Discovery of pyrrolo[2,1-f][1,2,4]triazine C6-ketones as potent, orally active p38α MAP kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2011.05.091

Pyrrolo[2,1-f][1,2,4]triazine based inhibitors of p38α have been prepared exploring functional group modifications at the C6 position. Incorporation of aryl and heteroaryl ketones at this position led to potent inhibitors with efficacy in in vivo models o

Full text of DOI:10.1016/j.bmcl.2011.05.091

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4633–4637
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of pyrrolo[2,1-f][1,2,4]triazine C6-ketones as potent, orally active
p38a
MAP kinase inhibitors
⇑
Alaric J. Dyckman , Tianle Li, Sidney Pitt, Rosemary Zhang, Ding Ren Shen, Kim W. McIntyre,
Kathleen M. Gillooly, David J. Shuster, Arthur M. Doweyko, John S. Sack, Kevin Kish, Susan E. Kiefer,
John A. Newitt, Hongjian Zhang, Punit H. Marathe, Murray McKinnon, Joel C. Barrish, John H. Dodd,
Gary L. Schieven, Katerina Leftheris
Bristol-Myers Squibb, Research and Development, Princeton, NJ 08543-4000, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Pyrrolo[2,1-f][1,2,4]triazine based inhibitors of p38
a have been prepared exploring functional group
Received 31 January 2011
Revised 20 May 2011
Accepted 23 May 2011
Available online 30 May 2011
modifications at the C6 position. Incorporation of aryl and heteroaryl ketones at this position led to
potent inhibitors with efficacy in in vivo models of acute and chronic inflammation.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
p38a MAP kinase
MAPK14
Inhibitors
Structure–activity relationships
Pyrrolotriazine
Ketone
X-ray structure
Rat adjuvant arthritis model
p38 MAP (mitogen-activated protein) kinase is a member of a
serine-threonine kinase family involved in a stress response signal
transduction pathway. It is widely expressed in many cell types,
administration. These aspects, along with the ability to simulta-
neously affect multiple cytokines and inflammatory mediators,
and while there are four known isoforms of p38 (
it is p38 that has been shown to be on the critical path to pro-
inflammatory cytokine production.1 Upon activation by a number
of extracellular stimuli, p38 phosphorylates and activates intra-
cellular substrates such as transcription factors, including ATF-2
and NF- B, and MAPKAP-kinases, which in turn regulate the bio-
synthesis of pro-inflammatory mediators (notably TNF
1). Biotherapeutic treatments, including the soluble TNF
a, b, c, and d),
a
H
N
H
N
N
H
O
HN
O
HN
N
O
N
H
a
O
O
Met 109
N
N
N
Met 109
N
N
HN
N
j
2
N
1
a
and IL-
a
receptor
H
N
(etanercept), the IL-1 receptor antagonist (anakinra), and anti-
HN
N
R2
Met 109
5
TNF antibodies (infliximab, adalimumab) have provided clinical
a
O
O
6
3 R1=Et, R2 = OMe
4 R1= Pr, R2
Pr
validation for anti-cytokine approaches to treating rheumatoid
arthritis, Crohn0s disease and psoriasis.2 Additional preclinical
studies suggest that anti-cytokine therapies have potential in the
treatment of stroke and cardiovascular disease.3 Small molecule
N
R1 NH
N
n
= c
7
F
H2N
Met 109
O
Cl
N
N
based inhibition of p38a offers an alternative approach to block
Met 109
O
NH2
NH
production of these cytokines with the potential benefits of re-
duced cost (production and patient costs) and ease of
HO
5
6
OH
(Roche)
(Leo Pharma)
O
⇑
Corresponding author. Tel.: +1 609 252 3593; fax: +1 609 252 7410.
E-mail address: alaric.dyckman@bms.com (A.J. Dyckman).
Figure 1. p38
a inhibitors from BMS (1–4) Roche (5) and Leo (6) illustrating
elements demonstrated or proposed to interact with Met109.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.05.091

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A. J. Dyckman et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4633–4637
Table 1
O
N
O
N
C50 SAR with C6-phenyl ketone
O
NH
HN
O
a-d
e
NH
N
N
EtO
5'
R
HN
1'
N
7
8
5
O
6
N
N
Cl
N
R
f
O
O
N
N
N
N
N
O
11 R = CO2H
H2N
9
Compd
R
p38ac IC50, nM
hPBMCd IC50, nM
27
g
OH
10
12 R = CONHi Pr
O
O
19a
6
Scheme 1. Synthesis of pyrrolotriazine C6 ketones. Reagents and conditions: (a)
LiAlH4, THF; 0 °C; (b) Jones reagent, acetone; (c) PhMgBr, THF; (d) Jones reagent,
acetone; (e) POCl3 100 °C; (f) aniline, DIPEA, DMF, 60–100 °C; (g) isopropyl amine,
BOP, DMF.
N
H
O
O
N
N
H
20a
45
<4.1
F
H
11
CO2H
CONH2
CONHMe
CONHEt
CONHiPr
>1000
7
14
11
27
—
N
21b
22a
23b
12
HN
230
170
180
99
O
O
R
N
N
N
H
N
H
HN
13 R = OEt
14 R = Cl
15 R = H
e
a,b
N
24a
25a
26a
4
3
3
<8.2
<8.2
<4.1
O
O
c,d
14
N
O
N
N
H
N
16
N
N
H
O
O
H
N
H
H
N
N
O
HN
HN
f
g,h
O
O
O
O
N
O
O
O
N
N
15
N
N
N
O
N
N
H
N
N
18
17
N
27a
88
—
Scheme 2. Ketone synthesis from elaborated PTZ. Reagents and conditions: (a)
NaOH, THF, H2O, MeOH; (b) SOCl2; (c) LiAlH4, THF; 0 °C (d) Jones reagent, acetone;
(e) indole, Et2AlCl, DCM; (f) 2-chloroquinoxaline, 1,3-dimethylimidazolium iodide,
4-MePhSO2Na, NaH, DMF, 55–70 °C; (g) 3-bromopyridine, Mg(s), THF; (h) MnO2,
THF.
F
H
N
28b
29b
240
230
—
—
OH
O
O
H
N
OMe
have stimulated continued efforts by numerous organizations to
develop safe, potent and orally active p38
We, along with our collaborators, have previously reported on a
a
inhibitors.4
a
Prepared in analogy to 11 utilizing the appropriately substituted aniline in place
of 10.
variety of novel, selective and potent p38a inhibitors (Fig. 1 and 1–
b
Prepared in analogy to 12 using the appropriate amine.
Assay variability measured using a standard control was <30% (n = 77).
Assay variability measured using a standard control was <85% (n = 65).
4).5 X-ray co-crystallography studies indicated several common
binding features of these inhibitors, including a key interaction
with the backbone NH of Met109. This contact has been noted in
c
d
the majority of p38
a inhibitors for which structural information
has been disclosed.6 In the case of triaminotriazine 1,5a this hydro-
gen bond interaction is indirect via the intermediacy of a water
molecule whereas direct interactions were observed with the ni-
trile of cyanopyrimidine 25b and an amide carbonyl of pyrrol-
o[2,1-f][1,2,4]triazine (PTZ) 35d and 4.5f We were intrigued by the
reports that this interaction was observed or proposed with aryl
ketones in 57 or 6,8 respectively, and set out to investigate whether
a ketone would be a suitable replacement for the C6-amide in the
PTZ chemotype.9
advanced PTZ-C6-ester intermediate 13.5f Conversion of 13 to acid
chloride 14 allowed for ketones to be prepared via Friedel–Crafts
acylation,10 while conversion to aldehyde 15 allowed the target
molecules to be obtained by treatment with organometallic re-
agents and subsequent oxidation or, in the case of example 17,
reaction with 2-chloroquinoxaline under umpolung catalysis
conditions.11
Table 1 displays the C50 SAR with a series of compounds bearing
a phenyl ketone at C6. Compounds were evaluated for activity in
The preparation of PTZ C6-ketones was accomplished following
several routes. As shown in Scheme 1, the C6-ketone could be
introduced early in the sequence by modification of known pyrrol-
otriazine ester 75d through conversion to the corresponding alde-
hyde, addition of phenylmagnesium bromide and oxidation to
ketone 8. Chlorination of 8 with POCl3 followed by displacement
with an appropriately substituted aniline afforded either the final
products directly, or intermediate carboxylic acid 11 which could
in turn be utilized to prepare a range of C50 amides. Alternative
synthetic approaches (Scheme 2) relied on the availability of
biochemical (p38
a) and cellular assays (inhibition of LPS stimu-
lated TNF
a
response in hPBMCs).5a Examples of both aniline and
carboxamide functionalities at C50 were examined, following SAR
points from our earlier series.5g C50-anilino derivative 20 showed
greater activity in the cellular based assay than predicted by the
corresponding level of p38
a enzyme inhibition. While this could
be related to unidentified off target activity, another consideration
is that the morpholino-benzamide moiety of 20 has been described
in earlier reports as binding to the pocket revealed by the DFG-out
conformation of p38a, a binding mode that can lead to differences

A. J. Dyckman et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4633–4637
4635
Table 2
Combined C6 and C50 SAR
H
1'
HN
5'
N
R2
5
O
O
6
N
N
R1
N
Compd
R1
R2
p38a d IC50, nM
hPBMCe IC50, nM
30
⁄(C6 = CH2OH)c
H
nPr
cPr
cPr
cPr
>1000
55
19
—
>1000
240
15
31a
32a
cPr
12
300
Me
33a
34a
35a
36a
37a
38a
39a
40a
41a
18
2-Methyl-phenyl
Me
Me
Me
Me
Me
Me
Me
cPr
cPr
cPr
cPr
cPr
cPr
cPr
cPr
cPr
cPr
cPr
cPr
12
59
14
36
140
35
51
8
40
19
15
10
10
44
18
5
110
2-Methoxy-phenyl
3-Methoxy-phenyl
3-Fluoro-phenyl
1700
1100
>2000
—
>2000
890
120
290
170
1400
100
68
670
730
270
57
>2000
>2000
4-Fluoro-phenyl
Benzo[d][1,3]dioxol-5-yl
(6-Methylpyridin-2-yl)
(6-Methylpyridin-2-yl)
2-Pyridyl
3-Pyridyl
(Quinoxalin-2-yl)
(1H-pyrrol-2-yl)
17
42b
43b
44b
45b
46b
16
(1H-pyrrol-3-yl)
(1-Methyl-1H-pyrrol-2-yl)
(1-Methyl-1H-pyrrol-3-yl)
(Furan-2-yl)
(1H-Indol-3-yl)
(1-Methyl-1H-indol-2-yl)
(1-Methyl-1H-indol-3-yl)
11
52
55
47b
48b
a
Prepared in analogy to 11 and 18 utilizing appropriate organometallic reagents and substituted anilines.
Prepared in analogy to 16.
Prepared as shown in Scheme 2, step (c).
Assay variability measured using a standard control was <30% (n = 77).
Assay variability measured using a standard control was <85% (n = 65).
b
c
d
e
in binding kinetics.5g,6 Despite the impressive cellular activity, lia-
however other substituents led to a decrease in enzyme and/or cel-
lular potency. Heteroaryl ketone substituents were also investi-
gated. The 6-methylpyridin-2-yl ketone analogs were prepared
with N-Me and N-cyclopropyl C50 amides and in each case the
in vitro activity was reduced as compared to the corresponding
phenyl ketones (39 vs 22, 40 vs 24). A deleterious effect on
in vitro potency was noted upon N-methylation of the pyrrole
and indole derivatives (42 vs 44, 43 vs 45, 16 vs 48). Furanyl ketone
46, isosteric to 42 but lacking a hydrogen bond donor, showed
favorable enzyme activity. This suggests that the unsubstituted
pyrroles are not picking up significant hydrogen bonding interac-
tions and that the negative N-methyl effect is steric in nature, with
the substituent possibly interfering with the interaction between
Met109 and the ketone carbonyl. Translation of biochemical to cel-
lular activity was variable among the compounds examined, rang-
ing from 10-fold or less (16, 18, 33, 39, 41–43) to greater than 90-
fold for quinoxalinyl derivative 17.12
bilities including CYP inhibition (IC50:2C9 350 nM, 3A4 470 nM)
deterred further evaluation of 20. The remaining C50 SAR efforts fo-
cused on carboxamide substitution. Carboxylic acid 11 showed
very little activity in the biochemical assay, while the primary
amide 21 was found to inhibit p38
a with single digit nanomolar
activity, highlighting the importance of the amide functionality.
Simple alkyl amides (12, 22, 23) were also found to show good
inhibition in enzyme and cell based assays. Activity was dimin-
ished with aryl amide 27 and 2-hydroxyethyl (28) or 2-methyoxy-
ethyl (29) analogs.
We have previously observed enhanced inhibition of p38
a
through incorporation of cyclopropyl or heterocyclyl amide sub-
stituents at C50, rationalized through improved hydrogen bond do-
nor ability of the benzamide NH.5f Consistent with those earlier
findings, optimal enzymatic and cellular activity in the phenyl ke-
tones was found with cyclopropyl-amide 24, isoxazol-3-yl-amide
25, and acyl carbamate 26. However, in vitro metabolic stability
of 26 (hLM 0.16 nmol/min/mg) was lower than cyclopropyl amide
24 (hLM 0.08 nmol/min/mg) and poor solubility was noted with
in vivo formulations of 25. As a result we chose to focus on methyl
and cyclopropyl amides for SAR evaluation at C6.
Direct comparison between the C6-ketone and C6-amide PTZs
can be made by examining p38
(4 nM) and 45f (13 nM). Propyl ketone 31, sterically similar to the
N-propyl amide of 4, provided comparable level of p38 inhibition
a IC50 values for 31 (19 nM) 24
a
indicating that the C6 ketone was an effective amide surrogate. The
enzyme activity of phenyl ketone 24 was improved slightly, possi-
bly a result of enhanced hydrophobic interactions suggested by X-
ray crystallography.
Modifications to the C6 position were initiated with N-methyl
and N-cyclopropyl amides at C50 (Table 2). The C6-hydroxymethyl
intermediate 30 was found to possess little activity against p38
a
but activity was restored to a moderate level after oxidation to
aldehyde 15. Further improvements were observed with alkyl
and alkynyl ketones 31 and 32, with activity approaching that ob-
served with phenyl ketone 24. In the series of substituted phenyl
ketones (33–38) 2-methyl substitution was well tolerated,
Examination of the X-ray structure of 24 co-crystallized with
unphosphorylated p38a (Fig. 2) confirmed the proposed binding
mode, including interaction of the ketone carbonyl with Met109,
as expected by analogy to 3 and 4.5e,f,13 The phenyl ring of the C6
ketone is oriented along a hydrophobic surface created by residues

4636
A. J. Dyckman et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4633–4637
1.5
Veh (PEG)
3
1.0
4
24
0.5
0.0
7
9
11
13
15
17
19
21
Study Day
Figure 4. Rat adjuvant arthritis study using 3 (squares), 4 (triangles), 24 (circles).
Lewis rats (n = 8/group) were immunized with complete Freund0s adjuvant on day
0. On day 11, twice-daily oral treatment was initiated with vehicle (PEG300) or
compound (10 mg/kg/dose). Hind paw volume increases were determined by
Figure 2. 13X-ray co-crystal structure of 24 and unphosphorylated p38
foreground residues removed for clarity.
a with the
⁄
plethysmometry on the days indicated. p <0.05 versus vehicle, Student0s t test.
inflammation for their ability to inhibit TNF
a production in re-
5000
4000
3000
2000
sponse to an LPS challenge in vivo. Select examples are shown in
Figure 3, along with the vehicle control and C6-amide analogs (3
and 4) for comparison. The compounds in the study were dosed
at 5 mg/kg 2 h prior to LPS challenge and all showed significant
inhibition of the TNF
efficacious, with 5 of 8 mice studied showing no detectable levels
of serum TNF (LLQ 200 pg/ml). The level of inhibition demon-
a response. Aryl ketone 24 was particularly
a
strated by 24 was also statistically superior to C6-amide compound
3 (p < 0.05). Furthermore, 24 displayed an extended duration of ac-
tion, with a 5 mg/kg dose giving 95% inhibition of TNF
even when administered 6 h prior to LPS challenge, with 2 of 8
a response
5 of 8 Mice
<LLQ
1000
0
mice showing no detectable levels of TNF
(data not shown).
a in that particular study
Preliminary evaluation of selectivity in this series was obtained
against a panel of 26 additional enzymes. Aside from p38 b (IC50
19 nM), compound 24 did not show significant off-target activity.14
An oral pharmacokinetic study in rats (10 mg/kg in PEG400)
showed acceptable exposure for compound 24 (Cmax 752 ng/ml,
C4h 550 ng/ml, AUC0–4h 2300 ng h/ml). As a result of its superior
Vehicle
3
4
22
23
24
Figure 3. Inhibition of LPS-induced TNF
a
release by 3, 4, 22, 23, and 24 in mouse.
BALB/c female mice (Harlan, 6–8 weeks of age, n = 8/treatment) were dosed with
compounds (5 mg/kg) in PEG 300 by oral gavage in a volume of 0.1 ml. Control mice
received PEG300 alone (‘vehicle’). Two hours later, mice were injected intraperi-
toneally with 50
lg/kg lipopolysaccharide (LPS; Escherishia coli O111:B4; Sigma).
in vitro profile, results in the murine LPS-TNFa model and rat phar-
Blood samples were collected 90 min after LPS injection. Serum was separated and
analyzed for the level of TNFa by commercial ELISA assay (BioSource) according to
macokinetic properties, compound 24 was examined for efficacy in
a rodent model of arthritis (rat adjuvant arthritis). The study
(Fig. 4) was run with the compounds (10 mg/kg, b.i.d, po) first
administered near the time of disease onset (day 11) and contin-
uing through the end of the study on day 20. Compounds 3 and
4 were included in this study enabling a direct comparison of the
C6 amide and C6 ketone pyrrolotriazine compounds. All three com-
pounds were highly efficacious in this study, showing statistically
significant inhibition of paw swelling. Although aryl ketone 24 ap-
peared to provide the greatest activity with a 73% reduction in paw
swelling, statistical differentiation between the three treatment
groups was not possible.
In conclusion, structural analysis of the p38
ture of pyrrolo[2,1-f][1,2,4]triazine compounds from our labs,
along with additional reports of aryl ketone derived inhibitors
led to the rational design of the PTZ-C6-ketone p38
Members of this series were found to be selective and highly po-
tent in vitro as well as being orally efficacious in rodent models
of acute and chronic inflammation.
the manufacturer0s instructions. Data shown are mean standard deviation. ⁄p
<0.005 versus vehicle by Student0s t test.
in the hinge region which seems to readily accommodate this
structural feature. This is depicted as the transparent surface in
Figure 2. PTZ based p38
a inhibitors have previously been found
to bind with the DFG loop in both the ‘-out’ and ‘-in’ conforma-
tions.5d–g,6b In the case of 24 the structure revealed a conventional
DFG-in orientation of the protein, with the C50 amide being in-
volved in a hydrogen bonding network with Glu71 and Asp168.
The phenyl ring of the aniline benzamide sits in a hydrophobic
pocket just beyond the Thr106 ‘gatekeeper residue’, the hydroxyl
of which makes a potential contact with the aniline NH.
In addition to TNF
onize the production of several additional cytokines from hPBMC
cells stimulated with LPS (IC50:IL-1 <8 nM, IL-1b 41 nM, IL-6
173 nM, IL-10 21 nM). The cytokine suppressive activity was main-
tained in a whole blood assay, with 24 inhibiting the LPS induced
production of IL-6 from monkey whole blood (IC50 382 nM).
C6 ketone derivatives with demonstrated potency in the hPBMC
cellular assay (IC50 <300 nM) and acceptable in vitro metabolic sta-
bility (data not shown) were examined in a mouse model of acute
a co-crystal struc-
a, compound 24 was found to potently antag-
a inhibitors.
a
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McIntyre, K. W.; Pitt, S.; Shen, D. R.; Shuster, D. J.; Yang, X.; Zhang, R.; Behnia,
K.; Zhang, H.; Marathe, P. H.; Doweyko, A. M.; Tokarski, J. T.; Sack, J. S.; Pokross,
M.; Kiefer, S. E.; Newitt, J. A.; Barrish, J. C.; Dodd, J.; Schieven, G. L.; Leftheris, K.
J. Med. Chem. 2008, 51, 4; (e) Leftheris, K.; Hynes, J. Jr.; Dyckman, A.; Li, T.; Lin,
S.; Wrobleski, S. T.; Wu, H.; Zhang, R.; Gillooly, K. M.; Loo, D.; McIntyre, K. W.;
Pitt, S.; Shen, D. R.; Shuster, D. J.; Doweyko, A.; Sack, J.; Barrish, J. C.; Dodd, J.;
Schieven, G. L. Abstracts of Papers, 229th ACS National National Meeting; 2005,
San Diego, CA, United States; Medi-298.; (f) Liu, C.; Lin, J.; Wrobleski, S. T.; Lin,
S., ; Hynes, J., Jr.; Wu, H.; Dyckman, A. J.; Li, T.; Wityak, J.; Gillooly, K. M.; Pitt, S.;
Shen, D. R.; Zhang, R. F.; McIntyre, K. W.; Salter-Cid, L.; Shuster, D. J.; Zhang, H.;
9. For additional examples of aryl ketone based p38a inhibitors see: Revesz, L.;
Blum, E.; Di Padova, F. E.; Buhl, T.; Feifel, R.; Gram, H.; Hiestand, P.; Manning,
U.; Rucklin, G. Bioorg. Med. Chem. Lett. 2004, 14, 3601.
10. Okauchi, T.; Itonaga, M.; Minami, T.; Owa, T.; Kitoh, K.; Yoshino, H. Org. Lett.
2000, 2, 1485.
11. Miyashita, A.; Suzuki, Y.; Iwamoto, K.-I.; Oishi, E.; Higashino, T. Heterocycles
1998, 49, 405.
12. While serum protein binding data was not available for the compounds, an
analysis of calculated lipophilicity of aryl ketone analogs was conducted as a
possible surrogate marker. For 24, an experimentally derived log P value (4.3)
was matched closely by c log P (4.75) so that computational method was
utilized. Comparison of compounds with very good translation (24 c log P 4.75,
43 c log P 3.27, 16 c log P 4.65) to those with poor translation (36 c log P 4.13,
38 c log P 3.92, 17 c log P 4.44) did not reveal a useful correlation.
13. Binding interactions between 24 and unphosphorylated p38a based on X-ray
crystallographic analysis (2.2 Å resolution). Hydrogen bond distances are given
in angstroms with key protein residues labeled. The X-ray coordinates have
been deposited with the RCSB Protein Data Bank (RCSB ID Code: rcsb065758
and PDB ID Code: 3S4Q).
14. Selectivity: (IC50 > 25
IGF1R, JAK3, Jnk1, LCK, MEK/ERK, MET. MK2, PKA, PKC
VEGF_R2) (IC50 >10 M for IKK2) (IC50 >5 M for PDE-3, -4, -7).
lM for p38d p38
c
, Akt, cdk2, Emt, FGFR1, HER1, HER2,
a
, PKCd, PKCh, PKCf, Syk,
l
l