U.S. patent application number 17/161186 was filed with the patent office on 2022-03-24 for 7-substituted 1-aryl-naphthyridine-3-carboxylic acid amides and use thereof.
This patent application is currently assigned to Bayer Aktiengesellschaft. The applicant listed for this patent is Bayer Aktiengesellschaft, Bayer Pharma Aktiengesellschaft. Invention is credited to Melissa BOULTADAKIS ARAPINIS, Markus BRECHMANN, Till FREUDENBERGER, Maximillian Andreas KULLMANN, Tobias MARQUARDT, Thomas MONDRITZKI, Alexander STRAUB, Henrik TELLER, Hanna TINEL, Alexandros VAKALOPOULOS, Matthias Beat WITTWER.
Application Number | 20220089591 17/161186 |
Document ID | / |
Family ID | 1000005497322 |
Filed Date | 2022-03-24 |
United States Patent
Application |
20220089591 |
Kind Code |
A1 |
TELLER; Henrik ; et
al. |
March 24, 2022 |
7-SUBSTITUTED 1-ARYL-NAPHTHYRIDINE-3-CARBOXYLIC ACID AMIDES AND USE
THEREOF
Abstract
The present application relates to novel 7-substituted
1-arylnaphthyridine-3-carboxamides, to processes for their
preparation, to their use, alone or in combinations, for the
treatment and/or prevention of diseases, and to their use for the
production of medicaments for the treatment and/or prevention of
diseases, in particular for the treatment and/or prevention of
cardiovascular disorders and/or renal disorders.
Inventors: |
TELLER; Henrik; (Schwaan,
DE) ; VAKALOPOULOS; Alexandros; (Hilden, DE) ;
BOULTADAKIS ARAPINIS; Melissa; (Dusseldorf, DE) ;
STRAUB; Alexander; (Wuppertal, DE) ; TINEL;
Hanna; (Wuppertal, DE) ; BRECHMANN; Markus;
(San Francisco, CA) ; WITTWER; Matthias Beat;
(Riehen, CH) ; KULLMANN; Maximillian Andreas;
(Leichlingen, DE) ; FREUDENBERGER; Till; (Velbert,
DE) ; MONDRITZKI; Thomas; (Essen, DE) ;
MARQUARDT; Tobias; (Wuppertal, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bayer Aktiengesellschaft
Bayer Pharma Aktiengesellschaft |
Leverkusen
Berlin |
|
DE
DE |
|
|
Assignee: |
Bayer Aktiengesellschaft
Leverkusen
DE
Bayer Pharma Aktiengesellschaft
Berlin
DE
|
Family ID: |
1000005497322 |
Appl. No.: |
17/161186 |
Filed: |
January 28, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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16333079 |
Mar 13, 2019 |
10927109 |
|
|
PCT/EP2017/072339 |
Sep 6, 2017 |
|
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17161186 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 45/06 20130101;
C07D 491/107 20130101; A61K 31/551 20130101; A61P 9/00 20180101;
A61P 9/06 20180101; C07D 471/04 20130101; A61K 31/4375 20130101;
A61P 13/00 20180101; C07D 519/00 20130101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; A61P 9/06 20060101 A61P009/06; A61K 31/4375 20060101
A61K031/4375; A61K 31/551 20060101 A61K031/551; A61K 45/06 20060101
A61K045/06; C07D 491/107 20060101 C07D491/107; C07D 519/00 20060101
C07D519/00; A61P 9/00 20060101 A61P009/00; A61P 13/00 20060101
A61P013/00 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 14, 2016 |
EP |
16188728.6 |
Dec 6, 2016 |
EP |
16202509.2 |
Claims
1-11. (canceled)
12: A method of treatment of heart failure, coronary heart disease,
atrial and ventricular arrhythmia, renal failure and nephropathy,
comprising administering a compound of formula (I), ##STR00375##
wherein X is halogen, R.sup.1 is hydrogen, or is --NR.sup.4R.sup.5,
wherein R.sup.4 is hydrogen, methyl, (C.sub.2-C.sub.4)-alkyl or
(C.sub.3-C.sub.6)-cycloalkyl, wherein (C.sub.2-C.sub.4)-alkyl is
optionally substituted by hydroxyl or up to trisubstituted by
fluorine: and R.sup.5 is (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, 3- to 6-membered saturated
heterocyclyl or (C.sub.1-C.sub.4)-alkylsulfonyl, wherein
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl and 3- to
6-membered saturated heterocyclyl are optionally up to
trisubstituted, identically or differently, by methyl,
difluoromethyl, trifluoromethyl, hydroxyl, hydroxycarbonyl, oxo,
methoxy, difluoromethoxy, trifluoromethoxy or cyano, and
additionally up to tetrasubstituted by fluorine, or R.sup.4 and
R.sup.5 together with the nitrogen atom to which they are bonded
form a saturated or partially unsaturated, 3- to 6-membered
monocyclic or 6- to 10-membered bicyclic heterocycle which
optionally contains one or two further, identical or different
heteroatoms selected from the group consisting of N, O, S, SO and
SO.sub.2 as ring members, wherein the 3- to 6-membered monocyclic
and the 6- to 10-membered bicyclic heterocycle are optionally
substituted by 1 to 5 substituents independently selected from the
group consisting of (C.sub.1-C.sub.4)-alkyl, difluoromethyl,
trifluoromethyl, hydroxy, hydroxycarbonyl, oxo,
(C.sub.1-C.sub.3)-alkoxy, difluoromethoxy, trifluoromethoxy, cyano,
(C.sub.1-C.sub.3)-alkoxycarbonyl, aminocarbonyl,
mono-(C.sub.1-C.sub.3)-alkylaminocarbonyloxy,
--NHC(.dbd.O)R.sup.14A, --CH.sub.2NHC(.dbd.O)R.sup.14B, and
--OC(.dbd.O)R.sup.15, and additionally up to tetrasubstituted by
fluorine, wherein (C.sub.1-C.sub.4)-alkyl is optionally mono- or
disubstituted, identically or differently, by hydroxyl or
(C.sub.1-C.sub.3)-alkoxy, and up to tetrasubstituted by fluorine,
R.sup.14A and R.sup.14B are independently (C.sub.1-C.sub.3)-alkyl
or cyclopropyl, and wherein R.sup.15 is (C.sub.1-C.sub.4)-alkyl,
R.sup.2 is a group of the formula ##STR00376## wherein * marks the
point of attachment to the nitrogen atom of the amide moiety,
R.sup.6A is hydrogen or (C.sub.1-C.sub.4)-alkyl, R.sup.6B is
hydrogen, (C.sub.1-C.sub.4)-alkyl, cyclopropyl, monofluoromethyl,
difluoromethyl, trifluoromethyl, methoxymethyl or
trifluoromethoxymethyl, R.sup.7 is (C.sub.1-C.sub.6)-alkyl or
(C.sub.3-C.sub.5)-cycloalkyl which is up to tetrasubstituted by
fluorine, wherein (C.sub.1-C.sub.6)-alkyl is optionally substituted
by amino, hydroxy, or (C.sub.1-C.sub.6)alkoxy and up to
pentasubstituted by fluorine, wherein (C.sub.1-C.sub.6)-alkoxy is
optionally up to pentasubstituted by fluorine, L.sup.1 is a bond or
a group of the formula
--C(R.sup.8AR.sup.8)--(C(R.sup.9AR.sup.9B)).sub.m--, wherein m is 0
or 1, R.sup.8A is hydrogen or methyl, R.sup.8B is hydrogen, methyl,
trifluoromethyl, pentafluoroethyl or trifluoromethoxymethyl,
R.sup.9A and R.sup.9B are independently hydrogen or methyl,
Ar.sup.2 is phenyl, wherein phenyl is optionally mono- to
trisubstituted, identically or differently, by fluorine, chlorine,
(C.sub.1-C.sub.3)-alkyl, difluoromethoxymethyl,
trifluoromethoxymethyl or trifluoromethyl, or Ar.sup.2 is a 5- to
10-membered monocyclic, bicyclic or tricyclic carbocycle or
heterocycle which optionally contains one or two further identical
or different heteroatoms selected from the group consisting of N
and O as ring members, wherein the 5- to 10-membered monocyclic,
bicyclic or tricyclic carbocycle or heterocycle is optionally up to
trisubstituted by identical or different substituents from the
group consisting of (C.sub.1-C.sub.3)-alkyl, trifluoromethyl and
(C.sub.1-C.sub.4)alkoxycarbonyl and furthermore up to
tetrasubstituted by fluorine, Ar.sup.1 is a group of the formula
##STR00377## wherein *** marks the point of attachment to the
nitrogen atom, R.sup.3A is fluorine, chlorine, trifluoromethyl or
methyl, R.sup.3B is hydrogen or fluorine, and R.sup.3C is hydrogen,
fluorine, chlorine or methyl: or Ar.sup.1 is a pyridine ring which
is attached via a ring carbon atom, wherein the pyridine ring is
optionally mono- or disubstituted by fluorine, chlorine, cyano,
methyl or trifluoromethyl, or an N-oxide, a salt, a solvate, a salt
of the N-oxide, a solvate of the N-oxide, or a solvate of the salt
thereof.
13. (canceled)
14. (canceled)
15: A method for treatment of heart failure, coronary heart
disease, atrial and ventricular arrhythmia, renal failure and
nephropathy, comprising administering a pharmaceutical combination
comprising a compound of formula (I), ##STR00378## wherein X is
halogen, R.sup.1 is hydrogen, or is --NR.sup.4R.sup.5, wherein
R.sup.4 is hydrogen, methyl, (C.sub.2-C.sub.4)-alkyl or
(C.sub.3-C.sub.6)-cycloalkyl, wherein (C.sub.2-C.sub.4)-alkyl is
optionally substituted by hydroxyl or up to trisubstituted by
fluorine: and R.sup.5 is (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, 3- to 6-membered saturated
heterocyclyl or (C.sub.1-C.sub.4)-alkylsulfonyl, wherein
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl and 3- to
6-membered saturated heterocyclyl are optionally up to
trisubstituted, identically or differently, by methyl,
difluoromethyl, trifluoromethyl, hydroxyl, hydroxycarbonyl, oxo,
methoxy, difluoromethoxy, trifluoromethoxy or cyano, and
additionally up to tetrasubstituted by fluorine, or R.sup.4 and
R.sup.5 together with the nitrogen atom to which they are bonded
form a saturated or partially unsaturated, 3- to 6-membered
monocyclic or 6- to 10-membered bicyclic heterocycle which
optionally contains one or two further, identical or different
heteroatoms selected from the group consisting of N, O, S, SO and
SO.sub.2 as ring members, wherein the 3- to 6-membered monocyclic
and the 6- to 10-membered bicyclic heterocycle are optionally
substituted by 1 to 5 substituents independently selected from the
group consisting of (C.sub.1-C.sub.4)-alkyl, difluoromethyl,
trifluoromethyl, hydroxy, hydroxycarbonyl, oxo,
(C.sub.1-C.sub.3)-alkoxy, difluoromethoxy, trifluoromethoxy, cyano,
(C.sub.1-C.sub.3)-alkoxycarbonyl, aminocarbonyl,
mono-(C.sub.1-C.sub.3)-alkylaminocarbonyloxy,
--NHC(.dbd.O)R.sup.14A, --CH.sub.2NHC(.dbd.O)R.sup.14B, and
--OC(.dbd.O)R.sup.15, and additionally up to tetrasubstituted by
fluorine, wherein (C.sub.1-C.sub.4)-alkyl is optionally mono- or
disubstituted, identically or differently, by hydroxyl or
(C.sub.1-C.sub.3)-alkoxy, and up to tetrasubstituted by fluorine,
R.sup.14A and R.sup.14B are independently (C.sub.1-C.sub.3)-alkyl
or cyclopropyl, and wherein R.sup.15 is (C.sub.1-C.sub.4)-alkyl,
R.sup.2 is a group of the formula ##STR00379## wherein * marks the
point of attachment to the nitrogen atom of the amide moiety,
R.sup.6A is hydrogen or (C.sub.1-C.sub.4)-alkyl, R.sup.6B is
hydrogen, (C.sub.1-C.sub.4)-alkyl, cyclopropyl, monofluoromethyl,
difluoromethyl, trifluoromethyl, methoxymethyl or
trifluoromethoxymethyl, R.sup.7 is (C.sub.1-C.sub.6)-alkyl or
(C.sub.3-C.sub.5)-cycloalkyl which is up to tetrasubstituted by
fluorine, wherein (C.sub.1-C.sub.6)-alkyl is optionally substituted
by amino, hydroxy, or (C.sub.1-C.sub.6)alkoxy and up to
pentasubstituted by fluorine, wherein (C.sub.1-C.sub.6)-alkoxy is
optionally up to pentasubstituted by fluorine, L.sup.1 is a bond or
a group of the formula
--C(R.sup.8AR.sup.8B)--(C(R.sup.9AR.sup.9B)).sub.m--, wherein m is
0 or 1, R.sup.8A is hydrogen or methyl, R.sup.8B is hydrogen,
methyl, trifluoromethyl, pentafluoroethyl or
trifluoromethoxymethyl, R.sup.9A and R.sup.9B are independently
hydrogen or methyl, Ar.sup.2 is phenyl, wherein phenyl is
optionally mono- to trisubstituted, identically or differently, by
fluorine, chlorine, (C.sub.1-C.sub.3)-alkyl, difluoromethoxymethyl,
trifluoromethoxymethyl or trifluoromethyl, or Ar.sup.2 is a 5- to
10-membered monocyclic, bicyclic or tricyclic carbocycle or
heterocycle which optionally contains one or two further identical
or different heteroatoms selected from the group consisting of N
and O as ring members, wherein the 5- to 10-membered monocyclic,
bicyclic or tricyclic carbocycle or heterocycle is optionally up to
trisubstituted by identical or different substituents from the
group consisting of (C.sub.1-C.sub.3)-alkyl, trifluoromethyl and
(C.sub.1-C.sub.4)alkoxycarbonyl and furthermore up to
tetrasubstituted by fluorine, Ar.sup.1 is a group of the formula
##STR00380## wherein *** marks the point of attachment to the
nitrogen atom, R.sup.3A is fluorine, chlorine, trifluoromethyl or
methyl, R.sup.3B is hydrogen or fluorine, and R.sup.3C is hydrogen,
fluorine, chlorine or methyl: or Ar.sup.1 is a pyridine ring which
is attached via a ring carbon atom, wherein the pyridine ring is
optionally mono- or disubstituted by fluorine, chlorine, cyano,
methyl or trifluoromethyl, or an N-oxide, a salt, a solvate, a salt
of the N-oxide, a solvate of the N-oxide, or a solvate of the salt
thereof, in combination with one or more further active ingredients
selected from the group consisting of active hypotensive
ingredients, active antiarrhythmic ingredients, vasopressin
receptor antagonists, PDE 5 inhibitors, platelet aggregation
inhibitors, sGC activators and sGC stimulators.
16: A method of treatment of heart failure, coronary heart disease,
atrial and ventricular arrhythmia, renal failure and nephropathy,
comprising administering a pharmaceutical composition comprising a
compound of formula (I), ##STR00381## wherein X is halogen, R.sup.1
is hydrogen, or is --NR.sup.4R.sup.5, wherein R.sup.4 is hydrogen,
methyl, (C.sub.2-C.sub.4)-alkyl or (C.sub.3-C.sub.6)-cycloalkyl,
wherein (C.sub.2-C.sub.4)-alkyl is optionally substituted by
hydroxyl or up to trisubstituted by fluorine; and R.sup.5 is
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl, 3- to
6-membered saturated heterocyclyl or
(C.sub.1-C.sub.4)-alkylsulfonyl, wherein (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl and 3- to 6-membered saturated
heterocyclyl are optionally up to trisubstituted, identically or
differently, by methyl, difluoromethyl, trifluoromethyl, hydroxyl,
hydroxycarbonyl, oxo, methoxy, difluoromethoxy, trifluoromethoxy or
cyano, and additionally up to tetrasubstituted by fluorine, or
R.sup.4 and R.sup.5 together with the nitrogen atom to which they
are bonded form a saturated or partially unsaturated, 3- to
6-membered monocyclic or 6- to 10-membered bicyclic heterocycle
which optionally contains one or two further, identical or
different heteroatoms selected from the group consisting of N, O,
S, SO and SO.sub.2 as ring members, wherein the 3- to 6-membered
monocyclic and the 6- to 10-membered bicyclic heterocycle are
optionally substituted by 1 to 5 substituents independently
selected from the group consisting of (C.sub.1-C.sub.4)-alkyl,
difluoromethyl, trifluoromethyl, hydroxy, hydroxycarbonyl, oxo,
(C.sub.1-C.sub.3)-alkoxy, difluoromethoxy, trifluoromethoxy, cyano,
(C.sub.1-C.sub.3)-alkoxycarbonyl, aminocarbonyl,
mono-(C.sub.1-C.sub.3)-alkylaminocarbonyloxy,
--NHC(.dbd.O)R.sup.14A, --CH.sub.2NHC(.dbd.O)R.sup.14B, and
--OC(.dbd.O)R.sup.15, and additionally up to tetrasubstituted by
fluorine, wherein (C.sub.1-C.sub.4)-alkyl is optionally mono- or
disubstituted, identically or differently, by hydroxyl or
(C.sub.1-C.sub.3)-alkoxy, and up to tetrasubstituted by fluorine,
R.sup.14A and R.sup.14B are independently (C.sub.1-C.sub.3)-alkyl
or cyclopropyl, and wherein R.sup.15 is (C.sub.1-C.sub.4)-alkyl,
R.sup.2 is a group of the formula ##STR00382## wherein * marks the
point of attachment to the nitrogen atom of the amide moiety,
R.sup.6A is hydrogen or (C.sub.1-C.sub.4)-alkyl, R.sup.6B is
hydrogen, (C.sub.1-C.sub.4)-alkyl, cyclopropyl, monofluoromethyl,
difluoromethyl, trifluoromethyl, methoxymethyl or
trifluoromethoxymethyl, R.sup.7 is (C.sub.1-C.sub.6)-alkyl or
(C.sub.3-C.sub.5)-cycloalkyl which is up to tetrasubstituted by
fluorine, wherein (C.sub.1-C.sub.6)-alkyl is optionally substituted
by amino, hydroxy, or (C.sub.1-C.sub.6)alkoxy and up to
pentasubstituted by fluorine, wherein (C.sub.1-C.sub.6)-alkoxy is
optionally up to pentasubstituted by fluorine, L.sup.1 is a bond or
a group of the formula
--C(R.sup.8AR.sup.8B)--(C(R.sup.9AR.sup.9B)).sub.m--, wherein m is
0 or 1, R.sup.8A is hydrogen or methyl, R.sup.8B is hydrogen,
methyl, trifluoromethyl, pentafluoroethyl or
trifluoromethoxymethyl, R.sup.9A and R.sup.9B are independently
hydrogen or methyl, Ar.sup.2 is phenyl, wherein phenyl is
optionally mono- to trisubstituted, identically or differently, by
fluorine, chlorine, (C.sub.1-C.sub.3)-alkyl, difluoromethoxymethyl,
trifluoromethoxymethyl or trifluoromethyl, or Ar.sup.2 is a 5- to
10-membered monocyclic, bicyclic or tricyclic carbocycle or
heterocycle which optionally contains one or two further identical
or different heteroatoms selected from the group consisting of N
and O as ring members, wherein the 5- to 10-membered monocyclic,
bicyclic or tricyclic carbocycle or heterocycle is optionally up to
trisubstituted by identical or different substituents from the
group consisting of (C.sub.1-C.sub.3)-alkyl, trifluoromethyl and
(C.sub.1-C.sub.4)alkoxycarbonyl and furthermore up to
tetrasubstituted by fluorine, Ar.sup.1 is a group of the formula
##STR00383## wherein *** marks the point of attachment to the
nitrogen atom, R.sup.3A is fluorine, chlorine, trifluoromethyl or
methyl, R.sup.3B is hydrogen or fluorine, and R.sup.3C is hydrogen,
fluorine, chlorine or methyl; or Ar.sup.1 is a pyridine ring which
is attached via a ring carbon atom, wherein the pyridine ring is
optionally mono- or disubstituted by fluorine, chlorine, cyano,
methyl or trifluoromethyl, or an N-oxide, a salt, a solvate, a salt
of the N-oxide, a solvate of the N-oxide, or a solvate of the salt
thereof, in combination with an inert, non-toxic, pharmaceutically
suitable excipient.
17: The method of claim 12, wherein the compound of formula (I) is
##STR00384## or a salt thereof.
18: The method of claim 12, wherein the compound of formula (I) is
##STR00385## or a salt thereof.
19: The method of claim 12, wherein the compound of formula (I) is
##STR00386## or a salt thereof.
20: The method of claim 12, wherein the compound of formula (I) is
##STR00387## or a salt thereof.
21: The method of claim 12, wherein the compound of formula (I) is
##STR00388## or a salt thereof.
22: The method of claim 12, wherein the compound of formula (I) is
##STR00389## or a salt thereof.
23: The method of claim 12, wherein the compound of formula (I) is
##STR00390## or a salt thereof.
24: The method of claim 12, wherein the compound of formula
##STR00391## (I) is or a salt thereof.
25: The method of claim 12, wherein the compound of formula (I) is
##STR00392## or a salt thereof.
26: The method of claim 15, wherein the compound of formula (I) is
##STR00393## or a salt thereof.
27: The method of claim 15, wherein the compound of formula (I) is
##STR00394## or a salt thereof.
28: The method of claim 15, wherein the compound of formula (I) is
##STR00395## or a salt thereof.
29: The method of claim 15, wherein the compound of formula (I) is
##STR00396## or a salt thereof.
30: The method of claim 15, wherein the compound of formula (I) is
##STR00397## or a salt thereof.
31: The method of claim 15, wherein the compound of formula (I) is
##STR00398## or a salt thereof.
32: The method of claim 15, wherein the compound of formula (I) is
##STR00399## or a salt thereof.
33: The method of claim 15, wherein the compound of formula (I) is
##STR00400## or a salt thereof.
34: The method of claim 15, wherein the compound of formula (I) is
##STR00401## or a salt thereof.
35: The method of claim 16, wherein the compound of formula (I) is
##STR00402## or a salt thereof.
36: The method of claim 16, wherein the compound of formula (I) is
##STR00403## or a salt thereof.
37: The method of claim 16, wherein the compound of formula (I) is
##STR00404## or a salt thereof.
38: The method of claim 16, wherein the compound of formula (I) is
##STR00405## or a salt thereof.
39: The method of claim 16, wherein the compound of formula (I) is
##STR00406## or a salt thereof.
40: The method of claim 16, wherein the compound of formula (I) is
##STR00407## or a salt thereof.
41: The method of claim 16, wherein the compound of formula (I) is
##STR00408## or a salt thereof.
42: The method of claim 16, wherein the compound of formula (I) is
##STR00409## or a salt thereof.
43: The method of claim 16, wherein the compound of formula (I) is
##STR00410## or a salt thereof.
Description
[0001] The present application relates to novel 7-substituted
1-arylnaphthyridine-3-carboxamides, to processes for their
preparation, to their use, alone or in combinations, for the
treatment and/or prevention of diseases, and to their use for the
production of medicaments for the treatment and/or prevention of
diseases, in particular for the treatment and/or prevention of
cardiovascular disorders and/or renal disorders.
[0002] Muscarinergic receptors are receptors which are positioned
on the membrane and, as endogenous ligands, can bind the
acetylcholine (ACh) neurotransmitter (acetylcholine receptors), but
also be activated by muscarine. There are five subtypes of these G
protein-coupled receptors (M1-M5) which are expressed in almost all
kinds of tissue in the human organism. They are encountered both in
the central and in the peripheral nervous system, and in many
organs of the vegetative nervous system.
[0003] The M2 type (M2R) is expressed predominantly in the heart.
At the cellular level, M2R stimulation by the acetylcholine agonist
brings about inhibition of adenylcyclase and activation of the
inwardly rectifying potassium channel (IKACh channel, GIRK: G
protein activated inwardly rectifying K+ channel; also Kir3.x).
This increases potassium conductivity, which leads to
hyperpolarization of the muscle cells. Accordingly, the cells
become more difficult to depolarize, which leads to an adverse
chronotropic and dromotropic effect, and so the heart rate drops.
M2R is the main mediator of the parasympathetic control of heart
function, which is controlled by the vagus nerve. The right vagus
nerve reduces the heart rate via the sinus node; the left vagus
nerve predominantly increases the atrioventricular conduction time
via the atrioventricular node (AV node). Overall, the influence of
the vagus nerve on the resting heart rate is predominant compared
to the sympathetic nerve. The effects of stimulation of M2R are
thus opposed to those of beta-adrenergic stimulation.
[0004] The activation of the M2 receptor by the endogenous
acetylcholine agonist, but also by synthetic analogues such as
carbachol, oxotremorin-M or iperoxo (Schrage et al., Biochem.
Pharmacol. 2014, 90(3), 307-319), is effected by binding of the
agonist to what is called the orthosteric binding site of the
receptor and a resultant change in conformation of the receptor or
stabilization of the active receptor conformation. The conventional
naturally occurring muscarine receptor agonists include, as well as
the endogenous acetylcholine (ACh) agonist, various plant alkaloids
such as arecoline, muscarine, and also pilocarpine (Neubig et al.,
Pharmacol Rev., 2003, 55, 597-606). The orthosteric binding site of
all muscarinic acetylcholine receptors is highly evolutionarily
conserved and has a high sequence and structural homology between
the various subtypes. Therefore, many of the known agonists are
unselective with respect to the various subtypes of the muscarinic
acetylcholine receptors (Kruse et al., Mol Pharmacol., 2013, 84(4),
528-540). M2R has, as well as an orthosteric binding site, an
allosteric binding site as well (Gregory et al., Current
Neuropharmacol., 2007, 5(3), 157-167). The oldest known allosteric
modulator is gallamine (Clark and Mitchelson, Br. J. Pharmac.,
1976, 58, 323-331).
[0005] Allosteric modulators have distinct differences from
conventional orthosteric ligands. The allosteric modulator itself
has no direct influence on receptor activation. The allosteric
binding instead results in modulation of the binding affinity
and/or effectiveness of the orthosteric agonist. The effect of an
allosteric modulator can thus be displayed only in the presence of
the endogenous ligand. This results in specificity in terms of
space and time in the allosteric effect (Conn et al., Nat. Rev.
Drug Disc., 2009, 8, 41-54; Conn et al, Nat. Rev. Drug. Disc.,
2014, 13, 692-708). Furthermore, the effect of an allosteric
modulator is self-limiting when it stabilizes the binding of the
agonist in high concentrations. This in turn results, in principle,
in a more favourable pharmacological safety profile compared to
agonists, since toxic effects caused by receptor overactivation are
limited (Christopoulos, Mol. Pharmacol., 2014, 86, 463-478).
[0006] The mutual influencing of allosteric and orthosteric ligands
in terms of affinity and intrinsic activity, which is referred to
as cooperativity, is determined by both ligands. In the case of a
positive allosteric modulator of M2R, the effects of ACh
(orthosteric ligand) are enhanced (positive cooperativity). Because
of their ability to modulate receptor conformations in the presence
of an orthosteric ligand, allosteric ligands can bring about fine
adjustment of pharmacological effects (Wang et al., J. Pharmacol.
Exp. Therap., 2009, 331, 340-348). In the case of the positive
allosteric modulator of M2R, this suggests an advantageous effect
profile, a reduced risk of side effects and a starting point for
the development of more subtype-selective ligands compared to a
full agonist.
[0007] The crystal structure of the positive allosteric M4R and M2R
ligand LY2119620
(3-amino-5-chloro-N-cyclopropyl-4-methyl-6-[2-(4-methylpiperazi-
n-1-yl)-2-oxoethoxy]thieno[2,3-b]pyridine-2-carboxamide) in the
complex with M2R has been published. The allosteric binding site of
M2R is spatially adjacent to but clearly delimited from the
orthosteric binding site and, compared to the other muscarinic
receptor subtypes, exhibits lower conservation, i.e. has greater
differences in sequence (Kruse et al., Nature, 2013, 504, 101-106).
LY2119620 was described as an unselective M2R/M4R positive
allosteric modulator (Croy et al., Molecular Pharmacology, July
2014 86, 1, 106-115; Schober et al., Molecular Pharmacology, July
2014 86, 1, 116-123).
[0008] M2R as a constituent of the autonomic nervous system plays
an important role in the pathogenesis and progression of
cardiovascular disorders. Autonomic imbalance characterized by
vagal (parasympathetic) weakening and dominance of the sympathetic
nervous system is closely correlated to increased morbidity and
mortality. The clinical and prognostic significance of autonomic
imbalance is well documented in various cardiovascular disorders,
including heart failure (HF), heart rhythm disorders,
ischaemia/reperfusion (I/R), hypertension (He et al., Br. J.
Pharmacol. 2014, Epub) and chronic kidney disease (Ranpuria et al.,
Nephrol Dial Transplant. 2008, 23(2), 444-4499). Particularly in
the case of patients having comorbidities such as diabetes,
autonomic imbalance can contribute to increased morbidity and
mortality (Vinik et al., Diabet Med., 2011, 28(6), 643-651).
Baroreceptor reflex dysfunctions, such as hypertensive crises or
variability in high blood pressure, as signs of a dysfunctional
autonomic nervous system, often accompany the acute phase of
ischaemic or haemorrhagic stroke (Sykora et al., Stroke, 2009,
40(12), 678-682).
[0009] The frequent observation of comorbidity between
cardiovascular and psychological disorders, such as between heart
failure and depression, is probably based on common pathomechanisms
that accompany the autonomic imbalance (Halaris et al., Mod Trends
Pharmacopsychiatri., 2013, 28, 144-161). Chronic stress shifts the
homeostatic equilibrium of the autonomic nervous system. Reduced
vagal tone contributes to pro-inflammatory status, with impairment
of neurotransmitter regulation, especially serotonergic
transmission. Other psychological disorders have also been
connected to autonomic dysregulation, for example attention
deficit/hyperactivity disorder (ADHD), which is characterized by
loss of inhibition, lack of emotional self-control, inattentiveness
and hyperactivity (Rash and Aguirre-Camacho, Atten Defic Hyperact
Disord., 2012, 4(4), 167-177).
[0010] Boosting parasympathetic activity by means of a positive
allosteric modulator, including expected anti-inflammatory effects,
elevation of nitrogen monoxide (NO), regulation of redox state,
improvement of mitochondrial function and of calcium regulation,
could therefore constitute a novel therapeutic principle,
especially in the case of cardiovascular disorders. There are
numerous pointers that the modulation of parasympathetic activity
can be considered as a potential therapy target in the event of
chronic heart failure. Vagal nerve stimulation in dogs that have
recovered from myocardial infarction significantly lowered the
incidence of sudden cardiac death, and mortality in rats suffering
from chronic heart failure (De Ferrari, J. Cardiovasc. Transl.
Res., 2014, 7(3), 310-320). In a dog model with heart failure (LVEF
35%) and an implanted vagal stimulator, it was shown that, in the
treatment group compared to the sham group, a significant
improvement in the left-ventricular ejection fraction (LVEF) and
reduction in the end-systolic and -diastolic volumes (LVESV, LVEDV)
occurred, as did a significant reduction in heart rate within 3
months. The described effect of the VNS was additive to
beta-blocker administration (De Ferrari, J. Cardiovasc. Transl.
Res., 2014, 7(3), 310-320). The plasma level for TNF-.alpha. and
IL-6 and the myocardial protein expression thereof was lowered by
vagal stimulation in this animal model, which suggests that
boosting of the parasympathetic nervous system, as well as the
effects on LV remodelling, also has positive effects on
pro-inflammatory cytokines.
[0011] Based on experimental preclinical data, the first clinical
studies on vagal stimulation in patients having chronic heart
failure have now been done, as already established in the treatment
of epilepsy and depression. The effect of boosting the
parasympathetic system via direct vagal nerve stimulation (VNS) was
assessed in a non-randomized observation study with 32 patients
having left-ventricular (LV) systolic dysfunction, and the results
suggest that vagal stimulation has a favourable effect on quality
of life, stamina and LV remodelling (De Ferrari G M et al., Eur.
Heart J., 2011, 32, 847-855). In the multi-centre open-label
feasibility study ANTHEN-HF, the safety, compatibility and efficacy
of vagal stimulation in patients having chronic stable symptomatic
heart failure with reduced ejection fraction (HFrEF) were examined
in addition to the standard treatment (Premchand R K et al., J.
Card. Fail., 2014, 20(11), 808-816). The continuous vagal nerve
stimulation employed in this study led to an improvement in the
ejection fraction, variability of heart rate, NYHA class and
quality of life. The first placebo-controlled clinical study
NECTAR-HF, in contrast, did not show any significant effect of
vagal nerve stimulation on the heart function of HF patients after
6 months (Zannad et al., Eur. Heart J., 2015, 36(7), 425-433). The
only improvement was in quality of life. The INOVATE-HF study with
650 HF patients was unable to show any effects of this treatment in
relation to mortality and hospitalization. (Gold et al., J Am Coll
Cardiol., 2016, Mar. 29. pii: S0735-1097(16)32404-4. doi:
10.1016/j.jacc.2016.03.525). Quality of life and walking distance
were significantly improved.
[0012] As well as the infection risk and the potential risks of a
surgical intervention, treatment by means of electrical stimulation
of the vagal nerve is limited by side effects such as dysphonia,
coughing and oropharyngeal pain (Premchand R K et al., J. Card.
Fail., 2014, 20(11), 808-816). Medication-assisted boosting of the
parasympathetic nervous system by a direct effect on M2R could
constitute a novel therapy option.
[0013] Atrial fibrillation is the most common persistent heart
rhythm disorder, and the prevalence thereof increases with age
(Chen et al., Circ. Res., 2014, 114(9), 1500-1515). Atrial
fibrillation and heart failure often occur together in a mutually
beneficial relationship. Thus, the prevalence of atrial
fibrillation increases with the clinical severity of heart failure
(Maisel and Stevenson, Am. J. Cardiol., 2003, 91, (suppl) 2D-8D).
Clinical data suggest that patients where heart failure is
accompanied by atrial fibrillation have a poor prognosis. Both
lethality (total lethality, sudden death and pump failure) and
morbidity (hospitalization) were found to be significantly
increased in this group of patients.
[0014] In the treatment of atrial fibrillation, there are two
distinct treatment strategies: what is called rate control with
adjustment and if at all possible normalization of ventricular
frequency, and what is called rhythm control, comprising measures
intended to establish or maintain a sinusoidal rhythm. An effective
treatment consists of a combination of non-medication-assisted and
medication-assisted or intervention measures (Levalter T,
Fortbildungsprogramm Pharmazie, 2011, 5, 106-127).
[0015] For medication-assisted rhythm control after cardioversion,
beta-blockers, class I and class III antiarrhythmics are used
according to the underlying cardiac disorder and the extent of
left-ventricular pumping function impairment. In patients having
permanent atrial fibrillation and in oligosymptomatic (frequently
older) patients having persistent or paroxysmal atrial
fibrillation, simple rate control with retention and allowance of
the atrial fibrillation is often the therapy of choice. Primarily
medicaments that affect the refractory period or the conduction
capacity of the AV node are used. In principle, this effect can be
achieved by stimulation of the M2R, which plays the key
physiological role at this point, for example with the aid of a
positive allosteric modulator. The drugs available to date are
beta-blockers, digitalis, calcium antagonists and, in individual
cases, amiodarone, which are used with consideration of the
lifestyle, underlying cardiac disorder and any secondary disorders.
Especially in patients having reduced left ventricular pumping
function and severe heart failure, however, the options for
medication-assisted therapy are inadequate. Calcium antagonists are
contraindicated in this group of patients. As the most recent
studies have shown, treatment with digoxin leads to increased
mortality of patients having atrial fibrillation (Leong-Sit and
Tang, Curr. Opin. Cardiol., 2015, Epub). For beta-blockers, a lack
of effectiveness in patients having atrial fibrillation and heart
failure was shown in a meta analysis (Leong-Sit and Tang, Curr.
Opin. Cardiol., 2015, Epub). The medical demand for novel efficient
and safe treatments for rate control is correspondingly high. This
could be achieved by medications assisted stimulation of M2R.
[0016] The problem addressed by the present invention is that of
identifying and providing novel substances which constitute potent,
positive allosteric modulators of the muscarinic M2 receptor and as
such are suitable for treatment and/or prevention particularly of
cardiovascular disorders and/or renal disorders.
[0017] 1-Benzyl-substituted 4-oxo-1,4-dihydroquinoline-3-carboxylic
acids have been described as allosteric modulators of the M1
muscarine receptor for treatment of neurodegenerative disorders
such as Alzheimer's and schizophrenia (Scammells et al., ACS Chem.
Neurosci., 2013, 4 (7), 1026-1048; Mistry et al., J. Med. Chem.
2013, 56, 5151-5172). Among other documents, EP 0945435 B1
discloses pyridonecarboxylic acid derivatives having antibacterial
activity. WO 2002/085886-A2, WO 2003/050107-A1 and WO
2005/026145-A2 claim 7-piperidino-substituted quinolonecarboxylic
acid derivatives, and WO 2005/026165-A1 and WO 2005/049602-A1
various 7-pyrrolidino-substituted quinolonecarboxylic acid
derivatives, and EP 1650192-A1 specific
7-azetidinylquinolonecarboxylic acid derivatives having
antimicrobial/antibacterial activity. WO 2005/009971-A1 and JP
2005012561 disclose quinolone derivatives which can be used as
platelet aggregation inhibitors. WO 2015/189560-A1 discloses
1,4-dihydroquinoline derivatives as NPRC agonists for treatment of
cardiovascular disorders. Quinolonecarboxylic acid derivatives as
MCT modulators are described in WO 2016/081464-A1, in particular
for the treatment of tumour disorders and inflammatory
processes.
[0018] The present invention relates to compounds of the general
formula (I)
##STR00001##
in which X represents halogen, R.sup.1 represents hydrogen, [0019]
or [0020] represents --NR.sup.4R.sup.5, [0021] where [0022] R.sup.4
represents hydrogen, methyl, (C.sub.2-C.sub.4)-alkyl or
(C.sub.3-C.sub.6)-cycloalkyl, [0023] where (C.sub.2-C.sub.4)-alkyl
may be substituted by hydroxy or up to trisubstituted by fluorine
and [0024] R.sup.5 represents (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, 3- to 6-membered saturated
heterocyclyl or (C.sub.1-C.sub.4)-alkylsulfonyl, [0025] where
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl and 3- to
6-membered saturated heterocyclyl may be up to trisubstituted by
identical of different substituents from the group consisting of
methyl, difluoromethyl, trifluoromethyl, hydroxy, hydroxycarbonyl,
oxo, methoxy, difluoromethoxy, trifluoromethoxy and cyano and
furthermore up to tetrasubstituted by fluorine, [0026] or [0027]
R.sup.4 and R.sup.5 together with the nitrogen atom to which they
are attached form a saturated or partially unsaturated 3- to
6-membered monocyclic or 6- to 10-membered bicyclic heterocycle
which may contain one or two further identical or different
heteroatoms from the group consisting of N, O, S, SO and SO.sub.2
as ring members, [0028] where the 3- to 6-membered monocyclic and
the 6- to 10-membered bicyclic heterocycle may each be substituted
by 1 to 5 substituents independently of one another selected from
the group consisting of (C.sub.1-C.sub.4)-alkyl, difluoromethyl,
trifluoromethyl, hydroxy, hydroxycarbonyl, oxo,
(C.sub.1-C.sub.3)-alkoxy, difluoromethoxy, trifluoromethoxy, cyano,
(C.sub.1-C.sub.3)-alkoxycarbonyl, aminocarbonyl,
mono-(C.sub.1-C.sub.3)-alkylaminocarbonyloxy,
--NHC(.dbd.O)R.sup.14A, CH.sub.2NHC(.dbd.O)R.sup.14B and
--OC(.dbd.O)R.sup.15, and additionally up to tetrasubstituted by
fluorine, [0029] where (C.sub.1-C.sub.4)-alkyl may be mono- or
disubstituted by identical or different substituents from the group
consisting of hydroxy and (C.sub.1-C.sub.3)-alkoxy, and up to
tetrasubstituted by fluorine, [0030] R.sup.14A and R.sup.14B
independently of one another represent (C.sub.1-C.sub.3)-alkyl or
cyclopropyl, [0031] and in which [0032] R.sup.15 represents
(C.sub.1-C.sub.4)-alkyl, R.sup.2 represents a group of the
formula
[0032] ##STR00002## [0033] in which [0034] * marks the point of
attachment to the nitrogen atom of the amide moiety, [0035]
R.sup.6A represents hydrogen or (C.sub.1-C.sub.4)-alkyl, [0036]
R.sup.6B represents hydrogen, (C.sub.1-C.sub.4)-alkyl, cyclopropyl,
monofluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl or
trifluoromethoxymethyl, [0037] R.sup.7 represents
(C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.5)-cycloalkyl which is up
to tetrasubstituted by fluorine, [0038] where
(C.sub.1-C.sub.6)-alkyl may be substituted by amino, hydroxy,
(C.sub.1-C.sub.6)-alkoxy and up to pentasubstituted by fluorine,
[0039] where (C.sub.1-C.sub.6)-alkoxy may be up to pentasubstituted
by fluorine, [0040] L.sup.1 represents a bond or a group of the
formula --C(R.sup.8AR.sup.8B)--(C(R.sup.9AR.sup.9B)).sub.m--,
[0041] in which [0042] m represents 0 or 1, [0043] R.sup.8A
represents hydrogen or methyl, [0044] R.sup.8B represents hydrogen,
methyl, trifluoromethyl, pentafluoroethyl or
trifluoromethoxymethyl, [0045] R.sup.9A and R.sup.9B each
independently of one another represent hydrogen or methyl, [0046]
Ar.sup.2 represents phenyl, [0047] where phenyl may be mono- to
trisubstituted by identical or different substituents from the
group consisting of fluorine, chlorine, (C.sub.1-C.sub.3)-alkyl,
difluoromethoxymethyl, trifluoromethoxymethyl and trifluoromethyl,
[0048] or [0049] represents a 5- to 10-membered monocyclic,
bicyclic or tricyclic carbocycle or heterocycle which may contain
one or two further identical or different heteroatoms from the
group consisting of N and/or O as ring members, [0050] where the 5-
to 10-membered monocyclic, bicyclic or tricyclic carbocycle or
heterocycle may be up to trisubstituted by identical or different
substituents from the group consisting of (C.sub.1-C.sub.3)-alkyl,
trifluoromethyl and (C.sub.1-C.sub.4)-alkoxycarbonyl and
furthermore up to tetrasubstituted by fluorine, Ar.sup.1 represents
a group of the formula
[0050] ##STR00003## [0051] in which [0052] *** marks the point of
attachment to the nitrogen atom, [0053] R.sup.3A represents
fluorine, chlorine, trifluoromethyl or methyl, [0054] R.sup.3B
represents hydrogen or fluorine [0055] and [0056] R.sup.3C
represents hydrogen, fluorine, chlorine or methyl, or [0057]
represents a pyridine ring which is attached via a ring carbon
atom, [0058] where the pyridine ring may be mono- or disubstituted
by fluorine, chlorine, cyano, methyl or trifluoromethyl, and the
N-oxides, salts, solvates, salts of the N-oxides and solvates of
the N-oxides and salts thereof.
[0059] Compounds of the invention are the compounds of the formula
(I) and the salts, solvates and solvates of the salts thereof, the
compounds that are encompassed by formula (I) and are of the
formulae mentioned below and the salts, solvates and solvates of
the salts thereof and the compounds that are encompassed by formula
(I) and are cited below as working examples and the salts, solvates
and solvates of the salts thereof if the compounds that are
encompassed by formula (I) and are mentioned below are not already
salts, solvates and solvates of the salts.
[0060] Compounds according to the invention are likewise N-oxides
of the compounds of the formula (I) and the salts, solvates and
solvates of the salts thereof.
[0061] Preferred salts in the context of the present invention are
physiologically acceptable salts of the compounds of the invention.
Also encompassed are salts which are not themselves suitable for
pharmaceutical applications but can be used, for example, for the
isolation, purification or storage of the compounds of the
invention.
[0062] A suitable pharmaceutically acceptable salt of the compounds
of the present invention may be, for example, an acid-addition salt
of a compound of the present invention bearing a sufficiently basic
nitrogen atom in a chain or in a ring, such as an acid-addition
salt with an inorganic acid, or "mineral acid", such as
hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric
acid, sulfamic acid, bisulfuric acid, phosphoric acid or nitric
acid, for example, or with an organic acid such as formic acid,
acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid,
propionic acid, butyric acid, hexanoic acid, heptanoic acid,
undecanoic acid, lauric acid, benzoic acid, salicylic acid,
2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid,
cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic
acid, nicotinic acid, pamoic acid, pectinic acid, 3-phenylpropionic
acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid,
trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic
acid, benzenesulfonic acid, paratoluenesulfonic acid,
methanesulfonic acid, 2-naphthalenesulfonic acid,
naphthalenedisulfonic acid, camphorsulfonic acid, citric acid,
tartaric acid, stearic acid, lactic acid, oxalic acid, malonic
acid, succinic acid, malic acid, adipic acid, alginic acid, maleic
acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid,
glucoheptanoic acid, glycerophosphoric acid, aspartic acid,
sulfosalicylic acid or thiocyanic acid, for example.
[0063] Further, another suitable pharmaceutically acceptable salt
of a sufficiently acidic compound of the present invention is an
alkali metal salt, for example a sodium or potassium salt, an
alkaline earth metal salt, for example a calcium, magnesium or
strontium salt, or an aluminium or zinc salt, or an ammonium salt
derived from ammonia or from an organic primary, secondary or
tertiary amine having 1 to 20 carbon atoms, such as ethylamine,
diethylamine, triethylamine, ethyldiisopropylamine,
monoethanolamine, diethanolamine, triethanolamine,
dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol,
tris(hydroxymethyl)aminomethane, procaine, dibenzylamine,
N-methylmorpholine, arginine, lysine, 1,2-ethylenediamine,
N-methylpiperidine, N-methylglucamine, N,N-dimethylglucamine,
N-ethylglucamine, 1,6-hexanediamine, glucosamine, sarcosine,
serinol, 2-amino-1,3-propanediol, 3-amino-1,2-propanediol,
4-amino-1,2,3-butanetriol, or a salt with a quarternary ammonium
ion having 1 to 20 carbon atoms, such as tetramethylammonium,
tetraethylammonium, tetra(n-propyl)ammonium,
tetra(n-butyl)ammonium, N-benzyl-N,N,N-trimethylammonium, choline
or benzalkonium.
[0064] Those skilled in the art will further recognize that it is
possible for acid addition salts of the claimed compounds to be
prepared by reaction of the compounds with the appropriate
inorganic or organic acid via any of a number of known methods.
Alternatively, alkali and alkaline earth metal salts of acidic
compounds of the present invention are prepared by reacting the
compounds of the present invention with the appropriate base via a
variety of known methods.
[0065] The present invention includes all possible salts of the
compounds of the present invention as single salts, or as any
mixture of said salts, in any ratio.
[0066] In the present text, in particular in the Experimental
Section, for the synthesis of intermediates and of examples of the
present invention, when a compound is mentioned as a salt form with
the corresponding base or acid, the exact stoichiometric
composition of said salt form, as obtained by the respective
preparation and/or purification process, is, in most cases,
unknown. Unless specified otherwise, suffixes to chemical names or
structural formulae relating to salts, such as "hydrochloride",
"trifluoroacetate", "sodium salt", or ".times.HCl",
".times.CF.sub.3COOH", ".times.Na.sup.+", for example, mean a salt
form, the stoichiometry of this salt not being specified. This
applies analogously to cases in which synthesis intermediates or
example compounds or salts thereof have been obtained as solvates,
for example hydrates, by the preparation and/or purification
processes described.
[0067] Solvates in the context of the invention are described as
those forms of the compounds of the invention which form a complex
in the solid or liquid state by coordination with solvent
molecules. Hydrates are a specific form of the solvates in which
the coordination is with water. Solvates preferred in the context
of the present invention are hydrates.
[0068] The compounds of the invention may, depending on their
structure, exist in different stereoisomeric forms, i.e. in the
form of configurational isomers or else, if appropriate, as
conformational isomers (enantiomers and/or diastereomers, including
those in the case of atropisomers). The present invention therefore
encompasses the enantiomers and diastereomers, and the respective
mixtures thereof. It is possible to isolate the stereoisomerically
homogeneous constituents from such mixtures of enantiomers and/or
diastereomers in a known manner. Preference is given to employing
chromatographic methods for this purpose, especially HPLC
chromatography on achiral or chiral separation phases. In the case
of carboxylic acids as intermediates or end products, separation is
alternatively also possible via diastereomeric salts using chiral
amine bases.
[0069] In the context of the present invention, the term
"enantiomerically pure" is understood to the effect that the
compound in question with respect to the absolute configuration of
the chiral centres is present in an enantiomeric excess of more
than 95%, preferably more than 98%. The enantiomeric excess, ee, is
calculated here by evaluating an HPLC analysis chromatogram on a
chiral phase using the formula below:
ee = Enantiomer .times. .times. 1 .times. .times. ( area .times.
.times. percent ) - Enantiomer .times. .times. 2 .times. .times. (
area .times. .times. percent ) Enantiomer .times. .times. 1 .times.
.times. ( area .times. .times. percent ) + Enantiomer .times.
.times. 2 .times. .times. ( area .times. .times. percent ) .times.
100 .times. % . ##EQU00001##
[0070] If the compounds of the invention can occur in tautomeric
forms, the present invention encompasses all the tautomeric
forms.
[0071] The present invention also encompasses all suitable isotopic
variants of the compounds of the invention. An isotopic variant of
a compound according to the invention is understood here to mean a
compound in which at least one atom within the compound according
to the invention has been exchanged for another atom of the same
atomic number, but with a different atomic mass from the atomic
mass which usually or predominantly occurs in nature ("unnatural
fraction"). The expression "unnatural fraction" is understood to
mean a fraction of such an isotope higher than its natural
frequency. The natural frequencies of isotopes to be employed in
this connection can be found in "Isotopic Compositions of the
Elements 1997", Pure Appl. Chem., 70(1), 217-235, 1998. Examples of
isotopes which can be incorporated into a compound of the invention
are those of hydrogen, carbon, nitrogen, oxygen, phosphorus,
sulfur, fluorine, chlorine, bromine and iodine, such as .sup.2H
(deuterium), .sup.3H (tritium), .sup.13C, .sup.14C, .sup.15N,
.sup.17O, .sup.18O, .sup.32P, .sup.33P, .sup.33S, .sup.34S,
.sup.35S, .sup.36S, .sup.18F, .sup.36Cl, .sup.82Br, .sup.123I,
.sup.124I, .sup.129I and .sup.131I. Particular isotopic variants of
a compound according to the invention, especially those in which
one or more radioactive isotopes have been incorporated, may be
beneficial, for example, for the examination of the mechanism of
action or of the active ingredient distribution in the body; due to
the comparatively easy preparability and detectability, especially
compounds labelled with .sup.3H or .sup.14C isotopes are suitable
for this purpose. In addition, the incorporation of isotopes, for
example of deuterium, can lead to particular therapeutic benefits
as a consequence of greater metabolic stability of the compound,
for example an extension of the half-life in the body or a
reduction in the active dose required; such modifications of the
compounds of the invention may therefore possibly also constitute a
preferred embodiment of the present invention. With regard to the
treatment and/or prophylaxis of the disorders specified here, the
isotopic variant(s) of the compounds of the general formula (I)
preferably contain deuterium ("deuterium-containing compounds of
the general formula (I)"). Isotopic variants of the compounds of
the general formula (I) into which one or more radioactive isotopes
such as .sup.3H or .sup.14C have been incorporated are beneficial,
for example, in medicament and/or substrate tissue distribution
studies. Because of their easy incorporability and detectability,
these isotopes are particularly preferred. It is possible to
incorporate positron-emitting isotopes such as .sup.18F or .sup.11C
into a compound of the general formula (I). These isotopic variants
of the compounds of the general formula (I) are suitable for use in
in vivo imaging applications. Deuterium-containing and
.sup.13C-containing compounds of the general formula (I) can be
used within the scope of preclinical or clinical studies in mass
spectrometry analyses (H. J. Leis et al., Curr. Org. Chem., 1998,
2, 131). Isotopic variants of the compounds of the invention can be
prepared by commonly used processes known to those skilled in the
art, for example by the methods described further down and the
procedures described in the working examples, by using
corresponding isotopic modifications of the respective reagents
and/or starting compounds.
[0072] Isotopic variants of the compounds of the general formula
(I) can in general be prepared by processes known to those skilled
in the art as described in the schemes and/or examples described
here, by replacing a reagent with an isotopic variant of the
reagent, preferably a deuterium-containing reagent. According to
the deuteration sites desired, it is possible in some cases to
incorporate deuterium from D.sub.2O either directly into the
compounds or into reagents which can be used for the synthesis of
such compounds (Esaki et al., Tetrahedron, 2006, 62, 10954; Esaki
et al., Chem. Eur. J., 2007, 13, 4052). Another useful reagent for
incorporation of deuterium into molecules is deuterium gas. A rapid
route for incorporation of deuterium is the catalytic deuteration
of olefinic bonds (H. J. Leis et al., Curr. Org. Chem., 1998, 2,
131; J. R. Morandi et al., J. Org. Chem., 1969, 34 (6), 1889) and
acetylenic bonds (N. H. Khan, J. Am. Chem. Soc., 1952, 74 (12),
3018; S. Chandrasekhar et al., Tetrahedron, 2011, 52, 3865). For
direct exchange of hydrogen for deuterium in hydrocarbons
containing functional groups, it is also possible to use metal
catalysts (i.e. Pd, Pt and Rh) in the presence of deuterium gas (J.
G. Atkinson et al., U.S. Pat. No. 3,966,781). Various deuterated
reagents and synthesis units are commercially available from
companies like, for example, C/D/N Isotopes, Quebec, Canada;
Cambridge Isotope Laboratories Inc., Andover, Mass., USA; and
CombiPhos Catalysts, Inc., Princeton, N.J., USA. Further
information relating to the prior art with regard to
deuterium-hydrogen exchange can be found, for example, in Hanzlik
et al., J. Org. Chem., 1990, 55, 3992-3997; R. P. Hanzlik et al.,
Biochem. Biophys. Res. Commun., 1989, 160, 844; P. J. Reider et
al., J. Org. Chem., 1987, 52, 3326-3334; M. Jarman et al.,
Carcinogenesis, 1993, 16(4), 683-688; J. Atzrodt et al., Angew.
Chem., Int. Ed. 2007, 46, 7744; K. Matoishi et al., 2000, J. Chem.
Soc, Chem. Commun., 1519-1520; K. Kassahun et al., WO
2012/112363.
[0073] The term "deuterium-containing compound of the general
formula (I)" is defined as a compound of the general formula (I) in
which one or more hydrogen atoms have been replaced by one or more
deuterium atoms and in which the frequency of deuterium in every
deuterated position in the compound of the general formula (I) is
higher than the natural frequency of deuterium, which is about
0.015%. More particularly, in a deuterium-containing compound of
the general formula (I), the frequency of deuterium in every
deuterated position in the compound of the general formula (I) is
higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably
higher than 90%, 95%, 96% or 97%, even further preferably higher
than 98% or 99%, in this position or these positions. It will be
apparent that the frequency of deuterium in every deuterated
position is independent of the frequency of deuterium in other
deuterated positions.
[0074] The selective incorporation of one or more deuterium atoms
into a compound of the general formula (I) can alter the
physicochemical properties (for example acidity [A. Streitwieser et
al., J. Am. Chem. Soc., 1963, 85, 2759; C. L. Perrin et al., J. Am.
Chem. Soc., 2007, 129, 4490], basicity [C. L. Perrin, et al., J.
Am. Chem. Soc., 2003, 125, 15008; C. L. Perrin in Advances in
Physical Organic Chemistry, 44, 144; C. L. Perrin et al., J. Am.
Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int.
J. Pharm., 1984, 19(3), 271]) and/or the metabolic profile of the
molecule, and cause changes in the ratio of parent compound to
metabolites or the amounts of metabolites formed. Such changes may
lead to particular therapeutic benefits and therefore be preferable
under particular circumstances. Reduced rates of metabolism and
metabolic switching, where the ratio of metabolites is changed,
have been reported (D. J. Kushner et al., Can. J. Physiol.
Pharmacol., 1999, 77, 79; A. E. Mutlib et al., Toxicol. Appl.
Pharmacol., 2000, 169, 102). These changes in the exposure to
parent compound and metabolites can have important consequences
with respect to the pharmacodynamics, tolerability and efficacy of
a deuterium-containing compound of the general formula (I). In some
cases deuterium substitution reduces or eliminates the formation of
an undesired or toxic metabolite and enhances the formation of a
desired metabolite (e.g. Nevirapine: A. M. Sharma et al., Chem.
Res. Toxicol., 2013, 26, 410; Uetrecht et al., Chemical Research in
Toxicology, 2008, 21, 9, 1862; Efavirenz: A. E. Mutlib et al.,
Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases the
major effect of deuteration is to reduce the rate of systemic
clearance. As a result, the biological half-life of the compound is
increased. The potential clinical benefits would include the
ability to maintain similar systemic exposure with decreased peak
levels and increased trough levels. This could result in lower side
effects and enhanced efficacy, depending on the particular
compound's pharmacokinetic/pharmacodynamic relationship. Indiplon
(A. J. Morales et al., Abstract 285, The 15.sup.th North American
Meeting of the International Society of Xenobiotics, San Diego,
Calif., Oct. 12-16, 2008), ML-337 (C. J. Wenthur et al., J. Med.
Chem., 2013, 56, 5208), and Odanacatib (K. Kassahun et al.,
WO2012/112363) are examples for this deuterium effect. Still other
cases have been reported in which reduced rates of metabolism
result in an increase in exposure of the drug without changing the
rate of systemic clearance (e.g. Rofecoxib: F. Schneider et al.,
Arzneim. Forsch. Drug. Res., 2006, 56, 295; Telaprevir: F. Maltais
et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs showing
this effect may have reduced dosing requirements (e.g. lower number
of doses or lower dosage to achieve the desired effect) and/or may
produce lower metabolite loads.
[0075] A compound of general formula (I) may have multiple
potential sites of attack for metabolism. To optimize the
above-described effects on physicochemical properties and metabolic
profile, deuterium-containing compounds of general formula (I)
having a certain pattern of one or more deuterium-hydrogen
exchange(s) can be selected. Particularly, the deuterium atom(s) of
deuterium-containing compound(s) of general formula (I) is/are
attached to a carbon atom and/or is/are located at those positions
of the compound of general formula (I), which are sites of attack
for metabolizing enzymes such as e.g. cytochrome P.sub.450.
[0076] In the context of the present invention, unless specified
otherwise, the substituents are defined as follows:
[0077] Alkyl per se and "Alk" and "alkyl" in alkoxy, alkylsulfonyl,
alkylaminocarbonyloxy and alkoxycarbonyl are a linear or branched
alkyl radical having generally 1 to 6 and preferably 1 to 4 or 1 to
3 carbon atoms, by way of example and with preference methyl,
ethyl, n-propyl, isopropyl, tert-butyl, isobutyl
(2-methylprop-1-yl), n-pentyl and n-hexyl.
[0078] Alkoxy is, by way of example and with preference, methoxy,
ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and
n-hexoxy.
[0079] Alkylaminocarbonyloxy is an alkylaminocarbonyloxy radical
having one or two (independently chosen) alkyl substituents.
(C.sub.1-C.sub.3)-Alkylaminocarbonyloxy is, for example, a
monoalkylaminocarbonyloxy radical having 1 to 3 carbon atoms or a
dialkylaminocarbonyloxy radical having 1 to 3 carbon atoms in each
alkyl substituent. Preferred examples include:
methylaminocarbonyloxy, ethylaminocarbonyloxy,
n-propylaminocarbonyloxy, isopropylaminocarbonyloxy,
tert-butylaminocarbonyloxy, n-pentylaminocarbonyloxy,
n-hexylaminocarbonyloxy, N,N-dimethylaminocarbonyloxy,
N,N-diethylaminocarbonyloxy, N-ethyl-N-methylaminocarbonyloxy,
N-methyl-N-n-propylaminocarbonyloxy,
N-isopropyl-N-n-propylaminocarbonyloxy,
N-tert-butyl-N-methylaminocarbonyl, N-ethyl-N-n-pentylaminocarbonyl
and N-n-hexyl-N-methylaminocarbonyloxy.
[0080] Alkylsulfonyl in the context of the invention is a
straight-chain or branched alkyl radical which has 1 to 4 carbon
atoms and is attached via a sulfonyl group. Preferred examples
include: methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,
isopropylsulfonyl, n-butylsulfonyl and tert-butylsulfonyl.
[0081] By way of example and with preference, alkoxycarbonyl is
methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,
isopropoxycarbonyl and tert-butoxycarbonyl.
[0082] Carbocycle in the context of the invention is a mono-, poly-
or spirocyclic, preferably mono- or bicyclic, saturated carbocycle
having a total of 3 to 6 ring atoms. A monocyclic saturated
carbocycle is referred to synonymously as cycloalkyl. Examples
include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,
cycloheptenyl, cycloheptadienyl, spiro[2.3]hexyl, spiro[2.4]heptyl,
spiro[2.5]octyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl,
bicyclo[2.2.2]octyl, tricyclo[3.3.1.13,7]decyl. Monocyclic
cycloalkyl having 3 to 5 carbon atoms is preferred. Preferred
examples include: cyclopropyl, cyclobutyl, cyclopentyl,
bicyclo[2.2.1]heptyl and bicyclo[1.1.1]pent-1-yl.
[0083] Heterocyclyl is a mono-, poly- or spirocyclic, preferably
mono-, bi- or spirocyclic, nonaromatic heterocyclic radical having
generally 3 to 10 ring atoms and up to 3, preferably up to 2,
heteroatoms and/or hetero groups from the group consisting of N, O,
S, SO and SO.sub.2. For the purposes of the present invention, the
definition bicyclic heterocycle embraces bicyclic spirocyclic
heterocyclyl radicals. The heterocyclyl radicals can be saturated
or partially unsaturated. Preference is given to 4- to 6-membered
monocyclic saturated heterocyclyl radicals having one nitrogen atom
and to those having a further heteroatom from the group consisting
of N and O, and also to 6- to 7-membered bi- or spirocyclic
saturated heterocyclyl radicals having one nitrogen atom. Preferred
examples include: azetidinyl, pyrrolidinyl, piperidinyl,
piperazinyl, oxazolidinyl, imidazolidinyl, morpholinyl,
tetrahydropyrimidine, azabicyclo[3.1.0]hexyl, azaspiro[2.4]heptyl
and 2-oxa-6-azaspiro[3.3]hept-6-yl. Halogen represents fluorine,
chlorine, bromine and iodine, preferably fluorine or chlorine.
[0084] In the formula of the group that R.sup.1, R.sup.2, Ar.sup.1
or L.sup.1 may represent, the end point of the line marked by the
symbol #.sup.1; *, ** and *** does not represent a carbon atom or a
CH.sub.2 group but is part of the bond to the respective atom to
which R.sup.1, R.sup.2, Ar.sup.1 and L.sup.1, respectively, is
attached.
[0085] When radicals in the compounds of the invention are
substituted, the radicals may be mono- or polysubstituted, unless
specified otherwise. In the context of the present invention, all
radicals which occur more than once are defined independently of
one another. When radicals in the compounds of the invention are
substituted, the radicals may be mono- or polysubstituted, unless
specified otherwise. Substitution by one substituent or by two
identical or different substituents is preferred.
[0086] In the context of the present invention, the term
"treatment" or "treating" includes inhibition, retardation,
checking, alleviating, attenuating, restricting, reducing,
suppressing, repelling or healing of a disease, a condition, a
disorder, an injury or a health problem, or the development, the
course or the progression of such states and/or the symptoms of
such states. The term "therapy" is understood here to be synonymous
with the term "treatment".
[0087] The terms "prevention", "prophylaxis" and "preclusion" are
used synonymously in the context of the present invention and refer
to the avoidance or reduction of the risk of contracting,
experiencing, suffering from or having a disease, a condition, a
disorder, an injury or a health problem, or a development or
advancement of such states and/or the symptoms of such states.
[0088] The treatment or prevention of a disease, a condition, a
disorder, an injury or a health problem may be partial or
complete.
[0089] Preference is given in the context of the present invention
to compounds of the formula (I) in which
in which X represents fluorine, chlorine or bromine, R.sup.1
represents hydrogen, [0090] or [0091] represents NR.sup.4R.sup.5,
[0092] in which [0093] R.sup.4 represents hydrogen, methyl or
ethyl, and [0094] R.sup.5 represents (C.sub.1-C.sub.3)-alkyl which
is up to tetrasubstituted by fluorine, [0095] where
(C.sub.1-C.sub.3)-alkyl may be substituted by hydroxy, [0096] or
[0097] R.sup.4 and R.sup.5 together with the nitrogen atom to which
they are attached form a saturated 4- to 6-membered monocyclic or
6- to 9-membered bicyclic heterocycle which may contain one or two
further identical or different heteroatoms from the group
consisting of N and O as ring members, [0098] where the 4- to
6-membered monocyclic and the 6- to 9-membered bicyclic heterocycle
may each be substituted by 1 to 4 substituents independently of one
another selected from the group consisting of
(C.sub.1-C.sub.4)-alkyl, difluoromethyl, trifluoromethyl, hydroxy,
oxo, (C.sub.1-C.sub.3)-alkoxy, difluoromethoxy, trifluoromethoxy,
(C.sub.1-C.sub.3)alkoxycarbonyl,
(C.sub.1-C.sub.3)-alkylaminocarbonyloxy and --OC(.dbd.O)R.sup.15
and furthermore up to tetrasubstituted by fluorine, [0099] where
(C.sub.1-C.sub.4)-alkyl may be mono- or disubstituted by identical
or different substituents from the group consisting of hydroxy and
(C.sub.1-C.sub.3)-alkoxy, and up to tetrasubstituted by fluorine,
and where [0100] R.sup.15 represents (C.sub.1-C.sub.4)-alkyl,
R.sup.2 represents a group of the formula
[0100] ##STR00004## [0101] in which [0102] * marks the point of
attachment to the nitrogen atom of the amide moiety, [0103]
R.sup.6A represents hydrogen or (C.sub.1-C.sub.4)-alkyl, [0104]
R.sup.6B represents methyl, ethyl, isopropyl, cyclopropyl,
monofluoromethyl, difluoromethyl or trifluoromethyl, and [0105]
R.sup.7 represents (C.sub.1-C.sub.4)-alkyl which is up to
pentasubstituted by fluorine, (C.sub.3-C.sub.5)-cycloalkyl which is
up to tetrasubstituted by fluorine, methoxymethyl or
trifluoromethoxymethyl, [0106] L.sup.1 represents a bond or a group
of the formula --CR.sup.8AR.sup.8B--, [0107] in which [0108]
R.sup.8A represents hydrogen, [0109] R.sup.8B represents hydrogen,
methyl, trifluoromethyl, pentafluoroethyl or
trifluoromethoxymethyl, [0110] Ar.sup.2 represents phenyl, [0111]
where phenyl may be mono- to trisubstituted by identical or
different substituents from the group consisting of fluorine and
chlorine, [0112] or [0113] represents a 5- to 7-membered bicyclic
carbocycle or 5- or 6-membered monocyclic heterocycle which
contains one nitrogen atom as ring member, [0114] where the 5- to
7-membered bicyclic carbocycle or the 5- or 6-membered monocyclic
heterocycle may in each case be substituted by
(C.sub.1-C.sub.4)-alkoxycarbonyl and additionally up to
tetrasubstituted by fluorine, Ar.sup.1 represents a group of the
formula
[0114] ##STR00005## [0115] in which [0116] *** marks the point of
attachment to the nitrogen atom, [0117] R.sup.3A represents
fluorine, chlorine, trifluoromethyl or methyl, [0118] R.sup.3B
represents hydrogen or fluorine [0119] and [0120] R.sup.3C
represents hydrogen, fluorine, chlorine or methyl, or represents a
pyridine ring which is attached via a ring carbon atom, [0121]
where the pyridine ring may be mono- or disubstituted by fluorine,
chlorine or cyano, and the salts, solvates and solvates of the
salts thereof.
[0122] Particular preference is given in the context of the present
invention to compounds of the formula (I)
in which X represents fluorine, chlorine or bromine, R.sup.1
represents NR.sup.4R.sup.5, [0123] in which [0124] R.sup.4
represents methyl or ethyl, and [0125] R.sup.5 represents methyl,
2-hydroxyethyl or 2-hydroxypropyl, [0126] or [0127] represents a
heterocycle, attached via a nitrogen atom, of the formula
[0127] ##STR00006## [0128] in which [0129] ** marks the point of
attachment to the remainder of the molecule, [0130] R.sup.10
represents fluorine, methyl, hydroxy, hydroxymethyl,
methoxycarbonyl or acetyloxy, [0131] p represents the number 0, 1
or 2, [0132] where, in the case that the substituents R.sup.10
occur more than once, their meanings may in each case be identical
or different, [0133] Y.sup.1 represents --NH--, --N(CH.sub.3)-- or
--O--, R.sup.2 represents a group of the formula
[0133] ##STR00007## [0134] in which [0135] * marks the point of
attachment to the nitrogen atom of the amide moiety, [0136]
R.sup.6A represents hydrogen, methyl or ethyl, [0137] R.sup.6B
represents methyl, ethyl, trifluoromethyl, isopropyl or
cyclopropyl, and [0138] R.sup.7 represents methyl, ethyl,
difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,
pentafluoroethyl, isopropyl, isobutyl, methoxymethyl,
trifluoromethoxymethyl or cyclopropyl, [0139] R.sup.11 represents
hydrogen, [0140] R.sup.12 represents methoxycarbonyl, [0141]
R.sup.13 represents hydrogen or tert-butoxycarbonyl, [0142] L.sup.1
represents a bond or a group of the formula --CR.sup.8AR.sup.8B--,
[0143] in which [0144] R.sup.8A represents hydrogen, [0145]
R.sup.8B represents hydrogen, methyl or trifluoromethyl, [0146]
Ar.sup.2 represents phenyl, [0147] where phenyl may be mono- to
disubstituted by identical or different substituents from the group
consisting of fluorine and chlorine, Ar.sup.1 represents a group of
the formula
[0147] ##STR00008## [0148] in which [0149] *** marks the point of
attachment to the nitrogen atom, [0150] R.sup.3A represents
fluorine or chlorine, [0151] and [0152] R.sup.3C represents
hydrogen or fluorine, and the salts, solvates and solvates of the
salts thereof.
[0153] Very particular preference is given in the context of the
present invention to compounds of the formula (I)
in which X represents fluorine, R.sup.1 represents a heterocycle,
attached via a nitrogen atom, of the formula
##STR00009## [0154] in which [0155] ** marks the point of
attachment to the remainder of the molecule, R.sup.2 represents a
group of the formula
[0155] ##STR00010## [0156] in which [0157] * marks the point of
attachment to the nitrogen atom of the amide moiety, [0158]
R.sup.7A represents trifluoromethyl, ethyl or cyclopropyl, [0159]
R.sup.7B represents methyl or ethyl, [0160] R.sup.7C represents
trifluoromethyl or pentafluoroethyl, Ar.sup.1 represents a group of
the formula
[0160] ##STR00011## [0161] in which [0162] *** marks the point of
attachment to the nitrogen atom, and the salts, solvates and
solvates of the salts thereof.
[0163] Very particular preference is given in the context of the
present invention to compounds of the formula (I)
in which X represents fluorine, R.sup.1 represents a heterocycle,
attached via a nitrogen atom, of the formula
##STR00012## [0164] in which [0165] ** marks the point of
attachment to the remainder of the molecule, R.sup.2 represents a
group of the formula
[0165] ##STR00013## [0166] in which [0167] * marks the point of
attachment to the nitrogen atom of the amide moiety, Ar.sup.1
represents a group of the formula
[0167] ##STR00014## [0168] in which [0169] *** marks the point of
attachment to the nitrogen atom, and the salts, solvates and
solvates of the salts thereof.
[0170] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
X represents fluorine, R.sup.1 represents a heterocycle, attached
by a nitrogen atom, of the formula
##STR00015## [0171] in which [0172] ** marks the point of
attachment to the remainder of the molecule, [0173] R.sup.10
represents fluorine, methyl, hydroxy, hydroxymethyl,
methoxycarbonyl or acetyloxy, [0174] p represents the number 0, 1
or 2, [0175] where, in the case that the substituents R.sup.10
occur more than once, their meanings in each case may be identical
or different, R.sup.2 represents a group of the formula
[0175] ##STR00016## [0176] in which [0177] * marks the point of
attachment to the nitrogen atom of the amide moiety, Ar.sup.1
represents a group of the formula
[0177] ##STR00017## [0178] in which [0179] *** marks the point of
attachment to the nitrogen atom, and the salts, solvates and
solvates of the salts thereof.
[0180] The present invention also provides compounds of the general
formula (I)
##STR00018##
in which X represents halogen, R.sup.1 represents hydrogen [0181]
or [0182] represents --NR.sup.4R.sup.5, [0183] in which [0184]
R.sup.4 represents hydrogen, methyl, (C.sub.2-C.sub.4)-alkyl or
(C.sub.3-C.sub.6)-cycloalkyl, [0185] where (C.sub.2-C.sub.4)-alkyl
may be substituted by hydroxy or up to three times by fluorine, and
[0186] R.sup.5 represents (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, 3- to 6-membered saturated
heterocyclyl or (C.sub.1-C.sub.4)-alkylsulfonyl, [0187] where
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl and 3- to
6-membered saturated heterocyclyl may be substituted up to three
times by identical or different substituents from the group
consisting of methyl, difluoromethyl, trifluoromethyl, hydroxy,
hydroxycarbonyl, oxo, methoxy, difluoromethoxy, trifluoromethoxy,
cyano and furthermore up to four times by fluorine, [0188] or
[0189] R.sup.4 and R.sup.5 together with the nitrogen atom to which
they are attached form a saturated or partially unsaturated 3- to
6-membered monocyclic or 6- to 10-membered bicyclic heterocycle
which may contain one or two further identical or different
heteroatoms from the group consisting of N, O, S, SO and/or
SO.sub.2 as ring members, [0190] where the 3- to 6-membered
monocyclic and the 6- to 10-membered bicyclic heterocycle may each
be substituted by 1 to 5 substituents independently of one another
selected from the group consisting of (C.sub.1-C.sub.4)-alkyl,
difluoromethyl, trifluoromethyl, hydroxy, hydroxycarbonyl, oxo,
(C.sub.1-C.sub.3)-alkoxy, difluoromethoxy, trifluoromethoxy, cyano,
(C.sub.1-C.sub.3)-alkoxycarbonyl, aminocarbonyl,
mono-(C.sub.1-C.sub.3)-alkylaminocarbonyloxy,
--NHC(.dbd.O)R.sup.14A, --CH.sub.2NHC(.dbd.O)R.sup.14B,
--OC(.dbd.O)R.sup.15 and furthermore up to tetrasubstituted by
fluorine, [0191] where (C.sub.1-C.sub.4)-alkyl may be mono- or
disubstituted by identical or different substituents from the group
consisting of hydroxy and (C.sub.1-C.sub.3)-alkoxy and up to
tetrasubstituted by fluorine, [0192] R.sup.14A and R.sup.14B
independently of one another represent (C.sub.1-C.sub.3)-alkyl or
cyclopropyl, [0193] and where [0194] R.sup.15 represents
(C.sub.1-C.sub.4)-alkyl, R.sup.2 represents a group of the
formula
[0194] ##STR00019## [0195] in which [0196] * marks the point of
attachment to the nitrogen atom of the amide moiety, [0197]
R.sup.6A represents hydrogen, methyl, ethyl, n-propyl, isopropyl,
tert-butyl, isobutyl, (2-methyl-prop-1-yl) or cyclopropyl, [0198]
R.sup.6B represents hydrogen, methyl, ethyl, n-propyl, isopropyl,
tert-butyl, isobutyl, (2-methyl-prop-1-yl), cyclopropyl,
monofluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl or
trifluoromethoxymethyl, [0199] R.sup.7 represents
(C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.5)-cycloalkyl which is up
to tetrasubstituted by fluorine, [0200] where
(C.sub.1-C.sub.6)-alkyl may be substituted by amino, hydroxy,
(C.sub.1-C.sub.6)-alkoxy and up to pentasubstituted by fluorine,
[0201] where (C.sub.1-C.sub.6)-alkoxy may be up to pentasubstituted
by fluorine [0202] L.sup.1 represents a bond or a group of the
formula --C(R.sup.8AR.sup.8B)--(C(R.sup.9AR.sup.9B)).sub.m--,
[0203] in which [0204] m represents 0 or 1, [0205] R.sup.8A
represents hydrogen or methyl, [0206] R.sup.8B represents hydrogen,
methyl, trifluoromethyl, pentafluoroethyl or
trifluoromethoxymethyl, [0207] R.sup.9A and R.sup.9B independently
of one another represent hydrogen or methyl, [0208] Ar.sup.2
represents phenyl, [0209] where phenyl may be mono- to
trisubstituted by identical or different substituents from the
group consisting of fluorine, chlorine, (C.sub.1-C.sub.3)-alkyl,
difluoromethoxymethyl, trifluoromethoxymethyl and/or
trifluoromethyl, [0210] or [0211] represents a 5- to 10-membered
monocyclic, bicyclic or tricyclic carbocycle or heterocycle which
may contain one or two further identical or different heteroatoms
from the group consisting of N and/or S as ring members, [0212]
where the 5- to 10-membered monocyclic, bicyclic or tricyclic
carbocycle or heterocycle may be up to trisubstituted by identical
or different substituents from the group consisting of
(C.sub.1-C.sub.3)-alkyl, trifluoromethyl,
(C.sub.1-C.sub.4)-alkoxycarbonyl and furthermore up to
tetrasubstituted by fluorine, Ar.sup.1 represents a group of the
formula
[0212] ##STR00020## [0213] in which [0214] *** marks the point of
attachment to the nitrogen atom, [0215] R.sup.3A represents
fluorine, chlorine, trifluoromethyl or methyl, [0216] R.sup.3B
represents hydrogen or fluorine [0217] and [0218] R.sup.3C
represents hydrogen, fluorine, chlorine or methyl, or [0219]
represents a pyridine ring which is attached via a ring carbon
atom, [0220] where the pyridine ring may be mono- or disubstituted
by fluorine, chlorine, cyano, methyl or trifluoromethyl, and the
N-oxides, salts, solvates, salts of the N-oxides and solvates of
the N-oxides and salts thereof.
[0221] Preference in the context of the present invention is given
to compounds of the formula (I), in which
X represents fluorine, R.sup.1 represents a heterocycle, attached
via a nitrogen atom, of the formula
##STR00021## [0222] in which [0223] ** marks the point of
attachment to the remainder of the molecule, R.sup.2 represents a
group of the formula
[0223] ##STR00022## [0224] in which [0225] * marks the point of
attachment to the nitrogen atom of the amide moiety, Ar.sup.1
represents a group of the formula
[0225] ##STR00023## [0226] in which [0227] *** marks the point of
attachment to the nitrogen atom, and salts, solvates and solvates
of the salts thereof.
[0228] Preference in the context of the present invention is given
to compounds of the formula (I), in which
X represents fluorine, R.sup.1 represents a heterocycle, attached
via a nitrogen atom, of the formula
##STR00024## [0229] in which [0230] ** marks the point of
attachment to the remainder of the molecule, R.sup.2 represents a
group of the formula
[0230] ##STR00025## [0231] in which [0232] * marks the point of
attachment to the nitrogen atom of the amide moiety, Ar.sup.1
represents a group of the formula
[0232] ##STR00026## [0233] in which [0234] *** marks the point of
attachment to the nitrogen atom, and salts, solvates and solvates
of the salts thereof.
[0235] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
X represents fluorine or chlorine,
[0236] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
X represents fluorine, and the N-oxides, salts, solvates, salts of
the N-oxides and solvates of the N-oxides or salts thereof.
[0237] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
X represents chlorine, and the N-oxides, salts, solvates, salts of
the N-oxides and solvates of the N-oxides or salts thereof.
[0238] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
X represents bromine, and the N-oxides, salts, solvates, salts of
the N-oxides and solvates of the N-oxides or salts thereof.
[0239] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.1 represents NR.sup.4R.sup.5, [0240] in which [0241] R.sup.4
represents methyl or ethyl, and [0242] R.sup.5 represents methyl,
2-hydroxyethyl or 2-hydroxypropyl, and the N-oxides, salts,
solvates, salts of the N-oxides and solvates of the N-oxides or
salts thereof.
[0243] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.1 represents a heterocycle, attached via a nitrogen atom, of
the formula
##STR00027## [0244] in which [0245] ** marks the point of
attachment to the remainder of the molecule, [0246] R.sup.10
represents fluorine, methyl, hydroxy, hydroxymethyl,
methoxycarbonyl or acetyloxy, [0247] p represents the number 0, 1
or 2, [0248] where, in the case that the substituents R.sup.10
occur more than once, their meanings may in each case be identical
or different, [0249] Y.sup.1 represents --NH--, --N(CH.sub.3)-- or
--O--, and the N-oxides, salts, solvates, salts of the N-oxides and
solvates of the N-oxides or salts thereof.
[0250] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.1 represents a heterocycle, attached via a nitrogen atom, of
the formula
##STR00028## [0251] in which [0252] ** marks the point of
attachment to the remainder of the molecule, and the N-oxides,
salts, solvates, salts of the N-oxides and solvates of the N-oxides
and salts thereof.
[0253] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.1 represents a heterocycle, attached via a nitrogen atom, of
the formula
##STR00029## [0254] in which [0255] ** marks the point of
attachment to the remainder of the molecule, and the N-oxides,
salts, solvates, salts of the N-oxides and solvates of the N-oxides
and salts thereof.
[0256] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.1 represents a heterocycle, attached via a nitrogen atom, of
the formula
##STR00030## [0257] in which [0258] ** marks the point of
attachment to the remainder of the molecule, and N-oxides, salts,
solvates, salts of the N-oxides and solvates of the N-oxides and
salts thereof.
[0259] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.1 represents a heterocycle, attached via a nitrogen atom, of
the formula
##STR00031## [0260] in which [0261] ** marks the point of
attachment to the remainder of the molecule, and N-oxides, salts,
solvates, salts of the N-oxides and solvates of the N-oxides and
salts thereof.
[0262] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.1 represents trans-(3R,4R)-3,4-dihydroxypyrrolidin-1-yl of
the formula
##STR00032## [0263] in which [0264] ** marks the point of
attachment to the remainder of the molecule, and the salts,
solvates and solvates of the salts thereof.
[0265] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.1 represents cis-(R,S)-3,4-dihydroxypyrrolidin-1-yl of the
formula
##STR00033## [0266] in which [0267] ** marks the point of
attachment to the remainder of the molecule, and the salts,
solvates and solvates of the salts thereof.
[0268] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.1 represents a heterocycle, attached via a nitrogen atom, of
the formula
##STR00034## [0269] in which [0270] ** marks the point of
attachment to the remainder of the molecule, and the N-oxides,
salts, solvates, salts of the N-oxides and solvates of the N-oxides
or salts thereof.
[0271] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.2 represents a group of the formula
##STR00035## [0272] in which [0273] * marks the point of attachment
to the nitrogen atom of the amide moiety, [0274] R.sup.6A
represents hydrogen, methyl or ethyl, [0275] R.sup.6B represents
methyl, ethyl, trifluoromethyl, isopropyl or cyclopropyl, and
[0276] R.sup.7 represents methyl, ethyl, difluoromethyl,
trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, isopropyl,
isobutyl, methoxymethyl, trifluoromethoxymethyl or cyclopropyl, and
the N-oxides, salts, solvates, salts of the N-oxides and solvates
of the N-oxides or salts thereof.
[0277] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.2 represents a group of the formula
##STR00036## [0278] in which [0279] * marks the point of attachment
to the nitrogen atom of the amide moiety, [0280] R.sup.6A
represents hydrogen, methyl or ethyl, [0281] R.sup.6B represents
methyl, ethyl, trifluoromethyl, isopropyl, tert-butyl or
cyclopropyl and [0282] R.sup.7 represents methyl, ethyl,
difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,
pentafluoroethyl, isopropyl, isobutyl, methoxymethyl,
trifluoromethoxymethyl or cyclopropyl, and the N-oxides, salts,
solvates, salts of the N-oxides and solvates of the N-oxides and
salts thereof.
[0283] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.2 represents a group of the formula
##STR00037## [0284] in which [0285] * marks the point of attachment
to the nitrogen atom of the amide moiety, [0286] L.sup.1 represents
a bond or a group of the formula --CR.sup.8AR.sup.8B--, [0287] in
which [0288] R.sup.8A represents hydrogen, [0289] R.sup.8B
represents hydrogen, methyl or trifluoromethyl, [0290] Ar.sup.2
represents a group of the formula
[0290] ##STR00038## [0291] in which [0292] #.sup.1 marks the point
of attachment to the remainder of the molecule, and the N-oxides,
salts, solvates, salts of the N-oxides and solvates of the N-oxides
or salts thereof.
[0293] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.2 represents a group of the formula
##STR00039## [0294] in which [0295] * marks the point of attachment
to the nitrogen atom of the amide moiety, [0296] R.sup.7A
represents trifluoromethyl, ethyl or cyclopropyl, [0297] R.sup.7B
represents methyl or ethyl, [0298] R.sup.7C represents
trifluoromethyl or pentafluoroethyl, and the N-oxides, salts,
solvates, salts of the N-oxides and solvates of the N-oxides or
salts thereof.
[0299] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.2 represents a group of the formula
##STR00040## [0300] in which [0301] * marks the point of attachment
to the nitrogen atom of the amide moiety, and the N-oxides, salts,
solvates, salts of the N-oxides and solvates of the N-oxides or
salts thereof.
[0302] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.2 represents a group of the formula
##STR00041## [0303] in which [0304] * marks the point of attachment
to the nitrogen atom of the amide moiety, and the N-oxides, salts,
solvates, salts of the N-oxides and solvates of the N-oxides and
salts thereof.
[0305] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.2 represents a group of the formula
##STR00042## [0306] in which [0307] * marks the point of attachment
to the nitrogen atom of the amide moiety, and the N-oxides, salts,
solvates, salts of the N-oxides and solvates of the N-oxides and
salts thereof.
[0308] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.2 represents a group of the formula
##STR00043## [0309] in which [0310] * marks the point of attachment
to the nitrogen atom of the amide moiety, [0311] R.sup.7A
represents trifluoromethyl, ethyl or cyclopropyl, and the N-oxides,
salts, solvates, salts of the N-oxides and solvates of the N-oxides
or salts thereof.
[0312] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.2 represents a group of the formula
##STR00044## [0313] in which [0314] * marks the point of attachment
to the nitrogen atom of the amide moiety, [0315] R.sup.7B
represents methyl or ethyl, and the N-oxides, salts, solvates,
salts of the N-oxides and solvates of the N-oxides or salts
thereof.
[0316] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.2 represents a group of the formula
##STR00045## [0317] in which [0318] * marks the point of attachment
to the nitrogen atom of the amide moiety, [0319] R.sup.7C
represents trifluoromethyl or pentafluoroethyl, and the N-oxides,
salts, solvates, salts of the N-oxides and solvates of the N-oxides
or salts thereof.
[0320] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.2 represents (2S)-1,1,1-trifluorobutan-2-yl of the
formula
##STR00046## [0321] in which [0322] * marks the point of attachment
to the nitrogen atom of the amide moiety, and the salts, solvates
and solvates of the salts thereof.
[0323] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.2 represents (1S)-1-cyclopropyl-2,2,2-trifluoroethyl
##STR00047## [0324] in which [0325] * marks the point of attachment
to the nitrogen atom of the amide moiety, and the salts, solvates
and solvates of the salts thereof.
[0326] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.2 represents a group of the formula
##STR00048## [0327] in which [0328] * marks the point of attachment
to the nitrogen atom of the amide moiety, and the salts, solvates
and solvates of the salts thereof.
[0329] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
[0330] R.sup.2 represents a group of the formula
##STR00049## [0331] in which [0332] * marks the point of attachment
to the nitrogen atom of the amide moiety, and salts, solvates and
solvates of the salts thereof.
[0333] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.2 represents a group of the formula
##STR00050## [0334] in which [0335] * marks the point of attachment
to the nitrogen atom of the amide moiety, and salts, solvates and
solvates of the salts thereof.
[0336] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.2 represents a group of the formula
##STR00051## [0337] in which [0338] * marks the point of attachment
to the nitrogen atom of the amide moiety, and salts, solvates and
solvates of the salts thereof.
[0339] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.2 represents 1,1,1,3,3,3-hexafluoropropan-2-yl, and the
salts, solvates and solvates of the salts thereof. A further
particular embodiment of the present invention encompasses
compounds of the formula (I) in which R.sup.2 represents
3,3,4,4,4-pentafluorobutan-2-yl, and the salts, solvates and
solvates of the salts thereof.
[0340] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.2 represents 1,1,1,2,2-pentafluoropentan-3-yl, and the salts,
solvates and solvates of the salts thereof.
[0341] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
R.sup.2 represents 1,1,1-trifluoro-2-methylpropan-2-yl, and the
salts, solvates and solvates of the salts thereof.
[0342] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
Ar.sup.1 represents a group of the formula
##STR00052## [0343] in which [0344] *** marks the point of
attachment to the nitrogen atom, and the N-oxides, salts, solvates,
salts of the N-oxides and solvates of the N-oxides or salts
thereof.
[0345] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
Ar.sup.1 represents a group of the formula
##STR00053## [0346] in which [0347] *** marks the point of
attachment to the nitrogen atom, and the N-oxides, salts, solvates,
salts of the N-oxides and solvates of the N-oxides or salts
thereof.
[0348] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
Ar.sup.1 represents a group of the formula
##STR00054## [0349] in which [0350] *** marks the point of
attachment to the nitrogen atom, and the N-oxides, salts, solvates,
salts of the N-oxides and solvates of the N-oxides or salts
thereof.
[0351] A further particular embodiment of the present invention
encompasses compounds of the formula (I) in which
Ar.sup.1 represents a group of the formula
##STR00055## [0352] in which [0353] *** marks the point of
attachment to the nitrogen atom, and the N-oxides, salts, solvates,
salts of the N-oxides and solvates of the N-oxides or salts
thereof.
[0354] The individual radical definitions specified in the
respective combinations or preferred combinations of radicals are,
independently of the respective combinations of the radicals
specified, also replaced as desired by radical definitions of other
combinations.
[0355] Very particular preference is given to combinations of two
or more of the abovementioned preferred ranges and embodiments.
[0356] The radical definitions specified as preferred, particularly
preferred and very particularly preferred apply both to the
compounds of the formula (I) and correspondingly toward all
intermediates.
[0357] The invention further provides a process for preparing
compounds of the formula (I) according to the invention,
characterized in that
[A] a compound of the formula (II-A)
##STR00056## [0358] in which X, R.sup.2 and Ar.sup.1 have the
meanings given above, [0359] and [0360] Hal represents fluorine,
chlorine, bromine or iodine, preferably chlorine, is reacted with a
compound of formula (III)
[0360] ##STR00057## [0361] in which R.sup.1 has the meaning given
above and where R.sup.1 does not represent hydrogen, to give the
carboxamide of the formula (I-A) according to the invention
[0361] ##STR00058## [0362] in which X, R.sup.1, R.sup.2 and
Ar.sup.1 have the meanings given above and where R.sup.1 does not
represent hydrogen, or [B] a compound of the formula (IV)
[0362] ##STR00059## [0363] in which X, R.sup.1 and Ar.sup.1 have
the meanings given above, is reacted with a compound of the formula
(V)
[0363] ##STR00060## [0364] in which R.sup.2 has the meaning given
above, to give the carboxamide of the formula (I) according to the
invention
[0364] ##STR00061## [0365] in which X, R.sup.1, R.sup.2 and
Ar.sup.1 have the meanings given above, and, if appropriate, the
compounds of the formula (I) thus obtained are separated into their
enantiomers and/or diastereomers and/or converted with the
appropriate (i) solvents and/or (ii) bases or acids to their
solvates, salts and/or solvates of the salts.
[0366] The reaction (II-A)+(III).fwdarw.(I-A) can be carried out
via a nucleophilic substitution reaction or via a transition
metal-mediated coupling reaction.
[0367] The nucleophilic substitution reaction is preferably carried
out in the presence of a base. Suitable bases for the process step
(II-A)+(III).fwdarw.(I-A) are the customary inorganic or organic
bases. These preferably include alkali metal hydroxides, for
example lithium hydroxide, sodium hydroxide or potassium hydroxide,
alkali metal or alkaline earth metal carbonates such as lithium
carbonate, sodium carbonate, potassium carbonate or caesium
carbonate, alkali metal alkoxides such as lithium tert-butoxide,
sodium tert-butoxide or potassium tert-butoxide, alkali metal
hydrides such as sodium hydride or potassium hydride, or organic
amines such as N,N-diisopropylethylamine (DIPEA),
1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Preference is given to
using N,N-diisopropylethylamine (DIPEA). The reaction is carried
out generally within a temperature range from 0.degree. C. to
+100.degree. C., preferably at +23.degree. C. to +80.degree. C.
[0368] Inert solvents for the process step
(II-A)+(III).fwdarw.(I-A) are, for example, ethers such as diethyl
ether, dioxane, tetrahydrofuran, glycol dimethyl ether or
diethylene glycol dimethyl ether, hydrocarbons such as benzene,
toluene, xylene, hexane, cyclohexane or mineral oil fractions,
halohydrocarbons such as dichloromethane, trichloromethane,
tetrachloromethane, 1,2-dichloroethane, trichloroethylene or
chlorobenzene, or other solvents such as acetone, ethyl acetate,
acetonitrile, pyridine, dimethyl sulfoxide, N,N-dimethylformamide
(DMF), N,N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone
(NMP). It is likewise possible to use mixtures of the solvents
mentioned. Preference is given to using dimethylformamide (DMF) or
N-methylpyrrolidone (NMP).
[0369] In a preferred embodiment, the transition metal-mediated
coupling reaction for the process step (II-A)+(III).fwdarw.(I-A) is
carried out in the presence of a palladium catalyst. Suitable
palladium catalysts are, for example, palladium(II) acetate,
palladium(II) chloride, bis(triphenylphosphine)palladium(II)
chloride, bis(acetonitrile)palladium(II) chloride,
tetrakis(triphenylphosphine)palladium(0),
bis(dibenzylideneacetone)palladium(0),
tris(dibenzylideneacetone)palladium(0) or
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride,
optionally in combination with a suitable phosphine ligand, for
example triphenylphosphine, tri-tert-butylphosphine,
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (S-Phos),
1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene
(Q-Phos), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(Xantphos), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP),
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl or
2-di-tert-butylphosphino-2'-(N,N-dimethylamino)biphenyl.
[0370] The palladium-catalysed coupling reaction
(II-A)+(III).fwdarw.(I-A) is generally carried out in the presence
of a base. Suitable bases are especially alkali metal carbonates
such as sodium carbonate, potassium carbonate or caesium carbonate,
alkali metal phosphates such as sodium phosphate or potassium
phosphate, alkali metal fluorides such as potassium fluoride or
caesium fluoride, or alkali metal tert-butoxides such as sodium
tert-butoxide or potassium tert-butoxide. The reaction is carried
out in an inert solvent, for example toluene, 1,2-dimethoxyethane,
tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide (DMSO),
N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA) or
mixtures thereof, within a temperature range from +80.degree. C. to
+200.degree. C., preferably at +80.degree. C. to +150.degree. C.,
where heating by means of a microwave apparatus may be
advantageous.
[0371] Preference is given to using, for this coupling reaction, a
catalyst/ligand/base system consisting of palladium(II) acetate,
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) and
caesium carbonate or potassium carbonate, and 1,4-dioxane as
solvent.
[0372] The coupling reaction (II-A)+(III).fwdarw.(I-A) may, in a
further preferred embodiment, also be carried out with the aid of a
copper(I) catalyst, such as copper(I) oxide, bromide or iodide, in
the presence of a copper ligand such as
trans-N,N'-dimethyl-1,2-cyclohexanediamine, 8-hydroxyquinoline or
1,10-phenanthroline, and of an inorganic or organic carbonate base,
such as potassium carbonate, caesium carbonate or
bis(tetraethylammonium) carbonate. Suitable inert solvents for this
reaction are in particular toluene, xylene, 1,4-dioxane,
acetonitrile, dimethyl sulfoxide (DMSO), N,N-dimethylformamide
(DMF) or mixtures thereof, optionally with addition of water.
Preference is given to using a system consisting of copper(I)
iodide, trans-N,N'-dimethyl-1,2-cyclohexanediamine and potassium
carbonate in dimethylformamide. The reaction is carried out
generally within a temperature range from +50.degree. C. to
+200.degree. C., preferably at +60.degree. C. to +150.degree.
C.
[0373] The coupling reaction (IV)+(V).fwdarw.(I) [amide formation]
can be effected either by a direct route with the aid of a
condensing or activating agent or via the intermediate stage of a
carbonyl chloride, carboxylic ester or carbonyl imidazolide
obtainable from (IV).
[0374] Suitable for use as condensing agents or activating agents
are, for example, carbodiimides such as N,N'-diethyl-,
N,N'-dipropyl-, N,N'-diisopropyl-, N,N'-dicyclohexylcarbodiimide
(DCC) or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (EDC), phosgene derivatives such as
N,N'-carbonyldiimidazole (CDI), isopropyl chloroformate or isobutyl
chloroformate, 1,2-oxazolium compounds such as
2-ethyl-5-phenyl-1,2-oxazolium 3-sulfate or
2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds
such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline,
.alpha.-chlorenamines such as
1-chloro-N,N,2-trimethylprop-1-en-1-amine, 1,3,5-triazine
derivatives such as
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,
phosphorus compounds such as n-propanephosphonic anhydride (T3P,
PPACA), diethyl cyanophosphonate, diphenylphosphoryl azide (DPPA),
bis(2-oxo-3-oxazolidinyl)phosphoryl chloride,
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate or
benzotriazol-1-yloxytris(pyrrolidino)phosphonium
hexafluorophosphate (PyBOP), or uronium compounds such as
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU),
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU),
O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TCTU),
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU) or
2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TPTU), optionally in combination with further
auxiliaries such as 1-hydroxybenzotriazole (HOBt) or
N-hydroxysuccinimide (HOSu), and also as bases alkali metal
carbonates, for example sodium carbonate or potassium carbonate, or
tertiary amine bases such as triethylamine, N-methylmorpholine
(NMM), N-methylpiperidine (NMP), N,N-diisopropylethylamine (DIPEA),
pyridine or 4-N,N-dimethylaminopyridine (DMAP). Condensing or
activating agents used with preference are
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU) in combination with
N,N-diisopropylethylamine (DIPEA), and also n-propanephosphonic
anhydride (T3P, PPACA) in combination with
N,N-diisopropylethylamine (DIPEA).
[0375] The compounds of the formula (II-A) can be prepared by
reacting a carboxylic acid compound of the formula (VI-A)
##STR00062## [0376] in which X, Hal and Ar.sup.1 have the meanings
given above, with a compound of the formula (V)
[0376] ##STR00063## [0377] in which R.sup.2 has the meaning given
above, to give the carboxamide of the formula (II-A) according to
the invention
[0377] ##STR00064## [0378] in which X, Hal, R.sup.2 and Ar.sup.1
have the meanings given above.
[0379] Compounds of the formula (I-B) can be prepared analogously
to the reaction (VI-A)+(V).fwdarw.(II-A) by reacting a carboxylic
acid compound of the formula (VI-B)
##STR00065## [0380] in which X and Ar.sup.1 have the meanings given
above, with a compound of the formula (V)
[0380] ##STR00066## [0381] is in which R.sup.2 has the meaning
given above, to give the carboxamide of the formula (I-B) according
to the invention
[0381] ##STR00067## [0382] in which X, R.sup.2 and Ar.sup.1 have
the meanings given above.
[0383] The coupling reaction (VI-A)+(V).fwdarw.(II-A) or
(VI-B)+(V).fwdarw.(I-B) [amide formation] can be effected either by
a direct route with the aid of a condensing or activating agent or
via the intermediate stage of a carbonyl chloride, carboxylic ester
or carbonyl imidazolide obtainable from (VI), analogously to the
conditions and reagents already described for the reaction
(IV)+(V).fwdarw.(I). If HATU is used as activating agent in the
coupling reaction to give (II-A), it is possible that either an
individual defined product of the general formula (II-A) is
obtained, or else a mixture with a "HATU adduct". A "HATU adduct"
in the present context refers to a pseudohalide compound where the
Hal substituent in the general formula (II-A) is replaced by the
3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol group, also referred to as
1-hydroxy-7-azabenzotriazole. Such a mixture of a halogen compound
of the general formula (II-A) and a "HATU adduct" can also be used,
analogously to the reaction described, as reactant for the further
reaction (after (I) or (VIII)).
[0384] In the case of a two-stage reaction regime via the carbonyl
chlorides or carbonyl imidazolides obtainable from (VI), the
coupling with the amine component (V) is carried out in the
presence of a customary base, for example sodium carbonate or
potassium carbonate, triethylamine, DIPEA, N-methylmorpholine
(NMM), N-methylpiperidine (NMP), pyridine, 2,6-dimethylpyridine,
4-N,N-dimethylaminopyridine (DMAP),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
1,5-diazabicyclo[4.3.0]non-5-ene (DBN), sodium methoxide or
potassium methoxide, sodium ethoxide or potassium ethoxide, sodium
tert-butoxide or potassium tert-butoxide, or sodium hydride or
potassium hydride.
[0385] The carbonyl imidazolides themselves are obtainable by known
methods by reaction of (VI) with N,N'-carbonyldiimidazole (CDI) at
elevated temperature (+60.degree. C. to +150.degree. C.) in a
correspondingly relatively high-boiling solvent such as
N,N-dimethylformamide (DMF). The preparation of the carbonyl
chlorides is accomplished in a customary manner by treating (VI)
with thionyl chloride or oxalyl chloride in an inert solvent such
as dichloromethane or THF.
[0386] Inert solvents for the coupling reactions mentioned
are--according to the method used--for example ethers such as
diethyl ether, diisopropyl ether, methyl tert-butyl ether,
tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or
bis(2-methoxyethyl) ether, hydrocarbons such as benzene, toluene,
xylene, pentane, hexane or cyclohexane, halohydrocarbons such as
dichloromethane, trichloromethane, carbon tetrachloride,
1,2-dichloroethane, trichloroethylene or chlorobenzene, or polar
aprotic solvents such as acetone, methyl ethyl ketone, ethyl
acetate, acetonitrile, butyronitrile, pyridine, dimethyl sulfoxide
(DMSO), N,N-dimethylformamide (DMF), N,N'-dimethylpropyleneurea
(DMPU) or N-methylpyrrolidinone (NMP). It is also possible to use
mixtures of such solvents. Preference is given to using
N,N-dimethylformamide (DMF) and dichloromethane (DCM) in
combination with triethylamine. The couplings are generally
conducted within a temperature range from 0.degree. C. to
+130.degree. C., preferably at +20.degree. C. to +30.degree. C.
[0387] Depending on their respective substitution pattern, the
compounds of the formula (IV-A) can be prepared by reacting
either
[C] a compound of the formula (VII-A)
##STR00068## [0388] in which X, Hal and Ar.sup.1 have the meanings
given above, [0389] and [0390] T represents (C.sub.1-C.sub.4)-alkyl
or benzyl in a first step with a compound of the formula (III)
[0390] ##STR00069## [0391] in which R.sup.1 has the meaning given
above and where R.sup.1 does not represent hydrogen, to give a
compound of the formula (VIII-A)
[0391] ##STR00070## [0392] in which X, T, R.sup.1 and Ar.sup.1 have
the meanings given above and where R.sup.1 does not represent
hydrogen, and optionally, in a second step, removing the ester
radical T to give the carboxylic acid of the formula (IV-A)
according to the invention
[0392] ##STR00071## [0393] in which X, R.sup.1 and Ar.sup.1 have
the meanings given above and where R.sup.1 does not represent
hydrogen, or [D] a compound of the formula (VI-A)
[0393] ##STR00072## [0394] in which X, Hal and Ar.sup.1 have the
meanings given above, with a compound of formula (III)
[0394] ##STR00073## [0395] in which R.sup.1 has the meaning given
above and where R does not represent hydrogen, to give the
carboxylic acid of the formula (IV-A) according to the
invention
[0395] ##STR00074## [0396] in which X, R.sup.1 and Ar.sup.1 have
the meanings given above and where R.sup.1 does not represent
hydrogen.
[0397] The reaction (VII-A)+(III).fwdarw.(VIII-A) [route C] or the
reaction (VI-A)+(III).fwdarw.(IV-A) [route D] can be carried out
via a nucleophilic substitution reaction or a transition
metal-mediated coupling reaction analogously to the conditions and
reagents already described for the reaction
(II-A)+(III).fwdarw.(I-A).
[0398] In a preferred embodiment, the reaction is conducted
according to route C as a nucleophilic substitution reaction in the
presence of a base, preference being given to using
N,N-diisopropylethylamine (DIPEA). Preference is given to using
dimethylformamide (DMF), N-methylpyrrolidone (NMP) or acetonitrile
as solvent.
[0399] In a preferred embodiment, the reaction is conducted
according to route D as a transition metal-mediated coupling
reaction in the presence of a suitable palladium catalyst.
Preference is given to using a system of palladium(II) acetate in
combination with 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(xantphos), caesium carbonate or potassium carbonate and
1,4-dioxane as solvent.
[0400] The removal of the ester group T in process step
(VIII-A).fwdarw.(IV-A) is carried out by customary methods, by
treating the ester in an inert solvent with an acid or a base, with
conversion of the salt of the carboxylic acid initially formed in
the latter variant to the free carboxylic acid by subsequent
treatment with acid. In the case of the tert-butyl esters, the
ester cleavage is preferably effected with an acid. Benzyl esters
can alternatively also be cleaved by hydrogenation (hydrogenolysis)
in the presence of a suitable catalyst, for example palladium on
activated carbon. Suitable solvents for these reactions are water
and the organic solvents customary for ester cleavage. These
include in particular alcohols such as methanol, ethanol,
n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as
diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane,
or other solvents such as dichloromethane, acetonitrile,
N,N-dimethylformamide or dimethyl sulfoxide. It is equally possible
to use mixtures of these solvents. In the case of a basic ester
hydrolysis, preference is given to using mixtures of water with
tetrahydrofuran.
[0401] Suitable bases for a hydrolysis reaction are the customary
inorganic bases. These especially include alkali metal or alkaline
earth metal hydroxides, for example lithium hydroxide, sodium
hydroxide, potassium hydroxide or barium hydroxide, or alkali metal
or alkaline earth metal carbonates, such as sodium carbonate,
potassium carbonate or calcium carbonate.
[0402] Suitable acids for the ester hydrolysis are generally
sulfuric acid, hydrogen chloride/hydrochloric acid, hydrogen
bromide/hydrobromic acid, phosphoric acid, acetic acid,
trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or
trifluoromethanesulfonic acid, or mixtures thereof, optionally with
addition of water. Preference is given to using aqueous
hydrochloric acid (18 percent) in a water/tetrahydrofuran
mixture.
[0403] The ester cleavage is generally conducted within a
temperature range from -20.degree. C. to +100.degree. C.,
preferably at 23.degree. C. to +120.degree. C.
[0404] Depending on the particular substitution pattern, the
compounds of the formula (VI-A) and of the formula (VIII-A) can be
prepared by, in analogy to known processes (see, for example, EP
0607825 A1, p. 25-26), reacting a 2,6-dichloronicotinoylacrylate
derivative of the formula (IX-A)
##STR00075## [0405] in which X, Hal and T have the meanings given
above [0406] and [0407] Y represents a leaving group such as
dimethylamino, methoxy or ethoxy, and in a first stage, preferably
in the presence of a suitable base, with an aminopyridine compound
of the formula (X)
[0407] ##STR00076## [0408] in which Ar.sup.1 has the meanings given
above and then, in a second step, reacting this in the presence of
a suitable base to give the ester compound of the formula
(VII-A)
[0408] ##STR00077## [0409] in which X, Hal, Ar.sup.1 and T have the
definition given above, and then optionally converting the ester
compound (VII) under hydrolysis conditions in a further step to the
carboxylic acid compound (VI-A)
[0409] ##STR00078## [0410] in which X, Hal and Ar.sup.1 have the
meanings given above, under the reaction conditions known in the
literature.
[0411] Compounds of the formula (VI-B) and of the formula (VII-B)
can be prepared analogously to the reaction
(IX-A)+(X).fwdarw.(VII-A).fwdarw.(VI-A) by reacting, analogously to
known processes (see, for example, EP 0607825 A1, p. 25-26), a
2,6-dichloronicotinoylacrylate derivative of the formula (IX)
##STR00079## [0412] in which X and T have the definitions given
above [0413] and [0414] Y represents a leaving group such as
dimethylamino, methoxy or ethoxy, and in a first stage, preferably
in the presence of a suitable base, with an aminopyridine compound
of the formula (X)
[0414] ##STR00080## [0415] in which Ar.sup.1 has the meanings given
above, and then, in a second step, reacting this in the presence of
a suitable base to give the ester compound of the formula
(VII-B)
[0415] ##STR00081## [0416] in which X, Ar.sup.1 and T have the
meaning given above, and then optionally converting the ester
compound (VII) under hydrolysis conditions in a further step into
the carboxylic acid compound (VI-B)
[0416] ##STR00082## [0417] in which X and Ar.sup.1 have the
meanings given above, under the reaction conditions known in the
literature.
[0418] The compounds of the formula (IX) are known from the
literature (see, for example, EP 0607825 A1) or can be prepared in
analogy to processes known from the literature. The compounds of
the formulae (III), (V) and (X) are commercially available or
described as such in the literature, or they can be prepared in a
way obvious to the person skilled in the art, in analogy to methods
published in the literature. Numerous detailed methods and
literature data for preparation of the respective starting
materials can also be found in the Experimental Part in the section
relating to the preparation of the starting compounds and
intermediates. The separation of stereoisomers (enantiomers and/or
diastereomers) of the inventive compounds of the formula (I) can be
achieved by customary methods familiar to those skilled in the
art.
[0419] Preference is given to employing chromatographic methods on
achiral or chiral separation phases for this purpose. Separation of
the compounds of the invention into the corresponding enantiomers
and/or diastereomers can, if appropriate, also be conducted at the
early stage of the intermediates (II), (IV) or (VIII), which are
then reacted further in separated form in accordance with the
reaction sequence described above. For such a separation of the
stereoisomers of intermediates, preference is likewise given to
employing chromatographic methods on achiral or chiral separation
phases. Alternatively, separation can also be effected via
diastereomeric salts of the carboxylic acids of the formula (IV)
with chiral amine bases.
[0420] The preparation of the compounds of the invention can be
illustrated by way of example by the following reaction
schemes:
##STR00083##
##STR00084##
##STR00085##
##STR00086##
##STR00087##
[0421] Further inventive compounds of the formula (I) can, if
appropriate, also be prepared by transformations of functional
groups of individual radicals or substituents, especially those
listed under R.sup.1 and R.sup.2, proceeding from other compounds
of the formula (I) or precursors thereof obtained by the above
processes. These transformations are conducted by customary methods
familiar to the person skilled in the art and include, for example,
reactions such as nucleophilic or electrophilic substitution
reactions, transition-metal-mediated coupling reactions,
preparation and addition reactions of metal organyls (e.g. Grignard
compounds or lithium organyls), oxidation and reduction reactions,
hydrogenation, halogenation (e.g. fluorination, bromination),
dehalogenation, amination, alkylation and acylation, the formation
of carboxylic esters, carboxamides and sulfonamides, ester cleavage
and hydrolysis, and the introduction and removal of temporary
protecting groups.
[0422] The invention relates, in a further aspect, to intermediates
of the general formula (II)
##STR00088## [0423] in which X, R.sup.2 and Ar.sup.1 have the
meanings given above for compounds of the formula (I) [0424] and
[0425] Hal represents fluorine, chlorine, bromine or iodine,
preferably chlorine.
[0426] The invention relates, in a further aspect, to intermediates
of the general formula (IV)
##STR00089## [0427] in which X, R.sup.1 and Ar.sup.1 have the
meanings given above for compounds of the formula (I).
[0428] The invention relates, in a further aspect, to the use of a
compound of the general formula (II)
##STR00090## [0429] in which X, R.sup.2 and Ar.sup.1 have the
meanings given above for compounds of the formula (I) [0430] and
[0431] Hal represents fluorine, chlorine, bromine or iodine,
preferably chlorine. [0432] or [0433] a compound of the general
formula (IV)
[0433] ##STR00091## [0434] in which X, R.sup.1 and Ar.sup.1 have
the meanings given above for compounds of the formula (I), for
preparation of a compound of the general formula (I) as defined
above.
[0435] The compounds according to the invention have an
unforeseeable useful spectrum of pharmacological and
pharmacokinetic activity.
[0436] They are therefore suitable for use as medicaments for
treatment and/or prophylaxis of diseases in humans and animals. The
compounds of the invention have valuable pharmacological properties
and can be used for treatment and/or prophylaxis of disorders in
humans and animals.
[0437] The compounds according to the invention are positive
allosteric modulators of the muscarinic M2 receptor and are
therefore suitable for treatment and/or prevention of disorders and
pathological processes, especially cardiovascular disorders and/or
renal disorders, wherein the M2 receptor is involved in
dysregulation of the autonomic nervous system or an imbalance
between the activity of the sympathetic and parasympathetic portion
of the autonomic nervous system.
[0438] The present invention provides positive allosteric
modulators of the muscarinic M2 receptor. Allosteric modulators
have distinct differences from conventional orthosteric ligands.
The effect of an allosteric modulator is self-limiting when it
stabilizes the binding of the agonist in high concentrations.
Furthermore, the effect of an allosteric modulator can be displayed
only in the presence of the endogenous ligand. The allosteric
modulator itself has no direct influence on receptor activation.
This gives rise to specificity of the allosteric effect in terms of
space and time. The mutual influencing of allosteric and
orthosteric ligands in terms of affinity and intrinsic activity,
which is referred to as cooperativity, is determined by the two
ligands. In the case of a positive allosteric modulator, the
effects of the orthosteric ligand are enhanced (positive
cooperativity). Because of its ability to modulate receptor
conformations in the presence of an orthosteric ligand, allosteric
ligands can bring about fine adjustment of pharmacological
effects.
[0439] In the context of the present invention, disorders of the
cardiovascular system or cardiovascular disorders are understood to
mean, for example, the following disorders: acute and chronic heart
failure, arterial hypertension, coronary heart disease, stable and
unstable angina pectoris, myocardial ischaemia, myocardial
infarction, shock, atherosclerosis, cardiac hypertrophy, cardiac
fibrosis, atrial and ventricular arrhythmias, tachycardia,
transitory and ischaemic attacks, stroke, pre-eclampsia,
inflammatory cardiovascular disorders, peripheral and cardiac
vascular disorders, peripheral perfusion disorders, arterial
pulmonary hypertension, spasms of the coronary arteries and
peripheral arteries, thromboses, thromboembolic disorders, oedema
development, for example pulmonary oedema, cerebral oedema, renal
oedema or heart failure-related oedema, and restenosis such as
after thrombolysis treatments, percutaneous transluminal
angioplasty (PTA), transluminal coronary angioplasty (PTCA), heart
transplants and bypass operations, and micro- and macrovascular
damage (vasculitis), reperfusion damage, arterial and venous
thromboses, microalbuminuria, myocardial insufficiency, endothelial
dysfunction, peripheral and cardiac vascular disorders, peripheral
perfusion disorders, heart failure-related oedema, elevated levels
of fibrinogen and of low-density LDL and elevated concentrations of
plasminogen activator/inhibitor 1 (PAI 1).
[0440] In the context of the present invention, the term "heart
failure" also includes more specific or related types of disease,
such as acutely decompensated heart failure, right heart failure,
left heart failure, global failure, ischaemic cardiomyopathy,
dilated cardiomyopathy, congenital heart defects, heart valve
defects, heart failure associated with heart valve defects, mitral
valve stenosis, mitral valve insufficiency, aortic valve stenosis,
aortic valve insufficiency, tricuspid stenosis, tricuspid
insufficiency, pulmonary valve stenosis, pulmonary valve
insufficiency, combined heart valve defects, myocardial
inflammation (myocarditis), chronic myocarditis, acute myocarditis,
viral myocarditis, diabetic heart failure, alcoholic
cardiomyopathy, cardiac storage disorders, heart failure with
preserved ejection fraction (HFpEF), diastolic heart failure and
heart failure with reduced ejection fraction (HfrEF), systolic
heart failure.
[0441] In the context of the present invention, the term atrial and
ventricular arrhythmias also includes more specific or related
types of disease, such as: atrial fibrillation, paroxysmal atrial
fibrillation, intermittent atrial fibrillation, permanent atrial
fibrillation, atrial flutter, sinusoidal arrhythmia, sinusoidal
tachycardia, passive heterotopia, active heterotopia, escape
systoles, extrasystoles, impulse conduction disorders, sick sinus
syndrome, hypersensitive carotid sinus, tachycardias, AV node
reentry tachycardia, atriventricular reentry tachycardia, WPW
syndrome (Wolff-Parkinson-White), Mahaim tachycardia, hidden
accessory conduction pathway, permanent junctional reentry
tachycardia, focal atrial tachycardia, junctional ectopic
tachycardia, atrial reentry tachycardia, ventricular tachycardia,
ventricular flutter, ventricular fibrillation, sudden cardiac
death.
[0442] In the context of the present invention, the term coronary
heart disease also encompasses more specific or related types of
disease, such as: ischaemic heart disease, stable angina pectoris,
acute coronary syndrome, unstable angina pectoris, NSTEMI (non-ST
elevation myocardial infarction), STEMI (ST elevation myocardial
infarction), ischaemic heart muscle damage, heart rhythm
dysfunctions and myocardial infarction.
[0443] The compounds according to the invention are further
suitable for the prophylaxis and/or treatment of polycystic kidney
disease (PCKD) and of the syndrome of inappropriate ADH secretion
(SIADH).
[0444] The compounds of the invention are also suitable for the
treatment and/or prophylaxis of kidney disorders, in particular of
acute and chronic renal insufficiency and acute and chronic renal
failure.
[0445] In the context of the present invention, the term "acute
renal insufficiency" encompasses acute manifestations of kidney
disease, of kidney failure and/or renal insufficiency with and
without the need for dialysis, and also underlying or related renal
disorders such as renal hypoperfusion, intradialytic hypotension,
volume deficiency (e.g. dehydration, blood loss), shock, acute
glomerulonephritis, haemolytic-uraemic syndrome (HUS), vascular
catastrophe (arterial or venous thrombosis or embolism),
cholesterol embolism, acute Bence-Jones kidney in the event of
plasmacytoma, acute supravesicular or subvesicular efflux
obstructions, immunological renal disorders such as kidney
transplant rejection, immune complex-induced renal disorders,
tubular dilatation, hyperphosphataemia and/or acute renal disorders
which can be characterized by the need for dialysis, including in
the case of partial resections of the kidney, dehydration through
forced diuresis, uncontrolled blood pressure rise with malignant
hypertension, urinary tract obstruction and infection and
amyloidosis, and systemic disorders with glomerular factors, such
as rheumatological-immunological systemic disorders, for example
lupus erythematosus, renal artery thrombosis, renal vein
thrombosis, analgesic nephropathy and renal-tubular acidosis, and
x-ray contrast agent- and medicament-induced acute interstitial
renal disorders.
[0446] In the context of the present invention, the term "chronic
renal insufficiency" encompasses chronic manifestations of kidney
disease, of kidney failure and/or renal insufficiency with and
without the need for dialysis, and also underlying or related renal
disorders such as renal hypoperfusion, intradialytic hypotension,
obstructive uropathy, glomerulopathy, glomerular and tubular
proteinuria, renal oedema, haematuria, primary, secondary and
chronic glomerulonephritis, membranous and membranoproliferative
glomerulonephritis, Alport syndrome, glomerulosclerosis,
tubulointerstitial disorders, nephropathic disorders such as
primary and congenital kidney disease, renal inflammation,
immunological renal disorders such as kidney transplant rejection,
immune complex-induced renal disorders, diabetic and non-diabetic
nephropathy, pyelonephritis, renal cysts, nephrosclerosis,
hypertensive nephrosclerosis and nephrotic syndrome, which can be
characterized diagnostically, for example, by abnormally reduced
creatinine and/or water excretion, abnormally elevated blood
concentrations of urea, nitrogen, potassium and/or creatinine,
altered activity of renal enzymes, for example glutamyl synthetase,
altered urine osmolarity or urine volume, elevated
microalbuminuria, macroalbuminuria, glomerular and arteriolar
lesions, tubular dilatation, hyperphosphataemia and/or the need for
dialysis, and also for renal cell carcinomas, after partial
resections of the kidney, dehydration through forced diuresis,
uncontrolled blood pressure increase with malignant hypertension,
urinary tract obstruction and infection and amyloidosis and
systemic disorders with glomerular factors, such as
rheumatological-immunological systemic disorders, for example lupus
erythematosus, and renal artery stenosis, renal artery thrombosis,
renal vein thrombosis, analgesic nephropathy and renal-tubular
acidosis.
[0447] In addition, X-ray contrast agent- and medicament-induced
chronic interstitial renal disorders, metabolic syndrome and
dyslipidaemia. The present invention also encompasses the use of
the compounds according to the invention for treatment and/or
prophylaxis of sequelae of renal insufficiency, for example
pulmonary oedema, heart failure, uraemia, anaemia, electrolyte
disorders (for example hyperkalaemia, hyponatraemia) and disorders
in bone and carbohydrate metabolism. In addition, the compounds
according to the invention are also suitable for treatment and/or
prophylaxis of pulmonary arterial hypertension (PAH) and other
forms of pulmonary hypertension (PH), of chronic obstructive
pulmonary disease (COPD), of acute respiratory distress syndrome
(ARDS), of acute lung injury (ALI), of alpha-1-antitrypsin
deficiency (AATD), of pulmonary fibrosis, of pulmonary emphysema
(for example pulmonary emphysema caused by cigarette smoke), of
cystic fibrosis (CF), of acute coronary syndrome (ACS), heart
muscle inflammations (myocarditis) and other autoimmune cardiac
disorders (pericarditis, endocarditis, valvolitis, aortitis,
cardiomyopathies), cardiogenic shock, aneurysms, sepsis (SIRS),
multiple organ failure (MODS, MOF), inflammatory disorders of the
kidney, chronic intestinal disorders (IBD, Crohn's Disease, UC),
pancreatitis, peritonitis, rheumatoid disorders, inflammatory skin
disorders and inflammatory eye disorders.
[0448] The compounds according to the invention can also be used
for treatment and/or prophylaxis of asthmatic disorders of varying
severity with intermittent or persistent characteristics
(refractive asthma, bronchial asthma, allergic asthma, intrinsic
asthma, extrinsic asthma, medicament- or dust-induced asthma), of
various forms of bronchitis (chronic bronchitis, infectious
bronchitis, eosinophilic bronchitis), of Bronchiolitis obliterans,
bronchiectasis, pneumonia, idiopathic interstitial pneumonia,
farmer's lung and related diseases, of coughs and colds (chronic
inflammatory cough, iatrogenic cough), inflammation of the nasal
mucosa (including medicament-related rhinitis, vasomotoric rhinitis
and seasonal allergic rhinitis, for example hay fever) and of
polyps.
[0449] The compounds described in the present invention are also
active compounds for control of central nervous system disorders
characterized by disturbances of the NO/cGMP system. In particular,
they are suitable for improving perception, concentration, learning
or memory after cognitive impairments like those occurring in
particular in association with situations/diseases/syndromes such
as mild cognitive impairment, age-associated learning and memory
impairments, age-associated memory losses, vascular dementia,
craniocerebral trauma, stroke, dementia occurring after strokes
(post-stroke dementia), post-traumatic craniocerebral trauma,
general concentration impairments, concentration impairments in
children with learning and memory problems, Alzheimer's disease,
Lewy body dementia, dementia with degeneration of the frontal lobes
including Pick's syndrome, Parkinson's disease, progressive nuclear
palsy, dementia with corticobasal degeneration, amyolateral
sclerosis (ALS), Huntington's disease, demyelinization, multiple
sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV
dementia, schizophrenia with dementia or Korsakoff's psychosis.
They are also suitable for treatment and/or prevention of central
nervous system disorders such as states of anxiety, tension and
depression, bipolar disorder, CNS-related sexual dysfunctions and
sleep disturbances, and for controlling pathological disturbances
of the intake of food, stimulants and addictive substances.
[0450] Furthermore, the compounds according to the invention are
also suitable for the treatment and prophylaxis of urological
disorders such as: urine incontinence, in particular stress
incontinence, urge incontinence, reflex incontinence and overflow
incontinence, detrusor hyperactivity, neurogenic detrusor
hyperactivity, idiopathic detrusor hyperactivity, benign prostate
hyperplasia (BPH syndrome), lower urinary tract symptoms
(LUTS).
[0451] The compounds according to the invention are furthermore
suitable for the treatment and/or prevention of gastroenterological
disorders such as oesophagus disorders, emesis, achalasia,
gastrooesophageal reflux disease, stomach disorders such as
gastritis, disorders of the intestine such as diarrhoea,
constipation, malassimilation syndrome, bile acid loss syndrome,
Crohn's disease, ulcerative colitis, microscopic colitis and
irritable bowel syndrome.
[0452] The compounds according to the invention are further
suitable for the treatment and/or prevention of states of pain such
as menstruation disorders, dysmenorrhoea, endometriosis, premature
birth, tocolysis.
[0453] Because of their profile of biochemical and pharmacological
properties, the compounds according to the invention are also
especially suitable for treatment and/or prevention of heart
failure, coronary heart disease, atrial and ventricular arrhythmia,
kidney failure and nephropathy.
[0454] The compounds of the invention can additionally be used for
the treatment and/or prophylaxis of primary and secondary Raynaud's
phenomenon, of microcirculation impairments, claudication,
peripheral and autonomic neuropathies, diabetic neuropathies,
diabetic microangiopathies, diabetic retinopathy, diabetic ulcers
on the extremities, gangrene, CREST syndrome, erythematosis,
onychomycosis, rheumatic disorders and for promoting wound
healing.
[0455] The compounds of the invention are additionally suitable for
treatment and/or prevention of ophthalmologic disorders, for
example glaucoma, age-related macular degeneration (AMD), of dry
(non-exudative) AMD, wet (exudative, neovascular) AMD, choroidal
neovascularization (CNV), diabetic retinopathy, atrophic changes to
the retinal pigment epithelium (RPE), hypertrophic changes to the
retinal pigment epithelium, macular oedema, diabetic macular
oedema, retinal vein occlusion, choroidal retinal vein occlusion,
macular oedema due to retinal vein occlusion, angiogenesis at the
front of the eye, for example corneal angiogenesis, for example
following keratitis, cornea transplant or keratoplasty, corneal
angiogenesis due to hypoxia (as a result of extensive wearing of
contact lenses), pterygium conjunctiva, subretinal oedema and
intraretinal oedema. In addition, the compounds of the invention
are suitable for treatment and/or prevention of elevated and high
intraocular pressure as a result of traumatic hyphaema, periorbital
oedema, postoperative viscoelastic retention or intraocular
inflammation.
[0456] Moreover, the compounds according to the invention are
suitable for the treatment and/or prophylaxis of hepatitis,
neoplasms, osteoporosis, glaucoma and gastroparesis.
[0457] In addition, the compounds of the invention are also
suitable for controlling cerebral blood flow and are effective
agents for controlling migraine. They are also suitable for the
prophylaxis and control of sequelae of cerebral infarct (Apoplexia
cerebri) such as stroke, cerebral ischaemias and skull-brain
trauma. The compounds of the invention can also be used for
controlling pain, neuralgias and tinnitus.
[0458] The aforementioned well-characterized diseases in humans can
also occur with comparable aetiology in other mammals and can
likewise be treated therein with the compounds of the present
invention.
[0459] In the context of the present invention, the term
"treatment" or "treating" includes inhibition, retardation,
checking, alleviating, attenuating, restricting, reducing,
suppressing, repelling or healing of a disease, a condition, a
disorder, an injury or a health problem, or the development, the
course or the progression of such states and/or the symptoms of
such states. The term "therapy" is understood here to be synonymous
with the term "treatment".
[0460] The terms "prevention", "prophylaxis" and "preclusion" are
used synonymously in the context of the present invention and refer
to the avoidance or reduction of the risk of contracting,
experiencing, suffering from or having a disease, a condition, a
disorder, an injury or a health problem, or a development or
advancement of such states and/or the symptoms of such states.
[0461] The treatment or prevention of a disease, a condition, a
disorder, an injury or a health problem may be partial or
complete.
[0462] The present invention thus further provides for the use of
the compounds of the invention for treatment and/or prevention of
disorders, especially of the aforementioned disorders.
[0463] The present invention further provides for the use of the
compounds of the invention for production of a medicament for
treatment and/or prevention of disorders, especially of the
aforementioned disorders.
[0464] The present invention further provides a medicament
comprising at least one of the compounds of the invention for
treatment and/or prevention of disorders, especially of the
aforementioned disorders.
[0465] The present invention further provides for the use of the
compounds of the invention in a method for treatment and/or
prevention of disorders, especially of the aforementioned
disorders.
[0466] The present invention further provides a method of treatment
and/or prevention of disorders, especially of the aforementioned
disorders, using an effective amount of at least one of the
compounds of the invention.
[0467] The present invention further provides the compounds
according to the invention for use in a method of treatment and/or
prevention of disorders, especially of the aforementioned
disorders.
[0468] The compounds of the invention can be used alone or, if
required, in combination with one or more other pharmacologically
active substances, provided that this combination does not lead to
undesirable and unacceptable side effects. The present invention
therefore further provides medicaments comprising at least one of
the compounds of the invention and one or more further drugs,
especially for treatment and/or prevention of the aforementioned
disorders. Preferred examples of combination active ingredients
suitable for this purpose include: [0469] hypotensive drugs, by way
of example and with preference from the group of calcium
antagonists, angiotensin All antagonists, ACE inhibitors, NEP
inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin
inhibitors, alpha-receptor blockers, beta-receptor blockers,
mineralocorticoid receptor antagonists, and rho kinase inhibitors
and the diuretics; [0470] antiarrhythmics, by way of example and
with preference sodium channel blockers, beta receptor blockers,
potassium channel blockers, calcium antagonists, If channel
blockers, digitalis, parasympatholytics (vagolytics),
sympathomimetics and other antiarrhythmics such as adenosine,
adenosine receptor agonists and vernakalant; [0471] compounds
having a positive inotropic effect, for example cardiac glycosides
(digoxin), beta-adrenergic and dopaminergic agonists such as
isoprenaline, adrenaline, noradrenaline, dopamine or dobutamine;
[0472] vasopressin receptor antagonists, by way of example and with
preference conivaptan, tolvaptan, lixivaptan, mozavaptan,
satavaptan, SR-121463, RWJ 676070 or BAY 86-8050, and also the
compounds described in WO 2010/105770, WO2011/104322 and WO
2016/071212; [0473] natriuretic peptides, for example atrial
natriuretic peptide (ANP), natriuretic peptide type B (BNP,
nesiritide) natriuretic peptide type C (CNP) or urodilatin; [0474]
activators of cardial myosins, for example omecamtiv mecarbil
(CK-1827452); [0475] calcium sensitizers, for example levosimendan;
[0476] compounds which modulate the energy metabolism of the heart,
by way of example and with preference etomoxir, dichloroacetate,
ranolazine or trimetazidine, full or partial adenosine A1 receptor
agonists such as GS-9667 (known beforehand as CVT-3619),
capadenoson, neladenoson and BAY 1067197; [0477] compounds which
modulate the heart rate, for example ivabradine; [0478] compounds
which inhibit the degradation of cyclic guanosine monophosphate
(cGMP) and/or cyclic adenosine monophosphate (cAMP), for example
inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and/or 5,
especially PDE 5 inhibitors such as sildenafil, vardenafil and
tadalafil, udenafil, desantafil, avanafil, mirodenafil, lodenafil
or PF-00489791; [0479] antithrombotics, by way of example and with
preference from the group of the platelet aggregation inhibitors,
the anticoagulants or the profibrinolytic substances; [0480]
bronchodilatory agents, by way of example and with preference from
the group of the beta-adrenergic receptor agonists, such as
especially albuterol, isoproterenol, metaproterenol, terbutalin,
formoterol or salmeterol, or from the group of the
anticholinergics, such as especially ipratropium bromide; [0481]
anti-inflammatory agents, by way of example and with preference
from the group of the glucocorticoids, such as especially
prednisone, prednisolone, methylprednisolone, triamcinolone,
dexamethasone, beclomethasone, betamethasone, flunisolide,
budesonide or fluticasone and also non-steroidal anti-inflammatory
drugs (NSAIDs) such as, in particular, acetylsalicylic acid
(Aspirin), ibuprofen and naproxen, 5-aminosalicylic acid
derivatives, leukotriene antagonists, TNF-alpha inhibitors and
chemokine receptor antagonists such as CCR1, 2 and/or 5 inhibitors;
[0482] lipid metabolism modifiers, for example and with preference
from the group of thyroid receptor agonists, cholesterol synthesis
inhibitors, preferred examples being HMG-CoA reductase inhibitors
or squalene synthesis inhibitors, of ACAT inhibitors, CETP
inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or
PPAR-.delta. agonists, cholesterol absorption inhibitors, lipase
inhibitors, polymeric bile acid adsorbents, bile acid reabsorption
inhibitors and lipoprotein(a) antagonists; [0483] compounds which
inhibit the signal transduction cascade, by way of example and with
preference from the group of the kinase inhibitors, especially from
the group of the tyrosine kinase and/or serine/threonine kinase
inhibitors; [0484] compounds which inhibit the degradation and
alteration of the extracellular matrix, by way of example and with
preference inhibitors of the matrix metalloproteases (MMPs),
especially inhibitors of chymase, stromelysin, collagenases,
gelatinases and aggrecanases (in this context particularly of
MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13) and of
metalloelastase (MMP-12) and neutrophile elastase (HNE), such as
sivelestat or DX-890; [0485] compounds which block the binding of
serotonin to its receptor by way of example and with preference
antagonists of the 5-HT.sub.2b receptor; [0486] organic nitrates
and NO donors, for example sodium nitroprusside, nitroglycerin,
isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1,
and inhaled NO; [0487] NO-independent but haem-dependent
stimulators of soluble guanylate cyclase, such as in particular the
compounds described in WO 00/06568, WO 00/06569, WO 02/42301, WO
03/095451, WO 2011/147809, WO 2012/004258, WO 2012/028647 and WO
2012/059549; [0488] NO- and haem-independent activators of soluble
guanylate cyclase, such as especially the compounds described in WO
01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and
WO 02/070510; [0489] compounds which increase the synthesis of
cGMP, for example sGC modulators such as, by way of example and
with preference, riociguat, cinaciguat, vericiguat or BAY 1101042;
[0490] prostacyclin analogues, by way of example and with
preference iloprost, beraprost, treprostinil or epoprostenol;
[0491] compounds which inhibit soluble epoxide hydrolase (sEH), for
example N,N'-dicyclohexylurea,
12-(3-adamantan-1-ylureido)dodecanoic acid or
1-adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}urea; [0492]
active compounds which modulate glucose metabolism, for example
insulins, biguanides, thiazolidinediones, sulfonylureas, acarbose,
DPP4 inhibitors, GLP-1 analogues or SGLT-1 inhibitors.
[0493] In a preferred embodiment of the invention, the compounds
according to the invention are used in combination with a kinase
inhibitor, by way of example and with preference bortezomib,
canertinib, erlotinib, gefitinib, imatinib, lapatinib,
lestaurtinib, lonafarnib, nintedanib, dasatinib, nilotinib,
bosutinib, axitinib, telatinib, imatinib, brivanib, pazopanib,
pegaptinib, pelitinib, semaxs anib, sorafenib, regorafenib,
sunitinib, tandutinib, tipifarnib, vatalanib, fasudil, lonidamine,
leflunomide, BMS-3354825 or Y-27632.
[0494] In a preferred embodiment of the invention, the compounds
according to the invention are used in combination with a serotonin
receptor antagonist, by way of example and with preference
PRX-08066.
[0495] Antithrombotic agents are preferably understood to mean
compounds from the group of the platelet aggregation inhibitors,
the anticoagulants or the profibrinolytic substances.
[0496] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a platelet
aggregation inhibitor, by way of example and with preference
aspirin, clopidogrel, ticlopidine or dipyridamole.
[0497] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
thrombin inhibitor, by way of example and with preference
dabigatran, ximelagatran, melagatran, bivalirudin or clexane.
[0498] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a GPIIb/IIIa
antagonist, by way of example and with preference tirofiban or
abciximab.
[0499] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
factor Xa inhibitor, by way of example and with preference
rivaroxaban, edoxaban (DU-176b), apixaban, otamixaban, fidexaban,
razaxaban, fondaparinux, idraparinux, PMD-3112, YN-150, KFA-1982,
EMD-503982, MCN-17, mLN-1021, DX 9065a, DPC 906, JTV 803,
SSR-126512 or SSR-128428.
[0500] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with heparin or with
a low molecular weight (LMW) heparin derivative.
[0501] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a vitamin K
antagonist, by way of example and with preference coumarin.
[0502] Hypotensive agents are preferably understood to mean
compounds from the group of calcium antagonists, angiotensin All
antagonists, ACE inhibitors, endothelin antagonists, renin
inhibitors, alpha-receptor blockers, beta-receptor blockers,
mineralocorticoid receptor antagonists, rho kinase inhibitors, and
the diuretics.
[0503] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a calcium
antagonist, by way of example and with preference nifedipine,
amlodipine, verapamil or diltiazem.
[0504] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with an alpha-1
receptor blocker, by way of example and with preference prazosin.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with a beta receptor
blocker, by way of example and with preference propranolol,
atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol,
bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol,
metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol,
labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or
bucindolol.
[0505] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with an
angiotensin All antagonist, by way of example and with preference
losartan, candesartan, valsartan, telmisartan or embursatan,
irbesartan, olmesartan, eprosartan or azilsartan or a dual
angiotensin All antagonist/NEP inhibitor, for example and with
preference Entresto (LCZ696, valsartan/sacubitril).
[0506] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with an
ACE inhibitor, by way of example and with preference enalapril,
captopril, lisinopril, ramipril, delapril, fosinopril, quinopril,
perindopril or trandopril.
[0507] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with an
endothelin antagonist, by way of example and with preference
bosentan, darusentan, ambrisentan, avosentan, macitentan,
atrasentan or sitaxsentan.
[0508] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
TGFbeta antagonist, by way of example and with preference
pirfenidone or fresolimumab.
[0509] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
TNFalpha antagonist, by way of example and with preference
adalimumab.
[0510] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a renin
inhibitor, by way of example and with preference aliskiren, SPP-600
or SPP-800.
[0511] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with
HIF-PH inhibitors, by way of example and with preference molidustat
or roxadustat.
[0512] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a
mineralocorticoid receptor antagonist, by way of example and with
preference spironolactone or eplerenone, finerenone.
[0513] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
rho kinase inhibitor, by way of example and with preference
fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095,
SB-772077, GSK-269962A or BA-1049.
[0514] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a diuretic, for
example furosemide, torasemide, bumetanide and piretanide, with
potassium-sparing diuretics, for example amiloride and triamterene,
with aldosterone antagonists, for example spironolactone, potassium
canrenoate and eplerenone, and also thiazide diuretics, for example
hydrochlorothiazide, chlorthalidone, xipamide and indapamide.
[0515] Lipid metabolism modifiers are preferably understood to mean
compounds from the group of the CETP inhibitors, thyroid receptor
agonists, cholesterol synthesis inhibitors such as HMG-CoA
reductase inhibitors or squalene synthesis inhibitors, the ACAT
inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or
PPAR-.delta. agonists, cholesterol absorption inhibitors, polymeric
bile acid adsorbents, bile acid reabsorption inhibitors, lipase
inhibitors and the lipoprotein(a) antagonists.
[0516] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a CETP
inhibitor, by way of example and with preference torcetrapib
(CP-529 414), anacetrapib, JJT-705 or CETP vaccine (Avant).
[0517] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a thyroid
receptor agonist, by way of example and with preference
D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome
(CGS 26214).
[0518] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with an HMG-CoA
reductase inhibitor from the class of statins, by way of example
and with preference lovastatin, simvastatin, pravastatin,
fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
[0519] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a squalene
synthesis inhibitor, by way of example and with preference
BMS-188494 or TAK-475.
[0520] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with an ACAT
inhibitor, by way of example and with preference avasimibe,
melinamide, pactimibe, eflucimibe or SMP-797.
[0521] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with an MTP
inhibitor, by way of example and with preference implitapide,
BMS-201038, R-103757 or JTT-130.
[0522] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a PPAR-gamma
agonist, by way of example and with preference pioglitazone or
rosiglitazone.
[0523] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
PPAR-.delta. agonist, by way of example and with preference GW
501516 or BAY 68-5042.
[0524] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a cholesterol
absorption inhibitor, by way of example and with preference
ezetimibe, tiqueside or pamaqueside.
[0525] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a lipase
inhibitor, by way of example and with preference orlistat.
[0526] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a polymeric bile
acid adsorber, by way of example and with preference
cholestyramine, colestipol, colesolvam, CholestaGel or
colestimide.
[0527] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a bile acid
reabsorption inhibitor, by way of example and with preference ASBT
(=IBAT) inhibitors, for example AZD-7806, S-8921, AK-105,
BARI-1741, SC-435 or SC-635.
[0528] In a preferred embodiment of the invention, the compounds of
the invention are administered in combination with a lipoprotein(a)
antagonist, by way of example and with preference gemcabene calcium
(CI-1027) or nicotinic acid.
[0529] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with sGC
modulators, by way of example and with preference riociguat,
cinaciguat, vericiguat or BAY 1101042.
[0530] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with an
active ingredient which modulates glucose metabolism, by way of
example and with preference insulin, a sulfonylurea, acarbose, DPP4
inhibitors, GLP-1 analogues or SGLT-1 inhibitor.
[0531] Particular preference is given to combinations of the
compounds according to the invention with one or more further
active ingredients selected from the group consisting of active
hypotensive ingredients, active antiarrhythmic ingredients,
vasopressin receptor antagonists, PDE 5 inhibitors, platelet
aggregation inhibitors, sGC activators and sGC stimulators.
[0532] The present invention further provides medicaments which
comprise at least one compound of the invention, typically together
with one or more inert, non-toxic, pharmaceutically suitable
excipients, and for the use thereof for the aforementioned
purposes.
[0533] The compounds of the invention can act systemically and/or
locally. For this purpose, they can be administered in a suitable
manner, for example by the oral, parenteral, pulmonal, nasal,
sublingual, lingual, buccal, rectal, dermal, transdermal,
conjunctival or otic route, or as an implant or stent.
[0534] The compounds of the invention can be administered in
administration forms suitable for these administration routes.
[0535] Suitable administration forms for oral administration are
those which work according to the prior art and release the
compounds of the invention rapidly and/or in a modified manner and
which contain the compounds of the invention in crystalline and/or
amorphized and/or dissolved form, for example tablets (uncoated or
coated tablets, for example with gastric juice-resistant or
retarded-dissolution or insoluble coatings which control the
release of the compound of the invention), tablets or films/oblates
which disintegrate rapidly in the oral cavity, films/lyophilizates,
capsules (for example hard or soft gelatin capsules), sugar-coated
tablets, granules, pellets, powders, emulsions, suspensions,
aerosols or solutions.
[0536] Parenteral administration can bypass an absorption step
(e.g. take place intravenously, intraarterially, intracardially,
intraspinally or intralumbally) or include an absorption (e.g. take
place inhalatively, intramuscularly, subcutaneously,
intracutaneously, percutaneously or intraperitoneally).
Administration forms suitable for parenteral administration include
preparations for injection and infusion in the form of solutions,
suspensions, emulsions, lyophilizates or sterile powders.
[0537] For the other administration routes, suitable examples are
inhalable medicament forms (including powder inhalers, nebulizers,
metered aerosols), nasal drops, solutions or sprays, tablets,
films/oblates or capsules for lingual, sublingual or buccal
administration, suppositories, ear or eye preparations, vaginal
capsules, aqueous suspensions (lotions, shaking mixtures),
lipophilic suspensions, ointments, creams, transdermal therapeutic
systems (e.g. patches), milk, pastes, foams, sprinkling powders,
implants or stents.
[0538] Oral and parenteral administration are preferred, especially
oral, intravenous and intrapulmonary (inhalative)
administration.
[0539] The compounds of the invention can be converted to the
administration forms mentioned. This can be accomplished in a
manner known per se by mixing with inert, non-toxic,
pharmaceutically suitable excipients. These excipients include
carriers (for example microcrystalline cellulose, lactose,
mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers
and dispersing or wetting agents (for example sodium
dodecylsulfate, polyoxysorbitan oleate), binders (for example
polyvinylpyrrolidone), synthetic and natural polymers (for example
albumin), stabilizers (e.g. antioxidants, for example ascorbic
acid), colourants (e.g. inorganic pigments, for example iron
oxides) and flavour and/or odour correctors.
[0540] In general, it has been found to be advantageous in the case
of parenteral administration to administer amounts of about 0.001
to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg, of body weight to
achieve effective results. In the case of oral administration the
dosage is about 0.01 to 100 mg/kg, preferably about 0.01 to 20
mg/kg and most preferably 0.1 to 10 mg/kg of body weight.
[0541] It may nevertheless be necessary in some cases to deviate
from the stated amounts, specifically as a function of body weight,
route of administration, individual response to the active
ingredient, nature of the preparation and time or interval over
which administration takes place. Thus in some cases it may be
sufficient to manage with less than the abovementioned minimum
amount, while in other cases the upper limit mentioned must be
exceeded. In the case of administration of greater amounts, it may
be advisable to divide them into several individual doses over the
day.
[0542] The working examples which follow illustrate the invention.
The invention is not restricted to the examples.
A. Examples
Abbreviations and Acronyms
TABLE-US-00001 [0543] GP General Procedure abs. absolute AIBN
azobis(isobutyronitrile) aq. aqueous, aqueous solution br. broad
(in NMR signal) Ex. Example Bu butyl c concentration approx. circa,
about cat. catalytic CDI carbonyldiimidazole CI chemical ionization
(in MS) d doublet (in NMR) d day(s) DCM dichloromethane dd doublet
of doublets (in NMR) de diastereomeric excess DEA diethylamine
dist. distilled DIPEA N,N-diisopropylethylamine DMAP
4-N,N-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl
sulfoxide dt doublet of triplets (in NMR) ee enantiomeric excess EI
electron impact ionization (in MS) ent enantiomerically pure,
enantiomer eq. equivalent(s) ESI electrospray ionization (in MS) Et
ethyl GC gas chromatography GC/MS gas chromatography-coupled mass
spectrometry h hour(s) HATU
O-(7-azabenzotriazol-1-y1)-N,N,N',N'-tetramethyluronium
hexafluorophosphate HPLC high-pressure, high-performance liquid
chromatography conc. concentrated (in the case of a solution) LC
liquid chromatography LC/MS liquid chromatography-coupled mass
spectrometry lit. literature (reference) m multiplet (in NMR) M
molar (in solution) Me methyl min minute(s) MS mass spectrometry
NBS 1-bromopyrrolidine-2,5-dione NMR nuclear magnetic resonance
spectrometry q (or quart) quartet (in NMR) qd quartet of doublets
(in NMR) quant. quantitative (in chemical yield) quint quintet (in
NMR) rac racemic, racemate RP reverse phase (in HPLC) RT room
temperature Rt retention time (in HPLC, LC/MS) s singlet (in NMR)
sept septet (in NMR) SFC supercritical liquid chromatography t
triplet (in NMR) tBu tert-butyl td triplet of doublets (in NMR) TFA
trifluoroacetic acid THF tetrahydrofuran UV ultraviolet
spectrometry cf. see v/v volume to volume ratio (of a solution)
Xantphos 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene tog.
together
HPLC and LC/MS Methods:
Method 1:
[0544] Instrument: Waters ACQUITY SQD UPLC System; column: Waters
Acquity UPLC HSS T3 1.8.mu.50.times.1 mm; mobile phase A: 1 l of
water+0.25 ml of 99% strength formic acid, mobile phase B: 1 l of
acetonitrile+0.25 ml of 99% strength formic acid; gradient: 0.0 min
90% A.fwdarw.1.2 min 5% A.fwdarw.2.0 min 5% A; oven: 50.degree. C.;
flow rate: 0.40 ml/min; UV detection: 208-400 nm.
Method 2:
[0545] MS instrument: Waters (Micromass) QM; HPLC instrument:
Agilent 1100 series; column: Agilent ZORBAX Extend-C18 3.0.times.50
mm 3.5 micron; mobile phase A: 1 l of water+0.01 mol of ammonium
carbonate, mobile phase B: 1 l of acetonitrile; gradient: 0.0 min
98% A.fwdarw.0.2 min 98% A.fwdarw.3.0 min 5% A.fwdarw.4.5 min 5% A;
oven: 40.degree. C.; flow rate: 1.75 ml/min; UV detection: 210
nm
Method 3:
[0546] MS instrument type: Thermo Scientific FT-MS; instrument type
UHPLC+: Thermo Scientific UltiMate 3000; column: Waters, HSST3,
2.1.times.75 mm, C18 1.8 .mu.m; mobile phase A: 1 l of water+0.01%
formic acid; mobile phase B: 1 l of acetonitrile+0.01% formic acid;
gradient: 0.0 min 10% B.fwdarw.2.5 min 95% B.fwdarw.3.5 min 95% B;
oven: 50.degree. C.; flow rate: 0.90 m/min; UV detection: 210
nm/Optimum Integration Path 210-300 nm.
Method 4:
[0547] Instrument: Waters ACQUITY SQD UPLC System; column: Waters
Acquity UPLC HSS T3 1.8.mu. 50.times.1 mm; mobile phase A: 1 l of
water+0.25 ml of 99% strength formic acid, mobile phase B: 1 l of
acetonitrile+0.25 ml of 99% strength formic acid; gradient: 0.0 min
95% A.fwdarw.6.0 min 5% A.fwdarw.7.5 min 5% A; oven: 50.degree. C.;
flow rate: 0.35 ml/min; UV detection: 210-400 nm.
Method 5:
[0548] Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290;
column: Waters Acquity UPLC HSS T3 1.8.mu. 50.times.2.1 mm; mobile
phase A: 1 l of water+0.25 ml of 99% strength formic acid, mobile
phase B: 1 l of acetonitrile+0.25 ml of 99% strength formic acid;
gradient: 0.0 min 90% A.fwdarw.0.3 min 90% A.fwdarw.1.7 min 5%
A.fwdarw.3.0 min 5% A oven: 50.degree. C.; flow rate: 1.20 ml/min;
UV detection: 205-305 nm.
Method 6:
[0549] Instrument: Thermo DFS, Trace GC Ultra; column: Restek
RTX-35, 15 m.times.200 .mu.m.times.0.33 .mu.m; constant helium flow
rate: 1.20 ml/min; oven: 60.degree. C.; inlet: 220.degree. C.;
gradient: 60.degree. C., 30.degree. C./min->300.degree. C.
(maintain for 3.33 min).
Further Details:
[0550] The percentages in the example and test descriptions which
follow are, unless indicated otherwise, percentages by weight;
parts are parts by weight. Solvent ratios, dilution ratios and
concentration data for liquid/liquid solutions are based in each
case on volume.
[0551] In the case of purifications of compounds of the invention
by preparative HPLC by the described methods in which the eluents
contain additives, for example trifluoroacetic acid, formic acid or
ammonia, the compounds of the invention can be obtained in salt
form, for example as trifluoroacetate, formate or ammonium salt, if
the compounds of the invention contain a sufficiently basic or
acidic functionality. Such a salt can be converted to the
corresponding free base or acid by various methods known to the
person skilled in the art.
[0552] Purity figures are generally based on corresponding peak
integrations in the LC/MS chromatogram, but may additionally also
have been determined with the aid of the 1H NMR spectrum. If no
purity is indicated, the purity is generally 100% according to
automated peak integration in the LC/MS chromatogram, or the purity
has not been determined explicitly.
[0553] Stated yields in % of theory are generally corrected for
purity if a purity of <100% is indicated. In solvent-containing
or contaminated batches, the formal yield may be ">100%"; in
these cases the yield is not corrected for solvent or purity.
[0554] The descriptions of the coupling patterns of 1H NMR signals
that follow have in some cases been taken directly from the
suggestions of the ACD SpecManager (ACD/Labs Release 12.00, Product
version 12.5) and have not necessarily been strictly scrutinized.
In addition to these .sup.1H NMR data, there may be additional
broadened signals--owing to the prevailing molecular dynamics (in
particular in the range of 2.50-4.20 ppm)--which are not separately
indicated. In some cases, the suggestions of the SpecManager were
adjusted manually. Manually adjusted or assigned descriptions are
generally based on the optical appearance of the signals in
question and do not necessarily correspond to a strict, physically
correct interpretation. In general, the stated chemical shift
refers to the centre of the signal in question. In the case of
broad multiplets, an interval is given. Signals obscured by solvent
or water were either tentatively assigned or have not been listed.
Significantly broadened signals--caused, for example, by rapid
rotation of molecular moieties or because of exchanging
protons--were likewise assigned tentatively (often referred to as a
broad multiplet or broad singlet) or are not listed.
[0555] The .sup.1H NMR data of selected examples are stated in the
form of .sup.1H NMR peak lists. For each signal peak, first the 6
value in ppm and then the signal intensity in round brackets are
listed. The .delta. value/signal intensity number pairs for
different signal peaks are listed with separation from one another
by commas. The peak list for an example therefore takes the
following form: .beta..sub.1 (intensity.sub.1), .delta..sub.2
(intensity.sub.2), . . . , .beta..sub.i (intensity.sub.i), . . . ,
.beta..sub.n (intensity.sub.n).
[0556] The intensity of sharp signals correlates with the height of
the signals in a printed example of an NMR spectrum in cm and shows
the true ratios of the signal intensities in comparison with other
signals. In the case of broad signals, several peaks or the middle
of the signal and the relative intensity thereof may be shown in
comparison to the most intense signal in the spectrum. The lists of
the .sup.1H NMR peaks are similar to the conventional .sup.1H NMR
printouts and thus usually contain all peaks listed in a
conventional NMR interpretation. In addition, like conventional
.sup.1H NMR printouts, they may show solvent signals, signals of
stereoisomers of the target compounds which are likewise provided
by the invention, and/or peaks of impurities. The peaks of
stereoisomers of the target compounds and/or peaks of impurities
usually have a lower intensity on average than the peaks of the
target compounds (for example with a purity of >90%). Such
stereoisomers and/or impurities may be typical of the particular
preparation process. Their peaks can thus help in identifying
reproduction of our preparation process with reference to
"by-product fingerprints". An expert calculating the peaks of the
target compounds by known methods (MestreC, ACD simulation, or
using empirically evaluated expected values) can, if required,
isolate the peaks of the target compounds, optionally using
additional intensity filters. This isolation would be similar to
the peak picking in question in conventional .sup.1H NMR
interpretation. A detailed description of the presentation of NMR
data in the form of peak lists can be found in the publication
"Citation of NMR Peaklist Data within Patent Applications" (cf.
Research Disclosure Database Number 605005, 2014, 1 Aug. 2014 or
http://www.researchdisclosure.com/searching-disclosures). In the
peak picking routine described in Research Disclosure Database
Number 605005, the parameter "MinimumHeight" can be set between 1%
and 4%. Depending on the type of chemical structure and/or
depending on the concentration of the compound to be analysed, it
may be advisable to set the parameters "MinimumHeight" to values of
<1%.
[0557] Melting points and melting point ranges, if stated, are
uncorrected.
[0558] All reactants or reagents whose preparation is not described
explicitly hereinafter were purchased commercially from generally
accessible sources. For all other reactants or reagents whose
preparation likewise is not described hereinafter and which were
not commercially obtainable or were obtained from sources which are
not generally accessible, a reference is given to the published
literature in which their preparation is described.
General Procedures
GP1
[0559] N,N-Diisopropylethylamine (1.4-1.5 eq., or 2.4-3.0 eq. when
the amine was used in hydrochloride form) and HATU (1.0-1.65 eq.)
were added to a solution of the corresponding carboxylic acid (1
eq.) in DMF (0.08-0.12M), and the mixture was stirred at RT for 30
min. Subsequently, the appropriate amine (1.04-1.5 eq.) was added
and the mixture was stirred at room temperature for a further
0.15-2 h. The reaction was then terminated by the addition of water
and 1 M aqueous hydrochloric acid. The precipitate was filtered
off, taken up in DCM, dried over magnesium sulfate and filtered,
and the solvent was removed under reduced pressure. Alternatively,
the acidification was followed by extraction with ethyl acetate,
drying of the combined organic phases over magnesium sulfate or
sodium sulfate, filtration and removal of the solvent under reduced
press sure. The crude product was then purified either by normal
phase chromatography (silica gel, mobile phase: cyclohexane/ethyl
acetate mixtures or dichloromethane/methanol mixtures) or by
preparative RP-HPLC (water/acetonitrile gradient). Alternatively,
the reaction mixture was diluted with a little acetonitrile, water
and formic acid and the crude solution obtained was purified by
RP-HPLC (water/acetonitrile gradient). Further alternatives for
work-up, if carried out, are described with the respective
experiment.
GP2
[0560] Potassium carbonate or caesium carbonate (1.5-2.5 eq.) was
baked in a reaction vessel under reduced pressure. The vessel was
cooled to RT and flooded with argon. Palladium acetate (0.1-0.36
eq.), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos,
0.18-0.36 eq.) and dioxane (0.04-0.12M) were added, and the
suspension was degassed in an argon stream at room temperature for
10 min. Subsequently, the appropriate amide (1.0-10 eq.) and the
appropriate 7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine (1.0 eq.)
were added. The mixture was stirred at 80-110.degree. C. for 1 h
(or until conversion was complete by analytical HPLC or thin-layer
chromatography with appropriate mobile phase mixtures). The mixture
was then cooled to RT and all volatile components were removed
under reduced pressure, or alternatively the reaction mixture was
poured into water, the pH was adjusted to pH 1 with 1M aqueous
hydrochloric acid, the mixture was extracted with ethyl acetate,
the combined organic phases were washed with saturated aqueous
sodium chloride solution, dried over magnesium sulfate and
filtered, and the solvent was removed under reduced pressure. The
crude product was then purified either by normal phase
chromatography (mobile phase: cyclohexane/ethyl acetate mixtures or
dichloromethane/methanol mixtures) or by preparative RP-HPLC
(water/acetonitrile gradient). Alternatively, the reaction mixture
was diluted with a little acetonitrile, water and formic acid or
TFA and the crude solution obtained was purified by RP-HPLC
(water/acetonitrile gradient). Further alternatives for work-up, if
carried out differently, are described with the respective
experiment.
GP3
[0561] The appropriate amine (1.2 eq.) and DIPEA (1.5-3.5 eq.) were
added to a solution of the appropriate
7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine in DMF (0.10-0.22 M).
The reaction solution was stirred at RT overnight. The crude
product was subsequently, after aqueous work-up and extraction with
the appropriate organic solvent, purified either by normal-phase
chromatography (mobile phase: cyclohexane/ethyl acetate mixtures or
dichloromethane/methanol mixtures) or by preparative RP-HPLC
(water/acetonitrile gradient). Alternatively, the reaction mixture
was diluted with a little acetonitrile, water and formic acid and
the crude solution obtained was purified by RP-HPLC
(water/acetonitrile gradient). Further alternatives for work-up, if
carried out, are described with the respective experiment.
STARTING COMPOUNDS AND INTERMEDIATES
Example 1A Ethyl
7-chloro-1-(2,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyrid-
ine-3-carboxylate
##STR00092##
[0563] 21.8 ml (125 mmol) of DIPEA were added to a solution of 6.00
g (17.8 mmol) of ethyl
2-[(2,6-dichloro-5-fluoropyridin-3-yl)carbonyl]-3-ethoxyacrylate
(preparation described in U.S. Pat. No. 4,840,954 A, Example G,
step 1, page 7) and 3.23 g (24.9 mmol) of 2,6-difluoroaniline in 30
ml of dichloromethane, and the mixture was stirred at RT for 4 h.
2.47 g (17.8 mmol) of potassium carbonate were then added, and the
mixture was heated under reflux overnight. The mixture was diluted
with 200 ml of dichloromethane and washed twice with 150 ml of 1 M
aqueous hydrochloric acid. The organic phase was dried over sodium
sulfate and filtered, and the solvent was removed under reduced
pressure. The mixture was diluted with 80 ml of tert-butyl methyl
ether and the precipitate was filtered off with suction and washed
with 10 ml of tert-butyl methyl ether. This gave 3.22 g (45% of
theory, 95.7% pure) of the title compound.
[0564] LC-MS (Method 1): R.sub.t=0.96 min; MS (ESIpos): m/z=383
[M+H]+.
[0565] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=8.95 (s, 1H),
8.57 (d, 1H), 7.80-7.71 (m, 1H), 7.50-7.43 (m, 2H), 4.25 (q, 2H),
1.26 (t, 3H).
Example 2A
7-Chloro-1-(2,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8--
naphthyridine-3-carboxylic acid
##STR00093##
[0567] 3.22 g (8.41 mmol) of ethyl
7-chloro-1-(2,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyrid-
ine-3-carboxylate were initially charged in 25.2 ml of water, 25.2
ml of 36 percent strength aqueous hydrochloric acid and 25.2 ml of
THF were added and the mixture was stirred at 110.degree. C. for 4
h. The reaction mixture was cooled to RT and the precipitate was
filtered off with suction, washed twice with 30 ml of water and
dried under high vacuum. This gave 4.1 g (quantitative, 96.8% pure)
of the title compound.
[0568] LC-MS (Method 1): R.sub.t=0.96 min; MS (ESIpos): m/z=355
[M+H].sup.+.
[0569] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=13.70 (s, 1H),
9.25 (s, 1H), 8.76 (d, 1H), 7.80-7.72 (m, 1H), 7.51-7.43 (m,
2H).
Example 3A
7-Chloro-1-(2,6-difluorophenyl)-6-fluoro-4-oxo-N-[(2S)-1,1,1-tr-
ifluorobutan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00094##
[0571] According to GP1, 1.00 g (2.82 mmol) of
7-chloro-1-(2,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyrid-
ine-3-carboxylic acid was reacted with 553 mg (3.38 mmol) of
(2S)-1,1,1-trifluorobutan-2-amine hydrochloride in the presence of
1.29 g (3.38 mmol) of HATU and 1.96 ml (11.3 mmol) of DIPEA in 20
ml of DMF. The reaction solution was stirred for 1 min and added to
a mixture of water, 1M aqueous hydrochloric acid and ethyl acetate.
The phases were separated and the aqueous phase was extracted four
times with 50 ml of ethyl acetate. The combined organic phases were
washed with saturated aqueous sodium chloride solution, dried over
sodium sulfate and filtered, and the solvent was removed under
reduced pressure. The crude product was dissolved in a little ethyl
acetate and purified by normal phase chromatography
(cyclohexane/ethyl acetate, 5:1). The fractions were combined and
concentrated under reduced pressure and the residue was lyophilized
from acetonitrile overnight. This gave 331 mg (25% of theory, 100%
pure) of the title compound.
[0572] LC-MS (Method 3): R.sub.t=2.32 min; MS (ESIpos): m/z=464
[M+H].sup.+.
[0573] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.84 (d, 1H),
9.12 (s, 1H), 8.72 (d, 1H), 7.80-7.72 (m, 1H), 7.51-7.44 (m, 2H),
4.85-4.71 (m, 1H), 1.96-1.83 (m, 1H), 1.75-1.61 (m, 1H), 0.98 (t,
3H).
Example 4A Ethyl
7-chloro-1-(2,4,6-trifluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthy-
ridine-3-carboxylate
##STR00095##
[0575] 43.5 ml (250 mmol) of DIPEA were added to a solution of 12.0
g (35.7 mmol) of ethyl
2-[(2,6-dichloro-5-fluoropyridin-3-yl)carbonyl]-3-ethoxyacrylate
(U.S. Pat. No. 4,840,954 A, Example G, step 1, page 7) and 7.35 g
(49.9 mmol) of 2,4,6-trifluoroaniline in 60 ml of dichloromethane,
and the mixture was stirred at RT for 4 h. Subsequently, 4.93 g
(35.7 mmol) of potassium carbonate were added and the mixture was
heated under reflux overnight. The mixture was then diluted with
200 ml of dichloromethane and washed three times with 150 ml of 1 M
aqueous hydrochloric acid. The organic phase was dried over sodium
sulfate and filtered, and the solvent was removed under reduced
pressure. The mixture was diluted with 100 ml of tert-butyl methyl
ether and the precipitate was filtered off with suction and washed
three times with 20 ml of tert-butyl methyl ether and dried under
high vacuum. This gave 8.80 g (58% of theory, 94.6% pure) of the
title compound.
[0576] LC-MS (Method 1): R.sub.t=1.01 min; MS (ESIpos): m/z=401
[M+H]+.
[0577] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=8.97 (s, 1H),
8.56 (d, 1H), 7.67-7.56 (m, 2H), 4.26 (q, 2H), 1.28 (t, 3H).
Example 5A
7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1-
,8-naphthyridine-3-carboxylic acid
##STR00096##
[0579] 8.80 g (21.9 mmol) of ethyl
7-chloro-1-(2,4,6-trifluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthy-
ridine-3-carboxylate were initially charged in 66.2 ml of water,
66.2 ml of 36 percent strength aqueous hydrochloric acid and 66.2
ml of THF were added and the mixture was stirred at 110.degree. C.
for 4 h. The reaction mixture was cooled to RT and the precipitate
was filtered off with suction, washed four times with 40 ml of
water and dried under high vacuum. This gave 7.37 g (89% of theory,
99% pure) of the title compound.
[0580] LC-MS (Method 3): R.sub.t=1.84 min; MS (ESIpos): m/z=373
[M+H].sup.+.
[0581] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=13.67 (s, 1H),
9.28 (s, 1H), 8.76 (d, 1H), 7.68-7.59 (m, 2H).
Example 6A
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,-
6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic
acid
##STR00097##
[0583] At RT, 5.89 ml (33.8 mmol) of DIPEA were added to a solution
of 3.60 g (9.66 mmol) of
7-chloro-1-(2,4,6-trifluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthy-
ridine-3-carboxylic acid and 1.48 g (10.6 mmol) of
(3R,4R)-pyrrolidine-3,4-diol hydrochloride in 50 ml of DMF. The
mixture was stirred at RT for a further 1 h. 150 ml of water and
100 ml of aqueous 1M hydrochloric acid were then added and the
precipitate formed was filtered off with suction. The precipitate
was washed with water and dried under high vacuum. This gave 3.96 g
(93% of theory, 100% pure) of the title compound.
[0584] LC-MS (Method 3): R.sub.t=1.23 min; MS (ESIpos): m/z=440
[M+H]+.
[0585] .sup.1H NMR (500 MHz, DMSO-d6): .delta. [ppm]=15.01 (s, 1H),
9.05 (s, 1H), 8.07 (d, 1H), 7.64-7.54 (m, 2H), 5.30-5.14 (m, 2H),
4.09-3.64 (m, 4H), 3.28-3.21 (m, 0.6H, partly under the water
resonance), 3.15-3.01 (m, 1H).
Example 7A
6-Fluoro-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-
-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic
acid
##STR00098##
[0587] According to GP2, 100 mg (268 .mu.mol) of
7-chloro-1-(2,4,6-trifluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthy-
ridine-3-carboxylic acid were reacted with 32.6 mg (322 .mu.mol) of
(4S)-4-hydroxypyrrolidin-2-one in the presence of 92.7 mg (671
.mu.mol) of potassium carbonate, 6.0 mg (27 .mu.mol) of palladium
acetate and 33 mg (54 .mu.mol) of Xantphos in 2.4 ml of dioxane at
90.degree. C. for 1 h. The reaction mixture was diluted with 1 ml
of aqueous 1M hydrochloric acid and 1 ml of DMSO and purified
directly by prep. HPLC (acetonitrile/water with formic acid, C18
RP-HPLC). This gave 61.7 mg (42% of theory, 80% pure) of the title
compound.
[0588] LC-MS (Method 3): R.sub.t=1.19 min; MS (ESIpos): m/z=438
[M+H].sup.+.
Example 8A
7-[(3S,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,-
6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic
acid
##STR00099##
[0590] At RT, 280 .mu.l (1.61 mmol) of DIPEA were added to a
solution of 240 mg (644 .mu.mol) of
7-chloro-1-(2,4,6-trifluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthy-
ridine-3-carboxylic acid and 73.0 mg (708 .mu.mol) of
(3R,4R)-pyrrolidine-3,4-diol in 3.3 ml of DMF. The mixture was
stirred at RT for a further 1 h. The reaction mixture was diluted
with 0.4 ml of aqueous 1M hydrochloric acid and 1 ml of
acetonitrile and purified directly by prep. HPLC
(acetonitrile/water with formic acid, C18 RP-HPLC). This gave 232
mg (74% of theory, 94.4% pure) of the title compound.
[0591] LC-MS (Method 1): R.sub.t=0.69 min; MS (ESIpos): m/z=440
[M+H]+.
[0592] .sup.1H NMR (500 MHz, DMSO-d6): .delta. [ppm]=15.01 (s, 1H),
9.05 (s, 1H), 8.07 (d, 1H), 7.64-7.55 (m, 2H), 5.33-5.10 (m, 2H),
4.10-3.63 (m, 4H), 3.29-3.20 (m, 0.8H, partly under the water
resonance), 3.15-3.00 (m, 1H).
Example 9A
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,-
6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic
acid
##STR00100##
[0594] At RT, 409 .mu.l (2.35 mmol) of DIPEA were added to a
solution of 250 mg (671 .mu.mol) of
7-chloro-1-(2,4,6-trifluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthy-
ridine-3-carboxylic acid and 103 mg (738 .mu.mol) of
cis-pyrrolidine-3,4-diol hydrochloride in 3.5 ml of DMF. The
mixture was stirred at RT for a further 1 h. The reaction mixture
was acidified with 7 ml of aqueous 1 M hydrochloric acid, 15 ml of
water were added and the precipitate was filtered off with suction.
The residue was washed with water and lyophilized. This gave 256 mg
(86% of theory, 99% pure) of the title compound.
[0595] LC-MS (Method 1): R.sub.t=0.71 min; MS (ESIpos): m/z=440
[M+H]+.
[0596] .sup.1H NMR (500 MHz, DMSO-d6): .delta. [ppm]=15.0 (s, 1H),
9.05 (s, 1H), 8.05 (d, 1H), 7.63-7.54 (m, 2H), 5.15-4.89 (m, 2H),
4.13-3.86 (m, 3H), 3.61 (br. s, 1H), 3.21 (br. s, 1H), 3.04 (br. s,
1H).
Example 10A
6-Fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl-
)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
##STR00101##
[0598]
7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylic acid (800 mg, 2.15 mmol) was initially
charged in 8 ml of DMF, (3S)-pyrrolidin-3-ol (206 mg, 2.36 mmol)
and N,N-diisopropylethylamine (1.3 ml, 7.5 mmol) were added and the
mixture was stirred at RT for 2 h. The reaction mixture was added
to water, and 1M hydrochloric acid and ethyl acetate were added.
The organic phase was removed and the aqueous phase was extracted
three times with ethyl acetate. The combined organic phases were
washed once with sat. sodium chloride solution, dried over sodium
sulfate and concentrated. The product was stirred with
acetonitrile, filtered off, washed with a little cold acetonitrile
and dried. This gave 770 mg (85% of theory, 100% pure) of the title
compound.
[0599] LC-MS (Method 1): R.sub.t=0.82 min; MS (ESIpos): m/z=424
[M+H].sup.+
[0600] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (2.22),
0.008 (2.03), 1.909 (0.87), 2.074 (16.00), 3.222 (0.71), 3.875
(0.53), 4.309 (0.50), 5.024 (1.35), 7.565 (2.70), 7.586 (4.97),
7.608 (2.81), 8.037 (5.77), 8.068 (5.70), 9.043 (10.89), 15.025
(9.55).
Example 11A
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-7-(3H-[1,2,3]t-
riazolo[4,5-b]pyridin-3-yloxy)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxamide
##STR00102##
[0602] According to GP1, 500 mg (1.34 mmol) of
7-chloro-1-(2,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyrid-
ine-3-carboxylic acid were reacted with 283 mg (1.61 mmol) of
(1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in the
presence of 612 mg (1.61 mmol) of HATU and 935 .mu.l (5.37 mmol) of
DIPEA in 10 ml of DMF. The reaction solution was stirred at RT for
1 h and added to a mixture of water and ethyl acetate. The phases
were separated and the aqueous phase was extracted four times with
50 ml of ethyl acetate. The organic phases were combined, washed
with 50 ml of buffer pH 7 and twice with 50 ml of saturated aqueous
sodium chloride solution, dried over sodium sulfate, filtered and
concentrated. The substance was dissolved in ethyl acetate and
applied to silica gel and purified by normal phase chromatography
(cyclohexane-ethyl acetate gradient). The fractions were combined
and concentrated under reduced pressure and the residue was
lyophilized from acetonitrile overnight. This gave 534 mg (66% of
theory, 99% pure) of the title compound.
[0603] LC-MS (Method 3): R.sub.t=2.21 min; MS (ESIpos): m/z=594
[M+H].sup.+.
[0604] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.01 (d, 1H),
8.96 (s, 1H), 8.88 (d, 1H), 8.74 (dd, 1H), 8.63 (dd, 1H), 7.65 (dd,
1H), 7.05-6.97 (m, 2H), 4.42-4.37 (m, 1H), 1.28-1.17 (m, 1H),
0.71-0.51 (m, 3H), 0.36-0.28 (m, 1H).
Example 12A
6-Fluoro-4-oxo-7-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-N-[(2S)-1,1,1-
-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyrid-
ine-3-carboxamide
##STR00103##
[0606] According to GP1, 500 mg (1.34 mmol) of
7-chloro-1-(2,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyrid-
ine-3-carboxylic acid were reacted with 263 mg (1.61 mmol) of
(S)-1,1,1-trifluorobutan-2-amine hydrochloride in the presence of
612 mg (1.61 mmol) of HATU and 935 .mu.l (5.37 mmol) of DIPEA in
9.5 ml of DMF. The reaction solution was stirred at RT for 1 h and
added to a mixture of water and ethyl acetate. The phases were
separated and the aqueous phase was extracted four times with 50 ml
of ethyl acetate. The organic phases were combined, washed with 50
ml of buffer pH 7 and twice with 50 ml of saturated aqueous sodium
chloride solution, dried over sodium sulfate, filtered and
concentrated. The substance was dissolved in ethyl acetate and
applied to silica gel and purified by normal phase chromatography
(cyclohexane-ethyl acetate gradient). The fractions were combined
and concentrated under reduced pressure and the residue was
lyophilized from acetonitrile overnight. This gave 522 mg (66% of
theory, 99% pure) of the title compound.
[0607] LC-MS (Method 3): R.sub.t=2.19 min; MS (ESIpos): m/z=582
[M+H].sup.+.
[0608] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.85 (d, 1H),
8.97 (s, 1H), 8.87 (d, 1H), 8.74 (dd, 1H), 8.63 (dd, 1H), 7.65 (dd,
1H), 7.06-6.96 (m, 2H), 4.81-4.66 (m, 1H), 1.94-1.81 (m, 1H),
1.73-1.59 (m, 1H), 0.96 (t, 3H).
Example 13A tert-Butyl
4-[6-{[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-3-fluoro-5-oxo--
8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]piperazine-1-c-
arboxylate
##STR00104##
[0610]
7-Chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-
-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(60.0 mg, 122 .mu.mol) was initially charged in 1.2 ml of
acetonitrile, tert-butyl piperazine-1-carboxylate (45.3 mg, 243
.mu.mol) and N,N-diisopropylethylamine (74 .mu.l, 430 .mu.mol) were
added and the mixture was stirred at room temperature for 2 h. The
reaction solution was concentrated under reduced pressure and used
without further purification for the next step. This gave 113 mg of
the target compound (quantitative yield, purity about 69%).
[0611] LC-MS (Method 3): R.sub.t=2.61 min; MS (ESIpos): m/z=644
[M+H].sup.+
Example 14A tert-Butyl
(2S)-4-[6-{[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-3-fluoro-5-
-oxo-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]-2-methyl-
piperazine-1-carboxylate
##STR00105##
[0613]
7-Chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-
-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(60.0 mg, 122 .mu.mol) was initially charged in 1.2 ml of DMF,
tert-butyl (2S)-2-methylpiperazine-1-carboxylate (34.1 mg, 170
.mu.mol) and N,N-diisopropylethylamine (74 .mu.l, 430 .mu.mol) were
added and the mixture was stirred at room temperature for 1 h. The
reaction solution was taken up in ethyl acetate and extracted three
times with a semisaturated ammonium chloride solution. The combined
aqueous phases were re-extracted once with ethyl acetate. The
combined organic phases were dried over sodium sulfate, filtered
and concentrated under reduced pressure. This gave 82 mg of the
target compound (91% of theory, purity 90%).
[0614] LC-MS (Method 3): R.sub.t=2.64 min; MS (ESIpos): m/z=658
[M+H].sup.+
Example 15A Ethyl
7-chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naph-
thyridine-3-carboxylate
##STR00106##
[0616] 21.8 ml (125 mmol) of DIPEA were added to a solution of 6.00
g (17.8 mmol) of ethyl
2-[(2,6-dichloro-5-fluoropyridin-3-yl)carbonyl]-3-ethoxyacrylate
(U.S. Pat. No. 4,840,954, 1989, Example G, step 1, page 7) and 3.25
g (25.0 mmol) of 2-amino-3,5-difluoropyridine in 30 ml of
dichloromethane, and the mixture was stirred at RT for 4 h. 2.47 g
(17.8 mmol, 1 eq.) of potassium carbonate were then added, and the
mixture was heated under reflux overnight. A further equivalent of
potassium carbonate was then added, and the mixture was again
heated under reflux overnight. A further equivalent of potassium
carbonate was then added, and stirring of the mixture under reflux
was continued for a further 3 d. The mixture was diluted with 200
ml of dichloromethane and washed twice with 200 ml of 1 M aqueous
hydrochloric acid. The organic phase was dried over sodium sulfate
and filtered, and the solvent was removed under reduced pressure.
The mixture was diluted with 80 ml of tert-butyl methyl ether and
the precipitate was filtered off with suction, washed with 10 ml of
tert-butyl methyl ether and dried under high vacuum. This gave 3.73
g (54% of theory, 99% pure) of the title compound.
[0617] LC-MS (Method 1): R.sub.t=0.93 min; MS (ESIpos): m/z=384
[M+H]+.
[0618] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=8.92 (s, 1H),
8.66 (d, 1H), 8.56 (d, 1H), 8.44-8.37 (m, 1H), 4.26 (q, 2H), 1.28
(t, 3H).
Example 16A
7-Chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naph-
thyridine-3-carboxylic acid
##STR00107##
[0620] 3.60 g (9.38 mmol) of ethyl
7-chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naph-
thyridine-3-carboxylate were initially charged in 28.3 ml of water,
28.3 ml of 36 percent strength aqueous hydrochloric acid and 28.3
ml of THF were added and the mixture was stirred at 110.degree. C.
for 4 h. Subsequently, twice in each case 28.3 ml of 36 percent
strength aqueous hydrochloric acid were added in succession, and
the mixture was stirred at 110.degree. C. for 2 d. The reaction
mixture was cooled to RT and the precipitate was filtered off with
suction, washed with water and dried under high vacuum. This gave
3.25 g (96% of theory, 99% pure) of the title compound.
[0621] LC-MS (Method 1): R.sub.t=0.90 min; MS (ESIpos): m/z=356
[M+H].sup.+.
[0622] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=13.71 (s, 1H),
9.18 (s, 1H), 8.76 (d, 1H), 8.68 (dd, 1H), 8.46-8.39 (m, 1H).
Example 17A
1-(3,5-Difluoropyridin-2-yl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-f-
luoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
##STR00108##
[0624] At RT, 2.57 ml (14.8 mmol) of DIPEA were added to a solution
of 1.50 g (4.22 mmol) of
7-chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naph-
thyridine-3-carboxylic acid and 648 mg (4.64 mmol) of
(3R,4R)-pyrrolidine-3,4-diol hydrochloride in 21 ml of DMF. The
mixture was stirred at RT for a further 2 h. The mixture was
acidified with aqueous 1M hydrochloric acid and then diluted with
100 ml of water and 50 ml of ethyl acetate. The phases were
separated and the aqueous phase was extracted twice with 50 ml of
ethyl acetate. The combined organic phases were washed twice with
50 ml of a pH 7 buffer solution and once with 50 ml of saturated
aqueous sodium chloride solution, dried over sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
stirred with 20 ml of tert-butyl methyl ether and decanted off, and
the precipitate was dried under high vacuum. This gave 1.41 g (78%
of theory, 99% pure) of the title compound.
[0625] LC-MS (Method 3): R.sub.t=1.07 min; MS (ESIpos): m/z=423
[M+H].sup.+.
[0626] .sup.1H NMR (500 MHz, DMSO-d6): .delta. [ppm]=15.02 (s, 1H),
8.96 (s, 1H), 8.66-8.61 (m, 1H), 8.41-8.34 (m, 1H), 8.07 (d, 1H),
5.34-5.06 (m, 2H), 4.14-3.59 (m, 4H), 3.44-3.20 (m, 1H, partly
under the water resonance), 3.19-3.01 (m, 1H).
Example 18A
1-(3,5-Difluoropyridin-2-yl)-6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-
-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
##STR00109##
[0628] According to GP3, 81 mg (928 .mu.mol) of (S)-3-pyrrolidinol
and 0.514 ml (2.95 mmol) of DIPEA were added to 300 mg (843
.mu.mol) of
7-chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naph-
thyridine-3-carboxylic acid in 3.1 ml of DMF, and the mixture was
stirred at RT for 1 h. Another 20 mg (232 .mu.mol) of
(S)-3-pyrrolidinol were then added, and the mixture was stirred at
RT for 1 h. The reaction mixture was diluted with water and
purified directly by preparative HPLC (acetonitrile/water with
formic acid, C18 RP-HPLC). This gave 244 mg (72% of theory, 100%
pure) of the title compound.
[0629] LC-MS (Method 3): R.sub.t=1.36 min; MS (ESIpos): m/z=407
[M+H].sup.+.
Example 19A
1-(3,5-Difluoropyridin-2-yl)-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,-
4-dihydro-1,8-naphthyridine-3-carboxylic acid
##STR00110##
[0631] At RT, 857 .mu.l (4.92 mmol) of DIPEA were added to a
solution of 500 mg (1.41 mmol) of
7-chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naph-
thyridine-3-carboxylic acid and 169 mg (1.55 mmol) of
3-hydroxyazetidine hydrochloride in 7 ml of DMF. The mixture was
stirred at RT for a further 2.5 h. The mixture was acidified with
aqueous 1M hydrochloric acid and diluted with 30 ml of water and 30
ml of ethyl acetate. The precipitate was filtered off with suction
(first product fraction). The phases were separated and the aqueous
phase was extracted twice with 15 ml of ethyl acetate. The combined
organic phases were washed twice with 15 ml of buffer pH 7 and once
with 15 ml of saturated aqueous sodium chloride solution, dried
over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was stirred with 10 ml of tert-butyl methyl
ether and decanted off, and the precipitate was dried under high
vacuum (second product fraction). This gave 476 mg (86% of theory,
99% pure) of the title compound in total.
[0632] LC-MS (Method 3): R.sub.t=1.35 min; MS (ESIpos): m/z=393
[M+H].sup.+.
[0633] .sup.1H NMR (500 MHz, DMSO-d6): .delta. [ppm]=14.98 (s, 1H),
8.95 (s, 1H), 8.62 (d, 1H), 8.39-8.31 (m, 1H), 8.05 (d, 1H), 5.80
(d, 1H), 4.81-3.50 (m, 5H).
Example 20A
1-(3,5-Difluoropyridin-2-yl)-6-fluoro-7-(3-hydroxy-3-methylazetidin-1-yl)-
-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
##STR00111##
[0635] At RT, 857 .mu.l (4.92 mmol) of DIPEA were added to a
solution of 500 mg (1.41 mmol) of
7-chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naph-
thyridine-3-carboxylic acid and 191 mg (1.55 mmol) of
3-methylazetidin-3-ol hydrochloride in 7 ml of DMF. The mixture was
stirred at RT for a further 2 h. The mixture was acidified with
aqueous 1 M hydrochloric acid and diluted with 40 ml of water, and
the precipitate was filtered off with suction. The precipitate was
washed with 5 ml of water three times and dried under high vacuum.
This gave 534 mg (93% of theory, 99% pure) of the title
compound.
[0636] LC-MS (Method 3): R.sub.t=1.43 min; MS (ESIpos): m/z=407
[M+H].sup.+.
[0637] .sup.1H NMR (500 MHz, DMSO-d6): .delta. [ppm]=14.98 (s, 1H),
8.95 (s, 1H), 8.62 (d, 1H), 8.39-8.32 (m, 1H), 8.06 (d, 1H), 5.72
(s, 1H), 4.48-3.49 (m, 4H), 1.38 (s, 3H).
Example 21A Ethyl
(2Z)-2-[(2,6-dichloro-5-fluoropyridin-3-yl)carbonyl]-3-ethoxyacrylate
##STR00112##
[0639] Ethyl 3-(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxopropanoate
(19.5 g, 69.6 mmol) and triethyl orthoformate (23.1 ml, 140 mmol)
were initially charged in acetic anhydride (46 ml, 490 mmol) and
the mixture was stirred at 140.degree. C. overnight. The reaction
mixture was then concentrated under reduced pressure and reacted
further in the subsequent steps without further work-up.
Quantitative conversion was assumed.
[0640] LC-MS (Method 1): R.sub.t=1.00 min; MS (ESIpos): m/z=336
[M+H].sup.+
Example 22A Ethyl
7-chloro-1-(2-chloro-4,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylate (atropisomer mixture)
##STR00113##
[0642] Under argon, ethyl
(2Z)-2-[(2,6-dichloro-5-fluoropyridin-3-yl)carbonyl]-3-ethoxyacrylate
(24.0 g, 71.4 mmol) and 2-chloro-4,6-difluoroaniline (16.3 g, 100
mmol) were initially charged in 120 ml of dichloromethane, and
N,N-diisopropylethylamine (87 ml, 500 mmol) was added at room
temperature. The reaction solution was stirred at room temperature
for 4 h. Potassium carbonate (9.87 g, 71.4 mmol) was then added and
the mixture was stirred under reflux overnight. The reaction
mixture was cooled, diluted with 300 ml of dichloromethane and
washed three times with in each case 180 ml of 1 M hydrochloric
acid. The organic phase was dried over sodium sulfate, filtered and
concentrated under reduced pressure. The suspension thus obtained
was stirred in 150 ml of tert-butyl methyl ether. The solution was
concentrated under reduced pressure. The resulting crude product
was purified by silica gel chromatography (mobile phase:
cyclohexane/ethyl acetate 10/1 then 5/1 then 2/1). This gave 13.75
g of the target compound (46% of theory, purity 99%).
[0643] LC-MS (Method 3): R.sub.t=1.98 min; MS (ESIpos): m/z=417
[M+H].sup.+
Example 23A
7-Chloro-1-(2-chloro-4,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylic acid (atropisomer mixture)
##STR00114##
[0645] Ethyl
7-chloro-1-(2-chloro-4,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylate (6.00 g, 99% pure, 14.2 mmol) was
suspended in 43 ml of THF. Water (43 ml) and conc. hydrochloric
acid (43 ml) were added and the mixture was left to stir at a bath
temperature of 110.degree. C. for 4 h. Most of the organic solvent
was removed under reduced pressure. 20 ml of water were added to
the suspension and the precipitate formed was filtered off. This
gave 5.12 g of the target compound (92% of theory, purity 99%).
[0646] LC-MS (Method 3): R.sub.t=1.93 min; MS (ESIpos): m/z=389
[M+H].sup.+
[0647] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (3.01),
0.008 (2.85), 2.327 (0.79), 2.671 (0.75), 7.752 (1.44), 7.758
(2.19), 7.774 (2.10), 7.782 (6.12), 7.794 (2.31), 7.805 (5.86),
7.816 (1.78), 8.760 (8.43), 8.778 (8.40), 9.250 (16.00), 13.654
(2.73).
Example 24A
7-Chloro-1-(2-chloro-4,6-difluorophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-trif-
luoroethyl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(atropisomer mixture)
##STR00115##
[0649]
7-Chloro-1-(2-chloro-4,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-
-1,8-naphthyridine-3-carboxylic acid (atropisomer mixture, 1.50 g,
3.85 mmol) was initially charged in 34 ml of DMF. HATU (1.47 g,
3.85 mmol) and N,N-diisopropylethylamine (1.6 ml, 9.3 mmol) were
added and the mixture was pre-stirred at room temperature for 30
min. (1S)-1-Cyclopropyl-2,2,2-trifluoroethanamine hydrochloride
(745 mg, 4.24 mmol) was then added and the mixture was left to stir
at room temperature for 2 min. The reaction was worked up directly,
without reaction monitoring. The mixture was added to 340 ml of
water. The solids that precipitated out were filtered off and dried
under high vacuum. This gave 2.13 g of the target compound (62% of
theory, purity 57%).
[0650] LC-MS (Method 3): R.sub.t=2.46 min; MS (ESIpos): m/z=510
[M+H].sup.+
Example 25A
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(atropisomer mixture)
##STR00116##
[0652] At RT, 2.57 ml (14.8 mmol) of DIPEA were added to a solution
of 500 mg (1.29 mmol) of
7-chloro-1-(2-chloro-4,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylic acid (atropisomer mixture) and 648 mg
(4.64 mmol) of (3R,4R)-pyrrolidine-3,4-diol hydrochloride in 21 ml
of DMF. The mixture was stirred at RT for a further 12 h. The
mixture was stirred into 100 ml of water and the precipitate was
filtered off with suction. The precipitate was washed with water
and dried under high vacuum. This gave 463 mg (78% of theory, 99%
pure) of the title compound.
[0653] LC-MS (Method 3): R.sub.t=1.30 min; MS (ESIpos): m/z=456
[M+H]+.
[0654] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=15.04 (s, 1H),
9.01 (s, 1H), 8.07 (d, 1H), 7.80-7.69 (m, 1H),), 5.22 (br. s, 2H),
4.09-3.64 (m, 4H), 3.28-3.17 (m, 1H), 3.11-2.94 (m, 1H).
Example 26A
1-(2,6-Difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro--
4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
##STR00117##
[0656] At RT, 1.72 ml (9.87 mmol) of DIPEA were added to a solution
of 1.00 g (2.82 mmol) of
7-chloro-1-(2,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyrid-
ine-3-carboxylic acid and 433 g (3.10 mmol) of
(3R,4R)-pyrrolidine-3,4-diol hydrochloride in 15.4 ml of DMF. The
mixture was stirred at RT for a further 2 h. The mixture was then
acidified with aqueous 1M hydrochloric acid and diluted with 200 ml
of water and 100 ml of ethyl acetate. The phases were separated and
the aqueous phase was extracted twice with 50 ml of ethyl acetate.
The combined organic phases were washed twice with 25 ml of buffer
pH 7 and once with 50 ml of saturated aqueous sodium chloride
solution, dried over magnesium sulfate, filtered and concentrated
under reduced pressure. This gave 1.03 g (87% of theory, 100% pure)
of the title compound.
[0657] LC-MS (Method 3): R.sub.t=1.19 min; MS (ESIpos): m/z=422
[M+H].sup.+.
[0658] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=15.04 (s, 1H),
9.01 (s, 1H), 8.08 (d, 1H), 7.78-7.68 (m, 1H),), 7.47-7.39 (m, 2H),
5.28-5.14 (m, 2H), 4.09-3.62 (m, 4H), 3.26-3.15 (m, 1H), 3.08-2.96
(m, 1H).
Example 27A Ethyl
(2Z)-3-ethoxy-2-[(2,5,6-trichloropyridin-3-yl)carbonyl]acrylate
##STR00118##
[0660] Ethyl 3-oxo-3-(2,5,6-trichloropyridin-3-yl)propanoate (1.6
g, 5.40 mmol) and (diethoxymethoxy)ethane (1.80 ml, 1.3 mmol) were
initially charged, and acetic anhydride (3.31 ml, 35.1 mmol) was
added. The mixture was stirred at 140.degree. C. overnight. The
mixture was concentrated and reacted further without any further
purification (100% conversion assumed).
Example 28A Ethyl
6,7-dichloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridin-
e-3-carboxylate
##STR00119##
[0662] Under argon, ethyl
(2Z)-3-ethoxy-2-[(2,5,6-trichloropyridin-3-yl)carbonyl]acrylate
(assumed: 1.90 g, 5.39 mmol) from the precursor and
2,4,6-trifluoroaniline (1.11 g, 7.54 mmol) were initially charged
in 50 ml of dichloromethane. N,N-Diisopropylethylamine (6.6 ml, 38
mmol) was added and the mixture was stirred again at RT for 4 h.
Potassium carbonate (745 mg, 5.39 mmol) was then added and the
mixture was stirred at reflux overnight. The reaction mixture was
diluted with 120 ml of dichloromethane and washed twice with 40 ml
of 1M hydrochloric acid, dried and concentrated. The residue was
purified on silica gel (mobile phase cyclohexane/ethyl
acetate=4:1). The product-containing fractions were concentrated.
This gave 0.298 g (13% of theory, 100% pure) of the title
compound.
[0663] LC-MS (Method 1): R.sub.t=1.08 min; MS (ESIpos): m/z=417
[M+H].sup.+.
Example 29A
6,7-Dichloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridin-
e-3-carboxylic acid
##STR00120##
[0665] 292 mg of ethyl
6,7-dichloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridin-
e-3-carboxylate (700 .mu.mol) were initially charged in THF (4.0
ml, 49 mmol), ethanol (2.0 ml, 34 mmol) and water (1.0 ml) and, at
RT, acidified with conc. hydrochloric acid (about 2 ml) and then
stirred at 110.degree. C. for 4 d. The precipitate was filtered
off, washed with water and dried under high vacuum overnight. This
gave 253 mg (90% of theory, 97% pure) of the title compound.
[0666] LC-MS (Method 3): R.sub.t=1.99 min; MS (ESIpos): m/z=389
[M+H].sup.+.
Example 30A
6-Chloro-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluor-
ophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
##STR00121##
[0668] 253 mg of
6,7-dichloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridin-
e-3-carboxylic acid (97% pure, 631 .mu.mol) were dissolved in DMF
(6.0 ml, 78 mmol). (3R,4R)-Pyrrolidine-3,4-diol hydrochloride (99.8
mg, 97% pure, 694 .mu.mol) and N,N-diisopropylethylamine (384
.mu.l, 2.2 mmol) were added and the mixture was stirred at RT for 1
h. The mixture was diluted with 20 ml of water, 5 ml of 1N
hydrochloric acid and 20 ml of ethyl acetate. The organic phases
were separated, and the aqueous phase was extracted three times
with 20 ml of ethyl acetate. The combined org. phases were washed
twice with 20 ml of buffer (pH 7) and 20 ml of sat. aqueous sodium
chloride solution, dried over magnesium sulfate, filtered and
concentrated. This gave 172 mg (57% of theory, 95% pure) of the
title compound.
[0669] LC-MS (Method 3): R.sub.t=1.33 min; MS (ESIpos): m/z=456
[M+H].sup.+
[0670] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.150 (0.50),
0.008 (4.41), 0.146 (0.53), 1.157 (0.75), 1.175 (1.58), 1.193
(1.14), 1.211 (0.80), 1.229 (0.63), 1.263 (0.54), 1.988 (2.86),
2.327 (0.86), 2.366 (0.56), 2.670 (1.04), 2.710 (0.65), 2.731
(7.25), 2.891 (9.16), 3.940 (5.63), 4.003 (0.85), 4.021 (1.18),
4.038 (1.09), 4.056 (0.63), 4.176 (0.54), 4.194 (0.51), 5.210
(10.86), 5.216 (10.51), 5.754 (0.55), 7.582 (5.35), 7.604 (9.75),
7.626 (5.44), 7.952 (1.08), 8.314 (15.84), 9.065 (16.00), 14.776
(6.50).
Example 31A
7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthy-
ridine-3-carbonyl chloride
##STR00122##
[0672] To a solution of 300 mg (805 .mu.mol) of
7-chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthy-
ridine-3-carboxylic acid in 6 ml of THF were added 180 .mu.l (2.40
mmol) of thionyl chloride and the mixture was stirred under reflux
for a further 3 h, and then all the volatile components were
removed under reduced pressure. The crude product was used in the
next step without further workup (conversion was assumed to be
quantitative).
Example 32A
7-Chloro-N-(2,6-dichlorophenyl)-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)--
1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00123##
[0674] At RT, 340 .mu.l (2.40 mmol) of triethylamine and 156 mg
(963 .mu.mol) of 2,6-dichloroaniline were added to a solution of
314 mg (803 .mu.mol) of
7-chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthy-
ridine-3-carbonyl chloride in 20 ml of dichloromethane. The mixture
was stirred at RT for 30 min and at 50.degree. C. overnight. The
reaction mixture was concentrated and taken up in dichloromethane,
washed twice with 1 M aqueous hydrochloric acid, dried over
magnesium sulfate and filtered, and the solvent was removed under
reduced pressure. The crude product was purified by preparative
HPLC (column: acetonitrile/water/0.1% of formic acid).
[0675] This gave 255 mg (61% of theory, 100% pure) of the title
compound.
[0676] LC-MS (Method 1): R.sub.t=1.28 min; MS (ESIpos): m/z=516
[M+H].sup.+
[0677] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.50),
-0.008 (5.02), 0.008 (4.03), 0.146 (0.49), 1.245 (0.63), 1.260
(0.75), 1.275 (0.44), 2.073 (11.19), 2.328 (0.67), 2.367 (0.63),
2.524 (2.42), 2.670 (0.76), 2.710 (0.70), 2.891 (0.41), 7.381
(3.22), 7.402 (6.06), 7.422 (4.60), 7.596 (16.00), 7.608 (4.71),
7.616 (13.09), 7.629 (7.60), 7.652 (4.03), 8.767 (6.42), 8.786
(6.40), 9.250 (10.90), 11.287 (9.23).
Example 33A Ethyl
2-[(2,5-dichloropyridin-3-yl)carbonyl]-3-(dimethylamino)acrylate
##STR00124##
[0679] At RT, 1.34 ml (15.39 mmol) of oxalyl chloride and 4 drops
of DMF were added to 2.0 g (10.42 mmol) of 2,5-dichloronicotinic
acid in 27 ml of dichloromethane, and the mixture was stirred at RT
for 1.5 h. The clear solution was then concentrated, toluene was
added and the mixture was concentrated again (twice). The
intermediate obtained was dissolved in 67 ml of toluene, and 2.17
ml (15.60 mmol) of triethylamine and 1.94 g (13.54 mmol) of ethyl
(2E)-3-(dimethylamino)acrylate were added. The mixture was stirred
at 90.degree. C. for 2.5 h, filtered and evaporated to dryness. The
crude product was purified by silica gel chromatography (solvent:
cyclohexane/ethyl acetate=1:1). This gave 4.10 g (quantitative
yield, about 95% pure) of the title compound.
[0680] LC-MS (Method 1): R.sub.t=0.76 min; MS (ESIpos): m/z=317
[M+H].sup.+
Example 34A Ethyl
6-chloro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-car-
boxylate
##STR00125##
[0682] 770 .mu.l (7.60 mmol) of 2,4-difluoroaniline in 3.8 ml of
THF were added to a solution of 2.00 g (6.31 mmol) of ethyl
2-[(2,5-dichloropyridin-3-yl)carbonyl]-3-(dimethylamino)acrylate in
15 ml of ethanol, and the reaction mixture was stirred at RT
overnight. Subsequently, the solvent was removed under reduced
pressure, the residue was taken up in 20 ml of DMF, and 1.31 g
(9.48 mmol) of potassium carbonate were added. The suspension was
then stirred at 100.degree. C. for 1 h, subsequently cooled to RT
and added to 50 ml of water. The precipitate was filtered off and
washed three times with water. This gave 1.06 g (46% of theory, 91%
pure) of the title compound which was used without further
purification for the next step.
[0683] LC-MS (Method 1): R.sub.t=0.99 min; MS (ESIpos): m/z=365
[M+H].sup.+
[0684] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. ppm=8.80 (d,
1H), 8.78 (s, 1H), 8.59 (d, 1H), 7.80-7.88 (m, 1H), 7.57-7.65 (m,
1H), 7.31-7.39 (m, 1H), 4.24 (q, 2H), 1.28 (t, 3H).
Example 35A
6-Chloro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-car-
boxylic acid
##STR00126##
[0686] 127 mg (3.02 mmol) of lithium hydroxide monohydrate were
added to a suspension of 1.10 g (3.02 mmol) of ethyl
6-chloro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-car-
boxylate in 10 ml of THF and 3.6 ml of water, and the reaction
mixture was stirred at room temperature for 1 h. The mixture was
then diluted with 20 ml of THF and 20 ml of water and the pH was
adjusted to pH 1 with 1M aqueous hydrochloric acid. Ethyl acetate
was added and the aqueous phase was extracted three times with
ethyl acetate. The organic phase was dried over sodium sulfate,
filtered and the solvent was removed under reduced pressure. This
gave 0.90 g (86% of theory, 97% pure) of the title compound.
[0687] LC-MS (Method 1): R.sub.t=0.96 min; MS (ESIpos): m/z=337
[M+H].sup.+
[0688] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. ppm=13.98 (br
s, 1H), 9.10 (s, 1H), 8.95 (d, 1H), 8.80 (d, 1H), 7.80-7.89 (m,
1H), 7.58-7.67 (m, 1H), 7.26-7.47 (m, 1H).
Example 36A
6-Chloro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-car-
bonyl chloride
##STR00127##
[0690] 58 .mu.l (670 .mu.mol) of oxalyl chloride and DMF (catalytic
amounts) were added to a solution of 150 mg (446 .mu.mol) of
6-chloro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-car-
boxylic acid in 3 ml of THF. The reaction mixture was stirred at
room temperature for 1 h and under reflux for a further hour.
Subsequently, all volatile components were removed under reduced
pressure. The crude product was used in the next step without
further workup (conversion was assumed to be quantitative).
Example 37A
7-Chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-1-(2,-
4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00128##
[0692]
7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylic acid (100 mg, 268 .mu.mol) was initially
charged in 2.5 ml of acetonitrile, and
(1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride (51.8
mg, 295 .mu.mol) and N,N-diisopropylethylamine (190 .mu.l, 1.1
mmol) were added. T3P solution (propylphosphonic acid cyclic
anhydride, 50% in ethyl acetate, 190 .mu.l, 320 .mu.mol) was then
added. The reaction solution was stirred at room temperature
overnight. Water was then added to the reaction mixture and the
precipitated solid was filtered off and dried under high vacuum.
This gave 145 mg of the target compound (quantitative yield).
[0693] LC-MS (Method 3): R.sub.t=2.42 min; MS (ESIpos): m/z=494
[M+H].sup.+
[0694] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.150 (0.74),
0.146 (0.69), 0.335 (4.38), 0.348 (3.99), 0.359 (2.50), 0.567
(5.66), 0.579 (6.91), 0.590 (7.00), 0.624 (1.67), 0.651 (2.50),
0.670 (4.11), 0.687 (2.47), 1.224 (2.32), 1.237 (3.75), 1.245
(3.07), 1.257 (3.55), 1.268 (2.06), 2.328 (1.49), 2.366 (1.19),
2.669 (1.43), 2.710 (1.01), 4.370 (2.03), 4.391 (3.66), 4.411
(3.61), 4.433 (1.94), 5.754 (2.89), 7.602 (6.41), 7.624 (12.45),
7.647 (6.50), 8.709 (9.33), 8.728 (9.33), 9.157 (16.00), 9.972
(6.97), 9.996 (6.88).
Example 38A N-Benzyl-1,1,1,2,2-pentafluorobutan-3-amine
(racemate)
##STR00129##
[0696] To a solution of 2.00 g (12.2 mmol) of
3,3,4,4,4-pentafluorobutan-2-one in 10 ml of dichloromethane were
added, at 0.degree. C., 5.40 ml (18.3 mmol) of titanium
tetraisopropoxide and 2.66 ml (24.4 mmol) of benzylamine. The
mixture was stirred at RT for a further 90 min before being cooled
down again to 0.degree. C. Subsequently, 2.14 g (34.1 mmol) of
sodium cyanoborohydride, 36 ml of methanol and 3 .ANG. molecular
sieve were added. The mixture was warmed to RT and stirred for a
further 2 d. A little water and ethyl acetate were then added and
the reaction solution was filtered. The filtrate was washed twice
with saturated aqueous sodium bicarbonate solution and once with
saturated aqueous sodium chloride solution. The organic phase was
dried over sodium sulfate and filtered, and the solvent was removed
under reduced pressure. The residue was purified twice by means of
normal phase chromatography (ethyl acetate/cyclohexane 1/20), and
1.65 g (48% of theory; 91% purity) of the title compound were
obtained.
[0697] LC-MS (Method 6): R.sub.t=2.17 min; MS (ESIpos): m/z=254
[M+H].sup.+.
[0698] .sup.1H NMR (500 MHz, DMSO-d6): .delta. [ppm]=7.28-7.36 (m,
4H), 7.20-7.27 (m, 1H), 3.83 (dd, 1H), 3.72 (dd, 1H), 3.22-3.30 (m,
1H), 2.43-2.48 (m, 1H), 1.20 (d, 3H).
Example 39A 1,1,1,2,2-Pentafluorobutan-3-amine hydrochloride
(racemate)
##STR00130##
[0700] To a solution of 1.50 g (5.92 mmol) of
N-benzyl-1,1,1,2,2-pentafluoropentan-3-amine in 27.4 ml of methanol
were added 150 mg of palladium on charcoal (10%), and hydrogenation
was effected at standard pressure and room temperature for 6 h. The
reaction mixture was then filtered through a Millipore filter and
the solvent was removed under reduced pressure. The receiver
containing the solvent distilled off was then transferred to a
flask and admixed with 4 N aqueous hydrochloric acid in dioxane and
concentrated again. The residue was stirred with diethyl ether and
the precipitate was filtered off with suction and dried under high
vacuum. This gave 456 mg (39% of theory, 100% pure) of the title
compound.
[0701] .sup.1H NMR (500 MHz, DMSO-d6): .delta. [ppm]=9.21 (br. s,
3H), 4.40-4.29 (m, 1H), 1.41 (d, 3H).
Example 40A N-Benzyl-1,1,1,2,2-pentafluoropentan-3-amine
(racemate)
##STR00131##
[0703] To a solution of 2.00 g (11.4 mmol) of
1,1,1,2,2-pentafluoropentan-3-one in 10 ml of dichloromethane were
added, at 0.degree. C., 5.03 ml (17.0 mmol) of titanium
tetraisopropoxide and 2.48 ml (22.7 mmol) of benzylamine. The
mixture was stirred at RT for a further 90 min before being cooled
down again to 0.degree. C. Subsequently, 2.00 g (31.8 mmol) of
sodium cyanoborohydride, 36 ml of methanol and 3 .ANG. molecular
sieve were added. The mixture was warmed to RT and stirred for a
further 2 d. The reaction solution was then admixed with a little
water and ethyl acetate and filtered. The filtrate was washed twice
with saturated aqueous sodium bicarbonate solution and once with
saturated aqueous sodium chloride solution. The organic phase was
dried over sodium sulfate and filtered, and the solvent was removed
under reduced pressure. The residue was purified by means of normal
phase chromatography (ethyl acetate/cyclohexane 1/20), and 989 mg
(25% of theory; 76% purity) of the title compound were
obtained.
[0704] LC-MS (Method 1): R.sub.t=1.27 min; MS (ESIpos): m/z=268
[M+H].sup.+
[0705] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=7.21-7.36 (m,
5H), 3.73-3.85 (m, 2H), 3.05-3.20 (m, 1H), 1.63-1.75 (m, 1H),
1.49-1.61 (m, 1H), 1.15-1.20 (m, 1H), 0.96 (t, 3H).
Example 41A 1,1,1,2,2-Pentafluoropentan-3-amine hydrochloride
(racemate)
##STR00132##
[0707] 75 mg of palladium on charcoal (10%) were added to a
solution of 980 mg (2.75 mmol, 75% pure) of the compound from
Example 40A in 11.3 ml of methanol, and the mixture was
hydrogenated at atmospheric pressure and room temperature for 6 h.
The reaction mixture was then filtered through a Millipore filter
and the solvent was removed under reduced pressure. The receiver
containing the solvent distilled off was then transferred to a
flask, 4 M aqueous hydrochloric acid in dioxane was added and the
mixture was concentrated again. The residue was stirred with
diethyl ether and the precipitate was filtered off with suction and
dried under high vacuum. This gave 379 mg (65% of theory, 100%
pure) of the title compound.
[0708] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=8.97 (br. s,
3H), 4.16-4.28 (m, 1H), 1.67-1.94 (m, 2H), 1.05 (t, 3H).
Example 41B Ethyl
7-chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3--
carboxylate
##STR00133##
[0710] To a solution of 12.1 g (38.0 mmol) of ethyl
2-[(2,6-dichloropyridin-3-yl)carbonyl]-3-ethoxyacrylate (CAS
157373-27-8) and 7.83 g (53.2 mmol) of 2,4,6-trifluoroaniline in
60.5 ml of DCM were added 46.4 ml (266 mmol) of DIPEA, and the
mixture was stirred at RT for 4 h. Subsequently, 5.26 g (38.0 mmol)
of potassium carbonate were added and the mixture was heated under
reflux overnight. The mixture was diluted with 200 ml of DCM and
washed twice with 150 ml of 1 M aqueous hydrochloric acid. The
organic phase was dried over sodium sulfate and filtered, and the
solvent was removed under reduced pressure. The suspension obtained
was stirred with 80 ml of tert-butyl methyl ether, and the
precipitate was filtered off with suction, washed with 10 ml of
tert-butyl methyl ether and dried under high vacuum. This gave 8.60
g (58% of theory, 99% pure) of the title compound.
[0711] LC-MS (Method 1): R.sub.t=0.97 min; 383 [M+H].sup.+.
Example 41C
7-chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3--
carboxylic acid
##STR00134##
[0713] 8.60 g (22.5 mmol) of ethyl
7-chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3--
carboxylate (Example 100A) were initially charged in 67.7 ml of
water, 67.7 ml of 36% strength aqueous hydrochloric acid and 67.7
ml of THF were added and the mixture was stirred at 110.degree. C.
for 4.5 h. The reaction mixture was cooled to RT. The precipitate
was filtered off with suction, washed with water and dried under
high vacuum. This gave 7.87 g (98% of theory, 99% pure) of the
title compound.
[0714] LC-MS (Method 1): R.sub.t=0.95 min; MS (ESIpos): m/z=355
[M+H].sup.+.
[0715] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=13.83 (s, 1H),
9.27 (s, 1H), 8.78 (d, 1H), 7.82 (d, 1H), 7.67-7.59 (m, 2H).
Example 42A
6-Fluoro-7-(morpholin-4-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1-
,8-naphthyridine-3-carboxylic acid
##STR00135##
[0717] At RT, 840 .mu.l (4.80 mmol) of DIPEA were added to a
solution of 600 mg (1.61 mmol) of
7-chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthy-
ridine-3-carboxylic acid and 200 .mu.l (2.30 mmol) of morpholine in
8.0 ml DMF. The mixture was stirred at RT overnight. The reaction
mixture was diluted with acetonitrile, a little water and formic
acid and the crude product was purified by preparative HPLC
(column: acetonitrile/water/0.1% of formic acid). This gave 658 mg
(97% of theory, 100% pure) of the title compound.
[0718] LC-MS (Method 3): R.sub.t=1.76 min; MS (ESIpos): m/z=424
[M+H].sup.+
[0719] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.48),
0.146 (0.51), 2.328 (0.72), 2.367 (0.64), 2.671 (0.77), 2.711
(0.64), 3.558 (12.72), 3.570 (14.98), 3.602 (16.00), 3.615 (13.62),
5.754 (1.56), 7.568 (4.70), 7.591 (8.79), 7.613 (4.66), 8.159
(7.09), 8.192 (7.01), 9.099 (13.11), 14.766 (1.97).
Example 43A
7-Chloro-6-fluoro-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-4-oxo-1-(2,4,6-tr-
ifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00136##
[0721] 3.8 ml (6.40 mmol) of
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide
(T3P, 50% in DMF) were added dropwise to a solution of 600 mg (1.61
mmol) of
7-chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthy-
ridine-3-carboxylic acid, 296 mg (1.77 mmol) of
1,1,1,3,3,3-hexafluoropropan-2-amine and 840 .mu.l (4.80 mmol) of
DIPEA in 14 ml of ethyl acetate. The mixture was stirred at
80.degree. C. overnight. The reaction mixture was poured into water
and ethyl acetate, and the phases were separated. The organic phase
was washed with water, dried over sodium sulfate and filtered, and
the solvent was removed under reduced pressure. The residue was
dissolved in a little acetonitrile, filtered over a Millipore
filter and purified in three runs by preparative HPLC (column:
acetonitrile/water/0.1% of formic acid). This gave 414 mg (49% of
theory, 100% pure) of the title compound.
[0722] LC-MS (Method 3): R.sub.t=2.47 min; MS (ESIpos): m/z=522
[M+H].sup.+
[0723] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.77),
-0.008 (7.00), 0.146 (0.77), 2.073 (0.49), 2.328 (0.60), 2.367
(0.60), 2.671 (0.69), 2.711 (0.60), 6.375 (0.60), 6.394 (1.45),
6.412 (2.11), 6.418 (2.09), 6.437 (2.25), 6.454 (1.48), 6.472
(0.55), 7.616 (5.90), 7.638 (11.25), 7.660 (5.93), 8.756 (9.74),
8.774 (9.85), 9.288 (16.00), 10.694 (6.45), 10.720 (6.28).
Example 44A
7-Chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-N-(1,1,1,3,3,3-hexafluorop-
ropan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00137##
[0725] 1.7 ml (2.80 mmol) of
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide
(T3P, 50% in ethyl acetate) were added dropwise to a solution of
250 mg (703 .mu.mol) of
7-chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naph-
thyridine-3-carboxylic acid, 129 mg (773 .mu.mol) of
1,1,1,3,3,3-hexafluoropropan-2-amine and 370 .mu.l (2.10 mmol) of
DIPEA in 10 ml of ethyl acetate. The mixture was stirred at
80.degree. C. overnight. 50 ml of water were added to the reaction
mixture. The precipitate was filtered off with suction, washed with
water and dried under high vacuum. This gave 259 mg (69% of theory,
94% pure) of the title compound.
[0726] LC-MS (Method 3): R.sub.t=2.34 min; MS (ESIpos): m/z=505
[M+H].sup.+
[0727] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (1.14),
0.146 (1.21), 0.931 (1.84), 0.949 (3.59), 0.967 (1.98), 1.175
(0.70), 1.243 (2.59), 1.260 (2.64), 1.273 (1.61), 1.298 (0.51),
1.487 (1.14), 1.496 (1.19), 1.668 (0.58), 1.988 (0.51), 2.328
(1.28), 2.366 (0.93), 2.670 (1.21), 2.710 (0.89), 6.406 (1.45),
6.424 (2.05), 6.448 (2.17), 6.467 (1.38), 8.399 (2.33), 8.405
(2.89), 8.426 (4.48), 8.443 (2.54), 8.449 (2.66), 8.615 (0.49),
8.682 (10.68), 8.688 (9.63), 8.753 (9.52), 8.772 (9.52), 8.922
(0.42), 9.184 (1.75), 9.217 (16.00), 9.284 (0.44), 10.705 (5.78),
10.731 (5.69).
Example 45A
7-Chloro-4-oxo-N-[1,1,1,2,2-pentafluoropentan-3-yl]-1-(2,4,6-trifluorophe-
nyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (racemate)
##STR00138##
[0729] 1.6 ml (2.80 mmol) of
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide
(T3P, 50% in ethyl acetate) were added dropwise to a solution of
250 mg (705 .mu.mol) of
7-chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3--
carboxylic acid, 166 mg (775 .mu.mol) of
1,1,1,2,2-pentafluoropentan-3-amine hydrochloride (racemate) and
490 .mu.l (2.80 mmol) of DIPEA in 7.0 ml of ethyl acetate. The
mixture was stirred at 80.degree. C. overnight. 50 ml of water were
added to the reaction mixture. The aqueous phase was extracted
twice with ethyl acetate. All organic phases were dried over sodium
sulfate and filtered, and the solvent was removed under reduced
pressure. This gave 360 mg (89% of theory, 90% pure) of the title
compound.
[0730] LC-MS (Method 3): R.sub.t=2.45 min; MS (ESIpos): m/z=514
[M+H].sup.+
[0731] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.93),
-0.008 (7.96), 0.008 (8.00), 0.146 (0.79), 0.834 (0.71), 0.852
(1.07), 0.950 (1.23), 0.968 (0.79), 1.180 (0.89), 1.234 (2.12),
1.266 (0.69), 1.285 (0.99), 1.302 (0.54), 1.410 (15.56), 1.427
(15.60), 1.497 (0.62), 2.328 (1.15), 2.367 (0.93), 2.671 (1.07),
2.711 (0.83), 4.998 (0.77), 5.020 (1.35), 5.044 (1.59), 5.062
(1.61), 5.086 (1.31), 5.107 (0.69), 7.596 (6.17), 7.618 (11.61),
7.640 (6.35), 7.648 (2.20), 7.754 (0.50), 7.773 (12.55), 7.794
(13.00), 7.811 (1.47), 7.832 (1.53), 8.741 (12.74), 8.762 (12.37),
8.772 (1.71), 8.793 (1.37), 9.057 (0.40), 9.143 (16.00), 9.273
(1.69), 9.986 (6.15), 10.010 (5.94).
Example 46A
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[1,1,1,2,2-pentafluorope-
ntan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbo-
xamide (diastereomer mixture)
##STR00139##
[0733] According to GP3, 360 mg (700 .mu.mol) of
7-chloro-4-oxo-N-[1,1,1,2,2-pentafluoropentan-3-yl]-1-(2,4,6-trifluorophe-
nyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide were reacted with
81.9 mg (586 .mu.mol) of (3R,4R)-pyrrolidine-3,4-diol hydrochloride
and 430 .mu.l (2.50 mmol) of DIPEA in 4 ml of DMF. Aqueous 1N
hydrochloric acid was added and the reaction mixture was extracted
with ethyl acetate. The organic phase was dried over sodium sulfate
and filtered, and the solvent was removed under reduced pressure.
The crude product was purified by preparative HPLC (column:
acetonitrile/water/0.1% of formic acid). This gave 242 mg (60% of
theory, 100% pure) of the title compound.
[0734] LC-MS (Method 3): R.sub.t=1.86 min; MS (ESIpos): m/z=581
[M+H].sup.+
[0735] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.008 (2.01),
0.946 (7.17), 0.965 (16.00), 0.983 (7.77), 1.618 (0.90), 1.636
(1.25), 1.644 (1.05), 1.652 (1.50), 1.662 (1.35), 1.671 (1.20),
1.679 (1.40), 1.697 (1.00), 1.920 (1.30), 2.073 (0.80), 2.329
(0.80), 2.368 (0.70), 2.524 (2.46), 2.671 (0.85), 2.711 (0.75),
3.055 (2.76), 3.087 (3.71), 3.239 (2.36), 3.262 (1.76), 3.353
(3.76), 3.606 (2.06), 3.627 (1.71), 3.929 (3.46), 4.050 (3.46),
4.826 (0.80), 4.850 (1.15), 4.876 (1.10), 4.902 (0.85), 5.144
(4.97), 5.152 (4.97), 5.235 (5.02), 5.244 (4.87), 6.770 (7.32),
6.792 (7.52), 7.544 (2.71), 7.566 (4.82), 7.584 (2.76), 8.268
(8.58), 8.290 (8.13), 8.815 (14.50), 10.470 (4.97), 10.495
(4.76).
Example 47A
7-Chloro-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophen-
yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (racemate)
##STR00140##
[0737] 1.6 ml (2.80 mmol) of
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide
(T3P, 50% in ethyl acetate) were added dropwise to a solution of
250 mg (705 .mu.mol) of
7-chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3--
carboxylic acid, 155 mg (775 .mu.mol) of
3,3,4,4,4-pentafluorobutan-2-amine hydrochloride (racemate) and 490
.mu.l (2.80 mmol) of DIPEA in 7.0 ml of ethyl acetate. Stirring was
continued at 80.degree. C. for 30 minutes. The solvent was removed
under reduced pressure and the crude product was purified by
preparative HPLC (column: acetonitrile/water/0.1% of formic acid).
This gave 325 mg (83% of theory, 90% pure) of the title
compound.
[0738] LC-MS (Method 3): R.sub.t=2.37 min; MS (ESIpos): m/z=500
[M+H].sup.+
[0739] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (1.17),
-0.008 (16.00), 0.008 (8.86), 0.146 (1.23), 0.849 (0.84), 0.942
(1.10), 0.959 (0.65), 1.233 (1.59), 1.283 (0.62), 1.409 (11.07),
1.426 (10.77), 1.487 (0.55), 2.327 (1.53), 2.366 (1.43), 2.524
(9.70), 2.670 (1.62), 2.710 (1.46), 5.020 (0.94), 5.042 (1.20),
5.060 (1.20), 5.086 (1.01), 7.595 (4.38), 7.617 (8.11), 7.639
(4.35), 7.772 (8.18), 7.793 (8.31), 7.811 (0.97), 7.832 (1.04),
8.741 (8.18), 8.761 (7.89), 8.772 (1.07), 8.793 (0.88), 9.142
(10.90), 9.272 (1.14), 9.985 (4.28), 10.009 (4.19).
Example 48A
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluorobu-
tan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbox-
amide (diastereomer mixture)
##STR00141##
[0741] According to GP3, 325 mg (650 .mu.mol) of
7-chloro-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophen-
yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (racemate) were
reacted with 76.1 mg (545 .mu.mol) of (3R,4R)-pyrrolidine-3,4-diol
hydrochloride and 400 .mu.l (2.30 mmol) of DIPEA in 3.7 ml of DMF.
Aqueous 1N hydrochloric acid was added and the reaction mixture was
extracted with ethyl acetate. The organic phase was dried over
sodium sulfate and filtered, and the solvent was removed under
reduced pressure. The crude product was purified by preparative
HPLC (column: acetonitrile/water/0.1% of formic acid). This gave
239 mg (65% of theory, 100% pure) of the title compound.
[0742] LC-MS (Method 3): R.sub.t=1.76 min; MS (ESIpos): m/z=567
[M+H].sup.+
[0743] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: 1.388 (15.08),
1.401 (16.00), 2.672 (0.88), 3.053 (3.67), 3.086 (4.68), 3.601
(3.82), 3.929 (6.14), 4.052 (6.04), 5.005 (2.33), 5.146 (6.42),
5.237 (6.35), 6.768 (5.34), 6.790 (5.44), 7.564 (8.09), 8.261
(5.29), 8.283 (5.16), 8.808 (8.64), 10.549 (4.91), 10.573
(4.81).
Example 49A
7-Chloro-4-oxo-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-1-(2,4,6-trifluoro-
phenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00142##
[0745] 1.6 ml (2.80 mmol) of
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide
(T3P, 50% in ethyl acetate) were added dropwise to a solution of
250 mg (705 .mu.mol) of
7-chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3--
carboxylic acid, 127 mg (775 .mu.mol) of
1,1,1-trifluoro-2-methylpropan-2-amine hydrochloride and 490 .mu.l
(2.80 mmol) of DIPEA in 7.0 ml of ethyl acetate. The mixture was
stirred at 80.degree. C. for 30 minutes. The solvent was removed
under reduced pressure and the reaction mixture was diluted with 50
ml of water. The precipitate formed was filtered off, washed with
water and dried. This gave 297 mg (88% of theory, 97% pure) of the
title compound.
[0746] LC-MS (Method 3): R.sub.t=2.34 min; MS (ESIpos): m/z=464
[M+H].sup.+
[0747] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.062 (0.91),
-0.008 (0.99), 0.008 (1.16), 1.653 (16.00), 7.597 (1.19), 7.618
(2.22), 7.641 (1.22), 7.767 (2.50), 7.788 (2.63), 8.746 (2.59),
8.767 (2.51), 9.080 (3.17), 10.101 (2.55).
Example 50A
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-4-oxo-N-(1,1,1-trifluoro-2-methy-
lpropan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-ca-
rboxamide
##STR00143##
[0749] According to GP3, 297 mg (666 .mu.mol) of
7-chloro-4-oxo-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-1-(2,4,6-trifluoro-
phenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide were reacted
with 102 mg (733 .mu.mol) of (3R,4R)-pyrrolidine-3,4-diol
hydrochloride and 410 .mu.l (2.30 mmol) of DIPEA in 6.0 ml of DMF.
20 ml of water and aqueous 1N hydrochloric acid were added to the
reaction mixture. The precipitate formed was filtered off, washed
with water and dried. This gave 272 mg (77% of theory, 100% pure)
of the title compound.
[0750] LC-MS (Method 3): R.sub.t=1.73 min; MS (ESIpos): m/z=531
[M+H].sup.+
[0751] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (1.79),
0.008 (1.49), 1.634 (16.00), 2.073 (5.68), 3.052 (0.77), 3.083
(1.03), 3.226 (0.66), 3.235 (0.76), 3.257 (0.63), 3.268 (0.68),
3.348 (1.35), 3.593 (0.56), 3.603 (0.65), 3.621 (0.52), 3.630
(0.49), 3.923 (0.97), 4.046 (0.97), 6.759 (1.98), 6.782 (2.03),
7.545 (0.73), 7.567 (1.31), 7.585 (0.74), 8.266 (2.23), 8.289
(2.10), 8.739 (3.50), 10.653 (2.89).
Example 51A
7-Chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-1-(2,4,6-trifl-
uorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00144##
[0753] 26 ml (45.0 mmol) of
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide
(T3P, 50% in ethyl acetate) were added dropwise to a solution of
4.00 g (11.3 mmol) of
7-chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthy-
ridine-3-carboxylic acid, 2.18 g (12.4 mmol) of
(1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride and 7.9
ml (45.0 mmol) of DIPEA in 110 ml of ethyl acetate. Stirring was
continued at 80.degree. C. for 30 minutes. The solvent was removed
under reduced pressure and the reaction mixture was diluted with
150 ml of water. The precipitate was filtered off, washed with
water and dried. This gave 5.30 g (95% of theory, 96% pure) of the
title compound.
[0754] LC-MS (Method 3): R.sub.t=2.33 min; MS (ESIpos): m/z=476
[M+H].sup.+
[0755] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.55),
-0.062 (4.39), 0.008 (4.02), 0.146 (0.52), 0.322 (1.81), 0.335
(3.73), 0.348 (3.42), 0.361 (1.95), 0.370 (1.38), 0.566 (5.17),
0.580 (6.61), 0.589 (5.43), 0.609 (2.33), 0.623 (1.38), 0.645
(1.67), 0.652 (2.21), 0.666 (3.50), 0.679 (1.90), 0.688 (2.13),
0.694 (2.24), 0.716 (0.40), 0.850 (0.43), 0.934 (1.01), 1.157
(1.38), 1.175 (2.70), 1.193 (1.52), 1.202 (0.83), 1.215 (1.55),
1.223 (2.13), 1.235 (3.76), 1.244 (3.07), 1.256 (3.56), 1.265
(2.10), 1.275 (1.49), 1.282 (1.41), 1.300 (0.57), 1.486 (0.80),
1.989 (4.83), 2.329 (1.01), 2.367 (0.89), 2.524 (4.77), 2.671
(1.03), 2.711 (0.83), 4.003 (0.43), 4.021 (1.18), 4.039 (1.15),
4.056 (0.40), 4.243 (0.49), 4.261 (0.40), 4.341 (0.60), 4.361
(1.87), 4.382 (3.22), 4.403 (3.04), 4.424 (1.61), 4.444 (0.43),
7.594 (6.32), 7.617 (11.78), 7.639 (6.18), 7.699 (0.43), 7.776
(11.69), 7.797 (12.21), 8.748 (12.18), 8.769 (11.75), 8.940 (0.46),
9.126 (16.00), 10.025 (6.55), 10.049 (6.26).
Example 52A
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(3R,4R)-3,4-dihydroxypyrro-
lidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine--
3-carboxamide
##STR00145##
[0757] According to GP3, 5.30 g (11.1 mmol) of
7-chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-4-oxo-1-(2,4,6-trifl-
uorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide were
reacted with 1.87 g (13.4 mmol) of (3R,4R)-pyrrolidine-3,4-diol
hydrochloride and 6.8 ml (39.0 mmol) of DIPEA in 50 ml of DMF. 400
ml of water and aqueous 1N hydrochloric acid were added to the
reaction mixture. The precipitate was filtered off, washed with
water and dried. This gave 5.47 g (91% of theory, 100% pure) of the
title compound.
[0758] LC-MS (Method 3): R.sub.t=1.71 min; MS (ESIpos): m/z=543
[M+H].sup.+
[0759] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.74),
-0.061 (4.97), -0.008 (6.91), 0.008 (5.18), 0.146 (0.66), 0.324
(1.75), 0.334 (2.68), 0.346 (2.68), 0.358 (2.07), 0.370 (1.01),
0.510 (1.88), 0.522 (2.81), 0.535 (2.49), 0.547 (2.58), 0.556
(2.24), 0.567 (2.75), 0.578 (2.32), 0.588 (2.16), 0.598 (1.73),
0.612 (1.10), 0.626 (1.37), 0.636 (1.52), 0.647 (2.47), 0.657
(2.16), 0.662 (2.11), 0.670 (2.03), 0.682 (1.01), 0.691 (0.72),
0.944 (1.48), 1.165 (0.82), 1.177 (1.44), 1.186 (1.99), 1.198
(3.15), 1.206 (2.49), 1.218 (3.32), 1.231 (2.32), 1.238 (1.99),
1.263 (1.33), 1.398 (0.59), 2.328 (0.85), 2.367 (0.78), 2.524
(2.62), 2.670 (0.80), 2.711 (0.68), 2.731 (3.21), 2.891 (3.89),
3.056 (3.25), 3.088 (4.25), 3.230 (2.62), 3.239 (2.98), 3.261
(2.35), 3.272 (2.32), 3.353 (4.10), 3.600 (2.37), 3.609 (2.71),
3.627 (2.20), 3.637 (1.99), 3.927 (3.89), 4.050 (3.89), 4.356
(1.39), 4.377 (2.41), 4.398 (2.39), 4.418 (1.25), 5.145 (3.74),
5.233 (3.53), 6.772 (8.20), 6.794 (8.43), 7.543 (3.17), 7.566
(5.60), 7.583 (3.19), 7.953 (0.51), 8.271 (9.72), 8.293 (9.13),
8.798 (16.00), 10.558 (5.71), 10.582 (5.45).
Example 53A
1,1,1,2,2-Pentafluoro-N-[(1S)-1-phenylethyl]pentan-3-imine
##STR00146##
[0761] 1,1,1,2,2-Pentafluoropentan-3-one (50.0 g, 284 mmol) was
initially charged in 21 of diethyl ether and cooled to 0.degree. C.
(1S)-1-Phenylethanamine (34.4 g, 284 mmol) and triethylamine (79
ml, 570 mmol) were then added rapidly, and at an internal
temperature of 0.degree. C. titanium(IV) chloride (1 M in toluene,
140 ml, 140 mmol) was subsequently slowly added dropwise. The ice
bath was then removed and the mixture was warmed to RT. The
reaction mixture was subsequently heated under reflux for 1 h and
then stirred at RT overnight. Kieselguhr was added to the reaction
mixture, the mixture was stirred for 1 h and then filtered through
kieselguhr and the kieselguhr was washed thoroughly with diethyl
ether. The filtrate was concentrated at water bath temperature of
20.degree. C. The crude product was used for the next step without
further purification. This gave 79 g (quantitative yield) of the
title compound.
Example 54A
1,1,1,2,2-Pentafluoro-N-[(1S)-1-phenylethyl]pentan-3-amine
hydrochloride (enantiomerically pure)
##STR00147##
[0763] 1,1,1,2,2-Pentafluoro-N-[(1S)-1-phenylethyl]pentan-3-imine
(79 g, 283 mmol) was initially charged in 640 ml of
dichloromethane, 130 ml of DMF and molecular sieve 3 .ANG. were
then added and the mixture was stirred at RT for 1 h. The reaction
mixture was cooled to -50.degree. C., and trichlorosilane (86 ml,
850 mmol) was slowly added dropwise. After 30 min and at an
internal temperature of -70.degree. C. to -50.degree. C., the
mixture was quenched first with saturated sodium bicarbonate
solution and then with solid sodium bicarbonate until a pH of 7 had
been reached. Dichloromethane was added and the phases were
separated. The organic phase was dried over sodium sulfate, 200 ml
of hydrogen chloride in diethyl ether (2 M solution) were then
added and the crude product was concentrated under reduced
pressure. This gave 48.6 g (54% of theory) of the title
compound.
[0764] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=7.82 (br. s,
1H), 7.26-7.60 (m, 5H), 4.13 (br. s, 1H), 3.20 (br. s, 1H),
1.40-1.77 (m, 5H), 0.80 (t, 3H).
Example 55A 1,1,1,2,2-Pentafluoropentan-3-amine hydrochloride
(enantiomerically pure)
##STR00148##
[0766] 48.6 g (153 mmol) of
1,1,1,2,2-pentafluoro-N-[(1S)-1-phenylethyl]pentan-3-amine
hydrochloride (enantiomerically pure, from Example 54A) were
dissolved in 250 ml of ethanol, 4.86 g of palladium(II) hydroxide
(20% on carbon) were added and the mixture was then hydrogenated at
RT and standard pressure overnight. The precipitate was filtered
off and washed thoroughly, and the filtrate was concentrated
carefully. This gave 31.7 g (97% of theory) of the title
compound.
[0767] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.16 (br. s,
3H), 4.12-4.28 (m, 1H), 3.47 (br. s, 1H), 1.69-1.96 (m, 2H), 1.06
(t, 3H).
Example 56A
3,3,4,4,4-Pentafluoro-N-[(1S)-1-phenylethyl]butan-2-imine
##STR00149##
[0769] 3,3,4,4,4-Pentafluorobutan-2-one (200 g, 1.23 mol) was
initially charged in 6.41 of diethyl ether and cooled to
-40.degree. C. (1S)-1-Phenylethanamine (160 ml 1.2 mol) and
triethylamine (340 ml, 2.5 mol) were then added rapidly, and at an
internal temperature of 0.degree. C. titanium(IV) chloride (1 M in
toluene, 620 ml, 620 mmol) was subsequently slowly added dropwise.
The ice bath was then removed and the mixture was warmed to RT. The
reaction mixture was subsequently heated under reflux for 1 h and
then stirred at RT overnight. Celite was added to the reaction
mixture, the mixture was stirred for 1 h and then filtered through
Celite and the Celite was washed thoroughly with diethyl ether. The
filtrate was concentrated at water bath temperature of 25.degree.
C. Cyclohexane was added to the residue and the residue was once
more filtered off through Celite and washed with cyclohexane. The
filtrate was concentrated at water bath temperature of 25.degree.
C. The crude product was used for the next step without further
purification. This gave 289 g (88% of theory) of the title
compound.
Example 57A
3,3,4,4,4-Pentafluoro-N-[(1S)-1-phenylethyl]butan-2-amine
hydrochloride (enantiomerically pure)
##STR00150##
[0771] 3,3,4,4,4-Pentafluoro-N-[(1S)-1-phenylethyl]butan-2-imine
(239 g, 901 mmol) was initially charged in 1.91 of dichloromethane,
420 ml of DMF and molecular sieve 3 .ANG. were then added and the
mixture was stirred at RT for 1 h. The reaction mixture was then
cooled to -50.degree. C., and trichlorosilane (270 ml, 2.7 mol) was
slowly added dropwise. After 30 min and at an internal temperature
of -70.degree. C. to -50.degree. C., the mixture was carefully
quenched with semiconcentrated sodium hydroxide solution until a pH
of 7 had been reached. Dichloromethane was added and the phases
were separated. The organic phase was dried over sodium sulfate,
2.21 of hydrogen chloride in diethyl ether (2 M solution) were then
added and the crude product was concentrated under reduced
pressure. This gave 192 g (70% of theory) of the title
compound.
[0772] LC-MS (Method 1): R.sub.t=1.22 min; MS (ESIpos): m/z=268
[M-HCl+H].sup.+
Example 58A 3,3,4,4,4-Pentafluorobutan-2-amine hydrochloride
(enantiomerically pure)
##STR00151##
[0774] 192 g (632 mmol) of
3,3,4,4,4-pentafluoro-N-[(1S)-1-phenylethyl]butan-2-amine
hydrochloride (enantiomerically pure, from Example 57A) were
dissolved in 1.21 of ethanol, 19.2 g of palladium(II) hydroxide
(20% on carbon) were added and the mixture was then hydrogenated at
RT and standard pressure overnight. The precipitate was filtered
off and washed thoroughly, and the filtrate was concentrated
carefully. This gave 117 g (93% of theory) of the title
compound.
[0775] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.29 (br. s,
3H), 4.22-4.44 (m, 1H), 1.42 (d, H).
Example 59A
7-Chloro-6-fluoro-4-oxo-N-[1,1,1,2,2-pentafluoropentan-3-yl]-1-(2,4,6-tri-
fluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(racemate)
##STR00152##
[0777]
7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylic acid (200 mg, 537 .mu.mol) was initially
charged in 1.3 ml of acetonitrile, and
1,1,1,2,2-pentafluoropentan-3-amine hydrochloride (racemate, 138
mg, 644 .mu.mol) and N,N-diisopropylethylamine (370 .mu.l, 2.1
mmol) were added, followed by 380 .mu.l (50% pure, 640 .mu.mol) of
T3P solution (pros panephosphonic acid cyclic anhydride, 50% in
ethyl acetate). The reaction solution was stirred overnight and
then added to water. The mixture was freed from acetonitrile and
extracted three times with dichloromethane. The combined organic
phases were dried over sodium sulfate, filtered and concentrated
under reduced pressure. This gave 282 mg of the target compound
(97% of theory, purity 98%).
[0778] LC-MS (Method 3): R.sub.t=2.53 min; MS (ESIpos): m/z=532
[M+H].sup.+
Example 60A
7-Chloro-6-fluoro-4-oxo-N-[1,1,1,2,2-pentafluoropentan-3-yl]-1-(2,4,6-tri-
fluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(enantiomerically pure)
##STR00153##
[0780]
7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylic acid (5.00 g, 13.4 mmol) was initially
charged in 33 ml of acetonitrile. 3.44 g, (16.1 mmol) of
1,1,1,2,2-pentafluoropentan-3-amine hydrochloride (enantiomerically
pure, from Example 55A) and N,N-diisopropylethylamine (9.3 ml, 54
mmol) were added. T3P solution (propanephosphonic acid cyclic
anhydride, 50% in ethyl acetate, 9.5 ml, 50% pure, 16 mmol) was
then added and the mixture was stirred at room temperature
overnight. Water was added to the reaction solution. A viscous
suspension was formed. This was acidified with dilute hydrochloric
acid and stirred at room temperature for 1 h. The solid was
filtered off, then washed with water and dried under high vacuum.
This gave 6.69 g of the compound (84% of theory, purity 90%).
[0781] LC-MS (Method 5): R.sub.t=1.67 min; MS (ESIpos): m/z=532
[M+H].sup.+
Example 61A tert-Butyl
4-[3-fluoro-5-oxo-6-{[1,1,1,2,2-pentafluoropentan-3-yl]carbamoyl}-8-(2,4,-
6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]-2-(hydroxymethyl)pip-
erazine-1-carboxylate (diastereomer mixture)
##STR00154##
[0783]
7-Chloro-6-fluoro-4-oxo-N-[1,1,1,2,2-pentafluoropentan-3-yl]-1-(2,4-
,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(enantiomerically pure from Example 60A, 200 mg, 90% pure, 338
.mu.mol) was initially charged in 1.7 ml of DMF, and
N,N-diisopropylethylamine (590 .mu.l, 3.4 mmol) and tert-butyl
(2-(hydroxymethyl)piperazine-1-carboxylate (80.5 mg, 372 .mu.mol)
were added at room temperature. The reaction solution was stirred
at room temperature for 1 h. The reaction solution was admixed with
water and extracted three times with ethyl acetate. The combined
organic phases were twice washed with water, dried over sodium
sulfate, filtered and concentrated. The crude product was purified
by silica gel chromatography (mobile phase: cyclohexane/ethyl
acetate=2/1). This gave 204 mg of the target compound (85% of
theory, purity 100%) as a diastereomer mixture of two
diastereomers.
[0784] LC-MS (Method 5): R.sub.t=1.62 min; MS (ESIpos): m/z=712
[M+H].sup.+
Example 62A
7-Chloro-6-fluoro-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifl-
uorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(racemate)
##STR00155##
[0786]
7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylic acid (200 mg, 537 .mu.mol) was initially
charged in 1.3 ml of acetonitrile.
1,1,1,2,2-Pentafluorobutan-3-amine hydrochloride (racemate, 129 mg,
644 .mu.mol) and N,N-diisopropylethylamine (370 .mu.l, 2.1 mmol)
were added, followed by 380 .mu.l (50% pure, 640 .mu.mol) of T3P
solution (propanephosphonic acid cyclic anhydride, 50% in ethyl
acetate). The reaction solution was stirred overnight. The reaction
solution was added to water and precipitated. The solid was
filtered off and dried under high vacuum overnight. This gave 250
mg of the compound (76% of theory, purity 84%).
[0787] LC-MS (Method 3): R.sub.t=2.45 min; MS (ESIpos): m/z=518
[M+H].sup.+
Example 63A
7-Chloro-6-fluoro-4-oxo-N-(3,3,4,4,4-pentafluoro-2-methylbutan-2-yl)-1-(2-
,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00156##
[0789]
7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylic acid (1.50 g, 4.03 mmol) was initially
charged in 38 ml of acetonitrile.
3,3,4,4,4-Pentafluoro-2-methylbutan-2-amine hydrochloride (1.12 g,
5.23 mmol) and N,N-diisopropylethylamine (3.5 ml, 20 mmol) were
added, followed by 3.6 ml (50% pure, 6.0 mmol) T3P solution
(propanephosphonic acid cyclic anhydride, 50% in ethyl acetate).
The reaction solution was stirred at room temperature overnight.
Water was then added to the reaction solution. Under reduced
pressure, the solution was freed almost completely from
acetonitrile, and gradually a solid precipitated on evaporation.
The solid obtained was washed with water. The solid was dried under
high vacuum. This gave 1.96 g of the target compound (91% of
theory, 99% pure).
[0790] LC-MS (Method 3): R.sub.t=2.50 min; MS (ESIpos): m/z=532
[M+H].sup.+
Example 64A
Ethyl(2Z)-2-[(2,6-dichloro-5-fluoropyridin-3-yl)carbonyl]-3-ethoxyacrylat-
e
##STR00157##
[0792] Ethyl 3-(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxopropanoate
(500 mg, 1.79 mmol) and (diethoxymethoxy)ethane (590 .mu.l, 3.6
mmol) were initially charged in acetic anhydride (1.2 ml, 12 mmol)
and stirred at 140.degree. C. overnight. The reaction solution was
concentrated and, without further purification, reacted further in
the next step.
[0793] LC-MS (Method 1): R.sub.t=1.01 min; MS (ESIpos): m/z=336
[M+H].sup.+
Example 65A Ethyl
7-chloro-6-fluoro-1-(4-fluoro-2,6-dimethylphenyl)-4-oxo-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylate
##STR00158##
[0795] Ethyl
(2Z)-2-[(2,6-dichloro-5-fluoropyridin-3-yl)carbonyl]-3-ethoxyacrylate
(9.36 g, 27.8 mmol) and 4-fluoro-2,6-dimethylaniline (4.65 g, 33.4
mmol) were initially charged in 47 ml of dichloromethane, and
N,N-diisopropylethylamine (34 ml, 194.9 mmol) was added at room
temperature (exothermic). The reaction solution was stirred at room
temperature for 4 h. Subsequently, potassium carbonate (3.85 g,
27.84 mmol) was added and the mixture was stirred under reflux
overnight. The reaction mixture was then cooled, diluted with
dichloromethane and washed with 1M hydrochloric acid until the
colour changed. The organic phase was dried over sodium sulfate,
filtered, concentrated and dried under high vacuum. The crude
product was purified by silica gel chromatography (mobile phase:
cyclohexane/ethyl acetate: 5/1 to cyclohexane/ethyl acetate: 3/1).
This gave 6.47 g of the target compound (58% of theory, purity
99%).
[0796] LC-MS (Method 3): R.sub.t=2.00 min; MS (ESIpos): m/z=393
[M+H].sup.+
[0797] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (0.95),
0.008 (0.78), 1.254 (2.75), 1.271 (5.79), 1.289 (2.77), 1.975
(16.00), 2.523 (0.61), 4.205 (0.87), 4.222 (2.65), 4.240 (2.61),
4.258 (0.82), 5.754 (3.81), 7.188 (2.22), 7.211 (2.23), 8.543
(1.72), 8.561 (5.10).
Example 66A
7-Chloro-6-fluoro-1-(4-fluoro-2,6-dimethylphenyl)-4-oxo-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylic acid
##STR00159##
[0799] Ethyl
7-chloro-6-fluoro-1-(4-fluoro-2,6-dimethylphenyl)-4-oxo-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylate (6.47 g, 99% pure, 16.3 mmol) was
suspended in 49 ml of THF. 49 ml of water and 49 ml of conc.
hydrochloric acid were added and the mixture was left to stir at a
bath temperature of 110.degree. C. for 4 h. Most of the THF was
removed under reduced pressure. With ice cooling, 100 ml of water
were added to the aqueous phase. A solid precipitated out. This was
filtered off and rinsed three times with water. This gave 5.35 g of
the target compound (89% of theory, purity 99%).
[0800] LC-MS (Method 1): R.sub.t=1.03 min; MS (ESIpos): m/z=365
[M+H].sup.+
[0801] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: 1.957 (16.00),
1.975 (0.43), 7.195 (2.23), 7.218 (2.20), 8.775 (1.30), 8.794
(1.29), 8.871 (2.87).
Example 67A
7-Chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-1-(4-fluoro--
2,6-dimethylphenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00160##
[0803]
7-Chloro-6-fluoro-1-(4-fluoro-2,6-dimethylphenyl)-4-oxo-1,4-dihydro-
-1,8-naphthyridine-3-carboxylic acid (1.00 g, 2.74 mmol) was
initially charged in 25.5 ml of acetonitrile, and
(1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride (530 mg,
3.02 mmol) and N,N-diisopropylethylamine (1.9 ml, 11 mmol) were
added, followed by 1.9 ml (3.29 mmol) of T3P solution
(propanephosphonic acid cyclic anhydride, 50% in ethyl acetate).
The reaction solution was stirred at room temperature overnight.
More (1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride
(144 mg, 823 .mu.mol), 0.32 ml (1.1 mmol) T3P solution
(propanephosphonic acid cyclic anhydride, 50% in ethyl acetate) and
N,N-diisopropylethylamine (0.48 ml, 2.74 mmol) were added. Stirring
of the reaction solution was continued at room temperature over the
weekend. The mixture was subsequently freed from acetonitrile and
extracted twice with dichloromethane. The combined organic phases
were dried over sodium sulphate, filtered and dried under high
vacuum. The residue was purified by column chromatography (silica
gel, mobile phase: dichloromethane/cyclohexane=7.5/1). This gave
1.05 g (99% pure, 78% of theory) of the target compound.
[0804] LC-MS (Method 1): R.sub.t=1.28 min; MS (ESIpos): m/z=486
[M+H].sup.+
[0805] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.008 (1.25),
0.339 (0.87), 0.353 (0.89), 0.364 (0.51), 0.554 (0.81), 0.567
(1.37), 0.582 (1.20), 0.601 (0.63), 0.610 (0.52), 0.651 (0.46),
0.666 (0.81), 0.671 (0.70), 0.684 (0.55), 1.219 (0.47), 1.231
(0.87), 1.240 (0.65), 1.251 (0.75), 1.264 (0.44), 1.957 (16.00),
4.361 (0.43), 4.382 (0.73), 4.402 (0.73), 4.422 (0.40), 5.754
(3.95), 7.193 (3.42), 7.216 (3.43), 8.709 (7.53), 8.726 (2.88),
10.138 (1.51), 10.162 (1.49).
Example 68A
7-Chloro-6-fluoro-4-oxo-N-(3,3,4,4,4-pentafluorobutan-2-yl)-1-(2,4,6-trif-
luorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(enantiomerically pure)
##STR00161##
[0807]
7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylic acid (500 mg, 1.34 mmol) was initially
charged in 5 ml of acetonitrile. 3,3,4,4,4-Pentafluorobutan-2-amine
hydrochloride (enantiomerically pure) (321 mg, 1.61 mmol) and
N,N-diisopropylethylamine (930 .mu.l, 5.4 mmol) were added. T3P
solution (propanephosphonic anhydride solution 50% in ethyl
acetate) (950 .mu.l, 50% pure, 1.6 mmol) was then added and the
mixture was stirred at room temperature overnight. The reaction
solution was added to water. The acetonitrile was evaporated and
the residue was extracted with dichloromethane three times. The
combined organic phases were dried over sodium sulphate, filtered
and concentrated by evaporation. This gave 785 mg (99% of theory,
88% pure) of the title compound.
[0808] LC-MS (Method 5): R.sub.t=1.60 min; MS (ESIpos): m/z=518
[M+H].sup.+
[0809] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (1.04),
-0.008 (8.48), 0.008 (8.27), 0.146 (1.00), 0.891 (0.71), 0.910
(0.58), 1.157 (2.01), 1.175 (4.01), 1.193 (2.59), 1.244 (2.51),
1.259 (2.92), 1.356 (0.67), 1.411 (14.66), 1.429 (14.62), 1.455
(0.92), 1.473 (0.84), 1.511 (2.26), 1.528 (2.21), 1.864 (0.50),
1.988 (6.56), 2.328 (1.46), 2.367 (1.80), 2.671 (1.50), 2.711
(1.75), 4.003 (0.58), 4.021 (1.50), 4.039 (1.55), 4.057 (0.54),
5.000 (0.71), 5.022 (1.34), 5.045 (1.59), 5.065 (1.55), 5.088
(1.25), 5.109 (0.67), 7.270 (0.58), 7.337 (0.71), 7.347 (0.71),
7.367 (1.21), 7.385 (1.13), 7.401 (1.50), 7.418 (0.84), 7.467
(0.75), 7.490 (0.58), 7.604 (6.02), 7.626 (11.07), 7.648 (5.81),
8.412 (0.50), 8.574 (0.46), 8.687 (0.92), 8.702 (10.11), 8.721
(9.78), 8.750 (0.50), 9.055 (1.21), 9.173 (16.00), 9.877 (0.46),
9.896 (0.50), 9.938 (5.89), 9.961 (5.68).
Example 69A 1-tert-butyl 2-ethyl
(2R,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate
##STR00162##
[0811] Ethyl (3S)-3-hydroxy-D-prolinate (1.13 g, 7.08 mmol) was
initially charged in 50 ml of dichloromethane. Triethylamine (3.0
ml, 21 mmol) and di-tert-butyl dicarbonate (1.8 ml, 7.8 mmol) were
added and the mixture was stirred at room temperature overnight.
The reaction mixture was washed with saturated aqueous sodium
bicarbonate solution. The organic phase was dried over sodium
sulphate, filtered and concentrated by evaporation. The residue was
taken up in ethyl acetate and washed twice with 1M hydrochloric
acid. The organic phase was dried over sodium sulphate, filtered
and concentrated by evaporation. This gave 1.3 g (57% of theory,
80% pure) of the title compound.
[0812] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 1.152 (0.77),
1.170 (1.65), 1.178 (1.69), 1.188 (0.96), 1.195 (3.23), 1.213
(1.56), 1.321 (16.00), 1.383 (8.03), 1.988 (0.75), 3.266 (0.62),
3.294 (0.42), 3.404 (0.44), 3.409 (0.43), 3.423 (0.42), 4.019
(0.41), 4.037 (0.44), 4.046 (0.70), 4.064 (0.85), 4.082 (0.46),
4.111 (0.57), 4.129 (0.54), 4.150 (1.28), 4.156 (0.42), 4.167
(1.45), 4.433 (0.46), 4.449 (0.53), 5.398 (1.16), 5.410 (1.11).
Example 70A tert-butyl
(2S,3S)-3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate
##STR00163##
[0814] Under argon, 1-tert-butyl 2-ethyl
(2R,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate (1.30 g, 5.01 mmol)
was initially charged in 20 ml of THF and cooled to 0.degree. C.
Lithium borohydride (10 ml, 2.0 M, 20 mmol) was added at 0.degree.
C. and the mixture was stirred at room temperature overnight. The
reaction mixture was cooled to 0.degree. C. and saturated aqueous
ammonium chloride solution was added carefully. Dichloromethane was
added and the mixture was separated on an Extrelut cartridge. The
organic phase was concentrated by evaporation and the residue was
dried under high vacuum. This gave 506 mg (37% of theory, 80% pure)
of the title compound.
[0815] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 1.391 (16.00),
1.409 (2.86), 1.860 (0.40), 3.601 (0.62), 3.608 (0.58), 3.615
(0.78), 3.629 (0.46), 3.633 (0.42).
Example 71A (2S,3S)-2-(hydroxymethyl)pyrrolidin-3-ol
hydrochloride
##STR00164##
[0817] 1-tert-butyl 2-ethyl
(2R,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate (506 mg, 1.95 mmol)
was initially charged in 20 ml of 4N aqueous hydrochloric acid in
dioxane and stirred at room temperature overnight. The reaction
mixture was concentrated by evaporation and the residue was dried
under high vacuum. This gave 380 mg (127% of theory, 80% pure) of
the title compound.
[0818] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (1.17),
-0.008 (10.39), 0.008 (8.46), 0.146 (1.12), 0.912 (0.42), 1.130
(0.62), 1.180 (0.99), 1.235 (1.17), 1.259 (1.59), 1.276 (1.51),
1.292 (1.07), 1.308 (0.84), 1.356 (3.67), 1.596 (1.31), 1.847
(3.37), 1.857 (3.45), 1.862 (3.72), 1.872 (5.90), 1.876 (5.04),
1.881 (5.11), 1.884 (4.79), 1.891 (4.81), 1.895 (5.01), 1.900
(4.59), 1.954 (1.36), 1.974 (3.15), 1.985 (4.12), 1.998 (5.48),
2.008 (7.59), 2.032 (4.96), 2.042 (3.97), 2.055 (1.89), 2.067
(1.84), 2.073 (2.08), 2.090 (0.97), 2.104 (1.54), 2.115 (2.06),
2.139 (1.81), 2.148 (1.44), 2.182 (0.84), 2.328 (1.96), 2.367
(1.04), 2.524 (1.24), 2.666 (1.02), 2.670 (1.44), 2.675 (0.99),
2.711 (0.45), 3.150 (3.84), 3.161 (5.23), 3.174 (6.15), 3.187
(6.55), 3.201 (5.83), 3.212 (6.23), 3.236 (5.95), 3.241 (5.93),
3.260 (3.82), 3.306 (6.40), 3.322 (7.64), 3.343 (6.05), 3.364
(2.90), 3.450 (8.83), 3.462 (8.88), 3.474 (8.33), 3.490 (7.32),
3.502 (6.38), 3.609 (10.64), 3.631 (10.54), 3.638 (14.78), 3.660
(13.59), 3.680 (3.32), 3.699 (3.27), 3.708 (2.68), 3.712 (3.00),
3.733 (11.88), 3.746 (12.38), 3.762 (9.30), 3.774 (9.13), 4.073
(4.22), 4.106 (5.66), 4.266 (4.34), 4.274 (4.49), 4.300 (16.00),
4.669 (2.95), 4.678 (4.94), 5.329 (0.72), 7.112 (1.49), 7.240
(1.56), 7.368 (1.41), 8.748 (2.90), 9.193 (1.39), 9.383 (1.81),
10.016 (0.45).
Example 72A Ethyl 3-(2,6-dichloropyridin-3-yl)-3-oxopropanoate
##STR00165##
[0820] Under argon, 1500 ml of THF were initially charged and
2,6-dichloronicotinic acid (200 g, 1.04 mol) was added.
4-Dimethylaminopyridine (63.6 g, 521 mmol) and
1,1'-carbonyldiimidazole (253 g, 1.56 mol) were added a little at a
time (evolution of gas). The mixture was stirred at room
temperature for 24 h. A precipitate formed (suspension 1). In
another flask, potassium 3-ethoxy-3-oxopropanoate (266 g, 1.56 mol)
was initially charged in 1000 ml of THF, and magnesium chloride
(179 g, 1.87 mol) was added. The suspension was stirred at
50.degree. C. for 24 h (suspension 2). Suspension 2 was
subsequently added to suspension 1 and stirred at room temperature
for 24 h. The mixture was then stirred into 5 l of ice and about 20
l of water and adjusted to pH 4 using about 500 ml of hydrochloric
acid/water (1:1). The mixture was subsequently extracted twice with
ethyl acetate. The org. phase was washed with 10% strength NaCl
solution. The phases were separated, dried over magnesium sulphate,
concentrated by evaporation and dried under high vacuum. This gave
255 g of the target compound (93.5% of theory).
[0821] LC-MS (Method 1): R.sub.t=0.89 min; MS (ESIpos): m/z=261
[M+H].sup.+
Example 73A Ethyl
(2Z)-2-[(2,6-dichloropyridin-3-yl)carbonyl]-3-ethoxyacrylate
##STR00166##
[0823] Ethyl 3-(2,6-dichloropyridin-3-yl)-3-oxopropanoate (4 g, 15
mmol) and (diethoxymethoxy)ethane (5 ml, 30 mmol) were initially
charged and acetic anhydride (11.7 ml, 99 mmol) was added. The
reaction mixture was stirred at 140.degree. C. for 24 h and, after
cooling, the mixture was concentrated by evaporation. This gave 5.3
g of the target compound (109% of theory).
Example 74A N-benzyl-1,1-dicyclopropylmethanimine
##STR00167##
[0825] Dicyclopropylmethanone (13 ml, 110 mmol) was initially
charged in 430 ml of diethyl ether and cooled to -40.degree. C.
1-Phenylmethanamine (12 ml, 110 mmol) and triethylamine (32 ml, 230
mmol) were then added quickly, and titanium(IV) chloride (57 ml, 57
mmol, IM in toluene) was slowly added dropwise at an internal
temperature of 0.degree. C. The ice bath was then removed and the
mixture was allowed to warm to RT. The mixture was then stirred
under reflux for 1 h. The mixture was stirred at room temperature
for another 3 h. Celite was then added, and the mixture was stirred
for 1 h. The mixture was then filtered off through celite, washing
repeatedly with diethyl ether. At a bath temperature of 30.degree.
C., the filtrate was carefully concentrated by evaporation. This
gave 18.86 g of the target compound (73% of theory, purity
88%).
[0826] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.542 (1.44),
0.550 (3.04), 0.558 (4.43), 0.562 (2.41), 0.565 (2.73), 0.571
(3.30), 0.578 (5.02), 0.585 (2.16), 0.664 (2.05), 0.671 (4.51),
0.678 (3.98), 0.683 (5.39), 0.690 (3.22), 0.700 (1.42), 0.830
(0.46), 0.839 (1.51), 0.843 (2.02), 0.851 (8.62), 0.855 (8.05),
0.863 (8.85), 0.868 (9.08), 0.877 (5.06), 0.881 (2.92), 0.887
(7.68), 0.894 (1.79), 0.901 (0.41), 0.907 (0.50), 0.922 (0.49),
0.956 (1.93), 0.966 (4.42), 0.971 (4.39), 0.979 (4.47), 0.984
(4.15), 0.996 (1.28), 1.186 (0.70), 1.198 (1.38), 1.206 (1.44),
1.218 (2.55), 1.230 (1.31), 1.238 (1.20), 1.250 (0.55), 1.929
(0.78), 1.942 (1.59), 1.949 (1.59), 1.954 (0.98), 1.963 (3.02),
1.971 (0.92), 1.975 (1.51), 1.984 (1.44), 1.997 (0.66), 2.104
(0.65), 2.115 (1.21), 2.122 (1.09), 2.128 (0.77), 2.134 (2.24),
2.142 (0.78), 2.147 (1.20), 2.153 (1.01), 2.166 (0.60), 2.299
(7.88) 3.217 (0.51), 3.313 (4.75), 4.582 (16.00), 7.142 (0.84),
7.162 (1.77), 7.174 (1.38), 7.180 (2.56), 7.191 (2.64), 7.202
(1.07), 7.208 (1.78), 7.212 (1.21), 7.230 (1.81), 7.235 (0.73),
7.249 (2.09), 7.255 (1.43), 7.260 (2.42), 7.268 (1.78), 7.276
(10.04), 7.282 (12.94), 7.289 (1.48), 7.299 (6.19), 7.303 (2.61),
7.315 (0.93), 7.318 (1.58).
Example 75A N-benzyl-1,1-dicyclopropyl-2,2,2-trifluoroethanamine
hydrochloride
##STR00168##
[0828] N-benzyl-1,1-dicyclopropylmethanimine (35.4 g, 89% purity,
158 mmol) was initially charged in a mixture of 320 ml of
acetonitrile and 70 ml of DMF and cooled to 0.degree. C. Potassium
hydrogen difluoride (39.5 g, 506 mmol) was added at 0.degree. C.,
and TFA (22 ml, 280 mmol) was added to the mixture at 0.degree. C.
Trimethyl(trifluoromethyl)silane (82 ml, 550 mmol) was then added
dropwise. The reaction mixture was stirred at room temperature for
4 h. The reaction solution was cooled to 0.degree. C., and
potassium hydrogen difluoride (9.26 g, 119 mmol) and
trimethyl(trifluoromethyl)silane (18 ml, 120 mmol) were added. The
reaction solution was stirred further at room temperature
overnight. Potassium hydrogen difluoride (9.26 g, 119 mmol),
trifluoroacetic acid (4.9 ml, 63 mmol) and
trimethyl(trifluoromethyl)silane (12 ml, 79 mmol) were added and
stirring was continued at room temperature for 3.5 h.
Trimethyl(trifluoromethyl)silane (23 ml, 160 mmol) was then added
and the mixture was stirred at 60.degree. C. for 2.5 h. Saturated
aqueous sodium carbonate solution was added and the mixture was
extracted twice with ethyl acetate. The combined organic phases
were washed once with saturated aqueous sodium chloride solution,
dried over sodium sulphate and filtered. 4 M HIC in dioxane (400
ml, 1.6 mol) was then added to the filtrate and the mixture was
concentrated on a rotary evaporator at a water bath temperature of
30.degree. C. The residue was purified by flash chromatography
(cyclohexane/dichloromethane 20/1 to cyclohexane/dichloromethane
10/1). This gave 10.64 g of the target compound (22% of theory,
purity 99%).
[0829] LC-MS (Method 1): R.sub.t=1.31 min; MS (ESIpos): m/z=270
[M-HCl+H].sup.+
[0830] .sup.1H NMR (400 MHz, DMSO-d6) delta [ppm]: -0.008 (1.25),
0.008 (1.56), 0.591 (10.11), 0.750 (13.34), 0.876 (1.90), 0.952
(1.06), 1.091 (6.01), 1.236 (1.18), 1.906 (0.42), 2.329 (0.82),
2.367 (0.46), 2.571 (0.49), 2.589 (0.63), 2.671 (0.80), 2.711
(0.55), 3.615 (0.68), 4.212 (4.68), 5.107 (0.66), 7.358 (13.21),
7.375 (16.00), 7.502 (7.66).
Example 76A 1,1-Dicyclopropyl-2,2,2-trifluoroethanamine
hydrochloride
##STR00169##
[0832] Under argon,
N-benzyl-1,1-dicyclopropyl-2,2,2-trifluoroethanamine hydrochloride
(10.6 g, 34.8 mmol) was initially charged in 200 ml of ethanol, and
1 M hydrochloric acid in ethanol (170 ml) and palladium on
activated carbon (3.70 g, 10% pure) were added. The mixture was
hydrogenated at atmospheric pressure and room temperature for 60
min. The mixture was filtered through celite, 4 M hydrochloric acid
in dioxane (87 ml, 350 mmol) was added and the mixture was
concentrated by evaporation at a water bath temperature of
30.degree. C. Diethyl ether was added to the residue, the mixture
was stirred for 10 min and the solid obtained was filtered off.
This gave 6.39 g of the target compound (84% of theory) which were
reacted further without further purification.
[0833] LC-MS (Method 1): R.sub.t=0.49 min; MS (ESIpos): m/z=180
[M-HCl+H].sup.+
[0834] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.489 (2.34),
0.502 (4.38), 0.512 (7.72), 0.524 (12.33), 0.535 (11.32), 0.546
(9.58), 0.557 (10.43), 0.569 (9.17), 0.581 (11.40), 0.591 (13.47),
0.603 (8.94), 0.614 (4.93), 0.626 (3.21), 0.778 (2.86), 0.791
(6.70), 0.803 (9.45), 0.815 (13.47), 0.827 (13.55), 0.838 (11.65),
0.850 (13.01), 0.862 (13.43), 0.874 (9.35), 0.886 (6.06), 0.899
(2.37), 1.056 (4.75), 1.070 (9.13), 1.078 (10.15), 1.091 (16.00),
1.099 (6.84), 1.105 (8.35), 1.113 (7.66), 1.126 (3.14), 8.942
(2.96).
Example 77A
N-benzyl-1,1-dicyclopropyl-2,2,3,3,3-pentafluoropropan-1-amine
hydrochloride
##STR00170##
[0836] Under argon, N-benzyl-,1-dicyclopropylmethanimnine (4.00 g,
20.1 mmol) was initially charged in a mixture of 40 ml of
acetonitrile and 8.9 ml of DMF and cooled to 0.degree. C. Potassium
hydrogen difluoride (5.02 g, 64.2 mmol) was added at 0.degree. C.
and TFA (2.8 ml, 36 mmol) was added to the mixture at 0.degree. C.
Trimethyl(pentafluoroethyl)silane (12 ml, 70 mmol) was then added
dropwise. The reaction mixture was stirred at room temperature for
3 days. The mixture was stirred at 60.degree. C. for 7.5 h. 20 ml
of acetonitrile and 4.5 ml of DMF were added and the mixture was
cooled to 0.degree. C. At 0.degree. C., potassium hydrogen
difluoride (1.88 g, 24.1 mmol), TFA (770 .mu.l, 10 mmol) and
trimethyl(pentafluoroethyl)silane (5.3 ml, 30 mmol) were added and
stirring was continued at room temperature overnight. Saturated
aqueous sodium carbonate solution was added and the mixture was
extracted twice with ethyl acetate. The combined organic phases
were washed with saturated aqueous sodium chloride solution, dried
over sodium sulphate and filtered. 4M HCl in dioxane (50 ml, 200
mmol) was then added to the filtrate and the mixture was
concentrated by evaporation. The residue was purified by silica gel
chromatography (mobile phase: cyclohexane/dichloromethane: 20/1).
The production fractions were combined, 4 M HCl in dioxane (50 ml,
200 mmol) was added and the mixture was concentrated by evaporation
at a water bath temperature of 30.degree. C. This gave 2.14 g of
the target compound (30% of theory, purity 99%).
[0837] LC-MS (Method 1): R.sub.t=1.39 min; MS (ESIpos): m/z=320
[M-HCl+H].sup.+
[0838] 1H NMR (400 MHz, DMSO-d6) delta [ppm]: 0.008 (1.21), 0.331
(1.50), 0.354 (4.75), 0.365 (5.92), 0.376 (5.94), 0.385 (4.06),
0.397 (2.65), 0.450 (2.43), 0.461 (3.95), 0.470 (6.34), 0.482
(6.37), 0.491 (5.64), 0.502 (3.07), 0.515 (2.14), 0.648 (6.10),
0.659 (6.45), 0.668 (6.49), 0.680 (7.00), 0.690 (6.84), 0.703
(4.80), 0.909 (2.14), 0.930 (4.98), 0.944 (7.05), 0.957 (4.27),
0.978 (1.50), 2.329 (0.40), 3.568 (11.42), 4.046 (14.52), 7.064
(0.43), 7.098 (0.47), 7.128 (0.48), 7.194 (2.29), 7.212 (5.53),
7.229 (4.28), 7.279 (6.89), 7.298 (16.00), 7.316 (12.69), 7.331
(13.22), 7.349 (5.73).
Example 78A 1,1-Dicyclopropyl-2,2,3,3,3-pentafluoropropan-1-amine
hydrochloride
##STR00171##
[0840] Under argon, 90 ml of ethanol, 45 ml of 1M hydrochloric acid
in ethanol and 964 mg (10%) of palladium on activated carbon were
added to
N-benzyl-1,1-dicyclopropyl-2,2,3,3,3-pentafluoropropan-1-amine
hydrochloride (3.22 g, 9.06 mmol). The mixture was hydrogenated at
atmospheric pressure and room temperature for 45 min. The mixture
was filtered through celite, washing well with ethanol, 23 ml of 4M
hydrochloric acid in dioxane were added and the mixture was
concentrated by evaporation at a water bath temperature of
30.degree. C. Diethyl ether was added to the residue, the mixture
was stirred for 10 min and the solid obtained was filtered off. The
product was reacted further without purification. This gave 1.64 g
of the target compound (68% of theory).
[0841] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.150 (1.30),
-0.008 (13.14), 0.008 (11.58), 0.146 (1.12), 0.540 (12.55), 0.550
(12.29), 0.572 (11.02), 0.605 (12.52), 0.791 (12.35), 0.875
(10.67), 1.060 (4.89), 1.080 (11.64), 1.094 (16.00), 1.128 (3.30),
2.328 (2.12), 2.366 (0.80), 2.670 (2.12), 2.710 (0.65), 8.767
(1.97).
Example 79A
N-[(E)-cyclopropylmethylene]-2-methylpropane-2-sulfinamide
(Enantiomer 1)
##STR00172##
[0843] Under argon, (S)-2-methylpropane-2-sulfinamide (8.65 g, 71.3
mmol) was initially charged in 430 ml of dichloromethane and
cyclopropanecarbaldehyde (11 ml, 140 mmol) and anhydrous copper(II)
sulphate (34.2 g, 214 mmol) were added at room temperature. The
mixture was stirred at room temperature overnight. The reaction
mixture was filtered through celite, washing with diethyl ether,
and the filtrate was concentrated by evaporation and dried under
high vacuum. This gave 15.3 g of the target compound (99% of
theory, purity about 80%).
[0844] LC-MS (Method 1): R.sub.t=0.73 min; MS (ESIpos): m/z=174
[M+H].sup.+
[0845] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.952 (0.47),
0.958 (0.76), 0.964 (0.55), 0.967 (0.45), 0.970 (0.53), 1.041
(0.67), 1.055 (1.45), 1.061 (0.80), 1.068 (0.56), 1.070 (0.52),
1.082 (1.02), 1.092 (16.00), 5.751 (1.54), 7.389 (0.82), 7.409
(0.82).
Example 80A
N-[1-cyclopropyl-2,2,3,3,3-pentafluoropropyl]-2-methylpropane-2-sulfinami-
de (Diastereomer 1)
##STR00173##
[0847] In a glovebox,
N-[(E)-cyclopropylmethylene]-2-methylpropane-2-sulfinamide
(Enantiomer 1) (5.00 g, 28.9 mmol) was, together with
tetramethylammonium fluoride (6.45 g, 69.3 mmol), initially charged
under argon. After 14 h, the reaction vessel was removed from the
glovebox, 110 ml of THF were added and, at -55.degree. C., a
solution of trimethyl(pentafluoroethyl)silane (13 ml, 72 mmol),
dissolved in 170 ml of THF, was added slowly to the mixture. After
the addition had ended, the mixture was stirred for 30 min, and 50
ml of saturated aqueous ammonium chloride solution and 165 ml of
water were then added carefully at -30.degree. C. The aqueous phase
was extracted twice with tert-butyl methyl ether. The combined
organic phases were washed in each case once with water and
saturated aqueous sodium chloride solution. The organic phase was
dried over sodium sulphate, filtered and concentrated by
evaporation. The crude product was purified on silica gel (mobile
phase: cyclohexane 100% to cyclohexane/ethyl acetate 2/1). This
gave 4.9 g of the target compound (58% of theory, >95%).
[0848] LC-MS (Method 1): R.sub.t=0.92 min; MS (ESIpos): m/z=294
[M+H].sup.+
Example 81A 1-Cyclopropyl-2,2,3,3,3-pentafluoropropan-1-amine
hydrochloride (Enantiomer 1)
##STR00174##
[0850]
N-[1-cyclopropyl-2,2,3,3,3-pentafluoropropyl]-2-methylpropane-2-sul-
finamide (Diastereomer 1) (4.10 g, 14.0 mmol) was initially charged
in 130 ml of diethyl ether and 25 ml of methanol. 2 N hydrochloric
acid in diethyl ether (130 ml, 250 mmol) was then added dropwise at
room temperature, and the mixture was stirred at room temperature
for 2.5 h. At a water bath temperature of 30.degree. C., the
reaction mixture was substantially concentrated by evaporation. The
residue was stirred with 10 ml of acetonitrile, filtered off and
washed with a few drops of acetonitrile. This gave 2.1 g of the
target compound (65% of theory, purity 98%).
[0851] LC-MS (Method 1): R.sub.t=0.31 min; MS (ESIpos): m/z=190
[M-HCl+H].sup.+
[0852] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.543 (2.57),
0.556 (4.32), 0.569 (5.47), 0.584 (3.62), 0.604 (0.54), 0.669
(0.44), 0.685 (1.59), 0.699 (3.25), 0.718 (8.78), 0.733 (16.00),
0.748 (15.55), 0.759 (5.58), 0.767 (3.55), 1.019 (0.99), 1.038
(2.50), 1.045 (5.40), 1.050 (3.89), 1.064 (3.94), 1.077 (3.57),
1.103 (14.10), 1.270 (0.53), 2.330 (0.40), 2.363 (0.83), 3.167
(10.46), 3.671 (6.50), 3.685 (5.12), 3.697 (4.27), 3.712 (3.56),
3.723 (7.42), 3.739 (2.98), 3.751 (2.86), 3.765 (2.47), 4.059
(0.82), 9.207 (10.25).
Example 82A
N-[(E)-cyclopropylmethylene]-2-methylpropane-2-sulfinamide
(Enantiomer 2)
##STR00175##
[0854] Under argon, (R)-2-methylpropane-2-sulfinamide (13.0 g, 107
mmol) was initially charged in 640 ml of dichloromethane, and
cyclopropanecarbaldehyde (15.0 g, 214 mmol) and anhydrous
copper(II) sulphate (51.2 g, 321 mmol) were added at room
temperature. The mixture was stirred at room temperature overnight.
The reaction mixture was filtered through celite, washing with
diethyl ether, and the filtrate was concentrated by evaporation and
dried under high vacuum. This gave 18.9 g of the target compound
(100% of theory, purity about 98%).
[0855] LC-MS (Method 1): R.sub.1=0.72 min; MS (ESIpos): m/z=174
[M+H].sup.+
[0856] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.952 (0.48),
0.958 (0.77), 0.964 (0.57), 0.967 (0.47), 0.969 (0.54), 1.055
(0.76), 1.061 (0.80), 1.068 (0.57), 1.070 (0.53), 1.081 (1.07),
1.092 (16.00), 7.389 (0.83), 7.409 (0.82).
Example 83A
N-[1-cyclopropyl-2,2,3,3,3-pentafluoropropyl]-2-methylpropane-2-sulfinamid-
e (Diastereomer 2)
##STR00176##
[0858] In a glovebox,
N-[(E)-cyclopropylmethylene]-2-methylpropane-2-sulfinamide
(Enantiomer 2) (5.10 g, 98% purity, 28.8 mmol) was, together with
tetramethylammonium fluoride (6.45 g, 69.2 mmol), initially charged
under argon. After 14 h, the reaction vessel was removed from the
glovebox, 110 ml of THF were added and, at -55.degree. C., a
solution of trimethyl(pentafluoroethyl)silane (13 ml, 72 mmol),
dissolved in 170 ml of THF, was added slowly to the mixture. After
the addition had ended, the mixture was stirred for 30 min, and 50
ml of saturated aqueous ammonium chloride solution and 165 ml of
water were then added carefully at -30.degree. C. The aqueous phase
was extracted twice with tert-butyl methyl ether. The combined
organic phases were washed in each case once with water and
saturated aqueous sodium chloride solution. The organic phase was
dried over sodium sulphate, filtered and concentrated by
evaporation. The crude product was purified on silica gel (mobile
phase: cyclohexane 100% to cyclohexane/ethyl acetate 2/1). This
gave 5.8 g of the target compound (69% of theory, >95%).
[0859] LC-MS (Method 1): R.sub.t=0.92 min; MS (ESIpos): m/z=294
[M+H-]
Example 84A 1-Cyclopropyl-2,2,3,3,3-pentafluoropropan-1-amine
hydrochloride (Enantiomer 2)
##STR00177##
[0861]
N-[1-cyclopropyl-2,2,3,3,3-pentafluoropropyl]-2-methylpropane-2-sul-
finamide (Diastereomer 2) (5.00 g, 17.0 mmol) was initially charged
in 150 ml of diethyl ether and 31 ml of methanol. 2 N hydrochloric
acid in diethyl ether (150 ml, 2.0 M, 300 mmol) was then added
dropwise at room temperature, and the mixture was stirred at room
temperature for 2.5 h. At a water bath temperature of 30.degree.
C., the reaction solution was substantially concentrated by
evaporation. The residue was stirred with 10 ml of acetonitrile,
filtered off and washed with a few drops of acetonitrile. This gave
2.5 g of the target compound (64% of theory, purity 98%).
[0862] LC-MS (Method 1): R.sub.t=0.33 min; MS (ESIpos): m/z=190
[M-HCl+H].sup.+
[0863] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (1.70),
0.008 (1.55), 0.549 (4.38), 0.565 (4.26), 0.574 (3.54), 0.586
(2.02), 0.688 (2.56), 0.706 (9.75), 0.723 (16.00), 0.743 (10.93),
0.765 (2.53), 0.783 (0.70), 1.014 (0.92), 1.029 (1.97), 1.046
(3.89), 1.058 (3.39), 1.072 (2.94), 1.086 (1.64), 1.103 (0.66),
2.329 (0.53), 2.671 (0.54), 3.669 (2.36), 3.683 (2.43), 3.695
(2.47), 3.710 (2.40), 3.722 (2.51), 3.737 (2.41), 3.748 (2.39),
3.763 (2.17), 9.063 (5.76).
Example 85A
N-[(1E)-2,2-dimethylpropylidene]-2-methylpropane-2-sulfinamide
(Enantiomer 1)
##STR00178##
[0865] Under argon, (S)-2-methylpropane-2-sulfinamide (15.0 g, 124
mmol) was initially charged in 650 ml of dichloromethane, and
pivalaldehyde (27 ml, 250 mmol) and anhydrous copper(II) sulphate
(59.3 g, 371 mmol) were added at room temperature. The mixture was
stirred at room temperature for 4 days. The reaction mixture was
filtered through celite, washing with diethyl ether, and the
filtrate was concentrated by evaporation and dried under high
vacuum. This gave 22.7 g of the target compound (97% of
theory).
[0866] LC-MS (Method 1): R.sub.t=0.93 min; MS (ESIpos): m/z=190
[M+H].sup.+
[0867] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 1.013 (0.56),
1.079 (2.03), 1.102 (15.53), 1.113 (1.97), 1.120 (16.00), 1.271
(1.00), 7.814 (1.55).
Example 86A
2-Methyl-N-[1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl]propane-2-sulfi-
namide (Diastereomer 1)
##STR00179##
[0869] In a glovebox,
N-[(E)-2,2-dimethylpropylidene]-2-methylpropane-2-sulfinamide
(Enantiomer 1) (3.50 g, 18.5 mmol) was, together with
tetramethylammonium fluoride (4.13 g, 44.4 mmol), initially charged
under argon. After 14 h, the reaction vessel was removed from the
glovebox, 56 ml of THF were added and, at -78.degree. C., a
solution of trimethyl(pentafluoroethyl)silane (8.1 ml, 46 mmol),
dissolved in 82 ml of THF, was added slowly to the mixture. The
reaction mixture was stirred at -78.degree. C. for 3.5 h. At about
-50.degree. C., saturated aqueous ammonium chloride solution and
water were added to the reaction solution. The aqueous phase was
extracted twice with ethyl acetate. The combined organic phases
were washed in each case once with water and saturated aqueous
sodium chloride solution. The organic phase was dried over sodium
sulphate, filtered and concentrated by evaporation. The residue was
purified by silica gel (mobile phase: cyclohexane, then
cyclohexane/ethyl acetate: 5/1). This gave 4.25 g of the target
compound (73% of theory, purity 98%, >95%).
[0870] LC-MS (Method 4): R.sub.t=3.30 min; MS (ESIpos): m/z=310
[M+H].sup.+
[0871] .sup.1H NMR (400 MHz, DMSO-d6) [ppm]: -0.008 (1.33), 0.008
(0.58), 1.054 (0.45), 1.058 (0.43), 1.104 (7.77), 1.106 (7.67),
1.178 (16.00), 1.201 (1.02), 2.519 (0.54), 2.524 (0.57), 5.114
(0.43), 5.137 (0.41).
Example 87A 1,1,1,2,2-Pentafluoro-4,4-dimethylpentan-3-amine
hydrochloride (Enantiomer 1)
##STR00180##
[0873]
2-Methyl-N-[1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl]propane-2-
-sulfinamide (Diastereomer 1) (4.14 g, 98% purity, 13.1 mmol) was
initially charged in 240 ml of diethyl ether and 48 ml of methanol.
2 N hydrochloric acid in diethyl ether (240 ml, 480 mmol) was then
added, and the mixture was stirred at room temperature for 2.5 h.
At a water bath temperature of 35.degree. C., the reaction solution
was substantially concentrated by evaporation. The residue was
stirred with about 5 ml of diethyl ether and filtered off and the
residue was dried. 20 ml of 20% strength potassium hydroxide
solution was added and the mixture was extracted three times with
dichloromethane. 2 N hydrochloric acid in diethyl ether was added
to the combined organic phases and the mixture was concentrated by
evaporation at a bath temperature of 35.degree. C. and dried under
high vacuum. This gave 2.94 g of the target compound (89% of
theory), which were used without further purification for the next
step.
[0874] LC-MS (Method 1): R.sub.1=0.81 min; MS (ESIpos): m/z=206
[M-HCl+H].sup.+
Example 88A
N-[(1E)-2,2-dimethylpropylidene]-2-methylpropane-2-sulfinamide
(Enantiomer 2)
##STR00181##
[0876] Under argon, (R)-2-methylpropane-2-sulfinamide (15.0 g, 124
mmol) was initially charged in 650 ml of dichloromethane, and
pivalaldehyde (27 ml, 250 mmol) and anhydrous copper(II) sulphate
(59.3 g, 371 mmol) were added at room temperature. The mixture was
stirred at room temperature for 4 days. More copper sulphate (24.7
g, 155 mmol) was added and stirring was continued at room
temperature overnight. The reaction mixture was filtered through
celite, washing with diethyl ether, and the filtrate was
concentrated by evaporation and dried under high vacuum. This gave
20.15 g of the target compound (86% of theory).
[0877] LC-MS (Method 1): R.sub.1=0.94 min; MS (ESIpos): m/z=190
[M+H].sup.4
[0878] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 1.078 (14.51),
1.102 (16.00), 1.113 (1.88), 1.120 (15.93), 1.270 (1.08), 5.290
(0.56), 7.814 (1.44).
Example 89A
2-Methyl-N-[1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl]propane-2-sulfi-
namide (Diastereomer 2)
##STR00182##
[0880] Under argon! for drying, the flask and the
tetramethylammonium fluoride were placed in a glovebox overnight!
N-[(1E)-2,2-dimethylpropylidene]-2-methylpropane-2-sulfinamide
(Enantiomer 2) (4.38 g, 80% purity, 18.5 mmol), together with
tetramethylammonium fluoride (4.13 g, 44.4 mmol), was initially
charged under argon in a glovebox. After 14 h, the reaction vessel
was removed from the glovebox, 56 ml of THF were added and, at
-78.degree. C., a solution of trimethyl(pentafluoroethyl)silane
(8.1 ml, 46 mmol), dissolved in 82 ml of THF, was added slowly to
the mixture. The reaction mixture was stirred at -70'C for 3 h and
then, slowly thawing, stirred at room temperature overnight.
Saturated aqueous ammonium chloride solution and water were added
carefully to the reaction solution. The aqueous phase was extracted
twice with ethyl acetate. The combined organic phases were washed
in each case once with water and saturated aqueous sodium chloride
solution. The organic phase was dried over sodium sulphate,
filtered and concentrated by evaporation. The residue was purified
on silica gel (mobile phase: 100% cyclohexane, then
cyclohexane/ethyl acetate: 2/1). This gave 3.81 g of the target
compound (65% of theory, purity 98%, >90%).
[0881] LC-MS (Method 4): R.sub.t=3.30 min; MS (ESIpos): m/z=310
[M+H].sup.+
[0882] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 1.054 (0.40),
1.059 (0.42), 1.104 (7.59), 1.106 (7.75), 1.178 (16.00), 1.201
(1.05), 5.113 (0.42).
Example 90A 1,1,1,2,2-Pentafluoro-4,4-dimethylpentan-3-amine
hydrochloride (Enantiomer 2)
##STR00183##
[0884]
2-Methyl-N-[1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl]propane-2-
-sulfinamide (Diastereomer 2) (3.73 g, 12.0 mmol) was initially
charged in 220 ml of diethyl ether and 44 ml of methanol. 2 N
hydrochloric acid in diethyl ether (220 ml, 440 mmol) was then
added and the mixture was stirred at room temperature for 2.5 h. At
a water bath temperature of 35.degree. C., the reaction solution
was substantially concentrated by evaporation. The residue was
stirred with diethyl ether and dried under high vacuum. This gave
2.48 g of the target compound (81% of theory, purity 95%).
[0885] LC-MS (Method 1): R.sub.t=0.80 min; MS (ESIpos): m/z=206
[M-HCl+H].sup.+
Example 91A
7-Chloro-N-[1-cyclopropyl-2,2,3,3,3-pentafluoropropyl]-6-fluoro-4-oxo-1-(-
2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(Enantiomer 1)
##STR00184##
[0887]
7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylic acid (300 mg, 805 .mu.mol) was initially
charged in 7.5 ml of acetonitrile.
1-Cyclopropyl-2,2,3,3,3-pentafluoropropan-1-amine hydrochloride
(Enantiomer 1) (204 mg, 98% purity, 886 .mu.mol) and
N,N-diisopropylethylamine (560 .mu.l, 3.2 mmol) were added. T3P
solution (propanephosphonic acid cyclic anhydride, 50% in ethyl
acetate; 570 .mu.L, 970 .mu.mol) was then added to the mixture. The
reaction solution was stirred at room temperature overnight. Water
was added to the mixture and the precipitated solid was filtered
off, washed with water and dried under high vacuum. This gave 439
mg of the target compound (99% of theory, purity 99%).
[0888] LC-MS (Method 3): R.sub.t=2.53 min; MS (ESIpos): m/z=544
[M+H].sup.+
[0889] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (10.22),
-0.008 (9.36), 0.008 (8.14), 0.146 (0.95), 0.328 (1.83), 0.338
(2.78), 0.350 (2.78), 0.363 (2.07), 0.373 (1.05), 0.542 (2.14),
0.554 (3.12), 0.566 (2.71), 0.580 (2.58), 0.589 (2.34), 0.600
(2.68), 0.612 (2.54), 0.622 (2.10), 0.668 (1.29), 0.688 (2.51),
0.699 (2.31), 0.712 (2.14), 0.734 (0.81), 1.243 (0.85), 1.264
(1.76), 1.276 (2.64), 1.285 (2.07), 1.297 (2.58), 2.073 (0.58),
2.328 (1.53), 2.367 (1.05), 2.670 (1.56), 2.711 (0.88), 4.442
(0.68), 4.466 (1.63), 4.488 (2.00), 4.507 (2.03), 4.530 (1.63),
4.554 (0.64), 7.602 (5.39), 7.624 (10.27), 7.646 (5.42), 8.719
(9.63), 8.738 (9.63), 9.167 (16.00), 10.048 (5.32), 10.072
(5.32).
Example 92A
7-Chloro-N-[1-cyclopropyl-2,2,3,3,3-pentafluoropropyl]-6-fluoro-4-oxo-1-(-
2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(Enantiomer 2)
##STR00185##
[0891]
7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylic acid (300 mg, 805 .mu.mol) was initially
charged in 7.5 ml of acetonitrile.
1-Cyclopropyl-2,2,3,3,3-pentafluoropropan-1-amine hydrochloride
(Enantiomer 2) (204 mg, 98% purity, 886 .mu.mol) and
N,N-diisopropylethylamine (560 .mu.l, 3.2 mmol) were added. T3P
solution (propanephosphonic acid cyclic anhydride, 50% in ethyl
acetate; 570 .mu.l, 970 .mu.mol) was then added to the mixture. The
reaction solution was stirred at room temperature overnight. Water
was added to the mixture and the precipitated solid was filtered
off, washed with water and dried under high vacuum. This gave 422
mg of the target compound (96% of theory, purity 100%).
[0892] LC-MS (Method 3): R.sub.t=2.52 min; MS (ESIpos): m/z=544
[M+H].sup.+
[0893] .sup.1H NMR (400 MHz, DMSO-d6) .delta. [ppm]: -0.149 (0.93),
-0.008 (7.99), 0.008 (6.97), 0.146 (0.89), 0.316 (0.84), 0.328
(2.12), 0.338 (3.25), 0.351 (3.23), 0.363 (2.48), 0.374 (1.19),
0.530 (0.88), 0.542 (2.44), 0.553 (3.54), 0.566 (3.10), 0.579
(2.86), 0.589 (2.57), 0.600 (3.16), 0.611 (2.79), 0.622 (2.43),
0.633 (2.04), 0.646 (1.15), 0.667 (1.46), 0.678 (1.71), 0.688
(2.81), 0.700 (2.63), 0.713 (2.41), 0.721 (1.24), 0.734 (0.78),
1.243 (0.60), 1.256 (120), 1.264 (1.77), 1276 (2.90), 1.285 (2.34),
1.296 (2.85), 1.308 (1.57), 1.317 (1.00), 1.329 (0.42), 2.074
(2.03), 2.328 (0.75), 2.367 (0.58), 2.671 (0.77), 2.711 (0.55),
4.442 (0.77), 4.466 (1.97), 4.488 (2.26), 4.508 (2.30), 4.530
(1.93), 4.554 (0.71), 7.601 (5.75), 7.623 (11.11), 7.646 (5.82),
8.719 (9.38), 8.738 (9.40), 9.167 (16.00), 10.048 (6.22), 10.072
(6.09).
Example 93A
7-Chloro-N-(1,1-dicyclopropyl-2,2,2-trifluoroethyl)-6-fluoro-4-oxo-1-(2,4-
,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00186##
[0895]
7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylic acid (100 mg, 268 .mu.mol),
1,1-dicyclopropyl-2,2,2-trifluoroethanamine hydrochloride (63.7 mg,
295 .mu.mol) and N,N-diisopropylethylamine (160 .mu.l, 940 .mu.mol)
were initially charged in 2.4 ml of ethyl acetate. T3P solution
(propanephosphonic acid cyclic anhydride, 50% in ethyl acetate; 630
.mu.l, 1.1 mmol) was added and the mixture was stirred at
80.degree. C. for 2 h. Water was added and the mixture was
extracted twice with ethyl acetate. The combined organic phases
were washed with saturated aqueous sodium chloride solution, dried
over sodium sulphate, filtered and concentrated by evaporation. The
residue was purified by preparative HPLC (RP18 column, mobile
phase: acetonitrile/water gradient with addition of 0.1% TFA). The
combined product fractions were concentrated by evaporation. The
residue was dissolved in dichloromethane and washed twice with
saturated aqueous sodium bicarbonate solution. The combined organic
phases were reextracted twice with dichloromethane. The combined
organic phases were dried over sodium sulphate, filtered and
concentrated by evaporation. This gave 101 mg of the target
compound (70% of theory, purity 99%).
[0896] LC-MS (Method 1): R.sub.t=1.33 min; MS (ESIpos): m/z=534
[M+H].sup.+
[0897] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (1.44),
-0.008 (11.48), 0.008 (10.40), 0.146 (1.35), 0.486 (1.29), 0.499
(2.28), 0.509 (4.55), 0.521 (5.24), 0.532 (5.99), 0.544 (3.36),
0.554 (2.88), 0.578 (1.80), 0.589 (3.87), 0.603 (4.52), 0.610
(5.81), 0.625 (7.01), 0.636 (5.63), 0.646 (6.26), 0.658 (7.40),
0.671 (6.17), 0.683 (5.48), 0.697 (5.66), 0.707 (5.99), 0.720
(4.25), 0.730 (2.79), 0.744 (1.02), 1.234 (1.17), 1.527 (1.98),
1.541 (4.13), 1.548 (4.34), 1.563 (7.58), 1.577 (4.04), 1.584
(3.72), 1.597 (1.59), 2.323 (1.65), 2.328 (2.22), 2.366 (1.05),
2.523 (5.48), 2.665 (1.77), 2.670 (2.40), 2.710 (1.17), 5.754
(0.48), 7.599 (5.66), 7.621 (10.64), 7.643 (5.84), 8.754 (10.37),
8.773 (10.40), 9.117 (16.00), 9.409 (12.46).
Example 94A
7-Chloro-N-(1,1-dicyclopropyl-2,2,3,3,3-pentafluoropropyl)-6-fluoro-4-oxo-
-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00187##
[0899]
7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylic acid (140 mg, 376 .mu.mol),
1,1-dicyclopropyl-2,2,3,3,3-pentafluoropropan-1-amine hydrochloride
(110 mg, 413 .mu.mol) and N,N-diisopropylethylamine (230 .mu.l, 1.3
mmol) were initially charged in ethyl acetate. T3P solution
(propanephosphonic acid cyclic anhydride, 50% in ethyl acetate; 890
.mu.l, 1.5 mmol) was added and the mixture was stirred at
80.degree. C. for 2 h. Water was added and the mixture was
extracted twice with ethyl acetate. The combined organic phases
were washed with saturated aqueous sodium chloride solution, dried
over sodium sulphate, filtered and concentrated by evaporation. The
residue was purified by preparative HPLC (RP18 column, mobile
phase: acetonitrile/water gradient with addition of 0.1% TFA). The
combined product fractions were concentrated by evaporation. The
residue was dissolved in dichloromethane and washed twice with
saturated aqueous sodium bicarbonate solution. The combined organic
phases were reextracted twice with dichloromethane. The combined
aqueous phases were dried over sodium sulphate, filtered and
concentrated by evaporation. This gave 88 mg of the target compound
(40% of theory, purity 99%).
[0900] LC-MS (Method 1): R.sub.t=1.44 min; MS (ESIpos): m/z=584
[M+H].sup.+
[0901] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.61),
-0.008 (4.76), 0.008 (4.40), 0.146 (0.56), 0.489 (1.21), 0.501
(2.46), 0.511 (3.85), 0.524 (5.52), 0.537 (5.23), 0.546 (3.52),
0.559 (2.46), 0.597 (1.64), 0.609 (3.74), 0.624 (4.52), 0.631
(6.04), 0.645 (6.88), 0.657 (5.30), 0.668 (6.10), 0.681 (6.68),
0.695 (5.21), 0.708 (1.89), 0.737 (2.53), 0.751 (5.27), 0.763
(5.87), 0.774 (4.85), 0.786 (3.29), 0.800 (1.19), 1.233 (0.96),
1.589 (1.67), 1.604 (3.78), 1.611 (4.10), 1.625 (6.63), 1.639
(3.88), 1.660 (1.40), 2.328 (0.83), 2.367 (0.48), 2.671 (0.90),
2.710 (0.50), 5.755 (0.47), 7.597 (5.68), 7.619 (10.97), 7.641
(5.82), 8.759 (9.67), 8.778 (9.61), 9.126 (16.00), 9.386
(11.83).
Example 95A
7-Chloro-6-fluoro-4-oxo-N-[1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl]-
-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(Enantiomer 1)
##STR00188##
[0903]
7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylic acid (300 mg, 805 .mu.mol) was initially
charged in 7.5 ml of acetonitrile.
1,1,1,2,2-Pentafluoro-4,4-dimethylpentan-3-amine hydrochloride
(Enantiomer 1) (214 mg, 100% purity, 886 .mu.mol) and
N,N-diisopropylethylamine (560 .mu.l, 3.2 mmol) were added. A T3P
solution (propanephosphonic acid cyclic anhydride, 50% in ethyl
acetate; 570 .mu.l, 970 .mu.mol) was added. The reaction solution
was stirred at room temperature overnight. More
1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-amine hydrochloride
(Enantiomer 1) (97 mg, 403 .mu.mol) was added to the reaction
solution and the mixture was stirred at room temperature for 2
days. More 1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-amine
hydrochloride (Enantiomer 1) (97 mg, 403 .mu.mol),
N,N-diisopropylethylamine (280 .mu.l, 1.6 mmol) and a T3P solution
(propanephosphonic acid cyclic anhydride, 50% in ethyl acetate; 285
.mu.l, 480 .mu.mol) were added to the reaction solution and the
mixture was stirred at room temperature for 2 days. The reaction
solution was diluted with dichloromethane and washed twice with
water. The combined aqueous phases were reextracted with
dichloromethane. The combined organic phases were dried over sodium
sulphate, filtered and concentrated by evaporation. The residue was
purified by silica gel (mobile phase: cyclohexane/ethyl acetate
gradient: ethyl acetate 4% to 32%). This gave 318 mg of the target
compound (71% of theory, purity 100%).
[0904] LC-MS (Method 5): R.sub.t=1.72 min; MS (ESIpos): m/z=560
[M+H].sup.+
Example 96A
7-Chloro-6-fluoro-4-oxo-N-[1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-yl]--
1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(Enantiomer 2)
##STR00189##
[0906]
7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylic acid (300 mg, 805 .mu.mol) was initially
charged in 7.5 ml of acetonitrile.
1,1,1,2,2-Pentafluoro-4,4-dimethylpentan-3-amine hydrochloride
(Enantiomer 2) (214 mg, 100% purity, 886 .mu.mol) and
N,N-diisopropylethylamine (560 .mu.l, 3.2 mmol) were added. A T3P
solution (propanephosphonic acid cyclic anhydride, 50% in ethyl
acetate; 570 .mu.l, 970 .mu.mol) was added. The reaction solution
was stirred at room temperature overnight. More
1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-amine hydrochloride
(Enantiomer 2) (97 mg, 403 .mu.mol) was added to the reaction
solution and the mixture was stirred at room temperature for 2
days. More 1,1,1,2,2-pentafluoro-4,4-dimethylpentan-3-amine
hydrochloride (Enantiomer 2) (97 mg, 403 .mu.mol),
N,N-diisopropylethylamine (280 .mu.l, 1.6 mmol) and a T3P solution
(propanephosphonic acid cyclic anhydride, 50% in ethyl acetate; 285
.mu.l, 480 .mu.mol) were added to the reaction solution and the
mixture was stirred at room temperature for 2 days. The reaction
solution was diluted with dichloromethane and washed twice with
water. The combined aqueous phases were reextracted with
dichloromethane. The combined organic phases were dried over sodium
sulphate, filtered and concentrated by evaporation. The residue was
purified by silica gel (mobile phase: cyclohexane/ethyl acetate
gradient: ethyl acetate 4% to 32%). This gave 373 ng of the target
compound (82% of theory, purity 99%).
[0907] LC-MS (Method 5): R.sub.t=1.73 min; MS (ESIpos): m/z=560
[M+H].sup.+
Example 97A
7-Chloro-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluoropheny-
l)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomerically
pure)
##STR00190##
[0909] 16.5 ml (28.2 mmol) of
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide
(T3P, 50% in ethyl acetate) were added dropwise to a solution of
2.50 g (7.05 mmol) of
7-chloro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthy-
ridine-3-carboxylic acid, 1.55 g (7.75 mmol) of
3,3,4,4,4-pentafluorobutan-2-amine hydrochloride (enantiomerically
pure) and 3.7 ml (21.1 mmol) of DIPEA in 70 ml of ethyl acetate.
The mixture was stirred at 80.degree. C. overnight. The reaction
mixture was concentrated by evaporation and poured onto water. The
precipitate was filtered off, dissolved in DCM, dried over sodium
sulphate and filtered and the solvent was removed under reduced
pressure. The crude product was used for the next step without
further purification. This gave 3.35 g (95% of theory, 100% pure)
of the title compound.
[0910] LC-MS (Method 3): R.sub.t=2.34 min; MS (ESIpos): m/z=500
[M+H].sup.+
[0911] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.92),
0.146 (0.85), 0.928 (1.24), 0.943 (1.22), 1.175 (0.71), 1.244
(1.98), 1.259 (2.16), 1.274 (1.27), 1.409 (15.77), 1.426 (16.00),
1.488 (0.94), 1.988 (1.17), 2.328 (1.68), 2.367 (1.01), 2.670
(1.82), 2.711 (1.04), 4.998 (0.81), 5.020 (1.36), 5.043 (1.68),
5.062 (1.73), 5.086 (1.43), 5.107 (0.78), 7.595 (5.78), 7.618
(11.30), 7.640 (5.82), 7.773 (10.54), 7.794 (11.10), 8.741 (11.23),
8.761 (10.77), 9.142 (15.95), 9.986 (6.05), 10.010 (5.92).
Example 98A
7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-y-
l]-1-(2,4,6-tris
fluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(enantiomerically pure)
##STR00191##
[0913] According to GP3, 5.00 g (10.0 mmol) of
7-chloro-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophen-
yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (enantiomerically
pure) were reacted with 1.36 g (11.0 mmol) of (3S)-pyrrolidin-3-ol
hydrochloride and 7.0 ml (40.0 mmol) of N,N-diisopropylethylamine
in 37 ml of dimethylformamide. The reaction mixture was poured onto
water and extracted three times with ethyl acetate. The combined
organic phases were washed once with sat. sodium chloride solution,
dried over sodium sulphate and concentrated by evaporation. The
crude product was purified by normal-phase chromatography
(cyclohexane/ethyl acetate gradient). This gave 4.99 g (88% of
theory, 97% pure) of the title compound.
[0914] LC-MS (Method 1): R.sub.t=1.04 min; MS (ESIpos): m/z=551
[M+H].sup.+
[0915] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.51),
0.147 (0.51), 1.157 (0.52), 1.175 (1.05), 1.193 (0.49), 1.385
(14.87), 1.402 (14.89), 1.788 (0.91), 1.921 (1.77), 1.989 (2.75),
2.329 (0.83), 2.367 (0.42), 2.671 (0.79), 2.711 (0.44), 3.051
(1.08), 3.083 (1.84), 3.163 (2.28), 3.185 (2.68), 3.518 (2.49),
3.534 (2.97), 4.021 (0.47), 4.039 (0.47), 4.270 (1.69), 4.387
(1.43), 4.961 (2.74), 4.984 (1.50), 5.007 (1.64), 5.052 (3.17),
6.744 (1.70), 6.773 (2.76), 6.798 (2.07), 7.530 (3.28), 7.553
(6.61), 7.575 (3.83), 8.265 (3.13), 8.286 (2.86), 8.805 (16.00),
10.551 (6.33), 10.575 (6.15).
Working Examples
Example 1
1-(2,6-Difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-(4,4,4-trifluoro-2-methylbutan-2-yl)-1,4-dihydro-1,8-naph-
thyridine-3-carboxamide
##STR00192##
[0917] According to GP1, 99.9 mg (237 .mu.mol) of
1-(2,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro--
4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were reacted
with 40.1 mg (284 .mu.mol) of 4,4,4-trifluoro-2-methylbutan-2-amine
in the presence of 108 mg (284 .mu.mol) of HATU and 103 .mu.l (593
.mu.mol) of DIPEA in 2.4 ml of DMF. The reaction mixture was
purified directly by preparative HPLC [at UV max: 265 nm, column:
Chromatorex C18, 10 .mu.m, 125.times.30 mm, solvent:
acetonitrile/0.05% formic acid gradient (0 to 3 min 10%
acetonitrile, to 15 min 90% acetonitrile and a further 3 min 90%
acetonitrile)]. The product fractions were combined, freed from the
solvent and lyophilized. This gave 107 mg (82% of theory, 99% pure)
of the title compound.
[0918] LC-MS (Method 3): R.sub.t=1.76 min; MS (ESIpos): m/z=545
[M+H].sup.+.
[0919] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.10 (s, 1H),
8.67 (s, 1H), 8.00 (d, 1H), 7.77-7.66 (m, 1H), 7.47-7.36 (m, 2H),
5.18 (br. s, 2H), 4.09-3.51 (br. m, 4H), 3.27-2.86 (m, 4H).
Example 2
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-1-(2,6-difluoropheny-
l)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-
-naphthyridine-3-carboxamide
##STR00193##
[0921] According to GP1, 99.9 mg (237 .mu.mol) of
1-(2,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro--
4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were reacted
with 49.9 mg (284 .mu.mol) of
(1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in the
presence of 108 mg (284 .mu.mol) of HATU and 103 .mu.l (593
.mu.mol) of DIPEA in 2.4 ml of DMF. The reaction mixture was then
purified directly by preparative HPLC [at UV max: 265 nm, column:
Chromatorex C18, 10 .mu.m, 125.times.30 mm, solvent:
acetonitrile/0.05% formic acid gradient (0 to 3 min 10%
acetonitrile, to 15 min 90% acetonitrile and a further 3 min 90%
acetonitrile)]. The product fractions were combined, freed from the
solvent and lyophilized. This gave 100 mg (77% of theory, 99% pure)
of the title compound.
[0922] LC-MS (Method 3): R.sub.t=1.77 min; MS (ESIpos): m/z=543
[M+H].sup.+.
[0923] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.49 (d, 1H),
8.78 (s, 1H), 8.02 (d, 1H), 7.76-7.67 (m, 1H), 7.46-7.38 (m, 2H),
5.19 (br. s, 2H), 4.45-4.32 (m, 1H), 4.11-3.53 (br. m, 4H),
3.27-2.89 (m, 2H), 1.27-1.16 (m, 1H), 0.70-0.49 (m, 3H), 0.38-0.28
(m, 1H).
Example 3
1-(2,6-Difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyr-
idine-3-carboxamide
##STR00194##
[0925] According to GP1, 100 mg (237 .mu.mol) of
1-(2,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro--
4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were reacted
with 46.6 mg (285 .mu.mol) of (2S)-1,1,1-trifluorobutan-2-amine
hydrochloride in the presence of 108 mg (285 .mu.mol) of HATU and
103 .mu.l (593 .mu.mol) of DIPEA in 2.4 ml of DMF. The reaction
mixture was then diluted with 2 ml of aqueous hydrochloric acid and
purified by preparative HPLC [at UV max: 265 nm, column:
Chromatorex C18, 10 .mu.m, 125.times.30 mm, solvent:
acetonitrile/0.05% formic acid gradient (0 to 3 min 10%
acetonitrile, to 15 min 90% acetonitrile and a further 3 min 90%
acetonitrile)]. The product fractions were combined, freed from the
solvent and lyophilized. This gave 32.7 mg (26% of theory, 100%
pure) of the title compound.
[0926] LC-MS (Method 1): R.sub.t=0.92 min; MS (ESIpos): m/z=531
[M+H].sup.+.
[0927] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.36 (d, 1H),
8.79 (s, 1H), 8.02 (d, 1H), 7.77-7.67 (m, 1H), 7.47-7.38 (m, 2H),
5.19 (br. s, 2H), 4.81-4.67 (m, 1H), 4.10-3.56 (br. m, 4H),
3.27-2.90 (m, 2H), 1.94-1.82 (m, 1H), 1.71-1.58 (m, 1H), 0.97 (t,
1H).
Example 4
1-(2,6-Difluorophenyl)-6-fluoro-7-[(2-hydroxyethyl)(methyl)amino-
]-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-
-carboxamide
##STR00195##
[0929] According to GP3, 50.0 mg (108 .mu.mol) of
7-chloro-1-(2,6-difluorophenyl)-6-fluoro-4-oxo-N-[(2S)-1,1,1-trifluorobut-
an-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxamide were reacted
with 8.91 mg (119 .mu.mol) of 2-(methylamino)ethanol in the
presence of 66 .mu.l (0.38 mmol) of DIPEA in 0.5 ml of DMF. The
mixture was then diluted with acetonitrile, water and 0.2 ml of
aqueous hydrochloric acid and the crude solution was purified by
preparative HPLC (acetonitrile/water with formic acid, C18
RP-HPLC). The product fractions were combined, concentrated under
reduced pressure and lyophilized from acetonitrile/water overnight.
This gave 37.9 mg (70% of theory, 100% pure) of the title
compound.
[0930] LC-MS (Method 3): R.sub.t=1.97 min; MS (ESIpos): m/z=503
[M+H].sup.+.
[0931] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.33 (d, 1H),
8.81 (s, 1H), 8.01 (d, 1H), 7.75-7.65 (m, 1H), 7.45-7.37 (m, 2H),
4.80-4.67 (m, 2H), 3.51-3.35 (m, 4H), 3.05 (s, 3H), 1.94-1.82 (m,
1H), 1.71-1.58 (m, 1H), 0.97 (t, 3H).
Example 5
N-(Bicyclo[1.1.1]pent-1-yl)-1-(2,6-difluorophenyl)-7-[(3R,4R)-3,-
4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
-carboxamide
##STR00196##
[0933] According to GP1, 100 mg (237 .mu.mol) of
1-(2,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro--
4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were reacted
with 34.1 mg (285 .mu.mol) of bicyclo[1.1.1]pentan-1-amine
hydrochloride in the presence of 108 mg (285 .mu.mol) of HATU and
103 .mu.l (593 .mu.mol) of DIPEA in 2.4 ml of DMF. The reaction
mixture was then diluted with 2 ml of aqueous hydrochloric acid and
purified twice by preparative HPLC [at UV max: 265 nm, column:
Chromatorex C18, 10 .mu.m, 125.times.30 mm, solvent:
acetonitrile/0.05% formic acid gradient (0 to 3 min 10%
acetonitrile, to 15 min 90% acetonitrile and a further 3 min 90%
acetonitrile)]. The product fractions were combined, freed from the
solvent and lyophilized. This gave 3 mg (2% of theory, 100% pure)
of the title compound.
[0934] LC-MS (Method 3): R.sub.t=1.65 min; MS (ESIpos): m/z=487
[M+H].sup.+.
Example 6
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2S)-1,1,1-trif-
luorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-
-carboxamide
##STR00197##
[0936] According to GP3, 417 mg (717 .mu.mol) of
6-fluoro-4-oxo-7-(1-[1,2,3]triazol[4,5-b]pyridin-1-yloxy)-N-[(2S)-1,1,1-t-
rifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridin-
e-3-carboxamide were reacted with 120 mg (861 .mu.mol) of
(3R,4R)-pyrrolidine-3,4-diol hydrochloride in the presence of 437
.mu.l (2.51 mmol) of DIPEA in 7.25 ml of DMF. The reaction solution
was then added to 80 ml of water and acidified with 2 ml of aqueous
1M hydrochloric acid and the precipitate was filtered off with
suction and washed with water. The residue was taken up in 6 ml of
acetonitrile and purified by preparative HPLC (acetonitrile/water
with formic acid, C18 RP-HPLC). The product fractions were combined
and concentrated under reduced pressure and the residue was
lyophilized from acetonitrile/water overnight. This gave 296 mg
(74% of theory, 99% pure) of the title compound.
[0937] LC-MS (Method 3): R.sub.t=1.78 min; MS (ESIpos): m/z=549
[M+H].sup.+.
[0938] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.34 (d, 1H),
8.84 (s, 1H), 8.02 (d, 1H), 7.62-7.53 (m, 2H), 5.20 (br. s, 2H),
4.82-4.67 (m, 1H), 4.13-3.54 (br. m, 4H), 3.28-2.95 (m, 2H),
1.94-1.81 (m, 1H), 1.72-1.57 (m, 1H), 0.97 (t, 1H).
Example 7
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(3R,4R)-3,4-dihyd-
roxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro--
1,8-naphthyridine-3-carboxamide
##STR00198##
[0940] According to GP1, 1.00 g (2.28 mmol) of
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 480 mg (2.73 mmol) of
(1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in the
presence of 1.04 g (2.73 mmol) of HATU and 991 .mu.l (5.69 mmol) of
DIPEA in 23 ml of DMF. The mixture was then acidified with aqueous
1M hydrochloric acid and diluted with 200 ml of water and 100 ml of
ethyl acetate. The phases were separated and the aqueous phase was
extracted twice with 60 ml of ethyl acetate. The combined organic
phases were washed with 50 ml of buffer pH 7 and with 50 ml of
saturated aqueous sodium chloride solution, dried over magnesium
sulfate, filtered and concentrated under reduced pressure. The
residue was purified by normal phase chromatography
(cyclohexane/ethyl acetate) and the fractions was combined,
concentrated under reduced pressure and lyophilized from
acetonitrile/water overnight. This gave 1.05 g (83% of theory, 100%
pure) of the title compound.
[0941] LC-MS (Method 3): R.sub.t=1.81 min; MS (ESIpos): m/z=561
[M+H].sup.+.
[0942] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.48 (d, 1H),
8.83 (s, 1H), 8.02 (d, 1H), 7.62-7.52 (m, 2H), 5.20 (br. s, 2H),
4.45-4.31 (m, 1H), 4.11-3.55 (br. m, 4H), 3.29-2.95 (m, 2H),
1.26-1.14 (m, 1H), 0.70-0.48 (m, 3H), 0.38-0.28 (m, 1H).
Example 8
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[3,3,4,4,4-penta-
fluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine--
3-carboxamide (diastereomer mixture)
##STR00199##
[0944] According to GP1, 2.77 g (6.31 mmol) of
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 1.51 g (7.57 mmol) of
3,3,4,4,4-pentafluorobutan-2-amine hydrochloride (racemate) in the
presence of 2.88 g (7.57 mmol) of HATU and 3.84 ml (22.1 mmol) of
DIPEA in 30 ml of DMF. The reaction solution was subsequently added
dropwise to a mixture of 3 ml of aqueous 1M hydrochloric acid and
300 ml of ice-water. The precipitate formed was filtered off, dried
and purified by normal phase chromatography (cyclohexane/ethyl
acetate). This gave 2.40 g (65% of theory, 100% pure) of the title
compound.
[0945] LC-MS (Method 3): R.sub.t=1.84 min; MS (ESIpos): m/z=585
[M+H].sup.+.
[0946] 2.40 g of the title compound (diastereomer mixture) were
separated by chiral SFC into the diastereomers (preparative SFC:
column Daicel Chiralpak AD, 5 .mu.m, 250.times.30 mm; mobile phase:
85% carbon dioxide, 15% isopropanol; temperature: 38.degree. C.;
flow rate: 130 ml/min; pressure: 140 bar; UV detection: 210
nm.)
[0947] This gave (in the sequence of elution from the column) 1.15
g of diastereomer 1 from Example 9 (99% de) R.sub.t=3.23 min, 1.09
g of diastereomer 2 from Example 10 (94% de) R.sub.t=4.79 min.
[0948] [Analytical SFC: column Daicel Chiralpak AD-3, 3 .mu.m,
100.times.4.6 mm; mobile phase: 90% carbon dioxide, 10%
isopropanol; temperature: 60.degree. C.; flow rate: 3.0 ml/min;
pressure: 130 bar; UV detection: 220 nm].
[0949] Diastereomer 1 was re-purified by normal phase
chromatography (cyclohexane/ethyl acetate). This gave 903 mg (24%
of theory, 99% purity) of the compound from Example 9.
[0950] Diastereomer 2 was re-purified by normal phase
chromatography (cyclohexane/ethyl acetate). This gave 912 mg (25%
of theory, 99% purity) of the compound from Example 10.
Example 9
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[3,3,4-
,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naph-
thyridine-3-carboxamide (diastereomer 1)
[0951] LC-MS (Method 3): R.sub.t=1.84 min; MS (ESIpos): m/z=585
[M+H].sup.+.
[0952] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.46 (d, 1H),
8.84 (s, 1H), 8.01 (d, 1H), 7.62-7.53 (m, 2H), 5.20 (br. s, 2H),
5.10-4.93 (m, 1H), 4.11-3.55 (br. m, 4H), 3.29-2.95 (m, 2H), 1.39
(d, 3H).
Example 10
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[3,3,-
4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-nap-
hthyridine-3-carboxamide (diastereomer 2)
[0953] LC-MS (Method 3): R.sub.t=1.84 min; MS (ESIpos): m/z=585
[M+H].sup.+.
[0954] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.47 (d, 1H),
8.84 (s, 1H), 8.01 (d, 1H), 7.62-7.54 (m, 2H), 5.20 (br. s, 2H),
5.10-4.93 (m, 1H), 4.11-3.57 (br. m, 4H), 3.29-2.96 (m, 2H), 1.39
(d, 3H).
[0955] The following working examples were prepared analogously to
Example 8 according to GP1:
TABLE-US-00002 IUPAC name Structure LC-MS (method): retention time;
detected mass .sup.1H NMR amine used Example (yield, purity) 11
7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2S)-1,1,1-t-
rifluoro-4-
methylpentan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridin-
e-3-carbox- amide ##STR00200## LC-MS (Method 1): R.sub.t = 1.07 mm;
MS (ESIpos): m/z = 577 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d6)
.delta. [ppm]: 0.008 (1.63), 0.882 (15.82), 0.898 (15.97), 0.940
(15.69), 0.956 (16.00), 1.527 (0.65), 1.562 (2.61), 1.590 (2.10),
1.640 (2.07), 1.650 (3.07), 1.676 (3.98), 1.703 (1.66), 2.328
(0.72), 2.366 (0.49), 2.524 (2.17), 2.670 (0.75), 2.710 (0.47),
3.070 (0.79), 3.696 (0.83), 3.904 (1.68), 4.017 (1.18), 4.815
(1.32), 4.838 (1.35), 4.857 (0.78), 5.201 (2.98), 7.554 (2.23),
7.558 (2.44), 7.575 (4.26), 7.580 (4.31), 7.597 (2.46), 7.993
(6.91), 8.025 (6.83), 8.847 (12.23), 10.316 (4.89), 10.340 (4.71).
(2S)-1,1,1-trifluoro-4-methylpentan-2-amine hydrochloride (75% of
theory, 99% pure) 12
N-(bicyclo[1.1.1]pent-1-yl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6--
fluoro-4-oxo-
1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00201## LC-MS (Method 1): R.sub.t = 0.91 min; MS (ESIpos): m/z
= 505 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d6) .delta. [ppm]:
2.074 (0.98), 2.094 (16.00), 2.477 (2.52), 2.519 (0.42), 5.188
(0.90), 7.557 (0.60), 7.579 (1.03), 7.599 (0.60), 7.949 (1.39),
7.981 (1.36), 8.696 (2.25), 10.195 (1.71).
bicyclo[1.1.1]pentan-1-amine hydrochloride (69% of theory, 100%
pure) 13
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-(4,4,4-triflu-
oro-2-methyl-
butan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-car-
boxamide ##STR00202## LC-MS (Method 3): R.sub.t = 1.8 mm; MS
(ESIpos): m/z = 563 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d6)
.delta. [ppm]: 1.480 (16.00), 2.902 (0.72), 2.932 (2.07), 2.963
(2.01), 2.992 (0.69), 3.908 (0.59), 5.192 (1.67), 7.552 (1.20),
7.573 (2.17), 7.595 (1.21), 7.980 (2.69), 8.012 (2.63), 8.724
(4.96), 10.086 (3.27). 4,4,4-trifluoro-2-methylbutan-2-amine
hydrochloride (92% of theory, 100% pure) 14
7-[(3R,45)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2R)-1,1,1-t-
rifluoro-4-
methylpentan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridin-
e-3-carbox- amide ##STR00203## LC-MS (Method 1): R.sub.t = 1.07 mm;
MS (ESIpos): m/z = 577 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d6)
.delta. [ppm]: -0.008 (2.52), 0.008 (2.37), 0.882 (15.72), 0.898
(15.79), 0.940 (15.66), 0.956 (16.00), 1.528 (0.63), 1.534 (0.59),
1.555 (1.28), 1.563 (2.58), 1.571 (1.29), 1.591 (2.06), 1.640
(1.99), 1.650 (2.98), 1.676 (3.84), 1.704 (1.62), 1.713 (1.08),
2.329 (0.42), 2.524 (1.33), 2.671 (0.45), 3.070 (0.76), 3.694
(0.77), 3.912 (1.65), 4.018 (1.13), 4.816 (1.26), 4.839 (1.29),
4.858 (0.73), 5.201 (4.77), 7.556 (3.83), 7.578 (6.91), 7.599
(3.80), 7.994 (7.11), 8.026 (6.94), 8.848 (12.19), 10.318 (4.80),
10.342 (4.57). (2R)-1,1,1-trifluoro-4-methylpentan-2-amine
hydrochloride (73% of theory, 97% pure) 15
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-N-[(2R)-3-methylbutan-
-2-yl]-4-
oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00204## LC-MS (Method 3): R.sub.t = 1.67 mm; MS (ESIpos): m/z
= 509 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d6) .delta. [ppm]:
-0.008 (2.45), 0.008 (1.92), 0.900 (14.25), 0.918 (16.00), 0.924
(14.85), 0.941 (14.39), 1.098 (14.84), 1.115 (14.90), 1.731 (0.46),
1.747 (1.23), 1.764 (1.75), 1.778 (1.69), 1.795 (1.13), 1.811
(0.41), 2.328 (0.43), 2.519 (1.74), 2.524 (1.27), 2.671 (0.43),
3.070 (0.46), 3.269 (0.67), 3.276 (0.53), 3.680 (0.48), 3.887
(2.02), 3.903 (2.66), 3.908 (2.44), 3.921 (2.64), 3.938 (2.04),
3.954 (1.12), 5.191 (3.01), 7.550 (2.38), 7.571 (4.17), 7.592
(2.37), 7.992 (5.69), 8.024 (5.64), 8.711 (9.43), 9.868 (3.38),
9.890 (3.30). (2R)-3-methylbutan-2-amine (75% of theory, 99% pure)
16
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-N-[(2S)-3-methylbutan-
-2-yl]-4-
oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00205## LC-MS (Method 3): R.sub.t = 1.67 mm; MS (ESIpos): m/z
= 509 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d6) .delta. [ppm]:
0.008 (1.40), 0.901 (14.31), 0.918 (16.00), 0.925 (14.98), 0.942
(14.43), 1.099 (14.84), 1.116 (14.86), 1.731 (0.49), 1.748 (1.30),
1.765 (1.85), 1.778 (1.73), 1.795 (1.14), 3.063 (0.51), 3.680
(0.53), 3.888 (2.11), 3.904 (2.84), 3.922 (2.79), 3.939 (2.15),
5.194 (4.39), 7.550 (2.81), 7.572 (4.99), 7.593 (2.71), 7.994
(6.12), 8.026 (6.00), 8.713 (11.30), 9.870 (3.57), 9.892 (3.45).
(2S)-3-methylbutan-2-amine (77% of theory, 100% pure) 17
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-N-[(2S)-1-methoxy-3-m-
ethylbutan-
2-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-car-
boxamide ##STR00206## LC-MS (Method 3): R.sub.t = 1.58 mm; MS
(ESIpos): m/z = 539 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d6)
.delta. [ppm]: -0.008 (1.71), 0.008 (1.47), 0.912 (10.53), 0.929
(10.84), 1.903 (0.49), 1.920 (0.75), 1.936 (0.74), 1.953 (0.46),
3.269 (16.00), 3.352 (0.72), 3.365 (0.83), 3.377 (1.17), 3.390
(1.12), 3.439 (1.10), 3.453 (1.22), 3.464 (0.76), 3.477 (0.70),
3.919 (0.46), 3.965 (0.52), 3.980 (0.91), 3.994 (0.99), 4.002
(1.00), 4.017 (0.87), 5.192 (1.07), 7.553 (0.86), 7.573 (1.56),
7.594 (0.86), 8.000 (2.37), 8.031 (2.31), 8.723 (4.24), 9.926
(1.34), 9.949 (1.29). (2S)-1-methoxy-3-methylbutan-2-amine
hydrochloride (87% of theory, 99% pure) 18
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-triflu-
orophenyl)-N-
[(2S)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-carboxa-
mide ##STR00207## LC-MS (Method 1): R.sub.t = 0.89 min; MS
(ESIpos): m/z = 535 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d6)
.delta. [ppm]: -0.008 (3.40), 1.366 (15.93), 1.383 (16.00), 2.328
(0.75), 2.367 (0.46), 2.670 (0.72), 2.710 (0.46), 3.065 (0.82),
3.692 (0.82), 3.906 (1.71), 4.011 (1.21), 4.842 (0.45), 4.861
(1.18), 4.882 (1.82), 4.902 (1.87), 4.920 (1.20), 5.199 (4.80),
7.555 (2.86), 7.577 (5.42), 7.598 (2.83), 7.990 (8.04), 8.022
(7.89), 8.837 (14.74), 10.383 (5.19), 10.406 (4.90).
(2S)-1,1,1-trifluoropropan-2-amine (77% of theory, 99% pure) 19
N-[(1R)-1-cyclopropylethyl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6--
fluoro-4-oxo-
1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00208## LC-MS (Method 3): R.sub.t = 1.63 min; MS (ESIpos): m/z
= 507 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d6) .delta. [ppm]:
-0.150 (0.68), -0.008 (6.67), 0.008 (5.02), 0.146 (0.68), 0.218
(1.10), 0.229 (1.68), 0.241 (2.46), 0.249 (2.36), 0.261 (1.43),
0.266 (1.39), 0.278 (2.30), 0.287 (2.75), 0.299 (1.94), 0.310
(1.26), 0.322 (0.55), 0.394 (0.65), 0.402 (0.65), 0.414 (1.85),
0.425 (2.27), 0.435 (2.59), 0.447 (3.11), 0.461 (2.75), 0.469
(2.01), 0.482 (1.59), 0.491 (0.62), 0.940 (0.45), 0.952 (0.87),
0.960 (1.30), 0.972 (2.27), 0.980 (1.46), 0.992 (2.14), 1.004
(1.10), 1.012 (0.74), 1.215 (15.87), 1.231 (16.00), 2.327 (1.13),
2.366 (1.00), 2.523 (3.85), 2.670 (1.23), 2.710 (1.10), 3.064
(0.55), 3.482 (0.42), 3.498 (1.39), 3.518 (2.56), 3.535 (2.49),
3.553 (1.33), 3.571 (0.49), 3.679 (0.62), 3.917 (1.39), 5.189
(4.15), 7.546 (3.17), 7.568 (5.73), 7.589 (3.21), 7.975 (6.25),
8.007 (6.19), 8.708 (10.85), 9.864 (4.05), 9.884 (3.92).
(1R)-1-cyclopropylethanamine (76% of theory, 100% pure) 20
N-[(1S)-1-cyclopropylethyl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6--
fluoro-4-oxo-
1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00209## LC-MS (Method 3): R.sub.t = 1.62 mm; MS (ESIpos): m/z
= 507 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d6) .delta. [ppm]:
-0.149 (0.42), -0.008 (4.00), 0.008 (2.96), 0.146 (0.42), 0.207
(0.46), 0.218 (1.12), 0.229 (1.67), 0.241 (2.46), 0.249 (2.39),
0.261 (1.42), 0.266 (1.39), 0.278 (2.32), 0.287 (2.75), 0.299
(1.93), 0.310 (1.19), 0.321 (0.56), 0.394 (0.60), 0.402 (0.67),
0.414 (1.84), 0.425 (2.23), 0.435 (2.56), 0.448 (3.05), 0.456
(1.96), 0.461 (2.72), 0.470 (1.98), 0.482 (1.60), 0.491 (0.60),
0.502 (0.44), 0.940 (0.44), 0.952 (0.88), 0.960 (1.26), 0.972
(2.25), 0.980 (1.44), 0.984 (1.40), 0.992 (2.16), 1.005 (1.09),
1.012 (0.74), 1.215 (15.91), 1.232 (16.00), 2.328 (0.61), 2.367
(0.60), 2.524 (2.23), 2.670 (0.65), 2.710 (0.58), 3.073 (0.54),
3.484 (0.40), 3.501 (1.35), 3.520 (2.49), 3.537 (2.46), 3.556
(1.30), 3.573 (0.44), 3.673 (0.56), 3.909 (1.32), 5.190 (4.47),
7.547 (2.51), 7.568 (4.49), 7.589 (2.51), 7.976 (6.25), 8.008
(6.18), 8.709 (10.70), 9.864 (4.05), 9.884 (3.89).
(1S)-1-cyclopropylethanamine (77% of theory, 100% pure) 21
N-(dicyclopropylmethyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluo-
ro-4-oxo-1-
(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00210## LC-MS (Method 1): R.sub.t = 0.94 min; MS (ESIpos): m/z
= 533 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d6) .delta. [ppm]:
-0.149 (1.11), -0.008 (9.56), 0.008 (7.59), 0.146 (1.11), 0.299
(15.57), 0.311 (15.27), 0.322 (4.14), 0.370 (2.56), 0.393 (6.91),
0.415 (5.85), 0.452 (4.99), 0.472 (6.31), 0.498 (1.92), 1.016
(2.82), 1.029 (5.25), 1.036 (3.41), 1.049 (4.99), 1.061 (2.60),
2.328 (2.22), 2.367 (1.11), 2.670 (2.13), 2.710 (1.07), 3.221
(2.22), 3.239 (4.44), 3.261 (4.74), 3.280 (2.86), 3.903 (1.79),
5.189 (5.16), 7.545 (3.50), 7.568 (6.27), 7.588 (3.58), 7.988
(9.09), 8.020 (8.75), 8.709 (16.00), 9.892 (5.03), 9.914 (4.82).
1,1-dicyclopropylmethanamine (61% of theory, 99% pure) 22
N-(1,1-difluoro-2-methylpropan-2-yl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-
-1-yl]-6-
fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-ca-
rboxamide ##STR00211## LC-MS (Method 1): R.sub.t = 0.93 min; MS
(ESIpos): m/z = 531 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d6)
.delta. [ppm]: -0.008 (1.57), 0.008 (1.50), 1.434 (16.00), 2.073
(0.74), 2.328 (0.48), 2.670 (0.52), 3.910 (0.55), 5.192 (1.49),
6.277 (0.88), 6.420 (1.62), 6.562 (0.73), 7.554 (1.10), 7.577
(1.94), 7.597 (1.10), 7.987 (2.44), 8.019 (2.41), 8.750 (4.28),
10.232 (3.14). 1,1-difluoro-2-methylpropan-2-amine hydrochloride
(57% of theory, 100% pure) 23
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-(1,1,1-triflu-
oro-2-
methylpropan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridin-
e-3-carbox- amide ##STR00212## LC-MS (Method 3): R.sub.t = 1.77
min; MS (ESIpos): m/z = 549 [M + H].sup.+ .sup.1H NMR (400 MHz,
DMSO-d6) .delta. [ppm]: -0.008 (0.89), 0.008 (0.56), 1.633 (16.00),
2.520 (0.82), 2.524 (0.74), 3.908 (0.50), 5.194 (1.18), 7.557
(0.97), 7.579 (1.58), 7.600 (0.89), 8.008 (2.21), 8.040 (2.14),
8.775 (3.54), 10.561 (2.95). 1,1,1-trifluoro-2-methylpropan-2-amine
hydrochloride (63% of theory, 100% pure) 24
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-N-(2,4-dimethylpentan-3-yl)-6--
fluoro-4-oxo-
1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00213## LC-MS (Method 3): R.sub.t = 1.87 mm; MS (ESIpos): m/z
= 537 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d6) .delta. [ppm]:
-0.008 (0.92), 0.008 (0.71), 0.865 (13.39), 0.877 (15.46), 0.881
(16.00), 0.893 (13.11), 1.810 (0.43), 1.827 (1.26), 1.844 (2.06),
1.860 (2.00), 1.877 (1.16), 2.524 (0.55), 3.640 (0.71), 3.656
(1.27), 3.666 (0.90), 3.672 (0.89), 3.681 (1.31), 3.697 (0.75),
3.911 (0.57), 5.198 (1.63), 7.550 (1.24), 7.572 (2.16), 7.592
(1.23), 8.013 (3.06), 8.045 (2.98), 8.727 (5.38), 9.761 (1.66),
9.786 (1.59). 2,4-dimethylpentan-3-amine (57% of theory, 100% pure)
25
N-(2-cyclopropylpropan-2-yl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-
-fluoro-4-
oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00214## LC-MS (Method 3): R.sub.t = 1.79 min; MS (ESIpos): m/z
= 521 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d6) .delta. [ppm]:
0.397 (5.62), 0.414 (4.00), 1.290 (0.69), 1.311 (16.00), 1.325
(0.79), 5.187 (1.10), 7.550 (0.76), 7.572 (1.33), 7.593 (0.73),
7.993 (1.77), 8.024 (1.73), 8.680 (3.16), 9.863 (2.07).
2-cyclopropylpropan-2-amine (95% of theory, 100% pure) 26
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2)-1-(trifl-
uorometh-
oxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-
-carbox- amide (diastereomer mixture) ##STR00215## LC-MS (Method
3): R.sub.t = 1.78 min; MS (ESIpos): m/z = 579 [M + H].sup.+
.sup.1H NMR (400 MHz, DMSO-d6) .delta. [ppm]: -0.008 (2.02), 0.008
(1.73), 0.922 (6.79), 0.941 (16.00), 0.959 (7.44), 1.550 (0.56),
1.568 (0.97), 1.585 (1.26), 1.603 (1.40), 1.622 (0.89), 1.633
(0.55), 1.651 (1.04), 1.663 (1.19), 1.669 (1.15), 1.682 (1.27),
1.698 (0.74), 1.716 (0.46), 2.074 (1.63), 2.328 (0.45), 2.524
(1.32), 2.671 (0.43), 3.069 (0.51), 3.685 (0.52), 3.911 (1.21),
4.148 (2.09), 4.162 (2.31), 4.176 (3.98), 4.183 (4.11), 4.194
(4.10), 4.211 (2.53), 5.193 (3.51), 7.552 (2.57), 7.574 (4.50),
7.595 (2.53), 7.995 (6.24), 8.026 (6.06), 8.762 (10.71), 9.985
(2.62), 10.005 (2.44). 1-(trifluoromethoxy)butan-2-amine
hydrochloride (racemate) (54% of theory, 100% pure) 27
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(3)-1,1,1,2,-
2-pentafluoro-
pentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-ca-
rboxamide (diastereomer mixture) ##STR00216## LC-MS (Method 3):
R.sub.t = 1.93 mm; MS (ESIpos): m/z = 599 [M + H].sup.+ .sup.1H NMR
(400 MHz, DMSO-d6) .delta. [ppm]: 0.944 (7.18), 0.962 (16.00),
0.981 (7.74), 1.619 (0.90), 1.638 (1.31), 1.654 (1.50), 1.663
(1.39), 1.673 (1.34), 1.681 (1.41), 1.699 (1.00), 1.922 (1.31),
2.329 (0.58), 2.672 (0.66), 3.079 (0.81), 3.693 (0.86), 3.905
(1.75), 4.012 (1.22), 4.852 (1.12), 4.879 (1.06), 5.208 (3.80),
7.557 (3.27), 7.579 (5.89), 7.599 (3.25), 8.005 (7.21), 8.037
(7.04), 8.850 (14.56), 10.377 (4.69), 10.402 (4.39).
1,1,1,2,2-pentafluoropentan-3-amine hydrochloride (racemate) (85%
of theory, 99% pure) 28
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-(2-methylpentan-3-y-
l)-4-oxo-1-
(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(diastereomer mixture) ##STR00217## LC-MS (Method 3): R.sub.t =
1.80 mm; MS (ESIpos): m/z = 523 [M + H].sup.+ .sup.1H NMR (400 MHz,
DMSO-d6) .delta. [ppm]: 0.008 (1.53), 0.851 (4.76), 0.869 (11.65),
0.878 (11.15), 0.888 (7.46), 0.896 (16.00), 0.915 (10.32), 1.380
(0.55), 1.397 (0.79), 1.414 (1.00), 1.436 (1.06), 1.454 (0.71),
1.538 (0.78), 1.550 (0.92), 1.568 (1.02), 1.584 (0.72), 1.602
(0.49), 1.794 (0.89), 1.810 (1.24), 1.824 (1.23), 1.840 (0.80),
2.328 (0.45), 3.680 (0.42), 3.764 (0.53), 3.777 (0.93), 3.788
(1.29), 3.799 (1.63), 3.811 (1.29), 3.822 (0.87), 3.834 (0.59),
3.907 (0.94), 5.199 (2.67), 7.551 (2.01), 7.573 (3.53), 7.594
(1.96), 7.999 (4.29), 8.031 (4.21), 8.716 (8.19), 9.768 (2.51),
9.792 (2.39). 2-methylpentan-3-amine hydrochloride (racemate) (31%
of theory, 100% pure)
Example 29
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-(2-methylpe-
ntan-3-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-
-carboxamide (diastereomer 1)
[0956] 37 mg of
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-(2-methylpentan-
-3-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-car-
boxamide (diastereomer mixture) were separated into the
diastereomers by chiral HPLC (preparative HPLC: column Daicel.RTM.
Chiralpak OX-H, 5 .mu.m, 250.times.20 mm; mobile phase: 80%
n-heptane/20% isopropanol; flow rate 15 ml/min; temperature:
35.degree. C., detection: 265 nm).
[0957] Diastereomer 1: 13 mg (>99% de)
[0958] R.sub.t=6.27 min [analytical HPLC: column Daicel.RTM.
Chiralpak OX-H, 1 ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase:
75% isohexane/25% isopropanol+0.2% DEA; detection: 265 nm].
[0959] LC-MS (Method 3): R.sub.t=1.80 min; MS (ESIpos): m/z=523
[M+H].sup.+
Example 30
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-(2-methylpe-
ntan-3-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-
-carboxamide (diastereomer 2)
[0960] 37 mg of
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-(2-methylpentan-
-3-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-car-
boxamide (diastereomer mixture) were separated into the
diastereomers by chiral HPLC (preparative HPLC: column Daicel.RTM.
Chiralpak OX-H, 5 .mu.m, 250.times.20 mm; mobile phase: 80%
n-heptane/20% isopropanol; flow rate 15 ml/min; temperature:
35.degree. C., detection: 265 nm).
[0961] Diastereomer 2: 13 mg (>99% de)
[0962] R.sub.t=7.35 min [analytical HPLC: column Daicel.RTM.
Chiralpak OX-H, 1 ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase:
75% isohexane/25% isopropanol+0.2% DEA; detection: 265 nm].
[0963] LC-MS (Method 3): R.sub.t=1.80 min; MS (ESIpos): m/z=523
[M+H].sup.+
Example 31
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2)--
1-(trifluoromethoxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8--
naphthyridine-3-carboxamide (diastereomer 1)
[0964] 218 mg of
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2)-1-(trifluo-
romethoxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyrid-
ine-3-carboxamide (diastereomer mixture) were separated into the
diastereomers by chiral HPLC (preparative HPLC: column Daicel.RTM.
Chiralpak ID, 5 .mu.m, 250.times.20 mm; mobile phase: 85%
n-heptane/15% isopropanol; flow rate 15 ml/min; temperature:
30.degree. C., detection: 220 nm).
[0965] Diastereomer 1: 63.7 mg (99% de)
[0966] R.sub.t=5.50 min [analytical HPLC: column Daicel.RTM.
Chiralpak ID, 1 ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase:
80% isohexane/20% propanol; detection: 220 nm].
[0967] LC-MS (Method 3): R.sub.t=1.78 min; MS (ESIpos): m/z=579
[M+H].sup.+
Example 32
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2)--
1-(trifluoromethoxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8--
naphthyridine-3-carboxamide (diastereomer 2)
[0968] 218 mg of
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2)-1-(trifluo-
romethoxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyrid-
ine-3-carboxamide (diastereomer mixture) were separated into the
diastereomers by chiral HPLC (preparative HPLC: column Daicel.RTM.
Chiralpak ID, 5 .mu.m, 250.times.20 mm; mobile phase: 85%
n-heptane/15% isopropanol; flow rate 15 ml/min; temperature:
30.degree. C., detection: 220 nm).
[0969] Diastereomer 2: 64.2 mg (97.6% de)
[0970] R.sub.t=6.23 min [analytical HPLC: column Daicel.RTM.
Chiralpak ID, 1 ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase:
80% isohexane/20% propanol; detection: 220 nm].
[0971] LC-MS (Method 3): R.sub.t=1.78 min; MS (ESIpos): m/z=579
[M+H].sup.+
Example 33
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(3)--
1,1,1,2,2-pentafluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,-
8-naphthyridine-3-carboxamide (diastereomer 1)
[0972] 292 mg of
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(3)-1,1,1,2,2--
pentafluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyr-
idine-3-carboxamide (diastereomer mixture) were separated into the
diastereomers by chiral HPLC (preparative HPLC: column Daicel.RTM.
Chiralpak IA, 5 .mu.m, 250.times.20 mm; mobile phase: 85%
n-heptane/15% isopropanol; flow rate 15 ml/min; temperature:
30.degree. C., detection: 220 nm).
[0973] Diastereomer 1: 111.6 mg (>99% de)
[0974] R.sub.t=6.10 min [analytical HPLC: column Daicel.RTM.
Chiralpak IA, 1 ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase:
80% isohexane/20% isopropanol; detection: 265 nm].
[0975] LC-MS (Method 3): R.sub.t=1.93 min; MS (ESIpos): m/z=599
[M+H].sup.+
Example 34
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(3)--
1,1,1,2,2-pentafluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,-
8-naphthyridine-3-carboxamide (diastereomer 2)
[0976] 292 mg of
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(3)-1,1,1,2,2--
pentafluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyr-
idine-3-carboxamide (diastereomer mixture) were separated into the
diastereomers by chiral HPLC (preparative HPLC: column Daicel.RTM.
Chiralpak IA, 5 .mu.m, 250.times.20 mm; mobile phase: 85%
n-heptane/15% isopropanol; flow rate 15 ml/min; temperature:
30.degree. C., detection: 220 nm).
[0977] Diastereomer 2: 110.1 mg 99.5% de)
[0978] R.sub.t=6.76 min [analytical HPLC: column Daicel.RTM.
Chiralpak IA, 1 ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase:
80% isohexane/20% isopropanol; detection: 265 nm].
[0979] LC-MS (Method 3): R.sub.t=1.93 min; MS (ESIpos): m/z=599
[M+H].sup.+
Example 35
(3R,4R)-1-[3-Fluoro-5-oxo-6-{[(2S)-1,1,1-trifluorobutan-2-yl]ca-
rbamoyl}-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]-4-hy-
droxypyrrolidin-3-yl acetate
##STR00218##
[0981]
(7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2S)-1,-
1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthy-
ridine-3-carboxamide (60.0 mg, 109 .mu.mol) was dissolved in
dichloromethane (1.0 ml), and dimethylaminopyridine (1.34 mg, 10.9
.mu.mol) was added. At 0.degree. C., acetyl chloride (5.4 .mu.l, 77
.mu.mol) was added dropwise, and the mixture was stirred at RT for
3 h. The reaction mixture was concentrated and the residue was
taken up in acetonitrile and purified by preparative HPLC
(acetonitrile/water with formic acid, C18 RP-HPLC). The product
fractions were combined, concentrated and lyophilized from
acetonitrile/water overnight. This gave 25.9 mg (39% of theory, 99%
pure) of the title compound.
[0982] LC-MS (Method 3): R.sub.t=2.07 min; MS (ESIpos): m/z=591
[M+H].sup.+
[0983] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.90),
-0.008 (7.72), 0.008 (6.90), 0.146 (0.88), 0.952 (2.34), 0.971
(5.26), 0.989 (2.57), 1.625 (0.47), 1.642 (0.53), 1.651 (0.53),
1.661 (0.51), 1.668 (0.53), 1.685 (0.41), 1.852 (0.41), 1.871
(0.49), 1.881 (0.58), 1.897 (0.45), 1.990 (16.00), 2.328 (0.68),
2.523 (1.81), 2.670 (0.68), 2.710 (0.41), 4.139 (0.45), 4.738
(0.51), 4.951 (0.41), 5.607 (0.94), 7.555 (1.38), 7.577 (2.51),
7.599 (1.40), 8.036 (2.20), 8.067 (2.20), 8.858 (5.18), 10.300
(1.75), 10.324 (1.68).
[0984] The following reactions were prepared analogously to Example
1 according to GP1:
TABLE-US-00003 IUPAC name Structure LC-MS (method): retention time;
detected mass .sup.1H NMR amine used Example (yield, purity) 36
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2R)-1,1,1-t-
rifluoro-
butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-car-
boxamide ##STR00219## LC-MS (Method 3): R.sub.t = 1.78 min; MS
(ESIpos): m/z = 549 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d6)
.delta. [ppm]: -0.149 (0.60), -0.008 (5.32), 0.008 (4.91), 0.147
(0.57), 0.950 (7.28), 0.969 (16.00), 0.987 (7.85), 1.604 (1.06),
1.622 (1.40), 1.629 (1.28), 1.639 (1.74), 1.647 (1.55), 1.657
(1.47), 1.664 (1.70), 1.682 (1.28), 1.851 (1.32), 1.860 (1.51),
1.868 (1.47), 1.879 (1.74), 1.885 (1.51), 1.895 (1.32), 1.904
(1.13), 1.914 (0.98), 2.328 (1.36), 2.366 (0.94), 2.524 (4.68),
2.670 (1.43), 2.710 (0.98), 3.067 (0.79), 3.691 (0.87), 3.906
(1.81), 4.012 (1.25), 4.735 (1.43), 4.754 (1.36), 5.200 (4.83),
7.558 (3.89), 7.580 (6.87), 7.601 (3.89), 7.999 (7.58), 8.030
(7.51), 8.840 (13.17), 10.329 (5.21), 10.353 (5.02).
(2R)-1,1,1-trifluorobutan-2-amine hydrochloride (69% of theory, 99%
pure) 37
6-chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-7-[(3R,4R)-3,4-dih-
ydroxypyr-
rolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridi-
ne-3-car- boxamide ##STR00220## LC-MS (Method 3): R.sub.t = 1.89
mm; MS (ESIpos): m/z = 577.11 [M + H].sup.+ .sup.1H NMR (400 MHz,
DMSO-d6) .delta. [ppm]: -0.008 (1.73), 0.008 (1.41), 0.320 (1.55),
0.330 (2.59), 0.342 (2.48), 0.353 (1.79), 0.365 (1.00), 0.522
(1.67), 0.534 (2.52), 0.547 (2.55), 0.553 (2.84), 0.571 (2.95),
0.580 (2.20), 0.591 (1.98), 0.601 (1.63), 0.615 (0.97), 0.630
(1.27), 0.639 (1.31), 0.650 (2.61), 0.660 (2.01), 0.667 (1.80),
0.685 (0.98), 0.693 (0.58), 1.170 (0.48), 1.182 (1.01), 1.190
(1.45), 1.203 (2.41), 1.212 (1.79), 1.223 (2.40), 1.235 (1.31),
1.244 (0.87), 2.329 (0.60), 2.367 (0.41), 2.524 (2.02), 2.671
(0.70), 2.711 (0.47), 3.683 (0.57), 3.930 (5.71), 4.342 (1.32),
4.363 (2.25), 4.384 (2.19), 4.405 (1.19), 5.188 (9.80), 5.196
(9.81), 7.564 (3.82), 7.585 (6.78), 7.607 (3.80), 8.284 (16.00),
8.856 (13.94), 10.356 (5.25), 10.379 (5.07).
(1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride (81% of
theory, 99% pure) 38
6-chloro-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-t-
rifluoro-
butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-car-
boxamide ##STR00221## LC-MS (Method 3): R.sub.t = 1.86 min; MS
(ESIpos): m/z = 565 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d6)
.delta. [ppm]: -0.008 (1.70), 0.008 (1.59), 0.951 (7.25), 0.970
(16.00), 0.988 (7.86), 1.609 (1.08), 1.626 (1.45), 1.633 (1.27),
1.644 (1.73), 1.652 (1.56), 1.662 (1.48), 1.669 (1.66), 1.687
(1.24), 1.832 (0.43), 1.850 (1.31), 1.860 (1.52), 1.869 (1.52),
1.879 (1.75), 1.885 (1.54), 1.895 (1.33), 1.904 (1.13), 1.913
(0.96), 2.328 (0.61), 2.367 (0.50), 2.524 (1.95), 2.671 (0.63),
2.711 (0.53), 3.671 (0.56), 3.930 (5.75), 4.735 (1.45), 4.750
(1.34), 5.185 (13.17), 5.192 (13.00), 7.566 (4.26), 7.588 (7.94),
7.610 (4.20), 8.279 (13.40), 8.865 (12.98), 10.212 (5.29), 10.236
(4.98). (2S)-1,1,1-trifluorobutan-2-amine hydrochloride (72% of
theory, 99% pure) 39
1-(3,5-difluoropyridin-2-yl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-
-fluoro-4-
oxo-N-[(2)-3,3,4,4,4-pentafluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-
-3-car- boxamide (diastereomer mixture) ##STR00222## LC-MS (Method
3): R.sub.t = 1.71 min; MS (ESIpos): m/z = 568 [M + H].sup.+
.sup.1H NMR (400 MHz, DMSO-d6) .delta. [ppm]: -0.149 (0.43), -0.008
(4.17), 0.008 (3.72), 0.146 (0.45), 1.389 (16.00), 1.405 (15.88),
2.328 (0.93), 2.367 (0.71), 2.524 (2.99), 2.670 (0.91), 2.711
(0.68), 3.067 (0.88), 3.691 (1.06), 3.918 (3.12), 4.976 (1.14),
4.997 (1.93), 5.018 (2.30), 5.041 (2.36), 5.063 (2.17), 5.084
(1.55), 5.102 (1.09), 5.200 (5.07), 7.997 (7.54), 8.028 (7.69),
8.329 (2.76), 8.351 (5.01), 8.373 (2.71), 8.616 (11.67), 8.622
(10.91), 8.837 (7.39), 8.844 (8.07), 10.451 (7.34), 10.475 (7.07).
3,3,4,4,4-pentafluorobutan-2-amine hydrochloride (racemate) (78% of
theory, 99% pure) 40
1-(2-chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl-
]-6-fluoro-
4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3--
carbox- amide (atropisomer mixture) ##STR00223## LC-MS (Method 3):
R.sub.t = 1.83 mm; MS (ESIpos): m/z = 565 [M + H].sup.+ .sup.1H NMR
(400 MHz, DMSO-d6) .delta. [ppm]: 0.008 (1.02), 0.949 (4.31), 0.958
(5.08), 0.967 (9.96), 0.977 (9.85), 0.985 (5.50), 0.995 (4.62),
1.603 (0.66), 1.614 (0.80), 1.621 (1.07), 1.638 (1.64), 1.648
(1.55), 1.657 (1.71), 1.664 (1.33), 1.674 (1.24), 1.681 (0.93),
1.692 (0.76), 1.852 (1.27), 1.862 (1.49), 1.870 (1.55), 1.880
(1.71), 1.898 (1.31), 1.905 (1.13), 1.915 (0.91), 2.328 (0.73),
2.366 (0.58), 2.524 (2.35), 2.670 (0.78), 2.710 (0.62), 3.018
(0.87), 3.220 (0.93), 3.693 (0.95), 3.891 (1.82), 4.013 (1.37),
4.734 (1.57), 4.750 (1.47), 5.202 (4.19), 7.686 (0.84), 7.693
(1.27), 7.709 (1.69), 7.717 (2.44), 7.728 (3.11), 7.732 (3.15),
7.740 (3.53), 7.751 (3.53), 7.763 (2.35), 8.004 (7.55), 8.035
(7.54), 8.794 (16.00), 10.347 (3.64), 10.351 (3.73), 10.371 (3.57),
10.375 (3.55). (2S)-1,1,1-trifluorobutan-2-amine hydrochloride (83%
of theory, 100% pure) 41
1-(2-chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl-
]-6-fluoro-
4-oxo-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,4-dihydro-1,8-naphthyridi-
ne-3- carboxamide (atropisomer mixture) ##STR00224## LC-MS (Method
3): R.sub.t = 1.85 mm; MS (ESIpos): m/z = 565 [M + H].sup.+ .sup.1H
NMR (400 MHz, DMSO-d6) .delta. [ppm]: -0.008 (1.27), 0.008 (0.95),
1.634 (16.00), 2.524 (0.91), 3.894 (0.45), 5.193 (1.23), 7.709
(0.41), 7.717 (0.65), 7.726 (0.67), 7.732 (0.70), 7.739 (0.91),
7.749 (0.72), 7.764 (0.59), 8.012 (1.99), 8.044 (1.97), 8.723
(3.93), 10.582 (2.93). 1,1,1-trifluoro-2-methylpropan-2-amine (96%
of theory, 99% pure) 42
1-(2-chloro-4,6-difluorophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroet-
hyl]-7-
[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-nap-
hthy- ridine-3-carboxamide (atropisomer mixture) ##STR00225## LC-MS
(Method 3): R.sub.t = 1.86 min; MS (ESIpos): m/z = 577 [M +
H].sup.+ .sup.1H NMR (400 MHz, DMSO-d6) .delta. [ppm]: -0.149
(0.75), -0.008 (7.24), 0.008 (5.85), 0.146 (0.80), 0.317 (1.19),
0.328 (2.21), 0.340 (2.61), 0.351 (2.36), 0.363 (1.54), 0.374
(0.62), 0.526 (2.24), 0.543 (2.26), 0.555 (2.21), 0.565 (2.36),
0.575 (2.54), 0.586 (2.24), 0.596 (1.92), 0.610 (1.29), 0.624
(1.02), 0.634 (1.34), 0.644 (1.92), 0.655 (2.24), 0.668 (1.99),
0.677 (1.49), 1.167 (0.47), 1.179 (1.00), 1.187 (1.42), 1.199
(2.44), 1.209 (1.87), 1.220 (2.44), 1.232 (1.34), 1.241 (0.85),
1.253 (0.42), 2.327 (1.12), 2.366 (0.77), 2.523 (3.66), 2.665
(0.95), 2.670 (1.24), 2.710 (0.82), 3.015 (0.85), 3.221 (0.90),
3.687 (0.95), 3.894 (1.79), 4.013 (1.37), 4.340 (0.80), 4.359
(1.64), 4.378 (2.12), 4.399 (1.64), 4.418 (0.75), 5.199 (4.33),
7.684 (0.85), 7.691 (1.39), 7.701 (1.37), 7.707 (1.59), 7.715
(2.76), 7.724 (2.84), 7.730 (2.86), 7.737 (3.66), 7.747 (3.09),
7.761 (2.36), 8.008 (7.12), 8.039 (7.07), 8.785 (16.00), 10.486
(4.95), 10.510 (4.70). (1S)-1-cyclopropyl-2,2,2-trifluoroethanamine
hydrochloride (81% of theory, 99% pure) 43
1-(2-chloro-4,6-difluorophenyl)-N-[(1S)-1-cyclopropylethyl]-7-[(3R,4R)--
3,4-dihy-
droxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carb-
oxamide (atropisomer mixture) ##STR00226## LC-MS (Method 3):
R.sub.t = 1.67 min; MS (ESIpos): m/z = 523 [M + H].sup.+ .sup.1H
NMR (400 MHz, DMSO-d6) .delta. [ppm]: -0.008 (6.44), 0.008 (2.37),
0.217 (1.40), 0.228 (2.02), 0.240 (2.94), 0.251 (2.63), 0.264
(1.75), 0.277 (2.10), 0.285 (2.72), 0.292 (2.28), 0.305 (1.58),
0.401 (0.92), 0.412 (1.75), 0.422 (2.76), 0.433 (3.20), 0.443
(3.59), 0.453 (3.51), 0.459 (2.85), 0.467 (3.11), 0.479 (1.88),
0.487 (1.23), 0.959 (1.27), 0.964 (1.45), 0.971 (2.02), 0.977
(2.10), 0.984 (1.93), 0.991 (1.93), 0.996 (1.71), 1.004 (1.14),
1.213 (12.01), 1.220 (11.79), 1.230 (11.88), 1.236 (10.48), 2.328
(1.01), 2.366 (0.75), 2.519 (5.57), 2.670 (1.01), 2.710 (0.70),
3.008 (0.70), 3.488 (1.14), 3.507 (2.24), 3.524 (2.98), 3.540
(2.10), 3.560 (1.05), 3.669 (0.75), 3.894 (1.75), 5.186 (5.92),
7.676 (1.01), 7.682 (1.40), 7.693 (1.71), 7.698 (1.84), 7.706
(2.54), 7.717 (3.07), 7.722 (3.07), 7.729 (3.42), 7.739 (2.98),
7.751 (2.15), 7.980 (7.80), 8.011 (7.63), 8.653 (16.00), 9.881
(3.29), 9.887 (3.20), 9.902 (3.16), 9.906 (2.94).
(S)-1-cyclopropylethanamine (84% of theory, 99% pure) 44
1-(2-chloro-4,6-difluorophenyl)-N-[(1R)-1-cyclopropylethyl]-7-[(3R,4R)--
3,4-dihy-
droxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carb-
oxamide (atropisomer mixture) ##STR00227## LC-MS (Method 3):
R.sub.t = 1.67 mm; MS (ESIpos): m/z = 523 [M + H].sup.+ .sup.1H NMR
(400 MHz, DMSO-d6) .delta. [ppm]: -0.008 (1.78), 0.008 (1.48),
0.218 (1.23), 0.229 (2.01), 0.240 (2.94), 0.252 (2.71), 0.265
(1.58), 0.279 (2.08), 0.286 (2.81),
0.294 (2.36), 0.307 (1.73), 0.328 (0.45), 0.392 (0.43), 0.402
(0.78), 0.413 (1.63), 0.423 (2.69), 0.434 (3.19), 0.445 (3.77),
0.454 (3.59), 0.459 (2.86), 0.467 (3.19), 0.480 (2.03), 0.487
(1.31), 0.501 (0.65), 0.959 (1.18), 0.964 (1.36), 0.972 (1.93),
0.977 (2.11), 0.984 (1.88), 0.992 (2.01), 0.997 (1.81), 1.004
(1.23), 1.010 (1.05), 1.213 (11.53), 1.220 (12.21), 1.229 (12.16),
1.236 (11.68), 2.328 (0.53), 2.367 (0.48), 2.524 (1.93), 2.671
(0.60), 2.711 (0.50), 3.006 (0.70), 3.227 (0.78), 3.486 (1.16),
3.505 (2.36), 3.522 (3.27), 3.539 (2.36), 3.558 (1.18), 3.575
(0.40), 3.677 (0.78), 3.898 (1.76), 5.188 (5.70), 7.676 (0.85),
7.684 (1.66), 7.692 (1.36), 7.700 (1.63), 7.707 (3.09), 7.715
(2.56), 7.730 (3.99), 7.738 (2.84), 7.749 (2.66), 7.754 (2.44),
7.979 (8.26), 8.011 (8.16), 8.653 (16.00), 9.886 (3.74), 9.904
(3.77). (R)-1-cyclopropylethanamine (91% of theory, 99% pure)
Example 45
1-(3,5-Difluoropyridin-2-yl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fl-
uoro-4-oxo-N-[(2)-3,3,4,4,4-pentafluorobutan-2-yl]-1,4-dihydro-1,8-naphthy-
ridine-3-carboxamide (diastereomer 1)
[0985] 486 mg of
1-(3,5-difluoropyridin-2-yl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-f-
luoro-4-oxo-N-[(2)-3,3,4,4,4-pentafluorobutan-2-yl]-1,4-dihydro-1,8-naphth-
yridine-3-carboxamide (diastereomer mixture) were separated into
the diastereomers by chiral HPLC (preparative HPLC: column
Daicel.RTM. Chiralpak IE, 5 .mu.m, 250.times.20 mm; mobile phase:
70% n-heptane/30% isopropanol+0.2% diethylamine; flow rate 15
ml/min; temperature: 25.degree. C., detection: 270 nm).
[0986] Diastereomer 1: 172.5 mg (>99% de)
[0987] R.sub.t=4.82 min [analytical HPLC: column Daicel.RTM.
Chiralpak IE, 1 ml/min; 3 .mu.m, 50.times.4.6 mm; mobile phase: 80%
isohexane/20% isopropanol+0.2% diethylamine; detection: 220
nm].
Example 46
1-(3,5-Difluoropyridin-2-yl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-
-1-yl]-6-fluoro-4-oxo-N-[(2)-3,3,4,4,4-pentafluorobutan-2-yl]-1,4-dihydro--
1,8-naphthyridine-3-carboxamide (diastereomer 2)
[0988] 486 mg of
1-(3,5-difluoropyridin-2-yl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-f-
luoro-4-oxo-N-[(2)-3,3,4,4,4-pentafluorobutan-2-yl]-1,4-dihydro-1,8-naphth-
yridine-3-carboxamide (diastereomer mixture) were separated into
the diastereomers by chiral HPLC (preparative HPLC: column
Daicel.RTM. Chiralpak IE, 5 .mu.m, 250.times.20 mm; mobile phase:
70% n-heptane/30% isopropanol+diethylamine; flow rate 15 ml/min;
temperature: 25.degree. C., detection: 270 nm).
[0989] Diastereomer 2: 160.3 mg (>99% de)
[0990] R.sub.t=7.11 min [analytical HPLC: column Daicel.RTM.
Chiralpak IE, 1 ml/min; 3 .mu.m, 50.times.4.6 mm; mobile phase: 80%
isohexane/20% isopropanol+0.2% diethylamine; detection: 220
nm].
Example 47
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrroli-
din-1-yl]-6-fluoro-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,-
8-naphthyridine-3-carboxamide (atropisomer 1)
[0991] 103 mg of
1-(2-chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyr-
idine-3-carboxamide (atropisomer mixture) were separated into the
atropisomers by chiral HPLC (preparative HPLC: column Daicel.RTM.
Chiralpak IG, 5 .mu.m, 250.times.20 mm; mobile phase: 75%
n-heptane/25% isopropanol+0.2% diethylamine; flow rate 15 ml/min;
temperature: 30.degree. C., detection: 265 nm).
[0992] Atropisomer 1: 38 mg (>99% de)
[0993] R.sub.t=4.71 min [analytical HPLC: column Daicel.RTM.
Chiralpak IG, 1 ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase:
70% isohexane/30% isopropanol+0.2% diethylamine; detection: 265
nm].
Example 48
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrroli-
din-1-yl]-6-fluoro-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,-
8-naphthyridine-3-carboxamide (atropisomer 2)
[0994] 103 mg of
1-(2-chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyr-
idine-3-carboxamide (atropisomer mixture) were separated into the
atropisomers by chiral HPLC (preparative HPLC: column Daicel.RTM.
Chiralpak IG, 5 .mu.m, 250.times.20 mm; mobile phase: 75%
n-heptane/25% isopropanol+0.2% diethylamine; flow rate 15 ml/min;
temperature: 30.degree. C., detection: 265 nm).
[0995] Atropisomer 2: 40 mg (>99% de)
[0996] R.sub.t=5.95 min [analytical HPLC: column Daicel.RTM.
Chiralpak IG, 1 ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase:
70% isohexane/30% isopropanol+0.2% diethylamine; detection: 265
nm].
Example 49
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrroli-
din-1-yl]-6-fluoro-4-oxo-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,4-dihyd-
ro-1,8-naphthyridine-3-carboxamide (atropisomer 1)
[0997] 119 mg of
1-(2-chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,4-dihydro-1,8-nap-
hthyridine-3-carboxamide (atropisomer mixture) were separated into
the atropisomers by chiral HPLC (preparative HPLC: column YMC
Chiralart Amylose SA, 5 .mu.m, 250.times.30 mm; mobile phase: 80%
n-heptane/20% isopropanol+0.2% diethylamine; flow rate 30 ml/min;
temperature: 30.degree. C., detection: 265 nm).
[0998] Atropisomer 1: 26 mg (>99% de)
[0999] R.sub.t=4.86 min [analytical HPLC: column YMC Chiralart
Amylose SA, 1 ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase: 70%
n-heptane/30% isopropanol+0.2% diethylamine; detection: 265
nm].
Example 50
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrroli-
din-1-yl]-6-fluoro-4-oxo-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,4-dihyd-
ro-1,8-naphthyridine-3-carboxamide (atropisomer 2)
[1000] 119 mg of
1-(2-chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,4-dihydro-1,8-nap-
hthyridine-3-carboxamide (atropisomer mixture) were separated into
the atropisomers by chiral HPLC (preparative HPLC: column YMC
Chiralart Amylose SA, 5 .mu.m, 250.times.30 mm; mobile phase: 80%
n-heptane/20% isopropanol+0.2% diethylamine; flow rate 30 ml/min;
temperature: 30.degree. C., detection: 265 nm).
[1001] Atropisomer 2: 25 mg (99% de)
[1002] R.sub.t=5.42 min [analytical HPLC: column YMC Chiralart
Amylose SA, 1 ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase: 70%
n-heptane/30% isopropanol+0.2% diethylamine; detection: 265
nm].
Example 51
1-(2-Chloro-4,6-difluorophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-tri-
fluoroethyl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-d-
ihydro-1,8-naphthyridine-3-carboxamide (atropisomer 1)
[1003] 103 mg of
1-(2-chloro-4,6-difluorophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethy-
l]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-
-naphthyridine-3-carboxamide (atropisomer mixture) were separated
into the atropisomers by chiral HPLC (preparative HPLC: column
Daicel.RTM. Chiralpak AD-H, 5 .mu.m, 250.times.20 mm; mobile phase:
80% n-heptane/20% ethanol; flow rate 25 ml/min; temperature:
40.degree. C., detection: 210 nm).
[1004] Atropisomer 1: 30 mg (99% de)
[1005] R.sub.t=6.04 min [analytical HPLC: column Daicel.RTM.
Chiralpak A, 1 ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase: 80%
isohexane/20% ethanol; detection: 235 nm].
Example 52
1-(2-Chloro-4,6-difluorophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-tri-
fluoroethyl]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-d-
ihydro-1,8-naphthyridine-3-carboxamide (atropisomer 2)
[1006] 103 mg of
1-(2-chloro-4,6-difluorophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethy-
l]-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-
-naphthyridine-3-carboxamide (atropisomer mixture) were separated
into the atropisomers by chiral HPLC (preparative HPLC: column
Daicel.RTM. Chiralpak AD-H, 5 .mu.m, 250.times.20 mm; mobile phase:
80% n-heptane/20% ethanol; flow rate 25 ml/min; temperature:
40.degree. C., detection: 210 nm).
[1007] Atropisomer 2: 30 mg (89% de)
[1008] R.sub.t=7.33 min [analytical HPLC: column Daicel.RTM.
Chiralpak A, 1 ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase: 80%
isohexane/20% ethanol; detection: 235 nm].
Example 53
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-7-(3-hydro-
xy-3-methylazetidin-1-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8--
naphthyridine-3-carboxamide
##STR00228##
[1010] 50 mg of
N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-7-(3H-[1,2,3]t-
riazolo[4,5-b]pyridin-3-yloxy)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxamide (84.3 .mu.mol) were dissolved in DMF
(980 .mu.l). 3-Methylazetidin-3-ol hydrochloride (20.8 mg, 169
.mu.mol) and N,N-diisopropylethylamine (51 .mu.l, 290 .mu.mol) were
added and the mixture was stirred at RT for 2 h. 0.3 ml of 1 N
hydrochloric acid and 1 ml of acetonitrile were then added, and the
reaction mixture was purified by preparative HPLC
(acetonitrile/water with formic acid, C18 RP-HPLC). The product
fractions were combined, concentrated and lyophilized from
acetonitrile/water overnight. This gave 36.2 mg (78% of theory, 99%
pure) of the title compound.
[1011] LC-MS (Method 1): R.sub.t=1.13 min; MS (ESIpos): m/z=545
[M+H].sup.+
[1012] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (2.92),
0.008 (2.80), 0.314 (0.84), 0.325 (1.33), 0.337 (1.27), 0.349
(1.02), 0.360 (0.50), 0.512 (0.90), 0.522 (1.35), 0.535 (1.27),
0.545 (1.38), 0.564 (1.40), 0.574 (1.14), 0.585 (1.02), 0.594
(0.87), 0.608 (0.52), 0.625 (0.77), 0.634 (0.73), 0.645 (1.26),
0.656 (1.01), 0.667 (0.95), 1.177 (0.55), 1.185 (0.79), 1.198
(1.31), 1.206 (0.92), 1.218 (1.38), 1.230 (0.71), 1.382 (16.00),
2.328 (0.67), 2.367 (0.45), 2.670 (0.60), 2.711 (0.41), 3.896
(0.45), 4.350 (0.73), 4.372 (1.28), 4.394 (1.17), 4.413 (0.68),
5.673 (9.48), 7.535 (2.55), 7.557 (4.79), 7.579 (2.54), 8.000
(4.69), 8.028 (4.62), 8.835 (8.40), 10.440 (2.87), 10.464
(2.65).
Example 54
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-7-(3-hydro-
xyazetidin-1-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyri-
dine-3-carboxamide
##STR00229##
[1014] 50 mg of
N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-7-(3H-[1,2,3]t-
riazolo[4,5-b]pyridin-3-yloxy)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxamide (84.3 .mu.mol) were dissolved in DMF
(980 .mu.l). Azetidin-3-ol hydrochloride (18.5 mg, 169 .mu.mol) and
N,N-diisopropylethylamine (51 .mu.l, 290 .mu.mol) were added and
the mixture was stirred at RT for 2 h. 0.3 ml of 1 N hydrochloric
acid and 1 ml of acetonitrile were then added, and the reaction
mixture was purified by preparative HPLC (acetonitrile/water with
formic acid, C18 RP-HPLC). The product fractions were combined,
concentrated and lyophilized from acetonitrile/water overnight.
This gave 32.2 mg (71% of theory, 99% pure) of the title
compound.
[1015] LC-MS (Method 1): R.sub.t=1.08 min; MS (ESIpos): m/z=531
[M+H].sup.+
[1016] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.55),
-0.008 (6.99), 0.008 (4.19), 0.146 (0.49), 0.314 (2.27), 0.324
(3.51), 0.337 (3.32), 0.348 (2.57), 0.360 (1.23), 0.511 (2.49),
0.522 (3.55), 0.534 (3.29), 0.545 (3.63), 0.563 (3.70), 0.573
(2.93), 0.584 (2.64), 0.594 (2.21), 0.608 (1.40), 0.624 (1.96),
0.634 (1.95), 0.644 (3.27), 0.655 (2.74), 0.660 (2.57), 0.667
(2.47), 0.676 (1.25), 0.689 (0.81), 1.164 (0.76), 1.176 (1.47),
1.185 (2.06), 1.197 (3.32), 1.205 (2.49), 1.217 (3.15), 1.229
(1.72), 1.238 (1.19), 1.250 (0.49), 2.328 (0.85), 2.366 (0.70),
2.524 (4.17), 2.670 (0.85), 2.710 (0.57), 3.821 (1.08), 4.330
(1.23), 4.350 (2.42), 4.371 (3.53), 4.392 (3.34), 4.412 (1.87),
4.501 (0.94), 4.517 (2.23), 4.528 (3.61), 4.544 (3.31), 4.555
(1.74), 4.571 (0.57), 5.741 (9.80), 5.757 (9.35), 7.532 (5.86),
7.555 (10.75), 7.577 (5.65), 7.992 (9.11), 8.020 (8.88), 8.832
(16.00), 10.439 (6.76), 10.462 (6.37).
Example 55
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-7-[(2-hydr-
oxyethyl)(methyl)amino]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-na-
phthyridine-3-carboxamide
##STR00230##
[1018] 80 mg of
N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-7-(3H-[1,2,3]t-
riazolo[4,5-b]pyridin-3-yloxy)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxamide (135 .mu.mol) were dissolved in DMF (980
.mu.l). 2-(Methylamino)ethanol (20.3 mg, 270 .mu.mol) and
N,N-diisopropylethylamine (82 .mu.l, 470 .mu.mol) were added and
the mixture was stirred at RT for 2 h. 0.2 ml of 1 N hydrochloric
acid and 2 ml of acetonitrile were added, and the reaction mixture
was purified by preparative HPLC (acetonitrile/water with formic
acid, C18 RP-HPLC). The product fractions were combined,
concentrated and lyophilized from acetonitrile/water over night.
This gave 45.1 mg (62% of theory, 99% pure) of the title
compound.
[1019] LC-MS (Method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=533
[M+H].sup.+
[1020] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.80),
-0.008 (7.20), 0.146 (0.77), 0.319 (1.97), 0.329 (3.20), 0.341
(3.09), 0.353 (2.45), 0.365 (1.17), 0.513 (2.13), 0.525 (3.31),
0.538 (2.91), 0.548 (3.25), 0.567 (3.33), 0.577 (2.75), 0.588
(2.40), 0.598 (2.05), 0.612 (1.25), 0.626 (1.68), 0.636 (1.63),
0.647 (2.93), 0.657 (2.53), 0.663 (2.40), 0.670 (2.37), 0.679
(1.15), 0.691 (0.80), 1.166 (0.59), 1.178 (1.23), 1.187 (1.81),
1.199 (3.04), 1.208 (2.21), 1.219 (2.99), 1.231 (1.63), 1.240
(1.12), 1.252 (0.48), 2.327 (1.49), 2.366 (1.23), 2.523 (5.39),
2.669 (1.60), 2.710 (1.20), 3.076 (9.76), 3.442 (6.83), 3.470
(5.87), 4.331 (0.40), 4.351 (1.63), 4.373 (2.85), 4.393 (2.80),
4.414 (1.49), 4.713 (2.96), 4.725 (6.51), 4.738 (3.01), 7.539
(5.52), 7.561 (10.56), 7.583 (5.60), 7.994 (9.63), 8.028 (9.44),
8.849 (16.00), 10.436 (6.37), 10.459 (6.16).
Example 56
N-(Dicyclopropylmethyl)-1-(3,5-difluoropyridin-2-yl)-6-fluoro-7-
-(3-hydroxy-3-methylazetidin-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-c-
arboxamide
##STR00231##
[1022] 50 mg of
1-(3,5-difluoropyridin-2-yl)-6-fluoro-7-(3-hydroxy-3-methylazetidin-1-yl)-
-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (123
.mu.mol) were dissolved in DMF (980 .mu.l). HATU (56.2 mg, 148
.mu.mol), N,N-diisopropylethylamine (54 .mu.l, 308 .mu.mol) and
1,1-dicyclopropylmethanamine (15.1 mg, 135 .mu.mol) were added and
the mixture was stirred at RT for 2 h. 0.1 ml of 1 M hydrochloric
acid and 1 ml of acetonitrile were added, and the reaction mixture
was purified by preparative HPLC (acetonitrile/water with formic
acid, C18 RP-HPLC). The product fractions were combined,
concentrated and lyophilized from acetonitrile/water overnight.
This gave 48.7 mg (78% of theory, 99% pure) of the title
compound.
[1023] LC-MS (Method 1): R.sub.t=1.04 min; MS (ESIpos): m/z=500
[M+H].sup.+
[1024] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (3.14),
0.008 (2.56), 0.300 (6.52), 0.387 (1.96), 0.397 (2.30), 0.416
(1.48), 0.455 (1.94), 0.475 (2.68), 1.031 (2.06), 1.044 (2.01),
1.382 (16.00), 2.323 (0.44), 2.328 (0.58), 2.524 (1.88), 2.670
(0.60), 3.235 (1.02), 3.254 (2.27), 3.276 (2.41), 3.928 (0.72),
5.676 (6.09), 7.985 (4.45), 8.014 (4.40), 8.292 (1.04), 8.298
(1.18), 8.316 (1.67), 8.319 (1.81), 8.337 (1.07), 8.343 (1.16),
8.591 (5.22), 8.597 (4.96), 8.753 (9.26), 9.856 (2.93), 9.878
(2.87).
Example 57
6-Fluoro-7-[(2S)-2-(hydroxymethyl)piperidin-1-yl]-4-oxo-N-[(2S)-
-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naph-
thyridine-3-carboxamide
##STR00232##
[1026] 50 mg of
6-fluoro-4-oxo-7-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-N-[(2S)-1,1,1-
-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyrid-
ine-3-carboxamide (86.0 .mu.mol) were dissolved in DMF (980 .mu.l).
(2S)-Piperidin-2-ylmethanol (19.8 mg, 172 .mu.mol) and
N,N-diisopropylethylamine (52 .mu.l, 300 .mu.mol) were added and
the mixture was stirred at RT for 2 h. 0.3 ml of 1 M hydrochloric
acid and 1 ml of acetonitrile were then added to the reaction
mixture, and the product was purified by preparative HPLC
(acetonitrile/water with formic acid, C18 RP-HPLC). The product
fractions were combined, concentrated and lyophilized from
acetonitrile/water overnight. This gave 37.3 mg (77% of theory, 99%
pure) of the title compound.
[1027] LC-MS (Method 3): R.sub.t=2.25 min; MS (ESIpos): m/z=561
[M+H].sup.+
[1028] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149
(0.55),-0.008 (4.87), 0.008 (4.03), 0.146 (0.52), 0.948 (7.19),
0.967 (16.00), 0.985 (7.82), 1.344 (1.09), 1.376 (1.34), 1.471
(1.90), 1.530 (3.44), 1.549 (5.64), 1.577 (2.47), 1.606 (1.34),
1.624 (1.56), 1.631 (1.36), 1.641 (1.83), 1.649 (1.65), 1.659
(1.59), 1.666 (1.77), 1.684 (1.47), 1.703 (0.91), 1.723 (1.95),
1.740 (1.83), 1.832 (0.43), 1.851 (1.31), 1.861 (1.54), 1.869
(1.56), 1.879 (1.74), 1.886 (1.54), 1.896 (1.34), 1.905 (1.15),
1.914 (0.98), 2.367 (0.70), 2.519 (3.11), 2.524 (2.47), 2.711
(0.66), 2.925 (1.07), 2.955 (1.99), 2.988 (1.07), 3.479 (1.00),
3.495 (1.47), 3.506 (2.47), 3.520 (2.63), 3.536 (1.90), 3.559
(1.20), 3.574 (2.02), 3.588 (1.77), 3.616 (0.68), 3.855 (1.79),
3.888 (1.68), 4.288 (2.04), 4.662 (3.01), 4.676 (6.53), 4.689
(2.97), 4.737 (1.41), 4.758 (1.32), 7.531 (1.43), 7.535 (1.41),
7.550 (3.99), 7.555 (4.15), 7.573 (4.28), 7.578 (3.88), 7.597
(1.36), 8.001 (8.41), 8.036 (8.14), 8.869 (13.96), 10.274 (5.15),
10.298 (4.94).
Example 58
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-7-[(2S)-2--
(hydroxymethyl)piperidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-
-1,8-naphthyridine-3-carboxamide
##STR00233##
[1030] 50 mg of
N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-7-(1H-[1,2,3]t-
riazolo[4,5-b]pyridin-1-yloxy)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxamide 50 mg of
N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-7-(3H-[1,2,3]t-
riazolo[4,5-b]pyridin-3-yloxy)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxamide (84.3 .mu.mol) were dissolved in DMF
(980 .mu.l). (2S)-Piperidin-2-ylmethanol (19.4 mg, 169 .mu.mol) and
N,N-diisopropylethylamine (51 .mu.l, 290 .mu.mol) were added and
the mixture was stirred at RT for 2 h. 0.3 ml of 1 N hydrochloric
acid and 1 ml of acetonitrile were added to the reaction mixture,
and the product was purified by preparative HPLC
(acetonitrile/water with formic acid, C18 RP-HPLC). The product
fractions were combined, concentrated and lyophilized from
acetonitrile/water overnight. This gave 36.5 mg (75% of theory, 99%
pure) of the title compound.
[1031] LC-MS (Method 1): R.sub.t=1.21 min; MS (ESIpos): m/z=573
[M+H].sup.+
[1032] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.72),
-0.008 (6.54), 0.008 (5.08), 0.147 (0.62), 0.318 (1.64), 0.330
(2.51), 0.342 (2.47), 0.353 (1.96), 0.516 (1.76), 0.528 (2.59),
0.539 (2.36), 0.550 (2.63), 0.568 (2.76), 0.579 (2.15), 0.589
(2.00), 0.599 (1.66), 0.613 (1.02), 0.628 (1.49), 0.637 (1.40),
0.648 (2.51), 0.659 (2.08), 0.664 (1.98), 0.670 (1.96), 1.189
(1.51), 1.201 (2.61), 1.209 (1.87), 1.221 (2.57), 1.233 (1.44),
1.377 (1.34), 1.472 (2.00), 1.532 (3.55), 1.551 (5.84), 1.577
(2.55), 1.723 (1.98), 1.740 (1.87), 2.328 (1.13), 2.367 (0.70),
2.524 (3.19), 2.670 (1.08), 2.711 (0.70), 2.924 (1.10), 2.954
(2.10), 2.987 (1.15), 3.479 (1.00), 3.495 (1.47), 3.506 (2.59),
3.520 (2.74), 3.536 (1.95), 3.574 (2.08), 3.587 (1.85), 3.859
(1.95), 3.892 (1.79), 4.286 (2.17), 4.352 (1.30), 4.373 (2.30),
4.394 (2.32), 4.414 (1.25), 4.662 (2.95), 4.675 (6.42), 4.688
(2.87), 7.533 (1.59), 7.547 (3.89), 7.553 (4.38), 7.569 (4.48),
7.576 (3.85), 7.590 (1.53), 8.006 (8.95), 8.041 (8.61), 8.860
(16.00), 10.414 (5.44), 10.437 (5.10).
Example 59
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-7-[(4S)-4--
hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro--
1,8-naphthyridine-3-carboxamide
##STR00234##
[1034] According to GP1, 61.7 mg (80% pure, 113 .mu.mol) of
6-fluoro-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluoro-
phenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 29.7 mg of
(1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride (169
.mu.mol) in the presence of 64.4 mg (169 .mu.mol) of HATU and 98
.mu.l (560 .mu.mol) of DIPEA in 3.0 ml of DMF. The reaction mixture
was diluted with 0.5 ml of aqueous hydrochloric acid and purified
by preparative HPLC [at UV max: 265 nm, column: Chromatorex C18, 10
.mu.m, 125.times.30 mm, solvent: acetonitrile/0.05% formic acid
gradient (0 to 3 min 10% acetonitrile, to 15 min 90% acetonitrile
and a further 3 min 90% acetonitrile)]. The product fractions were
combined, freed from the solvent and lyophilized. This gave 27.2 mg
(43% of theory, 100% pure) of the title compound.
[1035] LC-MS (Method 3): R.sub.t=1.80 min; MS (ESIpos): m/z=559
[M+H].sup.+
Example 60
N-tert-Butyl-7-(dimethylamino)-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00235##
[1037]
7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylic acid (120 mg, 322 .mu.mol) was initially
charged in 2.4 ml of DMF, HATU (147 mg, 386 .mu.mol) and
N,N-diisopropylethylamine (200 .mu.l, 1.1 mmol) were added and the
mixture was stirred at room temperature for 30 min.
2-Methylpropan-2-amine (41 .mu.l, 390 .mu.mol) was added and the
mixture was stirred at room temperature for 5 min. After 5 min,
water was added to the reaction mixture. The resulting suspension
was allowed to stand overnight. The next morning, a solid that
could be removed by filtration with suction had formed. This
residue was purified by column chromatography (silica gel; mobile
phase: dichloromethane/methanol gradient: 100/0 to 100/1). This
gave 23 mg (16% of theory) of the target compound.
[1038] LC-MS (Method 3): R.sub.t=2.32 min; MS (ESIpos): m/z=437
[M+H].sup.+
Example 61
7-(Dimethylamino)-6-fluoro-N-(2-methylbutan-2-yl)-4-oxo-1-(2,4,-
6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00236##
[1040]
7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylic acid (120 mg, 322 .mu.mol) was initially
charged in 2.4 ml of DMF, HATU (147 mg, 386 .mu.mol) and
N,N-diisopropylethylamine (200 .mu.l, 1.1 mmol) were added and the
mixture was stirred at room temperature for 30 min.
2-Methylbutan-2-amine (45 .mu.l, 390 .mu.mol) was added and the
mixture was stirred at room temperature for 5 min. After 5 min,
water was added to the reaction mixture. The resulting suspension
was allowed to stand overnight. The next morning, a solid that
could be removed by filtration with suction had formed. This
residue was purified by column chromatography (silica gel; mobile
phase: dichloromethane/methanol gradient: 100/0 to 100/1). This
gave 19 mg (13% of theory) of the target compound.
[1041] LC-MS (Method 3): R.sub.t=2.42 min; MS (ESIpos): m/z=451
[M+H].sup.+
Example 62
7-(Dimethylamino)-6-fluoro-4-oxo-N-(1,1,1-trifluoro-2-methylpro-
pan-2-yl)-1-(2,4,6-trifluoro-phenyl)-1,4-dihydro-1,8-naphthyridine-3-carbo-
xamide
##STR00237##
[1043]
7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylic acid (120 mg, 322 .mu.mol) was initially
charged in 2.4 ml of DMF, HATU (147 mg, 386 .mu.mol) and
N,N-diisopropylethylamine (200 .mu.l, 1.1 mmol) were added and the
mixture was stirred at room temperature for 30 min.
1,1,1-Trifluoro-2-methylpropan-2-amine (49.1 mg, 386 .mu.mol) was
added and the mixture was stirred at room temperature for 5 min.
After 5 min, water was added to the reaction mixture. The resulting
suspension was allowed to stand overnight. The next morning, a
solid that could be removed by filtration with suction had formed.
This residue was purified by column chromatography (silica gel;
mobile phase: dichloromethane/methanol gradient: 100/0 to 100/1).
This gave 30 mg (19% of theory) of the target compound.
[1044] LC-MS (Method 3): R.sub.t=2.42 min; MS (ESIpos): m/z=491
[M+H].sup.+
Example 63
7-(Dimethylamino)-6-fluoro-4-oxo-N-(4,4,4-trifluoro-2-methylbut-
an-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxa-
mide
##STR00238##
[1046]
7-Chloro-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxylic acid (120 mg, 322 .mu.mol) was initially
charged in 2.4 ml of DMF, HATU (147 mg, 386 .mu.mol) and
N,N-diisopropylethylamine (200 .mu.l, 1.1 mmol) were added and the
mixture was stirred at room temperature for 30 min.
4,4,4-Trifluoro-2-methylbutan-2-amine hydrochloride (68.6 mg, 386
.mu.mol) was added and the mixture was stirred at room temperature
for 5 min. After 5 min, water was added to the reaction mixture.
The resulting suspension was allowed to stand overnight. The next
morning, a solid that could be removed by filtration with suction
had formed. This residue was purified by column chromatography
(silica gel; mobile phase: dichloromethane/methanol gradient: 100/0
to 100/1). This gave 24 mg (15% of theory) of the target
compound.
[1047] LC-MS (Method 3): R.sub.t=2.42 min; MS (ESIpos): m/z=505
[M+H].sup.+
Example 64
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-7-{[(2S)-2-
-hydroxypropyl](methyl)amino}-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro--
1,8- naphthyridine-3-carboxamide
##STR00239##
[1049]
7-Chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-
-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(60.0 mg, 122 .mu.mol) was initially charged in 1.2 ml of DMF,
(2S)-1-(methylamino)propan-2-ol (21.7 mg, 243 .mu.mol) and
N,N-diisopropylethylamine (74 .mu.l, 430 .mu.mol) were added and
the mixture was stirred at room temperature for 2 h.
Acetonitrile/water was added and the reaction solution was purified
by preparative HPLC (RP18 column, mobile phase: acetonitrile/water
gradient with addition of 0.1% TFA). The product fractions were
combined and concentrated to dryness under reduced pressure. The
residue was taken up in dichloromethane and extracted twice with
saturated aqueous sodium bicarbonate solution. The combined aqueous
phases were re-extracted once with dichloromethane. The combined
organic phases were dried over sodium sulfate, filtered and
concentrated under reduced pressure. This gave 47 mg of the target
compound (70% of theory).
[1050] LC-MS (Method 3): R.sub.t=2.15 min; MS (ESIpos): m/z=547
[M+H].sup.+
[1051] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. [ppm]: -0.149
(0.68), -0.059 (5.17), -0.008 (4.04), 0.008 (3.41), 0.146 (0.41),
0.318 (1.61), 0.328 (2.49), 0.340 (2.44), 0.352 (1.95), 0.364
(0.96), 0.512 (1.71), 0.523 (2.54), 0.535 (2.29), 0.547 (2.57),
0.555 (1.96), 0.566 (2.64), 0.576 (2.19), 0.586 (1.99), 0.597
(1.62), 0.611 (1.01), 0.625 (1.41), 0.636 (1.41), 0.646 (2.39),
0.656 (2.07), 0.662 (2.01), 0.670 (2.00), 0.678 (1.03), 0.690
(0.76), 0.834 (7.90), 0.849 (7.89), 1.166 (0.69), 1.178 (1.23),
1.186 (1.66), 1.198 (2.72), 1.207 (1.98), 1.219 (2.71), 1.231
(1.99), 1.251 (0.59), 2.074 (0.65), 2.329 (0.46), 2.671 (0.42),
3.160 (4.79), 3.460 (2.29), 3.490 (1.88), 3.705 (1.53), 4.354
(1.31), 4.375 (2.27), 4.396 (2.20), 4.417 (1.17), 4.738 (5.75),
4.750 (5.64), 5.755 (2.37), 7.561 (3.16), 7.582 (5.63), 7.603
(3.10), 7.989 (8.41), 8.023 (8.17), 8.841 (16.00), 10.441 (5.22),
10.464 (5.04).
Example 65
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[ethyl(2-hydroxyp-
ropyl)amino]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naph-
thyridine-3-carboxamide (diastereomer mixture)
##STR00240##
[1053]
7-Chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-
-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(80.0 mg, 162 .mu.mol) was initially charged in 1.6 ml of
acetonitrile, 1-(ethylamino)propan-2-ol (33.4 mg, 324 .mu.mol;
racemate) and N,N-diisopropylethylamine (99 .mu.l, 570 .mu.mol)
were added and the mixture was stirred at room temperature for 2 h.
The reaction solution was then concentrated under reduced pressure.
The residue was taken up in ethyl acetate, and water was added. The
aqueous phase was acidified with 1 M hydrochloric acid and
extracted twice. The organic phase was extracted once with
saturated aqueous sodium bicarbonate solution and once with
saturated aqueous sodium chloride solution, dried over sodium
sulfate, filtered and concentrated under reduced pressure. This
gave 76 mg of the target compound (82% of theory).
[1054] LC-MS (Method 3): R.sub.t=2.23 min; MS (ESIpos): m/z=561
[M+H].sup.+
[1055] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. [ppm]: -0.149
(0.87), -0.008 (7.43), 0.008 (7.19), 0.146 (0.84), 0.329 (2.28),
0.342 (2.25), 0.514 (1.80), 0.525 (2.61), 0.549 (2.52), 0.568
(2.61), 0.577 (2.19), 0.588 (2.07), 0.626 (1.32), 0.647 (2.43),
0.851 (6.17), 1.013 (5.51), 1.157 (1.05), 1.175 (2.52), 1.185
(1.74), 1.197 (2.94), 1.206 (2.22), 1.217 (2.82), 1.238 (1.89),
1.988 (3.09), 2.328 (1.86), 2.367 (0.93), 2.670 (1.86), 2.711
(1.05), 3.061 (0.93), 3.418 (2.19), 3.455 (2.55), 3.575 (1.14),
3.710 (1.59), 4.021 (0.84), 4.039 (0.81), 4.350 (1.20), 4.370
(2.22), 4.391 (2.22), 4.412 (1.17), 4.736 (4.04), 4.748 (3.96),
7.566 (3.06), 7.588 (5.51), 7.607 (3.12), 7.996 (8.21), 8.031
(8.03), 8.843 (16.00), 10.439 (5.21), 10.463 (5.00).
Example 66
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[ethyl(2-hydroxyp-
ropyl)amino]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naph-
thyridine-3-carboxamide (diastereomer 1)
[1056] 69 mg of
N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-7-[ethyl(2-hydroxypropyl)amin-
o]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine--
3-carboxamide (diastereomer mixture) were separated into the
diastereomers by chiral HPLC (preparative HPLC: column Daicel.RTM.
Chiralpak AD-H, 5 .mu.m, 250.times.20 mm; mobile phase: 80%
n-heptane/20% isopropanol; flow rate 15 ml/min; temperature:
25.degree. C., detection: 210 nm).
[1057] Diastereomer 1: 30 mg (>99% de)
[1058] R.sub.t=1.37 min [analytical HPLC: column Daicel.RTM.
Chiralpak AD, 1 ml/min; 3 .mu.m, 50.times.4.6 mm; mobile phase: 80%
isohexane/20% isopropanol; detection: 220 nm].
[1059] LC-MS (Method 3): R.sub.t=2.25 min; MS (ESIpos): m/z=561
[M+H].sup.+
[1060] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. [ppm]: -0.008
(1.84), 0.008 (1.52), 0.321 (1.83), 0.331 (2.88), 0.343 (2.85),
0.355 (2.22), 0.367 (1.10), 0.503 (0.76), 0.515 (1.97), 0.526
(2.98), 0.539 (2.67), 0.550 (2.97), 0.557 (2.12), 0.568 (3.14),
0.578 (2.48), 0.589 (2.26), 0.599 (1.84), 0.613 (1.18), 0.627
(1.69), 0.637 (1.61), 0.648 (2.73), 0.659 (2.37), 0.664 (2.19),
0.670 (2.15), 0.680 (1.11), 0.684 (1.10), 0.692 (0.80), 0.852
(6.50), 0.863 (6.50), 1.012 (5.79), 1.165 (0.66), 1.177 (1.26),
1.185 (1.75), 1.198 (2.95), 1.206 (2.09), 1.218 (2.89), 1.230
(1.55), 1.238 (1.05), 1.250 (0.45), 2.328 (0.82), 2.333 (0.60),
2.367 (0.56), 2.519 (3.02), 2.524 (2.34), 2.666 (0.58), 2.670
(0.80), 2.675 (0.58), 2.710 (0.51), 3.075 (0.94), 3.419 (2.44),
3.454 (2.73), 3.578 (1.05), 3.708 (1.64), 4.347 (1.48), 4.368
(2.54), 4.389 (2.50), 4.410 (1.34), 4.735 (4.60), 4.747 (4.46),
7.566 (3.23), 7.587 (5.73), 7.606 (3.23), 7.996 (9.12), 8.031
(8.91), 8.843 (16.00), 10.440 (6.11), 10.463 (5.86).
Example 67
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[ethyl(2-hydroxyp-
ropyl)amino]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naph-
thyridine-3-carboxamide (diastereomer 2)
[1061] 69 mg of
N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-7-[ethyl(2-hydroxypropyl)amin-
o]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine--
3-carboxamide (diastereomer mixture) were separated into the
diastereomers by chiral HPLC (preparative HPLC: column Daicel.RTM.
Chiralpak AD-H, 5 .mu.m, 250.times.20 mm; mobile phase: 80%
n-heptane/20% isopropanol; flow rate 15 ml/min; temperature:
25.degree. C., detection: 210 nm).
[1062] Diastereomer 2: 30 mg (>99% de)
[1063] R.sub.t=2.31 min [analytical HPLC: column Daicel.RTM.
Chiralpak AD, 1 ml/min; 3 .mu.m, 50.times.4.6 mm; mobile phase: 80%
isohexane/20% isopropanol; detection: 220 nm].
[1064] LC-MS (Method 3): R.sub.t=2.25 min; MS (ESIpos): m/z=561
[M+H].sup.+
[1065] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. [ppm]: 0.318
(1.80), 0.328 (2.83), 0.340 (2.58), 0.514 (1.98), 0.525 (3.01),
0.537 (2.55), 0.548 (2.78), 0.567 (2.79), 0.576 (2.35), 0.588
(2.12), 0.626 (1.52), 0.647 (2.48), 0.657 (2.17), 0.851 (6.26),
1.013 (5.57), 1.177 (1.33), 1.185 (1.71), 1.198 (2.72), 1.218
(2.67), 1.230 (1.43), 2.328 (1.15), 2.671 (1.04), 3.063 (1.04),
3.420 (2.39), 3.453 (2.67), 3.585 (1.11), 3.711 (1.63), 4.350
(1.49), 4.371 (2.39), 4.393 (2.19), 4.413 (1.31), 4.737 (4.38),
4.749 (4.05), 7.567 (3.32), 7.588 (5.50), 7.607 (2.95), 7.997
(7.99), 8.032 (7.81), 8.844 (16.00), 10.440 (5.11), 10.463
(5.00).
Example 68
1-(2-Chloro-4,6-difluorophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-tri-
fluoroethyl]-6-fluoro-7-(2-oxa-6-azaspiro[3.3]hept-6-yl)-4-oxo-1,4-dihydro-
-1,8-naphthyridine-3-carboxamide trifluoroacetate (atropisomer
mixture)
##STR00241##
[1067]
7-Chloro-1-(2-chloro-4,6-difluorophenyl)-N-[(1S)-1-cyclopropyl-2,2,-
2-trifluoroethyl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxami-
de (atropisomer mixture, purity 57%, 90.0 mg, 176 .mu.mol) was
initially charged in 1.7 ml of DMF, ethanedioic acid
2-oxa-6-azaspiro[3.3]heptane (1:1) (46.7 mg, 247 .mu.mol) and
N,N-diisopropylethylamine (150 .mu.l, 880 .mu.mol) were added and
the mixture was stirred at room temperature overnight.
Acetonitrile/water was added and the reaction solution was purified
by preparative HPLC (RP18 column, mobile phase: acetonitrile/water
gradient with addition of 0.1% TFA). (Fraction 1). The product
fractions were combined and concentrated to dryness under reduced
pressure. The residue was taken up in dichloromethane and extracted
twice with saturated aqueous sodium bicarbonate solution. The
combined aqueous phases were re-extracted once with
dichloromethane. The combined organic phases were dried over sodium
sulfate, filtered and concentrated under reduced pressure. This
gave 74 mg of the target compound (60% of theory, purity 98%).
[1068] LC-MS (Method 3): R.sub.t=2.28 min; MS (ESIpos): m/z=573
[M-TFA+H].sup.+
[1069] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. [ppm]: 0.006
(0.44), 0.313 (0.41), 0.322 (0.73), 0.331 (0.87), 0.341 (0.77),
0.350 (0.49), 0.524 (0.72), 0.536 (0.69), 0.544 (0.68), 0.552
(0.50), 0.561 (0.59), 0.571 (0.77), 0.580 (0.71), 0.587 (0.60),
0.597 (0.45), 0.635 (0.46), 0.644 (0.64), 0.652 (0.79), 0.663
(0.77), 0.672 (0.54), 1.188 (0.50), 1.197 (0.83), 1.205 (0.69),
1.213 (0.78), 1.222 (0.48), 2.073 (6.12), 2.519 (0.49), 4.339
(0.49), 4.355 (0.83), 4.372 (0.98), 4.388 (0.77), 4.649 (16.00),
7.680 (0.58), 7.686 (0.77), 7.699 (1.02), 7.704 (1.35), 7.718
(0.63), 7.724 (1.34), 7.745 (1.11), 7.999 (2.73), 8.022 (2.68),
8.777 (6.49), 10.453 (1.61), 10.471 (1.53).
Example 69
7-[3,3-Bis(hydroxymethyl)azetidin-1-yl]-1-(2-chloro-4,6-difluor-
ophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-1,4-di-
hydro-1,8-naphthyridine-3-carboxamide (atropisomer mixture)
##STR00242##
[1071]
1-(2-Chloro-4,6-difluorophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-trifluo-
roethyl]-6-fluoro-7-(2-oxa-6-azaspiro[3.3]hept-6-yl)-4-oxo-1,4-dihydro-1,8-
-naphthyridine-3-carboxamide trifluoroacetate (atropisomer mixture,
70.0 mg, 102 .mu.mol) was initially charged in trifluoroacetic acid
(640 .mu.l, 8.3 mmol), 640 .mu.l of water and 0.2 ml of
acetonitrile were added and the mixture was stirred at room
temperature for 4 days. The reaction solution was purified by
preparative HPLC (RP18 column, mobile phase: acetonitrile/water
gradient with addition of 0.1% TFA). The product fractions were
concentrated under reduced pressure and the residue was taken up in
dichloromethane and washed twice with saturated aqueous sodium
bicarbonate solution. The combined aqueous phases were re-extracted
once with dichloromethane. The combined organic phases were dried
over sodium sulfate, filtered and concentrated under reduced
pressure. This gave 60 mg of the target compound (98% of theory,
purity 98%).
[1072] LC-MS (Method 3): R.sub.t=1.91 min; MS (ESIpos): m/z=591
[M+H].sup.+
[1073] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. [ppm]: -0.149
(0.88), -0.008 (7.82), 0.008 (6.52), 0.146 (0.86), 0.312 (0.99),
0.323 (1.77), 0.334 (2.13), 0.346 (1.93), 0.358 (1.22), 0.523
(1.69), 0.538 (1.80), 0.561 (1.93), 0.572 (2.02), 0.583 (1.74),
0.593 (1.49), 0.606 (1.08), 0.621 (0.83), 0.631 (1.13), 0.641
(1.55), 0.652 (1.82), 0.667 (1.60), 0.675 (1.19), 0.687 (0.69),
1.162 (0.44), 1.175 (0.80), 1.183 (1.16), 1.195 (1.99), 1.205
(1.55), 1.215 (1.96), 1.227 (1.22), 1.235 (1.13), 2.073 (0.77),
2.328 (1.16), 2.366 (0.80), 2.523 (4.37), 2.670 (1.30), 2.710
(0.94), 3.465 (15.72), 3.479 (16.00), 4.118 (0.91), 4.333 (0.66),
4.353 (1.33), 4.373 (1.77), 4.392 (1.35), 4.411 (0.64), 4.831
(5.11), 4.844 (12.10), 4.858 (5.06), 7.667 (1.27), 7.673 (1.82),
7.690 (2.10), 7.697 (3.45), 7.713 (3.43), 7.720 (3.87), 7.731
(2.57), 7.742 (1.71), 7.967 (6.38), 7.996 (6.33), 8.758 (14.51),
10.481 (4.03), 10.505 (3.90).
Example 70
7-[3,3-Bis(hydroxymethyl)azetidin-1-yl]-1-(2-chloro-4,6-difluor-
ophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-1,4-di-
hydro-1,8-naphthyridine-3-carboxamide (atropisomer 1)
[1074] 55 mg of
7-[3,3-bis(hydroxymethyl)azetidin-1-yl]-1-(2-chloro-4,6-difluorophenyl)-N-
-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-1,4-dihydro-1,8--
naphthyridine-3-carboxamide (atropisomer mixture) were separated
into the atropisomers by chiral HPLC (preparative HPLC: column
Daicel.RTM. Chiralpak OX-H, 5 .mu.m, 250.times.20 mm; mobile phase:
80% n-heptane/20% ethanol+0.2% diethylamine; flow rate 20 ml/min;
temperature: 23.degree. C., detection: 220 nm). The product
fractions were concentrated at 30.degree. C.
[1075] Atropisomer 1: 22 mg (>99% stereochemically pure)
[1076] R.sub.t=4.16 min [analytical HPLC: column Daicel.RTM.
Chiralpak OX, 1 ml/min; 3 .mu.m, 50.times.4.6 mm; mobile phase: 90%
n-hexane/20% ethanol+0.2% diethylamine; detection: 220 nm].
[1077] LC-MS (Method 3): R.sub.t=1.90 min; MS (ESIpos): m/z=591
[M+H].sup.+
[1078] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. [ppm]: -0.149
(0.82), -0.008 (7.57), 0.008 (6.50), 0.146 (0.85), 0.312 (1.26),
0.322 (2.17), 0.335 (2.11), 0.346 (1.65), 0.358 (0.85), 0.508
(1.45), 0.519 (2.22), 0.531 (1.98), 0.543 (2.14), 0.561 (2.22),
0.571 (1.81), 0.582 (1.59), 0.593 (1.32), 0.606 (0.80), 0.621
(1.15), 0.631 (1.15), 0.642 (1.95), 0.652 (1.73), 0.664 (1.54),
1.099 (0.82), 1.118 (1.51), 1.135 (0.71), 1.182 (1.26), 1.194
(2.14), 1.202 (1.56), 1.214 (2.14), 1.226 (1.21), 1.234 (1.13),
2.327 (1.56), 2.366 (0.91), 2.523 (4.89), 2.670 (1.54), 2.710
(0.91), 2.820 (0.41), 3.465 (15.78), 3.479 (16.00), 4.131 (0.93),
4.348 (1.13), 4.370 (1.92), 4.392 (1.84), 4.411 (0.99), 4.831
(5.19), 4.844 (12.24), 4.857 (5.10), 7.666 (1.29), 7.673 (1.92),
7.690 (2.17), 7.697 (3.49), 7.713 (3.60), 7.720 (3.95), 7.731
(2.66), 7.967 (7.27), 7.996 (7.03), 8.758 (15.86), 10.482 (4.56),
10.506 (4.42).
Example 71
7-[3,3-Bis(hydroxymethyl)azetidin-1-yl]-1-(2-chloro-4,6-difluor-
ophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-1,4-di-
hydro-1,8-naphthyridine-3-carboxamide (atropisomer 2)
[1079] 55 mg of
7-[3,3-bis(hydroxymethyl)azetidin-1-yl]-1-(2-chloro-4,6-difluorophenyl)-N-
-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-1,4-dihydro-1,8--
naphthyridine-3-carboxamide (atropisomer mixture) were separated
into the atropisomers by chiral HPLC (preparative HPLC: column
Daicel.RTM. Chiralpak OX-H, 5 .mu.m, 250.times.20 mm; mobile phase:
80% n-heptane/20% ethanol+0.2% diethylamine; flow rate 20 ml/min;
temperature: 23.degree. C., detection: 220 nm). The product
fractions were concentrated at 30.degree. C.
[1080] Atropisomer 2: 22 mg (>98.5% stereochemically pure)
[1081] R.sub.t=6.25 min [analytical HPLC: column Daicel.RTM.
Chiralpak OX, 1 ml/min; 3 .mu.m, 50.times.4.6 mm; mobile phase: 90%
n-hexane/20% ethanol+0.2% diethylamine; detection: 220 nm].
[1082] LC-MS (Method 3): R.sub.t=1.90 min; MS (ESIpos): m/z=591
[M+H].sup.+
[1083] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. [ppm]: -0.149
(0.93), -0.008 (8.98), 0.008 (6.74), 0.146 (0.86), 0.323 (1.38),
0.333 (2.14), 0.346 (2.11), 0.359 (1.59), 0.370 (0.79), 0.513
(1.52), 0.525 (2.14), 0.538 (1.90), 0.552 (1.76), 0.560 (1.66),
0.572 (2.11), 0.582 (1.80), 0.593 (1.66), 0.604 (1.35), 0.616
(0.90), 0.630 (1.00), 0.640 (1.17), 0.651 (1.83), 0.661 (1.73),
0.675 (1.62), 0.696 (0.55), 1.101 (1.42), 1.119 (2.80), 1.137
(1.35), 1.175 (0.90), 1.183 (1.31), 1.196 (2.18), 1.205 (1.56),
1.216 (2.11), 1.228 (1.24), 2.323 (1.42), 2.327 (1.83), 2.366
(1.52), 2.523 (5.46), 2.670 (1.73), 2.710 (1.35), 2.825 (0.59),
2.843 (0.59), 3.465 (15.86), 3.479 (16.00), 4.127 (0.90), 4.333
(1.14), 4.354 (1.90), 4.374 (1.87), 4.395 (1.00), 4.830 (5.36),
4.844 (12.75), 4.857 (5.22), 7.667 (1.24), 7.673 (1.90), 7.690
(2.14), 7.697 (3.46), 7.713 (3.52), 7.720 (3.84), 7.732 (2.63),
7.967 (7.02), 7.995 (6.88), 8.758 (15.14), 10.480 (4.53), 10.503
(4.32).
Example 72
1-(2-Chloro-4,6-difluorophenyl)-N-[(1S)-1-cyclopropyl-2,2,2-tri-
fluoroethyl]-6-fluoro-7-{[(2S)-2-hydroxypropyl](methyl)amino}-4-oxo-1,4-di-
hydro-1,8-naphthyridine-3-carboxamide (atropisomer mixture)
##STR00243##
[1085]
7-Chloro-1-(2-chloro-4,6-difluorophenyl)-N-[(1S)-1-cyclopropyl-2,2,-
2-trifluoroethyl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxami-
de (atropisomer mixture, purity 57%, 90.0 mg, 176 .mu.mol) was
initially charged in 1.8 ml of DMF, (2S)-1-(methylamino)propan-2-ol
(31.4 mg, 353 .mu.mol) and N,N-diisopropylethylamine (110 .mu.l,
620 .mu.mol) were added and the mixture was stirred at room
temperature overnight. The reaction solution was added to water and
the resulting solid was stirred for about 30 min and then filtered
off, washed with water and dried under high vacuum. The residue was
purified by thick-layer chromatography (mobile phase:
cyclohexane/ethyl acetate=2/1). This gave 31 mg of the target
compound (31% of theory, purity 98%).
[1086] LC-MS (Method 3): R.sub.t=2.20 min; MS (ESIpos): m/z=563
[M+H].sup.+
[1087] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. [ppm]: -0.149
(0.69), -0.008 (7.05), 0.008 (5.36), 0.146 (0.72), 0.314 (1.84),
0.325 (3.49), 0.336 (4.05), 0.348 (3.84), 0.360 (2.56), 0.525
(3.62), 0.545 (3.56), 0.552 (3.49), 0.563 (3.49), 0.573 (4.02),
0.584 (3.59), 0.593 (3.12), 0.607 (2.03), 0.623 (1.53), 0.632
(2.09), 0.642 (2.90), 0.653 (3.59), 0.667 (3.34), 0.676 (2.68),
0.807 (11.54), 0.822 (7.64), 1.165 (0.78), 1.178 (1.59), 1.185
(2.34), 1.198 (4.02), 1.207 (2.99), 1.218 (3.84), 1.230 (2.12),
1.238 (1.43), 1.250 (0.65), 2.073 (0.53), 2.328 (1.72), 2.366
(1.03), 2.524 (4.96), 2.670 (1.81), 2.710 (1.06), 3.011 (1.40),
3.175 (6.49), 3.422 (2.50), 3.447 (2.50), 3.470 (1.72), 3.681
(2.50), 4.339 (1.31), 4.359 (2.68), 4.378 (3.27), 4.397 (2.46),
4.418 (1.09), 4.723 (5.02), 4.730 (6.80), 4.735 (5.99), 4.743
(5.68), 7.690 (1.28), 7.697 (2.00), 7.708 (2.56), 7.713 (2.50),
7.721 (4.05), 7.736 (6.83), 7.743 (5.74), 7.757 (6.11), 7.995
(13.35), 8.029 (13.13), 8.791 (14.07), 8.795 (16.00), 10.460
(7.42), 10.484 (7.14).
Example 73
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrroli-
din-1-yl]-6-fluoro-N-(2-methylbutan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyrid-
ine-3-carboxamide (atropisomer mixture)
##STR00244##
[1089]
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin--
1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic
acid (80.0 mg, 176 .mu.mol) was initially charged in 1.2 ml of DMF,
HATU (80.1 mg, 211 .mu.mol) and N,N-diisopropylethylamine (110
.mu.l, 610 .mu.mol) were added and the mixture was stirred at room
temperature for 30 min. 2-Methylbutan-2-amine (18.4 mg, 211
.mu.mol) was added and the mixture was stirred at room temperature
overnight. Acetonitrile/water/TFA was added and the reaction
solution was purified by preparative HPLC (RP18 column, mobile
phase: acetonitrile/water gradient with addition of 0.1% TFA). The
product fractions were very substantially concentrated under
reduced pressure and the residue was extracted twice with
dichloromethane. The combined organic phases were washed twice with
saturated aqueous sodium bicarbonate solution. The combined aqueous
phases were re-extracted with dichloromethane. The combined organic
phases were dried over sodium sulfate, filtered and concentrated
under reduced pressure. This gave 58 mg of the target compound (62%
of theory, purity 99%).
[1090] LC-MS (Method 3): R.sub.t=1.82 min; MS (ESIpos): m/z=525
[M+H].sup.+
Example 74
N-tert-Butyl-1-(2-chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dih-
ydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carb-
oxamide (atropisomer mixture)
##STR00245##
[1092]
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin--
1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic
acid (100 mg, 219 .mu.mol) was initially charged in 3.1 ml of DMF,
HATU (100 mg, 263 .mu.mol) and N,N-diisopropylethylamine (130
.mu.l, 770 .mu.mol) were added and the mixture was stirred at room
temperature for 30 min. 2-Methylpropan-2-amine (19.3 mg, 263
.mu.mol) was added and the mixture was stirred at room temperature
overnight. Acetonitrile/water/TFA was added and the reaction
solution was purified by preparative HPLC (RP18 column, mobile
phase: acetonitrile/water gradient with addition of 0.1% TFA). The
product fractions were very substantially concentrated under
reduced pressure and the residue was extracted twice with
dichloromethane. The combined organic phases were washed twice with
saturated aqueous sodium bicarbonate solution. The combined aqueous
phases were re-extracted with dichloromethane. The combined organic
phases were dried over sodium sulfate, filtered and concentrated
under reduced pressure. This gave 86 mg of the target compound (76%
of theory, purity 99%).
[1093] LC-MS (Method 3): R.sub.t=1.71 min; MS (ESIpos): m/z=511
[M+H].sup.+
Example 75
1-(3,5-Difluoropyridin-2-yl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-
-1-yl]-6-fluoro-N-(2-methylbutan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-
-3-carboxamide
##STR00246##
[1095]
1-(3,5-Difluoropyridin-2-yl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-y-
l]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(57.0 mg, 135 .mu.mol) was initially charged in 1.4 ml of DMF, HATU
(61.6 mg, 162 .mu.mol) and N,N-diisopropylethylamine (94 .mu.l, 540
.mu.mol) were added and the mixture was stirred at room temperature
for 10 min. 2-Methylbutan-2-amine (24 .mu.l, 200 .mu.mol) was added
and the reaction mixture was stirred at room temperature for 2 h.
Acetonitrile/water/TFA were added and the reaction solution was
purified by preparative HPLC (RP18 column, mobile phase:
acetonitrile/water gradient with addition of 0.1% TFA). The product
fractions were substantially concentrated under reduced pressure
and the residue was made basic with saturated aqueous sodium
bicarbonate solution and extracted twice with dichloromethane. The
combined organic phases were dried over sodium sulfate, filtered
and concentrated under reduced pressure. This gave 55 mg of the
target compound (82% of theory, purity 98%).
[1096] LC-MS (Method 3): R.sub.t=1.63 min; MS (ESIpos): m/z=492
[M+H].sup.+
Example 76
1-(3,5-Difluoropyridin-2-yl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-
-1-yl]-6-fluoro-N-(3-methylpentan-3-yl)-4-oxo-1,4-dihydro-1,8-naphthyridin-
e-3-carboxamide
##STR00247##
[1098]
1-(3,5-Difluoropyridin-2-yl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-y-
l]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(57.0 mg, 135 .mu.mol) was initially charged in 1.4 ml of DMF, HATU
(61.6 mg, 162 .mu.mol) and N,N-diisopropylethylamine (140 .mu.l,
810 .mu.mol) were added and the mixture was stirred at room
temperature for 10 min. 3-Methylpentan-3-amine hydrochloride (27.9
mg, 202 .mu.mol) was added and the reaction mixture was stirred at
room temperature for 2 h. Acetonitrile/water/TFA was added and the
reaction solution was purified by preparative HPLC (RP18 column,
mobile phase: acetonitrile/water gradient with addition of 0.1%
TFA). The product fractions were substantially concentrated under
reduced pressure and the residue was made basic with saturated
aqueous sodium bicarbonate solution and extracted twice with
dichloromethane. The combined organic phases were dried over sodium
sulfate, filtered and concentrated under reduced pressure. This
gave 51 mg of the target compound (74% of theory, purity 98%).
[1099] LC-MS (Method 3): R.sub.t=1.74 min; MS (ESIpos): m/z=506
[M+H].sup.+
Example 77
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-N-(3-ethylpentan-3-yl)-
-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3--
carboxamide
##STR00248##
[1101]
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-tr-
ifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(75.0 mg, 81% pure, 138 .mu.mol) was initially charged in 1.9 ml of
DMF, 3-ethylpentan-3-amine (19.1 mg, 166 .mu.mol),
N,N-diisopropylethylamine (84 .mu.l, 480 .mu.mol) and HATU (63.1
mg, 166 .mu.mol) were added and the mixture was stirred at room
temperature for 4 h. Acetonitrile/water/TFA was added and the
reaction solution was purified by preparative HPLC (RP18 column,
mobile phase: acetonitrile/water gradient with addition of 0.1%
TFA). The product fractions were substantially concentrated under
reduced pressure and the aqueous residue was made basic with
saturated aqueous sodium bicarbonate solution and extracted twice
with dichloromethane. The combined organic phases were dried over
sodium sulfate, filtered and concentrated under reduced pressure.
This gave 59 mg of the target compound (78% of theory, purity
98%).
[1102] LC-MS (Method 5): R.sub.t=1.41 min; MS (ESIpos): m/z=537
[M+H].sup.+
[1103] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. [ppm]: -0.008
(1.80), 0.008 (1.47), 0.768 (6.83), 0.786 (16.00), 0.805 (7.41),
1.699 (1.98), 1.718 (6.06), 1.736 (5.80), 1.755 (1.82), 2.328
(0.52), 2.366 (0.40), 2.670 (0.59), 4.030 (0.92), 4.991 (0.91),
7.545 (1.37), 7.567 (2.66), 7.589 (1.38), 7.979 (2.75), 8.011
(2.73), 8.667 (4.92), 9.612 (2.83).
Example 78
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-(3-methylpe-
ntan-3-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-
-carboxamide
##STR00249##
[1105]
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-tr-
ifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(75.0 mg, 81% pure, 138 .mu.mol) was initially charged in 1.9 ml of
DMF, 3-methylpentan-3-amine hydrochloride (22.8 mg, 166 .mu.mol),
N,N-diisopropylethylamine (84 .mu.l, 480 .mu.mol) and HATU (63.1
mg, 166 .mu.mol) were added and the mixture was stirred at room
temperature for 4 h. Acetonitrile/water/TFA was added and the
reaction solution was purified by preparative HPLC (RP18 column,
mobile phase: acetonitrile/water gradient with addition of 0.1%
TFA). The product fractions were substantially concentrated under
reduced pressure and the aqueous residue was made basic with
saturated aqueous sodium bicarbonate solution and extracted twice
with dichloromethane. The combined organic phases were dried over
sodium sulfate, filtered and concentrated under reduced pressure.
This gave 63 mg of the target compound (85% of theory, purity
98%).
[1106] LC-MS (Method 5): R.sub.t=1.35 min; MS (ESIpos): m/z=523
[M+H].sup.+
[1107] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. [ppm]: -0.008
(1.46), 0.008 (1.29), 0.814 (6.64), 0.833 (15.52), 0.851 (7.27),
1.234 (0.50), 1.279 (16.00), 1.613 (0.42), 1.631 (1.48), 1.649
(1.89), 1.665 (2.44), 1.684 (1.96), 1.703 (0.49), 1.769 (0.57),
1.787 (2.03), 1.806 (2.32), 1.822 (1.86), 1.841 (1.35), 2.073
(8.37), 2.328 (0.49), 2.523 (1.67), 2.670 (0.52), 4.031 (1.20),
4.989 (1.19), 7.546 (1.83), 7.568 (3.46), 7.590 (1.84), 7.977
(3.61), 8.008 (3.53), 8.669 (6.19), 9.728 (3.98).
Example 79
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-(2-methylbu-
tan-2-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3--
carboxamide
##STR00250##
[1109]
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-tr-
ifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(75.0 mg, 81% pure, 138 .mu.mol) was initially charged in 1.9 ml of
DMF, 2-methylbutan-2-amine (19 .mu.l, 170 .mu.mol),
N,N-diisopropylethylamine (84 .mu.l, 480 .mu.mol) and HATU (63.1
mg, 166 .mu.mol) were added and the mixture was stirred at room
temperature for 4 h. Acetonitrile/water/TFA was added and the
reaction solution was purified by preparative HPLC (RP18 column,
mobile phase: acetonitrile/water gradient with addition of 0.1%
TFA). The product fractions were substantially concentrated under
reduced pressure and the aqueous residue was made basic with
saturated aqueous sodium bicarbonate solution and extracted twice
with dichloromethane. The combined organic phases were dried over
sodium sulfate, filtered and concentrated under reduced pressure.
This gave 63 mg of the target compound (88% of theory, purity
98%).
[1110] LC-MS (Method 5): R.sub.t=1.29 min; MS (ESIpos): m/z=509
[M+H].sup.+
[1111] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. [ppm]: -0.008
(0.76), 0.008 (0.52), 0.848 (1.75), 0.867 (4.17), 0.885 (1.87),
1.341 (16.00), 1.703 (0.53), 1.722 (1.62), 1.740 (1.54), 1.759
(0.45), 2.073 (3.41), 2.518 (0.96), 2.523 (0.79), 4.032 (0.61),
4.989 (0.60), 5.754 (0.54), 7.547 (0.88), 7.569 (1.67), 7.591
(0.89), 7.970 (1.66), 8.001 (1.63), 8.673 (2.83), 9.810 (2.01).
Example 80
N-tert-Butyl-7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro--
4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamid-
e
##STR00251##
[1113]
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-tr-
ifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(75.0 mg, 81% pure, 138 .mu.mol) was initially charged in 1.9 ml of
DMF, 2-methylpropan-2-amine (17 .mu.l, 170 .mu.mol),
N,N-diisopropylethylamine (84 .mu.l, 480 .mu.mol) and HATU (63.1
mg, 166 .mu.mol) were added and the mixture was stirred at room
temperature over the weekend. Acetonitrile/water/TFA was added and
the reaction solution was purified by preparative HPLC (RP18
column, mobile phase: acetonitrile/water gradient with addition of
0.1% TFA). The product fractions were concentrated under reduced
pressure and the residue was dissolved in dichloromethane/a little
methanol. The organic phase was washed twice with saturated aqueous
sodium bicarbonate solution. The combined aqueous phases were
re-extracted once with dichloromethane. The combined organic phases
were dried over sodium sulfate, filtered and concentrated under
reduced pressure. This gave 42 mg of the target compound (60% of
theory, purity 98%).
[1114] LC-MS (Method 3): R.sub.t=1.72 min; MS (ESIpos): m/z=495
[M+H].sup.+
[1115] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. [ppm]: 0.008
(1.47), 1.388 (16.00), 2.073 (1.33), 4.028 (0.44), 4.989 (0.44),
7.547 (0.61), 7.569 (1.21), 7.591 (0.63), 7.957 (1.13), 7.989
(1.12), 8.679 (2.13), 9.865 (1.33).
Example 81
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-7-(p-
iperazin-1-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-c-
arboxamide
##STR00252##
[1117] tert-Butyl
4-[6-{[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-3-fluoro-5-oxo--
8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]piperazine-1-c-
arboxylate (113 mg, 69% pure, 121 .mu.mol) was initially charged in
0.72 ml of dichloromethane, trifluoroacetic acid (360 .mu.l, 4.7
mmol) was added and the mixture was stirred at room temperature for
1 h. The reaction solution was concentrated under reduced pressure,
acetonitrile/water/TFA was added and the product was purified by
preparative HPLC (RP18 column, mobile phase: methanol/water
gradient with addition of 0.1% TFA). The product fractions were
substantially concentrated. The residue was taken up in ethyl
acetate and the aqueous phase was made basic using saturated
aqueous sodium bicarbonate solution. The aqueous phase was
extracted three times with ethyl acetate. The combined organic
phases were dried over sodium sulfate, filtered and concentrated
under reduced pressure. The crude product was purified further by
thick-layer chromatography (mobile phase: dichloromethane/2M
ammonia in methanol=20/1). This gave 43 mg of the target compound
(65% of theory, purity 99%).
[1118] LC-MS (Method 3): R.sub.t=1.36 min; MS (ESIpos): m/z=544
[M+H].sup.+
[1119] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. [ppm]: -0.149
(0.64), -0.008 (6.43), 0.008 (5.61), 0.146 (0.68), 0.319 (2.04),
0.329 (3.29), 0.342 (3.21), 0.353 (2.50), 0.365 (1.25), 0.504
(0.82), 0.516 (2.18), 0.528 (3.29), 0.541 (3.07), 0.550 (3.43),
0.568 (3.57), 0.578 (2.79), 0.589 (2.54), 0.599 (2.07), 0.613
(1.29), 0.628 (1.86), 0.638 (1.71), 0.648 (3.14), 0.659 (2.61),
0.665 (2.43), 0.671 (2.39), 0.680 (1.18), 0.693 (0.79), 1.170
(0.64), 1.182 (1.32), 1.190 (1.89), 1.202 (3.18), 1.211 (2.32),
1.223 (3.18), 1.235 (2.07), 1.243 (1.29), 1.256 (0.57), 2.073
(0.96), 2.328 (1.21), 2.367 (1.04), 2.524 (4.82), 2.663 (12.39),
2.675 (16.00), 2.687 (12.50), 2.710 (1.39), 3.440 (12.39), 3.452
(15.11), 3.464 (11.71), 4.333 (0.43), 4.353 (1.64), 4.374 (2.89),
4.395 (2.86), 4.415 (1.54), 5.754 (0.43), 7.555 (5.61), 7.577
(10.82), 7.599 (5.71), 8.060 (9.39), 8.094 (9.29), 8.876 (15.57),
10.387 (6.43), 10.411 (6.29).
Example 82
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-7-[(3S)-3--
methylpiperazin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naph-
thyridine-3-carboxamide
##STR00253##
[1121] tert-Butyl
(2S)-4-[6-{[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-3-fluoro-5-
-oxo-8-(2,4,6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]-2-methyl-
piperazine-1-carboxylate (81.5 mg, 90% pure, 112 .mu.mol) was
initially charged in 0.66 ml of dichloromethane, trifluoroacetic
acid (330 .mu.l, 4.3 mmol) was added and the mixture was stirred at
room temperature for 1 h. The reaction solution was diluted with
dichloromethane and washed three times with saturated aqueous
sodium chloride solution. The combined aqueous phases were
re-extracted with dichloromethane. The combined organic phases were
dried over sodium sulfate, filtered and concentrated under reduced
pressure. Acetonitrile/water/TFA was added and the reaction
solution was purified by preparative HPLC (RP18 column, mobile
phase: acetonitrile/water gradient with addition of 0.1% TFA). The
product fractions were substantially concentrated. The residue was
taken up in ethyl acetate and the aqueous phase was made basic
using saturated aqueous sodium bicarbonate solution. The aqueous
phase was extracted three times with ethyl acetate. The combined
organic phases were dried over sodium sulfate, filtered and
concentrated under reduced pressure. The crude product was purified
further by thick-layer chromatography (mobile phase:
dichloromethane/2 N ammonia solution in methanol=20/1). This gave
26.3 mg of the target compound (40% of theory, purity 95%).
[1122] LC-MS (Method 3): R.sub.t=1.40 min; MS (ESIpos): m/z=558
[M+H].sup.+
[1123] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. [ppm]: -0.149
(0.92), -0.008 (8.28), 0.008 (6.83), 0.146 (0.92), 0.320 (1.78),
0.330 (2.85), 0.342 (2.76), 0.354 (2.17), 0.365 (1.07), 0.516
(1.90), 0.527 (2.85), 0.540 (2.64), 0.549 (2.97), 0.568 (3.09),
0.578 (2.40), 0.588 (2.20), 0.599 (1.81), 0.613 (1.10), 0.628
(1.60), 0.638 (1.54), 0.648 (2.73), 0.659 (2.29), 0.664 (2.11),
0.670 (2.11), 0.680 (1.10), 0.693 (0.80), 0.837 (15.47), 0.852
(16.00), 0.919 (0.53), 1.169 (0.62), 1.182 (1.22), 1.190 (1.75),
1.202 (2.82), 1.210 (2.08), 1.222 (2.82), 1.234 (1.99), 1.242
(1.16), 1.255 (0.53), 2.119 (0.42), 2.302 (2.94), 2.323 (1.22),
2.328 (1.34), 2.366 (0.74), 2.524 (4.36), 2.573 (3.06), 2.605
(1.51), 2.666 (0.95), 2.670 (1.28), 2.675 (0.92), 2.711 (0.74),
2.805 (2.64), 2.834 (2.05), 2.965 (1.40), 2.972 (1.57), 2.998
(2.52), 3.027 (1.57), 3.869 (3.06), 3.896 (3.06), 3.972 (2.43),
4.004 (2.29), 4.355 (1.45), 4.375 (2.52), 4.397 (2.49), 4.417
(1.37), 7.577 (4.93), 7.599 (9.26), 7.622 (4.96), 7.630 (1.75),
8.053 (8.55), 8.088 (8.37), 8.890 (14.58), 8.913 (0.50), 10.390
(5.67), 10.414 (5.34).
Example 83
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-7-(2-oxa-6-
-azaspiro[3.3]hept-6-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxamide
##STR00254##
[1125]
7-Chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-
-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(1.20 g, 2.43 mmol) was initially charged in 23 ml of DMF,
ethanedioic acid 2-oxa-6-azaspiro[3.3]heptane (1:1) (644 mg, 3.40
mmol) and N,N-diisopropylethylamine (2.1 ml, 12 mmol) were added
and the mixture was stirred at room temperature overnight. Water
was added to the reaction solution and the resulting precipitated
solid was filtered off and dried under high vacuum. The crude
product was purified by silica gel chromatography (mobile phase:
100% dichloromethane to dichloromethane/methanol=100/1). This gave
1.0 g of the target compound (73% of theory, purity 99%).
[1126] LC-MS (Method 3): R.sub.t=2.20 min; MS (ESIpos): m/z=557
[M+H].sup.+
Example 84
7-[3,3-Bis(hydroxymethyl)azetidin-1-yl]-N-[(1S)-1-cyclopropyl-2-
,2,2-trifluoroethyl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro--
1,8-naphthyridine-3-carboxamide
##STR00255##
[1128]
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-7-(2-oxa-6-aza-
spiro[3.3]hept-6-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-napht-
hyridine-3-carboxamide (65.0 mg, 117 .mu.mol) was initially charged
in trifluoroacetic acid (730 .mu.l, 9.5 mmol), 730 .mu.l of water
and 730 .mu.l of acetonitrile were added and the mixture was
stirred at room temperature for two days. The reaction solution was
purified by preparative HPLC (RP18 column, mobile phase:
acetonitrile/water gradient with addition of 0.1% TFA). The product
fractions were concentrated under reduced pressure and the residue
was taken up in dichloromethane and washed twice with saturated
aqueous sodium bicarbonate solution. The combined aqueous phases
were re-extracted with dichloromethane. The combined organic phases
were dried over sodium sulfate, filtered and concentrated under
reduced pressure. This gave 45 mg of the target compound (66% of
theory, purity 99%).
[1129] LC-MS (Method 3): R.sub.t=1.86 min; MS (ESIpos): m/z=575
[M+H].sup.+
[1130] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. [ppm]: -0.149
(0.42), -0.008 (3.70), 0.008 (3.30), 0.146 (0.41), 0.316 (1.31),
0.326 (2.15), 0.338 (2.07), 0.350 (1.69), 0.362 (0.80), 0.510
(1.45), 0.521 (2.09), 0.534 (1.89), 0.545 (2.18), 0.553 (1.61),
0.564 (2.23), 0.575 (1.72), 0.585 (1.64), 0.595 (1.33), 0.609
(0.83), 0.624 (1.13), 0.634 (1.13), 0.645 (1.97), 0.655 (1.70),
0.668 (1.59), 1.163 (0.46), 1.175 (0.92), 1.183 (1.27), 1.195
(2.15), 1.204 (1.50), 1.215 (2.10), 1.228 (1.24), 1.236 (1.21),
2.074 (10.78), 2.328 (0.75), 2.366 (0.47), 2.670 (0.66), 2.710
(0.41), 3.475 (15.83), 3.488 (16.00), 4.130 (0.94), 4.349 (1.22),
4.369 (1.91), 4.390 (1.84), 4.410 (0.97), 4.835 (5.32), 4.848
(12.45), 4.861 (5.07), 5.754 (4.77), 7.532 (3.99), 7.554 (7.54),
7.576 (3.92), 7.963 (6.93), 7.992 (6.79), 8.808 (12.92), 10.463
(4.45), 10.487 (4.20).
Example 85 tert-Butyl
4-[({7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-tri-
fluorophenyl)-1,4-dihydro-1,8-naphthyridin-3-yl}carbonyl)amino]-3,3-difluo-
ropiperidine-1-carboxylate
##STR00256##
[1132]
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-tr-
ifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(50.0 mg, 73% pure, 83.1 .mu.mol) was initially charged in 1.2 ml
of DMF, HATU (37.9 mg, 99.7 .mu.mol) and N,N-diisopropylethylamine
(36 .mu.l, 210 .mu.mol) were added and the mixture was stirred at
room temperature for 30 min. tert-Butyl
4-amino-3,3-difluoropiperidine-1-carboxylate (23.6 mg, 99.7
.mu.mol) was added and the mixture was left to stir at room
temperature for 2 h. Acetonitrile/water/TFA was added and the
reaction solution was purified by preparative HPLC (RP18 column,
mobile phase: acetonitrile/water gradient with addition of 0.1%
TFA). The product fractions were very substantially concentrated
under reduced pressure and the residue was extracted twice with
dichloromethane. The combined organic phases were washed twice with
saturated aqueous sodium bicarbonate solution. The combined aqueous
phases were re-extracted with dichloromethane. The combined organic
phases were dried over sodium sulfate, filtered and concentrated
under reduced pressure. This gave 48 mg of the target compound (87%
of theory, purity 99%).
[1133] LC-MS (Method 3): R.sub.t=1.81 min; MS (ESIpos): m/z=658
[M+H].sup.+
[1134] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. [ppm]: -0.008
(0.48), 1.157 (0.55), 1.175 (1.10), 1.193 (0.55), 1.427 (16.00),
1.988 (2.06), 4.021 (0.59), 4.038 (0.53), 5.192 (0.56), 7.572
(0.73), 7.995 (0.80), 8.026 (0.78), 8.807 (1.58), 10.314 (0.54),
10.337 (0.51).
Example 86 Methyl
4-[({7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-tri-
fluorophenyl)-1,4-dihydro-1,8-naphthyridin-3-yl}carbonyl)amino]bicyclo[2.2-
.1]heptane-1-carboxylate
##STR00257##
[1136]
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-tr-
ifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(50.0 mg, 98% pure, 112 .mu.mol) was initially charged in 1.6 ml of
DMF, HATU (50.9 mg, 134 .mu.mol) and N,N-diisopropylethylamine (49
.mu.l, 280 .mu.mol) were added and the mixture was stirred at room
temperature for 30 min. Methyl
4-aminobicyclo[2.2.1]heptane-1-carboxylate (22.6 mg, 134 .mu.mol)
was added and the mixture was left to stir at room temperature for
2 h. Acetonitrile/water/TFA was added and the reaction solution was
purified by preparative HPLC (RP18 column, mobile phase:
acetonitrile/water gradient with addition of 0.1% TFA). The product
fractions were very substantially concentrated under reduced
pressure and the residue was extracted twice with dichloromethane.
The combined organic phases were washed twice with saturated
aqueous sodium bicarbonate solution. The combined aqueous phases
were re-extracted with dichloromethane. The combined organic phases
were dried over sodium sulfate, filtered and concentrated under
reduced pressure. This gave 52 mg of the target compound (78% of
theory, purity 99%).
[1137] LC-MS (Method 3): R.sub.t=1.68 min; MS (ESIpos): m/z=591
[M+H].sup.+
[1138] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. [ppm]: -0.008
(0.56), 0.008 (0.54), 1.584 (6.18), 1.725 (0.82), 1.751 (1.60),
1.765 (1.06), 1.903 (0.99), 1.917 (1.54), 1.943 (0.96), 2.006
(0.84), 2.083 (0.44), 2.124 (3.16), 2.138 (3.63), 2.155 (4.94),
2.279 (1.00), 3.693 (16.00), 4.255 (2.00), 6.860 (1.01), 6.880
(1.82), 6.899 (1.04), 7.997 (1.62), 8.029 (1.61), 8.522 (3.08),
10.228 (2.05).
Example 87
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-N-(3-ethylpentan-3-yl)-
-6-fluoro-4-oxo-1-(2,4,6-tris
fluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00258##
[1140]
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-tr-
ifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(50.0 mg, 73% pure, 83.1 .mu.mol) was initially charged in 1.2 ml
of DMF, HATU (37.9 mg, 99.7 .mu.mol) and N,N-diisopropylethylamine
(36 .mu.l, 210 .mu.mol) were added and the mixture was stirred at
room temperature for 30 min. 3-Ethylpentan-3-amine (11.5 mg, 99.7
.mu.mol) was added and the mixture was stirred at room temperature
overnight. Acetonitrile/water/TFA was added and the reaction
solution was purified by preparative HPLC (RP18 column, mobile
phase: acetonitrile/water gradient with addition of 0.1% TFA). The
product fractions were very substantially concentrated under
reduced pressure and the residue was extracted twice with ethyl
acetate. The combined organic phases were washed twice with
saturated aqueous sodium bicarbonate solution. The combined aqueous
phases were re-extracted with ethyl acetate. The combined organic
phases were dried over sodium sulfate, filtered and concentrated
under reduced pressure. This gave 36 mg of the target compound (80%
of theory, purity 99%).
[1141] LC-MS (Method 3): R.sub.t=1.99 min; MS (ESIpos): m/z=537
[M+H].sup.+
[1142] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (0.97),
0.008 (0.75), 0.770 (6.80), 0.789 (16.00), 0.807 (7.33), 1.702
(1.95), 1.720 (5.99), 1.739 (5.74), 1.757 (1.74), 2.524 (0.69),
3.918 (0.49), 5.191 (1.51), 7.549 (1.11), 7.571 (1.93), 7.592
(1.09), 7.991 (2.75), 8.023 (2.69), 8.671 (4.76), 9.621 (2.85).
Example 88
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-(3-methylpe-
ntan-3-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-
-carboxamide
##STR00259##
[1144]
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-tr-
ifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(40.0 mg, 73% pure, 66.5 .mu.mol) was initially charged in 0.93 of
DMF, HATU (30.3 mg, 79.8 .mu.mol) and N,N-diisopropylethylamine (29
.mu.l, 170 .mu.mol) were added and the mixture was stirred at room
temperature for 30 min. 3-Methylpentan-3-amine hydrochloride (11.0
mg, 79.8 .mu.mol) was added and the mixture was stirred at room
temperature for 2 h. Acetonitrile/water/TFA was added and the
reaction solution was purified by preparative HPLC (RP18 column,
mobile phase: acetonitrile/water gradient with addition of 0.1%
TFA). The product fractions were very substantially concentrated
under reduced pressure and the residue was extracted twice with
dichloromethane. The combined organic phases were washed twice with
saturated aqueous sodium bicarbonate solution. The combined aqueous
phases were re-extracted with dichloromethane. The combined organic
phases were dried over sodium sulfate, filtered and concentrated
under reduced pressure. This gave 29 mg of the target compound (83%
of theory, purity 99%).
[1145] LC-MS (Method 3): R.sub.t=1.88 min; MS (ESIpos): m/z=523
[M+H].sup.+
[1146] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.008 (2.16),
0.817 (6.77), 0.835 (15.54), 0.854 (7.44), 1.282 (16.00), 1.616
(0.41), 1.634 (1.39), 1.652 (1.86), 1.668 (2.36), 1.687 (1.89),
1.705 (0.53), 1.773 (0.62), 1.791 (2.07), 1.809 (2.44), 1.826
(1.91), 1.844 (1.39), 3.908 (0.77), 5.190 (2.41), 7.550 (1.66),
7.572 (3.01), 7.593 (1.62), 7.990 (3.59), 8.022 (3.54), 8.673
(6.67), 9.737 (4.26).
Example 89
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-N-(2-methylbu-
tan-2-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3--
carboxamide
##STR00260##
[1148]
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-tr-
ifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(50.0 mg, 73% pure, 83.1 .mu.mol) was initially charged in 1.2 ml
of DMF, HATU (37.9 mg, 99.7 .mu.mol) and N,N-diisopropylethylamine
(36 .mu.l, 210 .mu.mol) were added and the mixture was stirred at
room temperature for 30 min. 2-Methylbutan-2-amine (12 .mu.l, 100
.mu.mol) was added and the mixture was stirred at room temperature
for 2 h. Acetonitrile/water/TFA was added and the reaction solution
was purified by preparative HPLC (RP18 column, mobile phase:
acetonitrile/water gradient with addition of 0.1% TFA). The product
fractions were very substantially concentrated under reduced
pressure and the residue was extracted twice with ethyl acetate.
The combined organic phases were washed twice with saturated
aqueous sodium bicarbonate solution. The combined aqueous phases
were re-extracted with ethyl acetate. The combined organic phases
were dried over sodium sulfate, filtered and concentrated under
reduced pressure. This gave 34 mg of the target compound (80% of
theory, purity 99%).
[1149] LC-MS (Method 3): R.sub.t=1.76 min; MS (ESIpos): m/z=509
[M+H].sup.+
[1150] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.008 (1.67),
0.851 (1.89), 0.869 (4.29), 0.888 (1.90), 1.343 (16.00), 1.706
(0.62), 1.724 (1.70), 1.743 (1.61), 1.761 (0.47), 3.909 (0.41),
5.186 (1.22), 7.551 (0.86), 7.573 (1.45), 7.593 (0.83), 7.982
(1.87), 8.014 (1.83), 8.676 (3.26), 9.818 (2.08).
Example 90
N-tert-Butyl-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro--
4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamid-
e
##STR00261##
[1152]
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-tr-
ifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(60.0 mg, 73% pure, 99.7 .mu.mol) was initially charged in 1.4 ml
of DMF, HATU (45.5 mg, 120 .mu.mol) and N,N-diisopropylethylamine
(43 .mu.l, 250 .mu.mol) were added and the mixture was stirred at
room temperature for 30 min. 2-Methylpropan-2-amine (8.75 mg, 120
.mu.mol) was added and the mixture was stirred at room temperature
for 2 h. Acetonitrile/water/TFA was added and the reaction solution
was purified by preparative HPLC (RP18 column, mobile phase:
acetonitrile/water gradient with addition of 0.1% TFA). The product
fractions were very substantially concentrated under reduced
pressure and the residue was extracted twice with dichloromethane.
The combined organic phases were washed twice with saturated
aqueous sodium bicarbonate solution. The combined aqueous phases
were re-extracted with dichloromethane. The combined organic phases
were dried over sodium sulfate, filtered and concentrated under
reduced pressure. This gave 26 mg of the target compound (52% of
theory, purity 99%).
[1153] LC-MS (Method 3): R.sub.t=1.66 min; MS (ESIpos): m/z=495
[M+H].sup.+
[1154] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.008 (1.87),
1.245 (0.76), 1.260 (0.86), 1.275 (0.48), 1.390 (16.00), 5.185
(0.79), 7.551 (0.52), 7.573 (0.92), 7.594 (0.53), 7.970 (1.13),
8.002 (1.11), 8.682 (2.04), 9.872 (1.36).
Example 91
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-(4,4,-
4-trifluoro-2-methylbutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8--
naphthyridine-3-carboxamide
##STR00262##
[1156] According to GP1, 80.0 mg (182 .mu.mol) of
7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 45.3 mg (255 .mu.mol) of
4,4,4-trifluoro-2-methylbutan-2-amine hydrochloride in the presence
of 83.1 mg (219 .mu.mol) of HATU and 95 .mu.l (550 .mu.mol) of
DIPEA in 730 .mu.l of DMF. The crude product was purified by
preparative HPLC (column: acetonitrile/water/0.1% of formic acid).
This gave 88.9 mg (87% of theory, 100% pure) of the title
compound.
[1157] LC-MS (Method 3): R.sub.t=1.84 min; MS (ESIpos): m/z=563
[M+H].sup.+
[1158] .sup.1H NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.08 (s, 1H),
8.72 (s, 1H), 7.98 (d, 1H), 7.53-7.61 (m, 2H), 4.87-5.10 (m, 2H),
3.83-4.11 (m, 3H), 3.48-3.69 (m, 1H), 3.12-3.27 (m, 1H), 2.87-3.09
(m, 3H), 1.48 (s, 6H).
Example 92
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[3,3,-
4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-nap-
hthyridine-3-carboxamide (diastereomer mixture)
##STR00263##
[1160] According to GP1, 150 mg (341 .mu.mol) of
7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 95.4 mg (478 .mu.mol) of
3,3,4,4,4-pentafluorobutan-2-amine hydrochloride (racemate) in the
presence of 156 mg (410 .mu.mol) of HATU and 180 .mu.l (1.00 mmol)
of DIPEA in 1.4 ml of DMF. The crude product was purified by
preparative HPLC (column: acetonitrile/water/0.1% of formic acid).
This gave 149 mg (75% of theory, 100% pure) of the title
compound.
[1161] LC-MS (Method 3): R.sub.t=1.87 min; MS (ESIpos): m/z=585
[M+H].sup.+
[1162] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.46 (d, 1H),
8.84 (s, 1H), 8.00 (d, 1H), 7.53-7.61 (m, 2H), 4.89-5.12 (m, 3H),
3.85-4.12 (m, 3H), 3.47-3.70 (m, 1H), 2.91-3.28 (m, 2H), 1.39 (d,
3H).
[1163] 146 mg of the title compound (diastereomer mixture) were
separated by chiral HPLC into the diastereomers (preparative HPLC:
column Daicel Chiralcel OX-H, 5 .mu.m, 250.times.30 mm; mobile
phase: 80% n-heptane, 20% ethanol; temperature: 25.degree. C.; flow
rate: 40 ml/min; UV detection: 265 nm.)
[1164] This gave (in the sequence of elution from the column) 56.0
mg of diastereomer 1 (99% de) R.sub.t=6.40 min and 55.8 mg of
diastereomer 2 (98% de) R.sub.t=8.57 min.
[1165] [Analytical HPLC: column Daicel OX-3, 3 .mu.m, 50.times.4.6
mm; mobile phase: 80% isohexane, 20% ethanol; UV detection: 220
nm].
[1166] Diastereomer 1 was additionally purified by preparative HPLC
(column: acetonitrile/water/0.1% formic acid, giving 41.0 mg (21%
of theory, 100% pure) of the title compound from Example 93.
[1167] Diastereomer 2 was additionally purified by preparative HPLC
(column: acetonitrile/water/0.1% formic acid, giving 42.0 mg (21%
of theory, 100% pure) of the title compound from Example 94.
Example 93
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[3,3,-
4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-nap-
hthyridine-3-carboxamide (diastereomer 1)
[1168] LC-MS (Method 3): R.sub.t=1.89 min; MS (ESIpos): m/z=585
[M+H].sup.+
[1169] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.46 (d, 1H),
8.84 (s, 1H), 8.00 (d, 1H), 7.54-7.61 (m, 2H), 4.91-5.10 (m, 3H),
3.84-4.12 (m, 3H), 3.43-3.67 (m, 1H), 3.12-3.28 (m, 1H), 2.88-3.11
(m, 1H), 1.39 (d, 3H).
Example 94
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[3,3,-
4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-nap-
hthyridine-3-carboxamide (diastereomer 2)
[1170] LC-MS (Method 3): R.sub.t=1.89 min; MS (ESIpos): m/z=585
[M+H].sup.+
[1171] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.46 (d, 1H),
8.84 (s, 1H), 8.00 (d, 1H), 7.54-7.61 (m, 2H), 4.92-5.09 (m, 3H),
3.85-4.11 (m, 3H), 3.42-3.68 (m, 1H), 3.12-3.28 (m, 1H), 2.92-3.11
(m, 1H), 1.39 (d, 3H).
Example 95
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[1-(t-
rifluoromethoxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naph-
thyridine-3-carboxamide (diastereomer mixture)
##STR00264##
[1173] According to GP1, 120 mg (273 .mu.mol) of
7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 74.0 mg (382 .mu.mol) of
1-(trifluoromethoxy)butan-2-amine hydrochloride (racemate) in the
presence of 125 mg (328 .mu.mol) of HATU and 140 .mu.l (820
.mu.mol) of DIPEA in 1.1 ml of DMF. The crude product was purified
by preparative HPLC (column: acetonitrile/water/0.1% of formic
acid). This gave 103 mg (65% of theory, 100% pure) of the title
compound.
[1174] LC-MS (Method 1): R.sub.t=0.99 min; MS (ESIpos): m/z=579
[M+H].sup.+
[1175] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.99 (br d,
1H), 8.76 (s, 1H), 8.00 (d, 1H), 7.53-7.61 (m, 2H), 4.79-5.20 (m,
2H), 4.11-4.23 (m, 3H), 3.77-4.10 (m, 3H), 3.43-3.74 (m, 1H),
2.85-3.26 (m, 2H), 1.52-1.73 (m, 2H), 0.94 (t, 3H).
[1176] 100 mg of the title compound (diastereomer mixture) were
separated by chiral HPLC into the diastereomers (preparative HPLC:
column Chiralpak AD-H, 5 .mu.m, 250.times.30 mm; mobile phase: 80%
n-heptane, 20% ethanol; temperature: 25.degree. C.; flow rate: 40
ml/min; UV detection: 265 nm.) This gave (in the sequence of
elution from the column) 23.6 mg of diastereomer 1 (99% de)
R.sub.t=10.77 min and 13.5 mg (9% of theory, 100% pure) of
diastereomer 2 (98% de) R.sub.t=12.40 min.
[1177] [Analytical HPLC: column Chiraltek AD-3, 3 .mu.m; mobile
phase: 80% isohexane, 20% ethanol; UV detection: 220 nm].
[1178] Diastereomer 1 was additionally purified by preparative HPLC
(column: acetonitrile/water/0.1% formic acid, giving 4.30 mg (3% of
theory, 100% pure) of the title compound from Example 96.
Example 96
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[1-(t-
rifluoromethoxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naph-
thyridine-3-carboxamide (diastereomer 1)
[1179] LC-MS (Method 3): R.sub.t=1.87 min; MS (ESIpos): m/z=579
[M+H].sup.+
[1180] .sup.1H-NMR (500 MHz, DMSO-d6): .delta. [ppm]=9.98 (br d,
1H), 8.76 (s, 1H), 8.00 (d, 1H), 7.54-7.60 (m, 2H), 4.91-5.07 (m,
2H), 4.13-4.22 (m, 3H), 3.82-4.10 (m, 3H), 3.44-3.66 (m, 1H),
3.12-3.29 (m, 1H), 2.93-3.11 (m, 1H), 1.63-1.72 (m, 1H), 1.53-1.63
(m, 1H), 0.94 (t, 3H).
Example 97
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[1-(t-
rifluoromethoxy)butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naph-
thyridine-3-carboxamide (diastereomer 2)
[1181] LC-MS (Method 3): R.sub.t=1.87 min; MS (ESIpos): m/z=579
[M+H].sup.+
[1182] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.99 (br d,
1H), 8.76 (s, 1H), 8.00 (d, 1H), 7.53-7.61 (m, 2H), 4.90-5.08 (m,
2H), 4.13-4.23 (m, 3H), 3.79-4.10 (m, 3H), 3.45-3.69 (m, 1H),
3.11-3.27 (m, 1H), 2.86-3.11 (m, 1H), 1.53-1.72 (m, 2H), 0.94 (t,
3H).
Example 98
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2S)-
-1,1,1-trifluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naph-
thyridine-3-carboxamide
##STR00265##
[1184] According to GP1, 50.0 mg (114 .mu.mol) of
7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 26.1 mg (159 .mu.mol) of
(2S)-1,1,1-trifluorobutan-2-amine hydrochloride in the presence of
51.9 mg (137 .mu.mol) of HATU and 59 .mu.l (340 .mu.mol) of DIPEA
in 460 .mu.l of DMF. The crude product was purified by preparative
HPLC (column: acetonitrile/water/0.1% of formic acid). This gave
47.2 mg (76% of theory, 100% pure) of the title compound.
[1185] LC-MS (Method 1): R.sub.t=0.98 min; MS (ESIpos): m/z=549
[M+H].sup.+
[1186] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.33 (d, 1H),
8.84 (s, 1H), 8.00 (d, 1H), 7.54-7.61 (m, 2H), 4.84-5.23 (m, 2H),
4.67-4.83 (m, 1H), 3.81-4.16 (m, 3H), 3.42-3.70 (m, 2H), 2.95-3.14
(m, 1H), 1.83-1.93 (m, 1H), 1.58-1.70 (m, 1H), 0.97 (t, 3H).
Example 99
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-[(2R)-3-met-
hylbutan-2-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridi-
ne-3-carboxamide
##STR00266##
[1188] According to GP1, 50.0 mg (114 .mu.mol) of
7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 13.9 mg (159 .mu.mol) of (2R)-3-methylbutan-2-amine in
the presence of 51.9 mg (137 .mu.mol) of HATU and 59 .mu.l (340
.mu.mol) of DIPEA in 460 .mu.l of DMF. The crude product was
purified by preparative HPLC (column: acetonitrile/water/0.1% of
formic acid). This gave 21.6 mg (37% of theory, 100% pure) of the
title compound.
[1189] LC-MS (Method 3): R.sub.t=1.74 min; MS (ESIpos): m/z=509
[M+H].sup.+
[1190] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.87 (d, 1H),
8.71 (s, 1H), 8.00 (d, 1H), 7.53-7.60 (m, 2H), 4.88-5.10 (m, 2H),
3.80-4.16 (m, 4H), 3.47-3.72 (m, 1H), 3.12-3.27 (m, 1H), 2.88-3.11
(m, 1H), 1.72-1.81 (m, 1H), 1.10 (d, 3H), 0.93 (d, 3H), 0.91 (d,
3H).
Example 100
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-[(2S)-3-methylbutan-2-
-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbo-
xamide
##STR00267##
[1192] According to GP1, 50.0 mg (114 .mu.mol) of
7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 13.9 mg (159 .mu.mol) of (2S)-3-methylbutan-2-amine in
the presence of 51.9 mg (137 .mu.mol) of HATU and 59 .mu.l (340
.mu.mol) of DIPEA in 460 .mu.l of DMF. The crude product was
purified by preparative HPLC (column: acetonitrile/water/0.1% of
formic acid). This gave 52.0 mg (90% of theory, 100% pure) of the
title compound.
[1193] LC-MS (Method 3): R.sub.t=1.74 min; MS (ESIpos): m/z=509
[M+H].sup.+
[1194] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.87 (d, 1H),
8.71 (s, 1H), 7.99 (d, 1H), 7.53-7.60 (m, 2H), 4.79-5.23 (m, 2H),
3.81-4.10 (m, 4H), 3.44-3.71 (m, 1H), 2.86-3.23 (m, 2H), 1.72-1.81
(m, 1H), 1.10 (d, 3H), 0.93 (br d, 3H), 0.91 (br d, 3H).
Example 101
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(3R,4S)-3,4-dihydroxypyrro-
lidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-napht-
hyridine-3-carboxamide
##STR00268##
[1196] According to GP1, 50.0 mg (114 .mu.mol) of
7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 28.0 mg (159 .mu.mol) of
(1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in the
presence of 51.9 mg (137 .mu.mol) of HATU and 59 .mu.l (340
.mu.mol) of DIPEA in 460 .mu.l of DMF. The crude product was
purified by preparative HPLC (column: acetonitrile/water/0.1% of
formic acid). This gave 36.9 mg (58% of theory, 100% pure) of the
title compound.
[1197] LC-MS (Method 3): R.sub.t=1.85 min; MS (ESIpos): m/z=561
[M+H].sup.+
[1198] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.47 (d, 1H),
8.83 (s, 1H), 8.01 (d, 1H), 7.53-7.61 (m, 2H), 4.91-5.09 (m, 2H),
4.33-4.43 (m, 1H), 3.86-4.14 (m, 3H), 3.39-3.67 ((m, 1H), 3.13-3.27
(m, 1H), 2.92-3.12 (m, 1H), 1.16-1.25 (m, 1H), 0.50-0.69 (m, 3H),
0.29-0.37 (m, 1H).
Example 102
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-[(2S)-1-methoxy-3-met-
hylbutan-2-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridi-
ne-3-carboxamide
##STR00269##
[1200] According to GP1, 30.0 mg (68.3 .mu.mol) of
7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 11.2 mg (95.6 .mu.mol) of
(2S)-1-methoxy-3-methylbutan-2-amine in the presence of 31.2 mg
(81.9 .mu.mol) of HATU and 36 .mu.l (200 .mu.mol) of DIPEA in 270
.mu.l of DMF. The crude product was purified by preparative HPLC
(column: acetonitrile/water/0.1% of formic acid). This gave 32.1 mg
(87% of theory, 100% pure) of the title compound.
[1201] LC-MS (Method 3): R.sub.t=1.64 min; MS (ESIpos): m/z=539
[M+H].sup.+
[1202] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.93 (d, 1H),
8.72 (s, 1H), 8.00 (d, 1H), 7.53-7.61 (m, 2H), 4.82-5.15 (m, 2H),
3.81-4.14 (m, 4H), 3.50-3.73 (m, 1H), 3.34-3.49 (m, 3H), 3.13-3.24
(m, 1H), 2.88-3.10 (m, 1H), 1.87-1.97 (m, 1H), 0.92 (d, 6H).
Example 103
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-N-(2,4-dimethylpentan-3-yl)-6-fl-
uoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbo-
xamide
##STR00270##
[1204] According to GP1, 30.0 mg (68.3 .mu.mol) of
7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 11.0 mg (95.6 .mu.mol) of 2,4-dimethylpentan-3-amine
in the presence of 31.2 mg (81.9 .mu.mol) of HATU and 36 .mu.l (200
.mu.mol) of DIPEA in 270 .mu.l of DMF. The crude product was
purified by preparative HPLC (column: acetonitrile/water/0.1% of
formic acid). This gave 29.1 mg (79% of theory, 100% pure) of the
title compound.
[1205] LC-MS (Method 3): R.sub.t=1.94 min; MS (ESIpos): m/z=537
[M+H].sup.+
[1206] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.76 (d, 1H),
8.72 (s, 1H), 8.02 (d, 1H), 7.53-7.60 (m, 2H), 4.91-5.07 (m, 2H),
3.80-4.15 (m, 3H), 3.48-3.74 (m, 2H), 2.89-3.28 (m, 2H), 1.80-1.90
(m, 2H), 0.88 (dd, 12H).
Example 104
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-[2-methylpentan-3-yl]-
-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3--
carboxamide (diastereomer mixture)
##STR00271##
[1208] According to GP1, 100 mg (228 .mu.mol) of
7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 32.2 mg (319 .mu.mol) of 2-methylpentan-3-amine in the
presence of 104 mg (273 .mu.mol) of HATU and 120 .mu.l (680
.mu.mol) of DIPEA in 920 .mu.l of DMF. The crude product was
purified by preparative HPLC (column: acetonitrile/water/0.1% of
formic acid). This gave 68.5 mg (58% of theory, 100% pure) of the
title compound.
[1209] LC-MS (Method 3): R.sub.t=1.85 min; MS (ESIpos): m/z=523
[M+H].sup.+
[1210] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.77 (d, 1H),
8.71 (s, 1H), 8.00 (d, 1H), 7.53-7.61 (m, 2H), 4.90-5.09 (m, 2H),
3.86-4.16 (m, 3H), 3.72-3.85 (m, 1H), 3.41-3.69 (m, 1H), 3.13-3.28
(m, 1H), 2.90-3.12 (m, 1H), 1.77-1.87 (m, 1H), 1.51-1.62 (m, 1H),
1.35-1.47 (m, 1H), 0.84-0.92 (m, 9H).
[1211] 65.0 mg of the title compound (diastereomer mixture) were
separated by chiral HPLC into the diastereomers (preparative HPLC:
column Daicel Chiralcel OX-H, 5 .mu.m, 250.times.20 mm; mobile
phase: 80% n-heptane, 20% ethanol; temperature: 23.degree. C.; flow
rate: 20 ml/min; UV detection: 220 nm.)
[1212] This gave (in the sequence of elution from the column) 26.1
mg (22% of theory, 100% purity) of diastereomer 1 from Example 105
(99% de) R.sub.t=11.82 min and 32.0 mg (27% of theory, 100% purity)
of diastereomer 2 from Example 106 (99% de) R.sub.t=15.94 min.
[1213] [Analytical HPLC: column Chiraltek OX-3, 3 .mu.m; mobile
phase: 80% n-heptane, 20% ethanol; UV detection: 220 nm].
Example 105
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-[2-methylpentan-3-yl]-
-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3--
carboxamide (diastereomer 1)
[1214] LC-MS (Method 3): R.sub.t=1.89 min; MS (ESIpos): m/z=523
[M+H].sup.+
[1215] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.77 (d, 1H),
8.71 (s, 1H), 8.00 (d, 1H), 7.53-7.60 (m, 2H), 4.91-5.07 (m, 2H),
3.85-4.15 (m, 3H), 3.76-3.83 (m, 1H), 3.43-3.64 (m, 1H), 3.11-3.28
(m, 1H), 2.92-3.10 (m, 1H), 1.77-1.86 (m, 1H), 1.51-1.61 (m, 1H),
1.36-1.47 (m, 1H), 0.84-0.92 (m, 9H).
Example 106
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-[2-methylpentan-3-yl]-
-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3--
carboxamide (diastereomer 2)
[1216] LC-MS (Method 3): R.sub.t=1.89 min; MS (ESIpos): m/z=523
[M+H].sup.+
[1217] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.77 (d, 1H),
8.71 (s, 1H), 8.00 (d, 1H), 7.48-7.66 (m, 2H), 4.88-5.11 (m, 2H),
3.86-4.15 (m, 3H), 3.76-3.83 (m, 1H), 3.44-3.69 (m, 1H), 3.13-3.29
(m, 1H), 2.87-3.11 (m, 1H), 1.76-1.86 (m, 1H), 1.51-1.62 (m, 1H),
1.29-1.47 (m, 1H), 0.84-0.93 (m, 9H).
Example 107
6-Fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-N-(4,4,4-trifluoro-2-met-
hylbutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-c-
arboxamide
##STR00272##
[1219] According to GP1, 50.0 mg (118 .mu.mol) of
6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl-
)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were reacted with
23.1 mg (130 .mu.mol) of 4,4,4-trifluoro-2-methylbutan-2-amine
hydrochloride in the presence of 53.9 mg (142 .mu.mol) of HATU and
82 .mu.l (470 .mu.mol) of DIPEA in 750 .mu.l of DMF. The crude
product was purified by preparative HPLC (column:
acetonitrile/water/0.1% of formic acid). This gave 51.0 mg (79% of
theory, 100% pure) of the title compound.
[1220] LC-MS (Method 3): R.sub.t=2.06 min; MS (ESIpos): m/z=547
[M+H].sup.+
[1221] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.09 (s, 1H),
8.72 (s, 1H), 7.98 (d, 1H), 7.56 (t, 2H), 4.95-5.04 (m, 1H),
4.18-4.37 (m, 1H), 3.34-4.01 (m, 3H), 3.06-3.27 (m, 1H), 2.95 (q,
2H), 1.72-1.98 (m, 2H), 1.48 (s, 6H).
Example 108
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-7-[(3S)-3-hydroxypyr-
rolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridin-
e-3-carboxamide
##STR00273##
[1223] According to GP1, 50.0 mg (118 .mu.mol) of
6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl-
)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were reacted with
22.8 mg (130 .mu.mol) of
(1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in the
presence of 53.9 mg (142 .mu.mol) of HATU and 82 .mu.l (470
.mu.mol) of DIPEA in 750 .mu.l of DMF. The crude product was
purified by preparative HPLC (column: acetonitrile/water/0.1% of
formic acid). This gave 50.3 mg (78% of theory, 100% pure) of the
title compound.
[1224] LC-MS (Method 3): R.sub.t=2.07 min; MS (ESIpos): m/z=545
[M+H].sup.+
[1225] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.48 (d, 1H),
8.83 (s, 1H), 8.01 (d, 1H), 7.53-7.60 (m, 2H), 4.97-5.04 (m, 1H),
4.21-4.43 (m, 2H), 3.34-4.03 (m, 3H), 3.01-3.29 (m, 1H), 1.74-1.98
(m, 2H), 1.16-1.25 (m, 1H), 0.50-0.69 (m, 3H), 0.30-0.37 (m,
1H).
Example 109
6-Fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-N-[1-(trifluoromethoxy)b-
utan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbo-
xamide (diastereomer mixture)
##STR00274##
[1227] According to GP1, 100 mg (236 .mu.mol) of
6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl-
)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were reacted with
50.3 mg (260 .mu.mol) of 1-(trifluoromethoxy)butan-2-amine
hydrochloride (racemate) in the presence of 108 mg (283 .mu.mol) of
HATU and 160 .mu.l (940 .mu.mol) of DIPEA in 1.5 ml of DMF. The
crude product was purified by preparative HPLC (column:
acetonitrile/water/0.1% of formic acid). This gave 89.3 mg (67% of
theory, 100% pure) of the title compound.
[1228] LC-MS (Method 3): R.sub.t=2.08 min; MS (ESIpos): m/z=563
[M+H].sup.+
[1229] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.00 (br d,
1H), 8.75 (s, 1H), 8.00 (d, 1H), 7.56 (br t, 2H), 4.95-5.04 (m,
1H), 4.24-4.35 (m, 1H), 4.12-4.24 (m, 3H), 3.33-4.07 (m, 3H),
3.02-3.29 (m, 1H), 1.74-2.00 (m, 2H), 1.55-1.73 (m, 2H), 0.94 (t,
3H).
[1230] 88.0 mg of the title compound (diastereomer mixture) were
separated by chiral HPLC into the diastereomers (preparative HPLC:
column Daicel Chiralpak IE 5 .mu.m 250.times.20 mm; mobile phase:
85% n-heptane, 15% ethanol+0.2% DEA; temperature: 23.degree. C.;
flow rate: 20 ml/min; UV detection: 220 nm.)
[1231] This gave (in the sequence of elution from the column) 22.6
mg (17% of theory, 95% purity) of diastereomer 1 from Example 110
(99% de) R.sub.t=11.90 min and 24.7 mg (19% of theory, 95% purity)
of diastereomer 2 from Example 111 (93% de) R.sub.t=13.32 min.
[1232] [Analytical HPLC: column Daicel Chiralpak IE-3, 3 .mu.m,
50.times.4.6 mm; mobile phase: 90% n-heptane, 10% ethanol+0.2% DEA;
flow rate: 1.0 ml/min; UV detection: 220 nm].
Example 110
6-Fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-N-[1-(trifluoromethoxy)b-
utan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbo-
xamide (diastereomer 1)
[1233] LC-MS (Method 3): R.sub.t=2.08 min; MS (ESIpos): m/z=563
[M+H].sup.+
[1234] .sup.1H-NMR (500 MHz, DMSO-d6): .delta. [ppm]=10.00 (d, 1H),
8.75 (s, 1H), 8.00 (d, 1H), 7.56 (br t, 2H),4.96-5.03 (m, 1H),
4.23-4.36 (m, 1H), 4.13-4.22 (m, 3H), 3.36-4.04 (m, 2H), 2.96-3.29
(m, 1H), 1.74-2.00 (m, 2H), 1.54-1.73 (m, 2H), 0.94 (t, 3H).
Example 111
6-Fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-N-[1-(trifluoromethoxy)b-
utan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbo-
xamide (diastereomer 2)
[1235] LC-MS (Method 3): R.sub.t=2.08 min; MS (ESIpos): m/z=563
[M+H].sup.+
[1236] .sup.1H-NMR (500 MHz, DMSO-d6): .delta. [ppm]=10.00 (d, 1H),
8.75 (s, 1H), 8.00 (d, 1H), 7.53-7.59 (m, 2H), 4.96-5.03 (m, 1H),
4.23-4.35 (m, 1H), 4.13-4.22 (m, 3H), 3.33-4.01 (m, 3H), 3.05-3.29
(m, 1H), 1.73-1.99 (m, 2H), 1.54-1.72 (m, 2H), 0.94 (t, 3H).
Example 112
6-Fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluoro-
butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carb-
oxamide (diastereomer mixture)
##STR00275##
[1238] According to GP1, 100 mg (236 .mu.mol) of
6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl-
)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were reacted with
51.9 mg (260 .mu.mol) of 3,3,4,4,4-pentafluorobutan-2-amine
hydrochloride (racemate) in the presence of 108 mg (283 .mu.mol) of
HATU and 160 .mu.l (940 .mu.mol) of DIPEA in 1.5 ml of DMF. The
crude product was purified by preparative HPLC (column:
acetonitrile/water/0.1% of formic acid). This gave 107 mg (80% of
theory, 100% pure) of the title compound.
[1239] LC-MS (Method 3): R.sub.t=2.10 min; MS (ESIpos): m/z=569
[M+H].sup.+
[1240] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.47 (d, 1H),
8.84 (s, 1H), 8.00 (d, 1H), 7.56 (t, 2H),4.95-5.08 (m, 2H),
4.19-4.37 (m, 1H), 3.34-4.06 (m, 3H), 3.01-3.28 (m, 1H), 1.73-1.98
(m, 2H), 1.39 (d, 3H).
[1241] 105 mg of the title compound (diastereomer mixture) were
separated by chiral SFC into the diastereomers (preparative SFC:
column Chiralpak AD, 250.times.20 mm; mobile phase: 80% carbon
dioxide, 20% isopropanol; temperature: 40.degree. C.; flow rate: 60
ml/min; UV detection: 210 nm.) This gave (in the sequence of
elution from the column) 39.2 mg (29% of theory, 100% purity) of
diastereomer 1 from Example 113 (99% de) R.sub.t=2.07 min and 32.8
mg (25% of theory, 100% purity) of diastereomer 2 from Example 114
(99% de) R.sub.t=2.59 min.
[1242] [Analytical SFC: column AD; mobile phase: 80% carbon
dioxide, 20% isopropanol; flow rate: 3.0 ml/min; UV detection: 210
nm].
Example 113
6-Fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluoro-
butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carb-
oxamide (diastereomer 1)
[1243] LC-MS (Method 3): R.sub.t=2.11 min; MS (ESIpos): m/z=569
[M+H].sup.+
[1244] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.47 (d, 1H),
8.84 (s, 1H), 8.00 (d, 1H), 7.57 (br t, 2H),4.95-5.08 (m, 2H),
4.21-4.37 (m, 1H), 3.36-4.05 (m, 3H), 3.01-3.27 (m, 1H), 1.72-1.98
(m, 2H), 1.39 (d, 3H).
Example 114
6-Fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluoro-
butan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carb-
oxamide (diastereomer 2)
[1245] LC-MS (Method 3): R.sub.t=2.11 min; MS (ESIpos): m/z=569
[M+H].sup.+
[1246] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.47 (d, 1H),
8.84 (s, 1H), 8.00 (d, 1H), 7.53-7.60 (m, 2H), 4.96-5.07 (m, 2H),
4.26-4.34 (m, 1H), 3.34-3.98 (m, 3H), 3.00-3.26 (m, 1H), 1.70-2.01
(m, 2H), 1.39 (d, 3H).
Example 115
6-Fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-N-[(2S)-1,1,1-trifluorob-
utan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbo-
xamide
##STR00276##
[1248] According to GP1, 50.0 mg (118 .mu.mol) of
6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl-
)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were reacted with
21.3 mg (130 .mu.mol) of (2S)-1,1,1-trifluorobutan-2-amine
hydrochloride in the presence of 53.9 mg (142 .mu.mol) of HATU and
82 .mu.l (470 .mu.mol) of DIPEA in 750 .mu.l of DMF. The crude
product was purified by preparative HPLC (column:
acetonitrile/water/0.1% of formic acid). This gave 46.8 mg (74% of
theory, 100% pure) of the title compound.
[1249] LC-MS (Method 3): R.sub.t=2.05 min; MS (ESIpos): m/z=533
[M+H].sup.+
[1250] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.34 (d, 1H),
8.83 (s, 1H), 8.00 (d, 1H), 7.53-7.61 (m, 2H), 4.96-5.05 (m, 1H),
4.68-4.79 (m, 1H), 4.19-4.39 (m, 1H), 3.33-4.04 (m, 3H), 3.02-3.28
(m, 1H), 1.72-1.97 (m, 3H), 1.58-1.70 (m, 1H), 0.97 (t, 3H).
Example 116
6-Fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-N-[2-methylpentan-3-yl]-4-oxo--
1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(diastereomer mixture)
##STR00277##
[1252] According to GP1, 100 mg (236 .mu.mol) of
6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl-
)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were reacted with
35.8 mg (260 .mu.mol) of 2-methylpentan-3-amine hydrochloride
(racemate) in the presence of 108 mg (283 .mu.mol) of HATU and 160
.mu.l (940 .mu.mol) of DIPEA in 1.5 ml of DMF. The crude product
was purified by preparative HPLC (column: acetonitrile/water/0.1%
of formic acid). This gave 90.1 mg (75% of theory, 100% pure) of
the title compound.
[1253] LC-MS (Method 3): R.sub.t=2.10 min; MS (ESIpos): m/z=507
[M+H].sup.+
[1254] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.78 (d, 1H),
8.71 (s, 1H), 8.00 (d, 1H), 7.56 (br t, 2H), 4.96-5.03 (m, 1H),
4.20-4.38 (m, 1H), 3.35-4.05 (m, 4H), 3.01-3.30 (m, 1H), 1.73-1.98
(m, 3H), 1.51-1.62 (m, 1H), 1.36-1.47 (m, 1H), 0.84-0.92 (m,
9H).
[1255] 99 mg of the title compound (diastereomer mixture) were
separated by chiral HPLC into the diastereomers (preparative HPLC:
column Daicel Chiralpak AY-H 5 .mu.m 250.times.20 mm; mobile phase:
70% n-heptane, 30% ethanol+0.2% DEA; temperature: 60.degree. C.;
flow rate: 15 ml/min; UV detection: 260 nm.)
[1256] This gave (in the sequence of elution from the column) 21.0
mg (17% of theory, 100% purity) of diastereomer 1 from Example 117
(97% de) R.sub.t=4.45 min and 23.0 mg (19% of theory, 100% purity)
of diastereomer 2 from Example 118 (76% de) R.sub.t=7.56 min.
[1257] [Analytical HPLC: column Daicel Chiralpak AY-H 5 .mu.m
250.times.4.6 mm; mobile phase: 70% isohexane, 30% ethanol+0.2%
DEA; temperature: 60.degree. C.; flow rate: 1.0 ml/min; UV
detection: 260 nm].
Example 117
6-Fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-N-[2-methylpentan-3-yl]-4-oxo--
1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(diastereomer 1)
[1258] LC-MS (Method 3): R.sub.t=2.10 min; MS (ESIpos): m/z=507
[M+H].sup.+
[1259] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.78 (d, 1H),
8.71 (s, 1H), 8.00 (d, 1H), 7.53-7.59 (m, 2H), 4.98-5.01 (m, 1H),
4.26-4.32 (m, 1H), 3.36-4.10 (m, 4H), 2.99-3.27 (m, 1H), 1.76-1.94
(m, 3H), 1.52-1.60 (m, 1H), 1.37-1.45 (m, 1H), 0.84-0.92 (m,
9H).
Example 118
6-Fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-N-[2-methylpentan-3-yl]-4-oxo--
1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(diastereomer 2)
[1260] LC-MS (Method 3): R.sub.t=2.11 min; MS (ESIpos): m/z=507
[M+H].sup.+
[1261] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.78 (d, 1H),
8.71 (s, 1H), 8.00 (d, 1H), 7.53-7.60 (m, 2H), 4.96-5.02 (m, 1H),
4.24-4.34 (m, 1H), 3.33-4.08 (m, 3H), 3.07-3.29 (m, 1H), 1.75-1.96
(m, 3H), 1.51-1.63 (m, 1H), 1.36-1.47 (m, 1H), 0.83-0.92 (m,
9H).
Example 119
6-Fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-N-[(2S)-3-methylbutan-2-yl]-4--
oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00278##
[1263] According to GP1, 50.0 mg (118 .mu.mol) of
6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl-
)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were reacted with
11.3 mg (130 .mu.mol) of (2S)-3-methylbutan-2-amine in the presence
of 53.9 mg (142 .mu.mol) of HATU and 62 .mu.l (350 .mu.mol) of
DIPEA in 750 .mu.l of DMF. The crude product was purified by
preparative HPLC (column: acetonitrile/water/0.1% of formic acid).
This gave 45.2 mg (78% of theory, 100% pure) of the title
compound.
[1264] LC-MS (Method 3): R.sub.t=1.99 min; MS (ESIpos): m/z=493
[M+H].sup.+
[1265] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.88 (d, 1H),
8.70 (s, 1H), 7.99 (d, 1H), 7.56 (br t, 2H), 4.95-5.03 (m, 1H),
4.19-4.37 (m, 1H), 3.33-4.10 (m, 4H), 3.01-3.26 (m, 1H), 1.70-1.96
(m, 3H), 1.10 (d, 3H), 0.88-0.95 (m, 6H).
Example 120
6-Fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-N-[(2R)-3-methylbutan-2-yl]-4--
oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00279##
[1267] According to GP1, 50.0 mg (118 .mu.mol) of
6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl-
)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were reacted with
11.3 mg (130 .mu.mol) of (2R)-3-methylbutan-2-amine in the presence
of 53.9 mg (142 .mu.mol) of HATU and 62 .mu.l (350 .mu.mol) of
DIPEA in 750 .mu.l of DMF. The crude product was purified by
preparative HPLC (column: acetonitrile/water/0.1% of formic acid).
This gave 45.8 mg (79% of theory, 100% pure) of the title
compound.
[1268] LC-MS (Method 3): R.sub.t=1.99 min; MS (ESIpos): m/z=493
[M+H].sup.+
[1269] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.88 (d, 1H),
8.70 (s, 1H), 7.99 (d, 1H), 7.56 (br t, 2H),4.96-5.03 (m, 1H),
4.21-4.37 (m, 1H), 3.36-4.11 (m, 4H), 3.02-3.28 (m, 1H), 1.71-1.97
(m, 3H), 1.10 (d, 3H), 0.88-0.96 (m, 6H).
Example 121
6-Fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-N-[(2R)-1-methoxy-3-methylbuta-
n-2-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-ca-
rboxamide
##STR00280##
[1271] According to GP1, 50.0 mg (118 .mu.mol) of
6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl-
)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were reacted with
20.0 mg (130 .mu.mol) of (2R)-1-methoxy-3-methylbutan-2-amine
hydrochloride in the presence of 53.9 mg (142 .mu.mol) of HATU and
62 .mu.l (350 .mu.mol) of DIPEA in 750 .mu.l of DMF. The crude
product was purified by preparative HPLC (column:
acetonitrile/water/0.1% of formic acid). This gave 45.5 mg (74% of
theory, 100% pure) of the title compound.
[1272] LC-MS (Method 3): R.sub.t=1.88 min; MS (ESIpos): m/z=523
[M+H].sup.+
[1273] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.94 (d, 1H),
8.72 (s, 1H), 8.00 (d, 1H), 7.52-7.60 (m, 2H), 4.94-5.05 (m, 1H),
4.29 (br s, 1H), 3.96-4.03 (m, 1H), 3.50-3.94 (m, 2H), 3.34-3.49
(m, 3H), 3.27 (s, 3H), 2.90-3.24 (m, 1H), 1.74-1.99 (m, 3H), 0.92
(d, 6H).
Example 122
N-(2,4-Dimethylpentan-3-yl)-6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4--
oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00281##
[1275] According to GP1, 50.0 mg (118 .mu.mol) of
6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl-
)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were reacted with
15.0 mg (130 .mu.mol) of 2,4-dimethylpentan-3-amine in the presence
of 53.9 mg (142 .mu.mol) of HATU and 62 .mu.l (350 .mu.mol) of
DIPEA in 750 .mu.l of DMF. The crude product was purified by
preparative HPLC (column: acetonitrile/water/0.1% of formic acid).
This gave 50.7 mg (82% of theory, 100% pure) of the title
compound.
[1276] LC-MS (Method 3): R.sub.t=2.19 min; MS (ESIpos): m/z=521
[M+H].sup.+
[1277] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.77 (d, 1H),
8.72 (s, 1H), 8.01 (d, 1H), 7.56 (br t, 2H), 4.96-5.03 (m, 1H),
4.21-4.36 (m, 1H), 3.37-3.98 (m, 4H), 3.01-3.27 (m, 1H), 1.74-1.96
(m, 4H), 0.88 (dd, 12H).
Example 123
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[1,1,1-trifluor-
o-3-methylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyrid-
ine-3-carboxamide (diastereomer mixture)
##STR00282##
[1279] According to GP1, 100 mg (228 .mu.mol) of
7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 36.4 mg (250 .mu.mol, 97% pure) of
1,1,1-trifluoro-3-methylbutan-2-amine (racemate) in the presence of
104 mg (273 .mu.mol) of HATU and 160 .mu.l (910 .mu.mol) of DIPEA
in 2.0 ml of DMF. The crude product was purified by preparative
HPLC (column: acetonitrile/water/0.1% of formic acid). This gave
52.0 mg (41% of theory, 100% pure) of the title compound.
[1280] LC-MS (Method 3): R.sub.t=1.94 min; MS (ESIpos): m/z=563
[M+H].sup.+
[1281] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.53 (d, 1H),
8.84 (s, 1H), 8.04 (d, 1H), 7.58 (br t, 2H),4.92-5.08 (m, 2H),
4.71-4.81 (m, 1H), 3.86-4.12 (m, 3H), 3.47-3.68 (m, 1H), 2.88-3.25
(m, 2H), 2.18-2.30 (m, 1H), 1.02 (d, 3H), 0.96 (d, 3H).
Example 124
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-(1,1,1-trifluor-
o-2-methylpropan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyri-
dine-3-carboxamide
##STR00283##
[1283] According to GP1, 50.0 mg (114 .mu.mol) of
7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 15.9 mg (125 .mu.mol) of
1,1,1-trifluoro-2-methylpropan-2-amine in the presence of 51.9 mg
(137 .mu.mol) of HATU and 59 .mu.l (340 .mu.mol) of DIPEA in 1.0 ml
of DMF. The crude product was purified by preparative HPLC (column:
acetonitrile/water/0.1% of formic acid). This gave 45.0 mg (72% of
theory, 100% pure) of the title compound.
[1284] LC-MS (Method 3): R.sub.t=1.87 min; MS (ESIpos): m/z=549
[M+H].sup.+
[1285] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.55 (s, 1H),
8.77 (s, 1H), 8.01 (d, 1H), 7.54-7.61 (m, 2H), 4.89-5.10 (m, 2H),
3.79-4.14 (m, 3H), 3.44-3.67 (m, 1H), 3.12-3.28 (m, 1H), 2.87-3.12
(m, 1H), 1.63 (s, 6H).
Example 125
6-Fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-N-(1,1,1-trifluoro-2-met-
hylpropan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3--
carboxamide
##STR00284##
[1287] According to GP1, 20.0 mg (47.2 .mu.mol) of
6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl-
)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were reacted with
6.60 mg (52.0 .mu.mol) of 1,1,1-trifluoro-2-methylpropan-2-amine in
the presence of 21.6 mg (56.7 .mu.mol) of HATU and 25 .mu.l (140
.mu.mol) of DIPEA in 420 .mu.l of DMF. The crude product was
purified by preparative HPLC (column: acetonitrile/water/0.1% of
formic acid). This gave 18.0 mg (72% of theory, 100% pure) of the
title compound.
[1288] LC-MS (Method 1): R.sub.t=1.10 min; MS (ESIpos): m/z=533
[M+H].sup.+
[1289] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.56 (s, 1H),
8.77 (s, 1H), 8.01 (d, 1H), 7.53-7.61 (m, 2H), 4.96-5.03 (m, 1H),
4.20-4.35 (m, 1H), 3.37-4.07 (m, 3H), 2.98-3.26 (m, 1H), 1.74-2.00
(m, 2H), 1.63 (s, 6H).
Example 126
6-Fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-N-[1,1,1-trifluoro-3-met-
hylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-c-
arboxamide (diastereomer mixture)
##STR00285##
[1291] According to GP1, 65.0 mg (154 .mu.mol) of
6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl-
)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were reacted with
24.6 mg (169 .mu.mol, 97% pure) of
1,1,1-trifluoro-3-methylbutan-2-amine (racemate) in the presence of
70.1 mg (184 .mu.mol) of HATU and 80 .mu.l (460 .mu.mol) of DIPEA
in 1.3 ml of DMF. The crude product was purified by preparative
HPLC (column: acetonitrile/water/0.1% of formic acid). This gave
54.0 mg (64% of theory, 99% pure) of the title compound.
[1292] LC-MS (Method 3): R.sub.t=2.16 min; MS (ESIpos): m/z=547
[M+H].sup.+
[1293] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.54 (d, 1H),
8.84 (s, 1H), 8.04 (d, 1H), 7.54-7.60 (m, 2H), 4.97-5.04 (m, 1H),
4.71-4.82 (m, 1H), 4.24-4.36 (m, 1H), 3.33-4.10 (m, 3H), 2.97-3.27
(m, 1H), 2.20-2.28 (m, 1H), 1.71-2.00 (m, 2H), 1.03 (d, 3H), 0.96
(d, 3H).
Example 127
1-(3,5-Difluoropyridin-2-yl)-6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-
-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-c-
arboxamide (diastereomer mixture)
##STR00286##
[1295] According to GP1, 100 mg (246 .mu.mol) of
1-(3,5-difluoropyridin-2-yl)-6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-
-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were reacted
with 54.0 mg (271 .mu.mol) of 3,3,4,4,4-pentafluorobutan-2-amine
hydrochloride (racemate) in the presence of 112 mg (295 .mu.mol) of
HATU and 170 .mu.l (980 .mu.mol) of DIPEA in 2.2 ml of DMF. The
crude product was purified by preparative HPLC (column:
acetonitrile/water/0.1% of formic acid). This gave 100 mg (74% of
theory, 100% pure) of the title compound.
[1296] LC-MS (Method 3): R.sub.t=1.98 min; MS (ESIpos): m/z=552
[M+H].sup.+
[1297] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.46 (d, 1H),
8.83 (d, 1H), 8.61 (d, 1H), 8.30-8.37 (m, 1H), 8.00 (d, 1H),
4.93-5.09 (m, 2H), 4.20-4.39 (m, 1H), 3.35-4.06 (m, 3H), 3.01-3.28
(m, 1H), 1.73-1.98 (m, 2H), 1.39 (br d, 3H).
[1298] 98.0 mg of the title compound (diastereomer mixture) were
separated by chiral HPLC into the diastereomers (preparative HPLC:
column Daicel Chiralpak IE 5 .mu.m 250.times.20 mm; mobile phase:
70% n-heptane, 30% ethanol+0.2% DEA; temperature: 35.degree. C.;
flow rate: 15 ml/min; UV detection: 265 nm.)
[1299] This gave (in the sequence of elution from the column) 46.0
mg of diastereomer 1 (99% de) R.sub.t=8.64 min and 47.0 mg of
diastereomer 2 (99% de) R.sub.t=12.08 min.
[1300] [Analytical HPLC: column Daicel Chiralpak IE, 5 .mu.m,
250.times.4.6 mm; mobile phase: 70% n-heptane, 30% ethanol+0.2%
DEA; temperature: 35.degree. C.; flow rate: 1.0 ml/min; UV
detection: 265 nm].
[1301] Diastereomer 1 was additionally purified by preparative HPLC
(column: acetonitrile/water/0.1% formic acid, giving 40.0 mg (30%
of theory, 100% pure) of the title compound from Example 128.
[1302] Diastereomer 2 was additionally purified by preparative HPLC
(column: acetonitrile/water/0.1% formic acid, giving 42.0 mg (31%
of theory, 100% pure) of the title compound from Example 129.
Example 128
1-(3,5-Difluoropyridin-2-yl)-6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-
-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-c-
arboxamide (diastereomer 1)
[1303] LC-MS (Method 3): R.sub.t=1.97 min; MS (ESIpos): m/z=552
[M+H].sup.+
[1304] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.46 (d, 1H),
8.83 (d, 1H), 8.60-8.63 (m, 1H), 8.31-8.37 (m, 1H), 8.00 (d, 1H),
4.95-5.08 (m, 2H), 4.22-4.36 (m, 1H), 3.36-4.04 (m, 3H), 2.95-3.27
(m, 1H), 1.73-1.96 (m, 2H), 1.39 (br d, 3H).
Example 129
1-(3,5-Difluoropyridin-2-yl)-6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-
-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-c-
arboxamide (diastereomer 2)
[1305] LC-MS (Method 3): R.sub.t=1.97 min; MS (ESIpos): m/z=552
[M+H].sup.+
[1306] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=10.46 (br d,
1H), 8.83 (d, 1H), 8.61 (d, 1H), 8.30-8.38 (m, 1H), 8.00 (d, 1H),
4.93-5.10 (m, 2H), 4.22-4.37 (m, 1H), 3.36-4.07 (m, 3H), 2.96-3.29
(m, 1H), 1.73-1.98 (m, 2H), 1.39 (br d, 3H).
Example 130
N-(2,6-Dichlorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro--
4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamid-
e
##STR00287##
[1308] According to GP3, 255 mg (494 .mu.mol) of
7-chloro-N-(2,6-dichlorophenyl)-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)--
1,4-dihydro-1,8-naphthyridine-3-carboxamide were reacted with 75.8
mg (543 .mu.mol) of (3R,4R)-pyrrolidine-3,4-diol hydrochloride and
300 .mu.l (1.70 mmol) of N,N-diisopropylethylamine in 5 ml of
dimethylformamide. The crude product was diluted with a little
acetonitrile and purified by preparative HPLC (column:
acetonitrile/water/0.1% of formic acid). This gave 216 mg (75% of
theory, 100% pure) of the title compound.
[1309] LC-MS (Method 3): R.sub.t=1.82 min; MS (ESIpos): m/z=583
[M+H].sup.+
[1310] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.947 (0.79),
1.257 (3.15), 2.328 (0.67), 2.366 (0.53), 2.671 (0.73), 2.710
(0.55), 2.731 (4.61), 2.890 (5.57), 3.054 (1.06), 3.705 (0.95),
3.912 (1.83), 4.029 (1.36), 5.216 (3.69), 7.360 (2.39), 7.380
(4.91), 7.400 (3.33), 7.562 (3.25), 7.581 (16.00), 7.601 (11.10),
7.952 (0.78), 8.062 (4.69), 8.093 (4.59), 8.929 (8.31), 11.845
(8.05).
Example 131
N-[1-(2-Chlorophenyl)-2,2,2-trifluoroethyl]-7-[(3R,4R)-3,4-dihydroxypyrro-
lidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-napht-
hyridine-3-carboxamide (diastereomer mixture)
##STR00288##
[1312] According to GP1, 100 mg (228 .mu.mol) of
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 52.5 mg (250 .mu.mol) of
1-(2-chlorophenyl)-2,2,2-trifluoroethanamine (racemate) in the
presence of 104 mg (273 .mu.mol) of HATU and 120 .mu.l (680
.mu.mol) of DIPEA in 1.4 ml of DMF. The crude product was purified
by preparative HPLC (column: acetonitrile/water/0.1% of formic
acid). This gave 104 mg (71% of theory, 98% pure) of the title
compound.
[1313] LC-MS (Method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=631
[M+H].sup.+
[1314] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.55),
-0.008 (5.54), 0.146 (0.64), 2.074 (0.71), 2.329 (1.11), 2.367
(0.95), 2.671 (1.20), 2.711 (0.93), 3.064 (1.11), 3.696 (1.09),
3.897 (2.04), 4.021 (1.60), 5.203 (4.37), 6.404 (0.75), 6.423
(2.53), 6.445 (3.43), 6.465 (2.39), 7.484 (1.62), 7.499 (4.37),
7.503 (4.83), 7.517 (4.54), 7.522 (4.79), 7.533 (3.68), 7.551
(7.45), 7.566 (7.05), 7.589 (4.65), 7.607 (12.96), 7.627 (7.80),
8.050 (8.75), 8.082 (8.62), 8.861 (16.00), 11.447 (5.70), 11.470
(5.39).
Example 132
N-(2,6-Dichlorobenzyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro--
4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamid-
e
##STR00289##
[1316] According to GP1, 100 mg (228 .mu.mol) of
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 44.1 mg (250 .mu.mol) of
1-(2,6-dichlorophenyl)methanamine in the presence of 104 mg (273
.mu.mol) of HATU and 120 .mu.l (680 .mu.mol) of DIPEA in 1.4 ml of
DMF. The crude product was purified by preparative HPLC (column:
acetonitrile/water/0.1% of formic acid). This gave 121 mg (89% of
theory, 100% pure) of the title compound.
[1317] LC-MS (Method 1): R.sub.t=1.00 min; MS (ESIpos): m/z=597
[M+H].sup.+
[1318] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.53),
-0.008 (5.53), 0.008 (3.79), 0.146 (0.53), 2.367 (0.81), 2.519
(3.30), 2.524 (2.91), 2.711 (0.74), 3.046 (0.63), 3.671 (0.60),
3.903 (1.44), 4.809 (10.37), 4.823 (10.16), 5.181 (4.47), 7.379
(3.42), 7.398 (5.05), 7.401 (5.23), 7.420 (5.84), 7.525 (16.00),
7.545 (12.28), 7.569 (5.33), 7.591 (3.09), 7.953 (7.16), 7.985
(6.98), 8.782 (12.02), 10.219 (2.47), 10.232 (4.91), 10.245
(2.14).
Example 133
6-Chloro-N-(2,6-dichlorophenyl)-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro--
1,8-naphthyridine-3-carboxamide
##STR00290##
[1320] A solution of 79.4 mg (490 .mu.mol) of 2,6-dichloroaniline
in 1.0 ml of DMF was added to a solution of 158 mg (446 .mu.mol) of
6-chloro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-car-
bonyl chloride in 1.0 ml of DMF, and 19.6 mg (490 .mu.mol) of
sodium hydride (60% in mineral oil) were then added. The mixture
was then stirred at RT for 2 h. The reaction was terminated by
addition of water, acetonitrile and formic acid and the crude
product was purified by preparative HPLC (column:
acetonitrile/water/0.1% of formic acid). This gave 36.0 mg (16% of
theory, 93% pure) of the title compound.
[1321] LC-MS (Method 1): R.sub.t=1.24 min; MS (ESIpos): m/z=480
[M+H].sup.+
[1322] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=11.41 (s, 1H),
9.02 (s, 1H), 8.92 (d, 1H), 8.81 (d, 1H), 7.85-7.94 (m, 1H),
7.57-7.67 (m, 3H), 7.32-7.44 (m, 2H).
Example 134
6-Chloro-N-[1-(2-chlorophenyl)-2,2,2-trifluoroethyl]-1-(2,4-difluoropheny-
l)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (racemate)
##STR00291##
[1324] According to GP1, 150 mg (446 .mu.mol) of
6-chloro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-car-
boxylic acid were reacted with 140 mg (668 .mu.mol) of
1-(2-chlorophenyl)-2,2,2-trifluoroethanamine (racemate) in the
presence of 203 mg (535 .mu.mol) of HATU and 230 .mu.l (1.30 mmol)
of DIPEA in 1.5 ml of DMF. The crude product was purified by
preparative HPLC (column: acetonitrile/water/0.1% of formic acid).
This gave 197 mg (83% of theory, 99% pure) of the title
compound.
[1325] LC-MS (Method 1): R.sub.t=1.37 min; MS (ESIpos): m/z=528
[M+H].sup.+
[1326] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=11.03 (d, 1H),
8.96 (s, 1H), 8.90 (d, 1H), 8.80 (d, 1H),7.74-7.91 (m, 1H),
7.48-7.67 (m, 5H),7.31-7.41 (m, 1H), 6.43-6.53 (m, 1H).
Example 135
6-Chloro-1-(2,4-difluorophenyl)-4-oxo-N-[1-(trifluoromethoxy)propan-2-yl]-
-1,4-dihydro-1,8-naphthyridine-3-carboxamide (racemate)
##STR00292##
[1328] According to GP1, 150 mg (446 .mu.mol) of
6-chloro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-car-
boxylic acid were reacted with 120 mg (668 .mu.mol) of
1-(trifluoromethoxy)propan-2-amine hydrochloride (racemate) in the
presence of 203 mg (535 .mu.mol) of HATU and 310 .mu.l (1.80 mmol)
of DIPEA in 1.5 ml of DMF. The crude product was purified by
preparative HPLC (column: acetonitrile/water/0.1% of formic acid).
This gave 159 mg (77% of theory, 100% pure) of the title
compound.
[1329] LC-MS (Method 1): R.sub.t=1.21 min; MS (ESIpos): m/z=462
[M+H].sup.+
[1330] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. [ppm]=9.69 (d, 1H),
8.86-8.89 (m, 2H), 8.73 (d, 1H), 7.81-7.89 (m, 1H), 7.62 (ddd, 1H),
7.33-7.39 (m, 1H), 4.33-4.42 (m, 1H), 4.16-4.23 (m, 2H), 1.27 (d,
3H).
Example 136
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-[1,1,1-trifluoro-3-methylbutan-2-yl]-1,4-dihydro-1,8-naph-
thyridine-3-carboxamide (diastereomer mixture)
##STR00293##
[1332] According to GP1, 200 mg (83% pure, 364 .mu.mol) of
1-(2-chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 58.3 mg (97%, 401 .mu.mol) of
1,1,1-trifluoro-3-methylbutan-2-amine in the presence of 166 mg
(437 .mu.mol) of HATU and 190 .mu.l (1.10 mmol) of DIPEA in 3.2 ml
of DMF. The crude product was purified by preparative HPLC (column:
acetonitrile/water/0.1% of formic acid). This gave 210 mg (100% of
theory, 100% pure) of the title compound.
[1333] LC-MS (Method 3): R.sub.t=1.95 min; MS (ESIpos): m/z=579
[M+H].sup.+
[1334] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.42),
0.008 (3.45), 0.146 (0.45), 0.953 (9.63), 0.962 (10.81), 0.969
(10.83), 0.979 (9.65), 1.019 (9.50), 1.025 (9.91), 1.036 (10.14),
1.042 (9.33), 2.224 (1.64), 2.234 (1.74), 2.241 (2.15), 2.251
(2.15), 2.267 (1.51), 2.285 (0.59), 2.328 (0.63), 2.367 (0.54),
2.524 (2.19), 2.670 (0.65), 2.711 (0.54), 2.732 (2.24), 2.891
(2.92), 3.015 (0.96), 3.225 (0.99), 3.687 (1.01), 3.893 (1.99),
4.013 (1.51), 4.747 (1.32), 4.769 (1.91), 4.789 (1.28), 5.201
(5.09), 5.754 (5.44), 7.688 (0.85), 7.695 (1.33), 7.710 (1.74),
7.719 (2.68), 7.728 (2.97), 7.734 (3.17), 7.742 (3.82), 7.751
(3.28), 7.765 (2.51), 8.041 (7.79), 8.073 (7.68), 8.802 (16.00),
10.536 (3.12), 10.545 (3.29), 10.561 (3.10), 10.569 (3.09).
Example 137
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[1,1,1-trifluor-
o-3-methylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyrid-
ine-3-carboxamide (diastereomer 1)
[1335] 52.0 mg of
7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[1,1,1-trifluor-
o-3-methylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyrid-
ine-3-carboxamide (diastereomer mixture) were separated into the
diastereomers by chiral HPLC (preparative HPLC: column Daicel
Chiralcel OX-H, 5 .mu.m, 250.times.20 mm; mobile phase: 80%
n-heptane/20% ethanol; flow rate 15 ml/min; temperature: 25.degree.
C., detection: 210 nm).
[1336] Diastereomer 1: 19.5 mg (>99% ee)
[1337] R.sub.t=1.30 min [HPLC: column Daicel OX-3; 3 .mu.m,
50.times.4.6 mm; mobile phase: 80% isohexane/20% ethanol;
detection: 220 nm].
[1338] Diastereomer 1 was additionally purified by preparative HPLC
(column: acetonitrile/water/0.1% formic acid, giving 14.0 mg (100%
pure) of the title compound.
[1339] LC-MS (Method 3): R.sub.t=1.96 min; MS (ESIpos): m/z=563
[M+H].sup.+
[1340] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.79),
-0.008 (7.62), 0.008 (5.42), 0.146 (0.71), 0.953 (15.75), 0.970
(16.00), 1.017 (13.54), 1.034 (13.74), 2.203 (0.62), 2.221 (1.58),
2.230 (1.66), 2.237 (2.09), 2.247 (2.12), 2.254 (1.55), 2.264
(1.47), 2.328 (1.13), 2.366 (1.21), 2.523 (4.06), 2.670 (1.19),
2.710 (1.24), 3.036 (0.62), 3.406 (0.90), 3.583 (0.68), 3.803
(0.45), 3.821 (0.45), 4.034 (2.34), 4.738 (1.24), 4.747 (1.35),
4.761 (1.83), 4.770 (1.89), 4.783 (1.30), 4.793 (1.19), 5.004
(2.00), 7.556 (3.89), 7.577 (7.37), 7.600 (3.87), 8.025 (7.37),
8.057 (7.37), 8.845 (13.43), 10.514 (4.94), 10.540 (4.77).
Example 138
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[1,1,1-trifluor-
o-3-methylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyrid-
ine-3-carboxamide (diastereomer 2)
[1341] 52.0 mg of
7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[1,1,1-trifluor-
o-3-methylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyrid-
ine-3-carboxamide (diastereomer mixture) were separated into the
diastereomers by chiral HPLC (preparative HPLC: column Daicel
Chiralcel OX-H, 5 .mu.m, 250.times.20 mm; mobile phase: 80%
n-heptane/20% ethanol; flow rate 15 ml/min; temperature: 25.degree.
C., detection: 210 nm).
[1342] Diastereomer 2: 21.5 mg (90.4% ee)
[1343] R.sub.t=1.77 min [HPLC: column Daicel OX-3; 3 .mu.m,
50.times.4.6 mm; mobile phase: 80% isohexane/20% ethanol;
detection: 220 nm].
[1344] Diastereomer 2 was additionally purified by preparative HPLC
(column: acetonitrile/water/0.1% formic acid), giving 15.0 mg (100%
pure) of the title compound.
[1345] LC-MS (Method 3): R.sub.t=1.97 min; MS (ESIpos): m/z=563
[M+H].sup.+
[1346] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.48),
-0.008 (4.54), 0.008 (3.45), 0.146 (0.46), 0.930 (3.74), 0.949
(12.03), 0.953 (15.89), 0.970 (16.00), 1.017 (13.01), 1.034
(13.22), 2.204 (0.59), 2.221 (1.53), 2.231 (1.58), 2.238 (2.01),
2.248 (2.01), 2.255 (1.48), 2.264 (1.41), 2.281 (0.53), 2.328
(0.69), 2.367 (0.75), 2.451 (0.77), 2.468 (2.26), 2.524 (2.47),
2.671 (0.75), 2.711 (0.78), 3.023 (0.62), 3.594 (0.64), 3.951
(0.80), 4.039 (2.22), 4.738 (1.17), 4.747 (1.32), 4.761 (1.74),
4.771 (1.76), 4.784 (1.25), 4.793 (1.16), 5.006 (1.69), 7.556
(3.68), 7.578 (6.92), 7.600 (3.70), 8.026 (7.19), 8.057 (7.07),
8.266 (0.77), 8.846 (12.46), 10.515 (4.82), 10.540 (4.65).
Example 139
6-Fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-N-[1,1,1-trifluoro-3-met-
hylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-c-
arboxamide (diastereomer 1)
[1347] 54.0 mg of
6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-N-[1,1,1-trifluoro-3-met-
hylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-c-
arboxamide (diastereomer mixture) were separated into the
diastereomers by chiral HPLC (preparative HPLC: column Daicel
Chiralpak IE, 5 .mu.m, 250.times.20 mm; mobile phase: 70%
n-heptane/30% isopropanol; flow rate 15 ml/min; temperature:
25.degree. C., detection: 270 nm).
[1348] Diastereomer 1: 21.5 mg (>99% ee)
[1349] R.sub.t=2.20 min [HPLC: column Daicel IE-3; 3 .mu.m,
50.times.4.6 mm; mobile phase: 80% isohexane/20% isopropanol;
detection: 220 nm].
[1350] LC-MS (Method 1): R.sub.t=1.13 min; MS (ESIpos): m/z=547
[M+H].sup.+
[1351] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.42),
-0.008 (3.86), 0.008 (3.14), 0.955 (15.68), 0.971 (16.00), 1.018
(13.42), 1.036 (13.72), 1.234 (0.52), 1.814 (0.98), 2.205 (0.64),
2.222 (1.58), 2.231 (1.64), 2.239 (2.10), 2.248 (2.10), 2.255
(1.60), 2.265 (1.50), 2.282 (0.54), 2.328 (0.88), 2.366 (0.72),
2.524 (2.80), 2.670 (0.94), 2.710 (0.76), 3.841 (0.46), 4.299
(1.22), 4.739 (1.24), 4.748 (1.36), 4.762 (1.78), 4.771 (1.82),
4.785 (1.30), 4.794 (1.20), 5.015 (1.18), 7.549 (2.90), 7.570
(5.35), 7.591 (3.08), 8.024 (7.85), 8.056 (7.69), 8.843 (13.18),
10.526 (4.95), 10.551 (4.79).
Example 140
6-Fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-N-[1,1,1-trifluoro-3-met-
hylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-c-
arboxamide (diastereomer 2)
[1352] 54.0 mg of
6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-N-[1,1,1-trifluoro-3-met-
hylbutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-c-
arboxamide (diastereomer mixture) were separated into the
diastereomers by chiral HPLC (preparative HPLC: column Daicel
Chiralpak IE, 5 .mu.m, 250.times.20 mm; mobile phase: 70%
n-heptane/30% isopropanol; flow rate 15 ml/min; temperature:
25.degree. C., detection: 270 nm).
[1353] Diastereomer 2: 19.5 mg (96.8% ee)
[1354] R.sub.t=3.41 min [HPLC: column Daicel IE-3; 3 .mu.m,
50.times.4.6 mm; mobile phase: 80% isohexane/20% isopropanol;
detection: 220 nm].
[1355] LC-MS (Method 1): R.sub.t=1.14 min; MS (ESIpos): m/z=547
[M+H].sup.+
[1356] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.008 (2.57),
0.858 (0.51), 0.954 (15.74), 0.971 (16.00), 1.018 (13.62), 1.035
(13.86), 1.233 (0.75), 1.827 (1.03), 2.204 (0.66), 2.222 (1.61),
2.232 (1.70), 2.239 (2.10), 2.248 (2.14), 2.255 (1.59), 2.265
(1.52), 2.282 (0.58), 2.329 (0.88), 2.367 (0.58), 2.670 (0.86),
2.711 (0.56), 3.814 (0.49), 4.294 (1.27), 4.739 (1.29), 4.748
(1.37), 4.763 (1.82), 4.771 (1.85), 4.786 (1.26), 4.794 (1.24),
5.008 (2.70), 7.549 (4.18), 7.571 (7.89), 7.593 (4.22), 8.025
(7.63), 8.057 (7.57), 8.843 (13.71), 10.527 (4.93), 10.552
(4.78).
Example 141
1-(2-Chloro-4,6-difluorophenyl)-N-(1,1-difluoro-2-methylpropan-2-yl)-7-[(-
3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphth-
yridine-3-carboxamide (atropisomer mixture)
##STR00294##
[1358] According to GP1, 100 mg (83% pure, 182 .mu.mol) of
1-(2-chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 30.1 mg (97% pure, 200 .mu.mol) of
1,1-difluoro-2-methylpropan-2-amine hydrochloride in the presence
of 83.1 mg (219 .mu.mol) of HATU and 130 .mu.l (730 .mu.mol) of
DIPEA in 1.6 ml of DMF. The crude product was purified by
preparative HPLC (column: acetonitrile/water/0.1% of formic acid).
This gave 97.0 mg (97% of theory, 100% pure) of the title
compound.
[1359] LC-MS (Method 3): R.sub.t=1.80 min; MS (ESIpos): m/z=547
[M+H].sup.+
[1360] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: 10.25 (s, 1H),
8.70 (s, 1H), 8.01 (d, 1H), 7.68-7.79 (m, 2H), 6.25-6.58 (m, 1H),
5.19 (brs, 2H), 3.79-4.06 (m, 3H), 3.56-3.78 (m, 1H), 3.12-3.28 (m,
1H), 2.93-3.11 (m, 1H), 1.43 (s, 6H).
Example 142
1-(2-Chloro-4,6-difluorophenyl)-N-(1,1-difluoro-2-methylpropan-2-yl)-7-[(-
3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphth-
yridine-3-carboxamide (atropisomer 1)
[1361] 97.0 mg of
1-(2-chloro-4,6-difluorophenyl)-N-(1,1-difluoro-2-methylpropan-2-yl)-7-[(-
3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphth-
yridine-3-carboxamide (atropisomer mixture) were separated into the
atropisomers by chiral HPLC (preparative HPLC: column Daicel
Chiralpak IA, 5 .mu.m, 250.times.20 mm; mobile phase: 75%
n-heptane/25% isopropanol+0.2% DEA; flow rate 15 ml/min;
temperature: 35.degree. C., detection: 220 nm).
[1362] Atropisomer 1: 34.4 mg (>99% ee)
[1363] R.sub.t=9.05 min [HPLC: column Daicel Chiralpak IA, 1
ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase: 80% n-hexane/20%
isopropanol+0.2% DEA; detection: 235 nm].
[1364] LC-MS (Method 3): R.sub.t=1.76 min; MS (ESIpos): m/z=547
[M+H].sup.+
[1365] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.25 (s,
1H), 8.70 (s, 1H), 8.01 (d, 1H), 7.68-7.77 (m, 2H), 6.22-6.58 (m,
1H), 5.19 (brs, 2H), 3.79-4.08 (m, 3H), 3.59-3.78 (m, 1H),
3.15-3.28 (m, 1H), 2.89-3.10 (m, 1H), 1.44 (s, 6H).
Example 143
1-(2-Chloro-4,6-difluorophenyl)-N-(1,1-difluoro-2-methylpropan-2-yl)-7-[(-
3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphth-
yridine-3-carboxamide (atropisomer 2)
[1366] 97.0 mg of
1-(2-chloro-4,6-difluorophenyl)-N-(1,1-difluoro-2-methylpropan-2-yl)-7-[(-
3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphth-
yridine-3-carboxamide (atropisomer mixture) were separated into the
atropisomers by chiral HPLC (preparative HPLC: column Daicel
Chiralpak IA, 5 .mu.m, 250.times.20 mm; mobile phase: 75%
n-heptane/25% isopropanol+0.2% DEA; flow rate 15 ml/min;
temperature: 35.degree. C., detection: 220 nm).
[1367] Atropisomer 2: 5.50 mg (>99% ee)
[1368] R.sub.t=13.64 min [HPLC: column Daicel Chiralpak IA, 1
ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase: 80% n-hexane/20%
isopropanol+0.2% DEA; detection: 235 nm].
[1369] LC-MS (Method 3): R.sub.t=1.76 min; MS (ESIpos): m/z=547
[M+H].sup.+
[1370] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 10.25 (s, 1H),
8.70 (s, 1H), 8.01 (d, 1H), 7.67 s 7.77 (m, 2H), 6.25-6.58 (m, 1H),
5.14-5.24 (m, 2H), 3.78-4.08 (m, 3H), 3.57-3.77 (m, 1H), 3.12-3.27
(m, 1H), 2.92-3.11 (m, 1H), 1.43 (s, 6H).
Example 144
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-N-(1,1,1,3,3,3-hexafluo-
ropropan-2-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridi-
ne-3-carboxamide
##STR00295##
[1372] According to GP3, 80.0 mg (153 .mu.mol) of
7-chloro-6-fluoro-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-4-oxo-1-(2,4,6-tr-
ifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide were
reacted with 23.5 mg (169 .mu.mol) of (3R,4R)-pyrrolidine-3,4-diol
hydrochloride and 93 .mu.l (540 .mu.mol) of DIPEA in 1.5 ml of DMF.
The crude product was purified by preparative HPLC (column:
acetonitrile/water/0.1% of formic acid). This gave 88.0 mg (98% of
theory, 100% pure) of the title compound.
[1373] LC-MS (Method 3): R.sub.t=1.91 min; MS (ESIpos): m/z=589
[M+H].sup.+
[1374] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.63),
-0.008 (5.64), 0.008 (4.87), 0.146 (0.63), 2.073 (0.88), 2.328
(0.91), 2.367 (0.67), 2.670 (0.95), 2.711 (0.67), 3.081 (1.16),
3.708 (1.16), 3.903 (2.10), 4.025 (1.68), 5.208 (3.85), 6.280
(0.49), 6.297 (1.23), 6.316 (1.75), 6.340 (1.86), 6.358 (1.23),
7.569 (3.78), 7.590 (6.79), 7.611 (3.78), 8.033 (8.96), 8.065
(8.79), 8.969 (16.00), 11.296 (5.95), 11.321 (5.67).
Example 145
1-(3,5-Difluoropyridin-2-yl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-f-
luoro-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyr-
idine-3-carboxamide
##STR00296##
[1376] According to GP3, 249 mg (493 .mu.mol) of
7-chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-N-(1,1,1,3,3,3-hexafluorop-
ropan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide were
reacted with 75.8 mg (543 .mu.mol) of (3R,4R)-pyrrolidine-3,4-diol
hydrochloride and 300 .mu.l (1.70 mmol) of DIPEA in 5 ml of DMF.
The crude product was purified by preparative HPLC (column:
acetonitrile/water/0.1% of formic acid). This gave 197 mg (70% of
theory, 100% pure) of the title compound.
[1377] LC-MS (Method 3): R.sub.t=1.79 min; MS (ESIpos): m/z=572
[M+H].sup.+
[1378] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.150 (0.81),
0.146 (0.81), 0.950 (1.31), 0.966 (1.16), 2.327 (1.26), 2.367
(1.26), 2.670 (1.46), 2.710 (1.26), 3.060 (0.86), 3.717 (0.96),
3.905 (2.68), 4.017 (1.92), 5.118 (0.91), 5.207 (3.43), 6.309
(1.56), 6.328 (2.32), 6.351 (2.37), 6.369 (1.56), 8.034 (6.06),
8.066 (6.21), 8.340 (2.37), 8.346 (2.78), 8.367 (4.74), 8.384
(2.47), 8.390 (2.68), 8.633 (8.98), 8.933 (16.00), 11.291 (7.32),
11.317 (7.07).
Example 146
6-Fluoro-7-(morpholin-4-yl)-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(-
2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(racemate)
##STR00297##
[1380] According to GP1, 100 mg (236 .mu.mol) of
6-fluoro-7-(morpholin-4-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1-
,8-naphthyridine-3-carboxylic acid were reacted with 51.9 mg (260
.mu.mol) of 3,3,4,4,4-pentafluorobutan-2-amine hydrochloride
(racemate) in the presence of 108 mg (283 .mu.mol) of HATU and 120
.mu.l (710 .mu.mol) of DIPEA in 2.3 ml of DMF. The crude product
was purified by preparative HPLC (column: acetonitrile/water/0.1%
of formic acid). This gave 86.0 mg (64% of theory, 100% pure) of
the title compound.
[1381] LC-MS (Method 3): R.sub.t=2.33 min; MS (ESIpos): m/z=569
[M+H].sup.+
[1382] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (1.35),
-0.008 (14.16), 0.008 (14.02), 0.146 (1.44), 1.389 (12.85), 1.407
(12.72), 1.988 (0.85), 2.327 (2.07), 2.366 (1.84), 2.523 (7.64),
2.670 (2.20), 2.710 (1.84), 3.506 (8.45), 3.517 (14.92), 3.529
(14.38), 3.596 (15.28), 3.608 (16.00), 3.619 (9.17), 3.741 (0.58),
4.038 (0.40), 5.015 (1.39), 5.034 (1.35), 7.550 (5.12), 7.572
(9.75), 7.594 (5.12), 8.103 (8.94), 8.137 (8.76), 8.711 (0.49),
8.907 (15.60), 10.344 (5.26), 10.368 (5.17).
Example 147
N-[(1S)-Cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-7-(morpholin-4-yl)-4-o-
xo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00298##
[1384] According to GP1, 80.0 mg (189 .mu.mol) of
6-fluoro-7-(morpholin-4-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1-
,8-naphthyridine-3-carboxylic acid were reacted with 36.5 mg (208
.mu.mol) of (1S)-cyclopropyl-2,2,2-trifluoroethanamine
hydrochloride in the presence of 86.2 mg (227 .mu.mol) of HATU and
99 .mu.l (570 .mu.mol) of DIPEA in 1.8 ml of DMF. The crude product
was purified by preparative HPLC (column: acetonitrile/water/0.1%
of formic acid). This gave 91.9 mg (89% of theory, 100% pure) of
the title compound.
[1385] LC-MS (Method 3): R.sub.t=2.33 min; MS (ESIpos): m/z=545
[M+H].sup.+
[1386] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.68),
-0.008 (8.06), 0.008 (4.92), 0.146 (0.68), 0.320 (1.83), 0.330
(2.93), 0.343 (2.81), 0.354 (2.06), 0.366 (1.15), 0.508 (0.77),
0.521 (1.90), 0.532 (2.93), 0.545 (2.88), 0.551 (3.23), 0.570
(3.35), 0.579 (2.48), 0.590 (2.25), 0.600 (1.83), 0.614 (1.12),
0.630 (1.52), 0.640 (1.50), 0.650 (3.00), 0.660 (2.32), 0.667
(2.08), 0.672 (2.01), 0.686 (1.10), 0.694 (0.68), 1.172 (0.59),
1.185 (1.19), 1.193 (1.64), 1.205 (2.76), 1.214 (2.11), 1.225
(2.69), 1.237 (1.52), 1.246 (1.01), 1.258 (0.45), 2.073 (1.10),
2.328 (0.82), 2.367 (0.94), 2.524 (3.40), 2.670 (0.91), 2.710
(1.01), 3.509 (8.88), 3.520 (15.46), 3.532 (14.62), 3.549 (1.52),
3.600 (15.77), 3.612 (16.00), 3.622 (9.04), 4.353 (1.50), 4.374
(2.60), 4.396 (2.48), 4.415 (1.36), 7.550 (5.06), 7.573 (9.77),
7.595 (5.15), 7.603 (1.62), 8.112 (8.78), 8.146 (8.62), 8.896
(14.52), 10.361 (5.67), 10.384 (5.51).
Example 148
6-Fluoro-7-(morpholin-4-yl)-4-oxo-N-[1,1,1,2,2-pentafluoropentan-3-yl]-1--
(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(racemate)
##STR00299##
[1388] According to GP1, 100 mg (236 .mu.mol) of
6-fluoro-7-(morpholin-4-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1-
,8-naphthyridine-3-carboxylic acid were reacted with 55.5 mg (260
.mu.mol) of 1,1,1,2,2-pentafluoropentan-3-amine hydrochloride
(racemate) in the presence of 108 mg (283 .mu.mol) of HATU and 120
.mu.l (710 .mu.mol) of DIPEA in 2.3 ml of DMF. The crude product
was purified by preparative HPLC (column: acetonitrile/water/0.1%
of formic acid). This gave 108 mg (78% of theory, 100% pure) of the
title compound.
[1389] LC-MS (Method 3): R.sub.t=2.42 min; MS (ESIpos): m/z=583
[M+H].sup.+
[1390] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (1.17),
-0.008 (10.68), 0.008 (8.97), 0.146 (1.22), 0.943 (7.08), 0.962
(16.00), 0.980 (7.66), 1.157 (0.90), 1.175 (1.80), 1.193 (0.95),
1.234 (0.41), 1.624 (0.86), 1.642 (1.22), 1.650 (1.13), 1.659
(1.44), 1.669 (1.31), 1.677 (1.26), 1.685 (1.44), 1.703 (0.99),
1.907 (1.44), 1.988 (3.20), 2.328 (1.35), 2.366 (1.89), 2.523
(5.00), 2.670 (1.58), 2.710 (1.94), 3.508 (6.76), 3.519 (12.21),
3.531 (11.85), 3.547 (1.58), 3.597 (12.57), 3.610 (12.94), 3.620
(7.35), 4.021 (0.81), 4.038 (0.72), 4.831 (0.86), 4.857 (1.08),
4.883 (1.08), 4.907 (0.86), 7.551 (4.01), 7.573 (7.80), 7.595
(4.10), 8.113 (6.94), 8.147 (6.85), 8.914 (11.67), 10.266 (4.42),
10.291 (4.28).
Example 149
6-Fluoro-7-(morpholin-4-yl)-4-oxo-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-
-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00300##
[1392] According to GP1, 80.0 mg (189 .mu.mol) of
6-fluoro-7-(morpholin-4-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1-
,8-naphthyridine-3-carboxylic acid were reacted with 34.0 mg (208
.mu.mol) of 1,1,1-trifluoro-2-methylpropan-2-amine hydrochloride in
the presence of 86.2 mg (227 .mu.mol) of HATU and 99 .mu.l (570
.mu.mol) of DIPEA in 1.8 ml of DMF. The crude product was purified
by preparative HPLC (column: acetonitrile/water/0.1% of formic
acid). This gave 87.6 mg (87% of theory, 100% pure) of the title
compound.
[1393] LC-MS (Method 3): R.sub.t=2.34 min; MS (ESIpos): m/z=533
[M+H].sup.+
[1394] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (2.83),
0.008 (2.66), 1.636 (16.00), 2.073 (1.35), 2.670 (0.47), 2.710
(0.42), 3.504 (2.00), 3.514 (3.57), 3.526 (3.45), 3.596 (3.60),
3.609 (3.83), 3.619 (2.21), 7.552 (1.12), 7.574 (2.09), 7.596
(1.15), 8.115 (1.92), 8.149 (1.92), 8.840 (3.18), 10.452
(2.69).
Example 150
N-(1,1-Difluoro-2-methylpropan-2-yl)-6-fluoro-7-(morpholin-4-yl)-4-oxo-1--
(2,4,6-trifluoro-phenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00301##
[1396] According to GP1, 80.0 mg (189 .mu.mol) of
6-fluoro-7-(morpholin-4-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1-
,8-naphthyridine-3-carboxylic acid were reacted with 30.3 mg (208
.mu.mol) of 1,1-difluoro-2-methylpropan-2-amine hydrochloride in
the presence of 86.2 mg (227 .mu.mol) of HATU and 99 .mu.l (570
.mu.mol) of DIPEA in 1.8 ml of DMF. The crude product was purified
by preparative HPLC (column: acetonitrile/water/0.1% of formic
acid). This gave 128 mg (quantitative, 100% pure) of the title
compound.
[1397] LC-MS (Method 1): R.sub.t=1.17 min; MS (ESIpos): m/z=515
[M+H].sup.+
[1398] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.008 (2.62),
1.439 (16.00), 2.073 (1.40), 2.328 (0.43), 2.670 (0.45), 3.500
(2.43), 3.510 (4.30), 3.522 (4.05), 3.595 (4.20), 3.607 (4.50),
3.618 (2.59), 6.277 (0.88), 6.419 (1.63), 6.562 (0.74), 7.550
(1.32), 7.572 (2.49), 7.594 (1.34), 8.095 (2.20), 8.129 (2.19),
8.817 (3.74), 10.135 (2.90).
Example 151
6-Fluoro-7-(morpholin-4-yl)-4-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1-(2-
,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00302##
[1400] According to GP1, 80.0 mg (189 .mu.mol) of
6-fluoro-7-(morpholin-4-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1-
,8-naphthyridine-3-carboxylic acid were reacted with 34.0 mg (208
.mu.mol) of (2S)-1,1,1-trifluorobutan-2-amine hydrochloride in the
presence of 86.2 mg (227 .mu.mol) of HATU and 99 .mu.l (570
.mu.mol) of DIPEA in 1.8 ml of DMF. The crude product was purified
by preparative HPLC (column: acetonitrile/water/0.1% of formic
acid). This gave 83.0 mg (82% of theory, 100% pure) of the title
compound.
[1401] LC-MS (Method 1): R.sub.t=1.20 min; MS (ESIpos): m/z=533
[M+H].sup.+
[1402] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.951 (7.27),
0.969 (16.00), 0.988 (7.90), 1.611 (1.05), 1.629 (1.46), 1.635
(1.29), 1.646 (1.77), 1.654 (1.58), 1.664 (1.52), 1.671 (1.69),
1.689 (1.27), 1.835 (0.42), 1.854 (1.32), 1.864 (1.52), 1.872
(1.57), 1.882 (1.75), 1.889 (1.54), 1.899 (1.38), 1.907 (1.15),
1.917 (0.96), 2.074 (0.67), 3.510 (8.13), 3.520 (14.34), 3.532
(13.50), 3.549 (1.33), 3.600 (14.03), 3.612 (14.78), 3.622 (8.39),
4.742 (1.52), 4.762 (1.43), 7.554 (4.14), 7.576 (8.01), 7.598
(4.19), 8.107 (6.29), 8.141 (6.26), 8.906 (11.53), 10.220 (4.83),
10.244 (4.71).
Example 152
1-(3,5-Difluoropyridin-2-yl)-6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-
-oxo-N-[(2S)-1,1,1-trifluorobutan-2-yl]-1,4-dihydro-1,8-naphthyridine-3-ca-
rboxamide
##STR00303##
[1404] According to GP1, 45.0 mg (11 .mu.mol) of
1-(3,5-difluoropyridin-2-yl)-6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-
-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were reacted
with 19.9 mg (122 .mu.mol) of (2S)-1,1,1-trifluorobutan-2-amine
hydrochloride in the presence of 50.5 mg (133 .mu.mol) of HATU and
77 .mu.l (440 .mu.mol) of DIPEA in 1.0 ml of DMF. The crude product
was purified by preparative HPLC (column: acetonitrile/water/0.1%
of formic acid). This gave 42.0 mg (74% of theory, 100% pure) of
the title compound.
[1405] LC-MS (Method 3): R.sub.t=1.95 min; MS (ESIpos): m/z=516
[M+H].sup.+
[1406] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (1.48),
-0.008 (16.00), 0.008 (9.38), 0.146 (1.14), 0.959 (6.81), 0.975
(6.86), 0.992 (2.91), 1.637 (1.30), 1.883 (2.23), 2.328 (1.72),
2.523 (6.83), 2.670 (1.32), 3.342 (1.11), 4.303 (1.46), 4.741
(1.40), 4.995 (2.89), 5.004 (2.91), 7.988 (5.03), 8.020 (5.01),
8.315 (1.59), 8.321 (1.72), 8.342 (2.65), 8.365 (1.51), 8.617
(5.62), 8.837 (15.23), 10.328 (3.10), 10.353 (2.89).
Example 153
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-1-(3,5-difluoropyridin-2-yl)--
6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyri-
dine-3-carboxamide
##STR00304##
[1408] According to GP1, 45.0 mg (11 .mu.mol) of
1-(3,5-difluoropyridin-2-yl)-6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-
-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were reacted
with 21.4 mg (122 .mu.mol) of
(1S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride in the
presence of 50.5 mg (133 .mu.mol) of HATU and 77 .mu.l (440
.mu.mol) of DIPEA in 1.0 ml of DMF. The crude product was purified
by preparative HPLC (column: acetonitrile/water/0.1% of formic
acid). This gave 45.0 mg (77% of theory, 100% pure) of the title
compound.
[1409] LC-MS (Method 3): R.sub.t=1.97 min; MS (ESIpos): m/z=528
[M+H].sup.+
[1410] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (1.00),
0.008 (9.61), 0.147 (1.11), 0.339 (2.15), 0.537 (2.19), 1.200
(2.37), 1.220 (2.40), 1.894 (1.33), 2.073 (6.17), 2.328 (2.12),
2.523 (6.89), 2.670 (2.26), 2.710 (1.15), 4.295 (1.69), 4.394
(2.30), 4.412 (2.37), 4.994 (3.62), 7.994 (6.31), 8.026 (6.39),
8.318 (2.08), 8.339 (3.55), 8.356 (1.79), 8.611 (6.67), 8.828
(16.00), 10.464 (2.69), 10.481 (2.76).
Example 154
1-(3,5-Difluoropyridin-2-yl)-6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-
-oxo-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,4-dihydro-1,8-naphthyridine-
-3-carboxamide
##STR00305##
[1412] According to GP1, 45.0 mg (11 .mu.mol) of
1-(3,5-difluoropyridin-2-yl)-6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-
-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were reacted
with 15.5 mg (122 .mu.mol) of
1,1,1-trifluoro-2-methylpropan-2-amine in the presence of 50.5 mg
(133 .mu.mol) of HATU and 58 .mu.l (330 .mu.mol) of DIPEA in 1.0 ml
of DMF. The crude product was purified by preparative HPLC (column:
acetonitrile/water/0.1% of formic acid). This gave 42.0 mg (74% of
theory, 100% pure) of the title compound.
[1413] LC-MS (Method 3): R.sub.t=1.94 min; MS (ESIpos): m/z=516
[M+H].sup.+
[1414] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm: 10.56 (s,
1H), 8.78 (s, 1H), 8.61 (d, 1H), 8.30-8.37 (m, 1H), 8.01 (d, 1H),
4.99 (br d, 1H), 4.20-4.38 (m, 1H), 3.35-4.05 (m, 1H), 3.00-3.28
(m, 1H), 1.72-1.97 (m, 2H), 1.63 (s, 6H).
Example 155
7-[(3R,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2R)-1,1,1-tri-
fluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine--
3-carboxamide
##STR00306##
[1416] According to GP1, 30.0 mg (68.3 .mu.mol) of
7-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 13.4 mg (81.9 .mu.mol) of
(2R)-1,1,1-trifluorobutan-2-amine hydrochloride in the presence of
31.2 mg (81.9 .mu.mol) of HATU and 42 .mu.l (240 .mu.mol) of DIPEA
in 1.0 ml of DMF. Aqueous 1N hydrochloric acid and acetonitrile
were added to the crude product, which was then purified by
preparative HPLC (column: acetonitrile/water/0.1% of formic acid).
This gave 29.5 mg (78% of theory, 99% pure) of the title
compound.
[1417] LC-MS (Method 3): R.sub.t=1.84 min; MS (ESIpos): m/z=549
[M+H].sup.+
[1418] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (1.76),
0.008 (1.54), 0.949 (7.24), 0.967 (16.00), 0.985 (7.83), 1.603
(1.05), 1.621 (1.44), 1.628 (1.26), 1.638 (1.72), 1.646 (1.56),
1.656 (1.48), 1.663 (1.68), 1.681 (1.24), 1.831 (0.43), 1.850
(1.28), 1.859 (1.50), 1.868 (1.50), 1.878 (1.72), 1.884 (1.52),
1.894 (1.32), 1.903 (1.14), 1.913 (0.97), 2.328 (0.55), 2.367
(0.41), 2.524 (1.78), 2.671 (0.57), 2.711 (0.41), 3.027 (0.59),
3.212 (0.67), 3.589 (0.59), 4.036 (2.41), 4.733 (1.44), 4.753
(1.34), 5.003 (2.13), 7.555 (3.93), 7.577 (7.42), 7.599 (3.91),
7.988 (7.40), 8.019 (7.36), 8.838 (12.76), 10.322 (5.21), 10.346
(4.97).
Example 156
7-[(3S,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2R)-1,1,1-tri-
fluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine--
3-carboxamide
##STR00307##
[1420] According to GP1, 30.0 mg (68.3 .mu.mol) of
7-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid were
reacted with 13.4 mg (81.9 .mu.mol) of
(2R)-1,1,1-trifluorobutan-2-amine hydrochloride in the presence of
31.2 mg (81.9 .mu.mol) of HATU and 42 .mu.l (240 .mu.mol) of DIPEA
in 690 .mu.l of DMF. Aqueous 1N hydrochloric acid and acetonitrile
were added to the crude product, which was then purified by
preparative HPLC (column: acetonitrile/water/0.1% of formic acid).
This gave 30.6 mg (81% of theory, 99% pure) of the title
compound.
[1421] LC-MS (Method 3): R.sub.t=1.78 min; MS (ESIpos): m/z=549
[M+H].sup.+
[1422] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.47),
0.146 (0.47), 0.951 (7.20), 0.969 (16.00), 0.987 (7.86), 1.604
(1.09), 1.622 (1.40), 1.639 (1.71), 1.647 (1.56), 1.664 (1.67),
1.683 (1.25), 1.851 (1.21), 1.860 (1.56), 1.868 (1.48), 1.879
(1.67), 1.896 (1.36), 1.913 (0.93), 2.328 (1.48), 2.366 (1.21),
2.523 (4.71), 2.669 (1.44), 2.710 (1.13), 3.070 (0.86), 3.698
(0.86), 3.906 (1.75), 4.735 (1.52), 5.203 (3.70), 7.559 (3.04),
7.579 (5.37), 7.599 (2.92), 7.999 (8.02), 8.031 (7.82), 8.840
(14.75), 10.329 (5.14), 10.353 (4.87).
Example 157
6-Bromo-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-[1,1,1,2,2-penta-
fluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-
-3-carboxamide (diastereomer mixture)
##STR00308##
[1424] At RT, 160 mg (896 .mu.mol) of 1-bromopyrrolidine-2,5-dione
(NBS) and 10.0 mg (60.9 .mu.mol) of
2,2'-(E)-diazene-1,2-diylbis(2-methylpropanenitrile (AIBN) were
added to a solution of 242 mg (417 .mu.mol) of
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-[1,1,1,2,2-pentafluorope-
ntan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbo-
xamide in 5.0 ml of acetonitrile. The mixture was stirred at
60.degree. C. for 1 h. The reaction mixture was cooled,
concentrated to half of its volume (under reduced pressure) and
purified by preparative HPLC (column: acetonitrile/water/0.1% of
formic acid). This gave 103 mg (37% of theory, 100% pure) of the
title compound.
[1425] LC-MS (Method 3): R.sub.t=2.08 min; MS (ESIpos): m/z=659
[M+H].sup.+
[1426] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.81),
-0.008 (6.76), 0.008 (6.78), 0.146 (0.81), 0.943 (7.54), 0.961
(16.00), 0.979 (8.14), 1.620 (1.01), 1.656 (1.75), 1.664 (1.68),
1.682 (1.66), 1.699 (1.15), 1.920 (1.87), 2.111 (0.55), 2.328
(1.01), 2.367 (0.85), 2.524 (3.23), 2.671 (1.01), 2.711 (0.76),
3.733 (1.22), 3.929 (8.99), 4.826 (1.18), 4.851 (1.54), 4.877
(1.54), 4.901 (1.13), 5.188 (2.81), 7.567 (3.67), 7.588 (6.46),
7.608 (3.46), 8.473 (13.99), 8.881 (15.40), 10.242 (5.19), 10.266
(5.10).
Example 158
6-Bromo-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-[3,3,4,4,4-penta-
fluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine--
3-carboxamide (diastereomer mixture)
##STR00309##
[1428] At RT, 161 mg (907 .mu.mol) of 1-bromopyrrolidine-2,5-dione
(NBS) and 10.0 mg (60.9 .mu.mol) of AIBN were added to a solution
of 239 mg (422 .mu.mol) of
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluorobu-
tan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbox-
amide in 7.1 ml of acetonitrile. The mixture was stirred at
60.degree. C. for 1 h. The reaction mixture was cooled,
concentrated to half of its volume (under reduced pressure) and
purified by preparative HPLC (column: acetonitrile/water/0.1% of
formic acid). This gave 175 mg (64% of theory, 100% pure) of the
title compound.
[1429] LC-MS (Method 3): R.sub.t=1.98 min; MS (ESIpos): m/z=645
[M+H].sup.+
[1430] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.50),
-0.008 (4.75), 0.146 (0.50), 1.386 (15.73), 1.404 (16.00), 2.074
(4.75), 2.329 (0.69), 2.367 (0.52), 2.671 (0.69), 2.711 (0.53),
3.421 (1.36), 3.734 (1.34), 3.930 (9.47), 4.966 (0.78), 4.986
(1.47), 5.008 (1.78), 5.028 (1.79), 5.052 (1.47), 5.073 (0.82),
5.185 (9.07), 7.565 (3.88), 7.586 (6.91), 7.607 (3.78), 8.453
(1.24), 8.462 (11.09), 8.466 (10.96), 8.876 (15.27), 9.513 (0.44),
9.518 (0.44), 10.318 (5.44), 10.342 (5.29).
Example 159
6-Bromo-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-(1,1,1-trifluoro-
-2-methylpropan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyrid-
ine-3-carboxamide
##STR00310##
[1432] At RT, 196 mg (1.10 mmol) of 1-bromopyrrolidine-2,5-dione
(NBS) and 10.0 mg (60.9 .mu.mol) of AIBN were added to a solution
of 272 mg (513 .mu.mol) of
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-4-oxo-N-(1,1,1-trifluoro-2-methy-
lpropan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-ca-
rboxamide in 8.0 ml of acetonitrile. The mixture was stirred at
60.degree. C. for 1 h. The reaction mixture was cooled,
concentrated to half of its volume (under reduced pressure) and
purified by preparative HPLC (column: acetonitrile/water/0.1% of
formic acid). This gave 128 mg (41% of theory, 100% pure) of the
title compound.
[1433] LC-MS (Method 3): R.sub.t=1.95 min; MS (ESIpos): m/z=609
[M+H].sup.+
[1434] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (2.95),
0.008 (2.81), 1.632 (16.00), 2.523 (1.40), 3.928 (1.71), 5.176
(2.24), 5.184 (2.24), 7.567 (0.69), 7.587 (1.17), 7.607 (0.66),
8.463 (0.44), 8.473 (4.19), 8.807 (3.19), 10.425 (2.53).
Example 160
6-Bromo-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-7-[(3R,4R)-3,4-dihydr-
oxypyrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphth-
yridine-3-carboxamide
##STR00311##
[1436] At RT, 39 mg (219 .mu.mol) of 1-bromopyrrolidine-2,5-dione
(NBS) and 3.00 mg (18.4 .mu.mol) of AIBN were added to a solution
of 100 mg (184 .mu.mol) of
N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-7-[(3R,4R)-3,4-dihydroxypyrro-
lidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine--
3-carboxamide in 6.7 ml of acetonitrile. The mixture was stirred at
60.degree. C. for 4 h, a further 15 mg (84.3 .mu.mol) of NBS were
then added and the solution was stirred at 60.degree. C. overnight.
The reaction mixture was cooled, concentrated to half of its volume
(under reduced pressure) and purified by preparative HPLC (column:
acetonitrile/water/0.1% of formic acid). This gave 90.0 mg (79% of
theory, 100% pure) of the title compound.
[1437] LC-MS (Method 3): R.sub.t=1.02 min; MS (ESIpos): m/z=621
[M+H].sup.+
[1438] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.342 (4.23),
0.556 (5.62), 0.660 (4.02), 1.219 (3.63), 3.424 (2.52), 3.736
(2.56), 3.933 (12.28), 4.382 (3.45), 5.188 (16.00), 7.587 (8.46),
8.473 (9.13), 8.863 (9.13), 10.338 (4.81), 10.361 (5.05).
Example 161
6-Fluoro-7-(2-oxa-6-azaspiro[3.3]hept-6-yl)-4-oxo-N-[1,1,1,2,2-pentafluor-
opentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-ca-
rboxamide (racemate)
##STR00312##
[1440]
7-Chloro-6-fluoro-4-oxo-N-[1,1,1,2,2-pentafluoropentan-3-yl]-1-(2,4-
,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(racemate, 282 mg, 531 .mu.mol) was initially charged in 3.6 ml of
DMF, ethanedioic acid 2-oxa-6-azaspiro[3.3]heptane (1:1) (141 mg,
743 .mu.mol) and N,N-diisopropylethylamine (560 .mu.l, 3.2 mmol)
were added and the mixture was stirred at room temperature for 2 h.
More ethanedioic acid 2-oxa-6-azaspiro[3.3]heptane (1:1) (30.1 mg,
159 .mu.mol) and N,N-diisopropylethylamine (93 .mu.l, 530 .mu.mol)
were added, and the mixture was stirred at room temperature
overnight. Water was added to the mixture and the precipitated
solid was filtered off and then purified on a silica gel column
(mobile phase: cyclohexane/ethyl acetate=2/1). This gave 199 mg of
the target compound (62% of theory, purity 98%).
[1441] LC-MS (Method 3): R.sub.t=2.35 min; MS (ESIpos): m/z=595
[M+H].sup.+
[1442] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.56),
0.146 (0.63), 0.935 (3.05), 0.953 (6.63), 0.971 (3.23), 1.235
(0.77), 1.630 (0.56), 1.647 (0.70), 1.656 (0.65), 1.673 (0.63),
1.692 (0.45), 1.915 (0.59), 2.085 (0.97), 2.327 (0.90), 2.366
(1.04), 2.670 (0.99), 2.710 (1.06), 4.209 (0.47), 4.656 (16.00),
4.843 (0.56), 4.870 (0.50), 7.542 (1.67), 7.565 (3.27), 7.587
(1.69), 7.991 (2.57), 8.020 (2.57), 8.844 (4.63), 10.339 (1.90),
10.364 (1.85).
Example 162
6-Fluoro-7-(2-oxa-6-azaspiro[3.3]hept-6-yl)-4-oxo-N-[3,3,4,4,4-pentafluor-
obutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-car-
boxamide (racemate)
##STR00313##
[1444]
7-Chloro-6-fluoro-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,-
6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(racemate, 250 mg, 482 .mu.mol) was initially charged in 3.3 ml of
DMF, ethanedioic acid 2-oxa-6-azaspiro[3.3]heptane (1:1) (128 mg,
675 .mu.mol) and N,N-diisopropylethylamine (500 .mu.l, 2.9 mmol)
were added and the mixture was stirred at room temperature for 2 h.
More ethanedioic acid 2-oxa-6-azaspiro[3.3]heptane (1:1) (27.4 mg,
145 .mu.mol) and N,N-diisopropylethylamine (84 .mu.l, 480 .mu.mol)
were added, and the mixture was stirred at room temperature
overnight. Water was added to the reaction mixture and the
precipitated solid was filtered off. The solid was purified on a
silica gel column (mobile phase: cyclohexane/ethyl acetate=2/1).
This gave 165 mg of the target compound (58% of theory, purity
99%).
[1445] LC-MS (Method 3): R.sub.t=2.26 min; MS (ESIpos): m/z=581
[M+H].sup.+
[1446] .sup.1H-NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (2.46),
0.008 (2.00), 1.379 (4.40), 1.397 (4.88), 2.524 (1.24), 2.670
(0.42), 4.654 (16.00), 5.001 (0.45), 5.022 (0.45), 7.541 (1.69),
7.563 (3.22), 7.586 (1.72), 7.982 (2.85), 8.011 (2.85), 8.838
(4.94), 10.417 (1.91), 10.441 (1.84).
Example 163
6-Fluoro-7-(2-oxa-6-azaspiro[3.3]hept-6-yl)-4-oxo-N-(3,3,4,4,4-pentafluor-
o-2-methylbutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyrid-
ine-3-carboxamide (racemate)
##STR00314##
[1448]
7-Chloro-6-fluoro-4-oxo-N-(3,3,4,4,4-pentafluoro-2-methylbutan-2-yl-
)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(300 mg, 564 .mu.mol) was initially charged in 5.4 ml of DMF,
ethanedioic acid 2-oxa-6-azaspiro[3.3]heptane (1:2) (97.6 mg, 338
.mu.mol) and N,N-diisopropylethylamine (490 .mu.l, 2.8 mmol) were
added and the mixture was then stirred at room temperature for 3 h.
The reaction solution was added to water, resulting in the
formation of a fine precipitate. The aqueous suspension was then
acidified with 1 N hydrochloric acid. The precipitate was washed
thoroughly with water and dried under high vacuum. This gave 340 mg
of the target compound (94% of theory, purity 93%).
[1449] LC-MS (Method 3): R.sub.t=2.32 min; MS (ESIpos): m/z=595
[M+H].sup.+
[1450] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (2.38),
0.008 (2.11), 1.674 (15.31), 2.328 (0.46), 2.524 (1.28), 2.670
(0.46), 4.653 (16.00), 7.541 (1.72), 7.563 (3.03), 7.585 (1.72),
8.001 (3.03), 8.030 (3.00), 8.774 (5.32), 10.529 (3.97).
Example 164
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-(3,3,4,4,4-pent-
afluoro-2-methylbutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naph-
thyridine-3-carboxamide
##STR00315##
[1452]
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-tr-
ifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(30.0 mg, 68.3 .mu.mol) was initially charged in 0.47 ml of DMF.
HATU (31.2 mg, 81.9 .mu.mol), N,N-diisopropylethylamine (59 .mu.l,
340 .mu.mol) and 3,3,4,4,4-pentafluoro-2-methylbutan-2-amine
hydrochloride (1:1) (19.0 mg, 88.8 .mu.mol) were added to the
solution and the mixture was stirred at room temperature overnight.
Water was then added and the mixture was adjusted to about pH
neutral with 1 M hydrochloric acid. The precipitated solid was
filtered off, taken up in acetonitrile/water/TFA and purified by
preparative HPLC (RP18 column, mobile phase: acetonitrile/water
gradient with addition of 0.1% TFA). The product fractions were
concentrated under reduced pressure and the residue was taken up in
dichloromethane and washed twice with saturated aqueous sodium
bicarbonate solution. The combined aqueous phases were re-extracted
with dichloromethane. The combined organic phases were dried over
sodium sulfate, filtered and concentrated under reduced pressure.
This gave 31 mg of the target compound (75% of theory, purity
99%).
[1453] LC-MS (Method 1): R.sub.t=1.04 min; MS (ESIpos): m/z=599
[M+H].sup.+
[1454] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 1.680 (16.00),
3.903 (0.72), 4.012 (0.50), 5.198 (1.65), 7.555 (1.28), 7.576
(2.37), 7.597 (1.30), 8.014 (2.65), 8.045 (2.62), 8.778 (4.80),
10.565 (4.02).
Example 165
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-N-(2,3,3-trimethylbutan-2-yl)-1,4-dihydro-1,8-naphthyridine-3-car-
boxamide
##STR00316##
[1456]
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-tr-
ifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(60.0 mg, 137 .mu.mol) was initially charged in 0.93 ml of DMF.
HATU (62.3 mg, 164 .mu.mol), N,N-diisopropylethylamine (71 .mu.l,
410 .mu.mol) and 2,3,3-trimethylbutan-2-amine (20.5 mg, 178
.mu.mol) were added to the solution and the mixture was stirred at
room temperature for 2.5 h. Acetonitrile/water/TFA was then added
and the reaction mixture was purified by preparative HPLC (RP18
column, mobile phase: acetonitrile/water gradient with addition of
0.1% TFA). The product fractions were concentrated under reduced
pressure and the residue was taken up in dichloromethane and washed
twice with saturated aqueous sodium bicarbonate solution. The
combined aqueous phases were re-extracted twice with
dichloromethane. The combined organic phases were dried over sodium
sulphate, filtered and concentrated by evaporation. This gave 34 mg
of the target compound (47% of theory, purity 95%).
[1457] LC-MS (Method 1): R.sub.t=1.04 min; MS (ESIpos): m/z=537
[M+H].sup.+
[1458] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (0.57),
1.039 (16.00), 1.411 (11.99), 7.551 (0.52), 7.573 (0.93), 7.594
(0.52), 8.034 (1.09), 8.066 (1.08), 8.678 (1.90), 10.097
(1.36).
Example 166
7-[3,3-Bis(hydroxymethyl)azetidin-1-yl]-6-fluoro-4-oxo-N-(3,3,4,4,4-penta-
fluoro-2-methylbutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-napht-
hyridine-3-carboxamide
##STR00317##
[1460]
6-Fluoro-7-(2-oxa-6-azaspiro[3.3]hept-6-yl)-4-oxo-N-(3,3,4,4,4-pent-
afluoro-2-methylbutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naph-
thyridine-3-carboxamide (100 mg, 93% pure, 156 .mu.mol) was
initially charged in 1 ml of acetonitrile, 1 ml of water and 1 ml
of trifluoroacetic acid were added and the mixture was stirred at
room temperature for 2 days. The mixture was purified by
preparative HPLC (RP18 column, mobile phase: acetonitrile/water
gradient with addition of 0.1% TFA). The product fractions were
concentrated under reduced pressure and the residue was dissolved
in dichloromethane/a little methanol and washed twice with
saturated aqueous sodium bicarbonate solution. The combined aqueous
phases were reextracted twice with dichloromethane. The combined
organic phases were dried over sodium sulfate, filtered and
concentrated under reduced pressure. This gave 66 mg of the target
compound (68% of theory, purity 98%).
[1461] LC-MS (Method 3): R.sub.t=1.98 min; MS (ESIpos): m/z=613
[M+H].sup.+
[1462] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 1.676 (16.00),
3.471 (7.03), 3.484 (7.17), 4.127 (0.45), 4.834 (2.20), 4.847
(5.01), 4.861 (2.14), 7.532 (1.56), 7.553 (2.96), 7.575 (1.60),
7.973 (2.48), 8.001 (2.43), 8.754 (4.63), 10.561 (3.80).
Example 167
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(1S)-1-phenyle-
thyl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamid-
e
##STR00318##
[1464]
7-[(3R,4R)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-tr-
ifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (150
mg, 341 .mu.mol) was initially charged in 3.0 ml of DMF. HATU (156
mg, 410 .mu.mol), N,N-diisopropylethylamine (300 .mu.l, 1.7 mmol)
and (1S)-1-phenylethanamine (53 .mu.l, 410 .mu.mol) were added to
the solution and the mixture was stirred at room temperature for 2
d. Acetonitrile/water/TFA was added and the reaction solution was
purified by preparative HPLC (RP18 column, mobile phase:
acetonitrile/water gradient with addition of 0.1% TFA). The product
fractions were combined and freed from acetonitrile and the residue
was made basic with saturated aqueous sodium bicarbonate solution
and extracted three times with dichloromethane. The combined
organic phases were washed with saturated aqueous sodium
bicarbonate solution. The combined organic phases were dried over
sodium sulfate, filtered and concentrated under reduced pressure.
This gave 159 mg of the target compound (84% of theory, purity
98%).
[1465] LC-MS (Method 3): R.sub.t=1.74 min; MS (ESIpos): m/z=543
[M+H].sup.+
[1466] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (1.38),
0.008 (1.36), 1.486 (14.29), 1.503 (14.41), 2.328 (0.50), 2.671
(0.55), 3.058 (0.57), 3.675 (0.57), 3.908 (1.33), 5.126 (0.59),
5.143 (2.31), 5.162 (3.54), 5.180 (4.40), 5.195 (4.16), 7.244
(1.38), 7.261 (3.28), 7.273 (1.45), 7.278 (2.64), 7.282 (1.66),
7.341 (3.02), 7.361 (8.77), 7.379 (16.00), 7.384 (11.89), 7.401
(3.16), 7.405 (1.95), 7.545 (3.57), 7.567 (6.49), 7.588 (3.54),
7.992 (6.78), 8.023 (6.63), 8.726 (12.10), 10.325 (4.28), 10.345
(4.11).
Example 168
7-[3,3-Bis(hydroxymethyl)azetidin-1-yl]-6-fluoro-4-oxo-N-[3,3,4,4,4-penta-
fluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine--
3-carboxamide (racemate)
##STR00319##
[1468]
6-Fluoro-7-(2-oxa-6-azaspiro[3.3]hept-6-yl)-4-oxo-N-[3,3,4,4,4-pent-
afluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-
-3-carboxamide (racemate, 165 mg, 284 .mu.mol) was initially
charged in 1.8 ml of trifluoroacetic acid, 1.8 ml of water and 1.8
ml of acetonitrile were added and the mixture was stirred at room
temperature for 2 days. The reaction solution was purified by
preparative HPLC (RP18 column, mobile phase: acetonitrile/water
gradient with addition of 0.1% TFA). The product fractions were
concentrated under reduced pressure and the residue was taken up in
dichloromethane and washed twice with saturated aqueous sodium
bicarbonate solution. The combined aqueous phases were re-extracted
with dichloromethane. The combined organic phases were dried over
sodium sulfate, filtered and concentrated under reduced pressure.
This gave in 140 mg of the target compound (82% of theory, purity
99%).
[1469] LC-MS (Method 3): R.sub.t=1.91 min; MS (ESIpos): m/z=599
[M+H].sup.+
[1470] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.50),
-0.008 (4.12), 0.008 (3.62), 0.146 (0.50), 1.177 (0.47), 1.234
(1.73), 1.381 (9.75), 1.398 (9.79), 2.328 (0.67), 2.367 (0.63),
2.524 (2.11), 2.670 (0.78), 2.711 (0.73), 3.472 (15.61), 3.485
(16.00), 4.124 (0.93), 4.835 (4.98), 4.848 (11.73), 4.862 (4.96),
4.958 (0.48), 4.981 (0.84), 5.004 (0.99), 5.023 (1.01), 5.047
(0.86), 5.067 (0.48), 5.754 (2.05), 7.532 (3.90), 7.554 (7.40),
7.576 (3.99), 7.954 (6.69), 7.983 (6.62), 8.819 (12.01), 10.450
(4.38), 10.474 (4.27).
Example 169
7-[3,3-Bis(hydroxymethyl)azetidin-1-yl]-6-fluoro-4-oxo-N-[3,3,4,4,4-penta-
fluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine--
3-carboxamide (enantiomer A)
[1471] 69 mg of
7-[3,3-bis(hydroxymethyl)azetidin-1-yl]-6-fluoro-4-oxo-N-[3,3,4,4,4-penta-
fluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine--
3-carboxamide (racemate) were separated into the enantiomers by
chiral HPLC (preparative HPLC: column Daicel.RTM. Chiralpak AD-H, 5
.mu.m, 250.times.20 mm; mobile phase: 70% n-heptane/30%
isopropanol; flow rate: 19 ml/min; temperature: 25.degree. C.,
detection: 240 nm).
[1472] Enantiomer A: 66 mg (>99% ee)
[1473] R.sub.t=4.45 min [HPLC: column Daicel.RTM. Chiralcel OD-H, 1
ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase: 70% n-heptane/30%
isopropanol; detection: 240 nm].
Example 170
7-[3,3-Bis(hydroxymethyl)azetidin-1-yl]-6-fluoro-4-oxo-N-[3,3,4,4,4-penta-
fluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine--
3-carboxamide (enantiomer B)
[1474] 69 mg of
7-[3,3-bis(hydroxymethyl)azetidin-1-yl]-6-fluoro-4-oxo-N-[3,3,4,4,4-penta-
fluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine--
3-carboxamide (racemate) were separated into the enantiomers by
chiral HPLC (preparative HPLC: column Daicel.RTM. Chiralpak AD-H, 5
.mu.m, 250.times.20 mm; mobile phase: 70% n-heptane/30%
isopropanol; flow rate: 19 ml/min; temperature: 25.degree. C.,
detection: 240 nm).
[1475] Enantiomer B: 68 mg (>99% ee)
[1476] R.sub.t=5.99 min [HPLC: column Daicel.RTM. Chiralcel OD-H, 1
ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase: 70% n-heptane/30%
isopropanol; detection: 240 nm].
Example 171
7-[3,3-Bis(hydroxymethyl)azetidin-1-yl]-6-fluoro-4-oxo-N-[1,1,1,2,2-penta-
fluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-
-3-carboxamide (racemate)
##STR00320##
[1478]
6-Fluoro-7-(2-oxa-6-azaspiro[3.3]hept-6-yl)-4-oxo-N-[1,1,1,2,2-pent-
afluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridin-
e-3-carboxamide (racemate, 199 mg, 335 .mu.mol) was initially
charged in 2.1 ml of trifluoroacetic acid, 2.1 ml of water and 2.1
ml of acetonitrile were added and the mixture was stirred at room
temperature for 2 days. The reaction solution was purified by
preparative HPLC (RP18 column, mobile phase: acetonitrile/water
gradient with addition of 0.1% TFA). The product fractions were
concentrated under reduced pressure and the residue was taken up in
dichloromethane and washed twice with saturated aqueous sodium
bicarbonate solution. The combined aqueous phases were re-extracted
with dichloromethane. The combined organic phases were dried over
sodium sulphate, filtered and concentrated by evaporation. This
gave 168 mg of the target compound (81% of theory, purity 99%).
[1479] LC-MS (Method 3): R.sub.t=1.98 min; MS (ESIpos): m/z=613
[M+H].sup.+
[1480] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.008 (2.65),
0.939 (6.29), 0.957 (14.00), 0.975 (6.81), 1.157 (2.65), 1.175
(5.29), 1.193 (2.72), 1.235 (0.88), 1.615 (0.76), 1.632 (1.09),
1.640 (0.98), 1.649 (1.31), 1.658 (1.20), 1.667 (1.11), 1.675
(1.24), 1.694 (0.90), 1.917 (1.16), 1.989 (9.69), 2.329 (0.43),
2.670 (0.50), 2.711 (0.40), 3.473 (15.68), 3.486 (16.00), 4.003
(0.99), 4.021 (2.61), 4.039 (2.63), 4.057 (1.15), 4.133 (0.97),
4.838 (5.71), 4.851 (12.52), 4.864 (5.69), 4.897 (0.77), 7.533
(3.62), 7.555 (6.94), 7.577 (3.68), 7.585 (1.23), 7.964 (5.89),
7.993 (5.83), 8.826 (10.47), 10.373 (4.13), 10.397 (3.99).
Example 172
7-[3,3-Bis(hydroxymethyl)azetidin-1-yl]-6-fluoro-4-oxo-N-[1,1,1,2,2-penta-
fluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-
-3-carboxamide (enantiomer A)
[1481] 209 mg of
7-[3,3-bis(hydroxymethyl)azetidin-1-yl]-6-fluoro-4-oxo-N-[1,1,1,2,2-penta-
fluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-
-3-carboxamide (racemate) were separated into the enantiomers by
chiral HPLC (preparative HPLC: column Daicel.RTM. Chiralpak AD-H, 5
.mu.m, 250.times.20 mm; mobile phase: 90% n-heptane/10% ethanol;
flow rate: 19 ml/min; temperature: 25.degree. C., detection: 240
nm).
[1482] Enantiomer A: 84 mg (98.5% ee)
[1483] R.sub.t=14.72 min [HPLC: column Daicel.RTM. Chiralpak AD-H,
1 ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase: 90%
n-heptane/10% ethanol; detection: 240 nm].
Example 173
7-[3,3-Bis(hydroxymethyl)azetidin-1-yl]-6-fluoro-4-oxo-N-[1,1,1,2,2-penta-
fluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-
-3-carboxamide (enantiomer B)
[1484] 209 mg of
7-[3,3-bis(hydroxymethyl)azetidin-1-yl]-6-fluoro-4-oxo-N-[1,1,1,2,2-penta-
fluoropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-
-3-carboxamide (racemate) was separated into the enantiomers by
chiral HPLC (preparative HPLC: column Daicel.RTM. Chiralpak AD-H, 5
.mu.m, 250.times.20 mm; mobile phase: 90% n-heptane/10% ethanol;
flow rate: 19 ml/min; temperature: 25.degree. C., detection: 240
nm).
[1485] Enantiomer B: 75 mg (96.8% ee)
[1486] R.sub.t=17.24 min [HPLC: column Daicel.RTM. Chiralpak AD-H,
1 ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase: 90%
n-heptane/10% ethanol; detection: 240 nm].
Example 174
6-Fluoro-7-[3-(hydroxymethyl)piperazin-1-yl]-4-oxo-N-[1,1,1,2,2-pentafluo-
ropentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-c-
arboxamide (diastereomer mixture)
##STR00321##
[1488] tert-Butyl
4-[3-fluoro-5-oxo-6-{[1,1,1,2,2-pentafluoropentan-3-yl]carbamoyl}-8-(2,4,-
6-trifluorophenyl)-5,8-dihydro-1,8-naphthyridin-2-yl]-2-(hydroxymethyl)pip-
erazine-1-carboxylate (diastereomer mixture, 204 mg, 287 .mu.mol)
was initially charged in 1.6 ml of dichloromethane, tris
fluoroacetic acid (780 .mu.l, 10 mmol) was added and the mixture
was stirred at room temperature for 1.5 h. The dichloromethane was
evaporated and the residue was purified by preparative HPLC (RP18
column, mobile phase: acetonitrile/water gradient with addition of
0.1% TFA). The product fractions were concentrated and the residue
was dissolved in dichloromethane/a little methanol and washed twice
with saturated aqueous sodium bicarbonate solution. The combined
aqueous phases were re-extracted twice with dichloromethane. The
combined organic phases were dried over sodium sulfate, filtered
and concentrated under reduced pressure. This gave 63 mg of the
target compound (48% of theory, purity 96%) as a diastereomer
mixture of two diastereomers.
[1489] LC-MS (Method 3): R.sub.t=1.55 min; MS (ESIpos): m/z=612
[M+H].sup.+
[1490] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.55),
-0.008 (4.61), 0.008 (4.48), 0.146 (0.55), 0.943 (7.10), 0.961
(16.00), 0.980 (7.69), 1.142 (0.40), 1.622 (0.93), 1.640 (1.25),
1.647 (1.10), 1.656 (1.48), 1.666 (1.36), 1.675 (1.28), 1.683
(1.48), 1.701 (1.02), 1.924 (1.29), 2.086 (2.96), 2.324 (2.65),
2.368 (0.70), 2.574 (3.33), 2.604 (1.48), 2.637 (2.57), 2.668
(3.19), 2.694 (1.65), 2.711 (0.60), 2.842 (2.77), 2.872 (2.22),
2.971 (1.32), 2.997 (2.27), 3.025 (1.22), 3.145 (1.00), 3.159
(1.89), 3.172 (2.80), 3.186 (3.63), 3.200 (1.94), 3.214 (2.01),
3.228 (3.54), 3.241 (2.90), 3.254 (1.74), 3.268 (1.00), 3.952
(2.22), 3.984 (2.08), 4.040 (2.55), 4.071 (2.43), 4.599 (3.14),
4.612 (6.76), 4.625 (3.03), 4.829 (0.86), 4.856 (1.10), 4.881
(1.12), 4.906 (0.83), 5.755 (1.89), 7.513 (1.39), 7.541 (4.86),
7.564 (4.85), 7.592 (1.36), 8.058 (7.61), 8.092 (7.46), 8.894
(13.63), 10.304 (4.75), 10.329 (4.58).
Example 175
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-7-[(3R,4R)-3,4-dihydroxypyrro-
lidin-1-yl]-6-fluoro-1-(4-fluoro-2,6-dimethylphenyl)-4-oxo-1,4-dihydro-1,8-
-naphthyridine-3-carboxamide
##STR00322##
[1492]
7-Chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-1-(4--
fluoro-2,6-dimethylphenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxami-
de (80.0 mg, 165 .mu.mol) was initially charged in 1.6 ml of DMF,
(3R,4R)-pyrrolidine-3,4-diol hydrochloride (25.3 mg, 181 .mu.mol)
was added followed by N,N-diisopropylethylamine (0.17 ml, 0.99
mmol), and the mixture was stirred at room temperature overnight.
Acetonitrile/water/TFA was added to the reaction solution. The
precipitate formed was filtered off and dried under high vacuum.
This gave 76 mg of the target compound (84% of theory, purity
99%).
[1493] LC-MS (Method 3): R.sub.t=1.86 min; MS (ESIpos): m/z=553
[M+H].sup.+
[1494] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.324 (0.76),
0.334 (1.15), 0.347 (1.18), 0.358 (0.93), 0.370 (0.45), 0.503
(0.84), 0.514 (1.21), 0.527 (1.01), 0.537 (0.84), 0.548 (0.87),
0.567 (1.07), 0.578 (1.01), 0.588 (0.93), 0.600 (0.76), 0.612
(0.48), 0.625 (0.56), 0.635 (0.65), 0.646 (1.01), 0.656 (0.98),
0.670 (0.90), 1.174 (0.48), 1.183 (0.70), 1.194 (1.18), 1.203
(0.87), 1.215 (1.12), 1.227 (0.67), 1.235 (0.59), 1.940 (16.00),
1.951 (15.83), 2.328 (0.42), 2.670 (0.45), 3.883 (0.67), 4.342
(0.62), 4.363 (1.04), 4.384 (1.04), 4.404 (0.56), 5.171 (2.64),
7.164 (4.63), 7.188 (4.66), 8.009 (3.34), 8.041 (3.28), 8.429
(7.55), 10.623 (2.41), 10.646 (2.30).
Example 176
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-7-[2-(hydroxymethyl)-
-4-methylpiperazin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxamide (diastereomer mixture)
##STR00323##
[1496]
7-Chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-
-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(100 mg, 203 .mu.mol) was initially charged in 2 ml of DMF,
[4-methylpiperazin-2-yl]methanol (30.5 mg, 95% pure, 223 .mu.mol)
and N,N-diisopropylethylamine (0.177 ml, 1.01 mmol) were added and
the mixture was stirred at room temperature for 3 h.
Acetonitrile/water/TFA was added and the reaction solution was
purified by preparative HPLC (RP18 column, mobile phase:
acetonitrile/water gradient with addition of 0.1% TFA). The product
fractions were combined and freed from acetonitrile. The residue
was made basic using saturated aqueous sodium bicarbonate solution
and extracted three times with dichloromethane. The combined
organic phases were washed with saturated aqueous sodium
bicarbonate solution. The combined organic phases were dried over
sodium sulfate, filtered and concentrated under reduced pressure.
The fraction was re-purified by thick-layer chromatography (mobile
phase: dichloromethane/methanol=10/1). This gave 48 mg of the
target compound (39% of theory, purity 98%) as a diastereomer
mixture of two diastereomers.
[1497] LC-MS (Method 3): R.sub.t=1.38 min; MS (ESIpos): m/z=588
[M+H].sup.+
[1498] .sup.1H NMR (500 MHz, DMSO-d6) .delta.[ppm]: -0.007 (1.35),
0.006 (0.98), 0.335 (0.88), 0.340 (0.92), 0.345 (0.84), 0.350
(0.72), 0.519 (0.80), 0.529 (1.19), 0.539 (1.05), 0.547 (0.88),
0.555 (0.82), 0.571 (0.99), 0.579 (0.93), 0.588 (0.79), 0.597
(0.67), 0.633 (0.54), 0.642 (0.71), 0.650 (0.98), 0.654 (0.82),
0.659 (0.97), 0.662 (0.95), 0.670 (0.94), 0.676 (0.47), 0.679
(0.47), 1.188 (0.47), 1.195 (0.69), 1.204 (1.16), 1.211 (0.85),
1.220 (1.14), 1.230 (0.71), 1.236 (0.54), 1.837 (0.54), 1.844
(0.67), 1.861 (1.09), 1.867 (1.10), 1.884 (0.69), 1.891 (0.56),
1.989 (0.93), 1.996 (1.01), 2.012 (1.03), 2.019 (0.90), 2.113
(16.00), 2.516 (1.06), 2.520 (0.93), 2.524 (0.85), 2.697 (1.08),
2.719 (1.00), 2.830 (1.56), 2.853 (1.45), 3.028 (0.41), 3.051
(0.73), 3.076 (0.41), 3.594 (1.65), 3.606 (2.39), 3.618 (1.66),
3.784 (0.85), 3.811 (0.80), 4.261 (0.89), 4.359 (0.58), 4.376
(0.98), 4.393 (0.95), 4.409 (0.52), 4.700 (0.98), 4.710 (1.87),
4.720 (0.93), 7.518 (0.66), 7.541 (1.37), 7.552 (0.92), 7.564
(1.39), 7.586 (0.64), 8.032 (4.28), 8.060 (4.10), 8.869 (7.42),
10.394 (2.60), 10.413 (2.45).
Example 177
N-[(1R)-1-Cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-1-(4-fluoro-2,6-dime-
thylphenyl)-7-[(4S)-4-hydroxy-2-oxopyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8--
naphthyridine-3-carboxamide
##STR00324##
[1500] Potassium carbonate (34.1 mg, 0.28 mmol) was initially
charged and dried by heating the vessel. Under argon, palladium(II)
acetate (4 mg, 0.02 mmol) and
9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (16 mg, 0.03 mmol)
were added, followed by degassed dioxane (1.8 ml). The mixture was
stirred at room temperature for 10 min.
7-Chloro-N-[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-1-(4-fluoro-
-2,6-dimethylphenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(80.0 mg, 165 .mu.mol) and (4S)-4-hydroxypyrrolidin-2-one (20.0 mg,
198 .mu.mol) were added and the mixture was stirred at 80.degree.
C. overnight. The reaction solution was filtered and
acetonitrile/TFA/water was added, resulting in the precipitation of
a solid. The reaction solution was extracted twice with
dichloromethane. The residue was purified on a silica gel column
(mobile phase: dichloromethane/methanol=30/1). The residue was
freed from dichloromethane and re-purified by thick-layer
chromatography (mobile phase: dichloromethane/methanol=20/1). This
gave a total of 7 mg of the target compound (8% of theory, purity
99%).
[1501] LC-MS (Method 3): R.sub.t=1.88 min; MS (ESIpos): m/z=551
[M+H].sup.+
[1502] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (2.34),
0.008 (1.96), 0.348 (1.04), 0.361 (0.95), 0.372 (0.65), 0.383
(0.41), 0.541 (0.62), 0.553 (0.94), 0.569 (1.18), 0.586 (1.28),
0.596 (0.84), 0.607 (0.75), 0.617 (0.61), 0.644 (0.46), 0.653
(0.48), 0.664 (1.03), 0.674 (0.74), 0.681 (0.68), 1.141 (1.13),
1.207 (0.41), 1.216 (0.57), 1.228 (1.04), 1.236 (1.08), 1.248
(1.04), 1.260 (0.64), 1.268 (0.44), 1.948 (15.80), 1.952 (16.00),
2.117 (0.51), 2.278 (1.13), 2.326 (1.59), 2.523 (1.30), 2.808
(1.25), 2.824 (1.27), 2.852 (1.11), 2.868 (1.11), 3.338 (1.55),
3.704 (1.16), 3.717 (1.45), 3.731 (1.26), 3.744 (1.08), 4.358
(1.48), 4.379 (1.07), 4.399 (0.86), 4.420 (0.46), 5.318 (3.02),
5.327 (2.97), 7.181 (2.48), 7.204 (2.52), 8.530 (2.92), 8.554
(2.87), 8.690 (7.03), 10.281 (1.93), 10.304 (1.87).
Example 178
7-[(3S,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[(2S)-1,1,1-tri-
fluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine--
3-carboxamide
##STR00325##
[1504]
7-[(3S,4S)-3,4-Dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-tr-
ifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(30.0 mg, 68.3 .mu.mol) was dissolved in 0.7 ml of DMF, HATU (31
mg, 0.08 mmol) and DIPEA (42 .mu.l, 0.24 mmol) were added and the
mixture was stirred at room temperature for 30 min.
(S)-1,1,1-Trifluoro-2-butylamine hydrochloride (13.4 mg, 81.9
.mu.mol) was added and the mixture was stirred at room temperature
for 30 min. 0.5 ml of 1 N hydrochloric acid and 1 ml of
acetonitrile were added and the mixture was purified by preparative
HPLC (RP18 column, mobile phase: acetonitrile/water gradient). This
gave 24.3 mg (99% pure, 64% of theory) of the target compound.
[1505] LC-MS (Method 3): R.sub.t=1.78 min; MS (ESIpos): m/z=549
[M+H].sup.+
[1506] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (2.33),
0.008 (2.22), 0.950 (7.18), 0.969 (16.00), 0.987 (7.85), 1.604
(1.08), 1.622 (1.42), 1.629 (1.29), 1.639 (1.73), 1.647 (1.54),
1.657 (1.50), 1.664 (1.69), 1.682 (1.29), 1.851 (1.31), 1.861
(1.48), 1.869 (1.52), 1.879 (1.73), 1.886 (1.50), 1.895 (1.33),
1.904 (1.12), 1.914 (0.95), 2.328 (0.76), 2.367 (0.82), 2.524
(3.03), 2.670 (0.85), 2.711 (0.87), 3.073 (0.80), 3.695 (0.85),
3.904 (1.80), 4.014 (1.23), 4.734 (1.42), 4.755 (1.35), 5.201
(4.80), 7.558 (3.87), 7.580 (6.82), 7.601 (3.79), 7.999 (7.53),
8.031 (7.41), 8.841 (12.89), 10.329 (5.19), 10.353 (5.00).
Example 179
N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-7-[3-(hydroxymethyl)-
-4-methylpiperazin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-n-
aphthyridine-3-carboxamide (diastereomer mixture)
##STR00326##
[1508]
7-Chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-
-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(100 mg, 203 .mu.mol) was initially charged in 2 ml of DMF,
[1-methylpiperazin-2-yl]methanol dihydrochloride (47.6 mg, 95%
pure, 223 .mu.mol) and N,N-diisopropylethylamine (0.25 ml, 1.42
mmol) were added and the mixture was stirred at room temperature
for 3 h. Acetonitrile/water/TFA was added and the reaction solution
was purified by preparative HPLC (RP18 column, mobile phase:
acetonitrile/water gradient with addition of 0.1% TFA). The product
fractions were combined and freed from acetonitrile. The residue
was made basic using saturated aqueous sodium bicarbonate solution
and extracted three times with dichloromethane. The combined
organic phases were washed with saturated aqueous sodium
bicarbonate solution. The combined organic phases were dried over
sodium sulfate, filtered and concentrated under reduced pressure.
The fraction was re-purified by thick-layer chromatography (mobile
phase: dichloromethane/methanol=10/1). This gave 80 mg of the
target compound (66% of theory, purity 98%).
[1509] LC-MS (Method 3): R.sub.t=1.37 min; MS (ESIpos): m/z=588
[M+H].sup.+
[1510] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (2.54),
0.008 (2.44), 0.320 (0.70), 0.330 (1.13), 0.343 (1.11), 0.354
(0.86), 0.366 (0.43), 0.517 (0.75), 0.528 (1.13), 0.541 (1.03),
0.550 (1.17), 0.569 (1.20), 0.579 (0.95), 0.589 (0.86), 0.600
(0.71), 0.614 (0.44), 0.629 (0.61), 0.638 (0.58), 0.649 (1.05),
0.659 (0.90), 0.665 (0.84), 0.671 (0.81), 0.685 (0.41), 1.183
(0.45), 1.191 (0.64), 1.203 (1.10), 1.212 (0.80), 1.223 (1.09),
1.235 (0.67), 1.244 (0.41), 1.932 (0.57), 1.940 (0.71), 1.948
(0.92), 1.957 (0.94), 1.965 (0.73), 1.973 (0.61), 2.079 (0.61),
2.101 (1.15), 2.108 (1.16), 2.130 (0.70), 2.137 (0.62), 2.179
(16.00), 2.524 (0.77), 2.697 (1.34), 2.727 (1.23), 2.849 (0.99),
2.874 (1.10), 2.882 (1.17), 2.907 (0.98), 3.107 (0.61), 3.134
(1.08), 3.162 (0.62), 3.212 (0.61), 3.228 (0.90), 3.241 (1.15),
3.254 (1.03), 3.270 (0.72), 3.481 (0.67), 3.492 (0.98), 3.504
(0.87), 3.520 (0.82), 3.531 (0.54), 3.949 (0.97), 3.978 (0.88),
4.146 (1.17), 4.179 (1.10), 4.355 (0.56), 4.376 (1.00), 4.397
(0.97), 4.417 (0.50), 4.505 (1.26), 4.518 (2.74), 4.531 (1.23),
7.499 (0.64), 7.528 (1.83), 7.540 (0.75), 7.551 (1.81), 7.580
(0.61), 8.071 (3.31), 8.105 (3.22), 8.876 (5.71), 10.386 (2.30),
10.410 (2.21).
Example 180
1-(2-Chloro-4,6-difluorophenyl)-7-(dimethylamino)-6-fluoro-N-(1,1,1,3,3,3-
-hexafluoropropan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
##STR00327##
[1512]
7-Chloro-1-(2-chloro-4,6-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-
-1,8-naphthyridine-3-carboxylic acid (250 mg, 642 .mu.mol),
1,1,1,3,3,3-hexafluoropropan-2-amine (118 mg, 707 .mu.mol) and
N,N-diisopropylethylamine (340 .mu.l, 1.9 mmol) were initially
charged in 6.5 ml of ethyl acetate, T3P solution
(2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide
(1.5 ml, 50% pure, 2.6 mmol) was added and the mixture was stirred
at 80.degree. C. overnight. More,
1,1,1,3,3,3-hexafluoropropan-2-amine (53.6 mg, 321 .mu.mol),
N,N-diisopropylethylamine (57 .mu.l, 0.32 mmol) and T3P solution
(2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide)
(188 .mu.l, 50% pure, 325 .mu.mol) were added and the mixture was
stirred at 80.degree. C. overnight. More,
1,1,1,3,3,3-hexafluoropropan-2-amine (60 mg, 359 .mu.mol) and T3P
solution (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane
2,4,6-trioxide) (750 .mu.l, 50% purity, 1.3 mmol) were added to the
reaction mixture and stirring was continued at 80.degree. C. The
mixture was added to water and ethyl acetate and the phases were
separated. The aqueous phase was reextracted with ethyl acetate.
The combined organic phases were washed with saturated aqueous
sodium chloride solution, dried over sodium sulphate, filtered and
concentrated on a rotary evaporator. The residue was purified by
preparative HPLC (RP18 column, mobile phase:
acetonitrile/water+0.1% formic acid gradient). The
product-containing fractions were combined and lyophilized. The
crude product was re-purified by prep. HPLC (RP18 column, mobile
phase: acetonitrile/water+2% formic acid gradient). This gave 4 mg
(100% pure, 1% of theory) of the target compound.
[1513] LC-MS (Method 3): R.sub.t=1.33 min; MS (ESIpos): m/z=547
[M+H].sup.+
[1514] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.008 (2.86),
2.328 (0.40), 2.367 (0.43), 3.019 (16.00), 3.023 (15.23), 6.302
(0.75), 6.320 (0.99), 6.345 (1.00), 6.363 (0.65), 7.699 (1.01),
7.706 (1.39), 7.722 (1.62), 7.729 (2.54), 7.745 (2.44), 7.752
(2.62), 7.762 (1.88), 7.773 (1.09), 8.037 (4.69), 8.071 (4.62),
8.948 (8.99), 11.276 (3.01), 11.301 (2.88).
Example 181
7-(3,4-Dihydroxypiperidin-1-yl)-6-fluoro-4-oxo-N-(3,3,4,4,4-pentafluorobu-
tan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbox-
amide (diastereomer mixture)
##STR00328##
[1516]
7-Chloro-6-fluoro-4-oxo-N-(3,3,4,4,4-pentafluorobutan-2-yl)-1-(2,4,-
6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (150
mg, 290 .mu.mol) (enantiomerically pure) was initially charged in
2.9 ml of N,N-dimethylformamide, and trans-piperidine-3,4-diol
hydrochloride (49.0 mg, 319 .mu.mol) and N,N-diisopropylethylamine
(230 .mu.l, 1.3 mmol) were added. The reaction mixture was stirred
at 55.degree. C. for 8 h. The reaction mixture was cooled, diluted
with acetonitrile and purified by prep. RP-HPLC (column: Reprosil
125.times.30; 10.mu., flow rate: 50 ml/min, acetonitrile/water,
0.1% formic acid). The solvents were concentrated by evaporation
under reduced pressure and the residue was dried under high vacuum.
This gave 105 mg (61% of theory, 100% pure) of the title
compound.
[1517] LC-MS (Method 3): R.sub.t=1.93 min; MS (ESIpos): m/z=599
[M+H].sup.+
[1518] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.69),
-0.008 (6.10), 0.008 (6.04), 0.146 (0.75), 1.230 (1.66), 1.389
(12.14), 1.406 (12.23), 1.771 (1.42), 1.782 (1.57), 1.791 (1.57),
1.814 (1.30), 2.329 (0.82), 2.367 (0.63), 2.671 (0.91), 2.711
(0.63), 3.292 (4.47), 3.350 (2.26), 3.367 (1.51), 3.447 (2.63),
3.530 (1.48), 3.549 (1.69), 3.773 (2.87), 3.806 (2.51), 4.892
(7.52), 4.901 (7.61), 4.970 (0.63), 4.999 (7.34), 5.010 (8.15),
5.034 (1.30), 5.058 (1.12), 7.554 (4.32), 7.576 (7.67), 7.597
(4.26), 8.022 (8.51), 8.057 (8.39), 8.889 (16.00), 10.392 (5.55),
10.416 (5.37).
Example 182
7-(3,4-Dihydroxypiperidin-1-yl)-6-fluoro-4-oxo-N-(3,3,4,4,4-pentafluorobu-
tan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbox-
amide (Diastereomer 1)
[1519] 105 mg of
7-(3,4-dihydroxypiperidin-1-yl)-6-fluoro-4-oxo-N-(3,3,4,4,4-pentafluorobu-
tan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbox-
amide (diastereomer mixture) were separated into the diastereomers
by chiral HPLC (preparative HPLC: column Daicel.RTM. Chiralpak IF,
5 .mu.m, 250.times.20 mm; mobile phase: 80% n-heptane/20% ethanol;
flow rate 15 ml/min; temperature: 25.degree. C., detection: 210
nm).
[1520] Diastereomer 1: 46.5 mg (>99% de)
[1521] R.sub.t=1.411 min [HPLC: column Daicel.RTM. Chiralpak IF-3,
1 ml/min; 3 .mu.m, 50.times.4.6 mm; mobile phase: 80% isohexane/20%
ethanol; detection: 220 nm].
[1522] The material obtained was re-purified by prep. HPLC (column:
Reprosil 125.times.30; 10.mu., flow rate: 50 ml/min,
acetonitrile/water, 0.1% formic acid). The solvents were evaporated
under reduced pressure and the residue was dried under high vacuum.
This gave 36 mg (21% of theory, 100% pure) of the title
compound.
[1523] LC-MS (Method 3): R.sub.t=1.92 min; MS (ESIpos): m/z=599
[M+H].sup.+
[1524] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.88),
-0.008 (7.15), 0.008 (7.01), 0.146 (0.88), 1.205 (1.69), 1.230
(1.76), 1.238 (1.66), 1.389 (13.36), 1.406 (13.46), 1.762 (1.52),
1.771 (1.66), 1.781 (1.80), 1.804 (1.52), 1.814 (1.37), 2.324
(0.74), 2.328 (1.02), 2.666 (0.81), 2.670 (1.13), 2.675 (0.85),
2.711 (0.39), 3.272 (4.09), 3.283 (4.58), 3.351 (2.54), 3.368
(1.73), 3.419 (1.06), 3.445 (3.03), 3.527 (1.62), 3.548 (1.80),
3.571 (1.27), 3.773 (3.07), 3.778 (3.24), 3.805 (2.85), 4.890
(8.88), 4.899 (8.92), 4.969 (0.70), 4.997 (9.23), 5.007 (9.73),
5.033 (1.41), 5.057 (1.16), 5.077 (0.60), 7.555 (4.44), 7.577
(7.72), 7.598 (4.37), 8.023 (9.59), 8.057 (9.41), 8.889 (16.00),
10.392 (6.13), 10.415 (5.89).
Example 183
7-(3,4-Dihydroxypiperidin-1-yl)-6-fluoro-4-oxo-N-(3,3,4,4,4-pentafluorobu-
tan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbox-
amide (Diastereomer 2)
[1525] 105 mg of
7-(3,4-dihydroxypiperidin-1-yl)-6-fluoro-4-oxo-N-(3,3,4,4,4-pentafluorobu-
tan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbox-
amide (diastereomer mixture) were separated into the diastereomers
by chiral HPLC (preparative HPLC: column Daicel.RTM. Chiralpak IF,
5 .mu.m, 250.times.20 mm; mobile phase: 80% n-heptane/20% ethanol;
flow rate 15 ml/min; temperature: 25.degree. C., detection: 210
nm).
[1526] Diastereomer 2: 46.7 mg (98.6% de)
[1527] R.sub.t=1.818 min [HPLC: column Daicel.RTM. Chiralpak IF-3,
1 ml/min; 3 .mu.m, 50.times.4.6 mm; mobile phase: 80% isohexane/20%
ethanol; detection: 220 nm].
[1528] The material obtained was re-purified by prep. HPLC (column:
Reprosil 125.times.30; 10.mu., flow rate: 50 ml/min,
acetonitrile/water, 0.1% formic acid). The solvents were evaporated
under reduced pressure and the residue was dried under high vacuum.
This gave 38 mg (22% of theory, 100% pure) of the title
compound.
[1529] LC-MS (Method 1): R.sub.t=1.00 min; MS (ESIpos): m/z=599
[M+H].sup.+
[1530] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.53),
-0.008 (4.75), 0.008 (4.93), 0.146 (0.53), 1.141 (1.14), 1.205
(1.62), 1.229 (1.72), 1.388 (13.04), 1.405 (13.14), 1.771 (1.42),
1.781 (1.62), 1.791 (1.77), 1.814 (1.42), 1.824 (1.34), 2.117
(0.53), 2.328 (1.19), 2.670 (1.21), 3.270 (3.77), 3.292 (4.95),
3.348 (2.43), 3.365 (1.69), 3.448 (2.91), 3.530 (1.54), 3.552
(1.79), 3.774 (3.24), 3.800 (2.86), 4.891 (8.24), 4.901 (8.32),
4.999 (8.47), 5.009 (9.30), 5.034 (1.34), 5.058 (1.19), 5.077
(0.66), 7.554 (4.73), 7.576 (8.44), 7.598 (4.65), 8.022 (9.48),
8.056 (9.15), 8.889 (16.00), 10.391 (5.79), 10.415 (5.69).
Example 184
6-Fluoro-7-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-oxo-N-(3,3,4,4,4-pen-
tafluorobutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridin-
e-3-carboxamide (enantiomerically pure)
##STR00329##
[1532]
7-Chloro-6-fluoro-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,-
6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(70.0 mg, 135 .mu.mol) (enantiomerically pure) was initially
charged in 1.4 ml of N,N-dimethylformamide, and
(2R)-pyrrolidin-2-ylmethanol (15.0 mg, 149 .mu.mol) and
N,N-diisopropylethylamine (82 .mu.l, 470 .mu.mol) were added. The
reaction mixture was stirred at 55.degree. C. for 8 h. The reaction
mixture was cooled, diluted with acetonitrile and purified by prep.
RP-HPLC (column: Reprosil 125.times.30; 10.mu., flow rate: 50
ml/min, acetonitrile/water, 0.1% formic acid). The solvents were
evaporated under reduced pressure and the residue was dried under
high vacuum. This gave 51 mg (65% of theory, 100% pure) of the
title compound.
[1533] LC-MS (Method 1): R.sub.t=1.17 min; MS (ESIpos): m/z=583
[M+H].sup.+
[1534] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (3.44),
0.008 (3.51), 0.146 (0.41), 1.386 (13.38), 1.403 (13.45), 1.811
(3.37), 1.927 (3.17), 2.329 (0.89), 2.367 (0.93), 2.670 (0.96),
2.711 (0.96), 3.263 (2.00), 3.276 (3.17), 3.290 (3.65), 3.598
(0.62), 4.634 (0.62), 4.966 (0.65), 4.986 (1.17), 5.009 (1.38),
5.029 (1.34), 5.053 (1.17), 5.073 (0.62), 7.500 (1.51), 7.525
(6.09), 7.548 (6.23), 7.573 (1.62), 7.982 (8.77), 8.015 (8.57),
8.846 (16.00), 10.451 (5.85), 10.474 (5.68).
Example 185
6-Fluoro-7-[(2R)-2-(hydroxymethyl)piperidin-1-yl]-4-oxo-N-(3,3,4,4,4-pent-
afluorobutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-
-3-carboxamide (enantiomerically pure)
##STR00330##
[1536]
7-Chloro-6-fluoro-4-oxo-N-(3,3,4,4,4-pentafluorobutan-2-yl)-1-(2,4,-
6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(70.0 mg, 135 .mu.mol) (enantiomerically pure) was initially
charged in 1.4 ml of N,N-dimethylformamide, and
(2R)-piperidin-2-ylmethanol (17.1 mg, 149 .mu.mol) and
N,N-diisopropylethylamine (82 .mu.l, 470 .mu.mol) were added. The
reaction mixture was stirred at 55.degree. C. for 18 h. The
reaction mixture was cooled, diluted with acetonitrile and purified
by prep. RP-HPLC (column: Reprosil 125.times.30; 10.mu., flow rate:
50 ml/min, acetonitrile/water, 0.1% formic acid). The solvents were
evaporated under reduced pressure and the residue was dried under
high vacuum. This gave 47 mg (58% of theory, 99% pure) of the title
compound.
[1537] LC-MS (Method 3): R.sub.t=1.22 min; MS (ESIpos): m/z=597
[M+H].sup.+
[1538] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.42),
-0.008 (3.95), 0.008 (4.02), 0.146 (0.46), 1.388 (14.45), 1.406
(14.10), 1.470 (2.22), 1.520 (3.70), 1.529 (4.02), 1.549 (6.66),
1.577 (2.64), 1.721 (2.29), 1.741 (2.15), 2.328 (1.06), 2.367
(1.02), 2.671 (1.02), 2.711 (0.99), 2.919 (1.27), 2.949 (2.36),
2.981 (1.27), 3.475 (1.13), 3.492 (1.83), 3.503 (2.85), 3.518
(3.10), 3.533 (2.15), 3.558 (1.37), 3.574 (2.36), 3.587 (2.04),
3.852 (2.15), 3.885 (1.97), 4.287 (2.43), 4.660 (3.42), 4.673
(7.47), 4.687 (3.31), 4.967 (0.63), 4.988 (1.16), 5.010 (1.34),
5.030 (1.37), 5.055 (1.16), 5.076 (0.67), 7.533 (1.73), 7.546
(4.16), 7.553 (4.83), 7.569 (4.83), 7.576 (4.30), 7.589 (1.69),
7.996 (9.37), 8.031 (9.13), 8.870 (16.00), 10.399 (5.92), 10.423
(5.67).
Example 186
6-Fluoro-7-[4-hydroxy-4-(hydroxymethyl)piperidin-1-yl]-4-oxo-N-[3,3,4,4,4-
-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyr-
idine-3-carboxamide (enantiomerically pure)
##STR00331##
[1540]
7-Chloro-6-fluoro-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,-
6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(70.0 mg, 135 .mu.mol) (enantiomerically pure) was initially
charged in 1.4 ml of N,N-dimethylformamide, and
4-(hydroxymethyl)piperidin-4-ol hydrochloride (24.9 mg, 149
.mu.mol) and N,N-diisopropylethylamine (110 .mu.l, 610 .mu.mol)
were added. The reaction mixture was stirred at 55.degree. C. for 8
h. The reaction mixture was cooled, diluted with acetonitrile and
purified by prep. RP-HPLC (column: Reprosil 125.times.30; 10.mu.,
flow rate: 50 ml/min, acetonitrile/water, 0.1% formic acid). The
solvents were evaporated under reduced pressure and the residue was
dried under high vacuum. This gave 55 mg (66% of theory, 100% pure)
of the title compound.
[1541] LC-MS (Method 3): R.sub.t=1.99 min; MS (ESIpos): m/z=613
[M+H].sup.+
[1542] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.92),
-0.008 (8.27), 0.008 (7.14), 0.146 (0.92), 1.311 (4.72), 1.345
(6.17), 1.388 (13.79), 1.405 (13.76), 1.504 (2.72), 1.534 (4.37),
1.567 (2.07), 2.328 (1.00), 2.367 (1.00), 2.670 (1.00), 2.711
(0.89), 3.142 (11.28), 3.156 (11.34), 3.249 (2.98), 3.280 (5.93),
3.891 (4.66), 3.923 (4.28), 4.324 (14.08), 4.562 (3.31), 4.576
(7.56), 4.590 (3.25), 4.968 (0.65), 4.989 (1.15), 5.009 (1.39),
5.033 (1.45), 5.055 (1.18), 5.076 (0.65), 7.558 (5.37), 7.580
(10.13), 7.603 (5.34), 8.036 (9.12), 8.070 (8.86), 8.886 (16.00),
10.389 (6.11), 10.413 (5.85).
Example 187
7-[4,4-bis(hydroxymethyl)piperidin-1-yl]-6-fluoro-4-oxo-N-(3,3,4,4,4-pent-
afluorobutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-
-3-carboxamide (enantiomerically pure)
##STR00332##
[1544]
7-Chloro-6-fluoro-4-oxo-N-(3,3,4,4,4-pentafluorobutan-2-yl)-1-(2,4,-
6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(70.0 mg, 135 .mu.mol) (enantiomerically pure) were initially
charged in 1.4 ml of N,N-dimethylformamide, and
piperidin-4,4-diyldimethanol hydrochloride (27.0 mg, 149 .mu.mol)
and N,N-diisopropylethylamine (110 .mu.l, 610 .mu.mol) were added.
The reaction mixture was stirred at 55.degree. C. for 8 h. The
reaction mixture was cooled, diluted with acetonitrile and purified
by prep. RP-HPLC (column: Reprosil 125.times.30; 10.mu., flow rate:
50 ml/min, acetonitrile/water, 0.1% formic acid). The solvents were
evaporated under reduced pressure and the residue was dried under
high vacuum. This gave 45 mg (53% of theory, 100% pure) of the
title compound.
[1545] LC-MS (Method 3): R.sub.t=2.02 min; MS (ESIpos): m/z=626
[M+H].sup.+
[1546] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.58),
0.008 (4.01), 0.146 (0.58), 1.347 (6.26), 1.361 (7.91), 1.375
(6.74), 1.387 (9.36), 1.404 (8.55), 2.328 (0.61), 2.367 (0.68),
2.671 (0.66), 2.710 (0.68), 3.271 (14.94), 3.285 (16.00), 3.507
(5.81), 3.520 (7.20), 4.405 (4.49), 4.419 (9.86), 4.432 (4.11),
4.967 (0.48), 4.988 (0.76), 5.009 (0.91), 5.031 (0.89), 5.054
(0.76), 7.555 (3.37), 7.577 (6.24), 7.600 (3.27), 8.020 (5.48),
8.055 (5.27), 8.873 (9.38), 10.399 (3.85), 10.424 (3.63).
Example 188
6-Fluoro-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-7-[(2R)-2-(hydroxymethyl)p-
iperidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridi-
ne-3-carboxamide
##STR00333##
[1548]
7-Chloro-6-fluoro-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-4-oxo-1-(2,-
4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(50.0 mg, 95.8 .mu.mol) was initially charged in 1 ml of DMF,
(2R)-piperidin-2-ylmethanol (12.1 mg, 105 .mu.mol) and
N,N-diisopropylethylamine (58 .mu.l, 340 .mu.mol) were added and
the mixture was stirred at 55.degree. C. for 8 h. The reaction
solution was cooled and purified by preparative HPLC (RP18 column,
mobile phase: acetonitrile/water gradient with addition of 0.1%
formic acid). The product fractions were combined and concentrated
by evaporation. This gave 43 mg of the target compound (74% of
theory, purity 100%).
[1549] LC-MS (Method 3): R.sub.t=2.37 min; MS (ESIpos): m/z=601
[M+H].sup.+
[1550] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 1.378 (1.60),
1.476 (2.24), 1.534 (3.84), 1.555 (6.73), 1.725 (2.33), 1.743
(2.24), 2.328 (1.90), 2.366 (0.52), 2.670 (2.12), 2.710 (0.80),
2.930 (1.23), 2.960 (2.27), 2.992 (1.32), 3.494 (1.75), 3.506
(2.83), 3.520 (3.01), 3.535 (1.97), 3.578 (2.30), 3.866 (2.09),
3.899 (1.97), 4.298 (2.43), 4.679 (2.73), 4.692 (5.59), 4.705
(2.76), 6.325 (1.75), 6.347 (1.84), 7.547 (1.75), 7.567 (4.82),
7.583 (4.88), 7.604 (1.81), 8.034 (8.97), 8.068 (8.60), 8.541
(0.64), 8.995 (16.00), 11.231 (5.71), 11.256 (5.44).
Example 189
6-Fluoro-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-7-[4-hydroxy-4-(hydroxymet-
hyl)piperidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphth-
yridine-3-carboxamide
##STR00334##
[1552]
7-Chloro-6-fluoro-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-4-oxo-1-(2,-
4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(50.0 mg, 95.8 .mu.mol) was initially charged in 1 ml of DMF,
4-(hydroxymethyl)piperidin-4-ol hydrochloride (18.6 mg, 95% purity,
105 .mu.mol) and N,N-diisopropylethylamine (75 .mu.l, 430 .mu.mol)
were added and the mixture was stirred at 55.degree. C. for 8 h.
The reaction solution was cooled and purified by preparative HPLC
(RP18 column, mobile phase: acetonitrile/water gradient with
addition of 0.1% formic acid). The product fractions were combined
and concentrated by evaporation. This gave 30 mg of the target
compound (50% of theory, purity 100%).
[1553] LC-MS (Method 3): R.sub.t=2.05 min; MS (ESIpos): m/z=617
[M+H].sup.+
[1554] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.46),
-0.008 (5.62), 0.008 (3.80), 0.146 (0.44), 1.320 (4.64), 1.353
(5.97), 1.505 (2.67), 1.515 (3.07), 1.538 (4.37), 1.546 (4.30),
1.570 (2.28), 1.580 (1.92), 2.329 (0.77), 2.671 (0.81), 3.146
(11.34), 3.160 (11.17), 3.262 (3.24), 3.291 (7.90), 3.569 (0.46),
3.907 (4.70), 3.940 (4.16), 4.332 (14.24), 4.565 (3.63), 4.579
(8.00), 4.593 (3.38), 6.307 (1.30), 6.331 (1.78), 6.348 (1.80),
6.367 (1.23), 7.573 (5.26), 7.595 (9.59), 7.617 (5.06), 8.073
(9.13), 8.107 (8.75), 9.009 (16.00), 11.219 (5.76), 11.244
(5.41).
Example 190
1-(3,5-Difluoropyridin-2-yl)-6-fluoro-N-(1,1,1,3,3,3-hexafluoropropan-2-y-
l)-7-[(2R)-2-(hydroxymethyl)piperidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthyr-
idine-3-carboxamide
##STR00335##
[1556]
7-Chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-N-(1,1,1,3,3,3-hexaf-
luoropropan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(50.0 mg, 99.1 .mu.mol) was initially charged in 1 ml of DMF,
(2R)-piperidin-2-ylmethanol (12.6 mg, 109 .mu.mol) and
N,N-diisopropylethylamine (8.6 .mu.l, 50 .mu.mol) were added and
the mixture was stirred at 55.degree. C. for 8 h. More
(2R)-piperidin-2-ylmethanol (5.7 mg, 50 .mu.mol) and
N,N-diisopropylethylamine (8.6 .mu.l, 50 .mu.mol) were added and
the mixture was stirred at 55.degree. C. The reaction solution was
cooled and purified by preparative HPLC (RP18 column, mobile phase:
acetonitrile/water gradient with addition of 0.1% formic acid). The
product fractions were combined and concentrated by evaporation.
This gave 37 mg of the target compound (63% of theory, purity
99%).
[1557] LC-MS (Method 3): R.sub.t=2.26 min; MS (ESIpos): m/z=584
[M+H].sup.+
[1558] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.99),
-0.008 (7.81), 0.008 (7.07), 0.146 (0.93), 1.339 (1.30), 1.525
(9.67), 1.545 (8.81), 1.616 (2.67), 1.647 (2.17), 1.745 (3.97),
2.328 (1.86), 2.367 (0.68), 2.670 (1.98), 2.711 (0.68), 2.921
(2.17), 2.954 (1.61), 3.002 (1.74), 3.031 (0.99), 3.473 (1.74),
3.489 (3.22), 3.500 (6.02), 3.515 (7.75), 3.529 (6.20), 3.581
(2.54), 3.859 (4.59), 3.892 (4.28), 4.286 (3.16), 4.660 (3.10),
4.697 (4.90), 6.300 (1.05), 6.317 (2.67), 6.335 (3.78), 6.360
(3.91), 6.378 (2.60), 6.397 (0.99), 8.037 (9.92), 8.071 (10.23),
8.339 (4.53), 8.357 (4.09), 8.629 (16.00), 8.635 (15.32), 8.956
(9.80), 11.224 (12.84), 11.250 (12.34).
Example 191
7-[4,4-bis(hydroxymethyl)piperidin-1-yl]-6-fluoro-N-(1,1,1,3,3,3-hexafluo-
ropropan-2-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridi-
ne-3-carboxamide
##STR00336##
[1560]
7-Chloro-6-fluoro-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-4-oxo-1-(2,-
4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(50.0 mg, 95.8 .mu.mol) was initially charged in 1 ml of DMF,
piperidin-4,4-diyldimethanol hydrochloride (20.2 mg, 95% purity,
105 .mu.mol) and N,N-diisopropylethylamine (75 .mu.l, 430 .mu.mol)
were added and the mixture was stirred at 55.degree. C. for 8 h.
The reaction solution was cooled and purified by preparative HPLC
(RP18 column, mobile phase: acetonitrile/water gradient with
addition of 0.1% formic acid). The product fractions were combined
and concentrated by evaporation. This gave 52 mg of the target
compound (85% of theory, purity 100%).
[1561] LC-MS (Method 3): R.sub.t=2.07 min; MS (ESIpos): m/z=631
[M+H].sup.+
[1562] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 1.354 (7.76),
1.368 (10.28), 1.382 (8.05), 2.328 (1.17), 2.670 (1.30), 3.276
(15.51), 3.285 (16.00), 3.520 (7.34), 3.534 (9.74), 4.423 (5.58),
6.287 (0.42), 6.304 (1.10), 6.329 (1.52), 6.347 (1.61), 6.365
(1.05), 7.571 (4.40), 7.592 (8.22), 7.614 (4.45), 8.058 (7.63),
8.092 (7.49), 8.996 (13.58), 11.232 (5.36), 11.258 (5.09).
Example 192
6-Fluoro-7-[3-hydroxy-3-(hydroxymethyl)piperidin-1-yl]-4-oxo-N-[3,3,4,4,4-
-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyr-
idine-3-carboxamide (diastereomer mixture)
##STR00337##
[1564]
7-Chloro-6-fluoro-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,-
6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (100
mg, 94% purity, 182 .mu.mol) (enantiomerically pure) was initially
charged in 2 ml of DMF, 3-(hydroxymethyl)piperidin-3-ol (26.2 mg,
200 .mu.mol) and N,N-diisopropylethylamine (110 .mu.l, 640 .mu.mol)
were added and the mixture was stirred at room temperature for 18
h. The reaction solution was purified by preparative HPLC (RP18
column, mobile phase: acetonitrile/water gradient with addition of
0.1% formic acid). The product fractions were concentrated by
evaporation. This gave 88 mg of the target compound (79% of theory,
purity 100%).
[1565] LC-MS (Method 3): R.sub.t=2.03 min; MS (ESIpos): m/z=613
[M+H].sup.+
[1566] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (1.00),
-0.008 (14.16), 0.008 (7.76), 0.146 (0.94), 1.273 (2.39), 1.387
(15.20), 1.404 (15.48), 1.599 (1.18), 1.628 (4.19), 1.655 (4.40),
2.328 (1.52), 2.670 (1.59), 2.901 (1.97), 3.105 (1.39), 3.132
(4.12), 3.149 (6.34), 3.164 (4.43), 3.177 (1.49), 3.192 (1.28),
3.770 (2.53), 3.803 (2.25), 3.834 (2.81), 3.868 (2.35), 4.241
(10.29), 4.655 (3.15), 4.669 (6.20), 4.683 (2.84), 4.988 (1.25),
5.013 (1.42), 5.032 (1.42), 5.056 (1.18), 7.556 (3.71), 7.566
(4.71), 7.579 (4.68), 7.598 (2.01), 7.971 (7.48), 8.005 (7.34),
8.875 (16.00), 10.424 (5.44), 10.447 (5.23).
Example 193
6-Fluoro-7-[(2S,3S)-3-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl]-4-oxo-N-(-
3,3,4,4,4-pentafluoro-2-methylbutan-2-yl)-1-(2,4,6-trifluorophenyl)-1,4-di-
hydro-1,8-naphthyridine-3-carboxamide
##STR00338##
[1568]
7-Chloro-6-fluoro-4-oxo-N-(3,3,4,4,4-pentafluoro-2-methylbutan-2-yl-
)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(100 mg, 188 .mu.mol) was initially charged in 1.9 ml of DMF,
(2S,3S)-2-(hydroxymethyl)pyrrolidin-3-ol hydrochloride (37.6 mg,
244 .mu.mol) and N,N-diisopropylethylamine (150 .mu.l, 850 .mu.mol)
were added and the mixture was stirred at 55.degree. C. for 12 h.
The reaction solution was cooled and purified by preparative HPLC
(RP18 column, mobile phase: acetonitrile/water gradient with
addition of 0.1% formic acid). The product fractions were combined
and concentrated by evaporation. This gave 93 mg of the target
compound (81% of theory, purity 100%).
[1569] LC-MS (Method 3): R.sub.t=2.08 min; MS (ESIpos): m/z=613
[M+H].sup.+
[1570] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (3.03),
0.008 (2.80), 1.681 (16.00), 1.953 (1.23), 1.969 (1.25), 2.073
(0.51), 3.478 (1.10), 4.273 (0.92), 5.176 (1.16), 5.185 (1.14),
7.531 (1.06), 7.550 (1.89), 7.570 (1.10), 7.993 (2.68), 8.026
(2.62), 8.783 (5.55), 10.556 (4.22).
Example 194
6-Fluoro-7-[(2S,3S)-3-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl]-4-oxo-N-[-
3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-
-naphthyridine-3-carboxamide (enantiomerically pure)
##STR00339##
[1572]
7-Chloro-6-fluoro-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,-
6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(80.0 mg, 155 .mu.mol) was initially charged in 1.5 ml of DMF,
(2S,3S)-2-(hydroxymethyl)pyrrolidin-3-ol hydrochloride (30.9 mg,
201 .mu.mol) and N,N-diisopropylethylamine (120 .mu.l, 700 .mu.mol)
were added and the mixture was stirred at 55.degree. C. for 12 h.
The reaction solution was cooled and purified by preparative HPLC
(RP18 column, mobile phase: acetonitrile/water gradient with
addition of 0.1% formic acid). The combined product fractions were
concentrated by evaporation. This gave 75 mg of the target compound
(81% of theory, purity 100%).
[1573] LC-MS (Method 3): R.sub.t=1.98 min; MS (ESIpos): m/z=599
[M+H].sup.+
[1574] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (1.46),
-0.008 (11.75), 0.008 (11.23), 0.146 (1.43), 1.386 (12.95), 1.403
(13.01), 1.953 (3.41), 1.970 (3.44), 2.328 (1.14), 2.367 (0.42),
2.670 (1.17), 2.711 (0.42), 3.481 (3.05), 4.272 (2.50), 4.964
(0.62), 4.986 (1.10), 5.006 (1.33), 5.028 (1.30), 5.051 (1.14),
5.072 (0.58), 5.185 (2.82), 7.531 (2.89), 7.552 (5.16), 7.569
(2.86), 7.976 (7.30), 8.008 (7.08), 8.032 (0.42), 8.848 (16.00),
10.446 (5.71), 10.470 (5.52).
Example 195
7-[4,4-bis(hydroxymethyl)piperidin-1-yl]-1-(3,5-difluoropyridin-2-yl)-6-f-
luoro-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyr-
idine-3-carboxamide
##STR00340##
[1576]
7-Chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-N-(1,1,1,3,3,3-hexaf-
luoropropan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(50.0 mg, 99.1 .mu.mol) was initially charged in 1 ml of DMF,
piperidin-4,4-diyldimethanol hydrochloride (20.8 mg, 95% purity,
109 .mu.mol) and N,N-diisopropylethylamine (78 .mu.l, 450 .mu.mol)
were added and the mixture was stirred at 55.degree. C. overnight.
The reaction solution was cooled and purified by preparative HPLC
(RP18 column, mobile phase: acetonitrile/water gradient with
addition of 0.1% formic acid). The product fractions were combined
and concentrated by evaporation. This gave 36 mg of the target
compound (59% of theory, purity 99%).
[1577] LC-MS (Method 3): R.sub.t=1.96 min; MS (ESIpos): m/z=614
[M+H].sup.+
[1578] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 1.364 (0.66),
1.378 (1.01), 1.393 (0.69), 3.278 (1.57), 3.291 (1.64), 3.312
(16.00), 3.529 (0.79), 4.413 (0.47), 4.427 (1.05), 4.440 (0.47),
8.061 (0.74), 8.095 (0.72), 8.636 (0.86), 8.642 (0.82), 8.958
(1.64), 11.226 (0.46), 11.251 (0.44).
Example 196
6-Fluoro-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-7-(2-oxa-6-azaspiro[3.3]he-
pt-6-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-c-
arboxamide
##STR00341##
[1580]
7-Chloro-6-fluoro-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-4-oxo-1-(2,-
4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(100 mg, 100% purity, 192 .mu.mol) was initially charged in 2.1 ml
of DMF, ethanedioic acid 2-oxa-6-azaspiro[3.3]heptane (1:2) (71.8
mg, 249 .mu.mol) and N,N-diisopropylethylamine (120 .mu.l, 670
.mu.mol) were added and the mixture was stirred at 55.degree. C.
for 18 h. The reaction solution was allowed to stand at room
temperature over the weekend. The mixture was then purified by
preparative HPLC (RP18 column, mobile phase: acetonitrile/water
gradient with addition of 0.1% formic acid). The product fractions
were combined and concentrated by evaporation. This gave 89 mg of
the target compound (79% of theory, purity 99%).
[1581] LC-MS (Method 3): R.sub.t=2.31 min; MS (ESIpos): m/z=585
[M+H].sup.+
[1582] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (2.33),
0.008 (2.26), 4.656 (16.00), 6.297 (0.41), 6.316 (0.57), 6.339
(0.61), 7.556 (1.64), 7.578 (2.94), 7.600 (1.63), 8.020 (2.85),
8.049 (2.83), 8.965 (4.77), 11.258 (1.92), 11.284 (1.84).
Example 197
1-(3,5-Difluoropyridin-2-yl)-6-fluoro-N-(1,1,1,3,3,3-hexafluoropropan-2-y-
l)-7-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-oxo-1,4-dihydro-1,8-naphthy-
ridine-3-carboxamide
##STR00342##
[1584]
7-Chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-N-(1,1,1,3,3,3-hexaf-
luoropropan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(50.0 mg, 99.1 .mu.mol) was initially charged in 1 ml of DMF,
(2R)-pyrrolidin-2-ylmethanol (11 .mu.l, 99% purity, 110 .mu.mol)
and N,N-diisopropylethylamine (60 .mu.l, 350 .mu.mol) were added
and the mixture was stirred at 55.degree. C. overnight. The
reaction solution was cooled and purified by preparative HPLC (RP18
column, mobile phase: acetonitrile/water gradient with addition of
0.1% formic acid). The product fractions were combined, freed from
the solvent and lyophilized. This gave 30 mg (52% of theory, 98%
pure) of the title compound.
[1585] LC-MS (Method 3): R.sub.t=2.17 min; MS (ESIpos): m/z=570
[M+H].sup.+
[1586] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (1.37),
0.146 (1.76), 1.820 (7.75), 1.934 (7.70), 2.328 (2.31), 2.670
(2.69), 2.711 (0.66), 3.160 (2.09), 3.576 (1.54), 4.710 (1.43),
6.309 (2.91), 6.328 (4.23), 6.352 (4.40), 6.369 (2.97), 8.021
(10.28), 8.054 (10.17), 8.284 (2.97), 8.309 (3.30), 8.335 (3.68),
8.353 (1.87), 8.557 (1.87), 8.612 (16.00), 8.939 (11.22), 8.954
(9.68), 11.287 (12.70), 11.312 (12.10).
Example 198
1-(3,5-Difluoropyridin-2-yl)-6-fluoro-N-(1,1,1,3,3,3-hexafluoropropan-2-y-
l)-7-[4-hydroxy-4-(hydroxymethyl)piperidin-1-yl]-4-oxo-1,4-dihydro-1,8-nap-
hthyridine-3-carboxamide
##STR00343##
[1588]
7-Chloro-1-(3,5-difluoropyridin-2-yl)-6-fluoro-N-(1,1,1,3,3,3-hexaf-
luoropropan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(50.0 mg, 99.1 .mu.mol) was initially charged in 1 ml of DMF,
4-(hydroxymethyl)piperidin-4-ol hydrochloride (19.2 mg, 95% purity,
109 .mu.mol) and N,N-diisopropylethylamine (78 .mu.l, 450 .mu.mol)
were added and the mixture was stirred at 55.degree. C. overnight.
The reaction solution was cooled and purified by preparative HPLC
(RP18 column, mobile phase: acetonitrile/water gradient with
addition of 0.1% formic acid). The product fractions were combined
and freed from the solvent. The residue was purified by silica gel
chromatography (mobile phase: dichloromethane to ethyl acetate).
The product-containing fractions were combined, concentrated by
evaporation and lyophilized from acetonitrile/water overnight. This
gave 22.3 mg (37% of theory, 99% pure) of the title compound.
[1589] LC-MS (Method 1): R.sub.t=1.02 min; MS (ESIpos): m/z=600
[M+H].sup.+
[1590] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.70),
-0.008 (6.17), 0.008 (5.68), 0.146 (0.70), 1.235 (0.55), 1.284
(0.76), 1.298 (1.40), 1.312 (1.56), 1.347 (3.39), 1.383 (2.11),
1.491 (1.10), 1.524 (1.89), 1.543 (1.89), 1.566 (1.92), 1.598
(0.89), 2.041 (1.13), 2.328 (1.01), 2.366 (0.43), 2.670 (1.13),
2.710 (0.52), 3.147 (10.11), 3.162 (10.20), 3.233 (1.01), 3.266
(2.08), 3.912 (2.81), 4.329 (12.64), 4.564 (2.93), 4.578 (6.81),
4.592 (2.96), 6.318 (0.98), 6.343 (1.50), 6.360 (1.59), 6.379
(1.04), 8.076 (7.76), 8.110 (7.60), 8.354 (1.74), 8.360 (2.05),
8.382 (3.11), 8.399 (1.92), 8.405 (2.02), 8.638 (8.98), 8.645
(8.52), 8.969 (16.00), 11.212 (5.31), 11.238 (5.07).
Example 199
6-Fluoro-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-7-[(2R)-2-(hydroxymethyl)p-
yrrolidin-1-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyrid-
ine-3-carboxamide
##STR00344##
[1592]
7-Chloro-6-fluoro-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-4-oxo-1-(2,-
4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(50.0 mg, 95.8 .mu.mol) was initially charged in 1 ml of DMF,
(2R)-pyrrolidin-2-ylmethanol (11 .mu.l, 99% purity, 110 .mu.mol)
and N,N-diisopropylethylamine (58 .mu.l, 340 .mu.mol) were added
and the mixture was stirred at 55.degree. C. for 8 h. The reaction
solution was cooled and purified by preparative HPLC (RP18 column,
mobile phase: acetonitrile/water gradient with addition of 0.1%
formic acid). The product fractions were combined and freed from
the solvent. The residue was re-purified by preparative HPLC (RP18
column, mobile phase: acetonitrile/water gradient with addition of
0.1% formic acid). The product fractions were combined and freed
from the solvent. The residue was purified by silica gel
chromatography (ethyl acetate/cyclohexane gradient). After
concentration by evaporation the residue was re-purified by
preparative HPLC (RP18 column, mobile phase: acetonitrile/water
gradient with addition of 0.1% formic acid). The product-containing
fractions were combined, concentrated by evaporation and
lyophilized from acetonitrile/water overnight. This gave 14.2 mg
(25% of theory, 99% pure) of the title compound.
[1593] LC-MS (Method 3): R.sub.t=2.27 min; MS (ESIpos): m/z=587
[M+H].sup.+
[1594] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.99),
0.146 (0.93), 1.821 (3.92), 1.933 (3.51), 2.328 (1.13), 2.367
(0.90), 2.670 (1.25), 2.711 (0.87), 3.346 (1.19), 3.603 (0.64),
4.641 (0.64), 6.299 (1.39), 6.317 (2.03), 6.341 (2.15), 6.360
(1.36), 7.518 (1.74), 7.540 (6.68), 7.563 (6.85), 7.587 (1.92),
8.020 (8.68), 8.052 (8.57), 8.974 (16.00), 11.291 (6.45), 11.316
(6.16).
Example 200
6-Fluoro-7-[6-hydroxy-1,4-diazepan-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluorobu-
tan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbox-
amide (diastereomer mixture)
##STR00345##
[1596] 1,4-Diazepan-6-ol dihydrobroaide (37.6 mg, 135 .mu.mol) was
initially charged in 0.26 ml of DMF and N,N-diisopropylethylamine
(170 .mu.l, 970 .mu.mol).
7-Chloro-6-fluoro-4-oxo-N-(3,3,4,4,4-pentafluorobutan-2-yl)-1-(2,4,6-trif-
luorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(enantiomerically pure) (100 mg, 193 .mu.mol) was dissolved in 0.79
ml of DMF and slowly added dropwise to the first mixture and
stirred at room temperature overnight. The reaction solution was
diluted with acetonitrile, water and TFA and purified by
preparative HPLC (RP18 column, mobile phase: acetonitrile/water
gradient with addition of 0.1% TFA). The combined product fractions
were concentrated by evaporation. The residue was dissolved in
dichloromethane and washed twice with saturated aqueous sodium
bicarbonate solution. The combined aqueous phases were re-extracted
twice with dichloromethane. The combined organic phases were dried
over sodium sulphate, filtered and concentrated by evaporation.
This gave 37 mg of the target compound (32% of theory, purity
99%).
[1597] LC-MS (Method 3): R.sub.t=1.43 min; MS (ESIpos): m/z=598
[M+H].sup.+
[1598] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (1.01),
-0.008 (8.78), 0.008 (8.35), 0.146 (1.01), 0.853 (0.86), 1.234
(1.21), 1.387 (11.18), 1.404 (11.23), 2.156 (0.61), 2.328 (1.59),
2.366 (0.56), 2.570 (3.81), 2.670 (4.29), 2.697 (1.59), 3.627
(1.89), 3.854 (1.84), 3.878 (1.67), 4.729 (1.49), 4.989 (0.98),
5.010 (1.09), 5.033 (1.14), 5.754 (11.43), 7.541 (3.56), 7.547
(3.63), 7.564 (4.21), 7.584 (1.51), 7.993 (7.97), 8.027 (7.80),
8.868 (16.00), 10.414 (4.90), 10.438 (4.79).
Example 201
N-[1-cyclopropyl-2,2,3,3,3-pentafluoropropyl]-7-[(3R,4R)-3,4-dihydroxypyr-
rolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-nap-
hthyridine-3-carboxamide (enantiomer 1)
##STR00346##
[1600]
7-Chloro-N-[1-cyclopropyl-2,2,3,3,3-pentafluoropropyl]-6-fluoro-4-o-
xo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(enantiomer 1) (100 mg, 184 .mu.mol) was initially charged in 1 ml
of DMF. (3R,4R)-pyrrolidine-3,4-diol hydrochloride (30.8 mg, 221
.mu.mol) was added, N,N-diisopropylethylamine (160 .mu.l, 920
.mu.mol) was added and the mixture was stirred at room temperature
overnight. Water/acetonitrile/TFA were added and the reaction
solution was purified by preparative HPLC (RP18 column, mobile
phase: acetonitrile/water gradient with addition of 0.1% TFA). The
combined product fractions were concentrated by evaporation. The
residue was dissolved in dichloromethane and a little methanol and
washed twice with saturated aqueous sodium bicarbonate solution.
The combined aqueous phases were re-extracted twice with
dichloromethane. The combined organic phases were dried over sodium
sulphate, filtered and concentrated by evaporation. This gave 103
mg of the target compound (90% of theory, purity 98%).
[1601] Enantiomer 1: ee>97%, R.sub.t=7.703 min [analytical HPLC:
column Daicel.RTM. Chiralpak IA, 5 .mu.m, 250.times.4.6 mm; 1
ml/min, 30.degree. C.; mobile phase: 80% isohexane/20% ethanol;
detection: 220 nm].
[1602] LC-MS (Method 1): R.sub.t=1.06 min; MS (ESIpos): m/z=611
[M+H].sup.+
[1603] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.56),
-0.008 (4.36), 0.008 (4.16), 0.146 (0.52), 0.308 (0.79), 0.320
(1.84), 0.332 (2.92), 0.345 (3.15), 0.357 (2.45), 0.369 (1.11),
0.486 (0.86), 0.497 (2.37), 0.509 (3.34), 0.521 (2.94), 0.533
(2.22), 0.545 (1.02), 0.566 (1.01), 0.576 (1.14), 0.587 (2.39),
0.599 (2.71), 0.609 (2.26), 0.620 (1.96), 0.633 (1.13), 0.650
(1.29), 0.670 (2.35), 0.683 (2.68), 0.696 (2.09), 0.717 (0.67),
1.207 (0.50), 1.219 (1.14), 1.227 (1.75), 1.240 (2.91), 1.249
(2.16), 1.260 (2.69), 1.272 (1.47), 1.281 (0.95), 2.328 (0.94),
2.367 (0.61), 2.670 (0.98), 2.711 (0.58), 3.066 (1.02), 3.700
(1.05), 3.906 (2.19), 4.022 (1.54), 4.434 (0.67), 4.457 (1.66),
4.479 (2.15), 4.501 (2.09), 4.522 (1.69), 4.545 (0.63), 5.202
(4.77), 7.556 (3.48), 7.577 (6.29), 7.597 (3.48), 8.011 (9.15),
8.043 (8.99), 8.838 (16.00), 10.542 (6.29), 10.566 (6.04).
Example 202
N-[1-cyclopropyl-2,2,3,3,3-pentafluoropropyl]-7-[(3R,4R)-3,4-dihydroxypyr-
rolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-nap-
hthyridine-3-carboxamide (enantiomer 2)
##STR00347##
[1605]
7-Chloro-N-[l-cyclopropyl-2,2,3,3,3-pentafluoropropyl]-6-fluoro-4-o-
xo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(enantiomer 2) (100 mg, 184 .mu.mol) was initially charged in 1 ml
of DMF. (3R,4R)-pyrrolidine-3,4-diol hydrochloride (30.8 mg, 221
.mu.mol) and N,N-diisopropylethylamine (160 .mu.l, 920 .mu.mol)
were added and the mixture was stirred at room temperature
overnight. Water/acetonitrile/TFA were added and the reaction
solution was purified by preparative HPLC (RP18 column, mobile
phase: acetonitrile/water gradient with addition of 0.1% TFA). The
combined product fractions were concentrated by evaporation. The
residue was dissolved in dichloromethane and a little methanol and
washed twice with saturated aqueous sodium bicarbonate solution.
The combined aqueous phases were re-extracted twice with
dichloromethane. The combined organic phases were dried over sodium
sulphate, filtered and concentrated by evaporation. This gave 105
mg of the target compound (92% of theory, purity 98%).
[1606] Enantiomer 2: ee>96.5%. R.sub.t=6.54 min [analytical
HPLC: column Daicel.RTM. Chiralpak IA, 5 .mu.m, 250.times.4.6 mm; 1
mil/min, 30.degree. C.; mobile phase: 80% isohexane/20% ethanol;
detection: 220 nm].
[1607] LC-MS (Method 1): R.sub.t=1.06 min; MS (ESIpos): m/z=611
[M+H].sup.+
[1608] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.68),
0.146 (0.64), 0.308 (0.75), 0.321 (1.88), 0.333 (2.90), 0.345
(3.19), 0.357 (2.48), 0.369 (1.09), 0.487 (0.83), 0.499 (2.31),
0.511 (3.27), 0.523 (2.86), 0.534 (2.19), 0.547 (1.02), 0.566
(0.95), 0.588 (2.37), 0.600 (2.70), 0.609 (2.25), 0.621 (1.97),
0.634 (1.13), 0.650 (1.24), 0.671 (2.36), 0.684 (2.66), 0.696
(2.08), 0.718 (0.67), 1.206 (0.50), 1.227 (1.70), 1.239 (2.83),
1.249 (2.23), 1.260 (2.64), 1.271 (1.51), 1.293 (0.42), 2.328
(0.94), 2.367 (0.42), 2.671 (0.99), 2.710 (0.41), 3.074 (1.03),
3.691 (1.09), 3.903 (2.19), 4.017 (1.59), 4.432 (0.64), 4.455
(1.67), 4.477 (2.14), 4.498 (2.12), 4.520 (1.69), 4.544 (0.63),
5.203 (5.43), 7.555 (4.56), 7.577 (8.29), 7.598 (4.45), 8.012
(8.76), 8.044 (8.61), 8.838 (16.00), 10.543 (6.02), 10.568
(5.80).
Example 203
N-(1,1-dicyclopropyl-2,2,2-trifluoroethyl)-7-[(3R,4R)-3,4-dihydroxypyrrol-
idin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphth-
yridine-3-carboxamide
##STR00348##
[1610]
7-Chloro-N-(1,1-dicyclopropyl-2,2,2-trifluoroethyl)-6-fluoro-4-oxo--
1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(70.0 mg, 131 .mu.mol) was initially charged in 0.7 ml of DMF.
(3R,4R)-pyrrolidine-3,4-diol hydrochloride (22.0 mg, 157 .mu.mol)
and N,N-diisopropylethylamine (110 .mu.l, 660 .mu.mol) were added
and the mixture was stirred at room temperature overnight.
Water/acetonitrile/TFA were added and the reaction solution was
purified by preparative HPLC (RP18 column, mobile phase:
acetonitrile/water gradient with addition of 0.1% TFA). The
combined product fractions were concentrated by evaporation.
[1611] The residue was dissolved in dichloromethane and a little
methanol and washed twice with saturated aqueous sodium bicarbonate
solution. The combined aqueous phases were re-extracted twice with
dichloromethane. The combined organic phases were dried over sodium
sulphate, filtered and concentrated by evaporation. This gave 71 mg
of the target compound (88% of theory, purity 98%).
[1612] LC-MS (Method 1): R.sub.t=1.04 min; MS (ESIpos): m/z=601
[M+H].sup.+
[1613] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.68),
-0.008 (5.38), 0.008 (4.77), 0.146 (0.65), 0.458 (1.16), 0.469
(2.08), 0.481 (3.81), 0.493 (4.94), 0.505 (5.07), 0.516 (3.30),
0.527 (2.52), 0.552 (1.70), 0.564 (3.47), 0.578 (4.05), 0.586
(5.38), 0.600 (4.90), 0.608 (3.68), 0.622 (4.87), 0.633 (4.05),
0.645 (5.89), 0.658 (4.94), 0.672 (1.97), 0.685 (2.55), 0.699
(4.87), 0.710 (5.55), 0.723 (4.26), 0.733 (2.72), 0.747 (1.02),
1.175 (0.65), 1.518 (1.60), 1.533 (3.51), 1.540 (3.74), 1.553
(6.26), 1.567 (3.51), 1.574 (3.17), 1.589 (1.36), 1.988 (1.16),
2.086 (5.69), 2.328 (1.09), 2.367 (0.71), 2.670 (1.23), 2.711
(0.78), 3.072 (0.95), 3.684 (1.02), 3.901 (2.04), 4.021 (1.67),
5.198 (4.36), 5.754 (3.34), 7.553 (3.88), 7.575 (6.98), 7.595
(3.91), 8.034 (9.12), 8.066 (8.99), 8.776 (16.00), 9.878
(11.85).
Example 204
N-[1-cyclopropyl-2,2,3,3,3-pentafluoropropyl]-6-fluoro-7-(2-oxa-6-azaspir-
o[3.3]hept-6-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyri-
dine-3-carboxamide (enantiomer 1)
##STR00349##
[1615]
7-Chloro-N-[1-cyclopropyl-2,2,3,3,3-pentafluoropropyl]-6-fluoro-4-o-
xo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(enantiomer 1) (150 mg, 276 .mu.mol) was initially charged in 1.5
ml of DMF, and N,N-diisopropylethylamine (480 .mu.l, 2.8 mmol) and
ethanedioic acid 2-oxa-6-azaspiro[3.3]heptane (1:2) (59.6 mg, 207
.mu.mol) were added at room temperature. The reaction solution was
stirred at room temperature overnight. Water/acetonitrile/TFA were
added and the reaction solution was purified by preparative HPLC
(RP18 column, mobile phase: acetonitrile/water gradient with
addition of 0.1% TFA). This gave 160 mg of the target compound (94%
of theory, purity 98%).
[1616] LC-MS (Method 1): R.sub.t=1.21 min; MS (ESIpos): m/z=607
[M+H].sup.+
[1617] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.97),
-0.008 (7.80), 0.146 (0.88), 0.310 (0.64), 0.323 (0.97), 0.335
(0.97), 0.346 (0.82), 0.493 (0.74), 0.504 (1.09), 0.517 (0.92),
0.528 (0.70), 0.580 (0.80), 0.593 (0.86), 0.680 (0.88), 1.222
(0.58), 1.234 (1.01), 1.254 (0.88), 2.073 (9.20), 2.327 (1.58),
2.366 (0.74), 2.670 (1.58), 2.710 (0.74), 4.272 (0.43), 4.446
(0.70), 4.468 (0.86), 4.489 (0.82), 4.511 (0.64), 4.655 (16.00),
7.541 (1.70), 7.563 (3.25), 7.585 (1.73), 7.999 (2.88), 8.027
(2.85), 8.833 (5.07), 10.507 (1.95), 10.531 (1.91).
Example 205
7-[3,3-bis(hydroxymethyl)azetidin-1-yl]-N-[1-cyclopropyl-2,2,3,3,3-pentaf-
luoropropyl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naph-
thyridine-3-carboxamide (enantiomer 1)
##STR00350##
[1619]
N-[1-cyclopropyl-2,2,3,3,3-pentafluoropropyl]-6-fluoro-7-(2-oxa-6-a-
zaspiro[3.3]hept-6-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-nap-
hthyridine-3-carboxamide (enantiomer 1) (150 mg, 247 .mu.mol) was
initially charged in trifluoroacetic acid (1.5 ml, 20 mmol), 1.5 ml
of water and 1.5 ml of acetonitrile were added and the mixture was
stirred at room temperature for 2 days. The reaction solution was
purified by preparative HPLC (RP18 column, mobile phase:
acetonitrile/water gradient with addition of 0.1% TFA). The
combined product fractions were concentrated by evaporation. The
residue was dissolved in dichloromethane and washed twice with
saturated aqueous sodium bicarbonate solution. The combined aqueous
phases were re-extracted twice with dichloromethane. The combined
organic phases were dried over sodium sulphate, filtered and
concentrated by evaporation. This gave a total of 115 mg of the
target compound (73% of theory, purity 98%).
[1620] LC-MS (Method 3): R.sub.t=1.99 min; MS (ESIpos): m/z=625
[M+H].sup.+
[1621] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.47),
0.146 (0.44), 0.304 (0.53), 0.316 (1.31), 0.328 (2.04), 0.340
(2.20), 0.352 (1.72), 0.365 (0.74), 0.483 (0.59), 0.495 (1.58),
0.507 (2.26), 0.519 (1.97), 0.531 (1.51), 0.542 (0.72), 0.563
(0.67), 0.585 (1.65), 0.597 (10.87), 0.607 (1.59), 0.618 (1.38),
0.630 (0.76), 0.648 (0.85), 0.669 (1.65), 0.682 (1.90), 0.694
(1.43), 0.715 (0.46), 1.223 (1.12), 1.235 (1.99), 1.245 (1.56),
1.256 (1.80), 1.268 (1.01), 2.329 (0.50), 2.671 (0.54), 3.475
(15.57), 3.488 (16.00), 4.131 (1.02), 4.425 (0.49), 4.448 (1.17),
4.470 (1.51), 4.492 (1.47), 4.514 (1.19), 4.537 (0.49), 4.838
(4.89), 4.851 (11.09), 4.864 (4.84), 7.532 (3.57), 7.554 (6.85),
7.576 (3.60), 7.971 (5.68), 8.000 (5.62), 8.814 (10.62), 10.540
(4.12), 10.564 (3.97).
Example 206
N-[1-cyclopropyl-2,2,3,3,3-pentafluoropropyl]-6-fluoro-7-(2-oxa-6-azaspir-
o[3.3]hept-6-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyri-
dine-3-carboxamide (enantiomer 2)
##STR00351##
[1623]
7-Chloro-N-[1-cyclopropyl-2,2,3,3,3-pentafluoropropyl]-6-fluoro-4-o-
xo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(enantiomer 2) (150 mg, 276 .mu.mol) was initially charged in 1.5
ml of DMF, and N,N-diisopropylethylamine (480 .mu.l, 2.8 .mu.mol)
and ethanedioic acid 2-oxa-6-azaspiro[3.3]heptane (1:2) (59.6 mg,
207 .mu.mol) was added at room temperature. The reaction solution
was stirred at room temperature overnight. Water/acetonitrile/TFA
were added and the reaction solution was purified by preparative
HPLC (RP18 column, mobile phase: acetonitrile/water gradient with
addition of 0.1% TFA). This gave 155 mg of the target compound (91%
of theory, purity 98%).
[1624] LC-MS (Method 1): R.sub.t=1.21 min; MS (ESIpos): m/z=607
[M+H].sup.+
[1625] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.311 (0.62),
0.323 (0.97), 0.335 (1.03), 0.347 (0.80), 0.494 (0.75), 0.505
(1.08), 0.517 (0.94), 0.529 (0.72), 0.580 (0.79), 0.592 (0.89),
0.601 (0.73), 0.613 (0.63), 0.646 (0.40), 0.667 (0.77), 0.680
(0.88), 0.692 (0.68), 1.222 (0.54), 1.234 (0.98), 1.245 (0.72),
1.255 (0.87), 1.267 (0.48), 2.073 (6.92), 4.423 (0.41), 4.447
(0.70), 4.468 (0.86), 4.490 (0.81), 4.512 (0.64), 4.656 (16.00),
7.541 (1.69), 7.563 (3.20), 7.585 (1.69), 7.999 (2.70), 8.028
(2.69), 8.833 (4.83), 10.508 (1.95), 10.532 (1.89).
Example 207
7-[3,3-bis(hydroxymethyl)azetidin-1-yl]-N-[1-cyclopropyl-2,2,3,3,3-pentaf-
luoropropyl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naph-
thyridine-3-carboxamide (enantiomer 2)
##STR00352##
[1627]
N-[1-cyclopropyl-2,2,3,3,3-pentafluoropropyl]-6-fluoro-7-(2-oxa-6-a-
zaspiro[3.3]hept-6-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-nap-
hthyridine-3-carboxamide (enantiomer 2) (145 mg, 239 .mu.mol) was
initially charged in 1.5 ml of trifluoroacetic acid, 1.5 ml of
water and 1.5 ml of acetonitrile were added and the mixture was
stirred at room temperature for 2 days. The reaction solution was
purified by preparative HPLC (RP18 column, mobile phase:
acetonitrile/water gradient with addition of 0.1% TFA). The
combined product fractions were concentrated by evaporation. The
residue was dissolved in dichloromethane and washed twice with
saturated aqueous sodium bicarbonate solution. The combined aqueous
phases were re-extracted twice with dichloromethane. The combined
organic phases were dried over sodium sulphate, filtered and
concentrated by evaporation. This gave a total of 109 mg of the
target compound (72% of theory, purity 98%).
[1628] LC-MS (Method 3): R.sub.t=1.99 min; MS (ESIpos): m/z=625
[M+H].sup.+
[1629] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (1.39),
-0.008 (10.57), 0.008 (10.54), 0.146 (1.26), 0.315 (1.31), 0.327
(2.02), 0.339 (2.27), 0.351 (1.72), 0.364 (0.76), 0.494 (1.61),
0.506 (2.27), 0.518 (1.97), 0.530 (1.58), 0.562 (0.68), 0.585
(1.64), 0.597 (1.88), 0.606 (1.56), 0.616 (1.37), 0.630 (0.76),
0.648 (0.85), 0.668 (1.64), 0.681 (1.91), 0.693 (1.47), 1.222
(1.17), 1.235 (2.13), 1.244 (1.56), 1.255 (1.86), 1.267 (1.01),
2.328 (1.50), 2.367 (0.98), 2.670 (1.31), 2.710 (0.82), 3.473
(15.78), 3.486 (16.00), 4.138 (1.01), 4.424 (0.46), 4.448 (1.17),
4.470 (1.53), 4.492 (1.50), 4.512 (1.15), 4.536 (0.49), 4.836
(5.16), 4.850 (11.96), 4.863 (5.00), 7.531 (3.88), 7.553 (7.18),
7.575 (3.74), 7.970 (6.53), 7.999 (6.39), 8.813 (11.85), 10.539
(4.31), 10.563 (4.01).
Example 208
N-(1,1-dicyclopropyl-2,2,3,3,3-pentafluoropropyl)-7-[(3R,4R)-3,4-dihydrox-
ypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-
-naphthyridine-3-carboxamide
##STR00353##
[1631]
7-Chloro-N-(1,1-dicyclopropyl-2,2,3,3,3-pentafluoropropyl)-6-fluoro-
-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxami-
de (65.0 mg, 111 .mu.mol) was initially charged in 0.61 ml of DMF.
(3R,4R)-pyrrolidine-3,4-diol hydrochloride (18.6 mg, 134 .mu.mol)
and N,N-diisopropylethylamine (97 .mu.l, 560 .mu.mol) were added
and the mixture was stirred at room temperature overnight. The
reaction solution was diluted with ethyl acetate, extracted twice
with water and washed with saturated aqueous sodium chloride
solution. The organic phase was dried over sodium sulphate,
filtered and concentrated by evaporation. The residue was purified
by thick-layer chromatography (mobile phase:
dichloromethane/methanol: 30/1). This gave 39 mg of the target
compound (52% of theory, purity 97%).
[1632] LC-MS (Method 3): R.sub.t=2.11 min; MS (ESIpos): m/z=651
[M+H].sup.+
[1633] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (1.39),
-0.008 (11.73), 0.146 (1.28), 0.458 (1.22), 0.481 (3.72), 0.494
(5.46), 0.507 (4.88), 0.516 (3.66), 0.530 (2.18), 0.573 (1.63),
0.585 (3.57), 0.607 (5.78), 0.621 (5.05), 0.642 (5.31), 0.653
(4.70), 0.665 (6.04), 0.678 (4.62), 0.746 (2.09), 0.759 (4.73),
0.771 (5.69), 0.782 (4.94), 0.795 (3.37), 1.236 (0.41), 1.583
(1.57), 1.603 (4.07), 1.618 (6.21), 1.633 (3.80), 1.652 (1.34),
2.328 (1.48), 2.367 (1.02), 2.670 (1.48), 2.711 (0.96), 2.731
(2.90), 2.891 (3.72), 3.069 (1.13), 3.692 (1.13), 3.902 (2.38),
4.017 (1.66), 5.202 (4.79), 7.551 (4.24), 7.573 (7.64), 7.594
(4.18), 7.952 (0.46), 8.036 (9.03), 8.068 (8.94), 8.781 (16.00),
9.849 (11.73).
Example 209
N-(1,1-dicyclopropyl-2,2,2-trifluoroethyl)-6-fluoro-7-(2-oxa-6-azaspiro[3-
.3]hept-6-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridin-
e-3-carboxamide
##STR00354##
[1635]
7-Chloro-N-(1,1-dicyclopropyl-2,2,2-trifluoroethyl)-6-fluoro-4-oxo--
1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(110 mg, 206 .mu.mol) was initially charged in 1.1 ml of DMF, and
N,N-diisopropylethylamine (360 .mu.l, 2.1 mmol) and ethanedioic
acid 2-oxa-6-azaspiro[3.3]heptane (1:2) (44.6 mg, 155 .mu.mol) were
added at room temperature. The reaction solution was stirred at
room temperature overnight. Water/acetonitrile/TFA were added and
the reaction solution was purified by preparative HPLC (RP18
column, mobile phase: acetonitrile/water gradient with addition of
0.1% TFA). The combined product fractions were concentrated by
evaporation. The residue was dissolved in dichloromethane and a
little methanol and washed twice with saturated aqueous sodium
bicarbonate solution. The combined aqueous phases were re-extracted
twice with dichloromethane. The combined organic phases were dried
over sodium sulphate, filtered and concentrated by evaporation.
This gave 103 mg of the target compound (83% of theory, purity
99%).
[1636] LC-MS (Method 1): R.sub.t=1.24 min; MS (ESIpos): m/z=597
[M+H].sup.+
[1637] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.008 (1.29),
0.467 (0.73), 0.477 (1.28), 0.489 (1.66), 0.501 (10.73), 0.512
(1.08), 0.523 (0.83), 0.549 (0.55), 0.561 (1.16), 0.575 (1.38),
0.583 (1.83), 0.597 (2.14), 0.612 (1.47), 0.621 (1.72), 0.635
(2.11), 0.648 (1.72), 0.661 (0.65), 0.674 (0.87), 0.688 (1.65),
0.699 (1.84), 0.711 (1.41), 0.723 (0.91), 1.157 (0.53).1.175
(1.07), 1.193 (0.55), 1.234 (0.46), 1.511 (0.59), 1.526 (1.23),
1.533 (1.33), 1.547 (2.25), 1.561 (1.23), 1.568 (1.10), 1.582
(0.48), 1.989 (1.96), 4.021 (0.56), 4.039 (0.57), 4.653 (16.00),
7.540 (1.63), 7.562 (3.02), 7.584 (1.63), 8.022 (2.63), 8.052
(2.62), 8.774 (4.75), 9.847 (3.87).
Example 210
7-[3,3-bis(hydroxymethyl)azetidin-1-yl]-N-(1,1-dicyclopropyl-2,2,2-triflu-
oroethyl)-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthy-
ridine-3-carboxamide
##STR00355##
[1639]
N-(1,1-dicyclopropyl-2,2,2-trifluoroethyl)-6-fluoro-7-(2-oxa-6-azas-
piro[3.3]hept-6-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphth-
yridine-3-carboxamide (101 mg, 169 .mu.mol) was initially charged
in 1.1 ml of trifluoroacetic acid, 1.1 ml of water and 1.1 ml of
acetonitrile were added and the mixture was stirred at room
temperature for 5 days. The reaction solution was purified by
preparative HPLC (RP18 column, mobile phase: acetonitrile/water
gradient with addition of 0.1% TFA). The combined product fractions
were concentrated by evaporation. The residue was dissolved in
dichloromethane and washed twice with saturated aqueous sodium
bicarbonate solution. The combined aqueous phases were re-extracted
twice with dichloromethane. The combined organic phases were dried
over sodium sulphate, filtered and concentrated by evaporation.
This gave 73 mg of the target compound (69% of theory, purity
98%).
[1640] LC-MS (Method 3): R.sub.t=2.04 min; MS (ESIpos): m/z=615
[M+H].sup.+
[1641] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.150 (0.53),
-0.008 (5.14), 0.008 (3.74), 0.146 (0.41), 0.477 (2.86), 0.490
(3.72), 0.501 (3.85), 0.523 (2.02), 0.549 (1.30), 0.560 (2.71),
0.575 (3.25), 0.583 (4.07), 0.597 (4.09), 0.617 (3.56), 0.638
(4.71), 0.651 (3.83), 0.664 (10.54), 0.679 (1.91), 0.693 (3.58),
0.704 (4.17), 0.716 (3.19), 0.727 (2.12), 1.233 (0.56), 1.398
(0.74), 1.513 (1.40), 1.528 (3.00), 1.535 (3.25), 1.549 (5.10),
1.563 (2.94), 1.570 (2.49), 1.584 (1.01), 2.073 (0.82), 2.328
(1.36), 2.366 (0.60), 2.670 (1.15), 2.710 (0.43), 3.472 (15.94),
3.485 (16.00), 4.119 (1.05), 4.834 (4.67), 4.847 (11.54), 4.861
(4.71), 7.530 (4.15), 7.551 (7.26), 7.573 (4.17), 7.992 (8.12),
8.021 (7.88), 8.752 (14.09), 9.875 (9.11).
Example 211
N-(1,1-dicyclopropyl-2,2,3,3,3-pentafluoropropyl)-6-fluoro-7-(2-oxa-6-aza-
spiro[3.3]hept-6-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-napht-
hyridine-3-carboxamide
##STR00356##
[1643]
7-Chloro-N-(1,1-dicyclopropyl-2,2,3,3,3-pentafluoropropyl)-6-fluoro-
-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxami-
de (100 mg, 171 .mu.mol) was initially charged in 0.93 ml of DMF,
and N,N-diisopropylethylamine (300 .mu.l, 1.7 mmol) and ethanedioic
acid 2-oxa-6-azaspiro[3.3]heptane (1:2) (37.0 ng, 128 .mu.mol) were
added at room temperature. The reaction solution was stirred at
room temperature overnight. Water/acetonitrile/TFA were added and
the reaction solution was purified by preparative HPLC (RP18
column, mobile phase: acetonitrile/water gradient with addition of
0.1% TFA). The combined product fractions were concentrated by
evaporation. The residue was dissolved in dichloromethane and a
little methanol and washed twice with saturated aqueous sodium
bicarbonate solution. The combined aqueous phases were re-extracted
twice with dichloromethane. The combined organic phases were dried
over sodium sulphate, filtered and concentrated by evaporation.
This gave 78 mg of the target compound (70% of theory, purity
99%).
[1644] LC-MS (Method 1): R.sub.t=1.29 min; MS (ESIpos): m/z=647
[M+H].sup.+
[1645] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.66),
-0.023 (0.56), -0.008 (5.12), 0.008 (4.77), 0.146 (0.63), 0.476
(1.08), 0.489 (1.56), 0.503 (1.47), 0.524 (0.69), 0.569 (0.47),
0.581 (1.08), 0.603 (1.73), 0.617 (1.90), 0.628 (1.56), 0.640
(1.72), 0.654 (1.83), 0.666 (1.34), 0.733 (0.65), 0.747 (1.38),
0.759 (1.65), 0.769 (1.41), 0.783 (0.97), 1.175 (0.44), 1.234
(0.81), 1.575 (0.48), 1.596 (1.18), 1.611 (1.90), 1.625 (1.10),
1.988 (0.81), 2.328 (0.74), 2.366 (0.55), 2.523 (1.79), 2.665
(0.58), 2.670 (0.79), 2.710 (0.54), 4.653 (16.00), 7.538 (1.67),
7.559 (3.03), 7.581 (1.69), 8.025 (3.04), 8.054 (2.96), 8.777
(5.19), 9.818 (3.56).
Example 212
7-[3,3-bis(hydroxymethyl)azetidin-1-yl]-N-(1,1-dicyclopropyl-2,2,3,3,3-pe-
ntafluoropropyl)-6-fluoro-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8--
naphthyridine-3-carboxamide
##STR00357##
[1647]
N-(1,1-dicyclopropyl-2,2,3,3,3-pentafluoropropyl)-6-fluoro-7-(2-oxa-
-6-azaspiro[3.3]hept-6-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-
-naphthyridine-3-carboxamide (75.0 mg, 116 .mu.mol) was initially
charged in 0.73 ml of trifluoroacetic acid, 0.73 ml of water and
0.73 ml of acetonitrile were added and the mixture was stirred at
room temperature for 5 days. The reaction solution was purified by
preparative HPLC (RP18 column, mobile phase: acetonitrile/water
gradient with addition of 0.1% TFA). The combined product fractions
were concentrated by evaporation. The residue was dissolved in
dichloromethane and a little methanol and washed twice with
saturated aqueous sodium bicarbonate solution. The combined aqueous
phases were re-extracted twice with dichloromethane. The combined
organic phases were dried over sodium sulphate, filtered and
concentrated by evaporation. This gave 44 mg of the target compound
(56% of theory, purity 98%).
[1648] LC-MS (Method 3): R.sub.t=2.16 min; MS (ESIpos): m/z=665
[M+H].sup.+
[1649] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.150 (0.64),
-0.008 (5.04), 0.008 (4.74), 0.146 (0.55), 0.491 (3.45), 0.504
(3.22), 0.526 (1.41), 0.582 (2.36), 0.604 (3.62), 0.618 (3.82),
0.645 (3.27), 0.658 (3.89), 0.671 (2.90), 0.752 (2.98), 0.764
(3.70), 0.776 (3.18), 1.235 (0.62), 1.599 (2.63), 1.614 (4.19),
1.627 (2.53), 2.328 (1.31), 2.368 (0.64), 2.670 (1.41), 2.710
(0.52), 3.471 (15.83), 3.484 (16.00), 4.132 (1.04), 4.835 (5.06),
4.849 (12.18), 4.862 (4.99), 7.528 (3.94), 7.551 (6.85), 7.572
(3.84), 7.995 (7.42), 8.024 (7.12), 8.757 (13.07), 9.846
(7.81).
Example 213
6-Fluoro-7-(2-oxa-6-azaspiro[3.3]hept-6-yl)-4-oxo-N-[1,1,1,2,2-pentafluor-
o-4,4-dimethylpentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-napht-
hyridine-3-carboxamide (enantiomer 1)
##STR00358##
[1651]
7-Chloro-6-fluoro-4-oxo-N-[1,1,1,2,2-pentafluoro-4,4-dimethylpentan-
-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxami-
de (enantiomer 1) (150 mg, 268 .mu.mol) was initially charged in
1.5 ml of DMF, and N,N-diisopropylethylamine (470 .mu.l, 2.7 mmol)
and ethanedioic acid 2-oxa-6-azaspiro[3.3]heptane (1:2) (57.9 mg,
201 .mu.mol) were added at room temperature. The reaction solution
was stirred at room temperature overnight. Water/acetonitrile/TFA
were added and the reaction solution was purified by preparative
HPLC (RP18 column, mobile phase: acetonitrile/water gradient with
addition of 0.1% TFA). The combined product fractions were
concentrated by evaporation. The residue was dissolved in
dichloromethane and washed twice with saturated aqueous sodium
bicarbonate solution. The combined aqueous phases were re-extracted
twice with dichloromethane. The combined organic phases were dried
over sodium sulphate, filtered and concentrated by evaporation.
This gave 123 mg of the target compound (72% of theory, purity
98%).
[1652] LC-MS (Method 1): R.sub.t=1.31 min; MS (ESIpos): m/z=623
[M+H].sup.+
[1653] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 1.102 (16.00),
4.657 (10.77), 4.678 (0.51), 4.708 (0.42), 4.753 (0.44), 4.780
(0.42), 7.539 (1.26), 7.561 (2.36), 7.583 (1.24), 8.032 (2.26),
8.061 (2.18), 8.856 (4.05), 10.687 (1.25), 10.713 (1.19).
Example 214
7-[3,3-bis(hydroxymethyl)azetidin-1-yl]-6-fluoro-4-oxo-N-[1,1,1,2,2-penta-
fluoro-4,4-dimethylpentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8--
naphthyridine-3-carboxamide (enantiomer 1)
##STR00359##
[1655] 1.6 ml of acetonitrile, 1.6 ml of water and 1.6 ml of
trifluoroacetic acid were added to
6-fluoro-7-(2-oxa-6-azaspiro[3.3]hept-6-yl)-4-oxo-N-[1,1,1,2,2-pentafluor-
o-4,4-dimethylpentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-napht-
hyridine-3-carboxamide (enantiomer 1) (120 mg, 98% purity, 189
.mu.mol), and the mixture was stirred at room temperature for 5
days. The reaction solution was purified directly by preparative
HPLC (RP18 column, mobile phase: acetonitrile/water gradient with
addition of 0.1% TFA). The combined product fractions were
concentrated by evaporation. The residue was dissolved in
dichloromethane and a little methanol and washed twice with
saturated aqueous sodium bicarbonate solution. The combined aqueous
phases were re-extracted twice with dichloromethane. The combined
organic phases were dried over sodium sulphate, filtered and
concentrated by evaporation. This gave a total of 102 mg of the
target compound (83% of theory, purity 98%).
[1656] LC-MS (Method 1): R.sub.t=1.14 min; MS (ESIpos): m/z=641
[M+H].sup.+
[1657] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (1.02),
0.008 (0.91), 1.104 (16.00), 2.328 (0.56), 2.670 (0.54), 3.472
(5.03), 3.486 (5.11), 4.680 (0.43), 4.707 (0.43), 4.754 (0.46),
4.780 (0.45), 4.839 (1.68), 4.853 (4.05), 4.866 (1.67), 7.530
(1.27), 7.552 (2.42), 7.574 (10.30), 8.004 (2.43), 8.033 (2.39),
8.837 (4.32), 10.716 (1.34), 10.742 (1.24).
Example 215
6-Fluoro-7-(2-oxa-6-azaspiro[3.3]hept-6-yl)-4-oxo-N-[1,1,1,2,2-pentafluor-
o-4,4-dimethylpentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-napht-
hyridine-3-carboxamide (enantiomer 2)
##STR00360##
[1659]
7-Chloro-6-fluoro-4-oxo-N-[1,1,1,2,2-pentafluoro-4,4-dimethylpentan-
-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxami-
de (enantiomer 2) (150 mg, 268 .mu.mol) was initially charged in
1.5 ml of DMF, and N,N-diisopropylethylamine (470 .mu.l, 2.7 mmol)
and ethanedioic acid 2-oxa-6-azaspiro[3.3]heptane (1:2) (57.9 mg,
201 .mu.mol) were added at room temperature. The reaction solution
was stirred at room temperature for 4 h. Water/acetonitrile/TFA
were added and the reaction solution was purified by preparative
HPLC (RP18 column, mobile phase: acetonitrile/water gradient with
addition of 0.1% TFA). The combined product fractions were
concentrated by evaporation. The residue was dissolved in
dichloromethane and a little methanol and washed twice with
saturated aqueous sodium bicarbonate solution. The combined aqueous
phases were re-extracted twice with dichloromethane. The combined
organic phases were dried over sodium sulphate, filtered and
concentrated by evaporation. This gave 122 mg of the target
compound (72% of theory, purity 98%).
[1660] LC-MS (Method 1): R.sub.t=1.31 min; MS (ESIpos): m/z=623
[M+H].sup.+
[1661] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (0.66),
0.008 (0.52), 1.102 (16.00), 2.524 (0.75), 4.656 (10.99), 4.678
(0.52), 4.706 (0.46), 4.752 (0.45), 4.778 (0.43), 7.539 (1.20),
7.561 (2.29), 7.583 (1.22), 8.032 (2.18), 8.061 (2.14), 8.856
(3.81), 10.686 (1.28), 10.713 (1.22).
Example 216
7-[3,3-bis(hydroxymethyl)azetidin-1-yl]-6-fluoro-4-oxo-N-[1,1,1,2,2-penta-
fluoro-4,4-dimethylpentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8--
naphthyridine-3-carboxamide (enantiomer 2)
##STR00361##
[1663] 1.6 ml of acetonitrile, 1.6 ml of water and 1.6 ml of
trifluoroacetic acid were added to
6-fluoro-7-(2-oxa-6-azaspiro[3.3]hept-6-yl)-4-oxo-N-[1,1,1,2,2-pentafluor-
o-4,4-dimethylpentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-napht-
hyridine-3-carboxamide (enantiomer 2) (120 mg, 98% purity, 189
.mu.mol), and the mixture was stirred at room temperature for 5
days. The reaction solution was purified directly by preparative
HPLC (RP18 column, mobile phase: acetonitrile/water gradient with
addition of 0.1% TFA). The combined product fractions were
concentrated by evaporation. The residue was dissolved in
dichloromethane and a little methanol and washed twice with
saturated aqueous sodium bicarbonate solution. The combined aqueous
phases were re-extracted twice with dichloromethane. The combined
organic phases were dried over sodium sulphate, filtered and
concentrated by evaporation. This gave a total of 97 mg of the
target compound (79% of theory, purity 98%).
[1664] LC-MS (Method 1): R.sub.t=1.14 min; MS (ESIpos): m/z=641
[M+H].sup.+
[1665] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (0.78),
0.008 (0.79), 1.105 (16.00), 3.473 (5.01), 3.486 (5.13), 4.681
(0.40), 4.707 (0.41), 4.754 (0.42), 4.781 (0.42), 4.839 (1.70),
4.853 (4.02), 4.866 (1.66), 7.530 (1.22), 7.552 (2.31), 7.574
(1.21), 8.004 (2.16), 8.033 (2.10), 8.838 (3.89), 10.716 (1.29),
10.742 (1.23).
Example 217
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[1,1,1,2,2-pent-
afluoro-4,4-dimethylpentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-
-naphthyridine-3-carboxamide (enantiomer 1)
##STR00362##
[1667]
7-Chloro-6-fluoro-4-oxo-N-[1,1,1,2,2-pentafluoro-4,4-dimethylpentan-
-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxami-
de (enantiomer 1) (100 mg, 179 .mu.mol) was initially charged in
0.97 ml of DMF. (3R,4R)-pyrrolidine-3,4-diol hydrochloride (29.9
mg, 214 .mu.mol) and N,N-diisopropylethylamine (160 .mu.l, 890
.mu.mol) were added and the mixture was stirred at room temperature
for 4 h. Water/acetonitrile/TFA were added and the reaction
solution was purified by preparative HPLC (RP18 column, mobile
phase: acetonitrile/water gradient with addition of 0.1% TFA). The
combined product fractions were concentrated by evaporation. The
residue was dissolved in dichloromethane and a little methanol and
washed twice with saturated aqueous sodium bicarbonate solution.
The combined aqueous phases were re-extracted twice with
dichloromethane. The combined organic phases were dried over sodium
sulphate, filtered and concentrated by evaporation. The residue was
purified on silica gel (mobile phase: isocratic:
dichloromethane/methanol=50/1). This gave 69 mg of the target
compound (60% of theory, purity 98%).
[1668] Enantiomer 1: de>88%. R.sub.t=5.356 min [analytical HPLC:
column Daicel.RTM. Chiralpak IA, 5 .mu.m, 250.times.4.6 mm; 1
mil/min, 70.degree. C.; mobile phase: 80% isohexane/20% ethanol;
detection: 220 nm].
[1669] LC-MS (Method 1): R.sub.t=1.12 min; MS (ESIpos): m/z=627
[M+H].sup.+
[1670] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (1.17),
0.008 (0.96), 1.109 (16.00), 2.523 (0.73), 3.903 (0.47), 4.761
(0.41), 4.787 (0.41), 5.205 (0.97), 7.554 (0.90), 7.576 (1.58),
7.596 (0.88), 8.044 (2.11), 8.076 (2.07), 8.861 (3.54), 10.720
(1.27), 10.747 (1.22).
Example 218
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-[1,1,1,2,2-pent-
afluoro-4,4-dimethylpentan-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-
-naphthyridine-3-carboxamide (enantiomer 2)
##STR00363##
[1672]
7-Chloro-6-fluoro-4-oxo-N-[1,1,1,2,2-pentafluoro-4,4-dimethylpentan-
-3-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxami-
de (enantiomer 2) (100 mg, 179 .mu.mol) was initially charged in
0.97 ml of DMF. (3R,4R)-pyrrolidine-3,4-diol hydrochloride (29.9
mg, 214 .mu.mol) and N,N-diisopropylethylamine (160 .mu.l, 890
.mu.mol) were added and the mixture was stirred at room temperature
for 4 h. Water/acetonitrile/TFA were added and the reaction
solution was purified by preparative HPLC (RP18 column, mobile
phase: acetonitrile/water gradient with addition of 0.1% TFA). The
combined product fractions were concentrated by evaporation. The
residue was dissolved in dichloromethane and a little methanol and
washed twice with saturated aqueous sodium bicarbonate solution.
The combined aqueous phases were re-extracted twice with
dichloromethane. The combined organic phases were dried over sodium
sulphate, filtered and concentrated by evaporation. The residue was
purified by silica gel (mobile phase: isocratic:
dichloromethane/methanol=50/1). This gave 72 mg of the target
compound (63% of theory, purity 98%).
[1673] Enantiomer 2: de>88.5%. R.sub.t=4.677 min [analytical
HPLC: column Daicel.RTM. Chiralpak IA, 5 .mu.m, 250.times.4.6 mm; 1
ml/min, 70.degree. C.; mobile phase: 80% isohexane/20% ethanol;
detection: 220 nm].
[1674] LC-MS (Method 1): R.sub.t=1.11 min; MS (ESIpos): m/z=627
[M+H].sup.+
[1675] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (1.06),
0.008 (0.99), 1.109 (16.00), 2.074 (0.44), 2.523 (0.76), 3.912
(0.47), 4.713 (0.41), 4.760 (0.42), 4.788 (0.41), 5.208 (10.00),
7.554 (0.82), 7.575 (1.47), 7.595 (0.79), 8.044 (2.15), 8.076
(2.10), 8.861 (3.89), 10.720 (1.28), 10.746 (1.21).
Example 219
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-trifluor-
ophenyl)-N-[(2R)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthyridine-
-3-carboxamide
##STR00364##
[1677]
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-tr-
ifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (100
mg, 228 .mu.mol) was initially charged in 1.0 ml of DMF, HATU (95.2
mg, 250 .mu.mol) and N,N-diisopropylethylamine (160 .mu.l, 910
.mu.mol) were added and (2R)-1,1,1-trifluoropropan-2-amine (25
.mu.l, 250 .mu.mol) was added. The reaction solution was stirred at
room temperature overnight. Acetonitrile/water/TFA were added and
the reaction solution was purified by preparative HPLC (RP18
column, mobile phase: acetonitrile/water gradient with addition of
0.1% TFA). The combined product fractions were concentrated by
evaporation. The residue was dissolved in dichloromethane and
washed twice with saturated aqueous sodium bicarbonate solution.
The combined aqueous phases were re-extracted twice with
dichloromethane. The combined organic phases were dried over sodium
sulphate, filtered and concentrated by evaporation. This gave 74 mg
of the target compound (60% of theory, purity 98%).
[1678] LC-MS (Method 1): R.sub.t=0.89 min; MS (ESIpos): m/z=535
[M+H].sup.+
[1679] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (3.06),
0.008 (2.77), 1.365 (15.90), 1.383 (16.00), 2.328 (0.77), 2.366
(0.83), 2.670 (0.83), 2.710 (0.77), 3.068 (0.77), 3.690 (0.81),
3.899 (1.79), 4.009 (1.19), 4.861 (1.19), 4.881 (1.83), 4.902
(1.85), 4.921 (1.15), 4.939 (0.42), 5.196 (3.96), 7.556 (3.94),
7.578 (7.04), 7.599 (3.87), 7.988 (7.81), 8.020 (7.73), 8.837
(13.58), 10.382 (5.10), 10.405 (4.90).
Example 220
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-N-(2,2,2-trifluor-
oethyl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxam-
ide
##STR00365##
[1681]
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-tr-
ifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(80.0 mg, 182 .mu.mol) was initially charged in 1.4 ml of DMF, HATU
(83.1 mg, 219 .mu.mol) and N,N-diisopropylethylamine (140 .mu.l,
820 .mu.mol) were added and 2,2,2-trifluoroethanamine (21.6 ng, 219
.mu.mol) was added. The reaction mixture was stirred at room
temperature for 2 hours. Acetonitrile/water/TFA were added and the
reaction solution was purified by preparative HPLC (RP18 column,
mobile phase: acetonitrile/water gradient with addition of 0.1%
TFA). The combined product fractions were concentrated by
evaporation. The residue was dissolved in dichloromethane and
washed twice with saturated aqueous sodium bicarbonate solution.
The combined aqueous phases were re-extracted twice with
dichloromethane. The combined organic phases were dried over sodium
sulphate, filtered and concentrated by evaporation. The residue was
purified by thick-layer chromatography (mobile phase:
dichloromethane/methanol=10/1). This gave 34 mg of the target
compound (35% of theory, purity 98%).
[1682] LC-MS (Method 1): R.sub.1=0.83 min; MS (ESIpos): m/z=521
[M+H].sup.+
[1683] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 2.074 (1.03),
2.328 (0.64), 2.367 (0.59), 2.670 (0.55), 2.711 (0.56), 3.058
(0.83), 3.677 (0.89), 3.902 (1.78), 4.192 (1.23), 4.217 (3.82),
4.233 (4.22), 4.241 (3.96), 4.257 (3.78), 4.282 (1.17), 5.196
(5.02), 7.556 (3.74), 7.578 (6.60), 7.599 (3.65), 7.995 (8.81),
8.026 (8.46), 8.838 (16.00), 10.299 (2.67), 10.316 (5.50), 10.332
(2.37).
Example 221
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-(2,2,2-trifluoroethyl)-1,4-dihydro-1,8-naphthyridine-3-ca-
rboxamide (atropisomer mixture)
##STR00366##
[1685]
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin--
1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic
acid (atropisomer mixture) (326 mg, 715 .mu.mol) was initially
charged in 3.1 ml of DMF, HATU (299 mg, 787 .mu.mol) and
N,N-diisopropylethylamine (500 .mu.l, 2.9 mmol) were added and
2,2,2-trifluoroethanamine (62 .mu.l, 790 .mu.mol) was added. The
reaction solution was stirred at room temperature for 3 days.
Acetonitrile/water/TFA were added and the reaction solution was
purified by preparative HPLC (RP18 column, mobile phase:
acetonitrile/water gradient with addition of 0.1% TFA). The
combined product fractions were concentrated by evaporation. The
residue was dissolved in dichloromethane and washed twice with
saturated aqueous sodium bicarbonate solution. The combined aqueous
phases were re-extracted twice with dichloromethane. The combined
organic phases were dried over sodium sulphate, filtered and
concentrated by evaporation. This gave 200 mg of the target
compound (49% of theory, purity 95%).
[1686] LC-MS (Method 3): R.sub.t=1.59 min; MS (ESIpos): m/z=537
[M+H].sup.+
[1687] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (1.90),
0.008 (1.89), 2.073 (6.60), 2.328 (0.43), 2.366 (0.46), 2.670
(0.51), 2.710 (0.49), 3.014 (0.51), 3.228 (0.52), 3.692 (0.57),
3.897 (1.15), 4.011 (0.80), 4.192 (0.87), 4.216 (2.57), 4.233
(2.83), 4.241 (2.64), 4.257 (2.58), 4.282 (0.79), 5.196 (3.43),
5.754 (16.00), 7.685 (0.54), 7.692 (0.86), 7.702 (0.91), 7.708
(0.98), 7.716 (1.72), 7.725 (1.81), 7.731 (1.85), 7.738 (2.30),
7.748 (2.06), 7.762 (1.52), 7.998 (5.32), 8.030 (5.29), 8.788
(10.64), 10.315 (1.72), 10.331 (3.64). 10.347 (1.65).
Example 222
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-(2,2,2-trifluoroethyl)-1,4-dihydro-1,8-naphthyridine-3-ca-
rboxamide (atropisomer 1)
[1688] 197 mg of
1-(2-chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-(2,2,2-trifluoroethyl)-1,4-dihydro-1,8-naphthyridine-3-ca-
rboxamide (atropisomer mixture) were separated into the
atropisomers by chiral HPLC (preparative HPLC: column Daicel.RTM.
Chiralpak IA, 5 .mu.m, 250.times.20 mm; mobile phase: 75%
n-heptane/25% isopropanol; flow rate 15 ml/min; temperature:
40.degree. C., detection: 220 nm).
[1689] Atropisomer 1: 84 mg (stereochemical purity 99%)
[1690] R.sub.t=10.527 min [analytical HPLC: column Daicel.RTM.
Chiralpak IA, 1 ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase:
80% n-heptane/20% isopropanol+0.2% DEA; detection: 235 nm].
[1691] LC-MS (Method 3): R.sub.1=1.59 min; MS (ESIpos): m/z=537
[M+H].sup.+
[1692] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (0.86),
0.008 (0.79), 2.073 (16.00), 2.328 (0.48), 2.670 (0.47), 3.896
(0.71), 4.192 (0.56), 4.216 (1.54), 4.233 (1.68), 4.241 (1.55),
4.257 (1.50), 4.282 (0.44), 5.195 (1.82), 7.685 (0.64), 7.691
(0.96), 7.708 (1.10), 7.715 (1.58), 7.738 (2.03), 7.763 (1.24),
7.999 (3.81), 8.030 (3.71), 8.788 (8.47), 10.315 (1.09), 10.332
(2.20), 10.348 (0.96).
Example 223
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-(2,2,2-trifluoroethyl)-1,4-dihydro-1,8-naphthyridine-3-ca-
rboxamide (atropisomer 2)
[1693] 197 mg of
1-(2-chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-(2,2,2-trifluoroethyl)-1,4-dihydro-1,8-naphthyridine-3-ca-
rboxamide (atropisomer mixture) were separated into the
atropisomers by chiral HPLC (preparative HPLC: column Daicel.RTM.
Chiralpak IA, 5 .mu.m, 250.times.20 mm; mobile phase: 75%
n-heptane/25% isopropanol; flow rate 15 ml/min; temperature:
40.degree. C., detection: 220 nm).
[1694] Atropisomer 2: 84 mg (stereochemical purity 99%)
[1695] R.sub.t=13.695 min [analytical HPLC: column Daicel.RTM.
Chiralpak IA, 1 ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase:
80% n-heptane/20% isopropanol+0.2% DEA; detection: 235 nm].
[1696] LC-MS (Method 3): R.sub.t=1.59 min; MS (ESIpos): m/z=537
[M+H].sup.+
[1697] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (0.69),
2.073 (16.00), 2.328 (0.42), 2.670 (0.40), 3.902 (0.66), 4.192
(0.49), 4.216 (1.51), 4.233 (1.61), 4.241 (1.49), 4.257 (1.48),
4.281 (0.45), 5.196 (2.26), 7.695 (0.64), 7.702 (0.93), 7.717
(0.95), 7.725 (2.09), 7.730 (10.75), 7.740 (1.30), 7.751 (10.78),
7.761 (0.81), 7.998 (3.70), 8.030 (3.57), 8.789 (8.25), 10.315
(1.05), 10.331 (2.13), 10.347 (0.95).
Example 224
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthy-
ridine-3-carboxamide (atropisomer mixture)
##STR00367##
[1699]
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin--
1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic
acid (atropisomer mixture) (200 mg, 439 .mu.mol) was initially
charged in 1.9 ml of DMF, HATU (184 mg, 483 .mu.mol) and
N,N-diisopropylethylamine (310 .mu.l, 1.8 mmol) were added and
(2S)-1,1,1-trifluoropropan-2-amine (48 .mu.l, 480 .mu.mol) was
added. The reaction solution was stirred at room temperature
overnight. Water was added and the reaction solution was stirred
briefly. The precipitated solid was filtered off and dried under
high vacuum. This gave 240 mg of the target compound (97% of
theory, purity 98%).
[1700] LC-MS (Method 3): R.sub.t=1.72 min; MS (ESIpos): m/z=551
[M+H].sup.+
[1701] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.936 (16.00),
0.951 (15.00), 1.364 (9.71), 1.370 (9.62), 1.382 (9.80), 2.327
(1.73), 2.366 (1.96), 2.409 (2.10), 2.669 (1.69), 2.690 (5.70),
2.710 (1.60), 2.961 (1.78), 3.889 (1.73), 4.880 (2.05), 5.196
(4.88), 7.715 (2.23), 7.749 (3.69), 7.993 (7.79), 8.025 (7.52),
8.790 (11.94), 10.401 (4.06), 10.425 (4.33).
Example 225
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthy-
ridine-3-carboxamide (atropisomer 1)
[1702] 238 mg of
1-(2-chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthy-
ridine-3-carboxamide (atropisomer mixture) were separated into the
atropisomers by chiral HPLC (preparative HPLC: column Daicel.RTM.
Chiralcel OX-II, 5 .mu.m, 250.times.20 mm; mobile phase: 75%
n-heptane/25% isopropanol; flow rate 15 ml/min; temperature:
45.degree. C., detection: 220 nm).
[1703] Atropisomer 1: 82 mg (stereochemical purity >99%)
[1704] R.sub.t=5.024 min [analytical HPLC: column Daicel.RTM.
Chiralpak OX-H, 1 mil/min; 5 .mu.m, 250.times.4.6 mm; mobile phase:
75% isohexane/25% 2-propanol; detection: 220 nm; 30.degree.
C.].
[1705] LC-MS (Method 3): R.sub.t=1.71 min; MS (ESIpos): m/z=551
[M+H].sup.+
[1706] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (1.60),
0.008 (2.07), 1.365 (15.87), 1.382 (16.00), 2.328 (0.50), 2.670
(0.58), 2.710 (0.44), 3.008 (0.82), 3.226 (0.85), 3.685 (0.85),
3.897 (1.62), 4.007 (1.21), 4.842 (0.45), 4.861 (1.19), 4.880
(1.79), 4.901 (1.84), 4.920 (1.18), 4.939 (0.42), 5.196 (4.26),
7.684 (1.46), 7.691 (2.04), 7.707 (2.51), 7.714 (3.53), 7.730
(1.57), 7.738 (4.02), 7.749 (2.24), 7.765 (2.80), 7.771 (1.97),
7.994 (7.83), 8.026 (7.66), 8.790 (15.94), 10.404 (5.16), 10.427
(4.94).
Example 226
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthy-
ridine-3-carboxamide (atropisomer 2)
[1707] 238 mg of
1-(2-chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-[(2S)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthy-
ridine-3-carboxamide (atropisomer mixture) were separated into the
atropisomers by chiral HPLC (preparative HPLC: column Daicel.RTM.
Chiralcel OX-H, 5 .mu.m, 250.times.20 mm; mobile phase: 75%
n-heptane/25% isopropanol; flow rate 15 ml/min; temperature:
45.degree. C., detection: 220 nm).
[1708] Atropisomer 2: 97 mg (stereochemical purity >99%)
[1709] R.sub.t=5.970 min [analytical HPLC: column Daicel.RTM.
Chiralpak OX-H, 1 mil/min; 5 .mu.m, 250.times.4.6 mm; mobile phase:
75% isohexane/25% 2-propanol; detection: 220 nm; 30.degree.
C.].
[1710] LC-MS (Method 3): R.sub.t=1.72 mm; MS (ESIpos): m/z=551
[M+H].sup.+
[1711] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (1.15),
0.008 (1.11), 1.371 (15.90), 1.388 (16.00), 3.040 (0.78), 3.214
(0.79), 3.687 (0.79), 3.892 (1.56), 4.007 (1.16), 4.842 (0.43),
4.861 (1.15), 4.881 (1.74), 4.901 (1.80), 4.920 (1.14), 4.938
(0.40), 5.197 (5.26), 7.696 (1.32), 7.703 (2.00), 7.719 (2.02),
7.726 (5.20), 7.740 (2.37), 7.750 (4.75), 7.761 (1.73), 7.993
(7.49), 8.025 (7.38), 8.788 (14.24), 10.401 (5.13), 10.425
(4.92).
Example 227
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-[(2R)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthy-
ridine-3-carboxamide (atropisomer mixture)
##STR00368##
[1713]
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin--
1-yl]-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic
acid (atropisomer mixture) (200 mg, 439 .mu.mol) was initially
charged in 1.9 ml of DMF, HATU (184 mg, 483 .mu.mol) and
N,N-diisopropylethylamine (310 .mu.l, 1.8 mmol) were added and
(2R)-1,1,1-trifluoropropan-2-amine (48 .mu.l, 480 .mu.mol) was
added. The reaction solution was stirred at room temperature
overnight. Water was added and the reaction solution was stirred
briefly. The precipitated solid was filtered off and dried under
high vacuum. This gave 237 mg of the target compound (96% of
theory, purity 98%).
[1714] LC-MS (Method 3): R.sub.t=1.72 min; MS (ESIpos): m/z=551
[M+H].sup.+
[1715] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: 0.936 (16.00),
0.951 (14.58), 1.369 (6.83), 1.382 (6.68), 2.327 (0.76), 2.366
(0.73), 2.410 (2.10), 2.427 (2.17), 2.671 (0.62), 2.690 (1.63),
2.709 (0.51), 2.945 (1.23), 2.961 (1.57), 2.978 (1.45), 3.695
(0.70), 3.897 (1.41), 4.861 (0.87), 4.880 (1.32), 4.899 (1.29),
5.194 (3.33), 7.717 (1.99), 7.741 (2.83), 7.992 (3.63), 8.024
(3.64), 8.788 (6.15), 10.401 (2.85), 10.424 (2.73).
Example 228
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-[(2R)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthy-
ridine-3-carboxamide (atropisomer 1)
[1716] 235 mg of
1-(2-chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-[(2R)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthy-
ridine-3-carboxamide (atropisomer mixture) were separated into the
atropisomers by chiral HPLC (preparative HPLC: column Daicel.RTM.
Chiralpak IE, 5 .mu.m, 250.times.20 mm; mobile phase: 80%
n-heptane/20% ethanol; flow rate 15 ml/min; temperature: 40.degree.
C., detection: 220 nm).
[1717] Atropisomer 1: 89.4 mg (stereochemical purity >99%)
[1718] R.sub.t=6.076 min [analytical HPLC: column Daicel.RTM.
Chiralpak IE, 1 m/min; 5 .mu.m, 250.times.4.6 mm; mobile phase: 80%
isohexane/20% ethanol; detection: 220 nm; temperature: 30.degree.
C.].
[1719] LC-MS (Method 3): R.sub.t=1.73 min; MS (ESIpos): m/z=551
[M+H].sup.+
[1720] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (1.70),
0.008 (1.45), 1.364 (14.98), 1.382 (15.05), 2.328 (0.41), 2.367
(0.45), 2.690 (1.41), 2.711 (0.46), 3.032 (0.73), 3.212 (0.75),
3.686 (0.73), 3.899 (1.50), 4.005 (1.04), 4.842 (0.41), 4.861
(1.09), 4.880 (1.66), 4.900 (1.68), 4.920 (1.05), 5.196 (4.33),
7.694 (1.34), 7.701 (2.01), 7.717 (2.15), 7.724 (4.15), 7.731
(3.32), 7.741 (2.73), 7.747 (3.08), 7.753 (3.30), 7.763 (1.74),
7.993 (7.70), 8.024 (7.55), 8.790 (16.00), 10.402 (4.83), 10.425
(4.63).
Example 229
1-(2-Chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-[(2R)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthy-
ridine-3-carboxamide (atropisomer 2)
[1721] 235 mg of
1-(2-chloro-4,6-difluorophenyl)-7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]--
6-fluoro-4-oxo-N-[(2R)-1,1,1-trifluoropropan-2-yl]-1,4-dihydro-1,8-naphthy-
ridine-3-carboxamide (atropisomer mixture) were separated into the
atropisomers by chiral HPLC (preparative HPLC: column Daicel.RTM.
Chiralpak IE, 5 .mu.m, 250.times.20 mm; mobile phase: 80%
n-heptane/20% ethanol; flow rate 15 ml/min; temperature: 40.degree.
C., detection: 220 nm).
[1722] Atropisomer 2: 95.7 mg (stereochemical purity >99%)
[1723] R.sub.t=7.196 min [analytical HPLC: column Daicel Chiralpak
IE, 1 ml/min; 5 .mu.m, 250.times.4.6 mm; mobile phase: 80%
isohexane/20% ethanol; detection: 220 nm; temperature: 30.degree.
C.].
[1724] LC-MS (Method 3): R.sub.t=1.73 min; MS (ESIpos): m/z=551
[M+H].sup.T
[1725] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (1.62),
0.008 (1.41), 1.244 (0.79), 1.258 (0.97), 1.272 (0.54), 1.370
(15.93), 1.388 (16.00), 2.366 (0.45), 2.710 (0.46), 3.012 (0.80),
3.240 (0.83), 3.692 (0.82), 3.892 (1.67), 4.008 (1.18), 4.842
(0.44), 4.861 (1.18), 4.880 (1.76), 4.901 (1.80), 4.920 (1.17),
4.938 (0.42), 5.196 (3.63), 7.686 (1.44), 7.693 (2.00), 7.709
(2.44), 7.716 (3.55), 7.740 (4.63), 7.748 (2.20), 7.758 (2.62),
7.762 (2.72), 7.769 (1.86), 7.993 (7.82), 8.024 (7.71), 8.788
(15.55), 10.401 (5.16), 10.424 (4.94).
Example 230
7-[3,3-bis(hydroxymethyl)azetidin-1-yl]-6-fluoro-N-(1,1,1,3,3,3-hexafluor-
opropan-2-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridin-
e-3-carboxamide
##STR00369##
[1727]
6-Fluoro-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-7-(2-oxa-6-azaspiro[-
3.3]hept-6-yl)-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridi-
ne-3-carboxamide (88.0 mg, 99% purity, 149 .mu.mol) was initially
charged in 930 .mu.l of acetonitrile, 930 .mu.l of water and 930
.mu.l of trifluoroacetic acid were added and the mixture was
stirred at room temperature for 18 h. The mixture was purified by
preparative HPLC (column: acetonitrile/water/0.1% formic acid). The
product fractions were concentrated under reduced pressure and the
residue was dissolved in a little dichloromethane and washed three
times with saturated aqueous sodium bicarbonate solution. The
combined organic phases were dried over sodium sulphate, filtered
and concentrated under reduced pressure. This gave 56.0 mg of the
target compound (62% of theory, purity 100%).
[1728] LC-MS (Method 3): R.sub.t=1.95 min; MS (ESIpos): m/z=603
[M+H].sup.+
[1729] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.90),
-0.008 (7.60), 0.008 (7.41), 0.146 (0.92), 1.157 (0.56), 1.175
(1.07), 1.193 (0.56), 1.989 (1.96), 2.328 (0.67), 2.367 (0.42),
2.671 (0.73), 2.711 (0.44), 3.475 (15.50), 3.489 (16.00), 4.021
(0.69), 4.039 (0.67), 4.142 (1.21), 4.842 (5.05), 4.855 (11.74),
4.868 (4.99), 6.294 (0.86), 6.312 (1.25), 6.336 (1.32), 6.354
(0.84), 7.546 (3.66), 7.568 (6.71), 7.590 (3.68), 7.991 (6.48),
8.020 (6.43), 8.945 (11.99), 11.295 (4.16), 11.320 (4.05).
Example 231
N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-7-(pyrrolidin--
1-yl)-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamid-
e
##STR00370##
[1731] According to GP3, 80.0 mg (162 .mu.mol) of
7-chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-6-fluoro-4-oxo-1-(2,-
4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
were reacted with 27 .mu.l (320 .mu.mol) of pyrrolidine and 110
.mu.l (650 .mu.mol) of N,N-diisopropylethylamine in 1.0 ml of
dimethylformamide. The crude product was diluted with a little
acetonitrile and purified by preparative HPLC (column:
acetonitrile/water/0.1% formic acid). This gave 51.1 mg (59% of
theory, about 96% pure) of the title compound.
[1732] LC-MS (Method 5): R.sub.t=1.66 min; MS (ESIpos): m/z=529
[M+H].sup.+
[1733] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.42),
0.146 (0.41), 0.319 (1.90), 0.329 (3.08), 0.342 (3.03), 0.353
(2.43), 0.365 (1.16), 0.500 (0.75), 0.512 (2.08), 0.523 (3.11),
0.536 (2.78), 0.547 (3.13), 0.555 (2.37), 0.566 (3.17), 0.576
(2.59), 0.587 (2.34), 0.597 (1.95), 0.611 (1.18), 0.626 (1.63),
0.636 (1.55), 0.647 (2.81), 0.657 (2.44), 0.663 (2.34), 0.670
(2.33), 0.682 (1.12), 0.691 (0.77), 1.166 (0.55), 1.178 (1.16),
1.187 (1.72), 1.198 (2.98), 1.208 (2.16), 1.219 (2.96), 1.231
(1.96), 1.239 (1.14), 1.252 (0.47), 1.840 (8.25), 2.329 (0.52),
2.671 (0.59), 4.334 (0.42), 4.353 (1.62), 4.374 (2.83), 4.396
(2.79), 4.416 (1.47), 7.536 (5.42), 7.558 (10.40), 7.580 (5.46),
7.975 (7.58), 8.007 (7.54), 8.821 (16.00), 10.476 (6.10), 10.500
(5.89).
Example 232
6-Bromo-7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluorob-
utan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carbo-
xamide (enantiomerically pure)
##STR00371##
[1735] At RT, 3.47 g (19.5 mmol) of 1-bromopyrrolidine-2,5-dione
(NBS) and 41.0 mg (250 .mu.mol) of
2,2'-(E)-diazene-1,2-diylbis(2-methylpropanenitrile) (AIBN) were
added to a solution of 4.99 g (9.07 mmol) of
7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-y-
l]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(enantiomerically pure) in 120 ml of acetonitrile. The mixture was
stirred at 60.degree. C. for 50 min. The reaction mixture was
cooled, concentrated to half of its original volume by evaporation
and poured onto water and dichloromethane. The phases were
separated and the aqueous phase was extracted twice with DCM. The
combined organic phases were washed once with sat. sodium chloride
solution, dried over sodium sulphate and concentrated. The crude
product was purified by normal-phase chromatography
(cyclohexane/ethyl acetate gradient). This gave 2.75 g (48% of
theory, 100% pure) of the title compound.
[1736] LC-MS (Method 1): R.sub.t=1.22 min; MS (ESIpos): m/z=629
[M+H].sup.+
[1737] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (2.11),
0.008 (1.87), 1.386 (9.88), 1.403 (10.35), 1.793 (1.40), 1.849
(1.45), 1.861 (0.98), 1.872 (1.33), 2.074 (0.47), 2.328 (0.74),
2.670 (0.92), 3.461 (1.15), 3.580 (1.46), 4.271 (2.45), 4.980
(3.99), 4.987 (4.14), 5.029 (1.16), 5.052 (0.98), 7.550 (3.37),
7.573 (5.83), 7.594 (3.28), 8.456 (16.00), 8.871 (12.06), 10.322
(4.09), 10.346 (4.07).
Example 233
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-N-[3-methyl-1-(trifluor-
omethoxy)butan-2-yl]-4-oxo-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-napht-
hyridine-3-carboxamide (diastereomer mixture)
##STR00372##
[1739]
7-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-fluoro-4-oxo-1-(2,4,6-tr-
ifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(75.0 mg, 171 .mu.mol) was initially charged in 1.3 ml of DMF, HATU
(77.9 mg, 205 .mu.mol) and N,N-diisopropylethylamine (130 .mu.l,
770 .mu.mol) were added and
3-methyl-1-(trifluoromethoxy)butan-2-amine hydrochloride (racemic)
(42.5 mg, 205 .mu.mol) was added. The reaction mixture was stirred
at room temperature overnight. Ethyl acetate was added and the
reaction solution was extracted three times with water and the
combined aqueous phases were re-extracted twice with ethyl acetate.
The combined organic phases were dried over sodium sulphate,
filtered and concentrated by evaporation. Acetonitrile/water/TFA
were added to the residue and the mixture was purified by
preparative HPLC (RP18 column, mobile phase: acetonitrile/water
gradient with addition of 0.1% TFA). The combined product fractions
were concentrated by evaporation. The residue was dissolved in
dichloromethane and washed twice with saturated aqueous sodium
bicarbonate solution. The combined aqueous phases were re-extracted
twice with dichloromethane. The combined organic phases were dried
over sodium sulphate, filtered and concentrated by evaporation.
This gave 68.6 mg of the target compound (66% of theory, purity
97%).
[1740] LC-MS (Method 3): R.sub.t=1.91 min; MS (ESIpos): m/z=593
[M+H].sup.+
[1741] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.008 (1.44),
0.008 (1.38), 0.960 (15.75), 0.977 (16.00), 1.939 (0.91), 1.956
(1.47), 1.973 (1.41), 1.989 (0.85), 2.328 (0.46), 2.524 (1.29),
2.670 (0.53), 3.073 (0.42), 3.679 (0.45), 3.915 (0.96), 4.115
(0.89), 4.128 (1.21), 4.146 (2.56), 4.170 (3.20), 4.181 (1.89),
4.200 (2.19), 4.214 (2.11), 4.225 (1.36), 4.239 (0.74), 5.196
(2.32), 7.553 (1.98), 7.575 (3.41), 7.596 (1.90), 8.014 (4.52),
8.045 (4.46), 8.768 (7.51), 10.088 (2.55), 10.109 (2.43).
Example 234
6-Fluoro-7-(3-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl)-4-oxo-N-[3-
,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8--
naphthyridine-3-carboxamide (diastereomer mixture)
##STR00373##
[1743]
7-Chloro-6-fluoro-4-oxo-N-(3,3,4,4,4-pentafluorobutan-2-yl)-1-(2,4,-
6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(enantiomerically pure) (30.0 mg, 57.9 .mu.mol) was initially
charged in 0.32 ml of DMF.
3-Methyl-1,3,7-triazaspiro[4.4]nonane-2,4-dione hydrochloride
(racemic) (14.3 mg, 69.5 .mu.mol) was added,
N,N-diisopropylethylamine (50 .mu.l, 290 .mu.mol) was added and the
mixture was stirred at room temperature overnight. The reaction
solution was diluted with acetonitrile/water/TFA and purified by
preparative HPLC (RP18 column, mobile phase: acetonitrile/water
gradient with addition of 0.1% TFA). The combined product fractions
were concentrated by evaporation. The residue was dissolved in
dichloromethane and washed twice with saturated aqueous sodium
bicarbonate solution. The combined aqueous phases were re-extracted
twice with dichloromethane. The combined organic phases were dried
over sodium sulphate, filtered and concentrated by evaporation.
This gave 35 mg of the target compound (90% of theory, purity
97%).
[1744] LC-MS (Method 3): R.sub.t=2.01 min; MS (ESIpos): m/z=651
[M+H].sup.+
[1745] .sup.1H NMR (400 MHz, DMSO-d6) .delta.[ppm]: -0.149 (0.51),
-0.008 (4.35), 0.146 (0.48), 1.387 (4.65), 1.404 (4.66), 2.054
(0.50), 2.247 (0.51), 2.328 (0.89), 2.670 (0.90), 2.839 (16.00),
4.989 (0.42), 5.012 (0.48), 5.030 (0.50), 5.053 (0.42), 5.754
(2.25), 7.540 (1.30), 7.562 (2.34), 7.583 (1.26), 8.057 (2.81),
8.089 (2.79), 8.645 (3.24), 8.862 (4.26), 10.407 (2.00), 10.431
(1.94).
Example 235
7-(2,4-Dioxo-1,3,7-triazaspiro[4.4]non-7-yl)-6-fluoro-4-oxo-N-[3,3,4,4,4--
pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyri-
dine-3-carboxamide (diastereomer mixture)
##STR00374##
[1747]
7-Chloro-6-fluoro-4-oxo-N-(3,3,4,4,4-pentafluorobutan-2-yl)-1-(2,4,-
6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(enantiomerically pure) (75.0 mg, 145 .mu.mol) was initially
charged in 0.79 ml of DMF. 1,3,7-Triazaspiro[4.4]nonane-2,4-dione
hydrochloride (racemic) (33.3 mg, 174 .mu.mol) was added,
N,N-diisopropylethylamine (130 .mu.l, 720 .mu.mol) was added and
the mixture was stirred at room temperature for 2 days. The
reaction solution was diluted with acetonitrile/water/TFA and
purified by preparative HPLC (RP18 column, mobile phase:
acetonitrile/water gradient with addition of 0.1% TFA). The
combined product fractions were concentrated by evaporation. The
residue was dissolved in dichloromethane and washed twice with
saturated aqueous sodium bicarbonate solution. The combined aqueous
phases were re-extracted twice with dichloromethane. The combined
organic phases were dried over sodium sulphate, filtered and
concentrated by evaporation. This gave 81 mg of the target compound
(87% of theory, purity 99%).
[1748] LC-MS (Method 3): R.sub.t=1.88 min; MS (ESIpos):
m/z=637[M+H].sup.+
[1749] .sup.1H NMR (400 MHz, DMSO-d6) .delta. [ppm]: -0.064 (0.65),
-0.008 (2.78), 0.008 (2.31), 1.235 (0.44), 1.387 (14.93), 1.404
(14.88), 2.063 (1.52), 2.236 (1.54), 2.324 (0.96), 2.328 (1.26),
2.367 (0.89), 2.523 (2.50), 2.670 (1.12), 2.675 (0.84), 2.710
(0.77), 3.589 (0.68), 4.967 (0.72), 4.989 (1.28), 5.012 (1.52),
5.031 (1.56), 5.056 (1.26), 5.075 (0.68), 7.545 (5.71), 7.567
(10.68), 7.589 (5.69), 8.053 (9.66), 8.085 (9.42), 8.390 (11.36),
8.865 (16.00), 10.409 (6.74), 10.433 (6.48), 10.876 (9.42).
B. Assessment of Pharmacological Efficacy
[1750] The pharmacological activity of the compounds of the
invention can be demonstrated by in vitro and in vivo studies as
known to the person skilled in the art. The application examples
which follow describe the biological action of the compounds of the
invention, without restricting the invention to these examples.
Abbreviations and Acronyms
TABLE-US-00004 [1751] B.sub.Max number of specific binding sites of
the radioligand CAFTY calcium free tyrode CHO chinese hamster ovary
CRE cAMP-responsive element DMEM Dulbecco's modified eagle medium
DMSO dimethyl sulfoxide FCS foetal calf serum FRET fluorescence
resonance energy transfer GIRK1/4 G-protein-coupled inward
rectifier potassium channel, member 1/4 HEPES
hydroxyethylpiperazine-ethanesulfonic acid HTRF homogeneous time
resolved fluorescence K.sub.d equilibrium dissociation constant
K.sub.i equilibrium inhibitor constant k.sub.off rate of
dissociation k.sub.on rate of association nM nanomolar MEM minimum
essential medium .mu.l microlitres .mu.M micromolar ml millilitres
mM millimolar mtClytin mitochondrial clytin min minutes NMS
N-Me-scopolamine PAM positive allosteric modulator PEI
polyethylenimine Pen/Strep penicillin/streptomycin sec seconds
B-1. Functional M2-GIRK1/4 Activation Test
[1752] Both the activation of the M2 receptor by orthosteric
agonists alone and the allosteric boosting of orthosterically
induced activation by positive allosteric modulators (PAMs) can be
determined by means of a cell-based functional GIRK1/4 activity
test. The binding of orthosteric agonists (endogenous ligand:
acetylcholine) to the M2 receptor leads to receptor activation or a
change in conformation of the receptor in the manner of a shift in
equilibrium in favour of the active receptor conformation. The
binding of the orthosteric agonists to the M2 receptor and hence
the activation thereof can be boosted by positive allosteric
modulators which bind not to the orthosteric binding site of the
agonists but to a separate allosteric binding site.
[1753] The agonist-induced change in conformation of the M2
receptor results in a G.alpha.i protein activation. The activation
of the G.alpha. subunit leads in turn to dissociation and hence
release of the Goy subunits from the G.alpha. subunit and the
activation of separate downstream signal transduction cascades. The
heterodimeric Goy complex released binds to the GIRK1/4 potassium
channel and induces a ligand-controlled channel activation or
opening (Reuveny et al., Nature, July 1994, 370, 143-146). Under
physiological conditions, the result is then a selective efflux of
potassium from the cell along the electrochemical gradient. The
export of positive charge leads to lowering of the transmembrane
potential and hence to hyperpolarization of the cell. The extent of
hyperpolarization can therefore be regarded as a measure of the
activation of the M2 receptor.
[1754] The test cell used is a recombinant CHO-DUKX cell line which
has been stably transfected with cDNA coding for the human M2
receptor and with cDNA coding for both GIRK/4 subunits
(CHO-DUKX-M2-GIRK). The transmembrane potential, or the relative
changes in the transmembrane potential as a function of substance
addition or M2 activation, is determined by means of a
voltage-sensitive dye (FLIPR Membrane Potential Assay Kit Blue,
Molecular Devices #R8034) and the measurement of cell fluorescence
using a proprietary fluorescence imaging instrument.
B-1.1. Determination of the Allosteric Potency of the Test
Substances (EC.sub.50 Value)
[1755] The test substances are dissolved in dimethyl sulfoxide
(DMSO) at a concentration of 10 mM and serially diluted with DMSO
in steps of 1:3.16 for a 10-point dose/activity analysis. In
accordance with the desired test concentrations, the substances are
pre-diluted in loading buffer (composition: 0.6 ml of FLIPR
Membrane Potential Assay Kit Blue (10 mg/ml), 0.6 ml of Brilliant
Black (10 mg/ml), 2 mM CaCl.sub.2 and 2 mM KCl ad 50 ml. sodium
gluconate Tyrode (PAA, #T21-155)).
[1756] The reporter cells cultivated in MEM alpha medium
(supplemented with 10% FCS, 2% Glutamax, 1 mg/ml genticin) were
sown with 2000 cells (measurement after 48 h) or 4000 cells
(measurement after 24 h) in 30 .mu.l per 384-well in
.mu.CLEAR/black Greiner cell culture plates (#781092) and incubated
at 37.degree. C. for 24 h or 48 h. The sowing medium consisted of
MEM alpha medium (supplemented with 5% FCS, 2% Glutamax, no
genticin).
[1757] For the particular measurement, the medium was removed and
the cells were laden with the voltage-sensitive dye for at least 6
min at room temperature (30 .mu.l of loading buffer per 384-well).
This was followed, in a first measurement, by the determination of
the fluorescence for the resting transmembrane potential for a
period of 5 sec. Thereafter, 10 .mu.l in each case of the test
substances diluted in loading buffer were added, followed by a
second measurement to determine the transmembrane potential for a
period of 50 sec in 1 se increments. Finally, the cells were
admixed with 10 .mu.l of agonist solution (acetylcholine dissolved
in loading buffer). Acetylcholine was used at the concentration
corresponding to the EC.sub.20, which had been determined in a
preliminary test. The M2-mediated GIRK1/4 activation or
hyperpolarization was then monitored in a third measurement over a
period of 60 sec. The EC.sub.50 value (degree of allosteric potency
of test compound) and the efficiency (measure of the boosting of
the acetylcholine effect at an EC.sub.20 acetylcholine
concentration) were determined with the aid of a 4-parameter
logistic function (Hill function).
B-1.2. Determination of Positive Cooperativity (a Factor)
[1758] The test substances were dissolved in DMSO at a
concentration of 10 mM and serially diluted with DMSO in steps of
1:3.16 for a 10-point dose/activity analysis. In accordance with
the desired test concentrations, the substances were pre-diluted in
loading buffer (see above).
[1759] The reporter cells cultivated in MEM alpha medium
(supplemented with 10% FCS, 2% Glutamax, 1 mg/ml genticin) are sown
with 2000 cells (measurement after 48 h) or 4000 cells (measurement
after 24 h) in 30 .mu.l per 384-well in .mu.CLEAR/black Greiner
cell culture plates (#781092) and incubated at 37.degree. C. for 24
h or 48 h. The sowing medium consisted of MEM alpha medium
(supplemented with 5% FCS, 2% Glutamax, no genticin).
[1760] For the particular measurement, the medium was removed and
the cells were laden with the voltage-sensitive dye for at least 6
min at room temperature (30 .mu.l of loading buffer per 384-well).
This was followed, in a first measurement, by the determination of
the resting transmembrane potential for a period of 5 sec in 1 sec
increments. Thereafter, 10 .mu.l in each case of the test
substances diluted in loading buffer are added, followed by a
second measurement to determine the transmembrane potential for a
period of 50 sec in 1 sec increments.
[1761] Finally, the cells are admixed with 10 .mu.l of agonist
solution (acetylcholine dissolved in loading buffer). In contrast
to the EC.sub.50 determination of the test substances (see B-1.1),
however, this is not done using one acetylcholine concentration;
instead, every concentration of the test substance is combined with
an acetylcholine 8-point dose-response curve. For the acetylcholine
dilution series, the agonist is serially prediluted in loading
buffer in accordance with the desired end concentrations, starting
with a maximum end concentration of 3 .mu.M in steps of 1:3.16. The
M2-mediated GIRK1/4 activation or hyperpolarization is then
monitored in a third measurement over a period of 60 sec in 1 se
increments. The shift in the acetylcholine dose-response curve in
the presence of increasing concentrations of the test substance is
analysed and quantified by means of GraphPad PRISM (Allosteric
EC.sub.50 shift). The .alpha. factor determined is a measure of the
strength and direction of the allosteric effect. .alpha.
values>1 reflect a lowering of the EC.sub.50 value or an
increase in the potency of the agonist (acetylcholine) in the
presence of allosterics and mean positive cooperativity between
orthosterics (acetylcholine) and allosterics (test substance).
Positive cooperativity is the hallmark of a positive allosteric
modulator. Conversely, .alpha. values<1 are indicative of
negative cooperativity between orthosterics and allosterics, and
hence characterize negative allosteric modulators. .alpha. values=1
mean no cooperativity between orthosteric and allosteric, meaning
that the binding affinities of orthosteric and allosteric to the
receptor do not affect one another. The greater the magnitude of
the .alpha. value, the greater the extent of cooperativity between
orthosteric and allosteric.
[1762] Table 1 below lists, for individual working examples, the
EC.sub.50 and efficiency values thus determined and the .alpha.
values from this assay (in some cases as mean values from two or
more independent individual determinations):
TABLE-US-00005 TABLE 1 Receptor activity Efficiency Cooperativity
Ex. No. EC.sub.50 [.mu.mol/L] [%] (alpha factor) 1 0.021 92 35 2
0.0355 96 3 0.038 97 4 0.038 89 5 0.069 99 6 0.00617 94 58 7
0.00564 93 57 8 0.0043 96 9 0.00199 91 39 10 0.00527 99 70 11
0.0058 100 60 12 0.02 90 40 13 0.0062 94 49 14 0.0055 100 49 15
0.00915 96 41 16 0.00845 99 42 17 0.0795 83 18 0.0205 99 43 19
0.016 98 20 0.013 92 21 0.003 100 22 0.01 95 42 23 0.0055 100 41 24
0.00135 100 57 25 0.00405 95 45 26 0.00403 100 27 0.00258 92 28
0.00315 100 29 0.0025 100 30 0.0026 100 31 0.00415 100 37 32 0.0043
100 54 33 0.00175 100 50 34 0.0012 100 53 35 0.0029 100 36 0.005 92
51 37 0.006 100 38 38 0.0101 100 39 0.0205 100 40 0.0023 98 41
0.0033 100 37 42 0.004 100 43 0.0075 100 44 0.012 100 45 0.00847
100 62 46 0.051 100 47 0.048 81 48 0.0018 78 42 49 0.068 74 50
0.0025 60 51 0.036 81 52 0.0013 83 53 0.016 100 30 54 0.025 100 30
55 0.025 96 56 0.035 100 57 0.0785 89 58 0.104 90 59 0.0915 97 60
0.0036 100 61 0.0022 94 62 0.0041 88 63 0.0039 92 64 0.012 96 65
0.03 89 14 66 0.035 92 67 0.01 95 68 0.032 92 69 0.0059 100 70 0.1
86 71 0.0042 94 26 72 0.011 89 73 0.0027 94 74 0.0039 95 75 0.087
100 76 0.029 100 77 0.0016 100 78 0.0028 100 79 0.0093 99 80 0.024
100 81 0.15 87 82 0.14 65 83 0.044 94 84 0.00835 88 39 85 0.033 100
86 0.014 95 87 0.0014 100 88 0.0022 100 89 0.00475 100 44 90 0.0185
95 30 91 0.0065 100 92 0.0066 100 93 0.012 100 94 0.0047 100 34 95
0.0155 100 96 0.016 96 97 0.013 97 98 0.0143 98 50 99 0.0355 96 100
0.0315 100 101 0.0135 100 102 0.295 92 103 0.0081 100 104 0.013 97
105 0.0075 97 106 0.0072 100 107 0.00355 92 108 0.0054 96 47 109
0.0077 100 110 0.019 100 111 0.0072 99 112 0.00425 100 33 113 0.002
100 35 114 0.007 94 115 0.00665 98 53 116 0.0035 97 117 0.0069 99
118 0.0028 100 119 0.0087 100 120 0.0105 96 121 0.125 100 122
0.00355 100 123 0.0031 100 124 0.018 100 125 0.012 97 126 0.0039 97
127 0.013 92 128 0.0098 90 129 0.066 95 130 0.0023 96 131 0.0046
100 132 0.01 99 133 1.6 81 134 1.83 55 135 2.61 75 136 0.0028 84
137 0.0033 91 138 0.0076 84 139 0.0034 100 140 0.0053 95 141 0.0034
97 142 0.039 99 143 0.0015 94 40 144 0.0045 98 67 145 0.0112 100 86
146 0.012 100 147 0.016 94 148 0.0187 96 149 0.021 92 150 0.024 93
151 0.024 100 152 0.053 100 153 0.048 99 154 0.097 100 155 0.011
100 156 0.011 100 157 0.0026 100 158 0.0037 100 159 0.0071 100 45
160 0.0073 100 38 163 0.025 93 164 0.002 100 45 165 0.0024 100 48
166 0.0044 100 31 167 0.0074 95 168 0.004 86 169 0.0038 99 34 170
0.0081 100 38 171 0.0013 95 172 0.0033 94 35 173 0.0025 99 39 175
0.073 83 176 0.11 91 177 0.53 77 178 0.017 99 179 0.027 100 180
0.0085 86 181 0.0130 83 182 0.0088 100 27 183 0.0423 96 184 0.0045
90 24 185 0.0064 83 13 186 0.0058 87 20 187 0.0099 90 25 188 0.026
97 189 0.03 100 190 0.0835 100 191 0.048 100 192 0.1275 100 193
0.0325 100 194 0.0315 94 195 0.058 100 196 0.063 100 197 0.051 100
198 0.033 100 199 0.014 100 200 0.12 73 201 0.0016 100 39 202 0.001
100 203 0.005 100 29 204 0.017 97 205 0.0031 100 25 206 0.01 100
207 0.0033 100 24 208 0.0018 100 27 209 210 0.0021 100 26 211 212
0.002 100 28 213 0.013 100 214 0.0021 100 215 0.0086 100 216 0.0015
99 217 0.0009 100 39 218 0.0006 100 39 219 0.0165 91 220 0.080 85
221 0.031 85 222 0.55 61 223 0.026 86 224 0.010 96 225 0.11 82 226
0.0067 93 31 227 0.011 94 228 0.0064 93 33 229 0.26 67 230 0.0097
97 36 231 0.0048 82 232 0.007 100 233 0.0023 100 234 0.0097 90 235
0.004 92
B-2. Functional Ca2+ Release Test by Means of M2-G.alpha.16
Reporter Cells
[1763] Any potentially agonistic or else potentially allosteric
effect of the test substances on the M2 receptor can be determined
by a functional Ca.sup.2+ release test. The activation of the M2
receptor by binding of orthosteric agonists (acetylcholine) or
other substances having an agonistic effect leads to a change in
conformation of the receptor, which, in the endogenous state,
results in G.alpha.i protein activation. However, coupling of the
M2 receptor to the exogenously expressed promiscuous G.alpha.q
protein G.alpha.16 results in G.alpha.16 protein activation after
activation of the M2 receptor, which causes--via a downstream
signal transduction cascade--intracellular Ca.sup.2+ release. The
extent of intracellular Ca.sup.2+ mobilization can therefore be
regarded as a measure of the activation of the M2 receptor.
[1764] The test cell used is a recombinant CHO cell line which has
been stably transfected with cDNA coding for the human M2 receptor
and the G.alpha.16 protein and with cDNA coding for the
mitochondrially expressed photoprotein clytin (mtClytin) (CHO
mtClytin G.alpha.16 M2). The determination of the intracellular
Ca.sup.2+ release as a function of substance addition or M2
activation is effected by means of a Ca.sup.2+-sensitive dye
(Fluo-8) and the measurement of cell fluorescence using a
FLIPR.sup.TETRA instrument (Molecular Devices).
B-2.1. Agonism Assay
[1765] The test substances are dissolved in DMSO at a concentration
of 10 mM and serially diluted with DMSO in steps of 1:3.16 for a
10-point dose/activity analysis. In accordance with the desired
test concentrations, the substances are prediluted in Fluo-8 buffer
(composition per 100 ml: 500 .mu.l probenecid, 2 ml Brilliant Black
(20 mg/ml), 440 .mu.l Fluo-8, 2 mM CaCl.sub.2) ad 100 ml CAFTY
Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl.sub.2, 5 mM
NaHCO.sub.3, pH 7.4)).
[1766] The reporter cells cultivated in MEM alpha medium
(supplemented with 10% FCS, 2% Glutamax) were sown with 3000 cells
in 30 .mu.l of sowing medium per 384-well in .mu.CLEAR/black
Greiner cell culture plates (#781092) and incubated at 37.degree.
C. for 24 h. The sowing medium consists of MEM alpha medium
(supplemented with 5% FCS, 2% Glutamax). For the respective
measurement, the medium is removed and the cells, after addition of
20 .mu.l in each case of Fluo-8 buffer per 384-well, were incubated
in an incubator at 37.degree. C. for 1 h. After addition of 10
.mu.l in each case per 384-well of the prediluted test substances,
cell fluorescence was measured for a period of 5 min in 1 sec
increments. The relative degree of maximum activation of the M2
receptor by the respective test substances is calculated by
normalizing the test signal to the signal corresponding to the
E.sub.Max concentration of acetylcholine (3 .mu.M).
B-2.2. Determination of the Positive Allosteric Modulator
Effect
[1767] In order to be able to determine the positive cooperativity
of the test substances in relation to the acetylcholine-mediated M2
receptor activation, reference agonist (acetylcholine) is then
added for a full dose-response analysis. For this purpose,
acetylcholine is serially diluted in Fluo-8 buffer in steps of
1:3.16 beginning with a maximum final concentration of 1 .mu.M.
After addition of 10 .mu.l in each case of agonist solution per
384-well, cell fluorescence is again measured for a period of 5 min
in 1 sec increments. The same assay plate is used as immediately
before for the M2 agonism assay. The shift in the acetylcholine
dose-response curve in the presence of increasing concentrations of
the test substance is analysed and quantified by means of GraphPad
PRISM (Allosteric EC.sub.50 shift) (see above).
B-3. Selectivity Test with Respect to Human Muscarinic
Acetylcholine Receptors
[1768] Any potentially agonistic effect, or else positive
allosteric effect, of the test substances on other human muscarinic
acetylcholine receptors can be determined in a functional Ca.sup.2+
release test (Eurofins; GPCRProfiler.RTM. Services in agonistic and
allosteric mode for Mx Receptors; cat#: HTS600GPCR).
[1769] The test cells used were the Chem-1 or Chem-4 cell lines
transfected with the particular receptor (ChemiScreen.TM. M1
Calcium-Optimized FLIPR Cell Lines, Eurofins; M1: HTS044C;
ChemiScreen.TM. Calcium-Optimized Stable Cell Line Human
Recombinant M2 Muscarininc Acetylcholine Receptor, Eurofins; M2:
HTS115C; ChemiScreen.TM. Human Recombinant M3 Muscarinic
Acetylcholine Receptor Calcium-Optimized Stable Cell Line,
Eurofins; M3: HTS116C; ChemiScreen.TM. Human Recombinant M4
Muscarinic Acetylcholine Receptor Calcium-Optimized Stable Cell
Line, Eurofins; M4: HTS117C; ChemiScreen.TM. M5 Calcium-Optimized
FLIPR Cell Lines, Eurofins; M5: HTS075C). The substance test is
conducted with a FLIPR.sup.TETRA instrument (Molecular
Devices).
B-3.1. Agonism Assay
[1770] In order to determine any potential agonistic effect of the
test substances, the respective test substances were added with a
final test concentration of 10 .mu.M or 1 .mu.M. Ca.sup.2+ release
or cell fluorescence is measured over a period of 180 sec. The
positive control used for normalization of the substance effect to
the receptor activation is a concentration of acetylcholine
corresponding to the E.sub.Max value.
[1771] After the agonism assay has ended, the assay plate is
incubated at 25.degree. C. for 7 min. After the incubation period,
the positive allosteric modulator assay is initialized.
B-3.2. Allosteric Modulator Assay
[1772] In order to examine any positive or negative allosteric
effect of the test substances on other human muscarinic
acetylcholine receptors and the M2 receptor itself, every substance
concentration is combined with an acetylcholine 8-point
dose-response curve. Addition of agonist solution is again followed
in turn by the measurement of cell fluorescence for a period of 180
sec. The shift in the acetylcholine dose-response curve (maximum
shift in the EC.sub.50 of acetylcholine) is analysed and quantified
by means of GraphPad PRISM (Sigmoidal dose-response (variable
slope)-EC.sub.50). Finally, quotients of the allosteric shift for
the M2 receptor and M4 receptor are formed, which function in turn
as a measure of the respective selectivity.
B-4. In Vitro M2 PAM Gi Assay
[1773] For the characterization of the test substances on positive
allosteric modulation of the human M2 receptor, the
carbachol-induced inhibition of the rise in cAMP due to forskolin
in recombinant M2 receptor-expressing CHO cells is measured, these
additionally expressing a luciferase gene under the control of a
cAMP-responsive element (CRE): 3000 cells in 25 .mu.l of full
medium (DMEM F12 PAN medium, 10% FCS, 1.35 mM Na pyruvate, 20 mM
Hepes, 4 mM Glutamax, 2% sodium bicarbonate, 1% Pen/Strep, 1%
100.times. non-essential amino acids) are sown per well of a 384
multititre plate (Greiner, TC Platte, black with clear base) and
incubated at 37.degree. C., 5% CO.sub.2 for 24 hours. Before the
measurement, the medium is replaced by 30 .mu.l of test medium
(Optimem) and incubated at 37.degree. C., 5% CO.sub.2 for 10
minutes. The test substance is prepared in DMSO in various
concentrations (starting concentration 10 mM, dilution factor 3.16)
as a doses response curve and pre-diluted 1:50 with calcium-free
Tyrode, 2 mM CaCl.sub.2, 0.01% BSA. 10 .mu.l of the prediluted
substance solution are added to the cells and incubated at
37.degree. C., 5% CO.sub.2 for 10 minutes. The M2 receptor is
activated by adding 10 .mu.l of carbachol in various concentrations
in calcium-free Tyrode, 2 mM CaCl.sub.2 and incubated at 37.degree.
C., 5% CO.sub.2 for 5 minutes. Adenylyl cyclase is activated by
adding 10 .mu.l of 1 .mu.M (final concentration) forskolin in
calcium-free Tyrode, 2 mM CaCl.sub.2 and incubated at 37.degree.
C., 5% CO.sub.2 for 5 hours. After removing the cell supernatant
and adding 20 .mu.l of Luci/Triton buffer (1:1), luminescence is
determined in a luminometer for 60 seconds.
[1774] Calcium-free Tyrode: 130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1
mM MgCl.sub.2, 4.8 mM NaHCO.sub.3, pH 7.4
[1775] Luci/Triton buffer (1:1): Luci buffer (20 mM tricine, pH
7.8, 2.67 mM magnesium sulfate, 0.1 mM EDTA, 4 mM DTT, 270 .mu.M
coenzyme A, 470 .mu.M D-luciferin, 530 .mu.M ATP) mixed 1:1 with
triton buffer (25 mM Tris aqueous hydrochloric acid, pH 7.8, 25 mM
Na.sub.2HPO.sub.4, 2 mM dithiothreitol, 3% Triton X-100, 10%
glycerin).
[1776] The EC.sub.50 value was determined with the aid of a
4-parameter logistic function (Hill function).
B-5. Competitive FRET Binding Test for Human M2 and M4
Receptors
[1777] The direct binding of the test substances to the M2 receptor
and the boosting of the binding (increasing affinity) of the
natural agonist acetylcholine to the M2 receptor in the presence of
the test substances (positive allosteric effect) is determined by
means of a FRET-based binding assay (HTRF Tag-Lite.RTM. binding
assay, Cisbio). For control of selectivity, the binding of the test
substances to the structurally related M4 receptor is examined
analogously. The HTRF Tag-Lite.RTM. assay is a homogeneous binding
assay and is based on the competitive binding of a fluorescent
ligand (probe) and the unlabelled test substance to the receptor,
which is expressed in living cells. The receptor in turn is
derivatized with a fluorescent donor dye (terbium cryptate), such
that excitation of the donor dye gives rise to a FRET signal
between the receptor and probe (acceptor) when the probe is bound
to the receptor. The acceptor probe used was a telenzepine
derivative conjugated with an HTRF fluorescent dye (red ligand;
L0040RED). The probe therefore binds in the conserved orthosteric
binding site both of the M2 and of the M4 receptor. The allosteric
binding site of the M2 receptor has been characterized by x-ray
crystallography and is postulated as being directly above the
orthosteric binding pocket (Kruse et al., Nature, 2013, 504,
101-106). Both the binding of unlabelled orthosteric agonists
(acetylcholine) to the orthosteric binding site and the binding of
allosteric modulators (test substances) to the allosteric binding
site therefore leads to a concentration-dependent competitive
displacement of the probe and hence to a decrease in the FRET-based
fluorescence signal.
[1778] All binding tests are conducted on white 384 microtitre
plates (small volume) in a total volume of 20 .mu.l. The HTRF
measurements are undertaken with a PHERAstar instrument (BMG
Lab-tech). For the muscarinic M2 or M4 receptor binding test,
SNAPed-M2-expressing cells (C1TT1M2) or SNAPed-M4-expressing cells
(C1TT1M4) are used, which have been labelled with a donor
fluorophore (Lumi4Tb; CELLCUST). The cells are incubated with the
acceptor probe in Tag-lite binding buffer (LABMED) in the presence
of test substance or acetylcholine. Subsequently, the fluorescence
signal is measured at wavelengths of 665 nm and 620 nm and the HTRF
quotient (signal at 665 nm/signal at 620 nm) is determined. The
relative specific signal is determined by subtracting the HTRF
quotient of negative control (Tag-lite buffer only without
probe).
B-5.1. Binding of the Test Substances
[1779] In order to determine the binding of the test substances to
the M2 or M4 receptor in the absence of orthosteric agonist, a
dose-response analysis of the test substances is undertaken in the
competitive format of the M2-Tag-Lite.RTM. or M4-Tag-Lite.RTM.
binding assay. The test substances are dissolved in DMSO at a
concentration of 10 mM and serially diluted with DMSO in steps of
1:3.16 for a dose-response analysis. The maximum test concentration
corresponds to 10 .mu.M. The molar concentration of the test
substance that brought about a half-maximum reduction in the HTRF
signal in relation to the maximum and remaining HTRF signal at the
highest substance concentration (EC.sub.50 of the binding) is
determined by means of GraphPad PRISM (Sigmoidal dose response). At
the same time, the strength of the competition effect is determined
by calculating the maximum decrease in the specific HTRF signal at
the highest substance concentration (% max. competition).
B-5.2. Binding of the Test Substances in Allosteric Mode
[1780] To examine the allosteric modulation of the M2 receptor by
the test compounds, firstly, a dose-response analysis of the test
substances in the competitive format of the M2-Tag-Lite.RTM. or
M4-Tag-Lite.RTM. binding assay in the presence of a concentration
of acetylcholine corresponding to the EC.sub.20 value is
undertaken, the latter being determined in a separate 11-point
acetylcholine dose-response analysis (3 .mu.M). The test substances
are dissolved in DMSO at a concentration of 10 mM and serially
diluted with DMSO in steps of 1:3.16 for a 10-point dose/activity
analysis. The maximum test concentration corresponds to 10 .mu.M.
The molar concentration of the test substance that brought about a
half-maximum reduction in the HTRF signal in relation to the
maximum and remaining HTRF signal at the highest substance
concentration in the presence of an acetylcholine concentration
corresponding to the EC20 value (EC.sub.50 of the binding) is
determined by means of GraphPad PRISM (Sigmoidal dose response). At
the same time, the strength of the competition effect is determined
by calculating the maximum decrease in the specific HTRF signal at
the highest substance concentration (% max. competition).
[1781] In order to examine the boosting of the binding of
acetylcholine to the M2 or M4 receptor, in addition, secondly, an
11-point dose-response analysis of acetylcholine in the competitive
format of the M2-Tag-Lite.RTM. or M4-Tag-Lite.RTM. binding assay
was undertaken in the absence or in the presence of 1 .mu.M or 10
.mu.M test substance. The shift in the acetylcholine dose-response
curve (maximum shift in the EC.sub.50 value of acetylcholine) was
analysed and quantified by means of GraphPad PRISM (Sigmoidal
dose-response).
B-6. Radioligand Binding Assay for Human M2 Receptors
[1782] The allosteric mechanism of action of the test substances
can be further investigated in detail and be quantified by various
radioligand binding assays. The binding of the allostere to the
allosteric binding site of the M2 receptor results in an increase
in the binding affinity of the orthosteric ligand for the M2
receptor in the case of positive cooperativity. The increase in the
binding affinity of the orthosteric ligand by the allostere in the
ternary complex consisting of orthostere, allostere and M2 receptor
is in turn due to modulation of the binding kinetics of the
orthostere. The allostere can alter the association and/or
dissociation rate of the orthostere at the M2 receptor. A lowering
of the dissociation rate reflects in this case a stabilization of
the ternary complex and accompanies therefore a lowering of the
dissociation constant of the orthosteric ligand under equilibrium
conditions (Lazareno, Determination of Allosteric Interactions
Using Radioligand-Binding Techniques in Methods in Molecular
Biology, vol. 259, Receptor Signal Transduction Protocols, 2nd ed.;
Kostenis and Mohr, Trends Pharmacol. Sci. 1996, 17(8),
280-283).
B-6.1. .sup.3H-Oxotremorine M Radioligand Binding Assay Under
Equilibrium Conditions
[1783] In order to check and to quantify the influence of the test
substances on the binding affinity of orthosteric agonists for the
M2 receptor, a radioligand binding assay under equilibrium
conditions can be conducted. In this case, the binding of the
radiolabelled M2 receptor agonist .sup.3H-oxotremorine M to the M2
receptor is investigated at different concentrations of
.sup.3H-oxotremorine M in the binding equilibrium (Croy et al.,
Mol. Pharmacol. 2014, 86, 106-115). Based on the amount of
radioactive agonist specifically bound to the M2 receptor as a
function of the agonist concentration (graphically represented as
the so-called Langmuir isotherm), firstly the equilibrium
dissociation constant K.sub.d of the agonist can be calculated as a
quantitative measure of its binding affinity for the M2 receptor
and secondly the concentration or number of specific binding sites
of the radioligand (agonist) B.sub.max in the absence or presence
of different concentrations of the test substances (positive
allosteric modulators) (Hulme and Trevethick, Brit. J. Pharmacol.
2010, 161, 1219-1237).
[1784] The radioligand binding assay for the M2 receptor
(Euroscreen, FAST-0261B) is carried out by means of
.sup.3H-labelled oxotremorine M (NET671) as agonist. The agonist
binding to the M2 receptor is carried out in triplicate on 96-well
microtitre plates (Master Block, Greiner, 786201) in binding buffer
(sodium/potassium phosphate buffer, pH 7.4). For this purpose, each
assay of M2 membrane extracts (20 .mu.g of protein/96 well) are
incubated with various concentrations of radiolabelled agonists
(0.2-100 nM) alone or in the presence of 1 .mu.M or 10 .mu.M test
substance or binding buffer alone in a total volume of 0.1 mL at
37.degree. C. for 60 min. The non-specific binding of
.sup.3H-labelled oxotremorine M to the membrane is determined by
co-incubating with N-methylscopolamine (NMS), an orthosteric
antagonist of the M2 receptor, in a 200-fold excess. In order to
stop the binding reaction, the samples are then filtered via GF/C
filter (Perkin Elmer, 6005174), which had previously been wetted
with 0.5% polyethylenimine (PEI) solution, for 2 h at room
temperature. The filters are washed six times each with 0.5 mL of
ice-cold wash buffer (10 mM sodium/potassium phosphate buffer, pH
7.4) and 50 .mu.L of Microscint 20 scintillation solution (Packard)
is added per assay. The samples are then incubated for 15 min on an
orbital shaker before the radioactivity is measured by means of a
TopCount.TM. instrument (1 min/well).
[1785] The test substances are dissolved in DMSO at a concentration
of 10 mM and further diluted in DMSO corresponding to the final
test concentration in order to obtain a 100-fold dilution of the
DMSO solution used in binding buffer.
[1786] The K.sub.d and B.sub.max of .sup.3H-oxotremorine M for the
M2 receptor are determined with the aid of a "one-site" specific
binding model (Croy et al., Mol. Pharmacol. 2014, 86, 106-115).
B-6.2. .sup.3H-NMS Competitive Radioligand Binding Assay Under
Equilibrium Conditions
[1787] In order to check and to quantify further the influence of
the test substances on the binding affinity of orthosteric agonists
for the M2 receptor, a competitive radioligand binding assay under
equilibrium conditions is also conducted. In this case, the binding
of the antagonistic radioligand .sup.3H-N-methylscopolamine
(.sup.3H-NMS) to the M2 receptor is determined in the absence or
presence of various concentrations of non-radiolabelled agonist
oxotremorine M (Croy et al., Mol. Pharmacol. 2014, 86, 106-115;
Schober et al., Mol. Pharmacol. 2014, 86, 116-123). The
radiolabelled probe (antagonist) and the non-labelled agonist
compete for the binding to the orthosteric binding site of the M2
receptor. The ability to displace the radiolabelled probe therefore
serves as a measure of the binding affinity of the agonist for the
receptor and can be quantified in accordance with the Cheng-Prusoff
equation as an equilibrium inhibition constant (K.sub.i) (Cheng and
Prusoff, Biochem. Pharmacol. 1973, 22(23), 3099-3108). In order to
further investigate the allosteric effect of the test substances,
the influence of the test substances on the K.sub.i of oxotremorine
M is determined.
[1788] The antagonist inhibition binding assay for the M2 receptor
(Euroscreen, FAST-0261B) is carried out on 96-well microtitre
plates (Master Block, Greiner, 786201) in binding buffer (50 mM
Tris buffer pH 7.4, 1 mM EDTA, 10 .mu.g/ml saponin) using
.sup.3H-NMS as M2 receptor antagonist. To adjust the binding
equilibrium, each assay of M2 membrane extracts (20 .mu.g of
protein/96 well) are incubated with a defined concentration of
radiolabelled antagonist (0.5 nM) alone or in the presence of
various concentrations of non-labelled agonists (oxotremorine M;
0.001 nM to 1 mM) with or without 1 .mu.M or 10 .mu.M test
substance or binding buffer alone in a total volume of 0.1 mL at
25.degree. C. for 2 h. The non-specific binding of .sup.3H-labelled
NMS to the membrane is determined by co-incubating with
non-radiolabelled acetylcholine in a 200-fold excess. In order to
stop the binding reaction, the samples are then filtered over GF/C
filters (Perkin Elmer, 6005174), which had previously been wetted
with 0.5% PEI solution, for 2 h at room temperature. The filters
are washed six times each with 0.5 mL of ice-cold wash buffer (10
mM sodium/potassium phosphate buffer, pH 7.4) and 50 .mu.L of
Microscint 20 scintillation solution (Packard) is added per assay.
The samples were then incubated for 15 min on an orbital shaker
before the radioactivity is measured by means of a TopCount.TM.
instrument (1 min/well).
[1789] The test substances are dissolved in DMSO at a concentration
of 10 mM and further diluted in DMSO corresponding to the final
test concentration in order to obtain a 100-fold dilution of the
DMSO solution used in binding buffer.
[1790] The K.sub.i values in the presence or absence of test
substance are quantified with the aid of the Cheng-Prusoff equation
(Cheng and Prusoff, Biochem. Pharmacol. 1973, 22(23), 3099-3108).
In this case, the IC.sub.50 values of the substances are determined
according to a four parameter logistic equation and the K.sub.d of
NMS determined in a radioligand binding assay under equilibrium
conditions (Schober et al., Mol. Pharmacol. 2014, 86, 116-123).
B-6.3. .sup.3H-Oxotremorine M Dissociation Kinetics Test
[1791] By means of a kinetic radioligand binding assay, the
kinetics of the dissociation of the radiolabelled agonist
.sup.3H-oxotremorine M for the M2 receptor in the presence or
absence of test substance can be investigated. By these means, the
influence of the allosteric activity of the test substances on the
dissociation constant (k.sub.off rate) of the M2 agonist can be
determined and thus the allosteric mechanism of the test substances
can be further characterized (Lazareno, Determination of Allosteric
Interactions Using Radioligand-Binding Techniques in Methods in
Molecular Biology, vol. 259, Receptor Signal Transduction
Protocols, 2nd ed.; Schrage et al., Biochem. Pharmacol., 2014, 90,
307-319).
[1792] The radioligand dissociation binding assay for the M2
receptor (Euroscreen, FAST-0261B) is carried out with
.sup.3H-labelled oxotremorine M (NET671) as agonist. The binding
reaction is carried out in binding buffer (sodium/potassium
phosphate buffer, pH 7.4) on 96-well microtitre plates (Master
Block, Greiner, 786201). For this purpose, each assay of M2
membrane extracts (20 .mu.g of protein/96 well) are pre-incubated
with a defined concentration of radiolabelled agonist (9.65 nM)
alone or in the presence of 1 .mu.M or 10 .mu.M test substance or
binding buffer alone at 37.degree. C. for 60 min. NMS is then added
in 200-fold excess at various time points (one time point per
assay) and the mixtures incubated in a total volume of 0.1 mL at
37.degree. C. In order to stop the binding reaction, the samples
are then filtered over GF/C filters (Perkin Elmer, 6005174), which
had previously been wetted with 0.5% PEI solution, for 2 h at room
temperature. The filters are washed six times each with 0.5 mL of
ice-cold wash buffer (10 mM sodium/potassium phosphate buffer, pH
7.4) and 50 .mu.L of Microscint 20 scintillation solution (Packard)
is added per assay. The samples are then incubated for 15 min on an
orbital shaker before the radioactivity is measured by means of a
TopCount.TM. instrument (1 min/well).
[1793] The test substances are dissolved in DMSO at a concentration
of 10 mM and further diluted in DMSO corresponding to the final
test concentration in order to obtain a 100-fold dilution of the
DMSO solution used in binding buffer.
[1794] The k.sub.off was determined with the aid of a "one phase"
exponential decay model of the dissociation (Hulme and Trevethick,
Brit. J. Pharmacol. 2010, 161, 1219-1237; Kostenis and Mohr, Trends
Pharmacol. Sci. 1996, 17(8), 280-283).
B-6.4. .sup.3H-M2-PAM Binding Test
[1795] Binding affinity of the test substances for the human M2
receptor can be determined directly using a radiolabelled test
substance as probe. To this end, a positive allosteric test
substance was radiolabelled by tritiation (.sup.3H-M2-PAM).
[1796] Using a radioligand binding test under equilibrium
conditions, it is possible, firstly, to determine the equilibrium
dissociation constante K.sub.d of the positive allosteric test
substance (.sup.3H-M2-PAM) as a quantitative measure of its binding
affinity for the M2 receptor and, secondly, to determine the number
of specific binding sites of the radioligand B.sub.max in the
absence or presence of an orthosteric agonist (acetylcholine)
(Hulme and Trevethick, Brit. J. Pharmacol. 2010, 161, 1219-1237;
Schober et al., Mol. Pharmacol. 2014, 86, 116-123). For the
.sup.3H-M2-PAM equilibrium binding test, M2 receptor cell membrane
preparations (CHO-S/hM2, 200 .mu.g) in incubation buffer (10 mM
Tris/HCl pH 7.4, 2 mM MgCl2, 120 mM NaCl, protease inhibitors, 0.3%
BSA) were incubated together with different concentrations of the
allosteric radioligand .sup.3H-M2-PAM (0.5-4000 nM) in the absence
or presence of acetylcholine (100 .mu.M) at 4.degree. C. for 1 h.
Unspecific binding is determined by addition of an excess of
non-radiolabelled allosteric ligand (M2-PAM) (10 .mu.M). To
terminate the binding reaction, the samples are filtered through a
Brandel filter system and washed with stop buffer (50 mM Tris/HCl
pH 7.4, 500 mM NaCl, 0.3% BSA). Beforehand, the filters were wetted
with 0.3% strength PEI solution. Kd and Bmax value of the
allosteric radioligand are determined based on a "one-site"
specific binding model (GraphPad Prism).
[1797] Using a competitive .sup.3H-M2-PAM binding test, it is
possible to determine the affinity of unlabelled allosteric test
substances for the binding site of the radioligand .sup.3H-M2-PAM
at the M2 receptor. (Croy et al., Mol. Pharmacol. 2014, 86,
106-115; Schober et al., Mol. Pharmacol. 2014, 86, 116-123). The
radiolabelled probe .sup.3H-M2-PAM) and the non-labelled allosteric
test substance compete for binding to the allosteric binding site
of the M2 receptor. The ability to displace the radiolabelled probe
therefore serves as a measure of the allosteric binding affinity of
the test sunstances for the receptor and can be quantified in
accordance with the Cheng-Prusoff equation as an equilibrium
inhibition constant (K.sub.i) (Cheng and Prusoff, Biochem.
Pharmacol. 1973, 22(23), 3099-3108). Here, displacement of the
radiolabelled allosteric probe is determined in the presence or
absence of orthosteric agonists (acetylcholine). Analogously to the
above-described .sup.3H-M2-PAM binding test, the .sup.3H-M2-PAM
competition binding test is carried out under equilibrium
conditions. Here, the membrane preparations comprising M2 receptor
are incubated with 1 nM .sup.3H-M2-PAM and various concentrations
of unlabelled test substance in the absence or presence of
acetylcholine (100 .mu.M). The K.sub.i values in the presence or
absence of acetylcholine are determined with the aid of the
Cheng-Prusoff equation (Cheng and Prusoff, Biochem. Pharmacol.
1973, 22(23), 3099-3108).
B-7. Effects of the Test Substances on Acetylcholine-Mediated
GIRK1/4 Channel Currents in Primary Atrial Rat Cardiomyocytes
[1798] The substance testing is carried out in accordance with a
patch clamp protocol described in the literature for the
electrophysiological measurement of acetylcholine-induced GIRK1/4
membrane currents in native rat atrial myocytes (Cheng and Prusoff,
Biochem. Pharmacol. 1973, 22(23), 3099-3108, see e.g. Beckmann and
Rinne et al., Cell. Physiol. Biochem. 2008, 21, 259-268).
[1799] An acetylcholine dose-response curve for GIRK1/4 activity is
initially determined in the absence of test substance (DMSO
control) by perfusing test solutions with increasing acetylcholine
concentration and measuring the resulting membrane currents. The
membrane currents or change in the membrane currents are measured
for a given ACh concentration for approx. 10 to 20 seconds. After
application of the maximum ACh concentration within a DRC series, a
solution of atropine (10 .mu.M) is perfused followed by washing out
of the substance solutions in order to ensure the M2 selectivity
and reversibility of M2 activation. Changes of the membrane
currents are appropriately recorded. Here, each acetylcholine
concentration of the membrane current measured is in each case
normalized to the maximum acetylcholine-induced membrane current
(I/IMax). An acetylcholine dose-response curve comprises in this
case five different concentrations (1 nM, 10 nM, 100 nM, 1 .mu.M,
10 .mu.M). The EC.sub.50 value is determined with the aid of a
4-parameter logistic function (Hill function).
[1800] In order to determine the allosteric effect of the test
substances on the M2 receptor, the acetylcholine dose-response
curve is determined for the GIRK1/4 membrane current in the
presence of a constant concentration of the respective test
substance (e.g. 1 .mu.M). For this purpose, after preincubation of
the cell with the test substance for approx. 20 seconds and
measurement of the membrane currents, a test solution comprising
the same substance concentration and a defined ACh concentration is
perfused for approx. 10 to 20 seconds and the membrane currents are
measured. After application of the maximum acetylcholine
concentration within a measurement series, the perfusion of a
solution with atropine (10 .mu.M) is in turn carried out in order
to check the M2 selectivity of the substance effect. The EC.sub.50
value in the presence of test substance is determined analogously
with the aid of a 4-parameter logistic function (Hill function)
(see above).
[1801] The shift in the acetylcholine dose-response curve is
determined and quantified by the change in the EC.sub.50 value for
acetylcholine in the absence or presence of the test substance.
B-8. Effects of the Test Substances on Isolated Perfused Rat
Heart
[1802] Male Wistar rats (strain: (HsdCpb:WU) with a body weight of
200-250 g are anaesthetized with Narcoren (100 mg/kg). The thorax
is opened and the heart is then exposed, excised and connected to a
Langendorff apparatus by placing a cannula into the aorta. The
heart is perfused retrogradely at 9 ml/min at constant flow with a
Krebs-Henseleit buffer solution (gassed with 95% O.sub.2 and 5%
CO.sub.2, pH 7.4, 35.degree. C.; with the following composition in
mmol/l: NaCl 118; KCl 3; NaHCO.sub.3 22; KH.sub.2PO.sub.4 1.2;
magnesium sulfate 1.2; CaCl.sub.2 1.8; glucose 10; Na pyruvate 2).
To measure the contractility of the heart, a balloon, made of thin
plastic film, which is attached to a PE tube and filled with water
is introduced via an opening in the left auricle of the heart into
the left ventricle. The balloon is connected to a pressure
transducer. The end-diastolic pressure is adjusted to 5-10 mmHg via
the balloon volume. The data are enhanced by a bridge amplifier and
registered on a computer using the LabChart software
(ADInstruments).
[1803] To investigate the allosteric effect of the test substances,
the hearts are perfused with addition of 300 nmol/l of the test
substance. After 15 min, carbachol is added cumulatively to the
perfusion solution in increasing concentrations. Lowering of the
heart rate resulting therefrom is compared, as dose-response curve,
with effects on hearts which had been treated with solvent in place
of test substance. The shift in the carbachol dose-response curve
is analysed and quantified by GraphPad PRISM (sigmoidal
dose-response).
B-9. Effects of the Test Substances on the Heart Rate in
Anaesthetized Rats
[1804] Male rats of the strain (WI) WU Br from the breeder Charles
River are anaesthetized initially with a 4-5% isoflurane inhalation
for approx. 3 min. Subsequently, anaesthesia is maintained using a
1.5% isoflurane inhalation. For this purpose, the anaesthetized
animals are fixed on a heated operating plate. By means of visual
inspection and between toe reflex, the depth of anaesthesia is
checked.
[1805] For the application of the test substance, an i.v. route
into the jugular vein is used. A caudal to cranial skin incision is
then made longitudinally and both the cervical musculature and the
salivary glands are severed. The right common carotid artery is
exposed and blood supply is arrested both proximally and distally.
Using microinstrumentation, a TIP catheter (1.2F) is introduced
into the vessel in order to measure the arterial pressure and the
heart rate.
[1806] Initially, both parameters are monitored for 10 min in the
basal state without substance addition. The substances to be
investigated are dissolved in suitable solvent mixtures and
subsequently administered at various dosages to a group of animals
in each case via the jugular vein by an infusion pump over 5 min. A
solvent-treated group is used as control under the same
experimental conditions. The arterial blood pressure and heart rate
with substance addition is determined for 20 min. The data are
registered with the PowerLab system (ADinstruments) and evaluated
using the LabChart program (ADinstruments).
B-10. Radiotelemetric Measurement of Blood Pressure and Heart Rate
of Conscious Rats
[1807] A commercially available telemetry system from Data Sciences
International DSI, USA, is employed for the measurements on
conscious rats described below. The system consists of 3 main
components: (1) implantable transmitters (Physiotel.RTM. telemetry
transmitter), (2) receivers (Physiotel.RTM. receiver), which are
linked via a multiplexer (DSI Data Exchange Matrix) to a (3) data
acquisition computer. The telemetry system makes it possible to
continuously record blood pressure, heart rate and body motion of
conscious animals in their usual habitat.
[1808] The studies are conducted on adult female rats (Wistar
Unilever/WU or Spontaneous Hypertensive Rat/SHR) with a body weight
of >200 g. After transmitter implantation, the experimental
animals are housed singly in type III Makrolon.RTM. cages. They
have free access to standard feed and water. The day/night rhythm
in the test laboratory is set by changing the illumination of the
room.
Transmitter Implantation:
[1809] The telemetry transmitters used (e.g. PA-C40 HD-S10, DSI)
are surgically implanted under aseptic conditions in the
experimental animals at least 14 days before the first experimental
use. For the implantation, the fasted animals are anaesthetized
with isoflurane (IsoFlo.RTM., Abbott, initiation 5%, maintenance
2%) and shaved and disinfected over a large area of their abdomens.
After the abdominal cavity has been opened along the linea alba,
the liquid-filled measuring catheter of the system is inserted into
the descending aorta in the cranial direction above the bifurcation
and fixed with tissue glue (Vetbond.TM., 3M). The transmitter
housing is fixed intraperitoneally to the abdominal wall muscle,
and the wound is closed layer by layer. Post-operatively, an
antibiotic (Ursocyclin.RTM. 10%, 60 mg/kg s.c., 0.06 ml/100 g body
weight, Serumwerk Bemburg AG, Germany) for infection prophylaxis
and an analgesic (Rimadyl.RTM., 4 mg/kg s.c., Pfizer, Germany) are
administered.
Substances and Solutions:
[1810] Unless stated otherwise, the substances to be studied are
administered orally to a group of animals in each case (M=6). In
accordance with an administration volume of 2 ml/kg of body weight,
the test substances are dissolved in suitable solvent mixtures. A
solvent-treated group of animals is used as control.
Experimental Outline:
[1811] The telemetry measuring system is configured for 24 animals.
Each of the instrumented rats living in the system is assigned a
separate receiving antenna (RPC-1 Receiver, DSI). The implanted
senders can be activated externally via an installed magnetic
switch and are switched to transmission during the pre-run of the
experiment. The signals emitted can be detected online by a data
acquisition system (Dataquest.TM. A.R.T. for Windows, DSI or
Ponemah, DSI) and processed accordingly. In the standard procedure,
the following are measured for 10-second periods in each case: (1)
systolic blood pressure (SBP), (2) diastolic blood pressure (DBP),
(3) mean arterial pressure (MAP), (4) heart rate (HR) and (5)
activity (ACT). These parameters are measured over 24 hours after
administration. The acquisition of measurements is repeated under
computer control at 5-minute intervals. The source data obtained as
absolute values are corrected in the diagram with the currently
measured barometric pressure (Ambient Pressure Reference Monitor,
APR-1, DSI).
Evaluation:
[1812] After the end of the experiment, the acquired individual
data are sorted using the analysis software (Dataquest.TM. A.R.T.
4.1 Analysis or Ponemah, DSI). The 2 hour time point before
substance application is assumed as the blank value. The data are
smoothed over a presettable period by determination of the means
(30 minute mean).
B-11. Effects of the Test Substances on the Heart Rate in
Anaesthetized Dogs
[1813] Male or female cross-breeds (Mongrels, Marshall
BioResources, USA) with a body weight between 20 and 30 kg are
anaesthetized with pentobarbital (30 mg/kg iv, Narcoren.RTM.,
Merial, Germany). Pancuronium chloride (Pancuronium-Actavis.RTM.,
Actavis, Germany, 1 mg/animal iv) serves here additionally as
muscle relaxant. The dogs are intubated and ventilated with an
oxygen-air mixture (40/60%) (approximately 5-6 L/min). The
ventilation is conducted using a ventilation device from GE
Healthcare (Avance), which also serves as anaesthesia monitor (CO2
analyser). The anaesthesia is maintained by a constant infusion of
pentobarbital (50 .mu.g/kg/min); fentanyl (10 .mu.g/kg/h) serves as
analgesic. An alternative to pentobarbital consists of using
isoflurane (1-2% by volume).
[1814] The dog is provided with the following: [1815] bladder
catheter for bladder emptying or measurement of urine flow [1816]
ECG leads to the extremities (for ECG measurement) [1817] insertion
of a NaCl-filled Fluidmedic-PE-300 loop into the A. femoralis. This
is linked to a pressure sensor (Braun Melsungen, Melsungen,
Germany) for measuring the systemic blood pressure [1818] insertion
of a NaCl-filled venous catheter (Vygon, Germany) into the V.
femoralis for infusing test substances or withdrawing blood. [1819]
insertion of a Millar Tip catheter (Typ 350 PC, Millar Instruments,
Houston, USA) via the left atrium or via a sluice for measuring the
heart haemodynamics incorporated into the A. carotis [1820]
insertion of a Swan-Ganz catheter (CCOmbo 7.5F, Edwards, Irvine,
USA) via the V. jugularis into the A. pulmonalis for measuring
cardiac output, oxygen saturation, pulmonary arterial pressures and
central venous pressure. [1821] provision of an ultrasound
flowmeter probe (Transsonic Systems, Ithaka, USA) to the Aorta
descendens for measuring aorta flow [1822] provision of an
ultrasound flowmeter probe (Transsonic Systems, Ithaka, USA) to the
left Aorta coronaria for measuring coronary flow [1823] placement
of a Braunule into the Venae cephalicae for infusing pentobarbital,
liquid substitution and for withdrawing blood (determination of the
substance plasma levels or other clinical blood values) [1824]
placement of a Braunule into the Venae saphenae for infusing
fentanyl and substance application
[1825] The primary signals are possibly amplified (Gould Amplifier,
Gould Instrument Systems, Valley View, USA) or Edwards Vigilance
Monitor (Edwards, Irvine, USA) and subsequently fed into the
Ponemah system (DataSciences Inc, Minneapolis, USA) for evaluation.
The signals are recorded continuously over the whole experimental
time course, further processed digitally by this software and
averaged over 30 s.
B-12. Effects of the Test Substances on the Heart Rate and Heart
Rate Variability in Healthy, Conscious does
[1826] To characterize test substances with regard to their effect
on heart rate, heart rate variability (HRV) and blood pressure,
telemetric measurements are conducted in healthy, male Beagle dogs.
Under isoflurane anaesthesia, a telemetry transmitter (model
L.sup.21, from Data Sciences International, USA) is firstly
implanted in the animals. After left-sided thoracotomy, pressure
sensors are then placed in the aorta and in the left ventricle. To
record an electrocardiogram (ECG), further electrodes are placed on
the heart. For wound healing, the animals are then placed back in
the pen under antibiotic (clindamycin, Zoetis, Germany) and
analgesic (fentanyl, Janssen, Germany) aftercare. By means of the
antennae installed in the animal pen, the blood pressure and ECG
signals are forwarded to a data acquisition computer and evaluated
by analysis software (Ponemah, Data Sciences International, USA).
The telemetry system makes it possible to continuously monitor
blood pressures and ECG signals in conscious animals. Technical
details can be found in the documentation from the manufacturing
company (Data Sciences International, USA).
[1827] The substances to be investigated are administered orally to
the healthy dogs in suitable solvent mixtures by means of a
gelatine capsule. A vehicle-treated group of animals is employed as
control. The telemetry measurement is started before substance
administration and recorded for a time period of several hours. The
time course is displayed graphically by means of data smoothed by
determination of means with the aid of the GraphPadPrism software
(GraphPad, USA). To analyse the HRV, the ECG data are subjected to
a frequency-domain heart rate variability analysis. For this
purpose, the R--R intervals of the recorded ECGs are used. Data
outside the previously defined range of 0.2 s-1.5 s are excluded
from the analysis. The excluded data are replaced by values which
had been obtained by linear interpolation. These data are converted
by spline interpolation into equally-spaced supporting points. To
analyse the heart rate variability, the data are further subdivided
in 30 s steps to packets of 300 s length. For each data packet, a
Fourier transformation is calculated. The power is further
calculated in three frequency bands (vlf=0.0033-0.04 l/s;
lf=0.04-0.15 l/s; hf=0.15-0.5 l/s). To characterize the test
substance, the total power (sum total of all three frequency bands)
of the HRV analysis is used.
* * * * *
References