Damage Incorporated: Discovery of the Potent, Highly Selective, Orally Available ATR Inhibitor BAY 1895344 with Favorable Pharmacokinetic Properties and Promising Efficacy in Monotherapy and in Combination Treatments in Preclinical Tumor Models

Article abstract of DOI:10.1021/acs.jmedchem.0c00369

The ATR kinase plays a key role in the DNA damage response by activating essential signaling pathways of DNA damage repair, especially in response to replication stress. Because DNA damage and replication stress are major sources of genomic instability, selective ATR inhibition has been recognized as a promising new approach in cancer therapy. We now report the identification and preclinical evaluation of the novel, clinical ATR inhibitor BAY 1895344. Starting from quinoline 2 with weak ATR inhibitory activity, lead optimization efforts focusing on potency, selectivity, and oral bioavailability led to the discovery of the potent, highly selective, orally available ATR inhibitor BAY 1895344, which exhibited strong monotherapy efficacy in cancer xenograft models that carry certain DNA damage repair deficiencies. Moreover, combination treatment of BAY 1895344 with certain DNA damage inducing chemotherapy resulted in synergistic antitumor activity. BAY 1895344 is currently under clinical investigation in patients with advanced solid tumors and lymphomas (NCT03188965).

Full text of DOI:10.1021/acs.jmedchem.0c00369

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Article
Damage Incorporated: Discovery of the Potent, Highly Selective,
Orally Available ATR Inhibitor BAY 1895344 with Favorable
Pharmacokinetic Properties and Promising Efficacy in Monotherapy
and in Combination Treatments in Preclinical Tumor Models
Ulrich Luecking, Lars Wortmann, Antje Margret Wengner, Julien Lefranc, Philip Lienau, Hans Briem,
Gerhard Siemeister, Ulf Boemer, Karsten Denner, Martina Schaefer, Marcus Koppitz, Knut Eis, Florian
Bartels, Benjamin Bader, Wilhelm Bone, Dieter Moosmayer, Simon J. Holton, Uwe Eberspächer, Joanna
Grudzinska-Goebel, Christoph Schatz, Gesa Deeg, Dominik Mumberg, and Franz von Nussbaum
J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.0c00369 • Publication Date (Web): 05 Jun 2020
Downloaded from pubs.acs.org on June 6, 2020
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Damage Incorporated: Discovery of the Potent, Highly Selective, Orally
Available ATR Inhibitor BAY 1895344 with Favorable Pharmacokinetic
Properties and Promising Efficacy in Monotherapy and in Combination
Treatments in Preclinical Tumor Models
Ulrich Lücking,* Lars Wortmann,* Antje M. Wengner, Julien Lefranc, Philip Lienau, Hans Briem,
Gerhard Siemeister, Ulf Bömer, Karsten Denner, Martina Schäfer, Marcus Koppitz, Knut Eis,
Florian Bartels, Benjamin Bader, Wilhelm Bone, Dieter Moosmayer, Simon J. Holton, Uwe
Eberspächer, Joanna Grudzinska-Goebel, Christoph Schatz, Gesa Deeg, Dominik Mumberg, and
Franz von Nussbaum
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Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany
ABSTRACT: The ATR kinase plays a key role in the DNA damage response by activating essential signaling pathways of DNA
damage repair, especially in response to replication stress. Since DNA damage and replication stress are major sources of
genomic instability, selective ATR inhibition has been recognized as a promising new approach in cancer therapy. We now
report the identification and preclinical evaluation of the novel, clinical ATR inhibitor BAY 1895344. Starting from quinoline
2 with weak ATR inhibitory activity, lead optimization efforts focusing on potency, selectivity, and oral bioavailability led to
the discovery of the potent, highly selective, orally available ATR inhibitor BAY 1895344, which exhibited strong
monotherapy efficacy in cancer xenograft models that carry certain DNA damage repair deficiencies. Moreover, combination
treatment of BAY 1895344 with certain DNA damage inducing chemotherapy resulted in synergistic antitumor activity.
BAY 1895344 is currently under clinical investigation in patients with advanced solid tumors and lymphomas
(NCT03188965).
INTRODUCTION
stabilizing replication forks, regulating cell cycle
progression, and activating DNA damage repair.4,11–14 Since
replication stress is a major source of genomic instability in
cancer, ATR has recently emerged as a promising target in
cancer therapy.15,16 Selective ATR inhibition leads to
increased replication stress and DNA damage, overall
resulting in cellular lethality. Promising preclinical data
provided a strong basis for the clinical evaluation of
selective ATR inhibitors, both in combination with selected
DNA damage inducing radio- or chemotherapy, and as
monotherapy, following synthetic lethality approaches by
treatment of tumors with certain DDR deficiencies.8 Cancer
cells with increased replication stress (e.g., oncogene-
induced via Ras activation or MYC amplification) or a
defective DDR (e.g., ATM loss of function) may provide the
potential for single-agent activity of a selective ATR
inhibitor, relying on the principle of synthetic lethality.17,18
Therapeutic efficacy of standard-of-care cancer treatments,
such as radio- and chemotherapy, relies on the induction of
DNA damage, which is particularly cytotoxic for
proliferating cells. DNA repair mechanisms may limit their
effectiveness, especially in cancers that have activated the
DDR to resist the lethal effects.19 Selective ATR inhibition
The DNA damage response (DDR) is a complex network
of signaling pathways that coordinates the detection and
repair of DNA damage to secure the integrity of the genome
of eukaryotic cells.1,2 DDR deficiencies are linked to human
pathologies, including cancer.3–5 Defects in or deregulation
of certain DDR components can promote tumorigenesis but
concurrently may increase the dependence of cancer cells
on alternative repair pathways. The kinases ataxia
telangiectasia and Rad3-related (ATR), ataxia telangiectasia
mutated (ATM), and DNA-dependent protein kinase (DNA-
PK) are key mediators of the DDR by responding to different
DNA damage insults, which are primarily DNA double-
strand breaks for ATM and DNA-PK, and replication stress
for ATR.6–9 These kinases belong to the phosphatidylinositol
3-kinase-related kinase (PIKK) family of serine/threonine
protein kinases, which also includes the mammalian target
of rapamycin (mTOR). The kinases of the PIKK family are
characterized by a high degree of homology in the kinase
domain.
DNA replication stress is a hallmark of cancer10 and ATR
plays a key role in the DNA replication stress response by
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may enhance sensitivity to certain DNA damage inducing
However, the electron-rich pyrrole moiety of the proposed
therapies, as well as to certain DNA damage repair
compromising therapies, providing a strong potential for
ATR inhibitors in anticancer therapy.13
structure 1 raised concerns about potential DMPK issues,
and therefore we elected to synthesize the corresponding
pyrazole analogue 2 instead. Due to the unprecedented
2,4,8-substitution pattern at the quinolone scaffold,
synthesis of target molecule 2 turned out to be challenging
and multiple synthetic routes were evaluated before the
synthesis was finally accomplished (see Scheme 2). Despite
all the effort, quinoline 2 revealed very low inhibitory
activity against ATR in the biochemical in vitro assay
compared to AZ20 [IC50: 5050 nM (2) vs 3 nM (AZ20)].
However, due to the difficulties encountered in the
synthesis of quinoline 2, we had also initiated the synthesis
of the corresponding naphthyridine analogue 3, before the
preparation of quinoline 2 was achieved. The additional
nitrogen at the 7-position of the naphthyridine core was
intended to simplify the synthesis with respect to the
desired 2,4,8-regiochemistry at the scaffold, since it was
envisaged to allow the introduction of the substituent at the
8-position (next to the ‘added’ nitrogen) by various
methods. This time our efforts paid off and the new
naphthyridine 3 surprisingly revealed promising ATR
inhibitory activity in vitro (IC50: 125 nM). Initial lead
optimization efforts then led to the identification of the new
lead compound BAY-937 which demonstrated further
improved in vitro activity, both in the biochemical (IC50: 59
nM, see Table 4) and in the cellular mechanistic assay in HT-
29 cells (IC50: 380 nM). The new lead compound also
revealed good selectivity against the structurally related
kinase ATM, based on the IC50 values from the
corresponding biochemical in vitro assays (ratio of IC50
values ATM/ATR ~332). However, selectivity against
mTOR, based on the IC50 values from the corresponding
cellular mechanistic assays, was low (ratio of IC50 values
mTOR/ATR ~13), which raised concerns about potential
toxic effects resulting from this off-target inhibition. BAY-
937 also demonstrated promising antiproliferative
activities in vitro against various cancer cell lines, for
example in the colorectal cancer (CRC) cell lines HT-29
(IC50: 704 nM) and LoVo (IC50: 315 nM). However, BAY-937
was characterized by a very low aqueous solubility of <1
mg/L and this impacts the oral bioavailability of only 14%
that we recorded in in vivo pharmacokinetic studies in rats,
even though BAY-937 has a high permeability coefficient
(Papp A–B) of 102 nm/s and a low efflux ratio of 2.1 in Caco-
2 cells (see Table 4). Moreover, the compound also raised
safety concerns due to its activity in the hERG patch clamp
assay in vitro (IC50: 5.8 µM). However, in in vivo efficacy
studies in the HT-29 xenograft model in mice, BAY-937
demonstrated moderate antitumor efficacy after twice daily
(b.i.d.) oral administration (po), and the compound was
finally selected as the new ATR lead structure.
However, the discovery of highly selective ATR inhibitors
is challenging.20 The high degree of homology of the kinases
of the PIKK family and related lipid kinases like
phosphatidylinositol 3-kinases (PI3Ks) increases the risk
for the inhibition of additional kinases, which may increase
toxicity or counteract the therapeutic effects of ATR
inhibition. So far, four ATR inhibitors are reported to have
entered clinical trials as single agents and in combination
therapy for the treatment of cancer.13 The structures and
preclinical properties of berzosertib (M6620/VX-970),21
discovered by Vertex and licensed to Merck KGaA, and
AstraZeneca’s ceralasertib (AZD6738),22 originating from
tool compound AZ20,23 were recently disclosed (Figure 1).
Moreover, clinical evaluation of M4344/VX-803, whose
structure has been disclosed recently24 has been initiated
(NCT02278250). In this report, we now describe the
discovery and preclinical evaluation of the potent, highly
selective, orally available ATR inhibitor BAY 1895344,25
which is currently under clinical investigation in patients
with advanced solid tumors and lymphomas
(NCT03188965).26
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H
N
N
O
NH2
H
N
H
N
N
N
N
N
N
N
N
O
N
N
O
S
O
O
O
O
S
S
O
HN
M6620
AZ20
AZD6738
(VX-970)
N
N
O
N
N
NH
F
N
H
F
O
N
N
N
N
NH2
N
O
N
N
N
N
O
BAY 1895344
M4344
(VX-803)
Figure 1. Structures of ATR inhibitors M6620 (VX-970), AZ20,
AZD6738, BAY 1895344 and M4344 (VX-803).
RESULTS AND DISCUSSION
Search for a New ATR Lead Structure. To identify a new
ATR lead structure, we initiated a high-throughput screen
(HTS) and also evaluated known ATR inhibitors in an in-
house homology model based on a published PI3Kγ crystal
structure.27
Scheme 1. Key Structural Modifications Leading to the
New ATR Lead Structure BAY-937
Tool compound AZ20, for instance, revealed two main
interactions with the ATP binding pocket of ATR in this
homology model (Scheme 1): one hydrogen bond via the
morpholine oxygen to the hinge region and an additional
hydrogen bond via the indole NH. Based on the overall
findings from these modeling studies, including evaluation
of the most interesting hits from the HTS, quinoline
derivative 1 was suggested as a new ATR inhibitor.
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N
NH
2
R
N
O
N
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19
Compd
R
ATR,
ATR,
Selectivity
vs mTOR,
ratio of
biochemi cellular
cal
IC50 [nM]
IC50
[nM]
cellular
IC50 values
O
O
O
O
125
38
424b
154b
5
3
4
N
Lead Optimization Efforts Culminating in Clinical
Candidate BAY 1895344. Lead optimization efforts
initially focused on the hinge-binding morpholine moiety of
BAY-937, by investigating the structure–activity
relationship (SAR) of ATR inhibitory activity in the
biochemical and in the cellular mechanistic assay in HT-29
cells. Since the low selectivity of BAY-937 against the
structurally related PIKK mTOR was considered a potential
toxicity issue, increasing selectivity against mTOR was
another important optimization parameter. Due to the
shorter syntheses, the structural variation of the hinge-
binding moiety was initially evaluated in the related 4-
isopropoxy series, using compound 3 as a point of
reference. Introduction of a methyl group at the 3-position
of the morpholine, with (R)-stereochemistry,23 gave
compound 4 with significantly improved inhibitory activity
against ATR in vitro in the biochemical (IC50: 38 nM, Table
1) and in the cellular assay (IC50: 154 nM). Moreover,
selectivity against the structurally related kinase mTOR,
based on the ratio of the IC50 values from the corresponding
cellular in vitro assays, was significantly improved to 25. In
contrast, (S)-enantiomer 9 revealed significantly reduced in
vitro activity against ATR (IC50: 1000 nM). However,
additional lead optimization efforts at the hinge-binding
moiety did not result in any further improvement of ATR
inhibitory activity in vitro, even though a broad variety of
substituted morpholines (5–14, 16, 17) and potential
morpholine bioisosteres (15, 18) were evaluated at this
position. Table 1 lists a selection of structurally diverse
analogues that were tested.28
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25
N
5
6
310
413
ND
ND
ND
ND
N
N
O
7
730
ND
ND
N
O
O
8
9
922
ND
ND
ND
ND
N
Table 1. Selected Examples of Lead Optimization Efforts
at the Hinge-Binding 2-Position and Key In Vitro
Propertiesa
1000
N
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aIC50 values are reported as arithmetic means of multiple
measurements except where stated otherwise (see SI for full
details); ND: not determined. bSingle measurement.
10
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1500
1510
1860
ND
ND
ND
ND
ND
ND
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7
8
9
O
O
To our surprise, we also recorded a very steep SAR with
respect to in vitro activity against ATR at the 8-position,
exemplified by the selected compounds of Table 2.28 The
presence and the position of the two nitrogen atoms of the
five-membered aromatic substituent at the 8-position are
important for very high ATR inhibitory activity. Pyrrole
analogues 19 (IC50: 339 nM, Table 2) and 20 (IC50: 589 nM),
for instance, revealed reduced activity against ATR
compared to inhibitor 3. Shifting of the nitrogen atoms
within the five-membered aromatic ring (22, IC50: 3400 nM;
23, IC50: 3690 nM) or the introduction of additional nitrogen
atoms into the five-membered ring (31, IC50: >20000 nM)
was also not tolerated with respect to in vitro activity. N-
Methylation of the pyrazole NH reduced ATR inhibitory
activity in vitro significantly [IC50: 12500 nM (25) vs
125 nM (3)]. Introduction of additional substituents at the
pyrazole ring reduced activity against ATR (24, IC50: 5640
nM; 26, IC50: 12700 nM), too. Moreover, no suitable
structural alternative for the pyrazole ring was identified
(21, 27–29, 32–35). For instance, attempts to mimic the NH
donor function of the pyrazole at the 8-position of
compound 3 failed (21, 32–35). The 8-unsubstituted
analogue 36 was also inactive against ATR in vitro.
N
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O
N
13
14
15
1970
8610
9440
ND
ND
ND
ND
ND
ND
O
O
N
N
CF3
Table 2. Selected Examples of Lead Optimization Efforts
at the 8-Position and Key In Vitro Propertiesa
O
R
8
H
N
N
O
N
O
N
H
F
F
Compd
R
ATR, biochemical ATR, cellular
IC50 [nM]
IC50 [nM]
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O
>20000
ND
ND
N
F
F
N
NH
3
125
424b
O
17
18
>20000
>20000b
ND
ND
ND
ND
N
NH
339
589
>3000b
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20
O
H
N
N
ND
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NH2
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3400
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>20000
>20000b
>20000
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3690
NH
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H
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5640
ND
ND
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>20000
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N
12500
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>20000
>20000
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ND
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NH
N
NH
H
26
27
12700
13200
ND
ND
aIC50 values are reported as arithmetic means of multiple
measurements except where stated otherwise (see SI for full
details); ND: not determined. bSingle measurement.
O
N
In contrast to the results of the structural variation at the
2- and 8-positions of the naphthyridine scaffold, we
recorded a broad SAR with respect to biochemical and
cellular activity against ATR at the 4-position. Our synthetic
approach offered the late-stage introduction of C–C, C–N, C–
O, and C–P bonds at the 4-position and many of the
resulting, structurally diverse compounds demonstrated
high ATR inhibitory activity in vitro. Table 3 shows a
selection of examples from the more than 600 analogues
that were synthesized in the course of the optimization
efforts at this position.28 Many of these compounds also
demonstrated potent antiproliferative activity against
selected cancer cell lines in vitro (Table 3). However, with
respect to the desired kinase selectivity profile, a much
tighter, unpredictable SAR was recorded. Lead compound
BAY-937 revealed significant in vitro activity against mTOR,
but many new compounds resulting from the structural
variation at the 4-position demonstrated significantly
improved selectivity against this off-target, for instance
sulfoximine29–31 45 and imidazole 47. Especially ortho-
substituted (hetero)aromatic substituents at the 4-position
of the naphthyridine scaffold, such as in compounds 39, 41,
42 or 47, which were expected to induce a certain twist of
O
28
29
NH2
17200
18100
ND
ND
N
>20000b
ND
30
NH
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the neighboring aromatic groups, attracted our interest
family or related lipid kinases like ATM, DNA-PK, or PI3K.
since such a twist was expected to disrupt crystal packing
and thereby increase aqueous solubility.32 However, many
of the corresponding compounds also revealed significantly
improved selectivity against mTOR. Unfortunately,
numerous mTOR-selective compounds demonstrated
insufficient selectivity against other kinases of the PIKK
Attempts to predict the selectivity properties of planned
analogues based on computational chemistry approaches
were unsuccessful. In a thorough preclinical evaluation,
BAY 1895344 revealed the best preclinical overall profile in
vitro and in vivo, and was ultimately selected as our clinical
candidate.
8
9
Table 3. Selected Examples of Lead Optimization Efforts at the 4-Position and Key In Vitro Propertiesa
10
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14
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N
NH
O
N
N
R
N
4
Compd
R
ATR,
ATR,
Selectivity
vs mTOR,
ratio of
HT-29
antiproliferation
IC50 [nM]
biochemic cellular
al
IC50
[nM]
IC50 [nM]
cellular
IC50 values
38
2
154b
34b
25
18
929b
93b
4
O
37
OH
N
5
59b
44
233b
38
N
S
O
O
BAY 1895344
7
8
36
61
50
160
N
N
44b
175b
F
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N
70b
42
16
381b
323b
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9
F
10
266b
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O S
HN
82b
66b
86b
30b
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125b
292b
268b
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10
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22
N
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O
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S
227b
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405b
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76b
263
61
192b
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N
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289b
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O
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ND: not determined. bSingle measurement.
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Preclinical Profile of BAY 1895344. BAY 1895344
demonstrated very potent inhibition of ATR in vitro, both in
the biochemical (IC50: 7 nM, Table 4) and in the cellular
mechanistic assay in HT-29 cells (IC50: 36 nM). Evaluation
of BAY 1895344 in an in-house kinase selectivity panel, as
well as by KINOMEscan profiling performed by DiscoverX
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(San Diego, CA, USA), revealed a very promising kinase
inhibitory potency of BAY 1895344 towards human CYP
selectivity profile. Of the 31 kinases in the in-house panel,
only the IC50 value from the biochemical mTOR assay (IC50:
35 nM) was of the same order of magnitude as for ATR (IC50:
7 nM). Although biochemical kinase profiling is a useful and
tractable first step in investigating kinase activity profiles, it
remains important to test compounds in relevant cellular
assays to determine activity and selectivity. Based on the
IC50 values from the corresponding cellular mechanistic
assays, which we consider to be more relevant,
BAY 1895344 showed good selectivity against mTOR (ratio
of IC50 values: mTOR/ATR 61). Moreover, BAY 1895344
revealed high selectivity against other related kinases, such
as DNA-PK (IC50: 332 nM), ATM (IC50: 1420 nM), and PI3K
isoforms was investigated in human liver microsomes using
a standard set of CYP isoform selective substrates. Up to the
highest test concentration (20 µM), no relevant change in
CYP1A2- and CYP2D6-mediated metabolite formation was
observed; thus, IC50 values could not be determined.
BAY 1895344 showed competitive inhibitory potency of
CYP2C8 (IC50: 9.8 µM) and CYP2C9 (IC50: 11 µM). The
inhibitory potential of BAY 1895344 towards CYP3A4-
dependent pathways was tested in the presence of the
model substrates midazolam and testosterone in co-
incubation (IC50: 7.0 µM and >20 µM, respectively) as well
as in pre-incubation assays in human liver microsomes.
Time-dependent inhibition of CYP3A4 was not observed. In
the Caco-2 model, a permeability coefficient (Papp A–B) of
211 nm/s and an efflux ratio of 0.7 was determined,
suggesting a good intestinal permeability of the compound.
The plasma protein binding of BAY 1895344 was
investigated in vitro in plasma from mouse, rat, dog, and
human and the unbound fraction (fu) was found to be
between 3.0% (human) and 17% (rat).
9
10
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49
50
51
52
53
54
55
56
57
58
59
60
(IC50: 3270 nM). In the KINOMEscan panel,
1 µM
BAY 1895344 exhibited activity against only six of a total of
468 kinases (403 of these were nonmutant kinases; for
more details, see the Supporting Information), for only
three of these kinases Kd values below 1 µM were recorded
[mTOR, cyclin G-associated kinase (GAK), and right open
reading frame kinase 2 (RIOK2); Kd = 24, 580, and 660 nM,
respectively].25 BAY 1895344 also demonstrated very
potent antiproliferative activity against various cancer cell
lines in vitro,25 for example in the CRC cell lines HT-29 (IC50:
160 nM) and LoVo (IC50: 71 nM), and in the B-cell lymphoma
cell line SU-DHL-8 (IC50: 9 nM). Lead compound BAY-937
and clinical candidate BAY 1895344 have an identical logD
value of 2.1, determined at pH 7.5, but BAY 1895344
demonstrated significantly improved aqueous solubility at
pH 6.5 (BAY 1895344: 34 mg/L vs BAY-937: <1 mg/L).33 In
line with our rationale to increase aqueous solubility by
disrupting the crystal packing, the small molecule X-ray
In vivo pharmacokinetic investigations revealed that
BAY 1895344 has a low blood clearance in rat and dog (1.2
L/h/kg and 0.79 L/h/kg) and a moderate blood clearance in
mouse (3.5 L/h/kg). The volume of distribution is high for
mouse and rat (8.8 L/kg and 1.7 L/kg) and intermediate to
high for dog (1.0 L/kg). The apparent half-life is
intermediate (1.3 h, rat) to short (0.17 h, mouse; 1.0 h, dog).
After oral administration, bioavailability is moderate in dog
(51%) to high in rat (87%). In the hERG patch clamp assay
in vitro, BAY 1895344 revealed no activity (IC50: >10 µM).
structure of BAY 1895344 shows
a twist of the
Table 4. Properties of Lead Compound BAY-937 and
Clinical Candidate BAY 1895344
naphthyridine scaffold relative to the ortho-methyl-
substituted pyrazole moiety at the 4-position (torsion
angle: 54.8°) (Figure 2). Additionally, the (3R)-methyl
substituent of the morpholine points out of the plane of the
naphthyridine scaffold.
BAY-937 BAY 1895344
ATR, biochemical, IC50 [nM]
59
7
Selectivity vs ATM, ratio of
biochemical IC50 values
332
202
ATR, cellular mechanistic
assay in HT-29, IC50 [nM]
380
13
36
61
Selectivity vs mTOR, ratio of
cellular mechanistic IC50
values
HT-29, IC50 [nM]a
LoVo, IC50 [nM]a
SU-DHL-8, IC50 [nM]a
logD, pH 7.5
Sw, pH 6.5 [mg/L]c
Papp A–B [nm/s]
Efflux ratio
704
315
NDb
2.1
160
71
9
Figure 2. X-ray structure of BAY 1895344.
2.1
34
In vitro pharmacokinetic studies with BAY 1895344
revealed high metabolic stability in liver microsome
preparations of human and rat origin tested at 1 µM
compound concentration, resulting in a predicted maximal
oral bioavailability (Fmax) of the parent compound after
incubation for 60 minutes of 86% and 88%, respectively. In
liver microsome preparations of mouse and dog origin, a
moderate metabolic stability was recorded (Fmax of 44% and
54%, respectively). Stabilities in hepatocytes were very
similar to those reported for liver microsomes. The
<1
102
2.1
211
0.7
CLb, human hepatocytes
[L/h/kg]
NDb
0.41
0.74
CLb, rat hepatocytes [L/h/kg] 0.64
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findings are well in line with the unbound plasma levels of
CLb, rat liver microsomes
[L/h/kg]
0.69
0.52
BAY 1895344 covering in vitro cellular IC50 values for the
full dosing interval.25
CLb, rat, in vivo, iv [L/h/kg]
Vss, rat, in vivo, iv [L/kg]
t1/2, rat, in vivo, iv [h]
1.5
2.0
0.93
14
1.2
1.7
1.3
87
To assess the activity of ATR inhibition with DNA damage
inducing cancer therapy, we investigated the in vivo
antitumor efficacy of BAY 1895344 in combination with the
standard-of-care chemotherapy drug carboplatin in the
platinum-resistant ATM protein low expressing CR5038
human CRC patient-derived xenograft (PDX) model in
NOD/SCID mice. Oral (po) once daily (q.d.) application of
BAY 1895344 at 20 mg/kg (reduced to 10 mg/kg from day
14) in an intermittent 2 days on and 5 days off dosing
schedule in combination with 40 mg/kg carboplatin applied
intraperitoneally (ip) once every week (1 day on/6 days off)
resulted in synergistic antitumor activity, with a T/C ratio
of 0.34 (p < 0.05 vs vehicle and respective monotherapies)
at acceptable tolerability, with a transient body weight loss
in the combination treatment group of 11–15% at days 11
to 14 and 28 to 31, whereby the BAY 1895344 dose was
reduced at day 14. All other treatments were well-tolerated,
with body weight loss <10% (Figure 4).
F, rat, in vivo, po [%]
hERG patch clamp, IC50 [µM]
5.8
>10
aCells were treated with test compounds for 96 h. ND: not
b
c
determined. The solid state of the test compounds was not
characterized.
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50
51
52
53
54
55
56
57
58
59
60
BAY 1895344 exhibited strong monotherapy efficacy in
various cancer xenograft models of different human cancer
types that carry certain defects in DNA damage repair.25
For example, BAY 1895344 exhibited strong antitumor
efficacy in the ATM-mutated SU-DHL-8 (ATMK1964E) human
germinal center B-cell-like diffuse large B-cell lymphoma
(GCB-DLBCL) cell line derived xenograft model in female
C.B-17 SCID mice, with a treatment-to-control (T/C) ratio of
–0.03 (p < 0.001 vs vehicle) at acceptable tolerability, after
oral (po) application of 50 mg/kg twice daily (b.i.d.) in an
intermittent 3 days on and 4 days off dosing schedule
(Figure 3).
Figure 4. Antitumor efficacy of BAY 1895344 in combination
with carboplatin in the CR5038 human CRC PDX model in
NOD/SCID mice (n = 10/group). BAY 1895344 (20 mg/kg, and
10 mg/kg from day 14, q.d., 2 days on/5 days off, po) in
combination with carboplatin (40 mg/kg, q.d., 1 day on/6 days
off, ip). Acceptable tolerability of treatments with a transient
body weight loss in the combination group at days 11 to 14 and
28 to 31 of 11–15%, otherwise <10%. *p < 0.05 vs vehicle and
respective monotherapies.
Figure 3. Antitumor efficacy of BAY 1895344 as monotherapy
in the SU-DHL-8 GCB-DLBCL xenograft model in female C.B-17
SCID mice (n = 9/group). The optimal dose and treatment
schedule for BAY 1895344 was 50 mg/kg (b.i.d. 3 days on/4
days off, po), based on best efficacy and tolerability in
previously tested human xenograft models in mice. Treatments
were well-tolerated, with a maximum body weight loss <10%.
***p < 0.001 vs vehicle.
We further tested the in vivo antitumor efficacy of
BAY 1895344 in combination with another DNA damage
repair compromising cancer drug, the PARPi olaparib, in the
PARPi-insensitive SUM149 (FANCD2K50N
,
FANCID515H
,
BRCA1N723X, TP53M237I) human triple-negative breast cancer
(TNBC) xenograft model. Combination treatment with
BAY 1895344 at sub-MTD and olaparib at MTD showed
potent antitumor efficacy, with a T/C ratio of –0.06 (p <
0.001 vs vehicle and respective monotherapies), pointing
towards a synergistic combination effect. All treatments
were well-tolerated, with a maximum body weight loss
<10% (Figure 5).
The association between in vivo antitumor efficacy and
ATR inhibition mediated by BAY 1895344 treatment has
been demonstrated via two different approaches, ATR
phosphorylation (pATR) as a direct measure of ATR kinase
activity, and H2AX phosphorylation (pH2AX) as an indirect
measure of ATR-mediated DNA repair. In tumor xenografts,
BAY 1895344 treatment led to a reduction of pATR and in
parallel to an increase of pH2AX indicating that blockade of
ATR activity correlated with increased DNA damage. These
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inducing therapies or certain DNA damage repair
compromising cancer therapies results in synergistic
activity and significant improvement of antitumor efficacy
compared to the respective single-agent treatments, as we
have demonstrated previously.25 However, the tolerability
of combination therapies inducing systemic DNA damage,
directly or by inhibition of parallel DDR pathways, needs
careful evaluation of dose and treatment schedule to ensure
safety. Limitations caused by co-treatment induced
systemic DNA damage could potentially be avoided in
combination with treatments that specifically target the
tumor only, such as local external beam radiation therapy
(EBRT) or certain targeted alpha therapies .25,34,35
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59
60
Synthesis. The successful synthesis of quinoline
derivative 2 is depicted in Scheme 2. Condensation of
commercially available N-acetylmorpholine (49) and
anthranilic acid derivative 50 with phosphoryl chloride
gave intermediate 51 in very good yield, which was then
cyclized under basic conditions to give the quinoline
scaffold 52 with the desired 2,4,8-regiochemistry in place.36
Alkylation of the hydroxyl group, followed by a Suzuki
reaction with boronic acid derivative 54 and final
deprotection of the tetrahydropyranyl (THP) group under
acidic conditions, gave rise to compound 2.
Figure 5. Antitumor efficacy of BAY 1895344 in combination
with the PARPi olaparib in the SUM149 human TNBC xenograft
model in nude mice (n = 10/group). BAY 1895344 (20 mg/kg,
b.i.d., 3 days on/4 days off, po) in combination with olaparib
(50 mg/kg, q.d., ip). Treatments were well-tolerated, with a
maximum body weight loss <10%. ***p < 0.001 vs vehicle and
respective monotherapies.
The data demonstrate and confirm that combination
treatment of BAY 1895344 with certain DNA damage
Scheme 2. Synthesis of Quinoline 2a
Br
H2N
O
O
O
Br
N
Br
N
O
N
O
N
O
50
N
O
a
b
O
OH
49
51
52
N
N
N
N
c
O
B
NH
N
O
O
O
O
8
2
O
N
N
N
N
O
O
Br
54
N
N
O
4
e
d
O
2
55
53
aReagents and conditions: (a) POCl3, DCE, rt to 80 °C, 93%; (b) LiHMDS, DMF, 0 °C to rt, 48%; (c) 2-iodopropane, K2CO3, MeCN, rt,
85%; (d) Pd(dppf)Cl2, Cs2CO3, 1,4-dioxane, 85 °C, microwave, 54%; (e) 2 M aq HCl, 97%.
1,7-Naphthyridine derivative 3 was prepared using a
similar synthetic approach (Scheme 3), which enabled the
rapid structural variation of all three substituents of the
central scaffold. Condensation of amide 49 and methyl 3-
amino-2-chloroisonicotinate (56) yielded intermediate 57,
Scheme 3. Synthesis of 1,7-Naphthyridine 3a
which was followed by cyclization under basic conditions to
give central building block 58. Suzuki coupling (59), ether
formation (60), and final deprotection gave the desired
2,4,8-trisubstituted naphthyridine 3.
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2
3
4
5
6
7
8
9
Cl
H2N
O
O
N
O
Cl
Cl
N
O
N
N
O
N
O
N
56
N
N
O
a
b
O
OH
49
58
57
N
N
O
c
B
N
N
N
O
O
54
NH
10
O
O
N
O
11
12
13
14
15
16
17
N
N
O
3
N
N
O
N
N
N
O
O
N
N
N
e
d
OH
60
59
aReagents and conditions: (a) POCl3, DCE, rt to 80 °C, 89%; (b) LiHMDS, DMF, rt, 65%; (c) Pd(dppf)Cl2, Cs2CO3, 1,4-dioxane, 80 °C,
54%; (d) 2-iodopropane, MeCN, 85 °C, 81%; (e) TFA, H2O, 59%.
18
19
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-Hydroxynaphthyridine derivatives like intermediate
59 were also utilized for rapid variation at the 4-position
(Scheme 4). For instance, in the synthesis of lead compound
BAY-937, intermediate 59 was converted into triflate 61. A
Suzuki
coupling
reaction
of
61
with
4-
(methylsulfonyl)phenylboronic acid pinacol ester and
deprotection of the pyrazole THP group under acidic
conditions provided BAY-937 in 51% overall yield from 59.
Scheme 4. Synthesis of BAY-937a
N
NH
O
N
N
N
N
N
N
N
O
O
O
O
N
N
N
N
N
N
a
b-c
O
S
O
F
O
F
OH
O S
O
BAY-937
F
59
61
aReagents and conditions: (a) N-phenyl-bis(trifluoromethanesulfonimide), DIPEA, DCM, rt, 88%; (b) 4-(methylsulfonyl)phenyl-
boronic acid pinacol ester, Pd(dppf)Cl2, Cs2CO3, 1,4-dioxane, 90 °C, 71%; (c) TFA, H2O, 81%.
The research synthesis of BAY 1895344 is outlined in
Scheme 5. Acetylation of commercial (3R)-3-methyl-
morpholine (62) gave amide 63, which was condensed with
56 and then cyclized to yield central intermediate 65. In
analogy to the synthesis of BAY-937, a first Suzuki reaction
introduced the protected pyrazole substituent at the 8-
position (66). A second Suzuki reaction was used to
introduce the methylpyrazole substituent at the 4-position,
which was followed by acidic deprotection of the THP group
to give BAY 1895344 in an overall yield of 28%.
Scheme 5. Synthesis of BAY 1895344a
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Cl
O
H2N
O
N
O
Cl
Cl
N
O
N
N
N
O
O
O
56
N
N
N
NH
O
a
c
b
5
O
OH
6
7
8
62
63
64
65
N
N
9
O
d
B
O
O
10
11
12
13
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
54
O
O
N
N
NH
B
N
N
N
N
O
N
O
N
N
O
N
O
68
O
N
N
N
N
N
N
e
f-g
O
N
O
F
OH
S
N
O
F
F
BAY 1895344
67
66
aReagents and conditions: (a) AcCl, K2CO3, DCM, rt, 95%; (b) POCl3, DCE, rt to 80 °C, quant.; (c) LiHMDS, THF, 0 °C to rt, 64%; (d)
Pd(dppf)Cl2, Cs2CO3, 1,4-dioxane, 90 °C, 72%; (e) N-phenyl-bis(trifluoromethanesulfonimide), DIPEA, DCM, rt, 86%; (f) Pd(PPh3)2Cl2,
aq K2CO3, DME, 130 °C, MW; (g) H2SO4, 78%.
CONCLUSION
for the treatment of cancers with selected DDR deficiencies
in monotherapy as well as in selected combinations by
improving the therapeutic efficacy of standard-of-care
therapies addressing DNA damage or DNA repair.
BAY 1895344 is currently under clinical investigation in
patients with advanced solid tumors and lymphomas
(NCT03188965).26
The integrity of the genome of eukaryotic cells is secured
by complex signaling pathways, known as the DNA damage
response (DDR). The serine/threonine protein kinase ATR
has been recognized as a promising new target in cancer
therapy since it plays a key role in the DNA replication
stress response pathway. Based on promising preclinical
data, four ATR inhibitors, from Merck KGaA (M6620,
M4344), AstraZeneca (AZD6738), and Bayer AG
EXPERIMENTAL SECTION
Synthetic Procedures
(BAY 1895344),
have
entered
clinical
studies.
General Methods and Materials. Commercially
available reagents and anhydrous solvents were used as
supplied, without further purification. All air- and moisture-
sensitive reactions were carried out in oven-dried (at
120 °C) glassware under an inert atmosphere of argon. A
Biotage Initiator Classic microwave reactor was used for
reactions conducted in a microwave oven. Reactions were
monitored by TLC and UPLC analysis with a Waters Acquity
UPLC MS Single Quad system; column: Acquity UPLC BEH
C18 1.7 µm, 50 × 2.1 mm; basic conditions: eluent A:
H2O + 0.2 vol% aq NH3 (32%), eluent B: MeCN; gradient: 0–
1.6 min 1–99% B, 1.6–2.0 min 99% B; flow: 0.8 mL/min;
acidic conditions: eluent A: H2O + 0.1 vol% formic acid
(99%), eluent B: MeCN; gradient: 0–1.6 min 1–99% B, 1.6–
2.0 min 99% B; flow: 0.8 mL/min; temperature: 60 °C; DAD
scan: 210–400 nm. Analytical TLC was carried out on
aluminum-backed plates coated with Merck Kieselgel 60
F254, with visualization under UV light at 254 nm. Flash
chromatography was carried out using a Biotage Isolera
One system with 200–400 nm variable detector.
BAY 1895344 resulted from extensive lead optimization
efforts starting from quinoline 2, which had been predicted
as a promising ATR inhibitor in modeling studies, but
revealed low in vitro activity against ATR. In addition to
increased biochemical and cellular ATR inhibitory activity,
high kinase selectivity against structurally related kinases
of the PIKK family as well as promising physicochemical and
DMPK properties were main optimization parameters.
Thorough variation of all substituents of lead structure
BAY-937 finally led to the discovery of the potent and highly
selective ATR inhibitor BAY 1895344, which potently
inhibits the proliferation of a broad spectrum of human
tumor cell lines characterized by certain mutations
affecting DDR pathways. In comparison to lead structure
BAY-937, clinical candidate BAY 1895344 shows
significantly improved aqueous solubility and oral
bioavailability across species. Moreover, BAY 1895344
revealed no activity in the hERG patch clamp assay.
Preclinical in vivo studies with BAY 1895344 demonstrated
strong monotherapy antitumor efficacy with good
tolerability in a variety of xenograft models of different
human cancer types carrying certain defects in DNA repair.
In addition, BAY 1895344 is likely to be particularly
efficacious in combination treatment with certain DNA
damage inducing therapies or certain DNA damage repair
compromising therapies.
Preparative HPLC was carried out with
a Waters
AutoPurification MS Single Quad system; column: Waters
XBridge C18 5 µm, 100 × 30 mm; basic conditions: eluent A:
H2O + 0.2 vol% aq NH3 (32%), eluent B: MeCN; gradient: 0–
0.5 min 5% B, flow: 25 mL/min; 0.51–5.50 min 10–100% B,
flow: 70 mL/min; 5.51–6.5 min 100% B, flow: 70 mL/min;
acidic conditions: eluent A: H2O + 0.1 vol% formic acid
(99%), eluent B: MeCN; gradient: 0–0.5 min 5% B, flow: 25
Taken together, the potent, highly selective, orally
available ATR inhibitor BAY 1895344 shows great promise
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mL/min; 0.51–5.50 min 10–100% B, flow: 70 mL/min;
mmol) in MeCN (50 mL) and the mixture was stirred for 8 h
at rt. Then, the mixture was diluted with H2O. The
precipitate was collected by filtration and dried under
2
3
4
5
6
7
8
9
5.51–6.5 min 100% B, flow: 70 mL/min; temperature:
25 °C; DAD scan: 210–400 nm. NMR spectra were recorded
at rt (22 ± 1 °C), unless otherwise noted, on Bruker Avance
III HD spectrometers. 1H NMR spectra were obtained at 300,
400, 500, or 600 MHz, and referenced to the residual solvent
signal (7.26 ppm for CDCl3, 2.50 ppm for DMSO-d6).13C NMR
spectra were obtained at 125 or 150 MHz and also
referenced to the residual solvent signal (39.52 ppm for
1
reduced pressure to give 53 (1.18 g, 3.30 mmol, 85%). H
NMR (400 MHz, DMSO-d6): δ = 7.85–7.89 (m, 2H, quinoline),
7.06 (t, J = 7.83 Hz, 1H, quinoline), 6.64 (s, 1H, quinoline),
5.02 (sept, J = 6.00 Hz, 1H, OCH), 3.73 (m, 8H, morpholine),
1.37 (d, J = 6.06 Hz, 6H, iPr). MS (ESI+): m/z = 351.1 [M+H]+.
4-Isopropoxy-2-(morpholin-4-yl)-8-[1-(tetrahydro-
2H-pyran-2-yl)-1H-pyrazol-5-yl]quinoline
1
DMSO-d6). H NMR data are reported as follows: chemical
(55).
A
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
shift (δ) in ppm, multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, quin = quintet, sept = septet, br = broad,
mixture of 53 (170 mg, 0.48 mmol), 1-(tetrahydro-2H-
pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-1H-pyrazole (54) (202 mg, 0.73 mmol), [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II)
[Pd(dppf)Cl2] (1:1 complex with DCM; 40 mg, 0.048 mmol),
and Cs2CO3 (630 mg, 1.94 mmol) in 1,4-dioxane (5 mL) was
stirred under argon for 3 h at 85 °C in a microwave reactor.
After cooling, the mixture was diluted with H2O and
extracted with DCM (3 ×). The combined organic phases
were dried (Na2SO4), filtered, and concentrated. The residue
was purified by preparative HPLC (basic conditions) to give
m
= multiplet), integration, and assignment. High-
resolution mass spectra were recorded on a Xevo G2-XS Tof
(Waters) instrument. Low-resolution mass spectra
(electrospray ionization, ESI) were obtained via HPLC-MS
(ESI) using a Waters Acquity UPLC system equipped with an
SQ 3100 Mass Detector; column: Acquity UPLC BEH C18 1.7
µm, 50 × 2.1 mm; eluent A: H2O + 0.05% formic acid (99%),
eluent B: MeCN + 0.05% formic acid (99%); gradient: 0–0.5
min 5% B, 0.5–2.5 min 5–100% B, 2.5–4.5 min 100% B; total
run time: 5 min; flow: 0.5 mL/min. Melting points were
determined with a Büchi B-540 melting point apparatus.
Optical rotations were recorded on a JASCO P-2000
polarimeter. The purity of all target compounds was at least
95%, as determined by LC-MS. A detailed description of all
LC-MS methods is given in the SI. Compound names were
generated using ICS software.
1
55 (111 mg, 0.26 mmol, 54%). H NMR (400 MHz, DMSO-
d6): δ = 7.97 (dd, J = 1.52, 8.34 Hz, 1H, quinoline), 7.55 (m,
1H, pyrazole), 7.53 (d, J = 6.88 Hz, 1H, quinoline), 7.24 (dd,
J = 7.33, 8.08 Hz, 1H, quinoline), 6.60 (s, 1H, quinoline), 6.35
(d, J = 1.77 Hz, 1H, pyrazole), 5.13 (dd, J = 2.40, 9.47 Hz, 1H,
NCHO), 5.01 (td, J = 6.06, 12.13 Hz, 1H, OCH), 3.76 (br d,
J = 11.12 Hz, 1H, OCH2), 3.59–3.68 (m, 4H, morpholine),
3.48–3.56 (m, 4H, morpholine), 3.12–3.21 (m, 1H, OCH2),
2.29–2.38 (m, 1H, alkylene-CH2), 1.95 (m, 1H, alkylene-CH2),
1.79 (m, 1H, alkylene-CH2), 1.34–1.53 (m, 9H, iPr, alkylene-
CH2). MS (ESI+): m/z = 423.0 [M+H]+.
Methyl 3-Bromo-2-{[1-(morpholin-4-yl)ethylidene]-
amino}benzoate (51). Under argon and at 0 °C,
phosphorus oxychloride (0.57 mL, 6.09 mmol) was added
to a solution of N-acetylmorpholine (49) (561 mg, 4.35
mmol) in DCE (3 mL) and the mixture was stirred at rt for
30 min. Methyl 2-amino-3-bromobenzoate (50) (500 mg,
2.17 mmol) was added and the reaction mixture was stirred
at 80 °C for 3 h. After cooling, the mixture was added to aq
NaHCO3 solution and extracted with DCM (3 ×). The
combined organic layers were dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue was
purified by flash chromatography (silica gel, EtOAc/MeOH
gradient 0–100%) to give 51 (700 mg, 2.05 mmol, 93%). MS
(ESI+): m/z = 341.1 [M+H]+.
4-Isopropoxy-2-(morpholin-4-yl)-8-(1H-pyrazol-5-
yl)quinoline (2). 2 M HCl (10 mL) was added to a solution
of 55 (104 mg, 0.25 mmol) in MeOH (30 mL) and the
mixture was stirred for 30 min at rt. Then, the mixure was
diluted with 1 N aq NaHCO3 solution, and the precipitate
was collected by filtration and dried under reduced
pressure to give 2 (82 mg, 0.24 mmol, 97%). LC-MS [Method
1
1]: Rt = 0.97 min. MS (ESI+): m/z = 339.2 [M+H]+. H NMR
(400 MHz, DMSO-d6): δ = 12.79–13.27 (m, 1H, pyrazole-
NH), 7.88–8.13 (m, 2H, quinoline), 7.45–7.83 (m, 1H,
pyrazole), 6.82–7.40 (m, 2H, quinoline, pyrazole), 6.55–6.75
(m, 1H, quinoline), 5.03 (m, 1H, OCH), 3.72–3.86 (m, 4H,
morpholine), 3.63–3.70 (m, 4H, morpholine), 1.40 (d,
J = 5.81 Hz, 6H, iPr); mixture of pyrazole tautomers. 13C
NMR (150 MHz, DMSO-d6): δ = 160.9, 159.2, 144.4, 140.9,
139.0, 128.5, 123.8, 121.7, 121.4, 118.4, 104.5, 90.3, 70.1,
66.1, 66.1, 45.6, 45.6, 21.6, 21.6. IR (ATR): ν = 3230–3340,
2970, 2865–2935, 2780–2835, 1614, 1407, 1122, 775 cm–1.
ESI-HRMS: m/z [M+H]+ calcd for C19H23N4O2: 339.1821,
found: 339.1817.
8-Bromo-2-(morpholin-4-yl)quinolin-4-ol (52). 1.0 M
Lithium bis(trimethylsilyl)amide in hexane (6.16 mL, 6.16
mmol) was added dropwise to solution of 51 (700 mg, 2.05
mmol) in DMF (10 mL) under argon and at 0 °C. The mixture
was stirred for 3 h at rt. H2O (2 mL) was added and the
mixture was concentrated under reduced pressure to
dryness. The residue was purified by flash chromatography
(silica gel, EtOAc/MeOH gradient 0–100%) to give 52 (310
1
mg, 0.98 mmol, 48%). H NMR (400 MHz, DMSO-d6): δ =
7.89 (dd, J = 1.52, 8.08 Hz, 1H, quinoline), 7.84 (dd, J = 1.39,
7.45 Hz, 1H, quinoline), 7.04 (t, J = 7.71 Hz, 1H, quinoline),
6.44 (s, 1H, quinoline), 3.66–3.78 (m, 4H, morpholine),
3.42–3.63 (m, 4H, morpholine). MS (ESI+): m/z = 309.0
[M+H]+.
Methyl 2-Chloro-3-{[1-(morpholin-4-yl)ethylidene]-
amino}isonicotinate (57). Under argon and at 0 °C,
phosphorus oxychloride (2.44 mL, 25.4 mmol) was added
to a solution of N-acetylmorpholine (49) (2.17 mL, 18.8
mmol) in anhydrous DCE (12 mL). The yellow solution was
stirred at rt for 30 min. Methyl 3-amino-2-chloropyridine-
4-carboxylate (56) (1.75 g, 9.4 mmol) was added and the
mixture was stirred at 80 °C for 3 h. The DCE was distilled
8-Bromo-4-isopropoxy-2-(morpholin-4-yl)quinoline
(53). K2CO3 (643 mg, 4.66 mmol) and 2-iodopropane (1.32
g, 7.76 mmol) were added to a solution of 52 (1.20 g, 3.88
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off and the residue was purified by column chromatography
107.6, 93.2, 70.6, 66.0, 66.0, 45.5, 45.5, 21.5, 21.5. IR (ATR):
(silica gel, EtOAc/MeOH 1:1) to give 57 (2.50 g, 8.4 mmol,
89%) as a yellow oil. 1H NMR (300 MHz, DMSO-d6): δ = 8.02
(d, J = 4.90 Hz, 1H, pyridine), 7.56 (d, J = 4.90 Hz, 1H,
pyridine), 3.77 (s, 3H, methyl), 3.57–3.68 (m, 4H,
morpholine), 3.47–3.57 (m, 4H, morpholine), 1.74 (s, 3H,
methyl). MS (ESI+): m/z = 298.2 [M+H]+.
ν = 3030–3650, 2976, 2852, 1612, 1431, 1228, 896–1080
cm–1. ESI-HRMS: m/z [M+H]+ calcd for C18H22N5O2:
340.1773, found: 340.1774.
2-(Morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-
1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl
Trifluoromethanesulfonate (61). Under argon, N,N-
diisopropylethylamine (25 µL, 0.15 mmol) was added to a
solution of 59 (28 mg, 0.073 mmol) and N-phenyl-bis(tri-
fluoromethanesulfonimide) (39 mg, 0.11 mmol) in
anhydrous DCM (3 mL). The reaction mixture was stirred at
rt for 16 h. The brown reaction solution was purified by
column chromatography (silica gel, EtOAc) to give 61 (34
8-Chloro-2-(morpholin-4-yl)-1,7-naphthyridin-4-ol
(58). Under argon and at 0 °C, 1.0 M lithium bis(trimethyl-
silyl)amide in THF (20.1 mL, 20.1 mmol) was added
dropwise to a solution of 57 (2.00 g, 6.7 mmol) in anhydrous
DMF (20 mL). The mixture was stirred at rt for 3 h, then H2O
(2 mL) was added and the mixture was concentrated. The
residue was purified by column chromatography (silica gel,
EtOAc/MeOH 1:1) to give 58 (1.16 g, 4.4 mmol, 65%) as a
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mg, 0.066 mmol, 88%) as a yellow oil. H NMR (400 MHz,
DMSO-d6): δ = 8.55 (d, J = 5.58 Hz, 1H, naphthyridine), 7.77
(s, 1H, naphthyridine), 7.62–7.66 (m, 2H, naphthyridine,
pyrazole), 6.99 (d, J = 1.77 Hz, 1H, pyrazole), 6.09 (dd,
J = 2.15, 9.51 Hz, 1H, NCHO), 3.65–3.81 (m, 9H, OCH2,
morpholine), 3.25–3.34 (m, 1H, OCH2), 2.32–2.43 (m, 1H,
alkylene-CH2), 1.94–2.03 (m, 2H, alkylene-CH2), 1.42–1.67
(m, 3H, alkylene-CH2). MS (ESI+): m/z = 514.2 [M+H]+.
1
light yellow solid. H NMR (400 MHz, DMSO-d6): δ = 11.62
(s, 1H, OH), 7.98 (d, J = 5.2 Hz, 1H, naphthyridine), 7.73 (d,
J = 5.2 Hz, 1H, naphthyridine), 6.62 (s, 1H, naphthyridine),
3.72–3.74 (m, 4H, morpholine), 3.63–3.65 (m, 4H,
morpholine). MS (ESI+): m/z = 266.1 [M+H]+.
2-(Morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-
1H-pyrazol-5-yl]-1,7-naphthyridin-4-ol (59). Under
argon, Pd(dppf)Cl2 (1:1 complex with DCM; 244 mg, 0.30
mmol) and Cs2CO3 (650 mg, 2.00 mmol) were added to a
suspension of 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-
4-[4-(Methylsulfonyl)phenyl]-2-(morpholin-4-yl)-8-
(1H-pyrazol-5-yl)-1,7-naphthyridine (BAY-937). Step a:
4-[4-(Methylsulfonyl)phenyl]-2-(morpholin-4-yl)-8-[1-
(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-
naphthyridine. Under argon, Pd(dppf)Cl2 (1:1 complex
with DCM; 25 mg, 0.03 mmol) and Cs2CO3 (391 mg, 1.2
mmol) were added to a suspension of 61 (154 mg, 0.30
mmol) and 4-(methylsulfonyl)phenylboronic acid pinacol
ester (169 mg, 0.60 mmol) in anhydrous 1,4-dioxane (3
mL). The reaction mixture was stirred at 90 °C for 2 h. The
mixture was chromatographed directly without workup
(silica gel, EtOAc) to give the title compound (110 mg, 0.21
mmol, 71%) as a yellow foam. MS (ESI+): m/z = 520.3
[M+H]+.
tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(54)
(556 mg, 2.00 mmol) and 58 (266 mg, 1.00 mmol) in
anhydrous 1,4-dioxane (4 mL). The reaction mixture was
stirred at 80 °C for 16 h. The brown reaction solution was
purified by column chromatography (silica gel, EtOAc) to
give 59 (206 mg, 0.54 mmol, 54%) as a yellow oil. MS
(ESI+): m/z = 382.3 [M+H]+.
4-Isopropoxy-2-(morpholin-4-yl)-8-[1-(tetrahydro-
2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine
(60). K2CO3 (44 mg, 0.31 mmol) was added to a solution of
59 (100 mg, 0.26 mmol) and 2-iodopropane (45 mg, 0.26
mmol) in anhydrous MeCN (6 mL). The suspension was
stirred at 85 °C for 7 h. The solvent was removed and the
residue that remained was purified by column
chromatography (silica gel, EtOAc) to give 60 (90 mg, 0.21
mmol, 81%) as a yellow oil. MS (ESI+): m/z = 424.3 [M+H]+.
Step b: 4-[4-(Methylsulfonyl)phenyl]-2-(morpholin-
4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine
(BAY-
937). A drop of H2O and TFA (2 mL, 26 mmol) were added
to 4-[4-(methylsulfonyl)phenyl]-2-(morpholin-4-yl)-8-[1-
(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naph-
thyridine (110 mg, 0.21 mmol) and the mixture was stirred
for 3 h at rt. The TFA was removed using a rotary
evaporator and the residue that remained was adjusted to
pH 7 using aq NaHCO3 solution. The aqueous phase was
extracted with DCM (3 ×). The combined organic layers
were dried (Na2SO4), filtered, and concentrated to dryness.
MeOH (5 mL) was added to the residue. The resulting
precipitated solid was collected by filtration and then dried
to give BAY-937 (75 mg, 0.17 mmol, 81%). LC-MS [Method
4]: Rt = 0.65 min. MS (ESI+): m/z = 436.3 [M+H]+. 1H NMR
(600 MHz, DMSO-d6): δ = 13.41 (br s, 1H, pyrazole-NH),
8.31–8.36 (m, 1H, naphthyridine), 8.11–8.16 (m, J = 8.28 Hz,
2H, phenyl), 7.84–7.88 (m, J = 8.28 Hz, 2H, phenyl), 7.64 (br
s, 1H, pyrazole), 7.56 (s, 1H, naphthyridine), 7.43 (br s, 1H,
pyrazole), 7.36 (d, J = 5.65 Hz, 1H, naphthyridine), 3.76-3.85
(m, 8H, morpholine), 3.33 (s, 3H, methyl). 13C NMR (150
MHz, DMSO-d6): δ = 157.3, 146.7, 141.8, 141.0, 139.7, 139.6,
139.6, 130.5, 130.5, 127.4, 127.4, 125.4, 117.2, 114.6, 108.0,
66.0, 66.0, 45.2, 45.2, 43.5. IR (ATR): ν = 3100–3650, 2800–
4-Isopropoxy-2-(morpholin-4-yl)-8-(1H-pyrazol-5-
yl)-1,7-naphthyridine (3). A drop of H2O and TFA (1 mL,
13 mmol) were added to 60 (80 mg, 0.19 mmol). After 10
min, the TFA was removed under reduced pressure and the
residue that remained was adjusted to pH 7 using aq
NaHCO3 solution. The aqueous phase was extracted with
DCM (3 ×). The combined organic phases were dried
(Na2SO4), filtered, and concentrated to dryness. The residue
was purified by column chromatography (silica gel, EtOAc)
to give 3 (40 mg, 0.12 mmol, 59%) as a yellow foam; mp 73–
74 °C. LC-MS [Method 3]: Rt = 2.80 min. MS (ESI+): m/z =
340.3 [M+H]+. 1H NMR (600 MHz, DMSO-d6): δ = 13.35 (br s,
1H, pyrazole-NH), 8.32 (d, J = 5.27 Hz, 1H, naphthyridine),
7.70 (d, J = 5.27 Hz, 1H, naphthyridine), 7.61 (s, 1H,
pyrazole), 7.36 (s, 1H, pyrazole), 6.87 (s, 1H,
naphthyridine), 5.01–5.10 (m, 1H, iPr), 3.78–3.81 (m, 4H,
morpholine), 3.71–3.74 (m, 4H, morpholine), 1.41 (d,
J = 6.02 Hz, 6H, iPr). 13C NMR (150 MHz, DMSO-d6): δ =
159.8, 159.7, 140.3, 139.9, 139.6, 139.4, 138.8, 122.6, 114.1,
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3005, 2150, 1608, 1303, 1153, 765 cm–1. ESI-HRMS: m/z
(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-pyrazole (54) (746 mg, 2.68 mmol)
in anhydrous 1,4-dioxane (7.5 mL). The reaction mixture
was stirred at 90 °C for 16 h. The brown reaction solution
was purified by column chromatography (silica gel, EtOAc)
to give 66 (506 mg, 1.28 mmol, 72%) as a yellow oil. 1H NMR
(400 MHz, DMSO-d6): δ = 11.50 (br s, 1H, OH), 8.33 (d,
J = 5.32 Hz, 1H, naphthyridine), 7.78 (d, J = 5.32 Hz, 1H,
naphthyridine), 7.60 (d, J = 1.52 Hz, 1H, pyrazole), 6.89–
6.95 (m, 1H, pyrazole), 6.59 (d, J = 4.31 Hz, 1H,
naphthyridine), 6.10 (ddd, J = 2.03, 9.63, 16.48 Hz, 1H,
NCHO), 4.20–4.41 (m, 1H), 3.90–4.10 (m, 2H), 3.58–3.79 (m,
3H), 3.37–3.51 (m, 1H), 3.09–3.30 (m, 2H), 2.32–2.43 (m,
1H), 1.91–2.03 (m, 2H), 1.40–1.64 (m, 3H), 1.15–1.23 (m,
3H). MS (ESI+): m/z = 396.3 [M+H]+.
[M+H]+ calcd for C22H22N5O3S: 436.1443, found: 436.1445.
(3R)-N-Acetyl-3-methylmorpholine (63). (3R)-3-
Methylmorpholine (62) (12.8 g, 127 mmol) and K2CO3 (52.7
g, 381 mmol) were suspended in DCM (300 mL). The
mixture was stirred at rt for 30 min, then acetyl chloride
(19.9 g, 254 mmol) was added and the mixture was stirred
at rt for 18 h. The precipitated solid was suction filtered and
washed with DCM (200 mL). The mother liquor was
concentrated to dryness to give 63 (17.19 g, 120.0 mmol,
95%) as a yellow oil. The crude product was used without
further purification in the next step.
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Methyl 2-Chloro-3-({1-[(3R)-3-methylmorpholin-4-
yl]ethylidene}amino)isonicotinate (64). Under argon
and at 0 °C, phosphorus oxychloride (17.1 mL, 188 mmol)
was added to a solution of 63 (9.0 g, 62.8 mmol) in
anhydrous DCE (78 mL) and the yellow solution was stirred
at rt for 30 min. Methyl 3-amino-2-chloropyridine-4-
carboxylate (56) (11.7 g, 62.8 mmol) was then added. The
mixture was stirred at 80 °C for 1 h, at rt overnight, and on
the next day at 80 °C for another 5 h. The DCE was distilled
off. The remaining mixture was taken up in DCM (200 mL)
and H2O (100 mL), Na2CO3 as a solid was added slowly to
adjust to pH 9, and the mixture was extracted with DCM
(3 ×). The combined organic phases were dried (Na2SO4),
filtered, and concentrated to dryness under reduced
pressure to give 64 (19.5 g, 62.7 mmol, quant.) as a brown
oil which was used without further purification in the next
step. MS (ESI-APCI+): m/z = 312.2 [M+H]+.
2-[(3R)-3-Methylmorpholin-4-yl]-8-[1-(tetrahydro-
2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl
Trifluoromethanesulfonate (67). Under argon, a solution
of 66 (1.20 g, 3.03 mmol), N-phenyl-bis(trifluoro-
methanesulfonimide) (1.30 g, 3.64 mmol) and N,N-di-
isopropylethylamine (1.37 mL, 7.89 mmol) in anhydrous
DCM (20 mL) was stirred for 3 d at rt. The solvent was
distilled off under reduced pressure and the residue was
chromatographed twice (silica gel, DCM/MeOH 98:2,
EtOAc) to give 67 (1.42 g, 2.62 mmol, 86%) as a yellow solid.
1H NMR (400 MHz, DMSO-d6): δ = 8.54 (d, J = 5.58 Hz, 1H,
naphthyridine), 7.73 (d, J = 2.79 Hz, 1H, naphthyridine),
7.61–7.67 (m, 2H, naphthyridine, pyrazole), 6.96–7.03 (m,
1H, pyrazole), 6.07–6.14 (m, 1H, NCHO), 4.44–4.51 (m, 1H),
4.08–4.18 (m, 1H), 3.94–4.05 (m, 1H), 3.60–3.84 (m, 3H),
3.39–3.55 (m, 1H), 3.21–3.32 (m, 2H), 2.31–2.46 (m, 1H),
1.92–2.03 (m, 2H), 1.50–1.65 (m, 1H), 1.45 (br s, 2H), 1.19–
1.28 (m, 3H). MS (ESI+): m/z = 528.2 [M+H]+.
8-Chloro-2-[(3R)-3-methylmorpholin-4-yl]-1,7-
naphthyridin-4-ol (65). Under argon and at 0 °C, a
solution of lithium bis(trimethylsilyl)amide (31.4 g, 187
mmol) dissolved in anhydrous THF (250 mL) was added
dropwise over 15 min to a solution of 64 (19.5 g, 62.8
mmol) in anhydrous THF (600 mL). The mixture was then
stirred at rt for 3 h. H2O (50 mL) was carefully added and
the mixture was concentrated to dryness under reduced
pressure. The residue was taken up in saturated aq NH4Cl
solution (600 mL) and extracted with DCM/iPrOH (4:1)
(4 ×). The combined organic phases were dried (Na2SO4),
filtered, and concentrated under reduced pressure to
dryness. The residue was recrystallized (MeCN, 250 mL) to
give pure product (7.6 g, 27.2 mmol). The mother liquor was
concentrated and the residue was recrystallized (MeCN,
125 mL) to give a second batch of pure product (3.6 g, 13.2
mmol). Overall, 11.2 g of compound 65 (40.1 mmol, 64%)
2-[(3R)-3-Methylmorpholin-4-yl]-4-(1-methyl-1H-
pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine
(BAY 1895344). Sulfonate 67 (500 mg, 0.95 mmol), 1-
methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
1H-pyrazole (68) (415 mg, 1.90 mmol), 2 M aq K2CO3
solution (1.4 mL), and Pd(PPh3)2Cl2 (67 mg, 0.094 mmol)
were solubilized in DME (60 mL). The reaction mixture was
stirred for 20 min at 130 °C under microwave irradiation.
After cooling to rt, the mixture was filtered through a silicon
filter and concentrated under reduced pressure. The crude
material was purified by flash column chromatography
(silica gel, hexane/EtOAc gradient 0–100%, followed by
EtOAc/EtOH 9:1). The desired fractions were concentrated
under reduced pressure and solubilized in concd H2SO4 (5
mL). The mixture was stirred for 3 h at rt. The mixture was
then poured into ice and basified using solid NaHCO3. The
suspension was filtered and the solid was stirred with EtOH
at 40 °C, filtered, and dried under reduced pressure to give
BAY 1895344 (280 mg, 0.75 mmol, 78%). LC-MS [Method 2]:
Rt = 0.99 min. MS (ESI+): m/z = 376.1 [M+H]+. 1H NMR (400
MHz, DMSO-d6): δ = 13.44 (br s, 1H, pyrazole-NH), 8.35 (d,
J = 5.32 Hz, 1H, naphthyridine), 7.56–7.68 (m, 3H, pyrazole,
naphthyridine), 7.42 (br s, 1H, pyrazole), 7.27 (d, J = 5.58
Hz, 1H, naphthyridine), 6.59 (d, J = 2.03 Hz, 1H, pyrazole),
4.60–4.69 (m, 1H, morpholine), 4.23 (br d, J = 11.66 Hz, 1H,
morpholine), 4.00–4.09 (m, 1H, morpholine), 3.78–3.85 (m,
1H, morpholine), 3.75 (m, 4H, methyl, morpholine), 3.69–
1
was obtained as a yellow-orange solid. H NMR (600 MHz,
DMSO-d6): δ = 11.12–12.07 (br s, 1H, OH), 7.97 (d, J = 5.27
Hz, 1H, naphthyridine), 7.72 (d, J = 5.27 Hz, 1H,
naphthyridine), 6.58 (s, 1H, naphthyridine), 4.37–4.44 (m,
1H, morpholine), 4.05–4.17 (m, 1H, morpholine), 3.98 (m,
1H, morpholine), 3.77 (m, 1H, morpholine), 3.65 (m, 1H,
morpholine), 3.49 (m, 1H, morpholine), 3.15–3.21 (m, 1H,
morpholine), 1.22 (d, J = 6.78 Hz, 3H, methyl). MS (ESI-
APCI+): m/z = 280.2 [M+H]+.
2-[(3R)-3-Methylmorpholin-4-yl]-8-[1-(tetrahydro-
2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-ol
(66). Under argon, Pd(dppf)Cl2 (1:1 complex with DCM; 146
mg, 0.18 mmol) and Cs2CO3 (2.33 g, 7.15 mmol) were added
to a suspension of 65 (500 mg, 1.79 mmol) and 1-
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3.74 (m, 1H, morpholine), 3.57 (m, 1H, morpholine), 1.30 (d,
1 h. MeOH was distilled off under reduced pressure and the
J = 6.59 Hz, 3H, methyl). 13C NMR (125 MHz, DMSO-d6): δ =
156.5, 145.2, 140.0, 139.6, 139.5, 138.2, 137.4, 137.4, 125.7,
117.1, 115.5, 108.2, 107.7, 70.3, 66.1, 47.3, 39.7, 37.2, 13.3.
ESI-HRMS: m/z [M+H]+ calcd for C20H22N7O: 376.1886,
found: 376.1879. [α]D –80.8 ± 1.04 (1.0000 g/ 100 mL
CHCl3).
residue that remained was adjusted to pH 7 using NaHCO3
solution. The aqueous phase was extracted with DCM
(3 × 20 mL). The combined organic phases were dried over
Na2SO4 and then concentrated to dryness. The residue was
chromatographed (silica gel, EtOAc) to give 4 as a yellow
solid. Yield: 45 mg (70%). LC-MS [Method 3]: Rt = 2.92 min.
MS (ESI+): m/z = 354.4 [M+H]+. 1H NMR (400 MHz, DMSO-
d6): δ = 13.38 (br s, 1H, pyrazole), 8.31 (d, J = 5.32 Hz, 1H,
naphthyridine), 7.69 (d, J = 5.07 Hz, 1H, naphthyridine),
7.60 (br s, 1H, pyrazole), 7.37 (br s, 1H, pyrazole), 6.82 (s,
1H, naphthyridine), 5.07 (m, 1H, CHO), 4.56–4.67 (m, 1H,
morpholine), 4.15 (br d, J = 11.41 Hz, 1H, morpholine), 4.05
(br dd, J = 2.91, 11.28 Hz, 1H, morpholine), 3.83 (br d, J =
11.41 Hz, 1H, morpholine), 3.71 (dd, J = 2.53, 11.41 Hz, 1H,
morpholine), 3.56 (dt, J = 2.66, 11.85 Hz, 1H, morpholine),
3.24–3.32 (m, 1H, morpholine), 1.41 (d, J = 6.08 Hz, 6H, iPr),
1.26 (d, J = 6.84 Hz, 3H, CH3). 13C NMR (101 MHz, DMSO-d6):
δ = 159.9, 158.9, 144.3, 140.4, 140.1, 139.5, 138.6, 122.4,
114.2, 107.4, 92.9, 70.6, 66.3, 47.4, 25.0, 21.5, 21.4, 13.2.
HRMS (ESI, [M + H]+): calcd for C19 H24 N5 O2, 354.1930;
found, 354.1934.
X-ray Structure Determination of BAY 1895344
9
Data for BAY 1895344 were collected at 100 K on a
Bruker system equipped with an APEX II CCD area detector
and Cu X-ray radiation (Cu Kα, λ = 1.54178 Å). X-ray data
collection and processing of data were performed using the
APEX II v2014.11.0 package.37 SHELXS was used for
structure solution and SHELXL was used for full-matrix
least-squares refinement on F2.38 All non-hydrogen atoms
were refined anisotropically. All hydrogen atoms were
placed in geometrically ideal positions using the riding
model. The isotropic temperature factors of all hydrogen
atoms were 1.2 and 1.5 times the size of the temperature
factors of the corresponding heavy atoms. The program XP
from SHELXTL version 6.14 was used for all molecular
representations.39 Light yellow prisms of BAY 1895344
were obtained by slow evaporation of an isopropyl acetate
solution of the compound at rt. A single crystal with
dimensions 0.07 × 0.06 × 0.04 mm3 was mounted on a
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60
4-Isopropoxy-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-
yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine (5). Step a:
1-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)ethanone.
3-
Oxa-8-azabicyclo[3.2.1]octane hydrochloride (1:1) (CAS
904316-92-3, 457 mg, 3.05 mmol) was dissolved in
pyridine (6.2 mL). The solution was flushed with argon.
Then, acetic anhydride (2.9 mL, 31 mmol) was added and
the reaction mixture was stirred for 3 h at rt. The mixture
was diluted with EtOAc. The resulting suspension was
filtered, and the filtrate was concentrated under reduced
pressure, diluted with EtOAc, and filtered again. The filtrate
was concentrated under reduced pressure to give 1-(3-oxa-
8-azabicyclo[3.2.1]octan-8-yl)ethanone. Yield: 578 mg
(quant.). 1H NMR (400 MHz, DMSO-d6): δ = 4.35 (d, J = 6.82
Hz, 1H), 4.11 (br s, 1H), 3.49–3.57 (m, 3H), 1.97 (s, 3H),
1.68–1.94 (m, 5H). Step b: Methyl 2-chloro-3-{(E)-[1-(3-
oxa-8-azabicyclo[3.2.1]octan-8-
CryoLoop using
a protective oil. Two independent
molecules of BAY 1895344 crystallized in the triclinic space
group P1 (Z = 2) with cell constants of a = 7.8579(3) Å, b =
11.3749(4) Å, c = 11.4596(4) Å, α = 68.330(2)°, β =
89.439(3)°, and γ = 88.361(1)°. The molecular formula is
C20H21N7O1 with a molecular weight of 375.44 g/mol. A total
of 23351 reflections of which 6531 are unique (Rint
=
0.0189) were collected. The final R values were R1 = 0.0430,
I > 2σ(I), and wR2 = 0.1280 for all data. The goodness-of-fit
of the data was 1.054. The absolute structure was
determined with a Flack parameter of –0.066(110).40 The
crystallographic data for BAY 1895344 have been
deposited with the Cambridge Crystallographic Data Centre
(CCDC) with deposition code CCDC 1983653.
yl)ethylidene]amino}isonicotinate.
An
analogous
4-Isopropoxy-2-[(3R)-3-methylmorpholin-4-yl]-8-
(1H-pyrazol-5-yl)-1,7-naphthyridine (4). Step a: 4-
Isopropoxy-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-
(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-
naphthyridine. K2CO3 (84 mg, 0.61 mmol) was added to a
method as described for 57 was used, with methyl 3-amino-
2-chloropyridine-4-carboxylate (56) (CAS 173435-41-1,
257 mg, 1.38 mmol) and 1-(3-oxa-8-azabicyclo[3.2.1]octan-
8-yl)ethanone (578 mg, 3.05 mmol) as the starting
materials and stirring overnight at rt and for 2 h at 85 °C.
solution
of
2-[(3R)-3-methylmorpholin-4-yl]-8-[1-
1
Yield: 247 mg (41% with 74 % purity). H NMR (400 MHz,
(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naph-
thyridin-4-ol (66; 200 mg, 0.51 mmol) and 2-iodopropane
(101 µL, 1.01 mmol) in anhydrous MeCN (4 mL). The
suspension was stirred at 85 °C for 3 h. The solvent was
removed and the residue that remained was
chromatographed (silica gel, EtOAc) to give 4-isopropoxy-
2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-
pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine as a yellow
oil. Yield: 60 mg (27%). MS (ESI): m/z = 438.4 [M + H]+. Step
b: 4-Isopropoxy-2-[(3R)-3-methylmorpholin-4-yl]-8-
(1H-pyrazol-5-yl)-1,7-naphthyridine (4). 4-Isopropoxy-
2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-
pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine (80 mg,
0.18 mmol) was dissolved in MeOH (2 mL), 2 N aqueous HCl
(2 mL, 4 mmol) was added, and the mixture was stirred for
DMSO-d6): δ = 8.03 (d, J = 4.94 Hz, 1H), 7.57 (d, J = 4.82 Hz,
1H), 4.11–4.58 (m, 2H), 3.81–3.95 (m, 1H), 3.75–3.81 (m,
3H), 3.40–3.73 (m, 3H), 2.54–2.63 (m, 1H), 1.86–1.97 (m,
3H), 1.71–1.85 (m, 3H). MS (ESI): m/z = 324.2 [M + H]+. Step
c:
8-Chloro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-
1,7-naphthyridin-4-ol. An analogous method as described
for 58 was used, with methyl 2-chloro-3-{(E)-[1-(3-oxa-8-
azabicyclo[3.2.1]octan-8-
yl)ethylidene]amino}isonicotinate (125 mg, 386 µmol) as
the starting material and stirring for 30 min at rt. Yield: 72.9
1
mg (61%). H NMR (400 MHz, DMSO-d6): δ = 11.17–12.35
(m, 1H), 7.96 (d, J = 5.32 Hz, 1H), 7.71 (d, J = 5.32 Hz, 1H),
6.50 (s, 1H), 4.56 (br s, 2H), 3.63–3.68 (m, 2H), 3.56–3.61
(m, 2H), 1.95–2.00 (m, 2H), 1.89–1.95 (m, 2H). MS (ESI+):
m/z = 292.1 [M+H]+. Step d: 8-Chloro-4-isopropoxy-2-(3-
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Journal of Medicinal Chemistry
oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,7-naphthyridine.
was added. The reaction mixture was stirred for 16 h at rt,
then concentrated under reduced pressure to give 1-
2
3
4
5
6
7
8
9
An analogous method as described for 60 was used, with 8-
chloro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,7-naph-
thyridin-4-ol (150 mg, 514 µmol) as the starting material
and stirring overnight at 85 °C. Yield: 105 mg (61%). 1H
NMR (400 MHz, DMSO-d6): δ = 7.98 (d, J = 5.31 Hz, 1H), 7.68
(d, J = 5.31 Hz, 1H), 6.78 (s, 1H), 5.03 (td, J = 5.97, 12.06 Hz,
1H), 4.78 (br s, 2H), 3.58–3.71 (m, 4H), 1.89–2.04 (m, 4H),
1.38 (d, J = 6.06 Hz, 6H). MS (ESI+): m/z = 334.1 [M+H]+.
[(3R,5S)-3,5-dimethylmorpholin-4-yl]ethanone. Yield: 0.64
1
g (95%). H NMR (400 MHz, DMSO-d6): δ = 4.00 (br s, 2H),
3.65 (d, J = 11.41 Hz, 2H), 3.44 (dd, J = 11.28, 2.91 Hz, 2H),
2.00 (s, 3H), 1.22 (br s, 6H). MS (ESI+): m/z = 158.0. Step b:
Methyl
2-chloro-3-[(E)-{1-[(3R,5S)-3,5-
dimethylmorpholin-4-yl]ethyl-
idene}amino]isonicotinate.
1-[(3R,5S)-3,5-
Step
e:
4-Isopropoxy-2-(3-oxa-8-
Dimethylmorpholin-4-yl]ethanone (0.54 g, 3.4 mmol) was
dissolved in DME (2.7 mL) and the reaction mixture was
cooled to 0 °C. Phosphorus oxychloride (0.46 mL, 4.3 mmol)
was added slowly and the reaction mixture was warmed to
rt. After 30 min, methyl 3-amino-2-chloropyridine-4-
carboxylate (56) (CAS 173435-41-1, 0.28 g, 1.5 mmol) was
added in one portion and the mixture was stirred at 80 °C.
After 6 h, the reaction mixture was cooled to rt and the
solvent was removed under reduced pressure. The crude
mixture was diluted with DCM and washed with saturated
NaHCO3 solution (3 ×). The organic phase was dried over
sodium sulfate and concentrated under reduced pressure.
The crude mixture was purified by flash chromatography
(gradient: 100% hexane to 100% EtOAc) to give methyl 2-
chloro-3-[(E)-{1-[(3R,5S)-3,5-dimethylmorpholin-4-
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60
azabicyclo[3.2.1]octan-8-yl)-8-{1-[tetrahydro-2H-
pyran-2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridine.
8-
Chloro-4-isopropoxy-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-
yl)-1,7-naphthyridine (104 mg, 312 µmol) was dissolved in
DME (2.2 mL), and K2CO3 (95 mg, 685 µmol) and H2O (0.6
mL) were added. The mixture was flushed with argon. 1-
(Tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-pyrazole (54) (CAS 903550-26-5,
130
mg,
467
µmol)
and
bis(triphenyl-
phosphine)palladium(II) dichloride (17.5 mg, 25 µmol)
were added and the mixture was stirred for 10 min at
130 °C in a microwave reactor. DCM was added and the
reaction mixture was filtered through a silicon filter. The
organic phase was separated and concentrated under
reduced pressure. The residue was purified by flash
chromatography (silica gel, gradient: hexane/EtOAc 0–
1
yl]ethylidene}amino]isonicotinate. Yield: 0.28 g (58%). H
NMR (300 MHz, DMSO-d6): δ = 8.01 (d, J = 4.90 Hz, 1H), 7.56
(d, J = 4.90 Hz, 1H), 3.96–4.30 (m, 2H), 3.76–3.80 (m, 3H),
3.67–3.75 (m, 2H), 3.51–3.63 (m, 2H), 1.71–1.84 (m, 3H),
1.25–1.37 (m, 3H), 1.30 (br d, J = 6.59 Hz, 3H). MS (ESI+):
100%)
to
give
4-isopropoxy-2-(3-oxa-8-
azabicyclo[3.2.1]octan-8-yl)-8-{1-[tetrahydro-2H-pyran-2-
yl]-1H-pyrazol-5-yl}-1,7-naphthyridine. Yield: 118 mg
(84%). H NMR (500 MHz, DMSO-d6): δ = 8.33 (d, J = 5.36
1
m/z
=
326.1. Step c: 8-Chloro-2-[(3R,5S)-3,5-
Hz, 1H), 7.73 (d, J = 5.04 Hz, 1H), 7.58 (d, J = 1.89 Hz, 1H),
6.85 (d, J = 1.89 Hz, 1H), 6.77 (s, 1H), 6.09 (dd, J = 2.36, 9.62
Hz, 1H), 5.02–5.08 (m, 1H), 4.62–4.68 (m, 2H), 3.55–3.72
(m, 5H), 3.24–3.29 (m, 1H), 2.35–2.41 (m, 1H), 1.85–2.02
(m, 6H), 1.53–1.62 (m, 1H), 1.43–1.51 (m, 2H), 1.40 (dd, J =
4.26, 5.83 Hz, 6H). MS (ESI+): m/z = 450.3 [M+H]+. Step f: 4-
Isopropoxy-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-8-
(1H-pyrazol-5-yl)-1,7-naphthyridine (5). An analogous
method as described for 3 was used, with 4-isopropoxy-2-
(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-8-{1-[tetrahydro-
2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridine (116
mg, 258 µmol) as the starting material. Yield: 45.7 mg
(48%). LC-MS [Method 4]: Rt = 0.64 min. MS (ESI+): m/z =
366.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ = 13.21–
13.71 (m, 1H, pyrazole-NH), 8.32 (d, J = 5.31 Hz, 1H, naph-
thyridine), 7.70 (d, J = 5.31 Hz, 1H, naphthyridine), 7.54–
7.66 (m, 1H, pyrazole), 7.31 (d, J = 1.77 Hz, 1H, pyrazole),
6.81 (s, 1H, naphthyridine), 5.07 (td, J = 6.13, 12.00 Hz, 1H,
CHO), 4.77 (br s, 2H, CHN), 3.76 (br d, J = 10.86 Hz, 2H,
CH2O), 3.64–3.67 (m, 2H, CH2O), 1.95–2.11 (m, 4H, CH2-
CH2), 1.41 (d, J = 6.06 Hz, 6H, iPr). 13C NMR (101 MHz,
DMSO-d6): δ = 159.8, 157.3, 144.1, 140.6, 139.4, 138.7,
138.6, 122.5, 114.2, 107.5, 107.4, 70.7, 70.6, 70.2, 55.8, 26.6,
21.5, 21.4. HRMS (ESI, [M+H]+): calcd for C20 H24 N5 O2,
366.1930; found, 366.1938.
dimethylmorpholin-4-yl]-4-isopropoxy-1,7-
naphthyridine. Methyl 2-chloro-3-[(E)-{1-[(3R,5S)-3,5-
dimethylmorpholin-4-yl]ethylidene}amino]isonicotinate
(0.28 g, 0.86 mmol) was dissolved in anhydrous THF (6 mL)
under inert atmosphere (argon). The reaction mixture was
cooled to 0 °C and a solution of lithium 1,1,1,3,3,3-
hexamethyldisilazan-2-ide (1.0 M in THF, 2.5 mL, 2.5 mmol)
was added slowly. The reaction mixture was stirred for 16
h at rt. The reaction was quenched with H2O and the mixture
was concentrated under reduced pressure. The crude 8-
chloro-2-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,7-
naphthyridin-4-ol (0.36 g) was used in the next step without
further purification. MeCN (10 mL) was added to 8-chloro-
2-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,7-naphthyridin-
4-ol (0.20 g, ca. 0.68 mmol). 2-Iodopropane (0.13 mL, 1.4
mmol) and K2CO3 (0.14 g, 0.81 mmol) were sequentially
added to the suspension. The reaction mixture was stirred
at 85 °C for 16 h, then cooled to rt, diluted with EtOAc, and
washed with H2O (3 ×). The organic phase was dried over
sodium sulfate and concentrated under reduced pressure to
give 8-chloro-2-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-4-
isopropoxy-1,7-naphthyridine, which was used in the next
1
step without further purification. Yield: 95 mg (42 %). H
NMR (400 MHz, DMSO-d6): δ = 7.98 (d, J = 5.32 Hz, 1H), 7.69
(d, J = 5.32 Hz, 1H), 6.67 (s, 1H), 5.06 (spt, J = 5.96 Hz, 1H),
4.55 (br dd, J = 3.55, 6.34 Hz, 2H), 3.84 (d, J = 11.41 Hz, 2H),
3.65 (dd, J = 3.68, 11.53 Hz, 2H), 1.40 (d, J = 5.83 Hz, 6H),
1.32 (d, J = 6.84 Hz, 6H). MS (ESI+): m/z = 336.2. Step d: 2-
[(3R,5S)-3,5-Dimethylmorpholin-4-yl]-4-isopropoxy-8-
(1H-pyrazol-5-yl)-1,7-naphthyridine (6). 8-Chloro-2-
[(3R,5S)-3,5-dimethylmorpholin-4-yl]-4-isopropoxy-1,7-
2-[(3R,5S)-3,5-Dimethylmorpholin-4-yl]-4-
isopropoxy-8-(1H-pyrazol-5-yl)-1,7-naphthyridine (6).
Step
yl]ethanone.
a:
1-[(3R,5S)-3,5-Dimethylmorpholin-4-
(3R,5S)-3,5-Dimethylmorpholine (CAS
45597-00-0, 0.50 g, 4.3 mmol) was dissolved in pyridine
(8.6 mL, 0.11 mol) and acetic anhydride (4.0 mL, 42 mmol)
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2
3
4
5
6
7
8
naphthyridine (0.10 g, 0.28 mmol) was dissolved in DME
(3 mL). 1-(Tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (54)
6.27 Hz, 3H). Step c: 8-Chloro-2-[(3R,5R)-3,5-
dimethylmorpholin-4-yl]-4-isopropoxy-1,7-
naphthyridine. Methyl 2-chloro-3-[(E)-{1-[(3R,5R)-3,5-
dimethylmorpholin-4-yl]ethylidene)}amino]isonicotinate
(0.12 g, 0.36 mmol) was dissolved in anhydrous THF
(2.5 mL) under inert atmosphere (argon). The reaction
mixture was cooled to 0 °C and a solution of lithium
(CAS 903550-26-5, 0.24 g, 0.84 mmol), K2CO3 (0.11 g, 0.84
mmol), bis(triphenylphosphine)palladium(II) dichloride
(20 mg, 30 µmol), and H2O (1.5 mL) were added
sequentially. The reaction mixture was heated under
microwave irradiation at 130 °C for 10 min. The crude
reaction mixture was cooled to ambient temperature,
filtered through a silicon filter and concentrated under
reduced pressure. The crude mixture was purified by
preparative HPLC (H2O + HCOOH/MeCN 50:50 to 30:70).
The purified product was concentrated under reduced
pressure, dissolved in DCM, and washed twice with
saturated NaHCO3 solution. The organic phase was dried
over sodium sulfate and concentrated under reduced
pressure to give 6 as a solid. Yield: 56 mg (54%). LC-MS
[Method 4]: Rt = 0.65 min. MS (ESI+): m/z = 368.3 [M+H]+.
1H NMR (400 MHz, DMSO-d6): δ = 13.37 (br s, 1H, pyrazole-
NH), 8.29 (d, J = 5.07 Hz, 1H, naphthyridine), 7.69 (d, J = 5.07
Hz, 1H, naphthyridine), 7.59 (s, 1H, pyrazole), 7.36 (s, 1H,
pyrazole), 6.69 (s, 1H, naphthyridine), 5.01–5.11 (m, 1H,
CHO), 4.49 (br s, 2H, CH2O), 3.88 (d, J = 11.41 Hz, 2H, CH2O),
3.68 (br dd, J = 3.55, 11.41 Hz, 2H, CHN), 1.41 (d, J = 6.08 Hz,
6H, iPr), 1.36 (d, J = 6.84 Hz, 6H, CH3). 13C NMR (101 MHz,
DMSO-d6) δ = 159.8, 157.5, 144.1, 140.6, 140.4, 139.5,
138.3, 122.1, 114.2, 107.1, 92.4, 70.8, 70.5, 45.9, 21.4, 18.2.
HRMS (ESI, [M+H]+): calcd for C20 H26 N5 O2, 368.2087;
found, 368.2082.
1,1,1,3,3,3-hexamethyldisilazan-2-ide (1.0
M in THF,
1.1 mL, 1.1 mmol) was added slowly. The reaction mixture
was stirred for 16 h at rt. The reaction was quenched with
H2O and the mixture was concentrated under reduced
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60
pressure.
The
crude
8-chloro-2-[(3R,5R)-3,5-
dimethylmorpholin-4-yl]-1,7-naphthyridin-4-ol (0.13 g)
was used in the next step without further purification.
MeCN (6.8 mL) was added to 8-chloro-2-[(3R,5R)-3,5-
dimethylmorpholin-4-yl]-1,7-naphthyridin-4-ol (0.14 g, ca.
0.46 mmol). 2-Iodopropane (0.10 mL, 0.90 mmol) and
K2CO3 (74 mg, 0.55 mmol) were sequentially added to the
suspension. The reaction mixture was stirred at 85 °C for 48
h, then cooled to rt, diluted with H2O, extracted with DCM
(3 ×), and the extract washed with saturated NaCl solution.
The organic phase was dried (silicon filter) and
concentrated under reduced pressure to give 8-chloro-2-
[(3R,5R)-3,5-dimethylmorpholin-4-yl]-4-isopropoxy-1,7-
naphthyridine, without further purification. Yield: 81 mg
(52% over two steps). 1H NMR (400 MHz, DMSO-d6):
δ = 8.06 (d, J = 5.32 Hz, 1H), 7.73 (d, J = 5.32 Hz, 1H), 6.85 (s,
1H), 5.02 (spt, J = 6.04 Hz, 1H), 4.17–4.25 (m, 2H), 4.02 (dd,
J = 3.55, 11.15 Hz, 2H), 3.61 (dd, J = 4.56, 11.15 Hz, 2H), 1.39
(dd, J = 1.90, 5.96 Hz, 6H), 1.26 (d, J = 6.34 Hz, 6H). MS
2-[(3R,5R)-3,5-Dimethylmorpholin-4-yl]-4-
isopropoxy-8-(1H-pyrazol-5-yl)-1,7-naphthyridine (7).
(ESI+): m/z
=
336.2. Step d: 2-[(3R,5R)-3,5-
Dimethylmorpholin-4-yl]-4-isopropoxy-8-(1H-pyrazol-
5-yl)-1,7-naphthyridine (7). 8-Chloro-2-[(3R,5R)-3,5-
dimethylmorpholin-4-yl]-4-isopropoxy-1,7-naphthyridine
(40 mg, 0.12 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(54) (CAS 903550-26-5, 50 mg, 0.18 mmol), 2 M aqueous
Step
yl]ethanone.
a:
1-[(3R,5R)-3,5-Dimethylmorpholin-4-
(3R,5R)-3,5-Dimethylmorpholine (CAS
591779-91-8, 0.50 g, 4.3 mmol) was dissolved in pyridine
(8.6 mL, 0.11 mmol) and acetic anhydride (4.0 mL, 42
mmol) was added. The reaction mixture was stirred for 16
h at rt, then concentrated under reduced pressure to give 1-
K2CO3
(0.18 mL,
0.36 mmol),
and
[(3R,5R)-3,5-dimethylmorpholin-4-yl]ethanone
in
1
bis(triphenylphosphine)palladium(II) dichloride (8.5 mg,
11 µmol) were added sequentially to DME (1.1 mL). The
reaction mixture was heated under microwave irradiation
at 130 °C for 10 min. The reaction mixture was cooled to
ambient temperature and filtered through a silicon filter
and concentrated under reduced pressure. The crude
quantitative yield. H NMR (400 MHz, DMSO-d6): δ = 3.84–
3.96 (m, 4H), 3.38–3.62 (m, 2H), 1.98–2.07 (m, 3H), 1.26 (br
d, J = 6.32 Hz, 6H). MS (ESI+): m/z = 158.0. Step b: Methyl
2-chloro-3-[(E)-{1-[(3R,5R)-3,5-dimethylmorpholin-4-
yl]ethylidene}amino]isonicotinate.
1-[(3R,5R)-3,5-
Dimethylmorpholin-4-yl]ethanone (0.70 g, 4.4 mmol) was
dissolved in DME (10 mL) and the reaction mixture was
cooled to 0 °C. Phosphorus oxychloride (0.59 mL, 6.4 mmol)
was added slowly and the reaction mixture was warmed to
rt. After 30 min, methyl 3-amino-2-chloropyridine-4-
carboxylate (56) (CAS 173435-41-1, 0.36 g, 1.9 mmol) was
added in one portion and the mixture was stirred at rt. After
48 h, the reaction was quenched with saturated NaHCO3
solution and the mixture was extracted with DCM (3 ×). The
organic phase was dried over sodium sulfate and
concentrated under reduced pressure. The crude mixture
was purified by flash chromatography (gradient: 100%
hexane to 100% EtOAc) to give methyl 2-chloro-3-[(E)-{1-
[(3R,5R)-3,5-dimethylmorpholin-4-yl]ethylidene}-
mixture was purified by preparative HPLC (H2O
+
HCOOH/MeCN 48:52 to 68:32) to give 7. Yield: 9.8 mg
(20%). LC-MS [Method 4]: Rt = 0.58 min. MS (ESI+): m/z =
368.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ = 13.41 (br s,
1H, pyrazole-NH), 8.36 (d, J = 5.32 Hz, 1H, naphthyridine),
7.73 (d, J = 5.32 Hz, 1H, naphthyridine), 7.59–7.64 (m, 1H,
pyrazole), 7.44 (d, J = 1.77 Hz, 1H, pyrazole), 6.83 (s, 1H,
naphthyridine), 5.04 (td, J = 6.05, 11.98 Hz, 1H, CHO), 4.20–
4.33 (m, 2H, CH2O), 4.02–4.20 (m, 2H, CHN), 3.67 (dd, J =
4.06, 11.15 Hz, 2H, CH2O), 1.41 (dd, J = 2.41, 5.96 Hz, 6H,
iPr), 1.26 (d, J = 6.34 Hz, 6H, CH3).
4-Isopropoxy-2-[(1S,4S)-2-oxa-5-
azabicyclo[2.2.1]heptan-5-yl]-8-(1H-pyrazol-5-yl)-1,7-
naphthyridine (8). Step a: 1-[(1S,4S)-2-Oxa-5-
azabicyclo[2.2.1]heptan-5-yl]ethanone was prepared
using an analogous method as described for 63, from
(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride
amino]isonicotinate. Yield: 0.12 g (18%). 1H NMR (400 MHz,
DMSO-d6): δ = 8.04 (t, J = 4.43 Hz, 1H), 7.56 (t, J = 4.89 Hz,
1H), 3.90–4.01 (m, 4H), 3.77 (d, J = 2.76 Hz, 3H), 3.48–3.59
(m, 2H), 1.79 (s, 3H), 1.33 (d, J = 6.53 Hz, 3H), 1.26 (d, J =
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(1:1) (CAS 31560-06-2, 100 mg, 737 µmol). Yield: 84.7 mg
pyrazole), 7.37 (d, J = 1.52 Hz, 1H, pyrazole), 6.65 (br s, 1H,
2
(81%). 1H NMR (400 MHz, DMSO-d6): δ = 4.59–4.72 (m, 1H),
4.56 (s, 1H), 3.70 (s, 1H), 3.61 (s, 1H), 3.32–3.44 (m, 1H),
3.12–3.23 (m, 1H), 1.84–2.02 (m, 3H), 1.77–1.84 (m, 1H),
1.73 (s, 1H). Step b: Methyl 2-chloro-3-({1-[(1S,4S)-2-
oxa-5-azabicyclo[2.2.1]heptan-5-
naphthyridine), 5.14 (s, 1H, CHO), 5.05 (td, J = 5.96, 11.91
Hz, 1H, iPr), 4.78 (s, 1H, CHN), 3.89 (br d, J = 7.35 Hz, 1H,
CH2O), 3.77 (br s, 1H, CH2N), 3.71 (br d, J = 10.14 Hz, 1H,
CH2O), 3.45–3.60 (m, 1H, CH2N), 1.95–2.04 (m, 2H, CH2-C),
1.42 (d, J = 3.55 Hz, 3H, CH3), 1.40 (d, J = 3.80 Hz, 3H, CH3).
3
4
5
6
7
8
9
4-Isopropoxy-2-[(3S)-3-methylmorpholin-4-yl]-8-
(1H-pyrazol-5-yl)-1,7-naphthyridine (9). The title
compound was prepared as described for its enantiomer 4.
The analytical data were identical to 4. [α]20D +66.13 (c = 1,
DMSO). LC-MS [Method 4]: Rt = 0.64 min. MS (ESI+): m/z =
354.2 [M+H]+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-Isopropoxy-2-[(2R)-2-methylmorpholin-4-yl]-8-
(1H-pyrazol-5-yl)-1,7-naphthyridine (10). Step a: 1-
[(2R)-2-Methylmorpholin-4-yl]ethanone was prepared
using an analogous method as described for 63, from (2R)-
2-methylmorpholine hydrochloride (1:1) (CAS 168038-14-
0, 500 mg, 3.63 mmol). Yield: 413 mg (75% with 95%
purity). 1H NMR (400 MHz, DMSO-d6): δ = 4.10–4.22 (m,
1H), 3.74–3.81 (m, 1H), 3.60–3.74 (m, 1H), 3.32–3.48 (m,
2H), 3.09 (ddd, J = 3.42, 11.72, 13.24 Hz, 0.5H), 2.77 (dd, J =
10.27, 13.05 Hz, 0.5H), 2.60 (dt, J = 3.68, 12.61 Hz, 0.5H),
2.21–2.31 (m, 0.5H), 1.94–2.04 (m, 3H), 1.08 (dd, J = 3.93,
6.21 Hz, 3H). Step b: Methyl 2-chloro-3-[(E)-{1-[(2R)-2-
methylmorpholin-4-yl]ethylidene}amino]isonicotinate
was prepared using an analogous method as described for
64, from methyl 3-amino-2-chloropyridine-4-carboxylate
(56) (CAS 173435-41-1, 269 mg, 1.44 mmol) and 1-[(2R)-2-
methylmorpholin-4-yl]ethanone (413 mg, 2.88 mmol).
Yield: 294 mg (63%). 1H NMR (400 MHz, DMSO-d6): δ = 8.02
(d, J = 4.82 Hz, 1H), 7.56 (d, J = 5.07 Hz, 1H), 3.99–4.17 (m,
2H), 3.80–3.90 (m, 1H), 3.42–3.59 (m, 2H), 3.32 (s, 3H),
2.85–3.08 (m, 1H), 2.62–2.74 (m, 1H), 1.75 (s, 3H), 1.12 (d, J
= 6.34 Hz, 3H). MS (ESI+): m/z = 312.1 [M+H]+. Step c: 8-
Chloro-2-[(2R)-2-methylmorpholin-4-yl]-1,7-
naphthyridin-4-ol was prepared using an analogous
method as described for 65, from methyl 2-chloro-3-[(E)-
{1-[(2R)-2-methylmorpholin-4-yl]ethylidene}-
amino]isonicotinate (294 mg, 944 µmol). Yield: 368 mg
(quant.). The crude was used in the next step without
further purification. 1H NMR (400 MHz, DMSO-d6): δ = 7.68
(d, J = 5.05 Hz, 1H), 7.61 (d, J = 5.05 Hz, 1H), 5.69 (s, 1H),
4.16 (br t, J = 14.27 Hz, 2H), 3.87 (dd, J = 2.02, 11.37 Hz, 1H),
3.48–3.59 (m, 2H), 2.66–2.76 (m, 1H), 2.40 (dd, J = 10.23,
12.76 Hz, 1H), 1.15 (d, J = 6.32 Hz, 3H), OH not visible. MS
(ESI+): m/z
=
280.1. [M+H]+. Step d: 8-Chloro-4-
isopropoxy-2-[(2R)-2-methylmorpholin-4-yl]-1,7-
naphthyridine was prepared using an analogous method
as described for 60, from 8-chloro-2-[(2R)-2-
methylmorpholin-4-yl]-1,7-naphthyridin-4-ol (368 mg,
1
1.32 mmol). Yield: 330 mg (74% with a purity of 95%). H
NMR (400 MHz, DMSO-d6): δ = 7.99 (d, J = 5.31 Hz, 1H), 7.68
(d, J = 5.56 Hz, 1H), 6.84 (s, 1H), 5.07 (td, J = 6.06, 12.13 Hz,
1H), 4.47 (br d, J = 12.88 Hz, 2H), 3.96 (dd, J = 2.27, 11.62
Hz, 1H), 3.52–3.62 (m, 2H), 2.95–3.03 (m, 1H), 2.65–2.72
(m, 1H), 1.39 (dd, J = 1.26, 6.06 Hz, 6H), 1.20 (d, J = 6.32 Hz,
3H). MS (ESI+): m/z = 322.1 [M+H]+. Step e: 4-Isopropoxy-
2-[(2R)-2-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-
1,7-naphthyridine (10) was prepared over two steps
using analogous methods as described for 66 and

Journal of Medicinal Chemistry
Page 20 of 42
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2
3
4
5
6
7
8
BAY 1895344, from 8-chloro-4-isopropoxy-2-[(2R)-2-
DMSO-d6): δ = 8.35 (dd, J = 1.27, 5.32 Hz, 1H), 7.77 (dd, J =
methylmorpholin-4-yl]-1,7-naphthyridine (330 mg, 1.03
mmol). Yield: 255 mg (67% over two steps). LC-MS [Method
0.76, 5.32 Hz, 1H), 7.08 (s, 1H), 6.84 (br d, J = 5.58 Hz, 1H),
6.16–6.24 (m, 1H), 4.99–5.07 (m, 1H), 3.65–3.92 (m, 4H),
3.58–3.65 (m, 1H), 3.35–3.37 (m, 1H), 3.24–3.33 (m, 2H),
2.89–2.94 (m, 1H), 2.32–2.40 (m, 1H), 1.91–2.03 (m, 2H),
1.54–1.64 (m, 1H), 1.42–1.48 (m, 8H), 0.99–1.05 (m, 1H),
0.53–0.60 (m, 1H). MS (ESI+): m/z = 436.2 [M+H]+. Step f:
4-Isopropoxy-2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-
yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine (11) was
prepared using an analogous method as described for
1
4]: Rt = 0.64 min. MS (ESI+): m/z = 354.2 [M+H]+. H NMR
(400 MHz, DMSO-d6): δ = 13.37 (br s, 1H, pyrazole-NH), 8.31
(d, J = 5.32 Hz, 1H, naphthyridine), 7.55–7.77 (m, 2H,
pyrazole, naphthyridine), 7.36 (s, 1H, pyrazole), 6.88 (s, 1H,
naphthyridine), 5.09 (spt, J = 6.00 Hz, 1H, iPr), 4.37 (br t, J =
13.43 Hz, 2H, CH2O), 4.01 (dd, J = 2.53, 11.41 Hz, 1H, CHO),
3.57–3.70 (m, 2H, CH2N), 3.06 (dt, J = 3.55, 12.42 Hz, 1H,
CH2N), 2.74 (dd, J = 10.77, 12.55 Hz, 1H, CH2N), 1.41 (d, J =
5.83 Hz, 6H, iPr), 1.23 (d, J = 6.08 Hz, 3H, CH3). 13C NMR (101
MHz, DMSO-d6) δ = 159.8, 159.4, 144.4, 140.4, 140.0, 139.4,
138.8, 122.5, 114.2, 107.5, 93.3, 71.1, 70.6, 65.7, 51.3, 44.8,
21.5, 18.9. HRMS (ESI, [M+H]+): calcd for C19H24N5O2,
354.1930; found, 354.1936.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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36
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43
44
45
46
47
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54
55
56
57
58
59
60
BAY 1895344,
from
4-isopropoxy-2-(2-oxa-5-
azabicyclo[4.1.0]heptan-5-yl)-8-{1-[tetrahydro-2H-pyran-
2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridine (85.0 mg, 195
µmol). Yield: 59 mg (82% with 95% purity). LC-MS [Method
1
1]: Rt = 0.79 min. MS (ESI+): m/z = 352.0 [M+H]+. H NMR
(400 MHz, DMSO-d6): δ = 13.54 (br s, 1H, pyrazole), 8.33 (d,
J = 5.32 Hz, 1H, naphthyridine), 7.73 (d, J = 5.32 Hz, 1H,
naphthyridine), 7.59–7.62 (m, 1H, pyrazole), 7.39 (s, 1H,
pyrazole), 6.86 (br s, 1H, naphthyridine), 5.04 (td, J = 5.99,
12.10 Hz, 1H, iPr), 3.92–4.03 (m, 2H, CH2O), 3.84 (dt, J =
3.80, 11.03 Hz, 1H, CH2N), 3.62 (br s, 1H, CH2N), 3.50–3.58
(m, 1H, CHO), 2.92–3.00 (m, 1H, CHN), 1.44 (dd, J = 2.91,
5.96 Hz, 6H, iPr), 1.06–1.17 (m, 1H, cyclopropyl), 0.56–0.63
(m, 1H, cyclopropyl). HRMS (ESI, [M+H]+): calcd for
C19H22N5O2, 352.1773; found, 352.1772.
4-Isopropoxy-2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-
yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine (11). Step a:
1-(2-Oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethanone was
prepared using an analogous method as described for 63,
from 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride (1:1)
(CAS 1354952-28-5, 500 mg, 3.69 mmol). Yield: 400 mg
(77%). MS (ESI+): m/z = 142.0 [M + H]+. Step b: Methyl 2-
chloro-3-{(E)-[1-(2-oxa-5-azabicyclo[4.1.0]heptan-5-
yl)ethylidene]amino}isonicotinate was prepared using
an analogous method as described for 64, from methyl 3-
amino-2-chloropyridine-4-carboxylate (56) (CAS 173435-
41-1, 264 mg, 1.42 mmol) and 1-(2-oxa-5-
azabicyclo[4.1.0]heptan-5-yl)ethanone (400 mg, 2.83
mmol). Yield: 155 mg (35%). 1H NMR (400 MHz, DMSO-d6):
δ = 8.03 (d, J = 5.13 Hz, 1H), 7.57 (d, J = 4.82 Hz, 1H), 3.73–
3.81 (m, 5H), 3.62–3.73 (m, 1H), 3.35–3.48 (m, 1H), 3.09–
3.32 (m, 1H), 2.78–2.91 (m, 1H), 1.91 (br s, 3H), 0.96 (br s,
1H), 0.48–0.62 (m, 1H). MS (ESI+): m/z = 310.0 [M+H]+.
Step c: 8-Chloro-2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-
yl)-1,7-naphthyridin-4-ol was prepared using an
analogous method as described for 65, from methyl 2-
chloro-3-{(E)-[1-(2-oxa-5-azabicyclo[4.1.0]heptan-5-
2-(3-Ethylmorpholin-4-yl)-4-isopropoxy-8-(1H-
pyrazol-5-yl)-1,7-naphthyridine (12). Step a: 1-(3-
Ethylmorpholin-4-yl)ethanone was prepared using an
analogous method as described for 63, from 3-
ethylmorpholine (CAS 55265-24-2, 500 mg, 4.12 mmol).
Yield: 789 mg (quant.). MS (ESI+): m/z = 158.0 [M+H]+. Step
b: Methyl 2-chloro-3-{(E)-[1-(3-ethylmorpholin-4-
yl)ethylidene]amino}isonicotinate was prepared using
an analogous method as described for 64, from methyl 3-
amino-2-chloropyridine-4-carboxylate (56) (CAS 173435-
41-1, 367 mg, 1.96 mmol) and 1-(3-ethylmorpholin-4-
yl)ethanone (789 mg, 4.52 mmol, 90% purity). Yield: 255
mg (40%). 1H NMR (400 MHz, DMSO-d6): δ = 8.02 (d, J = 5.02
Hz, 1H), 7.56 (d, J = 5.02 Hz, 1H), 3.68–3.79 (m, 5H), 3.32–
3.41 (m, 4H), 1.72 (s, 3H), 1.46 (s, 3H), 1.37 (s, 3H). MS
(ESI+): m/z = 326.1 [M+H]+. Step c: 8-Chloro-2-(3-
yl)ethylidene]amino}isonicotinate (155 mg, 500 µmol).
Yield: 82 mg (59%). 1H NMR (400 MHz, DMSO-d6): δ = 11.73
(br s, 1H), 7.97 (d, J = 5.07 Hz, 1H), 7.75 (d, J = 5.32 Hz, 1H),
6.80 (s, 1H), 3.72–3.89 (m, 4H), 3.37 (br d, J = 3.80 Hz, 1H),
2.76 (br d, J = 4.56 Hz, 1H), 0.98 (q, J = 6.34 Hz, 1H), 0.58 (td,
J = 4.06, 6.34 Hz, 1H). MS (ESI+): m/z = 278.0 [M+H]+. Step
ethylmorpholin-4-yl)-1,7-naphthyridin-4-ol
was
prepared using an analogous method as described for 65,
from methyl 2-chloro-3-{(E)-[1-(3-ethylmorpholin-4-yl)-
ethylidene]amino}isonicotinate (255 mg, 782 µmol). Yield:
341 mg (quant.). The material was used in the next step
without further purification. 1H NMR (400 MHz, DMSO-d6):
δ = 7.56–7.66 (m, 2H), 5.59 (s, 1H), 4.09 (br d, J = 14.95 Hz,
3H), 3.79–3.90 (m, 2H), 3.41–3.53 (m, 2H), 2.97 (dt, J = 3.68,
12.74 Hz, 1H), 1.67–1.81 (m, 1H), 1.42–1.53 (m, 1H), 0.89 (t,
J = 7.48 Hz, 3H). MS (ESI+): m/z = 294.1 [M+H]+. Step d: 8-
Chloro-2-(3-ethylmorpholin-4-yl)-4-isopropoxy-1,7-
naphthyridine was prepared using an analogous method
as described for 60, from 8-chloro-2-(3-ethylmorpholin-4-
yl)-1,7-naphthyridin-4-ol (241 mg, 821 µmol). Yield: 165
mg (60%). The material was used in the next step without
further purification. 1H NMR (400 MHz, DMSO-d6): δ = 7.97
(d, J = 5.31 Hz, 1H), 7.66 (d, J = 5.31 Hz, 1H), 6.78 (s, 1H),
5.05 (td, J = 6.03, 11.94 Hz, 1H), 4.46 (br s, 1H), 4.39 (br d, J
= 14.15 Hz, 1H), 3.83–3.99 (m, 2H), 3.43–3.60 (m, 2H), 3.14–
3.24 (m, 1H), 1.63–1.84 (m, 2H), 1.38 (dd, J = 5.94, 8.72 Hz,
d:
8-Chloro-4-isopropoxy-2-(2-oxa-5-
azabicyclo[4.1.0]heptan-5-yl)-1,7-naphthyridine was
prepared using an analogous method as described for 60,
from 8-chloro-2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-
1,7-naphthyridin-4-ol (82.0 mg, 295 µmol). Yield: 73 mg
1
(77%). H NMR (400 MHz, DMSO-d6): δ = 8.01 (d, J = 5.31
Hz, 1H), 7.73 (d, J = 5.31 Hz, 1H), 6.86 (s, 1H), 5.02 (td, J =
5.97, 12.06 Hz, 1H), 3.73–3.92 (m, 4H), 3.41 (dd, J = 3.41,
9.47 Hz, 1H), 2.94 (br d, J = 4.04 Hz, 1H), 1.43 (dd, J = 4.42,
5.94 Hz, 6H), 1.04 (q, J = 6.57 Hz, 1H), 0.59 (td, J = 4.04, 6.32
Hz, 1H). MS (ESI+): m/z = 320.3 [M+H]+. Step e: 4-
Isopropoxy-2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-
8-{1-[tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-
naphthyridine was prepared using an analogous method
as described for 66, from 8-chloro-4-isopropoxy-2-(2-oxa-
5-azabicyclo[4.1.0]heptan-5-yl)-1,7-naphthyridine (73.0
mg, 228 µmol). Yield: 85 mg (86%). 1H NMR (400 MHz,
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6H), 0.89 (t, J = 7.45 Hz, 3H). MS (ESI+): m/z = 336.1 [M+H]+.
Step e: 2-(3-Ethylmorpholin-4-yl)-4-isopropoxy-8-{1-
[tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-
7.80 (m, 1H), 6.70 (s, 1H), 4.24 (br d, J = 12.88 Hz, 2H), 4.02
(dd, J = 3.54, 11.37 Hz, 1H), 3.64–3.92 (m, 2H), 3.52–3.63 (m,
1H), 3.33–3.48 (m, 1H). MS (ESI+): m/z = 334.1 [M+H]+.
naphthyridine was prepared using an analogous method
as described for 66, from 8-chloro-2-(3-ethylmorpholin-4-
yl)-4-isopropoxy-1,7-naphthyridine (145 mg, 433 µmol).
Yield: 125 mg (52% with 74% purity). MS (ESI+): m/z =
452.4 [M+H]+. Step f: 2-(3-Ethylmorpholin-4-yl)-4-
isopropoxy-8-(1H-pyrazol-5-yl)-1,7-naphthyridine
(12) was prepared using an analogous method as described
for BAY 1895344, from 2-(3-ethylmorpholin-4-yl)-4-
isopropoxy-8-{1-[tetrahydro-2H-pyran-2-yl]-1H-pyrazol-
5-yl}-1,7-naphthyridine (125 mg, 277 µmol). Yield: 99 mg
(92% with 95% purity). LC-MS [Method 4]: Rt = 0.65 min.
MS (ESI+): m/z = 368.2 [M+H]+. 1H NMR (400 MHz, DMSO-
d6): δ = 13.36 (br s, 1H, pyrazole-NH), 8.29 (d, J = 5.32 Hz,
1H, naphthyridine), 7.68 (d, J = 5.32 Hz, 1H, naphthyridine),
7.60 (br s, 1H, pyrazole), 7.34 (br s, 1H, pyrazole), 6.81 (s,
1H, naphthyridine), 5.07 (td, J = 5.96, 11.91 Hz, 1H, CH), 4.40
(br s, 1H, CH2O), 4.23 (br d, J = 12.67 Hz, 1H, CH2O), 3.88–
4.09 (m, 2H, CH2O), 3.50–3.65 (m, 2H, CH2N), 3.21–3.29 (m,
1H, CHN), 1.76–1.98 (m, 1H, CH2), 1.59–1.74 (m, 1H, CH2),
Step
d:
8-Chloro-4-isopropoxy-2-[3-
(trifluoromethyl)morpholin-4-yl]-1,7-naphthyridine
was prepared using an analogous method as described for
60, from 8-chloro-2-[3-(trifluoromethyl)morpholin-4-yl]-
1,7-naphthyridin-4-ol (95.0 mg, 285 µmol). Yield: 70 mg
1
(65%). H NMR (400 MHz, CDCl3): δ = 7.98–8.14 (m, 1H),
9
7.72 (d, J = 5.52 Hz, 1H), 6.89–7.02 (m, 1H), 5.72–5.82 (m,
1H), 5.46–5.70 (m, 1H), 4.99–5.16 (m, 1H), 4.38–4.61 (m,
1H), 4.19–4.34 (m, 1H), 3.97–4.13 (m, 1H), 3.73–3.85 (m,
1H), 3.51–3.64 (m, 1H), 1.39 (dd, J = 6.02, 11.80 Hz, 6H). MS
(ESI+): m/z = 376.2 [M+H]+. Step e: 4-Isopropoxy-8-{1-
[tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-2-[3-
(trifluoromethyl)morpholin-4-yl]-1,7-naphthyridine
was prepared using an analogous method as described for
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
66,
from
8-chloro-4-isopropoxy-2-[3-
(trifluoromethyl)morpholin-4-yl]-1,7-naphthyridine (68.0
mg, 181 µmol). Yield: 77 mg (82%). 1H NMR (400 MHz,
DMSO-d6): δ = 8.41 (d, J = 5.32 Hz, 1H), 7.78 (d, J = 5.32 Hz,
1H), 7.61 (d, J = 1.77 Hz, 1H), 6.73–6.97 (m, 2H), 5.98 (dd, J
= 2.15, 9.51 Hz, 1H), 5.44 (br s, 1H), 5.04–5.13 (m, 1H), 4.14–
4.35 (m, 2H), 3.97–4.06 (m, 2H), 3.65–3.84 (m, 2H), 3.46–
3.57 (m, 1H), 3.20–3.29 (m, 2H), 2.30–2.35 (m, 1H), 1.88–
1.96 (m, 1H), 1.38–1.60 (m, 9H). MS (ESI+): m/z = 492.4
[M+H]+. Step f: 4-Isopropoxy-8-(1H-pyrazol-5-yl)-2-[3-
(trifluoromethyl)morpholin-4-yl]-1,7-naphthyridine
(14) was prepared using an analogous method as described
for BAY 1895344, from 4-isopropoxy-8-{1-[tetrahydro-2H-
pyran-2-yl]-1H-pyrazol-5-yl}-2-[3-
(trifluoromethyl)morpholin-4-yl]-1,7-naphthyridine (75.0
mg, 153 µmol). Yield: 22 mg (36%). LC-MS [Method 3]: Rt =
0.94 min. MS (ESI+): m/z = 408.2 [M+H]+. 1H NMR (400
MHz, DMSO-d6): δ = 13.37 (br s, 1H, pyrazole-NH), 8.37 (d, J
= 5.32 Hz, 1H, naphthyridine), 7.74 (d, J = 5.32 Hz, 1H,
naphthyridine), 7.60 (s, 1H, pyrazole), 7.31 (br s, 1H,
pyrazole), 6.99 (s, 1H, naphthyridine), 5.52 (br d, J = 6.34 Hz,
1H, iPr), 5.04–5.13 (m, 1H, CH), 4.22–4.43 (m, 2H, CH2O),
4.10 (br d, J = 9.63 Hz, 1H, CH2O), 3.84 (br d, J = 11.15 Hz,
1H, CH2O), 3.52–3.71 (m, 1H, CH2N), 3.33–3.49 (m, 1H,
CH2N), 1.41 (dd, J = 5.83, 10.90 Hz, 6H, iPr). 19F NMR (377
MHz, DMSO-d6): δ = –67.32. MS (ESI+): m/z = 408.3
[M + H]+. 13C NMR (101 MHz, DMSO-d6) δ = 160.1, 158.7,
144.9, 139.9, 139.4, 127.8, 124.9, 122.7, 114.2, 107.7, 93.1,
70.9, 65.8, 63.6, 51.1, 41.2, 21.6, 21.2. HRMS (ESI, [M + H]+):
calcd for C19H21N5O2F3, 408.1647; found, 408.1636.
1.40 (t, J = 6.46 Hz, 6H, iPr), 0.91 (t, J = 7.48 Hz, 3H, CH3). 13
C
NMR (101 MHz, DMSO-d6): δ = 159.7, 159.0, 144.1, 140.5,
140.2, 139.4, 138.5, 122.3, 114.2, 107.4, 92.9, 70.5, 67.4,
66.2, 53.1, 21.6, 21.3, 20.3, 10.9. HRMS (ESI, [M+H]+): calcd
for C20 H26 N5 O2, 368.2087; found, 368.2082.
4-Isopropoxy-2-[(2S)-2-methylmorpholin-4-yl]-8-
(1H-pyrazol-5-yl)-1,7-naphthyridine (13). The title
compound was prepared as described for its enantiomer
10. The analytical data were identical to 10. LC-MS [Method
4]: Rt = 0.64 min. MS (ESI+): m/z = 354.2 [M+H]+.
4-Isopropoxy-8-(1H-pyrazol-5-yl)-2-[3-
(trifluoromethyl)morpholin-4-yl]-1,7-naphthyridine
(14). Step a: 1-[3-(Trifluoromethyl)morpholin-4-
yl]ethanone was prepared using an analogous method as
described for 63, from 3-(trifluoromethyl)morpholine
hydrochloride (1:1) (CAS 1196152-13-2, 908 mg, 4.74
mmol). Yield: 886 mg (85% with 90% purity). 1H NMR (300
MHz, DMSO-d6): δ = 4.98 (br dd, J = 4.14, 9.61 Hz, 1H), 3.33–
4.23 (m, 6H), 2.05–2.12 (m, 3H). MS (ESI+): m/z = 198.0
[M + H]+. Step b: Methyl 2-chloro-3-[(E)-{1-[3-
(trifluoromethyl)morpholin-4-
yl]ethylidene}amino]isonicotinate was prepared using
an analogous method as described for 64, from methyl 3-
amino-2-chloropyridine-4-carboxylate (56) (CAS 173435-
41-1,
377
mg,
2.02
mmol)
and
1-[3-
4-Isopropoxy-8-(1H-pyrazol-5-yl)-2-[(3aR,6aS)-
tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl]-1,7-
(trifluoromethyl)morpholin-4-yl]ethanone (886 mg, 4.04
mmol, 90% purity). Yield: 451 mg (58% with 95% purity).
1H NMR (400 MHz, DMSO-d6): δ = 8.09 (d, J = 4.80 Hz, 1H),
7.60 (d, J = 4.80 Hz, 1H), 3.89–4.22 (m, 3H), 3.75–3.82 (m,
3H), 3.41–3.53 (m, 1H), 3.30 (s, 3H), 1.81–1.87 (m, 3H). MS
(ESI+): m/z = 366.2 [M+H]+. Step c: 8-Chloro-2-[3-
(trifluoromethyl)morpholin-4-yl]-1,7-naphthyridin-4-
ol was prepared using an analogous method as described
naphthyridine (15). Step a: 1-[(3aR,6aS)-Tetrahydro-
1H-furo[3,4-c]pyrrol-5(3H)-yl]ethanone was prepared
using an analogous method as described for 63, from
(3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride
(1:1) (CAS 57710-36-8, 400 mg, 2.67 mmol). Yield: 369 mg
1
(84%). H NMR (400 MHz, CDCl3): δ = 3.89–3.96 (m, 2H),
3.62–3.74 (m, 4H), 3.48 (dd, J = 4.04, 12.63 Hz, 1H), 3.35 (dd,
J = 4.80, 10.86 Hz, 1H), 2.90–3.07 (m, 2H), 2.05 (s, 3H). Step
b: Methyl 2-chloro-3-[(E)-{1-[(3aR,6aS)-tetrahydro-1H-
furo[3,4-c]pyrrol-5(3H)-yl]ethylidene}-
amino]isonicotinate was prepared using an analogous
method as described 64, from methyl 3-amino-2-
for
65,
from
methyl
2-chloro-3-[(E)-{1-[3-
(trifluoromethyl)morpholin-4-
yl]ethylidene}amino]isonicotinate (447 mg, 1.22 mmol).
1
Yield: 98 mg (20% with 82% purity). H NMR (400 MHz,
DMSO-d6): δ = 11.85 (br s, 1H), 8.01–8.09 (m, 1H), 7.72–
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7
8
chloropyridine-4-carboxylate (56) (CAS 173435-41-1, 293
4-Isopropoxy-8-(1H-pyrazol-5-yl)-2-(2,2,6,6-
tetrafluoromorpholin-4-yl)-1,7-naphthyridine
mg, 1.57 mmol) and 1-[(3aR,6aS)-tetrahydro-1H-furo[3,4-
c]pyrrol-5(3H)-yl]ethanone (365 mg, 2.35 mmol). Yield:
247 mg (46%). 1H NMR (400 MHz, DMSO-d6): δ = 7.99 (d, J
= 4.82 Hz, 1H), 7.53 (d, J = 5.07 Hz, 1H), 3.78–3.83 (m, 2H),
3.76 (s, 3H), 3.66 (br s, 2H), 3.53–3.62 (m, 2H), 3.35–3.42
(m, 2H), 2.98 (br s, 2H), 1.73 (s, 3H). MS (ESI+): m/z = 324.1
[M+H]+. Step c: 8-Chloro-2-[(3aR,6aS)-tetrahydro-1H-
furo[3,4-c]pyrrol-5(3H)-yl]-1,7-naphthyridin-4-ol was
prepared using an analogous method as described for 65,
from methyl 2-chloro-3-[(E)-{1-[(3aR,6aS)-tetrahydro-1H-
furo[3,4-c]pyrrol-5(3H)-yl]ethylidene}amino]isonicotinate
(16).
Step a: 1-(2,2,6,6-Tetrafluoromorpholin-4-yl)ethanone
was prepared using an analogous method as described for
63, from 2,2,6,6-tetrafluoromorpholine (CAS 65502-95-6,
1
500 mg, 3.14 mmol). Yield: 208 mg (33%). H NMR (400
MHz, DMSO-d6): δ = 4.33 (t, J = 8.53 Hz, 2H), 4.19 (t, J = 8.91
Hz, 2H), 2.11 (s, 3H). Step b: Methyl 2-chloro-3-{(E)-[1-
(2,2,6,6-tetrafluoromorpholin-4-
yl)ethylidene]amino}isonicotinate was prepared using
an analogous method as described for 64, from methyl 3-
amino-2-chloropyridine-4-carboxylate (56) (CAS 173435-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(240 mg, 741 µmol). Yield: 186 mg (86%). H NMR (400
41-1,
129
mg,
689
µmol)
and
1-(2,2,6,6-
MHz, DMSO-d6): δ = 11.06–12.23 (m, 1H), 7.93 (d, J = 5.32
Hz, 1H), 7.70 (d, J = 5.32 Hz, 1H), 6.34 (s, 1H), 3.83 (dd, J =
6.72, 8.74 Hz, 2H), 3.73 (br dd, J = 7.60, 10.90 Hz, 2H), 3.57–
3.66 (m, 2H), 3.40–3.50 (m, 2H), 2.99–3.10 (m, 2H). MS
tetrafluoromorpholin-4-yl)ethanone (208 mg, 1.03 mmol).
Yield: 140 mg (54%). 1H NMR (400 MHz, DMSO-d6): δ = 8.13
(d, J = 4.80 Hz, 1H), 7.61 (d, J = 4.80 Hz, 1H), 4.33–4.48 (m,
4H), 3.74 (s, 3H), 1.85 (s, 3H). MS (ESI+): m/z = 370.1
(ESI+): m/z
=
292.1 [M+H]+. Step d: 8-Chloro-4-
[M+H]+.
Step
c:
8-Chloro-2-(2,2,6,6-
isopropoxy-2-[(3aR,6aS)-tetrahydro-1H-furo[3,4-
c]pyrrol-5(3H)-yl]-1,7-naphthyridine was prepared
using an analogous method as described for 60, from 8-
chloro-2-[(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-
5(3H)-yl]-1,7-naphthyridin-4-ol (180 mg, 617 µmol). Yield:
170 mg (83%). 1H NMR (500 MHz, DMSO-d6): δ = 7.95 (d, J
= 5.04 Hz, 1H), 7.67 (d, J = 5.36 Hz, 1H), 6.49 (s, 1H), 5.01
(td, J = 5.99, 11.98 Hz, 1H), 3.77–3.89 (m, 4H), 3.53–3.66 (m,
4H), 3.07 (br dd, J = 3.47, 6.62 Hz, 2H), 1.40 (d, J = 5.99 Hz,
6H). MS (ESI+): m/z = 334.2 [M+H]+. Step e: 4-Isopropoxy-
2-[(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-
yl]-8-{1-[tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-
1,7-naphthyridine was prepared using an analogous
method as described for 66, from 8-chloro-4-isopropoxy-2-
[(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl]-1,7-
naphthyridine (170.0 mg, 509 µmol). Yield: 110 mg (48%).
1H NMR (400 MHz, DMSO-d6): δ = 8.30 (d, J = 5.32 Hz, 1H),
7.72 (d, J = 5.32 Hz, 1H), 7.10 (d, J = 1.77 Hz, 1H), 6.49 (s,
1H), 6.22 (dd, J = 2.28, 9.63 Hz, 1H), 5.02 (quin, J = 6.02 Hz,
1H), 3.81–3.93 (m, 2H), 3.67–3.76 (m, 3H), 3.47–3.62 (m,
4H), 3.22–3.31 (m, 2H), 3.00–3.09 (m, 2H), 2.32–2.40 (m,
1H), 1.91–2.04 (m, 2H), 1.43–1.65 (m, 3H), 1.42 (dd, J = 2.79,
6.08 Hz, 6H). MS (ESI+): m/z = 450.3 [M+H]+. Step f: 4-
Isopropoxy-8-(1H-pyrazol-5-yl)-2-[(3aR,6aS)-
tetrafluoromorpholin-4-yl)-1,7-naphthyridin-4-ol was
prepared using an analogous method as described for 65,
from
methyl
2-chloro-3-{(E)-[1-(2,2,6,6-
tetrafluoromorpholin-4-yl)ethylidene]amino}isonicotinate
(139 mg, 375 µmol). Yield: 35 mg (26%). 1H NMR (400 MHz,
DMSO-d6): δ = 12.09 (br s, 1H), 8.09 (d, J = 5.32 Hz, 1H), 7.82
(d, J = 5.32 Hz, 1H), 6.78 (s, 1H), 4.50–4.61 (m, 4H). MS
(ESI+): m/z
=
338.1 [M+H]+. Step d: 8-Chloro-4-
isopropoxy-2-(2,2,6,6-tetrafluoromorpholin-4-yl)-1,7-
naphthyridine was prepared using an analogous method
as described for 60, from 8-chloro-2-(2,2,6,6-
tetrafluoromorpholin-4-yl)-1,7-naphthyridin-4-ol (35 mg,
104 µmol). Yield: 50.7 mg (quant.). The material was used
1
in the next step without further purification. H NMR (400
MHz, DMSO-d6): δ = 8.12 (d, J = 5.32 Hz, 1H), 7.75–7.79 (m,
1H), 7.11 (s, 1H), 5.09–5.18 (m, 1H), 4.67 (br t, J = 8.87 Hz,
4H), 1.38–1.43 (m, 6H). MS (ESI+): m/z = 380.2 [M+H]+.
Step e: 4-Isopropoxy-2-(2,2,6,6-tetrafluoromorpholin-
4-yl)-8-{1-[(2R)-tetrahydro-2H-pyran-2-yl]-1H-pyr-
azol-5-yl}-1,7-naphthyridine was prepared using an
analogous method as described for 66, from 8-chloro-4-
isopropoxy-2-(2,2,6,6-tetrafluoromorpholin-4-yl)-1,7-
naphthyridine (48 mg, 107 µmol with 85% purity). Yield: 94
mg crude (quant.). The material was used in the next step
without further purification. MS (ESI+): m/z = 496.3
[M+H]+. Step f: 4-Isopropoxy-8-(1H-pyrazol-5-yl)-2-
(2,2,6,6-tetrafluoromorpholin-4-yl)-1,7-naphthyridine
(16) was prepared using an analogous method as described
tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl]-1,7-
naphthyridine (15) was prepared using an analogous
method as described for BAY 1895344, from 4-isopropoxy-
2-[(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl]-8-
{1-[tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-
naphthyridine (110.0 mg, 245 µmol). Yield: 36 mg (40%).
LC-MS [Method 4]: Rt = 0.62 min. MS (ESI+): m/z = 366.2
[M+H]+. 1H NMR (400 MHz, CDCl3): δ = 13.70 (br s, 1H,
pyrazole-NH), 8.39 (d, J = 5.32 Hz, 1H, naphthyridine), 7.74
(d, J = 5.35 Hz, 1H, naphthyridine), 7.71 (s, 1H, pyrazole),
7.24 (s, 1H, pyrazole), 6.17 (s, 1H, naphthyridine), 4.77–4.86
(m, 1H, CH), 3.94–4.15 (m, 4H, CH2O), 3.84 (dd, J = 3.55, 9.12
Hz, 2H, CH), 3.63–3.73 (m, 2H, CH2N), 3.18–3.27 (m, 2H,
CH2N), 1.52 (d, J = 5.83 Hz, 6H, iPr). 13C NMR (101 MHz,
DMSO-d6): δ = 159.2, 157.0, 143.5, 141.2, 140.5, 139.4,
138.2, 122.0, 114.2, 107.2, 93.6, 73.2, 70.7, 52.0, 42.8, 21.4.
HRMS (ESI, [M+H]+): calcd for C20 H24 N5 O2, 366.1930;
found, 366.1933.
for
BAY 1895344,
from
4-isopropoxy-2-(2,2,6,6-
tetrafluoromorpholin-4-yl)-8-{1-[tetrahydro-2H-pyran-2-
yl]-1H-pyrazol-5-yl}-1,7-naphthyridine (94 mg, 190 µmol).
Yield: 25 mg (29%). LC-MS [Method 3]: Rt = 0.96 min. MS
(ESI+): m/z = 412.2 [M+H]+. H NMR (400 MHz, DMSO-d6):
1
δ = 13.07 (br s, 1H, pyrazole-NH), 8.60 (br s, 1H, pyrazole),
8.33 (d, J = 5.32 Hz, 2H, naphthyridine, pyrazole), 7.61 (d, J
= 5.58 Hz, 1H, naphthyridine), 7.06 (s, 1H, naphthyridine),
5.09–5.18 (m, 1H, CH), 4.57–4.66 (m, 4H, CH2), 1.39–1.44
(m, 6H, iPr).
2-(3,3-Dimethylmorpholin-4-yl)-4-isopropoxy-8-
(1H-pyrazol-5-yl)-1,7-naphthyridine (17). Step a: 1-
(3,3-Dimethylmorpholin-4-yl)ethanone was prepared
using an analogous method as described for 63, from 3,3-
dimethylmorpholine hydrochloride (CAS 59229-64-0, 500
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mg, 3.23 mmol). Yield: 588 mg (99%). H NMR (400 MHz,
DMSO-d6): δ = 3.63–3.69 (m, 2H), 3.31–3.39 (m, 2H), 3.27 (s,
2H), 1.95 (s, 3H), 1.29 (s, 6H). MS (ESI+): m/z = 158.0
[M+H]+. Step b: Methyl 2-chloro-3-{(E)-[1-(3,3-
dimethylmorpholin-4-
8.62 Hz, 1H), 3.71 (d, J = 9.89 Hz, 1H), 3.58 (d, J = 9.89 Hz,
1H), 3.15 (s, 3H), 1.76 (s, 3H), 1.38 (s, 3H). Step b: Methyl
2-chloro-3-{(E)-[1-(3-methoxy-3-methylazetidin-1-
yl)ethylidene]amino}isonicotinate was prepared using
an analogous method as described for 64, from methyl 3-
amino-2-chloropyridine-4-carboxylate (56) (CAS 173435-
41-1, 273 mg, 1.46 mmol) and 1-(3-methoxy-3-
methylazetidin-1-yl)ethanone (535 mg, 3.36 mmol with
90% purity). Yield: 378 mg (67% with 81% purity). 1H NMR
(400 MHz, DMSO-d6): δ = 8.00–8.08 (m, 1H), 7.54 (d, J = 5.07
Hz, 1H), 4.03 (q, J = 7.10 Hz, 2H), 3.79 (s, 5H), 3.13–3.21 (m,
3H), 1.61 (s, 3H), 1.44 (s, 3H). MS (ESI+): m/z = 312.2
4
5
6
7
8
yl)ethylidene]amino}isonicotinate was prepared using
an analogous method as described for 64, from methyl 3-
amino-2-chloropyridine-4-carboxylate (56) (CAS 173435-
41-1, 273 mg, 1.46 mmol) and 1-(3,3-dimethylmorpholin-4-
yl)ethanone (588 mg, 3.36 mmol with 90% purity ). Yield:
162 mg (34%). 1H NMR (400 MHz, DMSO-d6): δ = 8.01 (dd, J
= 1.13, 4.89 Hz, 1H), 7.55 (t, J = 5.09 Hz, 1H), 3.95 (br s, 1H),
3.84 (br d, J = 10.79 Hz, 1H), 3.73–3.81 (m, 5H), 3.44–3.54
(m, 1H), 3.35–3.44 (m, 1H), 1.62–1.84 (m, 6H), 0.87–0.97
(m, 3H). MS (ESI+): m/z = 326.1 [M+H]+. Step c: 8-Chloro-
2-(3,3-dimethylmorpholin-4-yl)-1,7-naphthyridin-4-ol
was prepared using an analogous method as described for
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[M + H]+.
methylazetidin-1-yl)-1,7-naphthyridin-4-ol
prepared using an analogous method as described for 65,
from methyl 2-chloro-3-{(E)-[1-(3-methoxy-3-
Step
c:
8-Chloro-2-(3-methoxy-3-
was
methylazetidin-1-yl)ethylidene]amino}isonicotinate (378
mg, 1.21 mmol). Yield: 344 mg (quant.). 1H NMR (400 MHz,
DMSO-d6): δ = 11.67 (br s, 1H), 7.96 (d, J = 5.32 Hz, 1H), 7.72
(d, J = 5.32 Hz, 1H), 6.16 (s, 1H), 3.97–4.11 (m, 2H), 3.89 (d,
J = 9.12 Hz, 2H), 3.17–3.23 (m, 3H), 1.47 (s, 3H). MS (ESI+):
m/z = 280.1 [M+H]+. Step d: 8-Chloro-4-isopropoxy-2-(3-
methoxy-3-methylazetidin-1-yl)-1,7-naphthyridine
was prepared using an analogous method as described for
60, from 8-chloro-2-(3-methoxy-3-methylazetidin-1-yl)-
1,7-naphthyridin-4-ol (100 mg, 357 µmol). Yield: 77.5 mg
65,
from
methyl
2-chloro-3-{(E)-[1-(3,3-
dimethylmorpholin-4-yl)ethylidene]amino}isonicotinate
(162 mg, 496 µmol). Yield: 229 mg (quant.). The material
1
was used in the next step without further purification. H
NMR (400 MHz, DMSO-d6): δ = 7.59–7.78 (m, 2H), 5.69–5.84
(m, 1H), 3.88–4.37 (m, 4H), 3.73 (br t, J = 5.07 Hz, 2H), 1.44–
1.55 (m, 6H), OH not visible. MS (ESI+): m/z = 294.1 [M+H]+.
Step d: 8-Chloro-2-(3,3-dimethylmorpholin-4-yl)-4-
isopropoxy-1,7-naphthyridine was prepared using an
analogous method as described for 60, from 8-chloro-2-
(3,3-dimethylmorpholin-4-yl)-1,7-naphthyridin-4-ol (129
1
(67%). H NMR (400 MHz, DMSO-d6): δ = 7.98 (d, J = 5.32
Hz, 1H), 7.69 (d, J = 5.32 Hz, 1H), 6.36 (s, 1H), 4.96 (spt, J =
6.04 Hz, 1H), 3.92–4.10 (m, 4H), 3.22–3.25 (m, 3H), 1.49 (s,
3H), 1.39 (d, J = 6.08 Hz, 6H). MS (ESI+): m/z = 322.2 [M+H]+.
Step e: 4-Isopropoxy-2-(3-methoxy-3-methylazetidin-
1-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine (18). 8-
Chloro-4-isopropoxy-2-(3-methoxy-3-methylazetidin-1-
yl)-1,7-naphthyridine (69 mg, 214 µmol), 1-(tetrahydro-
2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-1H-pyrazole (54) (CAS 903550-26-5, 119 mg, 429
1
mg, 439 µmol). Yield: 72.8 mg (49%). H NMR (400 MHz,
DMSO-d6): δ = 8.06 (d, J = 5.30 Hz, 1H), 7.71 (d, J = 5.31 Hz,
1H), 6.93 (s, 1H), 5.01 (quin, J = 6.00 Hz, 1H), 3.83 (t, J = 5.05
Hz, 2H), 3.56–3.67 (m, 2H), 3.41 (s, 2H), 1.52–1.60 (m, 6H),
1.37 (d, J = 6.06 Hz, 6H). MS (ESI+): m/z = 336.1 [M+H]+.
Step e: 2-(3,3-Dimethylmorpholin-4-yl)-4-isopropoxy-
8-{1-[tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-
naphthyridine was prepared using an analogous method
as
described
for
66,
from
8-chloro-2-(3,3-
µmol),
and
bis(triphenylphosphine)palladium(II)
dimethylmorpholin-4-yl)-4-isopropoxy-1,7-naphthyridine
(72.8 mg, 217 µmol). Yield: 53 mg (56%). Step f: 2-(3,3-
Dimethylmorpholin-4-yl)-4-isopropoxy-8-(1H-pyrazol-
5-yl)-1,7-naphthyridine (17) was prepared using an
analogous method as described for BAY 1895344, from 2-
(3,3-dimethylmorpholin-4-yl)-4-isopropoxy-8-{1-
dichloride (18 mg, 26 µmol) were dissolved in DME (17 mL).
2 M Aqueous K2CO3 (0.24 mL, 472 µmol) was added and the
mixture was stirred for 10 min at 130 °C in a microwave
reactor. The mixture was diluted with EtOAc and filtered
through a silicon filter. The filtrate was concentrated under
reduced pressure. The residue was purified by preparative
HPLC (acidic conditions). The combined product fractions
were concentrated under reduced pressure, dissolved in
MeOH, and stirred with concd HCl at rt overnight. The
reaction mixture was quenched with saturated NaHCO3
solution and extracted with DCM. The combined organic
layers were dried (silicon filter) and concentrated under
reduced pressure to give 18. Yield: 52 mg (68%). LC-MS
[Method 4]: Rt = 0.64 min. MS (ESI+): m/z = 354.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6): δ = 13.47 (br s, 1H, pyrazole-
NH), 8.29 (d, J = 5.32 Hz, 1H, naphthyridine), 7.68 (d, J = 5.32
Hz, 1H, naphthyridine), 7.57–7.63 (m, 1H, pyrazole), 7.40 (s,
1H, pyrazole), 6.38 (s, 1H, naphthyridine), 4.98 (spt, J = 6.08
Hz, 1H, CH), 4.15 (d, J = 8.87 Hz, 2H, CH2N), 4.03 (d, J = 9.13
Hz, 2H, CH2N), 3.24–3.28 (m, 3H, OCH3), 1.53 (s, 3H, CH3),
1.41 (d, J = 5.83 Hz, 6H, iPr). HRMS (ESI, [M+H]+): calcd for
C19H24N5O2, 354.1930; found, 354.1952.
[tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-
naphthyridine (53.2 mg, 118 µmol). Yield: 46 mg (quant.).
LC-MS [Method 4]: Rt = 0.65 min. MS (ESI+): m/z = 368.2
[M+H]+. H NMR (400 MHz, DMSO-d6): δ = 13.39 (br s, 1H,
1
pyrazole-NH), 8.40 (d, J = 5.07 Hz, 1H, naphthyridine), 7.75
(d, J = 5.07 Hz, 1H, naphthyridine), 7.62 (br s, 1H, pyrazole),
7.42 (br s, 1H, pyrazole), 6.91 (s, 1H, naphthyridine), 4.95–
5.06 (m, 1H, CH), 3.81–3.92 (m, 2H, CH2O), 3.64 (br s, 2H,
CH2O), 3.41–3.48 (m, 2H, CH2N), 1.47 (s, 6H, CH3), 1.41 (d, J
= 6.08 Hz, 6H, iPr). HRMS (ESI, [M+H]+): calcd for
C20H26N5O2, 368.2087; found, 368.2082.
4-Isopropoxy-2-(3-methoxy-3-methylazetidin-1-yl)-
8-(1H-pyrazol-5-yl)-1,7-naphthyridine (18). Step a: 1-
(3-Methoxy-3-methylazetidin-1-yl)ethanone
prepared using an analogous method as described for 63,
from 3-methoxy-3-methylazetidine (CAS 877665-31-1, 500
was
1
mg, 4.9 mmol). Yield: 589 mg (75%). H NMR (400 MHz,
4-Isopropoxy-2-(morpholin-4-yl)-8-(1H-pyrrol-2-
DMSO-d6): δ = 4.01 (d, J = 8.87 Hz, 1H), 3.85 (dd, J = 1.01,
yl)-1,7-naphthyridine (19). Step a: tert-Butyl 2-[4-
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1
2
3
4
5
6
7
8
isopropoxy-2-(morpholin-4-yl)-1,7-naphthyridin-8-
CH2N), 1.39 (d, J = 5.81 Hz, 6H, iPr). HRMS (ESI, [M+H]+):
calcd for C19H23N4O2, 339.1821; found, 339.1813.
yl]-1H-pyrrole-1-carboxylate. Under argon, [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(1:1 complex with DCM; 20 mg, 24 µmol) was added to a
mixture of 8-chloro-4-isopropoxy-2-(morpholin-4-yl)-1,7-
naphthyridine (75 mg, 0.24 mmol) and [1-(tert-
4-Isopropoxy-2-(morpholin-4-yl)-1,7-
naphthyridine-8-carboxamide
(21).
8-Chloro-4-
(150
isopropoxy-2-(morpholin-4-yl)-1,7-naphthyridine
mg, 487 µmol) was dissolved in DMSO (7 mL). [1,1'-
Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(1:1 complex with DCM; 40 mg, 48.4 µmol), 0.4 M ammonia
in THF (6 mL, 2.4 mmol), and triethylamine (410 µL, 2.9
mmol) were added. The mixture was stirred at 100 °C under
carbon monoxide (13 bar) for 23 h. Then, the mixture was
filtered through Celite and washed with EtOAc and MeOH.
The filtrate was concentrated under reduced pressure. The
residue was purified by preparative HPLC (acidic
conditions) to give 21. Yield: 24 mg (14%). LC-MS [Method
butoxycarbonyl)-1H-pyrrol-2-yl]boronic
acid
(CAS
135884-31-0, 57 mg, 0.27 mmol) in MeCN (2 mL) and 2 M
aqueous K2CO3 (2 mL). The mixture was stirred in a
microwave oven at 130 °C for 10 min. After cooling, DCM
was added and the mixture was filtered using a Whatman
filter paper. The organic phase was concentrated and the
residue was purified by HPLC (basic conditions) to give tert-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
butyl
2-[4-isopropoxy-2-(morpholin-4-yl)-1,7-
naphthyridin-8-yl]-1H-pyrrole-1-carboxylate. Yield: 35 mg
1
(33%). H NMR (400 MHz, DMSO-d6): δ = 8.21 (d, J = 5.31
1
1]: Rt = 0.70 min. MS (ESI+): m/z = 317.0 [M+H]+. H NMR
Hz, 1H), 7.64 (d, J = 5.56 Hz, 1H), 7.38 (dd, J = 1.77, 3.28 Hz,
1H), 6.77 (s, 1H), 6.40 (dd, J = 1.77, 3.28 Hz, 1H), 6.30 (t, J =
3.20 Hz, 1H), 5.06 (quin, J = 6.00 Hz, 1H), 3.59–3.71 (m, 4H),
3.48–3.56 (m, 4H), 1.38 (d, J = 6.06 Hz, 6H), 0.93 (s, 9H).
Step b: 4-Isopropoxy-2-(morpholin-4-yl)-8-(1H-pyrrol-
2-yl)-1,7-naphthyridine (19). TFA (7 µL, 0.096 mmol) was
(400 MHz, DMSO-d6): δ = 8.48 (br s, 1H, NH), 8.22–8.32 (m,
1H, naphthyridine), 7.68–7.85 (m, 1H, naphthyridine), 7.60
(br s, 1H, NH), 6.84 (s, 1H, naphthyridine), 5.07 (quin d, J =
6.06, 12.02 Hz, 1H, CH), 3.58–3.81 (m, 8H, morpholine), 1.39
(m, 6H, iPr). 13C NMR (101 MHz, DMSO-d6): δ = 167.9, 163.1,
159.8, 159.0, 140.5, 138.5, 122.3, 115.9, 93.0, 70.7, 66.0,
45.2, 21.4. HRMS (ESI, [M+H]+): calcd for C16H21N4O3,
317.1614; found, 317.1610.
added to
a solution of tert-butyl 2-[4-isopropoxy-2-
(morpholin-4-yl)-1,7-naphthyridin-8-yl]-1H-pyrrole-1-
carboxylate (9 mg, 0.020 mmol) in DCM (2 mL) and the
reaction mixture was stirred at rt for 150 min. Additional
TFA (7 µL, 0.096 mmol) was added and the reaction mixture
was stirred overnight. Additional TFA (23 µL, 0.32 mmol)
was added and the reaction mixture was stirred for 8 h. The
mixture was basified by the addition of aqueous NaHCO3
solution and extracted with DCM (2 ×). The combined
organic phases were filtered using a Whatman filter paper
and concentrated to give 19. Yield: 9 mg (0.027 mmol, 79%
with 95% purity). LC-MS [Method 2]: Rt = 1.25 min. MS
(ESI+): m/z = 339.2 [M+H]+. 1H NMR (400 MHz, CDCl3):
δ = 11.53 (br s, 1H, pyrrole-NH), 8.28–8.36 (m, 1H, naph-
thyridine), 7.60 (d, J = 5.31 Hz, 1H, naphthyridine), 7.48 (br
s, 1H, pyrrole), 7.29 (s, 1H, pyrrole), 7.03 (br s, 1H, pyrrole),
6.38–6.45 (m, 1H, naphthyridine), 4.80 (td, J = 5.94, 11.87
Hz, 1H, CH), 3.89–4.03 (m, 4H, CH2O), 3.64–3.81 (m, 4H,
CH2N), 1.44–1.59 (m, 6H, iPr).
8-(1H-Imidazol-5-yl)-4-isopropoxy-2-(morpholin-4-
yl)-1,7-naphthyridine (22). Step a: 4-Isopropoxy-2-
(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-
imidazol-5-yl]-1,7-naphthyridine.
isopropoxy-2-(morpholin-4-yl)-1,7-naphthyridine
8-Chloro-4-
(100
mg, 325 µmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole (CAS
1029684-37-4,
207
mg,
746
µmol),
bis(triphenylphosphine)palladium(II) dichloride (64 mg,
98 µmol), and K2CO3 (103 mg, 748 µmol) were stirred in
DME (3 mL) and H2O (1 mL) for 24 h at 90 °C. Then, the
mixture was concentrated under reduced pressure. The
residue was purified by flash chromatography (silica gel,
DCM/MeOH 95:5) to give 4-isopropoxy-2-(morpholin-4-
yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-5-yl]-
1,7-naphthyridine. Yield: 137 mg (quant.). MS (ESI/APCI+):
m/z = 424.3 [M+H]+. Step b: 8-(1H-Imidazol-5-yl)-4-
isopropoxy-2-(morpholin-4-yl)-1,7-naphthyridine
(22). To a solution of 4-isopropoxy-2-(morpholin-4-yl)-8-
[1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-5-yl]-1,7-
naphthyridine (135 mg, 319 µmol) in MeOH (10 mL) was
added 2 M aqueous HCl (3 mL) and the mixture was stirred
for 1 h at rt. The mixture was concentrated under reduced
pressure, and to the residue was added saturated NaHCO3
solution. The aqueous phase was extracted with DCM. The
combined organic phases were dried over Na2SO4 and then
concentrated to dryness. The residue was purified by flash
chromatography (silica gel, DCM/MeOH 95:5) to give 22.
Yield: 29 mg (27%). LC-MS [Method 4]: Rt = 0.62 min. MS
(ESI+): m/z = 340.2 [M+H]+. 1H NMR (400 MHz, CDCl3): δ =
8.28–8.29 (m, 2H, imidazole, naphthyridine), 7.76 (s, 1H,
imidazole), 7.66 (d, J = 5.6 Hz, 1H, naphthyridine), 6.40 (s,
1H, naphthyridine), 4.78 (spt, J = 6.4 Hz, 1H, CH), 3.90–3.92
(m, 4H, morpholine), 3.68–3.70 (m, 4H, morpholine), 1.48
(d, J = 6.4 Hz, 6H, iPr), NH not visible. 13C NMR (101 MHz,
DMSO-d6): δ = 159.9, 159.6, 145.8, 139.7, 138.7, 136.6,
4-Isopropoxy-2-(morpholin-4-yl)-8-(1H-pyrrol-3-
yl)-1,7-naphthyridine (20). Under argon, [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(1:1 complex with DCM; 13 mg, 16 µmol) was added to a
mixture of 8-chloro-4-isopropoxy-2-(morpholin-4-yl)-1,7-
naphthyridine (50 mg, 0.16 mmol) and 3-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole
(CAS
214360-77-7, 34 mg, 0.18 mmol) in MeCN (1.5 mL) and 2 M
aqueous K2CO3 (1.5 mL). The mixture was stirred at 130 °C
in a microwave oven for 10 min. After cooling, DCM was
added and the mixture was filtered using a Whatman filter
paper. The organic phase was concentrated and the residue
was purified by preparative HPLC (acidic conditions) to give
20. Yield: 5 mg (9%). LC-MS [Method 4]: Rt = 0.62 min. MS
1
(ESI+): m/z = 339.2 [M+H]+. H NMR (400 MHz, DMSO-d6):
δ = 10.95 (br s, 1H, pyrrole-NH), 8.19 (d, J = 5.56 Hz, 1H,
naphthyridine), 8.07–8.10 (m, 1H, pyrrole), 7.45 (d, J = 5.31
Hz, 1H, naphthyridine), 6.99–7.02 (m, 1H, pyrrole), 6.81 (s,
1H, pyrrole), 6.79 (s, 1H, naphthyridine), 5.03 (quin, J = 6.06
Hz, 1H, CH), 3.75–3.83 (m, 4H, CH2O), 3.63–3.74 (m, 4H,
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Journal of Medicinal Chemistry
131.6, 130.1, 122.1, 112.6, 93.2, 70.5, 66.0, 45.6, 21.5. HRMS
(morpholin-4-yl)-1,7-naphthyridine (75 mg, 244 µmol) and
2
3
4
5
6
7
8
9
(ESI, [M+H]+): calcd for C18H22N5O2, 340.1773; found,
340.1792.
(1-methyl-1H-pyrazol-5-yl)boronic acid (CAS 720702-41-0,
34 mg, 268 µmol). Yield: 1 mg (1%), after preparative HPLC
(acidic conditions). LC-MS [Method 1]: Rt = 1.06 min. MS
(ESI+): m/z = 354.3 [M+H]+. 1H NMR (400 MHz, CDCl3):
δ = 8.42 (d, J = 5.32 Hz, 1H, naphthyridine), 7.81 (d, J = 5.32
Hz, 1H, naphthyridine), 7.59 (d, J = 1.77 Hz, 1H, pyrazole),
6.92 (d, J = 1.77 Hz, 1H, pyrazole), 6.38 (s, 1H, naph-
thyridine), 4.81 (td, J = 6.08, 12.17 Hz, 1H, CH), 4.06 (s, 3H,
CH3), 3.78–3.84 (m, 4H, morpholine), 3.64–3.70 (m, 4H,
morpholine), 1.51 (d, J = 6.08 Hz, 6H, iPr).
4-Isopropoxy-2-(morpholin-4-yl)-8-(1H-pyrazol-4-
yl)-1,7-naphthyridine (23). Step a: 2-(Morpholin-4-yl)-
8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-1,7-
naphthyridin-4-ol was prepared using an analogous
method as described for 22 (step a), from 8-chloro-2-
(morpholin-4-yl)-1,7-naphthyridin-4-ol (58) (2.0 g, 7.53
mmol)
and
1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-
(CAS
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
1
1003846-21-6, 3.14 g, 11.3 mmol). Yield: 1.4 g (49%). H
NMR (400 MHz, DMSO-d6): δ = 11.38 (s, 1H), 8.79 (s, 1H),
8.37 (s, 1H), 8.23 (d, J = 5.09 Hz, 1H), 7.61 (d, J = 5.09 Hz,
1H), 6.64 (s, 1H), 5.50 (m, 1H), 3.95 (m, 1H), 3.79 (m, 4H),
3.67 (m, 1H), 3.60 (m, 4H), 2.03 (m, 3H), 1.70 (m, 1H), 1.56
(m, 2H). Step b: 4-Isopropoxy-2-(morpholin-4-yl)-8-[1-
(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-1,7-
naphthyridine was prepared using an analogous method
as described for 60, from 2-(morpholin-4-yl)-8-[1-
(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-1,7-
4-Isopropoxy-8-(5-methyl-1H-pyrazol-3-yl)-2-
(morpholin-4-yl)-1,7-naphthyridine (26). The title
compound was prepared using an analogous method as
described for 20, from 8-chloro-4-isopropoxy-2-
(morpholin-4-yl)-1,7-naphthyridine (75 mg, 244 µmol) and
(5-methyl-1H-pyrazol-3-yl)boronic acid (CAS 1163248-54-
1, 34 mg, 268 µmol). Yield: 7 mg (8%). LC-MS [Method 4]: Rt
1
= 0.71 min. MS (ESI+): m/z = 354.3 [M+H]+. H NMR (400
MHz, DMSO-d6): δ = 8.22 (d, J = 5.30 Hz, 1H, naphthyridine),
7.85 (d, J = 5.31 Hz, 1H, naphthyridine), 7.54 (d, J = 1.52 Hz,
1H, pyrazole), 6.81 (s, 1H, naphthyridine), 6.22 (s, 1H,
pyrazole-NH), 5.07 (td, J = 5.97, 12.06 Hz, 1H, CH), 3.59–3.70
(m, 4H, morpholine), 3.51–3.58 (m, 4H, morpholine), 2.08
(s, 3H, CH3), 1.41 (d, J = 6.06 Hz, 6H, iPr).
4-Isopropoxy-8-(6-methoxypyridin-2-yl)-2-
(morpholin-4-yl)-1,7-naphthyridine (27). 8-Chloro-4-
mg, 227 µmol). Yield: 58 mg (77%). LC-MS [Method 4]: Rt =
0.62 min. MS (ESI+): m/z = 340.3 [M+H]+. 1H NMR (400
MHz, DMSO-d6): δ = 12.95 (s, 1H, pyrazole-NH), 8.66 (s, 1H,
pyrazole), 8.40 (s, 1H, pyrazole), 8.23 (d, J = 5.09 Hz, 1H,
naphthyridine), 7.55 (d, J = 5.09 Hz, 1H, naphthyridine),
6.84 (s, 1H, naphthyridine), 5.04 (m, 1H, CH), 3.79 (m, 4H,
morpholine), 3.69 (m, 4H, morpholine), 1.40 (m, 6H, iPr).
13C NMR (101 MHz, DMSO-d6): δ = 159.9, 159.5, 149.3,
139.9, 139.1, 129.8, 122.0, 120.5, 112.1, 93.1, 70.4, 66.1,
45.7, 21.5. HRMS (ESI, [M+H]+): calcd for C18H22N5O2,
340.1773; found, 340.1770.
isopropoxy-2-(morpholin-4-yl)-1,7-naphthyridine
(209
mg, 679 µmol), 2-(6-methoxypyridin-2-yl)-6-methyl-
1,3,6,2-dioxazaborocane-4,8-dione (CAS 1227700-45-9,
897 mg, 3.4 mmol), K2CO3 (469 mg, 3.40 mmol), copper(II)
acetate monohydrate (61.7 mg, 310 µmol), palladium(II)
acetate
(7.62
mg,
34.0
µmol),
tris(dibenzylideneacetone)dipalladium(0) (62.2 mg, 67.9
µmol), and dicyclohexyl[2',4',6'-tri(propan-2-yl)biphenyl-
2-yl]phosphane (XPhos, 129 mg, 272 µmol) were stirred in
DMF (3.1 mL) and isopropyl alcohol (780 µL) for 20 h at
100 °C and for 1 h at 100 °C in a microwave reactor. The
mixture was filtered, washed with EtOAc and MeOH, and the
filtrate was concentrated under reduced pressure. 250 mg
from the residue was purified by preparative HPLC (acidic
conditions) to give 27. Yield: 5 mg (2%). LC-MS [Method 4]:
Rt = 0.66 min. MS (ESI+): m/z = 381.2 [M+H]+. 1H NMR (400
MHz, CD2Cl2): δ = 8.35 (d, J = 5.32 Hz, 1H, pyridine), 7.78 (d,
J = 5.32 Hz, 1H, pyridine), 7.63 (t, J = 7.69 Hz, 1H, pyridine),
7.45 (d, J = 7.03 Hz, 1H, pyridine), 6.72 (d, J = 8.11 Hz, 1H,
pyridine), 6.34 (s, 1H, pyridine), 4.77 (spt, J = 6.04 Hz, 1H,
CH), 3.90 (s, 3H, OCH3), 3.68–3.74 (m, 4H, morpholine),
3.49–3.56 (m, 4H, morpholine), 1.43 (d, J = 6.08 Hz, 6H, iPr).
4-Isopropoxy-8-(4-methyl-1H-pyrazol-5-yl)-2-
(morpholin-4-yl)-1,7-naphthyridine (24). The title
compound was prepared using an analogous method as
described for 20, from 8-chloro-4-isopropoxy-2-
(morpholin-4-yl)-1,7-naphthyridine (50 mg, 162 µmol) and
(4-methyl-1H-pyrazol-5-yl)boronic acid (CAS 1562244-77-
2, 31 mg, 244 µmol). Yield: 16 mg (28%). LC-MS [Method 4]:
Rt = 0.67 min. MS (ESI+): m/z = 354.3 [M+H]+. 1H NMR (500
MHz, DMSO-d6): δ = 13.20 (br s, 1H, pyrazole-NH), 8.36 (br
d, J = 5.09 Hz, 1H, naphthyridine), 7.67 (d, J = 5.09 Hz, 1H,
naphthyridine), 7.42 (br s, 1H, pyrazole), 6.86 (br s, 1H,
naphthyridine), 5.04–5.11 (m, 1H, CH), 3.77 (br s, 4H,
morpholine), 3.68 (br s, 4H, morpholine), 2.23–2.40 (m, 3H,
CH3), 1.41 (d, J = 6.04 Hz, 6H, iPr). 13C NMR (101 MHz,
DMSO-d6): δ = 160.0, 159.4, 146.3, 140.8, 140.0, 139.2,
137.4, 122.2, 115.7, 113.5, 93.1, 70.7, 66.0, 45.3, 21.5, 10.8.
HRMS (ESI, [M+H]+): calcd for C19H24N5O2, 354.1930; found,
354.1925.
3-[4-Isopropoxy-2-(morpholin-4-yl)-1,7-
naphthyridin-8-yl]benzamide (28). The title compound
was prepared using an analogous method as described for
22 (step a), from 8-chloro-4-isopropoxy-2-(morpholin-4-
yl)-1,7-naphthyridine (200 mg, 650 µmol) and (3-
carbamoylphenyl)boronic acid (CAS 351422-73-6, 161 mg,
975 µmol). Yield: 177 mg (66%). LC-MS [Method 4]: Rt =
0.68 min. MS (ESI+): m/z = 393.3 [M+H]+. 1H NMR (400 MHz,
DMSO-d6): δ = 8.80 (s, 1H, phenyl), 8.37 (d, J = 5.34 Hz, 1H,
naphthyridine), 8.27 (m, 1H, phenyl), 7.97 (s, 1H, NH), 7.90
(d, J = 5.38 Hz, 1H, naphthyridine), 7.72 (m, 1H, phenyl),
4-Isopropoxy-8-(1-methyl-1H-pyrazol-5-yl)-2-
(morpholin-4-yl)-1,7-naphthyridine (25). The title
compound was prepared using an analogous method as
described for 20, from 8-chloro-4-isopropoxy-2-
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2
3
4
5
6
7
8
7.52 (m, 1H, phenyl), 7.31 (s, 1H, NH), 6.82 (s, 1H, naph-
Tetrakis(triphenylphosphine)palladium(0) (22.5 mg, 19.5
thyridine), 5.06 (m, 1H, CH), 3.68 (m, 8H, morpholine), 1.41
(m, 6H, iPr). 13C NMR (101 MHz, DMSO-d6): δ = 168.1, 160.0,
158.9, 153.7, 141.1, 139.1, 139.0, 133.5, 133.1, 130.3, 127.2,
127.0, 122.3, 114.3, 92.5, 70.5, 66.1, 45.3, 21.5. HRMS (ESI,
[M+H]+): calcd for C22H25N4O3, 393.1927; found, 393.1918.
µmol) was added under argon and the mixture was stirred
for 3 h at 130 °C. Saturated NaHCO3 solution was added, the
mixture was extracted with DCM, and the collected organic
phases were dried over sodium sulfate and concentrated
under reduced pressure. The residue was purified by flash
chromatography (silica gel, CHCl3/MeOH 50:1) to give 4-
isopropoxy-2-(morpholin-4-yl)-1,7-naphthyridine-8-
carbonitrile. Yield: 188 mg (97%). 1H NMR (400 MHz,
CDCl3): δ = 8.33 (d, J = 5.17 Hz, 1H), 7.89 (d, J = 5.22 Hz, 1H),
6.35 (s, 1H), 4.79 (m, 1H), 3.82 (m, 8H), 1.48 (m, 6H). Step
b: 4-Isopropoxy-2-(morpholin-4-yl)-8-(1H-tetrazol-5-
yl)-1,7-naphthyridine (31). To a solution of 4-isopropoxy-
2-(morpholin-4-yl)-1,7-naphthyridine-8-carbonitrile (184
mg, 617 µmol) in DMF (10 mL) were added sodium azide
(180 mg, 2.8 mmol) and ammonium chloride (147 mg, 2.8
mmol). The mixture was stirred at 125 °C for 6 d. The
suspension was filtered and the fitrate was concentrated
under reduced pressure. Citric acid (10%) was added, the
mixture was extracted with CHCl3, and the combined
organic phases were dried over sodium sulfate and
concentrated under reduced pressure. The residue was
purified by flash chromatography (silica gel, DCM/MeOH
9:1) to give 31. Yield: 25 mg (12%). LC-MS [Method 4]: Rt =
0.62 min. MS (ESI+): m/z = 342.2 [M+H]+. 1H NMR (400
MHz, DMSO-d6): δ = 8.43 (d, J = 5.21 Hz, 1H, naphthyridine),
7.91 (d, J = 5.11 Hz, 1H, naphthyridine), 6.87 (s, 1H, naph-
thyridine), 5.71 (s, 1H, NH), 5.10 (m, 1H, CH), 3.72 (br s, 8H,
morpholine), 1.41 (m, 6H, iPr). 13C NMR (101 MHz, DMSO-
d6): δ = 159.7, 159.4, 159.1, 141.6, 139.2, 122.7, 117.2, 93.2,
70.9, 66.1, 45.0, 36.0, 21.4. HRMS (ESI, [M+H]+): calcd for
C16H20N7O2, 342.1678; found, 342.1670.
4-Isopropoxy-2-(morpholin-4-yl)-8-(pyridin-3-yl)-
1,7-naphthyridine (29). The title compound was prepared
using an analogous method as described for 6 (step d), from
8-chloro-4-isopropoxy-2-(morpholin-4-yl)-1,7-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
naphthyridine (100 mg, 325 µmol) and pyridin-3-ylboronic
acid (CAS 1692-25-7, 60 mg, 487 µmol). Yield: 61.5 mg
(54%). LC-MS [Method 4]: Rt = 0.69 min. MS (ESI+): m/z =
351.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ = 9.30 (dd, J
= 0.76, 2.02 Hz, 1H, pyridine), 8.58 (dd, J = 1.77, 4.80 Hz, 1H,
pyridine), 8.48 (td, J = 1.86, 8.15 Hz, 1H, pyridine), 8.39 (d, J
= 5.31 Hz, 1H, pyridine), 7.75 (d, J = 5.31 Hz, 1H, pyridine),
7.49 (ddd, J = 0.76, 4.80, 8.08 Hz, 1H, pyrdidine), 6.84 (s, 1H,
pyridine), 5.07 (td, J = 5.97, 12.06 Hz, 1H, CH), 3.62–3.74 (m,
8H, morpholine), 1.41 (d, J = 5.81 Hz, 6H, iPr). 13C NMR (101
MHz, DMSO-d6): δ = 160.0, 159.2, 151.9, 150.9, 148.7, 141.2,
139.3, 137.6, 134.7, 122.7, 122.4, 114.7, 92.7, 70.6, 66.0,
45.2, 21.5. HRMS (ESI, [M+H]+): calcd for C20H23N4O2,
351.1821; found, 351.1819.
8-(1H-Indol-2-yl)-4-isopropoxy-2-(morpholin-4-yl)-
1,7-naphthyridine
(30).
8-Chloro-4-isopropoxy-2-
(morpholin-4-yl)-1,7-naphthyridine (144 mg, 468 µmol),
tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
1H-indole-1-carboxylate (CAS 1072944-96-7, 241 mg, 702
µmol), and tetrakis(triphenylphosphine)palladium(0) (108
mg, 93.6 µmol) were stirred in DMF (4 mL) and 2 M aqueous
Na2CO3 (580 µL, 1.2 mmol) for 20 h at 100 °C. The mixture
was filtered, washed with EtOAc and MeOH, and the filtrate
was concentrated under reduced pressure. The residue was
dissolved in DCM, and TFA (1.8 mL, 23 mmol) was added.
The mixture was stirred for 16 h at rt. Saturated NaHCO3
solution was added, the mixture was extracted with DCM,
and the collected organic phases were dried over sodium
sulfate and concentrated under reduced pressure. The
residue was purified by preparative HPLC (acidic
conditions) to give 30. Yield: 31.5 mg (17%). LC-MS
[Method 4]: Rt = 0.86 min. MS (ESI+): m/z = 389.3 [M+H]+.
1H NMR (400 MHz, DMSO-d6): δ = 11.68 (s, 1H, indole-NH),
8.35 (d, J = 5.32 Hz, 1H, naphthyridine), 7.87 (d, J = 1.01 Hz,
1H, indole), 7.67 (d, J = 5.49 Hz, 1H, naphthyridine), 7.63 (d,
J = 8.21 Hz, 1H, indole), 7.52 (dd, J = 0.76, 8.11 Hz, 1H,
indole), 7.13 (ddd, J = 1.14, 6.97, 8.11 Hz, 1H, indole), 6.99
(t, J = 7.40 Hz, 1H, indole), 6.90 (s, 1H, naphthyridine), 5.09
(spt, J = 6.00 Hz, 1H, CH), 3.76–3.88 (m, 8H, morpholine),
1.42 (d, J = 6.08 Hz, 6H, iPr). 13C NMR (101 MHz, DMSO-d6):
δ = 160.0, 159.7, 146.1, 140.7, 138.8, 136.4, 136.1, 128.6,
122.5, 122.4, 121.1, 119.1, 113.4, 111.9, 106.0, 93.2, 70.6,
66.1, 45.7, 21.5. HRMS (ESI, [M+H]+): calcd for C23H25N4O2,
389.1978; found, 389.1984.
3-[4-Isopropoxy-2-(morpholin-4-yl)-1,7-
naphthyridin-8-yl]pyridin-2(1H)-one (32). Step a: 4-
Isopropoxy-8-(2-methoxypyridin-3-yl)-2-(morpholin-
4-yl)-1,7-naphthyridine was prepared using an analogous
method as described for 30, from 8-chloro-4-isopropoxy-2-
(morpholin-4-yl)-1,7-naphthyridine (210 mg, 682 µmol)
and (2-methoxypyridin-3-yl)boronic acid (CAS 163105-90-
6, 157 mg, 1.0 mmol). Yield: 7 mg (3%). 1H NMR (400 MHz,
DMSO-d6): δ = 8.28 (d, J = 5.48 Hz, 1H), 8.23 (d, J = 4.93 Hz,
1H), 7.67–7.72 (m, 2H), 7.07 (dd, J = 4.94, 7.22 Hz, 1H), 6.76
(s, 1H), 5.04 (spt, J = 6.04 Hz, 1H), 3.73–3.80 (m, 3H), 3.59–
3.65 (m, 4H), 3.44–3.51 (m, 4H), 1.40 (d, J = 6.08 Hz, 6H). MS
(ESI+): m/z = 381.2 [M + H]+. Step b: 3-[4-Isopropoxy-2-
(morpholin-4-yl)-1,7-naphthyridin-8-yl]pyridin-
2(1H)-one (32).
A
mixture of 4-isopropoxy-8-(2-
methoxypyridin-3-yl)-2-(morpholin-4-yl)-1,7-
naphthyridine (311 mg, 817 µmol), acetic acid (14 mL, 250
mmol), and hydrobromic acid (2 mL, 37 mmol) was stirred
for 7 h at rt. Saturated NaHCO3 solution was added, the
mixture was extracted with DCM, and the collected organic
phases were dried over sodium sulfate and concentrated
under reduced pressure. The residue was purified by
preparative HPLC (acidic conditions) to give 32. Yield: 115
mg (38%). LC-MS [Method 4]: Rt = 0.61 min. MS (ESI+): m/z
= 367.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ = 11.69 (br
s, 1H, pyridone-NH), 8.24 (d, J = 5.58 Hz, 1H, naphthyridine),
7.67 (d, J = 5.32 Hz, 1H, naphthyridine), 7.49 (br s, 1H,
pyridone), 7.43 (br d, J = 5.32 Hz, 1H, pyridone), 6.74–6.81
(m, 1H, naphthyridine), 6.26 (br t, J = 6.46 Hz, 1H, pyridone),
4-Isopropoxy-2-(morpholin-4-yl)-8-(1H-tetrazol-5-
yl)-1,7-naphthyridine (31). Step a: 4-Isopropoxy-2-
(morpholin-4-yl)-1,7-naphthyridine-8-carbonitrile. 8-
Chloro-4-isopropoxy-2-(morpholin-4-yl)-1,7-
naphthyridine (200 mg, 650 µmol) and zinc cyanide (91.6
mg, 780 µmol) were suspended in DMF (10 mL).
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Journal of Medicinal Chemistry
5.04 (spt, J = 6.00 Hz, 1H, CH), 3.50–3.73 (m, 8H,
reduced pressure to give 34. Yield: 14 mg (52%). LC-MS
2
3
4
5
morpholine), 1.39 (d, J = 5.83 Hz, 6H, iPr). 13C NMR (101
MHz, DMSO-d6): δ = 163.1, 161.2, 159.8, 158.5, 155.0, 141.8,
140.1, 138.6, 135.3, 121.3, 114.1, 104.6, 92.8, 70.4, 66.0,
45.1, 21.5. HRMS (ESI, [M+H]+): calcd for C20H23N4O3,
367.1770; found, 367.1769.
[Method 4]: Rt = 0.62 min. MS (ESI+): m/z = 343.3 [M+H]+.
1H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 5.56 Hz, 1H, naph-
thyridine), 7.69 (d, J = 5.56 Hz, 1H, naphthyridine), 6.37 (s,
1H, naphthyridine), 4.71–4.86 (m, 2H, pyrrolidine, CH),
3.85–3.90 (m, 4H, morpholine), 3.58–3.71 (m, 6H,
morpholine, pyrrolidine), 3.40–3.56 (m, 2H, pyrrolidine),
2.38–2.59 (m, 1H, pyrrolidine), 2.27 (br d, J = 5.05 Hz, 1H,
pyrrolidine), 1.48 (d, J = 6.06 Hz, 6H, iPr), NH not visible.
6
7
8
9
6-[4-Isopropoxy-2-(morpholin-4-yl)-1,7-
naphthyridin-8-yl]pyridin-2(1H)-one (33). The title
compound was prepared using an analogous method as
described for 32 (step b), from 4-isopropoxy-8-(6-
methoxypyridin-2-yl)-2-(morpholin-4-yl)-1,7-
4-Isopropoxy-N-methyl-2-(morpholin-4-yl)-1,7-
naphthyridine-8-carboxamide (35). The title compound
was prepared using an analogous method as described for
21, from 8-chloro-4-isopropoxy-2-(morpholin-4-yl)-1,7-
naphthyridine (150 mg, 487 µmol) and 2 M methanamine
(1.5 mL, 2.9 mmol) in DMSO (6.9 mL). Yield: 35.5 mg (21%).
LC-MS [Method 1]: Rt = 0.52 min. MS (ESI+): m/z = 331.0
[M+H]+. 1H NMR (400 MHz, DMSO-d6): δ = 8.99 (br d, J = 4.82
Hz, 1H, NH), 8.26 (d, J = 5.07 Hz, 1H, naphthyridine), 7.76 (d,
J = 5.32 Hz, 1H, naphthyridine), 6.83 (s, 1H, naphthyridine),
5.01–5.12 (m, 1H, CH), 3.70–3.77 (m, 4H, morpholine),
3.64–3.70 (m, 4H, morpholine), 2.86 (d, J = 4.56 Hz, 3H, CH3),
1.39 (d, J = 6.08 Hz, 6H, iPr). 13C NMR (101 MHz, DMSO-d6):
δ = 166.6, 159.8, 159.0, 150.6, 140.7, 138.5, 122.3, 115.9,
93.0, 70.7, 66.0, 45.2, 25.9, 21.4. HRMS (ESI, [M+H]+): calcd
for C17H23N4O3, 331.1770; found, 331.1766.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
naphthyridine (27) (1.2 g, 3.14 mmol). Yield: 10.8 mg (1%).
LC-MS [Method 1]: Rt = 1.16 min. MS (ESI+): m/z = 367.3
[M+H]+. 1H NMR (400 MHz, CD2Cl2): δ = 13.81–14.00 (m, 1H,
pyridone), 8.34 (d, J = 5.32 Hz, 1H, naphthyridine), 7.80 (d, J
= 5.07 Hz, 1H, naphthyridine), 7.59 (d, J = 7.10 Hz, 1H,
pyridone), 7.46 (dd, J = 7.22, 9.00 Hz, 1H, pyridone), 6.42 (d,
J = 9.07 Hz, 1H, pyridone), 6.37 (s, 1H, naphthyridine), 4.76
(spt, J = 6.00 Hz, 1H, CH), 3.79–3.87 (m, 4H, morpholine),
3.63–3.70 (m, 4H, morpholine), 1.42 (d, J = 6.08 Hz, 6H, iPr).
MS (ESI+): m/z = 367.3 [M + H]+. HRMS (ESI, [M+H]+): calcd
for C20H23N4O3, 367.1770; found, 367.1768.
4-Isopropoxy-2-(morpholin-4-yl)-8-(pyrrolidin-3-
yl)-1,7-naphthyridine (34). Step a: tert-Butyl 4-[4-
isopropoxy-2-(morpholin-4-yl)-1,7-naphthyridin-8-
yl]-2,3-dihydro-1H-pyrrole-1-carboxylate was prepared
using an analogous method as described for 20, from 8-
chloro-4-isopropoxy-2-(morpholin-4-yl)-1,7-
4-Isopropoxy-2-(morpholin-4-yl)-1,7-naphthyridine
(36).
Under
argon,
[1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(1:1 complex with DCM; 53 mg, 65 µmol) and Cs2CO3 (847
mg, 2.60 mmol) were added to a suspension of [3-
(hydroxymethyl)phenyl]boronic acid (CAS 87199-15-3,
148 mg, 975 µmol) and 8-chloro-4-isopropoxy-2-
(morpholin-4-yl)-1,7-naphthyridine (200 mg, 650 µmol) in
anhydrous 1,4-dioxane (5.0 mL). The reaction mixture was
stirred at 130 °C for 6 h and overnight at 100 °C. The
mixture was concentrated under reduced pressure. The
residue was dissolved in MeOH, sodium borohydride was
added, and the mixture was stirred overnight at rt.
Saturated NaHCO3 solution was added, the mixture was
extracted with DCM, and the collected organic phases were
dried over sodium sulfate and concentrated under reduced
pressure. The residue was purified by flash
chromatography (silica gel, CHCl3/MeOH 95:5) and
preparative HPLC, to give 36 as major byproduct. Yield: 100
mg (56%). LC-MS [Method 4]: Rt = 0.61 min. MS (ESI+): m/z
= 274.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ = 8.84 (m,
1H, naphthyridine), 8.23–8.24 (m, 1H, naphthyridine),
7.65–7.67 (m, 1H, naphthyridine), 6.78 (s, 1H, naph-
thyridine), 5.02–5.05 (m, 1H, CH), 3.72–3.74 (m, 4H,
morpholine), 3.68–3.72 (m, 4H, morpholine), 1.38–1.40 (m,
6H, iPr). 13C NMR (101 MHz, DMSO-d6): δ = 159.7, 159.6,
149.5, 143.4, 139.6, 121.2, 114.4, 92.9, 70.5, 66.1, 45.2, 21.5.
HRMS (ESI, [M+H]+): calcd for C15H20N3O2, 274.1556; found,
274.1555.
naphthyridine (120 mg, 390 µmol) and tert-butyl 4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-
pyrrole-1-carboxylate (CAS 1401165-14-7, 127 mg, 429
1
µmol). Yield: 35 mg (20%). H NMR (400 MHz, DMSO-d6):
δ = 8.32 (s, 1H), 8.18 (d, J = 5.31 Hz, 1H), 7.48 (d, J = 5.05 Hz,
1H), 6.83 (s, 1H), 5.03 (quin, J = 6.00 Hz, 1H), 3.63–3.81 (m,
10H), 3.10–3.29 (m, 2H), 1.48 (s, 9H), 1.39 (d, J = 6.06 Hz,
6H). MS (ESI+): m/z = 441.5 [M+H]+. Step b: tert-Butyl 3-
[4-isopropoxy-2-(morpholin-4-yl)-1,7-naphthyridin-8-
yl]pyrrolidine-1-carboxylate. tert-Butyl 4-[4-isopropoxy-
2-(morpholin-4-yl)-1,7-naphthyridin-8-yl]-2,3-dihydro-
1H-pyrrole-1-carboxylate (29 mg, 65.8 µmol) was dissolved
in EtOH (30 mL), 10% palladium on carbon (7 mg, 6.58
µmol) was added, and the mixture was stirred under
hydrogen atmosphere for 3.5 h at rt. The reaction mixture
was filtered through Celite and the filtrate was concentrated
under reduced pressure to give tert-butyl 3-[4-isopropoxy-
2-(morpholin-4-yl)-1,7-naphthyridin-8-yl]pyrrolidine-1-
carboxylate. Yield: 37 mg (quant.). 1H NMR (400 MHz,
DMSO-d6): δ = 8.17 (d, J = 5.56 Hz, 1H), 7.58 (d, J = 5.56 Hz,
1H), 6.79 (s, 1H), 5.03 (td, J = 5.84, 11.81 Hz, 1H), 4.47 (br t,
J = 7.71 Hz, 1H), 3.65–3.88 (m, 10H), 3.48 (br s, 2H), 2.23 (br
d, J = 6.06 Hz, 2H), 1.37–1.42 (m, 15H). MS (ESI+): m/z =
443.4 [M+H]+. Step c: 4-Isopropoxy-2-(morpholin-4-yl)-
8-(pyrrolidin-3-yl)-1,7-naphthyridine (34). To
a
solution of tert-butyl 3-[4-isopropoxy-2-(morpholin-4-yl)-
1,7-naphthyridin-8-yl]pyrrolidine-1-carboxylate (33.0 mg,
74.6 µmol) in DCM (2 mL) was added TFA (1.0 mL, 13
mmol) and the mixture was stirred for 2 h at rt. The mixture
was diluted with H2O and NaHCO3 solution until pH >8. DCM
was added and the mixture was filtered through phase
separator paper. The filtrate was concentrated under
3,3-Dimethyl-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-
(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}butan-2-ol
(37). Step a: Methyl 2-[(3R)-3-methylmorpholin-4-yl]-
8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-
naphthyridine-4-carboxylate. In an autoclave, a mixture
of 2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-
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2
3
4
5
6
7
8
pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl
Diisopropylethylamine (3.1 mL, 18 mmol) and HATU (2.52
trifluoromethanesulfonate (67) (2.527 g, 4.79 mmol), 1,3-
bis(diphenylphosphino)propane (203 mg, 0.48 mmol),
palladium(II) acetate (108 mg, 0.48 mmol), and
triethylamine (1.3 mL, 9.6 mmol) in DMF (34 mL) and
MeOH (18 mL) was purged with carbon monoxide at rt. The
autoclave was pressured with carbon monoxide to 16.5 bar
and the mixture was stirred at rt for 30 min. The autoclave
was depressurized and then pressured with carbon
monoxide to 20.9 bar. The mixture was stirred at 80 °C for
20 h. The autoclave was depressurized and, after cooling,
the mixture was diluted with H2O and extracted with EtOAc
(2 ×). The combined organic phases were dried over sodium
sulfate, filtered, and concentrated. The residue was purified
by column chromatography (gradient: 100% hexane to
100% EtOAc) to give methyl 2-[(3R)-3-methylmorpholin-4-
yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-
naphthyridine-4-carboxylate. Yield: 1.537 g (73%). 1H NMR
(400 MHz, DMSO-d6): δ = 11.50 (s, 1H), 8.33 (d, J = 5.32 Hz,
1H), 7.77 (d, J = 5.32 Hz, 1H), 7.60 (d, J = 1.77 Hz, 1H), 6.91
(dd, J = 1.77, 15.46 Hz, 1H), 6.59 (d, J = 4.31 Hz, 1H), 6.02–
6.17 (m, 1H), 4.20–4.38 (m, 1H), 3.90–4.03 (m, 2H), 3.67–
3.77 (m, 2H), 3.57–3.65 (m, 1H), 3.34 (s, 3H), 3.20–3.29 (m,
1H), 3.08–3.20 (m, 1H), 2.26–2.40 (m, 1H), 1.89–1.99 (m,
2H), 1.52–1.65 (m, 1H), 1.39–1.49 (m, 2H), 1.15–1.21 (m,
3H). MS (ESI+): m/z = 438.2 [M+H]+. Step b: 2-[(3R)-3-
Methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-
yl)-1H-pyrazol-5-yl]-1,7-naphthyridine-4-carboxylic
g, 6.62 mmol) were added again and the reaction mixture
was stirred for 16 h at rt. H2O was added and the mixture
was stirred for 10 min. The aqueous phase was extracted
with EtOAc and the combined organic layers were washed
with half-saturated NaCl solution. The organic layer was
dried (silicon filter) and concentrated under reduced
pressure. The crude material was purified by flash column
chromatograpy (from hexane/EtOAc gradient 0–100% to
EtOAc/EtOH gradient 0–20%) to give N-methoxy-N-
methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-
naphthyridine-4-carboxamide. Yield: 1.05 g (quant.). 1H
NMR (400 MHz, DMSO-d6): δ = 8.40 (d, J = 5.32 Hz, 1H), 7.63
(s, 1H), 7.60 (d, J = 3.88 Hz, 1H), 7.43 (d, J = 5.32 Hz, 1H),
6.96 (dd, J = 1.77, 15.46 Hz, 1H), 6.06–6.14 (m, 1H), 4.51 (br
t, J = 6.59 Hz, 1H), 4.10–4.20 (m, 1H), 3.93–4.01 (m, 1H),
3.60–3.77 (m, 3H), 3.46–3.56 (m, 3H), 3.38–3.45 (m, 2H),
3.15–3.30 (m, 2H), 2.67–2.70 (m, 3H), 2.31–2.46 (m, 1H),
1.93–1.98 (m, 1H), 1.40–1.64 (m, 3H), 1.18–1.25 (m, 3H). MS
(ESI+): m/z
=
467.5 [M+H]+. Step d: 1-{2-[(3R)-3-
Methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-
yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}ethanone.
N-Methoxy-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-
[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-
naphthyridine-4-carboxamide (710 mg, 1.52 mmol) was
dissolved in THF (20 mL) and the mixture was cooled to
0 °C. 3.0 M MeMgBr in diethylether (1.5 mL, 4.6 mmol) was
added dropwise and the reaction mixture was stirred at 0 °C
for 30 min and at rt for 1.5 h. Additional 3.0 M MeMgBr in
diethylether (1.5 mL, 4.6 mmol) was added and the reaction
mixture was stirred for 16 h. The reaction was quenched
with saturated ammonium chloride solution and the
mixture was extracted with DCM. The organic phase was
filtered and concentrated under reduced pressure to give 1-
{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-
pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-
yl}ethanone, which was used without further purification.
1H NMR (400 MHz, DMSO-d6): δ = 8.41 (d, J = 5.58 Hz, 1H),
7.95 (d, J = 5.58 Hz, 1H), 7.84 (d, J = 3.04 Hz, 1H), 7.62 (t, J =
1.52 Hz, 1H), 6.87 (dd, J = 1.77, 14.19 Hz, 1H), 5.96–6.06 (m,
1H), 4.50–4.62 (m, 1H), 4.17 (br d, J = 13.18 Hz, 1H), 3.94–
4.02 (m, 1H), 3.57–3.80 (m, 5H), 3.41–3.55 (m, 1H), 3.19–
3.32 (m, 2H), 1.89–2.03 (m, 2H), 1.73–1.80 (m, 2H), 1.39–
1.62 (m, 3H), 1.22 (dd, J = 6.72, 14.32 Hz, 3H). MS (ESI+):
m/z = 422.3 [M+H]+. Step e: 3,3-Dimethyl-2-{2-[(3R)-3-
methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-
acid.
Methyl
2-[(3R)-3-methylmorpholin-4-yl]-8-[1-
(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naph-
thyridine-4-carboxylate (1.10 g, 2.51 mmol) was dissolved
in THF (11 mL) and MeOH (5 mL). 1.0 M Aqueous NaOH
(2.8 mL, 2.8 mmol) was added and the mixture was stirred
for 10 min at rt. The solvent was removed under reduced
pressure and the aqueous phase was acidified to pH 5 using
1 M aqueous HCl. The aqueous solution was lyophilized to
give 2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-
2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine-4-
carboxylic acid, without further purification. Yield: 1.10 g
(quant.). 1H NMR (400 MHz, DMSO-d6): δ = 8.45 (dd, J = 2.15,
5.45 Hz, 1H), 8.30 (d, J = 4.82 Hz, 1H), 7.54–7.63 (m, 1H),
7.41 (d, J = 5.07 Hz, 1H), 6.83 (dd, J = 1.77, 10.65 Hz, 1H),
5.94–6.05 (m, 1H), 4.36–4.48 (m, 1H), 4.06 (br t, J = 14.32
Hz, 1H), 3.94 (td, J = 3.93, 11.15 Hz, 1H), 3.67–3.76 (m, 2H),
3.58–3.67 (m, 1H), 3.37–3.51 (m, 1H), 3.09–3.29 (m, 2H),
2.31–2.41 (m, 1H), 1.89–2.01 (m, 2H), 1.38–1.63 (m, 3H),
1.18 (dd, J = 6.59, 10.14 Hz, 3H), OH not visible. MS (ESI+):
m/z = 424.0 [M+H]+. Step c: N-Methoxy-N-methyl-2-
[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-
pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine-4-
carboxamide. N-Methoxymethanamine hydrochloride
(1:1) (861 mg, 8.83 mmol) was dissolved in DMF (20 mL).
N,N-Diisopropylethylamine (3.1 mL, 18 mmol) and N-
[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-
yloxy)methylidene]-N-methylmethanaminium
naphthyridin-4-yl}butan-2-ol
(37).
1-{2-[(3R)-3-
Methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-
1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}ethanone (100 mg,
237 µmol) was dissolved in THF (2.0 mL) and the mixture
was cooled to 0 °C. 1.0 M tBuMgCl in THF (710 µL, 710
µmol) was added dropwise. The mixture was stirred at 0 °C
for 0.5 h and at rt for 1.5 h. The reaction was quenched with
H2O and 3 M aqueous HCl (0.5 mL) was added. The mixture
was stirred for 72 h at rt. The reaction was quenched with
NaHCO3 solution and the mixture was extracted with DCM.
The organic phase was dried (silicon filter) and
concentrated under reduced pressure. The crude material
was purified by preparative HPLC (basic conditions) to give
3,3-dimethyl-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-
hexafluorophosphate (HATU, 2.52 g, 6.62 mmol) were
added and the mixture was stirred for 10 min at rt. 2-[(3R)-
3-Methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-
yl)-1H-pyrazol-5-yl]-1,7-naphthyridine-4-carboxylic acid
(1.10 g, 2.21 mmol with 85% purity) was then added and
the mixture was stirred for 16
h
at rt. N,N-
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Journal of Medicinal Chemistry
pyrazol-5-yl)-1,7-naphthyridin-4-yl}butan-2-ol
as
a
yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-
naphthyridine (267 mg, 0.49 mmol) in MeOH (2.3 mL) and
2 N aqueous HCl (0.57 mL) was stirred for 1 h at rt. The
reaction mixture was diluted with saturated aqueous
NaHCO3 solution and extracted with EtOAc/THF (1:1) (2 ×).
2
3
4
5
6
7
8
9
mixture of diastereomers. Yield: 25 mg (24%). 1H NMR (400
MHz, DMSO-d6): δ = 13.31 (br s, 1H), 8.88–8.97 (m, 1H), 8.26
(d, J = 5.58 Hz, 1H), 7.59 (s, 1H), 7.32 (br s, 1H), 7.11 (br s,
1H), 5.59 (s, 1H), 4.53 (br s, 1H), 3.98–4.17 (m, 2H), 3.68–
3.87 (m, 2H), 3.58 (br t, J = 11.28 Hz, 1H), 3.23–3.32 (m, 1H),
1.70 (s, 3H), 1.17–1.28 (m, 3H), 0.95 (s, 9H). MS (ESI+): m/z
= 396.3 [M+H]+. Step f: (2S)-3,3-Dimethyl-2-{2-[(3R)-3-
methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-
The combined organic phases were filtered using
a
Whatman filter paper and then concentrated to dryness.
The residue was purified by preparative HPLC (basic
conditions) to give 38. Yield: 55 mg (24%). LC-MS [Method
1
naphthyridin-4-yl}butan-2-ol (37). The diastereomers of
3,3-dimethyl-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-
pyrazol-5-yl)-1,7-naphthyridin-4-yl}butan-2-ol (37) (210
mg) were separated by preparative chiral HPLC to give 3,3-
dimethyl-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-
pyrazol-5-yl)-1,7-naphthyridin-4-yl}butan-2-ol (37, single
diastereomer with unknown configuration of the alcohol
stereogenic center; 26 mg). Preparative chiral HPLC
method: instrument: Labomatic HD5000, Labocord-5000,
Gilson GX-241, Labcol Vario 4000; column: Chiralpak AD-H
4]: Rt = 0.60 min. MS (ESI+): m/z = 458.3 [M+H]+. H NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(400 MHz, DMSO-d6): δ = 13.21 (br s, 1H, pyrazole-NH), 8.32
(d, J = 5.32 Hz, 1H, naphthyridine), 7.63 (d, J = 5.22 Hz, 1H,
naphthyridine), 7.61 (s, 1H, pyrazole), 7.34 (d, J = 1.77 Hz,
1H, pyrazole), 6.83 (s, 1H, naphthyridine), 4.59 (br d, J =
4.56 Hz, 1H, morpholine), 4.13 (br d, J = 11.66 Hz, 1H,
morpholine), 4.04 (dd, J = 3.30, 11.41 Hz, 1H, morpholine),
3.82 (d, J = 11.41 Hz, 1H, morpholine), 3.69 (dd, J = 2.79,
11.41 Hz, 1H, morpholine), 3.54 (dt, J = 2.79, 11.79 Hz, 1H,
morpholine), 3.37–3.45 (m, 4H, piperazine), 3.22–3.31 (m,
5H, piperazine, morpholine), 3.00 (s, 3H, CH3), 1.27 (d, J =
6.84 Hz, 3H, CH3). 13C NMR (101 MHz, DMSO-d6): δ = 158.0,
156.3, 145.5, 140.8, 140.7, 139.0, 138.5, 123.2, 115.9, 107.5,
101.1, 70.5, 66.3, 51.1, 47.3, 45.5, 34.1, 13.2, one carbon not
visible (under solvent). HRMS (ESI, [M+H]+): calcd for
C21H28N7O3S, 458.1974; found, 458.1972. [α]20D –68.80 (c =
1, DMSO).
5µm, 250 × 30 mm; eluent A: hexane
+ 0.1 vol%
diethylamine (99%), eluent B: EtOH; isocratic: 90% A +
10% B; flow: 40.0 mL/min; UV 280 nm. Analytical chiral
HPLC method: instrument: Agilent HPLC 1260; column:
Chiralpak AD-H 5µm, 150 × 4.6 mm; eluent A: hexane + 0.1
vol% diethylamine (99%), eluent B: EtOH; isocratic: 90% A
+ 10% B; flow: 1.4 mL/min; temperature: 25 °C; DAD 280
t
nm; R = 3.97 min. LC-MS [Method 4]: Rt = 0.66 min. MS
4-(2-Fluoropyridin-3-yl)-2-[(3R)-3-
(ESI+): m/z = 396.3 [M+H]+. H NMR (400 MHz, DMSO-d6):
1
methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naph-
thyridine (39). 2-[(3R)-3-Methylmorpholin-4-yl]-8-[1-
(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-
δ = 13.30 (br s, 1H, pyrazole-NH), 8.92 (br d, J = 5.07 Hz, 1H,
naphthyridine), 8.26 (d, J = 5.58 Hz, 1H, naphthyridine),
7.59 (s, 1H, pyrazole), 7.32 (s, 1H, pyrazole), 7.10 (br s, 1H,
naphthyridine), 5.59 (br s, 1H, OH), 4.52 (br s, 1H,
morpholine), 4.00–4.17 (m, 2H, morpholine), 3.82 (br d, J =
11.15 Hz, 1H, morpholine), 3.68–3.77 (m, 1H, morpholine),
3.49–3.66 (m, 1H, morpholine), 3.17–3.31 (m, 1H,
morpholine), 1.71 (br s, 3H, CH3), 1.24 (d, J = 6.59 Hz, 3H,
CH3), 0.95 (s, 9H, tBu). HRMS (ESI, [M+H]+): calcd for
C22H30N5O2, 396.2400; found, 396.2392.
naphthyridin-4-yl trifluoromethanesulfonate (67) (0.25 g,
0.47 mmol) was dissolved in 1,4-dioxane (2.5 mL). (2-
Fluoropyridin-3-yl)boronic acid (CAS 174669-73-9, 0.20 g,
1.4 mmol) was added in one portion followed by the
addition of Cs2CO3 (0.62 g, 1.90 mmol) and [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(1:1 complex with DCM; 77 mg, 94 µmol). The reaction
mixture was heated for 4 h in a sealed tube at 110 °C. The
mixture was then cooled to rt and filtered. The solid was
washed with DCM and the filtrate was concentrated under
reduced pressure. The crude material was purified by flash
column chromatography (gradient of hexane/EtOAc 0-
100% and EtOAc/EtOH 0-20%). The combined product
fractions were concentrated under reduced pressure (~
140 mg), dissolved in MeOH (3 mL), and 3 N aqueous HCl
(10 mL) was added. The mixture was stirred for 2 h at rt and
then basified with 3 M aqueous NaOH. The suspension was
filtered and washed with H2O. The solid was dried under
reduced pressure at 60 °C to give 39. Yield: 109 mg (90%
with 95% purity). LC-MS [Method 4]: Rt = 0.66 min. MS
2-[(3R)-3-Methylmorpholin-4-yl]-4-[4-
(methylsulfonyl)piperazin-1-yl]-8-(1H-pyrazol-5-yl)-
1,7-naphthyridine
Methylmorpholin-4-yl]-4-[4-(methylsulfonyl)-
piperazin-1-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-
pyrazol-5-yl]-1,7-naphthyridine. A mixture of 2-[(3R)-3-
methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-
1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl
trifluoromethanesulfonate (67) (150 mg, 0.28 mmol) and 1-
(methylsulfonyl)piperazine (CAS 55276-43-2, 159 mg, 0.97
mmol) in MeCN (0.42 mL) was stirred at 70 °C for 8 h under
argon. After cooling, the reaction mixture was diluted with
EtOAc and THF, and washed with saturated aqueous NaCl
solution. The organic phase was filtered using a Whatman
filter paper and then concentrated to give 2-[(3R)-3-
methylmorpholin-4-yl]-4-[4-(methylsulfonyl)piperazin-1-
yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-
naphthyridine, which was used in the next step without
further purification. MS (ESI+): m/z = 542.4 [M+H]+. Step b:
2-[(3R)-3-Methylmorpholin-4-yl]-4-[4-
(38).
Step
a:
2-[(3R)-3-
1
(ESI+): m/z = 391.3 [M+H]+. H NMR (400 MHz, DMSO-d6):
δ = 13.44 (br s, 1H, pyrazole-NH), 8.44–8.48 (m, 1H,
pyridine), 8.32 (d, J = 5.32 Hz, 1H, pyridine), 8.18 (ddd, J =
1.90, 7.48, 9.63 Hz, 1H, pyridine), 7.59–7.67 (m, 3H,
pyridine, pyrazole), 7.43 (br s, 1H, pyridine), 7.17 (dd, J =
1.77, 5.32 Hz, 1H, pyrazole), 4.63 (br d, J = 4.56 Hz, 1H,
morpholine), 4.22 (br d, J = 12.17 Hz, 1H, morpholine),
3.98–4.10 (m, 1H, morpholine), 3.76–3.87 (m, 1H,
morpholine), 3.67–3.76 (m, 1H, morpholine), 3.50–3.63 (m,
1H, morpholine), 3.38 (br s, 1H, morpholine), 1.30 (d, J =
6.84 Hz, 3H, CH3). HRMS (ESI, [M + H]+): calcd for
(methylsulfonyl)piperazin-1-yl]-8-(1H-pyrazol-5-yl)-
1,7-naphthyridine (38). A solution of crude 2-[(3R)-3-
methylmorpholin-4-yl]-4-[4-(methylsulfonyl)piperazin-1-
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