.sub.2SO.sub.4),
concentrated and the residue (8 g) was purified using silica gel
column chromatography (ethyl acetate in heptane from 0 to 40%). The
desired fractions were combined and concentrated. This was purified
via preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10
.mu.m, 30.times.150 mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3
solution in water, MeOH) yielding methyl
(3*S)-3,7-dimethyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]thiazepine-6-
-carboxylate (640 mg) as a white powder. Method B; Rt: 0.74 min.
m/z: 269 (M-H).sup.- Exact mass: 270.1.
[0434] Methyl
(3*S)-3,7-dimethyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]thiazepine-6-carbox-
ylate (400 mg, 1.48 mmol) was dissolved in MeOH (40 mL). Under a
nitrogen atmosphere Pd/C (10%) (157 mg, 0.15 mmol) was added. The
reaction mixture was hydrogenated for 30 minutes. The reaction
mixture was filtered over decalite. The filtrate was evaporated to
dryness to afford methyl
(35)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6--
carboxylate (360 mg) as a white powder.
[0435] To a solution of methyl
(3S)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo-[3,4-f]thiazepine-6-
-carboxylate (72 mg) and 4-amino-2-trifluoromethylpyridine (51 mg,
0.32 mmol in THF (5 mL) was added lithium bis(trimethylsilyl)amide
(1.06 mL, 1 M in THF, 1.06 mmol) and the reaction mixture was
stirred 1 hour at room temperature. NH.sub.4Cl (sat., aq., 5 mL)
was added and the organic layer was separated. The aqueous layer
was extracted with DCM (2.times.5 mL) and the combined organic
layers were evaporated to dryness. The residue was purified via
prep. HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 .mu.m,
30.times.150 mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3 solution in
water, ACN) yielding compound 53 (60 mg) as a white powder. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.13 (d, J=6.8 Hz, 3H),
1.29-1.42 (m, 1H), 1.79-1.89 (m, 1H), 2.80-2.91 (m, 1H), 2.94-3.05
(m, 1H), 3.56-3.67 (m, 1H), 3.71 (s, 3H), 7.04 (d, J=9.6 Hz, 1H),
7.47 (s, 1H), 7.86 (dd, J=5.6, 2.0 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H),
8.64 (d, J=5.5 Hz, 1H), 10.94 (br s, 1H); Method D; Rt: 1.63 min.
m/z: 403 (M+H).sup.+ Exact mass: 402.1.
Compound 54:
(3*S)--N-(3-chloro-2,4-difluoro-phenyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-te-
trahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00108##
[0437] Compound 54 (24 mg) was prepared similarly as described for
compound 53, using 3-chloro-2,4-difluoroaniline instead of
4-amino-2-trifluoromethylpyridine. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.14 (d, J=6.8 Hz, 3H), 1.38 (q, J=12.4
Hz, 1H), 1.87 (br dd, J=14.1, 6.6 Hz, 1H), 2.76-2.89 (m, 1H), 3.12
(br dd, J=15.5, 6.6 Hz, 1H), 3.56-3.68 (m, 1H), 3.69 (s, 3H), 7.02
(d, J=9.6 Hz, 1H), 7.35 (td, J=9.0, 2.0 Hz, 1H), 7.42 (s, 1H), 7.65
(td, J=8.8, 5.8 Hz, 1H), 10.18 (br s, 1H); Method B; Rt: 0.94 min.
m/z: 402 (M-H).sup.- Exact mass: 403.1.
Compound 55:
(3*S)--N-[3-(difluoromethyl)-4-fluoro-phenyl]-3,7-dimethyl-1,1-dioxo-2,3,-
4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00109##
[0439] Compound 55 (55 mg) was prepared similarly as described for
compound 53, using 3-(difluoromethyl)-4-fluoro-aniline instead of
4-amino-2-trifluoromethylpyridine .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.13 (d, J=6.8 Hz, 3H), 1.36 (q, J=12.3
Hz, 1 H), 1.85 (br dd, J=13.9, 6.4 Hz, 1H), 2.76-2.90 (m, 1H),
2.92-3.02 (m, 1H), 3.57-3.74 (m, 4H), 7.01 (d, J=9.6 Hz, 1H), 7.22
(t, J=54.4 Hz, 1H), 7.33-7.40 (m, 1H), 7.41 (s, 1H), 7.74-7.86 (m,
1H), 8.06 (dd, J=6.4, 2.7 Hz, 1H), 10.48 (s, 1H); Method B; Rt:
0.91 min. m/z: 400 (M-H).sup.- Exact mass: 401.1.
Compound 56:
(3*S)--N-(3-cyano-4-fluoro-phenyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahy-
dropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00110##
[0441] Compound 56 (53 mg) was prepared similarly as described for
compound 53, using 5-amino-2-fluorobenzonitrile instead of
4-amino-2-trifluoromethylpyridine. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.13 (d, J=6.8 Hz, 3H), 1.35 (br q,
J=12.5 Hz, 1H), 1.84 (br dd, J=14.1, 6.4 Hz, 1H), 2.78-2.89 (m,
1H), 2.92-3.02 (m, 1H), 3.56-3.66 (m, 1H), 3.69 (s, 3H), 7.02 (d,
J=9.5 Hz, 1H), 7.43 (s, 1H), 7.53 (t, J=9.1 Hz, 1H), 7.95 (ddd,
J=9.2, 4.9, 2.7 Hz, 1H), 8.19 (dd, J=5.8, 2.7 Hz, 1H), 10.59 (s,
1H); Method B; Rt: 0.84 min. m/z: 375 (M-H).sup.- Exact mass:
376.1.
Compound 57:
(3*S)--N-(2-bromo-4-pyridyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyr-
rolo[3,4-f]thiazepine-6-carboxamide
##STR00111##
[0443] Compound 57 (25 mg) was prepared similarly as described for
compound 53, using 4-amino-2-bromopyridine instead of
4-amino-2-trifluoromethylpyridine. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.13 (d, J=6.8 Hz, 3H), 1.35 (q, J=12.3
Hz, 1H), 1.79-1.91 (m, 1H), 2.79-2.89 (m, 1H), 2.91-3.00 (m, 1H),
3.55-3.67 (m, 1H), 3.70 (s, 3H), 7.04 (d, J=9.6 Hz, 1H), 7.46 (s,
1H), 7.61 (dd, J=5.6, 1.9 Hz, 1H), 7.95 (d, J=1.8 Hz, 1H), 8.27 (d,
J=5.6 Hz, 1H), 10.78 (s, 1H); Method B; Rt: 0.84 min. m/z: 411
(M-H).sup.- Exact mass: 412.0.
Compound 58:
7-methyl-1,1-dioxo-3-(trifluoromethyl)-N-[2-(trifluoromethyl)-4-pyridyl]--
2,3-dihydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00112##
[0445] Methyl
7-methyl-1,1-dioxo-3-(trifluoromethyl)-2,3-dihydropyrrolo[3,4-f]thiazepin-
e-6-carboxylate (200 mg) and 4-amino-2-trifluoromethylpyridine (102
mg, 0.62 mmol) were dissolved in THF (4 mL). Lithium
bis(trimethylsilyl)amide (1.85 mL, 1 M in THF, 1.85 mmol) was added
dropwise to the reaction mixture and stirred at room temperature
for 2 hours. The reaction was quenched with NH.sub.4Cl (sat., aq.,
5 mL) and the organic layer was separated, dried (MgSO.sub.4),
filtered and concentrated in vacuum. The residue was purified via
prep. HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 .mu.m,
30.times.150 mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3 solution in
water, ACN) yielding compound 58 (10 mg). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 3.78 (s, 3H), 4.89 (br dd, J=11.1, 8.2
Hz, 1H), 5.82 (dd, J=12.2, 3.0 Hz, 1H), 6.86 (dd, J=12.2, 2.7 Hz,
1H), 7.79 (s, 1H), 7.89 (dd, J=5.5, 2.0 Hz, 1H), 8.20 (d, J=1.9 Hz,
1H), 8.67 (d, J=5.2 Hz, 1H), 8.69 (s, 1H), 11.27-11.32 (m, 1H);
Method D; Rt: 1.76 min. m/z: 455 (M+H).sup.+ Exact mass: 454.1.
Compound 59:
7-methyl-1,1-dioxo-3-(trifluoromethyl)-N-[2-(trifluoromethyl)-4-pyridyl]--
2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00113##
[0447] Compound 59 (118 mg) was prepared similarly as described for
compound 47, using 4-amino-2-trifluoromethylpyridine instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.64 (q, J=12.2 Hz, 1H), 2.06-2.15 (m, 1H), 2.87-2.98 (m, 1H),
3.13-3.29 (m, 1H), 3.68-3.80 (m, 3H), 4.20-4.32 (m, 1H), 7.61 (s,
1H), 7.87 (dd, J=5.5, 2.0 Hz, 1H), 8.07 (br d, J=9.9 Hz, 1H), 8.19
(d, J=2.0 Hz, 1H), 8.66 (d, J=5.5 Hz, 1H), 11.03 (s, 1H); Method D;
Rt: 1.75 min. m/z: 457 (M+H).sup.+ Exact mass: 456.1. This racemic
mixture was seperated in enantiomers 59a and 59b by preparative SFC
(Stationary phase: Chiralpak Diacel AD 20.times.250 mm, Mobile
phase: CO.sub.2, EtOH with 0.4% iPrNH.sub.2). Method H; Rt:
59a:1.65 min, 59b: 2.36 min.
Compound 60:
N-(3-cyano-4-fluoro-phenyl)-7-methyl-1,1-dioxo-3-(trifluoromethyl)-2,3,4,-
5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00114##
[0449] Compound 60 (139 mg) was prepared similarly as described for
compound 47, using 5-amino-2-fluorobenzonitrile instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.59-1.70 (m, 1H), 2.06-2.16 (m, 1H), 2.84-2.96 (m, 1H),
3.10-3.21 (m, 1H), 3.66-3.78 (m, 3H), 4.19-4.32 (m, 1H), 7.51-7.58
(m, 2H), 7.96 (ddd, J=9.2, 4.8, 2.6 Hz, 1H), 8.05 (d, J=10.3 Hz,
1H), 8.19 (dd, J=5.8, 2.7 Hz, 1H), 10.61-10.71 (m, 1H); Method D;
Rt: 1.73 min. m/z: 429 (M-H).sup.- Exact mass: 430.1. This racemic
mixture was seperated in enantiomers 60a and 60b by preparative SFC
(Stationary phase: Chiralpak Diacel AD 20.times.250 mm, Mobile
phase: CO.sub.2, EtOH with 0.4% iPrNH.sub.2). Method I; Rt:
60a:1.16 min, 60b: 1.61 min.
Compound 61:
(3S)--N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3-(trifluoromethyl)-3,4-d-
ihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00115##
[0451] Ethyl
4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (250 mg)
and (2S)-2-amino-3,3,3-trifluoropropan-1-ol hydrochloride (153 mg,
0.93 mmol) were dissolved in pyridine (2 mL) and stirred overnight
at room temperature. The volatiles were removed under reduced
pressure and the residue was purified on silica using a heptane to
EtOAc gradient yielding ethyl
3-fluoro-1-methyl-4-[[(1S)-2,2,2-trifluoro-1-(hydroxymethyl)ethyl]sulfamo-
yl]pyrrole-2-carboxylate (254 mg).
[0452] Ethyl
3-fluoro-1-methyl-4-[[(1S)-2,2,2-trifluoro-1-(hydroxymethyl)ethyl]sulfamo-
yl]-pyrrole-2-carboxylate (254 mg) and 3,4-difluoroaniline (0.071
mL, 0.7 mmol) were dissolved in THF (5 mL). Lithium
bis(trimethylsilyl)amide (2.8 mL, 1 M in THF, 2.8 mmol) was added
and the reaction mixture was stirred overnight at room temperature.
NH.sub.4Cl (sat., aq., 50 mL) was added and the organic layer was
removed.
[0453] The aqueous layer was extracted with DCM (2.times.5 mL) and
the combined organic layers were evaporated to dryness. The residue
was purified on silica using a heptane to EtOAc:EtOH 3:1 gradient
yielding
N-(3,4-difluorophenyl)-3-fluoro-1-methyl-4-[[(1S)-2,2,2-trifluoro-1-(hydr-
oxymethyl)ethyl]sulfamoyl]pyrrole-2-carboxamide (198 mg). Method B;
Rt: 0.91 min. m/z: 446 (M+H).sup.+ Exact mass: 445.1.
[0454] N-(3,4-difluorophenyl)-3-fluoro-1-methyl-4-[[(1S)-2,2,2-tri
fluoro-1-(hydroxymethyl)-ethyl]sulfamoyl]pyrrole-2-carboxamide (198
mg) and cesium fluoride (173 mg, 1.14 mmol) were dissolved in DMF
(5 mL) and heated overnight at 100.degree. C. The reaction mixture
was purified via prep. HPLC (Stationary phase: RP XBridge Prep C18
OBD-10 .mu.m, 30.times.150 mm, Mobile phase: 0.25%
NH.sub.4HCO.sub.3 solution in water, ACN) yielding compound 61 as a
white powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 3.83
(s, 3H), 4.29 (dd, J=12.7, 9.4 Hz, 1H), 4.49-4.62 (m, 1H), 4.91
(dd, J=13.0, 2.0 Hz, 1H), 7.37-7.46 (m, 1H), 7.46-7.52 (m, 1H),
7.58 (s, 1H), 7.86 (ddd, J=13.2, 7.5, 2.4 Hz, 1H), 8.75 (br s, 1H),
9.47 (s, 1H); Method B; Rt: 0.99 min. m/z: 426 (M+H).sup.+ Exact
mass: 425.1.
Compound 62: (3R)--N-(3,4-difluorophenyl)-3-[(1R)-1-methoxy
ethyl]-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepi-
ne-6-carboxamide
##STR00116##
[0456] Ethyl
4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (250 mg),
O-methyl-L-threonine (119 mg, 0.89 mmol) and Hunig's base (0.46 mL,
2.68 mmol) were dissolved in DCM (5 mL) and stirred overnight at
room temperature. The reaction mixture was directly loaded on a
silica cartridge and a gradient from heptane to EtOAc:EtOH:AcOH
3:1:0.1 was applied yielding
(2S,3R)-2-[(5-ethoxycarbonyl-4-fluoro-1-methyl-pyrrol-3-yl)sulfonylamino]-
-3-methoxy-butanoic acid as an off-white powder (310 mg).
[0457]
(2S,3R)-2-[(5-ethoxycarbonyl-4-fluoro-1-methyl-pyrrol-3-yl)sulfonyl-
amino]-3-methoxy-butanoic acid (310 mg) and 3,4-difluoroaniline (86
.mu.L, 0.85 mmol) were dissolved in THF (5 mL). Lithium
bis(trimethylsilyl)amide (4.23 mL, 1 M in THF, 4.23 mmol) was added
and the reaction mixture was stirred 2 hours at room temperature.
NH.sub.4Cl (sat., aq., 50 mL) was added and the organic layer was
removed. The aqueous layer was extracted with DCM (2.times.5 mL)
and the combined organic layers were evaporated to dryness. The
residue was purified on silica using a gradient from heptane to
EtOAc:EtOH:AcOH 3:1:0.1 yielding
(2S,3R)-2-[[5-[(3,4-difluoro-phenyl)carbamoyl]-4-fluoro-1-methyl-pyrrol-3-
-yl]sulfonylamino]-3-methoxy-butanoic acid as an off-white powder
(324 mg).
[0458]
(2S,3R)-2-[[5-[(3,4-difluorophenyl)carbamoyl]-4-fluoro-1-methyl-pyr-
rol-3-yl]-sulfonylamino]-3-methoxy-butanoic acid was dissolved in
THF (10 mL) and lithium aluminum hydride solution (1.44 mL, 1 M in
THF, 1.44 mmol) was added dropwise and the reaction mixture was
stirred overnight at room temperature. Sodium sulfate decahydrate
(348 mg, 1.08 mmol) was added followed by Na.sub.2SO.sub.4. The
reaction mixture was filtered and evaporated to dryness. The
residue was purified using a heptane to EtOAc:EtOH 3:1 gradient
yielding
N-(3,4-difluorophenyl)-3-fluoro-4-[[(1R,2R)-1-(hydroxymethyl)-2-methoxy-p-
ropyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide (50 mg).
[0459]
N-(3,4-difluorophenyl)-3-fluoro-4-[[(1R,2R)-1-(hydroxymethyl)-2-met-
hoxy-propyl]-sulfamoyl]-1-methyl-pyrrole-2-carboxamide (50 mg) was
dissolved in DMF (5 mL). Cesium fluoride (70 mg, 0.46 mmol) was
added and the reaction mixture was heated overnight at 100.degree.
C. The reaction mixture was directly loaded on a silica cartridge
and a gradient from heptane to EtOAc was applied yielding compound
62 (23.9 mg) as an off-white powder. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.13 (d, J=6.4 Hz, 3H), 3.28 (s, 3H),
3.55-3.65 (m, 1H), 3.77 (br dd, J=7.9, 3.3 Hz, 1H), 3.82 (s, 3H),
4.00 (dd, J=12.5, 9.0 Hz, 1H), 4.70 (dd, J=12.7, 1.2 Hz, 1H),
7.36-7.44 (m, 1H), 7.44-7.51 (m, 2H), 7.51-7.62 (m, 1H), 7.86 (ddd,
J=13.3, 7.5, 2.5 Hz, 1H), 9.42 (s, 1H); Method B; Rt: 0.99 min.
m/z: 416 (M+H).sup.+ Exact mass: 415.1.
Compound 63:
(3S)--N-(3,4-difluorophenyl)-3-[(S)-hydroxy(phenyl)methyl]-7-methyl-1,1-d-
ioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00117##
[0461] Compound 63 (32.7 mg) was prepared similarly as described
for compound 14, using (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol
instead of DL-alaninol. The ring closure was obtained after heating
overnight at 100.degree. C. in DMF and compound 63 was purified via
prep. HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 .mu.m,
30.times.150 mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3 solution in
water, ACN). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 3.80
(s, 3H), 3.85-3.96 (m, 1H), 4.01 (dd, J=12.4, 9.1 Hz, 1H), 4.72 (br
d, J=11.9 Hz, 1H), 4.86 (t, J=4.3 Hz, 1H), 5.67 (d, J=4.6 Hz, 1H),
7.25-7.31 (m, 1H), 7.31-7.48 (m, 8H), 7.79-7.90 (m, 1H), 9.44 (s,
1H); Method B; Rt: 0.98 min. m/z: 462 (M-H).sup.- Exact mass:
463.1.
Compound 64: (3R)--N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-[(1
S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5-
]oxathiazepine-6-carboxamide
##STR00118##
[0463] Compound 64 (124.8 mg) was prepared similarly as described
for compound 35, using 3-(difluoromethyl)-4-fluoro-aniline instead
of 3,4-difluoroaniline and heating overnight at 100.degree. C.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.22 (d, J=6.2 Hz,
3H), 3.35-3.46 (m, 1H), 3.55-3.67 (m, 1H), 3.83 (s, 3H), 3.99 (dd,
J=12.8, 9.0 Hz, 1H), 4.89 (dd, J=12.8, 1.8 Hz, 1H), 5.05 (br s,
1H), 7.21 (t, J=54.4 Hz, 1H), 7.35 (t, J=9.5 Hz, 1H), 7.47 (s, 1H),
7.61 (br s, 1H), 7.82 (dt, J=8.1, 4.1 Hz, 1H), 8.04 (dd, J=6.3, 2.5
Hz, 1H), 9.41-9.51 (m, 1H); Method B; Rt: 0.87 min. m/z: 432
(M-H).sup.- Exact mass: 433.1.
Compound 65: (3R)--N-(3-cyano-4-fluoro-phenyl)-3-[(1
S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5-
]oxathiazepine-6-carboxamide
##STR00119##
[0465] Compound 65 (29.2 mg) was prepared similarly as described
for compound 64, using 5-amino-2-fluorobenzonitrile instead of
3-(difluoromethyl)-4-fluoro-aniline. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.21 (d, J=6.2 Hz, 3H), 3.41 (br t, J=8.0
Hz, 1H), 3.61 (br s, 1H), 3.83 (s, 3H), 3.97 (dd, J=12.9, 9.1 Hz,
1H), 4.88-4.96 (m, 1H), 5.06 (br s, 1H), 7.49 (s, 1H), 7.51 (t,
J=9.2 Hz, 1H), 7.64 (br s, 1H), 8.05 (ddd, J=9.2, 4.9, 2.9 Hz, 1H),
8.20 (dd, J=5.7, 2.6 Hz, 1H), 9.51 (s, 1H); Method B; Rt: 0.81 min.
m/z: 407 (M-H).sup.- Exact mass: 408.1.
Compound 66:
(3R)--N-(2-bromo-4-pyridyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-3,-
4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00120##
[0467] Compound 66 (82.9 mg) was prepared similarly as described
for compound 64, using 4-amino-2-bromopyridine instead of
3-(difluoromethyl)-4-fluoro-aniline. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.21 (d, J=6.2 Hz, 3H), 3.34-3.46 (m,
1H), 3.56-3.66 (m, 1H), 3.83 (s, 3H), 4.01 (dd, J=12.8, 9.0 Hz,
1H), 4.92 (dd, J=12.7, 1.9 Hz, 1H), 5.07 (d, J=5.5 Hz, 1H), 7.54
(s, 1H), 7.61-7.70 (m, 1H), 7.72 (dd, J=5.6, 1.9 Hz, 1H), 8.02 (d,
J=1.8 Hz, 1H), 8.24 (d, J=5.5 Hz, 1H), 9.65 (br s, 1H); Method B;
Rt: 0.75 min. m/z: 443 (M-H).sup.- Exact mass: 444.0.
Compound 67:
N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3-
,4-f][1,2,5]thiadiazepine-6-carboxamide
##STR00121##
[0469] Carbamic acid, n-(2-aminopropyl)-, 1,1-dimethylethyl ester
(850 mg, 4.64 mmol) was dissolved in DCM (20 mL. Hunig's base (1.92
mL, 11.1 mmol) was added and then Ethyl
4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (1 g) was
added. The mixture was stirred at room temperature for 2 hours. The
mixture was washed with water and the organic layer was separated,
dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue
was purified by column chromatography using a gradient from 0 till
50% EtOAc in heptane over 15 column volumes. The product fractions
were concentrated in vacuum to yield ethyl
4-[[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]sulfamoyl]-3-fluoro-1-met-
hyl-pyrrole-2-carboxylate (1.3 g) as a white powder.
[0470] Ethyl
4-[[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]sulfamoyl]-3-fluoro-1-met-
hyl-pyrrole-2-carboxylate (1.3 g) was dissolved in 1,4-dioxane (15
mL). HCl (8 mL, 4 M in dioxane, 31.9 mmol) was added and the
mixture was stirred at room temperature for 16 hours. The
precipitated product was filtered off and dried under vacuum to
yield ethyl
4-[(2-amino-1-methyl-ethyl)sulfamoyl]-3-fluoro-1-methyl-pyrrole-2-carboxy-
late hydrochloride (1 g) as a white solid. Method B; Rt: 0.50 min.
m/z: 208 (M+H).sup.+ Exact mass: 307.1.
[0471] Ethyl
4-[(2-amino-1-methyl-ethyl)sulfamoyl]-3-fluoro-1-methyl-pyrrole-2-carboxy-
late hydrochloride (539 mg) and 3,4-difluoroaniline (0.19 mL, 1.88
mmol) were dissolved in THF (20 mL). Lithium
bis(trimethylsilyl)amide (7.8 mL, (1M in THF), 7.8 mmol) was added
dropwise to the reaction mixture. The mixture was stirred at room
temperature for 1 hour. The mixture was quenched with NH.sub.4Cl
(sat., aq., 15 mL). The reaction mixture was diluted with 2-MeTHF
and the organic layer was separated, dried (MgSO.sub.4), filtered
and concentrated in vacuum. The residue was triturated in DIPE,
filtered off and dried under vacuum to yield
4-[(2-amino-1-methyl-ethyl)sulfamoyl]-N-(3,4-difluorophenyl)-3-fluoro-1-m-
ethyl-pyrrole-2-carboxamide (500 mg) as a pale brown solid.
[0472] A microwave vial was charged with
4-[(2-amino-1-methyl-ethyl)sulfamoyl]-N-(3,4-difluorophenyl)-3-fluoro-1-m-
ethyl-pyrrole-2-carboxamide (200 mg), water (15 mL) and 1,4-dioxane
(3 mL). The vial was capped and the mixture was irradiated at
150.degree. C. for 6 hours. The mixture was neutralized with HCl
(aq., 1M). The mixture was extracted with DCM and the organic phase
was separated, dried (MgSO.sub.4), filtered and concentrated in
vacuo. The residue was purified via prep. HPLC (Stationary phase:
RP XBridge Prep C18 OBD-10 .mu.m, 30.times.150 mm, Mobile phase:
0.25% NH.sub.4HCO.sub.3 solution in water, MeOH) yielding compound
67 (16 mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.12
(d, J=6.9 Hz, 3H), 2.80 (dd, J=14.1, 8.5 Hz, 1H), 3.39 (dd, J=13.7,
1.6 Hz, 1H), 3.48-3.60 (m, 1H), 3.78 (s, 3H), 5.45 (br s, 1H),
7.26-7.31 (m, 1H), 7.31-7.35 (m, 1H), 7.35 (s, 1H), 7.36-7.43 (m,
1H), 7.78 (ddd, J=13.4, 7.4, 2.2 Hz, 1H), 10.45 (br s, 1H); Method
B; Rt: 0.91 min. m/z: 369 (M-H).sup.- Exact mass: 370.1.
Compound 68:
N-(3,4-difluorophenyl)-4-hydroxy-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyr-
rolo[3,4-f]thiazepine-6-carboxamide
##STR00122##
[0474] 1-penten-4-yne (6.2 g) and ethyl isocyanoacetate (35.3 g,
297 mmol) dissolved in dioxane (100 mL) was added dropwise to a
suspension of silver carbonate (3.88 g, 14.1 mmol) in dioxane (200
mL) between 80 and 90.degree. C. during 45 minutes. The reaction
mixture was stirred 2 hours at 80.degree. C. The reaction mixture
was filtered and concentrated. The residue was subjected to column
chromatography using a gradient from 10 till 100% EtOAc in heptane
over 10 column volumes yielding ethyl
3-allyl-1H-pyrrole-2-carboxylate (15.7 g) as an oil. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.28 (t, J=7.2 Hz, 3H), 3.48
(d, J=6.6 Hz, 2H), 4.22 (q, J=7.2 Hz, 2H), 4.93-4.98 (m, 1H),
4.98-5.06 (m, 1H), 5.93 (ddt, J=16.9, 10.1, 6.6, 6.6 Hz, 1H), 6.01
(t, J=2.4 Hz, 1H), 6.88 (t, J=2.9 Hz, 1H), 11.51 (br s, 1H); Method
D; Rt: 1.83 min. m/z: 180 (M+H).sup.+ Exact mass: 179.1.
[0475] Ethyl 3-allyl-1H-pyrrole-2-carboxylate (15.7 g) and methyl
iodide (14.3 g, 100 mmol) were dissolved in DMF (150 mL) and
stirred in an ice bath. NaH (4.37 g, 60% dispersion in mineral oil,
109 mmol) was added portionwise during 10 minutes and the reaction
mixture was stirred 1 hour. Another amount of NaH (2.27 g, 60%
dispersion in mineral oil, 56.8 mmol) was added portionwise
followed by methyl iodide (7.19 g, 50.6 mmol) and the reaction
mixture was stirred 1 hour in an ice bath. The reaction mixture was
quenched with ethanol (10 mL) and diluted with water (500 mL). The
mixture was extracted with EtOAc (3.times.200 mL). The combined
organic layers were dried (MgSO.sub.4), filtered and concentrated.
The residue was subjected to column chromatography using a gradient
from 0 till 100% EtOAc in heptane over 10 column volumes yielding
ethyl 3-allyl-1-methyl-pyrrole-2-carboxylate (13.2 g) as a light
yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.28
(t, J=7.2 Hz, 3H), 3.45 (d, J=6.6 Hz, 2H), 3.80 (s, 3H), 4.21 (q,
J=7.1 Hz, 2H), 4.93-5.04 (m, 2H), 5.86-5.97 (m, 2H), 6.97 (d, J=2.4
Hz, 1H); Method D; Rt: 2.07 min. m/z: 194 (M+H).sup.+ Exact mass:
193.1.
[0476] Osmium tetroxide (2.43 g, 2.5% in t-butanol, 0.239 mmol) was
added to ethyl 3-allyl-1-methyl-pyrrole-2-carboxylate (1156 mg,
5.982 mmol) in ACN (50 mL) and stirred 10 minutes. Water (10 mL)
was added followed by benzyloxycarbonylamino 4-chlorobenzoate (1.83
g, 5.98 mmol). The reaction mixture was stirred 2 hours and then
quenched with K.sub.2S.sub.2O.sub.5 (aq., sat., 10 mL), diluted
with water (100 mL) and extracted with EtOAc (2.times.100 mL). The
combined organic layers were washed with saturated NaHCO.sub.3
solution, dried (MgSO.sub.4), filtered and concentrated. The
residue was subjected to column chromatography using a gradient
from 10 till 100% EtOAc in heptane over column volumes yielding
ethyl
3-[3-(benzyloxycarbonylamino)-2-hydroxy-propyl]-1-methyl-pyrrole-2-carbox-
ylate (1.25 g) as a clear oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.27 (t, J=7.2 Hz, 3H), 2.67 (dd, J=14.0, 7.2 Hz, 1H),
2.81-2.96 (m, 2H), 3.00-3.08 (m, 1H), 3.60-3.75 (m, 1H), 3.78 (s,
3H), 4.19 (q, J=7.0 Hz, 2H), 4.57 (d, J=5.5 Hz, 1H), 5.00 (s, 2H),
6.01 (d, J=2.4 Hz, 1H), 6.94 (d, J=2.4 Hz, 1H), 7.06 (br t, J=5.6
Hz, 1H), 7.28-7.39 (m, 5H); Method D; Rt: 1.76 min. m/z: 361
(M+H).sup.+ Exact mass: 360.1.
[0477] Ethyl
3-[3-(benzyloxycarbonylamino)-2-hydroxy-propyl]-1-methyl-pyrrole-2-carbox-
ylate (920 mg) was dissolved in EtOH (100 mL). Under a nitrogen
atmosphere Pd/C (10%) (100 mg, 0.094 mmol) was added. The reaction
mixture was hydrogenated for 3 hours. The reaction mixture was
filtered over decalite. The filtrate was evaporated to dryness to
afford ethyl
3-(3-amino-2-hydroxy-propyl)-1-methyl-pyrrole-2-carboxylate (549
mg) as an oil. Method D; Rt: 1.00 min. m/z: 227 (M+H).sup.+ Exact
mass: 226.1.
[0478] Chlorosulfonic acid (2.06 g, 17.7 mmol) dissolved in
dichloromethane (10 mL) was added to ethyl
3-(3-amino-2-hydroxy-propyl)-1-methyl-pyrrole-2-carboxylate (500
mg) in DCM (25 mL) in an ice bath and stirred for 1 hour. ACN (150
mL) was added and the reaction mixture was stirred 1 hour.
Na.sub.2CO.sub.3 (2.58 g, 24.3 mmol) was added and the reaction
mixture was stirred 1 hour. Na.sub.2CO.sub.3 (2.58 g, 24.3 mmol)
was added and the reaction mixture was stirred for another 2 hours.
5 g Na.sub.2CO.sub.3 was added and the reaction mixture was stirred
over weekend. The reaction mixture was filtered and concentrated.
The residue was dissolved in DMF (5 mL), filtered and subjected as
such to column chromatography using a gradient from 10 till 100%
EtOAc in heptane over 10 column volumes yielding ethyl
4-hydroxy-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo-[3,4-f]thiazepine--
6-carboxylate (51 mg) as a clear resin.
[0479] Lithium bis(trimethylsilyl)amide (1.4 mL, 1 M in THF, 1.4
mmol) was added to a solution of ethyl
4-hydroxy-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo-[3,4-f]thiazepine--
6-carboxylate (51 mg) and 3,4-difluoroaniline (40 mg, 0.31 mmol) in
THF (10 mL) and stirred for 1 hour. The reaction mixture was
quenched with NH.sub.4Cl (sat., aq., 25 mL) and extracted with
EtOAc (50 mL). The organic layer was dried (Na.sub.2SO.sub.4),
filtered and concentrated. The residue was subjected to column
chromatography using a gradient from 10 til 100% EtOAc in heptane.
The product fractions were concentrated and the residue was
dissolved in methanol (5 mL), water was added until the product
crystallized. Compound 68 (15.5 mg) was filtered off as beige
crystals and dried in vacuo at 50.degree. C. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 2.92-3.09 (m, 2H), 3.21-3.27 (m, 2H),
3.49-3.59 (m, 1H), 3.68 (s, 3H), 5.06 (d, J=4.4 Hz, 1H), 7.34 (br
t, J=6.7 Hz, 1H), 7.38-7.47 (m, 3H), 7.82-7.90 (m, 1H), 10.48 (s,
1H); Method D; Rt: 1.76 min. m/z: 372 (M+H).sup.+ Exact mass:
371.1; MP: 229.0.degree. C.
Compound 69:
(3R)--N-(3,4-difluorophenyl)-3-[(1R)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2-
,3-dihydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00123##
[0481] To a solution of N-(tert-butoxycarbonyl)-L-threonine methyl
ester (10 g, 42.9 mmol) in CH.sub.2Cl.sub.2 (100 mL) was added
2-methoxypropene (8.22 mL, 85.7 mmol)) and camphorsulfonic acid
(100 mg, 0.43 mmol)) at 0.degree. C. under a nitrogen atmosphere.
The resulting solution was stirred at room temperature for 2 hours.
The reaction was then quenched with Et3N (5 mL) and the organic
solvents were removed in vacuo. Purification of the residue via
flash chromatography (silica gel, 0 to 15% EtOAc in heptanes)
afforded 03-tert-butyl 04-methyl
(4S,5R)-2,2,5-trimethyloxazolidine-3,4-dicarboxylate (10.5 g) as a
colorless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
1.25-1.54 (m, 18H), 3.66-3.72 (m, 3H), 3.86-3.91 (m, 1H), 4.06-4.13
(m, 1H) (rotamers).
[0482] To a stirred solution of methyltriphenylphosphonium bromide
(27.4 g, 76.7 mmol) in THF (77 mL) at 0.degree. C. was added KOtBu
(8.39 g, 74.8 mmol) in one portion. The resulting mixture was
stirred for one additional hour at the same temperature prior to
use. To a stirred solution of 03-tert-butyl 04-methyl
(4S,5R)-2,2,5-trimethyl-oxazolidine-3,4-dicarboxylate (10.5 g,
38.42 mmol) in CH.sub.2Cl.sub.2 (125 mL) was added DIBAL-H (1 M in
hexanes, 77 mL) dropwise over 1 hour at -78.degree. C. under a
nitrogen atmosphere. After an additional 2 hours at the same
temperature, the ylide THF suspension was added dropwise over 40
minutes. After an additional 15 minutes, the reaction mixture was
warmed to room temperature, and after an additional 3 hours at the
same temperature, the reaction mixture was warmed to 50.degree. C.
After an additional 14 hours at the same temperature, the reaction
mixture was cooled to room temperature, diluted with H.sub.2O (50
mL), then aqueous HCl (aq., 1 M, 150 mL), and the layers were
separated. The aqueous residue was extracted with EtOAc
(4.times.100 mL). The combined organic layers were washed with
brine (1.times.250 mL), dried (Na.sub.2SO.sub.4), filtered, and
concentrated under reduced pressure. The resulting residue was
purified by flash chromatography (1 to 23% EtOAc in heptane) on
silica gel to yield tert-butyl
(4R,5R)-2,2,5-trimethyl-4-vinyl-oxazolidine-3-carboxylate (4.5 g).
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.28 (d, J=6.0 Hz,
3H), 1.36-1.49 (m, 9H), 1.49-1.53 (m, 3H), 1.57-1.63 (m, 3H), 3.72
(br s, 1H), 3.78-3.89 (m, 1H), 5.08-5.29 (m, 2H), 5.44-5.92 (m,
1H).
[0483] Tert-butyl
(4R,5R)-2,2,5-trimethyl-4-vinyl-oxazolidine-3-carboxylate (4.5 g)
was dissolved in diethyl ether (150 mL) and HCl (47 mL, 4 M in
dioxane, 186 mmol) was added. The reaction mixture was stirred at
room temperature overnight and concentrated to dryness. The residue
was triturated in diethyl ether and concentrated to dryness. To
this residue was added a pre-mixed solution of 4.7 mL H.sub.2O in
47 mL 4 M HCl in dioxane cooled to 0.degree. C. using an ice/water
bath and the resulting mixture was stirred for 2 hours allowing to
warm to room temperature. The mixture was then diluted with toluene
(50 mL) and concentrated to dryness under reduced pressure. The
residue was then azeotroped with toluene (3.times.50 mL) to remove
all traces of water to afford (2R,3R)-3-aminopent-4-en-2-ol
hydrochloride (3.35 g). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.09 (d, J=6.3 Hz, 3H), 3.32-3.48 (m, 1H), 3.62-3.78 (m, 1H),
5.22-5.50 (m, 2H), 5.80 (ddd, J=17.3, 10.5, 7.9 Hz, 1H), 8.16 (br
s, 3H).
[0484] Methyl
3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (2.12 g)
was dissolved in DCM (200 mL) and (2R,3R)-3-aminopent-4-en-2-ol
(3.35 g, 32.1 mmol) and Hunig's base (13.9 mL, 80.4 mmol) were
added. The reaction mixture was stirred at room temperature for 1
hour. The reaction was quenched with NH.sub.4Cl (sat., aq., 40 mL).
The layers were separated and the organics were dried
(Na.sub.2SO.sub.4), filtered and concentrated to afford a brown
residue which was purified using silica gel column chromatography
(ethyl acetate in heptane from 0 to 100%) to afford methyl
3-bromo-4
[[(1R)-1-[(1R)-1-hydroxyethyl]allyl]sulfamoyl]-1-methyl-pyrrole-2-carboxy-
late (2.60 g) as an off white powder. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.96 (d, J=6.0 Hz, 3H), 3.55-3.67 (m,
2H), 3.82 (s, 3H), 3.86 (s, 3H), 4.57-4.77 (m, 1H), 4.97-5.10 (m,
2H), 5.71 (ddd, J=17.3, 10.5, 5.7 Hz, 1H), 7.35 (br s, 1H), 7.70
(s, 1H); Method B; Rt: 0.70 min. m/z: 379 (M-H).sup.- Exact mass:
380.0.
[0485] To a solution of methyl
3-bromo-4-[[(1R)-1-[(1R)-1-hydroxyethyl]allyl]sulfamoyl]-1-methyl-pyrrole-
-2-carboxylate (600 mg) in DMA (5 mL) purged with nitrogen was
added Hunig's base (0.3 mL, 1.73 mmol) and
bis(tri-tert-butylphosphine)palladium(0) (0.16 g, 0.31 mmol). The
reaction mixture was heated in the microwave for 5 minutes at
140.degree. C. The reaction mixture was diluted with methanol (60
mL) and purified via prep. HPLC (Stationary phase: RP XBridge Prep
C18 ODB-5 .mu.m, 30.times.250 mm, Mobile phase: 0.25%
NH.sub.4HCO.sub.3 solution in water, ACN) yielding methyl
(3R)-3-[(1R)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]-
thiazepine-6-carboxylate (160 mg). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.09 (d, J=6.4 Hz, 3H) 3.73-3.87 (m, 6H)
3.87-3.93 (m, 1H) 4.09 (br s, 1H) 4.94 (br d, J=4.0 Hz, 1H) 5.93
(dd, J=12.8, 2.6 Hz, 1H) 7.17 (dd, J=12.9, 2.8 Hz, 1H) 7.31 (br s,
1H) 7.69 (s, 1H); Method B; Rt: 0.60 min. m/z: 299 (M-H).sup.-
Exact mass: 300.1.
[0486] Methyl
(3R)-3-[(1R)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]-
-thiazepine-6-carboxylate (160 mg) and 3,4-difluoroaniline (76 mg,
0.59 mmol) were dissolved in THF (5 mL). Lithium
bis(trimethylsilyl)amide (2.4 mL, 1 M in THF, 2.4 mmol) was added
and the reaction mixture was stirred 60 minutes at room
temperature. 3,4-difluoroaniline (21 mg, 0.16 mmol) was added
followed by lithium bis(trimethylsilyl)amide (1 mL, 1 M in THF, 1
mmol). The reaction mixture was stirred at room temperature for 30
minutes. NH.sub.4Cl (sat., aq., 5 mL) was added and the organic
layer was separated. The aqueous layer was extracted with DCM
(2.times.5 mL) and the combined organic layers were evaporated to
dryness. The residue was purified using silica gel column
chromatography twice (ethyl acetate in heptane from 0 to 100%) and
then by prep. HPLC (Hypersyl C18 BDS-3 .mu.m, 100.times.4.6 mm)
Mobile phase (NH.sub.4HCO.sub.3 0.2% in water, ACN) to yield
compound 69 (68 mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.10 (d, J=6.4 Hz, 3H), 3.71 (s, 3H), 3.85-3.94 (m, 1H), 4.11
(br s, 1H), 4.92 (br s, 1H), 5.81 (dd, J=12.7, 2.5 Hz, 1H), 6.59
(dd, J=12.5, 2.6 Hz, 1H), 7.22 (br s, 1H), 7.39-7.47 (m, 2H), 7.57
(s, 1H), 7.82-7.88 (m, 1H), 10.74 (br s, 1H); Method B; Rt: 0.79
min. m/z: 396 (M-H).sup.- Exact mass: 397.1.
Compound 70:
(3R)--N-(3,4-difluorophenyl)-3-[(1R)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2-
,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00124##
[0488] Compound 69 (32 mg) was dissolved in MeOH (40 mL). Under a
nitrogen atmosphere Pd/C (10%) (24 mg, 0.022 mmol) was added. The
reaction mixture was hydrogenated for 60 minutes. The reaction
mixture was filtered over decalite and the filtrate was evaporated
to dryness to afford a white residue which was purified using
silica gel column chromatography (ethyl acetate in heptane from 0
to 100%) to yield compound 70 (23 mg) as a white powder. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.04 (d, J=6.2 Hz, 3H),
1.44 (q, J=12.1 Hz, 1H), 1.90 (br dd, J=14.1, 6.6 Hz, 1H), 2.78 (br
t, J=13.2 Hz, 1H), 3.02 (br dd, J=15.3, 5.4 Hz, 1H), 3.38-3.48 (m,
1H), 3.63-3.73 (m, 4H), 4.61 (br d, J=3.7 Hz, 1H), 6.69 (br d,
J=8.6 Hz, 1H), 7.38-7.47 (m, 3H), 7.81-7.89 (m, 1H), 10.48 (br s,
1H); Method B; Rt: 0.79 min. m/z: 398 (M-H).sup.- Exact mass:
399.1
Compound 71:
(3S)--N-(3-cyano-4-fluoro-phenyl)-7-methyl-1,1-dioxo-3-(3-pyridyl-methyl)-
-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00125##
[0490] Compound 71 (11.2 mg) was prepared similarly as described
for compound 38, using 5-amino-2-fluorobenzonitrile instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 2.66-2.76 (m, 1H) 2.88 (dd, J=14.1, 4.8 Hz, 1H) 3.82 (s, 3H)
3.86-3.98 (m, 1H) 4.03 (dd, J=12.7, 9.1 Hz, 1H) 4.67 (br d, J=12.3
Hz, 1H) 7.37 (dd, J=7.7, 4.8 Hz, 1H) 7.48-7.55 (m, 2H) 7.68-7.81
(m, 2H) 7.99-8.04 (m, 1H) 8.18 (dd, J=5.7, 2.6 Hz, 1H) 8.45-8.50
(m, 2H) 9.55 (s, 1H); Method B; Rt: 0.85 min. m/z: 456 (M+H).sup.+
Exact mass: 455.1.
Compound 72: tert-butyl
4-[6-[(3,4-difluorophenyl)carbamoyl]-7-methyl-1,1-dioxo-3,4-dihydro-2H-py-
rrolo[3,4-b][1,4,5]oxathiazepin-3-yl]piperidine-1-carboxylate
##STR00126##
[0492] To a cooled (-78.degree. C.) solution of tert-butyl
4-(1-amino-2-methoxy-2-oxoethyl)piperidine-1-carboxylate (1 g) in
THF (50 mL) was added dropwise lithium aluminium hydride (3.56 mL,
1 M in THF, 3.562 mmol) at -78.degree. C. The mixture was stirred
at -78.degree. C. for 3 hours and the mixture was allowed to rise
to room temperature. The mixture was further stirred at room
temperature for 16 hours. Sodium sulfate decahydrate (1.72 g, 5.34
mmol) was carefully added and the mixture was stirred at room
temperature for 10 minutes. Na.sub.2SO.sub.4 was added and the
mixture was filtered. The filtrate was concentrated in vacuum and
the residue was purified by column chromatography using a gradient
from 0 till 100% MeOH/NH.sub.3 (90/10) in DCM over 10 column
volumes. The product fractions were concentrated in vacuum to yield
tert-butyl 4-(1-amino-2-hydroxy-ethyl)piperidine-1-carboxylate (513
mg) as an oil.
[0493] Compound 72 (127 mg) was prepared similarly as described for
compound 14, using tert-butyl
4-(1-amino-2-hydroxy-ethyl)piperidine-1-carboxylate instead of
DL-alaninol and heating 6 hours at 110.degree. C. instead of 2
hours at 140.degree. C. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.12-1.27 (m, 2H), 1.40 (s, 9H), 1.71 (br t, J=12.7 Hz, 3H),
2.67 (br s, 2H), 3.47-3.55 (m, 1H), 3.82 (s, 3H), 3.90-4.05 (m,
2H), 3.96-4.01 (m, 1H), 4.71 (d, J=10.9 Hz, 1H), 7.35-7.45 (m, 1H),
7.45-7.51 (m, 2H), 7.62 (d, J=9.7 Hz, 1H), 7.85 (ddd, J=13.2, 7.4,
2.4 Hz, 1H), 9.42 (s, 1H); Method B; Rt: 1.13 min. m/z: 539
(M-H).sup.- Exact mass: 540.2.
Compound 73:
N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3-(4-piperidyl)-3,4-dihydro-2H--
pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00127##
[0495] Compound 72 (119 mg) was suspended in DCM (5 mL). TFA (0.25
mL, 3.30 mmol) was added and the mixture was stirred at room
temperature for 1 hour. The mixture was washed with sat.
NaHCO.sub.3 solution. The organic layer was separated, dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue was
purified via prep. HPLC (Stationary phase: RP XBridge Prep C18
OBD-10 .mu.m, 30.times.150 mm, Mobile phase: 0.25%
NH.sub.4HCO.sub.3 solution in water, ACN). The product fractions
were collected to yield compound 73 (21 mg) as a white solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.10-1.25 (m, 2H),
1.51-1.71 (m, 3H), 1.75 (s, 1H), 2.34-2.45 (m, 2H), 2.89-2.97 (m,
2H), 3.39-3.49 (m, 1H), 3.80-3.85 (m, 3H), 3.95 (dd, J=12.8, 9.0
Hz, 1H), 4.72 (dd, J=12.9, 1.9 Hz, 1H), 7.36-7.57 (m, 4H), 7.86
(ddd, J=13.2, 7.5, 2.5 Hz, 1H), 9.34-9.48 (m, 1H); Method B; Rt:
0.72 min. m/z: 441 (M+H).sup.+ Exact mass: 440.1.
Compound 74:
(3S)--N-(4-fluoro-3-methyl-phenyl)-7-methyl-1,1-dioxo-3-(3-pyridyl-methyl-
)-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00128##
[0497] Compound 74 (29 mg) was prepared similarly as described for
compound 38, using 4-fluoro-3-methylaniline instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 2.23 (d, J=1.5 Hz, 3H), 2.66-2.75 (m, 1H), 2.85-2.92 (m, 1H),
3.82 (s, 3H), 3.93 (br s, 1H), 3.99-4.11 (m, 1H), 4.67 (dd, J=12.5,
2.0 Hz, 1H), 7.10 (t, J=9.1 Hz, 1H), 7.37 (dd, J=7.7, 5.1 Hz, 1H),
7.45 (s, 1H), 7.49 (br d, J=4.6 Hz, 1H), 7.53-7.58 (m, 1H),
7.70-7.80 (m, 2H), 8.46 (d, J=5.1 Hz, 1H), 8.49 (s, 1H), 9.24 (s,
1H); Method B; Rt: 0.91 min. m/z: 445 (M+H).sup.+ Exact mass:
444.1.
Compound 75:
(3S)--N-[3-(difluoromethyl)-4-fluoro-phenyl]-7-methyl-1,1-dioxo-3-(3-pyri-
dylmethyl)-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00129##
[0499] Compound 75 (5 mg) was prepared similarly as described for
compound 38, using 3-(difluoromethyl)-4-fluoro-aniline instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 2.65-2.76 (m, 1H), 2.87 (br dd, J=14.3, 4.8 Hz, 1H), 3.83 (s,
3H), 3.93 (br s, 1H), 4.00-4.08 (m, 1H), 4.65 (dd, J=12.8, 2.2 Hz,
1H), 7.20 (t, J=48.0 Hz, 1H), 7.35-7.40 (m, 2H), 7.47 (s, 1H),
7.70-7.83 (m, 3H), 8.02 (dd, J=6.3, 2.5 Hz, 1H), 8.46 (dd, J=4.8,
1.5 Hz, 1H), 8.49 (d, J=2.0 Hz, 1H), 9.49 (s, 1H); Method B; Rt:
0.90 min. m/z: 481 (M+H).sup.+ Exact mass: 480.1.
Compound 76:
N-(3,4-difluorophenyl)-7-methyl-3-(1-methyl-4-piperidyl)-1,1-dioxo-3,4-di-
hydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00130##
[0501] Compound 73 (109 mg) was dissolved in MeOH (1 mL) and DCE (2
mL). The mixture was cooled on a ice bath and formaldehyde (22
.mu.L, 1.09 g/mL, 0.297 mmol) was added followed by sodium
cyanoborohydride (33 mg, 0.50 mmol). The mixture was stirred at
room temperature for 16 hours. The solvent was evaporated and the
residue was partioned between NaOH (aq., 1M) and Me-THF. The
organic layer was separated, dried (MgSO.sub.4), filtered and
evaporated. The residue was purified by column chromatography using
a gradient from 0 till 100% DCM/NH.sub.3 sol. in MeOH (90/10) in
DCM over 10 column volumes. The product fractions were concentrated
in vacuo. The product was crystallized from water:MeOH to yield
compound 76 (51 mg) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.24-1.47 (m, 3H), 1.64-1.83 (m, 4H),
2.09-2.16 (m, 3H), 2.71-2.84 (m, 2H), 3.39-3.53 (m, 1H), 3.82 (s,
3H), 3.95 (dd, J=12.9, 9.1 Hz, 1H), 4.73 (dd, J=13.0, 2.0 Hz, 1H),
7.36-7.53 (m, 3H), 7.58 (d, J=9.7 Hz, 1H), 7.86 (ddd, J=13.2, 7.4,
2.5 Hz, 1H), 9.38-9.43 (m, 1H); Method B; Rt: 0.75 min. m/z: 455
(M+H).sup.+ Exact mass: 454.1.
Compound 77:
(3R)--N-[2-(difluoromethyl)-4-pyridyl]-3-[(1S)-1-hydroxyethyl]-7-methyl-1-
,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00131##
[0503] Compound 77 (72.7 mg) was prepared similarly as described
for compound 64, using 2-(difluoromethyl)pyridin-4-amine instead of
3-(difluoromethyl)-4-fluoro-aniline. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.43 (d, J=6.4 Hz, 3H), 2.12 (s, 1H),
3.85 (tdd, J=9.2, 9.2, 4.8, 2.4 Hz, 1H), 3.96 (s, 3H), 4.19 (quin,
J=6.1 Hz, 1H), 4.35 (dd, J=13.0, 8.8 Hz, 1H), 4.90 (dd, J=13.0, 2.4
Hz, 1H), 5.18 (d, J=9.5 Hz, 1H), 6.62 (t, J=55.5 Hz, 1H), 7.10 (s,
1H), 7.71-7.73 (m, 1H), 7.74-7.75 (m, 1H), 8.53 (d, J=5.5 Hz, 1H),
9.05 (s, 1H); Method B; Rt: 0.71 min. m/z: 415 (M-H).sup.- Exact
mass: 416.1.
Compound 78:
N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3-[1-(2,2,2-trifluoroethyl)-4-p-
iperidyl]-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00132##
[0505] A microwave vial was charged with compound 73 (50 mg, 0.11
mmol), 2,2,2-trifluoroethyl trichloromethanesulfonate (34 mg, 0.11
mmol), K.sub.2CO.sub.3 (19 mg, 0.14 mmol) in acetone (1 mL). The
vial was capped and the mixture was stirred at 60.degree. C. for 16
hours. The mixture was concentrated and the residue was purified by
column chromatography using a gradient from 0 till 100% EtOAc in
Heptane over 10 column volumes. The product fractions were
concentrated in vacuo. The product was triturated in DIPE, filtered
off and dried under vacuum to give compound 78 (38 mg) as a white
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.28-1.44
(m, 2H), 1.44-1.54 (m, 1H), 1.64-1.76 (m, 2H), 2.20-2.36 (m, 2H),
2.89-2.98 (m, 2H), 3.05-3.20 (m, 2H), 3.42-3.56 (m, 1H), 3.82 (s,
3H), 3.92-4.04 (m, 1H), 4.68-4.76 (m, 1H), 7.36-7.51 (m, 3H), 7.59
(d, J=9.8 Hz, 1H), 7.86 (ddd, J=13.2, 7.5, 2.5 Hz, 1H), 9.38-9.43
(m, 1H); Method D; Rt: 2.06 min. m/z: 521 (M+H).sup.+ Exact mass:
522.1.
Compound 79:
N-(3,4-difluorophenyl)-3-isopropyl-7-methyl-1,1-dioxo-2,3-dihydropyrrolo[-
3,4-f]thiazepine-6-carboxamide
##STR00133##
[0507] Methyl
3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (2 g, 6.32
mmol) was dissolved in DCM (100 mL). To this was added Hunig's base
(4.36 mL, 25.3 mmol). To this was added 4-methyl-1-penten-3-amine
(1.71 g, 12.6 mmol) in DCM (100 mL). The resulting mixture was
stirred overnight and concentrated in vacuo and the residue was
purified using silica gel column chromatography (gradient elution:
EtOAc:heptane 0:100 to 100:0) yielding methyl
3-bromo-4-(1-isopropylallylsulfamoyl)-1-methyl-pyrrole-2-carboxylate
(1.88 g) as a beige powder which was used as such. Method B; Rt:
0.98 min. m/z: 379 (M+H).sup.+ Exact mass: 378.0.
[0508] Methyl
3-bromo-4-(1-isopropylallylsulfamoyl)-1-methyl-pyrrole-2-carboxylate
(1.70 g, 4.48 mmol) and TEA (0.62 mL, 0.73 g/mL, 4.48 mmol) in DMF
(10 mL) was stirred and purged with nitrogen for 5 minutes. Then
bis(tri-tert-butylphosphine)palladium(0) (458 mg, 0.90 mmol) was
added and stirring and purging was continued for 5 more minutes.
The mixture was heated under microwave irradiation to 100.degree.
C. for 75 minutes. The reaction mixture was cooled to room
temperature and filtered through a pad of dicalite and rinsed with
150 mL of EtOAc. Then the filtrate was concentrated in vacuo and
purified using silica gel column chromatography (gradient elution:
EtOAc:heptane 0:100 to 100:0) yielding a mixture of 2 isomers. This
mixture was purified via preparative HPLC (Stationary phase: RP
XBridge Prep C18 OBD-10 .mu.m, 30.times.150 mm, Mobile phase: 0.25%
NH.sub.4HCO.sub.3 solution in water, ACN) yielding methyl
3-isopropyl-7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]thiazepine-6-carb-
oxylate (203 mg). Method B; Rt: 0.88 min. m/z: 299 (M+H).sup.+
Exact mass: 298.1.
[0509] A mixture of methyl
3-isopropyl-7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]-thiazepine-6-car-
boxylate (101 mg, 0.34 mmol) and 3,4-difluoroaniline (49 mg, 0.37
mmol) in THF (5 mL) was treated with LiHMDS (0.64 mL, 1.06 M in
THF, 0.68 mmol) and this was stirred for 2 hours at room
temperature. The resulting mixture was quenched with NH.sub.4Cl
(aq. sat., 5 mL). Then brine (5 mL) was added and the layers were
separated. The water layer was extracted using EtOAc (2.times.10
mL). The combined extracts were concentrated in vacuo and the
obtained crude was purified using silica gel column chromatography
(gradient elution: EtOAc:heptane 0:100 to 100:0). The desired
fractions were concentrated in vacuo and the obtained residue was
purified via Prep HPLC (Stationary phase: RP XBridge Prep C18
OBD-10 .mu.m, 30.times.150 mm, Mobile phase: 0.25%
NH.sub.4HCO.sub.3 solution in water, ACN) yielding compound 79 as a
bright white solid (60.3 mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.47-1.51 (m, 3H) 1.51-1.56 (m, 3H) 3.20-3.24 (m, 1H)
3.20-3.24 (m, 2H) 4.30 (s, 2H) 4.53-4.63 (m, 1H) 6.21 (dd, J=12.32,
2.86 Hz, 1H) 6.49 (d, J=10.56 Hz, 1H) 7.15 (dd, J=12.32, 2.64 Hz,
1H) 7.76-7.89 (m, 2H) 7.95-8.05 (m, 1H) 8.43 (ddd, J=12.87, 7.37,
2.64 Hz, 1H) 10.23 (br s, 1H); Method D; Rt: 1.90 min. m/z: 396
(M+H).sup.+ Exact mass: 395.1. This racemic mixture was separated
in its enantiomers via preparative SFC (Stationary phase: Chiralpak
Diacel AD 20.times.250 mm, Mobile phase: CO.sub.2, EtOH+0.4
iPrNH.sub.2) yielding compound 79a and 79b. Method E; Rt: 79a:1.22
min, 79b: 2.09 min.
Compound 80:
N-(3,4-difluorophenyl)-3-(1-methoxy-1-methyl-ethyl)-7-methyl-1,1-dioxo-3,-
4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00134##
[0511] Ethyl
4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (250 mg,
0.89 mmol), 2-amino-3-methoxy-3-methylbutanoic acid (131 mg, 0.89
mmol) and Hunig's base (0.46 mL, 0.75 g/mL, 2.68 mmol) were
dissolved in DCM (5 mL) and stirred overnight at room temperature.
The reaction mixture was directly loaded on a silica cartridge and
a gradient from heptane to EtOAc:EtOH:AcOH 3:1:0.02 was applied
yielding
2-[(5-ethoxycarbonyl-4-fluoro-1-methyl-pyrrol-3-yl)sulfonylamino]-3-metho-
xy-3-methyl-butanoic acid (143 mg).
[0512]
2-[(5-ethoxycarbonyl-4-fluoro-1-methyl-pyrrol-3-yl)sulfonylamino]-3-
-methoxy-3-methyl-butanoic acid (143 mg, 0.38 mmol) and
3,4-difluoroaniline (38 .mu.L, 1.29 g/mL, 0.38 mmol) were dissolved
in THF (5 mL). Lithium bis(trimethylsilyl)amide (1.88 mL, 1 M in
THF, 1.88 mmol) was added and the reaction mixture was stirred
overnight at room temperature. NH.sub.4Cl (sat., aq., 5 mL) was
added and the organic layer was removed. The aqueous layer was
extracted with DCM (2.times.5 mL) and the combined organic layers
were evaporated to dryness. The residue was purified on silica
using a heptane to EtOAc:EtOH:AcOH 3:1:0.02 gradient yielding
2-[[5-[(3,4-difluorophenyl)-carbamoyl]-4-fluoro-1-methyl-pyrrol--
3-yl]sulfonylamino]-3-methoxy-3-methyl-butanoic acid (123 mg).
[0513]
2-[[5-[(3,4-difluorophenyl)carbamoyl]-4-fluoro-1-methyl-pyrrol-3-yl-
]sulfonylamino]-3-methoxy-3-methyl-butanoic acid (123 mg, 0.27
mmol) was dissolved in THF (10 mL) and LAH (0.27 mL, 1 M in THF,
0.27 mmol) was added drop wise. The reaction mixture was stirred
overnight at room temperature. LAH (0.27 mL, 1 M in THF, 0.27 mmol)
was added and stirring was continued for 24 hours. The reaction
mixture was quenched with sodium sulfate decahydrate (128 mg, 0.4
mmol) followed by addition of Na.sub.2SO.sub.4. After filtration
and evaporation an oily residue was obtained which was purified on
silica using a heptane to EtOAc:EtOH 3:1 gradient yielding
N-(3,4-difluorophenyl)-3-fluoro-4-[[1-(hydroxymethyl)-2-methoxy-2-methyl--
propyl]-sulfamoyl]-1-methyl-pyrrole-2-carboxamide (17 mg).
[0514]
N-(3,4-difluorophenyl)-3-fluoro-4-[[1-(hydroxymethyl)-2-methoxy-2-m-
ethyl-propyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide (17 mg,
0.038 mmol) and cesium fluoride (23 mg, 0.15 mmol) were dispensed
in DMF (5 mL) and heated to 100.degree. C. for 4 hours. The
reaction mixture was directly purified via prep. HPLC (Stationary
phase: RP)(Bridge Prep C18 OBD-10 .mu.m, 30.times.150 mm, Mobile
phase: 0.25% NH.sub.4HCO.sub.3 solution in water, ACN) yielding
compound 80 (6.3 mg) as a white powder. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.31-1.43 (m, 6H), 3.19 (s, 3H), 3.85 (br
s, 1H), 3.95 (s, 3H), 4.04 (dd, J=12.8, 8.8 Hz, 1H), 4.82-4.93 (m,
2H), 7.05 (s, 1H), 7.08-7.14 (m, 2H), 7.62-7.69 (m, 1H), 8.81 (s,
1H); Method B; Rt: 1.04 min. m/z: 428 (M-H).sup.- Exact mass:
429.1.
Compound 81:
N-(3,4-difluorophenyl)-3-isopropyl-7-methyl-1,1-dioxo-2,3,4,5-tetrahydrop-
yrrolo[3,4-f]thiazepine-6-carboxamide
##STR00135##
[0516] A hydrogenation flask was flushed with nitrogen and then
charged with Pd/C (10%) (10 mg, 0.0094 mmol). To this was added
under nitrogen compound 79 (50 mg, 0.13 mmol) in MeOH (30 mL). The
resulting suspension was then stirred under a hydrogen atmosphere
at room temperature for 90 minutes. Then the mixture was filtered
over a pad of dicalite under a constant nitrogen flow and this pad
was rinsed with MeOH (50 mL). The filtrate was concentrated in
vacuo and the obtained residue was purified using silica gel column
chromatography (gradient elution: EtOAc:heptane 0:100 to 100:0).
The desired fractions were concentrated in vacuo and dried in a
vacuum oven at 55.degree. C. yielding compound 81 (36 mg) as a
bright white powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 0.88 (d, J=3.74 Hz, 3H) 0.90 (d, J=3.52 Hz, 3H) 1.31-1.48 (m,
1H) 1.68 (dq, J=12.90, 6.56 Hz, 1H) 1.79-1.95 (m, 1H) 2.72-2.86 (m,
1H) 2.94-3.07 (m, 1H) 3.18-3.29 (m, 1H) 3.68 (s, 3H) 6.90 (d,
J=10.12 Hz, 1H) 7.35-7.49 (m, 3H) 7.78-7.92 (m, 1H) 10.48 (s, 1H);
Method B; Rt: 1.03 min. m/z: 396 (M-H).sup.- Exact mass: 397.1.
Compound 82:
N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-isopropyl-7-methyl-1,1-dioxo-2,3-
-dihydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00136##
[0518] Compound 82 (70.9 mg) was prepared similarly as described
for compound 79, using 3-(difluoromethyl)-4-fluoro-aniline instead
of 3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 0.95 (d, J=6.82 Hz, 3H) 0.98 (d, J=6.60 Hz, 3H) 1.85-2.01 (m,
1H) 3.72 (s, 3H) 3.91-3.98 (m, 1H) 5.70 (dd, J=12.43, 2.75 Hz, 1H)
6.57 (dd, J=12.43, 2.75 Hz, 1H) 7.06-7.43 (m, 3H) 7.58 (s, 1H)
7.78-7.87 (m, 1H) 8.06 (dd, J=6.27, 2.53 Hz, 1H) 10.75 (s, 1H);
Method B; Rt: 1.02 min. m/z: 426 (M-H).sup.- Exact mass: 427.1.
Compound 83:
N-(3,4-difluorophenyl)-3-(hydroxymethyl)-7-methyl-1,1-dioxo-3,4-dihydro-2-
H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00137##
[0520] Compound 83 (216 mg) was prepared similarly as described for
compound 14, using 2-amino-1,3-propanediol instead of DL-alaninol.
The ring closure was obtained after heating overnight at
100.degree. C. in DMF and compound 83 was purified on silica using
a gradient from heptane to EtOAc:EtOH 3:1. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 3.35-3.42 (m, 1H), 3.56 (dt, J=10.8, 5.2
Hz, 1H), 3.63-3.73 (m, 1H), 3.82 (s, 3H), 3.94 (dd, J=12.8, 8.8 Hz,
1H), 4.74 (dd, J=12.7, 1.9 Hz, 1H), 5.10 (dd, J=6.5, 5.0 Hz, 1H),
7.36-7.50 (m, 3H), 7.61 (d, J=9.7 Hz, 1H), 7.87 (ddd, J=13.2, 7.5,
2.6 Hz, 1H), 9.44 (s, 1H); Method B; Rt: 0.81 min. m/z: 386
(M-H).sup.- Exact mass: 387.1.
Compound 84:
(3R)--N-(3,4-difluorophenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2-
,3-dihydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00138##
[0522] Methyl
3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (10.8 g,
34.1 mmol) was dissolved in ACN (200 mL) and
(2S,3R)-3-aminopent-4-en-2-ol hydrochloride (4.99 g, 36.2 mmol) and
Hunig's base (14.7 mL, 0.75 g/mL, 85.3 mmol) were added. The
reaction mixture was stirred at room temperature overnight. The
reaction mixture was concentrated and the residue was purified
using silica gel column chromatography (EtOAc in heptane from 0 to
100%) to afford methyl
3-bromo-4-[[(1R)-1-[(1S)-1-hydroxyethyl]allyl]sulfamoyl]-1-methyl-pyrrole-
-2-carboxylate (11.4 g) as an off white powder. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 0.99 (d, J=6.4 Hz, 3H), 3.41-3.50
(m, 1H), 3.53-3.63 (m, 1H), 3.81 (s, 3H), 3.85 (s, 3H), 4.62 (br d,
J=5.1 Hz, 1H), 4.91-4.95 (m, 1H), 4.97 (d, J=0.7 Hz, 1H), 5.63-5.74
(m, 1H), 7.33 (br s, 1H), 7.69 (s, 1H); Method B; Rt: 0.68 min.
m/z: 379 (M-H).sup.- Exact mass: 380.0.
[0523] To a solution of methyl
3-bromo-4-[[(1R)-1-[(1S)-1-hydroxyethyl]allyl]sulfamoyl]-1-methyl-pyrrole-
-2-carboxylate (1.10 g, 2.89 mmol) in DMF (5 mL) purged with
nitrogen was added Hunig's base (0.55 mL, 0.75 g/mL, 3.17 mmol) and
bis(tri-tert-butylphosphine)palladium(0) (147 mg, 0.29 mmol). The
reaction mixture was heated in the microwave for 10 minutes at
130.degree. C. The reaction mixture was purified via preparative
HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 .mu.m,
50.times.150 mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3 solution in
water, ACN) yielding methyl
(3R)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2,3-dihydropyrrolo-
[3,4-f]thiazepine-6-carboxy late (380 mg). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.19 (d, J=6.2 Hz, 3H), 3.62-3.72 (m,
1H), 3.76-3.88 (m, 7H), 4.98 (br d, J=3.7 Hz, 1H), 6.07 (dd,
J=12.9, 2.8 Hz, 1H), 7.12 (dd, J=12.8, 2.6 Hz, 1H), 7.49 (br s,
1H), 7.69 (s, 1H); Method B; Rt: 0.59 min. m/z: 299 (M-H).sup.-
Exact mass: 300.1 and methyl
3-acetyl-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6--
carboxylate. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.46-1.59 (m,
1H), 2.12-2.20 (m, 1H), 2.22 (s, 3H), 2.77-2.87 (m, 1H), 3.58 (br
dd, J=15.7, 7.7 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 4.19 (br t,
J=9.5 Hz, 1H), 7.59 (s, 1H), 7.68 (br d, J=9.3 Hz, 1H); Method B;
Rt: 0.67 min. m/z: 299 (M-H).sup.- Exact mass: 300.1
[0524] Methyl
(3R)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]-
-thiazepine-6-carboxylate (95 mg, 0.32 mmol) and
3,4-difluoroaniline (53 mg, 0.41 mmol) were dissolved in THF (5
mL). Lithium bis(trimethylsilyl)amide (2 mL, 1 M in THF, 2 mmol)
was added and the reaction mixture was stirred at room temperature.
The reaction was quenched after 1 hour with NH.sub.4Cl (sat., aq.,
5 mL) and the organic layer was separated. The aqueous layer was
extracted with DCM (2.times.4 mL) and the combined organic layers
were dried (Na.sub.2SO.sub.4) and evaporated to dryness. The
residue was purified via preparative HPLC (Stationary phase: RP
XBridge Prep C18 OBD-10 .mu.m, 50.times.150 mm, Mobile phase: 0.25%
NH.sub.4HCO.sub.3 solution in water, ACN). The obtained product was
purified using silica gel column chromatography (EtOAc in heptane
from 0 to 100%) to afford compound 84 (62 mg). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 1.20 (d, J=6.2 Hz, 3H), 3.60-3.77
(m, 4H), 3.77-3.87 (m, 1H), 4.97 (br d, J=5.7 Hz, 1H), 5.96 (dd,
J=12.5, 2.6 Hz, 1H), 6.54 (dd, J=12.5, 2.6 Hz, 1H), 7.35-7.52 (m,
3H), 7.57 (s, 1H), 7.81-7.89 (m, 1H), 10.73 (br s, 1H); Method B;
Rt: 0.78 min. m/z: 396 (M-H).sup.- Exact mass: 397.1.
Compound 85:
N-(3-cyano-4-fluoro-phenyl)-3-isopropyl-7-methyl-1,1-dioxo-2,3,4,5-tetrah-
ydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00139##
[0526] Methyl 3-bromo-1-methyl-pyrrole-2-carboxylate (2.44 g, 11.1
mmol), tert-butyl N-(1-isopropylallyl)carbamate (2.65 g, 13.3 mmol)
and TEA (3 mL, 0.73 g/mL, 22.2 mmol) in DMF (5 mL) was stirred and
purged with nitrogen for 5 minutes. Then
bis(tri-tert-butylphosphine)palladium(0) (1.13 g, 2.22 mmol) was
added and stirring and purging was continued for 5 more minutes.
The mixture was heated under microwave irradiation to 100.degree.
C. for 60 minutes. The reaction mixture was cooled to room
temperature and filtered through a pad of dicalite and rinsed with
EtOAc (150 mL). Then the filtrate was concentrated in vacuo and
purified using silica gel column chromatography (gradient elution:
EtOAc:heptane 0:100 to 100:0) yielding methyl
3-[(E)-3-(tert-butoxycarbonylamino)-4-methyl-pent-1-enyl]-1-methyl-pyrrol-
e-2-carboxylate (3.31 g) as an oil. Method B; Rt: 1.18 min. m/z:
335 (M-H).sup.- Exact mass: 336.2.
[0527] A hydrogenation flask was flushed with nitrogen and then
charged with Pd/C (10%) (733 mg, 0.69 mmol). To this was added
under nitrogen methyl
3-[(E)-3-(tert-butoxycarbonylamino)-4-methyl-pent-1-enyl]-1-methyl-
-pyrrole-2-carboxylate (2.20 g, 6.54 mmol) in MeOH (35 mL). The
resulting suspension was then stirred under a hydrogen atmosphere
at room temperature for 90 minutes. Then the mixture was filtered
over a pad of dicalite under a constant nitrogen flow and this pad
was rinsed with MeOH (150 mL). The filtrate was concentrated in
vacuo and the obtained residue was purified using silica gel column
chromatography (gradient elution: EtOAc:heptane 0:100 to 100:0).
The desired fractions were concentrated in vacuo yielding methyl
3-[3-(tert-butoxycarbonylamino)-4-methyl-pentyl]-1-methyl-pyrrole-2-carbo-
xylate (2.16 g) as a bright white powder.
[0528] Methyl
3-[3-(tert-butoxycarbonylamino)-4-methyl-pentyl]-1-methyl-pyrrole-2-carbo-
xylate (250 mg, 0.74 mmol) in DCM (10 mL) was treated with
chlorosulfonic acid (246 .mu.L, 1.75 g/mL, 3.69 mmol) in DCM (5 mL)
at 0.degree. C. Then it was allowed to reach room temperature and
the stirred for another hour. The mixture was added dropwise to
ice-water (20 mL) and this was extracted with 2-MeTHF (2.times.20
mL). The combined extracts were dried on Na.sub.2SO.sub.4, filtered
and concentrated in vacuo yielding methyl
3-isopropyl-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-
-6-carboxylate (80 mg).
[0529] Methyl
3-isopropyl-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-
-6-carboxylate (80 mg, 0.27 mmol) and 5-amino-2-fluoro-benzonitrile
(36 mg, 0.27 mmol) in dry THF (5 mL) was treated with lithium
bis(trimethylsilyl)amide (1.3 mL, 1 M in THF, 1.3 mmol) and this
was stirred for 2 hours at room temperature. The resulting mixture
was quenched with NH.sub.4Cl (aq. sat., 5 mL). Then brine (5 mL)
was added and the layers were separated. The water layer was
extracted using EtOAc (2.times.20 mL). The combined extracts were
concentrated in vacuo and the obtained crude was purified using
silica gel column chromatography (gradient elution: EtOAc:heptane
0:100 to 100:0). The desired fractions were concentrated in vacuo
and the obtained residue was purified via preparative HPLC
(Stationary phase: RP XBridge Prep C18 OBD-10 .mu.m, 30.times.150
mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3 solution in water, ACN)
yielding compound 85 (17 mg) as a bright white solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 0.88 (d, J=3.30 Hz, 3H) 0.90
(d, J=3.08 Hz, 3H) 1.32-1.47 (m, 1H) 1.69 (dq, J=12.96, 6.54 Hz,
1H) 1.79-1.93 (m, 1H) 2.72-2.85 (m, 1H) 2.98-3.11 (m, 1H) 3.19-3.28
(m, 1H) 3.69 (s, 3H) 6.91 (d, J=10.34 Hz, 1H) 7.44 (s, 1H) 7.54 (t,
J=9.13 Hz, 1H) 7.95 (ddd, J=9.24, 4.84, 2.64 Hz, 1H) 8.18 (dd,
J=5.83, 2.75 Hz, 1H) 10.59 (s, 1H); Method B; Rt: 0.97 min. m/z:
403 (M-H).sup.- Exact mass: 404.1.
Compound 86:
N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-isopropyl-7-methyl-1,1-dioxo-2,3-
,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00140##
[0531] Compound 86 (17 mg) was prepared similarly as described for
compound 81, using compound 82 instead of compound 79. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 0.88 (d, J=3.30 Hz, 3H) 0.90
(d, J=3.30 Hz, 3H) 1.32-1.46 (m, 1H) 1.69 (dq, J=13.04, 6.73 Hz,
1H) 1.79-1.95 (m, 1H) 2.71-2.88 (m, 1H) 2.95-3.11 (m, 1H) 3.19-3.28
(m, 1H) 3.69 (s, 3H) 6.89 (d, J=10.34 Hz, 1H) 7.22 (t, J=54.36 Hz,
1H) 7.36 (t, J=9.46 Hz, 1H) 7.42 (s, 1H) 7.76-7.85 (m, 1H)
8.02-8.08 (m, 1H) 10.49 (s, 1H); Method B; Rt: 1.02 min. m/z: 428
(M-H).sup.- Exact mass: 429.1.
Compound 87:
(3R)--N-(3-cyano-4-fluoro-phenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-di-
oxo-dihydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00141##
[0533] Compound 87 (55 mg) was prepared similarly as described for
compound 84, using 5-amino-2-fluoro-benzonitrile instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.20 (d, J=6.2 Hz, 3H), 3.60-3.77 (m, 4H), 3.77-3.87 (m, 1H),
4.97 (d, J=5.7 Hz, 1H), 5.97 (dd, J=12.5, 2.6 Hz, 1H), 6.57 (dd,
J=12.5, 2.4 Hz, 1H), 7.40 (br d, J=9.5 Hz, 1H), 7.55 (t, J=9.1 Hz,
1H), 7.59 (s, 1H), 7.98 (ddd, J=9.2, 4.8, 2.8 Hz, 1H), 8.20 (dd,
J=5.7, 2.6 Hz, 1H), 10.85 (br s, 1H); Method B; Rt: 0.74 min. m/z:
403 (M-H).sup.- Exact mass: 404.1.
Compound 88:
(3R)--N-(3,4-difluorophenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2-
,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00142##
[0535] Methyl
(3R)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]-
-thiazepine-6-carboxylate (200 mg, 0.67 mmol) was dissolved in MeOH
(30 mL). Under a nitrogen atmosphere Pd/C (10%) (71 mg, 0.067 mmol)
was added. The reaction mixture was set under a hydrogen atmosphere
for 60 minutes. The reaction mixture was filtered over decalite and
the solids were washed with methanol (4.times.100 mL) and THF
(4.times.100 mL). The filtrate was evaporated to dryness to afford
methyl
(3R)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo-
[3,4-f]thiazepine-6-carboxylate (180 mg) as a white powder. Method
B; Rt: 0.59 min. m/z: 301 (M-H).sup.- Exact mass: 302.1.
[0536] Methyl
(3R)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo-
[3,4-f]thiazepine-6-carboxylate (90 mg, 0.24 mmol) and
3,4-difluoro-aniline (40 mg, 0.31 mmol) were dissolved in THF (5
mL). Lithium bis(trimethylsilyl)-amide (1.6 mL, 1 M in THF, 1.6
mmol) was added and the reaction mixture was stirred 1 hour at room
temperature. The reaction was quenched with NH.sub.4Cl (sat., aq.,
5 mL) and the organic layer was separated. The aqueous layer was
extracted with DCM (2.times.4 mL) and the combined organic layers
were dried (Na.sub.2SO.sub.4) and evaporated to dryness. The
residue was purified via preparative HPLC (Stationary phase: RP
XBridge Prep C18 OBD-10 .mu.m, 50.times.150 mm, Mobile phase: 0.25%
NH.sub.4HCO.sub.3 solution in water, ACN). The obtained product was
purified using silica gel column chromatography (ethyl acetate in
heptane from 0 to 100%) yielding compound 88 (35 mg). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.13 (d, J=6.2 Hz, 3H),
1.20-1.35 (m, 1H), 2.18 (br dd, J=14.3, 6.8 Hz, 1H), 2.67-2.80 (m,
1H), 3.02 (br dd, J=14.9, 6.5 Hz, 1H), 3.14-3.27 (m, 1H), 3.43-3.51
(m, 1H), 3.68 (s, 3H), 4.67 (d, J=5.9 Hz, 1H), 6.89 (d, J=10.1 Hz,
1H), 7.38-7.46 (m, 3H), 7.81-7.89 (m, 1H), 10.47 (s, 1H); Method B;
Rt: 0.78 min. m/z: 398 (M-H).sup.- Exact mass: 399.1.
Compound 89:
N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3-tetrahydropyran-4-yl-3,4-dihy-
dro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00143##
[0538] Compound 89 (320 mg) was prepared similarly as described for
compound 14, using 2-amino-2-(oxan-4-yl)ethan-1-ol hydrochloride
instead of DL-alaninol. The ring closure was obtained after heating
90 minutes at 110.degree. C. in DMF and compound 83 was purified on
silica using a gradient from heptane to EtOAc. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 1.24-1.44 (m, 2H), 1.60-1.79 (m,
3H), 3.20-3.29 (m, 2H), 3.42-3.51 (m, 1H), 3.81-4.04 (m, 6H), 4.72
(d, J=12.5 Hz, 1H), 7.36-7.50 (m, 3H), 7.62 (d, J=9.6 Hz, 1H), 7.86
(ddd, J=13.2, 7.5, 2.5 Hz, 1H), 9.42 (s, 1H); Method D; Rt: 1.80
min. m/z: 440 (M-H).sup.- Exact mass: 441.1. This racemic mixture
was seperated in enantiomers 89a (101 mg) and 89b (75 mg) by
preparative SFC (Stationary phase: Chiralpak Diacel AD 20.times.250
mm, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2). Method J; Rt:
89a: 1.39 min, 89b: 2.96 min.
Compound 90:
(3R)--N-(3-cyano-4-fluoro-phenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-di-
oxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00144##
[0540] Compound 90 (38 mg) was prepared similarly as described for
compound 88, using 5-amino-2-fluoro-benzonitrile instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.13 (d, J=6.2 Hz, 3H), 1.20-1.35 (m, 1H), 2.19 (br dd, J=14.2,
6.9 Hz, 1H), 2.71-2.81 (m, 1H), 3.05 (br dd, J=15.0, 6.4 Hz, 1H),
3.16-3.27 (m, 1H), 3.47 (sxt, J=6.4 Hz, 1H), 3.69 (s, 3H), 4.67 (d,
J=5.7 Hz, 1H), 6.90 (d, J=10.1 Hz, 1H), 7.44 (s, 1H), 7.54 (t,
J=9.1 Hz, 1H), 7.96 (ddd, J=9.1, 4.8, 2.8 Hz, 1H), 8.19 (dd, J=5.7,
2.6 Hz, 1H), 10.59 (s, 1H); Method B; Rt: 0.73 min. m/z: 405
(M-H).sup.- Exact mass: 406.1.
Compound 91:
N-(3-cyano-4-fluoro-phenyl)-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-
-b][1,4,5]oxathiazepine-6-carboxamide
##STR00145##
[0542] Ethyl 3-hydroxy-1-methyl-pyrrole-2-carboxylate (200 mg, 1.0
mmol) was dissolved in THF (8 mL) under nitrogen and NaH (60%
dispersion in mineral oil) (64 mg, 1.61 mmol) was added at room
temperature and stirred for 10 minutes before
2-(tert-butoxycarbonylamino)ethyl methanesulfonate (361 mg, 1.51
mmol) was added. The solution was heated overnight at 80.degree. C.
The solution was quenched with ice water diluted with EtOAc,
extracted twice with EtOAc, and the combined organics were dried
with MgSO.sub.4, filtered, and concentrated in vacuo. The residue
was purified on silica using gradient elution (heptane/EtOAc from
100/0 to 50/50) to yield ethyl
3-[2-(tert-butoxycarbonylamino)ethoxy]-1-methyl-pyrrole-2-carboxylate
(238 mg) as an oil.
[0543] Ethyl 3-[2-(tert-butoxy
carbonylamino)ethoxy]-1-methyl-pyrrole-2-carboxylate (235 mg, 0.68
mmol) was dissolved in DCM (4 mL) and chlorosulfonic acid (0.090
mL, 1.75 g/mL, 1.354 mmol) was added under inert atmosphere at
0.degree. C. and stirred for 2 hours. The solution was concentrated
in vacuo to give
4-(2-aminoethoxy)-5-ethoxy-carbonyl-1-methyl-pyrrole-3-sulfonic
acid (197 mg).
[0544]
4-(2-aminoethoxy)-5-ethoxycarbonyl-1-methyl-pyrrole-3-sulfonic acid
(197 mg, 0.6 mmol) was dissolved in DCM (4 mL) and SOCl.sub.2
(0.218 mL, 1.64 g/mL, 2.999 mmol) was added and the solution was
heated for 2 hours at 70.degree. C. The solution was coevaporated
with toluene until dryness. The residue was redissolved in MeOH and
quenched with NaHCO.sub.3(aq. sat.). The excess salts were filtered
off and the residue concentrated in vacuo. The crude was then
further purified on silica using a DCM/MeOH from 100/0 to 90/10
gradient to give ethyl
7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-ca-
rboxylate (85 mg) as a yellow solid. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.36 (t, J=7.2 Hz, 3H) 3.62-3.70 (m, 2H)
3.83 (s, 3H) 4.28-4.36 (m, 4H) 4.87 (br s, 1H) 7.03 (s, 1H).
[0545] Ethyl
7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-ca-
rboxylate (67 mg, 0.22 mmol) was dissolved in THF (4 mL) and
5-amino-2-fluoro-benzonitrile (33 mg, 0.24 mmol) was added followed
by lithium bis(trimethylsilyl)-amide (0.87 mL, 1 M in THF, 0.87
mmol) at room temperature under an inert atmosphere and stirred for
2 hours. The solution was quenched with NH.sub.4Cl (sat., aq.) and
the organics were removed in vacuo, diluted with DCM, separated,
dried with Na.sub.2SO.sub.4, filtered off, and concentrated in
vacuo. The crude was then purified via preparative HPLC to give
compound 91 (15 mg). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm 3.77-3.83 (m, 2H), 3.97 (s, 3H), 4.43-4.47 (m, 2H), 4.72 (t,
J=6.9 Hz, 1H), 7.11 (s, 1H), 7.18-7.22 (m, 1H), 7.72 (ddd, J=9.1,
4.5, 2.8 Hz, 1H), 7.96 (dd, J=5.4, 2.8 Hz, 1H), 8.86 (s, 1H);
Method B; Rt: 0.82 min. m/z: 363 (M-H).sup.- Exact mass: 364.1.
Compound 92:
(3S)-3-[cyclopropyl(hydroxy)methyl]-N-(3,4-difluorophenyl)-7-methyl-1,1-d-
ioxo-3
4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00146##
[0547] To a cooled solution of
(S)-(-)-3-boc-2,2-dimethyloxazolidine-4-carboxaldehyde in dry THF
(20 mL) at -78.degree. C. was added cyclopropylmagnesium bromide
(4.83 mL, 1M in THF, 4.83 mmol). The reaction mixture was warmed
slowly to room temperature and stirred for 4 hours. The reaction
mixture was quenched with water (20 ml) and then EtOAc was added
(10 ml) to extract the product (some NaCl was added to get all THF
out of the water layer). The water layer was extracted once more
with EtOAc. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and evaporated to dryness and the crude
oil was purified on silica (from 0% to 40% EtOAc in heptane). All
pure fractions were collected and evaporated to get tert-butyl
(4S)-4-[cyclopropyl(hydroxy)methyl]-2,2-dimethyl-oxazolidine-3-carboxylat-
e (679 mg) as a clear yellow oil. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 0.20-0.65 (m, 4H), 0.75-0.99 (m, 1H),
1.38-1.78 (m, 15H), 2.98-3.57 (m, 2H), 3.87-4.35 (m, 3H).
[0548] HCl (2.35 mL, 4 M in dioxane, 9.41 mmol) was added to a
solution of tert-butyl
(4S)-4-[cyclopropyl(hydroxy)methyl]-2,2-dimethyl-oxazolidine-3-carboxylat-
e (679 mg, 2.35 mmol) in 1,4-dioxane (10 mL). The reaction mixture
was stirred at rt for 150 minutes. The reaction mixture was
concentrated under reduced pressure to yield
(2S)-2-amino-1-cyclopropyl-propane-1,3-diol hydrochloride (308 mg)
which was used as such.
[0549] Ethyl
4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (667 mg,
2.47 mmol) was added to a solution of
(2S)-2-amino-1-cyclopropyl-propane-1,3-diol hydrochloride (308.26
mg, 2.35 mmol) and Hunig's base (2.56 mL, 0.75 g/mL, 14.8 mmol) in
DCM (15 mL) at room temperature under nitrogen atmosphere. The
reaction mixture was stirred at room temperature overnight. A part
of the DCM was concentrated and the reaction mixture was directly
purified on silica (heptane/ethyl acetate 100/0 to 0/100) to afford
ethyl
4-[[(1S)-2-cyclopropyl-2-hydroxy-1-(hydroxymethyl)ethyl]sulfamoyl]-3-fluo-
ro-1-methyl-pyrrole-2-carboxylate (756 mg). Method B; Rt: 0.66 min.
m/z: 363 (M-H).sup.- Exact mass: 364.1.
[0550] Lithium bis(trimethylsilyl)amide (5.5 mL, 1 M in THF, 5.5
mmol) was added dropwise to a solution of ethyl
4-[[(1S)-2-cyclopropyl-2-hydroxy-1-(hydroxymethyl)ethyl]sulfamoyl]-3-fluo-
ro-1-methyl-pyrrole-2-carboxylate (400 mg, 1.1 mmol) and
3,4-difluoroaniline (0.13 mL, 1.29 g/mL, 1.32 mmol) in THF (15 mL).
The reaction mixture was stirred at room temperature for 30 min.
The reaction mixture was quenched by adding water and diluted in
ethyl acetate. The aqueous layer was extracted twice with ethyl
acetate. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered off and concentrated under reduced
pressure. The residue was purified on silica (heptane/ethyl acetate
100/0 to 0/100) to afford
4-[[(1S)-2-cyclopropyl-2-hydroxy-1-(hydroxymethyl)ethyl]sulfamoyl]-N-(3,4-
-difluorophenyl)-3-fluoro-1-methyl-pyrrole-2-carboxamide (250
mg).
[0551] Cesium fluoride (272 mg, 1.79 mmol) was added to a solution
of
4-[[(1S)-2-cyclo-propyl-2-hydroxy-1-(hydroxymethyl)ethyl]sulfamoyl]-N-(3,-
4-difluorophenyl)-3-fluoro-1-methyl-pyrrole-2-carboxamide (200 mg,
0.45 mmol) in DMF (5 mL). The reaction mixture was stirred at
110.degree. C. for 7 hours. The reaction mixture was concentrated
and purified on silica (heptane/ethyl acetate 100/0 to 0/100). The
obtained product was purified via preparative SFC (Stationary
phase: Chiralpak Diacel AD 20.times.250 mm, Mobile phase: CO.sub.2,
EtOH-iPrOH (50-50)+0.4% iPrNH.sub.2) to yield compound 92a (34 mg);
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.25-0.50 (m, 4H),
0.98-1.10 (m, 1H), 3.03-3.14 (m, 1H), 3.56-3.67 (m, 1H), 3.83 (s,
3H), 4.00 (dd, J=12.8, 9.2 Hz, 1H), 4.91 (dd, J=12.8, 1.8 Hz, 1H),
5.00 (d, J=5.7 Hz, 1H), 7.35-7.50 (m, 3H), 7.60 (d, J=9.9 Hz, 1H),
7.87 (ddd, J=13.3, 7.5, 2.5 Hz, 1H), 9.43 (s, 1H); Method D; Rt:
1.78 min. m/z: 426 (M-H).sup.- Exact mass: 427.1, and 92b (11 mg);
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.17-0.47 (m, 4H),
0.95-1.08 (m, 1H), 3.04-3.18 (m, 1H), 3.82 (s, 4H), 3.93-4.10 (m,
1H), 4.74 (dd, J=12.7, 1.4 Hz, 1H), 5.00 (d, J=5.1 Hz, 1H),
7.34-7.49 (m, 4H), 7.86 (ddd, J=13.2, 7.5, 2.4 Hz, 1H), 9.35-9.48
(m, 1H); Method D; Rt: 1.77 min. m/z: 426 (M-H).sup.- Exact mass:
427.1 being the 2 epimers of compound 92. Method P; Rt: 92a: 1.88
min, 92b: 2.27 min.
Compound 93:
(3R)--N-(3,4-difluorophenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-di-
oxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00147##
[0553] Methylmagnesium bromide (12.7 mL, 3 M, 38.2 mmol) was added
to a solution of (R)-3-tert-butyl 4-methyl
2,2-dimethyloxazolidine-3,4-dicarboxylate (3 g, 1.08 g/mL, 11.6
mmol) in THF (100 mL) at -20.degree. C. under a nitrogen
atmosphere. The reaction mixture was stirred at 0.degree. C. for 4
h and then the reaction mixture was quenched with NH.sub.4Cl (sat.,
aq.) and diluted in EtOAc. The two layers were separated and the
aqueous layer was extracted with EtOAc (twice). The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified on
silica (heptane/EtOAc 100/0 to 70/30 to afford tert-butyl
(4R)-4-(1-hydroxy-1-methyl-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylate
(2.11 g) as a light yellow oil.
[0554] Compound 93 (188 mg) was prepared similarly as described for
compound 92, using tert-butyl
(4R)-4-(1-hydroxy-1-methyl-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylate
instead of tert-butyl
(4S)-4-[cyclopropyl(hydroxy)methyl]-2,2-dimethyl-oxazolidine-3-carboxylat-
e. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.13 (d, J=6.2
Hz, 3H), 1.20-1.35 (m, 1H), 2.19 (br dd, J=14.2, 6.9 Hz, 1H),
2.71-2.81 (m, 1H), 3.05 (br dd, J=15.0, 6.4 Hz, 1H), 3.16-3.27 (m,
1H), 3.47 (sxt, J=6.4 Hz, 1H), 3.69 (s, 3H), 4.67 (d, J=5.7 Hz,
1H), 6.90 (d, J=10.1 Hz, 1H), 7.44 (s, 1H), 7.54 (t, J=9.1 Hz, 1H),
7.96 (ddd, J=9.1, 4.8, 2.8 Hz, 1H), 8.19 (dd, J=5.7, 2.6 Hz, 1H),
10.59 (s, 1H); Method B; Rt: 0.73 min. m/z: 405 (M-H).sup.- Exact
mass: 406.1.
Compound 94:
(3S)--N-(3,4-difluorophenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-di-
oxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00148##
[0556] Compound 94 (300 mg) was prepared similarly as described for
compound 93, using
(S)-(-)-3-tert-butoxycarbonyl-4-methoxycarbonyl-2,2-dimethyl-1,3-oxazolid-
ine instead of (R)-3-tert-butyl 4-methyl
2,2-dimethyloxazolidine-3,4-dicarboxylate. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.06 (s, 3H), 1.25 (s, 3H), 3.55 (t,
J=9.4 Hz, 1H), 3.83 (s, 3H), 3.92 (dd, J=12.5, 9.0 Hz, 1H), 4.85
(s, 1H), 4.96 (d, J=11.4 Hz, 1H), 7.33-7.54 (m, 4H), 7.87 (ddd,
J=13.2, 7.5, 2.4 Hz, 1H), 9.43 (s, 1H); Method B; Rt: 0.88 min.
m/z: 414 (M-H).sup.- Exact mass: 415.1. MP: 234.1.degree. C.
Compound 95:
N-(3,4-difluorophenyl)-3-[hydroxy(3-pyridyl)methyl]-7-methyl-1,1-dioxo-3,-
4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00149##
[0558] To a solution of KOH (2.48 g, 44.2 mmol) in EtOH (100 mL) at
0.degree. C. was added 3-pyridinecarboxaldehyde (4.66 mL, 1.14
g/mL, 48.6 mmol) and ethyl isocyanoacetate (4.85 mL, 1.03 g/mL,
44.2 mmol). The reaction mixture was stirred for 3 hours and then
concentrated to yield an oil. This was redissolved in HCl (37% in
H.sub.2O, 50 mL) and heated at 60.degree. C. for 2 hours. The
formed precipitate was filtered off to give
2-amino-3-hydroxy-3-(3-pyridyl)propanoic acid (8.3 g).
[0559] In a 250 mL flask 2-amino-3-hydroxy-3-(3-pyridyl)propanoic
acid (8.3 g, 32.5 mmol) was dissolved in dry MeOH (50 mL) and
cooled till 5.degree. C. SOCl.sub.2 (11.8 mL, 1.64 g/mL, 163 mmol)
was added dropwise and after addition the reaction was heated at
reflux for 3 hours. The reaction mixture was concentrated to
dryness and partitioned between DCM and NaHCO.sub.3(sat., aq.). The
organic layer was dried over MgSO.sub.4 and evaporated to dryness
yielding methyl 2-amino-3-hydroxy-3-(3-pyridyl)propanoate (8.76 g)
as a light yellow oil.
[0560] Methyl 2-amino-3-hydroxy-3-(3-pyridyl)propanoate (8.76 g,
32.5 mmol), BOC-anhydride (7.32 g, 32.5 mmol) and Et3N (22.6 mL,
0.73 g/mL, 163 mmol) were dissolved in THF (150 mL) and stirred 3
hours at room temperature. The volatiles were removed under reduced
pressure and the residue was separated between water and 2-MeTHF.
The organic layer was removed and concentrated under reduced
pressure. The residue was purified on silica using a heptane to
EtOAc:EtOH 3:1 gradient yielding methyl
2-(tert-butoxycarbonylamino)-3-hydroxy-3-(3-pyridyl)propanoate (3.3
g). Method B; Rt: 0.65 min. m/z: 295 (M-H).sup.- Exact mass:
296.1.
[0561] Methyl
2-(tert-butoxycarbonylamino)-3-hydroxy-3-(3-pyridyl)propanoate (3.3
g, 11.1 mmol) was dispensed in dioxane (100 mL). LAH (12 mL, 1 M in
THF, 12 mmol) was added and the reaction mixture was stirred
overnight at 80.degree. C. The reaction mixture was quenched with
sodium sulfate decahydrate (550 mg, 1.7 mmol) and then dried with
MgSO.sub.4. The solids were filtered off and the filtrate was
evaporated to dryness. The residue was purified on silica using a
heptane to EtOAc:EtOH 3:1 gradient yielding tert-butyl
N-[2-hydroxy-1-(hydroxymethyl)-2-(3-pyridyl)ethyl]-carbamate (763
mg) as a white powder.
[0562] tert-butyl
N-[2-hydroxy-1-(hydroxymethyl)-2-(3-pyridyl)ethyl]carbamate (350
mg, 1.3 mmol) was dissolved in DCM (10 mL). TFA (300 .mu.L, 1.49
g/mL, 3.91 mmol) was added and the reaction mixture was stirred
overnight. TFA (300 .mu.L, 1.49 g/mL, 3.91 mmol) was added and the
reaction mixture was stirred for 2 days at 40.degree. C. Hunig's
base (2.25 mL, 0.75 g/mL, 13.04 mmol) was added and this reaction
mixture was used as such in the further synthesis.
[0563] Compound 95 (15.2 mg) was prepared similarly as described
for compound 63, using the previously described reaction mixture
instead of (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 3.80 (s, 3H), 3.91-3.97 (m,
1H), 3.97-4.06 (m, 1H), 4.82 (d, J=11.7 Hz, 1H), 4.99 (d, J=3.3 Hz,
1H), 5.91 (br s, 1H), 7.36-7.50 (m, 4H), 7.53 (br s, 1H), 7.78 (dt,
J=7.7, 1.8 Hz, 1H), 7.82-7.90 (m, 1H), 8.48 (dd, J=4.8, 1.5 Hz,
1H), 8.59 (d, J=1.8 Hz, 1H), 9.49 (s, 1H); Method B; Rt: 0.84 min.
m/z: 463 (M-H).sup.- Exact mass: 464.1.
Compound 96:
(3R)--N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-[(1S)-1-hydroxyethyl]-7-me-
thyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00150##
[0565] Compound 96 (177 mg) was prepared similarly as described for
compound 84, using 3-(difluoromethyl)-4-fluoro-aniline instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.20 (d, J=6.2 Hz, 3H), 3.64-3.76 (m, 4H), 3.76-3.88 (m, 1H),
4.96 (d, J=5.9 Hz, 1H), 5.96 (dd, J=12.5, 2.9 Hz, 1H), 6.56 (dd,
J=12.5, 2.6 Hz, 1H), 7.23 (t, J=54.4 Hz, 1H), 7.32-7.44 (m, 2H),
7.57 (s, 1H), 7.80-7.85 (m, 1H), 8.07 (dd, J=6.4, 2.4 Hz, 1H),
10.75 (br s, 1H); Method B; Rt: 0.81 min. m/z: 428 (M-H).sup.-
Exact mass: 429.1. MP: 182.3.degree. C.
Compound 97:
(3R)--N-(2-bromo-4-pyridyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2,-
3-dihydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00151##
[0567] Compound 97 (134 mg) was prepared similarly as described for
compound 84, using 4-amino-2-bromopyridine instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.21 (d, J=6.2 Hz, 3H), 3.64-3.91 (m, 5H), 4.98 (d, J=5.7 Hz,
1H), 5.99 (dd, J=12.5, 2.9 Hz, 1H), 6.56 (dd, J=12.5, 2.6 Hz, 1H),
7.42 (d, J=10.3 Hz, 1H), 7.59-7.67 (m, 2H), 7.97 (d, J=1.8 Hz, 1H),
8.29 (d, J=5.7 Hz, 1H), 11.04 (s, 1H); Method B; Rt: 0.69 min. m/z:
439 (M-H).sup.- Exact mass: 440.0.
Compound 98: (3R)-3-[(1
S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-N-(3,4,5-trifluoro-phenyl)-2,3-dihy-
dropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00152##
[0569] Compound 98 (146 mg) was prepared similarly as described for
compound 84, using 3,4,5-trifluoroaniline instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.21 (d, J=6.2 Hz, 3H), 3.54-3.74 (m, 4H), 3.76-3.90 (m, 1H),
4.98 (d, J=5.7 Hz, 1H), 5.98 (dd, J=12.5, 2.6 Hz, 1H), 6.54 (dd,
J=12.5, 2.4 Hz, 1H), 7.40 (br d, J=10.1 Hz, 1H), 7.54-7.66 (m, 3H),
10.85 (br s, 1H); Method B; Rt: 0.86 min. m/z: 414 (M-H).sup.-
Exact mass: 415.1. MP: 244.0.degree. C.
Compound 99: (3R)--N-(4-fluoro-3-methyl-phenyl)-3-[(1
S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]thiazepine-
-6-carboxamide
##STR00153##
[0571] Compound 99 (134 mg) was prepared similarly as described for
compound 84, using 4-fluoro-3-methylaniline instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.20 (d, J=6.2 Hz, 3H), 2.23 (d, J=1.5 Hz, 3H), 3.64-3.76 (m,
4H), 3.76-3.88 (m, 1H), 4.96 (br d, J=5.5 Hz, 1H), 5.94 (dd,
J=12.5, 2.6 Hz, 1H), 6.53 (dd, J=12.5, 2.6 Hz, 1H), 7.12 (t, J=9.2
Hz, 1H), 7.37 (br d, J=8.1 Hz, 1H), 7.48-7.53 (m, 1H), 7.54 (s,
1H), 7.63 (dd, J=6.9, 2.3 Hz, 1H), 10.49 (s, 1H); Method B; Rt:
0.80 min. m/z: 392 (M-H).sup.- Exact mass: 393.1.
Compound 100:
(3R)--N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-(1-hydroxy-1-methyl-ethyl)-
-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-ca-
rboxamide
##STR00154##
[0573] Compound 100 (216 mg) was prepared similarly as described
for compound 93, using 3-(difluoromethyl)-4-fluoro-aniline instead
of 3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.06 (s, 3H), 1.25 (s, 3H), 3.55 (br t, J=9.5 Hz, 1H), 3.83 (s,
3H), 3.94 (dd, J=12.5, 8.8 Hz, 1H), 4.86 (s, 1H), 4.95 (d, J=11.4
Hz, 1H), 7.06-7.37 (m, 2H), 7.47-7.53 (m, 2H), 7.77-7.85 (m, 1H),
8.04 (dd, J=6.3, 2.5 Hz, 1H), 9.47 (s, 1H); Method B; Rt: 0.90 min.
m/z: 446 (M-H).sup.- Exact mass: 447.1.
Compound 101:
(3S)--N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-(1-hydroxy-1-methyl-ethyl)-
-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-ca-
rboxamide
##STR00155##
[0575] Compound 101 (132.8 mg) was prepared similarly as described
for compound 94, using 3-(difluoromethyl)-4-fluoro-aniline instead
of 3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.06 (s, 3H), 1.25 (s, 3H), 3.55 (t, J=9.4 Hz, 1H), 3.83 (s,
3H), 3.93 (dd, J=12.5, 9.0 Hz, 1H), 4.86 (s, 1H), 4.95 (d, J=11.4
Hz, 1H), 7.05-7.39 (m, 2H), 7.45-7.55 (m, 2H), 7.77-7.85 (m, 1H),
8.04 (dd, J=6.3, 2.5 Hz, 1H), 9.47 (s, 1H); Method B; Rt: 0.89 min.
m/z: 446 (M-H).sup.- Exact mass: 447.1. MP: 214.4.degree. C.
Compound 102:
(3R)--N-(3,4-difluorophenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-di-
oxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00156##
[0577] A solution of tert-butyl
(2R)-2-(benzyloxycarbonylamino)hex-5-ynoate (5.03 g, 15.8 mmol) and
ethyl isocyanoacetate (5.10 g, 42.8 mmol) in dioxane (15 mL) was
added dropwise at 90.degree. C. during 45 minutes to a solution of
ethyl isocyanoacetate (1.50 g, 12.6 mmol) in dioxane (20 mL)
wherein silver carbonate (947 mg, 3.44 mmol) was suspended. The
reaction mixture was heated and stirred further at this temperature
during 3 hours. The reaction mixture was filtered while still hot
and concentrated. The residue was subjected to silica column
chromatography using a gradient from 10 till 100% EtOAc in heptane
resulting in ethyl
3-[(3R)-3-(benzyloxycarbonylamino)-4-tert-butoxy-4-oxo-butyl]-1H-pyrrole--
2-carboxylate (1.98 g) as a clear oil. TFA (5.3 mL, 1.49 g/mL, 69
mmol) was added to ethyl
3-[(3R)-3-(benzyloxycarbonyl-amino)-4-tert-butoxy-4-oxo-butyl]-1H-pyrrole-
-2-carboxylate (1.98 g, 4.6 mmol) in DCM (50 mL) and stirred for 3
hours. The reaction mixture was concentrated and redissolved in DMF
(50 mL). MeI (6.24 mL, 2.28 g/mL, 100 mmol) and Cs.sub.2CO.sub.3
(13 g, 40 mmol) were added and the reaction mixture was stirred
overnight. The reaction mixture was filtered and directly loaded on
a silica cartridge. A gradient from 0 till 100% EtOAc in heptane
was applied yielding ethyl
3-[(3R)-3-(benzyloxycarbonyl-amino)-4-methoxy-4-oxo-butyl]-1-methyl-pyrro-
le-2-carboxylate (1.70 g). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.26 (t, J=7.2 Hz, 3H), 1.76-1.87 (m, 1H), 1.87-2.00
(m, 1H), 2.67-2.78 (m, 2H), 3.62 (s, 3H), 3.78 (s, 3H), 3.94-4.06
(m, 1H), 4.19 (q, J=7.0 Hz, 2H), 5.05 (s, 2H), 5.93 (d, J=2.4 Hz,
1H), 6.96 (d, J=2.4 Hz, 1H), 7.27-7.42 (m, 5H), 7.77 (d, J=7.7 Hz,
1H); Method D; Rt: 2.07 min. m/z: 401 (M-H).sup.- Exact mass:
402.2.
[0578] Chlorosulfonic acid (112 mg, 0.96 mmol) was added to a
solution of ethyl
3-[(3R)-3-(benzyloxycarbonylamino)-4-methoxy-4-oxo-butyl]-1-methyl--
pyrrole-2-carboxylate (193 mg, 0.48 mmol) in DCM (20 mL) and
stirred for 1 hour. Thionyl chloride (285 mg, 2.4 mmol) was added
and the reaction mixture was stirred and refluxed 2 hours and then
cooled in an icebath and quenched with methanol (1 mL). The mixture
was poured in NaHCO.sub.3(aq. sat., 100 mL). The mixture was
extracted with DCM (2.times.50 mL) and the combined organic layers
were dried over magnesium sulfate, filtered and concentrated. The
residue was purified by column chromatography using a gradient from
0 till 100% EtOAc in heptane yielding 06-ethyl 03-methyl
(3R)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-3,6-di-
carboxylate (58.8 mg) as a white powder. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.29 (t, J=7.0 Hz, 3H), 1.61-1.74 (m,
1H), 2.16-2.26 (m, 1H), 2.81 (br dd, J=14.1, 12.1 Hz, 1H),
3.62-3.72 (m, 4H), 3.80 (s, 3H), 4.22-4.30 (m, 3H), 7.56 (s, 1H),
7.74 (d, J=9.9 Hz, 1H); Method D; Rt: 1.60 min. m/z: 329
(M-H).sup.- Exact mass: 330.1.
[0579] Methylmagnesium chloride (0.12 mL, 3 M, 0.35 mmol) was added
to 06-ethyl 03-methyl
(3R)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-3,6-di-
carboxylate (58.8 mg, 0.168 mmol) in THF (10 mL) at -78.degree. C.
The reaction mixture was allowed immediately to reach room
temperature. Another equal amount methylmagnesium chloride (0.12
mL, 3 M, 0.35 mmol) was added at -78.degree. C. and the reaction
mixture allowed to reach room temperature. Methylmagnesium chloride
(0.04 mL, 3 M, 0.12 mmol) was added at 20.degree. C. and the
reaction mixture was stirred for 15 minutes. The reaction mixture
was quenched with HCl (aq., 1M, 30 mL) diluted with brine (50 mL)
and extracted with EtOAc (3.times.50 mL). The combined organic
layers were dried over MgSO.sub.4, filtered and concentrated. The
residue was subjected to silica gel column chromatography using a
gradient from 0 till 100% EtOAc in heptane yielding ethyl
(3R)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropy-
rrolo[3,4-f]thiazepine-6-carboxylate (26 mg) as a clear oil. Method
D; Rt: 1.46 min. m/z: 329 (M-H).sup.- Exact mass: 330.1.
[0580] Lithium bis(trimethylsilyl)amide (0.32 mL, 1 M in THF, 0.32
mmol) was added to a solution of ethyl
(3R)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropy-
rrolo[3,4-f]thiazepine-6-carboxylate (26 mg, 0.0787 mmol) and
3,4-difluoro-aniline (21 mg, 0.16 mmol) in THF (2 mL) and stirred
for 30 minutes. Another 3 times this amount of 3,4-difluoroaniline
(21 mg, 0.16 mmol) and lithium bis(trimethylsilyl)-amide (0.32 mL,
1 M in THF, 0.32 mmol) were added and the reaction mixture was
stirred for 1 hour. The reaction mixture was quenched with
NH.sub.4Cl solution (aq. sat., 10 mL), diluted with brine (10 mL)
and extracted with EtOAc (50 mL). The organic layer was dried over
MgSO.sub.4, filtered and concentrated. The residue was subjected to
silica gel column chromatography using a gradient from 0 till 100%
EtOAc in heptane. The product fractions were concentrated and the
residue subjected to silica gel column chromatography using a
gradient from 5 till 30% iPrOH in heptane yielding compound 102 (12
mg) as a beige resin. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.20-1.31 (m, 6H), 1.47-1.59 (m, 1H), 1.70 (br s, 1H),
2.09-2.18 (m, 1H), 2.89-2.99 (m, 1H), 3.17 (td, J=7.7, 5.5 Hz, 1H),
3.39-3.51 (m, 1H), 3.74 (s, 3H), 4.67 (d, J=10.3 Hz, 1H), 7.09-7.18
(m, 2H), 7.19-7.25 (m, 1H), 7.70 (ddd, J=12.0, 7.2, 2.4 Hz, 1H),
8.20 (s, 1H); Method D; Rt: 1.58 min. m/z: 412 (M-H).sup.- Exact
mass: 413.1; MP: 218.2.degree. C.
Compound 103:
(3R)--N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-[(1S)-1-hydroxyethyl]-7-me-
thyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00157##
[0582] Compound 96 (109 mg, 0.25 mmol) was dissolved in MeOH (30
mL). Under a nitrogen atmosphere Pd/C (10%) (27 mg, 0.025 mmol) was
added. The reaction mixture was hydrogenated for 60 minutes. The
reaction mixture was filtered over decalite and the solids were
washed with THF (4.times.80 mL). The filtrate was evaporated to
dryness and the residue was purified using silica gel column
chromatography (EtOAc in heptane from 0 to 100%) to afford compound
103 (70 mg) as a white powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.13 (d, J=6.2 Hz, 3H), 1.19-1.37 (m, 1H), 2.19 (br dd,
J=14.3, 6.8 Hz, 1H), 2.71-2.81 (m, 1H), 3.05 (br dd, J=15.3, 6.1
Hz, 1H), 3.16-3.29 (m, 1H), 3.40-3.54 (m, 1H), 3.69 (s, 3H), 4.67
(d, J=5.7 Hz, 1H), 6.89 (d, J=10.1 Hz, 1H), 7.22 (t, J=54.2 Hz,
1H), 7.37 (t, J=9.6 Hz, 1H), 7.42 (s, 1H), 7.78-7.84 (m, 1H),
8.04-8.09 (m, 1H), 10.48 (s, 1H); Method B; Rt: 0.80 min. m/z: 430
(M-H).sup.- Exact mass: 431.1. MP: 274.7.degree. C.
Compound 104:
(3R)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-N-(3,4,5-trifluoro-phenyl-
)-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00158##
[0584] Compound 98 (75 mg, 0.18 mmol) was dissolved in MeOH (30
mL). Under a nitrogen atmosphere Pd/C (10%) (19 mg, 0.018 mmol) was
added. The reaction mixture was hydrogenated for 60 minutes. The
reaction mixture was filtered over decalite and the solids were
washed with THF (4.times.80 mL). The filtrate was evaporated to
dryness and the residue was purified using silica gel column
chromatography (EtOAc in heptane from 0 to 100%) to afford compound
104 (37 mg) as a white powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.13 (d, J=6.4 Hz, 3H), 1.19-1.36 (m, 1H), 2.18 (br dd,
J=14.2, 7.2 Hz, 1H), 2.71-2.80 (m, 1H), 3.02 (br dd, J=15.4, 5.9
Hz, 1H), 3.16-3.28 (m, 1H), 3.33-3.54 (m, 1H), 3.68 (s, 3H), 4.67
(d, J=5.9 Hz, 1H), 6.90 (d, J=10.3 Hz, 1H), 7.44 (s, 1H), 7.56-7.64
(m, 2H), 10.58 (s, 1H); Method B; Rt: 0.85 min. m/z: 416
(M-H).sup.- Exact mass: 417.1.
Compound 105:
(3R)-3-[cyclopropyl(hydroxy)methyl]-N-(3,4-difluorophenyl)-7-methyl-1,1-d-
ioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00159##
[0586] Compound 105 (310 mg) was prepared similarly as described
for compound 92, using
(R)-(-)-3-boc-2,2-dimethyloxazolidine-4-carboxaldehyde instead of
(S)-(-)-3-boc-2,2-dimethyloxazolidine-4-carboxaldehyde. The
obtained product was purified via preparative SFC (Stationary
phase: Chiralpak Diacel AD 20.times.250 mm, Mobile phase: CO.sub.2,
EtOH+0.4% iPrNH.sub.2) to yield compound 105a (60 mg); .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 0.16-0.27 (m, 1H), 0.27-0.36
(m, 1H), 0.36-0.48 (m, 2H), 0.94-1.09 (m, 1H), 3.13 (dt, J=7.5, 4.0
Hz, 1H), 3.72-3.80 (m, 1H), 3.83 (s, 3H), 4.04 (dd, J=12.8, 9.2 Hz,
1H), 4.75 (dd, J=12.7, 1.4 Hz, 1H), 5.01 (d, J=4.8 Hz, 1H),
7.33-7.52 (m, 4H), 7.86 (ddd, J=13.2, 7.5, 2.4 Hz, 1H), 9.45 (s,
1H); Method D; Rt: 1.77 min. m/z: 426 (M-H).sup.- Exact mass:
427.1; MP: 243.0.degree. C., and 105b (203 mg); .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 0.22-0.41 (m, 3H), 0.41-0.53 (m,
1H), 0.98-1.11 (m, 1H), 3.03-3.14 (m, 1H), 3.56-3.70 (m, 1H), 3.83
(s, 3H), 4.00 (dd, J=12.8, 9.2 Hz, 1H), 4.91 (dd, J=12.8, 1.8 Hz,
1H), 5.01 (d, J=5.5 Hz, 1H), 7.34-7.51 (m, 3H), 7.61 (d, J=9.7 Hz,
1H), 7.87 (ddd, J=13.2, 7.5, 2.4 Hz, 1H), 9.43 (s, 1H); Method D;
Rt: 1.77 min. m/z: 426 (M-H).sup.- Exact mass: 427.1; MP:
244.8.degree. C., being the 2 epimers of compound 105. Method K;
Rt: 105a: 1.98 min, 105b: 1.68 min.
Compound 106:
(3R)--N-(3-cyano-4-fluoro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1-
,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00160##
[0588] Compound 106 (134 mg) was prepared similarly as described
for compound 93, using 5-amino-2-fluoro-benzonitrile instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.06 (s, 3H), 1.25 (s, 3H), 3.55 (br t, J=9.5 Hz, 1H), 3.84 (s,
3H), 3.93 (dd, J=12.5, 9.0 Hz, 1H), 4.86 (s, 1H), 4.99 (d, J=11.4
Hz, 1H), 7.46-7.56 (m, 3H), 8.06 (ddd, J=9.2, 4.8, 2.9 Hz, 1H),
8.21 (dd, J=5.7, 2.9 Hz, 1H), 9.52 (s, 1H); Method B; Rt: 0.83 min.
m/z: 421 (M-H).sup.- Exact mass: 422.1; MP: 260.1.degree. C.
Compound 107:
(3S)--N-(3-cyano-4-fluoro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1-
,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00161##
[0590] Compound 107 (111.4 mg) was prepared similarly as described
for compound 94, using 5-amino-2-fluoro-benzonitrile instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.06 (s, 3H), 1.25 (s, 3H), 3.55 (br t, J=7.6 Hz, 1H), 3.84 (s,
3H), 3.93 (dd, J=12.4, 8.9 Hz, 1H), 4.86 (s, 1H), 4.99 (d, J=11.4
Hz, 1H), 7.46-7.56 (m, 3H), 8.06 (ddd, J=9.2, 4.9, 2.9 Hz, 1H),
8.21 (dd, J=5.7, 2.9 Hz, 1H), 9.52 (s, 1H); Method B; Rt: 0.85 min.
m/z: 421 (M-H).sup.- Exact mass: 422.1. MP: 259.8.degree. C.
Compound 108:
N-[2-(difluoromethyl)-4-pyridyl]-3-isopropyl-7-methyl-1,1-dioxo-2,3,4,5-t-
etrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00162##
[0592] Compound 108 (10.8 mg) was prepared similarly as described
for compound 85, using 2-(difluoromethyl)pyridin-4-amine instead of
5-amino-2-fluoro-benzonitrile. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 0.86-0.89 (m, 3H) 0.89-0.92 (m, 3H) 1.32-1.47 (m, 1H)
1.62-1.74 (m, 1H) 1.82-1.93 (m, 1H) 2.74-2.88 (m, 1H) 2.99-3.10 (m,
1H) 3.19-3.27 (m, 1H) 3.71 (s, 3H) 6.73-7.08 (m, 2H) 7.47 (s, 1H)
7.70-7.82 (m, 1H) 8.03 (d, J=1.76 Hz, 1H) 8.56 (d, J=5.72 Hz, 1H)
10.85 (s, 1H); Method B; Rt: 0.88 min. m/z: 411 (M-H).sup.- Exact
mass: 412.1.
Compound 109:
N-(4-fluoro-3-methyl-phenyl)-3-isopropyl-7-methyl-1,1-dioxo-2,3,4,5-tetra-
hydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00163##
[0594] Compound 109 (16.1 mg) was prepared similarly as described
for compound 85, using 4-fluoro-3-methylaniline instead of
5-amino-2-fluoro-benzonitrile. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 0.89 (dd, J=6.82, 3.52 Hz, 6H) 1.38 (q, J=11.88 Hz, 1H)
1.62-1.74 (m, 1H) 1.86 (br dd, J=13.97, 6.71 Hz, 1H) 2.22 (d,
J=1.32 Hz, 3H) 2.73-2.84 (m, 1H) 2.95-3.06 (m, 1H) 3.18-3.28 (m,
1H) 3.68 (s, 3H) 6.87 (br d, J=10.12 Hz, 1H) 7.10 (t, J=9.13 Hz,
1H) 7.39 (s, 1H) 7.45-7.54 (m, 1H) 7.58-7.66 (m, 1H) 10.23 (s, 1H);
Method B; Rt: 1.03 min. m/z: 392 (M-H).sup.- Exact mass: 393.1.
Compound 110:
N-(3,4-difluorophenyl)-3-(dimethylaminomethyl)-7-methyl-1,1-dioxo-3,4-dih-
ydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00164##
[0596] Compound 83 (105 mg, 0.27 mmol), MsCl (31 .mu.L, 1.48 g/mL,
0.41 mmol) and TEA (150 .mu.L, 0.73 g/mL, 1.08 mmol) were dissolved
in DCM (10 mL) and stirred for 2 hours. Water was added and a
precipitate appeared. This was filtered off, triturated with DIPE
and dried to yield
[6-[(3,4-difluorophenyl)carbamoyl]-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrr-
olo[3,4-b][1,4,5]oxathiazepin-3-yl]methyl methanesulfonate (64 mg)
as a white powder.
[0597]
[6-[(3,4-difluorophenyl)carbamoyl]-7-methyl-1,1-dioxo-3,4-dihydro-2-
H-pyrrolo[3,4-b]-[1,4,5]oxathiazepin-3-yl]methyl methanesulfonate
(10 mg, 0.021 mmol) was dissolved in dimethylamine (3 mL, 2M in
THF) and stirred for 4 hours at room temperature. The volatiles
were removed under reduced pressure and the residue was purified on
silica using a heptane to EtOAc gradient yielding compound 110 (2
mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.32 (s, 6H),
2.42 (dd, J=12.2, 5.8 Hz, 1H), 2.66 (dd, J=12.2, 9.6 Hz, 1H),
3.62-3.79 (m, 1H), 3.86-3.97 (m, 4H), 4.14 (dd, J=13.0, 5.7 Hz,
1H), 4.85 (dd, J=13.0, 2.4 Hz, 1H), 7.05 (s, 1H), 7.07-7.15 (m,
2H), 7.61-7.67 (m, 1H), 8.72 (s, 1H); Method B; Rt: 0.86 min. m/z:
413 (M-H).sup.- Exact mass: 414.1.
Compound 111:
(3R)--N-(2-bromo-4-pyridyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2,-
3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00165##
[0599] Compound 111 (20.5 mg) was prepared similarly as described
for compound 90, using 4-amino-2-bromopyridine instead of
5-amino-2-fluoro-benzonitrile. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.13 (d, J=6.2 Hz, 3H), 1.22-1.34 (m, 1H), 2.18 (br dd,
J=14.2, 6.7 Hz, 1H), 2.72-2.81 (m, 1H), 3.03 (br dd, J=14.7, 6.4
Hz, 1H), 3.16-3.28 (m, 1H), 3.47 (sxt, J=6.2 Hz, 1H), 3.70 (s, 3H),
4.68 (d, J=5.9 Hz, 1H), 6.92 (d, J=10.3 Hz, 1H), 7.47 (s, 1H), 7.62
(dd, J=5.6, 1.9 Hz, 1H), 7.96 (d, J=1.8 Hz, 1H), 8.27 (d, J=5.5 Hz,
1H), 10.78 (s, 1H); Method B; Rt: 0.67 min. m/z: 441 (M-H).sup.-
Exact mass: 442.0.
Compound 112:
(3R)--N-(4-fluoro-3-methyl-phenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,1-d-
ioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00166##
[0601] Compound 112 (56 mg) was prepared similarly as described for
compound 90, using 4-fluoro-3-methylaniline instead of
5-amino-2-fluoro-benzonitrile. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.13 (d, J=6.2 Hz, 3H), 1.29 (q, J=11.9 Hz, 1H),
2.13-2.24 (m, 4H), 2.70-2.79 (m, 1H), 3.02 (br dd, J=14.9, 6.5 Hz,
1H), 3.16-3.25 (m, 1H), 3.47 (sxt, J=6.2 Hz, 1H), 3.67 (s, 3H),
4.66 (d, J=5.7 Hz, 1H), 6.87 (d, J=10.1 Hz, 1H), 7.10 (t, J=9.2 Hz,
1H), 7.39 (s, 1H), 7.47-7.52 (m, 1H), 7.62 (dd, J=7.0, 2.2 Hz, 1H),
10.23 (s, 1H); Method B; Rt: 0.79 min. m/z: 394 (M-H).sup.- Exact
mass: 395.1. MP: 287.3.degree. C.
Compound 113:
(3S)--N-(3,4-difluorophenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-di-
oxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00167##
[0603] To a solution of methyl
3-acetyl-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]-thiazepine-6-
-carboxylate (1000 mg, 3.33 mmol) in THF (15 mL) under nitrogen
atmosphere at -78.degree. C. was added methylmagnesium bromide
(2.55 mL, 3 M in diethyl ether, 7.66 mmol). The reaction mixture
was stirred 90 minutes at -78.degree. C. methylmagnesium bromide
(2.55 mL, 3 M in diethyl ether, 7.66 mmol) was added to the
reaction mixture and the reaction was quenched with NH.sub.4Cl
(sat., aq., 4 mL) and allowed to reach room temperature. The
reaction mixture was filtered and the solids were washed with THF
(3.times.100 mL). The filtrate was washed with brine and dried
(Na.sub.2SO.sub.4), and concentrated to afford a white foam. The
residue was purified using silica gel column chromatography (EtOAc
in heptane from 0 to 100%) to afford methyl
3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo-
[3,4-f]-thiazepine-6-carboxylate (910 mg) as a white powder.
[0604] Methyl
3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo-
[3,4-f]thiazepine-6-carboxylate (220 mg, 0.63 mmol) and
3,4-difluoro-aniline (106 mg, 0.82 mmol) were dissolved in THF (5
mL). Lithium bis-(trimethylsilyl)amide (4.11 mL, 1 M in THF, 4.11
mmol) was added and the reaction mixture was stirred 4 hours at
room temperature. The reaction was quenched with NH.sub.4Cl (sat.,
aq., 5 mL) and the organic layer was separated. The aqueous layer
was extracted with 2-MeTHF (2.times.4 mL) and the combined organic
layers were evaporated to dryness. The residue was purified using
preparative HPLC (Stationary phase: RP)(Bridge Prep C18 OBD-10
.mu.m, 50.times.150 mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3
solution in water, ACN). The obtained product (222 mg) was
separated into its enantiomers via preparative SFC (Stationary
phase: Chiralpak Diacel AD 20.times.250 mm, Mobile phase: CO.sub.2,
EtOH+0.4 iPrNH.sub.2) yielding compound 113 (105 mg), .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.03 (s, 3H), 1.17 (s, 3H),
1.24-1.39 (m, 1H), 2.16 (br dd, J=13.9, 6.8 Hz, 1H), 2.66-2.78 (m,
1H), 3.03 (br dd, J=14.6, 6.1 Hz, 1H), 3.22-3.35 (m, 1H), 3.69 (s,
3H), 4.39 (s, 1H), 6.83 (br d, J=10.1 Hz, 1H), 7.38-7.46 (m, 3H),
7.81-7.88 (m, 1H), 10.47 (br s, 1H); Method D; Rt: 1.60 min. m/z:
412 (M-H).sup.- Exact mass: 413.1; MP: 217.7.degree. C. and
compound 102 (105 mg). Method F; Rt: 113: 1.15 min, 102: 1.85
min.
Compound 114:
N-(3,4-difluorophenyl)-3-(1-hydroxy-2-methyl-propyl)-7-methyl-1,1-dioxo-3-
,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00168##
[0606] To a cooled solution (-78.degree. C.) of ethyl
2-(dibenzylamino)acetate (2.0 g, 7.1 mmol) in dry THF was added
dropwise lithium bis(trimethylsilyl)amide (24.7 mL, 1 M in THF,
24.7 mmol) while keeping the temperature below -50.degree. C. The
solution was stirred for 30 min at -78.degree. C. The
isobutyraldehyde (2.32 mL, 0.79 g/mL, 24.7 mmol) was added slowly
keeping the temperature below -50.degree. C. and the reaction
mixture was stirred for 3 hours. The reaction mixture was warmed to
0.degree. C. and then it was quenched with NH.sub.4Cl (sat., aq.).
Then EtOAc was added to extract the product. The combined organic
layers were dried over Na.sub.2SO.sub.4, filtered and evaporated.
The residue was purified and separated into its 2 diastereoisomers
by silica gel column chromatography (0% to 50% EtOAc in heptane)
yielding diastereoisomer 1 (492 mg); .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 0.60 (d, J=6.8 Hz, 3H), 0.87-1.02 (m,
3H), 1.39 (t, J=7.2 Hz, 3H), 1.50-1.62 (m, 1H), 3.27 (d, J=9.9 Hz,
1H), 3.41 (d, J=13.2 Hz, 2H), 3.84 (dd, J=9.9, 3.1 Hz, 1H), 4.04
(d, J=13.2 Hz, 2H), 4.21-4.40 (m, 2H), 7.18-7.39 (m, 10H); Method
D; Rt: 2.54 min. m/z: 356 (M+H).sup.+ Exact mass: 355.2 and
diastereoisomer 2 (1.45 g); .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 0.35 (d, J=6.8 Hz, 3H), 0.92 (d, J=7.0 Hz, 3H), 1.43
(t, J=7.2 Hz, 3H), 2.08-2.20 (m, 2H), 3.32 (d, J=9.2 Hz, 1H), 3.44
(d, J=13.4 Hz, 2H), 3.83-3.87 (m, 1H), 3.90 (d, J=13.6 Hz, 2H),
4.23-4.45 (m, 2H), 7.20-7.28 (m, 2H), 7.29-7.38 (m, 8H); Method D;
Rt: 2.47 min. m/z: 356 (M+H).sup.+ Exact mass: 355.2
[0607] To a solution of diastereoisomer 2 (1.35 g, 3.81 mmol) in
dry THF (30 mL) was added LAH (2.29 mL, 1 M in THF, 4.57 mmol) at
-70.degree. C. The reaction mixture was warmed slowly to room
temperature and stirred overnight. LAH (0.20 mL, 1 M in THF, 0.20
mmol) was added and the reaction mixture was stirred 4.5 hours. The
reaction mixture was quenched carefully with EtOAc (30 mL) and it
was stirred for 5 minutes. Then Na.sub.2SO.sub.4.10H.sub.2O was
added and this was again stirred for 15 min. Then anhydrous
Na.sub.2SO.sub.4 was added. The solids were filtered off and the
filtrate was evaporated to dryness. The residue was purified on
silica (0% to 50% EtOAc in DCM) yielding
2-(dibenzylamino)-4-methyl-pentane-1,3-diol (1.19 g) as a clear
oil. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.65 (d, J=6.8
Hz, 3H), 0.89 (d, J=6.8 Hz, 3H), 1.44-1.73 (m, 2H), 1.99 (dtd,
J=13.6, 6.8, 6.8, 4.8 Hz, 1H), 2.79 (q, J=5.9 Hz, 1H), 3.61-3.86
(m, 6H), 3.96 (dd, J=11.1, 6.3 Hz, 1H), 7.14-7.45 (m, 10H); Method
D; Rt: 2.19 min. m/z: 314 (M+H).sup.+ Exact mass: 313.2.
[0608] Pd(OH).sub.2/C (50% w/w with respect to A) was added to a
solution of 2-(dibenzylamino)-4-methyl-pentane-1,3-diol in degassed
MeOH and the resulting suspension was stirred 1 hour at room
temperature under a hydrogen atmosphere. The reaction mixture was
filtered through a pad of dicalite and concentrated in vacuo to
yield 2-amino-4-methyl-pentane-1,3-diol (485 mg).sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 0.93 (d, J=6.6 Hz, 3H), 1.00 (d,
J=6.6 Hz, 3H), 1.79 (dq, J=13.5, 6.8 Hz, 1H), 2.44 (br s, 4H), 3.00
(q, J=4.7 Hz, 1H), 3.28 (dd, J=7.2, 5.0 Hz, 1H), 3.65-3.81 (m,
2H).
[0609] 2-amino-4-methyl-pentane-1,3-diol (485 mg, 3.64 mmol) was
suspended in DCM (20 mL) and DIPEA (1.26 mL, 0.75 g/mL, 7.28 mmol)
was added. The reaction mixture was stirred for 5 minutes. Ethyl
4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (982 mg,
3.64 mmol) was added. The suspension was stirred at room
temperature for 5 hours. The reaction mixture was diluted with some
DCM and then quenched with NaHCO.sub.3(aq. sat.). The water layer
was extracted two times more with DCM. The combined organic layers
were evaporated to dryness and the residue was purified by silica
gel chromatography (0% to 100% EtOAc in DCM) yielding ethyl
3-fluoro-4-[[2-hydroxy-1-(hydroxymethyl)-3-methyl-butyl]sulfamoyl]-1-meth-
yl-pyrrole-2-carboxylate (870 mg) as a white sticky solid. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.68 (d, J=6.6 Hz, 3H),
0.83 (d, J=6.8 Hz, 3H), 1.28 (t, J=7.0 Hz, 3H), 1.74-1.84 (m, 1H),
3.05-3.17 (m, 1H), 3.17-3.25 (m, 1H), 3.41-3.51 (m, 2H), 3.81 (s,
3H), 4.27 (q, J=7.0 Hz, 2H), 4.33 (t, J=5.5 Hz, 1H), 4.53 (d, J=5.7
Hz, 1H), 7.28 (br d, J=8.1 Hz, 1H), 7.52 (d, J=4.8 Hz, 1H); Method
D; Rt: 1.45 min. m/z: 367 (M+H).sup.+ Exact mass: 366.1.
[0610] To a solution of ethyl
3-fluoro-4-[[2-hydroxy-1-(hydroxymethyl)-3-methyl-butyl]-sulfamoyl]-1-met-
hyl-pyrrole-2-carboxylate (410 mg, 1.06 mmol) and
3,4-difluoro-aniline (0.13 mL, 1.29 g/mL, 1.28 mmol) in dry THF (10
mL) was added drop wise lithium bis(trimethylsilyl)amide (5.3 mL, 1
M in THF, 5.3 mmol) at room temperature under a nitrogen
atmosphere. The reaction mixture was stirred at room temperature
for 30 min. The reaction mixture was quenched with NH.sub.4Cl (aq.
sat.) and then diluted with EtOAc. The aqueous layer was extracted
twice with EtOAc. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was triturated with diethylether to form
N-(3,4-difluorophenyl)-3-fluoro-4-[[2-hydroxy-1-(hydroxymethyl)-3-methyl--
butyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide (253 mg) as a white
solid.
[0611]
N-(3,4-difluorophenyl)-3-fluoro-4-[[2-hydroxy-1-(hydroxymethyl)-3-m-
ethyl-butyl]-sulfamoyl]-1-methyl-pyrrole-2-carboxamide (253 mg,
0.55 mmol) and cesium fluoride (335 mg, 2.21 mmol) were dissolved
in dry DMF and heated overnight at 110.degree. C. The reaction
mixture was added slowly into an ice/water mixture. When the
suspension had reached room temperature, the formed yellow solid
was filtered off. The water layer was extracted with ether. The
solid and the ether-crude were redissolved in MeOH and evaporated
together with dicalite to be purified by silica gel chromatography
(0% to 75% EtOAc in DCM) yielding compound 114. This racemic
mixture was separated in enantiomers 114a (69 mg); .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 0.83 (d, J=6.8 Hz, 3H), 0.92 (d,
J=6.8 Hz, 3H), 2.01 (quind, J=6.8, 6.8, 6.8, 6.8, 3.0 Hz, 1H),
3.21-3.29 (m, 1H), 3.47-3.62 (m, 1H), 3.82 (s, 3H), 3.97 (dd,
J=12.7, 8.9 Hz, 1H), 4.89 (dd, J=12.7, 1.9 Hz, 1H), 4.95 (d, J=6.4
Hz, 1H), 7.31-7.68 (m, 4H), 7.87 (ddd, J=13.1, 7.4, 2.5 Hz, 1H),
9.43 (s, 1H); Method D; Rt: 1.83 min. m/z: 430 (M+H).sup.+ Exact
mass: 429.1; MP: 245.7.degree. C. and 114b (62 mg).sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 0.83 (d, J=6.8 Hz, 3H), 0.92 (d,
J=7.0 Hz, 3H), 2.01 (quind, J=6.8, 6.8, 6.8, 6.8, 3.1 Hz, 1H),
3.23-3.30 (m, 1H), 3.49-3.62 (m, 1H), 3.82 (s, 3H), 3.97 (dd,
J=12.7, 8.9 Hz, 1H), 4.89 (dd, J=12.5, 1.8 Hz, 1H), 4.95 (d, J=6.6
Hz, 1H), 7.33-7.51 (m, 3H), 7.52-7.65 (m, 1H), 7.87 (ddd, J=13.2,
7.5, 2.4 Hz, 1H), 9.43 (s, 1H); Method D; Rt: 1.84 min. m/z: 430
(M+H).sup.+ Exact mass: 429.1; MP: 247.3.degree. C., by preparative
SFC (Stationary phase: Chiralpak Diacel AD 20.times.250 mm, Mobile
phase: CO.sub.2, EtOH with 0.4% iPrNH.sub.2). Method K; Rt:
114a:1.18 min, 114b: 1.79 min.
Compound 115:
(3R)-3-[cyclopropyl(hydroxy)methyl]-N-[3-(difluoromethyl)-4-fluoro-phenyl-
]-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-c-
arboxamide
##STR00169##
[0613] Compound 115 (541 mg) was prepared similarly as described
for compound 105, using 3-(difluoromethyl)-4-fluoro-aniline instead
of 3,4-difluoroaniline. This racemic mixture was separated in its
epimers via preparative SFC (Stationary phase: Chiralpak Diacel AD
20.times.250 mm, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2)
yielding 115a (130 mg) .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 0.20-0.55 (m, 4H), 0.98-1.12 (m, 1H), 3.02-3.16 (m, 1H),
3.55-3.70 (m, 1H), 3.83 (s, 3H), 4.02 (dd, J=12.9, 9.1 Hz, 1H),
4.90 (dd, J=12.8, 1.8 Hz, 1H), 5.01 (br d, J=4.6 Hz, 1H), 7.02-7.40
(m, 2H), 7.47 (s, 1H), 7.60 (br s, 1H), 7.76-7.89 (m, 1H), 8.05
(dd, J=6.3, 2.5 Hz, 1H), 9.47 (s, 1H); Method D; Rt: 1.76 min. m/z:
458 (M-H).sup.- Exact mass: 459.1 and 115b (44 mg) .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 0.16-0.27 (m, 1H), 0.27-0.36 (m,
1H), 0.37-0.50 (m, 2H), 0.95-1.09 (m, 1H), 3.05-3.19 (m, 1H),
3.71-3.81 (m, 1H), 3.83 (s, 3H), 4.06 (dd, J=12.8, 9.2 Hz, 1H),
4.74 (dd, J=12.8, 1.3 Hz, 1H), 5.00 (br d, J=4.2 Hz, 1H), 7.02-7.57
(m, 4H), 7.75-7.86 (m, 1H), 8.03 (dd, J=6.4, 2.6 Hz, 1H), 9.48 (s,
1H); Method D; Rt: 1.76 min. m/z: 458 (M-H).sup.- Exact mass:
459.1; MP: 240.7.degree. C. Method N; Rt: 115a: 1.75 min, 115b:
2.01 min.
Compound 116:
N-(3-cyano-4-fluoro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-dio-
xo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00170##
[0615] Compound 116 (200 mg) was prepared similarly as described
for compound 113, using 5-amino-2-fluoro-benzonitrile instead of
3,4-difluoroaniline. This racemic mixture was separated in its
enantiomers via preparative SFC (Stationary phase: Chiralpak Diacel
AD 20.times.250 mm, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2)
yielding 116a (54 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.03 (s, 3H), 1.17 (s, 3H), 1.28-1.39 (m, 1H), 2.17 (br dd,
J=14.0, 6.5 Hz, 1H), 2.66-2.79 (m, 1H), 3.06 (br dd, J=14.9, 6.3
Hz, 1H), 3.22-3.29 (m, 1H), 3.69 (s, 3H), 4.39 (s, 1H), 6.84 (br d,
J=10.6 Hz, 1H), 7.45 (s, 1H), 7.54 (t, J=9.1 Hz, 1H), 7.96 (ddd,
J=9.2, 4.9, 2.6 Hz, 1H), 8.19 (dd, J=5.9, 2.6 Hz, 1H), 10.59 (s,
1H); Method D; Rt: 1.49 min. m/z: 419 (M-H).sup.- Exact mass: 420.1
and 116b (52 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.03 (s, 3H), 1.17 (s, 3H), 1.34 (q, J=11.5 Hz, 1H), 2.17 (br dd,
J=13.9, 6.8 Hz, 1H), 2.68-2.78 (m, 1H), 3.06 (br dd, J=14.5, 6.2
Hz, 1H), 3.23-3.29 (m, 1H), 3.69 (s, 3H), 4.39 (s, 1H), 6.84 (br d,
J=10.6 Hz, 1H), 7.45 (s, 1H), 7.54 (t, J=9.1 Hz, 1H), 7.96 (ddd,
J=9.1, 4.8, 2.8 Hz, 1H), 8.19 (dd, J=5.7, 2.6 Hz, 1H), 10.59 (s,
1H); Method D; Rt: 1.49 min. m/z: 419 (M-H).sup.- Exact mass:
420.1. Method F; Rt: 116a:1.29 min, 116b: 2.03 min.
Compound 117:
N-(3-cyano-4-fluoro-phenyl)-7-methyl-1,1-dioxo-3-(2,2,2-trifluoro-1-hydro-
xy-1-methyl-ethyl)-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamid-
e
##STR00171##
[0617] A DMF (5 ml) solution of methyl
3-acetyl-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6--
carboxylate (156 mg, 0.52 mmol), (trifluoromethyl)-trimethylsilane
(220 mg, 1.55 mmol) and TBAF (13.5 mg, 0.052 mmol) was stirred at
100.degree. C. for 2 hours. (Trifluoromethyl)trimethylsilane (220
mg, 1.55 mmol) and CsF (79 mg. 0.52 mmol) were added to the
reaction mixture. The reaction mixture was heated at 100.degree. C.
for 1 hour. Then the mixture was cooled to room temperature and HCl
(aq., 1M. 2 ml) was added. After 18 hours, the mixture was quenched
with NaHCO.sub.3 (aq. sat., 20 mL), and the product was extracted
with EtOAc (4.times.6 mL). The combined organic layers were dried
over Na.sub.2SO.sub.4, evaporation and purification through silica
gel column chromatography (EtOAc in heptane from 0 to 100%) yielded
methyl
7-methyl-1,1-dioxo-3-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-2,3,4,5-t-
etrahydropyrrolo[3,4-f]thiazepine-6-carboxylate (36 mg) as a yellow
powder. Method B; Rt: 0.76 min. m/z: 369 (M-H).sup.- Exact mass:
370.1.
[0618] Methyl
7-methyl-1,1-dioxo-3-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-2,3,4,5-t-
etrahydropyrrolo[3,4-f]thiazepine-6-carboxylate (36 mg, 0.097 mmol)
and 5-amino-2-fluoro-benzonitrile (17 mg, 0.13 mmol) were dissolved
in THF (5 mL). Lithium bis(trimethylsilyl)amide (0.63 mL, 1 M in
THF, 0.63 mmol) was added and the reaction mixture was stirred at
room temperature for 1 hour. The reaction was quenched with
NH.sub.4Cl (sat., aq., 5 mL) and the organic layer was separated.
The aqueous layer was extracted with EtOAc (2.times.10 mL) and the
combined organic layers were evaporated to dryness. The residue was
purified using preparative HPLC (Stationary phase: RP XBridge Prep
C18 OBD-10 .mu.m, 50.times.150 mm, Mobile phase: 0.25%
NH.sub.4HCO.sub.3 solution in water, ACN). The obtained product was
purified using silica gel column chromatography (EtOAc in heptane
from 0 to 100%) to afford compound 117 (18 mg) as a white powder.
.sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.20 (s, 3H),
1.38-1.46 (m, 1H), 2.13 (br dd, J=13.8, 7.0 Hz, 1H), 2.75-2.80 (m,
1H), 3.07-3.15 (m, 1H), 3.70 (s, 3H), 3.78 (br t, J=10.8 Hz, 1H),
6.16 (s, 1H), 7.23 (d, J=11.2 Hz, 1H), 7.49 (s, 1H), 7.55 (t, J=9.1
Hz, 1H), 7.96 (ddd, J=9.2, 4.8, 2.7 Hz, 1H), 8.19 (dd, J=5.7, 2.6
Hz, 1H), 10.63 (s, 1H); Method B; Rt: 0.86 min. m/z: 473
(M-H).sup.- Exact mass: 474.1.
Compound 118:
N-(3-cyano-4-fluoro-phenyl)-3-(1,1-difluoroethyl)-7-methyl-1,1-dioxo-2,3,-
4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00172##
[0620] At room temperature to a solution of methyl
3-acetyl-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6--
carboxylate (518 mg, 1.72 mmol) in DCM (7 mL) was added DAST (0.69
mL, 1.32 g/mL, 5.7 mmol). The reaction mixture was stirred for 18
hours. DAST (0.69 mL, 1.32 g/mL, 5.7 mmol) was added and the
reaction mixture was stirred for 18 hours, cooled to 0.degree. C.
and quenched by addition of NaCl (aq. sat., 2 mL). The aqueous
phase was separated and extracted with DCM (3.times.8 mL). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered
and concentrated. The residue was purified by silica gel column
chromatography (EtOAc in heptane 0-50%) to give methyl
3-(1,1-difluoroethyl)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,44]--
thiazepine-6-carboxylate (56 mg). Method B; Rt: 0.84 min. m/z: 321
(M-H).sup.- Exact mass: 322.1.
[0621] Methyl
3-(1,1-difluoroethyl)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]-
-thiazepine-6-carboxylate (56 mg, 0.15 mmol) and
5-amino-2-fluoro-benzonitrile (26 mg, 0.19 mmol) were dissolved in
THF (3 mL). Lithium bis(trimethylsilyl)amide (1 mL, 1 M in THF, 1
mmol) was added and the reaction mixture was stirred at room
temperature for 1 hour. The reaction was quenched with NH.sub.4Cl
(sat., aq., 5 mL) and the organic layer was separated. The aqueous
layer was extracted with EtOAc (2.times.10 mL) and the combined
organic layers were evaporated to dryness. The residue was purified
using silica gel column chromatography (EtOAc in heptane from 0 to
100%). The obtained product was purified via HPLC (Stationary
phase: RP)(Bridge Prep C18 OBD-10 .mu.m, 50.times.150 mm, Mobile
phase: 0.25% NH.sub.4HCO.sub.3 solution in water, ACN) to yield
compound 118 (21 mg). .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta.
ppm 1.48-1.59 (m, 1H), 1.64 (t, J=19.3 Hz, 3H), 2.04-2.11 (m, 1H),
2.77-2.88 (m, 1H), 3.09-3.19 (m, 1H), 3.69-3.86 (m, 4H), 7.50-7.70
(m, 3H), 7.96 (ddd, J=9.2, 4.8, 2.6 Hz, 1H), 8.19 (dd, J=5.8, 2.8
Hz, 1H), 10.64 (br s, 1H); Method B; Rt: 0.93 min. m/z: 425
(M-H).sup.- Exact mass: 426.1.
Compound 119:
N-(3-cyano-4-fluoro-phenyl)-3-(1-hydroxy-2-methyl-propyl)-7-methyl-1,1-di-
oxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00173##
[0623] Compound 119 (165 mg) was prepared similarly as described
for compound 114, using 5-amino-2-fluoro-benzonitrile instead of
3,4-difluoroaniline. This racemic mixture was separated in its
epimers via preparative SFC (Stationary phase: Chiralpak Diacel AD
20.times.250 mm, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2)
yielding 119a (49 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 0.83 (d, J=6.8 Hz, 3H), 0.92 (d, J=6.8 Hz, 3H), 1.95-2.08 (m,
1H), 3.23-3.30 (m, 1H), 3.48-3.62 (m, 1H), 3.83 (s, 3H), 3.97 (dd,
J=12.8, 9.0 Hz, 1H), 4.87-4.99 (m, 2H), 7.46-7.55 (m, 2H), 7.60 (d,
J=9.9 Hz, 1H), 8.05 (ddd, J=9.1, 4.8, 2.8 Hz, 1H), 8.21 (dd, J=5.7,
2.6 Hz, 1H), 9.52 (s, 1H); Method D; Rt: 1.75 min. m/z: 435
(M-H).sup.- Exact mass: 436.1; MP: 213.7.degree. C. and 119b (44
mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.84 (d, J=6.8
Hz, 3H), 0.92 (d, J=7.0 Hz, 3H), 2.02 (quind, J=6.8, 6.8, 6.8, 6.8,
3.0 Hz, 1H), 3.24-3.30 (m, 1H), 3.56 (qd, J=9.4, 1.7 Hz, 1H), 3.83
(s, 3H), 3.97 (dd, J=12.8, 9.0 Hz, 1H), 4.86-5.01 (m, 2H),
7.45-7.55 (m, 2H), 7.60 (d, J=9.9 Hz, 1H), 8.05 (ddd, J=9.2, 4.9,
2.6 Hz, 1H), 8.21 (dd, J=5.8, 2.8 Hz, 1H), 9.52 (s, 1H); Method D;
Rt: 1.75 min. m/z: 435 (M-H).sup.- Exact mass: 436.1; MP:
213.7.degree. C. Method N; Rt: 119a:1.50 min, 119b:
[0624] 2.78 min.
Compound 120:
(3R)--N-(3-cyano-4-fluoro-phenyl)-3-[cyclopropyl(hydroxy)methyl]-7-methyl-
-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00174##
[0626] Compound 120 (225 mg) was prepared similarly as described
for compound 105, using 5-amino-2-fluoro-benzonitrile instead of
3,4-difluoroaniline. This racemic mixture was separated in its
epimers via preparative SFC (Stationary phase: Chiralpak Diacel AD
20.times.250 mm, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2)
yielding 120a (84 mg).sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 0.23-0.52 (m, 4H), 0.98-1.11 (m, 1H), 3.03-3.14 (m, 1H),
3.57-3.69 (m, 1H), 3.83 (s, 3H), 4.01 (dd, J=12.8, 9.2 Hz, 1H),
4.94 (dd, J=12.8, 1.8 Hz, 1H), 5.01 (d, J=5.5 Hz, 1H), 7.45-7.55
(m, 2H), 7.62 (d, J=9.9 Hz, 1H), 8.06 (ddd, J=9.2, 4.8, 2.9 Hz,
1H), 8.21 (dd, J=5.8, 2.8 Hz, 1H), 9.52 (s, 1H); Method D; Rt: 1.69
min. m/z: 433 (M-H).sup.- Exact mass: 434.1 and 120b (36 mg).sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.15-0.28 (m, 1H),
0.28-0.36 (m, 1H), 0.36-0.49 (m, 2H), 0.95-1.08 (m, 1H), 3.09-3.16
(m, 1H), 3.73-3.81 (m, 1H), 3.83 (s, 3H), 4.05 (dd, J=12.8, 9.2 Hz,
1H), 4.77 (dd, J=12.5, 1.3 Hz, 1H), 5.02 (d, J=5.1 Hz, 1H),
7.41-7.58 (m, 3H), 8.04 (ddd, J=9.2, 4.8, 2.9 Hz, 1H), 8.19 (dd,
J=5.7, 2.6 Hz, 1H), 9.54 (s, 1H); Method D; Rt: 1.69 min. m/z: 433
(M-H).sup.- Exact mass: 434.1; MP: 233.9.degree. C. Method O; Rt:
120a:1.81 min, 120b: 2.77 min.
Compound 121:
(3S)--N-(3,4-difluorophenyl)-3-(1-fluoro-1-methyl-ethyl)-7-methyl-1,1-dio-
xo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00175##
[0628] Diethylaminosulfur trifluoride (90 .mu.L, 1 M, 0.09 mmol)
was added dropwise to a solution of compound 94 (25 mg, 0.06 mmol)
in DCM (0.46 mL, 1.33 g/mL, 7.2 mmol) at 0.degree. C. under a
nitrogen atmosphere. The reaction mixture was stirred at 0.degree.
C. for 15 minutes. The reaction mixture was allowed to reach room
temperature and concentrated under reduced pressure. The residue
was purified via preparative HPLC (Stationary phase: RP Vydac
Denali C18-10 .mu.m, 200 g, 5 cm, Mobile phase: 0.25%
NH.sub.4HCO.sub.3 solution in water, MeOH). The obtained product
was purified by preparative SFC (Stationary phase: Chiralpak Diacel
AD 20 microhm 2000 gr, Mobile phase: CO.sub.2, EtOH+0.4
iPrNH.sub.2) yielding compound 121 (46.9 mg). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.41 (dd, J=39.2, 22.2 Hz, 6H), 3.72-3.81
(m, 1H), 3.83 (s, 3H), 4.01 (dd, J=12.4, 9.1 Hz, 1H), 4.88 (d,
J=11.4 Hz, 1H), 7.34-7.54 (m, 3H), 7.82-7.93 (m, 2H), 9.43 (s, 1H);
.sup.19F NMR (377 MHz, DMSO-d.sub.6) .delta. ppm 144.56 (d, J=23.1
Hz, 1F), --141.28 (s, 1F), --137.61 (d, J=23.1 Hz, 1F); Method D;
Rt: 1.96 min. m/z: 416 (M-H).sup.- Exact mass: 417.1; MP:
239.8.degree. C.
Compound 122:
(3R)--N-(3-cyano-4-fluoro-phenyl)-3-(1-hydroxypropyl)-7-methyl-1,1-dioxo--
3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00176##
[0630] Compound 122 (262 mg) was prepared similarly as described
for compound 105, using ethylmagnesium bromide instead of
cyclopropylmagnesium bromide and 5-amino-2-fluoro-benzonitrile
instead of 3,4-difluoroaniline. The racemic mixture was separated
in its epimers via preparative SFC (Stationary phase: Kromasil
(R,R) Whelk-O 1 10/100, Mobile phase: CO.sub.2, EtOH+0.4%
iPrNH.sub.2) to yield compound 122a (113 mg); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.92 (t, J=7.4 Hz, 3H), 1.44 (dquin,
J=14.2, 7.2, 7.2, 7.2, 7.2 Hz, 1H), 1.65-1.79 (m, 1H), 3.35-3.44
(m, 1H), 3.44-3.56 (m, 1H), 3.83 (s, 3H), 3.98 (dd, J=12.7, 8.9 Hz,
1H), 4.93 (dd, J=12.8, 1.8 Hz, 1H), 4.98 (br d, J=5.9 Hz, 1H),
7.44-7.55 (m, 2H), 7.61 (br d, J=9.0 Hz, 1H), 8.05 (ddd, J=9.2,
5.0, 2.8 Hz, 1H), 8.21 (dd, J=5.7, 2.6 Hz, 1H), 9.51 (s, 1H);
Method D; Rt: 1.67 min. m/z: 421 (M-H).sup.- Exact mass: 422.1; MP:
222.3.degree. C., and 122b (102 mg); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.88 (t, J=7.4 Hz, 3H), 1.28-1.44 (m,
1H), 1.50-1.63 (m, 1H), 3.54-3.66 (m, 1H), 3.66-3.76 (m, 1H), 3.83
(s, 3H), 3.99 (dd, J=12.7, 9.1 Hz, 1H), 4.74 (dd, J=12.7, 1.0 Hz,
1H), 4.87 (d, J=5.3 Hz, 1H), 7.37 (br s, 1H), 7.49 (s, 1H), 7.52
(t, J=9.1 Hz, 1H), 8.05 (ddd, J=9.3, 4.9, 2.8 Hz, 1H), 8.19 (dd,
J=5.7, 2.6 Hz, 1H), 9.54 (s, 1H); Method D; Rt: 1.69 min. m/z: 421
(M-H).sup.- Exact mass: 422.1; MP: 252.2.degree. C. Method L; Rt:
122a: 2.81 min, 122b: 3.50 min.
Compound 123:
(3S)--N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3-(2,2,2-trifluoro-1-hydr-
oxy-ethyl)-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00177##
[0632] (Trifluoromethyl)trimethylsilane (0.82 mL, 0.96 g/mL, 5.6
mmol) was added to a solution of tert-butyl
(4S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylate (1.06 g, 4.62
mmol) and TBAF (0.11 mL, 1 M in THF, 0.11 mmol) in THF (28 mL) at
room temperature under a nitrogen atmosphere. The reaction mixture
was stirred overnight at room temperature. Tetrabutylammonium
fluoride (9.25 mL, 1 M, 9.25 mmol) was added to the reaction
mixture and stirring was continued overnight. The reaction mixture
was quenched with NaHCO.sub.3(aq. sat.), and extracted with EtOAc
(3 times). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure.
[0633] The residue was purified by silica gel column chromatography
(heptane/ethyl acetate 100/0 to 0/100) to afford tert-butyl
(4S)-2,2-dimethyl-4-(2,2,2-trifluoro-1-hydroxy-ethyl)oxazolidine-3-carbox-
ylate (1.42 g) as an oil.
[0634] HCl (4.6 mL, 4 M in dioxane, 18 mmol) was added dropwise to
a solution of tert-butyl
(4S)-2,2-dimethyl-4-(2,2,2-trifluoro-1-hydroxy-ethyl)oxazolidine-3-carbox-
ylate (1.38 g, 4.62 mmol) in 1,4-dioxane (40 mL). The reaction
mixture was stirred at room temperature for 2 hours. The reaction
mixture was concentrated under reduced pressure to yield
(2S)-2-amino-4,4,4-trifluoro-butane-1,3-diol (735 mg).
[0635] Ethyl
4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (1.06 g,
3.93 mmol) was added portion wise to a solution of
(2S)-2-amino-4,4,4-trifluoro-butane-1,3-diol (735 mg, 4.62 mmol)
and DIPEA (4.78 mL, 0.75 g/mL, 27.7 mmol) in DCM (30 mL). The
reaction mixture was stirred overnight at room temperature. The
reaction mixture was quenched with NH.sub.4Cl (sat., aq.) and
diluted in DCM. The two layers were separated and the aqueous layer
was extracted with DCM twice. The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered off and concentrated under
reduced pressure and the residue was purified by silica gel column
chromatography (heptane/ethyl acetate 100/0 to 0/100) to afford
ethyl
3-fluoro-1-methyl-4-[[3,3,3-trifluoro-2-hydroxy-1-(hydroxymethyl)propyl]s-
ulfamoyl]pyrrole-2-carboxylate (610 mg) as a beige solid. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.28 (s, 3H), 3.33-3.42 (m,
1H), 3.36 (s, 1H), 3.43-3.58 (m, 2H), 3.81 (s, 3H), 4.04 (dt,
J=7.0, 3.7 Hz, 1H), 4.27 (d, J=7.0 Hz, 2H), 4.56 (br t, J=5.2 Hz,
1H), 6.51 (br d, J=6.6 Hz, 1H), 7.52 (d, J=4.6 Hz, 1H), 7.75 (br s,
1H); Method B; Rt: 0.73 min. m/z: 391 (M-H).sup.- Exact mass:
392.1.
[0636] Lithium bis(trimethylsilyl)amide (7.8 mL, 1 M in THF, 7.8
mmol) was added dropwise to a solution of ethyl
3-fluoro-1-methyl-4-[[3,3,3-trifluoro-2-hydroxy-1-(hydroxyl-methyl)propyl-
]sulfamoyl]pyrrole-2-carboxylate (610 mg, 1.55 mmol) and
3,4-difluoroaniline (0.19 mL, 1.29 g/mL, 1.9 mmol) in THF (20 mL).
The reaction mixture was stirred overnight at room temperature.
Lithium bis(trimethylsilyl)amide (4.7 mL, 1 M in THF, 4.7 mmol) was
added and the reaction mixture was stirred for additional minutes.
The reaction mixture was quenched with NH.sub.4Cl (sat., aq.), and
diluted with EtOAc. The two layers were separated and the aqueous
layer was extracted with EtOAc twice. The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The residue was precipitated in DCM (small
amount) and diethyl ether to afford
N-(3,4-difluorophenyl)-3-fluoro-1-methyl-4-[[3,3,3-trifluoro-2-hydroxy-1--
(hydroxymethyl)propyl]sulfamoyl]pyrrole-2-carboxamide (300 mg) as a
beige solid. A second crop (280 mg) was obtained after purification
of the filtrate via silica gel column chromatography (heptane/ethyl
acetate 100/0 to 0/100).
[0637] Cesium fluoride (741 mg, 4.88 mmol) was added to a solution
of
N-(3,4-difluorophenyl)-3-fluoro-1-methyl-4-[[3,3,3-trifluoro-2-hydroxy-1--
(hydroxyl-methyl)propyl]sulfamoyl]pyrrole-2-carboxamide (580 mg,
1.22 mmol) in DMF (13 mL). The reaction mixture was heated
overnight at 105.degree. C. The reaction mixture was concentrated
under reduced pressure and the residue was purified via silica gel
column chromatography (heptane/ethyl acetate 100/0 to 0/100). The
obtained product was purified via preparative SFC (Stationary
phase: Chiralpak Diacel AS 20.times.250 mm, Mobile phase: CO.sub.2,
iPrOH+0.4 iPrNH.sub.2) yielding 1 epimer of compound 123 (30.7 mg).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 3.82 (s, 3H),
3.83-3.88 (m, 1H), 4.08 (br s, 1H), 4.18 (dd, J=13.0, 9.5 Hz, 1H),
4.86 (dd, J=12.9, 2.5 Hz, 1H), 6.93 (br d, J=6.1 Hz, 1H), 7.35-7.44
(m, 1H), 7.44-7.50 (m, 1H), 7.50 (s, 1H), 7.87 (ddd, J=13.3, 7.5,
2.5 Hz, 1H), 8.00 (br s, 1H), 9.43 (s, 1H); Method D; Rt: 1.82 min.
m/z: 454 (M-H).sup.- Exact mass: 455.1.
Compound 124:
(3R)--N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-(1-hydroxy
propyl)-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazep-
ine-6-carboxamide
##STR00178##
[0639] Compound 124 (445 mg) was prepared similarly as described
for compound 122, using 3-(difluoromethyl)-4-fluoro-aniline instead
of 5-amino-2-fluoro-benzonitrile. The racemic mixture was separated
in its epimers via preparative SFC (Stationary phase: Kromasil
(R,R) Whelk-O 1 10/100, Mobile phase: CO.sub.2, EtOH+0.4%
iPrNH.sub.2) to yield compound 124a (209 mg); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.92 (t, J=7.3 Hz, 3H), 1.44 (dquin,
J=14.2, 7.3, 7.3, 7.3, 7.3 Hz, 1H), 1.72 (dqd, J=14.1, 7.2, 7.2,
7.2, 3.1 Hz, 1H), 3.26-3.44 (m, 1H), 3.49 (br t, J=7.9 Hz, 1H),
3.83 (s, 3H), 3.99 (dd, J=12.7, 8.9 Hz, 1H), 4.89 (dd, J=12.7, 1.9
Hz, 1H), 4.98 (d, J=6.2 Hz, 1H), 7.03-7.40 (m, 2H), 7.47 (s, 1H),
7.58 (br s, 1H), 7.76-7.88 (m, 1H), 8.04 (dd, J=6.4, 2.6 Hz, 1H),
9.47 (s, 1H); Method D; Rt: 1.74 min. m/z: 446 (M-H).sup.- Exact
mass: 447.1, and 124b (159 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 0.88 (t, J=7.4 Hz, 3H), 1.29-1.44 (m, 1H), 1.49-1.64
(m, 1H), 3.55-3.65 (m, 1H), 3.66-3.77 (m, 1H), 3.83 (s, 3H), 4.00
(dd, J=12.7, 9.1 Hz, 1H), 4.62-4.76 (m, 1H), 4.86 (br d, J=4.8 Hz,
1H), 7.04-7.41 (m, 3H), 7.46 (s, 1H), 7.77-7.87 (m, 1H), 8.03 (dd,
J=6.3, 2.5 Hz, 1H), 9.49 (s, 1H); Method D; Rt: 1.77 min. m/z: 446
(M-H).sup.- Exact mass: 447.1; MP: 224.5.degree. C. Method M; Rt:
124a: 2.53 min, 124b: 3.56 min.
Compound 125:
N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-3-phenyl-2,4-dihydropyrrolo-
[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00179##
[0641] Compound 125 (85 mg) was prepared similarly as described for
compound 14, using 2-amino-2-phenylpropan-1-ol hydrochloride
instead of DL-alaninol and DCM instead of THF as a solvent in the
first step. The ring closure was obtained after heating 90 minutes
at 110.degree. C. in DMF and compound 125 was purified on silica
using a gradient from heptane to EtOAc. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.60 (s, 3H), 3.82 (s, 3H), 4.89-5.00 (m,
2H), 7.25-7.49 (m, 6H), 7.58 (d, J=7.6 Hz, 2H), 7.82-7.89 (m, 1H),
8.35 (s, 1H), 9.43 (s, 1H); Method D; Rt: 2.05 min. m/z: 446
(M-H).sup.- Exact mass: 447.1; MP: 256.6.degree. C.
Compound 126:
(3R)--N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-3-(2-pyridyl)-2,4-dih-
ydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00180##
[0643] Compound 126 (115 mg) was prepared similarly as described
for compound 125, using (2R)-2-amino-2-(2-pyridyl)propan-1-ol
instead of 2-amino-2-phenylpropan-1-ol hydrochloride. The ring
closure was obtained after heating 3 hours and compound 126 was
purified on silica using a gradient from heptane to EtOAc:EtOH 3:1.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.59 (s, 3H), 3.82
(s, 3H), 4.99 (d, J=13.3 Hz, 1H), 5.21 (d, J=13.3 Hz, 1H),
7.29-7.51 (m, 4H), 7.78-7.92 (m, 3H), 8.46-8.54 (m, 2H), 9.39 (s,
1H); Method D; Rt: 1.97 min. m/z: 447 (M-H).sup.- Exact mass:
448.1; MP: 270.5.degree. C.
Compound 127:
(3S)--N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-3-(2-pyridyl)-2,4-dih-
ydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00181##
[0645] Compound 127 (145 mg) was prepared similarly as described
for compound 126, using (2S)-2-amino-2-(2-pyridyl)propan-1-ol
instead of (2R)-2-amino-2-(2-pyridyl)propan-1-ol hydrochloride.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.55-1.62 (m, 3H),
3.82 (s, 3H), 4.99 (d, J=13.3 Hz, 1H), 5.21 (d, J=13.3 Hz, 1H),
7.29-7.50 (m, 4H), 7.79-7.92 (m, 3H), 8.47-8.53 (m, 2H), 9.39 (s,
1H); Method D; Rt: 1.98 min. m/z: 447 (M-H).sup.- Exact mass:
448.1; MP: 270.8.degree. C.
Compound 128:
(3S)--N-(3-cyano-4-fluoro-phenyl)-3,7-dimethyl-1,1-dioxo-3-(2-pyridyl)-2,-
4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00182##
[0647] Compound 128 (55 mg) was prepared similarly as described for
compound 127, using 5-amino-2-fluoro-benzonitrile instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.59 (s, 3H), 3.83 (s, 3H), 4.99 (d, J=13.3 Hz, 1H), 5.25 (d,
J=13.3 Hz, 1H), 7.31 (ddd, J=7.4, 4.8, 1.2 Hz, 1H), 7.48-7.55 (m,
2H), 7.78-7.84 (m, 1H), 7.84-7.90 (m, 1H), 8.08 (ddd, J=9.2, 4.9,
2.7 Hz, 1H), 8.21 (dd, J=5.7, 2.7 Hz, 1H), 8.47-8.51 (m, 1H), 8.53
(s, 1H), 9.47 (s, 1H); Method D; Rt: 1.89 min. m/z: 454 (M-H).sup.-
Exact mass: 455.1; MP: 235.0.degree. C.
Compound 129:
N-(3,4-difluorophenyl)-3-[methoxymethoxy(2-pyridyl)methyl]-7-methyl-1,1-d-
ioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00183##
[0649] To a cooled solution of ethyl 2-(dibenzylamino)acetate (2.0
g, 7.1 mmol) in dry THF (40 mL) was added dropwise lithium
bis(trimethylsilyl)amide (24.7 mL, 1 M in THF, 24.7 mmol) at
-70.degree. C. The solution was slowly warmed to -5.degree. C. and
it was stirred for 3 hours. Then the reaction mixture was cooled to
-70.degree. C. again and 2-pyridinecarboxaldehyde (2.36 mL, 24.7
mmol) was added slowly and it was stirred at -70.degree. C. for 45
minutes. The reaction mixture was warmed slowly to room temperature
and quenched with NH.sub.4Cl (aq., sat., 50 mL). This was extracted
with EtOAc (3.times.75 mL). The combined organic layers were dried
over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The
residue was purified and separated into its 2 diastereoisomers by
silica gel column chromatography (0% to 20% EtOAc in heptane)
yielding diastereoisomer 1 (827 mg); Method B; Rt: 1.23 min. m/z:
391 (M+H).sup.+ Exact mass: 390.2 and diastereoisomer 2 (813 mg);
Method B; Rt: 1.19 min. m/z: 391 (M+H).sup.+ Exact mass: 390.2.
[0650] To a solution of diastereoisomer 1 (827 mg, 0.72 mmol) in
dry DCM (5 mL) was added DIPEA (1.12 mL, 6.48 mmol) followed by
chloromethyl methyl ether (0.49 mL, 6.48 mmol) and the reaction
mixture was stirred at room temperature for 3 days. DIPEA (1.12 mL,
6.48 mmol) and chloromethyl methyl ether (0.49 mL, 6.48 mmol) were
added and the reaction mixture was stirred again for 3 days. The
reaction mixture was quenched with NaHCO.sub.3(aq., sat., 25 mL)
and extracted with EtOAc (3.times.25 mL). The combined organic
layers were dried over Na.sub.2SO.sub.4, filtered and evaporated to
dryness. The residue was purified on silica using a heptane to
EtOAc gradient yielding ethyl
2-(dibenzylamino)-3-(methoxymethoxy)-3-(2-pyridyl)propanoate (418
mg) as a clear oil. Method B; Rt: 1.35 min. m/z: 435 (M+H).sup.+
Exact mass: 434.2.
[0651] To a solution of ethyl
2-(dibenzylamino)-3-(methoxymethoxy)-3-(2-pyridyl)propanoate (418
mg, 0.96 mmol) in dry THF was added LAH (0.72 mL, 2M in THF, 1.44
mmol) at -70.degree. C. After addition the reaction mixture was
slowly warmed to room temperature and stirred 4.5 hours. The
reaction mixture was quenched carefully with EtOAc and the mixture
was stirred for 5 min. Then Na.sub.2SO.sub.4.10H.sub.2O was added
and this was again stirred for 15 min. Then anhydrous
Na.sub.2SO.sub.4 was added. The solids were filtered off and the
filtrate was evaporated to dryness. The residue was purified on
silica using a DCM to EtOAc gradient yielding
2-(dibenzylamino)-3-(methoxymethoxy)-3-(2-pyridyl)-propan-1-ol (316
mg) as a clear yellow oil.
[0652] Pd(OH).sub.2/C (150 mg) was added to a solution of
2-(dibenzylamino)-3-(methoxy-methoxy)-3-(2-pyridyl)propan-1-ol (316
mg, 0.81 mmol) in degassed MeOH and the resulting suspension was
stirred under H.sub.2 at room temperature overnight. The reaction
mixture was filtered through a pad of dicalite and concentrated in
vacuo yielding 2-amino-3-(methoxymethoxy)-3-(2-pyridyl)propan-1-ol
(119 mg).
[0653] 2-amino-3-(methoxymethoxy)-3-(2-pyridyl)propan-1-ol (119 mg,
0.56 mmol) was dissolved in DCM (4 mL) and Hunig's base (0.193 mL,
1.12 mmol) was added followed by ethyl
4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (151 mg,
0.56 mmol). After 4 hours, the reaction mixture was diluted with
DCM (5 mL) and then quenched with NaHCO.sub.3(aq., sat., 5 mL). The
water layer was extracted with DCM (2.times.5 mL). The combined
organic layers were evaporated to get a yellow foam. The crude was
recrystallized/triturated in DCM and it was stirred for 3 days. The
formed white solid was filtered off and washed with some DIPE to
obtain ethyl
3-fluoro-4-[[1-(hydroxymethyl)-2-(methoxymethoxy)-2-(2-pyridyl)ethyl]sulf-
amoyl]-1-methyl-pyrrole-2-carboxylate (140 mg).
[0654] To a solution of ethyl
3-fluoro-4-[[1-(hydroxymethyl)-2-(methoxymethoxy)-2-(2-pyridyl)ethyl]sulf-
amoyl]-1-methyl-pyrrole-2-carboxylate (98 mg, 0.22 mmol) and
3,4-difluoroaniline (0.027 mL, 0.26 mmol) in dry THF (3 mL) was
added dropwise lithium bis(trimethylsilyl)amide (0.88 mL, 1 M in
THF, 0.88 mmol) in a nitrogen atmosphere and it was stirred at room
temperature for 2.5 hours. Then the reaction mixture was quenched
with NH.sub.4Cl (aq., sat., 3 mL) and extracted with EtOAc
(3.times.3 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and evaporated to dryness. The residue
was purified on silica using a DCM to EtOAc gradient yielding
N-(3,4-difluorophenyl)-3-fluoro-4-[[1-(hydroxymethyl)-2-(methoxy-
methoxy)-2-(2-pyridyl)ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide
(128 mg) as a brown solid.
[0655]
N-(3,4-difluorophenyl)-3-fluoro-4-[[1-(hydroxymethyl)-2-(methoxymet-
hoxy)-2-(2-pyridyl)ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide
(128 mg, 0.24 mmol) and cesium fluoride (216 mg, 1.42 mmol) were
dissolved in dry DMF (3 mL) and heated at 110.degree. C. instantly.
The mixture was stirred at 110.degree. C. for 7 hours. The reaction
mixture was quenched with water (3 mL) and the product was
extracted with EtOAc (3.times.3 mL). The combined org layers were
evaporated and the residue was purified on silica using a DCM to
EtOAc gradient. The crude was purified via Prep HPLC (Stationary
phase: RP)(Bridge Prep C18 OBD-10 .mu.m, 30.times.150 mm, Mobile
phase: 0.25% NH.sub.4HCO.sub.3 solution in water, ACN) yielding
crude compound 129 and crude compound 141. The obtained crude
compound 129 was purified on silica using a DCM to EtOAc gradient
to obtain compound 129 (14 mg) as a beige solid. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 3.47 (s, 3H), 3.85-4.03 (m, 4H),
4.37-4.48 (m, 1H), 4.74 (dd, J=12.8, 2.0 Hz, 1H), 4.78-4.96 (m,
2H), 5.10 (d, J=4.0 Hz, 1H), 6.58-6.89 (m, 1H), 6.97-7.16 (m, 3H),
7.19-7.26 (m, 1H), 7.52-7.64 (m, 2H), 7.74 (td, J=7.7, 1.8 Hz, 1H),
8.42-8.53 (m, 1H), 8.64 (s, 1H); Method D; Rt: 1.88 min. m/z: 509
(M+H).sup.+ Exact mass: 508.1.
Compound 130:
(3R)--N-(3,4-difluorophenyl)-3-(1-hydroxypropyl)-7-methyl-1,1-dioxo-3,4-d-
ihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00184##
[0657] Compound 130 (414 mg) was prepared similarly as described
for compound 122, using 3,4-difluoroaniline instead of
5-amino-2-fluoro-benzonitrile. The racemic mixture was separated in
its epimers via preparative SFC (Stationary phase: Kromasil (R,R)
Whelk-O 1 10/100, Mobile phase: CO.sub.2, EtOH-iPrOH (50-50)+0.4%
iPrNH.sub.2) to yield compound 130a (130 mg); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.91 (t, J=7.4 Hz, 3H), 1.43 (dquin,
J=14.2, 7.3, 7.3, 7.3, 7.3 Hz, 1H), 1.62-1.82 (m, 1H), 3.34-3.44
(m, 1H), 3.44-3.56 (m, 1H), 3.82 (s, 3H), 3.98 (dd, J=12.8, 9.0 Hz,
1H), 4.90 (dd, J=12.7, 1.9 Hz, 1H), 4.98 (d, J=6.4 Hz, 1H),
7.34-7.44 (m, 1H), 7.44-7.51 (m, 2H), 7.60 (d, J=9.7 Hz, 1H), 7.87
(ddd, J=13.3, 7.5, 2.5 Hz, 1H), 9.42 (s, 1H); Method D; Rt: 1.76
min. m/z: 414 (M-H).sup.- Exact mass: 415.1; MP: 217.4.degree. C.,
and 130b (104 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.88 (t, J=7.4 Hz, 3H), 1.29-1.44 (m, 1H), 1.49-1.65 (m, 1H),
3.54-3.66 (m, 1H), 3.66-3.77 (m, 1H), 3.83 (s, 3H), 3.99 (dd,
J=12.8, 9.0 Hz, 1H), 4.63-4.79 (m, 1H), 4.86 (d, J=5.3 Hz, 1H),
7.25-7.55 (m, 4H), 7.86 (ddd, J=13.1, 7.4, 2.5 Hz, 1H), 9.45 (s,
1H); Method D; Rt: 1.78 min. m/z: 414 (M-H).sup.- Exact mass:
415.1; MP: 214.6.degree. C. Method S; Rt: 130a: 2.65 min, 130b:
3.46 min.
Compound 131:
N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-spiro[4,5-dihydro-2H-pyrrolo[3,-
4-f]thiazepine-3,3'-oxetane]-6-carboxamide
##STR00185##
[0659] Methyl
7-methyl-1,1-dioxo-spiro[2H-pyrrolo[3,4-f]thiazepine-3,3'-oxetane]-6-carb-
oxylate (450 mg, 1.51 mmol) was dissolved in methanol (200 mL).
Under a nitrogen atmosphere Et3N (420 .mu.L, 0.73 g/mL, 3 mmol) and
Pd/C (10%) (161 mg, 0.15 mmol) were added. The reaction mixture was
hydrogenated for 1 hour and then filtered over decalite and the
solids were washed with THF (4.times.80 mL). The filtrate was
evaporated to dryness to afford methyl
7-methyl-1,1-dioxo-spiro[4,5-dihydro-2H-pyrrolo[3,4-f]thiazepine-3-
,3'-oxetane]-6-carboxylate (430 mg) as a white powder.
[0660] Methyl
7-methyl-1,1-dioxo-spiro[4,5-dihydro-2H-pyrrolo[3,4-f]thiazepine-3,3'-oxe-
tane]-6-carboxylate (107 mg, 0.36 mmol) and 3,4-difluoroaniline (51
mg, 0.39 mmol) were dissolved in THF (3 mL). Lithium
bis(trimethylsilyl)amide (2.1 mL, 1 M in THF, 2.1 mmol) was added
and the reaction mixture was stirred at room temperature for 30
minutes. The reaction was quenched with NH.sub.4Cl (sat., aq., 5
mL) and the organic layer was separated. The aqueous layer was
extracted with EtOAc (2.times.5 mL) and the combined organic layers
were concentrated to dryness. The residue was purified using Prep
HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 .mu.m,
50.times.150 mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3 solution in
water, ACN) yielding compound 131 (80 mg) after recrystallization
from DCM as a white powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 2.13-2.25 (m, 2H), 2.84-2.99 (m, 2H), 3.69 (s, 3H),
4.29 (d, J=6.4 Hz, 2H), 4.64 (d, J=6.2 Hz, 2H), 7.39-7.46 (m, 3H),
7.78-7.89 (m, 2H), 10.49 (br s, 1H); Method B; Rt: 0.81 min. m/z:
396 (M-H).sup.- Exact mass: 397.1.
Compound 132:
N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-spiro[2H-pyrrolo[3,4-f]-thiazep-
ine-3,3'-oxetane]-6-carboxamide
##STR00186##
[0662] Compound 132 (84 mg) was prepared similarly as described for
compound 84, using 3-vinyloxetan-3-amine hydrochloride instead of
(2S,3R)-3-aminopent-4-en-2-ol hydrochloride. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 3.70 (s, 3H), 4.50 (d, J=6.4 Hz, 2H),
4.78 (d, J=6.2 Hz, 2H), 6.27 (d, J=12.8 Hz, 1H), 6.50 (d, J=12.8
Hz, 1H), 7.40-7.47 (m, 2H), 7.52 (s, 1H), 7.82-7.88 (m, 1H), 8.44
(br s, 1H), 10.76 (br s, 1H); Method B; Rt: 0.82 min. m/z: 394
(M-H).sup.- Exact mass: 395.1.
Compound 133:
N-(3,4-difluorophenyl)-3,3,7-trimethyl-1,1-dioxo-2,4-dihydropyrrolo-[3,4--
b][1,4,5]oxathiazepine-6-carboxamide
##STR00187##
[0664] Compound 133 (111 mg) was prepared similarly as described
for compound 83, using 2-amino-2-methyl-1-propanol instead of
2-amino-1,3-propanediol and ACN instead of THF in the first step.
The ring closure was obtained after heating 2 hours at 110.degree.
C. in DMF and compound 133 was purified on silica using a gradient
from heptane to EtOAc. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.29 (s, 6H), 3.81 (s, 3H), 4.40 (s, 2H), 7.37-7.45 (m, 3H),
7.76-7.88 (m, 2H), 9.38 (s, 1H); Method B; Rt: 1.01 min. m/z: 384
(M-H).sup.- Exact mass: 385.1.
Compound 134:
N-(3,4-difluorophenyl)-3-ethyl-3,7-dimethyl-1,1-dioxo-2,4-dihydropyrrolo[-
3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00188##
[0666] Compound 134 (121 mg) was prepared similarly as described
for compound 133, using 2-amino-2-methylbutan-1-ol instead of
2-amino-2-methyl-1-propanol. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 0.92 (t, J=7.4 Hz, 3H), 1.22 (s, 3H), 1.41-1.50 (m,
1H), 1.71-1.80 (m, 1H), 3.81 (s, 3H), 4.31-4.53 (m, 2H), 7.37-7.44
(m, 3H), 7.64 (s, 1H), 7.81-7.88 (m, 1H), 9.35 (s, 1H); Method B;
Rt: 1.07 min. m/z: 398 (M-H).sup.- Exact mass: 399.1. This racemic
mixture was separated in enantiomers 134a (49 mg) and 134b (52 mg)
by preparative SFC (Stationary phase: Chiralpak Diacel AS
20.times.250 mm, Mobile phase: CO.sub.2, EtOH with 0.4%
iPrNH.sub.2). Method T; Rt: 134a: 2.75 min, 134b: 2.92 min.
Compound 135:
N-(3-cyano-4-fluoro-phenyl)-3,3,7-trimethyl-1,1-dioxo-2,4-dihydropyrrolo[-
3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00189##
[0668] Compound 135 (39 mg) was prepared similarly as described for
compound 133, using 5-amino-2-fluoro-benzonitrile instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.30 (s, 6H), 3.82 (s, 3H), 4.41 (s, 2H), 7.45 (s, 1H), 7.53
(t, J=9.1 Hz, 1H), 7.80 (s, 1H), 8.03 (ddd, J=9.2, 4.8, 2.9 Hz,
1H), 8.16 (dd, J=5.7, 2.6 Hz, 1H), 9.46 (s, 1H); Method B; Rt: 0.94
min. m/z: 391 (M-H).sup.- Exact mass: 392.1.
Compound 136:
7-methyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)spiro[4,5-dihydro-2H-pyrrolo[-
3,4-f]thiazepine-3,3'-oxetane]-6-carboxamide
##STR00190##
[0670] Compound 136 (41 mg) was prepared similarly as described for
compound 131, using 3,4,5-trifluoroaniline instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 2.10-2.25 (m, 2H), 2.85-2.97 (m, 2H), 3.69 (s, 3H), 4.29 (d,
J=6.4 Hz, 2H), 4.64 (d, J=6.2 Hz, 2H), 7.47 (s, 1H), 7.54-7.65 (m,
2H), 7.84 (s, 1H), 10.61 (s, 1H); Method D; Rt: 1.67 min. m/z: 414
(M-H).sup.- Exact mass: 415.1.
Compound 137:
N-[3-(difluoromethyl)-4-fluoro-phenyl]-7-methyl-1,1-dioxo-spiro[4,5-dihyd-
ro-2H-pyrrolo[3,4-f]thiazepine-3,3'-oxetane]-6-carboxamide
##STR00191##
[0672] Compound 137 (64 mg) was prepared similarly as described for
compound 131, using 3-(difluoromethyl)-4-fluoro-aniline instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 2.10-2.33 (m, 2H), 2.86-3.00 (m, 2H), 3.70 (s, 3H), 4.29 (d,
J=6.4 Hz, 2H), 4.65 (d, J=6.2 Hz, 2H), 7.23 (br t, J=54.2 Hz, 1H),
7.37 (t, J=9.5 Hz, 1H), 7.45 (s, 1H), 7.77-7.89 (m, 2H), 8.06 (dd,
J=6.2, 2.4 Hz, 1H), 10.51 (s, 1H); Method D; Rt: 1.59 min. m/z: 428
(M-H).sup.- Exact mass: 429.1.
Compound 138:
N-(3-cyano-4-fluoro-phenyl)-7-methyl-1,1-dioxo-spiro[4,5-dihydro-2H-pyrro-
lo[3,4-f]thiazepine-3,3'-oxetane]-6-carboxamide
##STR00192##
[0674] Compound 138 (23 mg) was prepared similarly as described for
compound 131, using 5-amino-2-fluoro-benzonitrile instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 2.14-2.27 (m, 2H), 2.87-2.99 (m, 2H), 3.70 (s, 3H), 4.29 (d,
J=6.4 Hz, 2H), 4.64 (d, J=6.2 Hz, 2H), 7.46 (s, 1H), 7.55 (t, J=9.1
Hz, 1H), 7.84 (s, 1H), 7.97 (ddd, J=9.2, 4.8, 2.9 Hz, 1H), 8.19
(dd, J=5.8, 2.8 Hz, 1H), 10.61 (s, 1H); Method D; Rt: 1.48 min.
m/z: 403 (M-H).sup.- Exact mass: 404.1.
Compound 139:
N-[3-(difluoromethyl)-4-fluoro-phenyl]-7-methyl-1,1-dioxo-spiro[2H-pyrrol-
o[3,4-f]thiazepine-3,3'-oxetane]-6-carboxamide
##STR00193##
[0676] Compound 139 (108 mg) was prepared similarly as described
for compound 132, using 3-(difluoromethyl)-4-fluoro-aniline instead
of 3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 3.71 (s, 3H), 4.50 (d, J=6.2 Hz, 2H), 4.79 (d, J=6.4 Hz, 2H),
6.27 (d, J=12.8 Hz, 1H), 6.53 (d, J=12.8 Hz, 1H), 7.23 (t, J=54.2
Hz, 1H), 7.39 (t, J=9.6 Hz, 1H), 7.52 (s, 1H), 7.81-7.86 (m, 1H),
8.06 (dd, J=6.2, 2.4 Hz, 1H), 8.45 (br s, 1H), 10.78 (br s, 1H);
Method B; Rt: 0.83 min. m/z: 426 (M-H).sup.- Exact mass: 427.1.
Compound 140:
N-(3-cyano-4-fluoro-phenyl)-7-methyl-1,1-dioxo-spiro[2H-pyrrolo-[3,4-f]th-
iazepine-3,3'-oxetane]-6-carboxamide
##STR00194##
[0678] Compound 140 (23 mg) was prepared similarly as described for
compound 132, using 5-amino-2-fluoro-benzonitrile instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 3.71 (s, 3H), 4.51 (d, J=6.4 Hz, 2H), 4.79 (d, J=6.4 Hz, 2H),
6.28 (d, J=12.8 Hz, 1H), 6.54 (d, J=12.8 Hz, 1H), 7.53-7.58 (m,
2H), 7.98 (ddd, J=9.2, 4.9, 2.6 Hz, 1H), 8.19 (dd, J=5.8, 2.8 Hz,
1H), 8.46 (br s, 1H), 10.88 (br s, 1H); Method D; Rt: 1.48 min.
m/z: 401 (M-H).sup.- Exact mass: 402.1.
Compound 141:
N-(3,4-difluorophenyl)-3-[hydroxy(2-pyridyl)methyl]-7-methyl-1,1-dioxo-3,-
4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00195##
[0680] The crude compound 141 obtained in the synthesis of compound
129 was purified on silica eluting with a DCM to EtOAc gradient to
obtain compound 141a (3 mg) as a beige solid. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 3.87-4.04 (m, 3H), 4.25 (dd, J=12.8, 9.0
Hz, 1H), 4.40-4.53 (m, 1H), 4.82-4.97 (m, 1H), 5.00-5.12 (m, 1H),
6.96-7.21 (m, 3H), 7.27-7.37 (m, 1H), 7.42-7.49 (m, 1H), 7.58-7.73
(m, 1H), 7.76-7.88 (m, 1H), 8.49-8.60 (m, 1H), 8.80 (s, 1H); Method
B; Rt: 0.91 min. m/z: 465 (M+H).sup.+ Exact mass: 464.1.
[0681] Alternatively this compound can be synthesized as described
in compound 129 using 6-bromopyridine-2-carbaldehyde instead of
2-pyridinecarboxaldehyde. During the synthesis diastereomers were
separated in the final step using preparative HPLC (Stationary
phase: RP XBridge Prep C18 OBD-10 .mu.m, 30.times.150 mm, Mobile
phase: 0.25% NH.sub.4HCO.sub.3 solution in water, MeOH) yielding
compound 141a (5 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 3.87-4.04 (m, 3H), 4.25 (dd, J=12.8, 9.0 Hz, 1H), 4.40-4.53 (m,
1H), 4.82-4.97 (m, 1H), 5.00-5.12 (m, 1H), 6.96-7.21 (m, 3H),
7.27-7.37 (m, 1H), 7.42-7.49 (m, 1H), 7.58-7.73 (m, 1H), 7.76-7.88
(m, 1H), 8.49-8.60 (m, 1H), 8.80 (s, 1H); Method D; Rt: 1.76 min.
m/z: 465 (M+H).sup.+ Exact mass: 464.1 and compound 141b (14 mg);
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 3.81 (s, 3H), 4.03
(dd, J=12.6, 9.3 Hz, 1H), 4.13-4.21 (m, 1H), 4.82 (dd, J=12.3, 1.1
Hz, 1H), 4.90 (d, J=3.3 Hz, 1H), 5.91 (br s, 1H), 7.26-7.32 (m,
1H), 7.32-7.49 (m, 4H), 7.54 (d, J=7.7 Hz, 1H), 7.77-7.96 (m, 2H),
8.50-8.56 (m, 1H), 9.45 (s, 1H); Method D; Rt: 1.74 min. m/z: 465
(M+H).sup.+ Exact mass: 464.1. Method AD; Rt: 141a: 5.75 min and
6.63 min, 141b: 5.13 min and 6.00 min.
Compound 142:
N-(3,4-difluorophenyl)-3-(1-hydroxypropyl)-7-methyl-1,1-dioxo-3,4-dihydro-
-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00196##
[0683] Compound 142 (387 mg) was prepared similarly as described
for compound 92, using ethylmagnesium bromide instead of
cyclopropylmagnesium bromide. The racemic mixture was separated in
its epimers via preparative SFC (Stationary phase: Chiralpak Daicel
ID 20.times.250 mm, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2)
to yield compound 142a (141 mg); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.91 (t, J=7.4 Hz, 3H), 1.44 (dquin,
J=14.3, 7.3, 7.3, 7.3, 7.3 Hz, 1H), 1.64-1.79 (m, 1H), 3.34-3.44
(m, 1H), 3.44-3.55 (m, 1H), 3.82 (s, 3H), 3.98 (dd, J=12.8, 8.8 Hz,
1H), 4.90 (dd, J=12.5, 1.8 Hz, 1H), 4.98 (d, J=6.2 Hz, 1H),
7.34-7.44 (m, 1H), 7.44-7.51 (m, 2H), 7.60 (d, J=9.7 Hz, 1H), 7.87
(ddd, J=13.3, 7.5, 2.5 Hz, 1H), 9.42 (s, 1H); Method D; Rt: 1.75
min. m/z: 414 (M-H).sup.- Exact mass: 415.1; MP: 218.6.degree. C.,
and 142b (136 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.88 (t, J=7.4 Hz, 3H), 1.29-1.43 (m, 1H), 1.49-1.63 (m, 1H),
3.55-3.64 (m, 1H), 3.66-3.75 (m, 1H), 3.82 (s, 3H), 3.99 (dd,
J=12.7, 9.1 Hz, 1H), 4.68-4.75 (m, 1H), 4.86 (br d, J=4.2 Hz, 1H),
7.26-7.52 (m, 4H), 7.86 (ddd, J=13.2, 7.5, 2.4 Hz, 1H), 9.45 (s,
1H); Method D; Rt: 1.77 min. m/z: 414 (M-H).sup.- Exact mass:
415.1; MP: 212.6.degree. C. Method U; Rt: 142a: 3.06 min, 142b:
3.64 min.
Compound 143:
7-methyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)spiro[2H-pyrrolo[3,4-f]thiaze-
pine-3,3'-oxetane]-6-carboxamide
##STR00197##
[0685] Compound 143 (28 mg) was prepared similarly as described for
compound 132, using 3,4,5-trifluoroaniline instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 3.70 (s, 3H), 4.51 (d, J=6.4 Hz, 2H), 4.78 (d, J=6.2 Hz, 2H),
6.28 (d, J=12.8 Hz, 1H), 6.50 (d, J=12.8 Hz, 1H), 7.54 (s, 1H),
7.56-7.66 (m, 2H), 8.45 (br s, 1H), 10.88 (br s, 1H); Method B; Rt:
0.88 min. m/z: 412 (M-H).sup.- Exact mass: 413.1.
Compound 144:
N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-(1-hydroxypropyl)-7-methyl-1,1-d-
ioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00198##
[0687] Compound 144 (420 mg) was prepared similarly as described
for compound 142, using 3-(difluoromethyl)-4-fluoro-aniline instead
of 3,4-difluoroaniline. The racemic mixture was separated in its
epimers via preparative SFC (Stationary phase: Chiralpak Daicel ID
20.times.250 mm, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2) to
yield compound 144a (176 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 0.92 (t, J=7.3 Hz, 3H), 1.44 (dquin, J=14.2, 7.1, 7.1,
7.1, 7.1 Hz, 1H), 1.64-1.79 (m, 1H), 3.35-3.44 (m, 1H), 3.44-3.56
(m, 1H), 3.83 (s, 3H), 3.99 (dd, J=12.7, 8.9 Hz, 1H), 4.89 (dd,
J=12.8, 1.8 Hz, 1H), 4.98 (d, J=6.4 Hz, 1H), 7.03-7.41 (m, 2H),
7.47 (s, 1H), 7.59 (br s, 1H), 7.73-7.89 (m, 1H), 8.04 (dd, J=6.3,
2.5 Hz, 1H), 9.47 (s, 1H); Method D; Rt: 1.75 min. m/z: 446
(M-H).sup.- Exact mass: 447.1, and 144b (156 mg); .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 0.88 (t, J=7.4 Hz, 3H), 1.30-1.43
(m, 1H), 1.49-1.63 (m, 1H), 3.56-3.64 (m, 1H), 3.66-3.76 (m, 1H),
3.83 (s, 3H), 4.00 (dd, J=12.7, 9.1 Hz, 1H), 4.64-4.77 (m, 1H),
4.86 (d, J=5.5 Hz, 1H), 7.02-7.42 (m, 3H), 7.46 (s, 1H), 7.76-7.88
(m, 1H), 8.03 (dd, J=6.3, 2.5 Hz, 1H), 9.49 (s, 1H); Method D; Rt:
1.78 min. m/z: 446 (M-H).sup.- Exact mass: 447.1; MP: 224.6.degree.
C. Method U; Rt: 144a: 2.92 min, 144b: 3.49 min.
Synthesis of 2-amino-2-pyrazin-2-yl-propan-1-ol
[0688] A 100 ml flask was charged with acetylpyrazine (2.00 g, 16.4
mmol), NH.sub.3 (33 mL, 7 M in MeOH, 229 mmol) and ammonium
chloride (2.63 g, 49.1 mmol). Trimethylsilyl cyanide (6.2 mL, 0.793
g/mL, 49 mmol) was added and the mixture was stirred at room
temperature for 16 hours. The mixture was concentrated in vacuo.
The residue was was taken up in DCM and the precipitate was
filtered off. The filtrate was concentrated in vacuo and the
residue was purified by column chromatography using a gradient from
0 till 100% EtOAc-EtOH (3-1) in heptane. The product fractions were
concentrated in vacuo to yield
2-amino-2-pyrazin-2-yl-propanenitrile (1.9 g) as a pale yellow
oil.
[0689] 2-amino-2-pyrazin-2-yl-propanenitrile (1.9 g, 12.8 mmol) was
dissolved in acetic acid (6.3 mL). Hydrobromic acid in acetic acid
(30 mL) was added carefully and the mixture was stirred at
80.degree. C. for 1 hour. The mixture was cooled and poured out in
EtOAc (400 mL). The precipitate was filtered off and washed with
EtOAc and ACN and dried under vacuum to yield
2-amino-2-pyrazin-2-yl-propanamide trihydrobromide (5.2 g) as a
yellow solid.
[0690] 2-amino-2-pyrazin-2-yl-propanamide trihydrobromide (5.2 g,
12.7 mmol) was dissolved in MeOH (50 mL). H.sub.2SO.sub.4 (5 mL)
was carefully added (exotherm) and the mixture was heated at reflux
for 16 hours. The mixture was cooled and concentrated in vacuo. The
residue was dissolved in water (50 mL) and washed with EtOAc. The
water fraction was neutralized with Na.sub.2CO.sub.3, and extracted
with Me-THF (2.times.50 mL). The combined organic layers were dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue was
purified by column chromatography using a gradient from 0 till 100%
EtOAc-EtOH(3-1) in heptane. The product fractions were concentrated
in vacuo to yield methyl 2-amino-2-pyrazin-2-yl-propanoate (371 mg)
as a yellow oil.
[0691] Methyl 2-amino-2-pyrazin-2-yl-propanoate (371 mg, 2.05 mmol)
was dissolved in MeOH (10 mL) under N.sub.2 atmosphere. Sodium
borohydride (155 mg, 4.10 mmol) was added and the mixture was
stirred at room temperature for 16 hours. The mixture was
concentrated in vacuo. The residue was dissolved in Me-THF, dried
(MgSO.sub.4), filtered and concentrated in vacuo yielding
2-amino-2-pyrazin-2-yl-propan-1-ol (285 mg).
Compound 145:
N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-3-pyrazin-2-yl-2,4-dihydrop-
yrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00199##
[0693] Compound 145 (221 mg) was prepared similarly as described
for compound 125, using 2-amino-2-pyrazin-2-yl-propan-1-ol instead
of 2-amino-2-phenylpropan-1-ol hydrochloride. The ring closure was
obtained after heating 3 hours and compound 145 was crystallized
from ACN. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.63 (s,
3H), 3.82 (s, 3H), 4.98-5.14 (m, 2H), 7.38-7.52 (m, 3H), 7.88 (ddd,
J=13.2, 7.5, 2.5 Hz, 1H), 8.56-8.60 (m, 2H), 8.68 (s, 1H), 9.03 (d,
J=1.1 Hz, 1H), 9.43 (s, 1H); Method B; Rt: 0.96 min. m/z: 448
(M-H).sup.- Exact mass: 449.1. The racemic mixture was separated in
its epimers via preparative SFC (Stationary phase: Chiralpak Daicel
AS 20.times.250 mm, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2)
to yield compound 145a (89 mg); Method D; Rt: 1.83 min. m/z: 448
(M-H).sup.- Exact mass: 449.1, MP: 199.4.degree. C., and 145b (156
mg); Method D; Rt: 1.83 min. m/z: 448 (M-H).sup.- Exact mass:
449.1; MP: 199.4.degree. C. Method T; Rt: 145a: 3.51 min, 145b:
4.34 min.
Compound 146:
(3R)--N-(2-chloro-4-pyridyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-di-
oxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00200##
[0695] Compound 146 (214 mg) was prepared similarly as described
for compound 93, using 4-amino-2-chloropyridine instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.07 (s, 3H), 1.25 (s, 3H), 3.50-3.61 (m, 1H), 3.84 (s, 3H),
3.96 (dd, J=12.5, 8.8 Hz, 1H), 4.87 (s, 1H), 4.98 (dd, J=12.4, 1.0
Hz, 1H), 7.47-7.61 (m, 2H), 7.69 (dd, J=5.6, 1.9 Hz, 1H), 7.88 (d,
J=1.8 Hz, 1H), 8.27 (d, J=5.7 Hz, 1H), 9.69 (s, 1H); Method D; Rt:
1.53 min. m/z: 413 (M-H).sup.- Exact mass: 414.1, MP: 246.6.degree.
C.
Compound 147:
(3R)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-dioxo-N-(3,4,5-trifluoroph-
enyl)-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00201##
[0697] Compound 147 (259 mg) was prepared similarly as described
for compound 93, using 3,4,5-trifluoroaniline instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.07 (s, 3H), 1.25 (s, 3H), 3.50-3.60 (m, 1H), 3.83 (s, 3H),
3.92 (dd, J=12.4, 8.9 Hz, 1H), 4.86 (s, 1H), 4.95-5.04 (m, 1H),
7.43-7.59 (m, 2H), 7.65-7.79 (m, 2H), 9.49 (s, 1H); Method D; Rt:
1.84 min. m/z: 432 (M-H).sup.- Exact mass: 433.1.
Compound 148:
N-(3,4-difluorophenyl)-4,4-difluoro-7-methyl-1,1-dioxo-3,5-dihydro-2H-pyr-
rolo[3,4-f]thiazepine-6-carboxamide
##STR00202##
[0699] 2-iodoxybenzoic acid (3.71 g, 13.3 mmol) was added to a
solution of ethyl
3-[3-(benzyloxycarbonylamino)-2-hydroxy-propyl]-1-methyl-pyrrole-2--
carboxylate (2.12 g, 5.89 mmol) in EtOAc (50 mL) and stirred at
reflux temperature for 5 hours and 30 minutes. The reaction mixture
was filtered while still hot. The precipitate was washed with EtOAc
(150 mL). The organic layer was washed with NaHCO.sub.3(aq., sat.,
200 mL), dried over magnesium sulfate, filtered and concentrated.
The residue was purified on silica using a gradient from 0 till
100% EtOAc in heptane yielding ethyl
3-[3-(benzyloxycarbonylamino)-2-oxo-propyl]-1-methyl-pyrrole-2-carboxylat-
e (1.49 g) as a clear oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.24 (t, J=7.0 Hz, 3H), 3.76-3.93 (m, 7H), 4.16 (q,
J=7.2 Hz, 2H), 5.03 (s, 2H), 6.00 (d, J=2.4 Hz, 1H), 7.01 (d, J=2.4
Hz, 1H), 7.27-7.50 (m, 6H); Method D; Rt: 1.90 min. m/z: 357
(M-H).sup.- Exact mass: 358.2.
[0700] Diethylaminosulfur trifluoride (3.35 g, 20.8 mmol) was added
to a solution of ethyl
3-[3-(benzyloxycarbonylamino)-2-oxo-propyl]-1-methyl-pyrrole-2-carboxylat-
e (1.49 g, 4.16 mmol) in DCM (100 mL) and stirred overnight at room
temperature. The reaction mixture was quenched by pouring in
NaHCO.sub.3(aq., sat., 300 mL). The organic layer was dried over
sodium sulfate, filtered and concentrated. The residue was purified
on silica using a gradient from 0 till 100% EtOAc in heptane
yielding ethyl
3-[3-(benzyloxycarbonylamino)-2,2-difluoro-propyl]-1-methyl-pyrrole-2-car-
boxylate (371 mg) as a clear oil. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.27 (t, J=7.0 Hz, 3H), 3.32-3.49 (m,
4H), 3.80 (s, 3H), 4.20 (q, J=7.0 Hz, 2H), 5.04 (s, 2H), 6.08 (d,
J=2.2 Hz, 1H), 7.01 (d, J=2.6 Hz, 1H), 7.27-7.40 (m, 5H), 7.68 (br
t, J=6.2 Hz, 1H); Method D; Rt: 2.07 min. m/z: 379 (M-H).sup.-
Exact mass: 380.2.
[0701] Chlorosulfonic acid (7.8 g, 67 mmol) was added to a solution
of ethyl
3-[3-(benzyloxycarbonylamino)-2,2-difluoro-propyl]-1-methyl-pyrrole-
-2-carboxylate (365 mg, 0.96 mmol) in DCM (50 mL) and the reaction
mixture was stirred for 20 minutes. The reaction mixture was poured
in water (300 mL) and the organic layer was washed with
NaHCO.sub.3(aq., sat., 250 mL), dried over magnesium sulfate,
filtered and concentrated. The residue was purified on silica using
a gradient from 0 till 100% EtOAc in heptane yielding ethyl
4,4-difluoro-7-methyl-1,1-dioxo-3,5-dihydro-2H-pyrrolo[3,4-f]thiazepine-6-
-carboxylate (17 mg) as white crystals. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.31 (t, J=7.2 Hz, 3H), 3.66 (td, J=11.6,
7.2 Hz, 2H), 3.76-3.89 (m, 5H), 4.30 (q, J=7.1 Hz, 2H), 7.65 (s,
1H), 8.18 (t, J=6.8 Hz, 1H); Method D; Rt: 1.65 min. m/z: 307
(M-H).sup.- Exact mass: 308.1.
[0702] Lithium bis(trimethylsilyl)amide (0.33 mL, 1 M in THF, 0.33
mmol) was added to a solution of ethyl
4,4-difluoro-7-methyl-1,1-dioxo-3,5-dihydro-2H-pyrrolo[3,4-f]thiazepine-6-
-carboxylate (17 mg, 0.055 mmol) and 3,4-difluoroaniline (22 mg,
0.17 mmol) in THF (3 mL) and stirred for 30 minutes. The reaction
mixture was quenched with NH.sub.4Cl solution (aq., sat., 10 mL)
and extracted with EtOAc (50 mL). The organic layer was dried over
magnesium sulfate, filtered and concentrated. The residue was
purified on silica using a gradient from 10 till 100% EtOAc in
heptane yielding compound 148 (9.8 mg). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 3.39-3.50 (m, 2H), 3.61-3.70 (m, 2H),
3.72 (s, 3H), 7.39-7.49 (m, 2H), 7.55 (s, 1H), 7.81-7.88 (m, 1H),
8.14 (t, J=6.9 Hz, 1H), 10.62 (s, 1H); Method D; Rt: 1.72 min. m/z:
390 (M-H).sup.- Exact mass: 391.1.
Compound 149:
3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)-
-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00203##
[0704] Compound 149 (140 mg) was prepared similarly as described
for compound 113, using 3,4,5-trifluoroaniline instead of
3,4-difluoroaniline. The racemic mixture was separated in its
enantiomers via preparative SFC (Stationary phase: Chiralpak Daicel
AD 20.times.250 mm, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2)
to yield compound 149a (66 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.03 (s, 3H), 1.17 (s, 3H), 1.33 (br q, J=11.5 Hz, 1H),
2.17 (br dd, J=14.0, 6.9 Hz, 1H), 2.67-2.78 (m, 1H), 2.98-3.08 (m,
1H), 3.21-3.29 (m, 1H), 3.69 (s, 3H), 4.39 (s, 1H), 6.85 (d, J=10.8
Hz, 1H), 7.45 (s, 1H), 7.56-7.64 (m, 2H), 10.59 (s, 1H); Method D;
Rt: 1.70 min. m/z: 430 (M-H).sup.- Exact mass: 431.1, and 149b (63
mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.03 (s, 3H),
1.17 (s, 3H), 1.27-1.38 (m, 1H), 2.17 (br dd, J=14.0, 6.9 Hz, 1H),
2.67-2.78 (m, 1H), 2.98-3.08 (m, 1H), 3.23-3.30 (m, 1H), 3.69 (s,
3H), 4.39 (s, 1H), 6.85 (d, J=10.6 Hz, 1H), 7.45 (s, 1H), 7.56-7.64
(m, 2H), 10.59 (s, 1H); Method D; Rt: 1.70 min. m/z: 430
(M-H).sup.- Exact mass: 431.1. Method R; Rt: 149a: 2.83 min, 149b:
3.64 min.
Compound 150:
N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-(1-hydroxy-1-methyl-ethyl)-7-met-
hyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00204##
[0706] Compound 150 (45 mg) was prepared similarly as described for
compound 113, using 3-(difluoromethyl)-4-fluoro-aniline instead of
3,4-difluoroaniline. The racemic mixture was separated in its
enantiomers via preparative SFC (Stationary phase: Chiralpak Daicel
AD 20.times.250 mm, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2)
to yield compound 150a (23 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.03 (s, 3H), 1.17 (s, 3H), 1.34 (q, J=11.6 Hz, 1H),
2.17 (br dd, J=14.1, 6.8 Hz, 1H), 2.66-2.79 (m, 1H), 3.06 (br dd,
J=14.4, 6.5 Hz, 1H), 3.21-3.30 (m, 1H), 3.69 (s, 3H), 4.39 (s, 1H),
6.83 (d, J=10.8 Hz, 1H), 7.22 (t, J=54.2 Hz, 1H), 7.37 (t, J=9.6
Hz, 1H), 7.43 (s, 1H), 7.78-7.84 (m, 1H), 8.06 (dd, J=6.3, 2.3 Hz,
1H), 10.49 (s, 1H); Method D; Rt: 1.61 min. m/z: 444 (M-H).sup.-
Exact mass: 445.1, and 150b (22 mg); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.03 (s, 3H), 1.17 (s, 3H), 1.34 (br q,
J=12.0 Hz, 1H), 2.17 (br dd, J=13.9, 6.8 Hz, 1H), 2.68-2.79 (m,
1H), 3.01-3.11 (m, 1H), 3.19-3.30 (m, 1H), 3.69 (s, 3H), 4.39 (s,
1H), 6.83 (br d, J=10.6 Hz, 1H), 7.22 (t, J=54.2 Hz, 1H), 7.37 (t,
J=9.6 Hz, 1H), 7.43 (s, 1H), 7.78-7.84 (m, 1H), 8.06 (dd, J=6.2,
2.4 Hz, 1H), 10.49 (s, 1H); Method D; Rt: 1.61 min. m/z: 444
(M-H).sup.- Exact mass: 445.1. Method R; Rt: 150a: 2.92 min, 150b:
3.74 min.
Compound 151:
(3R)--N-[2-(difluoromethyl)-4-pyridyl]-3-(1-hydroxy-1-methyl-ethyl)-7-met-
hyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxam-
ide
##STR00205##
[0708] Compound 151 (359 mg) was prepared similarly as described
for compound 93, using 2-(difluoromethyl)pyridin-4-amine instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.06 (s, 3H), 1.25 (s, 3H), 3.49-3.61 (m, 1H), 3.85 (s, 3H),
3.97 (dd, J=12.5, 8.9 Hz, 1H), 4.88 (s, 1H), 4.97 (dd, J=12.9, 0.5
Hz, 1H), 6.91 (t, J=55.0 Hz, 1H), 7.48-7.61 (m, 2H), 7.77-7.85 (m,
1H), 8.09 (d, J=2.1 Hz, 1H), 8.53 (d, J=5.6 Hz, 1H), 9.75 (s, 1H);
Method B; Rt: 0.73 min. m/z: 429 (M-H).sup.- Exact mass: 430.1.
Compound 152:
(3S)--N-(3,4-difluorophenyl)-3,7,8-trimethyl-1,1-dioxo-2,3,4,5-tetrahydro-
pyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00206##
[0710] Methyl
(3S)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6--
carboxylate (200 mg, 0.73 mmol) was dissolved in acetic acid (5 mL)
and bromine (0.057 mL, 3.10 g/mL, 1.10 mmol) was added. The
solution was then refluxed for 4 hours and stirred at room
temperature 16 hours. The solution was then cooled to 0.degree. C.,
quenched with NaHCO.sub.3 and extracted with EtOAc. The combined
organics were dried with Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The crude was then purified on silica using
heptane/EtOAc from 100/0 to 50/50 to give methyl
(3S)-8-bromo-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiaz-
epine-6-carboxylate (202 mg).
[0711] Methyl
(3S)-8-bromo-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiaz-
epine-6-carboxylate (202 mg, 0.58 mmol) and 3,4-difluoroaniline
(0.069 mL, 1.29 g/mL, 0.69 mmol) are dissolved in THF (5 mL) and
LiHMDS (1.7 mL, 1 M, 1.7 mmol) was added. After 2 hours the
solution was quenched with NH.sub.4Cl (aq., sat.) and stirred for 5
min. The solution was then diluted with EtOAc, extracted and the
combined organics were dried with MgSO.sub.4, filtered off and
concentrated in vacuo. The crude was then purified on silica using
heptane/EtOAc 100/0 to 0/100 to give
(3S)-8-bromo-N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrah-
ydropyrrolo[3,4-f]thiazepine-6-carboxamide (228 mg). Method B; Rt:
0.97 min. m/z: 446 (M-H).sup.- Exact mass: 447.0.
[0712]
(3S)-8-bromo-N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5--
tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide (54 mg, 0.12 mmol)
was dissolved in DMF (2 mL). Tetramethyltin (0.025 mL, 0.18 mmol)
was added and the solution was flushed with nitrogen during 5
minutes before tetrakis(triphenylphosphine)palladium(0) was added.
The vial was then heated by microwave irradiation at 140.degree. C.
during 30 minutes. The solution was then filtered over dicalite and
washed with EtOAc. The filtrate was concentrated in vacuo and
purified on silica using heptane/EtOAc 100/0 to 80/20 and further
triturated with diethylether to give compound 152 (37 mg) as a
white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.12
(d, J=6.8 Hz, 3H) 1.15-1.39 (m, 1H) 1.83 (br dd, J=14.0, 7.2 Hz,
1H) 2.39-2.45 (m, 1H) 2.42 (s, 2H) 2.73-2.84 (m, 1H) 2.88-2.98 (m,
1H) 3.53 (s, 3H) 3.56-3.65 (m, 1H) 7.07 (d, J=9.5 Hz, 1H) 7.35-7.46
(m, 2H) 7.79-7.91 (m, 1H) 10.46 (s, 1H); Method B; Rt: 0.93 min.
m/z: 382 (M-H).sup.- Exact mass: 383.1.
Compound 153:
N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-3-pyrimidin-2-yl-2,4-dihydr-
opyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00207##
[0714] Compound 153 (205 mg) was prepared similarly as described
for compound 125, using 2-amino-2-pyrimidin-2-yl-propan-1-ol
instead of 2-amino-2-phenylpropan-1-ol hydrochloride.
2-amino-2-pyrimidin-2-yl-propan-1-ol was synthesized as described
for 2-amino-2-pyrazin-2-yl-propan-1-ol using 2-acetylpyrimidine
instead of acetylpyrazine. The ring closure was obtained after
heating 3 hours and compound 153 was crystallized from ACN. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.63 (s, 3H), 3.80 (s, 3H),
5.07-5.20 (m, 2H), 7.36-7.43 (m, 2H), 7.43-7.48 (m, 2H), 7.80-7.87
(m, 1H), 8.30-8.36 (m, 1H), 8.86 (d, J=4.9 Hz, 2H), 9.38 (s, 1H);
Method B; Rt: 1.01 min. m/z: 448 (M-H).sup.- Exact mass: 449.1. The
racemic mixture was separated in its enantiomers via preparative
SFC (Stationary phase: Chiralpak Daicel AD 20.times.250 mm, Mobile
phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2) to yield compound 153a (75
mg); Method D; Rt: 1.93 min. m/z: 448 (M-H).sup.- Exact mass:
449.1, MP: 228.3.degree. C., and 153b (73 mg); Method D; Rt: 1.94
min. m/z: 448 (M-H).sup.- Exact mass: 449.1; MP: 228.6.degree. C.
Method R; Rt: 153a: 4.67 min, 153b: 5.97 min.
Synthesis of (2R)-2-amino-2-methyl-3-phenyl-propan-1-ol
[0715] A solution of Z-L-alanine (5 g, 22.4 mmol) and benzaldehyde
dimethyl acetal (5.11 g, 33.6 mmol) in diethylether (50 mL) was
cooled to -78.degree. C. Boron trifluoride etherate (23.5 mL, 1.15
g/mL, 190 mmol) was added keeping the temperature below -70.degree.
C. After addition the reaction mixture was allowed to warm to
-15.degree. C. and stirring was continued over weekend at this
temperature. The reaction mixture was quenched in cooled
NaHCO.sub.3(sat., aq., 100 mL) and stirred for 30 minutes. The
organic layer was removed and evaporated under reduced pressure.
The residue was purified on silica using a heptane to heptane:EtOAc
1:1 yielding benzyl
(2S,4S)-4-methyl-5-oxo-2-phenyl-oxazolidine-3-carboxylate (6.2 g)
as an oil which solidified on standing. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.52 (d, J=7.0 Hz, 3H), 4.56 (q, J=6.9
Hz, 1H), 5.10 (br s, 2H), 6.58 (s, 1H), 7.31 (br s, 4H), 7.40-7.50
(m, 6H).
[0716] A solution of benzyl
(2S,4S)-4-methyl-5-oxo-2-phenyl-oxazolidine-3-carboxylate (1.5 g,
4.82 mmol) and benzyl bromide (572 .mu.l, 1.44 g/mL, 4.82 mmol) was
added dropwise to a solution of lithium bis(trimethylsilyl)amide
(5.78 mL, 1 M in THF, 5.78 mmol) in THF (5 mL) and stirred for 1
hour. The reaction mixture was quenched with NH.sub.4Cl (sat., aq.,
10 mL) and the organic layer was removed. The aqueous layer was
extracted with DCM (2.times.5 mL) and the combined organic layers
were evaporated to dryness and the residue was purified on silica
using a heptane to EtOAc gradient yielding benzyl
(2S,4R)-4-benzyl-4-methyl-5-oxo-2-phenyl-oxazolidine-3-carboxylate
(1.01 g). Method D; Rt: 2.38 min. m/z: 402 (M+H).sup.+ Exact mass:
401.1.
[0717] LiOH (121 mg, 5.03 mmol) dissolved in water (1 mL) was added
to a solution of benzyl
(2S,4R)-4-benzyl-4-methyl-5-oxo-2-phenyl-oxazolidine-3-carboxylate
(1.01 g, 2.52 mmol) in MeOH (10 mL). The reaction mixture was
stirred for 2 hours. HCl (aq., 1M, 5 mL) was added and the
volatiles were removed under reduced pressure. The residue was
purified on silica using a heptane to EtOAc gradient yielding
methyl (2R)-2-(benzyloxycarbonylamino)-2-methyl-3-phenyl-propanoate
(691 mg). Method B; Rt: 1.13 min. m/z: 328 (M+H).sup.+ Exact mass:
327.2.
[0718] Methyl
(2R)-2-(benzyloxycarbonylamino)-2-methyl-3-phenyl-propanoate (560
mg, 1.71 mmol) was dissolved in THF (10 mL). Lithium aluminum
hydride (5.13 mL, 1 M in THF, 5.13 mmol) was added and the reaction
mixture was stirred for 2 hours. THF (100 mL) was added and then
potassium sodium tartrate tetrahydrate (2.17 g, 7.7 mmol) dissolved
in water (3 mL) was added and the reaction mixture was stirred for
15 minutes. Na.sub.2SO.sub.4 was added and the reaction mixture was
stirred for 15 minutes. The precipitate was removed by filtration
and the filtrate was evaporated to dryness. The residue was
purified on silica using a heptane to EtOAc gradient yielding
benzyl N-[(1R)-1-benzyl-2-hydroxy-1-methyl-ethyl]carbamate (186
mg).
[0719] Benzyl N-[(1R)-1-benzyl-2-hydroxy-1-methyl-ethyl]carbamate
(186 mg, 0.62 mmol) and Pd/C (10%) (33 mg, 0.031 mmol) were
dispensed in MeOH (40 mL) and set under a hydrogen atmosphere
overnight. The reaction mixture was filtered and evaporated to
dryness yielding (2R)-2-amino-2-methyl-3-phenyl-propan-1-ol which
was used as such.
Compound 154:
(3R)-3-benzyl-N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-2,4-dihydropy-
rrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00208##
[0721] Compound 154 (111 mg) was prepared similarly as described
for compound 133, using (2R)-2-amino-2-methyl-3-phenyl-propan-1-ol
instead of 2-amino-2-methyl-1-propanol .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.15 (s, 3H), 2.80 (d, J=13.0 Hz, 1H),
3.00 (d, J=13.0 Hz, 1H), 3.82 (s, 3H), 4.40 (d, J=13.2 Hz, 1H),
4.57 (d, J=13.0 Hz, 1H), 7.24-7.38 (m, 5H), 7.38-7.46 (m, 2H), 7.47
(s, 1H), 7.57-7.80 (m, 1H), 7.81-7.90 (m, 1H), 9.40 (s, 1H); Method
B; Rt: 1.19 min. m/z: 460 (M-H).sup.- Exact mass: 461.1.
Compound 155:
(3S)-3-benzyl-N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-2,4-dihydropy-
rrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00209##
[0723] Compound 155 (92 mg) was prepared similarly as described for
compound 133, using (2S)-2-amino-2-methyl-3-phenyl-propan-1-ol
instead of 2-amino-2-methyl-1-propanol
(2S)-2-amino-2-methyl-3-phenyl-propan-1-ol was synthesized as
described for (2S)-2-amino-2-methyl-3-phenyl-propan-1-ol using
Z-D-alanine instead of Z-L-alanine. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.15 (s, 3H), 2.80 (d, J=13.0 Hz, 1H),
3.00 (d, J=13.2 Hz, 1H), 3.82 (s, 3H), 4.40 (d, J=13.2 Hz, 1H),
4.57 (d, J=13.2 Hz, 1H), 7.25-7.36 (m, 5H), 7.40-7.46 (m, 2H), 7.47
(s, 1H), 7.71-7.89 (m, 2H), 9.40 (s, 1H); Method B; Rt: 1.19 min.
m/z: 460 (M-H).sup.- Exact mass: 461.1.
Compound 156:
(3S)-3-benzyl-N-(3-cyano-4-fluoro-phenyl)-3,7-dimethyl-1,1-dioxo-2,4-dihy-
dropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00210##
[0725] Compound 156 (41 mg) was prepared similarly as described for
compound 155, using 5-amino-2-fluoro-benzonitrile instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.16 (s, 3H), 2.79 (d, J=13.2 Hz, 1H), 3.01 (d, J=13.2 Hz, 1H),
3.83 (s, 3H), 4.40 (d, J=13.2 Hz, 1H), 4.59 (d, J=13.0 Hz, 1H),
7.24-7.36 (m, 5H), 7.49 (s, 1H), 7.55 (t, J=9.1 Hz, 1H), 7.75 (s,
1H), 8.02 (ddd, J=9.2, 4.8, 2.9 Hz, 1H), 8.18 (dd, J=5.7, 2.6 Hz,
1H), 9.49 (s, 1H); Method B; Rt: 1.13 min. m/z: 467 (M-H).sup.-
Exact mass: 468.1.
Synthesis of (S)-2-(1-methylallyl)isoindoline-1,3-dione
[0726] DIBAL (11 mL, 1 M in heptane, 11 mmol) was added drop wise
to an anhydrous solution of methyl
(2S)-2-(benzyloxycarbonylamino)propanoate (2.50 g, 10.5 mmol) in
THF (50 mL) at -78.degree. C. After addition the solution was
carefully quenched with NaF (aq., sat.) at -78.degree. C. The
resulting mixture was stirred while allowing warming to room
temperature. More water was added and the reaction mixture was
extracted with EtOAc (3.times.25 mL). The combined extracts were
evaporated to dryness and the residue was purified on silica using
a heptane to EtOAc gradient yielding benzyl
N-[(1S)-1-methyl-2-oxo-ethyl]carbamate (1.13 g) as an oil.
[0727] Methyltriphenylphosphonium bromide (3.11 g, 8.69 mmol) was
suspended in toluene (50 mL) and cooled to 0.degree. C. Lithium
bis(trimethylsilyl)amide (8.2 mL, 1 M in toluene, 8.2 mmol) was
added. The reaction was stirred at 0.degree. C. for 30 minutes,
then cooled to -78.degree. C. and a solution of benzyl
N-[(1S)-1-methyl-2-oxo-ethyl]carbamate (1.13 g, 5.43 mmol) in
toluene (5 mL) was added. The solution was allowed to warm to room
temperature, stirred for 30 min, then quenched with sat NH.sub.4Cl
(aq., sat.) (20 mL). The layers were separated and the aqueous was
washed with EtOAc (10 mL). The combined organic layers were
evaporated to dryness and the residue was purified on silica using
a heptane to EtOAc gradient yielding benzyl
N-[(1S)-1-methylallyl]carbamate (230 mg) as an oil which solidified
on standing.
[0728] Benzyl N-[(1S)-1-methylallyl]carbamate (100 mg, 0.49 mmol)
was dissolved in HCl (37% in H.sub.2O, 3 mL) and heated for 30
minutes at 100.degree. C. The volatiles were removed under reduced
pressure and the residue was dissolved in THF (5 mL). Hunig's base
(0.84 mL, 0.75 g/mL, 4.9 mmol) and 1,3-isobenzofurandione (79 mg,
0.54 mmol) were added and the reaction mixture was stirred over
weekend. Hunig's base (0.84 mL, 0.75 g/mL, 4.9 mmol) was added and
the reaction mixture was heated at 50.degree. C. for 2 hours.
(S)-2-(1-methylallyl)isoindoline-1,3-dione formed in this reaction
mixture was found identical to
(*S)-2-(1-methylallyl)isoindoline-1,3-dione described in the
synthesis of compound 29. Method Q; Rt:
(*R)-2-(1-methylallyl)isoindoline-1,3-dione: 1.65 min,
(*S)-2-(1-methylallyl)isoindoline-1,3-dione and
(S)-2-(1-methylallyl)isoindoline-1,3-dione: 1.89 min.
Compound 157:
(3S)--N-(3-cyano-2,4-difluoro-phenyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetr-
ahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00211##
[0730] To methyl 3-bromo-1-methyl-pyrrole-2-carboxylate (10.0 g,
45.9 mmol) and 2-[(1S)-1-methylallyl]isoindoline-1,3-dione (10.2 g,
50.5 mmol) in DMF (50 mL) was added TEA (12.7 mL, 0.73 g/mL, 91.7
mmol) and this was stirred and purged with nitrogen for 5 minutes.
Then bis(tri-tert-butylphosphine)palladium(0) (1.17 g, 2.29 mmol)
was added and the mixture was stirred and heated in an oil bath at
110.degree. C. for 90 minutes. The resulting mixture was filtered
over a pad of dicalite, rinsed with EtOAc (300 mL) and concentrated
in vacuo. The crude was purified on silica (gradient elution:
EtOAc:heptane 0:100 to 100:0). The desired fractions were
concentrated under reduced pressure yielding methyl
3-[(E,3S)-3-(1,3-dioxoisoindolin-2-yl)but-1-enyl]-1-methyl-pyrrole-
-2-carboxylate (15.1 g) as a yellow oil.
[0731] A hydrogenation flask was flushed with nitrogen and then
charged with Pd/C (10%) (2.37 g, 2.22 mmol). To this was added
under nitrogen methyl
3-[(E,3S)-3-(1,3-dioxoisoindolin-2-yl)but-1-enyl]-1-methyl-pyrrole-
-2-carboxylate (15.4 g, 44.5 mmol) in THF (200 mL). The resulting
suspension was then stirred under a hydrogen atmosphere at room
temperature for 2 hours. Then the mixture was filtered over a pad
of dicalite under a constant nitrogen flow and this pad was rinsed
with THF (250 mL). The filtrate was concentrated in vacuo to yield
methyl
3-[(3S)-3-(1,3-dioxoisoindolin-2-yl)butyl]-1-methyl-pyrrole-2-carboxylate
(15.0 g).
[0732] Methyl 3-[(3
S)-3-(1,3-dioxoisoindolin-2-yl)butyl]-1-methyl-pyrrole-2-carboxylate
(15.0 g, 44.1 mmol) was dissolved in n-butanol (150 mL).
Ethylenediamine (118 mL) was added and stirred at room temperature
for 5 minutes and then heated at 90.degree. C. for 3 hours. The
mixture was cooled and concentrated in vacuo. The residue was
purified by column chromatography on silica using a gradient from 0
till 10% MeOH/NH.sub.3 in DCM. The product fractions were
concentrated in vacuo to yield methyl
3-[(3S)-3-aminobutyl]-1-methyl-pyrrole-2-carboxylate (9.1 g) as an
oil. Method B; Rt: 0.52 min. m/z: 211 (M+H).sup.+ Exact mass:
210.1.
[0733] Chlorosulfonic acid (55 mL, 1.75 g/mL, 832 mmol) was stirred
and cooled in an ice-acetone bath. A gentle nitrogen flow was
maintained. To this was added dropwise methyl
3-[(3S)-3-aminobutyl]-1-methyl-pyrrole-2-carboxylate (3.50 g, 16.6
mmol) in DCM (65 mL). After addition the resulting mixture was
added dropwise to an ice-cooled and stirring solution of
Na.sub.2CO.sub.3 (176 g) in ice cold water (1 L). After addition
the layers were separated and the water layer was extracted with
DCM (2.times.500 mL). The combined extracts were dried on
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude was
purified on silica gel using gradient elution (heptane/iPrOH 100:0
to 20:80) yielding methyl
(3S)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6--
carboxylate (1.95 g) as a clear oil. Method B; Rt: 0.73 min. m/z:
271 (M-H).sup.- Exact mass: 272.1.
[0734] Methyl
(3S)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6--
carboxylate (200 mg, 0.73 mmol) and
3-amino-2,6-difluoro-benzonitrile (0.16 g, 0.88 mmol) in dry THF (5
mL) was treated with lithium bis(trimethylsilyl)amide (2.2 mL, 1 M
in THF, 2.2 mmol) and this was stirred overnight at room
temperature. The resulting mixture was quenched with NH.sub.4Cl
(aq., sat., 5 mL). Then 5 mL of brine was added and the layers were
separated. The water layer was extracted using EtOAc (2.times.30
mL). The combined extracts were concentrated in vacuo and the
obtained crude was purified using silica gel column chromatography
(gradient elution: EtOAc:heptane 0:100 to 100:0). The desired
fractions were concentrated in vacuo and the obtained residue was
purified via preparative HPLC (Stationary phase: RP)(Bridge Prep
C18 OBD-10 .mu.m, 30.times.150 mm, Mobile phase: 0.25%
NH.sub.4HCO.sub.3 solution in water, ACN). The desired fractions
were concentrated under reduced pressure, co-evaporated with
methanol (2.times.25 mL) and dried in a vacuum oven at 55.degree.
C. for 18 hours yielding compound 157 (7.6 mg). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 1.14 (d, J=6.82 Hz, 3H) 1.31-1.45
(m, 1H) 1.81-1.91 (m, 1H) 2.77-2.89 (m, 1H) 3.07-3.18 (m, 1H)
3.58-3.67 (m, 1H) 3.70 (s, 3H) 7.03 (d, J=9.68 Hz, 1H) 7.40-7.51
(m, 2H) 8.06 (td, J=8.97, 6.05 Hz, 1H) 10.31 (s, 1H); Method B; Rt:
0.85 min. m/z: 393 (M-H).sup.- Exact mass: 394.1, MP: 247.5.degree.
C.
[0735] Methyl
(3S)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6--
carboxylate (140 mg, 0.51 mmol) and 5-amino-2-fluorobenzonitrile
(77 mg, 0.57 mmol) in THF (8 mL) was treated with LiHMDS (1 mL, 1 M
in THF, 1 mmol) and this was stirred for 2 hours at room
temperature. The resulting mixture was quenched with NH.sub.4Cl
(aq., sat., 5 mL). Then brine (5 mL) was added and the layers were
separated. The water layer was extracted with EtOAc (2.times.10
mL). The combined extracts were concentrated in vacuo and the
obtained crude was purified using silica gel column chromatography
(EtOAc:heptane 0:100 to 100:0). The desired fractions were
concentrated in vacuo and the obtained residue was purified via
preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10
.mu.m, 30.times.150 mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3
solution in water, ACN) yielding
(3S)--N-(3-cyano-4-fluoro-phenyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahyd-
ropyrrolo[3,4-f]thiazepine-6-carboxamide (41 mg) being identical to
compound 56. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.13
(d, J=6.60 Hz, 3H) 1.28-1.42 (m, 1H) 1.77-1.92 (m, 1H) 2.77-2.90
(m, 1H) 2.92-3.04 (m, 1H) 3.56-3.66 (m, 1H) 3.69 (s, 3H) 7.02 (d,
J=9.68 Hz, 1H) 7.43 (s, 1H) 7.54 (t, J=9.13 Hz, 1H) 7.95 (ddd,
J=9.19, 4.90, 2.86 Hz, 1H) 8.19 (dd, J=5.72, 2.64 Hz, 1H) 10.59 (s,
1H); Method B; Rt: 0.85 min. m/z: 375 (M-H).sup.- Exact mass:
376.1.
Compound 158:
N-[2-(difluoromethyl)-4-pyridyl]-3,3,7-trimethyl-1,1-dioxo-2,4-dihydropyr-
rolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00212##
[0737] Compound 158 (610 mg) was prepared similarly as described
for compound 133, using 2-(difluoromethyl)pyridin-4-amine instead
of 3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.30 (s, 6H), 3.82 (s, 3H), 4.43 (s, 2H), 6.91 (t, J=55.0 Hz,
1H), 7.49 (s, 1H), 7.77-7.81 (m, 1H), 7.82 (s, 1H), 8.03 (d, J=2.0
Hz, 1H), 8.54 (d, J=5.5 Hz, 1H), 9.69 (s, 1H); Method B; Rt: 0.82
min. m/z: 399 (M-H).sup.- Exact mass: 400.1, MP: 229.9.degree.
C.
Compound 159:
(3R)--N-(3-cyano-2,4-difluoro-phenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,-
1-di ox 0-2 3 4
5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00213##
[0739] Compound 159 (7 mg) was prepared similarly as described for
compound 88, using 3-amino-2,6-difluoro-benzonitrile instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.13 (d, J=6.2 Hz, 3H), 1.25-1.37 (m, 1H), 2.17-2.24 (m, 1H),
2.71-2.79 (m, 1H), 3.15-3.24 (m, 2H), 3.42-3.53 (m, 1H), 3.70 (s,
3H), 4.68 (d, J=5.7 Hz, 1H), 6.91 (d, J=10.1 Hz, 1H), 7.43-7.49 (m,
2H), 8.06 (td, J=8.9, 6.2 Hz, 1H), 10.31 (s, 1H); Method D; Rt:
1.71 min. m/z: 423 (M-H).sup.- Exact mass: 424.1.
Compound 160:
N-(3,4-difluorophenyl)-3,7-dimethyl-3-oxazol-2-yl-1,1-dioxo-2,4-dihydropy-
rrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00214##
[0741] Compound 160 (240 mg) was prepared similarly as described
for compound 153, using 1-(oxazol-2-yl)ethanone instead of
2-acetylpyrimidine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.63 (s, 3H), 3.81 (s, 3H), 4.88 (d, J=13.3 Hz, 1H), 5.11 (d,
J=13.3 Hz, 1H), 7.18 (d, J=0.8 Hz, 1H), 7.38-7.50 (m, 3H), 7.87
(ddd, J=13.2, 7.5, 2.4 Hz, 1H), 8.13 (d, J=0.8 Hz, 1H), 8.68 (s,
1H), 9.46 (s, 1H); Method B; Rt: 0.93 min. m/z: 439 (M+H).sup.+
Exact mass: 438.1. The racemic mixture was separated in its
enantiomers via preparative SFC (Stationary phase: Chiralpak Daicel
OD 20.times.250 mm, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2)
to yield compound 160a (88 mg); MP: 239.5.degree. C., and 160b (80
mg); MP: 240.2.degree. C. Method Y; Rt: 160a: 3.43 min, 160b: 3.73
min.
Synthesis of 2-amino-3-(2,2,2-trifluoroethylamino)butan-1-ol
[0742] Tert-butyl 4-acetyl-2,2-dimethyloxazolidine-3-carboxylate
(3.0 g, 12 mmol) and 2,2,2-trifluoroethylamine (1.47 mL, 1.24 g/mL,
18.5 mmol) were dissolved in DCM (50 mL) and stirred at room
temperature for 30 min. Then NaBH(OAc).sub.3 (3.40 g, 16.0 mmol)
was added and the reaction mixture was stirred overnight. The
reaction mixture was diluted with DCM (40 mL) and quenched with
Na.sub.2CO.sub.3 (aq., sat., 60 mL). The organic layer was
separated, dried over Na.sub.2SO.sub.4, filtered and evaporated to
dryness. The crude oil was purified on silica using a heptane to
EtOAc gradient yielding tert-butyl
2,2-dimethyl-4-[1-(2,2,2-trifluoroethylamino)ethyl]oxazolidine-3-carboxyl-
ate (4.2 g) as a clear oil. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 1.04 (d, J=6.6 Hz, 3H), 1.35-1.57 (m, 15H), 3.00-4.21
(m, 6H).
[0743] tert-butyl 2,2-dimethyl-4-[1-(2,2,2-tri
fluoroethylamino)ethyl]oxazolidine-3-carboxylate (3.73 g, 11.43
mmol) was dissolved in 1,4-dioxane (50 mL) and HCl (17 mL, 4 M in
1,4-dioxane, 68.6 mmol) was added at room temperature. After
stirring for 5 hours, the solvents were removed yielding crude
2-amino-3-(2,2,2-trifluoroethylamino)butan-1-ol hydrochloride which
was used as such in the next step.
Compound 161:
N-(3-cyano-4-fluoro-phenyl)-7-methyl-1,1-dioxo-3-[1-(2,2,2-trifluoroethyl-
amino)ethyl]-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxami-
de
##STR00215##
[0745] A mixture of 2-amino-3-(2,2,2-trifluoroethylamino)butan-1-ol
hydrochloride (2.13 g, 11.4 mmol) and Hunig's base (12.4 mL, 0.75
g/mL, 72.2 mmol) in dry DCM (75 mL) was stirred for 15 min to get a
clear yellow solution. Then ethyl
4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (3.08 g,
11.43 mmol) was added and the solution was stirred at room
temperature for 4 hours. The reaction mixture was quenched with
NaHCO.sub.3(aq., sat., 75 mL). The water layer was extracted with
DCM (2.times.50 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and evaporated to get a yellow oil. The
crude was purified on silica using a DCM to EtOAc gradient to
afford ethyl
3-fluoro-4-[[1-(hydroxymethyl)-2-(2,2,2-trifluoroethylamino)propyl]sulfam-
oyl]-1-methyl-pyrrole-2-carboxylate (4.55 g) as a yellow oil.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.84-0.97 (m, 3H),
1.28 (t, J=7.0 Hz, 3H), 1.85-2.10 (m, 1H), 2.76-2.91 (m, 1H),
2.99-3.52 (m, 5H), 3.82 (s, 3H), 4.27 (q, J=7.0 Hz, 2H), 4.54-4.77
(m, 1H), 7.44 (br s, 1H), 7.51-7.60 (m, 1H); Method D; Rt: 1.64
min. m/z: 418 (M-H).sup.- Exact mass: 419.1.
[0746] To a solution of ethyl
3-fluoro-4-[[1-(hydroxymethyl)-2-(2,2,2-trifluoroethylamino)propyl]sulfam-
oyl]-1-methyl-pyrrole-2-carboxylate (1.00 g, 2.38 mmol) and
5-amino-2-fluoro-benzonitrile (389 mg, 2.86 mmol) in dry THF (25
mL) was added lithium bis(trimethylsilyl)amide (1M in THF)
[4039-32-1] #JNJ-70824# (12 mL, 1 M in THF, 12 mmol). The reaction
mixture was stirred at room temperature for 5 hours. Then
NH.sub.4Cl (aq., sat., 30 mL) was added followed by EtOAc (30 mL)
and the mixture was stirred for 15 min. The two layers were
separated and the aqueous layer was extracted with EtOAc
(2.times.30 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to get a brown oil. The crude was purified on silica using a DCM to
EtOAc gradient yielding
N-(3-cyano-4-fluoro-phenyl)-3-fluoro-4-[[1-(hydroxymethyl)-2-(2,2,2-trifl-
uoroethylamino)propyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide
(818 mg).
[0747]
N-(3-cyano-4-fluoro-phenyl)-3-fluoro-4-[[1-(hydroxymethyl)-2-(2,2,2-
-trifluoroethylamino)propyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide
(818 mg, 1.61 mmol) and cesium fluoride (976 mg, 6.42 mmol) were
dissolved in dry DMF (12 mL) and heated at 110.degree. C. for 18
hours. The reaction mixture was quenched with cold water (15 mL)
and extracted with EtOAc (3.times.15 mL). The combined organic
layers were evaporated and the residue was purified on silica using
a DCM to EtOAc gradient to get a yellow foam. The 4 isomers were
separated via Prep SFC (Stationary phase: Chiralpak Daicel AS 20
microhm 500 gr, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2)
yielding compound 161a (89 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.08 (d, J=6.4 Hz, 3H), 2.30-2.43 (m, 1H), 2.71-2.84
(m, 1H), 3.12-3.41 (m, 2H), 3.53-3.63 (m, 1H), 3.83 (s, 3H), 4.00
(dd, J=12.7, 8.9 Hz, 1H), 4.84 (dd, J=12.8, 1.9 Hz, 1H), 7.44-7.56
(m, 2H), 7.60 (br s, 1H), 8.00 (ddd, J=9.2, 4.9, 2.7 Hz, 1H), 8.18
(dd, J=5.8, 2.7 Hz, 1H), 9.55 (s, 1H); Method D; Rt: 1.92 min. m/z:
488 (M-H).sup.- Exact mass: 489.1, compound 161b (70 mg); .sup.1H
NMR (400 MHz, DMSO-d.sub.6) ppm 1.08 (d, J=6.4 Hz, 3H), 2.31-2.43
(m, 1H), 2.70-2.85 (m, 1H), 3.13-3.41 (m, 2H), 3.53-3.64 (m, 1H),
3.83 (s, 3H), 4.00 (dd, J=12.7, 8.9 Hz, 1H), 4.84 (dd, J=12.7, 2.0
Hz, 1H), 7.47-7.57 (m, 2H), 7.62 (br s, 1H), 8.00 (ddd, J=9.2, 4.9,
2.8 Hz, 1H), 8.18 (dd, J=5.8, 2.7 Hz, 1H), 9.55 (s, 1H); Method D;
Rt: 1.92 min. m/z: 488 (M-H).sup.- Exact mass: 489.1, compound 161c
(15 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.07 (d,
J=6.5 Hz, 3H), 2.35 (q, J=7.4 Hz, 1H), 2.88-3.02 (m, 1H), 3.12-3.44
(m, 2H), 3.62-3.72 (m, 1H), 3.83 (s, 3H), 4.01 (dd, J=12.8, 9.0 Hz,
1H), 4.72 (dd, J=12.8, 1.3 Hz, 1H), 7.42-7.56 (m, 2H), 7.59 (br s,
1H), 8.02 (ddd, J=9.2, 4.9, 2.7 Hz, 1H), 8.18 (dd, J=5.8, 2.7 Hz,
1H), 9.56 (s, 1H); Method D; Rt: 1.93 min. m/z: 488 (M-H).sup.-
Exact mass: 489.1 and compound 161d (18 mg); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.07 (d, J=6.5 Hz, 3H), 2.35 (q, J=7.3
Hz, 1H), 2.89-3.03 (m, 1H), 3.13-3.45 (m, 2H), 3.63-3.73 (m, 1H),
3.83 (s, 3H), 4.01 (dd, J=12.8, 9.0 Hz, 1H), 4.72 (dd, J=13.1, 1.2
Hz, 1H), 7.43-7.56 (m, 2H), 7.60 (br s, 1H), 8.02 (ddd, J=9.2, 4.9,
2.7 Hz, 1H), 8.18 (dd, J=5.8, 2.7 Hz, 1H), 9.56 (s, 1H); Method D;
Rt: 1.93 min. m/z: 488 (M-H).sup.- Exact mass: 489.1. Method AA;
Rt: 161a: 3.69 min, 161b: 3.61 min, 161c: 3.75 min, 161d: 4.02
min.
Compound 162:
N-(3,4-difluorophenyl)-3,7-dimethyl-3-[(5-methylisoxazol-3-yl)methyl]-1,1-
-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00216##
[0749] DL-alanine methyl ester hydrochloride (12.8 g, 91.7 mmol)
was finely ground and added to DCM (250 mL). Benzophenone imine
(14.4 g, 1.62 g/mL, 79.5 mmol) was added and the mixture was
stirred overnight at room temperature. The mixture was filtered and
the filtrate was washed with water. The organic layer was separated
and concentrated in vacuo. The residue was purified on silica using
a gradient from 0 till 50% EtOAc in heptane yielding methyl
2-(benzhydrylideneamino)propanoate (15.7 g) as a clear oil.
[0750] Potassium tert-butoxide (3.74 g, 33.3 mmol) was added to a
cooled (-10.degree. C.) solution of methyl
2-(benzhydrylideneamino)propanoate (7.42 g, 27.8 mmol) and
3-(chloromethyl)-5-methylisoxazole (3.77 g, 27.8 mmol) in NMP (20
mL). The reaction mixture was stirred 1 hour and HCl (67 mL, 1 M in
H.sub.2O, 67 mmol) was added and the reaction mixture was stirred
overnight. The reaction mixture was then diluted with EtOAc (100
mL) and washed with brine (3.times.100 mL). The combined organic
layers were evaporated to dryness and the residue was purified on
silica using a heptane to EtOAc gradient yielding methyl
2-(benzhydrylideneamino)-2-methyl-3-(5-methylisoxazol-3-yl)propanoate
(4.44 g) as an oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.55 (s, 3H), 2.37-2.41 (m, 3H), 3.22 (s, 2H), 3.69-3.79 (m, 3H),
6.15 (s, 1H), 8.78 (br s, 3H).
[0751] Methyl
2-(benzhydrylideneamino)-2-methyl-3-(5-methylisoxazol-3-yl)propanoate
(4.44 g, 18.9 mmol) was dissolved in MeOH (50 mL) cooled in an ice
bath (-10.degree. C.). Sodium borohydride (2.15 g, 56.8 mmol) was
added and the reaction mixture was stirred overnight. Incomplete
conversion was seen. The volatiles were removed under reduced
pressure and the residue was redispensed in THF (100 mL) and
lithium aluminum hydride (18.9 mL, 1 M in THF, 18.9 mmol) was added
dropwise. The reaction mixture was stirred overnight. Sodium
sulfate decahydrate (27.4 g, 85.1 mmol) was added followed by
Na.sub.2SO.sub.4. The reaction mixture was filtered and the
volatiles were removed under reduced pressure and the residue was
purified on silica using a DCM to DCM:MeOH/NH.sub.3 9:1 gradient
yielding 2-amino-2-methyl-3-(5-methylisoxazol-3-yl)propan-1-ol
(1.41 g) as a clear oil. The filter cake was washed with MeOH and
the volatiles were removed from the filtrate. The residue was
purified on silica using a DCM to DCM:MeOH/NH.sub.3 9:1 gradient
yielding a second crop of
2-amino-2-methyl-3-(5-methylisoxazol-3-yl)propan-1-ol (455 mg) as a
light yellow oil.
[0752] Both fractions (1.44 g and 455 mg, 11.1 mmol), ethyl
4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (2.74 g,
10.2 mmol) and Hunig's base (4.37 mL, 0.75 g/mL, 25.4 mmol) were
dissolved in ACN (25 mL) and the reaction mixture was stirred
overnight. The volatiles were removed under reduced pressure and
the residue was purified on silica using a heptane to EtOAc
gradient yielding ethyl
3-fluoro-4-[[1-(hydroxymethyl)-1-methyl-2-(5-methylisoxazol-3-yl)ethyl]su-
lfamoyl]-1-methyl-pyrrole-2-carboxylate (2.42 g) as a yellow oil
which solidified overnight.
[0753] Ethyl
3-fluoro-4-[[1-(hydroxymethyl)-1-methyl-2-(5-methylisoxazol-3-yl)ethyl]su-
lfamoyl]-1-methyl-pyrrole-2-carboxylate (484 mg, 1.20 mmol) and
3,4-difluoroaniline (0.12 mL, 1.29 g/mL, 1.2 mmol) were dispensed
in THF (5 mL). Lithium bis(trimethylsilyl)amide (6 mL, 1 M in THF,
6 mmol) was added and the reaction mixture was stirred 3 hours at
room temperature. The reaction mixture was quenched with NH.sub.4Cl
(sat., aq., 10 mL) and the organic layer was removed. The aqueous
layer was extracted with DCM (2.times.5 mL) and the combined
organic layers were evaporated to dryness and the residue was
purified on silica using a heptane to EtOAc gradient yielding
N-(3,4-difluorophenyl)-3-fluoro-4-[[1-(hydroxymethyl)-1-methyl-2-
-(5-methylisoxazol-3-yl)ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide
(175 mg).
[0754]
N-(3,4-difluorophenyl)-3-fluoro-4-[[1-(hydroxymethyl)-1-methyl-2-(5-
-methylisoxazol-3-yl)ethyl]sulfamoyl]-1-methyl-pyrrole-2-carboxamide
(175 mg, 0.36 mmol) and cesium fluoride (219 mg, 1.44 mmol) were
dispensed in DMF (3 mL) and heated in a microwave tube at
110.degree. C. for 2 hours. The reaction mixture was directly
loaded on a silica cartridge and a heptane to EtOAc gradient was
applied yielding compound 162. This was separated into its
enantiomers via preparative SFC (Stationary phase: Chiralpak Diacel
AD 20.times.250 mm, Mobile phase: CO.sub.2, MeOH+0.4 iPrNH.sub.2)
yielding compound 162a (32 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.21 (s, 3H), 2.38-2.41 (m, 3H), 2.87 (d, J=13.9 Hz,
1H), 3.04 (d, J=13.9 Hz, 1H), 3.82 (s, 3H), 4.41 (d, J=13.0 Hz,
1H), 4.60 (d, J=13.0 Hz, 1H), 6.21 (d, J=0.9 Hz, 1H), 7.40-7.44 (m,
2H), 7.48 (s, 1H), 7.81-7.93 (m, 2H), 9.39 (s, 1H); Method B; Rt:
1.04 min. m/z: 465 (M-H).sup.- Exact mass: 466.1 and compound 162b
(33 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.21 (s,
3H), 2.37-2.41 (m, 3H), 2.87 (d, J=13.9 Hz, 1H), 3.04 (d, J=13.9
Hz, 1H), 3.82 (s, 3H), 4.41 (d, J=13.2 Hz, 1H), 4.60 (d, J=13.0 Hz,
1H), 6.21 (d, J=0.9 Hz, 1H), 7.38-7.45 (m, 2H), 7.48 (s, 1H),
7.80-7.93 (m, 2H), 9.39 (s, 1H); Method B; Rt: 1.04 min. m/z: 465
(M-H).sup.- Exact mass: 466.1, as white powders after
crystallization from an EtOAc:DIPE mixture. Method V; Rt: 162a:
3.82 min, 162b: 4.21 min.
Compound 163:
N-(3-cyano-4-fluoro-phenyl)-3-(1-hydroxypropyl)-7-methyl-1,1-dioxo-3,4-di-
hydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00217##
[0756] Compound 163 (132 mg) was prepared similarly as described
for compound 142, using 5-amino-2-fluoro-benzonitrile instead of
3,4-difluoroaniline. The racemic mixture was separated in its
epimers via preparative SFC (Stationary phase: Chiralpak Daicel AD
20.times.250 mm, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2) to
yield compound 163a (41 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 0.92 (t, J=7.4 Hz, 3H), 1.44 (dquin, J=14.2, 7.3, 7.3,
7.3, 7.3 Hz, 1H), 1.65-1.78 (m, 1H), 3.35-3.44 (m, 1H), 3.44-3.57
(m, 1H), 3.83 (s, 3H), 3.98 (dd, J=12.6, 8.8 Hz, 1H), 4.93 (dd,
J=12.8, 2.0 Hz, 1H), 4.99 (d, J=6.2 Hz, 1H), 7.45-7.56 (m, 2H),
7.62 (br d, J=8.6 Hz, 1H), 8.05 (ddd, J=9.2, 4.9, 2.8 Hz, 1H), 8.21
(dd, J=5.8, 2.7 Hz, 1H), 9.51 (s, 1H); Method D; Rt: 1.69 min. m/z:
421 (M-H).sup.- Exact mass: 422.1, and 163b (21 mg); .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 0.88 (t, J=7.3 Hz, 3H),
1.29-1.43 (m, 1H), 1.50-1.63 (m, 1H), 3.55-3.64 (m, 1H), 3.67-3.76
(m, 1H), 3.83 (s, 3H), 3.99 (dd, J=12.7, 9.1 Hz, 1H), 4.74 (dd,
J=13.1, 0.5 Hz, 1H), 4.88 (br d, J=5.3 Hz, 1H), 7.35 (br s, 1H),
7.49 (s, 1H), 7.52 (t, J=9.1 Hz, 1H), 8.05 (ddd, J=9.2, 4.9, 2.8
Hz, 1H), 8.19 (dd, J=5.8, 2.7 Hz, 1H), 9.54 (s, 1H); Method D; Rt:
1.70 min. m/z: 421 (M-H).sup.- Exact mass: 422.1; MP: 247.0.degree.
C. Method R; Rt: 163a: 4.44 min, 163b: 4.60 min.
Compound 164:
(3S)--N-[3-(difluoromethyl)-2,4-difluoro-phenyl]-3,7-dimethyl-1,1-dioxo-2-
,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00218##
[0758] Compound 164 (87 mg) was prepared similarly as described for
compound 157, using 3-(difluoromethyl)-2,4-difluoro-aniline instead
of 3-amino-2,6-difluoro-benzonitrile .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.14 (d, J=6.82 Hz, 3H) 1.29-1.52 (m, 1H)
1.79-1.99 (m, 1H) 2.74-2.93 (m, 1H) 3.12 (br dd, J=15.07, 6.05 Hz,
1H) 3.55-3.67 (m, 1H) 3.70 (s, 3H) 7.02 (br d, J=9.02 Hz, 1H)
7.17-7.56 (m, 3H) 7.77-7.99 (m, 1H) 10.13 (br s, 1H); Method B; Rt:
0.89 min. m/z: 418 (M-H).sup.- Exact mass: 419.1, MP: 227.7.degree.
C.
Compound 165:
(3S)--N-[2-(difluoromethyl)-4-pyridyl]-3,7-dimethyl-1,1-dioxo-2,3,4,5-tet-
rahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00219##
[0760] Compound 165 (84 mg) was prepared similarly as described for
compound 157, using 2-(difluoromethyl)pyridin-4-amine instead of
3-amino-2,6-difluoro-benzonitrile .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.13 (d, J=6.82 Hz, 3H) 1.29-1.44 (m, 1H)
1.79-1.93 (m, 1H) 2.78-2.91 (m, 1H) 2.92-3.03 (m, 1H) 3.56-3.68 (m,
1H) 3.71 (s, 3H) 6.73-7.12 (m, 2H) 7.47 (s, 1H) 7.75 (dd, J=5.50,
1.76 Hz, 1H) 8.03 (d, J=1.76 Hz, 1H) 8.56 (d, J=5.50 Hz, 1H) 10.84
(s, 1H); Method B; Rt: 0.74 min. m/z: 385 (M-H).sup.- Exact mass:
384.1.
Compound 166:
(3S)--N-(2-chloro-4-pyridyl)-3,7-dimethyl-1,1-dioxo-2,3,4,5-tetrahydropyr-
rolo[3,4-f]thiazepine-6-carboxamide
##STR00220##
[0762] Compound 166 (107 mg) was prepared similarly as described
for compound 157, using 2-chloropyridin-4-amine instead of
3-amino-2,6-difluoro-benzonitrile. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.13 (d, J=6.82 Hz, 3H) 1.27-1.47 (m, 1H)
1.79-1.91 (m, 1H) 2.78-2.90 (m, 1H) 2.91-3.04 (m, 1H) 3.55-3.67 (m,
1H) 3.70 (s, 3H) 7.04 (d, J=9.46 Hz, 1H) 7.47 (s, 1H) 7.58 (dd,
J=5.72, 1.76 Hz, 1H) 7.80 (d, J=1.76 Hz, 1H) 8.29 (d, J=5.50 Hz,
1H) 10.81 (br s, 1H); Method B; Rt: 0.76 min. m/z: 367 (M-H).sup.-
Exact mass: 368.1.
Compound 167:
N-(3,4-difluorophenyl)-3,7-dimethyl-3-[(1-methylpyrazol-3-yl)methyl]-1,1--
dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00221##
[0764] Compound 167 (435 mg) was prepared similarly as described
for compound 162, using 3-(chloromethyl)-1-methyl-1H-pyrazole
hydrochloride instead of 3-(chloromethyl)-5-methylisoxazole. The
racemic mixture was separated in its enantiomers via preparative
SFC (Stationary phase: Chiralpak Daicel AD 20.times.250 mm, Mobile
phase: CO.sub.2, MeOH+0.4 iPrNH.sub.2) to yield compound 167a
(154.1 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.21
(s, 3H), 2.83 (d, J=13.9 Hz, 1H), 2.98 (d, J=13.9 Hz, 1H), 3.80 (s,
3H), 3.82 (s, 3H), 4.40 (d, J=13.0 Hz, 1H), 4.53 (d, J=13.2 Hz,
1H), 6.14 (d, J=2.2 Hz, 1H), 7.38-7.45 (m, 2H), 7.46 (s, 1H), 7.60
(d, J=2.0 Hz, 1H), 7.80 (s, 1H), 7.81-7.88 (m, 1H), 9.37 (s, 1H);
Method B; Rt: 0.99 min. m/z: 464 (M-H).sup.- Exact mass: 465.1, and
167b (151.4 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.21 (s, 3H), 2.83 (d, J=13.9 Hz, 1H), 2.98 (d, J=13.9 Hz, 1H),
3.80 (s, 3H), 3.82 (s, 3H), 4.40 (d, J=13.0 Hz, 1H), 4.53 (d,
J=13.0 Hz, 1H), 6.14 (d, J=2.0 Hz, 1H), 7.38-7.45 (m, 2H), 7.46 (s,
1H), 7.60 (d, J=2.0 Hz, 1H), 7.80 (s, 1H), 7.81-7.87 (m, 1H), 9.37
(s, 1H); Method B; Rt: 0.99 min. m/z: 464 (M-H).sup.- Exact mass:
465.1. Method V; Rt: 167a: 3.93 min, 167b: 4.50 min.
Compound 168:
N-(3,4-difluorophenyl)-3,7-dimethyl-3-(6-methyl-2-pyridyl)-1,1-dioxo-2,4--
dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00222##
[0766] Compound 168 (118 mg) was prepared similarly as described
for compound 153, using 2-acetyl-6-methylpyridine instead of
2-acetylpyrimidine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.54-1.59 (m, 3H), 2.44-2.47 (m, 3H), 3.79-3.84 (m, 3H), 4.97 (d,
J=13.4 Hz, 1H), 5.21 (d, J=13.3 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H),
7.37-7.51 (m, 3H), 7.60 (d, J=7.9 Hz, 1H), 7.75 (t, J=7.8 Hz, 1H),
7.89 (ddd, J=13.2, 7.5, 2.5 Hz, 1H), 8.47 (s, 1H), 9.40 (s, 1H);
Method B; Rt: 1.26 min. m/z: 463 (M+H).sup.+ Exact mass: 462.1. The
racemic mixture was separated in its enantiomers via preparative
SFC (Stationary phase: Chiralpak Daicel AS 20.times.250 mm, Mobile
phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2) to yield compound 168a (37
mg); MP: 221.9.degree. C., and 168b (35 mg); MP: 221.5.degree. C.
Method T; Rt: 168a: 3.67 min, 168b: 4.66 min.
Compound 169:
(3S)--N-[3-(difluoromethyl)-4-fluoro-phenyl]-3,7-dimethyl-1,1-dioxo-3-(2--
pyridyl)-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00223##
[0768] Compound 169 (131 mg) was prepared similarly as described
for compound 127, using 3-(difluoromethyl)-4-fluoro-aniline instead
of 3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.55-1.62 (m, 3H), 3.82 (s, 3H), 4.99 (d, J=13.4 Hz, 1H), 5.20
(d, J=13.3 Hz, 1H), 7.04-7.41 (m, 3H), 7.47 (s, 1H), 7.79-7.89 (m,
3H), 8.05 (dd, J=6.3, 2.6 Hz, 1H), 8.48-8.52 (m, 2H), 9.44 (s, 1H);
Method B; Rt: 1.07 min. m/z: 479 (M-H).sup.- Exact mass: 480.1; MP:
208.8.degree. C.
Compound 170:
3,7-dimethyl-3-[(5-methylisoxazol-3-yl)methyl]-1,1-dioxo-N-(3,4,5-trifluo-
rophenyl)-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00224##
[0770] Compound 170 (102 mg) was prepared similarly as described
for compound 162, using 3,4,5-trifluoroaniline instead of
3,4-difluoroaniline. This was separated into its enantiomers via
preparative SFC (Stationary phase: Kromasil (R,R) Whelk-O 1 10/100,
Mobile phase: CO.sub.2, iPrOH+0.4 iPrNH.sub.2) yielding compound
170a (18 mg), .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.22
(s, 3H), 2.40 (s, 3H), 2.88 (d, J=14.1 Hz, 1H), 3.05 (d, J=13.9 Hz,
1H), 3.82 (s, 3H), 4.43 (d, J=13.2 Hz, 1H), 4.61 (d, J=13.2 Hz,
1H), 6.22 (s, 1H), 7.51 (s, 1H), 7.62-7.75 (m, 2H), 7.93 (s, 1H),
9.45 (s, 1H); Method B; Rt: 1.13 min. m/z: 483 (M-H).sup.- Exact
mass: 484.1 and compound 170b (29 mg), .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.17-1.27 (m, 3H), 2.40 (s, 3H), 2.88 (d,
J=13.9 Hz, 1H), 3.05 (d, J=14.1 Hz, 1H), 3.82 (s, 3H), 4.42 (d,
J=13.0 Hz, 1H), 4.61 (d, J=13.2 Hz, 1H), 6.21 (d, J=0.9 Hz, 1H),
7.51 (s, 1H), 7.62-7.70 (m, 2H), 7.93 (s, 1H), 9.45 (s, 1H); Method
B; Rt: 1.13 min. m/z: 483 (M-H).sup.- Exact mass: 484.1. Method X;
Rt: 170a: 4.81 min, 170b: 5.12 min.
Compound 171:
3-[(6-bromo-3-pyridyl)methyl]-N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dio-
xo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00225##
[0772] Compound 171 (102 mg) was prepared similarly as described
for compound 162, using 2-bromo-5-(bromomethyl)pyridine instead of
3-(chloromethyl)-5-methylisoxazole .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.13 (s, 3H), 2.72 (d, J=13.2 Hz, 1H),
3.04 (d, J=13.2 Hz, 1H), 3.82 (s, 3H), 4.41 (d, J=13.2 Hz, 1H),
4.64 (d, J=13.2 Hz, 1H), 7.38-7.47 (m, 2H), 7.49 (s, 1H), 7.63-7.67
(m, 1H), 7.67-7.73 (m, 1H), 7.76 (s, 1H), 7.80-7.88 (m, 1H), 8.31
(d, J=2.2 Hz, 1H), 9.40 (s, 1H); Method B; Rt: 1.11 min. m/z: 539
(M-H).sup.- Exact mass: 540.0, MP: 259.2.degree. C.
Compound 172:
N-(3,4-difluorophenyl)-3,7-dimethyl-3-[(6-methyl-2-pyridyl)methyl]-1,1-di-
oxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00226##
[0774] Compound 172 (196 mg) was prepared similarly as described
for compound 162, using 2-(bromomethyl)-6-methyl-pyridine instead
of 3-(chloromethyl)-5-methylisoxazole .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.23 (s, 3H), 2.42 (s, 3H), 2.99-3.11 (m,
2H), 3.81 (s, 3H), 4.49 (d, J=13.0 Hz, 1H), 4.62 (d, J=13.2 Hz,
1H), 7.12 (d, J=7.7 Hz, 1H), 7.20 (d, J=7.7 Hz, 1H), 7.38-7.45 (m,
2H), 7.46 (s, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.79-7.86 (m, 1H), 8.02
(s, 1H), 9.30 (s, 1H); Method B; Rt: 1.13 min. m/z: 475 (M-H).sup.-
Exact mass: 476.1, MP: 206.0.degree. C. This was separated into its
enantiomers via preparative SFC (Stationary phase: Chiralpak Diacel
AD 20.times.250 mm, Mobile phase: CO.sub.2, iPrOH+0.4 iPrNH.sub.2)
yielding compound 172a (65 mg) and compound 172b (36 mg). Method W;
Rt: 172a: 4.20 min, 172b: 4.40 min.
Compound 173:
N-(3,4-difluorophenyl)-3,7-dimethyl-3-[(1-methylimidazol-2-yl)methyl]-1,1-
-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00227##
[0776] Compound 173 (109 mg) was prepared similarly as described
for compound 162, using 2-chloromethyl-1-methyl-1H-imidazole
instead of 3-(chloromethyl)-5-methylisoxazole .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.29-1.36 (m, 3H), 2.96-3.10 (m, 2H),
3.64 (s, 3H), 3.75-3.83 (m, 3H), 4.51-4.66 (m, 2H), 6.82 (d, J=1.1
Hz, 1H), 7.06 (d, J=1.1 Hz, 1H), 7.38-7.46 (m, 3H), 7.79-7.87 (m,
1H), 8.07 (br s, 1H), 9.37 (s, 1H); Method B; Rt: 0.92 min. m/z:
464 (M-H).sup.- Exact mass: 465.1, MP: 297.1.degree. C.
Compound 174:
N-(3,4-difluorophenyl)-3,7-dimethyl-3-[(3-methylimidazol-4-yl)methyl]-1,1-
-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00228##
[0778] Compound 174 (109 mg) was prepared similarly as described
for compound 162, using 5-chloromethyl-1-methyl-1H-imidazole
instead of 3-(chloromethyl)-5-methylisoxazole .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.03-1.24 (m, 3H), 2.83 (d, J=15.0 Hz,
1H), 2.97 (d, J=15.0 Hz, 1H), 3.60 (s, 3H), 3.81 (s, 3H), 4.38 (d,
J=13.4 Hz, 1H), 4.65 (d, J=13.0 Hz, 1H), 6.80 (s, 1H), 7.38-7.45
(m, 2H), 7.46 (s, 1H), 7.53 (s, 1H), 7.79-7.91 (m, 2H), 9.39 (s,
1H); Method B; Rt: 0.87 min. m/z: 464 (M-H).sup.- Exact mass:
465.1, MP: 265.5.degree. C.
Compound 175:
N-(3,4-difluorophenyl)-3-[(2,5-dimethylpyrazol-3-yl)methyl]-3,7-dimethyl--
1,1-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00229##
[0780] Compound 175 (182 mg) was prepared similarly as described
for compound 162, using 5-(chloromethyl)-1,3-dimethyl-1H-pyrazole
instead of 3-(chloromethyl)-5-methylisoxazole. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 1.22 (s, 3H), 2.11 (s, 3H), 2.85 (d,
J=14.5 Hz, 1H), 3.01 (d, J=14.7 Hz, 1H), 3.72 (s, 3H), 3.81 (s,
3H), 4.38 (d, J=13.2 Hz, 1H), 4.65 (d, J=13.2 Hz, 1H), 5.96 (s,
1H), 7.38-7.48 (m, 3H), 7.81-7.92 (m, 2H), 9.39 (s, 1H); Method B;
Rt: 0.98 min. m/z: 478 (M-H).sup.- Exact mass: 479.1. This was
separated into its enantiomers via preparative SFC (Stationary
phase: Chiralpak Diacel AD 20.times.250 mm, Mobile phase: CO.sub.2,
EtOH+0.4 iPrNH.sub.2) yielding compound 175a (74 mg) and compound
175b (63 mg). Method R; Rt: 172a: 3.88 min, 172b: 5.31 min.
Compound 176:
N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-[(2,5-dimethylpyrazol-3-yl)methy-
l]-3,7-dimethyl-1,1-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6--
carboxamide
##STR00230##
[0782] Compound 176 was prepared similarly as described for
compound 175, using 3-(difluoromethyl)-4-fluoro-aniline instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.22 (s, 3H), 2.11 (s, 3H), 2.94 (dd, J=55.6, 14.6 Hz, 2H),
3.72 (s, 3H), 3.82 (s, 3H), 4.38 (d, J=13.2 Hz, 1H), 4.63 (d,
J=13.6 Hz, 1H), 5.96 (s, 1H), 7.23 (t, J=54.8 Hz, 1H), 7.32-7.42
(m, 1H), 7.46 (s, 1H), 7.76-7.84 (m, 1H), 7.76-7.84 (m, 1H), 7.88
(s, 1H), 7.97-8.03 (m, 1H), 9.44 (s, 1H); Method B; Rt: 0.98 min.
m/z: 510 (M-H).sup.- Exact mass: 511.2. This was separated into its
enantiomers via preparative SFC (Stationary phase: Chiralpak Diacel
AD 20.times.250 mm, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2)
yielding compound 176a (97 mg) and compound 176b (83 mg). Method R;
Rt: 176a: 3.61 min, 176b: 5.13 min.
Compound 177:
N-[3-(difluoromethyl)-4-fluoro-phenyl]-3,7-dimethyl-3-(6-methyl-2-pyridyl-
)-1,1-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00231##
[0784] Compound 177 (273 mg) was prepared similarly as described
for compound 168, using 3-(difluoromethyl)-4-fluoro-aniline instead
of 3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.52-1.62 (m, 3H), 2.44-2.48 (m, 3H), 3.78-3.86 (m, 3H), 4.97
(d, J=13.4 Hz, 1H), 5.20 (d, J=13.4 Hz, 1H), 7.04-7.42 (m, 2H),
7.47 (s, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.75 (br t, J=7.7 Hz, 1H),
7.79-7.87 (m, 1H), 8.05 (dd, J=6.4, 2.7 Hz, 1H), 8.46 (s, 1H),
9.41-9.47 (m, 1H); Method B; Rt: 1.15 min. m/z: 493 (M-H).sup.-
Exact mass: 494.1; MP: 210.2.degree. C. This was separated into
it's enantiomers via Prep SFC (Stationary phase: Chiralpak Diacel
AS 20.times.250 mm, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2)
yielding compound 177a (66 mg) and compound 177b (86 mg). Method T;
Rt: 177a: 3.09 min, 177b: 3.88 min.
Compound 178:
(3R)--N-(3-cyano-2,4-difluoro-phenyl)-3-[(1S)-1-hydroxyethyl]-7-methyl-1,-
1-dioxo-2,3-dihydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00232##
[0786] Compound 178 (26 mg) was prepared similarly as described for
compound 84, using 3-amino-2,6-difluorobenzonitrile instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.21 (d, J=6.2 Hz, 3H), 3.64-3.78 (m, 4H), 3.82 (ddt, J=10.1,
7.4, 2.7, 2.7 Hz, 1H), 4.98 (d, J=5.9 Hz, 1H), 5.98 (dd, J=12.5,
2.9 Hz, 1H), 6.70 (dd, J=12.5, 2.4 Hz, 1H), 7.41 (d, J=9.9 Hz, 1H),
7.47 (t, J=9.0 Hz, 1H), 7.59 (s, 1H), 8.06 (td, J=8.9, 6.2 Hz, 1H),
10.59 (br s, 1H); Method B; Rt: 0.73 min. m/z: 421 (M-H).sup.-
Exact mass: 422.1.
Compound 179:
N-(3-bromo-2,4-difluoro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-
-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00233##
[0788] Compound 179 (274 mg) was prepared similarly as described
for compound 113, using 3-bromo-2,4-difluoro-aniline instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.04 (s, 3H), 1.17 (s, 3H), 1.37 (q, J=11.7 Hz, 1H), 2.18 (br
dd, J=14.2, 7.2 Hz, 1H), 2.67-2.78 (m, 1H), 3.16-3.30 (m, 2H), 3.70
(s, 3H), 4.40 (s, 1H), 6.85 (br d, J=10.3 Hz, 1H), 7.31 (td, J=8.6,
1.9 Hz, 1H), 7.44 (s, 1H), 7.70 (td, J=8.7, 5.9 Hz, 1H), 10.15 (br
s, 1H); Method B; Rt: 0.86 min. m/z: 490 (M-H).sup.- Exact mass:
491.0, MP: 236.8.degree. C.
Compound 180:
(3R)--N-(3-chloro-4-fluoro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl--
1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00234##
[0790] Compound 180 (289 mg) was prepared similarly as described
for compound 93, using 3-chloro-4-fluoro-aniline instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.06 (s, 3H), 1.25 (s, 3H), 3.55 (br t, J=8.5 Hz, 1H), 3.83 (s,
3H), 3.93 (dd, J=12.5, 8.9 Hz, 1H), 4.85 (s, 1H), 4.96 (d, J=12.4
Hz, 1H), 7.38 (t, J=9.1 Hz, 1H), 7.45-7.57 (m, 2H), 7.65 (ddd,
J=9.0, 4.3, 2.6 Hz, 1H), 8.00 (dd, J=6.8, 2.6 Hz, 1H), 9.41 (s,
1H); Method D; Rt: 1.82 min. m/z: 430 (M-H).sup.- Exact mass:
431.1, MP: 234.1.degree. C.
Compound 181:
N-[3-(difluoromethyl)-4-fluoro-phenyl]-3,7-dimethyl-3-(5-methylisoxazol-3-
-yl)-1,1-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00235##
[0792] Compound 181 (151 mg) was prepared similarly as described
for compound 153, using 1-(5-methylisoxazol-3-yl)ethanone instead
of 2-acetylpyrimidine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.60 (s, 3H), 2.39-2.43 (m, 3H), 3.82 (s, 3H), 4.83 (d, J=13.3
Hz, 1H), 4.99 (d, J=13.3 Hz, 1H), 6.34 (d, J=1.1 Hz, 1H), 7.22 (t,
J=54.2 Hz, 1H), 7.37 (t, J=9.5 Hz, 1H), 7.47 (s, 1H), 7.80-7.85 (m,
1H), 8.05 (dd, J=6.4, 2.7 Hz, 1H), 8.56 (s, 1H), 9.47 (s, 1H);
Method B; Rt: 1.03 min. m/z: 483 (M+H).sup.+ Exact mass: 484.1. The
racemic mixture was separated in its epimers via preparative SFC
(Stationary phase: Chiralpak Daicel OD 20.times.250 mm, Mobile
phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2) to yield compound 181a (47
mg) and 181b (48 mg). Method Y; Rt: 181a: 3.07 min, 181b: 3.53
min.
Compound 182:
(3R)--N-[3-(difluoromethyl)-2,4-difluoro-phenyl]-3-(1-hydroxy-1-methyl-et-
hyl)-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine--
6-carboxamide
##STR00236##
[0794] Compound 182 (153 mg) was prepared similarly as described
for compound 93, using 3-(difluoromethyl)-2,4-difluoro-aniline
instead of 3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.04 (s, 3H), 1.25 (s, 3H), 3.53-3.63 (m, 1H), 3.87 (s,
3H), 3.99 (dd, J=12.5, 8.8 Hz, 1H), 4.83-5.03 (m, 2H), 7.15-7.78
(m, 4H), 8.17-8.34 (m, 1H), 9.36 (s, 1H); Method D; Rt: 1.79 min.
m/z: 464 (M-H).sup.- Exact mass: 465.1, MP: 182.1.degree. C.
Compound 183:
N-(3,4-difluorophenyl)-3-[hydroxy(4-pyridyl)methyl]-7-methyl-1,1-dioxo-3,-
4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00237##
[0796] To a cooled solution of ethyl 2-(dibenzylamino)acetate (10
g, 35.3 mmol) in dry THF (200 mL) was added dropwise lithium
bis(trimethylsilyl)amide (100 mL, 1 M in THF, 100 mmol) at
-70.degree. C. The solution was stirred for 1 hour. Then
4-pyridinecarboxaldehyde (6.6 mL, 1.137 g/mL, 70.6 mmol) was added
slowly. After complete addition the reaction mixture was warmed to
0.degree. C. over 1 hour. NH.sub.4Cl-solution (aq., sat., 150 mL)
was added and the product was extracted with EtOAc (3.times.200
mL). The combined organic layers were dried over Na.sub.2SO.sub.4,
filtered and evaporated. The residue was purified on silica using a
DCM to EtOAc gradient yielding ethyl
2-(dibenzylamino)-3-hydroxy-3-(4-pyridyl)propanoate (8.72 g) as a
yellow oil.
[0797] To a solution of ethyl
2-(dibenzylamino)-3-hydroxy-3-(4-pyridyl)propanoate (1.30 g, 2.56
mmol) in dry DCM/pyridine was added imidazole (524 mg, 7.69 mmol)
followed by TBDMS-C1 (1.16 g, 7.69 mmol) and the reaction mixture
was stirred at room temperature for 2 hours. More imidazole (524
mg, 7.69 mmol) and TBDMS-C1 (1.16 g, 7.69 mmol) were added and the
reaction mixture was stirred overnight. More imidazole (524 mg,
7.69 mmol) and TBDMS-C1 (1.16 g, 7.69 mmol) were added and the
reaction mixture was stirred overnight. Pyridine (15 mL) was added
and the reaction mixture was stirred overnight. The reaction
mixture was quenched with NaHCO.sub.3(aq., sat.) and the product
was extracted with DCM (3 times). The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered and evaporated to get a
yellow oil, this was purified and separated into its 2
diastereoisomers by silica gel column chromatography (0% to 50%
EtOAc in heptane) yielding diastereoisomer 1 (744 mg); .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. ppm -0.30 (s, 3H), --0.02 (s, 3H),
0.72 (s, 9H), 1.42 (t, J=7.1 Hz, 3H), 3.31 (d, J=14.0 Hz, 2H), 3.53
(d, J=9.9 Hz, 1H), 3.91 (d, J=14.0 Hz, 2H), 4.20-4.43 (m, 2H), 4.97
(d, J=9.9 Hz, 1H), 6.89-7.02 (m, 6H), 7.15-7.24 (m, 6H), 8.48-8.57
(m, 2H); Method D; Rt: 3.11 min. m/z: 505 (M+H).sup.+ Exact mass:
504.3 and diastereoisomer 2 (40 mg); .sup.1H NMR (400 MHz,
CHLOROFORM-d) 6 ppm -0.23 (s, 3H), 0.03 (s, 3H), 0.88 (s, 9H), 1.32
(t, J=7.1 Hz, 3H), 3.58 (d, J=4.5 Hz, 1H), 3.81 (d, J=14.3 Hz, 2H),
4.07-4.37 (m, 4H), 5.30 (d, J=4.5 Hz, 1H), 7.00-7.09 (m, 6H),
7.14-7.25 (m, 6H), 8.45-8.53 (m, 2H); Method D; Rt: 3.29 min. m/z:
505 (M+H).sup.+ Exact mass: 505.3.
[0798] To a cooled solution of diastereoisomer 1 (744 mg, 1.46
mmol) in dry DCM was added slowly DIBAL (3.5 mL, 1 M in heptane,
3.5 mmol) at -78.degree. C. under nitrogen atmosphere and
continuous stirring at this temperature for 4 hours. Extra DIBAL
(3.5 mL, 1 M in heptane, 3.5 mmol) was added and the reaction was
stirred for another 2 hours. The reaction mixture was quenched with
MeOH (6 mL) followed by potassium sodium tartrate (15 mL) at
-78.degree. C. Then the cooling bath was removed and the reaction
mixture was warmed slowly to room temperature. The product was
extracted with DCM (3.times.20 mL). The combined organic layers
were evaporated and purified on silica using a DCM to EtOAc
gradient to yield
3-[tert-butyl(dimethyl)silyl]oxy-2-(dibenzylamino)-3-(4-pyridyl)propan-1--
ol (611 mg) as a clear oil. Method B; Rt: 1.42 min. m/z: 463
(M+H).sup.+ Exact mass: 462.3.
[0799] Palladium hydroxide on carbon (91 mg, 0.65 mmol) was added
to a solution of
3-[tert-butyl(dimethyl)silyl]oxy-2-(dibenzylamino)-3-(4-pyridyl)propan-1--
ol (300 mg, 0.65 mmol) in degassed MeOH (6.5 mL) and the resulting
suspension was stirred at room temperature under hydrogen
atmosphere. After 18 hours the reaction mixture was filtered
through a pad of dicalite (eluent MeOH) and concentrated in vacuo.
The crude was used as such in the next step.
[0800] To a mixture of
2-amino-3-[tert-butyl(dimethyl)silyl]oxy-3-(4-pyridyl)propan-1-ol
(162 mg, 0.57 mmol) and Hunig's base (0.62 mL, 0.75 g/mL, 3.6 mmol)
in dry DCM (3.9 mL) was added ethyl
4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate (0.16 g,
0.57 mmol), the reaction mixture was stirred for 1 hour. The
reaction mixture was quenched with NaHCO.sub.3(aq., sat., 5 mL).
The 2 layers were separated. The water layer was extracted with DCM
(2.times.5 mL). The combined organic layers were evaporated and the
crude was purified on silica using a DCM to EtOAc gradient to
afford ethyl
4-[[2-[tert-butyl(dimethyl)silyl]oxy-1-(hydroxymethyl)-2-(4-pyridyl)ethyl-
]sulfamoyl]-3-fluoro-1-methyl-pyrrole-2-carboxylate (120 mg) as an
orange oil.
[0801] To a solution of ethyl
4-[[2-[tert-butyl(dimethyl)silyl]oxy-1-(hydroxymethyl)-2-(4-pyridyl)ethyl-
]sulfamoyl]-3-fluoro-1-methyl-pyrrole-2-carboxylate (120 mg, 0.23
mmol) and 3,4-difluoroaniline (0.035 mL, 1.29 g/mL, 0.35 mmol) in
dry THF (2.8 mL) was added slowly lithium bis(trimethylsilyl)amide
(1.4 mL, 1 M in THF, 1.4 mmol). The mixture was stirred for 3 hours
at room temperature. Then it was quenched with NH.sub.4Cl-solution
(aq., sat., 10 mL) and EtOAc was added (5 mL). The two layers were
separated and the aqueous layer was extracted with EtOAc
(2.times.10 mL). The combined organic layers were concentrated
under reduced pressure. The crude was purified on silica using a
DCM to EtOAc gradient to yield
4-[[2-[tert-butyl(dimethyl)silyl]oxy-1-(hydroxymethyl)-2-(4-pyridyl)ethyl-
]sulfamoyl]-N-(3,4-difluorophenyl)-3-fluoro-1-methyl-pyrrole-2-carboxamide
(104 mg) as a brown solid.
[0802]
4-[[2-[tert-butyl(dimethyl)silyl]oxy-1-(hydroxymethyl)-2-(4-pyridyl-
)ethyl]sulfamoyl]-N-(3,4-difluorophenyl)-3-fluoro-1-methyl-pyrrole-2-carbo-
xamide (104 mg, 0.17 mmol) and cesium fluoride (106 mg, 0.70 mmol)
were dissolved in DMF (2 mL) and heated at 110.degree. C. for 18
hours. The reaction mixture was quenched with cold water (5 mL) and
the product was extracted with EtOAc (3.times.5 mL). The combined
organic layers were evaporated and the crude was purified on silica
using a DCM to DCM:MeOH 9:1 gradient to obtain a brown foam. A
second purification was performed via preparative HPLC (Stationary
phase: RP XBridge Prep C18 OBD-10 .mu.m, 30.times.150 mm, Mobile
phase: 0.25% NH.sub.4HCO.sub.3 solution in water, ACN) to obtain
compound 183 (8 mg) as a mixture of 2 enantiomers. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 3.73-3.80 (m, 1H), 3.81 (s, 3H),
4.17 (dd, J=12.8, 9.2 Hz, 1H), 4.57 (d, J=8.5 Hz, 1H), 4.93 (dd,
J=12.9, 2.3 Hz, 1H), 6.10 (br s, 1H), 7.33-7.51 (m, 5H), 7.71 (br
s, 1H), 7.87 (ddd, J=13.2, 7.5, 2.5 Hz, 1H), 8.53-8.62 (m, 2H),
9.42 (s, 1H); Method D; Rt: 1.62 min. m/z: 463 (M-H).sup.- Exact
mass: 464.1.
Compound 184:
(3R)--N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-(hydroxymethyl)-7-methyl-1-
,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00238##
[0804] Diisobutylaluminum hydride (1.5 mL, 1 M in heptane, 1.5
mmol) was added dropwise during 5 minutes to a solution of 06-ethyl
03-methyl
(3R)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-3,6-di-
carboxylate (239 mg, 0.70 mmol) in 2-MeTHF (25 mL, 0.86 g/mL, 250
mmol) at -78.degree. C. and stirred 1 hour. Another amount of
diisobutylaluminum hydride (3 mL, 1 M, 3 mmol) was added and the
reaction mixture was stirred 15 minutes at -78.degree. C. The
reaction mixture was allowed to reach room temperature in a water
bath during 10 minutes and quenched with methanol (10 mL).
[0805] The reaction mixture was diluted with HCl (aq., 1 M, 10 mL)
and extracted with EtOAc (50 mL). The organic layer was separated,
dried over magnesium sulfate, filtered and concentrated. The
residue was purified on silica using a gradient from 0 till 100%
EtOAc in heptane yielding ethyl
(3R)-3-(hydroxymethyl)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f-
]thiazepine-6-carboxylate (62 mg) as a white powder. Method D; Rt:
1.31 min. m/z: 301 (M-H).sup.- Exact mass: 302.1.
[0806] Lithium bis(trimethylsilyl)amide in THF (1 mL, 1 M in THF, 1
mmol) was added to a solution of ethyl
(3R)-3-(hydroxymethyl)-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f-
]thiazepine-6-carboxylate (62 mg, 0.205 mmol) and
3-(difluoromethyl)-4-fluoro-aniline hydrochloride (51 mg, 0.26
mmol) in THF (3 mL) and stirred 3 hours. More
3-(difluoromethyl)-4-fluoro-aniline hydrochloride (102 mg, 0.52
mmol) and lithium bis(trimethylsilyl)amide in THF (2 mL, 1 M in
THF, 2 mmol) were added and stirred 1 hour. The reaction mixture
was quenched with NH.sub.4Cl (aq., sat.), diluted with brine and
extracted with EtOAc. The organic layer was dried over magnesium
sulfate, filtered and concentrated. The residue was purified on
silica using a gradient from 10 till 100% EtOAc in heptane and
further via preparative HPLC (Stationary phase: RP XBridge Prep C18
OBD-10 .mu.m, 30.times.150 mm, Mobile phase: 0.25%
NH.sub.4HCO.sub.3 solution in water, ACN) yielding compound 184 (11
mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.22-1.36 (m,
1H), 2.02 (br dd, J=14.3, 6.6 Hz, 1H), 2.75-2.85 (m, 1H), 2.99-3.09
(m, 1H), 3.26 (dt, J=10.3, 6.8 Hz, 1H), 3.38-3.53 (m, 2H), 3.69 (s,
3H), 4.76 (t, J=5.7 Hz, 1H), 6.91 (d, J=9.7 Hz, 1H), 7.07-7.40 (m,
2H), 7.42 (s, 1H), 7.78-7.84 (m, 1H), 8.06 (dd, J=6.2, 2.4 Hz, 1H),
10.49 (s, 1H); Method D; Rt: 1.50 min. m/z: 416 (M-H).sup.- Exact
mass: 417.1.
Compound 185:
N-(3-cyano-2,4-difluoro-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl-1,1-
-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00239##
[0808] A microwave tube was loaded with compound 179 (248 mg, 0.5
mmol), zinc cyanide (41 mg, 0.35 mmol), and DMF (5 mL). This
solution was purged with nitrogen for 10 minutes and
1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II) (37 mg,
0.05 mmol) was added. The tube was closed and stirred and heated
under microwave irradiation at 160.degree. C. for 30 minutes. The
reaction mixture was cooled and purged with nitrogen for 10 minutes
and Pd(PPh.sub.3).sub.4 (58 mg, 0.05 mmol) was added. The tube was
closed and stirred and heated under microwave irradiation at
160.degree. C. for 50 minutes. The reaction mixture was filtered
over a pad of dicalite, rinsed with 10 mL of acetonitrile and
concentrated in vacuo. The residue was purified using preparative
HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 .mu.m,
50.times.150 mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3 solution in
water, ACN) yielding compound 185 (17 mg). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.03 (s, 3H), 1.17 (s, 3H), 1.31-1.42 (m,
1H), 2.18 (br dd, J=13.5, 6.9 Hz, 1H), 2.67-2.78 (m, 1H), 3.15-3.29
(m, 2H), 3.70 (s, 3H), 4.40 (s, 1H), 6.85 (d, J=10.6 Hz, 1H),
7.42-7.48 (m, 2H), 8.07 (td, J=8.9, 6.1 Hz, 1H), 10.32 (br s, 1H);
Method B; Rt: 0.76 min. m/z: 437 (M-H).sup.- Exact mass: 438.1.
Compound 186:
(3R)--N-[3-(difluoromethyl)-2,4-difluoro-phenyl]-3-[(1S)-1-hydroxyethyl]--
7-methyl-1,1-dioxo-2,3-dihydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00240##
[0810] Compound 186 (72 mg) was prepared similarly as described for
compound 84, using 3-(difluoromethyl)-2,4-difluoro-aniline instead
of 3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.21 (d, J=6.2 Hz, 3H), 3.64-3.74 (m, 1H), 3.75 (s, 3H),
3.78-3.85 (m, 1H), 4.98 (d, J=5.9 Hz, 1H), 5.98 (dd, J=12.5, 2.6
Hz, 1H), 6.69 (dd, J=12.7, 2.5 Hz, 1H), 7.35 (t, J=52.0 Hz, 1H),
7.29-7.48 (m, 2H), 7.58 (s, 1H), 7.84-7.91 (m, 1H), 10.41 (br s,
1H); Method B; Rt: 0.78 min. m/z: 446 (M-H).sup.- Exact mass:
447.1.
Compound 187:
N-[3-(difluoromethyl)-4-fluoro-phenyl]-3,7-dimethyl-3-[(1-methylimidazol--
2-yl)methyl]-1,1-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-car-
boxamide
##STR00241##
[0812] Compound 187 (75 mg) was prepared similarly as described for
compound 173, using 3-(difluoromethyl)-4-fluoro-aniline instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.33 (s, 3H), 3.01-3.06 (m, 2H), 3.64 (s, 3H), 3.81 (s, 3H),
4.54 (d, J=13.2 Hz, 1H), 4.64 (d, J=13.4 Hz, 1H), 6.82 (d, J=1.1
Hz, 1H), 7.05 (d, J=1.1 Hz, 1H), 7.22 (t, J=54.4 Hz, 1H), 7.36 (t,
J=9.5 Hz, 1H), 7.45 (s, 1H), 7.76-7.81 (m, 1H), 8.00 (dd, J=6.3,
2.5 Hz, 1H), 8.08 (br s, 1H), 9.41 (s, 1H); Method B; Rt: 0.93 min.
m/z: 496 (M-H).sup.- Exact mass: 497.1, MP: 282.8.degree. C.
Compound 188:
(3R)--N-[3-(difluoromethyl)-2,4-difluoro-phenyl]-3-[(1S)-1-hydroxyethyl]--
7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamid-
e
##STR00242##
[0814] Compound 188 (96 mg) was prepared similarly as described for
compound 88, using 3-(difluoromethyl)-2,4-difluoro-aniline instead
of 3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.13 (d, J=6.2 Hz, 3H), 1.27-1.38 (m, 1H), 2.21 (br dd, J=14.0,
6.9 Hz, 1H), 2.66-2.80 (m, 1H), 3.16-3.27 (m, 2H), 3.44-3.52 (m,
1H), 3.70 (s, 3H), 4.67 (d, J=5.7 Hz, 1H), 6.90 (br d, J=10.1 Hz,
1H), 7.34 (br t, J=52.2 Hz, 1H), 7.30 (br t, J=9.5 Hz, 1H), 7.43
(s, 1H), 7.85-7.92 (m, 1H), 10.14 (br s, 1H); Method B; Rt: 0.88
min. m/z: 448 (M-H).sup.- Exact mass: 449.1, MP: 277.1.degree.
C.
Compound 189:
N-(3-cyano-4-fluoro-phenyl)-3-(difluoromethyl)-7-methyl-1,1-dioxo-2,3-dih-
ydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00243##
[0816] (S)-(-)-2-methyl-2-propanesulfinamide (21.2 g, 175 mmol) was
mixed with 1-ethoxy-2,2-difluoroethanol (20.1 g, 159 mmol).
Titanium(IV)ethoxide (50 mL, 1.09 g/mL, 238 mmol) was added to form
a clear, thick solution which was heated to 80.degree. C. with a
reflux condenser under nitrogen for 2 days. The mixture was cooled
to room temperature and diluted using EtOAc (500 mL). This was
poured into brine (500 mL) under vigorous stirring. This biphasic
mixture was filtered over a pad of dicalite which was rinsed with
EtOAc (500 mL). The layers of the filtrate were separated and the
organic layer was dried on Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The crude was purified on silica using
gradient elution (EtOAc:heptane 0:100 to 100:0) yielding
N-(1-ethoxy-2,2-difluoro-ethyl)-2-methyl-propane-2-sulfinamide
(18.3 g). Method B; Rt: 0.69 min. m/z: 230 (M+H).sup.+ Exact mass:
229.1.
[0817]
N-(1-ethoxy-2,2-difluoro-ethyl)-2-methyl-propane-2-sulfinamide
(18.0 g, 78.5 mmol) in DCM (300 mL) was cooled under a nitrogen
flow to -50.degree. C. To this was added vinylmagnesium bromide
(118 mL, 1 M, 118 mmol) drop wise under nitrogen and stirring,
maintaining the temperature below -47.degree. C. After complete
addition stirring was continued for 3 hours, allowed to reach
0.degree. C. and stirred for 2 hours. The reaction mixture was
quenched with NH.sub.4Cl (aq., sat.) and diluted with EtOAc (500
mL). The layers were separated and the aqueous layer was extracted
with EtOAc (2.times.250 mL). The combined organics were dried on
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified on silica using a gradient from heptane to EtOAc to
yield N-[1-(difluoromethyl)allyl]-2-methyl-propane-2-sulfinamide
(8.86 g). Method B; Rt: 0.71 min. m/z: 212 (M+H).sup.+ Exact mass:
211.1.
[0818] N-[1-(difluoromethyl)allyl]-2-methyl-propane-2-sulfinamide
(8.86 g, 42.0 mmol) was dissolved in MeOH (100 mL) and cooled to
0.degree. C. This was treated with HCl (21 mL, 4 M in dioxane, 84
mmol). The resulting mixture was stirred for 2 hours. The mixture
was concentrated in vacuo. The obtained residue was triturated with
diethylether, filtered, rinsed with diethylether (100 mL) and dried
in a vacuum oven to yield 1,1-difluorobut-3-en-2-amine
hydrochloride (5.4 g) as a white solid.
[0819] Methyl
3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (3.68 g,
11.6 mmol) was dissolved in pyridine (10 mL).
1,1-difluorobut-3-en-2-amine hydrochloride (2 g, 13.9 mmol) was
added and the mixture was stirred at room temperature for 19 hours.
The resulting mixture was concentrated in vacuo and the residue was
purified on silica (gradient elution: EtOAc:heptane 0:100 to 100:0)
yielding methyl
3-bromo-4-[1-(difluoromethyl)allylsulfamoyl]-1-methyl-pyrrole-2-carboxyla-
te (1200 mg). Method B; Rt: 0.84 min. m/z: 385 (M-H).sup.- Exact
mass: 386.0.
[0820] Methyl
3-bromo-4-[1-(difluoromethyl)allylsulfamoyl]-1-methyl-pyrrole-2-carboxyla-
te (200 mg, 0.52 mmol) and 5-amino-2-fluoro-benzonitrile (84 mg,
0.62 mmol) in dry THF (5 mL) was treated with lithium
bis(trimethylsilyl)amide (1.6 mL, 1 M in THF, 1.6 mmol) at room
temperature. After 1 hour at room temperature, lithium
bis(trimethylsilyl)amide (1 mL, 1 M in THF, 1 mmol) was added and
the mixture was stirred at room temperature for 1 hour. The mixture
was quenched with NH.sub.4Cl (aq., sat., 10 mL) and brine (10 mL).
The layers were separated and the water layer was extracted with
EtOAc (3.times.20 mL). The combined extracts were dried on
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude was
purified on silica (gradient elution: EtOAc:heptane 0:100 to 100:0)
yielding
3-bromo-N-(3-cyano-4-fluoro-phenyl)-4-[1-(difluoromethyl)allylsu-
lfamoyl]-1-methyl-pyrrole-2-carboxamide (210 mg).
[0821]
3-bromo-N-(3-cyano-4-fluoro-phenyl)-4-[1-(difluoromethyl)allylsulfa-
moyl]-1-methyl-pyrrole-2-carboxamide (210 mg, 0.43 mmol) in DMF (1
mL) with TEA (0.12 mL, 0.73 g/mL, 0.85 mmol) was purged with
nitrogen for 5 minutes. Then
bis(tri-tert-butylphosphine)palladium(0) (11 mg, 0.021 mmol) was
added and the mixture was heated under nitrogen in a sealed tube at
90.degree. C. for 2 hours. The mixture was poured on a silica plug
as such and a gradient from heptane to EtOAc was applied yielding
compound 189 (86 mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 3.74 (s, 3H) 4.38-4.59 (m, 1H) 5.74 (dd, J=12.54, 2.86 Hz, 1H)
6.07-6.49 (m, 1H) 6.76 (dd, J=12.54, 2.64 Hz, 1H) 7.56 (t, J=9.13
Hz, 1H) 7.68 (s, 1H) 7.98 (ddd, J=9.19, 4.90, 2.64 Hz, 1H)
8.03-8.34 (m, 2H) 10.93 (br s, 1H); Method B; Rt: 0.88 min. m/z:
409 (M-H).sup.- Exact mass: 410.1.
Compound 190:
3-[(2-chloro-4-pyridyl)methyl]-N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-di-
oxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00244##
[0823] Compound 190 (90 mg) was prepared similarly as described for
compound 162, using 2-chloro-4-(chloromethyl)pyridine instead of
3-(chloromethyl)-5-methylisoxazole .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.37 (s, 3H) 2.65 (d, J=12.9 Hz, 1H) 3.35
(d, J=13.2 Hz, 1H) 3.97 (s, 3H) 4.38 (d, J=13.2 Hz, 1H) 4.65 (s,
1H) 4.98 (br d, J=13.4 Hz, 1H) 7.07 (s, 1H) 7.09-7.18 (m, 2H) 7.26
(d, J=1.3 Hz, 1H) 7.32 (s, 1H) 7.61-7.69 (m, 1H) 8.39 (d, J=5.1 Hz,
1H) 8.61 (s, 1H); Method B; Rt: 1.07 min. m/z: 495 (M-H).sup.-
Exact mass: 496.1, MP: 225.0.degree. C.
Compound 191:
N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-3-(4-pyridylmethyl)-2,4-dih-
ydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00245##
[0825] Compound 190 (70 mg, 0.14 mmol) was dissolved in MeOH (25
mL) and Pd/C (10%) (15 mg, 0.014 mmol) was added and the reaction
mixture was set under a hydrogen atmosphere. After 2 hours the
solution was filtered over dicalite, concentrated in vacuo,
redissolved in DCM (30 mL), neutralized with NaHCO.sub.3(aq., sat.)
and the combined organics were concentrated in vacuo and purified
on silica using DCM/MeOH 100/0 to 90/10 to yield compound 191 (23
mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.15 (s, 3H)
2.74 (d, J=13.0 Hz, 1H) 3.07 (d, J=12.8 Hz, 1H) 3.82 (s, 3H) 4.40
(d, J=13.2 Hz, 1H) 4.63 (d, J=13.6 Hz, 1H) 7.30-7.36 (m, 2H)
7.40-7.46 (m, 2H) 7.49 (s, 1H) 7.78 (br s, 1H) 7.82-7.90 (m, 1H)
8.51-8.53 (m, 2H) 9.41 (s, 1H); Method B; Rt: 0.96 min. m/z: 461
(M-H).sup.- Exact mass: 462.1, MP: 276.0.degree. C.
Synthesis of 2-amino-2-(1-methylpyrazol-3-yl)propan-1-ol
[0826] A 30 ml tube was charged with ethyl
N-(diphenylmethylene)glycinate (2.5 g, 9.35 mmol),
3-bromo-1-methyl-1 h-pyrazole (1.51 g, 9.35 mmol), potassium
phosphate tribasic (6 g, 27.7 mmol) in toluene (15 mL) and the
mixture was purged with N.sub.2 for 5 minutes.
Bis(tri-tert-butylphosphine)palladium(0) (526 mg, 1.03 mmol) was
added and the vial was capped and the mixture was stirred at
100.degree. C. for 16 hours. The mixture was cooled and filtered
over decalite. The filtrate was concentrated in vacuo. The residue
was purified by column chromatography using a gradient from 0 till
100% EtOAc in heptane. The product fractions were concentrated in
vacuo to yield ethyl
2-(benzhydrylideneamino)-2-(1-methylpyrazol-3-yl)acetate (1.95 g)
as a pale yellow oil.
[0827] Ethyl
2-(benzhydrylideneamino)-2-(1-methylpyrazol-3-yl)acetate (1.95 g,
5.61 mmol) was dissolved in DMF (30 mL) under N.sub.2 atmosphere.
The mixture was cooled on a ice bath and NaH (60% dispersion in
mineral oil) (269 mg, 6.74 mmol) was added portionwise. The mixture
was stirred at 5.degree. C. for 30 minutes. Met (0.42 mL, 2.28
g/mL, 6.74 mmol) was added dropwise and the mixture was stirred at
5.degree. C. for 15 minutes and was then allowed to rise to room
temperature. The mixture was stirred at room temperature for 16
hours. The mixture was quenched with water and the mixture was
concentrated in vacuo. The residue was partitioned between water
and EtOAc and the organic layer was separated, washed with brine,
dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue
was purified by column chromatography using a gradient from 0 till
50% EtOAc in heptane. The product fractions were concentrated in
vacuo to yield ethyl
2-(benzhydrylideneamino)-2-(1-methylpyrazol-3-yl)propanoate (1.1 g)
as a yellow oil.
[0828] Ethyl
2-(benzhydrylideneamino)-2-(1-methylpyrazol-3-yl)propanoate (1.1 g,
3.04 mmol) was dissolved in diethylether (20 mL). HCl (3.7 mL, 1 M
in H.sub.2O, 3.7 mmol) was added and the mixture was stirred at
room temperature for 3 hours. The organic layer was separated and
the water layer was neutralized with NaHCO.sub.3. The water layer
was extracted with 2-MeTHF and the organic layer was dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue was
purified by column chromatography using a gradient from 0 till 100%
MeOH/NH3 (90/10) in DCM. The product fractions were concentrated in
vacuo to yield ethyl 2-amino-2-(1-methylpyrazol-3-yl)propanoate
(382 mg) as a clear oil. Method B; Rt: 0.52 min. m/z: 198
(M+H).sup.+ Exact mass: 197.1.
[0829] Ethyl 2-amino-2-(1-methylpyrazol-3-yl)propanoate (382 mg,
1.94 mmol) was dissolved in MeOH (10 mL) under N.sub.2. Sodium
borohydride (147 mg, 3.87 mmol) was added and the mixture was
stirred at room temperature for 16 hours. The mixture was
concentrated in vacuo. The residue was purified by column
chromatography using a gradient from 0 till 100% MeOH/NH3 (90/10)
in DCM. The product fractions were concentrated in vacuo to yield
2-amino-2-(1-methylpyrazol-3-yl)propan-1-ol (230 mg) as a clear
oil.
Compound 192:
N-(3,4-difluorophenyl)-3,7-dimethyl-3-(1-methylpyrazol-3-yl)-1,1-dioxo-2,-
4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00246##
[0831] Compound 192 (223 mg) was prepared similarly as described
for compound 125, using 2-amino-2-(1-methylpyrazol-3-yl)propan-1-ol
instead of 2-amino-2-phenylpropan-1-ol hydrochloride. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.59 (s, 3H), 3.79 (s, 3H),
3.82 (s, 3H), 4.81-4.92 (m, 2H), 6.33 (d, J=2.2 Hz, 1H), 7.36-7.50
(m, 3H), 7.60 (d, J=2.2 Hz, 1H), 7.87 (ddd, J=13.2, 7.5, 2.5 Hz,
1H), 8.16 (s, 1H), 9.33-9.38 (m, 1H); Method B; Rt: 1.05 min. m/z:
450 (M-H).sup.- Exact mass: 451.1. The racemic mixture was
separated in its enantiomers via preparative SFC (Stationary phase:
Chiralpak Daicel AD 20.times.250 mm, Mobile phase: CO.sub.2,
EtOH+0.4 iPrNH.sub.2) to yield compound 192a (85 mg); Method D; Rt:
1.85 min. m/z: 450 (M-H).sup.- Exact mass: 451.1, MP: 208.7.degree.
C., and 192b (85 mg); Method D; Rt: 1.86 min. m/z: 450 (M-H).sup.-
Exact mass: 451.1; MP: 209.2.degree. C. Method R; Rt: 192a: 4.17
min, 192b: 4.96 min.
Compound 193: (3R)--N-(3-chloro-4-fluoro-phenyl)-3-[(1
S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thi-
azepine-6-carboxamide
##STR00247##
[0833] Compound 193 (101 mg) was prepared similarly as described
for compound 88, using 3-chloro-4-fluoro-aniline instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.13 (d, J=6.4 Hz, 3H), 1.21-1.35 (m, 1H), 2.19 (br dd, J=14.3,
6.8 Hz, 1H), 2.70-2.81 (m, 1H), 3.03 (br dd, J=14.9, 6.5 Hz, 1H),
3.15-3.26 (m, 1H), 3.47 (sxt, J=6.3 Hz, 1H), 3.69 (s, 3H), 4.69 (d,
J=5.7 Hz, 1H), 6.91 (d, J=10.1 Hz, 1H), 7.38-7.45 (m, 2H), 7.61
(ddd, J=9.0, 4.4, 2.6 Hz, 1H), 8.00 (dd, J=6.9, 2.5 Hz, 1H), 10.46
(s, 1H); Method B; Rt: 0.92 min. m/z: 414 (M-H).sup.- Exact mass:
415.1, MP: 290.8.degree. C.
Compound 194: (3R)--N-(3-chloro-4-fluoro-phenyl)-3-[(1
S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-23-dihydropyrrolo[3,4-f]thiazepine--
6-carboxamide
##STR00248##
[0835] Compound 194 (89 mg) was prepared similarly as described for
compound 84, using 3-chloro-4-fluoro-aniline instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.20 (d, J=6.2 Hz, 3H), 3.62-3.74 (m, 4H), 3.76-3.88 (m, 1H),
4.96 (d, J=5.7 Hz, 1H), 5.96 (dd, J=12.5, 2.6 Hz, 1H), 6.55 (dd,
J=12.5, 2.4 Hz, 1H), 7.34-7.46 (m, 2H), 7.57 (s, 1H), 7.62 (ddd,
J=9.0, 4.3, 2.5 Hz, 1H), 8.00 (dd, J=6.8, 2.6 Hz, 1H), 10.71 (s,
1H); Method D; Rt: 1.63 min. m/z: 412 (M-H).sup.- Exact mass:
413.1; MP: 211.3.degree. C.
Compound 195:
(3R)--N-(4-fluoro-3-methyl-phenyl)-3-(1-hydroxy-1-methyl-ethyl)-7-methyl--
1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00249##
[0837] Compound 195 (274 mg) was prepared similarly as described
for compound 93, using 4-fluoro-3-methyl-aniline instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.06 (s, 3H), 1.25 (s, 3H), 2.23 (d, J=2.0 Hz, 3H), 3.47-3.61
(m, 1H), 3.83 (s, 3H), 3.93 (dd, J=12.5, 8.9 Hz, 1H), 4.85 (s, 1H),
4.90-5.00 (m, 1H), 7.09 (t, J=9.2 Hz, 1H), 7.46 (s, 1H), 7.47-7.55
(m, 2H), 7.57 (dd, J=7.0, 2.6 Hz, 1H), 9.22 (s, 1H); Method D; Rt:
1.75 min. m/z: 410 (M-H).sup.- Exact mass: 411.1.
Synthesis of ethyl
4-chlorosulfonyl-3-hydroxy-1-methyl-pyrrole-2-carboxylate
[0838] Chlorosulfonic acid (2 mL, 1.753 g/mL, 30 mmol) was cooled
to 0.degree. C. and to this stirring liquid was added ethyl
3-hydroxy-1-methyl-pyrrole-2-carboxylate (1 g, 5.9 mmol) portion
wise. After addition the mixture was allowed to reach room
temperature and then stirred for another hour. The resulting
mixture was added dropwise to a stirred ice-water mixture (100 mL)
keeping the temperature below 5.degree. C. The mixture was
extracted with Me-THF, dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The obtained crude was triturated in
cyclohexane, filtered and dried to yield ethyl
4-chlorosulfonyl-3-hydroxy-1-methyl-pyrrole-2-carboxylate (1.1
g).
Compound 196:
(3S)--N-(3,4-difluorophenyl)-3-(1-hydroxycyclopropyl)-7-methyl-1,1-dioxo--
3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00250##
[0840]
(S)-(-)-3-tert-butoxycarbonyl-4-methoxycarbonyl-2,2-dimethyl-1,3-ox-
azolidine (5 g, 3 mmol) was dissolved in THF (100 mL) and cooled to
0.degree. C. before titanium(IV) isopropoxide (2.9 mL, 0.96 g/mL,
9.6 mmol) was added while stirred over 10 minutes. Then
ethylmagnesium bromide (16 mL, 3 M, 48 mmol) was slowly added over
10 minutes to obtain a dark brown solution, and the solution was
stirred at 0.degree. C. and then allowed to reach room temperature.
After 16 hours the solution was quenched with NH.sub.4Cl (aq.,
sat.) and extracted with EtOAc, dried over MgSO.sub.4, filtered and
concentrated in vacuo. The obtained crude was purified on silica
using heptane/EtOAc: 100/0 to 80/20 to yield tert-butyl
(4S)-4-(1-hydroxycyclopropyl)-2,2-dimethyl-oxazolidine-3-carboxylate
(4.0 g) as light oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 0.29-0.73 (m, 4H) 1.35-1.49 (m, 15H) 3.74 (br d, J=81.0 Hz, 1H)
3.93-4.09 (m, 2H) 5.30 (br s, 1H).
[0841] NaH (933 mg, 60% dispersion in mineral oil, 23.3 mmol) was
dissolved in DMF (45 mL) and cooled to 0.degree. C. before a
solution of tert-butyl
(45)-4-(1-hydroxycyclopropyl)-2,2-dimethyl-oxazolidine-3-carboxylate
(3.0 g, 11.7 mmol) in THF (10 mL) was added. The solution was
stirred for 30 minutes and then benzyl bromide (1.5 mL, 1.44 g/mL,
13 mmol) was added. The solution was allowed to reach room
temperature and stirred for 16 hours. The solution was quenched
with NH.sub.4Cl (aq., sat.) and stirred for 10 minutes before being
extracted with EtOAc and washed three times with brine. The
combined organic layers were dried over MgSO.sub.4, filtered off
and concentrated in vacuo. The obtained crude was purified on
silica using heptane/EtOac from 100/0 to 50/50 to yield tert-butyl
(4S)-4-(1-benzyloxycyclopropyl)-2,2-dimethyl-oxazolidine-3-carboxylate
(2.8 g).
[0842] tert-butyl
(4S)-4-(1-benzyloxycyclopropyl)-2,2-dimethyl-oxazolidine-3-carboxylate
(2.8 g, 8.1 mmol) was dissolved in a mixture of MeOH (30 mL) and
THF (65 mL). HCl (25 mL, 1 M in H.sub.2O, 24.176 mmol) was added
dropwise and the solution was heated to 50.degree. C. and stirred
for 48 hours. The solution was then basified with K.sub.2CO.sub.3
and concentrated in vacuo. The crude was then diluted with DCM and
washed with water. The combined organic layers were concentrated in
vacuo and purified on silica using a gradient from DCM to
DCM/MeOH(NH.sub.3 7N) 9/1 to yield
(2S)-2-amino-2-(1-benzyloxycyclopropyl)ethanol (1.2 g). Method B;
Rt: 0.52 min. m/z: 208 (M+H).sup.+ Exact mass: 207.1.
[0843] (2S)-2-amino-2-(1-benzyloxycyclopropyl)ethanol (950 mg, 4.6
mmol) was dissolved in dry DCM and 2 g molecular sieves (4 .ANG.)
was added at room temperature under inert atmosphere.
4-methoxybenzaldehyde (0.69 mL, 1.119 g/mL, 5.5 mmol) was then
added and the solution was stirred at room temperature for 16
hours. The solution was rapidly filtered, concentrated in vacuo and
redissolved in MeOH (18 mL) and cooled to 0.degree. C. before
sodium borohydride (433 mg, 11.46 mmol) was added and the solution
then allowed to reach room temperature. After 2 hours the solution
was quenched with water, extracted with DCM, dried over
Na.sub.2SO.sub.4, filtered, concentrated and purified on silica
using heptane/EtOAc 100/0 to 10/90 to yield
(2S)-2-(1-benzyloxycyclopropyl)-2-[(4-methoxyphenyl)methylamino]ethanol
(1.38 g). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.59-0.71
(m, 2H) 0.87-1.03 (m, 2H) 2.68 (dd, J=7.0, 4.6 Hz, 1H) 3.56 (dd,
J=10.8, 7.0 Hz, 1H) 3.74 (dd, J=10.8, 4.6 Hz, 1H) 3.78-3.84 (m, 4H)
3.91-3.98 (m, 1H) 4.47-4.62 (m, 2H) 6.86 (d, J=7.7 Hz, 2H)
7.22-7.34 (m, 7H); Method B; Rt: 0.94 min. m/z: 328 (M+H).sup.+
Exact mass: 327.2.
[0844]
(2S)-2-(1-benzyloxycyclopropyl)-2-[(4-methoxyphenyl)methylamino]eth-
anol (1.13 g, 3.451 mmol) was dissolved in ACN (20 mL) and Hunig's
base (1.78 mL, 0.75 g/mL, 10.4 mmol) was added followed by ethyl
4-chlorosulfonyl-3-hydroxy-1-methyl-pyrrole-2-carboxylate (924 mg,
3.45 mmol). After 16 hours, the solution was quenched with
NaHCO.sub.3(aq., sat., 50 mL) and stirred for 10 minutes. The
solution was then extracted with EtOAc (3.times.50 mL). The
combined organics were dried over Na.sub.2SO.sub.4, filtered,
concentrated in vacuo and purified on silica using heptane/EtOAc
100/0 to 20/80 to yield ethyl
4-[[(1S)-1-(1-benzyloxycyclopropyl)-2-hydroxy-ethyl]-[(4-methoxyphenyl)me-
thyl]sulfamoyl]-3-hydroxy-1-methyl-pyrrole-2-carboxylate (800
mg).
[0845] Ethyl
4-[[(1S)-1-(1-benzyloxycyclopropyl)-2-hydroxy-ethyl]-[(4-methoxyphenyl)me-
thyl]sulfamoyl]-3-hydroxy-1-methyl-pyrrole-2-carboxylate (800 mg,
1.43 mmol) was dissolved in THF (15 mL). Triphenylphosphine (413
mg, 1.58 mmol) and di-tert-butyl azodicarboxylate (363 mg, 1.58
mmol) were added. After 16 hours, the solution was extracted with
EtOAc, washed with water and the combined organics dried over
MgSO.sub.4, filtered and concentrated in vacuo. The crude was
purified on silica using heptane/EtOAc 100/to 0/100 to yield ethyl
(3S)-3-(1-benzyloxycyclopropyl)-2-[(4-methoxyphenyl)methyl]-7-methyl-1,1--
dioxo-3,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxylate
(774 mg).
[0846] Ethyl (3 S)-3-(1-benzyloxy cyclopropyl)-2-[(4-methoxy
phenyl)methyl]-7-methyl-1,1-dioxo-3,4-dihydropyrrolo[3,4-b][1,4,5]oxathia-
zepine-6-carboxylate (774 mg, 1.43 mmol) was dissolved in THF (20
mL) and 3,4-difluoroaniline (0.16 mL, 1.29 g/mL, 1.58 mmol) and
LiHMDS (7 mL, 1 M in THF, 7 mmol) were added. After 2 hours at room
temperature the solution was quenched with NH.sub.4Cl (aq., sat.)
and extracted with EtOAc, the combined organic layers were dried
with MgSO.sub.4, filtered, concentrated in vacuo and the crude
purified on silica using heptane/EtOAc: 100/0 to 0/100 gradient
elution. The obtained crude was partitioned between EtOAc (50 ml),
10 mL HCl (aq., 1M) and water (20 mL) and stirred during 10
minutes. After extraction, the combined organic layers were dried
over MgSO.sub.4, filtered and concentrated in vacuo to yield (3
S)-3-(1-benzyloxycyclopropyl)-N-(3,4-difluorophenyl)-2-[(4-metho-
xyphenyl)methyl]-7-methyl-1,1-dioxo-3,4-dihydropyrrolo[3,4-b][1,4,5]oxathi-
azepine-6-carboxamide (621 mg) Method B; Rt: 1.41 min. m/z: 624
(M+H).sup.+ Exact mass: 623.1.
[0847]
(3S)-3-(1-benzyloxycyclopropyl)-N-(3,4-difluorophenyl)-2-[(4-methox-
yphenyl)methyl]-7-methyl-1,1-dioxo-3,4-dihydropyrrolo[3,4-b][1,4,5]oxathia-
zepine-6-carboxamide (100 mg, 0.16 mmol) was dissolved in DCM (2
mL) and TFA (1.23 mL, 1.49 g/mL, 16.0 mmol) was added at room
temperature. After 16 hours, the reaction was quenched with water
and NaHCO.sub.3(aq., sat.) and extracted with DCM. The combined
organic layers were dried over MgSO.sub.4, filtered, concentrated
in vacuo and purified on silica yielding
(3S)-3-(1-benzyloxycyclopropyl)-N-(3,4-difluorophenyl)-7-methyl--
1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
(70 mg). Method B; Rt: 1.21 min. m/z: 504 (M+H).sup.+ Exact mass:
503.1.
[0848]
(3S)-3-(1-benzyloxycyclopropyl)-N-(3,4-difluorophenyl)-7-methyl-1,1-
-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
(70 mg, 0.139 mmol) was dissolved in MeOH (20 mL) and HOAc (0.4 mL,
1.049 g/mL, 7.0 mmol) and 5 droplets 0.4% thiophene in THF were
added. Pd/C (10%) (15 mg, 0.014 mmol) was added. The solution was
hydrogenated at room temperature during 1 hour. The reaction
mixture was filtered over dicalite, concentrated in vacuo, purified
on silica using heptane/EtOAc 100/0 to 50/50 to yield compound 196
(12 mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.57-0.80
(m, 4H) 3.46-3.53 (m, 1H) 3.83 (s, 3H) 3.99-4.09 (m, 1H) 4.92 (dd,
J=12.5, 1.3 Hz, 1H) 5.50 (s, 1H) 7.36-7.53 (m, 4H) 7.87 (ddd,
J=13.1, 7.5, 2.4 Hz, 1H) 9.43 (s, 1H); Method B; Rt: 0.89 min. m/z:
412 (M-H).sup.- Exact mass: 413.1.
Compound 197:
3-[(6-chloro-3-pyridyl)methyl]-N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-di-
oxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00251##
[0850] Compound 197 (331 mg) was prepared similarly as described
for compound 162, using 2-chloro-5-(chloromethyl)pyridine instead
of 3-(chloromethyl)-5-methylisoxazole .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.13 (s, 3H), 2.75 (d, J=13.2 Hz, 1H),
3.06 (d, J=13.2 Hz, 1H), 3.82 (s, 3H), 4.41 (d, J=13.0 Hz, 1H),
4.64 (d, J=13.2 Hz, 1H), 7.38-7.46 (m, 2H), 7.49 (s, 1H), 7.52 (d,
J=8.1 Hz, 1H), 7.74-7.88 (m, 3H), 8.33 (d, J=2.2 Hz, 1H), 9.40 (s,
1H); Method B; Rt: 1.08 min. m/z: 495 (M-H).sup.- Exact mass:
496.1.
Compound 198:
N-(3-chloro-4-fluoro-phenyl)-3-[(6-chloro-3-pyridyl)methyl]-3,7-dimethyl--
1,1-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00252##
[0852] Compound 198 (109 mg) was prepared similarly as described
for compound 197, using 3-chloro-4-fluoro-aniline instead of
3,4-difluoroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.14 (s, 3H), 2.74 (d, J=13.2 Hz, 1H), 3.07 (d, J=13.4 Hz, 1H),
3.82 (s, 3H), 4.42 (d, J=13.2 Hz, 1H), 4.64 (d, J=13.2 Hz, 1H),
7.41 (t, J=9.0 Hz, 1H), 7.49 (s, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.63
(ddd, J=9.0, 4.4, 2.6 Hz, 1H), 7.76 (s, 1H), 7.80 (dd, J=8.4, 2.4
Hz, 1H), 7.97 (dd, J=6.8, 2.6 Hz, 1H), 8.33 (d, J=2.4 Hz, 1H), 9.38
(s, 1H); Method B; Rt: 1.13 min. m/z: 511 (M-H).sup.- Exact mass:
512.1.
Compound 199:
N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-3-(3-pyridylmethyl)-2,4-dih-
ydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00253##
[0854] Compound 197 (389 mg, 0.78 mmol), Pd/C (10%) (42 mg, 0.039
mmol) and TEA (0.22 mL, 0.73 g/mL, 1.57 mmol) were dispensed in THF
(50 mL) and set under a hydrogen atmosphere for 2 hours. The
reaction mixture was filtered and the residue was triturated in
DIPE yielding compound 199 as an off-white powder. This was
separated into its enantiomers via preparative SFC (Stationary
phase: Chiralpak Diacel AD 20.times.250 mm, Mobile phase: CO.sub.2,
EtOH+0.4 iPrNH.sub.2) yielding compound 199a (141 mg), .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.14 (s, 3H), 2.74 (d, J=13.2
Hz, 1H), 3.06 (d, J=13.4 Hz, 1H), 3.82 (s, 3H), 4.42 (d, J=13.2 Hz,
1H), 4.63 (d, J=13.2 Hz, 1H), 7.37 (dd, J=7.7, 5.3 Hz, 1H),
7.40-7.45 (m, 2H), 7.48 (s, 1H), 7.71-7.75 (m, 1H), 7.76 (s, 1H),
7.82-7.89 (m, 1H), 8.47 (d, J=5.0 Hz, 1H), 8.52 (s, 1H), 9.41 (s,
1H); Method B; Rt: 0.94 min. m/z: 461 (M-H).sup.- Exact mass:
462.1, MP: 267.1.degree. C. and compound 199b (136 mg), .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.14 (s, 3H), 2.74 (d, J=13.2
Hz, 1H), 3.06 (d, J=13.2 Hz, 1H), 3.82 (s, 3H), 4.42 (d, J=13.2 Hz,
1H), 4.63 (d, J=13.2 Hz, 1H), 7.37 (dd, J=7.8, 5.2 Hz, 1H),
7.40-7.47 (m, 2H), 7.49 (s, 1H), 7.71-7.75 (m, 1H), 7.76 (s, 1H),
7.82-7.89 (m, 1H), 8.46-8.53 (m, 2H), 9.41 (s, 1H); Method B; Rt:
0.94 min. m/z: 461 (M-H).sup.- Exact mass: 462.1, MP: 268.3.degree.
C. after trituration from DIPE. Method R; Rt: 197a: 4.57 min, 197b:
5.09 min.
Compound 200: (3R)--N-(4-fluoro-3-methyl-phenyl)-3-[(1
S)-1-hydroxyethyl]-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5-
]oxathiazepine-6-carboxamide
##STR00254##
[0856] Compound 200 (241 mg) was prepared similarly as described
for compound 35, using 4-fluoro-3-methyl-aniline instead of
3,4-difluoroaniline and heating 8 hours at 110.degree. C. The crude
product was purified via preparative HPLC (Stationary phase: RP
XBridge Prep C18 ODB-5 .mu.m, 30.times.250 mm, Mobile phase: 0.1%
TFA solution in water+5% ACN, ACN) yielding compound 200 (241 mg).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.21 (d, J=6.2 Hz,
3H), 2.23 (d, J=2.0 Hz, 3H), 3.36-3.46 (m, 1H), 3.55-3.66 (m, 1H),
3.83 (s, 3H), 3.98 (dd, J=12.7, 8.9 Hz, 1H), 4.88 (dd, J=12.7, 2.0
Hz, 1H), 5.04 (d, J=5.9 Hz, 1H), 7.09 (t, J=9.2 Hz, 1H), 7.44 (s,
1H), 7.48-7.55 (m, 1H), 7.55-7.67 (m, 2H), 9.21 (s, 1H); Method Z;
Rt: 7.32 min. m/z: 396 (M-H).sup.- Exact mass: 397.1.
Compound 201:
N-(3,4-difluorophenyl)-3,3-bis(hydroxymethyl)-7-methyl-1,1-dioxo-4,5-dihy-
dro-2H-pyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00255##
[0858] Compound 131 (55 mg, 0.14 mmol), water (0.200 ml), MeOH (3
mL), PTSA (0.57 mg, 0.003 mmol) and
2,6-ditert-butyl-4-methyl-phenol (0.5 mg, 0.002 mmol) were placed
in a sealed tube. The reaction was carried out by heating and
stirring for 132 hours at 80.degree. C. The reaction mixture was
purified via preparative HPLC (Stationary phase: RP XBridge Prep
C18 OBD-10 .mu.m, 50.times.150 mm, Mobile phase: 0.25%
NH.sub.4HCO.sub.3 solution in water, ACN) yielding compound 201 (10
mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.84-1.96 (m,
2H), 2.86-2.97 (m, 2H), 3.40-3.55 (m, 4H), 3.69 (s, 3H), 4.91 (br
s, 1H), 7.35-7.46 (m, 3H), 7.80-7.87 (m, 1H); Method B; Rt: 0.71
min. m/z: 414 (M-H).sup.- Exact mass: 415.1, and crude compound 202
(18 mg).
Compound 202:
N-(3,4-difluorophenyl)-3-(hydroxymethyl)-3-(methoxymethyl)-7-methyl-1,1-d-
ioxo-4,5-dihydro-2H-pyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00256##
[0860] The crude compound 202 (18 mg) obtained in the synthesis of
compound 201 was purified on silica using a heptane to EtOAc
gradient to yield compound 202 (12 mg); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.82-1.97 (m, 2H), 2.86-2.98 (m, 2H),
3.27-3.29 (m, 3H), 3.35-3.53 (m, 4H), 3.69 (s, 3H), 4.72 (br s,
1H), 6.94 (br s, 1H), 7.37-7.46 (m, 3H), 7.79-7.87 (m, 1H), 10.36
(br s, 1H); Method B; Rt: 0.81 min. m/z: 428 (M-H).sup.- Exact
mass: 429.1.
Compound 203:
N-(3,4-difluorophenyl)-3-(hydroxymethyl)-3,7-dimethyl-1,1-dioxo-2,4-dihyd-
ropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00257##
[0862] Compound 203 (196 mg) was prepared similarly as described
for compound 133, using 2-amino-2-methyl-propane-1,3-diol instead
of 2-amino-1,3-propanediol. This racemic mixture was separated into
its enantiomers using preparative SFC (Stationary phase: Chiralpak
Diacel AD 20.times.250 mm, Mobile phase: CO.sub.2, EtOH with 0.4%
iPrNH.sub.2) yielding compound 203a (46.6 mg); .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 1.26 (s, 3H), 3.19-3.29 (m, 1H),
3.68 (dd, J=10.9, 6.1 Hz, 1H), 3.81 (s, 3H), 4.47 (d, J=13.2 Hz,
1H), 4.56 (d, J=13.2 Hz, 1H), 5.06 (t, J=5.8 Hz, 1H), 7.37-7.45 (m,
3H), 7.70 (s, 1H), 7.81-7.88 (m, 1H), 9.33 (s, 1H); Method B; Rt:
0.85 min. m/z: 400 (M-H).sup.- Exact mass: 401.1; and compound 203b
(44.7 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.26 (s,
3H), 3.22-3.28 (m, 1H), 3.68 (dd, J=10.7, 6.1 Hz, 1H), 3.81 (s,
3H), 4.44-4.59 (m, 2H), 5.06 (t, J=5.8 Hz, 1H), 7.37-7.45 (m, 3H),
7.71 (s, 1H), 7.81-7.88 (m, 1H), 9.33 (s, 1H); Method B; Rt: 0.85
min. m/z: 400 (M-H).sup.- Exact mass: 401.1 as white powders after
crystallization from a EtOAc:DIPE mixture. Method R; Rt: 203a: 3.86
min, 203b: 4.39 min.
Compound 204:
N-(2-chloro-4-pyridyl)-3-(hydroxymethyl)-3,7-dimethyl-1,1-dioxo-2,4-dihyd-
ropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00258##
[0864] Compound 204 (205 mg) was prepared similarly as described
for compound 203, using 2-chloropyridin-4-amine instead of
3,4-difluoroaniline. The crude product was purified via preparative
HPLC (Stationary phase: RP XBridge Prep C18 ODB-5 .mu.m,
50.times.150 mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3 solution in
water, MeOH) yielding compound 204. This racemic mixture was
separated into its enantiomers using preparative SFC (Stationary
phase: Chiralpak Diacel AD 20.times.250 mm, Mobile phase: CO.sub.2,
EtOH with 0.4% iPrNH.sub.2) yielding compound 204a (44.2 mg);
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.27 (s, 3H),
3.26-3.29 (m, 1H), 3.68 (dd, J=10.8, 5.9 Hz, 1H), 3.82 (s, 3H),
4.48-4.61 (m, 2H), 5.08 (t, J=5.8 Hz, 1H), 7.50 (s, 1H), 7.67 (dd,
J=5.7, 2.0 Hz, 1H), 7.75 (s, 1H), 7.83 (d, J=1.5 Hz, 1H), 8.28 (d,
J=5.7 Hz, 1H), 9.58 (s, 1H); Method B; Rt: 0.72 min. m/z: 399
(M-H).sup.- Exact mass: 400.1; and compound 203b (48.7 mg); .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.27 (s, 3H), 3.25-3.29 (m,
1H), 3.64-3.72 (m, 1H), 3.82 (s, 3H), 4.48-4.61 (m, 2H), 5.03-5.13
(m, 1H), 7.50 (s, 1H), 7.67 (dd, J=5.6, 1.9 Hz, 1H), 7.75 (br s,
1H), 7.83 (d, J=1.8 Hz, 1H), 8.28 (d, J=5.5 Hz, 1H), 9.58 (br s,
1H); Method B; Rt: 0.85 min. m/z: 399 (M-H).sup.- Exact mass: 400.1
as white powders after crystallization from a EtOAc:DIPE mixture.
Method R; Rt: 204a: 4.58 min, 204b: 5.15 min.
Compound 205:
3-but-2-ynyl-N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyr-
rolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00259##
[0866] Compound 205 (243 mg) was prepared similarly as described
for compound 14, using 2-aminohex-4-yn-1-ol instead of DL-alaninol
and ACN instead of THF as a solvent in the first step. The ring
closure was obtained after heating overnight at 110.degree. C. in
DMF .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.78 (t, J=2.4
Hz, 3H), 2.32-2.47 (m, 2H), 3.68-3.78 (m, 1H), 3.81 (s, 3H), 3.95
(dd, J=13.0, 9.0 Hz, 1H), 4.67 (dd, J=12.8, 2.0 Hz, 1H), 7.36-7.48
(m, 3H), 7.77 (d, J=9.2 Hz, 1H), 7.82-7.88 (m, 1H), 9.45 (s, 1H);
Method B; Rt: 1.03 min. m/z: 408 (M-H).sup.- Exact mass: 409.1.
Compound 206:
3-[cyclopropyl(hydroxy)methyl]-N-(4-fluoro-3-methyl-phenyl)-7-methyl-1,1--
dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00260##
[0868] Compound 206 (361 mg) was prepared similarly as described
for compound 105, using 4-fluoro-3-methyl-aniline instead of
3,4-difluoroaniline. This racemic mixture was separated in its
epimers via preparative SFC (Stationary phase: Chiralpak Diacel ID
20.times.250 mm, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2)
yielding 206a (163 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 0.23-0.51 (m, 4H), 1.00-1.12 (m, 1H), 2.23 (d, J=2.0 Hz, 3H),
3.09 (q, J=6.5 Hz, 1H), 3.57-3.69 (m, 1H), 3.83 (s, 3H), 4.01 (dd,
J=12.8, 9.1 Hz, 1H), 4.90 (dd, J=12.7, 2.0 Hz, 1H), 5.00 (d, J=5.6
Hz, 1H), 7.09 (t, J=9.2 Hz, 1H), 7.44 (s, 1H), 7.47-7.55 (m, 1H),
7.55-7.64 (m, 2H), 9.22 (s, 1H); Method D; Rt: 1.80 min. m/z: 422
(M-H).sup.- Exact mass: 423.1 and 206b (32 mg); .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 0.17-0.48 (m, 4H), 0.96-1.09 (m,
1H), 2.23 (d, J=2.0 Hz, 3H), 3.05-3.18 (m, 1H), 3.71-3.81 (m, 1H),
3.83 (s, 3H), 4.05 (dd, J=12.7, 9.2 Hz, 1H), 4.74 (dd, J=13.2, 0.7
Hz, 1H), 4.90-5.08 (m, 1H), 7.09 (t, J=9.2 Hz, 1H), 7.35-7.47 (m,
2H), 7.47-7.54 (m, 1H), 7.56 (dd, J=6.9, 2.8 Hz, 1H), 9.24 (s, 1H);
Method D; Rt: 1.81 min. m/z: 422 (M-H).sup.- Exact mass: 423.1; MP:
234.7.degree. C. Method U; Rt: 206a: 4.19 min, 206b: 5.11 min.
Compound 207:
N-(3-chloro-4-fluoro-phenyl)-3-[cyclopropyl(hydroxy)methyl]-7-methyl-1,1--
dioxo-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00261##
[0870] Compound 207 (260 mg) was prepared similarly as described
for compound 105, using 3-chloro-4-fluoro-aniline instead of
3,4-difluoroaniline. This racemic mixture was separated in its
epimers via preparative SFC (Stationary phase: Chiralpak Diacel ID
20.times.250 mm, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2)
yielding 207a (148 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 0.20-0.55 (m, 4H), 0.96-1.12 (m, 1H), 3.09 (q, J=6.5 Hz, 1H),
3.56-3.69 (m, 1H), 3.83 (s, 3H), 4.00 (dd, J=12.8, 9.2 Hz, 1H),
4.91 (dd, J=12.7, 2.0 Hz, 1H), 5.00 (d, J=5.6 Hz, 1H), 7.38 (t,
J=9.1 Hz, 1H), 7.47 (s, 1H), 7.60 (d, J=9.9 Hz, 1H), 7.65 (ddd,
J=9.1, 4.3, 2.6 Hz, 1H), 8.00 (dd, J=6.8, 2.6 Hz, 1H), 9.41 (s,
1H); Method D; Rt: 1.88 min. m/z: 442 (M-H).sup.- Exact mass: 443.1
and 207b (45 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.16-0.49 (m, 4H), 0.95-1.09 (m, 1H), 3.08-3.17 (m, 1H), 3.71-3.81
(m, 1H), 3.83 (s, 3H), 4.04 (dd, J=12.7, 9.2 Hz, 1H), 4.75 (dd,
J=12.9, 1.1 Hz, 1H), 5.00 (d, J=4.9 Hz, 1H), 7.39 (t, J=9.1 Hz,
1H), 7.42-7.50 (m, 2H), 7.64 (ddd, J=9.0, 4.3, 2.6 Hz, 1H), 7.99
(dd, J=6.8, 2.6 Hz, 1H), 9.43 (s, 1H); Method D; Rt: 1.81 min. m/z:
442 (M-H).sup.- Exact mass: 443.1; MP: 215.8.degree. C. Method U;
Rt: 206a: 4.30 min, 206b: 5.41 min.
Compound 208:
3-[cyclopropyl(hydroxy)methyl]-7-methyl-1,1-dioxo-N-(3,4,5-trifluoropheny-
l)-3,4-dihydro-2H-pyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00262##
[0872] Compound 208 (289 mg) was prepared similarly as described
for compound 105, using 3,4,5-trifluoroaniline instead of
3,4-difluoroaniline. This racemic mixture was separated in its
epimers via preparative SFC (Stationary phase: Chiralpak Diacel ID
20.times.250 mm, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2)
yielding 208a (124 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 0.25-0.53 (m, 4H), 0.99-1.11 (m, 1H), 3.08 (q, J=6.5 Hz, 1H),
3.63 (q, J=8.4 Hz, 1H), 3.82 (s, 3H), 3.99 (dd, J=12.8, 9.2 Hz,
1H), 4.94 (dd, J=12.8, 1.8 Hz, 1H), 5.02 (d, J=5.6 Hz, 1H), 7.50
(s, 1H), 7.62 (br d, J=9.5 Hz, 1H), 7.66-7.77 (m, 2H), 9.49 (s,
1H); Method D; Rt: 1.91 min. m/z: 444 (M-H).sup.- Exact mass: 445.1
and 208b (43 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.16-0.50 (m, 4H), 0.95-1.08 (m, 1H), 3.08-3.16 (m, 1H), 3.72-3.81
(m, 1H), 3.82 (s, 3H), 4.04 (dd, J=12.7, 9.2 Hz, 1H), 4.77 (dd,
J=12.5, 1.1 Hz, 1H), 5.02 (d, J=4.9 Hz, 1H), 7.41-7.53 (m, 2H),
7.64-7.75 (m, 2H), 9.51 (s, 1H); Method D; Rt: 1.88 min. m/z: 444
(M-H).sup.- Exact mass: 445.1. Method U; Rt: 208a: 3.49 min, 208b:
4.27 min.
Compound 209:
N-[2-(difluoromethyl)-4-pyridyl]-3,7-dimethyl-3-[(5-methylisoxazol-3-yl)m-
ethyl]-1,1-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxami-
de
##STR00263##
[0874] Compound 209 (92 mg) was prepared similarly as described for
compound 162, using 2-(difluoromethyl)pyridin-4-amine instead of
3,4-difluoroaniline. This was separated into its enantiomers via
preparative SFC (Stationary phase: Kromasil (R,R) Whelk-O 1 10/100,
Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2) yielding compound
209a (23 mg), .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.22
(s, 3H), 2.40 (s, 3H), 2.89 (d, J=13.9 Hz, 1H), 3.04 (d, J=14.1 Hz,
1H), 3.83 (s, 3H), 4.44 (d, J=13.2 Hz, 1H), 4.62 (d, J=13.2 Hz,
1H), 6.21 (d, J=0.9 Hz, 1H), 6.91 (t, J=55.0 Hz, 1H), 7.54 (s, 1H),
7.79 (br d, J=5.6 Hz, 1H), 7.95 (br s, 1H), 8.03 (d, J=1.8 Hz, 1H),
8.55 (d, J=5.5 Hz, 1H), 9.71 (s, 1H); Method B; Rt: 0.88 min. m/z:
480 (M-H).sup.- Exact mass: 481.1 and compound 209b (19 mg),
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.22 (s, 3H), 2.40
(s, 3H), 2.91 (s, 1H), 3.04 (d, J=14.1 Hz, 1H), 3.83 (s, 3H), 4.44
(d, J=13.2 Hz, 1H), 4.61 (s, 1H), 6.21 (s, 1H), 6.91 (t, J=55.0 Hz,
1H), 7.54 (s, 1H), 7.79 (d, J=5.4 Hz, 1H), 7.95 (br s, 1H), 8.03
(d, J=1.8 Hz, 1H), 8.55 (d, J=5.7 Hz, 1H), 9.71 (s, 1H); Method B;
Rt: 0.86 min. m/z: 480 (M-H).sup.- Exact mass: 481.1. Method X; Rt:
209a: 5.56 min, 209b: 5.91 min.
Compound 210:
N-(3-cyano-4-fluoro-phenyl)-3-(hydroxymethyl)-3,7-dimethyl-1,1-dioxo-2,4--
dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00264##
[0876] Compound 210 (354 mg) was prepared similarly as described
for compound 203, using 5-amino-2-fluoro-benzonitrile instead of
3,4-difluoroaniline. This racemic mixture was separated into its
enantiomers using preparative SFC (Stationary phase: Chiralpak
Diacel AD 20.times.250 mm, Mobile phase: CO.sub.2, EtOH with 0.4%
iPrNH.sub.2) yielding compound 210a (96.6 mg); .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 1.27 (s, 3H), 3.19-3.28 (m, 1H),
3.68 (dd, J=10.6, 6.2 Hz, 1H), 3.82 (s, 3H), 4.49 (d, J=13.2 Hz,
1H), 4.57 (d, J=13.0 Hz, 1H), 5.07 (t, J=5.8 Hz, 1H), 7.45 (s, 1H),
7.52 (t, J=9.1 Hz, 1H), 7.73 (s, 1H), 8.03 (ddd, J=9.2, 5.0, 2.8
Hz, 1H), 8.17 (dd, J=5.7, 2.6 Hz, 1H), 9.42 (s, 1H); Method B; Rt:
0.79 min. m/z: 407 (M-H).sup.- Exact mass: 408.1; and compound 210b
(73.4 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.27 (s,
3H), 3.21-3.29 (m, 1H), 3.64-3.71 (m, 1H), 3.82 (s, 3H), 4.49 (d,
J=13.2 Hz, 1H), 4.57 (d, J=13.2 Hz, 1H), 5.07 (t, J=5.8 Hz, 1H),
7.45 (s, 1H), 7.52 (t, J=9.1 Hz, 1H), 7.73 (s, 1H), 8.01-8.05 (m,
1H), 8.16-8.19 (m, 1H), 9.42 (s, 1H); Method B; Rt: 0.80 min. m/z:
407 (M-H).sup.- Exact mass: 408.1 as white powders after
crystallization from a EtOAc:DIPE mixture. Method R; Rt: 210a: 4.21
min, 210b: 4.67 min.
Compound 211:
N-(3-chloro-4-fluoro-phenyl)-3,7-dimethyl-1,1-dioxo-3-(3-pyridylmethyl)-2-
,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00265##
[0878] Compound 198 (252 mg, 0.49 mmol), Pd/C (10%) (26 mg, 0.025
mmol), TEA (0.14 mL, 0.73 g/mL, 0.98 mmol) and thiophene (2.15 mL,
0.72 g/mL, 0.4% in DIPE, 0.074 mmol) were dispensed in THF (100 mL)
and set under a hydrogen atmosphere for 2 hours. More Pt/C (5%) (96
mg, 0.025 mmol) was added and the reaction mixture was stirred
overnight under a hydrogen atmosphere. Pd/C (10%) (52 mg, 0.049
mmol) was added and the reaction mixture was stirred overnight
under a hydrogen atmosphere. More Pd/C (10%) (52 mg, 0.049 mmol)
was added and the reaction mixture was stirred 2 days under a
hydrogen atmosphere. The reaction mixture was filtered and the
residue was purified on silica using a heptane to EtOAc gradient
and again via preparative HPLC (Stationary phase: RP XBridge Prep
C18 OBD-10 .mu.m, 30.times.150 mm, Mobile phase: 0.25%
NH.sub.4HCO.sub.3 solution in water, ACN) yielding compound 211 (87
mg) as a white powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.14 (s, 3H), 2.74 (d, J=13.0 Hz, 1H), 3.06 (d, J=13.2 Hz, 1H),
3.82 (s, 3H), 4.42 (d, J=13.0 Hz, 1H), 4.63 (d, J=13.2 Hz, 1H),
7.35-7.44 (m, 2H), 7.48 (s, 1H), 7.61-7.66 (m, 1H), 7.73 (br d,
J=7.7 Hz, 2H), 7.97 (dd, J=6.8, 2.6 Hz, 1H), 8.47 (dd, J=4.7, 1.7
Hz, 1H), 8.52 (d, J=1.5 Hz, 1H), 9.39 (s, 1H); Method B; Rt: 1.00
min. m/z: 477 (M-H).sup.- Exact mass: 478.1, MP: 211.5.degree.
C.
Compound 212: N-(3-chloro-4-fluoro-phenyl)-7-methyl-1,1-dioxo-spiro
[2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-3,3'-tetrahydrofuran]-6-ca-
rboxamide
##STR00266##
[0880] Compound 212 (243 mg) was prepared similarly as described
for compound 205, using (3-aminotetrahydrofuran-3-yl)methanol
instead of 2-aminohex-4-yn-1-ol. The ring closure was obtained
after heating 2 hours at 110.degree. C. in DMF. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 1.99-2.19 (m, 2H), 3.73-3.89 (m,
7H), 4.40-4.53 (m, 2H), 7.40 (t, J=9.1 Hz, 1H), 7.49 (s, 1H), 7.66
(ddd, J=9.1, 4.2, 2.5 Hz, 1H), 7.98 (dd, J=6.8, 2.6 Hz, 1H), 8.24
(br s, 1H), 9.36 (s, 1H); Method B; Rt: 0.96 min. m/z: 428
(M-H).sup.- Exact mass: 429.1. This was separated into its
enantiomers via preparative SFC (Stationary phase: Chiralpak Diacel
IC 20.times.250 mm, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2)
yielding compound 212a (97 mg) and compound 212b (14 mg). Method
AA; Rt: 212a: 4.78 min, 212b: 5.55 min.
Compound 213:
N-(2-chloro-4-pyridyl)-3,7-dimethyl-3-[(5-methylisoxazol-3-yl)methyl]-1,1-
-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00267##
[0882] Compound 213 (92 mg) was prepared similarly as described for
compound 162, using 4-amino-2-chloropyridine instead of
3,4-difluoroaniline. This was separated into its enantiomers via
preparative SFC (Stationary phase: Chiralpak Diacel AD 20.times.250
mm, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2) yielding compound
213a (25 mg), .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.22
(s, 3H), 2.38-2.41 (m, 3H), 2.88 (d, J=13.9 Hz, 1H), 3.04 (d,
J=13.9 Hz, 1H), 3.82 (s, 3H), 4.44 (d, J=13.0 Hz, 1H), 4.62 (d,
J=13.2 Hz, 1H), 6.21 (d, J=0.9 Hz, 1H), 7.55 (s, 1H), 7.66 (dd,
J=5.7, 1.8 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.95 (br s, 1H), 8.28
(d, J=5.5 Hz, 1H), 9.65 (br s, 1H); Method B; Rt: 0.92 min. m/z:
464 (M-H).sup.- Exact mass: 465.1 and compound 213b (23 mg),
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.19-1.24 (m, 3H),
2.37-2.43 (m, 3H), 2.88 (d, J=14.1 Hz, 1H), 3.04 (d, J=14.1 Hz,
1H), 3.82 (s, 3H), 4.44 (d, J=13.2 Hz, 1H), 4.62 (d, J=13.2 Hz,
1H), 6.21 (s, 1H), 7.55 (s, 1H), 7.67 (dd, J=5.7, 1.8 Hz, 1H), 7.82
(d, J=1.8 Hz, 1H), 7.95 (br s, 1H), 8.28 (d, J=5.7 Hz, 1H), 9.65
(s, 1H); Method B; Rt: 0.93 min. m/z: 464 (M-H).sup.- Exact mass:
465.1. Method R; Rt: 213a: 4.57 min, 213b: 4.87 min.
Compound 214:
3-(hydroxymethyl)-3,7-dimethyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)-2,4-di-
hydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00268##
[0884] Compound 214 (474 mg) was prepared similarly as described
for compound 203, using 3,4,5-trifluoroaniline instead of
3,4-difluoroaniline. This racemic mixture was separated into its
enantiomers using preparative SFC (Stationary phase: Chiralpak
Diacel AS 20.times.250 mm, Mobile phase: CO.sub.2, iPrOH with 0.4%
iPrNH.sub.2) yielding compound 214a (80 mg); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.27 (s, 3H), 3.18-3.28 (m, 1H), 3.68
(dd, J=10.9, 6.3 Hz, 1H), 3.81 (s, 3H), 4.49 (d, J=13.2 Hz, 1H),
4.57 (d, J=13.2 Hz, 1H), 5.07 (t, J=5.8 Hz, 1H), 7.46 (s, 1H),
7.64-7.74 (m, 3H), 9.39 (s, 1H); Method B; Rt: 0.94 min. m/z: 418
(M-H).sup.- Exact mass: 419.1; and compound 214b (75 mg); .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.27 (s, 3H), 3.21-3.30 (m,
1H), 3.68 (dd, J=10.8, 6.2 Hz, 1H), 3.81 (s, 3H), 4.47-4.60 (m,
2H), 5.07 (t, J=5.8 Hz, 1H), 7.46 (s, 1H), 7.64-7.74 (m, 3H), 9.39
(s, 1H); Method B; Rt: 0.95 min. m/z: 418 (M-H).sup.- Exact mass:
419.1 as white powders after crystallization from a EtOAc:DIPE
mixture. Method T; Rt: 214a: 2.90 min, 214b: 3.19 min.
Compound 215:
N-[2-(difluoromethyl)-4-pyridyl]-3-(hydroxymethyl)-3,7-dimethyl-1,1-dioxo-
-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00269##
[0886] Compound 215 was prepared similarly as described for
compound 203, using 2-(difluoromethyl)pyridin-4-amine instead of
3,4-difluoroaniline. This racemic mixture was separated into its
enantiomers using preparative SFC (Stationary phase: Chiralpak
Diacel AD 20.times.250 mm, Mobile phase: CO.sub.2, EtOH with 0.4%
iPrNH.sub.2) yielding compound 215a (78.3 mg); .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 1.27 (s, 3H), 3.23-3.29 (m, 1H),
3.68 (dd, J=10.8, 6.2 Hz, 1H), 3.82 (s, 3H), 4.46-4.62 (m, 2H),
5.08 (t, J=5.7 Hz, 1H), 6.91 (t, J=55.0 Hz, 1H), 7.50 (s, 1H),
7.71-7.80 (m, 2H), 8.05 (d, J=2.0 Hz, 1H), 8.54 (d, J=5.5 Hz, 1H),
9.65 (s, 1H); Method B; Rt: 0.72 min. m/z: 415 (M-H).sup.- Exact
mass: 416.1; and compound 215b (79.3 mg); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.27 (s, 3H), 3.24-3.29 (m, 1H), 3.68
(dd, J=10.7, 6.1 Hz, 1H), 3.82 (s, 3H), 4.46-4.62 (m, 2H), 5.08 (t,
J=5.8 Hz, 1H), 6.91 (t, J=55.0 Hz, 1H), 7.50 (s, 1H), 7.71-7.81 (m,
2H), 8.05 (d, J=2.0 Hz, 1H), 8.54 (d, J=5.5 Hz, 1H), 9.65 (s, 1H);
Method B; Rt: 0.72 min. m/z: 415 (M-H).sup.- Exact mass: 416.1 as
white powders after crystallization from a EtOAc:DIPE mixture.
Method R; Rt: 215a: 3.83 min, 215b: 4.26 min.
Compound 216:
l'-benzyl-N-(3,4-difluorophenyl)-7-methyl-1,1-dioxo-spiro[2,4-dihydropyrr-
olo[3,4-b][1,4,5]oxathiazepine-3,3'-pyrrolidine]-6-carboxamide
##STR00270##
[0888] Compound 216 (265 mg) was prepared similarly as described
for compound 212, using (3-amino-1-benzyl-pyrrolidin-3-yl)methanol
instead of (3-aminotetrahydrofuran-3-yl)methanol. .sup.1H NMR (400
MHz, DMSO-d.sub.6) ppm 1.93-2.05 (m, 2H), 2.45-2.48 (m, 1H), 2.54
(s, 1H), 2.68 (br d, J=8.1 Hz, 1H), 2.86 (br d, J=9.7 Hz, 1H), 3.61
(q, J=13.1 Hz, 2H), 3.81 (s, 3H), 4.37-4.55 (m, 2H), 7.25 (br d,
J=4.0 Hz, 1H), 7.32 (d, J=4.2 Hz, 4H), 7.38-7.48 (m, 3H), 7.80-7.88
(m, 1H), 8.12 (s, 1H), 9.34 (s, 1H); Method B; Rt: 1.19 min. m/z:
501 (M-H).sup.- Exact mass: 502.2.
Compound 217:
N-[2-(difluoromethyl)-4-pyridyl]-3,7-dimethyl-3-[(1-methylpyrazol-3-yl)me-
thyl]-1,1-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamid-
e
##STR00271##
[0890] Compound 217 (269 mg) was prepared similarly as described
for compound 167, using 2-(difluoromethyl)pyridin-4-amine instead
of 3,4-difluoroaniline. This was separated into it's enantiomers
via Prep SFC (Stationary phase: Chiralpak Diacel IC 20.times.250
mm, Mobile phase: CO.sub.2, EtOH+0.4 iPrNH.sub.2) yielding compound
176a (62.2 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
1.21 (s, 3H), 2.83 (d, J=13.9 Hz, 1H), 2.99 (d, J=13.9 Hz, 1H),
3.80 (s, 3H), 3.83 (s, 3H), 4.42 (d, J=13.2 Hz, 1H), 4.56 (d,
J=13.4 Hz, 1H), 6.15 (d, J=2.2 Hz, 1H), 6.92 (t, J=55.1 Hz, 1H),
7.52 (s, 1H), 7.59 (s, 1H), 7.75-7.87 (m, 2H), 8.02 (d, J=2.0 Hz,
1H), 8.55 (d, J=5.5 Hz, 1H), 9.68 (s, 1H); Method B; Rt: 0.85 min.
m/z: 479 (M-H).sup.- Exact mass: 480.1. and compound 176b (59.4
mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.22 (s, 3H),
2.83 (d, J=13.9 Hz, 1H), 2.99 (d, J=14.1 Hz, 1H), 3.80 (s, 3H),
3.83 (s, 3H), 4.42 (d, J=13.2 Hz, 1H), 4.56 (d, J=13.2 Hz, 1H),
6.15 (d, J=2.2 Hz, 1H), 6.92 (t, J=55.1 Hz, 1H), 7.52 (s, 1H), 7.59
(s, 1H), 7.78 (br d, J=3.7 Hz, 1H), 7.84 (s, 1H), 8.02 (d, J=2.0
Hz, 1H), 8.55 (d, J=5.5 Hz, 1H), 9.68 (s, 1H); Method B; Rt: 0.85
min. m/z: 479 (M-H).sup.- Exact mass: 480.1. Method AA; Rt: 217a:
5.76 min, 217b: 6.29 min.
Compound 218:
7-methyl-1,1-dioxo-3-[1-(2,2,2-trifluoroethylamino)ethyl]-N-(3,4,5-triflu-
orophenyl)-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00272##
[0892] Methyl
3-acetyl-7-methyl-1,1-dioxo-2,3,4,5-tetrahydropyrrolo[3,4-f]thiazepine-6--
carboxylate (550 mg, 1.83 mmol) and 2,2,2-trifluoroethylamine (7.31
mL, 1.24 g/mL, 91.6 mmol) were dissolved in methanol (70 mL) and
thiophene (1 mL, 4% in DiPE) and Pd/C (10%) (390 mg, 0.37 mmol)
were added successively. The reaction mixture was hydrogenated for
38 hours. Pd/C (10%) (390 mg, 0.37 mmol) was added to the reaction
mixture under a nitrogen atmosphere and was hydrogenated for 20
hours. Pd/C (10%) (390 mg, 0.37 mmol) was added to the reaction
mixture under a nitrogen atmosphere and was hydrogenated for 120
hours more. The reaction mixture was filtered over decalite and the
solids were washed with THF (3.times.100 mL). The filtrate was
concentrated to afford methyl
7-methyl-1,1-dioxo-3-[11-(2,2,2-trifluoroethylamino)ethyl]-2,3,4,5-tetrah-
ydropyrrolo[3,4-f]thiazepine-6-carboxylate (1.50 g). This was
separated into its 4 isomers via preparative SFC (Stationary phase:
Chiralpak Diacel AS 20.times.250 mm, Mobile phase: CO.sub.2,
EtOH+0.4 iPrNH.sub.2). The obtained 4 isomers were reacted with
3,4,5-trifluoroaniline using LiHMDS as a base in THF yielding
compound 218a (33 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.00 (d, J=6.6 Hz, 3H), 1.33 (br d, J=13.2 Hz, 1H), 2.01-2.13
(m, 2H), 2.53-2.67 (m, 1H), 2.74-2.82 (m, 1H), 3.01 (br dd, J=15.0,
6.6 Hz, 1H), 3.16-3.28 (m, 2H), 3.37-3.47 (m, 1H), 3.69 (s, 3H),
6.91 (d, J=10.3 Hz, 1H), 7.46 (s, 1H), 7.56-7.64 (m, 2H), 10.60 (s,
1H); Method D; Rt: 1.99 min. m/z: 497 (M-H).sup.- Exact mass:
498.1, compound 218b (78 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 0.99 (d, J=6.6 Hz, 3H), 1.38-1.48 (m, 1H), 1.92 (br dd,
J=14.4, 6.5 Hz, 1H), 2.20-2.30 (m, 1H), 2.67-2.82 (m, 2H), 3.00 (br
dd, J=14.4, 6.1 Hz, 1H), 3.15-3.36 (m, 2H), 3.37-3.47 (m, 1H), 3.69
(s, 3H), 6.94 (d, J=10.3 Hz, 1H), 7.47 (s, 1H), 7.55-7.64 (m, 2H),
10.61 (br s, 1H); Method D; Rt: 2.00 min. m/z: 497 (M-H).sup.-
Exact mass: 498.1, compound 218c (38 mg); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.99 (d, J=6.6 Hz, 3H), 1.38-1.48 (m,
1H), 1.88-1.95 (m, 1H), 2.24 (q, J=7.4 Hz, 1H), 2.67-2.82 (m, 2H),
3.01 (br dd, J=15.3, 5.8 Hz, 1H), 3.15-3.35 (m, 2H), 3.37-3.47 (m,
1H), 3.69 (s, 3H), 6.94 (d, J=10.3 Hz, 1H), 7.47 (s, 1H), 7.56-7.64
(m, 2H), 10.61 (s, 1H); Method D; Rt: 2.00 min. m/z: 497
(M-H).sup.- Exact mass: 498.1; MP: 216.2.degree. C. and compound
218d (34 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.00
(d, J=6.6 Hz, 3H), 1.28-1.38 (m, 1H), 2.01-2.13 (m, 2H), 2.54-2.67
(m, 1H), 2.73-2.82 (m, 1H), 3.01 (br dd, J=15.2, 5.7 Hz, 1H),
3.16-3.29 (m, 2H), 3.39-3.48 (m, 1H), 3.69 (s, 3H), 6.91 (d, J=10.3
Hz, 1H), 7.47 (s, 1H), 7.56-7.64 (m, 2H), 10.60 (s, 1H); Method D;
Rt: 1.99 min. m/z: 497 (M-H).sup.- Exact mass: 498.1, after
purification via preparative HPLC (Stationary phase: RP XBridge
Prep C18 OBD-10 .mu.m, 50.times.150 mm, Mobile phase: 0.25%
NH.sub.4HCO.sub.3 solution in water, MeOH). Method AB; Rt: 218a:
3.49 min, 218b: 3.15 min, 218c: 2.09 min, 218d: 2.26 min.
Compound 219:
3-[(6-chloro-3-pyridyl)methyl]-N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-di-
oxo-2H-pyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00273##
[0894] 2-amino-3-(6-chloro-3-pyridyl)-2-methyl-propan-1-ol (1.00 g,
4.98 mmol), methyl
3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (1.58 mg,
4.98 mmol) and Hunig's base (2.58 mL, 0.75 g/mL, 15 mmol) were
dissolved in ACN (20 mL) and the reaction mixture was stirred
overnight. The volatiles were removed under reduced pressure and
the residue was purified on silica using a heptane to EtOAc
gradient yielding methyl
3-bromo-4-[[1-[(6-chloro-3-pyridyl)methyl]-2-hydroxy-1-methyl-ethyl]sulfa-
moyl]-1-methyl-pyrrole-2-carboxylate (777 mg) as a white
powder.
[0895] Methyl
3-bromo-4-[[1-[(6-chloro-3-pyridyl)methyl]-2-hydroxy-1-methyl-ethyl]sulfa-
moyl]-1-methyl-pyrrole-2-carboxylate (777 mg, 1.62 mmol) and
3,4-difluoroaniline (162 .mu.L, 1.29 g/mL, 1.62 mmol) were
dissolved in THF (5 mL). Lithium bis(trimethylsilyl)amide (1M in
THF) (8 mL, 1 M in THF, 8 mmol) was added and the reaction mixture
was stirred overnight at room temperature. The reaction mixture was
quenched with NH.sub.4Cl (sat., aq., 10 mL) and the organic layer
was removed. The aqueous layer was extracted with DCM (2.times.5
mL) and the combined organic layers were filtered and evaporated to
dryness yielding crude
3-bromo-4-[[1-[(6-chloro-3-pyridyl)methyl]-2-hydroxy-1-methyl-ethyl]sulfa-
moyl]-N-(3,4-difluorophenyl)-1-methyl-pyrrole-2-carboxamide (833
mg).
[0896]
3-bromo-4-[[1-[(6-chloro-3-pyridyl)methyl]-2-hydroxy-1-methyl-ethyl-
]sulfamoyl]-N-(3,4-difluorophenyl)-1-methyl-pyrrole-2-carboxamide
(833 mg, 1.44 mmol) was dissolved in ACN (15 mL). 2-iodoxybenzoic
acid (606 mg, 2.16 mmol) was added and the reaction mixture was
heated at 80.degree. C. for 90 minutes. The reaction mixture was
filtered while still hot, evaporated to dryness and the residue was
purified on silica using a heptane to EtOAc gradient yielding
3-bromo-4-[[1-[(6-chloro-3-pyridyl)methyl]-1-methyl-2-oxo-ethyl]sulfamoyl-
]-N-(3,4-difluorophenyl)-1-methyl-pyrrole-2-carboxamide (721 mg).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.07 (s, 3H),
2.96-3.04 (m, 2H), 3.74 (s, 3H), 7.41-7.49 (m, 3H), 7.67 (s, 1H),
7.72 (dd, J=8.1, 2.4 Hz, 1H), 7.80-7.88 (m, 1H), 8.24 (s, 1H), 8.27
(d, J=2.2 Hz, 1H), 9.57 (s, 1H), 10.60 (s, 1H).
[0897] KOtBu (73.1 mg, 0.65 mmol) was added to a stirred suspension
of methyltriphenylphosphonium bromide (233 mg, 0.65 mmol) in THF (5
mL) at 0.degree. C. The suspension was stirred at 0.degree. C. for
10 min and then at room temperature for 1 hour.
3-bromo-4-[[1-[(6-chloro-3-pyridyl)methyl]-1-methyl-2-oxo-ethyl]sulfamoyl-
]-N-(3,4-difluorophenyl)-1-methyl-pyrrole-2-carboxamide (150 mg,
0.26 mmol) in THF (5 mL) was added dropwise to this solution at
0.degree. C. The reaction mixture was allowed to warm to room
temperature and stirred overnight. LCMS showed product formed. The
volatiles were removed under reduced pressure and the residue was
purified on silica using a heptane to EtOAc gradient yielding
3-bromo-4-[[1-[(6-chloro-3-pyridyl)methyl]-1-methyl-allyl]sulfamoyl]-N-(3-
,4-difluorophenyl)-1-methyl-pyrrole-2-carboxamide (118 mg) as a
white powder.
[0898]
3-bromo-4-[[1-[(6-chloro-3-pyridyl)methyl]-1-methyl-allyl]sulfamoyl-
]-N-(3,4-difluorophenyl)-1-methyl-pyrrole-2-carboxamide (118 mg,
0.21 mmol), bis(tri-tert-butylphosphine)palladium(0) (5 mg, 0.01
mmol) and Hunig's base (39 .mu.L, 0.75 g/mL, 0.23 mmol) were
dissolved in DMF (1 mL) and heated in the microwave at 150.degree.
C. for 5 minutes. Bis(tri-tert-butylphosphine)palladium(0) (5 mg,
0.01 mmol) was added and the reaction mixture was and heated in the
microwave at 150.degree. C. for 5 minutes. The reaction mixture was
directly loaded on a silica cartridge and a gradient from heptane
to EtOAc was applied yielding compound 219 (54 mg) after
crystallization from a DCM:DIPE mixture. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.13 (s, 3H), 2.83 (d, J=13.4 Hz, 1H),
3.42 (d, J=13.4 Hz, 1H), 3.70 (s, 3H), 5.61 (d, J=13.0 Hz, 1H),
6.40 (d, J=13.0 Hz, 1H), 7.40-7.55 (m, 4H), 7.61 (s, 1H), 7.80-7.88
(m, 2H), 8.36 (d, J=2.2 Hz, 1H), 10.70 (s, 1H); Method B; Rt: 1.06
min. m/z: 491 (M-H).sup.- Exact mass: 492.1.
Compound 220:
N-(3-cyano-4-fluoro-phenyl)-3,7-dimethyl-3-[(5-methylisoxazol-3-yl)methyl-
]-1,1-dioxo-2,4-dihydropyrrolo[3,4-b][1,4,5]oxathiazepine-6-carboxamide
##STR00274##
[0900] Compound 220 (124 mg) was prepared similarly as described
for compound 162, using 5-amino-2-fluoro-benzonitrile instead of
3,4-difluoroaniline. This was separated into its enantiomers via
preparative SFC (Stationary phase: Chiralpak Diacel AS 20.times.250
mm, Mobile phase: CO.sub.2, iPrOH+0.4 iPrNH.sub.2) yielding
compound 220a (28 mg), .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.22 (s, 3H), 2.40 (s, 3H), 2.88 (d, J=13.9 Hz, 1H), 3.05 (d,
J=13.9 Hz, 1H), 3.75-3.88 (m, 3H), 4.42 (d, J=13.2 Hz, 1H), 4.62
(d, J=13.0 Hz, 1H), 6.22 (s, 1H), 7.49-7.56 (m, 2H), 7.93 (s, 1H),
8.02 (ddd, J=9.2, 4.8, 2.9 Hz, 1H), 8.16 (dd, J=5.7, 2.6 Hz, 1H),
9.47 (s, 1H); Method B; Rt: 1.01 min. m/z: 472 (M-H).sup.- Exact
mass: 473.1 and compound 2210 (21 mg), .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.23 (s, 3H), 2.40 (s, 3H), 2.88 (d,
J=13.9 Hz, 1H), 3.05 (d, J=13.9 Hz, 1H), 3.83 (s, 3H), 4.42 (d,
J=13.0 Hz, 1H), 4.62 (d, J=13.2 Hz, 1H), 6.22 (d, J=0.9 Hz, 1H),
7.49-7.56 (m, 2H), 7.93 (s, 1H), 8.02 (ddd, J=9.2, 4.8, 2.9 Hz,
1H), 8.16 (dd, J=5.7, 2.6 Hz, 1H), 9.47 (s, 1H); Method B; Rt: 1.00
min. m/z: 472 (M-H).sup.- Exact mass: 473.1. Method AC; Rt: 220a:
4.96 min, 220b: 5.40 min.
Compound 221:
N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-3-(3-pyridylmethyl)-4,5-dih-
ydro-2H-pyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00275##
[0902] Compound 219 (48 mg, 0.097 mmol), Pd/C (10%) (5 mg, 0.005
mmol) and TEA (0.027 mL, 0.73 g/mL, 0.19 mmol) were dispensed in
MeOH (25 mL) and set under a hydrogen atmosphere for 2 hours. The
reaction mixture was filtered and evaporated to dryness. The
residue was purified on silica using a heptane to EtOAc gradient
yielding compound 221 (25 mg) as a white powder after
crystallisation from a DCM:DIPE mixture. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.02-1.09 (m, 5H), 2.64-2.68 (m, 1H),
3.00 (br s, 2H), 3.19-3.29 (m, 1H), 3.71 (s, 3H), 7.29 (s, 1H),
7.34 (t, J=6.2 Hz, 1H), 7.40-7.46 (m, 3H), 7.73 (br d, J=7.3 Hz,
1H), 7.80-7.91 (m, 1H), 8.44 (dd, J=4.7, 1.7 Hz, 1H), 8.51 (d,
J=1.5 Hz, 1H), 10.38 (s, 1H); Method B; Rt: 0.94 min. m/z: 459
(M-H).sup.- Exact mass: 460.1.
Compound 222:
3-(1-aminoethyl)-7-methyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)-2,3,4,5-tet-
rahydropyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00276##
[0904] To a suspension of compound 104 (740 mg, 1.42 mmol) in EtOAc
(200 mL) was added 2-iodoxybenzoic acid (477 mg, 1.70 mmol). The
suspension was heated at reflux for 2 hours. The reaction mixture
was filtered and the solids were washed with THF. The filtrate was
concentrated. To the residue in EtOAc (200 mL) was added
2-iodoxybenzoic acid (1.99 g, 7.09 mmol). The suspension was heated
at reflux for 20 hours. The reaction mixture was filtered and the
solids were washed with THF. The filtrate was concentrated in
vacuo. The residue was triturated in boiling DCM (20 mL) and the
white solid was filtered and washed with DCM (3 mL) yielding
(3R)-3-acetyl-7-methyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)-2,3,4,5-tetrah-
ydropyrrolo[3,4-f]thiazepine-6-carboxamide (350 mg). Method B; Rt:
0.93 min. m/z: 414 (M-H).sup.- Exact mass: 415.1.
[0905] To a stirred solution of
(3R)-3-acetyl-7-methyl-1,1-dioxo-N-(3,4,5-trifluorophenyl)-2,3,4,5-tetrah-
ydropyrrolo[3,4-f]thiazepine-6-carboxamide (150 mg, 0.36 mmol) in
dry MeOH (2 mL) and dry THF (2 mL), under nitrogen, was added zinc
chloride (0.071 mL, 1 M in diethylether, 0.071 mmol). After
stirring at ambient temperature for 30 minutes, this mixture was
treated with ammonium formate (274 mg, 4.30 mmol). After stirring
another hour at ambient temperature molecular sieves (1 g) were
added followed by sodium cyanoborohydride (47 mg, 0.71 mmol). The
reaction was then stirred at ambient temperature overnight. The
reaction mixture was filtered over decalite and the solids were
washed with 2-MeTHF (3.times.20 mL). The filtrate was washed with
water, Brine, dried (Na.sub.2SO.sub.4), filtered and concentrated.
The residue was purified using preparative HPLC (Stationary phase:
RP XBridge Prep C18 OBD-10 .mu.m, 50.times.150 mm, Mobile phase:
0.25% NH.sub.4HCO.sub.3 solution in water, ACN) yielding compound
222a (17 mg); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.99
(d, J=6.6 Hz, 3H), 1.30 (q, J=12.0 Hz, 1H), 2.01 (br dd, J=14.0,
6.7 Hz, 1H), 2.66-2.81 (m, 2H), 3.02 (br dd, J=15.1, 6.5 Hz, 1H),
3.16-3.25 (m, 1H), 3.69 (s, 3H), 7.44 (s, 1H), 7.55-7.64 (m, 2H),
10.07-11.08 (m, 1H); Method B; Rt: 0.75 min. m/z: 415 (M-H).sup.-
Exact mass: 416.1; MP: 227.5.degree. C. and compound 222b (43 mg);
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.97 (d, J=6.4 Hz,
3H), 1.35-1.46 (m, 1H), 1.87 (br s, 1H), 2.75-2.86 (m, 2H),
2.95-3.04 (m, 1H), 3.23-3.29 (m, 1H), 3.69 (s, 3H), 7.45 (s, 1H),
7.56-7.64 (m, 2H), 10.60 (br s, 1H); Method B; Rt: 0.76 min. m/z:
415 (M-H).sup.- Exact mass: 416.1; MP: 281.2.degree. C.
Compound 223:
3-[(2-chloro-4-pyridyl)methyl]-N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-di-
oxo-2H-pyrrolo[3,4-f]thiazepine-6-carboxamide
##STR00277##
[0907] 2-amino-3-(2-chloro-4-pyridyl)-2-methyl-propan-1-ol (an
intermediate used in the synthesis of compound 190) (1047 mg, 5.22
mmol), methyl
3-bromo-4-chlorosulfonyl-1-methyl-pyrrole-2-carboxylate (1.65 g,
5.22 mmol) and Hunig's base (2.7 mL, 0.75 g/mL, 15.7 mmol) were
dissolved in ACN (20 mL) and the reaction mixture was stirred
overnight. The volatiles were removed under reduced pressure and
the residue was purified on silica using a heptane to EtOAc
gradient yielding methyl
3-bromo-4-[[1-[(2-chloro-4-pyridyl)methyl]-2-hydroxy-1-methyl-ethyl]sulfa-
moyl]-1-methyl-pyrrole-2-carboxylate (880 mg) as a white
powder.
[0908] Methyl
3-bromo-4-[[1-[(2-chloro-4-pyridyl)methyl]-2-hydroxy-1-methyl-ethyl]sulfa-
moyl]-1-methyl-pyrrole-2-carboxylate (150 mg, 0.31 mmol) was
dissolved in ACN (15 mL). 2-iodoxybenzoic acid (131 mg, 0.47 mmol)
was added and the reaction mixture was heated at 80.degree. C. for
90 minutes. The reaction mixture was filtered while still hot,
evaporated to dryness and the residue was purified on silica using
a heptane to EtOAc gradient yielding methyl
3-bromo-4-[[1-[(2-chloro-4-pyridyl)methyl]-1-methyl-2-oxo-ethyl]su-
lfamoyl]-1-methyl-pyrrole-2-carboxylate (107 mg).
[0909] KOtBu (251 mg, 2.23 mmol) was added to a stirred suspension
of methyltriphenylphosphonium bromide (798 mg, 2.23 mmol) in THF
(10 mL) at 0.degree. C. The suspension was stirred at 0.degree. C.
for 10 min and then at room temperature for 1 hour. methyl
3-bromo-4-[[1-[(2-chloro-4-pyridyl)methyl]-1-methyl-2-oxo-ethyl]sulfamoyl-
]-1-methyl-pyrrole-2-carboxylate (107 mg, 0.22 mmol) in THF (5 mL)
was added dropwise to this solution at 0.degree. C. The reaction
mixture was allowed to warm to room temperature and stirred
overnight. The volatiles were removed under reduced pressure and
the residue was purified on silica using a heptane to EtOAc
gradient yielding methyl
3-bromo-4-[[1-[(2-chloro-4-pyridyl)methyl]-1-methyl-allyl]sulfamoyl]-1-me-
thyl-pyrrole-2-carboxylate (78 mg).
[0910] Methyl
3-bromo-4-[[1-[(2-chloro-4-pyridyl)methyl]-1-methyl-allyl]sulfamoyl]-1-me-
thyl-pyrrole-2-carboxylate (78 mg, 0.16 mmol),
bis(tri-tert-butylphosphine)palladium(0) (4 mg, 0.008 mmol) and
Hunig's base (0.031 mL, 0.75 g/mL, 0.18 mmol) were dissolved in DMF
(3 mL) and heated in the microwave at 150.degree. C. for 10
minutes. The reaction mixture was directly loaded on a silica
cartridge and a gradient from heptane to EtOAc was applied yielding
methyl
3-[(2-chloro-4-pyridyl)methyl]-3,7-dimethyl-1,1-dioxo-2H-pyrrolo[3,4-f]th-
iazepine-6-carboxylate (51 mg).
[0911] Methyl
3-[(2-chloro-4-pyridyl)methyl]-3,7-dimethyl-1,1-dioxo-2H-pyrrolo[3,4-f]th-
iazepine-6-carboxylate (51 mg, 0.13 mmol) and 3,4-difluoroaniline
(0.014 mL, 1.29 g/mL, 0.14 mmol) were dissolved in THF (5 mL).
Lithium bis(trimethylsilyl)amide (0.64 mL, 1 M in THF, 0.64 mmol)
was added and the reaction mixture was stirred overnight at room
temperature. The reaction mixture was quenched with NH.sub.4Cl
(sat., aq., 10 mL) and the organic layer was removed. The aqueous
layer was extracted with DCM (2.times.5 mL) and the combined
organic layers were filtered and evaporated to dryness. The residue
was purified via preparative HPLC (Stationary phase: RP)(Bridge
Prep C18 OBD-10 .mu.m, 30.times.150 mm, Mobile phase: 0.25%
NH.sub.4HCO.sub.3 solution in water, ACN) yielding compound 223 (11
mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.15 (s, 3H),
2.84 (d, J=12.8 Hz, 1H), 3.46 (d, J=12.8 Hz, 1H), 3.71 (s, 3H),
5.59 (d, J=13.0 Hz, 1H), 6.43 (br d, J=13.9 Hz, 1H), 7.38-7.51 (m,
5H), 7.66 (br s, 1H), 7.81-7.88 (m, 1H), 8.35 (d, J=4.8 Hz, 1H),
10.72 (br s, 1H); Method B; Rt: 1.02 min. m/z: 491 (M-H).sup.-
Exact mass: 492.1
Compound 224:
N-(3,4-difluorophenyl)-3-methyl-1,1-dioxo-2,3-dihydrothieno[3,4-f]thiazep-
ine-6-carboxamide
##STR00278##
[0913] Methyl 3-bromothiophene-2-carboxylate (5 g, 22.6 mmol) was
added portion wise to chlorosulfonic acid (7.6 mL, 1.73 g/mL, 113
mmol) at 0.degree. C. The reaction mixture was allowed to warm to
room temperature and was heated at 120.degree. C. for 3 hours. The
resulting mixture was added dropwise to a stirred ice-water mixture
(250 mL) keeping the temperature below 5.degree. C. The precipitate
was filtered and dissolved in 2-MeTHF, dried (MgSO.sub.4), filtered
and concentrated in vacuo to yield
3-bromo-4-chlorosulfonyl-thiophene-2-carboxylic acid (6.9 g) as a
brown oil.
[0914] Oxalyl chloride (10 mL) was added to
3-bromo-4-chlorosulfonyl-thiophene-2-carboxylic acid (6.9 g, 22.582
mmol), DMF (87 .mu.L, 0.944 g/mL, 1.13 mmol) in DCM (350 mL) and
stirred overnight. The reaction mixture was concentrated yielding
3-bromo-4-chlorosulfonyl-thiophene-2-carbonyl chloride (7.5 g) as a
yellow resin which was used as such.
[0915] 3-bromo-4-chlorosulfonyl-thiophene-2-carbonyl chloride (7.5
g, 23.1 mmol) was dissolved in toluene (180 mL). The mixture was
brought to reflux and 3,4-difluoroaniline (2.34 mL, 1.29 g/mL, 23.1
mmol) was added. The mixture was heated at reflux for 45 minutes.
The mixture was cooled and concentrated in vacuo. The residue was
purified by column chromatography using a gradient from 0 till 100%
EtOAc in heptane yielding
4-bromo-5-[(3,4-difluorophenyl)carbamoyl]thiophene-3-sulfonyl
chloride (5.7 g).
[0916] 3-buten-2-amine hydrochloride (762 mg, 7.08 mmol) was added
to ACN (20 mL) and the mixture was cooled on an ice bath. DIPEA
(3.66 mL, 0.75 g/mL, 21.2 mmol) was added and the mixture was
stirred until a clear solution was obtained.
4-bromo-5-[(3,4-difluorophenyl)carbamoyl]thiophene-3-sulfonyl
chloride (2.95 g, 7.08 mmol) was added and the mixture was stirred
at room temperature for 16 hours. The mixture was concentrated in
vacuo and the residue was partioned between water and DCM. The
organic layer was separated, dried (MgSO.sub.4), filtered and
concentrated in vacuo. The residue was recrystallized from ACN and
the precipitate was filtered off to yield
3-bromo-N-(3,4-difluorophenyl)-4-(1-methylallylsulfamoyl)thiophe-
ne-2-carboxamide (800 mg). Method B; Rt: 1.04 min. m/z: 451
(M+H).sup.+ Exact mass: 450.0.
[0917] A microwave vial was charged with
3-bromo-N-(3,4-difluorophenyl)-4-(1-methylallylsulfamoyl)thiophene-2-carb-
oxamide (200 mg, 0.443 mmol), Hunig's base (0.084 mL, 0.75 g/mL,
0.49 mmol) and DMF (5 mL) and purged with N.sub.2 for 5 minutes.
Bis(tri-tert-butylphosphine)palladium(0) (11 mg, 0.022 mmol) was
added and the vial was capped. The mixture was irradiated for 10
minutes at 150.degree. C. The mixture was concentrated in vacuo and
the residue was purified via preparative HPLC (Stationary phase:
RP)(Bridge Prep C18 OBD-10 .mu.m, 50.times.150 mm, Mobile phase:
0.25% NH.sub.4HCO.sub.3 solution in water, MeOH) yielding compound
224 (65 mg) as a white solid after crystallization from ACN.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.33 (d, J=7.3 Hz,
3H), 4.31 (br s, 1H), 5.79 (dd, J=13.1, 2.3 Hz, 1H), 6.82 (dd,
J=13.1, 2.3 Hz, 1H), 7.43-7.44 (m, 1H), 7.44-7.46 (m, 1H),
7.79-7.84 (m, 1H), 8.07-8.11 (m, 1H), 8.30 (s, 1H), 10.76 (br s,
1H); Method B; Rt: 0.96 min. m/z: 369 (M-H).sup.- Exact mass:
370.0; MP: 220.8.degree. C.
Compound 225:
N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-3,4-dihydro-2H-thieno[2,3-b-
][1,4,5]oxathiazepine-6-carboxamide
##STR00279##
[0919] Chlorosulfonic acid (1 mL, 1.73 g/mL, 16.109 mmol) was added
to chloroform (15 mL) and cooled on an ice bath. Ethyl
4-hydroxy-2-methylthiophene-3-carboxylate (1 g, 5.37 mmol)
dissolved in chloroform (5 mL) was added dropwise to the cooled
solution. The mixture was allowed to rise to r.t. and was stirred
at r.t. for 1 hour. The mixture was poured out in ice water and the
organic layer was separated. The organic layer was dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue was
purified by column chromatography using a gradient from 0 till 100%
EtOAc in heptane to yield ethyl
5-chlorosulfonyl-4-hydroxy-2-methyl-thiophene-3-carboxylate (523
mg).
[0920] 2-[(4-methoxyphenyl)methylamino]propan-1-ol (286 mg, 1.46
mmol) and Hunig's base (0.757 mL, 0.75 g/mL, 4.39 mmol) was
dissolved in ACN (7 mL). Ethyl
5-chlorosulfonyl-4-hydroxy-2-methyl-thiophene-3-carboxylate (417
mg, 1.46 mmol) was added and the mixture was stirred at room
temperature for 16 hours. The mixture was concentrated in vacuo and
the residue was purified by column chromatography using a gradient
from 0 till 100% EtOAc in heptane yielding ethyl
4-hydroxy-5-[(2-hydroxy-1-methyl-ethyl)-[(4-methoxyphenyl)methyl]sulfamoy-
l]-2-methyl-thiophene-3-carboxylate (359 mg). Method B; Rt: 1.20
min. m/z: 442 (M-H).sup.- Exact mass: 443.1.
[0921] Ethyl
4-hydroxy-5-[(2-hydroxy-1-methyl-ethyl)-[(4-methoxyphenyl)methyl]sulfamoy-
l]-2-methyl-thiophene-3-carboxylate (359 mg, 0.81 mmol) was
dissolved in dry THF (8 mL). Triphenylphosphine (234 mg, 0.89 mmol)
and di-tert-butyl azodicarboxylate (205 mg, 0.89 mmol) were added
at room temperature. The mixture was stirred for 30 minutes and
then concentrated in vacuo. The residue was purified by column
chromatography using a gradient from 0 till 100% EtOAc in heptane
to yield ethyl
2-[(4-methoxyphenyl)methyl]-3,7-dimethyl-1,1-dioxo-3,4-dihydrothieno[3,2--
b][1,4,5]oxathiazepine-6-carboxylate (275 mg).
[0922] Ethyl
2-[(4-methoxyphenyl)methyl]-3,7-dimethyl-1,1-dioxo-3,4-dihydrothieno[3,2--
b][1,4,5]oxathiazepine-6-carboxylate (275 mg, 0.65 mmol) and
3,4-difluoroaniline (0.078 mL, 1.29 g/mL, 0.78 mmol) was dissolved
in THF (5 mL). Lithium bis(trimethylsilyl)amide (1.9 mL, 1 M in
THF, 1.9 mmol) was added dropwise and the mixture was stirred at
room temperature for 2 hours. The mixture was quenched with
NH.sub.4Cl (aq., sat.). The mixture was diluted with 2-MeTHF and
the organic layer was separated, dried (MgSO.sub.4), filtered and
concentrated in vacuo. The product was purified by column
chromatography using a gradient from 0 till 50% EtOAc in heptane
yielding
N-(3,4-difluorophenyl)-2-[(4-methoxyphenyl)methyl]-3,7-dimethyl-1,1-dioxo-
-3,4-dihydrothieno[3,2-b][1,4,5]oxathiazepine-6-carboxamide (232
mg).
[0923]
N-(3,4-difluorophenyl)-2-[(4-methoxyphenyl)methyl]-3,7-dimethyl-1,1-
-dioxo-3,4-dihydrothieno [3,2-b][1,4,5]oxathiazepine-6-carboxamide
(116 mg, 0.23 mmol) was dissolved in dry DCM (3 mL) and TFA (3 mL,
1.49 g/mL, 39 mmol) was added under N.sub.2. The mixture was
stirred at room temperature for 16 hours. The mixture was
concentrated in vacuo and the residue was purified by column
chromatography using a gradient from 0 till 50% EtOAc in heptane
yielding compound 225 (63 mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.19 (d, J=7.0 Hz, 3H), 2.50 (s, 3H), 3.79 (q, J=7.5
Hz, 1H), 4.05 (dd, J=12.8, 8.3 Hz, 1H), 4.50 (dd, J=12.8, 2.6 Hz,
1H), 7.33-7.44 (m, 2H), 7.77-7.85 (m, 1H), 8.02 (d, J=8.2 Hz, 1H),
10.18 (s, 1H); Method D; Rt: 1.90 min. m/z: 387 (M-H).sup.- Exact
mass: 388.0. MP: 221.5.degree. C.
Compound 226:
N-(3,4-difluorophenyl)-3,7-dimethyl-1,1-dioxo-2,3-dihydropyrazolo[4,3-f]t-
hiazepine-6-carboxamide
##STR00280##
[0925] Methyl 5-amino-2-methyl-pyrazole-3-carboxylate (2.00 g, 12.9
mmol) was dissolved in THF (50 mL) and N-bromosuccinimide (2.52 g,
14.2 mmol) was added and stirred for 2 hours. The solution was
concentrated in vacuo, redissolved in DCM and washed with water.
The combined organics are evaporated till dryness and the crude
purified on silica using DCM/MeOH 100/0 to 90/10. The obtained
crude was redissolved in DIPE, and the remaining salts removed by
filtration. The filtrate was then concentrated in vacuo to yield
methyl 5-amino-4-bromo-2-methyl-pyrazole-3-carboxylate (2.0 g) as a
light orange solid.
[0926] To a cooled (0.degree. C.) solution of water (3.5 mL) was
added SOCl.sub.2 (0.642 mL, 1.64 g/mL, 8.84 mmol) and allowed to
warm to room temperature and stirred for 1 h. Then cuprous chloride
(19 mg, 0.20 mmol) was added and the solution cooled to -5.degree.
C.
[0927] In another solution of HCl (1.97 mL, 37% in H.sub.2O, 1.18
g/mL, 23.6 mmol) was added methyl
5-amino-4-bromo-2-methyl-pyrazole-3-carboxylate (500 mg, 1.97 mmol)
and cooled to -5.degree. C. before a solution of sodium nitrite
(149 mg, 2.16 mmol) in water (1 mL) was added to it. This solution
was then added to the first solution dropwise and cooling was
maintained at -5.degree. C. The solution was then allowed to warm
to 0.degree. C. and stirring was continued at this temperature for
2 hours, before it was allowed to warm to room temperature. EtOac
(20 mL) was added and the organic layer was concentrated in vacuo.
The residue was purified on silica using a heptane to EtOAc
gradient yielding methyl
4-bromo-5-chlorosulfonyl-2-methyl-pyrazole-3-carboxylate (544
mg).
[0928] Methyl
4-bromo-5-chlorosulfonyl-2-methyl-pyrazole-3-carboxylate (383 mg,
1.04 mmol) was dissolved in ACN (5 mL, 0.786 g/mL, 104 mmol). DIPEA
(0.715 mL, 0.75 g/mL, 4.15 mmol) and but-3-en-2-amine hydrochloride
(223 mg, 2.08 mmol) were added and the reaction mixture was stirred
5 hours. The solution was then concentrated in vacuo and directly
purified on silica using heptane/EtOAc 100 to 50/50 to yield methyl
4-bromo-2-methyl-5-(1-methylallylsulfamoyl)pyrazole-3-carboxylate
(98 mg).
[0929] Methyl
4-bromo-2-methyl-5-(1-methylallylsulfamoyl)pyrazole-3-carboxylate
(98 mg, 0.278 mmol) was dissolved in THF (5 mL) and
3,4-difluoroaniline (0.030 mL, 1.302 g/mL, 0.31 mmol) and LiHMDS
(0.835 mL, 1 M in THF, 0.84 mmol) was added at room temperature.
After 2 hours the solution was diluted with EtOAc and washed with
water. The combined organic layers were dried with MgSO.sub.4,
filtered, concentrated in vacuo and purified on silica using
heptane/EtOAc 100/0 to 50/50 yielding
4-bromo-N-(3,4-difluorophenyl)-2-methyl-5-(1-methylallylsulfamoyl)pyrazol-
e-3-carboxamide (70 mg).
[0930] To a solution of
4-bromo-N-(3,4-difluorophenyl)-2-methyl-5-(1-methylallylsulfamoyl)pyrazol-
e-3-carboxamide (70 mg, 0.16 mmol) in DMF (2 mL) was added Hunig's
base (0.054 mL, 0.75 g/mL, 0.31 mmol) and flushed under nitrogen.
The mixture was first heated to 100.degree. C. before
bis(tri-tert-butylphosphine)palladium(0) (8 mg, 0.016 mmol) was
added and the solution was then heated to 150.degree. C. for 5
minutes in the microwave. The reaction mixture was directly
purified on preparative HPLC (Stationary phase: RP XBridge Prep C18
ODB-5 .mu.m, 30.times.250 mm, Mobile phase: 0.25% NH.sub.4HCO.sub.3
solution in water, ACN) yielding compound 226 (26 mg). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.36 (d, J=7.3 Hz, 3H) 3.97 (s,
3H) 4.20-4.29 (m, 1H) 5.75 (dd, J=12.2, 2.5 Hz, 1H) 6.40 (dd,
J=12.1, 2.6 Hz, 1H) 7.41-7.50 (m, 2H) 8.02 (br s, 1H) 7.81-7.90 (m,
1H) 11.14 (br s, 1H); Method B; Rt: 0.90 min. m/z: 367 (M-H).sup.-
Exact mass: 368.1.
[0931] The following compounds were also synthesized according to
the procedures described above:
##STR00281## ##STR00282## ##STR00283## ##STR00284##
Biological Examples--Anti-HBV Activity of Compounds of Formula
(A)
[0932] The anti HBV activity was measured using the HepG2.117 cell
line, a stable, inducibly HBV producing cell line, which replicates
HBV in the absence of doxicycline (Tet-off system). For the
antiviral assay, HBV replication was induced, followed by a
treatment with serially diluted compound in 96-well plates in
duplicate. After 3 days of treatment, the antiviral activity was
determined by quantification of intracellular HBV DNA using
realtime PCR and an HBV specific primer set and probe.
[0933] Cytotoxicity of the compounds was tested using HepG2 cells,
incubated for 4 days in the presence of compounds. The viability of
the cells was assessed using a Resazurin assay. Results are
displayed in Table 1.
TABLE-US-00003 TABLE 1 anti HBV activity and cytotoxicity HBV-AVE-
TOX-HepG2- Compound HepG2.117 4d # EC50 (.mu.M) CC50 (.mu.M) 1 2.74
>25 2a 0.28 >25 2b 0.49 >25 3 >0.5 >25 4 1.09 >25
5 0.18 >25 6 3.98 >25 7a 0.13 >25 7b 0.007 >25 8 0.047
>25 9 0.036 >25 10a 0.22 >25 10b 0.006 >25 11 0.077
>25 12 0.35 >25 13 0.11 >25 14a 0.25 >25 14b 0.078
>25 15a 0.078 >25 15b >0.5 >25 16 0.23 >25 17
<0.098 >25 18 0.71 >25 19 0.19 >25 20 0.058 >25 21
0.15 >25 22 0.009 >25 23 0.005 10.62 24 0.068 >25 25 0.022
>25 26 0.027 >25 27 0.11 >25 28 0.89 >25 29 0.005
>25 30 0.013 >25 31 0.009 >25 32 0.003 >25 33 0.053
>25 34 0.056 >25 35 0.012 >25 36 0.005 >25 37 0.20
>25 38 0.005 >25 39 0.003 >25 40 0.022 >25 41 0.008
>25 42 0.081 >25 43 0.056 >25 44 0.17 >25 45 0.23
>25 46 0.33 >25 47 0.017 >25 48 0.084 >25 49 0.31
>25 50 0.002 >25 51 <0.002 >25 52 0.056 >25 53 0.19
>25 54 0.004 >25 55 0.003 >25 56 0.010 >25 57 0.013
>25 58 0.29 >25 59 0.24 >25 59a >0.5 >25 59b 0.14
>25 60 0.013 >25 60a 0.055 >25 60b 0.005 >25 61 0.074
>25 62 0.009 >25 63 0.24 >25 64 0.008 >25 65 0.007
>25 66 0.047 >25 67 0.069 >25 68 0.23 >25 69 0.033
>25 70 0.014 >25 71 0.003 >25 72 0.050 >25 73 0.48
>25 74 0.052 >25 75 0.007 >25 76 0.22 >25 77 0.23
>25 78 0.056 >25 79a 0.043 >25 79b 0.002 >25 80 0.018
>25 81 0.002 >25 82 0.004 >25 83 0.058 >25 84 0.010
>25 85 0.007 >25 86 0.005 >25 87 0.018 >25 88 0.011
>25 89a 0.19 >25 89b 0.017 >25 90 0.019 >25 91 0.13
>25 92a 0.031 >24 92b 0.17 >25 93 0.012 >25 94 0.080
>25 95 0.022 >25 96 0.005 >25 97 0.055 >25 98 0.008
>25 99 0.004 >25 100 0.003 >25 101 0.014 >25 102 0.009
>25 103 0.006 >25 104 0.007 >25 105a 0.007 >25 105b
0.011 >25 106 0.008 >25 107 0.080 >25 108 0.016 >25 109
0.003 >25 110 0.20 >25 111 0.089 >25 112 0.003 >25 113
0.12 >25 114a 0.022 >25 114b 0.008 >25 115a 0.008 >25
115b 0.007 >25 116a 0.022 >25 116b >0.35 >25 117 0.010
>25 118 0.013 >25 119a 0.011 >25 119b 0.006 >25 120a
0.007 >25 120b 0.011 >25 121 0.029 >25 122a 0.012 >25
122b 0.009 >25 123 0.019 >25 124a 0.005 >25 124b 0.004
>25 125 0.007 >25 126 0.062 >25 127 0.013 >25 128 0.024
>25 129 0.012 >25 130a 0.018 >25 130b 0.012 >25 131
0.023 >25 132 0.019 >25 133 0.011 >25 134a 0.008 >25
134b 0.007 >25 135 0.005 >25 136 0.016 >25 137 0.006
>25 138 0.029 >25 139 0.016 >25 140 0.062 >25 141a
0.030 >25 141b NA >25 142a 0.065 >25 142b >0.125 >25
143 0.024 >25 144a 0.019 >25 144b 0.063 >25 145 0.037
>25 145a 0.014 >25 145b 0.06 >25 146 0.055 >25 147
0.013 >25 148 0.077 >25 149a >0.125 >25 149b 0.010
>25 150a >0.125 >25 150b 0.005 >25 151 0.076 >25 152
0.014 >25 153 0.068 >25 153a >0.125 >25 153b 0.060
>25 154 0.008 >25 155 0.025 >25 156 0.009 >25 157 0.017
>25 158 0.031 >25 159 0.014 >25 160 0.0145 >25 160a
0.077 >25 160b 0.021 >25 161a 0.049 >25 161b >0.125
>25 161c 0.011 >25 161d 0.011 >25 162 0.003 >25 162a
0.033 >25 162b 0.011 >25 163 >0.125 >25 164 0.012
>25 165 0.068 >25 166 0.056 >25 167 0.041 >25 168 0.025
>25 168a >0.125 >25 168b 0.015 >25 169 0.017 >25
170a NA >25 170b 0.007 >25 171 0.008 >25 172 0.074 >25
172a 0.072 >25 172b 0.064 >25 173 0.017 >25 174 0.007
>25 175 0.004 >25 175a 0.021 >22.9 175b 0.003 >25 176
0.004 >25 176a 0.012 >25 176b NA >25 177 0.008 >25 177a
NA >25 177b 0.004 >25 178 0.016 >25 179 0.021 >25 180
0.005 >25 181 0.008 >25 181a 0.035 >25 181b 0.006 >25
182 0.010 >25 183 0.002 >25 184 0.020 >25 185 0.041 >25
186 0.011 >25 187 0.003 >25 188 0.011 >25 189 0.11 >25
190 0.006 >25 191 0.010 >25 192 0.056 >25
192a 0.036 >25 192b 0.024 >25 193 0.006 >25 194 0.006
>25 195 0.007 >25 196 0.065 >25 197 0.011 >25 198 0.011
>25 199 0.015 >25 199a 0.030 >25 199b 0.008 >25 200
0.084 >25 201 0.11 >25 202 0.025 >25 203a 0.094 >25
203b 0.059 >25 204a >0.125 >25 204b >0.125 >25 205
0.050 >25 206a 0.013 >25 206b 0.012 >25 207a 0.008 >25
207b 0.005 >25 208a 0.008 >25 208b 0.011 >25 209a 0.060
>25 209b 0.018 >25 210a 0.037 >25 210b 0.034 >25 211
0.007 >25 212 0.007 >25 213a 0.048 >25 213b 0.016 >25
214a 0.12 >25 214b 0.022 >25 215a 0.062 >25 215b >0.125
>25 216 0.034 >25 217a 0.025 >25 217b 0.10 >25 218a
>0.125 >25 218b 0.079 >25 218c 0.006 >25 218d 0.021
>25 219 NA >25 220a 0.007 >25 220b 0.034 >25 228
>0.5 >25 229 >0.5 >25 230 >0.5 >25 231 >0.5
>25 232 >0.5 >25 233 >0.5 >25 234 >0.5 >25 235
>0.5 >25 236 0.34 >25 237 >0.5 >25 238 0.077 >25
239 >0.5 >25 240 >0.25 >25 241 >0.25 >25 242
>0.13 >25 243 >0.5 >25 244 >0.5 >25 245 >25
>25 246 >0.13 >25 247 >0.13 >25
* * * * *