The discovery and evaluation of 3-amino-2(1H)-pyrazinones as a novel series of selective p38α MAP kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2020.127412

The discovery and optimisation of a novel series of potent and selective p38α inhibitors is described. Evaluating the structure-activity relationship of an aminoalkyl substituent at the 3 position of the 2(1H)-pyrazinone core, p38α potency was increased 20000-fold. The most advanced compound (25) demonstrated excellent in vivo properties suitable for an inhaled route of administration.

Full text of DOI:10.1016/j.bmcl.2020.127412

Bioorganic&MedicinalChemistryLetters30(2020)127412
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The discovery and evaluation of 3-amino-2(1H)-pyrazinones as a novel
series of selective p38α MAP kinase inhibitors
⁎
Piotr Rauboa,b, , Richard Evansb, Paul Willisb
a Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK
b AstraZeneca R&D Charnwood, Loughborough, UK
A R T I C L E I N F O
A B S T R A C T
Keywords:
P38α
The discovery and optimisation of a novel series of potent and selective p38α inhibitors is described. Evaluating
the structure-activity relationship of an aminoalkyl substituent at the 3 position of the 2(1H)-pyrazinone core,
p38α potency was increased 20000-fold. The most advanced compound (25) demonstrated excellent in vivo
properties suitable for an inhaled route of administration.
Kinases
Inflammation
COPD
AZD6703
AZD7624
The p38α mitogen-activated protein kinase (MAPK) is a proline-
directed serine/threonine kinase which plays a central role in the reg-
ulation of pro-inflammatory signalling, biosynthesis and activity of key
pro-inflammatory cytokines, including tumour necrosis factor alpha
(TNF-α) and interleukin-1b (IL-1β). It belongs to the p38 kinase family,
comprising 4 isoforms (p38α, p38β, p38γ, p38δ). Since its discovery in
1994,1 the p38α MAPK gained significant attention as a potential target
for the treatment of a number of diseases, such as rheumatoid arthritis,2
psoriasis,3 Crohn’s disease,2 chronic obstructive pulmonary disease
(COPD),4 asthma,5 and cancer.6 As a consequence of the important role
of mitogen-activated protein kinases in modulation of pro-in-
flammatory signalling, a number of highly selective inhibitors of p38 α
have been developed and advanced to clinical trials in inflammatory
diseases,7 such as rheumatoid arthritis or COPD.2,4 However, despite
demonstrating preclinical and clinical efficacy, development of several
structurally diverse oral p38α inhibitors e.g. BIRB-796, PH-797804,
losmapimod (Fig. 1) and AZD6703 (Fig. 2) was discontinued due to
adverse effects or lack of sustained efficacy.2a To improve the ther-
apeutic index, an inhaled route of delivery of p38α inhibitors has been
explored, with several inhaled p38α inhibitors such as JNJ-49095397
(RV568), PF-03715455 and AZD7624 (Fig. 1) being tested in clinical
trials in COPD or asthmatic patients.4 The need for more effective anti-
inflammatory agents to test the role of p38α inhibition in treatment of
COPD has long been recognised and pursued by a number of pharma-
ceutical companies.4a
core. At the outset, potent DFG-out (type II) inhibitors7d were explored
as represented by the generic structure of anilinoquinazolinone 1
(Fig. 2). However, despite excellent potency in a p38α enzyme assay
such inhibitors failed to deliver sufficient potency in the cell based
assay (pIC50 < 8.0) which in turn translated to a higher predicted
efficacious dose in human. In contrast, the oral DFG-in inhibitor
AZD6703, exhibited similar potency in the enzyme assay (IC50 16 nM)
and the whole blood assay (IC50 27 nM).7d However, the predicted ef-
ficacious dose in human for AZD6703 was too high for a dry powder
inhaler delivery. Taking all the above into account, we began searching
for new chemical equity that could deliver novel potent p38 α in-
hibitors with a suitable profile for an inhaled drug candidate.
We hypothesised that the removal of the fused phenyl ring of the
quinazolinone scaffold in AZD6703 might lead to analogous hetero-
cyclic structures such as the pyrimidone 2 or related the pyrazinone 3
(Scheme 1). Both templates 2 and 3 may provide an attractive platform
for lead generation of novel, potent p38 α inhibitors because they allow
opportunity for rapid exploration of substitution around heterocyclic
ring system to establish structure–activity relationships (SAR). More-
over, alternative groups to N-methyl piperazine in AZD6703 should be
also easily investigated. From the synthesis point of view, we were at-
tracted by the synthetic manipulability of 3,5-dihalo-2(1H)-pyr-
azinones8 therefore, we selected the 3,5-dibromo-2(1H)-pyrazinone 4
as our starting point for further evaluation. In this scaffold, the bromine
atom at the C3 position is a part of an imidoyl system and easily un-
dergoes nucleophilic aromatic substitution, whereas the more inert C5
bromine atom possesses vinylic character and requires metal-catalysed
In this communication, we report the identification and develop-
ment of a novel series of p38α inhibitors based on the 2(1H)-pyrazinone
⁎ Corresponding author at: Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK.
E-mail address: piotr.raubo@astrazeneca.com (P. Raubo).
https://doi.org/10.1016/j.bmcl.2020.127412
Received 6 April 2020; Received in revised form 3 July 2020; Accepted 12 July 2020
Availableonline15July2020
0960-894X/©2020ElsevierLtd.Allrightsreserved.

P. Raubo, et al.
Bioorganic&MedicinalChemistryLetters30(2020)127412
Fig. 1. Selected inhibitors of p38 tested in clinical trials.
Fig. 2. AstraZeneca p38 α inhibitors: AZD6703 (DFG-in) and 1 (DFG-out).
Scheme 1. The pyrazinone 3 as a mimic of the quinazolinone AZD6703.
Scheme 2. a) bromoacetonitrile, Et3N, THF, reflux, 88%; b) (COBr)2, CH2Cl2, DMFcat., reflux, 73%; c) RNH2, Et3N, THF, rt; d) cPrNH2, iPrMgCl, THF, rt; e)
HCOONH4, Pd/C, EtOH, μW, 100 °C.
cross-coupling reaction conditions thus providing orthogonal reactivity
and facilitating exploration of both vectors (C3 and C5). The key in-
termediate 3,5-dibromo-2(1H)-pyrazinone 7 was prepared in a short 2-
step sequence starting from the aniline 5, which was N-alkylated with
bromoacetonitrile to afford the amino acetonitrile 6 in excellent yield
(Scheme 2). Subsequently, the nitrile 6 reacted with oxalyl bromide in
the presence of catalytic amount of N,N-dimethylformamide to provide
the 2(1H)-pyrazinone 7 in good yield. Nucleophilic aromatic substitu-
tion of the bromine at the C3 position with corresponding amines fol-
lowed by formation of the N-cyclopropylamide and subsequent reduc-
tion of the C5 bromine using hydrogen transfer hydrogenation afforded
required amino pyrazinones 8a-r.
2

P. Raubo, et al.
Bioorganic&MedicinalChemistryLetters30(2020)127412
Scheme 3. a) MeONHMe∙HCl, iPrMgCl, THF, 0 °C, 96%; b) DIBAL-H, THF, 0 °C; c) (R)-10, Ti(OiPr)4, THF, rt; d) PhMgBr, CH2Cl2-Et2O, −50 °C (57%, 3 steps); e) HCl,
MeOH, dioxane, 50 °C - rt; f) 7, iPr2EtN, THF, 50 °C; g) HCOONH4, Pd/C, iPr2EtN, EtOH, 70 °C (63%, 3 steps); h) cPrNH2, iPrMgCl, THF, 0 °C, 99%; i) DMP, CH2Cl2, rt;
j) R1NHR2, NaBH(OAc)3, rt (30%, 2 steps).
Synthesis of the chiral analogue 20 started from the aldehyde 17
which was converted to the sulfinamide 18 in a 2-step sequence in-
volving condensation with the sulfinamide (S)-10 and subsequent ad-
dition of ethylmagnesium chloride (Scheme 5). After removal of the
tert-butylsulfinyl group, the resulting benzylamine was allowed to react
with 7, then the ester group was converted to the corresponding cy-
clopropyl amide and the C5 bromine was removed to give the alcohol
Scheme 4. a) 7, Et3N, THF, rt; b) N-(2-chloroethyl)pyrrolidine hydrochloride,
19. Subsequently, 19 was transformed to the pyrrolidine derivative 20
Cs2CO3, DMF, 80 °C; c) cPrNH2, cyclopentylmagnesium bromide, THF, rt; d)
via a corresponding mesylate.
HCOONH4, Pd/C, iPr2EtN, EtOH, μW, 100 °C (27%, 4 steps).
Synthesis of gem-dimethyl analogues 24 and 25 started from the
benzonitrile 21 (Scheme 6). Addition of in situ generated methyl cerium
reagent provided the gem-dimethyl benzylamine 22. Reaction between
22 and 7 followed by conversion of the ester group to the corresponding
cyclopropyl amide and removal of the C5 bromine and O-benzyl de-
protection afforded the phenol 23. Alkylation of the phenol group in 23
with N-(2-chloroethyl)pyrrolidine yielded 24. Likewise, alkylation with
1-bromo-2-chloroethane followed by displacement of the chlorine with
methylamine provided the secondary amine 25.
Synthesis of chiral analogues 14a-h (Scheme 3) began from the
commercially available methyl (S)-(+)-3-hydroxy-2-methylpropionate
which after protection of the hydroxy group as a tert-butyldimethylsilyl
ether (9) was converted to the corresponding Weinreb amide. The
subsequent reduction of Weinreb amide to aldehyde with diisobutyla-
luminium hydride (DIBAL-H), followed by condensation with (R)-tert-
butanesulfinamide {(R)-10} and stereoselective addition of phe-
nylmagnesium bromide resulted in the chirally enriched sulfinamide
11. After deprotection, the corresponding amine was allowed to react
with 7 and C5 bromine was removed to afford the hydroxy ester 12.
The ester 12 was subsequently converted in excellent yield to the cor-
responding cyclopropyl amide 13 on reaction with cyclopropylamine
and isopropylmagnesium chloride. The hydroxy group in 13 was then
oxidised to the corresponding aldehyde using Dess-Martin periodinane
and the resulting aldehyde underwent reductive amination with a range
of amines to yield 14a-g.
To deliver a potential inhaled candidate drug, a compound having
excellent potency in human peripheral blood mononuclear cell (PBMC)
based assay,4d,9 acceptable solubility and free fraction in plasma was
required as well as a long half-life in preclinical species combined with
low oral bioavailability was desired. Additionally, high lung retention
was necessary with a significant difference between lung and plasma
concentration at an efficacious dose. The SAR evaluation started with
an unsubstituted scaffold 8 (R = H) which exhibited promising p38α
enzyme inhibitory activity (pIC50 5.3, Table 1) and ligand efficiency (LE
0.36).10 A 3-amino derivative 8a was equally potent (pIC50 5.3) and
showed encouraging lipophilic ligand efficiency (LLE 4.9).10
Compound 16 was prepared in a similar fashion starting from the
benzylamine 15 and 7 as shown in Scheme 4.
Scheme 5. a) (S)-10, CuSO4, CH2Cl2, rt; b) EtMgCl, CH2Cl2, −78 °C (37%, 2 steps); c) HCl, MeOH, dioxane, rt; d) 7, Et3N, THF, rt; e) cPrNH2, cyclopentylmagnesium
bromide, THF, rt; f) HCOONH4, Pd/C, iPr2EtN, EtOH, μW, 100 °C (80%, 4 steps); g) CH3SO2Cl, Et3N, CH2Cl2, 0 °C; h) pyrrolidine, CH2Cl2, rt (32%, 2 steps).
3

P. Raubo, et al.
Bioorganic&MedicinalChemistryLetters30(2020)127412
Scheme 6. a) MeLi, CeCl3, THF, −78 °C, quant.; b) 7, iPr2EtN, THF, μW, 120 °C; c) cPrNH2, cyclopentylmagnesium bromide, THF, rt; d) HCOONH4, Pd/C, iPr2EtN,
EtOH, 70 °C (79%, 3 steps); e) N-(2-chloroethyl)pyrrolidine hydrochloride, Cs2CO3, DMF, 80 °C, 27%; f) BrCH2CH2Cl, K2CO3, MeCN, reflux; g) MeNH2, EtOH, μW,
100 °C (57%, 2 steps).
Table 1
SAR of the 3 position of the pyrazinone ring (8a-r).
Solubility (μM)a
hPPB (% free)
Rat Heps CLint
b
No.
R
p38 αpIC50
PBMCpIC50
logD7.4
LLE (enzyme)
8
H
5.3
5.3
6.1
6.4
7.0
7.6
6.6
7.1
7.3
7.8
ND
ND
ND
ND
ND
6.6
ND
6.7
ND
7.0
ND
0.4
1.1
1.5
3.0
2.6
3.2
3.7
3.0
2.9
ND
4.9
5.0
4.9
4.0
5.0
3.4
3.4
4.3
4.9
ND
ND
ND
80
71
11
17
12
4.8
15
25
ND
ND
1.1
< 1
3.3
4.5
59
8a
8b
8c
8d
8e
8f
NH2
ND
NHMe
> 1000
> 1000
405
NH-cPr
NHPh
NHCH2Ph
N(Me)CH2Ph
NHCH2-cHex
NHCH2CH2Ph
23
54
8g
8 h
8i
340
7.6
130
17
392
734
8j
6.7
8.0
ND
6.7
3.1
3.3
3.6
4.7
50
30
9
< 3
120
8k
344
8l
7.5
8.9
ND
7.8
3.7
3.3
3.8
5.6
168
270
8
140
26
8m
13
8n
8.2
7.9
7.4
7.1
3.1
3.0
5.1
4.9
385
258
23
12
19
22
8o
8p
8r
7.2
6.1
6.6
ND
2.7
2.9
4.5
3.2
351
8
7.4
3.4
< 19
24
pIC50 values are mean values between two and four independent experiments. ND means not determined; a) aqueous solubility at pH 7.4; b) μL/min/106 cell
Methylamine and cyclopropylamine analogues (8b and 8c) improved
potency further (pIC50 6.1 and 6.4, respectively) while retaining similar
LLE (~5.0). Better enzyme inhibition was achieved with the aniline 8d
(pIC50 7.0). However, this increase in p38α inhibition was compro-
mised by lower LLE (4.0). Encouragingly, homologation to the benzyl
amine 8e improved enzyme inhibitory activity (pIC50 7.6, LLE 5.0) and
8e showed encouraging potency in the cell assay (PMBC, pIC50 6.6). N-
Methylation of 8e resulted in 10-fold decrease of activity in the enzyme
assay (8f, pIC50 6.6). Similarly, saturation of the phenyl ring in 8e to the
corresponding cyclohexane 8g modestly lowered enzyme potency by
4

P. Raubo, et al.
Bioorganic&MedicinalChemistryLetters30(2020)127412
0.5 log unit while maintaining activity in cell. Homologation of 8e to
the corresponding phenyl ethyl amine 8h led to very high in vitro
clearance in rat hepatocytes. The R stereochemistry of the benzyl amine
(8i) was preferred over S (8j). The racemic 2-phenyl pyrrolidine ana-
logue 8k, despite being more potent in the enzyme assay, showed very
high clearance in rat in vitro. Similarly, high intrinsic clearance in rat
hepatocytes was observed for the bicyclic benzylamine 8L. Interest-
ingly, replacement of the methyl in 8i with an ethyl (8m) improved
enzyme potency by > 10-fold (pIC50 8.9). A similar potency increase
was observed for 8m in PMBCs (pIC50 7.8, ΔpIC50 + 0.8). Dimethyl
substitution was also well tolerated in both enzyme and cell assays (8n,
pIC50 8.2 and 7.4, respectively). Furthermore, we evaluated the effect of
substitution around the phenyl ring, as illustrated by isomeric struc-
tures 8o, 8p and 8r. Ortho-methoxy isomer 8o appeared to be the most
active regioisomer within this set and showed similar activity to 8e in
both enzyme and cell assays. All compounds in the Table 1 displayed
low plasma protein binding. This can potentially increase both free
drug concentration at the site of action (lung) and in-vivo systemic
blood clearance, thus improving the therapeutic index.
assay (with pIC50 9.7), but not better in PBMC’s. Chiral 2-methyl pi-
perazine analogues 14e and 14f showed similar profile with R-isomer
14e being more potent than S-enantiomer. The N-methyl piperazine
14g was similarly active to the corresponding morpholine 14c, but less
lipophilic and was cleared at a slower rate in rat hepatocytes. Phar-
macokinetics in rat was assessed for the piperazine 14b after iv dosing
(Table 4). In vivo clearance was high (50 mL/min/kg) and correlated
well with high in vitro CLint. Furthermore, a high volume of distribution
(5.5 L/kg) was observed consistent with a basic compound (pKa 8.4)
leading to a long half-life (t1/2 7.8 h).
In parallel, substitution of the phenyl ring in the benzylamine 8e
was investigated. As ortho-substitution (8o) seemed to be preferred over
meta (8p) or para (8r), the corresponding ortho-substituted ethers, such
as 16, were prepared and evaluated (Table 3).
The alkoxy substituent in 16, bearing a pyrrolidine ring, was well
tolerated in the enzyme assay (pIC50 7.5). Additionally, this modifica-
tion reduced lipophilicity and significantly increased solubility.
Therefore, we considered 16 as a good starting point for further ex-
ploration. Following previously generated SAR, the chiral (R)-ethyl
substituent was introduced at the benzylic position giving 20 which
showed 20-fold improvement in enzyme inhibition. Additionally, 20
also exhibited good cell potency (pIC50 7.9), solubility and reduced in
vitro clearance in rat hepatocytes. Enzyme and cell potency were further
increased with gem-substitution of the benzylic carbon in 24 (pIC50 9.5
and 8.2, respectively), however, this was compromised by very high in
vitro clearance in rat hepatocytes (157 μL/min/106 cell), which could
lead to a decrease in half life and shorter duration of action. Replacing
the pyrrolidine ring with the methyl amine (25) lowered logD7.4 and
reduced in vitro clearance without compromising p38α activity.
Pharmacokinetic data in rat were generated for 24 and 25 (Table 4).
25 displayed a superior pharmacokinetic profile to 24 with in vivo
clearance of 59 mL/min/kg (69% hepatic blood flow), increased vo-
lume of distribution (31.6 L/kg) leading to a longer half-life of 13 h. 25
was poorly bioavailable (6%) in rat. Low oral bioavailability may be
linked to high in vivo clearance, high basicity of the amine (measured
pKa 9.1) and low PAMPA permeability (Papp 4.2 × 10-6cm/s) due to the
presence of 3 hydrogen bond donors. Since clinical studies of several
We also investigated the effect of the substitution of the ethyl group
in 8m on p38α inhibition and physicochemical properties (Table 2).
The hydroxymethyl derivative 13 was first prepared and showed si-
milar activity to 8m in the enzyme assay (pIC50 8.6). However, this was
compromised by lower potency in PBMC (pIC50 7.1) for 13, likely due
to presence of the additional hydrogen bond donor and reduced per-
meability. Replacement of the hydroxyl in 13 with a dimethyl amino
group in 14a increased cell potency by 0.6 log units while maintaining
high enzyme potency (pIC50 8.8). The presence of the basic dimethy-
lamino group (calculated pKa 9.5) in 14a reduced lipophilicity and thus
increased LLE. Further improvement of cell potency was achieved with
the more lipophilic piperidine 14b (pIC50 8.4, calculated pKa 9.4). In-
terestingly, the less basic morpholine 14c was equipotent to 14b in the
enzyme assay, but despite higher lipophilicity showed lower potency in
cell. Noticeably, in vitro clearance in rat hepatocytes for 14c appeared
to be very high. Replacing the morpholine motif in 14c with the pi-
perazine ring provided the significantly less lipophilic and highly ligand
efficient 14d which was 8-fold more potent than 14c in the enzyme
Table 2
Exploration of chiral N-propyl amines (14a-g).
Solubility(μM)a
PPB (% free)
Rat Heps CLint
b
No
R
p38 α pIC50
PBMC pIC50
logD7.4
LLE (enzyme)
13
OH
8.6
8.8
8.8
7.1
7.7
8.4
2.6
2.0
3.0
6.0
6.8
5.9
870
843
908
30
60
38
19
18
61
14a
14b
NMe2
14c
14d
14e
14f
8.9
9.7
9.6
9.2
8.7
7.6
7.0
7.4
7.0
7.6
3.5
1.3
1.6
1.5
2.3
5.4
8.4
8.0
7.6
6.4
216
636
847
783
854
10
51
42
41
63
> 300
15
8.5
14
14g
30
pIC50 values are mean values between two and four independent experiments. ND means not determined; a) aqueous solubility at pH 7.4; b) μL/min/106 cell
5

P. Raubo, et al.
Bioorganic&MedicinalChemistryLetters30(2020)127412
Table 3
The effect of the substitution of the benzylic position in 2-alkoxy benzylamines.
Solubility (μM)a
670
PPB(% free)
54
Rat Heps CLint
55
a
No
16
R
p38 α pIC50
7.5
PBMC pIC50
ND
logD7.4
1.6
LLE (enzyme)
5.7
20
24
9.2
9.5
7.9
8.2
2.3
2.3
6.9
7.2
800
45
35
35
> 1000
157
25
9.6
7.7
8.2
7.3
1.6
1.6
8.0
6.1
650
730
41
69
20
AZD6703
< 3
pIC50 values are mean values between two and four independent experiments. ND means not determined; a) aqueous solubility at pH 7.4; b) μL/min/106 cell.
influence the work reported in this paper.
Table 4
Intravenous pharmacokinetic data for selected compounds.
Appendix A. Supplementary data
No
Species
Cliv (mL/min/kg)
Vdss (L/kg)
t1/2 (h)
F (%)
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bmcl.2020.127412.
14b
Rat
Rat
Rat
Dog
Rat
Dog
50
5.5
7.8
8
ND
ND
6a
24
99
16.6
31.6
6.4
25
59
13
6.6
0.7
1.7
25
16.5
26
ND
49a
68a
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AZD6703
1.9
24
3.3
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2014:105.
Declaration of Competing Interest
11. Selectivity data for 25: p38β (MAPK11) pIC50 6.6; p38γ (MAPK12) pIC50 < 5; p38δ
(MAPK13) pIC50 < 5; hMSK1 pIC50 8.2, hMAPKAPK2 pIC50 8.2. In general, com-
pounds in this series were found to be 10-fold selective over p38 β with pIC50 < 6.0
against p38γ and p38δ isoforms (for more details see Supporting Information).
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to
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